I NVASIVE aspergillosis is uncommon

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1 Catherine A. Staples, MD #{149}Eun-Young Kang, MD #{149} Joanne L. Wright, MD #{149}Peter Phillips, MD Nestor L. Muller, MD, PhD Invasive Pulmonary Aspergillosis in AIDS: Radiographic, CT, and Pathologic Findings PURPOSE: To review the radiographic and computed tomographic (CT) manifestations of invasive pulmonary aspergillosis and to correlate the imaging and pathologic findings in patients with acquired immunodeficiency syndrome (AIDS). MATERIALS AND METHODS: Chest radiographs, CT scans, and pathologic specimens were reviewed retrospeclively in 10 AIDS patients with proved invasive pulmonary aspergillosis. RESULTS: The most common radiographic finding was the presence of thick-walled cavitary lesions. Less common findings included nodules, consolidation, and pleural effusion. CT depicted more nodules and cavities than did radiography. The predominant pathologic abnormalities consisted of tissue invasion and abscess formation and angioinvasion with or without infarction. All patients had infection with Aspergillus fu migatus as well as other pathogens, the most common being cytomegalovirus and Pseudomonas aeruginosa. CONCLUSION: Thick-walled cavitary lesions are the most common radiologic manifestation of invasive pulmonary aspergillosis in AIDS. The findings are more numerous and better defined on CT scans. The radiologic findings reflect a spectrum of pathologic abnormalities. Index terms: Acquired immunodeficiency syndrome (AIDS), #{149}Aspergillosis, S Lung, infection, Radiology 1995; 196: I NVASIVE aspergillosis is uncommon in patients with acquired immunodeficiency syndrome (AIDS) presumably because the immune deficits in these patients affect mainly the T cells rather than granulocytes and macrophages (1-10). In 1994, Miller et al (10) reviewed the radiographic and clinical features of confirmed or presumed pulmonary aspergillosis in 36 patients with AIDS. These included six new patients, as well as the 30 patients who previously were reported in the literature. The most common radiographic manifestations included cavitary upper lobe disease, focal consolidation, and bilateral patchy or diffuse air-space consolidation. Very little information, however, is available about the pathologic findings in these patients (10). To our knowledge, descriptions of the radiologic features of AIDS-related thoracic aspergillosis in the radiology literature are limited to isolated case reports (8,9). Our purpose was to review the radiographic and computed tomographic (CT) findings of pulmonary aspergillosis in patients with AIDS and to correlate the imaging and pathologic findings. MATERIALS AND METHODS Review of the medical and laboratory records at our institution was performed to identify AIDS patients with proved pulmonary aspergillosis between August 1988 and December To allow comparison between the radiographic, CT, and pathologic findings, only those patients with gross lung specimens obtained at surgery or at were induded in the study. The medical charts were reviewed for pertinent clinical data that included age, sex, risk factors for infection with human immunodeficiency virus (HIV), length in years of HIV seropositivity, symptoms at initial examination, associated illnesses, and use of corticosteroids. Also tabulated were the CD4 cell counts and the presence of neutropenia (neutrophil count < 2,000). The study group included 10 homosexual men, one of whom was also an intravenous drug abuser. The mean age was 37.6 years (range, years). Preoperative or premortal diagnosis was made in six patients by detection of an Aspergillus organism in specimens obtained from one or more sites by means of thoracentesis (n = 2), bronchoalveolar lavage (n = 2), fine-needle aspiration biopsy (n = 2), and sputum culture (n = 1). Confirmation of the diagnosis was based on the identification of organisms in pathologic specimens obtained by means oflobectomy or pneumonectomy (n = 2) or (n = 8) (Table 1). All cases were due toaspergillusfumigatus. Chest radiographs obtained at presentation were reviewed retrospectively by two chest radiologists (C.A.S., N.L.M.) who reached a final decision by consensus. Two to six radiographs (mean, four radiographs) were evaluated over an average of 10 weeks (range, 2-40 weeks) in all patients. The observers assessed the