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Back to Infectious Diseases

Tuberculosis

Tuberculosis, also called TB, is caused by a bacterium, usually the Mycobacterium tuberculosis. If left untreated, more than 50% will die in a few years time. It causes about 2-3 million deaths per year out of 9-10 million cases and is especially prevalent in undeveloped, tropical countries.

Historical note

Due to the variety of its symptoms, TB was not identified as a unified disease until the 1820s and was not named tuberculosis until 1839 by J.L. Schoenlein. Some forms of the disease were probably known to the ancient Greeks, if not before, as the origins of the disease are in the first domestication of cattle (which also gave humanity viral poxes).

The bacillus-causing tuberculosis, Mycobacterium tuberculosis, was described on March 24, 1882 by Robert Koch. He received the Nobel Prize in physiology or medicine for this discovery in 1905. Koch did not believe that bovine (cattle) and human tuberculosis were similar, which held back the recognition of infected milk as a source of infection. Later, this source was eliminated by pasteurization. Koch announced a glycerine extract of the tubercle bacilli as a "remedy" for tuberculosis in 1890, calling it tuberculin. It was not effective, but was later adapted by von Pirquet for a test for pre-symptomatic tuberculosis.

The first genuine success was in immunizing against tuberculosis. Developed from attenuated bovine strain tuberculosis by Albert Calmette and Camille Guerin in 1906 was BCG (Bacillus of Calmette and Guerin). It was first used on humans on July 18, 1921 in France, although national arrogance prevented its widespread use in either the USA, Great Britain, or Germany until after World War II.

Tuberculosis caused the most widespread public concern in the 19th and early 20th centuries as the endemic disease of the urban poor. In 1815 England one in four deaths were of consumption; by 1918 one in six deaths in France were still caused by TB. After the establishment in the 1880s that the disease was contagious, TB was made a notifiable disease in Britain; there were campaigns to stop spitting in public places, and the infected poor were "encouraged" to enter sanatoria that rather resembled prisons. Whatever the purported benefits of the fresh air and labour in the sanatoria, 75% of those who entered were dead within five years (1908).

In Europe, deaths from TB fell from 500 out of 100,000 Europeans in 1850 to 50 out of 100,000 by 1950. Improvements in public health were reducing tuberculosis even before the arrival of antibiotics, although the disease's significance was still such that when the Medical Research Council was formed in Britain in 1913 its first project was tuberculosis.

It was not until 1946 with the development of the antibiotic streptomycin that treatment rather than prevention became a possibility. Prior to then only surgical intervention was possible as supposed treatment (other than sanatoria), including the pneumothorax technique: collapsing an infected lung to "rest" it and allow lesions to heal, which was an accomplished technique but was of little benefit and was discontinued after 1946.

Hopes that the disease could be completely eliminated have been dashed since the rise of drug-resistant strains in the 1980s. For example, TB cases in Britain, numbering around 50,000 in 1955, had fallen to around 5,500 in 1987, but in 2001 there were over 7,000 confirmed cases. Due to the elimination of public health facilities in New York in the 1970s, there was a resurgence in the 1980s. The number of those failing to complete their course of drugs was very high. NY had to cope with more than 20,000 "unnecessary" TB-patients with many multi-drug resistant strains (i.e., resistant to, at least, both Rifampin and Isoniazid). The resurgance of tuberculosis resulted in the declaration of a global health emergency by the World Health Orginization in 1993.

In 2003, by disabling a set of genes, researchers accidentally created a more lethal and rapidly reproducing strain of tuberculosis bacteria.

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Symptoms and signs

The TB bacillus can attack any part of the body and so can produce a series of different symptoms but always eventually creates the distinctive tubercles or tuberculous nodules, small lesions consisting of dead grayish matter containing TB bacteria.

Transmission of tuberculosis infection is usually from droplets coughed out by an infected person.

On the other hand, Mycobacterium bovis usually spreads through infected milk, although it too can spread via droplets. Humans are susceptible to this bacterium that causes bovine tuberculosis.

Children up to four years of age are more at risk than adults. Tuberculous meningitis and miliary tuberculosis (so named because the lesions formed resemble millet seeds), a form of TB septicaemia, is more common in the young than the old.

TB is divided into pulmonary and extra-pulmonary TB. The most common form in adults is pulmonary tuberculosis, the "classic" form of TB, in which the lungs are diseased. The disease begins gradually with coughing - later traces of blood are coughed up in the sputum (haemoptysis). Untreated, it leads to fever, weight-loss, and death. The term consumption arose because sufferers appear as if they were "consumed" from within by the disease.

After droplet infection, the MTB causes a local infection in the lung. After that, it moves to the hilar lymph nodes. The bacteria can later spread via the blood to all parts of the body. This is the reason that one can have TB in every organ, although pulmonary TB is most common. Other (extra-pulmonary) TB sites are lymph nodes, spinal column, kidneys, and so on. In 90% of the infected people the body is able to defend itself well enough so that a single exposure is often not sufficient to cause infection with TB. In 1% the primary infection causes subsequent tuberculosis. The remaining 9% will get TB later, due to reactivation of dormant bacilli, usually within a few years after the infection. But this can happen even decades later. Chances of tuberculosis reactivating in the body are increased in cases of acquired immunodeficiency - whether due to AIDS, drugs, or other causes. A depressed immune system also makes miliary tuberculosis more likely.

