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Journal of Tropical Pediatrics Advance Access originally published online on August 30, 2006
Journal of Tropical Pediatrics 2006 52(6):386-389; doi:10.1093/tropej/fml037
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© The Author [2006]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Clinical Review

Evidence Behind the WHO Guidelines: Hospital Care for Children: What is the Precision of Rapid Diagnostic Tests for Malaria?

Primary Reviewer: Allen Cheng

Menzies School of Health Research, Charles Darwin University, Australia

Secondary Reviewer: David Bell

World Health Organization Regional Office for the Western Pacific, Manila, Philippines

Correspondence: Allen Cheng, 4th Floor, Clinical Sciences Building, Royal Melbourne Hospital, Royal Parade, Parkville, Vic. 3050, Melbourne, Australia. E-mail < allenc{at}menzies.edu.au>.

The World Health Organization (WHO) has produced guidelines for the management of common illnesses in hospitals with limited resources. This series reviews the scientific evidence behind WHO's recommendations. The WHO guidelines, and more reviews are available at: http://www.ichrc.org

This review addresses the question: What is the precision of rapid diagnostic tests for malaria?

The WHO Pocketbook of Hospital Care for Children recommends preparation of blood smears for parasites as the investigation in suspected malaria. No mention of the rapid diagnostic testing (RDT) is made in the current edition.


   Introduction
Top
 Introduction
Methodology
 Results
 Recommendations
 References
 
Rapid immunochromogenic tests, in simple kit form, can provide results based on fingerprick or venous blood within minutes. They can be used by village health workers after as little as an hour of training [1]. Assays are based on the capture of parasite antigen by monoclonal antibodies incorporated into a test strip. Three types of antigens are targeted: parasite lactate dehydrogenase (pLDH), histidine-rich protein 2 (HRP-2, found in Plasmodium falciparum only) and aldolase (pan-malarial antigen, found in all malarial species). HRP-2 or P falciparum-specific pLDH assays are often combined with pan-specific pLDH or aldolase antigen assays in tests that can differentiate falciparum malaria (if the HRP-2 and pan-specific bands are positive) from non-falciparum malaria (if the pan-specific band only is positive). Some tests include pLDH antibodies for P. vivax-specific pLDH. A list of about 20 manufacturers of commercially available rapid tests with evidence of good manufacturing practice is available at the Western Pacific Regional Office website [2].


   Methodology
Top
 Introduction
 Methodology
Results
 Recommendations
 References
 
For this review, 145 studies were identified from the following sources:

  • PubMed [National Library of Medicine (NLM)/National Institutes of Health (NIH)] using the search strategy (rapid malaria) AND (specificity[Title/Abstract]) based on the work of Haynes and Wilczynski [3].
  • A WHO database of published reviews and trials of malarial RDTs (WPRO http://www.wpro.who.int/sites/rdt/reviews_trials/).
  • Reviews of malarial RDTs [4–7].


   Results
Top
 Introduction
 Methodology
 Results
Recommendations
 References
 
How sensitive and specific are malarial rapid diagnostic tests?
Studies of RDTs have demonstrated widely varying sensitivity, ranging from poor to 100%. Specificity has generally been good in most studies. It is difficult to compare studies due to different test manufacturers, possible batch-to-batch variation [8], possible geographic variation in malarial antigens [7], varying environmental conditions [9], varying proportions of pre-treated patients, differing gold standards [polymerase chain reaction (PCR) or microscopy], differing parasite densities, malarial species in disparate populations and inadequacies in study design and reporting.

In general, field studies in endemic countries have reported lower sensitivity, possibly related to assay degradation in hot and humid conditions or batch variability [8], and differing parasite densities in endemic populations compared with non-immune, traveller populations. Unpublished evidence suggests that HRP-2-based assays are more stable than pLDH or aldolase-based assays [7], although newer pLDH-based tests may have improved stability [9]. Sensitivity was also lower in low-level parasitaemia (<500–1000/µl) [8, 10–13], pregnancy (with lower parasitaemia related to placental sequestration) [14], non-falciparum malaria [15], pre-treated patients (particularly with the pLDH assay which closely correlates with parasitaemia) [16, 17] and the use of PCR (compared with microscopy) as the gold standard [18].

