Tocilizumab Use in COVID-19 Cytokine-release Syndrome: Retrospective Study of Two Centers

BACKGROUND

The COVID-19 pandemic has evolved into an unprecedented threat to human life and global economy. In the past few months intensive care units (ICU) globally are inundated by admissions of COVID-19 related respiratory failure. There is already enormous medical literature published on COVID-19, but clinicians across the world are searching for a pragmatic treatment approach for these patients. The pathogenesis of COVID-19 is still incompletely understood, but available evidence suggests disease severity is directly linked with increased inflammatory markers like cytokines (interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α) and chemokines.¹ Cytokine-release syndrome (CRS) is one of the key pathophysiological process involved in sudden deterioration with COVID-19 causing acute respiratory distress syndrome (ARDS) and other multiorgan failure (MOF).^1,2 Tocilizumab, a monoclonal antibody against IL-6 receptor, has been used “off-label” in some studies with variable success for these patients.^3–6 We used a structured protocol based on clinical, biochemical, and IL6 criteria for the identification of the subset of patients with CRS and used tocilizumab for their treatment.

MATERIALS AND METHODS

From 15 March to 15 May, we received a total of 112 COVID-19 patients in our ICU. The respiratory severity of illness was decided by clinical, radiological, and oxygenation using arterial blood gas (Table 1). Eighty-five of the 112 (76.57%) patients developed severe and critical category of illness. We did a retrospective case-control analysis of all severe and critical COVID-19 patients who developed deterioration in ICU. There were 22 patients in the severe and critical category who received tocilizumab in addition to conventional care.

RESULTS

The data from all 85 patients were collected.

DISCUSSION

The understanding of pathophysiology in respiratory failure caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is still evolving. There is a definitive role of host immune response to SARS-CoV-2 related ARDS and MOF.^1,7 The hypercytokinemia is seen with COVID-19 in many epidemiological studies while the CRS which is characterized by exuberant systemic inflammation and higher mortality is seen with severe illness.⁸ IL-6 is a major mediator in CRS, and its levels have been closely linked to SARS-CoV-2 viral load, ARDS severity, and outcome.^1,8–10

The timely detection of CRS and its treatment can improve outcomes in such patients.^1,3,6 We used a pragmatic protocol to identify these patients. In our study we started tocilizumab when IL-6 was ten times the upper limit of normal in the absence of any obvious bacterial or fungal infection as a marker of CRS. The mean IL6 in our patients was 205.26 and median 145.9. There was male preponderance in our patients, and hypertension was the commonest associated comorbidity. The mortality at day 7 (p = 0.007) and day 28 (p = 0.001) and need for escalation of respiratory support (p = 0.001) were statistically significant lower in the patients who received tocilizumab vs standard treatment (Table 3, Fig. 1). Recent studies involving a large number of patients from Italy and New York have reported worse outcomes in COVID-19 patients requiring invasive ventilation.^11,12 Avoiding invasive mechanical ventilation may itself be a strategy to reduce the overall mortality. The timely identification of CRS and administration of tocilizumab to the patients reduce the need for escalation of respiratory support such as invasive ventilation in these patients and hence reduced mortality. The ICU-LOS was higher in the tocilizumab group but was not statistically significant, which can be partly explained by the higher need for escalation in standard treatment group and early mortality. On reviewing the trends of inflammatory markers, only CRP showed a significant decline with the use of tocilizumab by day 3 (p = 0.033) as reported by other studies (Table 4 and Fig. 2).⁵

Hypercytokinemia is a hallmark of COVID-19; however, serum levels of cytokines observed are generally below the usual levels observed in CRS or similar disorders such as macrophage activation syndrome/reactive hemophagocytic lympho-histiocytosis (MAS/reHLH).^1,2 Thus, CRS should be considered with SARS-CoV-2 infection only in cases of overly exuberant systemic inflammation leading to critical illness such as ARDS or MOF.^8,9 We used tocilizumab only in patients with IL6 above 70 (10 times the upper limit of normal laboratory value).

