Limitations of rapid diagnostic testing in patients with suspected malaria

A diagnostic accuracy evaluation from Swaziland, a low-endemicity country aiming for malaria elimination

Nikhil Ranadive, Simon Kunene, Sarah Darteh, Nyasatu Ntshalintshali, Nomcebo Nhlabathi, Nomcebo Dlamini, Stanley Chitundu, Manik Saini, Maxwell Murphy, Adam Soble, Alanna Schwartz, Bryan Greenhouse, Michelle S. Hsiang

Research output: Contribution to journalArticle

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Abstract

Background. The performance of Plasmodium falciparum-specific histidine-rich protein 2-based rapid diagnostic tests (RDTs) to evaluate suspected malaria in low-endemicity settings has not been well characterized. Methods. Using dried blood spot samples from patients with suspected malaria at 37 health facilities from 2012 to 2014 in the low-endemicity country of Swaziland, we investigated the diagnostic accuracy of histidine-rich protein 2-based RDTs using qualitative polymerase chain reaction (PCR) (nested PCR targeting the cytochrome b gene) and quantitative PCR as reference standards. To explore reasons for false-negative and/or false-positive results, we used pfhrp2/3-specific PCR and logistic regression analyses of potentially associated epidemiological factors. Results. From 1353 patients, 93.0% of RDT-positive (n = 185) and 31.2% of RDT-negative samples (n = 340) were available and selected for testing. Compared with nested PCR, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of RDTs were 51.7%, 94.1%, 67.3%, and 89.1%, respectively. After exclusion of samples with parasite densities <100/ μL, which accounted for 75.7% of false-negative results and 33.3% of PCR-detectable infections, the sensitivity, specificity, PPV, and NPV were 78.8%, 93.7%, 62.3%, and 97.1%. Deletions of pfhrp2 were not detected. False-positivity was more likely during the second year and was not associated with demographics, recent malaria, health facility testing characteristics, or potential DNA degradation. Conclusions. In the low-transmission setting of Swaziland, we demonstrated low sensitivity of RDT for malaria diagnosis, owing to an unexpectedly high proportion of low-density infection among symptomatic subjects. The PPV was also low, requiring further investigation. A more accurate point-of-care diagnostic may be needed to support malaria elimination efforts.

Original languageEnglish (US)
Pages (from-to)1221-1227
Number of pages7
JournalClinical Infectious Diseases
Volume64
Issue number9
DOIs
StatePublished - 2017

Fingerprint

Swaziland
Routine Diagnostic Tests
Malaria
Polymerase Chain Reaction
Health Facilities
Point-of-Care Systems
Sensitivity and Specificity
Cytochromes b
Plasmodium falciparum
Infection
Parasites
Logistic Models
Regression Analysis
Demography
DNA

Keywords

  • Diagnostic accuracy
  • Low transmission
  • Malaria
  • Rapid Diagnostic Test
  • Subpatent infection

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

Cite this

Limitations of rapid diagnostic testing in patients with suspected malaria : A diagnostic accuracy evaluation from Swaziland, a low-endemicity country aiming for malaria elimination. / Ranadive, Nikhil; Kunene, Simon; Darteh, Sarah; Ntshalintshali, Nyasatu; Nhlabathi, Nomcebo; Dlamini, Nomcebo; Chitundu, Stanley; Saini, Manik; Murphy, Maxwell; Soble, Adam; Schwartz, Alanna; Greenhouse, Bryan; Hsiang, Michelle S.

In: Clinical Infectious Diseases, Vol. 64, No. 9, 2017, p. 1221-1227.

Research output: Contribution to journalArticle

Ranadive, N, Kunene, S, Darteh, S, Ntshalintshali, N, Nhlabathi, N, Dlamini, N, Chitundu, S, Saini, M, Murphy, M, Soble, A, Schwartz, A, Greenhouse, B & Hsiang, MS 2017, 'Limitations of rapid diagnostic testing in patients with suspected malaria: A diagnostic accuracy evaluation from Swaziland, a low-endemicity country aiming for malaria elimination', Clinical Infectious Diseases, vol. 64, no. 9, pp. 1221-1227. https://doi.org/10.1093/cid/cix131
Ranadive, Nikhil ; Kunene, Simon ; Darteh, Sarah ; Ntshalintshali, Nyasatu ; Nhlabathi, Nomcebo ; Dlamini, Nomcebo ; Chitundu, Stanley ; Saini, Manik ; Murphy, Maxwell ; Soble, Adam ; Schwartz, Alanna ; Greenhouse, Bryan ; Hsiang, Michelle S. / Limitations of rapid diagnostic testing in patients with suspected malaria : A diagnostic accuracy evaluation from Swaziland, a low-endemicity country aiming for malaria elimination. In: Clinical Infectious Diseases. 2017 ; Vol. 64, No. 9. pp. 1221-1227.
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abstract = "Background. The performance of Plasmodium falciparum-specific histidine-rich protein 2-based rapid diagnostic tests (RDTs) to evaluate suspected malaria in low-endemicity settings has not been well characterized. Methods. Using dried blood spot samples from patients with suspected malaria at 37 health facilities from 2012 to 2014 in the low-endemicity country of Swaziland, we investigated the diagnostic accuracy of histidine-rich protein 2-based RDTs using qualitative polymerase chain reaction (PCR) (nested PCR targeting the cytochrome b gene) and quantitative PCR as reference standards. To explore reasons for false-negative and/or false-positive results, we used pfhrp2/3-specific PCR and logistic regression analyses of potentially associated epidemiological factors. Results. From 1353 patients, 93.0{\%} of RDT-positive (n = 185) and 31.2{\%} of RDT-negative samples (n = 340) were available and selected for testing. Compared with nested PCR, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of RDTs were 51.7{\%}, 94.1{\%}, 67.3{\%}, and 89.1{\%}, respectively. After exclusion of samples with parasite densities <100/ μL, which accounted for 75.7{\%} of false-negative results and 33.3{\%} of PCR-detectable infections, the sensitivity, specificity, PPV, and NPV were 78.8{\%}, 93.7{\%}, 62.3{\%}, and 97.1{\%}. Deletions of pfhrp2 were not detected. False-positivity was more likely during the second year and was not associated with demographics, recent malaria, health facility testing characteristics, or potential DNA degradation. Conclusions. In the low-transmission setting of Swaziland, we demonstrated low sensitivity of RDT for malaria diagnosis, owing to an unexpectedly high proportion of low-density infection among symptomatic subjects. The PPV was also low, requiring further investigation. A more accurate point-of-care diagnostic may be needed to support malaria elimination efforts.",
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AU - Kunene, Simon

