搜索结果：The Journal of allergy and clinical immunology

Results from the IMPACT trial suggest that initiation of peanut oral immunotherapy (pnOIT) before age 4 years can increase chances of achieving desensitization and remission. We sought to assess sequential (linear) epitope-specific (es-)IgE and es-IgG4 profiles over the course of pnOIT and determine whether they can predict desensitization and remission outcomes. Participants in the IMPACT trial (NCT03345160) were randomized to pnOIT or placebo for 134 weeks. Desensitization and remission endpoints were assessed by oral food challenges to 5,000mg of peanut protein at 134 and 160 weeks, respectively. This study includes data from 93/96 (96.9%) participants from the peanut OIT group and 47/50 (94%) from the placebo group. Specific IgE and IgG4 levels to peanut, component proteins, and 64 allergenic epitopes were measured. Machine learning was used to develop predictive models for desensitization and remission. PnOIT was associated with an overall decrease in es-IgE and increase in es-IgG4 levels. Younger subjects (<2.3 years of age) had lower baseline es-IgE binding and lower fold-change in es-IgE and es-IgG4 binding during pnOIT. Participants who achieved desensitization had lower baseline es-IgE levels compared to those who did not achieve desensitization. A machine-learning model that included 9 es-IgE antibodies could predict remission with an overall performance of: accuracy 88.2%, AUC 88.2%, sensitivity 83.3%, and specificity 90.0%; this predictive performance was comparable to, but not superior to, models based on peanut IgE. Baseline epitope IgE profiles can predict remission outcome for children undergoing pnOIT. Age and baseline peanut IgE remain important factors across models. Notably, pnOIT prevented the epitope spreading of es-IgE observed in placebo-treated children, suggesting a treatment effect on the breadth of the allergic response that may be especially relevant in young children. These profiles may help identify patients who are more likely to benefit from pnOIT.

Artificial intelligence (AI), first defined in 1955 by John McCarthy, has transformed daily life across industries through applications such as chatbots, autonomous vehicles, and navigation systems. The 2022 release of ChatGPT marked a pivotal moment, highlighting AI's rapidly expanding potential. The health care industry is increasingly embracing AI-enabled tools across oncology, pathology, and radiology to augment disease screening and clinical workflows. Ambient listening technologies support clinical documentation, reduce administrative burden, and improve patient-physician interactions. Large language models combined with natural language processing are being evaluated for generating clinical summaries managing patient portal messaging and converting freehand notes to electronic health records, while also uncovering patterns in patient data to support more personalized treatments. Forward-thinking health systems are establishing informatics departments to optimize these models. Notably, with 1 in 6 adults sourcing health information from AI, rising to nearly one-quarter among individuals younger than 30 years, there is a growing need to ensure that these technologies provide accurate and reliable information to safeguard patient safety and support appropriate clinical use. PRACTALL, a collaboration between the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy & Clinical Immunology, aims to equip allergist-immunologists with essential AI insights highlighting tools for clinical practice, education, and research. By addressing potential pitfalls and biases, PRACTALL illustrates how AI can enhance efficiency, improve patient care, and alleviate administrative burdens in health care.

An estimated 33 million Americans have food allergy. Allergists are seeing an increasing number of patients for allergies to foods once thought to be rare causes of the disease. This study sought to characterize patient-reported allergies to sesame, other seeds, and herbs and spices in a nationwide patient registry. Survey data from the Food Allergy Research & Education Patient Registry were obtained for food allergy diagnosis, demographics, and reactions for participants who reported an allergy to sesame, other seeds, and/or herbs and spices. The dataset included 2,601 participants who reported a sesame (n = 1,195), other seed (n = 968), and/or herb and spice allergy (n = 616). Participants were 51% male and 56% White. Reporting a family income of less than $25,000 and non-White race were significantly more common among those reporting an herb and spice allergy (P < .0001 for both). The top three non-sesame seed allergens were sunflower, mustard, and flaxseed. The top five herb and spice allergens were garlic, black pepper, cinnamon, ginger, and curry. These diagnoses were made at less than age 18 years for about 80% of participants. Diagnosis at age 1 year or earlier was significantly more common among those reporting a sesame allergy (P < .0001). Epinephrine was administered for approximately one third of reported reactions regardless of the causative allergen. This study presents a large cohort to date of patient-reported non-sesame seed, and herb and spice allergies. The practicing allergist should be aware that allergies to these foods most commonly present in childhood, occur at higher rates in certain racial and economic groups, and can result in anaphylaxis requiring epinephrine.

