Performance and utility of more highly sensitive malaria rapid diagnostic tests

Hannah C Slater, Xavier C Ding, Sophia Knudson, Daniel J Bridges, Hawela Moonga, Neil J Saad, Martin De Smet, Adam Bennett, Sabine Dittrich, Laurence Slutsker, Gonzalo J Domingo, Hannah C Slater, Xavier C Ding, Sophia Knudson, Daniel J Bridges, Hawela Moonga, Neil J Saad, Martin De Smet, Adam Bennett, Sabine Dittrich, Laurence Slutsker, Gonzalo J Domingo

Abstract

Background: A new more highly sensitive rapid diagnostic test (HS-RDT) for Plasmodium falciparum malaria (Alere™/Abbott Malaria Ag P.f RDT [05FK140], now called NxTek™ Eliminate Malaria Ag Pf) was launched in 2017. The test has already been used in many research studies in a wide range of geographies and use cases.

Methods: In this study, we collate all published and available unpublished studies that use the HS-RDT and assess its performance in (i) prevalence surveys, (ii) clinical diagnosis, (iii) screening pregnant women, and (iv) active case detection. Two individual-level data sets from asymptomatic populations are used to fit logistic regression models to estimate the probability of HS-RDT positivity based on histidine-rich protein 2 (HRP2) concentration and parasite density. The performance of the HS-RDT in prevalence surveys is estimated by calculating the sensitivity and positive proportion in comparison to polymerase chain reaction (PCR) and conventional malaria RDTs.

Results: We find that across 18 studies, in prevalence surveys, the mean sensitivity of the HS-RDT is estimated to be 56.1% (95% confidence interval [CI] 46.9-65.4%) compared to 44.3% (95% CI 32.6-56.0%) for a conventional RDT (co-RDT) when using nucleic acid amplification techniques as the reference standard. In studies where prevalence was estimated using both the HS-RDT and a co-RDT, we found that prevalence was on average 46% higher using a HS-RDT compared to a co-RDT. For use in clinical diagnosis and screening pregnant women, the HS-RDT was not significantly more sensitive than a co-RDT.

Conclusions: Overall, the evidence presented here suggests that the HS-RDT is more sensitive in asymptomatic populations and could provide a marginal improvement in clinical diagnosis and screening pregnant women. Although the HS-RDT has limited temperature stability and shelf-life claims compared to co-RDTs, there is no evidence to suggest, given this test has the same cost as current RDTs, it would have any negative impacts in terms of malaria misdiagnosis if it were widely used in all four population groups explored here.

Keywords: Cross-sectional surveys; HS-RDT; Malaria diagnosis; Rapid diagnostic test.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Flow chart of identification of published studies. The breakdown on studies in the ‘included’ section is greater than the total number of studies as several studies fall into two categories
Fig. 2
Fig. 2
Performance of the HS-RDT against HRP2 concentration in PCR-confirmed specimens. Panels A and B show the sensitivity of the HS-RDT and co-RDT in samples grouped by different levels of HRP2 for a high-transmission setting (Uganda, A) and a low-transmission setting (Myanmar, B). Sensitivity is defined as the proportion of PCR-positive samples that are also detected by each RDT. The vertical lines on each bar are 95% binomial confidence intervals for each estimate. Panel C shows the probability of HS-RDT (red lines) and co-RDT (blue lines) positivity as a function of HRP2 concentration and panel D shows the probability of HS-RDT (red lines) and co-RDT (blue lines) as a function of parasite density by quantitative PCR. The shaded region indicates the 95% credible interval of the model fit
Fig. 3
Fig. 3
Comparison of PCR prevalence against HS-RDT prevalence. A shows all data used in this analysis (n = 18), and B shows a zoom-in of the samples with prevalence below 6%. The horizontal and vertical lines from each data point show the binomial confidence intervals associated with the PCR prevalence and HS-RDT prevalence estimates, respectively. The orange dashed line shows the fitted relationship derived from a previous meta-analysis of PCR and co-RDT prevalence surveys [3]. The grey diagonal line shows the x = y equivalence line between the HS-RDT and PCR. Additional details are provided on the sample type where necessary. **Unpublished studies. PNG Papua New Guinea, RCD reactive case detection, ACD active case detection
Fig. 4
Fig. 4
Sensitivity of the HS-RDT and co-RDT against PCR prevalence. The filled circles and triangles show the sensitivity of HS-RDT. The unfilled circles joined to the filled circles by a line show the sensitivity of the co-RDT in the same study, if this test was used. The triangles indicate studies where a co-RDT was not used. PCR is the gold-standard diagnostic against which sensitivity is calculated. The solid grey and dashed grey lines show the fit from a binomial generalised linear model of the relationship between PCR prevalence and sensitivity of the HS-RDT and co-RDT respectively. **Unpublished studies. RCD reactive case detection, ACD active case detection
Fig. 5
Fig. 5
Ratio of HS-RDT prevalence to co-RDT prevalence in 16 surveys from 15 studies. The circles show the estimated ratio, and the horizontal lines show the associated binomial 95% confidence intervals. The centre of the blue diamond shows the weighted mean estimated ratio (1.46) and the horizontal extents indicate the 95% confidence interval (1.26–1.70). **Unpublished studies. EAG easy access group, RCD reactive case detection, ACD active case detection

