Tuberculosis in Zambia

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Introduction

Tuberculosis is a highly contagious disease caused by the infection of the bacteria Mycobacterium Tuberculosis. This disease has plagued the lives of people for centuries, and is continuing to thrive in even more aggressive forms (10). The World Health Organization states that this deadly disease affects more people in South-East Asia, the Eastern Mediterranean, and African regions than other places around the world. Time Magazine states that 9.2 million more people were diagnosed with tuberculosis, mostly from developing countries and 1.7 million died from the disease (10). This discussion will focus on the tiny microbe, Mycobacterium Tuberculosis, and its damaging effects on the people of Zambia, Africa. (13)

Description of the Microbe

Mycobacterium tuberculosis
Mycobacterium tuberculosis. Image from http://www.microbiologybytes.com

Description and Genome Structure

Mycobacterium tuberculosis is a genus of Actinomycetes. It is a Gram-positive, acid-fast, rod-shaped aerobic bacterium. (4) The genome of M. Tuberculosis is 4,411,529 base pairs and contains around 4000 genes. The high guanine and cytosine concentration is reflective of the biased amino-acid content of the proteins. A large portion of M. Tuberculosis capacity to code is to produce enzymes involved in lipogenesis and lipolysis that ultimately help develop mycolic acids. (5)

Cell Structure

M. Tuberculosis has a specialized cell envelope resembling a modified Gram positive cell wall and characterized by a thick cell wall, multiple layers of peptidoglycan, and free lipids (3). The peptidoglycan is linked to chains of galactose, which are called galactans. These are galactans are attached to sugar polymers called arabinans, and thus form an arabinogalactan complex. The ends of these arabinans form ester linkages with mycolic acids, a unique feature to several groups of mycobacteria, including M. Tuberculosis (4).

Mycolic Acids and Impermeability

Mycolic acids are the major component of M. tuberculosis cell walls. M. tuberculosis has mycolic acids that are extremely diverse and have some of the longest-chain acids known, some up to 90 carbons. Mycolic acids are made up of a hydroxy acid backbone with 2 hydrocarbon chains—one of the chains being about 20 carbons in length and the other around three-folds longer. The long chain is composed of ketones, methoxyl groups, and cyclopropane rings. The mycolic acids help generate a thick waxy surface, prevents phagocytosis by macrophages. It also prevents antibiotics from penetrating the cell wall and offers protection from host defenses so that the M. tuberculosis can colonize its host over a longer period of time (4). M. tuberculosis is multi-drug resistant, due to its highly hydrophobic cell envelope that acts as a permeability barrier (3). It is this property of M. tuberculosis that makes it difficult to cure tuberculosis immediately.

Nutrient Uptake and Growth Rate

M. tuberculosis is characterized by slow growth rate, which is the result of the impermeable cell wall that resists nutrients from passing through the cell and prevents waste products to be excreted out of the cell directly. Hydrophilic solutes thus pass though the cell membrane through porins located on the outer lipid layers. The identity of the specific transporters and types of porins used to pass these nutrients are still being researched (5).

Morphology and Dormancy During its Pathogenic Stage

M. Tuberculosis is typically found to live in a human host for decades at a time. Once inside the host, this mycobacterium encounters a nutrient and oxygen deprived environment, along with stresses from the host’s immune responses. Researchers found that during these situations, the cell walls of the M. Tuberculosis thickened and it has an altered morphology, with the help of hydrolytic enzymes.. Also, after completing chromosomal replication, it will halt its growth. This lack of growth may allow the M. Tuberculosis adjust and survive against the host’s inflammatory responses as well (5).

Description of the Disease

Pathogenesis and Symptoms of Tuberculosis

The tuberculosis (TB) disease is caused by an advanced infection of the Mycobacterium tuberculosis bacteria. The majority of people who are infected do not develop the active TB disease, and are host to a latent tuberculosis infection. Although M. tuberculosis can also infect other parts of the body, such as the brain, kidneys, and spine, the worldwide epidemic of this bacteria reflects its most common infection site, the lungs (14). When the tuberculosis bacteria infects the lungs, it damages the pulmonary tissue by creating nodules, small aggregates of abnormal cells. This tissue damage results in the classic symptoms of pulmonary tuberculosis, which include a chronic cough (often with blood), chest pain, weakness, fever, and dramatic weight loss (14). Active TB infections are extremely contagious; the bacteria can be transferred to the air by coughing or speaking (15). On the other hand, latent TB infections are completely asymptomatic; they can only be identified through an antibody test (14). In latent TB infections, the bacteria is dormant and the disease is not contagious.

