Respiratory Medicine 164 (2020) 105903

Contents lists available at ScienceDirect

Respiratory Medicine
journal homepage: http://www.elsevier.com/locate/rmed

Review article

Non-surgical treatment options for pulmonary aspergilloma

Min Lang, MD, MSc a, *, Angela L. Lang, MD, MSc b, Nikunj Chauhan, MD c, Amanjit Gill, MD c
a
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
b
Department of Anesthesia, Critcal Care, and Pain Management, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
c
Department of Interventional Radiology, Cleveland Clinic Foundation, Cleveland, OH, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Aspergilloma, also known as mycetoma or fungus ball, is the most common manifestation of pulmonary
Aspergilloma involvement by Aspergillus species. The fungal ball typically forms within preexisting cavities of the lungs.
Aspergillosis Diagnosis requires both radiographic evidence along with serologic or microbiologic evidence of Aspergillus
Intracavitary
species involvement. While clinical features such as hemoptysis, chest pain, shortness of breath, cough, and fever
Endobronchial
are helpful in diagnosis, they are non-specific symptoms. Surgery is currently the mainstay of treatment for
Radiotherapy
Bronchial artery embolization aspergilloma but is associated with considerable mortality and morbidity. Alternative options exist for patients
who are poor surgical candidates and for those who prefer a less invasive treatment modality. Systemic treatment
with amphotericin B is ineffective and is not recommended as a monotherapy, but systemic azoles is effective in
approximately 50–80% of patients. Potential alternatives to surgery include intracavitary instillation or endo­
bronchial administration of antifungal medication, as well as direct transbronchial aspergilloma removal.
Bronchial artery embolization and radiotherapy are options to manage hemoptysis until definite eradication of
the aspergilloma. More rigorous studies are needed to better establish non-surgical treatment paradigm for
inoperable patients.

1. Introduction
Aspergilloma is a manifestation of chronic pulmonary aspergillosis
(CPA), a spectrum of diseases caused by long-term aspergillus infection
of the lung [1]. It is characterized by the formation of a mass of viable
and dead fungal material, inflammatory cells, fibrin, mucus, blood, and
tissue debris within preexisting cavities of the lung [2]. Aspergillus
fumigatus is by far the most common pathogenic species in humans [3].
They are notorious for being highly dispersable due to their remarkable
hydrophobicity, and their small size allows them to bypass mucociliary
clearance and reach lower airways. Other species such as Zygomycetes,
Fusarium, Flavus, Niger, Terreus can lead to aspergilloma formation as
well [4,5].
Various diseases that cause pulmonary scarring or cavities, such as
lung cancer, cystic fibrosis, bullous emphysema, tuberculosis, and pul­
monary abscesses predispose individuals to pulmonary aspergilloma.
Worldwide, tuberculosis is the most common antecedant disease (25%–
80%) for development of aspergilloma [6].
Aspergilloma can be subdivided into simple and complex types.
Simple aspergilloma are characterized by a single isolated cavitary
lesion with thin walls and normal surrounding lung parenchyma.
Complex aspergilloma develop in cavities with thick walls and are sur­
rounded by fibrotic pulmonary tissue, vascular adhesions, and thickened
pleura [7,8]. Patients with simple aspergilloma are often asymptomatic,
while those with complex aspergilloma commonly present with more
severe symptoms such as hemoptysis, bronchorrhea, chest pain, poor
nutrition status, and impaired respiratory function [9,10].
Approximately 7%–10% of aspergilloma cases resolve spontaneously
without treatment [11,12]. Those with persistent symptoms, such as
hemoptysis, require further treatment, of which surgery is the
gold-standard. The appropriate management for patients with asymp­
tomatic aspergilloma remains controversial [12]. Some authors advo­
cate surgical interventions in asymptomatic patients, as the
aspergilloma remains a risk for developing life-threatening hemoptysis
that carries a mortality rate of approximately 38% [13]. Surgery itself,
however, is not without risk; in studies performed after the year 2000,
the reported post-operative mortality and morbidity rates is approxi­
mately 4% and 33%, respectively [14–20]. Non-surgical options exist for
patients who have contraindications for surgery or for those that do not
wish to undergo an operation. These alternatives tend to carry less risk

* Corresponding author. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, Cleveland, OH, 44195, USA.
