WAO-ARIA consensus on chronic cough - Part III: Management strategies in primary and cough-specialty care. Updates in COVID-19.

Background: Chronic cough management necessitates a clear integrated care pathway approach. Primary care physicians initially encounter the majority of chronic cough patients, yet their role in proper management can prove challenging due to limited access to advanced diagnostic testing. A multidisciplinary approach involving otolaryngologists and chest physicians, allergists, and gastroenterologists, among others, is central to the optimal diagnosis and treatment of conditions which underly or worsen cough. These include infectious and inflammatory, upper and lower airway pathologies, or gastro-esophageal reflux. Despite the wide armamentarium of ancillary testing conducted in cough multidisciplinary care, such management can improve cough but seldom resolves it completely. This can be due partly to the limited data on the role of tests (eg, spirometry, exhaled nitric oxide), as well as classical pharmacotherapy conducted in multidisciplinary specialties for chronic cough. Other important factors include presence of multiple concomitant cough trigger mechanisms and the central neuronal complexity of chronic cough. Subsequent management conducted by cough specialists aims at control of cough refractory to prior interventions and includes cough-specific behavioral counseling and pharmacotherapy with neuromodulators, among others. Preliminary data on the role of neuromodulators in a proof-of-concept manner are encouraging but lack strong evidence on efficacy and safety. Objectives: The World Allergy Organization (WAO)/Allergic Rhinitis and its Impact on Asthma (ARIA) Joint Committee on Chronic Cough reviewed the recent literature on management of chronic cough in primary, multidisciplinary, and cough-specialty care. Knowledge gaps in diagnostic testing, classical and neuromodulator pharmacotherapy, in addition to behavioral therapy of chronic cough were also analyzed. Outcomes: This third part of the WAO/ARIA consensus on chronic cough suggests a management algorithm of chronic cough in an integrated care pathway approach. Insights into the inherent limitations of multidisciplinary cough diagnostic testing, efficacy and safety of currently available antitussive pharmacotherapy, or the recently recognized behavioral therapy, can significantly improve the standards of care in patients with chronic cough.

Insights into urticaria in pediatric and adult populations and its management with fexofenadine hydrochloride.

OBJECTIVE: The present narrative review provides a comprehensive update of the current knowledge on urticaria, both in adult and pediatric populations, and on the safety and efficacy of fexofenadine hydrochloride (HCl) as a treatment option. DATA SOURCE: A literature search was conducted on Embase and Medline. STUDY SELECTION: Clinical studies published in English and published between 1999 and 2020 were selected. RESULTS: Although the exact pathogenesis of urticaria is not fully understood, multiple pathways of mast cell activation are discussed to explain the existence of phenotypically different clinical manifestations of urticaria. An overview of the worldwide prevalence of chronic urticaria, including disease burden and patient's quality of life is provided. The impact of urticaria on patient's life differs on the basis of whether its form is acute or chronic, but pharmacological approaches are most often needed to control the disabling symptoms. A summary of the current management of urticaria recommended by different guidelines across countries (Global; European; American; Australian; Asian; Japanese) is presented. Non-sedating, second-generation H1-antihistamines are the preferred choice of treatment across several guidelines worldwide. Herein, the efficacy and safety of fexofenadine HCl, a representative second-generation H1-antihistamine approved for the treatment of urticaria, is discussed. The occurrence of urticaria manifestations in COVID-19 patients is also briefly presented. CONCLUSION: The burden of acute and chronic urticaria is high for patients. Second generation anti-histamines such as fexofenadine HCl can help managing the symptoms.

WAO-ARIA consensus on chronic cough - Part 1: Role of TRP channels in neurogenic inflammation of cough neuronal pathways.

BACKGROUND: Cough features a complex peripheral and central neuronal network. The function of the chemosensitive and stretch (afferent) cough receptors is well described but partly understood. It is speculated that chronic cough reflects a neurogenic inflammation of the cough reflex, which becomes hypersensitive. This is mediated by neuromediators, cytokines, inflammatory cells, and a differential expression of neuronal (chemo/stretch) receptors, such as transient receptor potential (TRP) and purinergic P2X ion channels; yet the overall interaction of these mediators in neurogenic inflammation of cough pathways remains unclear. OBJECTIVES: The World Allergy Organization/Allergic Rhinitis and its Impact on Asthma (WAO/ARIA) Joint Committee on Chronic Cough reviewed the current literature on neuroanatomy and pathophysiology of chronic cough. The role of TRP ion channels in pathogenic mechanisms of the hypersensitive cough reflex was also examined. OUTCOMES: Chemoreceptors are better studied in cough neuronal pathways compared to stretch receptors, likely due to their anatomical overabundance in the respiratory tract, but also their distinctive functional properties. Central pathways are important in suppressive mechanisms and behavioral/affective aspects of chronic cough. Current evidence strongly suggests neurogenic inflammation induces a hypersensitive cough reflex marked by increased expression of neuromediators, mast cells, and eosinophils, among others. TRP ion channels, mainly TRP V1/A1, are important in the pathogenesis of chronic cough due to their role in mediating chemosensitivity to various endogenous and exogenous triggers, as well as a crosstalk between neurogenic and inflammatory pathways in cough-associated airways diseases.

