Causal associations between pediatric asthma and united airways disease: a two-sample Mendelian randomization analysis.

Background: Prior observational research has indicated a potential link between pediatric asthma and united airways disease (UAD). However, these findings could be subject to confounding factors and reverse causation. Therefore, our study utilizes Mendelian randomization (MR) method to further investigate the causal relationship between pediatric asthma and UAD. Methods: We conducted a comprehensive two-sample Mendelian randomization (MR) analysis to investigate the association between pediatric asthma and seven groups of UAD, including chronic sinusitis, chronic rhinitis, nasopharyngitis and pharyngitis, chronic diseases of tonsils and adenoids, chronic laryngitis and laryngotracheitis, chronic bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD). The present study employed a range of methods for two-sample MR analysis, including inverse variance weighted (IVW), MR-Egger regression, Simple mode, weighted median, and weighted models. The conclusion of the MR analysis primarily relies on the IVW results, while other analytical methods are utilized as supplementary evidence to ensure result robustness in this MR analysis. And sensitivity analyses were conducted, including heterogeneity test, horizontal pleiotropy test, MR-PRESSO test, and leave-one-out analysis to validate the results. Results: The results of the MR analysis indicate significant causal effects of pediatric asthma on chronic rhinitis, nasopharyngitis and pharyngitis (IVW: OR = 1.15, 95%CI: 1.05-1.26, p-value = 0.003), chronic diseases of tonsils and adenoids (IVW: OR = 1.07, 95%CI: 1.00-1.15, p-value = 0.038), chronic bronchitis (IVW: OR = 1.51, 95%CI: 1.42-1.62, p-value <0.001), bronchiectasis (IVW: OR = 1.51, 95%CI: (1.30-1.75), p-value <0.001), and COPD (IVW: OR = 1.43, 95%CI: 1.34-1.51, p-value <0.001). However, no significant causal association was observed between pediatric asthma and chronic sinusitis (IVW: OR = 1.00, 95%CI: 1.00-1.00, p-value = 0.085), chronic laryngitis and laryngotracheitis (IVW: OR = 1.05, 95%CI: 0.90-1.21, p-value = 0.558). Conclusion: Our findings support a potential causal relationship between pediatric asthma and UAD, suggesting that pediatric asthma may be a potential risk factor for various UAD.

Sinonasal Symptoms in COPD: Burden and Associations with Clinical Markers of Disease.

Purpose: Sinonasal symptoms are prevalent in COPD, and knowledge of the relationship between these symptoms and clinical markers of COPD is limited. This study explores the associations between the burden of sinonasal symptoms and clinical markers and thresholds recommended for guiding treatment decisions in the GOLD guidelines. Patients and Methods: Sinonasal symptoms were quantified with the rhinological subscale of the Sino-Nasal-Outcome-Test (SNOT-22) in 93 COPD patients characterized by the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) 2012 diagnostic criteria for rhinosinusitis without nasal polyps (RSsNP). Associations between a high burden, defined as a SNOT22_rhinological score of ≥11, and the following markers were assessed by adjusted multivariable linear regressions; severity of dyspnea [modified Medical Research Council (mMRC)] and cough [Visual Analogue Scale (VAS)], physical activity [6-minute walking distance (6MWD)], mortality risk (BODE index), and HRQoL [disease-specific COPD Assessment Test (CAT) and St. Georges Respiratory Questionnaire (SGRQ), and physical component summary, Short Form-36 version 2.0 (PCS SF-36v2)]. Odds ratios for the association of a high burden and threshold levels for regular treatment were estimated by adjusted binomial logistic regression models. Results: A high burden was associated with greater severity of dyspnea and cough, lower 6MWD, higher BODE index and poorer HRQoL. The odds ratio of having CAT and SGRQ scores that are above the thresholds recommended for treatment was 5-7-fold greater in the high burden group. Conclusion: A high burden of sinonasal symptoms is positively associated with the clinical markers of symptom severity and mortality risk and is inversely associated with physical activity and HRQoL in COPD. These findings add further support that the UAD concept also applies to COPD. Enquiry about sinonasal symptoms in COPD patients should be incorporated into the clinical routine.

Management of United Airway Disease Focused on Patients With Asthma and Chronic Rhinosinusitis With Nasal Polyps: A Systematic Review.

BACKGROUND: The clinical approach to upper and lower respiratory diseases from a joint perspective, known as united airways disease (UAD), is challenging for health care professionals owing to a paucity of specific studies. OBJECTIVE: This study reviews recent scientific evidence on the management of asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) from a UAD perspective. METHODS: A systematic search of PubMed, Scopus, and Web of Science was conducted for 9 research questions, and studies published from January 2015 to July 2021 were included. Quality assessment was performed with the Critical Appraisal Skills Programme. RESULTS: In total, 32 publications met the inclusion criteria. Control of type 2 inflammation in UAD (reported in 9 studies) was associated with biologic therapies, for which an impact on asthma, CRSwNP, and/or aspirin/nonsteroidal anti-inflammatory drug-exacerbated respiratory disease outcomes was described in 9 studies. However, there was a lack of scientific evidence on clinical and/or biochemical markers associated with response to biologics in patients with UAD. The benefit on corticosteroid reduction in patients receiving biologics was reported in 9 studies. Three publications reported a positive impact of surgery on asthma and/or CRSwNP outcomes, and the effect of biologics on reducing the need of surgery was consistent across 6 studies. CONCLUSIONS: Our results underscore an overall scarcity of scientific evidence on the treatment strategies for these frequent coexisting entities from an UAD approach but also identify several research gaps and unmet needs that should be addressed to ensure optimal diagnosis, management, and follow-up of these patients.

