Development, Progression, and Mortality of Suspected Interstitial Lung Disease in COPDGene.

RATIONALE: Some with interstitial lung abnormalities (ILA) have suspected interstitial lung disease (ILD), a subgroup with adverse outcomes. Rates of development and progression of suspected ILD and their effect on mortality are unknown. OBJECTIVES: To determine rates of development and progression of suspected ILD and assess effects of individual ILD and progression criteria on mortality. METHODS: Participants from COPDGene were included. ILD was defined as ILA and fibrosis and/or FVC <80% predicted. Prevalent ILD was assessed at enrollment, incident ILD and progression at 5-year follow-up. CT progression was assessed visually and FVC decline as relative change. Multivariable Cox regression tested associations between mortality and ILD groups. RESULTS: Of 9,588 participants at enrollment, 267 (2.8%) had prevalent ILD. Those with prevalent ILD had 52% mortality after median 10.6 years, which was higher than ILA (33%; HR=2.0; p<0.001). The subgroup of prevalent ILD with fibrosis only had worse mortality (59%) than ILA (HR=2.2; p<0.001). 97 participants with prevalent ILD completed 5-year follow-up: 32% had stable CT and relative FVC decline <10%, 6% FVC decline ≥10% only, 39% CT progression only, and 22% both CT progression and FVC decline ≥10%. Mortality rates were 32%, 50%, 45%, and 46% respectively; those with CT progression only had worse mortality than ILA (HR=2.6; p=0.005). At 5-year follow-up, incident ILD occurred in 168/4,843 participants without prevalent ILD and had worse mortality than ILA (HR=2.5; p<0.001). CONCLUSION: Rates of mortality and progression are high among those with suspected ILD in COPDGene; fibrosis and radiologic progression are important predictors of mortality.

Assessment of pulmonary function in COPD patients using dynamic digital radiography: A novel approach utilizing lung signal intensity changes during forced breathing.

Objectives: To investigate the association of lung signal intensity changes during forced breathing using dynamic digital radiography (DDR) with pulmonary function and disease severity in patients with chronic obstructive pulmonary disease (COPD). Methods: This retrospective study included 46 healthy subjects and 33 COPD patients who underwent posteroanterior chest DDR examination. We collected raw signal intensity and gray-scale image data. The lung contour was extracted on the gray-scale images using our previously developed automated lung field tracking system and calculated the average of signal intensity values within the extracted lung contour on gray-scale images. Lung signal intensity changes were quantified as SImax/SImin, representing the maximum ratio of the average signal intensity in the inspiratory phase to that in the expiratory phase. We investigated the correlation between SImax/SImin and pulmonary function parameters, and differences in SImax/SImin by disease severity. Results: SImax/SImin showed the highest correlation with VC (rs = 0.54, P < 0.0001), followed by FEV1 (rs = 0.44, P < 0.0001), both of which are key indicators of COPD pathophysiology. In a multivariate linear regression analysis adjusted for confounding factors, SImax/SImin was significantly lower in the severe COPD group compared to the normal group (P = 0.0004) and mild COPD group (P=0.0022), suggesting its potential usefulness in assessing COPD severity. Conclusion: This study suggests that the signal intensity changes of lung fields during forced breathing using DDR reflect the pathophysiology of COPD and can be a useful index in assessing pulmonary function in COPD patients, potentially improving COPD diagnosis and management.

Idiopathic dendriform pulmonary ossification as the phenotype of interstitial lung abnormalities: CT-pathologic correlation and prevalence.

BACKGROUND AND PURPOSE: Idiopathic dendriform pulmonary ossification (DPO) is mostly asymptomatic, and detected incidentally in lung CT. There have been no reports on the precise CT-pathologic correlation and the prevalence of idiopathic DPO. This study aimed to clarify the histological background and prevalence of idiopathic DPO. MATERIALS AND METHODS: Sixteen patients with histologically confirmed idiopathic DPO (12 men and 4 women; mean age, 38.8 years; range 22-56 years) were identified in a nationwide epidemiological survey. Local HRCT findings of pre-biopsy examinations, such as branching, round, linear structures with or without high attenuation were compared side by side with histological findings. The attenuation of branching, round, and linear structures was classified into three-point levels on bone window images (width, 2500 HU; level, 500 HU). Furthermore, we collected continuous pulmonary CT images of 8111 cases for checking up metastasis from extrathoracic malignancy at a single institution, and evaluated the prevalence of interstitial lung abnormalities (ILAs) and DPO. RESULTS: In all 16 cases, branching (n = 15, 93%), round (n = 5, 31%), or linear (n = 5, 31%) structures were identified, histologically corresponding to dendriform ossification and cicatricial organizing pneumonia (OP)/fibrosis. Histologically, ossification was confirmed in all the 16 patients. However, in two cases, a highly attenuated structure could not be detected on the pre-biopsy CT of the same area. Regarding the prevalence of idiopathic DPO, 283 (3.5%) of 8111 patients had ILAs, of which a total of 26 (0.3% of all cases, 9.2% of ILAs cases) had DPO. CONCLUSION: Idiopathic DPO showed linear or branching structures with or without high attenuation on CT, corresponded to ossification, cicatricial OP/fibrosis. DPO was seen in 9.2% of ILAs cases. Idiopathic DPO is one of pathologic phenotypes of ILAs.

Interstitial Lung Abnormalities: Current Understanding.

Interstitial lung abnormalities (ILAs) are incidental findings on computed tomography scans, characterized by nondependent abnormalities affecting more than 5% of any lung zone. They are associated with factors such as age, smoking, genetic variants, worsened clinical outcomes, and increased mortality. Risk stratification based on clinical and radiological features of ILAs is crucial in clinical practice, particularly for identifying cases at high risk of progression to pulmonary fibrosis. Traction bronchiectasis/bronchiolectasis index has emerged as a promising imaging biomarker for prognostic risk stratification in ILAs. These findings suggest a spectrum of fibrosing interstitial lung diseases, encompassing from ILAs to pulmonary fibrosis.

Association between interstitial lung abnormality and mortality in patients with esophageal cancer.

PURPOSE: To investigate the relationship between interstitial lung abnormalities (ILAs) and mortality in patients with esophageal cancer and the cause of mortality. MATERIALS AND METHODS: This retrospective study investigated patients with esophageal cancer from January 2011 to December 2015. ILAs were visually scored on baseline CT using a 3-point scale (0 = non-ILA, 1 = indeterminate for ILA, and 2 = ILA). ILAs were classified into subcategories of non-subpleural, subpleural non-fibrotic, and subpleural fibrotic. Five-year overall survival (OS) was compared between patients with and without ILAs using the multivariable Cox proportional hazards model. Subgroup analyses were performed based on cancer stage and ILA subcategories. The prevalences of treatment complications and death due to esophageal cancer and pneumonia/respiratory failure were analyzed using Fisher's exact test. RESULTS: A total of 478 patients with esophageal cancer (age, 66.8 years ± 8.6 [standard deviation]; 64 women) were evaluated in this study. Among them, 267 patients showed no ILAs, 125 patients were indeterminate for ILAs, and 86 patients showed ILAs. ILAs were a significant factor for shorter OS (hazard ratio [HR] = 1.68, 95% confidence interval [CI] 1.10-2.55, P = 0.016) in the multivariable Cox proportional hazards model adjusting for age, sex, smoking history, clinical stage, and histology. On subgroup analysis using patients with clinical stage IVB, the presence of ILAs was a significant factor (HR = 3.78, 95% CI 1.67-8.54, P = 0.001). Subpleural fibrotic ILAs were significantly associated with shorter OS (HR = 2.22, 95% CI 1.25-3.93, P = 0.006). There was no significant difference in treatment complications. Patients with ILAs showed a higher prevalence of death due to pneumonia/respiratory failure than those without ILAs (non-ILA, 2/95 [2%]; ILA, 5/39 [13%]; P = 0.022). The prevalence of death due to esophageal cancer was similar in patients with and without ILA (non-ILA, 82/95 [86%]; ILA 32/39 [82%]; P = 0.596). CONCLUSION: ILAs were significantly associated with shorter survival in patients with esophageal cancer.

