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Maria Jose Santana,1 David Feeny,2 Sunita Ghosh,3 Dale C Lien41Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; 2Kaiser Permanente Center for Health Research, Portland, OR, USA; 3Cross Cancer Center, University of Alberta, Edmonton, Alberta, Canada; 4University of Alberta Hospital, Edmonton, Alberta, CanadaPurpose: Transplantation has the potential to produce profound effects on survival and health-related quality of life (HRQL). The inclusion of the patient’s perspective may play an important role in the assessment of the effectiveness of lung transplantation. Patient perspectives are assessed by patient-reported outcome measures, including HRQL measures. We describe how patients’ HRQL among different diagnosis groups can be used by clinicians to monitor and evaluate the outcomes associated with transplantation.Methods: Consecutive lung transplant recipients attending the lung transplant outpatient clinic in a tertiary institution completed the 15-item Health Utilities Index (HUI) questionnaire on a touchscreen computer. The results were available to clinicians at every patient visit. The HUI3 covers a range of severity and comorbidities in eight dimensions of health status. Overall HUI3 scores are on a scale in which dead = 0.00 and perfect health = 1.00; disability categories range from no disability = 1 to severe disability

Background: Baseline lung allograft dysfunction (BLAD) after lung transplant is associated with an increased risk of dying, but the association with health-related quality of life (HRQL) and exercise capacity is not known. We hypothesized that BLAD would be associated with reduced HRQL and 6-min walk distance (6MWD) at 1 y post-lung transplant., Methods: We analyzed patients who underwent lung transplants in our program from 2004 to 2018 who completed 1-y 36-item Short Form (SF-36) questionnaire and 6MWD testing. We secondarily analyzed the Beck Depression Inventory and Borg dyspnea scores in patients using the available data. We defined BLAD as a failure of both forced expiratory volume in 1 s and forced vital capacity to reach ≥80% predicted of a healthy reference population's lung function on 2 consecutive tests ≥3 wk apart at any time point posttransplant. We tested the relationship between BLAD status and SF-36 physical component summaries and 6MWD using least squares regression, adjusting for age at transplant, sex at birth, and primary lung disease., Results: Two hundred sixty-four patients were included, 96 (36%) of whom met the criteria for BLAD. Patients with interstitial lung disease as an indication for transplant and those who received older, female, and heavy smoking donors were at increased risk of BLAD. SF-36 physical component summary scores were lower in patients with BLAD (75 versus 85; P  = 0.0076), as were 6MWD values (528 versus 572 m; P  = 0.0053). BLAD was associated with lower SF-36 scores ( P  = 0.0025) and 6MWD ( P  = 0.0008) in adjusted regression models at 1 y posttransplant. We did not observe differences in Beck Depression Inventory or Borg scores., Conclusions: BLAD was associated with reduced HRQL and 6MWD scores at 1 y posttransplant in adjusted models. This suggests that poor posttransplant lung function could contribute to lower HRQL and exercise capacity in lung recipients and is worthy of further exploration in terms of causes, prevention, and treatment., (Copyright © 2025 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: Pulmonary blood flow can be assessed on ventilation-perfusion (VQ) scan with relative lung perfusion, with a 55% to 45% (or 10%) right-to-left differential considered normal. We hypothesized that wide perfusion differential on routine VQ studies at 3 mo posttransplant would be associated with an increased risk of death or retransplantation, chronic lung allograft (CLAD), and baseline lung allograft dysfunction., Methods: We conducted a retrospective cohort study on all patients who underwent double-lung transplant in our program between 2005 and 2016, identifying patients with a wide perfusion differential of >10% on a 3-mo VQ scan. We used Kaplan-Meier estimates and proportional hazards models to assess the association between perfusion differential and time to death or retransplant and time to CLAD onset. We used correlation and linear regression to assess the relationship with lung function at time of scan and with baseline lung allograft dysfunction., Results: Of 340 patients who met inclusion criteria, 169 (49%) had a relative perfusion differential of ≥ 10% on a 3-mo VQ scan. Patients with increased perfusion differential had increased risk of death or retransplantation ( P  = 0.011) and CLAD onset ( P  = 0.012) after adjustment for other radiographic/endoscopic abnormalities. Increased perfusion differential was associated with lower lung function at time of scan., Conclusions: Wide lung perfusion differential was common after lung transplant in our cohort and associated with increased risk of death, poor lung function, and CLAD onset. The nature of this abnormality and its use as a predictor of future risk warrant further investigation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Donor-specific antibodies (DSAs) have been associated with antibody-mediated rejection, chronic lung allograft dysfunction (CLAD), and increased mortality in lung transplant recipients. Our center performs transplants in the presence of DSA, and we sought to evaluate the safety of this practice with respect to graft loss, CLAD onset, and primary graft dysfunction (PGD)., Methods: We reviewed recipients transplanted from 2010 to 2017, classifying them as DSA positive (DSA + ) or negative. We