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Asthma is a chronic inflammatory airway disease characterized by bronchial hyperresponsiveness and reversibility. Despite considerable advances in asthma treatment based on our understanding of its pathophysiology, asthma exacerbations remain challenging. To reduce asthma exacerbations, it is essential to identify triggers, patients' risk factors, and underlying mechanisms. While exposure to viruses and environmental stimuli are known common triggers for asthma exacerbations, the key factors involved in asthma exacerbations have been identified as type 2 inflammation. Type 2 inflammatory biomarkers have been demonstrated to be useful in predicting individuals at risk of exacerbations. Furthermore, recent clinical trials of targeted biological therapy, which blocks the type 2 pathway, have supported the critical role of type 2 inflammation in asthma exacerbations. Although the specific mechanisms linking type 2 inflammation to asthma exacerbations have not yet been fully elucidated, increasing evidence shows that reduction/oxidation (redox) imbalance likely plays an important role in this association. Under type 2 inflammatory conditions, human airway epithelial cells activate 15-lipoxygenase-1 in complex with phosphatidylethanolamine binding protein-1, leading to the generation of electrophilic hydroperoxyl-phospholipids. When the accumulation of reactive lipid peroxidation surpasses a specific glutathione-dependent activity, these electrophilic compounds are not neutralized, leading to programmed cell death, ferroptosis. Reduced glutathione levels, caused by type 2 inflammation, may impair its ability to neutralize reactive lipid peroxidation. The accumulation of lipid peroxidation with intracellular redox imbalance may contribute to asthma exacerbations in individuals with type 2 inflammation. Inhibiting the ferroptotic pathway holds promise as a therapeutic strategy to alleviate asthma exacerbations.

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BACKGROUND: Despite clinical implications, the pathogenesis of mucus plugging in asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap (ACO) remains unclear. We hypothesized that distinct airway microbiomes might affect mucus plugging differently among ACO, asthma, and COPD and among different extents of airway eosinophilic inflammation. METHODS: The sputum microbiome, sputum cell differential count, and mucus plug score on computed tomography were cross-sectionally evaluated in patients with chronic airflow limitation. RESULTS: Patients with ACO, asthma, or COPD were enrolled (n = 56, 10, and 25). Higher mucus plug scores were associated with a greater relative abundance of the phylum Proteobacteria (rho = 0.29) only in patients with ACO and a greater relative abundance of the phylum Actinobacteria (rho = 0.46) only in patients with COPD. In multivariable models including only patients with ACO, the presence of mucus plugs was associated with a greater relative abundance of the phylum Proteobacteria and the genus Haemophilus, independent of smoking status, airflow limitation, and emphysema severity. Moreover, the mucus score was associated with a greater relative abundance of the genus Streptococcus (rho = 0.46) in patients with a high sputum eosinophil count (n = 22) and with that of the genus Haemophilus (rho = 0.46) in those with a moderate sputum eosinophil count (n = 26). CONCLUSIONS: The associations between mucus plugging and the microbiome in ACO differed from those in COPD and asthma. Greater relative abundances of the phylum Proteobacteria and genus Haemophilus may be involved in mucus plugging in patients with ACO and moderate airway eosinophilic inflammation.

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Objective Sleep restfulness is closely associated with mortality. Thus, it is an important sleep-related symptom in the general population. However, it is rarely evaluated in patients with obstructive sleep apnea (OSA) syndrome. The present study examined the importance of sleep restfulness in patients with OSA receiving continuous positive airway pressure (CPAP) therapy. Materials and Methods We administered sleep-related questionnaires, which included items such as subjective sleep duration and sleep restfulness, to 775 patients with OSA receiving CPAP therapy. Sleep restfulness was rated using a 5-point Likert-type scale, with the score of 5 indicating restfulness. Good adherence to CPAP therapy was defined as the use of CPAP therapy for at least 4 h per night in 70% of nights. Results We excluded 105 patients with lacking data. Thus, 670 patients were finally examined. In total, 29 (4.3%), 124 (18.5%), 139 (20.8%), 235 (35.1%), and 143 (14.3%) patients answered restless (1), somewhat restless (2), neither (3), somewhat restful (4), and restful (5) respectively. A total of 467 (69.7%) patients had good adherence to CPAP therapy. Multivariate logistic regression analysis showed that sleep restfulness was independently and positively associated with subjective sleep duration (≥ 7 hours) and good adherence to CPAP therapy. Conclusion Sleep restfulness was associated with subjective sleep duration and good adherence to CPAP therapy in patients with OSA. Favorable outcomes are significantly correlated with good adherence to CPAP therapy. Thus, sleep restfulness can be an indicator of a subtype that has favorable outcomes in patients after CPAP therapy.

