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ORIGINAL ARTICLE
Clinical course and prognostic factors of pulmonary aspergilloma JUNG-KYU LEE,1 YEON JOO LEE,2 SUNG SOO PARK,3 JONG SUN PARK,2 YOUNG-JAE CHO,2 YOUNG SIK PARK,1 HO IL YOON,2 CHOON-TAEK LEE2 AND JAE HO LEE2 1 2
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, and 3Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
ABSTRACT Background and objective: There is limited data on size change during natural progression of pulmonary aspergilloma. We aimed at elucidating the clinical course and prognosis of aspergilloma according to its size change. Methods: A multicentre retrospective observational study was performed in 143 adult pulmonary aspergilloma patients with serial chest computed tomography images. The clinical course and risk of haemoptysis according to the size change of the cavity or mass of aspergillomas was evaluated. Results: Median follow-up duration was 5.1 years.The size of aspergillomas changed in 39.2% of study subjects. Decreased and increased volumes of aspergilloma were observed in 13.3% and 25.9%, respectively. Patients with decreased volume had significantly higher C-reactive protein, and more severe bronchiectasis and tuberculosis-destroyed lung.Clinically significant haemoptysis occurred in 50.3% of patients and was significantly associated with the cavity and mass volume of aspergilloma, but not the extent of volume change. A mean cavity diameter of more than 22 mm and a mass diameter of more than 18 mm increased the risk of clinically significant haemoptysis. Conclusions: A significant portion of pulmonary aspergilloma changed size in our population. The prevalence of clinically significant haemoptysis was associated with absolute size of cavity and mass of aspergilloma. Key words: haemoptysis, lung disease, fungal, mycetoma, pulmonary aspergillosis.
Abbreviations: ABPA, allergic bronchopulmonary aspergillosis; aOR, adjusted odds ratio; AUC, area under the ROC curve; BMI, body mass index; CI, confidence interval; CNPA, chronic necrotizing pulmonary aspergillosis; CRP, C-reactive protein;
Correspondence: Jae Ho Lee, Department of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 463-707, Korea. E-mail: [email protected] Received 9 November 2013; invited to revise 15 January and 7 March 2014; revised 17 February and 9 March 2014; accepted 4 May 2014 (Associate Editor: Marcos Restrepo). © 2014 Asian Pacific Society of Respirology
SUMMARY AT A GLANCE Pulmonary aspergillomas remain stable in the majority of cases, but some of them increase or decrease in size, and the minority of them resolve completely. There is a high prevalence of haemoptysis in pulmonary aspergilloma, associated with absolute size of aspergilloma and mass-containing cavity.
CT, computed tomography; FEV1, forced expiratory volume in 1 s; IPA, invasive pulmonary aspergillosis; IQR, interquartile range; OR, odds ratio; ROC, receiver operating characteristic; TB, tuberculosis.
INTRODUCTION Aspergillus is a filamentous fungi associated with a wide spectrum of pulmonary diseases. Over 200 species of Aspergillus exist in the environment; however, only a few, including Aspergillus fumigatus, Aspergillus flavus and Aspergillus niger, are known to be human pathogens. Pulmonary aspergillosis has various clinical presentations and causes a range of clinical syndrome, including aspergilloma, invasive pulmonary aspergillosis (IPA), chronic necrotizing pulmonary aspergillosis (CNPA) and allergic bronchopulmonary aspergillosis (ABPA).1 Among them, the most common form of pulmonary involvement by Aspergillus species is aspergilloma: a fungal ball, composed of fungal mycelia, inflammatory cells and tissue debris that colonizes a previously existing cavity within the lung.2 Consequently, aspergillomas are usually observed in patients with cavitary lung disease, and it is most frequently associated with tuberculosis (TB). The British Tuberculosis Association reported the presence of aspergilloma in 15% of persistent cavities larger than 2.5 cm in patients with TB.3 In general, patients with aspergillomas are asymptomatic. In the majority of cases the aspergilloma Respirology (2014) doi: 10.1111/resp.12344
2 remains stable, and there is no invasion of surrounding tissues or blood vessels by Aspergillus. Furthermore, in 10% of cases, the aspergilloma spontaneously resolves or decreases in size.4 Rarely the aspergilloma increases in size. However, haemoptysis is a commonly reported complication associated with aspergillomas. Although in most cases aspergillomarelated haemoptysis is mild, severe haemoptysis can occur in patients with TB,5 and the reported mortality rate for aspergilloma-associated haemoptysis ranges from 2% to 14%.6 The risk factors associated with a poor prognosis of aspergilloma include severe underlying lung disease, increases in the number or size of aspergilloma, immunosuppression, human immunodeficiency virus infection and underlying sarcoidosis. Previous studies have associated the changes in lesion size with the clinical characteristics and prognosis of aspergilloma,7 but few studies have reviewed the size changes of aspergilloma with respect to the risk of haemoptysis, which is one of the most important factors when considering a prognosis of aspergilloma.8 Therefore, this study aimed at elucidating the clinical course of pulmonary aspergilloma and the prevalence of haemoptysis according to changes in lesion size.
