Rabies Encephalitis in Malaria-Endemic Area, Malawi, Africa

In a malaria-endemic area of Africa, rabies was an important cause of fatal central nervous system infection, responsible for 14 (10.5%) of 133 cases. Four patients had unusual clinical manifestations, and rabies was only diagnosed postmortem. Three (11.5%) of 26 fatal cases were originally attributed to cerebral malaria

Pharmacokinetics of anti-TB drugs in Malawian children: reconsidering the role of ethambutol

Background Current guidelines for dosing of anti-TB drugs in children advocate higher doses for rifampicin and isoniazid despite limited availability of paediatric data on the pharmacokinetics of these drugs, especially from Africa, where the burden of childhood disease remains high. Methods Thirty children aged 6 months to 15 years underwent intensive pharmacokinetic sampling for first-line anti-TB drugs at Queen Elizabeth Central Hospital, Blantyre, Malawi. Rifampicin, isoniazid, pyrazinamide and ethambutol were dosed at 10, 5, 25 and 20 mg/kg, respectively. Plasma drug concentrations were determined using sensitive, validated bioanalytical methods and summary pharmacokinetic parameters were estimated using non-compartmental analysis. Results The median (IQR) Cmax was 2.90 (2.08–3.43), 3.37 (2.55–4.59), 34.60 (32.30–40.90) and 1.20 (0.85–1.68) mg/L while the median (IQR) AUC0–∞ was 16.92 (11.10–22.74), 11.48 (7.35–18.93), 333.50 (279.50–487.2) and 8.65 (5.96–11.47) mg·h/L for rifampicin, isoniazid, pyrazinamide and ethambutol, respectively. For all drugs, pharmacokinetic parameters relating to drug absorption and exposure were lower than those published for adults, though similar to existing paediatric data from sub-Saharan Africa. Weight and/or dose predicted at least one measure of exposure for all drugs. Age-related decreases in CL/F for rifampicin and pyrazinamide and a biphasic elimination pattern of isoniazid were observed. Predicted AUC0–∞ for rifampicin dosed at 15 mg/kg was comparable to that of adults while the dose required to achieve ethambutol exposure similar to that in adults was 55 mg/kg or higher. Conclusions These data support recently revised WHO recommendations for dosing of anti-TB drugs in children, but dosing of ethambutol in children also appears inadequate by comparison with adult pharmacokinetic data

Seroprevalence of HTLV-1 and HTLV-2 amongst mothers and children in Malawi within the context of a systematic review and meta-analysis of HTLV seroprevalence in Africa

OBJECTIVES: Human T‐lymphotropic virus (HTLV)‐1 causes T‐cell leukaemia and myelopathy. Together with HTLV‐2, it is endemic in some African nations. Seroprevalence data from Malawi are scarce, with no reports on associated disease incidence. HTLV seroprevalence and type were tested in 418 healthy mothers from Malawi. In addition, we tested the sera of 534 children to investigate mother‐to‐child transmission. To provide context, we conducted a systematic review and meta‐analysis of HTLV seroprevalence in African women and children. METHODS: Stored samples from a previous childhood cancer and BBV study were analysed. ELISA was used for HTLV screening followed by immunoblot for confirmation and typing. Standard methods were used for the systematic review. RESULTS: HTLV seroprevalence was 2.6% (11/418) in mothers and 2.2% (12/534) in children. Three mothers carried HTLV‐1 alone, seven had HTLV‐2 and one was dually infected. Three children carried HTLV‐1 alone, seven had HTLV‐2 and two were dually infected. Only two corresponding mothers of the 12 HTLV‐positive children were HTLV positive. The systematic review included 66 studies of women and 13 of children conducted in 25 African countries. Seroprevalence of HTLV‐1 varied from 0 to 17% and of HTLV‐2 from 0 to 4%. CONCLUSIONS: In contrast to findings from other studies in Africa, the seroprevalence of HTLV‐2 was higher than that of HTLV‐1 in Malawi and one of the highest for the African region. The lack of mother–child concordance suggests alternative sources of infection among children. Our data and analyses contribute to HTLV prevalence mapping in Africa

