Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia: Imaging and Clinical Features of a Frequently Delayed Diagnosis.

OBJECTIVE. The purpose of this study was to assess features of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) on CT, clinical presentation, and delays in radiologic and clinical diagnosis in a series of 32 patients. MATERIALS AND METHODS. Medical records of patients with DIPNECH from the years 2000-2017 were obtained from an institutional data warehouse. Inclusion criteria were an available CT examination and either a pathologic diagnosis of DIPNECH or pathologic findings of multiple carcinoid tumorlets or carcinoid tumor with CT features suggesting DIPNECH. Two thoracic radiologists with 10 and 14 years of experience reviewed CT examinations and scored cases in consensus. RESULTS. All 32 patients were women, and most had never smoked (69%). The mean age at presentation was 61 years. Symptoms included chronic cough (59%) or dyspnea (28%), and the initial clinical diagnosis was asthma in 41%. DIPNECH was clinically suspected at presentation in only one case and was mentioned by the interpreting radiologist in only 31% of cases. CT characteristics included numerous nodules with a lower zone and peribronchiolar predominance, mosaic attenuation, and nodular bronchial wall thickening. Number of nodules at least 5 mm in diameter showed strong inverse correlations with the percentage predicted for both forced vital capacity and forced expiratory volume in 1 second and a moderate inverse correlation with total lung capacity percentage predicted. In cases with a follow-up CT interval of 3 years or longer, 85% of patients showed an increase in size of the largest nodule, and 70% had an increase in size in multiple nodules. CONCLUSION. Many cases of DIPNECH are originally missed or misdiagnosed by radiologists and clinicians. Awareness of the typical clinical and imaging features of DIPNECH may prompt earlier diagnosis of this condition.

Pulmonary Function Tests for the Radiologist.

Pulmonary function tests (PFTs) provide important quantitative information about lung function and can be used to elucidate pathologic conditions responsible for respiratory symptoms, assess the severity and course of disease, and evaluate the patient for suitability and timing for lung transplantation. They are typically used in tandem with chest imaging, along with other ancillary data, to arrive at a specific diagnosis. PFTs may provide the radiologist with clues to the diagnosis and grading of a wide variety of pulmonary diseases. In this review, the authors discuss the clinical use of PFTs, their major components, and important measurements and graphical representations that are essential for understanding and interpreting the results. The key components of PFT panels-static lung volumes, dynamic lung function (spirometry), and diffusion capacity-are explained. The authors present a general algorithmic approach for problem solving, with recognition of common patterns of results (obstructive, restrictive, mixed, nonspecific, and normal). Pulmonary diseases from each of the major patterns and chest imaging are illustrated, and correlations between particular PFT results and disease severity and morphology at imaging are examined. Common pitfalls encountered during interpretation are also highlighted. A basic understanding of the mechanics of PFTs, characteristic patterns in important diseases, and correlation between lung function and imaging findings may assist the radiologist in diagnosis and follow-up of key pulmonary diseases and strengthen the radiologist's role as part of a multidisciplinary diagnostic team. Online supplemental material is available for this article. ©RSNA, 2017.

Pulmonary effects of synthetic marijuana: chest radiography and CT findings.

OBJECTIVE: The purpose of this article is to present the first chest radiographic and CT descriptions of organizing pneumonia in response to smoking synthetic marijuana. CONCLUSION: Chest radiographs showed a diffuse miliary-micronodular pattern. Chest CT images showed diffuse centrilobular nodules and tree-in-bud pattern and a histopathologic pattern of organizing pneumonia with or without patchy acute alveolar damage. This distinct imaging pattern should alert radiologists to include synthetic marijuana abuse in the differential diagnosis.

Bronchiectasis: Mechanisms and Imaging Clues of Associated Common and Uncommon Diseases.

