Referential equations for pulmonary diffusing capacity generated from the Japanese population using the Lambda, Mu, or Sigma method and their comparisons with prior referential equations.

BACKGROUND: This study aimed to establish reference equations for single-breath lung carbon monoxide diffusing capacity (DLCO), alveolar volume (VA), and transfer coefficient of the lungs for carbon monoxide (KCO, sometimes written as DLCO/VA) in the Japanese population. A generalised additive model for location size and shape (GAMLSS) was used to build each equation. METHODS: To collect pulmonary function data throughout a broad age range, we prospectively obtained pulmonary function data from healthy volunteers and retrospectively obtained data from patients with normal diffusing capacity aged 16-85 years. RESULTS: In total, 702 tests were conducted. The validation group z-scores, except for DLCO in males, showed substantial discrepancies between the Global Lung Initiative (GLI) baseline prediction equations and the present study's prediction equations, indicating the need for a new reference value prediction approach. The root mean square errors of the DLCO, VA, and KCO reference values obtained from the present study's prediction equations were lower than those derived from the GLI and previous linear regression equations. CONCLUSIONS: Reference values obtained in this study were more appropriate for our sample than those derived from the existing baseline prediction equations. This research's contribution is the development of a more precise prediction equation that can be used to establish a reference value range for pulmonary diffusing capacity. ETHICS AND DISSEMINATION: This research does not include any dissemination plan (publications, data deposition and curation).

Respiratory Virus Infections during the COVID-19 Pandemic Revealed by Multiplex PCR Testing in Japan.

Under the strict quarantine policy imposed to combat the COVID-19 (coronavirus disease 2019) pandemic in Japan, the prevalence of respiratory infections by viruses other than SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has been largely unknown. However, such information on viral circulation is important in order to develop better management policies that are based on scientific data. Here, we retrospectively investigated respiratory virus infections in individuals who visited a community hospital with respiratory symptoms between June of 2020 and September of 2021 with the use of the BioFire FilmArray Respiratory Panel 2.1. Virus was detected in 65 out of a total of 328 subjects, with SARS-CoV-2 (67.7%), rhino/enterovirus (18.5%), and parainfluenza virus 3 (7.7%) accounting for most of the infections. No influenza virus or respiratory syncytial virus (RSV) infections were detected. The monthly cases of rhino/enterovirus infection were highest from winter to spring, with this temporal pattern differing from that of SARS-CoV-2. SARS-CoV-2 was detected more frequently (P < 0.001) in subjects with cough (31/104 cases, 29.8%) than in those without cough (13/224 cases, 5.8%), suggesting that cough might contribute to the prediction of COVID-19. Our findings also suggest that testing for rhino/enterovirus and parainfluenza virus 3, in addition to SARS-CoV-2, may be important for the rigorous diagnosis of respiratory virus infections. IMPORTANCE Influenza virus, RSV, adenovirus, and rhino/enterovirus were the major respiratory viruses before COVID-19 pandemic. Circulating respiratory viruses may have been affected by our strong quarantine policy during the COVID-19 pandemic. We checked the circulating respiratory viruses from our outpatients by using a multiplex PCR kit that had recently been released. SARS-CoV-2 was the most frequently detected virus, and it was followed by rhino/enterovirus and parainfluenza virus 3. No influenza virus or RSV infections were detected during our study period, suggesting that influenza virus and RSV became almost extinct. COVID-19 cases frequently experienced cough, and this frequency was statistically significantly higher than that observed in the cases without SARS-CoV-2 detection. The cough can be an indicator of COVID-19.

Imidafenacin, An Orally Active Muscarinic Receptor Antagonist, Improves Pulmonary Function In Patients With Chronic Obstructive Pulmonary Disease: A Multicenter, Randomized, Double-Blind, Placebo-Controlled 3×3 Crossover Phase II Trial.

