Maher A. Baz

Bronchoalveolar lavage galactomannan in diagnosis of invasive pulmonary aspergillosis among solid-organ transplant recipients.

ABSTRACT We review the experience at our institution with galactomannan (GM) testing of bronchoalveolar lavage (BAL) fluid in the diagnosis of invasive pulmonary aspergillosis (IPA) among solid-organ transplant recipients. Among 81 patients for whom BAL GM testing was ordered (heart, 24; kidney, 22; liver, 19; lung, 16), there were five cases of proven or probable IPA. All five patients had BAL GM of ≥2.1 and survived following antifungal therapy. The sensitivity, specificity, and positive and negative predictive values for BAL GM testing at a cutoff of ≥1.0 were 100%, 90.8%, 41.7%, and 100%, respectively. The sensitivity of BAL GM testing was better than that of conventional tests such as serum GM or BAL cytology and culture. Moreover, a positive BAL GM test diagnosed IPA several days to 4 weeks before other methods for three patients. Twelve patients had BAL GM of ≥0.5 but no evidence of IPA. Among these, lung transplant recipients accounted for 41.7% (5/12) of the false-positive results, reflecting frequent colonization of airways in this population. Excluding lung transplants, the specificity and positive predictive value for other solid-organ transplants increased to 92.9% and 62.5%, respectively (cutoff, ≥1.0). In conclusion, BAL GM testing facilitated more-rapid diagnoses of IPA and the institution of antifungal therapy among non-lung solid-organ transplant recipients and helped to rule out IPA.

Fungal infections in lung and heart-lung transplant recipients. Report of 9 cases and review of the literature.

We reviewed the pattern and incidence of fungal infections in patients undergoing lung and heart-lung transplantation at Duke University Medical Center from September 1992 until August 1995, and present here 9 illustrative cases. Of the 73 lung and heart-lung transplant recipients studied, 59 (81%) had positive fungal cultures at some point after transplantation. The cases presented here illustrate that lung transplant recipients are predisposed to a wide variety of fungal infections. The clinical pattern of these infections ranges from asymptomatic to rapidly progressive fatal disease. In addition to the reactivation of previous fungal infections and recent exposure to new environmental sources, the donor lung itself can be the source of fungal infection, as we showed by using molecular epidemiology techniques. Because of the associated morbidity and mortality, efforts should be directed at investigating prophylactic antifungal regimens in lung transplant recipients. Preliminary reports on the use of itraconazole and aerosolized amphotericin B have been encouraging. Prospective randomized studies are needed to assess the safety and cost effectiveness of different regimens. Fungal infections in patients after lung transplantation can significantly impede recovery and lead to substantial mortality.

Inspiratory muscle strength training improves weaning outcome in failure to wean patients: a randomized trial

IntroductionMost patients are readily liberated from mechanical ventilation (MV) support, however, 10% - 15% of patients experience failure to wean (FTW). FTW patients account for approximately 40% of all MV days and have significantly worse clinical outcomes. MV induced inspiratory muscle weakness has been implicated as a contributor to FTW and recent work has documented inspiratory muscle weakness in humans supported with MV.MethodsWe conducted a single center, single-blind, randomized controlled trial to test whether inspiratory muscle strength training (IMST) would improve weaning outcome in FTW patients. Of 129 patients evaluated for participation, 69 were enrolled and studied. 35 subjects were randomly assigned to the IMST condition and 34 to the SHAM treatment. IMST was performed with a threshold inspiratory device, set at the highest pressure tolerated and progressed daily. SHAM training provided a constant, low inspiratory pressure load. Subjects completed 4 sets of 6-10 training breaths, 5 days per week. Subjects also performed progressively longer breathing trials daily per protocol. The weaning criterion was 72 consecutive hours without MV support. Subjects were blinded to group assignment, and were treated until weaned or 28 days.ResultsGroups were comparable on demographic and clinical variables at baseline. The IMST and SHAM groups respectively received 41.9 ± 25.5 vs. 47.3 ± 33.0 days of MV support prior to starting intervention, P = 0.36. The IMST and SHAM groups participated in 9.7 ± 4.0 and 11.0 ± 4.8 training sessions, respectively, P = 0.09. The SHAM groups pre to post-training maximal inspiratory pressure (MIP) change was not significant (-43.5 ± 17.8 vs. -45.1 ± 19.5 cm H2O, P = 0.39), while the IMST groups MIP increased (-44.4 ± 18.4 vs. -54.1 ± 17.8 cm H2O, P < 0.0001). There were no adverse events observed during IMST or SHAM treatments. Twenty-five of 35 IMST subjects weaned (71%, 95% confidence interval (CI) = 55% to 84%), while 16 of 34 (47%, 95% CI = 31% to 63%) SHAM subjects weaned, P = .039. The number of patients needed to be treated for effect was 4 (95% CI = 2 to 80).ConclusionsAn IMST program can lead to increased MIP and improved weaning outcome in FTW patients compared to SHAM treatment.Trial RegistrationClinicalTrials.gov: NCT00419458

