Evaluation of C-reactive protein and haptoglobin as malaria episode markers in an area of high transmission in Africa

Field studies of malaria in endemic areas frequently use the presence or levels of parasitaemia, together with the measurement of fever, as the primary criteria with which to identify cases. However, since malaria cases do not always present with measurable fever, and since asymptomatic parasitaemia occurs, additional episode markers might be useful epidemiological tools. We have measured the C-reactive protein and haptoglobin levels in paediatric patients presenting to a village health post in the Kilombero District in Tanzania and in convalescent sera from the same patients, in order to evaluate these acute-phase reactants as alternative markers of Plasmodium falciparum episodes. Among afebrile patients, C-reactive protein levels were highly correlated with parasite density. High C-reactive protein levels are therefore probably indicative of recent clinical malaria episodes in currently afebrile individuals with high parasite densities. An appropriate case definition for malaria in epidemiological studies in endemic areas might therefore be hyperparasitaemia accompanied by either, or both, measurable fever and raised C-reactive protein levels. This would give less biased estimates of the overall burden of malaria morbidity than does a definition which requires measurable fever. Levels of haptoglobin were highly negatively correlated with parasitaemia, but did not appear to be useful episode markers because this correlation was probably not related to acute morbidity. However, haptoglobin can be useful to assess at community level the impact of interventions on parasitaemi

Patterns of resistance and DHFR/DHPS genotypes of Plasmodium falciparum in rural Tanzania prior to the adoption of sulfadoxine-pyrimethamine as first-line treatment.

A study was carried out to assess the patterns of resistance and occurrence of DHFR/DHPS genotypes of Plasmodium falciparum prior to the adoption of sulfadoxine-pyrimethamine (SP) as first-line treatment for uncomplicated malaria in Tanzania. Children under five years (n = 117) with clinical, uncomplicated malaria were randomly allocated to standard treatments of either chloroquine (CQ) (25 mg/kg) or SP (25 mg sulfadoxine and 1.25 mg pyrimethamine/kg). Patients were monitored for 28 days. Clinical recovery was achieved in 98% (n = 58) and 90% (n = 59) of the patients in the SP and CQ groups, respectively. Parasitologically, 14% of the patients in the SP group and 51% in the CQ group exhibited RII/RIII resistance. When relating pre-treatment blood drug levels to treatment outcome and the degree of parasite resistance to the number of mutations, no relationships could be detected. There was an overall significant increase in haemoglobin levels from day 0 to day 28 in both patient groups. Sulfadoxine-pyrimethamine produced an acceptable clinical response but the high degree of parasitological resistance (RII/RIII) observed two years prior to the introduction of the drug as first-line treatment is of concern, especially considering the long half-lives of sulfadoxine and pyrimethamine

4. Age dependence of the multiplicity of Plasmodium falciparum infections and of other malariological indices in an area of high endemicity

The relationship between age and various malariological indices in the Kilombero valley of Tanzania were examined by compiling data from 6 different community studies carried out between 1989 and 1996. The rate of acquisition of Plasmodium falciparum infection was highest in children 1-5 years of age, while recovery rates were lowest between the first birthday and early adolescence. As a result, peak prevalence was reached in 3-5 years old children. However, the prevalence of clinical malaria (estimated from the excess risk of axillary temperatures ≥37·5 °C attributable to parasitaemia) was highest in children under one year of age. The peak in multiplicity of infection (identified by polymerase chain reaction-restriction fragment length polymorphism of the msp2 locus) occurred in 3-7 years old children. There was a significant correlation between parasite density and multiplicity of infection in infants and young children (1-2 years of age) but not in older individual

Antimalarial resistance and DHFR/DHPS genotypes of Plasmodium falciparum three years after introduction of sulfadoxine-pyrimethamine and amodiaquine in rural Tanzania.

We assessed the efficacy of sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) and DHFR/DHPS genotypes of Plasmodium falciparum in rural Tanzania, 3 years after their introduction as first- and second-line treatments for uncomplicated malaria, respectively. Under five children with uncomplicated malaria were given standard treatments of either SP (n=66) or AQ (n=30) and treatment outcomes after 14 and 28 days were determined. Total treatment failure of 18 and 42.5% was observed for SP on days 14 and 28, respectively. For AQ, total treatment failure of 27 and 53% was found on day 14 and 28, respectively. On day 14, significantly lower SP total treatment failures were observed in 2004 compared with results from a study conducted in 1999 in the same location. No relationship was detected between clinical outcome and DHFR/DHPS genotypes, but the point mutation prevalence in parasites was higher than in 1999. Pre-treatment blood levels of SP were detected in a quarter of the study children: less than expected. We report unacceptably high levels of total treatment failures, both for first- and second-line treatments for uncomplicated malaria in Tanzania 3 years after their introduction, supporting the decision to replace them with artemisinin-based combination therapy

Severe childhood malaria in two areas of markedly different falciparum transmission in east Africa.

Malaria remains a major public health challenge in sub-Saharan Africa, yet our knowledge of the epidemiology of malaria in terms of patterns of mortality and morbidity is limited. We have examined the presentation of severe, potentially life-threatening malaria to district hospitals in two very different transmission settings: Kilifi, Kenya with low seasonal transmission and Ifakara, Tanzania with high seasonal transmission. The minimum annual rates of severe disease in children below five years in both populations were similar (46 per 1000 children in Kilifi and 51 per 1000 children in Ifakara). However, there were important differences in the age and clinical patterns of severe disease; twice as many patients were under one year of age in Ifakara compared with Kilifi and there was a four fold higher rate of cerebral malaria and three fold lower rate of malaria anaemia among malaria patients at Kilifi compared with Ifakara. Reducing malaria transmission in Ifakara by 95%, for example with insecticide-treated bed nets, would result in a transmission setting comparable to that of Kilifi and although this reduction may yield early successes in reducing severe malaria morbidity and mortality in young, immunologically naive children, place these same children at increased risk at older ages of developing severe and potentially different manifestations of malaria infection hence producing no net cohort gain in survivorship from potentially fatal malaria

Absence of Seasonal Variation in Malaria Parasitaemia in an Area of Intense Seasonal Transmission.

Parasitological surveys carried out in two villages of the Kilombero district of Tanzania indicated a very high prevalence of Plasmodium falciparum parasitaemia throughout the year (all ages mean prevalence = 69.2%) and a low, unstable prevalence of P. malariae (all ages mean prevalence = 4.5%). Fevers (temperature > or = 37.5 degrees C) in both children and adults showed irregular changes in prevalence over time, but there was no seasonal pattern. Neither was there seasonal variation in either P. falciparum parasite prevalence or parasite densities. This was despite marked seasonality in vectors caught in CDC light-traps and in estimated sporozoite inoculations determined by ELISA. The estimated mean annual inoculation rate was extremely high, over 300 infectious bites per person per year, the main vectors being members of the A. gambiae complex and Anopheles funestus. There was considerable variation between houses but even in houses with relatively low mosquito numbers the inoculation rate was sufficient to maintain a maximal P. falciparum prevalence. Heterogeneities in exposure cannot explain why the parasite prevalence is not always 100%. In areas of such high transmission, parasitaemias are likely to be determined mainly by the interaction of schizogony and anti-blood stage immunity, since parasites arising from new inoculations generally comprise only a small proportion of the total in the circulation. In any one individual, this will lead to periodic fluctuations in levels of parasitaemia. These are unlikely to show a close relationship to either seasonal variation in inoculations or to differences between households in the local inoculation rate