Inborn errors of immunity (IEI) are associated with substantial physical, psychological, and socioeconomic burdens that extend beyond recurrent infections and significantly affect health-related quality of life (HRQOL). Advances in diagnostics, including increased access to newborn screening and genetic testing, along with treatment advances have made patient-reported outcomes and shared decision-making (SDM) increasingly important components of comprehensive IEI care. The recently updated IEI practice parameters recommend routine assessment of HRQOL and perceived health, and the incorporation of SDM into clinical care. Validated general HRQOL instruments, including Short-Form 36, Pediatric Quality of Life Inventory, Patient-Reported Outcome Measurement Information System tools, and disease-specific measures such as the Common Variable Immunodeficiency Quality of Life and Primary Antibody Deficiency Quality of Life questionnaires, facilitate systematic assessment of patient experiences and priorities. This review highlights the role of SDM across several key areas of IEI care, including newborn screening for severe combined immunodeficiency, genetic testing, decisions regarding prophylactic antibiotics and immunoglobulin replacement therapy, IFN-&#x3b3; treatment in chronic granulomatous disease, and hematopoietic stem cell transplantation. These clinical contexts illustrate the importance of balancing medical considerations with patient and family values, psychosocial concerns, treatment burden, financial implications, and long-term quality of life.

In the last 15 years, the tobacco industry has marketed electronic cigarettes (e-cigarettes) as a tool to help adults to quit cigarette smoking, while also promoting their use in children and adolescents. As expected, this led to a marked increase in e-cigarette use (also called vaping) among children and adolescents in the U.S. Although the prevalence of vaping decreased after the 2019 EVALI epidemic and stricter regulations fueled by concurrent adoption of cigarette and marijuana smoking in youths, approximately 10% of middle- and high-school students in the U.S. report vaping. A growing body of experimental and epidemiologic evidence has implicated e-cigarette use in the pathogenesis of respiratory diseases such as chronic obstructive pulmonary disease (COPD), lung cancer, interstitial lung disease, and asthma. In this narrative review, we first evaluate the types and composition of e-cigarettes and trends in e-cigarette usage and then assess findings from experimental and epidemiologic studies of e-cigarette exposure and asthma published to date. We end by discussing future directions for research in this field while emphasizing the need for prevention of and screening for e-cigarette use in youths and adults, particularly those affected with asthma.

Aspirin-exacerbated respiratory disease (AERD) is defined by respiratory reactivity after cyclo-oxygenase 1 (COX-1) inhibition. This reactivity largely persists despite adequate control of the respiratory inflammation. More recently, monoclonal biologic agents targeting type 2 inflammation have been increasingly used in managing AERD and may significantly alter COX-1 reactivity. To systematically evaluate the effects of biologic therapies on aspirin/COX-1 reactivity in patients with AERD. A thorough literature review identified all studies evaluating the effects of omalizumab, dupilumab, mepolizumab, benralizumab, reslizumab, and tezepelumab on aspirin reactivity in AERD. A total of 652 articles were preliminarily reviewed and a total of 23 were identified for further evaluation and potential inclusion. Omalizumab and dupilumab were the most frequently studied biologics associated with complete or partial improvements in aspirin challenge thresholds. However, these studies are limited by very small numbers and in many cases are not controlled. Evidence was minimal to nonexistent for the other biologics. There are limited studies in the literature about biologic use specifically on COX-1 reactivity in AERD. The studies that have been completed are relatively small and predominantly non-randomized. Larger studies are needed to provide a more precise measurement of the effect of the various therapies on aspirin reactivity in AERD. Methods to predict resolution of aspirin reactivity in AERD are needed to appropriately counsel patients. Given the widespread use of biologic therapies in AERD, the lack of understanding regarding residual COX-1 reactivity even when the AERD is otherwise controlled presents an urgent future research need.