Prevention and Treatment

A range of different antibiotics exist for use against Mycobacterium tuberculosis. In latent infections, the most common drug used is isoniazid, which inhibits bacterial fatty acid biosynthesis. This prevent the bacteria from producing the mycolic acids required for its cell walls, which renders it unable to grow or divide (6). In active TB disease, isoniazid is used in conjunction with several other antibiotics to minimize the chance of developing drug-resistant strains of the bacteria. Other common antibiotics are Ethambutol, which stops cell wall biosynthesis, and Rifampin, which inhibits bacterial RNA polymerase (4).

The most common preventative treatment is the BCG vaccine. Use of the vaccine is uncommon in developed countries, but often distributed to babies is countries where the epidemic is prevalent, including Zambia (12). Unfortunately, the vaccine only proves to be about 50% effective, and is prohibitively expensive in some locations; companies are currently working on solutions to develop a more effective vaccine (4).

Current State of the Global Epidemic

Tuberculosis is one of the world's oldest known infectious diseases, with evidence for its existence dating back to ancient Egypt (10). Since then, it has continued to have a strong presence worldwide. According to the World Health Organization, global regions where a tuberculosis epidemic are currently most prevalent are eastern Europe, sub-Saharan Africa, and especially southeast Asia, which accounts for 34% of all new reported cases (13). The greatest proportion of deaths from TB occur in the African region, but the incedence of new cases there has begun to stabilize (13). Of African countries, Zambia has the sixth highest incedence (15). Although a gradual decline of per capita incedence exists, the overall global incedence rate of new tuberculosis cases continues to rise due to population growth (13).

Why is this disease a problem in Zambia

Rural health clinic in Livingstone, Zambia. Image by Christopher C. Jensen

After HIV/AIDS, Tuberculosis is the second most common cause of death from infectious disease. Tuberculosis (TB) infection is common in Zambia. Zambia, along with other countries in sub-Saharan Africa, has one of the highest rates of TB infection and is showing an increase in infection rate. During 1984-2005 the rate of infection increased from 100 reports of infection per 100,000 people to 580 reports of infection out of 100,000 people (8).

This increase is in part due to co infection with HIV. Zambia has the 10th highest co-infection rate in Africa with about 50%-70% of TB patients infected with HIV (15). Co-infection with HIV and TB is now a major public health problem for children in Zambia (1). Those who are co-infected are at an increased risk of morbidity and mortality (7). Because HIV weakens the immune system, people with HIV infection are more susceptible to TB infection. Also due to a diminished immune response, those who are co-infected with HIV and TB often don’t present the recognizable symptoms of TB, including coughing and visible legions of chest X-rays. The lack of immune response also makes mycobacterium difficult to detect using blood-based assays (10).

Interactions between tuberculosis and HIV are an insidious problem, not only because there is considerable geographic overlap between the two epidemics, but also because the compromised immune system resulting from HIV makes tuberculosis infection even more likely (13). In hosts that are infected with both TB and HIV, the problem is further complicated by interactions between the treatments for the two diseases. Antiretroviral therapy given for HIV decreases the effectiveness of rifampin (11). This problem could not only speed the progesss of the tuberculosis infection, but also facilitate development of drug-resistant strains. Additionally, the BCG vaccine, when distributed to HIV positive babies, makes them three times more likely to contract tuberculosis. Infants in developing countries are only routinely tested for HIV after 6 weeks of age; unfortunately, postponing BCG vaccination until this age for all children would increase TB infection overall (12).

