Long-term evaluation of the safety and efficacy of recombinant human pentraxin-2 (rhPTX-2) in patients with idiopathic pulmonary fibrosis (IPF): an open-label extension study.

BACKGROUND: Recombinant human pentraxin-2 (rhPTX-2) significantly decreased decline in percent predicted forced vital capacity (FVC) and stabilized 6-min walk distance (6MWD) in patients with idiopathic pulmonary fibrosis (IPF) during the 28-week, placebo-controlled, randomized period of the Phase II PRM-151-202 study. Interim (76-week) data from the open-label extension (OLE) demonstrated sustained safety and efficacy with rhPTX-2 treatment. Here, we present the entire long-term OLE safety and efficacy data to 128 weeks. METHODS: Patients who completed the randomized PRM-151-202 study period were eligible for the OLE, during which all patients received rhPTX-2, having started rhPTX-2 (i.e., crossed from placebo) or continued rhPTX-2 after Week 28. rhPTX-2 was administered in 28-week cycles, with 10 mg/kg intravenous infusions (60 min) on Days 1, 3, and 5 in the first week of each cycle, then one infusion every 4 weeks up to Week 128. The OLE primary objective was to assess the long-term safety and tolerability of rhPTX-2. Other outcomes included FVC, 6MWD, and patient-reported outcomes (descriptive analysis). RESULTS: All 111 patients who completed the randomized period entered the OLE (n = 37 started rhPTX-2; n = 74 continued rhPTX-2); 57 (51.4%) completed to Week 128. The treatment-emergent adverse event (TEAE) profile was consistent with the randomized period, with the majority of TEAEs graded mild or moderate. Serious TEAEs occurred in 47 patients (42.3%), most frequently IPF (n = 11; 9.9%), pneumonia (n = 7; 6.3%), and acute respiratory failure (n = 3; 2.7%). Three patients underwent lung transplantation. Most serious TEAEs (and all 14 fatal events) were considered unrelated to rhPTX-2 treatment. For patients starting vs continuing rhPTX-2, mean (95% confidence interval) changes from baseline to Week 128 were, respectively, - 6.2% (- 7.7; - 4.6) and - 5.7% (- 8.0; - 3.3) for percent predicted FVC and - 36.3 m (- 65.8; - 6.9) and - 28.9 m (- 54.3; - 3.6) for 6MWD; however, conclusions were limited by patient numbers at Week 128. CONCLUSIONS: Long-term treatment (up to 128 weeks) with rhPTX-2 was well tolerated in patients with IPF, with no new safety signals emerging in the OLE. The limited efficacy data over 128 weeks may suggest a trend towards a treatment effect. Trial registration NCT02550873; EudraCT 2014-004782-24.

Human Serum Albumin Misfolding in Aging and Disease.

Age-dependent conformational stability of human serum albumin was determined by the method of fluorescent bilayer liposome assay. After pre-heating at 80 °C, albumin in the sera of 74-year-old healthy subjects exhibited hydrophobic effects on liposomes and made liposomal membrane phospholipids more susceptible to hydrolysis by the lipolytic enzyme phospholipase A2. In contrast, albumin in the sera of 24-year-old individuals was stable at 80 °C and displayed no increased hydrophobic effects on liposomes. The results suggest that albumin in the sera of 74-year-old subjects is more easily converted to a misfolded form in which its protein structure is altered when compared to albumin in the sera of 24-year-old individuals. Misfolded albumin can lose its ability to carry out its normal homeostatic functions and may promote alterations in membrane integrity under inflammatory conditions. However, our investigation has limitations that include the lack of testing sera from large numbers of individuals across a broad range of age to validate our preliminary observations of age-dependent differences in albumin stability and its interactions with liposomes.

Lung disease associated with occupational styrene exposure.