METHODS Study design and participants A multicenter retrospective observational study was performed at the Seoul National University Hospital, Bundang Hospital and Boramae Medical Center between January 1995 and December 2012. Adult patients with pulmonary aspergilloma confirmed radiologically by chest computed tomography (CT) were included in the study. Patients with invasive/ semi-invasive aspergillosis or with a history of medical interventions or diseases including chemotherapy, long-term or high-dose immunosuppressive therapy, haematological disease, prolonged neutropenia and acquired immune deficiency syndrome, in which aspergillosis could convert to invasive/ semi-invasive aspergillosis were excluded from the study. This study was approved by the Institutional Review Board of Seoul National University Hospital (IRB No.: H-1304-082-481), Bundang Hospital (IRB No: B-1304-198-107) and Boramae Medical Center (IRB No.: 01-2013-61), and was performed in accordance with the tenets of the Declaration of Helsinki. Analysis of patient data Medical records and CT images from patients were retrospectively analysed for changes in the size of the aspergilloma mass and mass-containing cavity, and the prevalence and predictive factors of haemoptysis. Clinically significant haemoptysis was defined as a haemoptysis requiring emergency room visit, admission, embolotherapy or surgery. Medical records were reviewed for the results of serial pulmonary function tests, comorbidities (including underlying lung Respirology (2014)
J-K Lee et al.
disease, diseases related to coagulopathy), prothrombin time, platelet count, and the use of antiplatelet agents or anticoagulants. For each patient, the Charlson comorbidity index9 was calculated. Mean diameters of aspergilloma mass and masscontaining cavity were calculated from serial chest CT scans using the horizontal/longitudinal diameters and height estimates of each mass and cavity. The area and volume of each mass and cavity were considered equal to an area of a circle and a volume of a sphere with this mean diameter. Patients were categorized into one of three groups, depending on the changes in aspergilloma size, as determined between the initial-to-last ratio of mass volume, as follows: the decreased group, the volume of the aspergilloma decreased by more than half; the increased group, the volume of the aspergilloma increased more than twofold; and the stable group, the aspergilloma volume did not increase by twofold or decrease by more than half. IPA, CNPA and ABPA were assessed by the diagnostic criteria suggested by Kousha et al.1 The severity of TB and bronchiectasis was estimated from initial chest CT scans and used to evaluate the risk of haemoptysis due to aspergilloma. TB-destroyed lung was defined as a parenchymal destruction due to the previous TB, with the involvement of more than one lobe. Total lung area was divided into six lobes because lingular segment was counted as a separate lobe, and TB-destroyed lung was scored by counting involved lobes.10 The extent of bronchiectasis was scored in each lobe as follows: grade 0, no involvement of bronchiectasis; grade 1, bronchiectatic less than 25% of bronchi; grade 2, bronchiectatic in 25–49%; grade 3, bronchiectatic in 50–75% of bronchi; and grade 4, bronchiectatic more than 75% of bronchi. A definition of ‘bronchiectatic’ bronchi was as follows: non-tapering bronchus with internal diameter greater than the adjacent pulmonary artery or the presence of visible bronchi within 1 cm of the costal pleural surface or adjacent to the mediastinal pleural surface. The total bronchiectasis score was the sum of bronchiectasis grade of each lobe.11 Emphysema score was estimated as suggested by Martinez-Garcia et al.12 as follows: grade 0, absence of emphysema; grade 1, centriacinar emphysema in 2 or less pulmonary lobes; grade 2, centriacinar emphysema in 3–4 lobes; and grade 3, centriacinar emphysema in more than 4 lobes, or bullous or panacinar emphysema.
Statistical analysis The data are presented as medians and interquartile ranges (IQR) for age and means and standard deviations for the other continuous variables, and as numbers (%) for categorical variables. The differences of clinical characteristics and size change of aspergilloma were analysed by Kruskal–Wallis test. Linear mixed regression was used to evaluate changes in lesion size and lung function over time. The association of annual haemoptysis frequency with the size of the cavity and the mass was evaluated by multivariate linear regression analysis. All statistical analysis was performed after adjustment for age, sex, body © 2014 Asian Pacific Society of Respirology
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Pulmonary aspergilloma clinical course Table 1
Baseline characteristics of study subjects
A. Demographics
Figure 1
Flow diagram of the study population.
mass index (BMI), forced expiratory volume in 1 s (FEV1), prothrombin time, platelet count, bronchiectasis score, TB-destroyed lung score and emphysema score. Receiver operating characteristic (ROC) curve and multivariate logistic regression were applied to variables to evaluate lesion size and haemoptysis. Odd ratios (OR) and adjusted OR (aOR) were presented with 95% confidence intervals (CI). Statistical significance was determined with a P-value of 0.05. Data were analysed using PASW Statistics, version 18 (IBM, Armonk, NY, USA).
