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1.  Plasmodium falciparum antigenic variation: relationships between widespread endothelial activation, parasite PfEMP1 expression and severe malaria 
BMC Infectious Diseases  2014;14:170.
Background
Plasmodium falciparum erythrocyte membrane protein 1(PfEMP1) is a family of variant surface antigens (VSA) that mediate the adhesion of parasite infected erythrocytes to capillary endothelial cells within host tissues. Opinion is divided over the role of PfEMP1 in the widespread endothelial activation associated with severe malaria. In a previous study we found evidence for differential associations between defined VSA subsets and specific syndromes of severe malaria: group A-like PfEMP1 expression and the “rosetting” phenotype were associated with impaired consciousness and respiratory distress, respectively. This study explores the involvement of widespread endothelial activation in these associations.
Methods
We used plasma angiopoietin-2 as a marker of widespread endothelial activation. Using logistic regression analysis, we explored the relationships between plasma angiopoietin-2 levels, parasite VSA expression and the two syndromes of severe malaria, impaired consciousness and respiratory distress.
Results
Plasma angiopoietin-2 was associated with both syndromes. The rosetting phenotype did not show an independent association with respiratory distress when adjusted for angiopoietin-2, consistent with a single pathogenic mechanism involving widespread endothelial activation. In contrast, group A-like PfEMP1 expression and angiopoietin-2 maintained independent associations with impaired consciousness when adjusted for each other.
Conclusion
The results are consistent with multiple pathogenic mechanisms leading to severe malaria and heterogeneity in the pathophysiology of impaired consciousness. The observed association between group A-like PfEMP1 and impaired consciousness does not appear to involve widespread endothelial activation.
doi:10.1186/1471-2334-14-170
PMCID: PMC3986854  PMID: 24674301
Group A-like; Angiopoietin-2; Rosetting; Sequestration; Impaired consciousness; Cerebral malaria; Respiratory distress
2.  High HIV-1 incidence, correlates of HIV-1 acquisition, and high viral loads following seroconversion among men who have sex with men in Coastal Kenya 
AIDS (London, England)  2013;27(3):437-446.
Background
HIV-1 incidence estimates and correlates of HIV-1 acquisition in African men who have sex with men are largely unknown.
Methods
Since 2005, HIV-1-uninfected men who reported sex with men and women (MSMW) or sex with men exclusively (MSME) were followed at scheduled visits for collection of behavioural and clinical examination data and plasma for HIV-1 testing. Urethral or rectal secretions were collected from symptomatic men to screen for gonorrhoea. Poisson regression methods were used to estimate adjusted incidence rate ratios (aIRR) to explore associations between risk factors and incident HIV-1 infection. Plasma viral loads (PVL) were assessed over two years following seroconversion.
Results
Overall HIV-1 incidence in 449 men was 8.6 (95% confidence interval [CI]: 6.7–11.0) per 100 person-years (py). Incidence was 5.8 (95% CI: 4.2–7.9) per 100 py among MSMW, and 35.2 (95% CI: 23.8–52.1) per 100 py among MSME. Unprotected sex, receptive anal intercourse, exclusive sex with men, group sex, and gonorrhoea in the past 6 months were strongly associated with HIV-1 acquisition, adjusted for confounders. PVL in seroconverters was >4 log10 copies/mL at 230 (73.4%) of 313 visits in MSMW and 153 (75.0%) of 204 visits in MSME.
Conclusions
HIV-1 incidence is very high among MSM in coastal Kenya, and many seroconverters maintain high PVL for up to two years after infection. Effective HIV-1 prevention interventions, including treatment as prevention, are urgently needed in this population.
doi:10.1097/QAD.0b013e32835b0f81
PMCID: PMC3929859  PMID: 23079811
HIV-1 incidence; MSM; gonorrhoea; anal intercourse; viral load; sexually transmitted infection; group sex; Africa
3.  Premature mortality in active convulsive epilepsy in rural Kenya 
Neurology  2014;82(7):582-589.
Objective:
We estimated premature mortality and identified causes of death and associated factors in people with active convulsive epilepsy (ACE) in rural Kenya.
Methods:
In this prospective population-based study, people with ACE were identified in a cross-sectional survey and followed up regularly for 3 years, during which information on deaths and associated factors was collected. We used a validated verbal autopsy tool to establish putative causes of death. Age-specific rate ratios and standardized mortality ratios were estimated. Poisson regression was used to identify mortality risk factors.
