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Abstract Background Reports on the impact of COVID-19 pandemic on the quality of malaria care and burden in sub Saharan Africa have provided a mixed picture to date. The impact of the 2nd (Delta) and 3rd (Omicron) COVID-19 waves on outpatient malaria indicators and case management practices was assessed at three public health facilities with varying malaria transmission intensities in Uganda. Methods Individual level data from all patients presenting to the out-patient departments (OPD) of the three facilities (Kasambya, Walukuba and Lumino) between January 2019 and February 2022 were included in the analysis. Outcomes of interest included total number of outpatient (OPD) visits, proportion of patients suspected to have malaria, proportion of suspected malaria cases tested with a malaria diagnostic test, test positivity rates (TPR) and proportion of malaria cases prescribed artemether-lumefantrine (AL). Using the pre-COVID-19 trends between January 2019 and February 2020, interrupted time series analysis was used to predict the expected trends for these study outcomes during the 2nd wave (May 2021–August 2021) and 3rd wave (November 2021–February 2022). The observed trends of the study outcomes were compared with the expected trends. Results There were no significant differences between the observed versus expected overall outpatient visits in the 2nd wave, however, a significant decline in OPD attendance was observed during the 3rd wave (15,101 vs 31,154; incidence rate ratio (IRR) = 0.48 [0.41–0.56]). No significant differences in the overall observed versus expected proportions of suspected malaria cases and test positivity rates in both COVID waves. However, a significant decrease in the overall proportion of suspected malaria cases tested with a malaria diagnostic test was observed during the 3rd wave (99.86% vs 99.99%; relative percent ratio [RPR] = 0.99 [0.99–0.99]). Finally, a significant decline in the overall proportion of malaria cases prescribed AL was observed during the 2nd wave (94.99% vs 99.85%; RPR = 0.95 [0.92–0.98]) but not the 3rd wave. Conclusion Significant declines in OPD attendance and suspected malaria cases tested with malaria diagnostic test were observed during the 3rd COVID-19 wave, while AL prescription significantly reduced during the 2nd COVID-19 wave. These findings add to the body of knowledge highlighting the adverse impact of COVID-19 pandemic on the malaria which could explain the increase in the malaria burden observed during this period.

Abstract In malaria epidemiology, interpolation frameworks based on available observations are critical for policy decisions and interpreting disease burden. Updating our understanding of the empirical evidence across different populations, settings, and timeframes is crucial to improving inference for supporting public health. Here, via individual-based modeling, we evaluate a large, multicountry, contemporary Plasmodium falciparum severe malaria dataset to better understand the relationship between prevalence and incidence of malaria pediatric hospitalizations - a proxy of malaria severe outcomes- in East-Africa. We find that life-long exposure dynamics, and subsequent protection patterns in children, substantially determine the likelihood of malaria hospitalizations relative to ongoing prevalence at the population level. Unsteady transmission patterns over a lifetime in children -increasing or decreasing- lead to an exponential relationship of hospitalization rates versus prevalence rather than the asymptotic pattern observed under steady transmission. Addressing this increase in the complexity of malaria epidemiology is crucial to update burden assessments via inference models that guide current and future policy decisions.

Abstract Background Understanding the age patterns of disease is necessary to target interventions to maximise cost-effective impact. New malaria chemoprevention and vaccine initiatives target young children attending routine immunisation services. Here we explore the relationships between age and severity of malaria hospitalisation versus malaria transmission intensity. Methods Clinical data from 21 surveillance hospitals in East Africa were reviewed. Malaria admissions aged 1 month to 14 years from discrete administrative areas since 2006 were identified. Each site-time period was matched to a model estimated community-based age-corrected parasite prevalence to provide predictions of prevalence in childhood (PfPR2–10). Admission with all-cause malaria, severe malaria anaemia (SMA), respiratory distress (RD) and cerebral malaria (CM) were analysed as means and predicted probabilities from Bayesian generalised mixed models. Results 52,684 malaria admissions aged 1 month to 14 years were described at 21 hospitals from 49 site-time locations where PfPR2–10 varied from

Abstract Background Appropriate malaria management is a key malaria control strategy. The objective of this study was to determine health care worker adherence levels to malaria case management guidelines in the Busoga sub-region, Uganda. Methods Health facility assessments, health care worker (HCW), and patient exit interview (PEI) surveys were conducted at government and private health facilities in the sub-region. All health centres (HC) IVs, IIIs, and a sample of HC IIs, representative of the tiered structure of outpatient service delivery at the district level were targeted. HCWs at these facilities were eligible for participation in the study. For PEIs, 210 patients of all ages presenting with a history of fever for outpatient care at selected facilities in each district were targeted. Patient outcome measures included testing rates, adherence to treatment, dispensing and counselling services as per national guidelines. The primary outcome was appropriate malaria case management, defined as the proportion of patients tested and only prescribed artemether-lumefantrine (AL) if positive. HCW readiness (e.g., training, supervision) and health facility capacity (e.g. availability of diagnostics and anti-malarials) to provide malaria case management were also assessed. Data were weighted to cater for the disproportionate representation of HC IIs in the study sample. Results A total of 3936 patients and 1718 HCW from 392 facilities were considered in the analysis. The median age of patients was 14 years; majority (63.4%) females. Most (70.1%) facilities were HCIIs and 72.7% were owned by the government. Malaria testing services were available at > 85% of facilities. AL was in stock at 300 (76.5%) facilities. Of those with a positive result, nearly all were prescribed an anti-malarial, with AL (95.1%) accounting for most prescriptions. Among those prescribed AL, 81.0% were given AL at the facility, lowest at HC IV (60.0%) and government owned (80.1%) facilities, corresponding to AL stock levels. Overall, 86.9% (95%CI 79.7, 90.7) of all enrolled patients received appropriate malaria case management. However, only 50.7% (21.2, 79.7) of patients seen at PFPs received appropriate malaria management. Conclusion Adherence levels to malaria case management guidelines were good, but with gaps noted mainly in the private sector. The supply chain for AL needs to be strengthened. Interventions to improve practise at PFP facilities should be intensified.

