By Hussain, Tahziba
A quick glance at this review article provides an insight into the common and different features of M. leprae and M. tuberculosis and the diseases caused by these organisms. Table I provides the popular names, history, stigma, description of the disease, clinical features, classification and the types of disease manifestations, who are affected, Signs and Symptoms, Clinical examination, treatment regimens, reactions, relapses, immunity, infectiousness, risk groups, deformities, sequelae, transmission, prevention, complications, vaccination, laboratory studies, days of importance for both the diseases. Table II provides information regarding the causative organisms, M. leprae and M. tuberculosis, their size, genome, protein coding region, lost genes, pseudogenes, classification, predilection, incubation period, ecology, cell structure, metabolism, resistance, bacterial index, growth in vitro, experimental animals, etc. Table HI provides figures of M. leprae and M. tuberculosis, their genome, Lepromin and Tuberculin testing, Global scenario, Indian scenario, colonies of M. leprae and M, tuberculosis, drugs for treatment of tuberculosis and leprosy (MDT blister pack), and so on.
Keywords Leprosy; tuberculosis; M. tuberculosis; M. leprae; Genome; disease; treatment
INTRODUCTION
M. tuberculosis and M. leprae have many features in common, few differences, yet the disease outcome is varied requiring prolonged treatment, from 6 months to 24 months, and the response to treatment is subject to wide individual variations and may range from manageable clinical conditions to confinement up to several days and sometimes fatal. A quick glance at this table provides an insight into the details between M. leprae and M. tuberculosis.
Leprosy
Ever since ancient times, leprosy has been one of the most hated diseases. Leprosy, also known as Hansen disease, is a chronic infectious disease that, if left untreated, can cause debilitating deformities and slowly progress throughout one’s life. Leprosy is characterized by peripheral nerve damage and cutaneous lesions. In order to contract the disease, one has to live in close contact with an infected individual for a prolonged amount of time. These physical effects paired with the social stigma of being infected with this dreaded disease, often lead to those affected being afraid to come forward to seek treatment in the early stages of the disease.
Leprosy is often found in conditions connected with poverty: overcrowding, poor sanitation, and insufficient nutrition). According to current WHO data, the current global prevalence rate is around 1.4 cases per 10,000 people. Around 500,000 new cases of leprosy are registered each year, about 300 of which are in the United States. WHO has mounted a campaign to try to eliminate Hansen’s disease. Elimination is defined as less than one case per 10,000 people. Of the 24 countries where leprosy is endemic, 12 will meet the elimination goal by the end of the year 2000. These countries include Cameroon, Chad, Congo, Cote d’Ivoire, Ethiopia, Gabon, Gambia, Guinea Bissau, Mali, Papua New Guinea, Paraguay, and Sierra Leone. The remaining twelve are Angola, Brazil, Central African Republic, Democratic Republic of the Congo, India, Indonesia, Guinea, Madagascar, Mozambique, Myanmar, Nepal, and Niger. These countries account for 90% of the global prevalence. India alone has about 500,000 infected people, which represents 63% of the global occurrences and 87% of the cases for that region.
The bacillus Mycobacterium leprae causes leprosy. Mycobacterium leprae was discovered in 1873 by G. A. Hansen (hence the disease was subsequently named after him). At that time, it was the only bacterium that had been discovered to cause a human disease. Rod- shaped with rounded ends, Mycobacterium leprae occurs in large numbers, often grouped in bundles, in the lesions of patients with lepromatous leprosy. The bacilli also group in clumps surrounded by a capsule called globi, located both in intracellular and extra- cellular spaces. Viable bacilli stain with carbol-fuchsin as solid rods, whereas bacilli that stain irregularly are probably dead. In Figure 1 the top images are drawings of the human leprosy bacilli seen under a microscope in the bottom row. The right images show that the bacillus is viable because it is uniformly stained. The bacteriological staining and the middle images with empty cell walls at the extremities are dead forms of the bacillus. The Mycobacterium leprae grows in the vesicles within macrophages which must be activated by TH1 cells. Photograph courtesy of Wolstenholme et al. index (BI), calculated by counting six to eight stained smears, and shows how much bacillus is present. The smears are made by cutting the skin around the infected area with a scalpel and scraping fluid and tissue from it. This sample is them evenly spread on a slide and stained by the Ziehl-Neelsen method. The bacilli are then counted and expressed in a logarithmic scale. The BI is useful because the results are representative of many of the infected individual’s lesions.
TABLE 1
About the disease: Leprosy and Tuberculosis
TABLE 1
About the disease: Leprosy and Tuberculosis
TABLE I
About the disease: Leprosy and Tuberculosis
TABLE I
About the disease: Leprosy and Tuberculosis
TABLE I
About the disease: Leprosy and Tuberculosis
TABLE I
About the disease: Leprosy and Tuberculosis
TABLE I
About the disease: Leprosy and Tuberculosis
TABLE I
About the disease: Leprosy and Tuberculosis
TABLE I
About the disease: Leprosy and Tuberculosis
TABLE I
About the disease: Leprosy and Tuberculosis
TABLE I
About the disease: Leprosy and Tuberculosis
TABLE II
About the Organism: Leprosy and Tuberculosis
TABLE II
About the Organism: Leprosy and Tuberculosis
TABLE II
About the Organism: Leprosy and Tuberculosis
TABLE III
Figures, Genomic Organisation, Indian Scenario and the Global estimates: Leprosy and Tuberculosis
TABLE III
Figures, Genomic Organisation, Indian Scenario and the Global estimates : Leprosy and Tuberculosis.
TABLE III
Figures, Genomic Organisation, Indian Scenario and the Global estimates : Leprosy and Tuberculosis.
FIG. 1. Mycobacterium leprae, the causative agent of Hansen’s Disease (leprosy). A. When stained with a red dye and decolorized with acid-alcohol, M. leprae retains the red color (i.e., it is ‘acid-fast’), and appears as a rod-shaped bacillus when viewed under the conventional light microscope. Shorter fragments are produced when the bacilli are dead or dying. These red organisms are seen here within a human nerve, which is stained blue. M. leprae is the only bacterium that infects nerve. (Original magnification approx. 800). B. M. leprae as they appear under a scanning electron microscope, which reveals the surface of the organisms. M. leprae, like other mycobacteria, tend to cluster together. (Original magnification 5000). C. The inner features of M. leprae are observed in this ultra-thin section of the bacilli, magnified 29000 under a transmission electron microscope. The round and oval images seen in the upper portion of this photograph are bacilli which have been cut perpendicular to their length, like a slice of sausage. (Photographs by Mr. Greg McCormick, NHDP).