E-mail address: mlang@mgh.harvard.edu (M. Lang).

https://doi.org/10.1016/j.rmed.2020.105903
Received 7 October 2019; Accepted 17 February 2020
Available online 19 February 2020
0954-6111/© 2020 Elsevier Ltd. This article is made available under the Elsevier license (http://www.elsevier.com/open-access/userlicense/1.0/).
M. Lang et al.
Fig. 1. (A) Illustration of pulmonary aspergilloma. (Art by the CCF Medical art and photography department). (B, C) Radiographic and chest computed tomography
demonstration of the air crescent sign. (Reprinted with permission from Abramson S. The air crescent sign. Radiology 2001; 218:230–232).
and may be an option for primarily asymptomatic aspergilloma patients.
2. Diagnosis
Diagnosis of aspergilloma requires the combination of radiologic
evidence and direct serological or microbiologic evidence of Aspergillus
species. While clinical features including weight loss, productive cough,
hemoptysis, shortness of breath, chest pain, and fever can be helpful,
these symptoms are non-specific and may be associated with the un­
derlying pulmonary disease.
The typical radiographic appearances of aspergilloma are of a
rounded fungal ball inside a cavity, which is usually thick walled. Two
radiographic signs may aid the diagnosis: 1) the air crescent sign (Fig. 1B
and C), which is a crescent-shaped air space separating the fungal ball
from the cavity wall, and 2) the Monod sign, which is characterized by
the intracavitary mass gravitating freely depending on the patient’s
positions [21]. Pleural thickening may be an early sign of aspergilloma
formation which precedes the appearance of an obvious intracavitary
fungal ball [22]. Computed tomography (CT) demonstrates early stages
of aspergilloma much more readily than plain chest radiography.
If a fungal ball is observed on radiographic imaging, then a diagnosis
of aspergilloma can be confirmed with a positive serum Aspergillus IgG
test. Elevated levels of Aspergillus-specific IgG antibodies are almost
always found in patients with chronic pulmonary aspergillosis, regard­
less of the disease pattern [23–26]. The optimal cutoff value for IgG
antibodies, and the sensitivity and specificity of the test depend on the
enzyme immunoassay kits used. Newer assays can achieve a sensitivity
of 97% and a specificity of 98% [23,24]. If the test for IgG antibodies is
negative but radiographic imaging and clinical features of the patient
are highly suspicious of pulmonary aspergillosis, a different assay for
IgG antibodies should be performed. Alternatively, testing for serum
Aspergillus-specific IgE antibodies could be considered.
Aspergillus-specific IgE antibody is found to be elevated in up to 66% of
patients with CPA and can be useful when clinical suspicion is high,
especially in asthmatic and cystic fibrosis patients [22]. Assays for
Aspergillus cell wall components, specifically galactomannan (GM),
from bronchoalveolar lavage fluid (BALF) can also be considered when
diagnosis cannot be confirmed with serum IgG antibodies. Sensitivity of
GM tests on BALF ranges from 72.2% to 77.8%, and specificity ranges
from 77% to 90% [27,28]. Finally, a positive culture of Aspergillus
species or a positive Aspergillus polymerase chain reaction (PCR) assay
from respiratory samples support the diagnosis of aspergilloma but is not
sufficient on its own for diagnosis since airway colonization by Asper­
gillus species can be seen in chronic lung conditions including tuber­
culosis, chronic obstructive pulmonary disease (COPD),
non-tuberculous mycobacteriosis, lung cancer, and interstitial lung
disease [29].
