Introduction
Tuberculosis (TB) is an airborne contagious disease that is caused by the bacteria Mycobacterium tuberculosis, also called tubercle bacillus. TB spreads by the inhalation of the bacilli that is released into the air through cough, sneeze, or exhalation of an infected person. It can either occur as a short-term (acute) or long-term (chronic) illness. [1] Once the bacilli are in the lungs, they penetrate into the terminal alveoli where they multiply and spread to the lymph nodes and potentially to other areas of the body. At approximately 6 weeks after the initial infection, an immune response (hypersensitivity) to the tubercle bacilli is developed. In most cases, this hypersensitivity prevents any further multiplication of the infection and the only sign of TB is a positive tuberculin skin test. If the infection “resolves” some tubercle bacilli can lie dormant in the scar tissue and become active years later. In 1882, Robert Koch first described tubercle bacillus and Ziehl and Neelsen developed the acid-fast-bacillus smear that effectively diagnosed TB. [2]
Although TB primarily affects the lungs (pulmonary tuberculosis), it also affect other areas of the body (extrapulmonary tuberculosis). Only individuals with pulmonary TB are infectious. Pulmonary TB consists of approximately 85% of new cases. Approximately 15% of new TB cases are extrapulmonary TB, a high percentage of which are individuals infected with human immunodeficiency virus (HIV). The bones (especially the spine) and the kidneys are the most common areas infected with extrapulmonary TB. Other areas of the body often infected with extrapulmonary TB include female reproductive organs, abdominal cavity (TB peritonitis), joints, skin, adrenal glands and blood vessels. Tuberculosis pericarditis occurs when the heart’s ability to pump blood is compromised by the buildup of fluid in the pericardium. Miliary tuberculosis is a “life-threatening condition” that occurs when a large quantity of tubercle bacilli spread throughout the body and develops into tubercular lesions that cause significant “weight loss, severe anemia, and gradual wasting of the body.” Another serious and life-threatening condition resulting from TB infection is TB meningitis. TB meningitis occurs when the M. tuberculosis bacteria invade the membranes and fluid surrounding the brain and spinal cord. As for children, because of their underdeveloped immune systems, children less than 5 years old are at a higher risk of developing TB after infection, particularly the serious forms, such as miliary TB and TB meningitis. Children aged between 5 to 15 years are typically resistant to TB infection. Risk of developing TB increases with adolescence, stabilizes during adulthood, and rises again in the elderly. Risk factors, other than age, include malnutrition; alcohol; immunosuppressive drugs; tobacco smoking; air pollution; and diseases, including diabetes mellitus, silicosis, and HIV. [2] Tuberculosis is the leading cause of death in people who have HIV. HIV severely weakens the immune system and individuals infected with HIV are 20 times more likely to develop TB than those individuals who are not infected with HIV living in HIV-endemic countries, and 26 to 37 times more likely to develop TB in countries with a low prevalence of HIV. The number of HIV-TB cases and deaths are thought to have peaked in 2005 with 1.39 million cases and 480,000 deaths. [3]
Drug-resistant TB is caused by inconsistent treatment. This inconsistency results from patients not following treatment guidelines, wrong medications being prescribed or an unreliable drug supply. Multidrug-resistant TB (MDR-TB) is a “dangerous” form of drug-resistant TB and is defined as the resistance to at least isoniazid and rifampicin, the two most effective anti-TB medications. [4] Drug-resistant TB in the Russian Federation is graver than in other areas of the world. For example, in the Russian Federation an estimated 50% of MDR-TB cases are resistant to the four “first-line” drugs compared with the 12% in the rest of the world. Drug-resistant TB is treatable, but it consists of extensive chemotherapy with “second-line” anti-TB medications that cost significantly more and have more severe adverse reactions than first-line drugs. [5] Extensively drug-resistant TB (XDR-TB) is a form of TB that is resistant to the most effective anti-TB drugs and is caused by the poor management of MDR-TB. XDR-TB can be transmitted from person to person and is causing serious difficulties in global TB control, especially in areas where infection with HIV is prevalent.
