Host and pathogen response to bacteriophage engineered against Mycobacterium abscessus lung infection.

Two mycobacteriophages were administered intravenously to a male with treatment-refractory Mycobacterium abscessus pulmonary infection and severe cystic fibrosis lung disease. The phages were engineered to enhance their capacity to lyse M. abscessus and were selected specifically as the most effective against the subject's bacterial isolate. In the setting of compassionate use, the evidence of phage-induced lysis was observed using molecular and metabolic assays combined with clinical assessments. M. abscessus isolates pre and post-phage treatment demonstrated genetic stability, with a general decline in diversity and no increased resistance to phage or antibiotics. The anti-phage neutralizing antibody titers to one phage increased with time but did not prevent clinical improvement throughout the course of treatment. The subject received lung transplantation on day 379, and systematic culturing of the explanted lung did not detect M. abscessus. This study describes the course and associated markers of a successful phage treatment of M. abscessus in advanced lung disease.

De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor.

N-methyl-D-aspartate receptors (NMDARs) are members of the glutamate receptor family and participate in excitatory postsynaptic transmission throughout the central nervous system. Genetic variants in GRIN genes encoding NMDAR subunits are associated with a spectrum of neurological disorders. The M3 transmembrane helices of the NMDAR couple directly to the agonist-binding domains and form a helical bundle crossing in the closed receptors that occludes the pore. The M3 functions as a transduction element whose conformational change couples ligand binding to opening of an ion conducting pore. In this study, we report the functional consequences of 48 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M3 transmembrane helix. These de novo variants were identified in children with neurological and neuropsychiatric disorders including epilepsy, developmental delay, intellectual disability, hypotonia and attention deficit hyperactivity disorder. All 48 variants in M3 for which comprehensive testing was completed produce a gain-of-function (28/48) compared to loss-of-function (9/48); 11 variants had an indeterminant phenotype. This supports the idea that a key structural feature of the M3 gate exists to stabilize the closed state so that agonist binding can drive channel opening. Given that most M3 variants enhance channel gating, we assessed the potency of FDA-approved NMDAR channel blockers on these variant receptors. These data provide new insight into the structure-function relationship of the NMDAR gate, and suggest that variants within the M3 transmembrane helix produce a gain-of-function.

Deep Learning Classification of Usual Interstitial Pneumonia Predicts Outcomes.

Rationale: Computed tomography (CT) enables noninvasive diagnosis of usual interstitial pneumonia (UIP), but enhanced image analyses are needed to overcome the limitations of visual assessment. Objectives: Apply multiple instance learning (MIL) to develop an explainable deep learning algorithm for prediction of UIP from CT and validate its performance in independent cohorts. Methods: We trained an MIL algorithm using a pooled dataset (n = 2,143) and tested it in three independent populations: data from a prior publication (n = 127), a single-institution clinical cohort (n = 239), and a national registry of patients with pulmonary fibrosis (n = 979). We tested UIP classification performance using receiver operating characteristic analysis, with histologic UIP as ground truth. Cox proportional hazards and linear mixed-effects models were used to examine associations between MIL predictions and survival or longitudinal FVC. Measurements and Main Results: In two cohorts with biopsy data, MIL improved accuracy for histologic UIP (area under the curve, 0.77 [n = 127] and 0.79 [n = 239]) compared with visual assessment (area under the curve, 0.65 and 0.71). In cohorts with survival data, MIL-UIP classifications were significant for mortality (n = 239, mortality to April 2021: unadjusted hazard ratio, 3.1; 95% confidence interval [CI], 1.96-4.91; P < 0.001; and n = 979, mortality to July 2022: unadjusted hazard ratio, 3.64; 95% CI, 2.66-4.97; P < 0.001). Individuals classified as UIP positive by the algorithm had a significantly greater annual decline in FVC than those classified as UIP negative (-88 ml/yr vs. -45 ml/yr; n = 979; P < 0.01), adjusting for extent of lung fibrosis. Conclusions: Computerized assessment using MIL identifies clinically significant features of UIP on CT. Such a method could improve confidence in radiologic assessment of patients with interstitial lung disease, potentially enabling earlier and more precise diagnosis.

