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OBJECTIVE: To study the effect of posture on the hypercapnic ventilatory responses (HCVR). DESIGN: Nonrandomized controlled study. SETTING: Rehabilitation hospital and a pulmonary institute. PARTICIPANTS: Patients with neurologically stable C(5-8) tetraplegia (n=12) and healthy control subjects (n=7). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Supine and seated forced vital capacity (FVC) and HCVR, and supine and erect blood pressure. RESULTS: FVC in the sitting position was reduced in patients with tetraplegia (52+/-13% predicted); supine FVC was 21% higher (P=.0005). In the sitting position, HCVR was lower in patients than in controls (0.8+/-0.4 vs 2.46+/-0.3 L/min/mmHg, P<.001). Supine HCVR was not significantly different between the groups. When HCVR was normalized to FVC, there was still a significant difference between patients and controls in the sitting position. Patients with tetraplegia were orthostatic (mean supine blood pressure 91+/-13 mmHg vs mean erect blood pressure 61+/-13 mmHg, respectively, P<.0001). The magnitude of the orthostatism correlated with that of the postural change in HCVR (r=.93, P<.0001). CONCLUSIONS: Respiratory muscle weakness may contribute to the attenuated HCVR in tetraplegia. However, the observation that supine HCVR is still low even when normalized to FVC suggests a central posture-dependent effect on the HCVR, which may be linked to the postural effect on arterial blood pressure. © 2009 by the American Congress of Rehabilitation Medicine [ABSTRACT FROM AUTHOR]

Relapsing polychondritis (RP) is a rare disease characterized by recurrent inflammation of cartilaginous and other proteoglycan-rich tissues. Respiratory tract involvement is a common cause of morbidity and mortality in RP. We describe a patient whose clinical features at onset of disease were typical of asthma. Later, the patient developed symptoms and signs characteristic of RP. Tracheobronchomalacia necessitated airway support by stenting. The possibility that airway obstruction in the initial stages of RP is due to airway inflammation and that early, aggressive immunosuppressive treatment of RP may delay or prevent irreversible cartilaginous destruction and airway collapse are discussed. [ABSTRACT FROM AUTHOR]

Purpose: We studied the effect of O 2 supplementation on physiological response to exercise in patients with moderate to severe interstitial lung disease (ILD)., Methods: Thirteen patients (age 66 ± 10 yr, 7 males) with ILD (total lung capacity, 71% ± 22% predicted; carbon monoxide diffusion capacity, 44% ± 16% predicted) and 13 healthy individuals (age 50 ± 17 yr, 7 males) were tested. ILD patients performed symptom-limited cardiopulmonary exercise tests and constant work rate (WR) tests at 80% of the WR at the gas exchange threshold. Tests breathing room air (RA; 21% O 2 ) were compared with tests performed breathing 30% O 2 . Oxygen uptake (V̇O 2 ) kinetics were calculated from the constant WR test results., Results: In the ILD group, peak WR, peak V̇O 2 , and V̇O 2 at the gas exchange threshold improved significantly when breathing 30% O 2 compared with RA (mean ± SD, 75 ± 26 vs 66 ± 23 W, 17 ± 4 vs 15 ± 2 mL·kg -1 ·min -1 , and 932 ± 245 vs 854 ± 232 mL·min -1 ; P = 0.004, P = 0.001, and P = 0.01, respectively). O 2 saturation (SpO 2 %) at peak exercise was higher with 30% O 2 (97% ± 4% vs 88% ± 9%, P = 0.002). The time constant (tau) of V̇O 2 kinetics was faster in ILD patients while breathing 30% O 2 (41 ± 10 s) compared with RA (52 ± 14 s, P = 0.003). There was a negative linear relation between tau and SpO 2 % with RA ( r = -0.76, P = 0.006) and while breathing 30% O 2 ( r = -0.68, P = 0.02)., Conclusions: Using a clinically applicable level of O 2 supplementation (30%) improved maximal, aerobic exercise capacity and V̇O 2 kinetics in ILD patients, likely due to increased blood O 2 content subsequently increasing the O 2 delivery to the working muscles., (Copyright © 2024 by the American College of Sports Medicine.)

Background: Evaluation of unexplained exercise intolerance is best resolved by cardiopulmonary exercise testing (CPET) which enables the determination of the exercise limiting system in most cases. Traditionally, pulmonary function tests (PFTs) at rest are not used for the prediction of a respiratory limitation on CPET., Objective: We sought cut-off values on PFTs that might, a priori, rule-in or rule-out a respiratory limitation in CPET., Methods: Patients who underwent CPET in our institute were divided into two groups according to spirometry: obstructive and non-obstructive. Each group was randomly divided 2:1 into derivation and validation cohorts respectively. We analyzed selected PFTs parameters in the derivation groups in order to establish maximal and minimal cut-off values for which a respiratory limitation could be ruled-in or ruled-out. We then validated these values in the validation cohorts., Results: Of 593 patients who underwent a CPET, 126 were in the obstructive and 467 in the non-obstructive group. In patients with obstructive lung disease, forced expiratory volume in 1 second (FEV 1 ) ≥ 61% predicted could rule out a respiratory limitation, while FEV 1 ≤ 33% predicted was always associated with a respiratory limitation. For patients with non-obstructive spirometry, FEV 1 of ≥ 73% predicted could rule-out a respiratory limitation. Application of this algorithm might have saved up to 47% and 71% of CPETs in our obstructive and non-obstructive groups, respectively., Conclusion: Presence or absence of a respiratory limitation on CPET can be predicted in some cases based on a PFTs performed at rest., Competing Interests: Conflicts of interest The authors have nothing to declare., (Copyright © 2023 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Plasma asymmetric dimethylarginine (ADMA) is elevated in pulmonary arterial hypertension (PAH) and is associated with unfavorable outcomes., Objectives: The aim of this study was to assess changes in ADMA plasma levels for monitoring disease progression and outcomes during PAH-specific therapy., Methods: ADMA was measured at baseline and after at least 6 months of follow-up using enzyme-linked immunosorbent assay and high-performance liquid chromatography. Changes in ADMA were analyzed in relation to changes in established PAH markers, including hemodynamic status, N-terminal pro-brain natriuretic peptide (NT-proBNP) and risk assessment scores. Impact on survival was assessed using Kaplan-Meier curves and Cox proportional hazards models., Results: Between 2008 and 2019, ADMA samples were collected prospectively from 215 patients with PAH. Change in ADMA plasma level was a predictor of disease progression and survival. ΔADMA (median -0.03 μmol/L; 95% CI: -0.145 to 0.0135) was correlated with change in mean pulmonary arterial pressure (P < 0.005; r S  = 0.287) but was not significantly correlated with ΔNT-proBNP (P = 0.056; r S  = 0.135). Patients with decreased ADMA plasma levels at follow-up had better 3-year and 5-year survival rates (88% and 80%, respectively, vs 72% and 53% in those without decreases in ADMA) (P < 0.005; pulmonary hypertension-related mortality or lung transplantation). Patients with decreases in both ADMA and NT-proBNP had better survival rates compared with patients in whom only 1 parameter improved (P < 0.005). ΔADMA was a significant predictor of survival in Cox regression analysis and also when corrected for ΔNT-proBNP (HRs: 1.27 and 1.35, respectively; P < 0.005)., Conclusions: ADMA and NT-proBNP provide synergistic prognostic information for patients with PAH. ADMA could be used as an objective and distinct biomarker for monitoring treatment response in PAH., Competing Interests: Funding Support and Author Disclosures This research was partially funded by the Medical Scientific Fund of the Mayor of the City of Vienna (AP15173BGM/KP15173BGM). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. All rights reserved.)

