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Original Report |
1 Department of Radiology, University Hospitals Basel, Petersgraben 4, Basel
CH-4031, Switzerland.
2 Department of Pneumology, University Hospitals Basel, Basel CH-4053,
Switzerland.
3 Department of Hematology, University Hospitals Basel, Basel CH-4053,
Switzerland.
Received March 22, 2004;
accepted after revision June 8, 2004.
Address correspondence to S. Sonnet
(ssonnet{at}uhbs.ch).
Abstract
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CONCLUSION. High-resolution MDCT angiography has been shown to be a feasible technique to depict directly vessel occlusion in the setting of suspected fungal infections, especially for early diagnosis of angioinvasive pulmonary aspergillosis in immunosuppressed patients.
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As shown in earlier studies, the mortality rates for patients under appropriate antifungal therapy range from 30% to 80% [2]. Pulmonary surgical resection with acceptable morbidity and mortality rates can be considered as a therapeutic option even in profound neutropenia. A combination of surgical therapy and voriconazole might be a treatment of choice in highly suspected IPA; thus fungal infection was successfully managed in a selected patient group according to preliminary reports in 41 patients [3]. However, in the setting of invasive pulmonary aspergillosis, the lesions are often multiple and not always amenable to surgical resection. Major perioperative complications after thoracic surgery may be observed in up to 10% of patients [3]. An early diagnosis of IPA with timely IV antimycotic therapy had a significant impact on survival according to the results of Von Eiff et al. [4]. Delayed initiation of antifungal treatment later than 10 days after the onset of pulmonary aspergillosis resulted in a mortality rate of 90%, as compared with 41% with an earlier start of antimycotics. Alternative sensitive but invasive methods of diagnosis such as imagingguided percutaneous biopsy or open lung biopsy can be performed. The diagnostic yield to detect invasive pulmonary aspergillosis with bronchoalveolar lavage by bronchoscopy is only 30% [5].
Thus, early and correct imaging diagnosis and adequate therapy are mandatory for improved prognosis in neutropenic patients. CT with visualization of the halo sign reflecting the appearance of a hemorrhagic pulmonary nodule is an established early sign in IPA with a high sensitivity and specificity [6]. However, the halo sign may be seen in other diseases like mucormycosis, organizing pneumonia, pulmonary hemorrhage, Wegener granulomatosis, pulmonary metastases from hypervascular tumors, and so forth [7]. Pathoradiologic correlation studies showed that the halo sign around fungal lesions corresponded to a central fungal nodule surrounded by a rim coagulation necrosis due to vascular invasion causing thrombosis and ischemic necrosis [8, 9]. The purpose of this article was to evaluate the diagnostic capability of high-resolution pulmonary CT angiography with 16-MDCT to detect directly and early the angioinvasive pattern of pulmonary aspergillosis in immunosuppressed patients with fever of unknown origin.
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Four of 10 patients had acute leukemia; the remaining six had chronic leukemia, multiple myeloma, non-Hodgkin's lymphoma, diffuse large cell lymphoma, myelodysplastic syndrome, and immunosuppression after cardiac transplantation. Seven of 10 patients were treated with high-dose chemotherapy for induction–augmentation therapy. Three of 10 patients had undergone stem cell transplantation; two of 10 patients underwent bone marrow transplantation. One patient was under immunosuppression after cardiac transplantation. Four of 10 patients were neutropenic because of high-dose chemotherapy.
Pulmonary CT angiography was performed with 16-MDCT (Sensation 16; Siemens). Axial images had been obtained caudocranially by using 1.5-mm collimation, 30-mm table speed per rotation, and 0.5-sec gantry rotation time after IV administration of 90 mL of iopromide (Ultravist 300, Schering) at a flow rate of 3.5 mL/sec using care bolus (Siemens Medical Solutions). Contrast application was followed by a 60-mL saline flush at the same flow rate. Scanning was performed at 120 kV and 120 mAs. All images were evaluated by an experienced radiologist blinded to the clinical histories on a Leonardo workstation (Siemens) in standard lung window settings with 2-mm reconstructed slice thickness and a 1-mm reconstruction interval. The reviewer was only informed that the CT examinations were performed in immunosuppressed patients with fever of unknown origin.
Original axial data were evaluated for the presence of focal pulmonary lesions. After exact morphologic analysis with special respect to the halo sign, all detected lesions with a diameter of 10 mm or greater were evaluated for vascular occlusion, which was defined as an interruption of a vessel at the border of a focal lesion without depiction of the vessel inside the lesion or peripheral to the lesion.
CT angiograms were evaluated in axial, coronal, sagittal, and oblique directions using thin maximum-intensity-projection (MIP) reconstructions between 10- and 30-mm thicknesses to determine whether vascular occlusion existed. For data evaluation, only these vascular signs were considered. The results were then correlated with histology in eight of 14 detected lesions. In the remaining six of 14 lesions, diagnosis was determined by clinical and follow-up CT examinations.
A female patient undergoing stem cell transplantation for acute lymphatic leukemia had biopsy-proven fibrosing alveolitis after high-dose chemotherapy 3 years previously. High-dose chemotherapy was again given for recurrent leukemia and neutropenic antibiotic-resistant fever, yet CT revealed three nodules. Further evaluation revealed a pseudomembranous colitis, which resolved with adequate therapy. Analysis of previous CT scans revealed that the lesions were present 3 years previously.
