Clinical Question



How sensitive and specific are rapid diagnostic tests (RDTs) for diagnosing Plasmodium vivax and nonfalciparum malaria in endemic areas?



Bottom Line  



Vivax-specific RDTs were highly sensitive and specific when compared with microscopy (the gold standard) for detecting P vivax malaria. RDTs that can only distinguish Plasmodium falciparum from nonfalciparum malaria were less sensitive

Abba, Katharine

Garner, Paul

Takwoingi, Yemesi

LSTM Online Archive

Copyright 2015 American Medical Association. All rights reserved.Rapid Diagnostic Testing for Plasmodium vivaxand NonfalciparumMalaria in Endemic AreasYemisi Takwoingi, DVM; Katharine Abba, MSc; Paul Garner, MDApproximately 40%of theworld's population is at risk for Plasmo-dium vivax malaria.1 Resistance to chloroquine and other anti-malarials is more likely for Plasmodium falciparum than otherPlasmodium species, and spe-cies identification is important toselect appropriate treatment.The gold standard for diagnos-ingmalaria ismicroscopic examinationof thick and thinblood films.However, timely, high-quality microscopy may be unavailable inresource-poor settings. Immunochromatographic rapid diagnostictests (RDTs) are alternatives tomicroscopic diagnosis. Pan-specificRDTs distinguish P falciparum (ormixed) infections from infectionswith only nonfalciparumspecies; differentiationbetweennonfalci-parumspecies (Pvivax fromPlasmodiumovaleandPlasmodiumma-lariae) is notpossible.More recentlydeveloped, vivax-specificRDTscan detect P vivax monoinfection or co-infection. This JAMAClinical Evidence Synopsis summarizes a Cochrane review2 assess-ing the accuracy of RDTs for detecting P vivax and nonfalciparummalaria in endemic countries.Summary of FindingsIn 8 studies of vivax-specific RDTs, involving 3682 participants ofwhom 531 had vivax malaria, sensitivities ranged from 66% to100% and specificities ranged from 98% to 100%. In pooledanalyses, compared with microscopy, vivax-specific RDTs had asensitivity of 95% (95% CI, 86%-99%) and specificity of 99%(95% CI, 99%-100%) (Table). For pan-specific RDTs, the sensi-tivities from individual studies varied from 25% to 100% and hadwide 95% CIs. Specificities varied between 89% and 100% andhad narrow CIs. Where there were sufficient data, we comparedthe accuracy of commercial brands within each type of pan-specific RDT, and there was no association of commercial brandwith superior sensitivity or specificity. The variability and uncer-tainty in sensitivity estimates are probably due to the small num-ber of malaria cases in some studies. The mean specificity of eachof the 3 types of pan-specific RDTs was high (Table), with approxi-mately 1% to 2% of noncases being false-positives when com-pared with microscopy. Conversely, mean sensitivities were low,with false-negative rates for nonfalciparum species between11% and 22%.DiscussionIn P vivax endemic areas, vivax-specific RDTs have higher sensitiv-ity formalaria thanpan-specificRDTs.Pan-specificRDTsmaybeuse-ful in areas where themajority of malaria is caused by P falciparumor mixed infection because they are sensitive for the detection ofP falciparum.3When we updated our search in December 2014, we found 4additional studies that meet the review inclusion criteria. Threeof the studies, with sample sizes of 677 participants,4 1762participants,5 and 200 participants,6 respectively, comparedvivax-specific RDTs with microscopy. Their findings were consis-tent with those for studies included in the published review,although Vyas et al4 found a lower specificity (90%). Inclusion ofthe 3 new studies in an updated meta-analysis of vivax-specificRDTs gave a mean sensitivity of 94% (95% CI, 86%-98%) and amean specificity of 99% (95% CI, 98%-100%), similar to those ofthe original meta-analysis. The fourth new study by Chong et al,7with a