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Abstract
Background The optimal timing of tocilizumab treatment during the disease course of COVID-19 has yet to be adequately defined in the context of randomised controlled trials and the effect of tocilizumab on real-world populations remains unclear. We examined the effect of different timing of tocilizumab, on mortality, in a cohort of adults with COVID-19.
Methods All adults (≥18 years old) with confirmed COVID-19 admitted to four hospitals in the West of Scotland between 8 January 2021 and 31 March 2021 and who received tocilizumab were included in a retrospective observational cohort study. Patients were assigned to either an early (day of admission or first day after admission) or late (days 2–7 of admission) cohort based on tocilizumab initiation. The primary outcome was 90-day all-cause mortality in early versus late cohorts. Secondary outcomes were 28 and 180-day all-cause mortality.
Results 203 patients were included in the analysis (138 in the early cohort, 65 in the late cohort). Mortality in 90 days in the early cohort was 22% (n=30) compared with 45% (n=29) in the late cohort (p<0.001). The adjusted mortality was significantly higher in the late cohort compared with the early cohort (adjusted OR: 3.33; 95% CI: 1.29 to 8.54; p=0.012). The secondary outcomes demonstrated the same effect with higher rates of death in 28 days (late cohort adjusted OR: 3.28; 95% CI: 1.23 to 8.75; p=0.018) and 180 days (late cohort adjusted OR: 3.70; 95% CI: 1.45 to 9.45; p=0.006). The effect was seen whether the outcome was adjusted or unadjusted.
Conclusion Early administration of tocilizumab within the first 2 days of hospitalisation was associated with a significant survival benefit compared with late exposure. Late administration was associated with particularly high mortality. The observed association may be a result of residual confounders and further research is needed.
- COVID-19
- Viral infection
- Respiratory Infection
- Critical Care
Data availability statement
Data are available upon reasonable request. The data sets are available from the corresponding author on reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Landmark trials REMAP-CAP (Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community Acquired-Pneumonia) and RECOVERY (Randomised Evaluation of COVID-19 Therapy) have demonstrated that tocilizumab reduces mortality in severe COVID-19. However, considerable uncertainty remains regarding when the interleukin-6 (IL-6) blockade should be initiated.
WHAT THIS STUDY ADDS
Early administration of tocilizumab within the first 2 days of hospitalisation was associated with a significant survival benefit compared with late exposure suggesting that time from hospital admission to IL-6 treatment may be an important factor affecting mortality.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This study challenges unnecessary delays in treatment, possibly suggesting that tocilizumab should be administered as early as possible after patients meet the criteria for this therapy. The results generate an important hypothesis that should be a focus of further research in a prospective randomised controlled clinical trial.
Introduction
COVID-19 is a disease caused by the SARS-CoV-2 virus. Severe disease is characterised by a hyper-inflammatory response that can lead to the development of acute respiratory distress syndrome and multiorgan failure. Interleukin-6 (IL-6) is postulated to play an important role in the cytokine storm observed in severe COVID-19 and elevated levels of IL-6 have been associated with poor outcomes including respiratory failure and death.1
Tocilizumab, a monoclonal antibody and IL-6 receptor blocker, is thought to blunt the inflammatory cascade and has been the subject of COVID-19 treatment studies.2 Evidence for the optimal timing of administration of tocilizumab in COVID-19 has been conflicting and is complicated due to different patient populations, significant variation in the use of concomitant steroids and administration at varying time points in the COVID-19 disease course. However, the results of two large randomised controlled trials, REMAP-CAP and RECOVERY, demonstrated that tocilizumab was associated with a survival benefit in severe COVID-19.3 4 Participants in these trials had the highest mortality rates (control group mortality>30%) and a majority (>80%) were receiving steroids. There was significant overlap in the inclusion criteria between the trials: New organ failures; or hypoxaemia with markers of systemic inflammation.3 4 Of note, there were important differences: REMAP-CAP only recruited critically ill patients and the timing of tocilizumab administration differed between these trials. Specifically, the inclusion criteria for REMAP-CAP was within 24 hours of requiring advanced organ support; whereas administration in RECOVERY was triggered by the inflammatory response defined as a C-reactive protein (CRP)≥75 mg/L with participants eligible at any time point during admission.
The evidence from these trials has resulted in tocilizumab administration becoming standard practice in the treatment of severe COVID-19 and recommended as part of national and international guidelines.5 6 However, there remains substantial uncertainty regarding when the IL-6 blockade should be initiated with current WHO guidance unable to offer specific advice on the optimal timing during the disease course and identifying this as a focus for future research.6
We therefore conducted a multicentre retrospective cohort study to examine the effect of tocilizumab timing on mortality using real-world data in a defined population known to benefit from tocilizumab, all of whom received concomitant steroids.
Methods
Study design
We conducted a multicentre retrospective observational cohort study. The study protocol was reviewed by the local ethics committee screener (NHS Greater Glasgow and Clyde) and ethical approval was not deemed to be required for collection of individual patient data. Caldicott Guardian approval was granted for data collection.
Setting
The study setting was four acute hospital sites in Scotland’s largest health board, Greater Glasgow and Clyde in the West of Scotland (Glasgow Royal Infirmary, Inverclyde Royal, Queen Elizabeth University and Royal Alexandra Hospitals). These hospitals provide 3812 acute beds and 140 critical care beds serving a population of 1.3 million.7
Population
Adults (≥18 years old) admitted with confirmed COVID-19 between 8 January 2021 and 31 March 2021 and who received tocilizumab were included. This time period coincided with tocilizumab first being used outside of clinical trial conditions, enabling a window for examination of real-world data. Study recruitment finished at the end of March coinciding with the end of the second wave of COVID-19 in the UK. Our inclusion criteria were: Adults 18 years old or greater; admission to hospital with a confirmed COVID-19 diagnosis; received tocilizumab within 7 days of hospital admission; and met the inclusion criteria for either the REMAP-CAP or RECOVERY trials. Inclusion criteria were chosen to reflect the contemporaneous evidence base.
We excluded patients receiving tocilizumab after 7 days of hospital admission in addition to the specific exclusion criteria as defined by REMAP-CAP and RECOVERY (figure 1).
Flow diagram and inclusion/exclusion criteria. CRP, C-reactive protein; ICU, intensive care unit; PCR, polymerase chain reaction; REMAP-CAP, Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community Acquired-Pneumonia; RECOVERY, Randomised Evaluation of COVID-19 Therapy; TB, tuberculosis.
Patients were retrospectively assigned to either an early or late cohort. Early administration was defined as tocilizumab administration on the day of hospital admission or the first day after hospital admission. Late administration was defined as tocilizumab given between days 2 and 7 after hospital admission.
All eligible participants during the study period were included.
Procedures
Tocilizumab was administered at a dose of 8 mg/kg intravenously up to a maximum of 800 mg. A second dose of tocilizumab could be administered at the discretion of the senior doctor responsible for the patient’s care. This dosing regimen replicates the protocol of REMAP-CAP and RECOVERY and conforms to the current licensing for this drug.3 4 All patients concomitantly received dexamethasone 6 mg daily enterally or intravenously for 10 days as a standard of care. All sites worked to the same local guidelines for the selection and treatment of COVID-19 patients.
Data collection
Clinical and demographic data were obtained from patients’ electronic records (CareVue, Philips IntelliVue Clinical Information Portfolio; Clinical Portal) and from WardWatcher (Critical Care Audit Limited, Yorkshire) with permission from the Scottish Intensive Care Society Audit Group. Data were independently collected by two investigators (FM, CC); 10% of participants’ complete data sets were verified by a third investigator (AO).
Once each patient was assigned to a cohort (early vs late) the baseline date for all data collection was defined as the day of tocilizumab administration. As such all baseline variables were extracted from patient records on this date. All patients were followed up to 180 days from this baseline date or censored at death.
The date of death was collected from electronic patient records (Clinical Portal). This is linked to primary healthcare and general practice records via the community healthcare index number. This permitted reliable longitudinal follow-up of deaths for all patients residing in Scotland. All participants were residents of Scotland at study enrolment and follow-up.
Ethnicity was collected from electronic patient records and recorded as White, Asian, Black, Mixed or other. Respiratory support was defined as supplemental low-flow oxygen, non-invasive ventilation (NIV) which included continuous positive airway pressure ventilation (CPAP), high flow nasal oxygen (HFNO) or mechanical ventilation (MV).
A treatment escalation plan records and communicates the personalised and realistic goals of treatment for patients admitted to the hospital acutely unwell and is documented by senior medical staff. This generally follows the patient during the entirety of their hospital stay. This was recorded particularly well during the period of this study. Treatment escalation plans define the maximum organ support patients are likely to benefit from and for this study we have dichotomised this documentation into two groups: (1) ‘Level 3’ were patients who were likely to benefit from intensive care unit (ICU) and would be offered invasive MV (IMV) if required; (2) ‘Level 1 or 2’ were patients who were unlikely to benefit from ICU/IMV and maximum therapy would involve ward or high dependency level treatment (eg, supplemental oxygen, NIV, HFNO, vasopressors). We have used these data as a marker of multicomorbidity, frailty and limited functional capacity as these are the factors that most commonly influence escalation plans. The clinical decision to administer tocilizumab was not based on the escalation plan. This was a new and unfamiliar treatment for COVID-19 at the time and as such the decision to prescribe was based on the inclusion and exclusion criteria in the guidelines which applied to all patients (figure 1).
Partial pressure arterial oxygen:fraction of inspired oxygen (PaO2:FiO2 (PF)) ratio was used as a marker of illness severity.
The Scottish Index of Multiple Deprivation (SIMD) was used to categorise socioeconomic deprivation.8 This is a relative measure of deprivation across geographically defined data zones in Scotland and is a measure principally based on each patient’s home postcode. We used quintiles to allow fewer df in the modelling process thus allowing the inclusion of important clinical variables.
Outcomes
The primary outcome was the difference between the early and late exposure groups, in 90-day all-cause mortality. The secondary outcomes were differences between these groups, in 28-day and 180-day all-cause mortality.
Statistical analysis
Patient characteristics are summarised using counts and percentages for categorical data, means and SD, or medians, 25th and 75th percentiles for continuous data depending on the distribution. Differences in baseline characteristics between the cohorts were analysed with Wilcoxon rank-sum, Pearson χ² and Fisher’s exact tests. To understand the effect of early versus late tocilizumab on mortality, both adjusted and unadjusted logistic regression are described. Adjustment was undertaken to address any imbalances in the baseline characteristics between the cohorts; to adjust for known clinically important features corresponding to mortality in COVID-19; and a consideration of the significant covariates identified through unadjusted (univariable) logistic regression of each baseline characteristic (see additional file online supplemental table S1-S4).9–11 As such, all models were adjusted for: Age; ethnicity; oxygen administration and/or type of ventilatory support; CRP; and the treatment escalation plan in place. We conducted a sensitivity analysis and added sex into the model as this has previously been demonstrated to be important for COVID-19 survival (see additional file online supplemental table S5). The deprivation index (SIMD) was not included in the final model as both cohorts were very well matched and this characteristic did not correlate with mortality during univariable logistic regression (see additional file online supplemental table S1).
Supplemental material
The secondary outcomes are reported in the same way as unadjusted and adjusted ORs using logistic regression using the same models.
The dataset was 97.9% complete and imputation was not required to account for missing data (see additional file online supplemental table S6). Analyses were carried out using R V.4.3.0 (21 April 2023).12 Outputs are represented with forest plots of ORs and a Kaplan-Meier curve for the unadjusted outcomes. A significance value of p<0.05 was used throughout.
Results
Participant flow
A total of 254 patients were prescribed tocilizumab over the study period across four hospital sites. Of these, 203 patients who received the drug met the inclusion criteria and were included in the data analysis. 138 participants were included in the early cohort and 65 in the late cohort.
Baseline characteristics
The early and late cohorts were similar in most baseline characteristics. Both early and late cohorts were predominantly white men with a similar median body mass index (BMI) (32.0 (IQR 29.0–38.5) vs 32.2 (IQR 28.1–37.3)). Baseline oxygen support, PF ratios and socioeconomic status were also similar in both groups and there were no statistically significant differences (table 1).
Baseline demographics and characteristics on the day of tocilizumab
Of significance, the early group, as compared with the late group, were younger (57 years (IQR 49–63) vs 60 years (IQR 52.0–67.7)) and had a higher baseline CRP (142 (IQR 103–196) vs 96.5 (IQR 73.2–129.3)). The documented escalation plan was significantly different between the cohorts; in the early cohort there were more patients deemed appropriate for escalation to level 3 than in the late cohort (table 1).
Outcomes
Mortality in 90 days in the early cohort was 22% (n=30) compared with 45% (n=29) in the late cohort (p<0.001). The adjusted OR of death for late administration of tocilizumab compared with early administration was 3.3 (adjusted OR: 3.33; 95% CI: 1.29 to 8.54; p=0.012)(figure 2). Similarly the unadjusted logistic regression demonstrated statistically significant higher mortality in the late tocilizumab cohort (OR: 2.90; 95% CI: 1.54 to 5.47; p=0.001) (figure 2).
ORs of the mortality risk of late tocilizumab administration compared with early administration.
The secondary outcomes demonstrated the same effect with higher rates of death in 28 days (adjusted OR: 3.28; 95% CI: 1.23 to 8.75; p=0.018) and 180 days (adjusted OR: 3.70; 95% CI: 1.45 to 9.45; p=0.006) with the strongest association being seen in 180 days. Again this effect was seen whether the outcome was adjusted or unadjusted (figure 2).
The sensitivity analysis demonstrated that there was no significant change in outcomes when patient sex was added to the model; the statistically significantly increased mortality associated with late tocilizumab administration in 90 days remained (additional file online supplemental table S5). This was also true for both 28-day and 180-day mortality.
The Kaplan-Meier curve also demonstrates that the probability of survival is significantly higher in the early versus the late group through 90 days (figure 3).
Kaplan-Meier curve for survival through 90 days.
Mortality in the group as a whole was 25.1% (n=51) at day 28, 29.1% (n=59) at day 90 and 29.6% (n=60) at day 180 (additional file online supplemental table S7).
Hospital length of stay for survivors was less in the early cohort (9 days (IQR 6.0–19.58) vs 13 days (IQR 8.0–21.8)) though this was not significant (p=0.08) (additional file online supplemental table S7).
Missingness of the data variables applicable to all patients and outcomes was 2.9% (additional file online supplemental table S6).
Discussion
In this retrospective cohort study of patients with severe COVID-19 who met evidence-based criteria for tocilizumab, early administration within 2 days of hospital admission was associated with a statistically significant mortality benefit compared with late administration. The unadjusted crude mortality (22% vs 45%) demonstrates this statistically significant large effect (additional file online supplemental figure S1). The mortality benefit remains significant for all analysed time points up to 180 days. Moreover these results were consistent for both adjusted and unadjusted analysis.
