Clinical spectrum and severity of hemolytic anemia in glucose 6-phosphate dehydrogenase-deficient children receiving dapsone.

Drug-induced acute hemolytic anemia led to the discovery of G6PD deficiency. However, most clinical data are from isolated case reports. In 2 clinical trials of antimalarial preparations containing dapsone (4,4'-diaminodiphenylsulfone; 2.5 mg/kg once daily for 3 days), 95 G6PD-deficient hemizygous boys, 24 G6PD-deficient homozygous girls, and 200 girls heterozygous for G6PD deficiency received this agent. In the first 2 groups, there was a maximum decrease in hemoglobin averaging -2.64 g/dL (range -6.70 to +0.30 g/dL), which was significantly greater than for the comparator group receiving artemether-lumefantrine (adjusted difference -1.46 g/dL; 95% confidence interval -1.76, -1.15). Hemoglobin concentrations were decreased by ≥ 40% versus pretreatment in 24/119 (20.2%) of the G6PD-deficient children; 13/119 (10.9%) required blood transfusion. In the heterozygous girls, the mean maximum decrease in hemoglobin was -1.83 g/dL (range +0.90 to -5.20 g/dL); 1 in 200 (0.5%) required blood transfusion. All children eventually recovered. All the G6PD-deficient children had the G6PD A- variant, ie, mutations V68M and N126D. Drug-induced acute hemolytic anemia in G6PD A- subjects can be life-threatening, depending on the nature and dosage of the drug trigger. Therefore, contrary to current perception, in clinical terms the A- type of G6PD deficiency cannot be regarded as mild. This study is registered at http://www.clinicaltrials.gov as NCT00344006 and NCT00371735.

Roundtable discussion: what is the future role of the private sector in health?

BACKGROUND: The role for the private sector in health remains subject to much debate, especially within the context of achieving universal health coverage.This roundtable discussion offers diverse perspectives from a range of stakeholders--a health funder, a representative from an implementing organization, a national-level policy-maker, and an expert working in a large multi-national company--on what the future may hold for the private sector in health. DISCUSSION: The first perspective comes from a health funder, who argues that the discussion about the future role of the private sector has been bogged down in language. He argues for a 'both/and' approach rather than an 'either/or' when it comes to talking about health service provision in low- and middle-income countries.The second perspective is offered by an implementer of health insurance in sub-Saharan Africa. The piece examines the comparative roles of public sector actors, private sector actors and funding agencies, suggesting that they must work together to mobilize domestic resources to fund and deliver health services in the longer term.Thirdly, a special advisor working in the federal government of Nigeria considers the situation in that country. He notes that the private sector plays a significant role in funding and delivering health services there, and that the government must engage the private sector or forever be left behind.Finally, a representative from a multi-national pharmaceutical corporation gives an overview of global shifts that are creating opportunities for the private sector in health markets. SUMMARY: Overall, the roundtable discussants agree that the private sector will play an important role in future health systems. But we must agree a common language, work together, and identify key issues and gaps that might be more effectively filled by the private sector.

