Effect of artesunate plus sulfadoxine-pyrimethamine on haematological recovery and anaemia, in Kenyan children with uncomplicated, Plasmodium falciparum malaria.

Malaria-associated anaemia is a major public-health problem. Although the treatment of uncomplicated, Plasmodium falciparum malaria aims to clear the parasites, relieve the symptoms and permit haematological recovery, data on the impact of antimalarial treatment on haematological recovery are few. Haematological recovery and the prevalence of anaemia were therefore evaluated in 600 Kenyan children with uncomplicated malaria who were randomly assigned to one of three treatment groups. The children were given sulfadoxine-pyrimethamine (SP) on day 0, SP plus artesunate on day 0 (AS1), or SP on day 0 and artesunate on each of days 0-2 (AS3). Haemoglobin (Hb) concentrations were measured on days 0, 7, 14, 21 and 28, with haematological recovery defined as a day-28 Hb concentration of at least 11 g/dl. Only 96 (18%) of the 543 children who were anaemic (i.e. with <11.0 g Hb/dl) at enrolment achieved haematological recovery. The prevalence of anaemia fell from 91% on day 0 to 74% (252/340) by day 28 (P=0.065). Compared with SP alone, neither artesunate regimen resulted in higher Hb concentrations on day 28 (with means of 10.2, 9.9 and 10.2 g/dl for AS3, AS1 and SP, respectively; P=0.254), a higher frequency of haematological recovery (19%, 14% and 20% for AS3, AS1 and SP, respectively; P=0.301) or a greater reduction in the prevalence of anaemia (prevalences in the AS3, AS1 and SP arms falling from 90%, 89% and 93%, respectively, on day 0, to corresponding values of 71%, 82% and 69% on day 28; P=0.40). In fact, between days 0 and 7, the children in the AS3 arm showed a larger drop in mean Hb than the children in the other two treatment arms. In general, haematological recovery was most likely in older children who had mild anaemia at presentation and were parasitologically cured. Overall, the frequencies of haematological recovery were modest and not influenced by the artesunate treatments. Other factors contributing to anaemia need to be explored more fully.

Efficacy of Haemophilus influenzae type b vaccination of children: a meta-analysis.

Haemophilus influenzae type b (Hib) infection is a leading cause of meningitis and pneumonia in infants and children in developing countries, and yet the implementation of routine Hib vaccination is very slow. The aim of the present study was to quantify the protective efficacy of H. influenzae type b vaccination of young children. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials Register were searched. References of selected articles were also reviewed and experts contacted. Eight randomized trials were found that compared the efficacy of H. influenzae type b conjugate vaccine to placebo or no vaccine. Information on study design, patients enrolled, age, vaccine type, cases of invasive H. influenzae type b disease, adverse events, and items to assess potential for bias was recorded. The incidence of invasive H. influenzae type b infection formed the primary outcome. The odds ratio (OR) of developing Hib infection was combined using a random effects model to provide a measure of vaccine efficacy. The protective effect, defined as the relative risk reduction, was estimated as (1-OR). From eight trials, the protective efficacy of the Hib conjugate vaccine was 84% (OR 0.16; 95%CI 0.08-0.30) against invasive Hib disease, 75% (OR 0.25; 95%CI 0.08-0.84) against meningitis, and 69% (OR 0.31; 95%CI 0.10-0.97) against pneumonia. Serious adverse events were rare. The results provide firm evidence that Hib conjugate vaccines are safe and effective in reducing the risk of all forms of invasive Hib disease, further establishing that vaccination of children in developing countries can protect them from a potentially fatal yet preventable disease.

Blood transfusions for severe malaria-related anemia in Africa: a decision analysis.

Severe childhood malarial anemia is commonly treated using blood transfusion. Although transfusion may decrease short-term mortality, the risk of human immunodeficiency virus (HIV) transmission is considerable in Africa. We constructed a decision tree to weigh the short-term mortality benefit of transfusion against HIV infection risk. Probability estimates were derived from published studies. The base-case was a two-year-old child with a 13.5% mortality risk to be transfused with screened or unscreened blood (1% or 13% HIV contamination risk, respectively), with reduction of mortality to 5.5% by transfusion (odds ratio=2.7), and a 2.4% risk of fatal transfusion complications. A sensitivity analysis was performed to assess the influence of variation in these estimates. If a child developed acquired immunodeficiency syndrome, survival was weighed as one-tenth of normal survival. For the base-case, we found that transfusion with screened blood provided a survival benefit of 5%. In contrast, transfusion with unscreened blood decreased survival by 2%. Patients with a mortality risk < 5% derived no benefit from a transfusion with screened blood. Other important factors for the benefit of transfusion were the effectiveness of transfusion in reducing mortality and the risk of blood contamination. A blood transfusion was clearly beneficial if the mortality risk was high and the risk of contamination was low. Our findings can be used as a basis for a clinical transfusion policy that limits transfusions to situations in which they are likely to be beneficial. This will in turn optimize child survival and prevent unnecessary exposure of low risk children to the transfusion risks.

Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa.

