Center variability in the prognostic value of a cumulative acute cellular rejection "A-score" for long-term lung transplant outcomes.

The acute rejection score (A-score) in lung transplant recipients, calculated as the average of acute cellular rejection A-grades across transbronchial biopsies, summarizes the cumulative burden of rejection over time. We assessed the association between A-score and transplant outcomes in 2 geographically distinct cohorts. The primary cohort included 772 double lung transplant recipients. The analysis was repeated in 300 patients from an independent comparison cohort. Time-dependent multivariable Cox models were constructed to evaluate the association between A-score and chronic lung allograft dysfunction or graft failure. Landmark analyses were performed with A-score calculated at 6 and 12 months posttransplant. In the primary cohort, no association was found between A-score and graft outcome. However, in the comparison cohort, time-dependent A-score was associated with chronic lung allograft dysfunction both as a time-dependent variable (hazard ratio, 1.51; P < .01) and when calculated at 6 months posttransplant (hazard ratio, 1.355; P = .031). The A-score can be a useful predictor of lung transplant outcomes in some settings but is not generalizable across all centers; its utility as a prognostication tool is therefore limited.

Comparative Safety Analysis of Nabilone Versus Opioids: A Population-Based Cohort Study.

BACKGROUND: Some have advocated that nabilone be used rather than opioids to manage chronic, noncancer pain, since the former drug may have a better safety profile. OBJECTIVE: We compared the safety of incident nabilone use relative to incident opioid use with respect to multiple clinically important outcomes. DESIGN: A population-based, retrospective cohort study. SETTING: Province of Ontario, Canada. PARTICIPANTS: Persons aged 12 years and older, diagnosed with a musculoskeletal condition within the past 3 years prior to the index date. EXPOSURES: Incident nabilone use, with incident opioid use serving as the reference group. MEASUREMENTS: Within 3 months following the index date, we separately evaluated for pneumonia, motor vehicle accidents, falls or fractures, mental and behavioral disorder due to psychoactive substance use, and all-cause mortality. RESULTS: A total of 18,863 incident nabilone users were propensity score matched to an equal number of opioid users. In the overall matched analysis, incident nabilone users vs. incident opioid users had significantly lower rates of pneumonia (hazard ratio [HR] 0.78, 95% CI 0.63-0.96), falls or fractures (HR 0.56, 95% CI 0.50-0.64), and all-cause mortality (HR 0.79, 95% CI 0.65-0.95), but significantly higher rate of mental or behavioral disorder (HR 2.23, 95% CI 1.45-3.43). There was no significant difference between groups with respect to rate of motor vehicle accidents. LIMITATIONS: Unmeasured confounding may have influenced results. CONCLUSIONS: While usage of nabilone relative to opioids was associated with reduced rates of pneumonia, falls or fractures, and all-cause mortality, it was simultaneously associated with an increased rate of adverse mental health outcomes. This picture of mixed safety results raises concerns with the policy approach of broadly substituting use of opioids with nabilone. FUNDING SOURCE: Ontario Ministry of Health.

Association of ever use of e-cigarettes with health and lifestyle variables among young adults: a Canadian health measure survey study.

Research suggests that vaping raises oxidative stress levels and has been implicated in poor mental health. The objective of this study is to assess cross-sectional associations between quality of life (QOL) indicators and e-cigarette (EC) use in young Canadian adults. We used data from the 2016-2017 Canadian Health Measures Survey. We compared physical activity (daily steps), physiological measurements (high-density lipoprotein for cholesterol level), self-perceived life stress, mental health, and QOL between ever-use EC users and non-users. Multivariable binary or ordinal logistic regressions were used to calculate odds ratios (OR) with 95% confidence intervals (CI). Analyses included 905 participants (15-30 years) with 115 (12.7%) reporting EC use and 790 non-users. After adjusting for confounders, compared to non-users, EC users had significantly higher odds of being physically active (OR = 2.19, 95%CI: 1.14-4.20) but also with self-reported extreme life stress (OR = 2.68, 95%CI: 1.45-4.92). Albeit statistically non-significant, EC users also had higher odds of poorer QOL (OR = 1.12, 95%CI: 0.64-1.95). No statistically significant interactions between EC use, cigarette smoking, cannabis consumption and health outcomes were observed. CONCLUSION: Our study found that EC use was independently and significantly associated with increased odds of life stress and an indication of poorer QOL. Ongoing surveillance on young EC users is important to measure the long-term impact of vaping on their physical, mental health and quality of life to target for interventions. WHAT IS KNOWN: • E-cigarette use has been associated with high-risk behaviours and adverse mental health outcomes, such as depression and anxiety. WHAT IS NEW: • E-cigarette users had significantly higher odds of being physically active and higher amounts of life stress.

