The signs and symptoms of chronic urticaria (CU) are caused by the activation and degranulation of skin mast cells (MCs). Recent studies have added to our understanding of how and why skin MCs are involved and different in CU. Also, novel and relevant mechanisms of MC activation in CU have been identified and characterized. Finally, the use of MC-targeted and MC mediator-specific treatments has helped to better define the role of the skin environment, the contribution of specific MC mediators, and the relevance of MC crosstalk with other cells in the pathogenesis of CU. Here, we review these recent findings and their impact on our understanding of CU, with a focus on chronic spontaneous urticaria (CSU). Also, we highlight open questions, issues of controversy, and unmet needs, and we suggest what studies should be performed moving forward.
Chronic spontaneous urticaria (CSU) is a common skin disease without an etiology in the vast majority of cases. The similarity of symptoms and pathology to allergen-induced skin reactions supports that skin mast cell IgE receptor activation is also involved in CSU. Accumulating evidence also supports a role for blood basophils in disease expression. Blood basopenia is noted in active CSU disease with the recruitment of blood basophils to skin lesion sites. Blood basophils further display altered IgE receptor mediated degranulation patterns in two phenotypes that improve in remission. In active CSU subjects, changes in IgE receptor signaling molecule expression levels accompany the altered degranulation function in blood basophils. The success of therapies targeting IgE in CSU patients have also shown that altered blood basophil phenotypes and enumeration have potential use as a disease biomarker.
Hereditary angioedema (HAE) is a rare disorder characterized by cutaneous and submucosal swelling caused mostly by excessive local bradykinin production. Bradykinin is a vasoactive peptide generated by the limited proteolysis of high molecular weight kininogen (HMWK) by plasma kallikrein via the contact activation system. The contact activation system occurs not only in solution but also on the cell surface. Factor XII (FXII), prekallikrein, and HMWK are assembled on the endothelial cell surface via several proteins, including a trimer of a receptor for globular C1q domain in a Zn2+-dependent manner, and the reciprocal activation on the cell surface is believed to be physiologically important in vivo. Thus, the contact activation system leads to the activation of coagulation, complement, inflammation, and fibrinolysis. C1-inhibitor (C1-INH) is a plasma protease inhibitor that is a member of the serpin family. It mainly inhibits activated FXII (FXIIa), plasma kallikrein, and C1s. C1-INH hereditary deficiency induces HAE (HAE-C1-INH) due to excessive bradykinin production via the incomplete inhibition of plasma kallikrein and FXIIa through the low C1-INH level. HAE is also observed in patients with normal C1-INH (HAEnCI) who carry pathogenic variants in genes of factor XII, plasminogen, angiopoietin 1, kininogen, myoferlin, and heparan sulfate 3-O-sulfotransferase 6, which are associated with bradykinin production and/or vascular permeability. HAE-causing pathways triggered by pathogenic variants in patients with HAE-C1-INH and HAEnCI are reviewed and discussed.
Cryopyrin-associated periodic syndromes (CAPS) and Schnitzler syndrome (SchS) are autoinflammatory diseases that present with urticaria-like rashes. CAPS is characterized by periodic or persistent systemic inflammation caused by the dysfunction of the NLRP3 gene. With the advent of IL-1-targeted therapies, the prognosis of CAPS has improved remarkably. SchS is considered an acquired form of autoinflammatory syndrome. Patients with SchS are adults of relatively older age. The pathogenesis of SchS remains unknown and is not associated with the NLRP3 gene. Previously, the p.L265P mutation in the MYD88 gene, which is frequently detected in Waldenström macroglobulinemia (WM) with IgM gammopathy, was identified in several cases of SchS. However, because persistent fever and fatigue are symptoms of WM that require therapeutic intervention, it is a challenge to determine whether these patients truly had SchS or whether advanced WM was misidentified as SchS. There are no established treatments for SchS. The treatment algorithm proposed with the diagnostic criteria is to use colchicine as first-line treatment, and systemic administration of steroids is not recommended due to concerns about side effects. In difficult-to-treat cases, treatment targeting IL-1 is recommended. If targeted IL-1 treatment does not improve symptoms, the diagnosis should be reconsidered. We hope that the efficacy of IL-1 therapy in clinical practice will serve as a stepping stone to elucidate the pathogenesis of SchS, focusing on its similarities and differences from CAPS.
Background: The considerable prevalence and worse outcomes of asthma-COPD overlap (ACO) in COPD have been reported, and optimal introduction of ICS is essential for ACO. However, diagnostic criteria for ACO consist of multiple laboratory tests, which is challenging during this COVID-19 era. The purpose of this study was to create a simple questionnaire to diagnose ACO in patients with COPD.