Results:
There were 61 deaths among 754 people with ACE, yielding a rate of 33.3/1,000 persons/year. Overall standardized mortality ratio was 6.5. Mortality was higher across all ACE age groups. Nonadherence to antiepileptic drugs (adjusted rate ratio [aRR] 3.37), cognitive impairment (aRR 4.55), and age (50+ years) (rate ratio 4.56) were risk factors for premature mortality. Most deaths (56%) were directly related to epilepsy, with prolonged seizures/possible status epilepticus (38%) most frequently associated with death; some of these may have been due to sudden unexpected death in epilepsy (SUDEP). Possible SUDEP was the likely cause in another 7%.
Conclusion:
Mortality in people with ACE was more than 6-fold greater than expected. This may be reduced by improving treatment adherence and prompt management of prolonged seizures and supporting those with cognitive impairment.
doi:10.1212/WNL.0000000000000123
PMCID: PMC3963418  PMID: 24443454
4.  Fosphenytoin for seizure prevention in childhood coma in Africa: A randomized clinical trial☆☆☆★★★ 
Journal of Critical Care  2013;28(6):1086-1092.
Purpose
We conducted a double-blind trial to determine whether a single intramuscular injection of fosphenytoin prevents seizures and neurologic sequelae in children with acute coma.
Methods
We conducted this study at Kilifi District Hospital in coastal Kenya and Kondele Children's Hospital in western Kenya. We recruited children (age, 9 months to 13 years) with acute nontraumatic coma. We administered fosphenytoin (20 phenytoin equivalents/kg) or placebo and examined the prevalence and frequency of clinical seizures and occurrence of neurocognitive sequelae.
Results
We recruited 173 children (median age, 2.6 [interquartile range, 1.7-3.7] years) into the study; 110 had cerebral malaria, 8 had bacterial meningitis, and 55 had encephalopathies of unknown etiology. Eighty-five children received fosphenytoin and 88 received placebo. Thirty-three (38%) children who received fosphenytoin had at least 1 seizure compared with 32 (36%) who received placebo (P = .733). Eighteen (21%) and 15 (17%) children died in the fosphenytoin and placebo arms, respectively (P = .489). At 3 months after discharge, 6 (10%) children in the fosphenytoin arm had neurologic sequelae compared with 6 (10%) in the placebo arm (P = .952).
Conclusion
A single intramuscular injection of fosphenytoin (20 phenytoin equivalents/kg) does not prevent seizures or neurologic deficits in childhood acute nontraumatic coma.
doi:10.1016/j.jcrc.2013.09.001
PMCID: PMC3835934  PMID: 24135012
Coma; Child; Seizure; Prophylaxis; Anticonvulsants
5.  Prognostic Indicators of Life-Threatening Malaria are Associated with Distinct Parasite Variant Antigen Profiles 
Science translational medicine  2012;4(129):129ra45.
PfEMP1 is a family of cytoadhesive surface antigens expressed on erythrocytes infected with Plasmodium falciparum, the parasite that causes the most severe form of malaria. These surface antigens play a role in immune evasion and are thought to contribute to the pathogenesis of the malaria parasite. Previous studies have suggested a role for a specific subset of PfEMP1 called “group A” in severe malaria. To explore the role of group A PfEMP1 in disease, we measured the expression of the “var” genes that encode them in parasites from clinical isolates collected from children suffering from malaria. We also looked at the ability of these clinical isolates to induce rosetting of erythrocytes, which indicates a cytoadhesion phenotype that is thought to be important in pathogenesis. These two sets of data were correlated with the presence of two life-threatening manifestations of severe malaria in the children: impaired consciousness and respiratory distress. Using regression analysis, we show that marked rosetting was associated with respiratory distress, whereas elevated expression of group A-like var genes without elevated rosetting was associated with impaired consciousness. The results suggest that manifestations of malarial disease may reflect the distribution of cytoadhesion phenotypes expressed by the infecting parasite population.
doi:10.1126/scitranslmed.3003247
PMCID: PMC3491874  PMID: 22496547
6.  Estimating Individual Exposure to Malaria Using Local Prevalence of Malaria Infection in the Field 
PLoS ONE  2012;7(3):e32929.
Background
Heterogeneity in malaria exposure complicates survival analyses of vaccine efficacy trials and confounds the association between immune correlates of protection and malaria infection in longitudinal studies. Analysis may be facilitated by taking into account the variability in individual exposure levels, but it is unclear how exposure can be estimated at an individual level.
