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The safety and effectiveness of tocilizumab in older adult critically ill patients with COVID-19: a multicenter, cohort study

  • Ghazwa B. Korayem
    Affiliations
    Department of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University, P. O. Box 84428, Riyadh 11671, Saudi Arabia
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  • Ohoud Aljuhani
    Affiliations
    Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
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  • Ali F. Altebainawi
    Affiliations
    Pharmaceutical Care Services, King Salman Specialist Hospital, Hail Health Cluster, Ministry of Health, Saudi Arabia
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  • Abdulrahman I. Al Shaya
    Affiliations
    Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia

    King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

    College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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  • Lina I. Alnajjar
    Affiliations
    Department of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University, P. O. Box 84428, Riyadh 11671, Saudi Arabia

    Pharmaceutical Care Services, King Abdullah bin Abdulaziz University Hospital, Riyadh, Saudi Arabia
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  • Abdulrahman Alissa
    Affiliations
    Pharmaceutical Care Services, King Abdullah bin Abdulaziz University Hospital, Riyadh, Saudi Arabia
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  • Mohammed Aldhaeefi
    Affiliations
    Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia

    King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

    College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia

    Department of Clinical and Administrative Pharmacy Sciences, College of Pharmacy, Howard University, Washington, DC, USA
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  • Raed Kensara
    Affiliations
    King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

    College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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  • Hessa Al Muqati
    Affiliations
    Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia
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  • Abdulmohsen Alhuwahmel
    Affiliations
    College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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  • Omar Alhuthaili
    Affiliations
    College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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  • Ramesh Vishwakarma
    Affiliations
    Statistics Department, European Organization for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
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  • Namareq Aldardeer
    Affiliations
    Pharmaceutical Care Services, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
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  • Khalid Eljaaly
    Affiliations
    Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia

    College of Pharmacy, University of Arizona, Tucson, AZ, United States
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  • Aisha Alharbi
    Affiliations
    Pharmaceutical Care Department, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
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  • Shmeylan Al Harbi
    Affiliations
    Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia

    King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

    College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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  • Abdulmalik Al Katheri
    Affiliations
    Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia

    King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

    College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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  • Abdulkareem M. Al Bekairy
    Affiliations
    Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia

    King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

    College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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  • Ahmed Aljedai
    Affiliations
    Deputyship of Therapeutic Affairs, Ministry of Health, Riyadh, Saudi Arabia
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  • Khalid Al Sulaiman
    Correspondence
    Corresponding author: Khalid A. Al Sulaiman, Pharmaceutical Care Department, King Abdulaziz Medical City (KAMC)-Ministry of National Guard Health Affairs (MNGHA), King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS); PO Box 22490, 11426, Riyadh, Saudi Arabia.
    Affiliations
    Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia

    King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

    College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia

    Saudi Critical Care Pharmacy Research (SCAPE) Platform, Riyadh, Saudi Arabia
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Open AccessPublished:May 19, 2022DOI:https://doi.org/10.1016/j.ijid.2022.05.038

      Highlights

      • The hyperinflammatory stage in COVID-19 is characterized by surges of interleukin-6 (IL-6).
      • The role of tocilizumab (TCZ) (IL-6 inhibitor) in patients with COVID-19 is controversial.
      • TCZ has immunosuppressive effects, which can be questionable in older patients with COVID-19.
      • TCZ exhibited less in-hospital mortality but similar 30-day mortality in our study.
      • Our study found no difference between groups in the incidence of secondary infections.

      ABSTRACT

      Objectives

      Evidence supports tocilizumab (TCZ) benefit and safety in adult patients with severe COVID-19. However, its effectiveness in critically ill older adult patients remains questionable. Thus, the study aimed to evaluate the safety and effectiveness of TCZ in older critically ill patients with COVID-19.

      Methods

      A multicenter, retrospective study for all critically ill older adults (aged ≥65 years) with confirmed COVID-19 infection and admitted to the intensive care units (ICUs). Eligible patients were categorized into two groups based on TCZ use during ICU stay (control vs TCZ). Propensity score (PS) matching was used (1:1 ratio) based on the selected criteria. The primary outcome was the in-hospital mortality.

      Results

      A total of 368 critically ill older adult patients were included in the study. Fifty one patients (13.8%) received TCZ. The in-hospital mortality was lower in the TCZ group (HR 0.41; 95% CI 0.22–0.76, P-value = 0.005). Patients who received TCZ had lower odds of respiratory failure requiring mechanical ventilation (OR [95% CI]: 0.32 [0.10–0.98], P-value = 0.04). No statistically significant differences were found between the two groups for 30-days mortality, ventilator-free days, length of stay, and complications during ICU stay.

      Conclusion

      Tocilizumab use in critically ill older adult patients with COVID-19 is associated with lower in-hospital mortality and a similar safety profile.

      Keywords

      Introduction

      Since the novel severe acute respiratory sydnrome coronavirus 2 (SARS-CoV-2) emergence in 2019 (
      • Huang C
      • Wang Y
      • Li X
      • Ren L
      • Zhao J
      • Hu Y
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ), coronavirus disease 2019 (COVID-19) has caused more than four million deaths globally (World Health Organization,

      World Health Organization, WHO Coronavirus (COVID-19) Dashboard. https://covid19.who.int/, 2021 (Accessed 5 October 2021).

