Sarilumab use in severe SARS-CoV-2 pneumonia

Abstract

Background: Interleukin-6 signal blockade showed preliminary beneficial effects in treating inflammatory response against SARS-CoV-2 leading to severe respiratory distress. Herein we describe the outcomes of off-label intravenous use of Sarilumab in severe SARS-CoV-2-related pneumonia.

Methods: 53 patients with SARS-CoV-2 severe pneumonia received intravenous Sarilumab; pulmonary function improvement or Intensive Care Unit (ICU) admission rate in medical wards, live discharge rate in ICU treated patients and safety profile were recorded. Sarilumab 400 mg was administered intravenously on day 1, with eventual additional infusion based on clinical judgement, and patients were followed for at least 14 days, unless previously discharged or dead.

Findings: Of the 53 SARS-CoV-2^pos patients receiving Sarilumab, 39(73·6%) were treated in medical wards [66·7% with a single infusion; median PaO₂/FiO₂:146(IQR:120-212)] while 14(26·4%) in ICU [92·6% with a second infusion; median PaO₂/FiO₂: 112(IQR:100-141.5)].Within the medical wards, 7(17·9%) required ICU admission, 4 of whom were re-admitted to the ward within 5-8 days. At 19 days median follow-up, 89·7% of medical inpatients significantly improved (46·1% after 24 h, 61·5% after 3 days), 70·6% were discharged from the hospital and 85·7% no longer needed oxygen therapy. Within patients receiving Sarilumab in ICU, 64·2% were discharged from ICU to the ward and 35·8% were still alive at the last follow-up. Overall mortality rate was 5·7%.

Interpretation: IL-6R inhibition appears to be a potential treatment strategy for severe SARS-CoV-2 pneumonia and intravenous Sarilumab seems a promising treatment approach showing, in the short term, an important clinical outcome and good safety.

Keywords: Inflammation; Sarilumab; Severe sars-cov-2 pneumonia.

Fig. 1

A-H. Clinical course of SARS-CoV-2^pos patients treated with Sarilumab in medical wards and in the ICU. A) Individual disease course of SARS-CoV-2^pos patients in medical wards. Each individual disease course is depicted in a line from pre-treatment to maximum 22 days after Sariumab administration; Pink diamonds refer to transfer towards ICU; Green diamonds refer to transfer back from ICU to medical wards; Light blue diamonds refer to discharge from the hospital and black diamond refers to death. Black stars indicate repetition of infusion of Sarilumab during the follow-up. Respiratory support is highlighted for each patient as follows: light blue box for non invasive ventilation and light violet box for continuous positive airway pressure; B) Rate of clinical response to Sarilumab in SARS-CoV-2^pos patients within 14 days follow-up (24 h, 3,5,7 and 14 days) in medical wards. C) PaO₂/FiO₂ ratio in SARS-CoV-2^pos patients treated with Sarilumab based on their need to be transferred to ICU during the follow-up; comparison between baseline vs 3 days *p < 0.001; **p < 0.0001 refer to comparison between baseline vs 5, 7 days and last follow-up respectively; ^p < 0.01 for each time-point comparing patients trasferred to ICU vs patients not transferred to ICU after Sarilumab treatment. d-E) Example photos of pulmonary CT-scan of SARS-Cov-2^pos patients before (D) and 10 days after (E) Sarilumab treatment. Among the whole cohort, 12 (30.8%) and 2(14.3%) patients in the clinical ward or in the ICU underwent serial CT scan during hospitalization respectively. CT scan was not routinely performed in the initial phases of the pandemic. F) Individual disease course of SARS-CoV-2^pos patients in ICU. Each individual disease course is depicted in a line from pre-treatment to maximum 22 days after Sarilumab administration; Green diamonds refer to transfer towards medical wards and light blue diamond refers to discharge from the hospital. Black stars indicate repetition of infusion of Sarilumab during the follow-up. Respiratory support is highlighted for each patient as follows: light violet box for continuous positive airway pressure and orange box for endo-tracheal intubation; G) Rate of clinical response to Sarilumab in SARS-CoV-2^pos patients within 14 days follow-up (24 h, 3,5,7 and 14 days) in ICU. Severe and critical SARS-CoV-2 pneumonia was defined based on PaO₂/FiO₂ ratio <300 and/or multiorgan, respiratory failure or shock. H) WHO clinical progression scale across disease course in SARS-CoV-2 positive patients treated with Sarilumab in Medical Ward and ICU. * p < 0.05 and **p < 0.01 Wilcoxon test comparing pre-treatment WHO scale and 5, 7, 14 and 21 days after Sarilumab administration in ICU patients; ^ p < 0.05 Wilcoxon test comparing pre-treatment WHO scale and 5, 7, 14 and 21 days after Sarilumab administration in ICU patients.

Fig. 2

A-H. Clinical and biological baseline predictors of clinical outcome in SARS-Cov-2^pos patients treated with Sarilumab. A) Baseline IL-6 plasma levels in SARS-Cov-2^pos patients treated with Sarilumab based on clinical improvement at 3 days after Sarilumab treatment, *p = 0.001. B) Baseline PaO₂/FiO₂ in SARS-Cov-2^pos patients treated with Sarilumab based on clinical improvement at 3 days after Sarilumab treatment, *p = 0.004. C) Rate of clinical improvement at 3 days in SARS-Cov-2^pos patients treated with Sarilumab based on baseline IL-6 plasma levels, *p < 0.0001. D) Rate of clinical improvement at 3 days in SARS-Cov-2^pos patients treated with Sarilumab based on baseline PaO₂/FiO₂, p = 0.003. E) Baseline IL-6 plasma levels in SARS-Cov-2^pos patients based on transfer towards ICU within 14 days after Sarilumab treatment, *p = 0.05. F) Baseline PaO₂/FiO₂ in SARS-Cov-2^pos patients based on transfer towards ICU within 14 days after Sarilumab treatment, *p = 0.008. G) Kaplan-Meier analysis of transfer to ICU rate in SARS-Cov-2^pos patients treated with Sarilumab based on pre-treatment IL-6 plasma levels, p = 0.01. H) Kaplan-Meier analysis of transfer to ICU rate in SARS-Cov-2^pos patients treated with Sarilumab based on pre-treatment PaO₂/FiO₂, p = 0.03.

Fig. 3

A-CC. Development of multi-parametric nomogram predictive of transfer towards ICU in SARS-CoV-2^pos patients treated with Sarilumab in medical ward setting. A) Rate of transfer to ICU in SARS-CoV-2^pos patients treated with Sarilumab in medical wards based on pre-treatment IL-6 plasma levels (91.3 pg/ml), PaO₂/FiO₂ ratio value (142.5) and age category (<54 years, 55–74 years and >75 years respectively); Values are expressed as percentages. B) Odd ratios of transfer to ICU in SARS-CoV-2^pos patients treated with Sarilumab in medical wards based on the fulfillment of pre-treatment definite parameters; Values are expressed as Odd Ratio (95%CI); C) Nomogram for the computation of probability of transfer to ICU in SARS-CoV-2^pos patients treated with Sarilumab in medical wards. IL: Interleukin; ICU: Intensive Care Unit.