Methods: Among 100 COPD patients, 53 were diagnosed with ACO based on the Japanese Respiratory Society Guidelines for ACO. Firstly, 10 candidate questionnaire items were generated and further selected by a logistic regression model. An integer-based scoring system was generated based on the scaled estimates of items.
Results: Five items, namely a history of asthma, wheezing, dyspnea at rest, nocturnal awakening, and weather- or season-dependent symptoms, contributed significantly to the diagnosis of ACO in COPD. History of asthma was related to FeNO >35 ppb. Two points were assigned to history of asthma and 1 point to other items in the ACO screening questionnaire (ACO-Q), and the area under the receiver operating characteristic curve was 0.883 (95% CI: 0.806-0.933). The best cutoff point was 1 point, and the positive predictive value was 100% at a cutoff of 3 points or higher. The result was reproducible in the validation cohort of 53 patients with COPD.
Conclusions: A simple questionnaire, ACO-Q, was developed. Patients with scores ≥3 could be reasonably recommended to be treated as ACO, and additional laboratory testing would be recommended for patients with 1 and 2 points.
Background: Blood eosinophils are essential biomarkers that vary substantially over time in patients with COPD and asthma. However, no study has identified the changes and effects in the changes of the blood eosinophil counts over time in both diseases. This study aimed to demonstrate blood eosinophil variability in patients with COPD and severe asthma based on these backgrounds.
Methods: A total of 172 patients with COPD from the Hokkaido COPD cohort study and 96 patients with severe asthma from the Hokkaido Severe Asthma Cohort Study, whose blood eosinophil counts were measured annually over a 3-year period, were analyzed. The factors contributing to consistently high or low blood eosinophil counts were examined in each cohort. The stability of the eosinophil classification (<150, 150-299, ≥300 cells/μL) was compared based on the number of asthma-like features in patients with COPD and the smoking status in patients with severe asthma.
Results: Among all the patients, the most stable range of baseline blood eosinophil counts differed between the two diseases, with <150 cells/μL in COPD and ≥300 cells/μL in severe asthma. In COPD, the number of asthma-like features (bronchodilator reversibility, blood eosinophilia, and atopy) affects the blood eosinophil count variation patterns. In severe asthma, smoking status did not affect the blood eosinophil count variation patterns.
Conclusions: We identified variations in the blood eosinophil counts and their contributing factors in patients with COPD and severe asthma.
Background: The relationship between the season of birth, allergen sensitization, and allergic rhinitis have been inconsistent, and there are no studies that simultaneously consider vitamin D and allergen exposure. This study aimed to determine the associations between the season of birth, house dust mite (HDM) and Japanese cedar pollen (JCP) sensitization, and allergic rhinitis and pollinosis, while taking vitamin D levels and allergen exposure into account.
Methods: This study included 4323 participants in the Sub-Cohort Study of the Japan Environment and Children's Study. A logistic regression model was used to analyze the association between the season of birth and sensitization to JCP or HDM (judged by specific immunoglobulin E) at age 2 and allergic rhinitis or pollinosis at age 3, adjusted for HDM or JCP exposure and vitamin D levels with potential confounders.
Results: Participants born in spring or summer were more likely to have pollinosis than were those born in winter (adjusted odds ratio [aOR]: 2.08, 95% confidence interval [CI]: 1.13-3.82 for spring; aOR: 1.89, 95% CI: 1.03-3.47 for summer). Participants born in summer were more likely to have HDM sensitization than were those born in winter (Der p 1, aOR: 1.53, 95% CI: 1.10-2.15; Der f 1, aOR: 1.44, 95% CI: 1.03-2.01). Exposure to JCP and HDM were associated with pollinosis and HDM sensitization, respectively.
Conclusions: Spring and summer births were associated with the development of pollinosis, and summer birth was associated with HDM sensitization, even when vitamin D and allergen exposure were considered. Further studies on mechanisms other than vitamin D and allergen exposure are required.
Background: Multidisciplinary efforts to prospectively collect and analyze symptoms of hay fever are limited. We aimed to identify the characteristics of nasal and ocular symptoms of hay fever, using the AllerSearch smartphone application.
Methods: This mobile health-based prospective observational study using the AllerSearch smartphone application was conducted between February 1, 2018, and May 1, 2020. Individuals who downloaded AllerSearch from Japan and provided comprehensive self-assessments (including 17 items related to quality of life [QoL]-related items) were included. The characteristics and risk factors for allergic rhinitis (AR) and allergic conjunctivitis (AC) were identified using hierarchical heat maps and multivariate logistic regression.
