Defining Clinical and Immunological Predictors of Poor Immune Responses to COVID-19 mRNA Vaccines in Patients with Primary Antibody Deficiency.

Immune responses to coronavirus disease 2019 (COVID-19) mRNA vaccines in primary antibody deficiencies (PADs) are largely unknown. We investigated antibody and CD4+ T-cell responses specific for SARS-CoV-2 spike protein (S) before and after vaccination and associations between vaccine response and patients' clinical and immunological characteristics in PADs. The PAD cohort consisted of common variable immune deficiency (CVID) and other PADs, not meeting the criteria for CVID diagnosis (oPADs). Anti-S IgG, IgA, and IgG subclasses 1 and 3 increased after vaccination and correlated with neutralization activity in HCs and patients with oPADs. However, 42% of CVID patients developed such responses after the 2nd dose. A similar pattern was also observed with S-specific CD4+ T-cells as determined by OX40 and 4-1BB expression. Patients with poor anti-S IgG response had significantly lower levels of baseline IgG, IgA, CD19+ B-cells, switched memory B-cells, naïve CD8+ T-cells, and a higher frequency of EM CD8+ T-cells and autoimmunity compared to patients with adequate anti-S IgG responses. Patients with oPADs can develop humoral and cellular immune responses to vaccines similar to HCs. However, a subset of CVID patients exhibit impairment in developing such responses, which can be predicted by the baseline immune profile and history of autoimmunity.

Immunological and Clinical Phenotyping in Primary Antibody Deficiencies: a Growing Disease Spectrum.

PURPOSE: Although common variable immunodeficiency (CVID) is considered the most prevalent symptomatic primary antibody deficiency (PAD), there is a population with symptomatic PADs that do not meet criteria for CVID. We analyzed clinical and immunological profiles of patients with different PADs to better understand the differences and similarities between CVID and other PADs. METHODS: We extracted clinical and laboratory data of patients with PADs from electronic medical records. Patients were categorized into CVID, IgG subclass 2 deficiency (IgG2D), IgG deficiency (IgGD), and specific antibody deficiency (sAbD) based on basal immunoglobulin levels and pneumococcal vaccine responses. We compared clinical and immunological characteristics in these groups. RESULTS: All patients, regardless of PAD types, showed similar frequencies of infections, bronchiectasis, and interstitial lung disease (ILD). Hematopoietic malignancies were more frequently found in the CVID than in the IgG2D, IgGD, and sAbD groups, while the latter groups trended towards an increased frequency of connective tissue diseases (CTD). Low counts of natural killer (NK) cells were associated with malignancy, autoimmunity, and ILD in CVID but not in other PAD groups. CONCLUSIONS: Higher frequency of hematopoietic malignancy in CVID than in the other PADs and association of lower NK cell counts with non-infectious complications in CVID suggest a relationship between immune alterations and the development of non-infectious manifestations in PADs.

Considerations in the management of hereditary angioedema due to C1-INH deficiency in women of childbearing age.

Hereditary angioedema (HAE) is a rare, autosomal disorder that manifests with unpredictable episodes of severe swelling of the skin and mucous membranes. These attacks can be highly disfiguring and range in severity from mild to-in cases of airway swelling-life-threatening. Fluctuations in female sex hormones-such as the changes that occur during puberty, menses, contraceptive use, pregnancy, and menopause-can all affect the frequency and severity of HAE attacks. Disease management decisions for women of childbearing age may be more complex and require additional considerations since they could develop complications related to contraception, pregnancy, labor, delivery, and lactation. In addition, some HAE treatment options are contraindicated during pregnancy. Discussions about medications used to treat HAE should include a risk-benefit assessment of the woman's health status, her preferences, and other factors that are relevant to the choice of therapy. Planning prophylactic therapies that are effective and safe before, during, and after pregnancy can prevent gaps in treatment, ensure continuity of care, and reduce both disease burden and risk of adverse fetal outcomes. The 2020 US Hereditary Angioedema Association (HAEA) Medical Advisory Board and 2021 World Allergy Organization/European Academy of Allergy and Immunology (WAO/EAACI) Guidelines outline key considerations for managing HAE in females of childbearing age (15-45 years), with the goal of improving treatment efficacy and safety for this cohort of patients. Treatment decisions made in a collaborative manner involving the patient, HAE specialist and obstetric/gynecologic specialist, is the best approach to ensure optimal HAE management and safety in this patient population.

