Reduced decline of lung diffusing capacity in COPD patients with diabetes and metformin treatment.

We studied whether in patients with COPD the use of metformin for diabetes treatment was linked to a pattern of lung function decline consistent with the hypothesis of anti-aging effects of metformin. Patients of GOLD grades 1-4 of the COSYCONET cohort with follow-up data of up to 4.5 y were included. The annual decline in lung function (FEV1, FVC) and CO diffusing capacity (KCO, TLCO) in %predicted at baseline was evaluated for associations with age, sex, BMI, pack-years, smoking status, baseline lung function, exacerbation risk, respiratory symptoms, cardiac disease, as well as metformin-containing therapy compared to patients without diabetes and metformin. Among 2741 patients, 1541 (mean age 64.4 y, 601 female) fulfilled the inclusion criteria. In the group with metformin treatment vs. non-diabetes the mean annual decline in KCO and TLCO was significantly lower (0.2 vs 2.3, 0.8 vs. 2.8%predicted, respectively; p < 0.05 each), but not the decline of FEV1 and FVC. These results were confirmed using multiple regression and propensity score analyses. Our findings demonstrate an association between the annual decline of lung diffusing capacity and the intake of metformin in patients with COPD consistent with the hypothesis of anti-aging effects of metformin as reflected in a surrogate marker of emphysema.

Plasma Hsp90 levels in patients with systemic sclerosis and relation to lung and skin involvement: a cross-sectional and longitudinal study.

Our previous study demonstrated increased expression of Heat shock protein (Hsp) 90 in the skin of patients with systemic sclerosis (SSc). We aimed to evaluate plasma Hsp90 in SSc and characterize its association with SSc-related features. Ninety-two SSc patients and 92 age-/sex-matched healthy controls were recruited for the cross-sectional analysis. The longitudinal analysis comprised 30 patients with SSc associated interstitial lung disease (ILD) routinely treated with cyclophosphamide. Hsp90 was increased in SSc compared to healthy controls. Hsp90 correlated positively with C-reactive protein and negatively with pulmonary function tests: forced vital capacity and diffusing capacity for carbon monoxide (DLCO). In patients with diffuse cutaneous (dc) SSc, Hsp90 positively correlated with the modified Rodnan skin score. In SSc-ILD patients treated with cyclophosphamide, no differences in Hsp90 were found between baseline and after 1, 6, or 12 months of therapy. However, baseline Hsp90 predicts the 12-month change in DLCO. This study shows that Hsp90 plasma levels are increased in SSc patients compared to age-/sex-matched healthy controls. Elevated Hsp90 in SSc is associated with increased inflammatory activity, worse lung functions, and in dcSSc, with the extent of skin involvement. Baseline plasma Hsp90 predicts the 12-month change in DLCO in SSc-ILD patients treated with cyclophosphamide.

Impact of diffusing lung capacity before and after neoadjuvant concurrent chemoradiation on postoperative pulmonary complications among patients with stage IIIA/N2 non-small-cell lung cancer.

BACKGROUND AND OBJECTIVE: This study aims to evaluate the impact of diffusing capacity of the lung for carbon monoxide (DLco) before and after neoadjuvant concurrent chemoradiotherapy (CCRT) on postoperative pulmonary complication (PPC) among stage IIIA/N2 non-small-cell lung cancer (NSCLC) patients. METHODS: We retrospectively studied 324 patients with stage IIIA/N2 NSCLC between 2009 and 2016. Patients were classified into 4 groups according to DLco before and after neoadjuvant CCRT; normal-to-normal (NN), normal-to-low (NL), low-to-low (LL), and low-to-very low (LVL). Low DLco and very low DLco were defined as DLco < 80% predicted and DLco < 60% predicted, respectively. RESULTS: On average, DLco was decreased by 12.3% (±10.5) after CCRT. In multivariable-adjusted analyses, the incidence rate ratio (IRR) for any PPC comparing patients with low DLco to those with normal DLco before CCRT was 2.14 (95% confidence interval (CI) = 1.36-3.36). Moreover, the IRR for any PPC was 3.78 (95% CI = 1.68-8.49) in LVL group compared to NN group. The significant change of DLco after neoadjuvant CCRT had an additional impact on PPC, particularly after bilobectomy or pneumonectomy with low baseline DLco. CONCLUSIONS: The DLco before CCRT was significantly associated with risk of PPC, and repeated test of DLco after CCRT would be helpful for risk assessment, particularly in patients with low DLco before neoadjuvant CCRT.

