Background Alcohol hypersensitivity (AH), an exacerbation of respiratory symptoms in response to alcohol consumption, is common in aspirin-exacerbated respiratory disease and other forms of chronic rhinosinusitis (CRS). We speculated that these reactions relate to the activation of innate immune cells including basophils and, in particular, platelet-adherent basophils by polyphenolic compounds contained within eliciting alcoholic beverages. Objective We investigated the absolute numbers of these cells in patients with AH and the ability of relevant polyphenolic compounds to cause cellular activation. Methods Data were collected from 412 consecutive adults presenting to a tertiary care sinonasal clinic in whom the presence of AH was elicited. The CRS phenotype was determined and results from complete blood cell count and differential were analyzed. A subset of patients was invited to donate blood samples that were used to explore the ability of relevant compounds associated with alcohol consumption to activate platelet-nonadherent and platelet-adherent basophils. Activation was quantified by flow cytometry as up-regulated expression of CD63 and as secretion of lipid metabolites. Results Of the 412 patients enrolled, 69 (16.7%) endorsed having AH. Significantly higher platelet counts were seen in patients reporting AH. Red wine extract and several polyphenolic compounds produced basophil activation and this was primarily observed among platelet-adherent basophils. Platelet activation was further established as the release of thromboxane B2. Conclusion The presence of AH is associated with significantly higher platelet levels and compounds present in alcoholic beverages can directly mediate both their activation and the activation of platelet-adherent basophils.

