A randomized controlled trial of long-acting muscarinic antagonist and long-acting ß2 agonist fixed-dose combinations in patients with chronic obstructive pulmonary disease.

BACKGROUND: In chronic obstructive pulmonary disease (COPD) patients, combination treatment with long-acting muscarinic antagonist (LAMA) and long-acting ß2 agonist (LABA) increases forced expiratory volume in one second and reduces symptoms compared to monotherapy. In Japan, three different once-daily fixed-dose combinations (FDCs) have been prescribed since 2015, although a direct comparison of these FDCs has never been performed. The objective of the present study was to compare the effectiveness, preference, and safety of three LAMA/LABA FDCs-glycopyrronium/indacaterol (Gly/Ind), umeclidinium/vilanterol (Ume/Vil), and tiotropium/olodaterol (Tio/Olo)-in patients with COPD. METHODS: We enrolled 75 COPD outpatients (male:female ratio, 69:6; 77.4 ± 6.9 years). A prospective, randomized, crossover study was conducted on three groups using three FDCs: Gly/Ind; Ume/Vil; and Tio/Olo. Each medication was administered for 4 weeks before crossover (total 12 weeks). After each FDC administration, a respiratory function test and questionnaire survey were conducted. A comparative questionnaire survey of all three LAMA/LABA FDCs was conducted after 12 weeks (following administration of final FDC). RESULTS: No significant differences in COPD Assessment Test or modified Medical Research Council dyspnea questionnaire were reported in the surveys completed after each FDC administration; no significant differences in spirometric items were observed. In the final comparative questionnaire survey, patients reported better actual feeling of being able to inhale following Gly/Ind administration compared with Tio/Olo, although no significant differences in adverse events or other evaluations were reported. CONCLUSIONS: The three LAMA/LABA FDCs administered to COPD patients show similar effects and safety, although some minor individual preference was reported. Trial registration This study retrospectively registered with the University Hospital Medical Information Network Clinical Trials Registry (number UMIN000041342, registered on August 6, 2020).

Prevalence and causes of chronic cough in Japan.

BACKGROUND: Chronic cough is one of the most common symptoms of respiratory diseases and can adversely affect patients' quality of life and interfere with social activities, resulting in a significant social burden. A survey is required to elucidate the frequency and treatment effect of chronic cough. However, clinical studies that cover all of Japan have not yet been conducted. METHODS: Patients who presented with a cough that lasted longer than 8 weeks and visited the respiratory clinics or hospitals affiliated with the Japan Cough Society during the 2-year study period were registered. RESULTS: A total of 379 patients were enrolled, and those who did not meet the definition of chronic cough were excluded. A total of 334 patients were analyzed: 201 patients had a single cause, and 113 patients had two or more causes. The main causative diseases were cough variant asthma in 92 patients, sinobronchial syndrome (SBS) in 36 patients, atopic cough in 31 patients, and gastroesophageal reflux (GER)-associated cough in 10 patients. The time required to treat undiagnosed patients and those with SBS was significantly longer and the treatment success rate for GER-associated cough was considerably poor. CONCLUSIONS: We confirmed that the main causes of chronic cough were cough variant asthma, SBS, atopic cough, and their complications. We also showed that complicated GER-associated cough was more likely to become refractory. This is the first nationwide study in Japan of the causes and treatment effects of chronic cough.

[Intense 18F-fluorodeoxyglucose uptake due to allergic bronchopulmonary aspergillosis].

A 61-year-old woman was admitted with a tumor-like lesion in the middle lobe of the right lung which showed substantial uptake on 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET). The chief complaint was dry cough. On the basis of these findings, lung cancer was first to be ruled out. However, subsequent examinations showed Aspergillus fumigatus in sputum and aspergillus-specific IgE and IgG antibodies in the serum. The tumor-like lesion gradually disappeared. Allergic bronchopulmonary aspergillosis without clinical symptom of bronchial asthma was diagnosed with Rosenberg's clinical criteria. The patient's condition stabilized after treatment with inhaled corticosteroid and oral itraconazole. To our knowledge, this is the second report of allergic bronchopulmonary aspergillosis with tumor-like lesions in the lung showing intense 18FDG-PET uptake.

Eosinophilic Pneumonia Putatively Induced by Vancomycin: A Case Report.

