Mycobacterium tuberculosis (TB)

Aetiology

Mycobacterium tuberculosis (TB) is said to have now infected over a third of the world's population - over 2 billion people (both latent and active strains of TB) that will cause around 2 million deaths a year, from a disease that which was said to have been eradicated over three decades ago. TB is an old disease going back as far as the Egyptians in 4000BC when the bacterium was found in the spinal cord of ancient mummies. Although it was not until 24 March 1882 when Robert Koch lectured his colleagues about his findings on the bacterium Mycobacterium tuberculosis that the world finally knew what they were facing.

Prevalence and Epidemiology

Number of incidences of TB growing had been increasing steadily for years because of a number of factors such as when patients have been immune suppressed for whatever reason particularly HIV, Aids and diabetes mellitus but also patients in general who have been hospitalised, who are homelessness or who may be drug abusers, the popularity of world travel and immigration from countries with high number of diagnosed cases of TB, more resistance by bacteria to antibiotics (hence we have MTB (multi-drug resistant TB) and XTB (extensively drug resistant TB)) {{2 Knechel, Nancy A. 2009}}. Now the number of incidences, due to the World Health Organisation's Stop TB campaign to reduce the prevalence and number of deaths, has reduced the numbers of TB infections {{4 World Health Organisation 2010}} see table below.

Transmission and pathophysiology

TB is an airborne disease which is spread when a person infected with TB spreads droplet nuclei that contain the bacilli of TB when they cough, talk, spit or sneeze at a person without the TB mycobacterium, even a person singing can spread TB {{2 Knechel, Nancy A. 2009}}.

Our first line of defence against TB starts when the droplets are trapped in the upper respiratory system where mucus secreting goblet cells catch the bacilli and with the help of cilia present in the airways beat the trapped bacilli upwards and outwards.

If this initial defence does not completely remove the droplets which contain the Mycobacterium tuberculosis it then enters the alveoli of the lungs where a series of immunological events take place. The bacilli that reach the alveoli are engulfed by alveolar macrophages, a part of the innate immune system, which need no advance exposure to the bacteria to be able to attack and destroy the bacilli.

As part of the initial response the complement system activates the C3 protein which binds to the cell wall of the Mycobacterium tuberculosis {{6 Ferguson, J. Scott 2004; 2 Knechel, Nancy A. 2009}}. This in turn enhances the recognition of the macrophages to the mycobacterium thereby increasing the phagocytosis of the bacilli.

Phagocytosis of the bacilli initiates a cascade of events that can result in the successful control of the infection (latent tuberculosis) or progress to an active form of tuberculosis (primary progressive or extrapulmonary). The outcome of which is determined by the strength of the defences produced by the immune system of the infected person.

The macrophages produce cytokines and enzymes that continue the degradation of the bacilli. The cytokines attract to the site of the macrophages T helper cells, in an acquired immune response. These T-lymphocytes have been primed in the proximal lymph nodes and formulate granulomas around the bacilli. These granulomas contain the mycobacterium, dendrite cells and macrophages and restrict the replication and spread of the mycobacterium by producing a solid necrotic centre. And although our body's immune systems are able to produce such a spectacular response to these invaders in turn some of the bacilli are able to survive the hostile environment of the granuloma and even possess the ability to change phenotype in order to survive. It is these bacilli will most likely survive and break through the wall of the granuloma and develop into primary TB.

After a period of two to three weeks the solid necrotic of the granuloma develops into a casesious (cheese-like) necrosis. This environment restricts oxygen levels, has a low pH level and limited nutrition thereby restricting growth of the mycobacterium and enhancing the latency. There is also further development of fibrosis and calcification of the granuloma to control the infection; bacilli are contained in the dormant healed lesions. These lesions can contain bacilli in a latent state continuously unless the strength and quality of these defences are immunocompromised.

Signs and Symptoms

There are several different stages in TB these include latent (as discussed above), primary disease, progressive primary disease and extrapulmonary. A person in infected with latent TB will most likely present with no signs or symptoms of the disease until the bacilli present in the necrotic material inside the granuloma are reactivated if the immune system becomes compromised. A tuberculin skin test is the most effective procedure used when latent TB is being diagnosed {{8 Frieden, Thomas R. 2003}} which has been used since the 1900s.

