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Multiple Pulmonary Nodules in AIDS: Usefulness of CT in Distinguishing among Potential Causes¹

¹ From the Depts of Radiology (K.J.E., G.P.R., M.H.C., R.A.H., W.R.W.) and Medicine (R.M.J., L.H., A.T.), Univ of California, San Francisco; Dept of Radiology, Beth Israel Deaconess Medical Center, Boston, Mass (K.J.E.); and Div of Pulmonary and Critical Care Medicine (R.M.J., L.H., A.T.) and Dept of Radiology (R.A.H.), San Francisco General Hospital, Calif. Received Nov 4, 1998; revision requested Jan 5, 1999; final revision received Apr 6; accepted May 12. L.H. supported in part by National Institutes of Health, Univ of California, San Francisco Center for AIDS Research grant P30 MH59037. Address reprint requests to K.J.E., Department of Radiology, North Memorial Medical Center, 3300 Oakdale Ave North, Minneapolis, MN 55422 (e-mail: kedinburgh@subrad.com).

	Abstract

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PURPOSE: To determine whether the computed tomographic (CT) appearances of multiple pulmonary nodules in patients with acquired immunodeficiency syndrome (AIDS) can help differentiate the potential infectious and neoplastic causes.

MATERIALS AND METHODS: The thoracic CT scans obtained in 60 patients with AIDS and multiple pulmonary nodules were reviewed retrospectively by two thoracic radiologists who were blinded to clinical and pathologic data. The scans were evaluated for nodule size, distribution, and morphologic characteristics. CT findings were correlated with final diagnoses.

RESULTS: Thirty-six (84%) of 43 patients with opportunistic infection had a predominance of nodules smaller than 1 cm in diameter, whereas 14 (82%) of 17 patients with a neoplasm had a predominance of nodules larger than 1 cm (P < .001). Of the 43 patients with opportunistic infection, 28 (65%) had a centrilobular distribution of nodules; only one (6%) of 17 patients with a neoplasm had this distribution (P < .001). Seven (88%) of eight patients with a peribronchovascular distribution had Kaposi sarcoma (P < .001).

CONCLUSION: In patients with AIDS who have multiple pulmonary nodules at CT, nodule size and distribution are useful in the differentiation of potential causes. Nodules smaller than 1 cm, especially those with a centrilobular distribution, are typically infectious. Nodules larger than 1 cm are often neoplastic. A peribronchovascular distribution is suggestive of Kaposi sarcoma.

Index terms: Acquired immunodeficiency syndrome (AIDS), 60.2518 • Kaposi sarcoma, 60.346 • Lung, infection, 60.201, 60.202, 60.203, 60.217, 60.2518 • Lung neoplasms, 60.343, 60.346 • Lung, nodule, 60.281 • Lymphoma, AIDS-related, 60.343 • Mycobacteria, 60.203 • Thorax, CT, 60.12111, 60.12112, 60.12118 • Tuberculosis, pulmonary, 60.23

	Introduction

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Infectious and neoplastic diseases of the thorax remain major causes of morbidity and mortality in patients infected with the human immunodeficiency virus (HIV) (1). Although chest radiography is typically the first imaging examination performed, thoracic computed tomography (CT) may be performed, particularly when chest radiographs show questionable or nonspecific abnormalities. Multiple pulmonary nodules are among the more common CT findings (2) and may be secondary to a number of infections and neoplasms associated with HIV. The question of whether CT scans can help to differentiate among the infectious and neoplastic causes, however, has been examined in few studies. Because the diagnostic approach to and treatment of these diseases differ, CT would be an important diagnostic study to perform if specific CT features could help to differentiate among the potential causes. Therefore, we sought to determine whether specific CT features can help to differentiate between the various infectious and neoplastic causes of multiple pulmonary nodules in patients with the acquired immunodeficiency syndrome (AIDS).

	MATERIALS AND METHODS

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From July 1, 1993, through December 31, 1997, 244 patients with AIDS underwent thoracic CT at San Francisco General Hospital, a large urban county hospital, as part of their clinical evaluation. These patients were identified by means of a retrospective search of the hospital's clinical database by using the ICD-9 (International Classification of Diseases, 9th revision) codes for HIV infection and/or AIDS and thoracic CT scanning, and from the radiology department's thoracic CT scan log books. In these patients, CT scans were obtained when pulmonary disease was suspected clinically but the chest radiographs were normal or showed questionable or nonspecific abnormalities. CT scans were available for review in 188 patients. All of these scans were reviewed independently by two thoracic radiologists (K.J.E., G.P.R.) who were blinded to the clinical and pathologic data. With use of a detailed standardized evaluation form, each of the 188 CT scans were analyzed once by each of the two reviewers. The scans were evaluated for a variety of findings, including nodules, lymphadenopathy, pleural effusion, pneumothorax, airway disease, consolidation, and ground-glass opacification. Multiple pulmonary nodules were considered to be the primary abnormality in 65 patients.