Despite reports of pulmonary toxicity due to styrene, guidelines on acceptable styrene exposure levels have been based on risk of cancer and central nervous system and liver toxicity and not on respiratory effects. Many reports have linked exposure to styrene vapor in occupational settings to various forms of non-malignant pulmonary disorders including bronchiolitis, hypersensitivity pneumonitis, and occupational asthma. We report two cases in which the same tasks performed in a single workplace resulted in exposure to styrene vapor with subsequent development of acute respiratory symptoms associated with impaired gas exchange and imaging and histopathologic findings consistent with bronchiolitis and organizing pneumonia. Both patients gradually recovered once their workplace exposure to styrene was terminated. Clinicians, employers, and insurers should be aware of the potential for pulmonary toxicity from exposure to styrene.

Effect of Recombinant Human Pentraxin 2 vs Placebo on Change in Forced Vital Capacity in Patients With Idiopathic Pulmonary Fibrosis: A Randomized Clinical Trial.

Importance: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Approved therapies do not halt disease progression. Objective: To determine the effect of recombinant human pentraxin 2 vs placebo on change from baseline to week 28 in mean forced vital capacity (FVC) percentage of predicted value. Design, Setting, and Participants: Phase 2, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 7 countries of eligible patients with IPF (N = 117; aged 40-80 years; FVC ≥50% and ≤90% predicted; ratio of forced expiratory volume in the first second/FVC >0.70; diffusing capacity for carbon monoxide [Dlco] ≥25% and ≤90% predicted; and distance of ≥150 m on the 6-minute walk test). Study period was August 2015-May 2017. Interventions: Patients were randomized to receive either recombinant human pentraxin 2 (10 mg/kg intravenous every 4 weeks, n = 77) or placebo (n = 39) for 24 weeks, and stratified by concurrent IPF treatment status. Main Outcomes and Measures: The primary end point was the least-squares mean change in FVC percentage of predicted value from baseline to week 28 (minimal clinically important difference, decline of 2%-6%). Secondary end points included mean change in lung volumes (total, normal, and interstitial lung abnormalities) on high-resolution computed tomography (HRCT) and 6-minute walk distance (minimal clinically important difference, 24-45 m). Results: Of 117 randomized patients, 116 received at least 1 dose of study drug (mean age, 68.6 years; 81.0% men; mean time since IPF diagnosis, 3.8 years), and 111 (95.7%) completed the study. The least-squares mean change in FVC percentage of predicted value from baseline to week 28 in patients treated with recombinant human pentraxin 2 was -2.5 vs -4.8 for those in the placebo group (difference, +2.3 [90% CI, 1.1 to 3.5]; P = .001). No significant treatment differences were observed in total lung volume (difference, 93.5 mL [90% CI, -27.7 to 214.7]), quantitative parenchymal features on HRCT (normal lung volume difference, -1.2% [90% CI, -4.4 to 1.9]; interstitial lung abnormalities difference, 1.1% [90% CI, -2.2 to 4.3]), or measurement of Dlco (difference, -0.4 [90% CI, -2.6 to 1.7]). The change in 6-minute walk distance was -0.5 m for patients treated with recombinant human pentraxin 2 vs -31.8 m for those in the placebo group (difference, +31.3 m [90% CI, 17.4 to 45.1]; P < .001). The most common adverse events in the recombinant human pentraxin 2 vs placebo group were cough (18% vs 5%), fatigue (17% vs 10%), and nasopharyngitis (16% vs 23%). Conclusions and Relevance: In this preliminary study, recombinant human pentraxin 2 vs placebo resulted in a slower decline in lung function over 28 weeks for patients with idiopathic pulmonary fibrosis. Further research should more fully assess efficacy and safety. Trial Registration: clinicaltrials.gov Identifier: NCT02550873.

The presence or severity of pulmonary hypertension does not affect outcomes for single-lung transplantation.

