Allergic disease is common in the United States, and a growing number of otherwise qualified applicants and service members present with histories of food allergy, venom allergy, medication reactions, physical urticarias, or prior anaphylaxis. The challenge for clinicians is to translate a nuanced allergy-immunology evaluation into strict military accession and retention standards designed for readiness, austere care, and deployability, rather than for diagnosis alone. The current accession standard disqualifies a history of anaphylaxis other than to a single medication or medication class; systemic allergic reactions to biting or stinging insects unless limited to a large local reaction or accompanied by documentation of 3 years of maintenance venom immunotherapy; acute allergic reactions to fish, crustaceans, shellfish, peanuts, or tree nuts when food-specific IgE is accompanied by a correlating clinical history; and cold- or exercise-induced urticaria [1]. Retention standards are more functional and focus on recurrent anaphylaxis that persists despite treatment, requires long-term duty limitations, or prevents return to duty [2]. Newer therapeutic options, including oral immunotherapy (OIT) and omalizumab, raise reaction thresholds for selected patients but do not establish unrestricted tolerance.[3, 4] This latter point precludes serving in operational settings. A clinically useful waiver evaluation should differentiate sensitization from clinical allergy. Resolved allergy versus desensitization or sustained unresponsiveness should also be determined. The identification of cofactors that lower reaction thresholds, and specifying whether the individual can safely train, deploy, subsist on field rations, and function without refrigeration-dependent or injectable therapy is imperative. Major gaps remain. These include few military-specific outcome data on allergy waivers, limited validated biomarkers that predict future anaphylaxis severity, and no standardized pathway for cold- or exercise-induced urticaria comparable with the venom immunotherapy exception. Military allergy standards are risk standards, not allergy practice parameters. The operative question is whether the condition predicts unacceptable operational risk or duty limitation. IgE sensitization without a convincing clinical history should not be equated with food (or venom) allergy; conversely, a remote history of anaphylaxis requires objective documentation of resolution or durable risk reduction. A successful oral food challenge is the most useful way to document tolerance, but it must specify food form, dose schedule, cumulative amount, observation findings, and pass/fail outcome. Venom allergy is unique because DoDI explicitly recognizes a waiver-supporting pathway after 3 years of maintenance venom immunotherapy. Oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and omalizumab may reduce risk, but ongoing dependence on daily dosing, injections, or refrigeration may conflict with accession standards and deployment requirements.
Asthma is increasingly recognized not only as an inflammatory disorder but also as a disease rooted in airway epithelial barrier dysfunction. This review examines tight junction proteins (TJPs) including occludin, claudins, and ZO family members, as central regulators of epithelial integrity and potential therapeutic targets. Disruption of TJPs is an early and pivotal event in asthma, enabling allergen penetration, amplifying immune responses, and promoting airway remodeling. Mechanistic studies reveal TJP regulation involves intricate crosstalk with inflammatory pathways, cytoskeletal remodeling, and epigenetic modulation. Emerging strategies including biologics, small molecules, and targeted delivery systems, demonstrate preclinical efficacy in restoring barrier function, though patient heterogeneity and delivery limitations remain challenges. Restoring epithelial barrier integrity through TJP modulation represents a paradigm shift from conventional anti-inflammatory therapy to precision, disease-modifying interventions. Biomarker-guided, targeted approaches offer the potential to interrupt the self-perpetuating cycle of epithelial damage and inflammation, positioning barrier repair as a central goal in next-generation asthma management.
In 2011, the AAAAI/ACAAI Joint Task Force published the third practice parameter on allergen immunotherapy (AIT), summarizing the contemporary understanding of AIT immunologic mechanisms. Since, major advances have substantially expanded insight into this complex field. This review briefly revisits earlier concepts and then focuses on newer mechanistic findings and emerging ideas, that yet have to be developed further to better understand AIT mechanisms. Structural cells are now recognized as active contributors to the initiation of allergic inflammation; AIT reduces their pro-inflammatory activation. The innate immune system particularly type 2 innate lymphoid cells (ILC2s), plays an important role in initiating and sustaining allergic responses. AIT reduces the activation and/or number of the innate immune cells, potentially contributing to immune tolerance. Within the adaptive immune system Th2A and Tfh13 are the main pro-allergic effector cells, while regulatory T and B-cell subsets have been identified as key mediators of the long-term tolerance induced by AIT. Mechanistic differences between sublingual and subcutaneous AIT are also increasingly apparent: SCIT promotes serum allergen-specific IgG4 and serum blocking activity, while SLIT induces local nasal allergen-specific IgA1. Finally, AIT dose-response relationships vary between individuals, which may explain the clinical need for dose adjustments in some patients. The significance of molecular, proteomic, genetic and metabolic changes documented with AIT remains under investigation. Advances in understanding allergic immune responses and the complex immune changes (including cell plasticity) induced by AIT, might pave the way for enhanced AIT efficacy and predictive biomarkers in the future.