Resistance training prevents vertebral osteoporosis in lung transplant recipients

Background. Osteoporosis and vertebral fractures are a consequence of glucocorticoid immunosuppression therapy in lung transplant recipients (LTR). The purpose of this study was to determine the therapeutic efficacy of a 6-month program of specific resistance exercise designed to reverse glucocorticoid-induced vertebral osteoporosis. Methods. Sixteen lung transplant candidates were randomly and prospectively assigned to a group (n=8) that performed 6 months of exercise on a lumbar extensor machine or to a control group (n=8). Resistance exercise was initiated at 2 months after transplantation. Bone mineral density (BMD) of the lumbar vertebra (L2-3) was assessed using a dual-energy X-ray absorptiometer (DXA). DXA scans were performed before and 2 months after transplantation and after 6 months of lumbar extensor training or control period. Results. Lumbar BMD did not differ (P >0.05) between the two groups at study entry. Both the trained (0.63 to 0.54 g/cm2 of hydroxyapatite) and control groups (0.62 to 0.53 g/cm2 of hydroxyapatite) lost significant and comparable amounts (−14.5%) of BMD between study entry and 2 months posttransplantation. The control group lost further (P ≤0.05) lumbar BMD between 2 and 8 months posttransplantation (0.53 to 0.50 g/cm2 of hydroxyapatite), decreasing to values that were 19.5% less than pretransplantation baseline. Lumbar BMD in the trained group increased significantly (+9.2%) after 6 months (0.54 to 0.60 g/cm2 of hydroxyapatite) and returned to values that were within 5% of pretransplantation baseline. Conclusion. Mechanical loading associated with progressive resistance exercise, using a specific exercise that isolated the lumbar spine, was efficacious in preventing steroid-induced osteoporosis in LTR.

Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection

Background. Although the use of mycophenolate mofetil (MMF) has reduced the incidence of acute rejection in heart and kidney allograft recipients, its role in lung transplantation remains controversial. Therefore, we conducted a randomized, prospective, open-label, multicenter study in lung transplant recipients to determine whether MMF decreases episodes of acute allograft rejection when compared with azathioprine (AZA). Methods. Between March of 1997 and January of 1999, 81 consecutive lung transplant recipients from two centers were prospectively randomized to receive cyclosporine, corticosteroids, and either 2 mg/kg per day of AZA or 1 g twice daily of MMF. The primary study endpoint was biopsy-proven acute allograft rejection over the first 6 months posttransplant. Secondary endpoints included clinical rejection, cytomegalovirus (CMV) infection, adverse events, and survival. Surveillance bronchoscopies were performed at 1, 3, and 6 months, or if clinically indicated. Pathologists interpreting the biopsy results were blinded to the randomization. Results were analyzed according to intention-to-treat. Between group comparisons of means and proportions were made by using two sample t tests and Fisher’s exact tests, respectively. Six-month survival was calculated by the Kaplan-Meier method and compared by the log rank test. Results. Thirty-eight patients were prospectively randomized to receive AZA, and 43 MMF. The incidence of biopsy proven grade II or greater acute allograft rejection at 6 months was 58% in the AZA group and 63% in the MMF group (P =0.82). The 6-month survival rates in the MMF and AZA groups were 86% and 82%, respectively (P =0.57). Rates of CMV infection and adverse events were not significantly different between the two groups. Conclusions. Acute rejection rates and overall survival at 6 months are similar in lung transplant recipients treated with either MMF- or AZA-based immunosuppression.

