Tuberculosis: A Global Epidemic |
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Abstract: |
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Tuberculosis (TB) is a disease caused by the bacteria Mycobacterium tuberculosis. The bacteria are spread from person-to-person through airborne droplets when a person infected with TB talks, coughs or sneezes. A person infected with M. tuberculosis may either develop active or latent forms of TB depending on their body’s response. Those with latent TB are asymptomatic and are not contagious. If the infection progresses to the active stage, the person can spread the infection to others and treatment is required. Without treatment, over half of the people with active TB will die. The World Health Organization has declared tuberculosis a global health emergency and states that it is one of the world’s leading infectious killers. |
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Mycobacterium tuberculosis |
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Pathogenesis: |
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The cause of tuberculosis was first discovered by Robert Koch, a German physician and scientist. Koch won the Nobel Prize in Physiology and Medicine for his work in proving that TB was caused by the bacterium Mycobacterium tuberculosis. M. tuberculosis is a non-motile rod-shaped bacterium. It is an obligate aerobe and so it is typically found in the well-aerated upper lobes of the human lungs. The bacterium lacks an outer cell membrane and contains peptidoglycan in its cell wall, but is not characteristically gram-positive. Instead, M. tuberculosis is classified as an acid-fast bacterium (AFB), and only retains certain stains after being treated with acidic solution. |
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The bacterium is a facultative intracellular parasite, growing in phagocytic cells such as macrophages. It has a generation time of 15-20 hours, which is slow compared to other bacteria that can have generation times as fast as a few minutes. Its resistance to some staining reagents and ability to replicate within phagocytic cells is due to the high-lipid content of its cell wall. The bacteria are spread from person-to-person when an infected individual causes the bacteria to become airborne in droplets whenever they cough, sneeze, or talk. Repeated or prolonged exposure is typically required before an individual becomes infected, but a single cough can generate 3000 infective droplets and fewer than 10 mycobacterial bacilli may initiate a pulmonary infection (Sherris, 1990) |
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Culture of M. tuberculosis |
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Latent TB vs. Active TB: |
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Inoculation with the bacteria that cause TB results in either a latent infection or the active disease. Infection occurs when the bacteria reach the pulmonary alveoli and are taken up by inactivated alveolar macrophages. Because of the high-lipid content of their cell walls, the bacteria survive inside the macrophage and begin to replicate. The body’s immune response to the infection eventually results in the formation of a tubercle; an area of necrotic lung tissue surrounded by a layer of macrophages and other cells. Eventually, the outside of the tubercle calcifies, with the interior tissue exhibiting a “cheese-like” structure. At this point, the infection is contained and the bacteria are either killed by activated macrophages or remain dormant. A person is said to have latent TB at this stage and will test positive for TB but will be asymptomatic and is not contagious. If the immune response is inadequate, the bacteria can breakout of the tubercle and spread. A person with this form of active TB exhibits the following symptoms and is contagious. |
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A person with active TB must receive medical attention. Left unattended, over 50% of individuals with active TB will die. |
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Diagnosis: |
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Diagnosis of TB infection is done using the Ziehl-Neelsen method for acid-fast staining to detect the bacterium in the sputum of an infected individual. |
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The Mantoux skin test is also employed to detect TB infection. An individual is injected with tuberculin, a purified protein derivative (PPD), under the skin on the inside of the forearm. After 48-72 hours, the skin is checked at the site of injection for redness, swelling, and the area of induration is measured. If the area of induration is 10mm in diameter or greater, the test is considered positive. |
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Acid-fast staining of M. tuberculosis in sputum |
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Treatment: |
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The current treatment for active TB is the four frontline anti-tuberculosis drugs: isoniazid, rifampin, ethambutol, and pyrazinamide. These are required daily for a period of 6-12 months depending on the individual and severity of the infection. If diagnosed with latent TB, a course of isoniazid daily for 6-12 months may be given to prevent the disease from turning into the active form. |
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Unfortunately, non-compliance with the strict regimen for TB treatment as led to new strains that are resistant to the four frontline drugs. New second-line anti-tuberculosis drugs have been developed to combat the “multi-drug resistant tuberculosis” strains (MDR-TB), but continued non-compliance has led to even more virulent strains that are now labeled as “extensively drug-resistant tuberculosis” (XDR-TB). Many of the second-line drugs developed to combat MDR-TB are used for XDR-TB, with the exception that XDR-TB is resistant to three or more of the six classed of second-line drugs. |
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In some countries the Bacille Calmette-Guérin (BCG), TB vaccine is given to children. The vaccine is stated to be 80% effective for a period up to 15 years but has been shown to have variable efficacy in clinical trials. In the U.S. the BCG vaccine in not generally given due to a low incidence of TB and the desire to have more accurate Mantoux test results. Individuals given the BCG vaccine often present with a false positive on the TB skin test. |
