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1 Department of Radiology, Thomas Jefferson University Hospital, 111 S. 11th
St., 3390 Gibbon, Philadelphia, PA 19107.
2 Department of Radiology, University of Pennsylvania Hospital, Philadelphia, PA
19104.
Received June 11, 2002;
accepted after revision September 10, 2002.
Address correspondence to R. M. Shah.
Abstract
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MATERIALS AND METHODS. A retrospective search of our department's CT database from January 1998 through December 2000 revealed 153 cases of ground-glass opacity. Patients evaluated using bronchoscopy or open biopsy within 30 days (mean, 6.9 days) of imaging with ground-glass opacity as the predominant high-resolution CT finding were selected. There were 21 men and 16 women with a mean age of 51.4 years. Two chest radiologists, unaware of the clinical diagnoses, independently recorded lobular distributions. Consensus interpretation was used for discrepancies. Primary distributions were recorded as lobular (geographic ground-glass opacity marginated by septal anatomy), centrilobular (ground-glass opacity related to bronchovascular anatomy), or random.
RESULTS. Infectious and other histologic diagnoses fell into four diagnostic groups: atypical pneumonia, chronic infiltrative interstitial disease, acute air-space filling, and drug toxicity. Ground-glass opacity was most frequently associated with acute atypical pneumonia (n = 12, 32%), chronic infiltrative disease (n = 10, 27%), acute air-space filling (n = 6, 16%), and drug toxicity (n = 4, 11%). In five patients, a definitive diagnosis was not established. Ground-glass opacity was most commonly randomly distributed (n = 16, 43%), followed by lobular (n = 15, 41%) and centrilobular (n = 6, 16%) distributions. Distribution did not correlate with diagnostic group.
CONCLUSION. In unselected cases of ground-glass opacity evaluated at a tertiary institution, atypical infection and chronic infiltrative interstitial disease accounted for 59% of diagnoses. Distribution at a lobular level did not differentiate underlying causes.
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In many instances, ground-glass opacity is a secondary finding in which associated abnormalities including nodules or masses, interstitial changes, and consolidation contribute to a given diagnosis. Well-known examples include the halo sign of invasive aspergillosis and crazy paving in alveolar proteinosis [4, 5]. Furthermore, anatomic distribution of the ground-glass opacity at a lobular level can be used to suggest a diagnosis [6]. Centrilobular distributions are readily recognized in hypersensitivity pneumonitis and panlobular distributions in Pneumocystis carinii pneumonia [7, 8].
Much of the literature describes ground-glass opacity as a radiographic finding in small series of selected patients with established diagnoses. Our purpose was to establish the most frequently encountered diagnoses in an unselected patient population with widespread ground-glass opacity as the only abnormality or predominant abnormality shown on high-resolution CT. We hypothesized that diffuse ground-glass opacity as an isolated abnormality is associated with a limited differential diagnosis. We also examined whether the presence of a predominant distribution at the lobular level can be used to suggest a diagnostic category.
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Patient Population
Our study included 21 men and 16 women who were 24–82 years old
(mean, 51.4 years). Potential immunosuppression was documented in 24 (67%) of
37 patients. Fourteen patients had solid organ (n = 7) or hematologic
(n = 7) malignancies treated by chemotherapy or bone marrow
transplantation. Five patients were HIV-positive with a mean CD4 count of 24
cells per microliter. Three additional patients had recently received
solid-organ transplants, and two patients were undergoing steroid therapy for
obstructive lung or inflammatory bowel disease. A history of collagen vascular
disease was established in five patients.
Clinical Evaluation
Bronchoscopy or surgical lung biopsy was performed in all patients within a
mean of 6.9 days before high-resolution CT. Histologic diagnoses were
established in 20 (54%) of 37 patients, 13 of which were obtained by open lung
biopsy; six, by transbronchial biopsy; and one, at autopsy. In 17 patients
(46%), only results of bronchoalveolar lavage and respiratory culture were
available.
Radiographic Evaluation
CT scans were obtained with a helical scanner (HiSpeed Advantage; General
Electric Medical Systems, Milwaukee, WI). Thirty-one patients were imaged
using 5-mm axial sections; a pitch of 2; and a variety of high-resolution CT
protocols, including 1-mm axial sections at four levels (aortic arch, carina,
cardiac ventricles, and domes of the diaphragm [n = 5]), at 30-mm
intervals (n = 8), at 20-mm intervals (n = 14), or at 10-mm
intervals (n = 3). Six patients also underwent imaging in a prone
position, and nine had expiratory imaging in a supine position. An additional
six patients were imaged using contiguous 2-or 3-mm sections for the exclusion
of pulmonary emboli. Nine studies were contrast-enhanced.
