Abstract
BackgroundPlasmodium falciparum histidine-rich protein PFHRP2 measurement is used widely for diagnosis, and more recently for severity assessment in falciparum malaria. The Pfhrp2 gene is highly polymorphic, with deletion of the entire gene reported in both laboratory and field isolates. These issues potentially confound the interpretation of PFHRP2 measurements.MethodsStudies designed to detect deletion of Pfhrp2 and its paralog Pfhrp3 were undertaken with samples from patients in seven countries contributing to the largest hospital-based severe malaria trial (AQUAMAT). The quantitative relationship between sequence polymorphism and PFHRP2 plasma concentration was examined in samples from selected sites in Mozambique and Tanzania.ResultsThere was no evidence for deletion of either Pfhrp2 or Pfhrp3 in the 77 samples with lowest PFHRP2 plasma concentrations across the seven countries. Pfhrp2 sequence diversity was very high with no haplotypes shared among 66 samples sequenced. There was no correlation between Pfhrp2 sequence length or repeat type and PFHRP2 plasma concentration.ConclusionsThese findings indicate that sequence polymorphism is not a significant cause of variation in PFHRP2 concentration in plasma samples from African children. This justifies the further development of plasma PFHRP2 concentration as a method for assessing African children who may have severe falciparum malaria. The data also add to the existing evidence base supporting the use of rapid diagnostic tests based on PFHRP2 detection.
Highlights
Plasmodium falciparum histidine-rich protein PFHRP2 measurement is used widely for diagnosis, and more recently for severity assessment in falciparum malaria
This study examined the relationship between Pfhrp2 sequence and plasma PFHRP2 concentration in samples derived from a large group of African children treated for severe malaria in the AQUAMAT trial [23]
Samples Samples were obtained from children enrolled in the AQUAMAT trial, a large multinational trial comparing quinine and artesunate for the treatment of severe malaria in African children undertaken between October 2005 and July 2010 and described in detail elsewhere [23]
Summary
Plasmodium falciparum histidine-rich protein PFHRP2 measurement is used widely for diagnosis, and more recently for severity assessment in falciparum malaria. The Pfhrp gene is highly polymorphic, with deletion of the entire gene reported in both laboratory and field isolates. These issues potentially confound the interpretation of PFHRP2 measurements. Pfhrp did not show inheritance bias in the HB3 x Dd2 cross [15]; low-level transcription in the HB3 parent [16] could potentially explain this in part or in whole. In contrast to these studies on cultured isolates, prior to 2010 no field isolates had been reported which lacked either Pfhrp or Pfhrp. It is concerning that isolates from Mali lacking Pfhrp have been described [19]
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