There are limited data on allergy evaluation following suspected periprocedural hypersensitivity reactions, and skin testing for these reactions is not yet validated. We sought to describe the epidemiology of periprocedural reactions and safety and effectiveness of allergy testing in a contemporary US patient cohort. We performed a retrospective cohort study of adult patients evaluated at a tertiary-care academic center for presumed periprocedural hypersensitivity reaction from March 2013 to June 2023. We examined patient demographics, index reactions, tryptase levels, skin testing results, and tolerance of subsequent anesthesia. Over 10 years, 74 patients underwent comprehensive allergy evaluation. Testing was positive in 30% (22/74). The most common culprits included antibiotics (10, 45%), local anesthetics (3, 14%), and neuromuscular blocking agents (3, 14%). Of 29 patients who received subsequent anesthesia, 28 (97%) didn't have reactions. Patients with perioperative anaphylaxis were more likely to have positive testing compared to patients with low-grade reactions (63% vs 9%, P < .001). Fifty-one percent (19/37) of patients tested within &#x2264;6 months of index reaction had positive testing, versus 11% (4/38) tested at >6 months (P < .001). Periprocedural allergy testing was safe and effective in preventing future reactions. Testing was more likely to be positive if performed within 6 months of hypersensitivity reaction and in patients with high-grade index reactions. Antibiotics were the most common culprits; emerging agents like chlorhexidine and sugammadex were also identified. The landscape of POA is evolving, and formal US guidelines are needed to guide clinicians in evaluation.

As the prevalence of asthma, allergic rhinitis (AR), and atopic dermatitis (AD) rises globally, it is important to determine the prevalence of these diseases in different geographic regions to identify potential modifiable risk factors. We sought to determine the prevalence of asthma, AR, and AD in Sri Lankan children living in different climatic and geographical regions and to identify host and environmental risk factors. We recruited 5043 children (51.9% girls) age 10 to 19 years from 9 districts representing Sri Lanka using stratified multistage cluster sampling. Data were collected using the International Society for Allergies and Asthma in Childhood questionnaire for children. Statistical significance was estimated using Fisher exact and &#x3c7;2 tests for association. Prevalence of asthma, AR, and AD was 8.25%, 10.01%, and 2.8%, respectively. Children living in urban areas and children with higher body mass index were significantly more likely to have asthma. Children living in households that used cow dung for floors and clay/wattle and daub for walls were less likely to have asthma and AR, but not AD. The prevalence of asthma was higher in children living in houses with tiled floors (P = .03) and in which gas was used for cooking (P < .05), whereas prevalence of AR was significantly higher in households with domestic animals. The presence of other allergic diseases, BMI, and urbanicity together with certain environmental conditions was associated with the prevalence of these diseases. Therefore, environmental modification as well as lifestyle interventions may help to reduce the prevalence of these allergic diseases.

A disease-modifying therapy aims to alter natural history by delaying or reversing disease progression. This rostrum examines expert opinion regarding the concept of disease modification in food allergy and contextualizes relevant definitions, such as desensitization, sustained unresponsiveness, tolerance, and remission. It evaluates evidence-based disease-modifying effects of current and emerging therapeutic strategies from clinical and immunological to patient-centered perspectives. Evidence from oral, epicutaneous and sublingual immunotherapy demonstrates that desensitization is common and that a subset of patients consistently achieve sustained unresponsiveness or remission after treatment discontinuation. Studies to date have noted that younger age and lower baseline allergen-specific IgE may predict more durable responses, although findings are inconsistent across populations and allergens. Immunologic changes associated with these outcomes include suppression of Type 2 cellular responses, modulation of B-cell compartments and induction of blocking antibodies, but no clear link to a specific clinical state can be claimed. Currently approved biologics enhance protection during active treatment, but have limited evidence for direct disease modification, although they may facilitate tolerance when combined with allergen exposure. Patient-reported outcomes, especially quality of life and self-efficacy remain critical yet underutilized measures of therapeutic benefit. Clinical trial designs face multiple challenges in evaluating long-term disease modification. While the clinical states of desensitization, sustained unresponsiveness, tolerance and remission may involve partial or complete disease modification in food allergy, no consensus definition exists or relevant biomarker has been identified to date. Future work will require harmonized definitions, innovative trial designs and therapies targeting long-lived immunological memory with continued emphasis on patient-centered outcomes and real-world clinical relevance.

