Charles G. Alex

Cylex ImmuKnow assay levels are lower in lung transplant recipients with infection.

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 immunosuppression 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.

The protective role of laparoscopic antireflux surgery against aspiration of pepsin after lung transplantation.

BACKGROUND The goal of this study was to determine, in lung transplant patients, if laparoscopic antireflux surgery (LARS) is an effective means to prevent aspiration as defined by the presence of pepsin in the bronchoalveolar lavage fluid (BALF). METHODS Between September 2009 and November 2010, we collected BALF from 64 lung transplant patients at multiple routine surveillance assessments for acute cellular rejection, or when clinically indicated for diagnostic purposes. The BALF was tested for pepsin by enzyme-linked immunosorbent assay (ELISA). We then compared pepsin concentrations in the BALF of healthy controls (n = 11) and lung transplant patients with and without gastroesophageal reflux disease (GERD) on pH-monitoring (n = 8 and n = 12, respectively), and after treatment of GERD by LARS (n = 19). Time to the development of bronchiolitis obliterans syndrome was contrasted between groups based on GERD status or the presence of pepsin in the BALF. RESULTS We found that lung transplant patients with GERD had more pepsin in their BALF than lung transplant patients who underwent LARS (P = .029), and that pepsin was undetectable in the BALF of controls. Moreover, those with more pepsin had quicker progression to BOS and more acute rejection episodes. CONCLUSION This study compared pepsin in the BALF from lung transplant patients with and without LARS. Our data show that: (1) the detection of pepsin in the BALF proves aspiration because it is not present in healthy volunteers, and (2) LARS appears effective as a measure to prevent the aspiration of gastroesophageal refluxate in the lung transplant population. We believe that these findings provide a mechanism for those studies suggesting that LARS may prevent nonallogenic injury to the transplanted lungs from aspiration of gastroesophageal contents.

Inspiratory muscle training in patients with chronic obstructive pulmonary disease

The effects of 6 months of muscle training with an inspiratory pressure load equal to 30% of the maximal inspiratory pressure (PImax) was compared with sham training with a light inspiratory pressure load. In this double-blind randomly assigned study, 67 patients with chronic obstructive pulmonary disease were followed for 6 months. Both groups demonstrated improvements in performance of PImax, respiratory muscle endurance time for breathing against an inspiratory pressure load equal to 66% of PImax, 12-minute distance walk, and dyspnea. The treatment group did not demonstrate significant effects beyond those observed in the control group. Improvements in performance were related to improved coordination of the inspiratory muscles and desensitization to dyspnea.

Comparison of Sirolimus with Azathioprine in a Tacrolimus-based Immunosuppressive Regimen in Lung Transplantation

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).

Low vitamin D levels are associated with increased rejection and infections after lung transplantation

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.

Reliability and validity of the 12-minute distance walk in patients with chronic obstructive pulmonary disease.

Validity and test-retest liability of the 12-minute distance (12MD) walk, a measure of functional status, were examined in patients with chronic obstructive pulmonary disease. Four tests were administered at weekly intervals. Performance increased (p < .01) over the first three tests. Test-retest reliability was r34 = .98 (df = 46) for tests 3 and 4. The 12MD walk correlated with the Sickness Impact Profile, Physical Dimension (r = -.45); forced expiratory volume in 1 second % predicted ( r = .40); maximal inspiratory pressure (PImax) (r = .52); and exercise-related breathlessness (r = -.49). Exercise-related breathlessness and PImax accounted for 42% of the variance. The validity and reliability of the 12MD walk were supported.

Refractory post-transplant airway strictures: successful management with wire stents

OBJECTIVE Bronchial stenosis, malacia and dehiscence are major airway complications of lung transplantation. Our success in managing this problem evolved from the use of semi-rigid dilators, to balloon dilation and placement of a stent, which were initially silicone, thereafter wire balloon-expandable and finally wire self-expandable. METHODS From May, 1994 until July 1997, we performed a total of 49 single and 58 bilateral lung transplants. Symptoms of shortness of breath, verified by a drop in the forced expiratory volume in one second (FEV1), led to bronchoscopic inspection of the airway in lung transplant patients. Eighteen patients (16%) suffered a severe form of airway complication (dehiscence or stenosis) in 24 of 151 airways at risk (15.9%). These anastomotic strictures were recalcitrant to conventional therapy. Intervention consisted of rigid bronchoscopy, dilation of the stricture and placement of a stent. Flexible bronchoscopy and fluoroscopy were used for precise placement of the stent. As the initial stent, the Hood silicone stent was placed five times in four patients and the Dumont studded stent five times in four patients. The Palmaz wire stent was used as the initial stent 10 times in seven patients and the Wallstent used eight times in seven patients. Four patients had multiple stents. Balloon inflation moulded the wire stent to the airway. RESULTS There was no mortality resulting from the airway complication or any intervention. The most serious complication was a perforation of the airway using the semi-rigid dilator that necessitated immediate thoracotomy and re-anastomosis of the bronchus. Other complications necessitated repeat interventions due to restenosis or failure of the stents. The success of the stent placement was measured subjectively by the immediate ease of breathing enjoyed by each patient and objectively by the significant increase of the FEV1 from a pre-operative mean of 1.19 l (SD 0.64 l) to a post-operative mean of 2.06 l (SD 0.70 l) (P < 0001). The mean number of interventions according to the type of wire stent first used was significantly fewer with Wallstent insertion (1.28 (SD 0.48)) than in those patients in whom a Palmaz stent was inserted (5.22 (SD 2.38)) (P < 0008). CONCLUSION The airway complication of stricture, broncho-malacia or dehiscence following lung transplantation can be managed effectively and easily with the use of balloon catheter dilation followed by precise placement of a self-expandable wire stent. The Wallstent is the superior stent for this application.

Gastroesophageal reflux disease after lung transplantation: pathophysiology and implications for treatment.

BACKGROUND Gastroesophageal reflux disease (GERD) is thought to be a risk factor for the development or progression of chronic rejection after lung transplantation. However, the prevalence of GERD and its risk factors, including esophageal dysmotility, hiatal hernia and delayed gastric emptying after lung transplantation, are still unknown. In addition, the prevalence of Barretts esophagus, a known complication of GERD, has not been determined in these patients. The purpose of this study was to determine the prevalence and extent of GERD, as well as the frequency of these risk factors and complications of GERD in lung transplant patients. METHODS Thirty-five consecutive patients underwent a combination of esophageal function testing, upper endoscopy, barium swallow, and gastric emptying scan after lung transplantation. RESULTS In this patient population, the prevalence of GERD was 51% and 22% in those who had been retransplanted. Of patients with GERD,36% had ineffective esophageal motility (IEM), compared with 6% of patients without GERD (P = .037). No patient demonstrated hiatal hernia on barium swallow. The prevalence of delayed gastric emptying was 36%. The prevalence of biopsy-confirmed Barretts esophagus was 12%. CONCLUSION Our study shows that, after lung transplantation, more than half of patients had GERD, and that GERD was more common after retransplantation. IEM and delayed gastric emptying are frequent in patients with GERD. Hiatal hernia is rare. The prevalence of Barretts esophagus is not negligible. We conclude that GERD is highly prevalent after lung transplantation, and that delayed gastric emptying and Barretts esophagus should always be suspected after lung transplantation because they are common risks factors and complications of GERD.

Increased risk of venous thromboembolism with a sirolimus-based immunosuppression regimen in lung transplantation

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.

Functional Performance in Chronic Obstructive Pulmonary Disease Declines with Time

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.