During the 19th and 20th centuries, TB was the leading cause of death in many parts of the world, including the United States and Europe. Effective treatment of TB began with the discovery of the anti-TB drugs streptomycin (1943) and isoniazid (1952), and the introduction of the drug rifampicin (1965) led to the concept of combination chemotherapy. TB-control programs that focused on mass case reporting and case management were utilized in industrialized countries between 1950 and 1965, which led to a discernible decline in TB incidence rates. TB was considered a “conquered disease” and interest in the disease waned. However, the mass TB-control program was not implemented in the developing world and TB incidence rates increased. During the 1980s in sub-Saharan Africa, this increase was due to the rise of the HIV/AIDS epidemic and the neglect of TB control. TB incidence rates increased dramatically in the former Soviet Union after its dissolution because of the socioeconomic crisis that ensued, including the collapse of their health care system. That region of the world continues to experience high TB incidence rates. The “global incidence of TB” was approximately 8 million new cases in 1990. The increasing TB problem experienced worldwide led to the World Health Organization’s 1993 declaration that TB was a “global emergency.” [2] Direct observed treatment, short course (DOTS) is the global tuberculosis control strategy launched by the WHO in 1995. [6] The five basic components to the DOTS strategy include: [7]
- Political commitment including increased and sustained financing
- Case detection utilizing quality assured bacteriology
- Standardized treatment that includes patient supervision and support
- Effective drug supply and management system
- Monitoring and evaluation system, including impact measurement
The Stop TB Partnership, formerly the Stop TB Initiative, was established in 1998 and includes more than 1000 organizations, countries, and individuals committed to the ultimate goal of eliminating tuberculosis worldwide. The Stop TB Partnership has a Coordinating Board and seven “working groups” including DOTS expansion, Global Laboratory Initiative, MDR-TB, TB/HIV, New Drugs, New Diagnostics, and New Vaccines. The World Health Organization (WHO) is a leading agency in and the housing institution of the Stop TB Partnership. [3][8] The Stop TB Partnership has six main components:
- Pursue high-quality DOTS expansion and enhancement
- Address TB/HIV, MDR-TB, and other challenges
- Contribute to health system strengthening
- Engage all care providers
- Empower people with TB and their communities
- Enable and promote research [9]
The major targets for worldwide TB control put forth by the WHO are
- Incidence of TB should be falling by 2015.
- TB prevalence and death rates should be half of the 1990 levels by 2015. [3]
- At least 70% of incident smear-positive cases should be detected and treated in DOTS programs.
- At least 85% of incident smear-positive cases should be successfully treated.
According to the World Health Organization’s 2009 Global Tuberculosis Control Report, the TB incidence rate has been falling since 2004, prevalence and death rates will be halved by 2015 in at least three of the six WHO regions, the case detection rate was 63% in 2007, and the treatment success rate was 85% in 2006. Three regions met the treatment success target, Eastern Mediterranean (86%), Western Pacific (92%) and Southeast Asia (87%), as well as 59 countries. Treatment success rates in the African and Americas regions were 75% and 70% in the European region. [3]
Statistic
- More than 2 billion people, one third of the world’s population, are infected with TB.
- Tuberculosis is a “disease of poverty” with most TB deaths occurring in the developing regions of the world, and more than half of all deaths occurring in Asia. The majority of the TB cases in 2007 were in Asia (55%) and Africa (31%). Smaller percentages were found in the Eastern Mediterranean region (6%), European region (5%), and the Americas (3%).
- There were 9.27 million new cases of TB in 2007; 1.37 million were coinfected with HIV.
- The top five countries in terms of total number of TB cases in 2007 are India (2.0 million), China (1.3 million), Indonesia (0.53 million), Nigeria (0.46 million), and South Africa (0.46 million).
- 1.77 million people died from TB in 2007 (4500 deaths per day), where 456000 of those were individuals co-infected with HIV.
- 5% of all TB cases have MDR-TB.
- In 2007 there were approximately 0.5 million cases of MDR-TB and 27 countries make up 85% of those cases. The top five countries with the most cases of MDR-TB are India (131,000), China (112,000), the Russian Federation (43,000), South Africa (16,000), and Bangladesh (15,000).
