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The n e w e ng l a n d j o u r na l of m e dic i n e Case Records of the Massachusetts General Hospital Founded by Richard C. Cabot Eric S. Rosenberg, M.D., Editor Jo‑Anne O. Shepard, M.D., Associate Editor Sally H. Ebeling, Assistant Editor Nancy Lee Harris, M.D., Editor Alice M. Cort, M.D., Associate Editor Emily K. McDonald, Assistant Editor Case 14-2015: A 58-Year-Old Woman with Shortness of Breath Barry S. Shea, M.D., Amita Sharma, M.D., and Eugene J. Mark, M.D. Pr e sen tat ion of C a se Dr. Christopher J. Mutrie (Thoracic Surgery): A 58-year-old woman was seen in the outpatient pulmonary clinic of this hospital because of shortness of breath on exertion. The patient had been well until approximately 8 months before this presentation, when she noted shortness of breath while jogging her usual 4 miles daily. During the next 7 months, her symptoms gradually worsened until she became winded within 7 minutes after starting to jog or after climbing stairs, with associated leg fatigue. Approximately 1 month before this evaluation, she was seen at an outpatient clinic of another hospital. On examination, the vital signs and oxygen saturation were normal. The oropharyngeal mucosa had a cobblestone appearance, and there were scattered inspiratory wheezes throughout the lung fields. The peak expiratory flow rate measured 400 liters per minute (predicted value, 470). A chest radiograph showed reticular linear peripheral opacities predominantly involving the upper lung zones, without pleural effusions or pneumothorax. Results of electrocardiography were normal. Fluticasone (two puffs at a strength of 110 μg per puff, by inhalation twice daily) and an albuterol inhaler with a spacer were prescribed for use before exercise. Five days later, results of pulmonary-function tests and the blood level of d-dimer were normal. Dr. Amita Sharma: The initial chest radiograph showed mild volume loss, biapical pleural thickening, and peripheral nodular opacities in the upper lung zones (Fig. 1). One week later, computed tomography (CT) of the chest, performed without the administration of contrast material, confirmed the presence of bilateral peripheral nodules, which were broad-based and associated with nodular pleural thickening extending into the fissures. Linear bands in the parenchyma were seen adjacent to many peripheral nodules. A few peripheral opacities were present in the middle lung zone, but no abnormalities were seen in the lower lung zone. There was no hilar or mediastinal lymphadenopathy. Dr. Mutrie: The patient was referred to the outpatient pulmonary clinic of this hospital. She reported no orthopnea, paroxysmal nocturnal dyspnea, wheezing, pedal edema, cough, sputum production, rash, chills, chest pressure, palpitations, change in bowel habits, or urinary symptoms. She had osteopenia, migraine headaches, hyperlipidemia, seasonal allergies, intermittent mildly elevated aminotrans- From the Departments of Medicine (B.S.S.), Radiology (A.S.), and Pathology (E.J.M.), Massachusetts General Hospi‑ tal, and the Departments of Medicine (B.S.S.), Radiology (A.S.), and Pathology (E.J.M.), Harvard Medical School — both in Boston. N Engl J Med 2015;372:1749-58. DOI: 10.1056/NEJMcpc1415200 Copyright © 2015 Massachusetts Medical Society. n engl j med 372;18 nejm.org April 30, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on July 3, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. 1749 The n e w e ng l a n d j o u r na l of m e dic i n e medications included alendronate, simvastatin, and lorazepam (as needed for insomnia). She had no known allergies. She worked in an office. She drank wine occasionally, had stopped smoking 30 years earlier (after 3 years of smoking), and did not use illicit drugs. She exercised daily, walking and jogging 4 miles. Her father had cardiac arrhythmias, a sister had breast cancer, another sister possibly had systemic lupus erythematosus, a brother had type 1 diabetes mellitus, one of her children had diabetes mellitus, and another one of her children had a supraventricular arrhythmia. The physical examination was normal, without wheezing, cyanosis, clubbing, or lymphadenopathy. Results of pulmonary-function tests were normal; the forced vital capacity (FVC) was 3.45 liters (101% of the predicted value), the forced expiratory volume in 1 second (FEV1) 2.62 liters (97%), the ratio of FEV1 to FVC 0.76, the total lung capacity 5.30 liters (97%), and the carbon monoxide diffusing capacity 22.4 (92%). The blood level of aspartate aminotransferase was 56 U per liter (reference range, 9 to 32), the level of alanine aminotransferase was 60 U per liter (reference range, 7 to 30), and testing for antinuclear antibody (ANA) was positive at 1:40 dilution in a homogeneous and speckled pattern (reference range, negative at 1:40 and 1:160 dilutions). The complete blood count and white-cell differential count were normal, as were the anion gap and blood