The association between interleukin-6 inhibitors as treatment for COVID-19 and mental health problems in ICU survivors

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Van Gelder, Arief Lalmohamed, Toine C.G. Egberts, Arjen J.C. Slooter, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6571420/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective: To assess whether exposure to interleukin-6 (IL-6) inhibitors as treatment for critically ill COVID-19 patients is associated with a lower prevalence of mental health problems one year after ICU admission. Design: Retrospective cohort study using prospectively collected outcome data. Setting: Two university medical centers in the Netherlands: University Medical Center Utrecht (UMCU) and Radboud University Medical Center (Radboudumc). Patients: Adult ICU survivors admitted to the ICU for COVID-19 from September 1, 2020, to March 31, 2022, with available one-year follow-up data. Exposure: IL-6 inhibitors (tocilizumab or sarilumab) as treatment for COVID-19. Measurements and Main Results: Mental health problems were assessed using the Impact of Event Scale (IES-6 or IES-R) for post-traumatic stress disorder (PTSD) and the Hospital Anxiety and Depression Scale (HADS) for anxiety and depression. The primary outcome was a composite of PTSD, anxiety, and/or depression symptoms one year after ICU admission. Among 170 patients included in the primary analysis (119 exposed to IL-6 inhibitors, 51 unexposed), IL-6 inhibitor exposure was associated with a lower prevalence of mental health problems (adjusted odds ratio (aOR) 0.46, 95% confidence interval (CI) 0.22–0.93) and PTSD symptoms alone (aOR 0.45, 95% CI 0.20–0.97). No significant associations were found for anxiety (aOR 0.77, 95% CI 0.34–1.72) or depression (aOR 0.71, 95% CI 0.33–1.50) symptoms alone. Conclusions: Exposure to IL-6 inhibitors as treatment for critically ill COVID-19 patients was associated with a lower prevalence of mental health problems, primarily driven by a lower prevalence of PTSD symptoms, one year after ICU admission. These findings suggest a potential role for cytokine-targeted therapies in mitigating long-term mental health problems in ICU survivors, but further research is needed to establish causality. COVID-19 Interleukin-6 Inhibitors Critical Illness Intensive Care Unit Survivors Long-Term Outcomes Figures Figure 1 Figure 2 Figure 3 Key points Question: Does treatment with interleukin-6 (IL-6) inhibitors during ICU admission for COVID-19 reduce the prevalence of mental health problems one year later? Findings: In this multicenter cohort study of 170 COVID-19 ICU survivors, IL-6 inhibitor exposure was associated with a significantly lower prevalence of PTSD and of the composite outcome of PTSD, anxiety, or depression symptoms one year after ICU admission. Meaning: These findings suggest that IL-6 inhibition during critical illness may help mitigate long-term psychological burden in ICU survivors. 1. Introduction Survivors of intensive care unit (ICU) admissions face a high risk of developing long-term mental health problems, including symptoms of post-traumatic stress disorder (PTSD), anxiety, and depression, with prevalences reaching 17%, 34%, and 29%, respectively. [ 1 – 3 ] Various interventions, including ICU diaries, psychological support and early rehabilitation, have been explored to mitigate these outcomes. [ 4 – 6 ] However, the potential of pharmacological interventions during ICU admission to prevent such long-term mental health problems in ICU survivors is underexplored. Emerging evidence highlights the role of the immune system, particularly inflammatory processes, in the development of psychiatric disorders such as major depression. [ 7 – 10 ] Elevated levels of interleukin-6 (IL-6), a pro-inflammatory cytokine, have been consistently observed in patients with major depressive disorder, and longitudinal studies indicate that higher IL-6 levels can predict the later development of depression. [ 11 – 15 ] This evidence has led to the proposal of targeting cytokines such as IL-6 as potential therapeutic strategies for psychiatric conditions. [ 16 ] Trials have already begun exploring this immunomodulating approach, with a recent randomized controlled trial showing that infliximab, a tumor necrosis factor inhibitor, can improve depressive symptoms in patients with treatment-resistant depression and high baseline inflammatory biomarkers. [ 17 ] Additionally, a study assessing whether IL-6 inhibitors can effectively reduce depressive symptoms in individuals with low-grade inflammation, is recruiting patients. [ 18 ] Amid the COVID-19 pandemic, the IL-6 inhibitors tocilizumab and sarilumab were incorporated into treatment protocols for severe cases, following evidence from the REMAP-CAP and RECOVERY trials that demonstrated their efficacy in improving survival, increasing organ support–free days, and enhancing other clinical outcomes. [ 19 – 21 ] The widespread use of these agents in critically ill COVID-19 patients presents a unique opportunity to investigate whether IL-6 inhibition might mitigate the development of post-ICU mental health problems, which are also present in COVID-19 ICU survivors. [ 22 ] Indeed, targeting IL-6 for the treatment of long-term effects of COVID-19 has been suggested, and one observational study has shown a protective effect of anticytokine agents against depressive symptoms in COVID-19 survivors. [ 23 , 24 ] This study aimed to assess whether exposure to IL-6 inhibitors as treatment for critically ill COVID-19 patients is associated with a lower prevalence of mental health problems one year after ICU admission. 2. Methods 2.1 Study design and setting This study was conducted as a collaboration between two university medical centers in the Netherlands: the University Medical Center Utrecht (UMCU), with a 32-bed mixed ICU and the Radboud University Medical Center (Radboudumc) in Nijmegen, with a 26-bed mixed ICU. Both centers conduct ongoing prospective follow-up studies of ICU survivors, each approved by their respective medical research ethics committees (protocol 10/006 for the UMCU study, protocol 2016–2724 for the Radboudumc study). 2.2 Study population The UMCU follow-up cohort of ICU survivors was initiated in 2011 and includes all adult ICU patients admitted for at least 48 hours, who are still alive one year after ICU admission. [ 25 ] The Radboudumc follow-up cohort of ICU survivors is part of the larger MONITOR-IC study, which started in 2016 and includes all ICU patients of 16 years or older, who are admitted for at least 12 hours. [ 26 ] In the current study, ICU patients were included who were admitted with COVID-19 as primary diagnosis from September 1, 2020 to March 31, 2022, and alive one year after ICU admission with follow-up data available. COVID-19 diagnosis was confirmed through a positive SARS-CoV-2 PCR test on a nasopharyngeal swab or tracheal aspirate. If a patient was readmitted to the ICU during the same hospital admission, only clinical data from the initial ICU admission were used in the analysis. Patients admitted to the ICU during the first COVID-19 wave (March to September 2020) were not included. First, none of the patients in the first wave were exposed to IL-6 inhibitors. Second, this period was characterized by significant uncertainty, limited treatment options and visiting and isolation restrictions, leading to potentially different patient outcomes compared to later waves with more established treatment protocols. 2.3 Exposure to interleukin-6 inhibitors Exposure to IL-6 inhibitors was assessed for all included patients. Patients were considered exposed if they received IL-6 inhibitors tocilizumab or sarilumab at any point during their ICU stay or within the 5 days preceding ICU admission. If a patient was transferred from a different ICU, records were reviewed to determine whether an IL-6 inhibitor had been administered at the hospital of initial ICU admission. Patients who did not receive an IL-6 inhibitor were considered unexposed. The typical dose regimen of IL-6 inhibitors evolved over the study period due to medication shortages, shifting from a weight-based dose of up to 8 mg/kg (maximum 800 mg) to a fixed dose of 400 mg, which has shown equivalent effectiveness in treating COVID-19. [ 27 ] Because these dosing regimens were standardized and considered equivalent in efficacy, dose was not accounted for in the exposure definition. IL-6 inhibitor treatment for severe COVID-19 began in early 2021 in Dutch ICUs, following the guidelines of the Dutch Working Party on Antibiotic Policy (SWAB). The first recommendation, published on January 21, 2021, included a provisional suggestion to use tocilizumab in ICU patients, pending more data. [ 28 ] By March 2021, the advice was updated, recommending tocilizumab based on the RECOVERY trial criteria, which included patients with hypoxia (oxygen saturation < 92% or requiring oxygen therapy) and systemic inflammation (CRP ≥ 75 mg/L). [ 21 , 29 ] Sarilumab was later added as an alternative IL-6 inhibitor in October 2021. [ 30 ] Treatment with IL-6 inhibitors was first included in the World Health Organization’s living guideline “Therapeutics and COVID-19” in the July 6, 2021 edition. [ 31 ] 2.4 Outcome measurements One year after ICU admission, patients were assessed for mental health problems using validated and recommended questionnaires. [ 32 ] For PTSD, two versions of the Impact of Event Scale (IES) were employed depending on the cohort: the UMCU follow-up cohort utilized the revised IES (IES-R), which contains 22 questions, while the Radboudumc cohort used the IES-6, a 6-item version. [ 33 , 34 ] Both versions calculate a mean score by averaging the responses, with established cutoffs to identify PTSD symptoms—1.75 for the IES-6 and 1.6 for the IES-R. [ 35 , 36 ] For anxiety and depression, both centers used the Hospital Anxiety and Depression Scale (HADS), which comprises two subscales of 7 items each, scored on a 4-point Likert scale (0–3), giving a minimum of 0 and a maximum score of 21 on each subscale. A score of 8 or higher delineated borderline abnormal symptoms for either condition; for consistency, these will be referred to as 'symptoms' throughout this study. [ 37 ] The primary outcome was defined as a composite score: if a patient's score on any mental health questionnaire (IES or HADS) exceeded the respective cutoff, the patient was classified as having mental health problems. Secondary outcomes were the individual outcomes for PTSD, anxiety, and depression. Additionally, mental health problems were assessed at three months after ICU admission for patients in the Radboudumc cohort, using the same questionnaires and cut-off values. 2.5 Potential confounders and effect modifiers From the literature on post-ICU mental health problems, age, sex, BMI, pre-ICU mental health problems, ICU length of stay, APACHE IV score, daily Sequential Organ Failure Assessment (SOFA) scores, mechanical ventilation, sedative agent (propofol or midazolam), delirium during ICU stay and glucocorticoid use were identified as potential confounders. [ 38 – 40 ] Correlations between all identified potential confounders were assessed using Pearson, point-biserial, and Phi coefficients. Covariables with a correlation coefficient exceeding ± 0.7 were considered highly correlated, and only one was included in the model to minimize collinearity. ICU length of stay, mechanical ventilation, propofol sedation and midazolam sedation showed high correlation, and mechanical ventilation was retained in the model as it was considered least influenced by external factors. Pre-ICU mental health problems were classified as being present or not, and were based on available proxy indicators. For the UMCU follow-up cohort, baseline HADS scores were not available; instead, the use of psychiatric medications (antidepressants, antipsychotics, or anxiolytics) prior to ICU admission was used to indicate the presence of pre-ICU mental health problems. A detailed list of the medications considered for this classification is provided in Table S1 of the Supplementary material. For the Radboudumc cohort, pre-ICU mental health problems were determined using HADS scores measured at ICU admission, with scores above the cutoff indicating presence. The maximum daily SOFA score for each organ system was summed to calculate a total SOFA score for each ICU admission day. If the central nervous system (CNS) component of the SOFA score was not assessable due to sedation, the last CNS score recorded was carried forward. If no prior CNS score was available before sedation, a score of 0 was imputed (corresponding to a Glasgow Coma Scale score of 15). A delta SOFA score was calculated as the difference between the SOFA score on the first day of ICU admission and the SOFA score on the fourth ICU day (or the final ICU day if the length of stay was shorter) as a proxy for the progression of disease severity after ICU admission. This approach has demonstrated high predictive performance in ICU outcome models. [ 41 ] The SOFA score on day 1 and the delta SOFA score were included as covariables in the primary analysis. Delirium was measured by the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) in the UMCU cohort and by the Intensive Care Delirium Screening Checklist (ICDSC) in the Radboudumc cohort. [ 42 , 43 ] Based on the study by Raison et al. (2013), which found that anticytokine treatment was effective against major depressive disorder only in patients with a high baseline CRP level, CRP data was collected. For the current study, ‘baseline’ CRP was defined as the CRP measurement on the day of IL-6 inhibitor infusion for exposed patients, and on the day of ICU admission for non-exposed patients. Baseline CRP was unavailable for patients transferred from another ICU and for patients who received the IL-6 inhibitor on the ward instead of the ICU. 2.6 Data analysis Logistic regression analysis was performed with the composite outcome of symptoms of PTSD, anxiety and/or depression as the dependent variable, and IL-6 inhibitor exposure as the primary independent variable. Given the anticipated low number of events relative to the number of covariables, propensity scores were estimated to adjust for potential confounding, incorporating the selected potential confounders. If data on any outcome measurement was missing, the patient was excluded from the primary analysis. However, if answers to individual questionnaire items were missing, but the cutoff for symptoms was already met or could no longer be reached, the patient was retained in the dataset, a method successfully applied in previous research. [ 44 ] Missing data for covariables were imputed using the mean or median for continuous variables and the mode for categorical variables. To explore potential variations in treatment effects between treatment centers, stratified analyses were performed for the UMCU and Radboudumc cohorts separately. Furthermore, to investigate the hypothesis that anticytokine treatment is only effective in patients with high baseline CRP levels, patients were stratified into two groups based on baseline CRP: a baseline CRP below 75 mg/L and a baseline CRP of 75 mg/L or higher. As 75 mg/L was used as a criterion for initiating IL-6 inhibitor treatment in COVID-19 patients, this threshold was chosen as the cutoff for stratification. For both stratification analyses, propensity scores were recomputed and imputation for missing covariables was performed separately within each stratified group, ensuring that confounder adjustment remained appropriate within each subgroup. A third sensitivity analysis was performed in which calendar time was included as an additional continuous variable in the propensity score-adjusted model to assess possible time-varying confounding bias (i.e. evolving disease dynamics and treatment advancements over time). Statistical analyses were performed using R version 4.3.3, including packages ‘readxl’, ‘haven’, ‘dplyr’, ‘lubridate’, ‘tidyr’, ‘Table 1 ’, ‘officer’, ‘flextable’, ‘ggplot2’ and ‘psych’. [ 45 – 55 ] Results 3.1 Study population From September 1, 2020 to March 31, 2022, a total of 206 patients were admitted to the ICU for COVID-19 and included for one-year follow-up (136 in the UMC Utrecht cohort and 70 in the Radboudumc cohort). A total 36 patients were excluded due to missing outcome data, leaving 170 patients for the primary analysis, of whom 119 were exposed and 51 were not exposed to IL-6 inhibitors (Fig. 1). A sensitivity analysis comparing patients with and without missing outcomes showed that those with missing data were less likely to have mental health problems at ICU admission (Table S2, Supplementary material). The mean age of the study population was 60 years (SD 9.6), with 37% being female, 19% having pre-ICU mental health problems, and 75% experiencing delirium during ICU admission. No apparent differences were observed between patients exposed and unexposed to IL-6 inhibitors (Table 1 ). Three potential confounders had missing data (BMI missing for 2 patients, pre-ICU mental health problems missing for 1 patient, delirium missing for 12 patients) and were imputed. Figure 2 visualizes all included patients by ICU admission date, categorized according to their composite outcome and IL-6 inhibitor exposure status. Of the 170 patients included in the study, 36% (n = 57) met the composite outcome for mental health problems one year after ICU admission. Among them, 22% (n = 37) of patients had PTSD symptoms, 22% (n = 38) had anxiety symptoms, and 26% (n = 44) had depression symptoms. Of the 57 patients meeting the composite outcome, 44% (n = 25) exhibited symptoms of all three conditions (Fig. 3 ). 3.2 Association between IL-6 inhibitors and mental health problems one year after ICU admission Unadjusted logistic regression analysis showed a crude odds ratio (OR) of 0.55 (95% confidence interval (CI) 0.28–1.08) for the composite outcome of mental health problems when exposed to IL-6 inhibitors. For PTSD, anxiety or depression symptoms alone, crude ORs were 0.47 (95% CI 0.22–1.00), 0.91 (95% CI 0.42–1.98) and 0.77 (95% CI 0.37–1.61), respectively. When adjusted for estimated propensity scores, exposure to IL-6 inhibitors during ICU admission was associated with a lower prevalence of mental health problems one year after ICU admission (adjusted OR (aOR) 0.46, 95% CI 0.22–0.93). This association was also found for PTSD symptoms alone (aOR 0.45, 95% CI 0.20–0.97). For anxiety (aOR 0.77, 95% CI 0.34–1.72) and depression (aOR 0.71, 95% CI 0.33–1.50) symptoms alone, the direction of the association was the same but did not reach statistical significance. The regression analysis of mental health problems at three months after ICU admission (Table S3, Supplementary Material), available only for the Radboudumc cohort, showed no associations between exposure and outcome. Stratification by treatment center (UMC Utrecht or Radboudumc) and baseline CRP (≤ 75 or > 75 mg/L) showed no evidence of effect modification (Tables S4 and S5, Supplementary Material). The association was not influenced by calendar time, as indicated by beta-estimate changes of ≤ 10% for the primary and secondary outcomes when calendar time was included in the model as an additional continuous variable. Table 1 Patient characteristics of the overall study population and by interleukin-6 inhibitor exposure Overall n = 170 IL-6 inhibitor † n = 119 No IL-6 inhibitor † n = 51 Age in years, mean (SD) 60.1 (9.6) 60.1 (10.2) 60.1 (8.3) Female, n (%) 62 (36.5) 47 (39.5) 15 (29.4) BMI, median (IQR) a 29 (26–32) 29 (26–32) 29 (26–32) Pre-ICU mental health problems, n (%) b 32 (18.8) 24 (20.2) 8 (15.7) Pre-ICU use of psychiatric medication, n (%) c 33 (19.4) 24 (20.2) 9 (17.6) Antidepressants, n (%) 18 (10.6) 14 (11.8) 4 (7.8) Antipsychotics, n (%) 12 (7.1) 8 (6.7) 4 (7.8) Anxiolytics, n (%) 12 (7.1) 7 (5.9) 5 (9.8) ICU length of stay in days, median (IQR) 10 (7–18) 10 (6–18) 10 (8–18) APACHE IV score, mean (SD) 65.0 (19.2) 66.2 (19.9) 62.4 (17.1) SOFA on day 1, median (IQR)* 5 (3–7) 5 (3–7) 5 (2–7) Delta SOFA between day 1 and day 4 (or final day), mean (SD) 0.6 (3.4) 0.7 (3.4) 0.6 (3.3) Mechanical ventilation, n (%) 151 (88.8) 106 (89.1) 45 (88.2) Propofol sedation, n (%) 137 (80.6) 97 (81.5) 40 (78.4) Midazolam sedation, n (%) 121 (71.2) 88 (73.9) 33 (64.7) Delirium during ICU admission, n (%) d 127 (74.7) 90 (75.6) 37 (72.5) Glucocorticoids during ICU admission, n (%) 164 (96.5) 115 (96.6) 49 (96.1) Baseline CRP, median (IQR) e 101 (55.5–157.5) 113 (70.2–166) 79 (50.5–115) APACHE = Acute Physiology and Chronic Health Evaluation, BMI = body mass index, CRP = C-reactive protein, ICU = Intensive Care Unit, IL-6 = Interleukin-6, IQR = interquartile range, SD = standard deviation, SOFA = Sequential Organ Failure Assessment † Tocilizumab or sarilumab a Missing for 2 (1%) patients b Missing for 1 (0%) patient c Missing for 4 (2%) patients d Missing for 12 (7%) patients e Baseline CRP levels are only shown for patients who were not transferred from another ICU. For exposed patients, baseline CRP corresponds to the CRP on the day of IL-6 inhibitor administration during ICU admission (n = 68). For non-exposed patients, baseline CRP corresponds to CRP on the day of ICU admission (n = 35). Table 2 Primary analysis on mental health problems and exposure to IL-6 inhibitors Composite outcome of mental health problems (PTSD, anxiety and/or depression) Events / total (n) Absolute risk Crude OR (95% CI) Adjusted a OR (95% CI) IL-6 inhibitor 35 / 119 29% 0.55 (0.28–1.08) 0.46 (0.22–0.93) No IL-6 Inhibitor 22 / 51 43% Reference Reference Post-traumatic stress disorder Events / total (n) Absolute risk Crude OR (95% CI) Adjusted a OR (95% CI) IL-6 inhibitor 21 / 119 18% 0.47 (0.22–1.00) 0.45 (0.20–0.97) No IL-6 Inhibitor 16 / 51 31% Reference Reference Anxiety Events / total (n) Absolute risk Crude OR (95% CI) Adjusted a OR (95% CI) IL-6 inhibitor 26 / 119 22% 0.91 (0.42–1.98) 0.77 (0.34–1.72) No IL-6 Inhibitor 12 / 51 24% Reference Reference Depression Events / total (n) Absolute risk Crude OR (95% CI) Adjusted a OR (95% CI) IL-6 inhibitor 29 / 119 24% 0.77 (0.37–1.61) 0.71 (0.33–1.50) No IL-6 Inhibitor 15 / 51 29% Reference Reference CI = confidence interval, ICU = intensive care unit, IL-6 = interleukin-6, OR = odds ratio, PTSD = Post-traumatic stress disorder a Adjusted for propensity scores estimated based on age, sex, Body Mass Index, pre-ICU mental health problems, mechanical ventilation, Acute Physiology and Chronic Health Evaluation IV score, Sequential Organ Failure Assessment (SOFA) score on day 1, delta SOFA score between day 1 and day 4 (or the final ICU day if earlier), delirium during ICU admission and glucocorticoid use during ICU admission. Discussion In this study, exposure to the IL-6 inhibitors tocilizumab or sarilumab as treatment for critically ill COVID-19 patients was associated with a lower prevalence of mental health problems, primarily driven by a lower prevalence of PTSD symptoms. Studies on pharmacological interventions during ICU admissions to prevent long-term mental health problems in ICU survivors is challenging and thus limited. The concept of daily sedation interruption initially showed promise in reducing PTSD symptoms assessed at least six months after ICU admission. [ 56 , 57 ] However, other pharmacological strategies have not yielded positive results. For instance, an intraoperative IV dose of dexamethasone had no protective effect on PTSD, anxiety, or depression symptoms 18 months after cardiac surgery and ICU admission. [ 58 ] Similarly, we observed no significant differences in these symptoms one year after ICU discharge between patients exposed to glucocorticoids during admission and those who were not. [ 44 ] Evidence on the effect of IL-6 inhibitors on mental health problems primarily comes from studies in rheumatoid arthritis patients. Four studies investigating changes in depression and/or anxiety symptoms from baseline found improvement following tocilizumab treatment, though these improvements were often closely correlated with decreases in disease activity. [ 59 – 62 ] By contrast, a study assessing tocilizumab use for the prevention of graft-versus-host disease observed a worsening of depression and anxiety symptoms, even after accounting for the presence of the disease. [ 63 ] These findings suggest that the relationship between IL-6 inhibition and mental health is complex, and the potential direct antidepressant effects of IL-6 inhibitors remain uncertain. Differences in study populations, indications, and dosing regimens across these studies complicate comparisons to the current study. Previous studies investigating the associations between IL-6 inhibitors and mental health problems in COVID-19 ICU patients have produced mixed results. One study found that patients treated with standard care plus anti-cytokine therapy (anakinra or tocilizumab) showed improvements in depressive symptoms but not PTSD three months after ICU discharge, compared to those who received standard treatment alone. [ 24 ] Another study that assessed long-term outcomes six months after discharge observed no significant differences in anxiety or depression scores between patients who received anti-inflammatory treatment, including tocilizumab and dexamethasone, and those who did not​. [ 64 ] Conversely, a separate study reported more severe depression and anxiety symptoms in the tocilizumab-treated group three months after discharge, although these differences diminished by six months​. [ 65 ] Additionally, research has linked tocilizumab use with a reduction in the duration of delirium during ICU stay, but delirium itself has not consistently been associated with long-term mental health problems one year after ICU discharge​. [ 66 , 67 ] Future research should first focus on well-designed randomized controlled trials specifically assessing the psychiatric effects of IL-6 inhibition in populations with established mental health vulnerability, with careful consideration of timing, dosing, and patient selection criteria. Only once such effects are better understood, would it be appropriate to explore IL-6 inhibitors as a targeted intervention during ICU admission for preventing long-term mental health problems in ICU survivors. This study does have limitations. Outcomes were measured using patient-reported outcome measures (PROMs), which reflect the patient’s perspective but rely on self-report and may be less precise than structured diagnostic interviews. This may have led to some misclassification, although any resulting bias is likely non-differential and would more likely underestimate our findings. Also, the cut-off scores for the IES and HADS were chosen based on their strong correlation with validated clinical interviews, helping to mitigate some concerns about diagnostic accuracy.[ 36 , 37 , 68 , 69 ] Also, despite adjusting for known confounders in logistic regression analyses, the possibility of residual confounding remains. Moreover, as outcome was assessed after one year follow-up, other unmeasured factors may have influenced mental health status. No data on post-ICU treatment, such as participation in rehabilitation programs, were available. However, such influences are expected to be non-differential with respect to IL-6 inhibitor exposure and are therefore unlikely to have biased the observed associations. Lastly, a potential limitation is the exclusion of patients with missing outcomes, which may have introduced selection bias. In this cohort, patients with missing outcomes on the IES or HADS had a lower prevalence of pre-ICU mental health problems compared to those included in the primary analysis. Since pre-ICU mental health problems are associated with post-ICU PTSD, anxiety, and depression symptoms, it is likely that the excluded patients had a lower risk of developing these outcomes. As a result, the absolute prevalence of mental health problems in our included population may be slightly overestimated, and the observed association could be inflated. Conclusion This study found that exposure to IL-6 inhibitors as treatment for COVID-19 is associated with a lower prevalence of mental health problems (PTSD, anxiety and/or depression), primarily driven by a lower prevalence of PTSD symptoms, one year after ICU admission. Future research should prioritize clarifying the potential effects of anticytokine treatments on mental health problems before considering their use as preventive strategies for post-ICU mental health problems in the ICU population. Declarations Financial support None Conflict of interest: None Author Contribution Conceptualization: Arjen J.C. Slooter, Marieke Zegers, Mark van den Boogaard, Irene J. van Diem-Zaal. Methodology: Thomas G. van Gelder, Arief Lalmohamed, Toine C.G. Egberts, Marieke Zegers, Mark van den Boogaard, Irene J. van Diem-Zaal, Arjen J.C. Slooter. Formal analysis and investigation: Thomas G. van Gelder. Writing – original draft preparation: Thomas G. van Gelder. Resources: Arjen J.C. 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Clin Rheumatol. 2014;33:1055–60. Gossec L, Steinberg G, Rouanet S, Combe B. Fatigue in rheumatoid arthritis: quantitative findings on the efficacy of tocilizumab and on factors associated with fatigue. The French multicentre prospective PEPS Study. Clin Exp Rheumatol. 2015;33:664–70. Tiosano S, Yavne Y, Watad A, Langevitz P, Lidar M, Feld J, et al. The impact of tocilizumab on anxiety and depression in patients with rheumatoid arthritis. Eur J Clin Invest [Internet]. 2020;50. Available from: https://onlinelibrary.wiley.com/doi/ 10.1111/eci.13268 Behrens F, Burmester G-R, Feuchtenberger M, Kellner H, Kuehne C, Liebhaber A, et al. Characterisation of depressive symptoms in rheumatoid arthritis patients treated with tocilizumab during routine daily care. Clin Exp Rheumatol. 2022;40:551–9. Knight JM, Costanzo ES, Singh S, Yin Z, Szabo A, Pawar DS, et al. The IL-6 antagonist tocilizumab is associated with worse depression and related symptoms in the medically ill. Transl Psychiatry. 2021;11:58. Duindam HB, Kessels RPC, van den Borst B, Pickkers P, Abdo WF. Long-term cognitive performance and its relation to anti-inflammatory therapy in a cohort of survivors of severe COVID-19. Brain Behav Immun Health. 2022;25:100513. Chakravarty R, Jyani G, Paul S, Mohindra R, Goyal M, Suri V, et al. Depression, Anxiety, and Quality of Life in Patients Treated with Single Infusion Tocilizumab for COVID-19: A Follow-up, Controlled Study. Indian J Psychol Med [Internet]. 2023;45:47–52. Available from: http://journals.sagepub.com/doi/ 10.1177/02537176221140557 Alkhateeb T, Stollings JL, Sohn I, Liu D, Fleenor LM, Ely EW, et al. Tocilizumab is associated with reduced delirium and coma in critically ill patients with COVID-19. Sci Rep. 2024;14:11738. Wolters AE, Peelen LM, Welling MC, Kok L, de Lange DW, Cremer OL, et al. Long-Term Mental Health Problems After Delirium in the ICU*. Crit Care Med [Internet]. 2016;44:1808–13. Available from: http://journals.lww.com/00003246-201610000-00002 Neal LA, Busuttil W, Rollins J, Herepath R, Strike P, Turnbull G. Convergent validity of measures of post-traumatic stress disorder in a mixed military and civilian population. J Trauma Stress [Internet]. 1994;7:447–55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8087405 Brennan C, Worrall-Davies A, McMillan D, Gilbody S, House A. The Hospital Anxiety and Depression Scale: A diagnostic meta-analysis of case-finding ability. J Psychosom Res [Internet]. 2010;69:371–8. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0022399910001698 Additional Declarations No competing interests reported. Supplementary Files SupplementarymaterialTOPICSJoIC.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6571420","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":451135806,"identity":"997c7f03-9e0e-4b20-ab81-49f7cf72cecf","order_by":0,"name":"Thomas G. Van Gelder","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABIklEQVRIie2RMUvDQBTHXzi4LIddrwjmK1wopA4l+SpXAumiIHTp4HBSSDZd7bdIR8Hh4EGmDk4ixCFFyGwWwaU1aaVDm9rV4X7D/+69ez/ecAAGw7/GBlHn4GLXaEooDgfZ7kY2M1FvU+hGoXXI0woO1SklAPuFsNt3/4GQ+ccEyCh9xfK8eh44fUfRonULuyEsK8PZlI7dBdDrNI88rsvIfYrBFu2KtB4phgKZ171bsVq5olxrlCIDyo8qKwwDZP1vBXwktsr6D8XWUMXoC8I8S4GQv4o+riADXd2j5EjHXQXSneVR73KhQzfNhnGbYifJspBfGHSS6bxSsHbO8nD5NtG+IxAz/nmoAGFC18f2O/aw2prNnqLJoP3RYDAYDDU/PoJl3vxjzQkAAAAASUVORK5CYII=","orcid":"","institution":"University Medical Center Utrecht, Utrecht University","correspondingAuthor":true,"prefix":"","firstName":"Thomas","middleName":"G. Van","lastName":"Gelder","suffix":""},{"id":451135807,"identity":"552fc265-2e70-4aa2-9957-41dad199a174","order_by":1,"name":"Arief Lalmohamed","email":"","orcid":"","institution":"University Medical Center Utrecht, Utrecht University","correspondingAuthor":false,"prefix":"","firstName":"Arief","middleName":"","lastName":"Lalmohamed","suffix":""},{"id":451135808,"identity":"90c7f228-6e4e-4229-a2fa-c306d93dc0b3","order_by":2,"name":"Toine C.G. Egberts","email":"","orcid":"","institution":"University Medical Center Utrecht, Utrecht University","correspondingAuthor":false,"prefix":"","firstName":"Toine","middleName":"C.G.","lastName":"Egberts","suffix":""},{"id":451135809,"identity":"3b85011e-2965-4e29-96b0-b5fc6c69e63c","order_by":3,"name":"Arjen J.C. 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Diem-Zaal","email":"","orcid":"","institution":"University Medical Center Utrecht, Utrecht University","correspondingAuthor":false,"prefix":"","firstName":"Irene","middleName":"J.","lastName":"Diem-Zaal","suffix":""}],"badges":[],"createdAt":"2025-05-01 11:08:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6571420/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6571420/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82308227,"identity":"01944b49-72c8-47b7-8b8c-59a64d0ac832","added_by":"auto","created_at":"2025-05-09 01:32:31","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":67338,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eFlowchart of patient inclusion and exclusion\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eHADS = Hospital Anxiety and Depression Scale, IES = Impact of Event Scale, UMCU = University Medical Center Utrecht\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6571420/v1/111edf9dfb1cbb280dde4a27.jpeg"},{"id":82309080,"identity":"1d84250a-505d-46ce-b947-ad8a5b61bb3c","added_by":"auto","created_at":"2025-05-09 01:40:31","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":276500,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eScatter plot illustrating the relationship between intensive care unit (ICU) admission date (x-axis) and the composite outcome of mental health problems one year after ICU admission (y-axis). Patients who received interleukin-6 inhibitors are shown in red, while non-exposed patients are shown in blue.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6571420/v1/806fd92fbf5be53f7ee7be14.jpeg"},{"id":82308228,"identity":"f9710475-6749-4783-bfc8-47341df1b749","added_by":"auto","created_at":"2025-05-09 01:32:31","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":114851,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eOverlap of post-traumatic stress disorder (PTSD), anxiety, and depression symptoms one year after intensive care unit admission.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6571420/v1/51a28760c2aad88ec9608bea.jpeg"},{"id":82774358,"identity":"56b789f5-f9e5-49ea-ae6c-044cf33416db","added_by":"auto","created_at":"2025-05-15 07:02:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1434535,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6571420/v1/e71af0aa-d25e-4722-9112-45a9b38e972f.pdf"},{"id":82309081,"identity":"4d1c9b20-eca6-41e0-ba6e-9f5e85a20b50","added_by":"auto","created_at":"2025-05-09 01:40:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":217485,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementarymaterialTOPICSJoIC.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6571420/v1/46fc013500567f3c80349105.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The association between interleukin-6 inhibitors as treatment for COVID-19 and mental health problems in ICU survivors","fulltext":[{"header":"Key points","content":"\u003cp\u003e\u003cem\u003eQuestion:\u0026nbsp;\u003c/em\u003eDoes treatment with interleukin-6 (IL-6) inhibitors during ICU admission for COVID-19 reduce the prevalence of mental health problems one year later?\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFindings:\u003c/em\u003e In this multicenter cohort study of 170 COVID-19 ICU survivors, IL-6 inhibitor exposure was associated with a significantly lower prevalence of PTSD and of the composite outcome of PTSD, anxiety, or depression symptoms one year after ICU admission.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMeaning:\u003c/em\u003e These findings suggest that IL-6 inhibition during critical illness may help mitigate long-term psychological burden in ICU survivors.\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eSurvivors of intensive care unit (ICU) admissions face a high risk of developing long-term mental health problems, including symptoms of post-traumatic stress disorder (PTSD), anxiety, and depression, with prevalences reaching 17%, 34%, and 29%, respectively. [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Various interventions, including ICU diaries, psychological support and early rehabilitation, have been explored to mitigate these outcomes. [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] However, the potential of pharmacological interventions during ICU admission to prevent such long-term mental health problems in ICU survivors is underexplored.\u003c/p\u003e \u003cp\u003eEmerging evidence highlights the role of the immune system, particularly inflammatory processes, in the development of psychiatric disorders such as major depression. [\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Elevated levels of interleukin-6 (IL-6), a pro-inflammatory cytokine, have been consistently observed in patients with major depressive disorder, and longitudinal studies indicate that higher IL-6 levels can predict the later development of depression. [\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] This evidence has led to the proposal of targeting cytokines such as IL-6 as potential therapeutic strategies for psychiatric conditions. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eTrials have already begun exploring this immunomodulating approach, with a recent randomized controlled trial showing that infliximab, a tumor necrosis factor inhibitor, can improve depressive symptoms in patients with treatment-resistant depression and high baseline inflammatory biomarkers. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] Additionally, a study assessing whether IL-6 inhibitors can effectively reduce depressive symptoms in individuals with low-grade inflammation, is recruiting patients. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eAmid the COVID-19 pandemic, the IL-6 inhibitors tocilizumab and sarilumab were incorporated into treatment protocols for severe cases, following evidence from the REMAP-CAP and RECOVERY trials that demonstrated their efficacy in improving survival, increasing organ support\u0026ndash;free days, and enhancing other clinical outcomes. [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] The widespread use of these agents in critically ill COVID-19 patients presents a unique opportunity to investigate whether IL-6 inhibition might mitigate the development of post-ICU mental health problems, which are also present in COVID-19 ICU survivors. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] Indeed, targeting IL-6 for the treatment of long-term effects of COVID-19 has been suggested, and one observational study has shown a protective effect of anticytokine agents against depressive symptoms in COVID-19 survivors. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThis study aimed to assess whether exposure to IL-6 inhibitors as treatment for critically ill COVID-19 patients is associated with a lower prevalence of mental health problems one year after ICU admission.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design and setting\u003c/h2\u003e \u003cp\u003eThis study was conducted as a collaboration between two university medical centers in the Netherlands: the University Medical Center Utrecht (UMCU), with a 32-bed mixed ICU and the Radboud University Medical Center (Radboudumc) in Nijmegen, with a 26-bed mixed ICU. Both centers conduct ongoing prospective follow-up studies of ICU survivors, each approved by their respective medical research ethics committees (protocol 10/006 for the UMCU study, protocol 2016–2724 for the Radboudumc study).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Study population\u003c/h2\u003e \u003cp\u003eThe UMCU follow-up cohort of ICU survivors was initiated in 2011 and includes all adult ICU patients admitted for at least 48 hours, who are still alive one year after ICU admission. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] The Radboudumc follow-up cohort of ICU survivors is part of the larger MONITOR-IC study, which started in 2016 and includes all ICU patients of 16 years or older, who are admitted for at least 12 hours. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eIn the current study, ICU patients were included who were admitted with COVID-19 as primary diagnosis from September 1, 2020 to March 31, 2022, and alive one year after ICU admission with follow-up data available. COVID-19 diagnosis was confirmed through a positive SARS-CoV-2 PCR test on a nasopharyngeal swab or tracheal aspirate. If a patient was readmitted to the ICU during the same hospital admission, only clinical data from the initial ICU admission were used in the analysis.\u003c/p\u003e \u003cp\u003ePatients admitted to the ICU during the first COVID-19 wave (March to September 2020) were not included. First, none of the patients in the first wave were exposed to IL-6 inhibitors. Second, this period was characterized by significant uncertainty, limited treatment options and visiting and isolation restrictions, leading to potentially different patient outcomes compared to later waves with more established treatment protocols.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Exposure to interleukin-6 inhibitors\u003c/h2\u003e \u003cp\u003eExposure to IL-6 inhibitors was assessed for all included patients. Patients were considered exposed if they received IL-6 inhibitors tocilizumab or sarilumab at any point during their ICU stay or within the 5 days preceding ICU admission. If a patient was transferred from a different ICU, records were reviewed to determine whether an IL-6 inhibitor had been administered at the hospital of initial ICU admission. Patients who did not receive an IL-6 inhibitor were considered unexposed.\u003c/p\u003e \u003cp\u003eThe typical dose regimen of IL-6 inhibitors evolved over the study period due to medication shortages, shifting from a weight-based dose of up to 8 mg/kg (maximum 800 mg) to a fixed dose of 400 mg, which has shown equivalent effectiveness in treating COVID-19. [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] Because these dosing regimens were standardized and considered equivalent in efficacy, dose was not accounted for in the exposure definition.\u003c/p\u003e \u003cp\u003e IL-6 inhibitor treatment for severe COVID-19 began in early 2021 in Dutch ICUs, following the guidelines of the Dutch Working Party on Antibiotic Policy (SWAB). The first recommendation, published on January 21, 2021, included a provisional suggestion to use tocilizumab in ICU patients, pending more data. [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] By March 2021, the advice was updated, recommending tocilizumab based on the RECOVERY trial criteria, which included patients with hypoxia (oxygen saturation \u0026lt; 92% or requiring oxygen therapy) and systemic inflammation (CRP ≥ 75 mg/L). [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] Sarilumab was later added as an alternative IL-6 inhibitor in October 2021. [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] Treatment with IL-6 inhibitors was first included in the World Health Organization’s living guideline “Therapeutics and COVID-19” in the July 6, 2021 edition. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Outcome measurements\u003c/h2\u003e \u003cp\u003eOne year after ICU admission, patients were assessed for mental health problems using validated and recommended questionnaires. [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] For PTSD, two versions of the Impact of Event Scale (IES) were employed depending on the cohort: the UMCU follow-up cohort utilized the revised IES (IES-R), which contains 22 questions, while the Radboudumc cohort used the IES-6, a 6-item version. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] Both versions calculate a mean score by averaging the responses, with established cutoffs to identify PTSD symptoms—1.75 for the IES-6 and 1.6 for the IES-R. [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eFor anxiety and depression, both centers used the Hospital Anxiety and Depression Scale (HADS), which comprises two subscales of 7 items each, scored on a 4-point Likert scale (0–3), giving a minimum of 0 and a maximum score of 21 on each subscale. A score of 8 or higher delineated borderline abnormal symptoms for either condition; for consistency, these will be referred to as 'symptoms' throughout this study. [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe primary outcome was defined as a composite score: if a patient's score on any mental health questionnaire (IES or HADS) exceeded the respective cutoff, the patient was classified as having mental health problems. Secondary outcomes were the individual outcomes for PTSD, anxiety, and depression. Additionally, mental health problems were assessed at three months after ICU admission for patients in the Radboudumc cohort, using the same questionnaires and cut-off values.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Potential confounders and effect modifiers\u003c/h2\u003e \u003cp\u003eFrom the literature on post-ICU mental health problems, age, sex, BMI, pre-ICU mental health problems, ICU length of stay, APACHE IV score, daily Sequential Organ Failure Assessment (SOFA) scores, mechanical ventilation, sedative agent (propofol or midazolam), delirium during ICU stay and glucocorticoid use were identified as potential confounders. [\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e–\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] Correlations between all identified potential confounders were assessed using Pearson, point-biserial, and Phi coefficients. Covariables with a correlation coefficient exceeding ± 0.7 were considered highly correlated, and only one was included in the model to minimize collinearity. ICU length of stay, mechanical ventilation, propofol sedation and midazolam sedation showed high correlation, and mechanical ventilation was retained in the model as it was considered least influenced by external factors.\u003c/p\u003e \u003cp\u003ePre-ICU mental health problems were classified as being present or not, and were based on available proxy indicators. For the UMCU follow-up cohort, baseline HADS scores were not available; instead, the use of psychiatric medications (antidepressants, antipsychotics, or anxiolytics) prior to ICU admission was used to indicate the presence of pre-ICU mental health problems. A detailed list of the medications considered for this classification is provided in Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e of the Supplementary material. For the Radboudumc cohort, pre-ICU mental health problems were determined using HADS scores measured at ICU admission, with scores above the cutoff indicating presence. The maximum daily SOFA score for each organ system was summed to calculate a total SOFA score for each ICU admission day. If the central nervous system (CNS) component of the SOFA score was not assessable due to sedation, the last CNS score recorded was carried forward. If no prior CNS score was available before sedation, a score of 0 was imputed (corresponding to a Glasgow Coma Scale score of 15). A delta SOFA score was calculated as the difference between the SOFA score on the first day of ICU admission and the SOFA score on the fourth ICU day (or the final ICU day if the length of stay was shorter) as a proxy for the progression of disease severity after ICU admission. This approach has demonstrated high predictive performance in ICU outcome models. [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] The SOFA score on day 1 and the delta SOFA score were included as covariables in the primary analysis. Delirium was measured by the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) in the UMCU cohort and by the Intensive Care Delirium Screening Checklist (ICDSC) in the Radboudumc cohort. [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eBased on the study by Raison et al. (2013), which found that anticytokine treatment was effective against major depressive disorder only in patients with a high baseline CRP level, CRP data was collected. For the current study, ‘baseline’ CRP was defined as the CRP measurement on the day of IL-6 inhibitor infusion for exposed patients, and on the day of ICU admission for non-exposed patients. Baseline CRP was unavailable for patients transferred from another ICU and for patients who received the IL-6 inhibitor on the ward instead of the ICU.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Data analysis\u003c/h2\u003e \u003cp\u003eLogistic regression analysis was performed with the composite outcome of symptoms of PTSD, anxiety and/or depression as the dependent variable, and IL-6 inhibitor exposure as the primary independent variable. Given the anticipated low number of events relative to the number of covariables, propensity scores were estimated to adjust for potential confounding, incorporating the selected potential confounders.\u003c/p\u003e \u003cp\u003eIf data on any outcome measurement was missing, the patient was excluded from the primary analysis. However, if answers to individual questionnaire items were missing, but the cutoff for symptoms was already met or could no longer be reached, the patient was retained in the dataset, a method successfully applied in previous research. [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e] Missing data for covariables were imputed using the mean or median for continuous variables and the mode for categorical variables.\u003c/p\u003e \u003cp\u003eTo explore potential variations in treatment effects between treatment centers, stratified analyses were performed for the UMCU and Radboudumc cohorts separately. Furthermore, to investigate the hypothesis that anticytokine treatment is only effective in patients with high baseline CRP levels, patients were stratified into two groups based on baseline CRP: a baseline CRP below 75 mg/L and a baseline CRP of 75 mg/L or higher. As 75 mg/L was used as a criterion for initiating IL-6 inhibitor treatment in COVID-19 patients, this threshold was chosen as the cutoff for stratification. For both stratification analyses, propensity scores were recomputed and imputation for missing covariables was performed separately within each stratified group, ensuring that confounder adjustment remained appropriate within each subgroup. A third sensitivity analysis was performed in which calendar time was included as an additional continuous variable in the propensity score-adjusted model to assess possible time-varying confounding bias (i.e. evolving disease dynamics and treatment advancements over time).\u003c/p\u003e \u003cp\u003eStatistical analyses were performed using R version 4.3.3, including packages ‘readxl’, ‘haven’, ‘dplyr’, ‘lubridate’, ‘tidyr’, ‘Table\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e’, ‘officer’, ‘flextable’, ‘ggplot2’ and ‘psych’. [\u003cspan additionalcitationids=\"CR46 CR47 CR48 CR49 CR50 CR51 CR52 CR53 CR54\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e–\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]\u003c/p\u003e "},{"header":"Results","content":"\u003ch2\u003e3.1 Study population\u003c/h2\u003e\u003cp\u003eFrom September 1, 2020 to March 31, 2022, a total of 206 patients were admitted to the ICU for COVID-19 and included for one-year follow-up (136 in the UMC Utrecht cohort and 70 in the Radboudumc cohort). A total 36 patients were excluded due to missing outcome data, leaving 170 patients for the primary analysis, of whom 119 were exposed and 51 were not exposed to IL-6 inhibitors (Fig.\u0026nbsp;1). A sensitivity analysis comparing patients with and without missing outcomes showed that those with missing data were less likely to have mental health problems at ICU admission (Table S2, Supplementary material).\u003c/p\u003e\u003cp\u003eThe mean age of the study population was 60 years (SD 9.6), with 37% being female, 19% having pre-ICU mental health problems, and 75% experiencing delirium during ICU admission. No apparent differences were observed between patients exposed and unexposed to IL-6 inhibitors (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Three potential confounders had missing data (BMI missing for 2 patients, pre-ICU mental health problems missing for 1 patient, delirium missing for 12 patients) and were imputed.\u003c/p\u003e\u003cp\u003eFigure 2 visualizes all included patients by ICU admission date, categorized according to their composite outcome and IL-6 inhibitor exposure status.\u003c/p\u003e\u003cp\u003eOf the 170 patients included in the study, 36% (n = 57) met the composite outcome for mental health problems one year after ICU admission. Among them, 22% (n = 37) of patients had PTSD symptoms, 22% (n = 38) had anxiety symptoms, and 26% (n = 44) had depression symptoms. Of the 57 patients meeting the composite outcome, 44% (n = 25) exhibited symptoms of all three conditions (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003ch2\u003e3.2 Association between IL-6 inhibitors and mental health problems one year after ICU admission\u003c/h2\u003e\u003cp\u003eUnadjusted logistic regression analysis showed a crude odds ratio (OR) of 0.55 (95% confidence interval (CI) 0.28–1.08) for the composite outcome of mental health problems when exposed to IL-6 inhibitors. For PTSD, anxiety or depression symptoms alone, crude ORs were 0.47 (95% CI 0.22–1.00), 0.91 (95% CI 0.42–1.98) and 0.77 (95% CI 0.37–1.61), respectively.\u003c/p\u003e\u003cp\u003eWhen adjusted for estimated propensity scores, exposure to IL-6 inhibitors during ICU admission was associated with a lower prevalence of mental health problems one year after ICU admission (adjusted OR (aOR) 0.46, 95% CI 0.22–0.93). This association was also found for PTSD symptoms alone (aOR 0.45, 95% CI 0.20–0.97). For anxiety (aOR 0.77, 95% CI 0.34–1.72) and depression (aOR 0.71, 95% CI 0.33–1.50) symptoms alone, the direction of the association was the same but did not reach statistical significance.\u003c/p\u003e\u003cp\u003eThe regression analysis of mental health problems at three months after ICU admission (Table S3, Supplementary Material), available only for the Radboudumc cohort, showed no associations between exposure and outcome. Stratification by treatment center (UMC Utrecht or Radboudumc) and baseline CRP (≤ 75 or \u0026gt; 75 mg/L) showed no evidence of effect modification (Tables S4 and S5, Supplementary Material). The association was not influenced by calendar time, as indicated by beta-estimate changes of ≤ 10% for the primary and secondary outcomes when calendar time was included in the model as an additional continuous variable.\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics of the overall study population and by interleukin-6 inhibitor exposure\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003cp\u003en = 170\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIL-6 inhibitor\u003csup\u003e†\u003c/sup\u003e\u003c/p\u003e \u003cp\u003en = 119\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo IL-6 inhibitor\u003csup\u003e†\u003c/sup\u003e\u003c/p\u003e \u003cp\u003en = 51\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge in years, mean (SD)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.1 (9.6)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60.1 (10.2)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60.1 (8.3)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale, n (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62 (36.5)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47 (39.5)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (29.4)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, median (IQR)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (26–32)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (26–32)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (26–32)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePre-ICU mental health problems, n (%)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (18.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (20.2)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (15.7)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePre-ICU use of psychiatric medication, n (%)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (19.4)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (20.2)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (17.6)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntidepressants, n (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (10.6)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (11.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (7.8)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntipsychotics, n (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (7.1)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (6.7)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (7.8)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnxiolytics, n (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (7.1)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (5.9)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (9.8)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU length of stay in days, median (IQR)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (7–18)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (6–18)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (8–18)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPACHE IV score, mean (SD)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65.0 (19.2)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.2 (19.9)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62.4 (17.1)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOFA on day 1, median (IQR)*\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (3–7)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (3–7)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (2–7)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta SOFA between day 1 and day 4 (or final day), mean (SD)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.6 (3.4)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.7 (3.4)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.6 (3.3)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMechanical ventilation, n (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e151 (88.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e106 (89.1)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45 (88.2)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePropofol sedation, n (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e137 (80.6)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e97 (81.5)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40 (78.4)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMidazolam sedation, n (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e121 (71.2)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88 (73.9)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33 (64.7)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelirium during ICU admission, n (%)\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e127 (74.7)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90 (75.6)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37 (72.5)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucocorticoids during ICU admission, n (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e164 (96.5)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e115 (96.6)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49 (96.1)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline CRP, median (IQR)\u003csup\u003ee\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e101 (55.5–157.5)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e113 (70.2–166)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e79 (50.5–115)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eAPACHE = Acute Physiology and Chronic Health Evaluation, BMI = body mass index, CRP = C-reactive protein, ICU = Intensive Care Unit, IL-6 = Interleukin-6, IQR = interquartile range, SD = standard deviation, SOFA = Sequential Organ Failure Assessment\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003e\u003cb\u003e†\u003c/b\u003e\u003c/sup\u003eTocilizumab or sarilumab\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ea\u003c/sup\u003e Missing for 2 (1%) patients\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003eb\u003c/sup\u003e Missing for 1 (0%) patient\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ec\u003c/sup\u003e Missing for 4 (2%) patients\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ed\u003c/sup\u003e Missing for 12 (7%) patients\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003e \u003csup\u003ee\u003c/sup\u003e Baseline CRP levels are only shown for patients who were not transferred from another ICU. For exposed patients, baseline CRP corresponds to the CRP on the day of IL-6 inhibitor administration during ICU admission (n = 68). For non-exposed patients, baseline CRP corresponds to CRP on the day of ICU admission (n = 35).\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cem\u003ePrimary analysis on mental health problems and exposure to IL-6 inhibitors\u003c/em\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eComposite outcome of mental health problems\u003c/p\u003e \u003cp\u003e(PTSD, anxiety and/or depression)\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eEvents / total (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eAbsolute risk\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eCrude OR (95% CI)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eAdjusted\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e \u003cb\u003eOR (95% CI)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIL-6 inhibitor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 / 119\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29%\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.55 (0.28–1.08)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.46 (0.22–0.93)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo IL-6 Inhibitor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 / 51\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43%\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eReference\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eReference\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003ePost-traumatic stress disorder\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eEvents / total (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eAbsolute risk\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eCrude OR (95% CI)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eAdjusted\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e \u003cb\u003eOR (95% CI)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIL-6 inhibitor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 / 119\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18%\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.47 (0.22–1.00)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.45 (0.20–0.97)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo IL-6 Inhibitor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 / 51\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31%\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eReference\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eReference\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eAnxiety\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eEvents / total (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eAbsolute risk\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eCrude OR (95% CI)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eAdjusted\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e \u003cb\u003eOR (95% CI)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIL-6 inhibitor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 / 119\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22%\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.91 (0.42–1.98)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.77 (0.34–1.72)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo IL-6 Inhibitor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 / 51\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24%\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eReference\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eReference\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eDepression\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eEvents / total (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eAbsolute risk\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eCrude OR (95% CI)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eAdjusted\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e \u003cb\u003eOR (95% CI)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIL-6 inhibitor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 / 119\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24%\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.77 (0.37–1.61)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.71 (0.33–1.50)\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo IL-6 Inhibitor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 / 51\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29%\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eReference\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eReference\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eCI = confidence interval, ICU = intensive care unit, IL-6 = interleukin-6, OR = odds ratio, PTSD = Post-traumatic stress disorder\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003e \u003csup\u003ea\u003c/sup\u003e Adjusted for propensity scores estimated based on age, sex, Body Mass Index, pre-ICU mental health problems, mechanical ventilation, Acute Physiology and Chronic Health Evaluation IV score, Sequential Organ Failure Assessment (SOFA) score on day 1, delta SOFA score between day 1 and day 4 (or the final ICU day if earlier), delirium during ICU admission and glucocorticoid use during ICU admission.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, exposure to the IL-6 inhibitors tocilizumab or sarilumab as treatment for critically ill COVID-19 patients was associated with a lower prevalence of mental health problems, primarily driven by a lower prevalence of PTSD symptoms.\u003c/p\u003e\u003cp\u003eStudies on pharmacological interventions during ICU admissions to prevent long-term mental health problems in ICU survivors is challenging and thus limited. The concept of daily sedation interruption initially showed promise in reducing PTSD symptoms assessed at least six months after ICU admission. [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e] However, other pharmacological strategies have not yielded positive results. For instance, an intraoperative IV dose of dexamethasone had no protective effect on PTSD, anxiety, or depression symptoms 18 months after cardiac surgery and ICU admission. [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e] Similarly, we observed no significant differences in these symptoms one year after ICU discharge between patients exposed to glucocorticoids during admission and those who were not. [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eEvidence on the effect of IL-6 inhibitors on mental health problems primarily comes from studies in rheumatoid arthritis patients. Four studies investigating changes in depression and/or anxiety symptoms from baseline found improvement following tocilizumab treatment, though these improvements were often closely correlated with decreases in disease activity. [\u003cspan additionalcitationids=\"CR60 CR61\" citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e–\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e] By contrast, a study assessing tocilizumab use for the prevention of graft-versus-host disease observed a worsening of depression and anxiety symptoms, even after accounting for the presence of the disease. [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e] These findings suggest that the relationship between IL-6 inhibition and mental health is complex, and the potential direct antidepressant effects of IL-6 inhibitors remain uncertain. Differences in study populations, indications, and dosing regimens across these studies complicate comparisons to the current study.