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Occurrence of reactions, their diagnosis and management in leprosy patients treated with multidrug therapy; experience in the leprosy control program of the All Africa Leprosy and Rehabilitation Training Center (ALERT) in Ethiopia.

This paper reports on reactions in leprosy patients who were treated with multidrug therapy (MDT) in the leprosy control program of the All Africa Leprosy and Rehabilitation Training Center (ALERT) in Ethiopia. Only those reactions which occurred in patients who had not been treated with dapsone before MDT and which required treatment with prednisolone were included. Until the end of the second year of MDT a reversal reaction had been diagnosed in 43.6% of 266 borderline lepromatous (BL) patients and in 19.2% of 109 lepromatous leprosy (LL) patients, and an erythema nodosum leprosum (ENL) reaction in 2.7% and 11.1% of the patients, respectively. The reversal reactions were observed in 4.9% of the BL patients and in 0% of the LL patients at the time of diagnosis of leprosy, in 26.3% and 12.8% of the patients during the first year of MDT, and in 12.4% and 6.4% during the second year of MDT. ENL reactions were seen in 0.8% of BL patients at diagnosis, 1.1% in the first year and 0.8% in the second year and 2.8% at diagnosis, 5.5% in the first year, and 2.8% in the second year for LL patients. During a 3 1/2-year period, a total of 405 reactions were diagnosed among multibacillary (MB) patients on MDT; 365 of these reactions (90.1%) were reversal reactions and only 40 (9.9%) were ENL reactions. The point in time of the reversal reactions showed that the risk of reversal reaction is highest during the first year of MDT. Thereafter there is a gradual decline, although reactions were still observed during the fifth year of MDT. A reversal reaction was diagnosed in 21.0% of 438 BT patients; in 3.4% of the patients the reaction was present at the time of diagnosis of leprosy; in 10.3% it occurred during MDT, and in 7.3% during the first year after release from MDT. During a period of 3 1/2 years a total of 183 reversal reactions were diagnosed among BT patients. The point in time showed a declining trend in the risk of reversal reaction after starting MDT. The risk is highest during MDT, followed by the first 6 months after stopping MDT. However, reactions, although few, still occurred during the fourth year after stopping MDT. The analysis of the results of prednisolone treatment in 161 patients who were treated for nerve function loss in the field showed that 142 patients (88.2%) regained complete or partial recovery of the nerve function(s), while no improvement was observed in 19 patients (11.8%).(ABSTRACT TRUNCATED AT 400 WORDS)

Drug Therapy, Combination

Duration of multidrug therapy in paucibacillary leprosy patients; experience in the leprosy control program of the All Africa Leprosy and Rehabilitation Training Center (ALERT) in Ethiopia.

Multidrug therapy (MDT), according to the recommendations of a WHO Study Group of 1982, was introduced in the leprosy control program of the All Africa Leprosy and Rehabilitation Training Center (ALERT), Ethiopia, in January 1983. Of 6042 paucibacillary patients who were put on MDT during a period of 7 years, 5485 patients (90.8%) completed the course of MDT; 437 patients (7.2%) did not fulfill the requirement for clinic attendance and either discontinued MDT themselves or the treatment was discontinued by the service. The remaining 120 patients (2.0%) either died, were transferred, left the control area or continued MDT after 9 months. The urine spot test for the presence of dapsone showed a significantly higher proportion of positive results for patients on MDT than for patients on dapsone. The analysis of the compliance with the prescribed doses of MDT showed that of 963 patients, 81.9% received six doses of MDT and 18.1%, more than six doses; 82.6% of these 963 patients attended with 100% regularity, 12.7%, 3.6%, and 1.1% missed one, two, or three clinic appointments, respectively, while fulfilling the requirement for overall clinic attendance. Of the 429 patients who had not been treated with dapsone before MDT, the skin lesions were clinically active at the time of stopping MDT in 130 patients (30.3%). In all, except one of the 114 patients (0.9%) who attended for follow-up examinations, the skin lesions had become clinically inactive within 2 years after stopping MDT. The recommended duration of MDT is discussed based on findings in the ALERT leprosy control programs and observations by others.

