Tuberculosis or TB is an infectious disease caused by mycobacterium tuberculosis, and typically affects the lungs, although the disease can spread to and jeopardize other organs or organ systems. Tuberculosis is an airborne disease spread through coughing, sneezing, spitting and talking, and is often characterized by chesty cough, accompanied by sputum and or blood, chest pain, fatigue, fever, night sweats and weight loss. Tuberculosis can exhibit forms of drug resistance, which makes treatment difficult. Individuals with compromised immune systems have a higher chance of developing TB than healthy people, if exposed, and TB can be fatal if medical attention is not sought following infection. Nevertheless, TB can be successfully treated with anti-mycobacterial drugs, and a vaccine, Bacille Calmette Guerin, also known as BCG is used in some countries as a preventive measure.
The Lancet published an article titled Tuberculosis by G. Maartens & R.J. Wilkinson in 2007. It touched on the limitations of existing methods of prevention, diagnosis and treatment of TB, the impact HIV has on the disease, the struggles involved in developing new drugs to combat TB while keeping drug resistance in check at the same time, the complexities of preventive therapy, and the dire consequences which follows failure to complete treatment, to the individual in question, and on a larger scale to the rest of the population.
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Numerous critical points were brought up in the article. One of the main issues discussed was the high incidence of tuberculosis in developing countries, especially those in Africa, and the correlation between HIV infection and the development of tuberculosis. According to the article, the risk of developing tuberculosis increases shortly after HIV seroconversion, and even further with serious immunosuppression. High transmission rates between adults and children have also been strongly linked to HIV infection in developing countries like South Africa.
Multidrug-resistant tuberculosis is a matter of great concern, as treatment is long lasting, less effective, expensive, and poorly tolerated, when compared to treatment for regular cases that donââ‚¬â„¢t show drug-resistance. In addition, the amount of cases that present with multidrug-resistance are significantly higher in people who have previously suffered from tuberculosis and received treatment. Extensively drug-resistant (XDR) tuberculosis is of even greater concern, making treatment and restoration of good health virtually impossible.
Another subject discussed in the article is the origin and evolution of Mycobacteria tuberculosis. Bacterial genomics has been used to map the genomic sequences of mycobacterial lineages, and indicates that M tuberculosis and M bovis share a common ancestor, so M bovis did not give rise to M tuberculosis as was previously thought. The article states that analysis of unique sequence deletions in the genome of M tuberculosis, in 875 strains from 80 countries indicates that M tuberculosis arose and migrated together with human beings from Africa. In addition, six lineages of M tuberculosis have adapted to specific global populations, and these lineages persist in individuals of these populations even after migration to other parts of the world.
Each lineage has specificities in its mode of action as it colonizes a host. For instance, the East Asian lineage has been associated with several outbreaks of drug-resistant and drug-sensitive tuberculosis, in addition to its increased virulence in humans and other animals. On the other hand, the East Africanââ‚¬"Indian lineage is characterized by a specific deletion in its genome, which is associated with an immune-subverting phenotype that potentially increases its ability to persist and cause outbreaks in populations.
The tuberculosis article dwells on the numerous limitations on the existing methods of active and latent TB. Some are easily performed but have low yield, some are fast and sensitive, but not widely available in resource-limited settings, while others, have both shortened time and less labor consumption, but are very expensive. The need for an affordable and rapid diagnostic test with increased sensitivity cannot be over emphasized, but it still remains elusive despite all the effort that has been put into it.
The diagnosis of TB can be difficult as a result of the limitations of the most commonly used diagnostic test, TST. False positives occur in TST because the purified protein derivatives contain many antigens present in the BCG vaccine, and non-pathogenic mycobacteria. Also false positives are not uncommon in immune-compromised patients, and during the early stages of primary TB and in disseminated TB. The TST is not only compromised with BCG-vaccinated people, but also in those infected with HIV. Another diagnostic test used is the ELIspot analysis test, and although it performs better in the presence of HIV infection, or BCG vaccination, it cannot differentiate active from latent infection. Others like the Quantiferon test are still fairy new, and expensive to perform.