Sixty-three of the 65 patients had intrathoracic disease, which was proved with a variety of methods including sputum analysis, bronchoscopy, and biopsy. Sixty-two of the 63 patients with proved intrathoracic disease each had a single diagnosis. One patient had two diagnoses and was excluded from the study because the diagnosis responsible for the CT findings could not be determined. Two of the 62 patients with a single diagnosis had a diagnosis that was unrelated to HIV infection—one had sarcoidosis, and the other was a smoker with metastatic lung cancer—and thus they also were excluded from the study. The remaining 60 patients had an AIDS-related opportunistic infection, Kaposi sarcoma, or non-Hodgkin lymphoma. These 60 patients comprised the study group (Table 1).

Nodules were assessed for their size, distribution, and morphologic characteristics. The cases were classified into one of two groups, depending on whether most nodules were smaller or larger than 1 cm in diameter. Nodule distribution was described as being centrilobular (seen in relation to centrilobular structures) (3), peribronchovascular (associated with the bronchovascular structures of the axial interstitium) (4), miliary (innumerable and randomly distributed), or nonspecific (having no specific relationship to centrilobular structures or to the axial interstitium). Among the patients with a centrilobular distribution, the presence or absence of a "tree-in-bud" appearance—that is, bronchiolar dilatation and filling by mucus, pus, or fluid, resembling a branching tree and usually somewhat nodular in appearance—also was noted (5). Nodules were also evaluated for the presence of cavitation. In addition, each scan was assessed for the presence of lymphadenopathy (subcarinal nodes longer than 1.5 cm on the short axis, other nodes longer than 1.0 cm), low-attenuating lymphadenopathy (attenuation lower than that of muscle), pleural effusion, and airway disease (bronchial wall thickening or dilatation).

Statistical analyses were performed by using a commercially available software package (STATISTICA, version 4.0; StatSoft, Tulsa, Okla). All imaging data were evaluated as categoric outcome variables. The ² and Fisher exact tests were performed to identify the discriminating features. Statistical significance was defined as a P value less than .05. For the purposes of statistical analysis, patients with mycobacterial infection (M tuberculosis, M kansasii, or M avium-intracellulare complex) were treated as one group. Interobserver variability was assessed by using statistics. A value of greater than 0.7 was considered to be representative of substantial interobserver agreement (6).

	RESULTS

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Nodule Size
Forty-three patients had opportunistic infection, 36 (84%) of whom had a predominance of nodules smaller than 1 cm in diameter. Seventeen patients had a neoplasm; 14 (82%) of these patients had a predominance of nodules larger than 1 cm in diameter (Table 3). Conversely, 36 (92%) of 39 patients with a predominance of nodules smaller than 1 cm in diameter had opportunistic infection, whereas 14 (67%) of 21 patients with a predominance of nodules larger than 1 cm in diameter had a neoplasm. If most nodules were smaller than 1 cm, opportunistic infection was significantly more likely to be present; a predominance of nodules larger than 1 cm, however, favored a diagnosis of neoplasm (P < .001). Nodule size, however, was of no additional use in differentiating between bacterial infection and mycobacterial infection (P = .93) or between Kaposi sarcoma and lymphoma (P = .60).

View larger version (122K): [in this window] [in a new window]   Figure 1. Transverse thin-section CT scan obtained in a patient with bacterial bronchopneumonia. Nodules are smaller than 1 cm in diameter and have a centrilobular distribution. Many of these nodules also demonstrate a tree-in-bud appearance (arrows).

View larger version (123K): [in this window] [in a new window]   Figure 2. Transverse conventional CT scan obtained in a patient with Kaposi sarcoma. Nodules are larger than 1 cm in diameter, and most of them demonstrate a peribronchovascular distribution (arrows).

View larger version (96K): [in this window] [in a new window]   Figure 3. Transverse conventional CT scan obtained in a patient with lymphoma. Nodules (arrows) are larger than 1 cm in diameter and have a nonspecific distribution.

Morphologic Characteristics of the Nodules
Among the 29 patients with a centrilobular distribution, 15 (52%) demonstrated a tree-in-bud appearance; 14 (93%) of these 15 patients had opportunistic infection (Table 3). A tree-in-bud appearance, however, was not found to be statistically significant in enabling further differentiation between bacterial infection and mycobacterial infection (P = .12). Although only eight (13%) of 60 patients demonstrated nodule cavitation, all of these patients had opportunistic infection; none had a neoplasm (P = .04) (Table 3). Nodule cavitation, however, did not help to further differentiate between mycobacterial and bacterial infections (P = .42).

Additional Findings
Twenty-four (40%) of the 60 patients demonstrated lymphadenopathy (Table 4). Although the presence of lymphadenopathy was not useful for differentiating between opportunistic infection and neoplasm (P = .86) or between Kaposi sarcoma and lymphoma (P = .62), it was significantly more common in patients with mycobacterial infection (12 [71%] of 17 patients) than in patients with bacterial infection (six [25%] of 24 patients) (P = .001). Eight (33%) of 24 patients with lymphadenopathy demonstrated low-attenuating nodes, and six of these patients had mycobacterial infection. No patient with bacterial infection had low-attenuating nodes. Thus, among the patients with lymphadenopathy, the presence of low-attenuating lymph nodes was found to be statistically significant for further differentiating mycobacterial infection from bacterial infection (P = .04).

There was substantial interobserver agreement when each of the features (ie, nodule size, distribution, and morphologic characteristics, as well as the presence of lymphadenopathy, airway disease, and pleural effusion) were evaluated. The values ranged from 0.81 to 0.93. Specific values were as follows: nodule size, 0.92; peribronchovascular distribution, 0.85; centrilobular distribution, 0.93; tree-in-bud appearance, 0.86; cavitation, 0.93; lymphadenopathy, 0.82, low-attenuating lymphadenopathy, 0.81; pleural effusion, 0.92; and airway disease, 0.91.

	DISCUSSION

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A number of investigators (2,7–9) have described the CT features of the various infectious and neoplastic thoracic complications of AIDS. To our knowledge, no study has involved the specific evaluation of the CT features of multiple pulmonary nodules in patients with AIDS to determine which features are helpful for differentiating the potential infectious and neoplastic causes. The differentiation of opportunistic infection, Kaposi sarcoma, and lymphoma is clinically important because further diagnostic evaluation depends on which of these three entities is considered to be most likely present. If opportunistic infection is suspected, then further evaluation should include sputum analysis, blood cultures, and, possibly, bronchoalveolar lavage (1). If Kaposi sarcoma is suspected, then bronchoscopy should be performed to detect endobronchial lesions (10). If lymphoma is suspected, then the patient should undergo transbronchial, transthoracic, or open-lung biopsy to secure a tissue diagnosis (11).

In this study, the CT scans obtained in 60 patients with AIDS and multiple pulmonary nodules were evaluated for nodule size, distribution, and morphologic characteristics, as well as for the presence of lymphadenopathy, pleural effusion, and airway disease. Our data suggest that of these features, nodule size and distribution are the most useful for differentiating among opportunistic infection, Kaposi sarcoma, and lymphoma. A statistically significant correlation was found between nodule size and cause. A predominance of nodules smaller than 1 cm in diameter was suggestive of opportunistic infection, whereas a neoplasm was more likely to be present when there was a predominance of nodules larger than 1 cm. Nodule size had no further benefit in differentiating between bacterial infection and mycobacterial infection or between Kaposi sarcoma and lymphoma.

Nodule distribution also was found to be a discriminating feature. Although lymphomatous involvement of the lung can demonstrate a peribronchovascular distribution (11,12), the results of previous studies (13–15) have shown that a peribronchovascular distribution of nodules favors a diagnosis of Kaposi sarcoma. Our data support this finding: In our series, the presence of a peribronchovascular distribution was suggestive of Kaposi sarcoma. The presence of a centrilobular distribution of nodules also was found to be a statistically significant discriminator. When a centrilobular distribution was identified, opportunistic infection was likely and neoplasm was unlikely. A centrilobular distribution, however, was not found to be of further use for differentiating between bacterial infection and mycobacterial infection. Although Laissy et al (16) found that the presence of multiple nodules with a centrilobular distribution was the most common CT finding in 52 patients with AIDS and culture-proved mycobacterial infection, no comparison was made with other diagnoses.

With regard to the morphologic characteristics of nodules, a tree-in-bud appearance was suggestive of an infectious cause, but it was not found to be a statistically significant discriminator between bacterial and mycobacterial infections (P = .12). This lack of statistical significance, however, may have been due to the small number of patients with this finding in our series. Nodule cavitation also was a discriminating feature and was suggestive of opportunistic infection. Nodule cavitation, however, did not enable further differentiation between bacterial infection and mycobacterial infection. Although cavitating consolidation in AIDS has been described (17), to our knowledge, the predictive value of this finding has not been evaluated.