BACKGROUND Herein, we describe a case of eosinophilic pneumonia that was likely to have been induced by vancomycin. CASE REPORT A 65-year-old man on maintenance hemodialysis presented with chest pain and dyspnea. He subsequently developed methicillin-resistant Staphylococcus aureus-positive acute pleural empyema in an evacuated right-sided pneumothorax. Surgical thoracoscopic curettage was ultimately performed, but dyspnea recurred postoperatively. Computed tomography depicted widespread reticular shadowing of the left lung, and peripheral eosinophilia was detected. The proportion of eosinophils found in bronchoalveolar lavage fluid was also remarkable (43%). All symptoms and the results of laboratory tests immediately improved after the discontinuation of vancomycin and initiation of prednisolone therapy. CONCLUSIONS We attribute this case of eosinophilic pneumonia to vancomycin, because all other candidate causes were ruled out, and only vancomycin fulfilled the criteria of both drug-induced eosinophilic pneumonia and drug-induced lung injury. If confirmed, this constitutes the first reported case of vancomycin-induced eosinophilic pneumonia.

[Case of acute respiratory failure caused by drug-induced lung injury by shiniseihaito].

We present a case of acute respiratory distress syndrome (ARDS) caused by allergic reactions to shiniseihaito. An 84-year-old woman showed acute interstitial pneumonia followed by ARDS after taking shiniseihaito for the treatment of rhinitis. The ARDS were markedly improved with corticosteroid therapy. This case was diagnosed as being induced by shiniseihaito because it was compatible with 4 of 5 of Camus's criteria. The stimulation index of the drug lymphocyte stimulation test with shiniseihaito increased after corticosteroid therapy had been tapered and suggested that the mechanism of acute interstitial pneumonia in this case was allergic reaction induced by shiniseihaito. This is the seventh reported case of drug induced lung injury by shiniseihaito. We recommend careful observation when this medicine is prescribed.

[Two cases of AIDS diagnosed by onset of interstitial pneumonia].

Case 1: A 35-year-old man admitted for fever and respiratory failure during several weeks was found in chest computed tomography (CT) to have interstitial pneumonia, and the plasma beta-D-glucan level indicated Pneumocystis jiverocii pneumonia. Psoriasis from second-stage syphilis raised the suspicion of HIV infection. Serum anti-HIV-1 antibody proved positive and CD4-positive lymphocytes in peripheral blood were 18/microL. The man died despite treatment. Autopsy confirmed P. jiverocii pneumonia. Case 2: A 28-year-old man seen for a fever and respiratory failure was found in chest CT to have mild interstitial pneumonia. We checked for hypersensitivity pneumonitis, Mycoplasma pneumoniae pneumonia, etc. The plasma beta-D-glucan level indicated possible P. jirovecii pneumonia and immunodeficiency. Serum anti-HIV-1 antibody proved positive and CD4-positive lymphocytes in peripheral blood were 34/microL. The man was treated successfully, using trimethoprim with sulfamethoxazole for his interstitial pneumonia. His clinical symptoms were compatible with P. jirovecii pneumonia. P. jirovecii pneumonia with AIDS may present with more subacute or subtle symptoms than other immunosuppressive diseases, making it difficult to diagnose. Medical professionals should thus make it a point to familiarize themselves with AIDS prevention.

[Case of Behçet's disease with frequent recurrence of multiple pulmonary abscess-like opacities].

A 39-year-old woman, who had a history of recurrent oral and genital ulcerations and folliculitis and had had a low-grade fever since December 2003, consulted our hospital on February 5, 2004. Chest radiography and computed tomography (CT) showed multiple pulmonary abscess-like opacities. She was admitted to the Department of Respiratory Medicine and Allergology, Kinki University School of Medicine on February 19, 2004. A transbronchial lung biopsy showed nonspecific inflammation with lymphocytic infiltration. The patient was discharged after she showed improvement with antibiotic therapy. She was readmitted to our hospital on October 3, 2006, because of recurrence of pulmonary abscess-like opacities. Bronchoalveolar lavage showed lymphocytosis (53%) but yielded no significant bacteria on culture. Behçet's disease was diagnosed on the basis of the three major symptoms (recurrent oral and genital ulcerations and folliculitis). The frequent recurrence of pulmonary lesions was suspected to be due to immunological impairment associated with Behçet's disease, and the pulmonary lesions and inflammatory reaction tests showed improvement after colchicine was administered. The patient was discharged on October 28, 2006. To our knowledge this is the third reported case of frequently recurrent multiple pulmonary abscess-like opacities in Behçet's disease.

Which inhaled corticosteroid and long-acting ß-agonist combination is better in patients with moderate-to-severe asthma, a dry powder inhaler or a pressurized metered-dose inhaler?

