Annette Boehler

European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare lung disease, which occurs sporadically or in association with the genetic disease tuberous sclerosis complex (TSC) 1, 2. Sporadic LAM affects ∼1 in 400,000 adult females; in TSC, LAM occurs in 30–40% of adult females 3, 4 and exceptionally in males and children 5, 6. Patients with LAM usually develop progressive dyspnoea and recurrent pneumothorax, chylous collections and occasional haemoptysis 1. Extra pulmonary lymphadenopathy and cystic masses of the axial lymphatics termed lymphangioleiomyomas can result in abdominal and pelvic lymphatic obstruction 7. LAM is often associated with angiomyolipoma in the kidneys 8, and an increased frequency of meningioma 9. LAM varies in clinical features and rate of progression: this together with an absence of clear prognostic factors results in patients being given conflicting information about prognosis. Diagnosis is made by tissue biopsy (generally from the lung but occasionally from lymph nodes or lymphangioleiomyomas) and/or a combination of history and high-resolution computed tomography scanning (HRCT). Pathological diagnosis relies on characteristic LAM cell morphology and positive immunoreactivity to smooth muscle actin and HMB-45 antibodies. Increasingly HRCT is used to diagnose LAM without resorting to lung biopsy; however a number of conditions with multiple pulmonary cysts can mimic LAM. As LAM is rare, there have been no controlled trials of its management. Supportive treatment includes management of airflow obstruction and hypoxaemia with bronchodilators and oxygen respectively, specific treatment for surgical or pleural complications including pneumo- and chylothorax, and interventional treatment of renal lesions 10, 11. As LAM is a disease of females and is thought to be accelerated by oestrogen, oophorectomy, tamoxifen, progesterone and gonadotropin-releasing hormone (GnRH) analogues have been used without evidence that they are effective. The recent finding of abnormalities in the TSC1/2 genes resulting …

A review of lung transplant donor acceptability criteria

Abstract (A consensus report from The Pulmonary Council of the International Society for Heart and Lung Transplantation)

Lung Transplantation for Lymphangioleiomyomatosis

BACKGROUND Lymphangioleiomyomatosis is a rare disease of unknown origin that usually leads to progressive deterioration of lung function and eventual death from respiratory failure. It occurs in women of reproductive age and people with tuberous sclerosis. Lung transplantation is a recent therapeutic approach. METHODS We conducted a retrospective study by questionnaire of 34 patients, treated at 16 transplantation centers, who underwent lung transplantation for end-stage lymphangioleiomyomatosis between 1983 and 1995. RESULTS Of the 34 patients, 27 received single-lung transplants; 6, bilateral transplants; and 1, a heart-lung transplant. As of August 31, 1995, the actuarial survival calculated by the Kaplan-Meier method was 69 percent after one year and 58 percent after two years. Eighteen patients were alive 33 +/- 20 months (range, 3 to 74) after transplantation. Forced expiratory volume in one second increased from 24 +/- 12 percent of the predicted value before transplantation to 48 +/- 16 percent six months after transplantation. Five early deaths (within one month) were due to hemorrhage (in one patient), acute lung injury (in three), and dehiscence of the bronchial anastomosis (in one). Eleven late deaths (after one month) were due to infections (in eight patients), bronchiolitis obliterans (in two), and metastatic nephroblastoma (in one). Disease-associated problems were extensive pleural adhesions in 18 patients, leading to moderate-to-severe intraoperative hemorrhage in 4; pneumothorax in the native lung after single-lung transplantation in 6 patients; postoperative chylothorax in 3; and recurrent lymphangioleiomyomatosis in the allograft in 1 patient, who died of disseminated aspergillosis. CONCLUSIONS Although disease-related complications are frequent, lung transplantation can be a valuable therapy for patients with end-stage lymphangioleiomyomatosis.

