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Original Research |
1 Department of Diagnostic Radiology, Eberhard-Karls-University,
Hoppe-Seyler-Strasse 3, 72076 Tuebingen, Germany.
2 Department of Internal Medicine-Onocology, Eberhard-Karls-University,
Tuebingen, Germany.
3 Department of Medical Biometry, Eberhard-Karls-University, Tuebingen,
Germany.
Received April 3, 2005;
accepted after revision June 13, 2005.
Address correspondence to H. Brodoefel
(hbrodoefel{at}t-online.de).
Abstract
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MATERIALS AND METHODS. Three hundred ten serial CT scans (mean, 7.7) in 40 consecutive patients were reviewed retrospectively over a median follow-up of 112 days (range, 5-841 days). Along with underlying disease, hematopoietic stem cell transplantation, neutropenia, graft-versus-host disease or antifungal treatment, signs of IPA, and number or size of lesions were evaluated regarding outcome and radiologic dynamics.
RESULTS. On the day of IPA diagnosis, median lesion number and size were 3 or 3.1 cm2, respectively. Irrespective of antifungal therapy, 90% of patients showed an increase in lesion size and number until day 9 (median and mean). Lesion size subsequently showed a median plateau phase of 3.5 days (mean, 7), during which median lesion numbers dropped by 17%. Consequently, 42.5% of patients showed a complete radiologic remission within a median 80 days. Of all parameters, formation of cavitation most strongly predicted time until radiologic remission, which was 2.5 times as long in patients with cavitary lesions. Likewise, cavitations were strong precursors of beneficial outcome (odds ratio, 8.4; confidence interval [CI], 1.07-176).
CONCLUSION. The kinetics of radiologic signs of IPA adheres to a distinctive pattern with initial rise in number and size, followed by a plateau phase of size and gradual reduction. Both time until complete radiologic remission and outcome are independent of initial or maximum lesion size and number yet strongly influenced by cavitation.
Keywords: CT • infectious diseases • invasive pulmonary aspergillosis • lung disease
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Despite considerable progress in treatment regimens, IPA remains a life-threatening complication with a mortality rate of 30-80% [6, 8, 9]. Because the diagnosis of IPA is difficult to make on the basis of laboratory studies, prompt use of chest CT is generally accepted as the cornerstone of IPA diagnosis [10]. Accordingly, the initial CT presentation of IPA, notably the presence of the halo sign, the crescent sign, or cavitations, and their morphologic changes in the run of the first 2 weeks have been the subject of intensive study.
The size of IPA lesions increases within the first week of diagnosis despite adequate therapy [11]. However, because of a lack of systematic CT follow-up, the long-term fate of IPA lesions—that is, their change in morphology and size over several months—is not well known. Hence, through retrospective review of sequential CT scans, we examined the dynamics of IPA lesions after their initial manifestation to either complete remission, surgery, death of the patient, or fungal relapse. Our aims were to describe the whole course of IPA as seen on CT and to find signs predictive of both outcome and time until complete radiologic remission. The potential influence of other established risk factors on outcome and duration of radiologic pathology was also considered.
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Our patients were 28 men and 12 women (range, 18-75 years; mean, 49 years). The initial CT scan either followed the occurrence of a febrile episode in patients already receiving broad-spectrum antibiotics or the detection of a pulmonary infiltrate by chest radiograph during prolonged neutropenia (usually > 2 weeks).
CT examinations were obtained with either a single-detector CT scanner (Somatom Plus 4, Siemens Medical Solutions) or an MDCT scanner (Volume Zoom, Siemens Medical Engineering). Scanning parameters for helical CT of the chest with a single-detector CT scanner were 120 kVp, 120 mAs, 5-mm collimation, and a pitch of 1.5. Axial scans through the thorax were obtained during full inspiration. Additional thin-section CT scans were obtained with a 1.0-mm collimation and at a 10-mm slice interval. On the Volume Zoom scanner, a collimation of 4 x 1.0 mm and a slice width of 1.25 mm were chosen. The table speed rotation was 6 mm, and the rotation time was 0.75 seconds, with a pitch of 1.5. We used an increment of 1.2 mm. The tube voltage was 120 kV, and the tube current-time product was 90 mAs. Images were reconstructed with a high-spatial-frequency algorithm B70s kernel. Scans were viewed at the standard lung window setting (level, -700 H; width, 1,500 H).