The only known reservoir of this bacillus is humans, but diseases caused by bacilli are indistinguishable from M. leprae have been discovered in armadillos of the southern U.S. It is not known, however, if these bacilli can cause leprosy in humans. Although the direct means of transmission between humans is unknown, it is believed that the bacillus is expelled from the nose in respiratory droplets or from sores and thus can be spread through direct skin contact or by inhalation. Individuals with lepromatous leprosy have an enormous amount of bacilli, reaching to over seven billion organisms per gram of tissue. Mycobacterium leprae from nasal secretions can live outside of the human host for 36 hours, or as much as nine days in tropical climates. It is quite difficult, however, to determine when the bacillus was contracted because it has an incubation period of about five years, but it may take as many as 20 years for symptoms to develop). It has been found that leprosy is not a highly contagious disease. In fact, many adults that live in leprosy-affected areas seem to be immune, but children are more susceptible.
In the 1940s, scientists discovered that the drug dapsone stopped the progress of leprosy. Dapsone is an antibiotic that inhibits “folk acid synthesis by inhibition of di-hydropteroate synthetase.” Treatment with this drug required that the patient take dapsone for many years. Drug-resistant Mycobacterium leprae was found in the 1960s, thus the only treatment available became useless in some cases. Luckily, soon afterwards, rifampicin and clofazimine were found to very effective. Rifampin, an anti-tubercular drug stops the progression of leprosy so that the individual is no longer contagious and clofazimine reduces the number of mycobacteria in circulation. Some instances have been recorded where the bacilli has become drug resistant, but these times are typically when the drug treatment schedule is not followed correctly. In 1982, the World Health Organization (WHO) began recommending multi-drug therapy (MDT) for leprosy patients. MDT contains three drugs, clofazimine, dapsone, and rifampicin which kill “the germ cures the patient and pre\vents the occurrence of drug resistance.”
If MDT is started as soon as symptoms are detected, deformities can be avoided. MDT is very effective for another reason; it makes the individual non-infectious after the first treatment. Individuals with tuberculoid leprosy can be cured during a six-month course of MDT while patients with lepromatous leprosy require 12 months. In July of 1998, the U.S. Food and Drug Administration approved the use of thalidomide for leprosy treatment as an anti-inflammatory. Thalidomide inhibits the production of TFN-alpha, which can be over- produced in leprosy. When over-produced, TFN-alpha causes fever and night sweats. A short time ago three new drugs were demonstrated to have bactericidal activity against M. leprae. Collectively, called ROM, the drugs are ofloxacin-a fluoroquinolone, minocycline-a tetracycline which is believed to have both anti-bacterial and anti- inflammatory properties, and clarithromycin-a macrolide.
Mycobacterium Leprae
There are 113 species of mycobacteria. Two most important human pathogens of this genus are M. tuberculosis and M. leprae. The term Mycobacteria was coined by Lehman and Neuman (1886). According to 9th edition of Bergey’s Manual of Systemic Bacteriology, the genus Mycobacterium is classified as follows:
* Order: Actinomycetales
* Family: Mycobacteriaceae
* Genus: Mycobacteria
Mycobacteria are divisible into two major groups, the slow and rapid growers. The mycobacteria are acid fast aerobic, non-spore forming, and non-capsulated bacteria. Most of the species are non motile but the sliding motility in M. smegmatis and M. avium have been reported.
The bacilli are straight or slightly curved rod shaped organism with parallels sides and rounded ends, 1-8 m long, and 0.3 m in diameter. It divides by binary fission. It is obligate intracellular parasite, predominantly in macrophages, where the organisms commonly occur in clumps or ‘globi’ which may become very large, containing 100 of bacteria. In smaller clumps the organisms characteristically occur in parallel array resembling ‘bundles of cigars.’
The human being is the only known reservoir of infection in leprosy except for the fact that naturally occurring disease with organisms indistinguishable from M. leprae has also been detected among wild armadillos in parts of the Southern U.S.
The incubation period of M. leprae is as follows:
* Tuberculoid leprosy: 2.9-5.3 years
* Lepromatous leprosy: 9.3-11.6 years
* Mycobacteriophages-Only one phage, D29 is associated with M. leprae is equivocal and because it has only broad specificity it has no taxonomic value.
* Generation time: 11-13 days
Affecting predominately skin, nasal mucosa, and peripheral nerves. In armadillo M. leprae multiplies in the liver. Spleen and lymph nodes and skin containing 10^sup 9^-10^sup 10^ acid fast bacilli (AFB) per gram.
The minimal infective dose of M. leprae is 3-40 solidify staining bacteria. The viability of M. leprae is retained for 7-10 days in tissue or in homogenates of tissues stored at 4C. There is no difference in growth pattern or pathogenicity in mice or armadillos of M. leprae isolates from patients, irrespective of their type of leprosy. Race or geographic origin. Continuous serial passages of M. leprae over several years in normal mice did not increase or change their pathogenicity. Survival of M. leprae in nasal discharges: Suspensions of M. leprae survive exposure to 0.5 N sodium hypoxide for 20 minutes at room temperature as do M. tuberculosis.
At liquid nitrogen 196C, stored for indefinitely time. For optimum preservation of M. leprae the essential requirements include 10% w/v dimethylsulfoxide as the best protective agent over the critical cooling range -15C to -60C. M. leprae in suspension or in tissues can be stored up to 7 days at 4C, without significant loss of viability.
Cell wall consists of a cross linked peptidoglycan to which are attached polysaccharide chains (arabinogalactan) bearing mycolic acids. M. leprae has only α and β keto mycosides. Moreover, in M. leprae unlike in all other species of mycobacteria L- alanine is replaced completely by glycine in peptide moiety of the peptidoglycan.
Mycobacteria characteristically produce a variety of unusual lipids, which are frequently well associates. The lipids so far identified from M. leprae share these characteristics and include phosphatidyl inositol oligo mannosides, phthiocerol demycocerosate (PDIM), trace of cord factor, an attenuation indicator lipid and a mycoside of the phenol glycol type.
One of the earlier reported biochemical activities of M. leprae was its ability to oxidize a range of diphenols of which D- dihydroxy phenylalanine (DOPA) was chosen as the standard substrate because animal diphenoloxidases can only oxidize the L-isomer of DOPA. Although the nature of its activity remains controversial, DOPA oxidase activity is unique to M. leprae among Mycobacteria and therefore, is now one of the important tests for identifying M. leprae DOPA is also taken up by M. leprae.
Bacteria are protected from self destruction by their own oxygen free radical and those from the host by superoxide dismutase (SOD) and peroxidase. In addition, intracellular bacteria like M. leprae are protected from host H^sub 2^ O^sub 2^ by catalase as compared with those of other mycobacteria and no catalase.
Leprosy is a slowly progressing bacterial infection that affects the skin, peripheral nerves in the hands and feet, and mucous membranes of the nose, throat, and eyes. Destruction of the nerve endings causes the affected areas to lose sensation. Occasionally, because of the loss of feeling, the fingers and toes become mutilated and fall off, causing the deformities that are typically associated with the disease.
