Pneumonia is a disease, which by etiology, pathogenesis and morphological description unites the large group of various diseases of inflammations of respiratory compartment of the lungs. There are three ways of entrance of stimulants of pneumonia into the lungs - bronchogenic, hematogenic and lymphogenic. The first of them has a leading value. At first an inflammatory process occurs in the bronchiole, and then spreads to the parenchyma of the lungs (bronchopneumonia). If inflammation has mostly productively exudative character, it passes on to the interalveolar septa, known as interstitial pneumonia. Next to it, there is an independent infectious disease, which shows up in that among a complete health sharply catches a fire fibrinous inflammation of parenchyma of lungs is parenchymatos (lobar pneumonia) pneumonia.

Lobar pneumonia – in 95 % of cases is caused by s Fraenkel’s pneumococcus, or rarer by Friedländer’s diplobacillus, by streptococcus, staphylococcus, and Pfeiffer’s bacillus. A cold which decreases the immunobiological reactivity acts as a provoking factor. Disease often arises in persons with alcoholism, avitaminosis, cardiac insufficiency, and chronic overstrain. Morphological changes in lobar pneumonia occur in a certain sequence, which distinguishes a few stages of the process (К.Rokitansky) - stage of congestion (from 12 hours to 3 days), stage of red hepatization (1-3 days), stage of grey hepatization (2-6 days), and stage of resolution.

Pneumonia begins with a small of inflammation in the posterior or postero-lateral segments of the lungs round the colonies of pneumococcus. Inflammation spreads by contact and quickly absorbs one or few pulmonary substance. In the stage of congestion, the lung is megascopic in volume, with exudates in its tissue and is sanguineous. In the stage of red hepatization, the exudate is enriched with fibrin and red corpuscles. The lungs, under close view look the liver, and is crimson coloured on section. The color of the phlegm is rusty. On the 4-6th day, the composition of the exudate changes – red corpuscles disappear, but the number of neutrophils which phagocyte the pneumococcus increases. The surface of the lungs is grey color on section (stage of grey grained detritus it is possible to find remains of fibrins hepatization). During the period of convalescence exudate resolves.


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The cut surface of this lung demonstrates the typical appearance of a bronchopneumonia with areas of tan-yellow consolidation. Remaining lung is dark red because of marked pulmonary congestion. Bronchopneumonia (lobular pneumonia) is characterized by patchy areas of pulmonary consolidation. These areas become almost confluent in the left lower lobe on the bottom left of the photograph.The areas of consolidation are firmer than the surrounding lung.

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Here is another example of a bronchopneumonia. The lighter areas that appear to be raised on cut surface from the surrounding lung are the areas of consolidation of the lung


 Complications of lobar pneumonia are divided into pulmonary and extrapulmonary. The first group consists of carnification, empyema of the pleura, abscess formation, and gangrene. Extrapulmonary complications are pneumococcal inflammatory processes in different organs (lymphadenitis, meningitis, peritonitis, arthritis, etc.). The term “ bronchopneumonia” unites different primary inflammations of the lungs with localization of primary process in bronchial tubes. From here inflammation spreads to the pulmonary tissue and can be limited to the acini, by a particle, segment or particle. Bronchopneumonia occurs more frequently, than lobar. As children and people have an independent disease for years. Bronchopneumonia is complicated by acute respiratory and viral diseases (flu, measles). It can occur at insufficiency of circulation of blood, especially on a background of the stagnant pneumonia in lungs (stagnant pneumonia), at the protracted confinement to bed for heavy and weakened patients (hypostatic pneumonia), and in postoperation period.

In most cases, the cause of bronchopneumonia is aerogenic infection, but hematogenic and lymphogenic ways of transmission are also possible. The process begins in the bronchiole and spreads to the alveolar sacs. Bronchitis can be accompanied by peribronchitis. From peribronchial tissue infection spreads to the nearby alveolar tree (peribronchial pneumonia). Inflammation of alveolar tissue quite often is preceded by the collapse of alveolar passages. It could be a consequence of compression from outside or obstruction of the bronchial tube with exudates followed by suction of air from the alveolar ways which have lost connection with the respiratory passages.


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At higher magnification, the pattern of patchy distribution of a bronchopneumonia is seen. The consolidated areas here very closely match the pattern of lung lobules (hence the term "lobular" pneumonia).A bronchopneumonia is classically a "hospital acquired" pneumonia seen in persons already ill from another disease process. Typical bacterial organisms include: Staphylococcus aureus, Klebsiella, E. coli, Pseudomonas.


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This bronchopneumonia is more subtle, but there are areas of lighter tan consolidation. The hilum is seen at the lower right with radiating pulmonary arteries and bronchi.Many bronchopneumonias follow an earlier viral pneumonia, particularly in older persons in the winter months when influenza is more common.


Atelectasis is an active slump of the pulmonary tissue, which can occur due to shortage of surfactant, while collapse is a passive slump under pressure of exudate, air or tumor. The exception of part of alveolar ways from a respiratory function causes the development of vicarious (compensate) emphysema. Exudate at bronchopneumonia is composed of serous liquid with the admixture of leucocytes, desquamated cells of the alveolar epithelium, red corpuscles, and at times fibrin. That is why serous, purulent, desquamation, hemorrhagic and fibrinous pneumonia are distinguished.


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This is a lobar pneumonia in which consolidation of the entire left upper lobe has occurred. This pattern is much less common than the bronchopneumonia pattern. In part, this is due to the fact that most lobar pneumonias are due to Streptococcus pneumoniae (pneumococcus) and for decades, these have responded well to penicillin therapy so that advanced, severe cases are not seen as frequently. However, pneumoccoci, like most other bacteria, are developing more resistance to antibiotics. Severe pneumococcal pneumonia still occurs, even in young to middle aged persons (not just the very young and the very old) and has a mortality rate of 20%!


Macroscopically, there are inflammatory focuses which correspond to the collapsed bronchial tubes or particles which appear in lungs. They burst above the surface of cut, have yellow grey, grey or red color, are dense by touch, and sink in water. A turbid liquid which does not contain the blisters of air flows down during their squeezing. From the bronchiole, mucus-purulent exudate is pressed out.


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 A closer view of the lobar pneumonia demonstrates the distinct difference between the upper lobe and the consolidated lower lobe. Radiographically, areas of consolidation appear as infiltrates.


Bronchopneumonia mostly ends with convalescence, but complications - gangrene of lungs and carnification are possible. Interstitial (intermediate) pneumonia spreads mainly on intermediate tissue, in lumen of alveolar ways.

Intermediate pneumonia belongs to the atypical forms. It occurs in viral infections and lobar pneumonia. The process begins with bronchitis and spreads by lymphatic ways (lymphangitis) or hematogenously (system red lupus). Productive inflammation prevails at times (measles). Frequently is purulent lymphangitis. Distinguished types are peribronchial, interlobular and interalveolar pneumonia. Macroscopically, yellow ribbons which separate particles from induration are seen. Sometimes at purulent inflammation, the intervals of **sequestrum** and particles become separated. Such pneumonia supports the development of interstitial emphysema. Complications are abscess formation, empyema and mediastinitis.


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The pleural surface at the lower left demonstrates areas of yellow-tan purulent exudate. Pneumonia may be complicated by a pleuritis. Initially, there may just be an effusion into the pleural space. There may also be a fibrinous pleuritis. However, bacterial infections of lung can spread to the pleura to produce a purulent pleuritis. A collection of pus in the pleural space is known as empyema.


Pneumonia of children has some features:

 a) Inflammatory process develops mainly in the respiratory parts of lungs;

b) Infection occurs intrauterine or through aspiration of amniotic waters;

c) Hyaline membranes appear as a result of increased permeability of blood vessels;

d) infection is more frequent than in adults and spreads outside lungs – to kidneys, liver, cerebrum.


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Seen here are two lung abscesses, one in the upper lobe and one in the lower lobe of this left lung. An abscess is a complication of severe pneumonia, most typically from virulent organisms such as S. aureus. Abscesses are complications of aspiration, where they appear more frequently in the right posterior lung.


Bronchitis is divided into acute and chronic bronchitis (bronchitis acuta, bronchitis chronica). Among the etiologic factors of the acute inflammation of bronchial tubes, of important are viruses and bacteria which cause respiratory diseases. Among physical factors are the pathogenic action of dry or cold air, dust; and chemical factors are inhalation of  tobacco smoke, steams of chlorine, oxides of nitrogen etc. The inherited impairment of barrier mechanisms of mucus, insufficiency of cellular and humoral (IGA) protective factors of local importance supports the development of bronchitis. In reply to the pathogenic influence on the gland and goblet cells of mucus membrane of bronchial tubes, production of mucus increases. It results in shedding of ciliary the prismatic epithelium, baring of mucus and penetration of infection through the wall of bronchial tube.


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Seen here are lung abscesses grossly in which the purulent exudate has drained following sectioning to reveal the abscess cavities. Abscesses can be a source for septicemia and are difficult to treat.