Bronchiectasis is permanent irreversible dilatation of the airways and occurs in a variety of pathologic processes. Recurrent infection and inflammation and the resulting chemical and cellular cascade lead to permanent architectural changes in the airways. Bronchiectasis can confer substantial potential morbidity, usually secondary to recurrent infection. In severe cases of bronchiectasis, massive hemoptysis can lead to death. Thin-section computed tomography is the most sensitive imaging modality for the detection of bronchiectasis; findings include bronchial diameter exceeding that of the adjacent pulmonary artery and lack of normal tapering of terminal bronchioles as they course toward the lung periphery. The authors will review various causes of bronchiectasis, including common causes, such as recurrent infection or aspiration, and uncommon causes, such as congenital immunodeficiencies and disorders of cartilage development. The authors will also present an approach emphasizing the distribution (apical versus basal and central versus peripheral) and concomitant findings, such as nodules, cavities, and/or lymphadenopathy, that can assist in narrowing the differential diagnosis. Although an adequate understanding of these underlying causes in conjunction with their specific imaging appearances will allow radiologists to more confidently determine the process causing this common radiologic finding, clinical history and patient demographic characteristics play an integral role in determining a pertinent and concise differential diagnosis.

Pulmonary hypertension mortality trends in United States 1999-2019.

PURPOSE: Pulmonary hypertension (PH) is a heterogenous, often progressive disorder leading to right heart failure and death. Previous analyses show stable PH mortality rates from 1980 to 2001 but increasing from 2001 to 2010 especially among women and non-Hispanic (NH) Black. This study seeks to identify recent trends in PH mortality in the United States from 1999 to 2019. METHODS: Mortality rates among individuals more than or equal to 15 years of age were obtained from the Centers for Disease Control and Prevention's (CDC) Wide-Ranging Online Data for Epidemiology Research (WONDER) database. ICD-10 codes were used to identify individuals with PH. RESULTS: Between 1999 and 2019, PH was included as a cause on 429,105 recorded deaths. The average age-adjusted PH mortality rate was 7.9 per 100,000 individuals and increased by 1.9% per year. Higher age-adjusted mortality rates were experienced by females and NH Black persons. The crude mortality rate was 105.4 per 100,000 among those decedents 85 or older. From 1999 to 2019, mortality in PH and left heart disease co-occurrence increased at nearly double the annual rate of the overall PH group. CONCLUSIONS: Despite therapeutic advances for selected PH subgroups, the overall age-adjusted PH mortality rate increased significantly from 1999 to 2019 and previously reported racial disparities have persisted. These findings emphasize the need for additional study to improve outcomes in PH.

Review series: Aspects of interstitial lung disease: connective tissue disease-associated interstitial lung disease: how does it differ from IPF? How should the clinical approach differ?

The lung is frequently involved in connective tissue diseases (CTDs), although the frequency of lung manifestations varies according to the type of CTD. Interstitial lung diseases (ILD) are frequently seen in CTDs, particularly systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM) and rheumatoid arthritis (RA), accounting for a significant proportion of deaths. A large percentage of patients with CTD-associated ILD has limited and stable disease, not requiring treatment. However, a significant minority has severe and/or progressive disease, necessitating prompt initiation of treatment. CTD-ILD histological patterns include non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), organizing pneumonia (OP), diffuse alveolar damage (DAD) and lymphocytic interstitial pneumonia (LIP). NSIP is the most common pattern in all CTDs, except for RA, characterized by a higher frequency of UIP. ILD can present acutely or chronically, with acute presentations being more common in systemic lupus erythematosus and PM/DM. Idiopathic pulmonary fibrosis (IPF) is a progressively worsening ILD characterized by inflammation and fibrosis. The characteristic histological pattern of IPF is UIP. Interestingly, a UIP pattern is associated with a significantly better survival in CTD-related disease compared to the idiopathic variety. Prognosis in IPF is dismal, with a median survival since diagnosis of 2-3 years. No treatment regimen has been shown to improve survival in IPF. By contrast, although there have been only two randomized placebo-controlled trials investigating the effect of immunosuppressive treatment in SSc-associated ILD, clinical experience suggests that immunosuppressive drugs in CTD-related ILDs are capable of benefiting a significant proportion of patients, particularly those with certain histological patterns of disease. This review will essentially focus on CTD-associated ILD and will compare aspects of clinical presentation and management to those of IPF.

