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CLINICAL VIEWPOINT: Immunosuppression and COVID-19

Posted in Clinical Review Article,Comment,Online First,Special Feature on 15th Apr 2020

Correspondence to: Gavin Giovannoni, Blizard Institute, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK;  E. g.giovannoni@qmul.ac.uk
Conflict of interest statement: None declared
Provenance and peer review: Invited and internally reviewed
Dave first submitted: 13/4/20
Acceptance date: 14/4/20
Published online: 15/4/20
Published under a Creative Commons license


It is clear that the COVID-19 pandemic is a global health crisis with the potential to kill millions of people, particularly the elderly and people with comorbidities such as hypertension, smoking and cardiovascular and lung disease. It has also been assumed that people who are immunocompromised, for example people with multiple sclerosis (MS) on immunosuppressive disease-modifying therapies (DMTs) are also at increased risk of developing COVID-19 and severe COVID-19. But are they?

An important hypothesis being considered is that moderate immunosuppression may prevent severe complications associated with COVID-19 infection. The severe pulmonary complications of COVID-19 infection are consistent with ARDS (acute respiratory distress syndrome) caused by an over-exuberant immune response to the virus 1. As a result, several exploratory trials are being undertaken using various immunosuppressive therapies to try and dampen the immune response to the virus. Fingolimod (ClinicalTrials.gov Identifier: NCT04280588), a S1P modulator licensed for MS, and tocilizumab (ClinicalTrials.gov Identifier: NCT04331795), an anti-IL6-receptor antagonist licensed for rheumatoid arthritis, are currently being tested as a treatment for COVID-19 associated ARDS.

New data released on the 4th April 2020 from the UK’s Intensive Care National Audit & Research Centre suggests immunosuppression may protect against severe COVID 2. When comparing 2249 patients admitted to ITU in the UK with severe COVID-19 the proportion of immunocompromised patients was 3.7x lower than the proportion of immunocompromised patients admitted to ITU with viral pneumonia (the comparator) between 2017 and 2019 (2.3% vs. 8.5%, p<0.00001; Figure 1) 2. This clearly supports the current research strategy to test if immunosuppressive therapies may improve disease outcome in patients with COVID-19.

Covid-19 immunosuppression

Figure 1: Proportion of patients on immunosuppression with either severe COVID-19 or viral pneumonia. These data are derived from the ICNARC Case Mix Programme Database. The Case Mix Programme is the national clinical audit of patient outcomes from adult critical care coordinated by the Intensive Care National Audit & Research Centre (ICNARC). For more information on the representativeness and quality of these data, please contact ICNARC.

Does this mean we can now assume that immunosuppression protects against severe COVID-19 and COVID-19-related ARDS (adult respiratory distress syndrome)? Not yet. The UK’s ITU cohort of severe COVID-19 2 is almost certainly biased in that those patients who are deemed too frail and/or disabled with COVID-19 may never get to ITU, which may include a disproportionate number of immunosuppressed patients. Whereas this specific bias is unlikely to apply to ITU admissions between 2017 and 2019 (viral pneumonia cohort) when there was no such pressure on resources. Despite this caveat, this is an important bit of information that will be reassuring to people with MS on immunosuppression and their healthcare professionals.

I sincerely hope the wider MS community will reconsider their advice about not giving MS DMTs that are if anything mildly immunosuppressive to patients with active MS. By not treating our patients we may unintentionally be increasing their chances of developing severe COVID-19. Could our guidelines 3 be another example of the law of unintended consequences? Let’s hope the real-world data that is currently being collected will answer this question.

Another factor to be considered is that immunosuppression may not only affect the clinical manifestation of COVID-19, but the natural history of SARS-CoV-2. A particular concern is whether or not patients on immunosuppression who are infected with SARS-CoV-2 will have increased viral replication and shedding, i.e. will they become superspreaders? I suspect yes. A recent case report of a woman with systemic lupus erythematosus (SLE) on long-term glucocorticoids and her familial cluster of COVID-19, suggest that the long-term use of glucocorticoids might cause atypical SARS-CoV-2 infections; i.e.  a longer incubation period before developing COVID-19 and extra transmission of SARS-CoV-2 4 .

In light of the above the theoretical hazards posed by each DMT differ and, rather than imposing a blanket rule, decisions regarding treatment should be individualised and discussed with patients 5. For some patients having their active MS treated may be more important than the potential danger of being exposed to and acquiring a more severe COVID-19 infection. Any decision to start or continue an MS DMT during the COVID-19 pandemic will need to be taken carefully and will depend on the state of the COVID-19 pandemic and local circumstances.

References

  1. Ramanathan K, Antognini D, Combes A, et al. Planning and provision of ECMO services for severe ARDS during the COVID-19 pandemic and other outbreaks of emerging infectious diseases [Internet]. The Lancet Respiratory Medicine. 2020;Available from: http://dx.doi.org/10.1016/s2213-2600(20)30121-1
  2. Website [Internet]. [cited 2020 Apr 13];Available from: Icnarc Case Mix. 2020. “Report on 2249 Patients Critically Ill with COVID-19.” Intensive Care National Audit & Research Centre. April 4, 2020. https://www.icnarc.org/About/Latest-News/2020/04/04/Report-On-2249-Patients-Critically-Ill-With-Covid-19.
  3. Alasdair Coles and the MS Advisory Group. ABN GUIDANCE ON THE USE OF DISEASE-MODIFYING THERAPIES IN MULTIPLE SCLEROSIS IN RESPONSE TO THE THREAT OF A CORONAVIRUS EPIDEMIC [Internet]. Association of British Neurologists. 2020 [cited 2020 Apr 13];Available from: https://cdn.ymaws.com/www.theabn.org/resource/collection/65C334C7-30FA-45DB-93AA-74B3A3A20293/02.04.20_ABN_Guidance_on_DMTs_for_MS_and_COVID19_VERSION_4_April_2nd.pdf
  4. Han Y, Jiang M, Xia D, et al. COVID-19 in a patient with long-term use of glucocorticoids: A study of a familial cluster. Clin Immunol 2020;108413.
  5. Giovannoni G, Hawkes C, Lechner-Scott J, Levy M, Waubant E, Gold J. The COVID-19 pandemic and the use of MS disease-modifying therapies [Internet]. Multiple Sclerosis and Related Disorders. 2020;102073. Available from: http://dx.doi.org/10.1016/j.msard.2020.102073
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