Reminiscences
LEPROSY VISITED SAMUEL L MOSGHELLA, M.D.
LJnder the auspices of the World Health Organization (WHO), a workstudy program was developed in which I visited several treatment and study centers for leprosy. The centers included the Leprosy Study Centre and the Hospital of Tropical Medicine in London, the All Africa Leprosy and Rehabilitation Training Centre (ALERT) of Addis Ababa, the Instituto Nacional de Dermatologia of Caracas and Centro Dermatologico "Pascua," Hospital General (Servicio de Dermatologia), Instituto de Enfermedades Tropicales, Instituto Politecnico Nacional (Departamento de Microbiologia) and IMANS Hospital of Mexico City. At the Leprosy Study Centre in London, Harman emphasized the value of biopsy for clinical classification of leprosy: it is more reliable and informative than smears for the detection and study of Mycobacterium leprae. He advocated the histopathologie technique, which improves the fixation and staining of tissue sections, as recommended by Ridley,^ consultant pathologist at the Hospital for Tropical Diseases, London, for the diagnosis and classification of leprosy. The Zenker-formalin preparation is believed to fix skin and nerve tissues more effectively. The combination of a modified Masson's trichrome and Fite-Faraco stains shows not only the histopathology bet-
From the Department of Allergy and Dermatology, Lahey Clinic Foundation, Boston, Massachusetts.
ter but also permits the M. leprae to be seen in the same section. This technique not only is more economical but also increases the accuracy in diagnosis, facilitates the interpretation, and enhances the teaching of the histopathologic material. The combination of stains (mixture of trichrome and Fite-Faraco stains) is called the Triff stain.2 Reactions in Leprosy
During the discussion of leprosy with Ridley, two phases of the disease were dwelt on: the classification and nature of reactions in leprosy^ and the subgroup of lepromatous leprosy, lepromatous indeterminate (Ll).4 The reactions in leprosy are acute episodes during the chronic course of the infection and appear to have an allergic or immunologic basis or both. They are erythema nodosum leprosum (ENL) and the reversal and down-grading reactions and are associated with mycobacteria antigen and alteration in the immunoiogic balance between the host and the bacillus. During the downgrading and reversal reactions, changes take place in the cellmediated immunity to M. leprae. The histologic changes in reactions are unrelated to the activity or regression of the leprous granuloma. The downgrad-
Address for reprints: Samuel L. Moschella, M.D., Lahey Glinic Foundation, 152 Bay Street Rd., Boston, MA 02215.
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ing reactions are associated with a decline in immunity, increase in number of bacilli, extension of infection near tuberculoid and borderline leprosy, and occurrence most likely in untreated patients. The reversal reaction is observed in patients who are diagnosed as having near lepromatous or borderline leprosy and whose disease is associated with a reduction in the bacterial load and an increase in immunity. Both these reactions produce edema and swelling of the skin lesions which may lead to ulceration, fever when there is extensive cutaneous involvement, appearance of new lesions and nerve involvement, ln reversal reactions, tuberculoid patterns as well as an early influx of lymphocytes are seen histologically. The severity of the reaction, both clinically and histologically, correlates with the extent of the shift in the spectrum, that is, the reaction resulting from the shift from borderline lepromatous to borderline tuberculoid (BT) would be greater than that from typical borderline (BB) to BT. In ENL and its variants, the larger the bacterial mass present, the more severe the reaction; the necrotizing reaction (Lucio's phenomenon), which is potentially fatal, is seen in the most bacilliferous lepromatous leprosy, the diffuse subtype. Despite differences between these reactive states, it may be difficult at times to differentiate them. They may alternate with one another, and there are types intermediate between ENL and reversal; it may be impossible to classify them with a histopathologic study of a single biopsy specimen. The Subgroups
v
Ridley and Waters'* called attention to the subgroups of lepromatous leprosy, particularly LI because of its importance in the interpretation of the results of drug
