One-day systemic corticosteroid administration for asthma and future "short bursts" risk in real clinical practice.

OBJECTIVE: Systemic corticosteroid administration, also called short bursts (SB), is harmful for patients with asthma; however, the actual burden of one-day SB remains unsolved. This study aimed to elucidate the characteristics of patients requiring one-day SB against asthma in clinical practice. METHODS: Consecutive patients who regularly visited our hospital for asthma treatment between January 2019 and December 2020 were reviewed and followed for one year. SB was defined as ≥3 days of systemic corticosteroid treatment for an exacerbation. One-day SB was defined as one-day of systemic corticosteroid to treat an exacerbation. The one-day SB group included patients who received only one-day SB but no SB during the preceding year. Frequent SB was defined as that occurring ≥2 times/year. RESULTS: Data on 229 patients were analyzed. Among them, 2.6% (95% confidence interval 1.2-5.6%) were in the one-day SB group. The one-day SB group was female-dominant, obese, non-eosinophilic, and non-atopic. The median one-day SB was 1.5 times/year and almost half of one-day SB were performed by patients themselves. Independent of the low pulmonary function, high blood eosinophil count, and inhaled corticosteroid dose, one-day SB was associated with future frequent SB (adjusted odds ratio = 18.2, 95% confidence interval 1.1-288, P = 0.040, compared to the no SB group). CONCLUSIONS: Although one-day SB was not frequently experienced, even one-day SB without conventional SB was associated with future frequent SB. It is important to grasp the actual condition of one-day SB and to reinforce the treatment used.

Impact of adding pethidine on disinhibition during bronchoscopy with midazolam: a propensity score matching analysis.

BACKGROUND: We sometimes experience disinhibition during bronchoscopy with sedation. However, the impact of adding pethidine on disinhibition has not yet been investigated. This study aimed to examine the additive impact of pethidine on disinhibition during bronchoscopy with midazolam. METHODS: This retrospective study involved consecutive patients who underwent bronchoscopy between November 2019 and December 2020 (sedated with midazolam: Midazolam group) and between December 2020 and December 2021 (sedated with midazolam plus pethidine: Combination group). The severity of disinhibition was defined as follows: moderate, disinhibition that always needed restraints by assistants; and severe, disinhibition that needed antagonization of sedation by flumazenil to continue bronchoscopy. One-to-one propensity score matching was used to match baseline characteristics between both groups. RESULTS: After propensity score matching with depression, the type of bronchoscopic procedure, and the dose of midazolam, 142 patients matched in each group. The prevalence of moderate-to-severe disinhibition significantly decreased from 16.2% to 7.8% (P = 0.028) in the Combination group. The Combination group had significantly better scores for sensation after bronchoscopy and feelings toward bronchoscopy duration than did the Midazolam group. Although the minimum SpO2 during bronchoscopy was significantly lower (88.0 ± 6.2 mmHg vs. 86.7 ± 5.0 mmHg, P = 0.047) and the percentage of oxygen supplementation significantly increased (71.1% vs. 86.6%, P = 0.001) in the Combination group, no fatal complications were observed. CONCLUSIONS: Adding pethidine could reduce disinhibition occurrence in patients undergoing bronchoscopy with midazolam, with better subjective patient outcomes during and after bronchoscopy. However, whether more patients may need oxygen supplementation and whether hypoxia occurs during bronchoscopy should be considered. CLINICAL TRIAL REGISTRATION: UMIN000042635.

Allergy to Omalizumab: Lessons from a Reaction to the Coronavirus 2019 Vaccine.

Omalizumab can cause hypersensitivity reactions. We herein report the first case of an 18-year-old woman with refractory cough-predominant asthma that correlated with allergic reactions caused by omalizumab and the coronavirus disease 2019 (COVID-19) vaccine. The patient developed angioedema after taking omalizumab. She had previously experienced intense coughing immediately after receiving a COVID-19 vaccine. A skin prick test was positive for polysorbate 20, which was probably the cause of the allergic reactions to omalizumab and the COVID-19 vaccine. Clinicians should check for an allergic reaction, irrespective of its intensity, triggered by polysorbate and be careful when prescribing biologics to patients in order to avoid allergic reactions.

