Epidemiology of Buruli ulcer in the offin river valley of Ghana

Abstract

Buruli ulcer (BU) is a debilitating skin disease caused by Mycobacterium ulcerans. In the last decades, the disease has been reported from 34 countries with endemic foci typically occurring in rural areas where access to medical health facilities is a challenge. Since the exact mode of transmission of the pathogen is still not fully elucidated, early case detection and treatment of patients are key factors to control the disease. The first ever national active BU case search conducted in Ghana in 1999 identified the Offin river valley as one of the most BU endemic regions in Ghana. Based on recent anecdotal accounts indicating unstable transmission of M. ulcerans along the Offin river, we conducted as part of this PhD study, an exhaustive case search and household survey of 13 selected communities along the river. We observed an overall decline in the prevalence of BU. Subsequently, we installed an active surveillance system enabling the continued monitoring of the emergence of cases at the household level. By this system we were able to demonstrate that integration of control of several neglected tropical diseases such as leprosy and yaws was feasible and should be pursued to maximize the limited resources available for the control of these neglected tropical diseases. Until now, reservoirs and/or vectors of M. ulcerans are yet to be identified particularly for endemic settings in Africa. In the course of this PhD thesis, we conducted sero-epidemiological studies, assessing the exposure of populations sampled from Ghana and Cameroon to the pathogen by measuring humoral responses against the M. ulcerans-specific 18kDa small heat shock protein. We observed that exposure to M. ulcerans begins at approximately four years of age, coinciding with the age when children move out of their households and have more intense contact with the environment. Furthermore, by comparing the age when first humoral immune responses to M. ulcerans and to other pathogens with different modes of transmission occur, we observed an earlier onset of serological response to antigens of the mosquito transmitted malaria parasite P. falciparum and of soil transmitted Strongyloides helminths. In contrast, exposure to antigens of water transmitted Schistosoma worms shared a similar pattern of late onset of immune response with what we observed for M. ulcerans. Our data indicate that transmission of M. ulcerans occurs by contact with environmental sources of the pathogen outside of the small movement range of very young children. In recent years, the prevailing assumption was that the reservoir of M. ulcerans is somewhat fixed in space due to the highly focal occurrence of BU outbreaks. In this regard, a strong link between genotype and geographical origin of clinical M. ulcerans isolates has been reported. We compared whole genome sequences of a limited collection of clinical M. ulcerans strains, isolated from individuals living in the Offin river valley and identified two co-existing clonal complexes not separated in time and geographical location along the Offin river. To this observation we infer the presence of a reservoir of infection that is more mobile than previously assumed. Since prevention is complicated by elusive transmission pathways combined with the lack of a vaccine, the control of BU relies on adequate treatment of patients. To date, rifampicin is the only effective drug against BU. However, rifampicin hepatitis is a commonly reported side effect of rifampicin which is known to be aggravated in tuberculosis patients with pre–existing infection with the hepatitis B virus (HBV). We assessed the burden of HBV in the BU endemic Offin river basin by analyzing serum samples of the general population for the presence of the hepatitis B surface antigen (HBsAg). The overall serum HBsAg prevalence was high with 8% of the population being chronic carriers. If stratified by age, we observed a low serum HBsAg rate of 1.8% among children below 12 years of age compared to 11.1% for participants older than 12 years. By phylogenetic analysis based on the pre-S/S region of HBV, we could classify all isolates obtained from the Offin river basin as genotype E and serotype ayw4. In addition we identified two main HBV/E clusters. While one cluster was composed of only strains from the Offin river basin, the second cluster was in addition to Offin isolates also made up of strains from other parts of Ghana and West African countries like Niger, Nigeria and Benin. We conclude that transmission of HBV along the Offin river is mainly horizontal and recommend strict adhesion to vaccination protocols and periodic screening of populations within the river basin. Altogether, the multi-disciplinary approach of this PhD thesis to investigating various aspects of M. ulcerans transmission and epidemiology has resulted in key finding which add to the existing knowledge of the pathogen in Ghana and globally