Proteome-wide effects of naphthalene-derived secondary organic aerosol in BEAS-2B cells are caused by short-lived unsaturated carbonyls.

Exposure to air pollution causes adverse health outcomes, but the toxicity mechanisms remain unclear. Here, we investigated the dynamic toxicities of naphthalene-derived secondary organic aerosol (NSOA) in a human bronchial epithelial cell line (BEAS-2B) and identified the chemical components responsible for toxicities. The chemical composition of NSOA was found to vary with six simulated atmospheric aging conditions (C1-C6), as characterized by high-resolution mass spectrometry and ion mobility mass spectrometry. Global proteome profiling reveals dynamic evolution in toxicity: Stronger proteome-wide impacts were detected in fresh NSOA, but the effects declined along with atmospheric aging. While Nrf2-regulated proteins (e.g., NQO1) were significantly up-regulated, the majority (78 to 97%) of proteins from inflammation and other pathways were down-regulated by NSOA exposure (e.g., Rho GTPases). This pattern is distinct from the reactive oxygen species (ROS)-mediated toxicity pathway, and an alternative cysteine reaction pathway was revealed by the decreased abundance of proteins (e.g., MT1X) prone to posttranslational thiol modification. This pathway was further validated by observing decreased Nrf2 response in reporter cells, after preincubating NSOA with cysteine. Ethynyl-naphthalene probe was employed to confirm the alkylation of cellular proteome thiols on the proteome-wide level by fresh NSOA via in-gel fluorescence imaging. Nontarget analysis identified several unsaturated carbonyls, including naphthoquinones and hydroxylated naphthoquinones, as the toxic components responsible for cysteine reactivity. Our study provides insights into the dynamic toxicities of NSOA during atmospheric aging and identifies short-lived unsaturated carbonyls as the predominant toxic components at the posttranslational level.

Diffusing capacity of the lung for carbon monoxide: association with long-term outcomes after lung transplantation in a 20-year longitudinal study.

RATIONALE: The diffusing capacity of the lung for carbon monoxide corrected for haemoglobin (D LCOcor) measures gas movement across the alveolar-capillary interface. We hypothesised that D LCOcor is a sensitive measure of injurious allograft processes disrupting this interface. OBJECTIVES: To determine the prognostic significance of the D LCOcor trajectory on chronic lung allograft dysfunction (CLAD) and survival. METHODS: A retrospective analysis was conducted of all bilateral lung transplant recipients at a single centre, between January 1998 and January 2018, with one or more D LCOcor measurements. Low baseline D LCOcor was defined as the failure to achieve a D LCOcor >75% predicted. Drops in D LCOcor were defined as >15% below recent baseline. RESULTS: 1259 out of 1492 lung transplant recipients were included. The median (range) time to peak D LCOcor was 354 (181-737) days and the mean±sd D LCOcor was 80.2±21.2% pred. Multivariable analysis demonstrated that low baseline D LCOcor was significantly associated with death (hazrd ratio (HR) 1.68, 95% CI 1.27-2.20; p<0.001). Low baseline D LCOcor was not independently associated with CLAD after adjustment for low baseline forced expiratory volume in 1 s or forced vital capacity. Any D LCOcor declines ≥15% were significantly associated with death, independent of concurrent spirometric decline. Lower percentage predicted D LCOcor values at CLAD onset were associated with shorter post-CLAD survival (HR 0.75 per 10%-unit change, p<0.01). CONCLUSION: Low baseline D LCOcor and post-transplant declines in D LCOcor were significantly associated with survival, independent of spirometric measurements. We propose that D LCOcor testing may allow identification of a subphenotype of baseline and chronic allograft dysfunction not captured by spirometry. There may be benefit in routine monitoring of D LCOcor after lung transplantation to identify patients at risk of poor outcomes.

