Fabienne Nackers

Mycobacterium ulcerans infection: control, diagnosis, and treatment

The skin disease Buruli ulcer, caused by Mycobacterium ulcerans, is the third most common mycobacterial disease after tuberculosis and leprosy and mainly affects remote rural African communities. Although the disease is known to be linked to contaminated water, the mode of transmission is not yet understood, which makes it difficult to propose control interventions. The disease is usually detected in its later stages, when it has caused substantial damage and disability. Surgery remains the treatment of choice. Although easy and effective in the early stages of the disease, treatment requires extended excisions and long hospitalisation for the advanced forms of the disease. Currently, no antibiotic treatment has proven effective for all forms of M ulcerans infection and research into a new vaccine is urgently needed. While the scientific community works on developing non-invasive and rapid diagnostic tools, the governments of endemic countries should implement active case finding and health education strategies in their affected communities to detect the disease in its early stages. We review the diagnosis, treatment, and control of Buruli ulcer and list priorities for research and development.

Association of HIV infection and Mycobacterium ulcerans disease in Benin.

We investigated the association between Buruli ulcer and HIV by comparing the HIV-1/2 seroprevalence in a series of 426 Buruli ulcer patients and a sample of 613 residents of southern Benin. The overall HIV prevalence was 2.6% (11/426) among patients and 0.3% among controls (2/613), giving an odds ratio for the association between HIV and Buruli ulcer of 8.1 (95% confidence interval = 1.8–75; P = 0.003).

Chronic hepatitis B infection: long term comparison of children receiving interferon alpha and untreated controls.

Objectives: To investigate the virological outcome of chronic hepatitis B (CH-B) in children who received interferon alpha (IFN) compared with no treatment. Methods: Seventy-four children with CH-B (median age, 6.1 years; 44 boys) selected from a cohort of 158 cases were included and divided into two groups: IFN-treated (n = 37) and control (n = 37). The controls were matched with the treated children by baseline alanine aminotransferase (ALT) levels, sex and age. The Kaplan-Meier method was performed to estimate the time to clearance of hepatitis B e antigen (HbeAg) and hepatitis B surface antigen (HbsAg). Results: Mean duration of follow-up was comparable in two groups (5.2 ± 3.8 years in treatment group versus 5.2 ± 3.7 years in control group, NS). HBeAg and HBsAg loss occurred in 20 (54.1%) and three treated children versus 13 (35.1%) and one untreated children (NS), respectively. The 7-year cumulative HBeAg and HBsAg clearance rates were 47.5% and 8.9% after the first visit in the treatment group versus 33.5% and 4.0% in untreated children (NS), respectively. Elevated baseline ALT (two times upper limit of normal) had a significant effect on the long-term cumulative rate of HBeAg seroconversion in treated patients (P = 0.01) but not in the untreated group. Conclusions: These findings show that the overall long-term virological outcome does not differ significantly between IFN-treated and untreated children but that a significant benefit of treatment on the long term rate of HBeAg seroconversion is obtained in children with higher baseline ALT levels.

Prevalence of Buruli Ulcer in Akonolinga Health District, Cameroon: Results of a Cross Sectional Survey

Background Buruli ulcer (BU) is a chronic, indolent necrotizing disease of the skin and underlying tissues caused by Mycobacterium ulcerans, which may result in functional incapacity. In 2002, Médecins Sans Frontières (MSF) opened a BU programme in Akonolinga Hospital, Cameroon, offering antibiotic treatment, surgery and general medical care. Six hundred patients have been treated in the project to date. However, due to the nature of the disease and its stigmatization, determining the exact prevalence and burden of disease is difficult and current estimates may not reflect the magnitude of the problem. The objectives of this survey were to estimate the prevalence of BU in the health district of Akonolinga, describe the geographic extension of the highly endemic area within the health district, and determine the programme coverage and its geographical distribution. Methodology/Principal Findings We conducted a cross-sectional population survey using centric systematic area sampling (CSAS). A 15×15 km grid (quadrats of 225 km2) was overlaid on a map of Akonolinga district with its position chosen to maximize the area covered by the survey. Quadrats were selected if more than 50% of the quadrat was inside of the health district. The chiefdom located closest to the centre of each quadrat was selected and Buruli cases were identified using an active case finding strategy (the sensitivity of the strategy was estimated by capture-recapture). WHO-case definitions were used for nodules, plaque, ulcer, oedema and sequelae. Out of a total population of 103,000 inhabitants, 26,679 were surveyed within the twenty quadrats. Sensitivity of the case finding strategy was estimated to be 84% (95%CI 54–97%). The overall prevalence was 0.47% (n = 105) for all cases including sequelae and 0.25% (n = 56) for active stages of the disease. Five quadrats had a high prevalence of >0.6% to 0.9%, 5 a prevalence >0.3% to 0.6% and 10 quadrats <0.3%. The quadrats with the high prevalence were situated along the rivers Nyong and Mfoumou. Overall coverage of the project was 18% (12–27%) for all cases and 16% (9–18%) for active cases, but was limited to the quadrats neighbouring Akonolinga Hospital. Conclusions/Significance Prevalence was highest in the area neighbouring the Nyong River. Coverage was limited to the area close to the hospital and efforts have to be made to increase access to care in the high prevalence areas. Use of the CSAS method was particularly useful for project planning and to identify priority areas of intervention. An added benefit of the method is that the survey procedure incorporated an awareness campaign, providing information about the disease and treatment to the population.