levels of electrolytes, glucose, urea nitrogen, creatinine, calcium, total protein, albumin, globulin, total bilirubin, alkaline phosphatase, and angiotensin-converting enzyme; testing was negative for rheumatoid factor, IgG antibodies to anti–cyclic citrullinated peptide, antineutrophil cytoplasmic antibody (ANCA), and IgE antibodies to environmental allergens. Dr. Sharma: At a follow-up examination 2.5 months later, CT of the chest, performed at this hospital after the intravenous administration of contrast material, was largely unchanged (Fig. 2). An 8-mm nodule was seen in the left apex. Dr. Mutrie: A diagnostic procedure was performed. A B Figure 1. Radiographs of the Chest. Chest radiographs obtained in posteroanterior (Pan‑ el A) and lateral (Panel B) views show pleuroparen‑ chymal opacities (Panel A, arrows) in the upper lung zones. Differ en t i a l Di agnosis ferase levels, and breast calcifications; she had undergone excision of an adenomatous colonic polyp 2 years previously, as well as sinus surgery and a tonsillectomy in the distant past. Additional 1750 n engl j med 372;18 Important Features of the Case Dr. Barry S. Shea: This previously healthy, middleaged woman presented with insidious onset of dyspnea on exertion and a notable decrease in ex- nejm.org April 30, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on July 3, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. Case Records of the Massachuset ts Gener al Hospital A B D C Figure 2. CT Scan of the Chest. Approximately 2.5 months after the initial evaluation, CT was performed at the lung‑window setting after the ad‑ ministration of contrast material. Selected axial slices through the upper lung zones (Panels A, B, and C) and a cor‑ onal reformatted image (Panel D) show peripheral nodular opacities in the upper lung zones that are unchanged from the initial evaluation (Panels A, C, and D, arrows). An 8‑mm nodule is seen in the left apex (Panel B, arrow). Pleural thickening is best seen along the major fissures (Panel C, arrowheads). ercise tolerance during an 8-month period. The history does not include symptoms that are suggestive of some of the most common causes of chronic dyspnea on exertion. The progressive, nonepisodic nature of the symptoms and the absence of cough, wheezing, and chest discomfort argue against asthma as the main diagnosis. The minimal, remote history of smoking argues against chronic obstructive pulmonary disease, and no additional symptoms are present that suggest ischemic heart disease or heart failure. The physical examination that was performed in the outpatient pulmonary clinic was normal, although a previous examination had indicated the presence of inspiratory wheezes, suggesting a component of airways disease. Results of extensive laboratory testing were largely unremarkable, except for mild elevations in the serum aminotransferase levels. Results of pulmonary-function tests were normal, n engl j med 372;18 which is surprising given the severity of the patient’s dyspnea and functional decline. I will return to this observation later, because it turns out to be a key feature of the clinical scenario. I will first discuss the radiographic abnormalities, which help to narrow the differential diagnosis. Infection, Cancer, and Vasculitis Whenever multifocal nodular or consolidative opacities are seen on chest imaging, the differential diagnosis should include infection, cancer, and vasculitis. In this case, the duration of symptoms essentially rules out a typical viral or bacterial pneumonia. Chronic infections with predominant involvement of the upper lung zones, such as histoplasmosis, blastomycosis, and tuberculosis, should be considered; however, the absence of cough, fevers, and constitutional symptoms argues strongly against a diagnosis of any of these chron- nejm.org April 30, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on July 3, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. 1751 The n e w e ng l a n d j o u r na l ic infections. Furthermore, nothing in the patient’s history suggests exposure to tuberculosis or travel to regions where the relevant fungi are endemic. If this patient had cancer, the multifocal nature of her illness would indicate metastatic disease; however, patients with pulmonary metastases typically present with discrete nodules that involve the lung bases rather than the apexes.1 Nodular pleural thickening can be seen in patients with malignant mesothelioma, but multifocal disease is extremely rare, and the vast majority of mesothelioma cases are associated with a history of asbestos exposure.2 Patients with ANCA-associated vasculitides, granulomatosis with polyangiitis, microscopic polyangiitis, or the Churg–Strauss syndrome can present with multifocal nodular opacities or areas of dense consolidation on chest imaging. These diseases can occur despite negative ANCA titers, but in this case, the absence of fevers and constitutional symptoms argues against