Long-term efficacy and safety of subcutaneous C1-inhibitor in women with hereditary angioedema: subgroup analysis from an open-label extension of a phase 3 trial.

BACKGROUND: Women with hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) experience more frequent and severe angioedema attacks compared with men. Fluctuations in female sex hormones can influence HAE attack frequency and severity. Subcutaneous C1-INH (C1-INH [SC]) is indicated as routine prophylaxis to prevent HAE attacks. In this post hoc subgroup analysis, we evaluated the efficacy and safety of C1-INH (SC) in female subjects with HAE-C1INH enrolled in an open-label extension of the pivotal phase III COMPACT trial. METHODS: In this multicenter, randomized, parallel-arm trial, eligible subjects (age ≥ 6 years with ≥ 4 attacks over 2 consecutive months) received C1-INH (SC) 40 IU/kg or 60 IU/kg twice weekly for 52 to 140 weeks. Analyses of efficacy endpoints were performed for all female subjects and those of childbearing age (age ≥ 15 to ≤ 45 years), including subjects who became pregnant during the evaluation period. RESULTS: Overall, 91% (69/76) of female subjects were classified as responders (≥ 50% reduction in HAE attacks relative to the pre-study period); 82% experienced < 1 attack/4 weeks. The median number of attacks/month was 0.10, with 96% median reduction in attacks relative to the pre-study period. Results were similar in the subgroup of subjects of childbearing age. Four women who became pregnant during the trial and were exposed to C1-INH (SC) during the first trimester delivered healthy babies with no congenital abnormalities. CONCLUSIONS: C1-INH (SC) prophylaxis was safe and effective in women with HAE-C1INH, including those of childbearing age. Four women exposed to C1-INH (SC) during the first trimester had uneventful pregnancies and delivered healthy babies.Trial registration Clinicaltrials.gov identifier NCT02316353 (Registered December 10, 2014); https://clinicaltrials.gov/ct2/show/NCT02316353.

Safety, Costs, and Efficacy of Rapid Drug Desensitizations to Chemotherapy and Monoclonal Antibodies.

BACKGROUND: Rapid drug desensitization (RDD) is used to address hypersensitivity reactions to chemotherapeutics and monoclonal antibodies, allowing patients to be treated with optimal pharmacological agents. RDD protocols are tailored to each individual patient's reaction and needs, and protect against anaphylaxis, but overall risks, costs, and benefits have not been determined. OBJECTIVE: We investigated the safety, efficacy, costs, and life expectancy of patients in a large population undergoing RDD. METHODS: We analyzed 2177 RDD procedures performed in 370 patients with cancer, vasculitis, and hematological and connective tissue diseases who presented 402 reactions. A subgroup of carboplatin allergic patients with ovarian cancer treated with RDD was analyzed for costs and life expectancy and compared with a nonallergic control group. RESULTS: RDD allowed all patients to receive safely the full dose of the medication to which they were reactive. A gradual increase in the fraction of outpatient desensitizations from 81% to 98% was achieved through risk stratification. Of the 2177 desensitizations, 93% had no or mild reactions whereas 7% had moderate to severe reactions, which did not preclude the completion of the treatment, and there were no deaths. Overall health costs in the carboplatin allergic group were not higher than those in the nonallergic group treated with standard of care. Administration of carboplatin through RDD was as effective as standard administration with a nonsignificant increase in life expectancy in desensitized patients as compared with nonallergic, nondesensitized controls. CONCLUSIONS: RDD is cost effective and safe for allergic patients with cancer and chronic disease to remain on first line therapy.