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TB Globally: |
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Tuberculosis is a global epidemic with all the major regions of the world affected. The WHO estimates that the largest number of new TB cases occur in the South-East Asia region. This area accounts for 33% of the TB cases globally. However, the estimated incidence per capita in sub-Saharan Africa is nearly twice that of the South-East Asia Region, at nearly 400 cases per 100 000 population. |
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Scope of the Problem: |
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It is estimated about one-third of the human population is infected with active or latent TB, with one new infection occurring every second. Approximately 5-10% of people infected with M. tuberculosis will become sick or infectious at some point in their life. Each year, nearly 1.6 million people die from tuberculosis. Both the highest number of deaths and the highest mortality per capita are in the WHO Africa region, where HIV has led to rapid growth of the TB epidemic, and increases the likelihood of dying from TB. In the U.S. in 2004, the national active TB case rate was 4.9 cases per 100,000 persons, representing 14,511 reported cases, a decline of 3% from 2003. The majority of cases reported (60%) came from 7 states: California, Florida, Illinois, New York, New Jersey, Georgia, and Texas. In 1997, the CDC estimated that 1 in 17 persons has latent infection. |
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The Future: |
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Tuberculosis is being fueled by the spread of HIV, poverty and a lack of health services, and the emergence of drug-resistant strains. To combat the disease, not only will new anti-tuberculosis drugs be required, but also compliance with existing treatments enforced. The WHO’s program of Directly Observed Therapy, Short-course (DOTS), is achieving success but in rural and impoverished areas, non-compliance is still an issue. Where HIV infections are on the rise, TB infections are increasing as well. The WHO reports that TB is a leading cause of death among people who are HIV-positive, and it accounts for about 13% of AIDS deaths worldwide. As progress is made in controlling HIV in areas with high rates of infection, the incidents of TB deaths will stabilize as well. |
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Interview with an Expert: |
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Dr. Peter J. King is a professor of Biology in the School of Natural Sciences at St. Edward’s University. While an Assistant Professor in the Department of Biology at Stephen F. Austin State University, Dr. King worked on determining if M. tuberculosis alpha-crystallin protein may be useful for determining if individuals with a positive TB skin test harbor latent infections. His paper, “Alpha-Crystallin as a Potential Marker of Mycobacterium tuberculosis Latency”, details his work. |
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It seems the current acid-fast staining and skin test methods for detection of TB are unreliable and inadequate, and to get accurate results the bacteria need to be cultured, which is time consuming and requires additional laboratory equipment. This is correct. The biggest problem with culture and AF stain is that it requires active, productive infection to detect the bugs. The problem with skin test and radiologic assays (mainly chest X-ray detection of granulomas) is that they do not differentiate between previous exposure that has been cleared and latent or active infection. In developing countries (and even Europe until recently) MTB vaccination is routinely performed at birth to prevent meningeal TB (fatal). The vaccine doesn't work against lung TB but it saves lives. Unfortunately then you always appear TB-positive by tuberculin (skin) test. So you'd like to have a marker that is specific for latent TB infections. I read the paper you wrote on using Alpha-Crystallin as a marker for latent TB. Can this information be used to create better detection methods for not just latent TB but active TB as well? Are there other tests being developed that will be more accurate and can be administered rapidly in the field? Not sure that there need to be better detection methods for active TB. People with active TB have radiologic findings that are obvious and you can culture AF bugs from sputum. In the developing world, you just assume anyone with pulmonary problems has TB as 1 in 2 or 1 in 3 are latently infected. As far as field tests, there are companies working on that. Problem is Acr is probably produced in very small amounts so it may be difficult to detect from human samples even with complicated lab tests available (like Western blot, flow cytometry, etc). The treatment of TB requires taking a combination of the four frontline antibiotics (isoniazid, ethambutol, rifampin, and pyrazinamide), daily for a period of at least six months. Because non-compliance is an issue due to the current rigorous treatment method, which has now lead to the spread of MDR-TB and XDR-TB, what new treatment methods are being developed? Are new antituberculosis drugs in development that require fewer medications for a shorter period of time? I think the problem with non-compliance is obvious. Short-course Abx select for resistant bugs that then can be transmitted. I'm not sure about new TB Abx, I'm sure someone is working on them. My thought is that they're probably working on combination pills (ala HIV) that would make compliance easier. I know a big push is to develop programs that ensure compliance. In some countries they force you to comply by closely monitoring patients and making hem come in to take the Abx, but that is more difficult (if not impossible) in rural settings where people have to walk miles to go get treated. Unfortunately, what you really need is a vaccine for TB. |
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Links: |
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Discuss this topic on Blackboard |
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World TB Day - March24, 2007 |
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