Clinical characterization and risk factors associated with cytokine release syndrome induced by COVID-19 and chimeric antigen receptor T-cell therapy

Abstract

An excessive immune response during coronavirus disease (COVID-19) can induce cytokine release syndrome (CRS), which is associated with life-threatening complications and disease progression. This retrospective study evaluated the clinical characteristics of severe CRS (sCRS, grade 3-4) induced by severe COVID-19 (40 patients) or chimeric antigen receptor T-cell (CAR-T) therapy as a comparator (41 patients). Grade 4 CRS was significantly more common in the COVID-19 group (15/40 (35.7%) vs. 5/41 (12.2%), P = 0.008). The CAR-T group had more dramatic increase in cytokines, including IL-2, IL-6, IL-10, and IFN-γ. Interestingly, COVID-19 group had significantly higher levels for TNF-α (31.1 pg/ml (16.1-70.0) vs. 3.3 (1.8-9.6), P < 0.001) and lg viral loads were correlated with lg IL-6 (R² = 0.101; P < 0.001) and lg IL-10 (R² = 0.105; P < 0.001). The independent risk factor for COVID-19-related sCRS was hypertension history (OR: 4.876, 95% CI: 2.038-11.668; P < 0.001). Our study demonstrated that there were similar processes but different intensity of inflammatory responses of sCRS in COVID-19 and CAR-T group. The diagnose and management of severe COVID-19-related sCRS can learn lessons from treatment of sCRS induced by CAR-T therapy.

Fig. 1. Clinical symptoms in patients with grade 3–4 CRS in COVID-19 group (n = 40) and CAR-T group (n = 41).

Data were described as n(%) and median (IQR). Chi-square test and Mann–Whitney U test were used for statistical analysis. Y: yes (had related symptom); N: no (had no related symptom).

Fig. 2. Peak serum level of cytokine, procalcitonin (PCT), C-reactive protein (CRP), D-dimer (DDI), and ferritin in patients with grade 3–4 CRS in COVID-19 group (n = 40) and CAR-T group (n = 41).

Data were described as median (IQR). The Mann–Whitney U test was used for statistical analysis.

Fig. 3. Imaging features of the lungs in the COVID-19 and CAR-T groups.

a Transverse chest CT images from a 74-year-old man with grade 4 CRS in COVID-19 group showing bilateral diffuse ground-glass opacity, patchy and streak hyperdensities on day 29 after sCRS onset. b Transverse chest CT images from a 23-year-old woman with grade 4 CRS in CAR-T group showing bilateral patchy hyperdensities, with uneven internal density and pleural effusion on day 8 after sCRS onset.

Fig. 4. Correlation between viral load/tumor burden and cytokine levels with grade 3–4 CRS in COVID-19 group (n = 40) and CAR-T group (n = 41).

Pearson correlation and linear regression were used for statistical analysis. LDH lactate dehydrogenase.