      ). COVID-19 pneumonia can progress to acute respiratory distress syndrome, multiorgan dysfunction, or death (
      • Que Y
      • Hu C
      • Wan K
      • Hu P
      • Wang R
      • Luo J
      • et al.
      Cytokine release syndrome in COVID-19: a major mechanism of morbidity and mortality.
      ). This progression may be attributed to the body's inflammatory response exacerbating inflammatory mediators such as cytokines and chemokines, leading to cytokine storm (
      • Que Y
      • Hu C
      • Wan K
      • Hu P
      • Wang R
      • Luo J
      • et al.
      Cytokine release syndrome in COVID-19: a major mechanism of morbidity and mortality.
      ). Therefore, many treatment modalities such as antiviral therapy, antibiotic therapy, immunomodulating agents, and corticosteroids have been investigated to mitigate COVID-19 symptoms, reduce disease progression, and ultimately prevent mortality (
      RECOVERY Collaborative Group
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ; REMAP-CAP
      • Investigators REMAP-CAP
      • Gordon AC
      • Mouncey PR
      • Al-Beidh F
      • Rowan KM
      • Nichol AD
      • Arabi YM
      • et al.
      Interleukin-6 receptor antagonists in critically ill patients with Covid-19.
      ;
      • Shaffer L.
      15 drugs being tested to treat COVID-19 and how they would work.
      ).
      Critically ill patients with severe COVID-19 exhibit elevated inflammatory markers, including interleukin-6 (IL-6) (
      • Rizvi MS
      • Gallo De Moraes A.
      New decade, old debate: blocking the cytokine pathways in infection-induced cytokine cascade.
      ). Therefore, many studies have investigated using IL-6 targeting immunomodulators to treat COVID-19 (REMAP-CAP
      • Investigators REMAP-CAP
      • Gordon AC
      • Mouncey PR
      • Al-Beidh F
      • Rowan KM
      • Nichol AD
      • Arabi YM
      • et al.
      Interleukin-6 receptor antagonists in critically ill patients with Covid-19.
      ;
      • Rizvi MS
      • Gallo De Moraes A.
      New decade, old debate: blocking the cytokine pathways in infection-induced cytokine cascade.
      ;
      • Stone JH
      • Frigault MJ
      • Serling-Boyd NJ
      • Fernandes AD
      • Harvey L
      • Foulkes AS
      • et al.
      Efficacy of tocilizumab in patients hospitalized with Covid-19.
      ;
      • Al Sulaiman K
      • Aljuhani O
      • Bin Salah K
      • Korayem GB
      • Eljaaly K
      • Al Essa M
      • et al.
      Single versus multiple doses of tocilizumab in critically ill patients with coronavirus disease 2019 (COVID-19): a two-center, retrospective cohort study.
      ;
      RECOVERY Collaborative Group
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ). A randomized controlled trial by the RECOVERY Collaborative Group demonstrated tocilizumab's (TCZ) effectiveness in reducing mortality and improving clinical outcomes in hospitalized patients with COVID-19 (
      RECOVERY Collaborative Group
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ). A systematic review and meta-analysis including 17 observational studies that compared TCZ with systemic steroid versus standard of care in patients with severe COVID-19 reported a lower mortality rate in patients receiving TCZ (
      • Alkofide H
      • Almohaizeie A
      • Almuhaini S
      • Alotaibi B
      • Alkharfy KM.
      Tocilizumab and systemic corticosteroids in the management of patients with COVID-19: a systematic review and meta-analysis.
      ). Moreover, a recent systematic review and meta-analysis including 52 studies confirmed TCZ mortality benefits in the intensive care unit (ICU) and non-ICU patients regardless of the use of systemic corticosteroids, but TCZ did not significantly reduce mortality in the included observational studies (
      • Kyriakopoulos C
      • Ntritsos G
      • Gogali A
      • Milionis H
      • Evangelou E
      • Kostikas K.
      Tocilizumab administration for the treatment of hospitalized patients with COVID-19: a systematic review and meta-analysis.
      ).
      Even though most evidence supports the efficacy of TCZ use in patients with severe COVID-19 (
      • Van den Eynde E
      • Gasch O
      • Oliva JC
      • Prieto E
      • Calzado S
      • Gomila A
      • et al.
      Corticosteroids and tocilizumab reduce in-hospital mortality in severe COVID-19 pneumonia: a retrospective study in a Spanish Hospital.
      ; REMAP-CAP
      • Investigators REMAP-CAP
      • Gordon AC
      • Mouncey PR
      • Al-Beidh F
      • Rowan KM
      • Nichol AD
      • Arabi YM
      • et al.
      Interleukin-6 receptor antagonists in critically ill patients with Covid-19.
      ;
      • Kimmig LM
      • Wu D
      • Gold M
      • Pettit NN
      • Pitrak D
      • Mueller J
      • et al.
      IL-6 inhibition in critically ill COVID-19 patients is associated with increased secondary infections.
      ;
      • Kyriakopoulos C
      • Ntritsos G
      • Gogali A
      • Milionis H
      • Evangelou E
      • Kostikas K.
      Tocilizumab administration for the treatment of hospitalized patients with COVID-19: a systematic review and meta-analysis.
      ;
      • Mahale N
      • Rajhans P
      • Godavarthy P
      • Narasimhan VL
      • Oak G
      • Marreddy S
      • et al.
      A retrospective observational study of hypoxic COVID-19 patients treated with immunomodulatory drugs in a tertiary care hospital.
      ;
      RECOVERY Collaborative Group
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ), its effectiveness, specifically in patients with COVID-19 aged 65 years or older who are at higher risk of mortality, remains questionable (
      • Bhatraju PK
      • Ghassemieh BJ
      • Nichols M
      • Kim R
      • Jerome KR
      • Nalla AK
      • et al.
      Covid-19 in critically ill patients in the Seattle region - case series.
      ;
      • Grasselli G
      • Zangrillo A
      • Zanella A
      • Antonelli M
      • Cabrini L
      • Castelli A
      • et al.
      Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy.
      ). Older adult patients admitted to the ICU with COVID-19 have a higher number of comorbidities and a higher risk of death in the ICU (
      • Grasselli G
      • Zangrillo A
      • Zanella A
      • Antonelli M
      • Cabrini L
      • Castelli A
      • et al.
      Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy.
      ). A retrospective study conducted by our group has found that the overall ICU mortality within 30 days was 42.3%, and up to 40% of included patients were aged 65 years old or older, but we did not assess the use of TCZ in the previous study (
      • Al Sulaiman KA
      • Aljuhani O
      • Eljaaly K
      • Alharbi AA
      • Al Shabasy AM
      • Alsaeedi AS
      • et al.
      Clinical features and outcomes of critically ill patients with coronavirus disease 2019 (COVID-19): a multicenter cohort study.
      ). Although the RECOVERY trial that included both ICU and non-ICU patients reported mortality benefits with TCZ use in older adult patients (≥70–<80 years) and a respiratory rate (95% confidence interval [CI]) of 0.83 (0.72–0.94), this group only represented 24% of the included patients at baseline (
      RECOVERY Collaborative Group
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ). Another two-center study conducted by our group that included critically ill patients with COVID-19 compared the effectiveness and safety of two TCZ dosing regimens in adults older than 18 years with a mean age of 59.0 (standard deviation [SD] ± 12.8) (
      • Al Sulaiman K
      • Aljuhani O
      • Bin Salah K
      • Korayem GB
      • Eljaaly K
      • Al Essa M
      • et al.
      Single versus multiple doses of tocilizumab in critically ill patients with coronavirus disease 2019 (COVID-19): a two-center, retrospective cohort study.
      ). However, most of the previously conducted studies investigated TCZ efficacy and safety, focusing on adults aged 18 years or above with none of these studies addressing TCZ's benefit and risk in high-risk populations such as older adults (
      • Alkofide H
      • Almohaizeie A
      • Almuhaini S
      • Alotaibi B
      • Alkharfy KM.
      Tocilizumab and systemic corticosteroids in the management of patients with COVID-19: a systematic review and meta-analysis.
      ;
      • Van den Eynde E
      • Gasch O
      • Oliva JC
      • Prieto E
      • Calzado S
      • Gomila A
      • et al.
      Corticosteroids and tocilizumab reduce in-hospital mortality in severe COVID-19 pneumonia: a retrospective study in a Spanish Hospital.
      ;
      • Kimmig LM
      • Wu D
      • Gold M
      • Pettit NN
      • Pitrak D
      • Mueller J
      • et al.
      IL-6 inhibition in critically ill COVID-19 patients is associated with increased secondary infections.
      ;
      • Mahale N
      • Rajhans P
      • Godavarthy P
      • Narasimhan VL
      • Oak G
      • Marreddy S
      • et al.
      A retrospective observational study of hypoxic COVID-19 patients treated with immunomodulatory drugs in a tertiary care hospital.
      ;
      • Shaffer L.
      15 drugs being tested to treat COVID-19 and how they would work.
      ;
      • Stone JH
      • Frigault MJ
      • Serling-Boyd NJ
      • Fernandes AD
      • Harvey L
      • Foulkes AS
      • et al.
      Efficacy of tocilizumab in patients hospitalized with Covid-19.
      ). Therefore, this study aims to compare the safety and effectiveness of TCZ versus control in critically ill older adult patients (aged ≥65 years) with COVID-19.

      Methods

      Study design

      This study was a multicenter, retrospective cohort including critically ill older adult patients (aged ≥65 years) with confirmed COVID-19 and admitted to the ICUs at four hospitals in Saudi Arabia from March 1, 2020, until March 31, 2021. All patients were observed until they were discharged from the hospital or died during their stay. Because of the study's retrospective observational nature, informed consent from study participants was waived. This project was approved by the King Abdullah International Medical Research Center (KAIMRC) (IRB number NRC21R.434.10) as the primary site.