Frequency of glucose-6-phosphate dehydrogenase deficiency in malaria patients from six African countries enrolled in two randomized anti-malarial clinical trials.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is common in populations living in malaria endemic areas. G6PD genotype and phenotype were determined for malaria patients enrolled in the chlorproguanil-dapsone-artesunate (CDA) phase III clinical trial programme. METHODS: Study participants, aged > 1 year, with microscopically confirmed uncomplicated Plasmodium falciparum malaria, and haemoglobin ≥ 70 g/L or haematocrit ≥ 25%, were recruited into two clinical trials conducted in six African countries (Burkina Faso, Ghana, Kenya, Nigeria, Tanzania, Mali). G6PD genotype of the three most common African forms, G6PD*B, G6PD*A (A376G), and G6PD*A- (G202A, A542T, G680T and T968C), were determined and used for frequency estimation. G6PD phenotype was assessed qualitatively using the NADPH fluorescence test. Exploratory analyses investigated the effect of G6PD status on baseline haemoglobin concentration, temperature, asexual parasitaemia and anti-malarial efficacy after treatment with CDA 2/2.5/4 mg/kg or chlorproguanil-dapsone 2/2.5 mg/kg (both given once daily for three days) or six-dose artemether-lumefantrine. RESULTS: Of 2264 malaria patients enrolled, 2045 had G6PD genotype available and comprised the primary analysis population (1018 males, 1027 females). G6PD deficiency prevalence was 9.0% (184/2045; 7.2% [N = 147] male hemizygous plus 1.8% [N = 37] female homozygous), 13.3% (273/2045) of patients were heterozygous females, 77.7% (1588/2045) were G6PD normal. All deficient G6PD*A- genotypes were A376G/G202A. G6PD phenotype was available for 64.5% (1319/2045) of patients: 10.2% (134/1319) were G6PD deficient, 9.6% (127/1319) intermediate, and 80.2% (1058/1319) normal. Phenotype test specificity in detecting hemizygous males was 70.7% (70/99) and 48.0% (12/25) for homozygous females. Logistic regression found no significant effect of G6PD genotype on adjusted mean baseline haemoglobin (p = 0.154), adjusted mean baseline temperature (p = 0.9617), or adjusted log mean baseline parasitaemia (p = 0.365). There was no effect of G6PD genotype (p = 0.490) or phenotype (p = 0.391) on the rate of malaria recrudescence, or reinfection (p = 0.134 and p = 0.354, respectively). CONCLUSIONS: G6PD deficiency is common in African patients with malaria and until a reliable and simple G6PD test is available, the use of 8-aminoquinolines will remain problematic. G6PD status did not impact baseline haemoglobin, parasitaemia or temperature or the outcomes of anti-malarial therapy. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00344006 and NCT00371735.

Incidence and clinical characteristics of group A rotavirus infections among children admitted to hospital in Kilifi, Kenya.

BACKGROUND: Rotavirus, predominantly of group A, is a major cause of severe diarrhoea worldwide, with the greatest burden falling on young children living in less-developed countries. Vaccines directed against this virus have shown promise in recent trials, and are undergoing effectiveness evaluation in sub-Saharan Africa. In this region limited childhood data are available on the incidence and clinical characteristics of severe group A rotavirus disease. Advocacy for vaccine intervention and interpretation of effectiveness following implementation will benefit from accurate base-line estimates of the incidence and severity of rotavirus paediatric admissions in relevant populations. The study objective was to accurately define the incidence and severity of group A rotavirus disease in a resource-poor setting necessary to make informed decisions on the need for vaccine prevention. METHODS AND FINDINGS: Between 2002 and 2004 we conducted prospective surveillance for group A rotavirus infection at Kilifi District Hospital in coastal Kenya. Children < 13 y of age were eligible as "cases" if admitted with diarrhoea, and "controls" if admitted without diarrhoea. We calculated the incidence of hospital admission with group A rotavirus using data from a demographic surveillance study of 220,000 people in Kilifi District. Of 15,347 childhood admissions 3,296 (22%) had diarrhoea, 2,039 were tested for group A rotavirus antigen and, of these, 588 (29%) were positive. 372 (63%) rotavirus-positive cases were infants. Of 620 controls 19 (3.1%, 95% confidence interval [CI] 1.9-4.7) were rotavirus positive. The annual incidence (per 100,000 children) of rotavirus-positive admissions was 1,431 (95% CI 1,275-1,600) in infants and 478 (437-521) in under-5-y-olds, and highest proximal to the hospital. Compared to children with rotavirus-negative diarrhoea, rotavirus-positive cases were less likely to have coexisting illnesses and more likely to have acidosis (46% versus 17%) and severe electrolyte imbalance except hyponatraemia. In-hospital case fatality was 2% among rotavirus-positive and 9% among rotavirus-negative children. CONCLUSIONS: In Kilifi > 2% of children are admitted to hospital with group A rotavirus diarrhoea in the first 5 y of life. This translates into over 28,000 vaccine-preventable hospitalisations per year across Kenya, and is likely to be a considerable underestimate. Group A rotavirus diarrhoea is associated with acute life-threatening metabolic derangement in otherwise healthy children. Although mortality is low in this clinical research setting this may not be generally true in African hospitals lacking rapid and appropriate management.

