[Evaluation of the clinical classification of new cases of leprosy. Study conducted at the Marchoux Institute in Bamako, Mali]. / Evaluation de la classification clinique des nouveaux cas de lèpre. Etude réalisée á l'Institut Marchoux (Bamako, Mali).

INTRODUCTION: The difficulties related to the bacilloscopic diagnosis of leprosy, providing a more reliable classification of cases, in 1995 led the WHO to recommend the use of a new classification, in endemic countries, based on clinical criteria alone, in order to simplify the poly-chemotherapeutic regimens. According to our experience in the Marchoux Institute, this classification may lead to errors in diagnosis through overzealous or mis-interpretation of the two forms of leprosy. The aim of our study was to evaluate the concordance between this clinical classification and that based on a bacilloscopic examination. PATIENTS AND METHODS: We conducted a descriptive study of new cases of leprosy seen at the Marchoux Institute, without distinction in gender or age, from January to December 2000. All the patients included underwent clinical examination and a bacilloscopic exploration to provide a double classification. The concordance between the two classifications was assessed using the Kappa test. RESULTS: Two hundred new cases of leprosy were included. Out of 126 clinically multi-bacillary cases, 61 were confirmed bacteriologically, and 65 were false positives. Out of 74 clinical cases with few bacilli, 2 were bacteriologically multi-bacilli. The concordance between the two classifications was average (Kappa=0.40). There was a significant difference between the percentages of multi-bacilli observed in both classifications (p<10(-8)). DISCUSSION: The clinical classification may well overestimate the multi-bacillary form. In the absence of a reliable bacilloscopic apparatus, a more detailed clinical classification of leprosy forms must be developed.

Evaluation de la classification clinique des nouveaux cas de lèpre. Etude réalisée à lInstitut Marchoux (Bamako, Mali) / Evaluation of the clinical classification of new cases of leprosy. Study conducted at the Marchoux Institute in Bamako, Mali

INTRODUCTION: The difficulties related to the bacilloscopic diagnosis of leprosy, providing a more reliable classification of cases, in 1995 led the WHO to recommend the use of a new classification, in endemic countries, based on clinical criteria alone, in order to simplify the poly-chemotherapeutic regimens. According to our experience in the Marchoux Institute, this classification may lead to errors in diagnosis through overzealous or mis-interpretation of the two forms of leprosy. The aim of our study was to evaluate the concordance between this clinical classification and that based on a bacilloscopic examination. PATIENTS AND METHODS: We conducted a descriptive study of new cases of leprosy seen at the Marchoux Institute, without distinction in gender or age, from January to December 2000. All the patients included underwent clinical examination and a bacilloscopic exploration to provide a double classification. The concordance between the two classifications was assessed using the Kappa test.RESULTS: Two hundred new cases of leprosy were included. Out of 126 clinically multi-bacillary cases, 61 were confirmed bacteriologically, and 65 were false positives. Out of 74 clinical cases with few bacilli, 2 were bacteriologically multi-bacilli. The concordance between the two classifications was average (Kappa=0.40). There was a significant difference between the percentages of multi-bacilli observed in both classifications (p<10(-8)). DISCUSSION: The clinical classification may well overestimate the multi-bacillary form. In the absence of a reliable bacilloscopic apparatus, a more detailed clinical classification of leprosy forms must be developed.

[Systematic search for parasites among leprosy patients in Mali]. / Recherche systématique de parasites chez les lépreux au Mali.

