Efficacy of Tocilizumab in Patients With COVID-19 ARDS Undergoing Noninvasive Ventilation

Francesco Menzella; Matteo Fontana; Carlo Salvarani; Marco Massari; Patrizia Ruggiero; Chiara Scelfo; Chiara Barbieri; Claudia Castagnetti; Chiara Catellani; Giorgia Gibellini; Francesco Falco; Giulia Ghidoni; Francesco Livrieri; Gloria Montanari; Eleonora Casalini; Roberto Piro; Pamela Mancuso; Luca Ghidorsi; Nicola Facciolongo

Disclosures

Crit Care. 2020;24(589) 

In This Article

Discussion

In this study, we evaluated the effectiveness of TCZ in a cohort of COVID-19 critically ill patients treated with NIV. Notably, pre-ventilation PaO2/FiO2 ratio was similar to a cohort of invasively ventilated patients in intensive care unit (ICU),[17] therefore with a high level of impairment.

The mortality rate and the probability of being intubated or dying in the pulmonology unit using Kaplan-Meier method were significantly lower in patients treated with TCZ compared to those who were not treated. However, when we used Cox multivariate analyses, adjusting for age and Charlson comorbidity index, only the association with the reduced risk of being intubated or dying in our ward maintained the significance, because the association between TCZ treatment and reduced mortality risk was no longer significant. These results suggest that TCZ could be an effective therapeutic option for the treatment of critically ill COVID-19 patients receiving NIV; however, more data are needed to confirm the efficacy of TCZ in this group of patients, particularly from randomized controlled trials.

We also evaluated whether patients with a more inflammatory phenotype could have a different response to TCZ. We selected a baseline CRP level of 10 mg/dl as the best cut-off because in several studies CRP values higher than 10 mg/dL identified the patients with more severe inflammation.[18,19] However, we did not see any difference in TCZ-treated patients, neither for mortality nor for intubation/death between patients with baseline CRP ≥ 10 mg/dl and those with values < 10 mg/dl.

Due to a shortage of IV formulation, we administered SC TCZ. However, this formulation did not completely mimic the pharmacodynamic activity and the dosage of the IV formulation, even if we used SC dosages higher compared to those used in rheumatoid arthritis and other inflammatory conditions. It is important to note that the SC route takes some days to reach the peak plasma concentration after a single dose. This is due to the slow absorption through the lymphatic system into the systemic circulation.[15,16] To overcome these limitations, the patients were simultaneously treated with multiple separate injections of SC TCZ. This strategy was supported from the findings of a comparative pharmacokinetic/pharmacodynamic study of SC vs IV TCZ.[15] We did not observe significant differences in the mortality rate and in the proportion of patients who were intubated or died in the pulmonology unit between patients treated with SC TCZ and those untreated; however, possible differences in efficacy between the two formulations of TCZ in COVID-19 ARDS must be confirmed by larger studies. The small number of the patients treated with SC formulation may have influenced the negative results. In the literature, there are reports demonstrating the efficacy of SC TCZ in reducing the mortality of severe COVID-19 pneumonia.[13] We also observed at T3 and T7 a similar reduction of CRP levels in patients treated with IV and SC TCZ, confirming at the administered doses a similar anti-inflammatory activity of the two TCZ formulations.

After the initial viral phase, some patients with COVID-19 develop a hyperinflammatory phase, which is manifested with biological changes of cytokine storm, usually associated with a quick respiratory deterioration due to pneumonitis. In these patients, glucocorticoids at high doses and/or IVs TCZ have become the treatment of choice in real life.[20] Although some retrospective and observational studies using TCZ in severe COVID-19 have shown promising results,[9–13] other studies, including the preliminary results of randomized trials, and a systemic review and meta-analysis did not demonstrate a benefit for TCZ in improving clinical status or reducing the risk of ICU admission and mortality.[21,22] However, TCZ may be effective in particular subgroups of patients, as we showed in this study in patients underlying NIV or Somers et al. in patients requiring invasive mechanical ventilation.[23] In a recent randomized trial, the use of dexamethasone in patients hospitalized with COVID-19 resulted in lower 28-day mortality among patients who were receiving either invasive mechanical ventilation or oxygen alone at randomization, but not among those receiving no respiratory support.[8] Therefore, the combined use of TCZ and GCs may be useful in patients with severe COVID-19 pneumonia to prevent invasive mechanical ventilation and/or death. In this regard, a recent prospective study demonstrated that a therapeutic strategy constituted by a course of high dose methylprednisolone, followed by tocilizumab if needed, may accelerate respiratory recovery, lower hospital mortality, and reduce the likelihood of invasive mechanical ventilation in COVID-19-associated cytokine storm syndrome.[24] A treatment with high-dose glucocorticoids as first therapeutic choice may also be convenient since glucocorticoids are safe, widely available and inexpensive.

The risk of severe infection in patients with COVID-19 undergoing noninvasive ventilation and treated with TCZ is not well defined. Somers et al. demonstrated that superinfections were common in patients with severe COVID-19 treated with TCZ and requiring invasive mechanical ventilation.[23] In this study, patients who received TCZ were more than twice as likely to develop a superinfection than untreated controls, driven primarily by a large increase in ventilator-associated pneumonia. Staphylococcus aureus accounted for ~ 50% of bacterial pneumonia. We observed cavitating lung lesions in 2/41 (4.8%) patients treated with TCZ, while none of such lesions were observed in the untreated patients. Staphylococcus aureus was isolated in the first patient, while no infectious agent was identified at cultural examination in the second; however, antibiotic treatment resolved the lesions in both patients. Probably, our study underestimates the incidence of severe infections; however, all secondary infections were accurately reviewed to ensure careful reporting. Furthermore, differently from Somers et al. study, we have enrolled noninvasively ventilated patients who are less exposed to superinfections compared to those receiving invasive mechanical ventilation.

Main limitations of this study are the retrospective nature and the relatively small number of patients enrolled. An important observation to report is that humidified high-flow nasal cannula (HHFNC) was not routinely used in our hospital because of shortage of devices during the first period of the pandemic. Furthermore, we preferentially use NIV for our better experience on this technique. For these reasons, NIV has been utilized in patients with a moderate to severe disease in our Unit as the first choice. On the other hand, during the outbreak, there was also a low ICU bed availability, having some difficulties in treating many patients with mechanical ventilation. Another limitation is that TCZ route of administration was heterogeneous and there are not definitive data regarding similarities in effectiveness between IV and SC formulations, considering the different pharmacokinetic characteristics. Also differences in ICU strain with restrictions on ICU access during the study period, differences in the severity of COVID-19 pneumonia at admission, in comorbidities and age could have influenced patient mortality and then the positive results of TCZ. However, multivariate analysis was corrected by age and comorbidity index and the only factor influencing the treatment choice was drug availability. Strength of the study was that all patients were homogeneously followed-up using a common standardized protocol. Furthermore, in Reggio Emilia-hospitalized COVID-19 patients, the mortality rate reached a plateau 1 month after hospitalization;[25] therefore, our study had an adequate follow-up period (median was 60 days) to properly observe COVID-19 related deaths.

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