[Mapping, profile and training of immunization stakeholders, Benin, 2020]. / Cartographie, profil et formation des acteurs de la vaccination, Bénin, 2020.

Introduction: The Benin Immunization and Logistic Directorate commissioned this study to provide evidence-based data to improve the performance of the Expanded Programme on Immunization. The objectives were to identify immunization stakeholders, describe their profile, their geographical distribution and determine their training needs. Methods: In December 2020, we conducted a census of Benin's immunization stakeholders via their administrative files and telephone interviews. The data were collected in each departmental directorate and health zone by focal points using an Excel® grid. The authorizations of the ethics and personal data protection committees were obtained. Results: We identified 3, 893 immunization workers, 39 years old on average, 66% of whom were women, 53% were health care assistants, 77% were vaccinators, and 56% were government contract workers. About 96% of them worked in peripheral centers. Approximately 56% were untrained and 14% had been untrained for more than 5 years. More than half of the actors were not trained for their function. The proportion of actors needing training was estimated at 70%. The training needs were at least 72% in the departmental hospitals, zone hospitals and health centers. 98% of actors reported a need for training, including immunization (74%), vaccine management (69%), cold chain (61%), monitoring (61%), and maintenance (47%). Conclusion: The predominance of nurses' aides and women and the low proportion of trained personnel among immunization workers were also observed in other sub-Saharan African countries. Benin's Immunization and Logistics Directorate should mobilize sufficient resources to strengthen the technical capacities of the majority of immunization stakeholders.

Decision making process, programmatic and logistic impact of the transition from a single-dose vial to a multi-dose vial of the 13-valent pneumococcal vaccine in Benin.

BACKGROUND: Benin, a country eligible for Gavi support, changed the presentation of the 13-valent pneumococcal vaccine (PCV13) from the single-dose vial (SDV) to the multi-dose vial (MDV). The present work aims to evaluate the process of making this decision as well as programmatic and logistic impacts. METHODS: WHO protocol for post-introduction evaluation (PIE) was used. Programmatic impact was evaluated by comparing PCV13 coverage and dropout rates with a comparator vaccine administered simultaneously over similar 6-month periods prior to and after the transition. This impact was also appreciated from observation of multi-dose vial management practices during immunization sessions. Logistic impact was measured from the analysis of storage capacities, waste management and vaccine losses. RESULTS: Decision to move to PCV13 MDV was taken at EPI level. Activities planned to support this switch were partially implemented. Impact on vaccination coverage and PCV13 dropout rates in relation with the transition to PCV13 MDV was not detected. The study found that 63% of the health staff surveyed knew and applied WHO's multidose vial policy (MDVP). Vaccines opened vials were found in 83% of health facilities visited. PCV13 MDV (37%) was one of the 3 main vaccines found with open vials in health facility refrigerators. Vaccination risky practices were observed during immunization sessions in 83% of health facilities. The main risky practice was the lack of indication of the date and hour of opening vials (56%). There was a reduction of the volume occupied by vaccines at central store by 47%. Net storage volume per fully immunized child (FIC) decreased from 69.5 to 41 m3. PCV13 MDV allows for 40% reduction in the amount of waste produced by vaccination. PCV13 open vial loss rate has increased from 3 to 7%. CONCLUSION: Benin's experience in transition to an MDV presentation of PCV13 reveals the need for better preparation and planning.

Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial.

BACKGROUND: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions. METHODS: We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437. FINDINGS: Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts. INTERPRETATION: Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer. FUNDING: WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac.

Decrease in Mycobacterium ulcerans disease (Buruli ulcer) in the Lalo District of Bénin (West Africa).