Practice of multidrug therapy in leprosy (combination Dapsone + Rifampicine + Clofazimine) established since 1981, has significantly reduced the incidence of the disease. However, immunosuppression due to treatment of multi-drugs therapy induced adverse reactions with glucocorticoid and the change in host immune response due to the leprosy itself, might increase the risk of parasitic infections. To test this hypothesis, we carried out a case-control study at the "Institut Marchoux" in Bamako. Stool and urine samples from all patients included in the study were examined for parasites identification. In addition, we performed thick and thin blood film to identify malaria infection and skin biopsy (snip) to detect onchocerciasis. A total of 121 cases of leprosy and 219 controls aged 10-84 years old were included in the study from March 1999 to February 2000. Sixty two percent (n = 121) of cases were treated with glucocorticoid. The prevalence of infection due to Entamoeba coli and Entamoeba histolytica were higher in cases than in controls (p = 0.02). The prevalence of infection due to hookworms was higher in cases than in controls. There was no difference of the infections to the other intestinal parasites. Three cases of cryptosporidiosis and one case of isosporosis were observed in leprosy group vs none in the control group. There was no significant difference between cases and controls with regard to prevalence of Schistosoma haematobium, Trichomonas vaginalis and Onchocera volvulus. The prevalence of Plasmodium falciparum was 4.9% (6/121) in the leprosy case and 7.8% (17/219) in the control group. In conclusion, despite the corticotherapy and immunosuppression due to leprosy, there was no difference in prevalence of pathogenic parasites. Entomoeba coli, Entamoeba histolytica which have significantly higher prevalence among the cases were not pathogen therefore there was no higher risk of severe intestinal parasitosis among the cases of leprosy. Treatment with glycocorticoid in patients with leprosy did not suggest any impact on the prevalence of this parasitic infections. In addition, multidrug therapy did not show any effect on the carriage of Plasmodium falciparum.

Recherche systematique de parasites chez les lepreux au Mali / Systematic search for parasites among patients with leprosy in Mali

Practice of multidrug therapy in leprosy (combination Dapsone + Rifampicine + Clofazimine) established since 1981, has significantly reduced the incidence of the disease. However, immunosuppression due to treatment of multi-drugs therapy induced adverse reactions with glucocorticoid and the change in host immune response due to the leprosy itself, might increase the risk of parasitic infections. To test this hypothesis, we carried out a case-control study at the "Institut Marchoux" in Bamako. Stool and urine samples from all patients included in the study were examined for parasites identification. In addition, we performed thick and thin blood film to identify malaria infection and skin biopsy (snip) to detect onchocerciasis. A total of 121 cases of leprosy and 219 controls aged 10-84 years old were included in the study from March 1999 to February 2000. Sixty two percent (n = 121) of cases were treated with glucocorticoid. The prevalence of infection due to Entamoeba coli and Entamoeba histolytica were higher in cases than in controls (p = 0.02). The prevalence of infection due to hookworms was higher in cases than in controls. There was no difference of the infections to the other intestinal parasites. Three cases of cryptosporidiosis and one case of isosporosis were observed in leprosy group vs none in the control group. There was no significant difference between cases and controls with regard to prevalence of Schistosoma haematobium, Trichomonas vaginalis and Onchocera volvulus. The prevalence of Plasmodium falciparum was 4.9% (6/121) in the leprosy case and 7.8% (17/219) in the control group. In conclusion, despite the corticotherapy and immunosuppression due to leprosy, there was no difference in prevalence of pathogenic parasites. Entomoeba coli, Entamoeba histolytica which have significantly higher prevalence among the cases were not pathogen therefore there was no higher risk of severe intestinal parasitosis among the cases of leprosy. Treatment with glycocorticoid in patients with leprosy did not suggest any impact on the prevalence of this parasitic infections. In addition, multidrug therapy did not show any effect on the carriage of Plasmodium falciparum.

Association of NRAMP1 polymorphism with leprosy type but not susceptibility to leprosy per se in west Africans.

Twin and family studies indicate that host genetic factors influence susceptibility to leprosy and, possibly, leprosy type. Murine studies have suggested a role for the natural resistance-associated macrophage protein 1 (Nramp1) gene, which can influence cellular immune responses to intracellular pathogens. We evaluated a variation in the human homolog, NRAMP1, recently associated with tuberculosis susceptibility in West Africa. A total of 273 patients with leprosy and 201 controls from Mali were genotyped for NRAMP1 polymorphisms previously associated with tuberculosis. No association was found with leprosy per se (P = 0.83), but the NRAMP1 3'-untranslated region 4-bp insertion/deletion polymorphism was associated with leprosy type (P = 0.007). Heterozygotes were more frequent among multibacillary than paucibacillary leprosy cases. Thus, variation in or near the NRAMP1 gene may exert an influence on the clinical presentation of leprosy, possibly by influencing cellular immune response type.

