Interleukin-6 (IL-6) is a pleiotropic 26-kDa cytokine involved in numerous signaling pathways during both homeostasis and disease. Notably, IL-6 is implicated in the initiation and regulation of the host inflammatory response to septic and non-septic aggressions. During disease, IL-6 mediates fever, loss of appetite, weight loss, and anemia, and constitutes the main inductor of acute-phase proteins synthesis, including C-reactive protein (CRP) (1). Additionally, and relevant to the specific context of critical illness, IL-6 has been implicated in the development of vascular hyperpermeability, myocardial depression, and activation of coagulation, and correlates with vasoplegia during septic shock (2–5). Plasma concentration of IL-6 is subject to wide variations, ranging from 0 to 7 pg/ml in healthy subjects up to concentrations higher than 1 μg/ml during septic shock (6). Given its key role in the genesis of pro-inflammatory processes, it is commonly accepted, especially in the field of autoimmune diseases and cancer, that plasma IL-6 concentration represents a better predictor of the activity of the disease than other inflammatory markers such as CRP (1).

The negative prognostic impact of high IL-6 concentration has been recently highlighted during the SARS-CoV-2 pandemic, as an independent predictor of the severity of and mortality due to the coronavirus disease 2019 (7). Previously, numerous studies have examined the prognostic role of IL-6 concentration on intensive care unit (ICU) admission during sepsis, almost constantly finding a negative impact of high concentrations on survival (8). However, very little research has focused on other critically ill populations. These works, mainly small-sized and focused on acute heart failure, nevertheless seem to find a similar prognostic impact. Interestingly, high IL-6 concentrations in these non-septic patients appeared to be associated with the onset of vasoplegic shock, systemic hypoperfusion, and multiple organ failure (9–11). Conversely, the prognostic value of CRP, although routinely used as a marker of systemic inflammation, has been poorly investigated so far. A synthesis of the work carried out finds no prognostic interest of early CRP measurement in the ICU (12). However, these studies are heterogenous and most are limited to septic patients. Additionally, side-by-side comparison of CRP and IL-6 for prognostication has seldom been performed, although such analysis might have practical implications now that fast and relatively inexpensive IL-6 assays are broadly available.

Thus, it remains unclear whether high IL-6 concentration is associated with worse prognosis in the general population of critically ill patients, admitted for a wide range of septic and non-septic diagnoses and whether IL-6 yields a superior value than CRP in assessing prognosis.

In the present study, we aimed at assessing the association between IL-6 or CRP concentration and survival, the development of organ dysfunction, and the need for organ support among patients included in a large multicentric cohort of ICU patients.

Our study shows that in a general population of critically ill patients, high IL-6 and CRP concentrations associate with organ dysfunction, need for organ-support therapies, and worse 90-day survival. However, IL-6 seems to outperform CRP for patient prognostication. In addition, high IL-6, regardless of CRP value, associates with hemodynamic dysfunction characterized by reduced systolic and diastolic arterial pressure, coagulopathy, and hepatic and renal dysfunction. Finally, in reclassification analysis, IL-6 is associated with the greatest improvement of the prediction ability of SAPS-II or SOFA. Altogether, our results suggest that IL-6 should be preferred over CRP for the evaluation of critically patients’ outcomes.

Our study has several strengths. To date, this is the largest study to investigate the prognosis value of IL-6 in critically ill patients. Additionally, as our cohort is composed of a broad range of ICU admission diagnoses, our findings are not limited to septic patients and could be relevant to all critically ill patients. Lastly, few studies compared the prognostic value of IL-6 and CRP. In this regard, we showed a clear advantage of IL-6 over CRP.

Our conclusions join previous work that explored the prognostic interest of IL-6 in critically ill septic patients and confirm that IL-6 measurement is also interesting in non-septic patients. On a physiological perspective, it is noticeable that high IL-6 concentration associates with reduced diastolic arterial pressure, suggesting vasoplegia. This observation is of particular impact in the sub-group of non-septic patients and joins previous observations (9). Thus, vasoplegia, coagulopathy, and renal and hepatic dysfunctions are all mechanisms that could explain why the magnitude of the non-septic systemic inflammatory reaction as evaluated by IL-6 is associated with worse prognosis in these patients. This finding strengthens the interest of IL-6 measurement in this population. Further, very few studies have compared the prognostic impact of measuring IL-6 and CRP. In this perspective, our work strongly suggests that measuring IL-6 is preferable. Additionally, the combined analysis of the two biomarkers seems to show that the addition of CRP provides little benefit as compared to IL-6 alone. Interestingly, the impact of IL-6 on survival seems to be proportional to IL-6 concentration as demonstrated by a log-linear relationship, while the relationship between CRP and mortality seems to rapidly reach a plateau. This result illustrates that elevated CRP is associated with a worse outcome, but the magnitude of elevation is poorly informative.

It may seem surprising that CRP and IL-6 do not provide similar prognostic information given that IL-6 is the main inductor of CRP synthesis. Several factors may account for such discrepancy, including the participation of IL-1β and TNFα to CRP induction (18, 19), the role of liver function (20, 21), polymorphisms at the IL-6 receptor or CRP locus (22, 23), as well as the different kinetics of these two biomarkers. Additionally, CRP has been shown to exert regulatory activities such as the counteraction of circulating histone toxicity. Circulating histones are well-known damage-associated molecular patterns associated with IL-6 release, especially in the critical illness context (24, 25). Therefore, it can be hypothesized that the extent of IL-6 release might be directly related to the initial insult, while CRP elevation for a given IL-6 stimulus could also reflect a protective response. More generally, our work meets the fields of clinical immunology and oncology in the assumption that disease activity is best reflected by IL-6 rather than CRP (1).

