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* From the New York School of Medicine/New York University and Bellevue Medical Centers.
Corrrespondence to: Ioannis Vlahos, MRCP, FRCR, New York University Medical Center, 560 First Ave, IRM 236, New York, NY 10016; e-mail: francisg71{at}yahoo.co.uk
Key Words: alveolar sarcoidosis • high-resolution CT
Clinical Findings
A 30-year-old, male smoker with a history of IV drug use and hepatitis C presented with insidious onset of exertional dyspnea, fatigue, and weight loss. He denied cough, wheeze, orthopnea, paroxysmal nocturnal dyspnea, fever, night sweats, or recent IV drug use. There was no relevant occupational or travel history, exposure to organic or inorganic allergens, or exposure to tuberculosis. The patient’s HIV status was unknown, and he was taking no prescribed medications. On examination, he was afebrile and acyanotic, with a BP of 102/52 mm Hg and pulse rate of 62 beats/min. Oxygen saturation on room air was 97% with a mild exertional desaturation to 90%. Peak flow was measured as 400 to 450 L/min. Chest auscultation revealed scattered fine rales without rhonchi. There were no features of central or peripheral edema, and the remainder of the physical examination was unremarkable.
What Differential Diagnoses Would You Consider at This Point?
A CBC count including WBC differential was normal (5.2 x 109/L). The erythrocyte sedimentation rate was 2 mm/h. A metabolic panel demonstrated normal electrolytes and calcium (10.2 mg/dL). The alanine aminotransferase was mildly elevated (59 U/L). The liver panel was otherwise unremarkable. Urinalysis was normal. Blood culture results were negative. Pulmonary function tests demonstrated FVC, 78% of predicted; FEV1, 72% of predicted, and FEV1/FVC, 94% of predicted. Diffusion capacity of the lung for carbon monoxide was reduced to 62%.
Radiologic Findings
A chest radiograph (Fig 1
) demonstrated predominantly upper and mid-lung patchy, bilateral, ground-glass airspace opacities, asymmetrically greater on the right, without focal collapse or consolidation. No effusions were present. The cardiac, mediastinal, and hilar contours were unremarkable.
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Diagnosis: Alveolar sarcoidosis
Clinical Discussion
In this patient with a history of IV drug use and known hepatitis C, the presentation with exertional dyspnea and airspace opacities suggested a possible diagnosis of infection. In particular, pneumocystis was strongly considered, as there were risk factors for immunodeficiency.
HIV antibody testing, however, proved negative, and there were no other laboratory or clinical indicators to support an infectious etiology. Results of subsequent examinations for acid-fast and alcohol-fast bacilli and cultures for mycobacterial and other microorganisms were also negative.
Asymmetric pulmonary edema was considered unlikely, as there was no evidence of impaired cardiac function and no exposure to toxic agents associated with noncardiogenic pulmonary edema. In the absence of hemoptysis, diffuse pulmonary hemorrhage would be unlikely to present with the plain radiographic findings shown.
Secondary effects of hepatitis C virus infection on pulmonary function include hepatopulmonary syndrome and portopulmonary hypertension1; however, both conditions are usually associated with more advanced degrees of hepatic dysfunction. Given the low level of alanine aminotransferase elevation and absence of stigmata of chronic liver disease, these were considered clinically unlikely. In addition, presentation with ground-glass opacities would be atypical. On CT, peripheral basilar vascular dilatations are typical for hepatopulmonary syndrome, and there was no dilatation of the pulmonary arteries to support portopulmonary hypertension.
Desquamative interstitial pneumonia is an uncommon condition that may present with insidious exertional dyspnea and ground-glass opacities. Mean age, however, is typically older (42 years). Desquamative interstitial pneumonia represents an alveolar macrophage pneumonia, usually secondary to cumulative cigarette smoke exposure. In addition, ground-glass opacities are more typically basilar and subpleural in their distribution. Although sarcoid-like disease has been described in patients receiving treatment with interferon, a history of such therapy was absent.
In summary, the clinical course and pulmonary function test results in this case were a nonspecific indicator of interstitial lung disease. HRCT imaging was key to further characterizing the disease process, demonstrating features that were most compatible with alveolar sarcoidosis.
The prognostic significance of different morphologic appearances of parenchymal abnormalities in sarcoidosis and in particular of the alveolar type is uncertain. In general, patients with alveolar sarcoid are thought to have less physiologic impairment and a low frequency of extrathoracic sarcoid involvement.2 Some reports34 suggest rapid clearing of parenchymal opacities on steroid initiation. However, Akira et al5 correlated HRCT findings with pulmonary function test results over a mean follow-up of 7.4 years. Patients with a predominantly ground-glass opacity pattern were more likely to have honeycombing and an associated decline in FVC. Therefore, in patients with alveolar or ground-glass pattern sarcoidosis, it may be prudent to closely monitor disease progression.