used Kaplan-Meier estimation to test the association between DSA status and time to death or retransplant and time to CLAD onset. We further tested associations with severe PGD and rejection in the first year using logistic regression and Fisher exact testing., Results: Three hundred thirteen patients met inclusion criteria, 30 (10%) of whom were DSA + . DSA + patients were more likely to be female, bridged to transplant, and receive induction therapy. There was no association between DSA status and time to death or retransplant (log rank P  = 0.581) nor death-censored time to CLAD onset (log rank P  = 0.278), but DSA + patients were at increased risk of severe PGD (odds ratio 2.88; 95% confidence interval, 1.10-7.29; P  = 0.031) and more frequent antibody-mediated rejection in the first posttransplant year., Conclusions: Crossing DSA at time of lung transplant was not associated with an increased risk of death or CLAD in our cohort, but patients developed severe PGD and antibody-mediated rejection more frequently. However, these risks are likely manageable when balanced against the benefits of expanded access for sensitized candidates., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background App-based strategies are a promising solution to deliver nutrition and exercise interventions during social distancing. With limited RCT data in individuals with chronic disease, further information is required both to determine impact, and to guide delivery. The Heal-Me app is an evidence-based, theoretically informed nutrition and exercise solution that can be tailored for use across a range of individuals with chronic disease. As compared to controls receiving educational material, the aim of this study is to assess the acceptability, effectiveness, and cost of Heal-Me app programming delivered alongside two levels of dietitian and exercise-specialist support. Methods Heal-Me PiONEer is a 12-week, 3-arm RCT with randomization to one of three study groups (n=72 per group, 216 total). Group 1 (control: educational material), Group 2 (Heal-Me app + virtual group dietitian/exercise-specialist sessions), Group 3 (Heal-Me app + virtual group and 1-to-1 dietitian/exercise-specialist sessions). Inclusion criteria: adults with cancer, chronic lung disease or status post-transplantation from liver or lung transplant; previous completion of an exercise rehabilitation program; access to an internet-connected device. Study outcomes measured at study weeks 0 and 12 include: Primary - Lower Extremity Functional Scale; Secondary - virtual physical function tests, loneliness, resilience, anxiety, well-being and health-related quality of life; Exploratory outcomes - protein intake, behavioral beliefs around exercise and nutrition, adherence, adverse events, acceptability, and cost-utility. Conclusions The Heal-Me PiONEer RCT holds promise to provide a comprehensive understanding of the delivery and impact of app-based nutrition and exercise programming in a diverse group of participants with chronic disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Placing a new donor lung into a postpneumonectomy pleural space has many potential surgical challenges. We report the technical challenges we faced in a case of a 42-year-old man who had initially undergone a double-lung transplant for idiopathic pulmonary arterial hypertension. Unfortunately, his left transplanted lung failed, which required a left pneumonectomy. Eight years later, his remaining right lung failed. He was evaluated and deemed suitable for retransplant. Our report presents the first successful redo heart double-lung transplant surgery preceded by pneumonectomy. There were significant technical intraoperative challenges; however, the procedure was performed successfully with an uneventful postoperative course and follow-up., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Study Objectives: Difficulties in providing timely access to care have prompted interest in primary care delivery models for obstructive sleep apnea (OSA). Sustainable implementation of such models requires codesign with input from key stakeholders. The purpose of this study was to identify patient and provider perspectives on barriers and facilitators to optimal, patient-centered management of OSA in a primary care setting., Methods: This study was conducted in Alberta, Canada. Data from key stakeholders were collected through an online survey of primary care providers (n = 119), focus groups and interviews with patients living with OSA (n = 28), and workshops with primary care and sleep providers (n = 36). Quantitative survey data were reported using descriptive statistics, and qualitative data were analyzed using an inductive thematic approach., Results: Several barriers were identified, including poor specialist access, variable primary care providers knowledge of OSA, and lack of clarity about provider roles for OSA management. Barriers contributed to patients being poorly informed about OSA, leading them to separate OSA from their overall health and eroding trust in the system. Suggestions for improvement included integration of care providers in a comprehensive model of care, facilitated by improved system navigation and more effective use of technology. Themes were consistent across data collection methods and between stakeholder groups., Conclusions: Although primary care delivery models may improve access to OSA management, stakeholders identified important challenges in the current system. Innovative models of care, developed with input from patients and providers, may mitigate barriers and support optimal primary care management of OSA., (© 2021 American Academy of Sleep Medicine.)

Canadian lung transplant centers currently use a subjective and dichotomous "Status" ranking to prioritize waitlisted patients for lung transplantation. The lung allocation score (LAS) is an objective composite score derived from clinical parameters associated with both waitlist and post-transplant survival. We performed a retrospective cohort study to determine whether clinical judgment (Status) or LAS better predicted waitlist mortality. All adult patients listed for lung transplantation between 2007 and 2012 at three Canadian lung transplant programs were included. Status and LAS were compared in their ability to predict waitlist mortality using Cox proportional hazards models and C-statistics. Status and LAS were available for 1122 patients. Status 2 patients had a higher LAS compared to Status 1 patients (mean 40.8 (4.4) vs 34.6 (12.5), P = .0001). Higher LAS was associated with higher risk of waitlist mortality (HR 1.06 per unit LAS, 95% CI 1.05, 1.07, P < .001). LAS predicted waitlist mortality better than Status (C-statistic 0.689 vs 0.674). Patients classified as Status 2 and LAS ≥ 37 had the worst survival awaiting transplant, HR of 8.94 (95% CI 5.97, 13.37). LAS predicted waitlist mortality better than Status; however, the best predictor of waitlist mortality may be a combination of both LAS and clinical judgment., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Talc lung granulomatosis results from the intravenous use of medication intended for oral use. Talc (magnesium silicate) acts as filler in some oral medications; when injected intravenously, it deposits in the lungs leading to airflow obstruction and impaired gas exchange. Allocation of donor lungs to previous intravenous drug users is controversial. After a careful selection process, 19 patients with talc lung granulomatosis have received lung allografts in our program. Long-term survival for these patients is excellent and our results suggest the previous use of intravenous drugs should not necessarily preclude lung transplantation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To assess the effects of an Iyengar yoga program (IYP) on patients with chronic respiratory diseases., Methods: Patients attending lung transplant clinics in a tertiary institution were invited to participate in a two-phase, 12-week IYP that included 2 h biweekly classes. Doctors completed a formal physical and clinical assessment on candidates before enrollment. Patients with New York Association Class III or IV, or dyspnea grade IV were excluded. At baseline and at the end of 12-weeks, patients completed the Hospital Anxiety and Depression Scale (HADS), Chronic Respiratory Questionnaire (CRQ) and Health Utilities Index (HUI). Medication(s), 6 min walk test results and other clinical parameters were also recorded. Patients recorded the effects of the IYP on their daily living in journals. Nonparametric and qualitative methods were used to analyze the data., Results: Twenty-five patients diagnosed with pulmonary arterial hypertension and chronic obstructive pulmonary disease (mean age 60 years) were invited to participate. At the end of the 12-week period, changes in HADS anxiety and CRQ fatigue scores were statistically significant (P<0.05) and changes in HUI ambulation, pain, emotion and overall score were clinically important. The content of the journals revealed patients' improvement in breathing capacity, mobility, energy, sleep and included positive feedback such as: "increased tidal volume with slowing expiration", "I have an overall feeling of wellbeing" and "excellent amount of energy"., Conclusions: The findings suggest that yoga has significant potential to produce benefits. Potential benefits will be further explored in a national multisite study.

The introduction of generic immunosuppressant medications may present an opportunity for cost savings in solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. An interprofessional working group of the Canadian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in solid organ transplant recipients (SOTR) based on a review of the available data. Under current Health Canada licensing requirements, a demonstration of bioequivalence with the branded formulation in healthy volunteers allows for bridging of clinical data. Cyclosporine, tacrolimus, and sirolimus are designated as "critical dose drugs" and are held to stricter criteria. However, whether this provides sufficient guarantee of therapeutic equivalence in SOTR remains controversial, and failure to maintain an appropriate balance of immunosuppression may have serious consequences, including rejection, graft loss, and death. Published evidence supporting therapeutic equivalence of generic formulations in SOTR is lacking. Moreover, in the setting of multiple generic formulations the potential for uncontrolled product switching is a major concern, since generic preparations are not required to demonstrate bioequivalence with each other. Although close monitoring is recommended with any change in formulation, drug product switches are likely to occur without prescriber knowledge and may pose a significant patient safety risk. The advent of generic immunosuppression will require new practices including more frequent therapeutic drug and clinical monitoring, and increased patient education. The additional workload placed on transplant centers without additional funding will create challenges and could ultimately jeopardize patient outcomes. Until more robust clinical data are available and adequate regulatory safeguards are instituted, caution in the use of generic immunosuppressive drugs in solid organ transplantation is warranted.

