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Kilama M.,Infectious Diseases Research Collaboration | Smith D.L.,Johns Hopkins University | Hutchinson R.,London School of Hygiene and Tropical Medicine | Kigozi R.,Infectious Diseases Research Collaboration | And 9 more authors.
Malaria Journal | Year: 2014

Background: The Plasmodium falciparum entomological inoculation rate (PfEIR) is a measure of exposure to infectious mosquitoes. It is usually interpreted as the number of P. falciparum infective bites received by an individual during a season or annually (aPfEIR). In an area of perennial transmission, the accuracy, precision and seasonal distribution (i.e., month by month) of aPfEIR were investigated. Data were drawn from three sites in Uganda with differing levels of transmission where falciparum malaria is transmitted mainly by Anopheles gambiae s.l. Estimates of aPfEIR derived from human-landing catches - the classic method for estimating biting rates - were compared with data from CDC light traps, and with catches of knock down and exit traps separately and combined. Methods. Entomological surveillance was carried out over one year in 2011/12 in three settings: Jinja, a peri-urban area with low transmission; Kanungu, a rural area with moderate transmission; and Nagongera, Tororo District, a rural area with exceptionally high malaria transmission. Three sampling approaches were used from randomly selected houses with collections occurring once a month: human-landing collections (eight houses), CDC light traps (100 houses) and paired knock-down and exit traps each month (ten houses) for each setting. Up to 50 mosquitoes per month from each household were tested for sporozoites with P. falciparum by ELISA. Human biting rate (HBR) data were estimated month by month. P. falciparum Sporozoite rate (PfSR) for yearly and monthly data and confidence intervals were estimated using the binomial exact test. Monthly and yearly estimates of the HBR, the PfSR, and the PfEIR were estimated and compared. Results: The estimated aPfEIR values using human-landing catch data were 3.8 (95% Confidence Intervals, CI 0-11.4) for Jinja, 26.6 (95% CI 7.6-49.4) for Kanungu, and 125 (95% CI 72.2-183.0) for Tororo. In general, the monthly PfEIR values showed strong seasonal signals with two peaks from May-June and October-December, although the precise timing of the peaks differed between sites. Estimated HBRs using human-landing catches were strongly correlated with those made using CDC light traps (r2 = 0.67, p < 0.001), and with either knock-down catches (r2 = 0.56, p < 0.001) and exit traps (r2 = 0.82, p < 0.001) or the combined catches (r2 = 0.73, p < 0.001). Using CDC light trap catch data, the PfSR in Tororo was strongly negatively correlated with monthly HBR (r 2 = 0.44, p = 0.01). In other sites, no patterns in the PfSR were discernible because either the number P. falciparum of sporozoite positive mosquitoes or the total number of mosquitoes caught was too low. Conclusions: In these settings, light traps provide an alternative method for sampling indoor-resting mosquitoes to human-landing catches and have the advantage that they protect individuals from being bitten during collection, are easy to use and are not subject to collector bias. Knock-down catches and exit traps could also be used to replace human-landing catches. Although these are cheaper, they are subject to collector bias. © 2014 Kilama et al.; licensee BioMed Central Ltd.

Ochong E.,University of California at San Francisco | Tumwebaze P.K.,Infectious Diseases Research Collaboration | Byaruhanga O.,Infectious Diseases Research Collaboration | Greenhouse B.,University of California at San Francisco | Rosenthal P.J.,University of California at San Francisco
Antimicrobial Agents and Chemotherapy | Year: 2013