RESULTS Baseline characteristics of the study population Retrospective analysis was performed on a total of 143 patient records (Fig. 1). Patients’ characteristics and clinical profiles of the study group are shown in Table 1. The median follow-up duration was 5.1 years (IQR 2.3, 8.8), while the mean results of pulmonary function test of the group showed normal ventilatory patterns. TB was the most prevalent disease (60.8%), followed by chronic obstructive pulmonary disease (13.3%). On the basis of the Charlson comorbidity indexes, the majority of the patients did not have severe underlying medical conditions. Colonization of potentially pathogenic microorganism was shown in 12 patients as follows: non-TB mycobacterium in seven patients, Acinetobacter baumannii in two, Pseudomonas aeruginosa in two and Klebsiella pneumoniae in one. Among patients with radiologically confirmed pulmonary aspergilloma, 29.4% of patients were additionally confirmed in laboratory and/or microbiological methods as culture of respiratory sample and tissue biopsy, Aspergillus antigen or Aspergillus antibody titre test. Aspergilloma and haemoptysis: clinical course The size of the aspergillomas and number of lesions was assessed on the initial and follow-up CT scans of each patient, and the aspergilloma size and number © 2014 Asian Pacific Society of Respirology
Total (N = 143)
Male, n (%) Age, years, median (Q1, Q3) Body mass index, kg/m2 History of smoking Never, n (%) Ex, n (%) Current, n (%) Unknown, n (%) Pack-years Initial pulmonary function test (n = 123) FEV1, L % predicted FVC, L % predicted FEV1/FVC, % Change of lung function (n = 76) Follow-up duration, years, median (Q1, Q3) FEV1 change, mL/year† FVC change, mL/year†
79 (55.2) 61 (56, 69) 21.8 ± 5.3 67 (46.9) 45 (31.5) 16 (11.2) 15 (10.5) 27.0 ± 18.4 2.03 ± 0.79 80.8 ± 30.9 2.81 ± 0.90 79.9 ± 23.9 72.1 ± 15.7 3.7 (2, 6.2) −38.1 ± 3.9 −19.2 ± 8.9
B. Comorbidities and laboratory findings Total (N = 143) Charlson comorbidity index Respiratory disease, n (%) Tuberculosis Chronic obstructive pulmonary disease Non-tuberculosis Mycobacterium disease Interstitial lung disease Lung cancer Previous thoracic surgery Other disease, n (%)\ Diabetes mellitus Chronic liver disease Connective tissue disease Positive culture of Aspergillus species, n (%) Respiratory specimen Tissue Colonization of potentially pathogenic microorganism, n (%) Positive Aspergillus antigen test, n (%) Positive antigen titre Positive Aspergillus immunoglobulin G, n (%) Immunoglobulin G titre Aspergilloma confirmed by microbiological and/or labratory tests, n (%)
0.74 ± 1.27 87 (60.8) 19 (13.3) 6 (4.2) 2 (1.4) 2 (1.4) 7 (4.9) 18 (12.6) 3 (2.1) 2 (1.4)
13 (9.1) 31 (21.7) 12 (8.4) 10 (7.0) 0.71 ± 0.81 2 (1.4) 1.26 ± 0.09 42 (29.4)
†
Adjusted by age, sex and height. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity.
of lesions for each patient were compared (Table 2). Mean frequency of follow-up CT scan was 1.9 ± 1.0 times, and median interval time between the initial and follow-up CT was 2 years (IQR 0.92, 4.42). In 39.2% of patients the size of aspergilloma changed, while decreased aspergilloma volume was observed in 13.3% of patients, and increased aspergilloma Respirology (2014)
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J-K Lee et al.
Table 2 Clinical course of aspergilloma: radiologic findings and history of haemoptysis Total (N = 143) Follow-up duration, years, median (Q1, Q3) Volume change of mass, n (%) Stable Decreased Increased Conversion to invasive/semi-invasive form, n (%) Chronic necrotizing pulmonary aspergillosis, n (%) Bronchiectasis, n (%) Bronchiectasis score TB-destroyed lung, n (%) TB-destroyed lung score Emphysema, n (%) Emphysema score Clinically significant haemoptysis, n (%) Emergency room visit Admission Embolization Surgery Annual frequency of clinically significant haemoptysis Anticoagulation, n (%) Antiplatelet therapy, n (%)
5.1 (2.3, 8.8)
87 (60.8) 19 (13.3) 37 (25.9) 6 (4.2) 6 (100) 100 (69.9) 4.1 ± 5.0 56 (39.2) 0.8 ± 1.2 46 (32.2) 0.8 ± 1.3 72 (50.3) 52 (36.4) 66 (46.2) 50 (35.0) 30 (21.0) 0.49 ± 1.0 1 (0.7) 6 (4.2)
TB, tuberculosis.
volume was observed in 25.9% of patients. A complete resolution of the mass was observed in eight patients (5.6%). Although haematoma and inflammatory changes immediately after haemoptysis might mimic pulmonary aspergillomas in the radiological evaluation, aspergillomas may change in size over a long period unlike haematoma or inflammatory changes. So, we confirmed that pulmonary aspergillomas showed statistically significant size change over time in increased and decreased groups by using longitudinal changes of mass volume with linear mixed regression, and it suggested that mass changes in size were not short-term changes due to haematoma or inflammatory changes. Conversion to invasive or semi-invasive forms of pulmonary aspergillosis developed in 4.2% of patients, and all converted forms were CNPA. Clinically significant haemoptysis was apparent in 50.3% of study subjects (72 patients), and 21% (30 patients) required surgical resection owing to repetitive or uncontrolled haemoptysis.
