Increased mortality in elderly patients with acute respiratory distress syndrome is not explained by host response

Laura R A Schouten, Lieuwe D J Bos, A Serpa Neto, Lonneke A van Vught, Maryse A Wiewel, Arie J Hoogendijk, Marc J M Bonten, Olaf L Cremer, Janneke Horn, Tom van der Poll, Marcus J Schultz, Roelie M Wösten-van Asperen, MARS consortium, F M de Beer, L D Bos, G J Glas, J Horn, A J Hoogendijk, R T van Hooijdonk, M A Huson, T van der Poll, B P Scicluna, L R A Schouten, M J Schultz, M Straat, L A van Vught, L Wieske, M A Wiewel, E Witteveen, M J M Bonten, O L Cremer, J F Frencken, K van de Groep, P M Klein Klouwenberg, M E Koster-Brouwer, D S Ong, D M Verboom, Laura R A Schouten, Lieuwe D J Bos, A Serpa Neto, Lonneke A van Vught, Maryse A Wiewel, Arie J Hoogendijk, Marc J M Bonten, Olaf L Cremer, Janneke Horn, Tom van der Poll, Marcus J Schultz, Roelie M Wösten-van Asperen, MARS consortium, F M de Beer, L D Bos, G J Glas, J Horn, A J Hoogendijk, R T van Hooijdonk, M A Huson, T van der Poll, B P Scicluna, L R A Schouten, M J Schultz, M Straat, L A van Vught, L Wieske, M A Wiewel, E Witteveen, M J M Bonten, O L Cremer, J F Frencken, K van de Groep, P M Klein Klouwenberg, M E Koster-Brouwer, D S Ong, D M Verboom

Abstract

Background: Advanced age is associated with increased mortality in acute respiratory distress syndrome (ARDS) patients. Preclinical studies suggest that the host response to an injurious challenge is age-dependent. In ARDS patients, we investigated whether the association between age and mortality is mediated through age-related differences in the host response.

Methods: This was a prospective longitudinal observational cohort study, performed in the ICUs of two university-affiliated hospitals. The systemic host response was characterized in three predefined age-groups, based on the age-tertiles of the studied population: young (18 to 54 years, N = 209), middle-aged (55 to 67 years, N = 213), and elderly (67 years and older, N = 196). Biomarkers of inflammation, endothelial activation, and coagulation were determined in plasma obtained at the onset of ARDS. The primary outcome was 90-day mortality. A mediation analysis was performed to examine whether age-related differences in biomarker levels serve as potential causal pathways mediating the association between age and mortality.

Results: Ninety-day mortality rates were 30% (63/209) in young, 37% (78/213) in middle-aged, and 43% (84/196) in elderly patients. Middle-aged and elderly patients had a higher risk of death compared to young patients (adjusted odds ratio, 1.5 [95% confidence interval 1.0 to 2.3] and 2.1 [1.4 to 3.4], respectively). Relative to young patients, the elderly had significantly lower systemic levels of biomarkers of inflammation and endothelial activation. Tissue plasminogen activator, a marker of coagulation, was the only biomarker that showed partial mediation (proportion of mediation, 10 [1 to 28] %).

Conclusion: Little evidence was found that the association between age and mortality in ARDS patients is mediated through age-dependent differences in host response pathways. Only tissue plasminogen activator was identified as a possible mediator of interest.

Trial registration: This trial was registered at ClinicalTrials.gov (identifier NCT01905033 , date of registration July 23, 2013).