Polymorphisms in the Plasmodium falciparum multidrug resistance 1 (pfmdr1) gene impact sensitivity to multiple antimalarials. In Africa, polymorphisms at N86Y and D1246Y are common and have various impacts on sensitivity to different drugs. To gain insight into the fitness consequences of these polymorphisms, we cultured parasites isolated from children with malaria in Tororo, Uganda, where the multiplicity of infection is high, and used pyrosequencing to follow polymorphism prevalences in culture over time. Of 71 cultures, parasites in 69 were successfully analyzed at N86Y and parasites in 68 were successfully analyzed at D1246Y over 3 to 36 days of culture. For position 86, the sequences of 39/69 (56.5%) parasites remained stable (>90% prevalence over 2 to 17 time points), with 82.1% of these being stable for the 86Y mutation. For position 1246, the sequences of 31/68 (45.6%) parasites remained stable, with 64.5% of these being stable for the wild-type D1246 sequence (P-0.0002 for comparison of stable mutant genotypes for the two alleles). Defining allele selection as a>15% change in prevalence between the first and last samples assessed, for position 86, 11 samples showed selection, with selection toward 86Y occurring in 72.7% of alleles; for position 1246, 14 samples showed selection, with selection toward D1246 occurring in 64.3% of alleles (P-0.11 for comparison of selection of mutations at the two alleles). Among the 7 samples with selection at both alleles, 5 showed selection for both 86Y and D1246. Overall, consistent trends in the direction of selection were seen, although differences were not statistically significant. Our results suggest fitness advantages for parasites with the pfmdr1 86Y mutation and wild-type D1246, highlighting the complex interplay between drug resistance and fitness in malaria parasites. Copyright © 2013, American Society for Microbiology. All Rights Reserved.

Talisuna A.,Infectious Diseases Research Collaboration | Adibaku S.,Ministry of Health | Dorsey G.,San Francisco General Hospital | Kamya M.R.,Makerere University | Rosenthal P.J.,San Francisco General Hospital
Acta Tropica | Year: 2012

In the recent past there have been several reports of successes in malaria control, leading some public health experts to conclude that Africa is witnessing an epidemiological transition, from an era of failed malaria control to progression from successful control to elimination. Successes in control have been attributed to increased international donor support leading to increased intervention coverage. However, these changes are not uniform across Africa. In Uganda, where baseline transmission is very high and intervention coverage not yet to scale, the malaria burden is not declining and has even likely increased in the last decade. In this article we present perspectives for the future for Uganda and other malaria endemic countries with high baseline transmission intensity and significant health system challenges. For these high burden areas, malaria elimination is currently not feasible, and early elimination programs are inappropriate, as they would further fragment already fragmented and inefficient malaria control systems. Rather, health impacts will be maximized by aiming to achieve universal coverage of proven interventions in the context of a strengthened health system. © 2011 Elsevier B.V.

Jagannathan P.,San Francisco General Hospital | Muhindo M.K.,Infectious Diseases Research Collaboration | Kakuru A.,Infectious Diseases Research Collaboration | Arinaitwe E.,Infectious Diseases Research Collaboration | And 6 more authors.
Malaria Journal | Year: 2012

Background: The burden of malaria has decreased in parts of Africa following the scaling up of control interventions. However, similar data are limited from high transmission settings. Methods. A cohort of 100 children, aged six weeks to 10 months of age, were enrolled in an area of high malaria transmission intensity and followed through 48 months of age. Children were given a long-lasting insecticide-treated bed net (LLIN) at enrolment and received all care, including monthly blood smears and treatment with artemisinin-based combination therapy (ACT) for uncomplicated malaria, at a dedicated clinic. The incidence of malaria was estimated by passive surveillance and associations between malaria incidence and age, calendar time and season were measured using generalized estimating equations. Results: Reported compliance with LLINs was 98% based on monthly routine evaluations. A total of 1,633 episodes of malaria were observed, with a median incidence of 5.3 per person-year (PPY). There were only six cases of complicated malaria, all single convulsions. Malaria incidence peaked at 6.5 PPY at 23 months of age before declining to 3.5 PPY at 48 months. After adjusting for age and season, the risk of malaria increased by 52% from 2008 to 2011 (RR 1.52, 95% CI 1.10-2.09). Asymptomatic parasitaemia was uncommon (monthly prevalence <10%) and rarely observed prior to 24 months of age. Conclusions: In Tororo, despite provision of LLINs and prompt treatment with ACT, the incidence of malaria is very high and appears to be rising. Additional malaria control interventions in high transmission settings are likely needed. Trial registration. Current Controlled Trials Identifier NCT00527800. © 2012 Jagannathan et al.

