The primary ciliary dyskinesia-related genetic risk score is associated with susceptibility to adult-onset asthma.

BACKGROUND: Disturbance of mucociliary clearance is an important factor in the pathogenesis of asthma. We hypothesized that common variants in genes responsible for ciliary function may contribute to the development of asthma with certain phenotypes. METHODS: Three independent adult Japanese populations (including a total of 1,158 patients with asthma and 2,203 non-asthmatic healthy participants) were studied. First, based on the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/), we selected 12 common single-nucleotide polymorphisms (SNPs) with molecular consequences (missense, nonsense, and 3'-untranslated region mutation) in 5 primary ciliary dyskinesia (PCD)-related genes and calculated a PCD-genetic risk score (GRS) as a cumulative effect of these PCD-related genes. Second, we performed a two-step cluster analysis using 3 variables, including PCD-GRS, forced expiratory volume in 1 second (%predicted FEV1), and age of asthma onset. RESULTS: Compared to adult asthma clusters with an average PCD-GRS, clusters with high and low PCD-GRS had similar overall characteristics: adult-onset, female predominance, preserved lung function, and fewer features of type 2 immunity as determined by IgE reactivity and blood eosinophil counts. The allele frequency of rs1530496, a SNP representing an expression quantitative trait locus (eQTL) of DNAH5 in the lung, showed the largest statistically significant difference between the PCD-GRS-High and PCD-GRS-Low asthma clusters (p = 1.4 x 10-15). CONCLUSION: Genes associated with PCD, particularly the common SNPs associated with abnormal expression of DNAH5, may have a certain influence on the development of adult-onset asthma, perhaps through impaired mucociliary clearance.

Deep learning using multilayer perception improves the diagnostic acumen of spirometry: a single-centre Canadian study.

RATIONALE: Spirometry and plethysmography are the gold standard pulmonary function tests (PFT) for diagnosis and management of lung disease. Due to the inaccessibility of plethysmography, spirometry is often used alone but this leads to missed or misdiagnoses as spirometry cannot identify restrictive disease without plethysmography. We aimed to develop a deep learning model to improve interpretation of spirometry alone. METHODS: We built a multilayer perceptron model using full PFTs from 748 patients, interpreted according to international guidelines. Inputs included spirometry (forced vital capacity, forced expiratory volume in 1 s, forced mid-expiratory flow25-75), plethysmography (total lung capacity, residual volume) and biometrics (sex, age, height). The model was developed with 2582 PFTs from 477 patients, randomly divided into training (80%), validation (10%) and test (10%) sets, and refined using 1245 previously unseen PFTs from 271 patients, split 50/50 as validation (136 patients) and test (135 patients) sets. Only one test per patient was used for each of 10 experiments conducted for each input combination. The final model was compared with interpretation of 82 spirometry tests by 6 trained pulmonologists and a decision tree. RESULTS: Accuracies from the first 477 patients were similar when inputs included biometrics+spirometry+plethysmography (95%±3%) vs biometrics+spirometry (90%±2%). Model refinement with the next 271 patients improved accuracies with biometrics+pirometry (95%±2%) but no change for biometrics+spirometry+plethysmography (95%±2%). The final model significantly outperformed (94.67%±2.63%, p<0.01 for both) interpretation of 82 spirometry tests by the decision tree (75.61%±0.00%) and pulmonologists (66.67%±14.63%). CONCLUSIONS: Deep learning improves the diagnostic acumen of spirometry and classifies lung physiology better than pulmonologists with accuracies comparable to full PFTs.

Common exacerbation-prone phenotypes across asthma and chronic obstructive pulmonary disease (COPD).