Keywords: Aging; Biomarker; Critical care, intensive care, ARDS, host response; Mediation; Outcome.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Pathway analysis: stepwise mediation analysis assessing whether the association between age and mortality is mediated by age-dependent differences in biomarker levels. *Adjusted for ethnic background, gender, admission type, readmission, direct hit for ARDS, Charlson Comorbidity Index, APACHE-IV score adjusted for age, immunodeficiency, tidal volume per predicted body weight, positive end-expiratory pressure. C = average direct effect (ADE); A*B = average causal mediation effect (ACME). A’, B’, and C’—adjusted for confounders
Fig. 2
Fig. 2
Patient flow chart
Fig. 3
Fig. 3
Systemic levels of biomarker in ARDS patients stratified by age group. Systemic levels of a interleukin (IL)-6, b IL-8, c IL-10, d Fractalkine, e intracellular adhesion molecule (ICAM)-1, f angiopoetin 2:angiopoetin 1 (ANG2:ANG1), g platelet factor (PF) 4, h tissue plasminogen activator (tPA), i protein C, at onset of ARDS. Young adults, middle-aged adults, and elderly. Box and whisker diagrams depict the median and lower quartile, upper quartile, and their respective 1.5 IQR as whiskers—as specified by Tukey. Group differences between young adults and middle-aged adults, and young adults and elderly were tested by a Mann-Whitney U test. A p value < 0.05 was considered as statistical significant
Fig. 4
Fig. 4
Mediation analysis. a, b Tissue plasminogen activator is a mediator which partially explains the association between age and mortality. *Adjusted for ethnic background, gender, admission type, readmission, direct hit for ARDS, Charlson Comorbidity Index, APACHE-IV score adjusted for age, immunodeficiency, tidal volume per predicted body weight, and positive end-expiratory pressure. ADE, average direct effect; ACME, average causal mediation effect. A p value < 0.05 was considered as statistical significant