Our work also has several limitations. We used data and biological samples from a previous study with different objectives. The biological samples were expected to be taken within 24 h after ICU admission. Thus, concentrations obtained after a few hours of delay may be lower than those obtained immediately after admission considering the short half-life of IL-6; this may have influenced our results. Concentrations were consequently higher than the basal level. It is interesting to note, from a real-world perspective, that even a few hours of delay retains prognostic interest.

Additionally, this instantaneous capture of the dynamic course of different conditions is susceptible to influence the respective prognostic value of each biomarker. Thus, for some conditions (e.g., sepsis), the time between disease onset and hospital admission can be substantial. In such situation, peak IL-6 has often already passed while CRP is still rising. In other situations where the delay from disease onset is short, admission captures biomarkers at a time when IL-6 peaks and CRP is just growing. This is susceptible to introducing some disease-specific heterogeneities in the predictive value of the biomarkers. As an example, the lack of performance of IL-6 to predict the need for organ support in the septic population could reflect these differences in time from disease onset.

Furthermore, the main admission category was identified by the local FROG-ICU investigator as the main reason leading to ICU admission according to a predefined list. Therefore, patients with organ dysfunction(s) primarily caused by infection were classified into the sepsis/septic shock category, but it cannot be formally excluded that some patients classified into other admission categories could have presented, in addition to their non-septic primary disease, a mild infection influencing IL-6 and/or CRP concentration and thus, the results of our analysis.

Finally, CRP or IL-6 only reflects one limited aspect (essentially pro-inflammatory) of the host immune response to aggression. As the clinical situation likely results from the complex balance between several immune factors, it is likely that it would be even more interesting to focus on a combination of pro- and anti-inflammatory biomarkers to assess prognosis (8). Nevertheless, as other immune markers are rarely available in a routine fashion, such strategy might be more difficult to implement in clinical practice.

Future work should focus on the best timing and cutoff of IL-6 to assess the prognosis of critically ill patients. The usefulness of monitoring systemic inflammation with serial IL-6 measurement throughout ICU and hospital stay deserves further studies. Additionally, the potential interest of associating the value of IL-6 with clinical prognostic scores at the bedside to determine the prognosis and possibly the patient’s orientation, as suggested by our reclassification analyses, should be considered. Lastly, our work suggests the potential role of IL-6, rather than CRP, as an enrichment biomarker for therapeutic trials of interventions aimed at taming inflammation.

In a large prospective cohort of critically ill patients including both septic and non-septic patients, we showed that IL-6, rather than CRP, associates with organ dysfunction, need for organ support, and worse 90-day survival. Overall, IL-6 should be preferred over CRP to evaluate critically ill patients’ prognoses and possibly to guide potential therapeutic interventions aimed at taming inflammation.

N Deye, C Fauvaux, A Mebazaa, C Damoisel, D Payen, Hopital Lariboisiere (Paris); E Azoulay, AS Moreau, L Jacob, O Marie, Hopital Saint Louis (Paris); M Wolf, R Sonneville, R Bronchard, Hopital Bichat (Paris); I Rennuit, C Paugam, Hopital Beaujon (Clichy); JP Mira, A Cariou, A Tesnieres, Hopital Cochin (Paris); N Dufour, N Anguel, L Guerin, J Duranteau, C Ract, Hopital Bicetre (Le Kremlin-Bicetre); M Leone, B Pastene, Chu De Marseille (Marseille); T Sharshar, A Fayssoyl, Hopital Raymond Poincare (Garches); J-L Baudel, B Guidet, Hopital Saint-Antoine; Q Lu, W Jie Gu, N Brechot, A Combes, Hopital De La Pitie—Salpetriere (Paris); S Jaber, A Pradel, Y Coisel, M Conseil, Chu St Eloi (Montpellier); A Veillard Baron, L Bodson, Hopital Ambroise Pare (Boulogne); Jy Lefrant, L Elotmani, A Ayral, S Lloret, Chu Caremeau (Nimes); S Pily-Flouri, Jb Pretalli, Hopital Jean Minjoz (Besançon); Pf Laterre, V Montiel, Mf Dujardin, C Berghe, Clinique Saint-Luc (Belgium)

All data analyzed in this report are available upon reasonable request to the corresponding author. Requests to access these datasets should be directed to etienne.gayat@aphp.fr.

The studies involving human participants were reviewed and approved by Comité de Protection des Personnes—Ile de France IV, IRB n°00003835 Commission d’éthique biomédicale hospitalo-facultaire de l’hôpital de Louvain, IRB n°B403201213352. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

All the authors listed meet the authorship criteria. AP, LM, AM, and BC designed the study and contributed to data analysis and interpretation and drafting of the manuscript. CR, MS, EG, BD, and GC critically reviewed the analysis and made substantial contribution to the manuscript. All authors reviewed the manuscript and approved the final version.

This study received funding from the Programme Hospitalier de la Recherche Clinique (AON 10-216) and by a research grant from the Société Française d’Anesthésie—Réanimation. Abbott, Sphingotec, Roche Diagnostics, and Critical Diagnostics provided unrestricted free kits to Assistance Publique—Hôpitaux de Paris to conduct biomarker analyses. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication

BC was a member of an advisory board for Roche diagnostic. BD and GC are employees of Momentum Research and who received research grants from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Roche Diagnostics, Sanofi, Sulfagenix, Windtree Therapeutics Inc., and XyloCor Therapeutics Inc. CR received a research grant from Zoll Foundation. AM received speaker’s honoraria from Abbott, Novartis, Orion, Roche, and Servier, and fees as a member of the advisory board and/or steering committee from Cardiorentis, Adrenomed, MyCartis, Neurotronik, and Sphingotec. EG received a research grant from Sphingotec, and consultancy fees from Magnisense and Roche Diagnostics.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.