Jagannathan P.,San Francisco General Hospital | Eccles-James I.,San Francisco General Hospital | Bowen K.,San Francisco General Hospital | Nankya F.,Infectious Diseases Research Collaboration | And 12 more authors.
PLoS Pathogens | Year: 2014

Although evidence suggests that T cells are critical for immunity to malaria, reliable T cell correlates of exposure to and protection from malaria among children living in endemic areas are lacking. We used multiparameter flow cytometry to perform a detailed functional characterization of malaria-specific T cells in 78 four-year-old children enrolled in a longitudinal cohort study in Tororo, Uganda, a highly malaria-endemic region. More than 1800 episodes of malaria were observed in this cohort, with no cases of severe malaria. We quantified production of IFNγ, TNFα, and IL-10 (alone or in combination) by malaria-specific T cells, and analyzed the relationship of this response to past and future malaria incidence. CD4+ T cell responses were measurable in nearly all children, with the majority of children having CD4+ T cells producing both IFNγ and IL-10 in response to malaria-infected red blood cells. Frequencies of IFNγ/IL10 co-producing CD4+ T cells, which express the Th1 transcription factor T-bet, were significantly higher in children with ≥2 prior episodes/year compared to children with <2 episodes/year (P<0.001) and inversely correlated with duration since malaria (Rho = -0.39, P<0.001). Notably, frequencies of IFNγ/IL10 co-producing cells were not associated with protection from future malaria after controlling for prior malaria incidence. In contrast, children with <2 prior episodes/year were significantly more likely to exhibit antigen-specific production of TNFα without IL-10 (P = 0.003). While TNFα-producing CD4+ T cells were not independently associated with future protection, the absence of cells producing this inflammatory cytokine was associated with the phenotype of asymptomatic infection. Together these data indicate that the functional phenotype of the malaria-specific T cell response is heavily influenced by malaria exposure intensity, with IFNγ/IL10 co-producing CD4+ T cells dominating this response among highly exposed children. These CD4+ T cells may play important modulatory roles in the development of antimalarial immunity.

Homsy J.,University of California at San Francisco | Homsy J.,Centers for Disease Control and Prevention | Dorsey G.,University of California at San Francisco | Arinaitwe E.,Infectious Diseases Research Collaboration | And 7 more authors.
The Lancet Global Health | Year: 2014

Background: WHO recommends daily co-trimoxazole for children born to HIV-infected mothers from 6 weeks of age until breastfeeding cessation and exclusion of HIV infection. We have previously reported on the effectiveness of continuation of co-trimoxazole prophylaxis up to age 2 years in these children. We assessed the protective efficacy and safety of prolonging co-trimoxazole prophylaxis until age 4 years in HIV-exposed children. Methods: We undertook an open-label randomised controlled trial alongside two observational cohorts in eastern Uganda, an area with high HIV prevalence, malaria transmission intensity, and antifolate resistance. We enrolled HIV-exposed infants between 6 weeks and 9 months of age and prescribed them daily co-trimoxazole until breastfeeding cessation and HIV-status confirmation. At the end of breastfeeding, children who remained HIV-uninfected were randomly assigned (1:1) to discontinue co-trimoxazole or to continue taking it up to age 2 years. At age 2 years, children who continued co-trimoxazole prophylaxis were randomly assigned (1:1) to discontinue or continue prophylaxis from age 2 years to age 4 years. The primary outcome was incidence of malaria (defined as the number of treatments for new episodes of malaria diagnosed with positive thick smear) at age 4 years. For additional comparisons, we observed 48 HIV-infected children who took continuous co-trimoxazole prophylaxis and 100 HIV-unexposed uninfected children who never received prophylaxis. We measured grade 3 and 4 serious adverse events and hospital admissions. All children were followed up to age 5 years and all analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00527800. Findings: 203 HIV-exposed infants were enrolled between Aug 10, 2007, and March 28, 2008. After breastfeeding ended, 185 children were not infected with HIV and were randomly assigned to stop (n=87) or continue (n=98) co-trimoxazole up to age 2 years. At age 2 years, 91 HIV-exposed children who had remained on co-trimoxazole prophylaxis were randomly assigned to discontinue (n=46) or continue (n=45) co-trimoxazole from age 2 years to age 4 years. We recorded 243 malaria episodes (2·91 per person-years) in the 45 HIV-exposed children assigned to continue co-trimoxazole until age 4 years compared with 503 episodes (5·60 per person-years) in the 46 children assigned to stop co-trimoxazole at age 2 years (incidence rate ratio 0·53, 95% CI 0·39-0·71; p<0·0001). There was no evidence of malaria incidence rebound in the year after discontinuation of co-trimoxazole in the HIV-exposed children who stopped co-trimoxazole at age 2 years, but incidence increased significantly in HIV-exposed children who stopped co-trimoxazole at age 4 years (odds ratio 1·78, 95% CI 1·19-2·66; p=0·005). Incidence of grade 3 or 4 serious adverse events, hospital admissions, or deaths did not significantly differ between HIV-exposed, HIV-unexposed, and HIV-infected children. Interpretation: Continuation of co-trimoxazole prophylaxis up to 4 years of age seems safe and efficacious to protect HIV-exposed children living in malaria-endemic areas. Funding: Centers for Disease Control and Prevention Global AIDS Program, Doris Duke Charitable Foundation. © 2014 Homsy et al. Open Access article distributed under the terms of CC BY.