- In 2007, there were approximately 13.7 million prevalent cases of TB, which is a decrease from 13.9 million cases in 2006.
- Approximately 5% to 10% of individuals infected with M. tuberculosis will develop symptomatic TB at some point in their lifetime; the first 5 years of infection poses the greatest risk.
- Approximately two thirds of untreated individuals with TB will die within 5 to 8 years, with most deaths occurring within 18 months of symptom onset.
- XDR-TB cases have been found in 54 countries, including all WHO regions. [2][3]
Signs and Symptoms
The following list does not insure the presence of this health condition. Please see the text and your healthcare professional for more information.
Symptoms of pulmonary tuberculosis include a cough that may or may not be productive at the onset. The sputum will eventually include streaks of blood. The cough may last from weeks to months and can include chest pain and shortness of breath. Low-grade fever, night sweats, decreased appetite, and weight loss are common. Difficulty in breathing may result from pneumothorax and pleural effusion. Infection of the lymph nodes, including pus discharge, may occur if the TB bacilli spread from the lungs to the lymph nodes in the neck.
Symptoms of extrapulmonary tuberculosis vary depending on the type of infection. TB meningitis symptoms include headaches and drowsiness, which eventually results in a comatose state. If treatment is delayed, permanent brain damage can occur. TB peritonitis symptoms include a wide range of abdominal pain from cramps to intense pain similar to that experienced with appendicitis. TB infection of the joints results in a type of arthritis that commonly affects the hips and knees. TB of the kidneys may have little or no symptoms. [1]
Treatment Options
Conventional
The most common anti-TB medicines include isoniazid, rifampicin, pyrazinamide, and ethambutol. [10] The recommended treatment for TB is outlined in the DOTS strategy. For individuals whose sputum is smear positive, the DOTS guidelines recommend a short-course regimen that begins with an “intensive phase” of four drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol) for 2 months, then a “continuous phase” of rifampicin and isoniazid for 4 months. This regimen is conducted under direct observation to ensure proper compliance. If direct observation throughout the whole treatment is not possible, then the continuous phase should be 6 months. However, treatment is less effective without direct observation because of the high tendency of relapse. Medications for both treatment phases can be given daily or three times weekly. [6]
Nutritional Supplementation
The nutritional status of populations living in areas where tuberculosis is prevalent is compromised, weakening the immune system and increasing incident of the disease. While the manner in which malnutrition directly affects the immune response in pulmonary tuberculosis patients remains unclear in regards to which factors of the many are directly responsible for the down-regulation of the immune response, studies concur that poor nutrient intake slows recovery and increases morbidity and mortality. [11][12] This is further complicated in cases where HIV is also present. [13]
Vitamin A
Vitamin A was the first fat-soluble vitamin to be isolated. It was discovered in 1913 as a result of its ability to prevent night blindness and xerophthalmia (a drying and hardening of the mucous membrane that lines the eyelids). In 1932, beta-carotene (pro-vitamin A) was discovered to be the precursor to vitamin A and it is sometimes referred to as provitamin A. Vitamin A belongs to a class of compounds called retinoids, which only occur in animal products. Retinoids with vitamin A activity occur in nature in three different forms: a) the alcohol, retinol, b) the aldehyde, retinal or retinaldehyde, and c) the acid, retinoic acid. Vitamin A requires fats as well as minerals in order to be properly absorbed from the digestive tract. Substantial amounts of vitamin A are stored in the liver, and therefore, it does not need to be supplied in the diet on a daily basis.
Plasma Vitamin A levels are known to be low in tuberculosis patients though it is unknown whether Vitamin A status is directly related to onset and severity or whether the nutrient is depleted during the acute phase. [14] A study designed to address this question followed three hundred TB patients in Indonesia and determined that Vitamin A deficiency could be used as an indicator of the level of severity of the disease. [15] Complete follow-up of pulmonary TB patients indicates that plasma levels return to normal after recovery, without additional supplementation of Vitamin A. [16]
Vitamin D
Vitamin D is a fat-soluble vitamin that was isolated in 1930 and named calciferol. Since then more metabolites have been found, and the two major forms of this vitamin are now known to be vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D is actually a hormone precursor, which can be manufactured by the body. Therefore, in a classical sense, it is not actually an essential nutrient. However, since the disease rickets is related to vitamin D deficiency, it has been traditionally classified as a vitamin.
