Severe COVID-19 infection is associated with aberrant cytokine production by infected lung epithelial cells rather than by systemic immune dysfunction

The mechanisms explaining progression to severe COVID-19 remain poorly understood. It has been proposed that immune system dysregulation/over-stimulation may be implicated, but it is not clear how such processes would lead to respiratory failure. We performed comprehensive multiparameter immune monitoring in a tightly controlled cohort of 128 COVID-19 patients, and used the ratio of oxygen saturation to fraction of inspired oxygen (SpO2 / FiO2) as a physiologic measure of disease severity. Machine learning algorithms integrating 139 parameters identified IL-6 and CCL2 as two factors predictive of severe disease, consistent with the therapeutic benefit observed with anti-IL6-R antibody treatment. However, transcripts encoding these cytokines were not detected among circulating immune cells. Rather, in situ analysis of lung specimens using RNAscope and immunofluorescent staining revealed that elevated IL-6 and CCL2 were dominantly produced by infected lung type II pneumocytes. Severe disease was not associated with higher viral load, deficient antibody responses, or dysfunctional T cell responses. These results refine our understanding of severe COVID-19 pathophysiology, indicating that aberrant cytokine production by infected lung epithelial cells is a major driver of immunopathology. We propose that these factors cause local immune regulation towards the benefit of the virus.

COVIDOSE: Low-dose tocilizumab in the treatment of Covid-19

BackgroundInterleukin-6 (IL-6)-mediated hyperinflammation may contribute to the high mortality of coronavirus disease 2019 (Covid-19). Tocilizumab, an IL-6 receptor blocking monoclonal antibody, has been repurposed for Covid-19, but prospective trials and dose-finding studies in Covid-19 are lacking. MethodsWe conducted a phase 2 trial of low-dose tocilizumab in hospitalized adult patients with Covid-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) [≥] 40 mg/L who did not require mechanical ventilation. Dose cohorts were determined by a trial Operations Committee, stratified by CRP and epidemiologic risk factors. A range of doses from 40 to 200 mg (low-dose tocilizumab) was evaluated, with allowance for one repeat dose at 24-48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Outcomes were compared with retrospective controls with Covid-19. Correlative studies evaluating host antibody response were performed in parallel. FindingsA total of 32 patients received low-dose tocilizumab. This cohort had improved fever resolution (75{middle dot}0% vs. 34{middle dot}2%, p = 0{middle dot}001) and CRP decline (86{middle dot}2% vs. 14{middle dot}3%, p < 0{middle dot}001) in the 24-48 hours following drug administration, as compared to the retrospective controls (N=41). The probabilities of fever resolution or CRP decline did not appear to be dose-related (p=0{middle dot}80 and p=0{middle dot}10, respectively). Within the 28-day follow-up, 5 (15{middle dot}6%) patients died. For patients who recovered, median time to clinical recovery was 3 days (IQR, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (15{middle dot}6%) patients. Correlative biological studies demonstrated that tocilizumab-treated patients produced anti-SARS-CoV-2 antibodies comparable to controls. InterpretationLow-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with Covid-19. Results of this trial and its correlative biological studies provide rationale for a randomized, controlled trial of low-dose tocilizumab in Covid-19. FundingClinicalTrials.gov number NCT04331795. Study infrastructure was supported by NIH CTSA UL1 TR000430. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSMany patients with novel coronavirus disease 2019 (Covid-19) develop acute lung injury and hypoxic respiratory failure possibly due to a hyperinflammatory state similar to the cytokine release syndrome that occurs as a complication of chimeric antigen receptor T-cell therapy. Interleukin-6 (IL-6) has been implicated in both processes, leading to the hypothesis that patients with Covid-19 may benefit from IL-6 axis-directed therapies such as the IL-6 receptor-blocking monoclonal antibody tocilizumab. No dose-finding studies have been performed for tocilizumab in the setting of Covid-19. Added value of this studyThis prospective phase 2 clinical trial is, to our knowledge, the first to evaluate low-dose tocilizumab in patients with Covid-19 and the first to evaluate the effect of tocilizumab on anti-SARS-CoV-2 antibody response. Implications of all the available evidenceThe COVIDOSE study, together with retrospective and real-world evidence studies demonstrating the efficacy of tocilizumab, suggests that low-dose tocilizumab is a potential treatment for hyperinflammation among patients with Covid-19 and merits randomized, controlled testing in this patient population.