Plasmodium prevalence and artemisinin-resistant falciparum malaria in Preah Vihear Province, Cambodia: a cross-sectional population-based study

BackgroundIntensified efforts are urgently needed to contain and eliminate artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion. Médecins Sans Frontières plans to support the Ministry of Health in eliminating P. falciparum in an area with artemisinin resistance in the north-east of Cambodia. As a first step, the prevalence of Plasmodium spp. and the presence of mutations associated with artemisinin resistance were evaluated in two districts of Preah Vihear Province.MethodsA cross-sectional population-based study using a two-stage cluster sampling was conducted in the rural districts of Chhaeb and Chey Saen, from September to October 2013. In each district, 30 clusters of 10 households were randomly selected. In total, blood samples were collected for 1,275 participants in Chhaeb and 1,224 in Chey Saen. Prevalence of Plasmodium spp. was assessed by PCR on dried blood spots. Plasmodium falciparum positive samples were screened for mutations in the K13-propeller domain gene (PF3D7_1343700).ResultThe prevalence of Plasmodium spp. was estimated at 1.49% (95% CI 0.71–3.11%) in Chhaeb and 2.61% (95% CI 1.45–4.66%) in Chey Saen. Twenty-seven samples were positive for P. falciparum, giving a prevalence of 0.16% (95% CI 0.04–0.65) in Chhaeb and 2.04% (95% CI 1.04–3.99%) in Chey Saen. Only 4.0% of the participants testing positive presented with fever or history of fever. K13-propeller domain mutant type alleles (C580Y and Y493H) were found, only in Chey Saen district, in seven out of 11 P. falciparum positive samples with enough genetic material to allow testing.ConclusionThe overall prevalence of P. falciparum was low in both districts but parasites presenting mutations in the K13-propeller domain gene, strongly associated with artemisinin-resistance, are circulating in Chey Saen.The prevalence might be underestimated because of the absentees – mainly forest workers - and the workers of private companies who were not included in the study. These results confirm the need to urgently develop and implement targeted interventions to contain and eliminate P. falciparum malaria in this district before it spreads to other areas.

Time is (still) of the essence: quantifying the impact of emergency meningitis vaccination response in Katsina State, Nigeria

BACKGROUND In 2009, a large meningitis A epidemic affected a broad region of northern Nigeria and southern Niger, resulting in more than 75 000 cases and 4000 deaths. In collaboration with state and federal agencies, Médecins Sans Frontières (MSF) intervened with a large-scale vaccination campaign using polysaccharide vaccine. Here the authors analyze the impact (cases averted) of the vaccination response as a function of the timing and coverage achieved. METHODS Phenomenological epidemic models were fitted to replicate meningitis surveillance data from the Nigerian Ministry of Health/WHO surveillance system and from reinforced surveillance conducted by MSF in both vaccinated and unvaccinated areas using a dynamic, state-space framework to account for under-reporting of cases. RESULTS The overall impact of the vaccination campaigns (reduction in meningitis cases) in Katsina State, northern Nigeria, ranged from 4% to 12%. At the local level, vaccination reduced cases by as much as 50% when campaigns were conducted early in the epidemic. CONCLUSIONS Reactive vaccination with polysaccharide vaccine during meningitis outbreaks can significantly reduce the case burden when conducted early and comprehensively. Introduction of the conjugate MenAfriVac vaccine has reduced rates of disease caused by serogroup A Neisseria meningitidis in the region. Despite this, reactive campaigns with polysaccharide vaccine remain a necessary and important tool for meningitis outbreak response.

Association between haemoglobin variants S and C and Mycobacterium ulcerans disease (Buruli ulcer): a case-control study in Benin.

Risk factors for Buruli ulcer (BU) are poorly understood. We conducted a case‐control study in southern Benin to investigate the association between haemoglobin variants S or C and BU, and particularly the association between haemoglobinopathies HbSS/SC and BU osteomyelitis. We compared the haemoglobin genotype of 179 patients with BU and 44 with BU osteomyelitis to that of 242 community controls. We found no evidence of an increased risk of BU according to the presence of haemoglobin variants S and/or C [odds ratio adjusted for sex, age, region of residence and ethnicity: 1.24 (95%CI: 0.80–1.93), P = 0.34]. Haemoglobin variants S and C are unlikely to play a role in the BU burden. However, haemoglobinopathies HbSS/SC were more frequent among BU osteomyelitis patients than among controls (6.8%vs. 1.0%, Fishers exact P‐value = 0.045), which may suggest that those disorders facilitate growth of Mycobacterium ulcerans in the bone matrix.