Method and Findings
We studied three cohorts (Chonyi, Junju and Ngerenya) in Kilifi District, Kenya to assess measures of malaria exposure. Prospective data were available on malaria episodes, geospatial coordinates, proximity to infected and uninfected individuals and residence in predefined malaria hotspots for 2,425 individuals. Antibody levels to the malaria antigens AMA1 and MSP1142 were available for 291 children from Junju. We calculated distance-weighted local prevalence of malaria infection within 1 km radius as a marker of individual's malaria exposure. We used multivariable modified Poisson regression model to assess the discriminatory power of these markers for malaria infection (i.e. asymptomatic parasitaemia or clinical malaria). The area under the receiver operating characteristic (ROC) curve was used to assess the discriminatory power of the models. Local malaria prevalence within 1 km radius and AMA1 and MSP1142 antibodies levels were independently associated with malaria infection. Weighted local malaria prevalence had an area under ROC curve of 0.72 (95%CI: 0.66–0.73), 0.71 (95%CI: 0.69–0.73) and 0.82 (95%CI: 0.80–0.83) among cohorts in Chonyi, Junju and Ngerenya respectively. In a small subset of children from Junju, a model incorporating weighted local malaria prevalence with AMA1 and MSP1142 antibody levels provided an AUC of 0.83 (95%CI: 0.79–0.88).
Conclusion
We have proposed an approach to estimating the intensity of an individual's malaria exposure in the field. The weighted local malaria prevalence can be used as individual marker of malaria exposure in malaria vaccine trials and longitudinal studies of natural immunity to malaria.
doi:10.1371/journal.pone.0032929
PMCID: PMC3315550  PMID: 22479349
7.  Are diagnostic criteria for acute malnutrition affected by hydration status in hospitalized children? A repeated measures study 
Nutrition Journal  2011;10:92.
Introduction
Dehydration and malnutrition commonly occur together among ill children in developing countries. Dehydration (change in total body water) is known to alter weight. Although muscle tissue has high water content, it is not known whether mid-upper arm circumference (MUAC) may be altered by changes in tissue hydration. We aimed to determine whether rehydration alters MUAC, MUAC Z score (MUACz), weight-for-length Z-score (WFLz) and classification of nutritional status among hospitalised Kenyan children admitted with signs of dehydration.
Study procedure
We enrolled children aged from 3 months to 5 years admitted to a rural Kenyan district hospital with clinical signs compatible with dehydration, and without kwashiorkor. Anthropometric measurements were taken at admission and repeated after 48 hours of treatment, which included rehydration by WHO protocols. Changes in weight observed during this period were considered to be due to changes in hydration status.
Results
Among 325 children (median age 11 months) the median weight gain (rehydration) after 48 hours was 0.21 kg, (an increase of 2.9% of admission body weight). Each 1% change in weight was associated with a 0.40 mm (95% CI: 0.30 to 0.44 mm, p < 0.001) change in MUAC, 0.035z (95% CI: 0.027 to 0.043z, P < 0.001) change in MUACz score and 0.115z (95% CI: 0.114 to 0.116 z, p < 0.001) change in WFLz. Among children aged 6 months or more with signs of dehydration at admission who were classified as having severe acute malnutrition (SAM) at admission by WFLz <-3 or MUAC <115 mm, 21% and 19% of children respectively were above these cut offs after 48 hours.
Conclusion
MUAC is less affected by dehydration than WFLz and is therefore more suitable for nutritional assessment of ill children. However, both WFLz and MUAC misclassify SAM among dehydrated children. Nutritional status should be re-evaluated following rehydration, and management adjusted accordingly.
doi:10.1186/1475-2891-10-92
PMCID: PMC3180351  PMID: 21910909
Malnutrition; dehydration; MUAC; weight-for-length; anthropometry; children; Africa
8.  Mortality in Sickle Cell Anemia in Africa: A Prospective Cohort Study in Tanzania 
PLoS ONE  2011;6(2):e14699.
Background
The World Health Organization has declared Sickle Cell Anemia (SCA) a public health priority. There are 300,000 births/year, over 75% in Africa, with estimates suggesting that 6 million Africans will be living with SCA if average survival reaches half the African norm. Countries such as United States of America and United Kingdom have reduced SCA mortality from 3 to 0.13 per 100 person years of observation (PYO), with interventions such as newborn screening, prevention of infections and comprehensive care, but implementation of interventions in African countries has been hindered by lack of locally appropriate information. The objective of this study was to determine the incidence and factors associated with death from SCA in Dar-es-Salaam.
