James Church

Invasive bacterial co-infection in African children with Plasmodium falciparum malaria: a systematic review

BackgroundSevere malaria remains a major cause of pediatric hospital admission across Africa. Invasive bacterial infection (IBI) is a recognized complication of Plasmodium falciparum malaria, resulting in a substantially worse outcome. Whether a biological relationship exists between malaria infection and IBI susceptibility remains unclear. We, therefore, examined the extent, nature and evidence of this association.MethodsWe conducted a systematic search in August 2012 of three major scientific databases, PubMed, Embase and Africa Wide Information, for articles describing bacterial infection among children with P. falciparum malaria using the search string ‘(malaria OR plasmodium) AND (bacteria OR bacterial OR bacteremia OR bacteraemia OR sepsis OR septicaemia OR septicemia).’ Eligiblity criteria also included studies of children hospitalized with malaria or outpatient attendances in sub-Saharan Africa.ResultsA total of 25 studies across 11 African countries fulfilled our criteria. They comprised twenty cohort analyses, two randomized controlled trials and three prospective epidemiological studies. In the meta-analysis of 7,208 children with severe malaria the mean prevalence of IBI was 6.4% (95% confidence interval (CI) 5.81 to 6.98%). In a further meta-analysis of 20,889 children hospitalised with all-severity malaria and 27,641 children with non-malarial febrile illness the mean prevalence of IBI was 5.58 (95% CI 5.5 to 5.66%) in children with malaria and 7.77% (95% CI 7.72 to 7.83%) in non-malaria illness. Ten studies reported mortality stratified by IBI. Case fatality was higher at 81 of 336, 24.1% (95% CI 18.9 to 29.4) in children with malaria/IBI co-infection compared to 585 of 5,760, 10.2% (95% CI 9.3 to 10.98) with malaria alone. Enteric gram-negative organisms were over-represented in malaria cases, non-typhoidal Salmonellae being the most commonest isolate. There was weak evidence indicating IBI was more common in the severe anemia manifestation of severe malaria.ConclusionsThe accumulated evidence suggests that children with recent or acute malaria are at risk of bacterial infection, which results in an increased risk of mortality. Characterising the exact nature of this association is challenging due to the paucity of appropriate severity-matched controls and the heterogeneous data. Further research to define those at greatest risk is necessary to target antimicrobial treatment.

The expanding role of co-trimoxazole in developing countries.

Co-trimoxazole is an inexpensive, broad-spectrum antimicrobial drug that is widely used in developing countries. Before antiretroviral therapy (ART) scale-up, co-trimoxazole prophylaxis reduced morbidity and mortality in adults and children with HIV by preventing bacterial infections, diarrhoea, malaria, and Pneumocystis jirovecii pneumonia, despite high levels of microbial resistance. Co-trimoxazole prophylaxis reduces early mortality by 58% (95% CI 39-71) in adults starting ART. Co-trimoxazole provides ongoing protection against malaria and non-malaria infections after immune reconstitution in ART-treated individuals in sub-Saharan Africa, leading to a change in WHO guidelines, which now recommend long-term co-trimoxazole prophylaxis for adults and children in settings with a high prevalence of malaria or severe bacterial infections. Co-trimoxazole prophylaxis is recommended for HIV-exposed infants from age 4-6 weeks; however, the risks and benefits of co-trimoxazole during infancy are unclear. Co-trimoxazole prophylaxis reduces anaemia and improves growth in children with HIV, possibly by reducing inflammation, either through direct immunomodulatory activity or through effects on the intestinal microbiota leading to reduced microbial translocation. Ongoing trials are now assessing the ability of adjunctive co-trimoxazole to reduce mortality in children after severe anaemia or severe acute malnutrition. In this Review, we discuss the mechanisms of action, benefits and risks, and clinical trials of co-trimoxazole in developing countries.

Congenital and Postnatal CMV and EBV Acquisition in HIV-Infected Zimbabwean Infants

