COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study

Abstract

Background: A subset of patients with severe COVID-19 develop a hyperinflammatory syndrome, which might contribute to morbidity and mortality. This study explores a specific phenotype of COVID-19-associated hyperinflammation (COV-HI), and its associations with escalation of respiratory support and survival.

Methods: In this retrospective cohort study, we enrolled consecutive inpatients (aged ≥18 years) admitted to University College London Hospitals and Newcastle upon Tyne Hospitals in the UK with PCR-confirmed COVID-19 during the first wave of community-acquired infection. Demographic data, laboratory tests, and clinical status were recorded from the day of admission until death or discharge, with a minimum follow-up time of 28 days. We defined COV-HI as a C-reactive protein concentration greater than 150 mg/L or doubling within 24 h from greater than 50 mg/L, or a ferritin concentration greater than 1500 μg/L. Respiratory support was categorised as oxygen only, non-invasive ventilation, and intubation. Initial and repeated measures of hyperinflammation were evaluated in relation to the next-day risk of death or need for escalation of respiratory support (as a combined endpoint), using a multi-level logistic regression model.

Findings: We included 269 patients admitted to one of the study hospitals between March 1 and March 31, 2020, among whom 178 (66%) were eligible for escalation of respiratory support and 91 (34%) patients were not eligible. Of the whole cohort, 90 (33%) patients met the COV-HI criteria at admission. Despite having a younger median age and lower median Charlson Comorbidity Index scores, a higher proportion of patients with COV-HI on admission died during follow-up (36 [40%] of 90 patients) compared with the patients without COV-HI on admission (46 [26%] of 179). Among the 178 patients who were eligible for full respiratory support, 65 (37%) met the definition for COV-HI at admission, and 67 (74%) of the 90 patients whose respiratory care was escalated met the criteria by the day of escalation. Meeting the COV-HI criteria was significantly associated with the risk of next-day escalation of respiratory support or death (hazard ratio 2·24 [95% CI 1·62-2·87]) after adjustment for age, sex, and comorbidity.

Interpretation: Associations between elevated inflammatory markers, escalation of respiratory support, and survival in people with COVID-19 indicate the existence of a high-risk inflammatory phenotype. COV-HI might be useful to stratify patient groups in trial design.

Funding: None.

Figure 1

Longitudinal laboratory findings and escalation of respiratory support in the full cohort (n=269) (A) Daily numbers of patients by level of respiratory support, centred on day of symptom onset (discussed in the appendix [p 6]). (B–F) Laboratory results plotted against time from symptom onset. Locally estimated scatterplot smoothing curves were fitted from mean daily worst values for all patients, stratified by highest level of respiratory support required during admission, with patients who were ineligible for cardiopulmonary resuscitation or escalation of support beyond ward-based care included as a separate category. Shaded areas are 95% CIs. Missing data were imputed from the last value carried forward. Other parameters in the models used default settings, with a span of 50%, polynomial of degree 2, interpolation on a cell size of 0·2, and a Gaussian (fitted least squares) kernel.

Figure 2

Longitudinal laboratory findings and survival in patients given escalated respiratory support (n=90) (A) Daily numbers of patients by level of respiratory support, centred on day of increased respiratory support (discussed in the appendix [p 6]). (B–F) Laboratory results plotted against time from escalation of respiratory support. Locally estimated scatterplot smoothing curves were fitted from worst daily mean values for all patients given escalated respiratory support, stratified by overall survival within 28 days of admission. Shaded areas are 95% CIs. Missing data were imputed from the last value carried forward. Other parameters in the models used default settings, with a span of 50%, polynomial of degree 2, interpolation on a cell size of 0·2, and a Gaussian (fitted least squares) kernel.

Figure 3

Hyperinflammation and escalation-free survival (A) Kaplan-Meier plot of escalation-free survival (considering death or escalation of respiratory support as a combined endpoint) in patients eligible for respiratory support (censored at 28 days), plotted from the first day of data collection for each patient. Patients were stratified by whether they met the criteria for hyperinflammation (C-reactive protein >150 mg/L or ferritin >1500 μg/L) on the day of cohort entry (ie, admission to hospital). Predicted median survival is indicated by the dashed line for the group with hyperinflammation only. (B) Daily proportion of patients meeting the criteria for hyperinflammation (C-reactive protein concentration >150 mg/L or doubling within 24 h from >50 mg/L, or ferritin concentration >1500 μg/L) from the day of symptom onset until the day that respiratory support was escalated. 74% of the total population for whom escalation could be considered met the criteria for hyperinflammation by the time of escalation. *Patients without C-reactive protein or ferritin concentration recorded on the day of admission were included as a missing category.