Role of prostaglandin E2 in bronchoconstriction-triggered cough response in guinea pigs.

A feature of cough variant asthma is a heightened cough response to bronchoconstriction. The mediators of this response are unknown. This study was designed to elucidate the role of lipid mediators in bronchoconstriction-triggered cough response in an experimental animal model. We examined the influence of bronchoconstriction on cell components and mediators including prostaglandin E2 (PGE2) in bronchoalveolar lavage fluid (BALF). We studied the cough response to bronchoconstriction (CRB) by measuring the correlation between the increase in enhanced pause (Penh), an index of bronchoconstriction, and cough counts induced by methacholine (Mch) inhalation in conscious guinea pigs. We then examined the effects of intraperitoneal pretreatment with 16, 16-dimethyl-prostaglandin E2 (dm-PGE2) on CRB and cough counts. The total number of cells and cell components in the BALF were not influenced by bronchoconstriction. While levels of PGE2, prostaglandin I2, and cysteinyl leukotrienes were significantly increased, levels of prostaglandin D2, thromboxane B2, and substance P in the BALF were not. Dm-PGE2 significantly decreased the Mch-induced increase in Penh. Following bronchoconstriction by additional Mch inhalation, dm-PGE2 produced an increase in CRB and cough counts in a dose-dependent manner. Additionally, the heightened CRB following dm-PGE2 treatment was suppressed by pretreatment with PGE2 receptor (E-prostanoid EP) -1 and EP-3 antagonists in a dose-dependent manner, but not by EP-2 and EP-4 antagonists. The EP-1 antagonist also decreased cough counts. These results suggest that PGE2 acts as an exacerbating factor for bronchoconstriction-triggered cough. EP1 and EP3 may provide new therapeutic targets for cough variant asthma.

Effects of pirfenidone on increased cough reflex sensitivity in guinea pigs.

Pirfenidone, an antifibrotic drug with anti-inflammatory and antioxidant effects, delays fibrosis in idiopathic pulmonary fibrosis (IPF). Patients with IPF have a greater cough reflex sensitivity to inhaled capsaicin than healthy people, and cough is an independent predictor of IPF disease progression; however, the effects of pirfenidone on cough reflex sensitivity are unknown. After challenge with an aerosolized antigen in actively sensitized guinea pigs, pirfenidone was administered intraperitoneally, and the cough reflex sensitivity was measured at 48 h after the challenge. Bronchoalveolar lavage (BAL) was performed, and the tracheal tissue was collected. Pirfenidone suppressed the capsaicin-induced increase in cough reflex sensitivity in a dose-dependent manner. Additionally, increased levels of prostaglandin E2, substance P, and leukotriene B4, but not histamine, in the BAL fluid were dose dependently suppressed by pirfenidone. The decrease in neutral endopeptidase activity in the tracheal tissue was also alleviated by pirfenidone treatment. The total number of cells and components in the BAL fluid was not influenced. These results suggest that pirfenidone ameliorates isolated cough based on increased cough reflex sensitivity associated with allergic airway diseases, and potentially relieve chronic cough in IPF patients who often have increased cough reflex sensitivity. Prospective studies on cough-relieving effects of pirfenidone in patients with IPF are therefore warranted.

Successful treatment with chemotherapy and corticosteroids of pulmonary Mycobacterium abscessus infection accompanied by pleural effusion.

We describe a 50-year-old woman with rapidly progressive pulmonary Mycobacterium abscessus (M. abscessus) infection accompanied by pleural effusion and organizing pneumonia (OP). CT scan showed consolidation, centrilobular shadows, ground-glass opacity (GGO), and cavities. A transbronchial lung biopsy showed nonnecrotizing granuloma surrounded by infiltrative lymphocyte-dominant inflammatory cells, and lymphocytes in bronchoalveolar lavage fluid (BALF) were increased. We considered OP occurred secondary to M. abscessus infection because clarithromycin, amikacin, and imipenem/cilastatin administration resulted in partial improvement. We added corticosteroids to the regimen, which resulted in a remarkable improvement. We report a case of pulmonary M. abscessus infection involving pleural effusion that responded favorably to medical therapy including corticosteroids.

An effective case of bronchoscopic balloon dilatation for tuberculous bronchial stenosis.