Vitamin D is known as the “sunshine” vitamin. It is formed in the body by the action of the sun’s ultraviolet rays on the skin, converting the biological precursor 7-dehydroergosterol (found in animals and humans) into vitamin D3. Vitamin D3 is converted in the liver to 25-hydroxycholecalciferol (25-HCC) which is five times more active than vitamin D3. 25-HCC is then converted in the kidneys to 1,25-dihydroxycholecalciferol (1,25-HCC) which is 10 times more potent than vitamin D3. The active 1,25-HCC form of vitamin D is also called calcitriol. Since calcitriol is produced in the kidney and functions elsewhere in the body, it is considered a hormone, with the intestines and bone as its target.
Insufficient levels of Vitamin D are apparent in many infectious diseases and have been documented in TB patients likely due to its role in immune function. [17] This may be due to insufficient intake or insufficient metabolism of the nutrient. [18] Whether or not supplementation with Vitamin D, even in large amounts, influences outcome is not conclusive. [19] However, low Vitamin D levels may influence onset and severity. [20][21]
Other
In addition to the nutrients listed, the role of antioxidants as integrative therapy in patients with pulmonary TB was examined and found to offer hepatoprotective effect in a dose dependent manner. [22] The role of iron deficiency continues to be subject of debate as iron is scavenged by the bacteria causing greater deficiency, but the deficiency itself may inhibit bacterial growth. [23][24]
Herbal Supplementation
Use of traditional herbal medicines in regions where tuberculosis is prevalent has a long history [25] and presents both positive and negative treatment outcome potential for a variety of reasons. [26] Patients may attempt to self medicate with botanicals and postpone medical treatment, they may be inconsistent in taking prescribed drugs due to their belief in the herbal treatments or the herbs may interact with the drugs they are taking. [27] Many of the studies reviewing the use of traditional herbs have been surveys which request information from patients, family member and traditional healers. These surveys have not been conclusive except to demonstrate that a wide variety of treatments are used globally.
There are hundreds of traditional remedies used as treatments for symptoms of tuberculosis in all regions of the world. Many of the herbs used traditionally to treat TB have been investigated for their potential as candidates for drug development or as viable treatments as medical herbs. There is limited data that would allow recommendations to be made and the potential for interfering with conventional treatment is cautionary. Some of the herbs used include eucalyptus, garlic, chamomile, maca, alfalfa, valeriana, cat’s claw, aloe, nasturtium, rosemary, lobelia, witch hazel, devils club, [28][29] aluka, avocado, knob wood, African wormwood, [30] angelica, [31] some species of evodia [32] and muranga, though none of these have been substantiated in clinical settings. [33] Drug discovery efforts are underway with many traditionally used botanical such as those above. [34] While clinical evidence is lacking, traditional use and pre-clinical data indicate that there are potential candidates for future drug development.
Essential Oils
Essential oils have been used traditionally in many cultures to treat tuberculosis. Again, clinical evidence is lacking. However, pre-clinical studies have evaluated the bacteriostatic activity of several oils. These oils have several chemical constituents in common – Carvacrol, thymol, p-cymene, 1,8-cineole, limonene, and beta-pinene. [35]
The essential oil of Peppermint has been used in pre-clinical settings and a small clinical study with some positive findings in regard to treatment of pulmonary tuberculosis. [36][37] Further investigation is warranted to determine the viability of the oil for this purpose.
