Hraiech et al. Ann. Intensive Care (2019) 9:142 https://doi.org/10.1186/s13613-019-0616-6 RESEARCH Open Access Herpes simplex virus and Cytomegalovirus reactivation among severe ARDS patients under veno-venous ECMO Sami Hraiech1,2* , Eline Bonnardel3, Christophe Guervilly1,2, Cyprien Fabre2, Anderson Loundou2, Jean‑Marie Forel1,2, Mélanie Adda1,2, Gabriel Parzy1,2, Guilhem Cavaille1,2, Benjamin Coifard1,2, Antoine Roch1,2 and Laurent Papazian1,2 Abstract Background: Herpesviridae reactivation among non‑immunocompromised critically ill patients is associated with impaired prognosis, especially during acute respiratory distress syndrome (ARDS). However, little is known about herpes simplex virus (HSV) and Cytomegalovirus (CMV) reactivation occurring in patients with severe ARDS under veno‑venous extracorporeal membrane oxygenation (ECMO). We tried to determine the frequency of Herpesviridae reactivation and its impact on patients’ prognosis during ECMO for severe ARDS. Results: During a 5‑year period, 123 non‑immunocompromised patients with a severe ARDS requiring a veno‑ venous ECMO were included. Sixty‑seven patients (54%) experienced HSV and/or CMV reactivation during ECMO course (20 viral co‑infection, 40 HSV alone, and 7 CMV alone). HSV reactivation occurred earlier than CMV after the beginning of MV [(6–15) vs. 19 (13–29) days; p < 0.01] and after ECMO implementation [(2–8) vs. 14 (10–20) days; p < 0.01]. In univariate analysis, HSV/CMV reactivation was associated with a longer duration of mechanical ventila‑ tion [(22–52.5) vs. 17.5 (9–28) days; p < 0.01], a longer duration of ECMO [15 (10–22.5) vs. 9 (5–14) days; p < 0.01], and a prolonged ICU [29 (19.5–47.5) vs. 16 (9–30) days; p < 0.01] and hospital stay [44 (29–63.5) vs. 24 (11–43) days; p < 0.01] as compared to non‑reactivated patients. However, in multivariate analysis, viral reactivation remained associated with prolonged MV only. When considered separately, both HSV and CMV reactivation were associated with a longer dura‑ tion of MV as compared to non‑reactivation patients [29 (19.5–41) and 28 (20.5–37), respectively, vs. 17.5 (9–28) days; p < 0.05]. Co‑reactivation patients had a longer duration of MV [58.5 (38–72.3); p < 0.05] and ICU stay [51.5 (32.5–69) vs. 27.5 (17.75–35.5) and 29 (20–30.5), respectively] as compared to patients with HSV or CMV reactivation alone. In multivariate analysis, HSV reactivation remained independently associated with a longer duration of MV and hospital length of stay. Conclusions: Herpesviridae reactivation is frequent among patients with severe ARDS under veno‑venous ECMO and is associated with a longer duration of mechanical ventilation. The direct causative link between HSV and CMV reacti‑ vation and respiratory function worsening under ECMO remains to be confrmed. Keywords: ExtraCorporeal Membrane Oxygenation, Acute respiratory distress syndrome, Herpes simplex virus reactivation, Cytomegalovirus reactivation *Correspondence: sami.hraiech@ap‑hm.fr 1 Service de Médecine Intensive ‑ Réanimation, APHM, Hôpital Nord, Marseille, France Full list of author information is available at the end of the article © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. Hraiech et al. Ann. Intensive Care (2019) 9:142 Page 2 of 8 Background and ARDS, no study has investigated the occurrence Herpes simplex virus (HSV) and Cytomegalovirus (CMV) of HSV and/or CMV reactivation in patients under VV belong to the Herpesviridae family and are characterized ECMO. In this study, we aimed to assess the frequency of by an often asymptomatic primo-infection generally dur- herpesviruses reactivation during ECMO course and to ing childhood followed by a latency phase. In immuno- determine its impact on patients’ prognosis. compromised subjects, Herpesviridae are common viral causes of opportunistic infections. But HSV and CMV Methods reactivations are also frequently reported in intensive Study population care unit (ICU) non-immunocompromised patients [1, We conducted an observational, retrospective study in 2]. Reactivation ranges from 13 to 64% and 15 to 45% a medical ICU (ARDS and ECMO referee center) at the for HSV and CMV, respectively [3, 4]. Herpesviridae Marseille University Hospital between December 2011 reactivation in immunocompetent ICU patients is asso- and April 2017. Patients aged 18 or more, hospitalized ciated with poorer outcome [5]. HSV pulmonary reacti- in the ICU for severe ARDS requiring a VV ECMO for vation has been described to be associated with a longer 2 days or more were included. HSV and/or CMV reac- mechanical ventilation (MV) duration, ICU stay and tivation (see defnition