Leprosy 2 (Click to select text)

Leprosy is a chronic infectious disease of human beings that primarily affects the skin, mucous membranes and peripheral nerves. It is a disease that has existed for thousands of years, however, the formal discovery of the leprosy bacillus Mycobacterium leprae was not until 1874. Norwegian physician Gerhard Henrik Armaeur Hansen was the first to formally identify the bacillus, and in his recognition, leprosy is also referred to Hansen's disease. Leprosy is a disease that poorly understood by many health care professionals. Although there is some knowledge of the mechanism, transmission, and treatment of the disease, there are many questions that still remain. The following paper attempts to provide some background information on what is known about leprosy and then attempts to investigate certain aspects of the disease that are unknown. A description of the classification, mechanism of infection, transmission, distribution, and treatment of the disease will be provided. After reviewing the background material, a great deal of questions may arise as to how exactly this disease is spread from person to person and what conditions promote infection. For example, one may wish to investigate the following: 1) Mycobacterium leprae as yet to be cultured in laboratory media? Why? 2) Why is leprosy so prevalent in some parts of the world (i.e. India) but not in others? 3) How does leprosy become so widespread in a population? 4) Despite the discovery of drug treatments, why are over million people still infected? 5) Is there a genetic predisposition to leprosy? 6) Are there non-human sources for the disease? 7) Is there a vaccination for leprosy? These are just a few of the many issues currently under examination. Over the years, the use of modern molecular and immunological tools has become a valuable method in revealing what is known to date about the disease. However, until the epidemiology of the disease is completely understood, effective control and prevention of leprosy can be difficult. Classification of Leprosy Leprosy is classified according to symptoms and histopathology (abnormalities of tissue cells affected by the disease). Patients with leprosy are classified into two general groups: those diagnosed as having paucibacillary leprosy possess five or fewer skin lesions and those diagnosed with multibacillary leprosy have six or more skin lesions. The disease can be further classified on the basis of skin findings, motor and sensory changes, and biopsy findings as indeterminate (I), tuberculoid (T), borderline tuberculoid (BT), borderline (BB), borderline lepromatous (BL), and lepramtous (LL). Under the WHO classification, I, TT, and BT diseases are generally equivalent to paucibacillary leprosy while, BB, BL, and LL are equivalent to multibacillary disease (Jacobson & Krahenbuhl, 1999). Leprosy is classified according to a continuum with indeterminate being the earliest stage of the disease and lepramtous as the most advanced stage. Usually the disease is first diagnosed when a few or single macules (a patch of skin that is altered in color but usually not elevated) are found on the body. As the disease progress, the macules tend to become elevated from the skin (called papules and nodules) and become larger in number. As these nodules begin to spread, motor and sensory impairments begin to occur. Finally the last stage of the disease (the lepramotous phase) results in multiple nodules or lesions, loss of hair and secondary sexual characteristics, severe nerve damage with complete loss of sensation in the areas around the lesions, destruction and absorption of bone occur at this point which results in the loss of extremities, as well as a flattening of the bridge of the nose which produces the "leonine faces" associated with the disease. Mechanism of Infection As mentioned previously, leprosy infects the skin, mucous membrane, and peripheral nerves. Perhaps the most severe consequence of the disease is the loss of neural control that patients often experience in the later stages of the disease. Because of the severity of this infection, only the mechanisms of neural infection will be discussed. It is interesting to note that leprosy does not affect the nerves of the central nervous system. Why is this the case? This is because M. leprae specifically attacks the myelinating Schwann cells which facilitate the entry of the bacilli into the nerve. Since Schwann cells are the primary targets for this microorganism, it does not affect the nerves of the central nervous system because Schwann cells are found only in the peripheral nervous system. The main mechanism for infecting the peripheral nerves is that M. leprae binds to the G-domain of the a2 chain of the basal lamina sheath of the Schwann-cell axon unit. Binding to the surface of the nerve leads to internalization of the bacilli and establishment of Schwann cell infection (Weinstein et al, 1999). Schwann cells infected by the M. leprae lose their ability to maintain normal axonal contact and support, resulting is rapid disintegration of the myelin sheath (Weinstein et al, 1999). The degradation of the myelin sheath results in the calicification and permanent loss of neural function. The Transmission of Leprosy The exact mode of transmission between person-to person is not completely understood. However, it is hypothesized that the main mode of transmission of M. leprae can take place along the nasal mucosa. It has been found that multibaciallry patients tend to shed large numbers of M. leprae from their nose (van Beers et al, 1996). The disease is contracted from person to person via respiratory droplets that contain the bacilli. The possibility of transmission through the respiratory route is based in the following conclusions (from web reference #1): a) the inability of the organism to be found on the skin surface b) the large number of morphologically intact bacilli found in respiratory discharge c) the evidence that M. leprae can exist outside of the human bodies for several Although researchers have not yet reached definitive conclusions about this mode of transmission, this seems to be the most probable method. Also, the skin has been another portal of entry and exit of the disease. Untreated patients shed large numbers of bacteria from lesions or ulcers, or otherwise injured skin (van Beers et al, 1996). There is no evidence that the bacilli can penetrate intact skin, therefore, the skin of the recipient must be broken or injured as well. There has also been evidence that arthropods could possibly play a role in the transmission, however, the evidence is seen as circumstantial (van Beers et al, 1996). The Distribution of Leprosy Leprosy has been prevalent in almost every part of the world. Currently, the disease is now mainly limited to tropical and sub-tropical regions, especially those regions that are impoverished. Generally, leprosy is more prevalent in rural areas that in urban centers. Registered cases of leprosy have declined significantly in the past decade. In 1985, there were 5.4 million registered cases of leprosy worldwide and this number has fallen to below 1 million in 1998 (Jacobson & Krahenbuhl, 1999). The prevalence of the disease varies markedly from country to country, but the overwhelming majority of cases are present in developing countries. 92% of all cases are detected in just 16 countries, led by Brazil and India (Jacobson & Krahenbuhl, 1999). Although leprosy affects both sexes, the disease is generally more common in males than females by a ratio of 2:1 (van Beers et al, 1996). This male predominance is found in such areas as India, Hawaii, Venezuela and Cameroon (web reference #1). However, it is important to realize that this is sex dominance is not universal and that there are many where there is equal occurrence of leprosy in both sexes. Treatment of Leprosy Currently, there are six antileprosy drugs on the market today. However, the most common form of drug treatment is mulitdrug treatment (MDT). MDT involves the combination of three of the six antileprosy drugs- rifampicin, dapsone, and clofazimine. Dapsone and clofazimine in combination kill 99.99% of the bacilli within three months of infection and rifampicin is also highly bactericidal (Jacobson & Krahenbuhl, 1999). This type of treatment produces low side effects and relapse rates are extremely low. However, it is important remember, MDT can only be effective in treating the early stages of the disease. Early detection of the disease is crucial in its treatment. MDT has been quite effective in reducing the number of patients who develop mutlibacillary leprosy. Those with pacubacillary leprosy can generally be cured by 600 mg rifapicin, monthly, supervised, and 100 mg dapsone daily, unsupervised for 6 months, at which time therapy is discontinued (Jacobosn & Krahenbuh, 1999). The discovery of MDT is responsible for the significantly decline in the number of infected persons from 1985 to present. However, it is important to remember that MDT can only be effective when administered during the early stages of the disease. Now that some background material has been provided about the disease, an attempt will be made to answer some of the questions previously put forward 1) Why is it so difficult to culture M. leprae in a laboratory environment? This question is extremely difficult to answer. Many pathogenic bacteria can be cultured in laboratory media, however, this does not apply to M. leprae. It simply cannot survive. This presents a challenge to researchers because it is difficult to study something that cannot remain alive. If the bacilli could be cultured, so many questions to the disease could be answered. What is it about the bacilli that makes it unable to survive in laboratory conditions? Does it have to do with its structure? M. leprae measures 0.3-0.5 x 4.0-7.0 mm. Its cell wall is highly complex, and contains proteins, glycolipids, and mycolic acid (van Beers et al, 1996). Its genome size is 2.8 x 10 6 base pairs and its base composition of the DNA is different from most other mycobacteria. Although not a lot is known about these differences, perhaps further investigation into this matter would reveal some answers as to why it cannot be cultured in vitro. Its optimal growth temperature is 27-30° C and it divides only once in 12 to 14 days, perhaps another reason why it is difficult to be studied. Nevertheless, not being able to grow in laboratory media poses an extremely frustrating obstacle for researchers in studying the disease. 