APOL1-Mediated Kidney Disease.

This JAMA Insights reviews the origin of APOL1 high-risk genetic variants, defines APOL1-mediated kidney disease, and discusses recommendations for screening and management.

Sensing Sleeping Sickness: Local Symptom-Making in South Sudan.

Programs for neglected tropical diseases (NTDs) such as sleeping sickness increasingly involve patients and community workers in syndromic case detection with little exploration of patient understandings of symptoms. Drawing on concepts from sensorial anthropology, I investigate peoples' experiences of sleeping sickness in South Sudan. People here sense the disease through discourses about four symptoms (pain, sleepiness, confusion and hunger) using biomedical and ethnophysiological concepts and sensations of risk in the post-conflict environment. When identified together, the symptoms interlock as a complete disease, prompting people to seek hospital-based care. Such local forms of sense-making enable diagnosis and help control programs function.

Exploring the effect of human and animal population growth on vector-borne disease transmission with an agent-based model of Rhodesian human African trypanosomiasis in eastern province, Zambia.

This paper presents the development of an agent-based model (ABM) to investigate Trypanosoma brucei rhodesiense human African trypanosomiasis (rHAT) disease transmission. The ABM model, fitted at a fine spatial scale, was used to explore the impact of a growing host population on the spread of disease along a 75 km transect in the Luangwa Valley, Zambia. The model was used to gain a greater understanding of how increases in human and domestic animal population could impact the contact network between vector and host, the subsequent transmission patterns, and disease incidence outcomes in the region. Modelled incidence rates showed increases in rHAT transmission in both humans and cattle. The primary demographic attribution of infection switched dramatically from young children of both sexes attending school, to adult women performing activities with shorter but more frequent trips, such as water and firewood collection, with men more protected due to the presence of cattle in their routines. The interpretation of model output provides a plausible insight into both population development and disease transmission in the near future in the region and such techniques could aid well-targeted mitigation strategies in the future.

No evidence for association between APOL1 kidney disease risk alleles and Human African Trypanosomiasis in two Ugandan populations.

BACKGROUND: Human African trypanosomiasis (HAT) manifests as an acute form caused by Trypanosoma brucei rhodesiense (Tbr) and a chronic form caused by Trypanosoma brucei gambiense (Tbg). Previous studies have suggested a host genetic role in infection outcomes, particularly for APOL1. We have undertaken candidate gene association studies (CGAS) in a Ugandan Tbr and a Tbg HAT endemic area, to determine whether polymorphisms in IL10, IL8, IL4, HLAG, TNFA, TNX4LB, IL6, IFNG, MIF, APOL1, HLAA, IL1B, IL4R, IL12B, IL12R, HP, HPR, and CFH have a role in HAT. METHODOLOGY AND RESULTS: We included 238 and 202 participants from the Busoga Tbr and Northwest Uganda Tbg endemic areas respectively. Single Nucleotide Polymorphism (SNP) genotype data were analysed in the CGAS. The study was powered to find odds ratios > 2 but association testing of the SNPs with HAT yielded no positive associations i.e. none significant after correction for multiple testing. However there was strong evidence for no association with Tbr HAT and APOL1 G2 of the size previously reported in the Kabermaido district of Uganda. CONCLUSIONS/SIGNIFICANCE: A recent study in the Soroti and Kaberamaido focus in Central Uganda found that the APOL1 G2 allele was strongly associated with protection against Tbr HAT (odds ratio = 0.2, 95% CI: 0.07 to 0.48, p = 0.0001). However, in our study no effect of G2 on Tbr HAT was found, despite being well powered to find a similar sized effect (OR = 0.9281, 95% CI: 0.482 to 1.788, p = 0.8035). It is possible that the G2 allele is protective from Tbr in the Soroti/Kabermaido focus but not in the Iganga district of Busoga, which differ in ethnicity and infection history. Mechanisms underlying HAT infection outcome and virulence are complex and might differ between populations, and likely involve several host, parasite or even environmental factors.

A polymorphism in the haptoglobin, haptoglobin related protein locus is associated with risk of human sleeping sickness within Cameroonian populations.