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This is an abscessing bronchopneumonia in which several abscesses with irregular, rough-surfaced walls are seen within areas of tan consolidation. Lung abscesses, if large enough, will contain liquefied necrotic material and purulent exudate that often results in an air-fluid level by chest radiograph in the abscess


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At the left the alveoli are filled with a neutrophilic exudate that corresponds to the areas of consolidation seen grossly with the bronchopneumonia. This contrasts with the aerated lung on the right of this photomicrograph.


Acute bronchitis can be of independent nosology or the secondary sign of a series of other diseases (lobar pneumonia, uremia and so on). In the mucus membrane of the bronchial tubes almost all forms of catarrhal inflammation are developed – serous, purulent, fibrinous, fibrinous-hemorrhagic, and mucus. Destruction of the mucus membrane is sometimes possible with the development of ulcers. In such cases it is known as destructively ulcerous bronchitis. Predominance of this or other forms of catarrh depends on the pathogenic factor and resistance of the organism. Inflammation begins from the mucus membrane (endobronchitis), then spreads to the muscular layer (endomesobronchitis) and in the terminal phase affects all the layers (panbronchitis). Certainly, an inflammatory process can be stopped at the development on a certain layer.

Existing of acute bronchitis can be complicated with bronchopneumonia or peribronchial by intermediate pneumonia. Bronchopneumonia is mostly as a result of aspiration of infected mucus in the respiratory compartment of the lungs. Peribronchial intermediate pneumonia occurs as a result of transition of inflammation not only on peribronchial but also on interstitial tissue.

Serous and mucus catarrh quickly ends with convalescence. Purulent, fibrinous and fibrinous-hemorrhagic catarrh, and also an ulcerous-destructive bronchitis have the protracted course and often progresses to the chronic form or pneumonia.

Chronic inflammation of bronchial tubes is revealed in the following forms:

а) Chronic mucus or purulent catarrh with atrophy of mucus membrane, by the cystous regeneration of glands and metaplasia of prismatic epithelium into stratified squamous epithelium; 

b) Chronic productive inflammation is with formation of polyposis from granulation tissue (polyposis chronic bronchitis);

c) deformation of bronchial tube at maturation of granulation tissue, outgrowth of connective tissue in a muscular layer, sclerosis and atrophy of mucus (deforming chronic bronchitis).

Chronic bronchitis with the protracted course, except sclerotic changes, is accompanied by dystrophy of elastic, muscular and cartilaginous frameworks. That is why during cough, when intrabronchial pressure increases sharply, in the areas of the least resistance the wall of bronchial tube broadens and bursts. So, saccular bronchiectasis appear. At diffuse expansion of the bronchial tubes, they have a cylindrical form. Chronic bronchitis is always accompanied by the impairment of drainage function of bronchial tubes, which causes an increase in the period of timemucus spends in the lower parts, closing of airways of bronchiole and the development of bronchiolung complications (obstructive emphysema, chronic pneumonia, pneumofibrosis).


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At higher magnification can be seen a patchy area of alveoli that are filled with inflammatory cells. The alveolar structure is still maintained, which is why a pneumonia often resolves with minimal residual destruction or damage to the lung.


Bronchiectasis is inherited and acquired expansions of bronchial tubes in cylindrical or saccular forms. Inherited bronchiectasis occurs in connection with impairment of formation of the bronchial tree. They are marked with the chaotic location of structures of walls of bronchial tubes. Sometimes bronchioles are closed blindly in the parenchyma of lungs and cysts appear. In such cases, it known as cystous lung. Bronchiectasis is acquired with relation to the acute bronchitis, pneumonia, and collapse of lungs.

According to the form of expansion of bronchial tubes, saccade bronchiectasis (local thrusting out of wall) and cylinder bronchiectasis (diffuse expansion of airways of bronchial tube) are distinguished. Expansions of shallow bronchial tubes are known as bronchioloectasis. Lungs in such cases have a cellulous kind (pulmo сisticus).

At bronchiectasis there are the phenomena of chronic inflammation in the wall of bronchial tubes, metaplasia of prismatic epithelium into stratified squamous, dystrophic changes of elastic fibres, cartilaginous tissue and leiomyocyte and sclerosis. In the cavities of bronchiectasis mucus and purulent exudates accumulate. Based on this, abscesses, perifocal purulent pneumonia, perifocal fibrous, obstructive emphysema occur. Sclerosis develops in vessels in the presence of plural bronchiectasis and emphysema results in the development of hypertension in the lesser blood circulation and hypertrophy of the right ventricle of the heart. The symptoms of hypoxia appear with the disorder of trophism of tissues that follows. A very typical sign is the bulging of the distal phalanges of fingers and toes as “drumsticks”.

A combination of changes in the lungs and complications (pulmonary heart, general amyloidosis, hypoxic signs, sclerosis, etc.) at presence of bronchiectasis examined as new nosology is bronchiectatic disease.

Emphysema of lungs is the pathological state of the pulmonary tissue, characterized by the increased presence of air in it. Vesicular, diffuse obstructive, chronic, focus, compensating, primary panacinar, senile and interstitial types of emphysemas are distinguished. Development of vesicular emphysema is related to chronic bronchitis, bronchiolitis and by their consequences – plural bronchiectasis. It has been discovered, that there is a deficit of inhibitors of protease - elastase, collagenase in these diseases. Insufficiency of the important inhibitor; )1-antitrypsin can be genetically conditioned. Activation of elastase and collagenase causes the destruction of interalveolar septa leading to bigger cavities.


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At high magnification, the alveolar exudate of mainly neutrophils is seen. The surrounding alveolar walls have capillaries that are dilated and filled with RBC's. Such an exudative process is typical for bacterial infection. This exudate gives rise to the productive cough of purulent yellow sputum seen with bacterial pneumonias.

Diffuse obstructive emphysema (emphysema pulmonum obstructium diffusum chronicum) occurs at chronic diffuse bronchitis. Its development is by valvular mechanism. It happens because air accumulates in the alveolar ways during inhalation and remains even after exhalation due to the presence of mucus clots in shallow bronchial tubes and bronchioles. Air is accumulated  in the acinus, which becomes broadened as a result of the deficiency of elastic and collagen fibres. Huge dilation of the respiratory bronchiole and acinus result in centriacinar emphysema, while dilation of the large bronchial tubes and acinus result in panacinar emphysema. Stretching of walls of acinus results in thinning of interalveolar septa, expansion of interalveolar sac and formation of vesicular blisters. The capillary net of partitions empties. Thus, there is the considerable diminishing of the area of gaseous exchange and a ventilatory function of lungs is impaired. The damage of the capillary network of alveolar ways together with the sclerosis of interalveolar capillaries leads to the development of pulmonary hypertension and hypertrophy of the right ventricle of heart (pulmonary heart).


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More virulent bacteria and/or more severe pneumonias can be associated with destruction of lung tissue and hemorrhage. Here, alveolar walls are no longer visible because there is early abscess formation. There is also hemorrhage.


Chronic focus emphysema (emphysema pulmonum focale chronicum) occurs as a result of the expansion of acini and respiratory bronchiole round the old sites of tuberculous inflammation or post atack scars. Confluence of a few bullae results in bullous emphysema. Bullae (sub pleural blebs), which are located under the pleura, can break through the pleura cavity and cause spontaneous pneumothorax. This type of emphysema is not accompanied by pulmonary hypertension, as a capillary network is damaged in a limited area of lungs.     

Compensating emphysema (emphysema pulmonum vicarum s. compensatorium) is also called vicarious emphysema. It occurs after the surgical removal of part lungs or one of lungs. This type of emphysema is accompanied by compensatory hypertrophy and hyperplasia of the remaining structures of the lungs. The cause of primary (idiopathic) emphysema is unknown. It has such typical signs a atrophy of walls of alveolar ways, reduction of capillary wall, and pulmonary

Development of senile emphysema, more precisely are emphysemas in old men, related to age-old involution of lungs.


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At higher magnification, early abscessing pneumonia is shown. Alveolar walls are not clearly seen, only sheets of neutrophils.


Interstitial emphysema (emphysema pulmonum interstetiale) is characterized by the penetration of air into the  interstitial tissue. The cause of such phenomenon is the destruction of alveolar ways at strong coughing motions. Through the cells of the root of the lungs, air gets into the intercellular spaces of the mediastinum (pneumomediastinum), subcutaneous cells of the neck, thorax and head (hypodermic emphysema). At pressure on the skin of the areas of increased air, a characteristic crunch (crepitation) can be heard.


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This more focal abscess containing a neutrophilic exudate as well as dark blue bacterial colonies suggests aspiration or hematogenous spread of infection to the lung. Aspirated material from the oral-pharyngeal region contains bacterial flora. Hematogenous spread of infection to lungs could occur from septicemia or from infective endocarditis involving the right side of the heart.