The effect of dopamine on pulmonary diffusing capacity and capillary blood volume responses to exercise in young healthy humans.

NEW FINDINGS: What is the Central question? Does dopamine, a pulmonary vascular vasodilator, contribute to the regulation of pulmonary diffusing capacity and capillary blood volume responses to exercise and exercise tolerance? What are the main findings and their importance? Dopamine appears not to be important for regulating pulmonary diffusing capacity or pulmonary capillary blood volume during exercise in healthy participants. Dopamine blockade trials demonstrated that endogenous dopamine is important for maintaining exercise tolerance; however, exogenous dopamine does not improve exercise tolerance. ABSTRACT: Pulmonary capillary blood volume (Vc ) and diffusing membrane capacity (Dm ) expansion are important contributors to the increased pulmonary diffusing capacity (DLCO ) observed during upright exercise. Dopamine is a pulmonary vascular vasodilator, and recent studies suggest that it may play a role in Vc regulation through changes in pulmonary vascular tone. The purpose of this study was to examine the effect of exogenous dopamine and dopamine receptor-2 (D2 -receptor) blockade on DLCO , Vc and Dm at baseline and during cycle exercise, as well as time-to-exhaustion at 85% of V̇O2peak . We hypothesized that dopamine would increase DLCO , Vc , Dm and time-to-exhaustion, while D2 -receptor blockade would have the opposite effect. We recruited 14 young, healthy, recreationally active subjects ( V̇O2peak 45.8 ± 6.6 ml kg-1  min-1 ). DLCO , Vc and Dm were determined at baseline and during exercise at 60% and 85% of V̇O2peak under the following randomly assigned and double blinded conditions: (1) intravenous saline and placebo pill, (2) intravenous dopamine (2 µg kg-1  min-1 ) and placebo pill, and (3) intravenous saline and D2 -receptor antagonist (20 mg oral metoclopramide). Exogenous dopamine and dopamine blockade had no effect on DLCO , Vc and Dm responses at baseline or during exercise. Dopamine blockade reduced time-to-exhaustion by 47% (P = 0.04), but intravenous dopamine did not improve time-to-exhaustion. While dopamine modulation did not affect DLCO , Vc or Dm , the reduction in time-to-exhaustion with D2 -receptor blockade suggests that endogenous dopamine is important for exercise tolerance.

Use of mycophenolate mofetil and azathioprine for the treatment of chronic hypersensitivity pneumonitis-A single-centre experience.

INTRODUCTION: The optimal pharmacological management of chronic hypersensitivity pneumonitis (cHP) is unknown. Corticosteroids are often used as first line therapy but can be associated with side effects. There is a paucity of data examining the role of steroid-sparing agents in cHP. We aimed to determine the effect of mycophenolate mofetil (MMF) and azathioprine (AZA) on lung function and prednisolone dose in cHP patients. METHODS: Retrospective analysis of patients initiated on either MMF or AZA following a multidisciplinary team diagnosis of cHP. Changes in lung function and prednisolone dose up to 12 months before and after MMF/AZA initiation were analysed. RESULTS: Twenty two out of 30 patients remained on treatment at 12 months (18 MMF, 4 AZA). Steroid-sparing therapy resulted in a significant reduction in prednisolone dose from 16.2 ± 9.7 to 8.2 ± 4.2 mg daily (P = 0.002). Treatment with MMF or AZA for 12 months was associated with a significant improvement in carbon monoxide diffusing capacity (TLCO) (-0.55 ± 0.96 vs. +0.31 ± 0.58 mmol/kPa/min, P = 0.02). Although treatment reduced the rate of forced vital capacity decline (-111 ± 295 vs. +2.3 ± 319 mL), it was not significant (P = 0.22). CONCLUSION: MMF or AZA therapy in cHP is associated with an improvement in TLCO and reduction in prednisolone dose. There is a need for prospective trials.

Impact of hemoglobin levels on hemoglobin-adjusted carbon monoxide diffusion capacity after chemotherapy for testicular cancer.

