! Cytomegalovirus in critically ill patients Frédéric Pène Medical ICU, Hôpital Cochin, AP-HP, Paris, France Université Paris Descartes, Sorbonne Paris Cité Institut Cochin, Inserm U1016, CNRS UMR-8104 GrrrOH November 26 th 2013
Human Herpes Viruses International Committee on Taxonomy of Viruses Subfamily HHV Name Target tissues / cells Sanctuary cells Alphaherpesvirinae 1 HSV1 Mucous epithelium Neurones Alphaherpesvirinae 2 HSV2 Mucous epithelium Neurones Alphaherpesvirinae 3 VZV Mucous epithelium Neurones Gammaherpesvirinae 4 EBV Epithelium / Lymphocytes B Lymphocytes B Betaherpesvirinae 5 CMV Epithelium / Monocytes / Lymphocytes Monocytes / Lymphocytes Betaherpesvirinae 6 HHV6 Lymphocytes T Lymphocytes T Betaherpesvirinae 7 HHV7 Lymphocytes T Lymphocytes T Gammaherpesvirinae 8 KSHV / HHV8 Endothelial cells? Human Herpes viruses: Biology, Therapy, and Immunoprophylaxis. Arvin A, Campadelli-Fiume G, Mocarski E, et al., Cambridge University Press; 2007. www.ictvonline.org
Primary infection : often asymptomatic Serologic prevalence 30 to 90% Life-long latency in leukocytic sanctuaries Reactivation : Defective cell-mediated immunity (SOT, BMT, AIDS) CMV-related diseases in immunocompromised patients Fever Cytopenia (with or without SALH) Organ involvement (pneumonia, retinitis, colitis, encephalitis, myocarditis, hepatitis)
CMV reactivation rate in critically ill immunocompetent patients Detection Ag Histology Culture Culture Ag Ag >5 ICU days No No Overall reactivation rate 17% [11 24] Kalil & Florescu, Crit Care Med 2009
CMV reactivation rate in critically ill immunocompetent patients Detection Ag Histology Culture Culture Ag Ag >5 ICU days No No Overall reactivation rate 17% [11 24] Kalil & Florescu, Crit Care Med 2009
Virological tools to diagnose CMV reactivation Days after hospital admission pp65 antigenemia Jaber, Chest 2005 Limaye, JAMA 2008
Risk factors for CMV reactivation Positive CMV serology Age Male gender Sepsis Severity Mechanical ventilation Transfusion Use of corticosteroids Length of ICU stay
Pathophysiological mechanisms of CMV reactivation in immunocompetent hosts Cecal ligation and puncture LPS IL-1β TNF-α MCMV reactivation (Day 7 to 21) Cook, J Infect Dis 2002 & Cook, J Virol 2006
Depletion of γδ T-cells in critically ill patients P< 0.05 P< 0.05 Severe sepsis Non-septic shock Healthy Controls Grimaldi, Intensive Care Med (in press)
Variable CMV + (n = 40) CMV (n = 40) p value ICU LOS, days 41 ± 28 31 ± 22 0.04 MV duration, days 35 ± 27 24 ± 20 0.03 1 nosocomial infection VAP UTI CVC colonisation Bacteremia 30 (75%) 11 (28%) 18 (45%) 10 (25%) 15 (38%) 20 (50%) 10 (25%) 10 (25%) 9 (23%) 7 (18%) 0.04 0.8 0.09 0.78 0.05 In-ICU mortality 20 (50%) 11 (28%) 0.02
41.7% 31.6%
Risk factors of death or continued hospitalization by day 30 Multivariate analysis Variable Adjusted OR [95% CI] P value Burn unit 90 [8,3-980] < 0,001 Mechanical ventilation 10,2 [1,9-55,5] 0,007 Major infection 3 [1,1-8,4] 0,04 CMV viremia 4,3 [1,6-11,9] 0,005 CMV viremia > 1000 copies/ml 13,9 [3,2-69] < 0,001 Limaye et al.,
Immunomodulatory properties of CMV Subversion of antigen-presenting cells functions Monocytes Dendritic cells Inhibition of cytotoxicity by NK cells Rossini, Med Infl 2012 Susceptibility of CMV-infected mice to bacterial and fungal infections Hamilton, Infect Immun 1976 & J Infect Dis 1978 Immunocompromised patients (HSCT, solid organ transplantation) Direct organ involvement An independent risk factor for bacterial and fungal infections Kalil, Ann Intern Med 2005; Fukuda, Blood 2003; Bjorklund, Bone Marrow Transplant 2007 Immunocompetent critically ill patients A marker and / or an actor of post-aggressive immune suppression? Reactivation vs. real infection? Direct pathogenicity?
BAL Pulmonary biopsy CMV Cytopathogenic effect (nuclear inclusions)
CMV pneumonia histologically documented in 30 / 100 patients with worsening late ARDS
Polymicrobial sepsis induced by CLP Mice MCMV- (n = 24) Mice MCMV+ (n = 45) Ganciclovir-treated mice MCMV+ (n = 40) MCMV reactivation (Day 14) 0 100% 0
% pulmonary fibrosis at 3 wks
The potential pathogenic role of CMV seems clear in patients with acute lung injury and persistent respiratory failure in whom there is no isolation of bacterial agent as a cause of VAP. The best diagnostic test is not defined although lung biopsies should be considered in addition to the usual methods before starting specific treatment. Ongoing preventive trial NCT01503918 (NHS) Aciclovir/Valaciclovir vs. Ganciclovir/Valganciclovir vs. standard care No curative trial The PTH study: preemptive treatment of Herpesviridae in the ICU
Who and how to treat? Unresolving or worsening ARDS Positive (BAL, biopsy) Histology No alternative explanation Other organ involvement (liver, colon) With positive and histology Viremia without any attributable organ involvement Insufficient level of evidence: no treatment Available drugs Ganciclovir Foscarnet Cidofovir
Conclusions A marker of severity but a potential pathogenic role in critically ill patients development of bacterial infections Persistence of ARDS A large majority of patients with CMV reactivation do not require any specific treatment Treatment only if organ involvement confirmed by cytology or histology Prevention / Treatment : RCT required