 Bronchial asthma is a chronic disease of allergic nature, which is characterized by the attacks of expiratory dyspnoea. There are two main forms of bronchial asthma– atopic and infectiously allergic.      Atopic form occurs at influence of allergens of uninfectious origin on the respiratory tracts. . In the half of the cases, the disease is predefined by a dusty room in the complement of which high-allergic carbohydrates - products of disintegration of cellulose enter from a cotton plant. In addition to  a dusty room the special type of allergin which causes the bronchial asthma in childhood is found. From among other allergens such, as vegetable pollens, epidermis and wool of animals, medications (acetylsalicylic acid, morphine), domestic chemicals (detergents, varnishes) are important. The infectiously allergic form of bronchial asthma develops in patients with broncho-pulmonary pathology, caused by infectious agents – viruses, bacteria and mushrooms. Pathogenesis of both forms of bronchial asthma is similar. Immunological, pathochemical and patophysiological stages are selected. In the  atopic form the immunological stage is characterized by the hyperproduction and accumulation  of ІgЕ. These antibodies are adsorbed in the cells of bronchiole and at the repeated introduction of antigen in respiratory tracts, interact with it by the mechanism of anaphylaxis. The reaction of immediate type is formed; the attack of dyspnoea occurs in a few minutes after the action of the antigen. At infectiously allergic bronchial asthma the immunological stage is of the mechanism of hypersensitiveness of slow type, where the leading role is played not by antibodies, but by sensibilised lymphocytes. The dyspnoea appears in 12-36 hours after a contact with the allergen.

During the pathochemical stage under the action of an antigen-antibody complex active substances- histamine acetylcholine, prostaglandin, leukotriene are released. They disturb the function of target cells in the walls of the bronchiole, – leyomiocytes, goblet and other cells. It results in bronchiospasm, hypersecretions of mucus and edema of bronchiole. Eventually ventilation functions are strongly limited affecting exhalation mainly, when due to the additional tension of respiratory muscles high intrapulmonary pressure is created. Bronchiole adhere together, and exhalation is affected or generally becomes impossible. Disorder of respiration in patients with bronchial asthma is revealed as repeated attacks of dyspnoea. During an attack there is infiltration of walls of bronchiole by eosinophiles, neutrophiles, labrocytes,   and T-lymphocytes. There is an edema of mucus and submucus layers, obturation of bronchiole by mucus in which eosinophiles appear and epithelium shedding . In pulmonary tissue acute obstructive emphysema develops with the focus of atelectasis. Respiratory insufficiency which can lead to death of the patient during an attack, comes as a result. Before the chronic signs of bronchial asthma are the phenomena of diffuse chronic bronchitis, inflammation and hyalinosis of the basal membrane of bronchiole, sclerosis of intraalveolar partitions, chronic obstructive emphysema of lungs, pulmonary hypertension, hypertrophy of right ventricle of heart. 


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There is a localized foreign body giant cell response to the aspirated material seen here at high magnification. Aspirated material may also produce inflammation from chemical irritation, as with gastric contents.


Interstitial diseases of lungs are characterized by the primary inflammatory process in intraalveolar connective tissue (pneumonitis), also called fibrosing alveolitis. They end up with the development of diffuse pneumofibrosis.

Three nosology forms of fibrous alveolitis are distinguished:

1) idiopathic pulmonary fibrosis/chronic fibrosing alveolitis;

2) extrinsic allergic alveolitis (lung „farmer”, „poultry farmer”, „cattle-breeder”, „textile worker”, „pharmaceutist”;

3) toxic fibrous alveolitis.      


1) viral, bacterial, mycosis infection;

2) dust with the antigens of animal and vegetable origin;

3) medical preparations:, immunosuppressors, antitumor antibiotics, antidiabetic preparations and so on.

In pathogenesis the basic role is played by the immunocomplex damages of capillaries between alveolar partitions and stroma of lungs followed by cellular immune cytolysis.

Pathological anatomy is presented by three stages:

1) diffuse or granulomatous alveolitis with infiltration neutrophiles, lymphocytes, plasmatic cells;

2) disorganization of alveolar structures and pneumofibrosis;

3) forming of cellular  lungs with the development of the alveolar-capillary block, panacinar emphysema, bronchiolectasis, pulmonary hypertension, hypertrophy of the right ventricle.

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Almost the entire middle lobe of this right lung is involved by a chronic abscess as seen here on section. The area of abscess is yellow tan, and it was very firm.The infectious agent responsible here was Nocardia, which is known to produce chronic abscessing inflammation.


The syndrome of Hamman-Rich is an acute form of fibrous alveolitis, that occurs at systemic diseases of connective tissue and  active viral hepatitis.

Pneumofibrosis is a chronic process in lungs, which develops after the previous diseases of pulmonary tissue or interstitia. It is characterized by outgrowth of connective tissue, deep alteration of microcirculations, the development of pulmonary hypertension followed by hypertrophy of the right ventricle and pulmonary heart, hypoxia of pulmonary tissue, its alteration and deformation.


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This is a microscopic appearance of chronic abscessing inflammation with large areas of pink necrotic tissue present on the left that are bordered by granulation tissue with numerous prominent capillaries filled with blood.


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Here is the microscopic appearance of a viral pneumonia with interstitial lymphocytic infiltrates. Note that there is no alveolar exudate. Thus, the patient with this type of pneumonia will probably not have a productive cough. The most common causes for viral pneumonia are influenza, parainfluenza, adenovirus, and respiratory syncytial virus (RSV appears mostly in children).


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Cytomegalovirus can appear in immunocompromised hosts.


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This is respiratory syntytial virus (RSV) in a child. Note the giant cells which are part of the viral cytopathic effect. The inset demonstrates a typical giant cell with a round, pink intracytoplasmic inclusion. RSV accounts for many cases of pneumonia in children under 2 years, and can be a cause for death in infants 1 to 6 months of age or older.


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Here is the gross appearance of a lipid pneumonia in which there is an ill-defined, pale yellow area on the left. This yellow appearance explains the term "golden" pneumonia. There are two main types of lipid pneumonia: endogenous and exogenous.


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This is the microscopic appearance of an exogenous lipid pneumonia in which lipid vacuoles appear, mainly along airways, accompanied by an inflammatory response that can contain foreign body giant cells. The term exogenous refers to the origin of the lipid material outside the body. This material is aspirated into the bronchial tree.



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Here is the gross appearance of a lung with tuberculosis. Scattered tan granulomas are present, mostly in the upper lung fields. Some of the larger granulomas have central caseation. Granulomatous disease of the lung grossly appears as irregularly sized rounded nodules that are firm and tan. Larger nodules may have central necrosis known as caseation--a process of necrosis that includes elements of both liquefactive and coagulative necrosis).


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On closer inspection, the granulomas have areas of caseous necrosis. This is very extensive granulomatous disease. This pattern of multiple caseating granulomas primarily in the upper lobes is most characteristic of secondary (reactivation) tuberculosis. However, fungal granulomas (histoplasmosis, cryptococcosis, coccidioidomycosis) can mimic this pattern as well.


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This cast of the bronchial tree is formed of inspissated mucus and was coughed up by a patient during an asthmatic attack. The outpouring of mucus from hypertrophied bronchial submucosal glands, the bronchoconstriction, and dehydration all contribute to the formation of mucus plugs that can block airways in asthmatic patients.


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Between the bronchial cartilage at the right and the bronchial lumen filled with mucus at the left is a submucosa widened by smooth muscle hypertrophy, edema, and inflammation (mainly eosinophils). These are changes of bronchial asthma. The peripheral eosinophil count or the sputum eosinophils can be increased during an asthmatic attack.


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A closer view demonstrates the focal area of dilated bronchi with bronchiectasis. Bronchiectasis tends to be localized with disease processes such as neoplasms and aspirated foreign bodies that block a portion of the airways. Widespread bronchiectasis is typical for patients with cystic fibrosis who have recurrent infections and obstruction of airways by mucus throughout the lungs.


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This photomicrograph shows a bronchus with increased numbers of chronic inflammatory cells in the submucosa. Chronic bronchitis does not have characteristic pathologic findings, but is defined clinically as a persistent productive cough for at least three consecutive months in at least two consecutive years. Most patients are smokers. Often, there are features of emphysema as well. Since chronic bronchitis and emphysema often overlap, the term 'chronic obstructive pulmonary disease' (COPD) can be applied.


Professional diseases of lungs

Silicosis and anthracosis belong to the group of pneumoconiosis – professional diseases which are caused by the action of industrial dust.

The cause of silicosis is protracted inhalation of dust which contains the dioxide of silicon - SiO2. The crystalline oxide of silicon in a tissue fluid slowly dissolves and develops into colloid solution of silicic acid. The latter damages the tissue of lungs and initiates a fibrous process.

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Progressive massive fibrosis superimposed on coal workers' pneumoconiosis. The large, blackened scars are located principally in the upper lobe. Note the extensions of scars into surrounding parenchyma and retraction of adjacent pleura. (Courtesy of Dr. Werner Laquer, Dr. Jerome Kleinerman, and the National Institute of Occupational Safety and Health, Morgantown, WV.)


The same role in the pathogenesis of silicosis is played by the damage of the wall of lysosomes by the particles of quartz, as a result of which hydrolytic enzymes are emptied in the cytoplasm of macrophages. The products of autolysis of macrophages stimulate the proliferative activity of fibroblasts.