Diagnosis

A chest X-ray is essential in all cases of suspected pulmonary tuberculosis. The classical X-ray picture of post-primary tuberculosis is of bilateral, posterior apical, cavitation-forming, caseous lesions.

Sputum smears and cultures should be done for acid-fast bacilli if the patient is producing sputum. If no sputum is being produced, a laryngeal swab, bronchoscopy or fine needle aspiration should be considered. Other mycobacteria are also AFB. Further PCR or gene probe tests can distinguish M. tuberculosis from other mycobacteria. If this is not available, a culture of the AFB can distinguish the various forms of mycobacteria, although results from this may take 4-8 weeks for a conclusive answer.

The Mantoux test should be done in all cases of suspected tuberculosis, although the results must be interpreted carefully. Purified protein derivative (PPD) tuberculin, a precipitate of non-species-specific molecules obtained from filtrates of sterilized, concentrated cultures, is injected intradermally (into the skin) and read 48 to 72 hours later. A patient who has been exposed to the bacteria is expected to mount an immune response in the skin containing the bacterial proteins. An induration (hardened spot of skin) of more than 10mm to 10 Mantoux units is considered a positive result, indicating TB infection. A negative test does not exclude active tuberculosis, especially if the test was done within six to eight weeks of acquiring the infection, if the infection is overwhelming, or if the patient is immunocompromised.

There is no relation between the effectiveness of the BCG vaccine and a positive Mantoux test. After BCG vaccination, testing with a Mantoux test is not useful and unnecessary. One BCG is enough; revaccination is not useful. A previous BCG vaccination sometimes gives false-positive results. This makes the Mantoux test less useful in BCG vaccinated people. In order to improve the Mantoux test, several other tests are being developed. A promising one is a blood test that looks at the reaction of T-lymphocytes to the antigens ESAT6 and CFP10.

Tuberculosis should be suspected when a persistent respiratory illness in an otherwise healthy individual does not respond to regular antibiotics (such as penicillin or amoxicillin).

When someone is diagnosed with tuberculosis, all their close contacts should be screened for TB with a Mantoux test or a chest x-ray or both. In Britain the obsolete Heaf test is still used.

Treatment

The current accepted first-line therapy is a combination of the drugs rifampicin, isoniazid (INH), pyrizinamide, and ethambutol. Supplemental pyridoxine (vitamin B6) is often given with these drugs. After two months, the number of drugs is reduced. A typical treatment for a standard (i.e. non-drug resistant) strain of TB is 2HRZE / 4HR (= two months of INH, Rifampin, Pyrazinmid and Ethambutol followed by four months of Rifampin and INH). The number of relapses is about 2-3% this way. Medication can be given two or three times per week (different/higher dosages) with the same results as daily therapy.

Why four drugs? If only one drug is given, what ends up happening is that all the bacteria sensitive to that drug are killed and three months later, the patient will be infected with progeny of the bacteria that were resistant to that particular drug. Rifampicin and isoniazid are bactericidal agents that kill the bacteria, pyrizinamide acts well against the intracellular bacteria which are dormant inside macrophages and other cells, and ethambutol is a bacteriostatic agent that inhibits bacterial proliferation while the other drugs kill off the TB. Rifampin is the drug that gives the best "sterilization"; this means that it will kill dormant bacteria very well in order to lower the number of relapses after a successful treatment.

The World Health Organization (WHO) currently recommends DOTS or Directly Observed Treatment, Short-course. The mainstay of this is the DOT or Directly Observed Treatment portion which involves health care workers directly monitoring tuberculosis patients actually swallowing their anti-tuberculous therapy for at least the first two months of treatment. Treatment with properly implemented DOTS has a success rate exceeding 95% and prevents the emergence of further multi-drug resistant strains of tuberculosis.

Streptomycin is used if the initial 4-drug therapy fails, often in conjunction with other second-line drugs such as capreomycin, cycloserine, new macrolides, quinolones, and protionamide. Streptomycin and capreomycin are not available as oral medications and must be injected.

Adverse drug reactions are expected in 20-25% of patients but only 5% of all patients will have a severe enough reaction to warrant a change in their drug regimen. Hepatic damage is the most significant of the drug reactions.

Supervised therapy, in which the patient's continued use of their prescribed medication is ensured by direct observation, has a cure rate of about 98%.

Prevention

BCG immunization gives the receiver between 50% to 80% resistance to TB. In tropical areas where the incidence of atypical mycobacteria is high (exposure to non-TB mycobacteria gives some protection against TB), the effectiveness of BCGs is much lower than in areas where mycobacteria are much less prevalent. Infected people have a 10% chance to get active TB. Usually INH-prophylaxis is advised to people with positive mantoux (skin) tests. After taking six months of INH, the chance to get active TB is lowered to about 3%.

Before a BCG vaccination is given, a Heaf test (see Mantoux test) is often performed to determine whether a subject is already immune to TB. A Heaf test is also commonly used to determine whether someone already has TB, but the BCG vaccine is not effective in people who are suffering from the disease at the time of vaccination. In the United Kingdom, children aged 10-14 are typically immunized during school.

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