The Future of Tuberculosis Control - Essay Example

? Health Sciences and Medicine Topic: Tuberculosis 19th November Background Tuberculosis (TB) is an ancient scourge which has claimed human life throughout history (Daniel, 2006). The infectious disease has been a major public health problem especially in the developing world, killing millions of people annually. The bacterium Mycobacterium tuberculosis is the causative agent of TB in humans. Figure 1: Mycobacterium tuberculosis (also called tubercle bacilli) The World Health Organization (WHO) reports that the bacterium infects a third of the world’s population resulting in about 8 million cases and a mortality of 1.45 million annually (WHO, 2011). The highly virulent bacterium occurs in two forms, an active and a latent form. It has been reported that about a third of the current TB infections are in the latent form (Smith et al., 2003). The latent form of TB is characterized by presence of an infection without victims exhibiting active disease. People with the latent form of this disease usually are at a risk of reactivation especially if their immune system is compromised, such as in HIV/AIDS. In this form, the bacteria exist in the lungs in granulomas. Active TB occurs in several stages, starting from infection to tubercle formation. Active TB can develop in lungs (pulmonary), or it can be extrapulmonary. The most common sign and symptom of the active disease is cough. M. tuberculosis The causative agents of TB are bacteria of the genus Mycobacterium. Several species of this genus are known to cause TB. They are Mycobaterium tuberculosis, M. bovis, M. africanum, M. microti. M. tuberculosis is pathogenic to humans while M. bovis is pathogenic infects animals. Measuring 2-4 ?m in length and 0.2-0.5 ?m in width, these obligate aerobes are non-motile and non-sporulated rods. Mycobacterium is neither Gram negative nor Gram positive. They have the highest lipid content in their walls amongst all bacteria; serving as a carbon and energy reserve. In fact these lipids constitute more than half their dry weight. These lipids give the bacterium a waxy coat which makes them acid-fast, extremely hydrophobic, resistance to antibiotics and protected against the immune system of the host. It appears that the cell wall of these organisms play an important role in the virulence of the disease. The cell wall has three components; mycolic acid, cord factor, and wax-D. Constituting about 50% of the envelope lipid, mycolic acid plays an important role in the virulence and protects the bacterium from free oxygen radicals, lysozyme of the host, cationic proteins, and the complement system aided destruction by the host immune system. Cord factor gives the organism its characteristic serpentine chord like formation and is highly toxic to human cells. Wax-D in the cell envelope is the major component of Freund's complete adjuvant (Schlossberg, 2012). Pathogenesis and Transmission M. tuberculosis gains entry into the body via the alveolar after exposure from aerosol droplet. The virulence of this pathogen is attributed to several structural and physiological properties since they do not produce any toxins. Some general properties that make these organisms highly virulent are listed below: Ability of the pathogens to grow intracellular, rendering them protection against the antibodies, complement system, and lysozyme of the host The ability to bind directly to mannose receptors on the macrophages Ability to detoxify free oxygen radicals produced during their phagocytosis The slow generation time giving them the opportunity to evade immune system The high lipid content in their cell walls protecting them from antibiotics, acids, alkalis, or lytic enzymes (Todar, n.d). The pathogenesis of TB is rather complex and occurs in several stages. TB does not spread by shaking hands, touching, kissing, or sharing foods, drinks, tooth brush etc. The route of entry of the pathogen is through inhalation of small size respiratory droplet nuclei. Upon entry into the respiratory tract, the nuclei pass into the lower respiratory tract escaping nasopharynx and upper respiratory tract anatomical barriers (Schluger and Rom, 1998). Upon entry into the lungs, they are non-specifically phagocytosed by the resident alveolar macrophages. But since the macrophages are not activated at this point of time, they are unable to destroy the intracellular organism. Within 1-3 weeks, the organisms multiply unrestrictedly and cause the macrophages to burst. At this point the peripheral macrophages begin to enter the lungs but they too succumb to death since they are also not activated. Soon, peripheral lymphocytes begin to infiltrate into the lungs and this marks the beginning of the cell mediated immunity (CMI). The antigen presenting cells process and present the mycobacterial antigens to T helper cells. These T cells now become activated and release cytokines including ?