Use of Bronchoalveolar Lavage To Detect Galactomannan for Diagnosis of Pulmonary Aspergillosis among Nonimmunocompromised Hosts

ABSTRACT Pulmonary aspergillosis in nonimmunocompromised hosts, although rare, is being increasingly recognized. The diagnosis of pulmonary aspergillosis is difficult, since the recovery of Aspergillus from respiratory samples cannot differentiate colonization from invasion. We assessed the role of bronchoalveolar lavage (BAL) in detecting galactomannan (GM) for diagnosing pulmonary aspergillosis in 73 nonimmunocompromised patients with pulmonary infiltrates for whom the test was ordered. Six patients had pulmonary aspergillosis, two each with acute invasive pulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, and aspergilloma. All six patients had a BAL GM level of ≥1.18. The sensitivity, specificity, and negative predictive value (NPV) for a BAL GM level of ≥1.0 were 100%, 88.1%, and 100%, respectively. Notably, the positive predictive value (PPV) was only 42.9%, likely reflecting the low prevalence of pulmonary aspergillosis among nonimmunosuppressed patients. The combination of BAL microscopy and culture had a sensitivity and NPV similar to those of BAL GM detection but a higher specificity and PPV (92.5% and 54.6%, respectively). Moreover, a BAL GM test did not identify any cases that were not diagnosed by conventional methods like microscopy and culture. In conclusion, there was no conclusive benefit of determining BAL GM levels in the diagnosis of pulmonary aspergillosis among nonimmunocompromised hosts. Given the likelihood of false-positive results, a BAL GM test should not be ordered routinely in this population.

Pleural mesothelial cell transformation into myofibroblasts and haptotactic migration in response to TGF-β1 in vitro

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis noted in the pulmonary parenchyma. Pleural mesothelial cells (PMC) are metabolically dynamic cells that cover the lung and chest wall as a monolayer and are in intimate proximity to the underlying lung parenchyma. The precise role of PMC in the pathogenesis of pulmonary parenchymal fibrosis remains to be identified. Transforming growth factor (TGF)-beta1, a cytokine known for its capacity to induce proliferative and transformative changes in lung cells, is found in significantly higher quantities in the lungs of patients with IPF. High levels of TGF-beta1 in the subpleural milieu may play a key role in the transition of normal PMC to myofibroblasts. Here we demonstrate that PMC activated by TGF-beta1 undergo epithelial-mesenchymal transition (EMT) and respond with haptotactic migration to a gradient of TGF-beta1 and that the transition of PMC to myofibroblasts is dependent on smad-2 signaling. The EMT of PMC was marked by upregulation of alpha-smooth muscle actin (alpha-SMA), fibroblast specific protein-1 (FSP-1), and collagen type I expression. Cytokeratin-8 and E-cadherin expression decreased whereas vimentin remained unchanged over time in transforming PMC. Knockdown of smad-2 gene by silencing small interfering RNA significantly suppressed the transition of PMC to myofibroblasts and significantly inhibited the PMC haptotaxis. We conclude that PMC undergo EMT when exposed to TGF-beta1, involving smad-2 signaling, and PMC may be a possible source of myofibroblasts in IPF.

