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Steven D Nathan, Christopher S King Advanced Lung Disease Clinic, Inova Fairfax Hospital, Falls Church, VA, USA Abstract: Idiopathic pulmonary fibrosis (IPF) is a disease that carries a high mortality. Pulmonary hypertension (PH) frequently complicates the course of patients with IPF and is associated with significantly worse outcomes. Whether PH is a surrogate or driver of these worse outcomes remains unanswered, but the presence of PH represents an attractive target for therapy. This review delves into the various pulmonary vasoactive agents that have been subjected to study in IPF, the pitfalls of some of these prior studies, and attempts to lay a foundation for future study designs targeting PH in IPF. Keywords: phenotype, interstitial lung disease

The determination of optimal timing of liberation from mechanical ventilation requires a thorough assessment of multiple variables that can result in extubation failure. It is estimated that 5-20% of extubations fail. Traditional weaning parameters fail to predict extubation failure accurately, and attention has thus turned to improvements in extubation decision making through assessment of elements that may result in inability to protect the airway, such as excessive respiratory secretions, inadequate cough, and depressed mental status. Extubation is particularly controversial in patients with depressed mental status and inability to follow commands. When looking at univariate analyses, the reported studies are relatively evenly divided among those that did and did not find that inability to follow commands (ie, abnormal mental status) increases the risk of extubation failure. In addition, although extubation failure is a risk factor for poor overall outcome in heterogeneous populations, its impact on the patient failing with neurologic dysfunction has not been adequately determined. One limiting factor in all reported studies is how 'inability to follow commands' is defined. The majority of studies use the Glasgow coma score, but this is difficult to determine in the intubated patient. Moreover, using the cutoff of Glasgow coma score >/= 8, favored by many authors, is questionable, as some patients with higher scores may be unable to follow commands. Currently it is agreed that many patients who are unable to follow commands, but have the ability to clear pulmonary secretions, can be safely extubated. A prospective, randomized trial using a more specific definition of 'following commands' would certainly help remove some of the uncertainty in this patient population. [ABSTRACT FROM AUTHOR]

BACKGROUND: Vocal cord dysfunction (VCD) is difficult to diagnose. Laryngoscopy while the patient is symptomatic is the accepted standard method to establish a diagnosis of VCD, but patient characteristics and spirometry values are thought to be useful for predicting VCD. We sought to identify clinical and spirometric variables that suggest VCD. METHODS: We performed 2 parallel studies. First, 3 staff pulmonologists (who were blinded to the laryngoscopy results), scored 3 flow-volume loops from each PFT session on the likelihood that the inspiratory curve indicated VCD. We also performed a cross-sectional study of clinical characteristics and spirometric data from all patients who underwent laryngoscopy for any indication, including suspected VCD, over a 3-year period. We compared the laryngoscopy findings to the clinical characteristics, spirometry results, and the pulmonologists' assessments of the flow-volume loops. We used multivariate logistic regression to identify independent predictors of VCD. RESULTS: The pulmonologists agreed about which flow-volume loops predicted VCD (quadratic kappa range 0.55-0.76), but those ratings were not predictive of laryngoscopic diagnosis of VCD. During the study period, 226 patients underwent laryngoscopy. One hundred (44%) were diagnosed with VCD. Independent predictors of VCD included female sex (odds ratio 2.72, 95% confidence interval 1.55-4.75) and obesity (body mass index > 30 kg/m(2)) (odds ratio 2.06, 95% confidence interval 1.12-3.80). With spirometric data from the effort that had the best forced-vital-capacity, multivariate analysis found the ratio of the forced inspiratory flow at 25% of the inspired volume to forced inspiratory flow at 75% of the inspired volume (FIF(25%/75%)) predictive of VCD (odds ratio 1.97, 95% confidence interval 1.12-3.44). The diagnostic performance of these characteristics was poor; the area under the receiver-operating-characteristic curve was 0.68. With the spirometric data from the effort that had the subjectively determined best inspiratory curve, and after controlling for the reproducibility of the inspiratory curves, multivariate analysis found none of the spirometric variables predictive of VCD. CONCLUSIONS: VCD remains difficult to predict with spirometry or flow-volume loops. If VCD is suspected, normal flow-volume loop patterns should not influence the decision to perform laryngoscopy. [ABSTRACT FROM AUTHOR]

Asthma is a heterogeneous disorder with multiple clinical phenotypes. Phenotypes can be grouped into clinical or physiological, trigger-defined, and inflammatory phenotypes. Treatment based on inflammatory phenotyping improves clinical measures of asthma morbidity. Further study of individual asthma phenotypes will improve understanding of their immunologic and pathologic characteristics and improve diagnosis and therapy. Because asthma is a common disorder with nonspecific presenting features, other disorders are often misdiagnosed as asthma. A high index of suspicion for alternative diagnoses must be maintained when evaluating a patient who presents with clinical features suggestive of asthma, particularly if the patient presents with atypical symptoms or fails to respond to therapy. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Prophylaxis with unfractionated heparin (UFH) has been proven to reduce rates of venous thromboembolism (VTE) in hospitalized medical patients. While twice-daily (BID) and three-times-daily (TID) dosing regimens have been studied, the two have never been directly compared. We performed a metaanalysis to assess whether TID is superior to BID dosing in the prevention of VTE. METHODS: Medline, EMBASE, and Cochrane Controlled Trials Register from 1966 through December 2004 were searched for randomized trials comparing subcutaneously dosed UHF (either BID or TID) with placebo or control for VTE prophylaxis in medical patient populations. Two reviewers independently rated study quality on the basis of predetermined criteria. Data were extracted on patient age, hospital setting, comorbidities, VTE rates, and bleeding complications. RESULTS: Twelve studies were identified; 7,978 patients (1,664 patients in the TID arm, and 6,314 patients in the BID arm) were included. After adjustment for baseline risk, there was no difference in the overall rate (per 1,000 patient-days) of VTE (BID, 5.4; vs TID, 3.5; p = 0.87). TID heparin showed a trend toward a decrease in pulmonary embolism (PE) [BID, 1.5; vs TID, 0.5; p = 0.09] and in proximal DVT and PE (BID, 2.3; vs TID, 0.9; p = 0.05). The risk for major bleeding was significantly increased with TID heparin (BID, 0.35; vs TID, 0.96; p < 0.001). CONCLUSIONS: BID heparin dosing causes fewer major bleeding episodes, while TID dosing appears to offer somewhat better efficacy in preventing clinically relevant VTE events. Practitioners should use underlying risk for VTE and bleeding to individualize pharmacologic prevention. [ABSTRACT FROM AUTHOR]

GLTSCR1, a protein encoded by the Bicra gene, is a defining subunit of the SWI/SNF (also called mammalian BAF) chromatin remodeling subcomplex called GBAF/ncBAF. To determine the role of GLTSCR1 during mouse development, we generated a Bicra germline knockout mouse using CRISPR/Cas9. Mice with homozygous loss of Bicra were born at Mendelian ratios but were small, pale and died within 24 hours after birth. Histology indicated blood-related defects including defective erythroblastic islands and irregularly sized red blood cells. Gene expression profiling of fetal livers pinpointed a defect in liver resident macrophages involved in the last stage of erythrocyte maturation, resulting in accumulation of nucleated erythrocytes in Bicra-/- pups. Together, these results demonstrate that Bicra is critical for fetal liver macrophage function during development.

