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Postgraduate Education Corner: CHEST IMAGING AND PATHOLOGY FOR CLINICIANS |

Dyspnea on Exertion and Ground-Glass Infiltrates in an Ex-Smoker FREE TO VIEW

Mohit Chawla, MD; Nahal Boroumand, MD; Constantinos Alexandrou, MD; Diane Stover, MD, FCCP
Author and Funding Information

*From the Department of Medicine (Drs. Chawla, Alexandrou, and Stover), Section of Pulmonary Medicine, and Department of Pathology (Dr. Boroumand), Section of Thoracic Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.

Correspondence to: Mohit Chawla, MD, Department of Medicine, Section of Pulmonary Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: chawlam1@mskcc.org


The authors have no financial or other potential conflicts of interest to disclose.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2008;134(6):1320-1324. doi:10.1378/chest.07-2119
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A 64-year-old woman is referred to the Pulmonary Service because of an abnormal finding on CT scan of the chest. Her symptoms include dyspnea on exertion, nonproductive cough, postnasal drip, and occasional wheeze; however, there were no fevers, chills, rest dyspnea, or fatigue. Five months prior to our initial evaluation, cough prompted a chest radiograph. An abnormal finding led to CT imaging. This showed multiple areas of ill-defined ground-glass attenuation (GGA). She is an ex-smoker (30 pack-years) who resides, along with two cats, in the Northeast with travel to England, New Mexico, and Arizona. She worked near the World Trade Center at the time of its collapse. Previously, she worked as an inpatient social worker with multiple negative purified protein derivative test results, last in 2002. Concurrent medical history includes osteoarthritis, hypertension, dyslipidemia, and glaucoma. Medications include losartan, hydrochlorothiazide, atorvastatin, rofecoxib, timolol drops, bimatoprost drops, and albuterol by metered-dose inhaler; she is allergic to penicillin. Her physical examination is notable for obesity with normal chest auscultation and percussion. There is no clubbing. Pulmonary function test findings are consistent with mild obstructive airways disease. The diffusing capacity is normal; however, there is desaturation with exercise. Symptoms persisted along with fleeting infiltrates on CT scan despite a 2-week course of clarithromycin, 250 mg/d. Laboratory data were as follows: WBC, 11.4 × 103/μL (normal differential); erythrocyte sedimentation rate, 35 mm/h; creatinine phosphokinase, 84 U/L; angiotensin-converting enzyme, 53 U/L; and C-reactive protein, 0.83 mg/dL. Serum fungal serology findings are negative. Initially refusing bronchoscopy, the patient underwent a left thoracotomy and superior segmentectomy of the left lower lobe for diagnostic purposes.

Radiologic Findings

CT scan (7.5-mm sections; our initial scan after a course of clarithromycin) showed poorly defined areas of GGA predominantly in bilateral posterior segments of upper lobes and superior segments of lower lobes. Compared with 5 months prior, there is one area with improvement but another with worsening. There is no parenchymal cavitation, thoracic lymphadenopathy, or pleural effusion (Fig 1, 2). Positron emission tomography (PET)/CT scan showed no hypermetabolism.

Figure Jump LinkFigure 1 CT of the chest without contrast (7.5-mm sections; our initial scan after a course of clarithromycin) showing poorly defined areas of GGA predominantly in bilateral posterior segments of upper lobes and superior segments of lower lobesGrahic Jump Location
Figure Jump LinkFigure 2 CT of the chest without contrast (7.5-mm sections; our initial scan after a course of clarithromycin) showing poorly defined areas of GGA predominantly in bilateral posterior segments of upper lobes and superior segments of lower lobesGrahic Jump Location
What is the diagnosis?
What does the histopathology show?
Pathologic Findings
Left Lower Lobe, Superior Segment:

Benign lung parenchyma with lymphoid hyperplasia, intraalveolar and interstitial foamy macrophages, and focal interstitial fibrosis (Fig 3, 4). All stain and culture findings for organisms are negative.