Short peripheral blood leukocyte telomere length in rheumatoid arthritis-interstitial lung disease.

Shortened telomere lengths (TLs) can be caused by single nucleotide polymorphisms and loss-of-function mutations in telomere-related genes (TRG), as well as ageing and lifestyle factors such as smoking. Our objective was to determine if shortened TL is associated with interstitial lung disease (ILD) in individuals with rheumatoid arthritis (RA). This is the largest study to demonstrate and replicate that shortened peripheral blood leukocytes-TL is associated with ILD in patients with RA compared with RA without ILD in a multinational cohort, and short PBL-TL was associated with baseline disease severity in RA-ILD as measured by forced vital capacity percent predicted.

Imaging of Pulmonary Fibrosis: An Update, From the AJR Special Series on Imaging of Fibrosis.

Pulmonary fibrosis is recognized as occurring in association with a wide and increasing array of conditions, and it presents with a spectrum of chest CT appearances. Idiopathic pulmonary fibrosis (IPF), which corresponds histologically with usual interstitial pneumonia and represents the most common idiopathic interstitial pneumonia, is a chronic progressive fibrotic interstitial lung disease (ILD) of unknown cause. Progressive pulmonary fibrosis (PPF) describes the radiologic development of pulmonary fibrosis in patients with ILD of a known or unknown cause other than IPF. The recognition of PPF impacts management of patients with ILD-for example, in guiding initiation of antifibrotic therapy. Interstitial lung abnormalities are an incidental CT finding in patients without suspected ILD and may represent an early intervenable form of pulmonary fibrosis. Traction bronchiectasis and/or bronchiolectasis, when detected in the setting of chronic fibrosis, is generally considered evidence of irreversible disease, and progression predicts worsening mortality risk. Awareness of the association between pulmonary fibrosis and connective tissue diseases, particularly rheumatoid arthritis, is increasing. This review provides an update on the imaging of pulmonary fibrosis, with attention given to recent advances in disease understanding with relevance to radiologic practice. The essential role of a multidisciplinary approach to clinical and radiologic data is highlighted.

Incidence and severity of pulmonary embolism in COVID-19 infection: Ancestral, Alpha, Delta, and Omicron variants.

Little information is available regarding incidence and severity of pulmonary embolism (PE) across the periods of ancestral strain, Alpha, Delta, and Omicron variants. The aim of this study is to investigate the incidence and severity of PE over the dominant periods of ancestral strain and Alpha, Delta, and Omicron variants. We hypothesized that the incidence and the severity by proximity of PE in patients with the newer variants and vaccination would be decreased compared with those in ancestral and earlier variants. Patients with COVID-19 diagnosis between March 2020 and February 2022 and computed tomography pulmonary angiogram performed within a 6-week window around the diagnosis (-2 to +4 weeks) were studied retrospectively. The primary endpoints were the associations of the incidence and location of PE with the ancestral strain and each variant. Of the 720 coronavirus disease 2019 patients with computed tomography pulmonary angiogram (58.6 ± 17.2 years; 374 females), PE was diagnosed among 42/358 (12%) during the ancestral strain period, 5/60 (8%) during the Alpha variant period, 16/152 (11%) during the Delta variant period, and 13/150 (9%) during the Omicron variant period. The most proximal PE (ancestral strain vs variants) was located in the main/lobar arteries (31% vs 6%-40%), in the segmental arteries (52% vs 60%-75%), and in the subsegmental arteries (17% vs 0%-19%). There was no significant difference in both the incidence and location of PE across the periods, confirmed by multivariable logistic regression models. In summary, the incidence and severity of PE did not significantly differ across the periods of ancestral strain and Alpha, Delta, and Omicron variants.

Stepwise diagnostic algorithm for high-attenuation pulmonary abnormalities on CT.

