A total of 32 patients with physician-diagnosed ABPA were identified from medical records during the study period. Among these, 7 patients were eliminated from analysis for the reasons of pulmonary complications making image evaluation difficult in 5 patients (sequelae of pulmonary tuberculosis, n = 1; sequelae of pulmonary tuberculosis and aspergilloma, n = 2; simple aspergilloma, n = 2); and unfulfilled diagnostic criteria of ISHAM despite HAM on CT (no data on Aspergillus-specific IgE, n = 1; low level of IgE, n = 1). A total of 25 patients met the ISHAM criteria for ABPA and were enrolled in the study (Table 1). Median patient age was 65 years (IQR, 56–77 years) and female patients accounted for 60% of study participants. Smoking history was observed in 4 patients (16%) and a history of infantile asthma or CEP were present in a substantial minority of patients (32% and 28%, respectively), with some overlap. Tentative diagnoses from other hospitals or clinics included ABPA (n = 6, 24%), CEP (n = 7, 28%), and mycobacteriosis (TB, n = 4; non-tuberculous mycobacteria (NTM), n = 2) even if CT was obtained.
Table 1. Baseline characteristics of 25 patients with ABPA
Characteristic
|
All cases (n=25)
|
EP group (n=6)
|
Non-EP group (n=19)
|
p value
|
|
|
No. (%) or median (IQR)
|
|
|
Age at onset of ABPA (y), median (IQR)
|
65 (56–71)
|
67 (61–73)
|
65 (55–71)
|
n.s.
|
Sex, female
|
15 (60%)
|
4 (67%)
|
11 (58%)
|
n.s.
|
Bronchial asthma
|
|
|
|
|
Age at onset (y), median (IQR)
|
50.0 (36.0–64.0)
|
49.0 (31.5–50.0)
|
55.0 (38.0–66.5)
|
n.s.
|
Duration (y) between onset of asthma
and ABPA, median (IQR)
|
3.0 (0.4–16.0)
|
18.0 (4.2–24.5)
|
2.0 (0.5–8.0)
|
n.s.
|
History
|
|
|
|
|
Smoking status, never/former/current
|
21 (84%)/3 (12%)/1 (4%)
|
5 (83%)/1 (17%)/0 (0%)
|
16 (84%)/2 (11%)/1 (5%)
|
n.s.
|
Infantile asthma
|
8 (32%)
|
2 (33%)
|
6 (31.6%)
|
n.s.
|
CEP
|
8 (32%)
|
3 (50%)
|
5 (26%)
|
n.s.
|
Other respiratory disease
|
4 (16%)
|
0
|
4
|
|
COPD
|
2 (8%)
|
0
|
2
|
n.s.
|
sequelae of pulmonary tuberculosis
|
1 (4%)
|
0
|
1
|
n.s.
|
NTM
|
1 (4%)
|
0
|
1
|
n.s.
|
Tentative diagnosis
|
|
|
|
|
ABPA
|
6 (24%)
|
0 (0%)
|
6 (32%)
|
n.s.
|
CEP
|
7 (28%)
|
4 (67%)
|
3 (16%)
|
n.s.
|
TB
|
4 (16%)
|
0 (0%)
|
4 (21%)
|
n.s.
|
NTM
|
2 (8%)
|
1 (17%)
|
1 (5%)
|
n.s.
|
Pneumonia
|
2 (8%)
|
1 (17%)
|
1 (5%)
|
n.s.
|
LC
|
2 (8%)
|
0 (0%)
|
2 (11%)
|
n.s.
|
Bronchiectasis
|
1 (4%)
|
0 (0%)
|
1 (5%)
|
n.s.
|
Middle lobe syndrome
|
1 (4%)
|
0 (0%)
|
1 (5%)
|
n.s.
|
Laboratory data at diagnosis
|
|
|
|
|
Absolute eosinophil count (cells/μl),
median (IQR)
|
1540 (880–2330)
|
2385 (1663–2733)
|
1240 (560–1700)
|
n.s.
|
IgE (IU/ml), median (IQR)
|
2802 (1330–5182)
|
3010 (1131–4227)
|
2802 (1809–5182)
|
n.s.
|
Aspergillus-specific IgE (IU/ml),
median (IQR)
|
20.7 (7.0–33.4)
|
25.8 (8.6–31.5)
|
20.6 (1.7–33.7)
|
n.s.
|
Aspergillus-specific precipitating
antibodies or IgG
|
16 (64%)
|
6 (100%)
|
10 (53%)
|
p=0.0664
|
Fungal culture, beta-D glucan
|
|
|
|
|
Sputum or bronchial wash positive
|
11 (44%)
|
1 (17%)
|
10 (53%)
|
n.s.
