Tuberculosis





Tuberculosis, also called TB, phthisis, consumption, and nicknamed the white
plague, is the most common infectious disease in the world today. It is
caused by a bacterium, usually the Mycobacterium tuberculosis but any member
of the so called Tuberculosis complex will do. 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.

The Bacterium

The cause of tuberculosis, Mycobacterium tuberculosis (MTB) is a
Gram-positive aerobic bacterium that divides every 16-20 hours. This is
extremely slow compared to other bacteria which tend to have division times
measured in minutes (for example, E. coli can divide roughly every 20
minutes). It is a small rod-like bacillus which can withstand weak
disinfectants and can survive in a dry state for weeks but can only grow
within a host organism.

MTB is identified microscopically by its staining characteristics: it
retains certain stains after being treated with acidic solution, and is thus
classified as an "acid-fast bacillus" or "AFB". In the most common staining
technique, the Ziehl-Neelsen stain, AFB are stained a bright red which
stands out clearly against a blue background. Acid-fast bacilli can also be
visualized by fluorescent microscopy, and by auramine-rhodamine stain.

Close relatives of the bacterium infect cattle (Mycobacterium bovis), swine
and fowl (Mycobacterium avium). Infection occurs if the bacterium is
ingested. Mycobacterium bovis in particular has been estimated to be
responsible, for the period of the first half of the 20th century, for more
losses among farm animals than all other infectious diseases combined.

The Disease

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 T.B. 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 4 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 consumed 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 one won't get TB. In 1% the primary infection causes
subsequent tuberculosis. The remaining 9% will get TB later, due to
reactivation of dormant baccili, usaully within a few years after the
infection. But this can happen even decades later. Chances of tuberculosis
reactivating in the body is 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, cavitating, caseous lesions.

Sputum smears and cultures should be done for acid-fast bacili if the
patient is producing sputum. If no sputum is being produced, bronchoscopy or
fine needle aspiration should be considered. Atypical mycobacteria are also
AFB. One can distinguish these from "real" TB bacteria belonging tot the
Tuberculosis complex bij means of a specific PCR or other gen probe.

The Mantoux test should be done in all cases of suspected tuberculosis,
although the results must be interpreted carefully. Tuberculin units are
injected intradermally (into the skin) and read 48 to 72 hours later.
Tuberculin is the purified proteins of the M. tuberculosis bacteria; thus 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 6 to 8 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 unnecesary. One BCG is enough; revaccination is not useful. A
previous BCG vaccination sometimes give 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-lymfocytes 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 his/her close contacts
should be screened for TB with a Mantoux test and/or a chest x-ray. In
Britain the obsolete Heaf test is still used.

Treatment

The current accepted first-line therapy is a combination of the drugs
rifampicin, isoniazid, pyrizinamide and ethambutol. After 2 months, the
number of drugs is reduced. A typical treatment for a standaard (i.e.
non-drug resistant) is 2HRZE / 4HR (= 2 months of INH, Rifampin, Pyrazinmid
and Ethambutol followed bij 4 months of Rifampin and INH). The number of
relapses is about 2-3% this way. Medication can be given 2 or 3 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
succesful 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 his 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 are high
(exposure to non-TB mycobacteria give some protection against TB), the
effectiveness of BCGs are much lower than in areas where mycobacteria are
much less prevalent. Infected people have a chance of 10% to get active TB.
Usualy INH-prophylaxis is advised to people with positive mantoux (skin)
tests. After taking 6 months of INH, the chance to get active TB is lowered
to about 3%.

History

Due to the variety of 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 - 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 WW 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 per cent
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 impacting
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 defaulters(?) 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).

Tuberculosis as a subtext in art and literature

It has been speculated that the real-life ubiquity of illness and death due
to tuberculosis affected the portrayal of these issues in European art and
literature.

The titular heroine of La Boheme suffers from tuberculosis (a theme carried
over in the modern film adaptation Moulin Rouge).

The pale, "haunted" appearance of tuberculosis sufferers has been seen as an
influence on the works of Edgar Allan Poe and in vampire tales. In recent
years, this aesthetic has been revived by the "Goth" subculture.