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studies, but did not want to overemphasize it. The significance of recognizing this phase of lepromatous leprosy is to call attention to the fact that it has a more favorable prognosis than lepromatous leprosy does, and it has potential for a reversal reaction. These cases of LI indicate evidence of evolution from a pre-existing borderline state. This type behaves differently from lepromatous leprosy; it undergoes reversal reaction and, unlike BL, is more prone to show ENL. Three clinical types of Ll described in the first classification are patients who have symmetrical heavy lepromatous infiltration, a strongly positive smear for acid-fast bacilli, and a few residual asymmetrical borderline lesions (BB type). In the second classification are patients who show little deformity of the head, especially of the face, those who have strongly positive smears, and those in whom severe ENL may develop despite the relative absence of the clinical stigmata of lepromatous leprosy. In the third classification are older persons who have mild infiltration of the face, multiple erythematous macular and papular lesions of the trunk and limbs, asymmetrical anesthesia, and a characteristic histopathologic picture exhibiting less rounded macrophages, increase of lymphocytes in the granuloma, often numerous plasma cells, and nerve changes resulting from active involvement during the previous borderline stage of infection. In 1965 in response to the estimated 3,868,000 cases of leprosy in Africa and from 200,000 to 250,000 cases in Ethiopia, representatives of the American Leprosy Missions, the Leprosy Mission (London), the International Society for Rehabilitation of the Disabled, the Ministry of Public Health of the Ethiopian Government, and Haile Selassie I University met in Addis Ababa to form the All
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Africa Leprosy and Rehabilitation Training Gentre (ALERT) outside of Addis Ababa. Housed within ALERT is the Armauer Hansen Research Institute (AHRI) which is financed by the Scandinavian countries and is very actively engaged in immunologic research in leprosy. The hospital hosts about 250 patients for the medical and surgical treatment of the complications of the disease and for physical therapy. More than 5,000 patients are registered in the outpatient clinic. It is the center for a rural control program covering an area of 20,000 square kilometers with a population of more than 70,000. More than 2,000 patients are registered for treatment in 22 clinics. Frequent educational courses are given for physicians, surgeons, nurses, physiotherapists, occupational therapists, medical assistants, medical students, student nurses, and social workers. Since leprosy is an easily recognized disease in Ethiopia, healers and priests do not want to risk their reputations by treating leprosy and readily advise patients to seek medical help. Unfortunately, the revelation of the disease encourages begging because the patient believes he is being punished by God and begs in His name.-"" Authorities in Addis Ababa are becoming concerned because of the number of affected people in the streets of the city.5 Characteristics of Some Types Although lepromatous leprosy is the type most frequently seen, one from a region relatively free of tuberculoid leprosy is struck not only by the incidence of BT cases and the degree of neural involvement but also by the severity of the reversal reaction. These reactions require prolonged or interrupted courses of moderate to high doses of corticosteroids as well as B663 (Glofazimine, Lamprene, G30 320) given in an attempt
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to minimize permanent neural damage with its paralysis and deformities and its socioeconomic implications. The sulfone therapy was usually continued. Histoid leproma'^ was observed in the hospital and the clinic population of ALERT in relapsed and nonrelapsed patients and in those who became resistant to sulfone therapy. The diagnosis of this stage is made by the associated clinical characteristics and the changes in the bacteriologic and morphologic indexes, and in the drug-resistant cases by an additional feature, the failure of a therapeutic response to even significantly higher doses. Unfortunately, facilities for mouse footpad studies for these resistant and other problem cases are not currently available. AHRI provides serologic as well as urinary tests for the detection of DDS (Dapsone, Aviosulfone) which help to determine whether the patient's failure to improve results from lack of intake, or malabsorption, or resistance to the drug. I noticed only the described cutaneous lesions of histoid leproma; none of the subcutaneous types were seen. Papules and nodules may be few or many, may disseminate, may be firm, erythematous and hemispheric with a slight constriction around the base, or may be less inflamed and clinically resemble dermatofibromas. The so-called soft histoid nodules are less well defined and less firm and are arranged in groups with a tendency to fuse to form irregular plaques. At ALERT, there are presently three inpatients with disseminated cutaneous leishmaniasis (lepromatoid type of cutaneous leishmaniasis).7-« The lepromatoid type of leishmaniasis resembles the nodular type of lepromatous leprosy but differs in several ways, such as the characteristic involvement of the tip of the nose. The lesions are softer to the touch, and the lesions of the extremities, espe-
