Thin-Section CT Findings in 32 Immunocompromised Patients with Cytomegalovirus Pneumonia Who Do Not Have AIDS

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1 Tomás Franquet 1,2 Kyung S. Lee 3 Nestor L. Müller 1 Received January 27, 2003; accepted after revision April 21, Department of Radiology, Vancouver Hospital and Health Sciences Center and University of British Columbia, 855 W. 12th Ave., Vancouver BC V5Z 1M9, Canada. 2 Present address: Department of Radiology, Hospital de Sant Pau, Universitat Autónoma de Barcelona, Avda. Sant Antoni M. Claret 167, Barcelona 08025, Spain. Address correspondence to T. Franquet. 3 Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul , Korea. AJR 2003;181: X/03/ American Roentgen Ray Society Thin-Section CT Findings in 32 Immunocompromised Patients with Cytomegalovirus Pneumonia Who Do Not Have AIDS OBJECTIVE. The aim of this study was to review the thin-section CT findings in 32 immunocompromised patients without AIDS who had proven Cytomegalovirus pneumonia. MATERIALS AND METHODS. The causes of immunocompromise included bone marrow (n = 25) or solid organ transplantation (n = 5) and corticosteroid therapy (n = 2). The patients included 16 men and 16 women ranging in age from 22 to 70 years (mean age, 43 years). The CT scans were retrospectively reviewed by two thoracic radiologists for the presence, appearance, and distribution of parenchymal abnormalities. RESULTS. Bilateral abnormalities were seen in all patients. Areas of ground-glass opacification were seen in 21 (66%) of 32 patients. Ground-glass opacification was the predominant CT feature in nine cases (28%). In 19 of 32 patients, ground-glass attenuation was associated with other abnormalities. Multiple nodules were identified in 19 patients (59%). Nodules were bilateral in 15 patients and unilateral in four patients. Nodules were the only CT finding in three patients (9%). Areas of air-space consolidation were identified in 19 patients (59%). Air-space consolidation was the only CT finding in one patient (3%). Other less common CT findings included thickening of the bronchovascular bundles (n = 7) and the treein-bud appearance (n = 4). Pleural effusions were seen in seven patients. CONCLUSION. The thin-section CT manifestations of Cytomegalovirus pulmonary infection usually consist of a mixture of patterns, most commonly ground-glass attenuation, areas of consolidation, and small nodules. C ytomegalovirus pneumonia is a common life-threatening complication seen in immunocompromised patients. It occurs most commonly after bone marrow and solid organ transplantation and in patients with AIDS. The radiographic manifestations are variable and may consist of a reticular or reticulonodular pattern, ground-glass opacities, air-space consolidation, or a combination of these patterns [1, 2]. No specific radiographic finding alone is characteristic enough to allow differentiation of Cytomegalovirus pneumonia from other infections [1]. McGuinness et al. [3] described the thin-section CT findings in 21 patients with AIDS and Cytomegalovirus pneumonia. The most common abnormalities consisted of ground-glass attenuation, dense consolidation, and discrete pulmonary nodules or masses. The descriptions of the manifestations of Cytomegalovirus pneumonia in immunocompromised patients without AIDS have been limited to studies that included a small number of cases. In one series of 10 patients, the predominant abnormalities were small nodules, air-space consolidation, or a combination of both [4]. In another series of 10 patients, the most common CT pattern was of ground-glass attenuation, which was seen in all patients; small nodules were present in nine patients and consolidation, in seven patients [5]. The purpose of this study was to assess the thin-section CT findings in a relatively large number of immunocompromised patients without AIDS who had proven Cytomegalovirus pneumonia. Materials and Methods Patients We retrospectively reviewed 32 immunocompromised patients without AIDS who had a histologically proven diagnosis of Cytomegalovirus pulmonary infection and had undergone CT at one of our three institutions. Patients were identified through a review of the records of those who had undergone chest CT for a suspected pulmonary infection. The diagnosis of Cytomegalovirus infection in all patients was made AJR:181, October

