Diagnostic performance and comparison of ultrasensitive and conventional rapid diagnostic test, thick blood smear and quantitative PCR for detection of low-density Plasmodium falciparum infections during a controlled human malaria infection study in Equatorial Guinea

Maxmillian Mpina, Thomas C Stabler, Tobias Schindler, Jose Raso, Anna Deal, Ludmila Acuche Pupu, Elizabeth Nyakarungu, Maria Del Carmen Ovono Davis, Vicente Urbano, Ali Mtoro, Ali Hamad, Maria Silvia A Lopez, Beltran Pasialo, Marta Alene Owono Eyang, Matilde Riloha Rivas, Carlos Cortes Falla, Guillermo A García, Juan Carlos Momo, Raul Chuquiyauri, Elizabeth Saverino, L W Preston Church, B Kim Lee Sim, Bonifacio Manguire, Marcel Tanner, Carl Maas, Salim Abdulla, Peter F Billingsley, Stephen L Hoffman, Said Jongo, Thomas L Richie, Claudia A Daubenberger, Maxmillian Mpina, Thomas C Stabler, Tobias Schindler, Jose Raso, Anna Deal, Ludmila Acuche Pupu, Elizabeth Nyakarungu, Maria Del Carmen Ovono Davis, Vicente Urbano, Ali Mtoro, Ali Hamad, Maria Silvia A Lopez, Beltran Pasialo, Marta Alene Owono Eyang, Matilde Riloha Rivas, Carlos Cortes Falla, Guillermo A García, Juan Carlos Momo, Raul Chuquiyauri, Elizabeth Saverino, L W Preston Church, B Kim Lee Sim, Bonifacio Manguire, Marcel Tanner, Carl Maas, Salim Abdulla, Peter F Billingsley, Stephen L Hoffman, Said Jongo, Thomas L Richie, Claudia A Daubenberger

Abstract

Background: Progress towards malaria elimination has stagnated, partly because infections persisting at low parasite densities comprise a large reservoir contributing to ongoing malaria transmission and are difficult to detect. This study compared the performance of an ultrasensitive rapid diagnostic test (uRDT) designed to detect low density infections to a conventional RDT (cRDT), expert microscopy using Giemsa-stained thick blood smears (TBS), and quantitative polymerase chain reaction (qPCR) during a controlled human malaria infection (CHMI) study conducted in malaria exposed adults (NCT03590340).

Methods: Blood samples were collected from healthy Equatoguineans aged 18-35 years beginning on day 8 after CHMI with 3.2 × 103 cryopreserved, infectious Plasmodium falciparum sporozoites (PfSPZ Challenge, strain NF54) administered by direct venous inoculation. qPCR (18s ribosomal DNA), uRDT (Alere™ Malaria Ag P.f.), cRDT [Carestart Malaria Pf/PAN (PfHRP2/pLDH)], and TBS were performed daily until the volunteer became TBS positive and treatment was administered. qPCR was the reference for the presence of Plasmodium falciparum parasites.

Results: 279 samples were collected from 24 participants; 123 were positive by qPCR. TBS detected 24/123 (19.5% sensitivity [95% CI 13.1-27.8%]), uRDT 21/123 (17.1% sensitivity [95% CI 11.1-25.1%]), cRDT 10/123 (8.1% sensitivity [95% CI 4.2-14.8%]); all were 100% specific and did not detect any positive samples not detected by qPCR. TBS and uRDT were more sensitive than cRDT (TBS vs. cRDT p = 0.015; uRDT vs. cRDT p = 0.053), detecting parasitaemias as low as 3.7 parasites/µL (p/µL) (TBS and uRDT) compared to 5.6 p/µL (cRDT) based on TBS density measurements. TBS, uRDT and cRDT did not detect any of the 70/123 samples positive by qPCR below 5.86 p/µL, the qPCR density corresponding to 3.7 p/µL by TBS. The median prepatent periods in days (ranges) were 14.5 (10-20), 18.0 (15-28), 18.0 (15-20) and 18.0 (16-24) for qPCR, TBS, uRDT and cRDT, respectively; qPCR detected parasitaemia significantly earlier (3.5 days) than the other tests.

Conclusions: TBS and uRDT had similar sensitivities, both were more sensitive than cRDT, and neither matched qPCR for detecting low density parasitaemia. uRDT could be considered an alternative to TBS in selected applications, such as CHMI or field diagnosis, where qualitative, dichotomous results for malaria infection might be sufficient.

Keywords: Controlled human malaria infection; Low parasite density infections; Malaria; Malaria pre-exposure; Rapid diagnostic test; Thick blood smear.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Similarities and discrepancies in detection of P. falciparum cases by different diagnostic methods. Venn-diagram showing distribution of positive results according to the diagnostic test used with qPCR as the reference method. All samples were sorted by thick blood smear (TBS), ultrasensitive rapid diagnostic test (uRDT), and conventional rapid diagnostic test (cRDT). All cases were low parasite density P. falciparum infections that occurred during CHMI
Fig. 2
Fig. 2
Distribution of parasite density by qPCR of all malaria positive samples by TBS, uRDT, and cRDT. Red dots represent the geomean and error bars represent the 95% confidence intervals of each respective diagnostic test. Significance values were calculated using two-tailed Wilcoxon-test
Fig. 3
Fig. 3
Comparison of time to detection of parasites. Kaplan–Meier plot of the number of infections detected by time since CHMI qPCR (N = 24), TBS (N = 24), uRDT (N = 14) and cRDT (N = 10). All cases were low parasite density Pf infections that occurred during CHMI. P-value 

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