Sensory sentinels: Neuroimmune detection and food allergy.

Food allergy is classically characterized by an inappropriate type-2 immune response to allergenic food antigens. However, how allergens are detected and how that detection leads to the initiation of allergic immunity is poorly understood. In addition to the gastrointestinal tract, the barrier epithelium of the skin may also act as a site of food allergen sensitization. These barrier epithelia are densely innervated by sensory neurons, which respond to diverse physical environmental stimuli. Recent findings suggest that sensory neurons can directly detect a broad array of immunogens, including allergens, triggering sensory responses and the release of neuropeptides that influence immune cell function. Reciprocally, immune mediators modulate the activation or responsiveness of sensory neurons, forming neuroimmune feedback loops that may impact allergic immune responses. By utilizing cutaneous allergen exposure as a model, this review explores the pivotal role of sensory neurons in allergen detection and their dynamic bidirectional communication with the immune system, which ultimately orchestrates the type-2 immune response. Furthermore, it sheds light on how peripheral signals are integrated within the central nervous system to coordinate hallmark features of allergic reactions. Drawing from this emerging evidence, we propose that atopy arises from a dysregulated neuroimmune circuit.

Investigating the Correlation between Handedness and Emotion Regulation Strategies in Asthma and Allergy Patients.

Background: Asthma and allergic diseases are common chronic non-communicable conditions that can negatively impact the quality of life of patients. Psychological factors play a role in both the onset and progression of these conditions. The purpose of this study was to examine the relationship between handedness and emotion regulation and cognitive emotion regulation strategies in patients with asthma and allergies in Isfahan, central Iran. Methods: We employed a causal-comparative research design. The study population consisted of all patients visiting Asthma and Allergy Clinic in Isfahan. One hundred participants were selected through probability sampling. Data were collected using the Emotion Regulation Questionnaire and the Cognitive Emotion Regulation Strategies Questionnaire, and were analyzed using univariate analysis of variance (ANOVA). Results: Cognitive emotion regulation was significantly different between right-handed and left-handed patients with asthma and allergies (P=0.0001). A significant difference was also observed between the two groups in their emotion regulation strategies (P=0.031). The rate of positive and negative cognitive regulation strategies was higher in left-handed individuals with asthma and allergies, compared to right-handed individuals. Conclusion: Overall, handedness has a significant impact on the behavior and mental health of patients suffering from asthma and allergies. Therefore, handedness should be taken into consideration in interventions for emotion regulation.

Development of systemic and mucosal immune responses against gut microbiota in early life and implications for the onset of allergies.

The early microbial colonization of human mucosal surfaces is essential for the development of the host immune system. Already during pregnancy, the unborn child is prepared for the postnatal influx of commensals and pathogens via maternal antibodies, and after birth this protection is continued with antibodies in breast milk. During this critical window of time, which extends from pregnancy to the first year of life, each encounter with a microorganism can influence children's immune response and can have a lifelong impact on their life. For example, there are numerous links between the development of allergies and an altered gut microbiome. However, the exact mechanisms behind microbial influences, also extending to how viruses influence host-microbe interactions, are incompletely understood. In this review, we address the impact of infants' first microbial encounters, how the immune system develops to interact with gut microbiota, and summarize how an altered immune response could be implied in allergies.

Health care resource use and costs in patients with food allergies: a United States insurance claims database analysis.

Aims: Food allergies impose a large clinical and financial burden on patients and the health care system. However, little is known about the factors associated with health care resource use and costs. The aim of this study was to investigate health care resource use and costs in individuals with food allergies utilizing health care in the United States.Methods: We conducted a retrospective analysis of insurance claims data from the Merative™ MarketScan® Research Databases (indexed from January 1, 2015, to June 30, 2022). All-cause and food allergy-related health care resource use, direct medical, and out-of-pocket costs for medical services were estimated for 12 months post-index using International Classification of Diseases [ICD] codes.Results: Of 355,520 individuals with food allergies continuously enrolled in a health insurance plan for ≥12 months pre- and post-index, 17% had a food allergy-related emergency department visit and 0.9% were hospitalized. The top patient characteristics associated with all-cause and food allergy-related hospitalizations, all-cause costs, and food allergy-related outpatient visit costs was a Charlson Comorbidity Index score of ≥2. Food allergy-related direct medical and out-of-pocket costs were high among patients with a food allergy-related visit. Out-of-pocket cost per patient per year for outpatient visits, emergency department visits, and hospitalizations had an estimated mean of $1,631 for patients with food allergy-related visits, which is approximately 11% of the total costs for these services ($14,395 per patient per year).Limitations: Study limitations are primarily related to the nature of claims databases, including generalizability and reliance on ICD codes. Nevertheless, MarketScan databases provide robust patient-level insights into health care resource use and costs from a large, commercially insured patient population.Conclusion: The health care resource use of patients with food allergies imposes a burden on both the health care system and on patients and their families, especially if patients had comorbidities.

