Multi-Omic Biomarkers Improve Indeterminate Pulmonary Nodule Malignancy Risk Assessment.

The clinical management of patients with indeterminate pulmonary nodules is associated with unintended harm to patients and better methods are required to more precisely quantify lung cancer risk in this group. Here, we combine multiple noninvasive approaches to more accurately identify lung cancer in indeterminate pulmonary nodules. We analyzed 94 quantitative radiomic imaging features and 41 qualitative semantic imaging variables with molecular biomarkers from blood derived from an antibody-based microarray platform that determines protein, cancer-specific glycan, and autoantibody-antigen complex content with high sensitivity. From these datasets, we created a PSR (plasma, semantic, radiomic) risk prediction model comprising nine blood-based and imaging biomarkers with an area under the receiver operating curve (AUROC) of 0.964 that when tested in a second, independent cohort yielded an AUROC of 0.846. Incorporating known clinical risk factors (age, gender, and smoking pack years) for lung cancer into the PSR model improved the AUROC to 0.897 in the second cohort and was more accurate than a well-characterized clinical risk prediction model (AUROC = 0.802). Our findings support the use of a multi-omics approach to guide the clinical management of indeterminate pulmonary nodules.

Antisynthetase syndrome-related interstitial lung disease (ASyS-ILD): longitudinal imaging findings.

OBJECTIVES: Interstitial lung disease (ILD) impacts mortality in antisynthetase syndrome (ASyS). Computed tomographic (CT) patterns and evolution in ASyS ILD are not well described. We report longitudinal CT patterns in ASyS-ILD and their impact on survival. METHODS: This is a monocentric retrospective study of 47 patients with ASyS-ILD. Longitudinal CT patterns and fibrosis severity (severity of radiographic features indicating fibrosis) were analyzed by two radiologists in consensus. The association between imaging features and survival was examined using univariate Cox regression analysis. RESULTS: In total, 211 CT scans were analyzed with an average of 4 ± 2 CT scans/patient with a median follow-up of 79 months in 47 patients. Non-fibrotic patterns were present initially in 63.8% (n = 30) of patients, while fibrotic patterns occurred in 36.2% (n = 17). The initial non-fibrotic patterns/abnormalities resolved in 23.3% (n = 7), evolved in 6.7% (n = 2), persisted in 13.3% (n = 4), and progressed in 56.7% (n = 17), while initial fibrotic patterns persisted in 82.4% (n = 14) and progressed in 17.6% (n = 3). Radiographic progression of ILD (progression in CT pattern or increased fibrosis severity) occurred in 53.2% (n = 25) of patients. Advanced age and radiographic progression were associated with decreased survival (all p < 0.05). The presence of ground-glass opacities (GGO) and predominant lower lung distribution of abnormalities on initial CTs were associated with increased survival (all p < 0.05). CONCLUSION: Progression occurred in 56.7% of ASyS-ILD patients presenting with non-fibrotic patterns. Fibrotic patterns tended to persist. Age and radiographic progression were associated with reduced survival while the initial presence of GGO and predominant lower lobe distribution were associated with increased survival. KEY POINTS: • In ASyS-ILD, initial non-fibrotic patterns such as OP, cNSIP, or OP-cNSIP tended to progress to fNSIP. • Fibrotic patterns such as fNSIP or UIP in ASyS-ILD tended to persist without pattern changes. • GGO and lower lung predominance on initial CT were associated with better survival while advanced baseline age and radiographic ILD progression during follow-up were associated with decreased survival.

Outcomes of Hematopoietic Cell Transplantation in Patients with Mixed Response to Pretransplantation Treatment of Confirmed or Suspected Invasive Fungal Infection.

