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



In an a priori nested inflammatory biomarker study in a post-intensive care unit (ICU) rehabilitation trial (RECOVER; ISRCTN09412438), surviving adult ICU patients ventilated >48 h were enrolled at ICU discharge and blood sampled at ICU discharge (n=184) and 3 month follow-up (N=123). C-reactive protein (CRP), human neutrophil elastase (HNE), interleukin (IL)-1β, IL-6, IL-8, transforming growth factor β1 (TGFβ1) and secretory leucocyte protease inhibitor (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.



Many patients had persisting inflammation at 3 months (CRP >3 mg/L in 59%; >10 mg/L in 28%), with proinflammatory 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 co-morbidity (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 proinflammatory phenotype at 3 months than seronegative patients, despite undetectable HMCV by PCR testing.



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 proinflammatory phenotype despite the absence of detectable systemic viraemia.



ISRCTN09412438, post results.
Department of Anaesthesia, Critical Care and Pain Medicine, University of Edinburgh, Edinburgh, UK MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK Department of Critical Care, Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK.
David M
0000-0001-9500-241X
DM
Griffith
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
Steff
S
Lewis
MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Adriano G
AG
Rossi
MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Jillian
J
Rennie
School of Health in Social Science, University of Edinburgh, Edinburgh, UK.
Lisa
L
Salisbury
Department of Critical Care, Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK.
Judith L
JL
Merriweather
Department of Medical Microbiology, Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK.
Kate
K
Templeton
Department of Anaesthesia, Critical Care and Pain Medicine, University of Edinburgh, Edinburgh, UK MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK Department of Critical Care, Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK.
Timothy S
TS
Walsh
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D016638:Critical Illness / Q000534:rehabilitation*; D003587:Cytomegalovirus / Q000302:isolation & purification; D003586:Cytomegalovirus Infections / Q000150:complications; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007362:Intensive Care Units; D007902:Length of Stay / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D020127:Recovery of Function; D018746:Systemic Inflammatory Response Syndrome / Q000175:diagnosis / Q000534:rehabilitation* / Q000821:virology
D015415:Biomarkers; D018836:Inflammation Mediators; D002097:C-Reactive Protein
Assisted Ventilation; Exercise; Innate Immunity