Malaria PCR detection in Cambodian low-transmission settings: dried blood spots versus venous blood samples.

In the context of malaria elimination, novel strategies for detecting very low malaria parasite densities in asymptomatic individuals are needed. One of the major limitations of the malaria parasite detection methods is the volume of blood samples being analyzed. The objective of the study was to compare the diagnostic accuracy of a malaria polymerase chain reaction assay, from dried blood spots (DBS, 5 μL) and different volumes of venous blood (50 μL, 200 μL, and 1 mL). The limit of detection of the polymerase chain reaction assay, using calibrated Plasmodium falciparum blood dilutions, showed that venous blood samples (50 μL, 200 μL, 1 mL) combined with Qiagen extraction methods gave a similar threshold of 100 parasites/mL, ∼100-fold lower than 5 μL DBS/Instagene method. On a set of 521 field samples, collected in two different transmission areas in northern Cambodia, no significant difference in the proportion of parasite carriers, regardless of the methods used was found. The 5 μL DBS method missed 27% of the samples detected by the 1 mL venous blood method, but most of the missed parasites carriers were infected by Plasmodium vivax (84%). The remaining missed P. falciparum parasite carriers (N = 3) were only detected in high-transmission areas.

Performance of small cluster surveys and the clustered LQAS design to estimate local-level vaccination coverage in Mali

BackgroundEstimation of vaccination coverage at the local level is essential to identify communities that may require additional support. Cluster surveys can be used in resource-poor settings, when population figures are inaccurate. To be feasible, cluster samples need to be small, without losing robustness of results. The clustered LQAS (CLQAS) approach has been proposed as an alternative, as smaller sample sizes are required.MethodsWe explored (i) the efficiency of cluster surveys of decreasing sample size through bootstrapping analysis and (ii) the performance of CLQAS under three alternative sampling plans to classify local VC, using data from a survey carried out in Mali after mass vaccination against meningococcal meningitis group A.ResultsVC estimates provided by a 10 × 15 cluster survey design were reasonably robust. We used them to classify health areas in three categories and guide mop-up activities: i) health areas not requiring supplemental activities; ii) health areas requiring additional vaccination; iii) health areas requiring further evaluation. As sample size decreased (from 10 × 15 to 10 × 3), standard error of VC and ICC estimates were increasingly unstable. Results of CLQAS simulations were not accurate for most health areas, with an overall risk of misclassification greater than 0.25 in one health area out of three. It was greater than 0.50 in one health area out of two under two of the three sampling plans.ConclusionsSmall sample cluster surveys (10 × 15) are acceptably robust for classification of VC at local level. We do not recommend the CLQAS method as currently formulated for evaluating vaccination programmes.

Descriptive epidemiology of typhoid fever during an epidemic in Harare, Zimbabwe, 2012

Background Typhoid fever remains a significant public health problem in developing countries. In October 2011, a typhoid fever epidemic was declared in Harare, Zimbabwe - the fourth enteric infection epidemic since 2008. To orient control activities, we described the epidemiology and spatiotemporal clustering of the epidemic in Dzivaresekwa and Kuwadzana, the two most affected suburbs of Harare. Methods A typhoid fever case-patient register was analysed to describe the epidemic. To explore clustering, we constructed a dataset comprising GPS coordinates of case-patient residences and randomly sampled residential locations (spatial controls). The scale and significance of clustering was explored with Ripley K functions. Cluster locations were determined by a random labelling technique and confirmed using Kulldorffs spatial scan statistic. Principal Findings We analysed data from 2570 confirmed and suspected case-patients, and found significant spatiotemporal clustering of typhoid fever in two non-overlapping areas, which appeared to be linked to environmental sources. Peak relative risk was more than six times greater than in areas lying outside the cluster ranges. Clusters were identified in similar geographical ranges by both random labelling and Kulldorffs spatial scan statistic. The spatial scale at which typhoid fever clustered was highly localised, with significant clustering at distances up to 4.5 km and peak levels at approximately 3.5 km. The epicentre of infection transmission shifted from one cluster to the other during the course of the epidemic. Conclusions This study demonstrated highly localised clustering of typhoid fever during an epidemic in an urban African setting, and highlights the importance of spatiotemporal analysis for making timely decisions about targetting prevention and control activities and reinforcing treatment during epidemics. This approach should be integrated into existing surveillance systems to facilitate early detection of epidemics and identify their spatial range.