number, size, and the minimum and maximum wall thickness of pulmonary cavities and the presence of noncavitary nodules, irregular linear opacities, ground-glass opacities, and air-space consolidation. The presence of airway abnormalities, lymphadenopathy, pleural and pericardial effusions, and pneumothoraces was also assessed. Disease distribution was divided into upper and lower lung zone predominance. Previous radiographs were assessed to identify cystic lesions or other structural abnormalities that predated subsequent radiographic abnormalities related to aspergillosis. CT scans were available in seven patients. The CT examinations were performed with either a GE 9800 scanner (n = 3) or a 9800 HiLite Advantage scanner I From the Departments of Radiology (C.A.S.), Pathology (J.L.W.), and Infectious Diseases (PP.), University of British Columbia and St Paul s Hospital, Vancouver, and the Department of Radiology, University of British Columbia and Vancouver Hospital and Health Sciences Centre, 855 W 12th Ave. Vancouver, British Columbia, Canada V5Z 1M9 (E.Y.K., N.L.M.). Received September 2, 1994; revision requested October 26; revision received February 21, 1995; accepted February 22. Address reprint requests to N.L.M. C RSNA, 1995 Abbreviations: AIDS = acquired immunodeficiency syndrome, CMV = cytomegalovirus, HIV = human immunodeficiency virus, PCP = Pneumocystis carinii pneumonia. 409

2 Table 1 Summasy of Clinical Findings Patient No/Age (y) Years with HIV Positivity CD4 Cell Count (cells/mm3) Neutropenia Steroid Therapy Previous Disease That Caused Preexisting Cyst Method Diagnosis of Associated Pulmonary Disease Death Attributed Aspergillosis to 1/ No PCP Lobectomy Granulomatous PCP No 2/ No No PCP Thoracentesis, pneumonectomtion Streptococcal infec- No (pleural fluid) 3/ No... Thoracentesis, CMV 4/ No No PCP Bronchoscopy, CMV, Kaposi sarcoma, tuberculosis, M kansasii 5/ No... Fine-needle aspiration CMV biopsy, 6/ No Septic emboli Bronchoscopy, fineneedle CMV aspiration biopsy, 7/ No Pyogenic infection Sputum culture, CMV, Pseudomonas infection 8/ Autopsy CMV, Pseudomonas infection 9/ No... Autopsy Streptococcal pneu- No monia 10/ No... Autopsy CMV (n = 4) (GE Medical Systems, Milwaukee, Wis). Thin-section CT scans (1.5-mm collimation with a high-spatial-frequency reconstruction algorithm) were obtained in four patients and conventional 10-mm collimation scans in three patients. Intravenous contrast material was used in one patient. The CT scans were reviewed retrospectively by the two observers after review of the chest radiographs and then directly compared with the radiographs. Pathologic specimens were obtained in all 10 patients. They induded specimens obtamed at lobectomy (n = 1), pneumonectomy (n = 1), or (n = 8) (Table 1). All pathologic specimens were reviewed by an experienced lung pathologist (J.LW.). The diagnosis of tissue invasion was based on the presence of Aspergillus organisms within alveolar spaces associated with tissue necrosis. Aspergillus pneumonia was defined as a diffuse area of involvement with pronounced inflammatory reaction and abundant tissue necrosis. An Aspergillus abscess was characterized by the presence of a localized area of tissue necrosis that contained Aspergillus organisms, was well demarcated from the adjacent parenchyma, and did or did not have a fibrotic capsule. Angioinvasive aspergillosis was characterized by infiltration of the walls of small to mediumsize pulmonary arteries by fungal hyphae. It could be associated with thrombus formation and hemorrhagic infarction due to vascular obstruction. Clinical Data RESULTS The patients were known to be HIV positive for an average of 5.4 years (range, 2-10 years) before the diagnosis of invasive aspergillosis. One or more risk factors for the development of aspergillosis were present in eight of 10 patients (Table 1). All patients were symptomatic at presentation. The most common symptoms included cough (n = 8), fever (n = 4), and shortness of breath (n = 7). All patients have died. The average interval between presentation with radiographic findings of invasive aspergillosis and (n = 8) or surgical resection (n = 2) was 11 weeks. Death could be directly attributed to aspergillosis in seven patients. Chest Radiographic Findings The most common radiographic finding was thick-walled, cavitary lesions and was seen in eight (80%) of 10 patients (Table 