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

Background: Indolent systemic mastocytosis (ISM), the most frequent subtype of SM, requires better understanding.

Objective: To better understand the diagnostic journey, symptom severity, impact on quality of life and work/activities, and healthcare utilization of ISM.

Methods: Survey data were collected from 40 adults with documented ISM meeting WHO 2016 criteria, including validated questionnaires [ISM Symptom Assessment Form (ISM-SAF©), Short Form Quality of Life Survey (SF-12v1)]. Spearman correlation coefficients determined the associations between the ISM-SAF© total symptom score (TSS) and SF-12v1 scores. ISM burden was compared based on moderate/severe compared to mild TSS scores using Kruskal-Wallis and Fisher's Exact tests.

Results: Patients were aged 56.0±13.0 years, 65.0% female, 62.5% White and 22.5% Hispanic patients. ISM diagnosis took >2 years in 40%, required ≥6 visits in 47.5%, and was considered moderately/extremely difficult in 50% of patients. Nearly half experienced symptoms daily and rated severity somewhat/ significantly worsened since diagnosis. The overall TSS was 27.4±16.2 (mean±SD). SF-12 Physical Component Summary (PCS) (46.7±11.4) and Mental Component Summary (MCS) (47.6±10.2) scores were lower than the general population score of 50. Moderate correlations (P<.001) were found between TSS and the PCS (ρ = -0.6406; p<.001) and MCS (ρ = -0.5104; p<.001). Compared to patients with mild severity (TSS<28; n=21), patients with moderate/severe severity (TSS≥28; n=19) evidenced significantly higher skin and gastrointestinal symptom scores (both, P≤.001). ISM's impact on ability to work for pay was associated with TSS (P=.004). Symptom-directed treatment had limited effect.

Conclusions: ISM was self-reported as a burdensome condition in half the patients which markedly affected daily living.

Background: Toxicities associated with oral corticosteroids (OCS) are well described. Targeted biologics for severe asthma (SA) substantially reduce OCS exposure with the potential to reduce cumulative OCS-toxicities. The Glucocorticoid Toxicity Index (GTI) systematically assesses OCS-related toxicity; the GTI aggregate improvement score (AIS) is a bidirectional measure of total toxicity change with a minimal clinically important difference (MCID) of ≤ -10.

Objective: Longitudinal assessment of SA patients treated with biologic therapies to assess the trajectory of OCS-related toxicity and predictors of toxicity improvement.

Methods: 89 patients with SA had GTI assessments at baseline and after 1 and 3 years of biologic therapy.

Results: At 3 years, daily prednisolone use continued to decrease (6.9 mg/day (4.0,9.4) year-1 v 0.8 mg/day (0.0,3.7) year-3, p<0.001), OCS-related toxicity continued to decline (AIS at 3yrs -36 (-94, 19), and 61% (54/89) met the AIS MCID. There was a significant positive correlation between toxicity outcomes at year-1 and year-3 (rho 0.65, p<0.001). Nearly half (49%) met the AIS MCID at both year-1 and 3, but 29% of the cohort did not meet the AIS MCID at either timepoint. Toxicity change at year-1 was predictive of toxicity change at year-3 for 79%. Toxicity reduction was not proportional to OCS reduction, there were no pre-biologics characteristics that predicted toxicity reduction.

Conclusion: After 3 years of biologic treatment, 61% of SA patients had clinically significant toxicity improvement. Individual toxicity outcomes at year-1 are associated with longitudinal outcomes suggesting that for some, additional interventions are needed alongside OCS-reduction to decrease morbidity.

Background and objectives: Inhaled corticosteroid (ICS) and oral corticosteroid (OCS) are often used in asthma management. This study evaluated the long-term effect of ICS/OCS on osteoporosis, osteopenia, fractures, and bone metabolism in adult asthmatics in real-world clinical practice.