\u003c/p\u003e\u003cp\u003ePrevious studies investigating the associations between IL-6 inhibitors and mental health problems in COVID-19 ICU patients have produced mixed results. One study found that patients treated with standard care plus anti-cytokine therapy (anakinra or tocilizumab) showed improvements in depressive symptoms but not PTSD three months after ICU discharge, compared to those who received standard treatment alone. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] Another study that assessed long-term outcomes six months after discharge observed no significant differences in anxiety or depression scores between patients who received anti-inflammatory treatment, including tocilizumab and dexamethasone, and those who did not​. [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e] Conversely, a separate study reported more severe depression and anxiety symptoms in the tocilizumab-treated group three months after discharge, although these differences diminished by six months​. [\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e] Additionally, research has linked tocilizumab use with a reduction in the duration of delirium during ICU stay, but delirium itself has not consistently been associated with long-term mental health problems one year after ICU discharge​. [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eFuture research should first focus on well-designed randomized controlled trials specifically assessing the psychiatric effects of IL-6 inhibition in populations with established mental health vulnerability, with careful consideration of timing, dosing, and patient selection criteria. Only once such effects are better understood, would it be appropriate to explore IL-6 inhibitors as a targeted intervention during ICU admission for preventing long-term mental health problems in ICU survivors.\u003c/p\u003e\u003cp\u003eThis study does have limitations. Outcomes were measured using patient-reported outcome measures (PROMs), which reflect the patient’s perspective but rely on self-report and may be less precise than structured diagnostic interviews. This may have led to some misclassification, although any resulting bias is likely non-differential and would more likely underestimate our findings. Also, the cut-off scores for the IES and HADS were chosen based on their strong correlation with validated clinical interviews, helping to mitigate some concerns about diagnostic accuracy.[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e] Also, despite adjusting for known confounders in logistic regression analyses, the possibility of residual confounding remains. Moreover, as outcome was assessed after one year follow-up, other unmeasured factors may have influenced mental health status. No data on post-ICU treatment, such as participation in rehabilitation programs, were available. However, such influences are expected to be non-differential with respect to IL-6 inhibitor exposure and are therefore unlikely to have biased the observed associations. Lastly, a potential limitation is the exclusion of patients with missing outcomes, which may have introduced selection bias. In this cohort, patients with missing outcomes on the IES or HADS had a lower prevalence of pre-ICU mental health problems compared to those included in the primary analysis. Since pre-ICU mental health problems are associated with post-ICU PTSD, anxiety, and depression symptoms, it is likely that the excluded patients had a lower risk of developing these outcomes. As a result, the absolute prevalence of mental health problems in our included population may be slightly overestimated, and the observed association could be inflated.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study found that exposure to IL-6 inhibitors as treatment for COVID-19 is associated with a lower prevalence of mental health problems (PTSD, anxiety and/or depression), primarily driven by a lower prevalence of PTSD symptoms, one year after ICU admission. Future research should prioritize clarifying the potential effects of anticytokine treatments on mental health problems before considering their use as preventive strategies for post-ICU mental health problems in the ICU population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eFinancial support\u003c/h2\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConflict of interest:\u003c/strong\u003e \u003cp\u003eNone\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConceptualization: Arjen J.C. Slooter, Marieke Zegers, Mark van den Boogaard, Irene J. van Diem-Zaal. Methodology: Thomas G. van Gelder, Arief Lalmohamed, Toine C.G. Egberts, Marieke Zegers, Mark van den Boogaard, Irene J. van Diem-Zaal, Arjen J.C. Slooter. Formal analysis and investigation: Thomas G. van Gelder. Writing \u0026ndash; original draft preparation: Thomas G. van Gelder. Resources: Arjen J.C. Slooter, Toine C.G. Egberts; Supervision: Arief Lalmohamed, Toine C.G. Egberts, Irene J. van Diem-Zaal, Arjen J.C. Slooter\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eParker AM, Sricharoenchai T, Raparla S, Schneck KW, Bienvenu OJ, Needham DM. Posttraumatic stress disorder in critical illness survivors: a metaanalysis. Crit Care Med [Internet]. 2015;43:1121\u0026ndash;9. 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Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://linkinghub.elsevier.com/retrieve/pii/S0022399910001698\u003c/span\u003e\u003cspan address=\"https://linkinghub.elsevier.com/retrieve/pii/S0022399910001698\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, Interleukin-6 Inhibitors, Critical Illness, Intensive Care Unit Survivors, Long-Term Outcomes","lastPublishedDoi":"10.21203/rs.3.rs-6571420/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6571420/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e To assess whether exposure to interleukin-6 (IL-6) inhibitors as treatment for critically ill COVID-19 patients is associated with a lower prevalence of mental health problems one year after ICU admission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDesign:\u003c/strong\u003e Retrospective cohort study using prospectively collected outcome data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSetting: \u003c/strong\u003eTwo university medical centers in the Netherlands: University Medical Center Utrecht (UMCU) and Radboud University Medical Center (Radboudumc).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients: \u003c/strong\u003eAdult ICU survivors admitted to the ICU for COVID-19 from September 1, 2020, to March 31, 2022, with available one-year follow-up data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExposure: \u003c/strong\u003eIL-6 inhibitors (tocilizumab or sarilumab) as treatment for COVID-19.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMeasurements and Main Results: \u003c/strong\u003eMental health problems were assessed using the Impact of Event Scale (IES-6 or IES-R) for post-traumatic stress disorder (PTSD) and the Hospital Anxiety and Depression Scale (HADS) for anxiety and depression. The primary outcome was a composite of PTSD, anxiety, and/or depression symptoms one year after ICU admission.\u003c/p\u003e\n\u003cp\u003eAmong 170 patients included in the primary analysis (119 exposed to IL-6 inhibitors, 51 unexposed), IL-6 inhibitor exposure was associated with a lower prevalence of mental health problems (adjusted odds ratio (aOR) 0.46, 95% confidence interval (CI) 0.22–0.93) and PTSD symptoms alone (aOR 0.45, 95% CI 0.20–0.97). No significant associations were found for anxiety (aOR 0.77, 95% CI 0.34–1.72) or depression (aOR 0.71, 95% CI 0.33–1.50) symptoms alone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eExposure to IL-6 inhibitors as treatment for critically ill COVID-19 patients was associated with a lower prevalence of mental health problems, primarily driven by a lower prevalence of PTSD symptoms, one year after ICU admission. These findings suggest a potential role for cytokine-targeted therapies in mitigating long-term mental health problems in ICU survivors, but further research is needed to establish causality.\u003c/p\u003e","manuscriptTitle":"The association between interleukin-6 inhibitors as treatment for COVID-19 and mental health problems in ICU survivors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-09 01:32:26","doi":"10.21203/rs.3.rs-6571420/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0656e858-999c-499d-922c-ee9e25138811","owner":[],"postedDate":"May 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-15T06:53:51+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-09 01:32:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6571420","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6571420","identity":"rs-6571420","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}