2 Franquet et al. on the basis of both bronchoalveolar lavage and histologic findings. Histopathologic specimens were acquired with transbronchial biopsy (n = 15), open lung biopsy (n = 13), or autopsy (n = 4). The study included only patients in whom bronchoalveolar lavage fluid and biopsy showed no evidence of organisms other than Cytomegalovirus. The time interval between CT examination and the microbiologic diagnosis ranged from 1 to 16 days (median, 3 days). In all patients, when the interval between CT and microbiologic diagnosis was longer than 48 hr, the absence of significant interval change in the pattern of parenchymal abnormalities between the dates of CT and microbiologic diagnosis was ensured with sequential chest radiographs. The patients were 16 men and 16 women, who ranged in age from 22 to 70 years (mean age, 43 years). CT CT was performed on a Somaton Plus 4 CT scanner (Siemens, Erlangen, Germany), a 900 or Asteion CT scanner (Toshiba Medical Systems, Tokyo, Japan), or a HiLight scanner (General Electric Medical Systems, Milwaukee, WI). The scans were obtained at end inspiration using 1- or 2-mm collimation at 10- or 20-mm intervals from the apex of the lung to the diaphragm, using 120 kv and ma. The lungs were scanned at H for the window width and level settings of 600 to 700 H. The CT scans were jointly reviewed by two radiologists who were aware that all patients had a proven pulmonary viral infection; final decision on the findings was reached by consensus. The CT scans were assessed for the presence, extent, and anatomic distribution of ground-glass attenuation, air-space consolidation, nodules, centrilobular branching structures (tree-in-bud), thickening of the bronchovascular bundles, and pleural effusion. Ground-glass attenuation was defined as an area of hazy increased attenuation without obscuration of underlying vascular markings. Air-space consolidation was considered present if the opacities obscured the underlying vessels. Parenchymal nodules were subcategorized according to their distribution (centrilobular, peribronchovascular, subpleural, and random), location (upper or lower lung zone), marginal characteristics (smooth or irregular), and number (single or multiple). Centrilobular nodules were defined as parenchymal opacities located in the central portion of the secondary pulmonary lobule (lobular core). Nodules were also assessed to determine whether they were surrounded by a halo of groundglass attenuation or had associated findings, such as pleural effusion. The anatomic distribution was regarded as predominantly peripheral if abnormalities were seen mostly in the outer third of the lung, central if most were in the inner third of the lung, peribronchial if abnormalities occurred along the bronchovascular bundles, and random otherwise. The distribution was further subclassified as lobar, segmental, and patchy or nonsegmental. Zonal predominance was divided into upper or lower. Upper lung zone predominance was considered present if most of the abnormalities were above the level of tracheal carina and lower zone predominance, if the abnormalities were below that level. Results Cytomegalovirus infection was diagnosed in 30 patients who underwent organ transplantation: bone marrow (n = 25), kidney (n = 3), liver (n = 1), and heart (n = 1) transplantation. The remaining two patients were undergoing long-term corticosteroid therapy for CREST syndrome (calcinosis cutis, Raynaud s phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia). Findings on thin-section CT showed bilateral abnormalities in all patients (Table 1). Areas of ground-glass opacification were seen in 21 (66%) of 32 patients (Fig. 1). These areas had no zonal predominance and were patchy (n = 17) or diffuse (n = 3). In one case, groundglass opacities had a centrilobular location. Ground-glass opacification was the predominant CT feature in nine (28%) of 32 cases, but in only one patient (3%) was it the only finding seen