Primary and Postprimary TuberculosisCHAPTER 1

Based on the sequence of events following the first exposure to the tubercle bacilli, tuberculosis can be classified as primary tuberculosis and postprimary tuberculosis.

When infection with M. tuberculosis occurs in a person who has had no previous exposure to tubercle bacillus, it is referred to as “primary infection”. The usual route of invasion is by the lungs. The bacilli will be deposited in the alveoli and a small patch of caseous bronchopneumonia develops. This encapsulates later and is called as “primary focus” or “Ghon's focus”. The regional lymph node is soon involved and together they are called the “primary complex” (parenchymal lesion + lymph node).

The natural history of tuberculosis in the human host is influenced by age, sex, mycobacterial virulence, infecting dose, natural and acquired resistance, certain host factors resulting in a tendency of the disease to follow a pattern of progression 2according to Wallgren's timetable described in Sweden in 1948 in the era before chemotherapy or BCG. Early in the course of disease, tuberculin conversion after primary infection may result in mild illness, minority of those infected experience febrile episodes and erythema nodosum. Miliary tuberculosis and tuberculous meningitis occurred usually within six months of primary infection and were especially common in children under five years. Pleural effusion presumably due to seeding of the pleura from a lung focus also occurred early, usually within six to twelve months and was more common in young adults and unusual in small children. In young adults, the primary disease could progress with increasing infiltration and cavitation evident in one to two years or even later after the primary infection. This type of disease was labeled progressive primary or postprimary disease and occurred most commonly at puberty. Skeletal tuberculous lesions most commonly of the spine could also present one to five years after the primary infection. Lesions of the genitourinary tract and the skin made their appearance much later, commonly five to fifteen years after the primary infection. There are some limitations of this timetable. Every case of primary infection need not necessarily pass through all the stages enumerated above. Following the institution of chemotherapy, the time interval between the various stages may not be followed faithfully. In fact, the progress of the lesion may be aborted at any stage.

Healing of the primary lesions is the rule and most primary foci become quiescent and calcify. The caseous focus is gradually replaced by reticulin and collagen deposition. Eventually hyalinization and calcification are common. Some of the calcified foci, especially those in the lymph nodes may recrudesce at a later age and become the source of progressive pulmonary or extrapulmonary tuberculosis. Early generalization or dissemination is an invariable accompaniment of primary infection. The primary infection is accompanied by early lymphohematogeneous spread within hours or days from the site of initial implantation. Huebschman (1928) observed a group of nodular lesions in one or both apices of the lung that occasionally follow primary tuberculosis in children. These Huebschman foci heal and cause no further disease. Simon foci which are larger, single or multiple apical caseous nodules with a tendency to calcify are exaggerated form of these smaller foci. The importance of Simon foci lies in the pathogenesis of post-primary tuberculosis. Liquefaction of solid caseous foci is thought to be related to the onset of delayed type hypersensitivity with the release of hydrolytic enzymes by macrophages. Liquefaction may result in a caseous mass that may include the enlarged lymph nodes. Within the liquefied area, there are multiplying tubercle bacilli, and therefore, there is a risk of transmission of disease. Due to the liquefactive necrosis, there is extensive parenchymal destruction and cavitation. The cavity may communicate with an airway and thus promote bronchial spread to other parts of the lung, larynx and the alimentary tract. An acute fatal bronchopneumonia may result. In some of these cases, the inflammatory reaction is neutrophilic like in the case of bacterial pneumonia but AFB are demonstrable. Discharge 3of the liquefied material through the adjacent pleura results in pleural effusion, pneumothorax or empyema. Rupture of a caseous pulmonary focus into a blood vessel may result in a miliary tuberculosis, with the formation of multiple 0.5–2 mm tuberculosis foci in the lungs and in the other organs of the body. Encroachment on bronchi of pulmonary or lymph node caseous material may give rise to tuberculous bronchitis. Rupture of caseous glands into trachea or major bronchi causes collapse of lung or even sudden death by suffocation in young children.

In majority of cases, the primary infection is symptomless and is passed of unnoticed. The only indication will be a Mantoux conversion from a negative one to positive. This will only be possible if the previous status is known. A proportion will experience a short febrile illness at the time of tuberculin conversion, which is similar to many other febrile illnesses of childhood. Only a small minority with severe infection or low host resistance will manifest features of unwell with anorexia, fretfulness and failure to gain weight. Cough and wheeze may present because of compression of bronchial wall due to enlarged lymph nodes. Expectoration is not usual in children. Auscultation of the chest is usually unrewarding but occasionally crepitations may be heard over an extensive primary focus.