Leprosy is also known as Hansen’s disease after G. A. Hansen who in 1878, identified the bacillus Mycobacterium leprae that caused the disease. The infection is characterized by abnormal changes of the skin. These changes, called lesions, are at first flat and red. Upon enlarging, they have irregular shapes and a characteristic appearance. The lesions are typically darker in color around the edges with discolored pale centers. Because the organism grows best at lower temperatures the leprosy bacillus has a preference for the skin, the mucous membranes and the nerves. Infection in and destruction of the nerves leads to sensory loss. The loss of sensation in the fingers and toes increases the risk of injury. Inadequate care causes infection of open wounds. Gangrene may also follow, causing body tissue to die and become deformed.
Because of the disabling deformities associated with it, leprosy has been considered one of the most dreaded diseases since biblical times, though much of what was called leprosy in the Old Testament most likely was not the same disease. Its victims were often shunned by the community, kept at arm’s length, or sent to a leper colony. Many people still have misconceptions about the disease. Contrary to popular belief, it is not highly communicable and is extremely slow to develop. Household contacts of most cases and the medical personnel caring for Hansen’s disease patients are not at particular risk. It is very curable, although the treatment is long-term, requiring multiple medications.
The World Health Organization (WHO) puts the number of identified leprosy cases in the world, at the beginning of 1997, at about 890,000. Seventy percent of all cases are found in just three countries: India, Indonesia, and Myanamar (Burma). The infection can be acquired, however, in the Western Hemisphere as well. cases also occur in some areas of the Caribbean and even in southern Texas and Louisiana.
History of Leprosy
Leprosy has tormented humans throughout recorded history. The earliest possible account of a disease that many scholars believe is leprosy appears in an Egyptian Papyrus document written around 1550 B.C. Around 600 B.C. Indian writings describe a disease that resembles leprosy. In Europe, leprosy first appeared in the records of ancient Greece after the army of Alexander, the Great, came back from India and then in Rome in 62 B.C. coinciding with the return of Pompeii’s troops from Asia Minor.
Throughout its history, leprosy has been feared and misunderstood. For a long time leprosy was thought to be a hereditary disease, a curse, or a punishment from God. Before and even after the discovery of its biological cause, leprosy patients were stigmatized and shunned. For example, in Europe during the Middle Ages, leprosy sufferers had to wear special clothing, ring bells to warn others that they were close, and even walk on a particular side of the road, depending on the direction of the wind. Even in modern times, leprosy treatment has often occurred in separate hospitals and live-in colonies called leprosariums because of the stigma of the disease. Leprosy has been as prevalent in various areas as certain times throughout history that is has inspired art work and influenced other cultural practices.
The following is a timeline of the medical advances in leprosy.
1873: Gerhard Henrik Armauer Hansen of Norway was the first person to identify the germ that causes leprosy under a microscope. Hansen’s discovery of Mycobacterium leprae proved that leprosy was caused by a germ, and was thus not hereditary, from a curse, or from a sin.
FIG. 2. A plant of Chaulmoogra Nut.
Early 20th century: Until the late 1940 s, leprosy doctors all over the world treated patients by injecting them with oil from the chaulmoogra nut (Figure 2). This course of treatment was painful, and although some patients appeared to benefit, its long term efficacy was questionable.
1921: U.S. Public Health Service established the Gillis W. Long Hansen’s Disease Center in Carville, Louisiana, which became known as “Carville.” It became a center of research and testing to find a cure for leprosy and a live-in t\reatment center for leprosy patients.
1941: Identified and used at Carville. Promin successfully treated leprosy but unfortunately treatment with Promin required many painful injections
1950s: Dapsone pills, pioneered by Dr. R.G. Cochrane at Carville, became the treatment of choice for leprosy. Dapsone worked wonderfully at first, but unfortunately, M. leprae eventually began developing dapsone resistance.
1970s: The first successful multi-drug treatment (MDT) regimen for leprosy was developed through drug trials on the island of Malta
1981: The World Health Organization began recommending MDT, a combination of three drugs: dapsone, rifampicin, and clofazimine. MDT with these drugs takes from six months to a year or even more, depending on strength of leprosy infection.
Now: MDT with a combination of dapsone, rifampicin, and clofazimine is still the best treatment for preventing nerve damage, deformity, disability and further transmission Figure 3. Researchers are working on developing a vaccine and ways to detect leprosy sooner in order to start treatment earlier.
FIG. 3. The MDT blister pack.
Distribution of Leprosy
The total numbers of leprosy patients in the world vary from 10 to 12 million. The last estimate by the WHO made in 1975 was about 10.6 million. Of the estimated cases, Asia has the largest share with about 62%.
* Asia: 62%
* Africa: 34%
* South America: 3%
* Rest of world: 1%
However, in terms of intensity of the disease in the population the problem is about three times as intense in Africa as it is in Asia. Almost one billion people in the world live in high endemic areas where the prevalence of leprosy is at least 1/1000.
In countries where leprosy is endemic, the prevalence rates show marked variations with rates ranging from below one per 1000 to over 50 or more per 1000. In exceptional situations, rates as high as 250/ 1000 or more have been reported.
Leprosy is known to occur at all ages ranging from early infancy to very old ages, the youngest age reported for occurrence of leprosy is three weeks old in Martinique. The youngest case seen by the author was in an infant of two and a half months, where the diagnosis of tuberculoid leprosy was confirmed by histopathology. Occurrence of leprosy presumably for the first time, is not uncommon even after the age of 70. Although leprosy affects both sexes in most parts of the world, males are affected more frequently than females, often in the ration of 2:1.
FIG. 4. The portrait of leprosy.
These factors include climatic conditions, diet, nutrition, and socio-economic factors such as literacy, caste and so on, the association between leprosy and hot and humid climate has been pointed out by some workers, eating of fish and eating of cocoyam have also been incriminated in relation to leprosy, nutritional deficiencies, and their relationship to leprosy have also been studied, however, none of the studies on the above factors has clearly established a causal association between them and leprosy.
In the population, leprosy was found to contribute to about 1% of all deaths.
Method of Transmission of Leprosy
The exact mechanism of transmission of leprosy is not known. At least until recently, the most widely held belief was that the disease was transmitted by contact between cases of leprosy and healthy persons. More recently the possibility of transmission by the respiratory route is gaining ground. There are also other possibilities such as transmission through insects which cannot be completely ruled out.
The prevalence pool of leprosy in a population in general is in a constant flux resulting from inflow and outflow. The inflow is contributed by the occurrence of new cases, relapse of cured cases, and immigration of cases. The outflow is mainly through cure or inactivation of cases, death of cases, and emigration of cases. Of the various factors that influence the prevalence pool, the importance of inactivation of disease and mortality are less well recognized.