Comparison of two methods of leprosy case finding in the circle of Kita in Mali.

Kita is a health district of Mali, a leprosy-endemic country in West Africa. We conducted a comparative study of passive and active case finding of leprosy in this district in 1997. In May and June, a mobile team realized active case finding by visiting 32 villages of more than 1000 inhabitants. For 12 months, peripheral health center nurses did passive detection after information and education sessions about the signs of leprosy in the other 37 main villages of Kita. The active detection rate (4.31 per 10,000) was threefold higher than the passive rate (1.5 per 10,000) and allowed us to find earlier cases of leprosy. Active case finding identified children and single-lesion disease; the passive method did not. Cost for finding a new case was estimated at 72 US$ by mobile team detection and 36 US$ by passive case finding. Although the active method looked more expensive than the passive one, it was the only effective strategy to detect leprosy patients in remote and difficult-to-access areas. Based upon the results of the study, a flow chart is proposed for the choice of case-finding method when designing a leprosy elimination program.

Comparison of two methods of leprosy case finding in the circle of Kita in Mali

Kita is a health district of Mali, a leprosy-endemic country in West Africa. We conducted a comparative study of passive and active case finding of leprosy in this district in 1997. In May and June, a mobile team realized active case finding by visiting 32 villages of more than 1000 inhabitants. For 12 months, peripheral health center nurses did passive detection after information and education sessions about the signs of leprosy in the other 37 main villages of Kita. The active detection rate (4.31 per 10,000) was threefold higher than the passive rate (1.5 per 10,000) and allowed us to find earlier cases of leprosy. Active case finding identified children and single-lesion disease; the passive method did not. Cost for finding a new case was estimated at 72 US$ by mobile team detection and 36 US$ by passive case finding. Although the active method looked more expensive than the passive one, it was the only effective strategy to detect leprosy patients in remote and difficult-to-access areas. Based upon the results of the study, a flow chart is proposed for the choice of case-finding method when designing a leprosy elimination program.

[Nature and sensitivity of bacteria superinfecting plantar ulcers caused by leprosy at the Marchoux Institute, Bamako, Mali]. / Nature et sensibilité des bactéries surinfectant les maux perforants plantaires d'origine lépreuse à l'Institut Marchoux, Bamako, Mali.

To determine potential usefulness of antimicrobial agents and to guide their prescription in the treatment of leprosy plantar ulcers, we conducted an in vitro study about germs' nature and sensitivity to antibiotics. We took samples of plantar ulcers secretion from 107 patients at Marchoux Institute. 92.5% of those ulcers were infected. These samples revealed 145 strains of micro-organisms among those, Staphylococcus aureus (70 strains) and genus Pseudomonas (41 strains) were the most frequent. These bacteria were resistant to several antibiotics currently used at Marchoux Institute (tetracycline, penicillin, cotrimoxazol and erythromicin). Antibiotics, efficient at 80% on tested strains, were expensive for patients. They cannot be recommended for the treatment of local infections. These results outline that the main treatment in plantar ulcers is based upon antiseptic solutions and keeping feet at rest. Antibiotherapy in case of extension of local infection would be based on the results of a previous study of sensitivity.

[Disabilities observed in new cases of leprosy diagnosed in the Bamako district (Mali) in 1994]. / Les infirmités observées chez les nouveaux cas de lèpre dépistés dans le district de Bamako (Mali) en 1994.