Methods and Findings
A hospital-based cohort study was conducted, with prospective surveillance of 1,725 SCA patients recruited from 2004 to 2009, with 209 (12%) lost to follow up, while 86 died. The mortality rate was 1.9 (95%CI 1.5, 2.9) per 100 PYO, highest under 5-years old [7.3 (4.8–11.0)], adjusting for dates of birth and study enrollment. Independent risk factors, at enrollment to the cohort, predicting death were low hemoglobin (<5 g/dL) [3.8 (1.8–8.2); p = 0.001] and high total bilirubin (≥102 µmol/L) [1.7 (1.0–2.9); p = 0.044] as determined by logistic regression.
Conclusions
Mortality in SCA in Africa is high, with the most vulnerable period being under 5-years old. This is most likely an underestimate, as this was a hospital cohort and may not have captured SCA individuals with severe disease who died in early childhood, those with mild disease who are undiagnosed or do not utilize services at health facilities. Prompt and effective treatment for anemia in SCA is recommended as it is likely to improve survival. Further research is required to determine the etiology, pathophysiology and the most appropriate strategies for management of anemia in SCA.
doi:10.1371/journal.pone.0014699
PMCID: PMC3040170  PMID: 21358818
10.  Defining Clinical Malaria: The Specificity and Incidence of Endpoints from Active and Passive Surveillance of Children in Rural Kenya 
PLoS ONE  2010;5(12):e15569.
Background
Febrile malaria is the most common clinical manifestation of P. falciparum infection, and is often the primary endpoint in clinical trials and epidemiological studies. Subjective and objective fevers are both used to define the endpoint, but have not been carefully compared, and the relative incidence of clinical malaria by active and passive case detection is unknown.
Methods
We analyzed data from cohorts under active and passive surveillance, including 19,462 presentations with fever and 5,551 blood tests for asymptomatic parasitaemia. A logistic regression model was used to calculate Malaria Attributable Fractions (MAFs) for various case definitions. Incidences of febrile malaria by active and passive surveillance were compared in a subset of children matched for age and location.
Results
Active surveillance identified three times the incidence of clinical malaria as passive surveillance in a subset of children matched for age and location. Objective fever (temperature≥37.5°C) gave consistently higher MAFs than case definitions based on subjective fever.
Conclusion
The endpoints from active and passive surveillance have high specificity, but the incidence of endpoints is lower on passive surveillance. Subjective fever had low specificity and should not be used in primary endpoint. Passive surveillance will reduce the power of clinical trials but may cost-effectively deliver acceptable sensitivity in studies of large populations.
doi:10.1371/journal.pone.0015569
PMCID: PMC3002959  PMID: 21179571
11.  Iron Deficiency and Acute Seizures: Results from Children Living in Rural Kenya and a Meta-Analysis 
PLoS ONE  2010;5(11):e14001.
Background
There are conflicting reports on whether iron deficiency changes susceptibility to seizures. We examined the hypothesis that iron deficiency is associated with an increased risk of acute seizures in children in a malaria endemic area.
Methods
We recruited 133 children, aged 3–156 months, who presented to a district hospital on the Kenyan coast with acute seizures and frequency-matched these to children of similar ages but without seizures. We defined iron deficiency according to the presence of malarial infection and evidence of inflammation. In patients with malaria, we defined iron deficiency as plasma ferritin<30µg/ml if plasma C-reactive protein (CRP) was<50mg/ml or ferritin<273µg/ml if CRP≥50mg/ml, and in those without malaria, as ferritin<12µg/ml if CRP<10mg/ml or ferritin<30µg/ml if CRP≥10mg/ml. In addition, we performed a meta-analysis of case-control studies published in English between January 1966 and December 2009 and available through PUBMED that have examined the relationship between iron deficiency and febrile seizures in children.
Results
In our Kenyan case control study, cases and controls were similar, except more cases reported past seizures. Malaria was associated with two-thirds of all seizures. Eighty one (30.5%) children had iron deficiency. Iron deficiency was neither associated with an increased risk of acute seizures (45/133[33.8%] cases were iron deficient compared to 36/133[27.1%] controls, p = 0.230) nor status epilepticus and it did not affect seizure semiology. Similar results were obtained when children with malaria, known to cause acute symptomatic seizures in addition to febrile seizures were excluded. However, in a meta-analysis that combined all eight case-control studies that have examined the association between iron deficiency and acute/febrile seizures to-date, iron deficiency, described in 310/1,018(30.5%) cases and in 230/1,049(21.9%) controls, was associated with a significantly increased risk of seizures, weighted OR 1.79(95%CI 1.03–3.09).
