Abstract
Objective:
The aim of this study is to characterize chest CT findings of neutropenic patients with proven/probable invasive pulmonary aspergillosis (IPA).
Methods:
Hematological cancer patients admitted to our institution (2007–2017) were retrospectively enrolled if the diagnostic criteria of proven/probable IPA during the neutropenia were met (EORTC/MSG). Galactomannan (GM) was routinely measured in serum and chest CT-scan was routinely performed in case of recurrent/persistent fever. Bronchoscopy was performed in case of chest CT-scan abnormalities. Chest CT-scan and GM dosage were analyzed at the time of IPA suspicion. Chest lesions were classified using a clinical report form by two expert radiologists.
Results:
35 patients were identified. Peribronchial focal lesions were observed in 29 IPA (82.9%) by the first radiologist and in 31 (88.5%) by the second (k = 0.768). 12 weeks mortality was 20%.
Conclusion:
Peribronchial focal lesions are a common finding in early-IPA whatever the GM value during neutropenia and our findings reinforce the efficiency of a preemptive approach.
Advances in knowledge;
Peribronchial focal lesions, which are classically described in airway invasive aspergillosis, are a common finding in early-IPA in hematological cancer patients with prolonged neutropenia regardless of the GM value, and such peribronchial lesions should reinforce the possibility of IPA.
Introduction
Invasive pulmonary aspergillosis (IPA) is a life-threatening infection affecting hematological cancer patients with chemotherapy-induced neutropenia. CT-scan imaging plays a critical role in IPA diagnosis.1–4 In neutropenic patients, well-circumscribed lesions with or without the halo sign are highly suggestive findings of IPA, according to European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG) diagnostic criteria.5 Conversely, peribronchial consolidations are classically described in airway invasive aspergillosis in non-hematological cancer patients.6–8
The aim of this study is to describe chest CT findings of neutropenic hematological cancer patients with proven/probable IPA in a 10 year retrospective cohort. We hypothesize that our preemptive approach with serial serum galactomannan (GM), early chest CT-scan and bronchoscopy allow an earlier diagnosis. Thus, due to the initial airway pathway of Aspergillus hyphae preceding vascular involvement, some findings as peribronchial focal lesion on CT-scan, could be linked to this bronchial invasion phase.
Correlation between the radiological pattern and serum galactomannan-positive (GM-P) vs galactomannan-negative (GM-N) IPA was also described.
Methods
Hematological cancer patients admitted to the isolation ward of University Hospital of Lausanne, Switzerland for myeloablative chemotherapy between 2007 and 2017 were retrospectively enrolled if the diagnostic criteria of proven/probable IPA during the neutropenic phase (<0.5 G l−1) were met, according to the definitions of EORTC/MSG.5 This study was approved by the local ethical committee (Swiss-ethics 2016–02203). The diagnostic work-up for IPA was applied as previously described.9 Briefly, galactomannan (Platelia Aspergillus-Ag, Bio-Rad) was measured in serum twice weekly during the neutropenic phase. Chest CT-scan was performed in case of recurrent or persistent fever (≥5 days) despite using broad-spectrum antibiotics, and/or respiratory symptoms. Chest CT-scan and GM level were analyzed at the time of IPA suspicion. Bronchoscopy with bronchoalvelolar lavage (BAL) was performed, when feasible, in case of chest CT scan abnormalities. BAL fluid was routinely analyzed for cytology, GM, polymerase chain reaction (PCR) specific to Aspergillus fumigatus and bacterial/fungal cultures. Transbronchial biopsies were performed using radial ultrasound between May 2014 and March 2016 as previously described in our recent publication.10 GM threshold was set at an optical density index of 0.5, as recommended by the manufacturer.
Two expert chest radiologists reviewed the initial high resolution CT-scan with or without contrast enhancement at the time of IPA diagnosis. All chest lesions were classified using a clinical report form. Alveolar consolidations either subsegmental/segmental/lobar or peribronchial, as well as well-circumscribed nodules (>5 mm) were described. Precisely, peribronchial focal lesions were defined as focal peribronchial consolidations or nodules. Also, halo sign, air crescent sign, hypodense sign (density <10 UH for lesions > 10 mm), cavitated nodules, isolated ground glass opacities and tree-in-bud pattern were reported. The concomitant presence of halo sign and peribronchial focal lesions (in case of at least one peribronchial focal lesion and one halo sign) in the same lobe and segment was noted. The interobserver variability (concordance) between the two radiologists regarding chest lesions description was calculated using k (κ) statistics; k values can range from −1 (complete disagreement) to 1 (perfect agreement). For the interpretation of the degree of agreement, the following scale were used; k < 0.20 (poor), k = 0.21–0.40 (fair), k = 0.41–0.60 (moderate), k = 0.61–0.80 (good) and k = 0.81–0.99 (excellent).
