Weathering the storm of COVID-19: the role of cytokine inhibitors

The cytokine storm, arising from a dysregulated host response, has captivated mainstream and scientific media in recent times with its possible role leading to poor outcomes in COVID-19. It is characterized by the release of mediators, including chemokines, interleukins, interferons, and tumor necrosis factors. This innate response that commonly occurs in bacterial and viral infections is directed to combat and eliminate the infective pathogen. However, an uncontrolled, dysregulated response can lead to injury to the host. Specifically, the profound inflammatory response that occurs in the lung may interfere with alveolar-capillary gas exchange, resulting in impaired oxygenation, an important cause of mortality in COVID-19. Several drugs that are used in chronic inflammatory conditions have been repurposed and touted as possible inhibitors of the exaggerated immune response with a view to improving clinical outcomes. 

Cytokine levels in COVID-19

Chuan et al. retrospectively evaluated 452 patients admitted to the Tongji Hospital in Wuhan with COVID-19 infection. Among these, 286 were diagnosed to have severe infection characterized by tachypnea, oxygen saturation ≤93% while breathing room air, and a PaO₂/FiO₂ ratio of ≤300 mm Hg. The serum levels of C-reactive protein, ferritin, and procalcitonin were high in patients who had severe infection. The level of inflammatory cytokines, including IL-2R, IL-6, IL-10, and TNR- α were also higher in patients who had severe compared to non-severe infection. The authors concluded that a dysregulated immune response may trigger severe illness among patients with COVID-19 infection by inducing a cytokine storm leading to organ failure.¹

What really happens in the lung in COVID-19 pneumonia? 

Although several studies suggest raised levels of inflammatory mediators in COVID-19, it is pertinent to compare levels observed in other types of acute respiratory distress syndrome (ARDS). IL-6 levels may be considerably lower in patients with severe COVID-19 compared with levels that are typically seen in patients with the hyperinflammatory phenotype of ARDS.² Ackermann et al. evaluated autopsy findings in the lungs from patients who died of COVID-19 and compared it with patients who died of H1N1 pneumonia and those with uninfected lungs. The pulmonary involvement in COVID-19 was characterized by endothelial injury, presence of intracellular virus, and cell membrane disruption. Capillary microthrombi were nine times more common in COVID-19 compared to H1N1. Furthermore, new vessel formation was 2.7 fold higher in COVID-19.³ These changes suggest that the lung may be the primary focus of involvement in COVID-19; indeed, a marked systemic inflammatory response may not be the trigger for the pathophysiological changes observed in the lung. The current level of evidence does not substantiate the severity of the lung injury based on a dysregulated immune response with increased cytokine levels. 

Cytokine inhibitors in COVID-19? 

Tocilizumab, an IL-6 blocker, has been successfully used in the cytokine release syndrome that may follow chimeric antigen receptor-T cell therapy. This therapeutic modality involves genetic modification of the patient’s own T-cells to create a chimeric antigen receptor on the surface. The chimeric antigen receptor (CAR)-T cells identify and attach to abnormal antigens present on tumor cells and destroy them. Promising results have been demonstrated in end-stage cancer, especially in acute lymphocytic leukemia.⁴ CAR T-cell therapy may lead to a massive release of cytokines, including IL-6 and interferon γ into the bloodstream. The cytokine release syndrome (CRS) is characterized by a flu-like illness, which may lead to multiorgan failure in the severely ill. Largely based on its efficacy in the CRS associated with chimeric antigen receptor T-cell therapy in cancer⁵, tocilizumab has been repurposed as IL-6 blocker therapy in COVID-19. However, it is important to note that IL-6 levels are nearly 1000 times higher in CRS compared to the levels observed in COVID-19.²

What’s the evidence? 

IL-6 blockers

Among the key agents being evaluated in COVID-19, IL-6 receptor blockers, including tocilizumab and sarilumab, have evinced the most interest. 

In an observational study of 239 consecutive patients with COVID-19, tocilizumab was administered to patients who presented with severe disease, requiring ≥ 3 L of supplemental oxygen to maintain oxygen saturation > 93%, including patients who received mechanical ventilation. Later on during the study, the use of tocilizumab was extended to patients with high C-reactive protein levels. Intravenous tocilizumab 8 mg/kg was administered, with a maximum dose of 800 mg. A second dose was administered in patients with a high BMI. The investigators observed improved oxygenation and reduced level of inflammatory markers. Fourteen-day survival was higher than expected in tocilizumab treated patients; however, this study did not have a control arm.⁶

Two Italian studies evaluated the efficacy of tocilizumab in COVID-19 pneumonia. A retrospective observational study included 1351 patients, with 544 who had severe disease. Tocilizumab was administered in 179 patients with severe disease; a reduced requirement for mechanical ventilation and improved survival was noted among these patients.⁷ In contrast, in another Italian study, the use of tocilizumab did not result in amelioration of respiratory symptoms, requirement for intensive care, or improved survival. This study was stopped early at interim analysis after enrolment of 126 patients, one-third of the projected sample size.⁸