Severe eosinophilia and subsequent dermatologic immune-related adverse event with squamous cell carcinoma antigen elevation induced by nivolumab and ipilimumab.

Immune checkpoint inhibitors (ICIs) for malignant lesions are associated with immune-related adverse events (irAEs), but reports about severe eosinophilia induced by ICIs are scarce. A 73-year-old man with lung squamous cell carcinoma was treated by chemotherapy (carboplatin plus paclitaxel) and ICIs (nivolumab plus ipilimumab). After two cycles of chemotherapy, the ICIs were continued. After 5 months, the eosinophilia, which had exceeded 5000/µl, increasingly deteriorated, and the only detected irAE was a grade 1 rash. Under continuation of the ICIs, although the eosinophilia decreased, a grade 3 rash and severe pruritis subsequently appeared. Squamous cell carcinoma antigen (SCCA) was steeply increased simultaneously. A complete response had been achieved, and oral prednisolone markedly improved the rash, pruritis, and eosinophilia. Clinicians should be aware that precedent severe eosinophilia and subsequent severe irAE could occur in patients treated by nivolumab and ipilimumab, and SCCA elevation could be associated with dermatologic irAE.

Gender Differences in Smoking Initiation and Cessation Associated with the Intergenerational Transfer of Smoking across Three Generations: The Nagahama Study.

Global tobacco policies lowered overall and male smoking rates, but female smoking rates have remained unchanged. Parent-child studies revealed the effects of parental smoking, but gender differences had mixed results. We investigated the effects of long-term smoking behavior in families over three generations in order to clarify gender differences. A cross-sectional study in a community-based genome cohort was conducted using a self-reported questionnaire. A total of 8652 respondents were stratified by gender regarding smoking initiation. A logistic regression analysis was performed to analyze the family smoking history. A total of 2987 current smokers and ever-smokers were compared regarding smoking cessation. With respect to smoking initiation, women were affected by their smoking mothers (odds ratio (OR), 2.4; 95% confidence interval (CI), 1.8-3.2) and grandmothers (OR, 1.7; CI, 1.1-2.4). Women who continued smoking were affected only by their smoking mothers (OR, 1.6; CI, 1.05-2.49). In conclusion, gender differences in smoking initiation and cessation are possibly associated with family smoking history. Mothers and grandmothers were shown to have a strong influence on women with respect to both smoking initiation and cessation. Future research should focus on providing evidence for effective gender-specific intervention programs to curb long-term smoking in women.

Characteristics of patients with frequent systemic corticosteroid bursts for asthma in real clinical practice: are there frequent "short bursts?"

OBJECTIVE: The data on intermittent systemic corticosteroid therapy for asthma exacerbation, clinically called a "short burst," is limited. This study aimed to investigate the characteristics of patients with frequent systemic corticosteroid bursts for asthma in real clinical practice. METHODS: Consecutive patients who regularly visited our hospital for asthma treatment between January 2019 and December 2020 were reviewed. The number of systemic corticosteroid bursts during the past 1 year was collected, and those with frequent bursts (≥2 times/year) were defined as the Frequent group. RESULTS: Data on 236 patients were analyzed. Among them, 5.5% (95% confidence interval 3.2-9.2%) were in the Frequent group. In the Frequent group, 23% of patients had no unplanned visits, and 38% experienced at least one corticosteroid burst without visiting a physician (self-medication). One-third of patients did not undertake high-dose inhaled corticosteroid treatment, and three-fourths of patients did not undertake long-acting muscarinic antagonist treatment. Low pulmonary function and increased blood eosinophils were independently associated with the Frequent group (adjusted odds ratio = 0.73, 95% confidence interval 0.55-0.99, P = 0.039, per 10% predicted increase in a forced expiratory volume in 1 s; adjusted odds ratio = 1.15, 95% confidence interval 1.02-1.29, P = 0.025, per 100/µL increase in blood eosinophils). CONCLUSIONS: There was a certain rate of frequent corticosteroid bursts in real clinical practice. It is important to determine the actual condition, as some patients experienced "hidden" frequent bursts and have the option to reinforce the treatment.

Prevalence and characteristics of disinhibition during bronchoscopy with midazolam.

