Peter Olupot-Olupot

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.).

Was the "ABC" approach (abstinence, being faithful, using condoms) responsible for Uganda's decline in HIV?

Background to the debate: Uganda is one of the few African countries where rates of HIV infection have fallen, from about 15 percent in the early 1990s to about five percent in 2001. At the end of 2005, UNAIDS estimated that 6.7 percent of adults were infected with the virus. The reasons behind Ugandas success have been intensely studied in the hope that other countries can emulate the strategies that worked. Some researchers credit the success to the Ugandan governments promotion of “ABC behaviors”—particularly abstinence and fidelity. Uganda receives funds from the United States Presidents Emergency Plan for AIDS Relief, which promotes the ABC approach with a focus on abstinence-driven public health campaigns. Other researchers question whether the ABC approach was really responsible for the decline in HIV infection. Critics of the ABC approach also argue that by emphasizing abstinence over condom use, the approach leaves women at risk of infection, because in many parts of the world women are not empowered to insist on abstinence or fidelity.

Clinical and immunological outcomes of a national paediatric cohort receiving combination antiretroviral therapy in Uganda.

Objective:We aimed to evaluate clinical and immunological outcomes of paediatric patients receiving combination antiretroviral therapy (cART) enrolled in The AIDS Support Organization (TASO) Uganda national HIV/AIDS programme. Design:Observational study of patients (age <14 years) enrolled in 10 clinics across Uganda for which TASO has data. Methods:We extracted patient demographic, immunological and clinical outcomes from the TASO databases regarding age, sex, cART regimen, CD4 cell count and WHO stage at initiation, tuberculosis, mortality and adherence. Outcomes were analysed using Pearsons rank–order correlations, Wilcoxons rank sum tests, Cox proportional hazard model and survivor functions. Results:Of the total 770 HIV children on cART, median age was 9 years (interquartile range, 5–13 years), and median follow-up time was 377 days (interquartile range, 173–624 days). Seven hundred and fifty-one children (97.5%) initiated nonnucleoside reverse transcriptase inhibitor-based regimens. Three hundred and sixty-five children (47.5%) initiated cART with severe immune suppression (CD4 cell percentage <15). Of the 18 (2.3%) children that died, mortality was associated with lower CD4 cell percentage at initiation (B coefficient −0.144, standard error 0.06, P = 0.02). Of the total, 229 (30%) were single or double orphans and more likely to initiate cART at an older age (mean age, 9.25 vs. 8.35 years, P = 0.02) and have a lower CD4 cell count (median, 268 vs. 422 cells/μl, P ≤ 0.0001) and CD4 cell percentage (median 12.8 vs. 15.5%, P = 0.02) at initiation. Pulmonary tuberculosis was present in 43 (5.6%) patients at initiation and 21 (2.3%) after cART. Almost all patients (94.9%) demonstrated more than 95% adherence. Conclusion:Children on cART in Uganda demonstrate positive clinical outcomes. However, additional support is required to ensure timely cART access among orphans and young children.

Adherence to antiretroviral therapy among a conflict-affected population in Northeastern Uganda : a qualitative study

We aimed to determine patient and health worker concerns regarding antiretroviral adherence in a conflict-affected population using focus groups (n = 40) and semi-structured interviews (n = 11). Patient concerns include security attending clinics, food security, distance to health centers and access to health providers. During periods of famine and flooding, the lack of food security and only single daily meals makes taking multiple doses impossible. Possible facilitating strategies included mobile teams, increased security and regularity of drug stocks.

‘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.

Chronic viral hepatitis may diminish the gains of HIV antiretroviral therapy in sub-Saharan Africa.