Purpose: Transplantation has the potential to produce profound effects on survival and health-related quality of life (HRQL). The inclusion of the patient's perspective may play an important role in the assessment of the effectiveness of lung transplantation. Patient perspectives are assessed by patient-reported outcome measures, including HRQL measures. We describe how patients' HRQL among different diagnosis groups can be used by clinicians to monitor and evaluate the outcomes associated with transplantation., Methods: Consecutive lung transplant recipients attending the lung transplant outpatient clinic in a tertiary institution completed the 15-item Health Utilities Index (HUI) questionnaire on a touchscreen computer. The results were available to clinicians at every patient visit. The HUI3 covers a range of severity and comorbidities in eight dimensions of health status. Overall HUI3 scores are on a scale in which dead = 0.00 and perfect health = 1.00; disability categories range from no disability = 1 to severe disability <0.70. Single-attribute and overall HUI3 scores were used to compare patients' HRQL among different diagnosis groups. Random-effect models with time since transplant as a random variable and age, gender, underlying diagnoses, infections, and broncholitis obliterans syndrome as fixed variables were built to identify determinants of health status at 2-years posttransplantation., Results: Two hundred and fourteen lung transplant recipients of whom 61% were male with a mean age of 52 (19-75) years were included in the study. Chronic obstructive pulmonary disease and cystic fibrosis patients displayed moderate disability, while pulmonary fibrosis and pulmonary arterial hypertension patients displayed severe disability. Patients with chronic obstructive pulmonary disease had the worst pain level, whereas patients with pulmonary fibrosis had the worst emotion and cognition levels. A random-effect model confirmed that development of broncholitis obliterans syndrome was the most important determinant of health status (P = 0.03) compared to other variables, such as cytomegalovirus infections and underlying diagnoses., Conclusion: Descriptions of patients' HRQL among different diagnosis groups could be used by clinicians to assist individualized patient care.

Background: Cytomegalovirus (CMV) is an important infection in lung transplant recipients. Center-to-center variation in preventive and treatment strategies is unknown., Methods: An electronic survey was sent to 102 lung transplant programs registered with the International Society of Heart and Lung Transplantation and United Network for Organ Sharing., Results: Fifty-nine (58%) programs responded to the survey. For CMV prevention (D+/R-), 56 of the 59 (94.9%) programs used prophylaxis and two (3.4%) of them used preemptive therapy. For R+ patients, 86.4% used prophylaxis and 13.6% used preemptive strategy. Duration of prophylaxis was extremely variable ranging from 3 months to indefinite. Adjunctive prophylactic strategies included routine viral monitoring (51% D+/R-; 44% R+) and CMV immunoglobulin (32% D+/R-; 14% R+). The medication used for prophylaxis was valganciclovir with approximately half starting with intravenous ganciclovir. 9 of the 59 (15.2%) centers reported using specific CMV prophylaxis in D-/R- patients. Methods for viral monitoring included peripheral blood polymerase chain reaction, antigenemia, bronchoalveolar lavage viral culture, and bronchoalveolar lavage polymerase chain reaction. For treatment of CMV viremia, valganciclovir or intravenous ganciclovir were used. A total of 47.5% of centers routinely decreased immunosuppression at the time of viremia. Secondary antiviral prophylaxis was used routinely by 36 of the 59 (61%) centers., Conclusions: Although prophylaxis is the most commonly used preventive strategy, significant variation exists in the way it is implemented. Specifically, duration of prophylaxis is extremely variable. Uniform international guidelines would be of value in this population.

Purpose: This randomized controlled clinical trial examined the usefulness of including an assessment of health-related quality of life (HRQL) in the routine clinical care of lung-transplant patients. We hypothesized that the inclusion of HRQL in routine clinical care would improve patient-clinician communication, affect clinical management, and improve patients' HRQL., Methods: At the outpatient clinic, University of Alberta Hospital, patients were randomly assigned to intervention (completion of Health Utilities Index Mark 2 (HUI2) and Mark 3 (HUI3) on touch-screen computer with feedback to clinicians) and control group (completion of HUI2 and HUI3 on touch-screen computer without feedback). Feedback involved a graphical representation included in patients' chart. All clinical encounters were audio-taped. Changes in clinical management (medication changes, number of referrals and test ordered) were summed to produce an overall management composite. At the end of every visit, patients completed the EQ-5D., Results: Two hundred and thirteen patients were randomized (108 to intervention and 105 to control groups). There were statistically significant differences between the groups in mean number of issues discussed per encounter (P = 0.003; Cohen's d = 0.03) and mean management composite score (P = 0.001; Cohen's d = 0.41). EQ-5D index was not statistically significant different between the groups (P = 0.48)., Conclusions: We detected very small effects on patient-clinician communication and small effects on patient management, without detecting improvement in patient outcome.

The lung transplantation program at the University of Alberta has been in existence for 25 years. The current volume is 35-40 new lung transplants per year. We offer single-lung, bilateral lung, heart/lung and bilateral living lobar transplantation as options. Experience has allowed for widening of the indications and acceptance of patients with more risk. Donor evaluation and management has allowed for extended donors to be included in the donor pool. Results will likely continue to improve with increased understanding of the mechanisms and management of bronchiolitis obliterans syndrome. Our research interests have been in the areas of risk analysis, outcome assessment, and quality of life changes from transplantation.

Background: Many factors may limit survival from lung and heartlung transplantation, including malignancy., Objective: To investigate factors associated with the development of malignancy following transplantation and its effect on survival by retrospectively reviewing a population of lung transplant recipients., Methods: Data from 342 consecutive lung transplant patients were collected. Results were analyzed by fitting variables into a multivariate logistic regression model predicting the development of post-transplant malignancies. Covariates were selected based on crude associations that reached a level of significance at P ≤ 0.10. Length of survival was analyzed using the Kaplan-Meier method., Results: Fifty-eight subjects developed post-transplant malignancies, which were the cause of death of 14 patients. Twenty-one patients had a pretransplant malignancy, of whom six developed a malignancy posttransplant--of these, two were fatal recurrences. No risk factors were significantly associated with all forms of post-transplant malignancy. When adjusted for age at transplantation and donor smoking history, Epstein-Barr virus seropositivity at the time of transplant was significantly associated with a reduced risk of a post-transplant lymphoproliferative disorder (OR 0.17; 95% CI 0.05 to 0.59). The median survival time in individuals without a post-transplant malignancy was significantly shorter than in those with a post-transplant malignancy (P = 0.018 Wilcoxon [Breslow]). This may be secondary to the length of time required to develop malignancy and the fact that not all malignancies that developed were fatal. The median time to develop malignancy was greater than two years. In addition, the 14 patients who died as a result of their malignancy had a significantly shorter survival time than the 44 who died because of nonmalignant causes (P < 0.001)., Conclusions: Malignancy was not associated with an overall decrease in survival time when compared with those who did not develop a malignancy. Risk factors specific for the development of malignancies remain difficult to specify.

Background: Rejection remains a significant cause of morbidity and mortality after lung transplantation. The purpose of this study was to test the efficacy and safety of daclizumab (DZM) vs anti-thymocyte globulin (ATG) as a component of induction therapy., Methods: Fifty adults undergoing lung transplantation were randomized to receive either ATG or DZM during induction therapy. Patients were followed for 1 year after transplant., Results: Although there was no significant difference in the number of acute or chronic rejections between groups, there was a trend toward a delay in time to first acute rejection with DZM induction. Average absolute lymphocytes and average platelet count were significantly higher in the DZM group. Cytomegalovirus (CMV) serology mismatch was higher in the DZM group (7 vs 1, p = 0.05). The DZM group had a greater number of infections (83 vs 47, p = 0.02); however, the number of CMV infections was also significantly greater (18 vs 6, p = 0.03), corresponding to a higher incidence of CMV mismatch. A cost analysis revealed no difference between total drug costs, intensive-care unit (ICU) costs and total hospital costs. One-year survival was 96% in the DZM group and 88% in the ATG group., Conclusions: DZM is a safe component of induction therapy in lung transplantation. In addition, DZM may prolong freedom from acute rejection. Significant infections were more frequent in the DZM group, but this was likely due to a higher incidence of CMV mismatch. Both methods of induction therapy worked well, with excellent 1-year survival.

Background: Cardiovascular comorbidities have a negative impact on the health status and prognosis of patients with COPD. We determined whether nocturnal noninvasive (positive) mechanical ventilation (NIMV) can improve heart rate variability (HRV), decrease circulating natriuretic peptide levels, and improve functional performance of patients with very advanced COPD., Methods: A randomized, double-blind, parallel controlled trial was conducted in 23 participants with stable but advanced COPD. Participants received standard medical therapy plus nocturnal NIMV or standard medical therapy plus sham NIMV for 3 months., Results: After 3 months of NIMV therapy, the 24-h triangular interpolation of N-N intervals increased from 322 to 473 ms (p = 0.034), the 24-h HRV index (HRVI) increased from 21.8 to 29.9 ms (p = 0.035), nocturnal HRVI increased from 6.1 to 8.0 ms (p = 0.026), and the SD of the average N-N interval increased from 37 to 41 ms (p = 0.020). None of these indexes changed significantly in the control group. Additionally, compared with the control group, the pro-atrial natriuretic peptide levels declined significantly in the NIMV group (p = 0.013)., Conclusions: NIMV applied nocturnally over 3 months may improve HRV, reduce circulating natriuretic peptide levels, and enhance the functional performance of patients with advanced but stable COPD. While not definitive due to small sample size, these data suggest that nocturnal NIMV may reduce the impact of cardiac comorbidities in COPD patients.

