A Core Outcome Set for Efficacy of Acute Treatment of Hereditary Angioedema.

BACKGROUND: Clinical trials investigating drugs for the acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits the comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. OBJECTIVE: To achieve consensus on a core outcome set composed of key outcomes that ideally should be used in all clinical efficacy trials involving the acute treatment of hereditary angioedema attacks. METHODS: We conducted a Delphi consensus study involving all relevant parties: patients with hereditary angioedema, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two Internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. RESULTS: A total of 58 worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of 90% or greater was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, the need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. CONCLUSIONS: This international study obtained a high level of consensus on a core outcome set for the acute treatment of hereditary angioedema attacks, consisting of five key outcomes.

Definition, acronyms, nomenclature, and classification of angioedema (DANCE): AAAAI, ACAAI, ACARE, and APAAACI DANCE consensus.

BACKGROUND: Angioedema (AE) manifests with intermittent, localized, self-limiting swelling of the subcutaneous and/or submucosal tissue. AE is heterogeneous, can be hereditary or acquired, may occur only once or be recurrent, may exhibit wheals or not, and may be due to mast cell mediators, bradykinin, or other mechanisms. Several different taxonomic systems are currently used, making it difficult to compare the results of studies, develop multicenter collaboration, and harmonize AE treatment. OBJECTIVE: We developed a consensus on the definition, acronyms, nomenclature, and classification of AE (DANCE). METHODS: The initiative involved 91 experts from 35 countries and was endorsed by 53 scientific and medical societies, and patient organizations. A consensus was reached by online discussion and voting using the Delphi process over a period of 16 months (June 2021 to November 2022). RESULTS: The DANCE initiative resulted in an international consensus on the definition, classification, and terminology of AE. The new consensus classification features 5 types and endotypes of AE and a harmonized vocabulary of abbreviations/acronyms. CONCLUSION: The DANCE classification complements current clinical guidelines and expert consensus recommendations on the diagnostic assessment and treatment of AE. DANCE does not replace current clinical guidelines, and expert consensus algorithms and should not be misconstrued in a way that affects reimbursement of medicines prescribed by physicians using sound clinical judgment. We anticipate that this new AE taxonomy and nomenclature will harmonize and facilitate AE research and clinical studies, thereby improving patient care.

Analysis of questionnaire survey to determine worldwide trends in prescriptions of biologics for the treatment of unresponsive chronic urticaria.

Background: Chronic spontaneous urticaria (CSU) is a common condition treated by allergist/immunologists, but the only FDA-approved biologic medication, omalizumab, may be underutilized globally. Objective: This study was performed to determine the global prescription of omalizumab for treatment of CSU by allergists/immunologists. Methods: Anonymous questionnaire surveys were distributed online to World Allergy Organization (WAO) members worldwide. Categorical data were analyzed for descriptive analysis using one-way frequency tabulation in SAS 9.4. Results: There were 348 respondents (43 missing data); Average age 51 (range 28-90); M/F 48%/52%. 58% had > 15 years of clinical experience and 10% < 5; 42% worked in private clinics, 36% public hospitals, 24% academia, 18% private hospitals, and 4% in community practice. Eighty-two percent (82%) prescribed omalizumab for CSU patients and use of omalizumab was highest among young practitioners. The most significant barriers were cost (63%) and restricted formulary (24%). Drug safety (63%) and chances of adverse events (47%) were the most significant factors deciding treatment. Twenty-two percent (22%) reported 80-100% of CSU patients were complete responders to omalizumab; 34% preferred increasing frequency (q 2-weeks), and 18% preferred increasing dose (600 mg q 4-weeks) for partial or non-responders. UAS7, UCT, and CU-QoL were used to assess CSU by 55%, 29%, and 25% of respondents, respectively. Autoimmune thyroid disease (62%), thyroid abnormality (43%) and allergic rhinitis (35%) were the most frequent comorbidities reported. Conclusions: Most clinicians favored omalizumab over other potential treatments due to safety. Although younger clinicians were more likely to prescribe omalizumab, cost and formulary access were major barriers. Only 22% of respondents reported 80% or greater of their patients had complete response to omalizumab, indicating the need for novel CSU therapies.

Clinical outcomes of immunoglobulin treatment for patients with secondary antibody deficiency: Data from the Ontario immunoglobulin treatment case registry.