The course of silicosis is mostly chronic. In mucus and submucus membranes of the nose, larynx, trachea, interstitial of lungs and  lymphatic nodes the phenomena of atrophy, sclerosis and formation of silicotic nodules appear. They have a round or polygonal form with grey or grey black color. In some cases silicotic nodules are built from concentric located hyaline of connective tissue cells, in other - from the wrong directed collagenase bunches. In both cases a free dust or dust appears in macrophages. They are called as dustcontaining cells– coniophagocytes.

Three forms of silicosis are distinguished. At a miliary form shallow nodes prevail by a size from millet corn. At a tumor form silicotic nodules are large, resemble a tumor and occupy the greater part of pulmonary fate or and all of fate. The diffusely sclerotic form is characterized by the negligible quantity of miliary nodes and the predominance of diffuse outgrowth of connective tissue after motion of bronchial tubes, vessels and intraalveolar partitions.

During all forms of silicosis the development of chronic bronchitis, pneumosclerosis, pulmonary hypertension, hypertrophy of right ventricle of heart are observed. Sometimes silicotic nodules can be disintegration with the formation of silicate cavity. In the formation of cavities of importance is the instability of newly formed connective tissue. In particular, it is less steady to collagenosis. Tuberculosis often accompanies silicosis. In such cases the disease is called silicotuberculosis.

Anthracosis occurs at the protracted inhalation of coal dust. The disease is characterized by the development of connective tissue in the areas of the deposition of the coal dust – in intraalveolar partitions, bronchial tubes and vessels. Connective tissue overgrows round the accumulations of dust, not shown out coniophagocytes through a bronchial tree or lymphatic vessels. Such nodes are called anthracotic.

At the infiltration of lymphatic nodes by coal dust and their sclerosis there is the stagnation of lymph, hypoxia and acidosis of the stroma of lungs. This leads to black induration of lungs is developed.

Anthracosis is accompanied by chronic bronchitis, emphysema, pulmonary hypertension and bronchopneumonia. As a result of the disorders of blood circulation and direct influencing of coal dust sometimes there is necrosis and softening of pulmonary tissue with the formation of cavities. This form of anthracosis is accompanied by haemoptysis and, resembles secondary tuberculosis, through called black consumption.

The cancer of lungs occupies the first position among malignant tumors in men and the second – in women. The death rate for it is 26 %.

The cancer of bronchial tubes occurs mainly in smokers (90%). Of important role are the carcinogenic substances which penetrate blood and lymph.

To the precancer states belong chronic bronchitis, bronchiectasis,, and to the precancer changes – hyperplasia, displasia and metaplasia  of the epithelium.

As a rule, the cancer of lungs develops from the epithelium of bronchial tubes (bronchogenic, central cancer), rarely – from the epithelium of bronchiole and alveolar epithelium (pneumogenic, peripheral cancer). Pathogenesis of central cancer is related to such precancer changes, as basal-cellular hyperplasia, dysplasia and squamous cellular metaplasia of the epithelium of bronchial tubes. For the morphogenesis of peripheral cancer, the main characteristic is a wider spectrum of pre-tumor changes. Foremost, they are related to the development of pneumosclerosis after inflammation, to heart attack and so on. Substances which are instrumental in malignant transformation are created in the scar, namely the deposition of carcinogens, local immunosuppression, disorder of intercellular connections.

According to А.І.Strukov classification of cancer of lungs foresees a division after localization, character of growth, macroscopic form and microscopic kind.

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Lung carcinoma. The gray-white tumor tissue is seen infiltrating the lung substance. Histologically, this large tumor mass was identified as a squamous cell carcinoma.


According to localization the following forms are selected:

1) periapical (central) cancer which developes from an epithelium a barrel lobular and initial part of   bronchial tube, grows as a node or polypus of white color and dense consistency;

2) peripheral cancer which developes from the peripheral part of   bronchial tube and its branches, and also from alveolar epithelium, exophiticaly grows for a long time and often developes in the area of scar;

3) the mixed (massive) cancer  reveals itself as soft tissue of white color, which can occupy part or all of lung.

According to character of growth endophitic (endobronchial) and exophitic (exobronchial and peribronchial) cancers are distinguished.

According to macroscopic form a cancer is plague-like, polypus, endobronchial diffuse, ramified and nodal ramified cancer.

According to microscopic structure squarmous cellular (epidermoid) cancer, undifferentiated, anaplastic caner (finecellular, largecellular, oastmealcellular), golden-flatcellular cancer, of bronchial glands – adenoidno-cystous and mucoepidermoid are distinguished.


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Cytologic diagnosis of lung cancer is often possible. A, A sputum specimen shows an orange-staining, keratinized squamous carcinoma cell with a prominent hyperchromatic nucleus (arrow). B, A fine-needle aspirate of an enlarged lymph node shows clusters of tumor cells from a small cell carcinoma, with molding and nuclear atypia characteristic of this tumor; note the size of the tumor cells compared with normal polymorphonuclear leukocytes in the left lower corner.


         Metastasis outside an organ is a characteristic of a central cancer. At endophitic growth it spreads to the tissue of mediastinum, pericardium and pleura. Peripheral and mixed cancers spread within the limits of the organ, germinating tissue of the bronchial tubes and pleura. The cancer of lungs metastases by lymphogenic and hematogenic ways. Lymphogenic metastases occur in the peribronchial, bifurcational, neck and other lymphatic nodes, hematogenic – to the cerebrum, bones (mainly vertebrae), and adrenal glands. For central cancer, lymphogenic metastases are typical, for peripheral – hematogenic. First clinical sign of peripheral cancer, which developes in the area of scar and has a small sizes (microcarcinoma), related to the plural hematogenic metastases.


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Histologic appearance of lung carcinoma. A, Well-differentiated squamous cell carcinoma showing keratinization. B, Gland-forming adenocarcinoma. C, Small cell carcinoma with islands of small deeply basophilic cells and areas of necrosis. D, Large cell carcinoma, featuring pleomorphic, anaplastic tumor cells and absence of squamous or glandular differentiation.


         Permanent complication of cancer of lungs, especially central, is the development of atelectasis. Pneumonias, abscesses, bronchiectasis, bleeding which mask the course of cancer, develops as a result of the disorder of the drainage function. The distribution on the pleura causes the development of serous-hemorrhagic and hemorrhagic pleuritis, and also to carcinom of the pleura. Cachexia during the cancer of lungs develops later than during the cancer of the stomach.

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Bronchioloalveolar carcinoma with characteristic growth along pre-existing alveolar septa, without invasion. (Courtesy of Dr. Jerome B. Taxy, Department of Pathology, The University of Chicago, Pritzker School of Medicine, Chicago, IL.)


The pleuritis is the inflammation of pleura which frequently occurs as the complication of some of visceral pathologies. Often occurs at diseases of the lungs: pneumonias, ischemic heart disease, cancer, tuberculosis etc., at rheumatism and other system diseases of connective tissue (allergic pleuritis), and also diseases of kidneys (pleuritis of uremia). According to the character of inflammations pleuritis serous, fibrinous, sero-fibrinous, purulent, hemorrhagic types are distinguished.

Common Gram-positive pathogens include Staphylococcus and Streptococcus, each of which causes many types of infections. Three less common diseases caused by Gram-positive rod-shaped organisms are also discussed here: diphtheria, listeriosis, and anthrax. Nocardia are environmental Gram-positive bacteria that cause infections mainly in immunocompromised people. Clostridia, which are Gram-positive, are discussed with the anaerobes.


Staphylococcal Infections

Staphylococcus aureus organisms are pyogenic, nonmotile, Gram-positive cocci that form grapelike clusters. These bacteria cause a myriad of skin lesions (boils, carbuncles, impetigo, and scalded skin) and also cause osteomyelitis, pneumonia, endocarditis, food poisoning, and toxic shock syndrome . Here we review the general characteristics of S. aureus infection. Specific organ infections are described in other chapters. Staphylococcus epidermidis, a species that is related to S. aureus, causes opportunistic infections in catheterized patients, patients with prosthetic cardiac valves, and drug addicts. Staphylococcus saprophyticus is a common cause of urinary tract infections in young women.

Pathogenesis. S. aureus and other virulent staphylococci possess a multitude of virulence factors, which include surface proteins involved in adherence, secreted enzymes that degrade proteins, and secreted toxins that damage host cells. Staphylococci are distinguished by their large number of plasmids, which encode proteins involved in antibiotic resistance and other virulence factors.

S. aureus expresses surface receptors for fibrinogen (called clumping factor), fibronectin, and vitronectin, and uses these molecules as a bridge to bind to host endothelial cells. Staphylococci infecting prosthetic valves and catheters have a polysaccharide capsule that allows them to attach to the artificial materials and to resist host cell phagocytosis. The lipase of S. aureus degrades lipids on the skin surface, and its expression is correlated with the ability of the bacteria to produce skin abscesses. Staphylococci also have protein A on their surface, which binds the Fc portion of immunoglobulins.

