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Rapid Diagnostic Tests vs. Blood Smears for the Diagnosis of Malaria in the United States
Abstract & Commentary
By Brian G. Blackburn, MD, Clinical Assistant Professor in the Division of Infectious Diseases and Geographic Medicine at Stanford University School of Medicine.
By Michele Barry, MD, FACP, Dr. Barry is the Senior Associate Dean of Global Health at Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
The authors report no financial relationships relevant to this field of study.
This article originally appeared in the December 2009 issue of Travel Medicine Advisor. It was edited by Frank Bia, MD, MPH, and peer reviewed by Mary-Louise Scully, MD. Dr. Bia is Professor (Emeritus) of Internal Medicine (Infectious Disease and Clinical Microbiology), Yale University School of Medicine, and Dr. Scully is Director, Travel and Tropical Medicine Center, Sansum Clinic, Santa Barbara, Calif.; they both report no financial relationships relevant to this field of study.
Synopsis: Malaria rapid diagnostic tests (RDTs) performed very well compared to blood smears for the diagnosis of malaria in returned U.S. travelers. Using PCR as the gold standard, RDTs were 97% sensitive for diagnosing malaria, which was significantly more sensitive than smears. RDTs were 100% sensitive in detecting P. falciparum cases.
Source: Stauffer WM, et al. Diagnostic performance of rapid diagnostic tests versus blood smears for malaria in US clinical practice. Clin Infect Dis 2009;49:908-13.
Malaria is one of the most important diagnostic considerations in febrile returned travelers and can be fatal if not appropriately diagnosed and treated. Although blood smears traditionally have been regarded as the gold standard for the diagnosis of malaria, limitations have included the need for experienced laboratory personnel to properly perform and read the smears. Recently, polymerase chain reaction (PCR) has evolved as a diagnostic tool that may be more sensitive than blood smears, but PCR is neither widely nor rapidly available for point-of-care diagnosis.1
During the past several years, antigen-based rapid diagnostic tests (RDTs) have gained popularity for the diagnosis of malaria, often in field settings where they are particularly useful in obviating the technical requirements of blood smears. In 2007, the Food and Drug Administration approved the first RDT for use in the United States, the Binax Now Malaria Test. This immunochromatographic test detects two antigens: histidine-rich protein 2 (HRP-2), which is present only in Plasmodium falciparum; and Plasmodium aldolase, present in all Plasmodium spp. It, therefore, has the ability to differentiate falciparum malaria from other forms of malaria. In field studies, the test has been most sensitive in detecting P. falciparum and less sensitive for detecting the other malaria species.2-4 The test yields an easily readable result (similar to a pregnancy test) in 15 minutes. Although relatively well studied in the field, little data exist regarding this test in a U.S. diagnostic setting.5-7
The investigators, therefore, undertook a study of the performance of this RDT in the United States. In the study, they included all thick and thin blood smears from three hospitals in Minnesota (March 2003 to February 2006) that were done to evaluate for the presence of malaria; blood samples from these patients also were subjected to the malaria RDT. All positive and discrepant results subsequently were evaluated by malaria PCR, with the latter regarded as the gold standard. The patients were ill returning travelers, most of whom had been visiting friends or relatives.
Among the 95 (11%) PCR-confirmed cases of malaria, out of 852 smears performed, the RDTs were more sensitive than smears for detecting malaria (97% vs. 85%; p = .003), and for detecting the 74 cases of P. falciparum malaria (100% vs. 88%; p = .003). The negative predictive values of the RDTs were 98% and 100% for all cases of malaria and P. falciparum cases, respectively.Parasitemia ranged from < 0.1% to 18%, although more detailed parasitemia data were not presented. The RDT did result in eight (1%) false positives out of the 852 samples tested (all negative by PCR); seven of these eight had been treated recently with antimalarials.
These data demonstrate that in this setting, the sensitivity and negative predictive value of the Binax Now Malaria Test is at least as good as, and possibly better than, blood smears. Although current recommendations indicate that these tests should be used as an adjunct to smears and not as replacements for them, such impressive data have the potential to change clinical practice. Clearly, life-threatening falciparum malaria will be lower on the differential diagnosis if a patient's malaria RDT is negative; this finding has the potential to influence clinical decision-making regarding additional workup, admission, and empiric treatment of such patients. The rapid availability of the results and easy use by personnel without advanced training are attractive qualities, especially in a non-endemic country like the United States, where most centers are not experienced in diagnosing or treating malaria.
Several limitations do apply to these data. This population was mostly non-immune, which most likely means parasitemia was generally higher than in previous field--based trials of this RDT in endemic areas.2-4 This likely explains, at least in part, the increased sensitivity seen in this study, as the RDT is less sensitive for patients with lower parasitemia. Whether the results would be applicable to other patient populations, therefore, is not clear. Unfortunately, only minimal parasitemia data are presented by the authors. Another important limitation is that only a single smear was analyzed for each patient. It is common practice for at least three smears to be examined per patient when malaria is being considered if the initial smears are negative. This possibly would have increased the sensitivity of smears and perhaps even lowered the sensitivity of RDTs if some patients who might have been discovered to have low-level parasitemia by smear were RDT negative. Importantly, smear negative/RDT negative cases were not confirmed to be true negatives by PCR and, thus, low-level malaria infections could have been missed. It is in this group that RDTs perform most poorly, and where better data are needed. It is also important to note that RDTs are less sensitive for non-falciparum malaria. Although the negative predictive value was high in this study for these cases, RDT results should be confirmed by smears or PCRs whenever possible. Lastly, RDTs can remain positive for weeks after clinical malaria resolves, leading to the possibility of false positives, especially after anti-malarial treatment, as demonstrated in this study.
These limitations aside, the data are encouraging and show that this malaria RDT may have an important role in the evaluation of febrile returned travelers in developed countries. A caveat: Travelers in the field have been shown to incorrectly use the RDTs, and self-use should be recommended only after appropriate instruction and training.8