Chronic lung allograft dysfunction phenotype and prognosis by machine learning CT analysis.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the principal cause of graft failure in lung transplant recipients and prognosis depends on CLAD phenotype. We used a machine learning computed tomography (CT) lung texture analysis tool at CLAD diagnosis for phenotyping and prognostication compared with radiologist scoring. METHODS: This retrospective study included all adult first double lung transplant patients (January 2010-December 2015) with CLAD (censored December 2019) and inspiratory CT near CLAD diagnosis. The machine learning tool quantified ground-glass opacity, reticulation, hyperlucent lung and pulmonary vessel volume (PVV). Two radiologists scored for ground-glass opacity, reticulation, consolidation, pleural effusion, air trapping and bronchiectasis. Receiver operating characteristic curve analysis was used to evaluate the diagnostic performance of machine learning and radiologist for CLAD phenotype. Multivariable Cox proportional hazards regression analysis for allograft survival controlled for age, sex, native lung disease, cytomegalovirus serostatus and CLAD phenotype. RESULTS: 88 patients were included (57 bronchiolitis obliterans syndrome (BOS), 20 restrictive allograft syndrome (RAS)/mixed and 11 unclassified/undefined) with CT a median 9.5 days from CLAD onset. Radiologist and machine learning parameters phenotyped RAS/mixed with PVV as the strongest indicator (area under the curve (AUC) 0.85). Machine learning hyperlucent lung phenotyped BOS using only inspiratory CT (AUC 0.76). Radiologist and machine learning parameters predicted graft failure in the multivariable analysis, best with PVV (hazard ratio 1.23, 95% CI 1.05-1.44; p=0.01). CONCLUSIONS: Machine learning discriminated between CLAD phenotypes on CT. Both radiologist and machine learning scoring were associated with graft failure, independent of CLAD phenotype. PVV, unique to machine learning, was the strongest in phenotyping and prognostication.

Significance of phenotype change after chronic lung allograft dysfunction onset.

Definitions for chronic lung allograft dysfunction (CLAD) phenotypes were recently revised (2019 ISHLT consensus). Post-CLAD onset phenotype transition may occur as a result of change in obstruction, restriction, or RAS-like opacities (RLO). We aimed to assess the prevalence and prognostic implications of these transitions. This was a single-center, retrospective cohort study of bilateral lung transplants performed in 2009-2015. CLAD phenotypes were determined per ISHLT guidelines. CLAD phenotype transition was defined as a sustained change in obstruction, restriction or RLO. We specifically focused on phenotype changes based on RLO emergence. Association of RLO development with time to death or retransplant were assessed using Kaplan-Meier and Cox proportional hazards models. Among 211 patients with CLAD, 47 (22.2%) experienced a phenotype transition. Nineteen patients developed RLO. Development of RLO phenotype after CLAD onset was associated with a shorter time to death/retransplant when considering the entire CLAD patient cohort (HR = 4.00, CI 2.74-5.83, P < 0.001) and also when restricting the analysis to only patients with a Non-RLO phenotype at CLAD onset (HR 9.64, CI 5.52-16.84, P < 0.0001). CLAD phenotype change based on emergence of RAS-like opacities implies a worse outcome. This highlights the clinical importance of imaging follow-up to monitor for phenotype transitions after CLAD onset.

Airway Oscillometry Detects Spirometric-Silent Episodes of Acute Cellular Rejection.

Rationale: Acute cellular rejection (ACR) is common during the initial 3 months after lung transplant. Patients are monitored with spirometry and routine surveillance transbronchial biopsies. However, many centers monitor patients with spirometry only because of the risks and insensitivity of transbronchial biopsy for detecting ACR. Airway oscillometry is a lung function test that detects peripheral airway inhomogeneity with greater sensitivity than spirometry. Little is known about the role of oscillometry in patient monitoring after a transplant.Objectives: To characterize oscillometry measurements in biopsy-proven clinically significant (grade ≥2 ACR) in the first 3 months after a transplant.Methods: We enrolled 156 of the 209 double lung transplant recipients between December 2017 and March 2019. Weekly outpatient oscillometry and spirometry and surveillance biopsies at Weeks 6 and 12 were conducted at our center.Measurements and Main Results: Of the 138 patients followed for 3 or more months, 15 patients had 16 episodes of grade 2 ACR (AR2) and 44 patients had 64 episodes of grade 0 ACR (AR0) rejection associated with stable and/or improving spirometry. In 15/16 episodes of AR2, spirometry was stable or improving in the weeks leading to transbronchial biopsy. However, oscillometry was markedly abnormal and significantly different from AR0 (P < 0.05), particularly in integrated area of reactance and the resistance between 5 and 19 Hz, the indices of peripheral airway obstruction. By 2 weeks after biopsy, after treatment for AR2, oscillometry in the AR2 group improved and was similar to the AR0 group.Conclusions: Oscillometry identified physiological changes associated with AR2 that were not discernible by spirometry and is useful for graft monitoring after a lung transplant.