BACKGROUND: Despite the increasing number of cases of secondary antibody deficiency (SAD) and immunoglobulin (Ig) utilization, there is a paucity of data in the literature on clinical and patient-reported outcomes in this population. OBJECTIVE: To describe immunoglobulin utilization patterns, clinical and patient-reported outcomes in patients with SAD on immunoglobulin replacement therapy (IgRT). METHODS: A cross-sectional study of patients with secondary antibody deficiency enrolled in the Ontario Immunoglobulin Treatment (ONIT) Case Registry from June 2020 to September 2022 was completed. Demographics, comorbidities, indications for immunoglobulin treatment, clinical infections at baseline and post IgRT, and patient-reported outcomes were collected and analyzed. RESULTS: There were 140 patients (58 males; 82 females; median age 68) with SAD during the study period; 131 were on subcutaneous Ig (SCIG) and 9 were on intravenous Ig (IVIG). The most common indication was chronic lymphocytic leukemia (CLL) (N = 52). IgRT reduced the average annual number of infections by 82.6%, emergency room (ER) visits by 84.6%, and hospitalizations by 83.3%. Overall, 84.6% of patients reported their health as better compared to before IgRT. Among those patients who switched from IVIG to SCIG (N = 35), 33.3% reported their health as the same, and 62.9% reported their health as better. CONCLUSIONS: This study demonstrates that IgRT significantly improved clinical outcomes and patient-reported general health state in patients with SAD. This study also further supports the use of SCIG in patients with SAD.

Hereditary Angioedema: A Review of the Current and Evolving Treatment Landscape.

Hereditary angioedema (HAE) is a rare disease characterized by sudden and often unprovoked episodes of swelling that can be potentially life-threatening when it involves the upper airway. The treatment options for both acute episodes of HAE and LTP, used to minimize the frequency and severity of angioedema attacks, were limited historically to very few options, had considerable side effects, and/or had considerable burden of treatment. Fortunately, through the elucidation of the pathophysiology of HAE, the development of newer targeted therapies has been possible both for acute therapy and long-term prophylaxis and even more are on the horizon. Because of the rapid development of these therapies, it can be challenging for clinicians to keep abreast of newer and developing treatments for HAE. This review article will outline the current and potential future treatments for HAE. It will also highlight important considerations when treating special HAE patient populations including women and pediatric patients.

Second-dose mRNA COVID-19 vaccine safety in patients with immediate reactions after the first dose: A case series.

Background: The rates of suspected allergic reactions to the first dose of the coronavirus disease 2019 (COVID-19) mRNA vaccines have been reported to be as high as 2%, with an anaphylaxis incidence up to 2.5 per 10,000 individuals. Anaphylaxis in response to the first dose may be considered a contraindication to administration of the second dose, even though the second dose is necessary for optimal protection against severe disease. Many individuals with anaphylactic reactions to the first dose still want to receive a second dose. However, there are few published data to support the safety of administration of a second dose in this population. Objective: The primary objective of this study was to determine the percentage of patients tolerating a second COVID-19 mRNA vaccine dose after an immediate reaction to the first dose. Methods: This was a retrospective chart review of 47 patients at a Canadian hospital who had immediate, suspected allergic reactions following their first COVID-19 mRNA vaccine dose and received a second dose within our allergy clinic. Results: Of 47 patients, 46 tolerated the second dose; 43% of patients developed mild, transient symptoms. There were no patients who developed anaphylaxis or needed epinephrine after the second dose. Conclusion: Our case series adds to current evidence that administration of a second COVID-19 mRNA vaccine dose has a good safety profile in patients with a history of immediate reactions after the first dose, including those with a history of anaphylaxis in response to the first dose.

Monoclonal antibody treatment of COVID-19 in a pregnant woman with common variable immunodeficiency.

BACKGROUND: Since the first reported case of COVID-19, infections due to the virus have ranged from mild to severe. Patients with inborn errors of immunity are thought to be at increased risk for infections such as COVID-19 due to the nature of their disease and being immunocompromised. Similarly, pregnant women by nature of physiological changes in immunity are susceptible to infections and consequently are felt to be at greater risk of contracting COVID-19 with potential grave consequences for not only the mother but also the fetus. Early treatment with novel therapeutics against the SARS-CoV-2 virus to prevent progression and these complications is paramount. CASE PRESENTATION: A 31-year-old woman with a 22-year history of common variable immunodeficiency on subcutaneous immunoglobulin replacement therapy and 24 weeks pregnant with her third child presented to the Emergency Department with two-day history of pharyngitis that progressed to include nasal and chest congestion, non-productive cough and shortness of breath. Her vitals indicated temperature of 35 degrees Celsius, heart rate of 109 beats per minute, blood pressure 142/92 mmHg, respiratory rate 22/min and an oxygen saturation of 99% on room air. A workup was done and she was found to be positive for SARS-CoV-2 virus confirmed by PCR. She had a close contact, her husband, who had tested positive a few days prior. She had been previously vaccinated with three doses of the Moderna COVID-19 (Spikevax ®) vaccine. As she met the criteria for monoclonal antibody treatment, she received Sotrovimab on the same day of testing positive and tolerated it well with no side-effects. Her symptoms resolved within two to three days. CONCLUSION: Our case, is the first to our knowledge, of a pregnant patient with common variable immunodeficiency diagnosed with COVID-19 and symptomatic successfully receiving treatment with Sotrovimab. Her rapid resolution of symptoms makes the use of monoclonal antibodies such as Sotrovimab a safe and useful option in this unique population.

The international WAO/EAACI guideline for the management of hereditary angioedema - The 2021 revision and update.

Hereditary Angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2), by providing guidance on common and important clinical issues, such as: 1) How should HAE be diagnosed? 2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? 3) What are the goals of treatment? 4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast feeding women? 5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.

Understanding attitudes and obstacles to vaccination against COVID-19 in patients with primary immunodeficiency.

BACKGROUND: Patients with primary immunodeficiency (PID) are at increased risk for infections such as SARS-CoV-2 (COVID-19), due to the nature of their diseases and being immunocompromised. At this time, four vaccines against COVID-19 (Pfizer-BioNtech's Comirnaty®, Moderna's Spikevax®, AstraZeneca's Vaxzevria®, Johnson & Johnson's Janssen®) have been approved for use by Health Canada. Due to the novelty of these vaccines, clinical studies in patients with PID are ongoing. Despite limited evidence, Canada's National Advisory Committee on Immunization (NACI) recommend that patients with PID without any contraindications should be vaccinated with any of the approved vaccines as the potential benefits of being immunized against the virus likely outweigh the risks of contracting a severe infection. The aim of this study was to understand the perceptions regarding COVID-19 vaccination among patients with PID and to identify specific factors related to vaccine hesitancy. METHODS: The Canadian Immunodeficiencies Patient Organization (CIPO) conducted an online survey of its members to evaluate uptake of the COVID-19 vaccines by patients with PID. Data was collected using a self-administered online questionnaire. The survey was conducted between March and April 2021. RESULTS: At the time of survey, among 370 respondents who had not received the COVID-19 vaccine, 302 respondents (81.6%) indicated they were very or somewhat likely to get vaccinated against COVID-19; and 68 respondents (18.4%) indicated they were somewhat or very unlikely, undecided, or not planning to get vaccinated. A large majority of respondents indicated they had a diagnosis of PID (67.8%) and/or specified their type of PID (27.7%). The most common reason for vaccine hesitancy was primarily due to uncertainty about immune response given an underlying immunodeficiency. Other concerns included unknown long-term side effects of COVID-19 vaccination, pre-existing history of allergic reactions, limited amount of data, lack of investigation of safety and effectiveness of COVID-19 vaccines in those with medical conditions, and skepticism of the underlying science and/or the medical system. CONCLUSIONS: The results point to the importance of ongoing patient outreach, education, and up-to-date information on the rapidly evolving scientific knowledge and evidence on COVID-19 relevant to the PID community, from clinical trials to real-world evidence and observational studies.

Monitoring patients with uncomplicated common variable immunodeficiency: a systematic review.

BACKGROUND: Non-infectious complications have become a major cause of morbidity and mortality in patients with Common Variable Immunodeficiency (CVID). The monitoring of patients with CVID prior to the development of non-infectious complications is not well defined. OBJECTIVE: Our objectives were to systematically review the current literature on the monitoring of CVID patients without non-infectious complications and to develop recommendations for such monitoring. METHODS: MEDLINE and EMBASE were searched from January 1st, 2000 to March 25th, 2021. Studies on any aspects of CVID monitoring were included. Studies that included only children, on monitoring CVID patients with existing non-infectious complications, or in the format of case reports were excluded. RESULTS: Nine studies on CVID monitoring, including 3 cohort studies, 3 experts' opinions, 2 consensus statements and a single guideline report were identified. These studies revealed that clinical assessment and bloodwork were preformed every 6 to 12 months in asymptomatic patients. Some centers performed computerized tomography scan of the chest every 2-5 years to identify chronic lung disease, although the majority did chest imaging in accordance with clinical indications. Pulmonary function tests were done annually at most centers. Most studies did not address the role of abdominal imaging to screen for liver diseases or endoscopy to screen for gastric cancer in asymptomatic patients with uncomplicated CVID. CONCLUSIONS: There is paucity of evidence-based information to guide the routine monitoring of CVID patients without non-infectious complications. Prospective studies are needed to determine the best monitoring practices in this group of patients.

The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update.

Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast-feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.

Demographic and clinical characteristics of patients with hereditary angioedema in Canada.

BACKGROUND: Data on the clinical and demographic features of Canadian patients with hereditary angioedema (HAE) are lacking. OBJECTIVE: To describe the clinical and demographic features in a large Canadian HAE cohort and compare them with patients with HAE in other countries. METHODS: An online questionnaire was distributed to the members of 2 Canadian HAE patient groups to collect information on demographics and HAE clinical characteristics. All participants 18 years of age or older with HAE type I or II were eligible. Frequency, location, prodromes, and triggers of HAE attacks, including types of HAE treatment, were characterized. RESULTS: Among the 90 participants who completed the online survey, 57% self-identified as having HAE type 1 and 26% HAE type II. The average diagnostic delay was 11 years. In the preceding 6 months, 24% of the participants had no attacks and 35% experienced greater than 5 attacks. The most frequently affected regions of the body were the abdomen (83%), arms orlegs (63%), face (41%), and larynx or throat (41%). Approximately 87% of the participants reported having access to C1 inhibitor at home, and 69% reported using it for long-term prophylaxis. CONCLUSION: Canadian patients with HAE share common clinical characteristics with patients with HAE in other countries. They had a delay in HAE diagnosis and a high burden of disease, as indicated by the high frequency of attacks in the preceding 6 months. This study provides a better understanding of the demographic and clinical characteristics of Canadian patients with HAE.

Characterizing telemedicine use in clinical immunology and allergy in Canada before the COVID-19 pandemic.

RATIONALE: There exists a geographic barrier to access CIA care for patients who live in rural communities; telemedicine may bridge this gap in care. Herein we characterized the use of telemedicine in CIA at a population-based level and single centre. METHODS: Before the COVID-19 pandemic, telemedicine care was provided via the Ontario Telemedicine Network (OTN) in Ontario, Canada. Descriptive data were collected from the OTN administrative database and from electronic medical records at a single academic centre during 2014 to 2019. The potential distance travelled and time saved by telemedicine visits were calculated using postal codes. RESULTS: A total of 1298 telemedicine visits was conducted over OTN, with an average of 216 visits per year. Only 11% of the allergists/immunologists used telemedicine to provide care before the COVID-19 pandemic. In the single centre that provided the majority of the telemedicine care, 66% patients were female and the overall mean age was 46. The most common diagnosis was immunodeficiency (40%), followed by asthma (13%) and urticaria (11%). Most patients required at least one follow-up via telemedicine. The average potential two-way distance travelled per visit was 718 km and the average potential time travelled in total was 6.6 h. CONCLUSION: Telemedicine was not widely used by allergists/immunologists in Ontario, Canada before the COVID-19 pandemic. It could offer a unique opportunity to connect patients who live in remote communities and allergists/immunologists who practice in urban centres in Canada. Independent of the current pandemic, our study further highlights the need for more physicians to adopt and continue telemedicine use as well as for healthcare agencies to support its use as a strategic priority once the pandemic is over.

Hereditary Angioedema in Pregnancy.

IMPORTANCE: Hereditary angioedema is a rare disease of potentially life-threatening attacks of angioedema that can affect patients of all ages, including women of childbearing age. Pregnancy can affect the course of the disease and the choice of treatment used. It is important for the care providers to recognize this disease and understand its mechanism in order to provide appropriate care for the patients. OBJECTIVE: The goal of this article is to provide an overview of hereditary angioedema and guideline for management of pregnant patients with hereditary angioedema. EVIDENCE ACQUISITION: A search of the available English language literature was performed on PubMed and Ovid MEDLINE using the key words hereditary angioedema and pregnancy. Additional articles were selected from the reference lists of the reviewed articles. RESULTS: The data for hereditary angioedema in pregnant patients come from observational studies, case reports, retrospective reviews, and questionnaires. The course of hereditary angioedema can be variable between different patients and pregnancies. Plasma-derived C1 inhibitor concentrate is both safe and effective as treatment for attacks and as preventive therapy in pregnancy. With proper recognition, understanding of the disease, and appropriate medical management, most patients will undergo successful pregnancy and delivery. CONCLUSIONS AND RELEVANCE: Clinicians should maintain high suspicion for this disease when patients present with recurrent episodes of angioedema without urticaria or severe abdominal pains of unclear etiology. Treatment plans during pregnancy and delivery should be individualized, and the patient's care should be shared by a clinician experienced in the management of this disease.

Impact of lanadelumab in hereditary angioedema: a case series of 12 patients in Canada.

BACKGROUND: Hereditary angioedema (HAE) is a rare autosomal dominant disease resulting in recurring episodes of swelling, leading to considerable patient morbidity and mortality. Lanadelumab is a plasma kallikrein inhibitor that is approved as 1st line therapy in Canada for long term prophylaxis of HAE attacks. OBJECTIVE: To describe our clinical findings from a case series of adult patients with HAE type 1/2 who have been initiated on lanadelumab. METHODS: A chart review of HAE type 1/2 patients at three academic centers in Canada was undertaken with demographic and clinical data extracted. Patients were included if they had been receiving lanadelumab for at least 6 months. Patients with other causes of angioedema were excluded. RESULTS: 12 patients meeting enrollment criteria were identified. Compared to pre-lanadelumab, patients had mean reductions of 72% and 62% in attack rate and treated attack rate respectively. 3 patients reported complete remission from attacks after starting lanadelumab. Most patients had significant improvements in HAE impact on social outings. CONCLUSION: Our case series findings support the 2019 International/Canadian HAE guideline that lanadelumab is an effective therapy for long term prophylaxis. In our patient population, initiation of lanadelumab improved disease control, minimized the burden of treatment and improved HAE impact on social outings.

Vaccine response following anti-CD20 therapy: a systematic review and meta-analysis of 905 patients.

The objective of this study was to perform a systematic review of the literature on vaccine responsiveness in patients who have received anti-CD20 therapy. PubMed and EMBASE were searched up to 4 January 2021 to identify studies of vaccine immunogenicity in patients treated with anti-CD20 therapy, including patients with hematologic malignancy or autoimmune disease. The primary outcomes were seroprotection (SP), seroconversion (SC), and/or seroresponse rates for each type of vaccine reported. As the pandemic influenza vaccine (2009 H1N1) has standardized definitions for SP and SC, and represented a novel primary antigen similar to the COVID-19 vaccine, meta-analysis was conducted for SC of studies of this vaccine. Pooled estimates, relative benefit ratios (RBs), and 95% confidence intervals (CIs) were calculated using a random-effects model. Thirty-eight studies (905 patients treated with anti-CD20 therapy) were included (19 studies of patients with hematologic malignancies). Patients on active (<3 months since last dose) anti-CD20 therapy had poor responses to all types of vaccines. The pooled estimate for SC after 1 pandemic influenza vaccine dose in these patients was 3% (95% CI, 0% to 9%), with an RB of 0.05 (95% CI, 0-0.73) compared with healthy controls and 0.22 (95% CI, 0.09-0.56) compared with disease controls. SC compared with controls seems abrogated for at least 6 months following treatment (3-6 months post anti-CD20 therapy with an RB of 0.50 [95% CI, 0.24-1.06] compared with healthy and of 0.44 [95% CI, 0.23-0.84] compared with disease controls). For all vaccine types, response to vaccination improves incrementally over time, but may not reach the level of healthy controls even 12 months after therapy.

Quality of life in patients with hereditary angioedema in Canada.