Endobronchial tuberculosis often causes bronchial stenosis. Balloon dilation is a minimally invasive and effective bronchoscopic intervention for bronchial stenosis; however, reports on balloon dilation in older individuals are limited. We present a case of a 77-year-old woman with endobronchial tuberculosis and clarify the efficacy and safety of balloon dilation. She presented with dyspnea, right lung atelectasis, and respiratory failure 55 days after initiation of antituberculosis therapy. We performed bronchoscopic balloon dilatation for the right main bronchial stenosis. Consequently, respiratory failure rapidly improved. Chest computed tomography (CT) showed improved lung atelectasis; however, severe bronchial stenosis and rhonchi persisted. Therefore, we performed a second balloon dilatation. CT 3 months after the first balloon dilation showed right upper bronchial stenosis and right lung middle lobe atelectasis. Restenosis was absent 21 months after third balloon dilatation. Bronchoscopic balloon dilation is effective for restenosis with repeated treatment and can be safely performed in older individuals.

Heightened cough response to bronchoconstriction in cough variant asthma.

BACKGROUND AND OBJECTIVE: The pathophysiology of cough variant asthma (CVA) is poorly understood. We compared bronchoconstriction-triggered cough between CVA patients and normal control (NC) subjects. METHODS: There were two protocols in the study. We measured bronchial responsiveness to methacholine (MCh) and counted the number of coughs in nine CVA patients and seven NC subjects (study A). Using partial and full flow-volume curves, expiratory flow of the partial flow-volume curve at 40% above residual volume level (PEF40) and FEV(1) were used to measure bronchoconstriction. Mild bronchoconstriction was defined as a 35% fall in PEF40 (PC(35) -PEF40), and more severe bronchoconstriction as a 20% fall in FEV1 (PC20) -FEV(1) ). In study B, the same measurements were obtained in six CVA patients before and after therapy. RESULTS: In study A, more coughs were provoked at PC35 -PEF40 in CVA patients (median, 60 coughs/32 min post challenge; range, 12-135) than in NC subjects (median, 0/32 min; range, 0-13; P < 0.05). At PC20 -FEV1 , more coughs were provoked in CVA patients (median, 60/32 min; range, 12-150) than in NC subjects (median, 20/32 min; range, 0-54; P < 0.05). In study B, the six CVA patients who underwent re-examination after treatment had less coughs at PC35 -PEF40 (median, 3/32 min; range, 0-14) and PC(20) -FEV1 (median, 13/32 min; range, 3-26) after therapy than before therapy (median, 54/32 min; range, 33-125 and 52/32 min, 45-96, respectively; P < 0.05). CONCLUSIONS: We identified heightened cough response to bronchoconstriction as a feature of CVA.

Effects of macrolides on antigen-induced increases in cough reflex sensitivity in guinea pigs.

BACKGROUND: Macrolides are antibiotics that have anti-inflammatory activities. Hence, they are used for both acute and chronic inflammatory airway diseases. However, the effects of these agents on allergic airway disorders presenting with an isolated chronic cough, such as non-asthmatic eosinophilic bronchitis and eosinophilic tracheobronchitis with cough hypersensitivity (atopic cough), still remain to be elucidated. OBJECTIVE: To determine if macrolides are effective in the management of chronic cough caused by eosinophilic airway inflammation. METHODS: The cough reflex sensitivity to inhaled capsaicin was measured at 48h after challenge with an aerosolized antigen in actively sensitized guinea pigs. The 14-, 15- or 16-membered macrolides (erythromycin, azythromycin, or josamycin, respectively) were given intraperitoneally every 12h after the antigen challenge. Bronchoalveolar lavage and the resection of the tracheal tissue were performed immediately after the measurement of the cough response to capsaicin. RESULTS: The antigen-induced increase in the number of coughs elicited by capsaicin inhalation was significantly reduced by treatments with erythromycin and azythromycin, but not with josamycin. Erythromycin dose-dependently inhibited the increases in the substance P, prostaglandin E(2) and leukotriene B(4) levels, but not the histamine levels, in the bronchoalveolar lavage fluid. However, erythromycin did not influence the antigen-induced decrease in the neutral endopeptidase (NEP) activity in the tracheal tissue. CONCLUSIONS: Both 14- and 15-membered, but not 16-membered, macrolides could reduce the antigen-induced cough reflex hypersensitivity by inhibiting the antigen-induced release of the afferent sensory nerve sensitizers. These macrolides may be therapeutically useful for the treatment of isolated chronic cough based on cough reflex hypersensitivity in allergic airway diseases such as non-asthmatic eosinophilic bronchitis and atopic cough.

Bronchoconstriction-triggered cough is impaired in typical asthmatics.