      Study participants

      We included all older adult patients (age ≥65 years) admitted to the ICUs with confirmed COVID-19. Patients were diagnosed with COVID-19 using reverse transcriptase-polymerase chain reaction (RT-PCR) nasopharyngeal or throat swabs. Patients were excluded if the ICU length of stay (LOS) ≤ 1 day, died within the first 24 hours of ICU admission, were labeled as “do-not-resuscitate,” received TCZ before ICU admission or after 24 hours of ICU admission (Figure 1). Eligible patients were then categorized based on TCZ use during ICU stay into two groups (control vs TCZ). TCZ has been approved for the treatment in patients with severe COVID-19 in Saudi Arabia, according to the Saudi Ministry of Health guidelines for COVID-19 management in critically ill patients (Saudi Ministry of Health,

      Saudi Ministry of Health. Saudi MoH protocol for patients with suspected of/confirmed with COVID-19: supportive care and antiviral treatment of suspected or confirmed COVID-19 infection (Version 3.1), https://www.moh.gov.sa/Ministry/MediaCenter/Publications/Documents/MOH-therapeutic-protocol-for-COVID-19.pdf. Accessed 29/5/2022.

      ). TCZ was administered as a single dose of 4–8 mg/kg based on the actual body weight (maximum 800 mg) through IV infusion; a repeated dose was given based on clinical assessment (Saudi Ministry of Health,

      Saudi Ministry of Health. Saudi MoH protocol for patients with suspected of/confirmed with COVID-19: supportive care and antiviral treatment of suspected or confirmed COVID-19 infection (Version 3.1), https://www.moh.gov.sa/Ministry/MediaCenter/Publications/Documents/MOH-therapeutic-protocol-for-COVID-19.pdf. Accessed 29/5/2022.

      ).
      Figure 1
      Figure 1Flowchart of patients admitted to the ICU (before propensity score match). ICU, intensive care unit.

      Study settings

      The study was conducted at four hospitals representing three regions in Saudi Arabia: King Abdulaziz Medical City (Riyadh), King Abdulaziz University Hospital (Jeddah), King Abdullah bin Abdulaziz University Hospital (Riyadh), and King Salman Specialist Hospital (Hail). The primary center was King Abdulaziz Medical City - National Guard Health Affairs (NGHA) (Riyadh).

      Data collection

      Each patient's data were collected and handled using KAIMRC Research Electronic Data Capture (REDCap®) version 9.1.2 software. The following demographic and laboratory data were collected within 24 hours of ICU admission: comorbidities, vital signs, renal profile (i.e., estimated glomerular filtration rate [eGFR]), liver function tests (i.e., total bilirubin, alanine aminotransferase, aspartate aminotransferase), coagulation profile (i.e., international normalized ratio, activated partial thromboplastin time, platelets count), and inflammatory and surrogate markers (ferritin, d-dimer, and C-reactive protein [CRP]). Moreover, severity score baseline (i.e., Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA)), Glasgow Coma Score (GCS), acute kidney injury (AKI), prone positioning, the needs for mechanical ventilation (MV) and MV parameters (e.g., lowest arterial oxygen tension [PaO2]/fraction of inspired oxygen [FiO2] ratio, highest FiO2 requirement) within 24 hours of ICU admission were documented. In addition, early use of corticosteroids and pharmacological venous thromboembolism prophylaxis were recorded for the eligible patients.

      Study outcomes

      The study aims to assess the effectiveness and safety of TCZ use in critically ill older adult patients (aged ≥65 years) with COVID-19. The primary outcome was the in-hospital mortality compared between patients who received TCZ versus the control group during the ICU stay. The secondary outcomes were the 30-day mortality, hospital LOS, ICU LOS, ventilator-free days (VFDs), and ICU-related complication(s) during the ICU stay (i.e., acute kidney injury, acute liver injury, secondary fungal infection, respiratory failure requiring MV, and the use of inotropes/vasopressors as supportive measures).
      The in-hospital mortality (primary outcome) was defined as death occurring for any cause during hospital stay; patients who were discharged from the hospital alive were presumed to survive. The remaining secondary outcome definitions are provided in the Supplementary file (Table S1).

      Statistical analysis

      We presented continuous variables as mean and SD, or median with lower and upperquartile (Q1, Q3) , as appropriate. Whilecategorical variables as number (percentage). The normality assumptions were assessed for all numerical variables using the Shapiro-Wilk test and graphical representations using histograms and Q-Q plots. Model fit was assessed using the Hosmer-Lemeshow goodness-of-fit test.
      Baseline characteristics and outcome variables were compared between the two study groups for statistical differences. For categorical variables, we used the chi-square or Fisher's exact test. While, for normally distributed continuous variables we used Student t-test and, Mann-Whitney U testfor other non-normally distributed continuous variables . Multivariable Cox proportional hazards regression analysis were performed for the 30-day and in-hospital mortality. Multivariable logistic and negative binomial regression analysis  were used for the other outcomes considered in this study. The odds ratios (OR), hazard ratio (HR), or estimates with the 95% CIs were reported as appropriate. Regression analysis was done by considering the PS as one of the covariates in the model. No imputation was made for missing data because the cohort of patients in our study was not derived from random selection. We considered a P-value of <0.05 statistically significant and used SAS version 9.4 for all statistical analyses.
      PS matching procedure (Proc PS match) (SAS, Cary, North Carolina) was used to match patients who received TCZ (active group) to patients who did not (control group) based on patient's age, APACHE II score, use of systemic corticosteroids, and AKI status within 24 hours of ICU admission. A greedy nearest neighbor matching method was used in which one patient who received TCZ matched with one patient who did not, which eventually produced the smallest within-pair difference among all available pairs with treated patients. Patients were matched only if the difference in the logits of the propensity scores for pairs of patients from the two groups was less than or equal to 0.5 times the pooled estimate of the SD.

      Results

      A total of 1094 patients admitted to the ICU were screened; 368 older adult patients (aged ≥65 years) were eligible based on the eligibility criteria as shown in Figure 1. Of those, 51 patients (13.8%) received TCZ during their ICU stay. After PS matching (1:1 ratio), 94 patients were included based on predefined criteria. All included patients received TCZ within 24 hours of ICU admission. A total of twenty four patients (47%) received a single dose of TCZ.

