Medical Mycology November 2013, 51, 811–817

Clinical characteristics and treatment outcomes

of chronic pulmonary aspergillosis
BYUNG WOO JHUN1, KYEONGMAN JEON1, JUNG SEOP EOM, JI HYUN LEE, GEE YOUNG SUH,
O JUNG KWON & WON-JUNG KOH
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University
School of Medicine, Seoul, Korea

Chronic pulmonary aspergillosis (CPA) is a relatively uncommon disease that has

been poorly characterized. This study investigated the clinical features and treatment
outcomes of CPA through a retrospective review of records of patients with newly
diagnosed CPA between January 2008 and January 2012. A total of 70 CPA patients,
which included 51 (73%) males, had a median age of 55 years. Fifty-seven patients
(81%) had a history of pulmonary tuberculosis and pulmonary disease caused by non-
tuberculous mycobacteria (NTM) was a primary underlying condition in 32 patients
(46%). Most patients (n ⫽ 66; 99%) were treated with oral itraconazole, for a median of
6.4 months. Treatment response of 73% of patients was based on alleviation of symp-
toms and in 44% on computed tomography. Laboratory tests improved for more than
60% of patients and overall favorable responses were achieved in 44 patients (62%).
Five of the latter (11%) had to restart antifungal therapy after a median of 9.2 months
after therapy. Death occurred in 10 patients (14%). This study suggested that NTM lung
disease was an important risk factor for CPA development. While treatment with oral
itraconazole for approximately 6 months was moderately effective in treating CPA, a
more effective treatment is required.
Keywords aspergillosis, nontuberculous mycobacteria, itraconazole, treatment
outcome

Introduction differences between CNPA (previously known as sub-

acute invasive pulmonary aspergillosis) and CCPA are the
Pulmonary aspergillosis can be categorized as invasive,
prolonged time frame and genetic predisposition of
chronic, or allergic (i.e., allergic bronchopulmonary asper-
defects in innate immunity in CCPA patients [2]. Some
gillosis) according to the recent guidelines from the Infec-
authors distinguish chronic fibrosing pulmonary aspergil-
tious Diseases Society of America (IDSA) [1]. Chronic
losis (CFPA) from CCPA [3]. Since distinction between
forms of pulmonary aspergillosis consist of simple aspergil-
these subtypes is difficult, many investigators describe
loma, chronic cavitary pulmonary aspergillosis (CCPA), and
CCPA, CFPA, and CNPA as chronic pulmonary aspergil-
chronic necrotizing pulmonary aspergillosis (CNPA) [1].
losis (CPA) [4–7].
CCPA is defined as multiple cavities with or without
CPA is a relatively uncommon disease that has been
aspergilloma in association with pulmonary and systemic
poorly characterized and as a result the clinical character-
symptoms and an increase in inflammatory markers. The
istics of patients remain unclear. Although it causes con-
siderable morbidity and mortality, the optimal therapeutic
Received 23 January 2013; Received in final revised form 5 April 2013; regimen and treatment duration for CPA have not been
Accepted 14 May 2013
established. Since 43 cases of CPA were diagnosed between
1These authors contributed equally to this paper. 1995 and 2007 at our institution [8], we conducted a
Correspondence: Won-Jung Koh, Division of Pulmonary and Critical
Care Medicine, Department of Medicine, Samsung Medical Center,
retrospective cohort study of patients recently diagnosed
Sungkyunkwan University School of Medicine, Seoul, Korea. Tel: ⫹82 with CPA to investigate the clinical characteristics and
(2) 3410 3429; Fax: ⫹ 82 (2) 3410 3849; E-mail: wjkoh@skku.edu treatment outcomes.
© 2013 ISHAM DOI: 10.3109/13693786.2013.806826

Downloaded from https://academic.oup.com/mmy/article-abstract/51/8/811/999366

by guest
on 19 February 2018
 812 Jhun et al.

Methods Samsung Medical Center approved the study protocol.