BACKGROUND AND OBJECTIVE: Cough is an essential innate protective behavior, which is experienced by even healthy individuals. The mechanism of cough triggered by bronchoconstriction is not yet clear. The aim of this study was to investigate the relation between bronchoconstriction and cough caused by methacholine (Mch) inhalation in typical asthmatics and normal healthy subjects. METHODS: We measured bronchial responsiveness to Mch and counted the number of coughs induced by Mch inhalation in 15 typical asthmatics and 20 normal subjects. RESULTS: After inhalation of Mch at the concentration causing 20% or more decrease in forced expiratory volume in 1 second (FEV(1)) (PC(20)-FEV(1)), coughs were provoked in normal subjects (number of cough: 22.5/32 min, range: 3.3-45). Conversely, coughs were hardly provoked in typical asthmatics (median number of cough: 2/32 min, range: 0-4). CONCLUSIONS: Although typical asthmatics have increased airway responsiveness, their cough response to bronchoconstriction is impaired.

Internal Pancreatic Fistula with Pleural Effusion Showing Elevated Levels of Amylase That Emerged 29 Years after Abdominal Surgery.

A 65-year-old woman presented to a hospital with complaints of dyspnea and lumbar pain. Chest computed tomography (CT) showed left pleural effusion. Thoracentesis showed pleural effusion with elevated levels of amylase. Enhanced CT showed fluid accumulation from the thoracic crus of the diaphragm to the left iliopsoas muscle. Based on the postoperative notes following left nephrectomy performed 29 years ago, we suspected that the internal pancreatic fistula had resulted from the postoperative scar. Conservative management was performed. However, occlusion of the pancreatic fistula failed. Subsequently, she underwent pancreatic body tail spleen merger resection, and the pleural effusion disappeared.

Evaluation of airway hyperresponsiveness and exhaled nitric oxide as risk factors for airway remodeling in patients with stable asthma.

Chronic eosinophilic airway inflammation, airflow limitation, and airway hyperresponsiveness (AHR) are distinctive features of bronchial asthma. Exhaled nitric oxide (eNO) is a marker of eosinophilic airway inflammation. Airway remodeling due to chronic airway inflammation results in fixed airway obstruction. Asthmatic patients have been reported to have greater declines in forced expiratory volume in 1 second (FEV(1)) over time than nonasthmatic patients. This longitudinal observational study aimed to elucidate outcomes and risk factors for the decline in FEV(1) in patients with stable asthma. Postbronchodilator FEV(1) was measured in 30 outpatients with stable asthma every 6 months for 5 years. We calculated the rate of decline in postbronchodilator FEV(1) (deltaFEV(1)/year) in each subject and adjusted deltaFEV(1)/year with predictive FEV(1). Patients were examined while their asthma was well controlled. In the first observation period, we measured AHR to methacholine (the provocative concentration of methacholine causing a 20% fall in FEV(1) [PC(20)]). In the second observation period (defined as the period over 2 years from start of observation), we measured methacholine PC(20) and eNO. The mean deltaFEV(1)/year (SEM) was -36 +/- 4 mL/year and the adjusted deltaFEV(1)/year (SEM) was -0.015 +/- 0.001/year. Adjusted deltaFEV(1)/year did not correlate with eNO measured during the second observation period or methacholine PC(20) measured during the first observation period. On the other hand, methacholine PC(20) measured during the latter period was correlated significantly with adjusted deltaFEV(1)/year. Persistent AHR may be a risk factor for longitudinal decline in FEV(1) in asthma patients even if their asthma is stable and well controlled by inhaled corticosteroid.

[A case of Churg-Strauss syndrome with methylprednisolone sodium succinate allergy].

A 63-year-old man with a history of therapy for asthma was admitted to a neighborhood hospital for treatment of a lower limb blister, accompanied by edema, pain and systemic fever. Churg-Strauss syndrome was diagnosed based on an increase in peripheral blood eosinophils, positive MPO-ANCA and other findings. He was given an injection of methylprednisolone sodium succinate; however his lower limb pain, fever and peripheral blood eosinophilia worsened. Therefore, steroid-resistant Churg-Strauss syndrome was diagnosed, for which he was referred to our hospital for more intensive treatment. His lower limb pain, fever, peripheral blood eosinophilia and inflammatory reactions improved immediately after switching treatment to oral prednisolone. Since a challenge test using an intravenous infusion of methylprednisolone sodium succinate worsened the lower limb pain, fever and peripheral blood eosinophilia, a drug allergy was diagnosed together with Churg-Strauss syndrome.

[A case of severe asthma exacerbation complicated with cerebral edema and diffuse multiple cerebral micro-bleeds].