Conclusions
Iron deficiency is not associated with an increased risk of all acute seizures in children but of febrile seizures. Further studies should examine mechanisms involved and the implications for public health.
doi:10.1371/journal.pone.0014001
PMCID: PMC2982825  PMID: 21103365
12.  The quality of stored umbilical cord and adult-donated whole blood in Mombasa, Kenya 
Transfusion  2009;50(3):611-616.
BACKGROUND
In sub-Saharan Africa umbilical cord blood may be a useful source of blood for transfusion. Before clinical trials, evidence is needed that cord blood donations, which vary greatly in volume, can be collected and stored into a fixed volume of anticoagulant-preservative solution obviating the need for prestorage processing.
STUDY DESIGN AND METHODS
Twenty-four umbilical cord whole blood (UC-WB) donations were collected into 21 mL of CPDA-1 and refrigerated for 35 days. The Kenya Blood Transfusion Service provided 12 adult-donated whole blood (AD-WB) controls. Supernatant hemoglobin (Hb) and potassium were assayed at 7-day intervals.
RESULTS
UC-WB red blood cell hemolysis and potassium loss increased throughout storage but did not differ significantly with cord blood volume. Hemolysis rates did not differ significantly between UC-WB and AD-WB but UC-WB potassium loss was slightly but significantly greater than AD-WB on Days 2, 7, and 14 (p < 0.05). In the AD-WB controls, eight were low volume (<405 mL), two had total Hb of less than 45 g, and two showed hemolysis greater than 0.8% by Day 28.
CONCLUSION
Variable volumes of UC-WB can be stored for 35 days without prestorage processing and further work into its suitability for transfusion to children is justified. The quality of conventional AD-WB is a concern and needs further evaluation.
doi:10.1111/j.1537-2995.2009.02489.x
PMCID: PMC2948540  PMID: 19912583
13.  Malaria in patients with sickle cell anemia: burden, risk factors, and outcome at the outpatient clinic and during hospitalization 
Blood  2009;115(2):215-220.
Approximately 280 000 children are born with sickle cell anemia (SCA) in Africa annually, yet few survive beyond childhood. Falciparum malaria is considered a significant cause of this mortality. We conducted a 5-year prospective surveillance study for malaria parasitemia, clinical malaria, and severe malarial anemia (SMA) in Dar-es-Salaam, Tanzania, between 2004 and 2009. We recorded 10 491 visits to the outpatient clinic among 1808 patients with SCA and 773 visits among 679 patients without SCA. Similarly, we recorded 691 hospital admissions among 497 patients with SCA and 2017 in patients without SCA. Overall, the prevalence of parasitemia was lower in patients with SCA than in patients without SCA both at clinic (0.7% vs 1.6%; OR, 0.53; 95% CI, 0.32-0.86; P = .008) and during hospitalization (3.0% vs 5.6%; OR, 0.46; 95% CI, 0.25-0.94; P = .01). Furthermore, patients with SCA had higher rates of malaria during hospitalization than at clinic, the ORs being 4.29 (95% CI, 2.63-7.01; P < .001) for parasitemia, 17.66 (95% CI, 5.92-52.71; P < .001) for clinical malaria, and 21.11 (95% CI, 8.46-52.67; P < .001) for SMA. Although malaria was rare among patients with SCA, parasitemia during hospitalization was associated with both severe anemia and death. Effective treatment for malaria during severe illness episodes and further studies to determine the role chemoprophylaxis are required.
doi:10.1182/blood-2009-07-233528
PMCID: PMC2843825  PMID: 19901265
14.  The Level and Duration of RSV-Specific Maternal IgG in Infants in Kilifi Kenya 
PLoS ONE  2009;4(12):e8088.
Background
Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in infants. The rate of decay of RSV-specific maternal antibodies (RSV-matAb), the factors affecting cord blood levels, and the relationship between these levels and protection from infection are poorly defined.