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Rationale: There have been meta-analyses that showed reduced retinal nerve fiber layer (RNFL) thickness, which is a surrogate marker of glaucoma, in patients with obstructive sleep apnea (OSA). However, the sample sizes in these reports were small (<300), and the mechanism of RNFL thinning in patients with OSA was not revealed.Objectives: To investigate the relationship of RNFL thickness with nocturnal hypoxemia or hypoxemic burden in a large-scale study.Methods: In this epidemiological study, 8,309 community residents were enrolled. The actigraphy-modified 3% oxygen desaturation index (acti-ODI3%) and cumulative percentage of sleep time with oxygen saturation <90% (acti-CT90) modified by objective sleep duration using actigraphy were measured. The hypoxemic burden is shown as acti-CT90. Circumpapillary RNFL thickness was determined using optical coherence tomography.Results: Multivariable logistic analysis models revealed that an increase in acti-CT90 was significantly associated with mean RNFL thinning after adjusting for several factors in participants without glaucoma diagnosed or treated previously (ß = -0.037; P = 0.009). There were significant differences in mean RNFL thickness among participants stratified according to acti-CT90 (>1.5 vs. ⩽1.5; P = 0.04). Although acti-ODI3% was significantly associated with acti-CT90 (ß = 0.72; P < 0.0001), acti-ODI3% was not significantly associated with mean RNFL thickness in the multivariable logistic analysis (ß = -0.011; P = 0.48). In addition, acti-CT90 was significantly associated with mean RNFL thickness both in the elderly (⩾60 yr; ß = -0.058; P = 0.002) and nonelderly (<60 yr; ß = -0.054; P = 0.007).Conclusions: Acti-CT90, but not acti-ODI3%, was associated with mean RNFL thinning in participants irrespective of age in the elderly or nonelderly. Further prospective studies are required to investigate whether the prevention of hypoxic burden, which was shown as acti-CT90 in this study, is favorable for RNFL thinning.

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BACKGROUND: Asthma in the elderly needs more attention in an aging society. However, it is likely to remain underdiagnosed and undertreated. This study aimed to clarify clinical characteristics of new-onset asthma in the elderly, describing the prevalence, predictive factors, and comorbidities after asthma diagnosis of new-onset asthma in the elderly in the general population. METHODS: This community-based prospective cohort study enrolled 9804 generally healthy participants (30-74 years old) in Nagahama City, and conducted a follow-up assessment after 5 years. Elderly participants were those aged ≥65 years at baseline. Patients with new-onset asthma were defined as participants without asthma at baseline assessment and with asthma at the follow-up assessment. RESULTS: Among the 7948 participants analyzed in this study, 28 (1.4%) elderly and 130 (2.2%) non-elderly had new-onset asthma. Multiple logistic regression analysis revealed low forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and high blood eosinophil counts at baseline as predicting factors for new-onset asthma in the elderly. Additionally, subsequent incidence of new-onset asthma was higher in elderly participants with both predictors (high blood eosinophil counts and low FEV1/FVC at baseline) than those with none or one of the predictors before asthma diagnosis. Lastly, elderly patients with new-onset asthma had more frequent comorbidity of moderate to severe sleep disordered breathing than those non-elderly. CONCLUSIONS: Eosinophilic inflammation and airflow obstruction may predict subsequent new-onset asthma after the age of 65 years. Revealing the characteristics of new-onset asthma in the elderly can aid in the prevention of underdiagnosed asthma.

