Inflammation Profiling of Critically Ill Coronavirus Disease 2019 Patients

Abstract

Objectives: Coronavirus disease 2019 is caused by severe acute respiratory syndrome-coronavirus-2 infection to which there is no community immunity. Patients admitted to ICUs have high mortality, with only supportive therapies available. Our aim was to profile plasma inflammatory analytes to help understand the host response to coronavirus disease 2019.

Design: Daily blood inflammation profiling with immunoassays.

Setting: Tertiary care ICU and academic laboratory.

Subjects: All patients admitted to the ICU suspected of being infected with severe acute respiratory syndrome-coronavirus-2, using standardized hospital screening methodologies, had daily blood samples collected until either testing was confirmed negative on ICU day 3 (coronavirus disease 2019 negative), or until ICU day 7 if the patient was positive (coronavirus disease 2019 positive).

Interventions: None.

Measurements and main results: Age- and sex-matched healthy controls and ICU patients that were either coronavirus disease 2019 positive or coronavirus disease 2019 negative were enrolled. Cohorts were well-balanced with the exception that coronavirus disease 2019 positive patients were more likely than coronavirus disease 2019 negative patients to suffer bilateral pneumonia. Mortality rate for coronavirus disease 2019 positive ICU patients was 40%. We measured 57 inflammatory analytes and then analyzed with both conventional statistics and machine learning. Twenty inflammatory analytes were different between coronavirus disease 2019 positive patients and healthy controls (p < 0.01). Compared with coronavirus disease 2019 negative patients, coronavirus disease 2019 positive patients had 17 elevated inflammatory analytes on one or more of their ICU days 1-3 (p < 0.01), with feature classification identifying the top six analytes between cohorts as tumor necrosis factor, granzyme B, heat shock protein 70, interleukin-18, interferon-gamma-inducible protein 10, and elastase 2. While tumor necrosis factor, granzyme B, heat shock protein 70, and interleukin-18 were elevated for all seven ICU days, interferon-gamma-inducible protein 10 transiently elevated on ICU days 2 and 3 and elastase 2 increased over ICU days 2-7. Inflammation profiling predicted coronavirus disease 2019 status with 98% accuracy, whereas elevated heat shock protein 70 was strongly associated with mortality.

Conclusions: While many inflammatory analytes were elevated in coronavirus disease 2019 positive ICU patients, relative to healthy controls, the top six analytes distinguishing coronavirus disease 2019 positive ICU patients from coronavirus disease 2019 negative ICU patients were tumor necrosis factor, granzyme B, heat shock protein 70, interleukin-18, interferon-gamma-inducible protein 10, and elastase 2.

Keywords: biomarkers; coronavirus disease 2019; host response; inflammation; intensive care unit.

Figure 1.

A, Subjects plotted in two dimensions following dimensionality reduction by stochastic neighbor embedding (tSNE). Purple dots represent coronavirus disease 2019-positive (COVID-19+) subjects, yellow dots represent COVID-19− subjects. The dimensionality reduction shows that based on daily plasma analyte concentrations, the two cohorts are distinct and easily separable. The axes are dimension less. B, Feature classification demonstrating the top 15 inflammatory analytes that classify COVID-19 status in ICU patients’ days 1–3 with their % association. HSP = heat shock protein, IL = interleukin, IFN-γ = interferon-gamma, IP = interferon-gamma-inducible protein, M-CSF = macrophage colony-stimulating factor, MIG = monokine induced by gamma interferon, TNF = tumor necrosis factor.

Figure 2.

Time course for the top six inflammatory analytes between coronavirus disease 2019 (COVID-19)+ and COVID-19– ICU patients. Daily values are represented as mean (± sem). *p < 0.01. HSP = heat shock protein, IL = interleukin, IP = interferon-gamma-inducible protein, TNF = tumor necrosis factor.