In our study, mortality was higher in critical COVID-19-associated ARDS patients given favipiravir and tocilizumab. Patients who died were elderly (> 65 years), had high APACHE II score, high SOFA score on the day of tocilizumab administration and low PaO2/FIO2 ratio. Also they were mostly severe ARDS patients and had high inflammatory markers. High mortality was attributed to the use of tocilizumab as a salvage treatment, not as a routine treatment.
SARS-CoV-2 infection might cause a hyperimmune response associated with acute respiratory distress (ARDS), the latteris a leading cause of death for severe COVID-19 (17). Uncontrolled immune activation would result in cytokine storm, also known as cytokine release syndrome (CRS), appearing as overproduction of pro-inflammatory cytokines and chemokines (18). Severe COVID-19 patients always present elevated inflammatory markers, among which the elevation of IL-6 is associated with severity of COVID-19. The upregulated expression of IL-6 receptor (IL-6R) was also detected in COVID-19 patients (19). Therefore, IL-6/IL6R might serve as a messenger not only for transmitting inflammatory signals throughout the lung and other organs but also by activating cellular signal pathway, thus causing ARDS and multiple organ dysfunction. It is reasonable to speculate that IL-6 blockade is beneficial for avoiding poor prognosis.
In more than one year, a relatively high number of different types of trials have evaluated the effects of tocilizumab. So far, the growing body of studies assessing the efficacy and safety of tocilizumab for treatment of SARS-CoV-2-associated hyperinflammation, severe pneumonia, and ARDS has yielded mixed results.
Jordan et al. (20) used a single dose of 400 mg tocilizumab IV in 27 patients at the beginning of the pandemic (13 March 2020-11 April 2020). Twenty-one patients were in MV upon admission to the ICU, and six patients were receiving nasal oxygen therapy; Tocilizumab was administered while 22 patients were on MV. All patients received azithromycin and hydroxychloroquine. While the median PaO2/FIO2 ratio on the day of tocilizumab administration was 161 mmHg, it was 201–300 mmHg in 6 (29%) patients, 101–200 mmHg in 9 (43%) patients, and < 100 mmHg in 3 (14%) patients. Among 21 intubated patients, 15 were extubated after a median of 8 days after tocilizumab administration, 9 were discharged from the hospital within a median of 14 days, and 2 patients died. In this study, where the mean IL-6 level was 356.07 ± 616 pg/ml, only 1 of the 6 non-intubated patients had respiratory deterioration and became intubated(20). Inhibition of IL-6/IL-6R blockade by tocilizumab detected by measuring CRP. We tought that a single 400 mg dose of tocilizumab does not uniformly block all cellular IL-6Rα, particularly if there is a large amount of circulating IL6Rα/IL6 complexes. Since our patients had high IL-6 levels, two doses of 400 mg tocilizumab were applied to most of our patients.
Zhao et al. (21) compiled studies investigating the use of tocilizumab in severe COVID-19 patients. They analyzed 10 studies, which included a total of 1675 patients, and found that only one study was a randomized controlled trial, while the others were retrospective observational studies. In that randomized controlled trial, total of 675 patients received tocilizumab, while 1000 patients received standard care. ? Mortality was significantly lower in the tocilizumab group [(132/675) 19.5%] vs [(283/1000), 28.3% (OR 0.47; 95% CI 0.36–0.60; p < 0) ,00001). However, a high level of heterogeneity was detected (I2 = 0.74, p < 0.0001). In the standard care group, hydroxychloroquine, lopinavir/ritonavir, remdesivir, azithromycin, low molecular weight heparin (LMWH) and/or methylprednisolone were administered (21). In our study, all patients received standard methylprednisolone, LMWH and favipiravir treatments in addition to tocilizumab, therefore a homogeneous treatment regimen was applied too all patients.
In the study of Somers et al. (22) in which they investigated the use of tocilizumab in COVID-19 patients with MV, 78 of 154 patients were given tocilizumab, while 76 patients did not. Median follow-up was 47 days (28–67 days), and the tocilizumab group was younger (mean age 55 vs. 60 years), had less chronic lung disease (10 vs 28%). The hazard of death was found as 45% decreased by inverse probability weighting (IPTW) analysis [hazard ratio 0.55 (95% CI 0.33–0.90)] for patients who received tocilizumab. However, the superinfection rate (54% vs 26%, p < 0.001) increased in the tocilizumab group. In this study, the PaO2/FIO2 ratio of the tocilizumab group was lower (median 155 vs 198; p = 0.001). Tocilizumab was associated with a lower hazard of death after adjusting for demographics (HR 0.54 95% CI O.29 − 1). In this observational controlled study, tocilizumab reduced the risk of death in COVID-19 patients who needed MV. Although it increased the risk of secondary bacterial pneumonia, this was not a factor which increased mortality (22). In our study, the median age of the patients was 69.8 (24–71), and the median age of the patients who died was 71.5 (37–87), our patients were older than the study by Somers et al.. Sixteen (26.7%) of our patients had chronic obstructive pulmonary disease and all of our patients were receiving MV or NIMV. The PaO2/FIO2 of the group who died on the day of tocilizumab administration was very low at 94.8 ± 98.2 mmHg.
Mortality rates for tocilizumab-treated patients with COVID-19 of the seven studies ranged from 3.2–38.6%. This differences most probably based on the quailty of care including surge capacity of the ICU. In a prospective study by Toniati et al. (10) from Italy, 100 COVID-19 ARDS patients who needed MV were evaluated. Tocilizumab was administered in two doses of 8 mg/kg, similar to our study. A third dose was also administered according to the clinical response. The mortality rate was found as 20% (n = 20). In our study, a single dose of 400 mg tocilizumab was administered to 83.3% of the patients, while two doses of 400 mg IV tocilizumab were administered to remaining 16.7%. None of our patients received the third dose. Our high mortality rate (66.6%) was attributed to the severity of our patients and to the use of tocilizumab as a salvage treatment. In another prospective single-arm study, 63 severe COVID-19 patients were given tocilizumab and the mortality was 11%. It has been reported that administration of tocilizumab within the first 6 days of hospital admission increases the probability of survival (HR: 2.2, 95% CL 1.3–6.7; p < 0.05) (23). However, none of these studies included COVID-19 associated ARDS patients in the critical ICU, different from our study. In the studies mentioned above, all-cause mortality, the risk of ICU admission and the need for MV were found similar between tocilizumab and control group, similar to our results. Tocilizumab add-on treatment for patients with severe COVID-19 patients was associated with a better treatment outcome compared with those without tocilizumab treatment (23, 24). In our study, we attributed the mortality rate of 66.7% in patients receiving tocilizumab to the fact that we gave tocilizumab treatment as an add-on treatment to our patients receiving favipiravir, that all of our patients had ARDS and most of them had severe ARDS.
In our study, advanced age, high APACHE score and high SOFA score on the day of tocilizumab administration and low PaO2/FIO2 ratio were determined as independent risk factors for mortality. Our patient group was older than previous tocilizumab studies, and all of them were critically ill with severe ARDS and had organ failure.
Our study is the first study in Turkey to examine the use of tocilizumab as an add-on treatment to favipiravir in patients with critical COVID-19-associated ARDS. However, our study has some limitations. First, it is a retrospective and single-center study. All patients received favipiravir and tocilizumab, all surviving patients received corticosteroid therapy, while not all patients who died received corticosteroid therapy.
In conclusion; our findings addressed the potential role of tocilizumab in critical COVİD-19 patients to prevent intubation. Our study also highlight the need for adequately powered randomized controlled trials which further evaluates efficacy of tocilizumab in critical COVID-19 ARDS patients.