Extending cytomegalovirus prophylaxis in high-risk (D+/R-) lung transplant recipients from 6 to 9 months reduces cytomegalovirus disease: A retrospective study.

RATIONALE: Cytomegalovirus (CMV)-seronegative recipients receiving a seropositive allograft (D+/R-) are at a high risk of developing CMV disease. Our program increased the duration of CMV prophylaxis from 6 to 9 months in May 2013. Here, we present the impact on the incidence of CMV infection, disease, side effects, rejection, and other factors. METHODS: Retrospective cohort of 241 CMV (D+/R-) patients transplanted between January 1, 2008, and December 31, 2017. Blood CMV testing was done according to protocol. All patients received ganciclovir/valganciclovir as prophylaxis. We compared the incidence and timing of CMV infection and disease up to 6 months after cessation of prophylaxis between patients who received 9 months (May 2013 onwards) and a historical control group who received 6 months of prophylaxis (prior to May 2013). CMV infection was defined as detectable CMV viremia in the absence of symptoms. CMV disease was defined as CMV syndrome or tissue-invasive disease. Side effects of prophylaxis and CMV resistance were recorded. RESULTS: A total of 116 patients were included in the 6-month group and 125 in the 9-month group. The extended 9-month CMV prophylaxis delayed the onset of CMV infection (median time to CMV infection after lung transplantation 295 vs 353 days, P < .01) but did not significantly reduce the incidence of CMV infection (65% vs 64%, P = .06, log-rank). The 9-month prophylaxis delayed the onset and decreased the incidence of CMV disease from 50% in the 6-month group to 42% (P = .02 log-rank). There was no difference in the rate of adverse effects (leukopenia in 32% in both groups, P = .53) or development of CMV resistance between the two groups (4 cases in both groups, P = .92). There were no significant differences in overall survival or the rate of chronic lung allograft dysfunction between the groups. CONCLUSIONS: Extending duration of CMV prophylaxis from 6 to 9 months resulted in a delayed and decreased incidence of CMV disease in our lung transplant population. The absolute risk reduction achieved by extended CMV prophylaxis was 8%. The incidence of CMV infection, and ganciclovir resistance and side effects were similar between the two groups. Our results suggest that extending CMV prophylaxis in the highest risk CMV D+/R- group is effective in reducing CMV disease.

One-Year Outcomes in Caregivers of Critically Ill Patients.

BACKGROUND: Few resources are available to support caregivers of patients who have survived critical illness; consequently, the caregivers' own health may suffer. We studied caregiver and patient characteristics to determine which characteristics were associated with caregivers' health outcomes during the first year after patient discharge from an intensive care unit (ICU). METHODS: We prospectively enrolled 280 caregivers of patients who had received 7 or more days of mechanical ventilation in an ICU. Using hospital data and self-administered questionnaires, we collected information on caregiver and patient characteristics, including caregiver depressive symptoms, psychological well-being, health-related quality of life, sense of control over life, and effect of providing care on other activities. Assessments occurred 7 days and 3, 6, and 12 months after ICU discharge. RESULTS: The caregivers' mean age was 53 years, 70% were women, and 61% were caring for a spouse. A large percentage of caregivers (67% initially and 43% at 1 year) reported high levels of depressive symptoms. Depressive symptoms decreased at least partially with time in 84% of the caregivers but did not in 16%. Variables that were significantly associated with worse mental health outcomes in caregivers were younger age, greater effect of patient care on other activities, less social support, less sense of control over life, and less personal growth. No patient variables were consistently associated with caregiver outcomes over time. CONCLUSIONS: In this study, most caregivers of critically ill patients reported high levels of depressive symptoms, which commonly persisted up to 1 year and did not decrease in some caregivers. (Funded by the Canadian Institutes of Health Research and others; ClinicalTrials.gov number, NCT00896220.).