BACKGROUND: Disinhibition is sometimes experienced during bronchoscopy with sedation. However, data on disinhibition during bronchoscopy are scarce. We examined the prevalence and characteristics of disinhibition during bronchoscopy with midazolam. METHODS: This retrospective study analyzed consecutive patients who underwent bronchoscopy between November 2019 and December 2020. The severity of disinhibition was defined as follows: mild, disinhibition sometimes requiring restraints by assistants; moderate, disinhibition always requiring restraints by assistants; and severe, disinhibition requiring antagonization of sedation by flumazenil to continue bronchoscopy. RESULTS: Among 251 eligible patients who were sedated using midazolam, 36 (14.3%; 95% confidence interval [CI], 10.5%-19.2%), 42 (16.7%; 95% CI, 12.6%-21.8%), and 7 (2.8%; 95% CI, 1.4%-5.6%) experienced mild, moderate, and severe disinhibition, respectively. Depression (odds ratio [OR] 2.77; 95% CI, 1.20-6.41), endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) (OR 10.23; 95% CI, 1.02-103.01, referred to brushing/bronchial washing/observation), and increased administration of midazolam (OR 1.20; 95% CI, 1.02-1.42, per 1-mg increase) were independently associated with moderate-to-severe disinhibition. Patients experiencing moderate disinhibition reported significantly better scores for discomfort during bronchoscopy. Besides the maximum systolic and diastolic blood pressures during bronchoscopy, the changes in hemodynamic and respiratory statuses during bronchoscopy or complications did not significantly differ between patients experiencing moderate-to-severe disinhibition and those experiencing none-to-mild disinhibition. CONCLUSIONS: Moderate-to-severe disinhibition occurred in 19.5% of patients during bronchoscopy with midazolam. We should focus on disinhibition when patients have depression or are planning to undergo EBUS-TBNA, and sparing the administration of midazolam might reduce the occurrence of disinhibition. CLINICAL TRIAL REGISTRATION: UMIN000038571.

Drastically Progressive Ethambutol-induced Optic Neuropathy after Withdrawal of Ethambutol: A Case Report and Literature Review.

Ethambutol-induced optic neuropathy (EON) is a well-known complication, although low-dose ethambutol seldom causes EON. An 85-year-old man with non-tuberculous mycobacterial lung disease was taking antibiotics, including low-dose ethambutol. On day 85 of treatment, the diagnosis of EON was made. Despite prior discontinuation, his best corrected visual acuity drastically deteriorated from 20/17 (right eye) and 20/20 (left eye) to 20/330 (right eye) and 20/1,000 (left eye) within 3 weeks, and this symptom did not resolve. To our knowledge, there have been no reported cases with drastically progressing and irreversible EON even after the withdrawal of low-dose and short-term ethambutol.

Ground-glass opacity as a paradoxical reaction in miliary tuberculosis: A case report and review of the literature.

A paradoxical reaction (PR) is an excessive immune response occurring during antitubercular therapy (ATT), but is rare in patients with miliary tuberculosis. A 78-year-old woman complained of general malaise, loss of appetite, and fever for 10 days. Chest computed tomography (CT) showed diffuse, bilateral, discrete miliary nodules. The patient was treated with ATT for miliary tuberculosis. Nine days after starting the treatment, she developed a spiking fever and worsening malaise. Repeat CT showed new localized ground-glass opacity (GGO) in the right upper lobe. After excluding possible etiologies, she was diagnosed with PR due to ATT. She was successfully managed with oral prednisolone while continuing ATT. The GGO diminished and did not recur after discontinuation of the steroids. We reviewed 28 reported cases of miliary tuberculosis with a PR in patients not infected with human immunodeficiency virus. Those not on immunosuppressive therapy were likely to develop a PR early. This case illustrates that a PR may present as localized GGO in miliary tuberculosis in the lung of patients treated with ATT. In cases of a PR with marked symptoms, steroid therapy may be valuable.

Per cent low attenuation volume and fractal dimension of low attenuation clusters on CT predict different long-term outcomes in COPD.