Figure Jump LinkFigure 3 Left lower lobe, superior segment, including alveolar septa (single arrow), foamy macrophages within alveolar septum (opposing double arrows), and intraaalveolar macrophages (double arrows) [hematoxylin-eosin, original × 20]Grahic Jump Location
Figure Jump LinkFigure 4 Left lower lobe, superior segment, again showing intraaalveolar macrophages (hematoxylin-eosin, original × 40)Grahic Jump Location

Diagnosis: Exogenous lipoid pneumonia

Foci of GGA represent a broad differential, not always simplified by clinical correlation. The differential in this case includes nonspecific interstitial pneumonia, desquamative interstitial pneumonia, cryptogenic organizing pneumonia, acute hypersensitivity pneumonitis, drug toxicity, interstitial lung disease related to collagen vascular disease, chronic eosinophilic pneumonia, aspiration, bronchoalveolar carcinoma, and infection. Laboratory data did not support a diagnosis of collagen vascular disease. Less likely is infection given the variable response to antibacterials and negative fungal serology findings. The waxing and waning nature of the GGA make aspiration, cryptogenic organizing pneumonia, eosinophilic pneumonia, and hypersensitivity pneumonitis more probable. Initial history did not reveal any exposures to suggest hypersensitivity or risk factors for aspiration. However, after pathologic diagnosis, the patient did reveal a history of long-term nocturnal use of nasal mineral oil drops.

This case represents a common radiographic finding in a rare clinical scenario. Lipoid pneumonia is due to exogenous or endogenous etiologies; the former can be acute or chronic. Acute exogenous lipoid pneumonia is caused by aspiration of massive amounts of petroleum-based products.1,2 Chronic pulmonary involvement is seen due to aspiration over an extended period of time. Ingested lipid-based compounds, even for benign reasons like constipation3 or dietary supplementation,4 do not stimulate the cough reflex and it becomes difficult to clear these by the mucociliary action of the respiratory tract. These compounds also reach the alveoli by inhalation57 or embolization following rectal or intracutaneous administration.3,6,8 Occupational hazards with potential inhalational insults include mechanical work,9 spraying pesticides or paint,5 and a curious form of entertainment, fire-eating.10 Subsequently, there is stimulation of inflammation and, variably, fibrosis.1,11 Commonly the culprit is mineral oil, a mixture of inert, long-chain, saturated hydrocarbons,9 broken down by emulsification and engulfed by macrophages, which are nonspecific if present on BAL; however, they may be diagnostic in a compatible clinical setting.12

Patients can present with cough, dyspnea, fever, or without symptoms9; however, asymptomatic patients present with abnormal radiographic findings.6 Although nonspecific, plain chest radiograph findings include alveolar opacities, interstitial changes, a combination of these, or a mass-like lesion.13 CT findings include GGA, focal consolidation, interstitial thickening, and nodular lesions.14 Mediastinal adenopathy, cavitations, and pleural effusions are rare. Nonspecific hypodensities in the abnormal lung parenchyma, consistent with the density of adipose tissue, are common but not pathognomonic.9,12,15 Low-attenuation CT findings (− 35 to − 75 Hounsfield units) in areas of consolidation may represent fat density due to clustering of lipid vacuoles.4,12 Care should be taken in interpreting density as diagnostic because inflammation surrounding the lipid can have a higher CT attenuation, with acute lesions being the highest.16 Furthermore, normal parenchyma surrounded by inflammatory exudates may have an average CT density similar to fat.14 Due to volume averaging, traditional CT is not always able to distinguish lesions from surrounding inflammation. It is suggested to reserve CT attenuation analysis to mass-like lesions in the chronic stage or to early compact lesions, representing significant alveolar filling.16

