Re: ‘Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review and meta-analysis’ by Tleyjeh et al.

To the Editor

Tleyjeh and colleagues reported that tocilizumab reduces the risk of mechanical ventilation in hospitalized patients with coronavirus disease 2019 (COVID-19), with no definitive evidence of a reduction in short-term mortality or an increased risk of infection [1]. These are crucial findings which could alleviate pressures faced by critical care services around the world. The UK government has made tocilizumab and sarilumab widely available to patients with severe COVID-19 following a concerning surge in cases due to the emergence of a more transmissible lineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) named ‘variant of concern 202012/01’ (VOC) [2]. In the light of this, we would like to make further comment.

The proportion of spike protein mutations accumulated by VOCs without the detection of intermediary forms is much higher than expected from molecular clock estimates [3,4], initiating the exploration of potential evolutionary processes underlying the origin of this phenomenon. Recent data from the COVID-19 Genomics UK (COG) consortium show considerable within-host genetic diversity of SARS-CoV-2 due to de novo mutations in random samples of infected patients. Importantly, the number of within-host variants was found to increase with longer duration of infection [5]. Chronic SARS-CoV-2 infection (>100 days) has been described in immunocompromised patients and hypothesized as a possible origin for VOCs, where protracted infection combined with compromised immunity allows for continued viral replication and accumulation of genetic diversity, undetected by genomic epidemiological surveillance [3,6,7]. Studies have also reported within-host viral genetic diversity to be higher in severe COVID-19 than in mild disease [8]. If prolonged, severe infection can explain evolutionary leaps of SARS-CoV-2; this raises questions on the consequences for viral evolution of the widespread use of potent immunomodulatory therapy in severe COVID-19.

Critical illness in COVID-19 is believed to result from the development of a hyperinflammatory state on top of the unresolved viral infection [9]. In these patients, immunomodulation can improve clinical outcome, likely by ameliorating the excessive inflammatory response and subsequent tissue damage and lung injury. However, the impact of immunomodulation on the underlying virus remains largely unknown. IL-6 is a multifunctional cytokine which induces acute-phase protein production, stimulates the maturation of cytotoxic T cells, and modulates B-cell differentiation into antibody-producing plasma cells. Therefore, therapy directed against IL-6 function may dampen host antiviral responses and impair viral clearance [10]. Among the 24 studies included by Tleyjeh and colleagues, none has reported data on SARS-CoV-2 viral kinetics in relation to tocilizumab administration. Two trials set out to do so in their protocols [11,12] but did not present these endpoints in their published reports [13,14]. Emerging observational evidence suggests that tocilizumab use is associated with delayed viral clearance; however, this was driven by a higher initial viral load [10].

The implications of administering immunomodulatory therapy for SARS-CoV-2 viral kinetics are uncertain, but prolongation of viral clearance and benefit to viral genetic diversification remain possibilities. At a time when new selective pressures are being introduced with the rollout of vaccination programmes, these factors may accelerate SARS-CoV-2 evolution and pose new challenges for the risk–benefit assessment of using immunomodulation in patients with severe COVID-19 (Fig. 1 ). Robust data assessing the effect of immunomodulation on viral kinetics are urgently required. The vast majority of studies to date have focused on the incidence of secondary infections to determine tocilizumab safety, but have disregarded its effects on the infectious agent at the core of this disease. Future studies can no longer afford to ignore the impact on viral kinetics when evaluating immunosuppressive treatments for COVID-19.

Fig. 1.

Immunosuppression in patients with severe coronavirus disease 2019 (COVID-19): a balancing act.

Author contributions

DK wrote the first draft of the manuscript. DP and JB reviewed and amended the first and subsequent drafts. All authors approved the final manuscript for submission.

Transparency declaration

The authors declare no conflicts of interest. DP and JB are supported by the NIHR.

Editor: L. Leibovici