The effect of distance on observed mortality, childhood pneumonia and vaccine efficacy in rural Gambia.

We investigated whether straight-line distance from residential compounds to healthcare facilities influenced mortality, the incidence of pneumonia and vaccine efficacy against pneumonia in rural Gambia. Clinical surveillance for pneumonia was conducted on 6938 children living in the catchment areas of the two largest healthcare facilities. Deaths were monitored by three-monthly home visits. Children living >5 km from the two largest healthcare facilities had a 2·78 [95% confidence interval (CI) 1·74-4·43] times higher risk of all-cause mortality compared to children living within 2 km of these facilities. The observed rate of clinical and radiological pneumonia was lower in children living >5 km from these facilities compared to those living within 2 km [rate ratios 0·65 (95% CI 0·57-0·73) and 0·74 (95% CI 0·55-0·98), respectively]. There was no association between distance and estimated pneumococcal vaccine efficacy. Geographical access to healthcare services is an important determinant of survival and pneumonia in children in rural Gambia.

Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial.

BACKGROUND: Pneumonia is estimated to cause 2 million deaths every year in children. Streptococcus pneumoniae is the most important cause of severe pneumonia. We aimed to assess the efficacy of a nine-valent pneumococcal conjugate vaccine in children. METHODS: We undertook a randomised, placebo-controlled, double-blind trial in eastern Gambia. Children age 6-51 weeks were randomly allocated three doses of either pneumococcal conjugate vaccine (n=8718) or placebo (8719), with intervals of at least 25 days between doses. Our primary outcome was first episode of radiological pneumonia. Secondary endpoints were clinical or severe clinical pneumonia, invasive pneumococcal disease, and all-cause admissions. Analyses were per protocol and intention to treat. FINDINGS: 529 children assigned vaccine and 568 allocated placebo were not included in the per-protocol analysis. Results of per-protocol and intention-to-treat analyses were similar. By per-protocol analysis, 333 of 8189 children given vaccine had an episode of radiological pneumonia compared with 513 of 8151 who received placebo. Pneumococcal vaccine efficacy was 37% (95% CI 27-45) against first episode of radiological pneumonia. First episodes of clinical pneumonia were reduced overall by 7% (95% CI 1-12). Efficacy of the conjugate vaccine was 77% (51-90) against invasive pneumococcal disease caused by vaccine serotypes, 50% (21-69) against disease caused by all serotypes, and 15% (7-21) against all-cause admissions. We also found an efficacy of 16% (3-28) against mortality. 110 serious adverse events arose in children given the pneumococcal vaccine compared with 131 in those who received placebo. INTERPRETATION: In this rural African setting, pneumococcal conjugate vaccine has high efficacy against radiological pneumonia and invasive pneumococcal disease, and can substantially reduce admissions and improve child survival. Pneumococcal conjugate vaccines should be made available to African infants.

The epidemiology and consequences of maternal malaria: a review of immunological basis.

Millions of women who become pregnant in malaria-endemic areas are at increased risk of contracting malaria infection that jeopardises the outcome of pregnancy. The complication of this infection for mother and baby are considerable. In absence of any other reason, it was thought that the increased risk of infection during pregnancy was related to suppression of pre-existing malaria immunity. Although this concept is plausible, the significantly higher risk of maternal malaria and consequences in primigravidae compared with multigravidae suggests that there are more to mere immunosuppression in pregnancy. The mechanisms underlying some of the striking epidemiological and clinical features of malaria in pregnancy could be related to differences in the strains of parasite populations infecting pregnant women occasioned by the cyto-adherent properties of human placenta, presence or absence of anti-adhesion antibodies acquired from previous pregnancies or the elevated production of some pro-inflammatory cytokines in response to parasitisation of human placenta. Malaria infection of placenta causes a shift from Th2 to Th1 cytokine profile that may be detrimental to pregnancy. The increased susceptibility in the first pregnancy can be explained by the absence of anti-adhesion antibody in the primigravida that is being exposed for the first time to a different strain of malaria parasite sub-population that adhere exclusively to chondroitin sulphate A and hyaluronic acid (HA) in the placenta. In reviewing the epidemiology and consequences of maternal malaria, we have highlighted possible immunological and molecular basis that could account for the higher impact of malaria in pregnancy especially among primigravidae. These factors could be the basis for future research and vaccine formulation.

