How long do rapid diagnostic tests remain positive after anti-malarial treatment?

Abstract

Background: Rapid diagnostic tests (RDTs) are increasingly becoming a paradigm for both clinical diagnosis of malaria infections and for estimating community parasite prevalence in household malaria indicator surveys in malaria-endemic countries. The antigens detected by RDTs are known to persist in the blood after treatment with anti-malarials, but reports on the duration of persistence (and the effect this has on RDT positivity) of these antigens post-treatment have been variable.

Methods: In this review, published studies on the persistence of positivity of RDTs post-treatment are collated, and a bespoke Bayesian survival model is fit to estimate the number of days RDTs remain positive after treatment.

Results: Half of RDTs that detect the antigen histidine-rich protein II (HRP2) are still positive 15 (5-32) days post-treatment, 13 days longer than RDTs that detect the antigen Plasmodium lactate dehydrogenase, and that 5% of HRP2 RDTs are still positive 36 (21-61) days after treatment. The duration of persistent positivity for combination RDTs that detect both antigens falls between that for HRP2- or pLDH-only RDTs, with half of RDTs remaining positive at 7 (2-20) days post-treatment. This study shows that children display persistent RDT positivity for longer after treatment than adults, and that persistent positivity is more common when an individual is treated with artemisinin combination therapy than when treated with other anti-malarials.

Conclusions: RDTs remain positive for a highly variable amount of time after treatment with anti-malarials, and the duration of positivity is highly dependent on the type of RDT used for diagnosis. Additionally, age and treatment both impact the duration of persistence of RDT positivity. The results presented here suggest that caution should be taken when using RDT-derived diagnostic outcomes from cross-sectional data where individuals have had a recent history of anti-malarial treatment.

Keywords: Fever; Malaria; RDT.

Fig. 1

Observed and predicted proportion of RDT negative individuals at 14 and 28 days after treatment from leave-one-out cross-validation. The black line represents 1:1 for observations and predictions

Fig. 2

Fitted relationship between proportion of RDTs still positive within a given sample of individuals, and length of time (number of days) after treatment was first administered. All study groups were used in this fitted relationship. The posterior distribution median (blue line) and 95% credible intervals (light blue shaded area) is displayed

Fig. 3

Fitted relationship between proportion of RDTs still positive within a given sample of individuals, and length of time (number of days) after treatment was first administered, separated by the type of RDT used to monitor patients during the follow-up period. The fitted relationship for study groups monitored with RDTs that detect pLDH only (N study groups = 21) is shown in the top panel (with shaded 95% credible intervals), and the fitted relationship for study groups monitored with RDTs that detect pLDH in combination with HRP2 (N study groups = 6) is in the middle panel (with shaded 95% credible intervals), and the fitted relationship for study groups monitored with RDTs that detect HRP2 only (N study groups = 40) is in the bottom panel (with shaded 95% credible intervals)

Fig. 4

Fitted relationship between proportion of RDTs still positive within a given sample of individuals, and length of time (number of days) after treatment was first administered, separated by the type of anti-malarial medication administered to patients on day 0 of the analysis. The dark green line (with shaded 95% credible intervals) shows the fitted relationship for individuals who received an ACT on day 0 (N study groups = 44), and the fitted relationship for individuals who received a non-ACT anti-malarial medication (either artemisinin monotherapy, chloroquine, quinine, primaquine, sulfadoxine-pyrimethamine, and mefloquine—full details in Additional file 1: Table S1; N study groups=23) is shown by the light green line (with shaded 95% credible intervals)

Fig. 5

Both panels show the fitted relationship between proportion of RDTs still positive within a given sample of individuals, and length of time (number of days) after treatment was first administered, separated by the type of anti-malarial medication administered to patients on day 0 of the analysis. Top panel: fitted relationship by type of anti-malarial medication amongst study groups tested with a pLDH-only RDT. Middle panel: fitted relationship type of anti-malarial medication amongst study groups tested with a HRP2/pLDH combination RDT. Bottom panel: fitted relationship by type of anti-malarial medication amongst study groups tested with a HRP2-only RDT. In each panel, the fitted relationship for individuals who received an ACT is shown by the pink line (with shaded 95% credible intervals), and the fitted relationship for individuals who received a non-ACT is shown by the blue line (with shaded 95% credible intervals)

Fig. 6

Fitted relationship between proportion of RDTs still positive within a given sample of individuals, and length of time (number of days) after treatment was first administered, separated by age. Children 5 years of age or under (N study groups = 28) are represented by the dark blue line and shaded 95% credible intervals; adults 14 years of age or older (N study groups = 3) are represented by the light blue line and shaded 95% credible intervals. Mixed and unknown ages (N study groups = 36) are represented by the dotted blue line (credible intervals are not shown)