on CT. In 19 of 32 patients, ground-glass attenuation was associated with other abnormalities, including areas of air-space consolidation (n = 12), nodules (n = 13), thickening of the bronchovascular bundles (n = 7), and the tree-in-bud pattern (n = 2). Multiple nodules were identified in 19 (59%) of 32 patients (Fig. 2). Nodules were bilateral in 15 patients and unilateral in four patients. In 16 cases, nodules were associated with areas of ground-glass attenuation (n = 13) and with air-space consolidation (n = 8). Nodules were the only CT finding in three patients (9%). All nodules in all cases were smaller than 10 mm in diameter. In 12 cases (63%), the nodules had irregular margins (Fig. 3), and in seven cases (37%), the nodules had a halo of ground-glass attenuation (Fig. 4). The nodules had a centrilobular (n = 10), subpleural (n = 5), or random (n = 4) distribution. Areas of air-space consolidation were identified in 19 patients (59%). In 16 (84%) of these 19 patients, these areas had a lobular or subsegmental distribution, whereas in three (16%) of 19 patients, they had a segmental distribution. Air-space consolidation was the predominant CT feature in six (19%) of 32 patients (Fig. 5). The consolidation involved predominantly the lower lung zones (n = 7) or was randomly distributed (n = 12) (Fig. 6). Air-space consolidation was the only CT finding in one (3%) of the 32 patients (Fig. 7). A peripheral distribution was found in four of seven patients with predominant air-space consolidation. Other less common CT findings included thickening of the bronchovascular bundles (n = 7) and the tree-inbud appearance (n = 4) (Fig. 8). Pleural effusions were seen in seven patients. Histopathologic material was available for review in all cases and was correlated with the findings on thin-section CT. Areas of groundglass attenuation or consolidation seen on CT scans corresponded to areas of the exudative or proliferative phase of diffuse alveolar damage. The predominant histologic findings in these patients were interstitial fibroblastic proliferation and lymphocytic infiltration associated with type 2 pneumocyte hyperplasia, hyaline membrane formation, and intraalveolar exudates with or without organization. The six patients with poorly defined centrilobular nodules seen on CT had bronchiolar and peribronchiolar accumulations of macrophages, RBCs, and fibrin. In two cases, the nodules were surrounded by a halo of ground-glass attenuation. The halo in these cases consisted of a zone of less dense inflammatory reaction and hemorrhage. Diagnostic cytomegalic cells with intracytoplasmic and intranuclear inclusions were seen in all pathologic specimens. No apparent differences were found among the 25 patients with bone marrow transplants, the five patients with solid organ transplants, and the two patients being treated with longterm corticosteroids. Discussion Viral infections are a relatively common cause of morbidity and mortality in immunocompromised patients [6]. Cytomegalovirus is one of the most common causes of life-threatening opportunistic pulmonary infection in patients with bone marrow transplants [7]. Cytomegalovirus pneumonia, usually resulting from reactivation of a previous latent infection, has been reported in 10 40% of recipients of bone marrow transplants [8]. It is a serious complication that characteristically occurs during the postengraftment period ( days after transplantation) [7, 9]. In our study group, 25 (78%) of 32 patients with Cytomegalovirus pneumonia were recipients of bone marrow transplants. Cytomegalovirus pneumonia is also seen with increased frequency in recipients of solid organ transplants and in AIDS patients. The clinical features of Cytomegalovirus pneumonia include fever, nonproductive cough, dyspnea, and hypoxemia. Diagnostic criteria for cytomegalovirus pneumonia are the detection of Cytomegalovirus organisms by culture, charac AJR:181, October 2003