AU - Darteh, Sarah

AU - Ntshalintshali, Nyasatu

AU - Nhlabathi, Nomcebo

AU - Dlamini, Nomcebo

AU - Chitundu, Stanley

AU - Saini, Manik

AU - Murphy, Maxwell

AU - Soble, Adam

AU - Schwartz, Alanna

AU - Greenhouse, Bryan

AU - Hsiang, Michelle S.

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N2 - Background. The performance of Plasmodium falciparum-specific histidine-rich protein 2-based rapid diagnostic tests (RDTs) to evaluate suspected malaria in low-endemicity settings has not been well characterized. Methods. Using dried blood spot samples from patients with suspected malaria at 37 health facilities from 2012 to 2014 in the low-endemicity country of Swaziland, we investigated the diagnostic accuracy of histidine-rich protein 2-based RDTs using qualitative polymerase chain reaction (PCR) (nested PCR targeting the cytochrome b gene) and quantitative PCR as reference standards. To explore reasons for false-negative and/or false-positive results, we used pfhrp2/3-specific PCR and logistic regression analyses of potentially associated epidemiological factors. Results. From 1353 patients, 93.0% of RDT-positive (n = 185) and 31.2% of RDT-negative samples (n = 340) were available and selected for testing. Compared with nested PCR, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of RDTs were 51.7%, 94.1%, 67.3%, and 89.1%, respectively. After exclusion of samples with parasite densities <100/ μL, which accounted for 75.7% of false-negative results and 33.3% of PCR-detectable infections, the sensitivity, specificity, PPV, and NPV were 78.8%, 93.7%, 62.3%, and 97.1%. Deletions of pfhrp2 were not detected. False-positivity was more likely during the second year and was not associated with demographics, recent malaria, health facility testing characteristics, or potential DNA degradation. Conclusions. In the low-transmission setting of Swaziland, we demonstrated low sensitivity of RDT for malaria diagnosis, owing to an unexpectedly high proportion of low-density infection among symptomatic subjects. The PPV was also low, requiring further investigation. A more accurate point-of-care diagnostic may be needed to support malaria elimination efforts.

AB - Background. The performance of Plasmodium falciparum-specific histidine-rich protein 2-based rapid diagnostic tests (RDTs) to evaluate suspected malaria in low-endemicity settings has not been well characterized. Methods. Using dried blood spot samples from patients with suspected malaria at 37 health facilities from 2012 to 2014 in the low-endemicity country of Swaziland, we investigated the diagnostic accuracy of histidine-rich protein 2-based RDTs using qualitative polymerase chain reaction (PCR) (nested PCR targeting the cytochrome b gene) and quantitative PCR as reference standards. To explore reasons for false-negative and/or false-positive results, we used pfhrp2/3-specific PCR and logistic regression analyses of potentially associated epidemiological factors. Results. From 1353 patients, 93.0% of RDT-positive (n = 185) and 31.2% of RDT-negative samples (n = 340) were available and selected for testing. Compared with nested PCR, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of RDTs were 51.7%, 94.1%, 67.3%, and 89.1%, respectively. After exclusion of samples with parasite densities <100/ μL, which accounted for 75.7% of false-negative results and 33.3% of PCR-detectable infections, the sensitivity, specificity, PPV, and NPV were 78.8%, 93.7%, 62.3%, and 97.1%. Deletions of pfhrp2 were not detected. False-positivity was more likely during the second year and was not associated with demographics, recent malaria, health facility testing characteristics, or potential DNA degradation. Conclusions. In the low-transmission setting of Swaziland, we demonstrated low sensitivity of RDT for malaria diagnosis, owing to an unexpectedly high proportion of low-density infection among symptomatic subjects. The PPV was also low, requiring further investigation. A more accurate point-of-care diagnostic may be needed to support malaria elimination efforts.

KW - Diagnostic accuracy

KW - Low transmission

KW - Malaria

KW - Rapid Diagnostic Test

KW - Subpatent infection

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