We report 8 cases of persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia in patients previously treated with anti-CD20 monoclonal antibodies. Polymerase chain reaction of nasopharyngeal swabs for SARS-CoV-2 was negative in most cases; viral cell cultures confirmed that viable SARS-Co-2 virus was present. Four patients were treated with anti-SARS-CoV-2 hyperimmune globulins with rapid resolution of disease., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Acute exacerbations of COPD (AECOPD) drastically affect the clinical course of the disease. We aimed to evaluate the treatment of AECOPD in the internal medicine departments in Israel, nationwide., Methods: The COPD Israeli survey (COPDIS) is the first national survey of patients admitted with AECOPD to internal medicine departments between 2017 and 2019. The survey includes prospective ( n  = 344) and retrospective ( n  = 1,166) data from 13 medical centers. We analyzed the pre-hospital, in-hospital, and pre-discharge care. Hospital evaluation, outcomes and discharge recommendations were assessed as well., Results: The mean (±SD) age was 74 (±8) years, and 54% were males. 74% had comorbidities, and 88% had a diagnosis of COPD in their history. 70% of the patients received systemic steroids and antibiotics during their hospitalization, yet upon discharge, a lower rate of antibiotics prescription (10%) was found. Treatment with most long-acting bronchodilators dramatically dropped during admission, compared with their pre-hospital use. Overall, a long-acting bronchodilator (LABD) was used by 47% before admission, 28% in-hospital, and was prescribed to 54% at discharge. The discharge plan included a referral to pulmonary rehabilitation in only 11% and a smoking cessation recommendation in 43% of active smokers. The in-hospital mortality was 3% and the 1-year mortality rate was 25%. In multivariate analysis, performing a chest X-ray (adjusted OR 0.64, 95% CI 0.46-0.90) and prescribing LABD at discharge (AOR 0.73, 95% CI 0.57-0.95) were independent predictors for lower 1-year mortality., Conclusion: Our results demonstrate AECOPD characteristics in Israel, and highlight several important gaps in AECOPD healthcare, which must be addressed to improve patient care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bar-Shai, Freund, Ovdat, Segel, Klempfner and Elis.)

Background: Nontuberculous mycobacterial (NTM) pleuritis is an uncommon manifestation of NTM infection. Case reports and small case series have shown a variable clinical course and high mortality rates., Objective: To describe patients' characteristics, clinical presentation and outcomes of NTM pleural infections., Methods: A systematic review of cases of NTM pleural infections published in PubMed-indexed journals from 1980 to 2021., Results: A total of 206 cases of NTM pleural infections were found and analyzed. Fifty-eight percent of cases were males. The mean age was 57.5 yrs (range 9-87 yrs). Forty-three percent of patients were immunosuppressed, and 43% had a chronic lung disease; thirty-two percent had neither risk factor. In addition to the pleural infection, 67% of cases had a concurrent pulmonary NTM infection, and in 18 cases there was another extrapulmonary site of NTM infection. In 29% of cases the pleural infection was the sole manifestation of NTM disease. The most common isolated mycobacterium was Mycobacterium avium complex (65%). Fifty-three percent and 26% of patients required pleural effusion drainage and a surgical intervention, respectively, to treat the infection, in addition to anti-NTM chemotherapy. Forty percent of patients developed pneumothorax, 16% suffered from empyema, and 16.5% had broncho-pleural fistula. The reported mortality rate was 24%., Conclusion: NTM pleural infections may arise in immunocompetent and immunosuppressed patients, with or without chronic lung disease or concurrent NTM pulmonary infection. These infections carry a poor prognosis and a high risk of complications requiring surgical interventions in addition to anti-NTM chemotherapy., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The transcription factor GATA2 plays a key role in the survival and self-renewal of hematopoietic stem and progenitor cells. Autosomal dominant variants in GATA2 cause a broad spectrum of heterogeneous phenotypes. Here, we present our experience with GATA2 deficiency in a retrospective multicenter analysis of computerized medical records of adult patients (age ≥18 years) treated between 2018 and 2022 at Shaare Zedek Medical Center in Jerusalem and Sheba Tel-Hashomer Medical Center in Ramat Gan, Israel. Two male and two female patients with GATA2 deficiency were identified. Three of the patients presented with symptoms in adult life and all patients were diagnosed as adults. Age at presentation was 10.5-36 years and age at diagnosis 24-47 years. Diagnosis was delayed in all patients by 1-24.5 years. The phenotypic diversity was notable. Patients presented with myelodysplastic syndrome (n=2), pulmonary alveolar proteinosis (n=1), and recurrent viral (n=1), bacterial (n=3), and mycobacterial (n=1) infections. Bone marrow biopsy revealed cytogenetic abnormalities in one patient (monosomy 7). Patients were diagnosed by exome sequencing (n=3) and Sanger sequencing of the coding exons in GATA2 (n=1). Novel heterozygous GATA2 variants (c.177C>A, p.Y59* and c.610dup, p.R204Pfs*78) were identified in two patients. Immune workup revealed B cell lymphopenia and monocytopenia in all tested patients. One patient died from overwhelming sepsis despite all patients being treated with antibiotics and anti-mycobacterials. Our cohort highlights the phenotypic diversity, late presentation, and delayed diagnosis of GATA2 deficiency. Increased awareness of this primary immune deficiency presenting in adult life is needed and should involve a high index of suspicion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shamriz, Zahalka, Simon, Lev, Barel, Mor, Tal, Segel, Somech, Yonath and Toker.)

Objective: Pulmonary oxygen uptake (V˙O 2 ) kinetics measured during the initiation of exercise mirror energetic transition during daily activity. The aim of this study was to elucidate the pathophysiological mechanisms of exercise limitation of patients with chronic iliofemoral vein obstruction after deep vein thrombosis by measuring V˙O 2 kinetics compared with patients with peripheral arterial disease (PAD) and healthy individuals., Methods: Eleven patients with iliofemoral vein obstruction (7 men; age, 20-65 years), seven patients with PAD (all men; age 44-60 years) and eight healthy participants (5 men; age 28-58 years) were studied. Participants performed upper and lower limb symptom-limited cardiopulmonary exercise tests on cycle ergometers; and four repeat lower limb tests at a constant work rate corresponding with 90% of the gas exchange threshold for determining V˙O 2 kinetics., Results: Phase I V˙O 2 amplitude in the constant work rate tests (percent increase over resting V˙O 2 ), representing the initial surge in cardiac output caused by the emptying of leg veins, was 59 ± 19% in the iliofemoral vein obstruction group, 73 ± 22% in PAD, and 85 ± 26% in healthy participants (P = .055 for iliofemoral vein obstruction vs healthy). Phase II V˙O 2 kinetics, which largely reflect the kinetics of O 2 consumption in the exercising muscles, were slower in iliofemoral vein obstruction (tau = 42 ± 6 seconds), and PAD (tau = 49 ± 19 seconds), compared with healthy participants (23 ± 4 seconds; P < .01)., Conclusions: Slow phase II V˙O 2 kinetics reflect a slow onset of muscular aerobic metabolism in both iliofemoral vein obstruction and PAD. The low amplitude phase I of V˙O 2 kinetics observed in iliofemoral vein obstruction suggests a damped cardiodynamic phase, consistent with decreased venous return from the obstructed veins. These abnormalities of V˙O 2 kinetics may contribute to exercise intolerance in iliofemoral vein obstruction and PAD., (Copyright © 2021 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Readmission after hospitalization for acute COPD exacerbation (AE-COPD) has been proposed as a healthcare quality indicator (QI) in Israel. We studied patients hospitalized for AE-COPD, towards determining whether AE-COPD readmission is an appropriate national QI in order to improve COPD patient care., Methods: Data were retrieved for all Clalit Health Service (CHS) members age 40-90 years hospitalized in CHS hospitals during 2016 with a diagnosis of acute COPD exacerbation. Information retrieved included demographics, medical history, Charleson comorbidity score, readmissions within 90 days, chronic medication use and family physician and pulmonologist visits. Patients readmitted within 90 days were compared to those who were not readmitted. Patients were also analyzed according to whether they were hospitalized during the year before the index hospitalization., Results: In 2016 there were 70,601 members with a recorded diagnosis of COPD in CHS. Of these, 1,203 patients (1.7%) were hospitalized in a CHS hospital with a diagnosis of acute COPD exacerbation during 2016. Average age was 70.6 years, 63% were men. 78% were active smokers. 61% of the patients were readmitted to internal medicine wards within 90 days of the index hospitalization. Patients who were readmitted were more likely to have been hospitalized during the year before the index hospitalization (Odds ratio (OR) 2.5, Confidence Interval ((CI)(1.85, 3.38)) and had a higher Charlson comorbidity score (OR 1.07 (CI 1.01, 1.11)). Healthcare utilization by patients who were readmitted, both before and after admission, was generally greater. One yr mortality was 15.1% and 9.2% in those readmitted and not readmitted, respectively (p = 0.003)., Conclusions: Readmitted COPD patients appear to be the sickest group of COPD patients with advanced disease and poor prognosis, and it may not be possible to prevent readmissions. This questions the utility of COPD readmissions as a healthcare quality indicator., (© 2022. The Author(s).)