2
Respiratory Medicine 164 (2020) 105903
3. Non-surgical treatments
While surgical resection is currently considered the gold standard of
treatment for symptomatic aspergilloma, many patients have contrain­
dications to surgery including poor respiratory reserve, multiple or
bilateral aspergilloma, and patient preference. The morbidity associated
with surgery is considerable and potential complications include hem­
orrhage, empyema, wound infection, tracheobronchitis, bronchopleural
fistula formation, and seeding of Aspergillus infection [30–32]. Fortu­
nately, as most patients with aspergilloma are asymptomatic, they may
not need treatment and can be observed conservatively, but this remains
an area of debate. The reported spontaneous resolution rate is approx­
imately 5% over 3 years, or 7%–10% of all cases [6,33,34]; but the
natural history of aspergilloma has not been extensively studied. For
inoperable patients that require treatment, there are several
alternatives.
4. Systemic administration of antifungal medication
4.1. Amphotericin B
Systemic administration of amphotericin B has a reported cure rate
of approximately 10%, which is similar to the spontaneous rate of res­
olution [35]. It appears to have a limited role even as an adjuvant
therapy to surgical resection. A review performed by Benhamed and
Woelffle found adjuvant amphotericin B did not affect morbidity or
survival in post-surgical patients [36]. Furthermore, the potential
complications associated with amphotericin B, particularly nephrotox­
icity, makes this option unfavorable [37]. Within recent years, aero­
solized amphotericin B administration through a nebulizer has shown
promise at treating pulmonary aspergillosis and may be effective as a
prophylaxis for invasive pulmonary aspergillosis in high-risk patients
[38–42]. Whether aerosolized amphotericin B will be effective at
treating aspergilloma has not been investigated.
4.2. Azoles
Itraconazole is the most tested of the azoles to treat aspergilloma due
to its relative low cost, oral route of administration, adequate lung
penetration, and good activity towards Aspergillus fumigatus. [43] In an
open international study consisting of 42 cases of aspergilloma, treat­
ment with 50–400 mg itraconazole daily led to symptomatic improve­
ment in 62% of cases with minor gastrointestinal side effects [44]. A
multicenter clinical trial demonstrated that daily dose of 200 mg of
itraconazole for a duration of six months is effective at treating asper­
gilloma, with a cure rate of 63.4% [45]. In a more recent prospective
study, Gupta et al. found patients treated with 200 mg of itraconazole
twice daily and those who received weight-based dosing had good
M. Lang et al.
Fig. 2. (A) Illustration demonstrating percutaneous instillation of antifungal
medication directly to the aspergilloma cavity via a pigtail catheter. (Art by the
CCF Medical art and photography department) (B, C) Demonstration of CT-
guided pigtail catheter placement within aspergilloma cavities.
3
Respiratory Medicine 164 (2020) 105903
clinical response - meaning control or decrease in hemoptysis, cough/­
expectoration, shortness of breath, and weight loss – and at least partial
radiographic improvement in 75%–85% of patients [43]. The Infectious
Disease Society of America (IDSA) recommends itraconazole at a dose of
200 mg orally every 12 h, similar to treatment of invasive pulmonary
aspergillosis, with the total duration of treatment dependent on the in­
dividual’s clinical and radiographic response [46].
Voriconazole is an alternative oral agent to itraconazole and is
indicated for treating resistant strains of Aspergillus fumigatus. It has
demonstrated efficacy against invasive pulmonary aspergillosis in a
pivotal 2002 study [47]. 144 and 133 patients with invasive pulmonary
aspergillosis were treated with voriconazole and amphotericin B,
respectively, in a large randomized, unblinded trial. 52.8% of the vor­
iconazole group had either complete or partial resolution of clinical
signs and symptoms at 12 weeks, compared to the 31.6% in the
amphotericin B group. Furthermore, the 12-week survival rate was
70.8% and 57.9% for the voriconazole and amphotericin B groups,
respectively. While this study demonstrated the effectiveness of vor­
iconazole in treating invasive pulmonary aspergillosis, a more severe
manifestation of pulmonary aspergillosis than aspergilloma, the use of
voriconazole to treat aspergilloma has only been reported in three case
reports where only 2 of the 3 patients were completely cured [48–50].
