Targeting Epithelium Dysfunction and Impaired Nasal Biofilms to Treat Immunological, Functional, and Structural Abnormalities of Chronic Rhinosinusitis.

Chronic rhinosinusitis (CRS) with (CRSwNP) or without (CRSsNP) nasal polyps is a prevalent and heterogeneous disorder existing as a spectrum of clinical conditions with complex underlying pathomechanisms. CRS comprises a broad syndrome characterized by multiple immunological features involving complex interactions between the genes, the microbiome, host- and microbiota-derived exosomes, the epithelial barrier, and environmental and micromilieu exposures. The main pathophysiological feature is an epithelial barrier disruption, accompanied by microbiome alterations and unpredictable and multifactorial immunologic overreactions. Extrinsic pathogens and irritants interact with multiple epithelial receptors, which show distinct expression patterns, activate numerous signaling pathways, and lead to diverse antipathogen responses. CRSsNP is mainly characterized by fibrosis and mild inflammation and is often associated with Th1 or Th17 immunological profiles. CRSwNP appears to be associated with moderate or severe type 2 (T2) or Th2 eosinophilic inflammation. The diagnosis is based on clinical, endoscopic, and imaging findings. Possible CRS biomarkers from the peripheral blood, nasal secretions, tissue biopsies, and nasally exhaled air are studied to subgroup different CRS endotypes. The primary goal of CRS management is to maintain clinical control by nasal douching with isotonic or hypertonic saline solutions, administration of nasal and systemic steroids, antibiotics, biologic agents, or, in persistent and more severe cases, appropriate surgical procedures.

Further Understanding of Neuro-Immune Interactions in Allergy: Implications in Pathophysiology and Role in Disease Progression.

The complicated interaction between the central and the autonomic (sympathetic, parasympathetic, and enteric) nervous systems on the one hand and the immune system and its components, on the other hand, seems to substantially contribute to allergy pathophysiology, uncovering an under-recognized association that could have diagnostic and therapeutic potentials. Neurons connect directly with and regulate the function of many immune cells, including mast cells, the cells that have a leading role in allergic disorders. Proinflammatory mediators such as cytokines, neurotrophins, chemokines, and neuropeptides are released by immune cells, which stimulate sensory neurons. The release of neurotransmitters and neuropeptides caused by the activation of these neurons directly impacts the functional activity of immune cells and vice versa, playing a decisive role in this communication. Successful application of Pavlovian conditioning in allergic disorders supports the existence of a psychoneuroimmunological interplay in classical allergic hypersensitivity reactions. Activation of neuronal homeostatic reflexes, like sneezing in allergic rhinitis, coughing in allergic asthma, and vomiting in food allergy, offers additional evidence of a neuroimmunological interaction that aims to maintain homeostasis. Dysregulation of this interaction may cause overstimulation of the immune system that will produce profound symptoms and exaggerated hemodynamic responses that will lead to severe allergic pathophysiological events, including anaphylaxis. In this article, we have systematically reviewed and discussed the evidence regarding the role of the neuro-immune interactions in common allergic clinical modalities like allergic rhinitis, chronic rhinosinusitis, allergic asthma, food allergy, atopic dermatitis, and urticaria. It is essential to understand unknown - to most of the immunology and allergy experts - neurological networks that not only physiologically cooperate with the immune system to regulate homeostasis but also pathogenetically interact with more or less known immunological pathways, contribute to what is known as neuroimmunological inflammation, and shift homeostasis to instability and disease clinical expression. This understanding will provide recognition of new allergic phenotypes/endotypes and directions to focus on specialized treatments, as the era of personalized patient-centered medicine, is hastening apace.

Workup and Clinical Assessment for Allergen Immunotherapy Candidates.

