Combining parasite lactate dehydrogenase-based and histidine-rich protein 2-based rapid tests to improve specificity for diagnosis of malaria Due to Plasmodium knowlesi and other Plasmodium species in Sabah, Malaysia.
Plasmodium knowlesi causes severe and fatal malaria in Malaysia. Microscopic misdiagnosis is common and may delay appropriate treatment. P. knowlesi can cross-react with "species-specific" parasite lactate dehydrogenase (pLDH) monoclonal antibodies used in rapid diagnostic tests (RDTs) to detect P. falciparum and P. vivax. At one tertiary-care hospital and two district hospitals in Sabah, we prospectively evaluated two combination RDTs for malaria diagnosis by using both a pan-Plasmodium-pLDH (pan-pLDH)/P. falciparum-specific-pLDH (Pf-pLDH) RDT (OptiMAL-IT) and a non-P. falciparum VOM-pLDH/Pf-HRP2 RDT (CareStart). Differential cross-reactivity among these combinations was hypothesized to differentiate P. knowlesi from other Plasmodium monoinfections. Among 323 patients with PCR-confirmed P. knowlesi (n = 193), P. falciparum (n = 93), and P. vivax (n = 37) monoinfections, the VOM-pLDH individual component had the highest sensitivity for nonsevere (35%; 95% confidence interval [CI], 27 to 43%) and severe (92%; CI, 81 to 100%) P. knowlesi malaria. CareStart demonstrated a P. knowlesi sensitivity of 42% (CI, 34 to 49%) and specificity of 74% (CI, 65 to 82%), a P. vivax sensitivity of 83% (CI, 66 to 93%) and specificity of 71% (CI, 65 to 76%), and a P. falciparum sensitivity of 97% (CI, 90 to 99%) and specificity of 99% (CI, 97 to 100%). OptiMAL-IT demonstrated a P. knowlesi sensitivity of 32% (CI, 25 to 39%) and specificity of 21% (CI, 15 to 29%), a P. vivax sensitivity of 60% (CI, 42 to 75%) and specificity of 97% (CI, 94 to 99%), and a P. falciparum sensitivity of 82% (CI, 72 to 89%) and specificity of 39% (CI, 33 to 46%). The combination of CareStart plus OptiMAL-IT for P. knowlesi using predefined criteria gave a sensitivity of 25% (CI, 19 to 32%) and specificity of 97% (CI, 92 to 99%). Combining two RDT combinations was highly specific for P. knowlesi malaria diagnosis; however, sensitivity was poor. The specificity of pLDH RDTs was decreased for P. vivax and P. falciparum because of P. knowlesi cross-reactivity and cautions against their use alone in areas where P. knowlesi malaria is endemic. Sensitive P. knowlesi-specific RDTs and/or alternative molecular diagnostic tools are needed in areas where P. knowlesi malaria is endemic.
Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia Infectious Disease Unit, Clinical Research Centre, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia mat_grigg@hotmail.com.
Matthew J
MJ
Grigg
Infectious Disease Unit, Clinical Research Centre, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia Sabah Department of Health, Kota Kinabalu, Sabah, Malaysia.
Timothy
T
William
Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia Infectious Disease Unit, Clinical Research Centre, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia.
Bridget E
BE
Barber
Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia Infectious Disease Unit, Clinical Research Centre, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia.
Uma
U
Parameswaran
Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia.
Elspeth
E
Bird
Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia.
Kim
K
Piera
Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia.
Ammar
A
Aziz
Sabah Department of Health, Kota Kinabalu, Sabah, Malaysia Kudat District Hospital, Kudat, Sabah, Malaysia.
Prabakaran
P
Dhanaraj
Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
Tsin W
TW
Yeo
Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia Royal Darwin Hospital, Darwin, Northern Territory, Australia.
Nicholas M
NM
Anstey
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal; D000953:Antigens, Protozoan / Q000032:analysis*; D002648:Child; D002675:Child, Preschool; D003429:Cross Reactions; D005260:Female; D006801:Humans; D007118:Immunoassay / Q000379:methods; D007770:L-Lactate Dehydrogenase / Q000032:analysis*; D008288:Malaria / Q000175:diagnosis*; D008296:Malaysia; D008297:Male; D008875:Middle Aged; D010961:Plasmodium / Q000737:chemistry / Q000302:isolation & purification*; D019095:Point-of-Care Systems; D011446:Prospective Studies; D015800:Protozoan Proteins / Q000032:analysis*; D012680:Sensitivity and Specificity; D055815:Young Adult
D000911:Antibodies, Monoclonal; D000953:Antigens, Protozoan; C514457:HRP-2 antigen, Plasmodium falciparum; D015800:Protozoan Proteins; D007770:L-Lactate Dehydrogenase