Tocilizumab for the treatment of COVID-19

Abstract

It has been one year since the first cases of pneumonia caused by the now designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were reported from Wuhan. Over these past months, clinicians taking care of patients with coronavirus disease 2019 (COVID-19) have learned that the exuberant inflammatory response triggered by the virus acts as a major contributor to the pathogenesis of acute respiratory distress syndrome (ARDS) and multiorgan failure, which occur in most of the fatal cases [1]. In the absence of antiviral drugs that clearly modify the clinical course of the infection, immunomodulation has emerged as the most promising therapeutic approach to COVID-19. The administration of low-to-intermediate-dose corticosteroids (dexamethasone 6 mg daily, equivalent to prednisone 40 mg, for 10 days) is the only treatment to date that have been proven, in the setting of a randomized controlled trial (RCT), to reduce the mortality among patients requiring respiratory support [2]. The early finding that interleukin-6 (IL-6) levels are elevated in severe COVID-19 and independently predict the risk of progression to ARDS and death focused clinical research efforts on this proinflammatory and pleiotropic cytokine [3,4]. Existing experience with tocilizumab – a humanized IgG1 monoclonal antibody targeting the IL-6-receptor – for the treatment of the cytokine release syndrome (CRS) in patients receiving chimeric antigen receptor (CAR) T-cell therapy rapidly paved the way for its offlabel use in cases of severe COVID-19 since the first weeks of the pandemic [5–7]. Nevertheless, accumulating evidence suggests that the term ‘cytokine storm’ may be misleading to define the hyper-inflammatory status observed in SARS-CoV-2 infection, since IL-6 levels are actually at least one magnitude order lower than those found in patients with CAR-T-therapy-associated CRS, sepsis, or other causes of ARDS [8]. The desperate need to find an effective therapy to improve the dismal prognosis of severe COVID-19 pneumonia and the well established and acceptable safety profile of tocilizumab led to its widespread use during the first pandemic wave. Indeed, 9.4% of the patients hospitalized through March 17 in a large multicenter registry in Spain received tocilizumab [9], and as many as 17.1% of those admitted to the intensive care unit until April in the US 4 [10]. It should be noted that the supporting evidence was essentially limited during spring and summer of 2020 to small, observational, case series with no control group [5–7]. Now, when the results of RCTs and controlled observational studies have become available, the time has come to critically review the role of tocilizumab in the management of COVID-19. Various large observational studies have reported marked reductions in the requirement of invasive mechanical ventilation (IMV) or all-cause mortality among COVID-19 patients treated with tocilizumab as compared to the standard of care alone. In a cohort study carried out in three Italian centers (n = 544 patients), Guaraldi et al. found that tocilizumab therapy reduced the risk of death (7.3% versus 20.0%, respectively), although no differences were observed in the progression to IMV (18.4% versus 15.6%). After adjustment for clinical covariates (including duration of symptoms and SOFA score), tocilizumab was associated with a significant reduction in this composite outcome (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.40–0.92) [11]. The SAM-COVID-19 study, that included 778 patients from 60 Spanish centers, reported a 68% decrease after the inverse probability of treatment weight (IPTW) adjustment in the risk of IMV or death for tocilizumab (HR: 0.32; 95% CI: 0.22–0.47) [12]. In the largest observational study published to date (STOP-COVID), Gupta et al. compared 433 critically ill patients that received tocilizumab within the first 2 days from ICU admission and 3,491 patients that did not receive this IL-6 blocker. After a median follow-up of 27 days, the risk of death among patients treated with tocilizumab had decreased by one-third (HR: 0.71; 95% CI. 0.56–0.92). This benefit was more evident in the subgroup with a partial pressure of arterial oxygen/fraction of inspired oxygen ratio (PaO2/FiO2) <200 and mechanically ventilated at ICU admission, and was not modified by the receipt of corticosteroid therapy [13]. A recently published single-center study also found that tocilizumab therapy improved the alveolar-arterial oxygen and the pulmonary vascular radiologic score (although the lung parenchymal score remained unchanged), favoring the early recovery of pulmonary vascular function [14]. Five RCTs evaluating the efficacy and safety of tocilizumab as immunomodulatory therapy for COVID-19 have been published to date [15–19] (Table 1). All the studies were multicenter and three of them were controlled with placebo [15,16,19]. The number of participants ranged from 126 to 438. Although inclusion criteria varied, all the patients had a molecular or serological (IgM assay) diagnosis of SARS-CoV