BACKGROUND: Fractal dimension (D) characterises the size distribution of low attenuation clusters on CT and assesses the spatial heterogeneity of emphysema that per cent low attenuation volume (%LAV) cannot detect. This study tested the hypothesis that %LAV and D have different roles in predicting decline in FEV1, exacerbation and mortality in patients with COPD. METHODS: Chest inspiratory CT scans in the baseline and longitudinal follow-up records for FEV1, exacerbation and mortality prospectively collected over 10 years in the Hokkaido COPD Cohort Study were examined (n=96). The associations between CT measures and long-term outcomes were replicated in the Kyoto University cohort (n=130). RESULTS: In the Hokkaido COPD cohort, higher %LAV, but not D, was associated with a greater decline in FEV1 and 10-year mortality, whereas lower D, but not %LAV, was associated with shorter time to first exacerbation. Multivariable analysis for the Kyoto University cohort confirmed that lower D at baseline was independently associated with shorter time to first exacerbation and that higher LAV% was independently associated with increased mortality after adjusting for age, height, weight, FEV1 and smoking status. CONCLUSION: These well-established cohorts clarify the different prognostic roles of %LAV and D, whereby lower D is associated with a higher risk of exacerbation and higher %LAV is associated with a rapid decline in lung function and long-term mortality. Combination of %LAV and fractal D may identify COPD subgroups at high risk of a poor clinical outcome more sensitively.

Drastically progressive lung cavity lesion caused by Actinomyces odontolyticus in a patient undergoing chemoradiotherapy: A case report and literature review.

Pulmonary actinomycosis reportedly forms 15% of all cases of actinomycosis, and pulmonary Actinomyces odontolyticus is particularly rare. A 60-year-old man with a hoarse voice was referred to our hospital. Lung squamous cell carcinoma was diagnosed at the clinical tumor-node-metastasis stage of cT2N2M0, and concurrent chemoradiotherapy was initiated. Further, a small cavity was also detected in the left upper lobe, but it was observed. During chemoradiotherapy, the small cavity lesion rapidly increased accompanying infiltration, and administration of short-term antibiotics did not improve the patient's condition. Bronchoscopy did not show any diagnostic results. Although a rapidly progressive malignant lesion could not be excluded and surgical management was considered, resection could not be performed because of the tight adhesion of the mass. Therefore, bronchoscopy was performed again, and the bronchial lavage culture showed a positive smear for the Actinomyces species. Further, using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), the bacteria was identified as A. odontolyticus. After long-term administration of amoxicillin, the lung cavity with infiltration gradually improved. To the best of our knowledge, there have been nine cases of pulmonary A. odontolyticus (excluding those with only empyema or pleural mass without lung lesions), which can occur in immunocompetent patients with persistent lung shadow. None of the cases showed drastic deterioration; therefore, the present case is the first to highlight that A. odontolyticus possibly produce drastically progressive lung cavity lesion. Further, repeated bronchoscopy and MALDI-TOF MS could help to diagnose pulmonary actinomycosis.

The prevalence and disease burden of severe eosinophilic asthma in Japan.

Background: There are limited data on the prevalence and burden of severe eosinophilic asthma (SEA) both in Japan and globally. This study aimed to assess the prevalence and burden of SEA in Japan. Methods: This study was a retrospective, observational cohort analysis using health records or health insurance claims from patients with severe asthma treated at Kyoto University Hospital. The primary outcome was the prevalence of SEA, defined as a baseline blood eosinophil count ≥300 cells/µL. Secondary outcomes included frequency and risk factors of asthma exacerbations, and asthma-related healthcare resource utilization and costs. Results: Overall, 217 patients with severe asthma were included; 160 (74%) had eosinophil assessments. Of these, 97cases (61%), 54cases (34%), and 33cases (21%) had a blood eosinophil count ≥150, ≥300, and ≥500 cells/µL, respectively. Proportion of SEA was 34%. Blood eosinophil count was not associated with a significantly increased frequency of exacerbations. In the eosinophilic group, lower % forced expiratory volume in 1 second and higher fractional exhaled nitric oxide were predictive risk factors, while the existence of exacerbation history was a predictive risk factor for asthma exacerbations in the non-eosinophilic group. Severe asthma management cost was estimated as ¥357,958/patient-year, and asthma exacerbations as ¥26,124/patient-year. Conclusions: Approximately, one-third of patients with severe asthma in Japan have SEA. While risk factors for exacerbations differed between SEA and severe non-eosinophilic asthma, both subgroups were associated with substantial disease and economic burden. From subgroup analysis, blood eosinophil counts could be an important consideration in severe asthma management.