Abstract Background Long-lasting insecticidal nets (LLINs) are the main vector control tool for pregnant women, but their efficacy may be compromised, in part, due to pyrethroid resistance. In 2017, the Ugandan Ministry of Health embedded a cluster randomized controlled trial into the national LLIN campaign, where a random subset of health subdistricts (HSDs) received LLINs treated with piperonyl butoxide (PBO), a chemical synergist known to partially restore pyrethroid sensitivity. Using data from a small, non-randomly selected subset of HSDs, this secondary analysis used quasi-experimental methods to quantify the overall impact of the LLIN campaign on pregnancy outcomes. In an exploratory analysis, differences between PBO and conventional (non-PBO) LLINs on pregnancy outcomes were assessed. Methods Birth registry data (n = 39,085) were retrospectively collected from 21 health facilities across 12 HSDs, 29 months before and 9 months after the LLIN campaign (from 2015 to 2018). Of the 12 HSDs, six received conventional LLINs, five received PBO LLINs, and one received a mix of conventional and PBO LLINs. Interrupted time-series analyses (ITSAs) were used to estimate changes in monthly incidence of stillbirth and low birthweight (LBW;

Abstract Background In Uganda, artemether-lumefantrine (AL) is first-line therapy and dihydroartemisinin-piperaquine (DP) second-line therapy for the treatment of uncomplicated malaria. This study evaluated the efficacy and safety of AL and DP in the management of uncomplicated falciparum malaria and measured the prevalence of molecular markers of resistance in three sentinel sites in Uganda from 2018 to 2019. Methods This was a randomized, open-label, phase IV clinical trial. Children aged 6 months to 10 years with uncomplicated falciparum malaria were randomly assigned to treatment with AL or DP and followed for 28 and 42 days, respectively. Genotyping was used to distinguish recrudescence from new infection, and a Bayesian algorithm was used to assign each treatment failure a posterior probability of recrudescence. For monitoring resistance, Pfk13 and Pfmdr1 genes were Sanger sequenced and plasmepsin-2 copy number was assessed by qPCR. Results There were no early treatment failures. The uncorrected 28-day cumulative efficacy of AL ranged from 41.2 to 71.2% and the PCR-corrected cumulative 28-day efficacy of AL ranged from 87.2 to 94.4%. The uncorrected 28-day cumulative efficacy of DP ranged from 95.8 to 97.9% and the PCR-corrected cumulative 28-day efficacy of DP ranged from 98.9 to 100%. The uncorrected 42-day efficacy of DP ranged from 73.5 to 87.4% and the PCR-corrected 42-day efficacy of DP ranged from 92.1 to 97.5%. There were no reported serious adverse events associated with any of the regimens. No resistance-associated mutations in the Pfk13 gene were found in the successfully sequenced samples. In the AL arm, the NFD haplotype (N86Y, Y184F, D1246Y) was the predominant Pfmdr1 haplotype, present in 78 of 127 (61%) and 76 of 110 (69%) of the day 0 and day of failure samples, respectively. All the day 0 samples in the DP arm had one copy of the plasmepsin-2 gene. Conclusions DP remains highly effective and safe for the treatment of uncomplicated malaria in Uganda. Recurrent infections with AL were common. In Busia and Arua, the 95% confidence interval for PCR-corrected AL efficacy fell below 90%. Further efficacy monitoring for AL, including pharmacokinetic studies, is recommended. Trial registration The trail was also registered with the ISRCTN registry with study Trial No. PACTR201811640750761

Abstract Background Although microscopy remains the gold standard for malaria diagnosis, little is known about its accuracy in the private health facilities in Uganda. This study evaluated the accuracy of malaria microscopy, and factors associated with inaccurate smear results at private health facilities in Entebbe Municipality, Uganda. Methods Between April and May 2018, all patients referred for a malaria smear in 16 private health facilities in Entebbe municipality were screened, and 321 patients were enrolled. A questionnaire was administered to collect demographic and clinical information, facility-based smear results were recorded from the participant’s consultation notes, and a research slide was obtained for expert microscopy during exit interview. A health facility assessment was conducted, and information on experience in performing malaria microscopy was collected from all facility personnel reading smears and the data was linked to the participant’s clinic visit. Results The test positivity rate of malaria parasitaemia was 15.0% by expert microscopy. The sensitivity, specificity and negative predictive value of the facility-based microscopy were high (95.8%, 90.1 and 99.2%, respectively). However; the positive predictive value (PPV) was low with 27/73 (63%) patients diagnosed with malaria not having the disease. Majority of the inaccurate results were from 2 of the 23 laboratory personnel reading the smears. The factors associated with inaccurate smear readings included being read by a technician; (1) who had less than 5 years’ experience in reading malaria smears (adjusted Odds Ratio [aOR] = 9.74, 95% confidence interval [CI] (1.06–89.5), p-value = 0.04), and (2) who was examining less than 5 smears a day (aOR = 38.8, 95% CI 9.65–156, p-value

