Inflammatory Biomarker Trends Predict Respiratory Decline in COVID-19 Patients

Abstract

In this single-center, retrospective cohort analysis of hospitalized coronavirus disease 2019 (COVID-19) patients, we investigate whether inflammatory biomarker levels predict respiratory decline in patients who initially present with stable disease. Examination of C-reactive protein (CRP) trends reveals that a rapid rise in CRP levels precedes respiratory deterioration and intubation, although CRP levels plateau in patients who remain stable. Increasing CRP during the first 48 h of hospitalization is a better predictor (with higher sensitivity) of respiratory decline than initial CRP levels or ROX indices (a physiological score of respiratory function). CRP, the proinflammatory cytokine interleukin-6 (IL-6), and physiological measures of hypoxemic respiratory failure are correlated, which suggests a mechanistic link. Our work shows that rising CRP predicts subsequent respiratory deterioration in COVID-19 and may suggest mechanistic insight and a potential role for targeted immunomodulation in a subset of patients early during hospitalization.

Keywords: COVID-19; CRP; D-dimer; IL-6; acute respiratory distress syndrome; cytokine storm; ferritin; inflammation; intensive care unit; intubation.

Conflict of interest statement

The authors declare no competing interests.

© 2020 The Author(s).

Figures

Graphical abstract

Figure 1

Initial CRP, D-Dimer, Procalcitonin, and IL-6 Levels Are Correlated with Mild, Progressive, and Severe Respiratory Failure Initial levels of (A) CRP, (B) D-dimer, (C) ferritin, (D) procalcitonin, and (E) IL-6 are shown for patients grouped into “mild” (n = 54), “progressive” (n = 29), and “severe” (n = 17) cohorts. Broken lines indicate the upper limit of the assay. Data are represented as median and IQR. Kruskal-Wallis and Dunn’s multiple comparison tests were performed. ∗p 

Figure 2

CRP Levels Are Associated with Physiological Measures of Disease Severity and Hypoxemic Respiratory Failure COVID-19 inpatients are grouped into mild, progressive, or severe cohorts defined by respiratory failure. (A) SOFA scores on admission. (B) SOFA respiratory scores on admission. (C) Correlation of SOFA scores to initial CRP. (D) Correlation of P/F ratios to initial CRP. Open black circles, mild; filled black circles, progressive; open red circles, severe. Data in (A) and (B) are represented as median and IQR. Kruskal-Wallis and Dunn’s multiple comparison tests were performed for (A) and (B); Spearman rank correlation was performed for (C) and (D). ∗p 2/FiO2; SOFA, sequential organ failure assessment.

Figure 3

Rise in CRP Predicts Respiratory Deterioration Requiring Intubation or HFNC COVID-19 inpatients are grouped into mild, progressive, or severe cohorts defined by respiratory failure. (A) Maximum CRP value during hospital course. The broken line indicates the upper limit of the assay. (B and C) Mean CRP values are shown as a function of (B) days after first recorded CRP level and (C) days after onset of first symptom. (D) CRP values taken 0–2 (%)/FiO2/respiratory rate (/min). (G) Area under the curve (AUC) with 95% confidence interval (CI) and the cutoff value with sensitivity (Sn), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV). For (A)–(D): open black circles, mild; filled black circles, progressive; open red circles, severe. (A) Median and interquartile range are plotted; (B–D) mean and standard deviation are plotted. Kruskal-Wallis and Dunn’s multiple comparison tests were performed for (A); a mixed effect model was used for (D). ∗p