References

    1. Mweu MM, Wambua J, Njuga F, Bejon P, Mwanga D. Bayesian evaluation of the performance of three diagnostic tests for Plasmodium falciparum infection in a low-transmission setting in Kilifi County, Kenya. Wellcome Open Res. 2019
    1. Coldiron ME, Assao B, Langendorf C, Sayinzoga-Makombe N, Ciglenecki I, de la Tour R, et al. Clinical diagnostic evaluation of HRP2 and pLDH-based rapid diagnostic tests for malaria in an area receiving seasonal malaria chemoprevention in Niger. Malar J. 2019;18(1):443.
    1. Wu L, van den Hoogen LL, Slater H, Walker PGT, Ghani AC, Drakeley CJ, et al. Comparison of diagnostics for the detection of asymptomatic Plasmodium falciparum infections to inform control and elimination strategies. Nature. 2015;528(7580):S86–93.
    1. Slater HC, Ross A, Felger I, Hofmann NE, Robinson L, Cook J, et al. The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density. Nat Commun. 2019;10(1):1433.
    1. Dalrymple U, Arambepola R, Gething PW, Cameron E. How long do rapid diagnostic tests remain positive after anti-malarial treatment? Malar J. 2018;17(1):228.
    1. Walker PGT, Cairns M, Slater H, Gutman J, Kayentao K, Williams JE, et al. Modelling the incremental benefit of introducing malaria screening strategies to antenatal care in Africa. Nat Commun. 2020;11(1):3799.
    1. Zakama AK, Ozarslan N, Gaw SL. Placental malaria. Curr Trop Med Rep. 2020
    1. Yimam Y, Nateghpour M, Mohebali M, Afshar MJA. A systematic review and meta-analysis of asymptomatic malaria infection in pregnant women in Sub-Saharan Africa: a challenge for malaria elimination efforts. PLoS ONE. 2021;16(4):e0248245.
    1. University of California, San Francisco. Assessing the effectiveness of targeted active case detection among high risk populations in Southern Lao PDR [Internet]. ; 2021 Feb [cited 2021 Apr 18]. Report No.: NCT03783299. Available from: .
    1. Bridges DJ, Miller JM, Chalwe V, Moonga H, Hamainza B, Steketee R, et al. Community-led Responses for Elimination (CoRE): a study protocol for a community randomized controlled trial assessing the effectiveness of community-level, reactive focal drug administration for reducing Plasmodium falciparum infection prevalence and incidence in Southern Province, Zambia. Trials. 2017;18(1):511.
    1. Saad N, De Cramer C, Vernaeve L, Etienne W, Huy R, Nguon C. The performance of Alere Malaria Ag P.f®, a highly sensitive malaria RDT (hsRDT) for screening, against PCR in Cambodia. In New Orleans; 2018.
    1. Das S, Jang IK, Barney B, Peck R, Rek JC, Arinaitwe E, et al. Performance of a high-sensitivity rapid diagnostic test for Plasmodium falciparum malaria in asymptomatic individuals from Uganda and Myanmar and naive human challenge infections. Am J Trop Med Hyg. 2017;97(5):1540–1550.
    1. Landier J, Haohankhunnatham W, Das S, Konghahong K, Christensen P, Raksuansak J, et al. Operational performance of a Plasmodium falciparum ultrasensitive rapid diagnostic test for detection of asymptomatic infections in eastern Myanmar. J Clin Microbiol. 2018
    1. Hofmann NE, Gruenberg M, Nate E, Ura A, Rodriguez-Rodriguez D, Salib M, et al. Assessment of ultra-sensitive malaria diagnosis versus standard molecular diagnostics for malaria elimination: an in-depth molecular community cross-sectional study. Lancet Infect Dis. 2018;18(10):1108–1116.
    1. Yeung S, McGregor D, James N, Kheang ST, Kim S, Khim N, et al. Performance of ultrasensitive rapid diagnostic tests for detecting asymptomatic Plasmodium falciparum. Am J Trop Med Hyg. 2019;102(2):307–309.