OBJECTIVES: We aimed to compare the diffusion capacity of carbon monoxide (DLCO), which was adjusted using the two equations the Cotes method and the Dinakara method, to assess bleomycin-induced lung injury in testicular cancer patients preparing for post-chemotherapy surgery. METHODS: Between November 1990 and October 2018, 89 patients with advanced testicular cancer were recruited into the study. All patients received chemotherapy and underwent DLCO measurements using the single-breath technique prior to surgery for residual tumor removal. RESULTS: The mean DLCO adjusted for hemoglobin using the Cotes and Dinakara methods was 69.5% and 86.0%, respectively (P < 0.001). According to the Cotes method, adjusted DLCO was severely diminished to below 65% in 40 patients (45%), whereas this proportion was only 16% according to the Dinakara method. We observed a significant correlation between hemoglobin levels and DLCO adjusted using the Cotes method (P < 0.001), but not using the Dinakara method. Four patients received a clinical diagnosis of bleomycin-induced pneumonitis (BIP), and all patients recovered after oral steroid therapy or observation. The DLCO adjusted by either methods was not well correlated with the development of BIP. No patients had major postoperative respiratory complications. CONCLUSIONS: We found that Cotes-adjusted DLCO may be influenced by anemia. We recommend the addition of Dinakara-adjusted DLCO, along with chest computed tomography, for preoperative risk assessment.

Pirfenidone in patients with idiopathic pulmonary fibrosis and more advanced lung function impairment.

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) demonstrate a range of lung function impairment. However, the efficacy of antifibrotics compared with placebo has not been assessed in patients with more advanced disease. This post-hoc analysis investigated the efficacy and safety of pirfenidone versus placebo in patients with IPF and more advanced lung function impairment, defined as percent predicted forced vital capacity (%FVC) < 50% and/or percent predicted carbon monoxide diffusing capacity <35%. METHODS: Patients randomised to pirfenidone 2,403 mg/day or placebo in the ASCEND (NCT01366209) and CAPACITY (NCT00287716; NCT00287729) trials with more advanced baseline lung function impairment (pirfenidone, n = 90; placebo, n = 80) were included. Mortality, lung function, hospitalisation, exercise capacity and dyspnoea were investigated over 52 weeks. RESULTS: At Week 52 versus placebo, pirfenidone was associated with significantly lower risks of all-cause mortality (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.09-0.86; p=0.0180), ≥10% absolute %FVC decline or all-cause mortality (HR 0.40; 95% CI 0.23-0.69; p=0.0006) and ≥10% absolute %FVC decline or respiratory-related hospitalisation or all-cause mortality (HR 0.46; 95% CI 0.28-0.76; p=0.0018). At Week 52, median treatment differences favouring pirfenidone were 36.7 m for 6-min walk distance and -8.0 points for the University of California-San Diego Shortness of Breath Questionnaire total score. Treatment-emergent adverse events (TEAEs) led to discontinuation in 14.4% and 21.3% of patients with pirfenidone and placebo, respectively. CONCLUSION: Pirfenidone demonstrated clinically relevant benefits across multiple domains in patients with IPF and more advanced disease without an increased risk of discontinuation due to TEAEs. CLINICAL TRIALS REGISTRATION: clinicaltrials. gov (ASCEND: NCT01366209; CAPACITY: NCT00287716; NCT00287729).

Long-term treatment with human immunoglobulin for antisynthetase syndrome-associated interstitial lung disease.

BACKGROUND: Interstitial lung disease-associated antisynthetase syndrome (AS-ILD) carries significant morbidity and mortality. Corticosteroids and immunosuppressive drugs are the mainstay of treatment. Human immunoglobulin (IVIg), an immunomodulator without immunosuppressive properties, is effective in myositis but the evidence supporting its use in ILD is scarce. OBJECTIVE: To describe clinical outcomes of AS-ILD patients receiving IVIg. METHODS: Retrospective analysis of AS-ILD patients. Linear mixed models using restricted maximum likelihood estimation was used to estimate the change in lung function and corticosteroid dose over time. RESULTS: Data from 17 patients was analyzed. Median follow-up was 24.6 months. Fourteen patients had refractory disease. The mean percent-predicted forced vital capacity (FVC%) (p = 0.048) and percent-predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (p = 0.0223) increased over time, while the mean prednisone dose (p < 0.001) decreased over time. Seven patients achieved a >10% increase in FVC%, including two who used IVIg as initial treatment. Five patients showed a >10% increase in DLCO% and TLC%. Nine (53%) patients experienced side effects. CONCLUSIONS: IVIg may be a useful complementary therapy in active progressive AS-ILD but is associated with potential side effects. Fssssurther investigation is required to determine the value of IVIg as an initial treatment in AS-ILD.