a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and the absence of peripheral eosinophilia and the absence of a history of asthma make the Churg–Strauss syndrome unlikely.3 Because infection, cancer, and vasculitis are all unlikely in this case, the radiographic abnormalities probably indicate the presence of an interstitial lung disease. Interstitial Lung Diseases with Predominant Involvement of the Upper Zones of m e dic i n e nopathy is almost always present, and the most commonly seen parenchymal abnormalities consist of reticular or nodular opacities along the bronchovascular bundles.4,5 Sarcoidosis is often difficult to rule out, but I think it is unlikely in this case. Therefore, the pattern of radiographic abnormalities does not suggest any of these classic interstitial lung diseases with predominant involvement of the upper zones. Idiopathic Interstitial Pneumonias Many interstitial lung diseases are idiopathic in origin. Idiopathic interstitial pneumonias are divided into the following seven distinct clinicopathological entities6: idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia, respiratory bronchiolitis–associated interstitial lung disease, desquamative interstitial pneumonia, and lymphoid interstitial pneumonia. Each of these entities is associated with typical radiographic features, and this patient’s chest CT findings are not characteristic of any of these entities, except possibly cryptogenic organizing pneumonia. Radiographs of patients with cryptogenic organizing pneumonia typically reveal air-space consolidation, which can be either unilateral or bilateral and is often patchy in distribution. In a minority of cases, the air-space consolidation can be confined to the subpleural region.7 The clinical presentation of cryptogenic organizing pneumonia is typically characterized by a subacute onset of cough and dyspnea, often with constitutional symptoms, although these can be absent.8 Cryptogenic organizing pneumonia should be included in the differential diagnosis in this case. However, it is important to note that the radiographic and histologic patterns associated with cryptogenic organizing pneumonia (namely, patterns indicative of organizing pneumonia with or without bronchiolitis obliterans) can be seen with other conditions, most notably viral infections, connective-tissue disease–associated interstitial lung disease, and drug-induced interstitial lung disease. Therefore, cryptogenic organizing pneumonia is a diagnosis of exclusion that can be made only when known causes of organizing pneumonia have been ruled out. When a pulmonologist is presented with a case of interstitial lung disease with predominant involvement of the upper zones, a number of disease entities should come to mind. These include two fairly common interstitial lung diseases, sarcoidosis and hypersensitivity pneumonitis, as well as rarer diseases, such as pulmonary Langerhans’-cell histiocytosis and the pneumoconioses (berylliosis, silicosis, and coal worker’s pneumoconiosis). The CT findings in this case are not characteristic of Langerhans’-cell histiocytosis, hypersensitivity pneumonitis, or the pneumoconioses; furthermore, this patient has no history of current smoking, which is almost universally present in patients with Langerhans’-cell histiocytosis, and no history of environmental exposures that suggest hypersensitivity pneumonitis or the pneumoconioses. Although patients with pulmonary Chronic Eosinophilic Pneumonia sarcoidosis can present with myriad radiographic Chronic eosinophilic pneumonia is another idiopatterns, bilateral hilar or mediastinal lymphade- pathic interstitial lung disease that is associated 1752 n engl j med 372;18 nejm.org April 30, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on July 3, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. Case Records of the Massachuset ts Gener al Hospital with the presence of peripheral opacities on chest imaging, a finding that is often referred to as the photographic negative of pulmonary edema. Patients with chronic eosinophilic pneumonia often present with cough, constitutional symptoms, and peripheral eosinophilia, but these features can be absent in 10 to 20% of patients. Approximately 50 to 60% of affected patients have a history of atopic disease.9,10 In this case, there is an absence of clinical features that are characteristic of chronic eosinophilic pneumonia, but because of the appearance of multifocal, peripheral, plaquelike opacities on chest CT studies, this disease should be considered high on the differential diagnosis. Chronic eosinophilic pneumonia shares many clinical and radiographic features with cryptogenic organizing pneumonia, and thus, on examination of lung-biopsy specimens from patients with chronic eosinophilic pneumonia, it is not uncommon to see both the histologic pattern of bronchiolitis obliterans with organizing pneumonia and eosinophilic inflammation.11 Chronic eosinophilic pneumonia is a diagnosis of exclusion that