Publications (10)110 Total impact
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Article: Pentoxifylline as an adjunct therapy in children with cerebral malaria.
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ABSTRACT: Pentoxifylline (PTX) affects many processes that may contribute to the pathogenesis of severe malaria and it has been shown to reduce the duration of coma in children with cerebral malaria. This pilot study was performed to assess pharmacokinetics, safety and efficacy of PTX in African children with cerebral malaria. Ten children admitted to the high dependency unit of the Kilifi District Hospital in Kenya with cerebral malaria (Blantyre coma score of 2 or less) received quinine plus a continuous infusion of 10 mg/kg/24 hours PTX for 72 hours. Five children were recruited as controls and received normal saline instead of PTX. Plasma samples were taken for PTX and tumour necrosis factor (TNF) levels. Blantyre Coma Score, parasitemia, hematology and vital signs were assessed 4 hourly. One child (20%) in the control group died, compared to four children (40%) in the PTX group. This difference was not significant (p = 0.60). Laboratory parameters and clinical data were comparable between groups. TNF levels were lower in children receiving PTX. The small sample size does not permit definitive conclusions, but the mortality rate was unexpectedly high in the PTX group.Malaria Journal 01/2010; 9:368. · 3.19 Impact Factor -
Article: Prognostic value of circulating pigmented cells in African children with malaria.
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ABSTRACT: Plasmodium falciparum malaria is a common cause of morbidity in African children, but identifying those who are likely to die is problematic. Previous studies suggested that circulating malarial pigment might be a useful predictor of severity, but none were large enough to detect any association with mortality. We used thick blood smears performed on admission for 26,296 children hospitalized with P. falciparum at 1 of 6 hospitals in the Severe Malaria in African Children network to assess the prognostic value of pigment-containing granulocytes, monocytes, and parasites. Although at all but one of the study sites the risk of mortality for subjects presenting with >5 pigmented granulocytes per 200 white blood cells was higher than in subjects with no pigmented granulocytes, adjusted odds ratios estimated through logistic regression, which included other established markers of severe malaria, suggested that associations between pigmented cells and mortality were moderate to nonexistent in most sites. The predictive ability of pigmented cells was low, as measured by the change in the area under the receiver operating characteristic curve of logistic regression models. Although high levels of pigmented cells were associated with a fatal outcome in some study sites, they were not useful predictors of outcome across Africa.The Journal of Infectious Diseases 01/2009; 199(1):142-50. · 6.41 Impact Factor -
Article: Burden, features, and outcome of neurological involvement in acute falciparum malaria in Kenyan children.
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ABSTRACT: Plasmodium falciparum appears to have a particular propensity to involve the brain but the burden, risk factors, and full extent of neurological involvement have not been systematically described. To determine the incidence and describe the clinical phenotypes and outcomes of neurological involvement in African children with acute falciparum malaria. A review of records of all children younger than 14 years admitted to a Kenyan district hospital with malaria from January 1992 through December 2004. Neurological involvement was defined as convulsive seizures, agitation, prostration, or impaired consciousness or coma. The incidence, pattern, and outcome of neurological involvement. Of 58,239 children admitted, 19,560 (33.6%) had malaria as the primary clinical diagnosis. Neurological involvement was observed in 9313 children (47.6%) and manifested as seizures (6563/17,517 [37.5%]), agitation (316/11,193 [2.8%]), prostration (3223/15,643 [20.6%]), and impaired consciousness or coma (2129/16,080 [13.2%]). In children younger than 5 years, the mean annual incidence of admissions with malaria was 2694 per 100,000 persons and the incidence of malaria with neurological involvement was 1156 per 100,000 persons. However, readmissions may have led to a 10% overestimate in incidence. Children with neurological involvement were older (median, 26 [interquartile range {IQR}, 15-41] vs 21 [IQR, 10-40] months; P<.001), had a shorter duration of illness (median, 2 [IQR, 1-3] vs 3 [IQR, 2-3] days; P<.001), and a higher geometric mean parasite density (42.0 [95% confidence interval {CI}, 40.0-44.1] vs 30.4 [95% CI, 29.0-31.8] x 10(3)/microL; P<.001). Factors independently associated with neurological involvement included past history of seizures (adjusted odds ratio [AOR], 3.50; 95% CI, 2.78-4.42), fever lasting 2 days or less (AOR, 2.02; 95% CI, 1.64-2.49), delayed capillary refill time (AOR, 3.66; 95% CI, 2.40-5.56), metabolic acidosis (AOR, 1.55; 95% CI, 1.29-1.87), and hypoglycemia (AOR, 2.11; 95% CI, 1.31-3.37). Mortality was higher in patients with neurological involvement (4.4% [95% CI, 4.2%-5.1%] vs 1.3% [95% CI, 1.1%-1.5%]; P<.001). At discharge, 159 (2.2%) of 7281 patients had neurological deficits. Neurological involvement is common in children in Kenya with acute falciparum malaria, and is associated with metabolic derangements, impaired perfusion, parasitemia, and increased mortality and neurological sequelae. This study suggests that falciparum malaria exposes many African children to brain insults.JAMA The Journal of the American Medical Association 06/2007; 297(20):2232-40. · 30.03 Impact Factor -
Article: Assessing developmental outcomes in children from Kilifi, Kenya, following prophylaxis for seizures in cerebral malaria.
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ABSTRACT: The purpose of the study was to develop a culture-informed measure of developmental outcome and to apply it to detect differences in developmental level between children with cerebral malaria enrolled in a clinical trial to control seizures during the acute phase of the illness. The instrument was administered to a sample of 180 children, three and 12 months after discharge from hospital. The measure demonstrated high internal consistency, good inter-observer reliability, age sensitivity and strong relations with parental report of child functioning. No association was found between performance, or change in performance, with the prophylactic regime administered. The results suggested that the use of Phenobarbital in controlling provoked seizures has no observable effect on cognitive function.Journal of Health Psychology 06/2007; 12(3):417-30. · 1.22 Impact Factor -
Article: Assessment of severe malnutrition among hospitalized children in rural Kenya: comparison of weight for height and mid upper arm circumference.
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ABSTRACT: Severe malnutrition has a high mortality rate among hospitalized children in sub-Saharan Africa. However, reports suggest that malnutrition is often poorly assessed. The World Health Organization recommends using weight for height, but this method is problematic and often not undertaken in practice. Mid upper arm circumference (MUAC) and the clinical sign "visible severe wasting" are simple and inexpensive methods but have not been evaluated in this setting. To evaluate MUAC and visible severe wasting as predictors of inpatient mortality at a district hospital in sub-Saharan Africa and to compare these with weight-for-height z score (WHZ). Cohort study with data collected at admission and at discharge or death. Predictive values for inpatient death were determined using the area under receiver operating characteristic curves. Participants were children aged 12 to 59 months admitted to a district hospital in rural Kenya between April 1, 1999, and July 31, 2002. MUAC, WHZ, and visible severe wasting as predictors of inpatient death. Overall, 4.4% (359) of children included in the study died while in the hospital. Sixteen percent (1282/8190) of admitted children had severe wasting (WHZ < or =-3) (n = 756), kwashiorkor (n = 778), or both. The areas under the receiver operating characteristic curves for predicting inpatient death did not significantly differ (MUAC: 0.75 [95% confidence interval, 0.72-0.78]; WHZ: 0.74 [95% confidence interval, 0.71-0.77]) (P = .39). Although sensitivity and specificity for subsequent inpatient death were 46% and 91%, respectively, for MUAC less than or equal to 11.5 cm, 42% and 92% for WHZ less than or equal to -3, and 47% and 93% for visible severe wasting, the 3 indices identified different sets of children and were independently associated with mortality. Clinical features of malnutrition were significantly more common among children with MUAC less than or equal to 11.5 cm than among those with WHZ less than or equal to -3. MUAC is a practical screening tool that performs at least as well as WHZ in predicting subsequent inpatient mortality among severely malnourished children hospitalized in rural Kenya. Visible severe wasting is also a potentially useful sign at this level, providing appropriate training has been given.JAMA The Journal of the American Medical Association 09/2005; 294(5):591-7. · 30.03 Impact Factor -
Article: Decorticate, decerebrate and opisthotonic posturing and seizures in Kenyan children with cerebral malaria.