What are the differences between the tests?
Generally, HRP2-based assays appear to be more sensitive than falciparum-specific pLDH RDT [8, 12, 13, 18–25]. This is supported by a systematic review of rapid tests in returned travellers [5]. Published data also indicates that the pLDH-based OptiMAL assay appears to be more sensitive than the aldolase antibodies used in the aldolase-based assays [8, 13, 26]. However, persistence of HRP-2 antigen is prolonged compared with pLDH, and thus cannot be used to predict post-treatment parasitaemia [27–30]. pLDH and aldolase closely correlates with parasitaemia; some studies suggest that they may be used for monitoring response to treatment if microscopy is not available [17, 31, 32].

Although studies in laboratory settings have demonstrated good sensitivity and specificity, several studies have reported poor sensitivity in field evaluations. Some reports assessed pLDH assays having sensitivities as low as 32–43% [8–14]. Other studies have demonstrated poor sensitivity of HRP-2 assays (as low as 5% for P. falciparum only) [33] and aldolase assays as low as 3–23% [8, 28]. Given this heterogeneity, it is suggested that candidate test kits be evaluated under local field conditions prior to widespread adoption.

What are the characteristics of rapid diagnostic tests in children?
Few studies were conducted in children specifically [24, 34–37]. At least one study has demonstrated increased sensitivity of a HRP-2 assay in children compared with adults, attributed to lower immunity and possibly less interference by antibodies [38]. Despite this, there is concern that the benefits of parasitological confirmation in children under 5 years may be outweighed by the risks of not treating children with false-negative tests [7]. No published studies were identified that specifically address this issue.

Are malaria rapid diagnostic tests cost-effective?
Few studies evaluated cost-effectiveness and results are unlikely to be generalizable due to variations in context. Rapid tests may be cost-effective in settings where microscopy is unavailable and treatment would be provided to all febrile patients [37] but field microscopy may be more cost-effective in some situations [39, 40], particularly where case-load is high. In areas where the prevalence of malaria is high, clinical diagnosis based on fever and/or anaemia may be even more cost-effective than microscopy or RDT [24, 41]. A decision on whether to adopt RDT should take into account the current alternatives in a region (such as quality microscopy services), the availability of skilled personnel and resources, the baseline prevalence of malaria (including intercurrent epidemics), the predominant malarial species and the cost of acquisition and deployment (including storage and transportation), and the capacity for training and supervision.


   Recommendations
Top
 Introduction
 Methodology
 Results
 Recommendations
References
 

  1. RDT storage and distribution should include a quality assurance system including monitoring of sensitivity, a cool chain where possible, appropriate instructions and training, and supervision (level 5).
  2. The cost-effectiveness of rapid tests should be evaluated locally prior to widespread adoption (level 5).
  3. Test performance, under field conditions, should be evaluated prior to adoption, and if possible, each batch should be evaluated in a reference laboratory (level 5). Assays may be susceptible to heat and humidity.
  4. If cost-effective, HRP-2-based assays are recommended if P. falciparum is the predominant species (either alone or as a mixed infection) (such as sub-Saharan Africa and lowland Papua New Guinea) (level 5).
  5. If cost-effective and adequately stable, combination HRP-2 or pLDH-based assays should be used in regions where multiple malarial species are present (level 5).
  6. HRP-2 tests should not be used for detection of parasitaemia following treatment (level 3b). Limited data suggests that aldolase and pLDH assays may be used to monitor the response to treatment (level 3b).