Objective: To evaluate the yield and cost effectiveness of transbronchial needle aspiration (TBNA) in the assessment of mediastinal and/or hilar lymphadenopathy., Design: Retrospective study., Setting: A university hospital., Population Studied: Ninety-six patients referred for bronchoscopy with computed tomographic evidence of significant mediastinal or hilar adenopathy., Results: Ninety-nine patient records were reviewed. Three patients had two separate bronchoscopy procedures. TBNA was positive in 42 patients (44%) and negative in 54 patients. Of the 42 patients with a positive aspirate, 40 had malignant cytology and two had cells consistent with benign disease. The positive TBNA result altered management in 22 of 40 patients with malignant disease and one of two patients with benign disease, thereby avoiding further diagnostic procedures. The cost of these subsequent procedures was estimated at $27,335. No complications related to TBNA were documented., Conclusions: TBNA is a high-yield, safe and cost effective procedure for the diagnosis and staging of bronchogenic cancer.

Objectives: To determine the diagnostic utility of bronchoscopy in a population of immunocompromised hosts in northern Alberta., Patients and Methods: Results from bronchoscopy in 86 immunocompromised patients who underwent a total of 101 procedures were retrospectively reviewed., Results: The overall diagnostic yield was 57% with the highest yield in patients on immunosuppressive drug therapy (80%) and the lowest yield in the group of bone marrow transplant patients (27%)., Conclusions: Bronchoscopy is a valuable tool for the evaluation of pulmonary disease in the immunocompromised host. Overall diagnostic yield of 57% is comparable with that reported in the literature.

A 64-year-old woman presented initially with a metastatic spindle-cell sarcoma of the lung of unknown primary. She suddenly died nine months later from hemopericardium with cardiac tamponade caused by partial hemorrhagic necrosis of pulmonary artery trunk sarcoma.

Autologous serum with or without platelet-activating factor (PAF) was instilled into one lung lobe of an anesthetized cat, and changes in the regional lung water content were monitored for 4 h with proton nuclear magnetic resonance (NMR) images and relaxation time measurements. With serum as an instillate, water was cleared with a half time of approximately 670 min; after 4 h, 86 +/- 6% of that instilled remained. With PAF added to the instillate, clearance was biphasic with an initial clearance half time of approximately 30 min followed by clearance similar to that observed after serum instillation; after 4 h, 35 +/- 4% of that instilled remained. In contrast, 4 h after instillation of serum or serum plus PAF, 91 +/- 3% and 82 +/- 5%, respectively, of the instilled 125I-labeled albumin remained in the lung (P = 0.06). From transverse magnetization relaxation curves we were able to resolve two relaxation components, which we have attributed to the instilled fluid in the air spaces (relaxation time = 177 +/- 7 ms) and the tissue-bound fluid (relaxation time = 25 +/- 1 ms).

Platelet-activating factor (PAF) has been implicated as a mediator of airway hyperresponsiveness. PAF, infused intra-arterially into the canine cervical trachea, causes adherence of neutrophils to vascular endothelium, increases vascular permeability, and increases the responsiveness of tracheal muscle to parasympathetic stimulation. We hypothesized that the increase in airway responsiveness induced by PAF in this model depends on the presence of neutrophils. To test this hypothesis, we perfused a cervical tracheal segment with autologous blood depleted of leukocytes or with similar leukocyte-depleted blood that had been repleted with its neutrophils. Fifteen minutes after the onset of perfusion with either leukocyte-depleted or neutrophil-repleted blood, PAF infusion was begun into the tracheal arterial vasculature. The contractile response of the tracheal muscle to parasympathetic stimulation was measured before and 15 and 30 min after the onset of PAF infusion. PAF did not significantly change the response of tracheal muscle during perfusion with neutrophil-depleted blood but increased the response of tracheal muscle during perfusion with neutrophil-repleted blood. We conclude that the increase in canine tracheal muscle response induced by intra-arterial PAF depends on neutrophils.

Platelet-activating factor (PAF) has potent effects on the respiratory airways that may be mediated through its ability to act as an inflammatory stimulant. To study its inflammatory properties in the airways, we infused PAF into the vasculature of the canine trachea and examined (1) the kinetics of neutrophil transit through the tracheal microcirculation, (2) accompanying changes in vascular permeability, and (3) the dependence of vascular permeability changes on neutrophil accumulation. Neutrophil kinetics were assessed by measuring the transit times of fluorescein isothiocyanate-labeled canine neutrophils by in vivo microscopy. Changes in vascular permeability were measured by the extravascular leakage of radiolabeled albumin and comparison of wet-to-dry weight ratios. The importance of neutrophils in increasing vascular permeability was assessed by perfusing the trachea with either autologous blood depleted of its leukocytes, or leukocyte-depleted blood replenished with neutrophils. Our data indicate that PAF causes rapid and prolonged neutrophil accumulation in the canine trachea and an increase in vascular permeability that is partially mediated by neutrophils.