Rationale: Little is known about hospitalization in other types of interstitial lung disease (ILD) besides idiopathic pulmonary fibrosis (IPF). Objectives: To determine the frequency of hospitalizations in various types of ILD and elucidate the association of hospitalization with outcomes. Methods: An analysis of the Pulmonary Fibrosis Foundation Patient Registry data was performed. Inpatient hospitalization rates and survival posthospitalization were compared for various types of ILD. Measurements and Main Results: Hospitalization rates were similar across ILD types: 40.6% of participants with IPF, 42.8% of participants with connective tissue disease-related ILD (CTD-ILD), 44.9% of participants with non-IPF idiopathic interstitial pneumonia (IIP), 46.5% of participants with chronic hypersensitivity pneumonitis (CHP), and 53.3% of participants with "other" ILD. All-cause hospitalization was not associated with decreased transplant-free survival (adjusted hazard ratio [AHR], 1.20; 95% confidence interval [CI] = 0.98, 1.46; P  = 0.0759) after adjusting for comorbidities and severity of illness; however, respiratory-related hospitalization was (AHR, 1.53; 95% CI = 1.23, 1.90; P  = 0.0001). Participants with CTD-ILD (HR, 0.43; 95% CI = 0.25, 0.75; P  = 0.0031) and non-IPF IIP (HR, 0.3; 95% CI = 0.15, 0.58; P  = 0.005) had a lower risk of death posthospitalization compared with those with IPF, whereas those with chronic hypersensitivity pneumonitis (HR, 0.67; 95% CI = 0.37, 1.20; P  = 0.1747) or other ILD (HR, 0.54; 95% CI = 0.19, 1.54; P  = 0.25) had a risk comparable with that for IPF. Conclusions: Rates of hospitalization are similar across ILD subtypes. The risk of death or transplant after posthospitalization is lower in patients with CTD-ILD and non-IPF IIP, compared with patients with IPF. In a mixed population of participants with ILD, all-cause hospitalizations were not associated with decreased transplant-free survival; however respiratory-related hospitalizations were.

Background: Oral treprostinil is a prostacyclin analogue approved to treat pulmonary arterial hypertension (PAH) by delaying disease progression and improving exercise capacity. Higher doses of oral treprostinil correlate with increased treatment benefit. Titrations may be challenging due to common side effects of prostacyclin-class therapies., Study Design and Methods: The multicenter, prospective, real-world, observational ADAPT Registry study followed adult patients with PAH for up to 78 weeks after initiating oral treprostinil (NCT03045029). Dosing, titration, and transitions of oral treprostinil were at the discretion of the prescriber. Patient-reported incidence and treatment of common side effects were collected to understand side effect management and tolerability. Insights from literature and expert recommendations were added to provide a consolidated resource for oral treprostinil use., Results: In total, 139 participants in ADAPT completed ≥1 weekly survey; (median age 60.0 years, 76 % female). Median treatment duration of oral treprostinil was 13.1 months. During early therapy (Months 1-5), 62 % (78/126) of patients reported headache and diarrhea, and 40 % (50/126) reported nausea. At Month 6, many patients who reported side effects during early therapy reported an improvement (61 % headache, 44 % diarrhea, 70 % nausea). Common side effect treatments, including acetaminophen, loperamide, and ondansetron, were effective. Approximately one-quarter of patients reporting the most common side effects were untreated at Month 6., Conclusion: Patient selection for, and initiation and titration of, oral treprostinil should be individualized and may include parenteral treprostinil induction-transition for faster titration. Assertive side effect management may help patients reach higher and more efficacious doses of oral treprostinil., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships that may be considered as potential competing interests: JC reports research funding from United Therapeutics Corporation. CK reports consulting and speaking fees from United Therapeutics; consulting fees from Merck & Co Inc.; and speaking fees from Altavant Sciences. JK reports consulting fees, speaking fees, grant funding, and travel reimbursement from United Therapeutics Corporation and Janssen Pharmaceuticals Inc; grant funding from Acceleron Pharma and Gossamer Bio; consulting fees and speaking fees from Bayer Corporation; and speaking fees and travel reimbursement from Actelion Pharmaceuticals Inc. MEW reports consulting fees, speaking fees, and travel reimbursement from United Therapeutics Corporation. MW reports consulting fees, speaking fees, and travel reimbursement from United Therapeutics and Actelion Pharmaceuticals Inc; consulting fees and speaking fees from Bayer Corporation; and consulting fees from Janssen Pharmaceuticals Inc. SS reports consulting fees, speaking fees, and grant funding from United Therapeutics Corporation and Janssen Pharmaceuticals Inc; consulting fees and grant funding from Bayer Corporation, Gossamer Bio, and Altavant Sciences Inc.; consulting fees from Merck & Co Inc., and Liquidia Corporation Inc; and grant funding from Keros Therapeutics Inc. SS is an associated editor for pulmonary vascular diseases at Respiratory Medicine. VL reports speaking fees and travel reimbursement from United Therapeutics Corporation; and consulting and speaking fees from Bayer Corporation. AA reports consulting fees from United Therapeutics Corporation. AR reports speaking fees from United Therapeutics Corporation; and consulting and speaking fees from Janssen Pharmaceuticals Inc. CM reports consulting fees and speaking fees from United Therapeutics Corporation and Janssen Pharmaceuticals Inc.; speaking fees from Bayer AG; and consulting fees from Merck Pharmaceutical (HK) Ltd. JB reports consulting fees and speaking fees from United Therapeutics Corporation; and speaking fees from Janssen Pharmaceuticals Inc. AK, MB, DL, NP are employees of United Therapeutics Corporation, and may own stock in United Therapeutics Corporation. AS has no declarations of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF), one of the most common forms of interstitial lung disease, is a poorly understood, chronic, and often fatal fibroproliferative condition with only two FDA-approved medications. Understanding the pathobiology of the fibroblast in IPF is critical to evaluating and discovering novel therapeutics. Using a decellularized lung matrix derived from patients with IPF, we generate three-dimensional hydrogels as in vitro models of lung physiology and characterize the phenotype of fibroblasts seeded into the hydrogels. When cultured in IPF extracellular matrix hydrogels, IPF fibroblasts display differential contractility compared with their normal counterparts, lose the classical myofibroblast marker α-smooth muscle actin, and increase expression of proinflammatory cytokines compared with fibroblasts seeded two-dimensionally on tissue culture dishes. We validate this proinflammatory state in fibroblast-conditioned media studies with monocytes and monocyte-derived macrophages. These findings add to a growing understanding of the lung microenvironment effect on fibroblast phenotypes, shed light on the potential role of fibroblasts as immune signaling hubs during lung fibrosis, and suggest intervention in fibroblast-immune cell cross-talk as a possible novel therapeutic avenue.

