False-negative malaria rapid diagnostic tests in Rwanda: impact of Plasmodium falciparum isolates lacking hrp2 and declining malaria transmission.

BACKGROUND: Rapid diagnostic tests (RDTs) for histidine rich protein 2 (HRP2) are often used to determine whether persons with fever should be treated with anti-malarials. However, Plasmodium falciparum parasites with a deletion of the hrp2 gene yield false-negative RDTs and there are concerns the sensitivity of HRP2-based RDTs may fall when the intensity of transmission decreases. METHODS: This observational study enrolled 9226 patients at three health centres in Rwanda from April 2014 to April 2015. It then compared the sensitivity of RDTs based on HRP2 and the Plasmodium lactate dehydrogenase (pLDH) to microscopy (thick smears) for the diagnosis of malaria. PCR was used to determine whether deletions of the histidine-rich central repeat region of the hrp2 gene (exon 2) were associated with false-negative HRP2-based RDTs. RESULTS: In comparison to microscopy, the sensitivity and specificity of HRP2- and pLDH-based RDTs were 89.5 and 86.2% and 80.2 and 94.3%, respectively. When the results for both RDTs were combined, sensitivity rose to 91.8% and specificity was 85.7%. Additionally, when smear positivity fell from 46 to 3%, the sensitivity of the HRP2-based RDT fell from 88 to 67%. Of 370 samples with false-negative HRP2 RDT results for which PCR was performed, 140 (38%) were identified as P. falciparum by PCR. Of the isolates identified as P. falciparum by PCR, 32 (23%) were negative for the hrp2 gene based on PCR. Of the 32 P. falciparum isolates negative for hrp2 by PCR, 17 (53%) were positive based on the pLDH RDT. CONCLUSION: This prospective study of RDT performance coincided with a decline in the intensity of malaria transmission in Kibirizi (fall in slide positivity from 46 to 3%). This decline was associated with a decrease in HRP2 RDT sensitivity (from 88 to 67%). While P. falciparum isolates without the hrp2 gene were an important cause of false-negative HRP2-based RDTs, most were identified by the pLDH-based RDT. Although WHO does not recommend the use of combined HRP2/pLDH testing in sub-Saharan Africa, these results suggest that combination HRP2/pLDH-based RDTs could reduce the impact of false-negative HRP2-based RDTs for detection of symptomatic P. falciparum malaria.

Impact Evaluation of Malaria Control Interventions on Morbidity and All-Cause Child Mortality in Rwanda, 2000-2010.

The impressive decline in child mortality that occurred in Rwanda from 1996-2000 to 2006-2010 coincided with a period of rapid increase of malaria control interventions such as indoor residual spraying (IRS); insecticide-treated net (ITN) distribution and use, and improved malaria case management. The impact of these interventions was examined through ecological correlation analysis, and robust decomposition analysis of contextual factors on all-cause child mortality. Child mortality fell 61% during the evaluation period and prevalence of severe anemia in children 6-23 months declined 71% between 2005 and 2010. These changes in malaria morbidity and mortality occurred concurrently with a substantial increase in vector control activities. ITN use increased among children under five, from 4% to 70%. The IRS program began in 2007 and covered 1.3 million people in the highest burden districts by 2010. At the same time, diagnosis and treatment with an effective antimalarial expanded nationally, and included making services available to children under the age of 5 at the community level. The percentage of children under 5 who sought care for a fever increased from 26% in 2000 to 48% in 2010. Multivariable models of the change in child mortality between 2000 and 2010 using nationally representative data reveal the importance of increasing ITN ownership in explaining the observed mortality declines. Taken as a whole, the evidence supports the conclusion that malaria control interventions contributed to the observed decline in child mortality in Rwanda from 2000 to 2010, even in a context of improving socioeconomic, maternal, and child health conditions.

Nationwide implementation of integrated community case management of childhood illness in Rwanda.

BACKGROUND: Between 2008 and 2011, Rwanda introduced integrated community case management (iCCM) of childhood illness nationwide. Community health workers in each of Rwanda's nearly 15,000 villages were trained in iCCM and equipped for empirical diagnosis and treatment of pneumonia, diarrhea, and malaria; for malnutrition surveillance; and for comprehensive reporting and referral services. METHODS: We used data from the Rwanda health management information system (HMIS) to calculate monthly all-cause under-5 mortality rates, health facility use rates, and community-based treatment rates for childhood illness in each district. We then compared a 3-month baseline period prior to iCCM implementation with a seasonally matched comparison period 1 year after iCCM implementation. Finally, we compared the actual changes in all-cause child mortality and health facility use over this time period with the changes that would have been expected based on baseline trends in Rwanda. RESULTS: The number of children receiving community-based treatment for diarrhea and pneumonia increased significantly in the 1-year period after iCCM implementation, from 0.83 cases/1,000 child-months to 3.80 cases/1,000 child-months (P = .01) and 0.25 cases/1,000 child-months to 5.28 cases/1,000 child-months (P<.001), respectively. On average, total under-5 mortality rates declined significantly by 38% (P<.001), and health facility use declined significantly by 15% (P = .006). These decreases were significantly greater than would have been expected based on baseline trends. CONCLUSIONS: This is the first study to demonstrate decreases in both child mortality and health facility use after implementing iCCM of childhood illness at a national level. While our study design does not allow for direct attribution of these changes to implementation of iCCM, these results are in line with those of prior studies conducted at the sub-national level in other low-income countries.