Primary tuberculosis may occur at any epithelial site, but it is now most uncommon to find new cases of infection in organs other than the lung. The disease is spread by infected aerosols coughed out by persons already suffering from active pulmonary tuberculosis. Only those particles which are respirable to alveolar level penetrate far enough to be successfully implanted in the lung; larger particles are deposited in the upper respiratory tract or the bronchial tree and are expelled. In the susceptible subject, establishment of the infection provokes the development of a small area of inflammatory reaction (the Ghon focus) followed soon afterwards by spread to the regional lymph nodes. These two elements make up the primary complex.
Primary tuberculosis is often subclinical and where symptoms do occur they are mostly systemic in nature. Typical features include fever, anorexia and lethargy, sometimes accompanied by mild respiratory symptoms such as an unproductive cough. In a small proportion of cases the development of erythema nodosum provides an important clue to the diagnosis. Otherwise, physical signs, other than fever, are likely to be few and nonspecific. Investigation of the patient should start with tuberculin skin testing which becomes positive 3-10 weeks after acquisition of the infection, unless there is some reason for cell-mediated immunity to be depressed. The most likely such reason is a preceding viral infection such as measles, which can itself contribute to the pathogenesis by rendering the patient more susceptible to tuberculosis. The chest x-ray may show either or both elements (lymphatic and parenchymal) of the primary complex. In young children the lymphatic element tends to be more evident and in adults, the pulmonary parenchymal part. In uncomplicated primary tuberculosis little sputum is produced and the isolation of the organism may require the examination of gastric washings taken first thing in the morning.
Most cases of primary tuberculosis heal without treatment, but in about 10-15% of cases progression of the infection results in the appearance of disease over the following two years. These complications may arise through spread of the infection with in the lung itself, by lymphatic spread or by bloodborne spread.
This form of tuberculosis is found in adults and in adolescents, but very seldom occurs in younger children. It affects the upper parts of the lung first, spreading caudally as time goes on and usually involving the contralateral lung in a similar fashion at a relatively early stage. The upper parts of the lung seem to be more susceptible, through a combination of better ventilation and poorer circulation. Organisms may reach the upper parts of the lung either by haematogenous dissemination from the primary complex, or as a result of intrabronchial spread from the Ghon focus. Histologically there is granulomatous inflammation with caseous necrosis, coalescence of adjacent tubercles and rupture into the bronchial lumen. As a result, such cases are likely to have sputum heavily contaminated with Mycobacterium tuberculosis and they will be infectious to others. Destruction of lung tissue is followed by fibrotic collapse and ultimately by calcification.
Clinically, progressive pulmonary tuberculosis presents as a subacute pneumonia with systemic and respiratory symptoms steadily worsening over weeks or a small number of months. Dominant symptoms include fever, sweating, weight loss, chest pain and productive cough, often with haemoptysis. Sputum examination for mycobacteria is likely to be positive both on a stained smear and on culture. The chest x-ray is always abnormal, advanced cases showing bilateral upper and middle zone irregular consolidation, often with cavitation and sometimes with lobar collapse or effusion. In early cases the disease may be localized, particularly to the apical or posterior segments of one upper lobe, and the opacities may have a soft or fluffy appearance.
Without treatment this form of tuberculosis has a mortality of about 50% and a further 25% of cases go on to a chronic stage of alternating remission and relapse. However, excellent results are obtained from antituberculosis chemotherapy, the small number of failures being found in those cases where the patient was moribund by the time treatment was started.
From the regional lymph nodes infection may spread by way of lymphatic vessels to the mediastinum, and beyond to supraclavicular and submandibular nodes in the neck or to retroperitoneal nodes in the abdomen. Infection may also reach the supraclavicular glands by spread across the pleural space from a subpleural Ghon focus in the upper lobe. Tuberculous mediastinal lymphadenopathy most often affects the paratracheal groups of glands. It may cause systemic symptoms but local symptoms are rare, only very occasional patients describing retrosternal pain. However, these glands may caseate and become necrotic, leading to the spread of infection through the bloodstream or to adjacent serous cavities. In the course of treatment of primary or lymphatic tuberculous it is quite common to observe new evidence of lymph node involvement. This does not necessarily mean that treatment is defective and in almost all cases a satisfactory outcome will be obtained without the need for alteration of the therapeutic regime.
The lymph nodes draining a segment or lobe of lung are arranged in a ring round the root of the relevant bronchus. If they become enlarged as part of a primary tuberculous complex they may compress the bronchus and obstruct it partially or completely. This is particularly seen in young children, possibly because of the narrow calibre of their airways and the immaturity of the cartilaginous elements of the bronchial walls. The most commonly affected bronchi are those of the middle lobe and the anterior segments of the upper lobes. Occasionally enlarged mediastinal glands compress the trachea or even the oesophagus.
These bronchial complications of tuberculosis, sometimes known as epituberculosis, seldom cause serious aggravation of symptoms and are usually detected by their effect on the chest x-ray. The commonest appearance is collapse of the affected segment or lobe, but in some cases partial obstruction allows persistent pyogenic infection in the distal part of the lung. In a few cases the bronchus is obstructed during expiration only, leading to overinflation of the affected lobe. This may be more easily detected by clinical examination unless radiographs are taken in both inspiration and expiration.