2) Why is leprosy so prevalent in some areas (i.e. India) but not others? As mentioned earlier, leprosy is prevalent in developing countries, one of which is India. India harbors more than two thirds of all the worlds' leprosy patients (Bhattacharya & Sehgal, 1999), which makes it safe to assume that this disease is a severe problem in this country. Why India? There are several under-developed countries in the world? Why has this disease been such a major health concern in only one of these developing countries? According to Bhattacharya & Sehgal (1999), one of the reasons why is it so difficult to control leprosy India is that within the country, the prevalence rates are widely varied in different regions. The disease does not seem to follow any clear-cut geographic boundary. This can make trying to target the highly affected areas very difficult. Also, although India is a developing country, industrialization and improvements in infrastructure are progressing. This results in the mass migration of workers from low endemic areas to high endemic areas and vice versa. This again makes it difficult to pinpoint high-risk areas. India is also a country in which malnutrition is widespread. Usually, malnutrition results in suppressed immunity and this could be another factor. Poor sanitary conditions are also characteristic of India. Does this provide a breeding ground for the disease? What is it about these poor environmental conditions that would allow the bacilli to grow and prosper? An exact explanation as to why India houses such a large percentage of leprosy patients is unknown and may be better understood once more information on the mechanism and transmission of the disease is known. 3) How does leprosy become so widespread throughout a population? It would seem logical that once a person living in an area contracts the disease, other living in close proximity are bound to contract it as well. Van Beers et al (1996) indicate that the risk of contracting leprosy from a household member can be five to ten times higher than not living with an infected person, especially if the infected person carries mulitbacillary leprosy. On the other hand, Klaster et al (1993) indicate that infection in endemic populations is widespread and not just restricted to household contacts. Whether a single group of people can be held accountable for the widespread infection of this disease remains questionable. The spread of the disease most likely involves many factors, such as the ones discuss in the above India example. The spread of infection involves a complex association of many factors and it is difficult to determine the importance of each factor. 4) Even with the discovery of MDT, there are still over one million people that have the disease. Why? As mentioned earlier, MDT is an effective therapy for leprosy if administered during the early stages of the disease. But, there are still many people worldwide that develop full-blown leprosy. Why? First of all, drug treatments are given to those individuals who have access to it and who can afford it. Many people that live in rural areas of under-developed countries probably do not have access to health services, or to the money needed to fund the services. Also, perhaps some people do not realize that they have the disease. They may mistake the premature macules for some other disease and not be concerned that it could be leprosy. It is difficult to determine the exact reason why so many people are still infected, however, it would be safe to assume that lack of medical resources, money, and knowledge and the main issues involved. 