Parasitaemia and fever in uncomplicated Plasmodium vivax malaria: A systematic review and individual patient data meta-analysis

Abstract

Background: Parasite density thresholds used for diagnosing symptomatic malaria are defined by the relationship between parasitaemia and fever. This relationship can inform the design and development of novel diagnostic tests but appropriate parasitaemia thresholds for Plasmodium vivax malaria remain poorly defined.

Methodology/principal findings: We undertook an individual patient data meta-analysis of P. vivax clinical trials mapped to the WorldWide Antimalarial Resistance Network (WWARN) repository and used parasitaemia centiles of febrile patients at enrolment to derive proportions of patients who would have been diagnosed at different parasite densities. Febrile and afebrile patients with recurrent infections were selected to estimate pyrogenic densities using receiver operating characteristic curve analysis. In total 13,263 patients from 50 studies were included in the analysis. In 27 studies (8,378 febrile patients) in which a parasitaemia threshold was not applied as an inclusion criterion, the median parasitaemia at enrolment was 3,280/µL (interquartile range, 968 - 8,320); 90% of patients had a parasitaemia above 278/µL (10th centile), and 95% above 120/µL (5th centile). The 10th centile was higher in children <5 years old (368/µL) compared to adults ≥15 years (240/µL). In high relapse periodicity regions (Southeast Asia and Oceania) febrile patients presented with lower parasitaemias (10th centile 185/µL vs. 504/µL) and a wider range of parasitaemias compared to those from low relapse periodicity regions (interquartile range 760/µL - 8,774/µL vs. 1,204/µL - 8,000/µL). In total 2,270 patients from 41 studies had at least one episode of recurrent P. vivax parasitaemia, of whom 43% (849/1,983) were febrile at their first recurrence. The P. vivax pyrogenic density at first recurrence was 1,063/µL, defining fever with 74% sensitivity and 65% specificity. The pyrogenic density was lower in young children compared to adults ≥15 years (935/µL vs. 1,179/µL).

Conclusions/significance: The derived parasitaemia centiles will inform the use of current and the design of novel point-of-care tests to diagnose patients with symptomatic vivax malaria. Variation by age and location should be considered when selecting diagnostic thresholds and interpreting results.

Trial registration: This trial was registered with PROSPERO: CRD42021254905. The date of the first registration was 17th May 2021.

Fig 1. Study and patient flow diagram.

Fig 2. Distribution of parasite density at enrolment in febrile participants presenting with P. vivax malaria.

The dashed lines indicate the 1^st, 5^th, 10^th, 25^th and 50^th parasitaemia centiles. Includes the 99% (8,378/8,453) of participants enrolled into 27 clinical efficacy studies who were symptomatic with a fever or history of fever.

Fig 3. Parasitaemia centiles for febrile participants at enrolment by A) age group (years) and B) relapse periodicity region.

The boxes describe the 25^th-75^th parasitaemia centiles with the 50^th centile at the internal line.

Fig 4. Parasitaemia centiles for febrile participants at enrolment by relapse periodicity region and age group (years).

The box describes the 25^th-75^th parasitaemia centiles with the 50^th centile at the internal line.

Fig 5. Percentage of participants with and without fever at the time recurrent parasitaemia was observed.

Fig 6. Parasite density distribution by fever status at first P. vivax recurrence.