Where leprosy treatment facilities exist, inactivation or cure due to specific treatment is an important mode of elimination of cases from the prevalence pool. Even in the absence of specific treatment, a majority of patients, particularly of the tuberculoid and indeterminate types, tend to get cured spontaneously. An earlier study in India had shown that over a period of 20 years, the extent of spontaneous regression among children with tuberculoid leprosy was about 90%. A study in Culion Island in the Philippines showed that among children self-healing occurred in 77.7% of cases. A later study in South India involving long-term follow-up of a high endemic population showed that among newly detected tuberculoid cases of all ages and both sexes, the rate of inactivation was 10.9% per year, the bulk of inactivation in the study being spontaneous.
The two portals of exit of M. leprae often described are the skin and the nasal mucosa. However, the relative importance of these two portals is not clear. It is true that the lepromatous cases show large numbers of organisms deep down in the dermis. However, whether they reach the skin surface in sufficient numbers is doubtful. Although there are reports of AFB being found in the desquamating epithelium of the skin, Weddell et al. (1963a) have reported that they could not find any AFB in the epidermis even after examining a very large number of specimens from patients and contacts.
Regarding the nasal mucosa, its importance has been recognized as early as 1898 by Schaeffer (1898), particularly that of the ulcerated mucosa. The quantity of bacilli from nasal mucosal lesions in lepromatous leprosy has been demonstrated by Shepard (1960) as large, with counts ranging from 10,000 to 10,000,000. Pedley (1973) has reported that the majority of lepromatous patients showed leprosy bacilli in their nasal secretions as collected through nose blows. Davey and Rees (1974) have indicated that nasal secretions from lepromatous patients can yield as much as 1 million viable organisms per day. The portal of entry of M. leprae into the human body is not definitely known. However, the two portals of entry seriously considered are the skin and the upper respiratory tract. With regard to the respiratory route of entry of M. leprae, the evidence in its favor is on the increase in spite of the long-held belief that the skin was the exclusive portal of entry. Rees and McDougall (1977) have succeeded in the experimental transmission of leprosy through aerosols containing M. leprae in immune-suppressed mice, suggesting a similar possibility in humans. Successful results have also been reported on experiments with nude mice when M. leprae was introduced into the nasal cavity through topical application.
In summary, although no firm conclusions can be reached with regard to the portal of entry, entry through the respiratory route appears most probable, although other routes, particularly broken skin, cannot be ruled out.
Sub-Clinical Infection in Leprosy
In spite of the fact that as yet there is no simple immunological test to identify sub-clinical infection with sufficient specificity and sensitivity, evidence accumulated in the past few years clearly indicate that sub-clinical infection does occur in leprosy as in many other communicable diseases. This evidence has mainly come from limited studies with in vitro tests for cell-mediated immunity (CMI) such as the lymphocyte transformation test (LTT) and serological tests for detecting humoral antibodies such as phenolic glycolipid I- based ELISA.
In addition to the above, skin tests with various preparations of lepromin, and more recently with soluble antigens from M. leprae, have also provided useful information on the occurrence of sub- clinical infection, although the specificity of these tests, particularly of integral lepromin, has been rather questionable. Zuniga et al. (1982), using a soluble skin test antigen prepared by the Convit method, have found that skin test positivity in a part of Venezuela was 19% among the general population (noncontacts), 36% among contacts outside the household, and 48% among household contacts. The gradation of reactivity clearly suggests the correlation between exposure and possible subclinical infection. However, in India no difference was seen in the distribution of skin test reactions to soluble antigens among cases, contacts, and general population.
Transmission by Contact
The term ‘contact’ in leprosy is generally not clearly defined. All that we know at present is that individuals who are in close association or proximity with leprosy patients have a greater chance of acquiring the disease. It is with reference to this observation that the early workers appear to have used the term ‘contact’ as method of transmission. However, it is the definition of contact by later workers with qualifications such as ‘skin to skin,’ ‘intimate,’ ‘repeated,’ and so on that has made it appear as if the disease could be acquired only under such conditions, and that the transmission involved some kind of ‘inunction’ or rubbing in of the organisms from the skin of affected persons into the skin of healthy subjects. Certainly, there is no proof that transmission takes place only through such inunction.
In general, closeness of contact is related to the dose of infection which, in turn, is related to the occurrence of disease. Of the various situations that promote close contact, contact within the household is the only one that is easily identified. In that area the relative risk for contacts was about four times that of non- contacts. The actual incidence among contacts and the relative risk for them appear to vary considerably in different studies. Attack rates for contacts of lepromatous leprosy have varied from 6.2 per 1000 per year in Cebu to 55.8 per 1000 per year in a part of South India.
The possibility of transmission of leprosy through the respiratory rout\e is gaining increasing attention in recent years. It is interesting to note that as early as 1898 this possibility has also been discussed at some length by Schuffer. The possibility of transmission through the respiratory route is based on:
1. The inability of the organisms to be found on the surface of the skin,
2. The demonstration of a large number of organisms in the nasal discharge,
3. The high proportion of morphologically intact bacilli in the nasal secretions, and
4. The evidence that M. leprae could survive outside the human host for several hours or days.
Transmission Through Insects
With the available evidence on intra-cutaneous inoculation as a successful method of transmission of M. leprae in the mouse footpad model and a similar situation possibly existing in human beings, the question arises whether insects could play any role in natural infection. Although a large number of experiments had been conducted in the past demonstrating AFB in biting insects, the question whether insect’s actually transmitted infection had remained unanswered.
Causes
The organism that causes leprosy is a rod-shaped bacterium called Mycobacterium leprae. This bacterium is related to Mycobacterium tuberculosis, the causative agent of tuberculosis. Because special staining techniques involving acids are required to view these bacteria under the microscope, they are referred to as acid-fast bacilli (AFB).
When Mycobacterium leprae invades the body, one of two reactions can take place.
In tuberculoid leprosy (TT), the milder form of the disease, the body’s immune cells attempt to seal off the infection from the rest of the body by surrounding the offending pathogen. Because this response by the immune system occurs in the deeper layers of the skin, the hair follicles, sweat glands, and nerves can be destroyed. As a result, the skin becomes dry and discolored and loses its sensitivity. Involvement of nerves on the face, arms, or legs can cause them to enlarge and become easily felt by the doctor. This finding is highly suggestive of TT. The scarcity of bacteria in this type of leprosy leads to it being referred to as paucibacillary (PB) leprosy. Seventy to eighty percent of all leprosy cases are of the tuberculoid type.
In lepromatous (LL) leprosy, which is the second and more contagious form of the disease, the body’s immune system is unable to mount a strong response to the invading organism. Hence, the organism multiplies freely in the skin. This type of leprosy is also called the multibacillary (MB) leprosy, because of the presence of large numbers of bacteria. The characteristic feature of this disease is the appearance of large nodules or lesions all over the body and face. Occasionally, the mucous membranes of the eyes, nose, and throat may be involved. Facial involvement can produce a lion- like appearance (leonine facies). This type of leprosy can lead to blindness, drastic change in voice, or mutilation of the nose. Leprosy can strike anyone; however, children seem to be more susceptible than adults.
