Risk associated with asymptomatic parasitaemia occurring post-antimalarial treatment

OBJECTIVE: Parasites may recur asymptomatically after initial clearance by antimalarial treatment. Current guidelines recommend treatment only when patients develop symptoms or at the end of follow-up. We wanted to assess prospectively the probability of becoming symptomatic and the risks of this practice. METHODS: We analysed data collected in 13 trials of uncomplicated paediatric malaria conducted in eight sub-Saharan African countries. These studies followed all cases of post-treatment asymptomatic parasitaemia until they developed symptoms or to the end of the 28-day follow-up period, at which time parasite genotypes were compared to pre-treatment isolates to distinguish between recrudescences and new infections. RESULTS: There were 425 asymptomatic recurrences after 2576 treatments with either chloroquine, sulfadoxine/pyrimethamine or amodiaquine, of which 225 occurred by day 14 and 200 between day 15 and day 28. By day 28, 42% developed fever (median time to fever = 5 days) and 30% remained parasitaemic but afebrile, while 23% cleared their parasites (outcome unknown in 4%). Young age, parasitaemia >/=500 parasites/microl; onset of parasitaemia after day 14, and treatment with amodiaquine were the main variables associated with higher risk of developing fever. CONCLUSION: In areas of moderate to intense transmission, asymptomatic recurrences of malaria after treatment carry a substantial risk of becoming ill within a few days and should be treated as discovered. Young children are at higher risk. The higher risk carried by cases occurring in the second half of follow-up may be explained by falling residual drug levels

A possible role for proguanil-dapsone against SP-resistant P.falciparum?

A two-armed trial was conducted in July 2000 in 4 villages near Muheza, Tanga Region, in Tanzania, asymptomatic children with P.falciparum parasitaemia > 200/ul (Mutabingwa et al. 2001 Trans Roy Soc Trop Med Hyg 95: 433-438). In one of the arms 188 children were treated with sulfadoxine-pyrimethamine and only 14.3% showed parasite clearance at day 7 (16.1% at day 14). The SP batch used was checked for good quality and the low clearance rate is indicative of one of the worst levels of SP resistance yet recorded in Africa. SP resistance in this area has increased from about 20% in 1995 (Trigg et all 1997 Acta Trop 63: 1865-189) to 45% in 1998/9 (Mutabingwa et al 2001 Lancet 358: 1218-1233) and is now 86

Rolling Back a Malaria Epidemic in South Africa

The authors discuss the success in malaria control in KwaZulu-Natal (reported by Barnes and colleagues), and its implications for the rest of Africa

Cost-Effectiveness Study of Three Antimalarial Drug Combinations in Tanzania

BACKGROUND: As a result of rising levels of drug resistance to conventional monotherapy, the World Health Organization (WHO) and other international organisations have recommended that malaria endemic countries move to combination therapy, ideally with artemisinin-based combinations (ACTs). Cost is a major barrier to deployment. There is little evidence from field trials on the cost-effectiveness of these new combinations. METHODS AND FINDINGS: An economic evaluation of drug combinations was designed around a randomised effectiveness trial of combinations recommended by the WHO, used to treat Tanzanian children with non-severe slide-proven malaria. Drug combinations were: amodiaquine (AQ), AQ with sulfadoxine-pyrimethamine (AQ+SP), AQ with artesunate (AQ+AS), and artemether-lumefantrine (AL) in a six-dose regimen. Effectiveness was measured in terms of resource savings and cases of malaria averted (based on parasitological failure rates at days 14 and 28). All costs to providers and to patients and their families were estimated and uncertain variables were subjected to univariate sensitivity analysis. Incremental analysis comparing each combination to monotherapy (AQ) revealed that from a societal perspective AL was most cost-effective at day 14. At day 28 the difference between AL and AQ+AS was negligible; both resulted in a gross savings of approximately US$1.70 or a net saving of US$22.40 per case averted. Varying the accuracy of diagnosis and the subsistence wage rate used to value unpaid work had a significant effect on the number of cases averted and on programme costs, respectively, but this did not change the finding that AL and AQ+AS dominate monotherapy. CONCLUSIONS: In an area of high drug resistance, there is evidence that AL and AQ+AS are the most cost-effective drugs despite being the most expensive, because they are significantly more effective than other options and therefore reduce the need for further treatment. This is not necessarily the case in parts of Africa where recrudescence following SP and AQ treatment (and their combination) is lower so that the relative advantage of ACTs is smaller, or where diagnostic services are not accurate and as a result much of the drug goes to those who do not have malaria