S. aureus produces multiple membrane-damaging (hemolytic) toxins, including α-toxin, which is a pore-forming protein that intercalates into the plasma membrane of host cells and depolarizes them;β-toxin, a sphingomyelinase; and δ-toxin, which is a detergent-like peptide. Staphylococcal γ-toxin and leukocidin lyse erythrocytes and phagocytic cells, respectively.

The exfoliative toxins produced by S. aureus are serine proteases that split the skin by cleaving the protein desmoglein 1, which is part of the desmosomes that hold epidermal cells tightly together. This can cause the superficial epidermis to split away from the deeper skin, making the patient vulnerable to secondary infections. Exfoliation can occur at the site of staphylococcal skin infection (bullous impetigo) or can be widespread, when secreted toxin from a localized infection causes disseminated loss of the superficial epidermis (staphylococcal scalded-skin syndrome).

Superantigens produced by S. aureus cause food poisoning and, of more concern, toxic shock syndrome (TSS). TSS came to public attention because of its association with the use of hyperabsorbent tampons, which became colonized with S. aureus during use. It is now clear that TSS can be caused by growth of S. aureus at many sites, most commonly the vagina and infected surgical sites. TSS is characterized by hypotension (shock), renal failure, coagulopathy, liver disease, respiratory distress, a generalized erythematous rash, and soft tissue necrosis at the site of infection. If not promptly treated, TSS can be fatal. TSS can also be caused by Streptococcus pyogenes.

As mentioned earlier, superantigens bind to conserved portions of MHC molecules and to relatively conserved portions of TCR β chains. In this manner, superantigens may stimulate up to 20% of T lymphocytes. The stimulation of so many T lymphocytes leads to massive T-lymphocyte proliferation and cytokine release. The high levels of cytokines can lead to capillary leak and shock and may cause vomiting by affecting the nervous system in the gut or the central nervous system

Morphology. Whether the lesion is located in the skin, lungs, bones, or heart valves, S. aureus causes pyogenic inflammation that is distinctive for its local destructiveness

Excluding impetigo, which is a staphylococcal or streptococcal infection restricted to the superficial epidermis, staphylococcal skin infections are centered around the hair follicles. A furuncle, or boil, is a focal suppurative inflammation of the skin and subcutaneous tissue, either solitary or multiple or recurrent in successive crops. Furuncles are most frequent in moist, hairy areas, such as the face, axillae, groin, legs, and submammary folds. Beginning in a single hair follicle, a boil develops into a growing and deepening abscess that eventually "comes to a head" by thinning and rupturing the overlying skin. A carbuncle is associated with deeper suppuration that spreads laterally beneath the deep subcutaneous fascia and then burrows superficially to erupt in multiple adjacent skin sinuses. Carbuncles typically appear beneath the skin of the upper back and posterior neck, where fascial planes favor their spread. Chronic abscess formation of apocrine gland regions, most frequently of the axilla, is known as hidradenitis suppurativa. Those of the nail bed (paronychia) or on the palmar side of the fingertips (felons) are exquisitely painful. They may follow trauma or embedded splinters and, if deep enough, destroy the bone of the terminal phalanx or detach the fingernail.

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Pyemic lung abscess in the center of section with complete destruction of underlying parenchyma within the focus of involvement.


Pathogenesis. The different species of streptococci produce many virulence factors and toxins. Many streptococci, including S. pyogenes and S. pneumoniae, have capsules that resist phagocytosis. S. pyogenes also expresses M protein, a surface protein that prevents bacteria from being phagocytosed, and a complement C5a peptidase, which degrades this chemotactic peptide. Poststreptococcal acute rheumatic fever is probably an autoimmune disease caused by antistreptococcal M protein antibodies that cross-react with cardiac myosin. Virulent S. pyogenes have been referred to as flesh-eating bacteria because they cause a rapidly progressive necrotizing fasciitis. Pneumolysin is a cytosolic bacterial protein released on disruption of S. pneumoniae. Pneumolysin inserts into target cell membranes and lyses them, greatly increasing tissue damage. This toxin also activates the classical pathway of complement, reducing complement available for opsonization of bacteria. Streptococci secrete a phage-encoded pyrogenic exotoxin that causes fever and rash in scarlet fever. S. mutans produces caries by metabolizing sucrose to lactic acid (which causes demineralization of tooth enamel) and by secreting high-molecular-weight glucans that promote aggregation of bacteria and plaque formation.


Listeria monocytogenes is a Gram-positive, motile facultative intracellular bacterium that causes severe food-borne infections. Miniepidemics of L. monocytogenes have been linked to dairy products, chicken, and hot dogs. Pregnant women, their neonates, the elderly, and immunosuppressed persons (e.g., transplant recipients or AIDS patients) are particularly susceptible to severe L. monocytogenes infection. In pregnant women (and pregnant sheep and cattle), L. monocytogenes causes an amnionitis that may result in abortion, stillbirth, or neonatal sepsis. In neonates, L. monocytogenes may cause disseminated disease (granulomatosis infantiseptica) and an exudative meningitis, both of which are also seen in immunosuppressed adults.

L. monocytogenes has leucine-rich proteins on its surface called internalins, which bind to E-cadherin on host epithelial cells and induce internalization of the bacterium.

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Pyemic lung abscess in the center of section with complete destruction of underlying parenchyma within the focus of involvement


Inside the cell, the bacteria escape from the membrane-bound phagolysosome by the action of a pore-forming protein, listeriolysin O, and two phospholipases. In the host cell cytoplasm, ACTA, a bacterial surface protein, binds to host cell cytoskeletal proteins and induces actin polymerization, which propels the bacteria into adjacent, uninfected host cells. Resting macrophages, which internalize L. monocytogenes through C3 activated on the bacterial surface, fail to kill the bacteria. In contrast, macrophages that are activated by IFN-γ phagocytose and kill the bacteria. Hence, unlike most other Gram-positive bacteria, protection against L. monocytogenes is mediated largely by IFN-γ produced by NK cells and T cells.



Bacillus anthracis is a large, spore-forming Gram-positive rod-shaped bacterium. These bacteria are common pathogens in farm and wild animals that have contact with soil contaminated with B. anthracis spores. Anthrax spores can be ground to a fine powder, making a potent biologic weapon. There are between 20,000 and 100,000 cases of anthrax each year, but recent use of the microbe as an agent of bioterrorism has heightened concern about in this organism. In 1979, accidental release of B. anthracis spores at a military research institute in Russia killed 66 people. In 2001, 22 people in the United States acquired B. anthracis; most cases were traced to powder (spores) delivered in the mail.

B. anthracis is typically acquired through exposure to animals or animal products such as wool or hides.There are three major anthrax syndromes: cutaneous, inhalational, and gastrointestinal anthrax. Cutaneous anthrax, which makes up 95% of naturally occurring infections, begins as a painless, pruritic papule that develops into a vesicle within 2 days. As the vesicle enlarges, striking edema may form around it, and there is regional lymphadenopathy. After the vesicle ruptures, the remaining ulcer becomes covered with a characteristic black eschar, which dries and falls off as the patient recovers. Bacteremia is rare with cutaneous anthrax.

Inhalational anthrax occurs when spores are inhaled. The organism grows and is carried to lymph nodes by phagocytes where the spores germinate, and the release of toxins causes hemorrhagic mediastinitis. After a prodromal illness of 1 to 6 days characterized by fever, cough, and chest or abdominal pain, there is abrupt onset of increased fever, hypoxia, and sweating. Frequently, anthrax meningitis develops due to bacteremia. Inhalational anthrax rapidly leads to shock and frequently death within 1 to 2 days.

Gastrointestinal anthrax is an uncommon form of this infection that is usually contracted by eating undercooked meat contaminated with B. anthracis. Initially, the patient has nausea, abdominal pain, and vomiting. Severe, bloody diarrhea rapidly develops, and mortality is over 50%.

Pathogenesis. B. anthracis produces potent toxins and a polyglutamyl capsule that is antiphagocytic. The anthrax toxin, produced by B. anthracis, is well understood86 (Fig. 8-22). The B subunit is referred to as the protective antigen because antibodies against this protein protect animals against the toxin. The protective antigen binds to a cell surface protein, and then a host protease clips off a 20-kDa fragment of the B subunit. The remaining 63-kDa fragments associate to form a heptamer. Anthrax toxin has two alternate A subunits: edema factor (EF) and lethal factor (LF), each named for the effect of the toxin in experimental animals. Three A subunits bind to the B heptamer, and this complex is endocytosed into the host cell. The low pH of the endosome causes a conformational change in the protective antigen heptamer, which then forms a selective channel in the endosome membrane through which EF and LF move into the cytoplasm. In the cytoplasm, EF binds to calcium and calmodulin to form an adenylate cyclase. The active EF converts adenosine triphosphate to cyclic adenosine monophosphate (cAMP). cAMP is an important signaling molecule in cells, and elevated cAMP leads to efflux of water from the cell to form edema. LF has a different mechanism of action. LF is a protease that destroys mitogen-activated protein kinase kinases (MAPKKs). MAPKKs regulate the activity of mitogen-activated protein kinases, which are important regulators of cell growth and differentiation (Chapter 3). The mechanism of cell death due to deregulation of mitogen-activated protein kinases is not understood. 