WAO-ARIA consensus on chronic cough - Part II: Phenotypes and mechanisms of abnormal cough presentation - Updates in COVID-19.

BACKGROUND: Chronic cough can be triggered by respiratory and non-respiratory tract illnesses originating mainly from the upper and lower airways, and the GI tract (ie, reflux). Recent findings suggest it can also be a prominent feature in obstructive sleep apnea (OSA), laryngeal hyperresponsiveness, and COVID-19. The classification of chronic cough is constantly updated but lacks clear definition. Epidemiological data on the prevalence of chronic cough are informative but highly variable. The underlying mechanism of chronic cough is a neurogenic inflammation of the cough reflex which becomes hypersensitive, thus the term hypersensitive cough reflex (HCR). A current challenge is to decipher how various infectious and inflammatory airway diseases and esophageal reflux, among others, modulate HCR. OBJECTIVES: The World Allergy Organization/Allergic Rhinitis and its Impact on Asthma (WAO/ARIA) Joint Committee on Chronic Cough reviewed the current literature on classification, epidemiology, presenting features, and mechanistic pathways of chronic cough in airway- and reflux-related cough phenotypes, OSA, and COVID-19. The interplay of cough reflex sensitivity with other pathogenic mechanisms inherent to airway and reflux-related inflammatory conditions was also analyzed. OUTCOMES: Currently, it is difficult to clearly ascertain true prevalence rates in epidemiological studies of chronic cough phenotypes. This is likely due to lack of standardized objective measures needed for cough classification and frequent coexistence of multi-organ cough origins. Notwithstanding, we emphasize the important role of HCR as a mechanistic trigger in airway- and reflux-related cough phenotypes. Other concomitant mechanisms can also modulate HCR, including type2/Th1/Th2 inflammation, presence or absence of deep inspiration-bronchoprotective reflex (lower airways), tissue remodeling, and likely cough plasticity, among others.

International Consensus on Allergen Immunotherapy II: Mechanisms, standardization, and pharmacoeconomics.

This article continues the comprehensive international consensus (ICON) statement on allergen immunotherapy (AIT). The initial article also recently appeared in the Journal. The conclusions below focus on key mechanisms of AIT-triggered tolerance, requirements in allergen standardization, AIT cost-effectiveness, and regulatory guidance. Potential barriers to and facilitators of the use of AIT are described in addition to future directions. International allergy specialists representing the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma and Immunology; and the World Allergy Organization critically reviewed the existing literature and prepared this summary of recommendations for best AIT practice. The authors contributed equally and reached consensus on the statements presented herein.

The ability of adults and children to visually identify peanuts and tree nuts.

BACKGROUND: Peanuts and tree nuts are common food allergens and are the leading cause of fatalities from food-induced anaphylaxis. Dietary avoidance is the primary management of these allergies and requires the ability to identify peanuts or tree nuts. OBJECTIVES: To investigate the ability of adults and children to visually identify peanuts and tree nuts. METHODS: A nut display was assembled that held peanuts and 9 tree nuts in a total of 19 different forms. Persons 6 years or older completed a worksheet to name the items. RESULTS: One-thousand one-hundred five subjects completed the study. The mean number of peanuts and tree nuts identified by all subjects was 8.4 (44.2%) out of a possible 19. The mean for children ages 6 to 18 was 4.6 (24.2%), compared with 11.1 (58.4%) for adults older than 18 (P < .001). The most commonly identified items were peanut in the shell and without the shell. The least identified was hazelnut (filbert) in the shell and without the shell. No difference was seen in the performance of peanut- or tree nut-allergic subjects compared with nonallergic subjects. Fifty percent of subjects with a peanut or tree nut allergy correctly identified all forms of peanuts or tree nuts to which they are allergic. Parents of peanut- or tree nut-allergic children did no better than parents of children without such allergy. CONCLUSIONS: Overall, both children and adults are unreliable at visually identifying most nuts. Treatment of nut allergies with dietary avoidance should include education for both adults and children on identification of peanuts and tree nuts.

Implications of venom hypersensitivity for a deploying soldier.

Venom immunotherapy (VIT) is a life-saving medical treatment for individuals allergic to Hymenoptera species. Delivery of VIT is a complex process that requires proper extract preparation, shipping, storage, refrigeration, and administration by qualified medical personnel in a facility that can manage a life-threatening allergic emergency (anaphylaxis). Successful VIT requires 3 to 5 years of uninterrupted maintenance injections, which may be difficult to maintain during deployments, particularly in combat operations. The complexity of VIT has resulted in service members being deemed nondeployable and has led to interruption or discontinuation of VIT for deployed service members in the past. We report the case of a 34-year-old Army National Guard soldier who successfully received maintenance VIT while deployed to Operation Iraqi Freedom. This case demonstrates that, with proper coordination and appropriate risk assessment, continuation of complex medical care, such as VIT, can be supported in a combat zone.

A comparison of two single-headed and two multi-headed allergen skin test devices.

Given the potential differences in performance of skin test devices, the purpose of this study was to prospectively assess the performance of two single-headed and two multiheaded devices for allergy skin testing in terms of wheal size, sensitivity, specificity, intradevice variability, and pain level. Two single-headed devices (Greer Pick, Duotip-Test) and two multiheaded devices (Multi-Test II, OMNI) were tested in 15 subjects in a prospective partially blind fashion looking at wheal reactions and pain using histamine and glycerol-saline on the arms and back. Differences among devices in wheal size and pain were noted. Sensitivity, specificity, and intradevice variability were calculated. Differences between corner and interior heads in multiheaded devices were analyzed. No significant differences were observed in wheal size between Greer Pick (7.1+/-1.4 mm) and Duotip-Test (7.2+/-1.6 mm). Multiheaded devices were significantly different in wheal size compared with each other and to the single-headed devices (Multi-Test II, 5.4+/-1.7 mm; OMNI, 3.3+/-1.2 mm). Single-headed devices were more sensitive (100% each, 95% CI of 92-100%) than the multiheaded devices. Multi-Test II was significantly more sensitive (83%, 95% CI of 78-87%) than OMNI (57%, 95% CI of 51-62%). There was significant intradevice variability for the multiheaded devices with corner heads being significantly more sensitive than interior heads. Specificities for all devices were equally good (-97%). Pain was greater for multiheaded devices than single-headed devices but was generally mild. In conclusion, this study supports the idea that single-headed devices may be more sensitive and consistent than multiheaded devices. Multi-Test II is more sensitive than OMNI. In multiheaded devices, corner heads are more sensitive than interior heads.

Asthma in pregnancy.

Asthma, one of the most common serious medical problems to complicate pregnancy, affects 3-8% of pregnancies in the United States. The goals of therapy in the pregnant asthmatic patient do not differ from those in non-pregnant patients. Inhaled corticosteroids (ICS) are preferred in the management of all levels of persistent asthma in pregnant patients, because these agents have been shown to reduce asthma exacerbations during pregnancy. Asthma in pregnancy is often undertreated due to physician and patient concerns over the effects of asthma medications on the fetus. However, undertreatment leads to loss of asthma control and increases in maternal morbidity, perinatal mortality, preeclampsia, preterm birth, and low birth weight infants. Recent prospective clinical cohort studies with active asthma management by NAEPP guidelines show no evidence of increased maternal or fetal morbidity or mortality. Therefore, it is critical for the mother to understand that failure to control asthma during pregnancy may lead to poor outcomes. A case study follows to highlight clinical pearls and pitfalls in the management of asthma in the pregnant patient.

Absence of oropharyngeal vaccinia virus after vaccinia (smallpox) vaccination.

BACKGROUND: With the resumption of the vaccinia (smallpox) vaccination, questions regarding transmission risk prompted this study to determine whether vaccinia virus could be detected in the oropharynx of adults recently vaccinated with vaccinia (smallpox) vaccine. German, Russian, and American studies on the oropharyngeal presence of vaccinia virus revealed conflicting results in different age groups. OBJECTIVE: To measure vaccinia viral particle or antigen presence in the oropharynx of adult health care workers after vaccination with vaccinia (smallpox) vaccine using viral culture and high-sensitivity assays (polymerase chain reaction [PCR] and electrochemiluminescence) and to determine whether there is an association between the presence of vaccinia virus and adverse reactions. METHODS: A total of 155 adults (primary vaccinees and revaccinees) were enrolled for 1 baseline and 5 subsequent throat swabs. The swabs were evaluated using viral culture, PCR, and electrochemiluminescence. RESULTS: Of the 155 participants, 144 had more than 2 throat swabs in the 2 weeks after vaccination. Of the 801 specimens evaluated, there were no positive results by culture, PCR, or electrochemiluminescence except in the control samples (n = 6), which were positive by all 3 methods. CONCLUSIONS: Based on the absence of detectable vaccinia virus in this study population, one can be 95% certain that the true rate of vaccinia virus in the oropharynx of adults during the 2 weeks after vaccination with vaccinia (smallpox) vaccine is 0% to 3.3%. These data should be reassuring to the medical community and support the Advisory Committee on Immunization Practice guidelines that respiratory precautions are not necessary after vaccinia (smallpox) vaccination in healthy adults.