-interferon. These cytokines in turn activate more B cells, T cells and macrophages. Macrophages, now being activated, are potent enough to kill the organisms. This vigorous CMI renders the individual positive to tuberculin test and it is this branch of the immune system which helps the individual to control the infection. The high lipid content and other cell wall components prevents the host from eliciting the humoral branch of immunity; the complement factors are unable to bind to the pathogen due to the said components on the pathogen cell wall. (The vigorous CMI poses a severe threat to the patient cause, tumor necrosis factor (TNF), released during the CMI, causes necrosis of the site of infection). Next tubercles begin to develop in the host lungs. The pathogen cannot multiply in the tubercle due to its low pH and anaerobic environment, but does survive in dormant state without any replication and low metabolism. They can survive in this state for long duration of time and develops into latent tuberculosis. A tubercle may invade bronchus and spread the disease to other parts of the lungs, or they may invade an artery or other blood vessel developing into peripheral/extrapulmonary tuberculosis encompassing almost all vital organs, but usually uro-genital system, bones and joints and the peritoneum. In the final stage of the disease, the center of the tubercle liquefies; this liquid is very conducive of mycobacterium growth leading to extracellular multiplication of the pathogen. Within days, due to the large amount of cytokines released due to CMI, necrosis of the lung tissue ensues and makes holes in them. This allows the pathogen to rapidly spread to other parts of the lungs. Untreated at this point, the disease can be fatal (Zuniga et al., 2012). Latent TB means that the person has the TB pathogen in them, but is not yet ill with the disease. They can, however, not transmit the germs to other people. One third of the people on this planet have latent TB (Druszczynska et al., 2012). Such people have 10% chance that they will come down with the disease in their lifetime; and those with compromised immune system have higher chances of getting sick with TB. Latent TB is detected by the skin test and the blood test mentioned below. Its treatment is important to control the global impact of the disease and its total eradication. Although latent TB is asymptomatic, its treatment is necessary. It is usually treated with an antibiotic called isoniazid and rifampicin. On an estimation, an untreated TB patient can infect anywhere from 10-15 people, hence its total eradication should be the priority for today’s health care system around the world. Diagnosis and Treatment There are several diagnostic tests available for TB. Some of them are fast, easy and reliable. Antibiotics, namely pyrazinamide, ethambutol, isoniazid and rifampicin are the remedy for active and latent TB; although cell mediated immunity is the body’s natural defense against TB. This cell-mediated defense however fails in cases where immune system is compromised. Drug resistant strains of the pathogen pose severe threat to TB patients. Risks of the disease include people with HIV/AIDS, citizens of a country where TB is very common, a health care worker, people on immunosuppressant drugs, and people using illegal drugs. Also people working or living in homeless shelters, jails, prisons etc. are also at higher risk. All above mentioned individuals should get checked for TB, the following mentioned test or a combination of several tests can help a doctor to reach to a conclusion on the disease status. The most common is the tuberculin or Mantoux Test: This is a skin test in which a small amount of purified protein derivative (PPD) is injected just under the skin of inner forearm. After 48-72 hours a health care specialist examines the site of injection for hardness, area of redness, bumps etc. A hard, raised red bump means a positive test for tuberculosis. A positive test means that the individual was infected with tuberculosis at some point of time; more tests are done to see if it is latent tuberculosis or the disease itself. But these results are known to be false positive and false negative, depending on age, HIV status, prior Bacillus Calmette-Guerin (BCG) vaccination etc. (CDC, 2011). Blood Test: This test is usually prescribed to individuals who have had prior BCG vaccination. Interferon-gamma release assays