Sex, Ethnicity, Body Mass Index, and Environmental Exposures Associated With NSAID-Exacerbated Respiratory Disease Symptom Sequence.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) has a triad of symptoms: nasal polyposis, asthma, and NSAID hypersensitivity. Little is known about symptom timing and disease progression. OBJECTIVE: The aim of this study is to characterize disease progression in N-ERD. METHODS: Patients with N-ERD were prospectively interviewed and classified into 4 groups based on their first symptom at initial N-ERD onset (asthma, nasal polyps, NSAID hypersensitivity, or all concurrently). Associations of patient characteristics with the 4 groups were examined, along with associations within the "asthma first" group. RESULTS: Patients (N = 240) were mostly female (68%) and self-identified as non-White (77%). Half (N = 119) reported asthma as the earliest symptom in the N-ERD triad. Compared with other groups, "asthma first" was associated with younger age of onset (25 years, standard error ±1.3, P < .001) and higher body mass index (BMI) (odds ratio [OR] = 1.3, 95% confidence interval [CI]: 1.06-1.7, P = .02). In this group, age of onset <20 years was associated with female sex, Latino ethnicity, and higher BMI (all P < .05). The "NSAID sensitivity first" group was significantly associated with male sex (OR = 3.3, 95% CI: 1.5-7.4, P = .004) and pollution exposure (OR = 4.4, 95% CI: 1.6-11.9, P = .003). At the initial presentation, 27% of patients were unaware of their N-ERD diagnosis. Black and Latino patients were more likely to be unaware of their N-ERD diagnosis compared with White (P = .003). The median diagnostic delay was 3 years (interquartile range: 0-5 years). CONCLUSIONS: In this cohort, N-ERD is highly variable in onset and progression, with sex, BMI, race and ethnicity, and environmental exposures significantly associated with disease patterns and diagnostic delay.

Inflammatory characteristics of central compartment atopic disease.

BACKGROUND: Central compartment atopic disease (CCAD) is an emerging phenotype of chronic rhinosinusitis with nasal polyposis (CRSwNP) characterized by prominent central nasal inflammatory changes. This study compares the inflammatory characteristics of CCAD relative to other phenotypes of CRSwNP. METHODS: A cross-sectional analysis of data from a prospective clinical study was performed on patients with CRSwNP who were undergoing endoscopic sinus surgery (ESS). Patients with CCAD, aspirin-exacerbated respiratory disease (AERD), allergic fungal rhinosinusitis (AFRS), and non-typed CRSwNP (CRSwNP NOS) were included and mucus cytokine levels and demographic data were analyzed for each group. Chi-squared/Mann-Whitney U tests and partial least squares discriminant analysis (PLS-DA) were performed for comparison and classification. RESULTS: A total of 253 patients were analyzed (CRSwNP, n = 137; AFRS, n = 50; AERD, n = 42; CCAD, n = 24). Patients with CCAD were the least likely to have comorbid asthma (p = 0.0004). The incidence of allergic rhinitis in CCAD patients did not vary significantly compared to patients with AFRS and AERD, but was higher compared to patients with CRSwNP NOS (p = 0.04). On univariate analysis, CCAD was characterized by less inflammatory burden, with reduced levels of interleukin 6 (IL-6), IL-8, interferon gamma (IFN-γ), and eotaxin relative to other groups and significantly lower type 2 cytokines (IL-5, IL-13) relative to both AERD and AFRS. These findings were supported by multivariate PLS-DA, which clustered CCAD patients into a relatively homogenous low-inflammatory cytokine profile. CONCLUSIONS: CCAD has unique endotypic features compared to other patients with CRSwNP. The lower inflammatory burden may be reflective of a less severe variant of CRSwNP.

Inheritance of NSAID-Exacerbated Respiratory Disease.