Survival and haematological recovery of children with severe malaria transfused in accordance to WHO guidelines in Kilifi, Kenya.

BACKGROUND: Severe anaemia requiring emergency blood transfusion is a common complication of malaria in children. To ensure access for urgent blood transfusion, the World Health Organization has developed clear guidelines with haemoglobin thresholds prevent unwarranted transfusion,. Few studies have reported outcome and haematological recovery of children with severe malaria where transfusion practice complies with WHO recommendations. METHODS: A prospective observational study of survivors of severe and complicated malaria transfused in accordance with WHO guidelines. Children were invited for review at one month post-discharge. Non-attendees were traced in the community to ascertain survival. RESULTS: Outcome was assessed in 213 survivors. Those transfused were younger, had a higher base deficit, mean lactate levels and a higher prevalence of respiratory distress. As expected mean admission haemoglobin (Hb) was significantly lower amongst transfused [5.0 g/dL SD: 1.9] compared to non-transfused children [8.3 g/dL SD: 1.7] (p < 0.001). At discharge mean Hb was similar 6.4 g/dL [SD: 1.5] and 6.8 g/dL [SD: 1.6] respectively (p = 0.08), most children remained moderately to severely anaemic. At one month follow up 166 children (78%) returned, in whom we found no differences in mean Hb between the transfused (10.2 g/dL [SD: 1.7]) and non-transfused (10.0 g/dL [SD: 1.3]) survivors (p = 0.25). The major factors affecting haematological recovery were young age (<24 months) and concomitant malaria parasitaemia; Hb being 8.8 g/dL [SD: 1.5] in parasitaemic individuals compared with 10.5 g/dL [SD: 1.3] in those without (p < 0.001). CONCLUSION: This data supports the policy of rational use of blood transfusion, as proposed in the WHO guidelines, for children with anaemia in areas where access to emergency transfusion is not guaranteed. We have provided empirical data indicating that transfusion does not influence superior recovery in haemoglobin concentrations and therefore cannot be justified on this basis alone. This may help resolve the disparity between international policy and current clinical practice. Effective anti-malarial treatment at discharge may prevent reoccurrence of anaemia.

Randomized trial of volume expansion with albumin or saline in children with severe malaria: preliminary evidence of albumin benefit.

BACKGROUND: Metabolic acidosis is the best predictor of death in children with severe falciparum malaria; however, its treatment presents a therapeutic dilemma, because acidosis and hypovolemia may coexist with coma, which can be associated with elevated intracranial pressure. We postulated that volume resuscitation with albumin might correct acidosis and hypovolemia with a lower risk of precipitating cerebral edema than crystalloid. In an open-label, randomized, controlled trial, we compared the safety of resuscitation with albumin to saline in Kenyan children with severe malaria. METHODS: We randomly assigned children with severe malaria and metabolic acidosis (base deficit, >8 mmol/L) to receive fluid resuscitation with either 4.5% albumin or normal saline. A control (maintenance only) group was only included for patients with a base deficit of <15 mmol/L. The primary outcome measure was the percentage reduction in base deficit at 8 h. Secondary end points included death, the requirement for rescue therapies, and neurological sequelae in survivors. RESULTS: Of 150 children recruited for the trial, 61 received saline, 56 received albumin, and 33 served as control subjects. There was no significant difference in the resolution of acidosis between the groups; however, the mortality rate was significantly lower among patients who received albumin (3.6% [2 of 56 patients]) than among those who received saline (18% [11 of 61]; relative risk, 5.5; 95% confidence interval, 1.2-24.8; P=.013). CONCLUSIONS: In high-risk children with severe malaria and acidosis, fluid resuscitation with albumin may reduce mortality. Our study design did not enable us to determine whether saline administration is preferable to fluid restriction or whether saline administration is actually hazardous. Further studies are needed to confirm our findings before definitive treatment recommendations can be made.