      Demographic and clinical characteristics

      Before PS matching, most patients were male (65.8%), with a mean age of 75.6 years (SD 7.88). The most common underlying comorbidities in our patients were hypertension (70.7%), diabetes mellitus (68.2%), and dyslipidemia (26.5%) (Table 1). There were some notable differences in the baseline characteristics between the two groups before PS matching. Patients who received TCZ were younger, received more systemic corticosteroids within 24 hours of ICU admission, had higher CRP and ferritin levels at baseline. After adjusting PS matching based on the selected criteria, all baseline and demographic characteristics were similar between the two groups except for diabetes mellitus, which was more prevalent in the control group, as listed in Table 1.
      Table 1Baseline characteristics.
      Before propensity scoreAfter propensity score
      Overall (N = 368)Control (N = 317)Tocilizumab (N = 51)P-valueOverall (N = 94)Control (N = 47)Tocilizumab (N = 47)P-value
      Age (years), mean (SD)75.6 (7.88)76.0 (7.98)73.4 (6.95)0.012
      Wilcoxon rank-sum test is used to calculate the P-value.
      73.1 (6.71)73.0 (6.45)73.2 (7.02)0.994
      Wilcoxon rank-sum test is used to calculate the P-value.
      Gender – male, n (%)237 (65.8)201 (65)36 (70.6)0.44
      Chi-square test is used to calculate the P-value.
      65 (69.9)32 (69.6)33 (70.2)0.945
      Chi-square test is used to calculate the P-value.
      Weight (kg), mean (SD)77.9 (15.66)77.9 (15.71)77.5 (15.49)0.934
      Wilcoxon rank-sum test is used to calculate the P-value.
      77.6 (14.44)77.8 (13.21)77.3 (15.69)0.872
      t-test is used to calculate the P-value.
      APACHE II score, median (Q1, Q3)15.0 (11, 25)16.0 (11, 25)14.0 (12, 26)0.457
      Wilcoxon rank-sum test is used to calculate the P-value.
      13.0 (11, 21)13.0 (10, 20)14.0 (12, 26)0.327
      Wilcoxon rank-sum test is used to calculate the P-value.
      SOFA score, median (Q1, Q3)5.0 (3.00, 8.00)5.0 (3.00, 8.00)4.0 (3.00, 9.00)0.504
      Wilcoxon rank-sum test is used to calculate the P-value.
      4.0 (3.00, 8.00)5.0 (3.00, 8.00)4.0 (3.00, 9.00)0.689
      Wilcoxon rank-sum test is used to calculate the P-value.
      Early use of systemic corticosteroids within 24 hours of admission, n (%)259 (71.5)216 (69.5)43 (84.3)0.03
      Chi-square test is used to calculate the P-value.
      77 (82.8)37 (80.4)40 (85.1)0.550
      Chi-square test is used to calculate the P-value.
      Prone status, n (%)81 (23.3)66 (22.1)15 (30.0)0.224
      Chi-square test is used to calculate the P-value.
      24 (26.7)9 (20.5)15 (32.6)0.192
      Chi-square test is used to calculate the P-value.
      Estimated Glomerular Filtration Rate (eGFR) baseline, median (Q1, Q3)63.00 (32.00, 87.00)62.00 (31.00, 86.00)68.50 (34.00, 96.00)0.179
      Wilcoxon rank-sum test is used to calculate the P-value.
      68.00 (38.00, 95.00)70.00 (40.50, 91.00)68.00 (34.00, 96.00)0.930
      Wilcoxon rank-sum test is used to calculate the P-value.
      AKI within 24 hours of ICU admission, n (%)114 (32.5)102 (33.9)12 (24.0)0.166
      Chi-square test is used to calculate the P-value.
      23 (24.7)11 (23.9)12 (25.5)0.856
      Chi-square test is used to calculate the P-value.
      Mechanical ventilation within 24 hours of ICU admission, n (%)266 (73.9)232 (75.1)34 (66.7)0.205
      Chi-square test is used to calculate the P-value.
      66 (71.0)35 (76.1)31 (66.0)0.282
      Chi-square test is used to calculate the P-value.
      Inotropes/vasopressors use within 24 hours of admission), n (%)89 (25.1)77 (25.4)12 (23.5)0.774
      Chi-square test is used to calculate the P-value.
      23 (24.7)11 (23.9)12 (25.5)0.856
      Chi-square test is used to calculate the P-value.
      Lactic acid baseline (mmol/L), median (Q1, Q3)1.7 (1.30, 2.30)1.8 (1.31, 2.33)1.6 (1.20, 2)0.165
      Wilcoxon rank-sum test is used to calculate the P-value.
      1.7 (1.27, 2.2)1.7 (1.31, 2.23)1.5 (1.2, 2)0.353
      Wilcoxon rank-sum test is used to calculate the P-value.
      Platelet count baseline (10^9/L), median (Q1, Q3)236.0 (178, 302)234.5 (176.5, 300.5)243.0 (198, 331)0.390
      Wilcoxon rank-sum test is used to calculate the P-value.
      251.5 (186, 307.5)262.0 (188, 321)240.0 (183, 304)0.761
      t-test is used to calculate the P-value.
      Total WBC baseline (10^9/L), median (Q1, Q3)9.5 (6.87, 12.90)9.6 (6.86, 12.95)9.2 (6.99, 12.60)0.519
      Wilcoxon rank-sum test is used to calculate the P-value.
      9.5 (6.53, 12.71)10.6 (6.53, 13.00)9.1 (6.47, 11.90)0.216
      Wilcoxon rank-sum test is used to calculate the P-value.
      International normalized ratio (INR), median (Q1, Q3)1.1 (1.04, 1.25)1.1 (1.04, 1.25)1.1 (1.05, 1.20)0.523
      Wilcoxon rank-sum test is used to calculate the P-value.
      1.1 (1.04, 1.25)1.1 (1.04, 1.32)1.1 (1.05, 1.17)0.472
      Wilcoxon rank-sum test is used to calculate the P-value.
      Activated partial thromboplastin time (aPTT) baseline (Seconds), median (Q1, Q3)30.7 (27.4, 34.9)30.9 (27.40, 35.40)30.1 (27.90, 33.30)0.334
      Wilcoxon rank-sum test is used to calculate the P-value.
      30.3 (26.95, 34.00)29.9 (26.80, 34.00)30.5 (28.10, 33.90)0.8
      Wilcoxon rank-sum test is used to calculate the P-value.
      Total bilirubin (μmol/L), median (Q1, Q3)9.0 (6.6, 12.95)9.0 (6.6, 12.5)9.7 (6.3, 14.3)0.511
      Wilcoxon rank-sum test is used to calculate the P-value.
      9.6 (7.1, 14.0)9.5 (7.5, 11.60)9.7 (6.50, 14.80)0.768
      Wilcoxon rank-sum test is used to calculate the P-value.
      Albumin baseline (gm/L), median (Q1, Q3)31.0 (28.00, 35.00)32.0 (28, 35)30.0 (27, 34)0.157
      Wilcoxon rank-sum test is used to calculate the P-value.
      31.0 (28, 35.5)33.0 (29, 36)30.0 (27, 34)0.063
      Wilcoxon rank-sum test is used to calculate the P-value.
      Alanine aminotransferase (ALT) Baseline (U\L), median (Q1, Q3)34.0 (23, 56)33.5 (23, 55.5)38.0 (24.00, 64.00)0.576
      Wilcoxon rank-sum test is used to calculate the P-value.
      37.0 (22.00, 66.00)35.0 (20.00, 72.00)38.0 (24, 64)0.931
      Wilcoxon rank-sum test is used to calculate the P-value.
      Aspartate aminotransferase (AST) Baseline (U\L), median (Q1, Q3)51.0 (35, 80)51.0 (35, 80)54.0 (38.00, 88.00)0.573
      Wilcoxon rank-sum test is used to calculate the P-value.
      48.5 (36.00, 77.00)48.0 (34.00, 77.00)50.0 (38, 85)0.812
      Wilcoxon rank-sum test is used to calculate the P-value.
      Creatine phosphokinase (CPK) baseline (U/l), median (Q1, Q3)139.0 (68, 378)136.5 (71, 361)174.0 (58, 483)0.834
      Wilcoxon rank-sum test is used to calculate the P-value.
      164.0 (69.00, 459.50)144.0 (72, 361)174.0 (58, 563)0.926
      Wilcoxon rank-sum test is used to calculate the P-value.
      C-reactive protein (CRP) baseline (mg/l), median (Q1, Q3)119.0 (48, 189)105.0 (37.25, 182)161.0 (71, 199)0.049
      Wilcoxon rank-sum test is used to calculate the P-value.
      137.0 (71, 182)128.5 (63, 182)159.5 (74.00, 186.45)0.506
      Wilcoxon rank-sum test is used to calculate the P-value.
      Procalcitonin (ng/ml), median (Q1, Q3)0.4 (0.14, 1.26)0.4 (0.16, 1.20)0.4 (0.12, 1.50)0.714
      Wilcoxon rank-sum test is used to calculate the P-value.
      0.4 (0.13, 1.50)0.4 (0.20, 1.77)0.4 (0.13, 0.99)0.397
      Wilcoxon rank-sum test is used to calculate the P-value.
      Fibrinogen level baseline (gm/l), median (Q1, Q3)5.2 (3.96, 7.02)5.2 (4, 7.01)5.4 (2.53, 7.27)0.438
      t-test is used to calculate the P-value.
      4.9 (2.53, 7.02)4.9 (2.58, 7.02)5.0 (2.47, 7.10)0.788
      t-test is used to calculate the P-value.
      d-dimer level baseline (mg/l), median (Q1, Q3)1.7 (0.88, 3.90)1.7 (0.88, 3.90)1.9 (0.85, 3.66)0.868
      Wilcoxon rank-sum test is used to calculate the P-value.
      1.7 (0.91, 3.07)1.5 (0.95, 3.07)1.7 (0.85, 2.72)0.798
      Wilcoxon rank-sum test is used to calculate the P-value.
      Ferritin level baseline (ug/l), median (Q1, Q3)636.6 (314, 1388)565.6 (293.80, 1295.00)1052.5 (648.85, 1887.00)0.007
      Wilcoxon rank-sum test is used to calculate the P-value.
      805.2 (433.40, 1487)555.2 (383.6, 1295)992.9 (648.85, 1689)0.065
      Wilcoxon rank-sum test is used to calculate the P-value.
      Blood glucose level baseline (mmol/L) , median (Q1, Q3)11.8 (8.3, 15.3)12.0 (8.4, 15.40)11.1 (8.1, 14.85)0.451
      Wilcoxon rank-sum test is used to calculate the P-value.
      11.1 (8.1, 15.7)11.1 (8.6, 17.1)11.0 (7.8, 14.85)0.517
      Wilcoxon rank-sum test is used to calculate the P-value.
      Lowest PaO2/FiO2 ratio within 24 hours of admission, median (Q1, Q3)83.9 (59.9, 130.6)82.5 (59.78, 136.1)89.2 (61.12, 124)0.920
      Wilcoxon rank-sum test is used to calculate the P-value.
      84.6 (59.33, 116.5)79.2 (59.25, 109.8)87.0 (61.12, 119.8)0.622
      Wilcoxon rank-sum test is used to calculate the P-value.
      Respiratory rate (RR) baseline (Breath per minute)baseline, median (Q1, Q3)26.0 (22, 32)26.0 (22, 32)28.0 (21.00, 32.00)0.757
      Wilcoxon rank-sum test is used to calculate the P-value.
      25.0 (20.50, 30.00)24.0 (20.00, 29.00)28.0 (21, 32)0.102
      Wilcoxon rank-sum test is used to calculate the P-value.
      Maximum temprature baseline (C°), median (Q1, Q3)37.2 (37.00, 37.80)37.2 (37, 37.9)37.1 (36.90, 37.50)0.127
      Wilcoxon rank-sum test is used to calculate the P-value.
      37.2 (37, 37.60)37.2 (37, 37.7)37.1 (37, 37.5)0.147
      Wilcoxon rank-sum test is used to calculate the P-value.
      Patient received nephrotoxic drugs/material during ICU stay, n (%)294 (82.4)251 (82.0)43 (84.3)0.69
      Chi-square test is used to calculate the P-value.
      80 (87)41 (91.1)39 (83.0)0.247
      Chi-square test is used to calculate the P-value.
      Comorbidity, n (%)
      Atrial fibrillation

