EDITORIAL 193 were asymptomatic. Symptomatic infections caused by HRP2- negative parasites were noted in Peru,8 but it is not clear if such parasites can commonly cause illness among Africans, who generally have high-level antimalarial immunity. Another limitation of HRP2-based RDTs is the inability of these assays to identify nonfalciparum malaria infections. Although the large majority of malaria infections are caused by P. falciparum in sub-Saharan Africa, non-falciparum infec- tions do play an important role. In a recent study of children in an urban cohort in Kampala, Uganda, where parasite spe- cies was determined by species-specific PCR, 94% of epi- sodes of symptomatic malaria were caused by P. falciparum (including mixed infections), but 4.6% were caused solely by P. malariae, 0.8% were caused solely by P. ovale, and 0.5% were caused solely by P. vivax.9 Thus, in this setting, about 6% of episodes of malaria would be missed by an HRP2- based RDT. Importantly, the landscape of malaria is changing. Aggressive control efforts are leading to marked decreases in the incidence of malaria and prevalence of malarial infection at a number of locations in Africa.10 These efforts may lead to improved control of P. falciparum infection compared with P. ovale and P. vivax infections, because the latter species are not eliminated by most antimalarials because of lack of activ- ity against chronic liver stages. Thus, with improving control, more malaria infections may be caused by non-falciparum parasites, and HRP2-based RDTs may have decreasing sensi- tivity for the diagnosis of malaria. Considering the limitations of RDTs for malaria, what is the appropriate course of action? One response would be to return to reliance on a clinical diagnosis of malaria. This approach might be reasonable in highly endemic areas, where most fevers in children are caused by malaria,11 but it will lead to many inappropriate treatments and will clearly be less desirable in areas with low to moderate or decreasing inci- dence of malaria.12 Another approach will be to rely fully on microscopy and push this diagnostic modality into rural areas with aggressive implementation and training efforts, which has been successful in some areas.13 However, it is unlikely that reliable microscopy can be brought to all areas of rural Africa, whereas RDTs can be used in nearly all clinical set- tings. Therefore, most likely, consistent with WHO guidelines, RDTs will increasingly be used for the diagnosis of malaria in Africa. Which RDT should be used? First, it is important that oversight of test manufacture, care in shipping and storage of tests, and rigorous quality control lead to the consistent avail- ability of high-quality tests. Second, serious consideration of the optimal antigen for RDTs is warranted. The HRP2-based RDT has been considered the best choice for Africa in large part because of its high sensitivity, but increasing prevalence of parasites that do not express HRP2 may challenge this assumption. The sensitivity of HRP2-based RDTs is limited because of their inability to recognize non-falciparum infec- tions, and as described in the work by Koita and others7 in AJTMH, it also may be limited by the circulation of P. falci- parum that does not express HRP2. These results suggest that the optimal RDT for Africa may need to be reconsidered. In particular, additional study of the sensitivity of HRP2-based and other RDTs is needed, and if the prevalence of HRP2- negative P. falciparum parasites or non-falciparum malaria parasites is increasing, the use of RDTs recognizing antigens other than HRP2 may be advisable. Received October 6, 2011. Accepted for publication October 7, 2011. Acknowledgments: The author is supported by grants from the National Institutes of Health and Medicines for Malaria Venture, and he is a Distinguished Clinical Scientist of the Doris Duke Charitable Foundation. Author’s address: Philip J. Rosenthal, Department or Medicine, University of California, San Francisco, CA, E-mail: prosenthal@ medsfgh.ucsf.edu. REFERENCES 1. World Health Organization, 2010. Guidelines for the Treatment of Malaria. Geneva, Switzerland: World Health Organization. 2. Wongsrichanalai C, Barcus MJ, Muth S, Sutamihardja A, Wernsdorfer WH, 2007. A review of malaria diagnostic tools: microscopy and rapid diagnostic test (RDT). Am J Trop Med Hyg 77: 119–127. 3. Murray CK, Gasser RA Jr, Magill AJ, Miller RS, 2008. Update on rapid diagnostic testing for malaria. Clin Microbiol Rev 21: 97–110. 4. Iqbal J, Siddique A, Jameel M, Hira PR, 2004. 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