The introduction of biologics in the treatment of severe asthma, has led to improved patient outcomes and increased discussions around remission. Due to varying descriptions of remission, there is a clear need for a standardised definition of remission as a target for patients. Remission has stringent criteria to achieve the best possible outcomes for patients; however not all patients achieve remission dependent on their disease severity and duration. Therefore, less stringent criteria should also be considered such as a patient state of minimal clinical disease activity (MCDA). To explore these definitions, a Steering Committee of respiratory healthcare professionals (HCPs) employed a systematic literature review (SLR) and modified Delphi consensus. Outputs of the SLR were used to draft consensus statements that underwent two rounds of review with the Steering Committee and one round of review with a wider group of HCPs. Initial definitions of MCDA and remission were drafted based on the consensus statements and finalised in a Steering Committee meeting. The definitions include criteria for asthma exacerbations, steroid use, lung function, and quality of life. These definitions serve as a starting point for improving disease management in patients with severe asthma and should be validated in real-world settings.

Bullous pemphigoid, chronic spontaneous urticaria, prurigo nodularis, and chronic prurigo of unknown origin are distinct chronic skin diseases with a high disease burden and an ongoing need for safe and effective therapies. Advances in our understanding of disease mechanisms have highlighted convergent type 2-associated neuroimmune pathways that may contribute to chronic itch and skin lesions across these conditions. In bullous pemphigoid, autoantibody binding of two dermal-epidermal junction proteins followed by complement system activation shapes the local immune environment to favor T helper cell 2 polarization and perpetuation of type 2 inflammation. In chronic spontaneous urticaria, mast cell activation and downstream mediators, including type 2 cytokines, may contribute to amplification of inflammation and itch. In prurigo nodularis, chronically activated itch sensory neurons induce an itch-scratch cycle with T-cell activation in parallel to mast cell degranulation, resulting in neurogenic inflammation that sustains the itch-scratch cycle. The pathogenesis of chronic prurigo of unknown origin is not well understood, but evidence to date points to interactions between skin barrier defects and immune and neural dysregulation triggering T helper cell 2 polarization. In this review, we discuss the role of type 2 inflammation in bullous pemphigoid, chronic spontaneous urticaria, prurigo nodularis, and chronic prurigo of unknown origin, and how this understanding is currently translated into new targeted therapeutic options.

Bronchodilator responsiveness (BDR) reflects airflow variability in asthma and is typically assessed after withholding therapy. However, its relevance under ongoing maintenance therapy remains unclear. To investigate the frequency and clinical relevance of residual bronchodilator responsiveness (rBDR) in patients with asthma receiving maintenance therapy. In 248 adults with moderate-to-severe asthma receiving inhaled corticosteroids (ICS), with or without long-acting bronchodilators, rBDR was assessed according to ERS/ATS 2005 and 2022 criteria. Maintenance therapy was continued, while short-acting bronchodilators were withheld for at least 12 hours before spirometry. Type-2 biomarkers, lung function including small airway function, patient-reported outcomes, and exacerbation rates were analysed according to rBDR status. rBDR was present in approximately 23% of patients and was consistent across both ERS/ATS criteria. Maintenance therapy did not differ by rBDR status. Patients with rBDR had higher type-2 biomarkers, despite high-dose ICS, including sputum eosinophils and FeNO, more frequent fixed airflow obstruction, and greater small airway dysfunction. They also exhibited increased clinical disease burden, with poorer asthma control and frequent exacerbations, independent of underlying lung function and type-2 inflammation. Residual bronchodilator responsiveness is frequent and identifies patients with refractory type 2 inflammation and poor disease control. rBDR integrates inflammatory activity and functional impairment into a simple, widely available measure and may serve as a practical marker to identify residual disease burden and guide treatment optimization in routine clinical care.