Haemoptysis and aspergilloma size changes Next, we assessed and compared the clinical characteristics of the three groups (Table 3). Interestingly, the stable group had fewer male subjects (stable 46% vs decreased 73.7% vs increased 67.6%; P = 0.020) and a higher BMI (stable 22.3 ± 4.2 vs decreased 19.7 ± 3.6 Respirology (2014)
vs increased 21.8 ± 7.7; P = 0.029). The decreased volume group had a significantly lower initial FEV1 (decreased 1.47 ± 0.75 vs stable 2.03 ± 0.78 vs increased 2.32 ± 0.71; P = 0.001), higher C-reactive protein (CRP) (decreased 0.69 ± 0.74 vs stable 0.31 ± 0.38 vs increased 0.34 ± 0.68; P = 0.040), more severe bronchiectasis and TB-destroyed lung and a higher proportion of emphysema. The longitudinal declines of FEV1 over time did not differ significantly between the groups. The initial-to-last cavity volume ratio as well as the initial-to-last mass volume ratio, representative of the change in aspergilloma volume and mass, differed significantly between groups. There was not a significant difference in the proportion of patients with any history of clinically significant haemoptysis and the annual frequency of clinically significant haemoptysis between groups.
Annual haemoptysis and aspergilloma Next, we evaluated whether there was any association between the prevalence of haemoptysis with the size or the change in size of the aspergilloma cavity or mass (Table 4). Multivariate analysis was performed, and the extent of volume change was additionally adjusted in analysis of volume and diameter in baseline CT. Initial-to-last ratios of volume of cavity and mass did not show any significant associations with clinically significant haemoptysis, either by univariate or multivariate analysis. However, the volume and mean diameter of aspergilloma-containing cavities and masses measured in the initial CT images were significantly associated with the annual frequency of clinically significant haemoptysis. This result was consistent in the multivariate analysis. Aspergilloma size associates with haemoptysis Using ROC curve analysis, we evaluated whether the mean diameter of cavity or mass in the initial CT image could be used to predict the development of clinically significant haemoptysis. The area under the ROC curve (AUC) of mean cavity diameter was 0.716 (P < 0.001), and a mean cavity diameter of more than 22.5 mm had a sensitivity of 68.1% and specificity of 69.0% to predict the development of clinically significant haemoptysis (Fig. 2). The AUC of mean mass diameter was 0.638 (P = 0.005), and a mean mass diameter of more than 18.2 mm had a sensitivity of 61.1% and specificity of 66.2%. Following this we assessed the risk of haemoptysis according to these cut-off values (Table 5). A mean cavity diameter of more than 22 mm and a mass diameter of more than 18 mm are associated with an increased risk of clinically significant haemoptysis by 3.92-fold and 2.89-fold, respectively (cavity diameter, aOR 3.40, 95% CI: 1.36–8.52; mass diameter, aOR 3.53, 95% CI: 1.44–8.61).
DISCUSSION In our study, pulmonary aspergilloma remained stable in the majority of cases. In 13.3% of cases, the © 2014 Asian Pacific Society of Respirology
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Pulmonary aspergilloma clinical course Table 3 Clinical characteristics according to the size change of pulmonary aspergilloma
Male, n (%) Age, years Body mass index, kg/m2 Initial FEV1, L FEV1 change, mL/year† CRP, mg/L Charlson comorbidity index Bronchiectasis, n (%) Bronchiectasis score TB-destroyed lung, n (%) TB-destroyed lung score Emphysema, n (%) Emphysema score Initial-to-last ratio of cavity volume (%) Initial-to-last ratio of mass volume (%) Clinically significant haemoptysis, n (%) Clinically significant haemoptysis per year Conversion to invasive/semi-invasive form, n (%)
Decreased (n = 19)
Stable (n = 87)
Increased (n = 37)
P-value
14 (73.7) 63.3 ± 12.9 19.7 ± 3.6 1.47 ± 0.75 −38.7 ± 8.1 0.69 ± 0.74 1.3 ± 2.3 17 (89.5) 8.8 ± 5.3 13 (68.4) 2.5 ± 0.9 12 (63.2) 2.7 ± 0.8 84.0 ± 56.8 17.8 ± 17.6 12 (63.2) 0.36 ± 0.85 0 (0)
40 (46) 61.5 ± 10.9 22.3 ± 4.2 2.03 ± 0.78 −30.2 ± 5.2 0.31 ± 0.38 0.7 ± 1.0 57 (65.5) 5.3 ± 5.1 28 (32.2) 2.0 ± 1.1 23 (26.4) 2.4 ± 0.9 126.7 ± 94.7 115.2 ± 37.3 38 (43.7) 0.48 ± 1.06 3 (3.4)
25 (67.6) 61.8 ± 13.3 21.8 ± 7.7 2.32 ± 0.71 −56.4 ± 11.7 0.34 ± 0.68 0.6 ± 1.0 26 (70.3) 5.0 ± 3.9 15 (40.5) 1.5 ± 0.6 11 (29.7) 2.5 ± 0.8 321.9 ± 277.1 1075.8 ± 1645.7 22 (59.5) 0.57 ± 0.94 3 (8.1)
0.020 0.878 0.029 0.001 0.070 0.040 0.285 0.121 0.022 0.014 0.017 0.008 0.708
ORIGINAL ARTICLE
Clinical course and prognostic factors of pulmonary aspergilloma JUNG-KYU LEE,1 YEON JOO LEE,2 SUNG SOO PARK,3 JONG SUN PARK,2 YOUNG-JAE CHO,2 YOUNG SIK PARK,1 HO IL YOON,2 CHOON-TAEK LEE2 AND JAE HO LEE2 1 2
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, and 3Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
