Journal of Allergy and Clinical Immunology-In Practice最新文献

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare form of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis, distinguished by a complex interplay between type 2 (T2) eosinophilic and non-T2 inflammatory pathways. Systemic glucocorticosteroids remain the mainstay of both induction and maintenance therapy, achieving remission in patients without poor prognostic factors, yet long-term dependence and toxicity remain pervasive challenges. Conventional immunosuppressive agents such as cyclophosphamide (CYC), azathioprine, and methotrexate have been widely used, and rituximab has shown similar remission rates to CYC for induction therapy. However, robust randomized controlled trial evidence supporting their efficacy in EGPA is limited. Biologic therapies targeting eosinophils through IL-5 or IL-5R blockade, notably mepolizumab and benralizumab, have markedly reduced relapse rates, steroid exposure, and improved remission rates in relapsing or refractory disease, with excellent tolerability. Their role in induction is yet to be assessed, alongside novel approaches targeting thymic stromal lymphopoietin and other non-T2 immune pathways. Future priorities include clarifying the contribution of vasculitic versus nonvasculitic mechanisms, the significance of ANCA status, and the immunobiology of relapse. Despite therapeutic inertia in the absence of definitive trials, the collective drive of clinicians and researchers promises to transform and advance management of EGPA in the years ahead.

Background: Netherton syndrome (NS) is a rare genetic disorder resulting from biallelic mutations in the serine protease inhibitor Kazal-type 5 (SPINK5) gene, which encodes the lymphoepithelial Kazal-type-related inhibitor (LEKTI). Although currently classified as a hyper-IgE syndrome, several manifestations contradict this categorization. Data on genotype-phenotype correlations remain limited, and pediatric outcomes of biologic therapies are inconsistent.

Objective: This study investigated the clinical, immunological features, genotype-phenotype correlations, and pediatric outcomes of various systemic and biologic therapies in detail.

Methods: Clinical, immunological, and treatment data from 8 patients were collected in a mixed retrospective-prospective design. Variants were categorized based on the affected bioreactive fragments (FR1-FR5) of the LEKTI protein.

Results: Among 6 SPINK5 variants, including 2 novel ones, 4 FR1-related variants were linked to severe phenotypes, whereas 2 FR5-related variants were associated with milder disease. The onset of skin features was significantly earlier in patients with allergic manifestations than in those without. Although no intrinsic developmental defects in T or B cells were identified, skin barrier disruption was associated with immune activation and skewing toward Th2/Th17 responses. Notably, increased programmed cell death protein-1 expression, expansion of CD4⁺IL-17⁺ T cells, and reduced frequencies of IFN-γ-producing CD4⁺ T cells correlated with clinical disease severity. In scaly erythroderma, secukinumab was most effective for scaling, whereas dupilumab was more effective for pruritus. The efficacy of dupilumab and infliximab was temporary, with rebound skin lesions observed during follow-up. Immunoglobulin therapy supported growth but revealed variable skin benefits.

Conclusion: The described findings support the concept of indirect immune dysregulation in NS due to a defective skin barrier, emphasizing the need for therapies that extend beyond single cytokine or receptor blockade.

Background: Pollen food allergy syndrome (PFAS), also called oral allergy syndrome, results from cross-reactivity between pollen allergens and plant-derived foods. While typically mild, PFAS can occasionally cause systemic reactions. A 2003 U.S. survey characterized its epidemiology and management; this study repeated the survey in 2023 to assess changes.

Objective: To evaluate changes in prevalence, clinical patterns, diagnostic practices, and management of PFAS among U.S. allergists over two decades.

Methods: A 16-question survey (7 original, 9 new) was electronically distributed to 737 randomly selected AAAAI members in October 2023, and results were compared with 2003 survey responses RESULTS: Sixty-seven allergists (9%) responded. Reported prevalence of PFAS increased in children (median 5% to 10%, p = 0.01) and adults (8% to 20%, p < 0.001). The proportion of allergists with patients experiencing systemic PFAS rose from 20% to 67%, though the median percentage of affected patients declined (5% to 1%). Grass pollen emerged as a key sensitizer, alongside birch and ragweed. Nut-induced PFAS was increasingly recognized, cited as a frequent trigger of systemic symptoms and a reason for epinephrine auto-injector (EAI) prescription. Overall, EAI prescribing declined, with 0% of allergists "always" prescribing in 2023 vs 30% in 2003. Diagnostic practices showed increased but limited use of component-resolved diagnostics, while dietary advice remained variable, especially for nut PFAS.

Conclusion: Allergists report higher estimated prevalence of PFAS, greater recognition of nut-induced and systemic PFAS, and evolving diagnostic and management practices. Findings underscore the need for updated guidelines on PFAS diagnosis and management.