There are better tests that allow for faster screening of drug resistant TB in the blood but it requires the use of laboratories, machines, and technicians that are not easily attainable by many developing nations including Zambia. Because of these limitations, TB can go undetected and untreated. Many who live in the more rural areas of Zambia don’t have access to health services which allow the disease to go further undetected and untreated (10).

What is being done to address this problem

Because the immune-suppressed HIV infected persons are highly susceptible to TB disease, the premise behind the strategy to address the problem of TB in Zambia is that by identifying TB patients with HIV infection, the people can be treated and cared for sooner in order to improve their prospects for survival.

Since the majority of TB patients in Zambia are co-infected with HIV, they are in danger of developing drug-resistant forms of TB. Another problem is that many AIDS drugs interfere with rifampin and other TB treatment drugs by reducing their effectiveness. With that said, the strategy behind treating these patients is to avoid interactions of the HIV drugs and TB drugs. This includes advising the patients to stop taking antiretroviral HIV drugs while they continue TB therapy with rifampin. Another solution is to substitute the components in TB drugs that can interact with HIV drugs with other components.

Treating Tuberculosis itself involves treating either latent TB or active TB. Latent TB is treated with preventive drug therapy with drugs such as Isoniazid for up to 9 months to destroy bacteria that may become active in the future. Active TB is treated with more medications concurrently including isoniazid, rifampin, ethambutol, and pyrazinamide. Depending on the progression of the disease, one or two of these drugs can be discontinued after treatment has begun lasted a couple months.

The other main obstacle of dealing with the TB epidemic is that HIV testing and counseling for TB patients in countries with high rates of TB and HIV can be extremely challenging because there is not enough clinical staff (8).

The original model of HIV testing was using the VTC model, which limited the number of TB patients who could be offered testing due to the lack of trained counselors and the long duration of the pretest counseling sessions.

The VCT model used an “opt-in” approach in which patients seek HIV testing and must consent to be tested. VCT requires pretest counseling sessions which last for 45 minutes. The new model called PITC is offered by health-care providers as part of routine clinical care with brief pretest counseling of less than 15 minutes. The consent to be tested is already implied with this strategy. The main difference is that VCT is client initiated while PITC is health-care provider initiated as part of routine clinical care.

Although the VCT model provided transportation allowances to part-time counselors so that VCT could be provided on-site in the two main urban clinics of Zambia, it was not sustainable. The assignment of full-time VCT counselors to TB clinics was also unsustainable. The PITC was a reasonable solution because it trained the TB clinic staff to provide this counseling.

In addition, PITC trained TB staff members to use HIV rapid test kits which allowed for same-day results. This was a breakthrough because it eliminated the need for patients to return to the clinic to pick up their results another day, which was not available with the VTC model.

Another great change made was that PITC shifted the task of HIV testing from laboratorians to health-care personnel. This eliminated the problem of a shortage of trained laboratory workers.

Since 2007, the Zambia Ministry of Health has recommended that all TB clinic staff members be trained in PITC and that these services be used in TB clinics throughout the country. A national TB/HIV coordinating committee developed specific guidelines and produced a training manual for PITC.

Although PITC patients can be tested much more efficiently with the PITC model, what remains a problem is the follow-up of patients with ART clinics. There is a shortage of staff at TB and ART clinics and referral forms are often never completed and returned to referring units. The future solution to this problem is the use of individual-level electronic medical records which will provide a better means of ensuring that data on HIV and TB care are shared with providers of TB and HIV services.

Concluding Thoughts

Home-based care is currently low in Zambia and other African countries. Having increased government support of home based care in Zambia could help in treatment of TB by teaching communities how to deal with the disease. This could be especially helpful to those living in the more rural areas of Zambia where treatment is less accessible (9).

Increased funding of research and diagnostic laboratories could help reduce the problem of TB infection. Diagnostics are critical to controlling the spread of an extremely contagious airborne disease.Studies have shown that a six month treatment of isoniazed (taken twice weekly) or a three month treatment of a combination of rifampicin and pyrazinamide (taken twice weekly) has proven effective in the prevention of TB in those infected with HIV (8). By funding and supplying this treatment to Zambia and other countries the rate of TB infection could possibly be decreased. The number of research facilities trained counselors has been low in Zambia (7). An increase of outside funding could help in the development of research facilities and clinics and the training of more TB counselors. Having supervised treatment could help in the distribution of drugs at the workplace or in the community, so that the entire course of medication is taken. This could result in more people being treated for the disease.