sample size of 185 participants assessed a type 3 pan-specific RDT against microscopy and polymerase chain reactionfor detection of nonfalciparum malaria. The study by Chong et alwas consistent with the included studies for type 3 RDTs, and isunlikely to change the conclusions of the review.Related article page 1009CLINICAL QUESTION How sensitive and specific are rapid diagnostic tests (RDTs) fordiagnosing Plasmodium vivax and nonfalciparummalaria in endemic areas?BOTTOM LINE Vivax-specific RDTs were highly sensitive and specific when compared withmicroscopy (the gold standard) for detecting P vivaxmalaria. RDTs that can only distinguishPlasmodium falciparum from nonfalciparummalaria were less sensitive.Evidence ProfileNo. of studies: 37 publications reporting 47 study cohortsStudy years: Conducted, 1998–2011; published, 1999–2013Last search date:December 31, 2013No. of participants: 22 862with symptoms suggestive ofuncomplicatedmalariaMen: 8304 (56%) Women: 6399 (44%); only 34 studies (14 703participants) reported sexRace/ethnicity:UnavailableAge range:0-94 years; 5 studies did not report ageSettings: Ambulatory health care settings in nonfalciparummalaria endemic areasCountries: 18 countries in Asia, Africa, and South AmericaClinical Review& EducationJAMAClinical Evidence Synopsisjama.com (Reprinted) JAMA September 8, 2015 Volume 314, Number 10 1065Downloaded From: http://jama.jamanetwork.com/ by a LIVERPOOL SCHOOL OF TROPICAL MEDICINE User  on 09/17/2015Copyright 2015 American Medical Association. All rights reserved.LimitationsStudy quality and descriptions and reporting of patient character-istics and reference standards were variable. Microscopy is imper-fect, and it is possible that an RDT result may have been accuratein some cases of discordant results between microscopy and RDT.However, studies using polymerase chain reaction as the refer-ence standard gave similar results to those using microscopy.Insufficient data were available to assess the effect of parasitedensity on test accuracy.Comparison of FindingsWith Current Practice GuidelinesTheWorldHealthOrganization recommendsdiagnosisbyeithermi-croscopy or RDT before starting antimalarial treatment.8 Localmalaria epidemiology, geography, resources, and infrastructurewillinfluence the decision to usemicroscopy or an RDT.Areas in Need of Future StudyResearch evaluating clinical algorithms using vivax-specific RDTs inendemic areas is needed.ARTICLE INFORMATIONAuthor Affiliations: Public Health, Epidemiologyand Biostatistics, University of Birmingham, UnitedKingdom (Takwoingi); Department of ClinicalSciences, Liverpool School of Tropical Medicine,United Kingdom (Abba, Garner).Corresponding Author: Yemisi Takwoingi, DVM,Public Health, Epidemiology, and Biostatistics,University of Birmingham, Birmingham B15 2TT,United Kingdom (y.takwoingi@bham.ac.uk).Section Editor:MaryMcGraeMcDermott, MD,Senior Editor.Conflict of Interest Disclosures: All authors havecompleted and submitted the ICMJE Form forDisclosure of Potential Conflicts of Interest.Dr Garner reports receiving grants from theDepartment for International Development (UnitedKingdom) and being amember of theWorld HealthOrganization Technical Expert Panel that writes theglobal guidelines for the treatment of malaria. Thispanel recommended the use of rapid diagnostictests as an option for testing people with suspectedmalaria in the second edition in 2010. No otherdisclosures were reported.Funders/Sponsors: The Cochrane reviewwasfunded by UK Aid (HRPC09 Evidence Building andSynthesis Research, Department for InternationalDevelopment [contract PO 5242]) from the UKgovernment for the benefit of developingcountries.Role of the Funder/Sponsor: The sponsor had norole in the design and conduct of the study;collection, management, analysis, andinterpretation of the