High-attenuation pulmonary abnormalities are commonly seen on CT. These findings are increasingly encountered with the growing number of CT examinations and the wide availability of thin-slice images. The abnormalities include benign lesions, such as infectious granulomatous diseases and metabolic diseases, and malignant tumors, such as lung cancers and metastatic tumors. Due to the wide spectrum of diseases, the proper diagnosis of high-attenuation abnormalities can be challenging. The assessment of these abnormal findings requires scrutiny, and the treatment is imperative. Our proposed stepwise diagnostic algorithm consists of five steps. Step 1: Establish the presence or absence of metallic artifacts. Step 2: Identify associated nodular or mass-like soft tissue components. Step 3: Establish the presence of solitary or multiple lesions if identified in Step 2. Step 4: Ascertain the predominant distribution in the upper or lower lungs if not identified in Step 2. Step 5: Identify the morphological pattern, such as linear, consolidation, nodular, or micronodular if not identified in Step 4. These five steps to diagnosing high-attenuation abnormalities subdivide the lesions into nine categories. This stepwise radiologic diagnostic approach could help to narrow the differential diagnosis for various pulmonary high-attenuation abnormalities and to achieve a precise diagnosis.Critical relevance statement Our proposed stepwise diagnostic algorithm for high-attenuation pulmonary abnormalities may help to recognize a variety of those high-attenuation findings, to determine whether the associated diseases require further investigation, and to guide appropriate patient management. Key points • To provide a stepwise diagnostic approach to high-attenuation pulmonary abnormalities.• To familiarize radiologists with the varying cause of high-attenuation pulmonary abnormalities.• To recognize which high-attenuation abnormalities require scrutiny and prompt treatment.

Bronchial epithelial gene expression and interstitial lung abnormalities.

INTRODUCTION: Interstitial lung abnormalities (ILA) often represent early fibrotic changes that can portend a progressive fibrotic phenotype. In particular, the fibrotic subtype of ILA is associated with increased mortality and rapid decline in lung function. Understanding the differential gene expression that occurs in the lungs of participants with fibrotic ILA may provide insight into development of a useful biomarker for early detection and therapeutic targets for progressive pulmonary fibrosis. METHODS: Measures of ILA and gene expression data were available in 213 participants in the Detection of Early Lung Cancer Among Military Personnel (DECAMP1 and DECAMP2) cohorts. ILA was defined using Fleischner Society guidelines and determined by sequential reading of computed tomography (CT) scans. Primary analysis focused on comparing gene expression in ILA with usual interstitial pneumonia (UIP) pattern with those with no ILA. RESULTS: ILA was present in 51 (24%) participants, of which 16 (7%) were subtyped as ILA with a UIP pattern. One gene, pro platelet basic protein (PPBP) and seventeen pathways (e.g. TNF-α signalling) were significantly differentially expressed between those with a probable or definite UIP pattern of ILA compared to those without ILA. 16 of these 17 pathways, but no individual gene, met significance when comparing those with ILA to those without ILA. CONCLUSION: Our study demonstrates that abnormal inflammatory processes are apparent in the bronchial airway gene expression profiles of smokers with and without lung cancer with ILA. Future studies with larger and more diverse populations will be needed to confirm these findings.

Prevalence and mortality associations of interstitial lung abnormalities in rheumatoid arthritis within a multicentre prospective cohort of smokers.

