Towards an evidence base in the treatment of severe febrile illness in East African children

Febrile illness is the primary cause of childhood outpatient attendance, admission to hospital and death in Africa. This series of studies were aimed at ascertaining the treatable causes of infection in children admitted to a district hospital typical of those found throughout East Africa, in an area of high transmission of malaria. The studies were also designed to determine the clinical correlates of infection and predictors of mortality, looking in particular at malaria, invasive bacterial disease and HIV infection. These studies also explored to what extent clinical examination by one group of staff was replicable by another.After informed consent a detailed history and structured examination was performed on all children admitted to the hospital. Blood was drawn for culture, microscopy for malaria, HIV testing, full blood count, bedside haemoglobin, blood glucose and lactate measurement and HRP-2 based rapid diagnostic test for falciparum malaria. Outcomes were recorded at death or discharge.Sufficient data was available on 3,639 children including 184 deaths (5.1%). Invasive bacterial disease was detected in 341 children (9.4%) and HIV in 142 (3.9%). Children with HIV and those with evidence of recent malaria were significantly more likely to have invasive bacterial disease. The most common organisms isolated were non-typhi Salmonella (46.9%), Strep, pneumoniae (16.4%) and Haemophilus influenzae b (11.4%). The most frequently encountered pathogen was P. falciparum, with 2,195 children found to have asexual parasitaemia (60.3%). Falciparum parasitaemia was detected in 100 children with invasive bacterial disease (29.3%). Falciparum malaria was detected in over half (51.6%) of childhood deaths, invasive bacterial disease was documented in 31.5%.In children with a positive blood slide for malaria, WHO severe malaria criteria identified 91.6% of the children that died. A multivariate analysis showed that signs of malnutrition, respiratory distress, altered consciousness, hypoxia according to pulse oximetry, hypoglycaemia, raised blood lactate, invasive bacterial disease and female sex were all associated with an increased risk of death. In children with negative blood slides signs of malnutrition, respiratory distress, altered consciousness, hypoglycaemia, raised blood lactate and invasive bacterial disease were all independently associated with mortality by multivariate analysis.WHO defined criteria of syndromes which would warrant antibiotics predicted 56% of cases of coinfection with invasive bacterial disease and malaria and 69.7% of cases of invasive bacterial disease in slide negative children. Treating all children with severe malaria for bacterial disease would result in 71% of children with coinfection being treated. In children with negative slides including severe anaemia or prostration as syndromes requiring antibiotic therapy would have resulted in 74.7% of children with invasive bacterial disease receiving antibiotic therapy. There was moderate agreement between staff over the presence of clinical signs in children, with hospital nurses performing as well as hospital clinical officers. Agreement was better in children over 18 months of age and in children who were not crying during examination.Current WHO guidelines on antibiotic use performed poorly in this setting. Gram negative infections were the most common cause of invasive infection and many of these are likely to be resistant to penicillin and other commonly used antibiotics. Consideration should be given to expanding the indications for antibiotic use and using more broad-spectrum antibiotics in severely ill children

Challenges to clinical research in a rural african hospital; a personal perspective from Tanzania.

UNLABELLED: This article is based on a talk given at the Japanese Society for Tropical medicine Annual Meeting in 2014. The severe febrile illness study was established in 2005. The aim of the project was to define the aetiology of febrile disease in children admitted to a hospital in Tanzania. Challenges arose in many areas: STUDY DESIGN: An initial plan to recruit only the severely ill was revised to enroll all febrile admissions leading to a more comprehensive dataset but much increased costs. Operationally a decision was made to set up a paediatric acute admissions unit (PAAU) in the hospital to facilitate recruitment and to provide appropriate initial care in line with perceived ethical obligations. This had knock on effects relating to the responsibilities that were taken on but also some unexpected positive outcomes. Study personnel: Local research staff were sometimes called upon to make up temporary shortfalls in the hospital staffing. Lack of staff made it impossible to recruit patients around the clock, seven days a week creating the challenge of ensuring representative sampling. Quality control: Studies based on clinical examination create unique quality control challenges-how to ensure that clinical staff are examining in a systematic and reproducible way. We designed a sub-study to both explore this and improve quality. SUMMARY: Setting up clinical research projects is severely resource poor settings creates many challenges including those of an operational, technical and ethical nature. Whilst there are no 'right answers' an awareness of these problems can help overcome them

Inpatient child mortality by travel time to hospital in a rural area of Tanzania.