data; preparation, review, orapproval of themanuscript; and decision to submitthemanuscript for publication.Submissions:We encourage authors to submitpapers for consideration as a JAMA ClinicalEvidence Synopsis. Please contact Dr McDermott atmdm608@northwestern.edu.REFERENCES1. Price RN, Tjitra E, Guerra CA, Yeung S, White NJ,Anstey NM. Vivax malaria: neglected and notbenign. Am J Trop Med Hyg. 2007;77(6)(suppl):79-87.2. Abba K, Kirkham AJ, Olliaro PL, et al. Rapiddiagnostic tests for diagnosing uncomplicatednonfalciparum or Plasmodium vivaxmalaria inendemic countries. Cochrane Database Syst Rev.2014;12:CD011431.3. Abba K, Deeks JJ, Olliaro P, et al. Rapiddiagnostic tests for diagnosing uncomplicatedP. falciparummalaria in endemic countries.Cochrane Database Syst Rev. 2011;7(7):CD008122.4. Vyas S, Puwar B, Patel V, Bhatt G, Kulkarni S,FancyM. Study on validity of a rapid diagnostic testkit vs light microscopy for malaria diagnosis inAhmedabad city, India. East Mediterr Health J. 2014;20(4):236-241.5. Herrera S, Vallejo AF, Quintero JP,Arévalo-Herrera M, CancinoM, Ferro S. Fieldevaluation of an automated RDT reader and datamanagement device for Plasmodiumfalciparum/Plasmodium vivaxmalaria in endemicareas of Colombia.Malar J. 2014;13:87.6. Satyasi SK, Poosapati RK. A study of evaluationof rapid diagnostic techniques of malaria in urbanslums of Vijayawada, Krishna District, AndhraPradesh, India. Res J Pharm Biol Chem Sci. 2014;5(4):1428-1449. http://www.rjpbcs.com/pdf/2014_5%284%29/%5B161%5D.pdf. Accessed June 18, 2015.7. Chong CK, Cho PY, Na BK, et al. Evaluation of theaccuracy of the EasyTest malaria Pf/Pan Ag, a rapiddiagnostic test, in Uganda. Korean J Parasitol. 2014;52(5):501-505.8. World Health Organization. Guidelines for thetreatment of malaria. http://whqlibdoc.who.int/publications/2010/9789241547925_eng.pdf?ua=1.Accessed February 12, 2015.Table. Summary of Accuracy of Rapid Diagnostic Tests for Diagnosing Plasmodium vivax and NonfalciparumMalariaRDTa RDT Target AntigenNo. ofStudiesMalariaCasesNo. ofParticipantsMedian Prevalence(Range), %Mean Sensitivity(95% CI), %Mean Specificity(95% CI), %RDTs for P vivaxMalaria (With or Without Other Plasmodium Species) Verified by MicroscopyVivax-specific Pf HRP-2 and pLDH-Pv 8 580 3682 19 (2-45) 95 (86-99) 99 (99-100)Pan-Specific RDTs for NonfalciparumMalariaVerified by microscopyType 2 Pf HRP-2 and aldolase 11 958 6879 14 (7-32) 78 (73-82) 99 (97-99)Type 3 Pf HRP-2 and pLDH-pan 23 1537 11234 10 (7-36) 78 (69-84) 99 (98-99)Type 4 pLDH-Pf and pLDH-pan 10 986 3831 27 (8-33) 89 (79-95) 98 (97-99)Verified by PCRType 3 Pf HRP-2 and pLDH-pan 5 300 1639 15 (7-33) 81 (72-88) 99 (97-99)Abbreviations: HRP-2, histidine-rich protein 2; PCR, polymerase chain reaction;Pf, Plasmodium falciparum; pLDH, plasmodium lactate dehydrogenase;Pv, Plasmodium vivax; RDT, rapid diagnostic test.Source: Data adapted from Abba et al, 2014,2 under the terms of the CreativeCommons Attribution Noncommercial license.a RDTs use different types of antibody or antibody combinations to detectPlasmodium antigens. Some antibodies aim to detect a particular specieswhereas others are panmalarial aiming to detect all Plasmodium species.Type 2 and type 3 RDTs use antibodies that detect the HRP-2 antigenexpressed only by P falciparum. Both RDTs also include pan-specificantibodies: type 2 detects aldolase and type 4 detects pLDH from allPlasmodium species. Type 4 RDTs use antibody combinations that detectP falciparum specific pLDH or pLDH from any Plasmodium species. Sevenstudies assessedmore than 1 RDT by giving participants all RDTs(head-to-head comparison).Clinical Review& Education JAMAClinical Evidence Synopsis1066 JAMA September 8, 2015 Volume 314, Number 10 (Reprinted) jama.comDownloaded From: http://jama.jamanetwork.com/ by a LIVERPOOL SCHOOL OF TROPICAL MEDICINE User  on 09/17/2015