Methods
A birth cohort (n = 635) in rural Kenya, was studied intensively to monitor infections and describe age-related serological characteristics. RSV specific IgG antibody (Ab) in serum was measured by the enzyme linked immunosorbent assay (ELISA) in cord blood, consecutive samples taken 3 monthly, and in paired acute and convalescent samples. A linear regression model was used to calculate the rate of RSV-matAb decline. The effect of risk factors on cord blood titres was investigated.
Results
The half-life of matAb in the Kenyan cohort was calculated to be 79 days (95% confidence limits (CL): 76–81 days). Ninety seven percent of infants were born with RSV-matAb. Infants who subsequently experienced an infection in early life had significantly lower cord titres of anti-RSV Ab in comparison to infants who did not have any incident infection in the first 6 months (P = 0.011). RSV infections were shown to have no effect on the rate of decay of RSV-matAb.
Conclusion
Maternal-specific RSV Ab decline rapidly following birth. However, we provide evidence of protection against severe disease by RSV-matAb during the first 6–7 months. This suggests that boosting maternal-specific Ab by RSV vaccination may be a useful strategy to consider.
doi:10.1371/journal.pone.0008088
PMCID: PMC2779853  PMID: 19956576
15.  Burden, features and outcome of neurological involvement in acute falciparum malaria in Kenyan children 
Context
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.
Objective
To determine the incidence and describe the clinical phenotypes and outcome of neurological involvement in African children with acute falciparum malaria.
Design, setting and patients
A review of records of all children younger than14 years admitted to a Kenyan District Hospital with malaria, from January 1992 through December 2004. Neurological involvement was defined as convulsive seizures, agitation, prostration, impaired consciousness or coma.
Outcome measures
The incidence, pattern and outcome of neurological involvement.
Results
Of 58,239 children admitted, 19,560(33.6%) had malaria as the primary clinical diagnosis. Neurological involvement was observed in 9,313(47.6%) children and manifested as seizures (6,563/17,517, 37.5%), agitation (316/11,193, 2.8%), prostration (3,223/15,643, 20.6%), impaired consciousness or coma (2,129/16,080, 13.2%). In children <5 years, the mean annual incidence of admissions with malaria was 2,694/100,000 and the incidence of malaria with neurological involvement was 1,156/100,000. However, re-admissions may have led to a 10% overestimate in the incidence. Children with neurological involvement were older (median [inter quartile range] age 26[15-41] vs 21[10-40] months, p<0.001), had a shorter duration of illness (2[1-3] vs 3[2-3] days, p<0.001) and a higher geometric mean parasite density (42.0 [95%CI 40.0-44.1] vs 30.4 [95%CI 29.0-31.8]×103/μl, p<0.001). Factors independently associated with neurological involvement included past history of seizures (adjusted OR 3.50 95%CI 2.78-4.42), fever ≤2 days (adjusted OR 2.02 95%CI 1.64-2.49), delayed capillary refill time (adjusted OR 3.66 95% CI 2.40-5.56), acidosis (adjusted OR 1.55 95% CI 1.29-1.87) and hypoglycemia (adjusted OR 2.11 95% CI 1.32-3.37). 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<0.001), and at discharge, 159 out of 7281 (2.2%) had neurological deficits.
Conclusions
Neurological involvement is common in children with acute falciparum malaria. It is associated with metabolic derangements, impaired perfusion, parasitemia and has increased mortality and neurological sequelae. The study suggests that malaria exposes many African children to brain insults.
doi:10.1001/jama.297.20.2232
PMCID: PMC2676709  PMID: 17519413
Neurological involvement; burden; acute falciparum malaria; children
16.  Breadth and Magnitude of Antibody Responses to Multiple Plasmodium falciparum Merozoite Antigens Are Associated with Protection from Clinical Malaria▿ †  
Infection and Immunity  2008;76(5):2240-2248.