Rhinovirus (RV) infections increase the risk for developing asthma and are the major trigger for disease exacerbations. Club cell secretory protein 16 (CC16) levels are decreased in asthma patients and inversely associated with inflammation and exacerbation frequency. This study aims to determine the impact of CC16 on rhinovirus A, type 1B (RV-A1B) infection in airway nasal epithelial cells in the context of asthma status. Human nasal epithelial cells (HNECs) from asthma and non-asthma participants in air-liquid interface culture were infected with RV-A1B, with and without rCC16. Viral RNA and the expression of host factors previously identified as associated with CC16 levels, including lysozyme, SPLUNC1, lactotransferrin and surfactant protein-D were quantified by RT-qPCR. Animal models and mouse tracheal epithelial cells (MTECs) sufficient and deficient in CC16 were infected with RV-A1B, with and without rCC16, to verify findings. HNECs from asthmatic individuals (n=7) had lower gene expression of CC16 and associated host defense factors under baseline conditions compared to non-asthmatic HNECs (n=7). While RV infection increased host factors in non-asthmatic HNECs, HNECs derived from asthmatic individuals failed to upregulate host factors in response to RV. rCC16 induced the expression of the host defense factors and reduced viral burden in HNECs from both non-asthma and asthma participants, which was in part dependent on integrin &#x3b1;2&#x3b2;1, VLA-2, interactions. Mice deficient in CC16 had worse RV infection, more inflammation and lower gene expression of host defense factors in their lungs compared to wild type mice. Secreted protein levels were verified from apical washings of MTECs from CC16-/-, which were significantly decreased compared to WT MTECs. Rescue studies in CC16-/- mice by delivery of rCC16 during RV infection resulted in decreased inflammatory cell recruitment and infection. Results suggest that CC16 reduces rhinovirus infection in epithelial cells by mediating the upregulation of host defense factors and that this mechanism may be defective in asthma patients who have low levels of CC16.

The activation of T lymphocytes is implicated in delayed-onset drug hypersensitivity. However, currently defined cellular and genetic risk factors are not sufficient for the development of comprehensive predictive tools, translatable across conventional drug classes, new modalities, and diverse reaction phenotypes. We sought to assess the frequency of interactions between drugs, HLA proteins, and T-cell receptors within human populations and the role of TNF-&#x3b1; as a critical regulator. To study the frequency and functionality of T-cell responses, a novel in vitro culture system was used to mimic the inflammatory microenvironment, achieved through 6-day culture of PBMCs from drug-naive and drug-tolerant individuals with a panel of drugs(metabolites) commonly associated with hypersensitivity, and TNF-&#x3b1;. T-cell proliferation was measured through [3H]-thymidine incorporation, and cytokine analysis was performed using the ELISpot assay. T-cell responses to antibiotics were frequently detectable in drug-tolerant and drug-naive individuals following the addition of TNF-&#x3b1;. Ninety percent and 60% of drug-naive individuals produced detectable T-cell responses to vancomycin and piperacillin, respectively. Similarly, T-cell responses to dapsone, sulfamethoxazole, and/or reactive nitroso metabolites were present at high frequencies (>65%). Drug immunogenicity was inhibited by the introduction of TNF-&#x3b1; antagonists and HLA-blocking antibodies. Assays performed using PBMC components (CD3+, CD4+, CD8+, CD45RO+, and CD45RA+) show that drugs readily prime and activate naive T cells, with CD4+CD45RA+ T cells preferentially activated. We challenge the central dogma that tolerant individuals do not express the correct immunologic receptors to mount a drug-specific T-cell response and that the cellular machinery for response elicitation is not limited to hypersensitive patients.