Background: Antiphospholipid syndrome (APS) may cause chronic thromboembolic pulmonary hypertension (CTEPH). Current knowledge regarding prevalence and risk factors for CTEPH among APS patients is limited. We sought to determine clinical features and biomarkers that could identify APS subjects suffering from CTEPH, and describe the prevalence, course and treatment outcomes of patients with APS-CTEPH., Methods: 504 APS patients were treated in our center during 2008 to 2019. We studied clinical and laboratory features of 69 APS patients, comparing 19 patients diagnosed with CTEPH (APS-CTEPH) and treated accordingly, with 50 consecutive age and gender matched patients with no evidence of pulmonary hypertension (APS-No-CTEPH)., Results: CTEPH prevalence was 3.8% in our APS cohort and was linked with the following parameters: primary APS (p < 0.05); prior pulmonary embolism (p < 0.001); recurrent venous thromboembolism (VTE) (p < 0.001); lower platelet counts (p < 0.001); triple anti-phospholipid antibodies positivity (p < 0.001), higher titers of anti-cardiolipin IgG (p < 0.001), anti-B2GPI IgG (p < 0.001), and high Russell viper venom time ratio (RVVT-ratio) (p < 0.05). Additionally, history of catastrophic APS was more prevalent in APS-CTEPH vs APS-No-CTEPH (p < 0.05). Of APS-CTEPH patients, 15/19 underwent pulmonary endarterectomy (PEA): In 12/15 the procedure was elective and resulted in good perioperative and long-term outcomes, while only 1 of 3 patients that underwent urgent PEA survived., Conclusions: CTEPH is relatively common in APS. Primary APS, prior PE, recurrent VTE, thrombocytopenia and specific anti-phospholipid antibodies predict CTEPH in APS. Active assessment for CTEPH in APS patients should be considered, as PEA was found to be effective and relatively safe, especially if electively performed., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Exercise ventilatory limitation conventionally defined by reduced breathing reserve (BR) may underestimate the effect of lung disease on exercise capacity in patients with mild to moderate obstructive lung diseases., Objective: To investigate whether ventilatory limitation may be present despite a normal BR in Cystic Fibrosis (CF)., Methods: Twenty adult CF patients (age 16-58y) with a wide range of pulmonary obstruction severity completed a symptom-limited incremental exercise test on a cycle ergometer. Operating lung volumes were derived from inspiratory capacity (IC) measurement during exercise and exercise tidal flow volume loop analysis., Results: six patients had a severe airway obstruction (FEV 1 <45% predicted) and conventional evidence of ventilatory limitation (low BR). Fourteen patients had mild to moderate-severe airway obstructive (FEV 1 46-103% predicted), and a normal BR [12-62 L/min, BR% (17-40)]. However, dynamic respiratory mechanics demonstrated that even CF patients with mild to moderate-severe lung disease had clear evidence of ventilatory limitation during exercise. IC was decreased by (median) 580 ml (range 90-1180 ml) during exercise, indicating dynamic hyperinflation. Inspiratory reserve volume at peak exercise was 445 ml (241-1350 ml) indicating mechanical constraint on the respiratory system. The exercise tidal flow met or exceeded the expiratory boundary of the maximal flow volume loop over 72% of the expiratory volume (range 40-90%), indicating expiratory flow limitation., Conclusion: Reduced BR as a sole criterion underestimates ventilatory limitation during exercise in mild to moderate-severe CF patients. Assessment of dynamic respiratory mechanics during exercise revealed ventilatory limitation, present even in patients with mild obstruction., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Ventricular septal motion abnormalities (VSMA) are common echocardiographic finding in patients with pulmonary hypertension (PHTN). This study sought to evaluate the relationship between echocardiographic findings and the classification of PHTN., Methods: This study retrospectively studied 146 consecutive patients referred for right heart catheterisation for clinically suspected PHTN. VSMA were defined as any echocardiographic description of leftward abnormal septal motion or position., Results: VSMA were present in 42 patients (29%). Patients with VSMA were younger and more likely to have prior pulmonary embolism. They also had less obstructive sleep apnoea, hypertension and dyslipidaemia. By echocardiography, patients with VSMA had lower left ventricular mass, left atrial size and lateral wall E/e' ratio. At cardiac catheterisation, PHTN was confirmed in all (100%) patients with VSMA (compared with 75% in patients without VSMA); 98% with VSMA had elevated pulmonary vascular resistance (compared with 55% without VSMA; p<0.005 for all). VSMA were found to have 91% sensitivity and 51% specificity for the diagnosis of pre-capillary PHTN. On multivariate analysis, VSMA were found to be strong independent predictors for the diagnosis of pre-capillary PHTN (HR, 9.15; 95% CI, 3.0-28.2; p<0.001). Left atrial enlargement was also a strong negative predictor for pre-capillary PHTN (HR, 0.14; 95% CI, 0.05-0.36; p<0.001)., Conclusion: Ventricular septal motion abnormalities were strongly associated with pre-capillary PHTN in patients with suspected PHTN. The findings suggest that patients with VSMA should be further evaluated by right heart catheterisation., (Copyright © 2021 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background The association of pulmonary and systemic arterial hypertension is believed to be mediated through hypertensive left heart disease. The purpose of the current study was to investigate whether pulmonary hypertension (PHT) is associated with systemic arterial hypertension among patients with apparently normal left ventricular diastolic function. Methods and Results Consecutive patients who had echocardiographic evaluation between 2007 and 2019 were enrolled. Patients with disease states that are known to be associated with PHT, including diastolic dysfunction, were excluded from the analysis. Estimated right ventricular systolic pressure was extracted for all patients from the echocardiographic reports. PHT was defined as estimated right ventricular systolic pressure >40 mm Hg. Multivariate logistic regression models were applied. Final study population included 25 916 patients with a median age of 59 (interquartile range, 44-69) years, of whom 12 501 (48%) were men and 13 265 (51%) had systemic arterial hypertension. Compared with normotensive patients, hypertensive patients were 3.2 times more likely to have PHT (95% CI, 2.91-3.53; P <0.001). A multivariate model adjusted for clinical and echocardiographic parameters that are known to be associated with PHT demonstrated that hypertensive patients are almost 3 times more likely to have PHT (95% CI, 2.45-3.15; P <0.001). The association was significant in multiple subgroups but was more significant among women compared with men (odds ratio, 3.1 versus 2.4; P for interaction <0.001). Conclusions PHT is associated with systemic arterial hypertension irrespective of left heart disease. The association is more pronounced among women.