Although high-resolution CT (HRCT) has allowed greater insight due to less volume-averaging effect and better spatial resolution, HRCT patterns are not pathognomonic.12 Furthermore, patterns change across the spectrum of disease. Acutely, areas of GGA are seen. As the unattended disease progresses, these foci consolidate into nodules. With time, there is distortion, fibrosis, and subsequent volume loss. In a prospective study, Seo et al16 induced lipoid pneumonia in pigs to follow HRCT findings. Foci of GGA were predominant immediately after instillation with progression to dense consolidations in 1 week. Throughout the 16-week follow-up, dense opacities waned as ground-glass developed. On histopathology, focal dense consolidations represented lipid-laden macrophages, lipid droplets, alveolar leukocytes, and alveolar wall cellular infiltrates. Intraalveolar exudate and alveolar wall infiltration correlated with ground glass as early as week 2. In areas of clearing lung, thickened interlobular septa were visualized, likely representing lymphatic drainage of lipid material and cellular infiltration. An earlier report17 demonstrated these thickened interlobular septa as Kerley B lines on plain chest radiograph. Volume loss manifests as fibrosis in the interlobular septa and pleura between weeks 8 and 12.16 These temporal relations date back to a plain radiographic review by Pierson.18 In particular, early dense consolidations were previously described as “rosettes” and “stippling” on plain chest radiograph, corresponding to airspace disease.19 Retrospective reviews of HRCT findings in exogenous lipoid pneumonia by Laurent et al12 and Lee et al14 also demonstrated similar radiopathologic correlates, including progressive inflammation, fibrosis, and parenchymal distortion.

With the introduction of HRCT, the alveolar and interstitial pattern of “crazy-paving” was described. Although classically associated with alveolar proteinosis,20 a retrospective analysis of 46 cases with crazy-paving discloses a variety of diseases with this pattern.21 A conglomerate of histopathologic findings including alveolar filling, inflammation, septal thickening, and interstitial fibrosis represent the crazy-paving pattern. Franquet et al22 described exogenous lipoid pneumonia on HRCT as patchy well-defined areas of ground-glass attenuation along with septal thickening, which is the classic radiographic description of crazy-paving. The presence of this pattern should oblige the clinician to consider lipoid pneumonia, however, only in the appropriate clinical setting because this is a rare presentation. Of note, on conventional CT imaging this is seen usually as alveolar opacification with ground-glass attenuation. The reticular network is difficult to resolve with traditional CT.

Although high signal intensity may represent fat, hemorrhage can have a similar intensity.16 A lack of specific signal intensity may be due to traditional MRI techniques, for which there are limited data regarding lipoid pneumonia.6,12 A case report of a hypermetabolic spiculated mass due to lipoid pneumonia reveals yet another entity resulting in false-positive results on PET scan.23 HRCT is the preferred imaging modality due to the shortcomings of plain chest radiograph, conventional CT, MRI, and PET.

Further diagnostic tools include fiberoptic bronchoscopy with BAL and transbronchial biopsy (TBBx). BAL fluid is grossly milky, oily, or hemorrhagic. Microscopically, there is a predominance of lymphocytes, rarely neutrophilic. Sudan black, sudan red, or oil red O can be utilized to stain fat.9,11 On TBBx, histologic findings include an abundance of lipid-laden macrophages in which vacuoles vary in size, although their presence is nonspecific. There is no obstruction of large or small airways. Fat stains are negative on paraffin sections of lung biopsy samples as the fat dissolves during the embedding process.9 As with radiographic imaging, the histopathology varies with time. Intraalveolar exudates and lipid-laden macrophages are seen early, while septal thickening and fibrosis are seen late. Exudates may persist if the patient remains exposed to the inciting agent. It is unclear if the diagnostic yield of BAL is improved by adding TBBx. Although the clinical history and radiographs may be sufficient, definitive diagnosis can be obtained with BAL and TBBx. If nondiagnostic, then one may consider open-lung biopsy.

The mainstay of treatment includes removing the inciting agent. Unproven therapies include steroids or lung lavage.6,24 Severe untreated disease may lead to cor pulmonale.24

HRCT findings and histopathology correlate temporally from the time of the initial event. Intraalveolar accumulation of lipoproteinaceous material is seen as focal consolidation or ground-glass attenuation. Type II pneumocyte hyperplasia, interstitial accumulation of macrophages, and interstitial fibrosis are seen on HRCT as a reticular network, over a ground-glass background.25 These findings are suggestive of lipoid pneumonia, however nonspecific.