Categorical variables concerning GM-P and GM-N IPA were studied with the Fisher-test. p value < 0.05 was considered statistically significant. Calculations were performed with SPSS Chicago, IL.
Results
A total of 35 patients with proven/probable IPA were identified (median age 52.7 years, range 22–79). Characteristics of patients are shown in Table 1. 24 (68.6%) patients had acute myeloid leukemia. Other underlying hematologic malignancies consisted of acute lymphoid leukemia (n = 3, 8.6%), refractory anemia with blast excess-2 (n = 5, 14.2%), multiple myeloma (n = 1, 2.9%) and chronic lymphoid leukemia (n = 2, 5.7%). Overall mortality at 12 weeks was 20%.
Table 1.
IPA characteristics
| Mean age | 52.7 |
|---|---|
| Male gender | 19 (54%) |
| Prolonged (≥10 days) neutropenia at IPA diagnosis | 32 (91%) |
| Antifungal prophylactic treatment at IPA diagnosis | 6 (17%) |
| Antibiotic treatment at IPA diagnosis | |
| Imipenem | 7 (20%) |
| Piperacillin-tazobactam | 11 (31%) |
| Cefepim | 9 (26%) |
| Proven IPA | 2 (6%) |
| Bronchoscopy | 30 (85%) |
| Antifungal treatment at bronchoscopy | 28 (80%) |
| Cytological pattern of white cells in BAL | |
| Alveolar lymphocytosis | 12 (34%) |
| Alveolar normal formula | 7 (20%) |
| Alveolar neutrophilia | 6 (17%) |
| GM positive in BAL | 20 (57%) |
| Aspergillus fumigatus PCR positive in BAL | 11 (31%) |
| Chemotherapy | |
| Induction or re-induction | 22 (63%) |
| Consolidation | 7 (20%) |
| Other | 5 (14%) |
| Hematopoietic autogenic stem cell transplant | 2 (6%) |
| Previous allogenic stem cell transplant | 3 (9%) |
BAL, bronchoalveolar lavage; IPA, invasive pulmonary aspergillosis.
A total of 28 CT-scan with contrast enhancement (80%) and 7 without (20%) were analyzed. Peribronchial lesions were observed in 29 IPA (82.9%), halo sign and hypodense sign were respectively found in 25 (71,4%) and 17 IPA (48.6%) by the first radiologist. Cavitated nodules were observed in four cases (11,4%), tree-in-bud pattern in two cases (5.7%) and no air crescent sign was noted by the first radiologist. The second radiologist identified peribronchial focal lesions in 31 IPA (88.5%, k = 0.768), halo sign and hypodense sign were respectively found in 26 (74.3%, k = 0.874) and 19 IPA (54.3%, k = 0.886). Cavitated nodules were observed in four cases (11.4%) and no air crescent sign was noted by the second radiologist. Representative cases are shown in Figure 1.
Figure 1.
Representative cases. (a) Nodule with sharp borders in a peribronchial location (arrow) at the level of the right lower lobe. (b) Three nodules at the level of the left upper lobe, one in a subpleural location, one in a peribronchial location, and one with peripheral (arrow) ground glass opacity (halo sign). (c,d) Nodule of the right upper lobe in a peribronchial location with a diameter of 24 mm on lung windowing (c) with a necrotic (arrow) component (hypodense sign) well assessed on the mediastinal window after contrast administration
18 proven/probable IPA were serum GM-P and 17 serum GM-N. Comparison of the radiological findings between the two groups is shown in Tables 2 and 3. At least one well-circumscribed lung lesion was observed in GM-P and in GM-N IPA. Halo sign was identified by the first radiologist in 14 (77.8%) GM-P and in 11 (64.7%) GM-N IPA (p = 0.470). Peribronchial lesions were identified in 16 (88.9%) GM-P and in 13 (76.5%) GM-N IPA by the first radiologist (p = 0.401). There were no significant differences between two groups regarding hypodense sign, cavitated nodules or ground glass opacities. Similar findings were reported by the second radiologist and are resumed in Table 3 with p and k values.
Table 2.
