29.06.2020

Characterization of the Inflammatory Response to Severe COVID-19 Illness

Epidemiology InfectiologyPulmonologyAnesthesia-intensive care
McElvaney OJ et al
Am J Respir Crit Care Med

Main result

The number of groups compared:

  • Healthy controls: n=15
  • COVID-19 patients hospitalized and stable at day 7: n=20
  • COVID-19 patients admitted to intensive care: n=20
  • Patients in intensive care for community-acquired pneumonia: n=15

The mean age ± standard deviation of all COVID-19 patients in the study was 55 ± 17 years and 62.5% were males. 30% are caregivers. Comorbidities are common: a history of lung disease in >25%, hypertension in 40%, diabetes in 20%, coronary artery disease in 18%, and chronic renal failure in 23%. 50% are active or weaned tobacco smokers.  On average, 7 days separate the onset of symptoms from the blood test.


Cytokine profile of COVID-19 patients:

  • Pro-inflammatory mediators levels: higher levels of interleukin 1β (IL-1β), IL-6, and soluble TNF 1 receptor in severe COVID-19 patients than in stable COVID-19 and in non-COVID-19 intensive care patients.
  • The anti-inflammatory IL-10 is not higher in the severe COVID-19 group, it is notably higher in patients in intensive care for non-COVID-19 pneumonia.

Immuno-metabolic markers in severe COVID-19 patients:

Muscle pyruvate kinase 2 (PKM2), activating hypoxia-inducible factor 1-alpha (HIF-1α) with pro-inflammatory action, is significantly higher in neutrophil cytosol (PNN) in severe COVID-19 patients than in healthy controls, as is its phosphorylated form promoting interaction with HIF-1α.
HIF-1α is also higher in the cytosol of PNN of severe COVID-19 patients than in healthy controls, favored by higher levels of cytosolic succinate that prevents degradation of HIF-1α.
Finally, in patients with severe COVID-19 compared to healthy controls, cytosolic lactate is higher with a higher ratio of cytosolic lactate to pyruvate in favor of a metabolic turn more than an overall increase in metabolism.


Levels of endogenous anti-inflammatory drugs in severe COVID-19 patients:

Circulating alpha-1 antitrypsin (AAT), an anti-inflammatory enzyme, is elevated in both severe COVID-19 patients and non-COVID-19 intensive care patients, to similar levels while IL-6 is higher in the former. Thus, the IL-6/AAT ratio is significantly higher in severe COVID-19 patients. In these patients, an increase in the IL-6/AAT ratio between day 0 and day 6 of ICU admission is associated with a less favorable outcome (death or prolonged ICU hospitalization). Conversely, a decrease in the ratio appears to be associated with clinical improvement.
In patients in intensive care for non-COVID-19 pneumonia, a less favorable outcome was associated with a smaller increase in the IL-6/AAT ratio.

Takeaways

It appears that the specificity of the inflammatory response in severe COVID-19 patients is the attenuation of interleukin-10 and alpha-1 antitrypsin-mediated anti-inflammatory activity rather than the elevation of pro-inflammatory cytokines that are also found in patients with severe non-COVID-19 pneumonia. The interleukin-6/alpha-1 antitrypsin ratio is representative of this imbalance. It might, therefore, be interesting to consider new therapeutic approaches but after replication of these results in larger studies.

Strength of evidence Weak

- low enrolment
- prospective or retrospective nature of the cohort not specified, as well as the study period
- duration of follow-up not specified
- no comparison of immune metabolic marker levels between severe, stable COVID-19 patients and non-COVID-19 intensive care patients

Objectives

To characterize the cytokine profile of patients with severe COVID-19 compared to non-severe COVID-19 patients and patients admitted to the intensive care unit for non-COVID-19 pneumonia and the possible underlying metabolic mechanisms.

Method

Analytical cohort study with a comparison between 4 cohorts:

healthy controls COVID-19 patients confirmed, hospitalized and symptomatic but stable at day 7 of onset of symptoms COVID-19 patients confirmed in intensive care for intubation and mechanical ventilation for hypoxemic respiratory failure patients hospitalized in intensive care for community-acquired pneumonia with intubation and mechanical ventilation

Confirmation of SARS-CoV-2 infection by RT-PCR on a nasopharyngeal specimen.
Blood samples were taken at the time of intubation and then every two days.
Hospitalization in intensive care was considered prolonged if it was more than 12 consecutive days.
Exclusion criteria: immunosuppression, long-term PO corticosteroid therapy, taking anti-interleukin 1 (IL1), anti-IL6 or anti-TNF drugs, known pregnancy, active neoplasia, or history of vasculitis or connective tissue disease.
Study of:
  • cytokines: IL-1β, IL-6, IL-8, IL-10, and soluble receptor TNF 1 (sTNFR1)
  • immuno-metabolic markers: muscle pyruvate kinase 2 (PKM2), phosphorylated PKM2, hypoxia-inducible factor 1-alpha (HIF-1α), cytosolic lactate, pyruvate. Comparisons of immune-metabolic marker levels were made after matching COVID-19 patients in intensive care with healthy controls by age, sex, and BMI.
Read paper

bibliovid.org and its content are bibliovid property.

Legal Notice