Nonallergic Diseases Associated With Foods.

Clinicians are faced with evaluating real and alleged reactions to foods that may be allergic or nonallergic. Pathogenesis, diagnosis, and treatment of various non-IgE-mediated diseases are discussed in this review. These food-related conditions range from mild to severe. Referral for an allergy workup may be pursued despite the lack of IgE-mediated symptoms. Diagnostic testing is available for defined non-IgE-mediated food diseases that are either immunologic or nonimmunologic. These include celiac disease and related disorders, carbohydrate maldigestion, pancreatic insufficiency, and histamine intolerance. In contrast, there is a paucity of definitive studies to prove food intolerance diseases. There are no definitive diagnostic criteria or testing for nonceliac gluten sensitivity. Functional gastrointestinal disorders, such as irritable bowel syndrome, are better stratified diagnostically but still lack reliable testing. Both nonceliac gluten sensitivity and irritable bowel syndrome are linked to dietary triggers including fermentable oligosaccharides, disaccharides, monosaccharides, and polyols. Therefore, dietary alteration alone may be diagnostic and therapeutic when all other conditions are ruled out. These conditions are important considerations when evaluating a patient with history of a food reaction. There is little evidence that foods are causative in other ailments such as acne, migraines, and nasal congestion and hypersecretion.

Pyroptosis Inhibition in Disease Treatment: Opportunities and Challenges.

Programmed cell death (PCD) is at the center of immune responses, with different types of PCD occurring based on bodily conditions at a given moment. The main three types of PCD include pyroptosis, necroptosis, and apoptosis. Both pyroptosis and necroptosis induce an inflammatory response while apoptosis avoids eliciting an inflammatory reaction. Recently, pyroptosis has come to the forefront of immunology research due to tremendous potential that has been revealed surrounding the regulators of pyroptosis. In addition to previously known regulators of pyroptosis (ZBP1 and NLRP3 genes), a family of proteins called Gasdermin has been discovered. Specifically, Gasdermin D (GSDMD), when cleaved, participates in the onset of pyroptosis of inflammatory diseases. The N-terminal cleaved portion of the molecule causes cellular membrane openings releasing interleukin-18 and IL-1ß, inducing pyroptosis. It is hypothesized that the inhibition of GSDMD using drugs such as Dimethyl Fumarate (DMF) and Disulfiram may halt the progression of certain inflammatory diseases including Multiple Sclerosis (MS), autoimmune encephalitis etc. While there is not yet a concrete treatment for pyroptic cell death in inflammatory disease using GSDMD inhibition, there is ample evidence to suggest that there may be success in future studies and therapeutic applications of GSDMD.

EP2 inhibition restores myeloid metabolism and reverses cognitive decline.

Nonsteroidal anti-inflammatory drugs alleviate pain and inflammation by inhibiting the cyclooxygenase pathway. This pathway has various downstream effects, some of which are beneficial. Prostaglandin E2 is a key downstream product in the cyclooxygenase pathway that modulates inflammation. A correlation between aging and increased expression of the prostaglandin E2 receptor, EP2, has been associated with inflammatory processes, cognitive aging, angiogenesis, and tumorigenesis. Therefore, inhibition of EP2 could lead to therapeutic effects and be more selective than inhibiting cyclooxygenase-2. Studies suggest that inhibition of EP2 restores age-associated spatial memory deficits and synaptic proteins and impairs tumorigenesis. The data indicate that EP2 signaling is important in myeloid cell metabolism and support its candidacy as a therapeutic target.

Mind-body connection: metabolite 4-ethylphenyl linked to anxiety behavior and oligodendrocyte modification in autism spectrum disorder.

The connection between byproducts of digestion in the gastrointestinal (GI) tract and neurocognitive disorders is an expanding area of research that has implications for autism spectrum disorder (ASD). Needham et al. (Needham et al. Nature 602: 647-653, 2022) revealed that mice with elevated levels of 4-ethylphenyl sulfate (4EPS), a GI tract-derived metabolite previously found at increased levels in the plasma of individuals with ASD, had altered brain activity, anxiety-influenced behavior, and reduced myelination of neuronal axons. This is a monumental step forward in the study of gut-derived neuroactive compounds, like 4EPS, and advances the understanding of their role in modulating behavior and brain activity in neurocognitive disorders.

Pharmacokinetic and pharmacodynamic comparison of epinephrine, administered intranasally and intramuscularly: An integrated analysis.

