SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best.

BACKGROUND: Data on immune responses to SARS-CoV-2 in patients with Primary Antibody Deficiencies (PAD) are limited to infected patients and to heterogeneous cohorts after immunization. METHODS: Forty-one patients with Common Variable Immune Deficiencies (CVID), six patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-receptor binding domain (RBD) antibody production, generation of Spike-specific memory B-cells, and Spike-specific T-cells before vaccination and one week after the second dose of BNT162b2 vaccine. RESULTS: The vaccine induced Spike-specific IgG and IgA antibody responses in all HD and in 20% of SARS-CoV-2 naive CVID patients. Anti-Spike IgG were detectable before vaccination in 4 out 7 CVID previously infected with SARS-CoV-2 and were boosted in six out of seven patients by the subsequent immunization raising higher levels than patients naïve to infection. While HD generated Spike-specific memory B-cells, and RBD-specific B-cells, CVID generated Spike-specific atypical B-cells, while RBD-specific B-cells were undetectable in all patients, indicating the incapability to generate this new specificity. Specific T-cell responses were evident in all HD and defective in 30% of CVID. All but one patient with XLA responded by specific T-cell only. CONCLUSION: In PAD patients, early atypical immune responses after BNT162b2 immunization occurred, possibly by extra-follicular or incomplete germinal center reactions. If these responses to vaccination might result in a partial protection from infection or reinfection is now unknown. Our data suggests that SARS-CoV-2 infection more effectively primes the immune response than the immunization alone, possibly suggesting the need for a third vaccine dose for patients not previously infected.

Health-Related Quality of Life in Patients with CVID Under Different Schedules of Immunoglobulin Administration: Prospective Multicenter Study.

OBJECTIVE: We assessed the health-related quality of life (HRQoL) in CVID adults receiving different schedules of immunoglobulin replacement therapy (IgRT) by intravenous (IVIG), subcutaneous (SCIG), and facilitated (fSCIG) preparations. For these patients, IgRT schedule was chosen after a period focused on identifying the most suitable individual option. METHODS: Three hundred twenty-seven participants were enrolled in a prospective, observational, 18-month study. Participants received IgRT for at least 2 years. The first 6 months were devoted to the educational process during which the choices related to IgRT were regularly re-assessed, and the shift to alternative regimen was permitted. During the following 12 months, clinical data were prospectively collected, and only patients who did not further modify their IgRT schedule were included in the analysis of HRQoL measured by CVID_QoL, a specific instrument, and by GHQ-12, a tool to assess minor psychiatric nonpsychotic disorders. RESULTS: Three hundred four patients were included in the analysis. CVID_QoL global score and its dimensions (emotional functioning, relational functioning, gastrointestinal symptoms) were similar in IVIG, SCIG, and fSCIG recipients. Patients receiving IgRT by different routes of administration reported similar capacity to make long-term plans, discomfort due to therapy, and concern to run out of medications. Multivariate analysis revealed the GHQ-12 status, but not the IgRT mode of administration, as the major factor impacting on treatment-related QoL items, and a significant impact of age on discomfort related to IgRT. CONCLUSIONS: IgRT schedules do not impact the HRQoL in CVID if the treatment is established after an extensive educational period focused on individualizing the best therapeutic regimen.

Functional CVIDs phenotype clusters identified by the integration of immune parameters after BNT162b2 boosters.