Objective: At present, there is no consensus on the best strategy for interpreting the cardiopulmonary exercise test's (CPET) results. This study is aimed at assessing the potential of using computer-aided algorithms to evaluate CPET data for identifying chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD)., Methods: Data from 234 CPET files from the Pulmonary Institute, at Sheba Medical Center, and the Givat-Washington College, both in Israel, were selected for this study. The selected CPET files included patients with confirmed primary CHF ( n = 73), COPD ( n = 75), and healthy subjects ( n = 86). Of the 234 CPETs, 150 (50 in each group) tests were used for the support vector machine (SVM) learning stage, and the remaining 84 tests were used for the model validation. The performance of the SVM interpretive module was assessed by comparing its interpretation output with the conventional clinical diagnosis using distribution analysis., Results: The disease classification results show that the overall predictive power of the proposed interpretive model ranged from 96% to 100%, indicating very high predictive power. Furthermore, the sensitivity, specificity, and overall precision of the proposed interpretive module were 99%, 99%, and 99%, respectively., Conclusions: The proposed new computer-aided CPET interpretive module was found to be highly sensitive and specific in classifying patients with CHF or COPD, or healthy. Comparable modules may well be applied to additional and larger populations (pathologies and exercise limitations), thereby making this tool powerful and clinically applicable., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2021 Or Inbar et al.)

Background: Methacholine challenge tests (MCTs) are used to diagnose airway hyperresponsiveness (AHR) in patients with suspected asthma where previous diagnostic testing has been inconclusive. The test is time consuming and usually requires referral to specialized centers. Simple methods to predict AHR could help determine which patients should be referred to MCTs, thus avoiding unnecessary testing. Here we investigated the potential use of baseline spirometry variables as surrogate markers for AHR in adults with suspected asthma., Methods: Baseline spirometry and MCTs performed between 2013 and 2019 in a large tertiary center were retrospectively evaluated. Receiver-operating characteristic curves for the maximal expiratory flow-volume curve indices (angle β, FEV1, FVC, FEV1/FVC, FEF 50% , FEF 25-75% ) were constructed to assess their overall accuracy in predicting AHR and optimal cutoff values were identified., Results: A total of 2983 tests were analyzed in adults aged 18-40 years. In total, 14% of all MCTs were positive (PC20 ≤ 16 mg/ml). All baseline spirometry parameters were significantly lower in the positive group (p < 0.001). FEF 50% showed the best overall accuracy (AUC = 0.688) and proved to be useful as a negative predictor when applying FEF 50%  ≥ 110% as a cutoff level., Conclusions: This study highlights the role of FEF 50% in predicting AHR in patients with suspected asthma. A value of ≥ 110% for baseline FEF 50% could be used to exclude AHR and would lead to a substantial decrease in MCT referrals.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, distinct pulmonary vascular disease caused by chronic obstruction of major pulmonary arteries, which can be cured by pulmonary endarterectomy. However, many CTEPH patients are not surgical candidates. Balloon pulmonary angioplasty (BPA) is an emerging technique used to treat inoperable CTEPH., Objectives: To describe the first Israeli experience with BPA for inoperable CTEPH., Methods: In 2017 we established a BPA program at our institution. We reviewed the outcomes to date of BPA in our center., Results: Forty-seven BPA procedures were performed in five patients with inoperable CTEPH (4-17 procedures/patient). Mean pulmonary artery pressure improved in all patients (median decrease 17 mmHg, range 10-26 mmHg). Pulmonary vascular resistance also improved (median decrease 11 Woods Units/m2, range 8-16 Woods Units/m2). Cardiac output increased in 4 of 5 patients and decreased in one. Functional capacity improved from New York Heart Association (NYHA) III to II in four patients; one patient was NYHA II at baseline without change after BPA. Six-minute walking distance improved by a median of 97 meters. (range 21-197 meters). Hemodynamic and functional improvements were sustained at follow-up 5-11 months after the last BPA procedure. BPA enabled 2 of 3 patients treated with parenteral prostanoids to be switched to oral therapy. There were no major complications., Conclusions: We successfully established BPA as a treatment for inoperable CTEPH in our center. BPA resulted in hemodynamic and clinical improvements that were sustained over time.

Background: Community-acquired pneumonia is among the most common infections affecting ulcerative colitis and Crohn's disease patients. Data regarding epidemiology and outcomes of pneumonia in inflammatory bowel disease patients is lacking. We aimed to identify predictors of adverse outcomes among inflammatory bowel disease patients treated for pneumonia., Methods: This was a retrospective cohort study that included adult patients admitted to Sheba Medical Center for pneumonia between 2012 and 2018. Data was collected from an electronic repository of all emergency department admissions and included tabular demographic and clinical variables and free-text physician records. Pneumonia cases were extracted using the International Classification of Diseases (ICD-10) coding., Results: Of 16,732 admissions with pneumonia, 97 were inflammatory bowel disease patients (45 Crohn's disease; 52 ulcerative colitis). We found a similar rate of 30-day mortality among inflammatory bowel disease and non-inflammatory bowel disease patients (12.1% versus 11.3%, p  = 0.824) and between Crohn's disease and ulcerative colitis patients (11.1% versus 11.5%, p  = 0.947). There was an increased hospitalization rate among inflammatory bowel disease patients (92.8% versus 85.6%, p  = 0.045), but similar hospitalization duration (4 versus 4 days, p  = 0.384). Crohn's disease patients had a shorter hospitalization duration compared with ulcerative colitis patients (3 versus 5.5 days, p  = 0.029). Bronchiectasis (adjusted odds ratio 60.95, 95% confidence interval 2.72-1364.39, p  = 0.01) and opioids use (adjusted odds ratio 13.21, 95% confidence interval 1.29-135.18, p  = 0.03) were associated with an increased 30-day mortality rate in inflammatory bowel disease patients., Conclusion: This is the first study to identify predictors of mortality in inflammatory bowel disease patients with pneumonia. The rate of mortality and hospitalization duration of stay were similar among inflammatory bowel disease and non-inflammatory bowel disease patients. Use of opioids and presence of bronchiectasis were associated with a higher risk of mortality in inflammatory bowel disease patients with pneumonia., Competing Interests: Conflict of interest statement: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: UK: speaker and advisory fees – Abbvie, Jannsen Takeda Medtronic; research support – Jannsen Takeda Medtronic. SBH: consulting and advisory board fees and/or research support – Abbvie, MSD, Janssen, Takeda, and CellTrion. BU: consultation fees – Takeda, Neopharm, Janssen and Abbvie. The remaining authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, distinct pulmonary vascular disease, which is caused by chronic obstruction of major pulmonary arteries. CTEPH can be cured by pulmonary endarterectomy (PEA). PEA for CTEPH is a challenging procedure, and patient selection and the perioperative management are complex, requiring significant experience., Objectives: To describe the establishment of a national CTEPH-PEA center in Israel and present results of surgery., Methods: In this study, we reviewed the outcomes of PEA in a national referral, multi-disciplinary center for CTEPH-PEA. The center was established by collaborating with a high-volume center in Europe. A multidisciplinary team from our hospital (pulmonary hypertension specialist, cardiac surgeon, cardiac anesthesiologist and cardiac surgery intensivist was trained under the guidance of an experienced team from the European center., Results: A total of 38 PEA procedures were performed between 2008 and 2018. We included 28 cases in this analysis for which long-term follow-up data were available. There were two hospital deaths (7%). At follow-up, median New York Heart Association (NYHA) class improved from III to I (P < 0.0001), median systolic pulmonary pressure decreased from 64 mmHg to 26 mmHg (P < 0.0001), and significant improvements were seen in right ventricular function and exercise capacity., Conclusions: A national center for performance of a rare and complex surgical procedure can be successfully established by collaboration with a high-volume center and by training a dedicated multidisciplinary team.

Background: Lung injury with development of the acute respiratory distress syndrome (ARDS) is a serious complication which can occur after major surgery, including cardiac surgery., Objective: The aim of our study was to compare the prevalence, risk factors, and mortality of ARDS following cardiac surgery according to the American-European Consensus Conference (AECC) definition and the new Berlin definition of ARDS., Methods: We performed a retrospective, observational study that included prospectively collected data from consecutive adult patients, aged from 18 to 92 years, who had undergone cardiac surgery (both on and off pump) at a large tertiary university hospital over 5 years (from September 2012 to September 2017)., Results: During the study period, 3,972 patients underwent cardiac surgery, and 3,946 patients were included in the study. Fifty-five patients developed ARDS (1.14%) according to the AECC definition and 59 patients (1.15%) according to the Berlin definition, with a mortality of 32.7 and 30.5%, respectively (18 patients). Multivariate regression analysis identified prior cardiac surgery, complex cardiac surgery, emergency procedures, and transfusion of > 3 packed red blood cell units as predictors for ARDS., Conclusion: The development of ARDS in patients after cardiac surgery is a rare but serious complication associated with significant mortality. Moreover, our findings showed that prevalence, mortality, and risk factors for developing ARDS were similar according to both the AECC and the new Berlin definition., (© 2019 S. Karger AG, Basel.)