BACKGROUND: Manual intramuscular epinephrine injection is the standard of care for treating severe allergic reactions and anaphylaxis. Epinephrine autoinjectors were approved on the basis of the assumption that their pharmacokinetic and pharmacodynamic profiles are equivalent to manual intramuscular injection; however, although there is emerging evidence for product-related differences in pharmacokinetic profiles, very little is known about the comparative pharmacodynamic profiles. OBJECTIVE: To compare pharmacokinetic and pharmacodynamic profiles of epinephrine delivered through manual intramuscular injection, autoinjectors, and intranasal spray. METHODS: This integrated analysis was based on data from 4 randomized cross-over phase 1 trials that compared the pharmacokinetics and pharmacodynamics of epinephrine using manual intramuscular epinephrine 0.3 mg injection, epinephrine 0.3 mg autoinjectors (Symjepi and EpiPen), and epinephrine 1 mg intranasal spray (neffy). RESULTS: Data from 175 participants showed that although neffy (1.0 mg intranasal spray) resulted in a maximum concentration (258 pg/mL) that was lower than or comparable with manual epinephrine intramuscular injection (254 pg/mL), Symjepi (438 pg/mL) and EpiPen (503 pg/mL), it led to comparable increases in systolic blood pressure (maximum effect [Emax], 16.9, 10.9, 14.9, and 18.1 mm Hg, respectively). The effect of neffy on diastolic blood pressure was also markedly more pronounced than that of other products (Emax, 9.32, 5.51, 5.78, and 5.93 mm Hg, respectively). CONCLUSION: Intranasal delivery of epinephrine using neffy increases systolic blood pressure more efficiently than do manual intramuscular injection and epinephrine autoinjectors, despite lower maximum plasma concentrations.

The Use of Flexible Rhinolaryngoscopy for Allergy-Immunology Practice.

Flexible rhinolaryngoscopy is an underused procedure that can provide allergists-immunologists and other physicians with several benefits over existing imaging techniques. In this article, we highlight the many benefits of flexible rhinolaryngoscopy and expand on its safety, cost-effectiveness, and convenience. This article also covers current procedure techniques and assesses the most common indications and relevant clinical findings for which flexible rhinolaryngoscopy can be used to evaluate the nasopharyngeal tract. Videos for the clinician showing some of the most common findings are included.

Aberrant Expression of ACO1 in Vasculatures Parallels Progression of Idiopathic Pulmonary Fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by mitochondrial dysfunction. However, details about the non-mitochondrial enzymes that sustain the proliferative nature of IPF are unclear. Aconitases are a family of enzymes that sustain metabolism inside and outside mitochondria. It is hypothesized that aconitase 1 (ACO1) plays an important role in the pathogenesis of IPF given that ACO1 represents an important metabolic hub in the cytoplasm. Objectives: To determine if ACO1 expression in IPF lungs shows specific patterns that may be important in the pathogenesis of IPF. To determine the similarities and differences in ACO1 expression in IPF, bleomycin-treated, and aging lungs. Methods: ACO1 expression in IPF lungs were characterized and compared to non-IPF controls by western blotting, immunostaining, and enzymatic activity assay. ACO1-expressing cell types were identified by multicolor immunostaining. Using similar methods, the expression profiles of ACO1 in IPF lungs versus bleomycin-treated and aged mice were investigated. Measurements and main results: Lower lobes of IPF lungs, unlike non-IPF controls, exhibit significantly high levels of ACO1. Most of the signals colocalize with von Willebrand factor (vWF), a lineage marker for vascular endothelial cells. Bleomycin-treated lungs also show high ACO1 expressions. However, most of the signals colocalize with E-cadherin and/or prosurfactant protein C, representative epithelial cell markers, in remodeled areas. Conclusions: A characteristic ACO1 expression profile observed in IPF vasculatures may be a promising diagnostic target. It also may give clues as to how de novo angiogenesis contributes to the irreversible nature of IPF.

Can PPAR γ Keep Cadmium in Check?

Cd, a naturally occurring endocrine toxin found in tobacco leaves, originates in the environment and enters the body through inhalation, targeting the lungs and kidneys. A study published by Larsen-Carey et al. revealed that cadmium mediates the persistence of classically activated lung macrophages to exacerbate lung injury. The research discovered a novel role for PPAR γ as an effective regulator for the alternative activation of macrophages in response to Cd and Cd-induced lung injury.

Age-Related Increase of Collagen/Fibrin Deposition and High PAI-1 Production in Human Nasal Polyps.

