According to the World Health Organization, a third of the world’s population is infected with Mycobacterium tuberculosis (World Health Organization). New cases were estimated to number 9.4 million with 1.8 million deaths in 2008 (Thomas). Gary Maartens and Robert J. Wilkinson published a review in the December, 2007 issue of The Lancet that outlines the current condition of tuberculosis(TB) in the world today. Specifically, the authors report on the status of research, diagnostic techniques, treatment options and the epidemic of HIV-associated tuberculosis in Africa.
Mycobacterium tuberculosis is the bacterial causative agent of a disease that has been a leading cause of death for much of earth’s history and still is for many developing countries. Maarten and Wilkinson noted recent regional changes in the incidence of TB with improvements made in many regions while incidence in sub-Saharan Africa has increased. This increase is correlated with the HIV epidemic in Africa and presents complex challenges in the task of controlling TB. In addition to HIV, multidrug-resistant and extensively drug-resistant (XDR) strains of tuberculosis account for increasing numbers of new cases and recurrent disease in previously treated patients. The authors state that 4% of patients worldwide have a multidrug-resistant strain. Included in that percentage are patients with XDR strains. One reported study of a tuberculosis outbreak in HIV-infected individuals showed that 24% of those patients had XDR strains and this resulted in a 98% fatality rate (52 of 53 patients). Genetic analysis of the bacterium indicated that transmission of the TB had been recent and it was noted that two-thirds of the affected patients had been hospitalized in the two years prior. The concern is that they may have acquired the XDR strain of TB while hospitalized, highlighting the need for better treatments and more precaution when treating these patients. Without improvements in rapid diagnosis and treatment, the incidence of drug-resistant strains will continue to rise.
Genomic analysis has become an important tool in understanding microorganisms and Mycobacterium tuberculosis has been extensively studied and its genes have been sequenced. Analysis conducted on 875 different strains of Mycobacterium tuberculosis from 80 countries has resulted in the discovery of six distinct lineages of TB that seem to have adaptations to specific populations of humans. As an example, the east African-Asian strain affects people of Indian origin, regardless of where they currently live. Another strain, W/Beijing, has less specificity, affecting people all over the world, but it also seems to be more virulent. Each of these strains is the result of mutations in the DNA of the bacterium. Different strains of TB have different mechanisms which allow them to modulate or suppress the immune system response. Many of these mechanisms have to do with the molecules that comprise the mycobacterial cell wall such as phenolic glycolipids. Two large studies have identified that membrane-associated proteins, molecular transporters, and ion channels play a vital role in the virulence of TB. These discoveries not only help scientists better understand the pathogenesis of tuberculosis; they also provide new targets for treatment.
In addition to the genetics of the bacteria, the genetic makeup of the host is critical. Specific receptors on human macrophages recognize specific molecules of the cell wall of Mycobacterium tuberculosis and trigger cellular signaling cascades that can result in greater host resistance or increased susceptibility to TB. Two of the receptors involved have a role in vitamin D activation and a deficiency of this vitamin has been noted in some tuberculosis cases, leading the authors to speculate about the possibility of vitamin D supplementation for prevention. Mutations in one of these cellular signaling pathways were shown in a series of studies to predispose individuals to “severe atypical mycobacterial infections.” This line of inquiry, identifying the specific genetic mutations that give rise to virulence factors in the bacteria or greater susceptibility in the host, could lead to huge advancements in the understanding and eventual eradication of TB, but the authors point out that these studies would need to be extensive, which equates to expensive.
Diagnosis and treatment for tuberculosis hasn’t significantly changed in decades. Microscopic analysis and bacterial culturing are the standard protocols used to detect a TB infection, but these techniques have drawbacks, the most obvious being the time and labor involved in culturing. Maarten and Wilkinson state the obvious by expressing a desire for a more sensitive test that is rapid and affordable. A few emerging candidates are discussed, including nucleic-acid amplification tests and enzyme-linked immunospot analysis (ELISpot analysis). Nucleic-acid amplification tests have not proven to be significantly better at identifying TB. They are also expensive and require specialized equipment, making them unsuitable for use in most developing countries with limited resources. The ELISpot analysis, however, has promise in that it shows greater sensitivity and specificity than the tuberculosis skin test (TST), particularly in differentiating between exposure to TB and an active infection. In addition to assessing whether a patient is dealing with a tuberculosis infection, it is critical to know whether the strain of TB is drug-resistant. Current methods of determining drug resistance require 6-8 weeks, but microscopic analysis of liquid culture growth can be done within 10 days and has the advantages of being inexpensive and easily available, even to locations with limited resources. HIV infection further complicates diagnosis of tuberculosis and a determination is frequently made based solely on clinical symptoms and x-rays. This can lead to faster treatment, but could also be a contributing factor in the creation of resistant strains.
