ASCIA Position Statement: Specific Treatments for COVID-19

At present, there are no proven pharmacological therapies for prevention or treatment of the COVID-19 respiratory disease that is caused by the novel coronavirus SARS-CoV-2.

ASCIA acknowledges the urgent need for effective therapies for the prevention and treatment of COVID-19.

As the situation regularly changes this document is reviewed and updated as required.

Content last updated 30 July 2020.

pdfASCIA HP Position Statement COVID-19 Treatments 2020 July Update179.44 KB 

Pharmacological treatments for COVID-19 can be divided into two classes:

  • Antiviral therapies -
    • Pharmacological, e.g. remdesivir, (TGA approved for COVID-19).
    • Biological, e.g. convalescent serum (see ASCIA Position Statement on Immunoglobulin Therapies for COVID-19)
  • Immunomodulatory therapies -
    • Anti-interleukin-6 (Anti-IL6), e.g. tocilizumab, siltuximab, sarilumab, JAK inhibitors (see below)
    • Corticosteroids, e.g. dexamethasone (see below)
    • Anti-interleukin 1 (Anti-IL1), e.g. anakinra
    • Intravenous Immunoglobulin G (IVIg) - NOT recommended (see ASCIA Position Statement on Immunoglobulin Therapies for COVID-19 and recommendation 5 in this Statement).

ASCIA is aware that many clinical trials are underway in Australia and internationally, and a number of resources are available to access details, including the following websites:

The aim of these trials is to provide clinical evidence for safety and efficacy of medications for the prevention and/or treatment of COVID-19. 

In the interim ASCIA does not usually recommend the off-label use of medications for the prevention or treatment of COVID-19 outside of these trials, for the following reasons:

  • Uncertain benefits.
  • Potential risk of harm.
  • Impact that inappropriate use of these medications has on continuity of supply for patients with immune diseases for which these medications are established treatments.

Whilst ASCIA recommends that experimental therapies for COVID-19 should be administered in the context of a clinical trial where available, it is recognised that circumstances may arise where this is not possible. ASCIA advises that treatments that lack robust supportive evidence of safety and efficacy in this setting should be considered with appropriate expert consultation.

The role of immunomodulation in COVID-19

Current management of COVID-19 is largely supportive, with respiratory support in cases that develop COVID-19 related acute respiratory distress syndrome (ARDS).

However, despite usual ventilation strategies, mortality remains high1. There are also reports of the ARDS being unusual and not responding to usual methods of ventilation2.  Alternative hypotheses have been suggested to explain this phenomenon.  Largely this is biologically explained by a cytokine storm syndrome3.

Corticosteroids

In July 2020 investigators from a large UK trial published a preliminary report showing survival benefits for patients treated with dexamethasone.4 ASCIA supports the process of enrolling patients into controlled trials of corticosteroids such as dexamethasone at different times during the disease course, to determine where these common and inexpensive medications might have a potential role in COVID-19.

IL-6 blockade

Based on the understanding of the possible contribution a cytokine storm syndrome to the increased mortality in COVID-19 related ARDS, IL-6 blockade may be beneficial. IL-6 is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine.

Tocilizumab (Actemra) is an inhibitory IL-6 receptor monoclonal antibody which has an established role for the treatment of life-threatening cytokine release syndrome caused by chimeric antigen receptor (CAR) T-cell therapy5.

ASCIA recommends that IL-6 inhibitors, such as tocilizumab, should be considered as an off-label treatment option for patients with COVID-19-related ARDS and hyperinflammation, and for use in clinical trials.

This recommendation is based on the confirmed efficacy of tocilizumab in a condition with similar pathogenesis5,6, and the following clinical reports suggesting benefit in patients with COVID-19:

  • The Society for Immunotherapy of Cancer statement on access to IL-6-targeting therapies for COVID-197 
  • Michot et al. Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related respiratory failure: a case report. Annals on Oncology 20208
  • Xu et al. Effective Treatment of Severe COVID-19 Patients with tocilizumab9
  • Morrison et al, Clinical characteristics and predictors of survival in adults with coronavirus disease 2019 receiving tocilizumab10.

There are also a number of hospital specific and national protocols that include consideration of anti-IL-6 monoclonal antibodies. These data favour the use of IL-6 inhibitors, such as tocilizumab, as an intervention to prevent progression of COVID-19 pneumonia, which may prevent ICU admission and ventilation.

