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Epidemiology and Pathology

Tuberculosis affects everyone from infants to the very aged. It is spread by droplet infection or by contaminated foods, particularly milk from herds infected with M. bovis. In many countries bovine tuberculosis has been almost completely eliminated following the pasteurization of milk and the control of infected cattle. Unfortunately, there is a reservoir in wild species and it is known to have infected buffalo and rhinoceros in East and southern Africa, for example. Reinfection of domestic cattle is thus always possible.

The first infection is most commonly in the lungs, but can be in any part of the body. Both M. tuberculosis and M. bovis can directly infect the skin, presenting as a serpiginous ulcer, although this is uncommon. Lupus vulgaris is a secondary (immune) infection. Transplacental infection is possible but very rare: there are about 150 well-documented cases in the literature, but it may become more frequent in HIV-positive mothers.

Even if AIDS is not taken into account, tuberculosis is most prevalent in crowded cities, yet there is also a high incidence in rural areas. In the tropics it is a household infection and WHO has reported an incidence five to ten times higher in household contacts than among the general population. Living and sleeping in proximity to an infected person in a crowded house or hut is more risky than using public transport or working in ill-ventilated buildings.

The susceptibility of a person to tuberculosis is influenced by genetic and ethnic factors, malnutrition, the quantum of bacteria entering the body, and other illness, such as diabetes, pneumoconiosis, infection with multiple parasites, and anemia, as well as AIDS. There is an individual and herd variation in immunity. The Moslem community of southern India, the North American Indians and Eskimos, many Africans, and Malays have a high susceptibility and morbidity. Extensive campaigns by WHO utilizing mass radiographic surveys, BCG vaccination, and education were very successful, but now the disease is once again a major health problem throughout the tropics and is becoming more common because of AIDS and drug resistance, as well as population movements.

Modern chemotherapy has made it possible for patients with active pulmonary tuberculosis to stay at home and have treatment without endangering other inhabitants of the house. As mentioned above, a bacillus-positive sputum will become negative after about 2 months of therapy. The real danger of spreading infection occurs before the disease is diagnosed. Ambulant treatment has encouraged many patients to accept the necessary regimen; previously, isolation or sanitarium treatment met with considerable resistance. Now the difficulty is to ensure that treatment is continuous and adequate.

There are also variations in the sensitivity of the organism to different drugs; for example, in southern India, where tuberculosis is common, the bacilli seem to be isoniazid-sensitive, whereas in the United Kingdom the response is not so good. p-Aminosalicylic acid is better tolerated by patients in the tropics. Thiacetezone is not tolerated by HIV-positive patients and may even be fatal. The atypical (nontuberculous) mycobacteria are also a cause of treatment failure, but the major therapeutic problem is the development of drug-resistant organisms, the frequency of which now varies from 7% to 20%. This is usually the result of inadequate and incomplete treatment: many patients do not feel the need to continue therapy for 6 or 8 months and abandon their pills as soon as they feel better. Poverty, the nonavailability of drugs in the regular market at normal cost, interference in the treatment by unqualified practitioners, and the side-effects of the drugs (e. g., tinnitus, deafness, neuropathies, hepatitis, gastroenteritis) all offer reasons for the failure of continuous treatment. Black market drugs at inadequate dosage add to the problem. Yet WHO reckons that 80% of patients can be cured with proper supervision and full treatment, and that even in the poorest countries a case reduction of 50% is possible.

A patient's resistance to tuberculosis is a very complex process, much of which is not yet fully understood. In very general terms, no two mycobacterial strains are genetically identical (as is the case with people), but if a person is infected with a virulent strain of tuberculosis, the outcome depends on the state of competence of the patient's cell-mediated immunity (CMI). With a competent CMI the body produces derivatives of the monocyte-macrophage cells that have the ability to kill and sequester mycobacteria. These derivatives are the activated macrophage, the epithelioid cells, and the Langhans giant cell. All these cells produce hydrogen peroxide and oxygen in forms which are toxic, such as hypochlorous acid and toxic enzymes: all of these kill mycobacteria. However, the effects are unfortunately not limited to the bacteria and these toxic products kill much more host tissue than mycobacteria, which is why the disease becomes chronic, resulting in persistent destruction as seen in fibrocaseous tuberculosis. This is known as hyperergic tuberculosis, a response which is characterized by the granulomatous reaction. It is the only effective defense and the only hope that the patient has of survival. A positive tuberculin skin test is an indication that CMI has developed, and there will be a sharp reduction in the number of mycobacteria and the development of a layer of palisaded epithelioid cells around the necrotic foci. Eventually there will be an outer layer of granulation tissue surrounding the necrotic foci and scars will form that contain any remaining mycobacteria.