OBJECTIVE: To investigate the association, if any, between child mortality and distance to the nearest hospital. METHODS: The study was based on data from a 1-year study of the cause of illness in febrile paediatric admissions to a district hospital in north-east Tanzania. All villages in the catchment population were geolocated, and travel times were estimated from availability of local transport. Using bands of travel time to hospital, we compared admission rates, inpatient case fatality rates and child mortality rates in the catchment population using inpatient deaths as the numerator. RESULTS: Three thousand hundred and eleven children under the age of 5 years were included of whom 4.6% died; 2307 were admitted from <3 h away of whom 3.4% died and 804 were admitted from ≥ 3 h away of whom 8.0% died. The admission rate declined from 125/1000 catchment population at <3 h away to 25/1000 at ≥ 3 h away, and the corresponding hospital deaths/catchment population were 4.3/1000 and 2.0/1000, respectively. Children admitted from more than 3 h away were more likely to be male, had a longer pre-admission duration of illness and a shorter time between admission and death. Assuming uniform mortality in the catchment population, the predicted number of deaths not benefiting from hospital admission prior to death increased by 21.4% per hour of travel time to hospital. If the same admission and death rates that were found at <3 h from the hospital applied to the whole catchment population and if hospital care conferred a 30% survival benefit compared to home care, then 10.3% of childhood deaths due to febrile illness in the catchment population would have been averted. CONCLUSIONS: The mortality impact of poor access to hospital care in areas of high paediatric mortality is likely to be substantial although uncertainty over the mortality benefit of inpatient care is the largest constraint in making an accurate estimate

Does sunlight drive seasonality of TB in Vietnam? A retrospective environmental ecological study of tuberculosis seasonality in Vietnam from 2010 to 2015.

BACKGROUND: Tuberculosis (TB) is a major global health burden, with an estimated quarter of the world's population being infected. The World Health Organization (WHO) launched the "End TB Strategy" in 2014 emphasising knowing the epidemic. WHO ranks Vietnam 12th in the world of high burden countries. TB spatial and temporal patterns have been observed globally with evidence of Vitamin D playing a role in seasonality. We explored the presence of temporal and spatial clustering of TB in Vietnam and their determinants to aid public health measures. METHODS: Data were collected by the National TB program of Vietnam from 2010 to 2015 and linked to the following datasets: socio-demographic characteristics; climatic variables; influenza-like-illness (ILI) incidence; geospatial data. The TB dataset was aggregated by province and quarter. Descriptive time series analyses using LOESS regression were completed per province to determine seasonality and trend. Harmonic regression was used to determine the amplitude of seasonality by province. A mixed-effect linear model was used with province and year as random effects and all other variables as fixed effects. RESULTS: There were 610,676 cases of TB notified between 2010 and 2015 in Vietnam. Heat maps of TB incidence per quarter per province showed substantial temporal and geospatial variation. Time series analysis demonstrated seasonality throughout the country, with peaks in spring/summer and troughs in autumn/winter. Incidence was consistently higher in the south, the three provinces with the highest incidence per 100,000 population were Tay Ninh, An Giang and Ho Chi Minh City. However, relative seasonal amplitude was more pronounced in the north. Mixed-effect linear model confirmed that TB incidence was associated with time and latitude. Of the demographic, socio-economic and health related variables, population density, percentage of those under 15 years of age, and HIV infection prevalence per province were associated with TB incidence. Of the climate variables, absolute humidity, average temperature and sunlight were associated with TB incidence. CONCLUSION: Preventative public health measures should be focused in the south of Viet Nam where incidence is highest. Vitamin D is unlikely to be a strong driver of seasonality but supplementation may play a role in a package of interventions

USP38, FREM3, SDC1, DDC, and LOC727982 Gene Polymorphisms and Differential Susceptibility to Severe Malaria in Tanzania