Background: Although long-acting muscarinic receptor antagonists are central to the management of chronic obstructive pulmonary disease (COPD), inhaled medicines may have technical difficulty in some patients and adherence barriers. Methods: A multicenter, randomized, double-blind, placebo-controlled 3×3 crossover Phase II trial was performed to evaluate the efficacy and safety of oral administration of the antimuscarinic agent imidafenacin in patients with COPD. Twenty-seven male COPD patients with % forced expiratory volume in 1 s (FEV1) ≥30% and <80% predicted were randomized to single oral dose of imidafenacin 0.1 mg, imidafenacin 0.2 mg, or placebo. Results: Maximum change in FEV1 with both doses of imidafenacin significantly improved from baseline to 24 hrs after administration when compared with a placebo. Area under the curve in FEV1 during 24 hrs after administration with 0.2 mg, but not 0.1 mg dose, was significantly improved when compared with a placebo, and the improvement was significantly based on dose-dependent manners. Plasma imidafenacin level was positively correlated with change in FEV1. All subjects with both doses of imidafenacin completed without moderate nor severe adverse events. Conclusion: A single oral dose of imidafenacin 0.1 mg or imidafenacin 0.2 mg may contribute to the improvement of pulmonary function with excellent safety and tolerability in patients with COPD. Trial registration: JapicCTI-121760 (Japan Pharmaceutical Information Center - Clinical Trials Information [JapicCTI]; http://www.clinicaltrials.jp/user/cteSearch_e.jsp).

[A Survey on the Concurrent Administration of Erlotinib and Gastric Acid Suppressing Medications among Doctors:Concern for Drug Interaction].

Erlotinibis known as a key drug for the treatment of non-small-cell lung cancer. It is known to interact with gastric acid suppressing medications(AS). Concurrent administration of erlotinibwith AS is reported to decrease AUC and Cmax of erlotinib. From the result of a survey on concurrent administration of erlotinib with AS in our hospital, we considered that intake of erlotinib between meals in the morning and intake of AS after dinner or at bedtime certainly reduce the chance of drug interactions to a minimum. We suggested a direction of use of erlotinibto the doctors who used to prescribe this medication in their daily medical practice. We surveyed the doctors' perceptions of drug interactions. The results of the survey showed that 29% of the doctors were not concerned about drug interactions, although 81% of the doctors approved our proposal. By providing a suggestion for drug administration by analyzing drug information, the expectations of the doctors can be met and it also demonstrates the efficiency of pharmacists.

Meteorological effects on severe hemoptysis: A hospital-based observational study.

BACKGROUND: Although some meteorological factor are likely to contribute to the onset of hemoptysis, few studies have investigated this issue, with none conducted in the Asia-Pacific region. Therefore, the present study aimed to evaluate the associations of meteorological factors with the occurrence of hemoptysis. Differences in the frequency of hemoptysis among several calendar variables were also assessed. METHODS: A total of 47 hemoptysis patients aged ≥ 20 years undergoing bronchial artery embolization in Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers from January 2012 to December 2017 were included in the study. All hemoptysis events were assembled in a single time series, and the proportion of hemoptysis days was 2.1%. The associations of meteorological variables with hemoptysis days were estimated as odds ratios with 95% confidence intervals by using multivariable-adjusted logistic regression models. The frequency of hemoptysis days was compared among several calendar variables using a chi-square test. RESULTS: Mean relative humidity was negatively associated with hemoptysis (P for trend = 0.02). The inverse association remained significant when only the hemoptysis events with no infectious lung diseases were used (P for trend=0.02). No significant difference was observed in the occurrence of hemoptysis among seasons, months, or other calendar variables (all P ≥ 0.21). CONCLUSIONS: Lower relative humidity was a significant risk factor for the development of hemoptysis. Clinicians should be aware of the potential for increases in hemoptysis events on days with low ambient humidity.

Seasonal and meteorological impacts on primary spontaneous pneumothorax.

