Akira Shiraki

Risk Factors for Drug-Resistant Pathogens in Community-acquired and Healthcare-associated Pneumonia

RATIONALE Identification of patients with drug-resistant pathogens at initial diagnosis is essential for treatment of pneumonia. OBJECTIVES To elucidate clinical features of community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP), and to clarify risk factors for drug-resistant pathogens in patients with CAP and HCAP. METHODS A prospective observational study was conducted in hospitalized patients with pneumonia at 10 institutions in Japan. Pathogens identified as not susceptible to ceftriaxone, ampicillin-sulbactam, macrolides, and respiratory fluoroquinolones were defined as CAP drug-resistant pathogens (CAP-DRPs). MEASUREMENTS AND MAIN RESULTS In total, 1,413 patients (887 CAP and 526 HCAP) were analyzed. CAP-DRPs were more frequently found in patients with HCAP (26.6%) than in patients with CAP (8.6%). Independent risk factors for CAP-DRPs were almost identical in patients with CAP and HCAP. These included prior hospitalization (adjusted odds ratio [AOR], 2.06; 95% confidence interval [CI], 1.23-3.43), immunosuppression (AOR, 2.31; 95% CI, 1.05-5.11), previous antibiotic use (AOR, 2.45; 95% CI, 1.51-3.98), use of gastric acid-suppressive agents (AOR, 2.22; 95% CI, 1.39-3.57), tube feeding (AOR, 2.43; 95% CI, 1.18-5.00), and nonambulatory status (AOR, 2.45; 95% CI, 1.40-4.30) in the combined patients with CAP and HCAP. The area under the receiver operating characteristic curve for counting the number of risk factors was 0.79 (95% CI, 0.74-0.84). CONCLUSIONS The clinical profile of HCAP was different from that of CAP. However, physicians can predict drug resistance in patients with either CAP or HCAP by taking account of the cumulative number of the risk factors. Clinical trial registered with https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000004001&language=E ; number UMIN000003306.

Role of Ca2+ mobilization and Ca2+ sensitization in 8-iso-PGF2α-induced contraction in airway smooth muscle

Background Isoprostanes are prostaglandin (PG)‐like compounds synthesized by oxidative stress, not by cyclooxygenase, and increase in bronchoalveolar lavage fluid of patients with asthma. The airway inflammation implicated in this disease may be amplified by oxidants. Although isoprostanes are useful biomarkers for oxidative stress, the action of these agents on airways has not been fully elucidated.

Interstitial pneumonia associated with MPO-ANCA: Clinicopathological features of nine patients

Myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) is a well known marker for small vessel vasculitis. Recent reports have demonstrated that interstitial pneumonia (IP) may rarely be associated with serum MPO-ANCA. Yet, little is known about the histological features. We reviewed surgical lung biopsy from nine patients with IP of uncertain etiology with serum MPO-ANCA. There was a male predominance (6:3) with a median age of 62.1. Histologically, eight patients presented with a usual interstitial pneumonia (UIP) pattern of pulmonary fibrosis, frequently accompanied by areas of nonspecific interstitial pneumonia (NSIP) pattern. One patient showed diffuse alveolar damage (DAD), and two patients showed mixture of UIP and DAD reflecting acute exacerbation of UIP. Microscopic honeycomb cysts were common, but fibroblastic foci were inconspicuous. The most frequent additional findings were small airway disease (9/9), and lymphoid follicles (7/9). Neither capillaritis nor vasculitis was seen in any of our cases. Three patients had microscopic hematuria, but none progressed to microscopic polyangiitis during the follow up. Mortality rate was 44% (median follow up 39.1 months). IP associated with MPO-ANCA showed characteristic histology dominated by UIP pattern. Vasculitis was not identified in our cohort, but small airways disease and lymphoid follicles were present in most cases. IP associated with MPO-ANCA may be a histologically distinctive disease from idiopathic pulmonary fibrosis. Mortality was relatively high and life threatening acute exacerbation may occur.

