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

Matthew Grigg, Timothy Williams, Bridget Barber, Uma Parameswaran, Elspeth Bird, Kim Piera, Ammar Aziz, Prabakaran Dhanaraj, Tsin Yeo, Nicholas Anstey

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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. 
Original languageEnglish
Pages (from-to)2053-2060
Number of pages8
JournalJournal of Clinical Microbiology
Volume52
Issue number6
DOIs
Publication statusPublished - Jun 2014

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Plasmodium knowlesi
Plasmodium
Malaysia
L-Lactate Dehydrogenase
Malaria
Parasites
Confidence Intervals
Routine Diagnostic Tests
Plasmodium malariae
histidine-rich proteins

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@article{f579c59af2314b0c8cf06702b737917b,
title = "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",
abstract = "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. ",
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author = "Matthew Grigg and Timothy Williams and Bridget Barber and Uma Parameswaran and Elspeth Bird and Kim Piera and Ammar Aziz and Prabakaran Dhanaraj and Tsin Yeo and Nicholas Anstey",
year = "2014",
month = "6",
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language = "English",
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pages = "2053--2060",
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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. / Grigg, Matthew; Williams, Timothy; Barber, Bridget; Parameswaran, Uma; Bird, Elspeth; Piera, Kim; Aziz, Ammar; Dhanaraj, Prabakaran; Yeo, Tsin; Anstey, Nicholas.

In: Journal of Clinical Microbiology, Vol. 52, No. 6, 06.2014, p. 2053-2060.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - 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

AU - Grigg, Matthew

AU - Williams, Timothy

AU - Barber, Bridget

AU - Parameswaran, Uma

AU - Bird, Elspeth

AU - Piera, Kim

AU - Aziz, Ammar

AU - Dhanaraj, Prabakaran

AU - Yeo, Tsin

AU - Anstey, Nicholas

PY - 2014/6

Y1 - 2014/6

N2 - 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. 

AB - 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. 

KW - histidine rich protein 2

KW - lactate dehydrogenase

KW - parasite antigen

KW - unclassified drug

KW - HRP-2 antigen, Plasmodium falciparum

KW - monoclonal antibody

KW - protozoal protein

KW - adult

KW - article

KW - clinical feature

KW - controlled study

KW - cross reaction

KW - diagnostic test accuracy study

KW - diagnostic value

KW - disease severity

KW - female

KW - human

KW - intermethod comparison

KW - major clinical study

KW - malaria falciparum

KW - Malaysia

KW - male

KW - microscopy

KW - nonhuman

KW - parasite identification

KW - parasitemia

KW - Plasmodium falciparum

KW - Plasmodium knowlesi

KW - Plasmodium knowlesi malaria

KW - Plasmodium vivax

KW - Plasmodium vivax malaria

KW - priority journal

KW - prospective study

KW - rapid test

KW - sensitivity and specificity

KW - validation process

KW - adolescent

KW - aged

KW - animal

KW - chemistry

KW - child

KW - clinical trial

KW - comparative study

KW - evaluation study

KW - hospital information system

KW - immunoassay

KW - isolation and purification

KW - malaria

KW - middle aged

KW - multicenter study

KW - Plasmodium

KW - preschool child

KW - procedures

KW - very elderly

KW - young adult

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Animals

KW - Antibodies, Monoclonal

KW - Antigens, Protozoan

KW - Child

KW - Child, Preschool

KW - Cross Reactions

KW - Female

KW - Humans

KW - Immunoassay

KW - L-Lactate Dehydrogenase

KW - Malaria

KW - Male

KW - Middle Aged

KW - Point-of-Care Systems

KW - Prospective Studies

KW - Protozoan Proteins

KW - Sensitivity and Specificity

KW - Young Adult

UR - http://www.scopus.com/inward/record.url?scp=84901659794&partnerID=8YFLogxK

U2 - 10.1128/JCM.00181-14

DO - 10.1128/JCM.00181-14

M3 - Article

VL - 52

SP - 2053

EP - 2060

JO - Journal of Clinical Microbiology

JF - Journal of Clinical Microbiology

SN - 0095-1137

IS - 6

ER -