Serum matrix metalloproteinase levels in polymyositis/dermatomyositis patients with interstitial lung disease.

OBJECTIVE: We aimed to clarify the clinical significance of serum levels of MMPs in interstitial lung disease (ILD) complicated with PM/DM (PM/DM-ILD). METHODS: We retrospectively analysed serum levels of seven subsets of MMPs in 52 PM/DM-ILD patients diagnosed at Kyoto University Hospital or Tenri Hospital from January 2005 to December 2014. The patients were sub-grouped based on the presence of anti-amimoacyl-tRNA synthetase antibody (anti-ARS antibody), anti-melanoma differentiation-associated protein 5 antibody (anti-MDA5 antibody) or lack of the antibodies (ARS-ILD, MDA5-ILD and other-ILD groups, respectively) and independently analysed. Eighteen PM/DM patients without ILD and 55 healthy control were also analysed. Associations between serum levels of MMPs and clinical findings including mortality were analysed. RESULTS: Among the MMPs analysed, MMP-7 serum levels in the ARS-ILD group were significantly higher compared with those in any of the other groups of PM/DM patients or in healthy controls. On the other hand, in the MDA5-ILD group, serum MMP-7 levels >5.08 ng/ml were associated with worse overall survival both in univariate (P = 0.017; odds ratio 18.0; 95% CI 1.69, 192.00) and multivariate (P = 0.027; odds ratio 14.60; 95% CI 1.11, 192.00) analyses. Immunohistochemical analysis suggested that MMP-7 was expressed in type II alveolar epithelial cells adjacent to the fibrotic lesions. CONCLUSION: Serum MMP-7 levels were higher in anti-ARS antibody-positive PM/DM-ILD patients, while higher serum MMP-7 levels among anti-MDA5 antibody-positive PM/DM-ILD patients were associated with a worse prognosis. Fibrotic processes may be associated with the elevation of serum MMP-7 levels.

Can the Sarcoidosis Health Questionnaire predict the long-term outcomes in Japanese sarcoidosis patients?

RATIONALE: The Sarcoidosis Health Questionnaire (SHQ) is the first sarcoidosis-specific health status questionnaire ever developed. Worse health status, as evaluated by the SHQ, may indicate higher risk for deterioration in the following 5 years. OBJECTIVES: To evaluate the association between SHQ scores and deterioration defined clinically at 5-year follow-up. METHODS: 122 patients with biopsy-supported sarcoidosis completed the SHQ and underwent evaluation with respect to organ involvement, chest radiograph, electrocardiogram, serum biomarker measurements, pulmonary function tests, and echocardiogram. Of these 122, 88 (72.1%) were available for pulmonary, cardiac, and non-pulmonary, non-cardiac deterioration assessment during the following 5 years. MEASUREMENTS AND MAIN RESULTS: Five-year deterioration was observed in 20 patients (23%). The SHQ total score was significantly associated with 5-year deterioration, after adjusting for cardiac involvement at baseline, with adjusted odds ratio (OR) of 0.54 (95% confidence interval [95% CI], 0.29-0.99). The association of the total SHQ with 5-year outcome was not significant when adjusted for left ventricular ejection fraction (LVEF) at baseline (adjusted OR, 0.61 [0.32-1.16]), whereas LVEF was significantly associated with 5-year outcome (adjusted OR, 0.92 [0.86-0.99]). The association between total SHQ score and 5-year deterioration was marginal when adjusted for baseline usage of systemic corticosteroid (CS)/immunosuppressive (IS) agents (adjusted OR, 0.58 [0.31-1.10]), whereas systemic CS/IS usage significantly predicted 5-year deterioration (adjusted odds ratio [OR], 3.46 [1.12-10.7]). There was a marginal correlation between the total SHQ and LVEF (rho = 0.19, p = 0.07) and a weak association between the total SHQ and systemic CS/IS usage (rho = -0.23, p = 0.03). The Physical Functioning domain scores of the SHQ were significantly associated with 5-year deterioration (adjusted OR, 0.45-0.51). CONCLUSIONS: Worse health status, as assessed by the SHQ score, can be a risk factor for 5-year deterioration of sarcoidosis, although usage of the CS/IS at baseline and lower LVEF at baseline are more predictive of 5-year deterioration.