The stages of active TB can show unspecific signs of the infection although during the early progressive stage symptoms can include fatigue, malaise, weight loss fever and/or chills during the night. A cough may also commence which starts as non-productive but can progress to a productive expectorate with a purulent sputum and have blood present.

The patient can also present wasting, finger clubbing, anaemia and rales {{2 Knechel, Nancy A. 2009}} when the TB progresses further. There are also different types of tests for the diagnosis of primary TB, which vary in price, speed, specific and reliability, mostly diagnosis is through the testing of sputum, but can also include culture testing, radiographic images and drug susceptibility testing on patients with a persistent cough and who still have a positive culture after three months of treatment {{8 Frieden, Thomas R. 2003}}.

In TB the most common area of infection is the lungs (pulmonary TB). If the disease spreads through the body (extrapulmonay TB) it can affect the central nervous system, the spine, abdomen, bones and joints, the heart's pleura, kidneys and genitourinary system {{2 Knechel, Nancy A. 2009; 8 Frieden, Thomas R. 2003}}. The treatment for these types of TB is generally the same as for pulmonary TB {{8 Frieden, Thomas R. 2003}}.

Treatment

The major drugs used in the treatment of TB are Isomazid, Rifampicin, Pyrazinamide, Ethambutol and Streptomycin - as according to the table shown below.

Treatment Patients Tuberculosis treatment* category Initial phase (daily or three times per Continuation phase week) (daily or three times per week)

I New cases of smear-positive pulmonary tuberculosis or severe 2 months H3R3Z3E3 or 2 months H3R3Z3S3 4 months H3R3 extrapulmonary tuberculosis or severe smear-negative pulmonary 2 months HRZE or 2 months HRZS 4 months HR tuberculosis or severe concomitant HIV disease 6 months HE

II Previously treated smear-positive pulmonary tuberculosis; 2 months H3R3Z3E3S3/1 month H3R3Z3E3 5 months H3R3E3 relapse; treatment failure; treatment after default 2 months HRZES/1 month HRZE 5 months HRE

III New cases of smear-negative pulmonary tuberculosis or 2 months H3R3Z3E3 4 months H3R3 with less severe forms of extrapulmonary tuberculosis 2 months HRZE 4 months HR 6 months HE

*Subscript after letters refers to the number of doses per week; daily has no subscript. H=isoniazid; R=rifampicin; Z=pyrazinamide; S=streptomycin, E=ethambutol.

A continuation phase of 6 months of HE has a higher failure and relapse rate than a continuation phase of 4 months of HR but can be used for mobile patients and those with limited access to health services; the HE regimen can also be used concomitantly with antiretroviral treatment of HIV-infected patients. CDC/ATS and BTS recommend treatment for such patients based on susceptibility testing, with regimens tailored to the susceptibility profile. WHO recommends susceptibility testing whenever possible for patients with treatment failure. WHO indicates that ethambutol need not be given in the initial phase of category III treatment if patients have non-cavitary, smear-negative pulmonary tuberculosis, or if patients are known to have a drug-susceptible organism, or for young children with primary tuberculosis.

The type and quantity of each drug administered depends upon the severity (pulmonary, extrapulmonary, military), type (MDR-TB or XDR-TB), person affected (child, adult, pregnant women etc) and any other underlying health issues the patient may have (HIV/AIDS, renal problems etc) {{11 World Health Organisation 2009}}.

Treatment for TB may be drawn out over a long period of time and may involve up to a year of taking medication but if detected early and the drug regime adhered to the prognosis for a full recovery is extremely good. Standard short course regimes can cure more than 95% of cases of new drug-susceptible TB by using a drug regime which incorporates using 2 or more of the recommended drug treatments rather than just one and also a treatment that is fully overlooked . With effective diagnosis and treatment the prevalenace and mortality rates decline in a positive and proactive means.

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