BACKGROUND AND OBJECTIVES: Chronic inflammatory airway diseases, including asthma and chronic obstructive pulmonary disease (COPD), are complex syndromes with diverse clinical symptoms due to multiple pathophysiological conditions. In this study, using common and shared risk factors for the exacerbation of asthma and COPD, we sought to clarify the exacerbation-prone phenotypes beyond disease labels, and to specifically investigate the role of the IL4RA gene polymorphism, which is related to type 2 inflammation, in these exacerbation-prone phenotypes. METHODS: The study population comprised patients with asthma (n = 117), asthma-COPD overlap (ACO; n = 37) or COPD (n = 48) and a history of exacerbation within the previous year. Cluster analyses were performed using factors associated with both asthma and COPD exacerbation. The association of the IL4RA gene polymorphism rs8832 with each exacerbation-prone phenotype was evaluated by multinomial logistic analyses using non-asthma non-COPD healthy adults as controls (n = 1,529). In addition, the genetic influence of rs8832 was also examined in asthma patients with allergic rhinitis and no history of exacerbation (n = 130). RESULTS: Two-step cluster analyses identified five clusters that did not necessarily correspond to the diagnostic disease labels. Cluster 1 was characterized by high eosinophil counts, cluster 2 was characterized by smokers with impaired lung function, cluster 3 was characterized by the presence of gastroesophageal reflux, cluster 4 was characterized by non-allergic females, and cluster 5 was characterized by allergic rhinitis and elevated total immunoglobulin E levels. A significant association with rs8832 was observed for cluster 5 (odds ratio, 3.88 (1.34-11.26), p = 0.013) and also for the type 2 exacerbation-prone phenotypes (clusters 1 and 5: odds ratio, 2.73 (1.45-5.15), p = 1.9 × 10-3). DISCUSSION: Our results indicated that the clinical heterogeneity of disease exacerbation may reflect the presence of common exacerbation-prone endotypes across asthma and COPD, and may support the use of the treatable traits approach for the prevention of exacerbations in patients with chronic inflammatory airway diseases.

Changes in interpretation of spirometry by implementing the GLI 2012 reference equations: impact on patients tested in a hospital-based PFT lab in a large metropolitan city.

BACKGROUND: The Global Lung Function Initiative (GLI-2012) focused on race/ethnicity as an important factor in determining reference values. This study evaluated the effects of changing from Canadian reference equations developed from an all-Caucasian cohort with European ancestry to the GLI-2012 on the interpretation of spirometry in a multiethnic population and aimed to identify the ethnic groups affected by discrepant interpretations. METHODS: Clinically indicated spirometry in a multiethnic population (aged 20-80 years) collected from 2018 to 2021 was analysed. The predicted and lower limit of normal (LLN) values were calculated using three sets of reference equations: Canadian, GLI-race/ethnic-based (GLI-Race) and GLI-race/ethnic-neutral (GLI-Other). We compared the prevalence of concordance in the abnormal diagnoses (defined as

Expression quantitative trait loci for ETV4 and MEOX1 are associated with adult asthma in Japanese populations.

ETS variant transcription factor 4 (ETV4) is a recently identified transcription factor that regulates gene expression-based biomarkers of asthma and IL6 production in an airway epithelial cell line. Given that ETV4 has not yet been implicated in asthma genetics, we performed genetic association studies of adult asthma in the ETV4 region using two independent Japanese cohorts (a total of 1532 controls and 783 cases). SNPs located between ETV4 and mesenchyme homeobox 1 (MEOX1) were significantly associated with adult asthma, including rs4792901 and rs2880540 (P = 5.63E-5 and 2.77E-5, respectively). The CC haplotype of these two SNPs was also significantly associated with adult asthma (P = 8.43E-7). Even when both SNPs were included in a logistic regression model, the association of either rs4792901 or rs2880540 remained significant (P = 0.013 or 0.007, respectively), suggesting that the two SNPs may have independent effects on the development of asthma. Both SNPs were expression quantitative trait loci, and the asthma risk alleles at both SNPs were correlated with increased levels of ETV4 mRNA expression. In addition, the asthma risk allele at rs4792901 was associated with increased serum IL6 levels (P = 0.041) in 651 healthy adults. Our findings imply that ETV4 is involved in the pathogenesis of asthma, possibly through the heightened production of IL6.

The impact of the COVID-19 pandemic on asthma treatment in Japan: Perspectives based on doctors' views.