BACKGROUND: Although several studies have suggested that primary spontaneous pneumothorax (PSP) might occur in clusters, only a few studies have found seasonal variations in PSP occurrence. Some meteorological parameters might be related to the occurrence of PSP occurrence, however, the effects of weather variations on the onset of PSP are still controversial. METHODS: We examined seasonal differences in the occurrence of PSP and the meteorological risk factors for PSP. All PSP patients aged <40 years who were admitted to Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers from April 2007 through March 2013 were included in the study. RESULTS: The incidence rates of PSP were 16.7 and 2.1 per 100,000 person-years in men and women, respectively. The frequency of PSP days among months and seasons was significantly different with a peak in September and autumn. Daily changes in maximum wind speed had positive associations with PSP days [crude OR =1.11 (95% CI: 1.02-1.21) per 1 m/s, P=0.02; multivariable-adjusted OR =1.11 (95% CI: 1.00-1.23) per 1 m/s, P=0.05]. CONCLUSIONS: PSP tends to cluster seasonally. Increased wind speed may play a role in the development of PSP.

Prevalence of asthma with airflow limitation, COPD, and COPD with variable airflow limitation in older subjects in a general Japanese population: the Hisayama Study.

BACKGROUND: Elucidating the prevalence of asthma and chronic obstructive pulmonary disease (COPD) is important for designing a public health strategy. Recent studies have discriminated a phenotype of COPD with variable airflow limitation (COPD-VAL) associated with asthma-COPD overlap syndrome. Its prevalence remains uncertain. The age and occupational distributions in the town of Hisayama and in Japan are nearly identical. Each disease's prevalence was estimated for the town's residents. METHODS: In 2008, town residents (≥ 40 years) were solicited to participate in a health checkup. Individuals with abnormal spirometry (forced expiratory volume in 1s/forced vital capacity [FEV1/FVC]<70% and/or %FVC<80%) were recommended for further evaluations. Two pulmonologists in a blinded fashion reviewed their medical records, including bronchodilator reversibility. Individuals with airflow limitation were classified as having asthma, COPD, COPD-VAL, or other diseases. The prevalence of each disease was then estimated. RESULTS: A total of 2100 residents (43.4% of residents in the age group) completed spirometry. In 455 residents with abnormal spirometry, 190 residents had further evaluations, and the medical records of 174 residents were reviewed. The prevalence of asthma with airflow limitation, COPD, and COPD-VAL, were 2.0%, 8.4%, and 0.9%, respectively. The prevalence of COPD and COPD-VAL were higher in men and smokers than in women and never-smokers. The prevalence of COPD, but not COPD-VAL or asthma, increased with age. CONCLUSION: The prevalence of asthma with airflow limitation, COPD, and COPD-VAL were estimated in a population of residents (≥ 40 years) in Hisayama.

Low-dose salbutamol suppresses airway responsiveness to histamine but not methacholine in subjects with asthma.

BACKGROUND: Airway hyperresponsiveness is a cardinal feature of asthma. Although the modulation of cholinergic neuroeffector transmission may play a role in airway responsiveness, in vivo evidence remains scarce. It is well known that histamine causes bronchoconstriction partly via vagal reflex, whereas methacholine does not. To investigate the significance of modulating neuroeffector transmission, we compared the effect of low-dose salbutamol-a ß2-adrenoceptor agonist-on airway responsiveness to histamine with that to methacholine. METHODS: We enrolled 12 subjects with stable asthma. After screening confirmed that inhalation of low-dose salbutamol (1µg) did not change their basic pulmonary function, subjects underwent measurement of airway responsiveness to inhaled histamine and methacholine with or without pretreatment with low-dose salbutamol, in a randomized, crossover fashion. Airway responsiveness was measured by an astograph by which respiratory conductance (Grs) was assessed by the forced oscillation method during continuous inhalation of histamine or methacholine in stepwise incremental concentrations. Airway responsiveness was calculated as the cumulative dose of bronchoconstrictors that induced a decrease of 35% in Grs. RESULTS: Inhalation of 1µg of salbutamol significantly attenuated airway responsiveness to histamine but not methacholine. This selective attenuation was observed irrespective of disease severity or phenotype, namely atopy or non-atopy. CONCLUSION: Low-dose salbutamol suppresses airway responsiveness to histamine but not methacholine in subjects with asthma. The present study may provide a novel insight into the bronchoprotective mechanism of ß2-adorenoceptor agonist in clinical settings.

