COVID-19 is more serious and has a higher mortality rate in older adults. The global mortality rate from COVID-19 is 4.84%(7). A retrospective study of 3,418 black and white patients (mean age, 54 years), reported a mortality rate of 9.36%(8). In our study of older patients with CRS, the mortality rate was 10.53%, which is higher than the reports cited above; however, age ≥ 65 years is recognized as a risk factor for mortality from COVID-19(9) and this was the rationale for the focus of our study on these patients.
CRS refers to an over-active, uncontrolled immune response, involving an overwhelming release of proinflammatory mediators. Increased levels of inflammatory cytokines and chemokines, including IL-6, interleukin 1β, inducible protein 10, and monocyte chemoattractant protein 1, may also be a cause of fatal complications in patients with COVID-19. In addition to antiviral treatment, IL-6 is the main mediator of CRS toxicity and its levels are related to the severity of CRS induced by chimeric antigen receptor (CAR) T cell therapy(5, 10). A systematic review and meta-analysis showed that patients with severe COVID-19 have significantly higher serum IL-6 levels than those with non-severe disease, and that increased mean IL-6 level was associated with higher patient mortality(11). In the five patients treated with tocilizumab in this study, initial levels of IL-6 were increased by > 10-fold compared with normal levels, and were rising at the beginning of the disease. After treatment with tocilizumab, IL-6 levels decreased significantly; however, the IL-6 levels of one patient who died continued to increase significantly, suggesting that IL-6 can be a predictor of prognosis.
Tocilizumab is a humanized recombinant monoclonal anti- IL-6R antibody. It binds to soluble IL-6R and membrane-bound IL-6R to inhibit IL-6 mediated cis- and trans- transcription(12, 13). Tocilizumab has been approved by the US Food and Drug Administration for the treatment of severe CAR T cell-induced CRS. After tocilizumab was administered once or twice, 69% of patients with CAR T cell therapy-induced CRS responded within 14 days, and their fever and hypotension subsided within a few hours, allowing vasopressors to be stopped within a few days(12, 14); however, clinical experience with tocilizumab in treatment for viral disease is very limited and the increased risk of opportunistic infections (including tuberculosis, fungal, or other viral infections) must be taken seriously(15).
A retrospective study of 21 patients with COVID-19 by Xu et al. reported a 75.0% reduction in oxygen uptake, CT scans showing 90.5% clearance of lung lesion opacity, and a significant 84.2% reduction of CRP within 5 days of tocilizumab treatment. No obvious adverse reactions were observed. These data provided evidence that treatment with tocilizumab could immediately improve the symptoms, and was an effective method to reduce mortality, in patients with severe and critical COVID-19(16). Another study involving 15 people showed that tocilizumab treatment could quickly reduce CRP levels in all patients, while IL-6 levels tended to increase first and then decrease. In contrast, untreated patients exhibited a continuous and significant increase in IL-6. Hence, repeat tocilizumab treatment was recommended for critically ill patients with elevated IL-6(17). In our study, we observed that clinical indicators were quickly relieved, and lung CT improved significantly, shortly after administration of tocilizumab to patients with severe COVID-19. These results are similar to those of previous studies, and support the positive therapeutic effects of tocilizumab for patients with severe COVID-19. Further, a systematic review indicated that preliminary investigations of the use of tocilizumab to treat COVID-19 demonstrate benefits, while further studies, such as randomized controlled trials, are needed(18).
The most interesting aspect of this study was the results of comparisons between the two patient groups. We analyzed disease severity and prognosis in all older patients with elevated IL-6 and found that those in the tocilizumab group had more serious disease; however, after the timely application of tocilizumab treatment, the rate of CT improvement and mortality were consistent with those in the group of patients with milder disease. These findings demonstrate that tocilizumab has a positive role in treatment of CRS and is effective against severe COVID-19.
Given the efficacy of tocilizumab in CRS and the key role of IL-6 in COVID-19, Liu et al. suggested that tocilizumab should be considered under the following circumstances. 1) Diagnostic criteria: Early diagnosis of CRS in patients with COVID-19 and rapid instigation of immunomodulatory therapy may be beneficial. 2) Disease severity grading system: Tocilizumab is only suitable for critically ill patients, while the risk-benefit assessment is focused on the symptomatic treatment of patients with mild disease. 3) Combined antiviral treatment: Based on experience with corticosteroids, immunosuppressants may delay viral clearance. Combining immunomodulators with antiviral drugs may be more beneficial(19). In our study, the use of tocilizumab did not cause serious adverse reactions.