Only a few Gram-negative bacteria are considered in this section. A number of important Gram-negative pathogens are discussed in the appropriate chapters of organ systems, including bacterial causes of gastrointestinal infections and urinary tract infections. Anaerobic Gram-negative organisms are considered later in this chapter.


Neisserial Infections

Neisseria are Gram-negative diplococci that are flattened on the adjoining sides, giving the pair the shape of a coffee bean. These aerobic bacteria have stringent nutritional requirements and grow best on enriched media such as lysed sheep's blood agar ("chocolate" agar). The two clinically significant Neisseria are Neisseria meningitidis and Neisseria gonorrhoeae.

N. meningitidis is a significant cause of bacterial meningitis, particularly among people between 5 and 19 years old. The organism is a common colonizer of the oropharynx and is spread by the respiratory route. Approximately 10% of the population is colonized at any one time, and each episode of colonization lasts, on average, for several months. An immune response leads to clearance of colonization in most people, and this response is protective against subsequent disease with the same strain of bacteria. There are at least 13 serotypes of N. meningitidis. Invasive disease mainly occurs when people living in crowded quarters, such as military barracks or college dormitories, encounter new strains to which they have not previously made an immune response. An outbreak of 61 cases of serogroup C N. meningitidis occurred in Edmonton, Canada, in 1999-2001. This serotype had not been previously identified in Edmonton, which presumably contributed to the high rate of disease. A vaccination campaign appears to have reduced the spread of disease.

Even in the absence of an immune response, only a small fraction of those infected with N. meningitidis get meningitis. The bacteria must invade respiratory epithelial cells and travel to the basolateral side of the cells to enter the blood. Once in the blood, the capsule of the bacteria reduces opsonization and destruction of the bacteria by complement proteins. Despite this, the efficacy of complement against N. meningitidis is shown by the high rates of disease among people who are deficient in the complement proteins that form the membrane attack complex (C5 to C9). If N. meningitidis escapes the host response, the consequences can be severe. Although antibiotic treatment of meningitis has greatly reduced mortality of N. meningitidis infection, the death rate is still about 10%.

N. gonorrhoeae is an important cause of sexually transmitted disease, infecting about 600,000 people each year in the United States. It is second only to Chlamydia trachomatis as a causative agent of STI. Infection in men causes urethritis. In women, N. gonorrhoeae infection is often asymptomatic and so might go untreated. Untreated infection can lead to pelvic inflammatory disease, which can cause infertility or ectopic pregnancy.

Although N. gonorrhoeae usually manifests as a local infection in the genital or cervical mucosa, pharynx, or anorectum, disseminated infections may occur. Like N. meningitidis, N. gonorrhoeae is much more likely to become disseminated in people who lack the complement proteins that form the membrane attack complex. Disseminated infection of adults and adolescents usually causes septic arthritis accompanied by a rash of hemorrhagic papules and pustules. Neonatal N. gonorrhoeae infection causes blindness and, rarely, sepsis. The eye infection, which is preventable by instillation of silver nitrate or antibiotics in the newborn's eyes, remains an important cause of blindness in some developing nations.

Pathogenesis. Both significant species of Neisseria use antigenic variation to escape the immune response. The existence of multiple serotypes of N. meningitidis results in meningitis in some people on exposure to a new strain, as discussed above. Neisseria species have additional mechanisms of antigenic variation such that a single clone of bacteria gives rise to multiple antigenic types, allowing newly arisen antigenic variants to escape the immune response. Neisseria adhere to and invade non-ciliated epithelial cells at the site of entry (nasopharynx, urethra, or cervix). Bacterial persistence or invasion depends on escape from immune defenses. Two surface proteins of Neisseria, both of which adhere the bacteria to host cells, undergo antigenic variation through different mechanisms. Although both N. meningitidis and N. gonorrhoeae use these mechanisms, they appear to be more important in N. gonorrhoeae.

Pseudomonas aeruginosa is an opportunistic aerobic Gram-negative bacillus that is a frequent, deadly pathogen of patients with cystic fibrosis, severe burns, or neutropenia.Most patients with cystic fibrosis die of pulmonary failure secondary to chronic infection with P. aeruginosa. In addition, species in the Burkholderia cepacia complex, which are transmitted between cystic fibrosis patients, opportunistically infect people with cystic fibrosis and often cause fatal infections. Both P. aeruginosa and B. cepacia complex bacteria can be very resistant to antibiotics, making these infections difficult to treat. Although Gram-positive cocci are most frequently present soon after extensive skin burns, P. aeruginosa eventually predominates, spreads locally, and causes sepsis. P. aeruginosa is a common cause of hospital-acquired infections; it has been cultured from washbasins, respirator tubing, nursery cribs, and even antiseptic-containing bottles.

P. aeruginosa also causes corneal keratitis in wearers of contact lenses, endocarditis and osteomyelitis in intravenous drug abusers, external otitis (swimmer's ear) in healthy individuals, and severe external otitis in diabetics.

Pathogenesis. P. aeruginosa has pili and adherence proteins that bind to epithelial cells and lung mucin, as well as an endotoxin that causes the symptoms and signs of Gram-negative sepsis. Pseudomonas also has a number of virulence factors that are distinctive. In the lungs of patients with cystic fibrosis, these bacteria secrete a mucoid exopolysaccharide called alginate, forming a slimy biofilm in which bacteria are protected from antibodies, complement, phagocytes, and antibiotics. The organisms also secrete an exotoxin and several other virulence factors. Exotoxin A is similar in structure to diphtheria toxin and, like diphtheria toxin, it inhibits protein synthesis by ADP-ribosylating EF-2, a ribosomal guanine nucleotide-binding protein (G-protein).P. aeruginosa also releases exoenzyme S, which ADP-ribosylates G-proteins, including p21 RAS, and so may interfere with host cell growth. The organisms also secrete a phospholipase C that lyses red blood cells and degrades pulmonary surfactant, and an elastase that degrades IgGs and extracellular matrix proteins. These enzymes may be important in tissue invasion and destruction of the cornea in keratitis. Finally, P. aeruginosa produces iron-containing compounds that are extremely toxic to endothelial cells and so may cause the vascular lesions that are characteristic of this infection

Yersinia pestis is a Gram-negative facultative intracellular bacterium that is transmitted by fleabites or aerosols and causes a highly invasive, frequently fatal systemic infection called plague. Plague, also named Black Death, caused three great pandemics that killed an estimated 100 million people in Egypt and Byzantium in the sixth century; one quarter of Europe's population in the fourteenth and fifteenth centuries; and tens of millions in India, Myanmar, and China at the beginning of the twentieth century. After 60 years of quiescence, plague epidemics occurred annually in Madagascar between 1995 and 1998, killing at least 40 people. Currently, wild rodents in the western United States are infected with Y. pestis, although human infections are rare. Y. enterocolitica and Y. pseudotuberculosis are genetically similar to Y. pestis; these bacteria cause fecal-orally transmitted ileitis and mesenteric lymphadenitis.

The pathogenic Yersinia proliferate within lymphoid tissue. These organisms have a complex of genes, called the Yop virulon, which enable the bacteria to kill host phagocytes, weakening the immune system. The Yop virulon includes a type III secretion system, which is a hollow syringelike structure that projects from the bacterial surface, binds to host cells and injects bacterial toxins, called Yops, into the cell. YopE, YopH, and YopT block phagocytosis by inactivating molecules that regulate actin polymerization. YopPJ inhibits the signaling pathways that are activated by LPS, blocking the production of inflammatory cytokines. Y. pestis ensures that fleas will spread the bacteria by blocking the gut of the flea. The flea must regurgitate before it feeds, and in doing so, the flea infects the rodent or human that it is biting.


Granuloma Inguinale

Granuloma inguinale, or donovanosis, is a chronic inflammatory disease caused by Calymmatobacterium donovani, a minute, encapsulated, coccobacillus that is closely related to the Klebsiella genus. The organism is sexually transmitted. Granuloma inguinale is uncommon in the United States and western Europe but is endemic in rural areas in certain tropical and subtropical regions. Untreated cases are characterized by the development of extensive scarring, often associated with lymphatic obstruction and lymphedema (elephantiasis) of the external genitalia. Culture of the organism is difficult, and PCR assays are still in development, so the diagnosis is made by morphologic examination of smears or biopsies of the ulcer.


Bacteria in the genus Mycobacterium are slender, aerobic rods that grow in straight or branching chains. Mycobacterium have a waxy cell wall composed of mycolic acid, which makes them acid fast, meaning they will retain stains even on treatment with a mixture of acid and alcohol. Mycobacteria stain weakly positive with Gram stain.


M. tuberculosis is responsible for most cases of tuberculosis; the reservoir of infection is humans with active tuberculosis. Oropharyngeal and intestinal tuberculosis contracted by drinking milk contaminated with M. bovis is rare in developed nations, but it is still seen in countries that have tuberculous dairy cows and unpasteurized milk.

