INFECTIOUS DISEASES

Edited by:

prof. E. Nikitin,

Honoured Science & Technics Worker of Ukraine,

prof. M. Andreychyn

Ternopil

Ukrmedknyga

2004

Approved by the Central Methodolo-

gical Committee of Higher Medical

Education as a manual for students

of the Higher Medical Schools of the

III-IV degree of accreditation

(protocol ¹ 2, 30.03.2004)

ББК 51.9я73

І 60

УДК 616.9(075.8)

Authors: E. Nikitin, M.D., Ph. D.; M. Andreychyn, M.D., Ph. D.; K. Servetskyy,

M.D., Ph. D.; V. Kachor, M.D.; A. Holovchenko, M.D.; E. Usychenko, M.D.

Колектив авторів: д-р мед. наук, проф. Нікітін Є.В., засл. діяч науки і техніки

України, д-р мед. наук, проф. Андрейчин М.А., д-р мед. наук,

проф. Сервецький К.Л., канд. мед. наук, доц. Качор В.О., канд. мед.

наук, доц. Головченко А.М., канд. мед. наук, доц. Усиченко Є.М.

Reviewers: A. Rudenko, Honoured Doctor of Ukraine; I. Sytnyk, M.D., Ph. D.;

L. Shevchenko, M.D., Ph. D.

Рецензенти: А.О. Руденко, д-р мед. наук, заслужений лікар України; І.О. Сит-

ник д-р мед. наук, проф.; Л.Ю. Шевченко, д-р мед. наук, проф.

Інфекційні хвороби: Підручник / Є.В. Нікітін, М.А. Андрейчин, К.Л.Сервець-

кий, В.О. Качор, А.М. Головченко, Є.М. Усиченко: За ред. Є.В. Нікітіна та

М.А. Андрейчина. – Тернопіль: Укрмедкнига, 2004. – 364 с.

ISBN 966-673-012-Х

The manual reveals etiology, pathogenesis, clinic, diagnosis, medical treatment, and

prophylaxis of widespread infectious diseases considering modern data. The authors of the

book generalized experience of this subject being tought at home and foreign medical

universities and academies, as well as infectious diseases departments, where they work.

Attention is paid to presentation of material, which has important clinical value.

This manual corresponds to the program of Ministry of Health of Ukraine and is designed

for the students of medical higher education institutions of III-IY accreditation levels.

У підручнику, з урахуванням сучасних відомостей, висвітлено етіологію, пато-

генез, клініку, діагностику, лікування та профілактику розповсюджених інфекцій-

них хвороб. Узагальнено досвід викладання цього предмету у вітчизняних і зарубіж-

них медичних університетах та академіях, а також кафедр інфекційних хвороб, на

яких працюють автори книги. Акцент зроблено на подання матеріалу, який має важ-

ливе клінічне значення.

Підручник відповідає програмі, затвердженій Міністерством охорони здоро-

в’я України, й адресується студентам медичних навчальних закладів III-IV рівнів

акредитації.

ISBN 966-673-012-Х

 Нікітін Є.В. та ін., 2004

І 60

ББК 51.9я73

УДК 616.9(075.8)

Contents

INTRODUCTION OF INFECTIOUS DISEASES ............................................................... 5

THE PRINCIPLES OF THE DIAGNOSTICS, TREATMENT AND PREVENTION

OF INFECTIOUS DISEASES............................................................................................... 22

TYPHOID FEVER AND PARATYPHOID ......................................................................... 37

BRUCELLOSIS ....................................................................................................................... 47

SHIGELLOSIS ......................................................................................................................... 57

SALMONELLOSIS ................................................................................................................. 67

CHOLERA ............................................................................................................................... 77

BOTULISM. TOXIC FOOD-BORNE DISEASES. CAMPYLOBACTERIOSIS ............ 88

PSEUDOTUBERCULOSIS .................................................................................................... 99

LEPTOSPIROSIS .................................................................................................................. 111

HERPETIC DISEASES ........................................................................................................ 122

ERYSIPELAS. ERYSIPELOTRIX ...................................................................................... 135

ANTHRAX ............................................................................................................................. 142

VIRAL HEPATITIS .............................................................................................................. 149

INFLUENZA......................................................................................................................... 163

ACUTE RESPIRATORY VIRAL DISEASES ................................................................... 179

MYCOPLASMA PNEUMONIAE INFECTION .............................................................. 198

MENINGOCOCCAL INFECTION .................................................................................... 202

DIPHTHERIA........................................................................................................................ 216

RICKETTSIOSIS ................................................................................................................... 233

VIRAL ENCEPHALITIS ..................................................................................................... 253

RABIES ................................................................................................................................... 263

TETANUS .............................................................................................................................. 272

MALARIA .............................................................................................................................. 279

PLAGUE ................................................................................................................................ 301

TULAREMIA ........................................................................................................................ 319

AQUIRED IMMUNODEFICIENCY SYNDROME ........................................................ 332

SEPSIS .................................................................................................................................... 352

Literature................................................................................................................................. 364

Infectious diseases

5Introduction of infectious diseases

INTRODUCTION

OF INFECTIOUS DISEASES

Nowadays there are about 2,500 well-known microorganisms that cause

infectious diseases. About 300 nosological forms have been distinctly described

(“nosos” means “disease” in Greek). According to the international classification

the infectious diseases relate to 13 classes and 975 rubrics. They constitute up

to 60-70 % of the total morbidity. In polyclinics 4-6 patients out of 10 suffer

from infectious diseases. The responsibility for the exposure of the infectious

morbidity is taken by the physicians of the “first line” – therapeutists, surgeons,

gynecologists and other specialists. Now it is distinctly ascertained that the

infectious agents are the basic or leading ethiological factor of the different

branches of the medical science.

Such fields of the internal diseases as rheumatology, pulmonology or

hepatology cannot be conceived without taking into consideration the infectious

factor. The infectious factor often determines the outcome of the surgery. The

gynecological, urological and eye diseases cannot be treated without considering

it. The association of the viral hepatitis B and C with the primary liver cancer is

undoubted, there is a certain connection between the cancer of the cervix of the

uterus and the virus of the herpes simplex, leucosis and Bercet’s lymphosarcoma.

The significance of the infections agents in bronchial asthma, arthritis,

meningoencephalitis is undoubted.

Besides these many new earlier unknown discuses have appeared. Only

during the last years such infections diseases as HIV, Legionnaires disease,

cryptosporidiosis, SARS, hemorrhagic fevers, caused by Marburg or Ebola virus,

hantavirus and others have appeared, they are responsible for the development

of the ulcer disease of the stomach, pneumonia, meningoencephalitis, cutaneous

diseases, lymphoadenopathy, heart and vessels diseases. Many researchers think

that the world is standing on the verge of the T-cell leucosis epidemic, which is

already widely spread in Japan and in some regions of Latin America. That is

why a physician of any speciality will more or less often encounter with the

infectious pathology.

The origin of the infectious diseases dates back from the ancient times. The

old archives that contain the man’s first descriptions of his thoughts with the

help of signs tell us that he already suffered from such diseases as leprosy,

hydrophobia, malaria, trachoma, fungous, helmintic and some other diseases.

Although the infectious diseases exist as long as life itself, their studying

started comparatively not long ago. It is one of the youngest branches of science.

Infectious diseases

The scientific history of the infectious diseases started at the end of the 19th

century when the term “infectious diseases” was introduced, and it was determined

that they were caused by the microorganisms i.e. the organisms that could be

found only with the help of a microscope.

The common feature of the majority of the infectious diseases is the possibility

of transmission from the affected organism to a healthy one, and the ability of

massive (epidemic) spreading. During the study of the infectious diseases the

terms “infection” and “infectious process” are usually used. They both originate

from the Latin words – “infectio” – “pollution”, “contamination” and “infecio”

– “to pollute”. At the modern level of the science development it is impossible

to give an exhaustive definition of the terms “infection” and “infectious process”

which would open all the sides of this conception. The term “infection” means

the penetration of a microorganism into another organism and their following

interaction under various conditions connected both with the microbe itself and

the qualities of the organism which receives it at the various stages of the

development of the organic world.

The term “infectious process” means the totality of the physiological, defensive

and pathologic reactions, which appear under the certain conditions of the

environment as an answer to the affection of the pathogenic microorganisms.

An infectious disease is the extreme stage of the infectious process

development, which manifests in different signs and changes of the biological,

chemical and epidemiological order.

According to all of these definitions it is obvious that the term “infection”

cannot be identified with the “intectious process”. The contents which we put

into the term “infectious process” does not let us make a complete image of the

infection as a general biological phenomenon. The concept “infection” is much

wider as infection is common to all the beings. The infectious process includes

the patterns common to the complicated organisms. The term “infectious process”

is used to identify all the dynamics of the pathologic changes connected with the

infection irrespective of the fact that they develop into a special qualitative

condition called an infectious disease or not.

The origin of the infectious diseases and their nature were discovered

owing to the brilliant success of bacteriology. That is why for a long period of

time the infectious process was identified only with the activity of the

microorganism without any consideration of the physiological aspects of the

macroorganism.

Later when the scientists started to pay more attention to the study of

pathogenesis i.e. the mechanism of the sickness processes development, they

advanced a thesis of the domination of the macroorganism in the infectious

process. It was a second mistake as it is impossible to separate something that

is by the nature closely connected and can be understood only in correlation.

Besides, the pathological process also has to be examined under the influence of

7Introduction of infectious diseases

the environment. So if the disease develops as a result of the violation of this

certain form of the organism’s adaptation to the environment at the change of its

conditions, then the infectious disease develops as the result of the influence of

the part of environment which belongs to the living organisms. In other words,

all the participants of the pathologic process are noted for the biological activity,

functional mobility and the ability to develop.

The penetration of a certain number of microorganisms into the macroorganism

is necessary for the infectious disease to develop. Besides, it has to be of a certain

quality i.e. pathogenicity and virulence. However, the development of the

pathological process depends on the general condition of the macroorganism

and its immune status. In case of the weak immune status the pathologic process

develops rapidly and the disease takes a severe course, in case of the comparatively

strong immune status the disease takes a mild course or may not develop at all.

Spreading of the disease and its severity depends on the environment – both on

the geographical position (in the tropics – overheating, in cold countries –

supercooling), and on the social sphere (a luxury villa and overcrowded facilities).

All these processes can be expressed in the formula: the infectious disease is pro

rate to the number and quality of the microbe (pathogenecity, virulence) and

invasively to the immune status and the environment. Each of the mentioned

factors is variable and they should be considered as dynamically developing with

the changing of the cause and effect.

Comparing an infectious disease with a non-infectious one we can point out

their mutual signs – intoxication and functional disorders of the organs and

systems, morphological changes and others. However, with all the similarities we

should mention the peculiarities of the infection diseases. This is, first of all, the

cyclical course with expressed periods (incubative, prodromal, high point, fading

healing). The second peculiarity is that the pathogen that caused the disease as a

living agent has its own “interests” – it lives, multiplies as it tries to preserve its

species – at the same time it adjusts, changes or remains in its constancy – the

death of the macroorganism is not “profitable” for it as the pathogen can die

with it as well. The third peculiarity is that the affected organism can become a

source of infection for healthy people. The common feature of the majority of

the infectious diseases is the possibility of transmission from the affected organism

to healthy one and the ability of massive (epidemic) spreading. The fourth peculiarity

consists of the immune processes which make the organism insensible to the

later affections in case of the same etiologic factor.

Different interrelations occur when organisms contact with one another, it

happens in nature all the time. To understand the infectious diseases we should

mention the basic types of such interrelations.

1. The meeting and contact of the organisms do not have any consequences,

any reaction. No symbiotic relations appear after it. In such cases we talk about

species inherited immunity. For example, a human immunity to the horned

livestock’s plague, to the hemorrhage septicemia of cats and others.

Infectious diseases

2. The meeting of the organisms results in the symbiotic commonwealth (in

Greek „symbiosis” means state of living together). There may be no reaction at

all on the part of both partners, the condition called saprophytosis („saprobe”

means microorganism that lives in the dead organic remains) appears. Some

researchers consider symbiosis to be any form of living together between the

representatives of different species. To this symbiosis they refer:

a) synoikia (Greek) – neutral living together during which one species

uses the other one as a place to live without harming it;

b) mutualism – the symbiosis that is profitable for both organisms;

e) commensalism (Lat. “com” – with, “mensa” – table) also (French –

“commensa” – dependent) interrelation when one organism gets a benefit

from the other without harming it;

d) parasitism – a microorganism feeds with the saps or tissues of the

master harming it. Most of the infectious diseases belong to this kind of

symbiosis.

Analyzing the pathogenic processes scientists divide the infectious diseases

into endogenous and exogenous ones. The endogenous diseases or autoinfections

develop from their own microflora which is situated on the skin, respiratory and

alimentary tracts, conjunctive, genital tracts. Because of the disorder of the

regulatory processes which provide the physiologic symbiotic balance, there

develop local, widely spread or even general infectious processes. Such

microorganisms are called conditionally pathogenic or half-parasites.

The diseases caused by the penetration of the microorganisms from the

environment and to which a macroorganism is not resistant are called exogenous

infectious diseases.

Such division is pretty relevant and only relatively right. Sometimes the

endogenous infectious disease becomes dangerous to the others because of

itself and because the symbionit acquires new biological qualities.

If the infectious disease is caused by one species of microorganism it is

called simple. If two or more microbe agents participate in the disease, then we

talk about mixed-infection. Joining one infection to the other may affect the

infectious process in different directions sometimes intensifying it, sometimes

decreasing its activity and manifestations. So while studying the infectious

pathology we should consider not only the pathogen itself but their associations.

Salmonella infection especially bent to join other infectious diseases and start

the secondary pathological process, this phenomena is called nosoparasitism (in

Greek “nosos” – disease).

The growing number of the diseases caused by the conditionally-pathogenic

pathogens is mostly connected with the changed reactivity of the organism and

especially immune response which as a rule in such cases forms very slowly and

is not valuable. The autoimmune processes activate and take a leading role in

pathogenesis and clinical manifestations.

9Introduction of infectious diseases

Many conditionally pathogenic as new discovered microorganisms are

characterized with intracellular localization of the pathogens. Such infections

can cause widely spread pathological disorders and they are more difficult with

their diagnosis and treatment.

An immune system is one of the major targets of the affection of the

environment negative factors according to the modern conception. There are six

basic factors:

Human demographics and behavior. The important factors in changing

human demographics include increases in the number of susceptible persons,

the use of day care and immigration. A number of factors cause a rise in

number of susceptible persons and the greater the population percentage that is

susceptible to the infectious diseases, the greater is the potential for the disease

transmission. In many countries in the developed world the number of seniors

is growing. Since aging is associated with an increased susceptibility to the

infectious diseases, the potential for the disease transmission is also increasing

in these countries. In the USA, the percentage of the population over 65 years

was about 4 % in 1900 and will reach almost 25 % in 2040. Certain underlying

diseases also place more patients at risk for various infectious diseases, and

these have also increased. For example, the reported incidence of diabetes mellitus

in the USA increased from 0.5 % of the nation’s population in 1935 to over 3 %

in 1995. It is estimated that there are actually 16 million persons with diabetes in

the USA, so the true incidence of this disease may be greater than 5 % of the

population. The rates for many malignancies are also increasing, and these patients

have increased susceptibility to infectious diseases from the disease process,

during chemotherapy and, in some cases, lifelong even after the cure. Some of

the most highly susceptible patients are those receiving immunosuppressive

therapy following organ transplantation. Almost 20,000 organ transplants were

performed in the USA in 1995. Worldwide the greatest factor increasing

susceptibility may be the spread of HIV, which has led to millions of persons at

increased risk for a variety of infectious diseases.

Such social changes as the increased use of day care also affect the emergence

of infectious diseases. The increasing frequency of both parents working outside

home or of single parent families led to a greater use of day care. The combination

of susceptible children, inadequate hygiene, frequent infections, and frequent

antimicrobial use is the perfect setting for the emergence of antimicrobial

resistance. Thus, it is no surprise that day care attendance has been an important

factor associated with the emergence of penicillin-resistant Streptococcus

pneumoniae. A recent study demonstrated a 4-fold greater relative risk for

colonization with a high-level penicillin-resistant Streptococcus pnenmoniae

among children attending day care.

The increase of immigration and changing the patterns of immigration also

contribute to the emergence of the infectious diseases. Between 1984 and 1992,

Infectious diseases

0.5-1.5 million immigrants and refugees were admitted to the USA each year. In

contrast to the previous waves of immigration many of these individuals came

from the parts of the world where certain infections such as tuberculosis are

common. This is an important factor in the resurgence of tuberculosis in the

USA as the percentage of patients who were foreign-born increased from 22 %

in 1986 to 37 % in 1996.

A variety of human behaviors also influence the emergence of the infectious

diseases. The impact of the sexual revolution on the frequency of gonorrhoea,

syphilis, and HIV is evident. Perhaps less evident is the impact of other changes

such as changes in eating habits. There are changes in the types of food that

people eat, how this food is prepared, and where the food is prepared. This can

result in the new exposures to unfamiliar food or the dependency upon others

to handle and prepare food safely. All these factors have contributed to the

emergence of some of the newer food borne diseases. Another important factor

influencing the emergence of resistance has been the unnecessary use of

antimicrobial agents. In 1992 over 110 million courses of antimicrobial drugs

were prescribed to outpatients in the USA. Since three-quarters of these drugs

are prescribed for upper respiratory infections that are often caused by viruses,

over half of these 110 million courses may be unnecessary.

Technology and industry. The impact of technology and industry falls

into three general areas. These include new technologies and products, changes

in food production processing and preservation, and changes in industrial

demographics. New technologies and products may have unexpected disease

implications such as the association of air conditioning and whirlpool spase

with Legionnaires disease, or new tampons with toxic shock syndrome, or the

fast-food hamburger with E. coli O157:H7.

The second area, the changes in how food is produced, processed, and preserved

has also been important. For example, in the last 50 years many of the new

agricultural production strategies involve intensive rearing of young animals

under environmental conditions that are conducive to the transmission of the

infectious diseases. These production strategies often depend upon increased

antimicrobial use. Thus, only substituting young animals for children, the situation

is similar to the day care setting and has resulted in an increase in antimicrobial

resistance for organisms that are transmitted through the food chain from animals

to humans. Between 1979 and 1989, the frequency of drug resistance in human

Salmonella isolates almost doubled from 17 % to 31 %. Today the resistance

in humans is the result of antimicrobial use in animals. The many changes in

food processing and preservation are also influencing disease emergence. The

recent emphasis on “natural” foods has led to use of fewer preservatives or

secondary barriers to prevent spoilage. Thus, some foods are protected only by

refrigeration. This has resulted in increasing problems with organisms that grow

in the cold, such as Listeria or Yersinia. The lack of secondary barriers also

11Introduction of infectious diseases

increases the risk of food handling errors leading to diseases such as botulism.

In the last 10 years, several outbreaks of botulism have occurred when “keep

refrigerated” foods were not kept refrigerated.

The third change, that of industrial demographics, is characterized by

consolidations of industry, larger market size, and wider geographic distribution

for a variety of food products. Although these changes have the potential for

greater quality control and better safety, when something goes wrong, it can really

go wrong. Thus, in 1994, an ice cream product produced by a single company in

Minnesota led to thousands of cases of salmonellosis in over 41 states.

Economic development and land use. Changes in economic development

and land use are often cited in discussions of emerging viral diseases.

Encroachment on rain forests, for instance, may lead to exposure to new agents

such as Ebola or Marburg viruses. However, such changes are also influencing

the emergence of other infectious diseases. For example, population growth and

spread lead to environmental change and pollution. The inadequacies of hygiene

and sanitation that exist in many of the “mega cities” in the developing world are

potential ticking time bombs for the emergence of infectious diseases. Other

types of development and land use practices are contributing to specific problems.

Conservation activities, such as those directed toward deer populations, have

contributed to the emergence of Lyme disease. Coastal agriculture expansion is

leading to blooms of toxic microorganisms, while coastal population growth is

leading to human faecal contamination of shellfish beds and transmission of a

variety of viral and bacterial pathogens.

International travel and commerce. Advances in technology have had

a rapid impact on international travel and commerce. A person or a food can be

almost anywhere in the world in 24-48 hours. This facility in travel and commerce

has increased the potential for the introduction of emerging pathogens to new

geographic areas by infected travellers, by contaminated food, or even by

transporting vehicles.

Microbial adaptation and change. As humankind is instituting a number

of changes, the microbes themselves are changing. This is leading to the evolution

of new pathogens, the development of new virulence factors, the development of

antimicrobial resistance, and tolerance to adverse environmental conditions. A

good example of this microbial change has been the emergence of E. coli 0157:H7,

which probably evolved from an entero-pathogenic E. coli that acquired Shigella

genes. As a food borne pathogen, it combines the worst of Shigella and Salmonella.

Like Shigella, this organism has a low infectious dose, requiring only a few

organisms to cause disease. This leads to subsequent person-to-person

transmission once the organism is introduced into a community and also poses a

high risk for cross-contamination in the kitchen. This organism is more similar

to Salmonella in its tolerance to adverse environmental conditions. Thus, it has

been associated with outbreaks that were caused by foods with pH 4.0, conditions

that are usually inhibitory to most bacterial pathogens.

Infectious diseases

The breakdown of public health measures. The breakdown of public

health measures has been the result of a series of often unrelated factors. Earlier

successes in the war against infectious diseases led to complacency. Thus, coupled

with limited resources and competing priorities in public health, often led to the

transfer of resources from infectious diseases to other areas or to newly emerging

infections.

The impact of the breakdown of public health measures can easily be seen

during wars, population movements, and natural disasters. One such example has

been the emergence of epidemic shigellosis in Africa. Since 1979, massive epidemics

of shigellosis caused by Shigella dysenteriae type 1 have occurred in cities,

rural areas, and refugee camps in Central and Southern Africa. The epidemics

have affected all age groups, often with case-fatality ratios greater than 10 %. In

1991 alone, the disease caused 60,000 deaths in Burundi and at least 200,000

deaths in the rest of Africa. In contrast to Shigella species, which are more

common in parts of the developed world, this organism is essentially resistant to

all available oral antimicrobial drugs. Some of the newer fluoroquinolones are

the last remaining effective oral agents.

Now even in developed countries approximately for 40 % of adult population

tap different imunopathologic states that explains atypical and lingering How

even of classic infectious diseases, more often development of mixed-infection,

superinfection, continuous, microbe carrying.

The diagnostic of the infectious disease should be as early as possible. Such

haste is connected not only with the necessity of assignina the conforming

treatment but also with the demand of carring out urgent preventive actions,

especially, if the disease has arisen in the collective. The diagnosis is grounded

on the combination of symptoms characteristic for this or that infectious process.

As in case with other diseases, the symptoms should be collected beginning with

the complains of a sick person, anamnestic information of the development of

illness symptoms, the nature of the epidemiological situation. Objective data

should be taking during the physical examination of the patient, and then at

auscultation, percussion and laboratory investigations.

At the identification of the infectious diseases as well as other diseases,

anamnesis is of great importance. It is necessary to point out one of the most

important peculiarities of the anamnestic data in infectious diseases, it is

epidemiological anamnesis. The epidemiological anamnesis should be extremely

careful and full. When the patient himself cannot give the necessary data (grave

condition, age), the information should be obtained from relatives or the people

around him.

Collecting the epidemiological anamnesis is as difficult as obtaining the

disease anamnesis, and the skill of its collecting needs to be developed just as the

skill of objective examining, the more so as collecting the correct anamnesis is

considered to be more difficult to learn than the procedure of the objective

13Introduction of infectious diseases

examination. At the inept approach to the patient and frivolous attitude to the

epidemiological anamnesis obtaining, the doctor cannot get the necessary

information. Sometimes it is difficult to take the correct anamnesis because in

case of the disease with a long incubative period the patient and his relatives can

forget some data, which are of the diagnostical and epidemiological value.

The following points are the most important for the epidemiological

anamnesis:

1. Way of living and living conditions of the patient. It is necessary to

explicitly find out whether the ambient situation could have promoted the intrusion

of an infectious agent. If during the last three weeks before the onset of the

disease the patient lived at the place of spreading of the infectious diseases, the

patient can have developed a similar disease. The information about the cases of

this or that infection in the patient’s house confirms this idea even more. The

use of unboiled water, milk, dirty fruit, pot herb, meat and fish products of poor

quality can be a source of intestinal infection. The wounds, bruises, splinters are

characteristic features of erypsipelas, tetanus, septic diseases.

2. The patient’s occupation. Thus the workers of cattle-breeding farms can

more often get sick with brucellosis, the agricultural workers – with leptospirosis,

hemorrhagic fever, tick epidemic typhus, the workers of rice fields are subject to

the infection of ankylostomidosis and strongyloidosis.

3. The previous diseases and preventive vaccinations. This information is

necessary as the previous diseases in a number of cases is evident against the

disease which is suspected at this moment. However, it is always necessary to take

into consideration that there is not a single infectious disease, which would not

repeat, though in rare cases. Such diseases as flu, malaria, shigellosis, diphtheria,

erypsipelas are the most recurring. And vice versa measles, epidemic typhus

results in a strong and continuous immunity which guarantees from the recurrence

of the diseases. Vaccination in anamnesis does not eliminate a possibility of the

disease caused by the same infection, but there are often distorted, atypical forms of

the disease, the so-called deleted forms in case of vaccination. Having taken the

epidemiological anamnesis one starts to inquire about the main complaints and

symptoms, paying attention to every detail in the sequence of their development.

The temperature rise is one of the earliest symptoms which gives ground to

think of an infection when there are still no other clinical manifestations of the

illness. The temperature which rises in the morning or in the evening up to 37 °C

usually is not considered normal. However, it is necessary to take into consideration

the individual peculiarities of the patient, as for some patients the normal

temperature limits are 37.0-37.3 °C, and on the contrary for a number of patients

the normal temperature does not rise above 36.2-36.3 °C and a slightest rise

even on some tenths of a degree already is evidence of abnormal temperature.

The temperature rise can be fast (acute), when the patient clearly marks

even the hour of the onset of the disease (ornithosis, leptospirosis, etc.). In case

Infectious diseases

of the fast temperature rise, as a rule, the patient marks the chills of different

grade – from slight chills up to severe chills (malaria). The temperature may

rise gradually in other diseases (typhoid, paratyphoids).

According to the grade of the fever there are distinguished the following

conditions: a subfebrile condition (37.0-37.9 °C), a moderate fever (38.0-39.9 °C),

a high fever (40.0-40.9 °C) and hyperpyrexia (41 °C and higher). Taking into

consideration the pathogenesis of the fever, the subfebrile condition should also

be considered as a fever.

The nature of the temperature curve. In some infectious diseases the

temperature curve is so characteristic that it determines the diagnosis (malaria,

typhoid fever). It is accepted to determine several types of a temperature curve,

which are of a diagnostic value.

The constant fever (febris continua) is characterized by the permanently

high body temperature often up to 39 °C and higher, the daily temperature

fluctuations are less than 1°C and observed in typhoid-paratyphoid diseases, Q- fever,

epidemic typhus, etc.

The remittent fever (f. remittens) is distinguished by daily fluctuations of the

body temperature from more than 1°C but not more than 2 °C (ornithosis, etc.).

The intermittent fever (f. intermittens) is manifested by the correct change

of the high or very high and normal temperature with daily fluctuations of 3-4 °C

(malaria, etc.).

The relapsing fever (f. recurrens) is characterized by the correct change of

the high-fever and fever-free periods that last several days (typhoid fever, etc.).

The undulating or undulant fever (f. undulans) is distinguished by a gradual

increase of the temperature up to the high points and then its gradual decrease

to the subfebrile and sometimes normal temperature; in 2-3 weeks the cycle is

repeated (visceral leishmaniasis, brucellosis, lymphogranulomatosis).

The hectic (exhausting) fever (f. hectica) – a prolonged fever with

considerable daily fluctuations (3-5°C) with the decrease to the normal or

subnormal temperature (sepsis, generalized virus infection, etc.).

The irregular (atypical) fever (f. irregularis) is characterized by large

daily amplitude, a various degree of a temperature increase, an indeterminate

duration. It stands closer to the hectic fever, but does not have a regular rythm

(sepsis, etc.).

The distorted (inverted) fever (f. inversa) is distinguished by a higher

morning temperature than the evening one.

Besides these generally accepted types we consider expedient to mention

two more: an acute undulating fever and a relapsing one.

The acute undulating fever (f. undulans acuta) in contrast to the undulate

one is characterized by relatively short waves (3-5 days) and by the absence of

remissions between the waves; the usual temperature curve represents a series

of damped waves, i.e. each subsequent wave is less expressed (in the altitude

15Acute respiratory viral diseases

and duration) than the previous one (typhoid, ornithosis, mononucleosis, etc.):

when the subsequent wave is caused by adding of a complication, the revertive

interrelations are observed, i.e. the second wave is more expressed, than the first

one (epidemic paratitis, flu, etc.).

The relapsing fever (f. recidiva) in contrast to the recurrent fever (the

regular alternating of the fever waves and apyrexy) is characterized by a relapse

(usually one) of the fever which develops in different terms (from 2 days to one

month and more) after the termination of the first temperature wave (typhoid,

ornithosis, etc.). The relapses develop in some of the patients (10-20 %). In this

connection if the relapse has an important diagnostic value, the absence of it does

not eliminate a possibility of the mentioned above diseases at all.

Each infectious disease can have different variants of a temperature curve,

among which some are more frequent, they are typical for this or that nosological

form. Sometimes they even allow to diagnose the disease quite accurately (tetrian

fever, etc.).

The duration of a feveris is an important value for the differential diagnosis.

A number of diseases are characterized by a short-term fever (herpangina, acute

shigellosis, etc.). And if, for example, the fever lasts more than 5 days, it already

allows to eliminate such frequently encountered diseases, as flu and other acute

respiratory virus diseases, angina (certainly, if there are no complications).

On the contrary, the long-term fever (more than a month) is observed

rather seldom and only in some infectious diseases which lend to the lingering

or chronic flow (brucellosis, toxoplasmosis, visceral leishmaniasis, tuberculosis).

Thus the grade and characteristic of a temperature curve and the duration of a

fever allow to differentiate certain groups of infectious diseases, among which

the differential diagnosis is based on other parameters.

For the differential diagnosis the interval between the onset of a fever and

the appearance of organic lesions is particularly important. In some infectious

diseases this period is less than 24 hours (herpetic infection, scarlatina, rubella,

meningococcemia), in others it lasts from 1 up to 3 days (measles, shigellosis),

and, at last, in a number of diseases it lasts more than 3 days (typhoid fever, virus

hepatitis).

The nature and level of the infectious diseases rate also matters. For example,

any feverishness during the epidemic of flu suggests a possibility of flu. The

indication to the contact with the people sick with measles, scarlatina, water-pox,

rubella and other droplet infections is important. These data are compared to

the terms of an incubation period. Other epidemiological data (the stay on the

territory which is endemic on malaria, and other diseases) also matters.

For the differential diagnosis the change of a temperature curve under the

influence of etiotropic medications is important. Delagilum stops malarial attacks,

in endemic typhus the temperature quickly becomes normal after the reception

of tetracyclines and others. There are a number of peculiarities of the fever

Infectious diseases

syndrome, which one can use for the differential diagnosis. The differential diagnosis

of a fever needs to be done to distinguish it from the body temperature rising of

another nature (thermal shock, hyperthyroidism).

The second component which is not less important for the diagnosis and

differential diagnosis of the infectious diseases is a rash on the skin –exanthema. It

is because the rashes are a symptom of many infectious diseases, besides, they are

well visible, quite often catch one’s eye even at the first examination of the patient.

There are exanthemas, characteristic of this or that infectious disease and

they are an obligatory component of a clinical symptomatology of this or that

infectious disease.

The expressiveness and nature of exanthemas can be miscellaneous and are

not always observed in other infectious diseases. Due to this factor their presence

or absence in different infectious diseases essentially differs.

The exanthemas in infectious diseases are rather diverse. They differ in

nature of different elements of an eruption, localization, terms of appearance,

stages of a rash, the dynamics of development of separate elements, etc. All these

features are taken into consideration while making a differential diagnosis. In the

diagnostics process the legible definition of separate elements of an eruption and

unified comprehension of the terms are very important. Dermatologists and

infectionists do not always define some elements of an eruption in the same way.

The following nomenclature is generally accepted in infectious diseases.

Roseola – is a small spot (diameter 2-5 mm) of pink, red or purple-red

color, more often with a spherical form. It is formed as a result of a local

vasodilatation of a papillary layer of skin. The roseola disappears when pressing

the eruption area with a transparent glass-spreading rod or when stretching a

skin and comes up again after the stopping of pressure (stretching) that is the

main distinctive feature of it.

The so-called punctate rash is close to roseola. It consists of a set of shallow

(in a diameter of about 1 mm) elements of the red color. At stretching the skin

these elements, as well as roseolas, disappear. Each element rises a little above the

level of the skin that stipulates a special “velvety” of the skin at the eruption area.

The macule (macula) represents an element of the eruption similar to the

roseola, but larger (5-20 mm), it does not stick above the level of the skin, its color is

the same as roseola’s. The development of the spot, as well as in case of roseola, is

based on vasodilatation. The form of maculae can be oval, spherical or more often

small or with festoon edges. Unlike the dermatologists the infectionists distinguish -

spot eruption, in which the elements of an eruption vary in diameter from 5 up to 10

mm, and “large-spot eruption” with the elements’ diameter of 11-20 mm. This distinction

has a differential – diagnostic value. For example, in a patient with rubella there is a

small-spot eruption, and in a patients with measles – a large-spot one.

Papule (papula) – a superficial formation without a cavity, rising above the

level of the skin. It has a mild or dense consistence, the reverse development

ends without the formation of a scar. There are inflammatory and noninflammatory

17Introduction of infectious diseases

papules. In the infectious diseases only inflammatory ones occur. They are caused

by the proliferation of epidermis and infiltrate development in the papillary layer

of derma with vasodilatation and limited edema. Papulas have the same color as

roseola and macula. There are papulas of a different size (1-20 mm). Small

papulas (1-1.5 mm) are called milliar ones, the larger (2-3 mm) papulars –

lenticularis ones. The confluence of separate papules results in the formation of

the eruptions elements called plaque.

Erythema – is vast fields of the bloodshot skin which are red, purple-red or

magenta. The erythema is formed as a result of large maculae joining. Therefore the

erythema has festoon blurry edges. Inside arythmetic fields there can be separate

fields of the skin with normal coloring. There is no expressed inflammatory process.

Unlike the infectionists the dermatologists consider that the term “erythema”

means inflammatory fields with a diameter from 2 cm up to several dosen

centimeters (active erythema), and also cyanosis conditioned by the venous

congestion (passive erythema).

Tubercle (tuberculum) — a formation without cavities which arise as a

result of the development of an inflammatory infiltrate of granulematous

constitution in derma. The hillock differs from a papule, it lies deep in the derma

and the infiltrate is determined at the palpation. The hillocks have legible borders

and a tendency to grouping. As against papules at further development the

hillock can narcotize, forming ulcers and leaving a scar. The hillocks develop in

dermal and visceral leishmaniasis, deep mycosis.

Node (nodus) — a limited dense formation with a diameter from 1 up to 5

cm and more that has a spherical or oval form and is situated in the deep layers

of derma and hypodermic fat. More often they develop as a result of the

inflammatory process.

In some cases they disappear without any traces (nodal erythema), in chronic

illnesses they ulcerate and heal leaving a scar.

Wheal (urtica) – an element of an acute inflammatory nature that has no

cavity. There develops an acute restricted edema of the skin papillary layer. It

develops owing to the trichangiectasia of the papillary layer of derma, the increase

of their penetrability and the outcome of protein-free exudation through a vascular

wall, which then compresses the vessels. As a result dense formations of different

size and form suddenly develop on the surface of the skin and rise above its level.

The cyanolic porcelain-white coloring in the center and the pink-red one on the

peripherals are typical. An itch and a burning sensation of the skin appear with

the development of a blister. The blisters develop in a serum disease, medicinal

allergy and sometimes in some infectious diseases (leptospirosis, virus hepatitis).

Vesicle (vesicula) — a small cavity formation containing serouse, less often

serouse-hemorrhagic fluid. The blister develops directly in the false skin, under

the keratinous layer, in middle or on border with derma. It rises above the level

of the skin as a half-round element with a diameter from 1.5 up to 5 mm.

Hereinafter a blister can dry out, forming a semidiaphanous yellowish or brown

Infectious diseases

crust. If a blister is opened (damaged), soaking superficial pink or red erosion

develops on its place.

Herpetic eruption (herpes) — a bunch of small closely set bubbles on the

erythematic inflammatory base (herpetic infection, surrounding deprive).

Pustule (pustula) is also a blister but its contents is cloudy (purulent)

because of a clump of a big amount of leucocytes.

Blister (bulla) — a cavity formation with a dimension of more than 5 mm

(up to 10 cm and more). The borders of a vesica are legible, the outline is round

or oval. The vesica rises above the level of the skin. It is usually unicameral and

rolls off after a puncture. The cover of a vesica can be tight and flabby. The

contents is serouse or serouse-hemorrhagic.

The vesicles can be situated on the background of the inflamed skin (a

violent form of erysipelas, anthrax, multiform exudative erythema, Stivens –

Johnson’s syndrome).

Hemorrhages (hemorrhage) – an extravasation into the skin of different

kinds and dimensions. They develop as a result of the erythrocytes yield from

veins to the ambient connecting tissue of derma or hypodermic fatty tissue. It

can be a result of the damage (breakage) of the vessel or heightened permeability

and fragility of a vascular wall.

According to the value and form hemorrhages are divided into the following

elements: petechias (petechiae) – dotted hemorrhages on the background of the

normal skin (primary petechias) or on the background of roseolas (secondary

petechias); purpura (purpura), in which the dimensions of the elements oscillate

from 2 up to 5 mm (the dermatologists consider purpura to be hemorrhages

with a diameter up to 2 cm): ecchymomas (ecchymosis) — hemorrhages of the

irregular-shaped form with a diameter of more than 5 mm.

Ecchymoses (sugillationes) – hemorrhages on places of injections that are

not the sort of an exanthema but have a diagnostic value as a parameter of a

heightened fragility of vessels, that is often observed in the development of a

hemorrhagic syndrome.

The hemorrhagic elements of the eruption are observed in many infectious

diseases and have a great value both for the differential diagnostics and for the

evaluation of the illness severity.

All the reviewed above exanthemas belong to the primary morphological

elements of the eruption. However, the secondary morphological elements of the

eruption also have a diagnostic value. The dyschromias of the skin, flake, peel,

anabrosis. ulcers, seams belong to them.

Erosion (erosio) – a defect of the epidermis which develops after opening

of the cavity primary elements (vesicles, pustules, vesica). The bottom of the

erosion is covered with epidermis or partially with the papillar layer of the

derma. By the size and form the erosion corresponds to the primary element.

After healing the erosion do not leave any stable changes of the skin.

Ulcer (ulcus) – a deep defect of the skin which affects the epidermis. derma,

19Introduction of infectious diseases

and sometimes underlying tissues. The ulcers develop as a result of the

disintegration of the primary infiltrating elements in the deep parts of the derma

– pimples, clusters, and the opening of the deep pustules. The form and the edges

of the ulcer are of great importance for differential diagnostics. The edges of the

ulcer can be undermined, vertical saucer-shaped, callous, mild, etc. The ulcer

always heals leaving a cicatrix. The ulcers develop both in the infectious diseases

(dermal leishmaniasis, anthrax, tularemia) and in the illnesses related with the

competence of other specialists (lues, tuberculosis, trophic ulcers, neoplasm).

Skin dischromia (dyschromia cutis) – a disorder of the pigmentation, which

develops on the place of the resolved morphological elements of the dermal eruption.

The expressiveness and duration of the hyperpegmentation are various. As a rule,

pigmentary spots are brown. Sometimes they are sharply distinguished, for example,

after measles maculepapulas eruption, especially in case of its hemorrhagic

impregnation. Sometimes it is only a hardly noticeable brown blot (for example, on

the place of typoid roseola), which disappears fast and does not leave any traces.

Scale (squama) is a loosened tearing away ceel of the corneous layer, which

lost its connection with the underlying epidermis. Depending on the size of the

flakes there is micro- and macrolaminar pityriasis.

Small-laminar, branny pityriasis (desquamatio pityriasiformis) is observed

in measles, branny lichen. The smallest flakes get detached and the skin looks as

though it is powered with flour.

Macrolaminar pityriasis (desquamatio lamallosa) is characterized with a

larger dimension of the flakes, and they can get detached from the skin by the

whole layers. The similar pityriasis is characteristic of scarlatina, pseudo-

tuberculosis, toxidermias. The pityriasis develops in the period of convalescence

from the infectious diseases and what is important for differential diagnostic – in

the late period of illnesses or during reconvalescence.

Crust (crusta) – a product of thickening and desiccation of different kinds

of other elements exudates of the eruption (pustules, vesicles, anabroses, ulcers).

There are serouse crusts (semidiaphanous or grayish), purulent (yellow or green-

yellow) and hemorrhagic (brown or dark red). The size of the crusts corresponds

to the size of the preceding element.

Cicatrix (cicatrix) – coarse-fibroid growth of the connecting tissue, which

substitutes deep defects of the skin.

The listed above elements of exanthema are basic and can be observed in

infectious diseases, the differential diagnostics is based on their exposure. In

case of the eruption it is necessary to identify the type of separate elements and,

besides, to specify other peculiarities of exanthema.

The very important signs are the terms of the eruption development.

The localization of the eruption elements and the place of the greatest

concentration of exanthema are of a diagnostic value. In some cases the sequence

of the rush development is of the diagnostic value. The duration of the eruption

elements existence is also important. Repeated rashes and the inclination for

Infectious diseases

joining the elements of the eruption can be of a diagnostics value.

Enanthema – the rashes on the mucous – can be observed less often in

infectious diseases and is less important for the differential diagnostics. However,

in a number of illnesses the changes of the mucous are rather informative at

their identification at the initial stage. The lesions of the oral cavity and eyes

conjunctiva are of the greatest practical value.

The most essential characteristic symptoms of the infectious diseases are the

hyperadenosises, icterus, catarrh of respiratory tract, diarrhea, meningeal symptoms.

Hyperadenosis is the result of the frequent involvement of the lymphatic

system in the infectious process. The degree of their affection can essentially

differ from a moderate enlargement to the development of a bubo with a diameter

of 3-5 cm. The ability to detect the changes of the lymph nodes is of great

importance in the differential diagnostics. This symptom is especially important

now when HIV-infection is widely spreading in all the areas. At the same time the

physicians quite often do not pay proper attention to the state of the lymph nodes

and do not always correctly carry out the examination for the differential diagnostics.

The improvement of the infectious diseases diagnostics is closely connected

with the development of microbiologic, gene-diagnostic. immunological methods

of investigation. The latest methodological achievements allow not only to

essentially raise the level of etiological confirmation of the diagnosis, but also to

present the detailed characteristic of the microbe behavior in the organism. In

particular, it is not possible to judge about the quantity of microbial bodies in

different substrates of the organism, to determine the availability and concentration

of antigens, toxins and even separate molecules of the microorganism. The gene-

diagnostics opens rather comprehensive possibilities, however, the biosensory

(including immunosensory) methods of investigation, which are already being

worked out in a number of the countries, are next in turn.

But a great number of the laboratory investigations that are available for a

doctor are not always important for the diagnosis and are sometimes

overestimated and distract the attention from the clinical diagnostics. The clinical

examination of the patient is of a primary importance and the laboratory and

instrumental methods are supplementary. Every laboratory test should be

evaluated according to its specific features, sensibility and informativity, it is

necessary to determine the indications and terms of the investigations in different

nosologic forms and to state their comparative diagnostic value.

The treatment of infectious diseases is more complicated task in comparison

with therapy of other palhologic conditions as besides the correction of the

disorders in the function of the organs and systems, it has a complicated task –

to eliminate and suppress the infectious agent.

In the historical aspect only from the 17th century when the improvement of

the agricultural production resulted in a better nutrition, it had an immediate effect

on the outcome of some infectious diseases. At the beginning of the 19lh century

21Introduction of infectious diseases

the improvement of the sanitary-hygienic control over food and water resulted in

the decrease of many infectious diseases transmission. Later the knowledge of the

specific etiology of the infectious diseases promoted the creation of the scientific

base for their prevention and treatment. In the 20th century when the methods of

immunization were widely used and especially when the antibiotics appeared the

morbidity and mortality from infectious diseases were considerably reduced. The

children’s mortality was sharply reduced. The lifetime in the developed countries

increased from 47 years on the average till 70 years.

Despite the increasing role of the microbial factor under different pathologic

conditions, the practice of treating patients in polyclinics and somatic hospitals has

not changed essentially. The treatment of the patients is mainly based on trial-and-

error assigning the coolest or the most available antibiotic, as there are no real

possibilities and the doctors striving to study the development of the infectious

process in dynamics. At its best a single-pass serological or microbiologic research

revealing the infectious agent is used as a sufficient argument for the statement of

the clinical diagnosis and assigning the therapy. Therefore it is not surprising that

there is no noticeable progress in outcomes of treatment, and there is an increase

of negative consequences such as the medical disease, immunodefence disorders,

development of dysbacteriosis, appearance of polyrefractory microorganisms.

Due to the technological achievements a large number of antibacterial and antiviral

drugs have been made. The availability of drugs considerably dilates therapeutic

capabilities, but also demands a scientifically reasonable differentiated approach.

The semi-centennial experience of the antibiotic therapy in the infectious

disease treatment has not justified the initial hopes. After a considerable increase

of the treatment efficiency of bacterial infections in the 50-60s, despite the appearance

of a broad spectrum of new antibiotics, the multiple increase of uptaken doses,

there have been no adequate progress in the results of treatment, but the

number of cases of the drugs intolerance and therapy complications have increased.

The indispensable condition of the therapy efficiency is the differentiated

approach to drugs in dependence on the way they act, capability to the intracellular

infiltration, bacteriostatic or bactericidal influence.

Control questions:

1. The origin of infectious diseases.

2. The main features of infectious diseases.

3. The basic types of interrelations between micro- and macroorganism.

4. Human demographics and behavior.

5. Microboial adaptation and changes.

6. The rate of pulic health measures.

7. The nature of temperature curve.

8. The exantemas in infectious diseases.

9. Another essential characteristics of infectious diseases.

Infectious diseases

THE PRINCIPLES OF THE DIAGNOSTICS,

TREATMENT AND PREVENTION OF

INFECTIOUS DISEASES

The principles of the infectious diseases diagnostics

In present time the diagnostics of the infectious diseases preserves the

traditional characteristics. The methods of the distinction of the diseases are

improved. The looking for new more effective methods are performed. The

necessity of further elaboration of the methods of diagnostics of infectious

diseases is connected with change of pathomorphology and clinic of infections.

The tendency to increase of number of asymptomatic, atypical, lindering forms

of infectious diseases occurs. The frequency of mixed infections of bacterial and

bacterial-viral etiology increases. These features are connected with change of all

the factors, which participate in development of infectious disease (microorganism,

macroorganism and conditions of environment). The courses of this transformation

are the increase of common specific reactivity of the organism, massive vaccination

and revaccination of the population, wide inculcation into practice of antibiotics

and other chemical drugs, increasing nonspecific allergization of the organism.

The early, exact and maximally concretive diagnostics is the basis for effective

therapy, prevention of complications and infavorable outcomes of the disease.

The early diagnostics of the infectious diseases is basis of antiepidemic and

prophylactic measures.

The diagnostics of infectious diseases is based on comprehensive and systemic

examination of the patient, including anamnesis, epidemiological anamnesis, physical

examination of the organs and systems, analysis of the results of laboratory and

instrumental examination of the patient.

Anamnesis of the disease (Anamnesis morbi)

The physician must take the history actively and carefully. It is necessary to

indicate features of the onset of the disease (an acute or gradual), presence of

the fever, chill, degree of increase of the temperature, it’s oscillations, duration, the

character of the stool, localization and intensity of the pains (headache, abdominal

pains, pains in the muscles and joints), violations of the sleep and other. The

epidemiological amamnesis permits to receive data about place, circumstances

and conditions of infection, and also about possible ways of the transmission of

the agent. The data about contact of patient with other patients with same

infection, about personal contact with animals (for example, professional), about

stay in endemic or epizootic focus have especial value.

23The principles of the diagnostics, treatment and prevention of infectious diseases

The data about food of the patient, wounds after bites of the insects, traumas,

operations, hemotransfusions have an important value too. Informations about

transferred infections in last time, about prophylactic vaccination, use of

immunoglobulines, glucocorticoides, antibacterial drugs are exceptionally important.

Clinical examination

There is the definite order of the clinical examination of the patients. At

first, it is necessary to evaluate the common state of the patient (preservation or

violation of the consciousness, excitement or brake action, adequacy of the

behavior).

Due to examination of the skin it is necessary to mark pale skin or hyperemia,

jaundice, humid or dry skin, and presence or absence of the rash. In presence of

the rash it’s localization, spread, and character (roseola, pethechias, papules or

vesicula) are marked.

Then conjunctives, mucous membrane of the mouth’s cavity are examinated.

Due to some infectious diseases (diphtheria, scarlet fever, and infectious

mononucleosis) the changes of the mucous membrane of the throat and tonsils

are developed. In these cases the degree of hyperemia and edema of mucous

membrane, presence of coats, it’s localization, color and spread are marked.

In some infectious diseases the enlarged lymphatic nodes are observed. It

may be enlarged of separate lymphatic nodes (tularemia) and multiple lymphatic

nodes (brucellosis, infectious mononucleosis, HIV-infection). It is necessary to

mark size of the lymphatic nodes, consistence, tenderness, motility.

There is the definite order of objective examination of the internal organs

(cardiovascular system, respiratory system, gastrointestinal tract, blood system,

immune system, urinary system, nervous system).

The rule evaluation of haemogramma has great meaning in diagnostics of

infectious diseases. The tests of haemogramma, connecting with clinics of the

disease help in diagnostics of many infectious diseases (infectious mononucleosis,

typhoid fever, viral hepatitis, HIV-infection and others). In leptospirosis,

haemorrhagic fever with renal syndrome the analysis of urine may help too.

In infectious pathology the largest part of common symptoms are nonspecific.

The high temperature, chill, vomiting, violation of the sleep, decrease of the appetite,

weakness are observed almost due to all infectious diseases. These symptoms have

not decisive meaning in diagnostics. Because, the pathognomonic symptoms have

great value. These symptoms are specific symptoms only for one nosologic form.

The classic examples are Filatov-Koplik’s spots in measles, crampic cough

with reprises in whooping cough, opistotonus in tetanus, haemorrhagic star-like

rash in meningoccemia, vesicular rash along turm of nerves in herpes Zoster,

hydrophobia in rabies and other.

Besides common (nonspecific) and pathognomonic symptoms, there is a great

group of signs with intermediate position. These signs are typical as for many

Infectious diseases

infectious diseases as for noninfectious diseases. So, enlarged liver may be in case

of typhoid fever, epidemic typhus fever, malaria, acute or chronical viral hepatitis,

sepsis, diseases of the blood, cirrhosis of the liver, acute and chronical heart’s

insufficiency. In typhoid fever, visceral leishmaniasis, diseases of the blood, sepsis

enlarged spleen are observed. There is no enlarged liver and spleen in grippe. The

different abdominal pains, diarrhea, cramps are symptoms from this group too.

In diagnostics the important moment is revelation of syndrome. Syndrome

is combination of the signs, caused by united pathogenesis (intoxication,

haemorrhagic, meningeal, colitis, hepatolienal, and syndrome of gastroenteritis,

jaundice, cholesthasis and other). The different syndromes have nonidentical

meaning. So, syndrome of intoxication occurs due to all infectious diseases.

Intoxicative syndrome plays the great role in evaluation of the severity of the

course and prognosis of the disease.

In present time near 1,500 syndromes and more than 5,000 diseases are

known. The identical syndrome may be due to different diseases. For example,

meningeal syndrome is observed in subarachnoidal hemorrhage, serous and

purulent meningitis, meningismis. Hemorrhagic syndrome occurs in viral hepatitis,

leprospirosis, and meningococcal infection, hemorrhagic fevers, in diseases of the

blood and other. The nosological form is characterized by few constant and

typical syndromes. For example, colitis syndrome and syndrome of intoxication

are observed in shigellosis. Symtomocomplex is combination of syndromes and

symptoms, which typical for absolute majority cases of nosological form.

Symptomocomplex has high specific, but it may be different in different periods

of the disease. For example, there is combination of syndromes of intoxication,

dyspeptic and other syndrome in prejaundiced period of viral hepatitis. Syndrome

of jaundice, hepatolienal syndrome and sometimes syndrome of cholesthasis are

observed in period of jaundice.

Laboratory methods

The different laboratory methods are used in diagnostics of infectious diseases

(bacteriological, virological, parasitological, immunofluorescennt and others). The

purpose of these methods is to establish etiology of the disease.

The bacteriological method includes sowing of the material on the nutritive

mediums, isolation of the clean culture of the agent, it’s identification.

The blood, urine, stool, cerebrospinal fluid may be material for the bacteriological

investigation. For example, in typhoid fever the bacteriological method is used for

isolation of agent from the blood, urine, stool (hemoculture, coproculture, urineculture).

In meningococcal infection the blood and cerebrospinal fluid are the material for

investigation. Besides that, smears from the pharynx and nose are investigated for

isolation of the agent. Bacteriological method is used in diagnostics of cholera,

shigellosis, salmonellosis, diphtheria and other diseases.

Parasitological investigation is based on microscopy of the thick drop and

blood’s smears (malaria), smears of the blood and bone marrow (leishmaniasis),

25The principles of the diagnostics, treatment and prevention of infectious diseases

smears of the blood and gland puncture (trypanosomomiasis), stool (amoebiasis

and balantidiasis).

The virological method is more complicated. In virological diagnostics the

culture of the tissues and hen’s embryo are used.

The bacteriological and virological methods may be complete, accelerated

and expressive. For example, expressive method is immunofluorescense method

(Cooms’s method). The method is based on specific fluorescence of the antigen-

antibody complex. The primarily material is processed by specific fluorescent

serum. The antigen-antibody reaction is basis of the serological methods of

laboratory diagnostics of infectious diseases. The serological reactions are used

for antibodies revelation in the blood serum of the patients. The investigations

are performed with well-known antigens.

Reaction of agglutination, passive (indirect) hemagglutination, precipitation,

and complement fixation have greatest spread.

In the last years immunofermentive method is used in specific diagnostics

of parasitaric and viral infections. The new method of serological diagnostics is

definition of belonging of antibodies to definite classes of immunoglobulines

(IgM, IgG, IgA and other). This method helps to identificate primary infectious

disease from repeated disease and infectious disease from artificial immunization.

In diagnostics some infectious diseases skin’s test with allergen is used.

The examples are positive intraskin reaction to tularine (tularemia), brucelline,

Burne’s test (brucellosis) and others.

The laboratory-instrumental methods of nonspecific character occupy the

considerable place in the diagnostics of infectious disease (biochemical, endoscopic,

hystological, ultrsoundic).

The principles and methods of the infectious diseases treatment.

The treatment of the infectious patients should be complex, etiotropic and

pathogenetic, and also individually depending on the state of the patient, on

severity and period of the disease. In complex therapy of infectious diseases

different remedies, directing to decrease of activity of the agent and neutralization

its toxins, increase protective powers of the organism are used.

The remedies of specific action are used with purpose to increase protective

powers of the organism. There are remedies, regulating immunogenesis (immuno-

stimulating therapy) and remedies of nonspecific action (vitamins, preparations

of the blood, preparations of pyrimidine – methyluracil, pentoxil).

In treatment of infectious diseases pathogenetic therapy is widely used.

Pathogenetic therapy is directed to correct the violation of homeostasis (correction

of water-electrolytic, protein balance, acid-alkaline state; liver, kidney, respiratory

and cardiovascular failure and to decrease allergic manifestations).

In treatment of infectious diseases it is necessary to mention the form and

period of the disease, severity of the course and features of the organism (age,

reactivity, accompanied diseases and other).

Infectious diseases

Some infectious diseases have declination to prolonged course and relapses.

For these patients it is necessary to use special principles of the therapy (immuno-

modulating therapy, interferones and other).

Chemotherapy of infectious diseases

The brilliant success in fighting of severe infectious diseases in many cases

is connected with application of antibiotics.

In medical practice near 500 antibiotics are used. However, the application

of antibiotics is accompanied by negative consequences: increase of antibiotic’s

resistant agents, depression of immunocompetentive system function, development

of nonspecific sensibilization, increasing of endogenic infections mixed infections

and superinfections.

The selection of antibiotic depends on the type of the agent. It is known, that

the remedies of the penicillin group have high efficiency for gram-positive

(streptococci, staphylococci, pneumococci) and gram-negative cocci (gonococci,

meningococci, and also for agent of Siberian ulcer, leptospirosis. Cephalosporins

have wide spectrum of the activity. They are effective such for gram-positive, as

for gram-negative microorganisms.

The remedies of streptomycin group are more effective for gram-negative

microorganism (plague, tularemia, and tuberculosis). Chloramphenicol is effective

for many gram-negative and gram-positive bacteriums, rickettsias, spirochetas.

Tetracyclines have wide spectrum of activity. They depress the growth of the

majority of gram-positive and gram-negative bacterium’s, rickettsias.

Aminoglycosides (monomicin, kanamycin and gentamicin) render the activity

to majority of gram-positive and gram-negative microorganisms. This antibiotics

are effective for resistant microorganisms to penicillin, chloramphenicol, tetracycline.

At the last decades the remedies of the new generation came into displacement

of natural antibiotics: half-synthetic penicillins (ampicillin, oxacillin, amoxicillin);

aminoglycosides (amikacin, tobramycin), tetracycline (doxycycline), rifampicins

(rifampicin, rifadin). These antibiotics are characterized by acid-resistant, ferment-

resistant wide spectrum of the activity.

Besides antibiotics, there are other kinds of medications that have influence

on the agent of the disease. Derivates of nitrofuran (furazolidone, furodonine and

furacillin) have a high antimicrobial activity. They are effective for many

gramnegative and gram-positive bacteria – resistant to antibiotics and sulfonamides,

and also for some protozoa (trychomonades, lamblia).

Sulfonamides don’t lose their value. However, recently the decrease of

their therapeutic action is observed connecting with appearance of the resistant

forms of the microorganisms.

However, different complications may be due to treatment of infectious

diseases by chemoremedies. There are 3 types of the complications in chemo-

therapy of infectious diseases: allergic, endotoxic and dysbacteriosis.

27The principles of the diagnostics, treatment and prevention of infectious diseases

Allergic reactions are observed more frequently. They are manifested by

capillartoxicosis, catarrhic change of mucous membranes, dermatitis edema.

Sometimes, anaphylactic shock arises. The development of allergic reaction doesn’t

depend from the dose and duration of application of the drug.

Endotoxic reactions arise, as a rule, after injection of the large shock doses

of antibiotics. These reactions depend on intensive disintegration of the

microorganisms with liberation of endotoxin.

In development of dysbacteriosis autoinfection arises due to reproduction

of the microorganisms naturally living in it, for example some kind of gram-

negative microorganisms and fungi from the Candida species.

Recently, antiviral remedies, interferon or inductors of endogenic interferon

are used in the treatment of infectious diseases.

Serotherapy of infectious diseases

In treatment of some infectious diseases homological and heterological immune

serums and immune gammaglobulines are used. Serums and gammaglobulines

are used for treatment and for prophylaxis of the infectious diseases.

There are antibacterial and antitoxical serums. Antitoxical serums contain

specific antibodies to toxins – antitoxins. The mechanism of the action of these

serums is neutralization of toxins, producing by the agent. Antitoxical serums

are serums against diphtheria, botulism, and tetanus.

The effect of the serum depends on the dose and date of its injection. The

result will be better if the serum will be injected early because serum inactivates

only toxins, circulating free in the blood. The duration of the toxin circulation in

blood is 1-3 days, and then toxins connect with cells and tissues.

