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 pO₂/FiO₂ 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.

Keywords: Anakinra; COVID-19; IL-1; IL-6; SARS-CoV-2; Tocilizumab.

Fig. 1

Flow-chart of the patients included in the study.

Fig. 2

Proposal of the therapeutic algorithm used in COVID-19 patients with moderate or severe pneumonia. COVID-19, coronavirus disease 2019; SpO2, oxygen saturation as measured by pulse oximetry in room air; SC, subcutaneously; d, day; IV, intravenously. *Since October 16, 2020, intravenous administration of remdesivir was available in Greece and since then it was given in both groups at the initial evaluation when disease duration was less than 10 days. ¹When more than 200 mg/d of Anakinra were used, as well as in obese patients or patients with oedema and critically ill patients the IV administration was preferred. ²Corticosteroids were not administered in the presence of lymphopenia (absolute number of lymphocytes <800/μL) at first evaluation or were stopped if lymphopenia was developing during management. ³Corticosteroids administration was also decided at physicians’ discretion according to other parameters of inflammation and severity such as, C-reactive protein ≥ 5 mg/dL, D-Dimers > 400 ng/mL, the extent of pulmonary infiltrates, SpO2 < 94% in room air and the presence of tachypnoea (breath rate >30/min). ⁴An additional second and/or third pulse therapy after at least 24-48 hours from the first dose was used according to the physicians’ discretion.

Fig. 3

The detailed combination therapies of patients in both treatment arms. 166 patients received corticosteroids (72 in Arm A and 94 in Arm B). Corticosteroids were discontinued permanently in 12 and transiently in 5 patients (Arm A) as well as, in 16 and 29 patients, respectively (Arm B). IVIG was administered in 135/169 (79.9%) of Arm B patients. Tocilizumab was given in 177 patients (Arm A, n=51; Arm B, n=126). Additional pulses (≥2) of tocilizumab were needed in 8 patients (Arm A) and 53 patients (Arm B). 77 patients received also remdesivir (31 in Arm A and 46 in Arm B).

Fig. 4

Kaplan-Meier analyses of efficacy outcomes. (A) Intubation: Analysis includes 18 events-intubations. Patients who died before intubation were excluded (n=4). (B) Mortality: Analysis includes 16 events-deaths in the total group of patients (n=311). Data from patients who were event-free at the end of follow-up were censored at 30 days (one death occurred at 58th day of hospitalization in ICU).

Fig. 5

Kaplan-Meier analyses of efficacy outcomes of “Larissa patients” and “Comparators”. (A) Intubation: Analysis includes 86 events-intubations in total. Patients who died before intubation were excluded (2 from “Larissa patients” and 7 from “Comparators”). (B) Mortality: Analysis includes 46 events-deaths in total. Data from patients who were event-free at the end of follow-up were censored at 30 days (one death occurred at 58th day of hospitalization in ICU).