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Systemic inflammation after critical illness: relationship with physical recovery, and exploration of potential mechanismsCorresponding AuthorDavid M Griffith MD ( REF _Ref308381550 \r 1, REF _Ref308381593 \r 3, REF _Ref308381596 \r 4)Senior Clinical Research Fellow,Anaesthesia, Critical Care and Pain Medicine,University of Edinburgh, Royal Infirmary of Edinburgh,57 Little France Crescent,EH16 4SA.david.m.griffith@ed.ac.ukTelephone: 0131 242 7364Co-AuthorsSteff Lewis PhD ( REF _Ref308381620 \r 2)Adriano G Rossi PhD ( REF _Ref308381593 \r 3)Jillian Rennie BSc ( REF _Ref308381593 \r 3)Lisa Salisbury PhD (5)Judith Merriweather PhD ( REF _Ref308381550 \r 1)Kate Templeton PhD ( REF _Ref308381596 \r 4)Timothy S Walsh MD ( REF _Ref308381550 \r 1, REF _Ref308381593 \r 3, REF _Ref308381596 \r 4)RECOVER Investigators (1) Author AffiliationsAnaesthesia, Critical Care and Pain Medicine, University of Edinburgh, Edinburgh, UKCentre for Population Health Sciences, University of Edinburgh, Edinburgh, UKMRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UKRoyal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UKSchool of Health in Social Science, University of Edinburgh, Edinburgh, UKKeywordsCritical Care, Inflammation, Physical Recovery, CytomegalovirusWord Count 3708AbstractBackgroundPhysical 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. MethodsIn 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.ResultsMany 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.ConclusionInflammation 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. Word count 241introductionSurvivors of critical illness suffer physical weakness and functional impairment that can be severe and long lasting. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7m4oin3h6","properties":{"formattedCitation":"[1,2]","plainCitation":"[1,2]"},"citationItems":[{"id":52,"uris":[""],"uri":[""],"itemData":{"id":52,"type":"article-journal","title":"Functional disability 5 years after acute respiratory distress syndrome","container-title":"New England Journal of Medicine","page":"1293-304","volume":"364","issue":"14","archive_location":"21470008","ISSN":"1533-4406","shortTitle":"Functional disability 5 years after acute respiratory distress syndrome","journalAbbreviation":"N Engl J Med","language":"English","author":[{"family":"Herridge","given":"Margaret S."},{"family":"Tansey","given":"Catherine M."},{"family":"Matte","given":"Andrea"},{"family":"Tomlinson","given":"George"},{"family":"Diaz-Granados","given":"Natalia"},{"family":"Cooper","given":"Andrew"},{"family":"Guest","given":"Cameron B."},{"family":"Mazer","given":"C. David"},{"family":"Mehta","given":"Sangeeta"},{"family":"Stewart","given":"Thomas E."},{"family":"Kudlow","given":"Paul"},{"family":"Cook","given":"Deborah"},{"family":"Slutsky","given":"Arthur S."},{"family":"Cheung","given":"Angela M."},{"family":"Canadian Critical Care Trials","given":"Group"}],"issued":{"date-parts":[["2011",4,7]]}}},{"id":252,"uris":[""],"uri":[""],"itemData":{"id":252,"type":"article-journal","title":"A framework for diagnosing and classifying intensive care unit-acquired weakness","container-title":"Crit Care Med","page":"S299-308","volume":"37","issue":"10 Suppl","source":"NLM","archive_location":"20046114","abstract":"Neuromuscular dysfunction is prevalent in critically ill patients, is associated with worse short-term outcomes, and is a determinant of long-term disability in intensive care unit survivors. Diagnosis is made with the help of clinical, electrophysiological, and morphological observations; however, the lack of a consistent nomenclature remains a barrier to research. We propose a simple framework for diagnosing and classifying neuromuscular disorders acquired in critical illness.","DOI":"10.1097/CCM.0b013e3181b6ef67","ISSN":"0090-3493","shortTitle":"A framework for diagnosing and classifying intensive care unit-acquired weakness","journalAbbreviation":"Critical care medicine","language":"eng","author":[{"family":"Stevens","given":"R. D."},{"family":"Marshall","given":"S. A."},{"family":"Cornblath","given":"D. R."},{"family":"Hoke","given":"A."},{"family":"Needham","given":"D. M."},{"family":"Jonghe","given":"B.","non-dropping-particle":"de"},{"family":"Ali","given":"N. A."},{"family":"Sharshar","given":"T."}],"issued":{"date-parts":[["2009",10]]}}}],"schema":""} [1,2] Understanding of the pathophysiological processes that result in neuromuscular dysfunction during critical illness is improving, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2q66dkqg75","properties":{"formattedCitation":"[3,4]","plainCitation":"[3,4]"},"citationItems":[{"id":264,"uris":[""],"uri":[""],"itemData":{"id":264,"type":"article-journal","title":"Myopathy in critically ill patients","container-title":"Crit Care Med","page":"2544-7","volume":"27","issue":"11","source":"NLM","archive_location":"10579278","abstract":"OBJECTIVE: To review myopathic changes occurring during intensive care treatment in the light of recent information about manifestation, clinical settings, pathophysiology, and histomorphologic changes. DATA SOURCES: The computerized MEDLINE database, bibliography of pertinent articles, and the author's personal files. STUDY SELECTION: Studies were selected according to their relevance to myopathic complications in critically ill patients. DATA EXTRACTION: All applicable data were extracted. DATA SYNTHESIS: Myopathic changes occur frequently in patients treated in the intensive care unit (ICU). Three main types have been identified: critical illness myopathy, myopathy with selective loss of myosin filaments, and acute necrotizing myopathy of intensive care. These histologic types probably represent variable expressions of a toxic effect not yet identified. Candidates for such myotoxic effects are the mediators of the systemic response in sepsis and high-dose administration of corticosteroids and muscle relaxants. The influence of these latter agents appears to be particularly important in the pathogenesis of myosin loss and myonecrosis. Experimental studies suggest that axonal damage attributable to critical illness neuropathy can be an additional factor triggering myopathies in the ICU. Muscle membrane inexcitability was recently identified as an alternative mechanism of severe weakness in ICU patients. CONCLUSIONS: Myopathic changes are surprisingly frequent in critically ill patients. The clinical importance of this finding is still unknown, but it is likely that weakness caused by myopathy prolongs ICU stay and rehabilitation. Because corticosteroids and muscle relaxants appear to trigger some types of ICU myopathy, they should be avoided or administered at the lowest doses possible. Sepsis, denervation, and muscle membrane inexcitability may be additional factors. Studies addressing the pathophysiology of myopathy in critically ill patients are urgently needed.","ISSN":"0090-3493 (Print) 0090-3493","shortTitle":"Myopathy in critically ill patients","journalAbbreviation":"Critical care medicine","language":"eng","author":[{"family":"Hund","given":"E."}],"issued":{"date-parts":[["1999",11]]}}},{"id":392,"uris":[""],"uri":[""],"itemData":{"id":392,"type":"article-journal","title":"Acute skeletal muscle wasting in critical illness","container-title":"Jama","page":"1591-600","volume":"310","issue":"15","source":"NLM","archive_location":"24108501","abstract":"IMPORTANCE: Survivors of critical illness demonstrate skeletal muscle wasting with associated functional impairment. OBJECTIVE: To perform a comprehensive prospective characterization of skeletal muscle wasting, defining the pathogenic roles of altered protein synthesis and breakdown. DESIGN, SETTING, AND PARTICIPANTS: Sixty-three critically ill patients (59% male; mean age: 54.7 years [95% CI, 50.0-59.6 years]) with an Acute Physiology and Chronic Health Evaluation II score of 23.5 (95% CI, 21.9-25.2) were prospectively recruited within 24 hours following intensive care unit (ICU) admission from August 2009 to April 2011 at a university teaching and a community hospital in England. Patients were recruited if older than 18 years and were anticipated to be intubated for longer than 48 hours, to spend more than 7 days in critical care, and to survive ICU stay. MAIN OUTCOMES AND MEASURES: Muscle loss was determined through serial ultrasound measurement of the rectus femoris cross-sectional area (CSA) on days 1, 3, 7, and 10. In a subset of patients, the fiber CSA area was quantified along with the ratio of protein to DNA on days 1 and 7. Histopathological analysis was performed. In addition, muscle protein synthesis, breakdown rates, and respective signaling pathways were characterized. RESULTS: There were significant reductions in the rectus femoris CSA observed at day 10 (-17.7% [95% CI, -25.9% to 8.1%]; P < .001). In the 28 patients assessed by all 3 measurement methods on days 1 and 7, the rectus femoris CSA decreased by 10.3% (95% CI, 6.1% to 14.5%), the fiber CSA by 17.5% (95% CI, 5.8% to 29.3%), and the ratio of protein to DNA by 29.5% (95% CI, 13.4% to 45.6%). Decrease in the rectus femoris CSA was greater in patients who experienced multiorgan failure by day 7 (-15.7%; 95% CI, -27.7% to 11.4%) compared with single organ failure (-3.0%; 95% CI, -5.3% to 2.1%) (P < .001), even by day 3 (-8.7% [95% CI, -59.3% to 50.6%] vs -1.8% [95% CI, -12.3% to 10.5%], respectively; P = .03). Myofiber necrosis occurred in 20 of 37 patients (54.1%). Protein synthesis measured by the muscle protein fractional synthetic rate was depressed in patients on day 1 (0.035%/hour; 95% CI, 0.023% to 0.047%/hour) compared with rates observed in fasted healthy controls (0.039%/hour; 95% CI, 0.029% to 0.048%/hour) (P = .57) and increased by day 7 (0.076% [95% CI, 0.032%-0.120%/hour]; P = .03) to rates associated with fed controls (0.065%/hour [95% CI, 0.049% to 0.080%/hour]; P = .30), independent of nutritional load. Leg protein breakdown remained elevated throughout the study (8.5 [95% CI, 4.7 to 12.3] to 10.6 [95% CI, 6.8 to 14.4] mumol of phenylalanine/min/ideal body weight x 100; P = .40). The pattern of intracellular signaling supported increased breakdown (n = 9, r = -0.83, P = .005) and decreased synthesis (n = 9, r = -0.69, P = .04). CONCLUSIONS AND RELEVANCE: Among these critically ill patients, muscle wasting occurred early and rapidly during the first week of critical illness and was more severe among those with multiorgan failure compared with single organ failure. These findings may provide insights into skeletal muscle wasting in critical illness.","DOI":"10.1001/jama.2013.278481","ISSN":"0098-7484","shortTitle":"Acute skeletal muscle wasting in critical illness","journalAbbreviation":"Jama","language":"eng","author":[{"family":"Puthucheary","given":"Z. A."},{"family":"Rawal","given":"J."},{"family":"McPhail","given":"M."},{"family":"Connolly","given":"B."},{"family":"Ratnayake","given":"G."},{"family":"Chan","given":"P."},{"family":"Hopkinson","given":"N. S."},{"family":"Phadke","given":"R."},{"family":"Dew","given":"T."},{"family":"Sidhu","given":"P. S."},{"family":"Velloso","given":"C."},{"family":"Seymour","given":"J."},{"family":"Agley","given":"C. C."},{"family":"Selby","given":"A."},{"family":"Limb","given":"M."},{"family":"Edwards","given":"L. M."},{"family":"Smith","given":"K."},{"family":"Rowlerson","given":"A."},{"family":"Rennie","given":"M. J."},{"family":"Moxham","given":"J."},{"family":"Harridge","given":"S. D."},{"family":"Hart","given":"N."},{"family":"Montgomery","given":"H. E."}],"issued":{"date-parts":[["2013",10,16]]}}}],"schema":""} [3,4] but there is little evidence that interventions delivered after injury has occurred can improve physical outcomes. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"g4s1llg0f","properties":{"formattedCitation":"[5]","plainCitation":"[5]"},"citationItems":[{"id":381,"uris":[""],"uri":[""],"itemData":{"id":381,"type":"article-journal","title":"An official American Thoracic Society Clinical Practice guideline: the diagnosis of intensive care unit-acquired weakness in adults","container-title":"Am J Respir Crit Care Med","page":"1437-46","volume":"190","issue":"12","source":"NLM","archive_location":"25496103","abstract":"RATIONALE: Profound muscle weakness during and after critical illness is termed intensive care unit-acquired weakness (ICUAW). OBJECTIVES: To develop diagnostic recommendations for ICUAW. METHODS: A multidisciplinary expert committee generated diagnostic questions. A systematic review was performed, and recommendations were developed using the Grading, Recommendations, Assessment, Development, and Evaluation (GRADE) approach. MEASUREMENT AND MAIN RESULTS: Severe sepsis, difficult ventilator liberation, and prolonged mechanical ventilation are associated with ICUAW. Physical rehabilitation improves outcomes in heterogeneous populations of ICU patients. Because it may not be feasible to provide universal physical rehabilitation, an alternative approach is to identify patients most likely to benefit. Patients with ICUAW may be such a group. Our review identified only one case series of patients with ICUAW who received physical therapy. When compared with a case series of patients with ICUAW who did not receive structured physical therapy, evidence suggested those who receive physical rehabilitation were more frequently discharged home rather than to a rehabilitative facility, although confidence intervals included no difference. Other interventions show promise, but fewer data proving patient benefit existed, thus precluding specific comment. Additionally, prior comorbidity was insufficiently defined to determine its influence on outcome, treatment response, or patient preferences for diagnostic efforts. We recommend controlled clinical trials in patients with ICUAW that compare physical rehabilitation with usual care and further research in understanding risk and patient preferences. CONCLUSIONS: Research that identifies treatments that benefit patients with ICUAW is necessary to determine whether the benefits of diagnostic testing for ICUAW outweigh its burdens.","DOI":"10.1164/rccm.201411-2011ST","ISSN":"1073-449x","shortTitle":"An official American Thoracic Society Clinical Practice guideline: the diagnosis of intensive care unit-acquired weakness in adults","journalAbbreviation":"American journal of respiratory and critical care medicine","language":"eng","author":[{"family":"Fan","given":"E."},{"family":"Cheek","given":"F."},{"family":"Chlan","given":"L."},{"family":"Gosselink","given":"R."},{"family":"Hart","given":"N."},{"family":"Herridge","given":"M. S."},{"family":"Hopkins","given":"R. O."},{"family":"Hough","given":"C. L."},{"family":"Kress","given":"J. P."},{"family":"Latronico","given":"N."},{"family":"Moss","given":"M."},{"family":"Needham","given":"D. M."},{"family":"Rich","given":"M. M."},{"family":"Stevens","given":"R. D."},{"family":"Wilson","given":"K. C."},{"family":"Winkelman","given":"C."},{"family":"Zochodne","given":"D. W."},{"family":"Ali","given":"N. A."}],"issued":{"date-parts":[["2014",12,15]]}}}],"schema":""} [5] A systematic review of exercise-based rehabilitation trials initiated after ICU discharge, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1i6q7mvj2u","properties":{"formattedCitation":"[6]","plainCitation":"[6]"},"citationItems":[{"id":22,"uris":[""],"uri":[""],"itemData":{"id":22,"type":"chapter","title":"Exercise rehabilitation following intensive care unit discharge for recovery from critical illness","container-title":"Cochrane Database of Systematic Reviews","publisher":"John Wiley & Sons, Ltd","publisher-place":"Chichester, UK","source":"CrossRef","event-place":"Chichester, UK","URL":"","language":"en","editor":[{"literal":"The Cochrane Collaboration"}],"author":[{"family":"Connolly","given":"Bronwen"},{"family":"Salisbury","given":"Lisa"},{"family":"O'Neill","given":"Brenda"},{"family":"Geneen","given":"Louise"},{"family":"Douiri","given":"Abdel"},{"family":"Grocott","given":"Michael PW"},{"family":"Hart","given":"Nicholas"},{"family":"Walsh","given":"Timothy S"},{"family":"Blackwood","given":"Bronagh"},{"literal":"for the ERACIP Group"}],"issued":{"date-parts":[["2015",6,22]]},"accessed":{"date-parts":[["2015",11,12]]}}}],"schema":""} [6] and our recently published rehabilitation trial (RECOVER), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"220uk9qhou","properties":{"formattedCitation":"[7]","plainCitation":"[7]"},"citationItems":[{"id":336,"uris":[""],"uri":[""],"itemData":{"id":336,"type":"article-journal","title":"Increased Hospital-Based Physical Rehabilitation and Information Provision After Intensive Care Unit Discharge: The RECOVER Randomized Clinical Trial","container-title":"JAMA Intern Med","source":"NLM","archive_location":"25867659","abstract":"Importance: Critical illness results in disability and reduced health-related quality of life (HRQOL), but the optimum timing and components of rehabilitation are uncertain. Objective: To evaluate the effect of increasing physical and nutritional rehabilitation plus information delivered during the post-intensive care unit (ICU) acute hospital stay by dedicated rehabilitation assistants on subsequent mobility, HRQOL, and prevalent disabilities. Design, Setting, and Participants: A parallel group, randomized clinical trial with blinded outcome assessment at 2 hospitals in Edinburgh, Scotland, of 240 patients discharged from the ICU between December 1, 2010, and January 31, 2013, who required at least 48 hours of mechanical ventilation. Analysis for the primary outcome and other 3-month outcomes was performed between June and August 2013; for the 6- and 12-month outcomes and the health economic evaluation, between March and April 2014. Interventions: During the post-ICU hospital stay, both groups received physiotherapy and dietetic, occupational, and speech/language therapy, but patients in the intervention group received rehabilitation that typically increased the frequency of mobility and exercise therapies 2- to 3-fold, increased dietetic assessment and treatment, used individualized goal setting, and provided greater illness-specific information. Intervention group therapy was coordinated and delivered by a dedicated rehabilitation practitioner. Main Outcomes and Measures: The Rivermead Mobility Index (RMI) (range 0-15) at 3 months; higher scores indicate greater mobility. Secondary outcomes included HRQOL, psychological outcomes, self-reported symptoms, patient experience, and cost-effectiveness during a 12-month follow-up (completed in February 2014). Results: Median RMI at randomization was 3 (interquartile range [IQR], 1-6) and at 3 months was 13 (IQR, 10-14) for the intervention and usual care groups (mean difference, -0.2 [95% CI, -1.3 to 0.9; P = .71]). The HRQOL scores were unchanged by the intervention (mean difference in the Physical Component Summary score, -0.1 [95% CI, -3.3 to 3.1; P = .96]; and in the Mental Component Summary score, 0.2 [95% CI, -3.4 to 3.8; P = .91]). No differences were found for self-reported symptoms of fatigue, pain, appetite, joint stiffness, or breathlessness. Levels of anxiety, depression, and posttraumatic stress were similar, as were hand grip strength and the timed Up & Go test. No differences were found at the 6- or 12-month follow-up for any outcome measures. However, patients in the intervention group reported greater satisfaction with physiotherapy, nutritional support, coordination of care, and information provision. Conclusions and Relevance: Post-ICU hospital-based rehabilitation, including increased physical and nutritional therapy plus information provision, did not improve physical recovery or HRQOL, but improved patient satisfaction with many aspects of recovery. Trial Registration: Identifier: ISRCTN09412438.","DOI":"10.1001/jamainternmed.2015.0822","ISSN":"2168-6106","shortTitle":"Increased Hospital-Based Physical Rehabilitation and Information Provision After Intensive Care Unit Discharge: The RECOVER Randomized Clinical Trial","journalAbbreviation":"JAMA internal medicine","language":"Eng","author":[{"family":"Walsh","given":"T. S."},{"family":"Salisbury","given":"L. G."},{"family":"Merriweather","given":"J. L."},{"family":"Boyd","given":"J. A."},{"family":"Griffith","given":"D. M."},{"family":"Huby","given":"G."},{"family":"Kean","given":"S."},{"family":"Mackenzie","given":"S. J."},{"family":"Krishan","given":"A."},{"family":"Lewis","given":"S. C."},{"family":"Murray","given":"G. D."},{"family":"Forbes","given":"J. F."},{"family":"Smith","given":"J."},{"family":"Rattray","given":"J. E."},{"family":"Hull","given":"A. M."},{"family":"Ramsay","given":"P."}],"issued":{"date-parts":[["2015",4,13]]}}}],"schema":""} [7] suggest no effect on physical recovery when the intervention is started during the post-ICU period. Reasons for this lack of response are uncertain, but could include an established neuromuscular deficit or persisting pathophysiological processes blocking muscle recovery. The inflammatory nature of most critical illness raises the possibility that persisting inflammation could directly interfere with neuromuscular regeneration.Damage to the neuromuscular unit occurs early during an episode of critical illness; identified risk factors include sepsis, inflammation, multiple organ failure and hyperglycaemia. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2ph2vq15bl","properties":{"formattedCitation":"[8]","plainCitation":"[8]"},"citationItems":[{"id":332,"uris":[""],"uri":[""],"itemData":{"id":332,"type":"article-journal","title":"ICU-acquired weakness and recovery from critical illness","container-title":"N Engl J Med","page":"1626-35","volume":"370","issue":"17","source":"NLM","archive_location":"24758618","DOI":"10.1056/NEJMra1209390","ISSN":"0028-4793","shortTitle":"ICU-acquired weakness and recovery from critical illness","journalAbbreviation":"The New England journal of medicine","language":"eng","author":[{"family":"Kress","given":"J. P."},{"family":"Hall","given":"J. B."}],"issued":{"date-parts":[["2014",4,24]]}}}],"schema":""} [8] Multiple studies have observed associations between inflammatory markers and muscle function in chronic inflammatory diseases, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"112vnqivl9","properties":{"formattedCitation":"{\\rtf [9\\uc0\\u8211{}12]}","plainCitation":"[9–12]"},"citationItems":[{"id":315,"uris":[""],"uri":[""],"itemData":{"id":315,"type":"article-journal","title":"Inflammatory response and body composition in chronic obstructive pulmonary disease","container-title":"American Journal of Respiratory & Critical Care Medicine","page":"1414-8","volume":"164","issue":"8 Pt 1","archive_location":"11704588","ISSN":"1073-449X","shortTitle":"Inflammatory response and body composition in chronic obstructive pulmonary disease","journalAbbreviation":"Am J Respir Crit Care Med","language":"English","author":[{"family":"Eid","given":"A. A."},{"family":"Ionescu","given":"A. A."},{"family":"Nixon","given":"L. S."},{"family":"Lewis-Jenkins","given":"V."},{"family":"Matthews","given":"S. B."},{"family":"Griffiths","given":"T. L."},{"family":"Shale","given":"D. J."}],"issued":{"date-parts":[["2001",10,15]]}}},{"id":128,"uris":[""],"uri":[""],"itemData":{"id":128,"type":"article-journal","title":"Markers of inflammation, proteolysis, and apoptosis in ESRD","container-title":"American Journal of Kidney Diseases","page":"1212-20","volume":"42","issue":"6","archive_location":"14655193","ISSN":"1523-6838","shortTitle":"Markers of inflammation, proteolysis, and apoptosis in ESRD","journalAbbreviation":"Am J Kidney Dis","language":"English","author":[{"family":"Raj","given":"Dominic S. C."},{"family":"Shah","given":"Hemangini"},{"family":"Shah","given":"Vallabh O."},{"family":"Ferrando","given":"Arny"},{"family":"Bankhurst","given":"Arthur"},{"family":"Wolfe","given":"Robert"},{"family":"Zager","given":"Philip G."}],"issued":{"date-parts":[["2003",12]]}}},{"id":397,"uris":[""],"uri":[""],"itemData":{"id":397,"type":"article-journal","title":"Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study","container-title":"American Journal of Medicine","page":"429-35","volume":"115","issue":"6","archive_location":"14563498","ISSN":"0002-9343","shortTitle":"Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study","journalAbbreviation":"Am J Med","language":"English","author":[{"family":"Roubenoff","given":"Ronenn"},{"family":"Parise","given":"Helen"},{"family":"Payette","given":"Helene A."},{"family":"Abad","given":"Leslie W."},{"family":"D'Agostino","given":"Ralph"},{"family":"Jacques","given":"Paul F."},{"family":"Wilson","given":"Peter W. F."},{"family":"Dinarello","given":"Charles A."},{"family":"Harris","given":"Tamara B."}],"issued":{"date-parts":[["2003",10,15]]}}},{"id":313,"uris":[""],"uri":[""],"itemData":{"id":313,"type":"article-journal","title":"Immune activation is associated with reduced skeletal muscle mass and physical function in chronic heart failure","container-title":"International Journal of Cardiology","page":"179-87","volume":"109","issue":"2","archive_location":"16024109","ISSN":"0167-5273","shortTitle":"Immune activation is associated with reduced skeletal muscle mass and physical function in chronic heart failure","journalAbbreviation":"Int J Cardiol","language":"English","author":[{"family":"Toth","given":"Michael J."},{"family":"Ades","given":"Philip A."},{"family":"Tischler","given":"Marc D."},{"family":"Tracy","given":"Russell P."},{"family":"LeWinter","given":"Martin M."}],"issued":{"date-parts":[["2006",5,10]]}}}],"schema":""} [9–12] making it a plausible risk factor for poor physical recovery after critical illness. The prevalence of persisting inflammation and its association with recovery have not been described in unselected critical care cohorts. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1n7mriber5","properties":{"formattedCitation":"[13]","plainCitation":"[13]"},"citationItems":[{"id":693,"uris":[""],"uri":[""],"itemData":{"id":693,"type":"article-journal","title":"Persistent inflammation and recovery after intensive care: A systematic review","container-title":"Journal of Critical Care","volume":"0","issue":"0","source":"","abstract":"Purpose\nPhysical weakness is common after critical illness; however, it is not clear how best to treat it. Inflammation characterizes critical illness, is associated with loss of muscle mass during critical illness, and potentially modifies post–intensive care unit (ICU) recovery. We sought to identify published reports on the prevalence of systemic inflammation after critical illness and its association with physical recovery.\nMethods\nThis is a systematic review of the literature from MEDLINE, EMBASE, CINAHL, CPCI-SSH, and CPCI-S from January 1982 to December 2011.\nResults\nFrom 7433 references, 207 full-text articles were reviewed, 57 were eligible, and 22 were included. Inflammation was present in most patients at ICU discharge according to C-reactive protein concentration (range, 70%-100%), procalcitonin (range, 89%-100%), tumor necrosis factor α (100%), and systemic inflammatory response syndrome criteria (range, 92%-95%). Fewer patients had elevated myeloperoxidase concentrations (range, 0%-56%). At hospital discharge, 9 (90%) of 10 chronic obstructive pulmonary disease patients had elevated C-reactive protein. No studies tested the association between inflammation and physical recovery.\nConclusions\nInflammation is present in most patients at ICU discharge, but little is known or has been investigated about persistent inflammation after this time point. No studies have explored the relationship between persistent inflammation and physical recovery. Further research is proposed.","URL":"","DOI":"10.1016/j.jcrc.2016.01.011","ISSN":"0883-9441","shortTitle":"Persistent inflammation and recovery after intensive care","journalAbbreviation":"Journal of Critical Care","language":"English","author":[{"family":"Griffith","given":"David M."},{"family":"Vale","given":"Matthew E."},{"family":"Campbell","given":"Christine"},{"family":"Lewis","given":"Steff"},{"family":"Walsh","given":"Timothy S."}],"issued":{"date-parts":[["2016",1,13]]},"accessed":{"date-parts":[["2016",2,22]]}}}],"schema":""} [13] The factors that modulate persistence and resolution of inflammation after critical illness have also not been studied. A possible mechanism of persistence is viral reactivation, particularly of human cytomegalovirus (HCMV), which frequently reactivates during ICU admission in previously exposed individuals and is associated with poorer ICU outcomes and higher mortality. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2nh1c58gi1","properties":{"formattedCitation":"{\\rtf [14\\uc0\\u8211{}19]}","plainCitation":"[14–19]"},"citationItems":[{"id":193,"uris":[""],"uri":[""],"itemData":{"id":193,"type":"article-journal","title":"Cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis","container-title":"Crit Care","page":"R77","volume":"15","issue":"2","source":"NLM","archive_location":"21362193","abstract":"INTRODUCTION: Sepsis has been identified as a risk factor for human cytomegalovirus (CMV) reactivation in critically ill patients. However, the contribution of CMV reactivation on morbidity and mortality is still controversial. Therefore, we analyzed the incidence and impact of CMV reactivation on outcome in patients with severe sepsis. METHODS: In a prospective longitudinal double-blinded observational study, 97 adult nonimmunosuppressed CMV-seropositive patients with new onset of severe sepsis were included. Leukocytes, plasma and tracheal secretions were examined weekly for CMV-DNA by PCR. Tracheal secretions were additionally tested for HSV (Herpes Simplex Virus)-DNA. The influence of CMV-reactivation on the endpoints was analysed by Cox proportional-hazard regression analysis. Time-dependency was evaluated by landmark analysis. RESULTS: Six out 97 died and five were discharged from the hospital within 72 hours and were excluded of the analysis. CMV reactivation occurred in 35 of the 86 (40.69%) analysed patients. HSV infection occurred in 23 of the 35 (65.7%) CMV reactivators. In 10 patients CMV-plasma-DNAemia appeared with a DNA-content below 600 copies/ml in four cases and a peak amount of 2,830 copies/ml on average. In patients with and without CMV reactivation mortality rates were similar (37.1% vs. 35.3%, P = 0.861), respectively. However, in the multivariate COX regression analyses CMV reactivation was independently associated with increased length of stay in the ICU (30.0, interquartile range 14 to 48 vs. 12.0, interquartile range 7 to 19 days; HR (hazard ratio) 3.365; 95% CI (confidence interval) 1.233 to 9.183, P = 0.018) and in the hospital (33.0, interquartile range 24 to 62 vs. 16.0, interquartile range 10 to 24 days, HR 3.3, 95% CI 1.78 to 6.25, P < 0.001) as well as prolonged mechanical ventilation (22.0, interquartile range 6 to 36 vs. 7.5, interquartile range 5 to 15.5 days; HR 2.6,CI 95% 1.39 to 4.94; P < 0.001) and impaired pulmonary gas exchange (six days, interquartile range 1 to 17, vs. three, interquartile range 1 to 7, days in reactivators vs. non-reactivators, P = 0.038). HSV reactivation proved not to be a risk factor for these adverse effects. CONCLUSIONS: These data indicate an independent correlation between CMV reactivation and increased morbidity in the well-defined group of nonimmunosuppressed patients with severe sepsis, but CMV reactivation had no impact on mortality in this group with low CMV-DNA plasma levels. Thus, the potential harms and benefits of antiviral treatment have to be weighed cautiously in patients with severe sepsis or septic shock.","DOI":"10.1186/cc10069","ISSN":"1466-609X (Electronic) 1364-8535 (Linking)","shortTitle":"Cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis","language":"eng","author":[{"family":"Heininger","given":"A."},{"family":"Haeberle","given":"H."},{"family":"Fischer","given":"I."},{"family":"Beck","given":"R."},{"family":"Riessen","given":"R."},{"family":"Rohde","given":"F."},{"family":"Meisner","given":"C."},{"family":"Jahn","given":"G."},{"family":"Koenigsrainer","given":"A."},{"family":"Unertl","given":"K."},{"family":"Hamprecht","given":"K."}],"issued":{"date-parts":[["2011"]]}}},{"id":169,"uris":[""],"uri":[""],"itemData":{"id":169,"type":"article-journal","title":"Human cytomegalovirus infections in nonimmunosuppressed critically ill patients","container-title":"Critical Care Medicine","page":"541-7","volume":"29","issue":"3","source":"NLM","archive_location":"11373417","abstract":"OBJECTIVE: To assess the occurrence of active human cytomegalovirus (HCMV) infection and HCMV disease and to evaluate potential risk factors in immunocompetent intensive care patients after major surgery or trauma. DESIGN: A prospective clinical study. SETTING: An anesthesiological intensive care unit (ICU) in a university hospital. PATIENTS: Fifty-six anti-HCMV immunoglobulin G (IgG) seropositive patients without manifest immunodeficiency whose simplified acute physiology score (SAPS II) value rose to >or=41 points during their ICU stay. INTERVENTIONS: Once a week, the patients were examined for active HCMV infection by polymerase chain reaction and by viral cultures from blood and lower respiratory tract secretions. Three times a week, detailed clinical examination for signs of HCMV disease was carried out. MEASUREMENTS AND MAIN RESULTS: Twenty of the 56 ICU patients (35.6%) who met the study criteria of a SAPS II score >40 points and anti-HCMV IgG seropositivity developed an active HCMV infection as diagnosed by the detection of HCMV DNA in leukocytes, plasma, or respiratory tract secretions. In seven patients, the virus was isolated in the respiratory tract secretions. Severe HCMV disease appeared in two patients with pneumonia or encephalitis respectively. In patients with active HCMV infection, the mortality tended to be higher (55%) than in those without (36%); the duration of intensive care treatment of the survivors was significantly longer in the patients with active HCMV infection (median 30 vs. 23 days; p = .0375). Univariate testing for factors associated with active HCMV infection showed the importance of sepsis at admission (p = .011) and prolonged pretreatment on the ward or in an external ICU (p = .002); the relevance of underlying malignant disease was borderline (p = .059). Multiple regression analysis identified only sepsis to be independently associated with active HCMV infection (p = .02; odds ratio, 4.62). CONCLUSIONS: Even in a group of ICU patients without manifest immunodeficit who were anti-HCMV IgG seropositive and had reached a SAPS II score of >or=41 points, active HCMV infection occurred frequently (35.6%). Septic patients were affected twice as often as the total study population. In 2 of the 20 cases, active HCMV infection progressed to severe HCMV disease. Proper diagnosis demands special clinical attention combined with extended virological examinations. Further studies in a larger patient group should evaluate the influence of HCMV on ICU mortality.","ISSN":"0090-3493 (Print) 0090-3493 (Linking)","shortTitle":"Human cytomegalovirus infections in nonimmunosuppressed critically ill patients","language":"eng","author":[{"family":"Heininger","given":"A."},{"family":"Jahn","given":"G."},{"family":"Engel","given":"C."},{"family":"Notheisen","given":"T."},{"family":"Unertl","given":"K."},{"family":"Hamprecht","given":"K."}],"issued":{"date-parts":[["2001",3]]}}},{"id":95,"uris":[""],"uri":[""],"itemData":{"id":95,"type":"article-journal","title":"Cytomegalovirus reactivation in critically ill immunocompetent patients","container-title":"JAMA","page":"413-22","volume":"300","issue":"4","source":"NLM","archive_location":"18647984","abstract":"CONTEXT: Cytomegalovirus (CMV) infection is associated with adverse clinical outcomes in immunosuppressed persons, but the incidence and association of CMV reactivation with adverse outcomes in critically ill persons lacking evidence of immunosuppression have not been well defined. OBJECTIVE: To determine the association of CMV reactivation with intensive care unit (ICU) and hospital length of stay in critically ill immunocompetent persons. DESIGN, SETTING, AND PARTICIPANTS: We prospectively assessed CMV plasma DNAemia by thrice-weekly real-time polymerase chain reaction (PCR) and clinical outcomes in a cohort of 120 CMV-seropositive, immunocompetent adults admitted to 1 of 6 ICUs at 2 separate hospitals at a large US tertiary care academic medical center between 2004 and 2006. Clinical measurements were assessed by personnel blinded to CMV PCR results. Risk factors for CMV reactivation and association with hospital and ICU length of stay were assessed by multivariable logistic regression and proportional odds models. MAIN OUTCOME MEASURES: Association of CMV reactivation with prolonged hospital length of stay or death. RESULTS: The primary composite end point of continued hospitalization (n = 35) or death (n = 10) by 30 days occurred in 45 (35%) of the 120 patients. Cytomegalovirus viremia at any level occurred in 33% (39/120; 95% confidence interval [CI], 24%-41%) at a median of 12 days (range, 3-57 days) and CMV viremia greater than 1000 copies/mL occurred in 20% (24/120; 95% CI, 13%-28%) at a median of 26 days (range, 9-56 days). By logistic regression, CMV infection at any level (adjusted odds ratio [OR], 4.3; 95% CI, 1.6-11.9; P = .005) and at greater than 1000 copies/mL (adjusted OR, 13.9; 95% CI, 3.2-60; P < .001) and the average CMV area under the curve (AUC) in log(10) copies per milliliter (adjusted OR, 2.1; 95% CI, 1.3-3.2; P < .001) were independently associated with hospitalization or death by 30 days. In multivariable partial proportional odds models, both CMV 7-day moving average (OR, 5.1; 95% CI, 2.9-9.1; P < .001) and CMV AUC (OR, 3.2; 95% CI, 2.1-4.7; P < .001) were independently associated with a hospital length of stay of at least 14 days. CONCLUSIONS: These preliminary findings suggest that reactivation of CMV occurs frequently in critically ill immunocompetent patients and is associated with prolonged hospitalization or death. A controlled trial of CMV prophylaxis in this setting is warranted.","DOI":"10.1001/jama.300.4.413","ISSN":"1538-3598 (Electronic) 0098-7484 (Linking)","shortTitle":"Cytomegalovirus reactivation in critically ill immunocompetent patients","language":"eng","author":[{"family":"Limaye","given":"A. P."},{"family":"Kirby","given":"K. A."},{"family":"Rubenfeld","given":"G. D."},{"family":"Leisenring","given":"W. M."},{"family":"Bulger","given":"E. M."},{"family":"Neff","given":"M. J."},{"family":"Gibran","given":"N. S."},{"family":"Huang","given":"M. L."},{"family":"Santo Hayes","given":"T. K."},{"family":"Corey","given":"L."},{"family":"Boeckh","given":"M."}],"issued":{"date-parts":[["2008",7,23]]}}},{"id":50,"uris":[""],"uri":[""],"itemData":{"id":50,"type":"article-journal","title":"Occult herpes family viral infections are endemic in critically ill surgical patients","container-title":"Critical Care Medicine","page":"1923-9","volume":"31","issue":"7","source":"NLM","archive_location":"12847384","abstract":"OBJECTIVE: Herpes family viruses have been recognized as pathogens for many years in immunosuppressed transplant or human immunodeficiency virus patients, but they have garnered little attention as potential pathogens in the nonimmunosuppressed critically ill. The objective of this study was to define the prevalence of and risk factors for development of herpes family virus infection in chronic critically ill surgical patients. DESIGN: Prospective epidemiologic study. SETTING: A 38-bed surgical intensive care unit in a major university hospital. PATIENTS: Nonimmunosuppressed intensive care unit patients in intensive care unit for >/=5 days. INTERVENTIONS: None; patients received no antiviral treatment during the study. MEASUREMENTS AND MAIN RESULTS: Weekly cultures for cytomegalovirus (CMV) and herpes simplex virus, viral serologies, and T-cell counts were performed. The prevalence (95% confidence interval) of positive respiratory cultures for herpes simplex or CMV was 35% (22-49%); 15% (5-25%) cultured positive for CMV, 23% (11-35%) cultured positive for herpes simplex virus, and one patient's respiratory secretions culturing positive for both CMV and herpes simplex virus. The prevalence of CMV viremia was only 5.8% (1-10%). CMV+ patients had longer hospital admissions, intensive care unit admissions, and periods of ventilator dependence than CMV- patients, despite having comparable severity of illness scores. CMV+ patients also had significantly higher numbers of blood transfusions, prevalence of steroid exposure, and prevalence of hepatic dysfunction, and all were immunoglobulin G positive at the beginning of the study. In contrast, herpes simplex virus-positive patients had lengths of hospital admissions, lengths of intensive care unit admissions, and periods of ventilator dependence comparable with patients without viral infections (p >.05). CONCLUSIONS: There is a significant prevalence (22-49%) of occult active herpes family viruses in chronic critically ill surgical patients. The clinical significance of these viral infections is unknown, although CMV+ patients have significantly higher morbidity rates than CMV- patients. Several factors suggest pathogenicity, but further study is needed to define causality.","DOI":"10.1097/m.0000070222.11325.c4","ISSN":"0090-3493 (Print) 0090-3493 (Linking)","shortTitle":"Occult herpes family viral infections are endemic in critically ill surgical patients","language":"eng","author":[{"family":"Cook","given":"C. H."},{"family":"Martin","given":"L. C."},{"family":"Yenchar","given":"J. K."},{"family":"Lahm","given":"M. C."},{"family":"McGuinness","given":"B."},{"family":"Davies","given":"E. A."},{"family":"Ferguson","given":"R. M."