A 36-year-old woman was admitted to the Intensive Care Unit for the treatment of severe asthma exacerbation. Her condition of asthma improved with systemic glucocorticosteroids, inhaled beta2-agonist, intravenous theophylline and inhaled anesthesia (isoflurane) under mechanical ventilation. Her consciousness was disturbed even after terminating isoflurane. Brain CT and MRI scan showed cerebral edema and diffuse multiple cerebral micro-bleeds. Glyceol, a hyperosmotic diuretic solution consisting of 10% glycerol and 5% fructose in saline, was administered to decrease cerebral edema. Her consciousness disturbance gradually recovered. Cerebral edema and hemorrhage improved. On the 69th hospital day, she was discharged from hospital without sequelae. This case is a rare one in which severe asthma exacerbation was complicated with cerebral edema and diffuse multiple cerebral hemorrhage. Inhaled anesthesia for asthma exacerbation should be used carefully to avoid delay of diagnosis of central nervous system complications.

[Asymptomatic pulmonary actinomycosis diagnosed by transbronchial lung biopsy (TBLB)].

A 65-year-old asymptomatic man was admitted to our hospital because a chest abnormal shadow had been pointed out on a medical examination. Our investigation resulted that the consolidation in the left lung had been initially documented in 2002, and had been expanding every year. Bronchofiberscopy showed flare, swelling and stenosis of the left B8, B9 and B10. Because the biopsy specimen from the B9 showed a mass of bacteria and surrounding granulation tissue, pulmonary actinomycosis was diagnosed. Pulmonary actinomycosis should be considered in the differential diagnosis of abnormal chest shadows regardless of the absence of symptoms.

Randomized phase II trial of OK-432 in patients with malignant pleural effusion due to non-small cell lung cancer.

To determine the optimum dose of OK-432 for intrathoracic administration, a multicenter randomized phase II trial was conducted in patients with malignant pleural effusion due to non-small cell lung cancer. Patients with histologically- or cytologically-proven malignant pleural effusions were randomized to arm A (10 Klinische Einheit (KE) of OK-432) or arm B (1 KE of OK-432). OK-432 was injected intrapleurally over 30 min on days 1 and 3 and the chest tube was clamped for 6 h. If control was inadequate on day 8, 10 KE was administered on days 8 and 10 in each treatment arm. Forty patients were enrolled and 38 patients were eligible (19 in arm A and 19 in arm B). The effusion control rate on day 8 was 79% in arm A and 53% in arm B, while control rates on day 28 were 74% and 84%, respectively. The median drainage time after administration was significantly shorter in arm A (4.0 +/- 1.2 days) than in arm B (7.0 +/- 1.7 days). The total drainage volume was also significantly less in arm A than in arm B. No grade 4 toxicities or treatment-related deaths were observed in either treatment arm. Intrathoracic injection of OK-432 is a feasible treatment for malignant pleural effusion. Although the malignant pleural effusion control rate was equivalent in each treatment arm, faster control and less drainage were achieved in arm A. A dose of OK-432 10 KE/body is, therefore, recommended for further trial.

[A case of left diaphragmatic eventration treated by thoracoscopic plication].

A 59-year-old woman was admitted to our hospital because of left diaphragmatic eventration due to a left phrenic nerve injury following surgery for recurrent thyroid cancer. She underwent plication by thoracoscopic surgery followed by marked expansion of the left lung and improvement of pulmonary function and dyspnea on exercise. Thoracoscopic plication for diaphragmatic eventration is a useful minimally invasive surgical technique.

[A case of broncho-pulmonary aspergillosis complicated by bronchial asthma attack].

A 55-year-old man was hospitalized for the treatment of severe asthma. However, his condition improved with steroid chemotherapy under artificial ventilation, but high fever and multiple patchy shadows of the lung that were not responsive to antibiotics appeared. We detected aspergillus hyphae, probably inhaled with a quantity of dust in the attic of his workplace, in the sputum. We diagnosed invasive broncho-pulmonary aspergillosis complicated with allergic broncho-pulmonary aspergillosis. His condition improved with anti-fungal drug treatment. We consider that the causes of invasive broncho-pulmonary aspergillosis in this case were massive inhalation of aspergillus conidia, artifical ventilation and steroid chemotherapy.

Pulmonary manifestations of anti-ARS antibody positive interstitial pneumonia--with or without PM/DM.