cannot be made definitively without first ruling out known causes of pulmonary eosinophilia, including drug-induced lung disease. Interstitial Lung Disease Associated with Connective-Tissue Disease Interstitial lung disease is a common manifestation of many connective-tissue diseases, including systemic sclerosis, rheumatoid arthritis, dermatomyositis, polymyositis, Sjögren’s syndrome, mixed connective-tissue disease, and systemic lupus erythematosus.12 The radiographic and histologic patterns of connective-tissue disease–associated interstitial lung disease often mimic those of the idiopathic interstitial pneumonias.13 In this case, there is no definitive clinical or laboratory evidence of a connective-tissue disease, although interstitial lung disease can occasionally precede the onset of systemic manifestations of a connective-tissue disease.14 Patients with polymyositis or dermatomyositis can present with muscle fatigue, dyspnea on exertion, and interstitial lung disease.15 This patient has only a weakly positive ANA titer, but ANA can be absent in up to 20% of patients with polymyositis or dermatomyositis.16 The histologic pattern of bronchiolitis obliterans with organizing pneumonia has been associated with these conditions, but it is rare; most affected patients have the histologic pattern of nonspecific intersti- tial pneumonia.15 Polymyositis is also a diagnosis of exclusion that can be made only when other causes of inflammatory myositis, most notably drug-induced myopathy, have been ruled out. Statin-Induced Myopathy and Interstitial Lung Disease The differential diagnosis now includes three entities — cryptogenic organizing pneumonia, chronic eosinophilic pneumonia, and inflammatory myositis–associated interstitial lung disease — none of which appear to fit this case perfectly. However, all three of these diseases have at least two things in common; they are all diagnoses of exclusion, and they all share features associated with a drug reaction. At this point, I return to a key feature of the case presentation — that the patient’s symptoms are greatly out of proportion to the normal results of pulmonary-function testing and the minimal abnormalities seen on chest imaging. The patient’s dyspnea could be attributed to her lung disease, since dyspnea is a complicated sensation that is difficult to quantify. However, what appears to be a dramatic decrease in exercise tolerance cannot be explained by her lung disease, given the minimal radiographic opacities and the completely normal results of pulmonary-function tests. Therefore, this clinical scenario is highly suggestive of a nonpulmonary cause of exercise limitation. If we were to ignore the parenchymal abnormalities in the lung for a moment, we would see a middle-aged woman with progressive dyspnea, decreased exercise tolerance, leg fatigue, and mildly elevated aminotransferase levels who is taking a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, also known as a statin. This clinical picture is highly suggestive of statin-induced myopathy, which could be the primary cause of the patient’s symptoms. Statins can cause a wide spectrum of myopathic injuries, ranging from asymptomatic elevations in serum creatine kinase levels to frank rhabdomyolysis. Myalgias have been reported in up to 10% of patients who are taking statins, although the incidence of myositis among such patients is probably less than 1%.17 Hepatic dysfunction can also be seen with statin use,18 and the elevated serum aminotransferase levels in this patient could be an important clue. Statin-induced interstitial lung disease has been described, although it is very rare. As of June 2007, n engl j med 372;18 nejm.org April 30, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on July 3, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. 1753 The n e w e ng l a n d j o u r na l only 162 cases of statin-induced interstitial lung disease had been reported to the Food and Drug Administration, with calculated rates of less than 1 reported case per 5 million prescriptions for the most commonly used statins.19 A review of statin-induced interstitial lung disease summarizes the existing literature on this topic, which consists entirely of case reports and series.19 The spectrum of associated radiographic features was broad and included diffuse ground-glass abnormalities, multifocal opacities, and fibrosis; pleural involvement was also described. In some cases, elevated eosinophil levels were present in the peripheral blood, bronchoalveolar-lavage fluid, or both; this finding is suggestive of a hypersensitivity reaction. Furthermore, in some cases, statininduced interstitial lung disease was associated with the development of suspected statin-induced systemic lupus erythematosus or dermatomyositis.20,21 A recent report also showed statin use to be associated with an increased incidence of interstitial lung abnormalities in smokers.22 m e dic i n e First, several years before the development