Precision medicine in united airways disease: A "treatable traits" approach.

United airways disease (UAD) is the concept that the upper and lower airways, which are anatomically and immunologically related, form a single organ. According to this concept, upper and lower airway diseases are frequently comorbid because they reflect manifestations of a single underlying disease at different sites of the respiratory tract. Allergic asthma-allergic rhinitis is the archetypal UAD, but emerging data indicate that UAD is a heterogeneous condition and consists of multiple phenotypes (observable clinical characteristics) and endotypes (pathobiologic mechanisms). The UAD paradigm also extends to myriad sinonasal diseases (eg, chronic rhinosinusitis with or without nasal polyps) and lower airway diseases (eg, bronchiectasis, chronic obstructive pulmonary disease). Here, we review currently known phenoendotypes of UAD and propose a "treatable traits" approach for the classification and management of UAD, wherein pathophysiological mechanisms and factors contributing to disease are identified and targeted for treatment. Treatable traits in UAD can be analyzed according to a framework comprising airway inflammation (eosinophilic, neutrophilic), impaired airway mucosal defense (impaired mucociliary clearance, antibody deficiency), and exogenous cofactors (allergic sensitizers, tobacco smoke, microbes). Appreciation of treatable traits is necessary in advancing the effort to deliver precise treatments and achieve better outcomes in patients with UAD.

Occupational rhinitis and occupational asthma: Association or progression?

BACKGROUND: Occupational asthma is the most frequently reported occupational respiratory disease in registries, and is often co-diagnosed with occupational rhinitis. We undertook a systematic review of the English-language epidemiologic literature linking these two conditions, with emphasis on progression from occupational rhinitis to occupational asthma. METHODS: PubMed and Embase were queried in a series of structured searches designed to identify studies comparing occupational asthma and occupational rhinitis incidence or prevalence in occupationally exposed individuals. RESULTS: The searches yielded a total of 109 unique citations, 15 of which yielded inferential data on the occupational rhinitis-asthma relationship. Nine of fifteen studies showed statistically significant associations between the occurrence of occupational rhinitis and occupational asthma among individual workers. CONCLUSIONS: Limited data support the notion that occupational rhinitis precedes the development of occupational asthma, particularly when high-molecular-weight (HMW) agents are involved. The relationship between the two conditions could not be evaluated in many relevant studies due to a lack of cross-tabulation of individual cases.

MicroRNA in United Airway Diseases.

The concept of united airway diseases (UAD) has received increasing attention in recent years. Sustained and increased inflammation is a common feature of UAD, which is inevitably accompanied with marked gene modification and tight gene regulation. However, gene regulation in the common inflammatory processes in UAD remains unclear. MicroRNA (miRNA), a novel regulator of gene expression, has been considered to be involved in many inflammatory diseases. Although there are an increasing number of studies of miRNAs in inflammatory upper and lower airway diseases, few miRNAs have been identified that directly link the upper and lower airways. In this article, therefore, we reviewed the relevant studies available in order to improve the understanding of the roles of miRNAs in the interaction and pathogenesis of UAD.

The risk of respiratory symptoms on allergen exposure increases with increasing specific IgE levels.

BACKGROUND: The relation between IgE sensitization and allergic respiratory symptoms has usually been evaluated by dichotomizing specific IgE levels. The aim of this study was to evaluate the association between specific IgE levels and risk of symptoms on allergen-related exposure, with special reference to allergen-related asthma-rhinitis comorbidity. METHODS: We considered 6391 subjects enrolled within the European Community Respiratory Health Survey 2, having information on cat/grass/D. pteronyssinus IgE levels and symptoms on exposure to animals/pollen/dust. The risk of oculonasal/asthmalike/both symptoms was evaluated by a multinomial logistic model. RESULTS: A clear positive association was observed between specific IgE levels to cat/grass/mite and the risk of symptoms on each allergen-related exposure (test for trend with P < 0.001). This trend was particularly pronounced when considering the coexistence of asthmalike and oculonasal symptoms. Compared to non-sensitized subjects, subjects with specific IgE to cat >= 3.5 kU/l presented relative risk ratios of 11.4 (95% CI 6.7-19.2), 18.8 (8.2-42.8), and 55.3 (30.5-100.2) when considering, respectively, only oculonasal symptoms, only asthmalike symptoms, or both. A similar pattern was observed when considering specific IgE to grass/mite and symptoms on exposure to pollen/dust. Also the proportion of people using inhaled medicines or visiting a general practitioner for breathing problems in the previous year increased with increasing sum of specific IgE to cat/grass/mite. CONCLUSION: Specific IgE level is the most important predictor of allergen-related symptoms. The risk of both oculonasal/asthmalike symptoms increases with specific IgE levels, suggesting that specific IgE contributes to the 'united airways disease'.