In treatment of some infectious diseases immune gammaglobulines are used,

obtained from the blood serum of the donors (homological). These remedies

have high concentration of antibodies. The balastic substances are absent in

these gammaglobulines. Iinjection of the gammaglobulines is not accompanied

by side reactions.

At the present time immunoglobulines are used in treatment of grippe, tick

encephalitis, staphylococcous infection, anthrax and other diseases. Due to application

of heterogeneous serum may be anaphylactic shock and serum’s disease. The

development of shock occurs immediately after injection of the serum. It is necessary

to inject serum by divided doses for prevention of development of shock. The

serum’s disease develops in 5-12 days after injection of the serum. The clinical

manifestations are fever, edema of mucous membranes, lymphadenitis, spotted-papular

rash. The duration of the disease is 6-12 days. The prognosis is usually favorable.

Sometimes the injection of the serum is accompanied by reaction only in the place

of the injection. Hyperemia and edema without fever occur.

Pathogenetic therapy

The pathogenetic therapy is based on study of important characteristics of

homeostasis and its violations in infectious diseases. In pathogenetic therapy it

Infectious diseases

is necessary to allow for tests of acid-alkaline state, water-electrolytic balance,

reological properties of the blood, and also disorder of microcirculation in the

organs and tissues. The basic methods of pathogenetic therapy are desintoxication,

rehydration, dehydration, and correction of the other violations of homeostasis.

In treatment of infectious diseases desintoxicative therapy is prescribed

more frequently. Crystalloid solutions (Ringer’s solution, threesalt, quartasalt

acesalt and other) and colloid solutions (neohemodesis, polyglucin, reopolyglucin,

albumin) are widely used.

The value of the pathogenetic therapy may be shown in the pattern of the

infectious-toxic shock treatment.

The number of pathogenetic factors is known in the development of infectious-

toxic shock. There are disorganization of blood circulation, violation of the

microcirculation in the organs and tissues. Disorder of blood supply is accom-

panied by aggravation of provision of oxygen to cells, and also by difficulty in

liberation of toxic products of metabolism from the cells.

Capillary system plays an important role in the development of shock. In

shock damage of liver, functional insufficiency of kidney are observed.

Maintenance of homeostasis is ensured by dynamic balance of biologically

active substances and their inhibitors (histamine, acetilcholine, catecholamines,

proteolitic ferments, kallikreine-kinine system, cyclic nucleoproteins and

prostaglandin’s ensure maintenance of homeostasis.

In shock one of the more early reaction of the organism on damage is

hyperfermentemia. Its biological meaning is concluded in supply of the organism

with energy and destruction of damaging factors. Analysis of condition and level

of ferments allows to consider pathogenetic based conclusion of proteolitic

ferment’s inhibitors in the therapy of shock.

One of the most important disorders of homeostasis is DIC-syndrome

(synonyms – thrombohemorrhagic syndrome, coagulopathy of consumption,

disseminated intravascular coagulopathies). The basis of this syndrome is

diffusive coagulation of blood in small vessels, development of blockade of

microcirculation in the organs (lungs, kidneys, liver and other), and deep disorders

of the functions of these organs. Serious hypoxia and acidosis develop, leading

unrarely to death. The formation of clots on the level of capillaries is connected

with surplus quantity of thrombin. Transformation of fibrinogen into fibrin

happens very quickly.

In the development of DIC-syndrome 3 clinical stages are differentiated:

- First stage is hypercoagulation of blood and formation of friable

microthrombs and development of blockade of microcirculation in organs;

- Second stage is hypocoagulation. This stage is characterized by deep

exhaustion of factors of coagulation. The clinical manifestations of the second

stage are profuse bleedings;

- Third stage is outcome and residual appearances of DIC-syndrome.

29The principles of the diagnostics, treatment and prevention of infectious diseases

Infectious-toxic shock may be caused by viruses, rickettsia, fungi, gram-positive

microorganisms (pneumococcus, streptococcus, staphylococcus) and gram-negative

microorganisms (meningococcus). The most frequent reasons of infectious-toxic

shock are infections of urinary tract (especially, in elderly age and in weakened

patients), infections of respiratory tract due to bacterial pneumonia (especially, in

condition of tracheotomy), complications of septic childbirth, septic abortions,

peritonitis of different origin, pancreonecrosis, sepsis of any origin. In infectious

clinics reasons of infectious-toxic shock are usually meningococcal infection,

typhoid fever, salmonellosis, diphtheria, leptospirosis and other diseases. Besides

hypotonia, toxinemia plays great role in clinic of infectious-toxic shock. Toxinemia

leads to damage of liver, kidneys and heart. The compulsory development of

DIC-syndrome is another important manifestation of infectious-toxic shock.

The basis of treatment of infectious-toxic shock is complex of measures,

including application of antibiotics and directed on improvement of blood

circulation therapy. The duration of infectious-toxic shock is very serious, with

high mortality (50 % of the patient die during the first 48 hours of the disease).

That’s why it is necessary to prescribe intensive therapy immediately. Broad

spectrum antibiotics are prescribed. Steroid hormones have important value in

the treatment of infectious-toxic shock. Hormones decrease general reaction of

the organism on toxin, positively impact on hemodynamics. Treatment by

glucocorticoids is conducted during 3-4 days, because depression of adrenocortical

function does not arise.

Infusion therapy should be started with injection of crystalloid solutions:

quartasalt, Ringer’s solution, glucose-polarizing admixture (5 % solution of

glucose with calcium chloride in dose 20-100 mg of 10 % solution per one liter

of glucose). Besides salt solutions, synthetic colloid solutions are used

(neoheamodes, polyglucin, reopolyglucin in dose 0.4-0.8 L) with purpose of

desintoxication and liquidation of hemodynamic disorders.

The basic principles of treatment of DIC-syndrome are heparinotherapy and

transfusion of fresh frozen plasma. It is necessary to inject to patients 2,500-500

units of heparin in isotonic solution of sodium chloride, solution of native or

fresh frozen plasma. In this case fresh frozen plasma is donator of plasminogen

and antithrombin. Content of antithrombin in fresh frozen plasma is up to 200-

250 % from norm. Daily dose of heparin is 10,000-15,000. Simultaneously

reopolyglucin is transfused as desagregant. Inhibitors of proteolitic ferments are

injected also (75,000-100,000 units trasilol or adequate doså of contrical).

Pathogenetic therapy is the basic principle of the treatment of hypovolemic

shock. Hypovolemic shock (on the base of dehydration) is more frequently

observed at cholera. Cholera is characterized by loss of fluid with stool and

vomiting, which reaches in very small period. The loss of fluid may exceed up to

2 times the body mass of the patient. Hypersecretory processes are the main

mechanism of diarrhea origin. They develop as a result of the exotoxin action –

Infectious diseases

cholerogen on ferment adenylcyclase and accumulation of cyclic 3,5-adenosine-

monophosphotase, leading to increase secretion of electrolytes and water. Deficit

of potassium arises; reaching sometimes one third of it’s content in the organism.

Thickening of the blood, hypovolemia, hemodynamic insufficiency, metabolic acidosis,

hypoxia and renal failure develop in consequence. The impetuous development

of the disease already at the first 8-12 hours leads to dehydration, reaching 10 %

from body’s mass and more. The clinical manifestations of dehydration are pinched

face, deeply sunken in the orbits, cold clammy skin. The skin is shriveled. The

turgor of the skin decrease (“washwoman’s hands”). A voice becomes hoarse.

The general cyanosis, prolonged tonic muscles cramps are observed. The

temperature is subnormal (34.5 °C). There is no pulse. The arterial pressure is

not determined. Anuria and hypovolemic shock develop.

The treatment of hypovolemic shock is conducted immediately. Treatment

consists from 2 stages: primary rehydration for compensation loss of fluid and

correction of continued fluid loss. Preliminarily heated solution up to 36-38 °C

is injected in stream with speed 70-120 mL in minute (up to 5-7 liters during

1.5-2 hours).

It is necessary to restore as a volume of circulating blood as a volume of

extracellular liquid, because rehydration must be intensive. In hypovolemic shock

it is necessary to use special salt solution: Phillips’s solution ¹ 1 (threesault),

Phillips’s solution ¹ 2 (desault), quartasault, acesault and other. Ionic composition

of these solutions is similar to composition of the patient’s fluid loss.

It is prohibited to prescribe the remedies with high molecular weight

(polyglucin, reopolyglucin). These remedies restore a volume of circulating blood,

but they don’t liquidate dehydration of the organs and tissues. It is prohibited to

inject heart’s glycosides. The heart’s glycosides increase shortenic ability of

myocard, but the heart is empty. The exhaustion of myocard develops as a

result. It may be death from heart’s stop. It is prohibited to inject pressory

amines (adrenaline, noradrenaline). These remedies increase arterial pressure

and cause change of microcirculation. The kidneys may perish as a result. So, the

treatment of cholera patients is concluded into injection of adequate quantity of

fluid relatively to losses.

Dehydration may develop due to other infections (shigellosis, salmonellosis,

toxical food-borne infections). However, in salmonellosis, shigellosis, toxical food-

borne infections there is combination of the signs of damage of gastrointestinal

tract (gastritis, gastroenteritis, or gastroenterocolitis), signs of general intoxication

and dehydration. In this diseases pathogenetic therapy is performed in 2 directions,

in dependence of predominated clinical manifestations (desintoxication and

rehydration).

In meningitis and meningoencephalitis pathogenetic therapy is directed to

elimination of the brain edema (dehydrative therapy) and intoxication. In case of

generalized form of meningococcal infection pathogenetic therapy is performed

31The principles of the diagnostics, treatment and prevention of infectious diseases

simultaneously with etiotropic therapy. Its basis is intoxication treatment.

Simultaneously dehydrative therapy is performed (lasix, mannitol).

In severe cases of meningococcal infection glucocorticoides are prescribed.

Dose depends on dynamics of the basic symptoms and presence of complications.

Usually, hydrocortisone in dose 3-7 mg/kg/day, prednisolon in dose 1-2 mg/

kg/day are prescribed.

Development of Waterhause-Fridrichsen’s syndrome is possible at fulminant

form of meningococcal infection, connected with hemorrhage into adrenal glands.

In such cases the therapy is directed to the struggle with adrenal glands

insufficiency (replacing therapy). The large doses of corticosteroid are prescribed.

Pathogenetic therapy is widely used in treatment of the patients with viral

hepatitis. Due to investigations of the last years it was shown that activation of

the processes of peroxide oxygenation of lipids plays the essential rose in the

pathogenesis of viral hepatitis and leads to alteration of structure and functions

of hepatocytes, thrombocytes and other cells membranes. Besides that, there is

correlation between activation of peroxide oxygenation of lipids and duration of

intoxication. Its worths to underline that simultaneously with activation of POL

(peroxide oxygenation of lipids) the considerable depression of antioxydantic

activity of the blood serum is marked.

The definition of the factors of intensification of the processes of peroxide

oxygenation of lipids in the patients with viral hepatitis B became the basis for

application of the remedies with antioxydantic mechanism of the action in complex

therapy.

The degree of immunity development in considerable measure determines

the possibility of formation of prolonged and chronic forms of the disease.

Owing this the great quantity of works were performed last years on study of

cell’s immunity and its role in pathogenesis of acute viral hepatitis B according

to the form, degree of gravity and period of the disease.

It was established that in patients with cyclic forms of acute viral hepatitis

during of the process of the disease the secondary immune deficiency develops,

with tendency to restoration of functions of immunocompetentive cells during

period of reconvalescence. Decreased quantity of T-helpers and T-suppressors

is observed. The subpopulation of T-suppressors was changed more than

subpopulation of T-helpers. The correlation of tests of T-system of immunity

and gravity of the disease course is marked. In patients with prolonged duration

of acute hepatitis the strong decreasing of T-helpers is observed.

The determination of the considerable role of immune mechanisms in

pathogenesis of viral hepatitis is pathogenic basis for application of immuno-

correcting therapy.

The application of preparations of thymoid gland – thymalin, tactivin, synthetic

peptide of thymus-thymogen may be used for to improvement of cell’s interactions,

disappearance of dysbalance in correlation of T-helpers and T-suppressors.

Infectious diseases

The data about molecular mechanisms of damage of hepatocytes’s membranes

were received last years. Because the remedies with stabilizative action to

hepatocyte’s membrane are used (carsil, legalon and other hepatoprotectors) in

complex therapy of acute viral hepatitis.

Pathogenetic therapy of acute viral hepatitis, directing to the struggle with

intoxication, regulation of water-electrolyte balance, regulation kallekrein- kininic

system, elimination of hemorrhagic syndrome is used in practice widely.

However, the application of different schemes of pathogenetic therapy with

use modern desintoxicative methods, doesn’t always conduct to favorable course

and outcomes of acute viral hepatitis, it doesn’t prevent development of complications

(acute hepatic encephalopathy), formation of prolonged course and relapses.

For this reason the looking for chemotherapeutic remedies, preventing

from replication of virus in hepatocytes is an actual question. The remedies with

antiviral action were received last years: arabinozid-nucleotid A, amphotherycin

B, virazol, aplizarin and other. However, the antiviral remedies application in

treatment of viral hepatitis doesn’t always are effective clinically, doesn’t give

complete elimination of viral antigens. Because, the application of these remedies

is limited in clinical practice.

The application of interferon and remedies, stimulating its produce is

perspective direction owing this. Interferones are low molecular proteins

depressing viruses reproduction. Leucocytaric and fibroblastic interferones may

be produced practically by all cells. Immune gamma-interferon is produced by

gamma-interferon immunocompetentive cells during immune response.

Interferon is the most important factor of nonspecific resistance. However,

interferon has influence to differentiation and activation of effectoric cells of

immune system. The activation of monocytes (macrophages) increases generation

of peroxide radicals, increased phagocytes activity are observed under influence

of interferon. Thus, at the present time interferon is used not only as antiviral

remedy, but also as important regulator of interaction between cells.

It is established that there is decreased produce of interferon in patients with

viral hepatitis B, especially in patient with severe duration of the disease. In fulminate

course of acute viral hepatitis B interferon is no revealed in the serum of blood.

In accordance with opinion of many investigators, virus of hepatitis B is

week inductor of interferon. The firm insufficiency of produce of interferon is

one from decisive factors of crossing infectious process into chronic form. The

application of interferon in infectious diseases may be possible in two directions:

injection of ready-made interferon (exogenic interferon) and stimulation of

synthesis of own interferon (endogenic interferon).

The decreased production of interferon in patients, decreased ability of virus

hepatitis B (VHB) to induce interferon output, and also low cytotoxicity of

natural killers are pathogenetic basis for interferontherapy application in patients

with hepatitis B and C.

33The principles of the diagnostics, treatment and prevention of infectious diseases

The considerable effeciency of leucocytic interferon is marked in patients

with medium and severe course of acute viral hepatitis B. The positive influence

of interferon on clinical manifestations dynamics, decreasing of intoxication and

improvement of biochemistric tests were observed.

The stimulation of endogenic interferon producing by organism is the most

perspective direction. At the present time some hundreds inductors of interferon

are known. The basic criteria of interferon inductors effeciency are their interferon-

inducing and antiviral action. Some remedies are more effective in viral infections

(larifan, ridostin, camedon, amixin, cycloferon and other).

Intensive therapy and reanimation

Many infectious diseases have declination to serious duration and

complications development. It may happen at fulminant course of some infectious

diseases (meningococcal infection, viral hepatitis B and other). The gravity of

course depends on degree of violation of water – electrolyte balance, acid-

alkaline state, blood coagulative system and other criterions of the patient state.

The methods of intensive therapy and reanimation are inculcated in clinical

practice last years. These methods are directed to restoration of vitalitive important

functions of the organism altered due to acute violations. Intensive therapy is

performed in the special department under control of express clinical laboratory

investigations. Efficiency of this therapy is determined by intensive observation

of the patient. The observation after a patient is performed continuously and

through short intervals of the time with fixation of physiological parameters

(registration of pulse, breath, arterial pressure, data of electrocardiogram,

electroencephalography and other tests of the patient state).

The methods of intensive therapy are pharmacotherapy, artificial pulmonary

ventilation, hyperbolic oxygenation, artificial hypothermia, oxygenation, hypothermic,

different methods of extracorporal hemodialysis (hemosorbtion, perfusion of liver,

abdominal hemodialysis, dialysis with help of artificial kidney apparatus and other).

Intensive therapy of infectious diseases includes antibacterial serums,

immunoglobulines, and different chemotherapeutic remedies. Intensive therapy is

used for treatment of the patients with meningococcal infection, malaria, typhoid

fever, salmonellosis, cholera, leptospirosis and other infectious diseases.

Prophylaxis of infectious diseases

At the last decades certain successes were achieved in fighting with infectious

diseases, massive epidemics of most dangerous infectious diseases (epidemic

typhus fever, plaque, smallpox, tick-borne relapsing fever and other). The

struggle is realized successfully with diphtheria, poliomyelitis, measles, and many

zoonozic infections. Undoubt success is achieved in malaria control. However,

the deliverance of humanity from malaria requires time, considerable efforts and

great expenses. More than billion cases of infectious diseases of gastrointestinal

and respiratory tract are registered in the world every year. For example, grippe

Infectious diseases

is registered in some years in 10-15 % of population only of the countries of

Europe and America. More than 75 millions of the people become ill by other

acute viral diseases of the respiratory tract. Pandemic of grippe acquires character

of the calamity and causes enormous economic detriment to all the countries.

Every years multiple cases of streptococcous and staphylococcous infections,

cholera, helminthiases, viral hepatitis, meningococcal infection and diseases caused

by conditional pathogenic flora are registered in the world.

Thus, prophylaxis of infectious diseases is actual question. The measures of

prophylaxis of infectious diseases may be conditionally divided on 2 groups:

general and special measures. The general measures are state measures, directed

on increase of material favorable condition, improvement of medical service, and

conditions of work and rest of the population, sanitary-technique, hydrotechnic

measures and also international measures in attitude to quarantine infections.

It is known about 3 links for development of epidemic process: the source

of infection, ways of the transmission and susceptibility of the organism. The

absence or rupture either of this links leads to cessation of epidemic process.

There are 3 groups of prophylactic measures:

1. The measures directing on the source of infection, its elimination.

2. The measures, directing on the mechanism of the transmission of infection.

Their purpose is rupture of the ways of transmission of infection.

3. The measures directing on increasing of unsusceptibility of population to

infection.

Prophylactic measures, directing on the source of infection play an important

role. It is known that when antroponozic infection the source of infection is a

sick man or carrier of the agent. The source of infection is sick animal at

zoonotic infections. Prophylactic measures of this group are diagnostic, isolative,

medical and regimen-limitary measures. In some infectious diseases hospitalization

into infectious hospital is obligatory (especially dangerous infections, typhoid

fever, epidemic typhus, diphtheria, meningococcal disease). In case of other diseases

isolation may be at home if epidemiological and clinical contraindications are

absent (shigellosis, escherihiosis, measles and others).

An important prophylactic measure is active revealing of carriers and their

sanation. Revealing of carriers is performed in focuses of infection, among

reconvalescents, and also among persons of food establishments, water pipe

stations, and children’s establishments. It is necessary to perform their

bacteriological examination and treatment.

Isolation of persons, contacting with patient is necessary in case of especially

dangerous infections (plague, cholera). The duration of isolation depends on

maximal incubation period: in plague – 6 days, in cholera – 5 days. This measure

is named observation. Observation is one of the quarantine measures. The word

“quarantine” was originated from Italian word “quarantine” (quaranta gieri –

40 days). At this historic period duration of incubation period was not known.

35The principles of the diagnostics, treatment and prevention of infectious diseases

Because isolation of patients with plague and some other infectious diseases

was 40 days.

The measures about sanitary guard of borders have an important meaning.

In 1969 on Universal Public Health Assembly “International medical-sanitary

rules” have been accepted. Infections, having international meaning are divided

on 2 groups:

Diseases, which are submitted to these rules (plague, cholera, yellow fever).

Diseases for international surveillance (epidemic typhoid fever, tick-borne

relapsing fever, grippe, poliomyelitis and malaria).

All countries-members of World Health Organization should report about

all cases of this diseases, and also perform proper antiepidemic measures. In

zoonozic infections prophylactic measures have one’s own features. If the source

of infection are domestic animals, than it is necessary to perform sanitary-veterinary

measures about their health. If the source of infection are mice and rats it is

necessary to perform deratization.

In prophylaxis of infectious diseases an important measure is influence on

mechanism of transmission of infection. Transmission of the agent from sick

man to healthy man is realized with help of different factors (water, food, air, dust,

soil and other). Prophylactic measures, directing on the second link of epidemic

process are divided on 3 groups: sanitary-hygienic, disinfection and disinsection.

The basic factors of transmission of the agent are food, water, rarely-flies, dirty

hands in case of intestinal infections with fecal-oral mechanism of transmission

of infection (typhoid fever, cholera, shigellosis). In prophylaxis of these infectious

diseases general sanitary and hygienic measures have the most important value.

Prophylactic measure, directed on the ways of transmission is disinfection,

which is performed in the focuses of infectious diseases, public place (railroad

station, transport, and public toilets).

At infections of the respiratory tract (measles, rubella, diphtheria, scarlet

fever, meningococcal infection, grippe) preventive measures are sanation of air,

application of respirators. Disinfection is performed only due to scarlet fever

and diphtheria, because the agents of the majority infections of respiratory tract

are nonresistant in environment.

At transismissive infections the method of disinsection has the great meaning,

directed on distruction of insects.

The measures, directed on the third link of epidemic process are increasing

of general nonspecific resistance of the organism and also specific prophylaxis.

Specific prophylaxis is directed on creation of artificial immunity (active or

passive) against infectious diseases.

Specific prophylaxis is performed with help of vaccines, anatoxins serums,

gammaglobulines. Vaccines and anatoxins create active immunity, serums and

gammaglobulines – passive immunity. Vaccines are divided on living and killed

vaccines.

Infectious diseases

Microorganisms with weakening of virulence are used for preparation of

vaccines. In 1798 Edward Jenner proposed vaccine against smallpox, containing

agent of cowpox. This agent has a little virulence for humans. Jenner called his

new method of preventing smallpox “vaccination”, from the Latin word “vacca”,

that is “a cow”. In 1885 Paster proposed vaccine against rabies from weakening

vaccine strain. Living vaccines are used for prophylaxis such infectious diseases,

as tularemia, poliomyelitis, yellow fever, measles and other. These vaccines create

tense and prolonged immunity (3-5-8 years).

Killed vaccines are divided on corpuscular and molecular (chemical). Killed

vaccines are used for prophylaxis of intestinal infections. Efficiency of killed

vaccines is less, than living vaccines. The duration of immunity is from 6 months

till 12 months.

Anatoxins are also used for creation of artificial active immunity. Anatoxins

have no toxic properties, but they preserve antigenic and immunogenic properties.

At the present time anatoxins are used for prophylaxis of diphtheria, tetanus,

botulism.

Artificial active immunity appears after injection of vaccine through few

weeks. Artificial passive immunity develops more quickly. It is caused by injection

of blood serum with ready antibodies (immune serums and immunoglobulines).

There are preparations used for prophylaxis of tetanus, measles, tick-encephalitis

and other infectious diseases.

Control questions:

1. Basic principles of anamnesis collection.

2. Principles of clinical examinations of infectious patients.

3. Value of additional methods of diagnostics.

4. The principles and methods of the infectious diseases treatment.

5. What are the remedies of specific action used for the treatment of the infectious diseases?

6. Basic principles of infectious diseases prophylaxis.

7. Groups of prophylactic measures and their characteristics.

37Typhoid fever and paratyphoid

TYPHOID FEVER AND PARATYPHOID

Typhoid fever, paratyphoid A and B are acute illnesses from the group of

intestinal infections. They are characterized by cyclic course, bacteremia, intoxication,

rash on the skin, lesions of the lymphatic apparatus of the small intestine. Besides

that, typhoid fever is characterized by high fever of different duration, development

of so-called status typhosus, hepatosplenomegaly, lesions of organs of the

gastrointestinal tract, relapses and various complications.

Historic reference

Typhoid fever is well known for a long time as an illness of mankind.

The causative agent of typhoid fever was described by Ebert in 1880. Pure

culture of the agent was isolated by Gafki in 1884.

Typhoid fever was one of the most widespread and serious infectious disease

in 19th century and in the beginning of 20

century in all countries of the world,

especially in the large towns due to groupment of the people. Building of waterpipe

and canalization allowed to decrease morbidity in the large towns. But almost

every calamity (hunger, earthquake) and wars were accompanied by outbreaks

of typhoid fever.

Now, the morbidity is sporadic in European countries. However, high level

of morbidity occurs in some countries due to features of climate, ecological

conditions and social factors (Mexico, India, Afghanistan, countries of Northern

Africa and other).

Etiology

The causative agent of typhoid is Salmonella typhi of Enterobacteriacea

family, genus Salmonella, serological group D.

Salmonella are not-spore-forming rods and motile by peretrichous flagella.

Like other enterobacteria, Salmonella have somatic (O) antigens which are

lipopolysaccharide components of the cell wall and flagellar (H) antigens, which

are proteins. There are approximately 60 O-antigens, which are designated by

numbers at letters. The Kauffmann-White scheme categorizes Salmonella on the

basis of somatic antigens, each group having a major determinant which is a

strongly reaching somatic antigens and one or more major somatic antigen.

Salmonella typhi also has a capsular or virulence (Vi) antigen composed of a

homopolymer of N-acetyl galactosaminuronic acid. The presence of Vi-antigen

on the cell surface may block agglutination by anti-O serum.

Salmonella can be differentiated from other Enterobacteriaceae on basis of

certain biochemical reactions, including fermentation. Most Salmonella ferment

Infectious diseases

glucose and mannose to produce acid and gas but do not ferment lactose or

sucrose; S.typhi does not produce gas. Thus, Salmonella typhi has some antigenic

and biochemical features. That is why typhoid fever is isolated from the other

diseases, caused by Salmonella. Salmonella organisms grow on the media with

addition of bile. The resistance of agent of typhoid fever and paratyphoid in the

environment is very high. They endure low temperatures very well. The agents

of typhoid fever and paratyphoid diseases survive from 1-2 till 25-30 days, in

food products.

Epidemiology

Typhoid fever is anthroponosis. The source of infection is sick man or

bacteriocarrier. The patients with typhoid fever discharge the agent with stool,

urine, rarely – with saliva and milk. The discharge of the agent is observed at the

end of incubation period, during all disease, and sometimes in the period of

reconvalescence. In some cases the discharge continues till three months (acute

carriers) or more than three months (chronic carriers). Chronic carriers may be

from six months till some years.

The mechanism of the infection transmission is fecal-oral. The factors of

transmission may be water, milk, various food-stuffs and contaminated feces of

the patient or bacterial carriers. Flies can play the supplementary role.

Susceptibility to agent of typhoid fever and paratyphoid diseases is rather

high, however clinical manifestation can be of different grade. The care rate of

typhoid fever and paratyphoid diseases depends on seasonal prevalence. It

increases in summer-autumn period, due to consumption of a huge amount of

flies, quite often from unknown sources, unwashed fruit and vegetables. The

strong immunity develops after disease.

Pathogenesis

The next phases are distinguished in the pathogenesis of typhoid fever:

1. Penetration of the causative agent into the organism.

2. Development of lymphadenitis and lymphangitis.

3. Bacteremia.

4. Intoxication.

5. Parenchymatous diffusion.

6. Discharge of the agent from the organism (excretory phase).

7. Allergic reaction, mainly of lymphoid tissue of the small intestinum.

8. Formation of immunity.

The first phase is penetration of the agent into the macroorganism. However,

penetration does not always lead to the development of the pathological process.

It depends on the quantity of the agent and the state of barrier functions (It is

stomach in this case). The further path of Salmonella typhi is lymphatic apparatus

of intestine.

39Typhoid fever and paratyphoid

The second phase is lymphadenitis, lymphangitis. Salmonellae achieve the

small intestine and actively penetrate into solitary follicules, Peyer’s patches.

There is the reproduction of the agents and formation of the focus of infection.

Microorganisms penetrate to regional lymphatic nodes (mesenterial) along the

lymphatic patches. There is the other focus of infection. In the lymphatic apparatus,

the typical morphological alterations with proliferation of tissue and formation

the large typhoid cells develop.

Bacteria achieve the definite quantity and enter into the blood circulation

through the thoracic duct. It is the next phase of pathogenesis – bacteremia. In

clinic bacteremia means the end of incubation period and beginning of the clinical

manifestations. The blood has bactericidal properties. It leads to the death of the

part of microbes. Intoxicative syndrome develops. Intoxication is the fourth

phase of pathogenesis. The action of endotoxins causes changes of the state of

the central nervous system, adynamia, fever, headaches, violations of dream, appetite.

The fifth phase of a pathogenesis is parenchymatous diffusion of microbes.

By the flow of the blood Salmonella of typhoid fever and paratyphoid also are

delivered over the organism, enter into all organs. Microbes are fixated especially

in liver, spleen, bone marrow, skin. Secondary focuses are formed (typhoid granulomas),

from which bacteria likewise from the primary focuses (lymphatic apparatus of the

intestine) enter into the blood, supporting bacteremia. The settling of microbes in

the reticuloendothelial system and their destruction in the structures of

reticuloendothelial system causes the cleaning of the organism from infection.

The sixth phase of pathogenesis is discharge of the agent from the organism.

The agents enter into the intestine from the liver through the bile ducts. They

are excreted into the external environment with feces of the patient. The part of

the agents repeatedly penetrates from the small intestine into lymphatic apparatus

of the intestine and cause sensibilization to microbes. The expressive changes of

lymphoid tissue develop due to repeated implantation of Salmonella typhi with

development of morphological changes from cerebral-like swelling to necrosis

and formation of ulcers.

This process is considered as the seventh phase of pathogenesis – allergic

response of lymphoid tissue of the small intestine. Eighth phase of pathogenesis

is formation of immunity and restoration of the physiological equilibrium.

Anatomic pathology

Sequential changes in tissue in the ileocecal area of the intestinal tract

occur during typhoid fever and have been classified into four phases:

1. Hyperplasia.

2. Necrosis and sloughing.

3. Ulceration.

4. Healing.

During the first week of clinical symptoms, hyperplastic changes occur in

Peyer’s patches in the ileum and in the lymphoid follicles in the cecum, causing

Infectious diseases

there tissue to project into the bowel lumen. The hyperplasia regresses after 7-

10 days or undergoes necrosis with sloughing of overlying mucosa leading to

the formation of characteristic ulcers that parallel the long axis of the ileum.

Small punctuate lesions develop in the cecum. Ulcers usually heal completely

with little residual scarring, but they may be the sites of hemorrhage or may

penetrate to the serosa and lead to bowel perforation.

Clinical manifestations

Typhoid fever and paratyphoid are characterized by cyclic course. There

are such periods during course of the infectious process: incubation, initial, period

of climax, early reconvalescence and outcomes.

The incubation period of typhoid fever is usually 10-14 days but it may be

from 7 to 21 days. The incubation period is influenced by the number of organisms

ingested. The duration of incubation period also depends on virulence of

microorganism and state of macroorganism.

Manifestations of enterocolitis occasionally occur within hours after the

ingestion of food or drink contaminated with S.typhi if the dose of organisms is

large. In these instances symptoms of nausea, vomiting and diarrhea usually

resolve completely before the onset of symptoms of typhoid fever.

The onset of typhoid fever is insidious in contrast to sepsis produced by

most other gram-negative organisms. The initial manifestations are nonspecific

and consist of fever, malaise, anorexia, headache and myalgias. Remittent fever is

prominent with gradually increasing evening temperature elevations from less

than 38 °C to values in the range of 40 °C by the end of the first week of illness.

The disease turns into the next stage (climax of the disease) at the end of the

first week. The appearance of the patients is very typical in this period. The skin is

pale. Patient is apathethic. Intoxication is increased. Temperature is constant and

most typical syndrome of typhoid fever and paratyphoid. At first the temperature

was described by Wunderlich in 19th century. Temperature curve riminds trapezium.

The phase of increase of the temperature is near one week. The phase of climax is

near two weeks. The phase of decrease of the temperature is near one week.

Temperature curve of Wunderlich occurs rarely. Temperature curve has wave-like

character more frequently (temperature curve of Botkin).

Chills and diaphoreses are seen in about one-third of the patient even in the

absence of antimicrobial therapy. Either constipation or diarrhea may occur.

Respiratory symptoms, including cough and sore throat may be prominent.

Neuropsychiatries manifestations, including confusion, dizziness, seizures, or acute

psychotic behavior, may be predominant in an occasional case. Status typhosus

is observed in serious course of the disease.

In present time patient with typhoid fever usually appears acutely ill. Fever

is usually prominent, and in many instances the pulse is slow relative to the

temperature.

41Typhoid fever and paratyphoid

In typhoid fever symptoms of violation of cardiovascular system are constant

and expressive. The basis of hemodynamic disorder is violation of the tonus of

the vessels, damage of heart muscle due to intoxication. Myocardiodystrophy

develops as a result. In typhoid fever relative bradycardia is the clinical feature

of cardiovascular disorders. The muffed heart sounds, systolic murmur at the

heart apex, hypotension are marked inrarely. Relative bradycardia develops due

to endotoxin action of the agent on X pair of cerebrospinal nerves.

Rose spots, 2-4 mm erythematous, maculopapular lesions that blanch on

pressure, appear on the upper abdomen or on the lateral surface of the body.

Roseolas are few (5-15) in number (Fig. 1). The lesions are transient and resolve

in hours to days. Rose spots are observed on the 7-10 day of the disease near in

half of patients. Sometimes they dissapears, sometimes exist longer than fever.

Cervical lymphoadenopathy may be present. Examination of the chest may

reveal moist rales. The abdomen is tender, especially in the lower quadrants-

Abdominal distention is common, and peristalsis is often hypoactive. The sensation

of displacing air – and fluid-filled loops of bowel on palpating of the abdomen is

considered to be characteristic. In percussion short sound is marked in ileocaecal

area due to enlarged mesenteric lymphatic nodes. Hepatomegaly is noted in

about 40-50 % of the patient, and a soft, tender spleen can be palpated in about

40-60 %. In about 10 % of the patients, changes in consciousness are present

and manifest as lethargy, delirium, or coma.

Without antimicrobial therapy, the disease pursues a prolonged course with

slow resolution of signs and symptoms 3-4 weeks after onset if there are no

complications. Sustained fever is common during the second and third weeks of

disease. Fever decreases slowly by lysis, unlike the resolution by crisis seen in

the preantibiotic era in many cases of pneumococcal pneumonia. Headache,

confusion, respiratory symptoms, and abdominal pain and distention gradually

resolve, and the pulse more characteristically reflects degree of fever acute

manifestations subsiding. Profound weight loss invariably occurs in untreated

patient. Many of the complications of typhoid fever occur during the period of

resolution in the third or fourth week after onset.

Complications

Complications of typhoid fever can be classified as secondary to toxemia

(myocarditis, hyperpyrexia, hepatic and bone marrow damage), secondary to local

gastrointestinal lesions (haemorrhage and perforation), secondary to prolonged

severe illness (suppurative parotitis decubiti, and pneumonia), secondary to growth

and persistence of typhoid fever bacilli (relapse, localized infection – meningitis,

endocarditis, osteomyelitis or arthritis) and secondary to therapy (bone marrow

suppression, hypersensitive reactions and toxic shock).

In the preantimicrobial era, 12-16 % of the patients with typhoid fever died,

frequently from complications in the third or fourth week of the disease. Fatalities

still occur occasionally, probably in less than one percent of the patients receiving

Infectious diseases

appropriate antimicrobial and pathogenetic therapy. However, in certain specific

geographic areas of Indonesia, India, and Nigeria, fatality rations of 9-32 % have

been reported last 10-15 years. It is likely that these results are consequent to

suboptimal health and medical care rather that an increase in the clinical severity

of typhoid fever.

The complications attributed to “toxemia” might be considered as manifes-

tations of severe disease. Toxic myocarditis occur in severely ill patients, frequently

children, and is manifested by tachycardia, weak pulse, muffled heart sounds, and

hypotension. The electrocardiogram shows low voltage and T-wave flattening or

inversion. Atrial or ventricular arrhythmia may occur.

Major intestinal hemorrhage is usually a late complication that occur during

the second or third week of illness. In the preantimicrobial era, gross intestinal

hemorrhage occurred in about 5-7 % of the patient with typhoid fever. The

incidence of hemorrhage requiring transfusions has been reduced to 1 or 2

percent, due to chloramphenicol use. There is an important sign of the massive

intestinal hemorrhage symptom of “scissors”. Suddenly the temperature is

decreased up to normal or subnormal. But tachycardia is observed. The arterial

pressure is reduced. Intestinal perforation usually occurs during third week of

illness. Perforation occurs in the terminal ileum where the number of lymphoid

aggregates is the largest and ulcerations most frequent. In general, perforation

has reported in recent years in one percent or less of cases as compared with 2-

5 % in several series collected in the preantibiotic era.

Relapse, a recurrence of the manifestation of typhoid fever after initial clinical

response, occur in about 8-12 % of the patient who have not received antimicrobial

therapy. The relapse rate was found to be doubled in patients receiving chloramphenicol

therapy for 2 weeks. Ampicillin probably does not affect the rate of relapse.

Localization of infection, which may lead to abscess formation, can occur in

almost any organ or tissue. Although bacteremia can be assumed to develop in

all patient with typhoid fever, localized infections such as meningitis, endocarditis,

osteomyelitis, or thyroiditis occur in less then one percent.

The chronic carrier state is detained as documented excretion of S. typhi in

stool or urine for a year or more. The chronic carrier state usually follows

typhoid fever but as many as one – third of the chronic carriers give no history

consistent with this illness. Underlying biliary or urinary tract diseases, especially

with stone formation, increase the probability of the chronic enteric or urinary

carrier state in patients with typhoid fever. One to 3 % of the patients with

typhoid fever become chronic enteric carriers; however, the incidence is higher

in older patients (at the sixth decade) and in women.

Clinical features of paratyphoid

Epidemiology, pathogens, morphology and clinics of paratyphoid A and B,

have, in principal, mutual signs with typhoid fever. However, paratyphoids have

some clinical features.

43Typhoid fever and paratyphoid

In paratyphoid A incubation period is shorter than in typhoid fever. It’s

duration is 8-10 days. The onset of the disease is an acute. Sometimes, the onset

of the disease is accompanied by cough, catarrh. Facial hyperemia, blood injection

of the sclera’s vessels, herpes on the lips are observed during examination. The

temperature is wave-like or remittent. The fever is accompanied by chills and

than by diaphoreses. In paratyphoid A the rash appeares in more early periods

than in typhoid fever. The rash is polymorphic. Roseolas, petechias and measles-

like rash may be observed. The intoxication is temperate. There is no status

typhosus. There is normal quantity of leukocytes in peripheral blood. But leukocy-

tosis and lymphocytosis may occur too.

In majority of the patients the disease has a moderate course. But the

severe forms may be observed too, with complications (intestinal hemorrhage,

intestinal perforation and other). The relapses are frequently observed in case of

paratyphoid A.

Paratyphoid B incubation period is 5-10 days. The onset of the disease is

acute, with expressive chill, myalgia and diaphoreses. At the initial period of the

disease the intoxication may be combined with symptoms of acute gastroenteritis.

The temperature is not prolonged. Status typhosus is absent in majority of the

patients. The symptoms of intoxication disappeares very quickly. The rash is

polymorphic, plenty. It appears at the earlier period. In some cases the course of

paratyphoid B may be severe with septic manifestations (purulent meningitis,

meningoencephalitis, septicopyemia). In peripheral blood leukocytosis and

neutrophylosis are observed.

Diagnosis

Definitive diagnosis of typhoid fever and paratyphoid is made on the basis

of pathogen isolation from the patient’s blood. Isolation of the organism from

stool, especially in endemic areas, does constitute strong presumptive evidence of

typhoid fever in the patient with a typical clinical course. Serologic studies may

be helpful, but in many cases of typhoid fever there is no increase in titer of

agglutinins during the course of infection, and other illnesses, especially infections

with other gram – negative bacilli, may cause nonspecific elevations of agglutinins

because of cross – reaching antigens. In untreated disease only about 50 % of

the patient have a fourfold or greater increase in titer of agglutinins (Widal’s

test) against typhoid fever O-antigen at any time during the course of disease.

Antimicrobial therapy may also impede immunologic response. Immunization

with typhoid fever vaccine may produce an impressive increase in titer of anti-

O-agglutinins and nonspecific changes in titer may occur during the course of

many febrile illnesses. Agglutinins against H-antigen, irrespective of change of

titer, are not of value in diagnosis. A number of other serodiagnostic methods,

e.g., detection of IgM antibody to S.typhi lipopolysaccharide antigen by an

enzymelinked immunosorbent assay (ELISA), are being studied and seen promising,

but none is ready for routine diagnostic use.

Infectious diseases

The majority of isolates of S.typhi from blood are obtained as a result of the

first blood culture, but a second or third culture should be collected in suspected

cases, as these culture significantly improve the percentage of positives. Stool

cultures become positive in about one – third to two – thirds of the patients

during the second through fourth week of illness.

Differential diagnosis

The differential diagnosis of typhoid fever requires consideration of many

disease processes characterized by fever and abdominal complaints. Early in the

disease the predominance of fever and upper respiratory tract symptoms may

suggest influenza or other viral infections. Cough and fever suggest acute

bronchitis and, when coupled with rales, raise the question of bacterial pneumonia.

Headache, confusion, and fever may prompt consideration of bacterial or aseptic

meningitis or meningoencephalitis. Delirium, catatonia, or coma may suggest a

diagnosis of psychosis or other neuropsychiatries illness. The abdominal findings

may lead to a consideration of acute appendicitis, acute cholecystitis, or intestinal

infarction. Bacillary, amebic or ischemic colitis may enter the differential diagnosis

if blood diarrhea occurs. As fever continues over a period of weeks, other

possibilities might include brucellosis, yersinosis, lymphoma, inflammatory bowel

disease, bacterial endocarditis, miliary tuberculosis, malaria, sepsis, epidemic typhus

and many other diseases.

Treatment

Antibacterial therapy is indicated to all patients. The basic preparation is

levomycetin (chloramfenicole) in tablets 0.5. It is administered per os (PO) in

dose of 0.5 gm (4 times per day) for half an hour before meal till the 10th day

of body temperature stabilization, a daily dose is reduced usually till 1.5 on the

last 4-5 days of treatment. At severe course of illness it is possible to increase a

daily dose gradually, on first days levomycetin should be taken up to 3 gm but

not more. If using of the levomycetin (PO) is impossible (a nausea, vomiting, a

pain in epigastric area) levomycetin succinate in bottles should be prescribed –

0.5 intramuscularly (IM) daily dose 3-4 gm or in suppositoriums, and in serious

cases intravenous or endolymphatic 0.5-1 ( 2 times in days) application.

When there is no effect after using of levomycetin during next 5 days and

there are contraindications, that is effective to prescribe ampicillin till the 10th

day of normal body temperature. Alternative remedies are bactrim, azitromicin

(sumamed) and fluoroquinolones derivates ciprofloxacin and ofloxacin, which

are effective in case of tolerance to levomycetin. Also cefalosporines of III

generation: cefoxim or ceftriaxone may be used.

To prevent relapses and formation of chronic bacteriocarrier the antibiotic

therapy is desirable for carrying out in a complex with Vi-antigen, stimulating

creation of specific immunity. Preparation of typhoid bacteria is injected on 400

45Typhoid fever and paratyphoid

mg threefold under a skin with 7 days interval or twice the same dose, or 800

mg with 10 days interval.

Plentiful drinking, sorbents (SÊN, Våsòà), sillard P, enterodes are prescribed

as desintoxication agents at mild disease course. Solution of glucose intravenously

(IV) with solution of ascorbic acid, qurtasault, acesault, lactasault, a solution of

donor albumin are injected at moderate disease course. If process has severe

course, reopolyglycin is injected both with polyionic colloid solutions at increasing

of intoxication for 7 days, prednisolonum 30-60 mg and more per day parenterally

during 5-7 days. Oxybarotherapy, plasmaferesis are indicated. Inhibitors of

proteolytic enzymes – contrical, gordoxe, trasylole should be prescribed.

Obligatory components of complex therapy are bed regime and diet ¹ 2.

For stimulation of nonspecific organism resistance and reparative process

methyluracil, pentoxil, thimalin are indicated

During antibiotic therapy the intestinal dysbacteriosis may develop. Nistatin

or levorin, one of bacterial remedies bificol, bifidumbacterin, lactobacterin are

indicated in such cases. If allergical reactions have appeared, calcii gluconate,

dimedrol, diprazin, tavegil, gismanal, zestra, loratidin, alegra, telfast are indicated.

A strict confinement to bed (position of the patient on back), cold on stomach

region, forbiding of feeding for 10-12 hours are necessary in case of intestinal

bleeding. Ascorbic acid in tablets, Vicasole, calcy chlorid, hypertonic solution of

sodii chloride 5-10 mL (IV), an aminocapronicy acid, etamsylat, adroxone, gelatinole,

infusions of the donor blood, saline solutions are indicated in such case.

The immediate surgical operation is indicated in case of intestinal wall perforation.

In case of infectional-toxic shock, dofamin, high doses of prednisolone, reopolyglycin,

quartasault or lactasault in a vein (a single dose 0.05-0.15 gm, in serious cases up to

0.4 gm) in isotonic solution of sodii chloridum, contrical are indicated.

Treatment of chronic bacteriocarrier is not developed. It is possible to

achieve the time termination of allocation salmonelas by realization of 10-day’s

course of treatment by ampicillin in a daily dose of 2 gm in combination with

immunostimalatores and di- or a monovalent vaccine in a combination with

cleared Vi-antigen.

Prophylaxis

Control of Salmonella typhi infection transmitted from person to person

depends on high standards of personal hygiene, maintenance of a supply of

uncontaminated water, proper sewage dispose and identification, treatment, and

follow-up of chronic carriers. Hand washing is of paramount importance in

controlling person to person spread although hands of convalescent carriers are

often contaminated after defecation detectable Salmonella are easily removed

by washing the hands with soap and water.

Typhoid fever vaccine, a saline suspension of aceton or heat/phenol killed

S.typhi enhances the resistance of human beings to infection with S.typhi under

experimental and natural conditions. Vaccine efficacy ranges from 51 to 67 %.

Infectious diseases

There is also renewed interest in testing the capsular polysaccharide of

S.typhi (Vi-antigen) as a parenteral typhoid fever vaccine.

Typhoid fever vaccine should be considered for persons with intimate

continuing exposure to a documented typhoid fever carrier and for persons

traveling to areas where there is a recognized appreciable risk to exposure to

typhoid fever.

Control questions:

1. Epidemiology of typhoid fever and paratyphoid.

2. Phases of typhoid fever pathogenesis.

3. Clinic of initial period of typhoid fever.

4. Clinical manifestations of acute phase.

5. Clinical manifestations of paratyphoid fever.

6. Clinical classification of typhoid fever.

7. Specific and nonspecific complications.

8. Clinic of the intestinal bleeding and its medical treatment.

9. Clinic of bowel perforation, tactician of doctor.

10. Changes in the clinical blood test due to typhoid fever.

11. Differential diagnosis of typhoid fever.

12. Laboratory diagnosis of typhoid fever.

13. Blood collection for hemoculture.

14. Collection of material for copro- and urine culture.

15. Antibacterial therapy of typhoid fever.

16. Pathogenetic therapy of typhoid fever and paratyphoid.

18. Antiepidemic measures in the place of typhoid fever outbreak.

19. Prophylaxis of typhoid fever.

47Brucellosis

BRUCELLOSIS

Brucellosis is disease of domestic and wild animals that is transmittable to

humans (zoonosis). The array of nonspecific signs and symptoms of brucellosis

led Simpson to remark “No disease, not excepting syphilis and tuberculosis, is

more protean in its manifestations”.

Historic reference

In 1859 Marston reported the first accurate description of brucellosis as a

distinct entity. Marston, an assistant surgeon in the Royal Artillery, detailed his

personal experience with “Mediterranian gastric remittent fever” while stationed

in Malta during Crimean War. The causative agent remained unknown until 1886,

when Bruce isolated Micrococcus (later Brucella) melitensis from the spleen

of a fatal case of Malta fever. Zammit, a physician working with the Mediterranean

Fever Commission (1904-1907) made observations that ultimately identified

goats as the reservoir of brucellosis in Malta. Restrictions on the consumption

of unpasteurized goats milk led to a dramatic decline in the incidence of brucellosis

among military personnel. Meanwhile in 1895, the Danish veterinarian Bernard

Bang identified Bacillus (later Brucella) abortus as the cause of contagious

abortions in cattle. The relationship between the agents of Malta fever and

Bang’s disease was not recognized until the 1920s from the work of American

bacteriologist Alice Evans, who recommended renaming the genus Brucella to

honor Bruce. In 1914 Traum isolated B. suis from aborting swine, and in 1966

Carmichael identified B. canis as the cause of contagious abortions in Beagle

dogs. B. ovis (1953) and B. neotomae (1957) were isolated from sheep and

wood rats, respectively, but neither is pathogenic for humans. In 1897, Wright

first applied the serum agglutination test to the diagnosis of brucellosis; this test

remains the standard against which other serologic methods are compared.

Etiology

Brucellae are small, gram-negative coccobacilli that are nonmotile and do

not form spores. They grow aerobically, although B. abortus and B. ovis may

require supplement for primary isolation. Nutritional requirements are relatively

simple. Any high-quality peptone-based media enriched with blood or serum can

be used; however, initial isolation may require prolonged (2-30 days) incubation.

Brucella strains are always catalase-positive, but oxidase and urease activities

and the production of H

S are variable. Traditionally, the major nomen species

of Brucella have been differentiated by selective inhibition of growth on media

containing dyes, such as thionin and basic fuchsin. A series of brucella-phages

can also be used for typing smooth and nonsmooth brucellae.

Infectious diseases

Although six nomen species of Brucella are recognized, the results of DNA-

DNA hybridization studies indicate that the genus comprises a single species

(B. melitensis) with multiple biovars. Nevertheless, the nomen species

designations are retained for taxonomic purposes and to avoid confusion.

Phylogenetically, Brucella spp. appear to have a common origin with free-living,

soil-dwelling organisms. Based on 16S rRNA sequences, Brucella spp. are

classified in the a-2 group of the a-proteobacteria together with Agrohacterium

tumefaciens and Bartonelta (Rochalimaea) henselae.

Chromosomal exchange among the brucellae by transformation, conjugation,

or transduction is unknown, and no plasmids or temperate bacteriophages have

been found. Studies using restriction endonuclease techniques indicate that B.

melitensis contains two independent chromosomes. In addition, the genes for

structural proteins, and functional enzymes have been cloned from B. abortus.

The major cell wall antigen of the brucellae is endotoxic lipo-polysaccharide

(LPS), the structure of which accounts for serologic cross-reactions among

smooth strains and with other gram-negative bacteria. The A and M antigens

first described by Wilson and Miles have been characterized; the A chain consists

of a homopolymer of l,2-linked-4-formamido-4,6-dideoxy-manno-pyranose residues,

whereas the M chain is identical except that every fifth glycose residue is linked

through the 1,3- rather than the 1,2-carbon atoms. Other outer membrane

proteins resemble the OmpF and OmpA of Escherichia coli.

Epidemiology

Brucellosis is a zoonosis and virtually all infections derive directly or

indirectly from animal exposure. The disease exists worldwide especially in the

Mediterranean basin, the Arabian peninsula, the Indian subcontinent, and in parts

of Mexico and Central and South America. Brucella abortus is found principally

in cattle, but other species such as buffalo, camels, and yaks can be of local

importance. Brucella melitensis occurs primarily in goats and sheep, although

camels appear to be an important source in some countries. Brucella suis

biovars 1-3 occur in domestic and feral swines and can cause abattoir-associated

infections. Brucella suis biovar 4 is confined to reindeer and caribou or their

predators in the tundra regions of subarctic. Brucella canis is found primarily in

kennel-raised dogs; it is the least common cause of human brucellosis. In animals,

brucellosis is a chronic infection that persists for the life of the animal. Localization

of brucellae within the female and male reproductive organs accounts for the

major clinical manifestations: abortion and sterility. Brucellae are shed in large

numbers in milk, urine, and products of pregnancy from infected animals. The

disease is transmitted to humans by direct contact with infected animals, their

carcasses, or via ingestion of unpasteurized milk or milk products. Occupations

associated with an increased risk of brucellosis include animal husbandry, veterinary

medicine, abattoir work, meat inspection, and laboratory science. The ingestion of

49Brucellosis

contaminated dairy products such as fresh goat’s milk cheese is the source most

likely to involve the general population. Meat products are rarely a source of

brucellosis because they are not usually eaten raw and the numbers of organisms

in muscle tissue are low. Unusual food “delicacies” such as blood and bone

marrow have also been implicated in the transmission of brucellosis. Human-to-

human transmission of brucellosis is extremely rare. Reports of sexual

transmission are circumstantial, but the potential exists because brucellae have

been isolated from human spermatozoa.

Accidental self-inoculation with live

Brucella vaccines is a risk for infection among ranchers and veterinarians.

Brucellosis in children is not rare as once thought, especially in areas where

B. melitensis is enzootic. The manifestations of brucellosis are similar in neonates,

children, and adults. It is not uncommon to observe outbreaks of the disease

within families especially when a common food source is involved.

The role of wildlife in the epidemiology of brucellosis remains controversial.

Wild hares in Europe are a reservoir for B. suis biovar 2 and can sporadically

transmit the disease to domestic and feral swines.

Pathogenesis

Brucella usually gain entry to the body through abrasious in the skin in the

course of handling infected animals or their carcasses. Accidental inoculation of

the conjunctival the eyes is another route of infection that is especially common

to veterinarians using live Brucella vaccines. Infect the respiratory tract is a

special risk for abattoir work engaged in the slaughter of infected animals.

Brucella melitensis is generally transmitted via ingestion of unpasteurizel products

and appears to be more resistant than B. abortus to inactivation by gastric

juices. Antacids and other drugs that decrease gastric acidity have been implicated

in brucellosis transmitted by the oral route. The incubation time from exposure

to the onset of symptoms is generally 2-3 weeks, although this may vary according

to the inoculum size and perhaps the route of inoculation. Subclinical infection is

suggested by the finding of antibodies to Brucella in individuals lacking symptoms

or signs of disease.

Spink compared brucellosis to typhoid fever, with bacteria entering the lymphatics

and replicating in regional lymph nodes. Hematogenous dissemination is then followed

by localization of bacteria in organs rich in elements of the reticuloendothelia system

(RES), including the liver, spleen, lymph nodes, bone marrow, and kidneys. Normal

human serum has bactericidal activity against some Brucella spp. and is able to

opsonize organisms for phagocytosis by polymorphonuclear (PMN) leukocytes.

Strains of B. melitensis are generally more resistant to bacteriolysis, which may

help explain the greater virulence of this species.

The brucellae are facultative intracellular pathogens that have the ability to

survive and even multiply within the phagocytic cells of the host. The mechanisms

by which the brucellae evade intracellular killing by PMN leukocytes is incompletely

Infectious diseases

understood; however, properties of the bacterial surface appear to enable it to

escape detection. Factors believed to contribute to the intracellular survival of

brucellae include the production of adenine and 5-guanosine monophosphate, which

suppress the loperoxidase-H

-halide system of neutrophils, substances that inhibit

phagosome-lysosome fusion in macrophages, and enzymes, such as superoxide

dismutase, that defend against oxidative destruction. Brucellae are also ingested by

macrophages of the RES, in which they initially survive and multiply. Growth of

the pathogen in the spleen appears to be important for the induction of cell-

mediated immunity, and bacterial cell wall endotoxin is a potent spleen mitogen.

The major virulence factor of the brucellae is smooth LPS. Nonsmooth

strains usually have reduced virulence and are more susceptible to killing by

normal serum from a variety of potential host species. Naturally nonsmooth species

(B. canis and B. ovis) have a greatly restricted host range and a limited capacity

to infect other species. Growth of B. abortus in placental tissues of cattle is

stimulated by the presence of erythritol, which may explain the localization of

brucellae in the genital tract of ungulates. Differences in host responses to various

Brucella spp. is suggested by experimental animal studies in which B.abortus

induces granulomas, whereas B. melitensis and B. suis produce tissue abscesses.

Anatomic pathology

The main factors of pathomorphologic disorders are allergic reactions, which

occur in places of brucella localization, and cause considerable focal changes.

The most vulnerable are connective tissue, vessels, neurologic and lymphatic

systems. Brucellosis granulomas form in acute period, gradually they are exposed

to fibrous transition or sclerosis, though some granulomas can even suppurate.

Such morphologic changes causes stable functional lesions of affected organs.

Clinical manifestations

The onset of symptoms of brucellosis is acute in approximately one-half of

cases and insidious in the remainder. They usually begin from 2 to 8 weeks after

inoculation. Symptoms are nonspecific (fever, sweats, malaise, anorexia, headache)

and patients are sometimes misdiagnosed as suffering from “the flu”. An “undulant”

fever pattern is observed if go untreated for long periods of time. Some patients

complain of malodorous sweat and a peculiar taste in their mouth. Depression is

common, and often in excess of the severity symptoms. In comparison to the

myriad of somatic complaints, physical abnormalities may be few. Mild

lymphadenopathy occurs in 10-20 % and splenomegaly in 20-30 % of cases.

Hepatomegaly is reported in 20-60 %, but may vary with the species of brucellae

or the presence of concomitant parasitic and protozoal infections in some populations.

Brucellosis is a systemic infection that can involve many organs and tissues.

When patients present with manifestations involving a specific organ, some authors

refer to this as “focal” or localized disease. However, there is little compelling

51Brucellosis

evidence to suggest that such complications necessarily represent a distinct

subset of patients. Nevertheless, when the infection involves the central nervous

system or cardiovascular structures, such cases are difficult to treat and the

outcome can be affected.

With appropriate treatment most patients recover within weeks to months,

although a minority will experience a more delayed recovery. Since it is necessary

to treat for prolonged periods of time, relapses are not uncommon, especially if

therapy is discontinued prematurely. Relapse is not due to antibiotic resistance,

since strains of brucellae isolated during relapse have been shown to have

antimicrobial sensitivity patterns identical to the original infecting organism.

Since the onset of symptoms of brucellosis can be insidious, it is often

difficult to distinguish acute from chronic forms of the disease. Spink defined

chronic brucellosis as symptoms persisting for more than 12 months after the

diagnosis was made.

Most patients with chronic brucellosis have persisting foci

of infection, such as suppurative lesions in bones, liver, or spleen. Some patients

who have had brucellosis will continue to complain of nonspecific symptoms,

such as fatigue, malaise, and depression, in the absence of objective evidence of

infection. Although low levels of brucella antibodies may be present in their

serum, they lack the elevated titers of IgG antibodies seen in chronic or relapsing

brucellosis. Symptoms in such patients resemble the “chronic fatigue syndrome”

and most likely represent a preexisting psychoneurosis.

Veterinarians using B. abortus strain 19 vaccine for immunizing cattle are

at risk of accidental self-inoculation by needle stick or conjunctival splash.

Although the vaccine has attenuated virulence for animals, it is capable of

producing brucellosis in man. Inoculation of strain 19 into individuals with

preexisting brucella antibodies generally causes localized inflammation at the

injection site and transient fever and chills. This response is self-limited, lasting

24-48 hours, and is thought to represent hypersensitivity to brucella antigens. In

contrast, individuals without preexisting antibodies are at risk of developing

brucellosis if the inoculum of vaccine is sufficient.

Gastrointestinal tract. Brucellosis, like typhoid fever, is an enteric fever in

which systemic symptoms generally predominate over complaints localized to

the gastrointestinal tract. Nevertheless, when sought, alimentary tract complaints

are elicited in up to 70 % of patients. These include anorexia, abdominal pain,

vomiting, diarrhea, or constipation. Hyperemia of the intestinal mucosa with

inflammation of Peyer’s patches has been reported. Inflammation of the ileum

has been documented radiographically and histologically in patients presenting

with colitis caused by B. melitensis.

