Sarah Kiguli

Mortality after Fluid Bolus in African Children with Severe Infection

BACKGROUND The role of fluid resuscitation in the treatment of children with shock and life-threatening infections who live in resource-limited settings is not established. METHODS We randomly assigned children with severe febrile illness and impaired perfusion to receive boluses of 20 to 40 ml of 5% albumin solution (albumin-bolus group) or 0.9% saline solution (saline-bolus group) per kilogram of body weight or no bolus (control group) at the time of admission to a hospital in Uganda, Kenya, or Tanzania (stratum A); children with severe hypotension were randomly assigned to one of the bolus groups only (stratum B). All children received appropriate antimicrobial treatment, intravenous maintenance fluids, and supportive care, according to guidelines. Children with malnutrition or gastroenteritis were excluded. The primary end point was 48-hour mortality; secondary end points included pulmonary edema, increased intracranial pressure, and mortality or neurologic sequelae at 4 weeks. RESULTS The data and safety monitoring committee recommended halting recruitment after 3141 of the projected 3600 children in stratum A were enrolled. Malaria status (57% overall) and clinical severity were similar across groups. The 48-hour mortality was 10.6% (111 of 1050 children), 10.5% (110 of 1047 children), and 7.3% (76 of 1044 children) in the albumin-bolus, saline-bolus, and control groups, respectively (relative risk for saline bolus vs. control, 1.44; 95% confidence interval [CI], 1.09 to 1.90; P=0.01; relative risk for albumin bolus vs. saline bolus, 1.01; 95% CI, 0.78 to 1.29; P=0.96; and relative risk for any bolus vs. control, 1.45; 95% CI, 1.13 to 1.86; P=0.003). The 4-week mortality was 12.2%, 12.0%, and 8.7% in the three groups, respectively (P=0.004 for the comparison of bolus with control). Neurologic sequelae occurred in 2.2%, 1.9%, and 2.0% of the children in the respective groups (P=0.92), and pulmonary edema or increased intracranial pressure occurred in 2.6%, 2.2%, and 1.7% (P=0.17), respectively. In stratum B, 69% of the children (9 of 13) in the albumin-bolus group and 56% (9 of 16) in the saline-bolus group died (P=0.45). The results were consistent across centers and across subgroups according to the severity of shock and status with respect to malaria, coma, sepsis, acidosis, and severe anemia. CONCLUSIONS Fluid boluses significantly increased 48-hour mortality in critically ill children with impaired perfusion in these resource-limited settings in Africa. (Funded by the Medical Research Council, United Kingdom; FEAST Current Controlled Trials number, ISRCTN69856593.).

Use of deferred consent for severely ill children in a multi-centre phase III trial

BackgroundVoluntary participation of a subject in research respects a subjects rights, strengthens its ethical conduct, and is formalized by the informed consent process. Clinical trials of life-saving interventions for medical emergencies often necessitate enrolment of patients where prior written individual informed consent is impossible. Although there are regulations and guidelines on protecting subjects in emergency research, these have been criticised for being limited and unnecessarily restrictive. Across Europe and the United States stringent regulations have resulted in a substantial decline of clinical trials involving emergency interventions.MethodsWe are conducting a trial of fluid resuscitation in children with hypovolaemic shock in six hospitals across three malaria-endemic African countries. The design is pragmatic as children are enrolled on clinical criteria alone and is being conducted in hospitals with facilities typical of many district hospitals across Africa. The trial aims to inform strategy for managing children with febrile illness and features of shock. In order to develop appropriate consent processes for the trial, we conducted a narrative review of current international recommendations for emergency consent.ResultsPractical or specific guidance was generally sparse or confusing with few examples in the literature to direct our informed consent process. For a sub-group of children who were critically sick or where parents themselves were otherwise too distressed to consider prior written consent, we opted for a modified form of deferred consent. This included verbal assent from guardians at the point of enrolment, with full written consent obtained after stabilising the child. For children who died prior to full written consent, ethical permission was received to waiver full consent.ConclusionsIn light of the controversy around guidance and regulations in this area we report how and why we have used a modified system of deferred consent in an emergency intervention trial in children. Although approved by all relevant ethics committees and operational in 3 countries in Africa, formal research is now necessary to explore the perceptions and experiences of parents, health workers, researchers and ethics committees of the modified method of deferred consent.