}],"issued":{"date-parts":[["2003",7]]}}},{"id":218,"uris":[""],"uri":[""],"itemData":{"id":218,"type":"article-journal","title":"Cytomegalovirus infection in critically ill patients: associated factors and consequences","container-title":"Chest","page":"233-41","volume":"127","issue":"1","source":"NLM","archive_location":"15653989","abstract":"OBJECTIVE: To determine the prevalence, associated findings, and consequences of cytomegalovirus (CMV) antigenemia in critically ill patients. DESIGN: A retrospective, case-control clinical study. SETTING: A 12-bed university hospital medical-surgical ICU. PATIENTS: Two hundred thirty-seven patients with fever for > 72 h, without proven evidence of bacteriologic and/or fungal origin, and whose pp65 antigenemia assays were studied. Patients with HIV infection and transplant recipients were excluded. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: CMV antigenemia was diagnosed within 20 +/- 12 days (mean +/- SD) after ICU admission in 17% patients in whom the pathology was suspected. The 40 patients in the CMV group were matched with 40 other patients in the control group. CMV infection was linked to renal failure (58% vs 33%, respectively; p = 0.02) and steroid use (55% vs 33%, respectively; p = 0.04). Patients with CMV had a significantly longer stay in the ICU (41 +/- 28 days vs 31 +/- 22 days, respectively; p = 0.04), a longer duration of mechanical ventilation (35 +/- 27 days vs 24 +/- 20 days, respectively; p = 0.03), a higher rate of nosocomial infection (75% vs 50%, respectively; p = 0.04), and a higher mortality (50% vs 28%, p = 0.02). CONCLUSIONS: CMV antigenemia is not an uncommon diagnosis in critically ill ICU patients with unexplained prolonged fever after 10 days of hospitalization, regardless of their immune system status. Although associated with a higher morbidity and mortality, the clinical significance of CMV is unknown. Further prospective studies should evaluate the impact on ICU outcome and whether CMV is truly a pathogen or simply another indicator of immunosuppression.","DOI":"10.1378/chest.127.1.233","ISSN":"0012-3692 (Print) 0012-3692 (Linking)","shortTitle":"Cytomegalovirus infection in critically ill patients: associated factors and consequences","language":"eng","author":[{"family":"Jaber","given":"S."},{"family":"Chanques","given":"G."},{"family":"Borry","given":"J."},{"family":"Souche","given":"B."},{"family":"Verdier","given":"R."},{"family":"Perrigault","given":"P. F."},{"family":"Eledjam","given":"J. J."}],"issued":{"date-parts":[["2005",1]]}}},{"id":117,"uris":[""],"uri":[""],"itemData":{"id":117,"type":"article-journal","title":"Active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients","container-title":"Critical Care Medicine","page":"1850-7","volume":"37","issue":"6","source":"NLM","archive_location":"19384219","abstract":"OBJECTIVE: To assess the incidence, risk factors, and outcome of active cytomegalovirus (CMV) infection in nonimmunosuppressed intensive care unit (ICU) patients. DESIGN: Prospective epidemiologic study. SETTING: A medical ICU in a university hospital. PATIENTS: Two hundred forty-two nonimmunosuppressed ICU patients mechanically ventilated for >or=2 days. INTERVENTIONS: Routine pp65 antigenemia and serology for CMV were performed at admission, and then weekly. Bronchoalveolar lavage viral cultures were done when pneumonia was suspected. MEASUREMENTS AND MAIN RESULTS: Thirty-nine of the 242 ICU patients (16.1%, confidence interval 11.5% to 20.7%) developed an active CMV infection, as diagnosed by positive antigenemia (85%) and/or positive rapid viral culture in bronchoalveolar lavage (26%). Antiviral treatment was initiated in 21 (54%) patients. ICU mortality (54% vs. 37%, p = 0.082) and in-hospital mortality (59% vs. 41%, p = 0.058) were increased in patients with active CMV infection, as compared with those without active CMV infection. Active CMV infection and Simplified Acute Physiology Score II at admission were associated with ICU death on multivariate analysis. The patients with active CMV infection had longer mechanical ventilation and longer ICU stay and were significantly more prone to developing bacterial nosocomial infections (p < 0.001). Logistic regression analysis showed that prior admission to other wards (p = 0.043; odds ratio [OR], 2.49), blood transfusions (p = 0.04; OR, 3.31), enteral feeding (p = 0.005; OR, 3.00), recent corticosteroid use before ICU admission (p = 0.08; OR, 2.26), and age (p = 0.07; OR, 1.026) were associated with the occurrence of active CMV infection. CONCLUSIONS: : Active CMV infection is common among previously healthy patients under mechanical ventilation in a medical ICU. Further studies are needed to evaluate the role of antiviral treatments to reduce both the incidence and the outcome impact of active CMV infection.","DOI":"10.1097/CCM.0b013e31819ffea6","ISSN":"1530-0293 (Electronic) 0090-3493 (Linking)","shortTitle":"Active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients","language":"eng","author":[{"family":"Chiche","given":"L."},{"family":"Forel","given":"J. M."},{"family":"Roch","given":"A."},{"family":"Guervilly","given":"C."},{"family":"Pauly","given":"V."},{"family":"Allardet-Servent","given":"J."},{"family":"Gainnier","given":"M."},{"family":"Zandotti","given":"C."},{"family":"Papazian","given":"L."}],"issued":{"date-parts":[["2009",6]]}}}],"schema":""} [14–19] HCMV infection (both latent and lytic) can modify the innate immune response, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"r8hf45nrn","properties":{"formattedCitation":"[20,21]","plainCitation":"[20,21]"},"citationItems":[{"id":20,"uris":[""],"uri":[""],"itemData":{"id":20,"type":"article-journal","title":"Human cytomegalovirus immunity and immune evasion","container-title":"Virus Research","page":"151-160","volume":"157","issue":"2","source":"PubMed","abstract":"Human cytomegalovirus (HCMV) infection induces both innate immune responses including Natural Killer cells as well as adaptive humoral and cell mediated (CD4+ helper, CD8+ cytotoxic and γδ T cell) responses which lead to the resolution of acute primary infection. Despite such a robust primary immune response, HCMV is still able to establish latency. Long term memory T cell responses are maintained at high frequency and are thought to prevent clinical disease following periodic reactivation of the virus. As such, a balance is established between the immune response and viral reactivation. Loss of this balance in the immunocompromised host can lead to unchecked viral replication following reactivation of latent virus, with consequent disease and mortality. HCMV encodes multiple immune evasion mechanisms that target both the innate and acquired immune system. This article describes the current understanding of Natural killer cell, antibody and T cell mediated immune responses and the mechanisms that the virus utilizes to subvert these responses.","DOI":"10.1016/j.virusres.2010.10.031","ISSN":"1872-7492","note":"PMID: 21056604","journalAbbreviation":"Virus Res.","language":"eng","author":[{"family":"Jackson","given":"Sarah E."},{"family":"Mason","given":"Gavin M."},{"family":"Wills","given":"Mark R."}],"issued":{"date-parts":[["2011",5]]},"PMID":"21056604"}},{"id":109,"uris":[""],"uri":[""],"itemData":{"id":109,"type":"article-journal","title":"Human cytomegalovirus induces systemic immune activation characterized by a type 1 cytokine signature","container-title":"J Infect Dis","page":"690-9","volume":"202","issue":"5","source":"NLM","archive_location":"20632887","abstract":"Mechanisms underlying the onset and perpetuation of chronic immune activation in individuals without overt infectious or autoimmune diseases are unclear. Cytomegalovirus (CMV) is a persistent virus that induces a permanent increase of highly differentiated, interferon-gamma-secreting effector T cells. We hypothesized that, because of this increase, CMV also induces a systemic inflammatory response. We measured acute phase proteins, cytokines, and chemokines in serum samples from renal transplant recipients who developed a primary CMV infection and healthy CMV serum-positive or -negative individuals. Primary CMV infection induced a clear proinflammatory response that was maintained during latency. This response was characterized by increased levels of acute phase proteins, such as serum amyloid-A and C-reactive protein, and type 1 cytokines, such as interleukin-18, interferon-inducible protein-10, and interferon-gamma. This continuous activation of the immune system may play a role in the pathogenesis of chronic allograft rejection and potentially contribute to the acceleration of chronic diseases.","DOI":"10.1086/655472","ISSN":"0022-1899","shortTitle":"Human cytomegalovirus induces systemic immune activation characterized by a type 1 cytokine signature","journalAbbreviation":"The Journal of infectious diseases","language":"eng","author":[{"family":"Berg","given":"P. J.","non-dropping-particle":"van de"},{"family":"Heutinck","given":"K. M."},{"family":"Raabe","given":"R."},{"family":"Minnee","given":"R. C."},{"family":"Young","given":"S. L."},{"family":"Donselaar-van der Pant","given":"K. A.","non-dropping-particle":"van"},{"family":"Bemelman","given":"F. J."},{"family":"Lier","given":"R. A.","non-dropping-particle":"van"},{"family":"Berge","given":"I. J.","non-dropping-particle":"ten"}],"issued":{"date-parts":[["2010",9,1]]}}}],"schema":""} [20,21] providing a biologically plausible mechanism for persisting inflammation.In the RECOVER trial we included, a priori, a nested study of inflammatory mediators in patients agreeing to regular blood sampling between enrolment (ICU discharge) and the primary outcome assessment (3 months post-randomisation). ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1r1e9npggq","properties":{"formattedCitation":"[22]","plainCitation":"[22]"},"citationItems":[{"id":347,"uris":[""],"uri":[""],"itemData":{"id":347,"type":"article-journal","title":"A randomised controlled trial evaluating a rehabilitation complex intervention for patients following intensive care discharge: the RECOVER study","container-title":"BMJ Open","volume":"2","issue":"4","source":"NLM","archive_location":"22761291","abstract":"INTRODUCTION: Patients who survive an intensive care unit admission frequently suffer physical and psychological morbidity for many months after discharge. Current rehabilitation pathways are often fragmented and little is known about the optimum method of promoting recovery. Many patients suffer reduced quality of life. METHODS AND ANALYSIS: The authors plan a multicentre randomised parallel group complex intervention trial with concealment of group allocation from outcome assessors. Patients who required more than 48 h of mechanical ventilation and are deemed fit for intensive care unit discharge will be eligible. Patients with primary neurological diagnoses will be excluded. Participants will be randomised into one of the two groups: the intervention group will receive standard ward-based care delivered by the NHS service with additional treatment by a specifically trained generic rehabilitation assistant during ward stay and via telephone contact after hospital discharge and the control group will receive standard ward-based care delivered by the current NHS service. The intervention group will also receive additional information about their critical illness and access to a critical care physician. The total duration of the intervention will be from randomisation to 3 months postrandomisation. The total duration of follow-up will be 12 months from randomisation for both groups. The primary outcome will be the Rivermead Mobility Index at 3 months. Secondary outcomes will include measures of physical and psychological morbidity and function, quality of life and survival over a 12-month period. A health economic evaluation will also be undertaken. Groups will be compared in relation to primary and secondary outcomes; quantitative analyses will be supplemented by focus groups with patients, carers and healthcare workers. ETHICS AND DISSEMINATION: Consent will be obtained from patients and relatives according to patient capacity. Data will be analysed according to a predefined analysis plan. TRIAL REGISTRATION: The trial is registered as ISRCTN09412438 and funded by the Chief Scientist Office, Scotland.","URL":"","DOI":"10.1136/bmjopen-2012-001475","ISSN":"2044-6055 (Electronic)","shortTitle":"A randomised controlled trial evaluating a rehabilitation complex intervention for patients following intensive care discharge: the RECOVER study","language":"eng","author":[{"family":"Walsh","given":"T. S."},{"family":"Salisbury","given":"L. G."},{"family":"Boyd","given":"J."},{"family":"Ramsay","given":"P."},{"family":"Merriweather","given":"J."},{"family":"Huby","given":"G."},{"family":"Forbes","given":"J."},{"family":"Rattray","given":"J. Z."},{"family":"Griffith","given":"D. M."},{"family":"Mackenzie","given":"S. J."},{"family":"Hull","given":"A."},{"family":"Lewis","given":"S."},{"family":"Murray","given":"G. D."}],"issued":{"date-parts":[["2012"]]}}}],"schema":""} [22] As the trial showed no effects on clinical outcomes, these data were suited to a cohort study design using both clinical and inflammatory mediator data as exposures, and the measures of physical function at 3 month follow-up as outcomes. We hypothesised that systemic inflammation is prevalent in ICU survivors following ICU discharge, and that the presence of persisting systemic inflammation is associated with poorer physical recovery. As an additional mechanistic analysis, we explored whether HCMV infection was associated with systemic inflammation and physical recovery.methodsRECOVER was a randomised trial of increased hospital-based physical rehabilitation and information provision for ICU survivors. The protocol, description of the intervention, and trial results have been published. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2qn4td1320","properties":{"formattedCitation":"[7,22,23]","plainCitation":"[7,22,23]"},"citationItems":[{"id":336,"uris":[""],"uri":[""],"itemData":{"id":336,"type":"article-journal","title":"Increased Hospital-Based Physical Rehabilitation and Information Provision After Intensive Care Unit Discharge: The RECOVER Randomized Clinical Trial","container-title":"JAMA Intern Med","source":"NLM","archive_location":"25867659","abstract":"Importance: Critical illness results in disability and reduced health-related quality of life (HRQOL), but the optimum timing and components of rehabilitation are uncertain. Objective: To evaluate the effect of increasing physical and nutritional rehabilitation plus information delivered during the post-intensive care unit (ICU) acute hospital stay by dedicated rehabilitation assistants on subsequent mobility, HRQOL, and prevalent disabilities. Design, Setting, and Participants: A parallel group, randomized clinical trial with blinded outcome assessment at 2 hospitals in Edinburgh, Scotland, of 240 patients discharged from the ICU between December 1, 2010, and January 31, 2013, who required at least 48 hours of mechanical ventilation. Analysis for the primary outcome and other 3-month outcomes was performed between June and August 2013; for the 6- and 12-month outcomes and the health economic evaluation, between March and April 2014. Interventions: During the post-ICU hospital stay, both groups received physiotherapy and dietetic, occupational, and speech/language therapy, but patients in the intervention group received rehabilitation that typically increased the frequency of mobility and exercise therapies 2- to 3-fold, increased dietetic assessment and treatment, used individualized goal setting, and provided greater illness-specific information. Intervention group therapy was coordinated and delivered by a dedicated rehabilitation practitioner. Main Outcomes and Measures: The Rivermead Mobility Index (RMI) (range 0-15) at 3 months; higher scores indicate greater mobility. Secondary outcomes included HRQOL, psychological outcomes, self-reported symptoms, patient experience, and cost-effectiveness during a 12-month follow-up (completed in February 2014). Results: Median RMI at randomization was 3 (interquartile range [IQR], 1-6) and at 3 months was 13 (IQR, 10-14) for the intervention and usual care groups (mean difference, -0.2 [95% CI, -1.3 to 0.9; P = .71]). The HRQOL scores were unchanged by the intervention (mean difference in the Physical Component Summary score, -0.1 [95% CI, -3.3 to 3.1; P = .96]; and in the Mental Component Summary score, 0.2 [95% CI, -3.4 to 3.8; P = .91]). No differences were found for self-reported symptoms of fatigue, pain, appetite, joint stiffness, or breathlessness. Levels of anxiety, depression, and posttraumatic stress were similar, as were hand grip strength and the timed Up & Go test. No differences were found at the 6- or 12-month follow-up for any outcome measures. However, patients in the intervention group reported greater satisfaction with physiotherapy, nutritional support, coordination of care, and information provision. Conclusions and Relevance: Post-ICU hospital-based rehabilitation, including increased physical and nutritional therapy plus information provision, did not improve physical recovery or HRQOL, but improved patient satisfaction with many aspects of recovery. Trial Registration: Identifier: ISRCTN09412438.","DOI":"10.1001/jamainternmed.2015.0822","ISSN":"2168-6106","shortTitle":"Increased Hospital-Based Physical Rehabilitation and Information Provision After Intensive Care Unit Discharge: The RECOVER Randomized Clinical Trial","journalAbbreviation":"JAMA internal medicine","language":"Eng","author":[{"family":"Walsh","given":"T. S."},{"family":"Salisbury","given":"L. G."},{"family":"Merriweather","given":"J. L."},{"family":"Boyd","given":"J. A."},{"family":"Griffith","given":"D. M."},{"family":"Huby","given":"G."},{"family":"Kean","given":"S."},{"family":"Mackenzie","given":"S. J."},{"family":"Krishan","given":"A."},{"family":"Lewis","given":"S. C."},{"family":"Murray","given":"G. D."},{"family":"Forbes","given":"J. F."},{"family":"Smith","given":"J."},{"family":"Rattray","given":"J. E."},{"family":"Hull","given":"A. M."},{"family":"Ramsay","given":"P."}],"issued":{"date-parts":[["2015",4,13]]}}},{"id":347,"uris":[""],"uri":[""],"itemData":{"id":347,"type":"article-journal","title":"A randomised controlled trial evaluating a rehabilitation complex intervention for patients following intensive care discharge: the RECOVER study","container-title":"BMJ Open","volume":"2","issue":"4","source":"NLM","archive_location":"22761291","abstract":"INTRODUCTION: Patients who survive an intensive care unit admission frequently suffer physical and psychological morbidity for many months after discharge. Current rehabilitation pathways are often fragmented and little is known about the optimum method of promoting recovery. Many patients suffer reduced quality of life. METHODS AND ANALYSIS: The authors plan a multicentre randomised parallel group complex intervention trial with concealment of group allocation from outcome assessors. Patients who required more than 48 h of mechanical ventilation and are deemed fit for intensive care unit discharge will be eligible. Patients with primary neurological diagnoses will be excluded. Participants will be randomised into one of the two groups: the intervention group will receive standard ward-based care delivered by the NHS service with additional treatment by a specifically trained generic rehabilitation assistant during ward stay and via telephone contact after hospital discharge and the control group will receive standard ward-based care delivered by the current NHS service. The intervention group will also receive additional information about their critical illness and access to a critical care physician. The total duration of the intervention will be from randomisation to 3 months postrandomisation. The total duration of follow-up will be 12 months from randomisation for both groups. The primary outcome will be the Rivermead Mobility Index at 3 months. Secondary outcomes will include measures of physical and psychological morbidity and function, quality of life and survival over a 12-month period. A health economic evaluation will also be undertaken. Groups will be compared in relation to primary and secondary outcomes; quantitative analyses will be supplemented by focus groups with patients, carers and healthcare workers. ETHICS AND DISSEMINATION: Consent will be obtained from patients and relatives according to patient capacity. Data will be analysed according to a predefined analysis plan. TRIAL REGISTRATION: The trial is registered as ISRCTN09412438 and funded by the Chief Scientist Office, Scotland.","URL":"","DOI":"10.1136/bmjopen-2012-001475","ISSN":"2044-6055 (Electronic)","shortTitle":"A randomised controlled trial evaluating a rehabilitation complex intervention for patients following intensive care discharge: the RECOVER study","language":"eng","author":[{"family":"Walsh","given":"T. S."},{"family":"Salisbury","given":"L. G."},{"family":"Boyd","given":"J."},{"family":"Ramsay","given":"P."},{"family":"Merriweather","given":"J."