ABSTRACT Background and objective: There is limited data on size change during natural progression of pulmonary aspergilloma. We aimed at elucidating the clinical course and prognosis of aspergilloma according to its size change. Methods: A multicentre retrospective observational study was performed in 143 adult pulmonary aspergilloma patients with serial chest computed tomography images. The clinical course and risk of haemoptysis according to the size change of the cavity or mass of aspergillomas was evaluated. Results: Median follow-up duration was 5.1 years.The size of aspergillomas changed in 39.2% of study subjects. Decreased and increased volumes of aspergilloma were observed in 13.3% and 25.9%, respectively. Patients with decreased volume had significantly higher C-reactive protein, and more severe bronchiectasis and tuberculosis-destroyed lung.Clinically significant haemoptysis occurred in 50.3% of patients and was significantly associated with the cavity and mass volume of aspergilloma, but not the extent of volume change. A mean cavity diameter of more than 22 mm and a mass diameter of more than 18 mm increased the risk of clinically significant haemoptysis. Conclusions: A significant portion of pulmonary aspergilloma changed size in our population. The prevalence of clinically significant haemoptysis was associated with absolute size of cavity and mass of aspergilloma. Key words: haemoptysis, lung disease, fungal, mycetoma, pulmonary aspergillosis.
Abbreviations: ABPA, allergic bronchopulmonary aspergillosis; aOR, adjusted odds ratio; AUC, area under the ROC curve; BMI, body mass index; CI, confidence interval; CNPA, chronic necrotizing pulmonary aspergillosis; CRP, C-reactive protein;
Correspondence: Jae Ho Lee, Department of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 463-707, Korea. E-mail: [email protected] Received 9 November 2013; invited to revise 15 January and 7 March 2014; revised 17 February and 9 March 2014; accepted 4 May 2014 (Associate Editor: Marcos Restrepo). © 2014 Asian Pacific Society of Respirology
SUMMARY AT A GLANCE Pulmonary aspergillomas remain stable in the majority of cases, but some of them increase or decrease in size, and the minority of them resolve completely. There is a high prevalence of haemoptysis in pulmonary aspergilloma, associated with absolute size of aspergilloma and mass-containing cavity.
CT, computed tomography; FEV1, forced expiratory volume in 1 s; IPA, invasive pulmonary aspergillosis; IQR, interquartile range; OR, odds ratio; ROC, receiver operating characteristic; TB, tuberculosis.
INTRODUCTION Aspergillus is a filamentous fungi associated with a wide spectrum of pulmonary diseases. Over 200 species of Aspergillus exist in the environment; however, only a few, including Aspergillus fumigatus, Aspergillus flavus and Aspergillus niger, are known to be human pathogens. Pulmonary aspergillosis has various clinical presentations and causes a range of clinical syndrome, including aspergilloma, invasive pulmonary aspergillosis (IPA), chronic necrotizing pulmonary aspergillosis (CNPA) and allergic bronchopulmonary aspergillosis (ABPA).1 Among them, the most common form of pulmonary involvement by Aspergillus species is aspergilloma: a fungal ball, composed of fungal mycelia, inflammatory cells and tissue debris that colonizes a previously existing cavity within the lung.2 Consequently, aspergillomas are usually observed in patients with cavitary lung disease, and it is most frequently associated with tuberculosis (TB). The British Tuberculosis Association reported the presence of aspergilloma in 15% of persistent cavities larger than 2.5 cm in patients with TB.3 In general, patients with aspergillomas are asymptomatic. In the majority of cases the aspergilloma Respirology (2014) doi: 10.1111/resp.12344
2 remains stable, and there is no invasion of surrounding tissues or blood vessels by Aspergillus. Furthermore, in 10% of cases, the aspergilloma spontaneously resolves or decreases in size.4 Rarely the aspergilloma increases in size. However, haemoptysis is a commonly reported complication associated with aspergillomas. Although in most cases aspergillomarelated haemoptysis is mild, severe haemoptysis can occur in patients with TB,5 and the reported mortality rate for aspergilloma-associated haemoptysis ranges from 2% to 14%.6 The risk factors associated with a poor prognosis of aspergilloma include severe underlying lung disease, increases in the number or size of aspergilloma, immunosuppression, human immunodeficiency virus infection and underlying sarcoidosis. Previous studies have associated the changes in lesion size with the clinical characteristics and prognosis of aspergilloma,7 but few studies have reviewed the size changes of aspergilloma with respect to the risk of haemoptysis, which is one of the most important factors when considering a prognosis of aspergilloma.8 Therefore, this study aimed at elucidating the clinical course of pulmonary aspergilloma and the prevalence of haemoptysis according to changes in lesion size.