Abstract Background Travel is a well-recognized risk factor for malaria. Within sub-Saharan Africa, travellers from areas of lower to higher transmission intensity are potentially at high risk of malaria. Long-lasting insecticidal nets (LLINs) are the primary tool for prevention of malaria, and their widespread use has contributed to substantial reductions in malaria burden. However, travellers often fail to use LLINs. To further explore the challenges and opportunities of using LLINs, travellers were interviewed in Uganda. Methods In August and September 2019, 20 participants attending outpatient clinics at Naguru General Hospital in Kampala with a history of travel out of Kampala within the previous 60 days were purposively selected. Data were collected through in-depth interviews and analysed thematically using NVivo 12. Results Of the 20 participants, 13 were male. Thirteen of the 20 participants tested positive for malaria by microscopy, and 5 reported using of LLINs during travel. The main reasons for travel were to attend social events (weddings, funerals, overnight prayers) and for work. travellers who attended social events reported using LLINs less commonly than those who travelled for work. Challenges to using LLINs during travel included: (1) limited access to LLINs; (2) challenges in planning ahead of travel; (3) lack of space or ability to hang LLINs while travelling; (4) impression that LLINs in lodging places were unhygienic; (5) cultural beliefs discouraging use of LLINs during social events; (6) participation in overnight ceremonies; and (7) doubts about efficacy of LLINs. Positive factors influencing use of LLINs during travel included knowledge regarding malaria prevention and good affordability and availability of LLINs. Conclusions Despite good traveller knowledge regarding malaria control measures, use of LLINs was limited. Use of LLINs in the prevention of malaria among travellers from low to high transmission settings needs to be prioritized. This calls for increased behaviour change oriented communication to improve traveller preparedness and consideration of use of repellents in situations where LLINs may not be feasible. The Uganda Ministry of Health and Malaria Control Division should use educational messages to increase awareness about the risks of getting malaria during overnight travel through the media. Truck drivers should be sensitized through their companies to use the available space at the back of the trucks for hanging nets and consider using pop-up nets.

Indoor residual spraying (IRS) of insecticide is one of the primary malaria vector control initiatives, but implementation is limited. Here, the authors show that discontinuation of IRS in Uganda was associated with increased malaria incidence, and introduction of IRS was associated with decreased incidence.

Abstract Background Malaria surveillance is critical for monitoring changes in malaria morbidity over time. National Malaria Control Programmes often rely on surrogate measures of malaria incidence, including the test positivity rate (TPR) and total laboratory confirmed cases of malaria (TCM), to monitor trends in malaria morbidity. However, there are limited data on the accuracy of TPR and TCM for predicting temporal changes in malaria incidence, especially in high burden settings. Methods This study leveraged data from 5 malaria reference centres (MRCs) located in high burden settings over a 15-month period from November 2018 through January 2020 as part of an enhanced health facility-based surveillance system established in Uganda. Individual level data were collected from all outpatients including demographics, laboratory test results, and village of residence. Estimates of malaria incidence were derived from catchment areas around the MRCs. Temporal relationships between monthly aggregate measures of TPR and TCM relative to estimates of malaria incidence were examined using linear and exponential regression models. Results A total of 149,739 outpatient visits to the 5 MRCs were recorded. Overall, malaria was suspected in 73.4% of visits, 99.1% of patients with suspected malaria received a diagnostic test, and 69.7% of those tested for malaria were positive. Temporal correlations between monthly measures of TPR and malaria incidence using linear and exponential regression models were relatively poor, with small changes in TPR frequently associated with large changes in malaria incidence. Linear regression models of temporal changes in TCM provided the most parsimonious and accurate predictor of changes in malaria incidence, with adjusted R2 values ranging from 0.81 to 0.98 across the 5 MRCs. However, the slope of the regression lines indicating the change in malaria incidence per unit change in TCM varied from 0.57 to 2.13 across the 5 MRCs, and when combining data across all 5 sites, the R2 value reduced to 0.38. Conclusions In high malaria burden areas of Uganda, site-specific temporal changes in TCM had a strong linear relationship with malaria incidence and were a more useful metric than TPR. However, caution should be taken when comparing changes in TCM across sites.