Radiology Discussion
Ground-glass opacities were mimicked on the plain chest radiograph and 5-mm CT sections, which lead to the consideration of pneumocystis infection in this patient with risk factors for HIV. HRCT, however, demonstrated that the apparent airspace opacities were due to myriad interstitial nodules, most consistent with alveolar sarcoidosis.
HRCT of sarcoidosis classically demonstrates parenchymal 1- to 2-mm nodules due to conglomerate granulomas in a perilymphatic and peribronchovascular distribution, involving the central axial interstitium, the fissures, and subpleural surfaces. Diagnostic considerations for perilymphatic nodules include lymphangitis carcinomatosis, coal workers’ pneumoconiosis, and silicosis. A history of underlying malignancy or relevant occupational history should aid in the differential.6
Occasionally larger accumulations of granulomas may result in macronodular opacities or areas of confluent parenchymal opacity.7 This pattern, which mimics airspace consolidation on the chest radiograph, occurs in approximately 10 to 20% of cases. Pure "ground-glass" abnormalities on chest radiographs were reportedly less common (0.6% of patients) in a study of > 1,600 patients by Tazi et al.8
Although this appearance may mimic ground glass even on conventional 5- to 7-mm CT images, 1-mm HRCT images usually demonstrate that these features, as in this case, are due to carpeting of the interstitium by myriad 
1-mm interstitial nodules. At the edges of these parenchymal opacities, small acinar rosettes may be apparent. Similar to other morphologic appearances of sarcoidosis, the distribution of disease is typically in the upper lobes and mid-lung zones, sparing the costophrenic angles. The appearances can occasionally be asymmetric and, therefore, mimic other causes of chronic parenchymal opacity such as infection, organizing pneumonia, or eosinophilic infiltration. The presence of symmetric mediastinal and hilar adenopathy, which is a common feature of alveolar-pattern sarcoidosis, may aid in diagnosis.8 Effusions are uncommon, as in conventional sarcoidosis.
Pathology Discussion
In sarcoidosis, T-cell accumulation within target organs leads to macrophage recruitment that subsequently transform into epithelioid cells. Nodular aggregates of these epithelioid cells become interstitial granulomas,910 each measuring < 0.4 mm.11 Granulomas may remain stable, resolve spontaneously or in response to therapy, or progress to fibrosis.
Transbronchoscopic biopsy is the tissue-sampling method of choice, with a diagnostic yield of 40 to 90%, depending largely on operator experience.12 Up to 10 biopsies may be optimal for obtaining the diagnosis in stage 1 disease.13 Combining transbronchial needle aspiration with transbronchial lung biopsy has been reported to increase the diagnostic yield.14 Surgical biopsy is generally regarded as the next diagnostic step following nondiagnostic bronchoscopy. High yields of 82 to 97% are reported with mediastinoscopy-guided biopsy.151617 It should be noted that the combination of finding multiple noncaseating granulomas in a transbronchial biopsy specimen plus a BAL fluid CD4/CD8 ratio of 
4:1 has a 100% positive predictive value in separating sarcoidosis from other interstitial lung diseases.18
It is likely that the limited areas of genuine ground-glass attenuation in patients with sarcoidosis are more commonly due to widespread microscopic interstitial granulomas of a size below the limit of resolution for HRCT rather than alveolitis.27 There may be limited secondary contribution to airspace opacity by compression of alveoli from coalescent interstitial nodules or occasionally by intrabronchial granulomas; however, the airways are usually patent demonstrating air bronchograms.
Pathologic correlation of ground-glass opacities identified in patients with sarcoidosis also suggests these opacities are due to the presence of interstitial granulomas alone without histologic evidence of alveolitis.111920 In a series of eight patients by Nishimura et al,11 ground-glass attenuation was present in six cases (75%). There was, however, no evidence of alveolitis in these patients at pathologic examination. In a larger series of 40 patients, Akira et al5 described a predominant CT ground-glass pattern in only 12.5% of sarcoid patients. It is possible that Nishimura et al11 overestimated the frequency of ground-glass opacities due to thick (5 mm) collimation and therefore volume averaging.
Conclusion
In this case, the initial clinical presentation and plain radiographic findings suggested a possible diagnosis of pneumocystis or other opportunistic infection. HRCT imaging, however, further characterized what had initially appeared as an airspace process as interstitial nodules most compatible with alveolar-type sarcoidosis. Histologic confirmation of noncaseating granulomas and exclusion of other infectious/inflammatory granulomatous disorders confirmed the diagnosis. Following initiation of steroid therapy, the patient had significant symptomatic improvement. Follow-up imaging 1 month later demonstrated significant improvement with only minimal residual parenchymal opacities.
Footnotes
Abbreviation: HRCT = high-resolution CT
The authors have no conflicts of interest to disclose.
Received for publication March 15, 2006. Accepted for publication July 27, 2006.
References
This article has been cited by other articles:
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  S. Raoof, D. P. Nadich, and W. D. Travis The New "Chest Imaging and Pathology for Clinicians" Section of CHEST Chest, November 1, 2006; 130(5): 1287 - 1289. [Full Text] [PDF]
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