Because it is the largest organ of the RES, the liver is probably always

involved in brucellosis; however, liver function tests are usually only slightly

elevated. The spectrum of pathologic findings in brucella hepatitis is varied.

Infection with B. abortus is characterized by granulomatous hepatitis

Infectious diseases

indistinguishable from sarcoidosis. The range of hepatic lesions caused by B.

melitensis includes small aggregates of mononuclear cells within portal triads

and larger aggregates extending into the parenchyma resembling viral hepatitis.

Occasionally one finds collections of mononuclear cells including histiocytes

forming loose granulomas. Brucella suis can cause suppurative abscesses

involving the liver and spleen. Hepatic lesions resolve with anti-microbial therapy

and, in the absence of other toxins, cirrhosis does not occur. Brucellosis is also a

rare cause of cholecystitis, pancreatitis, and spontaneous bacterial peritonitis.

Skeletal. Osteoarticular manifestations of brucellosis are reported in 20-60 %

of patients. The spectrum of bone and joint lesions includes arthritis, spondylitis,

osteomyelitis, tenosynovitis, and bursitis. Sacroiliitis is the most commonly reported

complication. Peripheral joints most often involved are hips, knees, and ankles.

Brucella are a rare cause of sterno-clavicular arthritis. Spondylitis is more common

in elderly patients, and may result in paraspinal abscesses.

Radiographic abnormalities are late findings, whereas bone scans may detect

inflammation early in the disease. Bone scan may be useful to differentiate hip

from sacroiliac involvement. In cases of spondylitis, the earliest radiographic

findings are straightening of the spine and disk space narrowing, followed by

epiphysitis as the main sign of bone destruction.

Computed tomography may

reveal early signs of joint destruction and is especially useful to detect paraspinal

abscess formation.

Analysis of synovial fluid from peripheral joint effusions reveals a predominance

of mononuclear cells, and brucellae are isolated in about 50 % of cases. A reactive

spondyloarthropathy has been described in some patients with brucellosis that is

believed to be caused by circulating immune complexes; however, no association

with a specific human leukocyte antigen (HLA) phenotype has been found.

Neurologic. Neurologic manifestations of brucellosis include meningitis,

encephalitis, meningovascular complications, parenchymatous dysfunctions, peripheral

neuropathy/radiculopathy, and psychosis. Rare cases of intracerebral and epidural

abscesses have also been reported. Central nervous system involvement occurs in

less than 5 % of patients and usually presents as acute or chronic meningitis.

Meningitis can be the presenting manifestation or it can occur late in the course of

brucellosis. There is little to distinguish it from other causes of meningitis except

that nuchal rigidity occurs in less than one-half of cases. Cerebrospinal fluid (CSF)

analysis reveals a lymphocytic pleocytosis, elevated protein content, and low to

normal glucose level. Cultures of CSF are positive in less than one-half of cases, but

the diagnosis is made by finding specific antibodies in the CSF.

Cardiovascular. Endocarditis occurs in less than 2 % of cases, but it accounts

for the majority of brucellosis-related deaths. Before effective antimicrobial therapy,

and surgery to replace infected heart valves, brucella endocarditis was nearly

always fatal. The aortic valve is involved more often than the mitral valve, and

aneurysms of the Valsalva sinus are especially common. Mycotic aneurysms of

53Brucellosis

the ventricles, brain, aorta, and other arteries have been reported. Rapid techniques

to recover brucellae from blood, combined with echocardiography, have improved

our ability to make a diagnosis. Although some cases have been treated

successfully with antibiotics alone, combined medical and surgical treatment is

usually required.

Other cardiovascular complications include myocarditis and

pericarditis.

Pulmonary. Respiratory symptoms are reported in up to 25 % of patients

with brucellosis, after inhalation of contaminated aerosols or via bacteremic spread

to the lungs. Respiratory involvement in brucellosis ranges from flulike symptoms

with a normal radiograph, to bronchitis, bronchopneumonia, solitary or multiple

nodules, lung abscesses, miliary lesions, hilar lymphadenopathy, and pleural effusions.

Rarely are brucelle identified in stains or cultures of expectorated sputum.

Genitourinary. Although brucellae can be recovered from the urine of ðàtients

with brucellosis, genitourinary complications are rare. In men, unilateral epididymo-

orchitis is the usual manifestation. Interstitial nephritis, exudative

glomerulonephritis, and IgA nephropathy have also been reported. Pyelonephritis

and abscess are rare complications and may resemble renal tuberculosis.

The principal manifestation of brucellosis in animals is abortion, and the

presence of erythritol in placental tissues of susceptible animals is believed to

play a role in the localizatiol of brucellae in the genital tract. Although brucellosis

can cause abortion in women, there is little evidence that the incident higher than

with other bacteremic infections.

Hematologic. The hematologic manifestations of brucellosis are variable,

including anemia, leukopenia, or thrombocytopenia. Pancytopenia is rare, but may

be associated with evidence of bone marrow erythrophagocytosis.

Cutaneous. Cutaneous manifestations of brucellosis have been reporte about

5 % of cases. Many transient, nonspecific lesions are described, including erythema

nodosum, papules, rashes and ulcers. Petechiae, purpura, and cutaneous vasculitis

have also been reported.

Diagnosis

Because the symptoms of brucellosis are nonspecific, it is imperative that

the clinician obtain a detailed history, including occupation, exposure to animals,

travel to enzootic areas, and ingestion of high-risk foods (unpasteurized dairy

products). Somatic complaints (weakness, fatigue, malaise, anorexia, body aches,

mental inattention, and depression) predominate over objective physical findings

(fever, malodorous sweats, lymphadenopathy, and hepatosplenomegaly).

Routine laboratory tests, such as the white blood cell (WBC) count may not

suggest an infectious process. The WBC count is usually normal or depressed,

rarely exceeding 10,000 ñells/mm

. Anemia, leukopenia, and thrombocytopenia

are ñommon. The erythrocyte sedimentation rate (ESR) is variable and of little

diagnostic value. The diagnosis of brucellosis is made with certainty when brucellae

are recovered from blood, bone marrow, or other tissues. The rate of isolation

Infectious diseases

from blood varies from 15 to 70 % depending on the methods and the duration

of incubation. Because brucellae are facultative intracellular pathogens, cultures

of bone marrow may have a higher yield than blood. The Castaneda biphasic

technique is said to improve the yield while avoiding the need for I subcultures.

Most clinical laboratories now employ rapid isolation methods (Bactec, DuPont

Isolator, etc.), which are satisfactory for isolating brucellae from blood when they

are maintained for a sufficient time (=30 days). The isolation time for Brucellae

may be reduced by lysis-concentration techniques and other systems capable of

detecting low concentrations of bacteria. Although preliminary studies with the

polymerase chain reaction (PCR) using rRNA sequences show promise, further

studies are needed to determine its role as a rapid diagnostic test for brucellosis.

Once a microorganism is isolated, many clinical laboratories employ rapid

identification systems based on the pattern of biochemical reactions. Biochemical

profiles for Brucella are not included in all corn-Rial computerized data bases

and brucellae have been identified as Moraxella.

²n the absence of bacteriologic confirmation, serologic tests are used to

make a presumptive diagnosis. Although a number of techniques have been

developed to measure Brucella antibodies, the serum agglutination test (SAT) is

the simplest and most widely used. The SAT measures the total quantity of

agglutinating antibodies. Treatment of the serum with agents that reduce disulfide

bonds (2-mercaptoethanol or dithiothreitol) permits the differentiation of

immunoglobulin classes, since they destroy the agglutinability of IgM but do not

alter IgG.

No single titer of Brucella antibodies is always “diagnostic”; however,

most cases of active infection will have titers 1:160 or greater, with IgG antibodies

being present. A decline in IgG antibodies over time is prognostic of a good

response to therapy, whereas a second rise in Ig G presages bacteriologic relapse.

The antigen used in the SAT is prepared from B. abortus 1119, which reacts with

other smooth brucellae (B. melitensis and B. suis). Since B. canis is a rough

species lacking smooth O-polysaccharide, it is necessary to use antigen prepared

from B. canis or B. ovis for serodiagnosis of canine brucellosis.

The use of standardized reagents and procedures in the performance and

interpretation of Brucella serologic tests cannot overemphasized. Although

enzyme-linked immunosorbent assay (ELISA) is reportedly more sensitive than

the SAT, the lack of a standardized antigen makes it difficult to compare results

from different laboratories. Reliable Brucella antigens for the SAT are

commercially available; however, the antigen used in the “febrile agglutinins”

screening test is insensitive unreliable for diagnosing brucellosis. False-negative

reactions can occur if serum is not diluted beyond 1:320 owing to a prozone, and

false positive reactions can occur with serum containing antibodies to the

organisms of cholera, tularemia, and yersiniosis. In very rare instances, false-

negative reactions result from the presence of serum-blocking substances. When

so-called “blocking antibodies” are suspected, they can be detected using other

serologic techniques, such as the Coombs test or a blocking antibody assay.

55Brucellosis

Differential diagnosis

Polyorganic lesions and multiple clinical manifestations complicate diagnostics

of brucellosis, especially on early stages (acute brucellosis). Acute beginning,

triad of clinical signs (chill, fever, sweat), hepatosplenomegaly require differentiation

with malaria, the same manifestations can be caused by sepsis. Continuous fever,

hepatosplenomegaly, bradycardia, leucopenia also are characteristic signs of

abdominal typhus. Diferential diagnosis with generalized form of tularemia, Q-

fever, infectious mononucleosis, rheumatism, lymphogranulematosis also should

be considered. Anyway, the final confirmation of diagnosis is possible only after

obtaining of results of laboratory methods of diagnostics.

Treatment

Treatment is carried out according to clinical period and gravity of disease

course. At acute brucellosis, relapses of subacute and chronic forms the antibiotics

are used, mainly: tetracyclin, aminoglygoside, tienamicines, levomycetin, rifampicin,

which often are administered in combination for better effect. For example:

streptomycin, gentamicin or kanamycin are used in combination with tetracyclin,

doxycycline or rifampicin. The course of the combined antibiotic therapy lasts

for 10 – 20 days and more. Then during 10 days inject levomycetin 0.5-1 (IM)

or (IV) twice per day, levomycetin 0.5 4 times per day or tienam 0.5-0.75 every

12 hours in a muscle. One of schemes of treatment provides using of medicines

of prolonged action – doxycycline 0.2 per day or 0.1 every 12 hours (PO)

during 20 days, and then 0.1 daily during 10 days.

Antibiotics must be injected during all feverish period and during 10 – 12

days after normalization of body temperature. They act selectively only on the

brucellas, freely circulating in blood and lymph. Taking into account, that brucellas

are localized intracellularly, and also in connection with probability of relapses,

through 7-10 days antibiotic therapy will be repeated by preparation which was

not prescribed yet, during 10-12 days.

Preparation of a choice may be bactrim (trimetoprim sulfamethaxazol) which

component “trimethoprim” influences on intracellularly posed brucellas. One of

the approved circuits provides indication of bactrim ( 2 tablets per day during

20 days then carry out 10-day course of treatment by tetracyclinum). The best

results are received at a combination of biseptole with rifampicin.

Antibacterial therapy is expedient for combining with an antibrucella

immunoglobulin in ampoules on 1.5 mL by two or three courses with an interval

of 20 days. Each course consists of 3 (IM) injections of immunoglobulin 2-4-

6 ml, 2-3 days.

The basic method of treatment of chronic brucellosis, which manifests with

focal disorders, is the vaccinotherapy. It consists of the medical polyvalent

brucellous inactivated vaccine. Two courses of accine intravenous injection are

most effective. Instead of a medical vaccine it is possible to use a brucellin.

Infectious diseases

Among nonspecific medicines prescibe butadion, acetylsalicylic acid, ibufrofen,

indomethacin, mefenemic acid.

In an exudative-proliferative stage of inflammation indicate rheopyrinum, in

proliferative-sclerotic ortophen (voltaren). Glucocorticoids are indicated at disorders

of central and perepheric nervous system, at myocarditis, orchitis and at other

expressed focal changes. Prednisolone is indicated in dose 20-30 mg per day during

2-3 weeks. Among antihistaminics use dimedrole, suprastin, tavegil etc. In complex

treatment prescribe an acid ascorbic, vitamin preparations of group B, rutin.

At calming infectious process, chronic and residual brucellosis – methyluracil,

natry nucleinic, prodigiosan, polybiolin, polyoxydony immuno-and biostimulators

timogen or T- activin are indicated. For a resorption of proliferation of a connecting

tissue and acceleration of neogenesis use lydasa, ronidas, gumisole, rumalone, an

extract of aloe. A pharmacotherapy is widely combined with physiotherapeutic methods.

Prophylaxis

Prevention of brucellosis in men depends on the control or eradication of

the disease in domestic animals. In addition, calfhood immunization using B.

abortus strain 19 vaccine and routine pasteurization of milk have resulted in a

dramatic decline in the incidence of human brucellosis. The use of B. melitensis

strain Rev-1 vaccine in countries where caprine brucellosis is enzootic has resulted

in a decrease in human brucellosis due to this species. Although no effective

vaccine exists for B. suis, improved swine husbandry practices have lowered the

incidence of porcine brucellosis. In the past, live-attenuated brucella vaccines

were used for human immunization in some countries; however, they were

restricted to high-risk personnel in areas of high endemicity. No vaccine is

coursely available for human use. Laboratory-acquired brucellosis can be

prevented by adherence to biosafety level 3 precautions.

Control questions:

1. Etiology of brucellosis.

2. Epidemiology of brucellosis.

3. Pathogenesis of brucellosis.

4. Anatomic pathology of disease.

5. Main clinical symptoms and signs of brucellosis.

6. Laboratory methods of brucellosis diagnostics.

7. Criteria of brucellosis diagnosis.

8. Differential diagnosis of brucellosis.

9. Treatment of brucellosis.

10. Prevention of brucellosis.

57Shigellosis

SHIGELLOSIS

Shigellosis is general infectious disease of human, caused by bacterium of

genus Shigella.

Shigellosis is characterized by principal damage of mucous membrane of

distal section of the large intestine. The disease is accompanied by symptoms of

general intoxication, abdominal spastic pain, frequent watery stool with admixture

of mucus and blood, and tenesmus.

Historic reference

The term “dysenteria” was used by Hippocrates to indicate a condition

characterized by frequent passage of stool containing blood and mucus

accompanied by straining and painful defecation.

In 1898 Shiga conclusively demonstrated that a bacterium was present in the

stools of many patients with shigellosis and that agglutinins could be demonstrated

in the serum of the infected patient. Two years later, Flexner found a similar but

serological different organism in stool of other patients with shigellosis acquired

in Philippines.

Etiology

The agents of shigellosis are regarded to genus Shigella, family

Enterobacteriacea. There are approximately 50 serotypes of Shigella.

According to modern international classification genus of Shigella is divided

into four groups: group A (S. dysentery), group B (S. flexneri), group C (S. bojdii),

group D (S. sonnei). Each group is divided into serologic types and subtypes.

All Shigellas are similar morphologically. They are small gram-negative

rods, nonmotile and nonencapsulated. Shigellas are facultative anaerobias. They

grow well on the simple nutritive mediums. Shigella contain thermostable somatic

O-antigen, including group and standard antigens.

Depending on character of toxinoformation Shigella are divided into two

groups. Shigella Grigoriev-Shiga’s belongs to the first group. They produce strong

exotoxin, having protein’s origin, and also endotoxin. All other types of Shigella

(Flexneri, Sonnei) are treated to the second group, they produce only endotoxin.

Endotoxin consists of proteins and lipopolysaccharide. Protein part of endotoxin

and exotoxin have expressive neurotropic action. Endotoxins has enterotropic action.

Epidemiology

The sources of infection are ill patients, persons in period of reconvalescence

and bacteriocarries. The patients with acute shigellosis are especially dangerous.

Infectious diseases

The patients with acute shigellosis discharge the agent during all period of

the disease, especially during period of expressive colitic syndrome. The persons

with obliterated, light forms of the disease are dangerous too. These persons

don’t address for medical help and don’t receive treatment. Because, these

“atypical” cases of acute shigellosis have predominant epidemiological meaning.

The patients with chronic shigellosis are dangerous for other persons, especially

in the period of aggravation.

The mechanism and factors of the transmission of the infection. The

mechanism of the transmission of the infection is fecal-oral. The transmission of

the infection is realized through contaminated food-stuffs and water. Infection of

food-stuffs, water, different objects happens due to direct contamination by infected

excrements, through dirty hands and also with participation of flies. The factors of

transmission have leading meaning in epidemiology of shigellosis. Depending on

factors of transmission there are the next ways of contamination - contact, alimentary

and water. Now, the alimentary way has more important meaning. Contamination

over food-staffs may be through contaminated vegetables and berries with insufficient

processing before use. Food-stuffs, prepared for use have the most important

meaning in transmission of the infection (milk, milk products, especially, sour

cream, meat stuffing and other meat products, bread, soft drinks, fruits, vegetables).

The susceptibility of human is high. It doesn’t depend on sex or age.

Shigellosis occurs as in infants as in seniors. However, the morbidity of adult

population is lower than children of early age.

Shigellosis is characterized by seasonal spread as the other intestinal

infections. It is registered more frequently in summer and autumn.

Pathogenesis

Pathogenesis of shigellosis is complicated. It is studied insufficiently. In some

cases the agents perish in the upper section of the gastrointestinal tract under the

influence of acidic conditions. In other cases Shigella may pass through intestine,

and it is excreted into environment without reply of the macroorganism.

Diverse theories of pathogenesis of shigellosis were pulled out in different

years. The next theories are known:

1. Bacteriemic theory. Reproduction of the agent in the blood is the basis of

pathogenesis of shigellosis according to this theory.

2. Toxico-infections Shiga’s-Brauer’s theory. Many positions of this theory

don’t lose one’s own meaning in modern ideas about pathogenesis of shigellosis.

3. Allergic theory. According to this theory, shigellosis is general allergic

infection disease.

4. Nervous-reflexious theory. According to this theory the damage of nervous

system has leading meaning in pathogenesis of shigellosis.

5. Theory of intracellular parasitism. According this theory, all features of

the shigellosis course are connected with parasitism of Shigella in the epithelium

of mucous membrane of distal section of the large intestine.

59Shigellosis

In was established by investigations of the last years that secondary immune

insufficiency plays considerable role in pathogenesis of shigellosis. At present

time it is known that development and course of the different forms of shigellosis

is connected with some factors. There are functional state of the organism;

interaction of the human’s organism, agent and environment; biological properties

of the agent (toxigenecity, invasiveness, fermentic activity and other).

Bacteremia of short duration may be observed in decreased resistance, in

entering of the large doses of the agent. However, bacteremia hasn’t essential

meaning in pathogenesis of shigellosis. Bacteremia is marked only in one third

of the patients with Grigoriev’s-Shiga’s shigellosis.

Toxins, which are absorbed from the intestine, play an important role in

pathogenesis of shigellosis. At first, toxins influence directly on the mucous

membrane of the intestine and substances, disposing under mucous membrane

(nervous endings, vessels, receptors). Second, toxins are absorbed and influence

to different sections of central nervous system. Involvement of small intestine in

pathological process from the first days of the disease is explained by toxinemia

(violation of its motile, absorbing and digestive functions). The evidence of

toxinemia is delivery of endotoxin into patient’s blood serum from the first days

of the disease and its delivery into urine.

Exotoxin of Shigella Grigoriev’s-Shiga’s and protein part of endotoxin

possesses significant neurotoxic action. Neurotoxins influence on the central

nervous system and peripheral gangiums of vegetative nervous system. It is

manifested by severe intoxicative syndrome and violation of all types of the

balance of substances.

Lipopolysaccharide part of endotoxin damages principally mucous membrane

of distal section of large intestine, and in a less degree, other sections of gastrointestinal

tract. It possesses cytotoxic action and causes activation of adenylcyclase.

Activation of adenylatecyclase leads to accumulation of cyclic 3,5-adenosine-

monophosphates, increased secretion of electrolytes and water. The violation of

water – electrolytes balance is observed in gastrointeritic variants of acute shigellosis

course. It is necessary to allow for degree of dehydration of the organism. Dehydration

of II-III degree develops in severe course of gastroenterocolitic and gastroenteritic

variant of acute shigellosis. In severe (hypertoxic) form it may be development of

hypovolemic shock and acute renal insufficiency.

Shigella toxins cause sensibilization of the mucous membrane of the intestine,

render damaging action on it with development of inflammatory changes and

erosions formation and ulcers in severe course of the disease.

Toxin stimulates discharge of biological active substances (histamine,

serotonine, kinines, prostaglandines) into blood, causes violation of microcirculation

of the blood in the intestine’s wall, increases intensity of inflammatory process

and disorders of functions of the intestine (motorics, absorbtion, secretion).

The violation of innervation of the intestine, microcirculation, electrolytic

balance and inflammatory changes of mucous membrane are manifested clinically

Infectious diseases

by sharp spastic pains in the stomach. Spasms of separate sections of the

intestine lead to excretion of scanty stool (“fractional stool”). Spastic shortening

of the muscles of sigmoid and rectum cause fecal urgency and tenesmus.

Allergic factor plays definite role in pathogenesis of shigellosis. Pathological

process develops in large intestine after preliminary sensibility. However, it was

shown experimentally, that shigellosis is not typical allergic disease.

However, intracellular parasitism was not confirmed due to biopsy of mucous

membrane of the intestine in the patients with shigellosis. It is not expected, that

phenomenon of intracellular parasitism plays certain role in shigellosis too.

In shigellosis, the invasion of Shigellas into epithelial cells is observed in

large intestine, principally in rectum. It is caused by comparatively prolonged

accumulation of intestinal content, toxins and bacteriums in the large intestine.

They create favorable conditions for invasion of the agent into epitheliocytes. It

is promoted by intestinal dysbacteriosis too. Intestinal dysbacteriosis develops

inrarely under influence of antibioticotherapy. This therapy causes destruction

of considerable part of symbiotic flora.

The disease may have prolonged or chronic course due to addition of

supplementary factors of chronic process. The cases of formation of chronic

shigellosis develops due to unfavorable premorbid state, delay of macroorganism

functions replacement, decreased activity of immune system.

The recovery of the patients is prolonged in presence of damages at any

portions of gastrointestinal tract (defects of masticatory apparatus, anomalies of

intestinal tube, gastritis, ulcerous disease, appendicitis, pancreatitis, hepatitis,

cholecystitis); presence of supplementary diseases (tuberculosis, brucellosis, malaria,

helminthiases); state of endocrine system, dysbalance of vitamins. The factors,

promoting to prolonged and chronic course of the disease, are late hospitalization

of the patients, incorrect treatment, violation of alimentary regime after discharge

of the patients from the hospital.

Immunity. In shigellosis postinfectious specific immunity is shaped and

typed-specific.The investigations of humoral immunity revealed dependence of

the level of blood serum immunoglobulins of the patients with shigellosis from

gravity of the disease, kind of the agent, and also, from treatment. Antibodies play

essential role in execution of functions of phagocytes. However, presence of

antibodies can not be used for rendering of diagnosis and for estimate of complete

sanation of the organism from the pathogen. In shigellosis humoral factors of

immunity preserve the meaning only during one year.

Immunological examination reveales depression of the tests T-system of

immunity with different course of acute shigellosis, which is more expressive in

the patients with severe, moderate and lingering course of the disease.

Decrease of the tests T-system of immunity is appearance of short duration.

It was mentioned a considerable decrease of functional activity and quantity of

T-lymphocytes in the patients with lingering course of shigellosis and in chronic

form of the disease.

61Shigellosis

Investigations of subpopulations of T- and B-lymphocytes were an important

stage for deciphering of violation of immune system in shigellosis. These data

allow to establish the most important links of pathogenetic process. Corrections

of these links may be the most perspective.

Detailed analysis of subpopulations of immune system had proved the presence

of secondary immune deficiency in shigellosis. So, decrease of T-supressors is observed

in case of moderate and severe course of acute shigellosis. In chronic form of the

disease the activity of T-supressors increases, but the level of T-helpers decreases.

However, the factors of cell immunity must be estimated according to humoral

and especially, local immunity. It is possible, that absence of the local immune

reaction is a risk factor of lingering, chronic forms of the disease development

and also for postdysenteric colites.

The local immune response of lymphoid tissue of intestine is promoted by

antibodies – forming cells of mucous membrane-produced antibodies of classes IgA,

IgG, IgM. The class of IgA has the leading role in the protection of the organism.

Thus, the secondary immune deficiency in patients with different forms of

shigellosis is connected in general with violation of regulative and effectoric

links of immune system. The causes of secondary immune deficiency development

is inhibitory influence of antigenic-toxic complexes of the agent at immune system

in infectious diseases.

It is known, that endotoxinemia is one of the mechanisms of pathogenesis

of shigellosis. Toxins of the agent render depressive influence on hemopoesis,

phagocytosis and cause the disorder of microcirculation. Correlation is marked

between degree of intoxication, level of depression of cell immunity and natural

resistance of the organism.

The study of different cells populations, their metabolic activity allow to

determine their role in different forms of shigellosis. These investigations give a

possibility of application of basic regulation of cell’s functions with use

immunocorrecting therapy for preventation of the formation of lingering, chronic

forms of the disease and postdysenteric colites.

Anatomic pathology

In shigellosis pathomorphologic changes are revealed, generally, in distal portion

of the large intestine (sigmoid, rectum). There are 4 stages of inflammatory changes:

1. Acute catarrhic inflammation.

2. Fibrinous necrotic.

3. Ulcerous and folliclic-ulcerous.

4. Stage of formation of scars.

At present time fibrinous-necrotic and ulcerous damages occur rarely.

Catarrhic inflammatory process is observed more frequently. It is confirmed by

data of pathologoanatomic investigations due to biopsy of rectum. Catarrhic

inflammation is characterized by edema, hyperemia of mucous membrane and

Infectious diseases

submucous layer of rectum. Small hemorrhages and erosions are observed in

the mucous membrane in the part of the patients. In rectoscopy mucous or

mucous-hemorrhagic exudation is revealed on the surface of mucous membrane

and in the intestine.

In microscopical investigation disorders of vessels are marked: increased

permeability, local hemorrhages. Edema of strome and basal membrane leads to

dystrophic changes of epithelium, in severe cases – to formation of ulcers and

erosions. Hyperproduction of mucus is typical.

Fibrinous-necrotic changes are manifested by dirty, gray and dense coats on

mucous of the intestine. The membranes consist of necrotic tissue, leukocytes

and fibrin. Necrosis may achieve submucous and muscleous and fated submucous

layer. Purulent damages and necrosis lead to formation of ulcers. In shigellosis

ulcers are superficial with dense borders.

The regeneration of epithelium begins on the 2-3 day of the disease in acute

phase of catarrhic inflammation. However, complete anatomical recovery may be

on 4-5 month after discharge the patient from the hospital even in mild course of

shigellosis. Regeneration comes slowly in the destructive changes in the intestine,

and disorders of vessels are preserved for a long time. Regeneration is combined

frequently with focuses of inflammatory changes. In chronic shigellosis the

morphological changes are characterized by multiple forms and flabby duration

of inflammatory process.

Clinical manifestations

There are the next clinical variants of acute shigellosis:

1. Colitic variant.

2. Gastroenterocolitic variant.

3. Gastroenteric variant.

Depending on gravity of the course of the disease there are mild, moderate

and severe course of shigellosis, and also carriers.

Colitic symptomocomplex is typical for shigellosis. Incubation period lasts

from 2 till 5 days, rarely – 7 days.

Mild course. Onset of the disease is acute. The temperate pains appears in

the lower part of the stomach, principally, in the left iliac area. These pains

precede act of the defecation. Tenesmus are observed in some patients. Stool is

from 3-5 till 10 times a day. It contains mucus, sometimes – blood. Temperature

is normal or subfebrile. Catarrhic inflammation of mucous membrane is observed

at rectorhomanoscopy, sometimes erosions and hemorrhages.

Moderate course. Onset of the disease is acute or with short prodromal

period. It is characterized by weakness, malaise, discomfort in the stomach. Then,

spasmatic pain appears in the lower part of the stomach, tenesmus. At first, stool

has fecal character. Then, mucus and blood appear in stool. Stool loses fecal

character and has appearance of “rectal spit” (excretion of scanty stool –

63Shigellosis

“fractional stool”), with mucus and blood. Stool is accompanied by fecal urgency

and tenesmus. Stool is from 10-15 times a day.

In patients with medium serious course of acute shigellosis temperature

increases up to 38-39 °C for 2-3 days. Subfebrile temperature is possible. The

patients complain of weakness, headache. It may be collapse, dizziness. The skin

is pale. Hypotonia, relative tachycardia are observed. Tenderness and condensation

of sigmoid are revealed. In the peripheral blood leukocytosis and temperate

neutrophylosis are observed. In coprocystoscopy erythrocytes (more then 30-

40 in the field of vision) are revealed. In rectorhomanoscopy diffusive catarrhic

inflammation, local changes (hemorrhages, erosions ulcers) are revealed. In patients

with moderate course of acute shigellosis functional and morphological restoration

may be prolonged – till 2-3 months.

Severe course. Onset of the disease is acute. Temperature is increased up

to 39 °C and higher. The patients complain of headache, harsh weakness, nausea,

something vomiting. Strong abdominal spasmodic pains, frequent stool with

smaller volume “without account”, with mucus and blood are marked.

There are hypotonia, harsh tachycardia, breathlessness, skin cyanosis. Harsh

tenderness at the left iliac area, especially in the area of sigmoid are marked

during palpation of the stomach. It is possible pasesis of intestine. There are

expressive leukocytosis neutrophylosis with shift to the left. ESR is accelerated.

During microscopical examination of stool erythrocytes are marked through

the field of the vision. In rectorhomanoscopy infusive catarrhic or fibrinous

inflammation, presence of the local changes (erosions, ulcers) are marked. The

functional and morphological restoration of intestine is longer than 3-4 months

in patients after colitic variant of acute shigellosis.

Gastroenterocolitic variant of shigellosis. The principal feature of this variant

of the acute shigellosis course is acute impetuous onset of the disease after short

incubation period (6-8 hours). More frequent way of the transmission of the infection

is alimentary. The factors of transmission are milk, milk products and other.

Intoxicative syndrome and symptoms of gastroenteritis are observed in the

initial period. The manifestations of enterocolitis predominate in the period of climax.

There are mild, moderate and severe course of gastroenterocolitic variant of

acute shigellosis. During estimate of the disease course gravity it is necessary to

allow for not only degree of intoxication and damage of gastrointestinal tract,

but also degree of dehydration, because repeated vomiting and plentiful diarrhea

are observed. It may lead to dehydration of I-II-III degree.

Gastroenteritic variant of shigellosis. The principal feature of this variant

of the acute shigellosis course is predominance of clinical symptoms of

gastroenteritis and presence of certain degree dehydration symptoms. Nowedays,

besides clinically distinct sings of the disease, lingering and obliterated course of

shigellosis is observed. Obliterated course is characterized by insignificant clinical

manifestations. The great ratio of the patients do not apply to physician. Careful

Infectious diseases

bacteriological examination of the patient with different gastrointestinal disorders

of unknown etiology has large meaning for correct diagnostics. In these patients

catarrhic inflammatory changes of mucous membrane of distal portion of rectum

is revealed in the majority of cases during rectorhomanoscopy (Fig. 2).

Clinical recovery comes through 2-3 weeks in the majority of the patients

with uncomplicated course of all variants of acute shigellosis. Complete functional

and morphological restoration of gastrointestinal tract happens in 1-2 months

and later. Relapses may arise in some part of the patients. The factors, promoting

to relapses of the disease are the violation of diet, alcohol use, incorrect therapeutic

tactics. The disease may have lingering course. Insufficient reactivity of the

organism, sharp decrease of cell immunity in acute period of the disease promote

to lingering course of shigellosis.

Lingering course of shigellosis. Shigellosis is estimated as lingering, if

clinical manifestations of the disease are observed over 3-4 weeks. Declination

to lingering course of the disease depends on gravity of the course of shigellosis

in acute period. Colitic variant of severe course of acute shigellosis has prolonged

course more frequently than moderate variant. The period of functional and

morphological restoration of the intestine is over 3 months. In some patients

lingering course is manifested only by persistent bacterioexcretion.

Bacterioexcretion is combined with prolonged inflammatory process in rectum.

Bacterioexcretion. Dysfunction of intestine is absent at the period of

examination and preceded 3 months in presence of bacterioexcretion (subclinical

bacterioexcretion) or excretion of Shigella after clinical recovery (reconvalescent

excretion) in this form of infectious process.

Diagnosis

The principal methods of diagnostics of shigellosis are bacteriological and

serological methods of investigation.

Excretion of coproculture of Shigella is more reliable method of confirmation

of diagnosis of shigellosis. It is necessary to take the material for bacteriological

investigation before beginning of the treatment.

Diagnosis may be confirmed by serological methods. Reaction of indirect

agglutination with standard erythrocytic diagnosticum is used more widely.

Diagnostic titer is 1:200 with increase of titer in 7-10 days.

Differential diagnosis

Differential diagnosis is performed with the following diseases – salmonellosis,

toxic food-borne infections, rotaviral gastroenteritis, amebiasis, balantidiasis, intestinal

shistosomiasis, trichocephaliasis, enterobiasis, cancer of large intestine, appendicitis,

ileus, hemorrhoids, diverticulitis, ischemic colitis, Crohn’s disease, non-specific ulcer

colitis, secondary colitis in patients with severe therapeutic pathology, radiation

affections and poisonings with different chemical and biologic substances.

65Shigellosis

Treatment

The complex of treatment is indicated, which depends on features of disease. In

the first days the diet ¹ 4, and diet ¹ 2 (till clinical convalescence) are indicated.

At mild course of shigellosis etiotropic agents are not applied, at disease of

average degree of gravity use basically preparations of nitrofuranes: furazolidon,

nifuroxasid 0.1 gm 4 times per day. Use derivatives of 8-oxyquinoline – enteroseptol,

intestopan, among other groups of preparations – intetrix, nalidix acid, ftalazol. At

ambulatory treatment of shigellosis with moderate stage of gravity sulfanilamid

preparations of prolonged action are indicated – phthazin, sulfadimethoxin.

In case of severe shigellosis course use antibiotics - ampicillin or a polymyxin;

when there is no effect – ciprofloxacin or ofloxacin in combination with gentamicin

or cefazolin are prescribed. Duration of course of etiotropic treatment at moderate

course of shigellosis is 2 - 3 days, at severe case it lasts not longer than 4 - 5 days.

A solution of regidron, in severe cases quartasault, lactosault are applying

per os with the purpose of desintoxication and rehydratation. For the adsorption

of bacterial toxins and metabolites from the intestine lumen and for their

subsequent removing from the organism enterodes, coal microspherical sorbents,

sillard P, smecta are used. Rectal pollination with sillard P in a dose 6 gm (1 - 3

procedures) is effective. There are proved methyluracil, pentoxyl, thymalin as

natural factors of nonspecific protection of the organism and stimulators of

regeneration. Calcy gluconate, dimedrol, suprastin, tavegil are indicated as

pathogenetic treatment.

According to parameters of coprocytogram use mono or polycomponental

fermental preparations. At presence of plenty of fat drops in feces pancreatin,

pancitrat, pancurmen, and at detection of a cellulose, amyl, muscular fibers -

pansinorm, festal, mezym-forte, abomin, vobensim are applied.

There are indicated widely vitamins preparations, these are ascorbic acid,

nicotinic acid, thiamin chlorid, riboflavin, pyridoxine hydrochloride, calcy pangamat,

folic acid, rutin. It is better to use per os the balanced vitamin complexes -

dekamevit, glutamevit.

Collibacterin, bifidumbacterin, bificol, lactobacterin, bactisubtil, linex, hilac

forte, α- bacterin, enterole-250 are indicated for elimination of intestinal dysbacteriosis

and restoration of the normal biocenosis. Course of treatment is 2 weeks and longer.

Collectings of herbs and fruits of a bilberry, mint peppery, knot-herb ordinary,

camomiles medicinal, herbs of a yarrow, centaury are helpful ordinary. Collecting

with the shepherd’s bag ordinary, grasses of St.-Johns wort are effective at

hemocolitis. Fermentative and putrefactive processes reduces at lingering colitis,

that is why collecting of grass of a sage-brush, a horsetail field, grasses of a

yarrow ordinary, roots of snakeweed are applied.

Broths and juices of herbs, oil of dog rose for microclysters after a cleansing

enema, 0.5 % solution of a colloid silver as medical clysters, insufflations of oxygen

are used locally for stimulation of reparative processes in the mucosa of colon.

Infectious diseases

Prophylaxis

Prophylaxis of shigellosis includes complex of measures, directed to revelate

the source of the infection, interrupt the ways of the transmission, increase of the

organism resistance. Keeping the rules of personal hygiene and rules of food’s

cooking plays the principal role in prophylaxis of the disease. Sanitary education

of population has an important meaning in shigellosis prophylaxis too.

Control questions:

1. Etiology of shigellosis.

2. Epidemiology of shigellosis.

3. Pathogenesis of shigellosis.

4. Anatomic pathology of disease.

5. Main clinical symptoms and signs of shigellosis.

6. Variants of shigellosis infection.

7. Laboratory methods of shigellosis diagnosis.

8. Criteria of shigellosis diagnosis.

9. Differential diagnostics of shigellosis.

10. Treatment of shigellosis.

11. Prophylaxis of shigellosis.

67Salmonellosis

SALMONELLOSIS

Sallmonellae are widely dispersed in nature, being found in the gastrointestinal

tracts of domesticated and wild mammals, reptiles, birds, and insects.

May present clinically as a gastroenteritis, enteric fever, a bacteremic syndrome,

or focal disease. An asymptomatic carrier state may also occur.

Historic reference

The term “salmonellosis” unites a large group of diseases, caused by multiply

serotypes of bacteria from genus Salmonellae (more than 2,000).

Sallmonellae are named for the pathologist Salmon who first isolated

S. choleraesuis from porcine intestine. The antigenic classification or serotyping

of Salmonella used today is the result of study of antibody interactions with

bacterial surface antigens by Kauffman and White in the 1920s to 1940s. Ames and

coworkers in 1973 reported the development of the test that uses S. typhimurium

auxotrophic mutants to test the mutagenic activity of chemical compounds.

Salmonellosis is disease of animals and humans. It is characterized by

essential damage of gastrointestinal tract, and more rarely by typhus-like or

septicopyemic duration.

Etiology

Salmonella are non-spore-forming gram negative rods of the family

Enterobacteriaceae. Salmonella are motile by peritrichous flagella. Salmonella

strains demonstrate sufficient differences in biochemical reactions, antigenic

structure, host adaptations, and geographical distribution to be grouped into 10

distinct subgroups, which have been variously designated in proposed taxonomic

schemes. Virtually all strains isolated in clinical laboratories and implicated in

disease in humans (more than 700 serotypes).

Like other enterobacteria, salmonella has somatic O-antigens, which are

lipopolysaccharide components of the cell wall, and flagella H-antigens, which are

proteins. There may be detached some serological groups on the basic of the

differences in structure of O-antigens. Salmonella preserve viability in external

environment for a long time: in water – 11-120 days, in the sea water – 15-27

days, in soil – 1-9 months, in sausage products – 60-130 days, in the eggs,

vegetables and fruits till 2,5 months. The optimal temperature for reproduction

is 35-37 °C. There are serological groups A, B, C, D, E and other.

Salmonella can be differentiated from other Enterobacteriaceae on the basis

of certain biochemical reactions, including fermentation reactions with specific sugars.

Salmonella organisms grow readily on simple media in aerobic or anaerobic

conditions. Cultures of specimens that are normally sterile, such as blood, joint

Infectious diseases

fluid, or cerebrospinal fluid, can be done on ordinary media such as blood agar.

Excretions or secretions, such as feces or sputum, which have high concentrations

of other microorganisms, are usually grown on selective or differential media,

such as bismuth sulfate agar or desoxychlorate agar, which contains inhibitors

of growth of non-pathogenic organisms of the normal flora.

Epidemiology

Animals suffering from primary or secondary salmonellosis, water swimming

birds and also human-sick or carries are the main sources of infection in

salmonellosis. Mechanism of transmission of infection is fecal-oral. The factors of

the transmission of the infection are food-stuffs of animal origin and other products

which are polluted by excretions of animals and humans. The promotive factors

are violation of the preservation and preparing of the food and also sanitary.

The diseases occur as separate sporadic cases and as outbreaks.

Susceptibility of human depends from the premorbidal state of the macroorganism

and from the quantity and variety (serotypes) of Salmonella.

Salmonella are primarily pathogens of lower animals. The reservoir of

infection in animals constitutes the principal source of nontyphoidal Salmonella

organisms that infect man, although infection may be transmitted from person to

person, Salmonella have been isolated from almost all animals species, including

poultry (chickens, turkeys and ducks), cows, pigs, pets (turtles, cats, dogs, mice,

guinea pigs and hamsters), other birds (doves, pigeons, parrots, starlings, sparrows),

sheep, seals, donkeys, lizards and snakes.

The most accurate information on sources of human salmonellosis is derived

from studies of outbreaks. Poultry (chickens, turkeys, ducks) and poultry products

(primarily eggs) are the most important sources of human infection and are estimated

to be responsible for about one-half of the common – vehicle epidemic. Salmonella

in feces of infected hens may contaminate the surface of egg shells or penetrate

into the interior of the egg through hairline cracks. In hens with ovarian infection,

organism may gain access to the yolk. Meat, especially beef and pork, are quite

often implicated, accounting for about 13 % of the outbreaks, and dairy products,

including raw and powdered milk account for about 4 % of the epidemics.

Cross-infection with spread by person to person is responsible for virtually

all the outbreaks in neonatal nerseries and in pediatric wards and is important in

many outbreaks among hospitalized adults.

The stage is set for cross-infection when Salmonella are introduced into

the hospital by admission, or for example, a patient with acute enterocolitis or as

asymptomatic carrier with other medical problem or by the introduction of a

contaminated common- course vehicle. Hospital personnel then may carry infection

on hands or clothing from patient to patient; in some cases fomites (dust, delivery

room, furniture), may be implicated in transmission. Hospital personnel who are

excreting Salmonella in stools may also occasionally transmit infection to patient.

69Salmonellosis

Pathogenesis

The development of disease after ingestion of Salmonella is influenced by

the number and virulence of the organisms and by multiple host factors.

A large number of Salmonella must be swallowed in most instances to

produce disease in healthy human being. However, in the event of infection with

unusually virulent organisms or in patients with reduced resistance, symptomatic

infection may result from extremely small inocula. Ingested organisms pass from

the mouth to the stomach. In the stomach Salmonella are exposed to gastric

acid and low pH, which reduce the number of viable organisms. Most Salmonella

are perished rapidly at 2.0 pH, which is readily achieved in the normal stomach.

Viable bacilli that survive then pass into the small intestine, where the organisms

may be further reduced in number or eliminated entirely. The antimicrobial

activity observed in the small bowel is related at least in part to the normal

microbial flora of the intestine, which elaborate short-chain fatty acids and perhaps

other substances capable of killing or inhibiting growth of Salmonella. Studies

in animals have shown that the increased susceptibility to Salmonella infection

produced by administration of antibiotics rapidly reverts to normal with

reestablishment of the normal intestinal flora.

Salmonella that survive the antibacterial mechanisms in the stomach and

upper small bowel may multiply in the small intestine. Multiplication of Salmonella

in the intestinal tract may be asymptomatic, associated only with transient excretion

of organism in stools, or symptomatic, associated with clinical manifestations of

either enterocolitis (acute gastroenteritis) enteric fever or bacteremia.

Blood stream invasion, which occurs with variable frequency, may lead to

localization of infection and suppuration at almost any site.

Local factors in the stomach and upper intestinal tract are important

determinants of the disease. Factors that neutralize the low pH of the stomach

or decrease the time the pathogen is exposed to stomach acid diminish local

bactericidal action and increase the probability that an infections inoculums will

reach the small intestine. The importance of gastric acidity as a defense mechanism

is emphasized by the increased incidence of severe Salmonella enterocolitis in

persons with achlorhydria, prior gastroectomy, gastroenterostomy, or vagotomy,

conditions that reduce acidity or cause faster gastric emptying time.

The oral administration of buffering compounds also increases susceptibility to

intestinal infection. It has been suggested that ingestion of organisms in food allows

for longer exposure to gastric acid, thereby necessitating the presence of a relatively

larger inoculums to produce disease, whereas water or other liquids, which have a

fast gastric transit time, may be less heavily contaminated and still cause disease.

The small intestine provides other protective mechanisms through motility

and normal flora. Alteration of the intestinal flora by antibiotics markedly reduces

the size of the inoculums required to produce Salmonella infection in animals

and humans and prolongs the convalescent carrier state. Prior antimicrobial

Infectious diseases

therapy also enhances the possibility of infection with antibiotic – resistant

Salmonella strains.

Age is an important determinant of disease produced by Salmonella.

Salmonella enterocolitis occurs with highest incidence in children less than 5

years old; newborns and infants less one year of age are especially susceptible.

The influence of age on incidence may reflect immaturity of humoral and cellular

immune mechanisms, diminished antibacterial action of the normal intestinal

flora, a high frequently of fecal – oral contamination, or other factors. In some

instances, increasing resistance with age is related to immunity consequent to

previous exposure to the organism, even though disease has not been produced.

Patient with impaired cellular and humoral immune mechanisms are at

increased risk for development of salmonellosis. Impairments of host defenses

caused by malnutrition, malignancy, infection with human immunodeficiency virus

or therapeutic measures such as corticosteroid or immunosuppressive therapy

also predispose to infection and disease.

Salmonella causing enterocolitis are thought to produce diarrhea by a true

infection with mucosal invasion and possibly by elaboration of an enterotoxin

that acts on upper intestinal transport. Salmonella invasion of intestinal mucosa

may lead to local production of inflammatory exudates of mediators that stimulate

electrolyte secretion and smooth muscle contraction.

There are two types of toxins: exotoxins and endotoxins. Exotoxins are the

toxic products of bacteria which are actively secreted into environment. Endotoxins

are toxic substances which are liberated only during the lysis of microbial cells.

The principal factor responsible for development of this disease is endotoxical

complex of Salmonella, but we should remember that these bacteria produce

even exotoxins. Exotoxins and endotoxins have toxical properties.

In salmonellosis the development of infectious process has next stages:

1. Colonization (setting) of pathogenic organism in the place of the inculcation.

2. Invasion and reproduction.

3. Death of the pathogenic bacteria and endotoxins liberation.

Infectious process may stop at the stage of colonization due to unknown

reasons. Invasion may be limited by nearest tissues. In majority cases it leads to

development of gastrointestinal forms of salmonellosis. For development of the

first stage of pathogenesis of salmonellosis the factors violating structural and

functional state of gastrointestinal tract play important role (dysbacteriosis,

hypovitaminosis and other). These conditions may promote to development of

the disease even due to small quantity of bacteria in food-stuffs.

In salmonellosis the principal pathologoanatomical changes develop in the

place of inculcation of the agent in the small intestine. Data about changes of small

intestine in gastrointestinal forms of salmonellosis may be received only as a

result of its biopsy. But biopsy is not used in practice. Investigation of material

during biopsy testifies dystrophical changes of epithelium, infiltration of epithelium

of mucous membrane by macrophages. Increased quantity of interepithelial

leukocytes, polymorphonuclear leukocytes and macrophages is marked.

71Salmonellosis

Anatomic pathology

Principal changes develop in lamina propria of mucous membrane of small

intestine in salmonellosis. These changes are accompanied by hyperemia,

hemorrhages, edema and intensification of cell infiltration. At the same time the

changes of the different parts of gastrointestinal tract develop. There is an acute

inflammatory process, dystrophic changes of epithelium, edema, hyperemia and cell

infiltration in stomach. There are dystrophy, erosions, hyperemia, edema in mucous

of large intestine. Changes in all parts of gastrointestinal tract are transient. They

are exposed to reverse development in clinical recovery of the patients.

In half of the patients with salmonellosis nonsharp violations of liver are

marked. These changes are considered as compensatory mechanism.

In connection with sufficient efficiency of modern methods of treatment the

fatal outcomes are rare. Dystrophic changes of parenchymatous organs were

revealed in autopsy of deceaseds from gastrointestinal forms of salmonellosis.

These changes were direct cause of death. Inrarely, edema of the lungs and brain,

hyperplasia of spleen and mesenteric lymph nodes may develop.

Clinical manifestations

In connection with considerable variability of clinical duration of salmonellosis

there are multitude classifications of this disease. The next classification is more

comfortable for practice use:

1) Localized (gastrointestinal) forms of salmonellosis:

a) Gastritic variant;

b) Gastroenteritic variant;

c) Gastroenterocolitic variant.

2) Generalized forms:

a) Typhus-like form;

b) Septic form (septicopyemia).

3) Carrier state:

a) Acute carriers;

b) Chronic carriers;

c) Transitory carriers.

Clinical symptoms of salmonellosis are studied sufficiently completely.

Gastrointestinal forms of salmonellosis are observed in most of cases of the

disease. According data of different authors they occur from 79 to 85 %.

Incubation period is from 4-6 hours up to some days. Onset of the disease

is an acute. Prodromal period is not typical or very short. Weakness, malaise,

and slight chill characterize it. Then temperature increases to subfebrile in moderate

and severe forms accordingly.

After ingestion of contaminated food or water, illness begins in many patients

with nausea and vomiting; these symptoms usually resolve within a few hours.

Myalgia and headache are common. The cardinal manifestation is diarrhea, which

may vary from a few loose stools to fulminate diarrhea. In most cases, stools are

loose, of moderate volume, and without blood, swamp-like (Fig. 3). In exceptional

Infectious diseases

cases, the stools may be watery and of great volume (“cholera-like”), or, in other

instances, of small volume and associated with tenesmus and gross blood (“shigellosis-

like”). Temperature elevations to 38-39 °C are common, as are chills; both appear in

the majority of patients in whom definitive diagnosis is established. Abdominal cramps

occur in about two-thirds of the patient and are often localized to the periumbilical

region or lower abdominal quadrants. Bowel sounds are increased and abdominal

tenderness is present. At microscopic examination, stool show a moderate number of

polymorphonuclear leukocytes and, occasionally, red blood cells. Cross blood is unusual

but may be seen in severe cases. Peripheral leukocyte count is usually normal, although

neuthrophilia with a shift to younger forms may be present.

The duration of fever is less than 2 days in the majority of cases. Diarrhea

usually persists less than 7 days, although, rarely, gastrointestinal symptoms may

last for several weeks. Prolonged fever and diarrhea suggest a complication or

a different diagnosis.

Localization of pain in the right lower quadrant of the abdomen in patients

with enterocolitis may lead to a diagnosis of acute appendicitis. At surgery, such

patients may have normal appendices or occasionally acute appendicitis rarely

with perforation.

Clinic of salmonellosis is characterized by symptoms of damage of

cardiovascular system. The basis of these violations is water-electrolytes loss

and change of reological properties of the blood.

Changes in organs of respiratory systems are not typical for uncomplicated

cases of gastrointestinal forms. But sometimes breathlessness may be observed.

Toxicosis takes place when localized forms of salmonellosis. It is manifested

by headache, pain in the muscles, mild ataxia, asymetric reflexes. Development of

toxic encephalitis is possible.

Electrolyte and water depletion may be severe during illness, leading to

hypovolemic shock. The disease is more severe in children, in seniors, and in

patient with achlorhydria, gastroectomy, gastroenterostomy, sickle cell anemia, or

other conditions that impair resistance to infection. The frequency of transient

bacteremia is less than 5 % in adults. It is increased in children and in persons

with severe preceded diseases. Bacteremia has been shown to occur in 8-16 %

of infants and children of 3 years age or younger who are hospitalized with

Salmonella enterocolitis. Salmonella intestinal infections has tendency to be

prolonged in children, who continue to excrete agent in stool for a longer time

than adults after subsidence of clinical manifestation of infection.

Salmonella enterocolitis may develop in hospitalized patients. The illness

may be a nosocomial infection or it may result of activation of pre-existing

asymptomic intestinal infection by antimicrobial therapy, of surgical diseases of

abdomen or from other causes.

In one-two third of children over 5 years and adults positive cultures are

observed during second or third week from the onset of the disease. In this time

majority of the patients have no symptoms of the disease.

73Salmonellosis

Salmonella can produce an illness characterized by fever and sustained

bacteremia without manifestations of enterocolitis. This syndrome may be caused

by any Salmonella serotypes. The clinical syndrome of salmonella bacteremia is

characterized by a hectic febrile course lasting for days or weeks. The organism

is isolated from blood, but stool cultures are often negative. More than 70 % of

cases of generalized forms of salmonellosis begin as gastrointestinal form with

dyspeptic manifestations. Then, in typhus like variant after subsidence of dyspeptic

manifestations the disease acquires signs of typhus infection. The second febrile

wave-like or incorrect type continues in most cases during 10-14 days. The principal

symptoms of the period of climax of the disease are weakness, adynamia, severe

headache, sleeplessness, pains of muscles and joints.

Typical typhus state is not characteristic for this variant of salmonellosis. In

majority of the patients enlarged liver and spleen, distantion of abdomen are observed.

Approximately, in 25 % of the patients scanty rose sports are observed. Rash

appears on 4-10 day, sometimes later. In peripheral blood leukocytosis is observed

only in early period of the disease. Then leukopenia is marked, but with neutrophilosis.

Sometimes typhus like variant may be without appearances of gastroenteritis. The

principal symptoms of beginning period in that cases are fever, chill, headache, weakness.

In the period of climax adynamia, pale skin, injections of scleras are observed.

There are single rose spots on the skin of abdomen and chest. In this

variant of generalized form of salmonellosis relapses may observed, and rarely,

complications, which are typical for typhus fever. Typhus like variant may be

with temperate manifestations of intoxication and dyspeptic appearances, with

short duration fever. There is marked catarrh, hyperemia of pharynx, laryngotra-

cheobronchitis in these patients rarely.

Septic variant (septicopyemia) is sepsis of Salmonella etiology. The

development of sepsis is evoked by sharp decrease of the immuneprotective

strengths of the organism of the patient. This variant of generalized of

Salmonellosis is characterized by acyclic development of the disease, prolonged

fever, chills, sweating, hepatosplenomegaly, sometimes development of jaundice,

plural purulent metastases in different organs and tissues.

Usually, the disease begins from manifestations of gastroenteritis. Then

typical septicopyemia develops with hectic fever. The signs of influence of

intoxication on central nervous system are marked from the first days of the

disease. They are manifested by irritation, violations of sleep, motive trouble,

sometimes delirium. The skin is pale. Rash may appear on the skin (petechias

or large hemorrhages).

The secondary purulent focuses may be in any organs and tissues. Localization

of infection may be in thyroid, brain membranes, bones, heart, lungs, kidneys,

adrenals, pancreas, spleen, liver, pericardium and soft tissues.

Complications

Meningitis is a rare complication of Salmonella infection and occur almost

exclusively in infants, particularly neonates. Even epidemics of meningitis have

Infectious diseases

been reported during outbreaks of Salmonella infection in hospital nurseries.

Clinical manifestations are the same as those of any bacterial meningitis in this

age group. The clinical course is usually long and marked by relapse. Acute

neurologic complications are common and include subdural empyema, cerebral

abscesses, and ventriculitis. Acute or chronic hydrocephalus may occur. Mortality

is high, despite appropriate antimicrobial therapy.

Pleuropulmonary disease. Pneumonia or empyema, the predominant types

of serious respiratory diseases, occur usually in elderly patients or in patients

with underlying diseases such as diabetes mellitus, malignancy, cardiovascular

disease, or pulmonary disease. Mortality is high.

Arterial infection. Salmonella infection may be with localization in major

vessels, including the thoracic and abdominal aortas, coronary arteries, peripheral

arteries. Atherosclerotic intrarenal aortic aneurysms are by far the most common

vascular sites of localization. The risk of endothelial infection is high in persons

over the age of 50 years who have Salmonella bacteremia.

The mechanism of arterial infection is through to be direct implantation at a

site of endothelial injury in the bacteremia patient on to extension from an

adjacent inflammatory lesion, such as vertebral osteomyelitis. Mortality is high.

Osteomyelitis and arthritis. Osteomyelitis can develop in normal bone but

especially likely to occur in patient with sickle – cell hemoglobinopathies, systemic

lupus erythematosus, immunosuppressive therapy, bone surgery or trauma.

Salmonella, not Staphylococcus, is the most common cause of osteomyelitis in

patients with sickle-cell anemia.

Salmonella may cause a metastatic supportive arthritis. Pyogenic arthritis

is much less frequent than reactive arthritis.

Splenic abscess and hepatic abscess. Splenic abscess is a rare complication

of Salmonella infection. Localization occurs after bacteremia in posttraumatic

subcapsular hematomas or splenic cysts. The clinical manifestation is one of

left upper quadrant tenderness, fever and leukocytosis.

Salmonella liver abscesses may occur. Usually, the patients have pre- existing

liver disease including amebic abscesses, ecchinococcal cysts, and hematomas.

Association with biliary tract disease exists in occasional cases.

Urogenital tract. Salmonella in stools of carriers or persons with acute

illness may gain access to the urinary tract to produce cystitis or pyelonephritis.

Localization of Salmonella blood form with abscess formation in kidneys, testicles,

or ovaries is also occasionally reported.

Bacteriocarrier of Salmonella is developed after disease. There are acute,

chronic and transitory carriers. Acute and chronic carriers are divided depending on

duration of excretion of Salmonella. Acute carrier has the duration of excretion of

Salmonella from 15 days till 3 months after clinical recovery. The persons, excreting

Salmonella over a year, are chronic carriers. The conditions of development of

transitory carrier are insignificant dose of the agent and its avirulence.

75Salmonellosis

Complications and outcomes of salmonellosis, as and multiple clinical forms

are exposed to wide oscillations. Even gastrointestinal forms of salmonellosis

with favorable duration are not finished clinical recovery.

Generalized form of salmonellosis, as rule, is accompanied by complications.

Exceeding expression of symptoms of salmonellosis frequently leads to collapse

(1.5-6 % of the cases). Collapse may develop at the first day of the disease on the

altitude of clinical manifestations before dehydration. Endotoxinemia plays leading

role in development of collapse. It is a manifestation of infectious-toxic shock.

Besides expressive hypodynamic disorders acute renal insufficiency, edema

of brain, edema of lungs and hemorrhagic syndromes develop. The development

of dysbacteriosis is connected with large doses of antibiotics use at any clinical

forms of salmonellosis. Dysbacteriosis may be compensated or latent.

Outcomes of salmonellosis depend on premorbidal state, age, clinical forms,

timely diagnostics and treatment.

Diagnosis

Diagnostics of salmonellosis is performed on the basis of epidemiological,

clinical and laboratory data. Bacteriological and serological methods are used for

confirmation of salmonellosis. The main materials for bacteriological investigation

are vomiting masses, water after irrigation of stomach, stool, blood, urine.

Serological investigations are used. These are reaction of agglutination (RA)

(7-8th day of the disease) and indirect hemagglutination (RIHA). RIHA is more

sensitive. It gives positive results on the 5th day of the disease. Diagnostical titer

is 1:200. Serological investigation should be done in dynamics of the disease.

Differential diagnosis

Differential diagnosis of salmonellosis is performed with other intestinal

diseases – shigellosis, toxic food-borne infections, esherichiasis, cholera; with

surgical diseases – appendicitis, pancreatitis, cholecyctitis, thrombosis of

mesenterial vessels; gynecological pathology and with therapeutic pathology

(myocardial infarction, chronic gastritis aggravation, enterocolitis, ulcerous disease),

with acute gastroenteritis of viral origin (enteroviral, rotaviral etiology), poisoning

by organic and inorganic poisons, poisoning by mushrooms.