3 CT of Cytomegalovirus Pneumonia TABLE 1 CT Findings of Bilateral Abnormalities Patient Ground-Glass Attenuation (n = 21) Consolidation (n = 19) Note. Dash ( ) = not present, +++ = predominant finding, + = present. teristic Cytomegalic inclusion bodies in bronchoalveolar lavage and transbronchial biopsy specimens, and absence of any other pulmonary pathogen identified by bacterial, fungal, or acidfast stains or cultures, combined with the presence of fever, respiratory symptoms, and abnormal findings seen on CT [7 9]. Chest radiography is the first imaging technique performed in the examination of an immunocompromised patient with fever. Leung et al. [10] described the radiographic findings of Cytomegalovirus pneumonia in 22 infectious episodes in 52 patients with bone marrow transplants. The most common radiographic findings consisted of parenchymal consolidation and multiple nodules smaller Multiple Nodules (n = 19) Nodules with Halo (n = 7) than 5 mm in diameter; in two cases, the findings on chest radiographs were normal. An increasing number of patients undergo CT, especially thin-section CT, if there is a high clinical suspicion for pneumonia with normal or questionable radiographic findings. The CT findings of Cytomegalovirus pneumonia have been variably described as consisting of ground-glass attenuation, consolidation, linear opacities, nodules, or masses. The findings in AIDS patients seem to differ from those in patients without AIDS. McGuinness et al. [3] described the thin-section CT findings in 21 AIDS patients with Cytomegalovirus pneumonia. The most common abnormalities consisted of ground-glass attenuation, Thickening of Bronchovascular Bundles (n = 7) Pleural Effusion (n = 7) Tree-in-Bud (n = 4) consolidation, and discrete pulmonary nodules or masses. These investigators reported that in AIDS, the possibility of Cytomegalovirus pneumonia should be considered, particularly in patients who had Kaposi s sarcoma and areas of dense consolidation or masslike opacities. Although consolidation is also commonly seen in patients without AIDS, it is not dense and does not result in masslike opacities. Our results concur with those of Moon et al. [5], who showed ground-glass attenuation to be the most frequent CT pattern in Cytomegalovirus pneumonia. In our study, ground-glass attenuation was found in 21 (66%) of our 32 patients, usually associated with air-space consolidation and nodules. AJR:181, October

4 Franquet et al. Fig year-old man with acute myeloid leukemia and bone marrow transplant. Thin-section (1-mm collimation) CT scan shows multifocal patchy areas of groundglass attenuation and poorly defined centrilobular nodules in both lungs. Fig year-old man with acute myeloid leukemia and bone marrow transplant. CT scan obtained at level of carina shows diffuse ground-glass attenuation and multiple poorly defined centrilobular opacities in both lungs. Fig year-old man with acute myeloid leukemia and bone marrow transplant. Thin-section (1-mm collimation) CT scan shows multiple scattered poorly defined centrilobular nodules. Focal areas of ground-glass attenuation are also visible. Fig year-old man with aplastic anemia and bone marrow transplant. Thinsection (1-mm collimation) CT scan shows multiple scattered bilateral lung nodules surrounded by halo of ground-glass attenuation. Fig year-old man who underwent heart transplantation. Thin-section (1-mm collimation) CT scan obtained at level of lung bases shows multiple scattered lung nodules in both lungs and peripheral patchy areas of consolidation in left lower lobe. Fig year-old man who underwent liver transplantation. Thin-section (1-mm collimation) CT scan obtained at level of carina shows multiple peripheral lobular areas of consolidation in both lungs AJR:181, October 2003