Pleuropulmonary pathology of vascular Ehlers–Danlos syndrome: spontaneous laceration, haematoma and fibrous nodules

Kawabata Y, Watanabe A, Yamaguchi S, Aoshima M, Shiraki A, Hatamochi A, Kawamura T, Uchiyama T, Watanabe A & Fukuda Y
(2010) Histopathology 56, 944–950
Pleuropulmonary pathology of vascular Ehlers–Danlos syndrome: spontaneous laceration, haematoma and fibrous nodules

Inhibition by the cold receptor agonists menthol and icilin of airway smooth muscle contraction

Menthol, known as a cold receptor agonist, has widely been used in the relief of respiratory symptoms such as coughing and chest congestion. Previous studies have demonstrated that menthol reduces bronchoconstriction and airway hyperresponsiveness. The aim of this study was to examine the effects of menthol and icilin, another cold receptor agonist, on airway smooth muscle contraction. Isometric force was monitored using epithelium-denuded tracheal smooth muscle tissues isolated from guinea pigs. Intracellular Ca(2+) concentrations were assessed by fura-2 fluorescence. (-)Menthol (0.01-1mM) inhibited contraction induced by methacholine (MCh, 0.01-10microM) and high extracellular K(+) concentrations (20-60mM) in a concentration-dependent manner. Moreover, the increases of intracellular Ca(2+) concentrations induced by MCh or high K(+) were significantly reduced by (-)menthol. Icilin (100microM) also significantly attenuated contraction induced by MCh or high K(+). The inhibitory effect of 1mM (-)menthol on MCh-induced contraction was significantly higher at cool temperature (24-26 degrees C) than at 37 degrees C. The present results demonstrate that inhibition of Ca(2+) influx plays an important role in the menthol-mediated inhibition of contraction in airway smooth muscle. Furthermore, our findings indicate that stimulation of unknown cold receptors may be involved in these mechanisms. These findings suggest that the use of menthol is beneficial for reducing respiratory symptoms because of its inhibitory effects on airway smooth muscle contraction.

Role of Ca2+ mobilization in desensitization of β-adrenoceptors by platelet-derived growth factor in airway smooth muscle

Platelet-derived growth factor (PDGF), which is released from eosinophils and fibroblasts, may be implicated in the pathophysiology of bronchial asthma. To examine the involvement of airway inflammation in beta-adrenergic desensitization, the present study was designed to determine whether pre-exposure to PDGF deteriorates beta-adrenoceptor function in airway smooth muscle. We focused on Ca(2+) signaling as an intracellular mechanism involved in this phenomenon. Isometric tension and F(340)/F(380) (an indicator of intracellular Ca(2+) concentration) induced by isoprenaline and other cAMP-related agents were simultaneously measured before and after exposure to PDGF in fura-2-loaded guinea-pig tracheal smooth muscle. Indomethacin was applied throughout the experiments to abolish prostaglandin synthesis by PDGF. After exposure of the tissues to 10 ng/ml PDGF for 15 min, the effects of isoprenaline, a beta-adrenoceptor agonist, and forskolin, a direct inhibitor of adenylyl cyclase, against methacholine-induced contraction were markedly reduced with increasing F(340)/F(380). However, in the presence of verapamil, an inhibitor of voltage-dependent Ca(2+) channels, the reduced responsiveness to isoprenaline and forskolin induced by pre-exposure to PDGF was reversed with reducing F(340)/F(380). Reduced responsiveness to isoprenaline by PDGF was also not observed in the presence of Ca(2+)-free solution. The inhibitory effects of db-cAMP, an analogue of cAMP, and theophylline, a nonselective inhibitor of phosphodiesterase, were not attenuated by PDGF. In conclusion, pre-exposure to PDGF causes impairment of the beta-adrenoceptors/adenylyl cyclase processes in airway smooth muscle that is independent of cyclooxygenase synthesis by PDGF. Ca(2+) mobilization by Ca(2+) influx through voltage-dependent Ca(2+) channels is involved in this heterologous desensitization of beta-adrenoceptors.