Symptoms
Well-defined skin lesions that are numb are the first symptoms of tuberculoid leprosy. Lepromatous leprosy is characterized by a chronic stuffy nose due to invasion of the mucous membranes, and the presence of nodules and lesions all over the body and face.
The incubation period varies anywhere from six months to ten years. On an average, it takes four years for the symptoms of tuberculoid leprosy to develop. Probably because of the slow growth of the bacillus, lepromatous leprosy develops even more slowly, taking an average of eight years for the initial lesions to appear.
It is not very clear how the leprosy bacillus is transmitted from person to person. Inhaling bacteria that are present in dust is thought to be one of the modes of transmission. However, even among people who live in the same household as the patient and are in close contact, only 5% get leprosy. It is obviously not a highly communicable disease. The incidence of leprosy is highest in the poverty belt of the globe. Therefore, environmental factors such as unhygienic living conditions, overpopulation, and malnutrition may also be contributing factors favoring the infection. The nine- banded armadillo is susceptible to this disease but it is still unclear if human infection is related to exposure to this animal.
In tuberculoid leprosy, a rash appears, consisting of one or a few flat, whitish areas. Areas affected by this rash are numb because the bacteria damage the underlying nerves.
In lepromatous leprosy, many small bumps or larger raised rashes of variable size and shape appear on the skin. There are more areas of numbness than in tuberculoid leprosy, and certain muscle groups may be weak.
Borderline leprosy shares features of both tuberculoid and lepromatous leprosy. If not treated, borderline leprosy may improve to resemble the tuberculoid form or worsen to become more like the lepromatous form.
The most severe symptoms of leprosy result from infection of the peripheral nerves, which causes a deterioration of a person’s sense of touch and a corresponding inability to feel pain and temperature. People with peripheral nerve damage may unknowingly burn, cut, or otherwise harm themselves. Repeated damage may eventually lead to loss of fingers and toes. Also, damage to peripheral nerves may cause muscle weakness, at times resulting in clawing of the fingers and a “drop foot” deformity. Skin infection can lead to areas of swelling and lumps, which can be particularly disfiguring on the face.
People with leprosy also may develop sores on the soles of the feet. Damage to the nasal passages can result in a chronically stuffy nose and, if untreated, complete erosion of the nose. Eye damage may lead to blindness. Men with lepromatous leprosy may experience erectile dysfunction (impotence) and become infertile, because the infection can reduce the amount of testosterone and sperm produced by the testes.
During the course of untreated or even treated leprosy, the body’s immune response may produce inflammatory reactions. These reactions can produce fever and inflammation of the skin, peripheral nerves, and less commonly the lymph nodes, joints, testes, kidneys, liver, and eyes.
Diagnosis
Diagnosis of leprosy is most commonly based on the clinical signs and symptoms. These are easy to observe and elicit by any health worker after a short period of training. In practice, most often persons with such complaints report on their own to the health centre. Only in rare instances is there a need to use laboratory and other investigations to confirm a diagnosis of leprosy. In an endemic country or area, an individual should be regarded as having leprosy if he or she shows ONE of the following cardinal signs.
Skin lesion: Skin lesions consistent with leprosy and with definite sensory loss, with or without thickened nerves The skin lesion can be single or multiple, usually less pigmented than the surrounding normal skin. Sometimes the lesion is reddish or copper- colored. A variety of skin lesions may be seen but macules (flat), papules (raised), or nodules are common. Sensory loss is a typical feature of leprosy. The skin lesion may show loss of sensation to pin pick and/or light touch. Thickened nerves, mainly peripheral nerve trunks constitute another feature of leprosy. A thickened nerve is often accompanied by other signs as a result of damage to the nerve. These may be loss of sensation in the skin and weakness of muscles supplied by the affected nerve. In the absence of these signs, nerve thickening by itself, without sensory loss and/or muscle weakness is often not a reliable sign of leprosy. The clinical system of classification for the purpose of treatment includes the use of number of skin lesions and nerves involved as the basis for grouping leprosy patients into multibacillary (MB) and paucibacillary (PB) leprosy.
Positive skin smears: In a small proportion of cases, rodshaped, red-stained leprosy bacilli, which are diagnostic of the disease, may be seen in the smears taken from the affected skin when examined under a microscope after appropriate staining. Leprosy can be classified on the basis of clinical manifestations and skin smear results. In the classification based on skin smears, patients showing negative smears at all sites are grouped as paucibacillary leprosy (PB), while those showing positive smears at any site are grouped as having multibacillary leprosy (MB).
A person presenting with skin lesions or with symptoms suggestive of nerve damage, in whom the cardinal signs are absent or doubtful should be called a “suspect case” in the absence of any immediately obvious alternate diagnosis. Such individuals should be told the basic facts of leprosy and advised to return to the centre, if signs persist for more than six months or if at any time, worsening is noticed.
The initial microscopic observations of human skin lesions by Hansen were soon followed by detailed histopathologic descriptions by Virchow and others, but the great variety of clinical and histologie findings prompted a variety of complex and confusing classification schemes during the first half of the 20th century. After several decades, the clinical, microbiological, histological, and immunological features of leprosy were formulated into a unified concept of an immunopathologic spectrum by Skinsnes in 1964. The host response to M. leprae was understood to be the basis of this diversity; specifically, that variations in cellular immunity (CMI) play a central role in the wide range of appearances in leprosy. A practical classification scheme developed by Ridley and Jopling based on this concept has enabled standardized comparisons of patients in different parts of the world.
This clinical and pathological classification system remains the diagnostic ‘gold standard’ in leprosy, with important implications for treatment and prognosis. \Although simplified classification systems have been promulgated by the World Health Organization and others, these are designed for use in countries where biopsies and histopathologic examination are too costly or not available. All patients in the United States have access to full diagnostic services for Hansen’s disease at no cost to them, through the National Hansen’s Disease Program. Under the Ridley-Jopling classification, at one extreme are patients with strong CMI to M. leprae, who therefore develop a granulomatous response to the organism and exhibit delayed hypersensitivity to it. They have one skin lesion with rare bacilli, and are termed ‘polar tuberculoid’ (TT). At the other extreme are patients with no effective CMI, who have numerous lesions and very large numbers of bacilli; these are termed ‘polar lepromatous’ (LL). Most patients fall into a broad ‘borderline’ category, with varying degrees of CMI inversely correlated with the number of bacilli in their lesions. These are classified as borderline tuberculoid (BT), mid-borderline (BB), or borderline lepromatous (BL). Representative histologie features of these classifications are presented in Figure 5. A full treatment of this subject is beyond the scope of this paper, and those interested are referred to several standard treatments on this subject
Immunologic and molecular studies of biopsies across this extraordinary spectrum of CMI responses to this relatively indolent pathogen have now produced an increasingly detailed description of the cellular and molecular events involved in CMI to M. leprae, identifying the participation of different populations of T lymphocytes and the contribution of different cytokines to the regulation of the response in different types of leprosy.