There is currently minimal evidence available to guide treatment decisions on the optimal timing of tocilizumab administration specifically in relation to the time from hospital admission. Defining the optimal window of timing for tocilizumab in moderate to severe COVID-19 is a crucial consideration. In severe disease where the inflammatory process has significantly advanced, IL-6 modulation may be futile as demonstrated in the COVACTA trial which included patients late in the critical disease process and failed to demonstrate a survival benefit with tocilizumab versus placebo.13 However early IL-6 modulation in mild to moderate disease or when viral replication is still occurring may potentially hamper the useful anti-viral T-cell response.14
Both RECOVERY and REMAP-CAP trials initiated treatment early (randomisation at a median of 2 days of hospitalisation in RECOVERY; <24 hours of advanced organ support for REMAP-CAP) suggesting tocilizumab may be more beneficial early in patients with rapidly progressive moderate to severe disease specifically around the time of clinical deterioration. Of note, the late cohort given tocilizumab beyond day 2 in our study had a particularly high mortality of 45%. Given that the control group mortality in REMAP-CAP and RECOVERY was 36% and 35%, respectively, it is imperative that timing is better defined to ensure that there is no harm associated with administration.3 4
An exploratory analysis by RECOVERY looking at treatment timing from admission to hospitalisation indicated that the effects of tocilizumab on 28-day mortality were similar for those assigned≤2 or >2 days since hospitalisation (p=0.89).4 A formal subgroup analysis was not carried out on this unfortunately. A prespecified subgroup analysis of 28-day mortality by RECOVERY in relation to the time since symptom onset found no significant difference between early (≤7 days) and late (>7 days) administration (p=0.30).4 We did not collect data on timing from symptom onset or how this related to the time of hospital presentation. This information was not consistently recorded in medical notes and can be subjective and potentially unreliable. Future prospectively recruited studies should consider how this variable is recorded and if collateral history would be required.
In contrast to the RECOVERY exploratory analysis, another retrospective study analysing factors predicting clinical response to tocilizumab in patients with severe COVID-19 found early administration of tocilizumab in relation to hospital admission was associated with better clinical response. Following adjustment for factors related to unfavourable outcomes, administration within the first 48 hours from admission was independently related to significant clinical improvement (OR: 1.98, 95% CI 1.1 to 3.55; p=0.02). The rate of improvement significantly decreased according to the time of administration: 70.2% in the first 48 hours from admission, 58.5% on days 3–7 and 45.1% after day 7 (p=0.03 and p=0.001, respectively).15
We recognise that CRP is an important inflammatory marker and relates to the severity of illness and outcomes in COVID-19 and as such have included CRP in all of the adjusted models. The effect of CRP on mortality was not found to be statistically significant in our study (additional file online supplemental tables S2-S5). The RECOVERY trial specifically used raised CRP as a trigger for selecting patients with hypoxia who might respond to IL-6 blockade. In REMAP-CAP, the effects of tocilizumab in prespecified subgroups of CRP were similar across all levels of CRP, however, they were strongest and statistically significant among patients with the highest CRP levels.3 Interestingly, the largest meta-analysis to date of IL-6 antagonists in patients with COVID-19 found that the association of these drugs with lower 28-day all-cause mortality was consistent across all subgroups of CRP.16 This suggests that CRP may not be the perfect biomarker for optimal timing or possibly that the trajectory and relative changes may be more important thus identifying the specific time point of significant deterioration. Mapping the CRP trajectory before immunosuppressive treatment would add more useful information to further studies.
The presence of co-infection both pre-tocilizumab and post-tocilizumab and the effect on outcomes is an important consideration in this study. Co-infection was an exclusion criterion for receiving tocilizumab in the guidelines and as such patients with clear evidence of co-infection were not administered tocilizumab or were excluded from the study. The low vasopressor use at the time of tocilizumab administration in both cohorts supports the absence of significant co-infection and is lower than the vasopressor use in REMAP-CAP (table 1).3 Tocilizumab is immunosuppressive and has, in some studies, been associated with an increased incidence of secondary infection.17 Randomised trials of tocilizumab have frequently assessed shorter-term mortality outcomes of 28 days or less.4 13 18 The WHO suggests the need for further research examining longer-term outcomes in COVID-19 and as such this study was designed to capture longer-term outcomes up to 180 days and therefore any effects of late co-infection on mortality. REMAP-CAP carried out a long-term follow-up study and demonstrated treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomised to control. This outcome offers some assurance that the early mortality benefit from IL-6 antagonists does not result in longer-term adverse outcomes in this particular group of patients.19 RECOVERY have specified further analysis of outcomes at 6 months, however this has not yet been published. Mortality in the REMAP-CAP and RECOVERY trials was 24.1% and 30.7%, respectively, at 28 days.16 Our real-world pooled 28-day mortality lies between these two landmark trials at 25.1% rising to 29.6% by 180 days. Interestingly our results show that although most deaths occurred by day 28, 15% (n=9) occurred between 28 days and 180 days suggesting that longer follow-up was appropriate and meaningful.