The impact of endemic and epidemic malaria on the risk of stillbirth in two areas of Tanzania with different malaria transmission patterns

BACKGROUND: The impact of malaria on the risk of stillbirth is still under debate. The aim of the present analysis was to determine comparative changes in stillbirth prevalence between two areas of Tanzania with different malaria transmission patterns in order to estimate the malaria attributable component. METHODS: A retrospective analysis was completed of stillbirth differences between primigravidae and multigravidae in relation to malaria cases and transmission patterns for two different areas of Tanzania with a focus on the effects of the El Niño southern climatic oscillation (ENSO). One area, Kagera, experiences outbreaks of malaria, and the other area, Morogoro, is holoendemic. Delivery and malaria data were collected over a six year period from records of the two district hospitals in these locations. RESULTS: There was a significantly higher prevalence of low birthweight in primigravidae compared to multigravidae for both data sets. Low birthweight and stillbirth prevalence (17.5% and 4.8%) were significantly higher in Kilosa compared to Ndolage (11.9% and 2.4%). There was a significant difference in stillbirth prevalence between Ndolage and Kilosa between malaria seasons (2.4% and 5.6% respectively, p < 0.001) and during malaria seasons (1.9% and 5.9% respectively, p < 0.001). During ENSO there was no difference (4.1% and 4.9%, respectively). There was a significant difference in low birthweight prevalence between Ndolage and Kilosa between malaria seasons (14.4% and 23.0% respectively, p < 0.001) and in relation to malaria seasons (13.9% and 25.2% respectively, p < 0.001). During ENSO there was no difference (22.2% and 19.8%, respectively). Increased low birthweight risk occurred approximately five months following peak malaria prevalence, but stillbirth risk increased at the time of malaria peaks. CONCLUSION: Malaria exposure during pregnancy has a delayed effect on birthweight outcomes, but a more acute effect on stillbirth risk

Molecular monitoring of the Leu-164 mutation of dihydrofolate reductase in a highly sulfadoxine/pyrimethamine-resistant area in Africa

The selection of point mutation at codon 164 (from isoleucine to leucine) of the dihydrofolate reductase (DHFR) enzyme in Plasmodium falciparum is associated with high sulfadoxine /pyrimethamine (SP) resistance. Using the yeast expression system that allows the detection of dhfr allele present at low level, the presence of this mutation had previously been reported between 1998–1999 in Muheza, Tanzania, an area of high SP resistance. Eighty five P. falciparum isolates, obtained from the same area between 2002 and 2003, were analysed for the presence of Leu-164 mutation, using standard protocol based on PCR-RFLP. None of the isolates had the Leu-164 mutation

Maternal peripheral blood level of IL-10 as a marker for inflammatory placental malaria