Because CT scans were promptly performed in all patients whenever IPA was suspected, we defined the day of the first CT scan as the very day of IPA diagnosis.
Follow-up images were obtained according to the established schedule of our institution, which includes approximately one chest CT per week in the preengraftment phase, with considerable variation based on individual complications. CT examinations in the postengraftment phase were performed according to individual risk assessment.
The initial chest CT and serial follow-up images were analyzed by two radiologists who were blinded to clinical information such as therapy or primary disease. In case of discrepancy, decisions were reached by consensus. The pattern, distribution, and extent of pulmonary abnormalities were classified as large nodules or masses (> 3 cm), small nodules (1-3 cm), very small nodules (< 1 cm), and consolidations or ground-glass opacities (GGOs). Consolidations and nodules were defined as areas of dense increase in attenuation with obscuration of the underlying vessel. GGO was defined as a hazy increase in lung attenuation without obscuration of the underlying pulmonary vasculature. The halo sign was recorded whenever a nodule was surrounded by a rim of GGO. Air crescents surrounding soft tissue were regarded as the crescent sign. In addition to the description of these features, the total number of lesions was registered for every CT scan and nodules or consolidations were classified according to size (< 1 cm; 1-3 cm; > 3 cm).
The largest nodule was identified in all sequential CT series and measured
along its longest axis and perpendicularly. Its area was estimated by length
x width x 
/ 4, assuming an ellipsoid shape for nodular
lesions. Regardless of the size of other nodules, the largest nodule was used
to define the size category of each patient. Irrespective of volume, reviewers
recorded the size of lesions that were cavitary on the initial CT and those
that became cavitary during follow-up. In addition, in patients with
cavitations, the size of the largest noncavitating lesion was registered.
Patients' records were reviewed for established risk factors of IPA such as neutropenia, HSCT, or GVHD, primary disease and intensity, or start of therapy. Along with a variety of high-resolution CT findings, the impact of these parameters on both radiologic remission and outcome was evaluated statistically. According to the associated risk and intensity of treatment, GVHD was classified into two groups: a low-risk group including patients with either no GVHD or grade l acute GVHD and limited chronic GVHD and a high-risk group comprising grades II-IV acute GVHD or extensive chronic GVHD (Table 1). Each patient's immune status was classified at the time of diagnosis according to the absence or presence of severe neutropenia. Antifungal therapy was categorized into standard versus intensified therapy regimens. Liposomal amphotericin B (AmBisome, Gilead-Sciences) (1-1.5 mg/kg), itraconazole (400 mg/day), voriconazole (400 mg/day), and caspofungin (50 mg/day) were classified as low-dose therapy doses, and AmBisome higher than 1.5 mg/kg and combination regimens such as AmBisome plus itraconazole or caspofungin were classified as intensified therapy. Both the start and end of therapy relative to radiologic diagnosis and complete remission of IPA were registered.
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Odds ratios (ORs) summarized 2 x 2 tables, which were estimated in 95% confidence intervals (CIs). Variables with skew distributions were described by median and range or treated as if log normally distributed—that is, geometric means (GMs) were computed, and in group comparisons, ratios of GMs were estimated and the respective CI. Times to events were analyzed similarly, considering censoring and with the estimation of the risk ratio. How metric variables depended on metric variables was estimated by linear regression. The effects of categoric variables on outcome and time until radiologic remission were tested in logistic regressions and analyses of variance, respectively.
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Initial patterns of high-resolution CT scans were very small nodular in 25% (10/40), small nodular in 27.5% (11/40), large nodular in 45% (18/40), and consolidations in 15% (6/40). In 17.5% (7/40) of patients, nodules and consolidations coexisted. Two patients (5%) presented with additional extensive GGOs; in one patient (2.5%), a mixture of GGOs and a very small miliary pattern was the dominant feature. Multiple lesions were encountered in 28 patients (median, 3.5; mean, 5.2; range, 2-20 lesions), whereas in 11 patients IPA was diagnosed as the solitary focus.