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ABSTRACT: Abnormal motor posturing is often observed in children with cerebral malaria, but the aetiology and pathogenesis is poorly understood. This study examined the risk factors and outcome of posturing in Kenyan children with cerebral malaria. Records of children admitted to Kilifi district hospital with cerebral malaria from January, 1999 through December, 2001 were reviewed for posturing occurring on or after admission. The clinical characteristics, features of raised intracranial pressure, number of seizures and biochemical changes in patients that developed posturing was compared to patients who did not. Of the 417 children with complete records, 163 (39.1%) had posturing: 85 on admission and 78 after admission to hospital. Decorticate posturing occurred in 80, decerebrate in 61 and opisthotonic posturing in 22 patients. Posturing was associated with age > or = 3 years (48.1 vs 35.8%, p = 0.01) and features of raised intracranial pressure on funduscopy (adjusted OR 2.1 95%CI 1.2-3.7, p = 0.009) but not other markers of severity of disease. Unlike decorticate posturing, decerebrate (adjusted OR 1.9 95%CI 1.0-3.5) and opisthotonic posturing (adjusted OR 2.9 95%CI 1.0-8.1) were, in addition, independently associated with recurrence of seizures after admission. Opisthotonus was also associated with severe metabolic acidosis (OR 4.2 95%CI 3.2-5.6, p < 0.001). Thirty one patients with posturing died. Of these, 19 (61.3%) had features suggestive of transtentorial herniation. Mortality and neurological deficits on discharge were greatest in those developing posturing after admission. Abnormal motor posturing is a common feature of cerebral malaria in children. It is associated with features of raised intracranial pressure and recurrence of seizures, although intracranial hypertension may be the primary cause.Malaria Journal 02/2005; 4:57. · 3.19 Impact Factor -
Article: Decorticate, decerebrate and opisthotonic posturing and seizures in Kenyan children with cerebral malaria
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ABSTRACT: Abstract Background Abnormal motor posturing is often observed in children with cerebral malaria, but the aetiology and pathogenesis is poorly understood. This study examined the risk factors and outcome of posturing in Kenyan children with cerebral malaria. Methods Records of children admitted to Kilifi district hospital with cerebral malaria from January, 1999 through December, 2001 were reviewed for posturing occurring on or after admission. The clinical characteristics, features of raised intracranial pressure, number of seizures and biochemical changes in patients that developed posturing was compared to patients who did not. Results Of the 417 children with complete records, 163 (39.1%) had posturing: 85 on admission and 78 after admission to hospital. Decorticate posturing occurred in 80, decerebrate in 61 and opisthotonic posturing in 22 patients. Posturing was associated with age ≥ 3 years (48.1 vs 35.8%, p = 0.01) and features of raised intracranial pressure on funduscopy (adjusted OR 2.1 95%CI 1.2–3.7, p = 0.009) but not other markers of severity of disease. Unlike decorticate posturing, decerebrate (adjusted OR 1.9 95%CI 1.0–3.5) and opisthotonic posturing (adjusted OR 2.9 95%CI 1.0–8.1) were, in addition, independently associated with recurrence of seizures after admission. Opisthotonus was also associated with severe metabolic acidosis (OR 4.2 95%CI 3.2–5.6, p < 0.001). Thirty one patients with posturing died. Of these, 19 (61.3%) had features suggestive of transtentorial herniation. Mortality and neurological deficits on discharge were greatest in those developing posturing after admission. Conclusion Abnormal motor posturing is a common feature of cerebral malaria in children. It is associated with features of raised intracranial pressure and recurrence of seizures, although intracranial hypertension may be the primary cause.Malaria Journal. 01/2005; -
Article: Population pharmacokinetics of artemether and dihydroartemisinin following single intramuscular dosing of artemether in African children with severe falciparum malaria.
