Rapid diagnostic tests for diagnosing uncomplicated P. falciparum malaria in endemic countries

Abstract

Background: Rapid diagnostic tests (RDTs) for Plasmodium falciparum malaria use antibodies to detect either HRP-2 antigen or pLDH antigen, and can improve access to diagnostics in developing countries.

Objectives: To assess the diagnostic accuracy of RDTs for detecting P. falciparum parasitaemia in persons living in endemic areas who present to ambulatory healthcare facilities with symptoms suggestive of malaria by type and brand.

Search strategy: We undertook a comprehensive search of the following databases: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; MEDION; Science Citation Index; Web of Knowledge; African Index Medicus; LILACS; IndMED; to January 14, 2010.

Selection criteria: Studies comparing RDTs with a reference standard (microscopy or polymerase chain reaction) in blood samples from a random or consecutive series of patients attending ambulatory health facilities with symptoms suggestive of malaria in P. falciparum endemic areas.

Data collection and analysis: For each study, a standard set of data was extracted independently by two authors, using a tailored data extraction form. Comparisons were grouped hierarchically by target antigen, and type and brand of RDT, and combined in meta-analysis where appropriate.

Main results: We identified 74 unique studies as eligible for this review and categorized them according to the antigens they detected. Types 1 to 3 include HRP-2 (from P. falciparum) either by itself or with other antigens. Types 4 and 5 included pLDH (from P. falciparum) either by itself or with other antigens. In comparisons with microscopy, we identified 71 evaluations of Type 1 tests, eight evaluations of Type 2 tests and five evaluations of Type 3 tests. In meta-analyses, average sensitivities and specificities (95% CI) were 94.8% (93.1% to 96.1%) and 95.2% (93.2% to 96.7%) for Type 1 tests, 96.0% (94.0% to 97.3%) and 95.3% (87.3% to 98.3%) for Type 2 tests, and 99.5% (71.0% to 100.0%) and 90.6% (80.5% to 95.7%) for Type 3 tests, respectively. Overall for HRP-2, the meta-analytical average sensitivity and specificity (95% CI) were 95.0% (93.5% to 96.2%) and 95.2% (93.4% to 99.4%), respectively. For pLDH antibody-based RDTs verified with microscopy, we identified 17 evaluations of Type 4 RDTs and three evaluations of Type 5 RDTs. In meta-analyses, average sensitivity for Type 4 tests was 91.5% (84.7% to 95.3%) and average specificity was 98.7% (96.9% to 99.5%). For Type 5 tests, average sensitivity was 98.4% (95.1% to 99.5%) and average specificity was 97.5% (93.5% to 99.1%). Overall for pLDH, the meta-analytical average sensitivity and specificity (95% CI) were 93.2% (88.0% to 96.2%) and 98.5% (96.7% to 99.4%), respectively. For both categories of test, there was substantial heterogeneity in study results. Quality of the microscopy reference standard could only be assessed in 40% of studies due to inadequate reporting, but results did not seem to be influenced by the reporting quality.Overall, HRP-2 antibody-based tests (such as the Type 1 tests) tended to be more sensitive and were significantly less specific than pLDH-based tests (such as the Type 4 tests). If the point estimates for Type 1 and Type 4 tests are applied to a hypothetical cohort of 1000 patients where 30% of those presenting with symptoms have P. falciparum, Type 1 tests will miss 16 cases, and Type 4 tests will miss 26 cases. The number of people wrongly diagnosed with P. falciparum would be 34 with Type 1 tests, and nine with Type 4 tests.

Authors' conclusions: The sensitivity and specificity of all RDTs is such that they can replace or extend the access of diagnostic services for uncomplicated P. falciparum malaria. HRP-2 antibody types may be more sensitive but are less specific than pLDH antibody-based tests, but the differences are small. The HRP-2 antigen persists even after effective treatment and so is not useful for detecting treatment failures.

1

Example map showing P. falciparum malaria endemicities and study locations

2

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

3

Study results of Type 1 RDTs plotted in ROC space (by RDT brand)

4

Forest plot of study results of Type 2, 3 and 5 RDTs (by RDT brand)

5

Study results of Type 4 RDTs plotted in ROC space (by RDT brand)

6

Summary ROC Plot comparing different RDT types verified with microscopy (points are meta‐analytical estimates, regions are 95% confidence regions, no regions could be computed for Type 2 and 5 due to small numbers of studies)

7

Summary ROC Plot comparing HRP‐2‐based and pLDH‐based RDTs across all studies verified with microscopy (points are meta‐analytical estimates, regions are 95% confidence regions)

8

Summary estimates of Type 1 RDTs plotted in ROC space (by RDT brand)

9

Summary estimates of Type 4 RDTs plotted in ROC space (by RDT brand)

10

Study results of Type 2, 3 and 5 RDTs plotted in ROC space (by RDT brand)

11

Summary estimates of Type 2 RDTs and study results plotted in ROC space (by RDT brand)

12

Summary estimates of Type 3 RDTs and study results plotted in ROC space

13

Summary estimates of Type 5 RDTs and study results plotted in ROC space

14

Paired comparison of Type 1 and Type 4 RDTs. Connecting lines link the direct comparison of pairs of tests in each study.

15

Paired comparison of HRP‐2‐based tests and pLDH‐based tests. Connecting lines link the direct comparison of pairs of tests in each study.

1. Test

Paracheck‐Pf.

2. Test

ParaSight‐F.

3. Test

ICT Malaria Pf.

4. Test

ParaHIT‐F.

5. Test

PATH.

6. Test

Determine Malaria Pf.

7. Test

Rapid Test Malaria.

8. Test

Diaspot Malaria.

9. Test

New Pf‐1 mini.

10. Test

Hexagon Malaria.

11. Test

Type 1 (All).

12. Test

CareStart Malaria Pf/Pan.

13. Test

ICT Malaria Pf/Pv.

14. Test

NOW malaria ICT.

15. Test

Type 2 (All).

16. Test

SD Malaria Antigen Bioline.

17. Test

First Response Malaria.

18. Test

OptiMAL/ OptiMAL 48.

19. Test

Parascreen.

20. Test

Type 3 (All).

21. Test

OptiMAL‐IT.

22. Test

Parabank.

23. Test

Type 4 (All).

24. Test

Carestart Pf/Pv.

25. Test

ParaSight Pf/Pv.

26. Test

Type 5 (All).

27. Test

HRP‐2 based tests.

28. Test

pLDH based tests.

29. Test

Type 1 (paired comparison with Type 4).

30. Test

Type 4 (paired comparison with Type 1).

31. Test

PCR adjusted microscopy, Type 1, Paracheck‐PF (All).

32. Test

PCR adjusted microscopy, Type 4, Parabank (All).

33. Test

PCR, Type 1, ParaSight‐F.

34. Test

PCR, Type 1, ParaHIT‐F.

35. Test

PCR, Type 1 (All).

36. Test

PCR, Type 3, SD Malaria Antigen (All).

37. Test

HRP‐2 based tests paired data.

38. Test

pLDH based tests paired data.

71. Test

PCR, Type 6, PALUTOP (All).

72. Test

PCR, Type 4, OptiMAL‐IT (All).