Clinical Characteristics of EGPA Patients in Comparison to GPA Subgroup with Increased Blood Eosinophilia from POLVAS Registry.

Objective: To characterize the eosinophilic granulomatosis with polyangiitis (EGPA) population from the POLVAS registry depending on ANCA status and diagnosis onset, including their comparison with the granulomatosis with polyangiitis (GPA) subset with elevated blood eosinophilia (min. 400/µl) (GPA HE) to develop a differentiating strategy. Methods: A retrospective analysis of the POLVAS registry. Results: The EGPA group comprised 111 patients. The ANCA-positive subset (n = 45 [40.54%]) did not differ from the ANCA-negative one in clinics. Nevertheless, cardiovascular manifestations were more common in ANCA-negative patients than in those with anti-myeloperoxidase (MPO) antibodies (46.97% vs. 26.92%, p = 0.045). Patients diagnosed before 2012 (n = 70 [63.06%]) were younger (median 41 vs. 49 years, p < 0.01), had higher blood eosinophilia at diagnosis (median 4,946 vs. 3,200/µl, p < 0.01), and more often ear/nose/throat (ENT) and cardiovascular involvement. GPA HE comprised 42 (13.00%) out of 323 GPA cases with reported blood eosinophil count. Both GPA subsets had a lower prevalence of respiratory, cardiovascular, and neurologic manifestations but more often renal and ocular involvement than EGPA. EGPA also had cutaneous and gastrointestinal signs more often than GPA with normal blood eosinophilia (GPA NE) but not GPA HE. The model differentiating EGPA from GPA HE, using ANCA status and clinical manifestations, had an AUC of 0.92, sensitivity of 96%, and specificity of 95%. Conclusion: Cardiovascular symptoms were more prevalent in the ANCA-negative subset than in the MPO-ANCA-positive one. Since EGPA and GPE HE share similarities in clinics, diagnostic misleading may result in an inappropriate therapeutic approach. Further studies are needed to optimize their differentiation and tailored therapy, including biologics.

Cellular immune response to SARS-CoV-2 in patients with primary antibody deficiencies.

Introduction: Primary antibody deficiencies (PAD) are inborn defects of the immune system that result in increased susceptibility to infections. Despite the reduced response to vaccination, PAD patients still benefit from it by reducing the risk of severe infections and complications. SARS-CoV-2 vaccines are recommended in PAD patients, but their immune effects are poorly studied. Here, we analyze virus-specific T-cell responses in PAD patients after booster vaccination against SARS-CoV-2. Patients and methods: The study included 57 adult PAD patients on long-term immunoglobulin replacement therapy (IgRT) diagnosed with X-linked agammaglobulinemia (XLA; n = 4), common variable immunodeficiency (CVID; n = 33), isotype defects or IgG subclass deficiency (n = 6), and unclassified IgG deficiency (n = 14). Of those, 49 patients (86%) received vaccination against SARS-CoV-2 using mRNA vaccine (Pfizer-BioNTech). T-cell responses were assessed at a median of 21 (13 - 30) weeks after the booster dose (mainly the third dose) using commercially available interferon-gamma release assay (IGRA) with recombinant SARS-CoV-2 spike S1 protein. Results: Vaccinated PAD patients showed an increased (3.8-fold, p = 0.004) release of IFN-γ upon S1 stimulation. In this group, we also documented higher serum levels of anti-SARS-CoV-2 IgG (4.1-fold, p = 0.01), although they were not associated with IGRA results. Further subgroup analysis revealed very similar IGRA responses in CVID and unclassified IgG deficiencies that were 2.4-fold increased compared to XLA and 5.4-fold increased compared to patients with isotype defects or IgG subclass deficiencies (e.g., vs. CVID: p = 0.016). As expected, CVID and XLA patients showed decreased serum titers of anti-SARS-CoV-2 antibodies compared to other studied groups (e.g., CVID vs. unclassified IgG deficiency: 4.4-fold, p = 0.006). The results did not depend directly on IgRT mode or dose, number of vaccine doses and time from the last booster dose, and clinical manifestations of PAD. Interestingly, anti-SARS-CoV-2 titers were positively correlated with serum immunoglobulin levels before IgRT (e.g., for IgA: r = 0.45, p<0.001; for IgG: r = 0.34, p = 0.009) and the percentage of peripheral blood NK cells (r = 0.48, p<0.001). Conclusions: Our results documented satisfactory in vitro cellular immune response in PAD patients after booster SARS-CoV-2 vaccination. Therefore, even patients with agammaglobulinemia should benefit from vaccination due to the apparent induction of cell-mediated immunity, which, together with IgRT, grants comprehensive protection against the pathogen.