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ABSTRACT: To determine the population pharmacokinetics of artemether and dihydroartemisinin in African children with severe malaria and acidosis associated with respiratory distress following an intramuscular injection of artemether. Following a single intramuscular (i.m.) injection of 3.2 mg kg-1 artemether, blood samples were withdrawn at various times over 24 h after the dose. Plasma was assayed for artemether and dihydroartemisinin by gas chromatography-mass spectrometry. The software program NONMEM was used to fit the concentration-time data and investigate the influence of a range of clinical characteristics (respiratory distress and metabolic acidosis, demographic features and disease) on the pharmacokinetics of artemether and dihydroartemisinin. A total of 100 children with a median age of 36.4 (range 5-108) months were recruited into the study and data from 90 of these children (30 with respiratory distress and 60 with no respiratory distress) were used in the population pharmacokinetic analysis. The best model to describe the disposition of artemether was a one-compartment model with first-order absorption and elimination. The population estimate of clearance (clearance/bioavailability, CL/F) was 14.3 l h-1 with 53% intersubject variability and that of the terminal half-life was 18.5 h. If it was assumed that artemisin displays "flip-flop" kinetics, the elimination half-life was estimated to be 21 min and the corresponding volume of distribution was 8.44 l, with an intersubject variability of 104%. None of the covariates could be identified as having any influence on the disposition of artemether. The disposition of dihydroartemisinin was fitted separately using a one-compartment linear model in which the volume of distribution was fixed to the same value as that of artemether. Assuming that artemether is completely converted to dihydroartemisinin, the estimated value of CL/F for dihydroartemisinin was 93.5 l h-1, with an intersubject variability of 90.2%. The clearance of dihydroartemisinin was formation rate limited. Administration of a single 3.2 mg kg-1 i.m. dose of artemether to African children with severe malaria and acidosis is characterized by variable absorption kinetics, probably related to drug formulation characteristics rather than to pathophysiological factors. Use of i.m. artemether in such children needs to be reconsidered.British Journal of Clinical Pharmacology 03/2004; 57(2):146-52. · 2.96 Impact Factor -
Article: Population pharmacokinetics of artemether and dihydroartemisinin following single intramuscular dosing of artemether in African children with severe falciparum malaria
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ABSTRACT: Aims To determine the population pharmacokinetics of artemether and dihydroartemisinin in African children with severe malaria and acidosis associated with respiratory distress following an intramuscular injection of artemether.Methods Following a single intramuscular (i.m.) injection of 3.2 mg kg−1 artemether, blood samples were withdrawn at various times over 24 h after the dose. Plasma was assayed for artemether and dihydroartemisinin by gas chromatography-mass spectrometry. The software program NONMEM was used to fit the concentration–time data and investigate the influence of a range of clinical characteristics (respiratory distress and metabolic acidosis, demographic features and disease) on the pharmacokinetics of artemether and dihydroartemisinin.Results A total of 100 children with a median age of 36.4 (range 5–108) months were recruited into the study and data from 90 of these children (30 with respiratory distress and 60 with no respiratory distress) were used in the population pharmacokinetic analysis. The best model to describe the disposition of artemether was a one-compartment model with first-order absorption and elimination. The population estimate of clearance (clearance/bioavailability, CL/F) was 14.3 l h−1 with 53% intersubject variability and that of the terminal half-life was 18.5 h. If it was assumed that artemisin displays ‘flip-flop’ kinetics, the elimination half-life was estimated to be 21 min and the corresponding volume of distribution was 8.44 l, with an intersubject variability of 104%. None of the covariates could be identified as having any influence on the disposition of artemether. The disposition of dihydroartemisinin was fitted separately using a one-compartment linear model in which the volume of distribution was fixed to the same value as that of artemether. Assuming that artemether is completely converted to dihydroartemisinin, the estimated value of CL/F for dihydroartemisinin was 93.5 l h−1, with an intersubject variability of 90.2%. The clearance of dihydroartemisinin was formation rate limited.Conclusions Administration of a single 3.2 mg kg−1 i.m. dose of artemether to African children with severe malaria and acidosis is characterized by variable absorption kinetics, probably related to drug formulation characteristics rather than to pathophysiological factors. Use of i.m. artemether in such children needs to be reconsidered.British Journal of Clinical Pharmacology 10/2003; 57(2):146 - 152. · 2.96 Impact Factor -
Article: Assessment of Severe Malnutrition Among Hospitalized Children in Rural KenyaComparison of Weight for Height and Mid Upper Arm Circumference
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ABSTRACT: Context Severe malnutrition has a high mortality rate among hospitalized children in sub-Saharan Africa. However, reports suggest that malnutrition is often poorly assessed. The World Health Organization recommends using weight for height, but this method is problematic and often not undertaken in practice. Mid upper arm circumference (MUAC) and the clinical sign “visible severe wasting” are simple and inexpensive methods but have not been evaluated in this setting.Objectives To evaluate MUAC and visible severe wasting as predictors of inpatient mortality at a district hospital in sub-Saharan Africa and to compare these with weight-for-height z score (WHZ).Design, Setting, and Participants Cohort study with data collected at admission and at discharge or death. Predictive values for inpatient death were determined using the area under receiver operating characteristic curves. Participants were children aged 12 to 59 months admitted to a district hospital in rural Kenya between April 1, 1999, and July 31, 2002.Main Outcome Measure MUAC, WHZ, and visible severe wasting as predictors of inpatient death.Results Overall, 4.4% (359) of children included in the study died while in the hospital. Sixteen percent (1282/8190) of admitted children had severe wasting (WHZ ≤−3) (n = 756), kwashiorkor (n = 778), or both. The areas under the receiver operating characteristic curves for predicting inpatient death did not significantly differ (MUAC: 0.75 [95% confidence interval, 0.72-0.78]; WHZ: 0.74 [95% confidence interval, 0.71-0.77]) (P = .39). Although sensitivity and specificity for subsequent inpatient death were 46% and 91%, respectively, for MUAC less than or equal to 11.5 cm, 42% and 92% for WHZ less than or equal to −3, and 47% and 93% for visible severe wasting, the 3 indices identified different sets of children and were independently associated with mortality. Clinical features of malnutrition were significantly more common among children with MUAC less than or equal to 11.5 cm than among those with WHZ less than or equal to −3.Conclusions MUAC is a practical screening tool that performs at least as well as WHZ in predicting subsequent inpatient mortality among severely malnourished children hospitalized in rural Kenya. Visible severe wasting is also a potentially useful sign at this level, providing appropriate training has been given. Figures in this Article Severe malnutrition has a high mortality rate among hospitalized children in sub-Saharan Africa.1- 2 The World Health Organization (WHO) gives clear guidelines for the management of children with severe malnutrition,3 and where standardized management protocols have been followed, mortality has been reduced.4- 5 However, recent reports suggest that there are problems in initially identifying severely malnourished children at hospital admission.5- 6 The WHO defines severe malnutrition requiring hospital admission as weight-for-height z scores (WHZs) of less than or equal to −3 or as less than or equal to 70% of the reference median using US National Center for Health Statistics (NCHS)/WHO reference values (severe wasting)3 or symmetrical edema involving at least the feet (edematous malnutrition, kwashiorkor).3 There are several reasons why screening by WHZ is potentially problematic and is frequently not undertaken in practice in sub-Saharan Africa. First, height is difficult to measure accurately in children at any time but especially so in a busy ward and when children are ill or distressed. The measurement of weight depends on the presence of properly calibrated and functioning scales, which often are not available.7 The actual weight-for-height determination depends on correctly recording 2 separate values and then looking up a third value on a chart, which must be readily available. In contrast, mid upper arm circumference (MUAC) is a simple, low-cost, objective method of assessing nutritional status. The MUAC is generally as good as, or better than, other anthropometric measures in predicting subsequent mortality in community-based studies (reviewed by Pelletier8). In Uganda, for example, MUAC was the strongest predictor of subsequent death of any anthropometric index among 3748 village children.9 Among hospital admissions, MUAC was found to be as effective as other nutritional indices in predicting death in a study of 352 children with diarrhea in Bangladesh.10 During famine, MUAC performed as well as body mass index among adults admitted to a feeding center in Sudan.11 The clinical sign of “visible severe wasting” is a component of the WHO Integrated Management of Childhood Illness evaluation that accounts for the likelihood that measuring facilities are not available at the primary care level in this setting. Given the challenges to the assessment of weight for height at the secondary (referral) level, evaluation of malnutrition is commonly performed by observation only, often without formal training. Despite being inexpensive, convenient, and apparently effective in other settings, MUAC and visible severe wasting have not been evaluated as predictors of mortality among hospitalized children in sub-Saharan Africa. Since 1998, we have conducted detailed clinical surveillance of all children admitted to Kilifi District Hospital in Kenya. Using data collected at admission and at discharge or death, we have previously reported that a small number of clinical features, including neurologic status, respiratory signs, temperature, and weight for age effectively predicted inpatient deaths despite a variety of underlying etiologies.12 Our principal aim in this analysis was to examine the predictive value for inpatient death of MUAC compared with WHZ among children aged 12 to 59 months. We also sought to determine whether there are any differences in the children identified by the 2 methods. Furthermore, we aimed to evaluate both the clinical sign of visible severe wasting as a predictor of subsequent inpatient death and also MUAC as an indicator of the presence of the current WHO standard definition of severe wasting, ie, WHZ less than or equal to −3.JAMA The Journal of the American Medical Association 294(5):591-597. · 30.03 Impact Factor
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2003–2004
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KEMRI-Wellcome Trust Research Programme
Kilifi, Coast Province, Kenya -
John Radcliffe Hospital
Oxford, ENG, United Kingdom
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