Dapsone

Relapses among leprosy patients treated with multidrug therapy: experience in the leprosy control program of the All Africa Leprosy and Rehabilitation Training Center (ALERT) in Ethiopia; practical difficulties with diagnosing relapses; operational procedures and criteria for diagnosing relapses.

Multidrug therapy (MDT), according to the recommendations of a WHO Study Group of 1982, was introduced in the leprosy control program of the All African Leprosy and Rehabilitation Training Center (ALERT), Ethiopia, in January 1983. Paucibacillary (PB) patients are treated with 6 months of MDT. Multibacillary (MB) patients are treated with at least 2 years of MDT and until skin-smear negativity. An analysis was made of the relapses which had been diagnosed among self-reporting patients in four rural districts and Addis Ababa. Among 3065 PB patients, 34 relapses (1.1%) were diagnosed during an average period of 6.1 years after stopping MDT (range 2 1/2 to 7 1/2 years). Among 2379 MB patients, 24 relapses (1.0%) were diagnosed during an average period of 4.7 years after stopping MDT (range 2 1/2 to 6 years). The estimated relapse rate per 1000 patient-years after release from MDT was 2.1 for PB patients and 2.4 for MB patients. From the analysis of the clinical, bacteriological, and histopathological findings, it was concluded that there was strong positive evidence for the diagnosis for 16 of the 34 relapses in the PB patients and for 0 of the 24 relapses in the MB patients. The main cause for overdiagnosis of MB relapses was that too much reliance had been put on skin-smear results, without a careful comparison of the results with those from before, during, and at completion of MDT; the diagnosis was based on the finding of positive smears in one set of smears only; insufficient attention was given to finding solid-staining bacilli; and findings in biopsies, if these were examined, did not confirm the diagnosis. The main cause of overdiagnosis of PB relapses was that too much reliance was put on histological findings, while these are often inconclusive for differentiating between a relapse and late reversal reaction. Recommendations are made on how to limit overdiagnosis of relapses. Operational procedures and criteria for making the diagnosis under conditions where facilities for back-up histological and mouse foot pad investigations are not available are proposed.

Clofazimine

Relapses in leprosy patients after release from dapsone monotherapy; experience in the leprosy control program of the all Africa Leprosy and Rehabilitation Training Center (ALERT) in Ethiopia.

Before implementation of multidrug therapy (MDT), leprosy patients who were clinically inactive, skin-smear negative and had been treated with dapsone monotherapy for at least 5 years (paucibacillary patients) or for at least 10 years (multibacillary patients) were released from treatment. An analysis was made of self-reporting relapses in 1081 paucibacillary (PB) patients and 1123 multibacillary (MB) patients who had been released in Addis Ababa and two rural districts of the leprosy control program of the All Africa Leprosy and Rehabilitation Training Center (ALERT). During an average period of 6.6 years after stopping dapsone, 44 relapses were diagnosed among the PB patients and 148 relapses among the MB patients. The overall relapse rate was 4.1% or 7.2 per 1000 patient-years after release from treatment for PB patients and 13.2% and 24.8, respectively, for MB patients. The annual relapse rate in PB patients did not differ significantly from year to year. However the relapse rate for MB patients was significantly lower during the fifth to seventh years after stopping treatment compared with the first 4 years. Based on clinical findings there was a strong suspicion of relapse with dapsone-resistant bacilli in 40.4% of MB relapses. It is concluded that the relapse rate for PB patients is acceptable. However, the relapse rate for MB patients is considered too high. It is strongly recommended to administer to all MB patients, including those who have been on long-term treatment with dapsone and have become clinically and bacteriologically inactive, a 2-year course of MDT.

Adolescent

Experimental murine leprosy. IX. Antibodies against Mycobacterium lepraemurium in C3H and C57BL mice with murine leprosy and in patients with lepromatous leprosy.