Patients with hematologic malignancy or bone marrow failure are typically required to achieve radiographic improvement or stabilization of invasive fungal infection (IFI) before hematopoietic cell transplantation (HCT) owing to a concern for progression before engraftment. Refractory IFI with a mixture of improvement and progression on serial imaging (ie, mixed response) poses a clinical dilemma, because a delay in HCT may allow for a hematologic relapse or other complications. Furthermore, HCT itself may yield the immune reconstitution necessary for clearance of infection. We sought to describe the characteristics and outcomes of patients who underwent HCT with mixed response IFI. We performed a chart review of all patients who underwent HCT between 2014 and 2020 in whom imaging within 6 weeks before HCT indicated a mixed response to treatment of a diagnosed IFI. Fourteen patients had evidence of a mixed response in low-to-moderate burden of diagnosed IFI by imaging before HCT, including 9 with pulmonary aspergillosis, 2 with hepatosplenic candidiasis (1 also with aspergillosis), and 4 with pulmonary nodules of presumed fungal etiology. Five had refractory severe neutropenia at evaluation for HCT (median, 95 days). All 14 patients showed radiographic stability or improvement in imaging following engraftment; no IFI-related surgeries were required, and no IFI-related deaths occurred. For patients without relapse who underwent HCT more than 1 year earlier, 7 of 8 (88%) were alive at 1 year. Our findings suggest that low-to-moderate burden IFI with mixed response is unlikely to progress on appropriate therapy before engraftment during allogeneic HCT.

The novel coronavirus disease (COVID-19) complicated by pulmonary embolism and acute respiratory distress syndrome.

Acute respiratory distress syndrome and coagulopathy played an important role in morbidity and mortality of severe COVID-19 patients. A higher frequency of pulmonary embolism (PE) than expected in COVID-19 patients was recently reported. The presenting symptoms for PE were untypical including dyspnea, which is one of the major symptoms in severe COVID-19, especially in those patients with acute respiratory distress syndrome (ARDS). We reported two COVID-19 cases with coexisting complications of PE and ARDS, aiming to consolidate the emerging knowledge of this global health emergency and raise the awareness that the hypoxemia or severe dyspnea in COVID-19 may be related to PE and not necessarily always due to the parenchymal disease.

Comparison of prediction models with radiological semantic features and radiomics in lung cancer diagnosis of the pulmonary nodules: a case-control study.

PURPOSE: To compare the ability of radiological semantic and quantitative texture features in lung cancer diagnosis of pulmonary nodules. MATERIALS AND METHODS: A total of N = 121 subjects with confirmed non-small-cell lung cancer were matched with 117 controls based on age and gender. Radiological semantic and quantitative texture features were extracted from CT images with or without contrast enhancement. Three different models were compared using LASSO logistic regression: "CS" using clinical and semantic variables, "T" using texture features, and "CST" using clinical, semantic, and texture variables. For each model, we performed 100 trials of fivefold cross-validation and the average receiver operating curve was accessed. The AUC of the cross-validation study (AUCCV) was calculated together with its 95% confidence interval. RESULTS: The AUCCV (and 95% confidence interval) for models T, CS, and CST was 0.85 (0.71-0.96), 0.88 (0.77-0.96), and 0.88 (0.77-0.97), respectively. After separating the data into two groups with or without contrast enhancement, the AUC (without cross-validation) of the model T was 0.86 both for images with and without contrast enhancement, suggesting that contrast enhancement did not impact the utility of texture analysis. CONCLUSIONS: The models with semantic and texture features provided cross-validated AUCs of 0.85-0.88 for classification of benign versus cancerous nodules, showing potential in aiding the management of patients. KEY POINTS: • Pretest probability of cancer can aid and direct the physician in the diagnosis and management of pulmonary nodules in a cost-effective way. • Semantic features (qualitative features reported by radiologists to characterize lung lesions) and radiomic (e.g., texture) features can be extracted from CT images. • Input of these variables into a model can generate a pretest likelihood of cancer to aid clinical decision and management of pulmonary nodules.

Accuracy of Digital Tomosynthesis of the Chest in Detection of Interstitial Lung Disease Comparison With Digital Chest Radiography.