Incidence of primary graft dysfunction after lung transplantation is altered by timing of allograft implantation.

The importance of circadian factors in managing patients is poorly understood. We present two retrospective cohort studies showing that lungs reperfused between 4 and 8 AM have a higher incidence (OR 1.12; 95% CI 1.03 to 1.21; p=0.01) of primary graft dysfunction (PGD) in the first 72 hours after transplantation. Cooling of the donor lung, occurring during organ preservation, shifts the donor circadian clock causing desynchrony with the recipient. The clock protein REV-ERBα directly regulates PGD biomarkers explaining this circadian regulation while also allowing them to be manipulated with synthetic REV-ERB ligands.

Outcomes of telehealth care for lung transplant recipients.

Telehealth uses videoconferencing to provide long-distance clinical care. Experience with telehealth in the setting of organ transplantation is limited. The purpose of this cohort study was to compare the impact of telehealth vs in-person follow-up of lung transplant recipients. Telehealth eligible patients were three or more years post-transplant and resided in Ontario outside the Greater Toronto Area. Patients with initial telehealth visits between July 1, 2009, and Dec 31, 2014, were retrospectively reviewed to assess outcomes of chronic lung allograft dysfunction progression and mortality until December 31, 2016, compared with eligible patients seen in-person. Of eligible patients (n = 204), 119 (58.3%) were seen via telehealth. Most patients (97%) rated telehealth as equivalent or superior to clinic visits. Telehealth visits resulted in significant out-of-pocket cost savings and travel distance savings for patients. There was no significant difference in mortality from the time of first visit (HR 0.81, 95% CI 0.49-1.32, P = 0.4) or from the time of transplant between groups (HR 0.72, 95% CI 0.43-1.17, P = 0.2). Telehealth can safely and effectively be used in select transplant recipients to increase access to care and reduce time and financial burdens for patients residing greater distances from primary transplant centers.

Comprehensive outcomes after lung retransplantation: A single-center review.

INTRODUCTION: Lung retransplantation is an important therapy for a growing population of lung transplant recipients with graft failure, but detailed outcome data are lacking. METHODS: We conducted a retrospective cohort study of adult lung retransplant in the Toronto Lung Transplant Program from 2001 to 2013 (n = 38). We analyzed the postoperative course, graft function, renal function, microbiology, donor-specific antibodies (DSA), quality of life, and survival compared to a control cohort of primary transplant recipients matched for age and era. RESULTS: Indication for retransplant was chronic lung allograft dysfunction in most retransplant recipients (35/38, 92%). The postoperative course was more complex after retransplant than primary (ventilation time, 8 vs 2 days, P < .01; ICU stay 14 vs 4 days, P < 0.01), and peak lung function was lower (FEV1 2.2L vs 3L, P < .01). Quality of life scores were comparable, as were renal function, microbiology, and donor-specific antibody formation. Median survival was 1988 days after primary and 1475 days after retransplant (P = .39). CONCLUSIONS: Lung retransplantation is associated with a more complex postoperative course and lower peak lung function, but the long-term medical profile is similar to primary transplant. Lung retransplantation can be beneficial for carefully selected candidates with allograft failure.

De Novo DQ Donor-Specific Antibodies Are Associated with Chronic Lung Allograft Dysfunction after Lung Transplantation.

RATIONALE: Despite increasing evidence about the role of donor-specific human leukocyte antigen (HLA) antibodies in transplant outcomes, the incidence and impact of de novo donor-specific antibodies (dnDSA) after lung transplantation remains unclear. OBJECTIVES: To describe the incidence, characteristics, and impact of dnDSA after lung transplantation. METHODS: We investigated a single-center cohort of 340 lung transplant recipients undergoing transplant during 2008 to 2011. All patients underwent HLA-antibody testing quarterly pretransplant and at regular intervals over the first 24 months after transplant. The patients received modified immunosuppression depending on their pretransplant sensitization status. Risk factors for dnDSA development, as well as the associations of dnDSA with patient survival and chronic lung allograft dysfunction (CLAD), were determined using multivariable analysis. MEASUREMENTS AND MAIN RESULTS: The cumulative incidence of dnDSA was 47% at a median of 86 days (range, 44-185 d) after lung transplantation. Seventy-six percent of recipients with dnDSA had DQ-DSA. Male sex and the use of ex vivo lung perfusion were associated with an increased risk of dnDSA, whereas increased HLA-DQB1 matching was protective. DQ-dnDSA preceded or coincided with the diagnosis of CLAD in all cases. Developing dnDSA (vs. no dnDSA) was associated with a twofold increased risk of CLAD (hazard ratio, 2.04; 95% confidence interval, 1.13-3.69). This association appeared to be driven by the development of DQ-dnDSA. CONCLUSIONS: dnDSA are common after lung transplantation, with the majority being DQ DSA. DQ-dnDSA are associated with an increased risk of CLAD. Strategies to prevent or treat DQ-dnDSA may improve outcomes for lung transplant recipients.