Sera from C3H and C57BL mice infected with Mycobacterium lepraemurium (MLM) and from human leprosy patients were examined for antibodies against MLM by a crossed immunoelectrophoresis (CIE) technique. Altogether antibodies against six or seven MLM antigens were found in the mouse sera. After a small inoculum of MLM, C3H mice produced more antibodies than C57BL mice. After a large inoculum both strains produced about the same amount of antibodies but showed qualitative differences in their response patterns. A serum pool from patients with lepromatous leprosy contained antibodies against six MLM antigens; five of these were identical with the antigens against which antibodies were found in infected mice. C57BL mice that had lost their delayed-type hypersensitivity to MLM during the course of a disseminated infection showed a fairly strong antibody response to three antigens and a weak response to three others. Since almost the same spectrum of antibodies, although in lower titres, could be demonstrated in C57BL mice with intact delayed-type hypersensitivity to the bacilli, these antibodies did not seem to interfere with the expression of cell-mediated immunity.

Animals

Comparative study of the 48-hour response to soluble antigens obtained from human and armadillo leprosy material in lepromatous leprosy patients and normal persons, contacts of leprosy patients.

We prepared antigens by precipitating with 80% ammonium sulfate supernatants of human and armadillo antigen at a concentration of 160 X 10(6) bacteria per ml. The precipitate was resuspended, dialyzed and filtered. The antigen obtained was inactivated with trypsin during 30 minutes. The tests made with these antigens were negative for the 48-hour test in lepromatous patients and highly positive in normal persons who were contacts of leprosy patients.

Animals

Biochemical, immunological and genetic studies in leprosy. II. Profile of immunoglobulins, complement components and C-reactive protein in sera of leprosy patients and healthy controls.

Various classes of immunoglobulins (IgA, IgM, IgG, IgD and IgE), complement components (C3 and C4) and C-reactive protein (CRP) were estimated in sera from normal healthy controls and leprosy (lepromatous and tuberculoid) patients from Ethiopia. Higher levels of IgA, IgM, IgG and IgD were found in lepromatous leprosy compared with normal healthy people while in tuberculoid leprosy only IgM, IgG and IgD levels were increased. Borderline leprosy patients showed increase in IgG level only. Although an increase in IgE was noted in lepromatous leprosy, it was not significant; the variations in IgE levels could be due to different socioeconomic background and exposure to intestinal parasites. C3 component was significantly reduced in leprosy patients compared with healthy controls while no difference in C4 component was observed. The results point towards an involvement of the "alternate pathway". A positive test against C-reactive protein antiserum was given by about 20% of the normal healthy controls while more than 60% lepromatous and tuberculoid leprosy patients were CRP positive. The results are discussed in relation to the status of immunoglobulins and complement components in leprosy and possible factors (environmental and genetic) which might affect them.

C-Reactive Protein

Lymphocyte transformation test in leprosy: decreased lymphocyte reactivity to Mycobacterium leprae in lepromatous leprosy, with no evidence for a generalized impairment.

Untreated leprosy patients were examined with respect to lymphocyte transformation in vitro after stimulation with mycobacterial and other microbial antigens, allogeneic lymphocytes, or nonspecific mitogens. Methods were used to circumvent technical variability. The results were compared with those obtained in controls matched for age, sex, race, and environment. No evidence was found for a generalized impairment of lymphocyte transformation in vitro, whereas a specific defect towards Mycobacterium leprae was demonstrable in lepromatous leprosy patients. The response to M. leprae, investigated in untreated and treated leprosy patients, decreased along the leprosy spectrum. Moreover, the results of the one-way mixed lymphocyte cultures showed that lymphocytes from leprosy patients had a normal stimulator and responder capacity, when they were tested against a panel of allogeneic lymphocytes. The influence of serum factors was investigated in untreated leprosy patients in the mixed lymphocyte culture. On average, tuberculoid as well as lepromatous sera showed a low-level depressive effect, but some sera showed a stimulatory effect. Therefore, a depressive effect of serum factors cannot be considered to be a general feature of leprosy. The correlation between the Mitsuda type of lepromin skin test and the lymphocyte reactivity in vitro to M. leprae was studied, and a positive correlation was found.

Antigens, Bacterial

Leprosy XII. Quantitative analysis of thymus-derived lymphocyte response to phytohemagglutinin in leprosy.