5 CT of Cytomegalovirus Pneumonia A B Fig year-old man with acute myeloid leukemia and bone marrow transplant. A, Thin-section (1-mm collimation) CT scan obtained at level of aortic arch shows poorly marginated peripheral nodule in right upper lobe. Note small left pleural effusion. B, CT scan obtained at level of inferior pulmonary veins shows focal area of consolidation surrounded by ground-glass opacity in left lower lobe. Angioinvasive pulmonary aspergillosis was suspected. In 10 patients with proven Cytomegalovirus pneumonia, Kang et al. [4] identified four different patterns on CT consisting of of multiple bilateral nodules (1 5 mm) in six patients (60%), ground-glass opacity in four (40%), airspace consolidation in four (40%), and reticular opacities in one (10%). Ground-glass opacity and nodules were seen as a part of a mixed pattern in all and in four cases (40%) respectively; air-space consolidation and nodules were the only CT finding in two patients (20%) each. In our study, 16 (84%) of 19 patients with nodules had a mixed pattern that included ground-glass opacities and air-space consolidation. Pathologic findings of Cytomegalovirus pneumonia included areas of acute interstitial pneumonia or diffuse alveolar damage and fo- Fig year-old man with chronic myelogenous leukemia and bone marrow transplant. Thin-section (1-mm collimation) CT scan shows poorly defined centrilobular nodules and peripheral tree-in-bud opacities. AJR:181, October 2003 cal inflammatory or hemorrhagic lesions [7]. Our CT findings correlated with these histopathologic findings. Patchy or diffuse areas of ground-glass opacity were present in 87% of our patients and corresponded histopathologically to areas of diffuse alveolar damage. The halo sign was found in 37% of patients presenting with a nodular pattern of disease. Previously used to describe the CT appearance of hemorrhagic nodules due to invasive aspergillosis [11], this sign has been shown to occur in association with hemorrhagic nodules of various causes [12]. In patients with Cytomegalovirus pneumonia and poorly defined nodules or nodules with an associated halo, histologic correlation showed the nodular opacities to represent focal areas of inflammation or hemorrhage. On the basis of our results, we consider that the most helpful findings with which to diagnose Cytomegalovirus pneumonia are the combination of nodules, ground-glass opacities, and areas of air-space consolidation. Our study has several limitations: it is retrospective and includes images obtained with different CT scanners and patients with varying intervals between the CT scan and bronchoalveolar lavage and biopsy diagnosis. In summary, the thin-section CT findings of Cytomegalovirus pneumonia in immunocompromised patients without AIDS usually consist of a mixture of patterns, most commonly ground-glass attenuation, air-space consolidation, and multiple small nodules. Some abnormalities in Cytomegalovirus pneumonia are often difficult to recognize on radiography but can easily be seen on thin-section CT. References 1. Olliff JF, Williams MP. Radiological appearances of cytomegalovirus infections. Clin Radiol 1989;40: Shulman LL. Cytomegalovirus pneumonitis and lobar consolidation. Chest 1987;91: McGuinness G, Scholes JV, Garay SM, Leitman BS, McCauley DI, Naidich DP. Cytomegalovirus pneumonitis: spectrum of parenchymal CT findings with pathologic correlation in 21 AIDS patients. Radiology 1994;192: Kang EY, Patz EF Jr, Müller NL. Cytomegalovirus pneumonia in transplant patients: CT findings. J Comput Assist Tomogr 1996;20: Moon JH, Kim EA, Lee KS, Kim TS, Jung KJ, Song HS. Cytomegalovirus pneumonia: high-resolution CT findings in ten non-aids immunocompromised patients. Korean J Radiol 2000;1: Logan PM, Primack SL, Staples C, Miller RR, Müller NL. Acute lung disease in the immunocompromised host: diagnostic accuracy of the chest radiograph. Chest 1995;108: Worthy SA, Flint JD, Müller NL. Pulmonary complications after bone marrow transplantation: high-resolution CT and pathologic findings. RadioGraphics 1997;17: Sable C, Donowitz G. Infection in bone marrow transplant recipients. Clin Infect Dis 1994;18: Heussel CP, Kauczor HU, Heussel G, Fischer B, Mildenberger P, Thelen M. Early detection of pneumonia in febrile neutropenic patients: use of thin-section CT. AJR 1997;169: Leung AN, Gosselin MV, Napper CH, et al. Pulmonary infections after bone marrow transplantation: clinical and radiographic findings. Radiology 1999; 210: Kuhlman JE, Fishman EK, Siegelman SS. Invasive pulmonary aspergillosis in acute leukemia: characteristic findings on CT, the CT halo sign, and the role of CT in early diagnosis. Radiology 1985;157: Primack SL, Hartman TE, Lee KS, Müller NL. Pulmonary nodules and the CT halo sign. Radiology 1994;190: