Lessons from pathophysiology: Use of individualized combination treatments with immune interventional agents to tackle severe respiratory failure in patients with COVID-19

Abstract

Aims: Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may lead to the development of severe respiratory failure. In hospitalized-patients, prompt interruption of the virus-driven inflammatory process by using combination treatments seems theoretically of outmost importance. Our aim was to investigate the hypothesis of multifaceted management of these patients. Methods: A treatment algorithm based on ferritin was applied in 311 patients (67.2% males; median age 63-years; moderate disease, n=101; severe, n=210). Patients with ferritin <500ng/ml received anakinra 2-4mg/kg/day ± corticosteroids (Arm A, n=142) while those with ≥500ng/ml received anakinra 5-8mg/kg/day with corticosteroids and γ-globulins (Arm B, n=169). In case of no improvement a single dose of tocilizumab (8mg/kg; maximum 800mg) was administered with the potential of additional second and/or third pulses. Treatment endpoints were the rate of the development of respiratory failure necessitating intubation and the SARS-CoV-2-related mortality. The proposed algorithm was also validated in matched hospitalized-patients treated with standard-of-care during the same period. Results: In overall, intubation and mortality rates were 5.8% and 5.1% (0% in moderate; 8.6% and 7.6% in severe). Low baseline pO 2 /FiO 2 and older age were independent risk factors. Comparators had significantly higher intubation (HR=7.4; 95%CI: 4.1-13.4; p<0.001) and death rates (HR=4.5, 95%CI: 2.1-9.4, p<0.001). Significant adverse events were rare, including severe secondary infections in only 7/311 (2.3%). Conclusions: Early administration of personalized combinations of immunomodulatory agents may be life-saving in hospitalized-patients with COVID-19. An immediate intervention (the sooner the better) could be helpful to avoid development of full-blown acute respiratory distress syndrome and improve survival.

Calprotectin and inflammation-associated serum biomarkers determine critical illness in COVID-19

“…A recent paper reported that elevated plasma levels of IL-6, IL-10 and IP-10 anticipated clinical progression of COVID-19 patients 28 . Our results are in line with the positive treatment outcomes with IL-6 receptor antagonists and with anakinra (the recombinant non-glycosylated form of IL-1ra) because they have showed the need to attenuate the exaggerated IL-6 responses and to enhance the weakened IL-1ra responses 29 . Tocilizumab and sarilumab were shown to decrease the number of days under organ dysfunction and 28-day mortality in the platform adaptive trials REMAP-CAP 30 and RECOVERY 31, respectively.…”

Interleukin-6 inhibitors reduce mortality in coronavirus disease-2019: An individual patient data meta-analysis from randomized controlled trials

“…Not only the included studies, but also other non-RCTs studies came to different results regarding the benefit of IL-6 inhibitors in COVID-19 patients. In a prospective open-label observational study from our department, the use of IL-1 and IL-6 inhibitors showed a reduction in both intubation and mortality rates [28] . On the other hand, there are many observational studies, whose results did not reveal any clinical improvement by using IL-6 inhibitors in COVID-19 patients [ 29 , 30 ].…”

Efficacy of Anakinra in the Management of Patients with COVID-19 Infection: A Randomized Clinical Trial

“…(www.clinicaltrials.gov, NCT04680949) [27] . Similarly, another non-randomized study, where ferritin was used as a biomarker to guide therapy, showed significantly improved clinical outcomes, including reduced mortality rates and progression to severe COVID-19 by early administration of therapy either with anakinra alone or in combination with steroids [30] .…”