Perturbations in electrolyte levels in kenyan children with severe malaria complicated by acidosis.

BACKGROUND: To date, information about the frequency of electrolyte disturbances among children with severe falciparum malaria is limited. METHODS: We describe changes in potassium, calcium, magnesium, and phosphate levels in 56 Kenyan children (42 who survived and 14 who died) admitted to the hospital with clinical features of severe malaria (impaired consciousness or deep breathing) complicated by acidosis (base deficit, >8 mmol/L). RESULTS: Mild-to-moderate hypercalcemia was common at admission, particularly among children with severe anemia. Severe hyperkalemia complicated falciparum malaria in 9 children (16%), of whom 7 (78%) died, generally soon after admission. Hypokalemia, hypomagnesemia, and hypophosphatemia were uncommon (<7% of children) at admission but developed in >30% of children within 24 h. Hypocalcemia was infrequent (<5% of children) at any time point. Apart from administration of potassium, electrolyte deficiencies were not corrected and were not associated with an adverse outcome. CONCLUSIONS: At admission to the hospital, hyperkalemia may complicate cases of acidosis due to severe malaria and is associated with high, early mortality. After admission, mild asymptomatic deficiencies in magnesium and phosphate levels were common but were not associated with any deleterious effect. Thus, routine correction when serial measurement of electrolyte levels cannot be performed is unwarranted. Asymptomatic potassium deficiency developed despite provision of this electrolyte at maintenance doses. Further studies are justified but are unlikely to be a major research priority because, as these data suggest, the impact on mortality would at most be limited.

Response to volume resuscitation in children with severe malaria.

OBJECTIVES: To examine whether hypovolemia is an important cause of the acidosis in children with severe malaria. DESIGN: Prospective phase 1 study examining the safety of volume expansion using detailed hemodynamic monitoring. SETTING: High-dependency unit of Kilifi District Hospital on the coast of Kenya. PATIENTS: Kenyan children admitted with clinical features of severe malaria (impaired consciousness or deep breathing) complicated by acidosis (base excess of less than -8). Three groups were considered: severe malarial anemia plus acidosis if hemoglobin of <5 mg/dL and base excess less than -8; moderate malaria acidosis if the base excess was between -8 and -15; severe malaria acidosis if the base excess was less than -15. INTERVENTIONS: Patients received between 10 and 40 mL/kg of either 0.9% normal saline or 4.5% human albumin solution. MEASUREMENTS AND MAIN RESULTS: A total of 53 children were recruited, and all had evidence of compensated shock at admission, with tachycardia, tachypnea, and prolonged capillary refill time. Mean central venous pressure (se) at admission was 2.9 cm H(2)O (0.5 cm H(2)O); in the severe malaria acidosis group, 44% had hypotension (systolic blood pressure of <80 mm Hg). Improvements of hemodynamic indices and a reduction in acidosis followed administration of either saline or albumin. By 8 hrs, mean central venous pressure had increased to 7.5 cm H(2)O (0.5 cm H(2)O, F = 34.4, p <.001) and was associated with a reduction in mean respiratory rate from 49 to 41 breaths/min (2 to 1 breaths/min, respectively; F = 7.0; p =.009), a reduction in tachycardia from 151 to 141 beats/min (5 to 3 beats/min, respectively; F = 3.4; p =.06), and a reduction in capillary refill time. No child developed evidence of the life threatening complications of pulmonary edema and increased intracranial pressure. CONCLUSIONS: Volume depletion is present at admission in the majority of children with severe malaria complicated by acidosis. Volume expansion corrects the hemodynamic abnormalities and is associated with improved organ function and reduction in acidosis. Formal trials of volume expansion are needed to determine whether volume expansion will reduce mortality.

Hypokalemia in children with severe falciparum malaria.