The rapid expansion of the poultry industry has significantly increased the demand for poultry meat and related products due to improvements in efficiency and cost-effectiveness. However, this rapid global commercialization has led to an increase in occupational asthma and chronic obstructive lung disease in poultry workers. Exposure to a complex mixture of organic and inorganic compounds, fumes, microorganisms, and particulate matter found in poultry barns has been linked to airway disease in workers. These airborne contaminants include allergens such as feathers, mites, feed dust, molds, ammonia, and bacterial endotoxins, which contribute to airway inflammation, hypersensitivity, and chronic lung damage. Workers may experience symptoms ranging from wheezing and chest tightness to chronic cough and dyspnea, which can progress to clinically significant respiratory conditions if unrecognized and unmanaged. In attempts to minimize these effects, best practices and strategies to reduce these pollutants are actively being researched and implemented. The role of healthcare providers is pivotal in early identification of at-risk workers, thorough occupational history-taking, appropriate diagnostic evaluation, and tailored management to prevent disease progression and improve outcomes. This review highlights the critical need for ongoing surveillance, preventive measures, and education to protect respiratory health in this vulnerable occupational group.
The review examines the application of machine learning (ML) and large language models (LLMs) to asthma management. We sought to identify clinically relevant applications, and particularly those that harness electronic health record data. We review methodological challenges and future directions for translating these tools into meaningful improvements in asthma care. ML applied to electronic health record data has been utilized across several domains of asthma management: predicting medication response to inhaled corticosteroids and biologics, improving inhaler adherence through digital inhaler systems, and predicting exacerbation risk with moderate-to-high accuracy. Tools for patient education include clinician-guided chatbots, as well as publicly available LLMs. Limitations include accuracy, hallucinations, and patient health literacy. ML and LLMs offer promising pathways towards personalized, data-driven asthma management. However, harnessing this potential will require rigorous external validation, transparent model design, equitable implementation, and adaptive clinician oversight. Collaboration among clinicians, data scientists, and policymakers will be essential to implement these tools for patient-centered asthma care.
Childhood asthma is the most common chronic non-communicable disease in children and a major global public health challenge. Although genetic predisposition contributes to asthma susceptibility, the high burden of disease—particularly in high-sociodemographic-index regions—points to a central role of environmental exposures characteristic of the modern environment. This review synthesizes current evidence linking ambient air pollution and heavy metal exposure to childhood asthma, with a focus on early-life vulnerability, underlying biological mechanisms, and implications for prevention. We reviewed epidemiological, toxicological, and mechanistic studies published through November 2025, prioritizing systematic reviews and meta-analyses while integrating recent cohort studies, intervention trials, and experimental research. Epidemiological findings consistently demonstrate that prenatal and early-childhood exposure to particulate matter (PM₂.₅, PM₁₀), traffic-related air pollutants (e.g., NO₂, black carbon), and ozone is associated with increased asthma incidence, wheezing, reduced lung function, and higher rates of exacerbations and healthcare utilization. In contrast, evidence for metal-related exposures is more heterogeneous. Toxic metals and metalloids, transition metals in particulate matter, and essential trace-element status may contribute to asthma risk through biologically plausible pathways, but associations appear to depend on exposure timing, exposure source, biomarker type, co-exposures, and population context. Mechanistic studies reveal shared and interacting pathways involving oxidative stress, airway epithelial barrier disruption, immune dysregulation, epigenetic modifications, and microbiome alterations. The effects of these exposures are magnified during critical developmental windows and modified by genetic susceptibility and social determinants of health, contributing to marked environmental health inequities. Overall, childhood asthma is strongly shaped by early-life exposure to air pollution and heavy metals through interconnected biological and social pathways. Addressing these preventable environmental risks is essential for effective asthma prevention and for reducing global disparities.
The aim of this review is to identify barriers and provide solutions to the implementation of inhaled corticosteroid-formoterol as rescue therapy within schools. GINA guidelines in 2019 and NAEPP in 2020 recommended inhaled corticosteroids combined with formoterol for a rescue inhaler over the traditional short-acting beta-agonist. The findings discussed in this article describe the barriers to the implementation of inhaled corticosteroids combined with formoterol for a rescue inhaler in school systems. Traditional asthma action plans, school nursing and parental education, and differences in dosing are some barriers identified. This paper provides solutions for the barriers, including updating and individualizing asthma action plans and providing thorough education to all parties on appropriate dosing for ICS-formoterol inhalers.