Individuals living in areas where malaria is endemic are repeatedly exposed to many different malaria parasite antigens. Studies on naturally acquired antibody-mediated immunity to clinical malaria have largely focused on the presence of responses to individual antigens and their associations with decreased morbidity. We hypothesized that the breadth (number of important targets to which antibodies were made) and magnitude (antibody level measured in a random serum sample) of the antibody response were important predictors of protection from clinical malaria. We analyzed naturally acquired antibodies to five leading Plasmodium falciparum merozoite-stage vaccine candidate antigens, and schizont extract, in Kenyan children monitored for uncomplicated malaria for 6 months (n = 119). Serum antibody levels to apical membrane antigen 1 (AMA1) and merozoite surface protein antigens (MSP-1 block 2, MSP-2, and MSP-3) were inversely related to the probability of developing malaria, but levels to MSP-119 and erythrocyte binding antigen (EBA-175) were not. The risk of malaria was also inversely associated with increasing breadth of antibody specificities, with none of the children who simultaneously had high antibody levels to five or more antigens experiencing a clinical episode (17/119; 15%; P = 0.0006). Particular combinations of antibodies (AMA1, MSP-2, and MSP-3) were more strongly predictive of protection than others. The results were validated in a larger, separate case-control study whose end point was malaria severe enough to warrant hospital admission (n = 387). These findings suggest that under natural exposure, immunity to malaria may result from high titers antibodies to multiple antigenic targets and support the idea of testing combination blood-stage vaccines optimized to induce similar antibody profiles.
doi:10.1128/IAI.01585-07
PMCID: PMC2346713  PMID: 18316390
17.  Evidence for Over-Dispersion in the Distribution of Clinical Malaria Episodes in Children 
PLoS ONE  2008;3(5):e2196.
Background
It may be assumed that patterns of clinical malaria in children of similar age under the same level of exposure would follow a Poisson distribution with no over-dispersion. Longitudinal studies that have been conducted over many years suggest that some children may experience more episodes of clinical malaria than would be expected. The aim of this study was to identify this group of children and investigate possible causes for this increased susceptibility.
Methodology and Principal Findings
Using Poisson regression, we chose a group of children whom we designated as ‘more susceptible’ to malaria from 373 children under 10 years of age who were followed up for between 3 to 5 years from 1998–2003. About 21% of the children were categorized as ‘more susceptible’ and although they contributed only 23% of the person-time of follow-up, they experienced 55% of total clinical malaria episodes. Children that were parasite negative at all cross-sectional survey were less likely to belong to this group [AOR = 0.09, (95% CI: 0.14–0.61), p = 0.001].
Conclusions and Significance
The pattern of clinical malaria episodes follows a negative binomial distribution. Use of lack of a clinical malaria episode in a certain time period as endpoints for intervention or immunological studies may not adequately distinguish groups who are more or less immune. It may be useful in such studies, in addition to the usual endpoint of the time to first episode, to include end points which take into account the total number of clinical episodes experienced per child.
doi:10.1371/journal.pone.0002196
PMCID: PMC2374912  PMID: 18493319
18.  Immunization coverage and risk factors for failure to immunize within the Expanded Programme on Immunization in Kenya after introduction of new Haemophilus influenzae type b and hepatitis b virus antigens 
BMC Public Health  2006;6:132.
Background
Kenya introduced a pentavalent vaccine including the DTP, Haemophilus influenzae type b and hepatitis b virus antigens in Nov 2001 and strengthened immunization services. We estimated immunization coverage before and after introduction, timeliness of vaccination and risk factors for failure to immunize in Kilifi district, Kenya.
Methods
In Nov 2002 we performed WHO cluster-sample surveys of >200 children scheduled for vaccination before or after introduction of pentavalent vaccine. In Mar 2004 we conducted a simple random sample (SRS) survey of 204 children aged 9–23 months. Coverage was estimated by inverse Kaplan-Meier survival analysis of vaccine-card and mothers' recall data and corroborated by reviewing administrative records from national and provincial vaccine stores. The contribution to timely immunization of distance from clinic, seasonal rainfall, mother's age, and family size was estimated by a proportional hazards model.
Results
Immunization coverage for three DTP and pentavalent doses was 100% before and 91% after pentavalent vaccine introduction, respectively. By SRS survey, coverage was 88% for three pentavalent doses. The median age at first, second and third vaccine dose was 8, 13 and 18 weeks. Vials dispatched to Kilifi District during 2001–2003 would provide three immunizations for 92% of the birth cohort. Immunization rate ratios were reduced with every kilometre of distance from home to vaccine clinic (HR 0.95, CI 0.91–1.00), rainy seasons (HR 0.73, 95% CI 0.61–0.89) and family size, increasing progressively up to 4 children (HR 0.55, 95% CI 0.41–0.73).
Conclusion
Vaccine coverage was high before and after introduction of pentavalent vaccine, but most doses were given late. Coverage is limited by seasonal factors and family size.
doi:10.1186/1471-2458-6-132
PMCID: PMC1475578  PMID: 16707013
19.  The quality of stored umbilical cord and adult-donated whole blood in Mombasa, Kenya 
Transfusion  2010;50(3):611-616.