Allergen Immunotherapy (AIT) is a well-established, efficient, and safe way to treat respiratory and insect-venom allergies. After determining the diagnosis of the clinically relevant culprit allergen, AIT can be prescribed. However, not all patients are eligible for AIT, since some diseases/conditions represent contraindications to AIT use, as described in several guidelines. Allergists are often preoccupied on whether an extensive workup should be ordered in apparently healthy AIT candidates in order to detect contra-indicated diseases and conditions. These preoccupations often arise from clinical, ethical and legal issues. The aim of this article is to suggest an approach to the workup and assessment of the presence of any underlying diseases/conditions in patients with no case history before the start of AIT. Notably, there is a lack of published studies on the appropriate evaluation of AIT candidates, with no globally accepted guidelines. It appears that Allergists are mostly deciding based on their AIT training, as well as their clinical experience. Guidance is based mainly on experts' opinions; the suggested preliminary workup can be divided into mandatory and optional testing. The evaluation for possible underlying neoplastic, autoimmune, and cardiovascular diseases, primary and acquired immunodeficiencies and pregnancy, might be helpful but only in subjects for whom the history and clinical examination raise suspicion of these conditions. A workup without any reasonable correlation with potential contraindications is useless. In conclusion, the evaluation of each individual candidate for possible medical conditions should be determined on a case-by-case basis.

Allergic Reactions to Current Available COVID-19 Vaccinations: Pathophysiology, Causality, and Therapeutic Considerations.

Vaccines constitute the most effective medications in public health as they control and prevent the spread of infectious diseases and reduce mortality. Similar to other medications, allergic reactions can occur during vaccination. While most reactions are neither frequent nor serious, anaphylactic reactions are potentially life-threatening allergic reactions that are encountered rarely, but can cause serious complications. The allergic responses caused by vaccines can stem from activation of mast cells via Fcε receptor-1 type I reaction, mediated by the interaction between immunoglobulin E (IgE) antibodies against a particular vaccine, and occur within minutes or up to four hours. The type IV allergic reactions initiate 48 h after vaccination and demonstrate their peak between 72 and 96 h. Non-IgE-mediated mast cell degranulation via activation of the complement system and via activation of the Mas-related G protein-coupled receptor X2 can also induce allergic reactions. Reactions are more often caused by inert substances, called excipients, which are added to vaccines to improve stability and absorption, increase solubility, influence palatability, or create a distinctive appearance, and not by the active vaccine itself. Polyethylene glycol, also known as macrogol, in the currently available Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines, and polysorbate 80, also known as Tween 80, in AstraZeneca and Johnson & Johnson COVID-19 vaccines, are excipients mostly incriminated for allergic reactions. This review will summarize the current state of knowledge of immediate and delayed allergic reactions in the currently available vaccines against COVID-19, together with the general and specific therapeutic considerations. These considerations include: The incidence of allergic reactions and deaths under investigation with the available vaccines, application of vaccination in patients with mast cell disease, patients who developed an allergy during the first dose, vasovagal symptoms masquerading as allergic reactions, the COVID-19 vaccination in pregnancy, deaths associated with COVID-19 vaccination, and questions arising in managing of this current ordeal. Careful vaccine-safety surveillance over time, in conjunction with the elucidation of mechanisms of adverse events across different COVID-19 vaccine platforms, will contribute to the development of a safe vaccine strategy. Allergists' expertise in proper diagnosis and treatment of allergic reactions is vital for the screening of high-risk individuals.

Bronchial hyperresponsiveness in patients with cholinergic urticaria.

BACKGROUND: Cholinergic urticaria is occasionally associated with bronchospasm, even in patients without a history of asthma; the underlying mechanism has not been elucidated. OBJECTIVE: To evaluate bronchial hyperresponsiveness (BHR) in patients with cholinergic urticaria compared with healthy adults and patients with chronic urticaria. METHODS: Patients with a history of cholinergic urticaria and a positive ergometric test result constitute the study group. History was reviewed and physical examination and spirometry were performed to exclude exercise-induced anaphylaxis and exercise-induced asthma. Patients with chronic urticaria and healthy volunteers were used as positive and negative controls, respectively. All 3 groups were evaluated for BHR using a methacholine challenge test. RESULTS: Fifty-nine adults participated in the study: 30 patients with cholinergic urticaria, 15 with chronic urticaria, and 14 healthy volunteers. BHR was demonstrated in 13 of 30 patients (43%) in the study group, 1 of 15 patients with chronic urticaria (7%), and 1 of 14 healthy volunteers (7%); the observed difference was statistically significant. Further analysis of the study group demonstrated the existence of 2 subpopulations of patients with cholinergic urticaria, which were discriminated on the basis of intensity and duration of symptoms, with 96.7% accuracy. In addition, a statistically significant correlation was found between patient age and disease duration and between intensity and frequency of symptoms. CONCLUSIONS: Evaluation of patients with cholinergic urticaria should probably include BHR. A formula based on duration and intensity of cholinergic urticaria symptoms is provided as a tool for the prediction of BHR.