Clinical Notes
Bacteriology is recommended by the WHO as the preferred method of TB case detection. Sputum smear microscopy is used first, followed by culture and drug susceptibility testing. In 2007, 5.5 million cases of TB were detected using DOTS programs, including 2.6 million smear-positive cases. The WHO recommends the strengthening of a global laboratory network to ensure access to high quality sputum smear microscopy conducted by highly trained personnel, and that all countries have a reference laboratory that is “well-resourced and fully functioning.” It is recommended that the laboratory network be based on four principles:
- Adoption of national standards based on international guidelines
- Decentralization of diagnostic services
- Communication among all levels of the network
- Functioning internal and external quality management [3][7]
References
- A. Cooper, T.G. Odle, R.J. Frey. Tuberculosis. In: Fundukian L, editor. The gale encyclopedia of alternative medicine. 3rd edition. Detroit (MI): Gale Group; 2009.
- A.D. Harries, C. Dye. Tuberculosis. Ann Trop Med Parasitol 2006; 100(5-6):415-431.
- World Health Organization. Global Tuberculosis Control WHO Report 2009. Available from: http://www.who.int/tb/publications/global_report/2009. Accessed on 1 October 2009.
- B. Laughon. New tuberculosis drugs in development. Curr Top Med Chem 2007;7:463-473.
- World Health Organization. Tuberculosis XDR-TB the facts. Available from: http://www.int/tb/challenges/xdr/facts_nov2007_en.pdf. Accessed on 1 October 2009.
- H.S. Cox, M. Morrow, P.W. Deutschmann. Long term efficacy of DOTS regimens for tuberculosis: systematic review. BMJ March2008; 336(7642):457-458.
- World Health Organization. The five elements of DOTS. Available from: http://www.who.int/tb/dots/whatisdots/en/print.html. Accessed on 1 October 2009.
- Stop TB Partnership. About the Stop TB Partnership. Available from: http://www.stoptb.org/stop_tb_initiative/. Accessed on 1 October 2009.
- World Health Organization. Tuberculosis fact sheet No. 104. Available from: http://www.who.int/mediacentre/factsheets/fs104/en/print/html. Accessed on 30 September 2009.
- World Health Organization. What is TB? How does it spread? March 2009. Available from: http://www.who.int/features/qa/08/en/print.html. Accessed on 1 October 2009.
- R. Hernandez-Pando, H. Orozco, D. Aguilar. Factors that deregulate the protective immune response in tuberculosis. Arch Immunol Ther Exp (Warsz). Sep-Oct2009;57(5):355-367.
- D.C. Macallan. Malnutrition in tuberculosis. Diagn Microbiol Infect Dis. Jun1999;34(2):153-157.
- M. van Lettow, W.W. Fawzi, R.D. Semba. Triple trouble: the role of malnutrition in tuberculosis and human immunodeficiency virus co-infection. Nutr Rev. Mar2003;61(3):81-90.
- M.L. Mathur. Role of vitamin A supplementation in the treatment of tuberculosis. Natl Med J India. Jan-Feb2007;20(1):16-21.
- J.W. Meer, K. van der Velden, W.M. Dolmans. Vitamin A deficiency and other factors associated with severe tuberculosis in Timor and Rote Islands, East Nusa Tenggara Province, Indonesia. Eur J Clin Nutr. Sep2009;63(9):1130-1135.
- G. Ramachandran, T. Santha, R. Garg, D. Baskaran, S.A. Iliayas, P. Venkatesan, R. Fathima, P.R. Narayanan. Vitamin A levels in sputum-positive pulmonary tuberculosis patients in comparison with household contacts and healthy ‘normals’. Int J Tuberc Lung Dis. Sep2004;8(9):1130-1133.
- A. Zittermann. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr. May2003;89(5):552-572.
- T.Y. Chan, C.H. Chan. Abnormal calcium and vitamin D metabolism in tuberculosis. Trop Geogr Med. 1994;46(5):280-282.
- C. Wejse, V.F. Gomes, P. Rabna, P. Gustafson, P. Aaby, I.M. Lisse, P.L. Andersen, H. Glerup, M. Sodemann. Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. May2009;179(9):843-850.
- P. Chocano-Bedoya, A.G. Ronnenberg. Vitamin D and tuberculosis. Nutr Rev. May2009;67(5):289-293.
- K.E. Nnoaham, A. Clarke. Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. Int J Epidemiol. Feb2008;37(1):113-119.
