INTERIM NOTES ON SELECTION OF TYPE OF MALARIA RAPID DIAGNOSTIC TEST IN RELATION TO THE OCCURRENCE OF DIFFERENT PARASITE SPECIES

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1 INTERIM NOTES ON SELECTION OF TYPE OF MALARIA RAPID DIAGNOSTIC TEST IN RELATION TO THE OCCURRENCE OF DIFFERENT PARASITE SPECIES Guidance for national malaria control programmes Prepared by Roll Back Malaria Department World Health Organization with the collaboration of the Regional Offices for Africa and the Western Pacific August Background Use of parasite-based diagnosis Parasitological confirmation of the diagnosis of malaria is part of good clinical practice and should always be part of malaria case management, with the following exceptions: Children under 5 years old in areas of high prevalence as there is not yet evidence that the benefits of parasitological confirmation outweigh the risk of not treating false negatives. a Cases of fever in established malaria epidemics where resources are limited (WHO 2004a) Where good quality diagnosis is not available (as an interim measure while capacity for parasite-based diagnosis is being developed). Justification for parasite-based diagnosis, including improved disease management and potential savings in health resources, are detailed elsewhere (WHO 2000). a The appropriateness of microscopy versus antigen-detecting rapid diagnostic tests depends on a number of factors including parasite prevalence, availability of skilled personnel and resources, the capacity for maintaining quality assurance of microscopy and RDT, and the need for quantitative assessment of parasite density. These are discussed elsewhere (Makler, Palmer et al. 1998; Hanscheid 1999; Moody 2002; WHO 2003). From here on, this document concentrates only on areas where diagnosis using antigen-detecting RDTs has been deemed appropriate. RDTs detecting anti-malaria antibodies have indications other than case management, and are not discussed here. a Technical Consultation to Review the Role of Laboratory Diagnosis to Support Malaria Disease Management: Focus on the Use of RDTs in Areas of High Transmission Deploying ACT Treatments (25-26 October 2004) Report in preparation 1

2 2. Types of Malaria Rapid Diagnostic Tests The three main groups of antigens detected by commercially available RDTs are: Histidine-rich protein 2 (HRP2), specific to P. falciparum Plasmodium lactate dehydrogenase (pldh), currently used in products that include P. falciparum-specific, pan-specific, and P. vivax-specific pldh antibodies Aldolase (pan-specific). Target antigens of commercially-available malaria rapid diagnostic tests. HRP2 pldh Aldolase P. falciparum-specific + + Pan-specific (all species) + + P. vivax-specific + Most commercial products include antibodies to: HRP2 alone (P. falciparum) HRP2 and aldolase (distinguishing P. falciparum/mixed infection from nonfalciparum alone) a Falciparum-specific pldh and pan-specific pldh (distinguishing P. falciparum/mixed infection from non-falciparum alone) HRP2 and pan-specific pldh HRP2, pan-specific pldh and vivax-specific pldh or Pan-specific aldolase only. RDT detecting both falciparum-specific and non-falciparum (or pan-specific) target antigens are commonly called combination or 'combo' tests. The products come in a number of formats: Plastic cassette Card Dipstick Hybrid cassette-dipsticks Cassettes tend to be simpler to perform than dipsticks, and this is likely to affect test accuracy. b 3. Choosing a Malaria Rapid Diagnostic Test Important considerations involved in choosing an RDT include: Sensitivity (and specificity) c a As products are commonly more sensitive to HRP2 than aldolase in P. falciparum-only infections, these will commonly appear as an HRP2 line only if the parasite density is low. b Unpublished report of WHO, Quality Assurance Project (USA), Research Institute for Tropical Medicine (Philippines) and Centre for Malaria, Parasitology and Entomology (Cambodia) at c The 'sensitivity' of an RDT for detecting malaria parasitaemia (or recent parasitaemia) depends on the concentration of circulating antigen in the patients' blood, and the ability of the labeled antibody on the RDT to bind the antigen and accumulate to form a visible line. In turn, this depends on the relationship 2