below) occurring after ECMO mortality [2, 6, 7]. CMV reactivation is also associated insertion was screened for these patients. Patients with with a higher mortality, MV duration and ICU length of immunosuppression (immunosuppressive treatments stay [8]. In particular, CMV has been identifed as a cause including corticosteroids > 0.5 mg/kg/day prednisone- of persistent acute respiratory distress syndrome (ARDS) equivalent within 30 days prior to inclusion, severe neu- [9] and has also been shown to increase the mortality in tropenia < 0.5 G/L of neutrophils, HIV seropositivity, ARDS patients [10]. However, despite these associations, bone marrow or solid organ transplantation), antiviral the debate on the proper pathogen role of Herpesviridae therapy against HSV and/or CMV prior to inclusion, or rather than being a witness of patients’ severity is still HSV/CMV reactivation known at the time of ECMO ongoing. Studies failed to demonstrate that CMV proph- insertion were excluded. ylaxis was able to decrease Il-6 plasma levels in CMV seropositive critically ill patients [11] or to decrease mor- HSV and CMV reactivation tality [12]. Te role of Herpesviridae pre-emptive treat- At the time of the study, HSV and CMV screening were ment among ICU patients has been recently evaluated in routinely performed twice weekly in all patients under a randomized controlled trial (RCT) (NCT 02152358). MV. Te data concerning HSV showed that preemptive acy- HSV reactivation was defned by a positive qualitative clovir did not decrease the duration of MV although throat sample (Virocult®) PCR. a trend towards lower mortality was found in treated CMV reactivation was defned by a positive quantita- patients [13]. tive blood PCR with a copy number > 500/ml. Te most frequent risk factors for CMV and HSV reac- When a broncho-alveolar lavage (BAL) was performed tivation in the ICU are patients severity, sepsis, prolonged for suspicion of ventilator-associated pneumonia, HSV MV [14], high-dose corticosteroid therapy, acute renal and CMV PCR were systematically realized in BAL and failure or massive transfusion [15], with a strong associa- blood. tion for MV and sepsis [16]. Patients under veno-venous CMV viral loads were converted in IU/ml and quali- extracorporeal membrane oxygenation (VV ECMO) for fed as “high reactivation” for viral loads greater than or severe ARDS [17] often combine several or all of these equal to 1000 IU/ml or “low reactivation” for viral loads risk factors [18]. Despite the uncertainties regarding the of 100–999 IU/ml [10]. exact role of Herpesviridae reactivation in immunocom- CMV antigenemia was also researched in case of reac- petent critically ill patients, it might add to the pulmo- tivation suspicion. nary pathology in patients with ARDS. In experimental studies, CMV reactivation led to increased pulmonary Baseline assessment and data collection fbrosis [19] and accessing bacterial pneumonia [20]. Te following data were retrospectively recorded from Tese fndings suggest that Herpesviridae-related pul- the patients’ medical fle: age, sex, Simplifed Acute Phys- monary pathology may be causally linked to the clinical iologic Score II (SAPS II) [21], Sequential Organ Failure disease course following ARDS onset, especially in the Assessment (SOFA) score [22], presence of co-morbidi- most severely ill patients who require prolonged mechan- ties, presence of previous immunosuppression, cause of ical ventilation, and might particularly concern patients ARDS, date of MV initiation, date of ECMO implemen- under ECMO. However, despite the tight link that seems tation, other organ failure associated with ARDS during to exist between Herpesviridae, mechanical ventilation ICU stay (in particular need for catecholamines or renal Hraiech et al. Ann. Intensive Care (2019) 9:142 Page 3 of 8 replacement therapy), blood transfusion, post-aggressive Ten a multivariate analysis was performed to assess pulmonary fbrosis (defned by an alveolar procollagen III the independent efect of viral reactivation on diferent higher than 9 µg/l) [23], time of HSV/CMV reactivation, outcomes. delay between MV and HSV/CMV reactivation, delay Multiple linear regression was used to construct mod- between ECMO and HSV/CMV reactivation, duration of els. Variables that were marginally signifcant (p < 0.10) MV (from the day of intubation to the day of MV wean- in the univariate analysis, and that had clinical relevance ing), ECMO duration (from the day of ECMO implemen- were included in the regression models. Beta coefcients tation to its removal or death), ECMO-free days at day 28, and their p values were presented.