A juvenile case of pulmonary lymphangitic carcinomatosis caused by sigmoid colon cancer with a component of micropapillary carcinoma.

Micropapillary carcinoma is known to be associated with a poor prognosis and high propensity for lymphovascular invasion and lymph node metastasis. Case reports on colorectal micropapillary carcinoma are relatively rare. We report here a 26-year-old woman who had sigmoid colon cancer with a micropapillary component. We made the diagnosis of pulmonary lymphangitic carcinomatosis but could not identify the primary lesion. We gave her chemotherapy as an occult primary cancer. But her respiratory condition did not improve and she died of respiratory failure. Autopsy was performed after her death. The final diagnosis was pulmonary lymphangitic carcinomatosis and multiple lymph node metastases of sigmoid colon cancer with a component of micropapillary carcinoma.

Activation of PI3K-Akt pathway mediates antiapoptotic effects of beta-adrenergic agonist in airway eosinophils.

beta-Adrenoceptor agonists reportedly decrease spontaneous apoptosis of peripheral blood eosinophils; however, its signaling pathway is unknown. Survival signals can be elicited by the activation of phosphatidylinositol 3-kinase (PI3K) and Akt, both of which are known to be potent regulators of apoptosis, and Akt in turn inactivates Forkhead transcription factors, including FKHR (Forkhead in rhabdomyosarcoma). We have investigated the effect of beta-agonists on apoptosis of local eosinophils isolated from the airways and the involvement of PI3K, Akt, and FKHR in its survival signal. Eosinophils obtained from immunized mice by bronchoalveolar lavage after allergen provocation underwent apoptosis in a time-dependent manner. Incubation of eosinophils with isoproterenol or formoterol dose-dependently inhibited both spontaneous eosinophil apoptosis and apoptosis induced by Fas receptor activation. Incubation with cAMP or forskolin also inhibited eosinophil apoptosis. The PI3K inhibitors wortmannin and LY-294002 and an Akt inhibitor, 1-L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate, but not a mitogen-activated protein kinase kinase inhibitor PD-98059, blocked isoproterenol-mediated eosinophil survival. Wortmannin also inhibited cAMP-mediated eosinophil survival. Isoproterenol rapidly induced phosphorylation of Akt and FKHR in eosinophils in a PI3K-dependent manner. These findings indicate that the PI3K-Akt-FKHR pathway conveys a critical survival signal induced by beta-agonists in airway eosinophils.

[A case of relapsing polychondritis successfully assessed for airway diameters under application of bi-level positive airway pressure (bilevel PAP)].

A 52-year-old man was admitted to our department because of hypercapnic respiratory failure. His illness had begun with scleritis 5 years before, followed by swelling of the fingers and auricular cartilages and saddle nose 3 years before, when a clinical diagnosis of relapsing polychondritis was made. His chest CT after intubation revealed diffuse airway narrowing with complete collapse of both main bronchi on expiration. Though his clinical status was stabilized after initiation of mechanical ventilation and pulse-dose corticosteroid treatment, he was difficult to wean from the ventilator with a conventional on-off trial. We therefore assessed the diameters of the central airways using dynamic CT under application of bilevel PAP, which confirmed an improvement in airway patency. He was then successfully weaned from artificial ventilation using bilevel PAP, initially through tracheotomy and subsequently via a nasal mask. To our knowledge, this is the first report that confirms the advantage of bilevel PAP objectively for a patient with labile airways.

[A case of tuberculosis pleuritis with high serum soluble IL-2 receptor].

A 56-year-old man was admitted to our hospital because of bilateral pleural effusion. Computed tomography revealed solitary mediastinal lymphadenopathy, splenomegaly and a small amount of ascites. No lung parenchymal lesion was seen. Although lymphocyte predominance without atypia and a high adenocine deaminase concentration in the pleural fluid were compatible with tuberculous pleurisy, no mycobacteria could be detected either with Ziehl-Nielsen stain or with PCR. Because the serum soluble interleukin 2 receptor (sIL-2 R) level was unexpectedly high (> 8,000 U/ml), and a level not previously reported in benign diseases, we performed thoracoscopy- and mediastinoscopy-assisted biopsies, both of which eventually confirmed the diagnosis of tuberculosis. After a 4-drug anti-tuberculous regimen was initiated, pleural effusion and ascites subsided, with a marked decrease in the sIL-2R level. This case indicates that in tuberculous pleurisy, serum sIL-2R can rise to a level suggestive of hematological malignancies, it and also illustrates the validity of thoracoscopy-assisted pleural biopsy in such situations.

Differential regulation by glucocorticoid of interleukin-13-induced eosinophilia, hyperresponsiveness, and goblet cell hyperplasia in mouse airways.

Interleukin (IL)-13 induces important features of bronchial asthma such as eosinophilic infiltration, airway hyperresponsiveness (AHR), and mucus hypersecretion. Although glucocorticoids suppress airway inflammation and remain the most effective therapy for asthma, the effects of glucocorticoids on the IL-13-dependent features are unknown. We studied the effects of dexamethasone on eotaxin production, eosinophil accumulation, goblet cell hyperplasia, and AHR after IL-13 administration into the airways of mice in vivo. MUC5AC gene expression, a marker of goblet cell hyperplasia, was also analyzed. IL-13 alone dose dependently induced AHR. Treatment with dexamethasone inhibited eotaxin expression and completely abolished eosinophil accumulation, but it did not affect AHR, MUC5AC overexpression, or goblet cell hyperplasia induced by IL-13. The effects of tumor necrosis factor-alpha on IL-13-induced AHR were also examined. Tumor necrosis factor-alpha did not affect AHR despite marked enhancement of eosinophil infiltration in IL-13-treated mice. These findings suggest that glucocorticoid is not sufficient to suppress IL-13-induced AHR or goblet cell hyperplasia and that eotaxin expression and eosinophilic inflammation do not have a causal relationship to the induction of AHR or goblet cell hyperplasia by IL-13. Control of steroid-resistant features induced by IL-13, including AHR and mucus production, may provide new therapeutic modalities for asthma.

[Clinical features of five cases of pulmonary Langerhans' cell histiocytosis].

We reviewed the clinical features of 5 cases of Langerhans' cell histiocytosis that had been referred because of pulmonary lesions. The most frequent symptom was persistent dry cough. Chest radiographs showed bilateral, symmetric reticulonodular infiltrates and accompanying cystic changes with an upper-field predominance. Pulmonary function testing (PFT) revealed moderate restrictive impairment in 3 patients. All the above features were in accordance with previous reports. The incidence of complications was, however, higher in the present cases than reported in the literature. Four cases were complicated with diabetes insipidus (DI), which caused polydipsia and polyuria on the initial presentation and was subsequently managed with intranasal desmopressin. In 4 cases, bone lesions were detected. A bone scintigram at 99mTc proved to be useful for surveillance. All patients had been followed up closely for longer than 2 years (median duration 2.8 years). Their clinical courses were generally stable without apparent decline in PFT, except that one patient with a psychiatric problem died from hypernatremia due to misuse of desmopressin. Immunosuppressive agents were given in only 2 patients including the one who died. Four transbronchial biopsies (TBB) were performed in 4 cases and at least 3 specimens were sampled from each. Histological diagnoses were made from TBB specimens in 3 patients, while the remaining 2 patients underwent an open lung biopsy. We conclude that TBB is acceptable as an initial diagnostic attempt. Multiple sampling may also contribute to preferable yield. Regarding patient management, we suggest that DI and bone lesions should be sought extensively as their incidence may be much higher than previously estimated.