It is a rare but more frequent in infants and children than in adults. The term epituberculosis is coined by Eliasberg and Neuland to describe the development of dense homogeneous shadows in the lungs of children with tuberculosis. These radiological appearances are due to lobar or segmental consolidation/collapse, and are associated with enlarged tuberculous lymph nodes at the hilum, and may rarely occur in elderly subjects who have lost their tuberculin sensitivity. The middle lobe is most often affected. Segmental lesions are seen in 43% of infected infants. The radiological appearances may be due to a collapse, inflammatory exudation, caseous pneumonia or any combination of these three. Collapse is produced by pressure of the lymph node on the bronchus, by the spread of tuberculous granulation tissue into the bronchus with resultant stenosis or by discharge of caseous material from the lymph node through the bronchial wall. Later the bronchial lesion may heal with residual scarring or fibrous stenosis. The most common pathological cause for the appearance is inflammatory exudate, either monocytic or polymorphonuclear. Epithelioid tubercles may also be present. The exudate is probably due to the discharge of caseous material into the bronchial lumen, with aspiration into a segment or lobe and a resultant exudative hypersensitivity reaction to the contained tuberculoprotein. It is not possible purely on radiological grounds to distinguish this appearance from caseous pneumonia, although the latter may be inferred from the absence of clinical illness and the later development of calcification. Clinically, there is a greater likelihood of wheeze or paroxysmal cough, dullness 4to percussion and diminished air entry. Bronchial breathing or crepitations may be found. In infants and young children sudden asphyxia resulting in death may occur. Treatment does not differ from that for primary tuberculosis, except that corticosteroids are utilized on the basis that a hypersensitivity reaction is often involved. The daily dose should be equivalent to prednisolone1–2 mg/kg and this should be continued for 4–6 weeks with a gradual reduction thereafter. Steroid therapy may need to be resumed if there is any subsequent radiological or febrile relapse. Steroid therapy may reduce the rate of residual bronchiectasis following this complication of primary pulmonary tuberculosis.

Distension by mucus, caseous tissue or secondary infection beyond a bronchial stenosis may result in bronchiectasis, especially following lobar or segmental lesions. The incidence is reduced by prompt chemotherapy and use of corticosteroid drugs.

Occasionally, a bronchus is compressed in such a way that a valve action results, with air being admitted to a portion of lung on inspiration but unable to escape on expiration. This results in distension of a segment or lobe, often with depression of the horizontal fissure or diaphragm and deviation of the mediastinum on expiration. The phenomenon is best shown on a chest film taken on expiration. The condition is rare but is more common in children under the age of 2 years. It usually resolves with chemotherapy and may be an indication for the use of corticosteroid drugs.

Calcification in a primary focus, or more commonly, in a lymph node, may later be extruded into a bronchus as a ‘broncholith’ which may present itself with hemoptysis.

This complication of primary tuberculosis has a characteristic racial distribution. It occurs in 1–2% of British, and 5–15% of Scandinavian patients. It is very unusual in Asians or Black population. It is also rare below the age of 7, with an increase in frequency up to puberty. It is more common in girls than boys in all ages and 80–90% of cases are females after puberty. The skin lesion is a manifestation of the Arthus phenomenon. Most commonly, tuberculin conversion precedes the eruptions by few days to few weeks. However, erythema nodosum (EN) may also occur later in primary or even postprimary disease. The characteristic EN lesions are tender, dusky red, and nodular in nature and are present on the anterior surface of the legs. They may occasionally be present on the anterior surfaces of thighs, the extensor surfaces of forearms, and rarely on the face and breasts. The nodule vary in size from 5–20 mm, with ill-defined margins they may become confluent. The lesions usually resolve over a week or two, with fading of the red color to 5purple, then brown with persistence of brownish pigments for several weeks. The lesions may recur. Systemic features like fever and arthralagias may accompany or precede the skin lesions. Erythrocyte sedimentation rate (ESR)is usually very high. Tuberculin test is always positive, and a negative test rules out the cause of EN as tubercular in orgin.

This, like erythema nodosum, is also a manifestation of hypersensitivity to the tubercle bacilli. Unlike erythema nodosum, which occurs in the first week of infection, it occurs within the first year. It is common in children, particularly from poor socioecnomic background. Usually one eye is involved but both eyes may be involved either simultaneously or succeessively. It is manifested as irritation, lachrymation or photophobia. The characteristic finding is small 1–3 mm shiny yellowish or gray bleb at the limbus with a sheaf of dilated vessels running out towards it from the edge of the conjuctival sac. The reaction subsides in a week or so, but recurrences are common. Any underlying tuberculosis should be treated by chemotherapy. Locally, the pupil is dilated with atropine, and 1% hydrocortisone drops rapidly relieve the symptoms.

Pleural effusion may sometimes accompany primary pulmonary tuberculosis in children under the age of puberty. Such effusions are usually small and transient, resolving with chemotherapy. Larger effusions are more common after puberty.