OBJECTIVES: Acidosis is now recognized as an important component of the severe malaria syndrome and a predictor of fatal outcome. Alterations in plasma potassium concentrations are commonly associated with acidosis. To date, there is little information about the changes in potassium in severe malaria. DESIGN: Prospective study examining the changes in plasma potassium in the first 24 hrs following admission in children with severe malaria. Urinary fractional excretion of potassium and the transtubular gradient of potassium were examined at admission. SETTING: High-dependency unit on the coast of Kenya. PATIENTS: Kenyan children admitted to hospital with clinical features of severe malaria (impaired consciousness or deep breathing) complicated by acidosis (base deficit >8). INTERVENTIONS: Children received standard therapy for severe malaria; in addition, they received boluses of either 0.9% saline or 4.5% human albumin solution to correct hypovolemia, and intravenous potassium replacement was prescribed to children who developed hypokalemia (plasma potassium <3 mmol/L). MEASUREMENTS AND MAIN RESULTS: Thirty-eight Kenyan children were recruited with severe malaria and acidosis. At admission, serum potassium was normal (3-5.5 mmol/L) in 31 (81.6%) and low (<3 mmol/L) in four (11%) children, and three (6.3%) children had hyperkalemia (>5.5 mmol/L). Plasma potassium decreased rapidly within 4-8 hrs of admission: 15 (40%) patients were hypokalemic (<3 mmol/L); of these, five (13%) had plasma potassium of <2.5 mmol/L. Fractional excretion of potassium and the transtubular gradient of potassium were above normal range, indicating renal potassium loss. CONCLUSIONS: Hypokalemia is a common complication of severe malaria; however, it is often not apparent on admission. On correction of acidosis, plasma potassium decreases precipitously, and thus careful, serial monitoring of serum potassium is suggested in patients with severe malaria complicated by acidosis.

Fluid management of severe falciparum malaria in African children.

Most African children with severe malaria who die do so on the day of admission as a result of the complications of falciparum malaria. We highlight the value of a rapid structured triage assessment to look for emergency signs that will prioritize initial management and implementation of basic life support. This can be delivered with few resources and by non-specialist medical personnel. Reduction in case fatality can only come through the wider appreciation of the need for and application of supportive therapies to treat the life-threatening complications. Hypovolaemia has emerged as a common feature of children presenting with severe malaria complicated by acidosis. Early recognition and prompt treatment may lead to improvements in outcome. We discuss the new evidence supporting the role of hypovolaemia in severe malaria and potential treatment options whilst awaiting the results of clinical trials.

Chlorproguanil-dapsone-artesunate versus chlorproguanil-dapsone: a randomized, double-blind, phase III trial in African children, adolescents, and adults with uncomplicated Plasmodium falciparum malaria.

This multi-center, randomized, parallel-group, double-blind, double-dummy study compared the efficacy and safety of chlorproguanil-dapsone-artesunate (CDA) and chlorproguanil-dapsone (CPG-DDS) in the treatment of falciparum malaria in Africa (Burkina Faso, Ghana, Mali, Nigeria). Six hundred patients (>or= 1 year of age) received CDA 2.0/2.5/4.0 mg/kg, and 292 CPG-DDS 2.0/2.5 mg/kg, once daily for 3 days. Day 28 parasitologic cure rate (polymerase chain reaction [PCR]-corrected, per-protocol population) was 89.1% (416/467) for CDA, non-inferior but also superior to CPG-DDS, 83.0% (176/212) (treatment difference 6.1%; 95% confidence interval [CI] 0.3, 11.9). Glucose-6-phosphate dehydrogenase (G6PD) genotype was available for 844/892 (95%) patients. Occurrences of a composite hemoglobin safety endpoint (hemoglobin drop >or= 40 g/L or >or= 40% versus baseline, hemoglobin < 50 g/L, or blood transfusion) were CDA 13/44 (30%), CPG-DDS 7/24 (29%) in G6PD-deficient patients versus CDA 4/448 (< 1%), CPG-DDS 6/221 (3%) in G6PD-normal patients. No deaths occurred. CDA was more efficacious than CPG-DDS. However, the hemolytic potential in G6PD-deficient patients does not support further development of CDA.

