RESUMEN
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)-{gamma} 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-{gamma} 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-{gamma} production might explain this observation. Author SummaryMast 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.
RESUMEN
BackgroundAssociation between DPP4 inhibitors and respiratory infection remains unclear. CardioVascular Outcomes Trials (CVOTs) conducted before the COVID-19 pandemic are available. We aimed to estimate the effect of DPP4 inhibitors on the risk of respiratory infections. MethodsWe updated a previous systematic review and meta-analysis, searching for CVOTs assessing a DPP4 inhibitor in patients with type 2 diabetes mellitus. We focused on placebo-controlled CVOTs. Our primary outcome was any respiratory infection. We added a sensitivity analysis integrating non-CVOTs and active-controlled CVOTs. FindingsWe included 47 714 patients in five placebo-controlled CVOTs. Median follow-up ranged from 1{middle dot}5 years to 3 years. 4 369 events of overall respiratory infection were reported (rate of 9{middle dot}2%). DPP4 inhibitors were not associated with a different risk compared to placebo (RR = 0{middle dot}99 [95% CI: 0{middle dot}93; 1{middle dot}04]). The sensitivity analysis integrating the non-CVOTs studies and the active-controlled CVOT reached 11 349 events among 82 644 participants (rate of 13{middle dot}7%). DPP4 inhibitors were not associated with a different risk of overall respiratory infection (RR = 1{middle dot}00 [95% CI: 0{middle dot}97; 1{middle dot}03]). InterpretationOur up-dated meta-analysis provides the most powerful and least biased estimation of the association of DPP4 inhibitors and the risk of overall (non COVID-19) respiratory infection. We did not find any effect of the DPP4 inhibitors on the risk of respiratory infection. Our results support the recently published practical recommendations for the management of diabetes in patients with COVID-19, suggesting that DPP4 inhibitors should not be discontinued regarding the COVID-19 pandemic. FundingNo source of funding Panel: Research in contextO_ST_ABSEvidence before this studyC_ST_ABSFrom before the COVID19 pandemic, respiratory infections are considered potential adverse effects of DPP4 inhibitors. Randomized trials assessing DPP4 inhibitors in patients with type 2 diabetes (T2D), their meta-analyses and pharmacovigilance studies reported conflicting results. Since the last meta-analyses assessing the risk of infections with DPP4 inhibitors, powerful cardiovascular outcomes randomized trials (CVOTs) became available. Recent practical recommendations for the management of diabetes during COVID-19 suggested that DPP4 inhibitors could be continued. We updated our previous meta-analysis of CVOTs and focused to the overall risk of respiratory infection associated with DPP4 inhibitors. We searched for published and unpublished CVOTs in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov, up to January 27, 2020, using key word as "diabetes mellitus", "hypoglycemic agents", "glucose control", "randomized controlled trial", "cardiovascular diseases". Added value of this studyWe included CVOTs comparing a DPP4 inhibitor versus placebo, in people with T2D, and analysed the risk of respiratory infection with DPP4 inhibitors. We focused on placebo-controlled CVOTs to avoid the pitfalls of small study effect and heterogeneous comparators. We added a sensitivity analysis integrating non-CVOTs and non-placebo CVOTs to challenge our results and to increase the statistical power. Our meta-analysis provides the most powerful and least biased estimation of the association of DPP4 inhibitors and the risk of overall (non COVID-19) respiratory infection. Our analyses integrated 11 349 events of any respiratory infections through 82 644 patients from randomized trials. Our results did not find any association between DPP4 inhibitors use and risk of non-COVID respiratory infections. Implications of all the available evidenceThe current COVID-19 pandemic has raised some questions about pros and cons of certain cardiovascular drugs. Our results support the recent practical recommendations for the management of diabetes in patients with COVID-19, suggesting that DPP4 inhibitors should not be discontinued regarding the COVID-19 pandemic.