Epidemiology. Tuberculosis is estimated to affect 1.7 billion individuals worldwide, with 8 to 10 million new cases and 1.7 million deaths each year. After HIV, tuberculosis is the leading infectious cause of death in the world. Infection with HIV makes people susceptible to rapidly progressive tuberculosis; over 50 million people are infected with both HIV and M. tuberculosis. From 1985 to 1992, the number of tuberculosis cases in the United States increased by 20% because of increase in disease among people with HIV, among immigrants, and among those in jail or homeless shelters. Because of increased public health efforts, the number of cases of tuberculosis has declined since 1993. Currently, there are about 16,000 new cases of active tuberculosis in the United States annually, and about 45% of these are in immigrants.

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Primary pulmonary tuberculosis, Ghon complex. The gray-white parenchymal focus is under the pleura in the lower part of the upper lobe. Hilar lymph nodes with caseation are seen on the left.

Tuberculosis flourishes wherever there is poverty, crowding, and chronic debilitating illness. In the United States, tuberculosis is mainly a disease of the elderly, the urban poor, and people with AIDS. Certain disease states also increase the risk: diabetes mellitus, Hodgkin's lymphoma, chronic lung disease (particularly silicosis), chronic renal failure, malnutrition, alcoholism, and immunosuppression.

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The morphologic spectrum of tuberculosis. A characteristic tubercle at low magnification (A) and in detail (B) illustrates central caseation surrounded by epithelioid and multinucleated giant cells. This is the usual response seen in patients who have developed cell mediated immunity to the organism. Occasionally, even in immunocompetent individuals, tubercular granulomas might not show central caseation (C); hence, irrespective of the presence or absence of caseous necrosis, special stains for acid-fast organisms need to be performed when granulomas are present in histologic section. In immunosuppressed individuals, tuberculosis may not elicit a granulomatous response ("nonreactive tuberculosis"); instead, sheets of foamy histiocytes are seen, packed with mycobacteria that are demonstrable with acid-fast stains (D). (D, Courtesy of Dr. Dominick Cavuoti, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)

It is important that infection with M. tuberculosis be differentiated from disease. Infection is the presence of organisms, which may or may not cause clinically significant disease. Most infections are acquired by person-to-person transmission of airborne droplets of organisms from an active case to a susceptible host. In most people, primary tuberculosis is asymptomatic, although it may cause fever and pleural effusion. Generally, the only evidence of infection, if any remains, is a tiny, fibrocalcific nodule at the site of the infection. Viable organisms may remain dormant in such lesions for decades. When the person's immune defenses are lowered, the infection may reactivate to produce communicable and potentially life-threatening disease.

Infection with M. tuberculosis typically leads to the development of delayed hypersensitivity to M. tuberculosis antigens, which can be detected by the tuberculin (Mantoux) test. About 2 to 4 weeks after infection, intracutaneous injection of purified protein derivative of M. tuberculosis (PPD) induces a visible and palpable induration that peaks in 48 to 72 hours. A positive tuberculin test result signifies cell-mediated hypersensitivity to tubercular antigens. It does not differentiate between infection and disease. False-negative reactions may be produced by certain viral infections, sarcoidosis, malnutrition, Hodgkin disease, immunosuppression, and (notably) overwhelming active tuberculous disease. False-positive reactions may also result from infection by atypical mycobacteria.

Pathogenesis. The pathogenesis of tuberculosis in a previously unexposed, immunocompetent person depends on the development of anti-mycobacterial cell-mediated immunity, which confers resistance to the bacteria and results in development of hypersensitivity to tubercular antigens. The pathological manifestations of tuberculosis, such as caseating granulomas and cavitation, are the result of the hypersensitivity that is part and parcel of the host immune response. Because the effector cells that mediate immunity also mediate hypersensitivity and tissue destruction, the appearance of hypersensitivity also signals the acquisition of immunity to the organism..

Macrophages are the primary cells infected by M. tuberculosis. Early in infection, tuberculosis bacilli replicate essentially unchecked, while later in infection, the T-helper response stimulates macrophages to contain the proliferation of the bacteria.

Clinical Features of Tuberculosis. Primary tuberculosis is the form of disease that develops in a previously unexposed, and therefore unsensitized, person. About 5% of newly infected people develop clinically significant disease. The elderly and profoundly immunosuppressed persons may lose their immunity to the tubercle bacillus and so may develop primary tuberculosis more than once. With primary tuberculosis, the source of the organism is exogenous.

While most patients with primary tuberculosis go on to have latent disease, progressive infection, with continued lung pathology, occurs in some. The diagnosis of progressive primary tuberculosis in adults can be difficult. Contrary to the usual picture of "adult type" (or reactivation) tuberculosis (apical disease with cavitation; see below), progressive primary tuberculosis more often resembles an acute bacterial pneumonia, with lower and middle lobe consolidation, hilar adenopathy, and pleural effusion; cavitation is rare, especially in patients with severe immunosuppression. Lymphohematogenous dissemination is a dreaded complication and may result in the development of tuberculous meningitis and miliary tuberculosis. Since similar lesions also occur following progression of secondary tuberculosis, these will be discussed with the latter.

Secondary tuberculosis is the pattern of disease that arises in a previously sensitized host. It may follow shortly after primary tuberculosis, but more commonly, it arises from reactivation of dormant primary lesions many decades after initial infection, particularly when host resistance is weakened. It may also result from exogenous reinfection because of waning of the protection afforded by the primary disease or because of a large inoculum of virulent bacilli. Reactivation of tuberculosis is more common in low-prevalence areas, while reinfection plays an important role in regions of high contagion.

Secondary pulmonary tuberculosis is classically localized to the apex of the upper lobes of one or both lungs. This may be because the high oxygen tension in the apices promotes growth of the bacteria. Because of the preexistence of hypersensitivity, the bacilli elicit a prompt and marked tissue response that tends to wall off the focus of infection. As a result of this localization, the regional lymph nodes are less prominently involved early in the secondary disease than they are in primary tuberculosis. On the other hand, cavitation occurs readily in the secondary form, resulting in dissemination of mycobacteria along the airways. Indeed, cavitation is almost inevitable in neglected secondary tuberculosis, and erosion into an airway becomes an important source of infection because the patient now coughs sputum that contains bacilli.

Localized secondary tuberculosis may be asymptomatic. When manifestations appear, they are usually insidious in onset. Systemic symptoms, probably related to cytokines released by activated macrophages (e.g., TNF and IL-1), often appear early in the course and include malaise, anorexia, weight loss, and fever. Commonly, the fever is low grade and remittent (appearing late each afternoon and then subsiding), and night sweats occur. With progressive pulmonary involvement, increasing amounts of sputum, at first mucoid and later purulent, appear. Some degree of hemoptysis is present in about half of all cases of pulmonary tuberculosis. Pleuritic pain may result from extension of the infection to the pleural surfaces. Extrapulmonary manifestations of tuberculosis are legion and depend on the organ system involved.

The diagnosis of pulmonary disease is based in part on the history and on physical and radiographic findings of consolidation or cavitation in the apices of the lungs. Ultimately, however, tubercle bacilli must be identified. Acid-fast smears and cultures of the sputum of patients suspected of having tuberculosis should be performed. Conventional cultures required up to 10 weeks, but liquid media-based culture can provide an answer within 2 weeks. PCR amplification of M. tuberculosis DNA allows for even more rapid diagnosis. PCR assays can detect as few as 10 organisms in clinical specimens, compared to more than 10,000 organisms required for smear-positivity. However, culture remains the gold standard because it also allows testing of drug susceptibility. Multidrug resistance is now seen more commonly than it was in past years; hence, currently, all newly diagnosed cases in the United States are treated with multiple drugs. The prognosis is generally good if infections are localized to the lungs, except when they are caused by drug-resistant strains or occur in aged, debilitated, or immunosuppressed individuals, who are at high risk for developing miliary tuberculosis (see below).

While HIV infection is associated with an increased risk of tuberculosis at all stages of the disease, the manifestations differ depending on the degree of immunosuppression. Patients with less severe immunosuppression (CD4+ T-cell counts greater than 300 cells/mm3) present with usual secondary tuberculosis (apical disease with cavitation). Patients with more advanced immunosuppression (CD4+ T-cell counts less than 200 cells/mm3) present with a clinical picture that resembles progressive primary tuberculosis (lower and middle lobe consolidation, hilar lymphadenopathy, and noncavitary disease). The extent of immunodeficiency also determines the frequency of extrapulmonary involvement, rising from 10% to 15% in mildly immunosuppressed patients to greater than 50% in those with severe immune deficiency. Other atypical features in HIV-positive patients that make the diagnosis of tuberculosis particularly challenging include an increased frequency of sputum-smear negativity for acid-fast bacilli compared to HIV-negative controls, false-negative PPD because of tuberculin anergy, and the lack of characteristic granulomas in tissues, particularly in the late stages of HIV.