of dyspnea, the patient had back pain radiating to the leg that impaired her exercise tolerance. Second, she has a child who had had a head injury 7 years earlier (as a teenager), with resulting functional impairment, and this situation continues to be stressful for the patient. Perhaps as a result of her child’s experience, this patient might have a tendency to react to any symptom she has with alarm. I explored the left chest by means of thoracoscopy. There were no pleural adhesions; there were pleural plaques, predominantly in the apex, and I could not feel the apical nodule that was seen on imaging. I performed an apical wedge resection, and the resection specimen contained the nodule. Cl inic a l Di agnosis Interstitial lung disease, possibly cryptogenic organizing pneumonia. Dr . B a r r y S . She a’s Di agnosis Summary On the basis of the clinical scenario provided, my unifying diagnosis for this patient is myopathy and interstitial lung disease due to statin use. The key to this diagnosis is the discordance between the patient’s dramatic functional limitation and the normal results of pulmonary-function testing and extent of radiographic abnormalities. Supporting information includes the presence of leg fatigue, elevated serum aminotransferase levels, and statin use. I would have obtained measurements of serum muscle enzymes (creatine kinase, aldolase, and lactate dehydrogenase) to assess for myositis, considered a trial of statin discontinuation, and evaluated the patient for other nonpulmonary causes of dyspnea and exercise limitation. Dr. Eugene J. Mark: The patient was seen by Drs. David Kanarek (Pulmonary and Critical Care) and Henning Gaissert (Thoracic Surgery). We have asked Dr. Gaissert for his impressions. Dr. Henning A. Gaissert: Dr. Kanarek thought that the features seen on the imaging studies were probably not indicative of sarcoidosis and favored a diagnosis of interstitial lung disease, possibly cryptogenic organizing pneumonia. I was asked to perform a lung biopsy. Two additional features of this patient’s history may have played a role in the presentation. 1754 of Statin-induced myopathy and interstitial lung disease. Pathol o gic a l Discussion Dr. Mark: The principal pathological feature was marked pleural thickening by dense fibroelastotic tissue (Fig. 3A). The process was relatively confined to the pleura, although there was extension into the lung parenchyma along lobular septa (Fig. 3B) and deformation of normal pulmonary architecture in the subpleural region (Fig. 3C). A few active fibroblastic foci were present in the areas of fibrosis extending into the subjacent lung (Fig. 3D). These findings are commonly associated with usual interstitial pneumonia, but they can be seen in patients with other conditions. An elastic-tissue stain revealed a prominent component of elastic tissue (Fig. 3E). These pathological features are distinctive and characteristic of idiopathic pleuroparenchymal fibroelastosis (PPFE). The histopathological findings associated with idiopathic PPFE include a particularly dense elastotic subpleural band, with more elastic tissue than collagen in the scar.23-28 There may be extension of fibrosis into the interstitium in the underlying lung. A few active fibroblastic foci may be present n engl j med 372;18 nejm.org April 30, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on July 3, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. Case Records of the Massachuset ts Gener al Hospital A B P P P D C P P A A P A L P E Figure 3. Lung-Biopsy Specimen. Panels A through D show hematoxylin and eosin staining of a lung‑biopsy specimen. Panel A shows marked fibrous thickening of the pleura (P), with sharp demarcation from the underlying lung (dashed line). Panel B shows that fi‑ brous tissue extends from the pleura (P) into the subjacent lung along a lobular septum (between dashed lines). Panel C shows alveolar simplification, with deformation and ectatic air spaces (A) beneath the pleura (P). Panel D shows an isolated active fibroblastic focus (oval) at the interface between the pleural fibrosis (P) and subjacent nor‑ mal lung (L). Panel E shows a Verhoeff–van Gieson elastic stain of the thickened pleura, revealing numerous thick elastic fibers in the collagenous tissue. at the interface of the elastotic scar in the sub- monia, and the absence of temporal heterogenepleural lung parenchyma. The absence of a dif- ity serves to differentiate this condition from usual fuse lymphocytic infiltrate serves to differentiate interstitial pneumonia. this condition from nonspecific interstitial pneuThe clinical features may be less distinctive n engl j med 372;18 nejm.org April 30, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on July 3, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. 