Advanced lung disease (ALD) that requires lung transplantation (LTX) is frequently associated with pulmonary hypertension (PH). Whether the presence of PH significantly affects the outcomes following single-lung transplantation (SLT) remains controversial. Therefore, we retrospectively examined the outcomes of 279 consecutive SLT recipients transplanted at our centre, and the patients were split into four groups based on their mean pulmonary artery pressure values. Outcomes, including long-term survival and primary graft dysfunction, did not differ significantly for patients with versus without PH, even when PH was severe. We suggest that SLT can be performed safely in patients with ALD-associated PH.

Dysregulation of galectin-3. Implications for Hermansky-Pudlak syndrome pulmonary fibrosis.

The etiology of Hermansky-Pudlak syndrome (HPS) pulmonary fibrosis (HPSPF), a progressive interstitial lung disease with high mortality, is unknown. Galectin-3 is a ß-galactoside-binding lectin with profibrotic effects. The objective of this study was to investigate the involvement of galectin-3 in HPSPF. Galectin-3 was measured by ELISA, immunohistochemistry, and immunoblotting in human specimens from subjects with HPS and control subjects. Mechanisms of galectin-3 accumulation were studied by quantitative RT-PCR, Northern blot analysis, membrane biotinylation assays, and rescue of HPS1-deficient cells by transfection. Bronchoalveolar lavage galectin-3 concentrations were significantly higher in HPSPF compared with idiopathic pulmonary fibrosis or that from normal volunteers, and correlated with disease severity. Galectin-3 immunostaining was increased in HPSPF compared with idiopathic pulmonary fibrosis or normal lung tissue. Fibroblasts from subjects with HPS subtypes associated with pulmonary fibrosis had increased galectin-3 protein expression compared with cells from nonfibrotic HPS subtypes. Galectin-3 protein accumulation was associated with reduced Galectin-3 mRNA, normal Mucin 1 levels, and up-regulated microRNA-322 in HPSPF cells. Membrane biotinylation assays showed reduced galectin-3 and normal Mucin 1 expression at the plasma membrane in HPSPF cells compared with control cells, which suggests that galectin-3 is mistrafficked in these cells. Reconstitution of HPS1 cDNA into HPS1-deficient cells normalized galectin-3 protein and mRNA levels, as well as corrected galectin-3 trafficking to the membrane. Intracellular galectin-3 levels are regulated by HPS1 protein. Abnormal accumulation of galectin-3 may contribute to the pathogenesis of HPSPF.

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.

IPF clinical trial design and endpoints.

PURPOSE OF REVIEW: There remains a dire need for therapies that impact the clinical course of patients with idiopathic pulmonary fibrosis (IPF). Indeed, there is a surge of interest in IPF therapeutics, with many candidate agents in various stages of development. Optimal design and implementation of the appropriate prospective clinical trials are essential to demonstrate clinical efficacy of promising drugs for the treatment of IPF. A key element in the success of such clinical trials is the choice of the best endpoint(s) to match the design of the study. RECENT FINDINGS: Although the results of many IPF clinical trials have been disappointing, these trials have provided valuable insights into the epidemiology and natural history of the disease and have sparked debate into the best clinical trial designs and endpoints. SUMMARY: This review will discuss the various clinical trial endpoints that have been used or proposed with a focus on their potential utility, as well as possible pitfalls that investigators should consider in the design of such studies. VIDEO ABSTRACT: http://links.lww.com/COPM/A13.

An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease.

BACKGROUND: The clinical utility of bronchoalveolar lavage fluid (BAL) cell analysis for the diagnosis and management of patients with interstitial lung disease (ILD) has been a subject of debate and controversy. The American Thoracic Society (ATS) sponsored a committee of international experts to examine all relevant literature on BAL in ILD and provide recommendations concerning the use of BAL in the diagnosis and management of patients with suspected ILD. PURPOSE: To provide recommendations for (1) the performance and processing of BAL and (2) the interpretation of BAL nucleated immune cell patterns and other BAL characteristics in patients with suspected ILD. METHODS: A pragmatic systematic review was performed to identify unique citations related to BAL in patients with ILD that were published between 1970 and 2006. The search was updated during the guideline development process to include published literature through March 2011. This is the evidence upon which the committee's conclusions and recommendations are based. RESULTS: Recommendations for the performance and processing of BAL, as well as the interpretation of BAL findings, were formulated by the committee. CONCLUSIONS: When used in conjunction with comprehensive clinical information and adequate thoracic imaging such as high-resolution computed tomography of the thorax, BAL cell patterns and other characteristics frequently provide useful information for the diagnostic evaluation of patients with suspected ILD.

Management of interstitial lung disease in elderly patients.

PURPOSE OF REVIEW: This review seeks to inform readers of evolving concepts of ageing-associated risks for developing interstitial lung disease (ILD) and current approaches to the diagnosis and management of ILD in elderly patients. RECENT FINDINGS: Various aspects of cellular and immune senescence have been identified that may explain the increased susceptibility of the elderly to developing fibrotic lung disease. New guidelines have been recently published concerning the diagnosis and management of idiopathic pulmonary fibrosis (IPF), which is highly prevalent in elderly patients. Nontransplant therapies that can have a significant impact on disease progression for patients with IPF have yet to be identified. Additionally, evidence is accumulating that abnormal gastroesophageal reflux and microaspiration may play a role in IPF pathogenesis. SUMMARY: High-resolution computed tomographic scanning of the thorax can play a key role in making a specific ILD diagnosis and be used to make a confident diagnosis of various forms of ILD, especially IPF, when combined with a consistent clinical presentation. Management of ILD in the elderly should be not only disease specific but potentially therapeutic, and supportive interventions should be tailored to each individual patient and not entail significant risk of adverse complications, especially for the frail elderly patient.

Neutrophil necrosis and annexin 1 degradation associated with airway inflammation in lung transplant recipients with cystic fibrosis.

BACKGROUND: Neutrophils sequestered in lower respiratory tract secretions in the inflamed lung may undergo apoptosis and/or necrosis and release toxic cellular contents that can injure airways or parenchyma. This study examined the viability of neutrophils retrieved from the proximal airways of lung transplant recipients with bacterial tracheobronchitis. METHODS: Integrity and stability of intracellular proteins in neutrophils from proximal airways and peripheral blood from lung transplant recipients with bacterial tracheobronchitis were analyzed via Western blot analysis and determination of neutrophil viability by morphologic appearance and flow cytometry. RESULTS: Neutrophils in tracheobronchial secretions from lung transplant recipients with cystic fibrosis who had normal chest radiographic imaging but bronchoscopic evidence of purulent tracheobronchitis post-transplant were necrotic and associated with degradation of intracellular protein annexin 1. The neutrophil influx was compartmentalized to large airways and not detected in peripheral bronchoalveolar airspaces sampled via bronchoalveolar lavage. Peripheral blood neutrophils from healthy subjects cultured in vitro demonstrated that annexin 1 degradation, particularly to a 33 kDa annexin 1 breakdown product (A1-BP), was associated with neutrophil necrosis, but not apoptosis. Although annexin 1 degradation was not specific to neutrophil necrosis, it was a sensitive marker of intracellular protein degradation associated with neutrophil necrosis. Annexin 1 degradation to 33 kDa A1-BP was not observed in peripheral blood neutrophils from healthy subjects, but annexin 1 appeared to be degraded in peripheral blood neutrophils of lung transplant recipients despite a normal morphologic appearance of these cells. CONCLUSIONS: Neutrophils were necrotic from the proximal airways of lung transplant recipients with bacterial tracheobronchitis, and this process may begin when neutrophils are still in the systemic circulation prior to sequestration in inflamed airways. Annexin 1 degradation to 33 kDa A1-BP may be useful as a sensitive marker to detect neutrophil necrosis.

Cryptogenic organising pneumonia: current understanding of an enigmatic lung disease.