Navigating Aspirin Hypersensitivity in Patients Undergoing Percutaneous Coronary Intervention.

Aspirin hypersensitivity continues to be a major clinical challenge in patients with coronary artery disease (CAD), particularly in those requiring percutaneous coronary intervention (PCI) in the absence of a validated alternative antiplatelet regimen. Although true aspirin allergies are uncommon, they can manifest with severe reactions such as angioedema or anaphylaxis, highlighting the critical role of diagnostic challenge tests and tolerance induction strategies. Here, a 61-year-old female with end-stage renal disease (ESRD) on hemodialysis presented with new-onset heart failure and elevated troponins in the setting of a hypertensive emergency. A subsequent left heart catheterization revealed severe multivessel disease, but PCI was deferred due to her history suggestive of aspirin-induced angioedema and the absence of a known optimal approach in this scenario. Given the feasibility of completing a desensitization protocol, aspirin desensitization was pursued, facilitating the successful placement of a drug-eluting stent. This case highlights the need for validated protocols to manage aspirin hypersensitivity, as the current treatment paradigm necessitates a highly individualized approach by the treating clinician.

Endoplasmic Reticulum Stress Promotes Telomerase Reverse Transcriptase Expression Contributes to Development of Allergic Rhinitis.

BACKGROUND: The Th2 cell polarization is a crucial factor in the pathogenesis of allergic diseases. The underlying mechanism requires further investigation. Telomerase has an immune-regulating ability. The aim of this study is to elucidate the association between telomerase and Th2 cell polarization in patients with allergic rhinitis (AR). METHODS: CD4+ T cells were isolated from blood samples collected from AR patients and healthy control subjects. RNA sequencing was employed to analyze RNA samples extracted from CD4+ T cells. An AR mouse model was established using the ovalbumin-alum protocol. RESULTS: High telomerase gene activity and high endoplasmic reticulum (ER) stress status were observed in CD4+ T-cells in patients with AR. Positive correlation between the telomerase reverse transcriptase (TERT) gene expression in CD4+ T cells and AR response in patients with AR. TERT facilitated the degradation of Foxp3 proteins in CD4+ T cells, resulting in the polarization of Th2 cells. Sensitization with the ovalbumin-alum protocol enhanced the Tert expression in CD4+ T cells by exacerbating ER stress. Conditional inhibition of the Tert or eukaryotic translation initiation factor 2-α (Eif2a) expression in CD4+ T cells effectively attenuated experimental AR in mice. CONCLUSIONS: Elevated amounts of telomerase in CD4+ T cells were found in CD4+ T cells of subjects with AR. Telomerase promoted Th2 cell polarization by inducing Foxp3 protein degradation and promotes GATA3 activation. Inhibition of TERT or eIF2a alleviated experimental AR.

Key factors that influence quality of life in patients with IgE-mediated food allergy vary by age.

BACKGROUND: While food allergy (FA) can be fatal, the greatest public health impact of FA arguably lies in its detrimental effect on quality of life (FAQOL). Understanding the factors that contribute to FAQOL at different ages is essential to develop personalized interventions that will improve FAQOL. OBJECTIVE: To determine the most influential factors that impact FAQOL across ages in well-phenotyped participants with confirmed FA. METHODS: One hundred and twenty-five individuals aged 2-28 years with IgE-mediated FA completed validated age-specific FAQOL questionnaires. The relationship between demographic/clinical variables and scores were analyzed to identify key predictors of FAQOL. RESULTS: Poor FAQOL was associated with increasing age, strict avoidance practices, reactions to trace exposures, and more severe reactions as assessed by epinephrine use, anaphylaxis, and/or treatment in the emergency department; FAQOL improved with time from the event. FAQOL was worse in subjects avoiding >2 versus ≤2 foods and in those avoiding milk, egg, soy, sesame, or wheat. Number of foods avoided had greatest impact on children ages 2-7 years, while total number of allergic reactions strongly impacted FAQOL in teens and adults; FAQOL of subjects ages 8-12 years appeared less affected by these variables compared to other age groups. A decision tree analysis identified key predictors of overall FAQOL (age, number of food avoidances, and time since epinephrine use) that can be used to guide intervention strategies to improve FAQOL. CONCLUSION: We directly compared FAQOL in extensively phenotyped children, teenagers, and adults with confirmed IgE-mediated FA. Age; timing, number, and severity of reactions; type and number of FA; and food avoidance practices influence FAQOL and should guide intervention strategies.