An accompanying halo sign was observed in 87.5% (35/40) at day 1, and its median duration was 5 days (mean, 8; range, 1-30 days). The exact prevalence of the halo sign after day 1 was 62.5%, 37%, and 17.5% at days 4, 8, and 16, respectively. Conversely, the crescent sign showed an increasing prevalence with 5%, 10%, 25%, and 45% at days 4, 8, 16, and 32 postdiagnosis, respectively. It appeared at a median 13 days postdiagnosis (mean, 13 days; range, 1-32 days). In the course of the disease, 22 patients (55%) developed cavitations, five of them multiple with a maximum of three. The median time period until the appearance of cavities was 21 days (mean, 30; range, 6-93 days).
Figures 1A and 1B summarizes the characteristics of CT kinetics. At the day of IPA diagnosis, the median size of the largest reference lesion was 3.1 cm2 (mean, 7.3; range, 0.2-55 cm2), and the median lesion number was 3 (mean, 4; range, 1-20). Ninety percent (36/40) of the reference lesions showed a further increase in size after primary diagnosis, reaching a maximum median area of 12.5 cm2 (mean, 15.9; range, 0.4-55 cm2) at day 9 (median and mean; range, 1-36). This initial increase in area paralleled an only moderate rise in lesion numbers, the latter reaching a peak of 5.2 lesions (mean and median, 3; range, 1-20), also at day 9. After the increase in lesion size and number over the first 9 days, the size of the lesions showed a median plateau phase of 3.5 days until day 12.5 since IPA diagnosis (mean, 7 days until day 16; range, 1-87). However, contrary to the sizes of lesions, median numbers did not plateau, and within the same time, the interval decreased by 17% to 2.5 (mean, 3.7; range, 1-12). After this stable phase, most patients (32/40) showed a decrease of lesion size. In 62.5% (25/40) of patients, a reduction down to 50% of maximum size was registered 31 days after the initial diagnosis of IPA (median and mean, 40; range, 6-90). At the same time, the median number of lesions dropped to 2 (mean, 2.8).
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According to the course of disease, all but two patients in our cohort were assigned to four groups (Table 2). The remaining two patients showed a primarily stable form of IPA until they died of primary disease. Figures 2A, 2B, 2C, 2D, 3A, 3B, 3C, 3D, 4A, 4B, 4C, and 4D provide examples of disease courses.
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Seventeen patients (42.5%) had a complete radiologic remission of disease within a median 80 days (mean, 85.5; range, 10-240). Therefore, time until complete improvement was 2.5 times (CI, 1.007-6.3) as long in patients who showed cavitation of at least one of their lesions (median, 95; mean, 109.5; range, 25-240 days) when compared with those that did not (median, 50; mean, 51; range, 10-110 days). As evident from Figure 5 in our cohort, the median time until complete regression of all observed cavitary lesions was 90 days (mean, 84; range, 15-160 days) and significantly longer than the time until regression of lesions without cavitation formation (median, 30; mean, 38.9; range, 9-96; risk ratio, 0.5; CI, 0.31-0.76). Size of cavitary lesions did not affect the time until complete radiologic remission (slope, 4.1 d/cm2; CI, 2.9-11.1).
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In nine patients (22%), complete remission was achieved through surgery within 30 days (median and mean, 77.3; range, 24-210 days) after IPA diagnosis with seven of the surgical resections performed early within the first 48 days. Indications for surgery were hemoptysis in three patients, removal of a solitary infectious focus before ablative chemotherapy for HSCT in four, before chemotherapy because of relapsing primary disease in one, and failure of medical therapy after HSCT in one patient.
Five of the 17 patients (29%) with remission without surgical intervention and four of the nine (44%) with surgical resection had a relapse of fungal disease (Table 3). The latter were diagnosed 270 days after the start of disease (median and mean, 224; range, 10-556 days) and 140 days after complete resolution of radiologic signs of IPA (median and mean, 161; range, 20-480 days). In three patients, relapse occurred during ongoing therapy and in six patients, a median 130 days (range, 20-330 days) after cessation of antifungal treatment.