Efficacy of TCM therapy of tonifying lung-kidney's Qi-deficiency in a case of idiopathic pulmonary fibrosis: A case report.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a special form of spontaneous, chronic, progressive interstitial fibrotic pneumonia of unknown cause, and treatments for IPF have shown a poor prognosis. This study reports a new treatment, traditional Chinese medicine (TCM) therapy, for tonifying Qi-deficiency of lung-kidney in a 64-year-old patient with IPF. PATIENT CONCERNS: A 64-year-old man, who complained of cough and asthma, was diagnosed as IPF with mild impairment in lung function by thoracic high-resolution computed tomography and pulmonary function test. He received an 18-month N-acetylcysteine monotherapy but had no improvement in lung function. DIAGNOSES: IPF with mild impairment in lung function was diagnosed. INTERVENTIONS: The Chinese herbal medicine composition was decocted in 300 ml water for oral administration with 150 ml decoction twice daily in June 2017. OUTCOMES: The pulmonary function test showed that diffusing capacity for carbon monoxide had increased to 81% of predicted back to normal after 2-month TCM monotherapy. And diffusing capacity for carbon monoxide had increased to 89% of predicted, and forced expiratory volume in 1 s/forced vital capacity ratio increased to 92% at 14-month follow-up. No adverse events occurred during the 14 months of therapy and observation. LESSONS: The treatment by TCM therapy of tonifying lung-kidney's Qi-deficiency for IPF can improve the pulmonary function and reverse disease progression; it may be considered as a complementary treatment for IPF with mild-to-moderate impairment. However, the insights provided in this case report require further exploration and verification.

Cyclophosphamide for Systemic Sclerosis-related Interstitial Lung Disease: A Comparison of Scleroderma Lung Study I and II.

OBJECTIVE: To compare safety and efficacy outcomes between the cyclophosphamide (CYC) arms of Scleroderma Lung Study (SLS) I and II. METHODS: Participants enrolled in the CYC arms of SLS I (n = 79) and II (n = 69) were included. SLS I and II randomized participants to oral CYC for 1 year and followed patients for an additional year off therapy (in SLS II, patients received placebo in Year 2). Eligibility criteria for SLS I and II were nearly identical. Outcomes included the forced vital capacity (FVC%)-predicted and DLCO%-predicted (measured every 3 mos) and quantitative radiographic extent of interstitial lung disease (measured at 1 and 2 yrs for SLS I and SLS II, respectively). Joint models were created to evaluate the treatment effect on the course of the FVC/DLCO over 2 years while controlling for baseline disease severity. RESULTS: SLS I and II CYC participants had similar baseline characteristics. After adjusting for baseline disease severity, there was no difference in the course of the FVC%-predicted (p = 0.535) nor the DLCO%-predicted (p = 0.172) between the SLS I and II CYC arms. In both groups, treatment with CYC led to a significant improvement in the FVC%-predicted from 3 to 12 months, but no significant improvement beyond this point. Treatment with CYC had no effect on the DLCO for either group. CONCLUSION: Treatment with 1 year of oral CYC led to similar improvements in lung function in both SLS I and II, although the effects were not sustained following cessation of CYC. These results suggest that increasing the duration of ILD therapy may improve outcomes for patients with systemic sclerosis-ILD.

Ventilation inhomogeneity and NO and CO diffusing capacity in ex-premature school children.

