Is IL-6 the Right Target in COVID-19 Severe Pneumonia?

To the Editor:

We read with great interest the article by McElvaney and colleagues, “Characterization of the Inflammatory Response to Severe COVID-19 Illness,” published in the Journal (1). Systemic inflammation that characterizes acute respiratory distress syndrome (ARDS) in coronavirus disease (COVID-19) is associated with a high mortality rate (2). The term “cytokine storm” has emerged to explain the immunopathogenesis of most severe forms of COVID-19, because the release of many inflammatory cytokines (e.g., IL-6) was correlated with the disease severity (3). However, immune pathogenesis is still unsettled and comparisons with community-acquired pneumonia (CAP) from other origins are scarce. Interestingly, McElvaney and colleagues showed that COVID-19 cytokinemia is distinct, with circulating levels of IL-6 significantly higher in patients with COVID-19 than in those with non–COVID-19 severe CAP (1). These results are challenged by an editorial by Sinha and colleagues showing that plasma concentrations of IL-6 in patients with severe COVID-19 were lower than those observed in patients with ARDS from other origins (4). However, such comparisons are only possible if the respiratory severity is comparable between both groups.

We performed a prospective study that is part of the LYMPHONIE project (clinicaltrials.gov NCT03505281). We included non–immune-compromised patients with severe pneumonia (at least two criteria of the quick Sequential Organ Failure Assessment score and/or need for mechanical ventilation or vasopressors). Patients with COVID-19 all tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by RT-PCR. Plasma was collected within 48 hours of hospital admission and the concentration of IL-6 quantified using a Luminex assay (R&D Systems). Oral consent was obtained from the patient or their legal representatives. Approval was obtained from the ethics committee (Comité de Protection des Personnes Sud-MEDITERRANEE V) (2017-A03404-49).

Thirty-six patients without COVID-19 were enrolled between November 2018 and February 2020 (before the COVID-19 pandemic started in Burgundy, France) and 27 patients with COVID-19 in March and April 2020. Median age (interquartile range) was 67.5 (63–76.5) and 64 (57–71) in the non–COVID-19 and COVID-19 groups, respectively (P = 0.0559). ICU admission was needed for 32 (89%) and 27 (100%) patients of the non–COVID-19 and COVID-19 groups, respectively (P = 0.07). Pa_O2:Fi_O2 ratios were not different between groups (115.9 [74.6–157.9] vs. 145 [86–175.7] mm Hg, respectively; P = 0.3073). The IL-6 plasma concentrations were higher in the patients without COVID-19 than in those with COVID-19 (460.4 [138.2–4434.7] vs. 121 [75.7–236.6] pg/ml; P = 0.0003) (Figure 1).

Figure 1.

Box plot showing the plasma concentration of IL-6 within 48 hours of hospitalization in 36 patients with non–COVID-19 and 27 patients with COVID-19 severe pneumonia (LYMPHONIE study, 2018–2020). COVID-19 = coronavirus disease.

Here, we showed that despite similar respiratory severity, plasma concentrations of IL-6 were dramatically lower in severe forms of COVID-19 than in CAP from other origins. Thus, although immune modulation is a promising therapeutic avenue that is likely to improve outcomes for COVID-19, the most relevant target and strategy remain to be found.