The prognosis in epituberculosis is good unless the infection spreads from the lymph node to the adjacent bronchial epithelium, causing tuberculous endobronchitis. If this happens, later fibrosis may lead to bronchostenosis and localized bronchiectasis.
Tuberculous infection may reach the pleura by direct extension from a pulmonary lesion, through the blood stream or as the result of leakage of caseous lymph nodes at the hilum of the lung or in the mediastinum. Of these, the last is probably the usual cause of tuberculous pleurisy seen in older children and young adults 6-12 months after the acquisition of tuberculous infection. The discharge of even small amounts of tuberculous material into the pleural space is capable, in sensitized subjects, of provoking the effusion of large amounts of serous fluid, containing high concentrations of protein and moderate numbers of lymphocytes, but very few bacilli. Direct smear examinations of pleural fluid are very seldom positive for mycobacteria and attempts to culture the organism are successful in only about 40% of cases. A more fruitful method of investigation is by pleural biopsy, which shows characteristic features in up to 75% of cases. The tuberculin test is almost always strongly positive - a negative test throws very serious doubt on the diagnosis. The condition is almost always unilateral and if an x-ray is taken after removal of the pleural fluid, the underlying lung usually appears to be normal.
Tuberculous pleurisy is a self limiting condition, but in untreated cases, pulmonary parenchymal tuberculosis follows within two years in about 15% of cases. Treatment, as for other forms of tuberculosis, is therefore indicated in all cases. The addition of corticosteroids for the first 3 months accelerates the rate of reabsorption of the effusion and may reduce the incidence of late pulmonary constriction from pleural fibrosis.
Bloodborne dissemination of tubercle bacilli is common after primary infection, probably arising from infected lymph nodes. In most cases this process is clinically silent but in a few it leads to overt miliary tuberculosis. The risk is greatest in the youngest children. About 90% of cases of overt miliary tuberculosis occur within a year of the acquisition of infection. The condition is marked by profound constitutional disturbance. Although the chest x-ray shows diffuse infiltration, respiratory symptoms are uncommon. Signs of meningitis are found in about 25% of cases.
The diagnosis depends on the appearance of the chest x-ray (diffuse micronodular opacities throughout both lungs), the tuberculin test (generally positive unless the patient is already moribund) and the isolation of the organism. Samples of sputum and gastric washings are frequently positive, and positive results may also be obtained from bone marrow or urine, even in the absence of other signs of renal infection.
Without treatment miliary tuberculosis is always fatal. However, as with most other forms of the disease, excellent results are obtained if treatment is started before the patient has become desperately ill.
Tubercle bacilli have the capacity to remain dormant, but viable, for long periods in healthy subjects. Where primary infection has healed spontaneously, a proportion of patients will continue to harbour organisms capable of causing disease in the future. Such reactivation to cause postprimary tuberculosis may occur in any organ, but it is most common in the lung. Reactivation is more likely to occur in patients with chronic disease causing general debility, such as alcoholism, malnutrition and diabetes mellitus, or with cellular immunodeficiency, particularly that caused by HIV infection. Immunosuppressant drug treatment has a similar effect and may be an indication for prophylactic chemotherapy in patients with a history of untreated tuberculosis in the past.
Postprimary pulmonary tuberculosis usually evolves slowly, and it is common for patients to report symptoms going on for several months before the diagnosis is made. The initial symptoms are usually respiratory, with persistent cough, purulent sputum sometimes containing blood, chest pain and eventually breathlessness. Later in the illness, systemic symptoms of fever, sweating, lethargy and weight loss also appear. The histopathology, anatomical distribution and radiographic features are the same as those described for progressive primary pulmonary tuberculosis but there may also be signs of previous, healed disease in the form of contraction of the upper lobes and calcification.
The diagnosis is made by bacteriological examination of sputum, but if none is available samples obtained by broncho-alveolar lavage may give positive results. The tuberculin test is likely to be positive, but less reliably so than in tuberculous disease which closely follows primary infection. Other investigations may yield a number of nonspecific signs of chronic disease such as normochromic, normocytic anaemia, hypoalbuminaemia and elevated serum levels of acute phase reactants.
When postprimary pulmonary tuberculosis reaches a far advanced stage, a second phase of dissemination may occur through the bloodstream or by the epithelial implantation of organisms coughed from the lungs. In this way secondary lesions may appear in the intestine and in the larynx. Laryngeal tuberculosis is usually a very late development associated with painful dysphagia, hoarseness and enhanced infectivity.
Where tuberculous infection reactivates in a patient with profound depression of cellular immunity, the clinical, radiographic and histopathological features may differ considerably from those described above. The disease is more likely to disseminate to other organs and its clinical presentation may be marked only by progressive constitutional disturbance. Histologically there may be little sign of granuloma formation or caseation, but lesions often contain large numbers of organisms. The chest x-ray usually does not show the features of overt miliary tuberculosis (described earlier) and cavitation seldom occurs. The tuberculin test is likely to be negative and the diagnosis depends on the identification of tubercle bacilli in bacteriological specimens or biopsies.
In HIV-infected subjects tuberculosis is particularly common. Among those who have previously had primary tuberculous infection and who have not received treatment, the rate of tuberculous disease is around 30%. Presumably most of this disease results from reactivation, and it is often discovered before the onset of severe immunodeficiency. When tuberculosis occurs in patients who already have other AIDS-defining conditions, the radiographic appearance is often surprisingly similar to that of primary disease in children .