This is one of the few studies that reported use of tocilizumab only in severely and critically ill patients with ARDS, who are more likely to have the benefit of the immunomodulators on CRS. We also used higher values of IL-6 (10 times upper limit of normal) as our inclusion criteria. The steroids were used in all our severe and critically ill patients for 7–10 days. In a recently published RECOVERY trial on COVID-19 patients, dexamethasone, statistically reduces the mortality by one-third in patients on mechanical ventilation (hazard ratio = 0.65, p = 0.003).¹³ The dramatic effect of dexamethasone in severe illness also proves the hypothesis that hyperinflammation significantly contributes to ARDS seen with COVID-19. The use of immunomodulator such as tocilizumab with specific action on IL6 and its possible synergistic action with steroids is likely responsible for good outcomes in our study.

The strength of this study was inclusion of only critically ill patients with IL6 value 10 times the upper limit of normal. This was important to separate the subset of CRS from hyperinflammation. The exclusion of secondary bacterial and fungal sepsis was another criterion. There are, however, a few limitations for our study retrospective cohort, small numbers of patients and effect of steroids on the outcomes. The effect size of outcome could have been exaggerated due to limited numbers of the patients in the study. Despite its limitations, this study proves use of simple pragmatic protocol for early identification of CRS and treatment with tocilizumab and steroids for 7–10 days can significantly improve the outcome in these patients.

CONCLUSION

Tocilizumab can improve outcome by reducing the need for invasive ventilation and mortality when used timely in patients with CRS. We propose a double-blind randomized study involving a larger sample size and using IL6 and other inflammatory markers to evaluate its potential therapeutic role of tocilizumab in CRS seen with COVID-19.

HIGHLIGHTS

• Cytokine release syndrome (CRS) can cause sudden deterioration in few patients of COVID-19 and can be identified using clinical deterioration with inflammatory markers and IL-6.
• Tocilizumab can improve outcome by reducing the need of invasive ventilation and mortality when used timely in patients with CRS.

REFERENCES

1. Jamilloux Y, Henry T, Belot A, Viel S, Fauter M, El Jammal T, et al. Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions. Autoimmun Rev 2020;19(7): 102567. DOI: 10.1016/j.autrev.2020.102567.

2. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis 2020. ciaa248. DOI: 10.1093/cid/ciaa248.

3. Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci USA 2020;117(20):10970–10975. DOI: 10.1073/pnas.2005615117.

4. Morena V, Milazzo L, Oreni L, Bestetti G, Fossali T, Bassoli C, et al. Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in Milan, Italy. Eur J Intern Med 2020;76:36–42. DOI: 10.1016/j.ejim.2020.05.011.

5. 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. Autoimmun Rev 2020;19(7): 102568. DOI: 10.1016/j.autrev.2020.102568.

6. Campochiaro C, Della-Torre E, Cavalli G, De Luca G, Ripa M, Boffini N, et al. Efficacy and safety of tocilizumab in severe COVID-19 patients: A single-centre retrospective cohort study. Eur J Intern Med 2020;76:43–49. DOI: 10.1016/j.ejim.2020.05.021.

7. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8(4):420–422. DOI: 10.1016/S2213-2600(20)30076-X.

8. Yang Y, Shen C, Li J, Yuan J, Yang M, Wang F, et al. Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome. medRxiv 2020;2020(3). DOI: 10.1016/S2213-2600(20)30076-X.

9. Chen X, Zhao B, Qu Y, Chen Y, Xiong J, Feng Y, et al. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. medRxiv 2020;2020(2). DOI: 10.1093/cid/ciaa449.

10. McGonagle D, Sharif K, O’Regan A, Bridgewood C. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev 2020;19(6): 102537. DOI: 10.1016/j.autrev.2020.102537.

11. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the new york city area. JAMA 2020;323(20):2052–2059. DOI: 10.1001/jama.2020.6775.

12. 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. JAMA 2020;323(16):1574–1581. DOI: 10.1001/jama.2020.5394.

13. Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med 2020 Jul17: NEJMoa2021436. DOI: 10.1056/NEJMoa2021436.