Objective: Our previous studies showed an age-related increased prevalence of nasal polyps (NP) and reduced production of S100A8/9 in elderly patients with chronic rhinosinusitis with NP (CRSwNP). In this study, we investigated an unbiased age-related gene expression profile in CRSwNP subjects and healthy controls, and further identified the differences in their tissue remodeling. Methods: Microarrays using NP and uncinate tissues from health controls (elderly, age ≥65 vs. non-elderly, age 18-49) were performed, and differentially regulated genes were analyzed. Quantitative real-time PCR (qPCR), Immunostaining, Periodic acid-Schiff (PAS), trichrome staining, Western blot, and ELISA were performed for further investigation. Results: Microarrays identified differentially expressed genes according to disease and age; 278 in NP vs. controls, 75 in non-elderly NP vs. non-elderly controls, and 32 in elderly NP vs. elderly controls. qPCR confirmed that the PLAT gene was downregulated and the SERPINB2 gene upregulated in NP vs. controls. The serous glandular cell-derived antimicrobial protein/peptide-related genes such as BPIFB3, BPIFB2, LPO, and MUC7 were remarkably reduced in NP, regardless of age. SERPINE1 gene (plasminogen activator inhibitor-1, PAI-1) expression was significantly increased in elderly NP versus elderly controls. IHC and western blot confirmed significantly decreased production of MUC7 and LPO in NP versus controls. There was a trend of age-related reduction of submucosal gland cells in normal controls. Trichrome and immunofluorescence staining demonstrated an age-related increase of collagen and fibrin deposition in NP, consistent with increased PAI-1 production. Conclusion: This study demonstrated age-related differential glandular remodeling patterns and fibrosis in NP and normal controls. PAI-1 expression was significantly increased in elderly NP versus elderly controls, suggesting PAI-1 as a potential treatment target in elderly NP.

The international WAO/EAACI guideline for the management of hereditary angioedema - The 2021 revision and update.

Hereditary Angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2), by providing guidance on common and important clinical issues, such as: 1) How should HAE be diagnosed? 2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? 3) What are the goals of treatment? 4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast feeding women? 5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.

Hormonal Effects on Asthma, Rhinitis, and Eczema.

Hormones significantly influence the pathogenesis of asthma, rhinitis, and eczema. This review aims to summarize relevant clinical considerations for practicing allergists and immunologists. The first section reviews the effects of sex hormones: estrogen, progesterone, and testosterone. The second concerns insulin production in the context of type 1 and type 2 diabetes. The third concludes with a discussion of thyroid and adrenal pathology in relationship to asthma, rhinitis, and eczema.

Matrix Metalloproteinase 7 Expression and Apical Epithelial Defects in Atp8b1 Mutant Mouse Model of Pulmonary Fibrosis.

Abnormalities in airway epithelia and lung parenchyma are found in Atp8b1 mutant mice, which develop pulmonary fibrosis after hyperoxic insult. Microarray and ingenuity pathway analysis (IPA) show numerous transcripts involved in ciliogenesis are downregulated in 14-month (14 M) -old Atp8b1 mouse lung compared with wild-type C57BL/6. Lung epithelium of Atp8b1 mice demonstrate apical abnormalities of ciliated and club cells in the bronchial epithelium on transmission electron microscopy (TEM). Matrix metalloproteinase 7 (MMP7) regulates of ciliogenesis and is a biomarker for idiopathic pulmonary fibrosis (IPF) in humans. Mmp7 transcript and protein expression are significantly upregulated in 14 M Atp8b1 mutant mouse lung. MMP7 expression is also increased in bronchoalveolar lavage fluid (BAL). Immunohistochemistry is localized MMP7 to bronchial epithelial cells in the Atp8b1 mutant. In conclusion, MMP7 is upregulated in the aged Atp8b1 mouse model, which displays abnormal ciliated cell and club cell morphology. This mouse model can facilitate the exploration of the role of MMP7 in epithelial integrity and ciliogenesis in IPF. The Atp8b1 mutant mouse is proposed as a model for IPF.

Lung fibrosis is induced in ADAR2 overexpressing mice via HuR-induced CTGF signaling.

Adenosine deaminase acting on RNA 2 (ADAR2), an RNA editing enzyme is involved in a site-selective modification of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA). Its role in the lungs is unknown. The phenotypic characterization of Adarb1 mice that lacked ADAR2 auto-regulation due to the deletion of editing complementary sequence (ΔECS mice) determined the functional role of ADAR2 in the lungs. ADAR2 protein expression increased in the ΔECS mice. These mice display immune cell infiltration and alveolar disorganization. The lung wet by dry ratio indicates there is no lung edema in ΔECS mice. Bronchoalveolar lavage (BAL) analysis of ΔECS mice reveals a significant increase in neutrophils. Interestingly, ΔECS mice spontaneously develop lung fibrosis as indicated by Sirius red staining of collagen fibers in the lung sections and a significant increase in hydroxyproline level in their lungs. ADAR2 expression increased significantly in a bleomycin mouse model, implicating a role of ADAR2 in lung fibrosis. Furthermore, there is a likely possibility that the genetically modified ΔECS mice does not model the physiological or pathophysiological process of lung fibrosis. Nevertheless, this model is useful in interrogating the role of ADAR2 in the lungs. The Ctgf mRNA and connective tissue growth factor (CTGF) protein significantly increased in ΔECS lungs and occurs in bronchial epithelial cells. There is a significant increase in Human antigen R (ELAVL1; HuR) protein levels in ΔECS lungs and suggests a role in stabilizing Ctgf mRNA. Lung mechanics such as total respiratory resistance, Newtonian resistance and tissue damping were increased, whereas inspiratory capacity was decreased in the ΔECS mice. Taken together, these data indicate that overexpression of ADAR2 causes spontaneous lung fibrosis via HuR-mediated CTGF signaling and implicate a role for ADAR2 auto-regulation in lung homeostasis. The identification of ADAR2 target genes in ΔECS mice would facilitate a mechanistic understanding of the role of ADAR2 in the lungs and provide a therapeutic strategy for lung fibrosis.

Is the mechanism of COVID-19 coagulopathy still a rabbit's hole?

The pathophysiology of COVID-19 is an enigma with its severity often determined by the extent of coagulopathy. Several regulatory pathways targeted by the SARS-CoV-2 include the renin-angiotensin system, von Willebrand Factor, and most importantly, the complement pathway. This article discusses these pathways to help design potential future therapies.

Anaphylaxis: Access to Epinephrine in Outpatient Setting.

Epinephrine is a lifesaving medication to treat systemic allergic reactions including anaphylaxis. Epinephrine autoinjectors (EAIs) are expensive, not available everywhere in the world, and shortages can limit their access. Epinephrine prefilled syringes and epinephrine kits are lower-cost alternatives to EAIs. Advantages, disadvantages, and costs of available products are discussed and the socioeconomic factors impacting access to EAIs described. EAIs designed for infants also are discussed.

Patient Communications: Why Is It Important to Quickly Use Epinephrine at the Onset of Symptoms and Signs of Anaphylaxis?

Delayed administration of epinephrine (adrenaline), the first-line and only effective treatment of a systemic allergic reaction (SAR) and anaphylaxis, is associated with increased mortality. However, epinephrine is underused because of a lack of consensus as to when it should be administered and an inappropriate fear of using epinephrine and potential adverse effects from the medication. The authors emphasize that SARs and anaphylaxis should be considered as a spectrum, and that affected individuals be educated on its safety and repeatedly given instructions as to when and how epinephrine should be used at the first symptoms or signs of SAR and anaphylaxis.

Calcium and vitamin D intake in allergic versus non-allergic children and corresponding parental attitudes towards dairy products.

BACKGROUND: It is hypothesized that parents of children with allergic conditions believe dairy products are potentially harmful to their child. OBJECTIVES: This study compares the calcium and vitamin D intake of allergic versus non-allergic children and parental beliefs about milk and dairy products. METHODS: A survey and food-frequency-questionnaire were administered to parents of children between 3 and 13 years, 110 with allergic disease (allergic rhinitis, asthma, food allergy, and/or atopic dermatitis) versus 110 without allergic disease. Calcium and vitamin D intake was calculated from the food-frequency-questionnaire and compared to National Institutes of Health recommendations. Associations between atopy, calcium and vitamin D intake, and beliefs were investigated using Chi-square test (α = 0.05). Distribution across subjects was investigated using Mann-Whitney-U test (α = 0.05). RESULTS: Fewer allergic (51.8%) versus non-allergic children (77.3%) met the recommended calcium intake (p < 0.001). Both had similar rates of insufficient vitamin D intake: 12.7% allergic and 17.3% non-allergic (p = 0.345). 81.7% of parents of allergic versus 94.0% of non-allergic children believe intake of dairy is important (p = 0.009). 23.7% of parents of allergic versus 8.0% of non-allergic children believe dairy negatively impacts their child (p = 0.003). 19.1% of parents of allergic children (excluding 3 with documented milk allergy) versus 2.0% of non-allergic believe their child is allergic or intolerant to dairy (p < 0.001). CONCLUSIONS: Children are at risk of insufficient calcium and vitamin D intake. Atopic children may be at increased risk for insufficient intake, due in part to parent's negative beliefs regarding dairy products. Physicians should counsel on the importance of micronutrient intake and how allergic conditions do or do not entail dietary restrictions.