During the rapidly spreading pandemic, providers were faced with the challenge of recommending investigational agents for the treatment of COVID-19. Since elevated IL-6 levels have been associated with ICU admission, ARDS, and death, we chose to prescribe tocilizumab in patients with suspected CRS [6]. We aimed to provide early administration of tocilizumab in patients not yet on mechanical ventilation but with signs of worsening disease. Results from the EMPACTA trial demonstrated that patients who received tocilizumab were 44% less likely to progress to mechanical ventilation or death [26]. In our cohort, 9 out of the 31 patients who received tocilizumab early progressed to invasive mechanical ventilation. In the future, we hope to explore the effects of tocilizumab timing, as there may be a window of opportunity for preventing progressive respiratory failure.
Our patients presented with typical manifestations of COVID-19 and signs and symptoms of cytokine release syndrome. Similar to previous reports, patients with more severe disease demonstrated transaminitis, along with abnormal blood counts such as neutrophilia, lymphopenia, and elevated NLR ratio [4, 27]. After receipt of tocilizumab, CRP levels decreased but unlike other studies, this effect was not sustained [10-12]. CRP started to increase again after day 10, which correlates with tocilizumab’s elimination half-life of 11 to 13 days [28]. Compared to other studies where reductions in CRP remained until day 14, our patients received lower dose and the majority did not receive a second dose [14, 17]. This suggests that tocilizumab’s effect on CRP may be dose-dependent and that re-dosing after 10 days may be warranted. Pharmacokinetic data has also suggested that at least two doses of tocilizumab is needed to achieve adequate drug levels in plasma [7]. As expected, repeat IL-6 levels, although only available for one third of our patients, increased quickly after tocilizumab administration. This effect is known to occur after competitive binding of tocilizumab to the IL-6 receptor, resulting in the temporary accumulation of free IL-6 in the serum [29]. We also 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 the effects of oxygenation after tocilizumab administration in COVID-19 patients. Studies have reported improvements in oxygenation while others did not [11, 13, 30]. We observed an overall increase in PaO2/FiO2 after tocilizumab, but it is unclear whether this was a drug effect or more so reflects the natural course of ARDS. Biran et al. found no association between tocilizumab and FiO2 reduction [17]. By day 30, extubation occurred in 13 out of 29 patients (44.8%). Rates of extubation for COVID-19 have only been recorded in a small study where 2 out of 3 patients were successfully extubated after receiving tocilizumab [10].
By our study endpoint, 36 patients (60.0%) demonstrated clinical improvement and 33 patients (55.0%) were discharged alive. Our discharge rate was very similar to the 56% reported by Somers et al. [15]. We observed a 30-day mortality rate of 15%, which falls within the range (13-27%) of previous studies [10, 12, 15-16, 30-31]. Many studies have already investigated the relationship of tocilizumab and mortality in COVID-19 patients, but with mixed findings. Salvarani et al. and Campochiaro found no significant difference in mortality in patients receiving tocilizumab [18, 31]. In contrast, several studies showed a decreased risk of death, lower hospital-related mortality, as well as reduced risk of all-cause mortality [15-17, 19-20]. However, it is important to note that many of these studies permitted steroid use with tocilizumab, a known confounder towards better survival [33]. When comparing our patients who received steroids with tocilizumab to those who did not, they surprisingly did worse. More patients died, less demonstrated clinical improvement, and less were discharged from the hospital alive despite having similar baseline COVID-19 disease severity. We believe this could be explained by the high doses of steroids used in our study, which took place prior to the RECOVERY trial. Majority of our patients received dosages greater than 6 mg daily of dexamethasone equivalents and were highly immunosuppressed.
Another hypothesis for worse outcomes when combining steroid with tocilizumab is the higher incidence of infectious complications in the steroid group (62.5% vs. 37.5%, p=0.57), although this was not statistically significant. Tocilizumab is immunosuppressive and has been linked to secondary infections [34-35]. In our study, we identified an overall infection rate of 26.7% within 30 days of receiving tocilizumab. Another study with a longer follow-up time of 8 weeks found a higher infection of incidence at 64.2%; however, they had a slightly broader definition for infections that included highly suspected infections in addition to confirmed infections [32]. Additional studies have reported infection rates possibly secondary to tocilizumab [15-17]. Somers et al. reported a two-fold higher incidence (54% vs. 26%, p<0.001) but more patients in the tocilizumab arm received steroids [15]. The one study that excluded concomitant steroids found a lower incidence of infections with tocilizumab (8.1% vs. 17.3%, p=0.03) [21]. Therefore, it remains unclear whether tocilizumab, when used by itself, increases the risk of infection.
Our study had several limitations. First, it was a small retrospective study with no matched control group. 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 [7]. Third, many patients received concomitant therapies that could impact clinical outcomes. Fourth, many of our infections were diagnosed based on tracheal aspirates because bronchoscopies were infrequent at the time. Lastly, the study was descriptive and not aimed to investigate predisposing risk factors for infectious complications or to determine tocilizumab efficacy.