Timothy Whelan

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

Management of the Potential Organ Donor in the ICU: Society of Critical Care Medicine/American College of Chest Physicians/Association of Organ Procurement Organizations Consensus Statement

This document was developed through the collaborative efforts of the Society of Critical Care Medicine, the American College of Chest Physicians, and the Association of Organ Procurement Organizations. Under the auspices of these societies, a multidisciplinary, multi-institutional task force was convened, incorporating expertise in critical care medicine, organ donor management, and transplantation. Members of the task force were divided into 13 subcommittees, each focused on one of the following general or organ-specific areas: death determination using neurologic criteria, donation after circulatory death determination, authorization process, general contraindications to donation, hemodynamic management, endocrine dysfunction and hormone replacement therapy, pediatric donor management, cardiac donation, lung donation, liver donation, kidney donation, small bowel donation, and pancreas donation. Subcommittees were charged with generating a series of management-related questions related to their topic. For each question, subcommittees provided a summary of relevant literature and specific recommendations. The specific recommendations were approved by all members of the task force and then assembled into a complete document. Because the available literature was overwhelmingly comprised of observational studies and case series, representing low-quality evidence, a decision was made that the document would assume the form of a consensus statement rather than a formally graded guideline. The goal of this document is to provide critical care practitioners with essential information and practical recommendations related to management of the potential organ donor, based on the available literature and expert consensus.

Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial

BACKGROUND Lysyl oxidase-like 2 (LOXL2) catalyses collagen cross-linking and is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the efficacy and safety of simtuzumab, a monoclonal antibody against LOXL2, in patients with IPF. METHODS In this randomised, double-blind, phase 2 trial, we recruited patients aged 45-85 years with definite IPF diagnosed prior to 3 years of screening from 183 hospitals and respiratory clinics in 14 countries. Eligible patients, stratified by baseline forced vital capacity (FVC), serum LOXL2 (sLOXL2) concentrations, and pirfenidone and nintedanib use, were randomly assigned (1:1) to inject 125 mg/mL simtuzumab or placebo subcutaneously once a week. The primary endpoints were progression-free survival, defined as time to all-cause death or a categorical decrease from baseline in FVC % predicted, in the intention-to-treat population, in patients with sLOXL2 concentrations in the 50th percentile or higher, and in patients with sLOXL2 concentrations in the 75th percentile or higher. Treatment duration was event-driven, and interim analyses were planned and conducted after approximately 120 and 200 progression-free survival events, respectively, occurred. We compared treatment groups with the stratified log-rank test. This study is registered with ClinicalTrials.gov, number NCT01769196. FINDINGS Patients with IPF were recruited between Jan 31, 2013, and June 1, 2015. The intention-to-treat population included 544 randomly assigned patients (272 patients in both groups), and the safety population included 543 randomly assigned patients who received at least one dose of study medication. The study was terminated when the second interim analysis met the prespecified futility stopping criteria in the intention-to-treat population. We noted no difference in progression-free survival between simtuzumab and placebo in the intention-to-treat population (median progression free survival times of 12·6 months and 15·4 months for simtuzumab and placebo, respectively; stratified HR 1·13, 95% CI 0·88-1·45; p=0·329) and in patients with baseline sLOXL2 in the 50th percentile or higher (median progression-free survival 11·7 months and 14·3 months for simtuzumab and placebo, respectively; stratified HR 1·03, 95% CI 0·74-1·43; p=0·851), or in the 75th percentile or higher (median progression-free survival 11·6 months and 16·9 months for simtuzumab and placebo, respectively; stratified HR 1·20, 95% CI 0·72-2·00; p=0·475). The incidence of adverse events and serious adverse events was similar between treatment groups. The most common adverse events in both the simtuzumab and placebo groups were dyspnoea, cough, upper respiratory tract infection, and worsening of IPF; and the most common grade 3 or 4 adverse events were worsening of IPF, dyspnoea, and pneumonia. INTERPRETATION Simtuzumab did not improve progression-free survival in a well-defined population of patients with IPF. Our data do not support the use of simtuzumab for patients with IPF. FUNDING Gilead Sciences Inc.