Airway hyperresponsiveness by methacholine challenge testing following negative exercise challenge.

BACKGROUND: Exercise challenge testing (ECT) to diagnose exercise-induced bronchospasm has been demonstrated to be an insensitive screening test to demonstrate the presence or absence of airway hyperreactivity. Previous studies have not compared this procedure to methacholine challenge testing (MCT) in a clinical setting. OBJECTIVE: To determine the frequency of positive MCT in subjects with exertional dyspnea, normal baseline spirometry, and negative ECT. METHODS: Observational study of 215 military patients at an Army Community Hospital referred for evaluation of exertional dyspnea with normal baseline spirometry. Subjects were further evaluated with ECT on a graded treadmill with pre- and postexercise spirometry. Those without evidence of bronchial hyperreactivity as defined by a 15% decrease in FEV1 postexercise were evaluated with methacholine challenge testing (MCT). RESULTS: Two hundred ten military subjects were evaluated. Eighty-two patients underwent ECT as the only method of bronchoprovocation testing with 25 positive tests (57 were negative but not referred for further testing). The remaining 128 patients with a negative ECT underwent MCT. Seventy-six (59%) had a negative MCT and 52 (41%) had a positive MCT. Of the positive MCT studies, 74% were positive at a methacholine concentration of 2.5 mg/mL or less. CONCLUSIONS: Our study demonstrates that a significant number of patients being evaluated for exertional dyspnea will have a positive MCT after a negative ECT. Our findings lead us to question the utility of ECT as an initial diagnostic test for the exercise-induced bronchospasm.

A novel connexin 26 gene mutation associated with features of the keratitis-ichthyosis-deafness syndrome and the follicular occlusion triad.

We report the case of a congenitally deaf white male with mild palmoplantar keratoderma, ichthyosiform scaling, follicular hyperkeratosis, and mild keratitis, features consistent with keratitis-ichthyosis-deafness syndrome. His major problem was severe, disfiguring, inflammatory dissecting folliculitis of the scalp, hidradenitis suppurativa, and cystic acne, features comprising the follicular occlusion triad. This unusual phenotype is associated with a novel heterozygous point mutation (C119T) in the gap junction beta2 gene that substitutes a valine for alanine at codon 40 (A40V) in the connexin 26 protein. Through Xenopus oocyte expression studies, this mutant protein was shown to significantly disrupt the function of the specialized gap junctions connecting the cytoplasm of adjacent cells critical for tissue homeostasis. Mutations within the connexin 26 protein are associated with syndromes involving both sensorineural deafness and hyperkeratotic skin disorders. This is the first report of an association between a connexin 26 protein mutation, follicular hyperkeratosis of keratitis-ichthyosis-deafness syndrome, and severe follicular occlusion triad.

Adverse reactions to vaccines.

(The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.) Immunization healthcare is becoming increasingly complex as the number and types of vaccines have continued to expand. Like all prescription drugs, vaccines may be associated with adverse events. The majority of these reactions are self-limited and not associated with prolonged disability. The media, Internet and public advocacy groups have focused on potentially serious vaccine-associated adverse events with questions raised about causal linkages to increasing frequencies of diseases such as autism and asthma. Despite a lack of evidence of a causal relationship to a variety of vaccine safety concerns, including extensive reviews by the Institute of Medicine, questions regarding vaccine safety continue to threaten the success of immunization programs. Risk communication arid individual risk assessment is further challenged by the public health success of vaccine programs creating the perception that certain vaccines are no longer necessary or justified because of the rare reaction risk. There is a need for improved understanding of true vaccine contraindications and precautions as well as host factors and disease threat in order to develop a patient specific balanced risk communication intervention. When they occur, vaccine related adverse events must be treated, documented and reported through the VAERS system. The increasing complexity of vaccination health care has led the Center of Disease Control and Prevention (CDC) to identify Vaccine Safety Assessment and Evaluation as a potential new specialty.