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Chapter 11 Hansen disease
Chapter 11
Hansen Disease THOMAS M. SHINNICK
Introduction Diagnosis Etiologic Agent The Clinical Spectrum Reactional States The Immunologic Spectrum Treatment
167 168 169
169 171
172 173 173
Summary
INTRODUCTION The first accurate description of Hansen disease appeared in about 600 B.C. in the writings of the Indian physician Sushruta, although references to diseases resembling it can be found in Indian and Chinese records from as early as 1400 B.C (Browne, 1975). Hansen disease probably entered the Western world in the third century B.C., spread slowly through the Mediterranean region and Europe, reached epidemic proportions in Western Europe in the 12th and 13th centuries, and then,
Principles of Medical Biology, Volume 9A Microbiology, pages 167-174. Copyright 9 1997by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 1-55938-814-5 167
168
THOMAS M. SHINNICK
gradually disappeared as living conditions and nutrition improved. Today, Hansen disease afflicts about 5.5 million persons worldwide, with most cases being found in tropical and subtropical regions--India, Africa, Southeast Asia, and Central and South America (Noordeen et al., 1992). In the United States, there are fewer than 200 new cases annually, and most are in the foreign-born population. Hansen disease is a chronic, infectious disease that primarily affects the peripheral nervous system, skin, and mucous membranes of the upper respiratory tract, especially nasal mucosa (reviewed in Ridley, 1988; Bryceson and Pfaltzgraff, 1990). In advanced disease, the eyes, testes, muscle, liver, spleen, and bone marrow can also be affected. The involvement of the peripheral nervous system in this disease leads to the development of crippling deformities of the hands and feet in 20-30% of patients, while involvement of the eyes can lead to blindness. In fact, Hansen disease is the leading cause of crippling of the hand in the world today. The World Health Organization estimates that 2 to 3 million individuals have deformities due to Hansen disease, including many persons who have completed chemotherapy and are considered cured of the infection, such that rehabilitation and physical therapy are major components of Hansen disease treatment and control programs (Noordeen et al., 1992). A consequence of these deformities is the psychological and social stigma that has historically been associated with Hansen disease.
DIAGNOSIS In general, Hansen disease is not a difficult disease for the clinician to diagnose. Diagnosis is usually based on clinical observation of the signs and symptoms of Hansen disease and a histologic examination of skin lesions for the presence of acid-fast bacilli and a characteristic inflammatory response. The hallmark signs of Hansen disease are: (1) skin lesions, (2) anesthesia within the lesions or in the distribution of a large peripheral nerve, and (3) enlarged peripheral nerves. The individual clinical manifestations of Hansen disease can resemble those of other diseases of the skin and nerves including cutaneous leishmaniasis, fungal infections (e.g., tinea versicolor), lupus erythematosus, lupus vulgaris, and sarcoidosis. However, the combination of a chronic skin disease and peripheral nerve involvement should always lead to the consideration of Hansen disease. Besides the histologic examination of biopsy specimens, there currently are no reliable, rapid laboratory diagnostic tests for Hansen disease. Routine hematologic tests are of little diagnostic value, and many Hansen disease patients have falsepositive serologic tests for syphilis or autoantibodies. Tests to detect characteristic antigens (phenolic glycolipid I or PGLI) or antibodies (anti-PGLI) can help confirm the suspicion of this disease, but these tests are not sufficiently specific or sensitive for definitive diagnosis nor are they commercially available. The lepromin skin test (the Mitsuda reaction) is useful for classifying Hansen disease patients but is of
169
Hansen Disease
little diagnostic value because many uninfected persons produce positive lepromin reactions.