An updated approach to determine minimal clinically important differences in idiopathic pulmonary fibrosis.

INTRODUCTION: Current medications for idiopathic pulmonary fibrosis (IPF) have not been shown to impact patient-reported outcome measures (PROMs), highlighting the need for accurate minimal clinically important difference (MCID) values. Recently published consensus standards for MCID studies support using anchor-based over distribution-based methods. The aim of this study was to estimate MCID values for worsening in IPF using only an anchor-based approach. METHODS: We conducted secondary analyses of three randomised controlled trials with different inclusion criteria and follow-up intervals. The health transition question in the 36-Item Short-Form Health Survey (SF-36) questionnaire was used as the anchor. We used receiver operating curves to assess responsiveness between the anchor and 10 variables (four physiological measures and six PROMs). We used an anchor-based method to determine the MCID values of variables that met the responsiveness criteria (area under the curve ≥0.70). RESULTS: 6-min walk distance (6MWD), the St George's Respiratory Questionnaire (SGRQ), physical component score (PCS) of SF-36 and University of California, San Diego, Shortness of Breath Questionnaire (UCSD SOBQ) met the responsiveness criteria. The MCID value for 6MWD was -75 m; the MCID value for SF-36 PCS was -7 points; the MCID value for SGRQ was 11 points; and the MCID value for the UCSD SOBQ was 11 points. CONCLUSIONS: The MCID estimates of 6MWD, SGRQ, SF-36 and UCSD SOBQ using only anchor-based methods were considerably higher compared to previously proposed values. A single MCID value may not be applicable across all classes of disease severity or durations of follow-up time.

Minimal clinically important difference in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing lung disease with an estimated median survival of 2-5 years and a significant impact on quality of life (QoL). Current approved medications, pirfenidone and nintedanib, have shown a reduction in annual decline of forced vital capacity but no impact on QoL. The minimal clinically important difference (MCID) is a threshold value for a change in a parameter that is considered meaningful by the patient rather than solely relying on statistically significant change in the parameter. This review provides a brief overview of the MCID methodology along with detailed discussion of reported MCID values for commonly used physiological measures and patient-reported outcome measures in IPF. While there is no gold standard methodology for determining MCID, there are certain limitations in the MCID literature in IPF, mainly the choice of death, hospitalisation and pulmonary function tests as sole anchors, and pervasive use of distribution-based methods which do not take into account the patient's input. There is a critical need to identify accurate thresholds of outcome measures that reflect patient's QoL over time in order to more precisely design and evaluate future clinical trials and to develop algorithms for patient-oriented management of IPF in outpatient clinics. EDUCATIONAL AIMS: To understand the concept of MCID and the methods used to determine these values.To understand the indications and limitations of MCID values in IPF.

CT Morphologic Characteristics and Variant Patterns of Interstitial Pulmonary Fibrosis in Systemic Lupus Erythematosus.

PURPOSE: To assess CT features of pulmonary fibrosis in patients with systemic lupus erythematosus (SLE) and to assess the presence of several distinctive patterns of fibrosis associated with connective tissue disease. MATERIALS AND METHODS: A cross-sectional retrospective analysis was performed. An institutional clinical database was queried for the years of 2005-2015 to identify CT examination reports of patients with SLE and fibrotic lung disease, which yielded 50 patients (median age, 49 years; age range, 22-71 years; 46 women). CT examination reports were scored by two subspecialty thoracic radiologists using a standard multilevel semiquantitative system. Readers noted the presence or absence of several recently described CT signs of variant patterns of fibrosis in connective tissue disease (the "anterior upper lobe," "straight-edge," and "exuberant honeycombing" signs), as well as two other morphologic characteristics (an "island-like" appearance of areas of well-defined fibrosis with angular margins surrounded by normal lung and confluent regions of lucent lung destruction). RESULTS: The most common CT patterns were characterized as either fibrotic nonspecific interstitial pneumonia (38%, 19 of 50) or variant fibrosis (44%, 22 of 50). CT signs of variant fibrosis were identified by both readers in up to 62% of patients, with good κ agreement (0.44-0.64); the island-like sign (62%) and anterior upper lobe sign (52%) were most commonly observed. Pulmonary function test results showed correlations with several imaging findings but did not show correlations with CT signs of variant fibrosis. CONCLUSION: When present, pulmonary fibrosis in SLE often has a distinctive appearance and may also manifest as several variant fibrotic patterns.Keywords: CT, Lung© RSNA, 2021See also the commentary by White in this issue.