Ip et al. conducted a retrospective observational study that evaluated the association between treatment with hydroxychloroquine or tocilizumab and mortality among hospitalized patients with COVID-19. In an exploratory analysis, 134 of 527 patients received tocilizumab. The authors observed a trend towards improved survival associated with tocilizumab treatment.⁹

A registry analysis from Michigan, US, evaluated the safety and efficacy of tocilizumab among a single-center cohort of patients with COVID-19 who required mechanical ventilation. The study included 154 patients; 78 patients received tocilizumab. Propensity scores were calculated by multivariable regression to adjust for confounders. The authors observed a 45% reduction in the hazard ratio for mortality with tocilizumab administration. Tocilizumab administration was also associated with improved clinical status on a 6-point ordinal scale. A significantly higher incidence of superinfections was observed with tocilizumab administration (54% vs. 26%; p<0.001), although there was no significant increase in the 28-day case fatality among those who developed superinfection.  

IL-1 blockers 

There are limited data with specific IL-1 blockers in patients with COVID-19. The efficacy of anakinra, an IL-1 blocker, has been evaluated in several preliminary case series. Anakinra was found to be safe and appeared to hasten clinical improvement in a small series of 29 patients.¹⁰ In another study, 52 patients were prospectively administered anakinra 100 mg twice daily for 72 hours, followed by once daily for 7 days. This group was compared to a retrospective control group of  44 patients. Anakinra reduced the need for invasive ventilation and reduced mortality without obvious adverse effects.¹¹

Future perspectives 

Several clinical trials that evaluate cytokine antagonists are ongoing. Sarilumab, another IL-6 inhibitor, is being trialed in hospitalized patients with severe COVID-19 (NCT04327388).¹² Sirukumab, an IL-6 antibody, combined with standard care, is being studied in a placebo-controlled trial. Anakinra, tocilizumab, and siltuximab are also being trialed solely or in combination and compared to standard care. The results from these trials may guide us regarding the future of cytokine blockade in patients with COVID-19.

The bottom line

• Although intuitive, cytokine blocker therapy has a long track record of failure in bacterial and viral infections.
• One of the major stumbling blocks has been to identify the time point at which the host response spirals out of control, for antagonist therapy to be effective. Given the current state of knowledge, we are unable to distinguish between an appropriate and injurious level of host response for effective timing of therapy.
• The host immune response clearly involves a complex interplay between several mediators; the response is neither linear nor uniform. 
• Long-acting cytokine inhibitors used in chronic inflammatory disease may lead to an increased risk of superinfections in critically ill patients. 
• A single cytokine such as IL-6 is unlikely to be the sole driver of the adaptive response for a specific antagonist to be effective. Hence, single mediator antagonism may be based on a hypothetically weak strategy. 
• Although early studies have shown promise, the results of adequately powered randomized controlled trials are awaited to explore potential benefit. 

References

1.         Qin C, Zhou L, Hu Z, et al. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. Published online March 12, 2020:ciaa248. doi:10.1093/cid/ciaa248

2.         Sinha P, Matthay MA, Calfee CS. Is a “Cytokine Storm” Relevant to COVID-19? JAMA Intern Med. Published online June 30, 2020. doi:10.1001/jamainternmed.2020.3313

3.         Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120-128. doi:10.1056/NEJMoa2015432

4.         Miliotou AN, Papadopoulou LC. CAR T-cell Therapy: A New Era in Cancer Immunotherapy. Curr Pharm Biotechnol. 2018;19(1):5-18. doi:10.2174/1389201019666180418095526

5.         Maude S, Barrett DM. Current status of chimeric antigen receptor therapy for haematological malignancies. Br J Haematol. 2016;172(1):11-22. doi:10.1111/bjh.13792

6.         Price CC, Altice FL, Shyr Y, et al. Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized COVID-19 Patients: Survival and Clinical Outcomes. Chest. Published online June 15, 2020. doi:10.1016/j.chest.2020.06.006

7.         Guaraldi G, Meschiari M, Cozzi-Lepri A, et al. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatol. Published online June 2020:S2665991320301739. doi:10.1016/S2665-9913(20)30173-9

8.         Roche rheumatoid arthritis drug fails to help COVID-19 patients in Italian study. Reuters. https://www.reuters.com/article/us-health-coronavirus-roche-hldg-idUSKBN23O3GG. Published June 18, 2020. Accessed July 19, 2020.

9.         Ip A, Berry DA, Hansen E, et al. Hydroxychloroquine and Tocilizumab Therapy in COVID-19 Patients – An Observational Study. medRxiv. Published online May 25, 2020:2020.05.21.20109207. doi:10.1101/2020.05.21.20109207

10.       Cavalli G, Luca GD, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020;2(6):e325-e331. doi:10.1016/S2665-9913(20)30127-2

11.       Huet T, Beaussier H, Voisin O, et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheumatol. 2020;2(7):e393-e400. doi:10.1016/S2665-9913(20)30164-8

12.       Sanofi: Press Releases, Monday, April 27, 2020. https://www.sanofi.com/en/media-room/press-releases/2020/2020-04-27-12-58-00. Accessed July 19, 2020. https://www.sanofi.com/media-room/press-releases/2020/2020-04-27 12-58-00 2022288