Zinc adjunct therapy reduces case fatality in severe childhood pneumonia: a randomized double blind placebo-controlled trial

BackgroundPneumonia is a leading cause of childrens deaths in developing countries and hinders achievement of the fourth Millennium Development Goal. This goal aims to reduce the under-five mortality rate, by two thirds, between 1990 and 2015.Few studies have examined the impact of zinc adjunct therapy on the outcome of childhood pneumonia. We determined the effect of zinc as adjunct therapy on time to normalization of respiratory rate, temperature and oxygen saturation. We also studied the effect of zinc adjunct therapy on case fatality of severe childhood pneumonia (as a secondary outcome) in Mulago Hospital, Uganda.MethodsIn this double blind, randomized, placebo-controlled clinical trial, 352 children aged 6 to 59 months, with severe pneumonia were randomized to zinc (20 mg for children ≥12 months, and 10 mg for those < 12 months) or a placebo once daily for seven days, in addition to standard antibiotics for severe pneumonia. Children were assessed every six hours. Oxygen saturation was normal if it was above 92% (breathing room air) for more than 15 minutes. The respiratory rate was normal if it was consistently (more than 24 hours) below 50 breaths per minute in infants and 40 breaths per minute in children above 12 months of age. Temperature was normal if consistently below 37.5°C. The difference in case fatality was expressed by the risk ratio between the two groups.ResultsTime to normalization of the respiratory rate, temperature and oxygen saturation was not significantly different between the two arms.Case fatality was 7/176 (4.0%) in the zinc group and 21/176 (11.9%) in the placebo group: Relative Risk 0.33 (95% CI 0.15 to 0.76). Relative Risk Reduction was 0.67 (95% CI 0.24 to 0.85), while the number needed to treat was 13. Among HIV infected children, case fatality was higher in the placebo (7/27) than in the zinc (0/28) group; RR 0.1 (95% CI 0.0, 1.0).Among 127 HIV uninfected children receiving the placebo, case fatality was 7/127 (5.5%); versus 5/129 (3.9%) among HIV uninfected group receiving zinc: RR 0.7 (95% CI 0.2, 2.2). The excess risk of death attributable to the placebo arm (Absolute Risk Reduction or ARR) was 8/100 (95% CI: 2/100, 14/100) children. This excess risk was substantially greater among HIV positive children than in HIV negative children (ARR: 26 (95% CI: 9, 42) per 100 versus 2 (95% CI: -4, 7) per 100); P-value for homogeneity of risk differences = 0.006.ConclusionZinc adjunct therapy for severe pneumonia had no significant effect on time to normalization of the respiratory rate, temperature and oxygen saturation. However, zinc supplementation in these children significantly decreased case fatality.The difference in case fatality attributable to the protective effect of zinc therapy was greater among HIV infected than HIV uninfected children. Given these results, zinc could be considered for use as adjunct therapy for severe pneumonia, especially among Highly Active Antiretroviral Therapynaïve HIV infected children in our environment.Clinical trials registration numberclinicaltrials.gov NCT00373100

Development of a competency-based curriculum in global child health.

Resident interest in global health is increasing; however, a paucity of literature on competency-based curricula in global child health is available. A collaborative group including members from the University of Minnesota (UMN) Department of Pediatrics, the UMN College of Education and Human Development, and the Makerere University Department of Paediatrics and Child Health in Kampala, Uganda, developed a competency-based global child health curriculum for pediatrics residents at UMN. The group defined competencies for each of the Accreditation Council for Graduate Medical Education competency domains and developed the curriculum via six steps: (1) defining competencies specific to global child health, (2) authoring goals and objectives for each competency, (3) assigning appropriate postgraduate training levels to each competency, (4) determining intended resident groups for each competency, (5) aligning the program with the existing residency education program, and (6) developing methods to evaluate acquisition of each competency. Faculty implemented the competency-based curriculum in 2009, and the curriculum is now freely available online for adaptation and use by other residency programs. Faculty are currently introducing evaluation methods, which will allow them, for the first time, to assess a trainees competency in global child health by the end of his or her residency. The authors believe that the development of this curriculum represents an important step forward in global health education for pediatric residents and that other residency programs, including those of nonpediatric specialties, can use the process as a model to develop global health curricula.