Patients
We reviewed the medical records of all patients with
positive serum Aspergillus precipitating antibodies or
Aspergillus species isolated from respiratory samples
between January 2008 and January 2012 at the Samsung
Medical Center, a 1961-bed referral hospital in Seoul,
South Korea.
CPA diagnosis was definite when it was associated
with the following: (i) compatible clinical symptoms, (ii)
compatible chest imagery findings, and (iii) a positive
serum Aspergillus precipitin test (Aspergillus fumigatus
IgG ELISA kit; IBL International, Hamburg, Germany) or
isolation of an Aspergillus species from a respiratory
sample (i.e., sputum, transtracheal aspirate, or bronchial
aspiration fluid) (Table 1) [8–11]. The presence of serum
Aspergillus galactomannan antigen was assessed using
Platelia Aspergillus antigen kit (Bio-Rad, Hercules, CA,
USA). Not all patients were tested for serum Aspergillus
antigen, due to the fact that the clinical usefulness of this
test is controversial in patients with non-invasive forms of
aspergillosis [12].
Informed consent was waived because of the retrospective
nature of the study.
Treatment outcomes and survival
Clinical improvement was defined as the disappearance of
more than half of the symptoms noted at the initial evalu-
ation and during follow-up visits. Radiological improve-
ment was defined as the partial or complete disappearance
of findings thought at first to be associated with CPA,
although abnormalities related to the lung disease that con-
tributed to CPA development could persist [8]. Favorable
response was defined as symptomatic improvement with
radiologic improvement or symptomatic improvement
despite no definite radiologic alterations after completion
of at least 6 months of antifungal therapy. Unfavorable
response was defined as worsening or no symptomatic
improvement regardless of radiologic change or treatment
duration, or discontinuation of antifungal therapy for any
other reason prior to 6 months.
Statistical analysis

Patient management and data collection
In Korea, voriconazole has not been approved for the ini-
tial treatment of CPA, patients were initially treated with
oral itraconazole (200 mg twice a day, itraconazole cap-
sule, Janssen Korea Ltd, Seoul, Korea) for at least 6
months. After treatment, laboratory examinations includ-
ing white blood cell (WBC) count, erythrocyte sedimen-
tation rate (ESR), and C-reactive protein (CRP), as well
as chest computed tomography (CT). In vitro drug
susceptibility tests of itraconazole against Aspergillus
isolates and measurement of blood levels of antifungal
agents were not performed.
Data were collected, in an anonymous manner, on
standardized forms, with follow-up data was last obtained
on 30 August 2012. The Institutional Review Board at
All data are presented as medians and interquartile ranges
(IQR) for continuous variables and as numbers (percent-
ages) for categorical variables. The data were compared
using the Mann-Whitney U test for continuous variables and
a Chi-squared or Fisher’s exact test for categorical variables.
All statistical analyses were performed using PASW 20.0
(SPSS Inc., Chicago, IL, USA) and a two-sided P ⬍ 0.05
was considered to indicate statistical significance.
Results
Patient characteristics
A total of 119 patients with clinically suspected pulmo-
nary aspergillosis who had positive precipitating serum
Aspergillus antibodies or Aspergillus species isolated from

Table 1 Diagnostic criteria for chronic pulmonary aspergillosis*.

Diagnostic
criteria Characteristics

Clinical • Chronic pulmonary or systemic symptoms (⬎ 3 months), including at least one of weight loss, productive cough, or hemoptysis;
• No overt immunocompromising conditions (e.g., hematological malignancy, neutropenia, organ transplantation);
• No dissemination.
Radiological • Cavitary pulmonary lesion with evidence of paracavitary infiltrates;
• New cavity formation or expansion of cavity size over time.
Laboratory • Elevated levels of inflammatory markers (C-reactive protein or erythrocyte sedimentation rate);
• Either a positive serum Aspergillus precipitin test or isolation of Aspergillus spp. from the pulmonary or pleural cavity.
*Modified from the references [9,10].

© 2013 ISHAM, Medical Mycology, 51, 811–817

Downloaded from https://academic.oup.com/mmy/article-abstract/51/8/811/999366

by guest
on 19 February 2018
 Chronic pulmonary aspergillosis 813

respiratory samples were identified during the study (NTM) was the primary underlying condition in 32 patients
period. A total of 49 patients with simple aspergilloma (46%), 17 had an earlier history of NTM lung disease and
(n ⫽ 29), allergic bronchopulmonary aspergillosis (n ⫽ 8), 15 had concurrent active NTM infections. Twenty-four
limited clinical data (n ⫽ 8), and immunocompromised (75%) of these also had a history of tuberculosis.
status (n ⫽ 4), who had hematologic malignancies, recent The majority (n ⫽ 28) of CPA patients with NTM lung
chemotherapy, and liver transplantations were excluded diseases had the upper lobe cavitary form, while four had
from the investigation. Consequentially, 70 patients with the nodular bronchiectatic form of the NTM lung disease.
newly diagnosed CPA were the basis of this study. The most common etiologic agent were members of the
Clinical characteristics of the study patients are shown Mycobacterium avium-intracellulare complex (n ⫽ 18),
in Table 2, which indicated that the median age was followed by M. abscessus-massiliense complex (n ⫽ 9),
55 years (IQR, 46–68 years), 51 (73%) were males, 45 M. kansasii (n ⫽ 4), and M. xenopi (n ⫽ 1).
(64%) were current or ex-smokers and the median body Other underlying lung conditions included chronic
mass index (BMI) was 18.0 kg/m2 (IQR, 16.0–19.6 kg/m2). obstructive pulmonary disease (COPD) (n ⫽ 35; 50%),
All patients presented with chronic pulmonary or systemic bronchiectasis (n ⫽ 18; 26%), previous thoracic surgery
symptoms, such as purulent sputum (n ⫽ 65, 93%), cough (n ⫽ 13; 19%), and a history of pneumothorax (n ⫽ 10;
(n ⫽ 63, 90%), hemoptysis (n ⫽ 30, 43%) and weight loss 14%). Only a small percentage of patients had underlying
(n ⫽ 16, 23%). The median duration of symptoms prior to systemic diseases which did not require immunosuppres-
diagnosis was 4 months (IQR, 3–6 months). sive agents or corticosteroids.
All patients had at least one underlying lung disease,
with tuberculosis being the most common (n ⫽ 57, 81%).
Chest CT findings
Pulmonary disease caused by nontuberculous mycobacteria
Chest CT findings in patients with CPA are shown in
Table 2 Clinical patients’ characteristics.
Table 3. One or more pulmonary cavities with paracavitary
infiltrates, including pleural thickening (n ⫽ 70, 100%) or
Characteristics Value
parenchymal infiltrate (n ⫽ 67, 96%) were the most com-
Age (years) 55 (46–68) mon CT abnormalities. The most common location of
Sex (male) 51 (73) cavitary lesions was the right upper lobe (n ⫽ 31, 44%).
Current or ex-smoker 45 (64) The median size of cavities was 48.5 mm (IQR, 39.0–
Body mass index (kg/m2) 18.0 (16.0–19.6)
FEV1 (%) 56 (44–79) 61.5 mm) and mycetomas were observed inside the cavi-
Underlying lung disease 70 (100) tary lesions in 25 patients (36%).
Previous tuberculosis 57 (81)
COPD 35 (50)
NTM lung disease 32 (46) Laboratory findings
Bronchiectasis 18 (26)
Previous thoracic surgery 13 (19) The results of laboratory tests for inflammatory markers
History of pneumothorax 10 (14) and microbiological studies for Aspergillus are shown
Bronchopleural fistula 9 (13)
Empyema 2 (3)
in Table 4. Levels of inflammatory markers such as CRP
Previous thoracic malignancy 1 (1)
Underlying systemic disease 21 (30)
Viral hepatitis 7 (10) Table 3 Chest computed tomography findings.
Heart failure 7 (10) Findings
Previous extrathoracic malignancy 6 (9)
Diabetes mellitus 5 (7) Cavity (or cavities) number
Chronic renal failure 3 (4) 1 60 (86)
Ankylosing spondylitis 2 (3) ⱖ2 10 (14)
Ulcerative colitis 1 (1) Location of cavity (or cavities)
Sjogren’s syndrome 1 (1) Right upper lobe 31 (44)
Chronic pulmonary or systemic symptoms Left upper lobe 30 (43)
Purulent sputum 65 (93) Both upper lobes 9 (13)
Cough 63 (90) Cavity size, mm 48.5 (39.0–61.5)
Hemoptysis 30 (43) Paracavitary infiltrates 70 (100)
Weight loss 16 (23) Pleural thickening 70 (100)
Duration of symptoms prior to diagnosis (months) 4 (3–6) Parenchymal infiltrate 67 (96)
Mycetoma 25 (36)
Data are shown as medians (interquartile range) or no. (%). Bronchiectasis 18 (26)
FEV1 (%), Forced expiratory volume in 1 second, percentage of Bronchopulmonary fistula 9 (13)
predicted value; COPD, Chronic obstructive pulmonary disease; NTM,
nontuberculous mycobacteria. Data are shown as medians (interquartile range) or no. (%).