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention. Diagnosis of BOS requires careful exclusion of other complications that can cause delayed lung allograft dysfunction http://ow.ly/AZmbr

Obliterative bronchiolitis after lung transplantation.

Despite marked improvements in early survival, long-term outcome after lung transplantation is still threatened by obliterative bronchiolitis (OB). Thought to be a manifestation of chronic allograft rejection, OB affects up to 65% of patients at 5 years after surgery and produces a relentless airflow obstruction. Early and late acute rejection are the primary risk factors for OB, but cytomegalovirus infection and airway ischemia may also play a role. In most patients, OB responds poorly to augmented immunosuppression and eventually leads to infectious complications and terminal respiratory failure. Because early diagnosis is associated with better prognosis, every effort should be made to detect OB in a preclinical stage. This may be best achieved by combining several techniques, such as surveillance transbronchial biopsy and bronchoalveolar lavage, measurements of ventilation distribution and exhaled nitric oxide, and expiratory computed tomography.

Lymphocytic airway infiltration as a precursor to fibrous obliteration in a rat model of bronchiolitis obliterans.

BACKGROUND Bronchiolitis obliterans is the most significant complication adversely affecting prolonged survival of lung allograft recipients. The evolution from the initial insult to the final pathologic entity is largely unknown. The aim of this study was to characterize the evolution of transplant-induced fibrous airway obliteration in a rat tracheal transplant model of bronchiolitis obliterans. METHODS Tracheal segments were transplanted from Brown Norway rats to Brown Norway rats (isografts) or to Lewis rats (allografts). Grafts were implanted into a subcutaneous pouch and an abdominal omental wrap. They were harvested at 14 different time points (from 1 day to 1 year after transplantation) and assessed histologically. RESULTS The fibrous airway obliteration developed only in allografts showing a triphasic time course: an initial ischemic phase (observed in both isografts and allografts) was followed by a marked lymphocytic infiltrative phase with complete epithelial loss (observed only in allografts, P<0.01), and finally by an obliterative phase with fibrous obliteration of the allograft airway lumen (P<0.01). CONCLUSIONS This animal model shows a distinct and reproducible triphasic time course in the development of obliterative airway lesions in allografts. It confirms that the mechanism leading to airway obliteration is immune mediated as only allografts showed this lesion and that lymphocytic infiltration is a precursor of the lesion in this model. The insights into the different phases demonstrated may lead to novel approaches regarding the type and timing of therapeutic interventions.

Extracorporeal Photopheresis After Lung Transplantation : A 10-Year Single-Center Experience

We report the largest single-center experience with extracorporeal photopheresis (ECP) for bronchiolitis obliterans syndrome (BOS) and recurrent acute rejection (AR) after lung transplantation. Lung transplant recipients undergoing ECP for BOS and recurrent AR were included (1997-2007). The rate of forced expiratory volume in 1 second (FEV1) decline was used as the primary measure and graft survival post-ECP as the secondary measure of efficacy. Twenty-four transplant recipients were included (BOS, n=12; recurrent AR, n=12). In recipients with BOS, decline in FEV1 was 112 mL/month before the start of ECP and 12 mL/month after 12 ECP cycles (P=0.011), mean (95% CI) change in rate of decline was 100 (28-171). Median patient survival was 7.0 (range, 3.0-13.6) years, median patient survival post-ECP 4.9 (range, 0.5-8.4) years. No ECP-related complications occurred. Extracorporeal photopheresis reduces the rate of lung function decline in recipients with BOS and is well tolerated. Furthermore, recipients with recurrent AR experience clinical stabilization. However, the underlying mechanism of ECP remains subject to further research.