The use of individual-level electronic medical records which will provide a better means of ensuring that data on HIV and TB care are shared with providers of TB and HIV services. The current existing TB and HIV drugs interact with each other, thereby reducing the effectiveness of both. Therefore, what can be done is creating new TB and HIV drugs which contain compounds that do not interact with each other.

Overall, Tuberculosis is a thriving disease and still difficult to treat, but continual research and global education about this disease can help spur prevention and treatment.

References

1. Chintu, Chifumbe, Ganapati Bhat, Chewe Luo, Mario Raviglione, Vinod Diwan, Herbert L. Dupont, and Alimuddin Zumla. "Seroprevalence of human immunodeficiency virus type 1 infection in Zambian children with tuberculosis." Pediactric Infectious Disease Journal 12.6 (1993). Lippincourt, Williams, and Wilkins. June 1993. Web. 26 Aug. 2009.

2. Cohen, Jon. “GLOBAL HEALTH: The New World of Global Health.” Science 13 January 2006: Vol. 311. no. 5758, pp. 162-167 DOI: 10.1126/science.311.5758.162

3. Cole, S.T., et al. “Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence.” Nature: Vol. 393, 537-544.

4. Foster, John W. and Slonczewski, Joan L. Microbiology: An Evolving Science. W.W. Norton & Company, Inc: 2009. p. 92, 268, 700-702.

5. Hett, Erik C. and Rubin, Eric J. “Bacterial Growth and Cell Division: a Mycobacterial Perspective.” American Society for Microbiology. p. 126-156, Vol. 72, No. 1, doi:10.1128/MMBR.00028-07

6. Timmins, Graham S., Sharon Master, Frank Rusnak, and Vojo Deretic. "Nitric Oxide Generated from Isoniazid Activation by KatG: Source of Nitric Oxide and Activity against Mycobacterium tuberculosis." Antimicrobial Agents and Chemotherapy 48.8 (2004). PubMed Central. American Society for Microbiology, 2 Apr. 2004. Web. 23 Aug. 2009.

7. Mwinga, A. "Provider-Initiated HIV Testing and Counseling of TB Patients --- Livingstone District, Zambia, September 2004--December 2006." CDC. 21 Mar. 2008. Web. 26 Aug. 2009.

8. Mwinga, A., M. Hosp, P. Godfrey-Faussett, M. Quigley, P. Mwaba, B. N. Mugala, O. Nyirenda, N. Luo, J. Pobee, A. M. Elliot, K. P.J.W McAdam, and J. D.H. Porter. "Twice weekly tuberculosis preventive therapy in HIV infection in Zambia." AIDS 12.18 (1998): 2447-457. Lippincourt, Williams, and Wilkins. 24 Dec. 1998. Web. 26 Aug. 2009.

9. Nsutebu, Emmanuel F. "Scaling-up HIV/AIDS and TB home-based care: lessons from Zambia." Oxford Journals 16.3 (2001): 240-47. Health Policy and Planning. Oxford University Press, 2001. Web. 22 Aug. 2009.

10. Park, Alice. "Tuberculosis: An Ancient Disease Continues to Thrive." Time. Time Inc., 2 Oct. 2008. Web. 22 Aug. 2009.

11. Treatments and Drugs. Mayo Clinic, 28 Jan. 2009. Web. 21 Aug. 2009.

12. TB Vaccine may be Dangerous to HIV Positive Babies.)

13. Tuberculosis. World Health Organization, 2009. Web. 22 Aug. 2009.

14. Tuberculosis (TB). Centers for Disease Control and Prevention, 1 June 2009. Web. 22 Aug. 2009.

15. "Zambia." Infectious Diseases. U.S. Agency for International Development, 2 June 2009. Web. 22 Aug. 2009.


Edited by Zachary Stevens, Steve Loh, Mary Parsons, Leslie Shing, students of Rachel Larsen