Monitoring of Nonsteroidal Immunosuppressive Drugs in Patients With Lung Disease and Lung Transplant Recipients: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

OBJECTIVES Immunosuppressive pharmacologic agents prescribed to patients with diffuse interstitial and inflammatory lung disease and lung transplant recipients are associated with potential risks for adverse reactions. Strategies for minimizing such risks include administering these drugs according to established, safe protocols; monitoring to detect manifestations of toxicity; and patient education. Hence, an evidence-based guideline for physicians can improve safety and optimize the likelihood of a successful outcome. To maximize the likelihood that these agents will be used safely, the American College of Chest Physicians established a committee to examine the clinical evidence for the administration and monitoring of immunosuppressive drugs (with the exception of corticosteroids) to identify associated toxicities associated with each drug and appropriate protocols for monitoring these agents. METHODS Committee members developed and refined a series of questions about toxicities of immunosuppressives and current approaches to administration and monitoring. A systematic review was carried out by the American College of Chest Physicians. Committee members were supplied with this information and created this evidence-based guideline. CONCLUSIONS It is hoped that these guidelines will improve patient safety when immunosuppressive drugs are given to lung transplant recipients and to patients with diffuse interstitial lung disease.

ISHLT Consensus ReportsPrimary Lung Graft DysfunctionReport of the ISHLT Working Group on Primary Lung Graft Dysfunction, part I: Definition and grading—A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation

From the Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Melbourne, Victoria, Australia; Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Institute for Advanced Organ Disease and Transplantation, Tampa General Hospital/University of South Florida, Tampa, Florida; Department of Surgery, Michigan State University, Ada, Michigan; Lung Transplant Program, University of Chicago, Chicago, Illinois; Lung Transplant Program, Harefield Hospital, Harefield, United Kingdom; Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Gainesville, Florida; Division of Pulmonary Medicine, Medical University of South Carolina, Charleston, South Carolina; Section of Lung Transplantation, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Section of Pulmonary and Critical Care, Department of Medicine, and Lung Transplant Program, University of Chicago, Chicago, Illinois; Department of Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio; National Pulmonary Hypertension Service (Newcastle), The Newcastle upon Tyne Hospitals NHS Foundation Trust, and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and the Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.

Cognitive function in idiopathic pulmonary fibrosis

The purpose of this study was to investigate whether there is evidence that individuals with severe idiopathic pulmonary fibrosis (IPF) have cognitive deficits when compared to individuals with healthy lungs. Participants completed five neuropsychological tests: Trail Making Test (TMT) A and B, Stroop Color Word Test (1, 2, 3), Hopkins Verbal Learning Test, Boston Naming Test, and Grooved Pegboard Test, additionally, the short form-36 and Beck Depression Index. Twelve participants (7 male, mean age 69.3, 9.4 years) comprised the severe IPF group defined by a diffusion capacity for carbon monoxide (DLCO) <30%. Thirty-four patients (22 male, mean age 63.2, 9.6 years) comprised the mild-to-moderate group with a DLCO >30%. Participating spouses (n = 15, 4 male) served as the control group and had a mean age of 66.0, 10.8 years. Controlling for gender and age, the severe group had a significantly longer mean TMT B time (69.4, 135.9 seconds) than the mild group and the control group (86.7 seconds vs 83.2 seconds; p = 0.004 and 0.008 respectively), suggesting inferior performance on tasks requiring speed divided attention. In addition, the severe group had a significantly lower number of correctly identified colors in the Stroop 3 test (22.4 vs 30.6 vs 38.6; p < 0.001), suggesting slower processing speeds when requiring suppression of a familiar response. Participants with severe IPF had worse cognitive function than mild IPF or control subjects. Further research is needed to explain these findings and to develop interventions tailored to address these deficits.

Lung Transplantation for Interstitial Lung Disease

For selected parenchymal lung disease patients who fail to respond to medical therapy and demonstrate declines in function that place them at increased risk for mortality, lung transplantation should be considered. Lung transplantation remains a complex medical intervention that requires a dedicated recipient and medical team. Despite the challenges, lung transplantation affords appropriate patients a reasonable chance at increased survival and improved quality of life. Lung transplantation remains an appropriate therapeutic option for selected patients with parenchymal lung disease.