Effects of sinus surgery in patients with cystic fibrosis after lung transplantation: a 10-year experience

Chronic infectious rhinosinusitis with Pseudomonas aeruginosa is common in cystic fibrosis and may result in allograft infection after lung transplantation. Sinus surgery followed by nasal care may reduce these adverse effects. Sinus surgery was performed in 37 patients with cystic fibrosis after transplantation. Bacteriology of sinus aspirates (n=771) and bronchoalveolar lavage (BAL) (n=256) was correlated with clinical data. Sinus surgery was successful in 54% and partially successful in 27% of patients. A significant correlation between negative sinus aspirates and negative BAL and between positive sinus aspirates and positive BAL (P <0.0001) was found. Successful sinus management led to a lower incidence of tracheobronchitis and pneumonia (P =0.009) and a trend toward a lower incidence of bronchiolitis obliterans syndrome (P =0.23). Sinus surgery followed by daily nasal douching may control posttransplant lower airway colonization and infection. In the long term, this concept may lead to less bronchiolitis obliterans syndrome by decreasing bronchiolar inflammation.

Osteoporosis before lung transplantation: association with low body mass index, but not with underlying disease

Due to progress in lung transplantation, post‐transplantation osteoporosis becomes an important problem. We determined bone mineral density (BMD) in 74 lung transplantation candidates, among them 24 patients with cystic fibrosis, 16 with chronic obstructive pulmonary disease, 14 with pulmonary fibrosis, and 11 with pulmonary hypertension. The mean T score (± SD) was − 2.6 ± 1.3 at femoral neck (FN), − 2.2 ± 1.6 at Wards triangle (WT) and −2.3 ± 1.5 at lumbar spine (LS). Osteoporosis was found in 61% of the patients at FN, 45% at WT and 50% at LS. Patients with different underlying lung diseases were similarly affected, not only those with cystic fibrosis but also others, including patients with pulmonary hypertension. No association was found between BMD and age, gender, menstrual condition in women and testosterone level in men. A negative correlation was found between chronic glucocorticoid use and T scores. Body mass index correlated positively (p < 0.01) with T scores at any site and the correlation was also significant for the 2 largest subgroups. Loss of lung function (FEV1) also was associated with lower T scores. No correlation was found between BMD and biochemical indices of bone turnover. Multivariate analysis revealed BMI and glucocorticoid use as independent risk factors. We conclude that osteoporosis is a very common condition in patients with end‐stage pulmonary disease, independent of the underlying diagnosis. In view of additional bone loss under immunosuppressive treatment after lung transplantation, early diagnosis and prevention of osteoporosis in the pretransplant period should receive high priority.

Ganciclovir/Valganciclovir Prophylaxis Decreases Cytomegalovirus-Related Events and Bronchiolitis Obliterans Syndrome after Lung Transplantation

BACKGROUND Until recently, cytomegalovirus (CMV) infection represented a major threat to lung transplant recipients. Preliminary studies have shown that antiviral prophylaxis might improve the outcome for these patients. METHODS We extended our initial pilot trial of prolonged prophylaxis with either oral ganciclovir (1 g 3 times per day) or valganciclovir (450 mg twice per day). The trial included 96 patients who were at risk for CMV-related events. RESULTS CMV prophylaxis resulted in a significant decrease in CMV-related events (i.e., active infection and disease), from 75% in a control group and for 274 cases from the literature who did not receive prophylaxis to a cumulative incidence of 27% (P < .001). Only 11% of the prophylaxis recipients experienced CMV disease (P = .002). Moreover, at 5 years, there was a significant decrease in the rate of bronchiolitis obliterans syndrome, from 60% to 43% (P = .002), and an improved rate of survival, from 47% to 73% (P= .036), irrespective of the immunosuppressive regimen received. CMV strains with UL97 mutations were recovered from 7 of 12 analyzed cases, but the presence of this mutation had no impact on the severity of CMV disease. CONCLUSIONS A regimen of prolonged ganciclovir or valganciclovir prophylaxis decreased the rate of active CMV infection and disease, reduced the incidence of bronchiolitis obliterans syndrome, and improved the survival rate. Drug-resistant CMV strains may occur, but such strains appeared to have no impact on the outcome of CMV-related events.