},{"family":"Huby","given":"G."},{"family":"Forbes","given":"J."},{"family":"Rattray","given":"J. Z."},{"family":"Griffith","given":"D. M."},{"family":"Mackenzie","given":"S. J."},{"family":"Hull","given":"A."},{"family":"Lewis","given":"S."},{"family":"Murray","given":"G. D."}],"issued":{"date-parts":[["2012"]]}}},{"id":93,"uris":[""],"uri":[""],"itemData":{"id":93,"type":"article-journal","title":"A rehabilitation intervention to promote physical recovery following intensive care: a detailed description of construct development, rationale and content together with proposed taxonomy to capture processes in a randomised controlled trial","container-title":"Trials","page":"38","volume":"15","issue":"1","source":"","abstract":"Increasing numbers of patients are surviving critical illness, but survival may be associated with a constellation of physical and psychological sequelae that can cause ongoing disability and reduced health-related quality of life. Limited evidence currently exists to guide the optimum structure, timing, and content of rehabilitation programmes. There is a need to both develop and evaluate interventions to support and expedite recovery during the post-ICU discharge period. This paper describes the construct development for a complex rehabilitation intervention intended to promote physical recovery following critical illness. The intervention is currently being evaluated in a randomised trial (ISRCTN09412438; funder Chief Scientists Office, Scotland).","DOI":"10.1186/1745-6215-15-38","ISSN":"1745-6215","note":"PMID: 24476530","shortTitle":"A rehabilitation intervention to promote physical recovery following intensive care","language":"en","author":[{"family":"Ramsay","given":"Pam"},{"family":"Salisbury","given":"Lisa G."},{"family":"Merriweather","given":"Judith L."},{"family":"Huby","given":"Guro"},{"family":"Rattray","given":"Janice E."},{"family":"Hull","given":"Alastair M."},{"family":"Brett","given":"Stephen J."},{"family":"Mackenzie","given":"Simon J."},{"family":"Murray","given":"Gordon D."},{"family":"Forbes","given":"John F."},{"family":"Walsh","given":"Timothy S."},{"family":"$author.lastName","given":"$author","dropping-particle":"firstName"}],"issued":{"date-parts":[["2014",1,29]]},"PMID":"24476530"}}],"schema":""} [7,22,23] Participants were recruited from 2 intensive care units in Edinburgh, Scotland from December 1, 2010, through January 31, 2013. Inclusion criteria were: receipt of >48 hours of continuous mechanical ventilation and deemed fit for ICU discharge. Exclusion criteria included a primary neurological diagnosis, receipt of palliative care, receipt of home ventilation, considered unable to provide informed consent, follow-up not feasible, discharge to a non-study hospital, aged <18 years, and enrolment in another RCT with similar endpoints. Both groups received existing ward-based physiotherapy, dietetics, occupational and speech/language therapy until hospital discharge. The intervention patients received enhanced hospital based physical rehabilitation and information provision that increased the frequency and intensity of multiple aspects of rehabilitation between enrolment and hospital discharge. RECOVER was approved by the Scotland A Research Ethics Committee (10/MRE0018). Patients provided specific consent for inclusion in the blood sampling sub-study during consent for the main study. The between-group comparison of outcomes in the trial found no clinically or statistically significant differences in measures of physical function, Health Related Quality of Life (HRQoL), psychological morbidity, or self-reported symptoms. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1kjje956uf","properties":{"formattedCitation":"[7]","plainCitation":"[7]"},"citationItems":[{"id":336,"uris":[""],"uri":[""],"itemData":{"id":336,"type":"article-journal","title":"Increased Hospital-Based Physical Rehabilitation and Information Provision After Intensive Care Unit Discharge: The RECOVER Randomized Clinical Trial","container-title":"JAMA Intern Med","source":"NLM","archive_location":"25867659","abstract":"Importance: Critical illness results in disability and reduced health-related quality of life (HRQOL), but the optimum timing and components of rehabilitation are uncertain. Objective: To evaluate the effect of increasing physical and nutritional rehabilitation plus information delivered during the post-intensive care unit (ICU) acute hospital stay by dedicated rehabilitation assistants on subsequent mobility, HRQOL, and prevalent disabilities. Design, Setting, and Participants: A parallel group, randomized clinical trial with blinded outcome assessment at 2 hospitals in Edinburgh, Scotland, of 240 patients discharged from the ICU between December 1, 2010, and January 31, 2013, who required at least 48 hours of mechanical ventilation. Analysis for the primary outcome and other 3-month outcomes was performed between June and August 2013; for the 6- and 12-month outcomes and the health economic evaluation, between March and April 2014. Interventions: During the post-ICU hospital stay, both groups received physiotherapy and dietetic, occupational, and speech/language therapy, but patients in the intervention group received rehabilitation that typically increased the frequency of mobility and exercise therapies 2- to 3-fold, increased dietetic assessment and treatment, used individualized goal setting, and provided greater illness-specific information. Intervention group therapy was coordinated and delivered by a dedicated rehabilitation practitioner. Main Outcomes and Measures: The Rivermead Mobility Index (RMI) (range 0-15) at 3 months; higher scores indicate greater mobility. Secondary outcomes included HRQOL, psychological outcomes, self-reported symptoms, patient experience, and cost-effectiveness during a 12-month follow-up (completed in February 2014). Results: Median RMI at randomization was 3 (interquartile range [IQR], 1-6) and at 3 months was 13 (IQR, 10-14) for the intervention and usual care groups (mean difference, -0.2 [95% CI, -1.3 to 0.9; P = .71]). The HRQOL scores were unchanged by the intervention (mean difference in the Physical Component Summary score, -0.1 [95% CI, -3.3 to 3.1; P = .96]; and in the Mental Component Summary score, 0.2 [95% CI, -3.4 to 3.8; P = .91]). No differences were found for self-reported symptoms of fatigue, pain, appetite, joint stiffness, or breathlessness. Levels of anxiety, depression, and posttraumatic stress were similar, as were hand grip strength and the timed Up & Go test. No differences were found at the 6- or 12-month follow-up for any outcome measures. However, patients in the intervention group reported greater satisfaction with physiotherapy, nutritional support, coordination of care, and information provision. Conclusions and Relevance: Post-ICU hospital-based rehabilitation, including increased physical and nutritional therapy plus information provision, did not improve physical recovery or HRQOL, but improved patient satisfaction with many aspects of recovery. Trial Registration: Identifier: ISRCTN09412438.","DOI":"10.1001/jamainternmed.2015.0822","ISSN":"2168-6106","shortTitle":"Increased Hospital-Based Physical Rehabilitation and Information Provision After Intensive Care Unit Discharge: The RECOVER Randomized Clinical Trial","journalAbbreviation":"JAMA internal medicine","language":"Eng","author":[{"family":"Walsh","given":"T. S."},{"family":"Salisbury","given":"L. G."},{"family":"Merriweather","given":"J. L."},{"family":"Boyd","given":"J. A."},{"family":"Griffith","given":"D. M."},{"family":"Huby","given":"G."},{"family":"Kean","given":"S."},{"family":"Mackenzie","given":"S. J."},{"family":"Krishan","given":"A."},{"family":"Lewis","given":"S. C."},{"family":"Murray","given":"G. D."},{"family":"Forbes","given":"J. F."},{"family":"Smith","given":"J."},{"family":"Rattray","given":"J. E."},{"family":"Hull","given":"A. M."},{"family":"Ramsay","given":"P."}],"issued":{"date-parts":[["2015",4,13]]}}}],"schema":""} [7]SamplingBlood was sampled at the time of randomisation (ICU discharge), and 3 months after ICU discharge by venepuncture or from an arterial line if present. Blood was stored at room temperature for 30 minutes and then centrifuged at 2500g for 10 minutes. Serum and plasma were stored at -70C prior to assay. Physical OutcomePhysical assessments included the Rivermead Mobility Index (RMI) (a validated measure of physical mobility ranging from 1 (unable to turn over in bed), to 15 (able to run)), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"10vgih2df8","properties":{"formattedCitation":"[24]","plainCitation":"[24]"},"citationItems":[{"id":247,"uris":[""],"uri":[""],"itemData":{"id":247,"type":"article-journal","title":"The Rivermead Mobility Index: a further development of the Rivermead Motor Assessment","container-title":"Int Disabil Stud","page":"50-4","volume":"13","issue":"2","source":"NLM","archive_location":"1836787","abstract":"This paper reports on a development of the Rivermead Motor Assessment Gross Function scale, the Rivermead Mobility Index (RMI), a new measure of mobility disability which concentrates on body mobility. An early development included a second scale concentrating on elective mobility, but the results showed this to be unreliable. The RMI comprises a series of 14 questions and one direct observation, and covers a range of activities from turning over in bed to running. Its inter-observer reliability was tested on two groups of patients (n = 23 and 20 respectively) and it is reliable to a limit of 2 points (out of 15). Its validity as a measure of mobility after head injury and stroke was tested by concurrent measurement of mobility using gait speed and endurance, and by standing balance. The RMI does form a scale. It is short, simple, and clinically relevant, and can be used in hospital or at home.","ISSN":"0259-9147 (Print) 0259-9147 (Linking)","shortTitle":"The Rivermead Mobility Index: a further development of the Rivermead Motor Assessment","language":"eng","author":[{"family":"Collen","given":"F. M."},{"family":"Wade","given":"D. T."},{"family":"Robb","given":"G. F."},{"family":"Bradshaw","given":"C. M."}],"issued":{"date-parts":[["1991",4]]}}}],"schema":""} [24] handgrip strength (HGS; a measure of forearm muscle strength in kg)), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1421lfm0ck","properties":{"formattedCitation":"[25]","plainCitation":"[25]"},"citationItems":[{"id":160,"uris":[""],"uri":[""],"itemData":{"id":160,"type":"article-journal","title":"Hand Grip Strength: age and gender stratified normative data in a population-based study","container-title":"BMC Res Notes","page":"127","volume":"4","source":"NLM","archive_location":"21492469","abstract":"BACKGROUND: The North West Adelaide Health Study is a representative longitudinal cohort study of people originally aged 18 years and over. The aim of this study was to describe normative data for hand grip strength in a community-based Australian population. Secondary aims were to investigate the relationship between body mass index (BMI) and hand grip strength, and to compare Australian data with international hand grip strength norms. METHODS: The sample was randomly selected and recruited by telephone interview. Overall, 3 206 (81% of those recruited) participants returned to the clinic during the second stage (2004-2006) which specifically focused on the collection of information relating to musculoskeletal conditions. RESULTS: Following the exclusion of 435 participants who had hand pain and/or arthritis, 1366 men and 1312 women participants provided hand grip strength measurement. The study population was relatively young, with 41.5% under 40 years; and their mean BMI was 28.1 kg/m2 (SD 5.5). Higher hand grip strength was weakly related to higher BMI in adults under the age of 30 and over the age of 70, but inversely related to higher BMI between these ages. Australian norms from this sample had amongst the lowest of the hand grip strength of the internationally published norms, except those from underweight populations. CONCLUSIONS: This population demonstrated higher BMI and lower grip strength in younger participants than much of the international published, population data. A complete exploration of the relationship between BMI and hand grip strength was not fully explored as there were very few participants with BMI in the underweight range. The age and gender grip strength values are lower in younger adults than those reported in international literature.","DOI":"10.1186/1756-0500-4-127","ISSN":"1756-0500 (Electronic) 1756-0500 (Linking)","shortTitle":"Hand Grip Strength: age and gender stratified normative data in a population-based study","language":"eng","author":[{"family":"Massy-Westropp","given":"N. M."},{"family":"Gill","given":"T. K."},{"family":"Taylor","given":"A. W."},{"family":"Bohannon","given":"R. W."},{"family":"Hill","given":"C. L."}],"issued":{"date-parts":[["2011"]]}}}],"schema":""} [25] the timed up and go test (TUG; a measure of lower limb strength and balance) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2bj4lvsd94","properties":{"formattedCitation":"[26]","plainCitation":"[26]"},"citationItems":[{"id":226,"uris":[""],"uri":[""],"itemData":{"id":226,"type":"article-journal","title":"The timed \"Up & Go\": a test of basic functional mobility for frail elderly persons","container-title":"J Am Geriatr Soc","page":"142-8","volume":"39","issue":"2","source":"NLM","archive_location":"1991946","abstract":"This study evaluated a modified, timed version of the \"Get-Up and Go\" Test (Mathias et al, 1986) in 60 patients referred to a Geriatric Day Hospital (mean age 79.5 years). The patient is observed and timed while he rises from an arm chair, walks 3 meters, turns, walks back, and sits down again. The results indicate that the time score is (1) reliable (inter-rater and intra-rater); (2) correlates well with log-transformed scores on the Berg Balance Scale (r = -0.81), gait speed (r = -0.61) and Barthel Index of ADL (r = -0.78); and (3) appears to predict the patient's ability to go outside alone safely. These data suggest that the timed \"Up & Go\" test is a reliable and valid test for quantifying functional mobility that may also be useful in following clinical change over time. The test is quick, requires no special equipment or training, and is easily included as part of the routine medical examination.","ISSN":"0002-8614 (Print) 0002-8614 (Linking)","shortTitle":"The timed \"Up & Go\": a test of basic functional mobility for frail elderly persons","language":"eng","author":[{"family":"Podsiadlo","given":"D."},{"family":"Richardson","given":"S."}],"issued":{"date-parts":[["1991",2]]}}}],"schema":""} [26] and the physical component of the Medical Outcomes Study Short Form 12 version 2 (PCS); a validated measure of HRQoL. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1f385mlonc","properties":{"formattedCitation":"[27]","plainCitation":"[27]"},"citationItems":[{"id":228,"uris":[""],"uri":[""],"itemData":{"id":228,"type":"article-journal","title":"A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity","container-title":"Med Care","page":"220-33","volume":"34","issue":"3","source":"NLM","archive_location":"8628042","abstract":"Regression methods were used to select and score 12 items from the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) to reproduce the Physical Component Summary and Mental Component Summary scales in the general US population (n=2,333). The resulting 12-item short-form (SF-12) achieved multiple R squares of 0.911 and 0.918 in predictions of the SF-36 Physical Component Summary and SF-36 Mental Component Summary scores, respectively. Scoring algorithms from the general population used to score 12-item versions of the two components (Physical Components Summary and Mental Component Summary) achieved R squares of 0.905 with the SF-36 Physical Component Summary and 0.938 with SF-36 Mental Component Summary when cross-validated in the Medical Outcomes Study. Test-retest (2-week)correlations of 0.89 and 0.76 were observed for the 12-item Physical Component Summary and the 12-item Mental Component Summary, respectively, in the general US population (n=232). Twenty cross-sectional and longitudinal tests of empirical validity previously published for the 36-item short-form scales and summary measures were replicated for the 12-item Physical Component Summary and the 12-item Mental Component Summary, including comparisons between patient groups known to differ or to change in terms of the presence and seriousness of physical and mental conditions, acute symptoms, age and aging, self-reported 1-year changes in health, and recovery for depression. In 14 validity tests involving physical criteria, relative validity estimates for the 12-item Physical Component Summary ranged from 0.43 to 0.93 (median=0.67) in comparison with the best 36-item short-form scale. Relative validity estimates for the 12-item Mental Component Summary in 6 tests involving mental criteria ranged from 0.60 to 107 (median=0.97) in relation to the best 36-item short-form scale. Average scores for the 2 summary measures, and those for most scales in the 8-scale profile based on the 12-item short-form, closely mirrored those for the 36-item short-form, although standard errors were nearly always larger for the 12-item short-form.","ISSN":"0025-7079 (Print) 0025-7079 (Linking)","shortTitle":"A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity","language":"eng","author":[{"family":"Ware","given":"J.","suffix":"Jr."},{"family":"Kosinski","given":"M."},{"family":"Keller","given":"S. D."}],"issued":{"date-parts":[["1996",3]]}}}],"schema":""} [27] BiomarkersTo detect on-going inflammation we measured C-reactive protein (CRP) concentration. To further characterise inflammatory phenotype, we measured cytokines active during the initiation (interleukin 1β (IL-1β), interleukin 6 (IL-6)), propagation (interleukin 8 (IL-8)), and resolution (transforming growth factor β1 (TGFβ1) and secretory leukocyte protease inhibitor (SLPI)) of inflammation. In addition, we measured human neutrophil elastase (HNE), a marker of on-going neutrophil degranulation or non-apoptotic neutrophil death, to assess persisting neutrophil activation. The biomarkers measured were pre-specified in an analysis plan submitted to the trial statistician (SL) prior to trial data being made available. Inflammatory biomarkers were assayed by ELISA. All assays were carried out in duplicate. Co-efficients of variation (CVs) were calculated for each duplicate pair. Where CVs were greater than 15% pipetting error was assumed, and assays were repeated.Human CytomegalovirusTo establish prior exposure to HCMV, a quantitative indirect anti-globulin enzyme immunoassay (VIDAS CMV G, bioMérieux, Lyon, France) was used. HCMV IgG antibody was quantified in arbitrary units/mL (aU/mL). As per the manufacturers instructions, patients with serum concentration of >6aU/mL were considered to have positive serology (evidence of previous exposure). In patients with evidence of previous exposure, quantitative HCMV PCR was carried out to establish the presence of active lytic infection (detectable HCMV DNA). The lower detection limit of this assay was 160IU/mL. AnalysisAll analyses were carried out using IBM SPSS Statistics version 21. P<0.05 was defined as statistically significant. Prevalence of systemic inflammationInflammation prevalence was estimated with reference to CRP measurements in healthy adults. The percentage of surviving patients at each time point that had a serum CRP concentration of greater than 3mg/L and 10mg/L representing the 90th and 99th centiles respectively was calculated. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1egrm8hnpl","properties":{"formattedCitation":"[28]","plainCitation":"[28]"},"citationItems":[{"id":317,"uris":[""],"uri":[""],"itemData":{"id":317,"type":"article-journal","title":"Solid phase radioimmunoassays for human C-reactive protein","container-title":"Clin Chim Acta","page":"13-23","volume":"117","issue":"1","source":"NLM","archive_location":"7333010","abstract":"Two new, rapid and sensitive radioimmunoassays for human C-reactive protein (CRP) have been established using antiserum coupled to magnetizable cellulose particles, which facilitate phase separation. A single antibody method, using solid phase anti-CRP, provides a sensitivity of 50 microgram/l with a 1-h incubation time and intra- and inter-assay coefficients of variation of 10%. A double antibody method, using fluid phase rabbit anti-CRP serum and solid phase sheep anti-rabbit IgG serum, provides a sensitivity of 3 microgram/l with an overnight incubation and intra- and inter-assay coefficients of variation of 10%. Among 468 sera from normal adult volunteer blood donors the median CRP concentration was 800 microgram/l, interquartile range 340-1700 microgram/l and range 70-29,000 microgram/l. Ninety percent of samples contained less than 3 mg/l and 99% less than 10 mg/l. Low levels (14-650 microgram/l) of CRP were detected both in amniotic fluids and in cerebrospinal fluids.","ISSN":"0009-8981 (Print) 0009-8981 (Linking)","shortTitle":"Solid phase radioimmunoassays for human C-reactive protein","language":"eng","author":[{"family":"Shine","given":"B."},{"family":"Beer","given":"F. C.","non-dropping-particle":"de"},{"family":"Pepys","given":"M. B."}],"issued":{"date-parts":[["1981",11,25]]}}}],"schema":""} [28]Inflammatory profileFor patients with complete paired data, biomarker concentration was reported at baseline and 3 months after ICU discharge. The median change in biomarker concentration between the 2 time-points was calculated and assessed using Wilcoxon signed rank tests. To place data in a clinical context, upper reference limits for biomarkers were derived from published studies of healthy cohorts, and proportions of patients exceeding these limits calculated. Relationship with physical recoveryThe relationship between RMI and each of the inflammatory biomarkers was tested using univariable linear regression. This analysis was repeated for HGS, TUG, and PCS of the SF-12v2. To control for the effects of confounding, multivariable linear models were constructed to account for relevant pre-existing patient characteristics (age, gender and functional comorbidity (as measured by the functional comorbidity index (FCI)), and acute illness severity (APACHE 2 score and days of mechanical ventilation during ICU stay). The FCI is a validated 18-point measure capturing co-existing co-morbidity and concurrent disease, which is strongly associated with self-reported physical HRQoL. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1p7f89m08c","properties":{"formattedCitation":"[29]","plainCitation":"[29]"},"citationItems":[{"id":207,"uris":[""],"uri":[""],"itemData":{"id":207,"type":"article-journal","title":"Assessment of long-term physical function in acute respiratory distress syndrome (ARDS) patients: comparison of the Charlson Comorbidity Index and the Functional Comorbidity Index","container-title":"Am J Phys Med Rehabil","page":"574-81","volume":"85","issue":"7","source":"NLM","archive_location":"16788388","abstract":"OBJECTIVE: It is often important to adjust for the effect of comorbid diseases on patient outcomes. This study compares the association between physical function in acute respiratory distress syndrome patients with scores on two comorbidity indices, the Charlson Comorbidity Index, designed to predict mortality, and the Functional Comorbidity Index (FCI), which was designed to predict physical function. DESIGN: This is a prospective, longitudinal, observational study. A total of 73 survivors of acute respiratory distress syndrome were contacted at 3, 6, and 12 mos. Patient comorbidity was evaluated with the Charlson Comorbidity Index and the FCI. Physical function was measured using the Medical Outcomes Study 36-Item Short Form Health Survey Physical Function Subscale and the Physical Component Subscale scores. RESULT: Mean FCI and Charlson Comorbidity Index scores correlated fairly strongly (Spearman rho = 0.62, P < 0.001). FCI, but not the Charlson Comorbidity Index, scores correlated with the Physical Function Subscale and Physical Component Subscale scores. After controlling for other potentially confounding variables such as age and severity of illness through regression analysis, the FCI score was still significantly associated with both Physical Function Subscale and Physical Component Subscale scores. CONCLUSIONS: The FCI is a better method of measuring comorbidity with physical function as the outcome. This study illustrates the importance of choosing the most appropriate comorbidity index for the outcome of interest.","DOI":"10.1097/01.phm.0000223220.91914.61","ISSN":"0894-9115 (Print) 0894-9115","shortTitle":"Assessment of long-term physical function in acute respiratory distress syndrome (ARDS) patients: comparison of the Charlson Comorbidity Index and the Functional Comorbidity Index","journalAbbreviation":"American journal of physical medicine & rehabilitation / Association of Academic Physiatrists","language":"eng","author":[{"family":"Groll","given":"D. L."},{"family":"Heyland","given":"D. K."},{"family":"Caeser","given":"M."},{"family":"Wright","given":"J. G."}],"issued":{"date-parts":[["2006",7]]}}}],"schema":""} [29]Due to a violation of linear regression model assumptions (non-normal distribution of predicted values of the outcome variable around the regression line) RMI, which was negatively skewed, required inverse natural log transformation (16-Ln(RMI)) prior to regression analysis. Inflammatory biomarkers, ventilator days, and TUG were positively skewed and required natural log transformation prior to regression analysis. For zero value biomarker concentrations, 0.001 was added to allow transformation.Role of Cytomegalovirus in post-ICU inflammation and recoveryThe percentage of patients with prior exposure to HCMV (HCMV IgG positive) and the proportion of these with lytic infection (detectable HCMV PCR) were reported at ICU discharge and at 3 months. The concentration of each inflammatory biomarker was compared between patients previously exposed to HCMV and those not previously exposed. To explore the potential for HCMV to affect physical function, physical outcomes were compared between these groups using an independent samples median test. In addition, to test whether HCMV sero-positivity confounds the association between inflammation (as measured by CRP and RMI) tested in the previous section, we added HCMV sero-positivity as an additional variable in the multivariable linear regression model. Our analysis plan aimed to assess the relationship between on-going lytic infection and measures of recovery, but the low number of patients with lytic infection meant meaningful comparisons could not made. Missing dataThe primary analysis was a complete case analysis. To ensure that the results of this analysis were not subject to bias introduced by assuming the missing patients were similar to those included, a sensitivity analysis was carried imputing data according to 2 different assumptions (see online supplement). ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2qbd75ejrs","properties":{"formattedCitation":"[30,31]","plainCitation":"[30,31]"},"citationItems":[{"id":680,"uris":[""],"uri":[""],"itemData":{"id":680,"type":"article-journal","title":"Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls","container-title":"BMJ","page":"b2393","volume":"338","source":"","DOI":"10.1136/bmj.b2393","ISSN":"0959-8138, 1468-5833","note":"PMID: 19564179","shortTitle":"Multiple imputation for missing data in epidemiological and clinical research","journalAbbreviation":"BMJ","language":"en","author":[{"family":"Sterne","given":"Jonathan A. C."},{"family":"White","given":"Ian R."},{"family":"Carlin","given":"John B."},{"family":"Spratt","given":"Michael"},{"family":"Royston","given":"Patrick"},{"family":"Kenward","given":"Michael G."},{"family":"Wood","given":"Angela M."},{"family":"Carpenter","given":"James R."}],"issued":{"date-parts":[["2009",6,29]]},"PMID":"19564179"}},{"id":679,"uris":[""],"uri":[""],"itemData":{"id":679,"type":"article-journal","title":"Review of Statistical Analysis with Missing Data","container-title":"Journal of Educational Statistics","page":"150-155","volume":"16","issue":"2","source":"JSTOR","DOI":"10.2307/1165119","ISSN":"0362-9791","journalAbbreviation":"Journal of Educational Statistics","author":[{"family":"Mislevy","given":"Robert J."}],"reviewed-author":[{"family":"Rubin","given":"Donald B."},{"family":"Little","given":"Roderick J. A."}],"issued":{"date-parts":[["1991"]]}}}],"schema":""} [30,31]RESULTSPatientsTwo hundred and forty patients were recruited to the RECOVER study; of these, 193 (80%) consented to blood sampling (Figure 1). Baseline characteristics of the included patients are shown in table 1.All (n=193)Lower tertile of CRP (<2.1mg/L) (n=41)Middle tertile of CRP (2.1-7.9mg/L) (n=41)Upper tertile of CRP (>7.9mg/L)(n=41)Age (mean (sd))61 (14)59 (13)62 (11)58 (15)Male (n (%))117 (61)24 (59)27 (66)24 (59)Functional Comorbidity Index (mean (sd))3 (2)3 (2)3 (2)3 (2)APACHE 2 (mean (sd))21 (7)22 (7)19 (8)21 (6)Days of mechanical ventilation (median (Q1, Q3)8 (5,14)8 (4,16)9 (5,14)9 (6,15)ICU length of stay (median (Q1, Q3)11 (7, 18)10 (7,18)11 (7,18)12 (8,19)Vasopressors (n (%))141 (73)28 (83)31 (76)31 (78)Renal replacement therapy (n (%))52 (27)10 (24)10 (24)12 (30)Diagnosis category (n (%))RespiratoryCardiovascularNeurologicalRenalGastrointestinalTraumaMiscellaneous 69 (34)53 (27)6 (3)3 (2)52 (27)5 (3)5 (3)17 (41)12 (29)1 (2)1 (2)6 (15)1 (2)3 (7)14 (34)15 (37)1 (2)0 (0)9 (22)2 (5)0 (0)15 (37)8 (20)1 (2)0 (0)16 (39)1 (2)0 (0)Table 1: Patient Characteristics presented for all consenting patients (n=193), and for patients grouped according to CRP tertile at 3 months after ICU discharge (n=123). Physical outcomesThe 3-month outcome data showing central tendency and dispersion is presented in table 2.MeasurenRivermead Mobility Index (median (Q1, Q3))17514 (12,15)Hand Grip Strength (kg) (mean (sd))15321.9 (8.8)Timed Up and Go (seconds) (median (Q1, Q3))14710.2 (7.7, 13.3)Physical Component Score of SF12v2 (mean (sd))16135.1 (11.4)Table 2: Physical outcome at 3 monthsPrevalence of systemic inflammationAt ICU discharge 141/184 (77% (95% CI 70-82%)) of patients had a CRP concentration of greater than 10mg/L and 173/184 (94% (95% CI 90-97%) had a CRP concentration of greater than 3mg/L. Three months after ICU discharge, 34/123 (28% (95% CI 21-36%)) of patients had a CRP concentration of greater than 10mg/L and 72/123 (59% (95% CI 50-67%)) of patients had a CRP concentration greater than 3mg/L. For complete cases (n=118) CRP concentration fell from 27.9 mg/L (10.4-63.1) at baseline to 4.4mg/L (1.2-12.0) at 3 months with a median change of -20.7 mg/L (95% CI -26.9 to -14.5; p<0.01). For this same complete case cohort (n=118), Figure 2 describes the inflammatory outcome of patients with CRP concentrations that had high (>10mg/L), medium (3-10mg/L) and low (<3mg/L) CRP concentration at ICU discharge. Inflammatory profileAt ICU discharge HNE, IL-6, IL-8 and SLPI were elevated compared to previously studied healthy populations (table 3). TGFβ1 concentration was reduced. Median concentrations of pro-inflammatory biomarkers (HNE, IL-6, IL-8) decreased significantly over the 3-month time horizon (with the exception of IL-1β which was low at both time points). Many patients still demonstrated elevated concentrations compared to the comparative healthy population values. For the pro-resolution biomarkers, TGFβ1 concentration further decreased at 3 months compared to baseline with values at both time points lower than healthy values. Most patients had suppressed levels of TGF β1 at both time points. SLPI concentrations decreased over the 3-month period, with most patients having higher values than comparator populations at both time points. Overall, the 3-month pattern at population level was of on-going inflammation (elevated CRP, HNE and IL8) with evidence of reduced pro-resolution signalling (reduced /suppressed TFGβ1). BiomarkerHealthy from previous studiesBaseline3 monthsChange from baseline to 3 monthsn mean (sd)[Ref] (median (IQR))Proportion elevated (%)Median (IQR)Proportion elevated (%)Hodges Lehman median difference (95% Confidence Interval)pHNE (ng/mL)11277.1 (35.5) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"18nvfu2su7","properties":{"formattedCitation":"[32]","plainCitation":"[32]2]"},"citationItems":[{"id":119,"uris":[""],"uri":[""],"itemData":{"id":119,"type":"article-journal","title":"Plasma neutrophil elastase and elafin imbalance is associated with acute respiratory distress syndrome (ARDS) development","container-title":"PLoS One","page":"e4380","volume":"4","issue":"2","source":"NLM","archive_location":"19197381","abstract":"BACKGROUND: We conducted an exploratory study of genome-wide gene expression in whole blood and found that the expression of neutrophil elastase inhibitor (PI3, elafin) was down-regulated during the early phase of ARDS. Further analyses of plasma PI3 levels revealed a rapid decrease during early ARDS development. PI3 and secretory leukocyte proteinase inhibitor (SLPI) are important low-molecular-weight proteinase inhibitors produced locally at neutrophil infiltration site in the lung. In this study, we tested the hypothesis that an imbalance between neutrophil elastase (HNE) and its inhibitors in blood is related to the development of ARDS. METHODOLOGY/PRINCIPAL FINDINGS: PI3, SLPI, and HNE were measured in plasma samples collected from 148 ARDS patients and 63 critical ill patients at risk for ARDS (controls). Compared with the controls, the ARDS patients had higher HNE, but lower PI3, at the onset of ARDS, resulting in increased HNE/PI3 ratio (mean = 14.5; 95% CI, 10.9-19.4, P<0.0001), whereas plasma SLPI was not associated with the risk of ARDS development. Although the controls had elevated plasma PI3 and HNE, their HNE/PI3 ratio (mean = 6.5; 95% CI, 4.9-8.8) was not significantly different from the healthy individuals (mean = 3.9; 95% CI, 2.7-5.9). Before the onset (7-days period prior to ARDS diagnosis), we only observed significantly elevated HNE, but the HNE-PI3 balance remained normal. With the progress from prior to the onset of ARDS, the plasma level of PI3 declined, whereas HNE was maintained at a higher level, tilting the balance toward more HNE in the circulation as characterized by an increased HNE/PI3 ratio. In contrast, three days after ICU admission, there was a significant drop of HNE/PI3 ratio in the at-risk controls. CONCLUSIONS/SIGNIFICANCE: Plasma profiles of PI3, HNE, and HNE/PI3 may be useful clinical biomarkers in monitoring the development of ARDS.","DOI":"10.1371/journal.pone.0004380","ISSN":"1932-6203","shortTitle":"Plasma neutrophil elastase and elafin imbalance is associated with acute respiratory distress syndrome (ARDS) development","journalAbbreviation":"PloS one","language":"eng","author":[{"family":"Wang","given":"Z."},{"family":"Chen","given":"F."},{"family":"Zhai","given":"R."},{"family":"Zhang","given":"L."},{"family":"Su","given":"L."},{"family":"Lin","given":"X."},{"family":"Thompson","given":"T."},{"family":"Christiani","given":"D. C."}],"issued":{"date-parts":[["2009"]]}}}],"schema":""} T [32] 145.2 (112.8-199.5)48110.3 (88.3-142.5)23-36.9 (-49.3,-23..6)<0.01IL-1β (pg/mL)1110.8 (0.1) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"b5k0g01dj","properties":{"formattedCitation":"[33]","plainCitation":"[33]13"},"citationItems":[{"id":5,"uris":[""],"uri":[""],"itemData":{"id":5,"type":"article-journal","title":"Serum levels of proinflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor α in mixed cryoglobulinemia","container-title":"Arthritis & Rheumatism","page":"3841-3847","volume":"60","issue":"12","source":"Wiley Online Library","abstract":"Objective\nNo single previous study has evaluated serum levels of the proinflammatory cytokines interleukin-1β (IL-1β), IL-6, and tumor necrosis factor α (TNFα) in patients with hepatitis C virus–associated mixed cryoglobulinemia (HCV-MC). This study was undertaken to evaluate serum levels of these cytokines in patients with HCV-MC.\nMethods\nSerum IL-1β, IL-6, and TNFα were assayed in 43 patients with HCV-MC, in 43 sex- and age-matched patients with chronic HCV without cryoglobulinemia, and in 43 sex- and age-matched controls.\nResults\nHCV-MC patients showed significantly higher mean IL-1β, IL-6, and TNFα levels than did the controls (P < 0.01) or the HCV patients (P ≤ 0.04). Serum levels of IL-6 and TNFα were significantly higher in HCV patients than in controls (P < 0.05).\nConclusion\nOur findings demonstrate elevated serum levels of IL-1β, IL-6, and TNFα in patients with HCV-MC. If the importance of IL-1β and IL-6 in the pathogenesis of MC is confirmed, these results will open the way for the evaluation of new therapies for MC.","DOI":"10.1002/art.25003","ISSN":"1529-0131","journalAbbreviation":"Arthritis & Rheumatism","language":"en","author":[{"family":"Antonelli","given":"Alessandro"},{"family":"Ferri","given":"Clodoveo"},{"family":"Ferrari","given":"Silvia Martina"},{"family":"Ghiri","given":"Emiliano"},{"family":"Goglia","given":"Fernando"},{"family":"Pampana","given":"Alessandro"},{"family":"Bruschi","given":"Fabrizio"},{"family":"Fallahi","given":"Poupak"}],"issued":{"date-parts":[["2009",12,1]]}}}],"schema":""} T [33] 0.0 (0.0-15.0)390.0 (0.0-7.6)300.0 (0.0,0.0)0.73IL-6 (pg/mL)1119 (12) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2ital5iv9t","properties":{"formattedCitation":"[33]","plainCitation":"[33]13"},"citationItems":[{"id":5,"uris":[""],"uri":[""],"itemData":{"id":5,"type":"article-journal","title":"Serum levels of proinflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor α in mixed cryoglobulinemia","container-title":"Arthritis & Rheumatism","page":"3841-3847","volume":"60","issue":"12","source":"Wiley Online Library","abstract":"Objective\nNo single previous study has evaluated serum levels of the proinflammatory cytokines interleukin-1β (IL-1β), IL-6, and tumor necrosis factor α (TNFα) in patients with hepatitis C virus–associated mixed cryoglobulinemia (HCV-MC). This study was undertaken to evaluate serum levels of these cytokines in patients with HCV-MC.\nMethods\nSerum IL-1β, IL-6, and TNFα were assayed in 43 patients with HCV-MC, in 43 sex- and age-matched patients with chronic HCV without cryoglobulinemia, and in 43 sex- and age-matched controls.\nResults\nHCV-MC patients showed significantly higher mean IL-1β, IL-6, and TNFα levels than did the controls (P < 0.01) or the HCV patients (P ≤ 0.04). Serum levels of IL-6 and TNFα were significantly higher in HCV patients than in controls (P < 0.05).\nConclusion\nOur findings demonstrate elevated serum levels of IL-1β, IL-6, and TNFα in patients with HCV-MC. If the importance of IL-1β and IL-6 in the pathogenesis of MC is confirmed, these results will open the way for the evaluation of new therapies for MC.","DOI":"10.1002/art.25003","ISSN":"1529-0131","journalAbbreviation":"Arthritis & Rheumatism","language":"en","author":[{"family":"Antonelli","given":"Alessandro"},{"family":"Ferri","given":"Clodoveo"},{"family":"Ferrari","given":"Silvia Martina"},{"family":"Ghiri","given":"Emiliano"},{"family":"Goglia","given":"Fernando"},{"family":"Pampana","given":"Alessandro"},{"family":"Bruschi","given":"Fabrizio"},{"family":"Fallahi","given":"Poupak"}],"issued":{"date-parts":[["2009",12,1]]}}}],"schema":""} T [33] 25.2 (8.0-85.5)456.7 (0.0-37.2)26-16.5 (-28.4, -8.1)<0.01IL-8 (pg/mL)1113.2 (2.5) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"25fku46qld","properties":{"formattedCitation":"[34]","plainCitation":"[34]13"},"citationItems":[{"id":8,"uris":[""],"uri":[""],"itemData":{"id":8,"type":"article-journal","title":"Clinical Utility of Serum Interleukin-8 and Interferon-Alpha in Thyroid Diseases, Clinical Utility of Serum Interleukin-8 and Interferon-Alpha in Thyroid Diseases","container-title":"Journal of Thyroid Research, Journal of Thyroid Research","page":"e270149","volume":"2011, 2011","source":"","abstract":"Serum interleukin-8 (IL-8) and interferon-alpha (IFN-&#x3b1;) levels have been estimated from a total of 88 individuals of which 19 were disease-free healthy individuals, and 69 were patients with thyroid diseases: goitre (), autoimmune diseases (), and carcinomas (). Both IL-8 and IFN-&#x3b1; were significantly higher in all the patients as compared to healthy individuals. Serum IL-8 levels showed significant positive correlation with disease stage in thyroid cancer patients. Higher serum IL-8 levels were associated with advanced disease stage while no significant correlation was observed between serum IFN-&#x3b1; levels and any of the clinicopathological parameters. IL-8 and IFN-&#x3b1; significantly correlated with each other in anaplastic carcinoma patients. Finally concluding, monitoring the serum IL-8 and IFN-&#x3b1; levels can help differentiate patients with thyroid diseases from healthy individuals, and IL-8 seems to have a role in the pathogenesis of thyroid diseases and may represent a target for innovative diagnostic and therapeutic strategies., Serum interleukin-8 (IL-8) and interferon-alpha (IFN-&#x3b1;) levels have been estimated from a total of 88 individuals of which 19 were disease-free healthy individuals, and 69 were patients with thyroid diseases: goitre (), autoimmune diseases (), and carcinomas (). Both IL-8 and IFN-&#x3b1; were significantly higher in all the patients as compared to healthy individuals. Serum IL-8 levels showed significant positive correlation with disease stage in thyroid cancer patients. Higher serum IL-8 levels were associated with advanced disease stage while no significant correlation was observed between serum IFN-&#x3b1; levels and any of the clinicopathological parameters. IL-8 and IFN-&#x3b1; significantly correlated with each other in anaplastic carcinoma patients. Finally concluding, monitoring the serum IL-8 and IFN-&#x3b1; levels can help differentiate patients with thyroid diseases from healthy individuals, and IL-8 seems to have a role in the pathogenesis of thyroid diseases and may represent a target for innovative diagnostic and therapeutic strategies.","DOI":"10.4061/2011/270149, 10.4061/2011/270149","ISSN":",","language":"en","author":[{"family":"Kobawala","given":"Toral P."