Nodding syndrome in Ugandan children—clinical features, brain imaging and complications: a case series

Objectives Nodding syndrome is a devastating neurological disorder of uncertain aetiology affecting children in Africa. There is no diagnostic test, and risk factors and symptoms that would allow early diagnosis are poorly documented. This study aimed to describe the clinical, electrophysiological and brain imaging (MRI) features and complications of nodding syndrome in Ugandan children. Design Case series. Participants 22 children with nodding syndrome brought to Mulago National Referral Hospital for assessment. Outcome measures Clinical features, physical and functional disabilities, EEG and brain MRI findings and a staging system with a progressive development of symptoms and complications. Results The median age of symptom onset was 6 (range 4–10) years and median duration of symptoms was 8.5 (range 2–11) years. 16 of 22 families reported multiple affected children. Physical manifestations and complications included stunting, wasting, lip changes and gross physical deformities. The bone age was delayed by 2 (range 1–6) years. There was peripheral muscle wasting and progressive generalised wasting. Four children had nodding as the only seizure type; 18 in addition had myoclonic, absence and/or generalised tonic–clonic seizures developing 1–3 years after the onset of illness. Psychiatric manifestations included wandering, aggression, depression and disordered perception. Cognitive assessment in three children demonstrated profound impairment. The EEG was abnormal in all, suggesting symptomatic generalised epilepsy in the majority. There were different degrees of cortical and cerebellar atrophy on brain MRI, but no hippocampal changes. Five stages with worsening physical, EEG and brain imaging features were identified: a prodrome, the development of head nodding and cognitive decline, other seizure types, multiple complications and severe disability. Conclusions Nodding syndrome is a neurological disorder that may be characterised as probably symptomatic generalised epilepsy. Clinical manifestations and complications develop in stages which might be useful in defining treatment and rehabilitation. Studies of risk factors, pathogenesis, management and outcome are urgently needed.

CD8 + T cells provide an immunologic signature of tuberculosis in young children

RATIONALE The immunologic events surrounding primary Mycobacterium tuberculosis infection and development of tuberculosis remain controversial. Young children who develop tuberculosis do so quickly after first exposure, thus permitting study of immune response to primary infection and disease. We hypothesized that M. tuberculosis-specific CD8(+) T cells are generated in response to high bacillary loads occurring during tuberculosis. OBJECTIVES To determine if M. tuberculosis-specific T cells are generated among healthy children exposed to M. tuberculosis and children with tuberculosis. METHODS Enzyme-linked immunosorbent spot assays were used to measure IFN-γ production in response to M. tuberculosis-specific proteins ESAT-6/CFP-10 by peripheral blood mononuclear cells and CD8(+) T cells isolated from Ugandan children hospitalized with tuberculosis (n = 96) or healthy tuberculosis contacts (n = 62). MEASUREMENTS AND MAIN RESULTS The proportion of positive CD8(+) T-cell assays and magnitude of CD8(+) T-cell responses were significantly greater among young (<5 yr) tuberculosis cases compared with young contacts (P = 0.02, Fisher exact test, P = 0.01, Wilcoxon rank-sum, respectively). M. tuberculosis-specific T-cell responses measured in peripheral blood mononuclear cells were equivalent between groups. CONCLUSIONS Among young children, M. tuberculosis-specific CD8(+) T cells develop in response to high bacillary loads, as occurs during tuberculosis, and are unlikely to be found after M. tuberculosis exposure. T-cell responses measured in peripheral blood mononuclear cells are generated after M. tuberculosis exposure alone, and thus cannot distinguish exposure from disease. In young children, IFN-γ-producing M. tuberculosis-specific CD8(+) T cells provide an immunologic signature of primary M. tuberculosis infection resulting in disease.

‘The Words Will Pass with the Blowing Wind’: Staff and Parent Views of the Deferred Consent Process, with Prior Assent, Used in an Emergency Fluids Trial in Two African Hospitals

Objective To document and explore the views and experiences of key stakeholders regarding the consent procedures of an emergency research clinical trial examining immediate fluid resuscitation strategies, and to discuss the implications for similar trials in future. Methods A social science sub-study of the FEAST (Fluid Expansion As Supportive Therapy) trial. Interviews were held with trial team members (n = 30), health workers (n = 15) and parents (n = 51) from two purposively selected hospitals in Soroti, Uganda, and Kilifi, Kenya. Findings Overall, deferred consent with prior assent was seen by staff and parents as having the potential to protect the interests of both patients and researchers, and to avoid delays in starting treatment. An important challenge is that the validity of verbal assent is undermined when inadequate initial information is poorly understood. This concern needs to be balanced against the possibility that full prior consent on admission potentially causes harm through introducing delays. Full prior consent also potentially imposes worries on parents that clinicians are uncertain about how to proceed and that clinicians want to absolve themselves of any responsibility for the child’s outcome (some parents’ interpretation of the need for signed consent). Voluntariness is clearly compromised for both verbal assent and full prior consent in a context of such vulnerability and stress. Further challenges in obtaining verbal assent were: what to do in the absence of the household decision-maker (often the father); and how medical staff handle parents not giving a clear agreement or refusal. Conclusion While the challenges identified are faced in all research in low-income settings, they are magnified for emergency trials by the urgency of decision making and treatment needs. Consent options will need to be tailored to particular studies and settings, and might best be informed by consultation with staff members and community representatives using a deliberative approach.

