Plasma cell-free DNA predicts pediatric cerebral malaria severity.
Infectious disease
Inflammation
Malaria
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
18 06 2020
18 06 2020
Historique:
received:
09
01
2020
accepted:
20
05
2020
entrez:
20
6
2020
pubmed:
20
6
2020
medline:
9
6
2021
Statut:
epublish
Résumé
BACKGROUNDPrediction of adverse outcomes in cerebral malaria (CM) is difficult. We hypothesized that cell-free DNA (cfDNA) levels would facilitate identification of severe and potentially fatal CM cases.METHODSIn this retrospective study, plasma from Malawian children with CM (n = 134), uncomplicated malaria (UM, n = 77), and healthy controls (HC, n = 60) was assayed for cfDNA using a fluorescence assay. Host and parasite cfDNA was measured by quantitative PCR. Immune markers were determined by ELISA, Luminex, or cytometric bead array.RESULTSTotal cfDNA increased with malaria severity (HC versus UM, P < 0.001; HC versus CM, P < 0.0001; UM versus CM, P < 0.0001), was elevated in retinopathy-positive (Ret+) CM relative to Ret- CM (7.66 versus 5.47 ng/μL, P = 0.027), and differentiated Ret+ fatal cases from survivors (AUC 0.779; P < 0.001). cfDNA levels in patients with non-malarial febrile illness (NMF, P = 0.25) and non-malarial coma (NMC, P = 0.99) were comparable with UM. Host DNA, rather than parasite DNA, was the major cfDNA contributor (UM, 268 versus 67 pg/μL; CM, 2824 versus 463 pg/μL). Host and parasite cfDNA distinguished CM by retinopathy (host, AUC 0.715, P = 0.0001; parasite, AUC 0.745, P = 0.0001), but only host cfDNA distinguished fatal cases (AUC 0.715, P = 0.0001). Total cfDNA correlated with neutrophil markers IL-8 (rs = 0.433, P < 0.0001) and myeloperoxidase (rs = 0.683, P < 0.0001).CONCLUSIONQuantifying plasma cfDNA is a simple assay useful in identifying children at risk for fatal outcome and has promise as a point-of-care assay. Elevated cfDNA suggests a link with host inflammatory pathways in fatal CM.FUNDINGNIH NCATS (AK), Burroughs-Wellcome (AK), and National Health and Medical Research Council of Australia (SJR).
Identifiants
pubmed: 32554925
pii: 136279
doi: 10.1172/jci.insight.136279
pmc: PMC7406267
doi:
pii:
Substances chimiques
Biomarkers
0
Cell-Free Nucleic Acids
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCATS NIH HHS
ID : TL1 TR001072
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002556
Pays : United States
Références
J Infect Dis. 2013 Aug 1;208(3):500-3
pubmed: 23630364
Nat Med. 2004 Feb;10(2):143-5
pubmed: 14745442
N Engl J Med. 2015 Mar 19;372(12):1126-37
pubmed: 25785970
J Infect Dis. 2006 Sep 15;194(6):837-45
pubmed: 16941352
Am J Trop Med Hyg. 2010 Feb;82(2):231-4
pubmed: 20133998
Malar J. 2009 Dec 15;8:295
pubmed: 20003529
Cold Spring Harb Protoc. 2017 Jun 1;2017(6):pdb.prot094730
pubmed: 27803271
Cancer Res. 2001 Feb 15;61(4):1659-65
pubmed: 11245480
J Infect Dis. 2015 Apr 1;211(7):1128-33
pubmed: 25344520
mBio. 2015 Sep 22;6(5):e01390-15
pubmed: 26396242
Crit Care Med. 2012 Mar;40(3):952-9
pubmed: 22343839
Sci Immunol. 2019 Oct 18;4(40):
pubmed: 31628160
Crit Care. 2005 Aug;9(4):R458-63
pubmed: 16137361
Heliyon. 2018 Jul 25;4(7):e00699
pubmed: 30094369
J Infect Dis. 2019 May 24;219(12):1994-2004
pubmed: 30452670
PLoS Med. 2012;9(8):e1001297
pubmed: 22927801
Blood Adv. 2019 Mar 12;3(5):724-728
pubmed: 30814057
Nat Rev Immunol. 2014 Nov;14(11):744-57
pubmed: 25324127
Sci Rep. 2017 Dec 12;7(1):17421
pubmed: 29234042
Nat Rev Cancer. 2011 Jun;11(6):426-37
pubmed: 21562580
Curr Opin Crit Care. 2014 Oct;20(5):557-65
pubmed: 25137401
BMC Med. 2017 Jan 24;15(1):15
pubmed: 28114931
PLoS One. 2013 Aug 29;8(8):e71539
pubmed: 24009663
Arch Ophthalmol. 2000 Jul;118(7):924-8
pubmed: 10900105
Trends Parasitol. 2016 May;32(5):378-391
pubmed: 26847654
Malar J. 2008 May 19;7:83
pubmed: 18489763
J Leukoc Biol. 2017 Sep;102(3):775-781
pubmed: 28465447
Nat Microbiol. 2019 Apr;4(4):663-674
pubmed: 30742071
Elife. 2017 Jun 07;6:
pubmed: 28590246
J Thromb Haemost. 2015 Sep;13(9):1653-64
pubmed: 26186686
Expert Rev Hematol. 2017 Jan;10(1):99-106
pubmed: 27936979
Front Immunol. 2019 Mar 19;10:502
pubmed: 30941136
J Infect Dis. 2009 Jun 1;199(11):1567-74
pubmed: 19432544
Curr Pharm Biotechnol. 2018;19(15):1203-1209
pubmed: 30636600
Eur J Hum Genet. 2018 Jul;26(7):937-945
pubmed: 29681621
Ophthalmology. 1993 Jun;100(6):857-61
pubmed: 8510897
Nat Rev Immunol. 2018 Feb;18(2):134-147
pubmed: 28990587
Malar J. 2006 Nov 08;5:103
pubmed: 17092335
Malar J. 2018 Nov 26;17(1):435
pubmed: 30477519
Nature. 2002 Oct 3;419(6906):498-511
pubmed: 12368864
mBio. 2016 Feb 16;7(1):e01300-15
pubmed: 26884431
Lancet. 1990 Nov 17;336(8725):1201-4
pubmed: 1978068
Cancer Biol Ther. 2019;20(8):1057-1067
pubmed: 30990132
PLoS One. 2010 Dec 29;5(12):e15291
pubmed: 21209923
F1000Res. 2017 Nov 22;6:2039
pubmed: 29250318
Nat Commun. 2017 Dec 7;8(1):1985
pubmed: 29215015
Lancet. 2018 Apr 21;391(10130):1608-1621
pubmed: 29631781
Ann N Y Acad Sci. 2001 Sep;945:234-8
pubmed: 11708485
Malar J. 2014 Jul 21;13:279
pubmed: 25047113
Cell Host Microbe. 2017 Nov 8;22(5):601-614.e5
pubmed: 29107642
Open Forum Infect Dis. 2017 Jul 22;4(3):ofx151
pubmed: 28948179
Am J Trop Med Hyg. 2002 Jun;66(6):686-91
pubmed: 12224575
J Infect Dis. 2012 Aug 1;206(3):309-18
pubmed: 22634877
Am J Pathol. 2012 Mar;180(3):1028-1039
pubmed: 22260922
Biol Res Nurs. 2016 Oct;18(5):477-88
pubmed: 27067611
Nature. 2001 Feb 15;409(6822):860-921
pubmed: 11237011
Am J Trop Med Hyg. 2017 May;96(5):1176-1184
pubmed: 28138045
Nat Commun. 2017 Nov 3;8(1):1282
pubmed: 29101363
J Thromb Haemost. 2015 Jun;13 Suppl 1:S82-91
pubmed: 26149054
PLoS Med. 2005 Aug;2(8):e204
pubmed: 16104831
J Infect Dis. 2015 Jun 15;211(12):1977-86
pubmed: 25351204
PLoS One. 2011;6(7):e21700
pubmed: 21747948
PLoS One. 2011;6(5):e19842
pubmed: 21611202