METHODS Study design and participants A multicenter retrospective observational study was performed at the Seoul National University Hospital, Bundang Hospital and Boramae Medical Center between January 1995 and December 2012. Adult patients with pulmonary aspergilloma confirmed radiologically by chest computed tomography (CT) were included in the study. Patients with invasive/ semi-invasive aspergillosis or with a history of medical interventions or diseases including chemotherapy, long-term or high-dose immunosuppressive therapy, haematological disease, prolonged neutropenia and acquired immune deficiency syndrome, in which aspergillosis could convert to invasive/ semi-invasive aspergillosis were excluded from the study. This study was approved by the Institutional Review Board of Seoul National University Hospital (IRB No.: H-1304-082-481), Bundang Hospital (IRB No: B-1304-198-107) and Boramae Medical Center (IRB No.: 01-2013-61), and was performed in accordance with the tenets of the Declaration of Helsinki. Analysis of patient data Medical records and CT images from patients were retrospectively analysed for changes in the size of the aspergilloma mass and mass-containing cavity, and the prevalence and predictive factors of haemoptysis. Clinically significant haemoptysis was defined as a haemoptysis requiring emergency room visit, admission, embolotherapy or surgery. Medical records were reviewed for the results of serial pulmonary function tests, comorbidities (including underlying lung Respirology (2014)
J-K Lee et al.
disease, diseases related to coagulopathy), prothrombin time, platelet count, and the use of antiplatelet agents or anticoagulants. For each patient, the Charlson comorbidity index9 was calculated. Mean diameters of aspergilloma mass and masscontaining cavity were calculated from serial chest CT scans using the horizontal/longitudinal diameters and height estimates of each mass and cavity. The area and volume of each mass and cavity were considered equal to an area of a circle and a volume of a sphere with this mean diameter. Patients were categorized into one of three groups, depending on the changes in aspergilloma size, as determined between the initial-to-last ratio of mass volume, as follows: the decreased group, the volume of the aspergilloma decreased by more than half; the increased group, the volume of the aspergilloma increased more than twofold; and the stable group, the aspergilloma volume did not increase by twofold or decrease by more than half. IPA, CNPA and ABPA were assessed by the diagnostic criteria suggested by Kousha et al.1 The severity of TB and bronchiectasis was estimated from initial chest CT scans and used to evaluate the risk of haemoptysis due to aspergilloma. TB-destroyed lung was defined as a parenchymal destruction due to the previous TB, with the involvement of more than one lobe. Total lung area was divided into six lobes because lingular segment was counted as a separate lobe, and TB-destroyed lung was scored by counting involved lobes.10 The extent of bronchiectasis was scored in each lobe as follows: grade 0, no involvement of bronchiectasis; grade 1, bronchiectatic less than 25% of bronchi; grade 2, bronchiectatic in 25–49%; grade 3, bronchiectatic in 50–75% of bronchi; and grade 4, bronchiectatic more than 75% of bronchi. A definition of ‘bronchiectatic’ bronchi was as follows: non-tapering bronchus with internal diameter greater than the adjacent pulmonary artery or the presence of visible bronchi within 1 cm of the costal pleural surface or adjacent to the mediastinal pleural surface. The total bronchiectasis score was the sum of bronchiectasis grade of each lobe.11 Emphysema score was estimated as suggested by Martinez-Garcia et al.12 as follows: grade 0, absence of emphysema; grade 1, centriacinar emphysema in 2 or less pulmonary lobes; grade 2, centriacinar emphysema in 3–4 lobes; and grade 3, centriacinar emphysema in more than 4 lobes, or bullous or panacinar emphysema.
Statistical analysis The data are presented as medians and interquartile ranges (IQR) for age and means and standard deviations for the other continuous variables, and as numbers (%) for categorical variables. The differences of clinical characteristics and size change of aspergilloma were analysed by Kruskal–Wallis test. Linear mixed regression was used to evaluate changes in lesion size and lung function over time. The association of annual haemoptysis frequency with the size of the cavity and the mass was evaluated by multivariate linear regression analysis. All statistical analysis was performed after adjustment for age, sex, body © 2014 Asian Pacific Society of Respirology
3
Pulmonary aspergilloma clinical course Table 1
Baseline characteristics of study subjects
A. Demographics
Figure 1
Flow diagram of the study population.
mass index (BMI), forced expiratory volume in 1 s (FEV1), prothrombin time, platelet count, bronchiectasis score, TB-destroyed lung score and emphysema score. Receiver operating characteristic (ROC) curve and multivariate logistic regression were applied to variables to evaluate lesion size and haemoptysis. Odd ratios (OR) and adjusted OR (aOR) were presented with 95% confidence intervals (CI). Statistical significance was determined with a P-value of 0.05. Data were analysed using PASW Statistics, version 18 (IBM, Armonk, NY, USA).