Although most patients have identifiable skin lesions by the time they seek medical attention, cutaneous nerves and their subcutaneous trunks are involved very early in the course of this infection. This nerve involvement produces the decrease or loss of sensation within skin lesions that is the telltale diagnostic sign differentiating HD from other skin lesions. Notably, the degree of early nerve injury is related to the patient’s immune response rather than to number of bacilli, i.e., neuropathy develops earlier and more severely in tuberculoid patients, who have very small numbers of bacilli and strong CMI, but severe neuropathy is usually delayed in lepromatous patients, who have abundant organisms but Ineffective CMI.
FIG. 5A. Higher magnification of portions of the same biopsies reveals the changing morphology of the macrophages across the spectrum. In TT lesions, macrophages have an epithelioid character with granular cytoplasm, and occasionally have coalesced into multinucleated giant cells (gc). In LL lesions macrophages characteristically have a vacuolated or ‘foamy’ appearance. BT, BB, and BL can be seen to have intermediate forms of these cells as well as combinations of these cell types.
FIG. 5B. This series of low-magnification images of biopsies across the spectrum demonstrates the decline in organization of the inflammatory infiltrate from the tuberculoid (TT) to the lepromatous (LL) poles.
At some periods, during the course of infection with M. leprae, prior to treatment, the bacilli may circulate in the bloodstream, and may infect deeper organs including the liver, spleen, lymph nodes, and bone marrow. Infection at these sites is usually self limited and not prolonged. This organism may also infect the iris and conjunctiva of the eye, possibly with serious consequences to vision. Discussion of details of these topics is also beyond the scope of this discussion and the sources noted above should be consulted.
Immunology of Leprosy
Although leprosy is a chronic infectious disease, it may to a great extent be considered as immunological disease. The causative organism, M. leprae, is virtually non-toxic and may occur in the tissues in large amounts almost without clinical symptoms. Most symptoms and important complications of the disease are due to immune reactions against antigenic constituents liberated from the bacilli. Most forms of nerve damage induced during reversal reactions are due to delayed type hypersensitivity reactions against bacillary antigens in the nerves, and erythematic nodosum leprosum in considered as a classical example of an immune complex disease in man.
Cellular immune reactions resulting in macrophage activation are considered to be responsible for inducing an increase in the ability to limit bacterial multiplication or for directly killing the intruding micro-organism and thus, essential for protective immunity and resistance against infection. However, the cellular immune response in also highly complex, involving the generation of various subsets of T lymphocytes with various functions.
The early events alter infection with M. leprae are incompletely known both with regard to the influence of port of entry and dose of infection and the behavior of the leprosy bacilli at this stage.
In M. leprae infection, after experimental inoculation, the bacilli are initially engulfed by neutrophilic granulocytes shortly thereafter, they are taken up by macrophages in which they continue to live and multiply until arrested in their growth when effective immunity develops, or they may continue to multiply and eventually kill the host if the resistance is inadequate.
In vivo, M. leprae is an obligate intracellular parasite residing mainly in macrophages and Schwann cells. Evidence of changed immunologie reactivity in individuals exposed to M. leprae but without clinical signs of the infection was first provided with the lymphocyte transformation test used to study individuals. Lymphocyte stimulation tests employing the purified antigenic preparation from M. leprae. The late lepromin reaction indicates the ability of the individual to develop cellular immunity against antigens of M. leprae.
In indeterminate leprosy, there is one or a few skin lesion, appearing as hypo pigmented macules in dark skinned people or faintly erythematous. The outer edges are without in duration and other vague, slight sensory loss in often seen, but the peripheral nerves are not thickened or tender.
Histologically, there is scattered infiltration of lymphocytes and histiocytes around skin appendages, peripheral nerves and vessels which is diagnosable as leprosy in cases exhibiting a cellular reaction within a dermal nerve, or having one or a few AFB in nerves, erector pili muscles or the sub-epidermal zone.
In immunoglobulin class specific solid phase radio immunoassay for anu-M. leprae antibodies, patients with strictly indeterminate leprosy did not behave differently from normal in the IgG anti-M. leprae assay whereas the IgM anti-M. leprae activity was higher in patients with indeterminate leprosy than in the control group of healthy individuals with known exposure to M. leprae, with virtually no overlap. Differential development of CD4 and CD8 cytotoxic T cells (CTL) in PBMC across the leprosy spectrum; IL-6 with IFN- gamma or IL-2 generate CTL in multibacillary patients.
The contribution of CD4 and CD8 T cells on the antigenspecific cytotoxic activity induced by whole Mycobacterium leprae in leprosy patients and normal controls (N) as well as the modulation of this activity by some cytokines has been evaluated. Peripheral blood mononuclear cells (PBMC) from N or from leprosy patients were stimulated with antigen in the presence or absence of cytokines for 7 days. M. leprae-stimulated PBMC were depleted of CD4 or CD8 antigen-bearing cells and employed as effector cells in a 4-hr [31Cr]-release assay against autologous M. leprae-pulsed macrophages. The results demonstrated that both CD4 and CD8 T cells contribute to M. leprae-induced cytotoxic activity, with differences observed in paucibacillary (PB) and multibacillary (MB) patients. CD8-mediated cytotoxic activity is higher than that of CD4 cells in PB patients, while in MB patients CD4 cytotoxicity is predominant. Our data also demonstrate that the generation of CD4 and CD8 cytotoxic T lymphocytes (CTL) can be modulated differentially by interleukin-4 (IL-4), IL-6, gamma interferon (IFN-gamma), or IL-2. Although MB patients developed the lowest CTL response, cytokines such as IL-6 plus IL-2 or IFN-gamma were able to generate both CD4 and CD8 cytotoxic T cells from MB patients. In PB patients, IL-6 plus IFN-gamma displayed the highest stimulation on CD8 effector cells. Thus, an important role may be assigned to IL-6, together with IL-2 or IFN-gamma, in the differentiation of M. leprae- specific CTL effector cells.
TREATMENTS
The major goals of the leprosy control program are early detection of patients; appropriate treatment; and adequate care for the prevention of disabilities and rehabilitation. Because leprosy is an infectious disease, antibiotic therapy plays a pivotal role in the management of newly diagnosed patients.