or IGRAs are done to see how an individual’s blood reacts to the TB pathogens. A positive test means a person has been infected with M. tuberculosis. A negative test means that latent tuberculosis or the disease is most probably absent. However, Cho et al (2012) warns that indeterminate and false negative results are not uncommon with this type of tests and that caution should be used when interpreting results of elderly, immune-compromised, chronic and severely diseased patients. Chest Radiograph: A radiograph of the chest is done to see any abnormalities in the lungs. Lesions in the chest indicate TB, but it is not a diagnosis of the disease. It can, however, be used to rule out positive skin test or blood test. Microbiology: A sputum smear is done for acid-fast bacilli and observed under a microscope. If the result is positive for acid-fast bacilli, the original sample is cultured on slants specific for M. tuberculosis; this is necessary since some acid-fast bacilli are not M. tuberculosis. A culture positive for M. tuberculosis confirms the diagnosis of TB. At this point drug resistance is also done to identify the most effective antibiotic for that patient (CDC, 2011). When extra-pulmonary TB is suspected, the following tests are prescribed. These include: computerized tomography (CT) Scan/ positron emission tomography (PET) Scan: X-rays taken at different angles are put together by a computer to create a detailed picture of the inner body. PET scans illuminate areas of inflammation using radiolabelled tracers. CT scan and PET scan together give 3-D structure which helps one to directly look at the TB lesions (NHS, 2012). Magnetic radio imaging (MRI): Radiowaves and magnetic fields are used to image inner body parts. Figure 2: X-ray (lungs). PET/CT (lungs) scan and MRI (brain) in TB patients Sources: 1. OxfordImmunotech,http://www.oxfordimmunotec.com/Tuberculosis_International 2. Wellcome Trust, http://wellcometrust.wordpress.com/2009/12/15/feature-cold-war-fighting-the-threat-of-latent-tb/ and 3. Sciencephotolibrary, http://www.sciencephoto.com/media/262893/enlarge Ultrasound imaging, biopsy and lumber puncture are also done in some cases to diagnose the disease. Treatment for TB varies with the type of TB; it is different for pulmonary TB, extrapulmonary, and latent TB. According to NHS (2012), pulmonary TB treatment lasts for 6 months, during which, both the active and the dormant pathogens of TB are killed completely. Two antibiotic, pyrazinamide and ethambutol are prescribed for the first two months along with isoniazid and rifampicin; the latter two are continued for a total of 6 months. They are to be taken every day. A person becomes non-infectious usually after 2 weeks of medication. For TB, it is crucial that the patient take their medication exactly as prescribed and complete the whole course without any miss. This is to prevent the pathogen from becoming resistant to the antibiotics. Extrapulmonary TB treatment last for a year with same combination of antibiotics as mentioned pyrazinamide and ethambutol for the active TB disease. If brain and heart are also affected by TB, then the doctor prescribes a corticosteroid along with the antibiotics. It is usually prednisolone for several weeks. For treatment for latent TB, the doctor prescribes either a combination of rifampicin and isoniazid for three months, or isoniazid alone for six months. For an otherwise healthy non-healthcare worker over the age of 35, latent TB is not treated; this is because the risks of liver damage increases with age over 35 with these antibiotics. However for an individual with HIV, or on chemotherapy, or on immunosuppressant drugs, or for any health care worker, latent TB has to be treated irrespective of age (NHS, 2012). Future perspectives of TB also need consideration. HIV-TB co-infection, multidrug-resistant and extensively-resistant strains of TB pathogens pose severe threat to the population globally. This threat calls for drastic research and development in the field of diagnosis, vaccines and drugs of TB. Today’s diagnosis of TB by the standard skin test have certain drawbacks of insensitivity and non-specificity when it comes to dealing with people with prior immunization with BCG, or immune compromised patients (HIV/AIDS) or for people on chemotherapy (cancer), and presence of environmental mycobacterium. The IGRAs are very expensive and almost non-practical in endemic countries. Hence more research needs to be done to develop more cost effective, practical, sensitive and specific diagnostic markers for TB. The present anti-tuberculosis drug therapy calls for a 4 antibiotics regimen for 2 months followed by 2 antibiotics