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cially of the knees and elbows, tend to coalesce to form diffuse irregular plaques. With the lesions of the lower extremities, there may be an associated lymphedema. In lepromatoid type, there is easy demonstration of leishmania in the hematoxylin and eosin-stained histopathologic slides. At AHRl, Godal and his collaborators are conducting immunologic studies, especially in the area of delayed hypersensitivity in leprosy. They have made the following observations: 1. Lepromatous patients fail to respond to M. leprae not only in the lepromin skin test but also in the lymphocyte transformation test (LTT), leukocyte migratory inhibition, and indirect macrophage migration inhibition tests. 2. The specific immunologic defect is limited to the lymphocyte in lepromatous leprosy and is long lasting even after treatment has reduced significantly or eliminated the antigenic load. 3. The lack of host resistance in lepromatous leprosy results from the mechanism of immunologic tolerance ("central failure"). Godal and associates emphasize the droplet route of transmission of the disease. In view of the high degree of transmission of M. leprae as manifested by the positive LTT to hospital personnel who practice and enjoy higher hygienic conditions, it was suggested that improvement of hygienic conditions would not enhance leprosy control and that the absence of disease in most medical personnel results from the development of effective immunity. Factors responsible for a downgrading of the disease are to a large extent unknown, but infections, especially viral, which are known to suppress cell-mediated immunity, may occasionally be re-
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sponsible. Since many who are exposed to M. leprae become immune without contracting the disease, those in whom tuberculoid leprosy develops exhibit a relative deficiency of immunity. The lepra reactions are caused by increased (reversal) or decreased (downgrading) immune response. The reversal reactions are characterized by a clinical deterioration which corresponds to the extent oi the shift in the Ridley classification and is precipitated by a rapid increase in cell-mediated immune responsiveness to M. leprae. This is demonstrable by tests j exhibiting a significant increase of lym-'^ phocyte transformation and of leukocyte migration inhibition. The LTT appears to j be useful not only for the classification of reactions but also for prognosis. I visited the leprosy clinic and research facilities at the Instituto Nacional de Dermatologia in Caracas, Venezuela, ln the outpatient clinic, 10 pregnant women and one woman who was 2 months postpartum with leprosy were examined. Two women who had borderline leprosy (BB) were experiencing a downgrading phenomenon to BL. The onset of the reaction was in the last trimester of pregnancy of one woman and 2 weeks postpartum of the other. Two of the patients, one having had 8 pregnan-| cies and the other 2 pregnancies (presentj pregnancies included), had never experi-' enced any reactions. The remaining 7 pregnant women had had ENL during 1 to 3 of their pregnancies. The onset of the ENL reaction was usually within the first trimester. There was an associated miscarriage in only one of these patients; she had a severe reaction and experienced immediate relief upon the loss of her child. Another patient had had 2 severe episodes of ENL very early in the first trimester in successive pregnancies; these reactions were not controlled by
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high doses of corticosteroids but subsided completely upon abortion. The ENL of one patient was the presenting sign and symptom of her disease. Ross of ALERT, Convit of Caracas, and Latapf of Mexico City confirmed the impression of the increased evidence of ENL during pregnancy but were not aware of, or impressed by, the possibility of pregnancy having a downgrading effect on leprosy. ,,. Research in the Field
Several interesting studies are being conducted at the Institute by Avila and Convit. Avila has been evaluating the lysozyme changes in the polymorphonuclear leukocytes of patients with lepromatous and tuberculoid leprosy on exposure not only to the bacilli of M. leprae but to other organisms; there were no significant differences in either type of leprosy. Convit evaluated the macrophage response and activity to the injection of dead M. leprae into the skin of tuberculoid and lepromatous patients. In patients with tuberculoid leprosy, the organisms are cleared at the inoculation site within 30 days in contrast to the failure to be cleared during a 3 months' period of observation in patients with lepromatous leprosy. Other injected materials were effectively cleared in both types of leprosy. Convit and his collaborators, like Godal and his group, believe that the lack of immunologic recognition of M. leprae as an antigen capable of eliciting delayed hypersensitivity responses in lepromatous leprosy is pre-existent and specific and is not produced by the disease itself. This does not apply to other antigens.'^ They compared 2 disease models, lepromatous leprosy and diffuse cutaneous leishmaniasis (DLL)io and
