Kim, H.J.

Abstract RATIONALE: Significant sex differences exist in the prevalence and severity of asthma across the lifespan. Asthma is more prevalent and severe in pubescent boys compared to girls but worse in girls and women after puberty. The transition to menopause brings significant reductions in estrogen and progesterone levels. In this study, we test the hypothesis that the effect of menopause on asthma prevalence and outcomes is modified by the use of female sex hormones. METHODS: We used data from nine two-year cycles (1999-2000 to 2015-2016) from NHANES to determine the association between menopause and asthma outcomes. We defined severe asthma based on GINA treatment classes 4&5. We used analytic sample weights to compute national estimates according to NHANES guidelines. Adult (age >18 years) women were considered to be menopaused if (1) they reported to be menopaused during the NHANES survey, (2) they had bilateral oophorectomy, or (3) they were ≥52 years. Weighted logistic regression analyses were used to adjust for age, race, body mass index (BMI), smoking, blood eosinophil count, female hormone therapy, and oral contraceptives. Analyses were performed using the SURVEY package in R. RESULTS: The cohorts’ clinical characteristics are listed in table 1. Compared to pre-menopause (weighted n=60,394,897), menopause (weighted n=52,364,594) was associated with higher rates of active asthma (9.2 vs. 8.9%, p=0.004) and severe asthma (5% vs. 1.8%, p<0.001), but not lifetime asthma (15.1 vs. 16.3%, p=0.063). Notably, postmenopausal women had higher BMIs (weighted median [IQR]: 28.1 [24.2-33.1] vs. 26.1 [22.6-32.1], p<0.001), longer asthma durations (weighted median [IQR]: 20.0 [7.0-41.0] vs. 15.0 [8.0-24.0], p<0.001), and lower lung functions (p<0.001) (table 1). Adjusted analysis did not show significant associations between menopause and lifetime asthma (adjusted OR, 1.074; 95% CI, 0.901-1.280), active asthma (adjusted OR, 1.072; 95% CI, 0.865-1.328), or severe asthma (adjusted OR, 1.369; 95% CI, 0.958-1.954). Interestingly, a history of female hormone therapy and oral contraceptives use was associated with a higher risk of lifetime asthma (adjusted OR, 1.191; 95% CI, 1.031-1.375 and adjusted OR, 1.287; 95% CI, 1.169-1.417 respectively). Among women with active asthma, menopause was not associated with non-severe exacerbations (adjusted OR, 1.335; 95% CI, 0.883-2.021) or with severe exacerbations requiring ER visits (adjusted OR, 1.416; 95% CI, 0.818-2.451). Conclusion: The increased prevalence of active asthma and severe asthma among menopausal women can largely be attributed to age-related changes, comorbidities, and hormone therapy use rather than menopause alone.