The foundation of diagnosing exogenous lipoid pneumonia remains clinical and radiographic; however, either transbronchial or surgical lung biopsy can be performed for confirmation. BAL demonstrating lipid-laden macrophages is not diagnostic alone; however, their absence excludes the diagnosis.26

After diagnosis, the patient discontinued use of mineral oil drops and was given low-dose clarithromycin to serve as an immunomodulator. Macrolides are known to blunt inflammation up-regulated by cytokine activity.27 The patient improved on this regimen. After a slow taper and discontinuation, she worsened clinically and this was supported by physiologic and radiographic parameters. She resumed clarithromycin with improvement.

The approach to therapy with long-term low-dose macrolides as immunomodulators in respiratory diseases is novel.27 They can be considered in therapy; however, as with steroids, macrolides have not been studied in a controlled fashion in managing lipoid pneumonia. Therefore, standard management should include discontinuation or avoidance of the agent and possibly an antiinflammatory.

Franquet T, Giménez A, Rosón N, et al. Aspiration diseases: findings, pitfalls, and differential diagnosis. Radiographics. 2000;20:673-685. [PubMed]
 
Bernabeu Mora R, Mendez Martinez P, Abellan Martinez MC, et al. Acute lipoid pneumonia caused by accidental aspiration of vaseline used in nasogastric intubation [in Spanish]. Arch Bronconeumol. 2000;36:485-487. [PubMed]
 
Sharif F, Crushell E, O'Driscoll K, et al. Liquid paraffin: a reappraisal of its role in the treatment of constipation. Arch Dis Child. 2001;85:121-124. [PubMed] [CrossRef]
 
Webb WR, Müller NL, Naidich DP. Diseases characterized primarily by parenchymal opacification. High-resolution CT of the lung. 2001;3rd ed New York, NY Lippincott Williams & Wilkins:393-396
 
Carby M, Smith SR. A hazard of paint spraying. Lancet. 2000;355:896. [PubMed]
 
Adkins D, Bensadoun E. An 85-year-old man with a lung mass. Chest. 2004;125:1121-1123. [PubMed]
 
Vethanayagam D, Pugsley S, Dunn EJ, et al. Exogenous lipid pneumonia related to smoking weed oil following cadaveric renal transplantation. Can Respir J. 2000;7:338-342. [PubMed]
 
Bandla HPR, Davis SH, Hopkins NE. Lipoid pneumonia: a silent complication of mineral oil aspiration. Pediatrics. 1999;103:19-22
 
Gondouin A, Manzoni P, Ranfaing E, et al. Exogenous lipid pneumonia: a retrospective multicentre study of 44 cases in France. Eur Respir J. 1996;9:1463-1469. [PubMed]
 
Karacan Ö, Yilmaz İ, Eyüboğlu FÖ. Fire-eater's pneumonia after aspiration of liquid paraffin. Turk J Pediatr. 2006;48:85-88. [PubMed]
 
Spickard A III, Hirschmann J. Exogenous lipoid pneumonia. Arch Intern Med. 1994;154:686-692. [PubMed]
 
Laurent F, Philippe JC, Vergier B, et al. Exogenous lipoid pneumonia: HRCT, MR, and pathologic findings. Eur Radiol. 1999;9:1190-1196. [PubMed]
 
Lee JY, Lee KS, Kim TS, et al. Squalene-induced extrinsic lipoid pneumonia: serial radiologic findings in nine patients. J Comput Assist Tomogr. 1999;23:730-735. [PubMed]
 
Lee JS, Im J-G, Song KS, et al. Exogenous lipoid pneumonia: high-resolution CT findings. Eur Radiol. 1999;9:287-291. [PubMed]
 
Lee KS, Müller NL, Hale V, et al. Lipoid pneumonia: CT findings. J Comput Assist Tomogr. 1995;19:48-51. [PubMed]
 
Seo JB, Im J-G, Kim WS, et al. Shark liver oil-induced lipoid pneumonia in pigs: correlation of thin-section CT and histopathologic findings. Radiology. 1999;212:88-96. [PubMed]
 
Brody JS, Levin B. Interlobular septa thickening in lipid pneumonia. AJR Am J Roentgenol Radium Ther Nucl Med. 1962;88:1061-1069
 
Pierson JW. Some unusual pneumonias associated with the aspiration of fats and oils in the lungs. AJR Am J Roentgenol. 1932;27:572-579
 