Results: Of the 9041 participants with hay fever, 58.8% had AR and AC, 22.2% had AR, and 5.7% had AC. The AR-AC comorbid cohort showed worse symptoms of hay fever and QoL scores than the other cohorts. Factors (odds ratio, 95% confidence interval) associated with AR-AC included a lower age (0.98, 0.97-0.98), female sex (1.31, 1.19-1.45), liver disease (1.58, 1.26-2.35), dry eye disease (1.45, 1.30-1.63), unknown dry eye disease status (1.46, 1.31-1.62), contact lens use discontinuation during the hay fever season (1.69, 1.28-2.23), and bedroom flooring material other than hardwood, carpet, tatami, or vinyl (1.91, 1.16-3.14).
Conclusions: Analysis of medical big data for hay fever performed using a mobile health app helped identify risk factors and characteristics of AC, AR, and AR-AC. Phenotyping of highly variable symptoms of hay fever, such as nasal and ocular symptoms, can facilitate better-quality clinical care.
Background: Although paranasal sinuses are one of the most representative organs affected by eosinophilic granulomatosis with polyangiitis (EGPA), they have not been studied sufficiently. The aim of this study was to compare computed tomography (CT) findings in paranasal sinuses of EGPA with those of other eosinophilic sinus diseases and elucidate the clinical relevance of their severity.
Methods: CT findings of paranasal sinuses in EGPA patients prior to therapeutic intervention (n = 30) were evaluated using the Lund-Mackay staging (LMS) system and compared with those of three control diseases [(NSAID-exacerbated respiratory disease (N-ERD), aspirin-tolerant asthma, and eosinophilic chronic rhinosinusitis without asthma (ECRS)]. We divided EGPA patients into three groups based on their LMS scores and examined their association with disease manifestation.
Results: Total scores of the LMS system in EGPA were significantly lower than those of N-ERD and ECRS without asthma. There was a large variation in total LMS scores in EGPA, suggesting considerable heterogeneity of their sinus lesions. Although EGPA with low LMS system scores showed only minor findings in maxillary and anterior ethmoid regions, those with high LMS system scores were characterized by high scores in the ostiomeatal complex. However, the frequencies of patients with a Five-Factor Score ≥2 and with cardiac involvement were significantly higher for EGPA with low LMS system scores.
Conclusions: Although paranasal sinus lesions in EGPA were less severe than those of other eosinophilic sinus diseases, their milder CT findings may be associated with a higher frequency of extra-respiratory organ involvement.
Background: Anaphylaxis is a potentially fatal severe systemic hypersensitivity reaction that causes symptoms in multiple organs such as the skin, respiratory tract, and gastrointestinal tract; however, no nationwide epidemiological survey on anaphylaxis has been conducted in Japan. This survey aimed to elucidate the triggers and treatment of anaphylaxis in Japan.
Methods: Between February 2015 and October 2017, we prospectively collected clinical data on the triggers and treatment of patients who developed anaphylaxis or were admitted to the emergency room with anaphylaxis in the training and teaching facilities of the Japanese Society of Allergology.
Results: This study included 79 of the 451 affiliated facilities (18%), and a total of 767 patients were enrolled; 73% of them were aged <18 years and 7% had in-hospital triggers. The most common triggers were food (68%), drugs (12%), food-dependent exercise-induced anaphylaxis (5%), insects (4%), and oral immunotherapy (3%), with drugs being the most common in-hospital trigger and food being the most common out-of-hospital trigger. Intramuscular injection of adrenaline was administered therapeutically to 38% of the patients, with 10% requiring multiple doses. Adrenaline auto-injectors were used in 12% of out-of-hospital patients.
Conclusions: The present survey revealed the most common triggers and treatments for anaphylaxis in Japan. Self-management and adrenaline administration as first-line treatment may not be done sufficiently. Therefore, it is necessary to thoroughly educate and train patients and physicians about anaphylaxis.
Background: In patients with wheat-dependent exercise-induced anaphylaxis (WDEIA), anaphylactic shock occurs frequently, therefore avoidance of wheat products is recommended. We aimed to evaluate efficacy and safety of long-term omalizumab treatment for adult patients with WDEIA.
Methods: In this phase 2, multicentre single-arm trial, 20 adult patients with WDEIA were enrolled (UMIN 000019250). All patients were administered 150-600 mg of omalizumab subcutaneously and evaluations (basophil activation and blood examination) were performed at regular intervals during administration period (0-48 weeks) and observation period (48-68 weeks). Primary endpoint was proportion of the patients who achieved a basophil activation rate below 10% with fractionated wheat preparations, and secondary endpoint was proportion of the patients with no allergic reactions after wheat products ingestion.