Organising pneumonia (OP) is currently recognised as a nonspecific lung injury response that is associated with a variety of imaging patterns obtained with high-resolution computed tomography (HRCT) of the chest and is characterised histopathologically by the presence of inflammatory cells and a connective tissue matrix within distal airspaces of the lungs. OP is associated with many conditions that include connective tissue disorders, various infections, drug reactions, hypersensitivity pneumonitis and aspiration. When OP cannot be linked to an associated condition and appears to be idiopathic, it is termed cryptogenic organising pneumonia.

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part I: Epidemiology, assessment of extrapulmonary conditions, candidate evaluation, selection criteria, and pathology statements.

Patients with connective tissue disease (CTD) and advanced lung disease are often considered suboptimal candidates for lung transplantation (LTx) due to their underlying medical complexity and potential surgical risk. There is substantial variability across LTx centers regarding the evaluation and listing of these patients. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization aims to clarify definitions of each disease state included under the term CTD, to describe the extrapulmonary manifestations of each disease requiring consideration before transplantation, and to outline the absolute contraindications to transplantation allowing risk stratification during the evaluation and selection of candidates for LTx.

IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants.

Bronchiolitis obliterans syndrome (BOS), a process of fibro-obliterative occlusion of the small airways in the transplanted lung, is the most common cause of lung transplant failure. We tested the role of cell-mediated immunity to collagen type V [col(V)] in this process. PBMC responses to col(II) and col(V) were monitored prospectively over a 7-year period. PBMCs from lung transplant recipients, but not from healthy controls or col(IV)-reactive Goodpasture's syndrome patients after renal transplant, were frequently col(V) reactive. Col(V)-specific responses were dependent on both CD4+ T cells and monocytes and required both IL-17 and the monokines TNF-alpha and IL-1beta. Strong col(V)-specific responses were associated with substantially increased incidence and severity of BOS. Incidences of acute rejection, HLA-DR mismatched transplants, and induction of HLA-specific antibodies in the transplant recipient were not as strongly associated with a risk of BOS. These data suggest that while alloimmunity initiates lung transplant rejection, de novo autoimmunity mediated by col(V)-specific Th17 cells and monocyte/macrophage accessory cells ultimately causes progressive airway obliteration.

The role of immunity and inflammation in lung senescence and susceptibility to infection in the elderly.

Advancing age is associated with a decline in the integrity of physical barriers and protection against invading pathogens, and age-related changes in the immune system are associated with increased susceptibility to the emergence of autoimmune phenomena, neoplasia, and infections. Respiratory tract infections can occur at any age, but the incidence of lower respiratory tract infections increases significantly with advanced age such that pneumonia is a leading cause of illness and death in the elderly. Changes in lung physiology and immune function coupled with inflammation induced by environmental exposures or endogenous factors such as predisposition to aspiration may, in part, account for the increase in susceptibility to respiratory infections. Additionally, age-associated alterations in immune regulation ("immunosenescence") with dysregulation of lung homeostasis may allow low-grade inflammatory changes that lead to anatomical and physiological changes that characterize the senescent lung. The presence of disease states in elderly populations, such as chronic obstructive pulmonary disease (COPD) or nonpulmonary organ system diseases, may increase the likelihood of developing severe respiratory infections. This article examines age-related changes in immune function that predispose elderly individuals to lung remodeling but focuses especially on lower respiratory tract infections. It will discuss risk factors, identify pathogens that typically lead to respiratory infections in the elderly, and review current approaches to treatment and prevention of respiratory infections in the elderly population.

Lung transplantation for advanced bronchiectasis.