Chronic rhinosinusitis (CRS) is a complex heterogeneous disease process with considerable impact on patient quality of life and is a disease which has proven very challenging to treat and manage. CRS is broadly divided into 2 subsets based on the presence or absence of nasal polyposis (NP): CRSwNP and CRSsNP, respectively. However, what we are truly after are the actual underlying drivers of inflammation in CRS regardless of polyp status—something that is best described as inflammatory endotypes. A robust understanding of the inflammatory drivers will eventually allow for much more targeted therapies and improved patient outcomes. In the June 2022 issue of the Annals of Allergy, Asthma & Immunology, Liu et al1Liu W Liu X Zhang N Li J Wen Y Wei Y et al.Microvessel quantification by fully convolutional neural networks associated with type 2 inflammation in chronic rhinosinusitis.Ann Allergy Asthma Immunol. 2022; 128: 697-704Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar report their study investigating the relationship of angiogenesis and CRS endotypes. They approach this through the development of machine-based learning methodologies for quantification of angiogenesis as well as appropriate proteomics and identification of relevant associations. A total of 59 patients with CRSwNP, 20 patients with CRSsNP, and 17 healthy control subjects were sampled and compared from the First Affiliated Hospital in Guangzhou, Guangdong, People's Republic of China. They discuss in detail the complexity of setting up a fully convolutional network and its improvements on prior techniques. Using this new tool to analyze hundreds of sample slides, they were able to reveal that angiogenesis correlated with markers of type 2 inflammation (interleukin-5, eosinophil cationic protein, total immunoglobulin E, and antigen-specific immunoglobulin E) but not to NP status. The article provides robust discussion of deep learning computer algorithms and inflammatory cytokine clustering analysis. The study is arguably limited by the relatively small sample size and significant differences in CRS demographics across the globe. For example, in the studied population, only 5% of patients with CRS had any history of comorbid asthma or allergic rhinitis, although, as the study reveals, there was still a significant type 2 inflammatory signature found in almost 40% of their patients. With these parameters, the authors set out to address the prevalence of angiogenesis. Angiogenesis is a complicated process and has previously been associated with both asthma and CRS with type 2 inflammatory features.2Azizzadeh Delshad A Jalali Nadoushan M Davati A Rostami A Expression of vascular endothelial growth factor in nasal polyp and chronic rhinosinusitis.Iran J Pathol. 2016; 11: 231-237PubMed Google Scholar,3Meyer N Akdis CA. Vascular endothelial growth factor as a key inducer of angiogenesis in the asthmatic airways.Curr Allergy Asthma Rep. 2013; 13: 1-9Crossref PubMed Scopus (69) Google Scholar Vascular endothelial growth factor (VEGF) has been identified in both conditions and found to play an important role. VEGF has an essential role in new blood vessel formation during embryonic development, muscle growth, injury response, and, as discussed subsequently and likely highly relevant here, hypoxic states. It exists in at least 5 different isoforms, each having widely varying distributions throughout the body. VEGF is highly enriched in respiratory tissues and is overexpressed in type 2 responses driven by inflammation and remodeling. Several studies have also implicated the regulation of different VEGF isoforms and their differential interactions with receptors in the development and progression of type 2 inflammatory airway and sinus disease. VEGF has been studied in the proliferation and migration of endothelial cells and vessels within the lung with high baseline levels and associated increases being found in patients with asthma characterized by type 2 disease. This increase in VEGF in these patients correlates with increased obstructive features.4Asai K Kanazawa H Kamoi H Shiraishi S Hirata K Yoshikawa J. Increased levels of vascular endothelial growth factor in induced sputum in asthmatic patients.Clin Exp Allergy. 2003; 33: 595-599Crossref PubMed Scopus (164) Google Scholar In addition, VEGF is produced by mast cells and enhances mast cell migration to sites of angiogenesis.5Boesiger J Tsai M Maurer M Yamaguchi M Brown LF Claffey KP et al.Mast cells can secrete vascular permeability factor/vascular endothelial cell growth factor and exhibit enhanced release after immunoglobulin E-dependent upregulation of fc epsilon receptor I expression.J Exp Med. 1998; 188: 1135-1145Crossref PubMed Scopus (298) Google Scholar Studies in CRS have revealed not only a significant increase in VEGF signatures in the disease process as a whole, but also especially during exacerbations of CRS symptoms, suggesting it may play a role in both progression and maintenance of the disease.6Divekar RD Samant S Rank MA Hagan J Lal D O'Brien EKO et al.Immunological profiling in chronic rhinosinusitis with nasal polyps reveals distinct VEGF and GM-CSF signatures during symptomatic exacerbations.Clin Exp Allergy. 2015; 45: 767-778Crossref PubMed Scopus (36) Google Scholar It is intriguing to speculate that the enhanced vascularization observed in this study reflects a synergistic combination of the influences of hypoxia in the sinuses along with that of hypoxia sensors, including especially the hypoxic-inducible factors (HIFs) HIF-1 alpha and HIF-2 alpha. In CRS, the combination of nasal mucosal swelling, metaplastic hypertrophy of the infundibulum and other sinus openings, and the growth of nasal polyps will all lead to the occlusion of the sinus ostia, decreasing oxygen concentrations in the sinus tissue. Hypoxia produces a highly proinflammatory state, that is driven in large part by activation of HIF-1. Studies have revealed low levels of oxygen in sinusitis,7Matsune S Kono M Sun D Ushikai M Kurono Y. Hypoxia in paranasal sinuses of patients with chronic sinusitis with or without the complication of nasal allergy.Acta Oto-laryngol. 2003; 123: 519-523Crossref PubMed Scopus (42) Google Scholar and an obvious indication of the prevalence of hypoxia is the near ubiquitous colonization of the sinuses of patients with CRS with anaerobic bacteria. Using a gene array exploratory approach, our group identified the robust up-regulation of HIF-1 in CRS compared with control tissue.8Payne SC Han JK Huyett P Negri J Kropf EZ Borish L et al.Microarray analysis of distinct gene transcription profiles in non-eosinophilic chronic sinusitis with nasal polyps.Am J Rhinol. 2008; 22: 568-581Crossref PubMed Scopus (36) Google Scholar Activation of HIF-1 initiates a response designed to promote increased oxygen delivery, resulting in particular in the expression of VEGF and inducing the expression of erythropoietin. Consistent with this concept, our studies and others have revealed hypoxic induction of VEGF from CRS stromal cells.9Early SB Hise K Han JK Borish L Steinke JW. Hypoxia stimulates inflammatory and fibrotic responses from nasal-polyp derived fibroblasts.Laryngoscope. 2007; 117: 511-515Crossref PubMed Scopus (40) Google Scholar However, hypoxia is also a potent proinflammatory stimulus and a stimulus that promotes tissue remodeling. Thus, several studies have revealed hypoxic induction of numerous proinflammatory cytokines and chemokines (CCL11 [eotaxin-1], CXCL8 [IL-8], CCL2 [MCP-1], CCL4 [MIP-1ß], and CXCL12 [SDF-1]), and VEGF itself has numerous proinflammatory effects, including accumulation of mononuclear phagocytic cells. In addition to VEGF, other factors driving a remodeling response to hypoxia that could contribute to NP formation are the increased production of fibrogenic cytokines, such as transforming growth factor-ß, IL-11, and several matrix metalloproteinases. Furthermore, consistent with the production of the latter cytokines, hypoxia promotes the increased deposition of procollagen and fibronectin.9Early SB Hise K Han JK Borish L Steinke JW. Hypoxia stimulates inflammatory and fibrotic responses from nasal-polyp derived fibroblasts.Laryngoscope. 2007; 117: 511-515Crossref PubMed Scopus (40) Google Scholar The current studies are therefore intriguing and suggest a novel consideration of the role of neovascularization and associated expression of factors such as the HIFs and VEGF in the pathogenesis of CRS. These factors make—in particular—VEGF an exciting potential target in the treatment of asthma, CRS, and other type 2 inflammatory diseases. Microvessel quantification by fully convolutional neural networks associated with type 2 inflammation in chronic rhinosinusitisAnnals of Allergy, Asthma & ImmunologyVol. 128Issue 6PreviewThe pathogenesis of chronic rhinosinusitis (CRS) is still unclear, and little is known about angiogenesis in this disease. We utilized a fully convolutional network (FCN), which has been extensively used in image processing to study angiogenesis in CRS. Full-Text PDF

