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.
Background Little information is available about the geo-economic variations in demographics, management, and outcomes of patients with acute respiratory distress syndrome (ARDS). We aimed to characterise the effect of these geo-economic variations in patients enrolled in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE). Methods LUNG SAFE was done during 4 consecutive weeks in winter, 2014, in a convenience sample of 459 intensivecare units in 50 countries across six continents. Inclusion criteria were admission to a participating intensive-care unit (including transfers) within the enrolment window and receipt of invasive or non-invasive ventilation. One of the trial's secondary aims was to characterise variations in the demographics, management, and outcome of patients with ARDS. We used the 2016 World Bank countries classification to define three major geo-economic groupings, namely European high-income countries (Europe-High), high-income countries in the rest of the world (rWORLD-High), and middle-income countries (Middle). We compared patient outcomes across these three groupings. LUNG SAFE is registered with ClinicalTrials.gov, number NCT02010073. Findings Of the 2813 patients enrolled in LUNG SAFE who fulfilled ARDS criteria on day 1 or 2, 1521 (54%) were recruited from Europe-High, 746 (27%) from rWORLD-High, and 546 (19%) from Middle countries. We noted significant geographical variations in demographics, risk factors for ARDS, and comorbid diseases. The proportion of patients with severe ARDS or with ratios of the partial pressure of arterial oxygen (PaO 2) to the fractional concentration of oxygen in inspired air (F I O 2) less than 150 was significantly lower in rWORLD-High countries than in the two other regions. Use of prone positioning and neuromuscular blockade was significantly more common in Europe-High countries than in the other two regions. Adjusted duration of invasive mechanical ventilation and length of stay in the intensive-care unit were significantly shorter in patients in rWORLD-High countries than in Europe-High or Middle countries. High gross national income per person was associated with increased survival in ARDS; hospital survival was significantly lower in Middle countries than in Europe-High or rWORLD-High countries. Interpretation Important geo-economic differences exist in the severity, clinician recognition, and management of ARDS, and in patients' outcomes. Income per person and outcomes in ARDS are independently associated.
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