Genome-wide association study of leprosy in Malawi and Mali.

Leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae. Despite recent improvements in disease control, leprosy remains an important cause of infectious disability globally. Large-scale genetic association studies in Chinese, Vietnamese and Indian populations have identified over 30 susceptibility loci for leprosy. There is a significant burden of leprosy in Africa, however it is uncertain whether the findings of published genetic association studies are generalizable to African populations. To address this, we conducted a genome-wide association study (GWAS) of leprosy in Malawian (327 cases, 436 controls) and Malian (247 cases, 368 controls) individuals. In that analysis, we replicated four risk loci previously reported in China, Vietnam and India; MHC Class I and II, LACC1 and SLC29A3. We further identified a novel leprosy susceptibility locus at 10q24 (rs2015583; combined p = 8.81 × 10-9; OR = 0.51 [95% CI 0.40 - 0.64]). Using publicly-available data we characterise regulatory activity at this locus, identifying ACTR1A as a candidate mediator of leprosy risk. This locus shows evidence of recent positive selection and demonstrates pleiotropy with established risk loci for inflammatory bowel disease and childhood-onset asthma. A shared genetic architecture for leprosy and inflammatory bowel disease has been previously described. We expand on this, strengthening the hypothesis that selection pressure driven by leprosy has shaped the evolution of autoimmune and atopic disease in modern populations. More broadly, our data highlights the importance of defining the genetic architecture of disease across genetically diverse populations, and that disease insights derived from GWAS in one population may not translate to all affected populations.

[Cutaneous tuberculosis in Bamako, Mali]. / Tuberculose cutanée à Bamako, Mali.

INTRODUCTION: Tuberculosis is the most common mycobacteriosis in sub-Saharan Africa. Cutaneous tuberculosis is rare and underdiagnosed due to its clinical polymorphism and to the smallness of technical equipment. This study aims to describe the epidemiological, clinical, histopathological aspects of cutaneous tuberculosis in Bamako (Mali). METHODS: We conducted a cross-sectional descriptive study from January 1991 to December 2008. The study was performed in the Department of Dermatology at the National Center for Disease Control and in the Department of Pneumophtisiology at the Hospital of Point G. The patients with tuberculosis confirmed by histological and/or biological examination were included in the study. RESULTS: Out of 4269 patients? medical records, 61 cases of cutaneous tuberculosis were identified (1.43%). Men accounted for 59% of the cases (36 patients) and women 41% (25 cases); sex-ratio was 1.44. The age of the patients ranged from 3 months to 61 years, with an average age of 27.56 ± 36 years. The average length of follow-up was 10.9 ± 10 months. The identified clinical forms were scrofuloderma (41 cases), ulcerative form (13 cases), verrucous form (4 cases), and tuberculous Lupus (3 cases). Tuberculosis was associated with HIV in 7 cases, with leprosy in 3 cases. CONCLUSION: Cutaneous tuberculosis is underdiagnosed in Mali. Efforts are needed to improve the accessibility and the technical equipment available in the Departments, in order to conduct an extensive interdisciplinary study on this pathology.

[Etiology of acquired hypochromic patches in dermatological area in Mali]. / Etiologies Des Hypochromies Acquises En Milieu Dermatologique.

INTRODUCTION: In dark skin patients, hypopigmentation is the most disfiguring condition. Very few studies on hypochromic disorders have been conducted in specialized health centers. The present study is aimed to describe the etiologies of hypochromic patches in dermatological area, in Bamako. METHODS: We carried out a cross sectional study in the Dermatology Clinic of the "Centre National d'Appui à la lutte contre la Maladie (CNAM, Ex Institut Marchoux)". All acquired hypochromic patches (HP) were selected. HP was defined as a "skin patch lighter in pigmentation than normal surrounding skin with a diameter of at least 1 cm". The diagnosis was mainly based on clinical findings. RESULTS: The prevalence of HP was 3.42% and the main causes were seborrheic dermatitis (23.3%), pytiriasis alba (20.15%), vitiligo (18.9%), pityriasis versicolore (18.5%) and leprosy (12.6%). CONCLUSION: There are many causes of HP including leprosy, a disease though rare to date, but still prevalent in dermatological area.