AIM: Ex-premature school children show mild-to-moderate airway obstruction and decreased CO diffusing capacity. Multiple breath nitrogen washout (N2MBW) and NO diffusing capacity (DLNO) measurements may provide new insight into long-term pulmonary and vascular impairment in bronchopulmonary dysplasia (BPD). METHODS: We examined a randomly selected group of 70 ex-premature children (gestational age <28 weeks or birth weight <1500 g; 42 with and 28 without BPD) and 38 term-born healthy controls of 8-13 years of age. Subjects performed N2MBW (lung clearance index, LCI; Sacin, and Scond), DLNO (membrane related diffusing capacity, Dm and pulmonary capillary volume, Vc), Fractional exhaled NO, CO diffusing capacity, conventional spirometry (FEV1, FVC, FEF25-75) and plethysmography (RV, TLC). Respiratory symptoms were assessed by questionnaire. RESULTS: Compared to healthy controls, the BPD group had higher z-scores for lung clearance index (P = 0.003), Sacin (P = 0.005), lower CO diffusing capacity (P = 0.025), DLNO (P = 0.022), DLNO/VA z-scores (P = 0.025) and a significant larger proportion had respiratory complaints. Amongst ex-premature children, the BPD group did not differ from the non-BPD group except for a decreased Dm (P = 0.023). Ex-premature with BPD showed predominantly airway obstruction (FEV1/FVC; P < 0.0001), signs of hyperinflation (RV/TLC-ratio; P = 0.028), and 25% had a positive bronchodilator response (>12% in FEV1). CONCLUSION: Ex-premature school children exhibited relatively mild but significant long-term respiratory symptoms and pulmonary peripheral impairment judged by N2MBW and DLNO measurements along with well-known airway obstruction. Larger longitudinal studies are needed to assess the clinical use of these advanced methods of assessing ventilation inhomogeneity and DLNO.

Bronchodilator Responses in Respiratory Impedance, Hyperinflation and Gas Trapping in COPD.

Hyperinflation, gas trapping and their responses to long-acting bronchodilator are clinically important in COPD. The forced oscillation technique (FOT) measures of respiratory system resistance and reactance are sensitive markers of bronchodilator response in COPD. The relationships between changes in resistance and reactance, and changes in hyperinflation and gas trapping, following long-acting bronchodilator (LA-BD) have not been studied. 15 subjects with mild-moderate COPD underwent FOT, spirometry then body plethysmography, before and 2 hours after a single 150 microg dose of the LA-BD indacaterol. Hyperinflation was quantified as the inspiratory capacity to total lung capacity ratio (IC/TLC), and gas trapping as residual volume to TLC ratio (RV/TLC). At baseline, FOT parameters were moderately correlated with IC/TLC (|r| 0.53-0.73, p < 0.05). At 2 hours post-LA-BD, there were moderate correlations between change in FOT and change in RV/TLC (|r| 0.60-0.82, p < 0.05). Baseline FOT parameters also correlated with the subsequent post-LA-BD change in both IC/TLC (|r| 0.54-0.62, p < 0.05) and RV/TLC (|r| 0.57-0.76, p < 0.05). FOT impedance reflects hyperinflation and gas trapping in COPD, and the potential for long-acting bronchodilator responsiveness. These results provide us with further insight into the physiological mechanisms of action of long-acting bronchodilator treatment, and may be clinically useful for predicting treatment responses.

Influence of Inhaled Amiloride on Lung Fluid Clearance in Response to Normobaric Hypoxia in Healthy Individuals.

Wheatley, Courtney M., Sarah E. Baker, Bryan J. Taylor, Manda L. Keller-Ross, Steven C. Chase, Alex R. Carlson, Robert J. Wentz, Eric M. Snyder, and Bruce D. Johnson. Influence of inhaled amiloride on lung fluid clearance in response to normobaric hypoxia in healthy individuals. High Alt Med Biol 18:343-354, 2017. AIM: To investigate the role of epithelial sodium channels (ENaC) on lung fluid clearance in response to normobaric hypoxia, 20 healthy subjects were exposed to 15 hours of hypoxia (fraction of inspired oxygen [FiO2] = 12.5%) on two randomized occasions: (1) inhaled amiloride (A) (1.5 mg/5 mL saline); and (2) inhaled saline placebo (P). Changes in lung fluid were assessed through chest computed tomography (CT) for lung tissue volume (TV), and the diffusion capacity of the lungs for carbon monoxide (DLCO) and nitric oxide (DLNO) for pulmonary capillary blood volume (VC). Extravascular lung water (EVLW) was derived as TV-VC and changes in the CT attenuation distribution histograms were reviewed. RESULTS: Normobaric hypoxia caused (1) a reduction in EVLW (change from baseline for A vs. P, -8.5% ± 3.8% vs. -7.9% ± 5.2%, p < 0.05), (2) an increase in VC (53.6% ± 28.9% vs. 53.9% ± 52.3%, p < 0.05), (3) a small increase in DLCO (9.6% ± 29.3% vs. 9.9% ± 23.9%, p > 0.05), and (4) CT attenuation distribution became more negative, leftward skewed, and kurtotic (p < 0.05). CONCLUSION: Acute normobaric hypoxia caused a reduction in lung fluid that was unaffected by ENaC inhibition through inhaled amiloride. Although possible amiloride-sensitive ENaC may not be necessary to maintain lung fluid balance in response to hypoxia, it is more probable that normobaric hypoxia promotes lung fluid clearance rather than accumulation for the majority of healthy individuals. The observed reduction in interstitial lung fluid means alveolar fluid clearance may not have been challenged.

RISE-SSc: Riociguat in diffuse cutaneous systemic sclerosis.

RISE-SSc is a randomized, double-blind, placebo-controlled phase 2 study investigating the efficacy and safety of riociguat in patients with diffuse cutaneous systemic sclerosis (dcSSc). Based on positive results from riociguat trials in patients with pulmonary hypertension and chronic thromboembolic pulmonary hypertension in combination with the known antiproliferative and antifibrotic effects seen in animal models, patients with SSc may benefit from treatment with riociguat. Patients with SSc meeting the ACR/EULAR systemic sclerosis classification criteria with diffuse cutaneous SSc (dcSSc) subset per LeRoy criteria, and a disease duration of less than or equal to 18 months will be randomized to placebo or riociguat 0.5 mg (up-titrated to a maximum dose of 2.5 mg TID over 10 weeks) and maintained on therapy for a total of 52 weeks. During the first 10 weeks of the long-term extension phase, placebo subjects will be up-titrated on riociguat, and all patients will be followed for up to 6 years. The primary endpoint of change in modified Rodnan skin score (mRSS) from baseline will be assessed at 52 weeks, as will be secondary endpoints such as mRSS progression and regression rates, patient quality of life, digital ulcer burden, and change in forced vital capacity and carbon monoxide diffusing capacity. This review will further define the clinical rationale for the use of riociguat in the treatment of SSc and provide details on study protocol, design, and outcome reporting. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02283762.

Azathioprine response in patients with fibrotic connective tissue disease-associated interstitial lung disease.

BACKGROUND: Azathioprine is a commonly prescribed therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). Combination therapy that included azathioprine was recently shown to increase the risk of death and hospitalization in patients with idiopathic pulmonary fibrosis. Whether azathioprine increases the risk of adverse outcomes in patients with fibrotic CTD-ILD, including those with CTD-associated usual interstitial pneumonia (UIP), remains unknown. METHODS: A retrospective cohort analysis was performed to determine the combined incidence rate of death, transplant and respiratory hospitalization associated with azathioprine exposure. A fibrotic CTD-ILD cohort treated with mycophenolate mofetil served as a comparator group. Incidence rates were compared with an incidence rate ratio (IRR) generated by negative binomial regression. Longitudinal pulmonary function response was then assessed using mixed effects linear regression models. RESULTS: Fifty-four patients were treated with azathioprine and forty-three with mycophenolate. Medication discontinuation due to non-respiratory side effects occurred in 27% and 5% of the azathioprine and mycophenolate cohorts, respectively. The combined incidence rate of adverse outcomes was 0.015 and 0.013 for azathioprine and mycophenolate, respectively (IRR 1.23; 95% CI 0.49-3.12; p = 0.66). Similar incidence rates were observed among those with CTD-UIP (IRR 0.83; 95% CI 0.21-3.31; p = 0.79). Both groups demonstrated pulmonary function stability over time, with the azathioprine group demonstrating a marginal improvement. CONCLUSIONS: A significant minority of patients could not tolerate azathioprine due to non-respiratory side effects. Of those who did tolerate azathioprine, a similar incidence of adverse outcomes was observed as those treated with mycophenolate. Both therapies were associated with stability in pulmonary function.

Efficacy of N-Acetylcysteine in Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.

There are a number of conflicting reports describing the clinical outcomes of using N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis. We have, therefore, performed a meta-analysis to evaluate the efficacy of N-acetylcysteine, compared with control, for the treatment of idiopathic pulmonary fibrosis.Original controlled clinical trials evaluating the efficacy of N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis were included in the analysis. Searches for relevant articles were carried out in July 2014 by 2 independent researchers using PubMed, Embase, Cochrane Central, and Google Scholar. Change in forced vital capacity, change in percentage of predicted vital capacity, change in percentage of predicted carbon monoxide diffusing capacity, changes in 6 minutes walking test distance, rate of adverse events, and rate of death were expressed as outcomes using RevMan 5.0.1.Five trials, with a total of 564 patients, were included in this meta-analysis. The meta-analysis showed that the control group had significant decreases in percentage of predicted vital capacity (standardized mean difference [SMD] = 0.37; 95% confidence interval [CI]: 0.13 to -0.62; P = 0.003) and 6 minutes walking test distance (SMD = 0.25; 95% CI: 0.02-0.48; P = 0.04). There were no statistically significant differences in forced vital capacity (SMD = 0.07; 95% CI: -0.13-0.27; P = 0.52), percentage of predicted carbon monoxide diffusing capacity (SMD = 0.12; 95% CI: -0.06-0.30; P = 0.18), rates of adverse events (odd ratio = 4.50; 95% CI: 0.19-106.41; P = 0.35), or death rates (odd ratio = 1.79; 95% CI: 0.3-5.12; P = 0.28) between the N-acetylcysteine group and the control group.N-Acetylcysteine was found to have a significant effect only on decreases in percentage of predicted vital capacity and 6 minutes walking test distance. N-acetylcysteine showed no beneficial effect on changes in forced vital capacity, changes in predicted carbon monoxide diffusing capacity, rates of adverse events, or death rates.

Biological effects of inhaled nitrogen dioxide in healthy human subjects.

PURPOSE: Several epidemiological studies indicate that inhaled nitrogen dioxide (NO2) at low concentrations have been statistically associated with adverse health effects. However, these results are not reflected by exposure studies in humans. The aim of the study was to assess the acute functional and cellular responses to different NO2 concentrations in healthy human subjects with various techniques. METHODS: Twenty-five subjects were exposed for 3 h to NO2 concentrations 0, 0.1, 0.5, and 1.5 ppm in a randomized crossover study design during 4 consecutive weeks. In each subject, lung function, diffusion capacity and exhaled nitric oxide were measured and inflammation markers were assessed in blood, nasal secretions, induced sputum and exhaled breath condensate. RESULTS: From all lung function indices under consideration, only intrathoracic gas volume was borderline significantly increased after 0.5 ppm (p = 0.048) compared to 0.1 ppm NO2. Regarding the cellular effect parameters, the macrophage concentration in induced sputum decreased with increasing NO2 concentration, although these changes were only borderline significant (p = 0.05). CONCLUSION: These results do not suggest a considerable acute adverse response in human subjects after 3 h of exposure to NO2 in the NO2 concentration range investigated in this study.

Inhaled Interferon and Diffusion Capacity in Idiopathic Pulmonary Fibrosis (IPF).

BACKGROUND: Using data from a previously reported phase 2 safety trial, testing inhaled interferon gamma (IFN-γ) for IPF, we analyzed effects on full pulmonary function tests (PFTs) for efficacy before and after therapy and designed a randomized controlled trial of inhaled IFN-γ to treat IPF. METHODS: Ten patients with IPF had received inhaled IFN-γ (Actimmune, InterMune) for 80 weeks. Full PFTs were available 20-50 weeks before Rx and monthly during Rx. Eighty-nine observations were used in the analysis. Linear mixed models for modeling longitudinal data were used to test if the PFT change over time was significantly different before and after IFN-γ. Autoregressive dependence structure with order one was consistently selected as the best one to model the intra-patient correlation over time. Normality assumption was confirmed. Significance level was set at 0.05. Using published literature and our data we performed a sample size calculation based on simulated data. RESULTS: The change over time in DLCO was significantly different before and after IFN-γ treatment. DLCO decreased over time before treatment but increased after treatment (p-value=0.03). Changes in TLC, FRC, RV and FVC were not statistically significant. With a sample size of 60, a placebo controlled, randomized trial has about 90% power to detect a significant difference in the change rate of DLCO in the groups of patients treated with IFN-γ vs placebo. CONCLUSIONS: DLCO was significantly improved following inhaled (IFN-γ) as treatment for IPF. Our data suggest that previous studies utilizing parenteral IFN-γ may have failed because of the mode of delivery. Future randomized, controlled, phase 3 trials, comparing the difference in PFT behavior (specifically DLCO) longitudinally may be more sensitive to drug effect and serve as a valuable clinical endpoint.