    1. Druetz T, Stresman G, Ashton RA, van den Hoogen LL, Joseph V, Fayette C, et al. Programmatic options for monitoring malaria in elimination settings: easy access group surveys to investigate Plasmodium falciparum epidemiology in two regions with differing endemicity in Haiti. BMC Med. 2020;18(1):141.
    1. Jang IK, Tyler A, Lyman C, Rek JC, Arinaitwe E, Adrama H, et al. Multiplex human malaria array: quantifying antigens for malaria rapid diagnostics. Am J Trop Med Hyg. 2020;102(6):1366–1369.
    1. Jang IK, Tyler A, Lyman C, Kahn M, Kalnoky M, Rek JC, et al. Simultaneous quantification of plasmodium antigens and host factor C-reactive protein in asymptomatic individuals with confirmed malaria by use of a novel multiplex immunoassay. J Clin Microbiol. 2019
    1. Acquah FK, Donu D, Obboh EK, Bredu D, Mawuli B, Amponsah JA, et al. Diagnostic performance of an ultrasensitive HRP2-based malaria rapid diagnostic test kit used in surveys of afebrile people living in Southern Ghana. Malar J. 2021;20(1):125.
    1. Galatas B, Mayor A, Gupta H, Balanza N, Jang IK, Nhamussua L, et al. Field performance of ultrasensitive and conventional malaria rapid diagnostic tests in southern Mozambique. Malar J. 2020;19(1):451.
    1. Girma S, Cheaveau J, Mohon AN, Marasinghe D, Legese R, Balasingam N, et al. Prevalence and epidemiological characteristics of asymptomatic malaria based on ultrasensitive diagnostics: a cross-sectional study. Clin Infect Dis. 2019;69(6):1003–1010.
    1. Liu Z, Soe TN, Zhao Y, Than A, Cho C, Aung PL, et al. Geographical heterogeneity in prevalence of subclinical malaria infections at sentinel endemic sites of Myanmar. Parasites Vectors. 2019;12(1):83.
    1. Manjurano A, Omolo JJ, Lyimo E, Miyaye D, Kishamawe C, Matemba LE, et al. Performance evaluation of the highly sensitive histidine-rich protein 2 rapid test for Plasmodium falciparum malaria in North-West Tanzania. Malar J. 2021;20(1):58.
    1. Mwesigwa J, Slater H, Bradley J, Saidy B, Ceesay F, Whittaker C, et al. Field performance of the malaria highly sensitive rapid diagnostic test in a setting of varying malaria transmission. Malar J. 2019;18(1):288.
    1. Owalla TJ, Okurut E, Apungia G, Ojakol B, Lema J, Murphy SC, et al. Using the ultrasensitive Alere Plasmodium falciparum malaria Ag HRP-2TM rapid diagnostic test in the field and clinic in northeastern Uganda. Am J Trop Med Hyg. 2020;103(2):778–84.
    1. Hartley M-A, Hofmann N, Keitel K, Kagoro F, Moniz CA, Mlaganile T, et al. Clinical relevance of low-density Plasmodium falciparum parasitemia in untreated febrile children: a cohort study. PLoS Med. 2020;17(9):e1003318.
    1. Hofmann NE, Antunes Moniz C, Holzschuh A, Keitel K, Boillat-Blanco N, Kagoro F, et al. Diagnostic performance of conventional and ultrasensitive rapid diagnostic tests for malaria in febrile outpatients in Tanzania. J Infect Dis. 2019;219(9):1490–1498.
    1. Plucinski MM, Rogier E, Dimbu PR, Fortes F, Halsey ES, Aidoo M. Estimating the added utility of highly sensitive histidine-rich protein 2 detection in outpatient clinics in sub-Saharan Africa. Am J Trop Med Hyg. 2017;97(4):1159–1162.
    1. Briand V, Cottrell G, Tuike Ndam N, Martiáñez-Vendrell X, Vianou B, Mama A, et al. Prevalence and clinical impact of malaria infections detected with a highly sensitive HRP2 rapid diagnostic test in Beninese pregnant women. Malar J. 2020;19(1):188.
    1. Unwin VT, Ahmed R, Noviyanti R, Puspitasari AM, Utami RAS, Trianty L, et al. Use of a highly-sensitive rapid diagnostic test to screen for malaria in pregnancy in Indonesia. Malar J. 2020;19(1):28.