The coronavirus disease 2019 (COVID-19) pandemic has had a great influence on medical practice in Japan. In this study, an online questionnaire-based survey was conducted among doctors routinely involved in the treatment of asthma. The questions included in the survey pertained to their thoughts on asthma treatment amidst COVID-19, changes in their clinical approach toward patients with asthma, and the behavioral changes in patients in the pandemic era. The results revealed a significant impact of the pandemic on asthma treatment. Regardless of whether or not they were directly involved in the treatment of patients with COVID-19, the doctors had avoided using nebulizers in outpatient wards/clinics and routine pulmonary function testing. An increase in canceled appointments and inappropriate/non-adherence to treatment among their patients were noticeable. Furthermore, the survey revealed an extensive impact of the pandemic on the doctors engaged in asthma treatment irrespective of the differences in their medical backgrounds.

ORMDL3/GSDMB genotype as a risk factor for early-onset adult asthma is linked to total serum IgE levels but not to allergic sensitization.

BACKGROUND: An orosomucoid-like 3 (ORMDL3)/gasdermin B (GSDMB) gene locus on chromosome 17q is consistently associated with childhood-onset asthma, which is highly atopic. As some evidence suggests the relationship between asthma and allergic sensitization reflects asthma patient susceptibility to augmented IgE responses driven by common environmental allergens rather than an increased asthma risk after allergen exposure, we aimed to determine any relationships between this locus region and childhood-onset adult asthma with regard to serum total IgE levels or allergic sensitization. METHODS: We conducted a case-control association study using three independent Japanese populations (3869 total adults) and analyzed the ORs for association of rs7216389, an expression quantitative trait locus for ORMDL3/GSDMB, with adult asthma according to onset age. Additionally, associations between the rs7216389 genotype and total serum IgE levels or allergic sensitization was examined. RESULTS: Rs7216389 was associated with both childhood-onset adult asthma (OR for asthmatic patients afflicted at the age of 10 years or younger = 1.61, p = 0.00021) and asthmatic patients with higher levels of total serum IgE (OR for asthmatic patients with IgE ≥1000IU/mL = 1.55, p = 0.0033). In both healthy controls and in the combined healthy and asthmatic individuals, rs7216389 was correlated with increased total serum IgE levels (p < 0.0005), but not allergic sensitization (p > 0.1). CONCLUSIONS: ORMDL3/GSDMB is an important susceptibility gene for childhood-onset adult asthma in Japanese populations and this association is linked to elevated total serum IgE levels but not to allergic sensitization.

Genetic impact of CDHR3 on the adult onset of asthma and COPD.

BACKGROUND: Adult-onset asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases caused by complex gene-environment interactions. A functional single nucleotide polymorphism of cadherin-related family member 3 (CDHR3), known as a receptor of rhinovirus-C, is associated with childhood-onset asthma especially in atopic individuals. OBJECTIVE: Here, we identified risk factors for adult-onset asthma and COPD, focusing on the impact of the CDHR3 variant in atopic individuals. METHODS: We conducted a longitudinal, retrospective, observational cohort study of 1523 healthy adults with baseline examinations at Tsukuba Medical Center Hospital in 2008 and retrospectively identified new-onset, physician-diagnosed asthma or COPD from 2009 to 2018. We assessed risk factors by the Cox regression analysis. The impact of CDHR3 variant rs6967330 was also examined in individuals with pre-existing atopy. RESULTS: Over 10 study years, 103 people developed airway diseases (79 asthma and 24 COPD; 52 females, average onset-age 55 years old, range 38-80). Higher body mass index (BMI) and lower forced expiratory volume in one second/forced vital capacity (FEV1 /FVC) ratio were significant risk factors (BMI: HR 1.072 [95% CI 1.005-1.14], P = .034; FEV1 /FVC ratio: HR 1.091 [1.044-1.14], P = .00011). Restriction to atopic individuals saw the A allele at rs6967330 and lower FEV1 /FVC ratio to associate with adult-onset disease (A allele: HR 2.89 [1.57-5.20], P = .00062; FEV1 /FVC ratio: HR 1.10 [1.04-1.17], P = .0010). CONCLUSION AND CLINICAL RELEVANCE: Genetic susceptibility to rhinovirus-C infection in atopic individuals is a risk factor for chronic airway diseases even in later life.

