key: cord-1051417-x5zmm88d authors: Radulescu, Amanda; Istrate, Alexandru; Muntean, Monica title: Treatment with Tocilizumab in Adult Patients with Moderate to Critical COVID‐19 Pneumonia: A Single‐Center Retrospective Study date: 2022-01-27 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2022.01.048 sha: affddf5d7bd4b76839ca5a5fdc74aca07c3a9664 doc_id: 1051417 cord_uid: x5zmm88d Objectives : To assess if tocilizumab (TCZ) timing is associated with improved survival. Material and methods : Retrospective analysis of data obtained from adult patients with moderate/severe/critical COVID-19 and treated with TCZ, admitted in the Teaching Hospital of Infectious Diseases, Cluj-Napoca, Romania (April 2020-April 2021). The database included: demographics, clinical data, CT scan results, the kinetics of Il-6, laboratory variables and the outcome until discharge. Results : A total of 221 patients received dexamethasone, antivirals, anticoagulants and 1-2 doses of TCZ, 8 mg/kg. Compared with patients admitted in 2020, in 2021, more received high flow oxygen/non-invasive ventilation but demographics, in-hospital mortality, and laboratory data did not differ significantly. In-hospital mortality was associated with age, disease severity, lung damage, ICU admission, cardiovascular comorbidities and Il-6>100 pg/mL at TCZ administration. In multivariate analysis the risk of death was significantly higher in patients with persistent inflammatory state, aOR 16.6 [95% CI 3.07-108.96], lung damage >40%, aOR 11.68 [95%CI 2.05-224.98] and cardiovascular comorbidities >2, aOR 3.65 [95%CI 1.06-12.53]. TCZ initiation at ≤3 days after admission showed improved survival, OR=0.39 [95% CI: 0.16-0.9]. Severe infections were found in 11 (4.9%) patients. Conclusion : Early initiation of TCZ seems beneficial and safe in patients with moderate to critical COVID‐19 pneumonia. The ongoing pandemic of coronavirus disease 2019 (COVID- 19) In an attempt to enhance the intervention towards cytokines storm, the use of IL-6 inhibitors has been demonstrated to be a potential option in moderate or severe COVID-19 pneumonia. The aim of the study was to evaluate if early treatment with TCZ is associated with a lower risk of in-hospital death and the interaction with personal characteristics, severity of disease, and systemic inflammation together with safety issues. The current study was performed in the Teaching Hospital of Infectious Diseases Cluj-Napoca, Romania, from 23 April 2020 (when TCZ was available) to 30 April 2021. We analyzed data from all adult patients with moderate to critical SARS-CoV-2 infection who received TCZ and concomitant medication against SARS-CoV-2 (dexamethasone, low molecular weight heparin, remdesivir/favipiravir/hydroxychloroquine) (Ministry of Health, We evaluated the patients' characteristics in the second and third pandemic waves (2020 vs. 2021) and the risk factors for in-hospital mortality, not always directly attributable to COVID-19. Data were collected on complications possibly related to TCZ treatment including: complex respiratory disease (bacterial, fungal pneumonia), bloodstream infections and liver toxicity. The occurrence of bacterial complications was confirmed by the physicians based on clinical, imaging and microbiological tests (blood cultures and deep respiratory samples). Acute liver injury was defined as alanine aminotransferase (ALT) of more than 150 U/L (UNV 50 U/L). Access to patient data has been authorized by our Teaching Hospital Ethical Committee. In the view of the retrospective design of this study, the requirement for patient consent was disregarded. Besides the descriptive analyses of clinical and laboratory tests, log2-transformed data were used for CRP and Il-6 kinetics. Hypothesis testing was performed using odds ratio with 95% confidence intervals and p-value from Fisher or Mann-Whitney tests, as appropriate, followed by logistic regression for the outcome by certain variables. Cumulative distribution plot and a log-rank test was used for the outcome by TCZ administration timing. Statistical analysis was performed by R 4.0 (R Core Team, 2020). Statistical significance was considered for p-values of < 0.05. Compared to patients admitted in 2020, more patients received high flow oxygen/noninvasive mechanical ventilation, most of them, 64% (142/221) in the medical wards, remdesivir as antiviral treatment, and TCZ was administered earlier in 2021. Age, gender, inhospital mortality, length of stay, comorbidities (except obesity) and laboratory data (white blood cell count, absolute lymphocyte count, CRP, ferritin, LDH, ALT) did not differ significantly in 2021 compared to 2020. In all patients a sharp decrease of CRP and almost normal ALT values were observed in days 3 and 7 after TCZ administration (Table 1, Figure 1 ). Among our patients, the in-hospital mortality was 11.3% (25/221). In patients younger than 60 years (37.1%, 82/221), in-hospital mortality was 9.7% (8/82), in those aged 50-59 years the rate was higher 13.5% (7/52) compared with the overall rate and in patients aged 60-79 years, 8.9% (10/112). The highest rate, 26% (7/27) was observed in patients > 80 years, although without statistical significance. In univariate analysis, the risk of in-hospital mortality was associated with age, CPS ≥6, >40% lung damage, ICU admission, > 2 cardiovascular and other comorbidities, Il-6>100 pg/mL. TCZ administration at less than 3 days after admission was associated with decreased in-hospital mortality, OR=0.39 [0.16-0.9] (p=.034). (Table 2, Figure 2 ). Cumulative distribution plot and a log-rank test were used for the outcome depending on TCZ timing and IL-6 dynamics in days 0, 1, 3, 7. At TCZ initiation the Il-6 levels were significantly higher in non-survivors with a similar kinetics in all patients (Table 2, Figure 3 ). Laboratory data in survivors and deceased are presented in dynamics at days 0, 3 and 7 after TCZ administration in Table 3 . A sharp decrease of CRP values was found in all patients but in non-survivors, LDH and D-dimers were 2-3 fold and 6 fold higher, respectively (Table 3, Figure 1 ) . Remdesivir showed some benefit albeit without statistical significance ( Table 2 ). In multivariate analysis the risk of in-hospital mortality was associated with persistent inflammatory state (CRP>75 mg/L in day 3), aOR 16.6 (95% confidence interval (CI) 3.07-108.96, p = .002), lung damage > 40%, aOR 11.68 (95% CI 2.05-224.98, p = .024), cardiovascular comorbidities >2, aOR 3.65 (95% CI 1.06-12.53, p = .037) and TCZ administration at more than 3 days after admission, aOR 3.76 (95% CI 1.06-15.14, p = .047). Globally, we did not find a significant increase in ALT levels after TCZ administration ( gentamicin-high 85%) and coagulase-negative staphylococci (two strains vancomycin susceptible). Four cases were aged less than 60 years, two of them being profoundly immunosuppressed (recent kidney transplant recipient and advanced pancreatic cancer, respectively). During the study period, Romania reported 1 055 265 COVID-19 cases and Cluj county registered 56 054 patients, ranked the second after the capital Bucharest (and surroundings). In the second COVID-19 pandemic wave there were up to 10 000 cases/day (November 2020), thereafter decreasing till the end of February 2021 to less than 3 000 cases/day. The Higher rates of complications were found in younger patients with no comorbidities and in those aged >60 years. Regarding in-hospital mortality increasing age and male gender were the most relevant risk factors but the complications were more deleterious in younger patients, in the presence of comorbidities, and a poor outcome was more frequently observed compared to older patients (Drake et al., 2021) . In our study, we also found the highest inhospital mortality in patients > 80 years, yet in patients aged 50-59 years, the rate was higher compared to the group of age 60-79 years (although not statistically significant) suggesting that severe disease, comorbidities and complications might be more important in younger patients compared with the older ones. Early reports suggested that IL-6 blockade with TCZ is beneficial in the treatment of severe Regarding the ferritin kinetics, it has been showed that its level could be correlated with IL-6 serum level (Conrozier et al., 2020) . However, ferritin also depends on IL-18 levels explaining why ferritin and CRP did not decrease at the same rate after IL-6 blockade. This observation is consistent with our results as we did not observe a significant decrease in the ferritin level within 7 days, neither in survivors nor in deceased. Comparable to Toniatti at al. (Toniati et al., 2020) we found that hypercoagulation state was not positively influenced in non survivors, showing a 6-fold increase of D-dimer values by day 7 after TCZ administration, and even in survivors no decrease was observed, suggesting that TCZ was able to act only on the inflammatory syndrome with no effect on downregulating hipercoagulation. The strength of our study was a comprehensive assessment at admission and repeatedly after TCZ administration. Even we lacked a control group, all patients had baseline factors predictive of poor outcome and since concomitant treatments were similar (all receiving dexamethasone, low molecular heparin and antivirals), it is highly probable that TCZ made the difference. We were able to assess disease severity related to presumably different SARS-CoV-2 variants by comparing patients admitted in the second and third pandemic waves. The present study has a number of limitations, inherent for an observational compared to a randomized controlled trial thus, we cannot preclude that the overall favorable results observed for TCZ treated patients may be explained by the natural course of the disease and other factors. We were not able to continue the follow-up in survivors till 28 days but discharge was considered only in those with a predictable good outcome. Our study suggests that early immunomodulatory therapy with TCZ is beneficial and safe during the COVID-19 cytokine storm in patients with moderate to critical COVID-19 pneumonia. Poor prognosis was associated with cardiovascular comorbidities, extended lung damage, respiratory failure, persistent hiperinflammatory and prothrombotic profiles. Committee, and all patients have signed an Informed consent. We thank all clinical, laboratory, and nursing staff who cared for the patients at Cluj-Napoca Teaching Hospital of Infectious Diseases; they are not responsible for the content of this article. ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Visual scoring of chest CT at hospital admission predicts hospitalization time and intensive care admission in Covid-19 Factors associated with deaths due to COVID-19 versus other causes: population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systematic literature review and meta-analysis of randomized controlled trials Biomarker variation in patients successfully treated with tocilizumab for severe coronavirus disease 2019 (COVID-19): results of a multidisciplinary collaboration Characterisation of in-hospital complications associated with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, multicentre cohort study variants of concern as of 15 TCZ for the treatment of COVID-19 Genomic characteristics and clinical effect of the emergent SARS-CoV-2 B UK: a whole-genome sequencing and hospital-based cohort study IL-6 serum levels predict severity and response to tocilizumab in COVID-19: An observational study Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial The Romanian Nationale Institute of Public Health) -Covid 19 Raport săptămânal de supraveghere The Romanian Nationale Institute of Public Health) -Informare privind cazurile de COVID-19 confirmate cu variante ale SARS-CoV-2 care determină îngrijorare (VOC) Effects of tocilizumab on mortality in hospitalized patients with COVID-19: a multicentre cohort study Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications COVID-19: consider cytokine storm syndromes and immunosuppression Does timing matter on tocilizumab administration? 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