The prevalence of chronic rhinosinusitis (CRS) is steadily increasing and becoming an increasing component of our medical practices. Most presentations of CRS with nasal polyposis (NP) (CRSwNPs) and close to half of CRS without NPs are associated with eosinophilia and type 2 (T2) inflammation (interleukin [IL]-4, IL-5, and IL-13). 1 Wang X. Zhang N. Bo M. et al. Diversity of TH cytokine profiles in patients with chronic rhinosinusitis: a multicenter study in Europe, Asia, and Oceania. J Allergy Clin Immunol. 2016; 138: 1344-1353 Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar ,2 Stevens W.W. Peters A.T. Tan B.K. et al. Associations between inflammatory endotypes and clinical presentations in chronic rhinosinusitis. J Allergy Clin Immunol Pract. 2019; 7 (e3): 2812-2820 Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar In the current issue of the Annals of Allergy, Asthma & Immunology, several state-of-the-art articles update our understanding of the pathogenesis of CRSwNPs and point to future interventions that will ameliorate the adverse impact CRS has on our patients’ quality of life.

BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna) and JNJ-78436735 (Johnson and Johnson/Janssen) are COVID-19 vaccines that were recently FDA-EUA approved in the USA. To date there has been little head-to-head evaluation of antibody responses to these vaccines.

Allergic contact dermatitis (ACD) is a T-cell mediated delayed hypersensitivity response, most commonly from cutaneous exposure. Rarely systemic contact dermatitis (SCD) can occur with ingestion of potential allergens as a subset of ACD, resulting in a diffuse skin eruption.

Allergic rhinitis (AR), most presentations of nasal polyposis (NP), and many presentations of chronic rhinosinusitis are type 2high disorders characterized by expression of interleukin (IL)-4, IL-5, and IL-13. Neutralization of IgE with anti-IgE (omalizumab) has proven efficacy in AR. Similarly, in addition to anti-IgE, blockade of IL-5/IL-5 (mepolizumab, reslizumab, benralizumab) and dual blockade of IL-4 and IL-13 with anti-IL-4R (dupilumab) have demonstrated efficacy in NP. However, these agents are expensive and future studies are essential to evaluate cost effectiveness in comparison with current medical and surgical therapies. This article reviews biologics as potential interventions in AR, chronic rhinosinusitis, and NP.

Until recently, chronic rhinosinusitis (CRS) was viewed as a chronic infectious disease of the sinuses caused by anaerobic bacteria. This dogma led to the concept that, as with any abscess in a closed space, the primary modalities of treatment should be surgical drainage and antibiotics. Not surprisingly, few patients responded favorably. Recent years have seen a revolution in our thinking, with the recognition that CRS is a chronic inflammatory disease—a syndrome comprising numerous chronic inflammatory diseases. This evolution in our thinking has greatly affected the therapeutic approaches offered to our patients, with effective therapeutic options becoming available. In the current issues of the Annals of Allergy, Asthma, & Immunology, several papers that summarize this updated understanding of the pathogenesis of CRS and the basis for individualized targeted therapeutics are presented. Use of endotypes, phenotypes, and inflammatory markers to guide treatment decisions in chronic rhinosinusitisAnnals of Allergy, Asthma & ImmunologyVol. 124Issue 4PreviewWith the advent of new treatment options for Chronic Rhinosinusitis (CRS) comes the ability for physicians to provide more individualized patient care. Physicians are now tasked with identifying who may be the best candidate for a particular therapy. In this review, existing biomarkers and potentially new methods that could guide treatment choices in CRS patients will be discussed. Full-Text PDF Mechanisms and treatment of olfactory dysfunction in chronic rhinosinusitisAnnals of Allergy, Asthma & ImmunologyVol. 124Issue 4PreviewChronic rhinosinusitis (CRS) is one of the most common chronic conditions in North America. Patients with CRS experience discolored nasal drainage, facial pain, difficulty breathing, and decreased sense of smell.1 CRS impairs quality of life, reduces productivity, and increases the risk of depression and sleep disorders.1 Full-Text PDF Biologics in chronic rhinosinusitis with nasal polyposisAnnals of Allergy, Asthma & ImmunologyVol. 124Issue 4PreviewChronic rhinosinusitis with nasal polyps (CRSwNP) is a common and heterogeneous inflammatory condition, for which the drivers of the underlying inflammation are not yet fully understood. The use of biologic therapies to target specifically relevant effector cells or cytokines in CRSwNP is a growing field of interest. The objectives of this review are to provide an update on the existing studies of biologics in CRSwNP and to identify potential future areas for further research. Full-Text PDF Epithelial cell function and remodeling in nasal polyposisAnnals of Allergy, Asthma & ImmunologyVol. 124Issue 4PreviewTo review the latest discoveries on airway epithelial cell diversity and remodeling in type 2 inflammation, including nasal polyposis. Full-Text PDF