BACKGROUND: Buruli ulcer (BU) is a chronic, necrotizing infectious skin disease caused by Mycobacterium ulcerans. In recent years, there has been a decrease in the number of new cases detected. This study aimed to show the evolution of its distribution in the Lalo District in Bénin from 2006 to 2017. METHODS: The database of the BU Detection and Treatment Center of Lalo allowed us to identify 1017 new cases in the Lalo District from 2006 to 2017. The annual prevalence was calculated with subdistricts and villages. The trends of the demographic variables and those related to the clinical and treatment features were analysed using Microsoft Excel® 2007 and Epi Info® 7. Arc View version® 3.4 was used for mapping. RESULTS: From 2006 to 2017, the case prevalence of BU in the Lalo District decreased by 95%. The spatial distribution of BU cases confirmed the foci of the distribution, as described in the literature. The most endemic subdistricts were Ahomadégbé, Adoukandji, Gnizounmè and Tchito, with a cumulative prevalence of 315, 225, 215 and 213 cases per 10,000 inhabitants, respectively. The least endemic subdistricts were Zalli, Banigbé, Lalo-Centre and Lokogba, with 16, 16, 10, and 5 cases per 10,000 inhabitants, respectively. A significant decrease in the number of patients with ulcerative lesions (p = 0.002), as well as those with category 3 lesions (p < 0.001) and those treated surgically (p < 0.001), was observed. The patients confirmed by PCR increased (from 40.42% in 2006 to 84.62% in 2017), and joint limitation decreased (from 13.41% in 2006 to 0.0% in 2017). CONCLUSION: This study confirmed the general decrease in BU prevalence rates in Lalo District at the subdistrict and village levels, as also observed at the country level. This decrease is a result of the success of the BU control strategies implemented in Bénin, especially in the Lalo District.

Improving clinical and epidemiological predictors of Buruli ulcer.

BACKGROUND: Buruli ulcer (BU) is a chronic necrotizing infectious skin disease caused by Mycobacterium ulcerans. The treatment with BU-specific antibiotics is initiated after clinical suspicion based on the WHO clinical and epidemiological criteria. This study aimed to estimate the predictive values of these criteria and how they could be improved. METHODOLOGY/PRINCIPAL FINDINGS: A total of 224 consecutive patients presenting with skin and soft tissue lesions that could be compatible with BU, including those recognized as unlikely BU by experienced clinicians, were recruited in two BU treatment centers in southern Benin between March 2012 and March 2015. For each participant, the WHO and four additional epidemiological and clinical diagnostic criteria were recorded. For microbiological confirmation, direct smear examination and IS2404 PCR were performed. We fitted a logistic regression model with PCR positivity for BU confirmation as outcome variable. On univariate analysis, most of the clinical and epidemiological WHO criteria were associated with a positive PCR result. However, lesions on the lower limbs and WHO category 3 lesions were rather associated with a negative PCR result (respectively OR: 0.4, 95%CI: 0.3-0.8; OR: 0.5, 95%IC: 0.3-0.9). Among the additional characteristics studied, the characteristic smell of BU was strongest associated with a positive PCR result (OR = 16.4; 95%CI = 7.5-35.6). CONCLUSION/SIGNIFICANCE: The WHO diagnostic criteria could be improved upon by differentiating between lesions on the upper and lower limbs and by including lesion size and the characteristic smell recognized by experienced clinicians.

Microdeletion on chromosome 8p23.1 in a familial form of severe Buruli ulcer.

Buruli ulcer (BU), the third most frequent mycobacteriosis worldwide, is a neglected tropical disease caused by Mycobacterium ulcerans. We report the clinical description and extensive genetic analysis of a consanguineous family from Benin comprising two cases of unusually severe non-ulcerative BU. The index case was the most severe of over 2,000 BU cases treated at the Centre de Dépistage et de Traitement de la Lèpre et de l'Ulcère de Buruli, Pobe, Benin, since its opening in 2003. The infection spread to all limbs with PCR-confirmed skin, bone and joint infections. Genome-wide linkage analysis of seven family members was performed and whole-exome sequencing of both patients was obtained. A 37 kilobases homozygous deletion confirmed by targeted resequencing and located within a linkage region on chromosome 8 was identified in both patients but was absent from unaffected siblings. We further assessed the presence of this deletion on genotyping data from 803 independent local individuals (402 BU cases and 401 BU-free controls). Two BU cases were predicted to be homozygous carriers while none was identified in the control group. The deleted region is located close to a cluster of beta-defensin coding genes and contains a long non-coding (linc) RNA gene previously shown to display highest expression values in the skin. This first report of a microdeletion co-segregating with severe BU in a large family supports the view of a key role of human genetics in the natural history of the disease.