Generalized form of salmonellosis is necessary to differentiate from sepsis

of different etiology, pneumonia, malaria, acute pyelonephritis, tuberculosis.

Treatment

The volume of medical actions depends on the clinical form and a stage of

gravity of disease. At gastrointestinal form immediately wash out stomach and

intestine with boiled water (isotonic solution of sodii chloridum is the best) then

give sorbents per os and give a warm drink. For restoration of hydro-electrolityc

balance and normalization of circulatory disorders there should be indicated per

os glucosole or rehydroni. Infusion therapy is indicated at expressed dehydration

Infectious diseases

– threesault, quartasault, lactasault. At severe stage of dehydratation one of the

specified solutions is infused in vein with rate 80-120 mL/min, 5-10 L of solution

is necessary on course of treatment. If hypotension and toxicosis are marked

prednisolon and hidrocortizon, polyglucin, reopoliglycin are infused in vein.

Pathogenetically 5 % solution of glucose is indicated with desintoxication purpose

and restoration of power balance, a solution of sodium hydrocarbonat for acidosis

correction, heparin for improvement of reologic properties of blood, preparations

of antiallergic action – calcii chloridi, dimedrol, tavegil, indomethacin are prescribed

in case of diarrhea (for inhibition of prostaglandines synthesis), calcium gluconate.

Antibiotics at gastrointestinal form of salmonellosis are not used.

However at syndrome of hemocolitis and lingering diarrhea furazolidon is

indicated in combination with fermental preparations – festal, panzynorm, pancreatin,

mezym-forte, pancitrat, vobensim. The broths of herbs has anti-inflammatory,

disinfectant and astringent properties, and also properties raising organism

reactivity. They are vitamin preparations, pentoxyl, methyluracil, thymalin, enterol-

250 also indicated. bificol, colibacterin, bifidumbacterin, linex is used at intestinal

dysbacteriosis.

At generalized form simultaneously with pathogenetic therapy there are

indicated antibiotics – levomycetin, ampicillin, monomycin, gentamycini sulfas,

cefazolin (kefzol), cefotaxim (claforan). At the septic form of disease antibiotics

are better to infuse parenteraly. For sanitation of chronic carriers of salmonelas

the specified antibiotics use in average therapeutic doses in combination with

preparations stimulating nonspecific and immunological reactivity (pentoxyl,

methyluracil, splenin, thymalin, T- activin).

Prophylaxis

The measures of prophylaxis are veterinary-surveillance upon animals and

production of meat and dairy industry, laboratory control of food stuffs.

It is necessary to reveal carriers on milk farms, in foods, children’s and

medical establishments. The maintenance of the rules of personal hygiene and

rules of food’s cooking plays an important role in prophylaxis of salmonellosis.

Control questions:

1. Etiology, epidemiology and incidence of salmonellosis.

2. Pathogenesis of salmonellosis.

3. Anatomic pathology of disease.

4. Main clinical symptoms and signs of salmonellosis.

5. Complications and outcomes of salmonellosis.

6. Laboratory methods of salmonellosis diagnosis.

7. Criteria of diagnosis.

8. Differential diagnosis of salmonellosis.

9. Treatment of salmonellosis.

10. Prophylaxis of salmonellosis.

77Ñholera

CHOLERA

Cholera is an acute anthroponosic infectious disease with fecal-oral mechanism

of transmission. Cholera is characterized by dehydration due to loss of the fluid

with watery diarrhoea and vomiting. Cholera is concerned to the group of the

diseases, which are submitted to “International medical-sanitary rules”.

Historic reference

Illness and death due to dehydrating diarrhea and vomiting can be recognized in

the writings of Hippocrates and Galen. The heartland of cholera is India, the Ganges

river’s delta. From there it has spred from time to time to many other countries.

There were 7 pandemic of cholera in the world. Fives pandemics of appalling

magnitude have occurred during the 19th century, spreading from India through

Asia Minor, Egypt and Russia.

In 1816 cholera broke out with unusual severity and high mortality in the

area of the Ganges river’s delta. Over the next 8 years it spread over much of

Asia and the Middle East, but did not invade Europe.

The great pandemic is of importance as being the first to invade Europe. It

started in India in 1828 and advancing slowly reached Iran in 1829, extending

thence by way of Astrakhan to Russia, Sweden, Northern Europe and England.

By 1832 it has spread over the whole Europe. In the same year 1832, it reached

Canada and thence extended to Fort Dearborn, where it infected the soldiers who

subsequently carried the disease down the Mississippi valley.

Cholera was also introduced into New York and Boston and spread from

there to south and west, so that by 1836 cholera was present in most parts of the

United States, not disappearing until 1838. It disappeared in Europe in 1839.

The next European outbreak, or third pandemic, lasted from 1844 to 1864

and was traced from India by the way of land and sea, that by land following the

caravan route by way of Iran and Russia and that by sea from Indian pilgrims

going to Mecca. This pandemic reached the United States in 1848.

The fourth great pandemic invaded Europe by the usual routes and continued

from 1865 to 1875. In 1865 it was carried by sea from Bombay to Arabia and

Mecca and was then spread by the returning pilgrims throughout Egypt, Syria,

and the Southern European ports to the East coast of Africa.

The fifth pandemic (1883-1896) began in India, reaching Egypt and Europe. It

was during this epidemic, in 1883 that Koch working in Egypt discovered the cause

of cholera, vibrio comma (Spirillum cholera). However, as the epidemic in Alexandria

soon subsided, he proceeded to India where, after a study of 42 cases of cholera and

28 autopsies, he gave confirmatory evidence of the etiology of the disease.

Infectious diseases

A very serious outbreak of cholera originated in 1891 in pilgrims from the

delta of the Ganges attending a religious festival. It was spread of cholera by

returning pilgrims and reached Europe in 1892. Almost a million deaths occurred

in Russia. It was during this epidemic that cholera appeared with great virulence

in Hamburg. In that city within 2 months there were nearly 17,000 cases and

over 8,000 deaths. This outbreak gave opportunity for those careful studies as

to the transmission of the disease to be later referred to.

It is usual to recognize a sixth pandemic (1900-1926) which began in Aravia

and spread over India, China and Philippines. This pandemic continued to cause

great mortality in Europe and from 1908 to 1910, there were reported some

71,000 cases and 26,000 deaths in Russia.

The seventh pandemic began in 1961. It is caused by a vibrio cholera El-Tor.

In 1905 Gotschlich isolated six peculiar strains of vibrio cholera from the

dead bodies of returned Mecca pilgrims at the quarantine camp of El Tor. These

strains, which produced hemolysins, came from typical cases of cholera and

agglutinated in the classical typing serum. However, not until 1961 when the “El

Tor” biotype produced an epidemic of major proportions in the Philippines was

there general agreement that hemolytic vibrio cholera could be responsible for

severe epidemic human disease.

Etiology

There are two forms of the vibrio cholera: classical biotype, which was

discovered by Koch in 1883 and El Tor biotype.

The vibrion is short. It is gram-negative and curved organism which, from

its shape, is often called the comma bacillus. Typically it is small, comma-shaped

rod. It frequently occurs in S-shapes, owing to the attachment of a pair of

organisms at their ends, and especially in the old and virulent cultures long

treads showing a somewhat spiral appearance may be seen. The vibrio cholera is

strictly aerobic and grows readily upon ordinary culture media. There are no

spores and capsules.

Vibrio cholera has two antigens – flagellar H-antigen and somatic O-antigen.

The somatic O- antigens do distinguish V. cholera Ogawa, Inaba and Hikojima,

which are responsible for epidemics.

V. cholera has 3 fractions of toxin. Cholerogen-exotoxin plays the most

important role in the development of dehydration. Cholerogen consists of two

types of toxin: cholerogen A and cholerogen B. Cholerogen A consists of peptide

A1 and peptide A2. Peptide A1 penetrates through the cells membrane. Then it

manifests the specific toxication. Peptide A2 connects peptide A1 with peptide B.

Peptide B is untoxic, it connects the whole molecule of toxin with cell receptors.

V. cholera survives in low temperature. The boiling kills V. cholera during one

minute. It survives in sea water (till 60 days).

Vibrio cholera is present in the intestine and in the rice water-like stool

during acute stage of infection.

79Ñholera

Epidemiology

Cholera is anthroponosic intestinal disease with tendency to pandemic spread.

Reservoir and source of infection is infected man. Discharge of vibrions is

realized with excrement.

The sources of infection may be sick man with typical or obliterated form

of cholera, reconvalescent after cholera and clinically healthy vibrio-carriers.

The patients with clinical picture of cholera are the most intensive source of

agents. They discharge till 10-20 liters of fluid with watery diarrhea during first

4-5 days of the disease with great content of vibrions (10

-10

vibrions in 1 mL).

The source of infection may be reconvalescents-vibriocarriers. They discharge

vibrions into environment in average during 2-4 weeks.

Healthy (transitory) carriers can discharge the agent periodically during

some month. The mechanism of transmission of the infection is fecal-oral. It is

realized by water, alimentary and contact ways. The leading way of the transmission

of the agents of cholera is water. This way may lead to epidemic distribution of

cholera. Infection may happen due to use of infected water and also after use

this water for wash of vegetables, fruits or bathing.

Food has also been implicated in some epidemics. The cases of cholera

were described due to infected milk use, boiled rice and other food-stuffs.

It is established that inhabitants of different water reservoirs (fish, crayfishes,

mollusks, frogs and other hydrobionts) are able to accumulate and preserve

vibrio El-Tor for a long time. They are temporary reservoir of infection and

may be factors of transmission of the agents.

The susceptibility to cholera is general and high. In endemic areas morbidity

is observed more frequently in children and elderly persons.

Pathogenesis

Cholera is cyclic infection with essential fermental systems damage of the

enterocytes. Vibrions cholera enter the organism through the mouth with water

or food. Some part of vibrions perishes under influence of acid medium of the

stomach. Another part of vibrions enters small intestine. Intestine reproduction

and destruction of vibrions is accompanied with discharge of large amount of

endo- and exotoxic substances. There is no inflammatory reactions.

Cholera is characterized by dehydration due to loss of fluid and salts with

watery stool and vomiting. Hypersecretory processes play the leading role in

the mechanism of the diarrhea origin. These processes are promoted by activation

of ferment adenylcyclase in the epithelial cells of the intestine under action of

exotoxin-cholerogen and accumulation of cyclic 3,5-adenosinemonophosphates,

leading to increase of secretion of electrolytes and water. In cholera the loss of

fluid with stool and vomiting reaches such a great volume in a short period,

practically not met during diarrhea of other etiology. The general volume may

exceed in some cases up to 2 times the body’s mass of the patient. The loss of

Infectious diseases

electrolytes plays essential role in pathophysiology of cholera. So, loss of potassium

may reach one third its content in the organism. It is manifested by disorder of

function of myocardium, damage of kidneys and also paresis of the intestine. In

cholera dehydration is isotonic. Fluid contains 135 mmole/L Na, 18 mmole/L K,

48 mmole/L HCO

and 100 mmole/L Cl (or 5g NaCl, 4g NaHCO

and 1g KCl

in 1 liter of defecations. An acute extracellular isotonic dehydration develops in

the patients with cholera. It is accompanied with decreasing of the volume of

circulated blood and hemoconcentration, leading to hemodynamic disorders and

violation of tissue metabolism. Hypovolemia, metabolic acidosis, hypoxia, thrombo-

hemorrhagic syndrome and acute renal failure develops.

Anatomic pathology

In cholera basic tragedy happens in a zone of the jejunal capillaries. Liquid

get into the intestine from them through the epithelium cells. A venous return is

diminished and as a result of that the heart’s return diminishes too. Blood

pressure decreases. The organism reacts with a tachycardia on that (there is no

cholera without tachycardia).

The other compulsory sign is decreased diuresis. It is explained by increase of

the water resorbtion by the renal canaliculi. If the loss continues venous flow diminishes

acutely. Tachycardia can not compensate it already and blood pressure decreases.

The organism includes a pressory mechanisms to preserve functions of the

vital important organs (heart, brain, kidneys). A capillary spasm begins. It improves

for some time blood supply of the heart and brain. Blood pressure is equated

but venous return decreases more. As a result of it oxygen transport to the

organs and tissues and metabolic products transport are violated. pH balance of

the organism changes to acidosis. The organism reacts on acidosis. It includes a

new compensatory mechanism. It is dyspnea. Respiratory alkalosis develops, but

it can not cause neutral pH balance due to violation of microcirculations.

A pressory mechanism is proper for kidneys too. The kidneys capillaries

are spasmated. Tissue acidosis develops. Resorbtion of water and products of

metabolism is alterated. That excludes the kidney as organ regulating homeostasis.

Renal filtration stops entirely under the decrease of blood pressure less than 80

mm. The kidney is sensitive for hypoxia. Hypoxia causes dystrophic changes in

the epithelium of the sinous canals.

These changes are reversible in case of moderate hypoxia (a renovation

period is not shorter than a week). But if the patient did not get from the

hypovolemic shock a necrosis of the sinous canals comes (death from anuria –

“shock kidney”). In case of prolonged loss of water all compensatory mechanisms

become unable to keep blood pressure. An original decompensation comes. It

coincides with the loss of the liquid equal to 8-12 % of the body’s weight. Then

the unreversable changes become and therapy is uneffective. The volume of loss

shouldn’t be more than 10 %.

81Ñholera

In accordance with WHO classification the patients with cholera may be

divided on three groups:

1. The first degree of dehydration. There are the patients which have loss of

fluid volume equaled to 5 % of body weight.

2. The second degree of dehydration. There are the patients which have loss

of fluid volume equal to 6-9 % of body weight.

3. The third degree of dehydration. The patients which have loss of fluid

volume over 10 % of body weight. That dehydration is dangerous for life if the

reanimation measures are not entertained.

According to classification of V. I. Pocrovsky patients can be divided in

four groups:

1. The first degree of dehydration with loss of fluid 1-3 % of body weight.

2. The second degree of dehydration with loss of fluid 4-6 % of body weight.

3. The third degree of dehydration with loss of fluid 7-9 % of body weight.

4. The fourth degree of dehydration with loss of fluid more then 10 % of

body weight.

It’s worth to underline that the clinical manifestation of the third degree of

dehydration (by the WHO classification) or the fourth degree (by classification

of V. I. Pocrovsky) is hypovolemic shock.

Clinical manifestations

Clinical manifestations of cholera, caused by classic vibrion and vibrion El-

Tor are similar.

Incubation period is from several hours till 5 days (in average 48 hours).

Cholera may be present in typical and untypical forms. In typical course the next

forms of the disease are differented in accordance with the degree of dehydration:

mild, moderate and severe form. In untypical course obliterated, fulminant forms

may be present.

The onset of the disease is an acute, as a rule. In case of mild course of

cholera the gradual development occurs in the part of the patients. The prodromal

period may be 1-1.5 days. The patients mark weariness, ailing, headache, sometimes

subfebrile temperature, heartbeating, sweet.

A diarrhoea is the first clinical manifestation of cholera. It appears suddenly,

without the pain, often at night or in the morning. Diarrhoea is accompanied by

gurgation in the stomach. After 1-2 defecation stool has typical shape. It is

cloudy, white, fluid, without smell and “rice water-like”.

The mild course (dehydration of the first degree). The loss of fluid is till

3 % of body weight. In majority patients stool may be till 10 time per day,

scanty. In one-third of the patients vomiting may occur 1-2 times. Thirst, light

dizziness, weakness trouble the patients. Their state is satisfactory. Skin is

humid, usual color. The mucous of the mouth is dry. There is no hypothermia.

Subfebrile temperature may be in the part of the patients. There are no changes

Infectious diseases

of the pulse and arterial pressure. An insignificant painfulment occurs due to

palpation of the stomach. The changes of the blood are not typical. There is no

blood condensation, changes of it’s pH and electrolytes balance.

After proper therapy a vomiting, dizziness, weakness disappear on the first

day. The stool become normal on the 2-3 day of the treatment.

Middle-severe course (dehydration of the second degree). The loss of

fluid is 4-6 %. There is considerable weakness, dizziness, thirst in patients. A

quantity of the defecation is from 10 till 20 times in a day. The stool is liquid,

plentiful. Dehydration appears already after 3-5 defecation at the half of the

patients. A vomiting is annexed early, and it is rice-water-like. The skin is pale.

The moderate cyanosis of lips and extremities may be in the part of the patients.

There is horse whishpering voice. Turgor of the skin decreases. The feature of

this degree of dehydration is appearance of the cramps without tonic tension.

The pulse is frequent up to 100 per minute. The arterial pressure is decreases

till 100 mm. There may be olyguria.

There are no changes of the red blood. Erythrocyte sedimentation rate (ESR)

is lightly accelerated. Leukocytosis, neutrophylosis with the shift of the formula to

the left, lymphopenia, monocytopenia and uneosinophilia occur in the part of the

patients. Hematocrit is 51-54 L/L. The relative density of the plasma is 1026-

1029. The change of electrolytes is insignificant. Hypokalemia and hypochlorinemia

are more expressed. Hypotension disappears usually through 20-30 minutes from

the onset of rehydration. Turgor is restored through 3-4 hours. The skin becomes

pink. A vomiting continues till a day. Rarely a vomiting is observed on the second

day. The stool becomes facesic through 1-3 days, and it becomes normal to 4-5

day. The general loss of the fluid is 5-7 liters in this patients.

Severe course (dehydration of the third degree) occurs more rarely,

approximately in 10 % of the patients. The loss of fluid is 7-9 % of body weight.

The detachment this degree of dehydration is connected with necessity of

prevention of development extremly severe course. There are no secondary

changes of the important system of the organism due to this degree of dehydration.

Because, it may be possible rapid compensation of dehydration and restoration

of electrolytes. The third degree is characterized by more intensive clinical

manifestations of dehydration and unfirm compensation.

The disease develops impetuously. The stool is watery, abundant from the

first hours of the disease. Sometimes the patient cannot count a quantity of

defecations. In patients sharp weakness, adynamia, severe thirst, cramps of the

muscles are observed. The state of the patients is serious and very serious.

A cyanosis of lips and extremities is observed. The skin is cold and shriveled.

The turgor decreases. The face is pinched, eyes are deeply sunken in the orbits.

In a third of the patients a symptom of “black eyeglasses” is observed. The

mucous of the mouth cavity is dry. The lips are dry too. Tongue is dry and

covered. A voice becomes hoarse. The cramps are often of long duration, with

83Ñholera

tonic character. Cramps are accompanied with pain. The cramps of the trunk

muscles and diaphragm are not observed. The temperature is 35.7-35.5

C. The

pulse is 120-130 per minute, weak. The arterial pressure is low 80/50 mm Hg.

Sometimes the breathlessness occurs. Renal failure is manifested with olyguria,

in 25 % of patient – with anuria. There are erythrocytosis, leucocytosis,

neutrophylosis with the shift of the formula to the left, lymphopenia, uneosinophilia.

The concentration of hemoglobin increases. Protein and leukocytes are observed

in urine. Hematocrit is 55-65 L/L in these patients. The relative density of

plasma is 1030-1035. There is considerable change of electrolytes. Hypokalemia,

hypochlorinemia are expressive.

Extremly severe course (dehydration of the forth degree) or decompensated

dehydration. It occurs more rarely than the other clinical variants. The loss of

fluid is 10 % of body weight and more. In this case the organism cannot compensate

the indigence of water-electrolytes balance and function of the significant organs.

It leads to hypovolemic shock. The relapsing vomiting is observed. Decompensated

dehydration may develop through 6-8 hours and even at the first 2-3 hours. The

state of the patients is serious and very serious. In the last hours diarrhoea and

vomiting may be absent. It is connected with paresis of the stomach and intestine

muscles, with hypokalemia and metabolic acidosis. At the same time there are

expressive symptoms of dehydration: cold clammy skin, intensive total cyanosis.

The color of the hand’s clusters, nouse, aural areas, lips and eyelids is violet

or black. The face is pinched, eyes deeply sunken in orbits. There is impression

of the suffering and entreaty about help on the face (facies cholerica).

The skin is shriveled. The turgor of the skin is decreased (“washwoman’s

hands”). A voice becomes hoarse. The temperature is 34.5

C. The generalized

tonic muscles cramps are observed, including muscles of the abdomen and back.

The agonizing hiccup may be due to clonic spasm of diaphragm. There is no

pulse. The arterial pressure is not determined. The breathing is frequent and

superficial. There is anuria. The condensation of the blood is observed. In

peripheral blood the concentration of hemoglobin increases. Expressive

leucocytosis, neutrophylosis, lymphopenia, uneosinophilia occur. Hematocrit is

higher than 66 L/L. The relative density of the plasma is 1036 and more. The

alterations of electrolytes are very expressive: hypokalemia, hypochlorinemia.

Hyponatremia is expressed in a smaller degree. Dehydration has isotonic character.

The deficit bicarbonium (more than 10mmol/L) leads to decompensated metabolic

acidosis and respiratory alkalosis.

Untreated patients die. The cause of the death is an acute heart’s failure (at

the first three days of the disease) or renal failure (up to 14-16 day).

Complications

The next complications may develop in patient with cholera: pneumonia,

sometimes abscesses, phlegmon. The number of complications are connected

Infectious diseases

with intensive therapy: pyrogenic reactions, phlebitis, thrombophlebitis,

hyperkalemia and other.

Diagnosis

The bacteriological research of material from the patient or corpse is the

principal method of laboratory diagnostics. The purpose of bacteriological method

is detachment of cholera¢s agent and it¢s identification.

The correct collection of the material has a great meaning for bacteriological

research as the delivery of material to the laboratory. A quantity of the material

is 0.1-0.2 gm, because the enormous quantity of the agent is contained at stool.

It is necessary to take a bigger quantity of the agent from the patient with light

form or carriers. The sowing is done to the dense or liquid nutritive mediums

near patient’s bed. If there is no possibility delivering of the material to the

laboratory, quickly, it is necessary adding of conservant, because vibrio cholera

begins to perish already at the first 1-2 hours in usual conditions. An alkaline

peptonic water is used for the sowing. The material for the sowing is necessary

to take till beginning of the treatment. The preliminary answer may be through

12 hours, the final – through 24 hours.

The serological methods may be also used for diagnostics of cholera. There are

methods of discovering antibodies to vibrio cholera in blood, the methods of detaching

antigens of vibrio cholera at stool and other materials. At the last years luminescent-

serological method is used. The result may be received through 1.5-2 hours.

Differential diagnosis

Differential diagnostics of cholera is performed with toxical food-borne infections,

esherichiosis, rotaviral gastroenteritis. In some untypical cases of cholera, especially

in obliterated course of the disease it is necessary to perform differentiation of

gastrointestinal form of salmonellosis, gastroenterocolitic variant of acute shigellosis,

poisoning with mashrooms, organic and inorganic chemical remedies.

Treatment

Patients needs immediate hospitalization in choleric department. They require

emergency treatment which should be started at the pre-admission stage. It’s

necessary to prescribe pathogenetic preparations with the purpose of

compensation of liquid and electrolytes loss, and corrections of metabolic changes.

Isotonic polyionic solutions – threesault, acesault, lactasault, quartasault, hlosault

are indicated. Quartasault is more effective.

Quantity of liquid, which should be infused for initial rehydratation (during

1-2 hours), should correspond to stage of the organism dehydratation. At III and

IV stages of dehydratation it makes accordingly 7-9-10 % of body weight and

more. Polyionic solutions infuse in vein initially-stream introduction, then

volumetric rate 70-120 mL/minute. To infuse liquid with such rate, it is necessary

to use simultaneously two and more systems for transfusion. Stream introduction

85Ñholera

of liquid is replaced by dropwise infusion after normalization of pulse, restoration

the arterial blood pressure and normalization of body temperature,

hemoconcentration and acidosis.

The next infusions of polyionic solutions is determined by rate of proceeding

loss of water and salts. The compensatory rehydratation is provided during

several days in severe cases. For definition of its volume it is necessary every 2

hours to determine quantity of excrements and vomitive masses to investigate

clinical (a pulse rate, the arterial pressure, body temperature) and every 4 – 6

hours laboratory (relative density of blood plasma, haematocrite number,

concentration of electrolytes in blood plasma and erythrocytes, pH, concentration

of standard Sodii hydrogenii) parameters.

For prevention of side reactions of polyionic solutions should be preliminary

warmed up to 38 – 40 °Ñ, at the first hours of treatment infuse prednisolon 0.5

gm/kg per day. At infusion there is plenty of solution threesault the metabolic

alkalosis and hyperkalemia can be developed. In these cases infusion therapy is

continued with solution desault.

It cases of not compensated hypokalemia it is necessary to infuse preparations

of potassium in addition. At a pernicious vomiting, cramps, anaphylactoid reaction

dimedrol or suprastin with promedol should be used. As at patients with severe

course of cholera the clotting develops, cordiamin, coffein or epinephrin of

hydrochlorid is contrindicated.

In case of I-II stages dehydration (liquid loss up to 6 % of body weight)

and more severe dehydration is managed by intravenous injection of saline

solutions, at absence of vomiting recommend to apply peroral indication of

glucosani in tablets or rehydroni in packages 18.9 gm: dissolve the content of 1

package in 1 L of boiled water and drink small portions.

Water-salt therapy should be over after appearance of excrements of normal

character and at prevalence of quantity of urine over quantity of excrements in

the last 6-12 hours.

Panangin or asparcam during 1 month are indicated during early

reconvalescence.

Antibiotics are the additional remedies. They accelerate clinical convalescence

and prevent the further allocation of choleric vibrioes. A remedy of a choice is

ciprofloxacin: 0.25-0.5 gm 2 times per day, in serious cases enlarge up to 0.75-2

times per day during 5-7 days or erythromicin, or laevomycetin. Tetracyclin and

doxycyclin are effective. However, for the last years the majority of choleric vibrio

culture, allocated on territory of Ukraine, appeared not to be sensitive to this antibiotic.

For sanitation of vibrio carriers use the same antibiotics during 3-5 days.

Complications of rehydration. It may be pyrogenic reaction to solutions,

hypokalemia, hyperkalemia.

Hypokalemia is observed more than 25 % of the patients with III degree of

dehydration. The clinical manifestations are: distention of the stomach, pain in

the stomach (hypokalemitic ileus).

Infectious diseases

The next formula may be used for correction of potassium:

where 1.44 – coefficient,

P – weight of the patient,

X – contant of potassium in patient’s serum.

5 – normal content of potassium in blood serum.

Hyperkalemia develops in 15 % of the patients. The clinical manifestations

are: red face and upper part of the body, cardialgia, typical changes of ECG,

bradycardia. In this case it is necessary to inject Phillips solution ¹2. Phillip’s

solution ¹ 1 is injected again after signs of hyperkalemia elimination.

Etiotropic therapy is performed with antibiotics. Antibiotics cause shortening

of diarrhoea duration and give possibility to decrease a quantity of fluid for injection.

Doxicycline is prescribed in dose 0.1 mg through 12 hours at the first day,

than 0.3-0.5 mg through 6 hours during 3 days. Tetracycline is used for teratment

of the patients with cholera in dose 0.3-0.5 mg through 6 hours during 5 days. It is

possible to use chloramphenicol in 0.5 mg dose through 6 hours during 5 days.

Prophylaxis

The measures of prophylaxis depend on epidemic situation in the country.

The information of world health organisation about cases of cholera in different

countries has an important meaning.

The incidence of disease can be diminished by sanitary-hygienic measures,

sanitary disposal of human feces, purification and protection of water supplies,

pasteurization of milk and milk products, strict sanitary supervision of preparation

and serring of flood exclusion of persons with diarrhea from handling food,

organization of the work about diseases of gastrointestinal tract and their

examination on cholera.

Specific prophylaxis of cholera is performed by corpuscular vaccine and

cholerogen-anatoxin.

Parenterally inoculated killed complete cell vaccine has been available for

years, this vaccine stimulates high titers of serum vibriocidal antibodies, but it

does not induce antibodies to toxin. Protection by vaccine has been induced for

approximately 1 years, with vaccine efficacy approximately 70 %. Local

gastrointestinal tract immunity against the organism and against the toxin should

provide a better, less reactogenic immunogen using recombinant DNA technology

an “attenuated” V. cholerae organism that lacks the genes for production of the

A and B subunits of toxin was created. A plasmid containing the subunit gene

was then constructed and inserted. Thus a candidate live V. cholera vaccine

containing all the cell-was antigens necessary for adherence and the capacity to

produce only the subunit of toxin has been engineered.

=−×× )5(44.1 XP

mL of 1 % KCl,

87Ñholera

Control questions:

1. Definition of cholera.

2. Etiology of cholera.

3. Classification of clinical forms of disease.

4. Clinical symptoms and signs of cholera.

5. Differential diagnosis with toxic food-borne diseases, esherihiosis, salmonellosis, shigelosis,

poisoning by salts of heavy metals.

6. Classic bacteriologic cholera diagnosis, methods of express-diagnosis.

7. Dehydration during cholera (dehydration primary, compensatory).

8. Etiotropic therapy and medical supervision after contacts with cholera patient.

9. Preventive measures in spot of cholera outbreak: quarantine measures, observation,

disinfection measures, immediate prophylaxis of cholera, specific prophylaxis and terms

of discharge from the hospital.

Infectious diseases

BOTULISM. TOXIC FOOD-BORNE DISEASES.

CAMPYLOBACTERIOSIS

BOTULISM

Botulism is a life-threatening infectious disease, produced by neurotoxins elaborated

by Clostridium botulinum. Botulism is characterized with intoxication of the organism

with the principal damage of the central and vegetative nervous system.

Historic reference

Because early accounts of botulism frequently incriminated sausages, the

name of the disease was derided from the Latin word for sausage – “botulus”.

Outbreaks of “sausage poisoning” were common in Germany during the nineteenth

century, and Justinius Kerner, poet and physician, published several monographs

on the subject. For a time, botulism was known as “Kerner’s disease”. Investigating

an outbreaks in 1895, the Belgian bacteriologits Van Ermengem performed classic

experiments in which he isolated the causative anaerobic spore-forming bacillus

from the incriminated ham and demonstrated that both the ham and a toxin

produced by the organism could induce a paralytic illness in cats.

Etiology

Clostridium botulinum is à gram-positive, anaerobic and forming spores

bacillus. Eight immunologically distinct toxin types have been described (types

A, B, C, D, E, F, G. Types À, Â and E most commonly cause disease in man; types F

and G have only rarely caused human illness. Types Ñ and D are associated with

animal botulism, especially in cattle, ducks and chickens.

One of the peculiarities of the agent is mobility. It is connected with presence

of flagellars. The spores of C.botulinum are heat resistant; they can withstand

100 °C for hours. Fortunately, the toxins are rather heat labile; boiling for 10

minutes or heating at 80°C for 30 minutes destroy them.

All serotypes of Ñlostridium botulinum produce neurotoxin. Neurotoxin is

protein, it consists of 19 aminoacids. Neurotoxin of Clostridium botulinum is

one of the most strong natural poisons.

Epidemiology

Botulism is saprozoonosis. The spores of C.botulinum are ubiquitous in

soil; the distribution of type A and B spores is worldwide. The principal reservoirs

of the agent of botulism are grass feeding animals, and rarely fish, mollusks and

crayfishes which absorbing the spores of C.botulinum with water and food.

89Botulism. Toxic food-borne diseases. Campylobacteriosis.

The human is infected by botulism due to use of the contaminated food by

spores. The greatest part of the cases of botulism is connected with use home-

canned food, for example mushrooms, vegetables, fish, meat and other.

The disease occurs under three circumstances: 1) botulism food poisoning

results from eating food that contains preformed toxin; 2) wound botulism occurs

when toxin is produced by C.botulinum organisms contaminating traumatic

wounds; 3) infant botulism is due to toxin production by C.botulinum within the

gastrointestinal tract of infants.

Pathogenesis

The vegetative forms of the agent and botulotoxin enter into the human

organism due to use contaminated food-stuffs. The action of the toxin is intensified

in the stomach under influence of proteolytic enzymes. The people are more

sensitive to serotypes of toxin A, B, E.

The toxin are absorbed primarily from the stomach and small bowel. The

digestive enzymes do not destroy the toxin molecules. The toxins interfere with

neurotransmission at peripheral cholinergic synapses by binding tightly to the

presynaptic membrane and presenting the release of the neurotransmitter

acetylcholine. Adrenergic fibers are spared. The effect of botulinus toxin on

cholinergic pathways in the central nervous system remains in dispute. The

motoneurones of spinal cord and oblong brain have special sensitiveness to

botulism. The bulbaric and paralytic syndromes develop as a result.

Hypoxia plays the leading role in the pathogenesis of botulism. The

development of progressive respiratory insufficiency is connected with depression

of the activity of the large motoneurones, innerving the respiratory muscles.

Anatomic pathology

The pathologoanalomic alterations in botulism have nonspecific character.

They are connected with deep hypoxia. There are hyperemia of the internal

organs, edema of the cerebrum, small hemorrhages into mucous membrane of the

gastrointestinal tract.

Clinical manifestations

The incubation period ranges from 2-12 hours till 10 days (in average 6-24

hours). There are the next leading syndromes in botulism: paralytic, gastrointestinal

and intoxicative syndromes. The onset of the disease is, as a rule, an acute. In

patients pain in the epigastric area, nausea, vomiting, diarrhea occur. The vomiting

and diarrhea are not prolonged. The temperature is normal or subfebrile. The

rapid fatigue, progressive muscle’s weakness are marked. The symptoms of the

defeat of the muscles, of cranial nerves and paralytic violations of innervation of

the internal organs develop through 3-4 hours after the onset of the disease.

These violations are characterized by symmetrical defeat.

Infectious diseases

The first typical signs of botulism are usually dryness in the mouth (Fig. 4)

and ophthalmoplegic symptoms. The patients complain of vision disorders, “net”

or “fog” in front of the eyes. The patients cannot read, because the paresis of the

accommodation and diplopia develop. Medriasis (Fig. 5), decreased reaction on

the light, the limitation of the eyes motion, sometimes full inmotility, ptosis (Fig. 6),

squint, horizontal nystagmus are observed.

The violations of the swallow and speech are early observed. These violations

is connected with damage of IX and XII nucleuses of cranial nerves pairs. In

patients dysphonia, dysarthria, nose shade of the voice are marked. The paresis

of the throat muscles develops. In the patients dysphagia appears as a result.

The liquid is poured out through the nose.

Botulism is accompanied with functional disorders of cardiovascular system.

The widening of the heart’s borders and muffed heart sounds are observed.

The violations of the functions of the gastrointestinal tract are accompanied

with dryness of the mucous membranes of the mouth, thirst, distention of the

abdomen, retention of stool, and intestine paresis.

The large motoneurones of the neck’s and chest’s portions of the spinal

cord are involved into the process. This process leads to development of paresis

and paralysis of the muscles. The patient may breathe with difficulty. The patient

must accept special position. The cough’s reflex disappears. The disorder and

break of breath is one of the leading causes of the death at botulism.

In terminal period the appearances of myoneuralgia are observed: myasthenia

and adynamia. The muscles have like-dough consistence. The recovery comes

slowly, during 1-1.5 months.

In peripheral blood moderate leukocytosis, neutrophylosis are marked with

shift of the formula to the left. In botulism the prognosis is always serious. When

adequate therapy is not applied the lethal outcomes compose near 25 %.

Diagnosis

The diagnosis is made on the basis of clinical manifestations of the disease,

epidemiological data and results of the laboratory researches. The toxin and the

agent may be revealed in the materials, collected from the patient (blood, vomitory

masses, water after irrigation of the stomach, stool) and also at the suspicious

food-stuffs. The reaction of neutralization may be used for revelation of toxin.

Differential diagnosis

Botulism may be confused with the Guillant-Barre syndrome, poliomyelitis, stroke,

myastenia gravis, tick paralysis, and poisoning due to curare or belladonna alkaloids.

Treatment

The first aid (independently of term, that pasted from the beginning of

disease) consists of careful lavage of stomach and intestine with 2-5 % solution

of a Sodii carbonate. It is necessary to remember, that at muscles paralysis of

91Botulism. Toxic food-borne diseases. Campylobacteriosis.

pharynx, larynx and tongue, the probe may penetrate into a trachea, therefore

before lavaging it is necessary to be convinced that the probe is in stomach.

After lavaging prescribe enterosorbent-SKN, enterodes, sillard P.

Medical antibotulism serums are injected at first hours of the disease.

Before determination of species of the infection inject mixture of serums types A

and E 10,000 IU and type B on 5,000 IU. After definition of specie of infection

monovalent serum is used. In serious cases during 1st day 4 – 6 medical doses

of serum are prescribed, 2 of them – intravenous by drops in isotonic solution of

Sodii chloride or 5 % solution of glucose. Before injection of serum intracutaneous

test is made. Serum is injected according the method of fractional deallergization

depending on degree of disease gravity during 2 – 4 days. Etiotropic agent is

specific treatment with homological plasma 250 mL, 1-2 times per day.

Nonspecific desintoxication therapy consists of injection of glucose solution,

polyionic solutions (lactasault, threesault, quartasault) and simultaneously diuretics

– furosemid (lasix).

For suppression of infection in a digestive tract ampicillin, oxacillin, levomycetin

or tetracyclin are indicated. A course of antibiotic therapy lasts for 5-7 days.

In serious cases and for prophylaxy of serum disease prednisolone on 40

mg per day or its analogues is indicated. At disorders of respiration of the

patient he is required to hospitalize to reanimation departament and transfer on

controlled artificial respiration immediately.

At failure of cardiovascular system there are prescribed cordiamin,

sulfocamphocain, cardiac glicosides, at disorders of nervous system – vitamin

preparations of group B, cocarboxylase, riboxin. At allergic reactions, development

of a serum disease there are used prednisolone, antihistaminics – suprastin and

also calcy gluconate, phencarole, terfenadin.

Prophylaxis

The observance of the sanitary and hygienic rules at processing, transportion,

keeping and preparing of the food-stuffs experts possibility of accumulation of

botulotoxin. It is necessary to perform the strict control under sterilization and

keeping preserved food-stuffs.

The explanation to the people of the rules of the procurement and preservation

of food-stuffs in home conditions has important value especially such food-stuffs

as meat, mushrooms, vegetables.

TOXIC FOOD-BORNE INFECTIONS

Toxic food-borne infections are acute transitory diseases, caused by

conditionally pathogenic bacteria. These bacteria are capable to produce exotoxin

(in food-stuffs). The disease is accompanied with symptoms of the damage of the

upper parts of the gastrointestinal tract (gastritis, gastroenteritis) and by violation

of the water-electrolyte balance.

Infectious diseases

Etiology

Many types of the conditionally pathogenic bacteria may be agents of the

toxic food-borne infections and produce exotoxin out of the human organism on

the different food-stuffs. Enterotoxins (thermoliable and thermostable) increase the

secretion of the fluids and salts into the stomach and intestine. Cytotoxins damage

the membranes of the epithelial cells and violate the protein synthetic processes.

The agents, producing enterotoxins are Clostridium perfringeus, Proteus vulgaris,

Proteus mirabilis, Bacillus cereus. These enterotoxins are also formed by agents

from the families of Klebsiella, Enterobacter, Citrobacter, Serrafia, Pseudomonas,

Aeromonas, Edwarsiella. The majority of these enterotoxins are thermoliable.

Epidemiology

Pathogenic organisms of the toxic food infections are widely spread in the

nature. They may be everywhere: in the fecal matters of human and animals; in

the soil; in the water; in air and on the different subjects. The way of the spread

of the infection is alimentary. The factors of the transmission of the disease are

solid products (sausages, eggs, meat and fish canned food) and liquid products

(soup, milk, juices, compotes, jellies, lemonade, beer, cocktails). They are the nutritive

mediums for bacteria.

The susceptibility to this group of diseases is very high, sometimes till 90-

100 %. The typical sign of the toxic food-borne infections is not only group but

explosive character of illness due to all participants of the outbreak become ill

during a short period (over a few hours). The toxic food-borne infections are

registered during the whole year, but especially in summer.

Pathogenesis

In toxic food infections exotoxin is contained in food, besides bacteria. Due

to this the incubation period is very short. Time of the of clinical manifestations

development after influence of toxins to the mucous membrane is from 30

minutes till 2-6 hours.

Pathogenesis and clinical manifestations of the disease depend on the type

and dose of exotoxin, and also from other toxical substances of microbial origin,

containing in the food-stuff. Enterotoxins (thermoliable and thermostable) are

connected with the epithelial cells of stomach and intestine and act to the fermental

system of the epitheliocytes, but don’t cause morphological changes in these

organs. Enterotoxin activates ferments adenylcyclase and guanylcyclase, increasing

formation of the biological active substances (cyclic adenosinemonophosphates

and cyclic guanidinmonophosphates) in the cells of the mucous membranes. All

these changes lead to the increase rate of secretion of water and salts into the

stomach and intestine and to the development of diarrhea and vomiting.

Anatomic pathology

Cytotoxins damage the membranes of the epithelial cells and violates synthetic

processes. It may increase the permeability of the intestinal wall for different

93Botulism. Toxic food-borne diseases. Campylobacteriosis.

types of the toxical substances, and for oneself microorganisms, development of

intoxication and violation of microcirculation and localized inflammatory alterations

of the intestinal mucous membrane.

Clinical manifestations

The clinical manifestations of the toxic food-borne infections caused by only

enterotoxins are less severe. In the majority of the cases of the disease there is

no fever and just considerable inflammatory changes of the mucous membrane

of the stomach and intestine.

The course of the disease become more severe due to accumulation of

enterotoxin and cytotoxin in the food-stuffs. The high fever and considerable

change of the mucous membrane of the gastrointestinal tract are observed.

In toxic food-borne infections there is combination of the signs of the damage of

the gastrointestinal tract (gastritis, gastroenteritis or gastroenterocolitis) and signs of

the general intoxication and dehydration. The incubation period is from 30 minutes to

24 hours (generally 2-6 hours). The beginning of the disease is an acute. At first the

nausea occurs. Frequently the replated, agonizing and unrestrained vomiting occurs.

Almost at the same time with vomiting the diarrhea starts. Stool is watery from 1 to

10-15 times a day. In considerable part of patients the disease is not accompanied by

severe pain in the stomach and increase of the body temperature of the body. However

the disease may be with spasmatic pains in the stomach, with the raise of the body

temperature up to 38-39 °C. The raise of the body temperature takes place at the early

hours of the disease and through 12-24 hours the temperature is reduced to normal.

During objective examination of the patients the pale skin, sometimes cyanosis,

cold extremities are observed. The tongue is coated. Stomach is soft and painful

in the epigastrium during palpation. The cardiovascular system also suffers.

There is bradycardia (during hyperthermia – tachycardia). The arterial pressure

decrease. In some cases collapse of short duration develops. Due to repeated

vomiting and plenty diarrhea the signs of dehydration develop. It may be possible

of the appearance of the muscle’s cramps of extremities, decrease of the diuresis

and reduced turgor of the skin. The liver and pancreas are not expanded. In

hemogram leukocytosis, neutrophylosis and temperate accelerate ESR are noted.

The duration of the disease in majority of the cases is 1-3 days. The toxical

food infection may be accompanied by severe complications. Hypovolemic shock

and an acute heart insufficiency, connecting with violations of electrolytic balance

(hypokalemia) are observed.

Diagnosis

The diagnosis of the toxic food-borne infections is made according the results

of the clinical symptoms estimation, epidemiological and laboratory data. The typical

signs are the impetuous development of the disease after short incubation period,

presence of symptoms of gastritis, gastroenteritis or gastroenterocolitis in

combination with intoxication, dehydration, disposition to the vascular dystonia.

Infectious diseases

It is necessary to consider the simultaneous disease of the group of the

persons, use one itself food-stuff, the features of this product, sanitary-hygienic

state of commercive institutions, public nutrition when taking epidemiologic data.

It is necessary to reveal the sick men or bacteriocarries among personnel of

these institutions, because they may be a source of infection of the food.

Materials for bacterial examination are suspicious food products, vomitory

masses, water after irrigation of the stomach, stool of the patient. Serological

methods does not have independent meaning in the diagnostics.

Differential diagnosis

Differential diagnosis of toxical food infection is performed with acute intestinal

infections (cholera, acute shigellosis, gastrointestinal form of yersiniosis, rotoviral

gastroenteritis, campylobacteriosis, dyspeptic variants of preicteric period of viral

hepatitis and others), with surgical diseases (acute appendicitis,

cholecystopancreatitis, thrombosis of mysentrical vessels, perforation of ulcers in

the stomach and duodenum), with gynecological diseases (ectopic pregnancy,

toxicosis of the pregnancy), with therapeutic diseases (myocardial infarction,

hypertension crisis), with neurological diseases (acute failure of cranial blood

circulation, subarachnoidal hemorrhage), with urological diseases (pyelonephritis,

acute renal failure). During the diagnostics it is necessary to consider the food

poisoning, poisoning by mushrooms, salts of hard metals.

Treatment

It is necessary to wash out a stomach and intestine to release them from

microbes and toxins as soon as possible. For a lavage it is better to use isotonic

solution of sodium chloridum, boiled water or 1-2 % solution of sodium

hydrocarbonate. Then give inside the activated microspherical coal (SKN brand).

Alternative preparations are sillard P, smecta, enterodes and other enterosorbents.

Their early indication promotes the fastest improvement of health state, preserves

intoxication, development of the serious form of bacterial endotoxicosis. In case

of development of infection-toxic shock we should immediately infuse in blood

colloid and cristaloid solutions: polyglucin, reopoliglycin, donor albumin, threeisault,

acesault, quartasault, and also glucocorticoides.

Etiotropic treatment is indicated only at serious forms with development of

colitic syndrome: furazolidon or enteroseptol. Antibiotics are indicated in case of

development of sepsis – levomycetin, gentamicin, ampicillin, ofloxacin (or tarivid).

Prophylaxis

Prophylaxis of the toxical food infection is concluded in prevention of infection

of the food-stuff, of the reproduction of the microorganisms in the food. It is necessary

to keep the food-stuffs and prepared food at the temperature from 2 till 4

The mechanization and automatization of the food objects, the elaboration of

the new methods of the preserving and storage of the food-stuff, the freezing at low

temperature are conductive to the successful prophylaxis of the toxical food infection.

95Botulism. Toxic food-borne diseases. Campylobacteriosis.

CAMPYLOBACTERIOSIS

Campylobacteriosis refers to the group of the infections caused by gram-negative

bacteria of the genus Campylobacter. Among the most common bacterial infections

of humans in all parts of the world, campylobacters cause, both diarrhoeal and

systemic illnesses and are highly associated with gastritis and peptic ulcer disease.

Campylobacter is derived from the Greek “campylo”, meaning curved, and “bacter”,

meaning rod, so named to distinguish this genus from identically appearing vibrios.

Etiology

Campylobacters are motile, non-spore-forming, comma-shaped gram-negative rods.

Originally isolated from aborted sheep fetuses in 1909, these and similar organisms

were called Vibrio fetus. There are now 14 recognized species within the genus.

Three types of illnesses are associated with Campylobacter species-enteric,

extraintestinal, and gastric. For each of these illnesses one Campylobacter species

predominates while other species are less commonly present. The prototype for

enteric infectionis C. jejuni, for extraintestinal infection it is C. fetus, and for

gastric infection it is C. pylori.

The campylobacters can be distinguished from other microorganisms oh the

basis of several standard criteria and can be distinguished from one another on

the basis of biochemical testing. Similar to other bacteria whose ecologic niche is

the gastrointestinal tract of mammals, the serotypic diversity of C. jejuni is enormous.

More than 90 different serotypes based on somatic O-antigens and 50 different

serotypes based on heat-labile (capsular and flagellar) antigens have been identified.

Epidemiology

Campylobacteriosis is a worldwide zoonosis. Campylobacters are commonly

found as commensals of the gastrointestinal tract of wild or domesticated cattle,

sheep, swine, goats, dogs, cats, rodents. Primary Campylobacter infections of

animals often occur early in life and may produce morbidity or mortality, but in

most infected animals a lifelong carrier state with specific immunity develops.

The vast reservoir in animals is probably the ultimate source for most enteric

Campylobacter infections of humans.

Direct contact with infected animals may result in transmission. Household

pets, especially young dogs and cats with diarrhea, have been implicated as

vectors for campylobacteriosis.

Since healthy dogs, cats, rodents, and birds may

excrete campylobacters.

As with other enteric pathogens, fecal-oral person-to-person transmission of

C. jejuni has been reported. Those in contact with the excreta of infected persons

who

;

are not toilet trained (such as infants) are themselves at risk for infection.

Perinatal transmission, from a mother who was not necessarily symptomatic

may be due to exposure in utero, during passage through the birth canal, or

during the first days of life.

Infectious diseases

Campylobacter jejuni infections occur year-round, but with a sharp peak òî

summer and early fall. Campylobacter fetus infections show the same seasonal

variation, but the peak is less marked.

Campylobacter jejuni and other campylobacters are important causes of

the acute diarrheal illnesses suffered by travelers visiting developing areas.

Pathogenesis

Not all Campylobacter infections produce illness. Although all factors

responsible for this phenomenon are not known, two of the most important

appear to be the dose of organisms reaching the small intestine and the specific

immunity of the host to the pathogen ingested. Among exposed persons who

become ill, the incubation period varies from 1 to 7 days, a characteristic that is

probably inversely related to the dose ingested.

Anatomic pathology

Campylobacter jejuni multiplies in human bile, a characteristic that aids

colonization of the bile-rich upper small intestine early in infection. The sites of

tissue injury include the jejunum, ileum, and colon, with similar pathologic features in

each. Inspection of affected tissues may reveal a diffuse, bloody, edematous, and

exudative enteritis, but pathologic examinations are generally performed on patients

with the most severe cases. Microscopic examination of rectal biopsy specimens

has shown a nonspecific colitis with an inflammatory infiltrate of neutrophils,

mononuclear cells, and eosinophills in the lamina propria; degeneration; atrophy;

loss of mucus; crypt abscesses in the epithelial glands; and ulceration of the mucosal

epithelium. Campylobacter outer membranes contain lipopolysaccharides with typical

endotoxic activity. Extracellular toxins with cytotoxic activities have been found, and

classic enterotoxins have been demonstrated, although generally at low concentrations.

Infected persons do not develop neutralizing antibodies to these toxins.

Clinical manifestations

The clinical manifestations of infections due to all of the Campylobacter

species that cause enteric illnesses appear identical, Ñ. jejuni may be regarded as

the prototype. Acute enteritis is the most common presentation of C. jejuni infection.

Symptoms may last from 1 day to 1 week or longer. Often there is a prodrome

with fever, headache, myalgia, and malaise 12-24 hours before the onset of intestinal

symptoms. The most common symptoms are diarrhea, malaise, fever, and abdominal

pain. Diarrhea may vary from loose stools to massive watery stools or grossly

bloody stools. Campylobacter enteritis is frequently self-limiting, with a gradual

improvement in symptoms over several days; however, illnesses lasting longer

than 1 week occur in about 10-20 % of patients seeking medical attention, and

relapses may be seen in another 5-10 % of untreated patients.

Infection may also be manifested as an acute colitis, with symptoms of fever,

abdominal cramps, and bloody diarrhea persisting for 1 week or longer. Fever

may be low grade or consist of daily peaks above 40 °C. Initially, stools may be

97Botulism. Toxic food-borne diseases. Campylobacteriosis.

watery, but as the illness progresses it may become frankly bloody; tenesmus is

a common symptom. Because of the propensity of Campylobacter infection for

young adults and this presenting clinical picture, it may be readily confused with

ulcerative colitis or Crohn’s disease.

Occasionally, acute abdominal pain may be the major or only symptom of

infection. Although any quadrant of the abdomen may be affected, it has been

right lower quadrant pain that has elicited the most attention. As with Yersinia

enterocolitica and Salmonella enteritidis, C. jejuni may cause pseudoappendicitis.

In most cases, the removed appendix has shown minimal or no inflammation.

Enlarged mesenteric nodes (mesentericadenitis) and terminal ileitis also may be

responsible for the symptoms.

Fever also may be the sole manifestation of C. jejuni infection. Temperature

elevation may be so severe and persistent that typhoid fever is the initial diagnosis

until C. jejuni is isolated from stools. Febrile convulsions in young children

before the onset of the enteric phase of illness also may occur.

Campylobacter fetus infection. In contrast to C. jejuni, C. fetus less

frequently causes diarrheal illness. Campylobacter fetus infection may cause

intermittent diarrhea or nonspecific abdominal pain without localizing signs.

The diarrheal illness may be manifested exactly like C. jejuni infection. Clinical

manifestations are similar, and sequel are uncommon. Campylobacter fetus also

may cause a prolonged relapsing illness characterized by fever, chills, and myalgias,

without a source of the infection being demonstrated. Occasionally, secondary

seeding to an organ will occur and lead to a more complicated infection and

sometimes to a fulminant fatal course.

Campylobacter fetus infections appear to have a tropism for vascular

sites; vascular necrosis occurs in patients with endocarditis and pericarditis.

Thrombophlebitis may be associated with C. fetus bacteremia, but whether it is

the primary event or a secondary manifestation of the infection is uncertain.

Infections during pregnancy primarily have been manifested by upper respiratory

symptoms, pneumonitis, fever, and bacteremia. Central nervous system (CNS)

infections with C. fetus occur in neonates and adults. The prognosis is poor for

premature infants. Infection is manifested as a meningoencephalitis with a

cerebrospinal fluid polymorphonuclear pleocytosis; subdural effusion may

complicate, infection.

Campylobacter fetus has been shown to cause a variety of other types of

localized infections, including septic arthritis, spontaneous bacterial peritonitis,

salpingitis, lung abscess, empyema, cellulitis, urinary tract infection, vertebral

osteomyelitis and cholecystitis.

Diagnosis

A clinical diagnosis of enteric campylobacteriosis may be made by demonstration

of the organisms in direct microscopy of feces or isolation of the organisms. The

use of serologic methods for diagnosis is at present a research only.

Infectious diseases

Differential diagnosis

Campylobacteriosis could take dysentery-like course, in this case it should be

differentiated with shigellosis, salmonellosis, esherichiosis, intestinal yersiniosis, intestinal

invagination. The main common signs of all these diseases are abdominal ache,

hemocolitis, intoxication. For correct diagnostics the characteristic clinical signs of

campylobacteriosis and corresponding laboratory findings should be considered.

Treatment

Fluid and electrolyte replacement are the cornerstones for treating diarrheal

illnesses. Patients with Campylobacter infections who are badly dehydrated

should undergo rapid volume expansion using intravenous solutions of electrolytes

in water. For those with less severe depletion, oral rehydration using glucose

and electrolyte solutions.

C. jejuni is susceptible to a wide variety of antimicrobial agents, including

erythromycin, the tetracyclines, aminoglycosides, chloramphenicol, nitrofurans.

C. fetus infections requires parenteral therapy, and erythromycin is not

always effective. When isolates are susceptible, ampicillin treatment has been

associated with good results. Patients with other serious infections also should

be treated with parenteral gentamicin or other aminoglycosides, ampicillin, or

chloramphenicol for at least 2 weeks.

Prophylaxis

Antimicrobial prophylaxis is effective, but because of increasing drug

resistence and the possibilities of side effects, are recommending to avoid

antimicrobial prophylaxis and, instead, use care in their consumption of

contaminated food and water.

Control questions:

1. Etiology of botulism.

2. Epidemiology and pathogenesis of botulism.

3. Basic clinical manifestations of botulism.

4. Principles of botulism treatment.

5. Prophylaxis of botulism.

6. Etiology of toxic food-borne infections.

7. Sources and ways of transmission of infection.

8. Clinical features of toxic food-borne infections.

9. Differential diagnosis of toxic food-borne infections.

10. Laboratory methods of diagnosis and their estimation.

11. Prophylaxis of toxic food-borne infections.

12. Infectious agents of campylobacterioses.

13. Epidemiology of campylobacterioses.

14. Clinical manifestations of campylobacterioses.

15. Principles of campylobacterioses treatment.

16. Prophylaxis of campylobacterioses.

99Pseudotuberculosis

PSEUDOTUBERCULOSIS

Pseudotuberculosis is an acute infectious disease characterized by the

polymorphism of the clinical manifestations, affection of the alimentary tract,

locomotor system, liver and other organs, general intoxication, exanthema and

frequently prolonged course with relapses.

Historic reference

The French scientists L. Malasser and W. Vignal first reported on the

pseudotuberculosis microbe. In 1883 they isolated it from the organs of a guinea

pig infected with the suspension of the caseous regenerated lymph node of the

child who had died from “tuberculosis” meningitis.

In 1885 C. Eberth introduced the term “pseudotuberculosis” when he observed

spontaneous epizootic in the rabbits, it was accompanied by an abrupt emaciation

of the animals. At the post-mortem examination of the dead animals the anatomic

pathological changes of the timer organs looked like the tuberculosis ones, but it

was impossible to discover the tuberculosis pathogen, and the morphological

characteristics of the isolated pathogen were identical to the microbe.

In 1889 A.Pfeiffer studied the characteristics of this microbe in detail and

gave it the name “Bacterium pseudotuberculosis rodentium”, he connected the

isolation of this pathogen with a certain clinical picture in animals.

Etiology

The pseudotuberculosis microbe is a polymorph bacillus, which does not

form spores and often has an ovoid form. It is Gram-negative, well painted by all

aniline dyes. The question of a capsule in the pseudotuberculosis bacteria is still

under discussion. The pseudotuberculosis bacteria grows at a temperature of 4-

30 °C are actively mobile, have flagellum, whose length is 3-5 times bigger than

the length of the body of the bacterial cell. At a temperature higher than 30 °C

the flagellum atrophy and the mobility of the bacteria ceases. The

pseudotuberculosis microbe is a facultative anaerobe, it is quite undemanding to

the nutrition, and that is why it grows well on the common dense nutrient media,

it can grow on the media without peptone. This characteristic of the pathogen

was used to distinguish the pseudotuberculosis bacteria from the plague pathogen.

The bacteria contain H-antigen and O-antigen, which determine their

variability. The H-antigen is thermolabile and is destroyed at boiling, it is

synthesized at a temperature of 2-30 °C best of all.

Different biologically active substances, which are necessary to initiate and

develop an infectious process, are produced in the process of the yersinia pathogen

100

Infectious diseases

vital activity. Besides this it is established that the yersiniosis pathogen strains

of different pathogenicity circulate in the human population.

Epidemiology

Before the 60s of the 19th century the epidemiology of the human yersiniosis

was almost unstudied. It is explained by the fact that the disease appeared in the

form of sporadic cases. In such situations it was often impossible to discover

the pathogen, find the disease source, discover the mechanism of its spreading.

The situation changed when the Far East scarlatiniform fever mainly manifested

by massive epidemic outbreaks was brought to light in the Far East.

Yersiniosis mainly embraces the urban population as in the cities there are

more opportunities for the development of big outbreaks among the contingents

of people united by public feeding. On the other hand, a more active revealing

and better diagnostics of the disease as compared with the rural area is of a

certain importance. Children fall ill the most often as compared with the other

age groups of the population. The epidemic outbreaks are quite often observed

in the organized collectives, especially, the preschool ones. First of all such

outbreaks depend on the conditions of the fruit and vegetables storage as well as

the condition of feeding the population.

Animals are a reservoir of the infection under the natural conditions. The

pseudotuberculosis microbe was isolated from the organs and excrement of

many kinds of the mammals, birds, reptiles, fish and arthropoda. Such a diverse

and spontaneous infection of many kinds of animals by the pseudotuberculosis

microbe gives a ground to think that none of them are a specific biological host

of this pathogen and it testifies that in case its ubicvator spreading in nature all

kinds of animals get involved in the general process of the microbe circulation

and serve as a short-term or prolonged reservoir of the pathogen depending on

the species susceptibility to it.

Rodents are the most frequent reservoir of the pseudotuberculosis microbe.

It is explained by the fact that on the one hand, rodents are distinguished by a

high susceptibility and sensitivity to the pseudotuberculosis microbe and on the

other hand, they are considerably widespread on the Earth and the speed of

their replication is high.