Interstitial lung disease in systemic sclerosis: a simple staging system.

RATIONALE: In interstitial lung disease complicating systemic sclerosis (SSc-ILD), the optimal prognostic use of baseline pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) is uncertain. OBJECTIVES: To construct a readily applicable prognostic algorithm in SSc-ILD, integrating PFTs and HRCT. METHODS: The prognostic value of baseline PFT and HRCT variables was quantified in patients with SSc-ILD (n = 215) against survival and serial PFT data. MEASUREMENTS AND MAIN RESULTS: Increasingly extensive disease on HRCT was a powerful predictor of mortality (P < 0.0005), with an optimal extent threshold of 20%. In patients with HRCT extent of 10-30% (termed indeterminate disease), an FVC threshold of 70% was an adequate prognostic substitute. On the basis of these observations, SSc-ILD was staged as limited disease (minimal disease on HRCT or, in indeterminate cases, FVC >or= 70%) or extensive disease (severe disease on HRCT or, in indeterminate cases, FVC < 70%). This system (hazards ratio [HR], 3.46; 95% confidence interval [CI], 2.19-5.46; P < 0.0005) was more discriminatory than an HRCT threshold of 20% (HR, 2.48; 95% CI, 1.57-3.92; P < 0.0005) or an FVC threshold of 70% (HR, 2.11; 95% CI, 1.34-3.32; P = 0.001). The system was evaluated by four trainees and four practitioners, with minimal and severe disease on HRCT defined as clearly < 20% or clearly > 20%, respectively, and the use of an FVC threshold of 70% in indeterminate cases. The staging system was predictive of mortality for all scorers, with prognostic separation higher for practitioners (HR, 3.39-3.82) than trainees (HR, 1.87-2.60). CONCLUSIONS: An easily applicable limited/extensive staging system for SSc-ILD, based on combined evaluation with HRCT and PFTs, provides discriminatory prognostic information.

Incidentally Detected Malignancies in Lung Transplant Explants.

Active malignancy diagnosed within 5 years is an absolute contraindication for lung transplantation. In this study, we evaluated the rate of incidental malignancies detected in explanted lungs at our institution and assessed the posttransplant survival in patients with nonsmall cell lung cancer (NSCLC). METHODS: A retrospective chart review of lung transplant recipients at our institution from February 1999 to June 2017 was conducted. A literature review was performed to evaluate the prevalence and survival outcomes in patients with unexpected malignancies. RESULTS: From 407 patients who underwent lung transplantation, 9 (2.2%) were discovered to have malignant neoplasms. There were 3 cases of adenocarcinoma, 3 cases of adenocarcinoma in situ, 2 cases of squamous cell carcinoma, and 1 case of metastatic renal cell carcinoma. An extensive literature review found 12 case reports or case series reporting malignancy discovered at the time of lung transplantation. The overall prevalence of incidental neoplasms among 6746 recipients is around 1.5% (n = 103). The most common neoplasms discovered included adenocarcinoma (n = 56, 54%) and squamous cell carcinoma (n = 29, 28%). The overall 3-year survival was 54.4% for patients with localized NSCLC compared to 5.7% for those with nonlocalized disease. CONCLUSIONS: Unidentified malignancies occur despite aggressive radiographic surveillance with poor posttransplant outcomes in patients with advanced malignancy. Malignancy-related radiographic findings may be missed pretransplant secondary to architectural distortion of lung parenchyma related to end-stage lung disease or because of the critical timing of surgery when donor lungs are available.