Weill H, Ferrans VJ, Gay RM, et al. Early lipoid pneumonia: roentgenologic, anatomic and physiologic characteristics. Am J Med. 1964;36:370-376. [PubMed]
 
Murch CR, Carr DH. Computed tomography appearances of pulmonary alveolar proteinosis. Clin Radiol. 1989;40:240-243. [PubMed]
 
Johkoh T, Itoh H, Müller NL, et al. Crazy-paving appearance at thin-section CT: spectrum of disease and pathologic findings. Radiology. 1999;211:155-160. [PubMed]
 
Franquet T, Giménez A, Bordes R, et al. The crazy-paving pattern in exogenous lipoid pneumonia: CT-pathologic correlation. AJR Am J Roentgenol. 1998;170:315-317. [PubMed]
 
Tahon F, Berthezéne Y, Hominal S, et al. Exogenous lipoid pneumonia with unusual CT pattern and FDG positron emission tomography scan findings. Eur Radiol. 2002;12:S171-S173. [PubMed]
 
Pugatch RD, Mark E. Case records of the Massachusetts General Hospital: weekly clinicopathological exercises. Case 33–1999: a 57-year-old woman with a pulmonary mass. N Engl J Med. 1999;341:1379-1385. [PubMed]
 
Rossi SE, Erasmus JJ, Volpacchio M, et al. “Crazy-paving” pattern at thin-section CT of the lungs: radiologic-pathologic overview. Radiographics. 2003;23:1509-1519. [PubMed]
 
Corwin RW, Irwin RS. The lipid-laden alveolar macrophage as a marker of aspiration in parenchymal lung disease. Am Rev Respir Dis. 1985;132:576-581. [PubMed]
 
Garey KW, Alwani A, Danziger LH, et al. Tissue reparative effects of macrolide antibiotics in chronic inflammatory sinopulmonary diseases. Chest. 2003;123:261-265. [PubMed]
 

Figures

Figure Jump LinkFigure 1 CT of the chest without contrast (7.5-mm sections; our initial scan after a course of clarithromycin) showing poorly defined areas of GGA predominantly in bilateral posterior segments of upper lobes and superior segments of lower lobesGrahic Jump Location
Figure Jump LinkFigure 2 CT of the chest without contrast (7.5-mm sections; our initial scan after a course of clarithromycin) showing poorly defined areas of GGA predominantly in bilateral posterior segments of upper lobes and superior segments of lower lobesGrahic Jump Location
Figure Jump LinkFigure 3 Left lower lobe, superior segment, including alveolar septa (single arrow), foamy macrophages within alveolar septum (opposing double arrows), and intraaalveolar macrophages (double arrows) [hematoxylin-eosin, original × 20]Grahic Jump Location
Figure Jump LinkFigure 4 Left lower lobe, superior segment, again showing intraaalveolar macrophages (hematoxylin-eosin, original × 40)Grahic Jump Location

Tables

References

Franquet T, Giménez A, Rosón N, et al. Aspiration diseases: findings, pitfalls, and differential diagnosis. Radiographics. 2000;20:673-685. [PubMed]
 
Bernabeu Mora R, Mendez Martinez P, Abellan Martinez MC, et al. Acute lipoid pneumonia caused by accidental aspiration of vaseline used in nasogastric intubation [in Spanish]. Arch Bronconeumol. 2000;36:485-487. [PubMed]
 
Sharif F, Crushell E, O'Driscoll K, et al. Liquid paraffin: a reappraisal of its role in the treatment of constipation. Arch Dis Child. 2001;85:121-124. [PubMed] [CrossRef]
 
Webb WR, Müller NL, Naidich DP. Diseases characterized primarily by parenchymal opacification. High-resolution CT of the lung. 2001;3rd ed New York, NY Lippincott Williams & Wilkins:393-396
 
Carby M, Smith SR. A hazard of paint spraying. Lancet. 2000;355:896. [PubMed]
 
Adkins D, Bensadoun E. An 85-year-old man with a lung mass. Chest. 2004;125:1121-1123. [PubMed]
 
Vethanayagam D, Pugsley S, Dunn EJ, et al. Exogenous lipid pneumonia related to smoking weed oil following cadaveric renal transplantation. Can Respir J. 2000;7:338-342. [PubMed]
 
Bandla HPR, Davis SH, Hopkins NE. Lipoid pneumonia: a silent complication of mineral oil aspiration. Pediatrics. 1999;103:19-22
 
Gondouin A, Manzoni P, Ranfaing E, et al. Exogenous lipid pneumonia: a retrospective multicentre study of 44 cases in France. Eur Respir J. 1996;9:1463-1469. [PubMed]
 
Karacan Ö, Yilmaz İ, Eyüboğlu FÖ. Fire-eater's pneumonia after aspiration of liquid paraffin. Turk J Pediatr. 2006;48:85-88. [PubMed]
 
Spickard A III, Hirschmann J. Exogenous lipoid pneumonia. Arch Intern Med. 1994;154:686-692. [PubMed]
 
Laurent F, Philippe JC, Vergier B, et al. Exogenous lipoid pneumonia: HRCT, MR, and pathologic findings. Eur Radiol. 1999;9:1190-1196. [PubMed]
 
Lee JY, Lee KS, Kim TS, et al. Squalene-induced extrinsic lipoid pneumonia: serial radiologic findings in nine patients. J Comput Assist Tomogr. 1999;23:730-735. [PubMed]
 
Lee JS, Im J-G, Song KS, et al. Exogenous lipoid pneumonia: high-resolution CT findings. Eur Radiol. 1999;9:287-291. [PubMed]
 
Lee KS, Müller NL, Hale V, et al. Lipoid pneumonia: CT findings. J Comput Assist Tomogr. 1995;19:48-51. [PubMed]
 
Seo JB, Im J-G, Kim WS, et al. Shark liver oil-induced lipoid pneumonia in pigs: correlation of thin-section CT and histopathologic findings. Radiology. 1999;212:88-96. [PubMed]
 
Brody JS, Levin B. Interlobular septa thickening in lipid pneumonia. AJR Am J Roentgenol Radium Ther Nucl Med. 1962;88:1061-1069
 
Pierson JW. Some unusual pneumonias associated with the aspiration of fats and oils in the lungs. AJR Am J Roentgenol. 1932;27:572-579
 
Weill H, Ferrans VJ, Gay RM, et al. Early lipoid pneumonia: roentgenologic, anatomic and physiologic characteristics. Am J Med. 1964;36:370-376. [PubMed]
 
Murch CR, Carr DH. Computed tomography appearances of pulmonary alveolar proteinosis. Clin Radiol. 1989;40:240-243. [PubMed]
 
Johkoh T, Itoh H, Müller NL, et al. Crazy-paving appearance at thin-section CT: spectrum of disease and pathologic findings. Radiology. 1999;211:155-160. [PubMed]
 
Franquet T, Giménez A, Bordes R, et al. The crazy-paving pattern in exogenous lipoid pneumonia: CT-pathologic correlation. AJR Am J Roentgenol. 1998;170:315-317. [PubMed]
 
Tahon F, Berthezéne Y, Hominal S, et al. Exogenous lipoid pneumonia with unusual CT pattern and FDG positron emission tomography scan findings. Eur Radiol. 2002;12:S171-S173. [PubMed]
 
Pugatch RD, Mark E. Case records of the Massachusetts General Hospital: weekly clinicopathological exercises. Case 33–1999: a 57-year-old woman with a pulmonary mass. N Engl J Med. 1999;341:1379-1385. [PubMed]
 
Rossi SE, Erasmus JJ, Volpacchio M, et al. “Crazy-paving” pattern at thin-section CT of the lungs: radiologic-pathologic overview. Radiographics. 2003;23:1509-1519. [PubMed]
 
Corwin RW, Irwin RS. The lipid-laden alveolar macrophage as a marker of aspiration in parenchymal lung disease. Am Rev Respir Dis. 1985;132:576-581. [PubMed]
 
Garey KW, Alwani A, Danziger LH, et al. Tissue reparative effects of macrolide antibiotics in chronic inflammatory sinopulmonary diseases. Chest. 2003;123:261-265. [PubMed]
 
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