3 Stability Ease of use (impacts on sensitivity and stability) Cost. Other general considerations are listed elsewhere (WHO 2003). 3.1 Species zones affecting RDT choice. The appropriateness of P. falciparum-specific, pan-specific and non-falciparum RDTs varies with the relative prevalence of the different human malaria species in the intended area of use. These areas can be categorized as: Zone 1. P. falciparum-only, or with non-falciparum species occurring almost always as co-infections with P. falciparum (Most areas of sub-saharan Africa and low-land Papua New Guinea) Zone 2. Falciparum and non-falciparum infections occurring commonly as single-species infections (Most endemic areas in Asia and the Americas, and isolated areas in Africa, particularly the Ethiopian highlands) Zone 3. Areas with non-falciparum malaria only (mainly vivax-only areas of East Asia and central Asia, and some highland areas elsewhere) Zone 1: Falciparum-only RDT generally indicated In areas where only falciparum malaria occurs, or non-falciparum malaria rarely occurs without co-infection of P. falciparum, RDTs that detect only P. falciparum are generally preferable on grounds of lower cost. Most (or all) commercially-available RDTs in this category detect HRP2. As treatment for P. falciparum is effective for treating blood-stages of non-falciparum parasites, and anti-relapse treatment for the liver stage of P. vivax and P. ovale is not normally given in endemic areas in Africa, there is usually little to be gained for case management by identifying co-infection with non-falciparum species. Most commercial RDT do not distinguish mixed infections from falciparum-only infections, so the only advantage of using a combined RDT in these areas is to detect rare infections involving non-falciparum parasites alone. In certain situations, combined RDTs may be appropriate if they have desired properties that falciparum-only RDTs do not have. This applies particularly to situations where it is required to monitor post-treatment parasitaemia, in which case between antigen concentration and parasite density, which may vary with the host (e.g. immunity) and with the parasite (WHO, 2004). In general, it is recommended that at least 95% of P. falciparum infections should be detected at 100 parasites per microlitre, and higher at higher parasite densities (WHO 2000; WHO 2003), which is probably similar to good field microscopy. The appropriateness of this figure depends on the clinical situation, and the available alternative methods of diagnosis. Lower sensitivity for non-falciparum parasites may be clinically acceptable. 3

4 pldh-detecting RDT may be used in preference to HRP2-detecting RDT. d However, in general, microscopy is the preferred tool for monitoring treatment outcomes. Zone 2. Combination RDT generally indicated Where falciparum and non-falciparum infections occur commonly as single species infections, combination tests detecting all species and distinguishing P. falciparum from non-falciparum infections are indicated. The use of RDTs that detect P. falciparum alone would result in dilemmas in the management of RDT-negative patients, some of whom will have malaria due to P. vivax, P. ovale or P. malariae. RDT negative patients must then be treated with chloroquine (accepting a high rate of unnecessary treatment of non-malaria cases), and the advantage of distinguishing non-malaria cases for specific disease management would be lost. Zone 3. Pan-specific or vivax-specific RDT generally indicated No falciparum occurs. RDT detecting non-falciparum species alone are appropriate (P. vivax-specific or pan-specific). Note As the above zones are part of a continuum of species distribution, difficult decisions in choice of RDT target species can occur. For instance, where a small proportion of non-falciparum single species infections occur (e.g. 1-4% of malaria patients) and P. falciparum infections greatly predominate, decisions on using combo rather than falciparum-only RDT will depend on available resources and the importance of distinguishing small numbers of non-falciparum malaria infections from non-malaria infections. 3.2 Comparison of RDTs detecting both P. falciparum and non-falciparum infections The intended conditions of use must be considered when choosing an RDT. If they are to be used in a remote area without temperature-controlled storage, stability (shelf-life) will be of great importance, compared to storage and use in temperaturecontrolled laboratories. If RDTs are to be used by isolated volunteer health workers, an easy-to-use format will be of greater importance than in a laboratory setting. There is unpublished evidence that HRP2-detecting RDT are more stable than pldhdetecting RDT. e There is some unpublished evidence that the aldolase band on a d In practice, this means using a combined RDT as no pldh products are available that include a single (P. falciparum or pan-specific) test line. Pan-specific aldolase may also be appropriate, but more evidence of duration of persistence is needed and sensitivity may be lower. e Unpublished multi-centre study coordinated by WHO involving commercially-available products. Two pldh detecting products consistently lost capacity to detect P. falciparum standardized cryopreserved samples faster than two HRP2-detecting products when stored at at 60 o C, 45 o C, and 35 o C, to an extent which could limit shelf-life in uncontrolled storage conditions. All the RDTs utilized different 4