© 2013 ISHAM, Medical Mycology, 51, 811–817

Downloaded from https://academic.oup.com/mmy/article-abstract/51/8/811/999366

by guest
on 19 February 2018
 814 Jhun et al.

Table 4 Laboratory findings in patients with chronic pulmonary Table 5 Responses to antifungal therapy and outcomes.
aspergillosis.
Characteristics
Laboratory tests
Medication
Inflammatory markers Itraconazole 69 (99)
White blood cell (μl) 7235 (5998–9943) Voriconazole 1 (1)
C-reactive protein (mg/dl) 2.4 (0.7–5.2) Duration of treatment (months) 6.4 (6.0–8.9)
Erythrocyte sedimentation rate (mm/h) 78 (42–103) Changes after treatment
Microbiological test Improvement in symptoms 51/70 (73)
Aspergillus antibody Improvement in CT findings 31/70 (44)
Positive 68/69 (99) Size of cavity 11/70 (16)
Negative 1/69 (1) Pleural thickening 20/70 (29)
Fungus culture Parenchymal infiltrate 26/70 (37)
Positive 18/68 (26) Mycetoma 1/70 (1)
Aspergillus fumigatus 13/68 (20) Improvement in laboratory test
A. flavus 3/68 (4) Decrease in CRP level 57/69 (83)
A. niger 1/68 (1) Decrease in ESR level 53/69 (77)
A. fumigatus ⫹ A. flavus 1/68 (1) Decrease in Aspergillus antibody titer 33/53 (62)
Negative 50/68 (74) Negative conversion of fungus culture 12/18 (67)
Aspergillus antigen Treatment outcomes
Positive 11/47 (23) Favorable response 44/70 (62)
Negative 36/47 (77) Unfavorable response 26/70 (38)
Adjunctive surgical resection 6/70 (9)
Data are shown as medians (interquartile range) or no. (%). Death 10/70 (14)
Median follow-up duration (months) 13.0 (9.3–21.0)

