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Interferon-γ production by natural killer cells and cytomegalovirus in critically ill patients*

Chiche, Laurent MD, PhD; Forel, Jean-Marie MD; Thomas, Guillemette MD; Farnarier, Catherine MD; Cognet, Céline PhD; Guervilly, Christophe MD; Zandotti, Christine MD; Vély, Frédéric PhD; Roch, Antoine MD, PhD; Vivier, Eric DVM, PhD; Papazian, Laurent MD, PhD

doi: 10.1097/CCM.0b013e318260c90e
Clinical Investigations

Objective: The mechanisms involved in cytomegalovirus reactivation in critically ill patients who were previously immunocompetent are still unknown. The current study was designed to evaluate the possible role of natural killer cells in the reactivation of cytomegalovirus in these patients.

Design: Prospective observational.

Setting: A medical intensive care unit of a university hospital.

Patients: Fifty-one subjects, including 15 patients who experienced cytomegalovirus reactivation (cases) during their intensive care unit stay and 15 patients who matched intensive care unit controls, selected from a cohort of consecutive nonimmunocompromised intensive care unit patients, as well as healthy controls.

Interventions: Tests included weekly systematic immunomonitoring and routine screening for cytomegalovirus infection until discharge from the intensive care unit or death. The immunophenotype and functions of natural killer cells were performed by flow cytometry, and serum levels of pro- and anti-inflammatory cytokines were determined by enzyme-linked immunosorbent assay.

Measurements and Main Results: The overall occurrence of cytomegalovirus reactivation in the cohort was 27%. No differences of natural killer cell effector functions were observed at admission between cases and controls. Instead, before cytomegalovirus reactivation, the ability of natural killer cells to secrete interferon-γ was significantly reduced in cases as compared with controls upon stimulation with antibody-coated target cells (p = .029) and with K562 cell stimulation (p = .029). No phenotypic or quantitative differences were observed between cases and controls. Cases exhibited higher levels of interleukin 10 (p = .031) and interleukin 15 (p = .021) than controls before cytomegalovirus reactivation.

Conclusions: Impaired natural killer cell function with reduced interferon-γ secretion precedes the occurrence of cytomegalovirus reactivation among previously immunocompetent critically ill patients.

From the Réanimation-Détresses Respiratoires et Infections Sévères, Assistance Publique Hôpitaux de Marseille, URMITE CNRS-UMR (LC, J-MF, GT, CG, LP), Université Aix-Marseille II, Marseille, France; Centre d’Immunologie de Marseille-Luminy (LC, EV), Aix Marseille Université, Marseille, France; Laboratoire d’Immunologie (LC, GT, CF, CC, FV, EV), Assistance Publique des Hôpitaux de Marseille, Hôpital de la Conception, Marseille, France; and Laboratoire de Virologie (CZ), Assistance Publique Hôpitaux de Marseille, Hôpital de la Timone, Marseille, France.

*See also p. 3313.

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Supported by grants from the Assistance Publique Hôpitaux de Marseille (Appel d’Offre Recherche and by a grant from the Société de Réanimation de Langue Française.

The authors have not disclosed any potential conflicts of interest.

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© 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins