Allergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology最新文献

Background: Primary antibody deficiencies (PAD) are characterized by a heterogeneous clinical presentation and low prevalence, contributing to a median diagnostic delay of 3-10 years. This increases the risk of morbidity and mortality from undiagnosed PAD, which may be prevented with adequate therapy. To reduce the diagnostic delay of PAD, we developed a screening algorithm using primary care electronic health record (EHR) data to identify patients at risk of PAD. This screening algorithm can be used as an aid to notify general practitioners when further laboratory evaluation of immunoglobulins should be considered, thereby facilitating a timely diagnosis of PAD.

Methods: Candidate components for the algorithm were based on a broad range of presenting signs and symptoms of PAD that are available in primary care EHRs. The decision on inclusion and weight of the components in the algorithm was based on the prevalence of these components among PAD patients and control groups, as well as clinical rationale.

Results: We analyzed the primary care EHRs of 30 PAD patients, 26 primary care immunodeficiency patients and 58,223 control patients. The median diagnostic delay of PAD patients was 9.5 years. Several candidate components showed a clear difference in prevalence between PAD patients and controls, most notably the mean number of antibiotic prescriptions in the 4 years prior to diagnosis (5.14 vs. 0.48). The final algorithm included antibiotic prescriptions, diagnostic codes for respiratory tract and other infections, gastro-intestinal complaints, auto-immune symptoms, malignancies and lymphoproliferative symptoms, as well as laboratory values and visits to the general practitioner.

Conclusions: In this study, we developed a screening algorithm based on a broad range of presenting signs and symptoms of PAD, which is suitable to implement in primary care. It has the potential to considerably reduce diagnostic delay in PAD, and will be validated in a prospective study. Trial registration The consecutive prospective study is registered at clinicaltrials.gov under NCT05310604.

Background: Pediatric food allergy is associated with excess familial food costs compared to families without allergy. Since the start of the COVID-19 pandemic, food prices have increased substantially.

Objective: To understand the temporal pattern of food insecurity amongst Canadian families with food allergy from the year prior to the pandemic, through May 2022.

Methods: Using data collected electronically from families reporting food allergy using a validated food security questionnaire, we estimated food insecurity, including categories of food insecurity (marginal, moderate, secure) in the year prior to the pandemic (2019; Wave 1), and the first (2020; Wave 2) and second years of the pandemic (2022; Wave 3).

Results: Participants in all waves were commonly in 2 + adult, 2 child households. Less than half of participants (Waves 1-3: 45.7%, 31.0%, and 22.9%, respectively) reported household incomes below the median Canadian. Common allergies were milk, eggs, peanuts and tree nuts. In Wave 1, 22.9% of families reported food insecurity; corresponding numbers at Waves 2 and 3 were 30.6% and 74.4%, respectively, representing an overall increase of 225.6%, including notable increases in severe food insecurity.

Conclusion: Canadian families with pediatric food allergy report higher rates of food insecurity compared to the general Canadian population, especially during the pandemic.

Severe asthma imposes a physical and economic burden on both patients and society. As chromatin regulators (CRs) influence the progression of multiple diseases through epigenetic mechanisms, we aimed to study the role of CRs in patients with severe asthma. Transcriptome data (GSE143303) from 47 patients with severe asthma and 13 healthy participants was downloaded from the Gene Expression Omnibus database. Enrichment analysis was performed to investigate the functions of differentially expressed CRs between the groups. We identified 80 differentially expressed CRs; they were mainly enriched in histone modification, chromatin organization, and lysine degradation. A protein-protein interaction network was then constructed. The analyzed immune scores were different between sick and healthy individuals. Thus, CRs with a high correlation in the immune analysis, SMARCC1, SETD2, KMT2B, and CHD8, were used to construct a nomogram model. Finally, using online prediction tools, we determined that lanatoside C, cefepime, and methapyrilene may be potentially effective drugs in the treatment of severe asthma. The nomogram constructed using the four CRs, SMARCC1, SETD2, KMT2B, and CHD8, may be a useful tool for predicting the prognosis of patients with severe asthma. This study provided new insights into the role of CRs in severe asthma.

Background: Hereditary angioedema (HAE), which is caused by C1-inhibitor (C1-INH) deficiency or dysfunction, is a rare and potentially life-threatening disease. In patients with HAE, excess production of bradykinin causes acute unpredictable recurrent attacks of angioedema in localized regions, including the larynx and intestines. Given the fact that HAE is an autosomal dominant disease, C1-INH produced in patients with HAE is 50% of that produced in healthy individuals. However, most patients with HAE present plasma C1-INH function of < 25% owing to the chronic consumption of C1-INH by kallikrein-kinin, contact, complement, coagulation, and fibrinolysis cascades. Recently, several therapeutic options have been developed for acute attacks and prophylaxis in the treatment of HAE; however, currently, there is no curative therapy for HAE.

Case presentation: Here we report the case of a 48-year-old male patient who presented with a long-standing history of HAE and underwent bone marrow transplantation (BMT) for acute myeloid leukemia (AML) at the age of 39 years and has been in complete remission of AML and HAE thereafter. Notably, after BMT, his C1-INH function gradually increased as follows: < 25%, 29%, 37%, and 45.6%. Since his 20 s, he intermittently presented with an acute attack of HAE once every 3 months from the initial attack. Further, after undergoing BMT, the number of acute attacks decreased to twice within 4 years until the age of 45 years, and subsequently, the patient has been free of acute attacks. C1-INH is mainly synthesized by hepatocytes, but it is known to be partially produced and secreted from peripheral blood monocytes, macrophages, endothelial cells, and fibroblasts. We speculate that the C1-INH function may be increased by extrahepatic production of C1-INH, possibly synthesized by differentiated cells derived from hematopoietic and mesenchymal stem cells after BMT.

Conclusions: This case report supports efforts to focus on extrahepatic production of C1-INH in the next strategy of new treatment development for HAE.

Background: Allergic rhinitis (AR) is a chronic disease with high prevalence. There are currently many treatments available. However, despite an often good therapeutic response, many patients still report impairment in quality of life (QoL) during the pollen season. A skewed T helper (Th)2 polarization is a well-acknowledged pathologic feature of AR. In animal models, local notch signaling in peripheral tissue seems crucial for Th2 cell differentiation and the development of AR. However, the involvement of Notch signaling in Th2 cell differentiation and the development of AR in humans remains unknown. Hence, the present study investigated the human expression of Notch receptors on CD4⁺ T-cells in nasal mucosa and blood. Correspondingly Notch ligand expression was assessed on nasal epithelial cells and neutrophils.

Methodology: Nasal brush and blood samples from 18 patients with pollen-induced AR and 22 healthy controls were collected outside the pollen season. Notch 1-4 and Jagged-1,2 and Delta-like ligand 1,3-4 was analyzed using flow cytometry.

Results: The fraction of CD4⁺Notch1⁺ and CD4⁺Notch4⁺ T-cells was higher in AR patients than in healthy control patients. Further, the expression levels of the Notch ligands JAG-1 and DLL-1 were increased in nasal epithelial cells from AR patients compared to healthy control patients. In addition, AR patients displayed higher expression of JAG-1 on neutrophils both in the nasal mucosa and in peripheral blood.

Conclusion: The present study is the first to demonstrate increased activity in the Notch1/4 - JAG-1/DLL-1 pathways among allergic individuals. Further propagating the importance of Notch signalling in AR and blocking JAG-1 and DLL-1-induced Notch signalling by nasal epithelial cells and Neutrophils are potential targets to reduce allergic airway inflammation.

Background: The mainstay of treatment for eosinophilic granulomatosis with polyangiitis (EGPA) is systemic corticosteroid therapy; some patients also receive intravenous immunoglobulins, other immunosuppressive agents, and biologics. Mepolizumab, an anti-interleukin-5 monoclonal antibody, induces remission and decreases the daily corticosteroid dose; however, the clinical efficacy of mepolizumab in EGPA and the prognosis with long-term treatment with this drug are unknown.

Methods: Seventy-one EGPA patients were treated at Hiratsuka City Hospital, Japan, between April 2018 and March 2022. We administered mepolizumab for a mean of 2.8 ± 1.7 years to 43 patients in whom remission could not be induced by conventional treatment. After excluding 18 patients who had received mepolizumab for less than 3 years, we classified 15 patients into a "super-responder group" (the daily dose of corticosteroids or other immunosuppressant could be decreased, or the interval between IVIG treatments could be prolonged) and 10 patients into a "responder group" (neither of these changes was achievable). Eosinophil numbers, serum IgG levels, daily doses of corticosteroids and other immunosuppressants, Birmingham Vasculitis Activity Score (BVAS), and relapse frequency before and after mepolizumab initiation were determined.

Results: Blood eosinophil count at diagnosis and the lowest serum IgG level before mepolizumab treatment were significantly higher in super-responders than in responders (p < 0.05). In super-responders, the prednisolone dose at last visit on mepolizumab treatment was lower than that before treatment (p < 0.01) and lower than that at last visit in the responders (p < 0.01). In both groups, peripheral blood eosinophil numbers and BVAS were lower after starting mepolizumab than before (p < 0.01). BVAS before mepolizumab (p < 0.05) and at last visit (p < 0.01) were lower in super-responders than in responders. Relapse rates every year after the start of mepolizumab were lower in super-responders than in responder groups (p < 0.01). In super-responders, relapse rates were lower during the 3 years following mepolizumab initiation (p < 0.01) and at last visit (p < 0.01) were significantly lower than after 1 year of treatment.

Conclusion: Mepolizumab treatment of super-responders sustainably reduced the relapse rate.

Background: IL-6 is a pleotropic cytokine that acts as a pro-inflammatory mediator and acute-phase response inducer, but has also been reported to possess anti-inflammatory properties. The objective of this study was to assess the validity of serum IL-6 test for diagnosis of asthma.

Methods: A literature search was conducted using PubMed, Embase, and Cochrane library from January 2007 to March 2021 to identify relevant studies. Eleven studies were included in this analysis, involving 1977 patients with asthma and 1591 healthy non-asthmatic controls. The meta-analysis was performed using Review Manager 5.3 software and Stata 16.0. Random effect model or fixed effect model (FEM) was used to estimate the standardized mean differences (SMDs) with 95% confidence intervals (CIs).

Results: The meta-analysis results revealed that the serum IL-6 levels were higher in asthmatic patients than healthy non-asthmatic controls (SMD 1.31, 95% CI 0.82-1.81, P < 0.00001). IL-6 levels are significantly elevated in pediatric patients with asthma (SMD 1.58, 95% CI 0.75-2.41, P = 0.0002) and mildly elevated in adult patients with asthma (SMD 1.08, 95% CI 0.27-1.90, P = 0.009). In addition, a subgroup analysis of asthma disease status showed that IL-6 levels were increased in stable (SMD 0.69, 95% CI 0.28-1.09, P = 0.009) and exacerbation asthma (SMD 2.15, 95% CI 1.79-2.52, P < 0.00001) patients.

Conclusion: The results of this meta-analysis suggest that serum IL-6 levels were significantly elevated in asthmatic patients as compared to normal population. IL-6 levels can be used as an auxiliary indicator to distinguish individuals with asthma from healthy non-asthmatic controls.

Background: COVID-19 disproportionately affects those with preexisting conditions, but little research has determined whether those with chronic diseases view the pandemic itself differently - and whether there are differences between chronic diseases. We theorized that while individuals with respiratory disease or autoimmune disorders would perceive greater threat from COVID-19 and be more supportive of non-pharmaceutical interventions (NPIs), those with autoimmune disorders would be less likely to support vaccination-based interventions.

Methods: We conducted a two-wave online survey conducted in February and November 2021 asking respondents their beliefs about COVID-19 risk perception, adoption and support of interventions, willingness to be vaccinated against COVID-19, and reasons for vaccination. Regression analysis was conducted to assess the relationship of respondents reporting a chronic disease and COVID-19 behaviors and attitudes, compared to healthy respondents adjusting for demographic and political factors.

Results: In the initial survey, individuals reporting a chronic disease had both stronger feelings of risk from COVID-19 as well as preferences for NPIs than healthy controls. The only NPI that was still practiced significantly more compared to healthy controls in the resample was limiting trips outside of the home. Support for community-level NPIs was higher among individuals reporting a chronic disease than healthy controls and remained high among those with respiratory diseases in sample 2. Vaccine acceptance produced more divergent results: those reporting chronic respiratory diseases were 6% more willing to be vaccinated than healthy controls, while we found no significant difference between individuals with autoimmune diseases and healthy controls. Respondents with chronic respiratory disease and those with autoimmune diseases were more likely to want to be vaccinated to protect themselves from COVID-19, and those with an autoimmune disease were more likely to report fear of a bad vaccine reaction as the reason for vaccine hesitancy. In the resample, neither those with respiratory diseases nor autoimmune diseases reported being more willing to receive a booster vaccine than healthy controls.

Conclusions: It is not enough to recognize the importance of health in determining attitudes: nuanced differences between conditions must also be recognized.

Background: The Champlain BASE™ and Ontario eConsult services are virtual platforms that serve to facilitate contact between primary care providers and specialists across Ontario, relaying patient-specific questions to relevant specialists via a secure web-based platform. Despite ample evidence regarding the general effectiveness of these platforms, their utility as it pertains to clinical concerns regarding COVID-19 vaccines has not yet been explored.

Methods: We performed a cross-sectional descriptive analysis of COVID-19 vaccine related eConsults on Ontario patients completed by five allergy specialists between February and October of 2021. 4318 COVID-19 vaccine-related eConsults were completed in total during this time; with 1857 completed by the five allergists participating in this analysis. Question types/content were categorized using a taxonomy developed through consensus on a weighted monthly sample of 499 total cases. Data regarding whether external resources were required to answer each eConsult, impact on primary care provider referral decisions, and allergy consultant response times were collected. A 2-question survey was completed by primary care providers following eConsultation and results were collected.

Results: 41.08% of eConsults received involved safety concerns regarding COVID-19 vaccine administration in the setting of prior allergic disease and another 36.1% involved a potential reaction the first dose of a COVID-19 vaccine. 72.1% of eConsults were answered by specialist without needing external resources, and only 9.8% of all eConsults received resulted in a recommendation for formal in-person referral to Clinical Immunology & Allergy specialist or another subspecialty. Average time to complete eConsult was 16.4 min, and 79.7% of PCP eConsult queries which would have traditionally resulted in formal consultation were resolved based on advice provided in the eConsult without need for in-person assessment.

Conclusions: Our study demonstrates the utility of the eConsult service as it pertains to COVID-19 vaccine-related concerns. The eConsult platform proved an effective tool in diverting the need for in-person assessment by an Allergist or other medical specialty. This is significant given the large volume of eConsults completed by Allergists, and demonstrates the impact of an effective electronic delivery of care model during a time of strained resources and public health efforts directed at mass vaccination.

Background: Primary immunodeficiency disorders (PID) are rare disorders with heterogeneous manifestations, overlapping with other diseases such as autoimmunity, malignancy, and infections. This makes the diagnosis very challenging and delays management. Leucocyte adhesion defects (LAD) are a group of PIDs in which patients lack adhesion molecules on leukocytes needed for their emigration through blood vessels to the site of infection. Patients with LAD can present with diverse clinical features including severe and life-threatening infections, early in life, and the absence of pus formation around infection or inflammation. There is often delayed umbilical cord separation, omphalitis, late wound healing, and a high white blood cell count. If not recognized and managed early, can lead to life-threatening complications and death.

Case presentation: LAD 1 is characterized by homozygous pathogenic variants in the integrin subunit beta 2 (ITGB2) gene. We report two cases of LAD1 with unusual presentations (post-circumcision excessive bleeding and chronic inflammation of the right eye) which were confirmed by flow cytometric analysis and genetic testing. We found two disease-causing ITGB2 pathogenic variants in both cases.

Conclusions: These cases highlight the importance of a multidisciplinary approach to recognizing clues in patients with uncommon manifestations of a rare disease. This approach initiates a proper diagnostic workup of primary immunodeficiency disorder leading to a better understanding of the disease, and appropriate patient counseling, and helps clinicians to be better equipped to deal with complications.