The results of this cohort observational study indicate that selective cytokine blockade with Tocilizumab or Anakinra in critically ill patients with moderate to severe ARDS pneumonia and need of mechanical ventilation seems to be well tolerated and to improve in-hospital survival rate.
Based on recent reports [3, 21], the pathobiology of interstitial pneumonia and acute respiratory failure by SARS-CoV-2 infection relies on the predominant role of hyper-inflammation in the context of a complex dysregulated immune function . As observed by others [3, 23], our patients showed a pronounced pro-inflammatory state at ICU admission with elevated serum CRP, D-Dimer, LDH and IL6 levels associated with lymphopenia. In this Due to the poor outcome observed in the first reports on COVID19 patients requiring ICU admission, the attractive hypothesis of controlling the exaggerated cytokine response by using different immunomodulating agents has been early proposed  and many randomized trials are ongoing.
TOCI and ANA, among immunomodulatory drugs, represent two treatment options in this context. TOCI, a selective interleukin-6 receptor antagonist, was approved for the treatment of autoimmune diseases and Chimeric Antigen Receptor T-Cell Therapy-Induced Cytokine Release Syndrome . Early reporting of clinical experiences with TOCI in COVID-19 patients have been recently published. In a single centre study from Wuhan including 15 patients TOCI appeared to be an effective treatment option in patients with cytokine storm . In a retrospective analysis of 25 unmatched ICU patients, TOCI at the median dose of 5,7 mg/Kg showed a significant reduction in invasive mechanical ventilation at day 14, although 90% of patients showed adverse events . A prospective multi-centre safety study on 66 patients reported no moderate to severe adverse events related to TOCI with a significant improvement in PaO2/FiO2 ratio, ferritin, C-reactive protein, D-dimer and lymphocytes count at day 14 . In a single-centre study including 100 unmatched COVID-19 patients with mechanical ventilation, the authors observed an improvement of the respiratory severity using a disease-specific scale and the decreasing of laboratory inflammation parameters after two intravenous administrations of 8 mg/kg of TOCI. A French retrospective case- control study reported a 50% difference in primary composite end-point (death and/or ICU admission) in 20 patients treated with TOCI (unreported dosage) compared to 25 controls .
As refers to ANA, it is a recombinant IL-1 receptor antagonist administered to treat autoinflammatory disorders and recently used in post-myocardial infarction remodelling and diabetes . In the context of COVID-19 acute respiratory distress syndrome, a retrospective study was conducted on 29 patients treated with high-dosage ANA compared to 16 controls; patients were non-invasively ventilated outside of the ICU. Compared with standard treatment, high-dose ANA was associated with a higher survival rate at 21 days and with a reduction in C-reactive protein and with progressive improvement in PaO2/FiO2. However, high-dose treatment was discontinued for adverse events in 24% of the treated patients .
To our knowledge, our study is the first to have evaluated the effects of the selective cytokine blockade on in-hospital mortality in ICU admitted patients requiring mechanical ventilation for ARDS due to COVID19. Beyond the significant risk reduction compared to our controls, the in-hospital mortality (36,2% in all the patients and 54% in those with invasive ventilation at ICU admission) observed in our patients treated with selective cytokine blockade was also lower than mortality observed in other reports, even when only patients underwent invasive ventilation are considered. A large case series of ICU patients coming from Wuhan, China, showed an overall mortality rate at day 28 of 39% but increased to 97% in patients with invasive mechanical ventilation. Interestingly, this high mortality rate in intubated patients has been attributed to possible late use of invasive ventilation . Another retrospective study coming from Wuhan enrolled 52 critically ill ICU patients with a 28-day mortality rate of 61,5% . An Italian case series of 73 intubated patients had a median follow-up time of 19 days with a mortality rate of 23,3% and with almost half of the patients studied still invasively ventilated at that time-point . In the Italian Lombardy ICU
Network series, the overall mortality rate of patients admitted in ICU was 48,3% (1926 died and 2062 alive) with 91 (4,4%) patients still in ICU on the date of publication . Among 5700 hospitalized patients in the New York Area, 373 patients needed ICU care with an ICU mortality rate of 78% . An early report from Washington State reported an ICU mortality rate of 67% in 21 critically ill patients . Finally, the ICNARC report on COVID-19 updated on 1st May showed an ICU mortality of 62% in 3508 patients with advanced respiratory support .
Remarkably, following previous reports, we did not observe any severe adverse event attributable to the use of TOCI or ANA . The rate of secondary infections, mostly ventilator acquired pneumonia and catheter-related bloodstream infections by Gram-positive microorganisms, was high compared to no-COVID19 patients admitted to our ICU (internal data from Prosafe- Giviti project https://giviti.marionegri.it) but the use of cytokine selective blockade therapy did not increase the risk in comparison with controls treated in our centre. Nevertheless, in our cohort, the incidence of adverse events by ANA and TOCI could have been underestimated because of frequent clinical and laboratory alterations occurring in critically ill patients with severe ARDS or other organ dysfunctions. In fact, in 5 patients treated with cytokine blocking agents and long ICU stay we observed late reactivation of herpes simplex virus type 1 and, besides, two COVID19 patients treated with TOCI in other hospitals were transferred to our ICU for acute liver failure, without ARDS, due to herpes simplex virus type 1 reactivation (submitted for publication elsewhere).
Our study had several limitations that are mainly due to the observational design and to the small size of the cohort studied. Although the use of propensity score for adjusting the multivariable analysis and for patients matching is considered an effective method in non-randomized trials, it is possible that some amount of unmeasured confounding factors still remains. Nevertheless, it is noteworthy the all the data analysis (unadjusted, adjusted without and with propensity score) pointed out the same signal with a potential benefit in terms of survival by using selective cytokine blockade. The change of intubation rules during the study period with more permissive use of non- invasive ventilation in patients with severe ARDS could have introduced a bias. However, the sensitivity analysis in patients with invasive ventilation at ICU admission (within 2 hours) confirmed the reduction in mortality by using TOCI and ANA (Table E3-E5). The small number of patients treated with ANA and the different timing of administration of the two drugs hinder more robust analysis on the potential different effect of TOCI and ANA on patient survival, even if Cox multivariable regression seem to indicate a greater effect when using TOCI.