Plasmodium falciparum Gametocyte Carriage Is Associated with Subsequent Plasmodium vivax Relapse after Treatment

Jessica T Lin,Phisit Khemawoot,Delia Bethell,Duong Socheat,Chanthap Lon,Harald Noedl,Youry Se,Naman K Shah,Mark M Fukuda,Sabaithip Sriwichai,Worachet Kuntawunggin,David L Saunders,Steven R Meshnick,Kurt Schaecher,Stuart D Tyner,Bryan L Smith

doi:10.1371/journal.pone.0018716

Jessica T Lin, Phisit Khemawoot + Show 14 more

Open Access

PDF Available

https://doi.org/10.1371/journal.pone.0018716

Copy DOI

Export

Save

Cite

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

Mixed P. falciparum/P. vivax infections are common in southeast Asia. When patients with P. falciparum malaria are treated and followed for several weeks, a significant proportion will develop P. vivax malaria. In a combined analysis of 243 patients recruited to two malaria treatment trials in western Cambodia, 20/43 (47%) of those with P. falciparum gametocytes on admission developed P. vivax malaria by Day 28 of follow-up. The presence of Pf gametocytes on an initial blood smear was associated with a 3.5-fold greater rate of vivax parasitemia post-treatment (IRR = 3.5, 95% CI 2.0–6.0, p<0.001). The increased rate of post-treatment P. vivax infection persisted when correlates of exposure and immunity such as a history of malaria, male gender, and age were controlled for (IRR = 3.0, 95% CI 1.9–4.7, p<0.001). Polymerase chain reaction (PCR) confirmed that only a low proportion of subjects (5/55 or 9.1%) who developed vivax during follow-up had detectable Pv parasites in the peripheral blood at baseline. Molecular detection of falciparum gametocytes by reverse transcriptase PCR in a subset of patients strengthened the observed association, while PCR detection of Pv parasitemia at follow-up was similar to microscopy results. These findings suggest that the majority of vivax infections arising after treatment of falciparum malaria originate from relapsing liver-stage parasites. In settings such as western Cambodia, the presence of both sexual and asexual forms of P. falciparum on blood smear at presentation with acute falciparum malaria serves as a marker for possible occult P. vivax coinfection and subsequent relapse. These patients may benefit from empiric treatment with an 8-aminoquinolone such as primaquine.

Highlights

Despite prevalence of both P. falciparum and P. vivax in South and Southeast Asia, Oceania, and parts of South America, mixed infections of the two species were rarely reported in the past, with cross-sectional prevalence rates reported at,5% [1]
This estimate is based on Polymerase chain reaction (PCR) detection methods, and on observations from longitudinal treatment trials conducted in the 1980s in which approximately one-third of patients treated for apparent P. falciparum monoinfection developed P. vivax infection within 28 days of treatment with short half-life antimalarials such as artesunate [4,5]
Subsequent antimalarial trials conducted in Southeast Asia and Papua New Guinea have continued to demonstrate high rates of P. vivax infection post-treatment, especially when follow-up is continued beyond the period when the antimalarials used are expected to maintain efficacious drug levels in the bloodstream [6,7]

Summary

Introduction

Despite prevalence of both P. falciparum and P. vivax in South and Southeast Asia, Oceania, and parts of South America, mixed infections of the two species were rarely reported in the past, with cross-sectional prevalence rates reported at ,5% [1]. In Thailand, it is estimated that 25–50% of malaria infections are mixed P. falciparum/P. vivax [1,2,3] This estimate is based on PCR detection methods, and on observations from longitudinal treatment trials conducted in the 1980s in which approximately one-third of patients treated for apparent P. falciparum monoinfection developed P. vivax infection within 28 days of treatment with short half-life antimalarials such as artesunate [4,5]. On the Thai-Burmese border, a retrospective analysis of 15 years of clinical trial data found that the cumulative 63-day risk of vivax malaria after Pf mono-infection was 51% following treatment with rapidly eliminated drugs [9] These high rates of coinfection have led some to advocate for presumptive treatment of liver-stage vivax infection with a full course of primaquine (antihypnozoite therapy) in all patients with microscopically confirmed malaria where both species are endemic [10]. We conducted a retrospective analysis of two malaria treatment trials of uncomplicated falciparum malaria to examine whether falciparum gametocyte carriage at presentation is associated with subsequent P. vivax relapse

Methods

Results

Conclusion