Asthma continues to pose a serious global health issue affecting billions of people and causing significant morbidity. It is immunologically heterogeneous disease, classified as Type 2 (Th2/ILC2-mediated, eosinophilic) or Type 1 (Th1-mediated, neutrophilic, steroid-resistant) inflammation. This review aims to evaluates current biologic therapies, emerging strategies, and challenges in asthma management and highlights the challenges and future directions in personalized asthma management. Current biologics for Type 2 asthma like anti-IgE (omalizumab), anti-IL-5 (mepolizumab, reslizumab, benralizumab), anti-IL-4/IL-13 (dupilumab) and anti-TSLP (tezepelumab) were effectively controlling severe eosinophilic asthma. Emerging therapies for Type 1 and mixed phenotypes include anti-TNF-α agents, CXCR2 antagonists, IL-17 blockers, JAK-STAT inhibitors and microbiome-based approaches and upstream epithelial cytokine-targeting therapies such as anti-TSLP agents. Dual or broad-spectrum strategies, such as bispecific antibodies and endotype-guided biologic selection offer more targeted interventions. Despite these advances, challenges persist regarding high costs, limited accessibility, absence of robust biomarkers, and potential risks of immunosuppression. Biologics have transformed severe Type 2 asthma management, but effective treatments for Type 1 and steroid-resistant asthma remain limited. Future directions involve multi-omics, machine learning and gene therapy to optimize personalized therapy and develop inclusive strategies for the diverse inflammatory endotypes.
Due to the rapid rise in the prevalence of food allergy, environmental exposures, in addition to genetic susceptibility, are likely contributors to allergic disease. In developed countries, individuals spend a substantial proportion of time indoors. Therefore, the indoor exposome provides a unique framework to examine factors driving the increase in the rates of food allergy. This review summarizes epidemiological and mechanistic evidence of the indoor exposome, consisting of the combined exposures to food antigens, microbes, and chemicals encountered in indoor environments during early life, and their influence on food allergy development. Indoor house dust contains detectable food allergens, which remain biologically active and may be linked to non-oral exposure, leading to allergic sensitization. In contrast, early-life exposures to diverse microbes and their products are associated with protection from allergic disease. Emerging evidence further demonstrates that indoor chemicals, including detergents, plasticizers, and pollutants, can disrupt epithelial barrier integrity or function as immune adjuvants, thus increasing susceptibility to food sensitization. Collectively, these findings highlight the indoor exposome as a complex and important determinant of food allergy risk. Improved understanding of how the indoor exposome influences food allergy development may inform future primary prevention or intervention strategies.
This review aims to clarify the early-life risk and protective factors associated with Infantile Atopic Dermatitis (IAD)—an inflammatory skin condition that typically develops between birth and two years of age. The goal was to examine recent findings on maternal, environmental, and microbial influences on IAD. Prenatal and postpartum maternal probiotic use may reduce IAD risk, though no significant alterations in infants’ gut microbiota were found. Infants with IAD exhibit higher Clostridia levels, while Verrucomicrobia are more abundant in non-IAD cases. Breastmilk from the mother of affected infants contains higher arachidonic acid and lower eicosapentaenoic acid, whereas formula-feeding may lower IAD risk. Seasonal influences such as reduced sunlight or humidity are associated with higher susceptibility. Elevated skin biomarkers, including TARC/CCL17 and IL-8, have been observed in infants who later develop IAD. Early antibiotic exposure, particularly during the first trimester, also increases risk. IAD is multifactorial, involving genetics, environment, and skin barrier dysfunction. Understanding the interplay between the microbiome, maternal influences, and environmental exposures may guide future preventive approaches. Further research into non-pharmacologic and microbiome-targeted interventions is warranted to delay or prevent IAD onset.
To systematically review current evidence on microbiota changes associated with dupilumab treatment across different anatomical sites in type 2 inflammatory diseases. Fifteen studies were included, comprising two randomized trials and thirteen observational studies, mostly in atopic dermatitis, with fewer data in chronic rhinosinusitis with nasal polyps and NSAID-exacerbated respiratory disease. The skin was the most frequently investigated site, followed by the sinonasal tract and gut. Across skin studies, dupilumab was consistently associated with reduced Staphylococcus aureus, increased microbial diversity, and enrichment of commensal taxa. Sinonasal studies suggested shifts toward more eubiotic microbial communities. Gut evidence was limited, although one study suggested modulation of tryptophan metabolism-related pathways. Dupilumab appears to exert compartment-specific and disease-dependent effects on the microbiome. The strongest evidence concerns the skin and sinonasal compartments, whereas gut microbiota changes remain poorly defined. Further prospective studies are needed to assess microbiota signatures as potential biomarkers of response.