Rapid Diagnostic Testing for Plasmodium vivax and Nonfalciparum Malaria in Endemic Areas

Clinical QuestionHow sensitive and specific are rapid diagnostic tests (RDTs) for diagnosing Plasmodium vivax and nonfalciparum malaria in endemic areas?Bottom Line Vivax-specific RDTs were highly sensitive and specific when compared with microscopy (the gold standard) for detecting P vivax malaria. RDTs that can only distinguish Plasmodium falciparum from nonfalciparum malaria were less sensitive.</p

Takwoingi, Yemisi

LSTM Research Portal

Copyright 2015 American Medical Association. All rights reserved.Rapid Diagnostic Testing for Plasmodium vivaxand Nonfalciparum Malaria in Endemic AreasYemisi Takwoingi, DVM; Katharine Abba, MSc; Paul Garner, MDApproximately 40% of the world's population is at risk for Plasmo-dium vivax malaria.1 Resistance to chloroquine and other anti-malarials is more likely for Plasmodium falciparum than otherPlasmodium species, and spe-cies identification is important toselect appropriate treatment.The gold standard for diagnos-ing malaria is microscopic examination of thick and thin blood films.However, timely, high-quality microscopy may be unavailable inresource-poor settings. Immunochromatographic rapid diagnostictests (RDTs) are alternatives to microscopic diagnosis. Pan-specificRDTs distinguish P falciparum (or mixed) infections from infectionswith only nonfalciparum species; differentiation between nonfalci-parum species (P vivax from Plasmodium ovale and Plasmodium ma-lariae) is not possible. More recently developed, vivax-specific RDTscan detect P vivax monoinfection or co-infection. This JAMAClinical Evidence Synopsis summarizes a Cochrane review2 assess-ing the accuracy of RDTs for detecting P vivax and nonfalciparummalaria in endemic countries.Summary of FindingsIn 8 studies of vivax-specific RDTs, involving 3682 participants ofwhom 531 had vivax malaria, sensitivities ranged from 66% to100% and specificities ranged from 98% to 100%. In pooledanalyses, compared with microscopy, vivax-specific RDTs had asensitivity of 95% (95% CI, 86%-99%) and specificity of 99%(95% CI, 99%-100%) (Table). For pan-specific RDTs, the sensi-tivities from individual studies varied from 25% to 100% and hadwide 95% CIs. Specificities varied between 89% and 100% andhad narrow CIs. Where there were sufficient data, we comparedthe accuracy of commercial brands within each type of pan-specific RDT, and there was no association of commercial brandwith superior sensitivity or specificity. The variability and uncer-tainty in sensitivity estimates are probably due to the small num-ber of malaria cases in some studies. The mean specificity of eachof the 3 types of pan-specific RDTs was high (Table), with approxi-mately 1% to 2% of noncases being false-positives when com-pared with microscopy. Conversely, mean sensitivities were low,with false-negative rates for nonfalciparum species between11% and 22%.DiscussionIn P vivax endemic areas, vivax-specific RDTs have higher sensitiv-ity for malaria than pan-specific RDTs. Pan-specific RDTs may be use-ful in areas where the majority of malaria is caused by P falciparumor mixed infection because they are sensitive for the detection ofP falciparum.3When we updated our search in December 2014, we found 4additional studies that meet the review inclusion criteria. Threeof the studies, with sample sizes of 677 participants,4 1762participants,5 and 200 participants,6 respectively, comparedvivax-specific RDTs with microscopy. Their findings were consis-tent with those for studies included in the published review,although Vyas et al4 found a lower specificity (90%). Inclusion ofthe 3 new studies in an updated meta-analysis of vivax-specificRDTs gave a mean sensitivity of 94% (95% CI, 86%-98%) and amean specificity of 99% (95% CI, 98%-100%), similar to those ofthe original meta-analysis. The fourth new study by Chong et al,7with a sample size of 185 participants assessed a type 3 pan-specific RDT against microscopy and polymerase