ETIOLOGIC AGENT It is generally accepted that Hansen disease results from an infection with Mycobacterium leprae, although this has not been rigorously proven because M. leprae has not yet been cultivated in vitro despite the fact that it was the first pathogenic bacterium to be associated with a particular disease. It was in 1873 that Armauer Hansen first observed rod-shaped bacteria in tissue biopsy specimens, and in 1874 he proposed that they were the cause of the disease that now bears his name (Hansen, 1874). M. leprae bacteria are Gram-positive, acid-fast rods ranging from 1 to 8 ~tm in length and 0.2 to 0.5 ~tm in width (reviewed in Shinnick, 1991). (Acid-fastness refers to the ability to retain the color of certain dyes, usually carbol fuchsin, following treatment with mild acid.) Several properties of the bacterium may contribute to features of the disease: (1) M. leprae grows very slowly (generation time of about 12 days), which may influence the length of time from infection to the appearance of clinical symptoms or the chronic nature of the infection, (2) M. leprae grows best at 30~ which may play a role in its affinity for cooler parts of the body such as skin and the paucity of skin lesions on the warmer parts of the body, (3) M. leprae is an obligate intracellular pathogen which replicates primarily in macrophages and Schwann cells, which may play roles in persistence, immune responsiveness, and tissue damage, (4) M. leprae is surrounded by a layer of mycolic acids and phenolic glycolipids, which may help it resist the bactericidal activities of macrophages, and (5) M. leprae is the only bacterial pathogen capable of entering peripheral nerves, which may play a role in the loss of nerve function and generation of disabilities. Humans are the primary host and reservoir for M. leprae, even though naturally acquired M. leprae infections have been observed in armadillos, chimpanzees, and Mangabey monkeys (Walsh et al., 1981). The mode of transmission of M. leprae from an infected person to a susceptible one remains unknown although it appears that infection occurs predominantly by the respiratory route. The primary portal for exit appears to be nasal secretions which in some patients can contain as many as 108 bacteria per ml (Davey and Rees, 1974). Other routes of transmission such as skin-to-skin contact may be responsible for some cases, and a few cases have resulted from accidental inoculation of susceptible individuals by needleprick or by tattooing.
THE CLINICAL SPECTRUM Most persons who are infected with M. leprae recover naturally. Only a few develop disease, and symptoms usually appear two to four years after infection, but
170
THOMAS M. SHINNICK
incubation periods as short as three months or as long as forty years have been observed. The earliest lesion usually is an ill-defined, slightly hypopigmented macule with or without associated sensory loss. This form of the disease, called indeterminant leprosy, may heal spontaneously (50-75% of patients) or may remain indeterminant or may progress to one of the common clinical forms of the disease. The established types of Hansen disease form a continuous spectrum which can range from a single lesion with no detectable bacteria to multiple lesions containing large numbers of bacteria, up to 5• 109 organisms per gram of tissue. The five-stage Ridley-Jopling classification system (Ridley and Jopling, 1966) places a patient in this spectrum based on clinical and histopathologic findings and also provides information on the infectiveness of the patient, long-term prognosis, and the types and likelihood of complications. The polar forms of the disease (tuberculoid, lepromatous) are clinically stable while the intermediate forms (borderline tuberculoid, borderline, borderline lepromatous) are relatively unstable and may progress toward either polar form. Table 1 summarizes some of the clinical and histological characteristics of the polar forms of Hansen disease (also reviewed in Kaplan and Cohn, 1986; Ridley, 1988; Sieling and Modlin, 1992). Tuberculoid (abbreviated TT) patients have one or a few skin lesions with well-defined, raised, erythematous margins. The lesions are usually hypopigmented in persons with dark skins and copper colored in persons with light skins. The lesion is anesthetic, and solitary peripheral nerves are commonly enlarged. Histologically, the lesion is a well-ordered granuloma containing epithelioid cells, multinucleated giant cells, and large numbers of lymphocytes. There are very few, if any, acid-fast bacilli present. The lepromin skin test produces a positive Mitsuda reaction in TT patients. Borderline tuberculoid (BT) lesions resemble tuberculoid lesions, but are smaller and more numerous