(normal range 0–0.3 mg/dl) or ESR (normal range
2–22 mm/h) were elevated in all study patients, with a
median of 2.4 mg/dl (IQR, 0.7–5.2 mg/dl) and 78 mm/h
(IQR, 42–103 mm/h), respectively, but only 17 (24%)
patients had a WBC count greater than 10,000/μl. Serum
Aspergillus precipitin antibody test results were available
for 69 patients, 68 (99%) of whom had positive results.
Sputum fungal cultures results were available for 68
patients, 18 (26%) of which were positive, i.e., 13 were
positive for A. fumigatus, three for A. flavus, one for
A. niger, while samples from one patient positive for two
Aspergillus species. Serum Aspergillus galactomannan
antigen tests were positive (index value ⬎ 0.55) in 23% of
patients (11/47).
Antifungal therapy response and outcomes of patients
with CPA
Clinical, radiological, and laboratory responses to anti-
fungal treatment are summarized in Table 5. All but one
patient (n ⫽ 69; 99%) were treated with oral itraconazole
with the remaining patient was initially treated with oral
voriconazole. The median duration of treatment for all
patients was 6.4 (IQR, 6.0–8.9) months, which included
54 (77%) who received antifungal therapy for at least 6
months and the remaining 16 (23%) patients being treated
for than 6 months. Antibiotics against NTM, as well as
antifungal therapy were administered in 15 patients with
concurrent active NTM lung disease. Rifampin was the
drug of choice for 10 patients with M. avium-intracellu-
lare complex (n ⫽ 8), M. kansasii (n ⫽ 1), and M. xenopi
(n ⫽ 1) lung disease. Patients with lung infections caused
Data are shown as medians (interquartile range) or no. (%).
CT, computed tomography; CRP, C-reactive protein; ESR, erythrocyte
sedimentation rate.
by M. abscessus-massiliense complex were treated with
amikacin, cefoxitin, and clarithromycin without rifampin
[13,14]. Clarithromycin was administered with itracon-
azole in 14 patients with concurrent active NTM lung
disease.
As shown in Table 5, treatment response rates were 73%
based on alleviation of symptoms and 44% based on chest
CT findings (Fig. 1). Of the 69 patients whose blood tests
were available, CRP and ESR levels decreased in 57 (83%)
and 53 (77%) samples, respectively. Follow-up serum
Aspergillus precipitin antibody data were available for
53 patients and the results of fungal culture in cases of
47 patients. Serum Aspergillus precipitin antibody titers
decreased in 33 (62%) patients and fungal culture negative
conversion occurred in 12 (67%) of 18 patients who had
positive culture results prior to treatment.
Finally, a total of 44 (62%) patients had favorable
responses to antifungal treatment. However, five of these
patients (11%) relapsed with worsening of symptoms
after a median of 9.2 (IQR, 4.7–16.8) months causing
their retreatments with itraconazole. Of the remaining
26 patients (38%) who did not respond favorably to anti-
fungal treatment, 16 were prematurely taken off the anti-
fungal treatment due to adverse reaction (n ⫽ 7), death
(n ⫽ 5), and lack of follow-up (n ⫽ 4). In addition, there
was no change (n ⫽ 4) or worsening (n ⫽ 6) of symptoms
despite the fact that these 10 patients had been on
treatment for at least 6 months.
© 2013 ISHAM, Medical Mycology, 51, 811–817

Downloaded from https://academic.oup.com/mmy/article-abstract/51/8/811/999366

by guest
on 19 February 2018

Fig. 1 Chest computed tomography of a 47-year-old woman with
chronic pulmonary aspergillosis who was treated for Mycobacterium
kansasii. (A) CT image shows mycetoma inside cavitary lesions with
pleural thickening in the right upper lobe and cavitary lesions with pleural
thickening and parenchymal infiltrate in the left upper lobe. (B) CT image
obtained after 8 months of itraconazole treatment shows disappearance
of the mycetoma in the right upper lobe and improvement of pleural
thickening and parenchymal infiltrate in the left upper lobe.
Adjunctive surgical resection was performed to manage
massive hemoptysis in six patients (9%) at a median of
5 (IQR, 4.5–6.0) months after diagnosis which included
bronchial arterial embolizations prior to surgery. Pulmo-
nary resections included lobectomy (n ⫽ 2), segmentectomy
(n ⫽ 2), and completion pneumonectomy (n ⫽ 1). There
were no major complications associated with surgery.
Death occurred in 10 patients (14%) involving three in
the favorable response group and seven in the unfavorable
response group with their negative outcomes attributed to
respiratory failure. The median duration between diagnosis
of CPA and death of 10 patients were 12.4 (IQR, 2.5–17.0)
months.
Adverse reactions to antifungal therapy
Adverse reactions associated with antifungal agents were
observed and were primarily associated with gastrointesti-
nal problems such as nausea (n ⫽ 11; 16%), anorexia
© 2013 ISHAM, Medical Mycology, 51, 811–817
Downloaded from https://academic.oup.com/mmy/article-abstract/51/8/811/999366
by guest
on 19 February 2018
Chronic pulmonary aspergillosis 815
(n ⫽ 10; 14 %), and diarrhea (n ⫽ 8; 11%). Both hepato-
toxicity (a liver transaminase level of ⱖ 120 IU/L) and
generalized edema was observed in five (7%) patients.
A fatal adverse reaction with severe QT prolongation
was noted in one patient. Overall, seven patients discontin-
ued treatment as a result of their adverse reactions and
the median treatment duration of these individuals was
2.3 months (IQR, 1.7–3.3 months).
Comparisons between patients who had favorable or
unfavorable treatment responses
We additionally evaluated the differences in clinical, radio-
logic, and laboratory data and outcomes between CPA
patients in the favorable and unfavorable response groups
(Table 6). Patients with favorable responses were younger
(P ⫽ 0.009) and had lower initial ESR levels (P ⫽ 0.039)
compared with patients with unfavorable responses.
The proportion of co-morbidities such as NTM disease
(P ⫽ 0.041) and chronic renal failure (P ⫽ 0.047) were sig-
nificantly higher in patients with unfavorable responses.
However, there was no significant difference in symptoms
and radiologic findings between the two groups. Finally,
mortality in the unfavorable response group was high com-
pared with the favorable response group (P ⫽ 0.032).
Discussion
The objective of this retrospective study was to describe
the clinical characteristics and treatment responses to oral
itraconazole in CPA cases. We found that NTM lung dis-
ease, as well as pulmonary tuberculosis was the important
underlying condition of CPA and about two-thirds of
patients with CPA had a favorable response to itraconazole
treatment for approximately 6 months.
Although the optimal therapeutic regimen and treatment
duration have not been established, previous studies have
reported good responses to the use of itraconazole in the
treatment of CPA [15–20]. De Beule et al. reported
a marked improvement or cure in 66% of CNPA patients
treated with itraconazole [15]. In the series by Dupont,
14 CNPA patients were treated with itraconazole for
2–7 months of which seven were cured and six improved
significantly [16]. In the current study, we also observed
favorable responses to itraconazole treatment in approxi-
mately two-thirds of patients with CPA. Although responses
rates may differ based on the duration of the treatment, as
well as the definition of responsiveness, these results sup-
port current recommendations from IDSA that itraconazole
be used as an initial CPA treatment [1].
The most common underlying diseases that predisposed
patients to CPA included pulmonary tuberculosis and
chronic obstructive pulmonary disease [21]. However,
 816 Jhun et al.

Table 6 Comparisons of patients who showed favorable and unfavorable responses.

Favorable Unfavorable
Characteristics (n ⫽ 44) (n ⫽ 26) P-value

Age (years) 49 (39–65) 59 (53–70) 0.009

Sex (male) 34/44 (77) 17/26 (65) 0.280
Current or ex-smoker 27/44 (61) 18/26 (69) 0.507
Body mass index (kg/m2) 18.5 (16.6–19.7) 17.6 (15.4–20.0) 0.421
FEV1 (%) 56 (46–81) 55 (40–78) 0.465
Co-morbidity
Previous tuberculosis 36/44 (82) 21/26 (81) 0.913
COPD 20/44 (46) 21/26 (81) 0.322
NTM disease 16/44 (36) 16/26 (62) 0.041
Heart failure 3/44 (7) 4/26 (15) 0.411
Chronic renal failure 0/44 (0) 3/26 (12) 0.047
Laboratory finding
WBC (μl) 7140 (5835–9293) 8010 (6143–10883) 0.117
CRP (mg/dl) 2.3 (0.7–5.1) 2.5 (1.1–5.4) 0.572
ESR (mm/h) 75 (39–89) 89 (46–120) 0.039
Albumin level (g/dl) 4.0 (3.6–4.4) 3.9 (3.5–4.2) 0.289
Aspergillus antibody titer 117 (58–200) 114 (34–200)
Symptoms
Cough 38/44 (86) 25/26 (96) 0.246
Sputum 41/44 (93) 24/26 (92) 0.891
Hemoptysis 19/44 (43) 11/26 (42) 0.943
Weight loss 8/44 (18) 8/26 (31) 0.226
CT findings
Cavity size, mm 46.0 (36.0–62.9) 52.0 (41.3–61.5) 0.258
Pleural thickening 44/44 (100) 26/26 (100) NA
Parenchymal infiltrate 42/44 (96) 25/26 (96) 0.889
Mycetoma 19/44 (43) 6/26 (23) 0.090
Death 3/44 (7) 7/26 (27) 0.032

Data are shown as median (interquartile range) or no. (%).

COPD, chronic obstructive pulmonary disease; NTM, nontuberculous mycobacteria, CT, computed tomography;
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

concurrent active or prior NTM are considered important
underlying conditions [3,4,22]. In addition, patients with a
history of pulmonary infection caused by NTM may have
a higher rate of subsequent CPA compared to those with a
history of pulmonary tuberculosis [3]. In our study, 15
patients with CPA had concurrent active NTM lung dis-
ease, which suggested that Aspergillus and NTM can co-
infect. Since Aspergillus co-infection in patients with NTM
disease is important, early microbiological testing should
be considered in patients with progressively worsening
symptoms or low response to treatment of underlying lung
disease accompanying cavitary lesions. This early labora-
tory intervention would provide a rapid and precise diag-
nosis and could improve treatment outcomes.
There are some limitations to this study. First, it was
unclear whether these patients had culture-confirmed prior
pulmonary tuberculosis despite the fact this was reported
as the most common underlying lung disease. Patients with
acid-fast bacilli-positive sputum or those displaying chest
radiographic findings that suggested active tuberculosis
had generally been presumed to have pulmonary tubercu-
losis and were treated empirically with antituberculous
drugs [14,23]. Second, the definition of favorable response
was not particularly precise in our study. We could not offer
the objective parameters such as the improvement of BMI
in this retrospective study. In addition, attributing symptom
changes to CPA could not be accurately measured in
patients with concurrent NTM lung disease after antifungal
treatment, as well as anti-NTM therapy. Third, median
follow-up durations of 13 months may not be sufficient to
evaluate treatment outcomes. The relatively lower mortal-
ity rate of 14% in the current study (compared to data
reported previously) may have been influenced by the rel-
atively short-term follow-up. Therefore, long-term fol-
low-up studies of the prognosis of CPA patients who
received long-term antifungal therapy may be required.
Fourth, since this is a retrospective analysis, data pertaining
to follow-up laboratory tests were available, which may not
allow for accurate examination of the association between
microbiological response and antifungal therapy. Lastly,
since 15 patients had concurrent active NTM disease when
CPA was diagnosed, the treatment outcomes of CPA may
have been influenced by the progression or improvement
of the underlying pulmonary condition rather than antifungal
© 2013 ISHAM, Medical Mycology, 51, 811–817