Local symptoms of chronic venous insufficiency after deep vein thrombosis (DVT) are well described, but little is known about the effect of residual venous obstruction on exercise capacity. We tested our hypothesis that chronic residual iliofemoral vein occlusion (IFVO) after DVT may impair exercise capacity. Nine post-DVT patients with residual IFVO and effort intolerance were studied; a comparison cohort consisted of 11 healthy volunteers. Exercise tolerance was assessed by bimodality incremental symptom-limited cardiopulmonary testing, using leg and arm ergometers. In healthy subjects, leg vein obstruction was modelled by application to the thighs of cuff tourniquets inflated to 30-40 mmHg. Leg exercise tolerance as measured by oxygen uptake at peak exercise (peak ⩒'O 2 ) was reduced in patients (median 50% predicted (range 36-83%) vs. 88% predicted (67-129%) in normal subjects, p < 0.001). Arm exercise tolerance was also reduced in patients, but less severely than in the legs - the median arm: leg ratio of peak ⩒'O 2 was 0.95 (0.77-1.43) in patients vs. a normal ratio of 0.73 (0.6-1.0) in healthy subjects (p < 0.003). In healthy subjects, bilateral leg vein obstruction by tourniquets reduced peak ⩒'O 2 in leg exercise to 76% predicted (range 55-108%; p < 0.001 vs. standard test). In conclusion, the comparison of arm vs. leg exercise capacity in post-DVT patients with residual IFVO and the effect of experimental venous obstruction (thigh tourniquets) in healthy subjects suggest that reduced exercise capacity in patients was at least partially caused by reduced venous return. Chronic venous obstruction should be recognized as a cause of exercise limitation.

Background: Symptom control is a primary goal in asthma. We hypothesized that administrative data regarding rescue inhaler purchases may correlate with asthma symptom control., Methods: We identified all patients who purchased short-acting beta-agonist (SABA) inhalers during the course of one year in the database of a Health Maintenance Organization (HMO). Primary physicians identified asthma patients and classified their asthma symptom control into three groups according to the Global Initiative for Asthma (GINA) guidelines. Asthma patients were asked to answer symptom questionnaires and grade their asthma control. SABA inhaler purchases were compared between asthma control groups as classified by the guidelines, the physicians and the patients. We also compared the agreement on asthma control between the three methods of classification., Results: Of 241 asthma patients, 83 completed the questionnaires. Using the GINA guidelines criteria, 26 were symptom controlled, 46 were partially controlled and 11 were uncontrolled. SABA inhaler purchases were not significantly lower in the controlled group. Using patients' overall impression of their asthma control, the mean numbers of SABA inhalers purchased were 1.5, 4.4 and 6.4 per year in the controlled, partially controlled and uncontrolled groups, respectively (p = 0.03). Patients' classification of asthma control had better agreement (kappa = 0.34) with GINA guidelines than physician's' agreement (kappa = 0.05)., Conclusion: When using administrative data for asthma patients, 2 or more SABA inhaler purchases in one year should alert the physician for the need for asthma control evaluation. Purchase of at least 4 SABA inhalers a year may be regarded as a marker for asthma that is not controlled.

Transthoracic Parametric Doppler (TPD) is a novel ultrasound technique recently developed for the investigation of pulmonary blood vessels. Lung Doppler Signals (LDS) recorded from TPD provide information regarding the functional mechanical characteristics of pulmonary blood vessels. We aimed to define the specific profile of LDS generated from TPD imaging in patients with pulmonary hypertension (PH), and to evaluate the diagnostic performance of LDS to detect PH using right heart catheterization (RHC) as gold standard reference. Seventy nine PH patients and 79 healthy controls matched for age, gender and BMI were recruited in a prospective case-control multicenter study. LDS recordings were performed by TPD consisting of a pulsed Doppler with a 2 MHz single element transducer. LDS were recorded within 24 h of RHC. Following LDS extraction, classification and performance evaluation were performed offline using a support vector machine (k-fold cross validation method). The best LDS parameters for PH detection were (1) peak velocity of the systolic (S) and diastolic (D) signals, (2) the rise slope of the S and D signals, and (3) time to peak of the S signal. Overall, the sensitivity and specificity of TPD for detection of PH were 82.7 % (95 % CI 81.3-84.1) and 87.4 % (95 % CI 86.3-88.5), respectively, with an area under the receiver operating curve of 0.95 (95 % CI 0.94-0.96). Detection rate of PH increased progressively with the level of mean pulmonary artery pressure. LDS recorded by TPD display a specific profile in PH and appears to be a promising and reliable tool for PH diagnosis. Further studies are required to confirm the clinical usefulness of LDS.

Objectives: The Cardio-vascular reserve index (CVRI) had been empirically validated in diverse morbidities as a quantitative estimate of the reserve assumed by the cardiovascular reserve hypothesis. This work evaluates whether CVRI during exercise complies with the cardiovascular reserve hypothesis., Design: Retrospective study based on a database of patients who underwent cardio-pulmonary exercise testing (CPX) for diverse indications., Methods: Patient's physiological measurements were retrieved at four predefined CPX stages (rest, anaerobic threshold, peak exercise and after 2min of recovery). CVRI was individually calculated retrospectively at each stage., Results: Mean CVRI at rest was 0.81, significantly higher (p<0.001) than at all other stages. CVRI decreased with exercise, reaching an average at peak exercise of 0.35, significant lower than at other stages (p<0.001) and very similar regardless of exercise capacity (mean CVRI 0.33-0.37 in 4 groups classified by exercise capacity, p>0.05). CVRI after 2min of recovery rose considerably, most in the group with the best exercise capacity and least in those with the lowest exercise capacity., Conclusions: CVRI during exercise fits the pattern predicted by the cardiovascular reserve hypothesis. CVRI decreased with exercise reaching a minimum at peak exercise and rising with recovery. The CVRI nadir at peak exercise, similar across groups classified by exercise capacity, complies with the assumed exhaustion threshold. The clinical utility of CVRI should be further evaluated., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Rationale: Expiratory flow limitation at resting tidal volume (EFLTV) presents a severe mechanical constraint in chronic lung diseases and has not yet been studied longitudinally in cystic fibrosis., Objectives: To study the effect of EFLTV as it emerged from simple spirometry on lung function and clinical status in cystic fibrosis., Methods: Best year spirometry that included tidal flow/volume curves and the related clinical data were retrospectively collected over 12 ± 3.0 yr/person from 108 subjects with cystic fibrosis. The year in which forced expiratory flow, midexpiratory phase (FEF25-75%, L/s) was equal to tidal peak expiratory flow (L/s) was defined as EFLTV-onset year., Measurements and Main Results: EFLTV occurred in 55 (51%) subjects, at age 23 ± 6 years. At EFLTV onset, tidal peak expiratory flow and FEF25-75% values were 1.44 ± 0.23 L/s and FEV1 was 62 ± 10% predicted. Within the following 2 years, FEV1 dropped to 48 ± 11% predicted, and 35 (63%) of the subjects reported shortness of breath at rest. Hospital days increased from 5.3 ± 24.6 to 24.12 ± 9.0 d/yr (P = 0.0001). Of the 55 subjects, 29 (53%) received transplant or died, with survival time being 6.9 ± 3.9 years., Conclusions: EFLTV onset may be an important pathophysiological event that could influence the natural history of lung function decline in subjects with cystic fibrosis. This may lead to a significant deterioration in lung function in the following 2 years alongside an increase in the number of hospitalization days. The monitoring of FEV1 alone does not offer as good a threshold signal, because values are only moderately reduced. Therefore, identifying EFLTV appearance is potentially a signal for therapeutic intervention. Further studies are warranted to confirm our findings.