Abstract RATIONALE: Women are more likely to develop asthma after puberty, and their symptoms can fluctuate during the menstrual cycle, pregnancy, and menopause. Menopausal women with asthma face unique challenges, as hormonal fluctuations during this stage can impact respiratory health. About one-third of women undergo hysterectomy before age 60, with most procedures occurring before natural menopause. While half of these surgeries preserve the ovaries, the other half include oophorectomy, creating distinct hormonal environments. Despite the traditional view of the uterus as hormonally inactive, there remains a critical gap in our understanding of the potential impact of hysterectomy on respiratory health.METHODS: We used data from nine two-year cycles (1999-2000 to 2015-2016) from NHANES to determine the association between hysterectomy and asthma phenotypes. Severe asthma was defined based on GINA treatment classes 4&5. Analytic sample weights were used according to published NHANES guidelines to create national estimates. Asthma status (lifetime, active, severe) was obtained for women without (weighted n=90,348,593) or with a history of hysterectomy (weighted n=22,310,898). Weighted logistic regression analyses were used to determine the impact of hysterectomy on asthma prevalence, severity, exacerbations, and asthma-related emergency room (ER) visits adjusting for age, race, body mass index (BMI), smoking history, blood eosinophil count, a history of unilateral or bilateral oophorectomy, female hormone therapy, and oral contraceptive use. Analyses were performed using the SURVEY package in R.RESULTS: Clinical characteristics of women with and without a history of hysterectomy are listed in Table 1. Overall, hysterectomy was associated with higher asthma prevalence (18.1 vs. 15.1%) and severity (5.1 vs. 2.9%). For all women, hysterectomy was associated with a higher risk for lifetime asthma (adjusted OR, 1.262; 95% CI, 1.1079-1.477) but not for active asthma (adjusted OR, 1.146; 95% CI, 0.93-1.412) or severe asthma (adjusted OR, 0.996; 95% CI, 0.748-1.325). Interestingly, oophorectomy was associated with a higher risk for lifetime asthma (adjusted OR, 1.228; 95% CI, 1.102-1.368 for unilateral; adjusted OR, 1.232; 95% CI, 1.232-1.513 for bilateral) and active asthma (adjusted OR, 1.417; 95% CI, 1.232-1.629 for unilateral; adjusted OR, 1.507; 95% CI, 1.143-1.986 for bilateral). Among women with active asthma, hysterectomy was associated with severe exacerbations requiring ER visits (adjusted OR, 1.845; 95% CI, 1.157-2.941) but not with non-severe exacerbations (adjusted OR, 1.176; 95% CI, 0.811-1.705).CONCLUSIONS: This study highlights the influence of hysterectomy on asthma risk and severity and emphasizes the role of female hormones in asthma pathogenesis.

Abstract Primary ciliary dyskinesia (PCD) results from mutations in over 50 genes that affect motile cilia (PMID: 29905515). PCD incidence is at least 1:7600 (PMID: 35051411). Asthma may be a PCD comorbidity (PMID: 36431268); and antigen stasis on the airway surface in PCD may predispose to asthma (PMID: 3831866). Methods. We analyzed the association between PCD and asthma in children ≤ 18 years old in two large electronic health record (EHR)-based databases: the Indiana Network for Patient Care Research (INPCR) cohort of 20 million EHRs and, in a validation cohort, TriNetX, with 112 million EHRs. We needed to address two issues. First, there is no ICD 10 code for PCD. Secondly, clinicians may confuse asthma and PCD in assessment. Therefore, we analyzed two diagnoses that, together, are unlikely to occur together in the absence of PCD: bronchiectasis (ICD10:J47) and situs inversus totalis (Q89.3) together (B-SIT). We asked whether subjects with B-SIT also had an asthma diagnosis ( ICD10 J45). We matched cases to controls, 1:3 in INPCR; and 1:1 in TriNetX, controlling for age, sex and race. We used conditional logistic regression adjusted for the matching strategy. For INPCR, we performed a conditional exact test: numbers were too small for adjusted models. This study was approved by the Indiana University and Case Western Reserve University IRBs. Results. In the initial INPCR study, 100% of children with B-SIT had an asthma diagnosis (p < 0.001). In the TriNetX validation cohort (Matched 1:1, n = 115 each), 84 children with B-SIT had asthma and 31 did not; in the controls, 12 had asthma and 103 did not (p = 2.2 x 10-16). The adjusted OR for B-SIT patients having asthma was 22.26 (95%CI: 10.80 – 45.91; p <0.001). Discussion. In two large EHR data sets, we found that most children with likely PCD (B-SIT) had a diagnosis of asthma. Local antigen stasis in PCD could contribute to the asthma phenotype in PCD, or perhaps even to asthma among patients heterozygous for PCD genes (PMID: 38457400). Additional studies are needed to understand the immunology, and this study is that it will need to be validated prospectively using airway reactivity testing after drug with-hold. In summary, children with PCD may need evaluation for airway reactivity. Further, providers should be alert to whether there are cardinal features of PCD among any of the children cared for with a diagnosis of asthma.