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

Background Parasite density thresholds for diagnosing symptomatic malaria are defined by the relationship between parasitaemia and fever; they inform the development of novel diagnostic tests. Thresholds for diagnosing Plasmodium vivax malaria remain poorly defined. Methods We undertook an individual patient data meta-analysis of P. vivax clinical trials mapped to the WorldWide Anti-Malarial Resistance Network (WWARN) repository and used parasitaemia centiles of febrile patients at enrolment to derive the proportion of patients who would have been diagnosed at different symptomatic parasite densities. Febrile and afebrile patients with recurrent infections during follow-up were selected to determine pyrogenic densities using receiver operating characteristic curve analysis. Results In total 13,263 patients from 50 studies were included in the analysis. In 27 studies that did not apply a parasitaemia threshold as an inclusion criterion, the median parasitaemia of 8,378 febrile patients 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 parasitaemia centile was higher in children < 5 years old (368/µL) compared to adults ≥15 years (240/µL). In regions of high relapse periodicity (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). Trial registration This trial was registered with PROSPERO: CRD42021254905. The date of the first registration was 17th May 2021.