      16 (4.4)12 (3.9)4 (7.8)0.2
      Fisher's exact test is used to calculate P-value.
      6 (6.5)2 (4.3)4 (8.5)0.414
      Fisher's exact test is used to calculate P-value.
      Heart failure54 (14.9)46 (14.8)8 (15.7)0.868
      Chi-square test is used to calculate the P-value.
      11 (11.8)4 (8.7)7 (14.9)0.354
      Chi-square test is used to calculate the P-value.
      Hypertension (HTN)256 (70.7)222 (71.4)34 (66.7)0.492
      Chi-square test is used to calculate the P-value.
      65 (69.9)35 (76.1)30 (63.8)0.2
      Chi-square test is used to calculate the P-value.
      Diabetes mellitus (DM)247 (68.2)218 (70.1)29 (56.9)0.06
      Chi-square test is used to calculate the P-value.
      59 (63.4)34 (73.9)25 (53.2)0.038
      Chi-square test is used to calculate the P-value.
      Dyslipidemia (DLP)96 (26.5)83 (26.7)13 (25.5)0.857
      Chi-square test is used to calculate the P-value.
      31 (33.3)19 (41.3)12 (25.5)0.106
      Chi-square test is used to calculate the P-value.
      Chronic kidney disease (CKD)65 (18)59 (19)6 (11.8)0.214
      Chi-square test is used to calculate the P-value.
      14 (15.1)9 (19.6)5 (10.6)0.228
      Chi-square test is used to calculate the P-value.
      Ischemic heart disease (IHD)45 (12.4)42 (13.5)3 (5.9)0.126
      Chi-square test is used to calculate the P-value.
      8 (8.6)6 (13.0)2 (4.3)0.13
      Fisher's exact test is used to calculate P-value.
      Chronic obstructive pulmonary disease (COPD)10 (2.8)9 (2.9)1 (2.0)0.706
      Fisher's exact test is used to calculate P-value.
      3 (3.2)2 (4.3)1 (2.1)0.544
      Fisher's exact test is used to calculate P-value.
      Asthma17 (4.7)16 (5.1)1 (2.0)0.319
      Fisher's exact test is used to calculate P-value.
      3 (3.2)2 (4.3)1 (2.1)0.544
      Fisher's exact test is used to calculate P-value.
      Cancer (any type)10 (2.8)8 (2.6)2 (3.9)0.585
      Fisher's exact test is used to calculate P-value.
      3 (3.2)1 (2.2)2 (4.3)0.57
      Fisher's exact test is used to calculate P-value.
      Deep vein thrombosis (DVT)4 (1.1)4 (1.3)0 (0.0)0.415
      Fisher's exact test is used to calculate P-value.
      1 (1.1)1 (2.2)0 (0)0.31
      Fisher's exact test is used to calculate P-value.
      Pulmonary embolism (PE)3 (0.8)2 (0.6)1 (2.0)0.336
      Fisher's exact test is used to calculate P-value.
      1 (1.1)0 (0)1 (2.1)0.32
      Fisher's exact test is used to calculate P-value.
      Liver disease (any type)9 (2.5)8 (2.6)1 (2.0)0.8
      Fisher's exact test is used to calculate P-value.
      3 (3.2)2 (4.3)1 (2.1)0.544
      Fisher's exact test is used to calculate P-value.
      Stroke35 (9.7)31 (10.0)4 (7.8)0.634
      Fisher's exact test is used to calculate P-value.
      9 (9.7)5 (10.9)4 (8.5)0.7
      Fisher's exact test is used to calculate P-value.
      AKI, acute kidney injury; APACHE II, Acute Physiology and Chronic Health Evaluation II; ICU, intensive care unit;PaO2/FiO2, arterial oxygen tension/fraction of inspired oxygen; Q1, first interquartile; Q3, third interquartile; SOFA, Sequential Organ Failure Assessment; SD, standard deviation; WBC, white blood cell count.
      a t-test is used to calculate the P-value.
      b Wilcoxon rank-sum test is used to calculate the P-value.
      c Chi-square test is used to calculate the P-value.
      d Fisher's exact test is used to calculate P-value.