The association between smoke habit and autoimmunity has been hypothesized a long time ago. Smoke has been found to play a pathogenic role in certain autoimmune disease as it may trigger the development of autoantibodies and act on pathogenic mechanism possibly related with an imbalance of the immune system. Indeed, both epidemiological studies and animal models have showed the potential deleterious effect caused by smoke. For instance, smoke, by provoking oxidative stress, may contribute to lupus disease by dysregulating DNA demethylation, upregulating immune genes, thereby leading to autoreactivity. Moreover, it can alter the lung microenvironment, facilitating infections, which, in turn, may trigger the development of an autoimmune condition. This, in turn, may result in a dysregulation of immune system leading to autoimmune phenomena. Not only cigarette smoke but also air pollution has been reported as being responsible for the development of autoimmunity. Large epidemiological studies are needed to further explore the accountability of smoking effect in the pathogenesis of autoimmune diseases., (Copyright © 2016 Elsevier B.V. All rights reserved.)

IgG4-related disease is a fibroinflammatory disease in which the organs involved share similar pathological findings. Chest disease has been recently clinically and radiologically characterized. Most reports advocate prompt immunosuppressive therapy and describe a fast and good response. We report 3 cases of untreated IgG4-related lung disease that on follow-up have been clinically asymptomatic and radiologically stable or improved. In some cases of IgG4-related lung disease immunosuppressive therapy may not be warranted., (Copyright © 2015 SEPAR. Published by Elsevier Espana. All rights reserved.)

Objective: To determine the effect of continuous positive airway pressure (CPAP) on tumor motion, lung volume, and dose to critical organs in patients receiving stereotactic body radiation therapy (SBRT) for lung tumors., Methods and Materials: After institutional review board approval in December 2013, patients with primary or secondary lung tumors referred for SBRT underwent 4-dimensional computed tomographic simulation twice: with free breathing and with CPAP. Tumor excursion was calculated by subtracting the vector of the greatest dimension of the gross tumor volume (GTV) from the internal target volume (ITV). Volumetric and dosimetric determinations were compared with the Wilcoxon signed-rank test. CPAP was used during treatment if judged beneficial., Results: CPAP was tolerated well in 10 of the 11 patients enrolled. Ten patients with 18 lesions were evaluated. The use of CPAP decreased tumor excursion by 0.5 ± 0.8 cm, 0.4 ± 0.7 cm, and 0.6 ± 0.8 cm in the superior-inferior, right-left, and anterior-posterior planes, respectively (P ≤ .02). Relative to free breathing, the mean ITV reduction was 27% (95% confidence interval [CI] 16%-39%, P<.001). CPAP significantly augmented lung volume, with a mean absolute increase of 915 ± 432 cm(3) and a relative increase of 32% (95% CI 21%-42%, P=.003), contributing to a 22% relative reduction (95% CI 13%-32%, P=.001) in mean lung dose. The use of CPAP was also associated with a relative reduction in mean heart dose by 29% (95% CI 23%-36%, P=.001)., Conclusion: In this pilot study, CPAP significantly reduced lung tumor motion compared with free breathing. The smaller ITV, the planning target volume (PTV), and the increase in total lung volume associated with CPAP contributed to a reduction in lung and heart dose. CPAP was well tolerated, reproducible, and simple to implement in the treatment room and should be evaluated further as a novel strategy for motion management in radiation therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Histoplasmosis is a common endemic human mycoses acquired mostly in the Americas. We reviewed 23 cases of histoplasmosis in Israeli travelers; 22 had traveled to Central or South America and one to North America. Fourteen cases had been exposed to bat habitats and were symptomatic, presenting ≤ 3 months after their return. Asymptomatic patients (N = 9) were diagnosed during the evaluation of incidental radiological findings or because a travel partner had been suspected of Histoplasma infection, 16-120 months after their return. Serological testing was positive in 75% of symptomatic cases but only 22% of asymptomatic cases. Histoplasmosis should be considered in travelers returning from the Americas with respiratory or febrile illness within weeks of return, particularly if exposed to bat habitats. Travel history is essential in patients presenting with pulmonary nodules, even years after travel to endemic countries., (© The American Society of Tropical Medicine and Hygiene.)

Objectives: Infusions of aminobisphonates (ABP) activate Vγ9δ2T cells in vivo and induce an acute inflammatory response in 30% of patients treated for osteoporosis. Following the observation of digital thrombosis in a systemic sclerosis (SSc) patient after treatment with an intravenous ABP, zoledronate (Zol), we evaluated whether patient and control peripheral blood (PB) mononuclear cell (MC, PBMC) acquire a prothrombotic phenotype in response to Zol., Results: Vγ9δ2T cells of both patients and healthy donors (HD) upregulated the CD69 activation antigen and secreted tumor necrosis factor (TNF)α in response to Zol in vitro. In addition, exposure to either Zol or lipopolysaccharide (LPS), or to both additively, induced expression of the highly procoagulant, tissue factor (TF)-1 on CD14+ monocytes. Importantly, only Zol-induced TF-1 was blocked by a monoclonal antibody to TNFα. Interestingly, we found that SSc, but not HD, Vδ1+ T cells were concurrently activated by Zol to produce interleukin (IL)-4. Addition of plasma from the blood of the SSc patient who developed critical digital ischemia after infusion of Zol, but neither plasma from a second patient with no adverse clinical response to Zol infusion nor of a HD, strongly enhanced Zol-induced monocyte TF-1, which could still be blocked by anti-TNFα., Conclusion: Aminobisphonates induced secretion of TNFα by Vγ9δ2+ T cells may lead to TNFα-dependent induction of procoagulant TF-1 induction on monocytes. In certain clinical settings, e.g., SSc, TF-1+ monocytes could play a role in triggering clinically relevant thrombosis.