Lung transplantation for interstitial lung disease

There have been over 120 diffuse parenchymal lung diseases (DPLD) identified, and these diseases have similar clinical and pathological findings. These diseases are associated with autoimmune disorders, environmental or drug exposures, or are idiopathic in nature. Unfortunately, many of these diseases have limited effective therapies and may require lung transplantation for ongoing survival. Because of changes that have been made in lung allocation, lung transplantation in patients with DPLD is becoming more common. For successful lung transplantation, the DPLD patient requires optimized global medical management. Once transplanted, patients typically have a change in their lifestyle that requires multiple medications, dedication to lifelong exercise, and chronic medical management; however, they also garner a survival benefit and significant improvement in quality of life. Part of the transplant process is to inform patients fully of the risks, costs, and benefits associated with the procedure. It is imperative that patients are evaluated early so that a relationship between transplant centers and patients can be established.

Lung Donation After Death Resulting From a Stanford Type A Aortic Dissection

The number of lung transplantations performed in the United States has increased at a modest pace over the past decades and reached an all-time high of 2,052 in 2015. However, the transplant wait list mortality remains unacceptably high with approximately one in five patients removed from the list because of death or being too sick for transplantation. The greatest limitation to performing lung transplantations is the relative lack of acceptable lung donors. Here we report the use of lungs from a donor who died as the result of adverse events related to a Stanford type A aortic dissection.

Pulmonary capillaritis in a patient with moderately positive anti‐PL‐12 antibodies

Dear Editor, Anti-PL-12 antibodies belong to a group of auto-antibodies directed against aminoacyl-tRNA synthetases. Also known as antisynthetase antibodies, they are associated with the antisynthetase syndrome (AS). AS is an autoimmune disorder characterized by the presence of myositis (dermatomyositis or polymyositis), arthritis, interstitial lung disease (ILD), fever, Raynaud’s phenomenon and ‘mechanic’s hands’ (scaly, fissured and hyperkeratotic erythema present on the lateral and palmar surfaces of hands and fingers). Unlike other autoimmune disorders, there are no set or established diagnostic criteria. Almost 90% of patients with AS have ILD; ILD can precede the appearance of other features by years. We describe a patient who presented with acute dyspnea and was found to have anti-PL-12 antisynthetase antibodies. Video-assisted thoracoscopic surgery (VATS) lung biopsy showed diffuse alveolar hemorrhages with accompanied widespread capillaritis. A previously healthy 32-year-old woman was admitted to an outside hospital with worsening shortness of breath. Her family history was negative for any connective tissue diseases. She worked as a data entry technician and had lived in the southern states of South Carolina and Georgia within the United States. Her physical examination was significant for oxygen desaturation with exertion and bilateral, basilar crackles. Otherwise, her skin, joints and remainder of her examination were unremarkable. A frontal and lateral chest radiograph and contrastenhanced computed tomography scan was performed (Fig. 1). The patient’s pulmonary function tests showed severe restriction. Her erythrocyte sedimentation rate was 54 mm/h. Anti-nuclear antibody, anti-smith, anti-ribonucleoprotein, anti-SSA (Sj€ ogren’s syndrome antigen A) Ro, anti-SSB La, anti-cardiolipin, beta-2-glycoprotein and scleroderma antibodies were all negative. The anti-neutrophil cytoplasmic antibody against myeloperoxidase (p-ANCA) and proteinase 3 (c-ANCA) were negative. Complement, creatine kinase and aldolase were normal. A myositis antibody panel was moderately positive for PL-12 antibodies (Mayo Medical Laboratories, Rochester, MN, USA). She underwent VATS right upper and lower lobe wedge biopsies (Fig. 2). The patient was started on prednisone. No cyclophosphamide was given. Her activities remained limited by dyspnea on exertion. She was discharged home on oxygen and prednisone and seen in our clinic 4 months after the initial presentation for a second opinion. She was initiated on rituximab infusion therapy 375 mg/m once weekly for 4 weeks in combination with intravenous methylprednisolone for 3 days and subsequent steroid taper. Mycophenolate was added as a steroid sparing agent and for maintenance immunosupression. Followup at 8 months since her initial presentation showed dramatic improvement in her dyspnea as well as a 20% and 40% improvement in her forced vital capacity and diffusing capacity for carbonmonoxide, respectively. Anti-PL-12 antibodies are less common than anti-Jo-1 and anti-PL-7. Anti-PL-12 antibodies are directed against alanyl-tRNA synthetase, one of eight aminoacyl-transfer RNA synthetases identified in AS. These enzymes catalyze the formation of an aminoacyl-tRNA complex during the translation phase of protein synthesis. The median age at presentation is around 50 to 60 years, but ranges from 22 to 87 years as described in