The site of neutrophil interaction with the vasculature during acute lung inflammation is controversial, but has been suggested to occur in the alveolar capillaries, in contrast with its location in postcapillary venules in nonpulmonary tissues. We studied the kinetics of neutrophil accumulation and the site of neutrophil-vascular interaction in the lung by examining directly the behavior of fluorescein isothiocyanate-labeled canine neutrophils utilizing in vivo fluorescence videomicroscopy through a window inserted into the chest wall of anesthetized dogs. The administration of fragments of the fifth component of complement (C5f) into either the airway or pulmonary artery resulted in neutrophil sequestration almost exclusively in pulmonary capillaries. Kinetically, there was a shift in the distribution of neutrophil transit times resulting in a marked prolongation of median transit time. This response occurred within seconds after intravascular C5f and within 5 minutes after airway C5f and was maintained for at least 30 minutes. Ultrastructural studies after airway C5f showed neutrophils in various stages of migration through the alveolar-capillary membrane and more than 90% of these neutrophils were seen to migrate from capillary rather than from venular sites. These data indicate that pulmonary inflammation differs from inflammation in other vascular beds primarily in the site of neutrophil localization and migration. This fundamental difference in the inflammatory response may serve to localize the inflammatory response to the alveolus, and (since cells were retained singly), indicates the inability of leukoaggregation adequately to explain the findings. Leukocyte accumulation in the lung may thus occur through alterations in the balance between delivery of neutrophils to the lung and the transit time of these cells across the capillary bed.

Through its ability to cause lipid peroxidation, nitrogen dioxide (NO2) may affect the functional properties of both the pulmonary epithelium and endothelium. We evaluated this possibility in 13 mongrel dogs by exposing these animals to 200 or 400 ppm NO2 for 1 h. The changes in pulmonary epithelial permeability (using a radioaerosol technique), FRC, and endothelial function (the removal of radiolabeled serotonin, [14C]5-HT, and prostaglandin E1, [3H]PGE1, from the pulmonary circulation) were measured at 1 h and at 2, 7, or 14 days after NO2 exposure. In another six dogs, we evaluated changes in cell population and albumin in bronchoalveolar lavage (BAL) fluid caused by NO2. In the first two days after NO2 exposure, focal pulmonary edema was documented on microscopy, radioaerosol clearance was delayed, and FRC decreased slightly. BAL showed a marked increase in albumin, but the removal of trace amounts of 5-HT and PGE1 by the endothelium was not altered. All physiologic abnormalities returned to normal with time.

Increases in pulmonary arterial pressure or blood flow raise peripheral white cell count by releasing sequestered leukocytes from the lung. The effects of altered hemodynamics, however, on the leukocyte sequestration site and on the distribution of leukocyte transit times through the pulmonary microcirculation are unknown. We used in vivo fluorescence videomicroscopy to study the passage of individual, fluorescein-isothiocyanate-labeled neutrophils through the pulmonary microcirculation of anesthetized dogs. Pulmonary hemodynamics were altered over a wide range. Regardless of the hemodynamic conditions, the only place that any of the 2,919 observed neutrophils stopped was in the capillaries. The periods of immobility had a wide range, from less than 1 to greater than 1,200 s. Because the cells remained motionless once they stopped and then accelerated suddenly as they regained the free-flowing stream, the obstructions must have been discrete. About a quarter of the capillary pathways had one site of high resistance. Another quarter offered two or more obstructions. In the remaining half, the neutrophils passed rapidly and without pause from arteriole to venule. Increases in pressure and flow decreased the number of times that individual cells stopped. These changes altered the median transit time by shifting the distribution of transit times between the slowest and fastest groups. We conclude that most of the total pathlength of perfused capillaries offers little resistance even to neutrophils. There are, however, focal areas in individual capillaries that offer high resistance to neutrophil passage.

Endotoxin causes pulmonary vascular neutrophil sequestration and injures the lung. Whether this is primarily due to a direct effect of endotoxin on the endothelium or is mediated by an action on the neutrophil is unclear. Canine neutrophils, isolated on plasma-Percoll gradients in vitro, were incubated with Salmonella enteriditis endotoxin, washed, and injected via wedged pulmonary arterial catheters into discrete lung zones of anesthetized dogs, whereas untreated neutrophils were administered into contralateral control lung zones. 113mIn-transferrin was administered intravenously 2 h before the animals were killed. Morphometry and extravascular protein accumulation were assessed at 4 h. Endotoxin treatment of neutrophils ex vivo induced a two- to three-fold increase in neutrophils in these lung zones (0.096 +/- 0.012 vs. 0.05 +/- 0.002 neutrophils/alveolar septal intercept, P less than 0.05). Extravascular-to-intravascular protein ratios in zones receiving endotoxin-treated neutrophils were significantly increased compared with control zones (0.146 +/- 0.02 vs. 0.079 +/- 0.02, P less than 0.05). Because complement fragments increase injury to endothelium in vitro, exogenous C5 fragments were administered to other dogs before administration of neutrophils but failed to significantly increase the extravascular protein signal (0.154 +/- 0.03 vs. 0.124 +/- 0.04). In summary, endotoxin treatment of neutrophils leads to neutrophil sequestration and increased pulmonary extravascular protein accumulation. C5 fragments failed to further enhance the protein accumulation. These data are consistent with an effect of endotoxin on the neutrophil to initiate neutrophil-endothelial interaction and subsequent lung injury.