BACKGROUND: Human African Trypanosomiasis (HAT) is a neglected disease targeted for elimination as a public health problem by 2020. Elimination requires a better understanding of the epidemiology and clinical evolution of HAT. In addition to the classical clinical evolution of HAT, asymptomatic carriers and spontaneous cure have been reported in West Africa. A genetic component to human susceptibility to HAT has been suggested to explain these newly observed responses to infection. In order to test for genetic associations with infection response, genetic polymorphism in 17 genes were tested (APOL1, IL1B, IL4, IL4R, IL6, IL8, IL12B, IL12RB1, IL10, TNFA, INFG, MIF, HLA-G, HLA-A, HP, HPR and CFH). METHODOLOGY: A case-control study was performed on 180 blood samples collected from 56 cases and 124 controls from Cameroon. DNA was extracted from blood samples. After quality control, 25 samples (24 controls and 1 case) were eliminated. The genotyping undertaken on 155 individuals including 55 cases and 100 controls were investigated at 96 loci (88 SNPs and 8 indels) located on 17 genes. Associations between these loci and HAT were estimated via a case-control association test. RESULTS: Analyses of 64 SNPs and 4 indels out of 96 identified in the selected genes reveal that the minor allele (T) of rs8062041 in haptoglobin (HP) appeared to be protective against HAT (p = 0.0002395, OR 0.359 (CI95 [0.204-0.6319])); indicating higher frequency in cases compared to controls. This minor allele with adjusted p value of 0.0163 is associated with a lower risk (protective effect) of developing sleeping sickness. CONCLUSION: The haptoglobin related protein HPR and HP are tightly linked and both are duplicated in some people and may lead to higher activity. This increased production could be responsible of the protection associated with rs8062041 even though this SNP is within HP.

Deadly Flies, Poor Profits, and Veterinary Pharmaceuticals: Sustaining the Control of Sleeping Sickness in Uganda.

Efforts to control neglected tropical diseases have increasingly focused on questions of implementation. But how should we conceptualize the implementation process? Drawing on ethnographic fieldwork between 2010 and 2012, in this article I explore efforts by a small-scale public-private partnership to use private veterinarians to sustainably control zoonotic sleeping sickness in Uganda. With a fundamental tension between business incentives and vector control, I show how divergences in knowledge, power, values, and social norms shaped project implementation and community responses. Reflecting more widely on the relationships between project plans and local realities, I argue that these encounters reveal the heuristic value in approaching global health interventions as evolving 'social experiments.' This metaphor reveals the uncertainty inherent to dominant narratives and models, the role of available expertise in defining the limits of action, and the need for continuous adaption to synchronize with emergent social and institutional topographies.

West-African trypanosomiasis in a returned traveller from Ghana: an unusual cause of progressive neurological decline.

West-African trypanosomiasis caused by Trypanosoma brucei gambiense is a rare imported infection presenting with somnolence, lymphadenopathy and wide-ranging neurological symptoms. A 67-year-old Caucasian man presented with a 10-month history of cognitive deterioration, ataxic gait, somnolence and urinary incontinence. His symptoms had progressed more rapidly over the course of a month prior to admission. Serological testing confirmed a diagnosis of West-African trypanosomiasis. The patient was successfully treated with eflornithine and made a good recovery. West-African trypanosomiasis should be considered in the differential diagnosis of unexplained cognitive decline in those with a relevant travel history. If left untreated, the condition is universally fatal.

Changing landscapes, changing practice: negotiating access to sleeping sickness services in a post-conflict society.

For several decades, control programmes for human African trypanosomiasis (HAT, or sleeping sickness) in South Sudan have been delivered almost entirely as humanitarian interventions: large, well-organised, externally-funded but short-term programmes with a strategic focus on active screening. When attempts to hand over these programmes to local partners fail, resident populations must actively seek and negotiate access to tests at hospitals via passive screening. However, little is known about the social impact of such humanitarian interventions or the consequences of withdrawal on access to and utilisation of remaining services by local populations. Based on qualitative and quantitative fieldwork in Nimule, South Sudan (2008-2010), where passive screening necessarily became the predominant strategy, this paper investigates the reasons why, among two ethnic groups (Madi returnees and Dinka displaced populations), service uptake was so much higher among the latter. HAT tests were the only form of clinical care for which displaced Dinka populations could self-refer; access to all other services was negotiated through indigenous area workers. Because of the long history of conflict, these encounters were often morally and politically fraught. An open-door policy to screening supported Dinka people to 'try' HAT tests in the normal course of treatment-seeking, thereby empowering them to use HAT services more actively. This paper argues that in a context like South Sudan, where HAT control increasingly depends upon patient-led approaches to case-detection, it is imperative to understand the cultural values and political histories associated with the practice of testing and how medical humanitarian programmes shape this landscape of care, even after they have been scaled down.

Identifying Darwinian selection acting on different human APOL1 variants among diverse African populations.