Addition of the long-acting muscarinic antagonist umeclidinium (UMEC) to the inhaled corticosteroid/long-acting &#x3b2;2-agonist (ICS/LABA) combination fluticasone furoate/vilanterol (FF/VI) improved lung function in adults with uncontrolled moderate to severe asthma in the CAPTAIN (Clinical study of Asthma Patients receiving Triple therapy through A single INhaler) study; however, the impact on symptoms requires further investigation. We sought to evaluate the effect of adding UMEC to FF/VI on asthma symptoms. The CAPTAIN study was a phase IIIA, randomized, controlled, 24- to 52-week study of patients with uncontrolled moderate to severe asthma despite ICS/LABA receiving once-daily single-inhaler FF/VI (100/25 or 200/25 &#x3bc;g) or FF/UMEC/VI (100/31.25/25, 100/62.5/25, 200/31.25/25, or 200/62.5/25 &#x3bc;g). Here, we compare the effect of pooled FF/UMEC 62.5/VI (100/62.5/25 and 200/62.5/25 &#x3bc;g) versus FF/VI (100/25 and 200/25 &#x3bc;g) on symptom control using prespecified analyses of change from baseline in Evaluating Respiratory Symptoms in Asthma (E-RS: Asthma) total and domain scores, and proportion of patients meeting an E-RS: Asthma total score responder threshold. We also performed post hoc analyses assessing the impact of baseline type 2 inflammation status on treatment response. Least-squares mean (95% CI) reductions from baseline in E-RS: Asthma total score exceeded the minimum clinically important difference (-2.0 units) and were numerically greater with FF/UMEC 62.5/VI (-2.89 [-3.15 to -2.64]; n = 814) versus FF/VI (-2.47 [-2.73 to -2.22]; n = 813). The proportion of responders (45% [n = 360] vs 41% [n = 327]) and odds of response (odds ratio, 1.18 [95% CI, 0.96 to 1.45]) were numerically greater with FF/UMEC 62.5/VI versus FF/VI. Similar trends were observed irrespective of type 2 status. Patients with symptomatic asthma may benefit from optimized treatment interventions, such as adding a long-acting muscarinic antagonist to ICS/LABA.

Chronic spontaneous urticaria (CSU) is a common immune-related skin disorder with an unclear pathogenesis and no universally accepted animal model. The passive cutaneous anaphylaxis (PCA) model is the commonly used model in CSU research. To propose a modification to the PCA model to improve its alignment with CSU, we established a recurrent PCA (Re-PCA) model via 6 repeated injections of 2,4-dinitrophenyl-human serum albumin (DNP-HSA)-specific IgE and DNP-HSA and compared it to the PCA model. We assessed vascular permeability, scratch frequency scoring, histologic staining, flow cytometry, reverse transcription PCR, enzyme-linked immunosorbent assay, and RNA sequencing to compare phenotypic differences. The Re-PCA model exhibited more stable and significant skin changes associated with chronic urticaria compared to the PCA model. Lesional tissues of Re-PCA mice showed significantly increased degranulated mast cells and demonstrated tissue infiltration. Compared to the PCA group, peripheral blood histamine and tryptase levels of Re-PCA mice were significantly elevated, and the gene expression profile of the Re-PCA lesions revealed enrichment of more genes and signaling pathways associated with CSU. Our recurrent IgE-mediated mouse model exhibited greater immunologic and transcriptional relevance to CSU than the commonly used PCA model, which will facilitate research into the pathogenesis of CSU and advance our understanding of its underlying mechanisms.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in children. Hypersensitivity reactions (HRs) to NSAIDs represent a diagnostic challenge, particularly because NSAIDs may act as aggravating factors or cofactors as in two phenotypes recently named NSAID-exacerbated food allergy (NEFA) and NSAID-induced food allergy (NIFA). To diagnose NSAID hypersensitivity/allergy (NH/A) and NEFA/NIFA phenotypes in children and adolescents, classify HRs to NSAIDs according to updated international guidelines, and identify clinical and immunologic predictors of true NH/A. We prospectively studied 336 children and adolescents with a history of HRs to NSAIDs, following international guidelines, which include challenges with the suspected NSAIDs. Primary outcomes were identification of NH/A phenotypes and their predictors. Hypersensitivity or allergy to NSADISs was diagnosed in 104 of 336 patients (31%). The most frequent phenotypes were single-NSAID-induced urticaria, angioedema, or anaphylaxis (55.8%) and NSAID-induced urticaria, angioedema, or anaphylaxis (22.1%). We excluded NH/A in 232 patients (69%), 48 of whom received the diagnosis of NEFA/NIFA. Sensitization to Pru p 3 was strongly associated with NEFA/NIFA. Non-hypersensitive or allergic reactions were associated with antipyretic use (odds ratio [OR] = 5.92; 95% CI, 3.60-9.72), urticaria (OR = 3.06; 95% CI, 1.77-5.28), and younger age (OR per 6-year increment = 0.64; 95% CI, 0.47-0.89). Internal validation showed good discrimination (area under the receiver operating characteristic curve, 0.82; cross-validated area under the receiver operating characteristic curve, 0.79). Approximately one third of children with suspected reactions had confirmed NH/A, whereas 14.3% had NEFA/NIFA. In 69% of patients, the NH/A label was removed. Many reactions during antipyretic use appear to be related to infection rather than true NSAID hypersensitivity.

