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Interstitial lung disease (ILD) results in profound symptom burden and carries high mortality. Palliative care (PC) is dedicated to improving quality of life in patients with serious illness. Early PC provision improves rates of advance care planning and symptom management in patients with ILD.What are the current perspectives on PC among ILD providers, and what are the barriers to PC in ILD specialty centers?A 24-question electronic survey was disseminated to providers at the 68 Pulmonary Fibrosis Foundation Care Centers across the United States from October 2020 to December 2020.The survey was completed by 128 participants representing all 68 Pulmonary Fibrosis Foundation Care Center Network sites. Most respondents were physicians. Most providers exhibit good knowledge of, feel comfortable assessing a patient's readiness for, and agree with the need for PC for patients with ILD. Providers are most likely to refer to PC at objective disease and/or symptomatic progression rather than at initial diagnosis. In comparison with providers who report referring their patients to PC, providers who report rare referral are more likely to cite lack local PC availability (P .01) and less likely to feel comfortable discussing prognosis/disease trajectory (P = .03) or feel it is important to address advance directives in ILD clinic (P = .02). There is a lack of standardized measures used to assess specific symptoms, overall symptom burden, or health-related quality of life across institutions. Discordance exists between self-reported and actual access to local inpatient and outpatient PC services.Most ILD providers use PC and are comfortable discussing PC. Barriers to PC identified in this survey include the following: perceived lack of local access to PC, lack of systematic tools to assess symptom burden, lack of established optimal timing of PC referral, and unclear need for specialized PC delivery.

Background Hospitalizations are common among patients with idiopathic pulmonary fibrosis (IPF). We investigated the impact of hospitalizations on outcomes in patients with IPF. Methods The IPF-PRO Registry is an observational US registry that enrolled patients with IPF that was diagnosed or confirmed at the enrolling center in the previous 6 months. Associations between patient characteristics and hospitalization, and between hospitalization and mortality, were analyzed using Cox regression models. Results A total of 1002 patients with IPF were enrolled into the IPF-PRO Registry. Over a median follow-up time of 23.7 months (maximum: 67.0 months), 568 patients (56.7%) had at least one hospitalization. Of these patients, 319 (56.2%) had at least one respiratory-related hospitalization and 120 (21.1%) had at least one hospitalization with ventilatory support. Younger age (HR 0.68 [95% CI 0.55, 0.84] per 5-year increase for patients Conclusions Data from the IPF-PRO Registry demonstrate that hospitalizations are common among patients with IPF. The risk of mortality during hospitalization or within 90 days of discharge was high, particularly among patients who were hospitalized for a respiratory cause or received ventilatory support. Trial registration ClinicalTrials.gov, NCT01915511. Registered 5 August 2013, https://clinicaltrials.gov/ct2/show/NCT01915511

Background Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease for which diagnosis and management remain challenging. Defining the circulating proteome in IPF may identify targets for biomarker development. We sought to quantify the circulating proteome in IPF, determine differential protein expression between subjects with IPF and controls, and examine relationships between protein expression and markers of disease severity. Methods This study involved 300 patients with IPF from the IPF-PRO Registry and 100 participants without known lung disease. Plasma collected at enrolment was analysed using aptamer-based proteomics (1305 proteins). Linear regression was used to determine differential protein expression between participants with IPF and controls and associations between protein expression and disease severity measures (percent predicted values for forced vital capacity [FVC] and diffusion capacity of the lung for carbon monoxide [DLco]; composite physiologic index [CPI]). Multivariable models were fit to select proteins that best distinguished IPF from controls. Results Five hundred fifty one proteins had significantly different levels between IPF and controls, of which 47 showed a |log2(fold-change)| > 0.585 (i.e. > 1.5-fold difference). Among the proteins with the greatest difference in levels in patients with IPF versus controls were the glycoproteins thrombospondin 1 and von Willebrand factor and immune-related proteins C-C motif chemokine ligand 17 and bactericidal permeability-increasing protein. Multivariable classification modelling identified nine proteins that, when considered together, distinguished IPF versus control status with high accuracy (area under receiver operating curve = 0.99). Among participants with IPF, 14 proteins were significantly associated with FVC % predicted, 23 with DLco % predicted, 14 with CPI. Four proteins (roundabout homolog-2, spondin-1, polymeric immunoglobulin receptor, intercellular adhesion molecule 5) demonstrated the expected relationship across all three disease severity measures. When considered in pathways analyses, proteins associated with the presence or severity of IPF were enriched in pathways involved in platelet and haemostatic responses, vascular or platelet derived growth factor signalling, immune activation, and extracellular matrix organisation. Conclusions Patients with IPF have a distinct circulating proteome and can be distinguished using a nine-protein profile. Several proteins strongly associate with disease severity. The proteins identified may represent biomarker candidates and implicate pathways for further investigation. Trial registration ClinicalTrials.gov (NCT01915511).

Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a variable clinical course and high mortality. We used data from a large national US registry of patients with IPF to investigate relationships between patient characteristics, including markers of disease severity, and mortality. Methods The analysis cohort comprised patients enrolled in the IPF-PRO Registry from its inception on 5 June 2014 to 26 October 2017. The primary criterion for inclusion in this registry is that patients must be diagnosed or confirmed with IPF at the enrolling centre within 6 months. Associations between patient characteristics and markers of disease severity at enrolment and mortality outcomes were investigated using univariable, multivariable and adjustment models. Results Among 662 patients enrolled, 111 patients died or had a lung transplant over a follow-up period of 30 months. The probability of being free of both events at month 30 was 50.6% (95% CI: 40.0, 60.2). When patient characteristics and markers of disease severity were jointly examined in a multivariable analysis, oxygen use at rest (hazard ratio [HR] 2.44 [95% CI: 1.45, 4.10]), lower forced vital capacity (FVC) % predicted (HR 1.28 [95% CI: 1.10, 1.49] per 10% decrease) and diffusion capacity for carbon monoxide (DLco) % predicted (HR 1.25 [95% CI: 1.04, 1.51] per 10% decrease) were significantly associated with increased risk of death or lung transplant. The risk of death or lung transplant increased with increasing age in patients ≥62 years old (HR 1.18 [95% CI: 0.99, 1.40] per 5-year increase), and decreased with increasing age in patients

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality. Patient characteristics associated with diagnostic delays are not well described.MethodsSubjects who had not been diagnosed with IPF prior to referral and received a new diagnosis of IPF at an enrolling centre for the IPF-PRO (Idiopathic Pulmonary Fibrosis Prospective Outcomes) Registry were characterised as having a longer (>1 year) or shorter (≤1 year) time from symptom onset to diagnosis and from first imaging evidence of fibrosis to diagnosis. Patient characteristics, evaluations and time to death or lung transplant were compared between these cohorts.ResultsAmong 347 patients with a symptom onset date, 49% were diagnosed with IPF >1 year after symptom onset. These patients were slightly younger and had more cardiac comorbidities than patients diagnosed ≤1 year after symptom onset. Among 454 patients with a date for imaging evidence of fibrosis, 78% were diagnosed with IPF ≤1 year later. A greater proportion of patients with >1 year versus ≤1 year from imaging evidence of fibrosis to diagnosis had cardiac comorbidities and gastro-oesophageal reflux. There was no significant difference in time to death or lung transplant between groups by time to diagnosis.ConclusionsThe time from symptom onset to diagnosis remains over 1 year in approximately half of the patients with IPF, but once imaging evidence is obtained, most of the patients are diagnosed within a year. Cardiac conditions and gastro-oesophageal disorders were more commonly reported in patients with a longer time to diagnosis.

BackgroundMatrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) play important roles in the turnover of extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). This study aimed to determine the utility of circulating MMPs and TIMPs in distinguishing patients with IPF from controls and to explore associations between MMPs/TIMPs and measures of disease severity in patients with IPF.MethodsThe IPF cohort (n = 300) came from the IPF-PRO Registry, an observational multicenter registry of patients with IPF that was diagnosed or confirmed at the enrolling center in the past 6 months. Controls (n = 100) without known lung disease came from a population-based registry. Generalized linear models were used to compare circulating concentrations of MMPs 1, 2, 3, 7, 8, 9, 12, and 13 and TIMPs 1, 2, and 4 between patients with IPF and controls, and to investigate associations between circulating levels of these proteins and measures of IPF severity. Multivariable models were fit to identify the MMP/TIMPs that best distinguished patients with IPF from controls.ResultsAll the MMP/TIMPs analyzed were present at significantly higher levels in patients with IPF compared with controls except for TIMP2. Multivariable analyses selected MMP8, MMP9 and TIMP1 as top candidates for distinguishing patients with IPF from controls. Higher concentrations of MMP7, MMP12, MMP13 and TIMP4 were significantly associated with lower diffusion capacity of the lung for carbon monoxide (DLCO) % predicted and higher composite physiologic index (worse disease). MMP9 was associated with the composite physiologic index. No MMP/TIMPs were associated with forced vital capacity % predicted.ConclusionsCirculating MMPs and TIMPs were broadly elevated among patients with IPF. Select MMP/TIMPs strongly associated with measures of disease severity. Our results identify potential MMP/TIMP targets for further development as disease-related biomarkers.

Summary 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.

In this retrospective study of a randomised trial of simtuzumab in idiopathic pulmonary fibrosis (IPF), prodromal decline in forced vital capacity (FVC) was significantly associated with increased risk of mortality, respiratory and all-cause hospitalisations, and categorical disease progression. Predictive modelling of progression-free survival event risk was used to assess the effect of population enrichment for patients at risk of rapid progression of IPF; C-index values were 0.64 (death), 0.69 (disease progression), and 0.72 (adjudicated respiratory hospitalisation) and 0.76 (all-cause hospitalisation). Predictive modelling may be a useful tool for improving efficiency of clinical trials with categorical end points.

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.

Background Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by abnormal proliferation of skin and osseous tissue frequently associated with underlying pulmonary disorders. Cardinal features include digital clubbing, periostitis and significant joint and bone pain. A number of recent reports have emerged of HOA and periostitis occurring in association with the antifungal agent voriconazole. Methods We present two additional cases of voriconazole-induced HOA and periostitis in lung transplant recipients with a review the medical literature. Results In both cases, symptoms were painful and severe enough to require opioid medication. Rapid improvement occurred within days of voriconazole cessation. A review of existing literature revealed an additional 17 cases of voriconazole-induced HOA and periostitis in lung transplant patients. Conclusion We highlight the importance of recognizing the association of voriconazole with painful HOA and periostitis in lung transplant patients receiving antifungal therapy. Management of this painful condition involves cessation of voriconazole therapy, which may necessitate alternative anti-fungal drug therapies as well as adjustment of immunosuppressive drug dosage since voriconazole is a strong drug-inducer.

Airway complications after lung transplantation are well described and can lead to significant morbidity and mortality. Treatment options for anastomotic dehiscence include expectant management, placement of endobronchial stents, or surgical repair. The use of fibrin sealant instilled by bronchoscopy to seal a dehiscence has not been well described. Our patient is a 57-year-old man who underwent orthotropic bilateral lung transplantation for end-stage chronic obstructive pulmonary disease. He was found to have a partial bronchial anastomosis dehiscence and was subsequently treated with endobronchial fibrin sealant glue instillation. This case illustrates the successful use of endobronchial fibrin sealant for bronchial anastomosis dehiscence.

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.

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.