The immune status of various leprosy patients was evaluated by using a micromethod to evaluate lymphocyte responses to phytohemagglutinin (PHA). In our study, whole blood was used and the degree of response to PHA stimulation was expressed in terms of unit volume of blood. A markedly decreased response to PHA stimulation was noted in patients with active lepromatous leprosy. Patients with active lepromatous leprosy who have been proved drug (DDS) resistant showed less response than did those of drug sensitive patients with active lepromatous disease, while the patients with active lepromatous leprosy complicated by erythema nodosum leprosum (ENL) showed higher response than did those of patients with no complicated ENL. Comparing the results obtained to those obtained using other methods for T cell analysis indicates that these results reflect the number of T lymphocytes in the leprosy patient. Thus, this simple method is of value in assaying the presence and responses of T lymphocytes in the leprosy patient.

Dapsone

Biochemical, immunological and genetic studies in leprosy. I. Changes in serum lactate dehydrogenase isoenzymes, creatine phosphokinase and aldolase activity in different forms of leprosy.

Serum lactate dehydrogenase isoenzymes, creatine phosphokinase and aldolase activity were determined in healthy control subjects and in lepromatous and tuberculoid leprosy patients from Ethiopia. Sera from lepromatous patients showed a higher total LDH activity compared with control subject. The values for tuberculoid leprosy patients were similar to those of controls. Sera from normal healthy controls showed a higher proportion of LDH-H form (72%) while lepromatous leprosy patient's sera exhibited a higher proportion of LDH-M form (55%). Tuberculoid leprosy patients showed a pattern similar to that of healthy controls. A possible significance of these observations is discussed. No significant variations were observed in fructose-1,6-diphosphate aldolase activity within the different types of disease and controls. Although creatine phosphokinase levels in different types of leprosy decreased significantly from those of normal healthy, it falls within the reported variation of the activity in normal sera.

Creatine Kinase

Ultrastructural changes in blood vessels of peripheral nerves in leprosy neuropathy. I. Tuberculoid and borderline-tuberculoid leprosy patients.

Radial or superficial peroneal nerve biopsies of 6 patients with tuberculoid or borderline-tuberculoid leprosy and 6 control nerve biopsies were examined by electron microscopy. Endoneurial blood vessels showed histopathology in all the leprosy patients. Changes, in particular, involved the basement membrane in postcapillary venules and venules. Multilayered parellel basement membranes, with collagen and ground substance, formed a thick coat ("hyaline zone") around the vessels. It is suggested that the zone inhibits passage of nutrients and metabolites and, thus, contributes to or is the main cause of the local destruction of (unmyelinated) nerve fibres and the lack of nerve fibre regeneration observed in this type of leprosy. The perivascular zone, presumably, is produced by pericytes in response to defects in the "blood-nerve barrier" of endoneurial vessels. In granulomata of leprosy skin lesions, a perivascular zone was not present. The endothelium of endoneurial vessels, in affected nerves, generally was normal. Occasionally, however, gaps and fenestrations were seen and there were histological indications that leakage of blood plasma had occurred through the gaps and through the basement membrane of the endothelium. Occlusion of endoneurial vessels was found only in the oldest patient and the degeneration of nerve fibres generally observed thus is considered not to be caused by ischaemia. Histopathology in epi-and perineurial vessels was definitely less pronounced than in endoneurial vessels.

Adolescent

Biochemical, immunological and genetic studies in leprosy. III. Genetic polymorphism of C3 and immunoglobulin profile in leprosy patients, healthy family members and controls.

148 members from 30 families (64 children) from Ethiopia, where one of more persons were affected with leprosy, were investigated for genetic polymorphism of C3, serum concentration of ss1C/ss1A-globulin and immunoglobulins A, G and M using high voltage agarose electrophoresis, immunoelectroassay and single radial immunodiffusion techniques respectively. The results are compared with related healthy controls. No association between C3 phenotypes and leprosy could be established through family studies. C3 concentration was, however, lower in leprosy patients. Difficulties and drawbacks of such studies with small families are discussed.

Adult

Induction of lepromin positivity by a candidate anti-leprosy vaccine Mycobacterium w in lepromin negative healthy contacts of multibacillary leprosy patients.