"Sometimes it is difficult for us to stand up and change this": an analysis of power within priority-setting for health following devolution in Kenya

Background Practices of power lie at the heart of policy processes. In both devolution and priority-setting, actors seek to exert power through influence and control over material, human, intellectual and financial resources. Priority-setting arises as a consequence of the needs and demand exceeding the resources available, requiring some means of choosing between competing demands. This paper examines the use of power within priority-setting processes for healthcare resources at sub-national level, following devolution in Kenya. Methods We interviewed 14 national level key informants and 255 purposively selected respondents from across the health system in ten counties. These qualitative data were supplemented by 14 focus group discussions (FGD) involving 146 community members in two counties. We conducted a power analysis using Gaventa’s power cube and Veneklasen’s expressions of power to interpret our findings. Results We found Kenya’s transition towards devolution is transforming the former centralised balance of power, leading to greater ability for influence at the county level, reduced power at national and sub-county (district) levels, and limited change at community level. Within these changing power structures, politicians are felt to play a greater role in priority-setting for health. The interfaces and tensions between politicians, health service providers and the community has at times been felt to undermine health related technical priorities. Underlying social structures and discriminatory practices generally continue unchanged, leading to the continued exclusion of the most vulnerable from priority-setting processes. Conclusions Power analysis of priority-setting at county level after devolution in Kenya highlights the need for stronger institutional structures, processes and norms to reduce the power imbalances between decision-making actors and to enable community participation

Research Article (PLOS ONE) Efficacy of a low-cost bubble CPAP system in treatment of respiratory distress in a neonatal ward in Malawi

Background: Respiratory failure is a leading cause of neonatal mortality in the developing world. Bubble continuous positive airway pressure (bCPAP) is a safe, effective intervention for infants with respiratory distress and is widely used in developed countries. Because of its high cost, bCPAP is not widely utilized in low-resource settings. We evaluated the performance of a new bCPAP system to treat severe respiratory distress in a low resource setting, comparing it to nasal oxygen therapy, the current standard of care.Methods: We conducted a non-randomized convenience sample study to test the efficacy of a low-cost bCPAP system treating newborns with severe respiratory distress in the neonatal ward of Queen Elizabeth Central Hospital, in Blantyre, Malawi. Neonates weighing >1,000 g and presenting with severe respiratory distress who fulfilled inclusion criteria received nasal bCPAP if a device was available; if not, they received standard care. Clinical assessments were made during treatment and outcomes compared for the two groups. Findings 87 neonates (62 bCPAP, 25 controls) were recruited. Survival rate for neonates receiving bCPAP was 71.0% (44/62) compared with 44.0% (11/25) for controls. 65.5% (19/29) of very low birth weight neonates receiving bCPAP survived to discharge compared to15.4% (1/13) of controls. 64.6% (31/48) of neonates with respiratory distress syndrome (RDS) receiving bCPAP survived to discharge, compared to 23.5% (4/17) of controls. 61.5% (16/26) of neonates with sepsis receiving bCPAP survived to discharge, while none of the seven neonates with sepsis in the control group survived.Interpretation: Use of a low-cost bCPAP system to treat neonatal respiratory distress resulted in 27% absolute improvement in survival. The beneficial effect was greater for neonates with very low birth weight, RDS, or sepsis. Implementing appropriate bCPAP devices could reduce neonatal mortality in developing countries

Using an Improved Phagocytosis Assay to Evaluate the Effect of HIV on Specific Antibodies to Pregnancy-Associated Malaria