for the next 4 months, every day. Not all patients follow this protocol strictly, and this leads to development of drug- resistant strains of mycobacterium and makes the treatment more prolonged and drastic. Therefore, more research needs to be done to find new molecules that are equally effective within shorter time duration and are compatible with AIDS drug regimen. In this regards, genomic sequences of more and more strains of the pathogen needs to be determined and find unique genes that are most crucial for their in vivo survival. These genes and their products should be the target of interest. As far as vaccine for TB is concerned, BCG is effective in children, but not so much in adults. Hence BCG vaccine needs to be improved for preventive purposes in adults and to prevent reactivation of latent TB. Development of improved pre-exposure vaccine, novel booster vaccine, creating recombinant-BCG vaccines for long lasting protection or one that induces better protection against disseminated forms of TB or increased protective immunity against TB will be the choice of future vaccine (Borsch and Veronique, 2007). In conclusion, tuberculosis is a preventable and curable disease. TB, the second most killer disease and present in about one third of world’s population, needs to be eradicated, and that too soon. The cost of present 6 months regimen is not adequate to facilitate effective treatment in poor endemic countries. Hence, new cost effective medications are needed to combat current TB situation. HIV-TB co-infection, multidrug-resistant and extensively-resistant strains of TB pathogens pose severe threat to the population globally. Current therapy of six months is the main cause of generation of drug resistant TB pathogens. Hence this duration needs to be shortened by discovering new drugs that cure the disease faster. In addition, research needs to be done to identify optimal therapy for TB in AIDS patients. An alternative to drug therapy should be looked into; one such novel method would be to pursue research to modulate the immune system itself. Although standard diagnostic tools, vaccines and drugs for TB are available, more research needs to be done in these fields to answer the urgency in the endemic countries, where HIV, the number one killer, is already posing a threat. Prophylactic vaccination should be a top agenda in this regards. Screening of the latently infected individuals should be of utmost priority in today’s world to control TB. The future of TB does not look bleak. Drug resistant strains of the pathogen pose severe threat to TB patients. Future research needs to be done to make the diagnostic tests for TB faster, cheaper, sensitive and more specific. Based on the current research, the future of TB looks promising. References Borsch, R.andVeronique, V. (2007). Cutting-edge science and the future of tuberculosis control. Bull of the World Health Organ, 85(5): 410-12. C.D.C. (2011). Diagnosis of Tuberculosis Disease. Retrieved from http://www.cdc.gov/tb/publications/factsheets/testing/diagnosis.htm . Cho, K., Cho, E., Kwon, S., Im, S., Sohn, I., Song, S. and Kim, S. (2012). Factors Associated with Indeterminate and False Negative Results of QuantiFERON-TB Gold In-Tube Test in Active Tuberculosis. TubercRespir Dis, 72(5): 416-425. Daniel, T.M. (2006). The History of Tuberculosis. Respiratory Medicine, 100(11):1862-1870. Druszczynska, M., Kowalewicz-Kulbat, M., Fol, M., Wlodarczyk, M. and Rudnicka, W. (2012). Latent M. tuberculosis infection--pathogenesis, diagnosis, treatment and prevention strategies. Pol J Microbiol, 61(1): 3-10. Mihret, A. (2012). The Role of Dendritic cells in Mycobacterium tuberculosis infection. Virulence, 3(7): 1-6. NHS. (2012). Diagnosing tuberculosis. Retrieved from http://www.nhs.uk/Conditions/Tuberculosis/Pages/Diagnosis.aspx Schlossberg, D . (2012). Tuberculosis. (Ed.). New York, NY: Springer-Verlag, LLC. Schluger, N.W. and Rom WN (1998). The Host Immune Response to Tuberculosis. Am J Respir Crit Care Med, 157: 679-691. Smith, K.C., Armitige, L. and Wanger, A. (2003). A review of tuberculosis: reflections on the past, present and future of a global epidemic disease. Expert Review of Anti-Infective Therapy, l (3): 483-491. Todar, K. (n.d). Mycobacterium tuberculosis and Tuberculosis.Retrieved from http:// textbookofbacteriology.net/tuberculosis.html. WHO (2011). Global tuberculosis control. WHO report 2011. Geneva, World Health Organization, 2011. Zuniga, J., Torres-Garcia, D., Santos-Mendoza, T., Rodriguez-Reyna, T., Granados, J. and Yunis, E. (2012). Cellular and humoral mechanisms involved in the control of tuberculosis. 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