|
sputum; wash; sputum & wash
|
4; 3;4
|
1; 0; 0
|
3; 4; 3
|
|
Aspergillus fumigatus
|
8 (32%)
|
0 (0%)
|
8 (42%)
|
n.s.
|
Aspergillus niger
|
2 (8%)
|
1 (17%)
|
1 (5%)
|
n.s.
|
Aspergillus fumigatus & niger
|
1 (4%)
|
0 (0%)
|
1 (5%)
|
n.s.
|
beta-D glucan (pg/ml)
|
11.1 (5.3–16.6)
|
6.6 (5.2–9.3)
|
11.7 (6.7–18.4)
|
p=0.0398
|
Chest CT findings
|
|
|
|
|
Central bronchiectasis
|
22 (88%)
|
4 (67%)
|
18 (95%)
|
n.s.
|
Mucoid impaction
|
19 (76%)
|
0 (0%)
|
18 (95%)
|
p=0.0006
|
HAM
|
13 (52%)
|
0 (0%)
|
12 (63%)
|
p=0.0052
|
Tree in bud
|
12 (48%))
|
3 (50%)
|
9 (47%)
|
n.s.
|
Enlarged lymph nodes
|
12 (48%)
|
3 (50%)
|
9 (47%)
|
n.s.
|
Fibrosis
|
0 (0%)
|
0 (0%)
|
0 (0%)
|
n.s.
|
Peripheral consolidation
|
16 (64%)
|
6 (100%)
|
10 (53%)
|
p=0.0571
|
Ground grass opacities
|
16 (64%)
|
6 100%)
|
10 (53%)
|
p=0.0571
|
Pulmonary function test
|
|
|
|
|
FEV1, L, median (IQR)
|
1.74 (1.46–2.25)
|
1.60 (1.27–2.35)
|
1.82 (1.48–2.25)
|
n.s.
|
FEV1, %, predicted, median (IQR)
|
82.6 (72.0–91.8)
|
73.3 (65.9–81.1)
|
85.8 (74.7–89.4)
|
|
Data are expressed as median and interquartile range (IQR) and categorical data are presented as number and percentage.
p values between the EP group and Non-EP group are shown. n.s., not significant.
All patients showed peripheral eosinophilia (median, 1540 cells/µl), elevated level of IgE (median, 2802 IU/ml) and positive reactions for Aspergillus-specific IgE (median, 20.7 IU/ml; IQR, 0.9–81.2 IU/ml). In addition, 64% of patients had a positive reaction for Aspergillus-specific antibodies, mainly representing IgG. Sputum culture was obtained in all 25 patients and cultures of bronchial wash obtained by bronchoscopy were available in 20 patients. Aspergillus spp. were identified in 44% of all patients: in sputum in 32%, bronchial wash in 35%, and both in 16%. A. fumigatus alone was cultured most commonly, in 32% of patients, followed by A. niger in 8%, and both A. fumigatus and A. niger in 4%.
The most common HRCT findings were central bronchiectasis (88%) and mucoid impaction (77%), with HAM found in 13 cases (52%). FEV1/FVC% was < 70% in 22% and most patients showed no evidence of any obstructive disorder.
<table >
Comparison between the EP and Non-EP groups
The baseline characteristics of the two groups (Table 1) did not differ significantly in terms of age at onset of ABPA, ratio of females, or duration between onset of asthma and onset of ABPA. A history of CEP was present in 50% of the EP group and 26% of the Non-EP group. With respect to tentative diagnoses, CEP was diagnosed in 67% of the EP group and in 16% of the non-EP group, whereas ABPA was present in 32% of the non-EP group and completely absent in the EP group. Median eosinophil count and IgE and Aspergillus-specific IgE titers at diagnosis tended to be higher in the EP group and positive reaction rates for Aspergillus-specific antibody also tended to be higher in the EP group (100% vs. 53%, p = 0.0664). Levels of beta-D-glucan, a fungal marker, were significantly higher in the Non-EP group (median, 11.7 pg/ml; IQR, 6.7–18.4 pg/ml) than in the EP group (median, 6.6 pg/ml; IQR, 5.2–9.3 pg/ml), but there was no significant difference in positive culture rates for fungi between the groups. These results indicate that the Non-EP group had a stronger relationship with fungal infection than did the EP group. On HRCT, the Non-EP group showed significantly higher rates of mucous changes in the bronchus, such as mucoid impaction (89% vs. 33%, p = 0.0006) and HAM (63% vs. 0%, p = 0.0052), compared with the EP group. In contrast, p-consolidation and GGO in HRCT were present in all patients in the EP group and in only 53% of the Non-EP group (p = 0.0571). Central bronchiectasis, lymph node swelling, tree-in-bud sign, and GGO were found at similar frequencies in both groups. On chest CT, the EP group had imaging findings of peripheral-dominant lung changes, whereas the Non-EP group showed changes mainly in bronchial regions.
Most patients in the EP group had received oral corticosteroids (5/6, 83%) and only 1 patient had received anti-fungal therapy (for positive A. niger culture), whereas most patients in the Non-EP group had received anti-fungal therapy (16/19, 84%). The median duration of follow-up for all patients was 4.6 years (IQR, 2.8–7.7 years). Both the EP and Non-EP groups experienced frequent exacerbations of shadows on X-rays or CT and all patients in both groups showed an appearance at recurrence similar to that on previous CT (Table 2)
Table 2
Comparison of characteristics and laboratory data at recurrence between the EP and Non-EP groups
Characteristic | EP group (n = 6) | Non-EP group (n = 19) | |
Recurrence | 4 (67%) | 15 (78%) | n.s. |
Therapy | | | |
Oral corticosteroids | 5 (83%) | 13/19 (68%) | n.s. |
Anti-fungal drugs | 1 (17%) | 16/19 (84%) | 0.0055 |
Duration (months) before recurrence, median (IQR) | 22.5 (20.5–22.9) | 20.5 (13.8–34.8) | n.s. |
Total follow-up period (years), median (IQR) Number of recurrences Number of recurrences Number of recurrences median (IQR) | 4.0 (2.6–7.7) | 4.6 (3.1–8.3) | n.s. |
Recurrence rate / y, median (IQR) | 0.23 (0.10–0.41) | 0.38 (0.14–0.67) | n.s. |
Phenotype at recurrence | EP: 4/4 (100%) | Non-EP: 16/16 (100%) | 0.0002 |
Data are expressed as median and interquartile range (IQR) and categorical data are presented as number and percentage. |
n.s., not significant. |
Relationship between peripheral eosinophil count and Aspergillus-specific IgE in EP and Non-EP groups
The relationships of peripheral eosinophils to Aspergillus-specific IgE were examined in both groups (Fig. 2). The EP group showed no significant correlation between the two (r = − 0.49, p = 0.3188), possibly due to the small sample size, whereas the Non-EP group displayed a strong positive correlation (r = − 0.7878, p = 0.0003). No significant correlation was seen between number of bronchial segments affected on HRCT and peripheral eosinophil count, total IgE, or Aspergillus-specific IgE in both groups (data not shown). Twelve patients in the Non-EP group showed HAM on HRCT, but no correlations were identified between the CT values of HAM and the blood data (eosinophil count, IgE, or Aspergillus-specific IgE) (data not shown).
Results of serial CT in two cases with antifungal treatment in the EP group
Here, we describe two representative cases illustrating the typical course and HRCT findings in the EP group (Fig. 3). Case 1: A 60-year-old woman with a history of infantile asthma. Her asthma control had been poor from the age of 57 years, and she experienced exacerbations needing oral corticosteroids about 5 times a year. In 201X, she was admitted to our hospital for further examination of eosinophilia (3680/µl) and abnormal shadows on chest X-ray. HRCT of the chest revealed bilateral peripheral-dominant infiltrative shadows with GGO, predominantly in the upper lobes (Fig. 3a). We administered systemic corticosteroid (prednisolone, 30 mg/day) under a presumptive diagnosis of eosinophilic pneumonia, and the abnormal shadows promptly disappeared. After treatment with oral corticosteroid (OCS), the diagnosis was changed to ABPA based on a positive reaction for Aspergillus-specific IgE (4.9 UA/ml), Aspergillus-specific antibodies evaluated by precipitating antibodies, and fulfillment of the ISHAM criteria. Two years later, abnormal shadows in the right lower lobe appeared after she injured herself in a fall (Fig. 3b). We initially treated her with OCS (prednisolone, 20 mg/day), but diabetic control worsened, and she was therefore switched to itraconazole. Antifungal treatment proved effective and mean morning peak flow increased from 280 L/min to 320 L/min, which was her personal best. Case 2: A 25-year-old man with atopic dermatitis. In 201X, the patient was admitted to our hospital with a productive cough that had appeared 2 months prior. He had been diagnosed with BA by a previous doctor and had received OCS for 1 week, but symptoms had continued and laboratory data showed marked eosinophilia. HRCT showed mild central bronchiectasis, tree-in-bud sign, GGO, and p-consolidation (Fig. 3c). A. niger was detected in cultures of sputum and bronchial wash from left B5, and eosinophils were elevated to 61% in bronchial alveolar lavage fluid from left B5. Based on these data, ABPA was diagnosed and treatment with OCS (0.5 mg/kg/day) and itraconazole (200 mg/day) was initiated. His symptoms and the abnormal shadows on chest XP improved steadily.