Background: TNF-α inhibitor and intravenous immunoglobulin (IVIG) are effective adjunctive therapies to glucocorticoids in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), but the optimal timing for this combination therapy remains unclear.

Objective: To compare the efficacy of different treatments in patients with SJS/TEN to identify the optimal timing.

Method: This multicenter retrospective study included patients with SJS/TEN treated with corticosteroids, with or without TNF-α inhibitors and/or IVIG, at three medical centers from July 2018 to January 2025. Patients were stratified into four treatment groups and compared for outcomes including cessation of new lesions, initiation of reepithelialization, and length of hospital stay.

Results: Among 139 patients with SJS/TEN, 40 received corticosteroid monotherapy, 30 received TNF-α inhibitors plus corticosteroids, 39 received IVIG plus corticosteroids, and 30 received triple combination with TNF-α inhibitors, IVIG, and corticosteroids. Compared with corticosteroid monotherapy, early initiation of TNF-α inhibitors within 13 days or IVIG within 7 days of rash onset was associated with significantly faster cessation of new lesion development and earlier reepithelialization, although no significant differences were observed in hospitalization. The triple combination with TNF-α inhibitors, IVIG, and corticosteroids was also associated with a significantly shorter time to cessation of new lesions and reduced reepithelialization time compared with corticosteroid monotherapy, but not with hospitalization. Notably, the triple combination group had the lowest cumulative and weight-adjusted corticosteroid doses.

Conclusions: For treating SJS/TEN, adding TNF-α inhibitors within 13 days of the onset of rash or IVIG within 7 days was associated with a significantly shorter time to new lesion cessation and reepithelialization, but later use provided no additional benefit.

Background: Chronic rhinosinusitis (CRS) is a common comorbidity affecting clinical outcomes in adults with asthma.

Objective: To assess the impact of CRS on long-term asthma outcomes in a real-world clinical setting.

Methods: This retrospective cohort study analyzed the medical records of 16,153 adults with asthma at the Ajou University Medical Center (Korea). Patients were classified into those with and without comorbid CRS. The CRS group was further stratified into the T2-high and T2-low CRS subgroups, based on blood eosinophil counts. Over a 10-year follow-up, long-term clinical outcomes, including asthma exacerbation (AE), hospitalization or emergency department (ED) visits, and systemic corticosteroid use, were estimated using Kaplan-Meier curves and Cox proportional hazards models; and longitudinal laboratory and lung function measures were analyzed using adjusted linear mixed-effects models.

Results: After propensity score matching, between-group comparisons were performed. The CRS group had higher risks of severe AE (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.51-2.87), overall AE (HR, 1.59; 95% CI, 1.36-1.86), hospitalization or ED visits (HR, 1.38; 95% CI, 1.08-1.78), and systemic corticosteroid use (HR, 1.44; 95% CI, 1.25-1.66). Further, these risks were persistently higher in the T2-high CRS subgroup than in the T2-low CRS subgroup (P<.001 for all). Throughout the follow-up period, the CRS group-particularly the T2-high subgroup-exhibited elevated blood/sputum eosinophils and FeNO levels, with greater lung function decline than in the non-CRS or T2-low CRS subgroups.

Conclusion: Comorbid CRS - particularly a T2-high CRS endotype - is associated with increased 10-year risks of AEs, hospitalizations/ED visits, and systemic corticosteroid use, as well as greater lung function decline, in adults with asthma.

Background: Generalized Bullous Fixed Drug Eruption (GBFDE) is a Severe Cutaneous Adverse Reaction (SCAR) characterized by widespread plaques with bullae. While regarded as less severe than Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), emerging reports suggest GBFDE may be similarly life-threatening. Comprehensive characterisation of GBFDE remains lacking.

Objective: To review the epidemiology, causative agents, clinical features, histology, outcomes and management of GBFDE.

Methods: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed and Embase databases were searched for studies from 1985 to 27^th October 2024. Original observational cases of GBFDE were included. Studies without quantitative patient data were excluded. Study quality was assessed using the Newcastle-Ottawa Scale. Data was analysed descriptively and comparative analyses performed.

Results: Of 347 publications reviewed, 83 studies comprising 430 cases were included. Median age was 56 years (IQR:41-75). Common causative agents include Non-Steroidal Anti-Inflammatory Drugs (NSAIDs,48.7%) that are available over-the-counter in many countries without prescription and antibiotics (30.9%). Median latency was 24 hours (IQR 12-72). Mucosal involvement does occur, but no cases involved ocular mucosa. Internal organ involvement was uncommon. Intensive Care Unit stay was required in 19.9%. Mortality was 15.2% and significantly associated with age (p=0.01). Median time to resolution was 11 days (IQR:8-17). Post-inflammatory hyperpigmentation occurred in 54.3%. Corticosteroids were the most commonly used treatment (22.4% topical, 50.6% systemic). Data was heterogeneous and the retrospective nature of reporting limited long-term outcome assessment.