RESULTS Baseline characteristics of the study population Retrospective analysis was performed on a total of 143 patient records (Fig. 1). Patients’ characteristics and clinical profiles of the study group are shown in Table 1. The median follow-up duration was 5.1 years (IQR 2.3, 8.8), while the mean results of pulmonary function test of the group showed normal ventilatory patterns. TB was the most prevalent disease (60.8%), followed by chronic obstructive pulmonary disease (13.3%). On the basis of the Charlson comorbidity indexes, the majority of the patients did not have severe underlying medical conditions. Colonization of potentially pathogenic microorganism was shown in 12 patients as follows: non-TB mycobacterium in seven patients, Acinetobacter baumannii in two, Pseudomonas aeruginosa in two and Klebsiella pneumoniae in one. Among patients with radiologically confirmed pulmonary aspergilloma, 29.4% of patients were additionally confirmed in laboratory and/or microbiological methods as culture of respiratory sample and tissue biopsy, Aspergillus antigen or Aspergillus antibody titre test. Aspergilloma and haemoptysis: clinical course The size of the aspergillomas and number of lesions was assessed on the initial and follow-up CT scans of each patient, and the aspergilloma size and number © 2014 Asian Pacific Society of Respirology
Total (N = 143)
Male, n (%) Age, years, median (Q1, Q3) Body mass index, kg/m2 History of smoking Never, n (%) Ex, n (%) Current, n (%) Unknown, n (%) Pack-years Initial pulmonary function test (n = 123) FEV1, L % predicted FVC, L % predicted FEV1/FVC, % Change of lung function (n = 76) Follow-up duration, years, median (Q1, Q3) FEV1 change, mL/year† FVC change, mL/year†
79 (55.2) 61 (56, 69) 21.8 ± 5.3 67 (46.9) 45 (31.5) 16 (11.2) 15 (10.5) 27.0 ± 18.4 2.03 ± 0.79 80.8 ± 30.9 2.81 ± 0.90 79.9 ± 23.9 72.1 ± 15.7 3.7 (2, 6.2) −38.1 ± 3.9 −19.2 ± 8.9
B. Comorbidities and laboratory findings Total (N = 143) Charlson comorbidity index Respiratory disease, n (%) Tuberculosis Chronic obstructive pulmonary disease Non-tuberculosis Mycobacterium disease Interstitial lung disease Lung cancer Previous thoracic surgery Other disease, n (%)\ Diabetes mellitus Chronic liver disease Connective tissue disease Positive culture of Aspergillus species, n (%) Respiratory specimen Tissue Colonization of potentially pathogenic microorganism, n (%) Positive Aspergillus antigen test, n (%) Positive antigen titre Positive Aspergillus immunoglobulin G, n (%) Immunoglobulin G titre Aspergilloma confirmed by microbiological and/or labratory tests, n (%)
0.74 ± 1.27 87 (60.8) 19 (13.3) 6 (4.2) 2 (1.4) 2 (1.4) 7 (4.9) 18 (12.6) 3 (2.1) 2 (1.4)
13 (9.1) 31 (21.7) 12 (8.4) 10 (7.0) 0.71 ± 0.81 2 (1.4) 1.26 ± 0.09 42 (29.4)
†
Adjusted by age, sex and height. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity.
of lesions for each patient were compared (Table 2). Mean frequency of follow-up CT scan was 1.9 ± 1.0 times, and median interval time between the initial and follow-up CT was 2 years (IQR 0.92, 4.42). In 39.2% of patients the size of aspergilloma changed, while decreased aspergilloma volume was observed in 13.3% of patients, and increased aspergilloma Respirology (2014)
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J-K Lee et al.
Table 2 Clinical course of aspergilloma: radiologic findings and history of haemoptysis Total (N = 143) Follow-up duration, years, median (Q1, Q3) Volume change of mass, n (%) Stable Decreased Increased Conversion to invasive/semi-invasive form, n (%) Chronic necrotizing pulmonary aspergillosis, n (%) Bronchiectasis, n (%) Bronchiectasis score TB-destroyed lung, n (%) TB-destroyed lung score Emphysema, n (%) Emphysema score Clinically significant haemoptysis, n (%) Emergency room visit Admission Embolization Surgery Annual frequency of clinically significant haemoptysis Anticoagulation, n (%) Antiplatelet therapy, n (%)
5.1 (2.3, 8.8)
87 (60.8) 19 (13.3) 37 (25.9) 6 (4.2) 6 (100) 100 (69.9) 4.1 ± 5.0 56 (39.2) 0.8 ± 1.2 46 (32.2) 0.8 ± 1.3 72 (50.3) 52 (36.4) 66 (46.2) 50 (35.0) 30 (21.0) 0.49 ± 1.0 1 (0.7) 6 (4.2)
TB, tuberculosis.
volume was observed in 25.9% of patients. A complete resolution of the mass was observed in eight patients (5.6%). Although haematoma and inflammatory changes immediately after haemoptysis might mimic pulmonary aspergillomas in the radiological evaluation, aspergillomas may change in size over a long period unlike haematoma or inflammatory changes. So, we confirmed that pulmonary aspergillomas showed statistically significant size change over time in increased and decreased groups by using longitudinal changes of mass volume with linear mixed regression, and it suggested that mass changes in size were not short-term changes due to haematoma or inflammatory changes. Conversion to invasive or semi-invasive forms of pulmonary aspergillosis developed in 4.2% of patients, and all converted forms were CNPA. Clinically significant haemoptysis was apparent in 50.3% of study subjects (72 patients), and 21% (30 patients) required surgical resection owing to repetitive or uncontrolled haemoptysis.