Spontaneous Pneumothoraces in Patients with Birt-Hogg-Dubé Syndrome.

RATIONALE: Spontaneous pneumothorax is a common complication of Birt-Hogg-Dubé syndrome (BHD). OBJECTIVES: The optimal approach to treatment and prevention of BHD-associated spontaneous pneumothorax, and to advising patients with BHD regarding risk of pneumothorax associated with air travel, is not well established. METHODS: Patients with BHD were recruited from the Rare Lung Diseases Clinic Network and the BHD Foundation and surveyed about disease manifestations and air travel experiences. RESULTS: A total of 104 patients completed the survey. The average age at diagnosis was 47 years, with an average delay from first symptoms of 13 years. Pulmonary cysts were the most frequent phenotypic manifestation of BHD, present in 85% of patients. Spontaneous pneumothorax was the presenting manifestation that led to the diagnosis of BHD in 65% of patients, typically after the second episode (mean, 2.4 episodes). Seventy-nine (76%) of 104 patients had at least one spontaneous pneumothorax during their lifetime, and 82% had multiple pneumothoraces. Among patients with multiple pneumothoraces, 73% had an ipsilateral recurrence, and 48% had a subsequent contralateral spontaneous pneumothorax following a sentinel event. The mean ages at first and second pneumothoraces were 36.5 years (range, 14-63 yr) and 37 years (range, 20-55 yr), respectively. The average number of spontaneous pneumothoraces experienced by patients with a sentinel pneumothorax was 3.6. Pleurodesis was generally performed after the second (mean, 2.4) ipsilateral pneumothorax and reduced the ipsilateral recurrence rate by half. A total of 11 episodes of spontaneous pneumothorax occurred among eight patients either during or within the 24-hour period following air travel, consistent with an air travel-related pneumothorax rate of 8% per patient and 0.12% per flight. Prior pleurodesis reduced the occurrence of a subsequent flight-related pneumothorax. CONCLUSIONS: Spontaneous pneumothorax is an important, recurrent manifestation of pulmonary involvement in patients with BHD, and pleurodesis should be considered following the initial pneumothorax to reduce the risk of recurrent episodes. In general, in patients with BHD, pneumothorax occurs in about 1-2 per 1,000 flights, and the risk is lower among patients with a history of prior pleurodesis.

A Phase II Clinical Trial of an Aromatase Inhibitor for Postmenopausal Women with Lymphangioleiomyomatosis.

RATIONALE: Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease that predominantly affects women and can worsen with pregnancy, estrogen treatment, and the menstrual cycle, suggesting an important role for estrogen in disease pathogenesis. OBJECTIVES: To assess the efficacy and safety of the aromatase inhibitor letrozole in the treatment of LAM. METHODS: Seventeen postmenopausal women with LAM were enrolled in this phase II trial and randomized to receive letrozole 2.5 mg daily (n = 9) or placebo (n = 8) for a period of 12 months. Five patients in each group were also taking sirolimus at baseline and remained on the drug throughout the treatment period. Lung function, exercise capacity, quality of life, and serum vascular endothelial growth factor D (VEGF-D) were measured at baseline and at 3-month intervals. RESULTS: Fifteen patients completed the study. Two patients withdrew. There were no differences in adverse events in the letrozole and placebo groups. The target enrollment of 25 patients per arm was not met, so the efficacy of letrozole could not be assessed as planned. After adjusting for sirolimus use, we found that the rate of change in FEV1 for all subjects was -3 ± 3 ml/mo (P = 0.4), and for serum VEGF-D, the rate of change was -0.024 ± 0.009 pg/ml/mo (P = 0.015), showing a steeper decline in the letrozole group (-0.029 ± 0.013; P = 0.025). All patients who were taking sirolimus had a reduction in VEGF-D levels from baseline to the last visit, compared with only half of the patients who were not taking sirolimus. In a post hoc analysis, eight matched letrozole-treated-placebo-treated pairs were constructed, six of which demonstrated better FEV1 improvement for the letrozole-treated patients. CONCLUSIONS: Letrozole treatment appears to be safe and well tolerated in postmenopausal patients with LAM, including those taking sirolimus. Enrollment in this trial was compromised by the publication of an effective treatment (sirolimus) in the same month as the study opened, resulting in limited power to detect treatment effects. Post hoc matched pairs exploration studies provide tentative support for additional studies of letrozole in LAM. Considering the reduced rate of lung function decline in postmenopausal patients, future studies will likely require enhanced study designs, such as selective enrollment of those with prognostic biomarkers predictive of decline. Clinical trial registered with www.clinicaltrials.gov (NCT01353209).