Perspectives on End-of-Life Treatment among Patients with COPD: A Multicenter, Cross-sectional Study in Japan.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality. Since patients with severe COPD may experience exacerbations and eventually face mortality, advanced care planning (ACP) has been increasingly emphasized in the recent COPD guidelines. We conducted a multicenter, cross-sectional study to survey the current perspectives of Japanese COPD patients toward ACP. "High-risk" COPD patients and their attending physicians were consecutively recruited. The patients' family configurations, understanding of COPD pathophysiology, current end-of-life care communication with physicians and family members, and preferences for invasive life-sustaining treatments including mechanical ventilation (MV) and cardiopulmonary resuscitation (CPR) were evaluated using a custom-made, structured, self-administered questionnaire. Attending physicians were also interviewed, and we evaluated the patient-physician agreement. Among the 224 eligible "high-risk" patients, 162 participated. Half of the physicians (54.4%) thought they had communicated detailed information; however, only 19.4% of the COPD patients thought the physicians did so (κ score = 0.16). Less than 10% of patients wanted to receive invasive treatment (MV, 6.3% and CPR, 9.4%); interestingly, more than half marked their decision as "refer to the physician" (MV 42.5% and CPR 44.4%) or "refer to family" (MV, 13.8% and CPR, 14.4%). Patients with less knowledge of COPD were less likely to indicate that they had already made a decision. Although ACP is necessary to cope with severe COPD, Japanese "high-risk" COPD patients were unable to make a decision on their preferences for invasive treatments. Lack of disease knowledge and communication gaps between patients and physicians should be addressed as part of these patients' care.

In Vitro Disease Modeling of Hermansky-Pudlak Syndrome Type 2 Using Human Induced Pluripotent Stem Cell-Derived Alveolar Organoids.

It has been challenging to generate in vitro models of alveolar lung diseases, as the stable culture of alveolar type 2 (AT2) cells has been difficult. Methods of generating and expanding AT2 cells derived from induced pluripotent stem cells (iPSCs) have been established and are expected to be applicable to disease modeling. Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by dysfunction of lysosome-related organelles, such as lamellar bodies (LBs), in AT2 cells. From an HPS type 2 (HPS2) patient, we established disease-specific iPSCs (HPS2-iPSCs) and their gene-corrected counterparts. By live cell imaging, the LB dynamics were visualized and altered distribution, enlargement, and impaired secretion of LBs were demonstrated in HPS2-iPSC-derived AT2 cells. These findings provide insight into the AT2 dysfunction in HPS patients and support the potential use of human iPSC-derived AT2 cells for future research on alveolar lung diseases.

Induction of airway remodeling and persistent cough by repeated citric acid exposure in a guinea pig cough model.

BACKGROUND: A previous study involving guinea pigs showed that repeated cough could increase peripheral airway smooth muscle area, which can also aggravate cough. The airway pathologic changes produced by prolonged cough are still unknown. OBJECTIVE: To study the airway pathologic changes in prolonged cough models of guinea pigs. METHODS: Guinea pigs were assigned to three treatment groups: citric acid inhalation (CA) alone, citric acid inhalation with codeine pretreatment (COD), or saline solution inhalation (SA). Animals were challenged with citric acid or saline solution three times weekly. The intervention period was 22 or 43 days. Animals were challenged with citric acid on the first and last days of exposure. Lung specimens were obtained for pathologic analysis 72 h after the last exposure. RESULTS: Compared with the other two groups, the CA group had increased frequency of cough on both 22 and 43 days of exposure. Tracheal basement membrane (BM) thickness was increased after 43 days of exposure, correlating with the frequency of cough. The area of airway smooth muscles (ASM index) in small airways increased in the CA group after both 22 and 43 days of exposure, compared with the SA group. Compared with the COD group, the ASM index in small airways increased in the CA group after 22 days of exposure instead of 43 days of exposure. CONCLUSIONS: An increase in peripheral smooth muscle area by repeated cough was confirmed. Moreover, this is the first study to show that tracheal BM thickness increased after prolonged exposure (43 days). Repeated cough may lead to airway remodeling, which was also associated with an increased frequency of cough.