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In those three patients with fungal relapse, in whom new lesions developed either at the location of a previous lesion (four lesions in two patients) or at the margins of a previous resection (one patient) or in postcavitary fibrotic tissue (one patient), relapse was interpreted as the reactivation of persistent microfoci; time until relapse was short in these cases: 20, 20, and 140 days after radiologic remission (GM, 38 days). For patients in whom recurrent lesions were found at anatomic sites that were initially unaffected and therefore regarded de novo rather than reactivated, however, the time to relapse was 4.4 times (CI, 0.98-19.6) as long after complete remission (GM, 167; range, 60-480 days). Similarly, the time until initial remission was 1.8 times (CI, 0.2-17) as long in patients with recurrence of foci as in those that showed true reinfection (GM, 75 and 41 days, respectively).
In contrast to patients with relapsed IPA, we found a smaller subset of five patients in our series (12.5%) who showed a bimodal course of disease. In these five patients, an initial phase of partial improvement was followed by progression in 144 days (median and mean, 142; range, 81-200) after initial diagnosis. This progression occurred in all but one case during standard antifungal therapy. In all five patients, relapse of IPA was accompanied by a halo sign and an increase in the size of existing nodules. A major increase in wall thickness also was noticed in four of six cavitary lesions. In addition, according to the definitions given earlier, we found a relapse of apparently cured lesions in four of five patients within this group.
Finally, seven patients (17.5%) in our series with a fulminant disease course at no point showed a decrease in number or size of lesions, despite adequate therapy. All these patients died a median of 20 days after the diagnosis of IPA (mean, 40; range, 5-64 days), and none developed either the crescent sign or cavitation.
In our series, 24 patients (60%) survived and 16 (40%) died, 8 (20%) of them because of IPA and at a median of 40 days postdiagnosis (mean, 70; range, 5-276 days). In detail, all seven patients with a fulminant disease course died because of IPA, two of them secondary to a cerebral manifestation and five because of IPA-related respiratory failure. Similarly, one of the patients with relapsing aspergillosis after initial remission died of IPA. All other deaths in our cohort were either related to pulmonary cytomegalovirus infection (n = 1) or refractory hematologic diseases (n = 7) and occurred 134 days postdiagnosis (mean, 158; range, 64-365 days).
Of all the parameters considered in our analysis, only the formation of cavitations had a statistically significant effect on outcome and time until 50% reduction of maximal lesion size or complete remission. Indeed, time to half maximal lesion size was 2.8 times (CI, 1.3-5.7) as long in the presence of cavitation as in its absence. Likewise, as evident from Figure 6, time until complete radiologic remission was 2.5 times (CI, 1.007-6.3) as long in patients with cavitary lesions as in those without. At the same time the chance to survive IPA was OR = 8.4 (CI, 1.07-176) times greater in patients with cavitary lesions than in those without (Table 4). Initial or maximal lesion size and number, intensity and start of antifungal therapy, initial distribution of foci (unilateral vs bilateral), and absence or presence of HSCT, GVHD, aplasia, and primary disease did not have a considerable influence on either outcome or radiologic duration of disease.
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Concerning the frequency of early characteristic CT signs of IPA, our results fit well with previously reported data [2, 16-19]. This is especially true for the halo sign, which is commonly seen as the most suggestive diagnostic hint and in our cohort was seen in 87.5% of patients at the first CT investigation. In neutropenic patients with infection by angioinvasive fungus, the halo sign is explained as a result of vascular invasion of small to medium vessels with subsequent ischemic necrosis. The typical nodules represent foci of infarction, whereas the halo corresponds to a rim of GGO that is secondary to alveolar hemorrhage [19-22]. The median 5-day duration of the halo sign in our cohort nicely compares to other sequential CT studies and emphasizes the ultimate need for prompt CT scans [11, 23, 24]. Of note, in our series, the halo sign served not only as a clue to early CT diagnosis but also as a marker of fungus activity. Indeed, in all cases of a biphasic course of IPA with progression after initial, yet only partial improvement, the halo sign proved a reliable marker, accompanying increase in lesion size. The frequency of the crescent sign was 25% at day 16 after diagnosis and increased to 45% at day 32. These results concur well with the literature data and, despite the unmatched specificity of the air crescent, once again disqualify the sign as a suitable tool for early IPA diagnosis [25].