Decision-making factors for best supportive care alone and prognostic factors after best supportive care in non-small cell lung cancer patients.

Among patients with non-small cell lung cancer (NSCLC), best supportive care (BSC) is well-known to improve patient's quality of life and prolong survival. This study aimed to clarify (1) the decision-making factors of BSC alone and (2) the prognostic factors after selection of no further anticancer therapies. We retrospectively reviewed the clinical data of patients with NSCLC between November 2004 and February 2014, who received BSC as only therapy and BSC after completion of anticancer therapies. One hundred eighteen patients received BSC alone. Among 860 patients treated with anticancer therapies, 236 were selected as control group, 160 of whom received BSC after anticancer therapy. The significant reasons for receiving BSC alone were: comorbidities of dementia, poor Eastern Cooperative Oncology Group performance status (ECOG-PS), patients' wishes, pulmonary comorbidities, wild type epidermal growth factor receptor (EGFR), relevant social background and psychiatric comorbidities. Poor prognostic factors at the start of BSC were poor ECOG-PS, presence of disseminated intravascular coagulation (DIC), and history of anticancer therapy. NSCLC patients with comorbidities, wild type EGFR, and relevant social background factors tended to receive BSC alone. Post-cancer therapy NSCLC patients and those with DIC and declining ECOG-PS have a shorter survival period from the start of BSC.

A cis-eQTL allele regulating reduced expression of CHI3L1 is associated with late-onset adult asthma in Japanese cohorts.

BACKGROUND: The chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in patients with asthma. We determined whether cis-expression quantitative trait loci (eQTLs) of the gene that encodes YKL-40, chitinase 3-like 1 (CHI3L1), are involved in the onset of asthma or in specific asthma phenotypes. METHODS: This case-control study, which was conducted at the University of Tsukuba, Japan, included a total of 2709 adults from the Tsukuba genome-wide association study (GWAS) cohort (734 healthy volunteers and 237 asthma patients), the Tsukuba replication cohort (375 healthy adult volunteers and 381 adult asthma patients), and the Hokkaido replication cohort (554 healthy adult volunteers and 428 adult asthma patients). Among 34 cis-eQTLs in CHI3L1 in the lung, rs946261 was associated with adult asthma in these Japanese cohorts. The genetic impact of rs946261 on asthma was also examined according to the age at onset and adult asthma clusters. RESULTS: In the Tsukuba GWAS cohort, the C allele at rs946261 was significantly associated with reduced expression of CHI3L1 mRNA in the lung and with development of asthma (odds ratio (OR) 1.27; P = 0.036). The association was also observed following analysis of the three Japanese cohorts (OR 1.16; P = 0.013). A stronger association was found with late-onset asthma that developed at 41 years of age or later (OR 1.24; 95% confidence interval (CI) 1.07-1.45; P = 0.0058) and with a specific asthma phenotype characterized by late onset, less atopy, and mild airflow obstruction (OR 1.29; 95% CI 1.03-1.61; P = 0.027). CONCLUSIONS: The genotype consisting of the cis-eQTL allele that reduces expression of CHI3L1 was specifically associated with late-onset adult asthma. Given the important role of YKL-40 in many pathophysiological processes, including cell growth, migration, chemotaxis, reorganization, and tissue remodeling, it may be involved in an important pathogenic role in the establishment of inflammation and remodeling in asthmatic airways. Our findings may indicate the presence of a specific endotype related to exaggerated activation of YKL-40 in the pathogenesis of late-onset adult asthma.

Association analyses of eQTLs of the TYRO3 gene and allergic diseases in Japanese populations.