5 combo RDT is less stable than the HRP2-detecting band, and similar to pldhdetecting bands. f There is a need for more data to compare the stability of pldh and aldolase. There is fairly consistent evidence that HRP2-detecting RDT are normally more sensitive than falciparum-specific pldh RDT (Jelinek, Grobusch et al. 1999; Lee, Aw et al. 1999; Ricci, Viani et al. 2000; Iqbal, Hira et al. 2001; Labbe, Pillai et al. 2001; Rubio, Buhigas et al. 2001; Tarimo, Minjas et al. 2001; Craig, Bredenkamp et al. 2002; Huong, Davis et al. 2002; Iqbal, Khalid et al. 2002; Mason, Kawamoto et al. 2002). g However, the sensitivity of HRP2 detection varies between P. falciparum isolates due to antigen variation and in some regions pldh could potentially be of similar sensitivity (Baker, McCarthy et al. 2005). Published field data indicates that the pldh antibodies used in the pldh-detecting 'Optimal' test variations are more sensitive than the aldolase antibodies used in the aldolase-detecting 'ICT' test variations (Cho, Kim et al. 2001; Huong, Davis et al. 2002; Mason, Kawamoto et al. 2002). Other products now have different pldh and aldolase monoclonal antibodies combined with HRP2, and the relative sensitivity of these is not well tested. There is a need for more data on pldh and aldolase antigen variation, and the geographical extent of HRP2 variation. Some RDT products include a pan-specific band only. In view of the above, these are likely to have lower sensitivity for P. falciparum than HRP2-detecting tests. They have some price advantage as less monoclonal antibodies are required, but are probably only well suited to areas with only non-falciparum malaria as the implications of overlooking a low-density P. falciparum infection may be serious. 3.3 Implications A combined RDT including detection of HRP2 is likely to retain sensitivity for P. falciparum longer than an RDT detecting falciparum-specific pldh, at ambient endemic country conditions. However, the pan-specific line (aldolase or pldh) will deteriorate faster than the HRP2 line so an HRP2 combined RDT may have reduced ability to detect non-falciparum infections while retaining good sensitivity for P. falciparum. As P. falciparum infection is potentially more severe, it can therefore be argued that in remote situations in areas where combined tests are indicated, RDT including HRP2 detection (HRP2/pLDH or HRP2/aldolase) are preferable to those relying on pldh detection alone. sets of monoclonal antibodies. A third HRP2-detecting RDT failed at all storage intervals including baseline testing, but was later shown to have faults in cassette design preventing antibody-antigen contact. f Unpublished data from Research Institute for Tropical Medicine, Alabang, Mintinpupa City, Philippines, of accelerated temperature stability testing of a small number of commercially-available RDTs. g 8 of the 11 studies listed indicate greater sensitivity of HRP2-detecting RDT, in some cases to a large degree, and including all that were performed in the field in endemic countries. It is possible that the greater temperature stability of HRP2-detecting RDT contributed to these results. 5

6 It should be noted that evidence is lacking on many currently available products, so considerable variation from the above general statements may occur with some RDTs. 3.4 Cost and quality RDTs can be purchased directly from most manufacturers, and this usually allows procurement of large batches at considerably lower cost than purchase through distributors. Cassette format RDTs are usually 10-20% higher priced than dipstick RDTs, though the latter sometimes require the procurer to provide wells, resulting in a similar total cost. Cassette RDTs when used by health workers are probably more reliable than dipstick RDTs, and so may provide savings through improved diagnosis. h Combined cassette RDTs may be obtained from manufacturers at prices per test of US$ and upward. Prices vary with time, and with the number of units purchased. WHO experience indicates that quality is not directly correlated with higher price. WHO recommends that all large purchases of RDT be checked for sensitivity before use and monitored at least 3 monthly during use. Evidence of good manufacturing practice is likely to indicate more reliable products. Advice on procurement and quality control are found elsewhere (WHO 2004b; WHO-WPRO 2005). 4. Conclusions HRP2-detecting tests are likely to have greater sensitivity than pldh- and aldolase-detecting tests for detection of current P. falciparum infection in most environments pldh and aldolase-detecting RDTs are likely to be less temperature stable than HRP2, and will therefore lose sensitivity more rapidly in uncontrolled storage RDTs detecting non-falciparum species offer little advantage in terms of case management in areas where P. falciparum predominates and non-falciparum species nearly always occur as co-infections. In such situations, particularly where tests will be stored without temperature control, RDTs detecting HRP2 offer advantages in terms of sensitivity, stability, cost and format When stored and used in temperature-controlled environments, pldhdetecting RDTs are likely to have greater sensitivity than aldolase in detection of non-falciparum infections (more recently available antibodies may differ) pldh detection has advantages over HRP2 detection for monitoring of effectiveness of treatment. Aldolase may have similar properties (Eisen and Saul 2000). Microscopy is generally the preferred tool for this purpose h Unpublished report of WHO, QAP, RITM and CMPE at 6