Results: During the omalizumab treatment, more than 80% of the patients achieved the basophil activation rate less than 10% against all fractionated wheat preparations, and 68.8% of the patients who achieved the primary endpoint experienced no allergic reaction. During the observation period, the proportion of the patients who achieved a basophil activation rate below 10% decreased gradually, and the proportion of patients with positive allergic reactions increased gradually thereafter and reached maximum of 46.7%. Severe adverse events were not observed during the study.
Conclusions: Long-term omalizumab treatment is safe and effective for adult patients with WDEIA when assessed by basophil activation rate with wheat allergens as well as allergic reactions after lifting of restrictions on wheat intake. However, this is not enough to achieve desensitization.
Background: Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder characterized by recurrent attacks of angioedema. HAE types I and II result from deficient or dysfunctional C1-esterase inhibitor (C1-INH). This Phase 3 study assessed the efficacy, pharmacokinetics (PK), and safety of subcutaneous (SC) C1-INH in Japanese patients with HAE.
Methods: The prospective, open-label, multicenter, single-arm Phase 3 study recruited patients with HAE types I or II to an initial run-in period, followed by a 16-week treatment period where patients received 60 IU/kg C1-INH (SC) twice weekly. The two primary endpoints were the time-normalized number of HAE attacks per month and C1-INH functional activity at Week 16.
Results: Nine patients entered the treatment period and completed the study. Treatment with C1-INH (SC) significantly reduced the mean monthly attack rate from 3.7 during the run-in period to 0.3 during treatment (exploratory p value of within-patient comparison = 0.004). After the last dose of C1-INH (SC) at Week 16, the mean trough concentration of C1-INH was 59.8%, and the mean area under the plasma concentration-time curve to the end of the dosing period and to the last sample were 5317.1 and 13,091.5 h•%, respectively. During the study, there were no deaths, serious adverse events, or adverse events leading to study discontinuation.
Background: The current diagnostics of fish allergy lack sufficient accuracy such that more reliable tests such as component-resolved diagnosis (CRD) are urgently needed. This study aimed at identifying fish allergens of salmon and grass carp and evaluating the sensitization pattern in fish allergic subjects from two distinct populations in Asia.
Methods: One hundred and three fish allergic subjects were recruited from Hong Kong (67 subjects) and Japan (46 subjects). Western blot and mass spectrometry were used to identify allergens from salmon and grass carp. Fish allergens were purified and tested against 96 sera on ELISA to analyze patients' sensitization pattern. The protein profiles of salmon meat prepared under different cooking methods until core temperature reached 80 °C were evaluated by SDS-PAGE and mass spectrometry.
Results: Three common allergens between salmon and grass carp, namely enolase, glycerldehyde-3-phosphate dehydrogenase (GAPDH) and parvalbumin, and two salmon-specific allergens collagen and aldolase were identified. Parvalbumin was the major allergen for both fishes showing an overall sensitization rate of 74.7%, followed by collagen (38.9%), aldolase (38.5%) and enolase (17.8%). Japanese subjects showed more diverse allergen sensitization pattern and more frequent IgE-binding to heat-labile salmon allergens. Compared with steaming and boiling, cooking by baking and frying retained more fish proteins inclusive of heat-labile allergens.
Conclusions: Fish allergic patients from different Asian populations show varying fish allergen sensitization profiles. The relevant extracts and components for diagnosis are population-dependent but parvalbumin and collagen are important biomarkers. Cooking methods modify allergen composition of salmon and appear to influence patients' allergic manifestations.
Background: Platelets play a modulatory role in inflammatory response by secreting a vast array of granules and disintegrating into membrane-bound microparticles upon activation. The interplay between eosinophils and platelets is postulated to be implicated in the pathology of allergic airway inflammation. In this study, we investigated whether activated platelets can induce eosinophil extracellular trap (EET) formation, a cellular process by which activated eosinophils release net-like DNA fibers.
Methods: Platelets were stimulated with the calcium ionophore, A23187, and the platelet agonists, thrombin and adenosine diphosphate (ADP). Platelet cultures were fractionated into conditioned medium (CM) and pellet, which were then overlaid on eosinophils to examine EET formation.
Results: The CM and pellet from A23187-activated platelets stimulated eosinophils to generate EET, whereas those from thrombin- or ADP-activated platelets failed to induce such generation. The EET-inducing activity of the A23187-activated platelet culture was linearly proportional to the number of activated platelets. Interestingly, while EET formation induced by the direct stimulation of eosinophils with A23187 was NADPH oxidase (NOX)-dependent, EET formation induced by A23187-activated platelets was NOX-independent and significantly inhibited by necroptosis pathway inhibitors.
Conclusions: Activated platelets and their products may induce EET formation, thereby potentiating their role in eosinophilic airway inflammation.