BACKGROUND: Autoantibodies against aminoacyl-tRNA synthetases (ARS) have been found to be highly specific for polymyositis and dermatomyositis (PM/DM) and to correlate strongly with complicating interstitial pneumonia (IP). The aim of the present study was to compare the clinical presentations of anti-ARS antibody-positive IP patients with or without manifestations of PM/DM. METHODS: We retrospectively examined 36 IP patients with anti-ARS antibodies. Sixteen patients presented with and 20 without the features of PM/DM. They were divided into PM/DM-IP and idiopathic-IP (IIP) groups. Clinical symptoms, findings on physical examination, laboratory data, pulmonary function, computed tomography (CT), and bronchoalveolar lavage fluid (BALF) cell counts were compared. RESULTS: Skin findings, myalgia, and elevation of serum creatinine kinase were found in the PM/DM-IP group. Features common to both groups included: volume loss in lower bilateral lobes; ground-glass opacities, reticular shadows and traction bronchiectasis on chest CT; high percentage of lymphocytes (IIP: 44.0% ± 21.0% (mean ± SD), PM/DM-IP: 50.5% ± 23.5%) and low CD4/8 ratios (IIP: 0.36 ± 0.34, PM/DM-IP: 0.44 ± 0.42) in BALF; decreased pulmonary function, including percentage of predicted vital capacity (VC) (IIP: 80.1% ± 15.4%, PM/DM-IP: 73.6% ± 16.4%), residual volume (RV) (IIP: 70.7% ± 21.7%, PM/DM-IP: 71.5% ± 17.1%), total lung capacity (TLC) (IIP: 73.4% ± 13.6%, PM/DM-IP: 71.6% ± 13.0%), and diffusing capacity DLco (IIP: 57.5% ± 26.7%, PM/DM-IP: 46.4% ± 10.3%). Both groups achieved good responses to initial corticosteroid or immunosuppressant therapy. CONCLUSION: Patients with anti-ARS antibody-positive IP have common pulmonary manifestations regardless of the presence of PM/DM.

Transformation to small-cell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma.

We report the case of a 52-year-old woman with lung adenocarcinoma treated with EGFR tyrosine kinase inhibitor (TKI) therapy. After disease progression, histological examination of a secondary biopsy specimen revealed small-cell lung cancer (SCLC) that was sensitive to standard SCLC treatment. Tumor markers, including ProGRP and NSE, were elevated. Transformation to SCLC is a mechanism for acquired resistance to EGFR-TKI therapy. Secondary biopsy is important for evaluation of genetic and histological changes and selection of appropriate treatment. Furthermore, ProGRP and NSE may be useful for early detection of SCLC transformation in cases resistant to EGFR-TKI therapy.

Pulmonary T-cell lymphoma with pulmonary arterial hypertension.

We report on a 73-year-old man with systemic lymphadenopathy and chest computed tomography (CT) findings of bilateral diffuse ground-glass opacities and interlobular septal thickening. He also had pulmonary arterial hypertension (PAH). Several lymph node biopsies were attempted, without a definitive diagnosis. A thoracoscopic lung biopsy was performed, and the specimen was diagnosed as peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Lymphoma cells had invaded lung vessels, resulting in PAH. We should include pulmonary lymphoma in the differential diagnosis of patients with PAH and chest CT findings of diffuse ground-glass opacities and interlobular septal thickening.

Bronchodilator effect of deep inspiration and bronchoconstriction-triggered cough.

BACKGROUND: Cough in the patients with cough variant asthma is triggered by bronchoconstriction, which responds to bronchodilator therapy. Following airway narrowing induced by inhaled methacholine, deep inspiration (DI) causes dilation of the airways in both asthmatic and non-asthmatic subjects. The aim of the present study was to investigate the relationship between bronchodilator effect of DI and bronchoconstriction-triggered cough. METHODS: We measured airway responsiveness to methacholine using partial and full flow-volume curves in 28 healthy adults. The expiratory flow at 40% above residual volume from the full forced vital capacity (MEF40) was obtained and the volume was used as the reference volume to determine the isovolume flow from the partial curve (PEF40). Coughs were counted for 32 min during and following the inhalation of methacholine at the provocative concentration which produced a 20% fall or more in FEV1from the post-saline value (PC20-FEV1). The bronchodilator effect of DI on bronchoconstriction induced by methacholine at the PC20-FEV1 concentration was expressed as the ratio of (MEF40-PEF40)/PEF40 (DI index). RESULTS: The number of coughs for 32 min during and following the inhalation of PC20-FEV1 concentration of methacholine was 39.3 +/- 29.7 (mean +/- SD)/32 min. The number of coughs during and following the inhalation was correlated with DI index (r = 0.57, p = 0.0015), but not with PC20-FEV1 or change in FEV1 or PEF40 by inhalation of the PC20-FEV1 concentration of methacholine. CONCLUSION: We found that methacholine-induced cough was associated with the bronchodilator effect of DI on methacholine induced-bronchoconstriction in normal subjects.