Disease susceptibility can arise as a consequence of adaptation to infectious disease. Recent findings have suggested that higher rates of chronic kidney disease (CKD) in individuals with recent African ancestry might be attributed to two risk alleles (G1 and G2) at the serum-resistance-associated (SRA)-interacting-domain-encoding region of APOL1. These two alleles appear to have arisen adaptively, possibly as a result of their protective effects against human African trypanosomiasis (HAT), or African sleeping sickness. In order to explore the distribution of potential functional variation at APOL1, we studied nucleotide variation in 187 individuals across ten geographically and genetically diverse African ethnic groups with exposure to two Trypanosoma brucei subspecies that cause HAT. We observed unusually high levels of nonsynonymous polymorphism in the regions encoding the functional domains that are required for lysing parasites. Whereas allele frequencies of G2 were similar across all populations (3%-8%), the G1 allele was only common in the Yoruba (39%). Additionally, we identified a haplotype (termed G3) that contains a nonsynonymous change at the membrane-addressing-domain-encoding region of APOL1 and is present in all populations except for the Yoruba. Analyses of long-range patterns of linkage disequilibrium indicate evidence of recent selection acting on the G3 haplotype in Fulani from Cameroon. Our results indicate that the G1 and G2 variants in APOL1 are geographically restricted and that there might be other functional variants that could play a role in HAT resistance and CKD risk in African populations.

Association between human African trypanosomiasis and the IL6 gene in a Congolese population.

Despite the importance of behavioural and environmental risk factors, there are arguments consistent with the existence of a genetic susceptibility to human African trypanosomiasis (HAT). A candidate gene association study was conducted in the Democratic Republic of Congo using a family-based sample which included a total of 353 subjects (86 trios; one case and parents (n=258) and 23 families with more than one case and parents (n=95)). Polymorphisms located on the IL1alpha, IL4, IL6, IL8, IL10, TNFalpha and IFNgamma genes were genotyped after re-sequencing of the genes for extensive SNP search. The T allele of the IL6(4339) SNP was significantly associated with a decreased risk of developing the disease (p=0.0006) and a suggestive association was observed for the IL1alpha(5417 T) SNP and an increased risk of developing the disease. These results suggest that genetic variability of the IL6 and to a lesser extent the IL1alpha gene are involved in the development of HAT. For the TNFalpha and IL10 gene polymorphisms, association results obtained here were different from those we observed in another population living under different epidemiologic conditions. This underlines the complexity of the interactions existing between host genetic polymorphisms, parasite diversity and behavioural and environmental risk factors in HAT.

[The impact of war on the evolution of sleeping sickness in west-central Côte d'Ivoire]. / L'impact de la guerre sur l'evolution de la THA dans le centre-ouest de la Côte d'Ivoire.

OBJECTIVE: To evaluate the situation of sleeping sickness in west-central Côte d'Ivoire from 2000 to 2003, in view of the war which broke out in September 2002. METHODS: Active surveys by medical teams and passive case detection. RESULTS: Between 2000 and 2003, 250 patients were diagnosed with sleeping sickness. At first it appeared that sleeping sickness prevalence had fallen since the beginning of political troubles. But this apparent drop was due to poor population coverage. Participation in medical surveys differed according to ethnic group, reflecting land use conflicts between ethnic communities. Such conflicts are common in this area, but have been exacerbated by the war. CONCLUSION: In war, assessing the importance of sleeping sickness by medical surveys only is very difficult. But detection of sleeping sickness cases by passive surveillance increased.

Host age and time of exposure in Trypanosoma brucei gambiense Human African Trypanosomiasis.

Human African Trypanosomiasis is related to behavioural risk factors but complex interactions exist between (i) environmental and behavioural risk factors, (ii) vector and (iii) human host. Our aim was to investigate the interrelationships between previously analysed risk factors and the roles of age and time of exposure according to ethnic group and migration status. However, this descriptive and retrospective study is based on cases only (no controls) and our results must therefore be regarded as hypothesis-generating. Individuals originating from areas where sleeping sickness is absent and who settle in an endemic area seem to develop the disease after a shorter time of exposure than native subjects from endemic areas. Our results emphasise the complexity of vector-transmitted disease epidemiology, involving behavioural and/or environmental risk factors on the one hand, and more individual ones such as ageing, immunity and genetic background on the other hand.

Measurement of risk in endemic areas of human African trypanosomiasis in Côte d'Ivoire.

An index of epidemiological risk was developed for the foci of human African trypanosomiasis (HAT) in the forest zone of Côte d'Ivoire, based on the following characteristics of Glossina palpalis palpalis populations: daily survival rate, apparent density of teneral males and females, and frequency of human-fly contact. The index agreed well with HAT prevalence. It varied according to ethnic groups and with seasonal changes in agricultural activities and fell rapidly to zero following the start of an anti-vector control campaign. Further studies in different biogeographical zones are desirable in order to substantiate the validity of the index.