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found them to have similar clinical, pathologic, parasitologic and immunologic characteristics.^ In Mexico City at the Centro Dermatologico "Pascua," cases of lepromatous leprosy in reaction, especially those involving the Lucio phenomenon, were studied. One patient with Lucio reaction had been treated mistakenly for 3 years by a referring physician with prednisone with the diagnosis of systemic lupus erythematosus. Latapi called attention to the effect of a secondary infection in precipitating the Lucio phenomenon and the occurrence of this type of reaction during the early phase of sulfone therapy in contrast to ENL, which appears later during effective therapy. Thalidomide is the most effective drug for ENL." It is of questionable therapeutic assistance in Lucio's phenomenon, which still requires corticosteroid therapy, sometimes at high doses. It is given freely to men with ENL and only to women who are unable to conceive or are receiving a parenteral anovulatory drug. Latapf was unable to give the incidence of leprosy in children but stated that tuberculoid, lepromatous, and indeterminate leprosy are seen equally among them, and that the occurrence of borderline leprosy is rare. The solitary nodule of tuberculoid leprosy of the face in children is infrequent but clinically characteristic. In Mexico, reactions are unusual in children and when they occur they are mostly of the ENL type. They occur usually prepubertally, between the ages of 11 and 13 years. In children, lepromatous leprosy responds very well to treatment but if untreated tends to progress relatively rapidly. Uribei2 stated that in patients up to 3 years of age the disease is predominantly tuberculoid; from 3 to 5 years of age, it is tuberculoid and indeterminate;
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from 5 years of age and older it is indeterminate and lepromatous. During rounds at the Instituto d Enfermedades Tropicales of Mexico City, and after having examined a patient with diffuse leishmaniasis, the clinical and immunologic similarities to lepromatous leprosy were discussed. The ideas were similar to those expressed in Ethiopia and Venezuela. At the Instituto Politecnico Nacional, Departamento de Microbiologia, the work of Estrada-Parra'3 and his group was discussed. Carbohydrate complexes which have been isolated from the capsule of M. leprae were found to be antigenic. Similar polysaccharide antigens have been identified in other mycobacteria as well as Nocardia. Group-specific polysaccharide antigens have been identified in lepromatous leprosy but not in tuberculoid leprosy." They have been tempted to speculate that the antigens may be an integral part of the immune complex responsible for the vasculitis of ENL. References 1. Ridley, D. S., Personal communication. 2. Wheeler, E. A., Hamilton, E. G., and Harman, D. )., An improved technique for the histo: pathological diagnosis and classification of leprosy. Leprosy Rev. 36:37, 1965. 3. Ridley, D. S., Reactions in leprosy. Leprosy Rev. 40:77, 1969.
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4. Ridley, D. S., and Waters, M. F., Significance of variations within the lepromatous group. Leprosy Rev. 40:143, 1969. 5. Giel, R., and van Luijk, J. N., Leprosy in the Ethiopian society. Int. J. Lepr. 38:187, 1970. 6. Rodriquez, J. N., The histoid leproma. Its characteristics and significance. Int. J. Lepr. 37:1, 1969. 7. Price, E. W., and Fitzherbert, M., Gutaneous leishmaniasis in Ethiopia. A clinical study in review of literature. Ethiopian Med. J. 3:57, 1965. 8. Balzer, R. J., Destombes, P., and Schaller, K. F., Pseudolepromatous cutaneous leishmaniasis in Ethiopia. Bull. Soc. Path. Exot. 53:293, 1960. 9. Gonvit, J., Pinardi, M. E., and Arias Rojas, F., Some considerations regarding the immunology of leprosy. Int. J. Lepr. 39{Pt. 2): 556, 1971. 10. Gonvit, ]., and Kerdel-Vegas, F., Disseminated cutaneous leishmaniasis; inoculation to laboratory animals, electron microscopy and fluorescent antibodies studies. Arch. Dermatol. 91:439, 1965. 11. Latapi, F., Saul, A., and Gomez-Vidal, M., Talidomida en el tratamiento de la reaccion leprosa. Pres anas de experiencia en Mexico. Gac. Med. Mex. 99:917, 1969. 12. Dra Maria Guadalupe Ayala Uribe, Personal communication. 13. Estrada-Parra, S., Galderon, S., Salazar-Mallen, M., et al., Immunochemistry and significance of Mycobacteria polysaccharide. Rev. Lat. Am. Microbiol. 9:1, 1967. 14. Galderon Manes, S., Salazar-Mallen, M., and Estrada-Parra, S., Nuevos datos en relacion con la composicion antigenica de Mycobacterium leprae. Rev. Invest. Salud Publica 27:117, 1967.