    1. Vásquez AM, Medina AC, Tobón-Castaño A, Posada M, Vélez GJ, Campillo A, et al. Performance of a highly sensitive rapid diagnostic test (HS-RDT) for detecting malaria in peripheral and placental blood samples from pregnant women in Colombia. PLoS ONE. 2018;13(8):e0201769.
    1. Vásquez AM, Vélez G, Medina A, Serra-Casas E, Campillo A, Gonzalez IJ, et al. Evaluation of highly sensitive diagnostic tools for the detection of P. falciparum in pregnant women attending antenatal care visits in Colombia. BMC Pregnancy Childbirth. 2020;20(1):440.
    1. Hofmann N, Mwingira F, Shekalaghe S, Robinson LJ, Mueller I, Felger I. Ultra-sensitive detection of Plasmodium falciparum by amplification of multi-copy subtelomeric targets. PLOS Med. 2015;12(3):e1001788.
    1. Abba K, Deeks JJ, Olliaro PL, Naing C-M, Jackson SM, Takwoingi Y, et al. Rapid diagnostic tests for diagnosing uncomplicated P. falciparum malaria in endemic countries. Cochrane Database Syst Rev [Internet]. 2011 [cited 2021 Jun 18];(7). Available from: .
    1. Osanjo GO, Onyango IA, Kimani J, Ochanda J, Oyugi J. Evaluation of malaria rapid diagnostic tests among children in a malaria endemic region in coastal Kenya. Afr J Pharmacol Ther [Internet]. 2017 Jul 6 [cited 2021 Jun 18];6(2). Available from: .
    1. Amimo F, Lambert B, Magit A, Sacarlal J, Hashizume M, Shibuya K. Plasmodium falciparum resistance to sulfadoxine-pyrimethamine in Africa: a systematic analysis of national trends. BMJ Glob Health. 2020
    1. WHO Malaria Policy Advisory Committee and Secretariat Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of eighth biannual meeting (September 2015) Malar J. 2016;15(1):117.
    1. Tagbor H, Bruce J, Agbo M, Greenwood B, Chandramohan D. Intermittent screening and treatment versus intermittent preventive treatment of malaria in pregnancy: a randomised controlled non-inferiority trial. PLoS ONE. 2010;5(12):e14425.
    1. Tagbor H, Cairns M, Bojang K, Coulibaly SO, Kayentao K, Williams J, et al. A non-inferiority, individually randomized trial of intermittent screening and treatment versus intermittent preventive treatment in the control of malaria in pregnancy. PLoS ONE. 2015;10(8):e0132247.
    1. Desai M, Gutman J, L’lanziva A, Otieno K, Juma E, Kariuki S, et al. Intermittent screening and treatment or intermittent preventive treatment with dihydroartemisinin-piperaquine versus intermittent preventive treatment with sulfadoxine-pyrimethamine for the control of malaria during pregnancy in western Kenya: an open-label, three-group, randomised controlled superiority trial. Lancet. 2015;386(10012):2507–19.
    1. Madanitsa M, Kalilani L, Mwapasa V, van Eijk AM, Khairallah C, Ali D, et al. Scheduled intermittent screening with rapid diagnostic tests and treatment with dihydroartemisinin-piperaquine versus intermittent preventive therapy with sulfadoxine-pyrimethamine for malaria in pregnancy in Malawi: an open-label randomized controlled trial. PLOS Med. 2016;13(9):e1002124.
    1. The Global Fund. List of Rapid Diagnostic Test (RDT) kits for Malaria classified according to the Global Fund Quality Assurance Policy [Internet]. 2021. Available from: .
    1. Jimenez A, Rees-Channer RR, Perera R, Gamboa D, Chiodini PL, González IJ, et al. Analytical sensitivity of current best-in-class malaria rapid diagnostic tests. Malar J. 2017;16(1):128.
    1. Martiáñez-Vendrell X, Jiménez A, Vásquez A, Campillo A, Incardona S, González R, et al. Quantification of malaria antigens PfHRP2 and pLDH by quantitative suspension array technology in whole blood, dried blood spot and plasma. Malar J. 2020;19(1):12.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe