Background: People with chronic obstructive pulmonary disease lead sedentary lives and could benefit from increasing their physical activity. The purpose of this study was to determine if an exercise-specific self-efficacy enhancing intervention could increase physical activity and functional performance when delivered in the context of 4 months of upper body resistance training with a 12-month follow-up.Methods: In this randomized controlled trial, subjects were assigned to: exercise-specific self-efficacy enhancing intervention with upper body resistance training (SE-UBR), health education with upper body resistance training (ED-UBR), or health education with gentle chair exercises (ED-Chair). Physical activity was measured with an accelerometer and functional performance was measured with the Functional Performance Inventory. Forty-nine people with moderate to severe chronic obstructive pulmonary disease completed 4 months of training and provided valid accelerometry data, and 34 also provided accelerometry data at 12 months of follow-up. The self-efficacy enhancing intervention emphasized meeting physical activity guidelines and increasing moderate-to-vigorous physical activity.Results: Differences were observed in light physical activity (LPA) after 4 months of training, time by group interaction effect (P=0.045). The SE-UBR group increased time spent in LPA by +20.68+/-29.30 minutes/day and the other groups decreased time spent in LPA by -22.43+/-47.88 minutes/day and -25.73+/-51.76 minutes/day. Changes in LPA were not sustained at 12-month follow-up. There were no significant changes in moderate-to-vigorous physical activity, sedentary time, or functional performance. Subjects spent most of their waking hours sedentary: 72%+/-9% for SE-UBR, 68%+/-10% for ED-UBR, and 74%+/-9% for ED-Chair.Conclusion: The self-efficacy enhancing intervention produced a modest short-term increase in LPA. Further work is needed to increase the magnitude and duration of effect, possibly by targeting LPA.

Osteoporotic fractures are well-known complications of organ transplantation. Fracture rates up to 35% have been previously reported following heart and lung transplantations. Our institutional pretransplant protocols include DXA scans, vitamin D screening, and appropriate antiresorptive therapy. We aimed to assess the incidence of fragility fractures following cardiac or lung transplantation. In a retrospective study 210 electronic medical records of patients who underwent LT (110 men, 100 women) and 105 HT (88 men, 17 women) between 2005 and 2010 were analyzed. Both clinical and radiographic fractures were recorded. DXA scans were obtained immediately after transplant. 17 out of 210 LT patients (8.0%) had fractures after transplantation and 9 out of 105 HT patients (8.6%) had fractures. The median time to the first fracture was 12 months and the mean time was 18 months for both LT and HT. In the HT recipients, the median femoral neck T score was statistically lower in the fracture group versus the nonfracture group. Similar results were seen in the LT patients. Conclusion. Our findings demonstrate a much lower incidence of fractures in heart and lung transplant recipients in comparison with earlier reports. Comprehensive bone care and early initiation of antiresorptive therapy are possible contributors to these improved outcomes.

BACKGROUND:Cytomegalovirus (CMV) is the most common opportunistic infection in lung transplantation. A recent multicenter, randomized trial (the AIRSAC study) comparing sirolimus to azathioprine in lung transplant recipients showed a decreased incidence of CMV events in the sirolimus cohort. To better characterize this relationship of decreased incidence of CMV events with sirolimus, we examined known risk factors and characteristics of CMV events from the AIRSAC database. METHODS:The AIRSAC database included 181 lung transplant patients from 8 U.S.-based lung transplant centers that were randomized to sirolimus or azathioprine at 3 months post-transplantation. CMV incidence, prophylaxis, diagnosis and treatment data were all prospectively collected. Prophylaxis and treatment of CMV were at the discretion of each institution. RESULTS:The overall incidence of any CMV event was decreased in the sirolimus arm when compared with the azathioprine arm at 1 year after lung transplantation (relative risk [RR] = 0.67, confidence interval [CI] 0.55 to 0.82, p < 0.01). This decreased incidence of CMV events with sirolimus remained significant after adjusting for confounding factors of CMV serostatus and CMV prophylaxis. CONCLUSIONS:These data support results from other solid-organ transplantation studies and suggest further investigation of this agent in the treatment of lung transplant recipients at high risk for CMV events.