The RECOVER Program: Disability Risk Groups and 1-Year Outcome after 7 or More Days of Mechanical Ventilation.

RATIONALE: Disability risk groups and 1-year outcome after greater than or equal to 7 days of mechanical ventilation (MV) in medical/surgical intensive care unit (ICU) patients are unknown and may inform education, prognostication, rehabilitation, and study design. OBJECTIVES: To stratify patients for post-ICU disability and recovery to 1 year after critical illness. METHODS: We evaluated a multicenter cohort of 391 medical/surgical ICU patients who received greater than or equal to 1 week of MV at 7 days and 3, 6, and 12 months after ICU discharge. Disability risk groups were identified using recursive partitioning modeling. MEASUREMENTS AND MAIN RESULTS: The 7-day post-ICU Functional Independence Measure (FIM) determined the recovery trajectory to 1-year after ICU discharge and was an independent risk factor for 1-year mortality. The 7-day post-ICU FIM was predicted by age and ICU length of stay. By 2 weeks of MV, ICU patients could be stratified into four disability groups characterized by increasing risk for post ICU disability, ICU and post-ICU healthcare use, and disposition. Patients less than 42 years with ICU length of stay less than 2 weeks had the best function and fewest deaths at 1 year compared with patients greater than 66 years with ICU length of stay greater than 2 weeks who sustained the worst disability and 40% 1-year mortality. Depressive symptoms (17%) and post-traumatic stress disorder (18%) persisted at 1 year. CONCLUSIONS: ICU survivors of greater than or equal to 1 week of MV may be stratified into four disability groups based on age and ICU length of stay. These groups determine 1-year recovery and healthcare use and are independent of admitting diagnosis and illness severity. Clinical trial registered with www.clinicaltrials.gov (NCT 00896220).

Normothermic ex vivo lung perfusion in clinical lung transplantation.

BACKGROUND: More than 80% of donor lungs are potentially injured and therefore not considered suitable for transplantation. With the use of normothermic ex vivo lung perfusion (EVLP), the retrieved donor lung can be perfused in an ex vivo circuit, providing an opportunity to reassess its function before transplantation. In this study, we examined the feasibility of transplanting high-risk donor lungs that have undergone EVLP. METHODS: In this prospective, nonrandomized clinical trial, we subjected lungs considered to be high risk for transplantation to 4 hours of EVLP. High-risk donor lungs were defined by specific criteria, including pulmonary edema and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PO(2):FIO(2)) less than 300 mm Hg. Lungs with acceptable function were subsequently transplanted. Lungs that were transplanted without EVLP during the same period were used as controls. The primary end point was primary graft dysfunction 72 hours after transplantation. Secondary end points were 30-day mortality, bronchial complications, duration of mechanical ventilation, and length of stay in the intensive care unit and hospital. RESULTS: During the study period, 136 lungs were transplanted. Lungs from 23 donors met the inclusion criteria for EVLP; in 20 of these lungs, physiological function remained stable during EVLP and the median PO(2):FIO(2) ratio increased from 335 mm Hg in the donor lung to 414 and 443 mm Hg at 1 hour and 4 hours of perfusion, respectively (P<0.001). These 20 lungs were transplanted; the other 116 lungs constituted the control group. The incidence of primary graft dysfunction 72 hours after transplantation was 15% in the EVLP group and 30% in the control group (P=0.11). No significant differences were observed for any secondary end points, and no severe adverse events were directly attributable to EVLP. CONCLUSIONS: Transplantation of high-risk donor lungs that were physiologically stable during 4 hours of ex vivo perfusion led to results similar to those obtained with conventionally selected lungs. (Funded by Vitrolife; ClinicalTrials.gov number, NCT01190059.).