All high-resolution CT images were independently reviewed by two chest radiologists who were unaware of results of the clinical evaluation to determine the predominant zonal and lobular distribution of ground-glass opacities. Ground-glass opacity was scored as lobular if it was marginated by septal anatomy. A designation of centrilobular was recorded if the ground-glass opacity appeared as indistinct rounded areas of ground glass with an apparent relationship to the bronchiolovascular anatomy. Those cases that could not be clearly identified as having a lobular or centrilobular distribution were scored as random ground-glass opacities. Disagreements in predominant distribution were decided by a consensus interpretation.
Statistical Analysis
Statistical analysis was performed with a version 8.2 SAS software package
(SAS Institute, Cary, NC). Observer agreement was determined with the kappa
statistic. Associations between the lobular distribution and the clinical
group were analyzed with the chi-square test.
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Atypical pneumonia accounted for ground-glass opacity in 12 (32%) of 37 patients (Figs. 1 and 2). Diagnoses established histologically or microbiologically or both included pneumocystis pneumonia (n = 8), cytomegalovirus pneumonia (n = 1), and respiratory syncytial virus pneumonia (n = 1). In two other patients, a diagnosis of nonspecified pneumonia was made on the basis of exclusion of other diagnoses and clinical responses to standard antibiotic regimens.
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Histologically confirmed chronic interstitial disease accounted for 10 diagnoses (27%), including desquamative interstitial pneumonia (n = 4), nonspecific interstitial pneumonitis (n = 1), and an additional five cases that were histologically described but not specifically classified (Figs. 3 and 4). These included two patients with systemic lupus erythematosus, one patient with inflammatory bowel disease, and two patients with diagnoses of unknown origin.
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In six patients (16%), acute air-space-filling processes other than infection accounted for ground-glass opacities (Figs. 5 and 6). Two patients had evidence of alveolar hemorrhage at bronchoalveolar lavage or open lung biopsy. In two patients, diffuse alveolar damage was diagnosed histologically from open lung biopsies and autopsy specimens. In an additional two patients, a diagnosis of pulmonary edema was made after exclusion of all other causes, response to diureses, and an appropriate cardiac or renal history or both.
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In four (11%) of 37 patients, pulmonary drug toxicity was diagnosed (Fig. 7). Included were three patients with supportive histology obtained at open or transbronchial biopsy who were receiving treatment with irinotecan hydrochloride, carmustine, and cyclophoshamide. In one patient receiving gemcitabine hydrochloride, a diagnosis of drug toxicity was made on the basis of dramatic clinical improvement after cessation of treatment and steroid therapy and after exclusion of other causes by bronchoalveolar lavage or transbronchial biopsy.
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In five cases (14%) with noncontributory bronchoalveolar lavage, a definitive diagnosis was not established. One patient had known rheumatoid arthritis, and another had documented scleroderma.
Clinical Significance of Ground-Glass Opacity Relative to Clinical
History
Among non–HIV-immunosuppressed patients (n = 16), diagnoses
of infectious diseases (n = 7) were most common, representing 44% of
cases, followed by pulmonary drug toxicity in four patients (25%). Infectious
causes included pneumocystis pneumonia (n = 3), cytomegalovirus
pneumonia (n = 1), respiratory syncytial virus (n = 1), and
pneumonia unspecified (n = 2). Additional causes of ground-glass
opacity included diffuse alveolar damage (n = 2), chronic
infiltrative interstitial disease nonspecified (n = 2), and alveolar
hemorrhage (n = 1).
Among HIV-positive immunosuppressed patients (n = 5), ground-glass opacity always represented pneumocystis pneumonia.
In patients with established collagen vascular disease (n = 4), ground-glass opacity was attributed to infiltrative interstitial disease (n = 3) and alveolar hemorrhage (n = 1).
In the presumed immunocompetent population without collagen vascular disease (n = 8), chronic infiltrative interstitial disease (n = 6) accounted for 75% of cases, and pulmonary edema (n = 2) accounted for 25%.
Assessment of Distribution of Ground-Glass Opacity on High-Resolution
CT
The two reviewers independently assessed the lobular distribution of
ground-glass opacity on high-resolution CT, recording the predominant pattern
as lobular, centrilobular, or random. All cases in which there was pattern
disagreement were jointly reviewed, and the predominant pattern was decided by
consensus. The consensus review showed random distributions to be most common,
seen in 16 (43%) of 37 cases, closely followed by lobular distributions, seen
in 15 cases (41%). Six cases (16%) revealed predominant centrilobular
distributions. Interobserver agreement for predominant pattern was fair
(
= 0.48). The differences in interpretation largely reflect the
tendency of observer 1 to more frequently assign a specific distribution and
the tendency of observer 2 to record a random distribution.