Platelet-activating factor (PAF) increases the bronchoconstrictor response of mammalian airways to cholinergic agonists and is thus implicated as a potential mediator of airway hyperreactivity. This study further defines the nature of the increase in airway responsiveness induced by PAF. We employed an in situ canine tracheal preparation, which allows differentiation of the effects PAF has on airway smooth muscle contraction from confounding effects it has on inducing airway edema and secretions. We found that PAF, infused regionally into tracheal arteries, increases the responsiveness of the trachealis muscle to parasympathetic stimuli in a dose-dependent manner. This effect occurred within 15 min. To determine whether the increase in trachealis muscle responsiveness resulted from effects localized to the trachea, we compared the effect of PAF on the tracheal segment with effects of the lower airways of the lung. Delivered to the arteries perfusing the tracheal segment, PAF did not increase lung resistance during vagus nerve stimulation. These data indicate that airway hyperresponsiveness elicited by PAF results from regional stimulation and/or release of mediators that augment tracheal contractility and that this effect is distinct from systemic effects elicited by PAF.

Although the lung is known to be a major site of neutrophil margination, the anatomic location of these sequestered cells within the lung is controversial. To determine the site of margination and the kinetics of neutrophil transit through the pulmonary microvasculature, we infused fluorescein isothiocyanate-labeled canine neutrophils into the pulmonary arteries of 10 anesthetized normal dogs and made fluorescence videomicroscopic observations of the subpleural pulmonary microcirculation through a window inserted into the chest wall. The site of fluorescent neutrophil sequestration was exclusively in the pulmonary capillaries with a total of 951 labeled cells impeded in the capillary bed for a minimum of 2 s. No cells were delayed in the arterioles or venules. Transit times of individual neutrophils varied over a wide range from less than 2 s to greater than 20 min with an exponential distribution skewed toward rapid transit times. These observations indicate that neutrophil margination occurs in the pulmonary capillaries with neutrophils impeded for variable periods of time on each pass through the lung. The resulting wide distribution of transit times may determine the dynamic equilibrium between circulating and marginated neutrophils.

Four adults, including a pregnant woman, and three children were admitted to hospital following accidental exposure to mercury vapour produced by heating mercury-gold amalgam. Initial symptoms and signs included a paroxysmal cough, dyspnea, chest pain, tachypnea, nausea, vomiting, fever and leukocytosis. Pulmonary function testing performed on the second day after exposure revealed air-flow obstruction and minor restrictive defects in three patients. The diffusing capacity of the lung for carbon monoxide was reduced in two of these patients. The mean initial blood mercury level (+/- one standard deviation) for the seven patients was 30.8 +/- 1.5 micrograms/dl. A computer analysis showed mercury to behave as a two-compartment system, the compartments having half-lives of 2 and 8 days. The four adults received chelation therapy with D-penicillamine, which did not affect the urinary excretion of mercury. The pregnant woman's infant, born 26 days after exposure, had no detectable clinical abnormalities. The levels of mercury in the blood of the mother and infant at birth and 6 days later were comparable, indicating free transfer of the metal across the placenta.

The three-dimensional structure of most enzymes is unknown; however, many enzymes may have structural motifs similar to those in the known structures of functionally related enzymes. Evidence is presented that an enzyme of unknown structure [Ile-transfer RNA (tRNA) synthetase] may share a functionally important structural motif with an enzyme of related function (Tyr-tRNA synthetase). This approach involves (i) identifying segments of Ile-tRNA synthetase that have been unusually conserved during evolution, (ii) predicting the function of one such segment by assuming a structural relation between Ile-tRNA synthetase and Tyr-tRNA synthetase, and (iii) testing the predicted function by mutagenesis and subsequent biochemical analysis. Random mutations were introduced by cassette mutagenesis into a ten-amino-acid segment of Ile-tRNA synthetase that was predicted to be involved in the formation of the binding site for isoleucine. Few amino acid substitutions appear to be tolerated in this region. However, one substitution (independently isolated twice) increased the Michaelis constant Km for isoleucine in the adenylate synthesis reaction by greater than 6000-fold, but had little effect on the Km for adenosine triphosphate, the apparent Km for tRNA, or the rate constant kcat.