2). The cavitary nodules or masses were 2-10 cm in diameter (mean, 6.2 cm) and had an average minimal wall thickness of 3 mm (range, 2-8 mm) and average maximal wall thickness of 9.4 mm (range, 5-15 mm). The cavitary lesions involved mainly the upper lobes in six (75%) of eight patients and the lower lung zones in two patients. The cavities were multiple in three patients (Fig 1). An intracavitary mass was noted on the radiographs in two patients (Fig 2). Less common radiographic findings at initial examination included noncavitary nodules in four (40%) of 10 patients, consolidation in six patients (60%), pleural effusion in two patients (20%), and irregular linear opacities in one patient (10%) (Table 2). A pneumopericardium and a hydropneumothorax were identified in one patient. Lymphadenopathy, airway lesions, and ground-glass opacities were not identified on any chest radiograph. Five patients had cystic or cavitary lesions before the development of aspergillosis. These lesions included cysts related to previous Pneumocystis carinii pneumonia (PCP) (Fig 2) in three patients, to septic emboli in one patient, and to necrotizing pyogenic pneumonia in one patient (Table 1). The other five patients had no evidence of cystic lesions on previous radiographs. CT Findings The interval between chest radiography at initial examination and CT (performed in seven patients) was 0-10 days (median, 3 days). CT demonstrated additional cavitary lesions in three patients and noncavitary nodules in four patients (Table 2). The cavities were better delineated from surrounding abnormalities on the CT scan than on the radiograph (Fig 2). Calcification of a cavity wall and an intracavitary mass were noted at CT in one patient (patient 1). No air crescents and no evidence of bronchiectasis were seen on the radiographs or CT scans in any of the patients. Pathologic Findings and Correlation with Imaging Findings Lung specimens obtained at lobectomy or pneumonectomy (patients #{149} Radiology August 1995

3 Table 2 Predominant Chest Radiographic, CT, and Pathologic Findings in AIDS Patients with Aspergillosis Patient No. Radiographic Findings CT Findings Pathologic Findings 1 One cavity with intracavitary mass, irregular Two cavities, intracavitary mass, irregular Abscess, adjacent angioinvasion, intracavilinear opacities linear areas of high attenuation tary mass 2 One cavity, consolidation, hydropneumo- One cavity, consolidation, hydropneumo- Abscess, empyema thorax thorax 3 Single cavity and single nodule, patchy consolidation, pneumopericardium, hydro- tion, pneumopericardium, hydropneumo- tissue invasion of pleura, heart, and Five cavities, 10 nodules, patchy consolida- Small airway invasion with necrosis; abscess; pen- 4 pneumothorax thorax One cavity with intracavitary mass, patchy Five nodules, one cavity with intracavitary consolidation mass, patchy consolidation cardium Tissue invasion, abscess, intracavitary mass 5 Consolidation with cavity Consolidation with cavity, one nodule Pneumonia, abscess, subpleural nodular tissue invasion 6 Four cavities, three nodules Four cavities, three nodules Tissue invasion, necrosis with abscesses, multiple intracavitary masses 7 Two cavities, patchy consolidation Four cavities, two nodules, patchy consolidation Angioinvasion with large infarct in right upper lobe, multiple bilateral infarcts 1-3 cm in diameter, pneumonia 8 Three cavities, nodule Not performed Angioinvasion with several infarcts, one large airway destroyed 9 Consolidation in right lung, wedge opacity Not performed Angioinvasion, infarction of lingula 10 Three nodules Not performed Angioinvasion with several lung infarcts, small airway lesions Figure 1. Patient 6. Cavitary aspergillosis in a 33-year-old man. (a) Posteroanterior chest radiograph shows three, large, irregular, thick-walled cavities in the left upper lobe; a small illdefined cavity in the right upper lobe; and nodules. The patient had previous cystic lesions that increased in size and wall thickness with the aspergillosis. (b) Photograph of the left upper lobe at shows multiple cavities that range in size from 0.3 to 5.0 cm. The smaller lesions appear centered on airways (arrow). At pathologic examination, the patient had Aspergillus abscesses with necrosis and tissue invasion. No bacteria were present in the lungs at. and 2) and (patients 3-10) were available in the 10 patients. At pathologic examination, all 10 patients had invasive aspergillosis. All 10 patients had associated pulmonary diseases that included infection with cytomegalovirus (CMV) in seven patients; streptococcal infection in two patients; infection with a Pseudomonas organism in two patients; granulomatous PCP in one patient; and Kaposi sarcoma, tuberculosis, and infection with Mycobacterium kansasii in one patient (Table 1). Eight of these 10 patients had cavitary lesions with or without associated noncavitary nodules and areas of consolidation, and one patient (patient 3) had invasion into the lung, as well as of the pleura, pericardium, and heart. The cavitary lesions seen on the radiographs and CT scans in the eight patients represented pulmonary infarcts (n = 2) or abscesses (n = 6). Two patients with abscesses also had invasion of nonvascular tissue with A I umigatus, with necrosis. Intracavitary masses of fungal hyphae and necrotic tissue were seen at pathologic examination in three patients. In two of these three patients, the intracavitary masses had been identified on the radiograph. Seven of the 10 patients had noncavitary nodules on radiographs and CT scans that were shown at pathologic examination to represent infarcts (n = 3) or nonvascular tissue invasion with A fumigatus, with or without associated necrosis (n = 4). Nodules in pathologic specimens correlated with nodular lesions on chest radiographs and on CT scans (Table 2). In two patients (patients 6 and 10), additional micronodules not depicted with radiography and CT were due to involvement of the airways with A fumigatus at the level of the distal respiratory bronchioles and alveolar ducts (Fig 1). In all seven patients with nodular lesions in pathologic specimens, CMV inclusions were also identified. In the six patients with areas of consolidation on radiographs and CT scans, the causes of the consolidation at pathologic examination were multifactorial and included pneumonia, angioinvasion with infarction, diffuse alveolar damage, and airway involvement at the level of the distal respiratory bronchioles and alveolar ducts (Table 2). In five of the six patients with consolidation, the organism identified was A fumigatus, whereas in Volume 196 #{149} Number 2 Radiology #{149} 411

4 the other patient, no organism was identified at pathologic examination. Coexisting infections with Pseudomonas and Streptococcus organisms were present within the areas of consolidation in three patients. Patient 1 also had prominent, irregular linear opacities on the chest radiograph and linear areas of increased attenuation on the CT scan. This could be directly correlated with granulomatous PCP in the pathologic specimen. There was no evidence to suggest that aspergillosis was responsible for the irregular linear pattern. Patient 2 also had an Aspergillus empyema. Patient 3 had pneumopericardium and pericardial effusion and thickening. This latter patient had a 2-cm defect in the pericardium that communicated with the left lower lobe. Multiple shallow ulcerations were seen at pathologic examination that correlated with multiple subpleural nodules at CT (Fig 3). In this patient, A furningatus was also present in the pericardium and myocardium. a. b. DISCUSSION Neutropenia and treatment with corticosteroids are well established risk factors for the development of invasive aspergillosis (10). Invasive aspergillosis also occurs in patients with advanced AIDS. Cystic pulmonary lesions in patients with AIDS have also been suggested as a possible risk factor for the development of pulmonary aspergillosis (4-10). In our study, five of 10 patients had cystic or cavitary lesions that predated the location and subsequent development of cavitary aspergillosis. Several forms of pulmonary aspergillosis have been described, including allergic noninvasive, semi-invasive, and invasive (6). These various forms usually occur in distinct subpopulations, although virtually all forms have been described in patients with AIDS (5,7,10,11). A range of pathologic manifestations was also observed in the present study and included angioinvasion, pneumonia, abscess formation, tissue invasion without obvious vascular invasion, chronic necrotizing cavitary aspergillosis, empyema, and myocardial invasion. Several patients had more than one manifestation. The results of previous clinical studies have shown that the