OBJECTIVE: To investigate the prevalence and mortality impact of interstitial lung abnormalities (ILAs) in RA and non-RA comparators. METHODS: We analysed associations between ILAs, RA, and mortality in COPDGene, a multicentre prospective cohort study of current and past smokers, excluding known interstitial lung disease (ILD) or bronchiectasis. All participants had research chest high-resolution CT (HRCT) reviewed by a sequential reading method to classify ILA as present, indeterminate or absent. RA cases were identified by self-report RA and DMARD use; non-RA comparators had neither an RA diagnosis nor used DMARDs. We examined the association and mortality risk of RA and ILA using multivariable logistic regression and Cox regression. RESULTS: We identified 83 RA cases and 8725 non-RA comparators with HRCT performed for research purposes. ILA prevalence was 16.9% in RA cases and 5.0% in non-RA comparators. After adjusting for potential confounders, including genetics, current/past smoking and other lifestyle factors, ILAs were more common among those with RA compared with non-RA [odds ratio 4.76 (95% CI 2.54, 8.92)]. RA with ILAs or indeterminate for ILAs was associated with higher all-cause mortality compared with non-RA without ILAs [hazard ratio (HR) 3.16 (95% CI 2.11, 4.74)] and RA cases without ILA [HR 3.02 (95% CI 1.36, 6.75)]. CONCLUSIONS: In this cohort of smokers, RA was associated with ILAs and this persisted after adjustment for current/past smoking and genetic/lifestyle risk factors. RA with ILAs in smokers had a 3-fold increased all-cause mortality, emphasizing the importance of further screening and treatment strategies for preclinical ILD in RA.

A Polygenic Risk Score for Idiopathic Pulmonary Fibrosis and Interstitial Lung Abnormalities.

Rationale: In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILAs) is unknown. Objectives: We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the MUC5B region on IPF, ILA, and ILA progression. Methods: We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the MUC5B region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression. Measurements and Main Results: We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case-control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio [OR] per SD of the score, 3.1; P = 7.1 × 10-95) and PRS-NO-M5B (OR per SD, 2.8; P = 2.5 × 10-87) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants. Conclusions: A common genetic variant risk score complements the MUC5B variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.

Advanced non-small-cell lung cancer treated with first-line pembrolizumab plus chemotherapy: tumor response dynamics as a marker for survival.

OBJECTIVES: The study investigated tumor burden dynamics on computed tomography (CT) scans in patients with advanced non-small-cell lung cancer (NSCLC) during first-line pembrolizumab plus chemotherapy, to provide imaging markers for overall survival (OS). METHODS: The study included 133 patients treated with first-line pembrolizumab plus platinum-doublet chemotherapy. Serial CT scans during therapy were assessed for tumor burden dynamics during therapy, which were studied for the association with OS. RESULTS: There were 67 responders, with overall response rate of 50%. The tumor burden change at the best overall response ranged from - 100.0% to + 132.1% (median of - 30%). Higher response rates were associated with younger age (p < 0.001) and higher programmed cell death-1 (PD-L1) expression levels (p = 0.01). Eighty-three patients (62%) showed tumor burden below the baseline burden throughout therapy. Using an 8-week landmark analysis, OS was longer in patients with tumor burden below the baseline burden in the first 8 weeks than in those who experienced ≥ 0% increase (median OS: 26.8 vs. 7.6 months, hazard ratio (HR): 0.36, p < 0.001). Tumor burden remained below their baseline throughout therapy was associated with significantly reduced hazards of death (HR: 0.72, p = 0.03) in the extended Cox models, after adjusting for other clinical variables. Pseudoprogression was noted in only one patient (0.8%). CONCLUSIONS: Tumor burden staying below the baseline burden throughout the therapy was predictive of prolonged overall survival in patients with advanced NSCLC treated with first-line pembrolizumab plus chemotherapy, and may be used as a practical marker for therapeutic decisions in this widely used combination regimen. CLINICAL RELEVANCE STATEMENT: The analysis of tumor burden dynamics on serial CT scans in reference to the baseline burden can provide an additional objective guide for treatment decision making in patients treated with first-line pembrolizumab plus chemotherapy for their advanced NSCLC. KEY POINTS: • Tumor burden remaining below baseline burden during therapy predicted longer survival during first-line pembrolizumab plus chemotherapy. • Pseudoprogression was noted in 0.8%, demonstrating the rarity of the phenomenon. • Tumor burden dynamics may serve as an objective marker for treatment benefit to guide treatment decisions during first-line pembrolizumab plus chemotherapy.

Autoantibodies against citrullinated and native proteins and prediction of rheumatoid arthritis-associated interstitial lung disease: A nested case-control study.