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BACKGROUND: Obesity and increased body mass index (BMI) are the known risk factors for adult-onset asthma. Serum free fatty acid (FFA) and other blood lipid levels are generally elevated in patients with obesity and may be involved in the onset of asthma. However, it remains largely unknown. This study aimed to elucidate the relationship between plasma fatty acids and new-onset asthma. METHODS: This community-based Nagahama Study in Japan enrolled 9804 residents. We conducted self-reporting questionnaires, lung function tests, and blood tests at baseline and 5 years later as follow-up. At the follow-up, plasma fatty acids were measured using gas chromatography-mass spectrometry. Body composition analysis was also measured at the follow-up. The associations between fatty acids and new-onset asthma were evaluated using a multifaceted approach, including targeted partial least squares discriminant analysis (PLS-DA). RESULTS: In PLS-DA for new-onset asthma, palmitoleic acid was identified as the fatty acid most associated with asthma onset. In the multivariable analysis, higher levels of FFA, palmitoleic acid, or oleic acid were significantly associated with new-onset asthma, independent of other confounding factors. The high body fat percentage itself was not the relevant factor, but showed a positive interaction with plasma palmitoleic acid for new-onset asthma. When stratified by gender, the impacts of higher levels of FFA or palmitoleic acid on new-onset asthma remained significant in females, but not in males. CONCLUSIONS: Elevated levels of plasma fatty acids, particularly palmitoleic acid, may be a relevant factor for new-onset asthma.

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Background: Airway microbiota in asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) remains unknown. Objective: This study with ACO-enriched population aimed to clarify airway microbiota in ACO and in mixed granulocytic inflammation, often detected in ACO and chronic airway diseases. Methods: This is an observational cross-sectional study. Patients with asthma with airflow limitation, ACO, and COPD were enrolled. Blood tests, pulmonary function, exhaled nitric oxide, and sputum tests were conducted. Sputum microbiota was evaluated using the 16S rRNA gene sequencing technique. Results: A total of 112 patients (13 asthma, 67 ACO, and 32 COPD) were examined. There were no significant differences in α-diversity among the 3 diseases. The relative abundances of phylum Bacteroidetes, class Bacteroidia, and genus Porphyromonas were associated with decreased eosinophilic inflammation, and were significantly lower in ACO than in COPD. In a comparison of sputum inflammatory subtypes, the proportion of Haemophilus was numerically highest in the mixed granulocytic subtype, followed by the neutrophilic subtype. Likewise, the proportion of Haemophilus was the highest in the intermediate-high (2%-8%) sputum eosinophil group and lowest in the severe (≥8%) eosinophil group. Clinically, Haemophilus proportion was associated with sputum symptoms. Finally, the proportion of Streptococcus was associated with higher blood eosinophil counts and most severe airflow limitation. Conclusions: Bacteroidia and Porphyromonas abundances in sputum are associated with the eosinophil-low phenotype, and ACO may be characterized by a decrease in these taxa. A mild elevation in sputum eosinophil does not preclude the presence of Haemophilus, which should be noted in the management of obstructive airway diseases.

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Patients and Methods: A questionnaire survey was administered to 18, 14, and 3 patients introduced to home self-injection of dupilumab or mepolizumab using a pen-type device for atopic dermatitis, asthma alone, and asthma plus chronic rhinosinusitis with nasal polyps, respectively. Results: All but one participant wished to continue self-injection. Most participants affirmed the reduction in copayment (88.6%) and saving time and labor for hospital visits (88.6%). Six patients who received dupilumab complained of side effects, but all, except for one, continued the treatment. Of the 13 patients who had previously used a syringe-type device, 10 preferred the pen type because of its ease of use, while 3 (23%) preferred the syringe type because of the self-adjustable injection speed for pain control. Conclusion: Administration of biologics using pen-type devices is easier, and the introduction of home self-injection leads to a reduction in outpatient visits and copayment.

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Sleep-disordered breathing (SDB) is often accompanied by noncommunicable diseases (NCDs), including gout. However, the association between serum uric acid (sUA) levels and NCDs is complicated in patients with SDB. We aimed to clarify this issue utilizing large-scale epidemiological data. This community-based study included 9850 inhabitants. SDB and its severity were assessed by a 3% oxygen desaturation index (3% ODI) corrected for sleep duration using wrist actigraphy. The associations between sUA and moderate to severe SDB (MS-SDB) and sUA and NCDs in patients with MS-SDB were analyzed. A total of 7895 subjects were eligible. In females, the prevalence of MS-SDB increased according to an elevation in sUA levels even after adjusting for confounders, and sUA ≥ 5 mg/dL was the threshold. These were not found in males. There was a positive interaction between sUA ≥ 5 mg/dL and female sex for MS-SDB. In females with MS-SDB, the prevalence of diabetes mellitus (DM) increased according to an elevation in sUA levels, and those with sUA ≥ 5 mg/dL showed a higher prevalence of DM than their counterparts. There is a clear correlation between sUA levels and the severity of SDB, and elevated sUA poses a risk for DM in females with MS-SDB.