The infection of humans can occur at a direct contact with domestic and

wild animals, birds while skinning them and processing the carcasses. A possible

mechanism of the infection of humans is using the food and water contaminated

by the discharge of rodents and birds – carriers of the pseudotuberculosis

microbe. Besides this there is a number of convincing investigations confirming

that soil is a reservoir of the pseudotuberculosis pathogens. The authors think

that the pseudotuberculosis microbe cannot exist in the soil for a long time

without reproduction as it cannot form spores. It has saprophytic and parasitic

characteristics and correspondingly has two natural biospheres of existing – the

101Pseudotuberculosis

warm-blooded animals and environment. The pseudotuberculosis pathogen was

isolated during the bacteriologic investigation of the soil from the fields where

vegetables and edible roots, as well as wash-outs from them (beet-roots, carrots,

cabbages, onions, potatoes).

The epidemiological examination of many outbreaks of the disease made it

possible to ascertain that among all the food staffs vegetables, edible roots, dry

food, some dry products, which are eaten without any thermal processing, are of

the most importance in the pathogen transmission. The importance of vegetables

and edible roots as a factor of the pathogen transmission was proved by the

isolation of the pseudotuberculosis microbe from them during the outbreaks, the

microbes were identical by their serologic variant to the cultures isolated from

the sick people who had eaten that food. Such outbreaks most often occur when

dishes from fresh cabbage are used as food at the public feeding places.

Besides vegetables and edible roots, the second important factor in the

pseudotuberculosis pathogen transmission is dairy products. Such dairy products

as cottage cheese, sour cream are the most important. It is necessary to note

that the pasteurization of milk (at a temperature of 65 °C for 30 minutes) does

not destroy the pathogen.

Water can also be a factor of the pseudotuberculosis microbe transmission

under the favorable conditions.

Pathogenesis

The pathogens mainly penetrate the human organism through the mouth

with the infected food and water. A further movement of the microbes to the

esophagus and then stomach characterizes this phase. The acid medium of the

stomach contents ruins most pathogenic microbes of the intestinal group perhaps

including the pseudotuberculosis pathogen. Having overcome the stomach barrier,

the pathogen gets into the intestines and an enteral phase develops, it is

characterized by the penetration of the microbe into the mucous membrane of

the intestines, then it goes to the regional mesenteric lymph nodes along the

lymph paths. Here they reproduce and accumulate, later overcoming the lymphatic

barrier the bacteria penetrate the blood and cause the reciprocal reaction of the

organism to the toxic substances, which get into the blood vessels during the

destruction and life of bacteria.

In rare cases an airborne way of infection, even marking out a pulmonary

form of this infection. The pseudotuberculosis microbe possesses pneumotropism

with the development of pneumonia and even lung abscess. As the clinical

picture of pneumonia develops in later terms of the disease in experimental

pseudotuberculosis, the lungs may be only an entrance gate for the development

of the generalized process. Taking into account all the mentioned above facts,

there is a ground to suppose that irrespective of the entrance gate

pseudotuberculosis immediately takes a course of a generalized infection.

102

Infectious diseases

The pathological process can stop at any of its phases. The pathogen of the

disease can be blocked by the secretory immunoglobulins even on the mucous

membranes of the intestines and respiratory tracts. While overcoming this barrier

yersinia pseudotuberculosis penetrate the regional lymph nodes. Different

macrophagal elements, immunoglobulins and immunocompetement cells take

defensive measures.

The clinical process has periods of remissions and acute conditions. The

recovery occurs after any phase. Thus, in human pseudotuberculosis there are

two expressed pathogenic stages: 1) the pathogen penetration, primary and regional

focal manifestations of the disease; 2) bacteriemia, hematogenic drift and septicemia,

which develops, as a rule, after the first period, though sometimes it is not

expressed distinctly.

The hematogenic dissemination of the pseudotuberculosis pathogen results in

the development of the phase of the secondary focal changes in the organs and

tissues. As a rule, this stage is accompanied by an expressed organism allergization.

The following phase of the pseudotuberculosis pathogenesis development is

the phase of the specific immunity increase, which is followed by the release of

the organism from the pathogen and recovery. Cultivating a strong antimicrobic

immunity completes the disease. The possibility of the development of the disease

chronic form is very rare.

Anatomic pathology

The pathoanatomists have found small necrotic or abscess-like grayish-white

nodes in the enlarged liver and spleen, as well as in the lungs. Many researchers

call these abscesses necrotic granulomas. Such granulomas with the central necrosis

are considered to be a characteristic symptom of pseudotuberculosis. Besides this,

there is swelling and necrosis of the lymph nodes follicles of the intestines and

mesentery, hyperemia of the peritoneum covering them, edema and infiltration of

the distal part of the iliac and proximal part of the large intestine, catarrhal-

desquamative and ulceric enteritis (ileitis), congestion plethora, brain edema, dystrophy

of the parenchymatous organs and hemorrhages in them. In some cases there is a

picture of catarrhal, phlegmonous and gangrenous appendicitis.

Clinical manifestations

The diversity of the pseudotuberculosis clinical manifestations, the

involvement of different organs and systems in the pathologic process are the

basis for the suggestions of numerous classifications of this disease. The least

cumbersome classification, though it does not lack drawbacks, is the classification

by N.U. Zalmower, which is based on the syndrome principle with the following

clinical forms:

1. A scarlatiniform characterized by the general intoxication symptoms, fine-

dot rash, fever.

103Pseudotuberculosis

2. An arthralgic form resulting in the joints affection, it takes a course of

arthralgia, less often – arthritis.

3. An abdominal form with the primary affection of different parts of the

alimentary tract, sometimes in the initial period.

4. A generalized form with the affection of different organs and systems

when it is impossible to pick out any main syndrome.

5. An icteric form, in which the affection of the liver with a jaundice syndrome

is the primary symptom.

The clinical manifestations of pseudotuberculosis are characterized by a

great polymorphism with the prevalence of the general intoxication, which makes

an early diagnostics extremely difficult. As well as other acute diseases

pseudotuberculosis has a certain cyclic recurrence. The development of the

cycle’s periods with a certain time limitation, which is accompanied by different

morphologic, immunologic and clinical changes, results in a characteristic picture

of the disease. There are following periods in pseudotuberculosis: an initial

period, a high point, a period of acute courses and relapses, convalescence.

Evaluating the descriptions of the clinic given in the literature and observing

the patients, it is necessary to note that in each certain case these periods can be

manifested in different ways depending on the reactivity of the macroorganism,

virulence of the pathogen, the time when the treatment began, the quantity of the

daily and course doses of the medications and other factors. All the periods of

the disease can be observed in the typical cases in half the patients (especially, in

case of the pathogenic therapy and short courses of some antibiotics). In other

cases some of them cannot be observed or they can be slightly manifested.

There can be only some symptoms of the initial period without a temperature

rise in the deleted forms of the disease.

Judging by the epidemiological history, the incubation period in this infection

most often lasts 7-10 days with the fluctuations from 3 to 18 days. In this period

the disease does not usually have any clinical manifestations, the people consider

themselves to be practically healthy and continue working.

The initial period is the time when the first symptoms of the disease develop

till the highest possible development of the clinical picture with the symptoms of

the local affection.

In most patients the disease has an acute course with a rapid temperature rise,

which is accompanied by chills. The prodromal phenomena in the form of malaise,

slight chills, the development of uncertain pains in the abdomen, which developed

1-2 days before the onset of the disease, were described only in some cases.

This period is clinically characterized by expressed polymorphism and

absence of specific symptoms typical of only this disease. The temperature rise

is accompanied by a headache of different intensity with its primary location in

the forehead and temple areas, pain in the muscles, joints, waist, general asthenia,

weakness and lack of appetite. In a number of cases the sick people complain of

104

Infectious diseases

the pain in the throat at swallowing. In some cases patients complain of pain in

the stomach, diarrhea 2-3 times a day, nausea and single or recourse vomiting.

There is brief fainting in some patients in the first hours of the disease together

with general asthenia. An early toxicosis resulting in a lethal outcome can develop

in rare cases, especially, in children during 2-4 days.

While examining the patients it is possible to observe hyperemia of face and

neck, some puffiness of the face, hyperemia of the conjunctiva and an injection of

the sclera vessels, there is a pale nose-lip triangle in some patients. There is often

herpetic rash on the lips and the nose wings, expressed hyperemia of the throat,

which is of different intensity, less often – an enanthema on the soft palate, angina.

During the first days of the disease the tongue has a grayish-white patch, which

begins to clear and becomes raspberry with expressed papilla on the third day.

There are symptoms of acute catarrh of the upper respiratory tract such as a

running nose, cough, pains in the throat at swallowing in most patients in the initial

period of the disease. Similar symptoms of the disease sometimes result in diagnosing

catarrh of the upper respiratory tract and difficulties in deciphering the outbreak.

Such diversity of symptoms testifies about the involvement of different organs

and systems in the pathological process even on the first days of pseudotuberculosis

infection, which is often the reason for a false diagnostics in this period. The most

part of such patients are treated at home, the smaller part is sent to a hospital with

the diagnoses: acute respiratory disease, polyarthritis, gastroenteritis, catarrhal angina,

scarlatina and others. These diagnoses often remain the final ones as a doctor

examines a patient for a second time only in the period of convalescence and does

not pay attention to some important symptoms of the disease (rash, “raspberry”

tongue, pain in the ileocecal area, etc.)

Rash is one of the most striking symptoms of this period. It develops on

the 1-4th day of the disease, sometimes on the 5-6th day. According to its

character it is often fine-spotted on the hyperemic background or normal skin.

During the first outbreak of the disease in some patients it is fine-spotted, and in

combination with angina, the enlargement of the submandibular lymph nodes,

“raspberry” tongue, the development of peeling typical of scarlatina in the later

period gave a ground to first diagnose “scarlatina” in all patients. Later during

the development of other pseudotuberculosis outbreaks and the exposure of the

sporadic cases of this disease it was found out that the rash can be spotty

(looking like German measles and measles) and confluent erythematous. The

spreading of the rash can be different, if it is spread all over the body, it is mainly

located on the symmetrical parts. The rash is not often found on the face and

neck. There is often hyperemia and swelling of the skin on the hands and feet –

the symptoms of “gloves” and “socks”. The petechial-hemorrhagic elements are

mainly localized in the natural folds of the skin and on each side of the chest.

The development of hemorrhages in the form of stripes and changes on the side

surfaces of the shoulders and in the area of the armpit line. There are endothelial

105Pseudotuberculosis

symptoms of plait, pinch with hemorrhages in the patients with a severe form.

The development of rash can be accompanied by the deterioration of the patients’

condition, pulse acceleration, hypotonia and even a collapse condition.

There is scaly laminar peeling on the skin of the chest, abdomen, lobes of

the ear and then on the dorsal surface of the hands, feet, palms during the 2-3rd

week of the disease. The duration of the initial period is 1-5 days.

The highest point of the pseudotuberculosis infection is manifested by the

maximum development of fever and other symptoms of intoxication and expressed

signs of the local affection. The highest point of the disease, especially, the first

days are characterized by considerable intoxication, which is manifested by the

affection of the central nervous system – general asthenia, hypotonia, dizziness,

intense headache, tactile hyperesthesia, photophobia, vomiting, insomnia, increased

excitability or suppression. In a severe course there are manifestations of

meningoencephalitis with the symptoms characteristic of it: a headache, nausea,

vomiting, drowsiness, suppression, consciousness disorders, signs of irritation of

the meninges and the substance of the brain. There are such meningeal symptoms

as rigidity of the neck muscles, Kernig and Brudzinsky symptoms, in the cerebrospinal

liquid the cytosis is more than 400 cells, the increased protein contents. Besides

the mentioned symptoms there are characteristic disorders of the vegetative nervous

system function. In some patients the affection of the nervous system is similar to

the intercostal and nape neuralgia or lumbosacral radiculitis.

The changes of the locomotor system are observed almost in all patients.

There is often arthralgia, sometimes with very intense pain in the sacrum, waist,

joints and less often – acute polyarthritis, which is characterized by swelling of

the tissues around the joints with skin hyperemia. The radiocarpal, interphalangeal,

knee and ankle joints are most often affected in pseudotuberculosis, less often –

shoulder and hip joints. Acute polyarthritis is often confused with the attacks of

acute rheumatism in case of the poor knowledge of the pseudotuberculosis

clinic. The pain syndrome depends on the severity of the disease and can be

weak or strong, hindering free movement. The joints are swollen, painful, hot.

Most patients complain of myalgia in the acute period of the disease. It

prevails in the muscles of the neck, abdomen, and extremities. In some cases

myalgia of the abdomen muscles is sharply expressed, which simulates “acute

abdomen”. In such cases it is necessary to pay attention even to slight

manifestations of other symptoms of the disease.

The submaxillary, neck and axillary lymph nodes can be enlarged in the

acute period of the disease. They are slightly painful, elastic, not united with one

another and the surrounding tissue.

The changes of the cardiovascular system at the highest point of the disease

are manifested by hypotonia, dullness of the heart sounds, and in some patients

there is a systolic murmur at the apex and extrasystole. In spite of the fact that

in a considerable number of patients the subjective symptoms of the heart

affection (pain, heartbeat, arrhythmia, and others) are extremely rare, the

106

Infectious diseases

electrocardiograms show changes, some of them are considerable. The decrease

of P and T waves voltage is the most frequent of them, less often – the deformation

as a result of the toxic-infectious influences on the cardiac muscle. There were

sometimes symptoms of its diffusive affection.

The respiratory organs also get involved in the pathological process in

pseudotuberculosis. Pain in the throat, hyperemia of the fauces mucous membrane,

spotted enanthema on the mucous membrane of the soft palate, rhinitis, cough,

dry rale in the lungs testify of their affection. There is dulling of the percussion

sound over the pulmonary fields and moist rale in the limited areas in some

patients who suffer a severe course of the disease. The x-ray investigations

usually demonstrate the intensification of the bronchial-vascular picture, the

opacity of the roots, less often – infiltration of the lung tissue.

In a mild case of the disease the affection of the alimentary tract is manifested

by complaints of a poor appetite, nausea, less often – vomiting diarrhea. The

stool is fluid or watery 3-5 times a day with admixture of mucous. The pain at

the abdomen is observed in a half of the patients and is often revealed only at

palpation. The tongue is furred, it becomes raspberry when it gets cleaned.

The changes of the alimentary tract are strongly expressed and prevail

over the rest ones in a more severe course. In this case a pseudotuberculosis

abdominal form is diagnosed. It is characterized with a pain in the epigastric area

of the abdomen, umbilical or right iliac area, less often -in the right hypochondrium

and left iliac area. The abdominal syndrome is clinically revealed primarily in the

form of the symptoms of mesenteric lymphadenitis, terminal ileitis, acute

appendicitis. Mesenteric adenitis of the pseudotuberculosis etiology without any

other manifestations is quite often observed in the countries of Western Europe.

The affection of the mesentery lymph nodes can occur in different periods of the

infectious process, more often in the initial period and at the high point of the

disease. In this case there is pain in the right iliac and paraumbilical area, the

palpation demonstrates an enlarged, painful and “grumbling” cecum and mesenteric

lymph nodes. Such patients come to hospital with various diagnoses: “acute

appendicitis”, “acute cholecystitis”. These patients can come to both infectious

and surgical hospitals, and only the carefully collected history of the disease and

the clinical investigation data allow to diagnose pseudotuberculosis.

The intensity of pain in the ileocecal area can be different. In some patients

that is revealed only at palpation, in others there are constant aches, in some

patients they are so intense that the patients groan and take a forced position

with their knees pulled to the abdomen. The patients cannot remain in the same

position for a long time. The pain subsides and ceases troubling the patients on

the 2-3th day from the time of their appearance. However, in 3-4 days they

recommence and become more intense.

The local manifestations of mesadenitis are usually accompanied by general

symptoms. They are temperature increase, sometimes up to 39 °C, chills, which

intensify with the development of pain in the abdomen, diarrhea – 2-3 stools a

107Pseudotuberculosis

day without admixture of mucous or blood, nausea, and vomiting in almost half

of the patients. Besides the patients complain of headaches, pains in the joints of

the upper and lower extremities, body muscles, general asthenia, sore throat.

The skin of the face, neck, chest is often hyperemic in the patients with

mesenteric lymphadenitis. In certain cases there is fine-spotted rash, which rise

above the skin in the area of the chest, abdomen, groin folds, axillary region,

forearms and thighs, the rash gets pale at pressing.

There is muscles tension and other symptoms of the peritoneum irritation, which

are very similar to the picture of the “acute abdomen” in case of a severe course of

the disease. However, in contrast to acute appendicitis in the mesadenitis patients the

pain in the abdomen do not increase when the abdominal press is strained. This new

symptom was observed in all the cases of pseudotuberculosis mesadenitis.

The clinic of acute appendicitis in pseudotuberculosis has its peculiarities

connected with the fact that besides the affection of the vermicular process the

patients have the manifestations of the main disease. As a rule, the patients, in

whom the appendicular syndrome develops during treatment in the infectious

hospitals or who arrived with the diagnosis “pseudotuberculosis” and have an

expressed appendicular syndrome are not operated on, and the disease has a

favorable outcome after the conservatory treatment. It is natural that such patients

should be carefully observed by both an infectious doctor and a surgeon in order

not to miss authentic appendicitis, whose pathogen can be pseudotuberculosis

along with other microbes. It is known that the pseudotuberculosis microbe is

isolated in about 7 % cases during the bacteriological investigation of the processes

ablated during the appendectomy. The surgical aspects of pseudotuberculosis are

of a great practical interest and need to be thoroughly studied.

Regional ileitis in the abdominal form of pseudotuberculosis is more often

observed in the relapse and remission period of the disease. In this case the

pains in the abdomen develop on the background of the seeming convalescence,

they are accompanied by a recurring rise of the body temperature up to 38-39 °C

and chills. The pain is usually moderate, it is of attack-like character. In 2-3 days

from pain development it becomes less intensive, in some cases it ceases troubling

a patient. However, on the 3-4th day they increase and become very intense.

In some patients pseudotuberculosis begins with the symptoms of regional

ileitis. In such cases the pseudotuberculosis symptoms are poorly expressed. This

results in the diagnostic mistakes. In case of regional ileitis the pain in the stomach

is often accompanied by nausea. In half of the patients there is vomiting, sometimes

repeated. The affection of the terminal part of the ileum can be accompanied by

watery stool up to 3 times a day without an admixture of mucous and blood. The

abdomen is sometimes bloated. The right iliac area is the most painful, there is also

muscle tension of the front wall of the abdomen. The similarity of the clinical

picture of regional ileitis to that of acute appendicitis is a characteristic feature. In

many cases it is extremely difficult to diagnose the case before a surgery.

108

Infectious diseases

The patients with the pseudotuberculosis abdominal form often have

gastroenteritis. Its development can be observed in all periods of the disease.

Gastroenteritis usually has a rapid development. The disease starts with pain in

the abdomen, nausea, vomiting, it is usually accompanied by the abdomen inflation,

watery or pasty stool up to 2-3 times a day, general asthenia, chills, headache and

other pseudotuberculosis manifestations. Sometimes gastroenteritis takes a chronic

course. In these cases patients complain of the periodic pain in the abdomen,

which disturb them, general asthenia, headache, general malaise. The stool in such

patients is unstable. There is an expressed asthenia right after the meals. The

pains in the abdomen can resemble attacks and do not have a distinct localization.

The symptoms of the general intoxication are often expressed.

The affection of the alimentary system is not only limited by the pathologic

changes of the gastrointestinal tract. The liver affection of any degree is often

observed in almost half of the patients, actually it is acute parenchymatous hepatitis,

its expressiveness depends on the severity of the disease. The affection of the liver

is manifested by the enlargement of its size, icteric color of the skin and scleras, the

bilirubin increase in the blood, it sometimes resembles the clinic of viral hepatitis.

The thorough comparison of the clinical symptoms with the biochemical

investigations shows the involvement of the pancreatic gland in the pathologic

process. The patients complain of pain in the abdomen, which resembles attacks

and is localized in the epigastric area, in the right and left hypochondrium. In

some cases it irradiates in waist or back. The patients complain of nausea,

vomiting and general asthenia. There can be watery stool. The amylase level of

blood and urine as well as the lipase activity in blood can confirm the diagnosis.

Some authors pay much attention to elastase. In 1986 V. A. Ivanis noted that the

elastase level depended on the severity of the disease and its indexes normalized

in the period of convalescence.

The generalized form of the disease is characterized by the combination of a

high temperature, exanthema, and severe intoxication with all the main syndromes

of the disease: terminal ileitis, parenchymatous hepatitis, acute polyarthritis,

meningeal symptoms and a long relapsing character.

Diagnosis

There are no reliable diagnostic tests on pseudotuberculosis among the

nonspecific laboratory signs. In particular the blood clinical analysis is not

informative. The changes of the morphological blood contents do not take place

in all the patients and are of a moderate character.

The specific laboratory diagnostics of pseudotuberculosis is very important

in its diagnosing. It is of primary importance in the mild and unexpressed forms

of the disease, especially, occurring in the form of separate sporadic cases.

The main material for the bacteriologic investigation is excrement and in

lesser degree – washouts from the fauces, urine and the appendicular processes,

which are ablated during the surgery. The pseudotuberculosis patients excrete

109Pseudotuberculosis

bacteria with mucous from the fauces, excrement, urine. The duration of their

excreting with mucous and urine is not long. The pseudotuberculosis pathogen

is found in excrement during all the disease and in the period of relapses. In

separate cases it can be excreted with excrement for about 75 days.

The serologic investigations began to be done after the discovery of the

Far East scarlatiniform fever. In the beginning the agglutination reaction with

alive cultures as an antigen was used, later a reaction of indirect hemagglutination

as well as the reaction of the bacterial lysis, method of fluorescent antibodies and

others. In spite of the fact that the pseudotuberculosis diagnostics is improving

every year, it does not satisfy the practical doctors so far. The percentage of the

bacteriologic confirmation of the diagnosis remains low, and the reaction of

indirect agglutination, which is used everywhere, is not enough sensitive and

specific. The reaction of coagglutination and immune ferment analysis, which

make it possible to discover both the antigen and antibodies to it during the first

3-5 days from the disease onset, is considered to be promising.

Differential diagnosis

The variety of pseudotuberculosis clinical manifestations often causes big

amount of diagnostic errors. Thus, acute beginning, intoxication, headache, cough,

face reddening can be considered as influenza. Fever, intoxication hepatomegaly,

lymphadenopathy, sore throat make us think about infectious mononucleosis. In

case of catarrhal manifestations, intoxication, characteristic skin eruption measles

and rubella should be excluded. The list of diseases to be considered in process

of pseudotuberculosis differential diagnostics could be continued. So such main

disease characteristics should be taken into account in order to make correct

diagnosis: period of disease, its recurrence, polyorganic disorders due to

pseudotuberculosis, correct interpretation of laboratory findings. Sometimes only

results of bacteriologic research can verify the diagnosis.

Treatment

It is impossible to agree with the recommendations of some author about

the possibility of treating the pseudotuberculosis patients at home. In spite of

some positive results the possibility of sudden acute forms development and

relapses obliges to treat the patients only in hospital and to follow thoroughly

the regimen and an according nursing.

The patients do not need a special diet. The nutrition is typical of the

patients with an acute fever. The food should be easily assimilating and high-

calorie, containing a sufficient amount of vitamins. A daily food allowance should

contain 3,200-3,500 kcal. The patients with the predominant liver affection, are

prescribed diet ¹ 5 containing a sufficient amount of carbohydrates and a

limitation of fat, especially, refractory.

The treatment depends on the clinical form, the period and gravity of disease.

Among etiotropic agents there are used levomycetin, metacyclin, tetracyclin,

110

Infectious diseases

streptomycin, gentamicin, ampicillin in moderate therapeutic doses during not

less than 7 days and more. At severe course of disease, the septic form the best

results can be gained if simultaneously use 2-3 antibiotics and one of them infuse

into vein: course of treatment prolongs up to 10-14 days, and through 6-7 days it

is replaced by preparations with the account of antibioticosensitivity of allocated

yersinias. Cefazolin (kefzol), cefotaxim (claforan) are effective as alternative

preparation may be bactrim (biseptol). Less effective are nitrofuranes and

sulfanilamid preparations.

With the purpose of desintoxication and rehydratation of the organism 5 %

solution of a glucose, a seralbum, reopolyglycin, threesault, quartasault are indicated.

Widely there are used vitamins, antihistamine preparations and agents stimulating

regenerative processes – diprazin, suprastin, tavegil, methyluracil (methacil), pentoxyl,

apylac, natrii nucleinic, thymalin etc. At gastroenterocolitic form enterosorbents (activated

microspherical coals, sillard P, enterosgel, smecta), replaceable fermental therapy

(festal, pancreatin, pancurmen, pancitrat), diet ¹ 4 are indicated. Colibacterin,

bificol and other biological preparations are indicated in case of development of

dysbacteriosis. At acute tonsillitis gargles should be indicated. Development of

arthritis, myocarditis, Reiter syndrome is the indication to use indomethacin,

ibufrofen, diclofenac-natrii (ortophen) and other not steroid preparations.

All the patients are prescribed vitamin therapy in the form of complex B,

vitamins A, C, PP and others.

The therapeutic tactics should be strictly individual in case of every patient

who is to be constantly looked after. Only an individual approach and a complex

of the treatment measures can bring invariable success and allow to achieve

good results.

Prophylaxis

In spite of the achieved success in the pseudotuberculosis study, the problems

of the specific prophylaxis have not been worked out so far.

A complex of nonspecific measures directed at the source and transmission

factors is widely used in the medicine to prevent the pseudotuberculosis spreading.

Control questions:

1. Etiology, epidemiology, and incidence of pseudotuberculosis.

2. Pathogenesis of pseudotuberculosis.

3. Anatomic pathology of disease.

4. Main clinical symptoms and signs of pseudotuberculosis.

5. Laboratory methods of pseudotuberculosis diagnostics.

6. Criteria of diagnosis.

7. Differential diagnosis of pseudotuberculosis.

8. Treatment of pseudotuberculosis.

9. Prophylaxis of pseudotuberculosis.

111Leptospirosis

LEPTOSPIROSIS

Leptospirosis is an acute generalized infectious disease, characterized by

extensive vasculitis, caused by spirochetes of the genus Leptospira. It is primarily

disease of wild and domestic mammals; humans are infected only through direct

or indirect contact with animals.

Historic reference

A. Weil (1886) was the first who described leptospirosis as an independent

disease, four cases with a high temperature, jaundice, hemorrhages and the renal

affection.

R. Virchout (1865) considered the described disease as a kind of typhoid

fever and called it “typhus biliosus” differentiating it from “katarrhalischen icterus“.

In 1888 in the book “Infectious Jaundice” S.P.Botkin’s disciple N.K.Vasiliev

informed about twelve cases of a similar disease but did not paid much attention

to the character of the temperature, the expressiveness of jaundice, the time

when hemorrhages and the renal affection appear, he comes to the conclusion

that the new disease is different from typhoid fever and catarrhal jaundice.

For a long time leptospirosis was divided into icteric and non-icteric forms.

The first description of non-icteric leptospirosis was given by W.A.Bashenin in

1928, he suggested naming me disease “water fever”.

Leptospirosis is registered in many countries.

Etiology

The leptospirosis pathogen belongs to the genus of Leptospira nogychi

and can be divided into 2 kinds – parasitic and saprophytic. There are hundreds

of serotypes in each kind. The body of the leptospira consists of a long axis

thread which is covered with a cytoplasmatic spiral that has a three-layer

membrane. The average length of leptospiras is 10-14 mkm, the number of cons –

10-12. There are no spores or capsules. Leptospiras have energetic and complex

movements. This explains their high invasive ability. Leptospiras do not get

well painted with common aniline dyes. Some special liquid media containing

animal (rabbit) serum are used to cultivate leptospiras. Leptospiras are unstable

in the environment but are adapted to living in water.

The leptospira life time in water oscilates within wide limits – from several

days to many months depending on pH, the salty composition and the microflora

of the reservoirs.

It has been discovered that leptospiras have hemolysin and also lipases that

can have a cytotoxic influence on the organs and tissues which are rich with

lipids. There is endotoxin in the leptospira cells.

112

Infectious diseases

The modem classification of leptospiras is based on their antigenic structure.

There have been discovered 200 serovars united in 25 serological groups.

There are two active serologic complexes among the antigens of leptospiras

each of them has a complex set of components. One of them is situated on the

cell surface and determines its typospecific qualities, the other – in the depth of

the microbe and characterizes genospecific peculiarities of leptospiras.

The vital capacity of leptospiras in the environment depends on many factors.

There is a considerable discrepancy in the whimsicality of leptospiras (the

necessary conditions of their survival are high humidity, warmth, pH of the

water and soil 7.0-7.4, the limited amount of salt). In the water of the rivers,

pools, lakes and marshes leptospiras remain viable for 5-10 days but in the sea

water they die in several hours. Leptospiras remain viable in the damp soil up to

270 days, in dry soil – not more than 3 days. Leptospiras can easily endure low

temperatures and remain viable during prolonged freezing, however, they quickly

die when warmed, dried if exposed to salt or acid.

Epidemiology

Leptospirosis is a zoonotic infection. The source of the infection is animals

wild, domestic and game animals (pigs, cattle, foxes, white foxes, nutrias and others).

They form anthropurgias foci.

The small mammals who live in the forests, near the reservoirs (volemice)

play the main role in maintenance the leptospirosis foci. Their infection takes a

form of a symptomless chronic process in the kidneys. Leptospiras multiply in

the tubules of the kidneys and go out with urine.

The natural foci are situated in low lying areas. They are marshes, flood-

lands, water-meadows, the marsh-ridden parts of the rivers and irrigation system,

overgrown with bushes and abundant grassy vegetation. The infection of people

in the natural foci is of a seasonal character (June-September), it usually occurs

during the agricultural work (mowing the meadows, collecting hay, growing rice,

flax, hemp and other abundantly irrigated crops, felling and during hunting, fishing,

gathering mushrooms, drinking water and washing with water from the

contaminated shallow reservoirs). The morbidity in the natural foci has a sporadic

or group character. The development of natural resources, unorganized rest

result in the immediate contact of people with nature and create an opportunity

for infecting people with leptospiras. The natural foci are the source of infection

for the domestic animals.

In recent years the gray rat has been playing a more important part in the

epidemiology of leptospirosis, its infectedness has been proved in many countries

of the world. For a long time leptospirosis was considered a disease of big cities,

mainly ports. However, in the present situation the intensive processes of

urbanization, creation of large cattle-breeding complexes, growing rice and other

elements of the economic activity of man gave changed the ecology of the gray

113Leptospirosis

rat, so the anthropurgias foci of leptospirosis can be both in the rural areas and

in the cities.

The foci which appear in the cattle-breeding industries as a result of bringing

animals that are leptospira-carriers or infecting the cattle, pigs m the natural foci

in the pastures, watering-places play the most important part in the epidemiology

of the disease. The agricultural animals often have leptospirosis in the obliterated,

symptomless form. That is why the sick animals are not isolated in time, they

excrete leptospiras into the environment and infect water, forage, pastures, soil.

In many big cities, especially ports, there is a high rate of leptospirosis

among the gray rats. This is the reason for the citizens to fall ill with leptospirosis

if due to their occupation they contact sinanthropos rodents or the things

contaminated by them.

The clinical symptoms of leptospirosis among dogs had been described before

the pathogen was discovered and the term “leptospirosis” appeared. In 1898 in

Stuttgart there was described a disease of dogs which had the following symptoms:

hemorrhagic gastroenteritis, ulcerative stomatitis, renal affection (Stuttgart disease).

The infection is mainly transmitted from animals to humans by water. The

contact way is considerably less important. The transmission of the infection

through food is rare. Humans can be infected while swimming in the reservoirs,

drinking water from them or using it for economic needs, during different kinds

of the agricultural work in the marsh-ridden places, when fishing. There have

been described some cases of leptospirosis infection among the personal of the

slaughter-houses, meat-packaging plants.

The leptospirosis incidence increases in June-September. In other months

some sporadic cases are registered, which are not connected with the infection in

the open reservoirs.

Leptospirosis can be considered as professional disease. The people who

are involved in the agricultural work in the marsh-ridden places fall ill more often,

they include cattle-breeders, the personal of meat-packaging plants, miners, dockers,

plumbers.

There have been some cases when people fell ill after being bitten by a

coypu rat, as well as the personal of the laboratories, who work with leptospiras.

The susceptibility of people to leptospirosis is high. A typospecific immunity

remains for a longtime after having the disease.

Pathogenesis

The pathogenesis of leptospirosis is characterized by changing several phases.

The first phase includes the pathogen penetration and a short-time primary

leptospiremia. The leptospiras penetrate the human organism through the skin

of the mucous membranes, travel along the lymph tracts, penetrate the blood and

then various organs – the liver, kidneys, adrenal glands, spleen, lungs and others.

This phase lasts 7-20 days, it corresponds to the incubate period.

114

Infectious diseases

The second phase includes secondary leptospiremia, it coincides with the

beginning of the clinical manifestations of the disease, the generalization of the

process. The leptospiras penetrate the organs and tissues with the blood flow

again, fix on the cell surface (especially, in the kidneys, liver, adrenal glands), can

overcome the hametoencephalic barrier. The leptospiras do not cause a destruction

and they do not parasites intracutaneously. They stick to the cell surface, can

stay in the inter-cell space.

The third phase is a phase of toxinemia that is accompanied by an expressed

fever. The most important pathogenic factor of this phase is capillary toxicosis.

The rupture of the capillary endothelium results in the diapedesious hemorrhages

into various organs and tissues. It is clinically manifested as a hemorrhagic

syndrome. Thrombocytopenia plays a part in the origin of the hemorrhagic

syndrome, it is connected with the influence of the leptospira lipase on the

phospholipids of thrombocytes membranes and their gluing together with the

formation of the primary thrombocytous congestion. The vessels of the liver,

kidneys, adrenal glands get affected most of all, there may develop Waterhause –

Fridrichsen syndrome. The degenerative and partially necrotic changes of the

liver parenchyma as well as hemolysis oferythrocytes under the affection of

hemolysins are the cause of jaundice which has a mixed character.

The influence of leptospiras and their metabolites on the cellular wall

results in the affection of the adrenal gland epithelium, all the cortical and subcortical

layer of the kidney that results in the uropoiesis affection. There is a possibility

of the development of renal insufficiency.

The fifth phase includes the formation of the sterile immunity. The tense

humoral immunity is combined with the expressed local organic and cellular

immunity. Then a stable recovery comes.

Anatomic pathology

Leptospirosis is characterized by the affection of the capillary endothelium

of a various organs and tissues. The walls of the vessels are fragile, their

permeability is increased, this is accompanied with numerous hemorrhages in the

kidneys, liver, lungs, endocardium and pericardium, mucous membrane of the

gastroenteral tract. The liver is enlarged, plethoric and with smooth surface.

The histological investigation shows an edema of the interstitial tissue,

dystrophy of the hepatic cells without an expressed cytoptesis of hepatocytes,

biliary thromboses in the central zone of the lobules.

The most considerable changes can be found in the kidneys. The kidneys

are considerably enlarged, there are such typical symptoms as a stroma edema,

numerous hemorrhages, a sharply expressed granular degeneration of the

convoluted tubules epithelium up to necrosis. The kidney affection in leptospirosis

can be considered as nephrosonephritis.

There are hemorrhages in the adrenal glands, sometimes considerable. The

muscle affection is also characteristic of leptospirosis, especially the affection of

115Leptospirosis

musculus gastrocnemius and musculus thoracic. There are hemorrhages of various

sizes; an uneven swelling of the fibers, degenerative changes in the synapses of the

muscular fiber and nerve, sometimes coagulation necrosis which causes myalgia.

Dystrophy and lipid dystrophy develops in the heart muscle, sometimes

there is interstitial myocarditis. There are hemorrhages in the lungs as well as in

other organs. There is often an edema of the meninx vasculosas.

Clinical manifestations

The course of leptospirosis can be mild, middle-moderate and severe. The

severity of the course depends on the microbe virulence, the dose of infection, the

reactivity of the microorganism.

The main criteria of the severity are follows: the degree of toxicity, the

expressiveness of the affection of the liver, kidneys, central nervous system, heart,

adrenal glands, hemorrhagic manifestations.

There are cycles in the leptospirosis course. There is and incubate period,

the beginning, height and convalescence.

The incubate period lasts 2-20 days (more often 7-10 days). The disease has

an acute onset. The patient can indicate not only to the date but even the hour of

the disease onset. The fever usually has a remitting or constant character, it

lasts 5-9 days then it falls down in the form of accelerated lysis. There can be

another wave (a relapse).

From the first hours the patients complain of intense headaches, pain in the

muscles, especially, musculus gastrocnemius, the muscles of the scalp, neck, back

and abdomen. In 1888 W. P. Vasiliev wrote that there is no such an intensive

myalgia in the musculus gastrocnemius in case of any other disease. The abdomen

pain can be so intense that there is a suggestion about an acute surgical pathology.

The symptoms of toxicity increase. The patients are flaccid, adynamic. The

patients has a characteristic appearance – the face is edemic, hyperemic, the

vessels of the scleras are injected.

There is often herpetic rash on the lips. In some patients (in 30 % cases) a

polymorphic symmetric rash which stays for several days appears on the third

– fifth day of the disease.

In some cases there is an enlargement and painfulness of the peripheral

lymph nodes. The liver gets enlarged early, on the second-third day of the

disease. Jaundice develops in the moderate severe – course as well as in the

severe course. The liver has a dense consistence, it is painful at palpation. In a

half of the patients the spleen gets enlarged.

There are considerable changes in the cardiovascular system: dull heart

sounds, sometime relative bradycardia, arrhythmia, extrasystole. In case of an

expressed toxicity the arterial pressure sharply decreases (up to collapse) as a

result of a decrease of the precapilary arteries.

The initial period of leptospirosis is characterized by the peculiar changes

in the central nervous system, in some patients there are such symptoms as

116

Infectious diseases

disorders of the consciousness and even unconsciousness, cramps besides an

expressed persistent headache, insomnia, delirium. In 10-40 % cases there are

meningeal symptoms: rigidity of the occipital muscles, Kernig’s sign, Brudzinsky’s

sign that are distinctly manifested on the fifth-eighth day of the disease. In such

patients the spinal puncture confirms the diagnosis of serous leptospirous

meningitis – cerebrospinal fluid flows out under an increased pressure, it is

transparent. The microscopia of the cerebrospinal fluid shows leptospiras, during

the regular one outside the dark field of vision – moderate lymphocytic pleocytosis.

The amount of protein is increased. Leptospirous meningitis usually has a

nonmalignant character, it usually lasts 8-10 days.

At the end of the first week, and sometimes earlier. Jaundice develops in some

patients (12-20 %). The intensity of jaundice and its duration depends on the

severity of the disease and can last several weeks (1-4). A moderate skin itching is

quite possible. The urine is dark, the color of the excrements is not changed.

With the development of jaundice the condition of the patients usually

worsens. The most severe manifestations of leptospirosis appear at the end of

the first week – at the beginning of the second week of the disease.

The hemorrhagic syndrome appears on the seventh-tenth day: petechial

eruption on skin, hemorrhages under the conjunctive, hemorrhages in the nose,

gums, stomach, intestine, uterus. The hemorrhages can be repeated, massive and

result in anemia. Many clinicians have observed that the expressiveness of the

hemorrhagic syndrome corresponds the severity of leptospirosis and has a certain

prognostic significance (Fig. 7). The degree of the kidneys affection is even

more significant while evaluating the severity of leptospirosis, the kidneys are

always affected to some degree in leptospirosis.

From the first days of the disease there can be oliguria, moderate proteinuria, in

the urine there are fresh erythrocytes, leukocytes as well as hyaline casts and the

cells of the renal epithelium. The symptom of the kidneys affection become the most

expressed from the seventh-tenth day of the disease. Oliguria can be followed by

anuria, an acute renal insufficiency may develop, m spite of the development of an

acute renal insufficiency, there is usually no edema and arterial hypertonia in

leptospirosis. Sometimes an acute renal insufficiency develops very early, on the

fourth day of the disease. It is an acute renal insufficiency resulting in uremia that is

a frequent cause of the lethal outcome of the disease. If the therapy is timely and

adequate, the kidneys affection in leptospirosis can be cured. Oliguria is followed by

polyuria, and function of the kidneys gets gradually normalized.

The second week corresponds to the height of the disease. At this time

jaundice becomes the most intensive, the hemorrhagic and meningeal syndromes

increase or appear for the first time. The changes in the cardiovascular system

increase: the pulse is rapid and weak, a systolic murmur is sounded in the apex

cordis, there can be extrasystolia. The electrocardiogram shows diffusive changes

of the myocardium.

117Leptospirosis

At this period of the disease the infiltrates connected with the hemorrhagic

foci are sometimes formed in lungs, this is accompanied by the sanguinolent

sputum secretion.

By the end of the second week the condition of the patients improves. The

headache and myalgia reduce, the jaundice intensity gradually decreases, a great

amount of urine begins to excrete. The patients feel weak for a long period. The

duration of the disease averages to 3-4 weeks. Some patients (20-60 %) may have

relapses. In 5-7 days after the feverish period the temperature rises again, headaches

and myalgia appear. The relapses and acute forms are not so severe as the first

phase, as a rule. The temperature does not usually rises very high, the fever does

not last more than 2-3 days. Some patients have 3-4 acute forms of relapses.

In leptospirosis the hemogram is characterized by the progressive anemia, a

low reticulocytes number. In the patients with a hemorrhagic syndrome there is

expressed thrombocytopenia, an increased period of the blood coagulability.

Leukocytosis is a characteristic feature. The number of leukocytes increases up

to 12-25 10

in 1 mkL. In the differential blood count there is neutrophilia with

a shift to the left, expressed lymphopenia. The ESR reaches 40-60 mm/h.

The bilirubin amount in blood increases in case of the icteric form. The level

of prothrombin may moderately decrease. The activity of transaminases is either

normal or slightly increased on the tenth-fifteenth day of the disease.

The asthenovegetative syndrome is a characteristic feature of the convales-

cence period. Anemia and proteinuria remain for a long time.

Some patients have eye affections – uveitis, iritis, iridocyclitis that develop

in 2 weeks and in several months after the onset of the disease. There can be

other complications in the acute period – massive hemorrhages, an acute renal

and hepatic insufficiency, uremia, myocarditis, an acute cardiovascular insufficiency.

Complications

The most common complications of leptospirosis, which are characteristic

for its severe course are infectious-toxic shock, renal-hepatic failure, massive

internal bleeding, DIC-syndrome, acute heart failure.

Diagnosis

It is quite difficult to diagnose leptospirosis, especially during the first days

of the disease. The bacteriological method is of a little practical importance

because leptospiras grow badly and slowly on the artificial media. The correctly

taken epidemiological history plays the most important part in diagnosing

leptospirosis. It is necessary to take into account the patient’s occupation, his

contact with agricultural animals, work in the meadows, swimming in the rivers

and ponds, the existence of rodents in the surroundings. The epidemiological

history not only determines the direction of diagnosis but gives an opportunity

to control the environment. The following peculiarities of the clinical symptoms

118

Infectious diseases

are taken into consideration: jaundice, accompanied by fever, myalgia, hematuria,

hemorrhages. The diagnosis based on the clinical-epidemiological investigation,

is confirmed by the laboratory data.

The materials used for diagnosing leptospirosis are blood, urine, cerebro-

spinal fluid.

The following methods of the laboratory diagnosis are used:

1. Bacteriological, bacterioscopic.

2. Serologic.

3. Biologic.

The bacteriologic investigation includes the primary microscopia of the

initial material and its inoculation of media for acquiring the leptospira clean

culture. The patient’s blood serum, cerebrospinal fluid or urine are centrifuged.

The fall out is investigated with microscope in a dark floor. Leptospiras are

found as thin sinous mobile threads that look grayish-whitish on the dark

background. That is necessary to note that the presence of leptospiras in blood

is undoubtedly indicative of leptospirosis, but the negative result does not allow

us to exclude the disease. The initial material inoculation of the water-serum

medium consists of the native rabbit serum. The inoculation is incubated for 30

days at a temperature of 28-30 °C, the inoculation is examined on the dark floor

of the microscope every 5-7 days.

The serologic investigations are done in the dynamics of the disease including

the convalescence period. The reaction of the microscopic agglutination and

lysis, as well as the complement fixation reaction are used to find antibodies in

the serum of the sick people.

The reaction of the microscopic agglutination and lysis are done by a drop

method with various serums of the patient’s blood and with those leptospira

serotypes which can be found hi this area. The results of the reaction are taken

into account with the help of a microscope with a dark floor. In the positive case

there are phenomena of sticking together, the leptospira agglomeration in form

of small “spiders” and different degrees of their lysis. The titer is considered to

be diagnostic when the serum is diluted 1:50-1:100.

The specific antibodies are discovered in the patient’s serum at the end of

the first – the beginning of the second week of the disease. The antibodies can

remain in patients for several years, that is why the investigation of the twin

serums are of a great diagnostic importance.

Leptospiras appear in liquor later than in the blood, that is why its

investigation (microscopia and inoculation of the same media as the blood) are

done when there are symptoms of meningitis. Urine can be investigated from the

first day to 3 months from the disease onset.

The guinea-pigs that are very sensitive to L. icterochaemorrahaigae are

used as a model for the biological test. The animals are infected by injecting the

infected material (blood, urine, cerebrospinal fluid taken sterile from the sick

119Leptospirosis

person) intraperitoneally, intracutaneously, intravenously, through the scarified

skm and mucous membranes. The material is taken at the time when the

bacteriological and bacterioscopic investigations are done. The animals die if

there are leptospiras in the initial material.

Differential diagnosis

However, in some cases there are diagnostic difficulties because of the

polymorphism of the clinical picture, separate symptoms of which make it difficult

to diagnose a disease (jaundice, fever, abdomen pain, myalgia, meningeal syndrome).

First of all it is required to differentiate the disease from flue, typhoid fever,

hemorrhagic fever with a renal syndrome (HFRS), virus hepatitis, meningitis.

In case of flue the headache has a distinct location (in the superciliary arch

area), there is no hepatosplenomegaly, jaundice. There are expressed catarrhal

symptoms. The hemogram shows leukopenia, neutropenia, the ESR is usually

normal. The fever last from 2-3 to 5 days.

If there are such symptoms as an acute onset of the disease, a high temperature,

intense headaches, the appearance of the patients, the liver and spleen enlargement,

it is necessary to differentiate leptospirosis from typhoid fever. However, the

following symptoms are characteristic of the initial period of typhoid fever:

Kiari-Avtsin’s sign, Govorov-Godelie’s sign, Rozenberg’s sign, and early increase

of the spleen. There appears massive roseole-petechial eruption on the side

surfaces of the breast, abdomen, extension surface of the extremities.

In HFRS there are no pains in the musculus gastrocnemius, there are such

characteristic symptoms as loin pains, Pasternatsky’s positive sign, petechial

eruption located in the area of the shoulders and armpits. There is prolonged

hypoisosthenuria, and in the urine fall out there are waxy casts, degenerative cells

of the renal epithelium besides erythrocytes, hyaline casts. There is no jaundice

and meningeal syndrome. The hemogram shows leukopenia at the increased

ESR at the onset of the disease.

Virus hepatitis has a gradual onset, without chills, the temperature rises at

the pre-icteric period. Muscle pains, scleritis, conjunctivitis are not characteristic

of it. There are no meningeal and renal syndromes. The activity of transaminases

is considerably increased. The hemogram shows leukopenia, low ESR.

If it is necessary to differentiate leptospirous meningitis form serous meningitis

of another etiology, it is necessary to take into account the epidemiological

history, pain in the musclus gastrocnemius; the development of the meningeal

syndrome in 4-6 days after the disease onset, the simultaneous affection of the

liver, kidneys; hemorrhagic syndrome.

Treatment

The most effective etiotropic agent is combination of antibiotics and

antileptospirosis immunoglobulin if they are indicated in an initial stage when

leptospires are in blood. Benzylpenicillin, tetracyclin, erythromicin and streptomycin

120

Infectious diseases

are indicated more often. The daily dose of benzylpenicillin can be changed from 3 to

12 millions units, however, the dose 6 – 8 millions units is more often indicated per

day (in a muscle). It dosage depends on gravity of the disease course. The maximal

dose of a preparation is indicated at development of meningitis. Ampicillin, oxacillin,

ampiox are effective semisynthetic penicillins. Benzylpenicillin or semisyntetic analogue

can be combined with streptomycin, tetracyclin is indicated 0.2-0.3 gm 4 times per

day, it less often, than penicillins, causes reaction such as Yarish-Gersgeimer, however

strengthens a permeability of vascular wall and promotes development of a

hemorrhagic syndrome. It is contrindicated at the icteric form of leptospirosis fever

and development of renal failure. Treatment with antibiotics is carried out during all

feverish period and 2-3 days of normal temperature. In case of occurrence of relapse

a new course of an antibiotic therapy must be indicated.

Clinical observations of last years has testified the inefficiency heterogeneous

antileptospirosis immunoglobulin, oppression of immune system by it. The allogenic

donor immunoglobulin which is effective in the first 3-5 days of disease are

applied in medical practice, has no side-effects. The preparation prevents

development of acute renal failure.

With the purpose of desintoxication and improvements of microcirculation in

a vein there are infused solution of glucose, reopolyglucin, rheogluman, threesaultl,

quartasault, and ascorbic acid. Good desintoxication effect is produced by the

preparations that neutralize ammonia: rnithine, ornicetil, glutargin. At severe

intoxication prednisolon and its analogues are indicated. The initial dose of

ðrednisolon is 60-120 mg and more, it is used for short course, quickly reducing

dose in process of clinical improvement. Enterosorbtion with using of granulated

coal SKN, sillard P, enterosgel, polyphepan can be effective. At the icteric form there

should be prescribed diets ¹ 5, 5A, and at pathology of kidneys – a diet ¹ 7.

At the development of the disseminated intravascular coagulation (DIC)

carry out a complex of medical actions according to hematological research. At I

stage (hypercoagulation) infuse in a vein heparin 2,500 units 4 times per day,

reopolyglycin, dipiridamol (curantyl), pentoxyfilin (trental) contricali in bottles,

ascorbic acid 5 % solution in ampoules 1 mL: 5-10 mL 2 times per day. At II

stages heparin can be infused under the control of blood clotting time, other

preparations (reopolyglycin, curantyl, trental) – in the same doses, as at I stage of

syndrome. At III stage of DIC infusing of heparin is not indicated. At

hypocoagulation there is indicated native plasma or cryoprecipitat of plasma,

trombocite mass. At hypofibrinolisis there are given acid aminocapronic, contrical,

gordox, at secondary hyperfibrinolysis – synthetic antifibrinolitics, inhibitors of

proteases – streptokinase, fibrinolysin are indicated.

At the bleeding with a tamponade cold, and infuse calcii chloridum, vicasol,

aminocapronic acid are used. Infusions of a blood plasma, a red cells mass,

albumin are indicated at bleeding. If hepatonephric insufficiency develops

simultaneously plasma transfusion of blood with infusion of erythrocytar and

121Botulism. Toxic food-borne diseases. Campylobacteriosis.

trombocytar mass 2-3 times, and are used instead of albuminous preparations, a

mixture of amino acids, for example alveosin-neo is recommended.

In occurrence of acute renal insufficiency (oliguria, hypoisosthenuria) there

should be repeated lavages of stomach and an intestine 2-4 % solution of sodium

hydrocarbonate, intravenous infusion of 40 % of glucose solution, euphyllin, mannit.

At later infuse furosemid (lasix). At development of metabolic acidosis indicate

natrii hydrocarbonas and Tris-buffer. If medicamental therapy is not effective and

oliguria stage lasts more than 3-4 days, there is a necessity in plasmaferesis or

plasmasorbtion or extracorporal dialysis by means of artificial kidney.

Prophylaxis

The deratization and sanitation veterinary measures are the essential part

of the prevention. Deratization is for decreasing of the activity of the natural

foci (wild rodents control) and the sanitation of the anthropurgias foci (the

sinanthropos rodents control).

One of the directions of leptospirosis prevention is the actions which break

the transmission of the disease by water in the natural foci (mechanization of

agricultural work, the supplying of workers with water-proof clothes, a ban to

swim in the infected reservoirs and to use unboiled water). Vaccination is

recommended for the people who permanently stay in the natural foci. The

people who belong to a group of high risk infection (cattle-breeders, veterinary

doctors, the meat packing plant personal, night-men, deratizators) should be

vaccinated with inactivated vaccine.

Control questions:

1. Definition of leptospirosis.

2. Mechanism of leptospirosis contamination.

3. Who can more likely get ill with leptospirosis?

4. What organs are damaged during leptospirosis infection?

5. Clinical manifestations and data of objective and laboratory examinationin in initial

period, height of illness and in the period of reconvalestation.

6. Differential diagnosis of leptospirosis with influenza, viral hepatitis, rash and abdominal

typhus, sepsis.

7. Complications of leptospirosis.

8. Principles of medical treatment of leptospirosis.

9. Leptospirosis prevention.

122

Infectious diseases

HERPETIC DISEASES

HERPES SIMPLEX VIRUS

Herpes simplex virus (HSV) infections are among the most common maladies

affecting humans. Often they are annoying and troublesome, occasionally they

are life-threatening.

Historic reference

The term “herpes” is derived from the Greek word meaning “to creep”, and

clinical descriptions of herpes labialis go back to the time of Hippocrates.

Astruc, physician to the king of France, is credited with the first description of

genital herpes in 1736. Between 1910 and 1920, the infectious nature of herpes

lesions was demonstrated by producing corneal lesions in rabbits with material

derived from herpes keratitis and labialis. As techniques for isolating and

characterizing the virus became more simplified and serologic procedures were

developed, our understanding of the HSV clinical spectrum has greatly expanded.

Studies during the past two decades have brought insights into the molecular

biology of HSV. the mechanisms of HSV latency and recurrence, and the first

successful approaches to therapy for certain types of HSV infections.

Etiology

Herpes simplex virus (herpesvirus hominis) shares many properties with

other members of the herpesvirus groups, which in humans includes varicella-

zoster, cytomegalovirus, Epstein-Barr virus, and human herpesviruses type 6 and 7.

The members of this group have an internal core containing double-stranded DNA,

an icosahedral capsid with 162 hollow capsomeres, and a lipid-containing laminated

membrane or envelope. The overall diameters of enveloped herpesviruses are

150-200 nm. Replication occurs primarily within the cell nucleus and is completed

by the addition of protein envelopes as the virus passes through the nuclear

membrane. Complete virus replication is associated with lysis of the productive

cell. All members of the human herpesvirus group can also establish latent states

within certain types of cells they infect, although the physical nature of the viruses

during periods of latency is unclear.

The development of monoclonal antibody and restriction enzyme technologies

have permitted an even finer definition of variations among individual HSV

isolates. It is now clear that HSV-1 and HSV-2 share certain glycoprotein antigens

(gB) and differ with respect to others (gG). Serologic differentiation between

HSV-1 and HSV-2 infections can be readily made by detection of type-specific

IgG antibodies.

123Herpetic diseases

Epidemiology

Herpes simplex viruses have a worldwide distribution.

There are no known

animal vectors for HSV, and although experimental animals can easily be infected,

humans appear to be the only natural reservoir. Direct contact, with transmission

through infected secretions, is the principal mode of spread. HSV-1 is transmitted

primarily by contact with oral secretions and HSV-2 by contact with genital

secretions. Transmission can occur both from overtly infected persons or from

asymptomatic excretors, although virus titers are higher in persons with active

lesions and thus transmissability may be greater. Approximately 15 % of the

adults may be excreting HSV-1 or HSV-2 at any given time depending on the

population studied. For example, because shedding of HSV-2 is related to sexual

activity, prostitutes may have unusually high rates of excretion.

The risk of heterosexual acquisition of HSV is greater in women than men,

and previous HSV-1 infection reduces the risk of subsequent HSV-2 infection.

Pathogenesis

On entry into skin sites HSV replicates locally in parabasal and intermediate

epithelial cells, which results in the lysis of infected cells and the instigation of a

local inflammatory response. This series of events results in the characteristic

lesion of superficial HSV infection, that is, a thin-walled vesicle on an inflammatory

base. Multinucleated cells are formed with ballooning degeneration, marked edema,

and characteristic Cowdry type A intranuclear inclusions. Such lesions are

indistinguishable from those caused by Varicella-zoster virus. Lymphatics and

regional lymph nodes draining the site of primary infection become involved.

Further virus replication may result in viremia and visceral dissemination,

depending on the immune competence of the host. In murine models the maturity

of macrophages at the site of local infection helps determine whether virus

remains localized or disseminates. Subsequently, other host defense mechanisms,

for example, the production of interferons, natural killer cells, protective antibodies,

and sensitized killer lymphocytes, are elicited to prevent the spread of infection.

Clinical manifestations

Primary HSV-1 infection is frequently asymptomatic but may present as

gingivostomatitis and pharyngitis most commonly in children under the age of 5

years but occasionally in older persons. Incubation periods range from 2 to 12 days

and are followed by fever and sore throat with pharyngeal edema and erythema.

Shortly after its onset, small vesicles develop on the pharyngeal and oral mucosa:

these rapidly ulcerate and increase in number, often involving the soft palate, buccal

mucosa. tongue, and floor of the mouth. Gums are tender and bleed easily and

lesions may extend to the lips and cheeks. Fever and toxicity may persist for many

days, and the patient complains of severe mouth pain. Breath is fetid, and cervical

adenopathy is present. In children, dehydration may result from poor intake, drooling,

124

Infectious diseases

and fever. In college-aged persons, primary HSV infection often presents as a posterior

pharyngitis or tonsilitis. Included in the age-related differential diagnosis are

streptococcal or diphtheritic pharyngitis, herpangina. aphthous stomatitis, Stevens-

Johnson’s syndrome, Vincent’s infection and infectious mononucleosis.

Herpes simplex virus infections of the eye are usually caused by HSV-1. Primary

infections may be manifested by a unilateral follicular conjunctivitis with regional

adenopathy and/or blepharitis with vesicles on the lid margin. Photophobia, chemosis,

excessive tearing, and edema of the eyelids may be present. Some patients develop

dendritic figures or coarse, punctate, epithelial opacities. If disease is limited to the

conjunctiva, healing takes place within 2-3 weeks. However, if systemic symptoms

and signs of stromal involvement are present, the healing phase may be delayed.

Spontaneous healing of the conjunctiva and cornea is usually complete.

Primary genital infection is most common in adolescents and in young

adults and is usually (in 70-95 % of the cases) caused by HSV-2. Incubation

periods are 2-7 days. In men, vesicular lesions on an erythematous base usually

appear on the glans penis or the penile shaft. In the female, lesions may involve

the vulva, perineum, buttocks, cervix, and vagina and are frequently accompanied

by a vaginal discharge). Extra-genital lesions occur during the course of primary

infection in 10-20 % of patients. Primary infection in both sexes may be associated

with fever, malaise, anorexia, and tender bilateral inguinal adenopathy. Although

vesicular lesions may persist for several days in men, in women they rapidly

ulcerate and become covered by a grayish-white exudate. Such lesions may be

exquisitely tender, and urethral involvement may result in dysuria or urinary

retention. Herpetic sacral radiculomyelitis accompanying genital infection may

also lead to urinary retention, neuralgias, and obstipation; in such patients a loss

of anal tone, diminished bulbocavernosus reflex, and cystometrographic evidence

of lower motor neuron dysfunction can sometimes be demonstrated. Lesions of

primary genital herpes may persist for several weeks before healing is complete.

Previous HSV-1 infection may reduce the severity and duration of a first episode

of genital herpes caused by HSV-2. In the diagnosis of genital herpes. other

sexually transmitted infections such as chancroid or syphilis, erosions secondary

to excoriation, genital manifestations of Behcet syndrome or erythema multiforme,

and local candidiasis must all be distinguished.