Background HIV-infected infants in sub-Saharan Africa have rapid disease progression. We hypothesized that co-infection with cytomegalovirus (CMV) or Epstein Barr virus (EBV) increases mortality in HIV-infected infants. Methods 257 antiretroviral therapy-naïve HIV-infected Zimbabwean infants were tested for CMV and EBV at 6 weeks of age by real-time PCR; if positive, birth samples were retrieved where available to distinguish congenital and postnatal infection. The impact of co-infection on mortality through 6 months was estimated using Kaplan-Meier and Cox proportional hazards methods. Results At 6 weeks, 203/257 (79%) HIV-infected infants were CMV-positive; 27 (11%) had congenital CMV, 108 (42%) postnatal CMV and 68 (26%) indeterminate timing of infection. By 6 months, 37/108 (34%) infants with postnatal CMV versus 16/54 (30%) CMV-negative infants died (adjusted hazard ratio (aHR) 1.1 [95%CI 0.6, 2.2]). At 6 weeks, 33/257 (13%) HIV-infected infants had EBV co-infection; 6 (2%) had congenital EBV, 18 (7%) postnatal EBV and 9 (4%) indeterminate timing of infection. By 6 months, 5/18 (28%) infants with postnatal EBV versus 72/224 (32%) EBV-negative infants died (aHR 0.8 [95%CI 0.3, 2.3]). Conclusions The vast majority of HIV-infants had acquired CMV by 6 weeks, and EBV co-infection occurred earlier than expected, with one in eight HIV-infected infants positive for EBV by 6 weeks. There was a high prevalence of congenital CMV infection and we identified 6 infants with congenital EBV infection, which has not previously been reported in Africa or in the context of HIV infection. Neither CMV nor EBV co-infection was associated with increased mortality.

Causes of impaired oral vaccine efficacy in developing countries

Oral vaccines are less immunogenic when given to infants in low-income compared with high-income countries, limiting their potential public health impact. Here, we review factors that might contribute to this phenomenon, including transplacental antibodies, breastfeeding, histo blood group antigens, enteric pathogens, malnutrition, microbiota dysbiosis and environmental enteropathy. We highlight several clear risk factors for vaccine failure, such as the inhibitory effect of enteroviruses on oral poliovirus vaccine. We also highlight the ambiguous and at times contradictory nature of the available evidence, which undoubtedly reflects the complex and interconnected nature of the factors involved. Mechanisms responsible for diminished immunogenicity may be specific to each oral vaccine. Interventions aiming to improve vaccine performance may need to reflect the diversity of these mechanisms.

Purpura fulminans in an acute preterm neonate

A baby was delivered by ventouse assistance at 35+6 weeks gestation following prolonged rupture of membranes and fetal distress in the second stage of labour. He was started on intravenous cefotaxime but at 13 h of age deteriorated with signs of septic shock and respiratory distress. He was admitted to the neonatal intensive care unit for resuscitation and ventilation. Blood cultures taken at 3 …

Helminth infestation complicating diabetic ketoacidosis

A 15-year-old girl of Somali origin, previously diagnosed with type 1 diabetes, resident in the UK for one month, presented with a 2-day history of vomiting, with biochemical investigations suggestive of diabetic ketoacidosis. Despite prompt correction of her ketoacidosis, her nausea persisted with associated self-induced vomiting. On further questioning she described a crawling sensation in her chest. 24 h after admission, she vomited a 17 cm live, round worm ( Ascaris lumbrocoides …

Exploring the relationship between environmental enteric dysfunction and oral vaccine responses

Oral vaccines significantly underperform in low-income countries. One possible contributory factor is environmental enteric dysfunction (EED), a subclinical disorder of small intestinal structure and function among children living in poverty. Here, we review studies describing oral vaccine responses and EED. We identified eight studies evaluating EED and oral vaccine responses. There was substantial heterogeneity in study design and few consistent trends emerged. Four studies reported a negative association between EED and oral vaccine responses; two showed no significant association; and two described a positive correlation. Current evidence is therefore insufficient to determine whether EED contributes to oral vaccine underperformance. We identify roadblocks in the field and future research needs, including carefully designed studies those can investigate this hypothesis further.

Immune responses to oral poliovirus vaccine in HIV-exposed uninfected Zimbabwean infants

ABSTRACT It remains uncertain whether HIV-exposed uninfected (HEU) infants have impaired responses to oral vaccines. We performed a cross-sectional study of 6-month-old infants recruited at birth to the ZVITAMBO trial in Zimbabwe between 1997–2001, before introduction of prevention of mother-to-child transmission interventions. We measured poliovirus-specific IgA to type 1–3 polio strains by semi-quantitative capture ELISA in cryopreserved serum samples collected from 85 HEU and 101 HIV-unexposed infants at 6 months of age, one month after their last immunisation with trivalent OPV. Almost all infants were breastfed, with the majority in both groups mixed breastfed (70.6% HEU versus 71.3% HIV-unexposed). Median (IQR) vaccine titers for HEU and HIV-unexposed infants were 1592 (618–4896) vs. 1774 (711–5431) for Sabin 1 (P = 0.46); 1895 (810–4398) vs. 2308 (1081–4283) for Sabin 2 (P = 0.52); and 1798 (774–4192) vs. 2260 (996–5723) for Sabin 3 (P = 0.18). There were no significant differences in vaccine titers between HEU and HIV-unexposed infants, suggesting that vertical HIV exposure does not impact oral poliovirus vaccine immunogenicity.