radiographic manifestations of invasive aspergillosis in patients with AIDS are heterogeneous; the most common abnormalities reported include cavi- C. Figure 2. Patient 1. Cavitary aspergillosis in a 38-year-old man. (a) Posteroantenor chest radiograph shows perihilar irregular linear opacities and patchy areas of consolidation. A thinwalled cyst is seen in the left upper lobe. PCP was diagnosed with bronchoscopy. (b) Seven months later, the chest radiograph shows an irregular cavity in the left upper lobe at the site of the previously noted cyst. A cavitary mass is noted centrally within the cavity. A few penhilar linear opacities are seen. (c) Thin-section CT scan through the upper lobes shows an inregular, thick-walled cavity with an intracavitany mass, which is also cavitated. A few, irregular linear areas of increased attenuation and subpleural cysts are seen in both lung apices. After left upper lobectomy, the predominant pathologic findings were an Aspergillus abscess with an intracavitary mass and adjacent angioinvasion. tary lesions (29%-42%), focal alveolar or nodular opacities (22%-57%), and bilateral interstitial or alveolar infiltrates (23%-55%) (1,2,10). The frequency of cavitary lesions was higher in our study; they were seen in 80% of patients on the chest radiographs and in 100% on CT scans. Similar to previous reports, cavities showed an upper lobe predominance (10). The frequencies of noncavitary pulmonary nodules (40%) and consolidation (60%) were similar to those of previous reports, but interstitial infiltrates were distinctly uncommon in our series. Irregular linear opacities seen in only one patient were due to granulomatous PCP at pathologic examination. CT scans, available in seven patients, better delineated abnormalities such as cavity wall thickness and yielded additional information in all seven patients. Pleural and pencardial effusions, nodules, and cavities with or without intracavitary masses were identified more commonly with CT than with radiography. One case of mediastinal lymphadenopathy was missed on the corresponding radiographs. All patients, however, had abnormal chest radiographs. Furthermore, the interval time between chest radiography and CT may have accounted for some of the differences between the radiographic and CT findings. All cavitary lesions examined pathologically could be attributed directly to aspergillosis and were either caused by infarcts, necrosis, or abscesses. Intracavitary masses on the chest radiograph correlated with the presence of intracavitary masses of 412 #{149} Radiology August 1995

5 Figure 3. Patient 3. Invasive pleuropulmonary, penicardial, and myocardial aspengillosis in a 47-year-old man. (a) Posteroantenor chest radiograph shows a left hydropneumothorax, illdefined subpleural nodules, and patchy consolidation in the left lower lobe. (b) Conventional CT scan through lower lung zones shows consolidation in the lingula and multiple nodules in the left lower lobe. A subpleural nodule has cavitated and ruptured into the pleural space (arrow). Note the pneumopencardium. (c) Low-power photomicrograph from a small area of consolidation shows tissue necrosis that involves a small airway and subtends alveolar ducts and alveoli. Scattered Aspergillus organisms could be identified in the necrotic tissue. (Hematoxylin-eosin stain; original magnification, x 34.) b. C. necrotic lung and Afumingatus at pathologic examination. Noncavitary nodular lesions apparent on radiographs were also correlated directly with infarcts or tissue invasion in all seven pathologic specimens with nodules. CMV inclusions were seen at pathologic examination in all seven patients with nodules. Although a recent report by McGuinness et al (12) noted masses and nodules in 57% of cases of CMV infection confirmed with cytopathologic examination, CMV was not the cause of nodules in our series. Mycobacterial infection, Kaposi sarcoma, and pneumonia due to Pseudomonas organisms may have accounted for some of the nodules in three patients. The pathogenesis of the consolidation in six patients with available pathologic correlation was heterogeneous and included tissue invasion with A fumigatus centered on distal respiratory bronchioles and alveolar ducts, pneumonia due to A fumigatus, infarction, diffuse alveolar damage, pyogenic pneumonia, and pneumonia with no obvious cause in one patient. Associated CMV