CTOTC-08: A multicenter randomized controlled trial of rituximab induction to reduce antibody development and improve outcomes in pediatric lung transplant recipients.

We conducted a randomized, placebo-controlled, double-blind study of pediatric lung transplant recipients, hypothesizing that rituximab plus rabbit anti-thymocyte globulin induction would reduce de novo donor-specific human leukocyte antigen antibodies (DSA) development and improve outcomes. We serially obtained clinical data, blood, and respiratory samples for at least one year posttransplant. We analyzed peripheral blood lymphocytes by flow cytometry, serum for antibody development, and respiratory samples for viral infections using multiplex PCR. Of 45 subjects enrolled, 34 were transplanted and 27 randomized to rituximab (n = 15) or placebo (n = 12). No rituximab-treated subjects versus five placebo-treated subjects developed de novo DSA with mean fluorescence intensity >2000. There was no difference between treatment groups in time to the primary composite outcome endpoint (death, bronchiolitis obliterans syndrome [BOS] grade 0-p, obliterative bronchiolitis or listing for retransplant). A post-hoc analysis substituting more stringent chronic lung allograft dysfunction criteria for BOS 0-p showed no difference in outcome (p = .118). The incidence of adverse events including infection and rejection episodes was no different between treatment groups. Although the study was underpowered, we conclude that rituximab induction may have prevented early DSA development in pediatric lung transplant recipients without adverse effects and may improve outcomes (Clinical Trials: NCT02266888).

A randomized controlled trial of liposomal cyclosporine A for inhalation in the prevention of bronchiolitis obliterans syndrome following lung transplantation.

Long-term survival after lung transplantation is limited by chronic allograft dysfunction. The aim of this study was to investigate the effect of locally augmented immunosuppression with liposomal cyclosporine A for inhalation (L-CsA-i) for the prevention of bronchiolitis obliterans syndrome (BOS). In a randomized, double-blind, placebo-controlled, multi-center Phase 3 study, 180 LT recipients in BOS grade 0 were planned to receive L-CsA-i or placebo in addition to triple-drug immunosuppression. L-CsA-i was administered twice daily via an Investigational eFlow nebulizer to recipients of single (SLT) and bilateral lung transplants (BLT) within 6-32 weeks posttransplant, and continued for 2 years. The primary endpoint was BOS-free survival. 130 patients were enrolled before the study was prematurely terminated for business reasons. Despite a 2-year actuarial difference in BOS-free survival of 14.1% in favor of L-CsA-i in the overall study population, the primary endpoint was not met (p = .243). The pre-defined per protocol analysis of SLT recipients (n = 24) resulted in a treatment difference of 58.2% (p = .053). No difference was observed in the BLT (n = 48) subpopulation (p = .973). L-CsA-i inhalation was well tolerated. Although this study failed to meet its primary endpoint, the results warrant additional investigation of L-CsA-i in lung transplant recipients.

[Bronchiolitis obliterans associated with Stevens-Johnson syndrome]. / Bronquiolitis obliterante asociada a síndrome de Stevens-Johnson.

Stevens-Johnson syndrome is a severe disease which is characterized by fever and mucocutaneous lesions. It has also been described as a small airway compromise in the form of bronchiolitis obliterans. We report a 22-year-old male patient with Stevens-Johnson syndrome due to antibiotic and antiepileptic drug treatment for brain abscess. After the improvement of mucocutaneous lesions, he went to the emergency department because of coughing and progressive shortness of breath. Pulmonary function test revealed a very severe irreversible obstructive defect and a computed tomography scan showed a mosaic attenuation pattern. We discuss this case of bronchiolitis obliterans associated with Stevens-Johnson because of its low incidence.

A proposal for a safe exposure level for diacetyl.