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) has been considered an acquired condition. Positive first-degree family history has been reported in 1% of cases. The geographic and genetic isolation of the Finnish population offers exceptional opportunities for inheritance studies. In this questionnaire study, we explored the familial aggregation of N-ERD in 66 Finnish families of patients with N-ERD. The majority of patients (67%) had a positive family history of NSAID intolerance, asthma, nasal polyposis, or N-ERD. Furthermore, 55% had a positive first-degree family history of asthma, 21% nasal polyposis, 20% NSAID intolerance, and 11% N-ERD. The prevalence of asthma, nasal polyposis, NSAID intolerance, and N-ERD among first-degree relatives was 13%, 5%, 4%, and 2%, respectively. We present the pedigrees of the 44 affected families. According to our findings, Finnish patients with N-ERD seem to have a genetic susceptibility to it.

Loss of smell in patients with aspirin-exacerbated respiratory disease impacts mental health and quality of life.

BACKGROUND: The impact of anosmia on quality-of-life (QoL) for patients with aspirin-exacerbated respiratory disease (AERD) is poorly understood. We aimed to investigate how the severity of smell loss and olfactory dysfunction (OD) in patients with AERD affects their QoL, mental health and physical well-being. METHODS: Five validated QoL questionnaires (Sinonasal Outcome Test-22, Asthma Control Test, Healthy Days Core Module-4, Short Form-36 and Patient Health Questionnaire-4) and two newly developed questionnaires assessing severity and consequences of OD were electronically sent to all 2913 patients in the Brigham and Women's Hospital AERD registry. Responses were received from 853 participants for analysis. RESULTS: Overall, 85% of participants reported a present diminished sense of smell and/or taste, and 30% categorized their OD severity was, "as bad as it can be." There were significant relationships between the severity of self-reported OD and both psychological distress and general health scores, even after adjusting for asthma control. Additionally, incidence rates for physically and mentally unhealthy days in the prior month were higher for patients with moderate or severe OD than for normosmic patients. Patients with diminished smell responded that they could not identify spoiled food (86%), did not enjoy food (71%), felt unsafe (63%) and had encountered dangerous situations (51%) as consequences of their OD. CONCLUSIONS: Anosmia and hyposmia severely impact the physical, emotional and mental health of AERD patients, and lead to safety concerns in their daily lives. The importance of olfaction and the relevance of OD to patients' QoL should be acknowledged and evaluated by clinicians caring for these patients.

Updates on treatment options in aspirin exacerbated respiratory disease.

PURPOSE OF REVIEW: The aim is to describe why this review is timely and relevant. Acetylsalicylic acid exacerbated respiratory disease (AERD) is a clinically significant disease affecting approximately 7% of all asthmatics or around 1,400,000 persons in the United States alone. A large portion of these patients remain undiagnosed. This review summarizes up to date knowledge on the pathophysiology, treatment opinions and provides an expert opinion on how to approach the AERD patient. RECENT FINDINGS: Findings describe the main themes in the literature covered by the article. Review of the current knowledge in terms of the key cells, cytokines/chemokines contributing to the acquired disease state of AERD. It also provides clinical approach toward the AERD patient with regards to current treatment options. SUMMARY: Summary describes the implications of the findings for clinical practice or research. This is an up-to-date review of the current literature, with insight into how to approach the management of an AERD patient.

Risk factors for severe adult-onset asthma: a multi-factor approach.

BACKGROUND: The aim was to identify risk factors for severe adult-onset asthma. METHODS: We used data from a population-based sample (Adult Asthma in Finland) of 1350 patients with adult-onset asthma (age range 31-93 years) from Finnish national registers. Severe asthma was defined as self-reported severe asthma and asthma symptoms causing much harm and regular impairment and ≥ 1 oral corticosteroid course/year or regular oral corticosteroids or waking up in the night due to asthma symptoms/wheezing ≥ a few times/month. Sixteen covariates covering several domains (personal characteristics, education, lifestyle, early-life factors, asthma characteristics and multiple morbidities) were selected based on the literature and were studied in association with severe asthma using logistic regressions. RESULTS: The study population included 100 (7.4%) individuals with severe asthma. In a univariate analysis, severe asthma was associated with male sex, age, a low education level, no professional training, ever smoking, ≥ 2 siblings, ≥ 1 chronic comorbidity and non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) (p < 0.05), and trends for association (p < 0.2) were observed for severe childhood infection, the presence of chronic rhinosinusitis with nasal polyps, and being the 1st child. The 10 variables (being a 1st child was removed due to multicollinearity) were thus entered in a multivariate regression model, and severe asthma was significantly associated with male sex (OR [95% CI] = 1.96 [1.16-3.30]), ever smoking (1.98 [1.11-3.52]), chronic comorbidities (2.68 [1.35-5.31]), NERD (3.29 [1.75-6.19]), and ≥ 2 siblings (2.51 [1.17-5.41]). There was a dose-response effect of the total sum of these five factors on severe asthma (OR [95% CI] = 2.30 [1.81-2.93] for each one-unit increase in the score). CONCLUSIONS: Male sex, smoking, NERD, comorbidities, and ≥ 2 siblings were independent risk factors for self-reported severe asthma. The effects of these factors seem to be cumulative; each additional risk factor gradually increases the risk of severe asthma.