In a hospital based study, 362 household contacts of multibacillary leprosy patients were screened for evidence of leprosy and 54 (14.9%) were found to be having leprosy. The remaining 308 apparently healthy contacts were lepromin tested and 109 (35.4%) were observed to be negative to Mitsuda lepromin. M.w vaccine was administered intradermally to 95 of these 109 lepromin negative contacts. Sixty eight of them could be retested for lepromin A reactivity. Fifty six (82.35%) manifested lepromin conversion. The twelve subjects who did not show lepromin conversion, received a second dose of the vaccine, and eleven subsequently became lepromin positive. The overall lepromin conversion rate was thus 98.5% (67 out of 68). Follow-up of these contacts upto a period of 30 months did not demonstrate reversion of lepromin positivity back to negativity status. No untoward effects of vaccination were observed except for local ulceration at the site of vaccine administration.

Adolescent

Depressive effect of serum from patients with leprosy on mixed lymphocyte reactions. Influence of anti-leprosy treatment.

Mixed leucocyte cultures, from two normal donors, were set up in media containing human serum from one of the following sources: (a) a pool of normal group AB donors; (b) Chinese, Malay or Indian patients with untreated leprosy; (c) the same patients after effective anti-leprosy treatment; (d) control Chinese, Malay or Indian subjects. Transformation was estimated by measuring the incorporation of tritiated thymidine in the last 24 hr of a 7-day culture period. Transformation was impaired in sera from treated lepromatous patients, but was less impaired or not impaired at all in sera from treated lepromatous patients. The loss of depressive activity after treatment was more marked in Chinese and Indian than in Malay patients. Transformation was also impaired, though to a lesser extent, in sera from patients with untreated tuberculoid leprosy; it was still impaired in sera from treated tuberculoid patients. There was no evidence of specificity in impairment of mixed lymphocyte reactivity and lymphocytotoxic antibodies appeared to play no role. The incidences of hepatitis B antigen and antibody and of anti-nuclear factor were not notably high.

Adolescent

Do human leukocyte antigens have a role to play in differential manifestation of multibacillary leprosy: a study on multibacillary leprosy patients from north India.

118 multibacillary leprosy patients with differential manifestations were studied for the antigens they expressed at MHC loci to investigate the role of human leukocyte antigens in the differential response to the same causative agent. While the lepromatous leprosy (LL) patients showed a significant increase of Bw60, DR2, DRw8 and DQw1, borderline lepromatous (BL) patients had Bw52, DR9 and DQw7 significantly more often as compared to the normal controls. A comparison of LL, BL and mid-borderline (BB) patients showed a significantly higher frequency of Bw60 in LL patients as compared to the BL. However, Bw52, Bw53, DR9 and DQw7 were found significantly more often in the BL patients as compared to the LL patients but the difference failed to reach significance after pc. A comparison of HLA antigens in BB patients with those of either the LL or BL patients did not show any significant differences.

Antigens, Bacterial

Experimental lepromatous leprosy in the white-handed gibbon (Hylobatus lar): successful inoculation with leprosy bacilli of human origin.

Leprosy bacilli of human origin were inoculated into a white-handed gibbon by the i.v. and i.p. routes, and also locally into ears, testis and around an ulnar nerve. The animal was observed closely during a period of nearly 15 years and did not exhibit any clinical evidence of cutaneous or neurological disease. At death, a wide range of tissues was taken for bacterial counts and histological examination, and a disseminated and progressive infection was demonstrated. Acid-fast bacilli were found in many sites; their morphological appearance distribution in nerves, and pattern of multiplication in mouse foot-pads, and also the presence of anti-mycobacterial antibody in the serum and the absence of specific lymphocyte transformation were all in keeping with an infection by Mycobacterium leprae, at an early lepromatous stage. This is probably the first fully documented report of experimental lepromatous infection in a primate. The findings are discussed in relation to the long incubation period of le promatous leprosy and the difficulties of diagnosing the disease at an early stage in man.

Animals

Leprosy in the Netherlands. A review of leprosy patients registered at the Department of Dermatology, University of Amsterdam in the years 1972-1976.

Recently, there has been a sharp increase in the number of leprosy patients in The Netherlands, due to an increased immigration from Surinam where leprosy is hyperendemic. The patients registered at the Dermatological Department of the University of Amsterdam during the years 1972-1976 were reviewed. It was found that 28% of the untreated patients had recently suffered a relapse. A substantial percentage took the medication irregularly or discontinued treatment prematurely and quite a few patients required other types of treatment besides chemotherapy, such as surgical treatment and physiotherapy.

Humans