Diacetyl is a naturally occurring compound that has been used in concentrated form as a food additive, particularly in butter flavorings. Inhalation of diacetyl and butter flavoring fumes has caused a variety of respiratory diseases in workers and consumers including bronchiolitis obliterans (BO), a relatively rare, severe, and irreversible lung disease. A safe level of exposure to diacetyl has not been established. We review the literature on diacetyl and flavoring toxicity and critique a recent proposal for an occupational exposure limit (OEL) of 0.2 ppm for diacetyl. We present unpublished data and novel analyses in support of our proposal for a safe level of exposure. Our findings indicate that a safe level of exposure exists around or below a time-weighted average of 1 ppb for an eight-hour workday. The levels of exposure we found to be unsafe include ranges that popcorn consumers may potentially be exposed to, indicating a risk of severe lung disease (including BO) for some consumers.

Severe scoliosis with an impaired pulmonary allograft function after pediatric unilateral lung transplantation.

Left-unilateral single-lobe lung transplantation from a living donor was performed in a 4-year-old boy who suffered from severe respiratory failure caused by bronchiolitis obliterans (BO) as a result of graft versus host disease (GVHD) after peripheral blood stem cell transplantation (PBSCT). The patient grew well during his early childhood years, with an excellent lung allograft function. However, severe thoracic scoliosis occurred 7 years after lung transplantation, which ultimately resulted in compression of the lung allograft followed by severe respiratory dysfunction, and the patient became dependent on mechanical ventilation support. Posterior spinal fusion of Th2-L3 with instrumentation and bone grafting was performed to correct scoliosis in the hope of recovering his thoracic capacity. The left thoracic volume was dramatically improved immediately after spinal fusion surgery, and the patient was ultimately weaned off of mechanical ventilation after a year of pulmonary rehabilitation.

Post-infectious bronchiolitis obliterans in children: Clinical and radiological evaluation and long-term results.

BACKGROUND AND OBJECTIVE: This study aims to evaluate clinical and radiological findings and treatment outcomes of the patients with PIBO. METHODS: One hundred fourteen children were enrolled. Initial demographic and clinical findings were evaluated. Pre- and post-treatment clinical and radiological findings were compared. RESULTS: The median age of the patients at initial pulmonary injury was 7,2 months, the median age at diagnosis was 17.5 months. Persistent wheezing was the most common complaint. Thirty-five patients had mechanical ventilation history. 82,5% of patients had clinical improvement. Bronchiectasis, atelectasis, hyperinflation and air trapping in HRCT improved significantly with treatment. Post-treatment Bhalla scores decreased from 8.3 to 6.5 (p= 0,001). Improvement was observed in radiological and clinical findings after treatment. CONCLUSIONS: This study is one of the largest studies in the literature and one of the few studies that evaluate clinical and radiological outcomes of patients with PIBO.

Overview of lung transplantation.

Although significant gains have been made in improving lung function and survival in cystic fibrosis (CF), ultimately respiratory failure is the leading cause of mortality in these patients. For CF patients with end stage lung disease, lung transplantation is an option for treatment. The field of lung transplantation has progressed markedly in the last 20 years. Nonetheless it remains a technically complex and challenging procedure, and patients are at risk for numerous short term and long term complications. Potential transplant recipients must be physically and psychologically prepared for the arduous process involved in lung transplantation. This article will review the history of lung transplantation, indications for transplantation, surgical techniques, and complications of transplantation.

Pirfenidone: anti-fibrotic agent with a potential therapeutic role in the management of transplantation patients.

Pirfenidone has a simple chemical structure, but may have profound implications for transplantation management. One of the leading causes of allograft failure is chronic allograft dysfunction, manifested by chronic inflammation and chronic fibrosis [Estenne, M., Hertz, M.I., 2002. Bronchiolitis obliterans after human lung transplantation. AJRCCM. 166, 440-444.]. This review summarizes the literature to date on Pirfenidone in the setting of transplantation, and those studies pertinent to the mechanisms of organ rejection and possible use of Pirfenidone in transplantation patients.

The role of bronchial artery revascularization in lung transplantation.