Current methods of treatment involve a cocktail of medications taken for at least six months. This protocol typically has good results, even in patients with HIV. The treatment strategy utilized internationally is called “directly observed treatment short course (DOTS).” This method of control has contributed to gains made in prevention, diagnosis, and treatment, but still has many shortcomings. The authors advocate a combined approach and point to very high adherence rates for HIV treatments with a more patient centered approach, which empowers the patient to take care of themselves rather than reporting to a clinic to be observed taking a medication.
The medications used to treat TB have changed very little and new medications are desperately needed, especially in light of the increase in drug-resistant strains. A commonly used medication, rifamycin is proving to be less effective in patients with HIV due to the development of resistance or because of some metabolic process reducing the concentration of the medication in their bodies. Fluoroquinolones have been shown to be effective but seem to be prone to rapid development of resistance and toxicity. The authors report on two new antimycobaterial drugs that have novel mechanisms of action and are in the process of testing.
The complications of treating patients with HIV and TB are many. Most of the symptoms of TB are due to immune response (immunopathological), but the immune systems of HIV patients are already suppressed. The medications to treat TB can further suppress the immune response leading to an increase in viral load and the possibility of more opportunistic infections. In addition, many of these medications have proven to be hepatotoxic, which HIV patients are even less equipped to handle. Complications can also include “paradoxical deterioration” whereby the treatment of HIV results in a worsening of TB symptoms. The important point is that more research is required to understand the immune system functionality in concurrent infections of TB and HIV.
The treatment of latent infections is aimed at preventing these infections from becoming active, particularly in immunocompromised patients. The most common strategy is a 6-12 month course of isoniazid. Although widely used, this treatment carries the same risks of medication resistance and hepatotoxicity as other TB drugs. Additional information on the physiology of latent infections could lead to better drugs and better strategies for treatment.
Vaccination, which is widely available in Europe, but not used in the United States, has shown some efficacy in preventing severe TB infections in children, but the length and strength of protection is in question. Tuberculosis is still transmitted, allowing the continued spread of the bacteria. Novel vaccines are being tested and a few show promise to provide better protection. The authors reiterate the need for large, long term studies.
Sub-Saharan Africa is experiencing an epidemic of HIV-associated tuberculosis. The capacity to manage this epidemic is severely hindered by socioeconomic, medical infrastructure, and political issues. Treating with antiretrovirals has reduced the number of cases of tuberculosis, but HIV patients are still much more likely to develop tuberculosis. The best preventative measure seems to be to reduce the incidence of HIV and the best treatment strategy is to identify and treat active tuberculosis. Treating both HIV and tuberculosis concurrently poses special problems. Many of the drugs have potentially negative interactions, either reducing efficacy or increasing toxicity. In addition, there is the possibility of immune reconstitution inflammatory syndrome. This disorder manifests as a worsening of TB symptoms in a patient that was improving, likely due to an improved immune response resulting from treatment of HIV. In essence, successful treatment of HIV results in an escalation of tuberculosis symptoms. Steroids used to treat the TB have some success, but at the risk of increased complications from HIV. There is a fine line in concurrently treating these diseases and much more to understand about it.
This article serves both as a reminder of the enormity of the problems associated with Mycobacterium tuberculosis and as a call to arms for more research. With a third of the world’s population affected, it is extremely surprising that we don’t have a symbol, a color, a celebrity backed telethon with accompanying song, or a three-day walk to raise awareness and money for research. I suppose part of the problem is that the problem is “over there” and so we in America are less aware. Preventing the spread of the bacteria seems to be the best option for a long term reduction in incidence, and a new vaccine would seem to be the logical next step. In reading the article, it seems the challenges in treating tuberculosis are almost overwhelming. Tuberculosis lives and multiplies in the macrophages of the human immune system, the very cells that would normally play a key role in eradication of a bacterial infection. This uncommon arrangement, in addition to the complexity of the interactions between humans and Mycobacterium tuberculosis, is key to understanding the disease in the hope of finding better solutions. If we could find a way to induce the body’s immune systems to attack the bacteria itself without the formation of tubercles or other negative effects, that would be an ideal solution. If that is not possible, we need to find those mechanisms or characteristics that are unique to the bacterium or its pathogenesis and create a drug to act on those. The challenges are many. The authors repeatedly used the term “political will” and it seems that this may be the key to resolving the problem of tuberculosis. While the article serves the purposes of reminding and rallying, it seems to be written for those already familiar with the disease and is poorly organized. The authors seem to “hopscotch” about with very little in the way of transition, making it difficult for a novice to assimilate the information. It is a good review of the current direction, but without the foundational information required to understand what it means.