Immunogenicity and serotype-specific efficacy of a 9-valent pneumococcal conjugate vaccine (PCV-9) determined during an efficacy trial in The Gambia.

This study aimed to determine the immunogenicity of a 9-valent pneumococcal conjugate vaccine (PCV-9) in a subgroup of Gambian children enrolled in a large vaccine efficacy trial. To place the antibody results in context, in this paper we also report previously unpublished data on serotype-specific clinical vaccine efficacy from the main trial. In the sub-study, a single 2-4 ml venous blood specimen was collected from 212 Gambian children 4-6 weeks after the administration of a third dose of PCV-9 or placebo. IgG antibodies to pneumococcal serotype 1, 4, 5, 6B, 9V, 14, 18C, 19F and 23F polysaccharides were measured by ELISA. The proportions of infants with antibody concentrations above 0.2, 0.35 and 1.0 microg/ml, and the geometric mean concentrations (GMCs) of anti-pneumococcal polysaccharide antibodies were substantially higher for each serotype in children who received three doses of PCV-9 than those in the placebo group. Among PCV-9 recipients, GMCs ranged between 2.61 and 11.09 microg/ml with the highest being against serotype 14 and the lowest against 9V polysaccharide. The estimated overall protective antibody level for all nine serotypes, based on the vaccine efficacy against vaccine-type invasive pneumococcal disease (IPD) of 77% (95% CI: 51, 90) observed in the trial, was 2.3 microg/ml (95% CI: 1.0, 5.0). The PCV-9 studied was immunogenic in a Gambian population where it was also found to be efficacious.

Electrolyte derangement in cerebral malaria: a case for a more aggressive approach to the management of hyponatraemia.

Although hyponatraemia has been consistently shown to occur in a large proportion of children with cerebral malaria, no statistical relationship has been established between the incidence of hyponatraemia and that of malaria-attributable mortality. However, hyponatraemia is not a benign state in other conditions (such as meningitis) or in surgical patients, and is likely to add to malarial deaths. The high mortality rate seen among cases of cerebral malaria, despite all efforts to curb it, therefore calls for a more aggressive approach to the management of hyponatraemia. Current methods for the administration of hypotonic saline and isotonic glucose solutions need review. In addition, children admitted with cerebral malaria should have their electrolyte status monitored to identify new or ongoing hyponatraemia. When hyponatraemia is discovered, it should be quickly and actively corrected.

Snake bites in children in The Gambia.

This is a retrospective study of the demographic features, treatment and outcome of 28 cases of snake bite admitted to the department of paediatrics of the Royal Victoria Hospital, Banjul, The Gambia over a 3-year period. The age range was 2-14 years and the male:female ratio was 2.1:1. Most bites were on the legs and occurred near home. Most snake bites presented early at hospital and marked swelling of the affected limb was the most common clinical sign. Shock, restlessness and regional adenitis of the affected limb were common in children who died. The case fatality rate was 14.3%. Most children did not receive specific antivenom therapy.

The host response in malaria and depression of defence against tuberculosis.

Malaria causes significant morbidity and mortality world-wide. Both asymptomatic and symptomatic malarial infections cause immune depression, which predisposes the host to infection with other microorganisms. Specific clinical investigations have shown, for example, that those with malaria-attributable anaemia are particularly likely to have Salmonella septicaemia, and that asymptomatic malarial infection causes diminished response to polysaccharide vaccine. The results of clinical studies and experiments with animal models have revealed that malarial parasites can decrease their vertebrate host's effective humoral and cellular immune responses. In this review, the possible ways in which this malaria-induced immune impairment could affect the host's response to Mycobacterium tuberculosis infection are considered. Could malarial infection be one of the reasons for the persistence of tuberculosis in malaria-endemic regions?