Jagannathan P.,San Francisco General Hospital | Kim C.C.,San Francisco General Hospital | Greenhouse B.,San Francisco General Hospital | Nankya F.,Infectious Diseases Research Collaboration | And 9 more authors.
Science Translational Medicine | Year: 2014

Although clinical immunity to malaria eventually develops among children living in endemic settings, the underlying immunologic mechanisms are not known. The Vγ2+subset of γδ T cells have intrinsic reactivity to malaria antigens, can mediate killing of Plasmodium falciparum merozoites, and expand markedly in vivo after malaria infection in previously naïve hosts, but their role in mediating immunity in children repeatedly exposed to malaria is unclear. We evaluated γδ T cell responses to malaria among 4-year-old children enrolled in a longitudinal study in Uganda. We found that repeated malaria was associated with reduced percentages of Vγ2+γδ T cells in peripheral blood, decreased proliferation and cytokine production in response to malaria antigens, and increased expression of immunoregulatory genes. Further, loss and dysfunction of proinflammatory Vγ2+ γδ T cells were associated with a reduced likelihood of symptoms upon subsequent P. falciparum infection. Together, these results suggest that repeated malaria infection during childhood results in progressive loss and dysfunction of Vγ2+γδ T cells that may facilitate immunological tolerance of the parasite.

Kizito J.,Infectious Diseases Research Collaboration | Kayendeke M.,Infectious Diseases Research Collaboration | Nabirye C.,Infectious Diseases Research Collaboration | Staedke S.G.,Infectious Diseases Research Collaboration | And 2 more authors.
Malaria Journal | Year: 2012

Background: Increasing access to health care services is considered central to improving the health of populations. Existing reviews to understand factors affecting access to health care have focused on attributes of patients and their communities that act as 'barriers' to access, such as education level, financial and cultural factors. This review addresses the need to learn about provider characteristics that encourage patients to attend their health services. Methods. This literature review aims to describe research that has identified characteristics that clients are looking for in the providers they approach for their health care needs, specifically for malaria in Africa. Keywords of 'malaria' and 'treatment seek*' or 'health seek*' and 'Africa' were searched for in the following databases: Web of Science, IBSS and Medline. Reviews of each paper were undertaken by two members of the team. Factors attracting patients according to each paper were listed and the strength of evidence was assessed by evaluating the methods used and the richness of descriptions of findings. Results: A total of 97 papers fulfilled the inclusion criteria and were included in the review. The review of these papers identified several characteristics that were reported to attract patients to providers of all types, including lower cost of services, close proximity to patients, positive manner of providers, medicines that patients believe will cure them, and timeliness of services. Additional categories of factors were noted to attract patients to either higher or lower-level providers. The strength of evidence reviewed varied, with limitations observed in the use of methods utilizing pre-defined questions and the uncritical use of concepts such as 'quality', 'costs' and 'access'. Although most papers (90%) were published since the year 2000, most categories of attributes had been described in earlier papers. Conclusion: This paper argues that improving access to services requires attention to factors that will attract patients, and recommends that public services are improved in the specific aspects identified in this review. It also argues that research into access should expand its lens to consider provider characteristics more broadly, especially using methods that enable open responses. Access must be reconceptualized beyond the notion of barriers to consider attributes of attraction if patients are to receive quality care quickly. © 2012 Kizito et al; BioMed Central Ltd.