Background: Pregnant women residing in malaria endemic areas are highly susceptible to Plasmodium falciparum malaria, particularly during their first pregnancy, resulting in low birth weight babies and maternal anaemia. This susceptibility is associated with placental sequestration of parasitised red blood cells expressing pregnancy-specific variant surface antigens. Acquisition of antibodies against these variant surface antigens may protect women and their offspring. Functions of such antibodies may include prevention of placental sequestration or opsonisation of parasitised cells for phagocytic clearance. Methodology/Findings: Here we report the development and optimisation of a new high-throughput flow cytometry-based phagocytosis assay using undifferentiated Thp-1 cells to quantitate the amount of opsonizing antibody in patient sera, and apply this assay to measure the impact of HIV on the levels of antibodies to a pregnancy malaria-associated parasite line in a cohort of Malawian primigravid women. The assay showed high reproducibility, with inter-experimental correlation of r2 = 0.99. In primigravid women, concurrent malaria infection was associated with significantly increased antibodies, whereas HIV decreased the ability to acquire opsonising antibodies (Mann-Whitney ranksum: p = 0.013). This decrease was correlated with HIV-induced immunosuppression, with women with less than 350×106 CD4+ T- cells/L having less opsonising antibodies (coef: −11.95,P = 0.002). Levels of antibodies were not associated with protection from low birth weight or anaemia. Conclusions/Significance: This flow cytometry-based phagocytosis assay proved to be efficient and accurate for the measurement of Fc-receptor mediated phagocytosis-inducing antibodies in large cohorts. HIV was found to affect mainly the acquisition of antibodies to pregnancy-specific malaria in primigravidae. Further studies of the relationship between opsonising antibodies to malaria in pregnancy and HIV are indicated.Ricardo Ataíde, Wina Hasang, Danny W. Wilson, James G. Beeson, Victor Mwapasa, Malcolm E. Molyneux, Steven R. Meshnick, Stephen J. Rogerso

Does Deworming Improve Growth and School Performance in Children?

Background The World Bank ranks soil-transmitted helminth infection as causing more ill health in children aged 5–15 years than any other infection. In light of this ranking, global agencies recommend regular, mass treatment with deworming drugs to children in developing countries. The World Health Organization (WHO) argues that “deworming helps meet the Millennium Development Goals”, in particular the six health-related goals:eradicate extreme poverty and hunger;achieve universal primary education;promote gender equality and empower women;reduce child mortality and improve maternal health; and combat HIV/AIDS, malaria, and other diseases. However, deworming campaigns cost money to deliver, and so we must be clear that WHO statements about the impact of these programmes are based on reliable evidence. In 2000, we systematically reviewed the reliable evidence from relevant controlled trials about the effects of anthelminth drugs for soil-transmitted helminth infection on child growth and cognition. This systematic review, published in The Cochrane Database and the BMJ, demonstrated uncertainty around the assumed benefit and concluded that it may be a potentially important intervention, but needed better evaluation. The BMJ published a large number of letters that criticised the findings, including from authors at the World Bank, the WHO, the United States Centers for Disease Control and Prevention, and the Pan American Health Organization. We do not feel that these criticisms were scientifically substantive enough to undermine the method or the conclusion. For example, several critics commented on the fact that the systematic review could not make any conclusions about the long-term effects of treatment—but, as we argued in our reply to these criticisms, “we were unable to find any randomised controlled trials that evaluated long term benefit, and the evidence of short term benefit was not, for us, convincing.” The research community quite correctly carried out further randomised controlled trials (RCTs) of repeated doses in community trials with longer follow-up compared with no intervention or placebo. In light of this additional research, we have now updated the original Cochrane review. An author of one of the trials included in the 2000 review, Ed Cooper, criticised the review for not taking into account heterogeneity in parasite burdens. Therefore, in the recently updated review, we conducted an additional subgroup analysis at trial level stratified by worm intensity and prevalence

Maternal–Fetal Microtransfusions and HIV-1 Mother-to-Child Transmission in Malawi