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The effect of inhaled corticosteroids (ICS) and biologics on the humoral immune response following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination in patients with asthma is unknown. We prospectively evaluated the humoral immune response 3 weeks (T1) and 6 months (T2) after the second dose of BNT162b2 in 30 SARS-CoV-2-naïve patients with asthma. We measured anti-spike immunoglobulin G (IgG) titers and serum-neutralizing activity against the ancestral SARS-CoV-2 strain. The anti-spike IgG titer and neutralizing activity did not differ significantly between the biologics and non-biologics groups at T1 (P = 0.708 and P = 0.417, respectively) or T2 (P = 0.299 and P = 0.492, respectively). In the multivariate analysis, age and sex were significantly associated with the magnitude of the humoral immune response; however, the use of biologics and ICS dose were not, suggesting that these would not affect BNT162b2 immunogenicity in patients with asthma. Larger studies are needed to validate these findings.

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Little is known about the association of prolonged cough, a common and troublesome symptom, with metabolic pathways. We aimed to clarify this association using data from the Nagahama cohort, a prospective study of participants from the general population. Self-report questionnaires on prolonged cough were collected at baseline and 5-year follow-up assessments. Blood tests at follow-up were used for gas chromatography-mass spectrometry-based metabolomics. The association between metabolites and prolonged cough was examined using the partial least squares discriminant analysis and multiple regression analysis. Among the 7432 participants, 632 had newly developed prolonged cough at follow-up, which was defined as "new-onset prolonged cough". Low plasma citric acid was significantly associated with new-onset prolonged cough, even after the adjustment of confounding factors including the presence of asthma, upper airway cough syndrome (UACS), and gastroesophageal reflux disease (GERD). A similar association was observed for isocitric acid, 3-hydroxybutyric acid, and 3-hydroxyisobutyric acid. The analysis of these four metabolites revealed that citric acid had the strongest association with new-onset prolonged cough. This significant association remained even when the analysis was confined to participants with UACS or GERD at baseline or follow-up, and these associations were also observed in participants (n = 976) who had prolonged cough at follow-up regardless of baseline status. In conclusion, low blood citric acid may be associated with prolonged cough.

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Sleep disordered breathing (SDB), mainly obstructive sleep apnea (OSA), constitutes a major health problem due to the large number of patients. Intermittent hypoxia caused by SDB induces alterations in metabolic function. Nevertheless, metabolites characteristic for SDB are largely unknown. In this study, we performed gas chromatography-mass spectrometry-based targeted metabolome analysis using data from The Nagahama Study (n = 6373). SDB-related metabolites were defined based on their variable importance score in orthogonal partial least squares discriminant analysis and fold changes in normalized peak-intensity levels between moderate-severe SDB patients and participants without SDB. We identified 20 metabolites as SDB-related, and interestingly, these metabolites were frequently included in pathways related to fructose. Multivariate analysis revealed that moderate-severe SDB was a significant factor for increased plasma fructose levels (ß = 0.210, P = 0.006, generalized linear model) even after the adjustment of confounding factors. We further investigated changes in plasma fructose levels after continuous positive airway pressure (CPAP) treatment using samples from patients with OSA (n = 60) diagnosed by polysomnography at Kyoto University Hospital, and found that patients with marked hypoxemia exhibited prominent hyperfructosemia and their plasma fructose levels lowered after CPAP treatment. These data suggest that hyperfructosemia is the abnormality characteristic to SDB, which can be reduced by CPAP treatment.

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Rationale: Subjects with preserved ratio impaired spirometry (PRISm) experience increased respiratory symptoms, although they present heterogeneous characteristics. However, the longitudinal changes in these symptoms and respiratory function are not well known. Objectives: To investigate PRISm from the viewpoint of respiratory symptoms in a longitudinal, large-scale general population study. Methods: The Nagahama study included 9,789 inhabitants, and a follow-up evaluation was conducted after 5 years. Spirometry and self-administered questionnaires regarding respiratory symptoms, including prolonged cough, sputum and dyspnea, and comorbidities were conducted. Results: In total, 9,760 subjects were analyzed, and 438 subjects had PRISm. Among the subjects with PRISm, 53% presented with respiratory symptoms; dyspnea was independently associated with PRISm. Follow-up assessment revealed that 73% of the subjects with PRISm with respiratory symptoms were consistently symptomatic, whereas 39% of the asymptomatic subjects with PRISm developed respiratory symptoms within 5 years. In addition, among subjects with respiratory symptoms without airflow limitation at baseline, PRISm was a risk factor for the development of airflow limitation independent of smoking history and comorbidities. Conclusions: This study demonstrated that 53% of the subjects with PRISm had respiratory symptoms; dyspnea was a distinct characteristic of PRISm. Approximately three-fourths of the symptomatic subjects with PRISm consistently complained of respiratory symptoms within 5 years. Together with our result that PRISm itself is an independent risk factor for the development of chronic obstructive pulmonary disease among subjects with respiratory symptoms, the clinical course of subjects with PRISm with symptoms requires careful monitoring.