- N.L. Skakun, El. Blikhar. Effect of antioxidants on lipid peroxidation and on liver function in patients with pulmonary tuberculosis. Farmakol Toksikol. Sep-Oct1986;49(5):112-114.
- D. Meyer. Iron chelation as therapy for HIV and Mycobacterium tuberculosis co-infection under conditions of iron overload. Curr Pharm Des. 2006;12(16):1943-1947.
- S. Denic, M.M. Agarwal. Nutritional iron deficiency: an evolutionary perspective. Nutrition. Jul-Aug2007;23(7-8):603-614.
- L.J. McGaw, N. Lall, J.J. Meyer, J.N. Eloff. The potential of South African plants against Mycobacterium infections. J Ethnopharmacol. 28Oct2008;119(3):482-500.
- C. Oeser, A. Escombe, R. Gilman, J. Friedland, C. Evans, J. Moore. Does Traditional Medicine use hamper efforts at tuberculosis control in urban Peru? Am. J. Trop. Med. Hyg. 2005;73(3):571–575.
- Z. Hu, X. Yang, P.C. Ho, S.Y. Chan, P.W. Heng, E. Chan, W. Duan, H.L. Koh, S. Zhou. Herb-drug interactions: a literature review. Drugs. 2005;65(9):1239-1282.
- M. Kobaisy, Z. Abramowski, L. Lermer, G. Saxena, R.E. Hancock, G.H. Towers, D. Doxsee, R.W. Stokes. Antimycobacterial polyynes of Devil’s Club (Oplopanax horridus), a North American native medicinal plant. J Nat Prod. Nov1997;60(11):1210-1213.
- T. Inui, Y. Wang, S. Deng, D.C. Smith, S.G. Franzblau, G.F. Pauli. Counter-current chromatography based analysis of synergy in an anti-tuberculosis ethnobotanical. J Chromatogr A. 1Jun2007;1151(1-2):211-215.
- S.P. Mativandlela, J.J. Meyer, A.A. Hussein, P.J. Houghton, C.J. Hamilton, N. Lall. Activity against Mycobacterium smegmatis and M. tuberculosis by extract of South African medicinal plants. Phytother Res. Jun2008;22(6):841-845.
- S. Deng, Y. Wang, T. Inui, S.N. Chen, N.R. Farnsworth, S. Cho, S.G. Franzblau, G.F. Pauli. Anti-TB polyynes from the roots of Angelica sinensis. Phytother Res. Jul2008;22(7):878-882.
- L.R. Barrows, E. Powan, C.D. Pond, T. Matainaho. Anti-TB activity of Evodia elleryana bark extract. Fitoterapia. Apr2007;78(3):250-252.
- S.P. Mativandlela, J.J. Meyer, A.A. Hussein, P.J. Houghton, C.J. Hamilton, L.J. Lall N.McGaw, N. Lall, J.J. Meyer, J.N. Eloff. The potential of South African plants against Mycobacterium infections. J Ethnopharmacol. 28Oct2008;119(3):482-500.
- A.S. Negi, J.K. Kumar, S. Luqman, D. Saikia, S.P. Khanuja. Antitubercular potential of plants: A brief account of some important molecules. Med Res Rev. 22Jul2009.
- J.G. Bueno-Sánchez, J.R. Martínez-Morales, E.E. Stashenko, W. Ribón. Anti-tubercular activity of eleven aromatic and medicinal plants occurring in Colombia. Biomedica. Mar2009;29(1):51-60.
- V.A. Shkurupiĭ, O.A. Odintsova, N.V. Kazarinova, K.G. Tkrachenko. Use of essential oil of peppermint (Mentha piperita) in the complex treatment of patients with infiltrative pulmonary tuberculosis. Probl Tuberk Bolezn Legk. 2006;(9):43-45.
- V.A. Shkurupiĭ, N.V. Kazarinova, A.P. Ogirenko, S.D. Nikonov, A.V. Tkachev, K.G. Tkachenko. Efficiency of the use of peppermint (Mentha piperita L) essential oil inhalations in the combined multi-drug therapy for pulmonary tuberculosis, Probl Tuberk. 2002;(4):36-39.