TABLE 1
Multi-drug Therapy for Multi-bacillary (MB) Leprosy
TABLE 3
Multi-drug Therapy for Single Lesion Pauci-bacillary (SLPB) Leprosy
There are several effective chemotherapeutic agents against M. leprae. Dapsone (Di-amino,diphenylsulfone, DDS), rifampicin (RFP), clofazimine (CLF, B663), ofloxacin (OFLX), and minocycline (MINO) constitute the backbone of the multidrug therapy (MDT) regimen recommended by WHO. Other chemotherapeutic agents, like Levofloxacin (LVFX), sparfloxacin (SPFX), and clarithromycin (CAM) are also effective against M. leprae. WHO has designed very practical kits containing medication for 28 days, dispensed in blister packs, for both PB and MB leprosy. The blister pack medication kit for Sinle lesion pauci-bacillary (SLPB) leprosy contains the exact dose for the one-time administration of the three components of the MDT regimen.
Following the classification according to the flowchart PB patients receive 600 mg RFP monthly, supervi\sed, and 100 mg dapsone daily, unsupervised, for 6 months. SLPB patients can be treated with a single therapeutic dose consisting of 600 mg RFP, 400 mg OFLX, and 100 mg MINO. MB cases are treated with 600 mg RFP and 300 mg clofazamine (CLF) monthly, supervised, and 100 mg dapsone and 50 mg CLF daily, for 12 months. Reduced doses of the above regimen are appropriately determined for children important to avoid drug resistance. An additional, 27 days of treatment with dapsone (and CLF) are mandatory and, health workers should ensure that regular and daily, uninterrupted drug intake is performed.
Multidrug Therapy (MDT)
MDT is a key element of the leprosy treatment and elimination strategy. Table 1 shows Multi-drug Therapy for Multi-bacillary (MB) Leprosy. For both PB and MB leprosy, RFP is central to the anti- leprosy drug regimen (Table 2). It has been proven that monotherapy in leprosy will result in the development of resistance to the drug used. Thus, monotherapy with dapsone or any other anti-leprosy drug should be considered unethical practice. Tables 3 and 4, respectively, show the pharmacological effects of each drug and the recommended laboratory monitoring.
TABLE 2
Multi-drug Therapy for Pauci-bacillary (PB) Leprosy
Rifampicin (RFP)
The drug is administered in a single monthly dose, a protocol for which no significant toxic effect has been reported. Exceptionally bactericidal against M. leprae, a single dose of 600 mg of RFP is capable of killing 99.9% or more of viable organisms. However, the rate of killing is not proportionately enhanced by subsequent doses. It has been suggested that RFP may exert a delayed antibiotic effect for several days, during which the organism’s multiplication is inhibited. The high bactericidal activity of RFP made feasible the application of the single monthly dose, which is cost-effective for leprosy-control programs. At the start of the treatment, the patient should be informed of the usual side effect of a slight reddish coloration of urine.
Diamino-Diphenylsulfone (DDS, Dapsone)
Until widespread resistant strains to the drug were reported, dapsone, which is bacteriostatic or weakly bactericidal against M. leprae, was for years the mainstay in the treatment regimen for leprosy. Subsequently, its use in combination with other drugs has become essential to slow or prevent the development of resistance. The drug has demonstrated an acceptable level of safety in the dosage used in MDT. Besides occasional cutaneous eruptions, side effects that necessitate discontinuation are rare. Patients known to be allergic to any of the sulpha drugs should be spared dapsone. Anemia, hemolysis, and methemoglobinemia may develop but are more significant in patient’s deficient for glucose-6- phosphodihydrogenase (G6PD).
TABLE 4
Pharmacological effect of drugs applied for Leprosy
Clofazimine (CLF)
CLF, which preferentially binds to mycobacterial DNA, both inhibits mycobacterial growth and exerts a slow bactericidal effect on M. leprae. Anti-inflammatory properties have been suggested, for the drug controls erythema nodosum leprosum reactions by mechanisms still poorly understood. Most active when administered daily, the dosage used for MDT is well tolerated and has not shown significant toxicity. Because CLF is a repository drug, stored in the body after administration and slowly excreted, it is given as a loading dose of 300 mg once a month to ensure that the optimal amount of CLF is maintained in the body tissue, even if patients occasionally miss their daily dose. Patients starting the MDT regimen for MB leprosy should be informed of side effects including brownish black discoloration and dryness of skin. These usually disappear within a few months of treatment suspension.
Recently three more drugs have shown bactericidal activity against M. leprae. These are ofloxacin (OFLX)-a fluoroquinolone, minocycline (MINO)-a tetracycline, and clarithromycin-a macrolide.
Ofloxacin (OFLX)
OFLX, a synthetic fluoroquinolone, acts as a specific inhibitor of bacterial DNA gyrase and has shown efficiency in the treatment of M. leprae. Chromosome resistance of negligible clinical relevance has been reported.
Minocycline
Minocycline (MINO) is a semi synthetic tetracycline. It achieves selective concentration in susceptible organisms and induces bacteriostasis by inhibiting protein synthesis. However, from the curative and cost-effectiveness points of view, the WHO- recommended, time-honored MDT remains to date the best combination regimen of the worldwide leprosy-control programs.
Treatment of PB Leprosy
In PB patients, it is assumed that 6 months of treatment with RFP alone can ensure a complete clearing of the bacteria. However, to prevent RFP resistance dapsone has been added. The attainment of clinical inactivity should not be the condition guiding the continuation of MDT in PB patients, because these patients are virtually always cleared of viable bacteria in 6 months with the WHO- MDT regimen. Hence, one should keep in mind that clinical activity in PB leprosy does not necessarily directly correlate with bacterial multiplication. In a substantial proportion of patients, clinical inactivity may not be achieved in 6 months even after a complete clearing of the organisms. Follow-up studies of PB patients in MDT’s field trials have shown that complete clearing of lesions takes 1-2 years after treatment discontinuation. The incidence of relapses in PB patients is very low, and, to date, the correlation between disease activity status at the time of treatment completion and subsequent relapse is not well documented. Nevertheless, the accuracy of the initial classification of patients in the PB category is a determining factor of long-term results.
Treatment of SLPB
In 1997, WHO initiated the supply of special ROM (R: rifampicin. O: Ofloxacin. M: minocycline) blister packs to India, Bangladesh, Nepal, and Brazil for the treatment of SLPB leprosy. The 7th WHO expert committee on leprosy recommended the use of a combination of RFP 600 mg, OFLX 400 mg and MINO 100 mg (ROM) for the treatment of two categories of leprosy patients. Patients presenting with SLPB leprosy could be treated with a single dose of ROM. Both experimental and clinical studies have shown the bactericidal effectiveness of these drugs, either alone or in combination. Therefore, for the treatment of SLPB leprosy, WHO advocates a flexible attitude to the decision of whether to use a single dose ROM or the standard WHO-MDT for 6 months.
Treatment of MB Leprosy
RFP remains the major component of the MDT regimens, clearing most RFP-susceptible strains of M. leprae with a few monthly doses. Recently, it has been shown that the daily combination of dapsone and CLF is highly bactericidal. The combination has been very effective on RFP-resistant mutants in an untreated MB leprosy patient within 3-6 months. For the treatment of MB leprosy, controlled and reliable clinical trials have demonstrated that MDT is generally effective within 24 months or less. Such observations led WHO to recommend 12 months as an acceptable duration for the MDT regimen in the efficient treatment of MB leprosy.
