key: cord-0781333-0tha9ljv
authors: Blot, Mathieu; Bourredjem, Abderrahmane; Binquet, Christine
title: Is IL-6 the Right Target in COVID-19 Severe Pneumonia?
date: 2021-01-01
journal: Am J Respir Crit Care Med
DOI: 10.1164/rccm.202007-2924le
sha: 06535749c0626923d5cc3e84ec7d7048c602a099
doc_id: 781333
cord_uid: 0tha9ljv

nan

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 (Figure 1) .

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. n Author disclosures are available with the text of this letter at www.atsjournals.org.

Characterization of the inflammatory response to severe COVID-19 illness

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

IL-6 may be a good biomarker for earlier detection of COVID-19 progression

Is a "cytokine storm" relevant to COVID-19?

To the Editor:We read with interest the recent article investigating coronavirus disease (COVID-19) inflammatory cytokine profiles by McElvaney and colleagues, in which, in critically ill patients requiring intensive care, circulatory IL-6 was elevated (1), as recent reports have indicated this cytokine as the strongest predictor of the need for mechanical ventilation (2) . However, we would like to raise a potential problem with the authors' interpretation of the results before discussing the application to IL-6-regulating medicines, as we think that it is not clear that IL-6 is a key molecule of severe inflammation like other proinflammatory cytokines, such as tumor necrosis factor and IL-1. There are several reports advocating both the proinflammatory and antiinflammatory potential of IL-6 against acute inflammatory responses, including acute respiratory distress syndrome and sepsis (3, 4) . Using genetically engineered animals (IL-6-deficient B6J129Sv mouse strain), we previously demonstrated that IL-6 serves as a protector in pulmonary hemorrhagic injury induced by bacterial endotoxins (LPS), at least partly through the regulation of proinflammatory cytokines and chemokines (5). However, in this study, interestingly, we also observed that IL-6 2/2 mice show devastating lung injury compared with littermate wild-type mice 3 days after intraperitoneal administration of LPS, whereas mortality at Day 7 was higher in wild-type than in IL-6 2/2 mice (repeated three times; K. Inoue and colleagues, unpublished data), suggesting that IL-6 can have opposite effects depending on the pathological phase of the host. We imagine that IL-6 has multiple roles in the inflammatory pathway, as proposed by Qiu and colleagues (6), although the role may differ according to animal species and strain and inflammation type. Indeed, we have confirmed that this cytokine is not valuable in acute oxidative lung injury induced by diesel exhaust particles in mice with the same genetic background as in the LPS experiments.Further research is needed to clarify the role of IL-6 in severe inflammatory conditions, including COVID-19-related conditions, and explore novel therapeutic options. n