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Treatment for TB has followed the conventional short course therapy for decades, using a combination of drugs for about six months. Directly observed treatment short course (DOTS) is the international control strategy for TB, and is very cost-effective, especially in developing countries. In spite of the success of DOTS, there is still need for new drugs, diagnostics and vaccines, reduction in the incidence of HIV, and increased advocacy, in order to make tuberculosis a thing of the past. As noted in the article, failure to complete therapy due to improved symptoms in patients can be very problematic, leading to longer infectious status, relapse, and drug resistance, the most threatening of them all. The effect of HIV infection on tuberculosis was also addressed in the article. HIV positive status not only increases the risk of TB development, but also creates errors in diagnostic tests, making TB even harder to detect. Also, adverse drug reaction between antiviral and TB drugs is a constant fear.
Some important experiments and studies were used extensively in this article to detail the escalating problems associated with tuberculosis. In one of such studies, 52 out of 53 HIV positive patients infected with extensively drug-resistant tuberculosis, possibly through nosocomial means, died within only 16 days of infection. This study not only shows the threat of extensively drug-resistant tuberculosis, but also stresses the need for new anti-mycobacterial drugs, especially those target designed to target XDR strains. Another study mentioned, points out the pleiotropic immune effects of vitamin D, which includes the activation of antimicrobial peptides. Vitamin D deficiency in certain immigrants to the United Kingdom was associated with development of tuberculosis. The results of this study suggest that vitamin D could play a role in a new method of intracellular killing of mycobacteria, and could possibly reduce TB infections via vitamin supplementation.
A series of studies done in the late 1990s helped shed some light on genetic determinants of susceptibility to mycobacterial infection. Results from these studies show that host genetic components of susceptibility seem to be distributed in several genes, and the genes implicated seem to vary between populations affected. Two large-scale studies mentioned in the article used microarray screening of mutated mycobacteria that had been passed through mice cells to give some insight as to why and how M tuberculosis can survive for so long in macrophages of a proper functioning immune system.
Both studies identified membrane-associated proteins with important roles in virulence, and small molecule transporters important in mycobacterial replication. Their results show that although mycobacteria rely on carbohydrate dependent aerobic condition to multiply rapidly in the early stages of infection, they can easily switch to lipids as an energy source later on in the course of the infection, and also during latency. Both studies also revealed the presence of a potassium efflux channel on these bacilli, which lower intracellular pH, thus protecting them against electrophile toxicity. These studies shed light on mycobacterial mode of pathogenesis, and hence, the possibility of developing new drugs to tackle tuberculosis.
The Tuberculosis article combined numerous findings and studies to help shed much needed light on the growing problems associated with tuberculosis. The article detailed the increased occurrence of TB in underdeveloped and developing countries, the adverse effects of HIV positive status on the disease, and the issue of emerging drug resistance. It addressed the fact that different lineages of M tuberculosis have adapted to specific populations, with some having higher virulence, persistence, or ability to cause epidemics than others. The potential use of vitamin D, mode of pathogenesis of M tuberculosis, and genetic determinants of susceptibility to TB to invent new drug targets were mentioned. Emphasis was placed on the need for affordable and rapid diagnostic tests with improved sensitivity in addition to ones that work equally well on individuals infected with HIV. The need for strict adherence to DOTS, additional advocacy, and increased awareness to aid in preventive measure were also stressed.
In my opinion, the near future of tuberculosis will remain bleak, as the need for novel diagnostic tests and drugs will likely remain unsatisfied. Development of these measures will take time, effort and resources, and in the meantime, the different lineages of TB are constantly mutating and evolving. Getting people to complete their treatment will probably continue to be a pain, and M tuberculosis will continue to have the opportunity to acquire drug resistance as long as drugs are the form of treatment available. In many second and third world countries, poor awareness for HIV prevention still exists; therefore, the risk of developing TB after being exposed to the pathogen and transmission to others will remain high. Development of multi-stage drugs that target M tuberculosis early on in infection, and then switch to prevention of replication and pili formation at a later point might be a better treatment option. This way, the bulk of the pathogens are killed off first, and then the few that remain due to drug resistance can be thwarted by preventing their replication, or horizontal transfer of the genes that code for their mode of drug resistance.
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