7 Cassettes are preferable to dipsticks in remote areas due to simplicity of preparation Cassette tests detecting both P. falciparum and non-falciparum parasites can be obtained for prices ranging from US$ per test, and there is no clear advantage in higher cost RDTs. Most products can be ordered directly from the manufacturers. All large batches of RDT should be tested after procurement and monitored throughout shelf-life. Evidence of good manufacturing practice and good field experience should be considered during procurement. Standard specifications for procurement should be followed (WHO 2004b; WHO-WPRO 2005) 7

8 List of HRP2-only cassette tests Numerous products are on the market. Price varies from about $0.65 upward. Note: This list does not imply any WHO endorsement of any RDT product, or results of testing, or rating or certification of any product whether or not included on this list. Product name Palutop dbest Malaria Rapid Test Malaria Pf-only Rapid Test Rapimal Immu-Sure Malaria Malaria Test Core Malaria Pf Malar-Check Pf Assure Malaria Pf Smart Check Malaria Hexagon Malaria KatQuick MakroMAL Malaria Pf test Visitect malaria Pf Paracheck ICT Malaria Pf ParaHIT Uni-Gold Malaria Pf FirstSign Malaria Pf Malaria Pf Manufacturer Alldiag Ameritek Biotech Trading Partners Cellabs Brittney Bio-Analytics C.A. Core Diagnostics Cumberland Genelabs GlobaleMed Human Gmbh KAT Medical Makro Medical Merlin Labs Omega Diagnostics Orchid Biomedical Systems R&R Marketing Span Diagnostics Trinity Biotech Unimed Vision Biotech Contact details of some manufacturers can be found at 8

9 List of HRP2-based P. falciparum / pan-species cassette tests Note: This list does not imply any WHO endorsement of any RDT product, or results of testing, or rating or certification of any product whether or not included on this list. Manufacturer Product CASSETTE TESTS HRP2/aldolase Cortez OneStep RapiCard Instatest onestep@rapidtest.com Craftsman Road, Suite E/F, Calabasas, California USA 'Tel: Fax: R&R ICT Malaria Pf/pan russellag@icon.co.za P.O. Box 912, Noordhoek 7985, Cape Town, South Africa Tel/Fax: Span ParaHIT-TOTAL spand@vsnl.com export@spandiag.com Road No. 6-G, Udhyognagar, Udhna (Surat) India Tel: /7143 Fax: / Merlin HRP2/pLDH Omega Zephyr Malaria Combo Test VISITECT Malaria Combo ParaScreen PAN/Pf bhudak@merlinlabs.com Merlin Labs, Inc., 6084 Corte Del Cedro, Carlsbad, CA 92009, USA Telephone: Fax: odl@omegadiagnostics.co.uk Omega House, Hillfoots Business Village, Alva, Clacks, FK12 5DQ Scotland, United Kingdom Tel: Fax: zephyr@tulipgroup.com Plot Nos M46/47, Phase IIIB, Verna Industrial Estate, Verna Goa , India Tel: , Fax: /2139 Unimed unimedinc@aol.com 1101 Grandview Drive, South San Francisco, CA 94080, USA Tel: (650) Fax: (650)