Abstract Background The World Health Organization (WHO) promotes long-lasting insecticidal nets (LLIN) and indoor residual house-spraying (IRS) for malaria control in endemic countries. However, long-term impact data of vector control interventions is rarely measured empirically. Methods Surveillance data was collected from paediatric admissions at Tororo district hospital for the period January 2012 to December 2019, during which LLIN and IRS campaigns were implemented in the district. Malaria test positivity rate (TPR) among febrile admissions aged 1 month to 14 years was aggregated at baseline and three intervention periods (first LLIN campaign; Bendiocarb IRS; and Actellic IRS + second LLIN campaign) and compared using before-and-after analysis. Interrupted time-series analysis (ITSA) was used to determine the effect of IRS (Bendiocarb + Actellic) with the second LLIN campaign on monthly TPR compared to the combined baseline and first LLIN campaign periods controlling for age, rainfall, type of malaria test performed. The mean and median ages were examined between intervention intervals and as trend since January 2012. Results Among 28,049 febrile admissions between January 2012 and December 2019, TPR decreased from 60% at baseline (January 2012–October 2013) to 31% during the final period of Actellic IRS and LLIN (June 2016–December 2019). Comparing intervention intervals to the baseline TPR (60.3%), TPR was higher during the first LLIN period (67.3%, difference 7.0%; 95% CI 5.2%, 8.8%, p

Abstract Background Understanding the relationship between malaria infection risk and disease outcomes represents a fundamental component of morbidity and mortality burden estimations. Contemporary data on severe malaria risks among populations of different parasite exposures are scarce. Using surveillance data, we compared rates of paediatric malaria hospitalisation in areas of varying parasite exposure levels. Methods Surveillance data at five public hospitals; Jinja, Mubende, Kabale, Tororo, and Apac were assembled among admissions aged 1 month to 14 years between 2017 and 2018. The address of each admission was used to define a local catchment population where national census data was used to define person-year-exposure to risk. Within each catchment, historical infection prevalence was assembled from previously published data and current infection prevalence defined using 33 population-based school surveys among 3400 children. Poisson regression was used to compute the overall and site-specific incidences with 95% confidence intervals. Results Both current and historical Plasmodium falciparum prevalence varied across the five sites. Current prevalence ranged from

Abstract Background Malaria control using long-lasting insecticidal nets (LLINs) and indoor residual spraying of insecticide (IRS) has been associated with reduced transmission throughout Africa. However, the impact of transmission reduction on the age distribution of malaria cases remains unclear. Methods Over a 10-year period (January 2009 to July 2018), outpatient surveillance data from four health facilities in Uganda were used to estimate the impact of control interventions on temporal changes in the age distribution of malaria cases using multinomial regression. Interventions included mass distribution of LLINs at all sites and IRS at two sites. Results Overall, 896,550 patient visits were included in the study; 211,632 aged 15 years. Over time, the age distribution of patients not suspected of malaria and those malaria negative either declined or remained the same across all sites. In contrast, the age distribution of suspected and confirmed malaria cases increased across all four sites. In the two LLINs-only sites, the proportion of malaria cases in 15 years increased from 40 to 61% and 29 to 39%, respectively. In the sites receiving LLINs plus IRS, these proportions increased from 19 to 44% and 18 to 31%, respectively. Conclusions These findings demonstrate a shift in the burden of malaria from younger to older individuals following implementation of successful control interventions, which has important implications for malaria prevention, surveillance, case management and control strategies.

Abstract Background Gaps remain in understanding the role of caregiver responses on time to seek appropriate care. The objective of this study was to describe caregiver responses to illness and the impact of these responses on time to seek appropriate care among children with malaria. Methods A case–control study of 325 children with severe (cases) and 325 children with uncomplicated (controls) malaria was conducted in Jinja, Uganda. Caregivers’ responses to their children’s illnesses and time to seek appropriate care were documented. Responses included staying at home, seeking care at drug shops, and seeking care at public health facilities classified into two types: (1) health facilities where caregiver initially sought care before enrollment, and (2) health facilities where children were provided appropriate care and enrolled in the study. Weighted Cox regression was used to determine risk factors for delays in time to seek appropriate care within 24 h of illness onset. Results Children staying home on self-medication was the most common initial response to illness among caregivers of controls (57.5%) and cases (42.4%, p

Abstract Objectives This study was set out to assess the level of adherence to antiretroviral therapy (ART) and its determinants among children receiving HIV treatment in Kabale district, south western Uganda, in order to inform interventions for improving pediatric ART adherence. Results Overall, 79% (121/153) of the children did not miss ART doses over the 7 days. Caregiver forgetfulness was the major reason for missing ART doses, 37% (13/35). Other reasons included transportation costs to the health facilities, 17%, (6/35) and children sitting for examinations in schools. Older children (11–14 years) were more likely to adhere to ART than the younger ones (0–10 years) (AOR = 6.41, 95% CI 1.31–31.42). Caregivers, who knew their HIV status, had their children more adherent to ART than the caregivers of unknown HIV status (AOR = 21.64: 95% CI 1.09–428.28). A significant proportion of children in two facilities 21.5% (32/153) missed ART doses within the previous week. Support for providers to identify clues or reminders to take drugs, extending HIV testing to caregivers and innovative models of ART delivery that alleviate transport costs to caregivers and allow sufficient drugs for children in school could enhance drug adherence among children.