Two main types of devices are used to facilitate the administration of inhaled corticosteroid (ICS) and long-acting ß-agonist (LABA) in combination, dry powder inhalers (DPIs) and pressurized metered-dose inhalers (pMDIs). There are few reports comparing the effects of the two devices, and it is unknown which should be recommended for asthma patients with given sets of characteristics. In the current study, the beneficial effects and side effects associated with DPIs and pMDIs were compared, and the question of which device should be recommended for asthma patients was investigated. A prospective, randomized, crossover, comparative study in adult outpatients with asthma was conducted using salmeterol/fluticasone propionate combination (SFC) 50 µg/250 µg, one inhalation of Adoair® 250 Diskus® twice daily or two inhalations of Adoair® 125 Aerosol twice daily, for 8 weeks. Questionnaires, exhaled nitric oxide (FeNO) tests and pulmonary function tests were administered after the use of each device for 8 weeks, and the results derived from each device were compared. Sixty-eight subjects were included in the final analysis. There were no significant differences between quality-of-life scores, FeNO, spirometry test results and forced oscillation results. With regard to patient preferences, 57.4% preferred the Adoair® Aerosol and 35.3% preferred the Adoair® Diskus®, as determined via the comparative evaluation questionnaire. Although DPI prescription accounts for the predominant market share of combined ICS/LABA in Japan, patients preferred a pMDI device to a DPI device. Compared to DPIs, pMDIs may be the preferential choice for patients with asthma.

[Survival by a young woman with malnutrition due to alcoholism and eating disorders and with acute respiratory distress syndrome due to severe pneumonia who showed increased serum neutrophil elastase activity].

A 30-year-old woman with malnutrition due to alcoholism and eating disorders was found to have acute respiratory distress syndrome (ARDS) and sepsis due to severe Streptococcus pneumoniae pneumonia. S. pneumoniae was detected by an in vitro rapid immunochromatographic assay for S. pneumoniae antigen in urine on the day of admission and by blood culture 2 days after admission. Symptoms and laboratory findings improved after treatment with sivelestat sodium hydrate, antibiotics, and mechanical ventilation. Treatment with sivelestat sodium hydrate also decreased serum neutrophil elastase activity. This case demonstrates the usefulness of early treatment with sivelestat sodium hydrate in ARDS due to severe pneumonia.

Questionnaire on switching from the tiotropium HandiHaler to the Respimat inhaler in patients with chronic obstructive pulmonary disease: changes in handling and preferences immediately and several years after the switch.

BACKGROUND: Tiotropium (Spiriva) is an inhaled muscarinic antagonist for patients with chronic obstructive pulmonary disease (COPD), and is available in two forms: the HandiHaler and the Respimat inhaler. The aim of this study was to investigate the handling of and preference for each device immediately after switching from the HandiHaler to the Respimat and 2-3 years after the switch. MATERIALS AND METHODS: The study comprised two surveys. A questionnaire was first administered to 57 patients with COPD (male:female 52:5, mean age 73.6±7.1 years) 8 weeks after switching from the HandiHaler (18 µg) to the Respimat (5 µg). A second similar but simplified questionnaire was administered to 39 of these patients who continued to use the Respimat and were available for follow-up after more than 2 years. Pulmonary function was also measured during each period. RESULTS: In the first survey, 17.5% of patients preferred the HandiHaler, and 45.6% preferred the Respimat. There were no significant changes in pulmonary function or in the incidence of adverse events after the switch. In the second survey, performed 2-3 years later, the self-assessed handling of the Respimat had significantly improved, and the number of patients who preferred the Respimat had increased to 79.5%. CONCLUSION: The efficacy of the Respimat was similar to that of the HandiHaler. This was clear immediately after the switch, even in elderly patients with COPD who were long-term users of the HandiHaler. The preference for the Respimat increased with continued use.

[Surviving case of Legionella pneumonia showing a high level of serum KL-6 and complicated with rhabdomyolysis].

A 66-year-old man was admitted to our hospital with pyrexia up to 40 degrees C since one day after taking a public bath. Since multiple infiltrations on the lung were shown by chest radiography, severe pneumonia was diagnosed. Administration of antibiotics meropenem and erythromycin yielded no detected effect. Furthermore, rifampicin induced severe liver dysfunction. Improvement of clinical symptoms was seen after ciprofloxacine (CPFX) was given. Interstitial pneumonia, increases in KL-6 up to a level of 3545 U/ml and acute respiratory failure were improved by taking methylprednisolone. Since Legionella antigen was found in the urine, the use of CPFX was continued. Rhabdomyolysis and acute renal failure were successfully treated by transfusion, diuretic therapy, and glucocorticoid therapy. This was a very rare case of survival after Legionella pneumonia complicated with acute respiratory failure, acute renal failure, rhabdomyolysis, and interstitial pneumonia accompanied with a high KL-6 level, and successfully treated with steroids and CPFX.