FASE-CPHG Study: identification of asthma phenotypes in the French Severe Asthma Study using cluster analysis.

BACKGROUND: In France, data regarding epidemiology and management of severe asthma are scarce. The objective of this study was to describe asthma phenotypes using a cluster analysis in severe asthmatics recruited in a real world setting. METHODS: The study design was prospective, observational and multicentric. The patients included were adults with severe asthma (GINA 4-5) followed-up in French Non Academic Hospital between May 2016 and June 2017. One hundred and seven physicians included 1502 patients. Both sociodemographic and clinical variables were collected. Hierarchical cluster analysis was performed by the Ward method followed by k-means cluster analysis on a population of 1424 patients. RESULTS: Five clusters were identified: cluster 1 (n = 690, 47%) called early onset allergic asthma (47.5% with asthma before 12 years), cluster 2 (n = 153, 10.5%): obese asthma (63.5% with BMI > 30 kg/m2), cluster 3 (n = 299, 20.4%): late-onset asthma with severe obstructive syndrome (89% without atopy), cluster 4 (n = 143, 9.8%): eosinophilic asthma (51.7% had more than 500 eosinophils/mm3), and cluster 5 (n = 139, 9.5%): aspirin sensitivity asthma (63% had severe asthma attacks). CONCLUSIONS: In our population of adults with severe asthma followed by pulmonologists, five distinct phenotypes were identified and are quite different from those mentioned in previous studies.

Treatment Outcomes in Aspirin-Exacerbated Respiratory Disease Based on the 12-Item Short Form Survey.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is optimally managed by endoscopic sinus surgery (ESS) followed by aspirin therapy after desensitization (ATAD). Most AERD quality of life (QOL) studies use the 22-item Sinonasal Outcomes Test (SNOT-22), which focuses predominantly on sinonasal outcomes. OBJECTIVE: This study seeks to assess QOL outcomes in AERD patients after ESS and ATAD via the 12-item Short Form Survey (SF-12), a well-validated QOL measure for general health status of chronic conditions. METHODS: Retrospective review of 112 AERD patients who underwent ESS followed by ATAD at our institution between 2016 and 2019. SF-12 was collected preoperatively, postoperatively/pre-AD, and serially post-AD (1-3, 4-6, 7-12, and >12 months). Optum® PRO CoRE software was used to compare data to national norms. ANOVA was performed comparing physical component summary (PCS), mental component summary (MCS) and eight health domains (physical functioning, role physical, general health, bodily pain, vitality, social functioning, role emotional, and mental health). RESULTS: AERD patients showed improvement in PCS scores across all timepoints after ESS and ATAD (p = 0.004). When stratified by gender, women demonstrated an improvement in PCS scores (p = 0.004). Within the domains, there were significant improvements in social functioning (SF), role physical (RP), and bodily pain (BP) at all timepoints (SF: p = 0.006; RP: p = 0.005; BP: p < 0.001). CONCLUSIONS: AERD patients undergoing ESS and ATAD show improvement in physical QOL and 3 of the 8 health domains as measured by the SF-12. Future studies can use the SF-12 to study the impact of AERD treatment versus other chronic diseases and health demographics.

Symptom Control of Patients With Chronic Rhinosinusitis With Nasal Polyps Under Maintenance Therapy With Daily Acetylsalicylic Acid.