   References
Top
 Introduction
 Methodology
 Results
 Recommendations
 References
 

  1. Mayxay M, Newton PN, Yeung S, et al. (2004) Short communication: an assessment of the use of malaria rapid tests by village health volunteers in rural Laos. Trop Med Int Health 9:325–9.[CrossRef][Web of Science][Medline]
  2. WHO. (2005) List of known commercially available antigen detecting malaria RDTs with adequate evidence of good manufacturing practiceWHO Western Pacific Regional Office [website: http://www.wpro.who.int/NR/rdonlyres/E3597CBA-2ED4-4FCC-AB1C-CE25FC6AA30E/0/M_D_Webbuy_Table8.pdf].
  3. Haynes RB and Wilczynski NL. (2004) Optimal search strategies for retrieving scientifically strong studies of diagnosis from Medline: analytical survey. Brit Med J 328:1040.[Abstract/Free Full Text]
  4. Moody A. (2002) Rapid diagnostic tests for malaria parasites. Clin Microbiol Rev 15:66–78.[Abstract/Free Full Text]
  5. Marx A, Pewsner D, Egger M, et al. (2005) Meta-analysis: accuracy of rapid tests for malaria in travelers returning from endemic areas. Ann Intern Med 142:836–46.[Abstract/Free Full Text]
  6. Cruciani M, Nardi S, Malena M, et al. (2004) Systematic review of the accuracy of the ParaSight-F test in the diagnosis of Plasmodium falciparum malaria. Med Sci Monit 10:MT81–8.[Web of Science][Medline]
  7. WHO. (2005) Interim notes on selection of type of malaria rapid diagnostic test in relation to the occurrence of different parasite speciesRegional Offices for Africa and Western Pacific [website: http://www.wpro.who.int/NR/rdonlyres/CF152D7C-25BA-49E7-86D2-DBEE4E5B5974/0/INTERIMNOTESONMALARIARDTS_RBM_final2_rev3.pdf].
  8. Mason DP, Kawamoto F, Lin K, et al. (2002) A comparison of two rapid field immunochromatographic tests to expert microscopy in the diagnosis of malaria. Acta Trop 82:51–9.[CrossRef][Web of Science][Medline]
  9. Moody AH and Chiodini PL. (2002) Non-microscopic method for malaria diagnosis using OptiMAL IT, a second-generation dipstick for malaria pLDH antigen detection. Br J Biomed Sci 59:228–31.[Medline]
  10. Farcas GA, Zhong KJ, Lovegrove FE, et al. (2003) Evaluation of the Binax NOW ICT test versus polymerase chain reaction and microscopy for the detection of malaria in returned travelers. Am J Trop Med Hyg 69:589–92.[Abstract/Free Full Text]
  11. Soto Tarazona A, Solari Zerpa L, Mendoza Requena D, et al. (2004) Evaluation of the rapid diagnostic test OptiMAL for diagnosis of malaria due to Plasmodium vivax. Braz J Infect Dis 8:151–5.[Medline]
  12. Iqbal J, Khalid N, Hira PR. (2002) Comparison of two commercial assays with expert microscopy for confirmation of symptomatically diagnosed malaria. J Clin Microbiol 40:4675–8.[Abstract/Free Full Text]
  13. Huong NM, Davis TM, Hewitt S, et al. (2002) Comparison of three antigen detection methods for diagnosis and therapeutic monitoring of malaria: a field study from southern Vietnam. Trop Med Int Health 7:304–8.[CrossRef][Web of Science][Medline]
  14. VanderJagt TA, Ikeh EI, Ujah IO, et al. (2005) Comparison of the OptiMAL rapid test and microscopy for detection of malaria in pregnant women in Nigeria. Trop Med Int Health 10:39–41.[CrossRef][Web of Science][Medline]
  15. Richardson DC, Ciach M, Zhong KJ, et al. (2002) Evaluation of the Makromed dipstick assay versus PCR for diagnosis of Plasmodium falciparum malaria in returned travelers. J Clin Microbiol 40:4528–30.[Abstract/Free Full Text]