Although primary infections are usually in perioral (Fig. 8), ocular or genital

areas, any skin site may be initially involved. Primary HSV skin infections may

be extensive and mimic herpes zoster, although a dermatomal distribution is not

usually maintained and the pain is less severe.

Primary perianal and anal HSV-2 infection is becoming increasingly well

recognized, both in women and in male homosexuals. Pain is the primary symptom,

with itching, tenesmus, and discharge also noted. Systemic complaints of fever,

chills, malaise, headache, difficulty in urinating, and sacral paresthesias may be present.

On examination, vesicles and ulcerations may be seen in perianal and sometimes in

125Herpetic diseases

anal areas. They may become confluent and result in a grayish ulcerating cryptitis

surrounded by a red edematous mucosa. Bilateral inguinal adenopathy is common.

The course is generally self-limited unless bacterial infection supervenes, with

healing occurring in 1-3 weeks. However, in the setting of the acquired

immunodeficiency syndrome (AIDS), herpes proctitis as well as other cutaneous

manifestations of HSV infection may be prolonged and progressive.

Recourse herpes labialis is frequently heralded by prodromal symptoms (pain,

burning, tingling, or itching) generally lasting for less than 6 hours but occasionally

as long as 24-48 hours. Vesicles appear most commonly at the vermillion border

of the outer lip and are associated with considerable pain. The lower lip is more

frequently involved, although individual patients may have stereotyped lesions at

similar sites during each recurrence. The lesion area is usually less than 100 mm

and lesions progress from the vesicle to the ulcer/crust stage within 48 hours.

Pain is most severe within the first 24 hours after the appearance of lesions.

Healing is generally complete within 8-10 days. Rarely, recurrences may occur in

the mouth or on the nose, chin or cheek. Systemic complaints do not usually

accompany recourse herpes labialis, although local adenopathy may occur.

Ocular infection may recur as keratitis, blepharitis or kerato-conjunctivitis.

Recourse keratitis is usually unilateral but is rarely (in 2-6 % of the cases)

bilateral. Two main types of keratitis may develop: dendritic ulceration or stromal

involvement. Branching dendritic ulcers that strain with fluorescein are virtually

diagnostic and are often accompanied by a loss in corneal sensation. Visual

acuity may be decreased because the ulcers frequently involve the pupillary

portion of the cornea. They may be accompanied by minimal anterior opacification

or deep stroma involvement. Occasionally, extensive ameboid corneal ulcers

may evolve, particularly if topical steroids have been applied. Superficial keratitis

usually heals, but recourse infection may lead to deep stromal involvement and

uveitis, which may in part be mediated by hypersensitivity reactions to viral or

altered cellular antigens. A gradual diminution in visual acuity takes place, and

individual attacks may last for several months with the formation of dense scars,

corneal thinning, and neovascularization. Permanent visual loss may result, and

rarely, rupture of the eyeball develops.

Recourse genital lesions in both sexes are generally associated with less

severe systemic symptoms and less extensive local involvement than are primary

attacks. A prodrome of tenderness, itching, burning or tingling is often noted for

several hours before a recurrence. Lesions in women are most often noted on

the labia minora, labia majora, and perineum and less commonly on the mons

pubis or buttocks. Lesions in men are most often found on the glans or penile

shaft. In women recurrences tend to be more severe. Healing generally occurs in

6-10 days. Virus shedding diminishes more slowly in women and can occur

between recurrences in both sexes. Occasionally, genital recurrences are associated

with headache and even with aseptic meningitis. Urethral stricture and labial

fusion have also been reported after recourse genital infections.

126

Infectious diseases

Recourse HSV-1 or HSV-2 infections may develop on extremities; occasionally

such lesions are associated with severe local neuralgia. Local edema and

lymphangitis may also occur during recurrences on extremities.

Relationship to other diseases

Erythema multiforme. Allergic cutaneous and mucous membrane disorders

may accompany or follow acute HSV infections. Up to 75 % of all cases of

erythema multiforme are regularly preceded by an attack of herpes simplex.

Both HSV-1 and HSV-2 may be involved, and the cutaneous manifestations range

from mild to severe (Stevens-Johnson syndrome) and may be recourse. Inactivated

HSV antigens injected intra-dermally into persons subject to erythema multiforme

have induced such attacks, and HSV antigen has been identified in skin biopsy

specimens from affected lesions.

Cancer. Although HSV has been suspected as a cause of cervical and other

cancers on the basis of both epidemiologic and laboratory studies, many recent

studies do not support its etiologic role in human cancers.

Idiopathic neurologic syndromes. Herpes simplex virus infections have been

implicated as possible factors involved in the pathogenesis of various neurologic

disorders of unknown etiology, including idiopathic facial paralysis (Bell’s palsy),

multiple sclerosis, atypical pain syndromes, ascending myelitis, trigeminal neuralgia,

Mollaret’s meningitis, and temporal lobe epilepsy. The associations are based on

the known predilection of HSV for nerve tissue, on serologic or nucleic acid

studies, and on the occasional observations of temporal relationships between

attacks of herpes labialis or genitalis and attacks of the neurologic syndrome.

Complications

Herpes simplex encephalitis is a rare complication of herpetic infection and

yet is one of the most common acute sporadic viral diseases of the brain.

Although little is known about the pathogenesis of HSV-1 encephalitis in humans,

the virus is believed to spread by neural routes into the brain during either

primary or recourse infection. Temporal lobes are the principal target areas of

the virus, and a necrotizing hemorrhagic encephalitis results.

Herpes simplex encephalitis occurs at all ages in both sexes, and in all

seasons. The clinical course may begin suddenly or after a brief influenzalike

prodrome. Headache, fever, behavioral disorders, speech difficulties, and focal

seizures are prominent features; olfactory hallucinations may be present.

Cerebrospinal fluid examination is variable but frequently shows a moderate

pleocytosis with mononuclear and polymorphonuclear leukocytes: protein levels

are slightly elevated, and glucose is generally normal. Infectious virus is rarely

present in cerebrospinal fluid during encephalitis, and brain biopsy with appropriate

histologic and cultural techniques is coursely the most reliable way to make the

diagnosis. Although various antibody and antigen assays may provide adjunctive

information. they are not sensitive enough to provide a sufficiently early diagnosis.

127Herpetic diseases

Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain

reaction assay of cerebrospinal fluid has been reported by certain research

laboratories. Herpes simplex virus encephalitis must be distinguished from other

forms of viral encephalitis, tuberculous and fungal meningitis, brain abscesses,

cerebrovascular accidents, and brain tumors.

The course in untreated patients is usually one of rapid deterioration over

several days that progresses to coma and death. Mortality in untreated biopsy-

proven cases is 60-80 %, and fewer than 10 % of the patients are left without

significant neurologic sequelae.

Diagnosis

Although experimental animals and embryonated eggs are susceptible to

infection with HSV strains, tissue cultures have largely replaced these hosts for

diagnostic purposes. Primary human embryonic kidney, rabbit kidney, and human

amnion cells readily support the replication of HSV. Continuous cell strains or

cell lines of human diploid origin and certain continuous monkey kidney cell lines

also support HSV replication, but to a lesser extent. Cytopathic effects usually

appear rapidly, within 24-48 hours if the virus inoculum is high. Cells become

rounded and clump, with rapid progression of cytopathic effects throughout the

cell monolayer. Ballooning degeneration and the formation of multinucleated syncytial

giant cells may be observed, particularly with HSV-2 isolates. Vesicles contain

their highest titers of virus within the first 24-48 hours, and specimens should be

collected early and promptly inoculated into tissue cultures. If a delay is unavoidable,

specimens can be stored in appropriate carrying medium at 4-9 °C for a few hours.

but for longer period they should be stored at -70 °C. Typing of isolates can be

accomplished by using a variety of serologic techniques including

immunohistochemistry or microneutralization. When tissue specimens such as

neural ganglia are being studied for the presence of virus, tissue explantation or

cell cocultivation techniques have proved useful in facilitating virus isolation.

The recent development of monoclonal antibodies to individual herpes virus

antigens should allow for the more precise identification and typing of HSV

isolates. HSV-1 and HSV-2 have both type-specific and cross-reactive antigens

that are useful for both grouping and type discrimination. Moreover, the cloning

of herpes DNA fragments in recombinant bacteria may permit the production of

probes to identify herpes genomes in the absence of infectious virus.

For a rapid diagnosis of skin or mucous membrane lesions, scrapings from

suspect lesions may be smeared, fixed with ethanol or methanol and stained with

Giemsa or Wright preparation. The presence of multinucleated giant cells indicates

infection with HSV or varicella-zoster virus. When using cytologic techniques,

e.g. the Papanicolaou cervicovaginal stain or the Paragon multiple stain, intranuclear

inclusions may also be seen. Alternatively, such material can be examined for

herpes antigens by immunohistochemical techniques or by in situ DNA hybridization.

128

Infectious diseases

Serologic techniques may be helpful in diagnosing primary HSV infections

but are rarely of value in recourse infections. A variety of assays have been used

including neutralization, complement fixation, passive hemagglutination, indirect

immunofluorescence, radioimmunoassay, enzyme immunoassays, complement-

mediated cytolysis, and antibody-dependent cellular cytolysis. During primary

infections, a fourfold or greater rise in titer is observed between acute and

convalescent sera. In recourse infections such rises may or may not be observed.

Many licensed enzyme immunoassays appear to give inaccurate information

concerning HSV-infecting subtypes.

Measurement of IgM HSV antibodies in infants may be helpful in the diagnosis

of neonatal infection. Such antibodies usually appear within the first 4 weeks of

life in infected infants and persist for many months. Measurement of IgM

antibodies in older persons has not proved useful in separating primary from

recourse infections.

Approaches to detect specific HSV antigens, antibodies, or DNA in cerebrospinal

fluid are under development. Such techniques may circumvent the need for invasive

procedures such as brain biopsy to make the diagnosis of herpes encephalitis.

Differential diagnosis

HSV causes various pathologies, which clinical manifestations can differ a

lot. Sometimes only complicated laboratory research helps to verify diagnosis of

HSV infection. The most common sign of HSV infection is vesicular eruption, so

differential diagnostics is necessary with diseases, which can be accomponied by

the same eruptive lesions. They are chicken-pox, VZV-infection, enterovirus

herpangina, Hand-Fuss-Mund Krankheit (HFMK), erysipelas, anthrax.

Treatment

A number of nucleoside derivatives interfere with the synthesis of HSV

DNA. Some of these (trifluorothymidine, vidarabine) are useful in and licensed

for the topical treatment of herpes keratitis. Vidarabine and acyclovir are also

useful for systemic HSV infections. None of these agents affects latent virus.

In the immunocompromised host, acyclovir is useful as both treatment and

suppression of recourse mucocutaneous HSV lesions. For the treatment of

acute episodes, virus shedding, local symptoms (pain), and time to healing can be

reduced by intravenous or oral regimens (400 mg five times per day). Acyclovir

is also useful in the prevention of herpetic recurrences in immunocompromised

hosts including transplant recipients, leukemics undergoing induction chemotherapy,

and patients with AIDS. Regimens of 200-400 mg from two to five times per day

have been satisfactory in preventing recurrences among seropositive patients.

Parenteral acyclovir is indicated for disseminated or central nervous system

HSV infections. In patients with biopsy-proven HSV encephalitis, acyclovir was

compared with vidarabine and found to be superior in reducing mortality. Doses

of 10 mg/kg every 8 hours for 14-21 days are recommended. In newborns with

129Herpetic diseases

disseminated HSV infections, acyclovir and vidarabine appear equivalent but

because of ease of administration, acyclovir is recommended.

Acyclovir has little acute toxicity. Drug-related neurotoxicity (disorientation,

hallucinations, tremors, ataxia, seizures) has been described rarely, and reversible

renal dysfunction may occur, particularly following a rapid bolus infusion.

Prophylaxis

Experimental vaccines against HSV have shown promise in animal models,

and some are undergoing human trials. Limited trials in humans, however, have

been unsuccessful, and it is unlikely that a human HSV vaccine will be generally

available in the near future.

The prevention of neonatal disease in the offspring of mothers with genital

infection presents special problems.

VARICELLA-ZOSTER VIRUS

Varicella-zoster virus (VZV) causes two distinct clinical diseases. Varicella,

or more commonly chickenpox, is the primary infection and results from exposure

of a susceptible individual to the virus. Chickenpox is ubiquitous and extremely

contagious, but for the most part, it is a benign illness characterized by a generalized

exanthematous rash. It occurs seasonally and in epidemics. Recurrence of infection

results in the more localized phenomenon known as herpes zoster, often referred

to as shingles, a common infection among the elderly.

Historic reference

Shingles has been recognized since ancient times as a unique clinical entity

because of the dermatomal vesicular rash; however, chickenpox was often confused

with smallpox. In 1875, Steiner successfully transmitted VZV by inoculation of

the vesicular fluid from an individual suffering from chickenpox to volunteers. The

infectious nature of VZV was further defined by von Bokay who observed

chickenpox in individuals who had close contact with others suffering from herpes

zoster. He correctly described the mean incubation period for the development of

chickenpox in susceptible patients as well as the average range in days. Kundratitz

in 1925 showed that the inoculation of vesicular fluid from patients with herpes

zoster into susceptible individuals resulted in chickenpox. Similar observations

were reported by Brunsgaard and others, and in 1943 Garland suggested that

herpes zoster was the consequence of the reactivation of latent VZV.

Since early in the twentieth century, similarities in the histopathologic findings

of skin lesions and in epidemiologic and immunologic studies indicated that varicella

and herpes zoster were caused by the same agent. Tyzzer described the

histopathology of skin lesions resulting from VZV infections and noted the development

of intranuclear inclusions and multinucleated giant cells. The histopathologic

descriptions were amplified by Lipschutz in 1921 for herpes zoster.

130

Infectious diseases

Etiology

Isolation of VZV in 1958 permitted a definition of the biology of this virus.

Viral isolates from patients with chickenpox and herpes zoster demonstrated

similar changes in tissue culture, specifically the appearance of eosinophilic

intranuclear inclusions and multinucleated giant cells. These findings are virtually

identical to those encountered with clinically available biopsy material. Taken

together, these data provided a universal acceptance that both diseases were

caused by VZV. By 1958, Weller and colleagues had been able to establish that

there were no differences between the viral agents isolated from patients with

these two clinical entities from either a biologic or immunologic standpoint.

Varicella-zoster virus is a member of the Herpesviridae family and shares

structural characteristics with other members of the family. The virus has

icosahedral symmetry containing centrally located double-stranded DNA with a

surrounding envelope. The size of the virus is approximately 150-200 nm and

has a lipid-containing envelope with glycoprotein spikes. The organization of the

viral genome is similar to other herpesviruses.

Varicella-zoster virus is highly cell associated and spreads from cell to cell

by direct contact. Virus can be isolated in a variety of continuous and

discontinuous cell culture systems of human and simian origin. Approximately

8-10 hours after infection, virus-specific immunofluorescence can be detected in

the cells immediately adjacent to the initial focus of infection. This parallels the

microscopic observation of the radial spread of cytopathology.

Epidemiology

The epidemiology of herpes zoster is somewhat different. Varicella-zoster

virus characteristically becomes latent after primary infection. It is presumed

that VZV establishes latency within the dorsal root ganglia. Reactivation leads

to herpes zoster, a sporadic disease. Histopathologic examination of the nerve

root after infection with VZV demonstrates characteristics indicative of VZV

infection. In those individuals who die after recent herpes zoster infection, an

examination of the dorsal root ganglia reveals satellitosis lymphocytic infiltration

in the nerve root, and degeneration of the ganglia cells. Intranuclear inclusions

can be found within the ganglia cells. Although it is possible to demonstrate the

presence of VZV by electron microscopy, it has not been possible to isolate this

virus in cultures usually from explants of dorsal root ganglia, as has been done

after herpes simplex virus infection. The biologic mechanism by which VZV

establishes latency remains a mystery at this time.

Herpes zoster is a disease that occurs at all ages, but it will afflict about 20 %

or more of the population overall, mainly among the elderly. Herpes zoster,

known also as shingles, occurs in individuals who are seropositive for VZV or

more specifically, in individuals who have had prior chickenpox. Herpes zoster

has occurred within the first 2 years of life in children born in women who have

had chickenpox during pregnancy. These particular cases likely reflect in utero

chickenpox with reactivation early in life.

131Herpetic diseases

Pathogenesis

The pathogenesis of VZV infection that results in chickenpox reflects the

natural history of the disease. Chickenpox occurs in susceptible individuals who are

exposed to virus after intimate contact. The appearance of a diffuse vesicular rash

has been well studied from a pathologic standpoint. Histopathologic findings in

human VZV infection, whether chickenpox or herpes zoster, are virtually identical.

The vesicles involve the corium and dermis. As viral replication progresses, the

epithelial cells undergo degenerative changes characterized by ballooning, with the

subsequent appearance of multinucleated giant cells and prominent eosinophilic

intranuclear inclusions. Under unusual circumstances, necrosis and hemorrhage

may appear in the upper portion of the dermis. As the vesicle evolves, the collected

fluid becomes cloudy as a consequence of the appearance of polymorphonuclear

leukocytes, degenerated cells, and fibrin. Ultimately, the vesicles either rupture and

release infectious fluid or gradually become reabsorbed.

Transmission is likely by the respiratory route, followed by localized replication

at an undefined site, which leads to seeding of the reticuloendothelial system and,

ultimately, viremia. The occurrence of viremia in patients with chickenpox is supported

by the diffuse and scattered nature of the skin lesions and can be verified in

selected cases by the recovery of virus from the blood. As noted, the mechanism of

the reactivation of VZV that results in herpes zoster is unknown.

Clinical manifestations

Herpes zoster, or shingles, is characterized by a unilateral vesicular eruption

with a dermatomal distribution. Thoracic and lumbar dermatomes are most

commonly involved (Fig. 9). Herpes zoster may involve the eyelids when the first

or second branch of the fifth cranial nerves is affected, but keratitis heralds a sight-

threatening condition, herpes zoster ophthalmicus. Although lesions on the tip of

the nose are said to presage corneal lesions, absence of such skin lesions does not

guarantee corneal sparing. Keratitis may be followed by severe iridocyclitis, secondary

glaucoma, or neuroparalytic keratitis. Ophthalmologic consultation should be

requested for any patient with suspected herpes zoster ophthalmicus. Generally,

the onset of disease is heralded by pain within the dermatome that precedes the

lesions by 48-72 hours. Early in the disease course erythematous, macropapular

lesions will appear that rapidly evolve into a vesicular rash. Vesicles may coalesce

to form bullous lesions. In the normal host these lesions continue to form over a

period of 3-5 days, with the total duration of disease being 10-15 days. However, it

may take as long as 1 month before the skin returns to normal.

Unusual cutaneous manifestations of herpes zoster, in addition to herpes zoster

ophthalmicus, include the involvement of the maxillary or mandibular branch of the

trigeminal nerve, which results in intraoral involvement with lesions on the pallet,

tonsillar fossa, floor of the mouth, and tongue. When the geniculate ganglion is

involved, the Ramsay-Hunt syndrome may occur, with pain and vesicles in the external

auditory meatus, loss of taste in the anterior two-thirds of the tongue.

132

Infectious diseases

No known factors are responsible for the precipitation of the events of

herpes zoster. If herpes zoster occurs in children, the course is generally benign

and not associated with progressive pain or discomfort. In adults, systemic

manifestations are mainly those associated with pain, as noted below.

The most significant clinical manifestations of herpes zoster are the associated

acute neuritis and, later, post-herpetic neuralgia. Post-herpetic neuralgia, although

uncommon in young individuals. may occur in as many as 25-50 % of patients

over the age of 50 years. It is estimated that as many as 50 % of individuals over

50 years of age will have debilitating pain that persists for over 1 month. Post-

herpetic neuralgia may cause constant pain in the involved dermatome or consist

of intermittent stabbing pain. Pain may be worse at night or on expose to temperature

changes. At its worst, the neuralgia can be incapacitating.

Extracutaneous sites of involvement include the central nervous system as

manifested by meningoencephalitis or encephalitis. The clinical manifestations

are similar to that of other viral infections of the central nervous system.

However, a rare manifestation of central nervous system involvement by herpes

zoster is granulomatous cerebral angiitis which usually follows zoster

ophthalmicus. It should be noted that involvement of the central nervous system

in cutaneous herpes zoster probably is more common than is recognized clinically.

Frequently, patients who undergo cerebrospinal fluid examination for other reasons

during episodes of shingles are found to have evidence of pleocytosis without

elevated cerebrospinal fluid protein levels. These patients are without signs of

meningeal irritation and frequently complain of headaches.

Classically, VZV infection involves dorsal root ganglia. Motor paralysis can

occur as a consequence of the involvement of the anterior horn cells in a

manner similar to that encountered with polio. Patients with involvement of the

anterior horn cells are particularly likely to have excruciating pain. Other neuro-

muscular disorders associated with herpes zoster include Guillain-Barre syndrome,

transverse myelitis, and myositis.

Herpes zoster in the immunocompromised host is more severe than in the

normal individual. Lesion formation continues for up to 2 weeks, and scabbing may

not take place until 3-4 weeks into the disease course. Patients with lymphoproliferative

malignancies are at risk for cutaneous dissemination and visceral involvement, including

varicella pneumonitis, hepatitis, and meningoencephalitis. However, even in the

immunocompromised patient disseminated herpes zoster is rarely fatal.

In recent years, herpes zoster has been recognized as a frequent infection in

individuals with human immunodeficiency virus (HIV) infection, occurring in 8-

11 percent of patients. Although the occurrence of cutaneous dissemination is

infrequent, complications such as VZV retinitis, acute retinal necrosis, and chronic,

progressive encephalitis have been reported.

Chronic herpes zoster may also occur in the immunocompromised host

particularly those individuals with a diagnosis of HIV infection. Individuals have

133Herpetic diseases

sustained new lesion formation with an absence of healing of the existing lesions.

These syndromes can be particularly debilitating and, interestingly, have been

associated with the isolation of VZV isolates resistant to acyclovir.

Diagnosis

The diagnosis of shingles is usually made by history and physical examination.

The recent development of monoclonal antibodies to individual herpes virus antigens

should allow for the more precise identification and typing of HSV isolates.

Differential diagnosis

Differential diagnosis of varicella and herpes zoster is less confusing than it

was 20-30 years ago. Smallpox or disseminated vaccinia was confused with

varicella because of the similar appearance of the cutaneous lesions. With the

worldwide eradication of smallpox and the discontinuation of vaccination, these

disease entities no longer confound the clinical diagnosis. For the most part the

characteristic skin rash with lesions in all stages of development provides the

basis for the clinical diagnosis of infection. The localization and distribution of a

vesicular rash makes the diagnosis of herpes zoster highly likely; however,

other viral exanthems can occasionally be confused with this disease.

Impetigo and varicella can also be confused clinically. Impetigo is usually

caused by group A (β-hemolytic) streptococci and often follows an abrasion of

the skin or inoculation of bacteria at the site of the skin break, and can lead to

small vesicles in the surrounding area. Systemic signs of disease may be present

if progressive cellulitis or secondary bacteremia develops. Unroofing these lesions

and careful Gram staining of the scraping of the base of the lesion should reveal

gram-positive cocci in chains, which are streptococci presumably, or gram-positive

cocci in clusters, which are staphylococci presumably, another cause of vesicular

skin lesions. Treatment for these latter infections is distinctly different from that

of chickenpox and requires administration of an appropriate antibacterial remedies.

In a smaller number of cases, disseminated vesicular lesions can be caused

by herpes simplex virus. In these cases, disseminated herpes simplex virus infection

is usually a consequence of an underlying skin disease such as atopic dermatitis

or eczema. In this situation, an unequivocal diagnosis can only be confirmed by

isolation of the virus in tissue culture.

More recently, it has been recognized that disseminated enteroviral infections,

particulary those caused by group A coxsackieviruses, can cause widespread

distal vesicular lesions. These rashes are more commonly morbilliform in nature

with a hemorrhagic component rather than vesicular or vesiculopustular

appearance. Generally these infections occur during the enterovirus season in

late summer and early fall and are associated with lesions of the oropharynx,

palms, and soles. This latter finding is most helpful in distinguishing enteroviral

disease from chickenpox.

134

Infectious diseases

Treatment

Acyclovir is approved for the treatment of herpes zoster in the normal

host. Adolescents and adults can receive up to 800 mg 5 times a day. Oral

therapy of herpes zoster in the normal host accelerates cutaneous healing and

reduces acute neuritis. The effect of therapy on post-herpetic neuralgia is marginal

at best. Properly designed and controlled clinical trials have not supported the

utility of corticosteroids as an adjunct to antiviral therapy.

Corticosteroid therapy alone has been suggested to be useful for decreasing

both acute neuritis and the frequency of post-herpetic neuralgia: however, these

data are controversial. In the immunocompromised host or with the appearance of

visceral complications such as varicella pneumonitis in the normal host, the use of

either intravenous acyclovir or vidarabine is of value. Vidarabine has been

extensively studied for the treatment of herpes zoster in the immunocompromised

hosts. Although efficacy is apparent, it has been replaced by acyclovir.

The management of acute neuritis and/or post-herpetic neuralgia can be

particularly problematic. It requires the judicious use of analgesics ranging from

non-narcotic to narcotic derivatives and may include the deployment of such

drugs as amitriptyline hydrochloride and fluphenazine hydrochloride.

Prophylaxis

Disease can be prevented by administering zoster immune globulin (ZIG),

derived from the sera of patients recovering from herpes zoster, or varicella

zoster immune globulin (VZIG) prepared from pooled plasma containing high

titers of specific antibody. Such preparations should be given within 96 hours

after exposure to be effective.

Control questions:

1. Etiology, epidemiology and incidence of herpes simplex virus infections.

2. Pathogenesis of herpes simplex virus (HSV) infections.

3. Main clinical symptoms and signs of primary HSV infections.

4. Clinical manifestations of recourse HSV infections.

5. Complications of HSV infections.

6. Etiology of Varicella-zoster virus (VZV) infections.

7. Pathogenesis of VZV infections.

8. Clinical manifestations of VZV infections.

9. Complications of VZV infections.

10. Laboratory methods of herpetic diseases diagnosis.

11. Differential diagnosis of herpetic infections.

12. Treatment of herpetic infections.

13. Herpetic diseases prophylaxis.

135Erysipelas. Erysipeloid

ERYSIPELAS. ERYSIPELOID

ERYSIPELAS

Erysipelas is an acute inflamation of the skin, with marked involvement of

cutaneus lymphatic vessels.

Etiology

Erysipelas is almost always caused by group A streptococci (sometimes by

group Ñ or G). Group Â streptococci cause erysipelas of newborn children.

Epidemiology

Erysipelas is common disease of infants, children of early age, and old

people. Formerly, the face was often involved, and antecedent streptococcal

respiratory tract infection preceded cutaneous involvement in about one-third of

patients, even though streptococci might not be found on culture when skin

lesions became evident.

Pathogenesis

Most interest is focused on streptococcal pyrogenic exotoxins (SPEs). In

edition to mediating the scarlatinal rush, SPE exibit a variety of adverse biologic

effects, including the multiorgan damage and lethal shock. There is an amino acid

homology of 50 % and immunologic reactivity between SPE A and staphylococcal

enterotoxins B and C. SPE of group A streptococcus is a superantigen and it is

a potent inducer of tumor necrosis factor.

The antistreptolysin O response after cutaneous streptococcal infection is

weak. There is experimental evidence to suggest that this may be due to local

inactivation of streptolysin O by skin lipids. The immune response to antiDNase

B is brisk, and antihyaluronidase reactivity is also a useful test in the serodiagnosis

of erysipelas.

Clinical manifestations

Now the localization of erysipelas has changed: 70-80 % of the lesions are

on the lower extremities and 5-20 % are on the face. Entry gates are commonly

skin ulcers, local trauma or abrasions, psoriatic or eczematous lesions, fungal

infections; in the neonate, erysipelas may develop from infection of the umbilical

stump. Predisposing factors include venous stasis, paraparesis, diabetes mellitus,

and alcohol addiction. Patients with the nephrotic syndrome are particularly

susceptible. Erysipelas tends to occur in areas of preexisting lymphatic obstruction

or edema (e.g. after radical mastectomy). Also, because erysipelas itself produces

136

Infectious diseases

lymphatic obstruction, it tends to recur in an area of earlier infection. Over a 3-

year period, the recurrence rate is about 30 %, predominantly in individuals with

venous insufficiency or lymphedema.

Streptococcal bacteremia occurs in about 5 % of patients with erysipelas;

group A, C, or G streptococci can be isolated on throat culture from about 20 %

of cases.

Erysipelas is a painful lesion with a bright red, edematous, indurated (“peau

d’orange”) appearance and an advancing, raised border that is sharply demarcated

from the adjacent normal skin. Fever is a feature. A common form of erysipelas

involves the bridge of the nose and the cheeks (Fig. 10). Uncomplicated erysipelas

remains confined primarily to the lymphatics and the dermis. Occasionally, the

infection extends more deeply, producing cellulitis, subcutaneous abscess, and

necrotizing fasciitis.

Leukocytosis is common sign of erysipelas. Group A streptococci usually

cannot be cultured from the surface of the skin lesion, and only rarely they can be

isolated from tissue fluid aspirated from the advancing edge of the lesion. In

cases of erysipelas complicating infected ulcers, group A streptococci have been

isolated from the ulcerated area in 30 % of patients.

Complications

Bacteremic spread of the streptococci may result in a variety of metastatic

foci of infection, for example, suppurative arthritis, endocarditis, meningitis or

brain abscess, osteomyelitis, liver abscess, and so forth. The local complications

are abscess and streptococcal cellulitis, skin necrosis and ulcers, thrombophlebitis,

otitis and others. Suppurative lymphadenitis may also occur.

Diagnosis

Diagnosis is usually easy due to characteristic manifestatioms of erysipelas.

It is difficult to isolate culture of erysipelas infectious agent from the lesion, but

it may occasionally be cultured from the blood.

Differential diagnosis

The diagnosis is made on the basis of characteristic manifestatioms of the

lesion and the clinical setting. Early herpes zoster involving the second division

of the fifth cranial nerve may resemble unilateral facial erysipelas but can be

distinguished by the pain and hyperesthesia preceding the skin lesions.

Occasionally contact dermatitis or giant urticaria may look like erysipelas but

can be distinguished by the absence of fever and the presence of pruritus.

Lesions closely resembling erysipelas, but apparently not due to streptococcal

infection, may occur recurrently in patients with familial Mediterranean fever.

Diffuse inflammatory carcinoma of the breast may mimic a low-grade erysipelas.

Erythema chronicum migrans, the cutaneous lesion of Lyme disease, resembles

137Erysipelas. Erysipeloid

erysipelas but is not painful and progresses much more slowly, and the associated

fever is less marked. An erysipelas-like skin lesion has occurred in several

patients with hypogammaglobulinemia and Campylobacter jejuni bacteremia.

Treatment

Treatment is carried out according to the clinical form and gravity of disease.

Antibiotics of penicillinic lines are effective. In case of initial and repeated

erysipelas benzylpenicillin has to be given during 7-10 days. At serious course,

complications, rapid local inflammatory changes, enlarge daily dose of preparation

up to 8 – 12 million units. Among semisynthetic penicillines, ampicillin, oxacillin,

amoxacillin (bactox, ospamox) are considered effective. At serious course of

disease, development of a sepsis one have to use a combination of two antibiotics,

for example ampicillin and gentamicin. For treatment of frequently relapsing

erysipelas one should apply ampicillin, ampiox, amoxyclav, oletetrin, lincomicin,

cefaloridin, cefazolin (kefzol), cefotaxim (claforan), at intolerance of antibiotics –

furazolidon, bactrim. Course of treatment is 8 -10 days. If the residual phenomena

of disease are keeping, after 7 – 10 days one should indicate repeated course of

treatment by other antibiotic. Indicate fluoroquinolones – ofloxacin, ciprofloxacin

(ciprobai, ciprobid) etc.

Patients with the mild form of erysipelas can be treated ambulatory, using

bactrim, furazolidon, furagin, chingamin (delagil) in average therapeutic doses

during 10 days.

At presence of expressed infiltration and pain syndrome indicate non steroid

anti-inflammatory preparations – indomethacin, mefanamic acid, paracetamol.

Indication of immunostimulators is proved – prodigiosan, sodii nucleinat, splenin,

methyluracil. The best results is reached in case of the combination of 2 – 3

imunostimulatores. Course of treatment is 10 days.

The patients with frequently relapsing erysipelas and the phenomena of

lymphostasis should administer, besides antibiotic therapy, prednisolon in tablets

0.005 gm – 20-30 mg per day with a gradual dose decline or its analogue.

It is expedient to apply preparations which reduce a permeability of capillaries

– rutin in tablets 0.02 gm, ascorutin in tablets, an ascorbic acid in tablets 0.05 gm,

calcii gluconat in tablets 0.5 gm, vitamin preparations of B group, retinoli acetat

and also desensitizing agents – dimedrol in tablets 0.05 gm, suprastin in tablets

0.025 gm, tavegil in tablets 0.001 gm, diazolin in tablets 0.05 gm.

The patients with serious form of erysipelas and expressed intoxication are

given reopoliglycin, 5 % solution of glucose with addition of corglykon,

cocarboxylase, ascorbic acid, diuretic preparations – furosemid, etacrin acid,

spironolacton (veroshpiron) are also indicated.

At bullous form large bubbles should be cut off and use bandage with

solution of aethacridin, 0.02 % solution of furacilin or ectericid with chlorophylypt,

juice of calanhoe – fifty-fifty with 0.5 % solution of novocain.

138

Infectious diseases

If purulent-septic process appeares, phlegmon is formed, applications with

30 % a solution of dimexidum with the dissolved antibiotic in a single dose

5000 units of heparinum in every 12 hours during 4-5 days are locally applied.

The same antibiotics are infused parenterally. Unguental bandages at local purulent

processes are contrindicated.

Local treatment is combined with indication of physiotherapeutic procedures:

in acute period ultra violet radiation and photoradiotherapy, during reconvalescence

period – inductothermy, electroforesis of potassii iodidi, calcii chloridi, lydasi;

ozocerit or parafin, radon baths.

After transferred initial, repeated and seldom relapsing erysipelas at presence

of the residual phenomena give bicillin-5 (in bottles 1,500,000 units): in muscle

in every 4 weeks during 3-4 months. The patients with often and repeated

relapses are treated. Bicillin-5 is infused monthly during 2-3 years. Necessity of

repeated injections with bicillin-5, it is expedient for checking with the help of

thermal imager researches. Paralelly with bicilinoprofilaxis stimulators of immune

system – methyluracil, prodigiosan, natrii nucleinici, fortifying treatment –

polyvitamines, eleuterococ extract, tinctura araliae, pantocrin etc are indicated.

The sanitation of chronic streptococcal infection, mycosis is indicated.

Prophylaxis

Adherense to good regimens of personal hygiene, with special attention to

frequent scrubbing with soap and water, is the most effective preventive measure

currently available. The in time treatment of streptococcal pharyngitis is of

much importance.

ERYSIPELOID

Erysipeloid is an acute, but slowly ewolwing, skin infection.

Historic reference

First isolated from mice by Robert Koch in 1878 and from swine by Louis

Pasteur in 1882, it was established as the etiologic agent of swine erysipelas in 1886

by Loeffler and as a human pathogen in 1909 when Rosenbach isolated it from a

patient with localized cutaneous lesions. Rosenbach coined the term “erysipeloid” to

avoid confusion with “erysipelas”, a superficial cellulitis with prominent lymphatic

involvement that is almost always caused by group A streptococci.

Etiology

Erysipelothrix rhusiopathiae is a straight or slightly curved aerobic or

facultatively anaerobic bacillary organism; it is 0.2-0.4 mm diameter and 0.8-2.5

mm in length. It is gram-positive but may appear gram-negative because it

“decolorize” readily. Organisms may be arranged singly, in short chains, in pairs

in a “V” configuration or grouped randomly. Nonbranching filaments that can

139Erysipelas. Erysipeloid

be greater than 60 mm in length are sometimes seen. There is a dual colonial

and microscopic appearance that varies with the medium, pH and temperature of

incubation. After growing for 24 hours at 37 °C, colonies are small and transparent

with a smooth glistening surface.

Erysipelothrix rhusiopathiae is sometimes confused with other gram-positive

bacilli, in particular with Listeria monocytogenes, Actinomyces

(Corynebacterium) pyogenes, and Arcanobacterium (Corynebacterium)

haemolyticum, but these three species are β-hemolytic on blood agar and do not

produce hydrogen sulfide in the butt on TSI agar slants. Furthermore, L.

monocytogenes is catalase-positive and motile.

Epidemiology

Erysipelothrix rhusiopathiae is found worldwide. It has been reported as a

commensal or a pathogen in a wide variety vertebrate and invertebrate species,

but the major reservoir believed to be domestic swine. It does not appear to

cause disease in fish but can persist for long periods of time in the mucoid

exterior slime of these animals. It may live long enough in soil to cause infection

weeks or months after initial contamination. The greatest commercial impact of

E. rhusiopathiae infection is due to disease in swine, but infection of turkeys,

ducks, and sheep is also important. The organism is ñîmmunicable from animals

to human by direct cutaneous contact. The risk of human infection with

Erysipelothrix is related to the opportunity for exposure to the organism, and

hence, most human cases are related to occupational exposure. Although infection

with Erysipelothrix has been associated with a wide variety of occupations,

those at greatest risk include, fisherman, fish handlers, butchers, slaughterhouse

workers, veterinarians, and housewives. Infection is especially common among

individuals who handle fish. “Whale finger” is erysipeloid seen in those who

sustain cuts to their fingers and hands while engaged in whaling. Human-to-

human transmission of infection has not been mentioned.

Pathogenesis

Abrasions or puncture wounds of the skin probably serve as the portal of

entry of E. rhusiopathiae in most cases of infection in humans and in other

animals. Erysipelothrix rhusiopathiae produces a neuraminidase and a

hyaluronidase. The activity of these enzymes may correlate with virulence. The

neuraminidase may have a role in the pathogenesis of arteritis and thrombocytopenia

in an experimental rat model of Erysipelothrix infection. The rhomboidal skin

lesions seen in swine are the result of thrombotic vasculitis of end arterioles.

Clinical manifestations

Three clinical categories of human disease have described: (1) erysipeloid,

a localized skin lesion, (2) a diffuse cutaneous eruption with systemic symptoms,

and (3) bacteremia, which is often associated with endocarditis.

140

Infectious diseases

The localized cutaneous form or “erysipeloid of Rosenbach”, a subacute

cellulitis, is the most common type of infection seen in humans. It is a cellulitis.

Because the organism is acquired through contact with infected animals, fish, or

their products, with organisms gaining entrance via cuts or abrasions on the

skin, most lesions are on the fingers. Following an incubation period of 2-7 days,

pain (which is often severe and described as burning, itching or throbbing) and

swelling of the involved digit or part of the hand develop. The lesion is well-

defined, slightly raised, and violaceous in color. As it spreads peripherally, the

central area fades. Vesiculation may occur. Regional lymphadenopathy and

lymphangitis occur in approximately one-third of cases. There may be arthritis

of an adjacent joint. Systemic symptoms are uncommon. Part of patients have

low-grade fever and arthralgias. Erysipeloid can be distinguished clinically from

staphylococcal or streptococcal cellulitis by the absence of suppuration, the lack

of pitting edema, the violaceous color, and the disproportionate pain. Because

pathogens are located only in deeper layers of the skin in cases of erysipeloid,

aspirates or biopsy specimens should be of the entire thickness of the dermis

and from the periphery of the lesion to maximize the chance of recovery of the

organism. Erysipeloid usually resolves without treatment within 3 or 4 weeks.

The diffuse cutaneous form, which is rare, occurs when the violaceous

cutaneous lesion progresses proximally from the site of inoculation or appears

at remote areas. Lesions may appear urticarial with the rhomboid pattern

characteristic of swine erysipelas. Fever and arthralgias are common. Blood

cultures are negative. The course is more protracted than in the localized form

and recurrence is common.

Systemic infection with E. rhusiopathiae is unusual. In approximately 60 %

of patients, E. rhusiopathiae endocarditis developed on previously normal heart

valves. In patients with bacteremia and/ or endocarditis, routine blood culture

techniques are adequate for recovery of the organism.

Complications

Complications of Erysipelothrix endocarditis include congestive heart failure,

myocardial abscess, aortic valve perforation, meningitis, and glomerulonephritis.

Bacteremia without endocarditis has been reported with increasing frequency.

It has occurred primarily in immunocompromised hosts. Brain abscess, osteo-

myelitis, and chronic arthritis have also been reported.

Diagnosis

Definitive diagnosis of infection with Erysipelothrix requires isolation of

the organism from a biopsy specimen or blood. There are no reliable serologic

tests for the diagnosis of infection in humans.

Differential diagnosis

Erysipeloid must be differentiated from erysipelas, arm of hand herpes

zoster, contact dermatitis and angioneurotic edema.

141Erysipelas. Erysipeloid

Treatment

Susceptibility data for E. rhusiopathiae are limited. Most strains are highly

susceptible to penicillins, cephalosporins, clindamycin, imipenem, and ciproflo-

xacin. Penicillin and imipenem are the most active agents in vitro. Susceptibility

to chloramphenicol, erythromycin, and tetracycline is variable. Most strains are

resistant to vancomycin, sulfonamides, trimethoprim-sulfamethoxazole, novobiocin,

teicoplanin, and aminoglycosides. Resistance to vancomycin is important because

this agent is often used empirically to treat bacteremia due to gram-positive

organisms. Use of fluoroquinolones may be considered in Erysipelothrix infections

when b-lactams are contraindicated. In cases of endocarditis, the duration of

intravenous antibiotic therapy should be 4-6 weeks, although shorter courses (2

weeks of intravenous therapy followed by 2-4 weeks of oral therapy) have been

successful. Although erysipeloid usually resolves spontaneously, healing is

hastened by antibiotic therapy.

Prophylaxis

Prevention of infection for those in high-risk occupations depends on the

use of protective attire such as gloves. Unprotected direct contact with animal

body tissues and secretions should be avoided. There are live attenuated vaccines

available for veterinary use. Use of vaccination along with other measures such

as improved waste disposal has helped to control swine erysipelas.

Control questions:

1. Etiology, epidemiology and incidence of erysipelas and erysipelotrix.

2. Pathogenesis of erysipelas and erysipelotrix.

3. Clinical manifestations of erysipelas and erysipelotrix.

4. Laboratory methods of diagnosis.

5. Criteria of diagnosis.

6. Differential diagnosis of erysipelas and erysipelotrix.

7. Treatment of erysipelas and erysipelotrix.

8. Prophylaxis of erysipelas and erysipelotrix.

142

Infectious diseases

ANTHRAX

Bacillus anthracis is a gram-positive spore-forming bacillus that can cause

acute infection in both animals and humans. It is primarily a disease of herbivores,

which acquire infection after coming into contact with soil-borne spores. In its

spore form it can persist in nature for prolonged periods, possibly years. The

distribution of anthrax is worldwide.

The disease occurs primarily in three forms: cutaneous, respiratory and

gastrointestinal. The incidence of anthrax has decreased in developed countries

but it remains a considerable health problem in developing countries.

Historic reference

The earliest known description of anthrax is found in the book of Genesis:

the fifth plague (1491 ÂÑ), which appears to have been anthrax, was described as

killing the Egyptians cattle. There are descriptions of anthrax involving both

animals and humans in the early literature of Hindus, Greeks, and Romans. In the

17th century, a pandemic referred to as “the black bane” swept through Europe,

causing many human and animal deaths. Later the disease in humans was

described as “the malignant pustule”.

Several distinguished microbiologists in the 19th century characterized the

pathology of the disease and attempted to develop a vaccine because of serious

problems with anthrax in the livestock industry. Pasteur developed and field tested

in sheep his attenuated spore vaccine in 1881. In 1939, Sterne reported his development

of an animal vaccine that is a spore suspension of an avirulent, noncapsulated live

strain. This is the animal vaccine currently recommended for use.

Occupational anthrax occurred 18th century in industrial European countries

such as England and Germany. Early in this century, in the United States, it

occurred in individuals who handled materials that had been woven from

contaminated animal fibers.

From the beginning of this century the annual number of cases reported in

developed countries has steadily decreased. This decrease is the result of the

use of a cell-free anthrax vaccine in humans who are in high-risk industrial

groups, decreased use of imported potentially contaminated animal products,

improved hygiene in industry, and improved animal husbandry.

Etiology

Pus or tissue from patients suspected to have anthrax should be stained by

both Gram stain, to reveal gram-positive bacilli, and polychrome methylene blue, to

show the polypeptide capsule. Bacilli are usually abundant in the specimen and

easy to culture on standard blood or nutrient agar. In heavily contaminated

143Anthrax

specimens such as stool it may be necessary to use selective agar or deconta-

mination methods that rely on the resistance of the anthrax spores to heat or

ethanol. The colonies are gray-white to white and nonhemolytic. Identification of

the isolate depends on biochemical tests, presence of a capsule, lack of motility,

catalase positivity, lysis by bacteriophage, penicillin susceptibility, and aerobic

endospore production. Commercially available test strips and fluorescent antibody

staining can be used to aid identification.

Epidemiology

Anthrax is usually a disease of herbivores and only incidentally infects

humans who come into contact with infected animals or their products. Because

anthrax remains a problem in developing countries, animal products imported

from these areas continue to pose a risk.

Human cases may occur in an industrial or in an agricultural environment.

Industrial cases result from contact with anthrax spores that contaminate raw

materials that are used in manufacturing processes. In the United States, occasional

epidemics occurred in industrial settings, probably related to the processing of

batches of highly contaminated imported animal fibers, particularly goat hair.

These epidemics were primarily of cutaneous anthrax.

One epidemic was recently reported in Switzerland. Within less than 3

years, 25 workers in one textile factory contracted the disease; 24 cases had

cutaneous and one inhalation anthrax. The infection was imported in goat hair

from Pakistan. The rarity of the illness contributed to a general lack of experience

and therefore hindered recognition of the clinical symptoms. In addition, repeated

attempts failed to identify the pathogenic agent conclusively.

Human cases of anthrax in an agricultural environment result from direct

contact with animals that are sick or have died from anthrax.

In Africa there have been multiple epidemics of human disease associated with

epizootics of anthrax in cattle. The largest reported agricultural outbreak occurred in

Zimbabwe, with more than 10,000 cases reported between 1979 and 1985. Endemic

cases continue to occur in the involved area. The majority of patients had cutaneous

infections located primarily on the exposed parts of the body; some gastrointestinal

cases were also reported. Domestic cattle deaths were noted. A similar large outbreak

of human and animal anthrax occurred in Chad, mainly in the Department of Chari

Baguirmi, from September to December 1988, infecting more than 50 % of donkeys

and horses. There were 716 human cases reported, with 88 deaths.

In African wildlife, which cannot easily be vaccinated and in which the other

aspects of control are not relevant, the disease remains a major cause of

uncontrolled mortality in herbivores.

Organisms can also be transmitted by a common vehicle such as food (meat),

although this is more rare. Large outbreaks have been reported in Thailand and

Russia. This last outbreak of human anthrax occurred in north central Russia in

1979, in which the government health authorities of the former U.S.S.R. reported

144

Infectious diseases

that the source of infection was contaminated meat. Officially there were 96 cases:

79 of gastrointestinal anthrax and 17 of cutaneous anthrax. However, there is novel

evidence concerning the real nature of this anthrax outbreak. Intelligence authorities

in the United States had initially reported hundreds of fatalities, including military

personnel, and had suspected that an explosion at a secret germ warfare facility in

Sverdlovsk had sent deadly anthrax spores airborne. The United States has repeated

this allegation, but it never formally accused the former U.S.S.R. of violating the

germ warfare treaty or substantiated its charge. The hospital records of the patients

affected by this outbreak including the autopsy reports have been unavailable.

Recently two Russian pathologists published hidden secret information

describing the necropsy of 42 cases, which consistently revealed pathologic

lesions diagnostic of inhalation anthrax. Main features include hemorrhagic

necrosis of the thoracic lymph nodes in the lymphatic drainage of the lungs and

hemorrhagic mediastinitis. This information underscores the potential use of B.

anthracis in biological warfare.

Pathogenesis

The virulence of B. anthracis is determined by the presence of three

components: edema toxin, lethal toxin, and capsular material. To exert their

effect within cells, both edema and lethal toxin require participation of a common

transport protein called protective antigen. The capsule material contains poly-

D-glutamic acid, which helps protect the bacillus from ingestion by phagocytes.

Production of the toxic factors is regulated by one plasmid and that of the

capsular material by a second plasmid.

The effects of anthrax toxin components on human neutrophils have been

studied in detail. Phagocytosis of opsonized and radiation killed B. anthracis was

not affected by the individual anthrax toxin components. However, a combination

of lethal toxin and edema toxin inhibited bacterial phagocytosis and blocked the

oxidative burst of polymorphonuclear neutrophils. The two-toxin combination

also increased intracellular cyclic AMP levels. These studies suggest that two of

the protein components of anthrax toxin increase host susceptibility to infection

by suppressing polymorphonuclear neutrophil function and impairing host resistance.

Experiments performed in animals suggest that spores deposited beneath the

skin or in the respiratory or intestinal mucosa germinate and the resulting vegetative

forms multiply and produce a toxin. The local lesion results from the action of the

toxin on the surrounding tissue, which causes tissue necrosis. The toxin or organisms

or both may disseminate by the vascular system, causing systemic symptoms and

signs of toxicity or bacteremia. Organisms are also often picked up by the lymphatic

system, resulting in lymphangitis and lymphadenopathy.

Anatomic pathology

The most significant findings at autopsy are those seen in patients who have

died of inhalation anthrax. The classic finding is that of hemorrhagic mediastinitis

145Anthrax

with enlarged, hemorrhagic lymphadenitis. There may be inflammation of the

pleura and some pleural effusion. Some patients may have hemorrhagic meningitis,

and hemorrhages may be seen in the gastrointestinal tract.

In deaths due to gastrointestinal anthrax there is typically hemorrhagic

enteritis, with congestion, thickening, and edema of the intestinal walls. Mucosal

ulcers with necrosis may be seen in the terminal ileum and cecum. The regional

lymph nodes are enlarged, edematous, and hemorrhagic with some necrosis.

There may be acute splenitis. Peritonitis with ascitic fluid is often present.

Clinical manifestations

Approximately 95 % of anthrax cases in developed counties are cutaneous

and 5 % are respiratory: confirmed epidemic cases of gastrointestinal anthrax

have often been reported in “Third World” countries.

Cutaneous anthrax. The clinical presentation of cutaneous anthrax is so

characteristic that the diagnosis is not often missed by physicians familiar with the

disease. Most of the cases occur in exposed skin areas mostly on the arms and

hands followed by the face and neck. The infection begins as a pruritic papule that

resembles an insect bite. The papule enlarges and within 1 or 2 days develops into

an ulcer surrounded by vesicles. The lesion is usually 1-3 cm in diameter and

usually remains round and regular. A characteristic black necrotic central eschar

develops later with associated edema. The lesion is most often painless and may

first be noticed because of pruritus. After 1-2 weeks the lesion dries, and the eschar

begins to loosen and shortly thereafter separates, revealing a permanent scar. There

may be regional lymphangitis and lymphadenopathy and some systemic symptoms

such as fever, malaise, and headache. Antibiotic therapy does not appear to change

the natural progression of the lesion itself: however, it will decrease or inhibit

development of edema and systemic symptoms. Differential diagnosis include

conditions due to potential contact with infected animals such as plague and tularemia.

Respiratory anthrax. Respiratory anthrax shows a biphasic clinical pattern

with a benign initial phase followed by an acute, severe second phase that is

almost always fatal. The initial phase begins as a nonspecific illness consisting of

malaise, fatigue, myalgia, mild fever, nonproductive cough, and, occasionally, a sensation

of precordial oppression.

The illness may cause disorder of upper respiratory tract such as a cold or

influenza. After 2-4 days, the patient may show signs of improvement. However,

there is then the sudden onset of severe respiratory distress characterized by

severe hypoxia and dyspnea. In several cases, subcutaneous edema of the chest

and neck has been described. The pulse, respiratory rate and temperature become

elevated. Physical examination reveals moist, crepitant rales over the lungs and

possibly evidence of pleural effusion. Radiographic examination of the chest may

reveal widening of the mediastinum and pleural effusion. Patients soon become

hypotensive and septicemia and meningitis may develop. Death occurs in most

146

Infectious diseases

persons with inhalation anthrax within 24 hours after the onset of the acute phase.

Inhalation anthrax is very difficult to diagnose early.

Gastrointestinal anthrax. The incubation period of gastrointestinal anthrax

is commonly 3-7 days. There are two clinical presentations following ingestion

of B. antracis - contaminated food: abdominal and oropharyngeal.

The symptoms of abdominal anthrax are initially nonspecific and include

nausea, vomiting, anorexia, and fever. Lesions are frequently described in the

cecum and adjacent areas of the bowel. Some reports have described lesions in

the large bowel, and rarely in the duodenum. With progression of the disease

abdominal pain, hematemesis. and bloody diarrhea develop. With further

progression toxemia develops, with shock, cyanosis, and death. The time from

onset of symptoms to death has most frequently varied from 2 to 5 days.

In the oropharyngeal form edema and tissue necrosis occur in the cervical

area. There are several reports describing the development of an inflammatory

lesion resembling a cutaneous lesion in the oral cavity involving the posterior

wall, the hard palate, or the tonsils. The main clinical features are sore throat,

dysphagia, fever, regional lymphadenopathy in the neck and toxemia. Most of

these patients die with toxemia and sepsis.

Meningitis. Meningitis, seen in less than 5 % of anthrax cases, may be a

complication of any of the three forms of primary anthrax infection.

Diagnosis

Of importance in considering a diagnosis of anthrax is a source of exposure

to the infectious agent. Only rarely cases have occurred for which the source of

infection could not be identified. Cutaneous anthrax should be suspected when

an individual describes a painless, pruritic papule, sometimes surrounded by

vesicles usually on an exposed part of the body. For the detection of anthrax

bacillus, sterile swabs should be soaked in the fluid of the vesicles, vesicular fluid

should reveal B. anthracis organisms microscopically and on culture. Anthrax

bacilli are easily seen on Gram stain smears and cultures from vesicular fluid.

An enzyme-lined immunosorbent assay (EL1SA) has been developed that

measures antibodies to the lethal and edema toxins. The diagnosis may be

confirmed serologically by demonstrating a fourfold change in liter in acute- and

convalescent-phase serum specimens collected 4 weeks apart or by a single

titer of greater than 1:32. Although extensive serologic studies have not been

conducted, antibody liters in some surveys of exposed individuals suggest some

degree of previous subclinical infection.

Differential diagnosis

Includes staphylococcal disease, plague and tularemia. The initial symptoms of

inhalation anthrax are nonspecific and resemble those of an upper respiratory tract

infection. Characteristically, with the sudden development of the acute phase there

is severe respiratory distress, and radiographic examination of the chest should

reveal widening of the mediastinum, a typical occurrence with inhalation anthrax.

147Anthrax

In gastrointestinal anthrax, the patient presents with signs and symptoms of

gastroenteritis. Organisms may be demonstrable in vomitus and feces from the

infected individual. The differential diagnosis includes diseases that cause

moderately severe gastroenteritis, such as shigellosis and Yersinia gastroenteritis.

In the cervical form, the signs and symptoms might suggest severe pharyngitis,

such as is sometimes seen with streptococcal infections.

In anthrax meningitis and in septicemia there should be a primary site of

infection. Cerebrospinal fluid (CSF) and blood contain B. anthracis.

Treatment

The basic agents are antibiotics and antianthrax immunoglobulin. Among

the antibiotics ciprofloxacin or ofloxacin are preparations of choice. At generalized

infection ciprofloxacin is used 0.4 or 0.5 gm twice a day. Course of treatment is

5-10 days. Benzylpenicillini natrium sodium salt 500,000-1 million units is effective,

6-8 times per day. At the generalized form of disease enlarge a daily dose of

preparation up to 12-24 million units. It is possible to use semipenicillines –

ampicillin or oxacillin. Course of treatment not less than 7-8 days. Alternative

preparations can be tetracyclin, levomycetin, streptomycin, gentamicin.

The best results are reached with the combined therapy of antibiotics and

antimalignant anthrax immunoglobulin. Last infuse in muscle in a dose from 20

up to 100 mL. Depend on clinical form and degree of gravity of disease.

Preliminary make intracutaneous test on sensitivity of organism to horse protein.

It is necessary in 1-2 days infuse immunoglobulin repeatedly before clinical

improvement. The course dose reaches sometimes 400 mL.

At serious current of disease use infusions of 5 % solution of glucose,

reopoliglycin, poliionic solutions, furosemid (lasix), glucocorticoides, oxygenotherapy.

Ðrophylaxis

Early in this century, as an example of health preventive intervention, a

formaldehyde disinfecting station was built by the British government in Liverpool.

All “dangerous” imported wool and goat hair were first washed in formaldehyde

baths, which successfully reduced contamination of the animal fibers with B. anthracis.

The resistance of the spore form of B. anthracis to physical and chemical agents

is reflected in the persistence of the organism in the inanimate environment. Organisms

have been demonstrated to persist for years in factories in which the environment

became contaminated during the processing of contaminated imported materials of

animal origin. Accordingly, they may serve as the source of infection for people who

work in the area. Special efforts are required to decontaminate this environment; one

method is to use paraformaldehyde vapor, which is successful in killing B. anthracis

spores. In the laboratory, surfaces may be decontaminated with either 5 % hypochlorite

or 5 % phenol (carbolic acid); instruments and other equipment may be autoclaved.

Employees should be educated about the disease and the recommendations

for working in a contaminated environment and for reducing the risk of developing

148

Infectious diseases

the disease. Medical consultation services should be available to the employees.

Adequate cleanup facilities and clothes-changing areas should be available so

that workers do not wear contaminated clothes home.

It should be noted that the risk of industrial infection has been reduced significantly

as the use of imported animal products decreased because of changing business

conditions, the increased use of synthetic materials, and the use of human vaccine.

Gastrointestinal anthrax can be prevented by forbidding the sale for

consumption of meat from sick animals or animals that have died from disease.

Depending on the circumstances, it may be important to alert individuals who

may come in contact with contaminated meat about the disease and about the

need to cook all meats thoroughly. Prophylactic penicillin may be used if

contaminated food has been ingested.

Animals that graze in areas known as anthrax districts should be vaccinated

annually with the animal vaccine. All animals suspected of dying from anthrax

should be examined microbiologically: blood or tissue smears can be examined

microscopically, and cultures can be set up from these same materials. Necropsies

with spillage of contaminated blood with resultant sporulation of organisms should

be avoided. All animals that have died with a confirmed diagnosis of anthrax should

be thoroughly burned and the remaining bones and other materials buried deeply.

Control of the disease in humans ultimately depends on control of the

disease in animals. Effective animal vaccines are available, and all cases should be

reported to state veterinary authorities.

Both an attenuated live vaccine and a killed vaccine have been developed.

However, the only human vaccine in current use is the killed vaccine derived from a

component of the exotoxin. This vaccine was field tested in employees of four

different textile mills in the United States, and an effectiveness of 92.5 % was

demonstrated. This vaccine should be used for all employees who may be exposed

to contaminated materials or environment. Additionally, anyone who comes into a

mill processing B.antracis - contaminated materials should also be vaccinated. Currently,

the vaccine is given parenterally with three doses at 2-week intervals followed by three

booster inoculations at 6-month intervals and the annual booster inoculations.

Veterinarians and other persons who, because of their occupation, have potential

contact with anthrax should also be immunized with the human anthrax vaccine.

Control questions:

1. Etiology, epidemiology and incidence of anthrax.

2. Pathogenesis of anthrax.

3. Anatomic pathology of disease.

4. Clinical manifestations of anthrax.

5. Laboratory methods of anthrax diagnosis.

6. Criteria of diagnosis.

7. Differential diagnosis of anthrax.

8. Treatment of anthrax.

9. Prophylaxis of anthrax.

149Viral hepatitis

VIRAL HEPATITES

The problem of the viral hepatites remains most actual, as these diseases

according to their spread step down only to acute respiratory and acute intestinal

infections. Viral hepatites is most frequent cause of chronic hepatitis and liver

cirrhosis. In some patients viral hepatites may have lethal outcomes.