The radiological and other features of adult primary tuberculosis are essentially similar to childhood primary disease. Primary tuberculosis poses diagnostic problems in adults. Prominent hilar and mediastinal glands and caseation are less frequent in adults except in patients with AIDS. Bronchial obstruction and dissemination are less common. As in children, endobronchial tuberculosis can complicate post-primary tuberculosis in adults. With increasing primary adult tuberculosis, endobronchial tuberculosis may occur as sequelae of adjacent parenchymal disease from which submucosal lymphatic spread lead to mucosal ulceration, hyperplastic polyp formation or fibrostenosis with atelectasis of the subtended lobe.

Post-primary tuberculosis is by far the most important type of tuberculosis, partly because it is much frequent and partly because smear-positive sputum is the main source of infection responsible for the persistence of the disease in the community. The disease is transmitted by contaminated aerosols smaller than 5 microns in size and can bypass the bronchial defense mechanism and reach the alveoli. In most of the cases (>90%), the alveolar macrophages and specific cell-mediated 6immunity prevent further multiplication of Mycobacteria and hence, the development of disease. The infected individuals usually remain asymptomatic and can be diagnosed only with a positive tuberculin reaction. In about 5% of individuals, the infection overcomes the above defense mechanisms and develops into primary tubercular disease (see above) within several weeks or months. In another 5–10% of individuals, late reactivation of an earlier asymptomatic infection leads to a predominantly chronic wasting disease after many months or years and the condition is called the postprimary or reactivation tuberculosis.

Postprimary pulmonary tuberculosis may arise in one of the three ways:

This is most likely to occur if the primary infection has occurred around the time of puberty.

This can occur at any time in patient's life. The original lesion need not necessarily be visible radiographically and the only evidence that it has occurred is a positive skin test. It is probable that the great majority of middle-aged and elderly men who develop postprimary tuberculosis do as a result of reactivation of lesions contracted many years previously. Waning of individual defenses at any time of life may result in the development of postprimary pulmonary tuberculosis. The risk factors and predisposing conditions for tuberculosis are given below in a tabulated form.

Most tuberculin positive individuals have sufficient immunity to control an episode of reinfection with tubercle bacilli and prevent the development of disease. Disease from reinfection may be more common in populations with a high prevalence of tuberculosis. Most cases of primary tuberculosis arise either from a progressive primary lesion (in young people) or from reactivation of a dormant primary or postprimary lesion (in the middle-aged or elderly).

In contrast to primary tuberculosis (TB), the localization of postprimary TB is apical or subapical. This area has been referred to as the ‘vulnerable region’ by Medlar. This site probably relates to the relatively higher oxygen tension in the region resulting from the effect of gravity on the ventilation-perfusion ratio in the upright lung. Presently, evidence suggests that this is possibly because of better survival of bacillus at this region as the higher oxygen tension has an unfavorable effect on the macrophage and thereby permits intracellular growth. This may also influence progressive primary disease that is more frequent in the apical and posterior segments of the upper lobe. Higher vascularity and consequently increased oxygen tension may determine the preferential multiplication of bacilli at other sites also, such as ends of long bones, vertebrae and the renal cortex. Similarly, mitral stenosis, which results in higher pulmonary arterial pressure and increased apical blood flow, confers a protective effect. Lowered blood flow may also be associated with decreased lymph flow and thus, lesser antigen clearance. The pathological lesions seen in postprimary tuberculosis are based on the findings of Medlar and Nayak et al.

The earliest lesion is probably an apical or subapical lobular pneumonia. These lesions are not well-documented because it is believed that the pneumonia gives way to a granuloma rapidly. An outline of the alveolar reticulin framework in the center of some of these granulomas may suggest such a transition. Assmann 8drew attention to the fact that the earliest lesions clearly visible in clinical TB consist of infiltrates not at the apex, but at the subapical and infraclavicular region. These infiterates are known as Assmann infiltrates or foci. The histopathological counterpart of these lesions is not known.

Nodular lesions (coin lesions, tuberculomas) are localized, well-defined areas of TB wherein the adjacent pulmonary parenchyma is usually normal or may show some scarring. A small nodule is less than a centimeter in diameter whereas larger nodule is more than a centimeter in diameter. Grossly, nodules are white to yellow in color and may vary in consistency from soft lesions that are largely necrotic to firm or hard lesions that are fibrosed or calcified. Small nodules have a central area of caseation, are surrounded by epitheliod cells and giant cells and are encapsulated by a fibrous wall. Large nodules are similar but show more caseation and less encapsulation. Healed nodules are of the size of small nodules, and are fibrosed or hyalinized or calcified. In the nodules anthracotic pigment may be identified. Active nodules especially of the small size are predominantly located in the apical and subapical regions and may be single or multiple.