BACKGROUND: TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family and functions to limit type 2 immune responses implicated in allergic sensitization. Recent studies have shown that multiple intronic variants of TYRO3 were associated with asthma, implying that genetic variation could contribute to errant immune activation. We therefore hypothesized that expression quantitative trait loci (eQTLs) of the TYRO3 gene influence the development of allergic diseases (including asthma and allergic rhinitis) in Japanese populations. METHODS: We performed a candidate gene case-control association study of 8 eQTLs of TYRO3 on atopy, asthma, and allergic rhinitis using 1168 unrelated Japanese adults who had GWAS genotyping. We then examined the genetic impact of rs2297377 (TYRO3) on atopy and allergic rhinitis in 2 other independent Japanese populations. RESULTS: A meta-analysis of 3 Japanese populations (a total of 2403 Japanese adults) revealed that rs2297377 was associated with atopy and allergic rhinitis (OR = 1.29 and 1.31; P = 0.00041 and 0.0010, respectively). The risk allele at rs2297377 correlated with decreased expression of TYRO3 mRNA. The gene-gene interaction between HLA-DPB1 and TYRO3 was not significant with regard to sensitization. The estimated proportion of atopy and allergic rhinitis cases attributable to the risk genotype was 14% and 16%, respectively. CONCLUSIONS: Our study identified TYRO3 as an important susceptibility gene to atopy and allergic rhinitis in Japanese.

Pasteurella multocida pneumonia with hemoptysis: A case report.

Pasteurella multocida, which colonizes upper respiratory and digestive tracts, is a leading cause of respiratory diseases in many host species. Here, we describe a case of P. multocida pneumonia with hemoptysis. A 72-year-old female diagnosed with bronchiectasis with a 36-year history presented with a worsened infiltrative and granular shadow in the lower right lobe and lingular segment. Bronchial lavage fluid culturing suggested Pasteurella pneumonia. P. multocida was confirmed by 16S rRNA sequencing. The patient was readmitted to our hospital because of hemoptysis, and she was treated successfully with antibiotic therapy. The possibility of P. multocida infection must be considered in patients who own pets.

Paraneoplastic limbic encephalitis with late-onset magnetic resonance imaging findings: A case report.

Paraneoplastic limbic encephalitis (PLE), a paraneoplastic neurological syndrome (PNS), is a rare nervous system disorder that results from the indirect effects of tumors and is commonly associated with small-cell lung cancer (SCLC). Previous studies have reported that magnetic resonance imaging (MRI) may be useful for diagnosing LE. Temporal lobe abnormalities are observed using T2-weighted and fluid-attenuated inversion recovery sequences; however, such abnormalities are detected in only 60% of patients with PLE. The present study describes a case of PLE associated with SCLC, in which LE was observed using MRI 26 days after the first convulsive seizure. Although the serum and cerebrospinal fluid analyses for onconeural antibodies were negative, the findings of this case indicate that PLE should be considered in the differential diagnosis, and that repeated brain MRI may be more helpful for diagnosis, as the brain MRI findings may be normal during the early stages of PLE.

Genetic association of the functional CDHR3 genotype with early-onset adult asthma in Japanese populations.

BACKGROUND: Recent studies have demonstrated that a coding SNP (rs6967330, Cys529→Tyr) in cadherin-related family member 3 (CDHR3), which was previously associated with wheezing illness and hospitalizations in infancy, could support efficient human rhinovirus C (RV-C) entry and replication. Here, we sought to examine the genetic contribution of this variant to the development of adult asthma. METHODS: We performed a candidate gene case-control association study of 2 independent Japanese populations (a total of 3366 adults). The odds ratios (ORs) for association of the A allele at rs6967330 with adult asthma were calculated according to age at onset of asthma. In addition, the effect of the CDHR3 genotype on the development of specific asthma phenotypes was examined. RESULTS: The A allele was associated with asthma (OR = 1.56; Mantel-Haenszel p = 0.0040) when the analysis was limited to patients with early-onset adult asthma. In addition, when the analysis was limited to atopic individuals, a stronger association of the CDHR3 variant with early-onset asthma was found, and interaction of the CDHR3 genotype with atopy was demonstrated. Finally, a significant association of this variant was specifically found with a phenotype of asthma characterized by atopy, early-onset, and lower lung function. CONCLUSIONS: Our study supports the concept that the CDHR3 variant is an important susceptibility factor for severe adult asthma in individuals who develop the disease in early life. The interaction between the CDHR3 variant and atopy indicates that genetic predisposition to early respiratory viral infection is combined with atopy in promoting asthma.