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Excessive daytime sleepiness (EDS) is a symptom of sleep apnea syndrome (SAS). In some patients with SAS who undergo continuous positive airway pressure (CPAP) therapy, EDS persists (residual EDS). However, knowledge of residual EDS in Japan is limited. Therefore, we examined EDS as defined by the Japanese version of the Epworth Sleepiness Scale (a score of ≥11) before and after long-term (≥1 year) CPAP therapy in 490 patients with SAS. Good adherence to CPAP therapy was defined as its use for at least 4 h during 70% of the nights. The prevalence of residual EDS was 9.4%. Residual EDS was negatively associated with good adherence to CPAP therapy. Furthermore, the longer the CPAP therapy duration after initiation, the lower the prevalence of residual EDS. Therefore, the findings on the prevalence of residual EDS and its association with CPAP therapy in Japan are probably similar to those of other countries.

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Servo-ventilation (SV) was developed for treating central sleep apnea. To date, primarily SV devices manufactured by Philips Respironics and ResMed are used. However, the difference in reaction to sleep-disordered breathing events between bilevel positive airway pressure AutoSV devices from Philips and adaptive SV devices from ResMed in clinical settings is unknown. Herein, we describe a case of central sleep apnea in which sleep-disordered breathing events were successfully controlled and sleepiness, sleep quality, and tolerance of the device were improved by changing from the bilevel positive airway pressure AutoSV device from Philips to the adaptive SV device from ResMed. Changing the SV devices can be a clinical option to appropriately control sleep-disordered breathing events in patients receiving SV therapy who present with persistent sleep-disordered breathing. CITATION: Hamada S, Togawa J, Sunadome H, Nagasaki T, Hirai T, Sato S. Good clinical response achieved by changing servo-ventilation devices in a patient with central sleep apnea: a case report. J Clin Sleep Med. 2023;19(8):1557-1561.

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Bronchial thermoplasty (BT) is effective in some severe asthma patients; however, the specific asthma phenotypes that produce a good response to BT are not fully understood. Clinical data were retrospectively reviewed in severe asthma patients who underwent BT at a single institution in Japan. At the follow-up assessment, the Asthma Quality of Life Questionnaire (AQLQ) scores (P = 0.003), maintenance oral corticosteroid doses (P = 0.027), and exacerbation frequency (P = 0.017) were significantly improved, while prebronchodilator-forced expiratory volume in 1 second (% predicted) did not significantly change (P = 0.19). When we grouped the patients into 2 groups according to their body mass index levels, the AQLQ scores were more improved in patients with overweight/obesity than those with normal weight (P = 0.01). This study showed that patients with non-controlled severe asthma exhibiting overweight/obesity and low quality of life had potential benefits from BT.

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In June 2021, Philips Respironics first advised the use of in-line bacterial filters in response to a recall of continuous positive airway pressure (CPAP) devices. However, the effects of using in-line filters with CPAP devices have not yet been examined in a clinical setting. Here, we retrospectively evaluated 160 patients with sleep-disordered breathing (SDB) who voluntarily used in-line bacterial filters. Patients' perceptions of CPAP pressure after using in-line filters were investigated via a verbal interview. Patients described CPAP pressure as very weak (13, 8.1%), somewhat weak (42, 26.2%), unchanged (103, 64.4%), or somewhat strong (2, 1.3%). Five of the thirteen patients (38.5%) who described CPAP pressure as very weak discontinued the use of in-line filters. The apnea-hypopnea index obtained from the CPAP devices did not change after using in-line filters (n = 129, p = 0.85). Hence, although in-line bacterial filters could change patients' perceptions of CPAP pressure, they did not influence SDB control.