Chest CT-scan findings of the first radiologist
| IPA | Peribronchial focal lesions | Peribronchial focal lesions (median number) | Halo sign | Hypodense sign | Air crescent sign | Cavitated nodules | |
|---|---|---|---|---|---|---|---|
| GM-P | 18 | 16 (89%) | 2 (range 0–24) | 14 (78%) | 10 (56%) | 0 | 0 |
| GM-N | 17 | 13 (77%) | 2 (range 0–11) | 11 (65%) | 7 (41%) | 0 | 4 (24%) |
| Total | 35 | 29 (83%) | 2 (range 0–24) | 25 (71%) | 17 (49%) | 0 | 4 (11%) |
| p value | 0.401 | 0.470 | 0.505 | 0.05 |
Serum galactomannan-positive (GM-P), serum galactomannan-negative (GM-N), invasive pulmonary aspergillosis (IPA).
Table 3.
Chest CT-scan findings of the second radiologist and k value
| IPA | Peribronchial focal lesions | Peribronchial focal lesions (median number) | Halo sign | Hypodense sign | Air crescent sign | Cavitated nodules | |
|---|---|---|---|---|---|---|---|
| GM-P | 18 | 17 (94%) | (range 0–27) | 14 (78%) | 11 (61%) | 0 | 0 |
| GM-N | 17 | 14 (82%) | (range 0–16) | 12 (71%) | 8 (47%) | 0 | 4 (24%) |
| Total | 35 | 31 (89%) | (range 0–27) | 26 (74%) | 19 (54%) | 0 | 4 (11%) |
| p value | 0.337 | 0.711 | 0.505 | 0.05 | |||
| k value (total) | 0.768 | 0.784 | 0.886 | 1.0 |
Serum galactomannan-positive (GM-P), serum galactomannan-negative (GM-N), invasive pulmonary aspergillosis (IPA).
The first radiologist found that in 12 IPA (70.6%), peribronchial focal lesion and an halo sign were in the same lobe, and in 11 (64.7%) cases both lesions were in the same segment. The respective findings of the second radiologist were 16 IPA (84.2%) and 12 (63.1%).
Prevalence of associated bacteremia was comparable, representing 5 (27.8%) cases in GM-P and 4 (23.5%) cases in GM-N IPA. Three patients underwent TBB during their bronchoscopy (8.5%) and in one case, intra-alveolar fibrin deposition was described. Concomitant lung infection was only identified in one (5.6%) GM-P IPA (Respiratory Syncytial Virus).
Discussion
CT-scan findings of IPA during the course of the disease course are well documented in hematologic cancer patients.2,3,11 Although focal lesions, either nodules or alveolar consolidations, have been frequently reported in IPA,12 the peribronchial distribution has rarely been described (9%) in this situation.13 While nodules, with a halo sign (between 71 and 74%) were frequently observed in our IPA cohort, as classically reported, peribronchial nodules or focal alveolar consolidations were surprisingly the most represented chest lesion (between 83 and 89%). We hypothesize that it will be probably linked to a novel observation in hematological cancer patients that could be attributed to a combined airway and angioinvasive form. In the past, latter findings have been mainly described in airway invasive aspergillosis in non-hematological cancer patients.14–16
In the prospective series of Bergeron et al,17 up to 38% of proven or probable IPA (n = 21) among hematological malignancies presented small airway lesions on the CT-scan, but these findings were clearly predominant among non-acute leukemia patients and were associated with leukocyte count >100/mm3 (>0.1 G l−1). In this last study, 41% of patients were extremely immunosuppressed after allogenic hematopoietic stem cell transplant (AHSCT). In contrast, only three cases underwent AHSCT (9%) in our study and this low prevalence may explain our mixed radiological pattern that could be attributed whether to airway and/or angioinvasive forms. Additionally, only few cases reports of airway invasive aspergillosis have been reported in hematological cancer patients, and showed that CT-scan abnormalities were particularly expressed as peribronchial focal lesions.6–8
Already in 1994, Logan et al18 proposed the peribronchial focal lesions as a CT finding suggestive of invasive airway aspergillosis. This latter study was limited to the description of CT-scan findings of nine pathologically proven airway invasive aspergillosis in hematological cancer patients. Concerning other discriminating CT features, Bergeron et al,17 considered alveolar consolidations to weakly discriminate between the airway and the angioinvasive form. The only other discriminating feature consists of centrilobular nodules with tree-in-bud pattern. However, we found this latter pattern in two cases (5.7%) only. The tree-in-bud pattern has been taken into consideration in current European guidelines for the description of airway invasive aspergillosis.19
Concerning confounding factors for peribronchial focal lesions, organising pneumonia could be discussed, as well as a concomitant pulmonary infection that was identified in only one IPA (5.6%) in this study. This latter rare finding may not fully explain the high rate of peribronchial focal lesions in our study population, the former being improbable in the overall context unless confirmed histologically (one case, representing 2.8% of IPA, being observed in this study).