Abstract Background Indoor residual spraying (IRS) is an efficient method of preventing malaria in homes, and community willingness to take up IRS is critical to its success. The first phase of IRS was conducted in Tororo district, Uganda between December 2014 and January 2015. High coverage rates (90%) were attained in the district. However, Mulanda sub-county had the lowest coverage of 78%, in the first round. This study assessed willingness and associated factors of IRS uptake among household heads for the next IRS campaign in Mulanda sub-county, Tororo district. Methods A household survey was conducted in all three parishes of Mulanda sub-county. A multistage sampling technique involving the village and household as the first and second sampling levels, respectively, was used to identify 640 households Household heads were interviewed using standard questionnaire. Seven key informants were also conducted to explore the impact of community IRS-perceptions on uptake. Bi-variable and multi-variable logistic regression analyses were used to identify factors associated with willingness to take up IRS. Qualitative data was analysed by thematic content analysis method. Results Most (79.9%) respondents were willing to take up repeat IRS. However this was below the target of 85%. Fear of insecticide adverse effects (62%) was the most common reason mentioned by 134 (21%) household heads who were not willing to take up IRS. Factors associated with to take up IRS were; age ≥ 35 years (AOR 1.9; 95% CI 1.08–3.51), higher socio-economic status (AOR 0.4; 95% CI 0.27–0.98), not taking IRS in previous round (AOR 0.1; 95% CI 0.06–0.23), not knowing reason for conducting IRS (AOR 0.4; 95% CI 0.24–0.78) and having an iron sheet roof (AOR 2.2; 95% CI 1.03–4.73). Community and religious leaders were the preferred sources of IRS information. Conclusions The level of willingness to take up IRS was low (79%) compared to the targeted 85%. Involvement of community and religious leaders in community sensitization on the efficacy and safety of the chemicals could increase uptake of IRS.

Abstract Background Environmental factors play a major role in transmission of malaria given their relationship to both the development and survival of the mosquito and parasite. The associations between environmental factors and malaria can be used to inform the development of early warning systems for increases in malaria burden. The objective of this study was to assess temporal relationships between rainfall, temperature and vegetation with malaria morbidity across three different transmission settings in Uganda. Methods Temporal relationships between environmental factors (weekly total rainfall, mean day time temperature and enhanced vegetation index series) and malaria morbidity (weekly malaria case count data and test positivity rate series) over the period January 2010–May 2013 in three sites located in varying malaria transmission settings in Uganda was explored using cross-correlation with pre-whitening. Sites included Kamwezi (low transmission), Kasambya (moderate transmission) and Nagongera (high transmission). Results Nagongera received the most rain (30.6 mm) and experienced, on average, the highest daytime temperatures (29.8 °C) per week. In the study period, weekly TPR and number of malaria cases were highest at Kasambya and lowest at Kamwezi. The largest cross-correlation coefficients between environmental factors and malaria morbidity for each site was 0.27 for Kamwezi (rainfall and cases), 0.21 for Kasambya (vegetation and TPR), and −0.27 for Nagongera (daytime temperature and TPR). Temporal associations between environmental factors (rainfall, temperature and vegetation) with malaria morbidity (number of malaria cases and TPR) varied by transmission setting. Longer time lags were observed at Kamwezi and Kasambya compared to Nagongera in the relationship between rainfall and number of malaria cases. Comparable time lags were observed at Kasambya and Nagongera in the relationship between temperature and malaria morbidity. Temporal analysis of vegetation with malaria morbidity revealed longer lags at Kasambya compared to those observed at the other two sites. Conclusions This study showed that temporal associations between environmental factors with malaria morbidity vary by transmission setting in Uganda. This suggests the need to incorporate local transmission differences when developing malaria early warning systems that have environmental predictors in Uganda. This will result in development of more accurate early warning systems, which are a prerequisite for effective malaria control in such a setting.

IntroductionA large proportion of children with uncomplicated malaria receive appropriate treatment late, contributing to progression of illness to severe disease. We explored contexts of caregiver delays in seeking appropriate care for children with severe malaria.MethodsThis qualitative study was conducted at the Children's Ward of Jinja Hospital, where children with severe malaria were hospitalized. A total of 22in-depth interviews were conducted with caregivers of children hospitalized with severe malaria. Issues explored were formulated based on the Partners for Applied Social Sciences (PASS) model, focusing on facilitators and barriersto caregivers'promptseeking and accessing ofappropriate care. The data were coded deductively using ATLAS.ti (version 7.5). Codes were then grouped into families based on emerging themes.ResultsCaregivers' rating of initial symptoms as mild illness lead to delays in response. Use of home initiated interventions with presumably ineffective herbs or medicines was common, leading to further delay. When care was sought outside the home, drug shops were preferred over public health facilities for reasons of convenience. Drug shops often provided sub-optimal care, and thus contributed to delays in access to appropriate care. Public facilities were often a last resort when illness was perceived to be progressing to severe disease. Further delays occurred at health facilities due to inadequate referral systems.ConclusionCommunities living in endemic areas need to be sensitized about the significance of fever, even if mild, as an indicator of malaria. Additionally, amidst ongoing efforts at bringing antimalarial treatment services closer to communities, the value of drug shops as providers ofrationalantimalarialtreatment needs to be reviewed.