The problem of the viral hepatitis is present under fixed attention of many

scientists of the whole world. At present time definite successes in study of

etiology, epidemiology, clinic, diagnostics of this polyetiological viral disease have

been possessed.

Etiology

At present time further viruses, causing viral hepatitis are known: virus of

hepatitis A (VHA), virus of hepatitis B (VHB), virus of hepatitis E (VHE), virus of

hepatitis D (VHD), associated with VHB, virus of hepatitis C (VHC), virus of

hepatitis G, and recently new types of probable causative agents of hepatitis

were discovered – Sen and TT viruses, the role of virus of hepatitis F is under

discussion. Search of new viruses, causing viral hepatitis continues. In literature

one may come across different names of disease, caused by these viruses: infection

hepatitis, epidemic hepatitis, serum hepatitis, syringe hepatitis. Uniting all these

terminis – Botkin’s disease. Indicated diseases caused by different viruses, possess

many in general, however highly essential clinical, epidemiological, biochemical

and immunological peculiarities that have been revealed. These peculiarities demand

conduction of differential diagnosis between them. As a result of the above said,

group of experts of WHO recommend to differentiate further variants of viral

hepatitis: viral hepatitis A (VHA); viral hepatitis B (VHB); viral hepatitis E

(VHE); viral hepatitis C (VHC); viral hepatitis D (VHD), viral hepatitis G (VHG).

Virus of hepatitis A (VHA). Agent was first discovered in 1973 by

Feinstone. This is RNA-containing virus. Complete viral bodies as well as empty

parts (capsules) with size of 27-30 nm can be noticed under electronic microscope.

On their surfaces capsomeres are seen. Nucleopeptide of VHA does not possess

surface projections and covering. Core structure is not revealed in the virion.

Virus contains 4 peptides (VP1-4), participating in reactions of immune precipitation.

It is assumed that VP1 and VP3 are located pertly on the surface and VP2 and

VP4 are present inside the virion. However, up till date, there is not authentic

informations about their meaning in relation to antiqenicity and immunogenicity.

VHA is stable during pH 3.0-9.0, sensitive to formaldehyde, may remain

preserved for a period of few months or even years during temperature + 4 °C,

for weeks – during room temperature. Complete inactivation of virus takes

150

Infectious diseases

place during 85

C in a period of 5 minutes. VHA is resistant to chlorine, in

comparison with other viruses of this group and may enter through barriers of

water cleaning stations. Complete inactivation of virus steps on during

concentration of chlorine 2.0 – 2.5 mg/L with exposition for a period of 15

minutes, of lime chloride – 10 mg/L during 15 minutes.

Virus of hepatitis A may reproduce in number of human and monkey cellular

cultures, from where viral antigen is obtained. It is necessary to remark, that

successful adaptation of VHA towards culture of cells is very much necessary for

study of biological properties, for obtaining of source of reagents for diagnostics

(antigen, antiserum), as well as for construction of vaccines (live, killed).

Virus of hepatitis B (VHB). VHB in natural condition is revealed in sick

people and carriers, in forest marmots, in carth squirrels, in Peiking ducks. This

DNA-containing virus is pathogenic for human and few types of primates – chimpanzee,

gorillas. VHB causes acute and persistent infection, primarily damages liver.

Virus consists of nucleus and covering. Further antigenic structure of VHB

is differentiated: HBsAg – surface, HBcAg – internal (core), HBeAg – reflects

infectiouness of virus.

Towards these antigens in organism of patients antibodies are produced:

anti-HBs, anti-HBc, anti-HBe.

Presence of HBsAg in human organism testifies the presence of acute and

latent proceeding infection. It is assumed, that prolonged conservation of HbsAg

in serum of the blood in sick man may testify transfer of the process into

chronic form. HBsAg is revealed in majority of patients in incubation stage.

HBcAg is practically not determined in blood and fixed in directly by DNA-

polymerize reactions, falling positive in acute period of disease, as well as after

many months and years in carriers. Soon after discovery of HBsAg in blood of

patients anti-HBc appear. Most often they are observed in carriers of infection.

In early stages of disease HBeAg is revealed, which is then replaced by anti-HBe.

Very important diagnostic information may be obtained by using methods of

determination of DNA HBV. For this purpose molecular hybridization of nucleic

acids and polymerize chain reaction (PCR) is used. Genospecific viral DNA is

observed in serum of blood, in bioptates of liver, in lymphocytes of peripheral

blood. Mentioned method enables to discover very small quantities of viral

DNA in investigated samples, which moderately increases reliability of diagnosis.

Virus of hepatitis C (VHC). Virion of virus of hepatitis C consists of

nucleus and lipid external membrane. Genome is represented by single chain

RNA. VHC is heavily resistant in environment, and particularly in biological

fluids such as preparations of blood, sperm and others. It is sensitive to chloroform,

to other desinfective solutions and high temperatures (100 °C and more).

Antigenic structure of VHC is less studied. It is established, that antibodies

(Ig of M and G class) are produced to virus in the organism of the patient. Their

discovery in blood serum of patient testifies presence of acute or chronic disease.

151Viral hepatitis

Antibodies may stick to definite level during 6-9 months, and thereafter their

titers in serum decrease upto complete disappearance.

Virus of hepatitis D (VHD). VHD represents itself as defective virus particle

of size 30 – 35 nm, contains internal antigen (HDAg), made up of small circular RNA

and surface covering, which is HBsAg VHB. It is considered that reproduction of

virus is possible only during presence of HBsAg in organism of patient, therefore

hepatitis D proceeds always as a coinfection or superinfection, joining to VHB.

Human’s organism replies to VHD infection by production of antibodies of

IgM class, which are used in diagnostics of the disease.

Virus of hepatitis E (VHE). Virus of hepatitis E has been isolated from

feces of patients with jaundice. Spherical particles similar to virus were able to

discover due to the method of immune electronic microscopy. Material for

investigation was collected from volunteers, infected by material from patients

with jaundice with assumed diagnosis of viral hepatitis E. It is supposed, that

VHE may be caused by few strains of virus of different antigens.

At present time a test-system, giving the possibility of discovering antigens

of virus in fecal matter has been elaborated. Serums of reconvalescenes are

used for that.

Epidemiology

Viral hepatitis A is an antroponosis. The source of disease is sick person in

prejaundice period and during 15-20 days of climax period of the disease and

virus carrier. Primary localization of virus is gastrointestinal tract. Mechanism

of transmission is fecal-oral. Virus is excreted from the organism of sick person

with feces. Specific factors of hepatitis A virus transmission are water and

blood. Character of water infection depends upon conditions of water supply

and its relation with fecal contamination. Intermediate factors of transmission

are flies, transferring virus with feces on products of nutrition, dishes.

Susceptibility to the disease is high. Mainly children and adults under 30

year fall ill.

The source of hepatitis B virus in nature is ill person with acute or chronic

form, healthy carrier. Natural way of transfer is sexual. Infection may be transferred

even during kisses through traumatized mucous, through milk of mother, through

placenta from ill mother to fetus (vertical path of transmission). Parenteral way

of the transmission includes blood and its preparations transfusion, injections,

manipulations, operative interventions.

Susceptibility to the disease is high. Most often drug addicts, homosexuals,

prostitutes, medical personnål (surgeons, obstetrician-gynecologists, workers of

hemodialysis departments, manipulative nurses, doctors-infectionists) fall ill with

hepatitis B.

Epidemiology of viral hepatitis D has been studied insufficiently. It is assumed,

that source of infection is sick person, basic path of transmission is parenteral.

152

Infectious diseases

Persons suffering from VHB or HBsAg–carriers are more susceptible.

Epidemiology of viral hepatitis E is identical to epidemiology of VHA, and

hepatitis C – to hepatitis B.

Pathogenesis

Pathogenesis of viral hepatitis is still not studied completely due to big

difficulties, caused by absence of accessible experimental model of the disease.

At the base of existing notions about pathogenesis of acute viral hepatitis lay

clinical observations, life time investigations of liver tissue and comparative

study of viral hepatitis in animals.

Entrance of the agent of the disease into the organism of patient takes place

perorally (VHA, VHE), by sexual way (VHB, VHC), parenterally (VHB, VHC, VHD

and not excluded for VHA and VHE), vertically (not excluded for all viral hepatitis).

The agent approaches regional lymphatic glands, where its massive

reproduction takes place – the second phase of pathogenetic process. The agent

causes damage of cells and their death. Organism replies on this negative influence

by immune reaction of reticular tissue of the lymphatic glands, executing “barrier”

function. This corresponds to period of incubation. On this level infections process

may stop. In insufficiency of “barrier” function the phase of generalization of

infection (primary virusemia) begins.

Virus continues to enter from lymphatic glands into blood in a large

quantities. Clinically this phase is manifested by signs of intoxication and beginning

of the damage of liver. In this phase viruses of hepatitis are connected with

thrombocytes. Due to composition of their phospholipid membrane they violate,

metabolism of arachidonic acid is intensified, that leads to increase in their

adhesive and aggregate activeness. Viruses of hepatitis also render action on

cells of endothelium of small vessels, cause destruction of the structure of their

biomembrane. As a result of such influence, highly active endoperoxides are

formed from arachidonic acid (compulsory component of phospholipids of

membrane), rendering powerful influence on adhesion and aggregation of

thrombocytes, erythrocytes. Such influence of viruses of hepatitis on the blood

cells and endothelium of vessels already in the phase of virusemia renders

essential influence on coagulative and anticoagulative system of the blood causes

disseminated intravascular coagulopathy. The first stage of DIÑ-syndrome

develops. Degree of these disorders depends on massivity of virusemia and

determines the disease course.

The phase of virusemia is confirmed by determination of HBsAg in the

blood of the patient. Besides virusemia parenchymatous diffusion also happens.

Viruses of hepatitis penetrates into the liver cells. Reproduction of virus is

realized in hepatocytes. Virus also revealed in erythrocytes, thrombocytes, in the

cells of pancreas, reticuloendothelial system. The inculcation of virus into

hepatocytes leads to disorder of intracellular metabolic process, especially in

153Viral hepatitis

membranes of hepatocytes. The lesion of membranes accelerates destruction of

hepatocytes.

The mechanism of the damage of hepatocytes, other cells of the organs and

systems is studied insufficiently. Syndrome of cytolisis also plays the leading

role in pathogenesis of viral hepatitis B. However, virus of hepatitis B doesn’t

possess the direct cytopathogenic action.

F.Dubleu, A. Bluger consider that immune reactions, connected with T-cells,

have the leading meaning in the pathogenesis of syndrome of cytolisis. The

penetration of virus into hepatocytes and reproduction in hepatocytes leads to

accumulation of viruses in surface membrane. Circulation of antigens in the

blood causes sensibilization of T-lymphocytes. The activation of T-lymphocytes

leads to distinction and depression of the agent and to differention of subpopulation

of T-lymphocytes. Effect of T-killer causes cytolisis of hepatocytes. Autoimmune

reactions intensify cytolitic syndrome and necrosis of liver.

Pathogenesis of viral hepatitis B is explained from viral-immunogenetic

position, because it is known that power of immune response is genetically

determinated. Immune reaction may be strong (in fulminate form of hepatitis),

flabby and adequate. Only adequate immune reaction promotes cyclic course

and favorable outcomes of the disease.

The scientific achievements of the last years opened new points of view to

pathogenesis and therapy of different forms of viral hepatitis. The study of

metabolic processes on the level of cell allowed to open new aggressive components,

which have negative influence on its structure and functions.

The surplus activity of the processes of free radical oxygenation renders

destructive influence on cells membranes. As a result free radicals are accumulated

in the cells. The process of lipids oxygenation is intensified (peroxide oxygenation

of lipids – POL). It is known that lipids are the basic structural component of the

cells. Antioxydant system of the organism is defending mechanism, supporting free

radical oxygenation of the physiological level. Due to research of the last years it

was shown that activation of the processes of peroxide oxygenation of lipids

plays the essential role in the pathogenesis of viral hepatitis and leads to alteration

of structure and functions of membrane of hepatocytes, thrombocytes and other

cells. It’s worth to underline that simultaneously with activation of POL the

considerable depression of antioxydantic activity of the blood serum is marked.

In case of extremely high activity of POL exhaustion of AOS takes place,

which leads to disorder of activity of cellular ferments, particullary of glucolysis,

glucohenolysis and to rupture of phoshorilation. As a result, cell loses energetic

potential. It leads to destruction of cell. Along with this permeability of membrane

of hepatocyte and its internal structural components are disturbed. Corrosion of

hepatocyte takes place, its synthetic, disintoxicative and other function are lost.

Disturbance of permeability of lysosomal membranes causes exit proteolytic

ferment into cytoplasm, which complete the death of hepatocyte.

154

Infectious diseases

At the last years data about molecular mechanism of the damage of

hepatocytes membranes were received. It is known that interferones cause

depression of reproduction of viruses.

Leukocytaric and fibroblastic interferones may be produced practically by

all cells. Immune gamma-interferon is produced by gamma-interferon

immunocompetentive cells during immune response.

Interferon may influence on complex of defensive reaction (phagocytosis,

inflammation, antigen expression). Interferon is the most important factor of nonspecific

resistance. However, interferon has influence on differentiation and activation of

effector cells of immune system. The activation of monocytes (macrophages), increased

generation of peroxide radicals, increased phagocytes activity are observed under

influence of interferon. Thus, at the present time interferon is considered not only as

antiviral remedy, but also as important regulator of interaction between cells. Due to

investigations of the last time it was established that antiviral effect of interferon is

not connected with direct interaction with viruses. Antiviral effect is connected with

change of metabolic processes in the cells.

It is established that there is decreased produce of interferon in the patients with

viral hepatitis B, especially in patient with severe course of the disease. In fulminate

course of acute viral hepatitis B interferon is not revealed in the blood serum.

Anatomic pathology

Morphological changes in liver take place in all tissual components –

parenchyma, connective tissue, reticuloendothelium, in lesser degree in bile pathway,

diffuse damage of the organs occurs. Degree of damage fluctuates from insignificant

dystrophic and single necrotic changes of epithelial tissue of lobules of liver

during mild forms till massive and submassive necroses of liver parenchyma.

Three variants of acute form of the disease are differentiated: acute cyclic,

cholestatic and massive necrosis of liver.

During acute cyclic form diffuse damage of epithelial and mesenchymial

elements is observed. Decompensation of beam structure with orderly placement

of hepatocytes with their considerable polymorphism is noted.

Along with the dystrophic changes, expressed processes of regeneration with

figures of mitosis and abundance of double nuclear cells are determined. Characteristics

are presence of scattered necrosis hepatocyties in all lobules. Changes of mesenchymial

elements inside the lobules are expressed in proliferation of Kupffer’s cells with

their change into macrophages. Cytoplasm of these cells are basophilic, contains bile

pigment. Capillaries in the center of lobules are dilated. Proliferation of

lymphohistocytary elements with admixtures of plasmatic cells eosinophills and

neutrophils are marked in the portal tract. Along with this, reticular hyperplasia of

spleen and portal lymphatic vessels is observed. Clinical manifestations of the disease

correspond to the severity of destructive changes in parenchyma of liver.

During cholestatic variant of viral hepatitis majority of morphological changes

are observed in intrahepatic bile passages with picture of cholangitis and pericholangitis.

155Viral hepatitis

Clinical manifestations

Clinical picture of all viral hepatites is very much similar and differs in

percent relation by severity of the course of the disease and its outcomes. Viral

hepatitis A and E are characterized by cyclic benign course with complete

reconvalescence. In hepatitis B, C and D medium serious and serious course,

lingering and chronic forms of disease and lethal consequences are inrarely observed.

Depending upon the expressiveness of clinical manifestations of the disease

and degree of functional disorders of liver, established by biochemical tests, light,

medium serious, serious and malignant (fulminate) forms of viral hepatitis are

differentiated. All atypical cases of the disease (non-jaundice, obliterated, subclinical)

are concerned to mild forms, because as clinical manifestations and functional

changes are weakly expressed in such patients.

During evaluation of severity of the disease, expressiveness of intoxication

and jaundice is taken into attention along with enlargement of sizes of liver and

spleen, loss in weight, level of bilirubin in blood serum.

High intoxication, polyarthralgia, expressed dyspeptic symptomocomplex are

typical for fulminate and serious forms of viral hepatitis. Prolonged intensive

jaundice, hypotonia, bradycardia, changing into tachycardia, slackness, subfebrile

temperature, decrease in diuresis, testifies about serious or even malignant course

of viral hepatitis with indefinite prognosis.

Laboratory tests are used for evaluation of severity of disease: tests of

concentration of general bilirubin in blood serum of patients, the prothrombin index.

Viral hepatitis have principally cyclic course. Incubation period is different.

In hepatitis A it is in average 15-30 days, during viral hepatitis B 30-180 days.

The disease begins with signs of general intoxication – so called pre-jaundice

period. There are the next variants of prejaundice period:

1) Dyspeptic variant – patients complain of appetite absence, nausea,

sometimes vomiting. Temperature is subfebrile. Duration of period is 3-7 days.

2) Astenovegetative variant – patients complain of weakness, headache,

malaise, decrease of appetite. Body temperature is subfebrile or 37-38 °C;

3) Influenza-like variant – patients complain of headache, weakness; muscular

pain, decrease of appetite. Body temperature is 37.5-39 °C, and in separate cases

39-40 °C. Duration of 2nd and 3rd variant of prejudice period is of 5-7 days;

4) Polyarthralgic variant – it is observed mainly during hepatitis B and C.

Patients complain of pain in joints, sometimes muscular pain, weakness, decrease

of appetite. During this, subfebrile temperature is in majority of the patients.

Duration of this period is 7-14 days;

5) Mixed type – all above mentioned signs of intoxication in various degree

of manifestation.

The next period of the disease is climax period. The state of the majority of the

patient becomes better. The temperature is normalized, urine becomes dark, colorness

stool. Scleras are icteric, jaundice grows gradually (Fig. 11). The further course of

the disease depends on degree of liver damage by the virus, which determines

156

Infectious diseases

the severity of the disease. During light course of viral hepatitis jaundice grows

in a period of 3-5 days. It is present on one level during one week. Disappearance

of jaundice is observed on 15-16 day. Urine becomes more light at the end of the

first-second week of the jaundice period, it is of yellow or orange color.

During medium serious and serious course of the disease yellowish coloring

of scleras and skin is more intensive, jaundice period is prolonged (20-45 days).

In majority of the patients the signs of cardiovascular system disorder are

observed. There are hypotonia, bradycardia, muffed hearts sounds. In 80-90 % of

the patients liver is enlarged, its surface is smooth, borders are curved, moderately

painful. In 30-40 % of patients spleen is palpated. During serious course of viral

hepatitis in some patients meteorism of abdomen, caused by disorders of digestion

(signs of damage of pancreas, secretory glands of stomach and disorders of

biocenosis of gastro-intestinal tract) is observed. In some patients skin itch is

observed – the so called cholestatic variant of the course of the disease.

Different changes are observed in central nervous system. Already during

mild course of viral hepatitis adynamia, slackness, disorders of sleep may be present.

In serious cases clear cerebral disorders caused by considerable dystrophic

changes in the liver, endogenic intoxication and increase of the activity of the

processes of POL are observed.

In the period of reconvalescence reverse development of symptomatic of

disease, normalization of biochemical indices is marked.

Outcomes of the disease. Viral hepatitis most often ends with complete

reconvalescence. In some patients may be cholecystitis, cholangitis, pancreatitis,

dyskinesia of bile excreting pathways after an acute hepatitis. In 5-10 % of

patients lingering course with periodical aggravations, caused by prolonged

persistence of virus is observed. In such cases chronic hepatitis develops. This

variant of the course of the disease is typical for viral hepatitis B and C; chronic

hepatitis may end up by liver cirrhosis.

Complications

The most threatening outcome of viral hepatitis is acute or subacute massive

nercosis of liver, during which picture of acute or subacute hepatic encephalopathy

is observed. An acute hepatic encephalopathy (AHE) is typical for acute hepatites.

The term “acute hepatic encephalopathy” denotes unconscious condition of

the patient with violation of reflex activity, convulsions, disorder of life vital

functions as a result of deep brake of action of cerebral cortex with its spread on

to subcortex and below laying parts of central nervous system. This sharp brake

action of nervous-psychic activity is characterized by disorder of movements,

sensibility, reflexes and by absence of reactions on different irritators.

Hepatic coma is an endogenic coma, caused by endogenic intoxication as a

result of loss of function and breakdown of liver.

There are the next stage of AHE – precoma I, precoma II and properly coma.

157Viral hepatitis

Precoma I is characterized by non constant disorder of consciousness,

unsuitability of mood, depression, lowered capability towards orientation, tremors,

inversion of sleep. Patients are irritated, sometimes – euphoric. They are troubled

by paroxysms of depression, doom, presentiment of death. Fainting, short time

unconsciousness, giddiness, hiccup, nausea, vomiting may be observed. Jaundice

grows. Bradycardia is changed by tachycardia. Tendon reflexes are raised. Such

condition prolongs from few hours to 1-2 days with moving into second stage.

In the second stage of precoma consciousness is more hampered, losses in

memory is a characteristic feature, alternated with attacks of tachymotor and

sensory exciment till delirium. During awakening orientation in time, space and

action is absent. Tendon reflexes are high. Jaundice raises sharply. Muffed heart

sounds, tachycardia, hypotonia are revealed.

Rhythm of respiration is disturbed. Liver begins to decrease in size. Hepatic

insufficiency is inrarely accompanied with hemorrhagic syndrome due to

development DIC-syndrome. In 1/3 of patients nasal hemorrhages, gastrointestinal

hemorrhages, uterine bleeding and hemorrhages of other localization are observed.

Diuresis decreases. Abdomen is inflated, peristaltic of intestine is decreased.

Such condition continues for 12 hours – 2 days.

During the third stage – properly coma – complete loss of consciousness

and disappearance of reflexes is marked. Pathological reflexes may be too. Rigidity

of muscles of extremities, hyperkineses, convulsive syndrome, and thereafter

complete areflexia are observed. Expressed tachycardia, hypotonia, disorder of

rhythm of respiration are revealed. Diuresis decreased considerably till anuria.

The death of the patients is through 6-24 hours. The patients perish from massive

hemorrhages or in development of severe metabolic acidosis.

Diagnosis

Preliminary diagnosis of viral hepatitis is based on epidemiological anamnesis,

finding of the development of the disease, clinical picture with account of

peculiarities of the ways of the transmission, duration of incubation period, presence

of prejaundice period, presence of typical subjective and objective signs with

account of the patients age.

Diagnosis is confirmed by routine and specific laboratory tests. In routine

blood test of the patients with viral hepatitis lymphocytosis is observed with

moderately expressed course and in serious course of the disease – anemia and

leucopenia. ESR is slightly decreased. In urine urobilin and bile pigments are

observed. During climax period, particularly during medium serious and serious

forms, there are no stercobilin in stool.

Increased content of general bilirubin, primarily on account of its direct fraction is

observed in blood serum during all jaundice period. Ratio of direct and indirect fraction

composes 3:1. In all patients already in pre-jaundice period of the disease, during all

jaundice period and in the period of early reconvalescence increased activity of ALT,

AST is observed, testifying about the presence of cytolytic processes in liver.

158

Infectious diseases

Specific antigens (HBsAg) and antibodies to antigens of all known at present

time viruses of hepatitis are revealed in the blood of patients with help of these

methods. Discovery of antibodies of class of IgM testifies about acute disease.

Discovery of other classes of immunoglobulins antibodies testifies about lingering

or chronic course of viral hepatitis or about earlier infectious process or about

disease in the past.

Differential diagnosis

Differential diagnosis of viral hepatites is necessary to perform with diseases

like leptospirosis, yersiniosis, mononucleosis, malaria, mechanic and hemolytic

jaundice, toxic hepatoses.

Leptospirosis is characterized by acute beginning of the disease, often with

chill, continuation of fever during of climax of the disease and jaundice, pain in

muscles, especially in calfs, hemorrhagic syndrome. In blood leucocytosis with

neuthrophillosis and shift in the formula to the left, accelerated ESR are observed.

Activity of ALT and AST is moderately raised or normal relation of direct and

indirect bilirubin 1:1. In blood serum concentration of urea and residual nitrogen

increases. Stool is colored. In urine erythrocytes, leukocytes, like wax cylinders

are marked in large quantity. Diuresis decreased till anuria.

In generalized forms of yersiniosis jaundice may be also observed, however

it is accompanied by fever, metastatic focuses in other organs and tissues,

leucocytosis with nuetrophilosis, accelerated ESR, aggravations and relapses.

Diagnosis is confirmed by serological methods with specific yersiniotic antigen.

In malaria there are clear alternation of attacks fever with chills, replaced

by heat and sweat and periods of apyrexia. Often painful, increased in size spleen

is marked. In blood hemolytic anemia, in fat drop blood and smear different

forms of malarial plasmodia are reveled. In blood serum indirect fraction of

bilirubin predominates.

In mechanic jaundice stones in gall bladder and bile passages, enlargement

of head of pancreas and other signs are revealed with help of ultrasound

investigation. In majority of the patients moderate increase of activity of ALT,

AST, leukocytosis, accelerated ESR are marked. Hemolitic jaundice is characterized

by anemia, accelerated ESR, increase of indirect fraction of bilirubin. Stercobilin

is always present in stool.

Differential diagnosis of viral hepatites with hepatoses is complicated and

demands from doctor thoughtful and painstaking work. During this essential

significance possesses correctly taken anamnesis.

Treatment

Treatment is used in complex and depends on the clinical form and gravity

of disease course. At mild course of a viral hepatitis in the acute period it is

possible to prescribe only semi-bed regime, diet ¹ 5, polyvitamines and

desensitizing preparations: calcium gluconate, diazolin, diprazin or tavegil. In

159Viral hepatitis

case of meteorism, feeling of gravity in epigastrium area after the meal, unstable

feces – festal, pancurmen, allochol, cholenzym are indicated.

At medioserious and serious current of the acute form of hepatitis a bed

regime is provided together with the specific treatment. Desintoxication therapy

consists of plentiful drink; 5 % solution of glucose, saline solutions, ringer’s solution,

threesault, quartasault, 20 % solution of sorbit (sorbitoli), donor Albumin (given in

vein), one of enterosorbents – SKN, carbaphosfer, carbosilan, sillard P, enterosgel,

polyphepan. The quantity of drunk liquid should be balanced with daily urine.

Polarizing admixture: 3.7 gm potassium of Sody chlorid and 12 units of insulin on

1 liter of 5 % solution of glucose is recommended. The preparations improving

metabolism in hepatocytes are indicated: ascorbinic acid, thiamin chlorid, pyridoxine

hydrochloride, cocarboxylase, potassy orotat, riboxin, cytochrom C, lipamid, calcii

pangamat. Last two preparations are indicated mainly in case of accompanying

hepatoses with fatty infiltration of liver (alcoholism, diabetes, thyrotoxicosis, obesity).

For acidosis decreasing 2 % solution of sodium of a hydrocarbonate 25-50 mL

per os 3-4 times per day or on 150-200 mL intravenously should be infused.

Among etiotropic agents human recombinative α-2-interferon has moderate

medical effect at acute virus hepatitis – reaferone, intron A, Realdironi or analogue

laferone in powder, in amp. 1,000, 000 IU: from 1st to 5-10th day of the icteric

period. Next days their efficiency falls. At acute hepatitis B laferon is infused

1,000, 000 IU 2 times per day during 5-6 days, then 1,000,000 IU 1 time per day

during 5 days. If medical effect is insufficient, there should be continued infusing 1

million UN 2 times per week during 2 weeks. It is worthy to use leicinferone as

the basic component which is the admixture of natural á-interferons of donor leucocytes,

the factor of necrosis of tumours and interleikin-1. However many clinicians challenge

expediency of indication of interferon for treatment of hepatitis in acute period. More

physiologic is the stimulation of endogenic interferonogenesis with the help of such

inductores, as mefanam acid, prodigiosan, pyrogenal, nifluril, cycloferon.

At threat of hepatonecrosis – glucocorticoids 150-200 mg are prescribed.

The dose of prednisolon per day must be reduced after the patient gets out of

extremely serious condition. The volume of infusion solutions is enlarged up to

30-50 mL/kg per day. Ornithin (ornicetyl) promotes a linkage and removing

out of organism nitrous bonds and improves a metabolism.

A lactulose reduces an adsorption of ammonia from intestine in blood,

especially in combination with neomycin. With the aim of oppression of processes

of an autolysis there should be used inhibitors of proteolytic enzymes contrical

or gordox each 8 hours (I V) intravenous dropping, at improvement of a condition

synthetic inhibitors. At retention of liquid in organism it is required to use

spironolacton (veroshpiron), kaliumsaving diuretics, or saluretics – furosemid,

etacrinic acid. Psychomotor exaltation is stopped by sodii hydroxybutyrate in

combination with sibazon (seduxen), haloperidol. At increasing of hepatic failure

antilymphocytic gamaglobulin is used during 1-5 days with the control of quantity

160

Infectious diseases

of lymphocytes in a periphery blood, apparatus methods of patients blood clearing,

hyperbaric oxygenation.

At cholestatic form of a virus hepatitis the are effective preparations which

form complexes inside intestine with cholic acids which can not be soaked up,

cholestiramin and bilignin. Fenobarbital is used which is the inductor of synthesis

of glucouroniltransferas. This enzym is necessary for conjugation of bilirubin

with glucuronic acid, and stimulating its egestion with bile. Fenobarbital is indicated

with combination of cyanocobalamin. Simultaneously for intensifying secretion

of bile nospan and cholenzym are indicated. After the termination of an acholia

duodenal tubages 5-10 % solution of magnesy sulfat (1/4 - 1/2 glasses), sorbit

or xilit (20 gm on 100 mL of hot water) 1 hour before breakfast are applied.

Bioflavonoids – convaflavin, carsili, legalone, silibor, quercetin are indicated

in case of the alonged reconvalescence. At hyperaminotransferasaemia – aevit

or tocopherol acetas, thymalin, T-activin, dipiridamol (curantyl), isoprinosin (has

also antiviral property) – give positive effects. Saparal, methyluracil ( methacil),

natry nucleinic, thymalin in a combination with dipiridamol, hofitol are also used.

Cholagogue agents – broths of flowers of immortele, hips, thyme, mints

peppery in dose of 1 dining spoon of a herb or a mixture to 1 glass of water are

indicated for convalescents. Fenobarbital with cyanocobalamin are applied during

10 days in case of hyperbilirubinemia with prevalence of untied fraction of

pigment; preparations of choice can be cordiamin or sibazone (seduxen) which

also stimulate glucoruniltransferase of hepatocytes. At hyperbilirubinemia mainly

at the expence of connected fraction stimulate a bile secretion using oxygen

cocktails with cholagogue herbs and honey. Vitohepat or cobamamid stimulate

neogenesis and hemopoes, accelerate regenerative processes in liver, course of

treatment lasts 15-20 days. At asthenia and hypoproteinemia, and also for

elimination of catabolitic influences of glucocorticoids which were used at the

acute period, anabolic hormones: such as methandrostenolon (nerobol), phenobolin

(nerobolil) or retabolil are indicated. For elimination of the asthenic phenomena,

there are used novopasit, tinctura of valeriana root (20 gm: 200 mL), herbs of

neetle, thyme, bromidums, and in rather serious cases – chlozepid (elenium),

sibazon ( seduxen), relanium, barbiturates.

At the dyspeptic phenomena caused by oppression of secretory function of

digestion organs, also allochol, liobily, cholenzym, festal, panzynorm forte, pancurmen,

pancreatin, pancitratit, vobensym are widely used.

At posthepatitic hepatomegalias without signs of cytolisis it is reasonable

to prescribe lydase – promoting a resorption of a fibrous tissue, 10 injections

every two days. It can be infused only after exclusion of inflammatory process

in hepatobiliar ways (control duodenal intubation is necessary).

Chemotherapeutic preparations are indicated in case of the bacterial

cholecystitis. At mild course of disease it is possible to use only a fortnight

course of nicodin, in case of serious disorders antibiotics or nitrofurans

preparations are indicated.

161Viral hepatitis

It is possible to define sensitivity of microorganisms, isolated from the bile,

to antibiotics. For such definition mediums are used, which content bile of the

patient as it influences on essentially activity of antibiotics. Use ampicillin,

carbenicilin dinatry salt, erythromicin, cefazolin, furazolidone, furagin, at Candida

infection sody salt of levorin. Chemiopreparations are prescribed in average

therapeutic doses during 7-8 days.

Specific therapy of chronic virus hepatitises is carried out by preparations

of α-interferon (intron A, roferon, realdiron, reaferon, laferon). They are effective in

case of low replicative activity of the virus determined in blood virus DNA

(HBeAg) at a hepatitis B and virus RNA at hepatitis C. The additional indication

is high activity of serum alanineaminotransferase. One of the specified preparations

inject (IM) or subcuteneous 3-5 million IU per day 3 times per week during 6

months. Treatment should be stopped, if positive results were not observed after

3 months. The positive effect is observed at 40-50 % of patients with hepatit B

and at 20-30 % of patients with hepatit C. At chronic hepatit D less than 10 %

of patients are released from viruses even if treatment lasts 1 year. In some

cases the success of immunotherapy of virus hepatites may be increased if

preliminary short course of glucocorticoids treatment (about 6 weeks) is

prescribed. Combined usage of interferon and thymalin, essentiale, lamivudin,

chenodesoxycholyc acids has been proved.

The side-effects of α-interferon are noticed at half of patients right after

injection, among them are headache, fever, myalgia, arthralgia, general weakness.

They can be prevented by means of analgetics. Among the remote side-effects

are: nausea, diarrhea, depression, irritability, leuco- and thrombocytopenia. Decreasing

of a dose of preparation allows to weak these disorders. There are serious

complications (sepsis, psychosis, autoimmune diseases), that demand an immediate

cancellation of interferonotherapy.

At chronic hepatitis B in a phase of replication peroral preparation lamivudin

(zeffix) is prescribed. It provides the same level of seroconversion, as standard

course of treatment by interferon.

At chronic hepatitis with low replicative activity of a virus preference is

given to pathogenetic agents improving metabolic and reparative processes in

liver, such as: silibor, carsil, liv-52, hepatofalk, planta, hepabenne, antral, tocopherol

acetat etc.

Prophylaxis

If the patient is hospitalized, he should be placed in a private room with

separate toilet facilities. The major reason for such isolation is to prevent the

spread of type A hepatitis. Even with lax precautions, such spread is very rare;

most patients with type A hepatitis are no longer excreting virus once they have

become symptomatic. Nevertheless, there are exceptions, and isolation is prudent.

Secretions and blood products should be handled with care gowns, masks, and

162

Infectious diseases

gloves are not necessary, but a prominent sign reading “needle and blood

precautions” is appropriate. Labeling of blood specimens from a patient with

hepatitis, is a common practice. It should be stressed, however, that all blood from

any patient should be handled as if potentially infectious.

If the patient with viral hepatitis is at home, the patient should be advised

about care in personal hygiene – careful hand washing. Attention also should be

paid to blood and blood products and the handling of cuts and lacerations.

Recommendations regarding the prevention of acute hepatitis are governed

by the type of viral hepatitis that is being considered. In the case of acute type A

hepatitis, all family members, and close personal contacts should receive immune

serum globulin (ISG) at a dosage of 2-5 mL in as soon as possible after exposure.

Office, factory, and school contacts do not need to be treated. Immune serum

globulin can be given for up to 4 weeks after exposure, but it probably is only

effective if given within 7-14 days.

In the case of acute type Â hepatitis, prophylaxis only needs to be provided

for “regular” sexual contacts. The best form of protection is argued Hepatitis Â

immune globulin (HBIG) at a dosage of 5 mL in as soon as possible and again 1

month later has been the conventional recommendation in this situation. However,

the efficacy of HBIG in preventing the sexual spread of acute type Â hepatitis has

not been well proved. In addition, there is now evidence that postexposure

immunization with HBV vaccine, can attenuate or prevent acute type Â hepatitis.

Vaccine should be given as soon as possible and then 1 month and 6 months later.

Control questions:

1. Etiologic classification of viral hepatitis.

2. Epidemiology of viral hepatitis.

3. Clinical forms of viral hepatitis.

4. Syndromes of pre-icteric period of viral hepatitis.

5. Basic criteria of viral hepatitis diagnosis.

6. Clinical manifestations of hepatitis.

7. Laboratory findings due to hepatitis.

8. Criteria of diagnosis of anicteric forms of viral hepatitis.

9. Clinic-laboratory signs of fulminative form of viral hepatitis.

10. Basic manifestations of chronic persistent hepatitis.

11. Basic manifestations of chronic active hepatitis.

12. Complications of viral hepatitis.

13. Consequences of viral hepatitis.

14. Differential diagnosis of viral hepatitis in a different periods of disease.

15. Medical treatment of patients depending on patient’s weight.

16. Prophylaxis of viral hepatitis.

17. Preventive measures in the spot of hepatitis outbreak.

163Influenza

INFLUENZA

Influenza is an acute infectious disease which occurs in epidemics and is

caused by a virus, it is characterized by an abrupt onset and such manifestations

as general intoxication and affection of the respiratory tract mucosa.

Together with the diseases of the cardiovascular system and tumors,

influenza takes the leading position in the human pathology. Influenza and other

acute respiratory diseases constitute about 75 % of all infectious diseases, and

85 – 90 % in epidemics, thus resulting in great social and economic damage.

Thus, in Ukraine in 1968-1972 in the epidemic period the economic damage

equaled 112 millions roubles (about $120 million according to the exchange

rate in those years). During the epidemic outbreak it equaled 420 million roubles.

The main thing is that besides relatively mild cases of the disease, there are

severe cases resulting in disability and sometimes death when children or old

people contract a disease. According to the USA statistics influenza takes the

tenth position concerning fatal outcomes.

Historic reference

The first pandemic which spread from Asia to Europe and America was

registered in 1580. There have been 23 great epidemics and pandemics since

that time. During the pandemic of 1780-1782 the modern term “flu” or “influenza”

appeared (from the French word “gripper” meaning catch, envelope, from the

Latin “influere” and Italian – “influenza” meaning penetrate, invade, instill).

In the manuscripts of the 14 – 15th centuries eight epidemics are mentioned,

their names are “mass epidemic”, “fatal infection”, “catarrhal fever”, “infectious

fever”, “quick catarrh” etc. Even the names show the essence of the disease. In

spite of it, the authenticity of the information is not absolute.

It is impossible to determine the regularity of epidemics in the past. In

some cases they were of local character affecting the population of few countries.

In other cases influenza spread pandemically and affected the population of

several continents.

Etiology

During the influenza pandemic of 1918-1919 filter-passing virus was more

often considered to be influenza pathogen. This notion was confirmed by the

classical experiments carried out by P. Zeiter who infected himself with washing

off taken from the nasopharynx of an influenza patient and bacteriologically filtered.

In 1933 English scientists W. Smith, K. Andrews, P. Loudlow isolated influenza

virus from a sick person, starting a new stage in the scientific study of the

164

Infectious diseases

influenza etiological structure. In 1940 T. Frensis and T. Magil isolated a virus

which was quite different from the ones isolated earlier. It was suggested to

name the first virus – influenza type A virus, and the virus isolated by T. Frensis

– type B. In 1947 R. Tailor isolated and described a new type of influenza virus

which was later named type C.

The influenza pathogen belongs to the group of orthomyxoviruses. Virions

have a ball form and a diameter of 100-120 nm, they have a core of a tightly

turned spiral of ribonucleic acid in the case of protein molecules.

On the external capsule there are glycoproteids in the form of a fence of

pins: hemagglutinins (HA) and neuraminidase (NA) causing the development of

a specific immunity after the disease.

The influenza virus quickly dies at drying, high temperature, it is resistant to

low temperatures, extremely sensitive to ultraviolet rays and many disinfectants.

A characteristic feature of influenza type A virus is the changeability of its

antigenic structure, changing under the influence of the population immunology.

Influenza B virus has a more stable antigenic structure and doesn’t change

so often. It has one neuraminidose but different hemagglutinins.

The most stable in relation to antigens is virus C. It causes only sporadic

diseases and small outbreaks. It is spread mostly in Ukraine, Moldova and other

southern regions.

Epidemiology

Influenza remains the most spread mass disease nowadays, which does not

recognize any borders and affects great masses of the population (up to 50 %

and more) at short periods of time. The influenza contagious character was

noticed even in 1735 by Gexgame during the epidemic in Scotland, he called the

disease “epidemicus”.

A sick person is the only source of the disease. The epidemiological role of

virus carriers has not been studied well. The virus quickly multiplies in the

epithelial tissue of the respiratory tract mucous membrane of a sick person and

in 24-48 hours there is an aerosol cloud with a great concentration of influenza

virus around a patient at sneezing and coughing. As the immunity of a specific

type forms very quickly, the virus disappears from the organism of a sick person

on the fifth day of the disease.

Influenza infection is spread with the help of small particle aerosol dispersion.

The mechanism of virus spreading is based on the condition that the virus is in

the air for a long time, it has an ability to keep its infectious force under

unfavorable conditions of the environment and the ability of virus particles to

move with air at long distances and penetrate different parts of respiratory

tracts infecting a person.

The influenza virus of full value can live and be infectious in the air for 2-3

hours. It can live for 1-2 days on the furniture and other surfaces. The ultraviolet

165Influenza

rays, humidity decrease and temperature increase and other factors shorten the

virus life time. The virus lives within the limits of 1-3 meters. The speed of

influenza spreading depends on the speed of people moving on the territory. The

considerable increase of transportation, the movement of great numbers of people

within separate countries, between countries and continents ensures a constant

possibility of the virus spreading at considerable distances and the ability to

infect people in any part of the globe.

There are small local epidemics and pandemics. The epidemics last 10-14 weeks.

The majority of people are naturally susceptible to influenza. The sick rate

depends on many factors. First of all, on the level of the population specific immunity

and on the circulation of the influenza virus serotypes.

The number of the influenza cases among adults has considerably decreased

during the last years, as for the children aged 7-14 the number of influenza cases

is growing slowly but steadily.

The influenza B sick rate tends to grow in all the age groups.

Pathogenesis

After penetrating the respiratory tracts, the virus sticks to the epithelial cells

which have receptors – things of the lipid and carbohydratic nature. When the virus

fixes on the cell surface receptors some complex enzymatic processes begin to occur,

they ensure its penetration a cell in which it reproduces. This complex multistage

process results in the cell death, and new virions born in the cells occupy new areas

of the mucous membranes. The virus multiplication cycle lasts 7-10 hours. Every

virion which penetrated a cell gives birth to 1,000 virions and there will be 10

them in a day. That’s why the influenza incubation period is so short.

If there were no obstacles for reproduction, the entire tissue of the respiratory

tract would be affected in 1-2 days and it would result in a lethal outcome. It

happens in rare cases – “quick influenza” develops and a patient dies in 2 days.

But it doesn’t usually happen so, because a cell, in which virus reproduces, produces

and secretes interferon. This interferon gets into the neighboring cells and after

that they are not defenseless against the virus invasion. Interferon prevents

virus protein from synthesis. The further development of virus infection depends

on the struggle of these two forces – virus genome and cell interferon: either it

stops at the very beginning or the disease lasts a short time and a patient gets

well or the infection spreads in the lungs and fatal pneumonia develops.

The cells affected by a virus are rejected and the products of their

decomposition are absorbed, causing a general feverish disease. At the same time

in the submucous membrane there develop inflammatory processes with distinctive

circulatory disorders, that clinically manifests by hemorrhage syndrome.

When the process spreads in the lung tissue, in severe cases with the

development of influenza pneumonia, there are signs of general edema with

scattered or confluent foci of hemorrhage.

166

Infectious diseases

Under these conditions the influenza virus easily penetrates the blood and

virusemia develops. However, virusemia at influenza doesn’t last long, as the

virus quickly dies under the influence of nonspecific immunity factors – interferon,

complement, properdin, β-lysines, β-inhibitors, histones, leukins, etc.

It is quite possible that the affection of the visceral organs at influenza is

connected with virusemia. However, the great majority of authors doubt the

specificity of such affections, as there are no specific receptors in all the other

organs, and they think that in the pathogenesis of affections the leading role

doesn’t belong to the cytopathogenic phenomena, it belongs to the organism

reaction to toxic products or other substances, which appear at the influenza

virus reproduction process.

Besides, it is a fact that even in the mild cases of the disease there are signs

of the organism hemopoietic and immune system considerable depression. The

number of leukocytes in blood decreases and their functions are suppressed.

Macrophages become less active. Due to it bacteria and viruses become more

active and the accompanying diseases take an acute form. So influenza infection

is mostly a combined virus-bacterial or virus-virus infection.

In conclusion it is necessary to note that interferon production is very

important for the disease outcome in the struggle between viruses and the

organism protective forces. Antibodies of class IgM appear only at the end of

the first week of the disease when the organism wins the first main battle, and

antibodies of class IgG in two weeks.

Anatomic pathology

There are three main groups of pathoanatomic changes at influenza: the first

one – primary changes, caused by the virus itself; the second ones – secondary

changes, caused by influenza virus in combination with cocci and bacterial flora;

the third ones – late changes in patients who had influenza and died of

complications or worsening of other diseases.

The most important morphological signs of the first group are dystrophic

changes of the respiratory epithelium and lungs with distinctive disorders of

microcirculation; sharp plethora, edema and pericellular infiltration of submucous

membrane and thickening of basal membrane.

The interalveolar septum of lung tissue are considerably thickened due to

plethora and edema with leukocytic-lymphoid infiltration. The walls of small

vessels and capillaries are thickened, in some vessels there are fibrous and

leukocyte thromboses. The cells of alveolar epithelium became partially

hyperplastic, in some places – died, there is a small microphagic exudate in the

alveoli lumens.

In the second group there remain signs of pure influenza infection, but more

or less they are prevailed by the purulent affections of the respiratory system

and serious blood circulation disorders in the lungs. Pyo-hemorrhagic and pyo-

167Influenza

necrotic tracheitis with a destruction of epithelium is developed in trachea. The

lung tissue is low-pneumatic, the surface of the incision is motley, with alternation

of large dark-red and gray foci. During microscopy massive foci of pyo-hemorrhagic

pneumonia are found.

In the third group there are different kinds of pneumonia with various

inflammatory exudate: purulent, pyo-hemorrhagic and abscess, plethora, edema

and in some places hemorrhages into parenchymal organs, and also changes,

which are characteristic of the accompanying chronic diseases.

Clinical manifestations

The incubation period at influenza is short – from several hours to 2-3 days.

Its duration depends on the dose and toxic characteristics of the virus. The

incubation period is short if the dose is big and the virulence is considerable.

Thus, its duration has a prognostic meaning for a doctor.

There have been different opinions about the preliminary symptoms of the

disease. It should be admitted that there is a prodromal period, which is

characterized by elevated temperature for a short period of time (2-3 hours),

slight malaise, chilliness, myalgias. These symptoms don’t last long and are usually

ignored by both a patient and a doctor. The disease begins to develop on the

next day. In some patients the disease develops so fast that a practically healthy

person becomes seriously ill in several minutes or hours.

The first symptoms are chilliness (always clear or poor manifested), high

temperature, headaches, dizziness, a syncope condition, fever, malaise, pain in different

parts of the body i.e. the symptoms of general intoxication. The headache is

located in the forehead, temples and over the brows, it can be of different intensity.

There is an early distinctive symptom – pain in the eye pupils especially intense at

the eye movement or pressing, hyperemia of conjunctivas and sometimes scleras.

Dizziness and syncope conditions are characteristic of teenagers and old people.

The fever which is one of the main symptoms of influenza does not last long – 1-

4 days (in 86 % patients). The “two-humped” character of the temperature is

connected with the condition when the chronic infection takes an acute form or a

secondary flora joins. Such symptoms as unconsciousness, delirium, convulsions

and meningeal manifestations are characteristic of children at intense toxicosis.

Such symptoms as malaise, pain in the limbs and muscles, bones or in the

whole body appear during the first hours of the disease and disappear when

fever and other signs of toxicosis decrease. Adynamia, malaise can be considerable

and are manifested from the first day of the disease. The skin on the face is

hyperemic during the first 2-3 days, in severe cases they become pale with

cyanotic shade. It is often a bad prognostic sign. Sweating is a characteristic

feature. Intoxication is a characteristic feature of influenza, its degree and frequency

vary in case of different microbes. In different epidemics there is hemorrhage

syndrome, in 10-20 % cases, its symptoms are nasal bleeding, sometimes recipro-

168

Infectious diseases

cal, hemorrhage in the fauces, metrorrhagia, short hemoptysis and gum bleeding

sickness. Cough appears during the first days of the disease, dry, excruciating,

heart-rending which is accompanied by the feeling of tickling, scratching behind

the breast bone. Almost all the patients have a catarrhal syndrome which has

such symptoms as rhinitis, pharyngitis, tracheitis. There are often such combined

affections of the mucous membrane as rhinopharyngitis, laryngotracheitis,

tracheobronchitis, etc. They usually appear in the first days of the disease. Such

symptoms as herpetic rash is quite frequent, but appears on the 3rd-4th day.

Photophobia and lacrimation are finite rare.

There are no specific changes on the skin. Different kinds of rash which

were described result from other reasons (taking drugs, accompanying diseases).

As it has been mentioned before, quite often there is herpetic rash, theoretically

there is a possibility of petechiae, hemorrhages, if we take into consideration the

affection of vessels and their hyperpermeability. There can be random rash.

A natural manifestation of the influenza infection is the affection of the

respiratory organs, as different pathological processes take place in them, they

are located on a certain level, but sometimes affect the entire area. The affection

of the upper respiratory tracts is accompanied with hyperemia and swelling of

mucous membrane, sometimes with slight hemorrhages. There is nasal obstruction,

rough breathing, and discharge of different nature and consistence: mucous,

mucopurulent and sttaguinolent – in severe cases. During rhinoscopy swelling

and hyperemia of mucous membrane can be seen, especially at the middle turbinate

bone. At the same time accessory nasal sinus can be affected (maxillary sinusitis,

frontal sinusitis, eustachitis with the development of otitis) with different nature

of affection – from catarrhal to purulent.

During fauces examination the hyperemia of tonsils, uvula palatina and

posterior wall of the throat could be found. Sometimes there are granules with

vascular injection and hemorrhages on the soft palate. The development of

influenza laryngitis and false croup is extremely dangerous, especially in children.

Patients become pale, cyanosis develops, they often breathe with the help of

additional musculature, the voice remains. Lethal outcomes are not rare, because

not only larynx is affected, but trachea and bronchi as well, they are full with

croupous superposition. The swelling of the mucous membrane of trachea and

bronchi results in their permeability and leads to the deterioration of lung

ventilation. Depending on the severity of the disease the degree of manifestations

is different – from the hidden forms, which can be found with the help of

pharmacological tests (aerosolic injection of eusporinum) to the severe forms

accompanied with dyspnea and cyanosis.

Complications

The most common and dangerous complication of influenza is pneumonia. It

is necessary to mention, that even during the first days of the disease there are

roentgenologic strengthening of the vessel picture in the inferiomedial parts, that

169Influenza

looks like indistinct infiltrate, and hurried breathing, shortening of the percussion

sound and appearance of so called “conductive” rhonchi, resemble pneumonia. But

they often disappear without any traces in 2 – 3 days. It may not be pneumonia,

but some circulatory disorders. Not everything is clear in the problem of pneumonia

origin. After the detection of pathogen it was considered that during the first three

days pneumonia is of virus etiology, on the 3-5 day – virus-bacterial, later –

bacterial etiology. There is a picture of the so called “big motley lung” on the

section. Hemorrhage pneumonia foci of different sizes can be seen along the whole

length, they are small and large and separated by some parts of unaffected tissue.

The foci of festering appear quite early. The rough beginning with severe toxicosis,

catarrhal syndrome, significant and diverse changes in the lungs, are characteristic

of influenza infection, which is complicated with pneumonia.

Diverse changes in the cardiovascular system have been described. The

vascular system is usually affected, and sometimes considerably, it is probably

connected with a toxic action of influenza virus on capillary vessels. Dilation of

capillaries, turbid background, sometimes formation of the arterial aneurysms, are

seen at the capillaroscopy. Arterial and venous pressure decreases, especially in

case of pneumonia, the speed of blood flow slows down. The pulse corresponds the

fever very often, there is sometimes tachycardia, especially at the beginning of the

disease, in some cases there is bradycardia. The heart sounds are muffled, heart

borders are widened, slight systolic murmur and sometimes extrasystoles appear.

All these manifestations disappear when the general condition of the patient becomes

better. There is elongation of the PQ interval, decreasing and notching, and sometimes

inversion of the wave T at different abductions on the ECG. These disorders are

interpreted as toxic and dystrophic. They are unstable and disappear in 1-2 weeks.

The myocarditis described at influenza is disputed by other authors. More severe

and diverse disorders are found in patients with chronic affections of the

cardiovascular system (coronary atherosclerosis, rheumatic heart diseases, etc.).

These disorders are not pathognomonic for influenza, and arise because of the

aggravation of the main disease under the influence of influenza infection.

There are various affections of the nervous system during the influenza

infection. The functional disorders of the vegetative nervous system are distinctively

manifested. We have already got acquainted with such symptoms as sweating,

changes of the pulse rate, dizziness etc. However, all these changes quickly

disappear. At the same time serious affections of the central and peripheral nervous

systems are observed, they are manifested as meningitis, meningoencephalitis,

radiculitis, neuritis, etc. The rate of these complications is different in different

epidemic outbreak. The pathogenesis of these diseases is still a difficult question.

Side by side with the theories of the toxic and parainfectious factors in their

development, it is possible, that the virus invasion plays a significant role.

The complications in the digestive system are less frequent, and there are

evidently no specific disorders, although fur, dryness in the mouth, decreased

170

Infectious diseases

appetite, and heaviness in the epigastrium are observed. These symptoms are

characteristic not only of influenza, but of any disease with fever. And now such

forms of influenza as gastrointestinal, intestinal and abdominal which were the

results of diagnostic mistakes are mentioned in conversations but not in literature.

The changes in the urinary tracts are manifested as pyelitis, pyelocystitis

and sometimes nephritis, which result from metabolic-dystrophic manifestations

of fever and bacterial superinfection.

The described affections of the endocrine system (adrenal gland, thyroid and

pancreas glands) are very rare and it is not possible to completely exclude the

influence of influenza virus in these cases.

Diagnosis

Besides careful clinical and epidemiological findings, modern methods of lab

diagnostics are used for influenza diagnosis and differential diagnosis of other

diseases.

Diagnosis does not seem to be difficult during epidemic outbreaks. However,

at the same time besides influenza there 30-60 % patients with the respiratory

tracts affection syndrome are registered, they are not of the influenza etiology, and

clinical diagnosis is even more difficult during a non-epidemic period. As we see,

influenza doesn’t have specific symptoms which are characteristic of it only, but

there are 3 strongly pronounced symptoms: abrupt onset with chilliness, general

intoxication and the affection of the upper respiratory tracts. But they also

accompany other acute respiratory diseases, and that is why there are many cases

when patients with the diagnosis “influenza” are taken to hospital, but they have

different other infectious and non-infectious diseases. That is why it is always

important first of all to take into account the epidemic situation in the region.

A short incubation period is characteristic of influenza that is why the

contacts with sick people, especially in the foci 1-3 days before the disease

should be taken into account. If it is possible it is advisable to make up a general

conception of the disease clinical picture in the people the patient contacted.

A careful and detailed physical examination of the patients, analysis and a

comparative evaluation of the revealed changes with the consideration of the

time past from the disease onset is also of great importance. It is important to

remember that the preceding therapy can have a considerable influence on the

natural disease course, sometimes changing or allaying some symptoms, and in

other cases, on the contrary, resulting in the development of the new symptoms

which are not typical of influenza. These can be various manifestations of the

medication disease: skin rash, lymphoadenopathy, the toxic affection of the liver,

hemogenic system, development of asthmatic syndrome, etc. Only a careful analysis

of all the clinical symptoms can reveal the main syndromes, the peculiar mosaic

of which is characteristic of one or another nosological form.

There is not any typical temperature curve. A relatively short febrile

temperature reaction (5-6 days) with a quick rise and maximum values during

171Influenza

the first 2-3 days and shortened lysis should be considered to be more or less

typical if the fever lasts longer than this period, it is always necessary to think

of a possibility of another disease or joining of a complication. The usage of

antibiotics, analgetics, sulfanilamides and glucocorticoides can considerably change

a natural course of the temperature curve.

The changes in the hemogram are manifested as leukopenia or normocytosis.

If there are no complications and accompanying diseases, there is absence or

decrease of the eosinophils, neutropenia and relative lymphocytosis in the

hemogram at influenza (the percentage of lymphocytes increases whereas their

absolute number is the same). ESR is normal or insignificantly increased. The

connection of the bacterial complications is accompanied with leukocytosis and

neutrophilia. It is important to take into account the absolute number of elements

of white blood in the dynamic of the disease.

The infection of the chicken embryos is universal method of the primary

isolation and cultivation of influenza virus. This method is more accessible and

sensitive than the infection of the laboratory animals. It is performed by insertion

of the virus containing material in the amniotic or allantoic cavities and causes

the infection of organs and tissues of the chicken embryo with the following

accumulation of the influenza viruses in the embryos liquid. The presence of the

influenza virus in the allantoic or amniotic liquid is stated by the hemagglutination

reaction (HAR). The simultaneous erythrocytes of the chicken an guinea pig

testifies in favor of the viruses A and B presence, various the agglutination of

only chicken erythrocytes suggests the presence of virus type C. In case of the

erythrocyte agglutination absence it is necessary to make 2-3 additional passages

by the way of embryos infection with the mixture of allantoic and amniotic liquid

from the previous passage. In case of the negative results of HAR after the

passages the investigation of the material is finished.

The methods of the influenza virus isolation in the tissue culture are preliminary

and demand the following pathogen cultivation on the chicken embryo. The

trypsineted cultures from the kidneys of monkeys and human foetus are the

most suitable for the influenza virus isolation.

The serological diagnostics of influenza ensures an accurate determination

of etiology by the way of revealing the quantitative growth of specific antibodies

in blood while the disease dynamics. The serological diagnostics is especially

important in case of the atypical or symptomless course of the influenza infection.

In such cases the discovery of antiinfluenza antibodies in the blood of the examined

people in the dynamics of the increasing concentration independently of

virusological investigation is the only truthful of the influenza virus participation

in the development of the disease and its cooperation with the human organism.

Among the methods of influenza serological diagnostic the reaction of

hemagglutination inhibition (RHAI) and the reaction of complement banding

(CB) is the most widely spread.

172

Infectious diseases

The immunefluorescent method is recommended by WHO as one of the

reliable means of quick deciphering of the etiology of acute respiratory diseases.

The sorting of patients with acute respiratory diseases is done on the bases of

the immunofluorescent method data, it is especially important for the prevention

of the cross infection of children of an early age. Being widely used this method

is an important and reliable means of control of the etiological structure of the

acute respiratory diseases in different periods according to the epidemic situation.

The essence of the immunefluorescent method is in specific reaction of antigen-

antibody which reveal the presence of viral antigens in the cells by the way of

joining antibodies to them, the antibodies are connected with the fluorescent

mark, which lights in the ultraviolet rays.

Differential diagnosis

An intoxication syndrome is the main in influenza, and various symptoms of

the syndrome can be expressed in different ways and occur in different

combinations. A headache and general malaise are the most frequent. But they

are typical of many other diseases, mainly the infectious ones, and do not have a

diagnostic value. In influenza there is no skin rash except a herpetic one. In

acute meningitis of different etiology there is a complete or incomplete meningeal

syndrome and typical changes of the spinal liquor. It is not meningitis but

meningism that is typical of the severe hypertoxic form of influenza. Meningism

is characterized with incomplete meningeal syndrome, liquor hypertension without

any inflammatory changes in the spinal liquor, the spinal puncture solves the

diagnostic problem in these cases.