Situational analysis of teaching and learning of medicine and nursing students at Makerere University College of Health Sciences.

BackgroundMakerere University College of Health Sciences (MakCHS) in Uganda is undergoing a major reform to become a more influential force in society. It is important that its medicine and nursing graduates are equipped to best address the priority health needs of the Ugandan population, as outlined in the government’s Health Sector Strategic Plan (HSSP). The assessment identifies critical gaps in the core competencies of the MakCHS medicine and nursing and ways to overcome them in order to achieve HSSP goals.MethodsDocuments from the Uganda Ministry of Health were reviewed, and medicine and nursing curricula were analyzed. Nineteen key informant interviews (KII) and seven focus group discussions (FGD) with stakeholders were conducted. The data were manually analyzed for emerging themes and sub-themes. The study team subsequently used the checklists to create matrices summarizing the findings from the KIIs, FGDs, and curricula analysis. Validation of findings was done by triangulating information from the different data collection methods.ResultsThe core competencies that medicine and nursing students are expected to achieve by the end of their education were outlined for both programs. The curricula are in the process of reform towards competency-based education, and on the surface, are well aligned with the strategic needs of the country. But implementation is inadequate, and can be changed:• Learning objectives need to be more applicable to achieving competencies.• Learning experiences need to be more relevant for competencies and setting in which students will work after graduation (i.e. not just clinical care in a tertiary care facility).• Student evaluation needs to be better designed for assessing these competencies.ConclusionMakCHS has made a significant attempt to produce relevant, competent nursing and medicine graduates to meet the community needs. Ways to make them more effective though deliberate efforts to apply a competency-based education are possible.

Burden of sickle cell trait and disease in the Uganda Sickle Surveillance Study (US3): a cross-sectional study

BACKGROUND Sickle cell disease contributes substantially to mortality in children younger than 5 years in sub-Saharan Africa. In Uganda, 20,000 babies per year are thought to be born with sickle cell disease, but accurate data are not available. We did the cross-sectional Uganda Sickle Surveillance Study to assess the burden of disease. METHODS The primary objective of the study was to calculate prevalence of sickle cell trait and disease. We obtained punch samples from dried blood spots routinely collected from HIV-exposed infants in ten regions and 112 districts across Uganda for the national Early Infant Diagnosis programme. Haemoglobin electrophoresis by isoelectric focusing was done on all samples to identify those from babies with sickle trait or disease. FINDINGS Between February, 2014, and March, 2015, 99,243 dried blood spots were analysed and results were available for 97,631. The overall number of children with sickle cell trait was 12,979 (13·3%) and with disease was 716 (0·7%). Sickle cell numbers ranged from 631 (4·6%) for trait and 23 (0·2%) for disease of 13,649 in the South Western region to 1306 (19·8%) for trait and 96 (1·5%) for disease of 6581 in the East Central region. Sickle cell trait was seen in all districts. The lowest prevalence was less than 3·0% in two districts. Eight districts had prevalence greater than 20·0%, with the highest being 23·9%. Sickle cell disease was less common in children older than 12 months or who were HIV positive, which is consistent with comorbidity and early mortality. INTERPRETATION Prevalence of sickle cell trait and disease were high in Uganda, with notable variation between regions and districts. The data will help to inform national strategies for sickle cell disease, including neonatal screening. FUNDING Cincinnati Childrens Research Foundation.

Child Neurology Practice and Neurological Disorders in East Africa

Neurological disorders, including neurodevelopmental disorders, have been identified by the World Health Organization (WHO) as one of the greatest threats to global public health. It is generally believed that these conditions are more prevalent in the developing than the developed world because of multiple known risk factors such as infections, malnutrition, and limited resources for obstetric and neonatal management. In East Africa, few investigations have been conducted to obtain data on the magnitude and description of neurological disorders among children, and the practice of child neurology is faced with challenges cutting across areas of health personnel, patient diagnosis, management, and rehabilitation. This article reviews the burden, types, and causes of neurological disorders in the East African region. The challenges and successes in the practice of child neurology and recommendations for the future are discussed.