Spleen tyrosine kinase inhibition attenuates airway hyperresponsiveness and pollution-induced enhanced airway response in a chronic mouse model of asthma.

BACKGROUND: Asthma is a chronic inflammatory disease characterized by airways hyperresponsiveness (AHR), reversible airflow obstruction, airway remodeling, and episodic exacerbations caused by air pollutants, such as particulate matter (PM; PM <2.5 µm in diameter [PM(2.5)]) and ozone (O(3)). Spleen tyrosine kinase (Syk), an immunoregulatory kinase, has been implicated in the pathogenesis of asthma. OBJECTIVE: We sought to evaluate the effect of Syk inhibition on AHR in a chronic mouse model of allergic airways inflammation and pollutant exposure. METHODS: We used a 12-week chronic ovalbumin (OVA) sensitization and challenge mouse model of airways inflammation followed by exposure to PM(2.5) plus O(3). Respiratory mechanics and methacholine (MCh) responsiveness were assessed by using the flexiVent system. The Syk inhibitor NVP-QAB-205 was nebulized intratracheally by using a treatment-based protocol 15 minutes before assessment of MCh responsiveness. RESULTS: Syk expression increased significantly in the airway epithelia of OVA-sensitized and OVA-challenged (OVA/OVA) mice compared with OVA-sensitized but PBS-challenged (OVA/PBS) control mice. OVA/OVA mice exhibited AHR to MCh, which was attenuated by a single administration of NVP-QAB-205 (0.3 and 3 mg/kg). PM(2.5) plus O(3) significantly augmented AHR to MCh in the OVA/OVA mice, which was abrogated by NVP-QAB-205. Total inflammatory cell counts were significantly higher in the bronchoalveolar lavage fluid from OVA/OVA than OVA/PBS mice and were unaffected by PM(2.5) plus O(3) or NVP-QAB-205. CONCLUSION: NVP-QAB-205 reduced AHR and the enhanced response to PM(2.5) plus O(3) to normal levels in an established model of chronic allergic airways inflammation, suggesting that Syk inhibitors have promise as a therapy for asthma.

Bronchodilator Efficacy of High-Flow Nasal Cannula in COPD: Vibrating Mesh Nebulizer Versus Jet Nebulizer.

BACKGROUND: Jet nebulizers are commonly used for bronchodilator therapy in COPD. High-flow nasal cannula with vibrating mesh nebulizer (HFNC-VMN) is a recently developed system; however, few studies have compared the efficacy of bronchodilator administration via HFNC-VMN to jet nebulizer in stable COPD. This study aimed to compare the effect of salbutamol administered via HFNC-VMN versus jet nebulizer on airway and lung function in subjects with stable COPD. METHODS: This randomized non-inferiority crossover physiologic study enrolled subjects with stable COPD. Salbutamol was nebulized via HFNC-VMN or jet nebulizer in random order with a 4-h washout period between crossover sequences. Spirometry, lung volume, and impulse oscillometry were performed at baseline and after each intervention. The primary outcome was change in FEV1 from baseline. Secondary outcomes included changes in other respiratory-related parameters and nebulization time compared between the 2 devices. RESULTS: Seventeen subjects were enrolled. HFNC-VMN and jet nebulizer both significantly improved FEV1 from baseline (P = .005 and P = .002, respectively). The difference between respiratory resistance at 5 Hz and 20 Hz significantly decreased after HFNC-VMN compared to baseline (P = .02), while no significant change was observed after jet nebulizer (P = .056). Area of reactance and resonant frequency of reactance were both significantly decreased (P = .035 and P = .03, respectively), and respiratory reactance at 5 Hz significantly increased (P = .02) in the HFNC-VMN group compared to baseline indicating improved lung mechanics, with no significant changes with the jet nebulizer. HFNC-VMN had a shorter nebulization time (6 [5-9] min vs 20 [16-22] min, respectively, P < .001). CONCLUSIONS: Bronchodilator therapy via HFNC-VMN was not inferior to jet nebulizer for subjects with stable COPD and can significantly improve airway oscillometry mechanics and decrease nebulization time compared to jet nebulizer.