Fibrocaseous TB includes lesions that reveal well-known features of TB such as caseation, consolidation, liquefaction and fibrosis. Grossly, various patterns are seen. The apical and posterior segments of the upper lobes are predominantly involved. Lymph node involvement is slight in comparison to primary TB. Retraction of lung parenchyma is often associated with pleural thickening. The most striking feature is the presence of one or more cavities. Cavities may assume varying sizes and may be so large so as to result in a severe loss of lung parenchyma. The wall of the cavity may be lined by TB granulation tissue or show varying fibrosis. Communication may or may not have been established with a bronchus. Traversing the wall or lumen along fibrous bands, are bronchi and branches of pulmonary artery. The caseous material may soften the wall of the arteries giving rise to Rasmussen's aneurysms. This may give rise to hemoptysis that may be fatal. Microscopically variable caseous necrosis, extensive fibrosis, numerous palisades of epitheliod cells and fibroblasts together with Langhans giant cell are seen. Cavities are lined by necrotic TB granulation tissue and show fibrosis. Occasional cavities may be lined in part by columnar or squamous epithelium. Acid-fast bacilli can be demonstrared more frequently in fibrocaseous lesions than in nodular TB. Acidfast bacilli were found more frequently in cavitary lesions in comparison to noncavitatory lesions. Smaller cavities may heal. Healing in general results in fibrosis and cicatrization extending between the upper pole of the hilum and apex, thus elevating the hilum on that side. This causes volume loss on the ipsilateral side. Simultaneously, the upper mediastinum would be pulled towards the side of the lesion distorting the trachea and giving a characteristic radiological appearance.9

Tuberculous bronchopneumonia occurs as a consequence of a larger dose of virulent organisms disseminating through the bronchus. Most of the time, the host immunity is compromised in these conditions.

Despite being closely associated with the lung parenchyma, bronchi do not appear to be frequently affected in pulmonary TB. In a majority of cases, the inflammation is nonspecific and typical granulomas may not been seen. In some cases, endobronchial TB, as discussed under primary pulmonary TB, may follow post-primary lesions and this is characterized by bronchial inflammation, ulceration, granuloma, small pseudopolyps and eventual healing by fibrosis. Bronchostenosis may give rise to post-stenotic dilatation of the bronchus. Bronchiectasis directly attributable to pulmonary TB is rare. In those instances when this is found, it usually occurs in the upper lobe and is relatively asymptomatic.

Rarely, TB affects the whole lung. This condition has a high mortality and results from diffuse bronchogenic spread or hematogeneous dissemination.

In the developed countries, the majority of patients with postprimary pulmonary tuberculosis are middle-aged or elderly, but in developing countries the age distribution is strikingly different with a predominance of young and middle-aged patients. Classically, the onset of symptoms occur over weeks to months. General symptoms like tiredness, malaise, weight loss, anorexia and weakness are very common and reported by majority of patients. Fever with night sweats is a classical symptom of tuberculosis and are more common in patients with more advanced form of the disease. Prolonged undiagnosed fever (PUO—pyrexia of unknown orgin) is one of the common presentations of tuberculosis. Fever is present in up to 60% of patients, which disappears rapidly within 1–2 weeks with therapy. Symptoms related to respiratory system include most importantly cough. Sputum may be mucoid, purulent or blood-stained. Hemoptysis is a classical symptom of pulmonary tuberculosis and may vary from mere blood staining of sputum to massive amount of hemoptysis. Chest pain is common and may vary from dull ache or tightness to pleuritic pain, but distinctly different form due to lung cancer. Elderly patients (>65 years) with TB are more likely to present with nonspecific complaints and atypical radiographic appearances. They usually have a lower body weight, less hemoptysis and more nonspecific symtoms. There may be no physical signs in pulmonary tuberculosis even with relatively advanced disease. Fever, anemia and cachexia will be present. Finger clubbing is seen in advanced cases of tuberculosis. The earliest chest sign is post-tussive crepitation in the upper 10lobes or apices. With advanced disease, fibrosis with cavity is the most common finding in postprimary tuberculosis. The findings are most often bilateral. There may be signs of consolidation also when the presentation is like pneumonia. Loss of lung volume in chronic cases is very common with shifting of mediastinum to the same side. Clinical findings of collapse are not the findings of tuberculosis except in very young individuals where the node may compress a lobe. Occasionally, bronchostenosis may produce collapse. Localized wheezes are heard sometimes as a result of associated chronic bronchitis or rarely due to tubercular bronchostenosis. Associated findings of pleural disease in the form of pleural effusion or pleural thickening may also be present. Fibrothorax may be present in more advanced and chronic cases. Empyema or bronchopleural fistula are other clinical findings. Post-tubercular bronchiectasis is another sequel of tuberculosis. Examination of the respiratory system is very important and findings of a cavity with fibrosis in association of history will strongly point towards tuberculosis as the underlying cause, particularly in countries with high prevalence of the disease.