Primary Tuberculosis. In countries where bovine tuberculosis and infected milk have been eliminated, primary tuberculosis almost always begins in the lungs. Typically, the inhaled bacilli implant in the distal airspaces of the lower part of the upper lobe or the upper part of the lower lobe, usually close to the pleura. As sensitization develops, a 1- to 1.5-cm area of gray-white inflammatory consolidation emerges, known as the Ghon focus. In most cases, the center of this focus undergoes caseous necrosis. Tubercle bacilli, either free or within phagocytes, drain to the regional nodes, which also often caseate. This combination of parenchymal lung lesion and nodal involvement is referred to as the Ghon complex. During the first few weeks, there is also lymphatic and hematogenous dissemination to other parts of the body. In approximately 95% of cases, development of cell-mediated immunity controls the infection. Hence, the Ghon complex undergoes progressive fibrosis, often followed by radiologically detectable calcification (Ranke complex), and despite seeding of other organs, no lesions develop.

Histologically, sites of active involvement are marked by a characteristic granulomatous inflammatory reaction that forms both caseating and noncaseating tubercles. Individual tubercles are microscopic; it is only when multiple granulomas coalesce that they become macroscopically visible. The granulomas are usually enclosed within a fibroblastic rim punctuated by lymphocytes. Multinucleate giant cells are present in the granulomas. Immunocompromised people do not form the characteristic granulomas.

Secondary Tuberculosis. The initial lesion is usually a small focus of consolidation, less than 2 cm in diameter, within 1 to 2 cm of the apical pleura. Such foci are sharply circumscribed, firm, gray-white to yellow areas that have a variable amount of central caseation and peripheral fibrosis. In favorable cases, the initial parenchymal focus undergoes progressive fibrous encapsulation, leaving only fibrocalcific scars. Histologically, the active lesions show characteristic coalescent tubercles with central caseation. Although tubercle bacilli can be demonstrated by appropriate methods in early exudative and caseous phases of granuloma formation, it is usually impossible to find them in the late, fibrocalcific stages. Localized, apical, secondary pulmonary tuberculosis may heal with fibrosis either spontaneously or after therapy, or the disease may progress and extend along several different pathways.

Progressive pulmonary tuberculosis may ensue in the elderly and immunosuppressed. The apical lesion enlarges with expansion of the area of caseation. Erosion into a bronchus evacuates the caseous center, creating a ragged, irregular cavity lined by caseous material that is poorly walled off by fibrous tissue. Erosion of blood vessels results in hemoptysis. With adequate treatment, the process may be arrested, although healing by fibrosis often distorts the pulmonary architecture. Irregular cavities, now free of caseation necrosis, may remain or collapse in the surrounding fibrosis. If the treatment is inadequate or if host defenses are impaired, the infection may spread by direct expansion via dissemination through airways, lymphatic channels, or the vascular system. Miliary pulmonary disease occurs when organisms drain through lymphatics into the lymphatic ducts, which empty into the venous return to the right side of the heart and thence into the pulmonary arteries. Individual lesions are either microscopic or small, visible (2-mm) foci of yellow-white consolidation scattered through the lung parenchyma (the word "miliary" is derived from the resemblance of these foci to millet seeds). Miliary lesions may expand and coalesce to yield almost total consolidation of large regions or even whole lobes of the lung. With progressive pulmonary tuberculosis, the pleural cavity is invariably involved, and serous pleural effusions, tuberculous empyema, or obliterative fibrous pleuritis may develop.

Endobronchial, endotracheal, and laryngeal tuberculosis may develop when infective material is spread either through lymphatic channels or from expectorated infectious material. The mucosal lining may be studded with minute granulomatous lesions, sometimes apparent only on microscopic examination.

Systemic miliary tuberculosis ensues when infective foci in the lungs seed the pulmonary venous return to the heart; the organisms subsequently disseminate through the systemic arterial system. Almost every organ in the body can be seeded. Lesions resemble those in the lung. Miliary tuberculosis is most prominent in the liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopian tubes, and epididymis.

Isolated-organ tuberculosis may appear in any of the organs or tissues seeded hematogenously and may be the presenting manifestation of tuberculosis. Organs that are typically involved include the meninges (tuberculous meningitis), kidneys (renal tuberculosis), adrenals (formerly an important cause of Addison disease), bones (osteomyelitis), and fallopian tubes (salpingitis). When the vertebrae are affected, the disease is referred to as Pott's disease. Paraspinal "cold" abscesses in these patients may track along the tissue planes to present as an abdominal or pelvic mass.

Lymphadenitis is the most frequent form of extrapulmonary tuberculosis, usually occurring in the cervical region ("scrofula"). In HIV-negative individuals, lymphadenopathy tends to be unifocal, and most patients do not have evidence of ongoing extranodal disease. HIV-positive patients, on the other hand, almost always demonstrate multifocal disease, systemic symptoms, and either pulmonary or other organ involvement by active tuberculosis.

In years past, intestinal tuberculosis contracted by the drinking of contaminated milk was fairly common as a primary focus of tuberculosis. In developed countries today, intestinal tuberculosis is more often a complication of protracted advanced secondary tuberculosis, secondary to the swallowing of coughed-up infective material. Typically, the organisms are trapped in mucosal lymphoid aggregations of the small and large bowel, which then undergo inflammatory enlargement with ulceration of the overlying mucosa, particularly in the ileum.

Mycobacterium Avium-Intracellulare Complex 

Mycobacterium avium (which includes three subspecies) and Mycobacterium intracellulare are separate species, but the infections they cause are so similar that they are simply referred to as Mycobacterium avium-intracellulare complex, or MAC. MAC is common in soil, water, dust, and domestic animals. Clinically significant infection with MAC is uncommon except among people with AIDS and low levels of CD4+ lymphocytes (<60 cells/mm3). 

In AIDS patients, MAC causes widely disseminated infections, and organisms proliferate abundantly in many organs, commonly including the lungs and gastrointestinal system. Unchecked by the immune response, the organisms reach very high levels: up to 104 organisms/mL of blood and 106 organisms/gm in tissue. Patients are feverish, with drenching night sweats and weight loss. In the rare case of MAC in a patient without HIV, the organisms primarily infect the lung, causing a productive cough and sometimes fever and weight loss.



Leprosy, or Hansen disease, is a slowly progressive infection caused by Mycobacterium leprae, affecting the skin and peripheral nerves and resulting in disabling deformities. M. leprae is, for the most part, contained within the skin, but leprosy is likely to be transmitted from person to person through aerosols from lesions in the upper respiratory tract. Inhaled M. leprae, like M. tuberculosis, is taken up by alveolar macrophages and disseminates through the blood, but grows only in relatively cool tissues of the skin and extremities. Despite its low communicability, leprosy remains endemic among an estimated 10 to 15 million people living in poor tropical countries. 

Pathogenesis. M. leprae is an acid-fast obligate intracellular organism that grows very poorly in culture but can be grown in the armadillo. It grows more slowly than other mycobacteria and grows best at 32° to 34°C, the temperature of the human skin and the core temperature of armadillos. Like M. tuberculosis, M. leprae secretes no toxins, and its virulence is based on properties of its cell wall. The cell wall is similar enough to that of M. tuberculosis that immunization with bacille Calmette-Guérin confers some protection against M. leprae infection. Cell-mediated immunity is reflected by delayed type hypersensitivity reactions to dermal injections of a bacterial extract called lepromin. 

Leprosy has two strikingly different patterns of disease. Patients with the less severe form, tuberculoid leprosy, have dry, scaly skin lesions that lack sensation. They often have large, asymmetric peripheral nerve involvement. The more severe form of leprosy, lepromatous leprosy, includes symmetric skin thickening and nodules. This is also called anergic leprosy, because of the unresponsiveness (anergy) of the host immune system. Cooler areas of skin, including the earlobes and feet, are more severely affected than warmer areas, such as the axilla and groin. In lepromatous leprosy, damage to the nervous system comes from widespread invasion of the mycobacteria into Schwann cells and into endoneural and perineural macrophages. In advanced cases of lepromatous leprosy, M. leprae is present in sputum and blood. People can also have intermediate forms of disease, called borderline leprosy. 

The T-helper lymphocyte response to M. leprae determines whether an individual has tuberculoid or lepromatous leprosy. Patients with tuberculoid leprosy have a TH1 response, with production of IL-2 and IFN-γ. As with M. tuberculosis, IFN-γ is critical to mobilizing an effective host macrophage response. IL-12, which is produced by antigen presenting cells, is important to the generation of TH1 cells (Chapter 6). Low levels of IL-12 or unresponsiveness of T cells to this cytokine may reduce the TH1 response, leading to lepromatous leprosy. In addition to TH1 cells, lymphocytes bearing the γ/δ T-cell receptor infiltrate the lesions of leprosy and produce IFN-γ in patients with tuberculoid leprosy. Patients with lepromatous leprosy have a defective TH1 response or a dominant TH2 response, with production of IL-4, IL-5, and IL-10, which may suppress macrophage activation in response to M. leprae. In some cases, antibodies are produced against M. leprae antigens. Paradoxically, these antibodies are usually not protective, but they may form immune complexes with free antigens that can lead to erythema nodosum, vasculitis and glomerulonephritis.