chain reactionfor detection of nonfalciparum malaria. The study by Chong et alwas consistent with the included studies for type 3 RDTs, and isunlikely to change the conclusions of the review.Related article page 1009CLINICAL QUESTION How sensitive and specific are rapid diagnostic tests (RDTs) fordiagnosing Plasmodium vivax and nonfalciparum malaria in endemic areas?BOTTOM LINE Vivax-specific RDTs were highly sensitive and specific when compared withmicroscopy (the gold standard) for detecting P vivax malaria. RDTs that can only distinguishPlasmodium falciparum from nonfalciparum malaria were less sensitive.Evidence ProfileNo. of studies: 37 publications reporting 47 study cohortsStudy years: Conducted, 1998–2011; published, 1999–2013Last search date: December 31, 2013No. of participants: 22 862 with symptoms suggestive ofuncomplicated malariaMen: 8304 (56%) Women: 6399 (44%); only 34 studies (14 703participants) reported sexRace/ethnicity: UnavailableAge range: 0-94 years; 5 studies did not report ageSettings: Ambulatory health care settings in nonfalciparummalaria endemic areasCountries: 18 countries in Asia, Africa, and South AmericaClinical Review & EducationJAMA Clinical Evidence Synopsisjama.com (Reprinted) JAMA September 8, 2015 Volume 314, Number 10 1065Downloaded From: http://jama.jamanetwork.com/ by a LIVERPOOL SCHOOL OF TROPICAL MEDICINE User  on 09/17/2015Copyright 2015 American Medical Association. All rights reserved.LimitationsStudy quality and descriptions and reporting of patient character-istics and reference standards were variable. Microscopy is imper-fect, and it is possible that an RDT result may have been accuratein some cases of discordant results between microscopy and RDT.However, studies using polymerase chain reaction as the refer-ence standard gave similar results to those using microscopy.Insufficient data were available to assess the effect of parasitedensity on test accuracy.Comparison of Findings With Current Practice GuidelinesThe World Health Organization recommends diagnosis by either mi-croscopy or RDT before starting antimalarial treatment.8 Localmalaria epidemiology, geography, resources, and infrastructure willinfluence the decision to use microscopy or an RDT.Areas in Need of Future StudyResearch evaluating clinical algorithms using vivax-specific RDTs inendemic areas is needed.ARTICLE INFORMATIONAuthor Affiliations: Public Health, Epidemiologyand Biostatistics, University of Birmingham, UnitedKingdom (Takwoingi); Department of ClinicalSciences, Liverpool School of Tropical Medicine,United Kingdom (Abba, Garner).Corresponding Author: Yemisi Takwoingi, DVM,Public Health, Epidemiology, and Biostatistics,University of Birmingham, Birmingham B15 2TT,United Kingdom (y.takwoingi@bham.ac.uk).Section Editor: Mary McGrae McDermott, MD,Senior Editor.Conflict of Interest Disclosures: All authors havecompleted and submitted the ICMJE Form forDisclosure of Potential Conflicts of Interest.Dr Garner reports receiving grants from theDepartment for International Development (UnitedKingdom) and being a member of the World HealthOrganization Technical Expert Panel that writes theglobal guidelines for the treatment of malaria. Thispanel recommended the use of rapid diagnostictests as an option for testing people with suspectedmalaria in the second edition in 2010. No otherdisclosures were reported.Funders/Sponsors: The Cochrane review wasfunded by UK Aid (HRPC09 Evidence Building andSynthesis Research, Department for InternationalDevelopment [contract PO 5242]) from the UKgovernment for the benefit of developingcountries.Role of the Funder/Sponsor: The sponsor had norole in the design and conduct of the study;collection, management, analysis, andinterpretation of the data; preparation, review, orapproval of the manuscript; and decision to submitthe manuscript for publication.Submissions: We encourage authors to submitpapers for consideration as a JAMA ClinicalEvidence Synopsis. Please contact Dr McDermott atmdm608@northwestern.edu.REFERENCES1. Price