The relevance of high-sensitivity C-reactive protein (hsCRP), a marker of low-grade systemic inflammation, remains unclear with regard to its association with severity and clinical outcomes in wheeze/asthma. We aimed to assess the role of hsCRP across different phenotypes and severity levels. We studied children with preschool wheeze (&#x2265;&#x2009;2 episodes), and patients with GINA-defined asthma (school-age/adult) compared with healthy controls (HCs) in the well-characterized ALLIANCE (All Age Asthma Cohort) study. HsCRP was measured (AU5800&#xae;-CRP-Latex test) in 944 study participants (pediatric: n&#x2009;=&#x2009;728; adult: n&#x2009;=&#x2009;216) at baseline. Age-stratified analyses (age groups 0-5, 6-18,&#x2009;&#x2265;&#x2009;18&#xa0;years) of standardized log10-transformed hsCRP concentrations (age, sex, BMI, site) were performed using univariable tests and regression models. The validated ASSESS score and its dimensions (exacerbations, lung function, inhaled corticosteroids, symptom control) were primary outcomes. Adult patients with asthma showed higher hsCRP than HCs (OR 2.22, 95% CI 1.56-3.24). Across all ages, hsCRP increased with clinical severity of wheeze/asthma. The ASSESS score correlated positively with hsCRP in patients aged&#x2009;&#x2265;&#x2009;6&#xa0;years (R&#x2009;=&#x2009;0.19, p&#x2009;=&#x2009;0.007). hsCRP was increased in school-age asthmatics with prior exacerbations (OR 1.37, 95% CI 1.01-1.87), and in adult asthmatics with impaired lung function (R&#x2009;=&#x2009;0.2, p&#x2009;=&#x2009;0.013). Inhaled corticosteroid use was associated with lower hsCRP in preschool wheezers (OR 0.66, 95% CI 0.50-0.85) but higher levels in adults (OR 1.99, 95% CI 1.02-4.09). HsCRP was increased in adult asthmatics compared to HCs and was associated with several severity-related clinical characteristics. ICS use was associated with higher hsCRP levels in adults, potentially reflecting greater disease severity, whereas ICS use in preschool wheezers was associated with lower hsCRP levels. These age-dependent effects may mirror varying disease courses across the lifespan and progression of asthma. The association of hsCRP with asthma severity in child- and adulthood may indicate its potential relevance for the course of disease and monitoring clinical outcomes. Future longitudinal studies are needed to assess, whether hsCRP may support therapy monitoring. ClinicalTrials.gov; Pediatric arm: NCT02496468, Registration date: 03 July 2015; Adult arm: NCT02419274, Registration date: 14 April 2015.

Asthma is characterized by airway inflammation and bronchoconstriction. Recent therapies have addressed inflammation but not bronchoconstriction. S-Nitrosoglutathione (GSNO) is an endogenous smooth muscle relaxant that also impacts &#x3b2;2-adrenergic (&#x3b2;2AR) response. Airway GSNO levels are often low in asthma. We studied the effects of inhaled GSNO (iGSNO) in human asthma. We measured the effects and metabolism of iGSNO, with a focus on FEV1, &#x3b2;2AR agonist response and fraction of exhaled NO (FeNO), and expression of GSNO metabolic genes from bronchoscopic biopsies using spatial transcriptomics. iGNSO increased FEV1 and B2AR response; the magnitude of increase was related, and additive, to the B2AR response (p < 0.001). AKR1A1, encoding a GSNO degrading enzyme, was upregulated in airway epithelium, and higher AKR1A1 expression was associated with reduced iGSNO bronchodilation. Sustained elevation in FeNO after iGSNO, indicating reduced GSNO catabolism, was a biomarker for iGSNO effect. iGSNO could represent personalized asthma therapy, augmenting B2AR agonist benefit.