Neutrophil trapping and nexocytosis, mast cell-mediated processes for inflammatory signal relay.

Neutrophils are sentinel immune cells with essential roles for antimicrobial defense. Most of our knowledge on neutrophil tissue navigation derived from wounding and infection models, whereas allergic conditions remained largely neglected. Here, we analyzed allergen-challenged mouse tissues and discovered that degranulating mast cells (MCs) trap living neutrophils inside them. MCs release the attractant leukotriene B4 to re-route neutrophils toward them, thus exploiting a chemotactic system that neutrophils normally use for intercellular communication. After MC intracellular trap (MIT) formation, neutrophils die, but their undigested material remains inside MC vacuoles over days. MCs benefit from MIT formation, increasing their functional and metabolic fitness. Additionally, they are more pro-inflammatory and can exocytose active neutrophilic compounds with a time delay (nexocytosis), eliciting a type 1 interferon response in surrounding macrophages. Together, our study highlights neutrophil trapping and nexocytosis as MC-mediated processes, which may relay neutrophilic features over the course of chronic allergic inflammation.

Venom component allergen IgE measurement in the diagnosis and management of insect sting allergy.

Accurate identification of the allergy-eliciting stinging insect(s) is essential to insuring effective management of Hymenoptera venom-allergic individuals with venom-specific immunotherapy (VIT). Diagnostic testing using whole venom extracts with skin tests and serological-based analyses remains the first level of discrimination for honeybee versus vespid venom sensitization in clinical history-positive patients. As a second-level evaluation, serological testing using molecular venom allergens can further discriminate genuine sensitization (honeybee venom: Api m 1, 3, 4, and 10 versus yellow jacket venom/Polistes dominula venom Ves v 1/Pol d 1 and Ves v 5/Pol d 5) from inter-species cross-reactivity [hyaluronidases (Api m 2, Ves v 2, Pol d 2) and dipeptidyl peptidases IV (Api m 5, Ves v 3, Pol d 3)]. Clinical laboratories use a number of singleplex, oligoplex, and multiplex immunoassays that employ both extracted whole venom and molecular venom allergens (highlighted above) for confirmation of allergic venom sensitization. Established quantitative singleplex autoanalyzers have general governmental regulatory clearance worldwide for venom allergic patient testing with maximally achievable analytical sensitivity (0.1 kUA/L) and confirmed reproducibility (inter-assay CVs<10%). Emerging oligo- and multiplex (fixed panel) assays conserve on serum and are more cost-effective, but they need regulatory clearance in some countries and are prone to higher rates of detecting asymptomatic sensitization. Ultimately, the patient's clinical history, combined with the proof of sensitization, is the final arbiter in the diagnosis of Hymenoptera venom allergy.

Alpha-Gal Syndrome and Cardiac Surgery.

Galactose-alpha-1,3-galactose (alpha-gal) is a carbohydrate expressed by all mammals except for humans and certain old-world primates. It can be found in a plethora of products derived from mammals, including milk, organs, skeletal muscle and gelatin, in addition to products prepared with mammalian cells or constituents. In the late 2000s, an association between tick bites and the development of immunoglobulin E antibodies to the alpha-gal carbohydrate was discovered. The term "alpha-gal syndrome" (AGS) was then coined to describe allergic reactions to mammalian meat or other alpha-gal-containing products derived from mammals. Symptoms are often delayed several hours from consumption and can be urticarial and/or gastrointestinal. Medications and bioprosthetic inserts derived from mammals were also noted to cause allergic reactions in affected patients. Cardiac surgery, in particular, is considered high risk, given that unfractionated heparin has a bovine or porcine origin and is administered in large doses for cardiopulmonary bypass. Bioprosthetic valves have similar origins and risks. Awareness of AGS in cardiac surgery patients can lead to decreased risk preoperatively and inform management perioperatively and postoperatively. In this narrative review, we have reviewed the published literature relevant to AGS in patients undergoing cardiac surgery and shared our treatment approach.

Understanding immune-mediated titanium allergy to in situ orthopaedic implants: a narrative review of the current literature.