Febrile illness is a major burden in African children, and non-malarial causes of fever are uncertain. In this retrospective exploratory study, we used metagenomic next-generation sequencing (mNGS) to evaluate serum, nasopharyngeal, and stool specimens from 94 children (aged 2-54 months) with febrile illness admitted to Tororo District Hospital, Uganda. The most common microbes identified were Plasmodium falciparum (51.1% of samples) and parvovirus B19 (4.4%) from serum; human rhinoviruses A and C (40%), respiratory syncytial virus (10%), and human herpesvirus 5 (10%) from nasopharyngeal swabs; and rotavirus A (50% of those with diarrhea) from stool. We also report the near complete genome of a highly divergent orthobunyavirus, tentatively named Nyangole virus, identified from the serum of a child diagnosed with malaria and pneumonia, a Bwamba orthobunyavirus in the nasopharynx of a child with rash and sepsis, and the genomes of two novel human rhinovirus C species. In this retrospective exploratory study, mNGS identified multiple potential pathogens, including 3 new viral species, associated with fever in Ugandan children.

BACKGROUND:Evidence for association between sickle cell and alpha thalassemia trait and severe malaria is compelling. However, for these polymorphisms associations with uncomplicated malaria, and for G6PD deficiency associations with uncomplicated and severe malaria, findings have been inconsistent. We studied samples from a three-arm case-control study with the objective of determining associations between common host erythrocyte polymorphisms and both uncomplicated and severe malaria, including different severe malaria phenotypes. METHOD:We assessed hemoglobin abnormalities, α-thalassemia, and G6PD deficiency by molecular methods in 325 children with severe malaria age-matched to 325 children with uncomplicated malaria and 325 healthy community controls. Conditional logistic regression was used to measure associations between specified genotypes and malaria outcomes. RESULTS:No tested polymorphisms offered significant protection against uncomplicated malaria. α-thalassemia homozygotes (_α/_α) had increased risk of uncomplicated malaria (OR 2.40; 95%CI 1.15, 5.03, p = 0.020). HbAS and α-thalassemia heterozygous (_α/αα) genotypes protected against severe malaria compared to uncomplicated malaria (HbAS OR 0.46; 0.23, 0.95, p = 0.036; _α/αα OR 0.51; 0.24, 0.77; p = 0.001) or community (HbAS OR 0.23; 0.11, 0.50; p

BackgroundLong-lasting insecticidal nets (LLINs) and indoor residual spraying of insecticide (IRS) are the primary vector control interventions used to prevent malaria in Africa. Although both interventions are effective in some settings, high-quality evidence is rarely available to evaluate their effectiveness following deployment by a national malaria control program. In Uganda, we measured changes in key malaria indicators following universal LLIN distribution in three sites, with the addition of IRS at one of these sites.Methods and findingsComprehensive malaria surveillance was conducted from October 1, 2011, to March 31, 2016, in three sub-counties with relatively low (Walukuba), moderate (Kihihi), and high transmission (Nagongera). Between 2013 and 2014, universal LLIN distribution campaigns were conducted in all sites, and in December 2014, IRS with the carbamate bendiocarb was initiated in Nagongera. High-quality surveillance evaluated malaria metrics and mosquito exposure before and after interventions through (a) enhanced health-facility-based surveillance to estimate malaria test positivity rate (TPR), expressed as the number testing positive for malaria/number tested for malaria (number of children tested for malaria: Walukuba = 42,833, Kihihi = 28,790, and Nagongera = 38,690); (b) cohort studies to estimate the incidence of malaria, expressed as the number of episodes per person-year [PPY] at risk (number of children observed: Walukuba = 340, Kihihi = 380, and Nagongera = 361); and (c) entomology surveys to estimate household-level human biting rate (HBR), expressed as the number of female Anopheles mosquitoes collected per house-night of collection (number of households observed: Walukuba = 117, Kihihi = 107, and Nagongera = 107). The LLIN distribution campaign substantially increased LLIN coverage levels at the three sites to between 65.0% and 95.5% of households with at least one LLIN. In Walukuba, over the 28-mo post-intervention period, universal LLIN distribution was associated with no change in the incidence of malaria (0.39 episodes PPY pre-intervention versus 0.20 post-intervention; adjusted rate ratio [aRR] = 1.02, 95% CI 0.36-2.91, p = 0.97) and non-significant reductions in the TPR (26.5% pre-intervention versus 26.2% post-intervention; aRR = 0.70, 95% CI 0.46-1.06, p = 0.09) and HBR (1.07 mosquitoes per house-night pre-intervention versus 0.71 post-intervention; aRR = 0.41, 95% CI 0.14-1.18, p = 0.10). In Kihihi, over the 21-mo post-intervention period, universal LLIN distribution was associated with a reduction in the incidence of malaria (1.77 pre-intervention versus 1.89 post-intervention; aRR = 0.65, 95% CI 0.43-0.98, p = 0.04) but no significant change in the TPR (49.3% pre-intervention versus 45.9% post-intervention; aRR = 0.83, 95% 0.58-1.18, p = 0.30) or HBR (4.06 pre-intervention versus 2.44 post-intervention; aRR = 0.71, 95% CI 0.30-1.64, p = 0.40). In Nagongera, over the 12-mo post-intervention period, universal LLIN distribution was associated with a reduction in the TPR (45.3% pre-intervention versus 36.5% post-intervention; aRR = 0.82, 95% CI 0.76-0.88, p < 0.001) but no significant change in the incidence of malaria (2.82 pre-intervention versus 3.28 post-intervention; aRR = 1.10, 95% 0.76-1.59, p = 0.60) or HBR (41.04 pre-intervention versus 20.15 post-intervention; aRR = 0.87, 95% CI 0.31-2.47, p = 0.80). The addition of three rounds of IRS at ~6-mo intervals in Nagongera was followed by clear decreases in all outcomes: incidence of malaria (3.25 pre-intervention versus 0.63 post-intervention; aRR = 0.13, 95% CI 0.07-0.27, p < 0.001), TPR (37.8% pre-intervention versus 15.0% post-intervention; aRR = 0.54, 95% CI 0.49-0.60, p < 0.001), and HBR (18.71 pre-intervention versus 3.23 post-intervention; aRR = 0.29, 95% CI 0.17-0.50, p < 0.001). High levels of pyrethroid resistance were documented at all three study sites. Limitations of the study included the observational study design, the lack of contemporaneous control groups, and that the interventions were implemented under programmatic conditions.ConclusionsUniversal distribution of LLINs at three sites with varying transmission intensity was associated with modest declines in the burden of malaria for some indicators, but the addition of IRS at the highest transmission site was associated with a marked decline in the burden of malaria for all indicators. In highly endemic areas of Africa with widespread pyrethroid resistance, IRS using alternative insecticide formulations may be needed to achieve substantial gains in malaria control.