with less-well defined edges. The lesions contain fewer epithelioid cells and multinucleated giant cells, and a few acid-fast bacilli are usually present. BT patients have positive Mitsuda reactions. Borderline (BB) patients have numerous lesions of various sizes. The lesions contain immature epithelioid cells, macrophages, and T-cells, but no multinucleated giant cells. Many bacilli are present. The Mitsuda reaction is variably positive in B B patients. Borderline iepromatous (BL) patients have large numbers of papules, plaques, or nodules. The lesions contain numerous acid-fast bacilli and undifferentiated macrophages, but no epithelioid or multinucleated giant cells. A few bacilli are also found in nasal secretions and these patients are considered infectious. The Mitsuda reaction is negative in B L patients. Lepromatous (LL) patients have extensive cutaneous involvement with numerous, small, bilaterally symmetrical, erythematous macules, papules, or nodules. Sensory loss is symmetrical and often affects the extremities. The
Hansen Disease
171
Table 1. Clinical, Histologic, and Immunologic Spectra
of Hansen Disease Ridley-Jopling Classification Feature
Tuberculoid
N u m b e r of lesions
few
Histology bacteria
Lepromatous many
-/+
+++
macrophages
few
many
lymphocytes
many
few
epithelioid cells
many
none
Nerve Involvement
+
+
A n t i b o d y Response
+/-
+++
Cellular Immune Response Mitsuda Reaction
+++
CD4§
1.9:1
0.6:1
CD4 §
+
+/-
Cytotoxic CD8 §
+
§ ratio
Suppressor CD8 §
--
+
TH1 subset (IFN, IL-2)
+
+/-
TH2 subset (IL-4, IL-10)
+
+++
lesions contain large numbers of foamy macrophages and acid-fast bacilli. Bacillemia is common. Because nasal secretions from LL patients contain large numbers of bacilli, these patients are considered the most infectious. The Mitsuda reaction is negative in LL patients.
REACTIONAL STATES About half of Hansen disease patients will experience clinically evident inflammatory reactions, which are responsible for much of the tissue damage associated with the disease. The two general classes of these reactions are reversal reactions and erythema nodosum leprosum. Reversal reactions can complicate all three borderline categories. Existing lesions develop erythema and swelling, new lesions may appear, and there is a shift towards tuberculoid histology (a so-called upgrading reaction). Major symptoms include fever and edema and erythema of the lesions which may lead to ulceration. An associated neuritis is common and often involves swelling of the infected nerves
172
THOMAS M. SHINNICK
and loss of motor function. Reversal reactions are histologically similar to delayedtype hypersensitivity reactions. E r y t h e m a nodosum leprosum (ENL) occurs in lepromatous and borderline lepromatous patients, most frequently in the first two years of treatment. Major symptoms include tender inflamed nodules, fever, and lymphadenopathy. Frequently, ENL is associated with polyarthralgia and painful neuritis that can result in loss of peripheral nerve function. Histologically, ENL is characterized by polymorphonuclear cell infiltration and deposits of IgG and complement, and hence it resembles an Arthus reaction.
THE IMMUNOLOGIC
SPECTRUM
Interestingly, the clinical and histologic spectrum is not related to the genetics of the bacterium, but rather to the immune responsiveness of the host. Histocompatibility alleles appear to play a role in determining what type of disease develops, but not in susceptibility to infection. Also, the distribution of patients along the spectrum varies in different populations. For example, lepromatous cases are more common in Caucasians (30-50% of all cases) than in Africans (<5% of all cases) (Fine, 1982). Tuberculoid disease is characterized by a strong cellular immune response to the M. leprae bacilli, and the tuberculoid lesions contain a predominance of CD4 + T-cells of the T-helper-1 (Th 1) subset (Table 1). The Thl subset is defined by the production of cytokines thought to be involved in generating protective immunity against intracellular pathogens. These cytokines include interferon-gamma, interleukin-2 (IL-2), and GM-CSF (granulocyte-macrophage colony stimulating factor). In tuberculoid leprosy, there is only a weak antibody reponse to M. leprae antigens. In contrast, lepromatous disease is characterized by a lack of a T-cell response to M. leprae antigens and a strong antibody response to M. leprae antigens. The lepromatous lesions contain numerous CD8 + suppressor T-cells which produce IL-4, IL-5, and IL- 10. These cytokines are thought to down-regulate the protective CD4 + T-cell response, and in vitro, this suppressor activity can be abrogated by the addition of neutralizing antibodies to IL-4. Incidentally, this immunosuppression