Efficacy and safety of mometasone furoate vs nedocromil sodium as prophylactic treatment for moderate/severe seasonal allergic rhinitis.

BACKGROUND: The preventive use of medications has been proposed to be effective in the treatment of seasonal rhinitis. OBJECTIVE: To evaluate the efficacy and safety of mometasone furoate and nedocromil sodium nasal sprays as prophylactic treatment for moderate to severe seasonal allergic rhinitis (SAR). PATIENTS: Sixty-one patients were recruited from 3 referral allergy centers. Inclusion criteria were history of SAR for 2 years or longer, sensitization to relevant local pollen (grasses, Parietaria, and olive), and age older than 12 years. METHODS: An open-label, randomized, parallel-group, "real-life" study design was used. Patients received mometasone furoate nasal spray once daily or nedocromil sodium nasal spray 3 times daily starting 2 to 4 weeks before the pollen season and continuing for up to 4 months. Instructions regarding the use of additional medications were given. Diary cards recording symptoms, use of medication, and adverse events were kept by the patients. RESULTS: All 61 patients completed the study. The prophylactic use of mometasone furoate vs nedocromil sodium led to significantly more days without symptoms (75.1% vs 54.5%; P < .001). The mometasone furoate group also had lower nasal symptom scores (mean, 1.4 vs 2.9; median, 0 vs 2; P < .001) and was more satisfied (93.1% vs 43.5%; P < .001). No serious adverse event was recorded, and there was no difference between the treatments in any adverse event. CONCLUSIONS: Prophylactic administration of mometasone furoate before the pollen season is safe and may lead to improved control of SAR compared with the use of nedocromil sodium.

Nasal polyps in patients with rhinitis and asthma.

The objective of this study was to investigate the prevalence of nasal polyposis in Greek patients with chronic rhinitis and asthma. We studied 3817 patients (2342 men and 1385 women) who were referred for allergy evaluation during 1990-1998 and diagnosed as having chronic rhinitis and asthma. Skin-prick tests with allergens common in Greece and controls were used in all subjects. A wheal with a mean diameter > or = 3 mm was considered as positive. According to the history of symptoms and the results of skin tests, patients were divided into the following groups: patients who have allergic rhinitis (seasonal, perennial), patients who have allergic asthma (seasonal, perennial), patients who have nonallergic rhinitis, and patients who have nonallergic asthma. All patients were examined for nasal polyps by anterior rhinoscopy and endoscopic investigation with a rigid or/and flexible endoscope. We found that 4.2% of the patients with chronic rhinitis and asthma (4.4% of the men and 3.8% of the women; p > 0.05) had nasal polyps. The prevalence of nasal polyps increased with age (p < 0.001) in both sexes. The prevalence of nasal polyps was 13% in patients with nonallergic asthma, 2.4% in patients with allergic asthma, 8.9% in patients with nonallergic rhinitis, and 1.7% in patients with allergic rhinitis. Nasal polyps were found in 3.6% of the patients with rhinitis and in 4.8% of the patients with asthma (p > 0.05). Nasal polyps were present more frequently (1) in patients with nonallergic respiratory disease (rhinitis, asthma) than in patients with allergic respiratory disease (10.8% versus 2.1%; p < 0.001) and (2) in patients with perennial respiratory allergy (rhinitis, asthma) than in patients with seasonal respiratory allergy (4.8% versus 0.4%; p < 0.001). We found that 4.2% of patients with chronic rhinitis and asthma had nasal polyps. Nasal polyps were present more frequently in nonallergic patients than in allergic patients and in patients with perennial allergy than in patients with seasonal allergy.