title: Association between Subclinical Malaria Infection and Inflammatory Host Response in a Pre-Elimination Setting.
abstract: BACKGROUND
  Subclinical infections in endemic areas of Southeast Asia sustain malaria transmission. These asymptomatic infections might sustain immunity against clinical malaria and have been considered benign for the host, but if they are associated with chronic low-grade inflammation this could be harmful. We conducted a case-control study to explore the association between subclinical malaria and C-reactive protein (CRP), an established biomarker of inflammation.
  
  
  METHODS
  Blood samples from asymptomatic villagers in Pailin, Western Cambodia were tested for malaria by high-volume ultra-sensitive polymerase chain reaction (uPCR) to determine the Plasmodium species. Plasma CRP concentration was measured in 328 individuals with parasitaemia (cases) and compared with: i) the same individual's value at the first time point when they had no detectable parasites (n = 282); and ii) age- sex- and village-matched controls (n = 328) free of Plasmodium infection. Plasma CRP concentrations were compared against thresholds of 3mg/L and 10mg/L. Subgroup analysis was carried out for cases with P vivax and P falciparum mono-infections.
  
  
  RESULTS
  Median plasma CRP level for all samples was 0.59mg/L (interquartile range: 0.24-1.64mg/L). CRP concentrations were higher in parasitaemic individuals compared with same-person-controls (p = 0.050); and matched-controls (p = 0.025). 4.9% of samples had CRP concentrations above 10mg/L and 14.6% were above 3mg/L. Cases were more likely to have plasma CRP concentrations above these thresholds than age/sex matched controls, odds ratio 3.5 (95%CI 1.5-9.8) and 1.8 (95%CI 1.1-2.9), respectively. Amongst cases, parasite density and CRP were positively correlated (p<0.001), an association that remained significant when controlling for age and fever. Individuals with P.vivax mono-infections had the highest plasma CRP concentrations with the greatest association with parasitaemia.
  
  
  CONCLUSIONS
  In this setting persistent malaria infections in asymptomatic individuals were associated with moderately elevated plasma CRP concentrations; chiefly evident in cases with P.vivax mono-infections. As well as interrupting malaria transmission within the community, treatment of asymptomatic malaria infections, in particular radical cure of vivax malaria, may benefit the health of infected individuals.
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Peto
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Rupam
authors.initials: R
authors.lastname: Tripura
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
authors.forename: Sue J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Thomas
authors.initials: T
authors.lastname: Althaus
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
authors.forename: Susanna
authors.initials: S
authors.lastname: Dunachie
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Chea
authors.initials: C
authors.lastname: Nguon
authors.affiliation: Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.|Worldwide Antimalarial Resistance Network, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Mehul
authors.initials: M
authors.lastname: Dhorda
authors.affiliation: Worldwide Antimalarial Resistance Network, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Cholrawee
authors.initials: C
authors.lastname: Promnarate
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chalk
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Mallika
authors.initials: M
authors.lastname: Imwong
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
authors.forename: Lorenz
authors.initials: L
authors.lastname: von Seidlein
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Day
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
authors.forename: Yoel
authors.initials: Y
authors.lastname: Lubell
mesh_terms: D000293:Adolescent; D000328:Adult; D058345:Asymptomatic Infections / Q000453:epidemiology*; D002097:C-Reactive Protein / Q000032:analysis; D002160:Cambodia; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007249:Inflammation; D016778:Malaria, Falciparum / Q000276:immunology*; D016780:Malaria, Vivax / Q000276:immunology*; D008297:Male; D018512:Parasitemia / Q000276:immunology; D010963:Plasmodium falciparum; D010966:Plasmodium vivax; D016133:Polymerase Chain Reaction
chemical_list: D002097:C-Reactive Protein