Are variable-number tandem repeats appropriate for genotyping Mycobacterium leprae?

Comparative genomics analysis of the Tamil Nadu strain of Mycobacterium leprae has uncovered several polymorphic sites with potential as epidemiological tools. In this study we compared the stability of two different markers of genomic biodiversity of M. leprae in several biopsy samples isolated from the same leprosy patient. The first type comprises five different variable-number tandem repeats (VNTR), while the second is composed of three single nucleotide polymorphisms (SNP). Contrasting results were obtained, since no variation was seen in the SNP profiles of M. leprae from 42 patients from 7 different locations in Mali whereas the VNTR profiles varied considerably. Furthermore, since variation in the VNTR pattern was seen not only between different isolates of M. leprae but also between biopsy samples from the same patient, these VNTR may be too dynamic for use as epidemiological markers for leprosy.

A public health approach for leprosy detection based on a very short term-training of primary health care workers in basic dermatology.

INTRODUCTION: In countries where leprosy control is integrated to general heath services, health workers, at primary health care level, often manage a large number of patients with skin diseases including leprosy. The distinction of leprosy from others skin diseases requires more skill and attention. Basic dermatological knowledge will help these staff to provide a better quality of care. A few years ago, a short term training programme focussed on leprosy and some common skin diseases was set up in Mali through a pilot project. This study will evaluate the impact of this training on the detection of leprosy at primary health care level. METHODS: health care workers from two health districts were invited to participate in the training. Trainee was submitted to an anonymous written test before training, immediately after and 12-18 months post-training using a standardized scoring system. The suspected or referred leprosy cases before and after training were compared. Data were recorded and analysed with the software Epi info version 6.04. RESULTS: Overall, 495 HCW attended the three anonymous written tests (before training, just after and 12-18 months later). The proportion of participants who gave correct answers before training, just after were respectively: 33 and 57% for correct diagnosis, 5 and 39% for test of sensation and 28 and 47% for referral. Eight patients suspected of leprosy were referred for further examination; in these, five cases of leprosy were detected. DISCUSSION: The training showed a huge improvement in the skill of the participants in managing leprosy patients. This study addresses how leprosy control can be improved by involving primary health care staff and by the implementation of only a single day's training on basic dermatology. CONCLUSION: The role of the dermatologist in this post-elimination era of leprosy needs to be reconsidered and adapted to the increasing need to take multiple programmes, inclusive of dermatology and leprosy, into primary health care services and those interested in leprosy control should fund these programmes.

High prevalence of non-leprotic hypochromic patches among children in a rural area of Mali, West Africa.

The identification of one or several hypochromic patches (HP) on the skin is a key stage in the diagnosis of leprosy on dark skin. However, HP are often caused by other disorder than leprosy. A study to determine the prevalence and causes of HP among children was carried out in a rural area of Mali in November 2001. All children under 15 years of age in two villages in an endemic area were screened by two dermatologists. Among the 1729 children seen, HP were identified in 71 patients, with a prevalence of 4.1%. The most common cause of HP was tinea versicolor, which was present in 39.4% of children with HP, followed by pityriasis alba in 31%, naevus achromicus in 24% and vitiligo in 5.6%. No case of leprosy was detected. Our study raises several points with practical consequences for the detection of leprosy cases: the high prevalence of non-leprous HP compared to leprosy, the reliability of the clinical diagnosis of leprosy, and the role of general health care workers in the detection of leprosy cases. Helping those who should be involved in that detection in distinguishing true cases from other hypochromic disorders appears to be a priority.

Definition of an algorithm for the management of common skin diseases at primary health care level in sub-Saharan Africa.

