Respiratory Impairment Predicts Response to IL-1 and IL-6 Blockade in COVID-19 Patients With Severe Pneumonia and Hyper-Inflammation

Della-Torre, Emanuel; Lanzillotta, Marco; Campochiaro, Corrado; Cavalli, Giulio; De Luca, Giacomo; Tomelleri, Alessandro; Boffini, Nicola; De Lorenzo, Rebecca; Ruggeri, Annalisa; Rovere-Querini, Patrizia; Castagna, Antonella; Landoni, Giovanni; Tresoldi, Moreno; Ciceri, Fabio; Zangrillo, Alberto; Dagna, Lorenzo

BACKGROUND: Restraining maladaptive inflammation is considered a rationale strategy to treat severe coronavirus disease-19 (COVID-19) but available studies with selective inhibitors of pro-inflammatory cytokines have not provided unequivocal evidence of survival advantage. Late administration is commonly regarded as a major cause of treatment failure but the optimal timing for anti-cytokine therapy initiation in COVID-19 patients has never been clearly established. OBJECTIVES: To identify a window of therapeutic opportunity for maximizing the efficacy of interleukin (IL)-1 and IL-6 blockade in COVID-19. METHODS: Survival at the longest available follow-up was assessed in severe hyper-inflamed COVID-19 patients treated with anakinra, tocilizumab, sarilumab, or standard of care, stratified according to respiratory impairment at the time of treatment initiation. RESULTS: 107 patients treated with biologics and 103 contemporary patients treated with standard of care were studied. After a median of 106 days of follow-up (range 3-186), treatment with biologics was associated with a significantly higher survival rate compared to standard therapy when initiated in patients with a PaO(2)/FiO(2) ≥ 100 mmHg (p < 0.001). Anakinra reduced mortality also in patients with PaO(2)/FiO(2) < 100 mmHg (p = 0.04). CONCLUSIONS: IL-1 and IL-6 blocking therapies are more likely to provide survival advantage in hyper-inflamed COVID-19 patients when initiated before the establishment of severe respiratory failure.