Assessment of water, sanitation, and hygiene practices and associated factors in a Buruli ulcer endemic district in Benin (West Africa).

BACKGROUND: Control of neglected tropical diseases (NTDs) requires multiple strategic approaches including water, sanitation and hygiene services (WASH). Buruli ulcer (BU), one of the 17 NTDs, remains a public health issue in Benin particularly in the district of Lalo. The availability of water as well as good hygiene are important for the management of Buruli ulcer particularly in the area of wound care one of the main component of the treatment of BU lesions. Given the growing importance of WASH in controlling NTDs and in order to assess the baseline for future cross-cutting interventions, we report here on the first study evaluating the level of WASH and associated factors in Lalo, one of the most BU-endemic districts in Benin. METHOD: A cross-sectional study was carried to assess WASH practices and associated factors in the district of Lalo. Data were collected from 600 heads of household using structured pretested questionnaire and observations triangulated with qualitative information obtained from in-depth interviews of patients, care-givers and community members. Univariate and multivariate analysis were carried to determine the relationships between the potential associated factors and the sanitation as well as hygiene status. RESULTS: BU is an important conditions in the district of Lalo with 917 new cases detected from 2006 to 2012. More than 49 % of the household surveyed used unimproved water sources for their daily needs. Only 8.7 % of the investigated household had improved sanitation facilities at home and 9.7 % had improved hygiene behavior. The type of housing as an indicator of the socioeconomic status, the permanent availability of soap and improved hygiene practices were identified as the main factors positively associated with improved sanitation status. CONCLUSIONS: In the district of Lalo in Benin, one of the most endemic for BU, the WASH indicators are very low. This study provides baseline informations for future cross-cutting interventions in this district.

Contribution of the community health volunteers in the control of Buruli ulcer in Bénin.

BACKGROUND: Buruli ulcer (BU) is a neglected tropical disease caused by Mycobacterium ulcerans. Usually BU begins as a painless nodule, plaque or edema, ultimately developing into an ulcer. The high number of patients presenting with ulcers in an advanced stage is striking. Such late presentation will complicate treatment and have long-term disabilities as a consequence. The disease is mainly endemic in West Africa. The primary strategy for control of this disease is early detection using community village volunteers. METHODOLOGY/PRINCIPAL FINDINGS: In this retrospective, observational study, information regarding Buruli ulcer patients that reported to one of the four BU centers in Bénin between January 2008 and December 2010 was collected using the WHO/BU01 forms. Information used from these forms included general characteristics of the patient, the results of diagnostic tests, the presence of functional limitations at start of treatment, lesion size, patient delay and the referral system. The role of the different referral systems on the stage of disease at presentation in the hospital was analyzed by a logistic regression analysis. About a quarter of the patients (26.5%) were referred to the hospital by the community health volunteers. In our data set, patients referred to the hospital by community health volunteers appeared to be in an earlier stage of disease than patients referred by other methods, but after adjustment by the regression analysis for the health center, this effect could no longer be seen. The Polymerase Chain Reaction (PCR) for IS2404 positivity rate among patients referred by the community health volunteers was not systematically lower than in patients referred by other systems. CONCLUSIONS/SIGNIFICANCE: This study clarifies the role played by community health volunteers in Bénin, and shows that they play an important role in the control of BU.

Clinical epidemiology of laboratory-confirmed Buruli ulcer in Benin: a cohort study.