Background: Between 25% and 35% of infants born to HIV-infected mothers become HIV-1 infected. One potential route of mother-to-child transmission (MTCT) could be through a breakdown in the placental barrier (i.e., maternal–fetal microtransfusions). Methods and Findings: Placental alkaline phosphatase (PLAP) is a 130-kD maternal enzyme that cannot cross the intact placental barrier. We measured PLAP activity in umbilical vein serum as an indicator of maternal–fetal microtransfusion, and related this to the risk of HIV-1 MTCT. A case-cohort study was conducted of 149 women randomly selected from a cohort of HIV-1-infected pregnant Malawians; these women served as a reference group for 36 cases of in utero MTCT and 43 cases of intrapartum (IP) MTCT. Cord PLAP activity was measured with an immunocatalytic assay. Infant HIV status was determined by real-time PCR. The association between cord PLAP activity and HIV-1 MTCT was measured with logistic regression using generalized estimating equations. Among vaginal deliveries, PLAP was associated with IP MTCT (risk ratio, 2.25 per $log_{10}$ ng/ml PLAP; 95% confidence interval, 0.95–5.32) but not in utero MTCT. In a multivariable model adjusted for HIV-1 RNA load, chorioamnionitis, and self-reported fever, the risk of IP MTCT almost tripled for every $log_{10}$ increase in cord PLAP activity (risk ratio, 2.87; 95% confidence interval, 1.05–7.83). Conclusion: These results suggest that during vaginal deliveries, placental microtransfusions are a risk factor for IP HIV-1 MTCT. Future studies are needed to identify factors that increase the risk for microtransfusions in order to prevent IP HIV-1 MTCT

Prediction of 60 day case-fatality after aneurysmal subarachnoid haemorrhage: results from the International Subarachnoid Aneurysm Trial (ISAT)

Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with substantial case-fatality. Our purpose was to examine which clinical and neuro-imaging characteristics, available on admission, predict 60 day case-fatality in aSAH and to evaluate performance of our prediction model. We performed a secondary analysis of patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomised multicentre trial to compare coiling with clipping in aSAH patients. Multivariable logistic regression analysis was used to develop a prognostic model to estimate the risk of dying within 60 days from aSAH based on clinical and neuro-imaging characteristics. The model was internally validated with bootstrapping techniques. The study population comprised of 2,128 patients who had been randomised to either endovascular coiling or neurosurgical clipping. In this population 153 patients (7.2%) died within 60 days. World Federation of Neurosurgical Societies (WFNS) grade was the most important predictor of case-fatality, followed by age, lumen size of the aneurysm and Fisher grade. The model discriminated reasonably between those who died within 60 days and those who survived (c statistic = 0.73), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.70). Several strong predictors are available to predict 60 day case-fatality in aSAH patients who survived the early stage up till a treatment decision; after external validation these predictors could eventually be used in clinical decision making

Malaria during pregnancy and foetal haematological status in Blantyre, Malawi

BACKGROUND: Although maternal anaemia often stems from malaria infection during pregnancy, its effects on foetal haemoglobin levels are not straightforward. Lower-than-expected cord haemoglobin values in malarious versus non-malarious regions were noted by one review, which hypothesized they resulted from foetal immune activation to maternal malaria. This study addressed this idea by examining cord haemoglobin levels in relation to maternal malaria, anaemia, and markers of foetal immune activation. METHODS: Cord haemoglobin levels were examined in 32 malaria-infected and 58 uninfected women in Blantyre, Malawi, in relation to maternal haemoglobin levels, malaria status, and markers of foetal haematological status, hypoxia, and inflammation, including TNF-α, TGF-β, and ferritin. All women were HIV-negative. RESULTS: Although malaria was associated with a reduction in maternal haemoglobin (10.8 g/dL vs. 12.1 g/dL, p < 0.001), no reduction in cord haemoglobin and no significant relationship between maternal and cord haemoglobin levels were found. Cord blood markers of haematological and hypoxic statuses did not differ between malaria-infected and uninfected women. Maternal malaria was associated with decreased TGF-β and increased cord ferritin, the latter of which was positively correlated with parasitaemia (r = 0.474, p = 0.009). Increased cord ferritin was associated with significantly decreased birth weight and gestational length, although maternal and cord haemoglobin levels and malaria status had no effect on birth outcome. CONCLUSION: In this population, cord haemoglobin levels were protected from the effect of maternal malaria. However, decreased TGF-β and elevated ferritin levels in cord blood suggest foetal immune activation to maternal malaria, which may help explain poor birth outcomes