Tuberculosis remains the most common infectious disease in the world with an estimated 1/3 of the worlds population infected, with 2.5million deaths annually (WHO, 2011) proving to be a formidable public health challenge that shows little sign of abating. TB is caused by Mycobacterium tuberculosis (M. tuberculosis) and is part of the M.tuberculosis complex along with M.bovis, M.caprae, M.africanum, M.microti and M.mungi, most of which can cause infection in humans. The majority of all TB cases are caused by M.tuberculosis and was first isolated by Robert Koch in 1882.
Tuberculosis is widespread throughout the world mainly due to increase in immigration from endemic countries such as ethnic groups from Indian subcontinent, black Africans and China. Infection rates have also increased from within prisons, homeless people, drug/alcohol abusers and HIV sufferers. It is particularly difficult to eradicate from these populations due to patients being inadequately treated and also remaining infectious for a very long period of time. This is especially true in cases of multi drug resistant M.tuberculosis ( MDR-TB).
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Humans are the only known natural reservoirs of infection and the current epidemic is being fuelled by two major factors. The HIV ( human immunodeficiency virus) infection and its association with active TB disease and M.tuberculosis increasing resistance to the most effective first line drugs. Other contributory factors being population expansion, active transmission in overcrowded prisons and the poor detection and cure rates in developing countries.
M.tuberculosis is acquired via inhalation of infected aerosols (droplet nuclei 1-5Âµm in diameter) containing M.tuberculosis from a person with active disease, typically via a cough. Large infectious particles are trapped on mucosal surfaces and removed by the ciliary action of respiratory tree however small tubercle bacilli can reach the alveolar spaces thereby establishing infection. Due to the aerosols size they can remain suspended in the air for several minutes increasing the likelihood of cross infection. Infection depends on factors such as immune status of any potential host, proximity with infected person and the bacterial load inhaled (Mathema B, et al 2008).
On inhalation of infected aerosols, they may escape the bronchial defences due to their size, thus allowing them to penetrate the alveoli where they are then ingested by macrophages and dendritic cells. M.tuberculosis which are ingested by macrophages, replicate internally and by resisting the bactericidal process of the macrophages, ultimately cause macrophage necrosis. The infected macrophages may also cross the alveolar barrier to cause systemic dissemination to reach distal organs and tissues (kidneys, brain and bone). This process allows M.tuberculosis to evade the immune system and survive indefinitely (Tufariello J.M et al 2004).
Granuloma formation prevents the tubercle bacilli from "consuming" the remaining lung tissue therefore preventing further bacterial spread. The granuloma is formed by primed CD4+ and CD8+ cells, dendritic cells, stromal cells, fibroblasts, macrophages and endothelial cells migrating to the site of infected macrophages, guided by chemokines produced by the infected macrophages. The CD4+ cells produce interferon Æ´ (IFN-Æ´) which recognises macrophages presenting antigens from M.tuberculosis and kill them therefore infection process is halted(Ahmad S. 2011). However in approx 90% of people infected the bacilli is capable of surviving the microbicidal mechanisms of host immune cells, remaining in a non-replicating state. This process is termed latent tuberculosis infection (LTBI) on formation of the granuloma.
Diagram 1: Pathogenesis of M.tuberculosis
(Reproduced with permission from Michael Shildh M.D PhD, Divison of Infectious Diseases)
The hallmark of M. tuberculosis Â in humans is its ability to establish a latent infection due to the failure in mounting a sufficient immune response to completely eliminate the pathogen which results in an estimated 1-2 billion people worldwide being infected (WHO,2011).
LBTI is defined as infection with M.tuberculosis within granulomas which remain non-replicating but retain their ability to come out of latency and cause disease when disruption of immune system occurs (Ulrich T et al ,2006). LBTI tends to present itself with a negative sputum and chest Xray showing pleural infiltrations. Old age, children <5 years of age, malnutrition, or any medical condition causing immunosuppression (HIV infection), poorly controlled diabetes, renal failure all enhance the chance of reactivation of LBTI to active disease (Dooley K.E, Chaisson R.E, 2009). Reactivation of LBTI can occur anywhere in the body where the tubercle bacilli was seeded however in the immunocompetent person re-infection occurs in the upper lobes of lungs ( higher O2 content supports good bacterial growth) . If a person has a good immune response , then re-infection will have clinical symptoms of post-primary TB infection however if they are significantly immuno-compromised they will present with disseminated or extra-pulmonary TB.
