Absence of severe COVID-19 in patients with clonal mast cells activation disorders: effective anti-SARS-CoV-2 immune response
Authors: Rossignol Julien , Ouedrani Amani , Livideanu Cristina Bulai , Barete Stéphane , Terriou Louis , Launay David , Lemal Richard , Greco Celine , Frenzel Laurent , Meni Cecile , Bodemere-Skandalis Christine , Polivka Laura , Collange Anne-Florence , Hachichi Hassiba , Bouzourine Sonia , Messaoud Djazira Nait , Negretto Mathilde , Vendrame Laurence , Jambou Marguerite , Gousseff Marie , Durupt Stéphane , Lega Jean-Christophe , Durand Jean-Marc , Gaudy Caroline , Damaj Gandhi , Gourin Marie-Pierre , Hamidou Mohamed , Bouillet Laurence , Le Mouel Edwige , Maria Alexandre , Zunic Patricia , Cabrera Quentin , Vincent Denis , Lavigne Christian , Riviere Etienne , Gourguechon Clement , Brignier Anne , Lhermitte Ludovic , Molina Thierry Jo , Bruneau Julie , Agopian Julie , Dubreuil Patrice , Ranta Dana , Mania Alexandre , Arock Michel , Staropoli Isabelle , Tournilhac Olivier , Lortholary Olivier , Schwartz Olivier , Chatenoud Lucienne , Hermine Olivier 
Published: September 2021

Mast cells are key actors of innate immunity and Th2 adaptive immune response which counterbalance Th1 response, critical for anti-viral immunity. Clonal Mast Cells Activation Disorders (cMCADs) such as mastocytosis and clonal mast cells activation syndrome are characterized by an abnormal mast cells accumulation and/or activation. No data have been published on the anti-viral immune response of patients with cMCADs. The aims of the study were to collected, in a comprehensive way, outcomes of cMCADs patients who experienced a biologically-proven COVID-19 and to characterize both anti-endemic coronaviruses and specific anti-SARS-CoV-2 immune responses in these patients. Clinical follow-up and outcome data were collected prospectively for one year within the French rare disease network CEREMAST encompassing patients from all over the country. Anti-SARS-CoV-2 and anti-endemic coronaviruses specific T-cells were assessed with an enzyme-linked immunospot assay (EliSpot) and anti-SARS-CoV-2 humoral response with dosage of circulating levels of specific IgG, IgA and neutralizing antibodies. Overall, 32 cMCADs patients were identified. None of them required non-invasive or mechanical ventilation; two patients were hospitalized to receive oxygen and steroid therapy. In 21 patients, a characterization of the SARS-CoV-2-specific immune response has been performed. A majority of patients showed a high proportion of circulating SARS-CoV-2-specific interferon (IFN)-γ producing T-cells and high levels of anti-Spike IgG antibodies with neutralizing activity. In addition, no defects in anti-endemic coronaviruses responses were found in patients with cMCADs compared to non-cMCADs controls. Patients with cMCADs frequently showed a spontaneous IFN-γ T-cell production in absence of any stimulation that correlated with circulating basal tryptase levels, a marker of mast cells burden. These findings underscore that patients with cMCADs might be not at risk of severe COVID-19 and the spontaneous IFN-γ production might explain this observation.

Author Summary

Mast cells are immune cells involved in many biological processes including the anti-microbial response. However, previous studies suggest that mast cells may have a detrimental role in the response against viruses such as SARS-CoV-2, responsible for COVID-19. When a mutation occurs in mast cells, it can lead to a group of diseases called clonal mast cells activation disorders (cMCADs), characterized by deregulated activation of these cells. Hence, patients with cMCADs might be more susceptible to severe COVID-19 than general population.

We therefore conducted a 1-year study in France to collect data from all cMCADs patients included in the CEREMAST rare disease French network and who experienced COVID-19. Interestingly, we did not find any severe COVID-19 (i.e. requiring non-invasive or mechanical ventilation) in spite of well-known risk factors for severe COVID-19 in a part of cMCADs patients.

We then have studied the immune response against SARS-CoV-2 and other endemic coronaviruses in these patients. We did not observe any abnormalities in the immune response either at the level of T and B lymphocytes. These findings underscore that these patients might not be at risk of severe COVID-19 as one might have feared.