Our study concerns 244 new cases of leprosy diagnosed in the Bamako district in 1994. 154/244 patients could be contacted and were examined in the Leprosy Department of the Marchoux Institute in Bamako. Results showed that the presence of leprosy induced physical disabilities was associated with male gender (59%), advanced age (68%) and multibacillary disease (68%). Disabilities were also more frequent among patients having a rural or manual occupation at the time of screening or afterwards. There was a significant increase (p < 0.001) in the prevalence of disabilities when comparing patients at the time of diagnosis (29%) and thereafter (48%). This means that in 40% of disability cases, lesions developed during or after the treatment. Disabilities were predominantly observed in hands (33%) and feet (29%) with more frequent lesions in lateral popliteal, superior ulnar and posterior tibial nerves. Our results seem to demonstrate the inadequacy of preventive measures and management. This stresses the need for adequate prevention and therapy of leprosy induced disabilities in order to obtain proper eradication of leprosy induced health problems.

[Leprosy as a cause of physical disability in rural and urban areas of Mali]. / Place de la lèpre parmi les handicaps physiques en zones rurale et urbaine au Mali.

We performed a cross-sectional study of populations from two areas of Mali, in May and June 1996. The aim of the study was to assess the extent to which leprosy causes physical disability in Mali. One area was rural (Circle of Bougouni), the other urban (Bamako District). We used a cluster sampling method, with 500 households selected for study in each of the two areas. All members of the households randomly selected were included in the study. For all survey sites, the number of households was proportional to the number of inhabitants. The total study population was 8,175, including 172 cases of physical handicap, 76 in Bamako and 96 in Bougouni. The prevalence of physical handicap was 21 per 1,000 inhabitants (25.3 per 1,000 in rural areas and 17.3 per 1,000 in the city). The difference in the prevalence of physical handicap between the two areas was statistically significant (p = 0.01). Ten per cent of the disabilities were caused by leprosy. The most common causes of disability other than leprosy were trauma and poliomyelitis. Leprosy mostly caused disabilities in rural areas. In both areas, leprosy caused more disabilities in men and boys (64% of cases) than in women and girls. The frequency of disabilities caused by leprosy increased with age, whereas the frequency of handicaps with other causes decreased with age. This study shows that leprosy is still a major cause of disability in countries in which it is endemic, such as Mali. Disability prevention measures and physical rehabilitation programs should be incorporated into the national program for the elimination of epilepsy.

[Evaluation of the elimination of leprosy in Burkina Faso]. / Evaluation de l'élimination de la lèpre au Burkina Faso.

During May and June 1997, we conducted a rapid survey on leprosy prevalence in 30 villages. It was to assess reaching of the leprosy elimination threshold (one case per 10,000 inhabitants) in Burkina Faso. We drew lots for the villages in ten provinces among which five had the highest prevalence rates of leprosy in 1996 and five had the lowest prevalence rates. We added a leprosy elimination monitoring to the survey. This monitoring consisted of visits to the health centers covering the 30 villages. We interviewed and clinically examined 33 cases of leprosy in treatment in those health centers. We found fifty-one patients of leprosy in visited villages. The prevalence rate of leprosy (6.74 per 10,000 inhabitants) was twice higher than the prevalence rate registered in the same villages. We detected 28 new cases of leprosy during the survey. Proportion of hidden cases of leprosy were 54.9%. We estimated geographical coverage of MDT at 75% in the 10 provinces. Eight of the 27 visited health centers (29.6%) did not get sufficient supply. The cure rate has fallen from 93 to 73 per cent between 1992 and 1997. Our results show that leprosy elimination threshold is not reached in Burkina Faso. Leprosy control activities that were declining during the last five years need to be reinforced.

Bactericidal activity of a single-dose combination of ofloxacin plus minocycline, with or without rifampin, against Mycobacterium leprae in mice and in lepromatous patients.

To develop a fully supervisable, monthly administered regimen for treatment of leprosy, the bactericidal effect of a single-dose combination of ofloxacin (OFLO) and minocycline (MINO), with or without rifampin (RMP), against Mycobacterium leprae was studied in the mouse footpad system and in previously untreated lepromatous leprosy patients. Bactericidal activity was measured by the proportional bactericidal method. In mouse experiments, the activity of a single dose of the combination OFLO-MINO was dosage related; the higher dosage of the combination displayed bactericidal activity which was significantly inferior to that of a single dose of RMP, whereas the lower dosage did not exhibit a bactericidal effect. In the clinical trial, 20 patients with previously untreated lepromatous leprosy were treated with a single dose consisting of either 600 mg of RMP plus 400 mg of OFLO and 100 mg of MINO or 400 mg of OFLO plus 100 mg of MINO. The OFLO-MINO combination exhibited definite bactericidal activity in 7 of 10 patients but was less bactericidal than the RMP-OFLO-MINO combination. Both combinations were well tolerated. Because of these promising results, a test of the efficacy of multiple doses of ROM in a larger clinical trial appears justified.

High relapse rate among lepromatous leprosy patients treated with rifampin plus ofloxacin daily for 4 weeks.

Fifty-one lepromatous leprosy patients, all of whom had relapsed after previous dapsone (DDS) monotherapy, were treated between 1990 and 1991 with 600 mg of rifampin (RMP) plus 400 mg of ofloxacin (OFLO) daily for 4 weeks, and the great majority of the patients were followed up at least once a year after completion of the treatment. After only 173 patient-years of follow-up, 5 relapses had been detected; the overall relapse rate was 10.0% (confidence limits, 1.7 and 18.3%), or 2.9 relapses (confidence limits, 0.4 and 5.4) per 100 patient-years. The unacceptably high relapse rate indicated that 4 weeks of treatment with daily RMP-OFLO was unable to reduce the number of viable Mycobacterium leprae organisms to a negligible level. In addition, the M. leprae from one of the relapses were proved to have multiple resistance to DDS, RMP, and OFLO. To avoid further relapses, the follow-up was terminated and the great majority of the patients were retreated with the standard 2-year multidrug therapy from 1994. No further relapse has been diagnosed since the beginning of retreatment.

Effect of HIV infection on leprosy: a three-year survey in Bamako, Mali.

From February 1992 until June 1994, all patients with histologically proven leprosy examined at the Leprology Unit of the Institut Marchoux in Bamako, Mali, were screened for HIV serology. In total, 740 leprosy patients have been tested; 553 known, previously treated leprosy cases and 187 new cases, mainly self-reporting and referred cases. The global seroprevalence in the sample was 1.5% (11/740), and increased from 1.3% in 1992 to 3.1% in 1994. HIV seroprevalence was higher in paucibacillary (PB) than in multibacillary (MB) cases (3.8% versus 0.8%, p < 0.05), and was slightly higher in new cases than in known, already treated cases (2.1% versus 1.3%), although not significantly. Among the 553 known, already treated leprosy patients, 1 out of 7 HIV-seropositive patients relapsed, as opposed to 34 out of 546 HIV-seronegative cases (14.2% versus 6.2%, p = 0.36). Among the new cases, none of the 37 patients with reaction and/or neuritis was HIV positive. In known, treated leprosy cases, there was no difference in the frequency of reactions and/or neuritis between HIV-positive and HIV-negative cases. Migration in a neighboring country appeared to be a risk factor for HIV seropositivity in our sample (chi 2 = 4.5, p = 0.04). In order to estimate the association of HIV with leprosy as compared to the general population, a control group of blood donors was set up, matched for age and sex. There was, however, no difference in HIV seroprevalence between the control group (9/735, 1.2%) and the leprosy group (1.5%). Although leprosy patients recruited for this study constitute a highly selected sample, it appears that HIV infection has little effect on leprosy, particularly on the PB/MB ratio, leprosy reactions and neuritis, but there is a suggestion the HIV infection might be associated with increased frequency of relapse.

