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

Abstract

BackgroundAdvanced 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.MethodsThis 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.ResultsNinety-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] %).ConclusionLittle 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 registrationThis trial was registered at ClinicalTrials.gov (identifier NCT01905033, date of registration July 23, 2013).

Respiratory Failure – Review of Basic Sciences and Application in COVID-19

“…The start of ARDS heralds a marked increase in mortality up to 50%. (36) It is comparable to the mortality of 43% from ARDS from other causes in the elderly patients (over 67 years) (37) and may reflect the older age predominance of COVID-19 complications. The hallmarks of this phase are:…”

The Impact of Aging in Acute Respiratory Distress Syndrome: A Clinical and Mechanistic Overview

“…Other investigators have reported no significant difference in mortality using a dichotomous age cut-off of 65 years, potentially supporting the notion that the relationship between age and ARDS may be more complex (44). While age is associated with ARDS mortality, there is no significant difference between ventilator or ICU free days, length of stay in ICU or length of stay in hospital between patients above 65 and those under 65 (12,45). Indeed, a number of studies have concluded that comorbidities rather than age primarily affect prognosis following ICU admission (46)(47)(48).…”

“…However, to date, no single specific ARDS biomarker has been validated (83). Analysis of systemic inflammatory mediators and endothelial activation markers in plasma from adults with ARDS found that, compared to younger patients, elderly patients had lower levels of inflammatory mediators and endothelial activation markers (interleukin (IL)-6, IL-8, IL-10, interferon-γ, fractalkine, intracellular adhesion molecule (ICAM)-1, E-selectin) and higher levels of platelet factor-4 and tissue plasminogen activator (tPA) (12). Furthermore, advanced age was found to be independently associated with increased plasma levels of tPA and decreased plasma levels of fractalkine and E-selectin (12).…”

“…ARDS is a heterogeneous disease process that may be triggered by a variety of direct or indirect pulmonary injuries including pneumonia, aspiration, non-protective mechanical ventilation, chest trauma, sepsis, and acute pancreatitis. Although ARDS can affect people of all ages, increasing age is a widely reported risk factor and is associated with increased mortality in ARDS patients (12,13). This relationship has been emphasized by the current Covid-19 pandemic, in which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of ARDS, has exhibited significant mortality among older patients (14)(15)(16).…”

Role of the renin-angiotensin system in the development of severe COVID-19 in hypertensive patients

“…Plasma ANG II level is increased in patients infected with H7N9 and H5N1, followed by a decrease in ACE2 activity, with no change in ACE activity ( 21 , 84 ). Further, ACE activity increased and ACE2 decreased in the bronchoalveolar lavage fluid of animals and patients with acute respiratory distress syndrome (ARDS) ( 52 , 70 , 71 ). Thus, it can be hypothesized that, with a decrease in ACE2 followed by SARS-CoV-2 infection, ANG II would increase.…”