Long-term survival of lung-transplant patients is 53% at 5 years and 31% at 10 years, lagging behind the survival of other solid organs recipients. Modern lung transplantation has seen a shift from early mortality and complications related to the bronchial anastomosis to late mortality secondary to progressive organ dysfunction; the complex disease process may include elements of bronchiolitis obliterans syndrome, obliterative bronchiolitis, chronic rejection, or chronic lung allograft dysfunction. Initial goals of bronchial artery revascularization include reducing the incidence of airway ischemia and improving bronchial healing. Benefits of restored bronchial artery circulation may extend beyond bronchial healing alone.

A case report of living-donor lobar lung transplantation for scleroderma-associated usual interstitial pneumonia: eight years and counting.

INTRODUCTION: Scleroderma-associated interstitial lung disease is a life-limiting complication of scleroderma, often requiring lung transplantation. Living-donor lobar lung transplantation (LDLLT) is a viable alternative to deceased-donor lung transplantation in specialized centers under select circumstances. CLINICAL CASE: A 47-year-old female underwent LDLLT after nine years of symptomatic scleroderma-associated usual interstitial pneumonia and three years awaiting deceased-donor lung transplantation. Her manifestations of scleroderma included mild sclerodactyly, periungual erythema, Raynaud's phenomenon, and gastroesophageal reflux, with positive antinuclear autoantibodies. Several years post-transplantation, manometry revealed feeble lower esophageal sphincteric pressure with ineffective esophageal motility. Bronchiolitis obliterans syndrome developed 64 months post-transplantation without evidence of aspiration or reflux on transbronchial biopsy. Currently, she has normal renal function and good allograft function [FEV1 1.52 L (73% predicted) and FVC 2.50 L (99% predicted)]. RELEVANCE: This is the second reported case of LDLLT in scleroderma, and the first reporting long-term pulmonary, renal, and esophageal function post-transplantation.

Are we near to an effective drug treatment for bronchiolitis obliterans?

Lung transplantation remains the only effective therapeutic option for well-selected patients with end-stage (cardio) pulmonary diseases such as emphysema, cystic fibrosis, lung fibrosis and pulmonary arterial hypertension. Although the results have improved lately, the long-term survival is still far behind other organ transplantations. This is mainly due to the development of chronic lung allograft dysfunction (CLAD), with bronchiolitis obliterans (BO) being the most frequent manifestation and restrictive CLAD or restrictive allograft syndrome (RAS) being a rather novel distinct entity, with a worse survival. Although the pathology of BO has been well described, this is not an obvious diagnosis after lung transplantation, because of the low sensitivity of transbronchial biopsies to detect BO. As a consequence, BO syndrome (BOS), the clinical correlate of BO, characterized by a progressive and obstructive decline in FEV1, has been introduced and is used worldwide to describe patients affected by this condition. BOS is the major long-term problem after lung transplantation, occurring in some 50% of patients within 5 years after the transplant procedure and causing up to 30% of late mortality between 3 and 5 years after transplantation. Its treatment remains very difficult, although recent advances have certainly improved the survival after diagnosis of BOS. We will here review the current therapeutic options to try to prevent BOS on the one hand and to treat BOS on the other hand.

[Clinical characteristics of bronchiolitis obliterans in pediatric patients].