      Outcomes

      In-hospital and 30-day mortality

      In a crude analysis, there was a significant difference in the in-hospital (37.8% vs 67.4%, P-value = 0.005) and 30-day (34.8% vs 56.5%, P-value = 0.04) mortality in patients who received TCZ compared with the control, respectively. In addition, after the Cox proportional hazards regression analysis, the in-hospital mortality was significantly lower in patients who received TCZ than in those who did not (HR 0.41; 95% CI 0.22–0.76, P-value = 0.005). Moreover, in patients who received TCZ, fewer deaths occurred within 30 days of admission than in patients who did not receive TCZ; however, this finding did not reach the statistical significance in regression analysis (HR 0.66; 95% CI 0.35–1.24, P-value = 0.19) as listed in Table 2. In a Kaplan-Meier curve, the administration of TCZ was associated with better survival outcomes in older adult patients with COVID-19 as shown in Figure 2.
      Table 2Regression analysis for the outcomes after propensity score matching.
      OutcomesCrude analysisP-value
      Chi-square test is used to calculate the P-value.
      HR (95% CI)P-value
      Cox proportional hazards regression analysis is used to calculate HR and P-value.
      ControlTocilizumab
      In-hospital mortality, n (%)
      Denominator of the percentage is the total number of patients.
      31 (67.4)17 (37.8)0.0050.41 (0.22–0.76)0.005
      30-day mortality, n (%)
      Denominator of the percentage is the total number of patients.
      26 (56.5)16 (34.8)0.040.66 (0.35–1.24)0.19
      P-value
      Wilcoxon rank-sum test is used to calculate the P-value.
      Beta coefficient (estimates) (95% CI)P-value
      Generalized linear model is used to calculate beta coefficient (estimates) and P-value.
      Ventilator-free days, mean (SD)
      Denominator of the percentage is the total number of patients.
      8.8 (12.5)12.3 (13.3)0.170.32 (−0.70 to 1.34)0.54
      ICU length of stay (days), median (Q1, Q3)
      Denominator is patients who survived.
      10.0 (3.00, 15.00)12.5 (8.00, 18.00)0.370.36 (−0.17 to 0.89)0.18
      Hospital length of stay (days), median (Q1, Q3)
      Denominator is patients who survived.
      25.0 (10.00, 40.00)22.0 (14.50, 36.00)0.840.20 (−0.30 to 0.71)0.43
      CI, confidence interval; HR, hazard ratio; ICU, intensive care unit; Q1, first interquartile; Q3, third interquartile; SD, standard deviation.
      a Denominator of the percentage is the total number of patients.
      b Denominator is patients who survived.
      c Chi-square test is used to calculate the P-value.
      d Wilcoxon rank-sum test is used to calculate the P-value.
      e Cox proportional hazards regression analysis is used to calculate HR and P-value.
      f Generalized linear model is used to calculate beta coefficient (estimates) and P-value.
      Figure 2
      Figure 2Overall survival plot during the hospital stay comparing patients who received tocilizumab versus the control group.

      Ventilator-free days and LOS

      The mean ventilator-free days was longer in crude analysis toward patients who received TCZ with a mean of 12.3 (±13.3) days compared with 8.8 (±12.5) days in the control group. However, it failed to reach the statistically significant difference after regression analysis with a beta coefficient (95% CI): 0.32 (−0.70 to 1.34), P-value = 0.54 (Table 2).
      The ICU and hospital LOS were not statistically significant in patients who received TCZ compared with the control group (12.5 [8.0–18.0] vs 10.0 [3.0–15.0], P-value = 0.37 and 22 [14.5–36.0] vs 25 [10.0–40.0], P-value = 0.84, respectively). Moreover, there was no significant difference in ICU LOS (beta coefficient, 95% CI: 0.36 [−0.17 to 0.89], P-value = 0.18) or hospital LOS (beta coefficient, 95% CI: 0.20 [−0.30 to 0.71], P-value = 0.43) between the two groups after regression analysis (Table 2).

      Complications during ICU stay

      Patients who received TCZ had lower odds of respiratory failure requiring MV (OR [95% CI]: 0.32 [0.10–0.98], P-value = 0.04). In addition, other complications during ICU such as AKI, liver injury, and secondary fungal infection were lower than the control; however, these results did not reach statistical significance (Table 3).
      Table 3Regression analysis for ICU complication(s) and supportive measure(s) after propensity score matching.
      OutcomesCrude analysisP-value
      Chi-square test is used to calculate the P-value.
      OR (95% CI)P-value
      Multivariate logistic regression analysis is used to calculate OR and P-value.
      ControlTocilizumab
      Acute kidney injury, n (%)
      Denominator of the percentage is the total number of patients.
      28 (60.9)24 (51.1)0.340.66 (0.29–1.52)0.33
      Liver injury, n (%)
      Denominator of the percentage is the total number of patients.
      5 (10.9)4 (8.5)0.70
      Fisher's exact test is used to calculate the P-value.
      0.76 (0.19–3.04)0.69
      Respiratory failure requiring MV, n (%)41 (89.1)34 (72.3)0.040.32 (0.10–0.98)0.04
      Inotropes/vasopressors use during ICU stay as supportive measures, n (%)
      Denominator of the percentage is the total number of patients.
      30 (69.8)27 (57.4)0.230.87 (0.38–1.98)0.74
      Secondary fungal infection, n (%)
      Denominator of the percentage is the total number of patients.
      8 (24.2)9 (23.7)0.960.93 (0.30–2.86)0.89
      CI, confidence interval; ICU, intensive care unit; MV, mechanical ventilation; OR, odds ratio.
      a Denominator of the percentage is the total number of patients.
      b Chi-square test is used to calculate the P-value.
      c Fisher's exact test is used to calculate the P-value.
      d Multivariate logistic regression analysis is used to calculate OR and P-value.

      Discussion

      This multicenter retrospective study found that the in-hospital mortality rate was significantly lower in older adult patients who received TCZ than those who did not. However, the 30-day mortality was numerically lower in the TCZ group but did not reach a statistically significant difference. In contrast, the in-hospital mortality was statistically significantly lower in older adult patients who received TCZ, which might be because of a longer follow-up period that may detect other hospital-related complications. Similarly, the odds of respiratory failure requiring MV were significantly lower in older adult patients with COVID-19 who received TCZ during the ICU stay.
      In our study, older adult patients with COVID-19 who received TCZ had a significant reduction in the in-hospital mortality. This result was consistent with previous studies’ findings showing survival benefit following TCZ administration among patients with COVID-19 (
      • Hermine O
      • Mariette X
      • Tharaux PL
      • Resche-Rigon M
      • Porcher R
      • Ravaud P
      CORIMUNO-19 Collaborative Group. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial.
      ;
      • Kimmig LM
      • Wu D
      • Gold M
      • Pettit NN
      • Pitrak D
      • Mueller J
      • et al.
      IL-6 inhibition in critically ill COVID-19 patients is associated with increased secondary infections.
      ;
      RECOVERY Collaborative Group
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ; REMAP-CAP
      • Investigators REMAP-CAP
      • Gordon AC
      • Mouncey PR
      • Al-Beidh F
      • Rowan KM
      • Nichol AD
      • Arabi YM
      • et al.
      Interleukin-6 receptor antagonists in critically ill patients with Covid-19.
      ;
      • Salama C
      • Han J
      • Yau L
      • Reiss WG
      • Kramer B
      • Neidhart JD
      • et al.
      Tocilizumab in patients hospitalized with Covid-19 pneumonia.
      ;
      • Soin AS
      • Kumar K
      • Choudhary NS
      • Sharma P
      • Mehta Y
      • Kataria S
      • et al.
      Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial.
      ;
      • Stone JH
      • Frigault MJ
      • Serling-Boyd NJ
      • Fernandes AD
      • Harvey L
      • Foulkes AS
      • et al.
      Efficacy of tocilizumab in patients hospitalized with Covid-19.
      ;
      • Van den Eynde E
      • Gasch O
      • Oliva JC
      • Prieto E
      • Calzado S
      • Gomila A
      • et al.
      Corticosteroids and tocilizumab reduce in-hospital mortality in severe COVID-19 pneumonia: a retrospective study in a Spanish Hospital.
      ). In our previous study, increasing the number of TCZ doses showed no significant difference in mortality, rather it showed higher odds of pneumonia in patients who received multiple TCZ doses (
      • Al Sulaiman K
      • Aljuhani O
      • Bin Salah K
      • Korayem GB
      • Eljaaly K
      • Al Essa M
      • et al.
      Single versus multiple doses of tocilizumab in critically ill patients with coronavirus disease 2019 (COVID-19): a two-center, retrospective cohort study.
      ). However, all these reports included adult patients with COVID-19 not specific to older adult patients. Unlike adult patients, older adult patients usually have multiple chronic conditions that complicate COVID-19 disease outcome or progression and management and increase their risk of mortality (
      • Salama C
      • Han J
      • Yau L
      • Reiss WG
      • Kramer B
      • Neidhart JD
      • et al.
      Tocilizumab in patients hospitalized with Covid-19 pneumonia.
      ; Saudi Ministry of Health,