Immunodeficiency, centromeric instability, facial anomalies (ICF) Syndrome is a rare autosomal recessive disorder caused by mutations in DNA methyltransferase 3 beta (DNMT3B), resulting in defective chromosomal methylation. The immunodeficiency is characterized by normal B cell counts but reduced/absent IgG levels leading to recurrent infections, as well as variable T cell immunodeficiency.

Introduction Standard therapy for patients with neutropenic fever is treatment with an antipseudomonal antibiotic. Patients with a history of self-reported penicillin allergy are often given alternative antibiotic regimens; however, up to 90% of these patients do not have IgE-mediated hypersensitivity and thus are inappropriately labeled as allergic. The effects of documented penicillin allergy on outcomes have been recognized: higher hospital charges, increased risk for surgical complications, and recently, increased rates of clostridium difficile infection and mortality in patients with hematologic malignancies. Methods A retrospective chart review was performed on patients admitted with ICD-9/10 diagnoses that identified them as having neutropenic fever/sepsis or acute leukemia. 1400 patients were identified and separated into two cohorts based on the presence of an antibiotic allergy. The outcomes investigated included AKI, clostridium difficile infection, mortality, MRSA and VRE colonizations. Results The absolute rates of AKI, clostridium difficile infection, mortality, MRSA and VRE colonizations were higher in the antibiotic allergy group compared to the non-allergy group: 6.8% difference in AKI, 1.9% in clostridium difficile infection, 7.6% in mortality, 0.2% in MRSA colonization, and 3.6% in VRE colonization. Conclusions We found higher rates of adverse events in patients at high risk of antibiotic use with documented antibiotic allergies. These findings confirm previously published work and extends the adverse outcomes of AKI, MRSA and VRE colonizations, further demonstrating that antibiotic allergy history is not benign. Thus, quality improvement opportunities exist to appropriately identify or disprove antibiotic allergies in patients who are at high risk for antibiotic use.

BACKGROUND:Positive expiratory pressure(PEP) breathing modalities are commonly prescribed in obstructive lung diseases, however practical methods of airway pressures(AP) quantification for therapeutic efficacy are lacking. Excessive dynamic airway collapse(EDAC) is characterized by expiratory central airway collapse leading to dyspnea and poor quality of life(QoL), with limited therapeutic options.PURPOSE:To measure AP and exertional dyspnea in EDAC patients during normal breathing and with use of pursed-lip breathing(PLB), nasal PEP device(nPEP), and oral-PEP valve(oPEP) during rest and exercise using an Esophageal Manometer.METHODS:EDAC patients exercised on a bicycle ergometer sequentially using normal breathing, PLB, nPEP, and oPEP for five-minute intervals. AP's were measured by continuous topographic upper airway manometry. Pre- and post-exercise BORG dyspnea scores were recorded and QoL measured with the St. George's respiratory questionnaire(SGRQ-C). The most effective and patient-preferred PEP modality was prescribed for daily activities and SGRQ-C repeated after one week.RESULTS:Three women with symptomatic EDAC participated. Expiratory laryngopharyngeal AP's during exercise with normal breathing, PLB, nPEP and oPEP in patient-1 were 1.7, 14, 4.5, and 7.3 mmHg, in patient-2; 2.3, 8, 8.3, and 12 mmHg, and in patient-3; 1, 15, unobtainable, and 9 mmHg, respectively. Maximal reduction in BORG scores occurred with PLB in patient 1 and with oPEP in patients 2 and 3. After 1 week mean SGRQ-C scores declined by 17-points.CONCLUSIONS:Upper airway manometry directly measures laryngopharyngeal pressures during rest and exercise and can be used to select and optimize PEP breathing techniques to improve respiratory symptoms in EDAC patients.