Role of Sphingosine-1-Phosphate in β-adrenoceptor Desensitization via Ca2+ Sensitization in Airway Smooth Muscle

BACKGROUND The correlation between inflammatory cells and airway smooth muscle plays fundamental roles in the pathophysiology of asthma. This study was designed to determine whether pre-exposure of airway smooth muscle to sphingosine-1-phosphate (S1P), which is released from mast cells by allergic reactions, causes a deterioration of β-adrenoceptor function. METHODS Isometric tension and the ratio of fluorescence intensities at 340 and 380 nm (F(340)/F(380)), an indicator of intracellular Ca2+ levels, were simultaneously measured using fura-2 loaded guinea-pig tracheal tissues. Intracellular cAMP levels were also measured. RESULTS Pre-exposure to S1P caused a reduction in the inhibitory effects of 0.3μM isoprenaline, a β-adrenoceptor agonist, and 10μM forskolin, a direct activator of adenylyl cyclase, against 1μM methacholine-induced contraction in concentration- and time- dependent manners. In contrast, the values of F(340)/F(380) were not augmented under this experimental condition. After incubation with S1P in the presence of 0.001-1μM Y-27632, a Rho-kinase inhibitor, the reduced responsiveness to forskolin induced by S1P was reversed in a concentration-dependent manner. Moreover, pre-treatment with pertussis toxin (PTX), an inhibitor of G(i), suppressed the loss of forskolin-induced relaxation induced by S1P. Pre-exposure to S1P markedly inhibited the augmentation of cAMP accumulation induced by forskolin. However, addition of Y-27632 and pre-exposure to PTX returned forsokin-induced cAMP accumulation to the control level. CONCLUSIONS Pre-exposure to S1P causes heterologus desensitization of β-adrenoceptors by increasing the sensitivity of airway smooth muscle to intracellular Ca2+. Ca2+ sensitization regulated by G(i) and Rho-kinase is involved in this phenomenon.

How Many Passes Are Needed for Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for Sarcoidosis? A Prospective Multicenter Study

Background: While endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is widely used as an initial diagnostic procedure for pathological confirmation of sarcoidosis, it is unclear how many passes are required to obtain diagnostic materials. Objectives: The aim of this study was to determine the number of needle passes needed for the diagnosis of stage I/II sarcoidosis using EBUS-TBNA. Methods: At three institutions, 109 patients with suspected stage I/II sarcoidosis were recruited and underwent 6 passes of EBUS-TBNA for the main target lesion. Additional EBUS-TBNA for other lesions was permitted. The cumulative yields of needle passes for detecting noncaseating epithelioid cell granulomas were analyzed. Results: A total of 109 patients underwent EBUS-TBNA for 184 lesions. EBUS-TBNA identified specimens containing granulomas in 81 of 92 patients (88%) with a final diagnosis of sarcoidosis. The cumulative yields through the first, second, third, fourth, fifth, and sixth passes for the main target lesion were 63, 75, 82, 85, 86 and 88%, respectively. In the 55 patients that underwent EBUS-TBNA for multiple lesions, the cumulative yields of 2 passes per lesion for 2 lesions (total of 4 passes) and of 4 passes for single lesions were 86 and 84%, respectively (p = 1.00). Conclusions: If rapid on-site cytological evaluation is not available, we recommend at least 4 passes per patient for either single or multiple lesions with EBUS-TBNA for pathological diagnosis of stage I/II sarcoidosis.