Introduction: Assessing the response to vaccinations is one of the diagnostic criteria for Common Variable Immune Deficiencies (CVIDs). Vaccination against SARS-CoV-2 offered the unique opportunity to analyze the immune response to a novel antigen. We identify four CVIDs phenotype clusters by the integration of immune parameters after BTN162b2 boosters. Methods: We performed a longitudinal study on 47 CVIDs patients who received the 3rd and 4th vaccine dose of the BNT162b2 vaccine measuring the generation of immunological memory. We analyzed specific and neutralizing antibodies, spike-specific memory B cells, and functional T cells. Results: We found that, depending on the readout of vaccine efficacy, the frequency of responders changes. Although 63.8% of the patients have specific antibodies in the serum, only 30% have high-affinity specific memory B cells and generate recall responses. Discussion: Thanks to the integration of our data, we identified four functional groups of CVIDs patients with different B cell phenotypes, T cell functions, and clinical diseases. The presence of antibodies alone is not sufficient to demonstrate the establishment of immune memory and the measurement of the in-vivo response to vaccination distinguishes patients with different immunological defects and clinical diseases.

B Cell Response Induced by SARS-CoV-2 Infection Is Boosted by the BNT162b2 Vaccine in Primary Antibody Deficiencies.

BACKGROUND: Patients with primary antibody deficiencies are at risk in the current COVID-19 pandemic due to their impaired response to infection and vaccination. Specifically, patients with common variable immunodeficiency (CVID) generated poor spike-specific antibody and T cell responses after immunization. METHODS: Thirty-four CVID convalescent patients after SARS-CoV-2 infection, 38 CVID patients immunized with two doses of the BNT162b2 vaccine, and 20 SARS-CoV-2 CVID convalescents later and immunized with BNT162b2 were analyzed for the anti-spike IgG production and the generation of spike-specific memory B cells and T cells. RESULTS: Spike-specific IgG was induced more frequently after infection than after vaccination (82% vs. 34%). The antibody response was boosted in convalescents by vaccination. Although immunized patients generated atypical memory B cells possibly by extra-follicular or incomplete germinal center reactions, convalescents responded to infection by generating spike-specific memory B cells that were improved by the subsequent immunization. Poor spike-specific T cell responses were measured independently from the immunological challenge. CONCLUSIONS: SARS-CoV-2 infection primed a more efficient classical memory B cell response, whereas the BNT162b2 vaccine induced non-canonical B cell responses in CVID. Natural infection responses were boosted by subsequent immunization, suggesting the possibility to further stimulate the immune response by additional vaccine doses in CVID.

Health-Related Quality of Life in Common Variable Immunodeficiency Italian Patients Switched to Remote Assistance During the COVID-19 Pandemic.

BACKGROUND: A rapidly expanding pandemic of the new coronavirus has become the focus of global scientific attention. Data are lacking on the impact of the pandemic caused by the severe acute respiratory syndrome coronavirus 2 on health-related quality of life among patients affected by primary antibody deficiencies (PADs). OBJECTIVE: To identify factors impacting the health-related-quality of life (HRQOL) among Italian patients affected by PADs switched to remote assistance at the time of the coronavirus disease 2019 pandemic. METHODS: The quality of life was surveyed in 158 patients with PADs by the Common Variable Immune Deficiency Quality of Life questionnaire, a disease-specific tool, and by the 12-item General Health Questionnaire, a generic tool to assess the risk of anxiety/depression. Since the beginning of the coronavirus disease 2019 epidemic, we shifted all patients with PADs to home therapy, and activated remote visits. Questionnaires were sent by email 4 weeks later. Common Variable Immune Deficiency Quality of Life questionnaire and 12-item General Health Questionnaire data scores were compared with the same set of data from a survey done in 2017. RESULTS: Of 210 patients, 158 (75%) agreed to participate. The quality of life was worse in the group of patients who were at risk of anxiety/depression at the study time. HRQOL was similar in patients forced to shift from hospital-based to home-based immunoglobulin treatment and in patients who continued their usual home-based replacement. The risk of anxiety/depression is associated with pandemia caused by the severe acute respiratory syndrome coronavirus 2 and with patients' fragility, and not with related clinical conditions associated with common variable immune deficiencies. Anxiety about running out of medications is a major new issue. CONCLUSIONS: The coronavirus disease 2019 epidemic impacted HRQOL and the risk of anxiety/depression of patients with PADs. The remote assistance program was a useful possibility to limit personal contacts without influencing the HRQOL.