Understanding the current epidemiology of malaria and the relationship between intervention coverage, transmission intensity, and burden of disease is important to guide control activities. We aimed to determine the prevalence of anemia, parasitemia, and serological responses to P. falciparum antigens, and factors associated with these indicators, in three different epidemiological settings in Uganda.In 2012, cross-sectional surveys were conducted in 200 randomly selected households from each of three sites: Walukuba, Jinja district (peri-urban); Kihihi, Kanungu district (rural); and Nagongera, Tororo district (rural) with corresponding estimates of annual entomologic inoculation rates (aEIR) of 3.8, 26.6, and 125.0, respectively. Of 2737 participants, laboratory testing was done in 2227 (81.4%), including measurement of hemoglobin, parasitemia using microscopy, and serological responses to P. falciparum apical membrane antigen 1 (AMA-1) and merozoite surface protein 1, 19 kilodalton fragment (MSP-119). Analysis of laboratory results was restricted to 1949 (87.5%) participants aged ≤ 40 years. Prevalence of anemia (hemoglobin < 11.0 g/dL) was significantly higher in Walukuba (18.9%) and Nagongera (17.4%) than in Kihihi (13.1%), and was strongly associated with decreasing age for those ≤ 5 years at all sites. Parasite prevalence was significantly higher in Nagongera (48.3%) than in Walukuba (12.2%) and Kihihi (12.8%), and significantly increased with age to 11 years, and then significantly decreased at all sites. Seropositivity to AMA-1 was 53.3% in Walukuba, 63.0% in Kihihi, and 83.7% in Nagongera and was associated with increasing age at all sites. AMA-1 seroconversion rates strongly correlated with transmission intensity, while serological responses to MSP-119 did not.Anemia was predominant in young children and parasitemia peaked by 11 years across 3 sites with varied transmission intensity. Serological responses to AMA-1 appeared to best reflect transmission intensity, and may be a more accurate indicator for malaria surveillance than anemia or parasitemia.

To assess different methods for determining cause of death from verbal autopsy (VA) questionnaire data, the intra-rater reliability of Physician-Certified Verbal Autopsy (PCVA) and the accuracy of PCVA, expert-derived (non-hierarchical) and data-driven (hierarchal) algorithms were assessed for determining common causes of death in Ugandan children. A verbal autopsy validation study was conducted from 2008-2009 in three different sites in Uganda. The dataset included 104 neonatal deaths (0-27 days) and 615 childhood deaths (1-59 months) with the cause(s) of death classified by PCVA and physician review of hospital medical records (the 'reference standard'). Of the original 719 questionnaires, 141 (20%) were selected for a second review by the same physicians; the repeat cause(s) of death were compared to the original,and agreement assessed using the Kappa statistic.Physician reviewers' refined non-hierarchical algorithms for common causes of death from existing expert algorithms, from which, hierarchal algorithms were developed. The accuracy of PCVA, non-hierarchical, and hierarchical algorithms for determining cause(s) of death from all 719 VA questionnaires was determined using the reference standard. Overall, intra-rater repeatability was high (83% agreement, Kappa 0.79 [95% CI 0.76-0.82]). PCVA performed well, with high specificity for determining cause of neonatal (>67%), and childhood (>83%) deaths, resulting in fairly accurate cause-specific mortality fraction (CSMF) estimates. For most causes of death in children, non-hierarchical algorithms had higher sensitivity, but correspondingly lower specificity, than PCVA and hierarchical algorithms, resulting in inaccurate CSMF estimates. Hierarchical algorithms were specific for most causes of death, and CSMF estimates were comparable to the reference standard and PCVA. Inter-rater reliability of PCVA was high, and overall PCVA performed well. Hierarchical algorithms performed better than non-hierarchical algorithms due to higher specificity and more accurate CSMF estimates. Use of PCVA to determine cause of death from VA questionnaire data is reasonable while automated data-driven algorithms are improved.