References

    1. Ely EW, Wheeler AP, Thompson BT, et al. Recovery rate and prognosis in older persons who develop acute lung injury and the acute respiratory distress syndrome. Ann Intern Med. 2002;136:25–36. doi: 10.7326/0003-4819-136-1-200201010-00007.
    1. Manzano F, Yuste E, Colmenero M, et al. Incidence of acute respiratory distress syndrome and its relation to age. J Crit Care. 2005;20:274–280. doi: 10.1016/j.jcrc.2005.05.008.
    1. Schouten LRA, Schultz MJ, van Kaam AH, et al. Association between maturation and aging and pulmonary responses in animal models of lung injury: a systematic review. Anesthesiology. 2015;123:389–408. doi: 10.1097/ALN.0000000000000687.
    1. Villar J, Ambrós A, Soler JA, et al. Age, PaO2/FIO2, and plateau pressure score: a proposal for a simple outcome score in patients with the acute respiratory distress syndrome. Crit Care Med. 2016;44:1361–1369. doi: 10.1097/CCM.0000000000001653.
    1. Herridge MS, Chu LM, Matte A, et al. The RECOVER program: disability risk groups and 1-year outcome after 7 or more days of mechanical ventilation. Am J Respir Crit Care Med. 2016;194:831–844. doi: 10.1164/rccm.201512-2343OC.
    1. Wunsch H, Linde-Zwirble WT, Angus DC, et al. The epidemiology of mechanical ventilation use in the United States. Crit Care Med. 2010;38:1947–1953. doi: 10.1097/CCM.0b013e3181ef4460.
    1. Montgomery RR, Shaw AC. Paradoxical changes in innate immunity in aging: recent progress and new directions. J Leukoc Biol. 2015;98:1–7. doi: 10.1189/jlb.5MR0315-104R.
    1. Shaw AC, Goldstein DR, Montgomery RR. Age-dependent dysregulation of innate immunity. Nat Rev Immunol. 2013;13:875–887. doi: 10.1038/nri3547.
    1. Ferrucci L, Harris TB, Guralnik JM, et al. Serum IL-6 level and the development of disability in older persons. J Am Geriatr Soc. 1999;47:639–646. doi: 10.1111/j.1532-5415.1999.tb01583.x.
    1. Cohen HJ, Harris T, Pieper CF. Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly. Am J Med. 2003;114:180–187. doi: 10.1016/S0002-9343(02)01484-5.
    1. Niwa Y, Kasama T, Miyachi Y, Kanoh T. Neutrophil chemotaxis, phagocytosis and parameters of reactive oxygen species in human aging: cross-sectional and longitudinal studies. Life Sci. 1989;44:1655–1664. doi: 10.1016/0024-3205(89)90482-7.
    1. Butcher SK, Chahal H, Nayak L, et al. Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans. J Leukoc Biol. 2001;70:881–886. doi: 10.1189/jlb.70.6.881.
    1. Oakley R, Tharakan B. Vascular hyperpermeability and aging. Aging Dis. 2014;5:114–125. doi: 10.14336/AD.2014.0500114.
    1. Franceschi C, Bonafè M, Valensin S, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244–254. doi: 10.1111/j.1749-6632.2000.tb06651.x.
    1. Saito H, Sherwood ER, Varma TK, Evers BM. Effects of aging on mortality, hypothermia, and cytokine induction in mice with endotoxemia or sepsis. Mech Ageing Dev. 2003;124:1047–1058. doi: 10.1016/j.mad.2003.08.002.
    1. Turnbull IR, Clark AT, Stromberg PE, et al. Effects of aging on the immunopathologic response to sepsis. Crit Care Med. 2009;37:1018–1023. doi: 10.1097/CCM.0b013e3181968f3a.
    1. Stanojcic M, Chen P, Xiu F, Jeschke MG. Impaired immune response in elderly burn patients: new insights into the immune-senescence phenotype. Ann Surg. 2016;264:195–202. doi: 10.1097/SLA.0000000000001408.
    1. Ginde AA, Blatchford PJ, Trzeciak S, et al. Age-related differences in biomarkers of acute inflammation during hospitalization for sepsis. Shock. 2014;42:99–107. doi: 10.1097/SHK.0000000000000182.
    1. Marik PE, Zaloga GP, NORASEPT II Study Investigators. North American Sepsis Trial II The effect of aging on circulating levels of proinflammatory cytokines during septic shock. Norasept II Study Investigators. J Am Geriatr Soc. 2001;49:5–9. doi: 10.1046/j.1532-5415.2001.49003.x.
    1. Kale S, Yende S, Kong L, et al. The effects of age on inflammatory and coagulation-fibrinolysis response in patients hospitalized for pneumonia. PLoS One. 2010;5:e13852. doi: 10.1371/journal.pone.0013852.
    1. Kelly E, MacRedmond RE, Cullen G, et al. Community-acquired pneumonia in older patients: does age influence systemic cytokine levels in community-acquired pneumonia? Respirology. 2009;14:210–216. doi: 10.1111/j.1440-1843.2008.01423.x.
    1. Glynn P, Coakley R, Kilgallen I, O’Neill S. Neutrophil CD11b and soluble ICAM-1 and E-selectin in community acquired pneumonia. Eur Respir J. 1999;13:1380–1385. doi: 10.1034/j.1399-3003.1999.13f24.x.
    1. Boldt J, Müller M, Heesen M, et al. Does age influence circulating adhesion molecules in the critically ill? Crit Care Med. 1997;25:95–100. doi: 10.1097/00003246-199701000-00019.