INTRODUCTION: Clinical recognition of potential immune-mediated allergic responses to implanted metal devices is increasing. For orthopaedic implants, while 'pure' compounds are used in specific circumstances, the majority of components are alloys - a combination of two or more distinct metals. Titanium is found commonly in many orthopaedic devices and is often championed as a 'hypoallergenic' option or inclusion. In the absence of a relevant previously published summary on the topic, this paper explores the current state-of-understanding of titanium allergy and proposes a patient management algorithm whereby such immune reactions are clinically-suggested. METHODS: A structured, systematic literature review was performed following PRISMA search principles to provide a contemporary summary-of-understanding in this area and to highlight clinical and knowledge deficiencies. RESULTS: Thirty-five topic-related articles were identified, the majority reflecting small case series' or proof-of-concept studies. The general standard of scientific evidence available was poor. Justification for arthroplasty utilization of titanium as a 'hypoallergenic' option is largely extrapolated from non-orthopaedic domains. CONCLUSIONS: Both ionic and conjugated titanium particles released from implant surfaces have the potential to trigger innate immune responses and true allergy. There exists no simple, high-sensitivity, screening test for titanium allergy. Conventional skin-patch testing is unreliable due to poor dermal penetration. Given established lymphocyte and macrophage activation pathways for allergy responses, in vitro methods using both cell-types show diagnostic promise. Surgical biopsy analysis from host-implant interfaces remains the contemporary 'gold-standard', however this represents an invasive, costly and highly-specialized approach not readily available in most settings. Further research to establish reliable/accessible diagnostic methods are indicated.

Identification of Alpha-Gal glycolipids in saliva of Lone-Star Tick (Amblyomma americanum).

Alpha-Gal Syndrome (AGS) is a delayed allergic reaction triggered by IgE antibodies targeting galactose-α-1,3-galactose (α-gal), prevalent in red meat. Its global significance has increased, with over 450,000 estimated cases in the United States alone. AGS is linked to tick bites, causing sensitization and elevated α-gal specific IgE levels. However, the precise mechanisms and tick intrinsic factors contributing to AGS development post-tick bites remain unclear. This study aims to characterize the alpha-gal conjugated lipid antigens in Amblyomma americanum (Am. americanum) salivary glands and saliva. Nanospray ionization mass spectrometry (NSI-MS) analysis revealed the identification of α-gal bound lipid antigens in Am. americanum saliva. Additionally, the activation of basophils by extracted alpha-gal bound lipids and proteins provides evidence of their antigenic capabilities.

Penicillin Allergy in China: Consequences of Inappropriate Skin Testing Practices and Policies.

Penicillins are the most frequently prescribed class of medications worldwide and first-line antibiotic of choice for most bacterial infections. They are also commonly labelled as the culprit of drug 'allergy'; leading to obligatory use of second-line antibiotics, suboptimal antibiotic therapy and increased antimicrobial resistance. However, the majority of reported penicillin 'allergy' labels are found to be incorrect after allergy testing, emphasising the importance of proper drug allergy testing and evaluation. Penicillin skin testing (PST) remains an important component of drug allergy diagnosis; however, its practice and policies significantly differ across the world. Inappropriate and non-evidence-based PST practices can lead to consequences associated with allergy mislabelling. Even within different regions of China, with a population exceeding 1.4 billion, there are marked differences in the implementation, execution and interpretation of PST. This review aims to examine the differences in PST between Mainland China, Hong Kong and the rest of the world. We critically analyse the current practice of 'pre-emptive' PST in Mainland China, which has a significant false-positive rate leading to high levels of penicillin allergy mislabelling. Non-evidence-based practices further compound the high false-positive rates of indiscriminatory PST. We postulate that inappropriate PST policies and practices may exacerbate the mislabelling of penicillin allergy, leading to unnecessary overuse of inappropriate second-line antibiotics, increasing antimicrobial resistance and healthcare costs. We advocate for the importance of more collaborative research to improve the contemporary workflow of penicillin allergy diagnosis, reduce mislabelling and promote the dissemination of evidence-based methods for allergy diagnosis.

Mycobacterium tuberculosis and Mycobacterium avium Coinfection in an Immunocompetent Patient.

Despite the increasing incidence of simultaneous mycobacterial and non-mycobacterial tuberculosis (TB) infection, little literature is available exploring the topic. Here, we present a case of a 22-year-old female diagnosed with pulmonary TB for four months with simultaneous multiple sputum cultures positive for non-tuberculous mycobacteria (NTM). Computed tomography of the chest without contrast reported linear areas of scarring involving both lung apices, more prominent on the left side. The patient completed intensive phase treatment for TB and is currently on isoniazid and rifampin with a referral to an infectious disease specialist for recommendations on treatment of Mycobacterium avium regimen in view of azithromycin allergy (intense cough and rash). While the coexistence of NTM is commonly attributed to colonization, differentiating colonization from disease is crucial considering the long duration of treatment, potential drug toxicity, risk of drug resistance, and significant cost of treatment. Clinical, microbiological, and radiological evidence should be considered for diagnosis of TB and NTM coinfection and expert consultation should be sought in formulating the treatment plan.

The Acari Hypothesis, IV: revisiting the role of hygiene in allergy.

Allergy and its manifestations were first appreciated in the 1870 s. Today, the mechanism by which specific substances elicit allergic reactions remains poorly understood. This is problematic from a healthcare perspective because the prevalence of allergic disease and its societal costs are substantial. Regarding mechanistic understanding of allergy, a new proposal, The Acari Hypothesis, has been forwarded. The Hypothesis, borne from consideration of alpha-gal syndrome, postulates that acarians, i.e., mites and ticks, are operative agents of allergy. By way of their pathogenic payloads and salivary pattern recognition receptor(s), acarians potentiate in human hosts the generation of IgE against acarian dietary elements. Those elements account for most, if not all, known human allergens. Inasmuch as acarian-human interactions occur on human epithelial surfaces, it is to be expected factors that influence the presence and/or operation of acarians on those surfaces influence the expression of allergic diseases. In this report, it is proposed that two adaptations of catarrhine primates, i.e., Old World monkeys, apes and humans, evolved to deter acarian species: firstly, the expansion of eccrine glands across the entirety of body surface area, and, secondly, the secretion of sweat by those glands. Contemporary hygienic practices that reduce and/or disrupt the operation of eccrine glands are likely responsible for the increase in allergic disease seen today.

Protocol for the systematic reviews on the desirable and undesirable effects of pharmacological treatments of allergic rhinitis informing the ARIA 2024 guidelines.

There is insufficient evidence regarding the comparative efficacy and safety of pharmacological treatments of allergic rhinitis (AR). In the context of informing the 2024 revision of the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines, we plan to perform three systematic reviews of randomized controlled trials (RCTs) comparing the desirable and undesirable effects (i) between intranasal and oral medications for AR; (ii) between combinations of intranasal and oral medications versus nasal or oral medications alone; and (iii) among different intranasal specific medications. We will search four electronic bibliographic databases and three clinical trials databases for RCTs examining patients ≥ 12 years old with seasonal or perennial AR. Assessed outcomes will include the Total Nasal Symptom Score, the Total Ocular Symptom Score, and the Rhinoconjunctivitis Quality-of-Life Questionnaire. We will assess the methodological quality of included primary studies by using the Cochrane risk-of-bias tool. If appropriate, we will perform a pairwise random-effects meta-analysis for each pair of assessed medication classes and outcomes, as well as a network meta-analysis to assess the comparative efficacy of intranasal medications among each other. Heterogeneity will be explored by sensitivity and subgroup analyses. This set of systematic reviews will allow for a comprehensive assessment of the effectiveness and safety of pharmacological interventions for AR and inform recommendations in the context of the ARIA guidelines.

Procedure for a standardized preparation of skin prick test solutions for the diagnosis of occupational type I allergies in the absence of commercial extracts.

In order to ensure valid diagnostics for occupational test allergen solutions despite the ongoing reduction in the availability of commercial test extracts, a plan B was initiated for the possible production of skin prick test (SPT) solutions in public pharmacies. For important occupational allergen sources (wheat and rye, storage mites, animal epithelia, mold material) laboratory extraction methods were analyzed in comparison to pharmacy compatible extraction methods regarding protein quantity and quality in SDS-PAGE combined with silver staining. Subsequently, using the example of bovine epithelia, adapted extraction procedures as well as in-process and final product controls were transferred to a public pharmacy. Allergen sources with a high protein content, such as wheat and rye grains as well as storage mites, showed good comparability of the extractable protein quantity and protein pattern, regardless of the applied extraction method. In contrast, allergen source materials with a low total protein content, such as animal epithelia and molds, can benefit from laboratory extraction conditions such as mechanical disruption and specific buffer additives. In the qualitative protein silver staining, characteristic protein patterns were identified for each allergen source. Depending on the extraction method, only minor differences in total protein patterns were observed in animal epithelia and molds. Using source materials from two suppliers, the resulting allergen extracts displayed clear differences in protein content in storage mites and quantitative and qualitative differences in molds. A practical preparation attempt of SPT solutions in a public pharmacy was successful. SPT solutions prepared with adapted pharmacy extraction methods showed a comparable protein and Bos d 2 allergen content and equivalent qualities in the protein pattern compared to a previously available commercial SPT solution. Accordingly, it can be assumed that standardized SPT solutions with sufficient allergen quality for occupational allergen sources can be prepared in public pharmacies if certified allergen sources with appropriate protein content are available.