Methods: This is a retrospective study investigating de-identified electronic health records from Ajou University Medical Center (Korea). Adult asthmatics receiving maintenance ICS with/without OCS for at least 1 year were enrolled. They were classified into the high/low-dose of ICS or OCS groups. Primary outcomes (incidences of osteoporosis, osteopenia, and fractures) and secondary outcomes (drug prescription and laboratory values related to bone metabolism including albumin and alkaline phosphatase [ALP]) were compared after 5 years of follow-up.

Results: After propensity score matching, both high- and low-dose OCS groups included 468 patients, and high/low-dose ICS groups each comprised 1,252 patients. The risk of osteoporosis/major fracture was higher (hazard ratio [95% CI]; 2.00 [1.15-3.57]/3.03 [1.04-11.11]) in the high-dose OCS group (especially in females aged ≥50 years) than in the low-dose group, although the ICS groups showed no significant differences. The high-dose ICS group showed a higher risk of osteopenia (1.92 [1.05-3.70]) than the low-dose ICS group. The linear mixed model of laboratory values showed significantly decreased serum albumin and increased ALP in the high-dose OCS group than in the low-dose OCS group.

Conclusions: The results of this study suggest that long-term use of OCS can increase the risk of osteoporosis and osteoporosis-related fractures, while long-term use of ICS may increase the risk of osteopenia in adult asthmatics.

Background: The non-canonical NF-κB2 pathway is integral in regulating immunological responses, supervising immune function, development and homeostasis. NFKB2 encodes the cytoplasmic precursor p100, which undergoes processing of its inhibitory C-terminal half to generate p52. Impeding C-terminal defects are well established to cause PID. In contrast, the mechanism of truncating N-terminal defects remains obscure.

Objective: We characterized clinical phenotypes associated with three distinct protein-defect types: (I) early truncations: typically occurring N-terminal relative to the NLS and affecting the RHD, predicting p100 expression to be halved and subsequent p52 generation by processing to be diminished (II) Central truncations: mainly affecting the ARD and predicting immediate expression of p52-like proteins and a 50% reduction of p100; and (III) C-terminal phosphorylation-/ubiquitination domain defects: causing expression of non-processable p100 with retained IκB-like activity and subsequently reducing generation of p52.

Methods: We performed literature research on PubMed, Clinvar and HGMD collecting clinical and immunological data on NFKB2 patients, focusing on comparing protein-defect-specific impacts.

Results: The highest prevalence of early-onset PID and antibody deficiency occurred in the CTD-defect group. Additionally, endocrinological abnormalities and T-cell-mediated autoimmunity were common and frequently required immunosuppression. An extensive immunological workup revealed patients with C-terminal defects to have pan-hypogammaglobulinemia and reduced specific antibody responses and markedly impaired B cell differentiation, but normal to elevated T cell counts. In contrast, pathogenic NFKB2 variants causing central or early truncating protein defects were only partially penetrant, with ameliorated symptoms and diminished T-cell-mediated autoimmunity.

Conclusion: Our work defines a clear genotype-phenotype correlation for NFKB2 mutations.

Background: Remission is proposed as a multicomponent outcome for patients with severe asthma.

Objective: This post hoc analysis of QUEST (NCT02414854) and TRAVERSE (NCT02134028) evaluated whether dupilumab treatment leads to clinical asthma remission (≥12 months with no severe exacerbations, zero oral corticosteroid use, stabilized or improved lung function, patient-reported asthma control <1.5) and assessed its durability in patients with uncontrolled, moderate to severe type 2 asthma (blood eosinophils ≥150 cells/μL or fractional exhaled nitric oxide ≥20 ppb at parent-study baseline) who are not receiving maintenance oral corticosteroids.

Methods: In QUEST, patients (aged ≥12 years) were randomized to dupilumab 200/300 mg or placebo every 2 weeks for 52 weeks. In TRAVERSE, all patients received dupilumab 300 mg every 2 weeks for up to 96 weeks. We assessed the proportion of patients meeting criteria for on-treatment clinical remission up to 48 weeks of TRAVERSE.