BACKGROUND:
In sub-Saharan Africa umbilical cord blood may be a useful source of blood for transfusion. Before clinical trials, evidence is needed that cord blood donations, which vary greatly in volume, can be collected and stored into a fixed volume of anticoagulant-preservative solution obviating the need for prestorage processing.
STUDY DESIGN AND METHODS:
Twenty-four umbilical cord whole blood (UC-WB) donations were collected into 21 mL of CPDA-1 and refrigerated for 35 days. The Kenya Blood Transfusion Service provided 12 adult-donated whole blood (AD-WB) controls. Supernatant hemoglobin (Hb) and potassium were assayed at 7-day intervals.
RESULTS:
UC-WB red blood cell hemolysis and potassium loss increased throughout storage but did not differ significantly with cord blood volume. Hemolysis rates did not differ significantly between UC-WB and AD-WB but UC-WB potassium loss was slightly but significantly greater than AD-WB on Days 2, 7, and 14 (p < 0.05). In the AD-WB controls, eight were low volume (<405 mL), two had total Hb of less than 45 g, and two showed hemolysis greater than 0.8% by Day 28.
CONCLUSION:
Variable volumes of UC-WB can be stored for 35 days without prestorage processing and further work into its suitability for transfusion to children is justified. The quality of conventional AD-WB is a concern and needs further evaluation.
doi:10.1111/j.1537-2995.2009.02489.x
PMCID: PMC2948540  PMID: 19912583
20.  Risk factors for high cerebral blood flow velocity and death in Kenyan children with Sickle Cell Anaemia: role of haemoglobin oxygen saturation and febrile illness 
British Journal of Haematology  2009;145(4):529-532.
High cerebral blood flow velocity (CBFv) and low haemoglobin oxygen saturation (SpO2) predict neurological complications in sickle cell anaemia (SCA) but any association is unclear. In a cross-sectional study of 105 Kenyan children, mean CBFv was 120 ± 34·9 cm/s; 3 had conditional CBFv (170–199 cm/s) but none had abnormal CBFv (>200 cm/s). After adjustment for age and haematocrit, CBFv ≥150 cm/s was predicted by SpO2 ≤ 95% and history of fever. Four years later, 10 children were lost to follow-up, none had suffered neurological events and 11/95 (12%) had died, predicted by history of fever but not low SpO2. Natural history of SCA in Africa may be different from North America and Europe.
doi:10.1111/j.1365-2141.2009.07660.x
PMCID: PMC3001030  PMID: 19344425
Sickle Cell Anaemia; Africa; transcranial Doppler ultrasound; mortality; cerebrovascular accidents
21.  Continuous EEG monitoring in Kenyan children with non-traumatic coma 
Archives of Disease in Childhood  2012;97(4):343-349.
Background
The aim of this study was to describe the EEG and clinical profile of seizures in children with non-traumatic coma, compare seizure detection by clinical observations with that by continuous EEG, and relate EEG features to outcome.
Methods
This prospective observational study was conducted at the paediatric high dependency unit of Kilifi District Hospital, Kenya. Children aged 9 months to 13 years presenting with acute coma were monitored by EEG for 72 h or until they regained consciousness or died. Poor outcome was defined as death or gross motor deficits at discharge.
Results
82 children (median age 2.8 (IQR 2.0–3.9) years) were recruited. An initial medium EEG amplitude (100–300 mV) was associated with less risk of poor outcome compared to low amplitude (≤100 mV) (OR 0.2, 95% CI 0.1 to 0.7; p<0.01). 363 seizures in 28 (34%) children were observed: 240 (66%) were electrographic and 112 (31%) electroclinical. In 16 (20%) children, electrographic seizures were the only seizure types detected. The majority (63%) of electroclinical seizures had focal clinical features but appeared as generalised (79%) or focal with secondary generalisation (14%) on EEG. Occurrence of any seizure or status epilepticus during monitoring was associated with poor outcome (OR 3.2, 95% CI 1.2 to 8.7; p=0.02 and OR 4.5, 95% CI 1.3 to 15.3; p<0.01, respectively).
Conclusion
Initial EEG background amplitude is prognostic in paediatric non-traumatic coma. Clinical observations do not detect two out of three seizures. Seizures and status epilepticus after admission are associated with poor outcome.
doi:10.1136/archdischild-2011-300935
PMCID: PMC3329232  PMID: 22328741

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