1755 The n e w e ng l a n d j o u r na l than the pathological features.29-32 Predominant involvement of the upper lung zones and a chronic progressive course are common. Pneumothorax is relatively common. There is a small number of reported cases; these consist principally of case reports in previous decades and small case series in recent decades. There is variation in the taxonomy at this time and no complete agreement about whether idiopathic PPFE should be viewed as a specific type of interstitial lung disease. The histopathological differential diagnosis of PPFE includes a particularly extensive pleural apical cap, asbestos-related pleural fibrosis, collagen vascular disease resulting in interstitial fibrosis with predominant pleural involvement, a drug reaction, and diffuse pleural scarring with myriad causes. The pathogenetic mechanisms of idiopathic PPFE are unclear. It is possible that the disease is a variant of usual interstitial pneumonia or nonspecific interstitial pneumonia, that the disease is some form of pneumoconiosis, that some cases in patients who have undergone lung transplantation represent chronic allograft rejection, or that the disease is an exaggerated form of a pleural apical cap. A few familial cases have been reported. Since the cause of PPFE is unknown, we were intrigued by Dr. Shea’s diagnosis, which was submitted shortly before the conference, and wondered if in fact the disease in this case might be related to statin use. However, on further review of the patient’s record, we found that the statin had been introduced only a few weeks before the visit to the pulmonary clinic and thus could not account for her symptoms or lung disease. We also belatedly noticed that the discrepancy between the patient’s symptoms of breathlessness and exercise tolerance had not been sufficiently highlighted; the patient had described dyspnea with exercise but was still able to complete her daily routine of walking and jogging 4 miles. Dr. Shea, we apologize for these oversights and appreciate your willingness to discuss the case further. Dr. Shea: PPFE is an interesting pathological diagnosis that has been identified as a distinct clinicopathological entity in recent decades. The original report of PPFE in the English literature described a series of patients with disease predominantly involving the upper lung zones that was characterized by dense fibroelastosis of the 1756 of m e dic i n e visceral pleura and adjacent lung parenchyma.30 In this initial report and several subsequent reports, many persons with this disease had had previous exposure to chemotherapeutic agents, had undergone bone marrow transplantation, or both.24,25,29,30 In one case series, one patient had been receiving a statin, and in another series, about half the patients had serologic features suggestive of an underlying autoimmune process. Therefore, although PPFE may be idiopathic in many cases, it may also occur as a secondary process in response to an underlying condition. The vast majority of patients with PPFE appear to have clinically significant impaired lung function, and most have disease progression over time, even when they are treated aggressively with glucocorticoids and immunosuppressive therapy.28 The pathological diagnosis of PPFE fits with the radiographic abnormalities seen in this case. However, it would not explain the apparently dramatic decrease in exercise tolerance described in the case history, given the minimal extent of disease and the normal results of pulmonaryfunction tests. If the patient’s functional decline was as substantial as she indicated, then alternative explanations would need to be explored. However, it appears that her functional impairment was not as substantial as had been implied in the case history. Dr. Mark: Would you comment on the findings on imaging studies in the context of this diagnosis, Dr. Sharma? Dr. Sharma: The CT findings correlate with the pathological findings. Dr. Shea’s differential diagnosis describes how we assess the distribution of disease, which is both predominant in the upper lung zones and peripheral. The combination of pleural thickening, linear densities, and pleuroparenchymal opacities is difficult to explain by any of the conditions that we considered, except for this new entity of PPFE. Although it is very rare, we may see it more in the future. Dr. Shea: An important question is whether autoimmune disease could play a role in this disease. Ankylosing spondylitis can be associated with pleuroparenchymal fibrosis with predominant involvement of the upper lung zones. Dr. Mark: How many people in the audience have thought of or made the diagnosis of idiopathic PPFE? Four out of 75. Even among a group of specialists, this diagnosis is not well recognized. n engl j med 372;18 nejm.org April 30, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on July 3, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. Case Records of the Massachuset ts Gener al Hospital Dr. Martin P. Solomon (Internal Medicine, Brigham and Women’s Hospital): I’m the patient’s primary care doctor, and I’d like to make a couple of points. One is that her presenting