inclusions were identified in four patients but did not contribute substantially to consolidation. In three patients with consolidation on radiographs but without pathologic correlation, infection with Pseudomonas organisms and streptococcal pneumonia likely contributed to the abnormalities. Invasion of the pleura was uncommon in our series and occurred in only two patients. The two patients with invasive pleuritis and empyema had effusions apparent on radiographs. Our study has several limitations. First, all patients had concomitant pulmonary complications other than aspergillosis. These associated infections likely contributed to the radiographic features of nodules, consolidation, and linear opacities in some patients. These infections, however, apparently did not cause cavitary lesions. The high frequency of associated infection probably reflects the advanced stage of AIDS in these patients. Associated illnesses were also prevalent in other series (10). Second, to directly compare the radiographic and CT findings with the macroscopic and histologic findings in pathologic specimens, the study was limited to patients who had undergone lobectomy, pneumonectomy, or. This likely biased the study to patients with severe complications. Third, only four patients underwent thin-section CT. This may account for the lack of visualization of airway abnormalities in patients with histologic evidence of airway invasion. Although the presence of thickwalled irregular cavitary lesions in patients with AIDS should suggest the possibility of invasive aspergillosis, other conditions must be considered in the differential diagnosis. PCP usually produces thin-walled cysts but occasionally may produce thickwalled cavities (13). Pyogenic abscesses, septic emboli, lymphoma, and bronchogenic carcinoma may also cause similar findings. Fungal infections other than invasive pulmonary Volume 196 #{149} Number 2 Radiology #{149} 413

6 aspergillosis may also produce cavitary lesions in patients with AIDS (13). The differential diagnosis of noncavitary nodules includes other disseminated fungal infections and mycobacterial infection, as well as AIDSrelated malignancies. In conclusion, invasive aspergillosis is an increasingly common infection with a high mortality in patients with advanced AIDS. Single or multiple upper lobe cavities with thick irregular walls are strongly suggestive of invasive aspergillosis. When invasive aspergillosis is suspected, CT may be helpful to better define the nature and extent of the abnormalities. #{149} References 1. Klapholz A, Solomon N, Perlman DC, Talavera W. Aspergillosis in the acquired immunodeficiency syndrome. Chest 1991; 100: Singh N, Yu VL, Rihs JD. Invasive aspengillosis in AIDS. South Med J 1991; 84: Fairley CK, Kent SJ, Street A, Mijch A, Hoy J. Invasive aspergillosis in AIDS. Aust NZ J Med 1991; 21: Lortholary 0, Meyohas MC, Dupont B, Cadranelj, Salmon-Ceron D. Invasive aspergillosis in patients with acquired tinmunodeficiency syndrome: report of 33 cases. AmJ Med 1993; 95: Denning DW, Follansbee SE, Scolaro M,. Norris 5, Edelstein H, Stevens DA. Pulmonary aspergillosis in the acquired imm#{252}- nodeficiency syndrome. N EnglJ Med 1991; 324: Fraser RS. Pulmonary aspergillosis: pathologic and pathogenetic features. Pathol Annu 1993; 28(pt 1): Wright JL, Lawson L, Chan N, Filipenko D. An unusual form of pulmonary aspergillosis in two patients with the acquired tinmunodeficiency syndrome. AmJ Clin Pathol 1993; 100: Morrison DL, Granton jt, Kesten 5, Balter MS. Cavitary aspergillosis as a complication of AIDS. Can Assoc RadiolJ 1993; 44: Torrents C, Alvarez-Castells A, Vicente de Vera P, Coll S, Solduga C, Puy R. Postpneumocystis aspergilloma in AIDS: CT features. J Comput Assist Tomogr 1991; 15: Miller WTJr, Sais GJ, Frank I, Gefter WB, AronchickJM, Miller WT. Pulmonary aspergillosis in patients with AIDS. Chest 1994; 105: Perves NK, Kleinerman J, Kattan M, et al Pseudomembranous necrotizing bronchial aspergillosis. Am Rev Respir EMs 1985; 131: % McGuinness C, Scholes jv, Garay SM, Leitman BS, McCauley DI, Naidich DP. Cytomegalovirus pneumonitis: spectrum of CT parenchymal findings with pathologic correlation in 21 AIDS patients. Radiology 1994; 192: Kuhlman JE, Kavuru M, Fishman EK, Siegelman SS. Pneumocystis carinii pneumonia: spectrum of parenchymal CT findings. Radiology 1990; 175: #{149} Radiology August 1995