[A case of a slow-growing, non-mucin-producing bronchioloalveolar carcinoma with a 9-year clinical history before thoracoscopic surgery].

A 73-year-old woman was followed up with high-resolution computed tomography (HRCT) from 2000 through 2002 because an area of ground-glass opacity in area S1 + 2 of the left upper lobe was found on HRCT in August 2000. The opacity was present on ordinary CT scans obtained in 1993, but had not been recognized. Thoracoscopic partial resection of the left lung was performed on October 8, 2002. Pathologic examination of the resected specimen showed localized bronchioloalveolar carcinoma (Noguchi's type B). Tumor doubling time was 1718 days from 1993 to August 2000 and 273 days from August 2000 through 2002. This case of adenocarcinoma with bronchioloalveolar growth was characterized by initial slow growth followed by accelerated growth, no mucin production, and a long interval from the detection of opacity to surgery.

Effects of inhaled aminophylline on airway constriction and inflammation in ovalbumin-sensitized guinea pigs.

BACKGROUND: The systemic administration of theophylline is useful for asthma treatment. However its narrow therapeutic range makes it difficult to use. Little is known about its potential in inhalation therapy, particularly repeated inhalation. OBJECTIVE: The purpose of this study is to investigate the therapeutic usefulness of inhaled aminophylline in an asthma model. METHODS: The effects of pretreatment with inhaled aminophylline (25 mg/mL for 30 min/dose) on airway response and inflammation after an ovalbumin (OVA) challenge and airway hypersensitivity to acetylcholine (Ach) were evaluated using guinea pigs sensitized with OVA. RESULTS: Aminophylline relaxed the ACh-induced contraction of tracheal smooth muscle in vitro in a concentration-dependent manner. Pretreatment with single-dose aminophylline inhalation suppressed OVA-induced airway constriction to the same extent as the intraperitoneal pretreatment with high-dose aminophylline (10-20 mg/kg). However, pretreatment with single-dose aminophylline inhalation did not suppress eosinophil infiltration into airways (neither bronchoalveolar lavage [BAL] fluid nor lung tissue) and did not suppress airway hyperreactivity to ACh, 24 h after OVA challenge. Repeated inhalation of aminophylline (twice daily for 7 days) suppressed the infiltration of eosinophils and suppressed airway hypersensitivity to ACh. In addition, high concentrations of aminophylline inhibited production of oxygen radicals by BAL cells. CONCLUSION: Single-dose inhalation treatment with aminophylline has transient but relatively strong bronchodilating effects due to delivery of high doses into local airways. Repeated inhalation treatment suppressed airway inflammation and hypersensitivity induced by allergens. Therefore, inhaled aminophylline may be useful for asthma treatment.

Efficacy of indacaterol on quality of life and pulmonary function in patients with COPD and inhaler device preferences.

BACKGROUND: Indacaterol is a novel, once-daily, inhaled, long-acting b2-agonist for patients with chronic obstructive pulmonary disease (COPD). The study objective was to evaluate the efficacy of indacaterol on quality of life and pulmonary function in patients with COPD in a real-world setting, and also to evaluate its inhaler device (Breezhaler®), which is important for both adherence and management. METHODS: Twenty-eight outpatients with COPD were treated with indacaterol (150 µg once daily for 8 weeks), and the effects on pulmonary function were evaluated using a questionnaire survey with the modified Medical Research Council (mMRC) dyspnea scale and COPD assessment test (CAT) before and after treatment. Similar investigations were also performed separately among different baseline medications. Moreover, original questionnaire surveys for indacaterol and its device were performed. RESULTS: Overall, mMRC dyspnea scale and CAT scores significantly improved (1.96±1.04 to 1.57±1.07 and 17.39±8.23 to 12.82±8.42, respectively; P<0.05). Significant improvements in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were also observed on pulmonary function tests (2.91±0.66 L to 3.07±0.65 L and 1.46±0.60 L to 1.58±0.59 L, respectively; P<0.05). Replacement therapy from salmeterol to indacaterol significantly improved mMRC and FVC values, but did not significantly improve CAT scores or other pulmonary functions. Add-on therapy with indacaterol significantly improved mMRC score, CAT score, FVC, and FEV1, regardless of whether tiotropium was used as a baseline treatment. All subjects in a questionnaire survey found the inhaler device easy to use. There were no serious adverse events leading to treatment discontinuation. CONCLUSION: Indacaterol is thought to be effective and well tolerated as a bronchodilator for the management of COPD. Treatment with indacaterol in addition to a long-acting muscarinic antagonist was also useful.