The American College of Chest Physicians (CHEST) Antithrombotic Therapy for Venous Thromboembolism Disease evidence-based guidelines are now updated in a more frequent, focused manner. Guidance statements from the most recent full guidelines and two subsequent updates have not been gathered into a single source. An international panel of experts with experience in prior antithrombotic therapy guideline development reviewed the 2012 CHEST antithrombotic therapy guidelines and its two subsequent updates. All guideline statements and their associated patient, intervention, comparator, and outcome questions were assembled. A modified Delphi process was used to select statements considered relevant to current clinical care. The panel further endorsed minor phrasing changes to match the standard language for guidance statements using the modified Grading of Recommendations, Assessment, Development, and Evaluations (ie, GRADE) format endorsed by the CHEST Guidelines Oversight Committee. The panel appended comments after statements deemed as relevant, including suggesting that statements be updated in future guidelines because of interval evidence. We include 58 guidance statements from prior versions of the antithrombotic therapy guidelines, with updated phrasing as needed to adhere to contemporary nomenclature. Statements were classified as strong or weak recommendations based on high-certainty, moderate-certainty, and low-certainty evidence using GRADE methodology. The panel suggested that five statements are no longer relevant to current practice. As CHEST continues to update guidance statements relevant to antithrombotic therapy for VTE disease, this article serves as a unified collection of currenrtly relevant statements from the preceding three guidelines. Suggestions have been made to update specific statements in future publications., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: L. B. K. reports receiving research funding from CSL Behring and Takeda to her institution for unrelated research. None declared S. M. S., S. C. W., K. D., G.-J. G., F. A. K., C. S. K., S. M., J. R. E. V., P. S. W., S. W., and L. K. M., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To examine trends in utilization and outcomes among patients with the acute respiratory distress syndrome (ARDS) requiring prolonged venovenous extracorporeal membrane oxygenation (VV ECMO) support., Design: Retrospective observational cohort study., Setting: Adult patients in the Extracorporeal Life Support Organization registry., Patients: Thirteen thousand six hundred eighty-one patients that required ECMO for the support of ARDS between January 2012 and December 2022., Interventions: None., Measurements and Main Results: Mortality while supported with VV ECMO and survival to hospital discharge based on ECMO duration were examined utilizing multivariable logistic regression. Among the 13,681 patients supported with VV ECMO, 4,040 (29.5%) were supported for greater than or equal to 21 days and 975 (7.1%) for greater than or equal to 50 days. Patients supported with prolonged VV ECMO were less likely to be discharged alive from the hospital compared with those with short duration of support (46.5% vs. 59.7%; p < 0.001). However, among patients supported with VV ECMO greater than or equal to 21 days, duration of extracorporeal life support was not significantly associated with mortality (odds ratio [OR], 0.99; 95% CI, 0.98-1.01; p = 0.87 and adjusted OR, 0.99; 95% CI, 0.97-1.02; p = 0.48). Even in those supported with VV ECMO for at least 120 days (n = 113), 52 (46.0%) of these patients were ultimately discharged alive from the hospital., Conclusions: Prolonged VV ECMO support of ARDS has increased and accounts for a substantial portion of cases. Among patients that survive for greater than or equal to 21 days while receiving VV ECMO support, duration is not predictive of survival to hospital discharge and clinical recovery may occur even after very prolonged VV ECMO support., Competing Interests: Dr. Rackley received funding from Inspira and Roche. Dr. King received funding from Merck, United Therapeutics, Altavant, and Janssen. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Background: The administration of inhaled prostanoids to patients with pulmonary hypertension (PH) related to idiopathic pulmonary fibrosis (IPF) and other fibrotic lung diseases improves functional outcomes. Selection of patients with IPF at risk for concomitant PH to undergo right heart catheterization (RHC) remains challenging. We sought to develop a clinical prediction tool based on common noninvasive parameters to identify PH in patients with IPF., Methods: A prediction model based on noninvasive parameters was derived from patients enrolled in the ARTEMIS-IPF randomized, placebo-controlled clinical trial. Predictor variables were tested for association with the presence of PH diagnosed based on RHC. The derived multivariable logistic regression model and associated point-score index were then externally validated in a real-world cohort of patients with IPF., Results: Of the 481 patients included in the ARTEMIS-IPF study, 9.8% (N = 47) were diagnosed with PH related to IPF. Four variables were associated with PH and were included in the final model: forced vital capacity/diffusing capacity for carbon monoxide ratio (F), oxygen saturation nadir during 6-minute walk test (6MWT) (O), race (R), and distance ambulated during 6MWT (D). A model containing continuous predictors (FORD calculator) and a simple point-score system (FORD index) performed similarly well in the derivation cohort (area under the curve [AUC]: 0.75 and 0.75, respectively) and validation cohort (AUC: 0.69 and 0.69, respectively)., Conclusions: The FORD models are simple, validated tools incorporating noninvasive parameters that can be applied to identify patients at risk of PH related to IPF who may benefit from invasive testing., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: A post-hoc analysis of the INCREASE trial and its open-label extension (OLE) was performed to evaluate whether inhaled treprostinil has a long-term survival benefit in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD)., Methods: Two different models of survival were employed; the inverse probability of censoring weighting (IPCW) and the rank-preserving structural failure time (RPSFT) models both allow construction of a pseudo-placebo group, thereby allowing for long-term survival evaluation of patients with PH-ILD receiving inhaled treprostinil. Time-varying stabilised weights were calculated by fitting Cox proportional hazards models based on the baseline and time-varying prognostic factors to generate weighted Cox regression models with associated adjusted HRs., Results: In the INCREASE trial, there were 10 and 12 deaths in the inhaled treprostinil and placebo arms, respectively, during the 16-week randomised trial. During the OLE, all patients received inhaled treprostinil and there were 29 and 33 deaths in the prior inhaled treprostinil arm and prior placebo arm, respectively. With a conventional analysis, the HR for death was 0.71 (95% CI 0.46 to 1.10; p=0.1227). Both models demonstrated significant reductions in death associated with inhaled treprostinil treatment with HRs of 0.62 (95% CI 0.39 to 0.99; p=0.0483) and 0.26 (95% CI 0.07 to 0.98; p=0.0473) for the IPCW and RPSFT methods, respectively., Conclusion: Two independent modelling techniques that have been employed in the oncology literature both suggest a long-term survival benefit associated with inhaled treprostinil treatment in patients with PH-ILD., Competing Interests: Competing interests: SDN has received consulting fees or payment or honoraria, from United Therapeutics, Boehringer-Ingleheim, Roche, Bellerophon Therapeutics, Altavant Sciences and Merck. SJ has received consulting fees or payment or honoraria from United Therapeutics, Bellerophon Therapeutics, Bayer and Acceleron Pharma, and has participated in advisory boards for Janssen Pharmaceuticals and Merck. CSK has received consulting fees or payment or honoraria, from Merck, Janssen Pharmaceuticals, United Therapeutics and Altavant Sciences. JMJ has nothing to disclose. AR has received payment or honoraria from Merck. CAM has received payment or honoraria from United Therapeutics and has participated on a data safety monitoring board or advisory board, for United Therapeutics, Merck and Janssen Pharmaceuticals. CD, DL, ES and PS are employees of and may have received stock or stock options from United Therapeutics. ABW has received grant support or consulting fees or payment or honoraria, from AI Therapeutics, ARIA-CV, Acceleron/Merck, Janssen Pharmaceuticals, and has participated in advisory boards for Insmed., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Prevention or treatment for acoustic injury has been met with many translational challenges, resulting in the absence of FDA-approved interventions. Localized hypothermia following noise exposure mitigates acute cochlear injury and may serve as a potential avenue for therapeutic approaches. However, the mechanisms by which hypothermia results in therapeutic improvements are poorly understood., Methods: This study performs the transcriptomic analysis of cochleae from juvenile rats that experienced noise-induced hearing loss (NIHL) followed by hypothermia or control normothermia treatment., Results: Differential gene expression results from RNA sequencing at 24 h post-exposure to noise suggest that NIHL alone results in increased inflammatory and immune defense responses, involving complement activation and cytokine-mediated signaling. Hypothermia treatment post-noise, in turn, may mitigate the acute inflammatory response., Discussion: This study provides a framework for future research to optimize hypothermic intervention for ameliorating hearing loss and suggests additional pathways that could be targeted for NIHL therapeutic intervention., Competing Interests: SRa and CK are inventors of the intellectual property used in this study. SRa and the University of Miami may receive royalties for the commercialization of the IP. SRa and CK are co-founders of RestorEar Devices LLC. RestorEar did not provide any financial support for the work described in this manuscript. All conflict of interests are disclosed to and managed by the University of Miami. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rincon Sabatino, Sangaletti, Griswold, Dietrich, King and Rajguru.)

Introduction: Exposure to occupational or recreational loud noise activates multiple biological regulatory circuits and damages the cochlea, causing permanent changes in hearing sensitivity. Currently, no effective clinical therapy is available for the treatment or mitigation of noise-induced hearing loss (NIHL). Here, we describe an application of localized and non-invasive therapeutic hypothermia and targeted temperature management of the inner ear to prevent NIHL., Methods: We developed a custom-designed cooling neck collar to reduce the temperature of the inner ear by 3-4°C post-injury to deliver mild therapeutic hypothermia., Results: This localized and non-invasive therapeutic hypothermia successfully mitigated NIHL in rats. Our results show that mild hypothermia can be applied quickly and safely to the inner ear following noise exposure. We show that localized hypothermia after NIHL preserves residual hearing and rescues noise-induced synaptopathy over a period of months., Discussion: This study establishes a minimally-invasive therapeutic paradigm with a high potential for rapid translation to the clinic for long-term preservation of hearing health., Competing Interests: SRa and CK are inventors of the intellectual property (IP) used in this study. SRa and the University of Miami may receive royalties for the commercialization of the IP. SRa and CK are co-founders of RestorEar Devices LLC. RestorEar did not provide any financial support for the work described in this manuscript. All conflict of interests for SRa are disclosed to and managed by the University of Miami. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rincon Sabatino, Rivero, Sangaletti, Dietrich, Hoffer, King and Rajgurua.)

Pulmonary vascular dysfunction in the absence of pulmonary hypertension (PH) has been observed in patients with idiopathic pulmonary fibrosis (IPF). We describe the prevalence and etiology of elevated pulmonary vascular resistance (PVR) without PH among patients with IPF. Hemodynamic, echocardiographic, and functional respiratory imaging (FRI) data was compared between patients with IPF without PH with normal (<3 wood units) and elevated PVR (≥3 wood units). Mortality between these two groups were compared to patients with IPF and PH. Of 205 patients with IPF, there were 146 patients without PH, of whom 114 (78.1%) had a normal PVR and 32 (21.9%) who had a high PVR. Functional testing and hemodynamics were similar in the two groups, except for the cardiac index which was significantly lower in patients with a high PVR (2.3 vs. 2.6 L/min/m 2 ; p  = 0.004). Echocardiographic comparison demonstrated a higher tricuspid regurgitant velocity in those with a high PVR (3.4 vs 3.0 m/s; p  = 0.046). FRI revealed proportionately fewer large vessels as a proportion of the vasculature in the patients without PH and elevated PVRs. Among patients without PH, PVR was associated with increased mortality. In conclusion, patients with IPF without PH but a high PVR appear to be a distinct phenotype with a prognosis between those with and without PH, likely reflecting the continuum of vascular dysfunction. The basis for this unique hemodynamic profile could not be definitively discerned although FRI suggested an aberrant anatomical vascular response., Competing Interests: S. D. N. is a consultant for United Therapeutics, Roche, Bellerophon, and Merck. He is on the speaker bureau for United Therapeutics and Boehringer‐Ingelheim. O. A. S. is a consultant for United Therapeutics, Janssen, and Altavant, and serves on the speaker bureau of United Therapeutics, Bayer, and Janssen. B. R. L. is an employee of Fluidda, Inc. C. S. K. is a consultant for United Therapeutics, Actelion, Altavant, Merck, and Boehringer‐Ingelheim. The remaining authors declare no conflict of interest., (© 2024 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Connective tissue diseases (CTDs) can be associated with various forms of pulmonary hypertension, including pulmonary arterial hypertension (PAH), pulmonary veno-occlusive disease, pulmonary venous hypertension, interstitial lung disease-associated pulmonary hypertension, chronic thromboembolic pulmonary hypertension, and sometimes a combination of several processes. The prevalence of PAH varies among the different CTDs, with systemic sclerosis (SSc) having the highest at 8%-12%. The most recent European Society of Cardiology/European Respiratory Society guidelines recommend routine annual screening for PAH in SSc and CTDs with SSc features. As CTDs can be associated with a myriad of presentations of pulmonary hypertension, a thorough evaluation to include a right heart catheterization to clearly delineate the hemodynamic profile is essential in developing an appropriate treatment plan. Treatment strategies will depend on the predominant phenotype of pulmonary vasculopathy. In general, management approach to CTD-PAH mirrors that of idiopathic PAH. Despite this, outcomes of CTD-PAH are inferior to those of idiopathic PAH, with those of SSc-PAH being particularly poor. Reasons for this may include extrapulmonary manifestations of CTDs, including renal disease and gastrointestinal involvement, concurrent interstitial lung disease, and differences in the innate response of the right ventricle to increased pulmonary vascular resistance. Early referral for lung transplant evaluation of patients with CTD-PAH, particularly SSc-PAH, is recommended. It is hoped that in the near future, additional therapies may be added to the armamentarium of effective treatments for CTD-PAH. Ultimately, a better understanding of the pathogenesis of CTD-PAH will be required to develop targeted therapies for this morbid condition., Competing Interests: Christopher S. King—Speaker: United Therapeutics, Actelion, Altavant; Consulting—UT, Merck. Oksana A Shlobin—Speaker B: UT, Janssen; Consulting: UT, Janssen, Aerovate, Aerami, Renzyvant, Merck; Educational: Total CME, Medscape. Vikramjit Khangoora—Consulting: Janssen. Elana J. Bernstein—Consulting: Boehringer Ingelheim; Contracted research: Boehringer Ingelheim, Pfizer, Kadmon., (© 2023 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Pulmonary hypertension is a debilitating condition that frequently develops in the setting of interstitial lung disease, likely related to chronic alveolar hypoxemia and pulmonary vascular remodeling. This disease process is likely to be identified more frequently by providers given recent advancements in definitions and diagnostic modalities, and provides practitioners with emerging opportunities to improve patient outcomes and quality of life. Despite years of data suggesting against the efficacy of pulmonary vasodilator therapy in patients with pulmonary hypertension due to interstitial lung disease, new data have emerged identifying promising advancements in therapeutics. The authors present to you a comprehensive review of pulmonary hypertension in interstitial lung disease, reviewing our current understanding of pathophysiology, updates in diagnostic approaches, and highlights of recent clinical trials which provide an effective approach for medical management.

Rationale and Objectives: Lung transplantation is a potentially life-saving treatment option for patients with idiopathic pulmonary fibrosis (IPF); however, not all eligible candidates get referred and listed for transplantation. Amongst IPF patients within the Pulmonary Fibrosis Foundation Patient Registry (PFF-R), we sought to determine the proportion of patients who undergo lung transplant listing and the characteristics associated with transplant listing., Methods: An analysis of IPF patients with at least six months of follow-up data was performed. Patients with well-established contraindications to lung transplantation were excluded. Two complementary analyses were performed. The "prevalent" population included all patients with IPF at time of enrollment into the registry. The "incident severe" population included all patients with IPF who progressed to GAP Stage 3., Results: Of the 2003 patients in the PFF-R, 475 patients were included in the "prevalent" population. Of this group, only 42 (8.8%) were either listed for or underwent lung transplant. Univariable analysis of the "prevalent" population found age (per 10 year increase, OR 0.531, p = 0.0025), percent predicted FVC (OR 0.572, p=<0.0001), percent predicted DLCO (OR 0.606, p < 0.0001), 6-min walk distance (per 50 m, OR 0.831, p = 0.019), and oxygen use at rest (OR 5.157, p < 0.0001) were predictive of listing. On multivariable analysis, age (per 10 year increase, OR 0.558, p = 0.0088), percent predicted FVC (OR 0.728, p = 0.0161), and oxygen use at rest (OR 3.264, p = 0.0029) remained significant predictors for lung transplant listing. The "incident severe" group consisted of 176 patients (8.8%). 24 patients (13.6%) from this cohort were either listed for or received a transplant. Only age (per 10 year increase, OR 0.0286, p = 0.0465) was associated with transplant listing on univariable analysis in the Incident severe population., Conclusion: Only a small proportion of potentially eligible patients with IPF are listed for lung transplantation, even when seen at pulmonary fibrosis centers of excellence. Advanced age appears to be the primary factor associated with failure to be listed. Further refinement of future registry data is required to more clearly delineate exact reasons for low rates of listing., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Purpose of Review: This review delineates current diagnostic and management strategies for pulmonary hypertension due to interstitial lung disease (PH-ILD)., Recent Findings: The INCREASE trial, a phase III multicenter, randomized, placebo-controlled trial demonstrated both improved 6-min walk distance and decreased disease progression with inhaled treprostinil. This pivotal trial led to inhaled treprostinil becoming the first FDA approved medication for treatment of PH-ILD. The availability of this treatment has generated subsequent recommendations for the screening for PH in patients with ILD. As a result, it is becoming increasingly important for clinicians to gain awareness and familiarity with the evolving management options for PH-ILD., Summary: The management of PH-ILD has its roots in goal-directed treatment of the underlying lung disease. However, recent medication advances and ongoing clinical studies are opening opportunities for more disease-specific treatment., Competing Interests: Conflict of InterestKDF and AC have no conflict of interest to report. CSK is a consultant for United Therapeutics, Actelion, Altavant, and Boehringer Ingelheim and serves on the advisory board for Actelion, United Therapeutics, Merck, and Boehringer Ingelheim., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: The Distance-Oxygen-Gender-Age-Physiology (DO-GAP) index has been shown to improve prognostication in idiopathic pulmonary fibrosis (IPF) compared to the Gender-Age-Physiology (GAP) score. We sought to externally validate the DO-GAP index compared to the GAP index for baseline risk assessment in patients with IPF. Additionally, we evaluated the utility of serial change in the DO-GAP index in predicting survival., Methods: We performed an analysis of patients with IPF from the Pulmonary Fibrosis Foundation-Patient Registry (PFF-PR). Discrimination and calibration of the two models were assessed to predict transplant-free survival and IPF-related mortality. Joint longitudinal time-to-event modelling was utilised to individualise survival prediction based on DO-GAP index trajectory., Results: There were 516 patients with IPF from the PFF-PR with available demographics, pulmonary function tests, 6-min walk test data and outcomes included in this analysis. The DO-GAP index (C-statistic: 0.73) demonstrated improved discrimination in discerning transplant-free survival compared to the GAP index (C-statistic: 0.67). DO-GAP index calibration was adequate, and the model retained predictive accuracy to identify IPF-related mortality (C-statistic: 0.74). The DO-GAP index was similarly accurate in the subset of patients taking antifibrotic medications. Serial change in the DO-GAP index improved model discrimination (cross-validated area under the curve: 0.83) enabling the personalised prediction of disease trajectory in individual patients., Conclusion: The DO-GAP index is a simple, validated, multidimensional score that accurately predicts transplant-free survival in patients with IPF and can be adapted longitudinally in individual patients. The DO-GAP may also find use in studies of IPF to risk stratify patients and possibly as a clinical trial end-point., Competing Interests: Conflict of interest: C.S. King is a consultant for United Therapeutics, Actelion, Altavant and Boehringer Ingelheim, and serves on the advisory boards for Actelion, United Therapeutics, Merck and Boehringer Ingelheim. Conflict of interest: O.A. Shlobin is a consultant for United Therapeutics, Janssen, and Altavant, and serves on the speaker bureau of United Therapeutics, Bayer and Janssen. Conflict of interest: S.D. Nathan is a consultant for United Therapeutics, Roche, Bellerophon and Merck. He is on the speakers’ bureaus for United Therapeutics and Boehringer Ingelheim. Conflict of interest: A. Chandel, R.V. Ignacio, J. Pastre, V. Khangoora, S. Aryal, A. Nyguist, A. Singhal and K.R. Flaherty have no conflicts of interest to report., (Copyright ©The authors 2023.)

COVID-19 related lung disease (CRLD) has emerged as an indication for lung transplantation (LT) in highly select patients. The prevalence and prognostic implication of coexisting pulmonary hypertension (PH) in patients with CRLD listed for LT is not known. Adult patients in the United Network for Organ Sharing database listed for LT for COVID-19 related acute respiratory distress syndrome or fibrosis through March 2022 were identified. The prevalence and impact of precapillary PH on pre- and posttransplantation survival was determined. Time-to-event analysis was used to compare outcomes between those with and without precapillary PH. We identified 245 patients listed for LT for CRLD who had right heart catheterization data available at the time of registry listing. Median age of the cohort was 54 years (interquartile range [IQR]: 46, 60), 56 (22.9%) were female, and the median lung allocation score was 81.3 (IQR: 53.3, 89.4). The prevalence of precapillary PH at the time of transplant listing was 27.9%. There was no significant difference in pretransplant mortality in patients with and without precapillary PH (sHR: 0.5; 95% confidence interval [CI]: 0.1-1.7, p  = 0.261). A total of 187 patients ultimately underwent LT; of those, 60 (31.0%) were identified as having precapillary PH during the waitlist period. Posttransplantation survival was similar between patients with and without pretransplant precapillary PH (hazard ratio: 0.96; 95% CI: 0.2-3.7, p  = 0.953). We observed a high rate of concomitant precapillary PH in patients listed for LT for CRLD. Though common, coexisting precapillary PH was not associated with a significant difference in either pre- or post-transplantation outcomes., Competing Interests: Steven D. Nathan is a consultant for United Therapeutics, Roche, Bellerophon, and Merck. He is on the speaker bureau for United Therapeutics and Boehringer‐Ingelheim. Oksana Shlobin is a consultant for United Therapeutics, Janssen and Altavant, and serves on the speaker bureau of United Therapeutics, Bayer and Janssen. Christopher S. King is a consultant for United Therapeutics, Actelion, Altavant, Merck and Boehringer‐Ingelheim. The other authors declare no conflicts of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Introduction: The gender-age-physiology (GAP) index is an easy-to-use baseline mortality prediction model in idiopathic pulmonary fibrosis (IPF). The GAP index does not incorporate exercise capacity parameters such as 6 min walk distance (6MWD) or exertional hypoxia. We evaluated if the addition of 6MWD and exertional hypoxia to the GAP index improves survival prediction in IPF., Methods: Patients with IPF were identified at a tertiary care referral centre. Discrimination and calibration of the original GAP index were assessed. The cohort was then randomly divided into a derivation and validation set and performance of the GAP index with the addition of 6MWD and exertional hypoxia was evaluated. A final model was selected based on improvement in discrimination. Application of this model was then evaluated in a geographically distinct external cohort., Results: There were 562 patients with IPF identified in the internal cohort. Discrimination of the original GAP index was measured by a C-statistic of 0.676 (95% CI 0.635 to 0.717) and overestimated observed risk. 6MWD and exertional hypoxia were strongly predictive of mortality. The addition of these variables to the GAP index significantly improved model discrimination. A revised index incorporating exercise capacity parameters was constructed and performed well in the internal validation set (C-statistic: 0.752; 95% CI 0.701 to 0.802, difference in C-statistic compared with the refit GAP index: 0.050; 95% CI 0.004 to 0.097) and external validation set (N=108 (C-statistic: 0.780; 95% CI 0.682 to 0.877))., Conclusion: A simple point-based baseline-risk prediction model incorporating exercise capacity predictors into the original GAP index may improve prognostication in patients with IPF., Competing Interests: Competing interests: SDN is a consultant and is on the speakers bureau for Boehringer-Ingelheim, Roche and United Therapeutics. The other authors have no conflicts of interest or disclosures pertinent to this manuscript., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

To compare complications and mortality between patients that required extracorporeal membrane oxygenation (ECMO) support for acute respiratory distress syndrome (ARDS) due to COVID-19 and non-COVID-19 viral pathogens., Design: Retrospective observational cohort study., Setting: Adult patients in the Extracorporeal Life Support Organization registry., Patients: Nine-thousand two-hundred ninety-one patients that required ECMO for viral mediated ARDS between January 2017 and December 2021., Interventions: None., Measurements and Main Results: The primary outcomes of interest were mortality during ECMO support and prior to hospital discharge. Time-to-event analysis and logistic regression were used to compare outcomes between the groups. Among 9,291 included patients, 1,155 required ECMO for non-COVID-19 viral ARDS and 8,136 required ECMO for ARDS due to COVID-19. Patients with COVID-19 had longer duration of ECMO (19.6 d [interquartile range (IQR), 10.1-34.0 d] vs 10.7 d [IQR, 6.3-19.7 d]; p < 0.001), higher mortality during ECMO support (44.4% vs 27.5%; p < 0.001), and higher in-hospital mortality (50.2% vs 34.5%; p < 0.001). Further, patients with COVID-19 were more likely to experience mechanical and clinical complications (membrane lung failure, pneumothorax, intracranial hemorrhage, and superimposed infection). After adjusting for pre-ECMO disease severity, patients with COVID-19 were more than two times as likely to die in the hospital compared with patients with non-COVID-19 viral ARDS., Conclusions: Patients with COVID-19 that require ECMO have longer duration of ECMO, more complications, and higher in-hospital mortality compared with patients with non-COVID-19-related viral ARDS. Further study in patients with COVID-19 is critical to identify the patient phenotype most likely to benefit from ECMO and to better define the role of ECMO in the management of this disease process., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Pulmonary hypertension (PH) complicates the course of many patients with fibrotic interstitial lung disease (ILD). Inhaled treprostinil (iTre) has been shown to improve functional ability and to delay clinical worsening in patients with PH resulting from ILD., Research Question: Do higher dosages of iTre have greater benefits in preventing clinical worsening and achieving clinical improvement?, Study Design and Methods: Post hoc analysis of the INCREASE study, a 16-week double-blind, randomized, placebo-controlled trial of iTre in patients with PH resulting from ILD. Four groups were identified based on the number of breaths per session (bps; < 9 and ≥ 9 bps) of active drug or placebo attained at 4 weeks. Patients were evaluated for clinical worsening (15% decrease in 6-min walkdistance, cardiopulmonary hospitalization, lung transplantation, or death) or clinical improvement (15% increase in the six-minute walk distance with a concomitant 30% reduction in N-terminal prohormone of brain natriuretic peptide without any clinical worsening event)., Results: At 4 weeks, 70 patients were at a dose of ≥ 9 bps (high-dosage group) and 79 patients were at a dose of < 9 bps (low-dosage group) in the iTre arm vs 86 patients in the high-dose group and 67 patients in the low-dose group in the placebo arm. Between weeks 4 and 16, 17.1% of patients in the high-dose treprostinil group and 22.8% in the low-dose treatment group experienced a clinical worsening event vs 33.7% and 34.3% of patients in the two placebo arms, respectively (P = .006). By week 16, 15.7% and 12.7% of patients in the high- and low-dose iTre groups, respectively, demonstrated clinical improvement vs 7% and 1.5% patients in the placebo arms (P = .003) INTERPRETATION: Higher dosages of iTre overall show greater benefit in terms of preventing clinical worsening and achieving clinical improvement. These data support the early initiation and uptitration of therapy to a dosage of at least 9 bps four times daily in patients with PH resulting from ILD., Trial Registry: ClinicalTrials.gov; No.: NCT02630316; URL: www., Clinicaltrials: gov., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Pulmonary hypertension may be idiopathic or related to a large variety of diseases. Various imaging examinations may be helpful in diagnosing and determining the etiology of pulmonary hypertension. Imaging examinations discussed in this document include chest radiography, ultrasound echocardiography, ventilation/perfusion scintigraphy, CT, MRI, right heart catheterization, and pulmonary angiography. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer-reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer-reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation., (Copyright © 2022 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Background: Coronavirus disease 2019 (COVID-19) requiring hospitalization is characterized by robust antibody production, dysregulated immune response, and immunothrombosis. Fostamatinib is a novel spleen tyrosine kinase inhibitor that we hypothesize will ameliorate Fc activation and attenuate harmful effects of the anti-COVID-19 immune response., Methods: We conducted a double-blind, randomized, placebo-controlled trial in hospitalized adults requiring oxygen with COVID-19 where patients receiving standard of care were randomized to receive fostamatinib or placebo. The primary outcome was serious adverse events by day 29., Results: A total of 59 patients underwent randomization (30 to fostamatinib and 29 to placebo). Serious adverse events occurred in 10.5% of patients in the fostamatinib group compared with 22% in placebo (P = .2). Three deaths occurred by day 29, all receiving placebo. The mean change in ordinal score at day 15 was greater in the fostamatinib group (-3.6 ± 0.3 vs -2.6 ± 0.4, P = .035) and the median length in the intensive care unit was 3 days in the fostamatinib group vs 7 days in placebo (P = .07). Differences in clinical improvement were most evident in patients with severe or critical disease (median days on oxygen, 10 vs 28, P = .027). There were trends toward more rapid reductions in C-reactive protein, D-dimer, fibrinogen, and ferritin levels in the fostamatinib group., Conclusion: For COVID-19 requiring hospitalization, the addition of fostamatinib to standard of care was safe and patients were observed to have improved clinical outcomes compared with placebo. These results warrant further validation in larger confirmatory trials., Clinical Trials Registration: Clinicaltrials.gov, NCT04579393., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Competing Interests: The authors declare no funding or conflicts of interest.

Purpose of Review: Despite improvements in available medical therapies, pulmonary arterial hypertension (PAH) remains a progressive, ultimately fatal disorder. Lung transplantation is a viable treatment option for PAH patients with advanced disease., Recent Findings: Recent guidelines from the International Society of Heart and Lung Transplantation (ISHLT) have updated recommendations regarding time of referral and listing for lung transplantation in PAH. The new guidelines emphasize earlier referral for transplant evaluation to ensure adequate time for proper evaluation and listing. They also incorporate objective risk stratification criteria to assist in decision-making regarding timing of referral and listing. With regards to the transplant procedure, bilateral lung transplantation has largely supplanted heart-lung transplantation as the procedure of choice for transplantation for advanced PAH. Exceptions to this include patients with PAH because of congenital heart disease and those with concurrent LV dysfunction. Use of mechanical support via venoarterial ECMO initiated before transplantation and continued into the early postoperative period is emerging as a standard of care and may help to reduce early posttransplant mortality in this population. There has been increased recognition of the importance of WHO Group 3 pulmonary hypertension. Many of the lessons learned from PAH may be applied when transplanting patients with severe WHO Group 3 pulmonary hypertension., Summary: Patients with PAH present unique challenges with regards to transplantation that require a therapeutic approach distinct from other lung disorders. Lung transplantations for PAH are high-risk endeavors best performed at centers with expertise in management of both PAH and extracorporeal support., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale: Patients with fibrotic interstitial lung disease often progress to the point of requiring supplemental oxygen. This is invariably accompanied by an impaired quality of life and limitations on activities of daily living. Objectives: This study aimed to assess the improvement in physical activity in patients with interstitial lung disease requiring supplemental oxygen treated with pulsed inhaled nitric oxide via INOpulse (Bellerophon Therapeutics). In addition, it sought to explore the safety and clinical benefits of INOpulse on multiple patient-reported outcomes. Methods: Ambulatory patients with fibrotic lung disease on supplemental oxygen were randomized in a 2:1 ratio to inhaled nitric oxide at 45 μg/kg ideal body weight/h (iNO45) or placebo for 4 months (3 months after baseline) of blinded treatment. The study assessed multiple exploratory efficacy endpoints, including moderate to vigorous physical activity as measured by actigraphy and patient-reported outcomes using the University of California San Diego shortness of breath questionnaire and the St. George's Respiratory Questionnaire (SGRQ). Results: A total of 44 patients (30 iNO45 and 14 placebo) were enrolled. A placebo-corrected clinical benefit of 12.3 min/d increase in MVPA was observed in the iNO45 group. Clinically meaningful beneficial trends were observed for the University of California San Diego shortness of breath questionnaire (6.05 points) and the SGRQ total (3.75) scores, as well as the SGRQ activity (5.84), and SGRQ impact (6.30) domains. Conclusions: INOpulse was well tolerated and associated with maintenance of physical activity and improved symptomatology in patients with interstitial lung disease who require supplemental oxygen. Further validation of this beneficial effect warrants further study in a phase-3 trial that is currently underway.

Background: Group 3 pulmonary hypertension (PH) describes a subpopulation of patients with PH due to chronic lung disease and/or hypoxia, with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) being two large subgroups. Claims database studies provide insights into the real-world treatment patterns and outcomes among these patients. However, claims data do not provide sufficient detail to assign the clinical subtype of PH required for identifying these patients., Methods: A panel of PH clinical experts and researchers was convened to discuss methodologies to identify patients with Group 3 PH associated with COPD or ILD in retrospective claims databases. To inform the discussion, a literature review was conducted to identify claims-based studies of Group 3 PH associated with COPD or ILD published from 2010 through June 2020., Results: Targeted title and abstract review identified 11 claims-based studies and two conference abstracts (eight based in the United States [US] and five conducted outside the US) that met search criteria. Based on insights from the panel and literature review, the following components were detailed across studies in the identification of Group 3 PH associated with COPD and ILD: (a) COPD or ILD identification, (b) PH identification, (c) defining the sequence between COPD/ILD and PH, and (d) other PH Group and Group 3 PH exclusions., Conclusion: This article provides recommended approaches and considerations for identifying and studying patients with Group 3 PH associated with COPD or ILD using administrative claims data that provide the foundation for future validation studies., (© 2022. The Author(s).)

Thromboelastography (TEG) evaluates viscoelastic properties of blood clot formation. The TEG 5000 analyzer is commonly used but prone to errors related to vibration or operator error. The TEG 6s was developed to overcome these limitations. Performance of TEG 6s compared with TEG 5000 has not been reported in extracorporeal membrane oxygenation (ECMO). We compared the agreement between devices via a single-center prospective observational study in hospitalized adult patients on ECMO. Data for both devices were collected daily for 3 days after ECMO initiation. Standard tests for method comparison were used. Thirty-four matching samples were available for analysis. Minimal bias was noted; however, the limit of agreement was wide for TEG parameters. Visually, agreement was better for values within the reference ranges of the tests. Lin's coefficients demonstrated moderate correlation for reaction time and alpha angle (0.58; 95% confidence interval [CI], 0.31-0.76 and 0.63; 95% CI, 0.40-0.78, respectively). Excellent correlation was demonstrated for kinetic time and maximum amplitude (0.88; 95% CI, 0.79-0.94 and 0.89; 95% CI, 0.79-0.94). The TEG 6s device may represent an acceptable surrogate for the TEG 5000 in patients on ECMO. However, limitations in reliability were noted, and the devices may not be interchangeable when results fall outside of the reference values., Competing Interests: Disclosure: H.J.D. serves as a consultant to Innovative ECMO Concepts Inc. The other authors have no conflicts of interest to report., (Copyright © ASAIO 2021.)

The COVID-19 pandemic has caused acute lung injury in millions of individuals worldwide. Some patients develop COVID-related acute respiratory distress syndrome (CARDS) and cannot be liberated from mechanical ventilation. Others may develop post-COVID fibrosis, resulting in substantial disability and need for long-term supplemental oxygen. In both of these situations, treatment teams often inquire about the possibility of lung transplantation. In fact, lung transplantation has been successfully employed for both CARDS and post-COVID fibrosis in a limited number of patients worldwide. Lung transplantation after COVID infection presents a number of unique challenges that transplant programs must consider. In those with severe CARDS, the inability to conduct proper psychosocial evaluation and pretransplantation education, marked deconditioning from critical illness, and infectious concerns regarding viral reactivation are major hurdles. In those with post-COVID fibrosis, our limited knowledge about the natural history of recovery after COVID-19 infection is problematic. Increased knowledge of the likelihood and degree of recovery after COVID-19 acute lung injury is essential for appropriate decision-making with regard to transplantation. Transplant physicians must weigh the risks and benefits of lung transplantation differently in a post-COVID fibrosis patient who is likely to remain stable or gradually improve in comparison with a patient with a known progressive fibrosing interstitial lung disease (fILD). Clearly lung transplantation can be a life-saving therapeutic option for some patients with severe lung injury from COVID-19 infection. In this review, we discuss how lung transplant providers from a number of experienced centers approach lung transplantation for CARDS or post-COVID fibrosis., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: This is the 2nd update to the 9th edition of these guidelines. We provide recommendations on 17 PICO (Population, Intervention, Comparator, Outcome) questions, four of which have not been addressed previously., Methods: We generate strong and weak recommendations based on high-, moderate-, and low-certainty evidence, using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology., Results: The panel generated 29 guidance statements, 13 of which are graded as strong recommendations, covering aspects of antithrombotic management of VTE from initial management through secondary prevention and risk reduction of postthrombotic syndrome. Four new guidance statements have been added that did not appear in the 9th edition (2012) or 1st update (2016). Eight statements have been substantially modified from the 1st update., Conclusion: New evidence has emerged since 2016 that further informs the standard of care for patients with VTE. Substantial uncertainty remains regarding important management questions, particularly in limited disease and special patient populations., (Copyright © 2021. Published by Elsevier Inc.)

Background: This is the 2nd update to the 9th edition of these guidelines. We provide recommendations on 17 PICO (Population, Intervention, Comparator, Outcome) questions, four of which have not been addressed previously., Methods: We generate strong and weak recommendations based on high-, moderate-, and low-certainty evidence, using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology., Results: The panel generated 29 guidance statements, 13 of which are graded as strong recommendations, covering aspects of antithrombotic management of VTE from initial management through secondary prevention and risk reduction of postthrombotic syndrome. Four new guidance statements have been added that did not appear in the 9th edition (2012) or 1st update (2016). Eight statements have been substantially modified from the 1st update., Conclusion: New evidence has emerged since 2016 that further informs the standard of care for patients with VTE. Substantial uncertainty remains regarding important management questions, particularly in limited disease and special patient populations., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Limited evidence exists regarding use of inhaled nitric oxide (iNO) in spontaneously breathing patients. We evaluated the effectiveness of continuous iNO via high-flow nasal cannula (HFNC) in COVID-19 respiratory failure., Methods: We performed a multicenter cohort study of patients with respiratory failure from COVID-19 managed with HFNC. Patients were stratified by administration of iNO via HFNC. Regression analysis was used to compare the need for mechanical ventilation and secondary endpoints including hospital mortality, length of stay, acute kidney injury, need for renal replacement therapy, and need for extracorporeal life support., Results: A total of 272 patients were identified and 66 (24.3%) of these patients received iNO via HFNC for a median of 88 h (interquartile range: 44, 135). After 12 h of iNO, supplemental oxygen requirement was unchanged or increased in 52.7% of patients. Twenty-nine (43.9%) patients treated with iNO compared to 79 (38.3%) patients without iNO therapy required endotracheal intubation ( P  = .47). After multivariable adjustment, there was no difference in need for mechanical ventilation between groups (odds ratio: 1.53; 95% confidence interval [CI]: 0.74-3.17), however, iNO administration was associated with longer hospital length of stay (incidence rate ratio: 1.41; 95% CI: 1.31-1.51). No difference was found for mortality, acute kidney injury, need for renal replacement therapy, or need for extracorporeal life support., Conclusion: In patients with COVID-19 respiratory failure, iNO delivered via HFNC did not reduce oxygen requirements in the majority of patients or improve clinical outcomes. Given the observed association with increased length of stay, judicious selection of those likely to benefit from this therapy is warranted., Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Perfluorinated alkyl substances (PFASs) are global, persistent, and toxic contaminants. We assessed PFAS concentrations in green (Chelonia mydas) and hawksbill (Eretmochelys imbricata) turtles from the North Pacific. Fifteen compounds were quantified via liquid chromatography tandem mass spectrometry from 62 green turtle and 6 hawksbill plasma samples from Hawai'i, Palmyra Atoll, and the Northern Marianas Islands. Plasma from 14 green turtles severely afflicted with fibropapillomatosis, and eggs from 12 Hawaiian hawksbill nests from 7 females were analyzed. Perfluorooctane sulfonate (PFOS) predominated in green turtle plasma; perfluorononanoic acid (PFNA) predominated in hawksbill tissues. Concentrations were greater in hawksbill than green turtle plasma (p < 0.05), related to trophic differences. Green turtle plasma PFOS concentrations were related to human populations from highest to lowest: Hawai'i, Marianas, Palmyra. Influence on fibropapillomatosis was not evident. PFASs were maternally transferred to hawksbill eggs, with decreasing concentrations with distance from airports and with clutch order from one female. A risk assessment of PFOS showed concern for immunosuppression in Kailua green turtles and alarming concern for hawksbill developmental toxicity. Perfluoroundecanoic (PFUnA) and perfluorotridecanoic (PFTriA) acid levels were correlated with reduced emergence success (p < 0.05). Studies to further examine PFAS effects on sea turtle development would be beneficial., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Optimal timing of mechanical ventilation in COVID-19 is uncertain. We sought to evaluate outcomes of delayed intubation and examine the ROX index (ie, [[Formula: see text]]/breathing frequency) to predict weaning from high-flow nasal cannula (HFNC) in patients with COVID-19., Methods: We performed a multicenter, retrospective, observational cohort study of subjects with respiratory failure due to COVID-19 and managed with HFNC. The ROX index was applied to predict HFNC success. Subjects that failed HFNC were divided into early HFNC failure (≤ 48 h of HFNC therapy prior to mechanical ventilation) and late failure (> 48 h). Standard statistical comparisons and regression analyses were used to compare overall hospital mortality and secondary end points, including time-specific mortality, need for extracorporeal membrane oxygenation, and ICU length of stay between early and late failure groups., Results: 272 subjects with COVID-19 were managed with HFNC. One hundred sixty-four (60.3%) were successfully weaned from HFNC, and 111 (67.7%) of those weaned were managed solely in non-ICU settings. ROX index >3.0 at 2, 6, and 12 hours after initiation of HFNC was 85.3% sensitive for identifying subsequent HFNC success. One hundred eight subjects were intubated for failure of HFNC (61 early failures and 47 late failures). Mortality after HFNC failure was high (45.4%). There was no statistical difference in hospital mortality (39.3% vs 53.2% , P = .18) or any of the secondary end points between early and late HFNC failure groups. This remained true even when adjusted for covariates., Conclusions: In this retrospective review, HFNC was a viable strategy and mechanical ventilation was unecessary in the majority of subjects. In the minority that progressed to mechanical ventilation, duration of HFNC did not differentiate subjects with worse clinical outcomes. The ROX index was sensitive for the identification of subjects successfully weaned from HFNC. Prospective studies in COVID-19 are warranted to confirm these findings and to optimize patient selection for use of HFNC in this disease., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2021 by Daedalus Enterprises.)

Background: D-dimer concentration has been used by institutions to identify candidates for intensified anticoagulant treatment for venous thromboembolism prevention and for the mitigation of the microthrombotic complications associated with COVID-19. Thromboelastography (TEG) maximum amplitude (MA) has been validated as a marker of hypercoagulability and MA ≥68 mm has been utilized as a marker of hypercoagulability in other conditions., Methods: The goal of this study was to evaluate the relationship between coagulation, inflammatory, and TEG parameters in patients with COVID-19 on extracorporeal membrane oxygenation (ECMO). We performed a single-center retrospective analysis of consecutive patients that received ECMO for the treatment of COVID-19. TEG, inflammatory, and coagulation markers were compared in patients with and without a thrombotic complication. Correlation tests were performed to identify the coagulation and inflammatory markers that best predict hypercoagulability as defined by an elevated TEG MA., Results: A total of 168 TEGs were available in 24 patients. C-reactive protein and fibrinogen were significantly higher in patients that developed a thrombotic event versus those that did not ( P = 0.04 and P = 0.04 respectively). D-dimer was negatively correlated with TEG MA ( P < 0.01), while fibrinogen was positively correlated ( P < 0.01). A fibrinogen >441 mg/dL was found to have a sensitivity of 91.2% and specificity of 85.7% for the detection of MA ≥68 mm., Conclusions: In critically ill patients with COVID-19 treated with ECMO, D-dimer concentration had an inverse relationship with degree of hypercoagulability as measured by TEG MA. D-dimer elevation may potentially reflect hemostatic perturbation in patients on ECMO or the severity of COVID-19 related sepsis rather than designate patients likely to benefit from anticoagulation. Fibrinogen concentration may represent a more useful marker of hypercoagulability in this population.

Progressive fibrosing interstitial lung disease (PF-ILD) describes a phenotypic subset of interstitial lung diseases characterized by progressive, intractable lung fibrosis. PF-ILD is separate from, but has radiographic, histopathologic, and clinical similarities to idiopathic pulmonary fibrosis. Two antifibrotic medications, nintedanib and pirfenidone, have been approved for use in patients with idiopathic pulmonary fibrosis. Recently completed randomized controlled trials have demonstrated the clinical efficacy of antifibrotic therapy in patients with PF-ILD. The validation of efficacy of antifibrotic therapy in PF-ILD has changed the treatment landscape for all of the fibrotic lung diseases, providing a new treatment pathway and opening the door for combined antifibrotic and immunosuppressant drug therapy to address both the fibrotic and inflammatory components of ILD characterized by mixed pathophysiologic pathways.

It has been suggested pleural effusions may develop in right heart failure in the absence of left heart disease. The incidence and prognostic significance of pleural effusions in pulmonary arterial hypertension is uncertain. Patients with pulmonary arterial hypertension followed at our tertiary care center were reviewed. Survival was examined based on the subsequent development of a pleural effusion. A total of 191 patients with pulmonary arterial hypertension met the inclusion criteria. The prevalence of pleural effusions on initial assessment was 7.3%. Among patients without a pleural effusion on initial imaging and at least one follow-up computerized tomography ( N  = 142), pleural effusion developed in 27.5% ( N  = 39) of patients. No alternative etiology of the effusion was identified in 19 (48.7%) cases and effusions deemed related to pulmonary arterial hypertension occurred at an incident rate of 38.6 cases per 1000 person-years. Of these, 14 (73.7%) were bilateral, 3 (15.8%) were right-sided, and 2 (10.5%) were left-sided. Effusion size was trace or small in 18 patients (94.7%). Development of a new pleural effusion was associated with attenuated survival in unadjusted survival analysis (HR: 3.80; 95% CI: 1.55-9.31), multivariate analysis (HR: 5.13; 95% CI: 1.86-14.16), and after the multivariate model was adjusted for concomitant pericardial effusion (HR: 4.86; 95% CI: 1.51-15.71). Negative impact on survival remained unchanged when effusions more likely related to an alternative cause were removed from analysis. In conclusion, pleural effusions can complicate pulmonary arterial hypertension in the absence of left heart disease. These effusions are frequently small in size, bilateral in location, and their presence is associated with decreased survival. Attenuated survival appears independent of the risk associated with a new pericardial effusion., (© The Author(s) 2021.)

The integrated stress response (ISR) maintains proteostasis by modulating protein synthesis and is important in synaptic plasticity, learning, and memory. We developed a reporter, SPOTlight, for brainwide imaging of ISR state with cellular resolution. Unexpectedly, we found a class of neurons in mouse brain, striatal cholinergic interneurons (CINs), in which the ISR was activated at steady state. Genetic and pharmacological manipulations revealed that ISR signaling was necessary in CINs for normal type 2 dopamine receptor (D2R) modulation. Inhibiting the ISR inverted the sign of D2R modulation of CIN firing and evoked dopamine release and altered skill learning. Thus, a noncanonical, steady-state mode of ISR activation is found in CINs, revealing a neuromodulatory role for the ISR in learning., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Aberrations in the coagulation system have been implicated in the pathogenesis of interstitial lung disease (ILD). Anticoagulants have been proposed as a potential therapy in ILD; however, a randomized controlled trial examining warfarin as a treatment for IPF was terminated early due to increased death rates. This has led some to speculate that warfarin specifically may be harmful in ILD, and use of direct oral anticoagulants (DOACs) could result in superior outcomes., Research Question: The goal of this study was to delineate the relationship between anticoagulation and outcomes in patients with ILD through an analysis of the Pulmonary Fibrosis Foundation Patient Registry., Study Design and Methods: An analysis of all patients in the Pulmonary Fibrosis Foundation Patient Registry was performed. Patients were stratified into three groups: no anticoagulation, DOAC use, or warfarin use. Survival was analyzed by using both Kaplan-Meier curves and Cox proportional hazards models., Results: Of 1,911 patients included in the analysis, 174 (9.1%) were given anticoagulants; 93 (4.9%) received DOACs, and 81 (4.2%) received warfarin. There was a twofold increased risk of death or transplant for patients receiving DOACS; for warfarin, the risk was over two and half times greater. DOACs were not associated with an increased risk of mortality following adjustment for confounding variables. However, even after adjustment, patients given the anticoagulant warfarin remained at increased risk of mortality. In patients with IPF, warfarin was associated with reduced transplant-free survival, but DOACs were not. There was no statistically significant difference in survival between those receiving warfarin and those receiving a DOAC., Interpretation: The need for anticoagulation is associated with an increased risk for death or transplant in patients with ILD, in both the IPF and non-IPF population. Further research is required to determine if warfarin and DOACs present varying safety profiles in patients with ILD., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)