symptom was breathlessness. We treated her for asthma but went ahead with the chest radiograph and further evaluation. Although fatigue has been mentioned, her primary symptom is still breathlessness. The social aspect of the history that was brought up by Dr. Gaissert is very important. This woman is surrounded by illness and tragedy; her child was struck by a car in front of her and is now dependent on her for care. The final point is that this woman, who is anxious and frightened, was first told she might have cancer and was then told that she had a rare disease that might require lung transplantation, which kept her in a state of panic. Although her dyspnea has not worsened and she is able to References 1. Boitsios G, Bankier AA, Eisenberg RL. Diffuse pulmonary nodules. AJR Am J Roentgenol 2010;194:W354-W366. 2. Hillerdal G. Malignant mesothelioma 1982: review of 4710 published cases. Br J Dis Chest 1983;77:321-43. 3. Seo P, Stone JH. The antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med 2004;117:39-50. 4. Müller NL, Kullnig P, Miller RR. The CT findings of pulmonary sarcoidosis: analysis of 25 patients. AJR Am J Roentgenol 1989;152:1179-82. 5. Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 2001;164: 1885-9. 6. American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society International multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2002;165:277-304. 7. Alasaly K, Muller N, Ostrow DN, Champion P, FitzGerald JM. Cryptogenic organizing pneumonia: a report of 25 cases and a review of the literature. Medicine (Baltimore) 1995;74:201-11. 8. King TE Jr, Mortenson RL. Cryptogenic organizing pneumonitis: the North American experience. Chest 1992; 102: Suppl:8S-13S. 9. Jederlinic PJ, Sicilian L, Gaensler EA. Chronic eosinophilic pneumonia: a report of 19 cases and a review of the literature. Medicine (Baltimore) 1988;67:154-62. perform her usual exercise routine, she is still in emotional distress. A lot of what we have to deal with now is iatrogenic panic, which is a very real entity. I also think the possibility of autoimmune disease is important because the patient has a sister with a history of systemic lupus erythematosus and a brother with type 1 diabetes mellitus. A nat omic a l Di agnosis Idiopathic pleuroparenchymal fibroelastosis. This case was presented at “Thoracic Pathology: Fifth Annual Course,” directed by Eugene J. Mark, M.D., and William D. Travis, M.D., and sponsored by the Harvard Medical School Department of Continuing Education. No potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. 10.Marchand E, Reynaud-Gaubert M, Lauque D, Durieu J, Tonnel AB, Cordier JF. Idiopathic chronic eosinophilic pneumonia: a clinical and follow-up study of 62 cases. Medicine (Baltimore) 1998;77:299312. 11.Cordier JF. Cryptogenic organising pneumonia. Eur Respir J 2006;28:422-46. 12. Fischer A, du Bois R. Interstitial lung disease in connective tissue disorders. Lancet 2012;380:689-98. 13. Castelino FV, Varga J. Interstitial lung disease in connective tissue diseases: evolving concepts of pathogenesis and management. Arthritis Res Ther 2010;12: 213. 14. Lee HK, Kim DS, Yoo B, et al. Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. 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(In Japanese.) 28.Reddy TL, Tominaga M, Hansell DM, n engl j med 372;18 nejm.org April 30, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on July 3, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. 1757 Case Records of the Massachuset ts Gener al Hospital et al. Pleuroparenchymal fibroelastosis: a spectrum of histopathological and imaging phenotypes. Eur Respir J 2012;40:37785. 29.von der Thüsen JH, Hansell DM, Tominaga M, et al. Pleuroparenchymal fibroelastosis in patients with pulmonary disease secondary to bone marrow transplantation. Mod Pathol 2011; 24: al. Pneumothorax and idiopathic pulmo1633-9. nary fibrosis. Jpn J Radiol 2010;28:672-9. 30.Frankel SK, Cool CD, Lynch DA, 32.Yousem SA. Pulmonary apical cap: a Brown KK. Idiopathic pleuroparenchymal distinctive but poorly recognized lesion in fibroelastosis: description of a novel clin- pulmonary surgical pathology. Am J Surg icopathologic entity. Chest 2004; 126: Pathol 2001;25:679-83. 2007-13. Copyright © 2015 Massachusetts Medical Society. 31. Iwasawa T, Ogura T, Takahashi H, et Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference material is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends, shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the images from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens, and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced, averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of the Case Record. The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail [email protected]. 1758 n engl j med 372;18 nejm.org April 30, 2015 The New England Journal of Medicine Downloaded from nejm.org by WEILIANG JIANG on July 3, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.