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAID)-exacerbated respiratory disease (NERD) is defined by intolerance to cyclooxygenase 1 inhibitors, chronic rhinosinusitis with recurrent nasal polyps, and/or intrinsic bronchial asthma. Long-term administration of acetylsalicylic acid (ASA) after desensitization has been used to mitigate these sequelae, but the optimal dose and balancing symptom relief and side effects remain unsettled. METHODS: Retrospective data analysis of 85 patients with NERD receiving maintenance therapy of 300 mg ASA was followed by questionnaires (our own, not validated and the Sino-Nasal Outcome Test-20). We received responses from 55 patients and examined 30 of them clinically. RESULTS: Patients with no ASA-associated side effects were 56.4% (56 of 85 patients) of the cohort. In this study, 60% (33 of 55 patients) continued prophylaxis of 300 mg ASA daily for an average of 34.7 months. Elective surgery was the most frequent cause of discontinuation of ASA (21.8%; 12 of 55 patients). Rhinomanometry values were significantly improved with ASA (P < .05; Wilcoxon), but there was no significant reduction in nasal polyposis or improvement in olfaction at the time of follow-up examination. CONCLUSIONS: Minor clinical improvements were identified. Side effects were well tolerated by most patients, and no serious sequelae occurred. The indications for long-term ASA therapy in NERD patients remain unsettled.

Aspirin-exacerbated respiratory disease: longitudinal assessment of a large cohort and implications of diagnostic delay.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) refers to the combination of asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), and acute respiratory tract reactions to ingestion of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). There have been no in the literature investigating diagnostic delay in AERD. We aimed to investigate whether delay of diagnosis of AERD is associated with poorer clinical outcomes as well as to characterize the role of specialty evaluation in diagnosis. METHODS: We conducted a retrospective observational study of 254 subjects with incident AERD diagnoses between 2009 and 2016 among Kaiser Permanente Northern California (KPNC) members. Descriptive and bivariate statistics were employed to analyze clinical characteristics and outcomes of AERD subjects with and without delay in diagnosis (defined as 1 year or greater from symptom onset to diagnosis). RESULTS: Of the 254 patients in the AERD cohort, 24.4% had a delayed diagnosis. Patients with allergies were significantly less likely to have a delay in diagnosis (p < 0.01). Patients with a delay in diagnosis were more likely to have 2 or more courses of systemic steroids (p = 0.04). Allergists, otolaryngologists, and primary care physicians diagnosed 56%, 36%, and 8% of patients, respectively. There was no association between provider specialty at time of diagnosis and delay in diagnosis (p = 0.22). CONCLUSION: A substantial proportion of AERD patients have a diagnostic delay. Patients with allergies have a lower risk for this delay. This study is the first to describe diagnostic delay in AERD patients.

Perimenstrual Asthma in Aspirin-Exacerbated Respiratory Disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a condition of the upper and lower respiratory tract characterized by reactions to nonsteroidal anti-inflammatory drugs. The Severe Asthma Research Program reported a strong association between perimenstrual asthma (PMA) and aspirin-sensitive asthma. OBJECTIVE: To evaluate the prevalence and characteristics of PMA among a cohort of patients with AERD. METHODS: Women 18 years and older enrolled in the Brigham and Women's AERD registry were surveyed about their reproductive, asthma, and sinus history. Subjects reporting the development of asthma before menopause were included. Continuous and categorical variables were compared between those reporting menstruation as a trigger for asthma symptoms and those who did not. Covariates expected a priori to have a positive effect on the odds of PMA were included in a multivariate logistic regression model to test associations between PMA and clinical factors. RESULTS: Among females of childbearing potential, 369 of 695 responded to the survey and 322 met inclusion criteria. Twenty-four percent of subjects (n = 74) reported PMA. Earlier age of AERD onset, concurrent worsening of sinus symptoms the week before or during menstruation, increased emergency department visits for asthma, and a change in the severity of respiratory symptoms at menopause were more common in PMA. Earlier age at first nonsteroidal anti-inflammatory drug-induced respiratory reaction and emergency department visits increased the odds of reporting PMA. CONCLUSIONS: PMA and increased sinus symptoms with menstruation are common in females with AERD. Females with AERD should be counseled about upper and lower respiratory symptom deterioration with menstruation.