Domiciliary High-Flow Nasal Cannula Oxygen Therapy for Patients with Stable Hypercapnic Chronic Obstructive Pulmonary Disease. A Multicenter Randomized Crossover Trial

Rationale: A growing evidence base suggests a benefit of using high‐flow nasal cannula oxygen therapy in the acute setting. However, the clinical benefit of domiciliary use of high‐flow nasal cannula oxygen therapy in patients with chronic hypercapnic respiratory failure due to chronic obstructive pulmonary disease remains unclear. Objectives: To evaluate the efficacy and safety of high‐flow nasal cannula oxygen therapy use in patients with stable chronic obstructive pulmonary disease. Methods: We conducted a multicenter, randomized crossover trial comparing high‐flow nasal cannula oxygen therapy plus long‐term oxygen therapy with long‐term oxygen therapy only in 32 adults with stable hypercapnic chronic obstructive pulmonary disease. Participants were randomized to receive either 6 weeks of high‐flow nasal cannula oxygen therapy/long‐term oxygen therapy using the myAIRVO 2 device followed by another 6 weeks of long‐term oxygen therapy only or long‐term oxygen therapy only followed by high‐flow nasal cannula oxygen therapy/long‐term oxygen therapy. The primary outcome was the change in quality of life as assessed by St. Georges Respiratory Questionnaire for chronic obstructive pulmonary disease. A linear mixed‐effects model was used to account for treatment effect, time effect, allocation effect, and participant effect. Results: Of 32 study participants, 29 completed the study. At the end of 12 weeks, high‐flow nasal cannula oxygen therapy/long‐term oxygen therapy treatment improved the mean total St. Georges Respiratory Questionnaire for chronic obstructive pulmonary disease score compared with long‐term oxygen therapy only (7.8 points; 95% confidence interval, 3.7 to 11.9; P < 0.01). Similarly, high‐flow nasal cannula oxygen therapy/long‐term oxygen therapy treatment improved the arterial partial pressure of carbon dioxide (adjusted treatment effect, −4.1 mm Hg; 95% confidence interval, −6.5 to −1.7 mm Hg), pH (adjusted treatment effect, +0.02; 95% confidence interval, 0.01 to 0.02), and median nocturnal transcutaneous carbon dioxide pressure (adjusted treatment effect, −5.1 mm Hg; 95% confidence interval, −8.4 to −1.8 mm Hg). High‐flow nasal cannula oxygen therapy/long‐term oxygen therapy treatment did not improve the arterial partial pressure of oxygen, dyspnea, spirometry, lung volume, 6‐minute walk test, or physical activity. The most frequent high‐flow nasal cannula oxygen therapy‐related adverse event encountered was nocturnal sweating (n = 6 [20.7%]). Four severe adverse events occurred (two in each group) and were deemed unrelated to the intervention. Conclusions: Six weeks of treatment with high‐flow nasal cannula oxygen therapy improved health‐related quality of life and reduced hypercapnia in patients with stable hypercapnic chronic obstructive pulmonary disease. &NA; Clinical trial registered with www.clinicaltrials.gov (NCT02545855) and www.umin/ac.jp (UMIN000017639).

Anti-glycyl tRNA synthetase antibody associated interstitial lung disease without symptoms of polymyositis/dermatomyositis.