Pulmonary alveolar proteinosis (PAP) is caused by accumulation of surfactant components in the alveoli and terminal airways. All forms of PAP are caused by insufficient surfactant clearance by alveolar macrophages. Autoimmune PAP, a rare, antibody-mediated disease, that compromises 90% of cases of PAP, is causes by IgG autoantibodies that block GM-CSF effect, a crucial step for macrophage maturation. Alveolar filling may progress to respiratory insufficiency, but the course of the disease is variable. Patients usually complain of dyspnea, mainly with exertion, and cough. Chest CT shows highly suggestive ground grass opacification crossed by heavy septal lines, leading to the typical "crazy paving" appearance. Bronchoalveolar lavage reveals "milky" fluid, containing semisolid remnants of surfactant components, packed as lamellar bodies. The surfactant appears granular and pink on PAS staining, and lung architecture is preserved. These cytological and pathological characteristics are diagnostic for PAP. In addition, a high titer of IgG anti GM-CSF autoantibodies is highly sensitive and specific for the diagnosis. The trigger for antibodies formation and their role (if any) in regulation GM-CSF activity in the normal state are unknown. Based on the specificity of these characteristics we suggest a structured framework for the diagnosis of Autoimmune PAP. Lung lavage with a large volume of saline is the standard therapy, and is effective in most patients. However, immune-modulatory therapy, by either supplying exogenous GM-CSF, or by inhibiting the CD20+ antibody forming cells, with Rituximab, is also effective in many patients. The precise role of each therapy, alone or in combination, should be systematically studied., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: The methacholine challenge test (MCT) is a test of bronchial hyperreactivity used as an aid in the diagnosis of asthma. MCT results are reported as the provocation concentration at which the forced expiratory volume in 1 second (FEV1) decreases 20% (PC20). The requirement for a 20% or greater decrease in FEV1 results in precipitous decreases in FEV1 in some patients., Objective: To improve MCT safety without compromising accuracy., Methods: We performed a retrospective analysis of 879 consecutive MCTs (derivation cohort). A novel protocol for MCT was developed and validated in a cohort of 564 MCTs performed in a second institution., Results: In comparison with a PC20 cutoff of less than 8 mg/mL, a provocation concentration at which the FEV1 decreases 10% (PC10) cutoff of 1 mg/mL or less has a sensitivity of 86%, a specificity of 98%, a positive predictive value (PPV) of 97%, and a negative predictive value (NPV) of 91%. We propose a novel 2-tiered protocol for MCT. If the PC10 is 1 mg/mL or less, bronchial hyperreactivity is present; if the PC10 is greater than 1 mg/mL, the test is continued until the provocative concentration is 8 mg/mL or a 20% decrease in FEV1 is achieved. Compared with the standard protocol, the proposed protocol has a sensitivity, specificity, PPV, NPV, and overall accuracy of 100%, 98%, 97.6%, 100%, and 99%, respectively. The modified protocol would have enabled us to avoid 26 of 42 cases (62%) in which a 40% or greater decrease in FEV1 occurred and would save 0.65 dose for every MCT performed. The 2-tiered protocol performed well in the validation cohort; sensitivity, specificity, PPV, NPV, and overall accuracy were 100%, 98%, 87%, 100%, and 98%, respectively., Conclusion: The proposed 2-tiered protocol is accurate, saves time, and avoids precipitous decreases in FEV1., (Copyright © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Immigrant populations moving from undeveloped countries with low asthma prevalence have shown increased asthma prevalence in their new Westernized environment. We compared the prevalence of asthma among Israeli born children of Ethiopian origin to that in non-Ethiopian children., Methods: Cross sectional study. Data was retrieved for children aged 6-18 years in four clinics with a large proportion of patients of Ethiopian origin. For each Israeli born child from Ethiopian origin we matched an Israeli born child of any other origin of the same age and gender, receiving primary care from the same physician at the same clinic. Asthma was defined as any visit to a primary care physician, emergency room or hospitalization related to asthma symptoms or subsequent purchasing of any asthma medication during 2008., Results: 1217 children of Ethiopian origin and 1217 matched controls were studied. More Ethiopian children came from families with a low socioeconomic status (23.9% vs. 17%, p < 0.001), and with significantly lower parental smoking (5.1% vs. 40.1%, p < 0.001). The prevalence of asthma was 92/1217 (7.5%) among children of Ethiopian origin, compared to 122/1217 (10.0%) among the control group (OR = 0.74, 95% CI: 0.56-0.98, p = 0.032). When adjusted for tobacco exposure, the OR for risk of asthma in the Ethiopian children was 0.80 (95% CI: 0.59-1.09, p = 0.16)., Conclusion: Asthma prevalence in the second generation of Israeli born children of Ethiopian origin does not seem to differ from other children in their community. This observation supports the theory that environmental exposures, rather than genetic factors, dictated the increase in asthma in this immigrant population., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Tiotropium, a Long-acting anticholinergic bronchodilator, has many beneficial effects in chronic obstructive pulmonary disease (COPD). Among them are: a bronchodilator effect which is additive to that of beta-adrenergic agonists, that persists long-term without tolerance; reduction of dyspnea; improved exercise tolerance; enhanced response to rehabilitation; improved quality of life; and reduced frequency of exacerbations and hospital admissions. Therefore, tiotropium is widely used, and has been added to the Health Basket by the Israel Ministry of Health. In March 2008, the manufacturer informed the US Food and Drug Administration (FDAI that ongoing safety monitoring had identified a possible increased risk of stroke in patients who take this medicine. In September 2008, Singh and colleagues published a meta-analysis suggesting an increased risk of cardiovascular events in COPD patients treated with tiotropium, although there was no difference in overall mortality. A month later, the UPLIFT investigators published a 4 year placebo-controlled trial of tiotropium involving 5993 patients, in which there were slightly less cardiovascular events in the treatment group, and a trend to reduced overall mortality. The authors review the benefits and safety data, and conclude that while the benefits of tiotropium in COPD are clear, the evidence of an adverse effect on cardiovascular mortality is not sufficiently convincing. Hence, the balance of evidence supports continued use of tiotropium, especially in severe COPD.

The chronic phase of pulmonary arterial hypertension (PAH) is associated with vascular remodeling, especially thickening of the smooth muscle layer of large pulmonary arteries and muscularization of small pulmonary vessels, which normally have no associated smooth muscle. Serotonin (5-hydroxytryptamine, 5-HT) has been shown to induce proliferation and hypertrophy of pulmonary artery smooth muscle cells (PASMC), and may be important for in vivo pulmonary vascular remodeling. Here, we show that 5-HT stimulates migration of pulmonary artery PASMC. Treatment with 5-HT for 16h increased migration of PASMC up to four-fold as monitored in a modified Boyden chamber assay. Increased migratory responses were associated with cellular morphological changes and reorganization of the actin cytoskeleton. 5-HT-induced alterations in morphology were previously shown in our laboratory to require cAMP [Lee SL, Fanburg BL. Serotonin produces a configurational change of cultured smooth muscle cells that is associated with elevation of intracellular cAMP. J Cell Phys 1992;150(2):396-405], and the 5-HT4 receptor was pharmacologically determined to be the primary activator of cAMP in bovine PASMC [Becker BN, Gettys TW, Middleton JP, Olsen CL, Albers FJ, Lee SL, et al. 8-Hydroxy-2-(di-n-propylamino)tetralin-responsive 5-hydroxytryptamine4-like receptor expressed in bovine pulmonary artery smooth muscle cells. Mol Pharmacol 1992;42(5):817-25]. We examined the role of the 5-HT4 receptor and cAMP in 5-HT-induced bovine PASMC migration. PASMC express 5-HT4 receptor mRNA, and a 5-HT4 receptor antagonist and a cAMP antagonist completely blocked 5-HT-induced cellular migration. Consistent with our previous report that a cAMP-dependent Cl(-) channel is required for 5-HT-induced morphological changes in PASMC, phenylanthranilic acid, a Cl(-) channel blocker, inhibited actin cytoskeletal reorganization and migration produced by 5-HT. We conclude that 5-HT stimulates PASMC migration and associated cytoskeletal reorganization through the 5-HT4 receptor and cAMP activation of a chloride channel.

The role of lymphocytes in the pathogenesis of lung fibrosis is not clear, but the weight of the evidence supports a pro-fibrotic effect for lymphocytes. The high-affinity interleukin-2 receptor (haIL-2R) is expressed on activated, but not quiescent, T lymphocytes. This selective expression of haIL-2R provides the basis for therapeutic strategies that target IL-2R-expressing cells. We hypothesized that elimination of activated lymphocytes by IL-2R-targeted chimeric proteins might ameliorate lung fibrosis. We investigated the effects of IL-2-Bax, a novel apoptosis-inducing IL-2R-targeted chimeric protein, on bleomycin-induced lung injury in mice. Treatment groups included (i) a single intratracheal instillation of bleomycin and twice-daily intraperitoneal injections of IL-2-Bax; (ii) intratracheal bleomycin and intraperitoneal IL-2-PE66(4Glu), an older-generation chimeric protein; (iii) intratracheal bleomycin/intraperitoneal PBS; (iv) intratracheal saline/intraperitoneal PBS. Lung injury was evaluated 14 days after intratracheal instillation by cell count in bronchoalveolar lavage (BAL) fluid, semi-quantitative and quantitative histomorphological measurements and by biochemical analysis of lung hydroxyproline. Bleomycin induced a BAL lymphocytosis that was significantly attenuated by IL-2-Bax and IL-2-PE66(4Glu). However, morphometric parameters and lung hydroxyproline were unaffected by the chimeric proteins. These results show that IL-2-Bax reduces the lymphocytic infiltration of the lungs in response to bleomycin, but this effect is not accompanied by a decrease in lung fibrosis.