},{"family":"Patel","given":"Girish H."},{"family":"Gajjar","given":"Dhara R."},{"family":"Patel","given":"Kamini N."},{"family":"Thakor","given":"Premal B."},{"family":"Parekh","given":"Urvi B."},{"family":"Patel","given":"Kirti M."},{"family":"Shukla","given":"Shilin N."},{"family":"Shah","given":"Pankaj M."},{"family":"Kobawala","given":"Toral P."},{"family":"Patel","given":"Girish H."},{"family":"Gajjar","given":"Dhara R."},{"family":"Patel","given":"Kamini N."},{"family":"Thakor","given":"Premal B."},{"family":"Parekh","given":"Urvi B."},{"family":"Patel","given":"Kirti M."},{"family":"Shukla","given":"Shilin N."},{"family":"Shah","given":"Pankaj M."}],"issued":{"date-parts":[["2011",3,8]]}}}],"schema":""} T [34] 27.3 (12.2-63.0)858.6 (1.2-33.3)51-14.4 (-20.0, -9.8)<0.01TGFβ1 (ng/mL)11636.4 (8.23) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"20a9dld97g","properties":{"formattedCitation":"[35]","plainCitation":"[35]13"},"citationItems":[{"id":69,"uris":[""],"uri":[""],"itemData":{"id":69,"type":"article-journal","title":"Variations in Serum Transforming Growth Factor-β1 Levels with Gender, Age and Lifestyle Factors of Healthy Japanese Adults","container-title":"Disease markers","page":"23-28","volume":"27","issue":"1","source":"PubMed Central","abstract":"Elevated serum or plasma Transforming Growth Factor-β1 (TGF-β1) levels have been linked to cancer and other diseases in numerous studies; however, very few studies have reported an association between circulating TGF-β1 and lifestyle factors in healthy people. We examined the association between serum TGF-β1 levels and gender, age, body mass index (BMI), smoking, and drinking in a large population-based cohort study (N = 9,142). Serum TGF-β1 levels were detected by the Quantikine enzyme-linked immunoassay kit (R&D Systems). The data indicated highly significant (p<0.0001) difference in serum TGF-β1 levels between men (mean value: 37.6 ± 0.12?ng/mL, N = 4888) and women (mean value: 35.1 ± 0.12?ng/ml, N = 4254). Serum TGF-β1 levels decreased with age (trend p < 0.0001) and were positively associated with obesity (trend p < 0.0001) in both men and women. We observed a significant trend with increased serum TGF-β1 levels corresponding to increased amount of tobacco and alcohol consumption in men (trend p < 0.0001). These findings suggest that serum TGF-β1 levels appear to be modulated by gender, age and lifestyle factors such as obesity, cigarette smoking, and alcohol drinking in healthy Japanese adults.","DOI":"10.3233/DMA-2009-0643","ISSN":"0278-0240","note":"PMID: 19822955\nPMCID: PMC3834674","journalAbbreviation":"Dis Markers","author":[{"family":"Lin","given":"Yingsong"},{"family":"Nakachi","given":"Kei"},{"family":"Ito","given":"Yoshinori"},{"family":"Kikuchi","given":"Shogo"},{"family":"Tamakoshi","given":"Akiko"},{"family":"Yagyu","given":"Kiyoko"},{"family":"Watanabe","given":"Yoshiyuki"},{"family":"Inaba","given":"Yutaka"},{"family":"Tajima","given":"Kazuo"},{"literal":"JACC Study Group"}],"issued":{"date-parts":[["2009"]]},"PMID":"19822955","PMCID":"PMC3834674"}}],"schema":""} T [35] 12.1 (8.5-16.04)0(91)*10.1 (7.8-12.5)0(97)*-2.0 (-2.9, -1.2)<0.01SLPI (ng/mL)11836.4 (2.3) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5fcgrjcrv","properties":{"formattedCitation":"[36]","plainCitation":"[36]13"},"citationItems":[{"id":12,"uris":[""],"uri":[""],"itemData":{"id":12,"type":"article-journal","title":"Secretory leukocyte protease inhibitor, an inhibitor of neutrophil activation, is elevated in serum in human sepsis and experimental endotoxemia","container-title":"Critical Care Medicine","page":"1276-1282","volume":"28","issue":"5","source":"PubMed","abstract":"OBJECTIVES: To document changes in serum secretory leukocyte protease inhibitor (SLPI) in human sepsis and in experimental endotoxemia in vivo. To compare changes in serum SLPI in human sepsis with changes in interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha. To determine whether or not changes in SLPI correlate with the severity of multiple organ dysfunction syndrome as measured by the maximal multiple organ dysfunction score. Finally, because neutrophils have been implicated in tissue injury associated with organ dysfunction, to determine whether recombinant human SLPI blocks activation of isolated human neutrophils.\nDESIGN: Case-control study and ex-vivo cellular assay.\nSETTING: Surgical intensive care unit and clinical research center of university hospitals; laboratory of a medical school.\nINTERVENTIONS: None.\nMEASUREMENTS AND MAIN RESULTS: There was a significant dose-dependent elevation (50.2+/-4.0 ng/mL, p = .01) in plasma SLPI 12 hrs after administration of lipopolysaccharide to seven healthy adults (36.4+/-2.3 ng/mL). Further, serum concentrations of SLPI (132+/-15 ng/mL) were elevated in septic surgical patients compared with healthy controls (43+/-2 ng/mL, p < .01) and nonseptic surgical controls (69+/-10 ng/mL, p = .01). Serum SLPI concentrations correlated (r2 = .71, p < .01) better with organ dysfunction as measured by maximal multiple organ dysfunction score than did serum IL-6 (r2 = .49, p < .01), IL-10 (r2 = .05, p = .22), or TNF-alpha (r2 = .02, p = .44). We found that recombinant human SLPI in vitro inhibits TNF-alpha-induced hydrogen peroxide production by human neutrophils (ID50 = 1-2 microg/mL).\nCONCLUSIONS: Serum SLPI is elevated in human sepsis and experimental endotoxemia. Maximal concentrations of serum SLPI correlate significantly with maximal multiple organ dysfunction scores in patients with sepsis. Secretory leukocyte protease inhibitor may function to limit ongoing neutrophil-mediated tissue injury associated with organ dysfunction.","ISSN":"0090-3493","note":"PMID: 10834665","journalAbbreviation":"Crit. Care Med.","language":"eng","author":[{"family":"Grobmyer","given":"S. R."},{"family":"Barie","given":"P. S."},{"family":"Nathan","given":"C. F."},{"family":"Fuortes","given":"M."},{"family":"Lin","given":"E."},{"family":"Lowry","given":"S. F."},{"family":"Wright","given":"C. D."},{"family":"Weyant","given":"M. J."},{"family":"Hydo","given":"L."},{"family":"Reeves","given":"F."},{"family":"Shiloh","given":"M. U."},{"family":"Ding","given":"A."}],"issued":{"date-parts":[["2000",5]]},"PMID":"10834665"}}],"schema":""} T [36] 59.3 (44.7-79.0)7847.4 (37.3-60.8)64-10.4 (-15.6, -5.4)<0.01Table 3: Inflammatory biomarker concentration at baseline and 3 months in patients that survived and had blood sampling at both time points. Median difference and p values have been calculated to reflect change over 3 months. To add context, mean (SD) concentrations in previous studied healthy populations are quoted and the proportion in our cohort with elevated biomarker concentration (>2sd above mean in previously studied healthy cohort) calculated. *Starred values represent proportion with abnormally low TGFβ1 concentration (<2 sd below mean in previously studied healthy cohort). Relationship with physical recoveryIn the univariable analysis, HNE and CRP were significantly associated with RMI 3 months after ICU discharge (table 4), with higher concentrations of these biomarkers being associated with poorer mobility. This association persisted when tested in multivariable linear regression models to adjust for potential confounding factors (age, gender, FCI, APACHE 2 score, and days of mechanical ventilation), suggesting HNE and CRP were independently associated with RMI 3 months after ICU discharge. IL-8 was significantly associated with HGS at 3 months on univariate testing. After adjustment for confounding, higher concentrations of CRP, IL-8 and SLPI were significantly associated with lower HGS.There was no significant association observed between inflammatory markers and the timed up and go test, or the PCS of the SF-12.UnadjustedAdjusted95% CI95% CIOutcomeBiomarkerβLowerUpperpβLowerUpperpRMICRP0.130.050.22<0.010.140.060.23<0.01HNE0.320.030.600.030.300.020.590.04IL-1 β-0.01-0.040.010.32-0.01-0.040.020.52IL-60.00-0.020.030.800.01-0.020.040.59IL-80.03-0.010.060.130.030.000.070.06TGF β0.05-0.340.430.800.07-0.310.450.73SLPI0.15-0.110.410.260.14-0.130.400.31TUGCRP0.64-0.020.100.150.050.010.110.10HNE0.15-0.040.330.130.14-0.050.320.15IL-1 β0.00-0.020.620.820.01-0.010.020.58IL-60.00-0.020.020.850.01-0.010.020.50IL-80.01-0.010.030.380.020.000.040.12TGF β-0.17-0.420.070.16-0.16-0.390.080.19SLPI0.08-0.090.250.340.05-0.120.210.58HGSCRP-0.51-1.570.550.35-0.95-1.85-0.060.04HNE-3.20-6.580.180.06-2.60-5.43-0.220.07IL-1 β0.03-0.290.350.870.01-0.270.280.97IL-6-0.050.380.280.76-0.12-0.400.150.38IL-8-0.51-0.90-0.130.01-0.41-0.75-0.080.02TGF β-1.37-5.813.080.54-1.76-5.552.040.36SLPI-2.90-5.900.090.06-2.72-5.33-0.110.04PCSCRP0.24-1.121.600.720.27-1.081.620.69HNE-0.62-5.083.850.79-0.64-5.093.820.78IL-1 β0.08-0.330.490.71-0.01-0.430.400.95IL-60.14-0.280.560.510.09-0.330.510.66IL-8-0.20-0.720.310.43-0.40-0.920.120.13TGF β0.21-0.555.960.94-0.01-5.695.721.00SLPI-1.68-5.582.220.40-1.61-5.582.360.42Table 4: Linear regression of individual biomarkers with physical outcome measures at 3 months after ICU discharge . All biomarkers were natural log transformed prior to analysis. RMI was inverse natural log transformed (Ln(16-RMI)). Timed up and go (TUG) was natural log transformed. Analysis was performed unadjusted then adjusted for potential confounders (age, gender, FCI, APACHE 2 score, days of mechanical ventilation). Ventilator days were natural log transformed. Analyses conducted on the cohort of 123 patients that had blood sampling at 3 months. A complete case analysis approach was employed.To add clinical context to this relationship we compared HNE and CRP concentration in patients with good mobility (upper 3 quartiles of RMI (RMI ≥11; n=144) and poor mobility (lower quartile of RMI (RMI <11; n=31) at the same time point. Patients with poor mobility had greater CRP concentration (median 11.1 mg/L (IQR 4.1-21.8) versus 3.7mg/L (IQR 0.9-9.7); median difference 7.3mg/L (95% CI 2.0-10.8; p<0.01)) and HNE concentration (median 117.0 ng/mL (IQR 102.6-172.1) versus 103.2 ng/mL (IQR 85.7-135.8); median difference 13.8ng/mL (95% CI -1.0-42.0; p=0.06)) when compared to patients with good mobility (Figure 3).Inflammatory biomarkers at ICU discharge were significantly correlated with biomarkers at 3 months (Table 5). To test whether inflammation at ICU discharge was an important confounder of the relationship between persistent inflammation (CRP at 3 months) and recovery (RMI at 3 months), we added CRP at ICU discharge to our earlier linear regression model (Table 6). We found no association between CRP at ICU discharge and RMI at 3 months, and adding it as a covariate to the model did not alter the relationship between CRP and RMI when both were measured at 3 months.BiomarkernB95% CIpLowerUpperCRP1180.370.140.61<0.01HNE1120.230.080.38<0.01IL-11110.760.650.89<0.01IL-61110.740.540.93<0.01IL-81111.030.7811.29<0.01TGF1160.330.200.45<0.01SLPI1180.680.520.83<0.01Table 5: Linear relationship between natural log transformed inflammatory biomarkers at baseline (ICU discharge) and follow up. Co-efficientsBLower 95% CIUpper 95% CIpOriginal analysis Ventilator days*0.05-0.130.230.58Age0.00-0.010.010.71Gender0.11-0.160.370.43APACHE 20.01-0.010.030.49FCI0.100.030.16<0.01CRP (3 months)*0.140.060.23<0.01Sensitivity analysis adjusting for baseline CRP Ventilator days*0.08-0.110.270.42Age0.00-0.010.011.00Gender0.08-0.190.360.56APACHE 20.01-0.020.020.63FCI0.110.040.17<0.01CRP*0.140.050.23<0.01CRP* (ICU discharge)0.04-0.090.160.59Table 6: sensitivity analysis showing effect of adjusting for CRP at baseline. Outcome variable was ln(16-RMI). *Ventilator days and CRP were natural log transformed. Analyses conducted on the cohort of 123 patients that had blood sampling at 3 months. A complete case analysis approach was employed.Role of cytomegalovirus in post-ICU inflammationAt ICU discharge, 115/183 (63%) of patients were HCMV IgG positive indicating previous exposure to HCMV (1 patient had insufficient sample to perform IgG analysis). Of the IgG positive patients, 13/114 patients (11%) had evidence of lytic infection (detectable HCMV DNA on plasma PCR assay) (1 patient had insufficient sample to perform the DNA PCR). At 3-month follow-up no patients had evidence of on-going lytic infection. At ICU discharge, patients previously exposed to HCMV had similar CRP concentrations, but greater concentrations of HNE and a lower concentration of the pro-resolution mediator TGFβ1 suggesting a more pro-inflammatory phenotype associated with previous HCMV exposure (table 7). At 3 months, despite an overall fall in inflammatory biomarkers, patients previously exposed to HCMV still had significantly greater circulating HNE and lower circulating TGFβ1. Very small differences in physical outcomes were noted according to previous HCMV exposure, although this reached statistical significance for the TUG test, which was slower in HCMV positive patients (Table 8). As HCMV exposure increases with age, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1iiog612nd","properties":{"formattedCitation":"[37]","plainCitation":"[37]"},"citationItems":[{"id":292,"uris":[""],"uri":[""],"itemData":{"id":292,"type":"article-journal","title":"Seroprevalence of cytomegalovirus infection in the United States, 1988-1994","container-title":"Clin Infect Dis","page":"1143-51","volume":"43","issue":"9","source":"NLM","archive_location":"17029132","abstract":"BACKGROUND: Cytomegalovirus (CMV) is a leading cause of congenital illness and disability, including hearing loss and mental retardation. However, there are no nationwide estimates of CMV seroprevalence among pregnant women or the overall population of the United States. METHODS: To determine CMV prevalence in a representative sample of the US population, we tested serum samples for CMV-specific immunoglobulin G from participants aged > or =6 years (n=21,639) in the third National Health and Nutrition Examination Survey (1988-1994). RESULTS: The prevalence of CMV infection was 58.9% in individuals > or =6 years old. CMV seroprevalence increased gradually with age, from 36.3% in 6-11-year-olds to 90.8% in those aged > or =80 years. CMV seroprevalence differed by race and/or ethnicity as follows: 51.2% in non-Hispanic white persons, 75.8% in non-Hispanic black persons, and 81.7% in Mexican Americans. Racial and/or ethnic differences in CMV seroprevalence persisted when controlling for household income level, education, marital status, area of residence, census region, family size, country of birth, and type of medical insurance. Among women, racial and/or ethnic differences were especially significant; between ages 10-14 years and 20-24 years, seroprevalence increased 38% for non-Hispanic black persons, 7% for non-Hispanic white persons, and <1% for Mexican Americans. CONCLUSIONS: On the basis of these results, we estimate that each year in the United States approximately 340,000 non-Hispanic white persons, 130,000 non-Hispanic black persons, and 50,000 Mexican American women of childbearing age experience a primary CMV infection. Given the number of women at risk and the significance of congenital disease, development of programs for the prevention of CMV infection, such as vaccination or education, is of considerable public health importance.","DOI":"10.1086/508173","ISSN":"1537-6591 (Electronic) 1058-4838 (Linking)","shortTitle":"Seroprevalence of cytomegalovirus infection in the United States, 1988-1994","language":"eng","author":[{"family":"Staras","given":"S. A."},{"family":"Dollard","given":"S. C."},{"family":"Radford","given":"K. W."},{"family":"Flanders","given":"W. D."},{"family":"Pass","given":"R. F."},{"family":"Cannon","given":"M. J."}],"issued":{"date-parts":[["2006",11,1]]}}}],"schema":""} [37] we assessed the potential confounding role of age (and other baseline variables) in the association between HCMV and physical recovery. Baseline characteristics according to HCMV IgG status are shown in table 9. None of the baseline variables (including age) differed significantly according to HCMV exposure group.We assessed whether HCMV sero-positivity may be a confounder in the relationship between inflammation (measured by CRP) and RMI. We found no independent relationship between HCMV sero-positivity and RMI at 3 months. The addition of HCMV sero-positivity as a covariate also had no influence on the strength of the relationship between ln(CRP) and ln(16-RMI), which remained highly significant (OR 0.15 (95% CI 0.06 – 0.24) p<0.01). These sensitivity analyses are presented in the online data supplement.Previous HCMV exposure Median (IQR)No previous HCMV exposureMedian (IQR)Hodges Lehman median difference (95% CI)pCRP (mg/L)Baseline25.4 (10.9, 62.3)27.9 (11.7, 56.8)-0.5 (-8.2, 8.2)0.833 months5.4 (1.7, 12.9)2.8 (0.81, 8.3)1.5 (-0.1, 3.9)0.06HNE (ng/mL)Baseline175.2 (133.4, 233.7)135.0 (108.7, 211.6)35.8 (14.0, 58.7)<0.013 months118.1 (95.6, 158.2)91.3 (76.2, 120.4)35.8 (13.4, 41.3)<0.01IL-1β (pg/mL)Baseline0.0 (0.0, 16.5)0.0 (0.0, 7.1)0.0 (0.0, 0.0)0.143 months0.0 (0.0, 16.0)0.0 (0.0, 2.5)0.0 (0.0, 0.0)0.62IL-6 (pg/mL)Baseline31.1 (8.5, 97.6)16.4 (6.5, 63.5)8.1 (0.0, 20.8)0.243 months7.1 (0.1, 51.2)1.5 (0.0, 14.3)8.1 (0.0, 20.8)0.32IL-8 (pg/mL)Baseline35.8 (14.7, 74.0)24.4 (11.2, 40.2)7.5 (-0.6, 17.2)0.073 months9.3 (1.9, 41.0)4.8 (0.3, 11.9)3.4 (0.0, 9.5)0.16TGFβ1 (ng/mL)Baseline10.7 (7.8, 15.3)14.3 (10.2, 17.8)-2.4 (-4.1, -2.4)0.033 months9.2 (7.5, 11.8)11.4 (9.8, 13.2)-1.7 (-2.9, -0.4)0.01SLPI (ng/mL)Baseline56.5 (41.4, 79.7)60.5 (48.2, 73.2)-2.9 (-9.7, 4.3)0.263 months46.6 (37.3, 63.4)47.9 (37.5, 59.0)-0.4 (-7.6, 7.0)0.79Table 7 – Biomarker Concentration according to HCMV exposure group. 115 exposed, 68 unexposed. 3 months: 76 exposed, 41 unexposed. Note Hodges Lehman median differences have been used which are based on the Hodges Lehman estimate of the sample median and not the true median which explains the discrepancy between the true median difference and the Hodges Lehman median difference estimate quoted.Previous HCMV exposure (n=115)No previous HCMV exposure (n=68)pRivermead Mobility Index (median (Q1, Q3))13 (11,14)14 (12,15)0.09Hand Grip Strength (kg) (mean (sd))21 (9)23 (9)0.29Timed up and go (s) (median (Q1, Q3))11 (8,14)10 (7,12)0.03Physical Component Score of SF12v2 (mean (sd))35 (11)35 (12)0.85Table 8 - Comparison of physical outcomes in ICU survivors at 3 months in patients with / without previous HCMV exposure. Rivermead Mobility Index data available for 106 exposed and 60 unexposed patients. Hand Grip Strength data available for 93 exposed and 52 unexposed patients. Timed Up and Go data available for 88 exposed and 51 unexposed patients. Physical component score of SF12v2 available for 95 exposed and 57 unexposed patients..Previous HCMV exposure (n=115)No previous HCMV exposure (n=68)Age (mean (sd))61 (14)61 (13)Male (n (%))69 (63)43 (60)Functional Comorbidity Index (mean (sd))3 (2)3 (2)APACHE 2 (mean (sd))21 (7)21 (8)Days of mechanical ventilation (median (Q1, Q3)8 (5,13)7 (4,16)ICU length of stay (median (Q1, Q3)11 (6,18)11 (6,20)Vasopressors (n (%))83 (73)49 (72)Renal replacement therapy (n (%))34 (30)15 (22)Table 9 – Baseline Characteristics according to HCMV exposure.discussionIn a pre-planned secondary analysis of patients enrolled in a randomised controlled trial of a rehabilitation intervention, we demonstrated a high prevalence of systemic inflammation in ICU survivors at ICU discharge and 3 months follow-up. We observed a significant relationship between inflammation and physical recovery that persisted after adjusting for measures of pre-existing comorbidity and acute illness severity. Patients had evidence of persisting pro-inflammatory and impaired pro-resolution signalling during the study period. In an exploratory analysis, we found a more pronounced pro-inflammatory phenotype in patients previously exposed to HCMV both at ICU discharge and 3 months follow-up. This supports the hypothesis that this might mediate, in part, the association between persisting inflammation and functional recovery. Our study had a number of strengths. First, the rates of enrolment and follow up were high, reducing the risk of attrition bias. We also undertook sensitivity analyses in which missing data were imputed to allow us to ensure potential bias from missing data was assessed. Second, we adjusted for likely confounders. The most important was the use of the FCI to adjust for pre-illness physical function (an important determinant of physical recovery after acute illness ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"SXUVPall","properties":{"formattedCitation":"[38]","plainCitation":"[38]"},"citationItems":[{"id":35,"uris":[""],"uri":[""],"itemData":{"id":35,"type":"article-journal","title":"Physical complications in acute lung injury survivors: a two-year longitudinal prospective study","container-title":"Crit Care Med","page":"849-59","volume":"42","issue":"4","source":"NLM","archive_location":"24247473","abstract":"OBJECTIVE: Survivors of severe critical illness frequently develop substantial and persistent physical complications, including muscle weakness, impaired physical function, and decreased health-related quality of life. Our objective was to determine the longitudinal epidemiology of muscle weakness, physical function, and health-related quality of life and their associations with critical illness and ICU exposures. DESIGN: A multisite prospective study with longitudinal follow-up at 3, 6, 12, and 24 months after acute lung injury. SETTING: Thirteen ICUs from four academic teaching hospitals. PATIENTS: Two hundred twenty-two survivors of acute lung injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At each time point, patients underwent standardized clinical evaluations of extremity, hand grip, and respiratory muscle strength; anthropometrics (height, weight, mid-arm circumference, and triceps skin fold thickness); 6-minute walk distance, and the Medical Outcomes Short-Form 36 health-related quality of life survey. During their hospitalization, survivors also had detailed daily evaluation of critical illness and related treatment variables. Over one third of survivors had objective evidence of muscle weakness at hospital discharge, with most improving within 12 months. This weakness was associated with substantial impairments in physical function and health-related quality of life that persisted at 24 months. The duration of bed rest during critical illness was consistently associated with weakness throughout 24-month follow-up. The cumulative dose of systematic corticosteroids and use of neuromuscular blockers in the ICU were not associated with weakness. CONCLUSIONS: Muscle weakness is common after acute lung injury, usually recovering within 12 months. This weakness is associated with substantial impairments in physical function and health-related quality of life that continue beyond 24 months. These results provide valuable prognostic information regarding physical recovery after acute lung injury. Evidence-based methods to reduce the duration of bed rest during critical illness may be important for improving these long-term impairments.","DOI":"10.1097/ccm.0000000000000040","ISSN":"0090-3493","shortTitle":"Physical complications in acute lung injury survivors: a two-year longitudinal prospective study","journalAbbreviation":"Critical care medicine","language":"eng","author":[{"family":"Fan","given":"E."