Systemic inflammation after critical illness: relationship with physical recovery and exploration of potential mechanisms

Background: Physical recovery following critical illness is slow, often incomplete, and is resistant to rehabilitation interventions. We aimed to explore the contribution of persisting inflammation to recovery, and investigated the potential role of human cytomegalovirus (HCMV) infection in its pathogenesis. 
Methods: In an a priori nested inflammatory biomarker study in a post-intensive care (ICU) rehabilitation trial (RECOVER; ISRCTN09412438), surviving adult ICU patients ventilated >48 hours were enrolled at ICU discharge and blood sampled at ICU discharge (n=184) and 3 month follow-up (N=123). CRP, HNE, IL-1β, IL-6, IL-8, TGFβ, and SLPI were measured. HCMV IgG status was determined (previous exposure), and DNA PCR measured among seropositive patients (lytic infection). Physical outcome measures including the Rivermead Mobility Index (RMI) were measured at 3 months.
Results: Many patients had persisting inflammation at 3 months (CRP >3mg/L in 59%; >10mg/L in 28%), with pro-inflammatory phenotype (elevated HNE, IL-6, IL-8, SLPI; low TGFβ1). Poorer mobility (RMI) was associated with higher CRP (β=0.13; p<0.01) and HNE (β=0.32; p=0.03), even after adjustment for severity of acute illness and pre-existing comorbidity (CRP β=0.14; p=<0.01; HNE β=0.30; p=0.04). Patients seropositive for HCMV at ICU discharge (63%) had a more pro-inflammatory phenotype at 3 months than seronegative patients, despite undetectable HMCV by PCR testing.
Conclusion: Inflammation is prevalent after critical illness and is associated with poor physical recovery during the first 3 months post-ICU discharge. Previous HCMV exposure is associated with a pro-inflammatory phenotype despite absence of detectable systemic viraemia.