      Saudi Ministry of Health. Saudi MoH protocol for patients with suspected of/confirmed with COVID-19: supportive care and antiviral treatment of suspected or confirmed COVID-19 infection (Version 3.1), https://www.moh.gov.sa/Ministry/MediaCenter/Publications/Documents/MOH-therapeutic-protocol-for-COVID-19.pdf. Accessed 29/5/2022.

      ). The mean age of patients included in our study was 73.2 years, which indicated an older population compared with the mean age of patients included in the REMAP-CAP and RECOVERY trials at 61.5 and 63.3 years, respectively (
      • Stone JH
      • Frigault MJ
      • Serling-Boyd NJ
      • Fernandes AD
      • Harvey L
      • Foulkes AS
      • et al.
      Efficacy of tocilizumab in patients hospitalized with Covid-19.
      ;
      RECOVERY Collaborative Group
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ). Even though our patients had a higher CRP level and a lower PaO2/FiO2 at baseline than those included in other studies, our mortality benefit is consistent with the previous studies (
      • Grasselli G
      • Zangrillo A
      • Zanella A
      • Antonelli M
      • Cabrini L
      • Castelli A
      • et al.
      Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy.
      ;
      RECOVERY Collaborative Group
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ;
      • Stone JH
      • Frigault MJ
      • Serling-Boyd NJ
      • Fernandes AD
      • Harvey L
      • Foulkes AS
      • et al.
      Efficacy of tocilizumab in patients hospitalized with Covid-19.
      ). All study patients in our cohort received their first dose of TCZ during their first day of ICU admission, which could justify the reduction of in-hospital mortality as early use might target the peak of the cytokine's releases; this agrees with some reported data from previous studies. The time to the first dose of TCZ in RECOVERY and REMAP-CAP trials was relatively consistent to our study with a median of 2 and 1.2 days, respectively (
      RECOVERY Collaborative Group
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ;
      • Stone JH
      • Frigault MJ
      • Serling-Boyd NJ
      • Fernandes AD
      • Harvey L
      • Foulkes AS
      • et al.
      Efficacy of tocilizumab in patients hospitalized with Covid-19.
      ).
      Patients with COVID-19 reported having high levels of IL-6 and other inflammatory biomarkers, such as cytokines, macrophage inflammatory protein 1 alpha, and tumor necrosis factor-α (
      • Aldhaeefi M
      • Tahir Z
      • Cote DJ
      • Izzy S
      • El Khoury J.
      Comorbidities and age are associated with persistent COVID-19 PCR positivity.
      ;
      • Bhatraju PK
      • Ghassemieh BJ
      • Nichols M
      • Kim R
      • Jerome KR
      • Nalla AK
      • et al.
      Covid-19 in critically ill patients in the Seattle region - case series.
      ;
      • Grasselli G
      • Zangrillo A
      • Zanella A
      • Antonelli M
      • Cabrini L
      • Castelli A
      • et al.
      Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy.
      ;
      • Soin AS
      • Kumar K
      • Choudhary NS
      • Sharma P
      • Mehta Y
      • Kataria S
      • et al.
      Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial.
      ) The mortality benefit of TCZ in patients with severe COVID-19 remains debatable (
      • Aldhaeefi M
      • Tahir Z
      • Cote DJ
      • Izzy S
      • El Khoury J.
      Comorbidities and age are associated with persistent COVID-19 PCR positivity.
      ;
      • Alkofide H
      • Almohaizeie A
      • Almuhaini S
      • Alotaibi B
      • Alkharfy KM.
      Tocilizumab and systemic corticosteroids in the management of patients with COVID-19: a systematic review and meta-analysis.
      ;
      • Bhatraju PK
      • Ghassemieh BJ
      • Nichols M
      • Kim R
      • Jerome KR
      • Nalla AK
      • et al.
      Covid-19 in critically ill patients in the Seattle region - case series.
      ;
      • Kyriakopoulos C
      • Ntritsos G
      • Gogali A
      • Milionis H
      • Evangelou E
      • Kostikas K.
      Tocilizumab administration for the treatment of hospitalized patients with COVID-19: a systematic review and meta-analysis.
      ;
      • Soin AS
      • Kumar K
      • Choudhary NS
      • Sharma P
      • Mehta Y
      • Kataria S
      • et al.
      Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial.
      ). This mortality reduction uncertainty could be explained by a theory suggesting this hyperinflammatory immune response represents a natural and possibly beneficial host response against infection and suggestive of macrophage activation (
      • Aldhaeefi M
      • Tahir Z
      • Cote DJ
      • Izzy S
      • El Khoury J.
      Comorbidities and age are associated with persistent COVID-19 PCR positivity.
      ;
      • Bhatraju PK
      • Ghassemieh BJ
      • Nichols M
      • Kim R
      • Jerome KR
      • Nalla AK
      • et al.
      Covid-19 in critically ill patients in the Seattle region - case series.
      ;
      • Grasselli G
      • Zangrillo A
      • Zanella A
      • Antonelli M
      • Cabrini L
      • Castelli A
      • et al.
      Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy.
      ;
      • Soin AS
      • Kumar K
      • Choudhary NS
      • Sharma P
      • Mehta Y
      • Kataria S
      • et al.
      Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial.
      ). In support of this theory,
      • Hermine O
      • Mariette X
      • Tharaux PL
      • Resche-Rigon M
      • Porcher R
      • Ravaud P
      CORIMUNO-19 Collaborative Group. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial.
      failed to show a mortality reduction among patients with COVID-19 receiving TCZ despite including patients with moderate disease (WHO-CPS score of 5), with a lower CRP than our patients, and early administration of TCZ.
      Moreover, our patients had higher rates of MV and comorbidities than those included in the COVINTOC trial, which also failed to show a mortality benefit of the TCZ (
      • Soin AS
      • Kumar K
      • Choudhary NS
      • Sharma P
      • Mehta Y
      • Kataria S
      • et al.
      Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial.
      ). Similarly,
      • Salama C
      • Han J
      • Yau L
      • Reiss WG
      • Kramer B
      • Neidhart JD
      • et al.
      Tocilizumab in patients hospitalized with Covid-19 pneumonia.
      and Stones et al. (
      • Stone JH
      • Frigault MJ
      • Serling-Boyd NJ
      • Fernandes AD
      • Harvey L
      • Foulkes AS
      • et al.
      Efficacy of tocilizumab in patients hospitalized with Covid-19.
      ) failed to demonstrate a mortality benefit of the TCZ despite 83% and 64.7% of the study's population being non–critically ill patients, respectively (
      • Alkofide H
      • Almohaizeie A
      • Almuhaini S
      • Alotaibi B
      • Alkharfy KM.
      Tocilizumab and systemic corticosteroids in the management of patients with COVID-19: a systematic review and meta-analysis.
      ;
      • Kyriakopoulos C
      • Ntritsos G
      • Gogali A
      • Milionis H
      • Evangelou E
      • Kostikas K.
      Tocilizumab administration for the treatment of hospitalized patients with COVID-19: a systematic review and meta-analysis.
      ). Our findings suggest that TCZ could reduce respiratory failure requiring MV and disease progression in high-risk patients such as older adult patients with COVID-19. This finding is contrary to the findings of the RECOVERY trial in which TCZ use did not result in a reduction of respiratory failure requiring MV among patients older than 80 years (
      RECOVERY Collaborative Group