},{"family":"Dowdy","given":"D. W."},{"family":"Colantuoni","given":"E."},{"family":"Mendez-Tellez","given":"P. A."},{"family":"Sevransky","given":"J. E."},{"family":"Shanholtz","given":"C."},{"family":"Himmelfarb","given":"C. R."},{"family":"Desai","given":"S. V."},{"family":"Ciesla","given":"N."},{"family":"Herridge","given":"M. S."},{"family":"Pronovost","given":"P. J."},{"family":"Needham","given":"D. M."}],"issued":{"date-parts":[["2014",4]]}}}],"schema":""} [38]). The FCI is a measure of important comorbidities, which correlates strongly with physical quality of life scores. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Jlw1UKvJ","properties":{"formattedCitation":"[39]","plainCitation":"[39]"},"citationItems":[{"id":132,"uris":[""],"uri":[""],"itemData":{"id":132,"type":"article-journal","title":"The development of a comorbidity index with physical function as the outcome","container-title":"J Clin Epidemiol","page":"595-602","volume":"58","issue":"6","source":"NLM","archive_location":"15878473","abstract":"BACKGROUND AND OBJECTIVES: Physical function is an important measure of success of many medical and surgical interventions. Ability to adjust for comorbid disease is essential in health services research and epidemiologic studies. Current indices have primarily been developed with mortality as the outcome, and are not sensitive enough when the outcome is physical function. The objective of this study was to develop a self-administered Functional Comorbidity Index with physical function as the outcome. METHODS: The index was developed using two databases: a cross-sectional, simple random sample of 9,423 Canadian adults and a sample of 28,349 US adults seeking treatment for spine ailments. The primary outcome measure was the SF-36 physical function (PF) subscale. RESULTS: The Functional Comorbidity Index, an 18-item list of diagnoses, showed stronger association with physical function (model R(2) = 0.29) compared with the Charlson (model R(2) = 0.18), and Kaplan-Feinstein (model R(2) = 0.07) indices. The Functional Comorbidity Index correctly classified patients into high and low function, in 77% of cases. CONCLUSION: This new index contains diagnoses such as arthritis not found on indices used to predict mortality, and the FCI explained more variance in PF scores compared to indices designed to predict mortality.","DOI":"10.1016/j.jclinepi.2004.10.018","ISSN":"0895-4356 (Print) 0895-4356","shortTitle":"The development of a comorbidity index with physical function as the outcome","journalAbbreviation":"Journal of clinical epidemiology","language":"eng","author":[{"family":"Groll","given":"D. L."},{"family":"To","given":"T."},{"family":"Bombardier","given":"C."},{"family":"Wright","given":"J. G."}],"issued":{"date-parts":[["2005",6]]}}}],"schema":""} [39] This may not have completely controlled for pre-illness physical function, but is more objective and valid than patient recall of physical abilities. Most previous studies of post-ICU recovery have made no adjustment for pre-illness health status. We did not adjust for case mix in our analysis primarily because the study was not powered to allow it, but reassuringly observed very little variation in case mix across CRP tertiles. Finally, the measured biomarkers were pre-defined to reflect initiation, propagation, and resolution of the acute inflammatory response to provide a balanced picture of the inflammatory profile. Our study had limitations. First, our assertion that inflammatory markers were elevated in ICU survivors was based on comparison with previously published data in other populations; these were limited by performance of the assays and the populations studied. Second, our analysis relied on the physical function metrics used in RECOVER, limiting the discriminant ability for studying the pathophysiological processes affecting muscle recovery. Third, our patients were ventilated for greater than 48 hours so our findings may not be generalizable to all ICU cohorts. Fourth, we did not adjust our formal analysis for multiple comparisons as it was considered explorative and hypothesis-generating. This may have led to type 1 error. Despite this, for our main endpoint (adjusted association between CRP and RMI), the p value of 0.001 would remain significant when measured against a Bonferroni-adjusted p value threshold of 0.002. Finally, we could not definitely attribute causality between inflammation and physical recovery because we were unable to establish temporality due to the complex nature of the inflammatory response and the trial design. Inflammatory persistence in ICU survivors is of potential clinical relevance. We have shown that it is highly prevalent, affecting 50-67% of survivors 3 months following ICU discharge. This finding is in keeping with a previous study in 24 anaemic ICU survivors that showed elevation of CRP up to 13 weeks after ICU discharge. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2ctdpspsoq","properties":{"formattedCitation":"[40]","plainCitation":"[40]"},"citationItems":[{"id":165,"uris":[""],"uri":[""],"itemData":{"id":165,"type":"article-journal","title":"Time course of anemia during six months follow up following intensive care discharge and factors associated with impaired recovery of erythropoiesis","container-title":"Crit Care Med","page":"1906-12","volume":"37","issue":"6","source":"NLM","archive_location":"19384207","abstract":"OBJECTIVES: Anemia is a common complication of critical illness, but its duration after intensive care discharge and possible contributory factors have not been studied. Our aim was to follow patients discharged anemic from the intensive care unit (ICU) for up to 6 months and determine the duration of and possible reasons for persisting anemia. DESIGN: Prospective observational cohort study of intensive care (ICU) survivors with moderate-severe anemia at the time of ICU discharge. Erythropoietic and inflammatory markers were measured at regular intervals over six months to assess red cell production and factors limiting recovery from anemia. SETTING: An 18-bed medico-surgical ICU in a Scottish university teaching hospital. PATIENTS: Patients who required >24 hrs of ventilatory support and were discharged from intensive care with hemoglobin < 100 g/L were studied prospectively over 6 months. 30 patients were recruited; 19 completed 6 months follow-up, 6 died during the study period, and 5 completed part of the follow up. Patients with ongoing renal failure or chronic hematologic disorders were excluded. MEASUREMENTS AND MAIN RESULTS: 47% (9 of 19) of patients completing 6 months follow up recovered from their anemia. The median time to recovery was 11 wks (1, 3 quartiles: 9, 26 wks). 10 patients (53%) were still anemic 6 months after ICU discharge. No patients developed iron, vitamin B12 or folate deficiency. An inappropriately low erythropoietin response to anemia was observed in virtually all patients and did not distinguish nonrecovering patients. Patients with delayed recovery or persisting anemia during the 13 wks following ICU discharge had higher levels of circulating inflammatory markers (IL-6 and C-reactive protein) and did not exhibit reticulocytosis during the weeks following discharge. CONCLUSIONS: Anemia persists in many patients following critical illness and is associated with ongoing inflammation, inappropriate erythropoietin response and poor marrow red cell production.","DOI":"10.1097/CCM.0b013e3181a000cf","ISSN":"0090-3493","shortTitle":"Time course of anemia during six months follow up following intensive care discharge and factors associated with impaired recovery of erythropoiesis","journalAbbreviation":"Critical care medicine","language":"eng","author":[{"family":"Bateman","given":"A. P."},{"family":"McArdle","given":"F."},{"family":"Walsh","given":"T. S."}],"issued":{"date-parts":[["2009",6]]}}}],"schema":""} [40] The aetiology of this inflammatory signal is unclear. Persistence of the acute inflammatory response is one mechanism, but other potential explanations such as pre-existing inflammation (with return to baseline), inter-current infection (for example sub-clinical), or an undiagnosed focus of inflammation (for example within lung or muscle) are also plausible. A high proportion of patients (28%) were readmitted to hospital between ICU discharge and 3 months follow-up in the RECOVER trial. Detailed data concerning the reasons for readmission are not available, and blood for inflammatory profiles was not collected during readmissions. It is possible that the condition requiring readmission resulted in worsening inflammation, which might explain some of our findings. Equally, a persisting inflammatory state may have limited recovery resulting in further hospitalisation. Further research is required to investigate this issue. Of the patients who had blood samples at 3 months, 11/123 (9%) were hospital inpatients at the time. These patients had elevated CRP concentrations (median 15.8 (IQR 11.5 – 36.0) mg/L versus 3.8 (IQR 1.0 – 9.4)). Inflammation at hospital discharge has been associated with higher longer term mortality following acute illness in previous studies, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"29j62mechf","properties":{"formattedCitation":"[41]","plainCitation":"[41]"},"citationItems":[{"id":14,"uris":[""],"uri":[""],"itemData":{"id":14,"type":"article-journal","title":"Inflammatory Markers at Hospital Discharge Predict Subsequent Mortality after Pneumonia and Sepsis","container-title":"American Journal of Respiratory and Critical Care Medicine","page":"1242-1247","volume":"177","issue":"11","source":"CrossRef","DOI":"10.1164/rccm.200712-1777OC","ISSN":"1073-449X, 1535-4970","language":"en","author":[{"family":"Yende","given":"Sachin"},{"family":"D'Angelo","given":"Gina"},{"family":"Kellum","given":"John A."},{"family":"Weissfeld","given":"Lisa"},{"family":"Fine","given":"Jonathan"},{"family":"Welch","given":"Robert D."},{"family":"Kong","given":"Lan"},{"family":"Carter","given":"Melinda"},{"family":"Angus","given":"Derek C."}],"issued":{"date-parts":[["2008",6]]}}}],"schema":""} [41] but ours is the first to explore the association with physical recovery following critical illness. Persisting physical disability was related to inflammatory response three months after ICU discharge but not ICU discharge, suggesting that chronic persistent inflammation is more important than acute inflammation. This may explain why IL-6 and IL-1, which are early pro-inflammatory mediators, were not associated with late physical function, whereas others (CRP, IL-8, HNE, and SLPI) were associated. Another potentially important consideration is that measurement of circulating soluble inflammatory biomarkers may not adequately characterise the host inflammatory response. For example, immune cell functions (e.g. neutrophil apoptosis) and inflammatory processes localised to specific sites (e.g. skeletal muscle or lung) may not be adequately described. Although our data should be interpreted with caution, they support the hypothesis that a persisting pro-inflammatory phenotype might mediate poorer physical recovery.Inflammation is important in acute muscle loss in ICU patients ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2lca7p5l66","properties":{"formattedCitation":"[8]","plainCitation":"[8]"},"citationItems":[{"id":332,"uris":[""],"uri":[""],"itemData":{"id":332,"type":"article-journal","title":"ICU-acquired weakness and recovery from critical illness","container-title":"N Engl J Med","page":"1626-35","volume":"370","issue":"17","source":"NLM","archive_location":"24758618","DOI":"10.1056/NEJMra1209390","ISSN":"0028-4793","shortTitle":"ICU-acquired weakness and recovery from critical illness","journalAbbreviation":"The New England journal of medicine","language":"eng","author":[{"family":"Kress","given":"J. P."},{"family":"Hall","given":"J. B."}],"issued":{"date-parts":[["2014",4,24]]}}}],"schema":""} [8] and is associated with muscle function in chronic inflammatory disease. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"v0gc4as78","properties":{"formattedCitation":"{\\rtf [9\\uc0\\u8211{}12]}","plainCitation":"[9–12]"},"citationItems":[{"id":315,"uris":[""],"uri":[""],"itemData":{"id":315,"type":"article-journal","title":"Inflammatory response and body composition in chronic obstructive pulmonary disease","container-title":"American Journal of Respiratory & Critical Care Medicine","page":"1414-8","volume":"164","issue":"8 Pt 1","archive_location":"11704588","ISSN":"1073-449X","shortTitle":"Inflammatory response and body composition in chronic obstructive pulmonary disease","journalAbbreviation":"Am J Respir Crit Care Med","language":"English","author":[{"family":"Eid","given":"A. A."},{"family":"Ionescu","given":"A. A."},{"family":"Nixon","given":"L. S."},{"family":"Lewis-Jenkins","given":"V."},{"family":"Matthews","given":"S. B."},{"family":"Griffiths","given":"T. L."},{"family":"Shale","given":"D. J."}],"issued":{"date-parts":[["2001",10,15]]}}},{"id":313,"uris":[""],"uri":[""],"itemData":{"id":313,"type":"article-journal","title":"Immune activation is associated with reduced skeletal muscle mass and physical function in chronic heart failure","container-title":"International Journal of Cardiology","page":"179-87","volume":"109","issue":"2","archive_location":"16024109","ISSN":"0167-5273","shortTitle":"Immune activation is associated with reduced skeletal muscle mass and physical function in chronic heart failure","journalAbbreviation":"Int J Cardiol","language":"English","author":[{"family":"Toth","given":"Michael J."},{"family":"Ades","given":"Philip A."},{"family":"Tischler","given":"Marc D."},{"family":"Tracy","given":"Russell P."},{"family":"LeWinter","given":"Martin M."}],"issued":{"date-parts":[["2006",5,10]]}}},{"id":128,"uris":[""],"uri":[""],"itemData":{"id":128,"type":"article-journal","title":"Markers of inflammation, proteolysis, and apoptosis in ESRD","container-title":"American Journal of Kidney Diseases","page":"1212-20","volume":"42","issue":"6","archive_location":"14655193","ISSN":"1523-6838","shortTitle":"Markers of inflammation, proteolysis, and apoptosis in ESRD","journalAbbreviation":"Am J Kidney Dis","language":"English","author":[{"family":"Raj","given":"Dominic S. C."},{"family":"Shah","given":"Hemangini"},{"family":"Shah","given":"Vallabh O."},{"family":"Ferrando","given":"Arny"},{"family":"Bankhurst","given":"Arthur"},{"family":"Wolfe","given":"Robert"},{"family":"Zager","given":"Philip G."}],"issued":{"date-parts":[["2003",12]]}}},{"id":397,"uris":[""],"uri":[""],"itemData":{"id":397,"type":"article-journal","title":"Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study","container-title":"American Journal of Medicine","page":"429-35","volume":"115","issue":"6","archive_location":"14563498","ISSN":"0002-9343","shortTitle":"Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study","journalAbbreviation":"Am J Med","language":"English","author":[{"family":"Roubenoff","given":"Ronenn"},{"family":"Parise","given":"Helen"},{"family":"Payette","given":"Helene A."},{"family":"Abad","given":"Leslie W."},{"family":"D'Agostino","given":"Ralph"},{"family":"Jacques","given":"Paul F."},{"family":"Wilson","given":"Peter W. F."},{"family":"Dinarello","given":"Charles A."},{"family":"Harris","given":"Tamara B."}],"issued":{"date-parts":[["2003",10,15]]}}}],"schema":""} [9–12] Inflammatory cytokines have an established role in regulating muscle mass; tumour necrosis factor α (TNFα), IL-6, and endotoxin cause muscle wasting ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"27p3ko9m2m","properties":{"formattedCitation":"[42]","plainCitation":"[42]"},"citationItems":[{"id":272,"uris":[""],"uri":[""],"itemData":{"id":272,"type":"article-journal","title":"Cachectin/TNF or IL-1 alpha induces cachexia with redistribution of body proteins","container-title":"American Journal of Physiology","page":"R659-65","volume":"256","issue":"3 Pt 2","archive_location":"2784290","ISSN":"0002-9513","shortTitle":"Cachectin/TNF or IL-1 alpha induces cachexia with redistribution of body proteins","journalAbbreviation":"Am J Physiol","language":"English","author":[{"family":"Fong","given":"Y."},{"family":"Moldawer","given":"L. L."},{"family":"Marano","given":"M."},{"family":"Wei","given":"H."},{"family":"Barber","given":"A."},{"family":"Manogue","given":"K."},{"family":"Tracey","given":"K. J."},{"family":"Kuo","given":"G."},{"family":"Fischman","given":"D. A."},{"family":"Cerami","given":"A."},{"literal":"et al."}],"issued":{"date-parts":[["1989",3]]}}}],"schema":""} [42] due to increased protein catabolism, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2ppsm0215p","properties":{"formattedCitation":"[43]","plainCitation":"[43]"},"citationItems":[{"id":251,"uris":[""],"uri":[""],"itemData":{"id":251,"type":"article-journal","title":"Stimulation of muscle protein degradation and prostaglandin E2 release by leukocytic pyrogen (interleukin-1). A mechanism for the increased degradation of muscle proteins during fever","container-title":"New England Journal of Medicine","page":"553-8","volume":"308","issue":"10","archive_location":"6402699","ISSN":"0028-4793","shortTitle":"Stimulation of muscle protein degradation and prostaglandin E2 release by leukocytic pyrogen (interleukin-1). A mechanism for the increased degradation of muscle proteins during fever","journalAbbreviation":"N Engl J Med","language":"English","author":[{"family":"Baracos","given":"V."},{"family":"Rodemann","given":"H. P."},{"family":"Dinarello","given":"C. A."},{"family":"Goldberg","given":"A. L."}],"issued":{"date-parts":[["1983",3,10]]}}}],"schema":""} [43] inhibition of protein synthesis, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"8ib66mpl2","properties":{"formattedCitation":"[44]","plainCitation":"[44]"},"citationItems":[{"id":231,"uris":[""],"uri":[""],"itemData":{"id":231,"type":"article-journal","title":"Effect of recombinant human tumour necrosis factor alpha on protein synthesis in liver, skeletal muscle and skin of rats","container-title":"Biochemical Journal","page":"493-7","volume":"258","issue":"2","archive_location":"2468333","ISSN":"0264-6021","shortTitle":"Effect of recombinant human tumour necrosis factor alpha on protein synthesis in liver, skeletal muscle and skin of rats","journalAbbreviation":"Biochem J","language":"English","author":[{"family":"Charters","given":"Y."