Background: To identify fine specificity anti-citrullinated protein antibodies (ACPA) associated with incident rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Methods: This nested case-control study within the Brigham RA Sequential Study matched incident RA-ILD cases to RA-noILD controls on time of blood collection, age, sex, RA duration, and rheumatoid factor status. A multiplex assay measured ACPA and anti-native protein antibodies from stored serum prior to RA-ILD onset. Logistic regression models calculated odds ratios (OR) with 95% confidence intervals (CI) for RA-ILD, adjusting for prospectively-collected covariates. We estimated optimism-corrected area under the curves (AUC) using internal validation. Model coefficients generated a risk score for RA-ILD. Findings: We analyzed 84 incident RA-ILD cases (mean age 67 years, 77% female, 90% White) and 233 RA-noILD controls (mean age 66 years, 80% female, 94% White). We identified six fine specificity antibodies that were associated with RA-ILD. The antibody isotypes and targeted proteins were: IgA2 to citrullinated histone 4 (OR 0.08 per log-transformed unit, 95% CI 0.03-0.22), IgA2 to citrullinated histone 2A (OR 4.03, 95% CI 2.03-8.00), IgG to cyclic citrullinated filaggrin (OR 3.47, 95% CI 1.71-7.01), IgA2 to native cyclic histone 2A (OR 5.52, 95% CI 2.38-12.78), IgA2 to native histone 2A (OR 4.60, 95% CI 2.18-9.74), and IgG to native cyclic filaggrin (OR 2.53, 95% CI 1.47-4.34). These six antibodies predicted RA-ILD risk better than all clinical factors combined (optimism-corrected AUC=0·84 versus 0·73). We developed a risk score for RA-ILD combining these antibodies with the clinical factors (smoking, disease activity, glucocorticoid use, obesity). At 50% predicted RA-ILD probability, the risk scores both without (score=2·6) and with (score=5·9) biomarkers achieved specificity ≥93% for RA-ILD. Interpretation: Specific ACPA and anti-native protein antibodies improve RA-ILD prediction. These findings implicate synovial protein antibodies in the pathogenesis of RA-ILD and suggest clinical utility in predicting RA-ILD once validated in external studies. Funding: National Institutes of Health.

Lung Cancer in Lung Transplant Recipients: Clinical, Radiologic, and Pathologic Characteristics and Treatment Outcome.

OBJECTIVE: This study aimed to investigate clinical and radiologic characteristics of lung cancer in lung transplant recipients and evaluate the treatment course and prognosis. METHODS: The study included 448 patients who underwent lung transplant between 2005 and 2021. All patients had pretransplant chest computed tomography (CT), 429 patients had posttransplant CT, whereas 19 had no posttransplant CT (median number of posttransplant CT, 6; range, 0-24). Medical records of these patients were reviewed to identify patients who developed lung cancer after lung transplant. Computed tomography and positron emission tomography/CT at the time of lung cancer diagnoses were reviewed to obtain imaging features. Demographics, tumor histology, stages, and survival were compared using Fisher exact test and Wilcoxon rank sum test. RESULTS: Among 448 lung transplant recipients with a median follow-up of 71.3 months after lung transplant, 15 patients (3.3%) developed posttransplant lung cancer (13 unilateral, 2 bilateral; 10 men, 5 women; median age, 63.1 years; median time from transplantation to cancer diagnosis, 3.1 years). Twelve cancers were in native lung, and 3 were in transplanted lung. The incidence of lung cancer was higher in single lung transplant recipients than in bilateral lung transplant recipients (10.3% vs 0.6%, respectively; P < 0.0001). Imaging manifestations varied according to tumor stages. Among 12 patients treated for lung cancer, 2 patients developed posttreatment acute respiratory distress syndrome. The median survival from cancer diagnosis of cancer was 6.2 months. CONCLUSIONS: Posttransplant lung cancer was noted in 3% of lung transplant recipients and was more common in unilateral transplant recipients. The prognosis upon diagnosis was poor with rapid clinical deterioration and serious posttreatment complications.