BACKGROUND: Malaria remains a major cause of mortality and morbidity in Africa. Many approaches to malaria control involve reducing the chances of infection but little is known of the relations between parasite exposure and the development of effective clinical immunity so the long-term effect of such approaches to control on the pattern and frequency of malaria cannot be predicted. METHODS: We have prospectively recorded paediatric admissions with severe malaria over three to five years from five discrete communities in The Gambia and Kenya. Demographic analysis of the communities exposed to disease risk allowed the estimation of age-specific rates for severe malaria. Within each community the exposure to Plasmodium falciparum infection was determined through repeated parasitological and serological surveys among children and infants. We used acute respiratory-tract infections (ARI) as a comparison. FINDINGS: 3556 malaria admissions were recorded for the five sites. Marked differences were observed in age, clinical spectrum and rates of severe malaria between the five sites. Paradoxically, the risks of severe disease in childhood were lowest among populations with the highest transmission intensities, and the highest disease risks were observed among populations exposed to low-to-moderate intensities of transmission. For severe malaria, for example, admission rates (per 1000 per year) for children up to their 10th birthday were estimated as 3.9, 25.8, 25.9, 16.7, and 18.0 in the five communities; the forces of infection estimated for those communities (new infections per infant per month) were 0.001, 0.034, 0.050, 0.093, and 0.176, respectively. Similar trends were noted for cerebral malaria and for severe malaria anaemia but not for ARI. Mean age of disease decreased with increasing transmission intensity. INTERPRETATION: We propose that a critical determinant of life-time disease risk is the ability to develop clinical immunity early in life during a period when other protective mechanisms may operate. In highly endemic areas measures which reduce parasite transmission, and thus immunity, may lead to a change in both the clinical spectrum of severe disease and the overall burden of severe malaria morbidity.

PIP: 3556 pediatric admissions with severe malaria over 3-5 years from five discrete communities in the Gambia and Kenya were recorded prospectively in a study of the relationship between parasite exposure and the development of effective clinical immunity against malaria. The exposure to Plasmodium falciparum infection in each community was determined through repeated parasitological and serological surveys among children and infants, while acute respiratory tract infections (ARI) were used as a comparison. Clear differences were observed in age, clinical spectrum, and rates of severe malaria between the five sites. The risks of severe disease in childhood were lowest in populations with the highest transmission intensities, while the highest disease risks were observed among populations exposed to low-to-moderate intensities of transmission. Similar trends were observed for cerebral malaria and severe malaria anemia, but not for ARI. The mean age of disease decreased with increasing transmission intensity.

Clinical signs for the recognition of children with moderate or severe anaemia in western Kenya.

Optimal treatment of Plasmodium falciparum-related paediatric anaemia can result in improved haematological recovery and survival. Clinical predictors are needed to identify children with anaemia in settings where laboratory measurements are not available. The use of conjunctival (eyelid), palmar, nailbed, and tongue pallor to detect children with moderate anaemia (haemoglobin, 5.0-7.9 g/dl) or severe anaemia (haemoglobin, < 5.0 g/dl) was evaluated among children seen at an outpatient and inpatient setting in a hospital in western Kenya. Severe nailbed or severe palmar pallor had the highest sensitivity (62% and 60%, resp.), compared with severe conjunctival pallor (sensitivity = 31%), to detect children with severe anaemia in the outpatient setting. Children with moderate anaemia were best identified by the presence of nailbed or palmar pallor (sensitivity = 90% for both signs), compared with conjunctival pallor (sensitivity = 81%). Clinical signs of respiratory distress, in addition to the presence of severe pallor, did not increase the recognition of children requiring hospitalization for severe anaemia. Among inpatients, the sensitivity of severe nailbed pallor (59%) was highest for detecting children with severe anaemia, although the sensitivity of severe conjunctival pallor and severe palmar pallor was the same (53% for both signs). Presence of conjunctival pallor (sensitivity = 74%) was similar in sensitivity to both nailbed and palmar pallor (70% for both signs) among children with moderate anaemia. The sensitivity of tongue pallor was low among all children evaluated. Low haemoglobin levels were significantly associated with the likelihood of being smear-positive for P. falciparum. This study demonstrates that clinical criteria can be used to identify children with moderate and severe anaemia, thus enabling implementation of treatment algorithms. Children aged < 36 months who live in an area with P. falciparum malaria should receive treatment with an effective antimalarial drug if they have pallor.

PIP: The ability of pallor of the conjunctiva, palms, nailbed, and tongue to identify children with Plasmodium falciparum-related anemia in developing country settings, where laboratory measurements are not available, was investigated in children attending Siaya District Hospital in western Kenya. Enrolled were all children 2 months to 5 years of age admitted to the hospital's inpatient unit in 1993-94 (n = 1048), and every fifth child presenting to the outpatient clinic (n = 1666). Severe nailbed or severe palmar pallor had the highest sensitivities (62% and 60%, respectively) in the detection of severe anemia in outpatients, while those with moderate anemia were best identified by nailbed or palmar pallor (90% sensitivity for both signs). The addition of clinical signs of respiratory distress to pallor did not increase the identification of children requiring hospitalization for severe anemia. Among inpatients, severe nailbed, conjunctival, and palmar pallor had sensitivities of 59%, 53%, and 53%, respectively, for detecting severe anemia. In the detection of moderate anemia, the sensitivities were 74%, 70%, and 70%, respectively, for conjunctival, nailbed, and palmar pallor. Tongue pallor had a low sensitivity among all children examined. Low hemoglobin levels were significantly associated with P. falciparum infection. It is recommended that all children under 36 months of age, in areas with P. falciparum malaria, should receive antimalarial treatment if they present with pallor.