In accordance with the results of Caillot et al. [11], both size and number of lesions showed an initial increase that was irrespective of type or intensity of administered antifungal treatment. Interestingly, both size and number of lesions showed a concomitant peak at day 9 (Figs. 1A and 1B). However, at follow-ups, numbers and sizes behaved differently in that the latter showed a median plateau phase of 3.5 days (mean, 7 days), whereas numbers promptly decreased. Although none of the patients with a fulminant disease course and subsequent rapid death experienced a decrease in size or number of lesions, lesions in all other patients showed a decreased size after the plateau phase. In 62.5% of the patients, size went down to half of the maximum after a median 31 days, 42.5% of them showing a complete radiologic resolution 90 days after diagnosis.
The strongest predictive value for time until radiologic IPA remission was the formation of cavitary lesions that evolved at a median 21 days in 22 of our 40 patients. The duration of radiologic IPA manifestation was 2.5 times as long in patients who developed cavitary lesions as in those who did not. At the same time, cavitations had a strong beneficial implication for the outcome, making survival 8.4 times more likely. This contradictory effect of cavitation on the radiologic kinetics of the disease and outcome is one of the major findings of our work and can be explained by its underlying pathology. Both the crescent sign and cavitation are the result of WBC recovery with release of proteases that lead to resorption of necrotic tissue at the periphery of lesions. Hence, both signs are markers of bone marrow recovery in patients with hematologic malignancies; their absence, however, often indicates a lack of granulocyte return in the setting of refractory malignancy or graft failure [26-28].
Of interest, the size of cavitary lesions did not have a relevant impact on the duration of lesions, probably because organization of cavitary walls depends more on their thickness than the overall lesion diameter.
Outcome was affected by neither the initial nor the maximal lesion size or number. In a similar way, other parameters—such as intensity or start of therapy, initial distribution of foci (unilateral vs bilateral), and absence or presence of HSCT, GVHD, aplasia, and primary disease—did not have a considerable impact on outcome or duration of IPA manifestation. As mentioned before, this is especially noteworthy for the failure of early antifungal therapy to prevent initial increase of size. At the same time, only 9 of the 17 patients with a monophasic remission of IPA received treatment until complete radiologic improvement, whereas in eight patients, therapy was stopped as soon as bone marrow recovery had occurred, notably a median 37 days before complete resolution of pulmonary lesions and at a median residual number and size of 1.8 lesions and 2.3 cm2, respectively. These observations concerning therapy effects on CT morphology confirm that the primary role of medical therapy is refined to bridging the time until bone marrow recovery [6, 11].
In our study, time until relapse in patients in whom new fungal infection developed was 4.4 times as long as in those with reactivation of microfoci. Conversely, in the latter group of patients, time until initial remission was 1.8 times as long compared with that in the first group (Table 3). The delay in achieving initial remission is likely associated with persistent micronodular foci, which for a certain period might serve as origins of fungal reactivation. Following from this, it seems tempting to identify patients with long periods of initial radiologic remission as candidates for prolonged medical prophylaxis. But ongoing research with more data is needed to determine whether slow radiologic remission with clearly defined thresholds can be established as a significant risk factor with implications for treatment.
Compared with previous studies [29-33], the beneficial effect of surgery was less clear in our cohort. The high frequency of reactivation of fungal infection postsurgery is probably related to our long-term follow-up. Also, the small number of resected patients in our series represents a major limitation to statistically powerful observations regarding the benefit of surgery. Nevertheless, in our study a low rate of IPA-related deaths (20%) was documented in patients receiving antifungal chemotherapy only. Taking into account our data regarding a complete radiologic remission of IPA irrespective of the size of cavities and considering surgery-associated risks, we do challenge the opinion that surgery should be the standard procedure for all patients with localized disease [29-34]. In our view, the benefit of surgery in scenarios other than the classical indications, such as hemoptysis, a planned HSCT, or failure of medical treatment, needs further evaluation through large randomized trials of medical versus medical-surgical treatment.
In summary, despite considerable individual differences, CT kinetics of IPA morphology adheres to distinctive primary patterns: A fulminant course of disease with a continuous increase in lesion size and number is opposed by triphasic kinetics. Irrespective of antifungal treatment, an initial rise in size and numbers is followed by a plateau phase of area and a gradual radiologic remission over weeks or months. The completion of radiologic cure is strongly delayed in patients with cavitary lesions, with the cavities resolving slowly and independent of size. The presence of cavities, however, correlates with improved patient survival.
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