  16. Palmer CJ, Bonilla JA, Bruckner DA, et al. (2003) Multicenter study to evaluate the OptiMAL test for rapid diagnosis of malaria in U.S. hospitals. J Clin Microbiol 41:5178–82.[Abstract/Free Full Text]
  17. Moody A, Hunt-Cooke A, Gabbett E, et al. (2000) Performance of the OptiMAL malaria antigen capture dipstick for malaria diagnosis and treatment monitoring at the Hospital for Tropical Diseases, London. Br J Haematol 109:891–4.[CrossRef][Web of Science][Medline]
  18. Rubio JM, Buhigas I, Subirats M, et al. (2001) Limited level of accuracy provided by available rapid diagnosis tests for malaria enhances the need for PCR-based reference laboratories. J Clin Microbiol 39:2736–7.[Abstract/Free Full Text]
  19. Jelinek T, Grobusch MP, Schwenke S, et al. (1999) Sensitivity and specificity of dipstick tests for rapid diagnosis of malaria in nonimmune travelers. J Clin Microbiol 37:721–3.[Abstract/Free Full Text]
  20. Lee MA, Aw LT, Singh M. (1999) A comparison of antigen dipstick assays with polymerase chain reaction (PCR) technique and blood film examination in the rapid diagnosis of malaria. Ann Acad Med Singapore 28:498–501.[Medline]
  21. Ricci L, Viani I, Piccolo G, et al. (2000) Evaluation of OptiMAL Assay test to detect imported malaria in Italy. New Microbiol 23:391–8.[Medline]
  22. Iqbal J, Hira PR, Sher A, et al. (2001) Diagnosis of imported malaria by Plasmodium lactate dehydrogenase (pLDH) and histidine-rich protein 2 (PfHRP-2)-based immunocapture assays. Am J Trop Med Hyg 64:20–3.[Abstract]
  23. Labbe AC, Pillai DR, Hongvangthong B, et al. (2001) The performance and utility of rapid diagnostic assays for Plasmodium falciparum malaria in a field setting in the Lao People's Democratic Republic. Ann Trop Med Parasitol 95:671–7.[CrossRef][Web of Science][Medline]
  24. Tarimo DS, Minjas JN, Bygbjerg IC. (2001) Malaria diagnosis and treatment under the strategy of the integrated management of childhood illness (IMCI): relevance of laboratory support from the rapid immunochromatographic tests of ICT Malaria P.f/P.v and OptiMal. Ann Trop Med Parasitol 95:437–44.[CrossRef][Web of Science][Medline]
  25. Craig MH, Bredenkamp BL, Williams CH, et al. (2002) Field and laboratory comparative evaluation of ten rapid malaria diagnostic tests. Trans R Soc Trop Med Hyg 96:258–65.[CrossRef][Web of Science][Medline]
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  28. Richter J, Gobels K, Muller-Stover I, et al. (2004) Co-reactivity of plasmodial histidine-rich protein 2 and aldolase on a combined immuno-chromographic-malaria dipstick (ICT) as a potential semi-quantitative marker of high Plasmodium falciparum parasitaemia. Parasitol Res 94:384–5.[CrossRef][Web of Science][Medline]
  29. Grobusch MP, Hanscheid T, Gobels K, et al. (2003) Comparison of three antigen detection tests for diagnosis and follow-up of falciparum malaria in travellers returning to Berlin, Germany. Parasitol Res 89:354–7.[Web of Science][Medline]
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  39. Kolaczinski J, Mohammed N, Ali I, et al. (2004) Comparison of the OptiMAL rapid antigen test with field microscopy for the detection of Plasmodium vivax and P. falciparum: considerations for the application of the rapid test in Afghanistan. Ann Trop Med Parasitol 98:15–20.[CrossRef][Web of Science][Medline]
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