Some concerns arose regarding this 12-month regimen for the treatment of high bacteriological index patients. Observations have shown that a high bacteriological index in MB patients correlates with a high risk for the development of adverse reactions and nerve damage during the second year of treatment. Also, a high bacteriological index at the start of the treatment regimen has been correlated not only with a slow disappearance of skin lesions but also with a high index at the end of the 12-month regimen compared with patients starting with a lower bacteriological index. However, it was found that most of the high bacteriological index patients will continue to improve after the completion of the 12-month regimen. Nevertheless, an additional 12 months of MDT for MB leprosy is needed for patients showing evidence of deterioration.
Provided there is a strict adherence to the regimen by the patient, the shortening of the MDT for MB leprosy from 24 months to 12 months will not lead to a higher risk for the development of resistance to RFP. Several studies have demonstrated that a few doses of RFP are able to clear all the organisms susceptible to RFP. The naturally occurring RFP-resistant mutants are very sensitive to the CLF-dapsone combination, leaving very little chance for any bacteria to survive 12 doses of MDT.
The prevalence of MB patients with a high bacterial index is decreasing in most programs. WHO has estimated their proportion among newly detected cases to less than 15%. There is evidence that 3-6 months of administration of MDT clears all live organisms. Also, for reasons of non-availability or non-reliability of skin smear services, increasing numbers of leprosy control programs are classifying leprosy patients on clinical criteria alone. A factor of supreme importance in the surveillance of the treatment is the determination by the control program of patients with high bacteriological index and those with high risk of developing reaction and neuritis. This surveillance should be done by both clinical and bacteriological methods. Such selected patients may be kept on surveillance for 1-2 years in order to detect deterioration and adverse reactions as early as possible. Signs of deterioration are an indication of the necessity of an additional course of 12 months of MDT. In general, reactions are successfully managed by a standard course of prednisolone. A key element of the surveillance is the education of patients at the end of the treatment program. The benefit of the treatment program would be seriously undermined if the patients were to ignore the symptoms and signs of relapses, and not report them at their slightest manifestation. MB leprosy patients who do not accept CLF can be treated with the monthly administr\ation of 24 doses of ROM.
MDT and M. leprae
Persisting M. leprae are defined as viable organisms which are fully susceptible to the drugs but survive despite adequate treatment with anti-leprosy drugs, probably because they are in a low or dormant metabolic state. To the best of our knowledge, drugs that can clear these persisting organisms are as yet undetermined, although RFP is known for its capability to kill persisting organisms in another mycobacterial disease, tuberculosis. Evidence so far accumulated has shown that persisting organisms, even though present, do not play a key role in the occurrence of relapses in leprosy among patients treated with MDT.
In most patients, the presence of dead bacilli in the skin and other tissues seems to be pathogenically insignificant and the dead organisms are gradually cleared away by the body’s phagocytic system. The results of several large-scale, long-term field trials show that the rate of clearance of dead bacilli is about 0.6-1.0 logs per year and is not enhanced by MDT. However, in a very small proportion of patients, antigens from dead bacilli can provoke immunological reactions, such as the (late) reversal reaction, causing serious nerve damage and subsequent disabilities. Patients should be aware of this potential advent. These reactions are effectively managed by corticosteroids such as prednisolone.
Although the risk of possible endogenous reactivation is negligible when adequate chemotherapy has been completed, evidence exist for other mycobacterioses, like tuberculosis, that immunosuppressive drugs, like prednisolone, can accelerate the multiplication of organisms in a dormant state and cause a disseminated reactivation. Nothing of the like has been documented in leprosy. In case steroid therapy is expected to exceed 4 months, prophylactic measures should be considered. Daily administration of 50 mg of CLF has been used in these cases and should be continued throughout the course of steroid therapy. However, these patients should not be reentered into the case registry.
MOT and Drug-Resistance
Resistance of M. leprae to existing major anti-leprosy drugs has been world wide reported. It has become imperative to develop parades to overcome this problem, the magnitude of which was selective. Actually resistance to Dapsone was the most reported. Subsequently regimens of the MDT were designed on the principle that they would be effective against all the strains of M. leprae regardless of their susceptibility to dapsone.
Reports on RFP-resistant leprosy came second to those of Dapsone in term of frequency. Currently, the problem of RFP-resistant leprosy is trivial; however, selective non-compliance with dapsone and/or CLF by patients may facilitate the selection of RFP- resistant strains. This resistance to RFP is believed to develop as a result of its use in monotherapy or in combination with dapsone, to dapsone-resistant patients.
It has been estimated that an advanced, untreated MB patient harbors about 11 logs live organisms. Out of these, the proportion of naturally-occurring drug-resistant mutants is estimated to be 1 in 7 logs for RFP; 1 in 6 logs each for dapsone and CLF. The organisms resistant to one drug will be susceptible to the other drugs in MDT as their mechanisms of action are different. To date, reports of relapses after treatment with MDT have been rare. Their management with the same regimen has been equally effective.
All experimental and clinical facts indicate that there is no antagonism among the drugs comprising MDT. The experience with MDT so far has shown the combination to be the most effective one. Recently, genetic profiles of drug-resistant strains have been elucidated (Table 5). Table 6 shows Mycobacterium leprae-resistant genes.
There are three important activities characterizing the sensitivity of M. leprae to these drugs:
1. The exquisite sensitivity to dapsone as compared with an MIC of 30 g/mL for sulfamethoxy pyridazine, representative as one of several long acting sulfonamides.
2. The very high bactericidal activity of rifampin.
3. Only three of the other drugs (ethionamide/prothionamide/ thiomide analogs) have bactericidal activity, though significantly less than rifampin.
TABLE 5
Laboratory monitoring for drugs used to treat Leprosy
Leprosy Reaction and Its Treatment
Leprosy affects all aspects of patients’ life. Its reactions, known under the label “Leprosy reactions” include among their worst consequences, irreversible nerve damage and disabilities. Fortunately, these reactions have become gradually well documented and, if timely detected, they are eventually preventable. They occur in all PB and MB (B group and LL type) patients, most commonly during chemotherapy. PB and MB (B group) cases develop type 1 reaction (reverse reaction: RR), and type 2 reaction (erythema nodosum leprosum: ENL) occurs in MB (LL type) patients. Some data seem to indicate a trend toward a reduction in the frequency and severity of ENL in MB leprosy patients on MDT. These data may be attributable to the anti-inflammatory effect of CLF. On the other hand, a temporary increase in the reporting of reversal reactions (type 1) has been noted in MB leprosy patients in their first year of MDT. The exact meaning of this observation remains unclear. One of the most likely explanations is the improvement of early and specific detection capability. Usually these reactions respond satisfactorily to prednisolon
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