Trajectories of Host-Response Subphenotypes in Patients With COVID-19 Across the Spectrum of Respiratory Support

Abstract

Background: Hospitalized patients with severe COVID-19 follow heterogeneous clinical trajectories, requiring different levels of respiratory support and experiencing diverse clinical outcomes. Differences in host immune responses to SARS-CoV-2 infection may account for the heterogeneous clinical course, but we have limited data on the dynamic evolution of systemic biomarkers and related subphenotypes. Improved understanding of the dynamic transitions of host subphenotypes in COVID-19 may allow for improved patient selection for targeted therapies.

Research question: We examined the trajectories of host-response profiles in severe COVID-19 and evaluated their prognostic impact on clinical outcomes.

Study design and methods: In this prospective observational study, we enrolled 323 inpatients with COVID-19 receiving different levels of baseline respiratory support: (1) low-flow oxygen (37%), (2) noninvasive ventilation (NIV) or high-flow oxygen (HFO; 29%), (3) invasive mechanical ventilation (27%), and (4) extracorporeal membrane oxygenation (7%). We collected plasma samples on enrollment and at days 5 and 10 to measure host-response biomarkers. We classified patients by inflammatory subphenotypes using two validated predictive models. We examined clinical, biomarker, and subphenotype trajectories and outcomes during hospitalization.

Results: IL-6, procalcitonin, and angiopoietin 2 persistently were elevated in patients receiving higher levels of respiratory support, whereas soluble receptor of advanced glycation end products (sRAGE) levels displayed the inverse pattern. Patients receiving NIV or HFO at baseline showed the most dynamic clinical trajectory, with 24% eventually requiring intubation and exhibiting worse 60-day mortality than patients receiving invasive mechanical ventilation at baseline (67% vs 35%; P < .0001). sRAGE levels predicted NIV failure and worse 60-day mortality for patients receiving NIV or HFO, whereas IL-6 levels were predictive in all patients regardless of level of support (P < .01). Patients classified to a hyperinflammatory subphenotype at baseline (< 10%) showed worse 60-day survival (P < .0001) and 50% of them remained classified as hyperinflammatory at 5 days after enrollment.

Interpretation: Longitudinal study of the systemic host response in COVID-19 revealed substantial and predictive interindividual variability influenced by baseline levels of respiratory support.

Keywords: COVID-19; acute lung injury; acute respiratory failure; biomarkers; host response; longitudinal; subphenotypes.

Figure 1

SARS-CoV-2 infection timelines and clinical group trajectories. A, Box-and-whisker plot showing that patients receiving NIV or HFO had the highest levels of plasma viral RNA load (RNA-emia) than the other groups (patients with available viral RNA load measurements at baseline by clinical group: LFO, n = 17; NIV or HFO, n = 12; IMV, n = 27; ECMO, n = 9). B, Line graph showing 60-day survival curves by Kaplan-Meier analysis for the four clinical groups at baseline. Patients receiving LFO achieved markedly improved survival compared with the other three groups. C, Diagram showing transition of clinical groups from baseline assignments to the maximum level of respiratory support required during the inpatient stay and then to 60-day outcome (0 = survivors, 1 = nonsurvivors). The greatest proportion of transitions occurred in patients receiving NIV or HFO. ECMO = extracorporeal membrane oxygenation; HFO = high-flow oxygen; IMV = invasive mechanical ventilation; LFO = low-flow oxygen; NIV = noninvasive ventilation.

Figure 2

A-D, Box-and-whisker plots showing baseline biomarker comparisons between clinical groups of different levels of respiratory support. Patients with higher levels of IL-6, procalcitonin, and angiopoietin 2 required increasing levels of respiratory support, whereas sRAGE levels were lower in patients receiving ECMO compared with the other groups. ECMO = extracorporeal membrane oxygenation; HFO = high-flow oxygen; IMV = invasive mechanical ventilation; LFO = low-flow oxygen; NIV = noninvasive ventilation; sRAGE = soluble receptor of advanced glycation end products.

Figure 3

Subphenotypic classifications at baseline, transitions over time, and prediction of outcome. A, Bar graph showing the proportion of hypoinflammatory (red) and hyperinflammatory (blue) subphenotypes by the Sinha model classified by level of respiratory support at baseline. B, Line graph showing that hyperinflammatory subphenotype patients by the Sinha model achieved worse survival in Kaplan-Meier curves and Cox proportional hazards models adjusted for age, time from hospital admission, and baseline level of respiratory support. C, Sankey plot showing transition of Sinha subphenotypes at each follow-up interval for patients with available follow-up samples on day 5. Overall, patients classified as hypoinflammatory remained stable (8% transitions), whereas 50% of patients classified as hyperinflammatory on day 1 were classified as hypoinflammatory by day 5. D, Line graph showing that among patients with both baseline (day 1) and follow-up (day 5) biospecimens, comparison of subphenotypic classifications by the Sinha model recorded the following transition categories: (1) patients classified as hyperinflammatory in both time points, ie, persistently hyperinflammatory or “persisters”; (2) patients classified as hypoinflammatory on day 1 but who were classified as hyperinflammatory on day 5, ie, emerging hyperinflammatory or “emergers”; (3) patients who were classified as hyperinflammatory on day 1 and as hypoinflammatory on day 5, ie, resolving baseline hyperinflammatory subphenotype or “resolvers”; and (4) patients who were classified as hypoinflammatory stably at both time points, or “hypoinflammatory.” Emergers and persisters according to the Sinha model showed higher 60-day mortality compared with resolvers and hypoinflammatory: logistic regression OR, 2.62 (95% CI, 1.12–6.89; P = .04) for emergers or persisters vs resolvers or hypoinflammatory. ECMO = extracorporeal membrane oxygenation; HFO = high-flow oxygen; HR = hazard ratio; IMV = invasive mechanical ventilation; LFO = low-flow oxygen; NIV = noninvasive ventilation.

Figure 4

Box-and-whisker plots showing biomarker levels by 60-day mortality and outcome of NIV or HFO trial. A-D, Nonsurvivors by 60 days showed higher baseline levels of IL-6, procalcitonin, sRAGE, and angiopoietin 2 compared with survivors, whereas during follow-up, nonsurvivors also showed higher levels of IL-6 and angiopoietin 2. E-H, Patients with successful trials of NIV or HFO showed lower levels of procalcitonin and sRAGE compared with those for whom NIV or HFO trials failed. HFO = high-flow oxygen; NIV = noninvasive ventilation; sRAGE = soluble receptor of advanced glycation end products.