Osterbauer B.,San Francisco General Hospital | Kapisi J.,Infectious Diseases Research Collaboration | Bigira V.,Infectious Diseases Research Collaboration | Mwangwa F.,Infectious Diseases Research Collaboration | And 3 more authors.
Malaria Journal | Year: 2012

Background: Malaria, malnutrition and anaemia are major causes of morbidity and mortality in African children. The interplay between these conditions is complex and limited data exist on factors associated with these conditions among infants born to HIV-uninfected and infected women. Methods. Two hundred HIV-exposed (HIV-uninfected infants born to HIV-infected mothers) and 400 HIV-unexposed infants were recruited from an area of high malaria transmission in rural Uganda. A cross-sectional survey was performed at enrolment to measure the prevalence of malaria parasitaemia, measures of malnutrition (z-scores <2 standard deviations below mean) and anaemia (haemoglobin <8 gm/dL). Multivariate logistic regression was used to measure associations between these conditions and risk factors of interest including household demographics, malaria prevention practices, breastfeeding practices, household structure and wealth index. Results: The prevalence of malaria parasitaemia was 20%. Factors protective against parasitaemia included female gender (OR = 0.66, p = 0.047), mother's age (OR = 0.81 per five-year increase, p = 0.01), reported bed net use (OR = 0.63, p = 0.03) and living in a well-constructed house (OR = 0.25, p = 0.01). Although HIV-unexposed infants had a higher risk of parasitaemia compared to HIV-exposed infants (24% vs 14%, p = 0.004), there was no significant association between HIV-exposure status and parasitaemia after controlling for the use of malaria preventative measures including bed net use and trimethoprim-sulphamethoxazole prophylaxis. The prevalence of stunting, underweight, and wasting were 10%, 7%, and 3%, respectively. HIV-exposed infants had a higher odds of stunting (OR = 2.23, p = 0.005), underweight (OR = 1.73, p = 0.09) and wasting (OR = 3.29, p = 0.02). The prevalence of anaemia was 12%. Risk factors for anaemia included older infant age (OR = 2.05 per one month increase, p = 0.003) and having malaria parasitaemia (OR = 5.74, p < 0.001). Conclusions: Compared to HIV-unexposed infants, HIV-exposed infants had a higher use of malaria preventative measures and lower odds of malaria parasitaemia. Having a better constructed house was also protective against malaria parasitaemia. HIV-exposure was the primary risk factor for measures of malnutrition. The primary risk factor for anaemia was malaria parasitaemia. These findings suggest the need to better target existing interventions for malaria, malnutrition and anaemia as well as the need to explore further the mechanisms behind the observed associations. © 2012 Osterbauer et al.; licensee BioMed Central Ltd.

Mawejje H.D.,Infectious Diseases Research Collaboration | Wilding C.S.,Vector Group | Rippon E.J.,Vector Group | Hughes A.,Vector Group | And 2 more authors.
Medical and Veterinary Entomology | Year: 2013

Insecticide resistance in the malaria vector Anopheles gambiae s.l. (Diptera: Culicidae) threatens insecticide-based control efforts, necessitating regular monitoring. We assessed resistance in field-collected An. gambiae s.l. from Jinja, Uganda using World Health Organization (WHO) biosassays. Only An. gambiae s.s. and An. arabiensis (≅70%) were present. Female An. gambiae exhibited extremely high pyrethroid resistance (permethrin LT50 > 2 h; deltamethrin LT50 > 5 h). Female An. arabiensis were resistant to permethrin and exhibited reduced susceptibility to deltamethrin. However, while An. gambiae were DDT resistant, An. arabiensis were fully susceptible. Both species were fully susceptible to bendiocarb and fenitrothion. Kdr 1014S has increased rapidly in the Jinja population of An. gambiae s.s. and now approaches fixation (≅95%), consistent with insecticide-mediated selection, but is currently at a low frequency in An. arabiensis (0.07%). Kdr 1014F was also at a low frequency in An. gambiae. These frequencies preclude adequately-powered tests for an association with phenotypic resistance. PBO synergist bioassays resulted in near complete recovery of pyrethroid susceptibility suggesting involvement of CYP450s in resistance. A small number (0.22%) of An. gambiae s.s. ×An. arabiensis hybrids were found, suggesting the possibility of introgression of resistance alleles between species. The high levels of pyrethroid resistance encountered in Jinja threaten to reduce the efficacy of vector control programmes which rely on pyrethroid-impregnated bednets or indoor spraying of pyrethroids. © 2012 The Royal Entomological Society.

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