Aeroallergens are well established triggers of allergic rhinitis and asthma, yet their contribution to allergic skin diseases such as atopic dermatitis (AD) and chronic urticaria (CU) remains incompletely understood. This article reviews the molecular basis of aeroallergen-driven skin disease in AD and CU as well as management strategies. Aeroallergen triggered skin disease involves epithelial barrier disruption, innate immune activation, and neuroimmune amplification. Allergen disruption of the epithelial barrier through PAR-2 and TLR-mediated signaling, induces alarmins that sustain an IL-31-driven itch-scratch cycle. Biologics targeting these pathways reshape these cytokine networks, while checkpoint inhibitors show promise for durable remission. In CU, house dust mite sensitization correlates with basophil hyperreactivity and greater disease severity. Aeroallergen triggered inflammation involves overlapping barrier dysfunction, innate immune activation, and neuroimmune pathways that extend beyond traditional IgE-mediated allergic responses. Future research should prioritize endotype-based patient stratification and quantify the impact of aeroallergen exposure on chronic skin disease trajectory.
Medication adherence is essential for effective management of allergic rhinitis (AR), yet real-world adherence to guideline-recommended pharmacotherapies remains poorly characterized. This systematic review and meta-analysis aims to estimate pooled adherence proportions to prescribed intranasal corticosteroids and oral antihistamines in adults with AR, further stratified by adherence measurement method and geographic region. Twelve studies encompassing 191,103 AR patients were included. Overall pooled adherence to both intranasal corticosteroids and oral antihistamines was 43
Allergic rhinitis affects up to one-quarter of the population in industrialized countries. This chronic inflammatory disease of the nasal mucosa is triggered by allergen exposure and mediated by immunoglobulin E, leading to immune dysregulation. Diagnosis typically relies upon skin prick tests, serum-specific immunoglobulin E levels and nasal allergen provocations. Differentiation from non-allergic rhinitis remains a diagnostic challenge. Recent research has identified novel microRNAs, small non-coding RNA regulating post-transcriptional gene expression, as key regulators of immunological pathways with great potential as disease-specific targets in diagnostics and therapy. The purpose of this review is to explore novel therapeutic and diagnostic possibilities regarding novel miRNAs. This functional review evaluated current evidence specific to miRNA expression in allergic and non-allergic rhinitis. Seven microRNAs (miR-29a, miR-135a, miR-143, miR-146a, miR-150-5p, miR-223, miR-451) are discussed as potential diagnostic markers and therapeutic agents in the future. Interventional studies, including human and animal studies, are reviewed. The available evidence suggested that selected microRNAs may show specificity and sensitivity as biomarkers for allergic and non-allergic rhinitis in future human trials. Therapeutic options involving miRNAs have shown great promise but still lack validation in clinical studies. In this review, we have identified several challenges in microRNA-based diagnostic approaches and suggested strategies to facilitate future development. MiRNA research in AR has revealed their role as both diagnostic biomarkers and therapeutic agents in several different mechanisms that are currently under investigation. Dysregulation of miRNA expression has been documented in asthma and allergic rhinitis, but data regarding non-allergic rhinitis remain limited.
Asthma remains a major health challenge affecting over 300 million people worldwide, with severe, steroid-resistant phenotypes affecting 5–10
Idiopathic Pulmonary Fibrosis is a type of interstitial lung disease characterized by lung scarring due to excessive extracellular matrix (ECM) deposition. The transforming growth factor-beta (TGF-β) signaling pathway is the master regulator of fibrosis, driving myofibroblast activation and differentiation, epithelial-mesenchymal transition (EMT), and inhibition of ECM degradation. While individual classes of non-coding RNAs (ncRNAs) have been studied in IPF, a comprehensive understanding of how microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (LncRNAs) collectively regulate canonical TGF-β signaling remains lacking. Addressing this gap, this systematic review was conducted which presents current evidence on the integrated roles of ncRNAs in modulating TGF-β signaling in IPF pathogenesis. A comprehensive search of PubMed and Web of Science databases (2015–2025), identified 45 eligible studies. miRNAs (19 antifibrotic, 11 profibrotic) directly targeted the core components of the TGF-β signaling pathway, whereas circRNAs (5 antifibrotic, 5 profibrotic) and LncRNAs (6 profibrotic) acted as competing endogenous RNAs and sponged their target miRNAs. Notably, all identified LncRNAs were profibrotic, amplifying the fibrotic signaling pathway. We found that ncRNAs critically fine-tune TGF-β signaling at multiple regulatory nodes, including ligand activation, receptor expression, Smad protein phosphorylation, nuclear translocation, and inhibitory feedback mechanism. The ncRNA-mediated regulatory mechanisms provide valuable insight into IPF pathogenesis and may help identify potential biomarkers and therapeutic targets. Future efforts should prioritize validating in vitro and animal model data in human samples, integrating regulatory network analysis, in vivo functional validation of RNA-based therapeutics, and exploring therapeutic delivery systems to develop an effective ncRNA-based antifibrotic therapy.