There is a heavy burden of HIV-hepatitis B virus (HBV) and HIV-hepatitis C virus (HCV) co-infection in many regions of the developing world. An often unmentioned illness, issues of poverty, socio-economic status, nutrition, access to medical care, and mistrust of Western-style medicine conspire to reduce the opportunity to receive clinical work-up and treatment for chronic viral hepatitis. We discuss key issues specific to the treatment of viral hepatitis and obstacles to success with this endeavor in the context of HIV co-infection in Africa. We predict that provision of viral hepatitis antiviral therapy will become a more pressing issue as more HIV-infected patients receive lifesaving combination antiretroviral therapy only to succumb thereafter from viral hepatitis-induced liver disease. Given the lessons learned from combination antiretroviral rollout in sub-Saharan Africa, establishing expertise and infrastructure for viral hepatitis care and antiviral therapy is relevant. Failure to act now may diminish the milestones and the gains made with antiretroviral therapy in the developing world.

WHO guidelines on fluid resuscitation in children: missing the FEAST data

The 2013 World Health Organization guidelines continue to recommend rapid fluid resuscitation for children with shock despite evidence that this can be harmful. Sarah Kiguli and colleagues call for WHO to think again

Orphanhood predicts delayed access to care in Ugandan children.

We aimed to determine patient characteristics, treatment challenges, and adherence outcomes according to orphanhood status in a prospective cohort of 101 HIV+ children in rural Uganda. Orphans were older at antiretroviral initiation (P = 0.0008) and more likely to be WHO stage-4 (P = 0.03) than nonorphans. More attention to improving access to antiretrovirals in pediatric populations, especially orphans, is needed.

Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub-Saharan Africa: Rationale and Design of the REACH Trial

Sickle cell anemia (SCA) is an inherited hematological disorder that causes a large but neglected global health burden, particularly in Africa. Hydroxyurea represents the only available disease‐modifying therapy for SCA, and has proven safety and efficacy in high‐resource countries. In sub‐Saharan Africa, there is minimal use of hydroxyurea, due to lack of data, absence of evidence‐based guidelines, and inexperience among healthcare providers.

Predicting mortality in sick African children: the FEAST Paediatric Emergency Triage (PET) Score

BackgroundMortality in paediatric emergency care units in Africa often occurs within the first 24 h of admission and remains high. Alongside effective triage systems, a practical clinical bedside risk score to identify those at greatest risk could contribute to reducing mortality.MethodsData collected during the Fluid As Expansive Supportive Therapy (FEAST) trial, a multi-centre trial involving 3,170 severely ill African children, were analysed to identify clinical and laboratory prognostic factors for mortality. Multivariable Cox regression was used to build a model in this derivation dataset based on clinical parameters that could be quickly and easily assessed at the bedside. A score developed from the model coefficients was externally validated in two admissions datasets from Kilifi District Hospital, Kenya, and compared to published risk scores using Area Under the Receiver Operating Curve (AUROC) and Hosmer-Lemeshow tests. The Net Reclassification Index (NRI) was used to identify additional laboratory prognostic factors.ResultsA risk score using 8 clinical variables (temperature, heart rate, capillary refill time, conscious level, severe pallor, respiratory distress, lung crepitations, and weak pulse volume) was developed. The score ranged from 0–10 and had an AUROC of 0.82 (95 % CI, 0.77–0.87) in the FEAST trial derivation set. In the independent validation datasets, the score had an AUROC of 0.77 (95 % CI, 0.72–0.82) amongst admissions to a paediatric high dependency ward and 0.86 (95 % CI, 0.82–0.89) amongst general paediatric admissions. This discriminative ability was similar to, or better than other risk scores in the validation datasets. NRI identified lactate, blood urea nitrogen, and pH to be important prognostic laboratory variables that could add information to the clinical score.ConclusionsEight clinical prognostic factors that could be rapidly assessed by healthcare staff for triage were combined to create the FEAST Paediatric Emergency Triage (PET) score and externally validated. The score discriminated those at highest risk of fatal outcome at the point of hospital admission and compared well to other published risk scores. Further laboratory tests were also identified as prognostic factors which could be added if resources were available or as indices of severity for comparison between centres in future research studies.