When CMI is suppressed, becoming too weak or nonexistent, the mycobacteria can proliferate unchecked and destroy host tissues directly. This is anergic tuberculosis, which, unchanged, is progressive and soon fatal. It is characterized by broad areas of contiguous noncaseous necrosis, large numbers of bacilli, and very little or no granulomatous reaction. Caseous necrosis is flecked with mineral deposits, hence calcification, and retains for a short time a ghost outline of previously vital tissue. The necrosis of anergic tuberculosis does not have calcification or recognizable tissue. The suppression of CMI may occur for unexpected reasons, such as grief, trauma, exposure to cold, cytotoxic agents, x-radiation in large doses, and corticosteroids, as well as the more recognized causes such as malnutrition, alcoholism, diabetes, malignancy, and, of course, the AIDS virus. The problem with this oversimplified explanation is that it is difficult to confirm in the laboratory and there is no general explanation why patients who have apparently successfully overcome the infection should suffer a breakdown of this protective immunity, allowing the disease to surge again. One of the suggested explanations is the difference in the genetic background of the host, but this is also very controversial. For all these reasons, the terms "hypersensitivity;" "immunity;" and "acute" are used less often. Much remains to be clarified, especially about the cell envelope and the associated and secreted protein. It is not even clear how the effective immune response in 90% of people succeeds in killing tubercle bacilli. As so often happens in medicine, the natural history of the disease is fully understood, the explanation of why it happens is not. Research continues, and is particularly oriented toward the development of a vaccine against tuberculosis.

Laboratory Diagnosis

The only real proof of tuberculosis is the isolation on smear or culture of M. tuberculosis from the patient's sputum, other body fluids, or tissues. The histological mark is the epithelioid granuloma with mononuclear and Langhans giant cells, together with caseating necrosis. Clinically the tuberculin test is almost universally accepted as a fairly reliable way to detect a current or previous tuberculous infection, but there are sources of error. When the tests are properly applied and material is fresh and active, it is an effective screening method unless the individual is immunosuppressed. Another source of error, in which the test may be positive, is previous BCG vaccination. Sensitivity to tuberculin may also be related to unrecognized infection with similar micro-organisms which are not tuberculous. This "false" sensitivity is particularly common in the tropics and subtropics and has a variable geographic distribution both in Africa and in India; it is more common in low-altitude populations than in those who live on the mountains. The responsible organism has not yet been identified. Thus, when there is a weak reaction to low doses of tuberculin and a strong reaction to a high dose, it may indicate a nonspecific reaction rather than tuberculosis.

During severe and overwhelming generalized infections (including HIV) the skin tests may remain negative, as seen in very sick, undernourished children. A similar misleading result can occasionally occur in bone tuberculosis. It is not common, but is well documented. Thus, a negative skin test does not totally exclude tuberculosis, nor in the tropics does a positive test necessarily prove its presence. The new y-interferon blood test, which is thought to be 98% specific and is without observer error, may solve many clinical problems.

Other laboratory tests do not differ in the tropics from those accepted elsewhere in the world, but unfortunately the host of parasitic infestations which are endemic in the tropics may confuse routine investigations. An elevated erythrocyte sedimentation rate (ESR), a raised eosinophil count, lymphocytosis, and anemia may all be due to the patient's "underlying normal" ill-health.

Sputum or gastric aspirates remain the most reliable method of diagnosis, particularly in children. Under the age of 1 year, it is the lungs which are most commonly infected and positive recovery of the bacilli is possible in about 75% of cases. In older children, even when very ill, the recovery rate of bacilli may be only 40%. Examination of effusions in the pleura, peritoneum, or joints, or of the pus from a spinal or other abscess, may demonstrate the organism on smear or culture, but failure to recognize the bacillus does not exclude active tuberculosis. Unfortunately, culture is a slow process, expensive, and not always readily available. Apart from the classical histological findings, the polymerase chain reaction, a method amplifying specific DNA sequences, is successful in detecting mycobacterial DNA in clinical specimens, including fluids.

The cerebrospinal fluid (CSF) will only contain tubercle bacilli in about 10% of initial samples. More information can be obtained from the ELISA assay and the polymerase chain reaction. There is a latex particle agglutination assay which is inexpensive and suitable for use in developing countries. The spinal fluid will usually be under pressure and clear, with an increased protein content and reduced glucose level: there is often an increased CSF white blood cell count, with 90%-95% monocytes.

Examining urine for the bacillus was once suggested as a way of confirming generalized tuberculosis, but this is positive in less than 7% of samples (except when there is active genitourinary tuberculosis), and is too inaccurate to be used. General hematological examination is usually normal in tuberculosis, but can be confusing when there is acute tuberculous pneumonia because the white blood cell count may be increased. When there is bone marrow involvement, there may be leukopenia. A patient who has multiple parasites is also likely to have an abnormal hematological background.

In many patients in the tropics the disease is a severe, acute infection and no time can be wasted in waiting for laboratory results which may be of dubious value. Even when the skin reaction is negative, if the clinical suspicion of tuberculosis is high, then therapy is often started and the patient reviewed, particularly as to the radiological findings, after about 2 months of treatment. Hypercalcemia is an infrequently recognized complication of tuberculosis, particularly in small children and those with disseminated infection; it probably occurs because vitamin B3 metabolites have a role in immunoregulation, and the level of these metabolites is regulated in granulomata by T-small cells.

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Copyright: Palmer and Reeder