    1. Bos Lieuwe D., Schouten Laura R., Schultz Marcus J. Promising but still uncertain steps towards better prediction of functional outcome in ICU patients. Journal of Thoracic Disease. 2016;8(8):E838–E840. doi: 10.21037/jtd.2016.07.08.
    1. Klein Klouwenberg PMC, Frencken JF, Kuipers S, et al. Incidence, predictors, and outcomes of new-onset atrial fibrillation in critically ill patients with sepsis. A cohort study. Am J Respir Crit Care Med. 2017;195:205–211. doi: 10.1164/rccm.201603-0618OC.
    1. Klein Klouwenberg PMC, van Mourik MSM, Ong DSY, et al. Electronic implementation of a novel surveillance paradigm for ventilator-associated events. Feasibility and validation. Am J Respir Crit Care Med. 2014;189:947–955. doi: 10.1164/rccm.201307-1376OC.
    1. Geboers DGPJ, de Beer FM, Tuip-de Boer AM, et al. Plasma suPAR as a prognostic biological marker for ICU mortality in ARDS patients. Intensive Care Med. 2015;41:1281–1290. doi: 10.1007/s00134-015-3924-9.
    1. van Vught LA, Wiewel MA, Hoogendijk AJ, et al. The host response in patients with sepsis developing intensive care unit-acquired secondary infections. Am J Respir Crit Care Med. 2017;196:458–470. doi: 10.1164/rccm.201606-1225OC.
    1. Bos LD, Schouten LR, van Vught LA, et al. Identification and validation of distinct biological phenotypes in patients with acute respiratory distress syndrome by cluster analysis. Thorax. 2017;72:876–883. doi: 10.1136/thoraxjnl-2016-209719.
    1. Hoogendijk AJ, Wiewel M A, van Vught L A, et al (2015) Plasma fractalkine is a sustained marker of disease severity and outcome in sepsis patients. Crit Care 19:412. doi: 10.1186/s13054-015-1125-0.
    1. van Vught LA, Scicluna BP, Hoogendijk AJ, et al. Association of diabetes and diabetes treatment with the host response in critically ill sepsis patients. Crit Care. 2016;20:252. doi: 10.1186/s13054-016-1429-8.
    1. Boshuizen M, Leopold JH, Zakharkina T, et al. Levels of cytokines in broncho-alveolar lavage fluid, but not in plasma, are associated with levels of markers of lipid peroxidation in breath of ventilated ICU patients. J Breath Res. 2015;9:036010. doi: 10.1088/1752-7155/9/3/036010.
    1. Frencken JF, van Vught LA, Peelen LM, et al. An unbalanced inflammatory cytokine response is not associated with mortality following Sepsis: a prospective cohort study. Crit Care Med. 2017;45:e493–e499. doi: 10.1097/CCM.0000000000002292.
    1. Wiewel MA, de Stoppelaar SF, van Vught LA, et al. Chronic antiplatelet therapy is not associated with alterations in the presentation, outcome, or host response biomarkers during sepsis: a propensity-matched analysis. Intensive Care Med. 2016;42:352–360. doi: 10.1007/s00134-015-4171-9.
    1. Bernard GR, Artigas A, Brigham KL, et al. Report of the American-European Consensus Conference on acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial coordination. J Crit Care. 1994;9:72–81. doi: 10.1016/0883-9441(94)90033-7.
    1. Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307:2526–2533. doi: 10.1001/jama.2012.5669.
    1. O’Shea JJ, Murray PJ. Cytokine signaling modules in inflammatory responses. Immunity. 2008;28:477–487. doi: 10.1016/j.immuni.2008.03.002.
    1. Yang XP, Mattagajasingh S, Su S, et al. Fractalkine upregulates intercellular adhesion molecule-1 in endothelial cells through CX3CR1 and the Jak Stat5 pathway. Circ Res. 2007;101:1001–1008. doi: 10.1161/CIRCRESAHA.107.160812.
    1. Levi M, van der Poll T, Büller HR. Bidirectional relation between inflammation and coagulation. Circulation. 2004;109:2698–2704. doi: 10.1161/01.CIR.0000131660.51520.9A.
    1. Song Y, Huang YT, Song Y, et al. Birthweight, mediating biomarkers and the development of type 2 diabetes later in life: a prospective study of multi-ethnic women. Diabetologia. 2015;58:1220–1230. doi: 10.1007/s00125-014-3479-2.
    1. Beulens JWJ, van der Schouw YT, Moons KGM, et al. Estimating the mediating effect of different biomarkers on the relation of alcohol consumption with the risk of type 2 diabetes. Ann Epidemiol. 2013;23:193–197. doi: 10.1016/j.annepidem.2012.12.014.
    1. Valeri L, Vanderweele TJ. Mediation analysis allowing for exposure-mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros. Psychol Methods. 2013;18:137–150. doi: 10.1037/a0031034.
    1. Tingley D, Yamamoto T, Hirose K, et al. Mediation: R package for causal mediation analysis. J Stat Softw. 2014;59:1–38. doi: 10.18637/jss.v059.i05.
