Rationale:
Coronavirus disease (COVID-19) is a global threat to
health. Its inflammatory characteristics are incompletely understood.
Objectives:
To define the cytokine profile of COVID-19 and to
identify evidence of immunometabolic alterations in those with severe
illness.
Methods:
Levels of IL-1β, IL-6, IL-8, IL-10, and sTNFR1
(soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy
volunteers, hospitalized but stable patients with COVID-19
(COVID
stable
patients), patients with COVID-19 requiring ICU
admission (COVID
ICU
patients), and patients with severe
community-acquired pneumonia requiring ICU support (CAP
ICU
patients).
Immunometabolic markers were measured in circulating neutrophils from patients
with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to
COVID-19 was also evaluated.
Measurements and Main Results:
IL-1β, IL-6, IL-8, and sTNFR1
were all increased in patients with COVID-19. COVID
ICU
patients could
be clearly differentiated from COVID
stable
patients, and demonstrated
higher levels of IL-1β, IL-6, and sTNFR1 but lower IL-10 than
CAP
ICU
patients. COVID-19 neutrophils displayed altered
immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2),
phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and
lactate. The production and sialylation of AAT increased in COVID-19, but this
antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT
ratio markedly higher in patients requiring ICU admission
(
P
< 0.0001). In critically unwell patients
with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality,
whereas improvement in IL-6:AAT was associated with clinical resolution
(
P
< 0.0001).
Conclusions:
The COVID-19 cytokinemia is distinct from that of other
types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo
immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may
predict outcomes in this population.
Premorbid conditions affect prognosis of acutely-ill aged patients. Several lines of evidence suggest geriatric syndromes need to be assessed but little is known on their relative effect on the 30-day survival after ICU admission. The primary aim of this study was to describe the prevalence of frailty, cognition decline and activity of daily life in addition to the presence of comorbidity and polypharmacy and to assess their influence on 30-day survival.Methods: Prospective cohort study with 242 ICUs from 22 countries. Patients 80 years or above acutely admitted over a six months period to an ICU between May 2018 and May 2019 were included. In addition to common patients' characteristics and disease severity, we collected information on specific geriatric syndromes as potential predictive factors for 30-day survival, frailty (Clinical Frailty scale) with a CFS > 4 defining frail patients, cognitive impairment (informant questionnaire on cognitive decline in the elderly (IQCODE) with IQCODE ≥ 3.5 defining cognitive decline, and disability (measured the activity of daily life with the Katz index) with ADL ≤ 4 defining disability. A Principal Component Analysis to identify co-linearity between geriatric syndromes was performed and from this a multivariable model was built with all geriatric information or only one: CFS, IQCODE or ADL. Akaike's information criterion across imputations was used to evaluate the goodness of fit of our models.
Results:We included 3920 patients with a median age of 84 years (IQR: 81-87), 53.3% males). 80% received at least one organ support. The median ICU length of stay was 3.88 days (IQR: 1.83-8). The ICU and 30-day survival were 72.5% and 61.2% respectively. The geriatric conditions were median (IQR): CFS: 4 (3-6); IQCODE: 3.19 (3-3.69); ADL: 6 (4-6); Comorbidity and Polypharmacy score (CPS): 10 (7-14). CFS, ADL and IQCODE were closely correlated. The multivariable analysis identified predictors of 1-month mortality (HR; 95% CI): Age (per 1 year increase): 1.02 (1.-1.03, p = 0.01), ICU admission diagnosis, sequential organ failure assessment score (SOFA) (per point): 1.15 (1.14-1.17, p < 0.0001) and
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