Downloaded from https://academic.oup.com/mmy/article-abstract/51/8/811/999366

by guest
on 19 February 2018

therapy. Rifampin used in the combination antibiotic therapy
for NTM lung disease caused by M. avium-intracellulare
complex, M. kansasii, or M. xenopi in our patients [24] could
have led to undetectable levels of serum itraconazole in these
individuals [25]. These could have in turn contributed to
higher unfavorable treatment response in patients with con-
current NTM lung disease.
In conclusion, pulmonary tuberculosis and NTM lung
disease were the important underlying conditions of
CPA. Treatment with oral itraconazole for approximately
6 months was moderately effective in treating CPA;
however, development of a more effective treatment is
necessary. Thus, further evaluation in a prospective, ran-
domized controlled study is required.
Declaration of interest: The authors report no conflicts of
interest. The authors alone are responsible for the content
and the writing of the paper.
This work was supported by the Samsung Biomedical
Research Institute grant, #SBRI C-B1-101.
References
1 Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis:
clinical practice guidelines of the Infectious Diseases Society of
America. Clin Infect Dis 2008; 46: 327–360.
2 Vaid M, Kaur S, Sambatakou H, et al. Distinct alleles of mannose-
binding lectin (MBL) and surfactant proteins A (SP-A) in patients
with chronic cavitary pulmonary aspergillosis and allergic bronchop-
ulmonary aspergillosis. Clin Chem Lab Med 2007; 45: 183–186.
3 Smith NL, Denning DW. Underlying conditions in chronic pulmonary
aspergillosis including simple aspergilloma. Eur Respir J 2011; 37:
865–872.
4 Ohba H, Miwa S, Shirai M, et al. Clinical characteristics and prog-
nosis of chronic pulmonary aspergillosis. Respir Med 2012; 106:
724–729.
5 Izumikawa K, Yamamoto Y, Mihara T, et al. Bronchoalveolar lavage
galactomannan for the diagnosis of chronic pulmonary aspergillosis.
Med Mycol 2012; 50: 811–817.
6 Cadranel J, Philippe B, Hennequin C, et al. Voriconazole for chronic
pulmonary aspergillosis: a prospective multicenter trial. Eur J Clin
Microbiol Infect Dis 2012; 31: 3231–3239.
7 Camuset J, Nunes H, Dombret MC, et al. Treatment of chronic pul-
monary aspergillosis by voriconazole in nonimmunocompromised
patients. Chest 2007; 131: 1435–1441.
8 Nam HS, Jeon K, Um SW, et al. Clinical characteristics and treatment
outcomes of chronic necrotizing pulmonary aspergillosis: a review of
43 cases. Int J Inf Dis 2010; 14: e479–482.
This paper was first published online on Early Online on 8 July 2013.
© 2013 ISHAM, Medical Mycology, 51, 811–817
Downloaded from https://academic.oup.com/mmy/article-abstract/51/8/811/999366
by guest
on 19 February 2018
Chronic pulmonary aspergillosis 817
9 Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic
cavitary and fibrosing pulmonary and pleural aspergillosis: case
series, proposed nomenclature change, and review. Clin Inf Dis 2003;
37(Suppl. 3): S265–280.
10 Zmeili OS, Soubani AO. Pulmonary aspergillosis: a clinical update.
QJM 2007; 100: 317–334.
11 Kohno S, Masaoka T, Yamaguchi H, et al. A multicenter, open-
label clinical study of micafungin (FK463) in the treatment of
deep-seated mycosis in Japan. Scand J Infect Dis 2004; 36:
372–379.
12 Park SY, Lee SO, Choi SH, et al. Serum and bronchoalveolar lavage
fluid galactomannan assays in patients with pulmonary aspergilloma.
Clin Infect Dis 2011; 52: e149–152.
13 Jeon K, Kwon OJ, Lee NY, et al. Antibiotic treatment of Mycobacte-
rium abscessus lung disease: a retrospective analysis of 65 patients.
Am J Respir Crit Care Med 2009; 180: 896–902.
14 Koh WJ, Jeon K, Lee NY, et al. Clinical significance of differentiation
of Mycobacterium massiliense from Mycobacterium abscessus. Am J
Respir Crit Care Med 2011; 183: 405–410.
15 De Beule K, De Doncker P, Cauwenbergh G, et al. The treatment
of aspergillosis and aspergilloma with itraconazole, clinical results
of an open international study (1982–1987). Mycoses 1988; 31:
476–485.
16 Dupont B. Itraconazole therapy in aspergillosis: study in 49 patients.
J Am Acad Dermatol 1990; 23: 607–614.
17 Caras WE, Pluss JL. Chronic necrotizing pulmonary aspergillosis:
pathologic outcome after itraconazole therapy. Mayo Clin Proc 1996;
71: 25–30.
18 Elliott JA, Milne LJ, Cumming D. Chronic necrotising pulmo-
nary aspergillosis treated with itraconazole. Thorax 1989; 44:
820–821.
19 Campbell JH, Winter JH, Richardson MD, Shankland GS,
Banham SW. Treatment of pulmonary aspergilloma with itraconazole.
Thorax 1991; 46: 839–841.
20 Yoshida K, Kurashima A, Kamei K, et al. Efficacy and safety of short-
and long-term treatment of itraconazole on chronic necrotizing pul-
monary aspergillosis in multicenter study. J Inf Chemother 2012; 18:
378–385.
21 Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary
aspergillosis. Chest 2002; 121: 1988–1999.
22 Kobashi Y, Fukuda M, Yoshida K, et al. Chronic necrotizing pulmo-
nary aspergillosis as a complication of pulmonary Mycobacterium
avium complex disease. Respirology 2006; 11: 809–813.
23 Koh WJ, Yu CM, Suh GY, et al. Pulmonary TB and NTM lung
disease: comparison of characteristics in patients with AFB smear-
positive sputum. Int J Tuberc Lung Dis 2006; 10: 1001–1007.
24 Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/
IDSA statement: diagnosis, treatment, and prevention of nontubercu-
lous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175:
367–416.
25 Tucker RM, Denning DW, Hanson LH, et al. Interaction of azoles
with rifampin, phenytoin, and carbamazepine: in vitro and clinical
observations. Clin Infect Dis 1992; 14: 165–174.