Author(s):
|
Ramakers, B.P.C.
; Giamarellos-Bourboulis, E.J.; Tasioudis, C.;
Coenen, M.J.
;
Kox, M.
;
Vermeulen, H.H.
;
Groothuismink, J.M.
;
Hoeven, J.G. van der
; Routsi, C.; Savva, A.; Prekates, A.; Diamantea, F.; Sinapidis, D.;
Smits, P.
; Toutouzas, K.;
Riksen, N.P.
;
Pickkers, P.
|
Subject:
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Radboudumc 0: Other Research RIHS: Radboud Institute for Health Sciences Radboudumc 15: Urological cancers RIHS: Radboud Institute for Health Sciences Radboudumc 16: Vascular damage RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 4: lnfectious Diseases and Global Health RIHS: Radboud Institute for Health Sciences Radboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 5: Inflammatory diseases RIHS: Radboud Institute for Health Sciences |
Organization:
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Intensive Care Human Genetics Health Evidence Pharmacology-Toxicology Internal Medicine |
Abstract:
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INTRODUCTION: Adenosine exerts anti-inflammatory and tissue-protective effects during systemic inflammation. While the tissue-protective effects might limit organ damage, its anti-inflammatory properties may induce immunoparalysis and impede bacterial clearance. The common 34C>T loss-of-function variant of AMPD1 (rs17602729) is associated with increased adenosine formation, but effects on immune function and outcome in sepsis patients are unknown. METHODS: The effects of the presence of the 34C>T variant on sepsis susceptibility, immune function, multi-organ dysfunction, and mortality in septic patients were studied. Patients suffering from community acquired pneumonia (CAP, initial cohort n = 285; replication cohort n = 212) and ventilator-associated pneumonia (VAP, n = 117; n = 33) and control patients without infection (n = 101) were enrolled. Genetic distributions of the AMPD1 SNP were CC 76%, CT 22%, and TT 2% in the initial cohort and CC 80%, CT 18%, and TT 2% in the replication cohort. RESULTS: The occurrence of septic CAP, but not septic VAP, was increased for the CT versus CC genotype (OR (95% CI) 2.0 (1.1-3.7); P = 0.02) in the initial cohort. The increased risk for the CT versus CC genotype was also observed in the replication cohort but did not reach statistical significance there (P = 0.38), resulting in an OR of the total group of 1.7 (95% CI 1.0-3.1), P = 0.07. In septic patients carrying the CT genotype, the ex vivo production of TNF-alpha by LPS-stimulated monocytes was attenuated (P = 0.005), indicative of a more pronounced immunoparalytic state in these patients. CONCLUSIONS: Presence of the AMPD1 34C>T variant is associated with higher infection susceptibility to CAP, but not to VAP. More pronounced immunoparalysis in these patients mediated by the anti-inflammatory effects of adenosine may account for this observation.
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