The development of brain edema is accompanied by sopor, coma, convulsions,

olygopnoe and bradycardia. These condition should be distinguished from coma

and convulsion syndrome of another nature. A general malaise, dizziness, fainting,

asthenisation, do not have a diagnostic value, but in combination with a headache

and retroorbital pain as well as with catarrhal symptoms might help diagnose

influenza. Nasal bleeding is the most frequent manifestation of the hemorrhagic

syndrome in influenza, but it also occur in other diseases and can help in

diagnostics only in combination with other characteristic symptoms. The

appearance of the blood admixture in sputum is almost always a bad symptom.

Acute hemorrhagic toxic edema of the lungs is one of the variants of hypertoxic

influenza, its clinical symptoms are asphyxia, cyanosis, bubbling breathing and

liquid pink foamy sputum. It must be distinguished from poisoning connected

with breathing in vapors of poisonous substances, acute left ventricular heart

insufficiency. Taking into account the epidemic situation, high temperature,

intoxication and tracheitis can help diagnose influenza.

The appearance of sputum containing blood (pus and blood) in influenza,

which is complicated by pneumonia, often testifies about the latter’s staphylococcus

nature. The pleura is often involved in the pathological process, severe respiratory

173Influenza

and cardiovascular insufficiency develops. Hemorrhagic pneumonia and influenza

should be distinguished from the croup pneumonia. In croup pneumonia there

are no symptoms of the upper respiratory tract affection which are characteristic

of influenza, the disease has a sudden onset with pain in the side and sudden

temperature rise, there is “liver” dullness over the affected lobe and bronchial

breathing with the following development of moist rale, the sputum is rusty

though there can be admixture of crimson blood in it.

The fever and vomiting, which are observed in influenza may be diagnosed

as alimentary toxic infection of salmonelesis or another etiology. But in influenza

there are other symptoms of intoxication which are considerably expressed,

they are combined with the nose stuffing, tickle in the throat, pain behind the

sternum and dry cough. Sometimes even in influenza there are pains in the

upper part of abdomen stipulated by mialgia. Diarrhea often occurs in this

disease. That is why in case of moderate toxicosis, vomiting, pain in the abdomen

and frequent watery stool with an admixture of slime and blood it is necessary

to think of some acute alimentary disease, but not influenza.

The development of symptoms of the upper respiratory tract in influenza

makes one distinguish this disease from other acute respiratory diseases caused

by adenoviruses respiratory-syncytial viruses, paragrippal viruses, rhinoviruses,

reoviruses, coronaviruses, ECHO-viruses, Koksaky viruses, mycoplasma pneumonia.

The catarrhal syndrome in influenza develops later and is less expressed

than intoxication. Tracheitis, to be more exact laryngotracheitis is the main

syndrome in influenza. Scattered dry rale together with hard breathing develop

when the inflammatory process spreads along the bronchial tree. The symptoms

of laryngotracheitis stay even in case of the development of pneumonia or

other complications, this helps to suspect influenza as the main disease. Rhinitis

and pharyngitis in influenza do not always occur and have peculiarities in the

form of dryness and stagnant hyperemia of the nose and throat mucous membranes,

absence of scanty discharge from the nose, spontaneous nasal bleeding.

Adenoviral infection is characterized by a more prolonged incubation period

(7-14 days). The fact that there are simultaneous cases with various clinical picture

in the foci of adenoviral infection is a characteristic feature; the clinical picture:

acute rhinitis, rhinopharyngitis, pharyngoconjunctivitis, covering conjunctivitis,

exhantema, hepatolienal syndrome, etc. A less acute than in influenza onset, moderate

intoxication in spite of the high and sometimes prolonged temperature reaction is

typical of the adenoviral infection. However the syndrome of intoxication is less

important as compared with the expressed catarrhal changes on the part of upper

respiratory tract and conjunctiva, which are of exudative character. The pathological

process sort of “crawls over” from one zone to another, and the involvement of

each new are of the respiratory tract is accompanied with a temperature rise which

results in the two or three top character of the temperature curve. Together with

this or some time later peculiar tonsillitis may develop together with exudative

174

Infectious diseases

pharyngitis which manifests itself with edema and bright hyperemia of the back

wall of the throat, on which one can see hypertrophic lymph follicles. If the disease

starts with rhinitis (it can be limited by it), the discharge from the nose can be

abundant, serouse. Laryngitis and tracheitis in contrast to influenza are not

characteristic of adenoviral infection.

If the adenoviral infection is complicated by pneumonia, in adults it has

approximately the same course as a moderate severe affection of the lungs in

influenza and can be cured by usual antibacterial therapy. The adenoviral infection

itself preserves its main clinical features, which allow to distinguish it from

influenza. In case of the combination of influenza and adenoviral infection the

disease has the symptoms characteristic of both nosological forms.

The respiratory-syncytial infection (RS) in adults is usually a sporadic

disease, which equally effects all the age groups. In contrast to influenza the

disease does not often have acute onset. The intoxication syndrome is expressed

moderately or slightly. The temperature is subfebrile or moderately febrile. The

changes of the upper parts of the respiratory tract are slightly expressed. The

symptoms of acute bronchitis which are often accompanied with bronchial spastic

component (continuous cough that is dry or has some scanty sputum, scattered

dry rale and rare medium bubbling moist rale, prolonged inhaling, difficult exhalation,

swelling of the lungs and others) dominate. The liver gets involved more often

in the respiratory-syncytial viral infection in adults than in other acute respiratory

diseases. At the high point of the disease it is enlarged and sensitive at pulpation,

the Orthner symptom becomes positive (pain at beating on the costal arc).

Paragrippal diseases in adults like RS-infection have a more gradual onset

the intoxication is slight or moderate as well as the temperature reaction, which

in fact lasts longer than in influenza. Rhinitis and pharyngitis are moderately

expressed, laryngitis is considered to be typical. There is no syndrome of false

croup in adults as compared with children.

The rhinoviral infection occurs only in adults. The disease is characterized

with subfebrile or normal temperature, slight intoxication symptoms or their

complete absence and expressed exudative inflammation of the nose mucous

membrane with abundant rhinorea, which is the main clinical symptom.

The coronaviral infection is also not severe disease, which is difficult to

distinguish from a rhinoviral one and which affects not only adults but also children,

and besides rhinitis the patients may have slight pharyngitis and even bronchitis.

ECHO- and Koksaky viruses can cause the diseases with affection of the

upper respiratory tract. But the involvement of the brain meninx and spinal

radices in the pathological process is more characteristic of the enteroviral infection.

Mycoplasma pneumonia can cause a respiratory disease in adults. It has a

gradual onset and has a course with both low and febrile temperature, relatively

slight symptoms of intoxication, slight affection of the upper parts of the respiratory

tract, prolonged and persistent bronchitis.

175Influenza

The disease named “legionaries” disease is given to a new disease, which

appeared in 1976 in the USA, its bacteriological nature was proved later. Now it

is determined that this disease is widely spread in all the countries. The most

cases are registered in the warm season. The elderly men suffering from different

chronic diseases or alcoholics, who use immunedepressors and smoke a lot fall

ill more frequently. The disease takes a course of severe progressive abscedic

pneumonia with parapneumonic pleuritis and affection of the parenchimal organs.

Ornitosis and Q-fever are diseases which must be no often differentiated

from influenza complicated with pneumonia. Both diseases are not accompanied

with affection of the upper respiratory tract but have an expressed intoxication

and prolonged fever hepatolienal syndrome and atypical affection of the lungs.

Well gathered epidemiological anamnesis (contact with birds or their discharge in

ornitosis, contact with different animals, usage of raw milk and other dairy products,

usage of cotton brought from endemic regions, helps to diagnose the disease.

It is necessary to say in conclusion that the differential diagnostics of

influenza and its complications in spite of the seeming simplicity is actually quite

difficult. The basis of diagnostics and differential diagnostics should be a careful

analysis of clinical epidemiological data which can allow either to suspect influenza

or doubt this diagnosis. The most simple clinical investigation of blood, urine

and spinal liquor help in the diagnostics. The serological, bacteriological and

immunefluorescent methods of investigation are of primary importance.

The virusological methods of diagnostics are used to isolate and identify the

influenza virus. As a rule these methods are used to find out the nature of the

outbreaks but not the sporadic cases of the disease because they are very

laborious and less sensitive as compared with the serologic methods.

Treatment

Among antiviral agents which are indicated at influenza type A, remantadin

is recommended in such doses: at 1st day 0.1 gm 3 times per day, at 2nd and 3-

rd day 0.1 gm 2 times, at 4th 0.1 gm after meal.

The positive effect at influenza of type A and B is at using adampromin.

synthetic preparation ribamidil (ribavirin) has positive influence on viruses of

grippe of types A and B which is indicated at a daily dose 0.3-0.6 gm during 5

days, however in clinical conditions rather inconsistent data are received.

Perspective combined indication of ribavirin with remantadin or adampromin as

medical aerosols is represented, adampromin influences on viruses of an influenza

A and B. similar antiviral property have midantan, deitiforin, arbidole.

As agent of a choice can be a human leukocytic interferon: 3-5 drops in each

nasal meatus through 1-2 hours not less than 5 times per day during 2-3 days

or as aerosole with the same frequency. Treatment of virus rhinitis includes:

unguent of oxolini, grease mucosa of nose 2-3 times per day 3-4 days. The

preparation is indicated at herpetic superinfection, however its efficiency is low.

176

Infectious diseases

The specified antiviral agents should be applied in the first days of disease, later

they are not effective.

To decrease a body temperature, and to reduce a headache and muscular

pain analgin, ascofen, upsarin with vitamin C, eferalgan, paracetamol are indicated.

As a preparation of a choice you can use non narcotic analgetic Amison, rendering

analgetic, anti-inflammatory, antipyretic and interferonogenic action. The fever is

the major adaptive and protective reaction of organism, induces synthesis of an

endogenic interferon. Antipyretic preparations are indicated only at a hyperpyrexia

and expressed cerebral and cardiovascular disorders in adegnote dose to lower

a body temperature on 1-1.5 °C.

As the stimulation of endogenic interferon formation amixin is applied 0.125-

0.25 gm per day for 2 days, then 0.125 gm in 48 hours for one week or in the

first 2-3 days; mefanam acid 0.5 gm 2 times per day is prescribed. For patients

polyvitamines, ascorutin are indicated. At excruciating tussis indicate codein

phosphat, codterpin, tablets against tussis, at labored nasal respiration – halazolin,

farmasolin or naphthyzin, efedrin hydrochloride, pinosol, at exaltation and disorders

of sleeping – mixture of behterev, fenobarbitalum for the night.

In serious cases of influenza and the weakened patient, with indicated specified

agents, infuse antiinfluenza donor immunoglobulin 3 mL (IM) unitary, sometimes

repeatedly in 6-12 hours.

Reopolyglucin, solution of albumin, isotonic solution of Sodium chloride, 5 % a

solution of glucose (IV) should be infused to treat severe toxicosis. For prevention

of hypertension in a pulmonary blood circle, it is necessary to infuse not more than

500-800 mL of liquids slowly and simultaneously to use diuretic preparations –

furosemid, diacarb, etacrinic acid. Appoint corglykon, sulfocamphocain, euphyllin,

inhalations of oxygen or carbogen.

Patients with especially serious (hypertoxic) form of influenza should be

treated in departament of intensive treatment. Antiinfluenza gamma-globulin or

a serum polyglobulin is prescribed in dose of 3-6 mL in 4-6 hours (in muscle or

even in vein). Infuse (IV) admixture of the following structure: blood plasma –

150-200 mL, solution of glucose 40 % 20 ml, mesaton 1 % or noradrenalin 0.2 %

1 ml, strophanthin 0.05 % or corglykon 0.06 % 0.5 1 ml, furosemid (lasix) 40-80 mg;

hydrocortizon 250-400 mg, euphyllin 2.4 % 1 ml, ascorbic acid solution 5 % 5-10 ml,

calcii chlorid solution 10 % 10 ml, polyglobulin – 3 mL. At disorders of cardiac

activity – corglykon or strophanthin are used. At increase of hypoxia and fluid

of lungs that should be prescribed to inhale oxygen-alcohol mixture on extremity

impose venous garrots, apply diuretic preparations.

In case of development of acute edema and brain swelling in a vein infuse

mannit (mannitole), furosemid (lasix), preparations of a potassium, glucocorticoids.

Widely use tinctura of the herbs, with sudorific, anti-inflammatory, soothing,

spasmolytic, expectorative and antimicrobial properties.

The collecting ¹ 1 consists of root of Altea medicinal (2 parts), buds of

birch white (1 part), flowers of elder black (1 part), rhizome with roots of inula

177Influenza

(1 part), grass of St.-John’s wort (7 parts), berries and leaves of raspberry

ordinary (2 parts), leaves of mint peppery (2 parts), buds of pine ordinary (2

parts), grass of a sage medicinal (2 parts), leaves of eucaliptus (2 parts);

The collecting ¹ 2 consists of root sweetflag (1 part), buds of a birch white

(2 parts), herbs of Origana ordinary (3 parts), a root of Valeriana medicinal (1

part), a herb of St.-John’s wort (3 parts), leaves of Viburn ordinary (2 parts), a

seed of flax sowing (2 parts), a herb of a yarrow ordinary (2 parts), fetuses of

fennel garden (2 parts). It is necessary to fill 4 or 6 dining spoons of the

collecting in a thermos (0.7-1 L) to fill up to top with abrupt boiled water, to

sustain 3-4 houres and to drink all within day in 3-4 receptions. Course of

treatment by such shock doses lasts 3-5 days. The next days use usual doses

making 2-3 dining spoons of an admixture 0.5 L of boiled water. Among other

medicinal herbs for preparation tinctures it is possible to use leaves of fragarias

wood, tussilagoes farfara, flowers of camomily calendulaes, an elder black, lindens.

For inhalations use broths of leaves of sage, eucalyptus, grasses of thyme, pine

buds, buds and young branches currants, birches, raspberries, a root of willow-leaf

inula, better acidified- then rinse a mouth, a throat and wash out a nose. Revaitl

garlick pearls is indicated to rise immunity. The heating of a thorax with the help

of Sinapismuses, mustard wrappings or pepper emplastry is prescribed. The

same agents put to a plantar surface of the feet and shins.

Antibiotics at an influenza are indicated in following cases: 1) at serious

course of disease (the hypertoxical form with encephalitis if disease begins with a

pneumonia); 2) to children of the first 2 years of the life, the pregnant, to weaken

patients, to persons of elderly and senile age; 3) at bacterial complications; 4) at

accompanying chronic diseases of inflammatory character which may become

aggravated at influenza. In other cases antibiotics are contrindicated, as they

strengthen allergization of organism and enlarge frequency of various complications.

Treatment of bacterial complications is necessary to start, before getting

results of bacterial inoculation and definitions of sensitivity on antibiotics of the

allocated microflora. At the pneumonia indicate benzylpenicillin or one of

semisynthetic penicillins. At a hypersensibility of organism to these preparations

one can use erythromicin, oleandomycin or doxycyclin. At ambulatory treatment

also frequently are indicated one of the combined preparations – oletetrin, tetraolen,

and at more serious current of pneumonia – vancomycin, tienam and antiinfluenza

gamma-globulin or polyglobulin. The expressed effect is spotted at a combination

of preparations of tetracyclines or cefalosporines with semisynthetic penicillins

and gentamicin, infused parenterally. At unsuccessful treatment after 5 – 7 days

choose antibiotic in view of sensitivity of microflora of sputum. Alternative

preparations may be a fusidin-natrii, bactrim, nitroxolin.

At serious bacterial complications of influenza apply macrolides of II-III

generations: sumamed, claritromicin, cefalosporines of III-IV generations – cefotaxim,

cefoperason, cedex, cefpirom, combinations of cefalosporines and penicillins with

178

Infectious diseases

inhibitors of β-lactamazes (clavulanic acid, sulbactam, tasobactam) and aminoglicosides.

Preparations of a choice may be ftorhinolones – ofloxacin, ciprofloxacin, pefloxacin

and others, which have high antibacterial activity and wide spectrum of action, including

influence on polyresistant Gram-negative and Gram-positive bacteries.

Use antitussive (glaucini hydrochloride, libexin, tusuprex), expectorating (terpin

hydrate, natrii benzoic, broth of a herb of termopsis, a root of althaea), mucolytic

(acetylcystein, bronchoclar, bromhexin, ambroxole, lasolvan, fluditec) agents, physical

methods of treatment.

Prophylaxis

Vaccines that include the prevalent strains of influenza viruses effectively

reduce the incidence of infection among vaccinees for 1 or 2 years after

vaccination. Vaccines is prepared as inactivated whole virus or as subunits of

the virus, either semi-purified viral hemagglutinin or disrupted virion components.

Both types of vaccine are equally protective. Under development are attenuated

live vaccines given intranasally. They have the advantage of eliciting specific

secretory antibody at the portal of virus entry.

Vaccination is especially important for the aged and for patients with

cardiac, pulmonary or other chronic diseases. Pregnant women whose 3rd

trimester occurs during the winter months should be vaccinated also. With the

presently available purified vaccines, local or constitutional reactions are uncommon

or minor, except sometimes in children.

Amantadine 100 mg orally can be used prophylactically against influenza A.

During influenza A epidemics, it should be given to family members and other

close contact of patients and to persons at high risk of increased morbility from

influenza. During administration of amantadine, persons at high risk of infection

who have not been vaccinated previously should receive vaccine, then amantadine

may be discontinued in 3 wk. If vaccine cannot be given, amantadine must be

continued for the duration of the epidemic, usually 6 or 8 weeks.

At the time of epidemic also can be used another chemical remedies (oxolinum,

tebrophenum) and interferon preparations.

Control questions:

1. Etiology, epidemiology and incidence of influenza.

2. Pathogenesis of influenza.

3. Anatomic pathology of disease.

4. Main clinical symptoms and signs of influenza.

5. Complications of influenza infection.

6. Laboratory methods of influenza diagnosis: the serological, bacteriological and immunefluorescent.

7. Criteria of diagnosis.

8. Differential diagnosis of influenza.

9. Treatment of bacterial complications of influenza.

10. Treatment of influenza.

11. Prophylaxis of influenza.

179Acute respiratory viral diseases

ACUTE RESPIRATORY VIRAL DISEASES

PARAGRIPPAL INFECTION

Paragrippe is an acute viral disease, accompanied with moderate intoxication

and affection of the respiratory tract with the predomination of laryngitis.

The problem is urgent because the paragrippal infections constitute an

essential part of the acute respiratory diseases with a viral etiology. The age

structure of the sickness rate indicates that a considerable percentage of cases is

primarily registered among children and a lower percentage among the adults.

Such complications as the development of laryngitis with croup and pneumonia

in some cases are dangerous for a patient’s life. In spite of the achieved success

in studying this infection, the problems of the disease pathogenesis and especially,

prophylaxis cannot be considerably investigated.

Historic reference

In 1952 in the Japanese city of Senday N.Kuroga isolated the hemagglutinin

virus from the lungs of a newborn child who had died from pneumonia and

named it “Senday” virus. In 1954 in the USA R.Chanock isolated the CA virus

(croup associated) from a patient with croup. In 1958 the same researcher

isolated two more viruses which adsorbed erythrocytes on the infected cells and

named them hemadsorption viruses (HA-1 and HA-2). All the three isolated

viruses had similarities with the influenza virus, that is why they were called

paragrippal in 1959. In 1960 K.Johnson and his co-authors isolated another

similar virus and named it M-25.

Etiology

Nowadays paragrippal viruses are divided into four antigen types. The

antigenic differences are based on the structural peculiarities of the superficial

nucleocapsid antigens. The viral genome consists of the single-lane RNA. These

viruses quickly die in the environment. They endure freezing well. The ultraviolet

rays are destructive to them.

Epidemiology

The paragrippal viruses of the human are widely spread pathogens of the

acute respiratory diseases, including the tropics. They circulate both among

adults and children. The etiologic meaning of the paragrippal infection in the

pathology of the respiratory tract reaches its maximum value in children under

3 years of age and progressively decreases in senior children.

180

Infectious diseases

The human society is a reservoir of the infection, there is always a certain

number of patients who keep or spread the infection. The infection is airborne. A

sick person most intensively secretes the pathogen during the first 2-3 days of the

disease. In case of a lingering course the secretion is prolonged. The duration of a

patient’s secretion of the virus into the environment lasts from 3 to 10 days. The

symptomless carriage is extremely rare. The infection occurs during the direct

contact. The virus spreads with big aerosol particles or slime drops and it retains

infection on the objects around the patient for a long time, however, the oral

infection is not of considerable importance. The disease occurs in the form of

sporadic cases and local outbursts. Epidemics have not been described. All age

groups are susceptible to the disease. The disease is registered all the year round.

Pathogenesis

All the four virus types are pathogenic for humans. The pathomorphologic

data are very limited as the disease usually ends with full healing.

The entering gate and the main reproduction place of the viruses is the

cylindrical epithelium of the upper respiratory tract. The inflammatory process

in them is characterized by a slow development. The viruses have a special

tropism to the mucous membrane of the pharynx and cause its edema and

swelling. There is hyperplasia of the epithelium, its nuclei become bigger and

lighter. During the acute stage on the 4-5th day there is an expressed leukocyte

infiltration of the epithelium with small foci of degeneration.

Anatomic pathology

One of the most characteristic symptoms of paragrippe is a peculiar growing

of the epithelium mostly in the medium and small bronchus. Along with the

abundant pillow like growth of the bronchus epithelium, there is some smaller

papillary growth. In most patients with paragrippe there is a greatly expressed

peribronchial lymphoid infiltration. As a rule, pneumonia has a small-foci character

and is observed in the spots of the expressed cells proliferation with follicle

nuclei. Pneumonia in paragrippe, in contrast to influenza and its combinations,

has a purulent nature, as well as bronchitis.

The affection of the nervous system in paragrippe does not occur very

often but it is not something extraordinary. Serous meningitis, meningoencephalitis,

polyneuritis and neuritis of the facial nerve have been described in children.

Clinical manifestations

The duration of the incubation period lasts from several hours to 7 days and

depends on the virus type. Thus in type 1 it is more prolonged – up to 5-6 days and

in type 3 it is shorter – 1-3 days. In the typical cases the disease develops gradually,

the temperature rises up to the subfebrile and only in 3-4 days reaches 39 °C.

During the first days in adults the intoxication is not well expressed and it

reveals in a slight indisposition, often without a fever, dryness and burning in the

181Acute respiratory viral diseases

nasopharynx, hoarse voice, stuffed nose, running nose and sometimes catarrhal

conjunctivitis. In the little children along with the mild forms there are more often

moderate and severe forms with the affection of the respiratory tract revealed in

the form of bronchitis or pneumonia. In the paragrippal infections the severity of

the course and the diffusion of the process considerably depends on the age and

the premorbid condition of the patients. The disease takes the most severe course

in newborn babies and in children during the first months of life.

During the following days in many patients the inflammatory process gets

down the respiratory tract. Pharyngitis is often observed, it is manifested by

hyperemia of the pharynx mucous membrane and painful swallowing. Most

authors consider laryngitis with slightly expressed stenosis to be the most

typical manifestation of the paragrippal infection.

In the mild courses of the disease the symptoms of laryngitis are manifested

by a sore throat dry rough cough, burning in the trachea without clinical symptoms

of bronchitis. The voice becomes hoarse. The fever is within the limits of 37.5-

38 °C. The outcome is favorable in case of the timely treatment. However, the

manifestations of laryngitis may intensively increase and stenosis of the pharynx

develops. Stenosis is clinically manifested by a labored loud breathing with a

more or less expressed retraction of the pliable areas of the thorax and

epigastrium. Croup is often the main and only manifestation of the disease. As a

manifestation of the main disease, croup develops during the first 1-2 days with

the temperature increase up to 38.5-39 °C and a rough barking cough. Only in

case of the croup viral nature, there is hyperemia of the mucous membrane of the

larynx, especially in the infraglottica area edema and plethora. The mucous

membrane is covered with blurred mucous. The course of the viral nature croup

without joining the bacterial flora is usually favorable.

As a rule, the severe forms of croup are observed in case of the mixed viral-

bacterial infection, when descending obturating stenotic laryngobronchitis develops.

In the pathogenesis of stenotic laryngotracheobronchitis it is not the constriction

of the glottis caused by the inflammatory changes in the infraglottica area that is

of main importance, but the obstruction of the lower respiratory tract because of

the fibrinous-necrotic process caused by joining the secondary bacterial flora.

The croup course in such cases is undulating with a long lasting high temperature,

expressed shortness of breath. Viscous sputum forms dry crusts, which result in

the bronchi occlusion and lead to frequent and severe bronchospasm as well as

atelectasis. The lethal outcomes are observed as the result of the development of

the diffusive process in the respiratory tract.

The bronchitis joining is usually observed on the 4-5th day of the disease, in

such cases one can hear dry rale over the lungs. Paragrippal pneumonia often

develops in the viral affection of the lower respiratory tract. They have an acute

development accompanied by a high temperature, expressed cyanosis, shortness

of breath and absence of distinct changes in the percussion sound, scanty

182

Infectious diseases

auscultation data. They usually take a non-malignant course. The joining of the

secondary bacterial flora considerably worsens the course of the disease: the

intoxication intensifies, the shortness of breath and cyanosis become more

expressed, the cough with sputum discharge becomes more frequent. The

percussion reveals the shorting of the percussion sound, a lot of moist rale can

be heard at the same areas.

Complications

Paragrippe can be complicated by tonsilitis, sinusitis, otitis, eustachiitis and

can cause the worsening of thc chronic unspecitic diseases of the lungs. Along

with the affection of the respiratory tract there are some changes of the nervous

system in many paragrippal patients, even in case of the mild course of the

disease. They are mainly some slightly expressed symptoms of the functional

malaise, headache, dizziness, aches all over the body etc. However, during the

clinical examination serouse meningitis with the posterior nuchae muscles rigidity

and symptoms of Kernig and Brudzinsky was diagnosed in some patients. The

cerebrospinal fluid flew out under the increased pressure, lymphocyte pleocytosis

oscillated in a wide range from 70 to 850 and higher in that case. The paragrippal

virus type 3 was most often found in the fluid. The normalization of the cerebrospinal

fluid and fading of the meningeal symptoms were not always parallel with the

catarrhal changes in the mucous membrane of the respiratory tract.

The reinfection with the paragrippal viruses, especially type 3, was registered

several times in adults and in children. The frequency of the reinfection remains

still unknown, it is possible that many patients are reinfected more than once.

The results of the observation in the series of the consequent outbursts of the

type 3 infection showed that 17 % of the children infected during the first

outburst were reinfected during the following outbursts, although the interval

between the outbursts did not exceed 9 months. The disease develops more

rarely in case of the reinfection and its course is much easier as compared with

that of the primary infection.

Diagnosis

The laboratory confirmation of the disease etiology is an important stage in

the examination of the patient. The main method used under the conditions of

the practical laboratories is an immunofluorescent test that is used for the

discovery of virus antigens in the epithelial cells of the upper respiratory tract.

This method provides a fast deciphering of the disease etiology.

Among the other express methods of diagnosis of the respiratory diseases

an immunoferment test on the solid phase has become widely spread, it is used

for the serological diagnostics. The radioimmunoassay and chain polymerize

reaction are also used.

Another direction in the serological diagnostics is the investigation of single

serum samples, it is aimed at the determination of IgM because it constitutes the

183Acute respiratory viral diseases

basis of the primary immune response. A test of immunosorbent hemadsorption

has been devised for this purpose. The laboratory diagnostics of the paragrippal

infection based on the isolation of viruses in the sensitive cell cultures has not

lost its importance.

Differential diagnosis

During the first days of the disease the clinical diagnosis is often difficult, as

some symptoms are similar to influenza. In such cases it is important to

thoroughly study the onset of the disease. Influenza is characterized by a sudden

onset and temperature increase up to 38 °C and higher and always more or less

expressed chill, and the catarrhal component absence. In paragrippe the

temperature increases gradually and there is a cough with sputum discharge

from the first days. Croup in paragrippe is often clinically manifested by the

symptoms of acute laryngitis, which is sometimes limited by the affection of the

infraglottica area of the larynx only, and the severity of the patient’s condition

depends on the severity of stenosis, the intoxication manifestations are less

expressed. In influenza, especially, in the severe cases, there are symptoms of

laryngotracheobronchitis and the severity depends on the intoxication degree.

Treatment

In mild and moderate cases bed regimen is recommended till the temperature

decreases. The dairy and vegetable diet, abundant drink (tea, cranberry juice, alkali

mineral water) are prescribed. Both adults and children are prescribed symptomatic

treatment (syrup, paracetamol, mucaltinum, inf. althaeae – to delute sputum, pertussin,

broncholytin, bromhexin – in case of the increased cough reflex and others).

In severe cases the following medicines are prescribed: immunoglobulin

(hyperimmune and normal), monoclone antibodies, interferon, ribamidil, bonaphtonum,

alpisarinum. The antibacterial medicines are prescribed in case of complications

with the bacterial flora. The hot foot baths, steam inhalations, corticosteroids are

the most effective in larynx stenosis.

Prophylaxis

The specific prophylaxis of the paragrippal infection has not been worked

out so far. The non-specific prophylaxis is similar to the one in other acute

respiratory virus diseases.

RESPIRATORY-SYNCYTIAL INFECTION

The respiratory-syncytial virus causes an acute respiratory disease in which

the lower parts of the respiratory tract are mainly affected with the development

of bronchitis, bronchiolitis and pneumonia. The urgency of the problem is also

due to the fact that the virus attacks the most sensitive age contingent – children

under the age of one year old.

184

Infectious diseases

Historic reference

The respiratory-syncytial virus was first isolated in 1956 by J.A.Morris and

his co-authors from the respiratory tract of a chimpanzee and a laboratory worker

who had been in contact with it. The increase of complementbound and neutralizing

antibodies was observed in the blood of the chimpanzee and the man after the

recovery. A year later R.Chanock and his co-authors reported on the isolation of

the virus from the children with the affection of the lower parts of the respiratory

tract. After this there were a number of reports on the role of the above mentioned

virus in the respiratory diseases in children and adults. The viruses isolated from

the humans and chimpanzees turned out to be identical. The pathogen received its

name as a result of the peculiar cytopathogenic effect in the cells of the sensitive

tissue cultures, it causes the formation of the syncytial areas.

Etiology

The RS virus has all the main characteristics of microviruses. Its peculiarity

is in the absence of hemagglutination hemadsorption and its inability to reproduce

in the chicken embryos. The antigenic structure of the virus is stable. The virus

is very sensitive to freezing, that is why it is recommended to immediately use it

for infection. The inoculum (nasal secrete) should be taken from the patients as

soon as possible when the clinical symptoms develop.

Epidemiology

The RS virus is a pathogenic microorganism of the respiratory tract, it is

airborne. It is highly contagious for the population of all age groups. The degree

of contagiousness is especially high under the conditions of the nosocomial

infection. However, it is still unclear which age groups of the population are

considered to be the reservoir and source of the infection at the periods of

annual seasonal increases of morbidity and between the epidemic periods. The

especially urgent problem of the healthy virus carriage without any clinical

symptoms for the RS virus still remains unsolved.

In the areas of the moderate climate the autumn-winter-spring seasonably is

considered to be finally ascertained, and the increase of the RS infection morbidity

is never observed in the summer, whereas in the tropical countries they can be

observed in the hot season as well. Not only children, but also adults are highly

susceptible to the RS infection in spite of the fact that in the majority of adults it

is usually reinfection. The transmission of the RS virus from man to man is fast

and effective.

In the experimental study of the RS virus transmission mechanisms, the

observations of the volunteers show that the infection occurs mainly through

the nose less frequently through the eyes. The study of the nosocomial outbreaks

of the RS infection confirmed the mentioned facts and determined that the per

oral infection does not play a considerable role in spreading the RS infection.

185Acute respiratory viral diseases

The social-economic conditions noticeably influence the beginning and

development of the RS infection epidemic outbreaks. There is a distinct correlation

between the degree of overcrowding and the frequency of the virus isolation.

Pathogenesis

The mucous membrane of the respiratory tract is an entrance gate for the RS

virus. The beginning of the virus replication occurs in the epithelial cells of the

nose and nasopharynx causing the local inflammation which sometimes leads to

the obstruction of the nasal paths and Eustachian tube. The process spreads to the

trachea, bronchus, bronchioles and the lungs parenchyma in the majority cases in

the children of an early age and in fewer cases in the people of other age groups.

Anatomic pathology

On the basis of the known tacts it is possible to come to the conclusion that

a severe affection of the bronchioles is typical of the RS infection. The considerable

proliferation of the epithelium with a big amount of mitosis figures and impurities

of the cytoplasm are observed in them. The multcellular offshoots appear in

them in the process of proliferation, they resemble symplasts in their form. The

symplasts jut out into the bronchioles opening like buds. Sometimes they

desquamate and partially obstruct the bronchus or fill the alveoli. There is a

round-cell infiltration and thickening of the intra-alveolar partitions around the

affected bronchus.

The virus is isolated in the nasal discharge a day before the disease onset

and during the first 7-9 days of the disease. There is virusemia in the experimental

infection.

Clinical manifestations

The incubation period lasts 4-5 days with the fluctuations from two to seven

days. The characteristic features of the initial period are a moderate affection of

the upper parts of the respiratory tract with the slightly expressed catarrhal

symptoms in the form of a labored nasal breathing, infrequent dry cough, scanty

nasal discharge. The hyperemia of the throat, airfoils, back wall of the throat is

expressed insignificantly. There is no temperature reaction or the temperature

is subfebrile with a shivering, moderate headache and myalgia. In case of the mild

form of the infection the symptoms disappear during 3-7 days and the recovery

comes. However, during the first days or on the following days the lower parts

of the respiratory tract very often get involved in the process, especially, in the

children of an early age. In several hours a child’s skin becomes cyanotic, an

asthmatic dyspnea develops up to 60 a minute with a prolonged whistling

expiration accompanied by pulling the compliant areas of the thorax. A number

of dry and mixed moist rales suddenly appear in the lungs, the rale can be heard

at a distance. The areas of a percussion sound shortening alternate the areas

with a box shade. An asthmatic syndrome is one of the typical symptoms of the

186

Infectious diseases

RS infection. The reverse development occurs very quickly – in 3-7 days, it

indicates the affection of the bronchial tubes only.

In the development of pneumonia the temperature rises up to 39-40 °C and

remains for a long time. The condition of the patient considerably worsens and the

reverse development of the process goes very slowly – up to 2-3 weeks. In such

patient’s blood analysis there is leukocytosis, neuthrophylia and increase of ESR.

The adults usually develop a mild form of the disease without fever and it is

limited by the upper part of the respiratory tract only. The infection and the

development of the disease occur irrespective of the presence of the high titers

of the virus neutralizing antibodies in the serum. The ability of the RS virus to

avoid the organism resistance mechanisms of the host and to cause the disease

during reinfection is still a matter of meditation.

Complications

The acute complications of RS infection in infants include apnea, respiratory

failure, and rarely secondary bacterial infection. The long term complications are

pulmonary function abnormalities.

Diagnosis

The methods of the laboratory diagnosis are the same as in case of paragrippe.

Differential diagnosis

A great similarity of the RS infection to other ARVI complicates the diagnosis

based on the clinical picture only. It is possible to clinically diagnose the disease

for certain in the children under one year old if there is bronchiolitis and

pneumonia with an asthmatic component on the background of the subfebrile

temperature because the RS virus causes the affection of the lower parts of the

respiratory tract in most patients. It is necessary to take into account the

prevalence of the bronchitis symptoms over the symptoms of the upper parts

of the respiratory tract affection accompanied by a slightly expressed intoxication.

The laboratory diagnostics methods are of major importance.

Treatment

Good supportive care is of the utmost importance in the management of

severely ill infants. Alleviation of the hypoxemia and monitoring of the infant’s

respiratory status and blood gas levels are essential in the management. Because

the hypoxemia is related to an unequal ratio of ventilation to perfusion, most

infants respond to relatively low concentrations of inspired oxygen of about 40 %.

Corticosteroids in controlled studies have failed to show benefit in the clinical

course of infants with bronchiolitis or in their pulmonary function during the

acute or convalescent stages. The use of bronchodilators in bronchiolitis and

other forms of RSV lower respiratory tract disease has been controversial, and

studies evaluating their use have given conflicting results.

187Acute respiratory viral diseases

Ribavirin, a synthetic nucleoside that is a broad-spectrum antiviral agent, is

the only currently approved specific treatment for RSV lower respiratory tract

disease in hospitalized infants. The drug is administered as a small-particle aerosol

into a tent, oxyhood, mask, or ventilator for a period of 12-20 hours each day,

usually for 2-5 days, depending on the time to improvement. Shorter and

intermittent periods of treatment may be as beneficial. Ribavirin also inhibits the

RSV-specific IgE response in the nasal secretions, which has been associated

with the development of wheezing and hypoxemia. Aerosolized ribavirin appears

to be well tolerated, and toxicity has not been reported in controlled studies.

Aerosol administration for 8-20 hours gives drug levels in secretions that are

hundreds of times greater than the median inhibitory concentration for RSV, but

relatively little is systemi-cally absorbed, and blood levels are low.

Prophylaxis

Prevention over treatment is the preferable but as of yet unattained goal

for control of RSV infection. The very young age at which RSV first attacks and

at which it has its greatest impact makes prophylactic intervention problematic.

Breast-feeding appears to offer the infant some protection against RSV lower

respiratory tract infection. Prevention of infection through interruption of

transmission of the virus is probably impossible at home. However, on hospital

wards attempts to prevent spread of the virus are warranted. RSV may be

spread by close contact and by direct inoculation of droplets of the secretions

from an infected person. In addition, however, RSV possibly may be spread

indirectly from hands that touch infectious secretions that contaminate surfaces

in the environment. Hence, careful handwashing by all personnel is of particular

importance. The use of eye-nose goggles has been shown to diminish appreciably

the nosocomial infection rate, presumably by decreasing self-inoculation of the

virus into the eyes and nose.

ADENOVIRAL INFECTION

Adenoviral infection is a disease developing mainly in children and having

the symptoms of the mucus affection of the respiratory tract, eyes, intestines as

well as lymphoid tissue.

Historic reference

The pathogens of the adenoviral diseases were first isolated in 1953 by W. Rowe

and his staff from the tissues of the surgically extracted glands and adenoids.

The belonging of the isolated viruses to the respiratory infection pathogens was

established in 1954 when M.R. Hilleman and J.H. Werner discovered the increase

of the neutralizing complement binding to them antibodies in the blood serum.

In April of 1954 F. Neva and J.F. Enders isolated a similar virus from the

excrement of a two-year-old child who had a fever accompanied by conjunctivitis,

188

Infectious diseases

pharyngitis and the increase of the neck and groin lymph nodes. A year later R.

J. Huebner and W.P .Rowe reported on the isolation of more than 100 cultures

of viruses from the nasopharynx, conjunctiva and excrement of the patients who

had different forms of the acute febrile diseases of the respiratory tract.

In 1956 the commission at the International committee of the nomenclatures

that studied viruses named the isolated viruses “Adenoviruses” as they had first

been isolated from the adenoids and the diseases caused by them got the name

“adenoviral diseases”.

In 1962 J.Trentin and his co-author R.Huebner together with their co-

authors made some experiments on the newbom hamsters that showed that the

adenoviruses were oncologically active.

Etiology

The adenoviruses constitute a family of Adenoviridae including two clans:

Mastadenovirus (M) (mammal) of more than 90 kinds and Aviadenovirus (A)

(birds) – 18 kinds. The gene of the adenoviruses is a lineal double spiral DNA.

They are thermolabile, get destroyed at 56 °C in 30 minutes, stable to pH 5-9.

They can be preserved in the frozen form. They can be lyophilized without losing

the infectious titer.

Epidemiology

The adenoviral diseases are registered everywhere all the year round, more

often in the cold seasons. The natural reservoir of the adenoviruses for humans

is a human. The infection is spread by both the people with the clinically expressed

disease and virus carriers. The adenoviruses are excreted from the respiratory

tract till the 25th day of the disease, and from excrement for two months.

Though the main way of the infection transmission is an airborne one, an alimentary

way cannot be excluded. In the period of the epidemic spread the adenoviruses

can also be isolated from the sewage. The diseases can be observed both in the

form of the epidemic outbreaks and sporadic cases. The epidemic process during

the outbreaks develops slowly. At first the single cases of the disease and then a

more rapid growth. Taking into account the meaning of the separate serotypes

in the pathology and the peculiarities of the epidemic process the adenoviruses

are divided into epidemic, latent and a group which role in the pathology is

unclear. The adenoviruses of the latent group also cause acute diseases but in

this case there is a less intensive coverage of people at outbreaks, a higher per

cent of the latent infection and a mild course are observed.

Pathogenesis

The adenoviruses usually affect different organs and tissues: the respiratory

tract, eyes, lymphoid tissues, intestines and urinary bladder.

189Acute respiratory viral diseases

The upper parts of the respiratory tract and conjunctivas are the most

frequent entrance gates. The virus penetrates the lower parts from the upper

part through the bronchial paths and causes atypical pneumonia in adults and

children. The virus intensively reproduced in the parenchyma of the lungs and in

the cells of the upper respiratory tract. Virusemia is one of the stages of the

adenoviral infection. Because of virusemia the virus can penetrate not only the

lower respiratory tract but also other organs and tissues by a hematogenic

way. In the diseases connected with the adenoviruses of the academic type,

virusemia is observed in the acute period from the 1st to the 8th day. In the

latent type cases the period of virusemia lasts up to 2-3 weeks.

Anatomic pathology

The viruses are supposed to affect the endothelium of the vessels and thus

cause the exudative type of affection, inclination towards the prolapse of fibrin,

necrotic changes in the mucus membrane (exudative pharyngitis, tonsillitis,

conjunctivitis).

Irrespective of the fact that an adenoviral disease has only respiratory or

respiratory and intestines symptoms the reproduction of the adenoviruses is

observed in the small intestine for longer periods of time (10 days and longer)

than in the respiratory tract.

An association of the adenoviruses with the immune deficiency conditions

has been described. They were isolated from the urine and excrements of the

AIDS patients as well as from the urine of the patients who were ill with other

immune deficiency illnesses.

Not only have the latent viruses a disposition for lymphadenopathy, but

also a group of the epidemic ones. Lymphadenopathy has such symptoms as the

increase of the tonsils, periphery lymph nodes, liver, spleen, tracheobronchial,

bronchopulmonal and mesenteric nodes.

Clinical manifestations

The disease caused by the adenoviruses is characterized by the polymorphism

of the clinical manifestations, that do not develop simultaneously. There are

symptoms of the affection of the respiratory tract, eyes, intestines mucous

membrane, the disease is accompanied by a prolonged fever and a moderately

expressed intoxication. The incubation period lasts 5-7 days with the fluctuations

from 4 to 12 days. The adenoviral infection is mainly characterized by a gradual

development of the disease with the accumulation of the clinical symptoms, the

replacement of some symptoms by others and the prevalence of the local symptoms

over the general ones. Besides, an acute onset of the disease is also possible. As

a rule the expressed catarrhal symptoms with a labored nasal breathing come to

the foreground. The intoxication is expressed by flabbiness, adynamia, the appetite

worsening, moderate and inconstant headaches, sometimes vomiting. The rise of

190

Infectious diseases

the temperature is usually gradual, in the beginning 37.2 °C, on the following days

– 38 °C and sometimes higher. The duration of the fever is 5-7 days less often –

up to 12 days.

The acute respiratory disease is the most frequent clinical manifestation.

There are usually no pathognomonic symptoms. In the beginning its diagnostics

is considerably difficult, especially, in the first cases because they do not practically

differ from catarrh caused by different other pathogens. The onset can be acute

or gradual. Already on the first day there is a labored nasal breathing, and on the

second-third day an abundant serous or serous-mucous discharge. There develops

hyperemia of the nasopharynx mucous membrane, edema of the uvula, hyperplasia

of the lymphoid tissue, especially, on the back wall of the throat. There is sometimes

a vesicular rash on the mucous membrane of the mouth cavity. The submandibular

lymph nodes and the ones on the back of the neck are enlarged. The cough is

usually dry, it becomes rough, barking when laryngitis develops. Sometimes the

voice becomes hoarse, but there is no aphonia. In contrast to influenza croup

develops in the first hours of the disease. The physical manifestations in the

lungs are absent or they are poorly expressed.

Acute pharyngitis. It is usually in the cold season of the year that the disease

is observed, the general condition often remains satisfactory. The main complaint

is pain in the throat at swallowing. Moderate hyperemia of the airfoils, back wall of

the throat with hyperplasia of the lyinphoid tissue can be noticed during the throat

examination. The mucous membrane of the throat, airfoils, uvula, tonsils is loosened,

edematic. On the surface of the tonsils there is a thin whitish patch in the form of

dots which covers the tonsils. The exudate often spreads beyond the borders of

the airfoils to the soft palate, back wall of the throat. The patches disappear during

5-6 days, but the edema of the mucous membranes of the throat and rhinitis

usually remain longer. At the same time the peripheral lymph nodes are often

enlarged. The cough is frequent, but not constant, it is moist, rarely dry.

Pharyngoconjunctival fever is the most typical clinical variant of the

adenoviral infection. The term “pharyngoconjunctival fever” (PCF) was proposed

by J.A. Bell and his co-authors (1965) while describing an outburst in the

children’s summer camp. They also most fully described the clinical form

characterized by the triad: fever, pharyngitis with the enlargement of the lymph

nodes and conjunctivitis. As a rule, the disease starts with the increase of the

temperature, which often increases up to 39-40 °C and remains for 2-10 days (5-

6 days on the average). There is a lytic temperature decrease. The main complaints

of the patients are redness and uncomfortable sensation in the eyes, watery eyes,

affection of the throat, headache. Somnolence and malaise often develop at the

end of the feverish condition. Nausea, vomiting, diarrhea and nasal bleeding are

observed very rarely. The bone-muscle aches and weakness are often observed

in adults. During the throat examination the hyperemia of the back wall of the

throat and lymphatic nodes is observed. The submaxillary lymph nodes are often

191Acute respiratory viral diseases

enlarged even if there is no pain in the throat. The disease is accompanied by the

one-side nonpurulent follicular conjunctivitis, which remains from several days

to three weeks and is manifested by the injection of the eye and eyelid vessels.

The enlargement of the parotid lymph nodes is sometimes observed. There is no

photophobia and pain in the eyes. The iris of the eye and cornea are usually not

involved in the process. The exudate is almost always serous. The clinical

symptoms (fever, pharyngitis and conjunctivitis) are manifested in different

combinations. The pharyngoconjunctival fever in the form of sporadic cases or

outbursts is registered in different countries.

Eye affection. The intensely expressed inflammation of the conjunctiva with

bright hyperemia and scarce discharge is a peculiarity of adenoviral conjunctivitis.

The inflamed mucous membrane of the conjunctiva looks like a “conflagration

without a fire”. Unlike in conjunctivitis of another etiology only the lower eyelid

is usually affected. In the beginning the inflammatory process in the eye develops

only on one side and only later the second eye gets involved in the process, but

the changes in it are less expressed. There are such forms of the eye affection as

catarrhal follicular membranous conjunctivitis and keratoconjunctivitis. The last

ones usually develop in adults; a long recurring course is typical of them.

In case of the catarrhal form hyperemia tissue infiltration, edema of the

eyelids and conjunctiva are observed. The edema and the infiltration of the

tissues usually disappear in 2-5 days, but the hyperemia of the conjunctiva

remains up to three weeks, sometimes – up to a month.

In case of the follicular form of conjunctivitis along with conjunctiva infiltration

and edema of the eyelids there is abundant eruption of the large follicles on the

conjunctiva. There is no discharge or it is scarce. One third of the patients have

a hemorrhage into the sclera of the eyeball. The hemorrhage dissolves slowly,

during 7-9 days and then during 3-4 days a vessels netting “sclera injection” can

be observed. Sometimes the hemorrhages are so large that the eye looks like a

rabbit’s one.

In case of membranous conjunctivitis the tissue infiltration, eyelid edema are

much more expressed (often a patient cannot even open the eye) than in catarrhal

or follicular forms, and the edema of the eyelids is soft in contrast to the diphtheritic

one. The hemorrhages into the conjunctiva and sclera of the eye are more massive.

The gray dense films appear on the 4-6th day of the disease. The bleeding surface

remains after their removal. The discharge is scanty, very often there is sanioserous

discharge. Parents say that “the child cries with bloody tears”.

In case of keratoconjunctivitis the disease has an acute onset and is manifested

by hyperemia and the conjunctiva edema. On the 2-3rd day together with the eyelid

edema, redness of the eyeball conjunctiva, lachrymal muscle and semilunar fold, the

hemorrhages appear on the eyelid conjunctiva and the hypodermic fold. In some

cases the films appear on the eyelid conjunctiva. The abundant eruption on the

eyelid conjunctiva and transitional folds of the superficial follicles is very typical. The

192

Infectious diseases

discharge is usually scanty. The enlargement and tenderness of the parotid and

sometimes submandibular lymph nodes are important diagnostic symptoms.

The typical changes in the cornea appear on the 7-14th day of the disease.

Their appearance often coincides with the disappearing of the inflammatory

processes in the conjunctiva. On the cornea, usually in the center, in the pupil zone,

there are delicate subepithelial round infiltrates, which do not tend to ulceration.

The disease is sometimes accompanied by the temperature increase. Quite often

the patients complain of a headache and general malaise. A patient considers the

dimness of the cornea to be a foreign body, photophobia and vision disorder. In

half of the patients only one eye is affected, but in some time (7-10 days) the

second eye can get involved in the process. The disease lasts from 8-10 days to 6-

7 weeks. The foci of dimness on the cornea dissolve slowly, during 3 months. In

some cases the dimness remains for a long time and causes the vision worsening.

Pneumonia. Among different forms of the adenoviral diseases pneumonia

causes the greatest alarm, especially, in the children of the young age. Clinically the

symptoms of the pneumonia in case of the adenoviral infection are expressed

quite distinctly. The disease has an acute onset with the temperature increase up

to 38-39 °C, the temperature curve is usually irregular, with oscillations, quite often

the fever period has a lingering character up to 20 days and longer. The temperature

reaction is not expressed or absent in the children of the first months. Pneumonia

is accompanied by the expressed catarrhal manifeslations in the upper respiratory

tract. The fauces mucous membrane is hyperemic, edematic, the tonsils are enlarged

and in some cases they are covered with whitish fur. The nasal discharge is

abundant. The discharge is mucous or mucopurulent. The cough is painful, often

excruciating, dry or with the discharge of the mucopurulent sputum. During the

first days of the disease the physical changes in the lungs may not be found, they

usually develop later. From the 3-4th day of the disease along with the shortening

of the resonance with the tympanic inflection there is a big amount of dry and

mixed moist rale. The rale can disappear, and then come back again. Sometimes an

asthmatic component joins these manifestations. The massive affection of the lung

tissues is revealed during the X-ray examination. The inflammatory foci flow together.

They dissolve slowly. A tendency to relapses, exacerbation and a slow reparation

of the inflammatory process in the lungs are characteristic of adenoviral pneumonia.

A severe course of pneumonia with an unfavorable outcome is usually observed in

the children of the early age, and in other patients who are weakened by previous

diseases or accompanied diseases. Pleuritis and abscesses can complicate

pneumonia, but it occurs comparatively rarely.

Complications

The changes of some inner organs and systems, which are typical of the

adenoviral disease (lymphadenopathy, hepatosplenic syndrome, changes in the

cardiovascular, nervous system, hematological changes) are more expressed in

193Acute respiratory viral diseases

case of pneumonia and occur more often comparing with the uncomplicated

course of the disease. Encephalitis and meningoencephalitis cases occur

sporadically. Adenoviruses have been implicated as a cause of pericarditis, chronic

interstitial fibrosis, congenital anomalies.

Diagnosis

The clinical diagnostics of the RS infection is based on the primary affection

of the lower parts of the respiratory tract, quite often with an asthmatic component

and respiratory insufficiency. The changes in the upper parts are less expressed.

The confirmation of the diagnosis is based on the laboratory investigations.

The collection of the material and the investigation methods are the same as in

case of other viral infections of the respirators tract.

Differential diagnosis

The problems in the differential diagnostics of the diseases which form this

group are due to the fact that different viruses can cause similar clinical syndromes

and first of all the syndrome of the acute disease of the respiratory tract.

The differential diagnostics is possible only in case of the typical course of

the disease during the clinical recognition of the nosologic forms taking into

consideration the peculiarities of the location of the pathological process, the

degree of the toxicosis, the presence and expressiveness of the catarrhal

manifestations as well as changes in other organs and systems.

Times, in contrast to influenza in the adenoviral diseases the local limited

outbreaks are registered, the incubation period in the infected patients is longer,

the catarrhal manifestations with an abundant discharge are considerably expressed,

there are typical changes in the fauces, the lymph nodes, liver and spleen are

enlarged, relapses occur later.

In contrast to paragrippe the onset of the adenoviral diseases is often acute.

the exudative component is more expressed, there is lymphoadenopathy one-side

conjunctivitis.

Treatment

Treatment will carry out in view of gravity of current and the clinical form

of disease. Localy there are used the etiotropic preparation desoxyribonucleasa

which is instilated into conjunctival bag and nasal courses as the solution. Apply

also a solution of oxolin, oxolin unguent, or florenal for pawning edges of blepharons

and for greasing mucosa of nose. As agent of a choice use solution of human

interferon as inhalations, dispersion or drops in a nose through every 1-2 hours

during 2-3 days. Efficiency of treatment above correlates than earlier it is begun.

Among inductores of interferon and imunomodulatores there are indicated amixin,

amizin, cycloferon, proteflazid, erbisol. At serious forms of disease human placental

or serumal immunoglobulin (3-6 mL unitary) is used, at absence of effect it is

given repeatedly in 6-8 houres or on next day. 5 % glucose solution with

194

Infectious diseases

ascorbic acid is infused according to the indications. Reopolyglucin, sault solutions,

humidified oxygen are used through a nasal catheter.

There are recommended a hot drinks of tinctura of raspberries, lime color,

flowers of a black elder, tea with lemon, sudorific collectings. For inhalations

there should be used warm broths of leaves of eucalypt, sage, pine buds, grasses

of thyme, buds of a birch (separately or in admixture), for a gargle of pharynx

and an oral cavity there are given broths of flowers chamomiles, calendula, grasses

of a yarrow, sage. There are indicated also sinapismuses on thorax and soles.

In case of rhinitis we instill into nose vasoconstrictive preparations,such

as: naphthyzin, ephedrin hydrochloride, pharmasolin. For cupping of inflammatory

process apply into nasopharynx faringosept or falimint. The other remedies

recommended are pectusin or terpin hydrate, ascorutin, calci of gluconate,

methyluracil, and also diazolinum, suprastin, tavegil, gismanal, zestra, loratidin,

alegra, telfast.

In case of bacterial complications antibiotics and others chemotherapeutic

agents are indicated in view of kind of the originator and its medicinal sensitivity.

benzylpenicillin sodic salt, ampicillin sodium salt, carbapenicilin dinatri salt, ampiox,

erythromycin, oleandomycin phosphas or doxycyclin hydrochloride, cefalosporines

(cefazolin, cefotaxim, ceftriaxon ) are used.

Prophylaxis

Because of the ubiquity and severity of adenovirus respiratory disease in

certain populations, vaccines were developed to prevent the disease. Although

these live and inactivated virus vaccines were reasonably effective, the findings

that adenoviruses were oncogenic and could combine with simiar virus 40 to

produce an even more oncogenic hybrid virus curtailed the use of parenteral

vaccines. Vaccines have also been produced by using capsid components free of

DNA. These vaccines have been effective in volunteer studies but are not currently

available for general administration.

Oral vaccines have been developed for use in military recruits. These

vaccines contain live adenovirus types 4 and 7 in an enteric-coated capsule.

These viruses are not attenuated, but advantage is taken of the fact that inoculation

of these adenoviruses into the gastrointestinal tract does not result in illness, in

contrast to inoculation into the respiratory tract. Their efficacy and safety have

been well established in the past 10 years, and the problem of acute respiratory

disease in recruits has been markedly diminished.

RHINOVIRAL INFECTION

Rhinoviral infection is an acute viral disease of the upper respiratory tract,

which is accompanied by the symptoms of the nose and nasopharynx mucous

membrane affection.

195Acute respiratory viral diseases

Historic reference

The infectious nature of contagious rhinitis (common cold) was proved in

1914 by W.Kruse and confirmed in 1916 by G.Foster. After that, especially after

1952, the virus agents were repeatedly isolated but their etiological role remained

unproved and only in 1960 in Solsbery D.Tyrell proposed a new virus cultivation

method and isolated a whole group of them during 1961 and 1962 and proved

their etiological role. They were named rhinoviruses after the proposal of

C.Andrewes. In 1963 rhinoviruses were included into the family of picornaviruses.

Etiology

The rhinoviruses of the human include 114 serotypes which cause an acute

respiratory disease without an expressed intoxication. The virus genome is

represented by non-fragmentary filament of the RNA. The viruses inactivate at a

temperature of 56 °C quickly in 10 minutes. They die at drying in the air in

several minutes.

Epidemiology

The rhinoviruses are widely spread and affect all the age groups of people

all the year round. The human viruses develop only in humans, no sensitive

laboratory animals have been found, sometimes it is possible to infect a chimpanzee.

The strains, which are cultivated on the human’s cells, were named H-strains, and

the ones on the monkey cells – M-strains. The virus replication takes place in

the epithelial cells of the nose and they are excreted with the nasal discharge

during 2 weeks. The virus is airborne. The transmission from the hands of an

infected person to the hands of the susceptible ones is possible, and then an auto-

infection of the nose or conjunctiva occurs.

Pathogenesis

The disease development mechanism has been studied on the volunteers

and on the organic cultures. The possibility of the disease development was

shown during the experiments on the volunteers when the virus was dropped

into the nose or rubbed in the mucous membrane of the nose or eye, whereas

rubbing into the back wall of the throat or insertion through the mouth did not

cause the disease. The virus was found in the nasal discharge in 24 hours or

maximum in 3-4 days. The rhinoviruses can join other pathogens of the lower

respiratory tract worsening the course of them. The virus-bacterial associations

are discovered quite often.

Clinical manifestations

The incubation period lasts 2-3 days. The disease starts with sneezing. feeling

of dryness, tickling in the throat, pain in the throat and slight cough. From the first

hours of the disease the leading symptom is rhinitis with abundant serouse discharge,

196

Infectious diseases

which is of a watery character in the beginning, then it becomes slimy and thickly

mucopurulent. On average rhinitis lasts 6-7 days but it can be prolonged up to 14

days. During this period the patients complain of a feeling of heaviness and

nagging pain in the sinuses. The skin at the nose entrance gets macerated, the

herpetic eruption develops on the lips. The mucous membrane of the front part

and back wall of the throat becomes moderately hyperemic, slightly edematic. The

small granularity develops in the area of the soft palate. The sclera vessels are

usually injected, the conjunctiva is hyperemic, and the eyes may be watery.

The symptoms of intoxication are not typical of the rhinoviral infection. The

general condition is slightly affected. The patients mention a slight malaise, headache

in the forehead area. The body temperature remains normal or slightly increased

during 1-2 days. The picture of the peripheral blood does not change.

Complications

The joining of the bacterial flora causes the complications: sinusitis, otitis,

bronchitis, and pneumonia.

Diagnosis

The rhinoviral infection is clinically diagnosed in case of the expressed

rhinitis with abundant rhinorrhea and pharyngitis, which develop during the first

hours of the disease without any intoxication symptoms. The confirmation of the

diagnosis is based on the laboratory investigations. The material collection and

the methods of the investigation are similar to the ones in other viral infections

of the respiratory tract.