OBJECTIVE: To analyze the clinical characteristics, image findings, laboratory examination, the therapeutic methods and clinical outcomes of bronchiolitis obliterans (BO) in pediatric patients. METHOD: Twenty-six pediatric patients with BO were reported. All data were collected from cases who were hospitalized in the Department of Pediatrics, First Affiliated Hospital of Guangzhou Medical College from June 1(st), 2009 to the April 30(th), 2011, and infectious agents, clinical manifestations, risk factors, changes in imageology, laboratory examination, therapeutic methods and treatment responses were analyzed. RESULT: The ranges of age at onset was 4.5 months-8 years in 26 cases (18 boys and 8 girls). The course of disease was (6.2 ± 3.5) months. The period of followed-up ranged from 2 to 24 months. The common clinical characteristics were persistent wheezing of different severity (26 cases, 100%), cough (24 cases, 92%), intolerance to exercise (22 cases, 85%), short of breath (21 cases, 81%), retraction (20 cases, 77%), wheezy phlegm (16 cases, 62%), keeping with crackles (10 cases, 38%), cyanosis around the mouth (3 cases, 12%) and no clubbed fingers (toes). In 18 cases the etiology was detected, mycoplasma (11 cases, 42%), respiratory syncytial virus (4 cases, 15%), parainfluenza virus (2 cases, 8%), influenza virus A (2 cases, 8%) and influenza virus B (2 cases, 8%), human bocavirus (HBoV) (1 case, 4%). There were 8 cases (31%) with combined infection. Chest X-ray in 10 cases indicated changes suggestive of bronchopneumonia (38%), in only 1 case there was an image of interstitial pneumonia disease (4%). All the patients were diagnosed by high-resolution computerized tomography (HRCT). All cases were demonstrated to have air retention, poor blood perfusion in lung, just like "Westemark sign" with HRCT. In 19 cases antineutrophil cytoplasmic antibody (ANCA) was determined and 10 patients (53%) were positive for P-ANCA, and 8 cases (42%) were positive for C-ANCA. All patients received oral corticosteroid and low doses azithromycin. In 13 cases (50%) the treatment effectively reduced the severity of disease and the frequency of cough and wheezing. The average number of days for symptom improvement was (7.1 ± 4.8) days. CONCLUSION: Respiratory infection plays an important role in BO in children. The chronic and persistent wheezing, cough, intolerance to exercises, short breath, retraction were the main clinical manifestations. But these symptoms are non-specific. Chest X-ray can not provide enough information for diagnosis. Classical "Westemark sign" with HRCT is an important sign. ANCA with a high positive rate (approximately 50%) suppose immuno-lesion in BO. Oral corticosteroid and methotrexate may relieve clinical symptoms.

[Bronchiolitis obliterans after Stevens-Johnson syndrome]. / Bronchiolitis obliterans na stevens-johnsonsyndroom.

BACKGROUND: Bronchiolitis obliterans is a non-reversible lung disease in which the inflammatory process ultimately leads to obstruction of the bronchioles. This condition often occurs after a lung or bone marrow transplantation, and sometimes respiratory tract infection. Clinical presentation is that of persistent and increasing airway obstruction. The gold standard for diagnosis is open lung biopsy. Treatment is symptomatic and aimed at preventing further lung damage. CASE DESCRIPTION: An 8-year-old girl was treated for a suspected pneumonia. Two weeks later she developed Stevens-Johnson syndrome followed by severe dyspnoea. A CT scan of the chest revealed findings consistent with bronchiolitis obliterans. Methylprednisone pulse therapy was ineffective. Due to respiratory insufficiency she underwent a lung transplantation, which to date has been successful. CONCLUSION: Bronchiolitis obliterans after Stevens-Johnson syndrome should be considered in patients with recurrent and progressive respiratory symptoms with typical findings on a CT scan. Lung transplantation is often the only therapeutic option.

Anti-inflammatory and immunomodulatory properties of azithromycin involved in treatment and prevention of chronic lung allograft rejection.

