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

Results

Out of 79 patients, 41 were treated with TCZ. Twenty-eight patients received IV TCZ (8 mg/kg—max 800 mg) by two consecutive infusions 12 h apart. Thirteen patients received SC TCZ ranging from 2 to 4 doses of 162 mg TCZ (administered simultaneously in a different injection site) per patient depending on drug availability and body weight, according to an internal protocol developed due to a temporary unavailability of IV formulation. Pharmacokinetically, 2 doses of 162 mg of SC TCZ administered simultaneously are equivalent to 4 mg/Kg IV.[15,16]

Table 1 shows the characteristics of the patients and concomitant treatments during the follow-up. In the TCZ treatment group, CRP levels were significantly lower at 72 h and 7 days after starting therapy compared with the standard therapy group (p = 0.02 and p = 0.001, respectively), while an increase in IL-6 levels was found at the same times, due to the known effect of TCZ that blocking IL-6 receptors increases the serum levels of free IL-6. At admission, patients treated with TCZ were younger, had a lower Charlson comorbidity index, and received more frequently hydroxychloroquine compared to the standard therapy group (p = 0.005, p = 0.002, and p = 0.05, respectively); however, the other evaluated parameters were not different, including the number of comorbidities and SOFA index.

CRP levels determined before TCZ administration (T0) and after 3 (T3) and 7 (T7) days were not significantly different between patients treated with IV TCZ and SC TCZ (11.2 ± 7.1 mg/dl vs 11.2 ± 7.5, p = 0.77; 5.9 ± 5.9 mg/dl vs 7.6 ± 7.9, p = 0.80; 1.1 ± 1.5 mg/dl vs 5.1 ± 8.5, p = 0.78; respectively).

In-hospital mortality rate was 38% (30/79 patients). Regarding all TCZ-treated patients, mortality rate was 24% (10/41 patients), while was 18% (5/28 patients) in the IV TCZ subgroup, 38% (5/13 patients) in the SC TCZ subgroup, and 53% (20/38 patients) in the subgroup of patients not treated with TCZ. The differences between the 3 subgroups were statistically significant (p = 0.0085). Figure 1 shows Kaplan-Meier estimates for the probability of dying during the follow-up. The probability of dying of all TCZ-treated patients was significantly lower compared to that of patients not treated with TCZ (log-rank p value = 0.0057). No significant differences were found between SC and IV TCZ-treated patients (log-rank p value = 0.092), the differences between IV TCZ-treated and untreated patients was significant (log-rank p value = 0.0017), but not the differences between SC TCZ-treated and untreated patients (log-rank p value = 0.53). However, last comparisons were limited by the low number of patients evaluated.

Figure 1.

a Differences in survival during the follow-up in noninvasively ventilated patients treated and not treated with TCZ (log-rank p value = 0.0057). b Differences in survival during the follow-up between patients treated with IV or SC TCZ, or not treated with TCZ. No significant differences were found between SC and IV TCZ -treated patients (log-rank p value = 0.092), and the differences between IV TCZ-treated and untreated patients was significant (log-rank p value = 0.0017), but not the difference between SC TCZ-treated and untreated patients (log-rank p value = 0.53)

Sixteen/41 (39%) patients treated with TCZ were intubated or died in the pulmonology unit: 9/28 (32%) treated with IV TCZ, 7/13 (54%) treated with SC TCZ, and 25/38 (66%) not treated with TCZ, respectively. The differences between the 3 subgroups were statistically significant (p = 0.037). The intubation rate was 7/28 in the IV TCZ group (25%), 2/13 in the SC TCZ group (15%), and 12/38 in the standard care group (31.6%, p = 0.507). Figure 2 shows Kaplan-Meier estimates for the probability of dying or being intubated during the follow-up. The probability of dying or being intubated was significantly lower in total patients treated with TCZ compared to those untreated (log-rank p value = 0.036). The difference was significantly lower in patients treated with IV TCZ (log-rank p value = 0.01), but not in patients treated with the SC formulation (log-rank p value = 0.45) compared to the untreated patients. At multivariate Cox proportional hazards analyses adjusted by sex and age, patients treated with tocilizumab had a significantly reduced risk of intubation or death during the follow-up period (HR 0.44, 95%CI 0.22–0.89, p = 0.022), while they did not have a reduced mortality (HR 0.55, 95%CI 0.22–1.35, p = 0.192).

Figure 2.

a Differences in probability of dying in the pulmonology unit or being intubated during the follow-up in noninvasively ventilated patients treated and not treated with TCZ (log-rank p value = 0.036). b Differences in probability of dying in the pulmonology unit or being intubated between patients treated with IV or SC TCZ, or not treated with TCZ. The difference was significantly lower in patients treated with IV TCZ compared to those untreated (log-rank p value = 0.01), but not in patients treated with the SC formulation (log-rank p value = 0.45)

A baseline CRP level of 10 mg/dl was selected to evaluate TCZ-treated patients according to their inflammatory status. Twenty-one patients had baseline CRP levels > 10 mg/dl (mean + SD, 17.0 + 5.0 mg/dl) and 20 patients < 10 mg/dl (5.2 + 2.4 mg/dl). No differences, neither for mortality nor for intubation/death, were observed between patients with baseline CRP > 10 mg/dl and those with values < 10 mg/dl (5/21, 24% vs 5/20, 25%, p = 0.90; and 7/21, 33.3% vs 9/20, 45.0%, p = 0.75, respectively).

Among the patients treated with TCZ, two developed cavitating lung lesions: 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.

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