A multidimensional classifier to support lung transplant referral in patients with pulmonary fibrosis.

BACKGROUND: Lung transplantation remains the sole curative option for patients with idiopathic pulmonary fibrosis (IPF), but donor organs remain scarce, and many eligible patients die before transplant. Tools to optimize the timing of transplant referrals are urgently needed. METHODS: Least absolute shrinkage and selection operator was applied to clinical and proteomic data generated as part of a prospective cohort study of interstitial lung disease (ILD) to derive clinical, proteomic, and multidimensional logit models of near-term death or lung transplant within 18 months of blood draw. Model-fitted values were dichotomized at the point of maximal sensitivity and specificity, and decision curve analysis was used to select the best-performing classifier. We then applied this classifier to independent IPF and non-IPF ILD cohorts to determine test performance characteristics. Cohorts were restricted to patients aged ≤72 years with body mass index 18 to 32 to increase the likelihood of transplant eligibility. RESULTS: IPF derivation, IPF validation, and non-IPF ILD validation cohorts consisted of 314, 105, and 295 patients, respectively. A multidimensional model comprising 2 clinical variables and 20 proteins outperformed stand-alone clinical and proteomic models. Following dichotomization, the multidimensional classifier predicted near-term outcome with 70% sensitivity and 92% specificity in the IPF validation cohort and 70% sensitivity and 80% specificity in the non-IPF ILD validation cohort. CONCLUSIONS: A multidimensional classifier of near-term outcomes accurately discriminated this end-point with good test performance across independent IPF and non-IPF ILD cohorts. These findings support refinement and prospective validation of this classifier in transplant-eligible individuals.

Pulmonologists' Perspectives on and Access to Palliative Care for Patients With Idiopathic Pulmonary Fibrosis in South Carolina.

Background: Idiopathic pulmonary fibrosis (IPF) is a serious illness with an unpredictable disease course and survival rates comparable with some cancers. Patients with IPF suffer considerable symptom burden, declining quality of life, and high health care resource utilization. Patients and caregivers report many unmet needs, including a desire for more education regarding diagnosis and assistance with navigating disease trajectory. Compelling evidence suggests that palliative care (PC) provides an extra layer of support for patients with serious illness. Research Question: The purpose of this survey was to gain perspectives regarding PC for patients with IPF by board-certified pulmonologists in South Carolina (SC). Study Design and Methods: A 24-item survey was adapted (with permission) from the Pulmonary Fibrosis Foundation PC Survey instrument. Data were analyzed and results are presented. Results: Pulmonologists (n = 32, 44%) completed the survey; 97% practice in urbanized settings. The majority agreed that PC and hospice do not provide the same service. There were varying views about comfort in discussing prognosis, disease trajectory, and addressing advance directives. Options for ambulatory and inpatient PC are limited and early PC referral does not occur. None reported initiating a PC referral at time of initial IPF diagnosis. Interpretation: Pulmonologists in SC who participated in this survey are aware of the principles of PC in providing comprehensive care to patients with IPF and have limited options for PC referral. PC educational materials provided early in the diagnosis can help facilitate and guide end-of-life planning and discussions. Minimal resources exist for patients in underserved communities.

Disparities in Lung Transplant among Patients with Idiopathic Pulmonary Fibrosis: An Analysis of the IPF-PRO Registry.