A 49-Year-Old Man With Cirrhosis and Pulmonary Fibrosis.

A 49-year-old man with a history of cryptogenic cirrhosis was referred to pulmonary clinic for evaluation prior to liver transplantation. Chest imaging obtained as part of the transplant workup had shown evidence of interstitial abnormalities. The patient noted shortness of breath on moderate exertion that was worsening over the past 2 to 3 years and associated with a nonproductive cough. He denied chest pain, chills, or fevers. His past medical history was significant for hypothyroidism. He did not have a history of alcohol consumption, smoking, or occupational exposures. He noted a family history of lung disease in his father and evidence of prominent clubbing in his sister and nephew. Workup for liver failure included a liver biopsy, which showed cirrhosis without evidence of autoimmune hepatitis.

The Spectrum of Interstitial Lung Disease in Connective Tissue Disease.

Interstitial lung disease (ILD) is a common cause of morbidity and mortality in patients with connective tissue disease (CTD). In a minority of patients the ILD may be the presenting (or only) manifestation of an underlying CTD. Diagnosis of CTD-related ILD relies on a multidisciplinary team including pulmonologists, pathologists, radiologists, and rheumatologists, as the imaging and pathologic findings may be indistinguishable from idiopathic interstitial pneumonias. Moreover, many patients with ILD are suspected of having an underlying CTD but do not meet all of the necessary criteria for a specific disorder. This article provides a pattern-based approach to the imaging of CTD-related ILD and also reviews relevant clinical, pathologic, and serologic data that radiologists should be familiar with as part of a multidisciplinary team.

Pharmacologic therapies for idiopathic pulmonary fibrosis, past and future.

Idiopathic pulmonary fibrosis (IPF) is a severe, progressive fibrotic disease of the lung of unknown etiology that affects approximately 150,000 patients in the United States. It carries a median survival of two to three years, but clinical course can vary markedly from patient to patient. There has been no established treatment for IPF, but recent advances in coordinated clinical trials through groups such as IPFnet and academia-industry partnerships have allowed this relatively rare disease to be studied in much greater depth. Historically, the default therapy for IPF was a combination of prednisone, N-acetylcysteine, and azathioprine, but recent trials have shown that this regimen actually increases mortality. An enormous body of work in recent years, spanning the bench to the bedside, has radically altered our understanding of the molecular mechanisms underlying IPF. Newer modalities, particularly those involving monoclonal antibodies targeted at specific pathways known to contribute to the fibrotic process, have generated a great deal of excitement in the field, and recent clinical trials on therapies such as pirfenidone and nintedanib herald a new era in targeted IPF therapies.

Surfactant gene polymorphisms and interstitial lung diseases.

Pulmonary surfactant is a complex mixture of phospholipids and proteins, which is present in the alveolar lining fluid and is essential for normal lung function. Alterations in surfactant composition have been reported in several interstitial lung diseases (ILDs). Furthermore, a mutation in the surfactant protein C gene that results in complete absence of the protein has been shown to be associated with familial ILD. The role of surfactant in lung disease is therefore drawing increasing attention following the elucidation of the genetic basis underlying its surface expression and the proof of surfactant abnormalities in ILD.