This study has several limitations. As a retrospective observational study, residual confounding is likely and cohort heterogeneity is present. We could not preclude that patient selection bias comes into play in the early exposure group, however during statistical analysis, we have attempted to address available imbalances in the cohorts that patient selection and heterogeneity may have contributed to. All important variables that impacted mortality identified through univariable analysis have been included in the model. Given that our results for both unadjusted and adjusted analysis were consistent and significant, this suggests that measured baseline characteristics are not exerting a substantial effect on outcome.
The use of timing from hospital admission may have inherent problems. Hospital admission between and within different settings can vary depending on resource availability, particularly during a pandemic when the healthcare system burden is high. We also did not have granular enough data to assess the exact time patients in the late group became eligible for tocilizumab. That is, some patients in the late group met the criteria earlier and could have received the drug sooner. However, every patient in this dataset was hospitalised specifically because of COVID-19 and therefore more detail on when the late group met the criteria would not change the interpretation that receiving tocilizumab late after hospital admission was associated with a much higher mortality.
In terms of missing data, although this was low overall, some data, especially those related to disease severity, could not be collected in retrospect and ethnicity was not available in 35%. Non-white ethnicity has been shown to have an effect on mortality, however given that our population in Glasgow is known to be>80% white, it is unlikely that this missing data would significantly affect our results.20 We did not collect information on comorbidities, however we have used documented escalation plans as surrogate markers of comorbidity and these are accounted for in the analysis. More comorbidity data would be of value in future studies. We also did not collect data on why patients received tocilizumab late in their hospital admission. The data collection time period coincided with initial use outside of trial conditions. Health board guidelines were available but may have taken time to bed in due to pressures on the system and the dynamic nature of treatment options at the time. Local and national guidelines also did not emphasise prompt administration and discouraged out-of-hours use. Additionally there were supply shortages of tocilizumab during this stage of the pandemic potentially leading to delays in treatment. A further limitation of this study is that, due to the seasonal nature of COVID-19, it is a reasonably small sample size although comparable to similar studies. It would therefore be useful to have a larger study analysis of this effect. If a larger observational study was undertaken then propensity score matching could be used to reduce bias due to confounding variables.
Conclusion
In this multicentre retrospective observational cohort study, early administration of tocilizumab within the first 2 days of hospitalisation was associated with a significant survival benefit compared with late exposure. Current evidence and national guidelines do not adequately address the timing of IL-6 inhibitors in COVID-19 and this study generates a hypothesis that needs to be addressed fully in order to guide clinicians treating patients with severe COVID-19. Our results suggest that time from hospital admission to IL-6 treatment may be an important factor affecting mortality. This study challenges unnecessary delays in treatment, possibly suggesting that if tocilizumab is to be given in the future then this should happen as soon as patients meet the criteria for this medication. Conversely, these data should make the clinician who is considering prescribing tocilizumab late after hospital admission consider alternative reasons for the patient’s deterioration and whether this medication is truly indicated.
In addition, longer-term outcomes beyond 28 days should be included in future studies given the potential severity of this disease and the incidence of death seen beyond this point in this study.
Data availability statement
Data are available upon reasonable request. The data sets are available from the corresponding author on reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants but Greater Glasgow and Clyde Ethics Committee exempted this study. Retrospective data collection.
Acknowledgments
We would like to thank Dr Samantha Carmichael and Dr Iain Mactier for help with patient identification and data collection. We thank Dr Brian Digby, Dr Barbara Miles, Professor Malcolm Sim and Dr Peter Stenhouse for permitting access to data across the health board critical care departments.
Footnotes
Contributors FM is the guarantor. Study conception and design: FM, AO, RL. Data collection: FM, CC, AO. Data analysis and interpretation: PH, FM. Writing of article: FM, PH, RL, AO, PM. Final review of article: All authors.
Funding This research was supported by a Catalytic Funding Challenge grant number 01/2021 provided by Pharmacy Services, Greater Glasgow and Clyde National Health Service.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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