Bacteraemia in cerebral malaria.

As part of a treatment trial of cerebral malaria, blood cultures were done in 276 Gambian children, aged between 1 and 9 years, with cerebral malaria. Fourteen (5%) of these were positive. The organisms isolated were Staphylococcus aureus (6), coliforms (4), Pseudomonas spp. (2), Salmonella spp. (1) and Streptococcus spp. (1). Thirteen of these children survived, most without appropriate antibiotic treatment. Most of the retrieved organisms were therefore suspected to be contaminants. Bacteraemia complicating cerebral malaria is not common in The Gambia, and routine antibiotic treatment of children with cerebral malaria is not warranted.

Biochemical and haematological variables in Gambian children with cerebral malaria.

Biochemical and haematological measurements were made in Gambian children who satisfied the criteria for the diagnosis of cerebral malaria over a 3-year period. Biochemical and haematological values were available for 388 and 624 children, respectively. Biochemical signs of renal and hepatic dysfunction were found and these may have contributed in a cumulative way to the high mortality seen in the study children. Cerebral involvement in children with cerebral malaria is only one, though the most important, manifestation of a multi-organ disease.

The effect of a monoclonal antibody to tumor necrosis factor on survival from childhood cerebral malaria.

Tumor necrosis factor (TNF) is thought to play a key role in the pathogenesis of cerebral malaria. A double-blind, placebo-controlled trial of an anti-TNF monoclonal antibody (B-C7) comprised 610 Gambian children with cerebral malaria, with mortality and residual neurologic sequelae as primary study end points. Sixty (19.9%) of 302 children who received B-C7 died compared with 64 (20.8%) of 308 children who received placebo (adjusted odds ratio [OR], 0.90; 95% confidence interval [CI], 0.57-1.42). Residual neurologic sequelae were detected in 15 (6.8%) of 221 survivors from the B-C7 group and in 5 (2.2%) of 225 survivors of the placebo group (adjusted OR, 3.35; 95% CI, 1.08-10.4). The monoclonal antibody used in this study did not improve survival in cerebral malaria and was associated with a significant increase in neurologic sequelae. A possible explanation of the latter observation is that the antibody acts to retain TNF within the circulation and thereby prolongs its effects on vascular endothelium.

A trial of artemether or quinine in children with cerebral malaria.

BACKGROUND: Cerebral malaria has a mortality rate of 10 to 30 percent despite treatment with parenteral quinine, a situation that may worsen with the spread of quinine resistance. Artemether is a new antimalarial agent that clears parasites from the circulation more rapidly than quinine, but its effect on mortality is unclear. METHODS: We conducted a randomized, unblinded comparison of intramuscular artemether and intramuscular quinine in 576 Gambian children with cerebral malaria. The primary end points of the study were mortality and residual neurologic sequelae. RESULTS: Fifty-nine of the 288 children treated with artemether died in the hospital (20.5 percent), as compared with 62 of the 288 treated with quinine (21.5 percent). Among the 418 children analyzed at approximately five months for neurologic disease, residual neurologic sequelae were detected in 7 of 209 survivors treated with artemether (3.3 percent) and 11 of 209 survivors treated with quinine (5.3 percent, P = 0.5). After adjustment for potential confounders, the odds ratio for death was 0.84 (95 percent confidence interval, 0.53 to 1.32) in the artemether group, and for residual neurologic sequelae, 0.51 (95 percent confidence interval, 0.17 to 1.47). There were fewer local reactions at the injection site with artemether than with quinine (0.7 percent vs. 5.9 percent, P = 0.001). CONCLUSIONS: Artemether is as effective as quinine in the treatment of cerebral malaria in children.