Mortality rates among hospitalized children in many government hospitals in sub-Saharan Africa are high. Pediatric emergency services in these hospitals are often sub-optimal. Timely recognition of critically ill children on arrival is key to improving service delivery. We present a simple risk score to predict inpatient mortality among hospitalized children. Between April 2010 and June 2011, the Uganda Malaria Surveillance Project (UMSP), in collaboration with the National Malaria Control Program (NMCP), set up an enhanced sentinel site malaria surveillance program for children hospitalized at four public hospitals in different districts: Tororo, Apac, Jinja and Mubende. Clinical data collected through March 2013, representing 50249 admissions were used to develop a mortality risk score (derivation data set). One year of data collected subsequently from the same hospitals, representing 20406 admissions, were used to prospectively validate the performance of the risk score (validation data set). Using a backward selection approach, 13 out of 25 clinical parameters recognizable on initial presentation, were selected for inclusion in a final logistic regression prediction model. The presence of individual parameters was awarded a score of either 1 or 2 based on regression coefficients. For each individual patient, a composite risk score was generated. The risk score was further categorized into three categories; low, medium, and high. Patient characteristics were comparable in both data sets. Measures of performance for the risk score included the receiver operating characteristics curves and the area under the curve (AUC), both demonstrating good and comparable ability to predict deathusing both the derivation (AUC =0.76) and validation dataset (AUC =0.74). Using the derivation and validation datasets, the mortality rates in each risk category were as follows: low risk (0.8% vs. 0.7%), moderate risk (3.5% vs. 3.2%), and high risk (16.5% vs. 12.6%), respectively. Our analysis resulted in development of a risk score that ably predicted mortality risk among hospitalized children. While validation studies are needed, this approach could be used to improve existing triage systems.

BACKGROUND:A better understanding of case management practices is required to improve inpatient pediatric care in resource-limited settings. Here we utilize data from a unique health facility-based surveillance system at six Ugandan hospitals to evaluate the quality of pediatric case management and the factors associated with appropriate care. METHODS:All children up to the age of 14 years admitted to six district or regional hospitals over 15 months were included in the study. Four case management categories were defined for analysis: suspected malaria, selected illnesses requiring antibiotics, suspected anemia, and diarrhea. The quality of case management for each category was determined by comparing recorded treatments with evidence-based best practices as defined in national guidelines. Associations between variables of interest and the receipt of appropriate case management were estimated using multivariable logistic regression. RESULTS:A total of 30,351 admissions were screened for inclusion in the analysis. Ninety-two percent of children met criteria for suspected malaria and 81% received appropriate case management. Thirty-two percent of children had selected illnesses requiring antibiotics and 89% received appropriate antibiotics. Thirty percent of children met criteria for suspected anemia and 38% received appropriate case management. Twelve percent of children had diarrhea and 18% received appropriate case management. Multivariable logistic regression revealed large differences in the quality of care between health facilities. There was also a strong association between a positive malaria diagnostic test result and the odds of receiving appropriate case management for comorbid non-malarial illnesses - children with a positive malaria test were more likely to receive appropriate care for anemia and less likely for illnesses requiring antibiotics and diarrhea. CONCLUSIONS:Appropriate management of suspected anemia and diarrhea occurred infrequently. Pediatric quality improvement initiatives should target deficiencies in care unique to each health facility, and interventions should focus on the simultaneous management of multiple diagnoses.

BACKGROUND: Verbal autopsy (VA) procedures can be used to estimate cause of death in settings with inadequate vital registries. However, the sensitivity of VA for determining malaria-specific mortality may be low, and may vary with transmission intensity. We assessed the diagnostic accuracy of VA procedures as compared to hospital medical records for determining cause of death in children under five in three different malaria transmission settings in Uganda, including Tororo (high), Kampala (medium), and Kisoro (low). METHODS AND FINDINGS: Caretakers of children who died in participating hospitals were interviewed using a standardized World Health Organization questionnaire. Medical records from the child's hospitalization were also reviewed. Causes of death based on the VA questionnaires and the medical records were assigned independently by physician reviewers and then compared. A total of 719 cases were included in the final analysis, 67 in Tororo, 600 in Kampala, and 52 in Kisoro. Malaria was classified as the underlying or contributory cause of death by review of medical records in 33 deaths in Tororo, 60 in Kampala, and 0 in Kisoro. The sensitivity of VA procedures for determining malaria deaths in Tororo was 61% (95% CI 44-78%) and 50% in Kampala (95% CI 37-63%). Specificity for determining malaria deaths in Tororo and Kampala was high (>88%), but positive predictive value varied widely, from 83% in Tororo to 34% in Kampala (difference 49%, 95% CI 31-67, p