A Randomized Evaluation of Quality-of-Life Therapy with Patients Awaiting Lung Transplantation

Research shows that patients wait‐listed for lung transplantation have very poor quality of life (QOL). This study evaluated the effectiveness of Quality‐of‐Life Therapy (QOLT) in improving QOL, mood disturbance and social intimacy in adults awaiting lung transplantation. Thirty‐five adults were randomized to QOLT (n = 17) or supportive therapy (ST; n = 18) and received individual, telephone‐based treatment sessions. QOL, mood and social intimacy assessments were conducted at baseline and at 1 and 3 months after treatment. Repeated measures analyses of variance showed significant Condition × Time interaction effects for all three primary outcome measures. Subsequent post hoc analyses showed that the two groups did not differ significantly at baseline, but did differ significantly at the 1‐ and 3‐month follow‐up assessments. When compared to ST patients, QOLT patients had significantly higher QOL scores at the 1‐ and 3‐month assessments, lower mood disturbance scores at the 3‐month assessment, and higher social intimacy scores at the 1‐month assessment. Results indicate that a patients QOL, mood state and relationship with the primary caregiver can be positively impacted by a brief psychological intervention prior to lung transplantation.

Bone Marrow-derived Stem-cell Repopulation Contributes Minimally to the Type Ii Pneumocyte Pool in Transplanted Human Lungs

Background. Lung transplant recipients are vulnerable to immunologic, infectious, ischemic, and toxic pulmonary injuries. The authors investigated whether type II pneumocytes in the lungs of cross-gender lung transplant patients show genotypic evidence to support repopulation of the lung by stem cells of bone marrow origin, and whether the degree of repopulation was related to rejection history. Methods. Recut sections were obtained from lung biopsy specimens from seven male recipients of transplanted lungs from female donors. Sequential immunohistochemistry and fluorescence in situ hybridization was performed on each section to evaluate for Y-chromosome–containing type II pneumocytes. Results. Y-chromosome–containing type II pneumocytes were found in 9 of 25 biopsy specimens from 5 of 7 gender-mismatched male lung transplant recipients, and accounted for 0% to 0.553% of type II pneumocytes. There was no evidence of polyploidy to suggest cell-cell fusion. The number of type II pneumocytes of male karyotype showed a statistically significant relationship to the cumulative number of episodes of acute cellular rejection. Conclusions. Lung transplant recipients develop low levels of pneumocyte repopulation by bone marrow-derived stem cells or their progeny. These cells contribute minimally to the type II pneumocyte proliferation that is often present in these patients as a sequela to alveolar injury.

Susceptibility of lung transplants to preformed donor-specific HLA antibodies as detected by flow cytometry.

BACKGROUND Preformed anti-HLA antibodies are known to have the potential to induce early graft damage in organ transplant recipients. However, in lung transplant recipients, little information exists about the significance of preformed antibodies directed to either class I or class II HLA antigens. METHODS A two-color flow cytometry cross-match was performed in 92 consecutive lung transplant recipients using serum obtained immediately before transplantation. The presence of preformed antibodies was correlated with the incidence of severe graft dysfunction manifested as pulmonary infiltrates and severe hypoxemia with onset in the first few hours after transplantation. RESULTS Six patients (6.5%) had low-level anti-donor IgG antibodies detected by flow cytometry, four against T and two against B lymphocytes. Three patients (50%) developed severe graft dysfunction with pulmonary infiltrates and hypoxemia. Two patients responded to treatment, but the third, who had an antibody highly specific for HLA-DR11, died at 48 hr after transplant. Results of histopathologic studies in this patient are consistent with hyperacute rejection and support a pathogenic role of these antibodies. In contrast, of 86 (93.5%) cases with a negative flow cytometry cross-match, only 4 (5%) had severe but reversible early graft dysfunction with pulmonary infiltrates and hypoxemia, attributed to ischemia-reperfusion injury (P<0.005). CONCLUSIONS Class II, and perhaps class I HLA antibodies at relatively low concentrations represent a risk factor for severe early pulmonary graft dysfunction, with the potential to progress to hyperacute rejection and death.