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Recently an association between blood glucose dysregulation and sleep disruption was suggested. The association between sleep disordered breathing, most of which is due to obstructive sleep apnea (OSA) in the general population, and diabetic severity, as well as the impact of antidiabetic treatment, remains unclear. This study aimed to investigate these associations as well as age and sex differences. This cross-sectional study evaluated 7,680 community participants as the main cohort (population-based cohort). OSA was assessed by the 3% oxygen desaturation index from pulse oximetry, which was corrected for sleep duration obtained by wrist actigraphy. For arguing the limitations for using pulse oximetry, 597 hospitalised patients, who were assessed by the apnea-hypopnea index from attended polysomnography, were also evaluated as the validation cohort (hospital-based cohort). Moderate-to-severe OSA was more prevalent as haemoglobin A1c (HbA1c) levels increased (<5.6%/5.6%-<6.5%/6.5%-<7.5%/≥7.5%, respectively) in both cohorts (p < 0.001), but only in those without antidiabetic treatment. The HbA1c level was an independent factor for moderate-to-severe OSA (population-based cohort, odds ratio [OR] 1.26, 95% confidence interval [CI] 1.10-1.45; hospital-based cohort, OR 1.69, 95% CI 1.22-2.33, per 1% increase). These associations were more prominent in the middle-aged (aged <60 years) than in the elderly (aged ≥60 years) and in women than in men in both cohorts. The prevalence of moderate-to-severe OSA in patients with antidiabetic treatment in the hospital-based cohort was ≥75% regardless of HbA1c levels. In conclusion, an association between the prevalence of OSA and HbA1c level even within or over the normal range was found only in patients without antidiabetic treatment and was more prominent in the middle-aged and in women.

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Objective The effects of continuous positive airway pressure (CPAP) devices on obstructive sleep apnea (OSA) in Japanese patients have not been reported. We assessed the effects of changing CPAP devices (from the Philips Respironics device to the ResMed device) on the control of OSA. Methods We retrospectively examined 13 patients with OSA who voluntarily changed from the Philips Respironics device to the ResMed device due to a Philips Respironics CPAP device recall. Data on the apnea-hypopnea index (AHI) were obtained from the CPAP devices for three months before and after changing the devices. Results The AHI obtained from the CPAP devices significantly decreased from 4.4 (3.1-10.7) events/h to 2.0 (0.8-3.6) events/h when patients changed devices (p=0.022). The AHI decreased to <5 events/h after changing devices in 4 patients, whereas it had been ≥5 events/h before changing devices in 6 patients. Conclusion Changing CPAP devices can decrease the AHI.

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RATIONALE: Bronchiectasis and bronchiolitis are differential diagnoses of asthma; moreover, they are factors associated with worse asthma control. OBJECTIVE: We determined clinical courses of bronchiectasis/bronchiolitis-complicated asthma by inflammatory subtypes as well as factors affecting them. METHODS: We conducted a survey of refractory asthma with non-cystic fibrosis bronchiectasis/bronchiolitis in Japan. Cases were classified into three groups, based on the latest fractional exhaled NO (FeNO) level (32 ppb for the threshold) and blood eosinophil counts (320/µL for the threshold): high (type 2-high) or low (type 2-low) FeNO and eosinophil and high FeNO or eosinophil (type 2-intermediate). Clinical courses in groups and factors affecting them were analysed. RESULTS: In total, 216 cases from 81 facilities were reported, and 142 were stratified: 34, 40 and 68 into the type 2-high, -intermediate and -low groups, respectively. The frequency of bronchopneumonia and exacerbations requiring antibiotics and gram-negative bacteria detection rates were highest in the type 2-low group. Eighty-seven cases had paired latest and oldest available data of FeNO and eosinophil counts; they were analysed for inflammatory transition patterns. Among former type 2-high and -intermediate groups, 32% had recently transitioned to the -low group, to which relatively low FeNO in the past and oral corticosteroid use contributed. Lastly, in cases treated with moderate to high doses of inhaled corticosteroids, the frequencies of exacerbations requiring antibiotics were found to be higher in cases with more severe airway lesions and lower FeNO. CONCLUSIONS: Bronchiectasis/bronchiolitis-complicated refractory asthma is heterogeneous. In patients with sputum symptoms and low FeNO, airway colonisation of pathogenic bacteria and infectious episodes are common; thus, corticosteroids should be carefully used.

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