Results: At QUEST baseline, 1,040 patients receiving dupilumab and 544 taking placebo had type 2 asthma; of those, 842 (dupilumab/dupilumab) and 437 (placebo/dupilumab) enrolled in TRAVERSE. At QUEST week 52 (year 1), 37.2% of patients receiving dupilumab met clinical remission criteria, compared with 22.2% taking placebo (all P < .001). At week 48 of TRAVERSE (year 2 overall), 42.8% (dupilumab/dupilumab) and 33.4% (placebo/dupilumab) of patients met clinical remission criteria. Overall, 29.5% of patients in the dupilumab/dupilumab group met the criteria at both years 1 and 2.

Conclusions: Dupilumab treatment enabled approximately one third of patients with type 2 asthma to meet the multicomponent end point for on-treatment clinical asthma remission for up to 2 years.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare form of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis associated with varying clinical presentations and overlapping multiorgan involvement. Asthma is a predominant feature of EGPA, typically in its prodromal phase, often severe, and precedes vasculitic complications. However, there is paucity of studies describing the prevalence and characteristics of EGPA in the asthma population.

Objective: To describe the clinical and serological characteristics and longitudinal therapeutic outcomes of patients with EGPA in the severe asthma (SA) cohort.

Methods: A retrospective study of patients with EGPA attending the multidisciplinary SA clinic in a tertiary hospital from 2011 to 2023 was conducted. Baseline demographics, organ manifestations, biological markers, lung function, and therapeutic outcomes were assessed.

Results: Twenty-three of 596 patients in the SA registry were identified to have EGPA. Median time interval between asthma and EGPA diagnosis was 10 years (range, 2.5-32 years). Almost all patients (95.7%) had peak blood eosinophil count of more than 1.0 × 10⁹/L (range, 0.47-14.08 × 10⁹/L). Upper airway involvement was the most detected manifestation in addition to asthma, followed by neuropathy and renal involvement. Patients who were treated with biologic therapy were significantly younger and had more upper airway, renal, and pulmonary involvement and lower Five Factor Score.

Conclusions: The prevalence of EGPA in the SA population was 3.9% in our cohort. Its diagnosis requires high clinical suspicion in patients with SA and blood eosinophilia, prompting stringent evaluation for extrapulmonary manifestations and multidisciplinary involvement.

Background: Small-airway function assessment is crucial for asthma diagnosis and management. Abnormalities in terminal airflow deserve attention.

Objective: This study investigated whether the ratio of forced expiratory volume in the second and third seconds to forced vital capacity ([FEV₃-FEV₁]/FVC) correlates with airway hyperresponsiveness (AHR) and inflammation in patients with preserved spirometry.

Methods: This cross-sectional study enrolled patients with FEV₁ ≥ 80% predicted, FEV₁/FVC ≥ 0.7, and recurring asthma-like symptoms. Data included demographics, fractional exhaled nitric oxide (FeNO), impulse oscillometry, and spirometry. Univariate and combined models predicting AHR was analyzed in 553 patients and validated in 561. Correlations between sputum inflammation and spirometrics were also assessed.

Results: AHR⁺ patients exhibited higher (FEV₃-FEV₁)/FVC ratios compared to AHR^-. This ratio showed the strongest association with the methacholine dose causing a 20% FEV₁ decrease (PD₂₀) and the response dose ratio (RDR)(r = -0.26 and 0.39, respectively; P < .001, both). The area under the receiver operating characteristic curve for AHR diagnosis using (FEV₃-FEV₁)/FVC was 0.751, increasing to 0.821 when combined with FeNO, confirmed in the validation cohort. (FEV₃-FEV₁)/FVC was superior to maximal expiratory flow at 50% of forced vital capacity for identifying eosinophilic airway inflammation characterized by elevated FeNO levels. It correlated better with sputum eosinophil count than with the other spirometrics.

Conclusion: Elevated (FEV₃-FEV₁)/FVC were evident in AHR⁺ patients with preserved FEV₁/FVC ratios. It serves as a sensitive marker of AHR and airway inflammation correlating with RDR, PD₂₀, and sputum eosinophils, suggesting its utility in monitoring patients at risk for uncontrolled asthma.