Allergic skin diseases arise from complex interactions between epithelial barrier dysfunction and immune dysregulation. This review examines how structural and functional defects in the epidermal barrier predispose to conditions such as atopic dermatitis, allergic contact dermatitis, and chronic spontaneous urticaria, and explores how mechanistic insights into these abnormalities guide therapeutic selection. Advances in molecular and genetic research have clarified the roles of filaggrin deficiency, lipid disorganization, altered skin pH, tight junction impairment, antimicrobial peptide imbalance, and microbiome disruption in driving barrier vulnerability and downstream immune activation. Parallel progress in immunology has identified key signaling pathways including JAK-STAT, IL-4/IL-13, OX40, BTK, and KIT that sustain inflammation and disease chronicity. These discoveries have led to the expansion of biologic and small-molecule therapies, with additional agents targeting barrier restoration and immune memory currently in development. Identification of specific epithelial and immune defects has provided a unifying framework for understanding susceptibility, chronicity, and relapse across allergic skin diseases. Ongoing research focused on epidermal barrier biology, microbiome modulation, and translational immunology has the potential to refine therapeutic selection, improve long-term disease control, and guide future drug development.
This review aims to summarize the effects of per- and poly-fluoroalkyl substances (PFAS) exposures on the lung, emphasizing data coverage across steps of human health risk assessments. There is expansive literature characterizing PFAS contamination in water, but recent studies have identified PFAS as a component of air pollution, thus impacts on the lung have been an increasing point of inquiry. Mounting evidence from human clinical/epidemiological, animal, and in vitro investigations supports relationships between PFAS exposures and adverse pulmonary outcomes including asthma, allergies, infections, and cancer. Focusing on toxicology studies using animal and in vitro lung cell models, exposures to PFAS modulated inflammation/immune responses, oxidative stress, mucus production, surfactant properties, and epithelial barrier integrity, representing important mechanisms impacting pulmonary health. There are expanding datasets linking PFAS exposures to adverse pulmonary outcomes; however, these data originated from mostly oral/ingestion exposure and not from volatilized or aerosolized PFAS exposure designs. Furthermore, there is a general lack of data informing dose-response modeling and risk characterization, representing gaps needed to characterize pulmonary health risks.
To review current evidence on biologic therapies targeting type 2 inflammation in patients with eosinophilic COPD and respiratory comorbidities who remain uncontrolled despite optimized triple inhaled therapy. Recent phase 3 trials have shown that dupilumab provides the most consistent benefit in eosinophilic COPD, reducing exacerbations and improving lung function and quality of life. Mepolizumab has shown a more limited effect, mainly on exacerbation reduction, whereas benralizumab has not demonstrated clear clinical benefit. Blood eosinophil count remains the main biomarker for treatment selection. Biologic therapies are advancing precision medicine in COPD, with dupilumab currently showing the strongest overall evidence. Careful patient selection is essential. Broader phenotyping may further improve management, as comorbidities such as chronic rhinosinusitis may contribute to symptom burden and support a multidisciplinary approach. Future studies should clarify long-term outcomes and optimal biologic selection.
Clinical management of allergic contact dermatitis (ACD) is increasingly challenging due to the growing number of allergens, complex exposure patterns, and evolving regulatory frameworks. This review aims to provide clinicians with an updated overview of well-known as well as new and emerging allergens relevant to the diagnosis and management of ACD. Recent literature highlights changing exposure patterns and the identification of several new and emerging allergens, particularly in rapidly expanding consumer markets such as cosmetics and products associated with medical devices. In addition, updated evidence has refined the clinical relevance of established allergen groups, including fragrances, metals, rubber chemicals, acrylates, and preservatives. Post-marketing surveillance of products and clinical patch test data continue to play an important role in detecting novel sensitizers and shifting exposure scenarios. Clinicians must remain vigilant, as exposure patterns continue to evolve with the introduction of new ingredients and products while established allergens persist. Ongoing surveillance and updated clinical awareness are essential to ensure accurate diagnosis and prevention of ACD.