Background: The predictive characteristics of different screening surveys for the recognition of individuals at risk for airflow obstruction (AFO) have not been evaluated simultaneously in the same population.Purpose: To compare five AFO/COPD screening questionnaires.Methods: 383 individuals completed the Veterans Airflow Obstruction Screening Questionnaire, Personal Level Screener for COPD (VAFOSQ), the 11-Q COPD Screening Questionnaire (11-Q), the COPD Population Screener (COPD-PS) and the Lung Function Questionnaire (LFQ) and performed spirometry. AFO was defined as forced expiratory volume in one second divided by the forced vital capacity (FEV1/FVC) < 0.7, fixed ratio (FR) or FEV1/FVC < lower limit of normal (LLN). The predictive characteristics of the five questionnaires were calculated and non-parametric receiver operating characteristic (ROC) curves estimated by logistic regression.Results: 376 participants completed at least two of the questionnaires and performed technically acceptable spirometry. AFO was present in 102 (27.1%) and 150 (39.9%) based on LLN and FR, respectively. The number of individuals positively selected by the VAFOSQ was 227, PLS 128, 11-Q 236, COPD-PS 217, and LFQ 328. The area under the ROC curves for the questionnaires was between 0.60 and 0.66 (LLN) and 0.58 and 0.66 (FR).Conclusions: Although these screening surveys have acceptable and similar predictive ability for the identification of AFO, their published thresholds lead to substantially different classification rates. The choice of an appropriate threshold for the identification of individuals with possible AFO/COPD should consider the underlying prevalence of AFO/COPD in the target population and the relative costs of misclassifying affected and unaffected cases.Clinical Trial Registration: None.Primary Source of Funding: Veterans Health Administration. Published by Elsevier Ltd.

Airflow obstruction has been defined using spirometric test results when the forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) ratio is below a fixed cutoff (<70%) or lower limits of normal (LLN) from reference equations that are based on values from a normal population. However, similar to other positive or abnormal diagnostic test results that are used to identify the presence of disease, perhaps airflow obstruction should be defined based on the values of FEV1/FVC for a population of individuals with known disease such as chronic obstructive pulmonary disease (COPD). Unfortunately, we do not know such a distribution of values of FEV1/FVC for patients with COPD since there is no gold standard for this syndrome or condition. Yet, we have used this physiologic definition of airflow obstruction based on a normal population to identify patients with COPD. In addition, we have defined airflow obstruction as either being present or absent. Instead, we should use a different approach to define airflow obstruction based on the probability or likelihood that the airflow obstruction is present which in turn would give us the probability or likelihood of a disease state such as COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality within the Veterans Healthcare Administration (VHA) and is frequently under-diagnosed. We developed the Veterans Airflow Screening Questionnaire (VAFOSQ) to improve the identification of Veterans with airflow obstruction (AFO), the most commonly used criterion for the diagnosis of COPD.We created an initial survey with 78 variables that have been associated with AFO. A total of 825 patients in 3 primary care clinics performed spirometry after bronchodilator administration and completed the initial survey. Best sets regression was used to build a model that predicted AFO optimally. A total of 195 of 825 (23.3%) patients had AFO and 7 items positively predicted AFO. When the questionnaire score was greater than 25, the VAFOSQ accurately identified AFO with an area under the receiver operating curve of 0.72. In a prospective validation cohort of 376 participants, the positive predictive value was 32% and negative predictive value 81%. The VAFOSQ is a reliable and valid instrument for the identification of veterans at risk for AFO who would benefit from further evaluation with spirometry and assessment for COPD. The VAFOSQ is straightforward to use and can be easily self-administered and self-scored enabling widespread application within the VHA.

Airflow obstruction has been defined using spirometric test results when the forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) ratio is below a fixed cutoff ( <70%) or lower limits of normal (LLN) from reference equations that are based on values from a normal population. However, similar to other positive or abnormal diagnostic test results that are used to identify the presence of disease, perhaps airflow obstruction should be defined based on the values of FEV 1/FVC for a population of individuals with known disease such as chronic obstructive pulmonary disease (COPD). Unfortunately, we do not know such a distribution of values of FEV1/FVC for patients with COPD since there is no gold standard for this syndrome or condition. Yet, we have used this physiologic definition of airflow obstruction based on a normal population to identify patients with COPD. In addition, we have defined airflow obstruction as either being present or absent. Instead, we should use a different approach to define airflow obstruction based on the probability or likelihood that the airflow obstruction is present which in turn would give us the probability or likelihood of a disease state such as COPD.