Chlorproguanil-dapsone-artesunate versus artemether-lumefantrine: a randomized, double-blind phase III trial in African children and adolescents with uncomplicated Plasmodium falciparum malaria.

BACKGROUND: Chlorproguanil-dapsone-artesunate (CDA) was developed as an affordable, simple, fixed-dose artemisinin-based combination therapy for use in Africa. This trial was a randomized parallel-group, double-blind, double-dummy study to compare CDA and artemether-lumefantrine (AL) efficacy in uncomplicated Plasmodium falciparum malaria and further define the CDA safety profile, particularly its hematological safety in glucose-6-phosphate dehydrogenase (G6PD) -deficient patients. METHODS AND FINDINGS: The trial was conducted at medical centers at 11 sites in five African countries between June 2006 and August 2007. 1372 patients (> or =1 to <15 years old, median age 3 years) with acute uncomplicated P. falciparum malaria were randomized (2:1) to receive CDA 2/2.5/4 mg/kg once daily for three days (N = 914) or six-doses of AL over three days (N = 458). Non-inferiority of CDA versus AL for efficacy was evaluated in the Day 28 per-protocol (PP) population using parasitological cure (polymerase chain reaction [PCR]-corrected). Cure rates were 94.1% (703/747) for CDA and 97.4% (369/379) for AL (treatment difference -3.3%, 95%CI -5.6, -0.9). CDA was non-inferior to AL, but there was simultaneous superiority of AL (upper 95%CI limit <0). Adequate clinical and parasitological response at Day 28 (uncorrected for reinfection) was 79% (604/765) with CDA and 83% (315/381) with AL. In patients with a G6PD-deficient genotype (94/603 [16%] hemizygous males, 22/598 [4%] homozygous females), CDA had the propensity to cause severe and clinically concerning hemoglobin decreases: the mean hemoglobin nadir was 75 g/L (95%CI 71, 79) at Day 7 versus 97 g/L (95%CI 91, 102) for AL. There were three deaths, unrelated to study medication (two with CDA, one with AL). CONCLUSIONS: Although parasitologically effective at Day 28, the hemolytic potential of CDA in G6PD-deficient patients makes it unsuitable for use in a public health setting in Africa. TRIAL REGISTRATION: ClinicalTrials.Gov NCT00344006.

Pre-transfusion management of children with severe malarial anaemia: a randomised controlled trial of intravascular volume expansion.

Symptomatic severe malarial anaemia (SMA) has a high fatality rate of 30-40%; most deaths occur in children awaiting blood transfusion. Blood transfusion services in most of Africa are not capable of delivering adequate supplies of safe blood in a timely manner to critically ill children with SMA. Contrary to widely held belief, hypovolaemia, rather than heart failure, has emerged as a common complication in such children. We examined the safety of pre-transfusion management (PTM) by volume expansion, aimed at stabilizing children and obviating the urgency for blood transfusion. Kenyan children with severe falciparum anaemia (haemoglobin <5 g/dl) and respiratory distress were randomly assigned to 20 ml/kg of 4.5% albumin or 0.9% saline or maintenance only (control) while awaiting blood transfusion. PTM was apparently safe since it did not lead to the development of pulmonary oedema or other adverse events. There was no significant difference in the primary outcome [mean percentage reduction in base excess between admission and 8 h (95% confidence interval)] between the control group 42% (19-66%) albumin group 44% (32-57%) and saline group 36% (16-57%); adjusted analysis of variance F=0.31, P=0.7. However, the number of children requiring emergency interventions was significantly greater in the control group, four of 18 (22%) than the saline group 0 of 20 (P=0.03). We have established the safety of this PTM in children with SMA whilst awaiting blood transfusion at a hospital with an adequate blood-banking program. The impact on mortality should be assessed where blood transfusion services are unable to supply emergency transfusions.