There is no clear evidence for increased risk of infection with short-term use of tocilizumab11.  The rate of bacterial infection attributable to long-term tocilizumab use in rheumatoid arthritis is approximately one infection per 100 person-years of treatment12.

Timing for administration of immunomodulatory therapies is likely to be critical to their potential effectiveness. Where tocilizumab is administered for COVID-19 related ARDS and hyperinflammation, it is recommended that treatment should be considered early in severe disease.

Recommendations

  1. ASCIA strongly endorses a collaborative, multidisciplinary approach to management of COVID-19.
  2. ASCIA recommends the use of therapies such as remdesivir (TGA approved for COVID-19) and dexamethasone, in appropriate patients with COVID-19.
  3. ASCIA recommends that clinicians in all specialties involved in the care of COVID-19 patients consider the use of tocilizumab (an inhibitory IL-6 receptor monoclonal antibody) early in critically ill patients, in consultation with a clinical immunologist or other specialist with experience in use of immunomodulatory therapies for systemic inflammatory diseases. Through its membership of clinical immunology specialists in Australia and New Zealand, ASCIA is available to facilitate consultation and collaboration if needed, regarding the administration of tocilizumab for COVID-19.
  4. ASCIA does not currently recommend the use of anakinra outside of clinical trials. However, there may be exceptional circumstances in which administration of this agent may be considered outside a clinical trial, with appropriate expert consultation.
  5. ASCIA recommends against the use of IVIg until data emerges of a potential benefit. However, IVIg as an Immunomodulatory therapy may have a role in the treatment of rarer SARS-CoV2 associated complications such as PIMS-TS or MIS-C.13, 14
  6. Consideration of using any treatments for COVID-19 (including tocilizumab) must balance potential clinical benefits with the theoretical risk of harm.

Further information

The situation regarding COVID-19 is rapidly changing, so it important to monitor information from ASCIA other organisations, Australian and New Zealand governments, that are available on the ASCIA COVID-19 webpage www.allergy.org.au/members/covid-19, which is reviewed daily and updated as required.

References

  1. Wu, C. et al. Risk Factors Associated with Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med (2020). https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2763184 
  2. Gattinoni, L. et al. Covid-19 Does not Lead to a ‘Typical’ Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. (2020).  https://www.atsjournals.org/doi/pdf/10.1164/rccm.202003-0817LE
  3. Mehta, P. et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet, 395, 1033–1034 (2020). https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/fulltext).
  4. The RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. NEJM 2020. https://www.nejm.org/doi/10.1056/NEJMoa2021436
  5. Le, R. Q. et al. FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome. Oncologist, 23, 943–947 (2018). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156173/
  6. Giavridis, T. et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med 24, 731–738 (2018). https://www.nature.com/articles/s41591-018-0041-7
  7. Ascierto, P. A. et al. Insights from immuno-oncology: the Society for Immunotherapy of Cancer Statement on access to IL-6-targeting therapies for COVID-19. J Immunother Cancer 8, (2020). https://www.sitcancer.org/research/covid-19-resources/il-6-editorial
  8. Michot, J.-M. et al. Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related respiratory failure: a case report. Ann Oncol. (2020). https://www.annalsofoncology.org/article/S0923-7534(20)36387-0/pdf 
  9. Xu, X. et al. Effective treatment of severe COVID-19 patients with tocilizumab. PNAS 2020. https://www.pnas.org/content/117/20/10970
  10. Morrison et al, Clinical characteristics and predictors of survival in adults with coronavirus disease 2019 receiving tocilizumab. J Autoimmun. 2020 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332925/
  11. Hill, J. A. et al. Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood, 131, 121–13 (2018). https://www.annalsofoncology.org/article/S0923-7534(20)36387-0/pdf
  12. Pawar, A. et al. Risk of serious infections in tocilizumab versus other biologic drugs in patients with rheumatoid arthritis: a multidatabase cohort study. Ann Rheum Dis. 78, 456–464 (2019). http://dx.doi.org/10.1136/annrheumdis-2018-214367 
  13. Feldstein, L. R et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. NEJM 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2021680
  14. Davies, P et al. Intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study. The Lancet Child & Adolescent Health July 2020. https://www.sciencedirect.com/science/article/pii/S2352464220302157

© ASCIA 2020

ASCIA is the peak professional body of clinical immunology/allergy specialists in Australia and New Zealand.

ASCIA resources are based on published literature and expert review, however, they are not intended to replace medical advice.

The content of ASCIA resources is not influenced by any commercial organisations.

For more information go to www.allergy.org.au

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