RN, Tjitra E, Guerra CA, Yeung S, White NJ,Anstey NM. Vivax malaria: neglected and notbenign. Am J Trop Med Hyg. 2007;77(6)(suppl):79-87.2. Abba K, Kirkham AJ, Olliaro PL, et al. Rapiddiagnostic tests for diagnosing uncomplicatednonfalciparum or Plasmodium vivax malaria inendemic countries. Cochrane Database Syst Rev.2014;12:CD011431.3. Abba K, Deeks JJ, Olliaro P, et al. Rapiddiagnostic tests for diagnosing uncomplicatedP. falciparum malaria in endemic countries.Cochrane Database Syst Rev. 2011;7(7):CD008122.4. Vyas S, Puwar B, Patel V, Bhatt G, Kulkarni S,Fancy M. Study on validity of a rapid diagnostic testkit vs light microscopy for malaria diagnosis inAhmedabad city, India. East Mediterr Health J. 2014;20(4):236-241.5. Herrera S, Vallejo AF, Quintero JP,Arévalo-Herrera M, Cancino M, Ferro S. Fieldevaluation of an automated RDT reader and datamanagement device for Plasmodiumfalciparum/Plasmodium vivax malaria in endemicareas of Colombia. Malar J. 2014;13:87.6. Satyasi SK, Poosapati RK. A study of evaluationof rapid diagnostic techniques of malaria in urbanslums of Vijayawada, Krishna District, AndhraPradesh, India. Res J Pharm Biol Chem Sci. 2014;5(4):1428-1449. http://www.rjpbcs.com/pdf/2014_5%284%29/%5B161%5D.pdf. Accessed June 18, 2015.7. Chong CK, Cho PY, Na BK, et al. Evaluation of theaccuracy of the EasyTest malaria Pf/Pan Ag, a rapiddiagnostic test, in Uganda. Korean J Parasitol. 2014;52(5):501-505.8. World Health Organization. Guidelines for thetreatment of malaria. http://whqlibdoc.who.int/publications/2010/9789241547925_eng.pdf?ua=1.Accessed February 12, 2015.Table. Summary of Accuracy of Rapid Diagnostic Tests for Diagnosing Plasmodium vivax and Nonfalciparum MalariaRDTa RDT Target AntigenNo. ofStudiesMalariaCasesNo. ofParticipantsMedian Prevalence(Range), %Mean Sensitivity(95% CI), %Mean Specificity(95% CI), %RDTs for P vivax Malaria (With or Without Other Plasmodium Species) Verified by MicroscopyVivax-specific Pf HRP-2 and pLDH-Pv 8 580 3682 19 (2-45) 95 (86-99) 99 (99-100)Pan-Specific RDTs for Nonfalciparum MalariaVerified by microscopyType 2 Pf HRP-2 and aldolase 11 958 6879 14 (7-32) 78 (73-82) 99 (97-99)Type 3 Pf HRP-2 and pLDH-pan 23 1537 11 234 10 (7-36) 78 (69-84) 99 (98-99)Type 4 pLDH-Pf and pLDH-pan 10 986 3831 27 (8-33) 89 (79-95) 98 (97-99)Verified by PCRType 3 Pf HRP-2 and pLDH-pan 5 300 1639 15 (7-33) 81 (72-88) 99 (97-99)Abbreviations: HRP-2, histidine-rich protein 2; PCR, polymerase chain reaction;Pf, Plasmodium falciparum; pLDH, plasmodium lactate dehydrogenase;Pv, Plasmodium vivax; RDT, rapid diagnostic test.Source: Data adapted from Abba et al, 2014,2 under the terms of the CreativeCommons Attribution Noncommercial license.a RDTs use different types of antibody or antibody combinations to detectPlasmodium antigens. Some antibodies aim to detect a particular specieswhereas others are panmalarial aiming to detect all Plasmodium species.Type 2 and type 3 RDTs use antibodies that detect the HRP-2 antigenexpressed only by P falciparum. Both RDTs also include pan-specificantibodies: type 2 detects aldolase and type 4 detects pLDH from allPlasmodium species. Type 4 RDTs use antibody combinations that detectP falciparum specific pLDH or pLDH from any Plasmodium species. Sevenstudies assessed more than 1 RDT by giving participants all RDTs(head-to-head comparison).Clinical Review & Education JAMA Clinical Evidence Synopsis1066 JAMA September 8, 2015 Volume 314, Number 10 (Reprinted) jama.comDownloaded From: http://jama.jamanetwork.com/ by a LIVERPOOL SCHOOL OF TROPICAL MEDICINE User  on 09/17/2015

English

Yemisi Takwoingi

Katharine Abba

Paul Garner

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JAMA

Rapid Diagnostic Testing for<i>Plasmodium vivax</i>and Nonfalciparum Malaria in Endemic Areas

https://research.lstmed.ac.uk/ws/files/22148438/JAMA_314_10_1065-1066.pdf

Rapid Diagnostic Testing for Plasmodium vivax and Nonfalciparum Malaria in Endemic Areas

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