In order to help primary health care (PHC) workers in developing countries in the care of common skin diseases, an algorithm for the management of pyoderma, scabies, superficial mycoses, contact dermatitis and referral of early leprosy cases (based on the identification of diseases through the presence of objective key signs, and on treatments by generic drugs) was elaborated. One thousand patients were seen by trained dermatologists, who established diagnoses and treatments; in addition, there was systematic recording of each key sign, according to the successive algorithm steps. We compared the diagnostics and treatments obtained for several combinations of diagnostic signs, with those of the dermatologists. Sensitivity, specificity, positive predictive value and negative predictive value of defined combinations were high for pyoderma, scabies and superficial mycoses. Values were less exact for dermatitis and leprosy, but were considered sufficient for the level of health care targeted. The apportionment of treatments between the algorithm and the dermatological approaches was considered appropriate in more than 80% of cases; mismanagement was possible in 7% of cases, with few predictable harmful consequences. The algorithm was found satisfactory for the management of the dermatological priorities according to the standards required at the PHC level.

[Predictive value of consultation reasons in the diagnosis of leprosy in Bamako (Mali)]. / Valeur prédictive des motifs de consultation pour le diagnostic de lèpre à Bamako (Mali).

INTRODUCTION: One of the weak points in the strategy for eliminating leprosy is the poor quality of screening. To overcome this, the World Health Organization (WHO) encourages endemic countries to run campaigns for the elimination of leprosy by circulating educational messages and mobilizing the medical community for early screening of cases. The aim of our study was to identify the motives for consultation with high predictive value for the diagnosis of leprosy and to determine the late diagnosis factors and hence assist the staff on site to improve the results of their leprosy elimination campaigns. PATIENTS AND METHODS: The study consisted, during the second trimester of 1999, in interviewing all the patients consulting for the first time the Marchoux Institute or the units screening for leprosy in the Bamako area. The interview recorded the motives for consultation, the delay before consulting and the reasons for late consulting. To assess their positive predictive value, the motives for consultation were related to the diagnosis retained (leprosy or not). RESULTS: One thousand one hundred and seventy seven patients were interviewed. The motive for consulting, "suspected leprosy", scored the highest positive predictive value (PPV) (80 p. 100): 12 cases of leprosy were diagnosed by 15 consultants having suspected leprosy. Neurological problems were the second motive for consultation (PPV=61.9 p. 100). The most frequent motive for consultation was spots or "macules" (20 p. 100 of consultations), but only provided a positive predictive value of 19 p. 100. Prior consultations and non-specialized treatments were identified as factors of delay in diagnosing leprosy (P<0.001). CONCLUSIONS: Diagnosis of leprosy cannot be based on the motives for dermatological consultation alone. The macules are the most apparent signs, but of low predictive value. Nevertheless, they are an early but non-specific sign of leprosy and are often neglected by the patient. Other than macules, attention must be paid to the neurological signs (dysesthesia, motor disorders) when screening for leprosy. These signs may appear early on, or be observed at a late stage in the progression of the disease.

[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.

[New cases of leprosy at the Marchoux Institute: a comparative study 1988-1997]. / Nouveaux cas de lèpre à l'Institut Marchoux (Bamako, Mali).

BACKGROUND: The prevalence of leprosy had declined greatly over the last decade. The purpose of this work was to determine whether changes in the epidemiology, clinical and bacteriological patterns occurred among patients with leprosy treated at the Marchoux Institute in 1988 and in 1997. PATIENTS AND METHODS: We conducted a descriptive cross-sectional study, reviewing retrospectively all files of patients with leprosy seen in 1988 in comparison with a prospective series of leprosy patients seen in 1997. Only new cases of leprosy, prior to treatment and with skin and/or nervous lesions irrespective of the bacilloscopy results, were included in the two series. RESULTS: We included 93 patients among 246 patient files in 1988. There were 119 new cases in 1997. The following variables showed changes: mean delay to consultation (41.2 months in 1988 versus 26.1 months in 1997; patient's suspicion of having leprosy (93 patients in 1988 versus 22 in 1997); notion of contact (35 cases in 1988 versus 45 in 1997). Multibacilli leprosy predominated over paucibacilli leprosy in 1988 (51 versus 42 cases). This trend was inverted in 1997 (44 versus 75) (p<0.009). Patients with grade 2 handicap were more numerous in 1988 (20 cases versus 2 cases, p<0.001). CONCLUSION: These findings demonstrate a change in the epidemiology, clinical and bacilloscopic pattern of patients with leprosy from 1988 to 1997.

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.

[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.