Background Gastroesophageal reflux disease (GERD) is common in a variety of chronic respiratory diseases, but little is known about GERD in the setting of COPD. The aims of this study were to determine the prevalence, presentation, and predictors of GERD based on proximal and distal esophageal pH monitoring in patients with severe COPD. Methods Forty-one COPD patients with a mean FEV 1 of 24% of predicted underwent dual-probe 24-h esophageal pH monitoring, and 1 patient underwent esophagogastroduodenoscopy. Results The prevalence of GERD was 57%. Elevated distal and proximal reflux were present in 41% and 46% of patients undergoing esophageal pH studies, respectively. Fifteen percent of these patients had abnormal proximal reflux despite having normal distal probe results. Most patients with GERD were not receiving acid blockers at the time of their referral, and only one third reported heartburn and/or acid regurgitation during the pH study. Only higher body mass index was predictive of reflux on regression analysis (odds ratio, 1.2; 95% confidence interval, 1.0 to 1.5; p=0.05). Conclusions GERD is common in advanced COPD. Patients are often asymptomatic and have a relatively high prevalence of isolated abnormal proximal reflux. Dual-probe monitoring is therefore well suited for detecting GERD in patients with advanced COPD.

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%. 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.

Background Idiopathic pulmonary fibrosis (IPF) is the second largest indication for lung transplantation worldwide. Average 90-day mortality rates for this procedure are 22%. It is unclear what factors predispose patients with IPF to this increased early posttransplant mortality. Pulmonary hypertension may increase the risk of development of early posttransplant complications through several mechanisms. We examined the effect of secondary pulmonary hypertension on 90-day mortality after lung transplantation for IPF. Methods An International Society for Heart and Lung Transplant Registry cohort study of 830 patients with IPF transplanted from January 1995 to June 2002 was undertaken. Risk factors were assessed individually and adjusted for confounding by a multivariable logistic regression model. Results In the univariate analysis, pulmonary hypertension and bilateral-lung transplantation were significant risk factors for increased 90-day mortality. Multivariate analysis confirmed that mean pulmonary artery pressure and bilateral procedure remain independent risk factors after adjustment for potential confounders. Recipient age, ischemia time, cytomegalovirus status mismatch, and donor age were not independent risk factors for early mortality. Conclusions Bilateral-lung transplantation carries a greater risk of early mortality than single-lung transplantation for IPF. Increasing pulmonary artery pressure is a risk factor for death after single-lung transplantation in IPF. Mean pulmonary artery pressure should be included in the overall risk assessment of patients with IPF evaluated for lung transplantation.

Background Severe primary graft dysfunction (PGD) is associated with poor early outcomes after lung transplantation (LTx). Less is known about lingering effects of severe PGD on pulmonary function. The study’s aim was to determine whether development of severe primary graft dysfunction in the perioperative period was associated with reduced long term rates of survival or with diminished long term pulmonary function. Methods A retrospective review was performed on LTx recipients who received their transplant during the period from 1992 through 2005. PGD severity over the first 48 hours post-transplant was graded using International Society for Heart Lung Transplantation criteria. Pulmonary function was evaluated yearly, and bronchiolitis obliterans syndrome (BOS) was determined from measurements of forced expiratory volume in 1 second (FEV1). Results A total of 374 patients survived at least 90 days post-transplant. Overall survival rates were worse in patients with Grade 3 PGD: 51% at 5 years and 11% at 10 years for patients with Grade 3 PGD; 64% at 5 years and 35% at 10 years for those with Grade 2 PGD; and 66% at 5 years and 38% at 10 years for Grade 0 to 1 PGD (p = 0.001). BOS-free survival rate for patients with Grade 3 PGD was lower compared to those with Grade 0 to 2 for bilateral lung recipients, but not for single-lung recipients. Bilateral lung recipients who developed Grade 3 PGD had a significantly worse mean FEV1 than those who did not. For single-lung recipients, PGD grade did not correlate with post-transplant pulmonary function. Conclusions Development of Grade 3 PGD in the early post-operative period negatively affects long-term survival, BOS-free survival and pulmonary function of bilateral lung transplant recipients who survive the peri-operative period.

Lung transplantation has become an accepted therapy for selected patients with advanced lung disease. One of the main limitations to successful lung transplantation is rejection of the transplanted organ. This article discusses the clinical presentation, treatment, and prevention of hyperacute, acute, and chronic rejection in the lung transplant recipient.

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.