The presence of lymphadenopathy was a significant finding as well. Although lymphadenopathy was not found to be statistically significant for differentiating between opportunistic infection and neoplasm or between Kaposi sarcoma and lymphoma, it was useful for differentiating mycobacterial infection from bacterial infection. Our data suggest that when lymphadenopathy is seen in patients with AIDS who have multiple pulmonary nodules that are smaller than 1 cm or have a centrilobular distribution, a mycobacterial cause is favored. Among the patients with lymphadenopathy, the presence of low-attenuating lymph nodes contributed to the further differentiation of mycobacterial infection from other diagnoses. This finding is consistent with those of previous studies (18–20), which have shown that necrotic lymphadenopathy is frequently found in patients with AIDS and tuberculosis.

The presence of pleural effusion also was a significant finding. Although pleural effusion was not found to be statistically significant for differentiating between opportunistic infection and neoplasm or between Kaposi sarcoma and lymphoma, it contributed to the differentiation between mycobacterial infection and bacterial infection. To our knowledge, this finding has not been previously reported, although Relkin et al (21) reported an increased prevalence of pleural effusion in AIDS-related tuberculosis compared with the tuberculosis in HIV-negative patients. The presence of airway disease was not found to be a statistically significant means to differentiate bacterial infection from other diagnoses (P = .11). This lack of statistical significance may have been due to the small number of patients with this finding in our series.

It is well documented that specific opportunistic infections and neoplasms in patients with AIDS occur predominantly within well-defined CD4 lymphocyte count ranges (1,17). Knowledge of how these counts correlate with radiographic and CT appearances can limit the differential diagnosis because certain conditions are uncommon above a specific count. One potential limitation of our study was that our patients tended to have low CD4 counts. The median CD4 count in our study group was only 32 cells per microliter (.034 cells x 10⁶/L). The CD4 counts among all the patients infected with HIV who underwent thoracic CT at our institution (from which our study group was derived) was similarly low (median, 58 cells/µL [.058 cells x 10⁶/L]). We believe that this was because our study was conducted at a county hospital that serves a largely indigent population who tended to have advanced HIV disease at initial presentation. Although our findings can only be applied at low CD4 counts, these patients are susceptible to all of the infectious and neoplastic thoracic complications of AIDS. Given the broad differential diagnosis in these severely immunocompromised patients, it is this population in whom the use of CT to help differentiate among these complications is particularly important.

Another potential limitation of our study was that we made no attempt to compare CT scans with chest radiographs. Our study group was a select population. In the vast majority of cases, CT was performed only when the diagnosis was not evident from the radiographic findings. When characteristic radiographic findings were seen, particularly with findings suggestive of P carinii pneumonia, Kaposi sarcoma, or focal bacterial pneumonia, we did not believe that CT was warranted.

A third limitation of our study was related to its retrospective nature, the result of which was varied CT scanning protocols. Conventional CT scans (10-mm collimation) were obtained in some cases, whereas thin-section scans (1.5-mm collimation) were obtained in others, as considered appropriate in individual cases. It is possible that had thin-section CT scans been obtained in all the patients, fewer cases would have been categorized as having a nonspecific distribution of nodules.

In conclusion, our data suggest that when multiple pulmonary nodules are seen in patients with AIDS, the size and distribution of these nodules are the CT features that are most useful for distinguishing among the potential causes and thereby allowing clinicians to focus on the diagnostic approach accordingly. When nodules are smaller than 1 cm in diameter, and especially when they demonstrate a centrilobular distribution, opportunistic infection is likely and neoplasm is unlikely. Among such patients, the presence of lymphadenopathy or pleural effusion favors a mycobacterial rather than bacterial cause. Conversely, when nodules are larger than 1 cm in diameter, a neoplastic cause is favored. In addition, a peribronchovascular distribution suggests a diagnosis of Kaposi sarcoma. Our data also suggest that assessment of these features is straightforward: There was substantial interobserver agreement.

	Footnotes

 
Author contributions: Guarantors of integrity of entire study, K.J.E., L.H., W.R.W.; study concepts and design, K.J.E., R.M.J., L.H., R.A.H., W.R.W.; definition of intellectual content, K.J.E., W.R.W.; literature research, K.J.E.; clinical studies, R.M.J., L.H.; data acquisition, K.J.E., R.M.J., G.P.R., M.H.C., A.T.; data analysis, K.J.E., R.M.J., L.H., W.R.W.; statistical analysis, L.H.; manuscript preparation, K.J.E.; manuscript editing and review, R.M.J., L.H., G.P.R., W.R.W.

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