One patient with fibrosis alveolitis on histology developed postoperative fever and showed a new nodular lesion on CT, which resolved spontaneously on follow-up CT and turned out to be a postoperative hematoma. Another patient with two lesions that developed after successful resected invasive pulmonary aspergillosis also recovered spontaneously; the lesions disappeared on follow-up CT and also turned out to be postoperative hematomas. These three lesions were determined to be postoperative hematomas because of the fast spontaneous resolution over time, CT morphology and density, close vicinity to clips, and fast recovery of the patient.
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In four of five lesions with histologically proven angioinvasion, vascular occlusion was detected by pulmonary CT angiography showing an interruption of pulmonary arteries directly at the border of the suspected lesion without depiction of the vessel inside the lesion or peripheral to the lesion (Figs. 1A, 1B, 1C, and 1D). For technical reasons, an exact correlation of occluded vessels detected on CT with occluded vessels identified histologically was not possible. However, angioinvasion was histologically proven in all the focal fungal lesions detected on CT angiography. The CT halo sign was present in only two of these five lesions with the proven angioinvasion. In one patient with a histologically proven angioinvasive mucormycosis, no vessel occlusion was detected on CT angiography (false-negative) in one of three lesions. In nine of nine lesions in which angioinvasive infection was excluded, CT angiography showed patent vessels. These lesions consisted of scar tissue (n = 3), hematomas (n = 3), diffuse large cell lymphoma (n = 1), air-space consolidation due to atypical Mycobacterium infection in the left lower lobe (n = 1), and diffuse alveolar damage (n = 1). The halo sign was present in the patient with the diffuse alveolar damage. Furthermore, the hematomas and the diffuse alveolar damage showed a nodular configuration. Patent vessels could be shown proximally and distally in closest vicinity of all these lesions. CT angiography did not show a peripheral vessel occlusion. In all hematomas, there was a displacement of smooth configured vessels but no interruption of a vessel at the border of the lesion. In scar tissues and the patient with an area of diffuse alveolar damage in the left lower lobe, according to fibrosing alveolitis confirmed by histology, a distortion of patent vessels crossing the peripheral parts of these lesions was observed, but not an occlusion. Furthermore, strong and patent vessels were detected in and peripheral to the tuberculous consolidation without alteration of size and contour (Figs. 2A, 2B, 2C, and 2D). In the patient with a large and solid diffuse large cell lymphoma, patent but tapered and partially irregular vessels were depicted within the lesion (Figs. 3A, 3B, 3C, and 3D). There were no interruptions of vessels at the border of all these lesions.
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Early diagnosis of angioinvasive pulmonary aspergillosis in immunosuppressed patients is critical for adequate and timely therapeutic intervention of this high-risk group. The diagnostic yield to detect Aspergillus infection with bronchoalveolar lavage by bronchoscopy is only 30%. A percutaneous needle-aspiration technique may be useful for confirming the diagnosis of fungal infection but represents a more invasive approach than CT angiography for diagnostic purposes.
The most common CT patterns in the setting of invasive pulmonary aspergillosis are segmental areas of consolidation and ground-glass attenuation or nodules surrounded by a halo [12]. Although the halo sign has been considered a major sign for early diagnosis of IPA in the appropriate clinical setting, this finding is nonspecific and can occur in immunosuppressed patients with an infectious cause (candidiasis, cytomegalovirus, herpes simplex virus, or coccidioidomycosis) or a noninfectious cause (metastatic angiosarcoma, Kaposi's sarcoma, pulmonary hemorrhage, or Wegener granulomatosis) [7].
According to pathoradiologic correlation studies, nodular pulmonary infiltrates correspond to areas of coagulation necrosis surrounded by a rim of hemorrhagic infarction associated with angioinvasion by Aspergillus species [8, 9]. According to these findings, the occlusion and angioinvasion by Aspergillus may be considered the earliest sign of disease even before secondary perinodular inflammatory reaction can occur. Thus, the direct detection of vessel occlusion up to a peripheral lesion by high-resolution MDCT angiography in the setting of unclear pulmonary infiltrates in an immunosuppressed patient may be a potential very early sign in the diagnosis of IPA. Hypothetically, the vessel occlusion secondary to angioinvasion by Aspergillus species may be found even earlier as the established halo sign. Furthermore, in three of five lesions with histologically proven angioinvasive fungal infection, MDCT angiography showed vessel occlusions in absence of a CT halo sign. Given the high mortality rate of invasive pulmonary aspergillosis in immunosuppressed patients, an early specific sign in the appropriate clinical setting for diagnosis is helpful and might also allow the selection of patients for curative lung resection.
The CT angiography technique allowed a sensitive detection of occlusion of peripheral vessels at the border of a suspicious fungal lesion. Because of the clinical setting of fever of unknown origin under adequate antibiotic therapy and nodular lesions, the imaging findings of this study suggest that this occlusion is due to angioinvasion. Hypothetically, a vasculitic change or a severe compression of the peripheral vessels may cause the same imaging finding. Because our initial histologic data correlate well with the observed vessel occlusion, we consider angioinvasion as the most plausible explanation for the positive CT angiography sign.
To our knowledge, this is the first clinical study showing prospectively direct peripheral vascular occlusions with high-resolution CT angiography in patients with angioinvasion by invasive pulmonary aspergillosis or mucormycosis in correlation with histology and clinical and CT follow-up. Initial results show that direct vessel occlusion at the level of a focal lesion may be accurately detected on MDCT angiography. This finding seems to be an important sensitive sign to detect early angioinvasion in the setting of suspected pulmonary fungal disease in immunosuppressed patients. Larger clinical studies are needed to establish the specificity and contribution of this promising early sign for patient treatment.
Acknowledgments
We thank G. Ralli and the entire CT technologist team for the valuable help
in the examinations and data handling.
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