BACKGROUND:Acute rejection remains a major source of morbidity after lung transplantation. Given the importance of this diagnosis, an international grading system was developed to standardize the diagnosis of acute lung-allograft rejection. The reliability of this grading system has not been adequately assessed by previous studies.METHODS:We examined the level of agreement in grading transbronchial biopsy specimens obtained from a large multicenter study (AIRSAC [Comparison of a Tacrolimus/Sirolimus/Prednisone Regimen vs Tacrolimus/Azathioprine/Prednisone Immunosuppressive Regimen in Lung Transplantation] trial). Biopsy specimens were initially graded for acute rejection and lymphocytic bronchiolitis by the site pathologist and subsequently graded by a central pathologist. Reliability of interobserver grading was evaluated using Cohen κ coefficients.RESULTS:A total of 481 transbronchial biopsy specimens were graded by both the site and central pathologists. The overall concordance rates were 74% and 89% for grade A and grade B biopsy specimens, respectively. When samples from biopsies performed at different time points after transplantation were assessed, there was a higher level of agreement early (≤ 6 weeks) after transplant compared with later time points for acute rejection. However, there was still only moderate agreement for both grade A (κ score 0.479; 95% CI, 0.29-0.67) and grade B (κ score 0.465; 95% CI, 0.08-0.85) rejection.CONCLUSIONS:These results expand upon previous reports of interobserver variability in grading transbronchial biopsy specimens after lung transplantation. Given the variability in grading these specimens, we advocate further education of the histopathologic findings in lung transplant biopsy specimens, as well as revisiting the current criteria for grading transbronchial biopsy specimens to improve concordance among lung transplant pathologists.TRIAL REGISTRY:ClinicalTrials.gov; No. NCT00321906; URL: www.clinicaltrials.gov.

Background: Evidence is increasingly convincing that lung transplantation is a risk factor of gastroesophageal reflux disease (GERD). However, it is still not known if the type of lung transplant (unilateral, bilateral, or retransplant) plays a role in the pathogenesis of GERD. Study Design: The records of 61 lung transplant patients who underwent esophageal function tests between September 2008 and May 2010, were retrospectively reviewed. These patients were divided into 3 groups based on the type of lung transplant they received: unilateral (n=25); bilateral (n=30), and retransplant (n=6). Among these groups we compared: (1) the demographic characteristics (eg, sex, age, race, and body mass index); (2) the presence of Barrett esophagus, delayed gastric emptying, and hiatal hernia; and (3) the esophageal manometric and pH-metric profile. Results: Distal and proximal reflux were more prevalent in patients with bilateral transplant or retransplant and less prevalent in patients after unilateral transplant, regardless of the cause of their lung disease. The prevalence of hiatal hernia, Barrett esophagus, and the manometric profile were similar in all groups of patients. Conclusions: Although our data show a discrepancy in prevalence of GERD in patients with different types of lung transplantation, we cannot determine the exact cause for these findings from this study. We speculate that the extent of dissection during the transplant places the patients at risk for GERD. On the basis of the results of this study, a higher level of suspicion of GERD should be held in patients after bilateral or retransplantation.

PURPOSE:Loss of skeletal muscle strength is commonly seen with chronic obstructive pulmonary disease (COPD). The study aim was to determine the effects of comprehensive upper-body resistance training (8 different lifts) and a self-efficacy enhancing intervention in COPD with respect to muscle strength, symptoms, functional status and exercise adherence.METHODS:This randomized trial had 3 groups: upper-body resistance training with an intervention to enhance self-efficacy (UBR + SE), upper-body resistance training and health education (UBR + HE), gentle chair exercises and health education (CE + HE). Subjects performed 16 weeks of supervised training, then 12 months of long-term maintenance at home. Outcomes were: muscle strength, dyspnea, functional status, self-efficacy, and adherence.RESULTS:Sixty-four subjects completed 16 wks of training: age 71 ± 8 yr, fat-free mass index 19 ± 3 kg/m2, forced expiratory volume in one second 58 ± 18 percent predicted. The UBR + SE intervention produced a 46% increase in strength compared to a 36% increase in the UBR + HE group (P = 0.054). The combined UBR + SE and UBR + HE groups produced a 41% increase in strength compared to an 11% increase in the CE+HE (P < 0.001). The combined UBR groups also demonstrated increases in lean arm mass (P = 0.003) and a trend toward decreased dyspnea (P = 0.053). There were no group differences in attrition, attendance and training progression. Fifty subjects completed long-term maintenance and the UBR + SE and UBR + HE groups retained some gains in muscle strength, 24% and 21% respectively, and the CE + HE group lost 3% of muscle strength from baseline.CONCLUSION:The study provides strong evidence that comprehensive resistance training increased strength and lean arm mass and that strength can be partially maintained through a simple home program using hand weights. It provides limited evidence that upper-body resistance training improved dyspnea and that the exercise-specific self-efficacy enhancing intervention was beneficial.