Phase 2, Double-Blind, Placebo-controlled Trial of a c-Jun N-Terminal Kinase Inhibitor in Idiopathic Pulmonary Fibrosis.

Rationale: Idiopathic pulmonary fibrosis is a fatal and progressive disease with limited treatment options. Objectives: To assess the efficacy and safety of CC-90001, an oral inhibitor of c-Jun N-terminal kinase 1, in patients with idiopathic pulmonary fibrosis. Methods: NCT03142191 was a phase 2, randomized (1:1:1), double-blind, placebo-controlled study in which patients received CC-90001 (200 or 400 mg) or placebo once daily for 24 weeks. Background antifibrotic treatment (pirfenidone) was allowed. The primary endpoint was change in percentage of predicted forced vital capacity (ppFVC) from baseline to Week 24; secondary endpoints included safety. Measurements and Main Results: In total, 112 patients received ≥1 dose of study drug. The study was terminated early due to a strategic decision made by the sponsor. Ninety-one patients (81%) completed the study. The least-squares mean changes from baseline in ppFVC at Week 24 were -3.1% (placebo), -2.1% (200 mg), and -1.0% (400 mg); the differences compared with placebo were 1.1% (200 mg; 95% CI: -2.1, 4.3; P=.50) and 2.2% (400 mg; 95% CI: -1.1, 5.4; P=.19). Adverse event frequency was similar in patients in the combined CC-90001 arms versus placebo. The most common adverse events were nausea, diarrhea, and vomiting, which were more frequent in patients in CC-90001 arms versus placebo. Fewer patients in the CC-90001 than in the placebo arm experienced cough and dyspnea. Conclusions: Treatment with CC-90001 over 24 weeks led to numerical improvements in ppFVC in patients with idiopathic pulmonary fibrosis compared to placebo. CC-90001 was generally well tolerated, consistent with previous studies. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT03142191.

Meaningful Endpoints for Idiopathic Pulmonary Fibrosis (IPF) Clinical Trials: Emphasis on 'Feels, Functions, Survives'. Report of a Collaborative Discussion in a Symposium with Direct Engagement from Representatives of Patients, Investigators, the National Institutes of Health, a Patient Advocacy Organization, and a Regulatory Agency.

Background: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF. Methods: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's 'feels, functions, survives' criteria. Results: Three themes emerged: 1) consensus on endpoints mirroring the lived experiences of patients with IPF; 2) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures (FDA Guidance for Industry (Multiple Endpoints in Clinical Trials) available at: https://www.fda.gov/media/162416/download). Conclusions: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences-namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.

Chronic Lung Injury after COVID-19 Pneumonia: Clinical, Radiologic, and Histopathologic Perspectives.

With the COVID-19 pandemic having lasted more than 3 years, concerns are growing about prolonged symptoms and respiratory complications in COVID-19 survivors, collectively termed post-COVID-19 condition (PCC). Up to 50% of patients have residual symptoms and physiologic impairment, particularly dyspnea and reduced diffusion capacity. Studies have also shown that 24%-54% of patients hospitalized during the 1st year of the pandemic exhibit radiologic abnormalities, such as ground-glass opacity, reticular opacity, bronchial dilatation, and air trapping, when imaged more than 1 year after infection. In patients with persistent respiratory symptoms but normal results at chest CT, dual-energy contrast-enhanced CT, xenon 129 MRI, and low-field-strength MRI were reported to show abnormal ventilation and/or perfusion, suggesting that some lung injury may not be detectable with standard CT. Histologic patterns in post-COVID-19 lung disease include fibrosis, organizing pneumonia, and vascular abnormality, indicating that different pathologic mechanisms may contribute to PCC. Therefore, a comprehensive imaging approach is necessary to evaluate and diagnose patients with persistent post-COVID-19 symptoms. This review will focus on the long-term findings of clinical and radiologic abnormalities and describe histopathologic perspectives. It also addresses advanced imaging techniques and deep learning approaches that can be applied to COVID-19 survivors. This field remains an active area of research, and further follow-up studies are warranted for a better understanding of the chronic stage of the disease and developing a multidisciplinary approach for patient management.