Lung transplant (LT) can be successfully performed on patients with advanced bronchiectatic lung disease with subsequent good posttransplant quality of life and long-term outcome. Most of the data are derived from patients with cystic fibrosis (CF), but LT can be effective in patients with non-CF bronchiectasis as well. Despite the presence of chronic lower respiratory tract infection with bacterial pathogens in these patients pretransplant, posttransplant infections do not generally have significant impact on survival, although infection with antibiotic-resistant bacteria may complicate posttransplant management. Although benefit of LT for young children with CF is somewhat controversial, LT can clearly benefit older children and adults with advanced lung disease due to bronchiectasis. This article reviews indications (and contraindications) for LT, discusses particular problems that may arise posttransplant, and provides a rationale for referring patients with bronchiectasis for LT.

Aging-Related and Gender Specific Albumin Misfolding in Alzheimer's Disease.

Aging-related protein misfolding and aggregation may play critical roles in the pathogenesis of numerous diseases. In the brain, extracellular aggregated amyloid-ß (Aß) is closely related to the death of neurons in individuals with Alzheimer's disease (AD). Albumin-Aß binding is important in preventing Aß fibril aggregation. However, because albumin is the most abundant and important antioxidant in the circulation, aging-related oxidative stress could have a significant effect on the molecular conformation and binding capacities of albumin. To investigate the link between misfolded albumin and AD, we developed fluorescent assays to determine the effects of misfolded albumin on membrane integrity in the presence of a lipolytic, inflammatory response-like enzyme, secretory phospholipase A2 (sPLA2). We found that misfolded albumin increased degradation of phospholipids in highly fluid bilayer membranes in the presence of sPLA2 due to hydrophobic effects of misfolded albumin. High amounts of misfolded albumin were present in sera of elderly (average 74 years) versus young (average 24 years) subjects (p < 0.0001). Albumin in cerebrospinal fluid (CSF) of elderly subjects, though present in small concentrations, had a 2- to 3-fold increased capacity to promote sPLA2-catalyzed membrane phospholipid degradation as compared with the same amount of albumin in serum (p < 0.0001). In addition, the fatty acid binding capacity of albumin in CSF from female subjects was considerably lower than values obtained for men, especially for individuals diagnosed with AD (p = 0.0006). This study suggests that inflammation, misfolded albumin and/or other dysfunctional proteins, and changes in membrane fluidity could alter cell membrane integrity and homeostasis and contribute to the pathogenesis of aging-related dementia and AD.

Treatment of primary sjögren's syndrome-related interstitial lung disease: a retrospective cohort study.

BACKGROUND: Interstitial lung disease (ILD) is a common complication of primary Sjögren's syndrome (pSS). Because there is a paucity of literature on the management of pSS-associated ILD (pSS-ILD), this retrospective cohort study assessed the efficacy of azathioprine and mycophenolate therapy in adult patients with pSS-ILD. METHODS: A retrospective cohort study was performed using electronic health records to identify adults meeting the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for pSS. The presence of pSS-ILD was confirmed by characteristic high-resolution computed tomography and/or histopathology findings. Sociodemographic, clinical, and pulmonary function test (PFT) data were abstracted for patients meeting the criteria and followed longitudinally from the date of their ILD diagnosis. PFT values were anchored on time of treatment start, and linear mixed-effects modeling was used to analyze changes in diffusion capacity for carbon monoxide (DLCO) and forced vital capacity (FVC) before and after treatment initiation. RESULTS: We identified 19 subjects who had pSS-ILD, of whom seven were treated with azathioprine and seven were treated with mycophenolate. Within the azathioprine treated group, FVC% slope change trended toward improvement from a rate of -9.8% per month pre-treatment to 2.1% per month post-treatment (p = 0.13). Within the mycophenolate treated group, FVC% slope change improved from a rate of 1.5% per month pre-treatment to 4.3% per month post-treatment (p = 0.02) and DLCO% slope changed from a rate of -3.8% to -1.3% per month (p = 0.01) after therapy start. CONCLUSIONS: Mycophenolate treatment was associated with significant improvement in PFTs of pSS-ILD patients over time, and azathioprine treatment followed a similar non-significanttrend. Additional prospective studies are needed to further evaluate these findings. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 136-147).