Chronic lung allograft rejection is the single most important cause of death in lung transplant recipients after the first postoperative year, resulting in a 5-year survival rate of approximately 50%, which is far behind that of other solid organ transplantations. Spirometry is routinely used as a clinical marker for assessing pulmonary allograft function and diagnosing chronic lung allograft rejection after lung transplantation (LTx). As such, a progressive obstructive decline in pulmonary allograft function (forced expiratory volume in 1 sec [FEV1]) in absence of all other causes (currently defined as bronchiolitis obliterans syndrome [BOS]) is considered to reflect the evolution of chronic lung allograft rejection. BOS has a 5-year prevalence of approximately 45% and is thought to be the final common endpoint of various alloimmunologic and nonalloimmunologic injuries to the pulmonary allograft, triggering different innate and adaptive immune responses. Most preventive and therapeutic strategies for this complex process have thus far been largely unsuccessful. However, the introduction of the neomacrolide antibiotic azithromycin (AZI) in the field of LTx as of 2003 made it clear that some patients with established BOS might in fact benefit from such therapy due to its various antiinflammatory and immunomodulatory properties, as summarized in this review. Particularly in patients with an increased bronchoalveolar lavage neutrophilia (i.e., 15%-20% or more), AZI treatment could result in an increase in FEV1 of at least 10%. More recently, it has become clear that prophylactic therapy with AZI actually may prevent BOS and improve FEV1 after LTx, most likely through its interactions with the innate immune system. However, one should always be aware of possible adverse effects related to AZI when implementing this drug as prophylactic or long-term treatment. Even so, AZI therapy after LTx can generally be considered as safe.

Irritant-induced airway disorders.

Thousands of persons experience accidental high-level irritant exposures each year but most recover and few die. Irritants function differently than allergens because their actions proceed nonspecifically and by nonimmunologic mechanisms. For some individuals, the consequence of a single massive exposure to an irritant, gas, vapor or fume is persistent airway hyperresponsiveness and the clinical picture of asthma, referred to as reactive airways dysfunction syndrome (RADS). Repeated irritant exposures may lead to chronic cough and continual airway hyperresponsiveness. Cases of asthma attributed to repeated irritant-exposures may be the result of genetic and/or host factors.

[Complications of lung transplantation]. / Complications de la transplantation pulmonaire: complications médicales.

In 2009 lung transplantation is a valuable therapeutic option for a number of patients suffering from end-stage pulmonary diseases. Lung transplantation frequently offers a major improvement in quality of life; however, long-term survival is often limited by the development of the bronchiolitis obliterans syndrome, which is the equivalent of a chronic pulmonary graft rejection. As the bronchiolitis obliterans syndrome is the commonest cause of death in the medium- and long-terms, all patients receive intense immunosuppressive treatment in order to prevent or stabilize this complication. This treatment induces a number of potentially severe complications including metabolic complications, infections and malignancies. The most frequent metabolic complications are arterial hypertension, chronic renal insufficiency, hyperlipidaemia, diabetes and osteoporosis. Bacterial, viral and fungal infections are the second commonest cause of mortality. They are to be considered as medical emergencies and require urgent assessment and targeted therapy after microbiological specimens have been obtained. They should not under any circumstances be treated empirically and it should also be kept in mind that the lung transplant recipient may present several concomitant infections. The most frequent malignancies are post-transplant lymphoproliferative disorders, cutaneous neoplasias, Kaposi's sarcoma, some peculiar types of head and neck neoplasia, bronchogenic carcinomas and cancers of the digestive tract. The respiratory physician should recognize the symptoms and signs of specific complications induced by the immunosuppressive regimen and the goal of this report is to give a general overview of the most frequently encountered complications. Their assessment and treatment, though, will most often require the input of other specialists and a multidisciplinary approach.

Lung transplantation, gastroesophageal reflux, and fundoplication.

Lung transplantation is an accepted treatment strategy for end-stage lung disease; however, bronchiolitis obliterans syndrome is a major cause of morbidity and mortality. This review explores the role of gastroesophageal reflux disease in bronchiolitis obliterans syndrome and the evidence suggesting the benefits of anti-reflux surgery in improving lung function and survival. There is a high prevalence of gastroesophageal reflux in patients post lung transplantation. This may be due to a high preoperative incidence, vagal damage and immunosuppression. Reflux in these patients is associated with a worse outcome, which may be due to micro-aspiration. Anti-reflux surgery is safe in selected lung transplant recipients; however there has been one report of a postoperative mortality. Evidence is conflicting but may suggest a benefit for patients undergoing anti-reflux surgery in terms of lung function and survival; there are no controlled studies. The precise indications, timing, and choice of fundoplication are yet to be defined, and further studies are required.