BACKGROUND: Buruli ulcer, caused by Mycobacterium ulcerans, was identified as a neglected emerging infectious disease by WHO in 1998. Although Buruli ulcer is the third most common mycobacterial disease worldwide, understanding of the disease is incomplete. We analysed a large cohort of laboratory-confirmed cases of Buruli ulcer from Pobè, Benin, to provide a comprehensive description of the clinical presentation of the disease, its variation with age and sex, and its effect on the occurrence of permanent functional sequelae. METHODS: Between Jan 1, 2005, and Dec 31, 2011, we prospectively collected clinical and laboratory data from all patients with Buruli ulcer diagnosed at the Centre de Dépistage et de Traitement de l'Ulcère de Buruli in Pobè, Benin. We followed up patients to assess the frequency of permanent functional sequelae. All analyses were done on cases that were laboratory confirmed. FINDINGS: 1227 cases of laboratory-confirmed Buruli ulcer were included in the analysis. Typically, patients with Buruli ulcer were children (median age at diagnosis 12 years) presenting with a unique (1172 [96%]) large (≥15 cm, 444 [36%]) ulcerative (805 [66%]) lesion of the lower limb (733 [60%]). Atypical clinical presentation of Buruli ulcer included Buruli ulcer osteomyelitis with no identifiable present or past Buruli ulcer skin lesions, which was recorded in at least 14 patients. The sex ratio of Buruli ulcer widely varied with age, with male patients accounting for 57% (n=427) of patients aged 15 years and younger, but only 33% (n=158) of those older than 15 years (odds ratio [OR] 2·59, 95% CI 2·04-3·30). Clinical presentation of Buruli ulcer was significantly dependent on age and sex. 54 (9%) male patients had Buruli ulcer osteomyelitis, whereas only 28 (4%) of female patients did (OR 2·21, 95% CI 1·39-3·59). 1 year after treatment, 229 (22% of 1043 with follow-up information) patients presented with permanent functional sequelae. Presentation with oedema, osteomyelitis, or large (≥15 cm in diameter), or multifocal lesions was significantly associated with occurrence of permanent functional sequelae (OR 7·64, 95% CI 5·29-11·31) and operationally defines severe Buruli ulcer. INTERPRETATION: Our findings have important clinical implications for daily practice, including enhanced surveillance for early detection of osteomyelitis in boys; systematic search for M ulcerans in osteomyelitis cases of non-specific aspect in areas endemic for Buruli ulcer; and specific disability prevention for patients presenting with osteomyelitis, oedema, or multifocal or large lesions. Our findings also suggest a crucial underestimation of the burden of Buruli ulcer in Africa and raise key questions about the contribution of environmental and physiopathological factors to the recorded heterogeneity of the clinical presentation of Buruli ulcer. FUNDING: Agence Nationale de la Recherche (ANR), Fondation Raoul Follereau, Fondation pour la Recherche Médicale (FRM), and Institut des Maladies Génétiques (IMAGINE).

Perceptions on the effectiveness of treatment and the timeline of Buruli ulcer influence pre-hospital delay reported by healthy individuals.

BACKGROUND: Delay in seeking treatment at the hospital is a major challenge in current Buruli ulcer control; it is associated with severe sequelae and functional limitations. Choosing alternative treatment and psychological, social and practical factors appear to influence delay. Objectives were to determine potential predictors for pre-hospital delay with Leventhal's commonsense model of illness representations, and to explore whether the type of available dominant treatment modality influenced individuals' perceptions about BU, and therefore, influenced pre-hospital delay. METHODOLOGY: 130 healthy individuals aged >18 years, living in BU-endemic areas in Benin without any history of BU were included in this cross-sectional study. Sixty four participants from areas where surgery was the dominant treatment and sixty six participants from areas where antibiotic treatment was the dominant treatment modality were recruited. Using a semi-structured interview we measured illness perceptions (IPQ-R), knowledge about BU, background variables and estimated pre-hospital delay. PRINCIPAL FINDINGS: The individual characteristics 'effectiveness of treatment' and 'timeline acute-chronic' showed the strongest association with pre-hospital delay. No differences were found between regions where surgery was the dominant treatment and regions where antibiotics were the dominant treatment modality. CONCLUSIONS: Individual characteristics, not anticipated treatment modality appeared predictors of pre-hospital delay.