Populations exposed to Plasmodium falciparum infection develop genetic mechanisms of protection against severe malarial disease. Despite decades of genetic epidemiological research, the sickle cell trait (HbAS) sickle cell polymorphism, ABO blood group, and other hemoglobinopathies remain the few major determinants in severe malaria to be replicated across different African populations and study designs. Within a case-control study in a region of high transmission in Tanzania (n = 983), we investigated the role of 40 new loci identified in recent genome-wide studies. In 32 loci passing quality control procedures, we found polymorphisms in USP38, FREM3, SDC1, DDC, and LOC727982 genes to be putatively associated with differential susceptibility to severe malaria. Established candidates explained 7.4% of variation in severe malaria risk (HbAS polymorphism, 6.3%; α-thalassemia, 0.3%; ABO group, 0.3%; and glucose-6-phosphate dehydrogenase deficiency, 0.5%) and the new polymorphisms, another 4.3%. The regions encompassing the loci identified are promising targets for the design of future treatment and control interventions

African glucose-6-phosphate dehydrogenase alleles associated with protection from severe malaria in heterozygous females in Tanzania.

X-linked Glucose-6-phosphate dehydrogenase (G6PD) A- deficiency is prevalent in sub-Saharan Africa populations, and has been associated with protection from severe malaria. Whether females and/or males are protected by G6PD deficiency is uncertain, due in part to G6PD and malaria phenotypic complexity and misclassification. Almost all large association studies have genotyped a limited number of G6PD SNPs (e.g. G6PD202 / G6PD376), and this approach has been too blunt to capture the complete epidemiological picture. Here we have identified 68 G6PD polymorphisms and analysed 29 of these (i.e. those with a minor allele frequency greater than 1%) in 983 severe malaria cases and controls in Tanzania. We establish, across a number of SNPs including G6PD376, that only female heterozygotes are protected from severe malaria. Haplotype analysis reveals the G6PD locus to be under balancing selection, suggesting a mechanism of protection relying on alleles at modest frequency and avoiding fixation, where protection provided by G6PD deficiency against severe malaria is offset by increased risk of life-threatening complications. Our study also demonstrates that the much-needed large-scale studies of severe malaria and G6PD enzymatic function across African populations require the identification and analysis of the full repertoire of G6PD genetic markers

WHO guidelines for antimicrobial treatment in children admitted to hospital in an area of intense Plasmodium falciparum transmission: prospective study

Objectives To assess the performance of WHO’s “Guidelines for care at the first-referral level in developing countries” in an area of intense malaria transmission and identify bacterial infections in children with and without malaria

Impact of Personal Cooling on Performance, Comfort and Heat Strain of Healthcare Workers in PPE, a Study From West Africa.

Background: Personal protective equipment (PPE) is an essential component of safely treating suspected or confirmed SARS-CoV-2 patients. PPE acts as a barrier to heat loss, therefore increasing the risk of thermal strain which may impact on cognitive function. Healthcare workers (HCWs) need to be able to prioritize and execute complex tasks effectively to ensure patient safety. This study evaluated pre-cooling and per-cooling methods on thermal strain, thermal comfort and cognitive function during simulated emergency management of an acutely unwell patient. Methods: This randomized controlled crossover trial was run at the Clinical Services Department of the Medical Research Unit The Gambia. Each participant attended two sessions (Cool and Control) in standard PPE. Cool involved pre-cooling with an ice slurry ingestion and per-cooling by wearing an ice-vest external to PPE. Results: Twelve participants completed both sessions. There was a significant increase in tympanic temperature in Control sessions at both 1 and 2 h in PPE (p = 0.01). No significant increase was seen during Cool. Effect estimate of Cool was -0.2°C (95% CI -0.43; 0.01, p = 0.06) post 1 h and -0.28°C (95% CI -0.57; 0.02, p = 0.06) post 2 h on tympanic temperature. Cool improved thermal comfort (p < 0.001), thermal sensation (p < 0.001), and thirst (p = 0.04). No difference on cognitive function was demonstrated using multilevel modeling. Discussion: Thermal strain in HCWs wearing PPE can be safely reduced using pre- and per-cooling methods external to PPE