5) Are there genetic factors associated with leprosy? This is rather difficult to assess but it should not be ignored. It was mentioned earlier that living in infected households can increase the risk of contracting the disease. However, individuals living in the same household share the same environment so it is difficult to assess genetic factors separately from environmental factors. However, can individuals possess an innate resistance to leprosy? Are people luckier than others? Again this is a difficult question to answer and due to the fact that M. leprae cannot be cultured in a laboratory. However, a few studies have attempted to answer this question. Skamene (1994) attempted to answer this question by using mice. A gene in mice, the bcg gene, has been known to control the susceptibility to various species of mycobacterium. This gene controls early phases of bacterial growth in mice. Unfortunately, this study did not infact conclude that this is the innate immunity gene because a) once again, M. leprae cannot be cultured in a lab and therefore could not be tested on these mice and b) do human posses a bcg gene that would control the susceptibility to leprosy? Once again, it is difficult to provide any definite conclusions. But studies such as this provide a good start in finding the answer. It has also been found that HLA (human leukocyte antigen) linked genes may play a role in the development of the type of leprosy that follows infection (van Beers et al, 1996). Immune response (Ir) or immune suppression (Is) genes are linked to HLA and these genes seem to control both the susceptibility to tubercloid leprosy and lepromatous leprosy (Mehra et al, 1995). This could provide evidence that certain genes could be isolated and could be responsible for the disease. Perhaps not just one gene can be isolated but perhaps a combination of genes could be responsible in immunity to leprosy. However, at this time it is difficult to tell. More research must be performed. 6) Are there non-human sources of the disease? Does M. leprae survive exclusively in man? Once again, this is difficult to assess because the bacillus is resistant to being cultured in laboratory settings. However, apart from human, the nine-banded armadillo, nude mouse, and some species of monkeys have been able to foster the disease. However, there has been no evidence to show that these animals can transmit the disease to humans. But, the fact still remains that it may be possible for the bacilli to survive in species other than humans. But, there is the possibility that certain species could be playing a role in transmitting the disease but they just have not been discovered as yet? It certainly is possible. If this is the case, what species of animals are they? Once again, there are no definite answers. 7) Is there a vaccination for leprosy? BCG vaccination was introduced as a vaccine for tuberculosis and the discovery that this actually could possibly be a vaccine against leprosy was discovered by accident. The BCG vaccination proved to be an effective agent against the development of leprosy, although the degree of protectiveness varied from 20-80% (web reference #2). The variance in protectiveness again indicates that is not a solution to the problem. A series of factors could be responsible for these results, i.e. the genetic make-up of the sample studied, the particular strain of the vaccine. It is difficult to determine if bcg is a vaccine for leprosy, however, it is a step in the right direction. By 2000, the WHO has set a target to eliminate leprosy in endemic countries. Meeting this target will depend upon the heavily committed researchers who will attempt to deal with the obstacles that belong to the disease. Researchers have managed to uncover some details of this puzzling disease, however, there is still so much not known. Today, leprosy is a poorly understood disease that contains a number of biological, social, and environmental factors that are responsible for the development of the disease. The relationship between these factors is complex and it is difficult to study each factor individually. Continued research into the descriptive aspects of the epidemiology is much needed in order to fully eradicate this disease. References Bhattacharya, S.N., & Sehgal, V.N. (1999). Leprosy in India. Clinics in Dermatology, 17:159-70. Jacobson, R.R., & Krahenbuhl. (1999). Leprosy. The Lancet, 353:655-60. Klaster, P.R., van Beers, S., Madijid, B., Day, R., & de Wit, M.Y.L. (1993). Detection of Mycobacterium leprae nasal carriers in populations which leprosy is endemic. Journal of Clinical Microbiology, 31: 2947-2951. Mehra, N.K., Rajalingam, R., Mitra, D.K., Taneja, V., & Giphart, M. (1995). Variants of HA-DR2/DR51 group haplotypes and susceptibility to tubercloid leprosy and pulmonary tuberculosis. As cited by van Beers, S.M., de Wit, M.Y.L., & Klatser, P.R. (1996). The epidemiology of Mycobacterium lepare: recent insight. FEMS Microbiology Letters, 136: 221-230. Skamene, E. (1994). Inflammatory vs protective host responses: the bcg gene story. Immunobiology, 191:451-460. van Beers, S.M., de Wit, M.Y.L., & Klatser, P.R. (1996). The epidemiology of Mycobacterium lepare: recent insight. FEMS Microbiology Letters, 136: 221-230. Weinstein, D.E., Freedman, V.H., & Kaplan, G. (1999). Molecular mechanism of nerve infection of leprosy. Trends in Microbiology, 7(5): 87-89. Web References #1 - http://who.int/lep/disease/Microbiology/transmis.htm #2 - http://www.webspawner.com/users/mlepbacillus/htm.