Quantification of Emphysema Progression at CT Using Simultaneous Volume, Noise, and Bias Lung Density Correction.

Background CT attenuation is affected by lung volume, dosage, and scanner bias, leading to inaccurate emphysema progression measurements in multicenter studies. Purpose To develop and validate a method that simultaneously corrects volume, noise, and interscanner bias for lung density change estimation in emphysema progression at CT in a longitudinal multicenter study. Materials and Methods In this secondary analysis of the prospective Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study, lung function data were obtained from participants who completed baseline and 5-year follow-up visits from January 2008 to August 2017. CT emphysema progression was measured with volume-adjusted lung density (VALD) and compared with the joint volume-noise-bias-adjusted lung density (VNB-ALD). Reproducibility was studied under change of dosage protocol and scanner model with repeated acquisitions. Emphysema progression was visually scored in 102 randomly selected participants. A stratified analysis of clinical characteristics was performed that considered groups based on their combined lung density change measured by VALD and VNB-ALD. Results A total of 4954 COPDGene participants (mean age, 60 years ± 9 [SD]; 2511 male, 2443 female) were analyzed (1329 with repeated reduced-dose acquisition in the follow-up visit). Mean repeatability coefficients were 30 g/L ± 0.46 for VALD and 14 g/L ± 0.34 for VNB-ALD. VALD measurements showed no evidence of differences between nonprogressors and progressors (mean, -5.5 g/L ± 9.5 vs -8.6 g/L ± 9.6; P = .11), while VNB-ALD agreed with visual readings and showed a difference (mean, -0.67 g/L ± 4.8 vs -4.2 g/L ± 5.5; P < .001). Analysis of progression showed that VNB-ALD progressors had a greater decline in forced expiratory volume in 1 second (-42 mL per year vs -32 mL per year; Tukey-adjusted P = .002). Conclusion Simultaneously correcting volume, noise, and interscanner bias for lung density change estimation in emphysema progression at CT improved repeatability analyses and agreed with visual readings. It distinguished between progressors and nonprogressors and was associated with a greater decline in lung function metrics. Clinical trial registration no. NCT00608764 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Goo in this issue.

Fleischner Society: Glossary of Terms for Thoracic Imaging.

Members of the Fleischner Society have compiled a glossary of terms for thoracic imaging that replaces previous glossaries published in 1984, 1996, and 2008, respectively. The impetus to update the previous version arose from multiple considerations. These include an awareness that new terms and concepts have emerged, others have become obsolete, and the usage of some terms has either changed or become inconsistent to a degree that warranted a new definition. This latest glossary is focused on terms of clinical importance and on those whose meaning may be perceived as vague or ambiguous. As with previous versions, the aim of the present glossary is to establish standardization of terminology for thoracic radiology and, thereby, to facilitate communications between radiologists and clinicians. Moreover, the present glossary aims to contribute to a more stringent use of terminology, increasingly required for structured reporting and accurate searches in large databases. Compared with the previous version, the number of images (chest radiography and CT) in the current version has substantially increased. The authors hope that this will enhance its educational and practical value. All definitions and images are hyperlinked throughout the text. Click on each figure callout to view corresponding image. © RSNA, 2024 Supplemental material is available for this article. See also the editorials by Bhalla and Powell in this issue.

Local heterogeneity of normal lung parenchyma and small airways disease are associated with COPD severity and progression.

BACKGROUND: Small airways disease (SAD) is a major cause of airflow obstruction in COPD patients and has been identified as a precursor to emphysema. Although the amount of SAD in the lungs can be quantified using our Parametric Response Mapping (PRM) approach, the full breadth of this readout as a measure of emphysema and COPD progression has yet to be explored. We evaluated topological features of PRM-derived normal parenchyma and SAD as surrogates of emphysema and predictors of spirometric decline. METHODS: PRM metrics of normal lung (PRMNorm) and functional SAD (PRMfSAD) were generated from CT scans collected as part of the COPDGene study (n = 8956). Volume density (V) and Euler-Poincaré Characteristic (χ) image maps, measures of the extent and coalescence of pocket formations (i.e., topologies), respectively, were determined for both PRMNorm and PRMfSAD. Association with COPD severity, emphysema, and spirometric measures were assessed via multivariable regression models. Readouts were evaluated as inputs for predicting FEV1 decline using a machine learning model. RESULTS: Multivariable cross-sectional analysis of COPD subjects showed that V and χ measures for PRMfSAD and PRMNorm were independently associated with the amount of emphysema. Readouts χfSAD (ß of 0.106, p < 0.001) and VfSAD (ß of 0.065, p = 0.004) were also independently associated with FEV1% predicted. The machine learning model using PRM topologies as inputs predicted FEV1 decline over five years with an AUC of 0.69. CONCLUSIONS: We demonstrated that V and χ of fSAD and Norm have independent value when associated with lung function and emphysema. In addition, we demonstrated that these readouts are predictive of spirometric decline when used as inputs in a ML model. Our topological PRM approach using PRMfSAD and PRMNorm may show promise as an early indicator of emphysema onset and COPD progression.

Impact of EASO/ESPEN-Defined Sarcopenic Obesity Following a Technology-Based Weight Loss Intervention.

BACKGROUND: Sarcopenic Obesity is the co-existence of increased adipose tissue (obesity) and decreased muscle mass or strength (sarcopenia) and is associated with worse outcomes than obesity alone. The new EASO/ESPEN consensus provides a framework to standardize its definition. This study sought to evaluate whether there are preliminary differences observed in weight loss or physical function in older adults with and without sarcopenic obesity taking part in a multicomponent weight loss intervention using these new definitions. METHODS: A 6-month, non-randomized, non-blinded, single-arm pilot study was conducted from 2018 to 2020 in adults ≥ 65 years with a body mass index (BMI) ≥ 30 kg/m2. Weekly dietitian visits and twice-weekly physical therapist-led exercise classes were delivered using telemedicine. We conducted a secondary retrospective analysis of the parent study (n = 53 enrolled, n = 44 completers) that investigated the feasibility of a technology-based weight management intervention in rural older adults with obesity. Herein, we applied five definitions of sarcopenic obesity (outlined in the consensus) to ascertain whether the response to the intervention differed among those with and without sarcopenic obesity. Primary outcomes evaluated included weight loss and physical function (30-s sit-to-stand). RESULTS: In the parent study, mean weight loss was - 4.6 kg (95% CI - 3.6, - 5.6; p < 0.001). Physical function measures of 30-s sit-to-stand showed a mean increase of 3.1 in sit-to-stand repetitions (+ 1.9, + 4.3; p < 0.001). In this current analysis, there was a significant decrease in weight and an increase in repetitions between baseline and follow-up within each group of individuals with and without sarcopenia for each of the proposed definitions. However, we did not observe any significant differences in the changes between groups from baseline to follow-up. CONCLUSIONS: The potential lack of significant differences in weight loss or physical function between older adults with and without sarcopenic obesity participating in a weight loss intervention may suggest that well-designed, multicomponent interventions can lead to similar outcomes irrespective of sarcopenia status in persons with obesity. Fully powered randomized clinical trials are critically needed to confirm these preliminary results.

Cardiopulmonary exercise testing on adaptive equipment in children and adults with Friedreich ataxia.

INTRODUCTION/AIMS: Traditional exercise is often difficult for individuals with Friedreich ataxia (FRDA), and evidence is limited regarding how to measure exercise performance in this population. We evaluated the feasibility, reliability, and natural history of adaptive cardiopulmonary exercise test (CPET) performance in children and adults with FRDA. METHODS: Participants underwent CPET on either an arm cycle ergometer (ACE) or recumbent leg cycle ergometer (RLCE) at up to four visits (baseline, 2 weeks, 4 weeks, and 1 year). Maximum work, oxygen consumption (peak VO2), oxygen (O2) pulse, and anaerobic threshold (AT) were measured in those who reached maximal volition. Test-retest reliability was assessed with intraclass coefficients, and longitudinal change was assessed using regression analysis. RESULTS: In our cohort (N = 23), median age was 18 years (interquartile range [IQR], 14-23), median age of FRDA onset was 8 years (IQR 6-13), median Friedreich Ataxia Rating Scale score was 58 (IQR 54-62), and GAA repeat length on the shorter FXN allele (GAA1) was 766 (IQR, 650-900). Twenty-one (91%) completed a maximal CPET (n = 8, ACE and n = 13, RLCE). Age, sex, and GAA1 repeat length were each associated with peak VO2. Preliminary estimates demonstrated reasonable agreement between visits 2 and 3 for peak work by both ACE and RLCE, and for peak VO2, O2 pulse, and AT by RLCE. We did not detect significant performance changes over 1 year. DISCUSSION: Adaptive CPET is feasible in FRDA, a relevant clinical trial outcome for interventions that impact exercise performance and will increase access to participation as well as generalizability of findings.

Progressive Pulmonary Fibrosis and Interstitial Lung Abnormalities: AJR Expert Panel Narrative Review.

Progressive pulmonary fibrosis (PPF) and interstitial lung abnormalities (ILA) are relatively new concepts in interstitial lung disease (ILD) imaging and clinical management. Recognition of signs of PPF, as well as identification and classification of ILA, are important tasks during chest high-resolution CT interpretation, to optimize management of patients with ILD and those at risk of developing ILD. However, following professional society guidance, the role of imaging surveillance remains unclear in stable patients with ILD, asymptomatic patients with ILA who are at risk of progression, and asymptomatic patients at risk of developing ILD without imaging abnormalities. In this AJR Expert Panel Narrative Review, we summarize the current knowledge regarding PPF and ILA and describe the range of clinical practice with respect to imaging patients with ILD, those with ILA, and those at risk of developing ILD. In addition, we offer suggestions to help guide surveillance imaging in areas with an absence of published guidelines, where such decisions are currently driven primarily by local pulmonologists' preference.

Central Role of CT in Management of Pulmonary Fibrosis.

With the approval of antifibrotic medications to treat patients with idiopathic pulmonary fibrosis and progressive pulmonary fibrosis, radiologists have an integral role in diagnosing these entities and guiding treatment decisions. CT features of early pulmonary fibrosis include irregular thickening of interlobular septa, pleura, and intralobular linear structures, with subsequent progression to reticular abnormality, traction bronchiectasis or bronchiolectasis, and honeycombing. CT patterns of fibrotic lung disease can often be reliably classified on the basis of the CT features and distribution of the condition. Accurate identification of usual interstitial pneumonia (UIP) or probable UIP patterns by radiologists can obviate the need for a tissue sample-based diagnosis. Other entities that can appear as a UIP pattern must be excluded in multidisciplinary discussion before a diagnosis of idiopathic pulmonary fibrosis is made. Although the imaging findings of nonspecific interstitial pneumonia and fibrotic hypersensitivity pneumonitis can overlap with those of a radiologic UIP pattern, these entities can often be distinguished by paying careful attention to the radiologic signs. Diagnostic challenges may include misdiagnosis of fibrotic lung disease due to pitfalls such as airspace enlargement with fibrosis, paraseptal emphysema, recurrent aspiration, and postinfectious fibrosis. The radiologist also plays an important role in identifying complications of pulmonary fibrosis-pulmonary hypertension, acute exacerbation, infection, and lung cancer in particular. In cases in which there is uncertainty regarding the clinical and radiologic diagnoses, surgical biopsy is recommended, and a multidisciplinary discussion among clinicians, radiologists, and pathologists can be used to address diagnosis and management strategies. This review is intended to help radiologists diagnose and manage pulmonary fibrosis more accurately, ultimately aiding in the clinical management of affected patients. ©RSNA, 2024 Supplemental material is available for this article.

FXN gene methylation determines carrier status in Friedreich ataxia.

BACKGROUND: Friedreich ataxia (FRDA) is typically caused by homozygosity for an expanded GAA triplet-repeat (GAA-TRE) in intron 1 of the FXN gene. Some patients are compound heterozygous for the GAA-TRE and another FXN pathogenic variant. Detection of the GAA-TRE in the heterozygous state, occasionally technically challenging, is essential for diagnosing compound heterozygotes and asymptomatic carriers. OBJECTIVE: We explored if the FRDA differentially methylated region (FRDA-DMR) in intron 1, which is hypermethylated in cis with the GAA-TRE, effectively detects heterozygous GAA-TRE. METHODS: FXN DNA methylation was assayed by targeted bisulfite deep sequencing using the Illumina platform. RESULTS: FRDA-DMR methylation effectively identified a cohort of known heterozygous carriers of the GAA-TRE. In an individual with clinical features of FRDA, commercial testing showed a paternally inherited pathogenic FXN initiation codon variant but no GAA-TRE. Methylation in the FRDA-DMR effectively identified the proband, his mother and various maternal relatives as heterozygous carriers of the GAA-TRE, thus confirming the diagnosis of FRDA. CONCLUSION: FXN DNA methylation reliably detects the GAA-TRE in the heterozygous state and offers a robust alternative strategy to diagnose FRDA due to compound heterozygosity and to identify asymptomatic heterozygous carriers of the GAA-TRE.

Deep Learning Assessment of Progression of Emphysema and Fibrotic Interstitial Lung Abnormality.

Rationale: Although studies have evaluated emphysema and fibrotic interstitial lung abnormality individually, less is known about their combined progression. Objectives: To define clinically meaningful progression of fibrotic interstitial lung abnormality in smokers without interstitial lung disease and evaluate the effects of fibrosis and emphysema progression on mortality. Methods: Emphysema and pulmonary fibrosis were assessed on the basis of baseline and 5-year follow-up computed tomography scans of 4,450 smokers in the COPDGene Study using deep learning algorithms. Emphysema was classified as absent, trace, mild, moderate, confluent, or advanced destructive. Fibrosis was expressed as a percentage of lung volume. Emphysema progression was defined as an increase by at least one grade. A hybrid distribution and anchor-based method was used to determine the minimal clinically important difference in fibrosis. The relationship between progression and mortality was evaluated using multivariable shared frailty models using an age timescale. Measurements and Main Results: The minimal clinically important difference for fibrosis was 0.58%. On the basis of this threshold, 2,822 (63%) had progression of neither emphysema nor fibrosis, 841 (19%) had emphysema progression alone, 512 (12%) had fibrosis progression alone, and 275 (6.2%) had progression of both. Compared with nonprogressors, hazard ratios for mortality were 1.42 (95% confidence interval, 1.11-1.82) in emphysema progressors, 1.49 (1.14-1.94) in fibrosis progressors, and 2.18 (1.58-3.02) in those with progression of both emphysema and fibrosis. Conclusions: In smokers without known interstitial lung disease, small changes in fibrosis may be clinically significant, and combined progression of emphysema and fibrosis is associated with increased mortality.

Suspected Interstitial Lung Disease in COPDGene Study.

Rationale: Although interstitial lung abnormalities (ILA), specific patterns of incidentally-detected abnormal density on computed tomography, have been associated with abnormal lung function and increased mortality, it is unclear if a subset with incidental interstitial lung disease (ILD) accounts for these adverse consequences. Objectives: To define the prevalence and risk factors of suspected ILD and assess outcomes. Methods: Suspected ILD was evaluated in the COPDGene (Chronic Obstructive Pulmonary Disease Genetic Epidemiology) study, defined as ILA and at least one additional criterion: definite fibrosis on computed tomography, FVC less than 80% predicted, or DLCO less than 70% predicted. Multivariable linear, longitudinal, and Cox proportional hazards regression models were used to assess associations with St. George's Respiratory Questionnaire, 6-minute-walk test, supplemental oxygen use, respiratory exacerbations, and mortality. Measurements and Main Results: Of 4,361 participants with available data, 239 (5%) had evidence for suspected ILD, whereas 204 (5%) had ILA without suspected ILD. In multivariable analyses, suspected ILD was associated with increased St. George's Respiratory Questionnaire score (mean difference [MD], 3.9 points; 95% confidence interval [CI], 0.6-7.1; P = 0.02), reduced 6-minute-walk test (MD, -35 m; 95% CI, -56 m to -13 m; P = 0.002), greater supplemental oxygen use (odds ratio [OR], 2.3; 95% CI, 1.1-5.1; P = 0.03) and severe respiratory exacerbations (OR, 2.9; 95% CI, 1.1-7.5; P = 0.03), and higher mortality (hazard ratio, 2.4; 95% CI, 1.2-4.6; P = 0.01) compared with ILA without suspected ILD. Risk factors associated with suspected ILD included self-identified Black race (OR, 2.0; 95% CI, 1.1-3.3; P = 0.01) and pack-years smoking history (OR, 1.2; 95% CI, 1.1-1.3; P = 0.0005). Conclusions: Suspected ILD is present in half of those with ILA in COPDGene and is associated with exercise decrements and increased symptoms, supplemental oxygen use, severe respiratory exacerbations, and mortality.

Incidence and Progression of Fibrotic Lung Disease in an At-Risk Cohort.

Rationale: Relatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis and develop preclinical pulmonary fibrosis (PrePF). Objectives: We defined the incidence and progression of new-onset PrePF and its relationship to survival among first-degree relatives of families with FIP. Methods: This is a cohort study of family members with FIP who were initially screened with a health questionnaire and chest high-resolution computed tomography (HRCT) scan, and approximately 4 years later, the evaluation was repeated. A total of 493 asymptomatic first-degree relatives of patients with FIP were evaluated at baseline, and 296 (60%) of the original subjects participated in the subsequent evaluation. Measurements and Main Results: The median interval between HRCTs was 3.9 years (interquartile range, 3.5-4.4 yr). A total of 252 subjects who agreed to repeat evaluation were originally determined not to have PrePF at baseline; 16 developed PrePF. A conservative estimate of the annual incidence of PrePF is 1,023 per 100,000 person-years (95% confidence interval, 511-1,831 per 100,000 person-years). Of 44 subjects with PrePF at baseline, 38.4% subjects had worsening dyspnea compared with 15.4% of those without PrePF (P = 0.002). Usual interstitial pneumonia by HRCT (P < 0.0002) and baseline quantitative fibrosis score (P < 0.001) are also associated with worsening dyspnea. PrePF at the initial screen is associated with decreased survival (P < 0.001). Conclusions: The incidence of PrePF in this at-risk population is at least 100-fold higher than that reported for sporadic idiopathic pulmonary fibrosis (IPF). Although PrePF and IPF represent distinct entities, our study demonstrates that PrePF, like IPF, is progressive and associated with decreased survival.

Perioperative management and outcomes for posterior spinal fusion in patients with Friedreich ataxia: A single-center, retrospective study.

BACKGROUND: Friedreich ataxia is a rare genetic disorder associated with progressive mitochondrial dysfunction leading to widespread sequelae including ataxia, muscle weakness, hypertrophic cardiomyopathy, diabetes mellitus, and neuromuscular scoliosis. Children with Friedreich ataxia are at high risk for periprocedural complications during posterior spinal fusion due to their comorbidities. AIM: To describe our single-center perioperative management of patients with Friedreich ataxia undergoing posterior spinal fusion. METHODS: Adolescent patients with Friedreich ataxia presenting for spinal deformity surgery between 2007 and 2023 were included in this retrospective case series performed at the Children's Hospital of Philadelphia. Perioperative outcomes were reviewed along with preoperative characteristics, intraoperative anesthetic management, and postoperative medical management. RESULTS: Seventeen patients were included in the final analysis. The mean age was 15 ± 2 years old and 47% were female. Preoperatively, 35% were wheelchair dependent, 100% had mild-to-moderate hypertrophic cardiomyopathy with preserved systolic function and no left ventricular outflow tract obstruction, 29% were on cardiac medications, and 29% were on pain medications. Intraoperatively, 53% had transesophageal echocardiography monitoring; 12% had changes in volume status on echo but no changes in function. Numerous combinations of total intravenous anesthetic agents were used, most commonly propofol, remifentanil, and ketamine. Baseline neuromonitoring signals were poor in four patients and one patient lost signals, resulting in 4 (24%) wake-up tests. The majority (75%) were extubated in the operating room. Postoperative complications were high (88%) and ranged from minor complications like nausea/vomiting (18%) to major complications like hypotension/tachycardia (29%) and need for extracorporeal membrane oxygenation support in one patient (6%). CONCLUSIONS: Patients with Friedreich ataxia are at high risk for perioperative complications when undergoing posterior spinal fusion and coordinated multidisciplinary care is required at each stage. Future research should focus on the utility of intraoperative echocardiography, optimal anesthetic agent selection, and targeted fluid management to reduce postoperative cardiac complications.

Characterization of Cardiac-Onset Initial Presentation in Friedreich Ataxia.

We examined the clinical features of Friedreich ataxia (FRDA) patients who present first with cardiac disease in order to understand the earliest features of the diagnostic journey in FRDA. We identified a group of subjects in the FACOMS natural history study whose first identified clinical feature was cardiac. Only 0.5% of the total cohort belonged to this group, which was younger on average at the time of presentation. Their cardiac symptoms ranged from asymptomatic features to heart failure with severe systolic dysfunction. Two of those individuals with severe dysfunction proceeded to heart transplantation, but others spontaneously recovered. In most cases, diagnosis of FRDA was not made until well after cardiac presentation. The present study shows that some FRDA patients present based on cardiac features, suggesting that earlier identification of FRDA might occur through enhancing awareness of FRDA among pediatric cardiologists who see such patients. This is important in the context of newly identified therapies for FRDA.

Idiopathic Pulmonary Fibrosis: A Genetic Disease That Involves Mucociliary Dysfunction of the Peripheral Airways.

Idiopathic pulmonary fibrosis (IPF) is an incurable complex genetic disorder that is associated with sequence changes in 7 genes (MUC5B, TERT, TERC, RTEL1, PARN, SFTPC, and SFTPA2) and with variants in at least 11 novel loci. We have previously found that 1) a common gain-of-function promoter variant in MUC5B rs35705950 is the strongest risk factor (genetic and otherwise), accounting for 30-35% of the risk of developing IPF, a disease that was previously considered idiopathic; 2) the MUC5B promoter variant can potentially be used to identify individuals with preclinical pulmonary fibrosis and is predictive of radiologic progression of preclinical pulmonary fibrosis; and 3) MUC5B may be involved in the pathogenesis of pulmonary fibrosis with MUC5B message and protein expressed in bronchiolo-alveolar epithelia of IPF and the characteristic IPF honeycomb cysts. Based on these considerations, we hypothesize that excessive production of MUC5B either enhances injury due to reduced mucociliary clearance or impedes repair consequent to disruption of normal regenerative mechanisms in the distal lung. In aggregate, these novel considerations should have broad impact, resulting in specific etiologic targets, early detection of disease, and novel biologic pathways for use in the design of future intervention, prevention, and mechanistic studies of IPF.