PURPOSE: The aim of the study was to assess the ability of chest digital tomosynthesis (DTS) for detection of interstitial lung disease (ILD) compared with conventional chest radiography. MATERIALS AND METHODS: We retrospectively reviewed 78 patients (60 males, 18 females, mean age = 53.05 years, range, 19-83 years) who underwent chest DTS for a 5-year interval (January 1, 2009-December 31, 2014). Of the 78 patients, 33 (42.3%) carried a diagnosis of ILD and 45 (57.7%) were not ILD. All computed tomography reports and medical records were reviewed. The conventional chest radiography and DTS were separately reviewed by 2 radiologists for the presence of ILD and the confidence in diagnosis. RESULTS: The diagnostic accuracy of DTS for the detection of ILD was better than conventional chest radiography (P < 0.05). Digital tomosynthesis had a sensitivity of 83.3% and negative predictive value of 89.0% that were statistically significantly better than conventional chest radiography (43.9% and 70.9%, respectively). Confidence in diagnosing ILD at DTS was higher than conventional chest radiography (P < 0.001) and had higher interobserver agreement than conventional chest radiography (P < 0.01). CONCLUSIONS: Digital tomosynthesis improves diagnostic performance and confidence in diagnosing ILD compared with conventional chest radiography. Digital tomosynthesis can be suggested as the initial diagnostic technique for patients with suspected ILD.

Tumor-derived Autoantibodies Identify Malignant Pulmonary Nodules.

Rationale: Screening for non-small cell lung cancer is associated with earlier diagnosis and reduced mortality but also increased harm caused by invasive follow-up of benign pulmonary nodules. Lung tumorigenesis activates the immune system, components of which could serve as tumor-specific biomarkers. Objectives: To profile tumor-derived autoantibodies as peripheral biomarkers of malignant pulmonary nodules. Methods: High-density protein arrays were used to define the specificity of autoantibodies isolated from B cells of 10 resected lung tumors. These tumor-derived autoantibodies were also examined as free or complexed to antigen in the plasma of the same 10 patients and matched benign nodule control subjects. Promising autoantibodies were further analyzed in an independent cohort of 250 nodule-positive patients. Measurements and Main Results: Thirteen tumor B-cell-derived autoantibodies isolated ex vivo showed greater than or equal to 50% sensitivity and greater than or equal to 70% specificity for lung cancer. In plasma, 11 of 13 autoantibodies were present both complexed to and free from antigen. In the larger validation cohort, 5 of 13 tumor-derived autoantibodies remained significantly elevated in cancers. A combination of four of these autoantibodies could detect malignant nodules with an area under the curve of 0.74 and had an area under the curve of 0.78 in a subcohort of indeterminate (8-20 mm in the longest diameter) pulmonary nodules. Conclusions: Our novel pipeline identifies tumor-derived autoantibodies that could effectively serve as blood biomarkers for malignant pulmonary nodule diagnosis. This approach has future implications for both a cost-effective and noninvasive approach to determine nodule malignancy for widespread low-dose computed tomography screening.

Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline.

BACKGROUND: This document provides clinical recommendations for the diagnosis of idiopathic pulmonary fibrosis (IPF). It represents a collaborative effort between the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. METHODS: The evidence syntheses were discussed and recommendations formulated by a multidisciplinary committee of IPF experts. The evidence was appraised and recommendations were formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: The guideline panel updated the diagnostic criteria for IPF. Previously defined patterns of usual interstitial pneumonia (UIP) were refined to patterns of UIP, probable UIP, indeterminate, and alternate diagnosis. For patients with newly detected interstitial lung disease (ILD) who have a high-resolution computed tomography scan pattern of probable UIP, indeterminate, or an alternative diagnosis, conditional recommendations were made for performing BAL and surgical lung biopsy; because of lack of evidence, no recommendation was made for or against performing transbronchial lung biopsy or lung cryobiopsy. In contrast, for patients with newly detected ILD who have a high-resolution computed tomography scan pattern of UIP, strong recommendations were made against performing surgical lung biopsy, transbronchial lung biopsy, and lung cryobiopsy, and a conditional recommendation was made against performing BAL. Additional recommendations included a conditional recommendation for multidisciplinary discussion and a strong recommendation against measurement of serum biomarkers for the sole purpose of distinguishing IPF from other ILDs. CONCLUSIONS: The guideline panel provided recommendations related to the diagnosis of IPF.

Chronic Obstructive Pulmonary Disease Alters Immune Cell Composition and Immune Checkpoint Inhibitor Efficacy in Non-Small Cell Lung Cancer.

RATIONALE: Chronic obstructive pulmonary disease (COPD) and non-small cell lung cancer (NSCLC) are interrelated diseases with substantial mortality, and the pathogenesis of both involves aberrant immune functioning. OBJECTIVES: To profile immune cell composition and function in patients with NSCLC and describe the effects of COPD on lung and tumor microenvironments. METHODS: We profiled resected lung and tumor tissue using flow cytometry and T-cell receptor sequencing in patients with and without COPD from a prospective cohort of patients undergoing resection of NSCLC. A murine cigarette smoke exposure model was used to evaluate the effect on pulmonary immune populations. A separate retrospective cohort of patients who received immune checkpoint inhibitors (ICIs) was analyzed, and their survival was quantified. MEASUREMENTS AND MAIN RESULTS: We observed an increased number of IFN-γ-producing CD8+ and CD4+ (T-helper cell type 1 [Th1]) lymphocytes in the lungs of patients with COPD. In both humans and mice, increased Th17 content was seen with smoke exposure, but was not associated with the development or severity of COPD. COPD-affected lung tissue displayed increased Th1 differentiation that was recapitulated in the matching tumor sample. PD-1 (programmed cell death protein 1) expression was increased in tumors of patients with COPD, and the presence of COPD was associated with progression-free survival in patients treated with ICIs. CONCLUSIONS: In patients with COPD, Th1 cell populations were expanded in both lung and tumor microenvironments, and the presence of COPD was associated with longer progression-free intervals in patients treated with ICIs. This has implications for understanding the immune mediators of COPD and developing novel therapies for NSCLC.

The Pseudocavitation Sign of Lung Adenocarcinoma: A Distinguishing Feature and Imaging Biomarker of Lepidic Growth.

PURPOSE: Our purpose was to evaluate whether pseudocavitation, characterized by round or oval areas of low attenuation in a lesion on computed tomography (CT), can help distinguish adenocarcinoma from other types of non-small cell lung cancer (NSCLC). We also sought to determine whether pseudocavitation is associated with lepidic growth on histopathology. MATERIALS AND METHODS: This retrospective HIPAA-compliant study was approved by our institutional review board. The need for informed consent was waived. CT scans and pathology records from 158 NSCLCs in 149 patients were retrospectively reviewed. The frequency of pseudocavitation was compared among types of NSCLC, specifically adenocarcinoma versus other types of NSCLC. Subgroup analysis of adenocarcinomas was performed to identify any difference in the frequency of pseudocavitation between adenocarcinomas with reported lepidic growth and those without lepidic growth. RESULTS: There was a significantly greater frequency of pseudocavitation in adenocarcinomas versus other types of NSCLC [19/86 (22.1%) vs. 4/72 (5.6%), P=0.007]. The sensitivity and specificity of the pseudocavitation sign for adenocarcinoma were 0.22 and 0.94, respectively. Among adenocarcinomas, the pseudocavitation sign was more frequent in tumors with lepidic growth versus those without lepidic growth [10/24 (41.7%) vs. 9/62 (14.5%), P=0.015]. CONCLUSIONS: Pseudocavitation at CT is more common in primary lung adenocarcinoma than in other types of NSCLC. It is also more common in adenocarcinomas with lepidic growth, suggesting a correlation between the imaging finding of pseudocavitation and the pathologic finding of lepidic growth. As the subtype of NSCLC guides treatment, predicting tumor pathology by imaging may improve diagnostic workup for patients with NSCLC.