To the Editor: The anti-aminoacyl tRNA synthetase (ARS) antibody syndrome has large association with interstitial lung disease (ILD). The ARSs are a set of cellular enzymes, each of which catalyzes the formation of aminoacyl tRNA from a specific amino acid and its cognate tRNA. They can be found in; 25–35% of patients with chronic inflammatory muscle disorders, polymyositis (PM) and dermatomyositis (DM). Autoantibody to glycyl tRNA synthase (anti-EJ) is a form of eight anti-ARS antibodies identified in patients with PM/DM. Each of these anti-ARS antibodies has been reported to be associated with a similar syndrome, anti-synthetase syndrome, characterized by myositis with a high frequency of interstitial lung disease (ILD) (50–80%), arthritis (50–90%), and skin lesions of the fingers referred to as ‘mechanic’s hands’ (70%). Among those symptoms, ILD is the most serious life-threatening complication. Some cases of ILD with antiARS-antibody were reported to have no symptoms of myositis. The similarity of clinical features in patients with different anti-ARS antibodies is known, but some reports indicated that there are certain differences in clinical symptoms associated with each of the anti-ARS antibodies. Among eight anti-ARS antibodies, the most common antibody in all patients is anti-Jo-1 (35%). Anti-EJ positive patients are fewer (5–20%), but for the cases with ILD, anti-EJ is the most common antibody (20–35%). Although pulmonary manifestations and radiological findings of ILD in patients with anti-EJ have been reported, no reports have described the pathological features. In this report we describe the radiological and pathological features of an anti-EJ antibody positive patient with ILD, who had the no symptoms of PM/DM. A 56-year-old woman presented progressive nonproductive cough and dyspnea on exertion, with Medical Research Council dyspnea scale of grade 2, for 3 months. Her X-ray showed abnormal shadows. She was a neversmoker and had no significant medical history. She had no other environmental risk factors for respiratory disease except for the use of feather comforter. She was admitted to the hospital for a detailed assessment of her respiratory problem. On physical examination, fine crackles were heard on chest auscultation. Though Raynaud’s phenomena, arthralgia, morning stiffness and xerostomia were found, they didn’t fulfill the diagnostic criteria of any certain connective tissue disease. The blood gas analysis showed a mild hypoxia. The C-reactive protein level was elevated (2.90 mg/dL). The serum levels of Krabs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) were increased (1045 U/mL and 149.6 ng/mL, respectively). The patient’s serum were positive for anti EJ antibody, but negative for antinuclear antibody, other types of anti-ARS antibodies, and other autoantibodies suggesting autoimmune disorders. Pulmonary function test showed slight respiratory disability and diffusion function disorder. Bronchoalveolar lavage (BAL) fluid with differential cell counts were performed in left B5. The total cell number was 5.69 × 10/mL, and lymphocytes dominated at 45% in which the CD4/8 ratio was as low as 0.19. Sets of chest X-ray and high resolution computed tomography (HRCT) were obtained on admission and 2 months after the biopsy. Chest X-ray on admission revealed infiltrative shadows in the bilateral lung(Fig. 1a) and HRCT showed diffuse ground-glass opacities and areas of consolidation along the bronchovascular bundles predominantly in the lower lobes (Fig. 1c) After a video-assisted thoracic surgical (VATS) biopsy, due to rapid progression of the dyspnea, the patient was treated with methylprednisolone 1 g/day for 3 days followed by 40 mg/day of prednisolone with Cyclosporine A, 150 mg/day, for 22 days. Due to the significant improvement of respiratory symptoms and radiographic abnormality, the patient was discharged 70 days after her admission. No recurrent ILD was identified with 4 months’ follow up. Follow up radiograms after the therapy showed remarkable improvement for both bilateral lung fields (Fig. 1b,d). Video-assisted thoracic surgical (VATS) lung biopsy was performed to the left lower lobe superior segment, S6, and anterior basal segment, S8. Both specimens showed similar histological findings. Under the light microscope, the lesion was characterized by the pattern of nonspecific interstitial pneumonia (NSIP), showing moderate cellular inflammatory cell infiltration and mild increase of fibroblast in the alveolar septa. There was a slight centriacinar accentuation, but basically all areas of the lobule were diffusely affected. No area with complete normal lung was found. In addition to the findings typically seen in ordinary NSIP cases, acute inflammatory processes such as exudative edema in both airspace and alveolar septa, presence of a few organizing pneumonia (OP) foci of Masson body type, scattered airspace fibrin, denudation of the pneumocytes, and enlargement of alveolar Disclosure: None of the authors have any financial and personal relationships with other people or organizations that could inappropriately influence. Pathology International 2014; 64: 148–150 doi:10.1111/pin.12140 bs_bs_banner