During the rapidly spreading pandemic, physicians were faced with the challenge of recommending investigational agents for the treatment of COVID-19. At our site, we chose to provide tocilizumab in patients with suspected CRS in order to reduce IL-6 levels, which has been associated with ICU admission, ARDS, and death when in excess . The first dose of tocilizumab was given at a median of two days from hospital admission and a majority of patients (66.7%) received tocilizumab while not on invasive mechanical ventilation. We aimed to provide early administration of tocilizumab in hopes of preventing progressive lung injury that would require invasive mechanical ventilation. Out of the 31 patients who received tocilizumab while not intubated, we observed only 9 patients who later required mechanical ventilation. In the future, we hope to evaluate the effects of tocilizumab on mechanical ventilation and the role of timing with clinical response.
Our patients presented with typical manifestations of COVID-19 and had signs and symptoms of cytokine release syndrome on the day of tocilizumab administration. Similar to previous reports, patients with more severe disease demonstrated transaminitis, along with abnormal blood counts such as neutrophilia, lymphopenia, and elevated NLR ratio [5, 22]. After receiving tocilizumab, we observed reductions in CRP, however unlike other studies, this effect was not sustained [10–12]. We believe our eventual rise in CRP beyond day 10 correlates with tocilizumab’s elimination half-life of 11 to 13 days . Sciascia et al. reported a sustained decrease in CRP for 14 days, but a large proportion of their patients received a second dose of tocilizumab (91% vs. 5%) along with higher doses (8 mg/kg). As such, tocilizumab’s effect on CRP may be dose-dependent and that re-dosing after 10 days may be warranted. When analyzing other laboratory parameters, there were improvements in both ferritin and absolute lymphocyte count, which is in agreement to previous reports [11, 12]. And although serial IL-6 levels were only available for one third of our patients, we observed an increase shortly after tocilizumab administration; previous studies have explained this effect to be from the temporary accumulation of IL-6 from the inhibition of receptor-mediated clearance [10–12]. Furthermore, we observed an increase in D-dimer that peaked at day seven, and then decreased. Some have correlated D-dimer with the risk of developing pulmonary embolism in COVID but this was not investigated in our study. No clear trends were seen for LDH or procalcitonin, suggesting that these markers are non-specific to COVID-19.
There are mixed results on oxygenation progression after tocilizumab administration in COVID-19 patients. Both Xu et al. and Capra et al. reported improvements in oxygenation in a majority of their patients but Rimland et al. observed no improvement [11, 13, 24]. In our study, we observed an overall increase in PaO2/FiO2 within 14 days of tocilizumab. However, it is unclear whether this improvement is due to tocilizumab or reflects the natural course of ARDS. When compared to Sciascia et al., our oxygenation improvement was not as impressive and could be due to having more patients on invasive mechanical ventilation (48.2% vs. 7.9%) . Furthermore, we observed successful extubation in 13 out of 29 patients (44.8%) within 30 days of tocilizumab administration. Rates of extubation for COVID-19 have only been recorded in a small study where 2 out of 3 patients were successfully extubated after tocilizumab .
We observed 36 patients (60.0%) achieving at least a 2-point reduction in the WHO COVID-19 ordinal scale and 33 patients (55.0%) discharged alive within the 30 days of receiving tocilizumab. Our discharge rate was higher than the 18% reported by Rimland et al. but lower than the 63% reported by Campochiaro et al. [24, 25]. We observed a 30-day mortality rate of 15%, which is comparable to prior studies ranging between 13% and 27% [10, 12, 14–16, 24, 25]. So far, only a few studies have compared mortality associated with tocilizumab versus standard of care in COVID-19 patients. Campochiaro et al. found no significant difference in 28-day mortality (15% vs. 22%, p = 0.15) whereas Somers et al. identified a 45% reduction in the risk of death (aHR 0.55, 95% CI 0.33–0.90) in mechanically ventilated patients [14, 25]. Guaraldi et al. also found tocilizumab to be associated with a reduced risk of all-cause mortality after adjusting for age, sex, recruiting center, duration of symptoms, and SOFA score (aHR 0.38, 95% CI 0.17–0.83) . Overall, these findings suggest a possile mortality benefit with tocilizumab, however it is important to recognize that many patients also received steroids, which has been independently associated with improved survival .
Historically, tocilizumab has been associated with secondary infections. In the rheumatoid arthritis population, a meta-analysis conducted by Navarro et al. found a 37.5% infection incidence in the tocilizumab group compared to 33.8% in the placebo group . In the chimeric antigen receptor modified (CAR) T population, 133 patients who received tocilizumab had an infection incidence of 23% within 90 days . In our COVID-19 study, we identified a higher proportion of infections within a shorter amount of time: 26.7% within 30 days. Additionally, Kimmig et al. found an even higher incidence of infection of 64.2% but they had a longer follow-up time at 8 weeks and a broader definition for infection, which also captured highly suspected infections . Another study by Somers et al. found a two-fold higher incidence of infections in patients who received tocilizumab at 28 days (54% vs. 26%, p < 0.001) but more patients in the tocilizumab arm received steroids . To date, the only study who excluded steroid use reported a 13% infection incidence at 28 days . Taken altogether, tocilizumab may increase the risk of infections, however better designed studies taking into account confounding factors are needed.
Our study had several limitations. First, it was a retrospective study with a small sample size. Second, the flat doses of 400 and 600 mg for tocilizumab could have resulted in lower than optimal doses if extrapolating from FDA-approved (8 mg/kg) doses for CAR T cell-induced CRS . Third, many patients received concomitant therapies that could impact clinical outcomes, such as IVIG and steroids. Fourth, many of our infections were diagnosed based on tracheal aspirates because bronchoscopies were infrequent at the time. The quality of the culture, in addition to the critical nature of the patient made diagnosis of pneumonia particularly challenging. Fifth, the study end point of 30 days precluded us from identifying long-term infectious complications post-tocilizumab. Lastly, this study was descriptive and not aimed to investigate predisposing risk factors for infectious complications or to determine tocilizumab efficacy.