BACKGROUND: Hereditary angioedema (HAE) is associated with decreased quality of life (QoL), which has typically been measured using a generic non-disease-specific questionnaire. OBJECTIVE: We aimed to assess the QoL in patients with HAE type I and II in Canada using a previously validated HAE-specific questionnaire. METHODS: An online questionnaire was sent to the members of two Canadian HAE patient groups to collect data on demographics, HAE clinical course, and QoL scores. All patients 18 years of age or older with HAE type I or II were eligible. The impact of the available clinical factors on the QoL scores was evaluated. Multiple linear regression was performed using clinically relevant factors to predict HAE QoL outcome. RESULTS: Among the 72 patients in the study, the mean total HAE QoL score was 102 (±23) (SD) on a scale of 25 to 135, with higher scores indicating better QoL. Although the total QoL scores correlated positively with patients' level of satisfaction and perceived control (P < .001 for both), it correlated negatively with the number of acute attacks (P = .03). Yet, the types of treatment did not have an impact on the QoL. Predictors, including sex, comorbidities, and the number of attacks, only explained 12% of the variance in the total QoL scores. CONCLUSION: HAE continues to impair QoL in Canadian patients despite receiving recommended treatment. Although the frequency of attacks affects QoL, patients' experience with their HAE care also affects QoL substantially. The study highlights the importance of considering patients' experience with their HAE care as physicians develop an appropriate management plan.

Impaired Memory B-Cell Response to Influenza Immunization in Patients With Common Variable Immunodeficiency (CVID).

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency characterized by low serum antibody levels and recurrent infections. The cellular response to immunization in patients with CVID has not been fully investigated. In this study, we aimed to characterize vaccination-induced influenza-specific memory B-cell responses in CVID. METHODS: Eleven individuals affected with CVID and 9 unaffected control individuals were immunized with the 2010-2011 non-adjuvanted seasonal influenza vaccine. Blood samples were collected on the day of vaccination and at week 8 and week 16 after vaccination, and PBMCs were immunophenotyped by flow cytometry. Influenza specific serology was determined using hemagglutination inhibition and microneutralization against vaccine antigens. Influenza-specific memory B-cell responses were determined by ELISpot. RESULTS: Individuals with CVID showed wide variability in the frequency of CD19+ B cells in blood. The CVID group had significantly reduced frequencies of CD19+CD27+ memory B cells. Frequencies of circulating T follicular helper (CD4+CXCR5+) cells were similar between those with CVID and healthy controls. In terms of serology, compared to healthy controls, the CVID group overall showed significantly reduced boosting to vaccine antigens by hemagglutination inhibition and microneutralization assays at 8 weeks compared to controls and failed to maintain responses by 16 weeks compared to controls, resulting in a post-vaccination geometric mean titer (GMT) ≥ 40 to strain A/H1N1 in only 27% at 8 weeks, and 22% at 12 weeks for patients with CVID vs 78% and 75%, respectively for healthy controls. In addition, there was a GMT ≥ 40 to A/H3N2 in only 9% at 8 weeks and 22% at 12 weeks for patients with CVID vs 56% and 50%, respectively for healthy controls. Healthy participants showed significant increases in flu-specific IgM-secreting memory B cells after vaccination, whereas patients with CVID showed non-signifi-cant mild increases. Before vaccination, patients with CVID had significantly lower frequencies of background level influenza-specific IgG and IgA memory B cells. Half of the patients with CVID showed an increase in influenza-specific IgG-secreting memory B cells post vaccination, whereas the other half showed none. All control participants exhibited an increase in influenza-specific IgG-secreting B cells. None of the patients with CVID developed influenza-specific IgA memory B-cell response post vaccination, compared to 5/8 in healthy controls. At week 16, the frequency of influenza-specific memory B-cell responses decayed but to non-zero baseline in healthy controls and to zero baseline in patients with CVID. CONCLUSIONS: Together, these data demonstrate that patients with CVID respond heterogeneously, but as a group poorly, to non-adjuvanted influenza vaccine, with a subgroup unable to generate influenza-specific memory B-cell responses. No patient with CVID was able to maintain memory response for prolonged periods. Together, our results suggest a defect in Ig class switching and memory B-cell maintenance in patients with CVID during a de novo vaccine immune response.