Aplastic Anemia and Good Syndrome in a Heavily Treated Stage IV Thymoma Patient: A Case Report and Review of the Literature.

Thymoma is an uncommon slowly growing neoplasm. It usually presents with paraneoplastic syndromes including the immunodeficiency syndrome called Good syndrome and hematological disorders. Pure red cell aplasia is a well-recognized complication of thymoma, and aplastic anemia is very rare in association with GS. We report a case of GS in a heavily treated patient with stage IV thymoma associated with a pure red cell aplasia and an amegakaryocytic thrombocytopenia that evolved into an AA and provide an up-to-date review of the relevant literature. This is the first case of the association of GS and AA with the coexistence of a heavily treated stage IV thymoma. The fatal outcome was not related to the progression of the thymoma, but rather to the severe infectious complications. The combination of lymphopenia and hypogammaglobulinemia typical of GS, coupled to the neutropenia, caused by bone marrow failure, was the main predisposing factor for the unfavourable outcome.

Autonomic cardiovascular control and diastolic dysfunction in hypertensive subjects.

BACKGROUND: Early hypertension is associated with left ventricular diastolic dysfunction due to increased end-diastolic pressure. This increase, through the cardiopulmonary reflexes, can influence autonomic cardiovascular control. METHODS: We assessed autonomic nervous system modulation of cardiovascular signals by power spectral analysis of RR interval and systolic arterial pressure variabilities in subjects with recently diagnosed hypertension with or without diastolic dysfunction and in normotensive control subjects. RESULTS: Both hypertensive groups had higher low-frequency (LF) power expressed in normalized units (NUs) than normotensive controls (p < 0.05; p < 0.001) during controlled breathing at rest. The LF spectral index measured after tilt was greater in hypertensive subjects with diastolic dysfunction than in those without (p < 0.05). LF NUs measured at rest correlated significantly with the E/A wave ratio and after tilt with the E-wave deceleration time. CONCLUSIONS: These results seem to indicate that in subjects with recently diagnosed hypertension sympathetic modulation of the sinus node prevails. During tilt, a maneuver designed to stimulate systemic arterial and cardiopulmonary baroreceptor reflexes, hypertensive subjects with diastolic dysfunction, who presumably also have higher end-diastolic pressures, seem to have greater sympathetic modulation of the sinus node than hypertensive subjects without diastolic dysfunction.

Lung MRI as a possible alternative to CT scan for patients with primary immune deficiencies and increased radiosensitivity.

BACKGROUND: Patients with common variable immunodeficiency (CVID) suffer from respiratory infections leading over time to permanent lung damage. Increased radiosensitivity has been described, and clinicians should consider a risk-benefit assessment when ordering a CT scan, in that the exact level of "safe" radiation exposure is unknown. METHODS: Twenty-one patients with CVID were evaluated with chest CT scan, MRI, and pulmonary function tests on the same day. MRI protocol included a T2-weighted rotating blade-like k-space covering sequence (time repetition, 2,000; echo train = 27; field of view, 400 mm; flip angle, 150; slice thickness, 5 mm) on axial and coronal planes. The bronchial and parenchymal abnormalities were compared with those identified by CT scan applying a modified Bhalla scoring system to assess bronchiectasis, bronchial wall thickening, number of bronchial generations involved, mucous plugging, consolidations, emphysema, bullae, and nodules. RESULTS: CT scan and MRI findings were comparable for moderate to severe degrees of bronchial and parenchymal alterations. A low concordance was found between MRI and CT scan for lower scores of bronchial abnormalities. CT scan allowed a better identification of peripheral airways abnormalities. CONCLUSIONS: Lung alterations in patients with higher radiation sensitivity, such as patients with CVID, might be evaluated by MRI, a radiation-free technique alternative to CT scan.