IFN-gamma production is upregulated in lung cells (LC) of bleomycin-treated C57BL/6 mice. The present study characterizes the time course, cellular source, and regulation of IFN-gamma expression in bleomycin-induced lung injury. IFN-gamma mRNA in LC from bleomycin-treated mice peaked 3 days after intratracheal instillation. IFN-gamma protein levels were increased at 6 days, as was the percentage of LC expressing IFN-gamma. CD4+, CD8+, and natural killer cells each contributed significantly to IFN-gamma production. IL-12 mRNA levels were increased at 1 day in LC of bleomycin-treated mice. Anti-IL-12 and anti-IL-18 antibodies decreased IFN-gamma production by these cells. To define the role of endogenous IFN-gamma in the evolution of bleomycin lung injury, we compared the effect of bleomycin in mice with a targeted knockout mutation of the IFN-gamma gene (IFN-gamma knockout) and wild-type mice. At 14 days after intratracheal bleomycin, total bronchoalveolar lavage cell counts and lung hydroxyproline were decreased in IFN-gamma knockouts compared with wild-type animals. There was no difference in morphometric parameters of fibrosis. Our data show that enhanced IFN-gamma production in the lungs of bleomycin-treated mice is at least partly IL-12 and IL-18 dependent. Absence of IFN-gamma in IFN-gamma knockout mice does not increase pulmonary fibrosis. Endogenous IFN-gamma may play a proinflammatory or profibrotic role in bleomycin-induced lung fibrosis.

The role of IL-4 in the development of lung fibrosis is as yet unclear. Bleomycin (Bleo) or saline (Sal) was injected intratracheally into three groups of C57BL/6J mice: transgenic animals that overexpressed IL-4 (IL-4 TG, n = 14), mice with a targeted knockout mutation of the IL-4 gene (IL-4 KO, n = 11), and wild-type (WT, n = 13) mice. At 14 days, lung fibrosis was evaluated by hydroxyproline measurement and by quantitative image analysis of fibrosis fraction and alveolar wall area fraction. Bronchoalveolar lavage cell counts in all Bleo-treated groups demonstrated an increased percentage of lymphocytes with a corresponding decrease in the percentage of macrophages. Comparing Bleo- to Sal-treated controls within each group of mice showed increases in all lung fibrosis parameters in IL-4 KO and WT, but not in any of the parameters in IL-4 TG mice. The severity of Bleo-induced fibrotic response was decreased in overexpressed IL-4 TG compared with IL-4 KO mice. These data negate a critical profibrotic role for IL-4 in Bleo-induced lung fibrosis.

Halofuginone, a coccidiostatic alkaloid, has anti-fibrotic properties, and may be useful as a therapeutic agent in lung fibrosis. To test this hypothesis we investigated the effect of halofuginone on bleomycin-induced lung fibrosis in Sprague-Dawley rats. Treatment groups included: (1) a single intratracheal (IT) instillation of 1.2U bleomycin, and intraperitoneal (IP) injection of halofuginone (0.5 mg/dose), every other day; (2) IT 1.2U bleomycin and IP distilled water (D.W.), every other day; (3) IT 0.8U bleomycin and daily IP halofuginone (0.5 mg/dose); (4) IT 0.8U bleomycin and daily IP D.W.; (5) IT saline and IP halofuginone, every other day; (6) IT saline and daily IP D.W.; (7) IT 0.625U bleomycin and oral halofuginone (10 mg/kg rodent lab chow); (8) IT 0.625U bleomycin and standard lab chow. Animals were studied 14 days after IT instillation. Lung injury was evaluated by total and differential cell count in bronchoalveolar lavage fluid, by a semi-quantitative morphological index of lung injury, and by biochemical analysis of lung hydroxyproline content. Overt signs of lung injury were apparent in bleomycin-treated rats by all measures. These changes were not affected by treatment with halofuginone, irrespective of the treatment regimen used. This study does not support the use of halofuginone to prevent or ameliorate lung fibrosis.

Intratracheal instillation (IT) of bleomycin is a widely used experimental model for lung fibrosis. In this study we describe the time-course of bleomycin-induced lung fibrosis in mice using computer-assisted morphometry. C57Bl/6J mice were treated with a single IT dose of bleomycin or control saline. Animals were killed 3, 6, 14 and 21 days post-IT. Lung injury was evaluated by analysis of bronchoalveolar lavage (BAL) fluid, hydroxyproline concentration in the lung, routine light microscopic examination resulting in a semiquantitative morphological index (SMI) of lung injury, and quantitative morphological measurements (fibrosis fraction and alveolar wall area fraction) aided by optimas image analysis software. Changes in BAL fluid attributed to bleomycin treatment include increased total cell count (days 14 and 21), and increased percentage of neutrophils (days 3 and 6) followed by a sustained increase in lymphocytes (days 6, 14 and 21). Hydroxyproline levels increased in bleomycin-treated mice on days 14 and 21. Median SMI grades were significantly elevated on days 3, 14 and 21. Computer-assisted morphometry demonstrated a 3-fold increase in fibrosis fraction and a 1.3-fold increase in wall area fraction in bleomycin-treated mice on day 14, with no further increase on day 21. These data also demonstrate that the most suitable time point for assessing lung fibrosis in this model is 14 days after IT instillation of bleomycin, based on the observation that at 14 days the animals developed extensive fibrosis, but had less variability in the fibrotic response and lower mortality than later at 21 days. Computer-assisted morphometry provides objective and quantitative measurements that are a useful tool for the evaluation of bleomycin-induced lung injury.

All-trans-retinoic acid (ATRA) has anti-fibrotic and antiinflammatory properties, and may be useful as a therapeutic agent in lung fibrosis. To test this hypothesis we investigated the effect of ATRA on bleomycin-induced lung fibrosis in Sprague-Dawley rats. Treatment groups included: (1) a single intratracheal (i.t.) instillation of bleomycin and daily intraperitoneal (i.p.) injection of 0.5 mg/kg per day ATRA; (2) i.t. bleomycin and i.p. ATRA, 2 mg/kg per day, (3) i.t. bleomycin and i.p. diluent (cottonseed oil); (4) i.t. saline and i.p. ATRA, 0.5 mg/kg per day, (5) i.t. saline and i.p. ATRA, 2 mg/kg per day; and (6) i.t. saline and i.p. diluent. Animals were studied 14 days after i.t. instillation. Lung injury was evaluated by total and differential cell count in bronchoalveolar lavage fluid, by a semi-quantitative morphological index of lung injury, and by biochemical analysis of lung hydroxyproline content. Overt signs of lung injury were apparent in bleomycin-treated rats by all measures. These changes were not affected by treatment with ATRA at either dose. This study does not support the use of ATRA to prevent or ameliorate lung fibrosis., (Copyright 2001 Academic Press)

To study the pattern of lymphokines in bleomycin-induced lung injury, T cells were isolated from lung interstitial tissue (LIL), peribronchial lymphatic tissue (PBLT), and bronchoalveolar lavage (BAL) fluid of bleomycin-"sensitive" C57Bl/6 and bleomycin-"resistant" BALB/c mice at 3, 6, and 14 days following intratracheal instillation of bleomycin or saline. After 48 hours in culture, conditioned media were collected and assayed with specific enzyme-linked immunosorbent assay (ELISA) for interferon (IFN)-gamma, interleukin (IL)-2, IL-4 and IL-5. In bleomycin-treated C57B1/6 mice, IFN-gamma production was increased up to 20-fold at 3 and 6 days in LIL, and at 3 days in PBLT lymphocytes. IL-4 production was slightly decreased in LIL and PBLT lymphocytes at 14 days. IL-2 and IL-5 were not changed by bleomycin. In BALB/c mice, IFN-gamma production was increased 5-fold at 14 days, and IL-2 production at 6 days, in LIL but not PBLT. IL-4 and IL-5 were not significantly changed. The increase in IFN-gamma may play a role in the pathogenesis of bleomycin-induced lung injury. Differences in the cytokine pattern between the strains of mice may contribute to the variable strain susceptibility in bleomycin-induced lung injury.