Background: Placental malaria (PM) is an important cause of maternal and foetal mortality in tropical areas, and severe sequelae and mortality are related to inflammation in the placenta. Diagnosis is difficult because PM is often asymptomatic, peripheral blood smear examination detects parasitemia as few as half of PM cases, and no peripheral markers have been validated for placental inflammation. Methods: In a cohort of Tanzanian parturients, PM was determined by placental blood smears and placental inflammation was assessed by histology and TNF mRNA levels. Maternal peripheral blood levels of several immune mediators previously implicated in PM pathogenesis, as well as ferritin and leptin were measured. The relationship between the levels of these soluble factors to PM and placental inflammation was examined. Results: Peripheral levels of TNF, TNF-RI, TNF-RII, IL-1, IL-10, and ferritin were elevated during PM, whereas levels of IFN-[gamma], IL-4, IL-5 and IL-6 were unchanged and levels of leptin were decreased. In receiver operating characteristic curve analysis, IL-10 had the greatest area under the curve, and would provide a sensitivity of 60% with a false positive rate of 10%. At a cut off level of 15 pg/mL, IL-10 would detect PM with a sensitivity of 79.5% and a specificity of 84.3%. IL-10 levels correlated with placental inflammatory cells and placental TNF mRNA levels in first time mothers. Conclusion: These data suggest that IL-10 may have utility as a biomarker for inflammatory PM in research studies, but that additional biomarkers may be required to improve clinical diagnosis and management of malaria during pregnancy.This work was supported by grants from Bill and Melinda Gates Foundation (grant 29202), NIH (R01 AI52059 and TW05509) and Puget Sound Partners for Global Health to P.E.D

Unraveling the Impact of Malaria Exposure Before Birth

Lars Hviid discusses a research article in PLoS Medicine that explores whether prenatal exposure to malaria is associated with increased susceptibility to malarial infection and anemia in infancy

Rapid increase of Plasmodium falciparum dhfr/dhps resistant haplotypes, after the adoption of sulphadoxine-pyrimethamine as first line treatment in 2002, in southern Mozambique

<p>Abstract</p> <p>Background</p> <p>In late 2002, the health authorities of Mozambique implemented sulphadoxine-pyrimethamine (SP)/amodiaquine (AQ) as first-line treatment against uncomplicated falciparum malaria. In 2004, this has been altered to SP/artesunate in line with WHO recommendations of using Artemisinin Combination Therapies (ACTs), despite the fact that all the neighbouring countries have abandoned SP-drug combinations due to high levels of SP drug resistance. In the study area, one year prior to the change to SP/AQ, SP alone was used to treat uncomplicated malaria cases. The study described here investigated the immediate impact of the change to SP on the frequency of SP and CQ resistance-related haplotypes in the <it>Plasmodium falciparum </it>genes <it>Pfdhfr, Pfdhps </it>and <it>Pfcrt </it>before and a year after the introduction of SP.</p> <p>Methods</p> <p>Samples were collected during two cross sectional surveys in early 2002 and 2003 involving 796 and 692 children one year or older and adults randomly selected living in Maciana, an area located in Manhiça district, Southern Mozambique. Out of these, 171 and 173 <it>P. falciparum </it>positive samples were randomly selected to measure the frequency of resistance- related haplotypes in <it>Pfdhfr, Pfdhps </it>and <it>Pfcrt </it>based on results obtained by nested PCR followed by sequence-specific oligonucleotide probe (SSOP)-ELISA.</p> <p>Results</p> <p>The frequency of the SP-resistance associated <it>Pfdhps </it>double mutant (SGEAA) haplotype increased significantly from 14% to 35% (P < 0.001), while the triple mutant <it>Pfdhfr </it>haplotype (CIRNI) remained high and only changed marginally from 46% to 53% (P = 0.405) after one year with SP as first-line treatment in the study area. Conversely, the combined <it>Pfdhfr/Pfdhps </it>quintuple mutant haplotype increased from 8% to 26% (P = 0.005). The frequency of the chloroquine resistance associated <it>Pfcrt</it>-CVIET haplotype was above 90% in both years.</p> <p>Conclusion</p> <p>These retrospective findings add to the general concern on the lifespan of the combination of SP/artesunate in Mozambique. The high frequency of quintuple <it>Pfdhfr</it>/<it>Pfdhps </it>haplotypes found here as early as 2002 most likely cause ideal conditions for the development of artesunate tolerance in the <it>P. falciparum </it>populations and may even endanger the sensitivity to the second-line drug, Coartem^®.</p