Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19

Abstract

Background: Coronavirus disease 2019 (COVID-19) can manifest as a viral-induced hyperinflammation with multiorgan involvement. Such patients often experience rapid deterioration and need for mechanical ventilation. Currently, no prospectively validated biomarker of impending respiratory failure is available.

Objective: We aimed to identify and prospectively validate biomarkers that allow the identification of patients in need of impending mechanical ventilation.

Methods: Patients with COVID-19 who were hospitalized from February 29 to April 9, 2020, were analyzed for baseline clinical and laboratory findings at admission and during the disease. Data from 89 evaluable patients were available for the purpose of analysis comprising an initial evaluation cohort (n = 40) followed by a temporally separated validation cohort (n = 49).

Results: We identified markers of inflammation, lactate dehydrogenase, and creatinine as the variables most predictive of respiratory failure in the evaluation cohort. Maximal IL-6 level before intubation showed the strongest association with the need for mechanical ventilation, followed by maximal CRP level. The respective AUC values for IL-6 and CRP levels in the evaluation cohort were 0.97 and 0.86, and they were similar in the validation cohort (0.90 and 0.83, respectively). The calculated optimal cutoff values during the course of disease from the evaluation cohort (IL-6 level > 80 pg/mL and CRP level > 97 mg/L) both correctly classified 80% of patients in the validation cohort regarding their risk of respiratory failure.

Conclusion: The maximal level of IL-6, followed by CRP level, was highly predictive of the need for mechanical ventilation. This suggests the possibility of using IL-6 or CRP level to guide escalation of treatment in patients with COVID-19-related hyperinflammatory syndrome.

Keywords: COVID-19; CRP; IL-6; hyperinflammation; mechanical ventilation; prediction; respiratory failure.

Fig 1

Consolidated Standards of Reporting Trials diagram. DNR/DNI, Do-not-resuscitate and do-not-intubate order; LMU, Ludwig Maximilian University.

Fig 2

IL-6 levels at presentation, maximal IL-6 levels before mechanical ventilation, and receiver operating characteristic (ROC) analysis of different parameters in the evaluation and validation cohorts. Box plots showing IL-6 levels at first assessment (A and B) and maximal IL-6 levels before mechanical ventilation (C and D) in the evaluation cohort and in the validation cohort; dashed lines represents the cutoff calculated from the evaluation cohort (IL-6 level at initial assessment >35 pg/mL, maximal IL-6 level >80 pg/mL). Data are represented as means ± SDs. ROC curve of maximal follow-up levels before mechanical ventilation in the evaluation (E) and validation cohorts (F).

Fig 3

CRP levels at presentation and maximal CRP levels before mechanical ventilation. Box plot showing CRP levels at first assessment (A and B) and maximal IL-6 levels before mechanical ventilation (C and D) in the evaluation cohort and in the validation cohort; dashed lines represents the cutoff calculated from the training cohort (CRP levels at assessment >32.5 mg/L, maximal CRP level >97 mg/L). Data are represented as means ± SDs.

Fig 4

Cutoffs and predictive values of maximal IL-6 and CRP level values in the combined cohort. Box plots depicting the maximal values of IL-6 and CRP levels in the overall cohort (A and B); dashed line represents the validated cutoff; dotted line represents the calculated improved cutoff from all patients (applicable only for IL-6). PPV and NPV as a function of different cutoffs are shown for IL-6 (C) and CRP (D) level values (dotted line represents cutoff for perfect NPV; dashed line represents cutoff for perfect PPV).

Fig 5

Time from when the maximal cutoff values of IL-6 or CRP level were exceeded to intubation in the combined cohort. Box plot depicting the time from when the IL-6 level (>65 ng/mL) and CRP level (>97 mg/L) cutoffs were exceeded to intubation in hours in the combined cohort. Data represented as median ± min/max are shown.