We hypothesize that our preemptive and exhaustive approach with serial serum GM, early chest CT-scan and bronchoscopy may also partially explain our findings by means of an early diagnosis in this hematological cancer patient cohort. Indeed, owing to the initial airway pathway of Aspergillus hyphae preceding vascular involvement, this first step could lead to bronchial invasion in some conditions, especially the lack of extreme immunosuppression, and express as peribronchial focal lesions on CT-scan. This hypothesis may be reinforced by the high rate of lobar and segmental matching between halo sign and peribronchial focal lesions. A secondary angioinvasion step could develop as a continuum from the initial airway invasion stage, this being facilitated by the proximity between bronchi and arteries.
The initial step of airway involvement could be transient with a variable duration, as is the duration of the perinodular ground glass halo in the angioinvasive form. This sequence duration, and the conditions required to express the airway phase, remain to be investigated in further studies.
Our 12 weeks mortality of 20%, significantly lower than other series (>40%), presumably reflect the effect of our preemptive approach.13 On the one hand, the high frequency of the halo sign observed in our study, classically described as an early sign during the first week of IPA, on the other hand the absence of air crescent sign, which is a classical late finding,12 reinforces our hypothesis.
Our study focused on hematological cancer patients presenting IPA during prolonged (≥10 days) neutropenia, a major and well-documented risk factor of IPA, and this fact may explains our findings. In this way, conversely to Bergeron et al,17 we did not focus on the severity of neutropenia. All patients, at the time of IPA diagnosis, had a neutrophil count <0.5 G l−1, with a transitory agranulocytosis phase (<0.1 G l−1) that lasted less than 72 h.
Interestingly, and as a consequence, the high prevalence of peribronchial focal lesion found in our study of patients with prolonged neutropenia, highlights the potential benefit of endobronchial, and even transbronchial samplings by bronchoscopy, as previously described in our recent study.10
In IPA, the central part of a nodule with a peripheral halo sign likely represents the pulmonary infarction secondary to fungal angioinvasion, while the surrounding halo of ground-glass opacity represents the perinodular alveolar hemorrhage. During neutropenia, the halo sign has shown the highest positive predictive value for IPA in several studies20,21 with low specificity. In the retrospective study of Greene et al,3 involving 235 patients with IPA, the vast majority of patients with IPA presented at least one macronodule ≥10 mm on chest CT imaging, with more than half of patients presenting with halo sign. Therefore, according to the authors, in high risk patients, the absence of a macronodule argues against a diagnosis of IPA.
More recently, the vessel occlusion sign,21 directly representing the fungal angio-invasion, has demonstrated a sensitivity of 94% and a specificity of 71% for the diagnosis of IPA, but requires iodine contrast administration and is applicable for lesions >10 mm. Our findings, if confirmed on larger cohort studies, could be considered as an additional feature suggesting IPA in hematological cancer patients with prolonged neutropenia.
Finally, because positive serum GM can represent a sign of disseminated and thus more advanced disease, we compared the radiological pattern between GM-P and GM-N IPA. Interestingly, no significant differences were observed between the groups. Literature comparing the radiological patterns of GM-P and GM-N IPA are lacking and no study has focused on hematological cancer patients. One study that described this aspect in a heterogeneous pool of patients comprising severe and mildly immunocompromised patients found that halo sign was significantly associated with GM-P, and peribronchial focal lesions were similarly found in both groups (40% of all cases).22 In our study, the halo sign was similarly observed in both groups and peribronchial focal lesions were found between 82.9 and 88.5% of all IPA patients.
Conclusions
In conclusion, peribronchial focal lesions, which are classically described in airway invasive aspergillosis, are a common finding in early-IPA in hematological cancer patients with prolonged neutropenia regardless of the GM value, and such peribronchial lesions should suggest and reinforce the possibility of an IPA. Our findings, additionally, reinforce the efficiency of a preemptive approach for IPA.
Contributor Information
Alessio Casutt, Email: alessio.casutt@gmail.com.
Jade Couchepin, Email: jade.couchepin@unil.ch.
Anne-Sophie Brunel, Email: asbrunel@chu-besancon.fr.
Alban Lovis, Email: alban.lovis@chuv.ch.
Pierre-Yves Bochud, Email: pierre-yves.bochud@chuv.ch.
Nathalie Keller, Email: nathalie.keller@chuv.ch.
Frédéric Lamoth, Email: frederic.lamoth@chuv.ch.
Catherine Beigelman-Aubry, Email: catherine.beigelman-aubry@chuv.ch.
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