is quite specific for M. leprae in that the patients are not more susceptible to other infections or to neoplasia. Reactional states result from changes in the immune response to the M. leprae bacilli. In reversal reactions, there is an influx of CD4 + and cytotoxic CD8 + T-cells into the BT, BB, or BL lesions, an augmented cell-mediated immune response to M. leprae antigens, and killing of the bacilli. The cytokine profile of the lesion also moves toward a Thl response with production of large amounts of interferongamma. Since the reversal reaction is quite similar to a delayed-type hypersensitivity reaction, it is usually treated with corticosteroid therapy. Immunologically, erythema nodosum leprosum resembles an Arthus reaction with evidence of T-cell involvement. Here, there also is an influx of CD4 + T-cells,
Hansen Disease
173
but the cytokine profile is more reminiscent of a Th2 response than a Th 1 response in that large amounts of IL-4 are produced which biases the response towards antibody production. Tissue damage appears to be mediated by local immune complex deposition and complement fixation. Another important feature of ENL is that large amounts of TNFct are produced, which may play a role in the immunopathology of this reaction as well as the accompanying fever. Interestingly, the administration of a drug that specifically down-regulates TNFct production (i.e., thalidomide) alleviates the ENL symptoms (Sampiao et al., 1992).
TREATMENT Effective chemotherapy can halt the progression of the disease and can rapidly render the patient noninfectious. The modern era of chemotherapy began in 1943 with the introduction of sulfones, and dapsone was the mainstay of treatment for the next 4 decades. However, by the early 1980s, an alarming number of cases resistant to dapsone therapy had been reported. To combat the emergence of the dapsone-resistant organisms, patients are now treated with combinations of two or three drugs (WHO, 1988). For patients who have few lesions and few bacteria per lesion (paucibacillary cases, usually TT and BT patients), the World Health Organization recommends a six month treatment regimen including dapsone and rifampin. For patients who have many lesions or many bacteria per lesion (i.e., multibacillary cases, usually BL and LL patients), a two year treatment regimen including dapsone, rifampin, and clofazimine is recommended. There is no commercially available, effective vaccine against Hansen disease.
SUMMARY Hansen disease is still a significant public health problem in many parts of the world, and as the mobility of the world's population increases, the likelihood that a U.S. physician will encounter a case of Hansen disease will increase. Despite the broad spectrum of immunologic, histologic, and clinical manifestations of this disease, a diagnosis of Hansen disease should be considered whenever a combination of skin lesions and sensory loss occur. Effective chemotherapeutic regimens with two or three drugs rapidly render the patient noninfectious, and help prevent the disabilities and crippling deformities associated with this disease.
REFERENCES Browne, S.G. (1975). Someaspects of the history of leprosy: the leprosyof yesteryear.Proc. Roy. Soc. Med. 68, 485-493. Davey, T.E, & Rees, R.J.W.(1974).The nasal discharge in leprosy:clinical and bacteriological aspects. Lepr. Rev. 45, 121-134. Fine, P.E.M. (1982). Leprosy:The epidemiologyof a slowgrowingbacterium. EpidemiologicReviews 4, 161-188.
174
THOMAS M. SHINNICK
Hansen, G.A. (1874). Causes of leprosy. Norsk. Mag. for Laegervidenskaben 4, 1-88. Kaplan, G., & Cohn, Z.A. (1986). The immunobiology of leprosy. Intl. Rev. Exp. Pathol. 28, 45-78. Noordeen, S.K., Lopez-Bravo, L., & Sundaresan, T.K. (1992). Estimated number of leprosy cases in the world. Bull. W.H.O. 70, 7-10. Ridling, D.S., & Jopling, W.H. (1966). Classification of leprosy according to immunity. A five-group system. Intl. J. Lepr. 34, 255-273. Sampaio, E.P., Moreira, A.L., Sarno, E.N., Malta, A.M., & Kaplan, G. (1992). Prolonged treatment with recombinant interferon-gamma induces erythema nodosum leprosum in lepromatous leprosy patients. J. Exp. Med. 175, 1729-1737. Shinnick, T. M. (1991). Mvcobacterium leprae. In: The Prokaryotes: A Handbook on the Biology of Bacteria: Ecophysiology, Isolation, Identification, Applications. 2nd edn. (Balows, A., Truper, H. G., Dworkin, M., Harder, W., & Schleifer, K.H., eds.), pp. 1271- 1282, Springer-Verlag, New York. Sixth Report of the WHO Expert Committee on Leprosy. (1988). World Health Organization Technical Report Series No. 768. Geneva. Walsh, G.P., Meyers, W.M., Binford, C.H., Gerone, P.J., Wolf, R.H., & Leininger, J.R. (1981). Leprosy--A zoonosis. Lepr. Rev. 52(Suppl. !), 77-83.
RECOMMENDED READINGS Bryceson, A., & Pfaltzgraff, R.E. (1990). Leprosy. 3rd edn. Churchill Livingstone, New York. Ridley, D.S. (1988). Pathogenesis of Leprosy and Related Diseases. Wright, London. Sieling, P.A., & Modlin, R.L. (1992). T cell and cytokine patterns in leprosy skin lesions. Springer Semin. Immunopathoi. 13, 413-426.
Hansen Disease THOMAS M. SHINNICK
Introduction Diagnosis Etiologic Agent The Clinical Spectrum Reactional States The Immunologic Spectrum Treatment
167 168 169
169 171
172 173 173
Summary
INTRODUCTION The first accurate description of Hansen disease appeared in about 600 B.C. in the writings of the Indian physician Sushruta, although references to diseases resembling it can be found in Indian and Chinese records from as early as 1400 B.C (Browne, 1975). Hansen disease probably entered the Western world in the third century B.C., spread slowly through the Mediterranean region and Europe, reached epidemic proportions in Western Europe in the 12th and 13th centuries, and then,
Principles of Medical Biology, Volume 9A Microbiology, pages 167-174. Copyright 9 1997by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 1-55938-814-5 167
168
THOMAS M. SHINNICK
gradually disappeared as living conditions and nutrition improved. Today, Hansen disease afflicts about 5.5 million persons worldwide, with most cases being found in tropical and subtropical regions--India, Africa, Southeast Asia, and Central and South America (Noordeen et al., 1992). In the United States, there are fewer than 200 new cases annually, and most are in the foreign-born population. Hansen disease is a chronic, infectious disease that primarily affects the peripheral nervous system, skin, and mucous membranes of the upper respiratory tract, especially nasal mucosa (reviewed in Ridley, 1988; Bryceson and Pfaltzgraff, 1990). In advanced disease, the eyes, testes, muscle, liver, spleen, and bone marrow can also be affected. The involvement of the peripheral nervous system in this disease leads to the development of crippling deformities of the hands and feet in 20-30% of patients, while involvement of the eyes can lead to blindness. In fact, Hansen disease is the leading cause of crippling of the hand in the world today. The World Health Organization estimates that 2 to 3 million individuals have deformities due to Hansen disease, including many persons who have completed chemotherapy and are considered cured of the infection, such that rehabilitation and physical therapy are major components of Hansen disease treatment and control programs (Noordeen et al., 1992). A consequence of these deformities is the psychological and social stigma that has historically been associated with Hansen disease.
DIAGNOSIS In general, Hansen disease is not a difficult disease for the clinician to diagnose. Diagnosis is usually based on clinical observation of the signs and symptoms of Hansen disease and a histologic examination of skin lesions for the presence of acid-fast bacilli and a characteristic inflammatory response. The hallmark signs of Hansen disease are: (1) skin lesions, (2) anesthesia within the lesions or in the distribution of a large peripheral nerve, and (3) enlarged peripheral nerves. The individual clinical manifestations of Hansen disease can resemble those of other diseases of the skin and nerves including cutaneous leishmaniasis, fungal infections (e.g., tinea versicolor), lupus erythematosus, lupus vulgaris, and sarcoidosis. However, the combination of a chronic skin disease and peripheral nerve involvement should always lead to the consideration of Hansen disease. Besides the histologic examination of biopsy specimens, there currently are no reliable, rapid laboratory diagnostic tests for Hansen disease. Routine hematologic tests are of little diagnostic value, and many Hansen disease patients have falsepositive serologic tests for syphilis or autoantibodies. Tests to detect characteristic antigens (phenolic glycolipid I or PGLI) or antibodies (anti-PGLI) can help confirm the suspicion of this disease, but these tests are not sufficiently specific or sensitive for definitive diagnosis nor are they commercially available. The lepromin skin test (the Mitsuda reaction) is useful for classifying Hansen disease patients but is of
169
Hansen Disease
little diagnostic value because many uninfected persons produce positive lepromin reactions.
ETIOLOGIC AGENT It is generally accepted that Hansen disease results from an infection with Mycobacterium leprae, although this has not been rigorously proven because M. leprae has not yet been cultivated in vitro despite the fact that it was the first pathogenic bacterium to be associated with a particular disease. It was in 1873 that Armauer Hansen first observed rod-shaped bacteria in tissue biopsy specimens, and in 1874 he proposed that they were the cause of the disease that now bears his name (Hansen, 1874). M. leprae bacteria are Gram-positive, acid-fast rods ranging from 1 to 8 ~tm in length and 0.2 to 0.5 ~tm in width (reviewed in Shinnick, 1991). (Acid-fastness refers to the ability to retain the color of certain dyes, usually carbol fuchsin, following treatment with mild acid.) Several properties of the bacterium may contribute to features of the disease: (1) M. leprae grows very slowly (generation time of about 12 days), which may influence the length of time from infection to the appearance of clinical symptoms or the chronic nature of the infection, (2) M. leprae grows best at 30~ which may play a role in its affinity for cooler parts of the body such as skin and the paucity of skin lesions on the warmer parts of the body, (3) M. leprae is an obligate intracellular pathogen which replicates primarily in macrophages and Schwann cells, which may play roles in persistence, immune responsiveness, and tissue damage, (4) M. leprae is surrounded by a layer of mycolic acids and phenolic glycolipids, which may help it resist the bactericidal activities of macrophages, and (5) M. leprae is the only bacterial pathogen capable of entering peripheral nerves, which may play a role in the loss of nerve function and generation of disabilities. Humans are the primary host and reservoir for M. leprae, even though naturally acquired M. leprae infections have been observed in armadillos, chimpanzees, and Mangabey monkeys (Walsh et al., 1981). The mode of transmission of M. leprae from an infected person to a susceptible one remains unknown although it appears that infection occurs predominantly by the respiratory route. The primary portal for exit appears to be nasal secretions which in some patients can contain as many as 108 bacteria per ml (Davey and Rees, 1974). Other routes of transmission such as skin-to-skin contact may be responsible for some cases, and a few cases have resulted from accidental inoculation of susceptible individuals by needleprick or by tattooing.
THE CLINICAL SPECTRUM Most persons who are infected with M. leprae recover naturally. Only a few develop disease, and symptoms usually appear two to four years after infection, but
170
THOMAS M. SHINNICK
incubation periods as short as three months or as long as forty years have been observed. The earliest lesion usually is an ill-defined, slightly hypopigmented macule with or without associated sensory loss. This form of the disease, called indeterminant leprosy, may heal spontaneously (50-75% of patients) or may remain indeterminant or may progress to one of the common clinical forms of the disease. The established types of Hansen disease form a continuous spectrum which can range from a single lesion with no detectable bacteria to multiple lesions containing large numbers of bacteria, up to 5• 109 organisms per gram of tissue. The five-stage Ridley-Jopling classification system (Ridley and Jopling, 1966) places a patient in this spectrum based on clinical and histopathologic findings and also provides information on the infectiveness of the patient, long-term prognosis, and the types and likelihood of complications. The polar forms of the disease (tuberculoid, lepromatous) are clinically stable while the intermediate forms (borderline tuberculoid, borderline, borderline lepromatous) are relatively unstable and may progress toward either polar form. Table 1 summarizes some of the clinical and histological characteristics of the polar forms of Hansen disease (also reviewed in Kaplan and Cohn, 1986; Ridley, 1988; Sieling and Modlin, 1992). Tuberculoid (abbreviated TT) patients have one or a few skin lesions with well-defined, raised, erythematous margins. The lesions are usually hypopigmented in persons with dark skins and copper colored in persons with light skins. The lesion is anesthetic, and solitary peripheral nerves are commonly enlarged. Histologically, the lesion is a well-ordered granuloma containing epithelioid cells, multinucleated giant cells, and large numbers of lymphocytes. There are very few, if any, acid-fast bacilli present. The lepromin skin test produces a positive Mitsuda reaction in TT patients. Borderline tuberculoid (BT) lesions resemble tuberculoid lesions, but are smaller and more numerous with less-well defined edges. The lesions contain fewer epithelioid cells and multinucleated giant cells, and a few acid-fast bacilli are usually present. BT patients have positive Mitsuda reactions. Borderline (BB) patients have numerous lesions of various sizes. The lesions contain immature epithelioid cells, macrophages, and T-cells, but no multinucleated giant cells. Many bacilli are present. The Mitsuda reaction is variably positive in B B patients. Borderline iepromatous (BL) patients have large numbers of papules, plaques, or nodules. The lesions contain numerous acid-fast bacilli and undifferentiated macrophages, but no epithelioid or multinucleated giant cells. A few bacilli are also found in nasal secretions and these patients are considered infectious. The Mitsuda reaction is negative in B L patients. Lepromatous (LL) patients have extensive cutaneous involvement with numerous, small, bilaterally symmetrical, erythematous macules, papules, or nodules. Sensory loss is symmetrical and often affects the extremities. The
Hansen Disease
171
Table 1. Clinical, Histologic, and Immunologic Spectra
of Hansen Disease Ridley-Jopling Classification Feature
Tuberculoid
N u m b e r of lesions
few
Histology bacteria
Lepromatous many
-/+
+++
macrophages
few
many
lymphocytes
many
few
epithelioid cells
many
none
Nerve Involvement
+
+
A n t i b o d y Response
+/-
+++
Cellular Immune Response Mitsuda Reaction
+++
CD4§
1.9:1
0.6:1
CD4 §
+
+/-
Cytotoxic CD8 §
+
§ ratio
Suppressor CD8 §
--
+
TH1 subset (IFN, IL-2)
+
+/-
TH2 subset (IL-4, IL-10)
+
+++
lesions contain large numbers of foamy macrophages and acid-fast bacilli. Bacillemia is common. Because nasal secretions from LL patients contain large numbers of bacilli, these patients are considered the most infectious. The Mitsuda reaction is negative in LL patients.
REACTIONAL STATES About half of Hansen disease patients will experience clinically evident inflammatory reactions, which are responsible for much of the tissue damage associated with the disease. The two general classes of these reactions are reversal reactions and erythema nodosum leprosum. Reversal reactions can complicate all three borderline categories. Existing lesions develop erythema and swelling, new lesions may appear, and there is a shift towards tuberculoid histology (a so-called upgrading reaction). Major symptoms include fever and edema and erythema of the lesions which may lead to ulceration. An associated neuritis is common and often involves swelling of the infected nerves
172
THOMAS M. SHINNICK
and loss of motor function. Reversal reactions are histologically similar to delayedtype hypersensitivity reactions. E r y t h e m a nodosum leprosum (ENL) occurs in lepromatous and borderline lepromatous patients, most frequently in the first two years of treatment. Major symptoms include tender inflamed nodules, fever, and lymphadenopathy. Frequently, ENL is associated with polyarthralgia and painful neuritis that can result in loss of peripheral nerve function. Histologically, ENL is characterized by polymorphonuclear cell infiltration and deposits of IgG and complement, and hence it resembles an Arthus reaction.