Haemoptysis and aspergilloma size changes Next, we assessed and compared the clinical characteristics of the three groups (Table 3). Interestingly, the stable group had fewer male subjects (stable 46% vs decreased 73.7% vs increased 67.6%; P = 0.020) and a higher BMI (stable 22.3 ± 4.2 vs decreased 19.7 ± 3.6 Respirology (2014)
vs increased 21.8 ± 7.7; P = 0.029). The decreased volume group had a significantly lower initial FEV1 (decreased 1.47 ± 0.75 vs stable 2.03 ± 0.78 vs increased 2.32 ± 0.71; P = 0.001), higher C-reactive protein (CRP) (decreased 0.69 ± 0.74 vs stable 0.31 ± 0.38 vs increased 0.34 ± 0.68; P = 0.040), more severe bronchiectasis and TB-destroyed lung and a higher proportion of emphysema. The longitudinal declines of FEV1 over time did not differ significantly between the groups. The initial-to-last cavity volume ratio as well as the initial-to-last mass volume ratio, representative of the change in aspergilloma volume and mass, differed significantly between groups. There was not a significant difference in the proportion of patients with any history of clinically significant haemoptysis and the annual frequency of clinically significant haemoptysis between groups.
Annual haemoptysis and aspergilloma Next, we evaluated whether there was any association between the prevalence of haemoptysis with the size or the change in size of the aspergilloma cavity or mass (Table 4). Multivariate analysis was performed, and the extent of volume change was additionally adjusted in analysis of volume and diameter in baseline CT. Initial-to-last ratios of volume of cavity and mass did not show any significant associations with clinically significant haemoptysis, either by univariate or multivariate analysis. However, the volume and mean diameter of aspergilloma-containing cavities and masses measured in the initial CT images were significantly associated with the annual frequency of clinically significant haemoptysis. This result was consistent in the multivariate analysis. Aspergilloma size associates with haemoptysis Using ROC curve analysis, we evaluated whether the mean diameter of cavity or mass in the initial CT image could be used to predict the development of clinically significant haemoptysis. The area under the ROC curve (AUC) of mean cavity diameter was 0.716 (P < 0.001), and a mean cavity diameter of more than 22.5 mm had a sensitivity of 68.1% and specificity of 69.0% to predict the development of clinically significant haemoptysis (Fig. 2). The AUC of mean mass diameter was 0.638 (P = 0.005), and a mean mass diameter of more than 18.2 mm had a sensitivity of 61.1% and specificity of 66.2%. Following this we assessed the risk of haemoptysis according to these cut-off values (Table 5). A mean cavity diameter of more than 22 mm and a mass diameter of more than 18 mm are associated with an increased risk of clinically significant haemoptysis by 3.92-fold and 2.89-fold, respectively (cavity diameter, aOR 3.40, 95% CI: 1.36–8.52; mass diameter, aOR 3.53, 95% CI: 1.44–8.61).
DISCUSSION In our study, pulmonary aspergilloma remained stable in the majority of cases. In 13.3% of cases, the © 2014 Asian Pacific Society of Respirology
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Pulmonary aspergilloma clinical course Table 3 Clinical characteristics according to the size change of pulmonary aspergilloma
Male, n (%) Age, years Body mass index, kg/m2 Initial FEV1, L FEV1 change, mL/year† CRP, mg/L Charlson comorbidity index Bronchiectasis, n (%) Bronchiectasis score TB-destroyed lung, n (%) TB-destroyed lung score Emphysema, n (%) Emphysema score Initial-to-last ratio of cavity volume (%) Initial-to-last ratio of mass volume (%) Clinically significant haemoptysis, n (%) Clinically significant haemoptysis per year Conversion to invasive/semi-invasive form, n (%)
Decreased (n = 19)
Stable (n = 87)
Increased (n = 37)
P-value
14 (73.7) 63.3 ± 12.9 19.7 ± 3.6 1.47 ± 0.75 −38.7 ± 8.1 0.69 ± 0.74 1.3 ± 2.3 17 (89.5) 8.8 ± 5.3 13 (68.4) 2.5 ± 0.9 12 (63.2) 2.7 ± 0.8 84.0 ± 56.8 17.8 ± 17.6 12 (63.2) 0.36 ± 0.85 0 (0)
40 (46) 61.5 ± 10.9 22.3 ± 4.2 2.03 ± 0.78 −30.2 ± 5.2 0.31 ± 0.38 0.7 ± 1.0 57 (65.5) 5.3 ± 5.1 28 (32.2) 2.0 ± 1.1 23 (26.4) 2.4 ± 0.9 126.7 ± 94.7 115.2 ± 37.3 38 (43.7) 0.48 ± 1.06 3 (3.4)
25 (67.6) 61.8 ± 13.3 21.8 ± 7.7 2.32 ± 0.71 −56.4 ± 11.7 0.34 ± 0.68 0.6 ± 1.0 26 (70.3) 5.0 ± 3.9 15 (40.5) 1.5 ± 0.6 11 (29.7) 2.5 ± 0.8 321.9 ± 277.1 1075.8 ± 1645.7 22 (59.5) 0.57 ± 0.94 3 (8.1)
0.020 0.878 0.029 0.001 0.070 0.040 0.285 0.121 0.022 0.014 0.017 0.008 0.708