},{"family":"Grimble","given":"R. F."}],"issued":{"date-parts":[["1989",3,1]]}}}],"schema":""} [44] inhibition of muscle cell differentiation, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"mptbhjqb0","properties":{"formattedCitation":"[45]","plainCitation":"[45]"},"citationItems":[{"id":131,"uris":[""],"uri":[""],"itemData":{"id":131,"type":"article-journal","title":"Tumor necrosis factor inhibits human myogenesis in vitro","container-title":"Molecular & Cellular Biology","page":"2295-301","volume":"8","issue":"6","archive_location":"3405207","ISSN":"0270-7306","shortTitle":"Tumor necrosis factor inhibits human myogenesis in vitro","journalAbbreviation":"Mol Cell Biol","language":"English","author":[{"family":"Miller","given":"S. C."},{"family":"Ito","given":"H."},{"family":"Blau","given":"H. M."},{"family":"Torti","given":"F. M."}],"issued":{"date-parts":[["1988",6]]}}}],"schema":""} [45] and reduced amino acid uptake. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"v8lvsvotm","properties":{"formattedCitation":"[46]","plainCitation":"[46]"},"citationItems":[{"id":67,"uris":[""],"uri":[""],"itemData":{"id":67,"type":"article-journal","title":"Effect of tumor necrosis factor or interleukin-1 on muscle amino acid uptake and the role of glucocorticoids","container-title":"Surgery, Gynecology & Obstetrics","page":"27-32","volume":"177","issue":"1","archive_location":"8322145","ISSN":"0039-6087","shortTitle":"Effect of tumor necrosis factor or interleukin-1 on muscle amino acid uptake and the role of glucocorticoids","journalAbbreviation":"Surg Gynecol Obstet","language":"English","author":[{"family":"Zamir","given":"O."},{"family":"Hasselgren","given":"P. O."},{"family":"James","given":"H."},{"family":"Higashiguchi","given":"T."},{"family":"Fischer","given":"J. E."}],"issued":{"date-parts":[["1993",7]]}}}],"schema":""} [46] It is possible that these processes “block” clinical responses to physical rehabilitation in the early post-ICU period, which might explain the negative results of intervention trials in the early post-ICU period, including the RECOVER trial. Future rehabilitation research should consider including measures of inflammation during recovery in order to understand its importance as an effect modifier, and potentially to inform the optimum timing of interventions. In addition, metrics such as muscle volume and muscle biopsy may provide greater insight into the pathophysiological relationship between inflammation and neuromuscular recovery in future studies. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"28a9qld561","properties":{"formattedCitation":"[4,47]","plainCitation":"[4,47]"},"citationItems":[{"id":392,"uris":[""],"uri":[""],"itemData":{"id":392,"type":"article-journal","title":"Acute skeletal muscle wasting in critical illness","container-title":"Jama","page":"1591-600","volume":"310","issue":"15","source":"NLM","archive_location":"24108501","abstract":"IMPORTANCE: Survivors of critical illness demonstrate skeletal muscle wasting with associated functional impairment. OBJECTIVE: To perform a comprehensive prospective characterization of skeletal muscle wasting, defining the pathogenic roles of altered protein synthesis and breakdown. DESIGN, SETTING, AND PARTICIPANTS: Sixty-three critically ill patients (59% male; mean age: 54.7 years [95% CI, 50.0-59.6 years]) with an Acute Physiology and Chronic Health Evaluation II score of 23.5 (95% CI, 21.9-25.2) were prospectively recruited within 24 hours following intensive care unit (ICU) admission from August 2009 to April 2011 at a university teaching and a community hospital in England. Patients were recruited if older than 18 years and were anticipated to be intubated for longer than 48 hours, to spend more than 7 days in critical care, and to survive ICU stay. MAIN OUTCOMES AND MEASURES: Muscle loss was determined through serial ultrasound measurement of the rectus femoris cross-sectional area (CSA) on days 1, 3, 7, and 10. In a subset of patients, the fiber CSA area was quantified along with the ratio of protein to DNA on days 1 and 7. Histopathological analysis was performed. In addition, muscle protein synthesis, breakdown rates, and respective signaling pathways were characterized. RESULTS: There were significant reductions in the rectus femoris CSA observed at day 10 (-17.7% [95% CI, -25.9% to 8.1%]; P < .001). In the 28 patients assessed by all 3 measurement methods on days 1 and 7, the rectus femoris CSA decreased by 10.3% (95% CI, 6.1% to 14.5%), the fiber CSA by 17.5% (95% CI, 5.8% to 29.3%), and the ratio of protein to DNA by 29.5% (95% CI, 13.4% to 45.6%). Decrease in the rectus femoris CSA was greater in patients who experienced multiorgan failure by day 7 (-15.7%; 95% CI, -27.7% to 11.4%) compared with single organ failure (-3.0%; 95% CI, -5.3% to 2.1%) (P < .001), even by day 3 (-8.7% [95% CI, -59.3% to 50.6%] vs -1.8% [95% CI, -12.3% to 10.5%], respectively; P = .03). Myofiber necrosis occurred in 20 of 37 patients (54.1%). Protein synthesis measured by the muscle protein fractional synthetic rate was depressed in patients on day 1 (0.035%/hour; 95% CI, 0.023% to 0.047%/hour) compared with rates observed in fasted healthy controls (0.039%/hour; 95% CI, 0.029% to 0.048%/hour) (P = .57) and increased by day 7 (0.076% [95% CI, 0.032%-0.120%/hour]; P = .03) to rates associated with fed controls (0.065%/hour [95% CI, 0.049% to 0.080%/hour]; P = .30), independent of nutritional load. Leg protein breakdown remained elevated throughout the study (8.5 [95% CI, 4.7 to 12.3] to 10.6 [95% CI, 6.8 to 14.4] mumol of phenylalanine/min/ideal body weight x 100; P = .40). The pattern of intracellular signaling supported increased breakdown (n = 9, r = -0.83, P = .005) and decreased synthesis (n = 9, r = -0.69, P = .04). CONCLUSIONS AND RELEVANCE: Among these critically ill patients, muscle wasting occurred early and rapidly during the first week of critical illness and was more severe among those with multiorgan failure compared with single organ failure. These findings may provide insights into skeletal muscle wasting in critical illness.","DOI":"10.1001/jama.2013.278481","ISSN":"0098-7484","shortTitle":"Acute skeletal muscle wasting in critical illness","journalAbbreviation":"Jama","language":"eng","author":[{"family":"Puthucheary","given":"Z. A."},{"family":"Rawal","given":"J."},{"family":"McPhail","given":"M."},{"family":"Connolly","given":"B."},{"family":"Ratnayake","given":"G."},{"family":"Chan","given":"P."},{"family":"Hopkinson","given":"N. S."},{"family":"Phadke","given":"R."},{"family":"Dew","given":"T."},{"family":"Sidhu","given":"P. S."},{"family":"Velloso","given":"C."},{"family":"Seymour","given":"J."},{"family":"Agley","given":"C. C."},{"family":"Selby","given":"A."},{"family":"Limb","given":"M."},{"family":"Edwards","given":"L. M."},{"family":"Smith","given":"K."},{"family":"Rowlerson","given":"A."},{"family":"Rennie","given":"M. J."},{"family":"Moxham","given":"J."},{"family":"Harridge","given":"S. D."},{"family":"Hart","given":"N."},{"family":"Montgomery","given":"H. E."}],"issued":{"date-parts":[["2013",10,16]]}}},{"id":681,"uris":[""],"uri":[""],"itemData":{"id":681,"type":"article-journal","title":"Ultrasound for the assessment of peripheral skeletal muscle architecture in critical illness: a systematic review","container-title":"Critical Care Medicine","page":"897-905","volume":"43","issue":"4","source":"PubMed","abstract":"OBJECTIVES: To critically evaluate and summarize identified evidence for the use of ultrasound to measure peripheral skeletal muscle architecture during critical illness.\nDATA SOURCES: Seven electronic databases (Medline, Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, Physiotherapy Evidence Database, Scopus, Excerpta Medica Database, and Web of Science [including Science Citations and Conference Proceedings]) and personal libraries were searched for relevant articles. Cross-referencing further identified references.\nSTUDY SELECTION: Quantitative study designs excluding abstracts, published in English, including adult critically ill patients in the ICU, evaluating peripheral skeletal muscle architecture during critical illness with ultrasound were included. Studies using ultrasonographic muscle data as outcome measures in interventional trials were excluded.\nDATA EXTRACTION: Performed by one reviewer using a standardized data extraction form and cross-checked by a second reviewer. Quality appraisal was undertaken by two independent reviewers-studies were classified, graded, and appraised according to standardized algorithms and checklists. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were adhered to.\nDATA SYNTHESIS: Seven studies with independent patient cohorts totaling 300 participants were included. One study adopted a case-control design, and the remainder were case series. Ultrasound data demonstrated deficits in a variety of peripheral skeletal muscle architecture variables across a range of muscle groups associated with critical illness. Ultrasound offered more accurate data compared to limb circumference measurement and has excellent reported reliability, but underestimated data acquired via more invasive muscle biopsy.\nCONCLUSION: Ultrasound provides clinical utility for assessing the trajectory of change in peripheral skeletal muscle architecture during critical illness, supplementing more detailed characterization, albeit rarely used, from muscle biopsy analysis. Adoption of standardized operating protocols for measurement will facilitate future meta-analysis of data.","DOI":"10.1097/CCM.0000000000000821","ISSN":"1530-0293","note":"PMID: 25559437","shortTitle":"Ultrasound for the assessment of peripheral skeletal muscle architecture in critical illness","journalAbbreviation":"Crit. Care Med.","language":"eng","author":[{"family":"Connolly","given":"Bronwen"},{"family":"MacBean","given":"Victoria"},{"family":"Crowley","given":"Clare"},{"family":"Lunt","given":"Alan"},{"family":"Moxham","given":"John"},{"family":"Rafferty","given":"Gerrard F."},{"family":"Hart","given":"Nicholas"}],"issued":{"date-parts":[["2015",4]]},"PMID":"25559437"}}],"schema":""} [4,47] Our finding of a pro-inflammatory phenotype in patients previously exposed to HCMV was unexpected. The original analysis was planned to explore the importance of active (lytic) infection but the small number of patients that this affected precluded this. Lytic infection is associated with activation of the innate immune system and previous studies have shown that this can last beyond the acute infection and into latency. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"isvnh330u","properties":{"formattedCitation":"[21]","plainCitation":"[21]"},"citationItems":[{"id":109,"uris":[""],"uri":[""],"itemData":{"id":109,"type":"article-journal","title":"Human cytomegalovirus induces systemic immune activation characterized by a type 1 cytokine signature","container-title":"J Infect Dis","page":"690-9","volume":"202","issue":"5","source":"NLM","archive_location":"20632887","abstract":"Mechanisms underlying the onset and perpetuation of chronic immune activation in individuals without overt infectious or autoimmune diseases are unclear. Cytomegalovirus (CMV) is a persistent virus that induces a permanent increase of highly differentiated, interferon-gamma-secreting effector T cells. We hypothesized that, because of this increase, CMV also induces a systemic inflammatory response. We measured acute phase proteins, cytokines, and chemokines in serum samples from renal transplant recipients who developed a primary CMV infection and healthy CMV serum-positive or -negative individuals. Primary CMV infection induced a clear proinflammatory response that was maintained during latency. This response was characterized by increased levels of acute phase proteins, such as serum amyloid-A and C-reactive protein, and type 1 cytokines, such as interleukin-18, interferon-inducible protein-10, and interferon-gamma. This continuous activation of the immune system may play a role in the pathogenesis of chronic allograft rejection and potentially contribute to the acceleration of chronic diseases.","DOI":"10.1086/655472","ISSN":"0022-1899","shortTitle":"Human cytomegalovirus induces systemic immune activation characterized by a type 1 cytokine signature","journalAbbreviation":"The Journal of infectious diseases","language":"eng","author":[{"family":"Berg","given":"P. J.","non-dropping-particle":"van de"},{"family":"Heutinck","given":"K. M."},{"family":"Raabe","given":"R."},{"family":"Minnee","given":"R. C."},{"family":"Young","given":"S. L."},{"family":"Donselaar-van der Pant","given":"K. A.","non-dropping-particle":"van"},{"family":"Bemelman","given":"F. J."},{"family":"Lier","given":"R. A.","non-dropping-particle":"van"},{"family":"Berge","given":"I. J.","non-dropping-particle":"ten"}],"issued":{"date-parts":[["2010",9,1]]}}}],"schema":""} [21] It has been reported that up to 40% of patients reactivate HCMV during critical illness ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"26pke6gtn","properties":{"formattedCitation":"[14]","plainCitation":"[14]"},"citationItems":[{"id":193,"uris":[""],"uri":[""],"itemData":{"id":193,"type":"article-journal","title":"Cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis","container-title":"Crit Care","page":"R77","volume":"15","issue":"2","source":"NLM","archive_location":"21362193","abstract":"INTRODUCTION: Sepsis has been identified as a risk factor for human cytomegalovirus (CMV) reactivation in critically ill patients. However, the contribution of CMV reactivation on morbidity and mortality is still controversial. Therefore, we analyzed the incidence and impact of CMV reactivation on outcome in patients with severe sepsis. METHODS: In a prospective longitudinal double-blinded observational study, 97 adult nonimmunosuppressed CMV-seropositive patients with new onset of severe sepsis were included. Leukocytes, plasma and tracheal secretions were examined weekly for CMV-DNA by PCR. Tracheal secretions were additionally tested for HSV (Herpes Simplex Virus)-DNA. The influence of CMV-reactivation on the endpoints was analysed by Cox proportional-hazard regression analysis. Time-dependency was evaluated by landmark analysis. RESULTS: Six out 97 died and five were discharged from the hospital within 72 hours and were excluded of the analysis. CMV reactivation occurred in 35 of the 86 (40.69%) analysed patients. HSV infection occurred in 23 of the 35 (65.7%) CMV reactivators. In 10 patients CMV-plasma-DNAemia appeared with a DNA-content below 600 copies/ml in four cases and a peak amount of 2,830 copies/ml on average. In patients with and without CMV reactivation mortality rates were similar (37.1% vs. 35.3%, P = 0.861), respectively. However, in the multivariate COX regression analyses CMV reactivation was independently associated with increased length of stay in the ICU (30.0, interquartile range 14 to 48 vs. 12.0, interquartile range 7 to 19 days; HR (hazard ratio) 3.365; 95% CI (confidence interval) 1.233 to 9.183, P = 0.018) and in the hospital (33.0, interquartile range 24 to 62 vs. 16.0, interquartile range 10 to 24 days, HR 3.3, 95% CI 1.78 to 6.25, P < 0.001) as well as prolonged mechanical ventilation (22.0, interquartile range 6 to 36 vs. 7.5, interquartile range 5 to 15.5 days; HR 2.6,CI 95% 1.39 to 4.94; P < 0.001) and impaired pulmonary gas exchange (six days, interquartile range 1 to 17, vs. three, interquartile range 1 to 7, days in reactivators vs. non-reactivators, P = 0.038). HSV reactivation proved not to be a risk factor for these adverse effects. CONCLUSIONS: These data indicate an independent correlation between CMV reactivation and increased morbidity in the well-defined group of nonimmunosuppressed patients with severe sepsis, but CMV reactivation had no impact on mortality in this group with low CMV-DNA plasma levels. Thus, the potential harms and benefits of antiviral treatment have to be weighed cautiously in patients with severe sepsis or septic shock.","DOI":"10.1186/cc10069","ISSN":"1466-609X (Electronic) 1364-8535 (Linking)","shortTitle":"Cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis","language":"eng","author":[{"family":"Heininger","given":"A."},{"family":"Haeberle","given":"H."},{"family":"Fischer","given":"I."},{"family":"Beck","given":"R."},{"family":"Riessen","given":"R."},{"family":"Rohde","given":"F."},{"family":"Meisner","given":"C."},{"family":"Jahn","given":"G."},{"family":"Koenigsrainer","given":"A."},{"family":"Unertl","given":"K."},{"family":"Hamprecht","given":"K."}],"issued":{"date-parts":[["2011"]]}}}],"schema":""} [14] so our previously exposed patients may have experienced reactivation at an early stage that was undetectable at our chosen measurement point. It is impossible to discriminate between the relative importance of latent and lytic infection in this study, but our data raise the possibility that HCMV is potentially important in post-ICU inflammation and recovery. Further research in this area is justified, because the clinical effects of HCMV activation are potentially modifiable by antiviral treatment. Two on-going RCTs (the GRAIL study: NCT01335932 and the CCC study: NCT010503918) may provide more information, but neither will report functional outcome, or longer term inflammatory resolution.We observed a mean 1 second increase in the time taken to perform the timed up and go test in individuals who were HCMV sero-positive. Whilst this difference is small, it is a potentially important finding in terms of hypothesis generation, particularly as the RECOVER study found no difference between intervention groups in relation to this measure. Despite this the study was never powered to detect such a difference, and the finding should be interpreted with caution.In conclusion, we have shown that a systemic pro-inflammatory state persists for at least 3 months in many patients recovering from critical illness, and is characterised by persisting pro-inflammatory signals and reduced pro-resolution signals. Persisting systemic inflammation is associated with poorer physical recovery. Although patients do not demonstrate evidence of on-going lytic HCMV infection, those with evidence of previous HCMV infection appear to demonstrate a more persisting pro-inflammatory state that lasts beyond the ICU discharge and is present in some patients 3 months later. Further research is warranted to explore the importance of persisting inflammation as a mediator of recovery following critical illness.AcknowledgementsAuthor ContributionsTSW and DMG conceived the study. TSW, DMG, AGR, and SL acquired funding. TSW, DMG, AGR, SL, LS, JM and KT designed the study. DMG and JR performed the biomarker assays. KT coordinated the HCMV analysis. All authors contributed to the interpretation of the summary data and reviewed the final manuscript. All authors approved the final peting interestsNo authors declare any relevant conflicts of interest in relation to this workfundingThis study was funded by the Chief Scientists Office, Scotland (CZH/4/531, ETM/221). KEY QUESTIONIs systemic inflammation prevalent during recovery from critical illness and is it associated with physical recovery?BOTTOM LINESystemic inflammation is highly prevalent during recovery from critical illness and is independently associated with physical recovery.WHY READ ON?We present inflammatory persistence as a plausible mechanism for poor physical function after critical illness and intriguing data that raise the possibility that HCMV infection may contribute. 140 CHARACTER TWEETPersistent systemic inflammation may impair physical recovery after critical illnessreferences ADDIN ZOTERO_BIBL {"custom":[]} CSL_BIBLIOGRAPHY 1 Herridge MS, Tansey CM, Matte A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011;364:1293–304.2 Stevens RD, Marshall SA, Cornblath DR, et al. A framework for diagnosing and classifying intensive care unit-acquired weakness. Crit Care Med 2009;37:S299–308. doi:10.1097/CCM.0b013e3181b6ef673 Hund E. 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Surg Gynecol Obstet 1993;177:27–32.47 Connolly B, MacBean V, Crowley C, et al. Ultrasound for the assessment of peripheral skeletal muscle architecture in critical illness: a systematic review. Crit Care Med 2015;43:897–905. doi:10.1097/CCM.0000000000000821FIGURE LEGENDSFigure SEQ Figure \* ARABIC 1 – Study Flow DiagramFigure SEQ Figure \* ARABIC 2 - Inflammatory fate of patients with low (<3mg/L), medium (3-10mg/L) and high (>10mg/L) CRP concentration. For the 118 patient with complete data at both time points, patients were categorised at ICU discharge, then again at 3 monthsFigure SEQ Figure \* ARABIC 3 – Box and whisker plots showing CRP and HNE concentration in patients with good mobility and poor mobility. Whiskers represent 10th and 90th centiles. ................
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