Imaging of small airways and emphysema.

High-resolution chest computed tomography (CT) is one of the most useful techniques available for imaging bronchiolitis because it shows highly specific direct and indirect imaging signs. The distribution and combination of these various signs can further classify bronchiolitis as either cellular/inflammatory or fibrotic/constrictive. Emphysema is characterized by destruction of the airspaces, and a brief discussion of imaging findings of this class of disease is also included. Typical CT findings include destruction of airspace, attenuated vasculatures, and hyperlucent as well as hyperinflated lungs.

Histiocytic disorders of the chest: imaging findings.

Histiocytic disorders of the chest comprise a broad spectrum of diseases. The lungs may be involved in isolation or as part of systemic disease. Some of these disorders are primary and have unknown etiology, and others result from a histiocytic response to a known cause. Among primary histiocytic disorders, pulmonary Langerhans cell histiocytosis (PLCH) is the most common; others include Erdheim-Chester disease and Rosai-Dorfman disease. Adult PLCH occurs almost exclusively in adults aged 20-40 years who smoke. Pediatric PLCH is extremely rare and typically occurs as part of multisystemic disease. Erdheim-Chester disease affects middle-aged and older adults; thoracic involvement usually occurs as part of systemic disease. Rosai-Dorfman disease affects children and young adults and manifests as painless cervical lymphadenopathy. Examples of secondary histiocytic disorders are storage diseases such as Gaucher disease, Niemann-Pick disease, and Fabry disease; pneumoconiosis such as silicosis and coal workers' pneumoconiosis; and infections such as Whipple disease and malakoplakia. These disorders are characterized at histopathologic examination on the basis of infiltration of alveoli or the pulmonary interstitium by histiocytes, which are a group of cells that includes macrophages and dendritic cells. Dendritic cells are a heterogeneous group of nonphagocytic antigen-presenting immune cells. Immunohistochemical markers help to distinguish among various primary histiocytic disorders. Characteristic radiologic findings in the appropriate clinical context may obviate biopsy to establish a correct diagnosis. However, in the absence of these findings, integration of clinical, pathologic, and radiologic features is required to establish a diagnosis.

Sarcoid-like reaction-computed tomography features in 12 patients.

PURPOSE: The aim of the study was to analyze the computed tomography (CT) findings of sarcoid-like reaction caused by underlying malignancy or immune modulation. METHODS: Twelve patients with pathologically proven sarcoidosis from underlying causes (malignancies, hepatitis C infection, and immune-modulatory treatment) in 2001 to 2011 were identified. All patients had chest CT scans, which were reviewed by 3 experienced thoracic radiologists. Medical records were also reviewed. Follow-up imaging, available in 11 patients, was assessed for response. RESULTS: All patients were white, 8 women and 4 men, with ages ranging from 26 to 72 years. Seven had underlying malignancy, 2 had inflammatory bowel disease, and 3 had liver disease caused by chronic hepatitis C viral infection. On CT, 92% (11/12) of patients had lymphadenopathy, 75% (9/12) had pulmonary nodules less than 5 mm, and 50% (6/12) had ground-glass opacity (GGO). In 42% (5/12) of patients, the dominant finding was discrete nodules (1-5 mm). In 33% (4/12) of patients, the dominant finding was ultrafine nodules with confluence, mimicking GGO. The most common distribution of lung nodules was perilymphatic, found in 78% (7 of the 9 patients with lung nodules). Follow-up was available in 10 patients, limited follow-up in 1, and no follow-up in 1. Six of the 11 patients who had follow-up had complete resolution of CT findings, 3 had partial resolution, and 2 had no resolution. CONCLUSIONS: Imaging features of patients with sarcoid-like reaction include lymphadenopathy, small nodules, and ultrafine nodules with confluence, mimicking GGO. Ultrafine nodules with confluence mimicking GGO were unexpectedly common in this series.