Background Connective tissue disease (CTD)–related lung dysfunction is a common cause of morbidity and mortality; however, few lung transplantations (LTs) are performed in this population secondary to uncertainty regarding the posttransplant survival, outcome, and management. Objectives The objectives were to evaluate the survival and the pulmonary and extrapulmonary courses of CTD after LT. Methods Survival outcomes of patients documented within the Organ Procurement and Transplantation Network who had undergone a LT for CTD were compared with those who underwent LT for chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In addition, the pulmonary and extrapulmonary courses of the CTD were evaluated after LT. Results From 1991 to 2009, there were 284 documented LT in patients with CTD. Post-LT cumulative survival of patients with CTD was less than that for COPD through 5 years, with a difference that peaked at 1 year (72.7% vs. 83.1%, P < 0.001). When patients with CTD were compared with those with IPF, a difference was only noted at 1 year (72.7% vs. 77.7%, P = 0.049). There were no documented post-LT pulmonary recurrences of the CTD, and extrapulmonary flares of the CTD were rare (1 possible flare per 20.3 patient-years and 1 probable flare per 81.0 patient-years). Conclusions Cumulative survival of patients with CTD who underwent LT is similar to those with IPF and slightly less than those with COPD, with an increased risk of mortality that was most prominent at 6 months after transplant followed by subsequent narrowing of the survival differences over time. Lung transplantation may be a viable therapeutic option for patients with end-stage lung dysfunction resulting from a CTD.

BACKGROUND:The prevalence of vitamin D deficiency in lung disease is greater than in the general population. Vitamin D deficiency may negatively affect immune and lung function. Accordingly, we hypothesized that lung transplant recipients with vitamin D deficiency are more susceptible to rejection and infections after transplantation. METHODS:Transplant outcomes were reviewed in a retrospective cohort of 102 lung transplant recipients who had 25-hydroxyvitamin D [25(OH)D] levels drawn during the near-transplant period (100 days pre- or post-transplant). RESULTS:In the near-transplant period, 80% of recipients were 25(OH)D-deficient and 20% were not 25(OH)D-deficient. Episodes of acute cellular rejection in the deficient group were more frequent than in the non-deficient group [mean 1.27 (0.99 to 1.55) vs 0.52 (0.12 to 0.93), p = 0.006]. The rejection rate in the deficient group was more than double that of the the non-deficient group [IRR 2.43 (1.30 to 4.52), p = 0.005]. Infectious episodes were also more frequent in the deficient group than in the non-deficient group [mean 4.01 (3.24 to 4.79) vs 2.71 (1.47 to 3.96), p = 0.04]. The mortality rate of recipients who remained 25(OH)D-deficient 1 year after transplant was almost 5-fold higher than in recipients who were not 25(OH)D-deficient [IRR 4.79 (1.06 to 21.63), p = 0.04]. CONCLUSIONS:Low serum 25(OH)D levels in lung transplant recipients were associated with increased incidence of acute rejection and infection. The mortality of recipients who remained deficient 1 year post-transplant was higher than that of recipients who maintained normal vitamin D levels at 1 year post-transplant.

BACKGROUND:Although gastroesophageal reflux disease (GERD) is highly prevalent in lung transplantation, the pathophysiology of GERD in these patients is unknown. We hypothesize that the pathophysiology of GERD after lung transplantation differs from that of a control population, and that the 30-d morbidity and mortality of laparoscopic antireflux surgery (LARS) are equivalent in both populations. METHODS:We retrospectively compared the pathophysiology of GERD and the 30-d morbidity and mortality of 29 consecutive lung transplant patients with 23 consecutive patients without lung transplantation (control group), all of whom had LARS for GERD between November 2008 and May 2010. RESULTS:Both groups had a similar prevalence of endoscopic esophagitis and Barrett's esophagus , comparable manometric profiles, and similar prevalence of abnormal peristalsis. However, hiatal hernia was more common in controls than in lung transplant patients (57% versus 24%; P = 0.04). Lung transplant patients had a higher prevalence and severity of proximal GERD (65% versus 33%; P = 0.04). The 30-d morbidity and mortality following LARS were similar in both groups regardless of the higher surgical risk of lung transplants (median ASA class: 3 versus 2 for controls, P < 0.001). CONCLUSIONS:These results show that despite similar manometric profiles, lung transplant patients are more prone to proximal reflux than the general population with GERD; the prevalence of endoscopic esophagitis and Barrett's esophagus is the same in both groups of patients; a hiatal hernia is uncommon after lung transplantation; and the morbidity and mortality of LARS are the same for lung transplant patients as the general population with GERD.

Causes of early readmissions following lung transplantation are not well understood, and the impact is poorly reported. We reviewed 221 consecutive lung transplantations and identified patients readmitted within 90 days. A case control analysis was performed to determine the characteristics that predict readmission and the impact of readmission on survival. Ninety (44%) of the 205 operative survivors required a total of 125 readmissions during the 90 days after transplantation. Twenty-eight patients (13.7%) required multiple readmissions. Causes for readmissions were pulmonary complication (59%), gastrointestinal (18%), cardiac (5%), metabolic (2.5%), neurological (2.5%), hematological (2%), and miscellaneous (11%). The sex, native disease, or type of transplant did not predict readmission. Requirement of cardiopulmonary bypass for transplantation showed a trend toward significance (P = 0.08). The 90-day conditional survival at 1, 3, and 5 years for those patients readmitted within 90 days were 76%, 59%, and 52%, respectively, compared to 93%, 80%, and 76% for patients not readmitted (P = 0.01). Requirement for readmission within 90 days following transplantation is associated with increased mortality. Sex, native disease, and type of transplant are not predictors of readmission or survival.

Purpose: It is well known that people with chronic obstructive pulmonary disease experience declines in functional performance, but little is known about the rate of decline. The purposes of this research were to describe the rate of decline in functional performance and to examine the contribution of disease severity, body composition, symptoms, and functional capacity. Functional performance was defined as the activities that people choose to engage in on a day-to-day basis. Methods: People (n = 108) with chronic obstructive pulmonary disease were enrolled and followed yearly for 3 yr with self-reported functional performance (Functional Performance Inventory), spirometry, lung volumes, diffusion capacity, body composition (dual-energy x-ray absorptiometry), dyspnea and fatigue (Chronic Respiratory Disease Questionnaire), and functional capacity (6-min walk distance (6MWD), isokinetic strength of knee flexors and extensors, handgrip strength, and maximal inspiratory pressure). A total of 88 subjects completed a (mean ± SD) of 2.7 ± 0.9 yr of follow-up. Results: Significant negative slopes were observed for functional performance (P = 0.001), spirometry (the ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC), P < 0.0001), diffusion capacity (P < 0.0001), and muscle strength (P < 0.0001)). The slopes for dyspnea, fatigue, and functional capacity were not significantly different from zero, but there was a wide individual variation. Hierarchical regression demonstrated that 31% of the variance in the slope of functional performance was accounted for by the hierarchical model, and the primary predictors were the slopes of the FEV1/FVC, 6MWD, and muscle strength (knee flexors/extensor and handgrip). Conclusions: Subjects experienced a slow decline in functional performance, associated with declines in functional capacity and increases in body fat. Symptoms were relatively stable and not associated with declines in functional performance.

Rationale: Lung transplantation has evolved into a life-saving therapy for select patients with end-stage lung diseases. However, long-term survival remains limited because of chronic rejection. Sirolimus is beneficial in preventing cardiac rejection and may decrease rejection after lung transplantation.Objectives: To determine the potential benefit versus risk of sirolimus in lung transplantation.Methods: We conducted a multicenter randomized, open label controlled trial comparing sirolimus (SIR) with azathioprine (AZA) in a tacrolimus-based immunosuppressive regimen in lung transplantation. The primary end point was the incidence of acute rejection at 1 year after transplantation between the two study groups.Measurements and Main Results: One hundred eighty-one patients were randomized to be included in this study. At 1 year after transplantation, there was no significant difference in the incidence of grade A acute rejection between the two study groups. Similarly, the incidence of chronic rejection and graft survival was no different between the two study groups. Cytomegalovirus infection was decreased in the SIR arm compared with the AZA arm (relative risk, 0.67 [95% confidence interval, 0.55, 0.82]; P < 0.01). There was a higher rate of adverse events leading to early discontinuation of SIR (64%) compared with AZA (49%) during the course of this study.Conclusions: Sirolimus, an mTOR inhibitor, did not decrease the incidence of acute rejection at 1 year compared with azathioprine in lung transplantation. These results differ from previous results in cardiac and renal transplantation and emphasize the need for multicenter randomized controlled trials in lung transplantation.Clinical trial registered with www.clinicaltrials.gov (NCT 00321906).

BACKGROUND:Sirolimus (rapamycin) is a potent anti-proliferative agent with immunosuppressive properties that is increasingly being used in solid-organ and hematopoietic stem cell transplantation. In addition, this drug is being investigated for treatment of a broad range of disorders, including cardiovascular disease, malignancies, tuberous sclerosis, and lymphangeioleiomyomatosis. In this study, we found an increased risk of venous thromboembolism (VTE) in lung transplant recipients treated with a sirolimus (SIR)-based immunosuppressive regimen. METHODS:One hundred eighty-one lung transplant recipients were enrolled in a prospective, multicenter, randomized, open-label trial comparing a tacrolimus (TAC)/SIR/prednisone immunosuppression regimen with a TAC/azathioprine (AZA)/prednisone immunosuppressive regimen. The differences in rates of VTE were examined. RESULTS:There was a significantly higher occurrence of VTE in the SIR cohort [15 of 87 (17.2%)] compared with the AZA cohort [3 of 94 (3.2%)] (stratified log-rank statistic = 7.44, p < 0.01). When adjusted for pre-transplant diagnosis and stratified by transplant center, this difference remained essentially unchanged (hazard ratio for SIR vs AZA = 5.2, 95% confidence interval 1.4 to 19.5, p = 0.01). CONCLUSION:Clinicians prescribing SIR should maintain a high level of vigilance for VTE, particularly among patients with other risk factors for this complication.

Background: Current monitoring systems of immunosuppression in solid-organ transplant recipients are typically focused on prevention of clinical toxicities of immunosuppressive drugs. Unfortunately, these strategies are often not tailored to the individual and do not determine the optimal level of immuno-suppression for these patients. Recently, the Cylex Immune Cell Function Assay (ImmuKnow; Cylex, Inc., Columbia, MD) was approved by the U.S. Food and Drug Administration (FDA) to measure global immune response in solid-organ transplant patients receiving immunosuppressive therapy. We sought to identify the level of functional immunity as measured by the ImmuKnow assay in lung transplant recipients and to correlate these values with the dose and trough levels of immunosuppression as well as other clinical parameters in lung transplant recipients.Methods: We assessed the functional immune response by the ImmuKnow assay in 143 sequential blood samples from 57 lung transplant recipients from Loyola University Medical Center.Results: The average ImmuKnow assay in stable lung transplant recipients was 244 +/- 138 adenosine triphosphate (ATP) ng/ml and the median level was 236 ATP ng/ml (range 5 to 669 ATP ng/ml), approximately 703 +/- 695 days after lung transplantation. There was no correlation between ImmuKnow levels and tacrolimus trough levels. Stepwise multiple regression analysis identified African American race as an independent predictor of ImmuKnow assay levels when age, gender and underlying diagnosis were taken into account (p < 0.04). Fifteen infected lung transplant recipients had a lower ImmuKnow level at the time of their infections as compared with stable lung transplant recipients (111 +/- 83 vs 283 +/- 143 ATP ng/ml, respectively, p = 0.0001). Sixteen of the remaining 42 patients had low ImmuKnow assay values (<225 ATP ng/ml), but did not have active infection. There were only 2 patients with acute rejection of Grade A1 in this cohort. There were no identifiable associations of the ImmuKnow level with either acute rejection episode.Conclusions: The Cylex ImmuKnow assay levels were lower in infected lung transplant recipients compared with non-infected recipients and increased with treatment of these infections. It remains unclear whether the ImmuKnow assay reflects over-immunosuppressed individuals at risk of infection or bone marrow suppression by infectious agents. Further investigation will determine the role of the ImmuKnow assay in tailoring immunosuppression in lung transplant recipients.

A 64-year-old man who had received a lung transplant later presented with an air embolism that caused ST-segment elevation myocardial infarction, multiple strokes, and death. Transesophageal echocardiography was used to document air bubbles crossing from a bronchial fistula to a pulmonary vein and into the left atrium. Spontaneous air was seen entering a pulmonary vein during positive-pressure ventilation and exiting through the left ventricular outflow tract. Autopsy confirmed the presence of a probe-patent bronchial-to-pulmonary vein fistula within a focus of necrosis and infection with Aspergillus flavus, an angioinvasive organism. The potential for intravascular gas arising from the anastomotic site should be considered when transplant recipients who present with myocardial or peripheral arterial infarction are evaluated.

Purpose: Early morbidity following lung transplantation consume significant amount of resources and may be a marker for early and late mortality. Prompt recognition and treatment of the causes may avert the serious consequences. The etiology however, for early readmissions after lung transplantation is poorly reported. We reviewed the causes of readmissions within 90 days following isolated lung transplantation and the impact of readmission on survival.