Table 1: Clinical presentation of Pulmonary TB
Always on Time
Marked to Standard
Chronic cough, often with haemoptysis
Pyrexia of unknown source
Exudative pleural effusion
Asymptomatic ( diagnosis via chest Xray)
Weight loss, general debility
HIV association with M.tuberculosis
TB is a particularly insidious problem for people with HIV due to the low CD4+ count they have as a result of becoming viral overloaded, attributed by the depletion of CD4+ and CD8+ T cells which normally mount an immune response to M.tuberculosis , therefore unable to overcome the bacterial infection. As a result of M.tuberculosis infection it causes the rapid acceleration from HIV to AIDS (acquired immune deficiency syndrome). It is usually the first disease to afflict an AIDS patient, before any other opportunistic infections. HIV/AIDS infected people face a mortality rate of 70 -90% usually within four months of developing symptoms and the infection usually targets other organs/tissues such lymph nodes, bones, liver .Strangely they often test negative for the tuberculin skin test as a result of their lack of T cells which are responsible in producing the tell tale raised red welt that signals infection. Despite highly effective drugs, disease and deaths caused by M.tuberculosis are increasing worldwide, being fuelled by the global HIV epidemic (Corbet E.L et al, 2003).
Treatment and Drug resistance
Disease due to strains of M.tuberculosis Â that are resistant to first-line drugs is a serious threat to global tuberculosis control. It is estimated that 17% of all new tuberculosis cases worldwide, harbour some form of drug resistance (WHO, 2011). Multidrug resistance (MDR-TB) and extensive drug resistant tuberculosis (XDR-TB) arise due to improper use of first line drugs commonly used to treat TB. MDR-TB is defined as tubercle bacilli resistant to Isoniazid and Rifampin, two most powerful anti-tuberculosis drugs. XDR-TB is defined as tubercle bacilli resistant to isoniazid, Rifampin , fluroquinolones and at least one of the three injectable second line drugs- Capreomycin, Kanamycin and Amikacin (Prabhudesai P.P, Singh R.V.P, 2009). Treatment of MDR-TB is expensive and lengthy, lasting 18-24months (until sputum proves negative on three consecutive monthly cultures). Drug therapy involves five different antibiotics to which the bacilli is sensitive to and inclusion of three never been used before.
Mutation is the biggest cause of resistance and the higher the bacterial load in the patient results in the higher number of drug resistant mutants. Resistance can also occur due to poor patient and doctor related causes. Patients with alcohol/drug addictions, impoverished and those with poor understanding of the importance in treatment regimens and doctors who mismanage drug regimens with improper dosage for too short a period and for prescribing a single anti TB drug, all lead to disruption of treatment and increased risk of MDR-TB and its subsequent increased cost in treatment. This can also arise due to failure in determining pre-existing resistance by subjecting the patient's sputum to culture and drug sensitivity testing according to WHO guidelines (Blumberg et al, 2003). Such tests are expensive and are not available in parts of the world where its needed the most such as India and Africa. The second line drugs mainly used in India are less effective, more toxic and more expensive (Ormerod L.P, 2005).
MDR-TB and XDR-TB can be fatal and cure rates extremely low which creates huge difficulties its management. In poorer countries Linezoid has been proven to be a successful third line drug in the management of MDR-TB and XDR-TB (Singla R et al, 2012) however its high toxicity profile and high cost in some countries have restricted its use. However , in India , a 600mg pill costs less than one US dollar making it cheaper than some second line drugs and current research has shown that a 300mg pill of Lineziod could reduce side effects of this drug without reducing efficacy (Koh W.J et al, 2012)
Inappropriate treatment is the most important factor of MDR-TB and XDR-TB and prevention of this can be assured by increasing knowledge of TB, early detection and appropriate treatment along with collaboration with health organisations and compliance with WHO guidelines by doctors and patients. Effective second line drugs should be available to clinicians with expertise in treating MDR-TB.
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Further research into the unique cellular and immunologic responses of the host that facilitate M. tuberculosis survival along with extensive research into its virulence factors would be beneficial in understanding of the disease process which in turn may open up potential targets for future drugs. This may help identify novel microbial and host factors that can be inhibited to improve the treatment of tuberculosis.
Co-morbidity between tuberculosis and HIV/AIDS patients kills thousands however less than 0.5% of HIV patients get screened for tuberculosis (Singh S et al, 2008). This should be increased in line with WHO guidelines to ensure they get the appropriate early treatment. Ensuring they have proper access to anti retroviral therapy (ART) will allow them to maintain an improved immune system more capable of defence against M.tuberculosis . This alone will prove challenging due to cost and availability of such ART drugs in Africa.
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