Of note, non-response to IL-1 and IL-6 blocking therapies has been commonly attributed to late administration of these agents at advanced disease stage but the optimal timing of anti-inflammatory treatment initiation in COVID-19 has never been clearly established.ĭuring the first COVID-19 surge that stroke Lombardy region (Italy) in the spring of 2020, our Institute hospitalized 954 patients and rapidly set in place contemporary open label observational studies of anakinra, sarilumab and tocilizumab to treat severe hyper-inflamed COVID-19 patients fulfilling common sets of inclusion criteria ( 3, 4, 9, 10, 13, 14). Similarly, recently published controlled investigations with anakinra also returned an overall unclear survival benefit compared to supportive therapies ( 10– 12). ![]() Yet, despite great expectations and encouraging outcomes from preliminary observational cohorts, tocilizumab and sarilumab lately failed to demonstrate an impact on disease mortality in open-label and randomized clinical trials ( 3– 8). Tocilizumab and sarilumab, on the other hand, are humanized monoclonal antibodies that block IL-6-mediated signal transduction by targeting both the membrane and soluble forms of the IL-6 receptor ( 3). In particular, anakinra is a recombinant replica of the IL-1 receptor antagonist that binds to soluble IL-1α and IL-1β preventing their pro-inflammatory activity ( 10). This hyper-inflammatory response resembles the “cytokine storm” observed during macrophage-activation syndrome and is characterized by excessive release of pro-inflammatory cytokines including interleukin (IL)-1, IL-6, tumor necrosis factor, and granulocyte–macrophage colony stimulating factor, among others ( 1, 2).īased on this hyper-inflammatory pathogenic background, targeting upstream molecules in the inflammatory cascade such as IL-1 and IL-6 soon appeared as a promising therapeutic strategy to contrast the progression of severe COVID-19, and high hopes were placed on the IL-1 and IL-6 blocking agents anakinra, tocilizumab, and sarilumab ( 3– 10). Life-threatening coronavirus disease-19 (COVID-19) is sustained by a maladaptive inflammatory response induced by the Severe Acute Respiratory Syndrome Coronavirus 2 (Sars-CoV-2) ( 1, 2). Anakinra reduced mortality also in patients with PaO 2/FiO 2 < 100 mmHg (p = 0.04).Ĭonclusions: 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. ![]() 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). Results: 107 patients treated with biologics and 103 contemporary patients treated with standard of care were studied. 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. Objectives: To identify a window of therapeutic opportunity for maximizing the efficacy of interleukin (IL)-1 and IL-6 blockade in COVID-19. 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.
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