Conclusions: GBFDE has very short latency and NSAIDs and antibiotics are the commonest triggers. Systemic dysfunction is less common than in SJS/TEN, but morbidity and mortality is significant particularly in the elderly. The widespread availability of over-the-counter NSAIDs may pose a risk for GBFDE.

Background: The Pediatric Eosinophilic Esophagitis Sign/Symptom Questionnaire for Caregivers (PESQ-C) is a novel clinical outcome assessment that was administered daily in EoE KIDS to assess signs (caregiver-observed eosinophilic esophagitis [EoE] symptoms) in patients aged 1 to 11 years.

Objective: This study aimed to validate this novel instrument.

Methods: Blinded baseline and week 16 data from the randomized, interventional, phase 3 EoE KIDS study (NCT04394351) were analyzed to evaluate the measurement properties of the PESQ-C, including reliability, construct and known-groups validity, responsiveness, and interpretation of change. Exit interviews at week 16 elicited caregivers' perspectives on patient experience before and after treatment to ascertain the level of change in PESQ-C scores that was considered meaningful.

Results: Caregivers completed the PESQ-C for 99 patients (median age, 8 years; 75.8% male; 82.8% White). Test-retest reliability scores (intraclass correlation coefficient, 0.94) exceeded the acceptable threshold for reliability (>0.70). As hypothesized, construct validity correlations with other clinical assessments measuring concepts similar to those of the PESQ-C were moderate at baseline and week 16, and PESQ-C scores discriminated among patient groups defined by EoE severity. Insufficient correlation with anchor measures precluded quantitative determination of meaningful change. In qualitative exit interviews performed with 69 caregivers, 83% felt that the patient experienced meaningful change; for patients with 2 or more days' improvements, 38% of caregivers said that even a 1-day improvement is meaningful.

Conclusion: This analysis confirmed the reliability and validity of the PESQ-C for evaluating caregiver-observed EoE signs in pediatric patients within a clinical study context. Exit interviews provided evidence supporting meaningful changes in EoE signs.

Background: Rhinitis and asthma often co-occur; however, studies on their associations with air pollution have always considered them separately.

Objective: We investigated the association between long-term air pollution exposure and rhinitis and asthma multimorbidity in adults.

Methods: We used data at inclusion from Constances, a large French population-based adult cohort. Current rhinitis (CR) and current asthma (CA) were defined by questionnaire. Annual exposure to nitrogen dioxide (NO₂), particulate matter 2.5 μm or less (PM_2.5), and black carbon were estimated by linking participants' residential address to land-use regression models. We performed cross-sectional multinomial logistic regressions between each air pollutant and CR alone, CA alone, and CR+CA (no-CR/no-CA being the reference) adjusted for age, sex, smoking, education level, and French deprivation index.

Results: Among the 177,968 participants included in the analyses (mean age 47 years; 54% female), 111,108 were classified as no-CR/no-CA (62%), 49,971 CR alone (28%), 6,435 CA alone (4%), and 10,454 CR+CA (6%). One interquartile range (IQR) increase of black carbon and NO₂ was significantly associated with the three phenotypes, with adjusted odds ratios from 1.04 to 1.13 for BC (IQR = 0.55-10^-5·m^-1), and from 1.06 to 1.14 for NO₂ (IQR = 13.7 μg·m^-3). For PM_2.5, one IQR increase (4.09 μg·m^-3) was significantly associated with CR alone and CR+CA. In all our analysis, the highest associations were observed for CR alone.

Conclusion: Our results show that long-term air pollution is more associated with rhinitis alone or with asthma multimorbidity than with asthma alone.

Blistering drug eruptions represent a spectrum of severe cutaneous adverse reactions characterized by epidermal and mucosal detachment, which present clinically as vesiculobullous lesions. These conditions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous fixed drug eruptions, and other blistering mimickers, are rare but potentially life-threatening. Prompt recognition and management are critical to improving outcomes. This Grand Rounds Review describes two clinical cases of patients presenting with a blistering eruption, guiding the reader through the diagnostic approach, including differential diagnosis and acute management. The differential diagnosis and evaluation of blistering drug eruptions are central, with a focus on distinguishing among drug-, infection-, and autoimmune-induced diseases. A structured, clinical-based approach to these complex reactions can significantly improve patient safety and long-term outcomes.