Rationale: Lung transplant offers the potential to extend life for patients with idiopathic pulmonary fibrosis (IPF); yet, this therapeutic modality is only available to a small proportion of patients. Objectives: To identify clinical characteristics and social determinants of health that differentially associate with lung transplant compared with death in patients with IPF. Methods: We evaluated data from the Idiopathic Pulmonary Fibrosis Prospective Outcomes (IPF-PRO) Registry, a multicenter U.S. registry of patients with IPF that was diagnosed or confirmed at the enrolling center in the previous 6 months. Patients were enrolled between June 2014 and October 2018. Patients who were listed for lung transplant were not eligible to enroll in the registry, but patients could be listed for transplant after enrollment. We performed a multivariable time-to-event analysis incorporating competing risks methodology to examine differential associations between prespecified covariates and the risk of lung transplant versus death. Covariates included factors related to lung transplant eligibility, clinical characteristics of IPF, and social determinants of health. Covariates were modeled as time independent or time dependent as appropriate. Results: Among 955 patients with IPF, event rates of lung transplant and death were 7.4% and 16.3%, respectively, at 2 years. Covariates with the strongest differential association were age, median zip code income, and enrollment at a center with a lung transplant program. Lung transplant was less likely (hazard ratio [HR], 0.13 [95% confidence interval (CI), 0.06-0.28] per 5-yr increase) and death more likely (HR, 1.41 [95% CI, 1.22-1.64] per 5-yr increase) among those older than 70 years of age. Higher median zip code income was associated with lung transplant (HR, 1.22 [95% CI, 1.13-1.31] per $10,000 increase) but not death (HR, 0.99 [95% CI, 0.94-1.04] per $10,000 increase). Enrollment at a center with a lung transplant program was associated with lung transplant (HR, 4.31 [95% CI, 1.76-10.54]) but not death (HR, 0.99 [95% CI, 0.69-1.43]). Oxygen use with activity was associated with both lung transplant and death, but more strongly with lung transplant. A higher number of comorbidities was associated with an increased likelihood of death but not lung transplant. Conclusions: For patients in the Idiopathic Pulmonary Fibrosis Prospective Outcomes Registry, median zip code income and access to a lung transplant center differentially impact the risk of lung transplant compared with death, regardless of disease severity measures or other transplant eligibility factors. Interventions are needed to mitigate inequalities in lung transplantation based on socioeconomic status. Clinical trial registered with www.clinicaltrials.gov (NCT01915511).

Risk factors for disease progression in idiopathic pulmonary fibrosis.

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.

Voriconazole-associated periostitis presenting as hypertrophic osteoarthropathy following lung transplantation report of two cases and review of the literature.

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.

Closure of a Post-Transplant Bronchial Dehiscence With Endobronchial Fibrin Sealant.

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.

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.

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.

Hepatorenal Acute Kidney Injury and the Importance of Raising Mean Arterial Pressure.

BACKGROUND: The efficacy of vasoconstrictors in hepatorenal syndrome (HRS) is variable. We hypothesized that the effectiveness of vasoconstrictor therapy in improving kidney function ultimately relates to the magnitude of the achieved mean arterial pressure (MAP) increase. METHODS: A retrospective study was conducted to identify cirrhotic individuals treated with vasoconstrictors for acute kidney injury (AKI) presumably caused by HRS to examine the relationship between change in MAP and change in serum creatinine (sCr) using multivariate mixed linear regression. RESULTS: Among 73 patients treated with midodrine/octreotide, change in MAP inversely correlated with change in sCr (p = 0.0005). The quartile with the greatest increase in MAP (+15.9 to +29.4 mm Hg) was associated with a subsequent absolute decrease in sCr. The strength of the correlation increased when the analysis was restricted to those who met the HRS criteria (n = 27, p = 0.002), where the third (+5.3 to +15.6 mm Hg) and fourth (+15.9 to +20.9 mm Hg) quartiles of MAP change were associated with a decrease in sCr. A similar but stronger correlation was found among 14 patients treated with norepinephrine either after failing midodrine/octreotide (n = 10) or de novo (n = 4; p = 0.002), where a rise in MAP of +19.2 to 25 mm Hg was associated with a larger reduction in sCr. Associations remained significant after adjustment for baseline parameters. CONCLUSIONS: The magnitude of MAP rise during HRS therapy with midodrine/octreotide or norepinephrine correlated with a reduction in sCr concentration. Our results suggest that achieving a pre-specified target of MAP increase might improve renal outcomes in hepatorenal AKI.

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.

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.

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.

Primary graft dysfunction and long-term pulmonary function after 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 (FEV(1)). 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 FEV(1) 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.

High prevalence of proximal and distal gastroesophageal reflux disease in advanced COPD.

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 FEV1 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.

Allograft rejection after lung transplantation.

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.

Invasive pneumococcal infections in adult lung transplant recipients.

An increased risk of invasive pneumococcal infection (IPI) has been described among kidney or heart transplant recipients, but the epidemiology of IPI among lung transplant recipients has not been previously reported. We undertook a single center, retrospective cohort study to define the incidence, timing, clinical, and microbiologic features of IPI in lung transplant patients. Fourteen out of 220 recipients (6.4%) developed IPI at a median of 1.3 years after transplantation (incidence rate: 22.7 cases per 1000 person-years). All patients were receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis at the time of diagnosis, and 10 (71%) had TMP-SMX-resistant isolates. All isolates were from the 23 valent polysaccharide vaccine-associated serogroups. The high incidence of IPI in lung transplant recipients is similar to that reported in kidney and heart recipients. Alternative prevention strategies, including use of the conjugated pneumococcal vaccine, should be explored in future studies.