THE IMMUNOLOGIC
SPECTRUM
Interestingly, the clinical and histologic spectrum is not related to the genetics of the bacterium, but rather to the immune responsiveness of the host. Histocompatibility alleles appear to play a role in determining what type of disease develops, but not in susceptibility to infection. Also, the distribution of patients along the spectrum varies in different populations. For example, lepromatous cases are more common in Caucasians (30-50% of all cases) than in Africans (<5% of all cases) (Fine, 1982). Tuberculoid disease is characterized by a strong cellular immune response to the M. leprae bacilli, and the tuberculoid lesions contain a predominance of CD4 + T-cells of the T-helper-1 (Th 1) subset (Table 1). The Thl subset is defined by the production of cytokines thought to be involved in generating protective immunity against intracellular pathogens. These cytokines include interferon-gamma, interleukin-2 (IL-2), and GM-CSF (granulocyte-macrophage colony stimulating factor). In tuberculoid leprosy, there is only a weak antibody reponse to M. leprae antigens. In contrast, lepromatous disease is characterized by a lack of a T-cell response to M. leprae antigens and a strong antibody response to M. leprae antigens. The lepromatous lesions contain numerous CD8 + suppressor T-cells which produce IL-4, IL-5, and IL- 10. These cytokines are thought to down-regulate the protective CD4 + T-cell response, and in vitro, this suppressor activity can be abrogated by the addition of neutralizing antibodies to IL-4. Incidentally, this immunosuppression is quite specific for M. leprae in that the patients are not more susceptible to other infections or to neoplasia. Reactional states result from changes in the immune response to the M. leprae bacilli. In reversal reactions, there is an influx of CD4 + and cytotoxic CD8 + T-cells into the BT, BB, or BL lesions, an augmented cell-mediated immune response to M. leprae antigens, and killing of the bacilli. The cytokine profile of the lesion also moves toward a Thl response with production of large amounts of interferongamma. Since the reversal reaction is quite similar to a delayed-type hypersensitivity reaction, it is usually treated with corticosteroid therapy. Immunologically, erythema nodosum leprosum resembles an Arthus reaction with evidence of T-cell involvement. Here, there also is an influx of CD4 + T-cells,
Hansen Disease
173
but the cytokine profile is more reminiscent of a Th2 response than a Th 1 response in that large amounts of IL-4 are produced which biases the response towards antibody production. Tissue damage appears to be mediated by local immune complex deposition and complement fixation. Another important feature of ENL is that large amounts of TNFct are produced, which may play a role in the immunopathology of this reaction as well as the accompanying fever. Interestingly, the administration of a drug that specifically down-regulates TNFct production (i.e., thalidomide) alleviates the ENL symptoms (Sampiao et al., 1992).
TREATMENT Effective chemotherapy can halt the progression of the disease and can rapidly render the patient noninfectious. The modern era of chemotherapy began in 1943 with the introduction of sulfones, and dapsone was the mainstay of treatment for the next 4 decades. However, by the early 1980s, an alarming number of cases resistant to dapsone therapy had been reported. To combat the emergence of the dapsone-resistant organisms, patients are now treated with combinations of two or three drugs (WHO, 1988). For patients who have few lesions and few bacteria per lesion (paucibacillary cases, usually TT and BT patients), the World Health Organization recommends a six month treatment regimen including dapsone and rifampin. For patients who have many lesions or many bacteria per lesion (i.e., multibacillary cases, usually BL and LL patients), a two year treatment regimen including dapsone, rifampin, and clofazimine is recommended. There is no commercially available, effective vaccine against Hansen disease.
SUMMARY Hansen disease is still a significant public health problem in many parts of the world, and as the mobility of the world's population increases, the likelihood that a U.S. physician will encounter a case of Hansen disease will increase. Despite the broad spectrum of immunologic, histologic, and clinical manifestations of this disease, a diagnosis of Hansen disease should be considered whenever a combination of skin lesions and sensory loss occur. Effective chemotherapeutic regimens with two or three drugs rapidly render the patient noninfectious, and help prevent the disabilities and crippling deformities associated with this disease.
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RECOMMENDED READINGS Bryceson, A., & Pfaltzgraff, R.E. (1990). Leprosy. 3rd edn. Churchill Livingstone, New York. Ridley, D.S. (1988). Pathogenesis of Leprosy and Related Diseases. Wright, London. Sieling, P.A., & Modlin, R.L. (1992). T cell and cytokine patterns in leprosy skin lesions. Springer Semin. Immunopathoi. 13, 413-426.