    1. Moore HB, Moore EE, Gonzalez E, et al. Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown: the spectrum of postinjury fibrinolysis and relevance to antifibrinolytic therapy. J Trauma Acute Care Surg. 2014;77:811–817. doi: 10.1097/TA.0000000000000341.
    1. Moore HB, Moore EE, Liras IN, et al. Acute fibrinolysis shutdown after injury occurs frequently and increases mortality: a multicenter evaluation of 2,540 severely injured patients. J Am Coll Surg. 2016;222:347–355. doi: 10.1016/j.jamcollsurg.2016.01.006.
    1. Montrucchio G, Lupia E, De Martino A, et al. Plasmin promotes an endothelium-dependent adhesion of neutrophils. Circulation. 1996;93:2152–2160. doi: 10.1161/01.CIR.93.12.2152.
    1. Baramova EN, Bajou K, Remacle A, et al. Involvement of PA/plasmin system in the processing of pro-MMP-9 and in the second step of pro-MMP-2 activation. FEBS Lett. 1997;405:157–162. doi: 10.1016/s0014-5793(97)00175-0.
    1. Zhao Y, Sharma AK, LaPar DJ, et al. Depletion of tissue plasminogen activator attenuates lung ischemia-reperfusion injury via inhibition of neutrophil extravasation. Am J Physiol Lung Cell Mol Physiol. 2011;300:L718–L729. doi: 10.1152/ajplung.00227.2010.
    1. Fulop T, Larbi A, Dupuis G, et al. Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? Front Immunol. 2017;8:1960. doi: 10.3389/fimmu.2017.01960.
    1. Narute P, Seam N, Tropea M, et al. Temporal changes in microrna expression in blood leukocytes from patients with the acute respiratory distress syndrome. Shock. 2017;47:688–695. doi: 10.1097/SHK.0000000000000806.
    1. Meduri GU, Headley S, Kohler G, et al. Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS: plasma IL-1β and IL-6 levels are consistent and efficient predictors of outcome over time. Chest. 1995;107:1062–1073. doi: 10.1378/chest.107.4.1062.
    1. Yokota Y, Wakai Y, Mine Y, et al. Degradation of host defenses against respiratory tract infection by Klebsiella pneumoniae in aged mice. Infect Immun. 1988;56:966–971.
    1. Wen J, Li C-M, Gu L, et al. Aging reduces the expression of lung CINC and MCP-1 mRNA in a P. aeruginosa rat model of infection. Inflammation. 2014;37:933–941. doi: 10.1007/s10753-014-9813-5.
    1. Mares CA, Ojeda SS, Li Q, et al. Aged mice display an altered pulmonary host response to Francisella tularensis live vaccine strain (LVS) infections. Exp Gerontol. 2010;45:91–96. doi: 10.1016/j.exger.2009.10.004.
    1. Mares CA, Sharma J, Ojeda SS, et al. Attenuated response of aged mice to respiratory Francisella novicida is characterized by reduced cell death and absence of subsequent hypercytokinemia. PLoS One. 2010;5:e14088. doi: 10.1371/journal.pone.0014088.
    1. Pinheiro da Silva F, Zampieri FG, Barbeiro DF, et al. Septic shock in older people: a prospective cohort study. Immun Ageing. 2013;10:21. doi: 10.1186/1742-4933-10-21.
    1. López-Otín C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell. 2013;153:1194–1217. doi: 10.1016/j.cell.2013.05.039.
    1. McDermid RC, Stelfox HT, Bagshaw SM. Frailty in the critically ill: a novel concept. Crit Care. 2011;15:301. doi: 10.1186/cc9297.
    1. Linge HM, Lee JY, Ochani K, et al. Age influences inflammatory responses, hemodynamics, and cardiac proteasome activation during acute lung injury. Exp Lung Res. 2015;41:216–227. doi: 10.3109/01902148.2014.999174.
    1. Rosas GO, Zieman SJ, Donabedian M, et al. Augmented age-associated innate immune responses contribute to negative inotropic and lusitropic effects of lipopolysaccharide and interferon gamma. J Mol Cell Cardiol. 2001;33:1849–1859. doi: 10.1006/jmcc.2001.1448.
    1. Milbrandt EB, Eldadah B, Nayfield S, et al. Toward an integrated research agenda for critical illness in aging. Am J Respir Crit Care Med. 2010;182:995–1003. doi: 10.1164/rccm.200904-0630CP.
    1. MacKinnon DP, Krull JL, Lockwood CM. Equivalence of the mediation, confounding and suppression effect. Prev Sci. 2000;1:173–181. doi: 10.1158/0008-5472.CAN-09-2490.
    1. Lin S, Wu H, Wang C, et al. Regulatory T cells and acute lung injury: cytokines, uncontrolled inflammation, and therapeutic implications. Front Immunol. 2018;9:1–10. doi: 10.3389/fimmu.2018.01545.
    1. Calfee CS, Delucchi K, Parsons PE, et al. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med. 2014;2:611–620. doi: 10.1016/S2213-2600(14)70097-9.
    1. Joynt GM, Gomersall CD, Tan P, et al. Prospective evaluation of patients refused admission to an intensive care unit: triage, futility and outcome. Intensive Care Med. 2001;27:1459–1465. doi: 10.1007/s001340101041.

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