PIP: HIV infection is a major risk factor for tuberculosis and other mycobacteria, but its association with leprosy remains unclear. From February 1992 to June 1994, all leprosy patients examined at the Leprology Unit of the Institut Marchoux, a reference center for leprosy in Mali, were screened for HIV infection. 740 leprosy patients were tested over the period; 553 known, previously treated cases and 187 newly diagnosed leprosy cases. 584 patients were multibacillary (MB) cases and 156 were paucibacillary (PB), with a large majority of MB cases among the known cases, due to the selected recruitment of those patients. There were 539 men of mean age 39.3 years and 201 women of mean age 37.7. New and known cases were of mean ages 30.7 and 41.6 years. Overall, 1.5% (11/740) were identified as HIV seropositive, increasing from 1.3% in 1992 to 3.1% in 1994. HIV seroprevalence was 3.8% among PB cases and 0.8% among MB cases, and was slightly higher in new cases than in known, already treated cases. Among the 553 known, already treated leprosy cases, 1 out of 7 HIV-seropositive patients relapsed, compared to 34 of 546 HIV-seronegative cases. Among the new cases, none of the 37 patients with reaction and/or neuritis was HIV positive. It appears that HIV infection has little effect upon leprosy, especially upon the PB/MB ratio, leprosy reactions and neuritis, but HIV infection may be associated with increased frequency of relapse.

Bactericidal activity of single dose of clarithromycin plus minocycline, with or without ofloxacin, against Mycobacterium leprae in patients.

Fifty patients with newly diagnosed lepromatous leprosy were allocated randomly to one of five groups and treated with either a month-long standard regimen of multidrug therapy (MDT) for multibacillary leprosy, a single dose of 600 mg of rifampin, a month-long regimen with the dapsone (DDS) and clofazimine (CLO) components of the standard MDT, or a single dose of 2,000 mg of clarithromycin (CLARI) plus 200 mg of minocycline (MINO), with or without the addition of 800 mg of ofloxacin (OFLO). At the end of 1 month, clinical improvement accompanied by significant decreases of morphological indexes in skin smears was observed in about half of the patients of each group. A significant bactericidal effect was demonstrated in the great majority of patients in all five groups by inoculating the footpads of mice with organisms recovered from biopsy samples obtained before and after treatment. Rifampin proved to be a bactericidal drug against Mycobacterium leprae more potent than any combination of the other drugs. A single dose of CLARI-MINO, with or without OFLO, displayed a degree of bactericidal activity similar to that of a regimen daily of doses of DDS-CLO for 1 month, suggesting that it may be possible to replace the DDS and CLO components of the MDT with a monthly dose of CLARI-MINO, with or without OFLO. However, gastrointestinal adverse events were quite frequent among patients treated with CLARI-MINO, with or without OFLO, and may be attributed to the higher dosage of CLARI or MINO or to the combination of CLARI-MINO plus OFLO. In future trials, therefore, we propose to reduce the dosages of the drugs to 1,000 mg of CLARI, 100 mg of MINO, and 400 mg of OFLO.

[Determining factors of non-compliance among patients undergoing polychemotherapy in the district of Bamako (Mali)]. / Facteurs déterminants de l'irrégularité des malades sous PCT dans le district de Bamako (Mali).

In order to examine the factors determining irregularity among patients undergoing multidrug therapy in Bamako district, we conducted a non-experimental study based, in the first instance, on medical records and later on a questionnaire. One thousand one hundred and seventy-five (1,175) treatment cards were reviewed in this way. The results of our study show that 3.1% of the patients fail to attend treatment sessions regularly and that multibacillary patients have more irregular attendance than paucibacillary patients. We have not observed any statistically meaningful difference between old and new patients as far as irregularity in attending multidrug therapy sessions is concerned. The second part of our research based on a questionnaire targeting a group of cases (36 patients who did not attend regularly) and a random control group (50 patients who attended treatment regularly but had missed at least one treatment) has shown that it is only for Item VI ("Have you ever missed your appointment because you perhaps considered yourself cured?") that a statistically meaningful difference emerges between cases and controls regarding the rates of affirmative responses (p < 0.05).

Leprosy reversal reaction in HIV-positive patients.

We report two cases of leprosy in HIV-infected patients who, by their clinical, histological and immunological features, enhance the evidence that HIV-positive leprosy does not differ from nonHIV-positive leprosy. Moreover, extensive studies of reversal reactions in HIV-positive patients might be of great interest in determining the exact pathogenesis of this leprosy reactional state.