Association of air pollutants, airborne occupational exposures, and chronic rhinosinusitis disease severity.

BACKGROUND: Previous work has shown that chronic rhinosinusitis (CRS) severity may be associated with particulate matter 2.5 (PM2.5 ) and black carbon (BC) in CRS patients without nasal polyps (CRSsNP). Data regarding occupational exposures, however, are lacking. We assessed the impact of PM2.5 , BC, as well as occupational airborne exposure on CRS disease severity. METHODS: Patients with CRS with nasal polyps (CRSwNP), CRSsNP, and aspirin-exacerbated respiratory disease (AERD) were identified from an institutionwide database. Spatial modeling from 37 pollutant monitoring sites in Allegheny County was used to estimate exposures. Patient occupations using the 2010 Standard Occupation Classification (SOC10) and airborne occupation exposures to vapors, gases, dusts, fumes, fibers and mists (VGDFFiM) or diesel fumes were recorded. Disease severity was measured by modified Lund-Mackay score (LMS), systemic corticosteroid therapy, and incidence of functional endoscopic sinus surgery (FESS). RESULTS: Two hundred thirty-four patients were included (CRSwNP, n = 113; CRSsNP, n = 96; AERD, n = 25). The prevalence of AERD among those with CRSwNP was 18%. Patients exposed to VGDFFiM or diesel fumes required higher steroid doses vs nonexposed patients (p = 0.015 and p = 0.03, respectively); patients with VGDFFiM levels >5% were more likely to undergo FESS vs nonexposed patients (p = 0.0378). There was no difference in PM2.5 and BC with regard to disease severity and FESS between CRSwNP, CRSsNP, and AERD patients. Steroid use was significantly higher in CRSwNP and AERD vs CRSsNP (p = 0.001). LMS was significantly higher in AERD as compared with CRSwNP and CRSsNP (p = 0.001). CONCLUSION: Occupational airborne exposure to VGDFFiM correlated with increased prevalence of FESS and need for corticosteroids in CRS patients. There was no difference in PM2.5 and BC levels and disease severity outcome measures between CRS subtypes in this subset.

Central compartment involvement in aspirin-exacerbated respiratory disease: the role of allergy and previous sinus surgery.

BACKGROUND: Evidence for a relationship between allergy and chronic rhinosinusitus with nasal polyps (CRSwNP) is equivocal. Central compartment (CC) atopic disease is a nasal inflammatory condition related to inhalant allergy. CC involvement is common in aspirin-exacerbated respiratory disease (AERD), a subset of CRSwNP, and we hypothesize it is related to allergic status. METHODS: This study was a retrospective analysis of a single-institution database for the January 2016 to February 2019 time period. Data regarding endoscopic CC findings, clinical allergy history, and results of allergy testing were collected. Statistical analysis was performed, with significance set at p < 0.05. RESULTS: Seventy-two AERD patients met the inclusion criteria. Fifty-nine patients had CC involvement (53 bilateral, 6 unilateral). For patients with documented allergy status, 100% of patients with endoscopic CC disease had clinical allergic rhinitis (AR), and 45 of 48 (93.8%) had positive allergy testing. Thirteen patients had no CC involvement (4 with clinical AR; 3 of 7 with positive allergy testing). CC endoscopic findings in AERD were significantly associated with clinical allergy (p < 0.0001, phi = 0.771). Overall, patients with CC involvement averaged 3.8 surgeries vs 3.2 for those without CC involvement (p = not statistically significant). However, patients with septal involvement averaged 4.2 surgeries vs 2.0 for those without septal involvement (p = 0.004). As the number of sinus surgeries increases, middle turbinate (MT) resection (r = 0.300, p = 0.022) and septal involvement (r = 0.372, p = 0.004) significantly increase. All patients with MT resection had septal disease, whereas none without CC disease had MT resection. CONCLUSION: Most AERD patients exhibit AR, and this correlates with CC disease. As the number of surgeries increases, MT resection may predispose to polyposis of the septum.