Correlation of Lobular Distribution with Diagnostic Group
Among the 12 diagnoses of diseases with infectious causes, random
distributions were identified in six cases; lobular distributions, in five;
and centrilobular distributions, in one (Figs.
1 and
2). Of the 10 cases
representing chronic infiltrative interstitial disease, random and lobular
distributions were each seen in four cases, and centrilobular distributions
were identified in two (Figs. 3
and 4). Among the six cases of
noninfectious air-space filling, random distributions were recognized in four
cases, with lobular and centrilobular distributions identified in one case
each (Figs. 5 and
6). Of the four cases
representing pulmonary drug toxicity, lobular distributions were present in
three and random distributions in one (Fig.
7).
Statistical analysis of the results of observer 1, observer 2, and the consensus interpretation revealed no association between distribution at the lobular level and the diagnostic group.
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When applied to clinical practice, our results show that isolated widespread ground-glass opacity is a significant finding. In our series of isolated widespread ground-glass abnormalities identified on unselected, consecutive patients having undergone CT, atypical infection and chronic infiltrative interstitial disease accounted for nearly two thirds of all cases. Noninfectious air-space filling, including edema, alveolar hemorrhage, and pulmonary drug toxicity together accounted for the remaining one third of cases.
Our results do not take into consideration a given patient's clinical history. In fact, choosing to evaluate consecutive CT cases we wanted to avoid bias based on clinical history. In many patients, a given clinical setting would not limit the potential diagnostic considerations. For example, in patients treated for malignancies or after bone marrow transplantation, opportunistic infection, edema, alveolar hemorrhage, and drug toxicity would be reasonable considerations. In at least 51% of cases, clinical history did not narrow the differential diagnosis on radiography. In the non–HIV-immunosuppressed group, infection accounted for 37% of cases, but drug toxicity was documented in more than 20%. As might be expected, ground-glass opacity represented pneumocystis pneumonia in all our patients with AIDS. A history of collagen vascular disease or lack of relevant history favored chronic infiltrative interstitial disease, identified in 75% of cases.
The 37 patients included in our final study population represent only 21% of the total number of cases identified with the pattern of widespread isolated ground-glass opacity. By including only those patients with complete pulmonary workup, including open lung biopsy or bronchoscopy with bronchoalveolar lavage or transbronchial biopsy, we limited the number of patients in our study and introduced the potential for significant selection bias. If all 153 patients with widespread ground-glass opacity had been reviewed, the relative frequencies of the diagnostic groups may have been different. We would have anticipated more frequently diagnosed pulmonary edema and a lesser occurrence of chronic infiltrative interstitial disease. Certainly a higher percentage of causes would have been undiagnosed. We also encountered pulmonary drug toxicity more commonly than expected.
It is also likely that some causes of isolated ground-glass opacity were not encountered in our study, including hypersensitivity pneumonitis and pulmonary alveolar proteinosis. Thus, the results of our study are not an exhaustive list of the causes of isolated ground-glass opacity. However, we believe that our study identifies the most common, clinically significant causes of this pattern of abnormality seen on radiographs.
We could not confirm our initial premise that characterization of
ground-glass opacity according to distribution of the lobular level (i.e.,
centrilobular, lobular, or random) could assist in narrowing the differential
diagnosis. Several factors are likely responsible. Foremost, few diseases
strictly adhere to a given distribution. Although several diseases may start
in the centrilobular region and initially manifest as centrilobular nodules,
more advanced stages of the same disease can involve entire pulmonary lobules
and manifest with lobular distributions. This finding would, at least, be
expected in cases of pulmonary edema and certain infections. In fact, at
consensus review, random distributions were recorded most frequently and
indicated that a particular case did not reveal a predominant lobular or
centrilobular distribution. Furthermore, radiographic differentiation of
lobular distribution may be difficult, as shown by only fair ( = 0.48)
interobserver agreement on the dominant pattern.
Widespread ground-glass opacity as the predominant high-resolution CT abnormality seen in consecutive patients with pathologic correlation is a significant finding. A diagnosis of pneumonia is made in one third of all cases and more frequently in patients with immunosuppression. A diagnosis of chronic infiltrative interstitial disease is made just as frequently among all cases and in as many as 80% of patients without underlying immunosuppression. Recognition of lobular or centrilobular distributions does not contribute to a more specific differential diagnosis.
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