10 Core CARD TESTS HRP2/aldolase card Binax* Core Malaria Pan-Pf NOW-Malaria (Card test) Aspect Court Road, 4 Temple Row, Birmingham B2 5HG, United Kingdom Tel: Fax: brian.conibere@unipath.com 217 Read Street, Portland, ME USA Tel: ext. 107 Fax: DIPSTICK- CASSETTE HYBRIDS Diamed Optimal IT p.jacquier@diamed.ch parasitology@diamed.ch Diamed SA, 1785, Cressier sur Morat, Switzerland Tel: Fax: Standard Diagnostics SD Bioline Target Antigen not specified Sanitoets (Pan) info@anytestkits.com South Africa Fax: johnhkim@standardia.com , Pajang-dong, Jangan-ku, Suwon-si, Kyonggi-do, Korea, Tel: Fax: Alldiag Pan lamy@alldiag.com 2 rue Ettoré Bugatti - BP 6 - F Strasbourg Cedex 2 France Tel: Fax: Notes: Always specify format (i.e. cassette) when ordering. Many manufacturers produce dipsticks by the same name. Supply. Most manufacturers of cheaper tests can rapidly increase capacity. Tests detecting P. falciparum and P. vivax (species-specific) pldh are marketed by Zephyr, Unimed, and Core. They are at higher price than the tests using pan-specific pldh. Falciparum/vivax/pan tests are also available from these companies. 10

11 All manufacturers above (except Cortez, Diamed, and Standard Diagnostics) produce cheaper cassette tests detecting P. falciparum only. Multiple other companies also produce these ( Some manufacturers produce aldolase-only tests. Other tests are available in dipstick format only (e.g. Premier Medical Corporation First response Malaria Pf/Pv). 11

12 References Baker, J., J. McCarthy, et al. (2005). "Genetic Diversity of Plasmodium falciparum Histidine-Rich Protein 2 and Its Effect on the Performance of PfHRP2-Based Rapid Diagnostic Tests." Journal of Infectious Disease In Press. Cho, D., K. H. Kim, et al. (2001). "Evaluation of rapid immunocapture assays for diagnosis of Plasmodium vivax in Korea." Parasitol Res 87(6): Craig, M. H., B. L. Bredenkamp, et al. (2002). "Field and laboratory comparative evaluation of ten rapid malaria diagnostic tests." Trans R Soc Trop Med Hyg 96(3): Eisen, D. P. and A. Saul (2000). "Disappearance of pan-malarial antigen reactivity using the ICT Malaria P.f/P.v kit parallels decline of patent parasitaemia as shown by microscopy." Trans R Soc Trop Med Hyg 94(2): Hanscheid, T. (1999). "Diagnosis of malaria: a review of alternatives to conventional microscopy." Clin Lab Haematol 21(4): Huong, N. M., T. M. Davis, 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(4): Iqbal, J., P. R. Hira, 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(1-2): Iqbal, J., N. Khalid, et al. (2002). "Comparison of two commercial assays with expert microscopy for confirmation of symptomatically diagnosed malaria." J Clin Microbiol 40(12): Jelinek, T., M. P. Grobusch, et al. (1999). "Sensitivity and specificity of dipstick tests for rapid diagnosis of malaria in nonimmune travelers." J Clin Microbiol 37(3): Labbe, A. C., D. R. Pillai, 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(7): Lee, M. A., L. T. Aw, et al. (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(4): Makler, M. T., C. J. Palmer, et al. (1998). "A review of practical techniques for the diagnosis of malaria." Ann Trop Med Parasitol 92(4): Mason, D. P., F. Kawamoto, et al. (2002). "A comparison of two rapid field immunochromatographic tests to expert microscopy in the diagnosis of malaria." Acta Trop 82(1): Moody, A. (2002). "Rapid diagnostic tests for malaria parasites." Clin Microbiol Rev 15(1): Ricci, L., I. Viani, et al. (2000). "Evaluation of OptiMAL Assay test to detect imported malaria in Italy." New Microbiol 23(4): Rubio, J. M., I. Buhigas, 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(7): Tarimo, D. S., J. N. Minjas, et al. (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(5): WHO (2000). New Perspectives: Malaria Diagnosis. Report of a joint WHO/USAID informal consultation October Geneva, World Health Organization. WHO (2003). Malaria Rapid Diagnosis: Making it Work. Meeting report January Manila, World Health Organization. WHO (2004a). Malaria epidemics: forecasting, prevention, early detection and control. From policy to practice. Report of an informal consultation, Leysin, Switzerland, 8-10 December, Geneva, World Health Organization. WHO (2004b). The Use of Malaria Rapid Diagnostic Tests. Manila, World Health Organization- WPRO. WHO-WPRO (2005). Malaria Rapid Diagnostic Tests: Making Rapid Diagnosis Work. World Health Organization - Regional Office for the Western Pacific. 12