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ). However, several studies concurred with our findings and reported that TCZ use is effective in preventing clinical worsening, disease progression, and the need for MV for patients at a higher risk of clinical worsening despite including patients with mild, moderate, and severe COVID-19. However, these results were uncertain about the effectiveness of TCZ in preventing disease progression among older adult patients with COVID-19, given the heterogeneity of the patient population included in these studies (
      • Hermine O
      • Mariette X
      • Tharaux PL
      • Resche-Rigon M
      • Porcher R
      • Ravaud P
      CORIMUNO-19 Collaborative Group. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial.
      ;
      • Salama C
      • Han J
      • Yau L
      • Reiss WG
      • Kramer B
      • Neidhart JD
      • et al.
      Tocilizumab in patients hospitalized with Covid-19 pneumonia.
      ;
      • Sciascia S
      • Aprà F
      • Baffa A
      • Baldovino S
      • Boaro D
      • Boero R
      • et al.
      Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19.
      ;
      • Stone JH
      • Frigault MJ
      • Serling-Boyd NJ
      • Fernandes AD
      • Harvey L
      • Foulkes AS
      • et al.
      Efficacy of tocilizumab in patients hospitalized with Covid-19.
      ;
      • Toniati P
      • Piva S
      • Cattalini M
      • Garrafa E
      • Regola F
      • Castelli F
      • et al.
      Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia, Italy.
      ;
      • Xu X
      • Han M
      • Li T
      • Sun W
      • Wang D
      • Fu B
      • et al.
      Effective treatment of severe COVID-19 patients with tocilizumab.
      ).
      In addition, patients treated with TCZ in this study had a trend of prolonged ICU and hospital LOS. This finding was consistent with the RECOVERY trial among patients older than 80 years (
      RECOVERY Collaborative Group
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ). Both mortality benefit and the improvement in the respiratory failure among our patients might explain the prolonged ICU and hospital LOS. In addition, having patients in a strictly controlled and isolated environment was one of the precautionary steps to avoid spreading infections during COVID-19 pandemic outside the hospitals.
      Regarding the ICU complications, there were no significant differences in the two study groups. TCZ is a potent immunomodulator that works through competitive inhibition of IL-6 binding to its receptor (
      • Al Sulaiman K
      • Aljuhani O
      • Bin Salah K
      • Korayem GB
      • Eljaaly K
      • Al Essa M
      • et al.
      Single versus multiple doses of tocilizumab in critically ill patients with coronavirus disease 2019 (COVID-19): a two-center, retrospective cohort study.
      ;
      RECOVERY Collaborative Group
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ). A major concern with administering such therapy among patients with patients with COVID-19 is the serious secondary infections. Several studies have reported more serious secondary infections following TCZ administration (
      • Alkofide H
      • Almohaizeie A
      • Almuhaini S
      • Alotaibi B
      • Alkharfy KM.
      Tocilizumab and systemic corticosteroids in the management of patients with COVID-19: a systematic review and meta-analysis.
      ;
      • Bhatraju PK
      • Ghassemieh BJ
      • Nichols M
      • Kim R
      • Jerome KR
      • Nalla AK
      • et al.
      Covid-19 in critically ill patients in the Seattle region - case series.
      ;
      • Kimmig LM
      • Wu D
      • Gold M
      • Pettit NN
      • Pitrak D
      • Mueller J
      • et al.
      IL-6 inhibition in critically ill COVID-19 patients is associated with increased secondary infections.
      ;
      • Stone JH
      • Frigault MJ
      • Serling-Boyd NJ
      • Fernandes AD
      • Harvey L
      • Foulkes AS
      • et al.
      Efficacy of tocilizumab in patients hospitalized with Covid-19.
      ). In contrast to these studies, we found a nonsignificant difference in the rate of secondary fungal infections. Several studies reported similar findings regarding secondary infections with TCZ versus standard of care (
      • Aldhaeefi M
      • Tahir Z
      • Cote DJ
      • Izzy S
      • El Khoury J.
      Comorbidities and age are associated with persistent COVID-19 PCR positivity.
      ;
      • Kyriakopoulos C
      • Ntritsos G
      • Gogali A
      • Milionis H
      • Evangelou E
      • Kostikas K.
      Tocilizumab administration for the treatment of hospitalized patients with COVID-19: a systematic review and meta-analysis.
      ;
      RECOVERY Collaborative Group
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ;
      • Sciascia S
      • Aprà F
      • Baffa A
      • Baldovino S
      • Boaro D
      • Boero R
      • et al.
      Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19.
      ;
      • Soin AS
      • Kumar K
      • Choudhary NS
      • Sharma P
      • Mehta Y
      • Kataria S
      • et al.
      Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial.
      ).
      As far as we know, this is one of the first multicenter studies that investigated the efficacy and safety of TCZ in critically ill older adult patients with COVID-19. In addition, PS matching was used to eliminate a greater portion of bias and create a balanced dataset. However, the study is not free of limitations. First, it was a retrospective study that included a relatively small sample size. Second, short follow-up duration may limit capturing further secondary infections or long-term complications. Finally, our study might be underpowered to detect a difference in long-term outcomes.

      Conclusion

      This study shows that TCZ administration among critically ill older adults with COVID-19 resulted in reduced in-hospital mortality without a significant increase of secondary infections or other ICU complications. Further robust randomized clinical trials evaluating the safety and efficacy of TCZ among older critically ill patients with COVID-19 are needed to confirm our findings.

      Declaration of Competing Interests

      The authors have no conflicts of interest to declare.

      Funding

      Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2022R78), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

      Ethics approval and consent to participate

      The study was approved by King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia (Ref.#. NRC21R.434.10). Throughout the study, participants' confidentiality was rigorously preserved by using an anonymous unique serial number for each individual and confining data to just the investigators. Informed consent was not required because of the research method, which was following the policies of the governmental and local research institutes.

      Acknowledgments

      We would like to thank Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2022R78), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. The authors would like to acknowledge all the investigators in the Saudi critical care pharmacy research (SCAPE) platform who participated in this project.

      Author contributions

      All authors contributed to data collections, analysis, drafted, revised, and approved the final version of the manuscript. All authors critically revised the manuscript, agreed to be fully accountable for ensuring the integrity and accuracy of the work, and read and approved the final manuscript.

      Availability of data and material

      The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request.

      Consent for publication

      Not applicable.

      Appendix. Supplementary materials

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