Pulmonary effects of i.v. injection of crushed oral tablets: "excipient lung disease".

OBJECTIVE: When crushed oral tablets are injected i.v., their filler material (excipient) can induce a potentially fatal foreign-body reaction in pulmonary arterioles, presenting as dyspnea and pulmonary hypertension with centrilobular nodules on CT. We will describe the imaging and pathologic features of "excipient lung disease." CONCLUSION: The radiologist has a critical role in recognizing and reporting excipient lung disease because the referring clinician may be unaware of the patient's i.v. drug abuse.

Organizing pneumonia in recipients of hematopoietic stem cell transplantation: CT features in 16 patients.

PURPOSE: To evaluate computed tomographic (CT) scans of patients with organizing pneumonia (OP) complicating hematopoietic stem cell transplantation (HSCT). MATERIALS AND METHODS: A review of patients who underwent HSCT at our institution identified 16 patients who had documented OP on biopsy. Computed tomographic scans were reviewed by 2 thoracic radiologists. RESULTS: Ground glass opacities (GGO) were seen in 15 patients, consolidation in 8 patients, linear opacities in 8 patients, traction bronchiectasis in 2 patients, and septal thickening in 2 patients. Ground glass opacity was the dominant abnormality in 7 patients, consolidation in 4 patients, and linear opacities in 5 patients. Peribronchovascular distribution was found in 4 patients, peripheral in 2 patients, diffuse in 3 patients; upper lung predominance was found in 10 patients, and lower lung predominance in 5 patients. CONCLUSION: The principal computed tomographic features of OP after HSCT are ground glass opacities, consolidation and linear opacities, with upper lung predominance. Allowing for a possible sampling bias, these findings differ from those reported in cryptogenic OP and OP from other causes.

Hypersensitivity pneumonitis: a historical, clinical, and radiologic review.

Most cases of hypersensitivity pneumonitis develop only after many years of inhaling allergens, which include microbes, animal or plant proteins, and certain chemicals that form haptens. The initial clinical presentation is either episodes of acute illness with dyspnea and prominent constitutional symptoms, such as fever, or an insidious onset of dyspnea, coughing, and weight loss, sometimes with superimposed acute episodes. The histopathologic process consists of chronic inflammation of the bronchi and peribronchiolar tissue, often with poorly defined granulomas and giant cells in the interstitium or alveoli. Fibrosis and emphysema may develop. The radiologic findings include diffuse ground-glass opacification, centrilobular ground-glass opacities, air trapping, fibrosis, lung cysts, and emphysema. The histologic and radiologic features in some cases may resemble those of usual interstitial pneumonia or nonspecific interstitial pneumonia. The diagnosis usually rests on a variable combination of findings from history, serology, radiography, lung biopsy, and bronchoalveolar lavage, which characteristically reveals a lymphocyte content of more than 30%, often with an increased CD4-to-CD8 ratio of T cells. Treatment includes avoiding the allergen, if possible, and, in severe cases, systemic corticosteroids. The long-term prognosis is usually good, but some patients develop severe respiratory insufficiency, and a few die of the disease.

Imaging of thoracic lymphatic diseases.

OBJECTIVE: This review will focus on radiographic description of lymphangiomas, lymphangiohemangiomas, pulmonary lymphangiomatosis, lymphangiectasis, lymphangioleiomyomatosis, lymphatic dysplasia, and traumatic lymphatic injury. CONCLUSION: Diseases of the thoracic lymphatic system have a wide variety of unique radiographic manifestations, all of which can be explained by the underlying pathophysiology and relationship to the normal distribution of lymphatics in the chest.