The IDSA recommends voriconazole for pulmonary aspergilloma at a
dose of 6 mg/kg IV every 12 h for one day, and 4 mg/kg IV every 12 h
thereafter; oral therapy can be 200–300 mg every 12 h [46].
Azoles have several disadvantages that preclude its use as a primary
treatment for aspergilloma. The overall efficacy of itraconazole is below
70% and has yet to be established for voriconazole. Furthermore, pro­
longed treatment duration, often more than six months, is required to
clear the infection and there have been cases of aspergilloma relapse
following the discontinuation of the antifungal [51]. Finally, due to the
delay in response, azoles are not helpful in treating patients presenting
with life-threatening hemoptysis.
5. Intracavitary instillation of antifungal medication
Direct intracavitary delivery of antifungal medication has been re­
ported since 1964 by Brouet and colleagues [52]. Direct delivery of
antifungal medication to the cavity increases aspergilloma penetration.
With modern CT guidance, catheter placement is accurate and relatively
straightforward (Fig. 2). Dynamic intravenous contrast enhancement
can also be performed to identify intervening thoracic vessels so they
can be avoided during catheter placement [53]. Most importantly, lung
function is preserved in the process of treatment, making this a good
alternative to surgery for patients with limited pulmonary reserve.
Length of hospital stay is significantly shorter for patients receiving
intracavitary instillation of amphotericin B (ICAB) than those who were
treated by surgery [54]. Furthermore, intracavitary instillation of anti­
fungals can be done on an outpatient basis.
The efficacy of intracavitary instillation amphotericin B varies be­
tween studies. Early case series on this technique by Brouet et al., Kra­
kowka et al., Shapiro et al. and Hargis et al., showed that 66.6%–100%
of patients exhibited clinical improvement such as cessation of hemop­
tysis [52,54–56]. Several case reports and series since then have further
demonstrated clinical success with ICAB [54,57–60]. Despite good
clinical outcome in most patients, radiographic clearance of the fungal
ball, however, was achieved in approximately 30% of cases. The reason
of this is unclear but may be due to: 1) delayed radiographic improve­
ment compared to clinical symptom resolution, 2) remnant mass on
imaging represents dead cells, and 3) ICAB was only able to prevent
invasion of the fungal ball into surrounding lung parenchyma rather
than clearance of the infection.
There are two large retrospective studies on ICAB treatment of
aspergilloma. In 1998, Giron and colleagues published the first large
cohort study consisting of 40 patients, all of whom were non-surgical
aspergilloma candidates due to poor respiratory function [61].
M. Lang et al.
Fig. 3. (A) Computed tomography image demonstrating pulmonary aspergilloma in the right lower lobe. (B) Digital subtraction angiogram of the left intercosto­
bronchial trunk demonstrating hyperplastic bronchial artery (arrow) with significant hypervascularity around the aspergilloma cavity.
CT-guided percutaneous injection of amphotericin B paste lead to the
cessation of hemoptysis in all patients [55]. The authors emphasized the
importance of using small caliber cannula for injection, complete filling
of the cavity as much as possible, and neuroleptanalgesia to prevent
coughing. The second large retrospective study published in 2013 [62]
demonstrated that hemoptysis ceased in 85% of cases, however, recur­
rence of severe hemoptysis occurred in 33% (6 of 18) of patients and
11% (2 of 18) died during a mean follow-up period of 18 months.
The total dose of amphotericin B required for aspergilloma clearance
is unclear; Kravitz et al. instilled 50 mg daily for 10 days, Giron et al.
treated the patients with 50 mg daily for at least 15 days, and Lee et al.
used 50 mg for 15 days [57,61,62]. The total dose of amphotericin B
used in Yamada et al. ranged from 250 mg to 1085 mg [63]. The optimal
regimen for ICAB has yet to be formally determined.
The method is not without potential complications, including
pneumothorax or subcutaneous emphysema following catheter place­
ment, or missing the cavity containing the fungal ball during ampho­
tericin B infusion [57,62]. Overall, ICAB appears to be an effective
short-term treatment for symptomatic pulmonary aspergilloma in
cases of oral or intravenous antifungal treatment failure.
6. Endobronchial instillation of antifungal medication
Endobronchial adminstration of antifungal medication has been
poorly studied. Based on animal studies that demonstrated safety of
atomized amphotericin B delivered endobronchially, Ramirez reported
the first series of such treatment in humans in 1964 [64]. The results
were impressive as all three patients showed marked clinical improve­
ment and clearance of the fungal infection. Yamada et al., Guleria et al.,
Hinerman et al., Ikemotoa et al., and Hamamoto et al. subsequently
found success with endobronchial treatments with amphotericin B, ke­
toconazole, fluconazole, and miconazole in a total of 9 patients [63,65,
66]. While all patients demonstrated symptom improvement, only 6
patients had complete clearance of the fungus ball. The technique of
administration, however, varied across studies. Guleria et al. delivered
medication directly into the cavity whereas Hinerman et al. adminis­
tered the antifungal at the mainstem bronchus; Ikemoto et al. delivered
endobronchial instillation through tracheal puncture. Furthermore, the
dose of antifungal medication required as well as the duration of treat­
ment remains to be established.
Compared to percutaneous intracavitary instillation of antifungals,
the endobronchial technique allows for frequent inspection for local
adverse effect or progression of the disease, and avoids the risk for
pneumothorax secondary to percutaneous needle puncture. However,
the drug delivery to the cavitary is less precise with the endobronchial
method, which may require longer treatment duration. Discomfort from
repeated bronchoscopy may also make this option less attractive.
4
Respiratory Medicine 164 (2020) 105903
7. Transbronchial removal of aspergilloma
Transbonchial removal of mycetoma through bronchoscopy is a
relatively recent technique described by Stather and colleagues [67].
The results from the case series are promising, as 6 of the 7 treated
patients exhibited complete resolution of the aspergilloma at 9 months
follow-up. The technique utilizes CT scan with virtual bronchoscopy
reconstruct for pre-procedural planning, flexible bronchoscope through
either a rigid bronchoscope or double-lumen endotracheal tube for ac­
cess, and biopsy forceps and basket retrieval device for aspergilloma
removal. The technique, however, is impossible in patients without a
direct airway leading to the aspergilloma. Other disadvantages include
the requirement of general anesthesia for the procedure and
post-procedural complications including hypoxemia and minor
hemoptysis.
Another transbronchial technique is direct intracavitary instillation
of itraconazole through bronchoscopy. Tani et al. described the tech­
nique in a single patient who failed oral voriconazole treatment [68].
Direct instillation of itraconazole was performed a total of 9 times with
an overall dose of 715 mg. Radiographic clearance was observed by the
fourth injection and the patient was successfully treated without
recurrence.
8. Treatment for hemoptysis
8.1. Bronchial artery embolization
CPA can be complicated by life-threatening hemoptysis. For patients
who are poor surgical candidates or have extensive disease, bronchial
artery embolization (BAE) can be an important treatment option for
short-term control of hemoptysis. In the majority of instances, hemop­
tysis arises from the bronchial arteries due to changes in the terminal
vascular bed, but collateral or variant supply can arise from other sys­
temic arteries including intercostal, subclavian, or internal mammary
arteries (Fig. 3) [69]. Successful embolization semi-permanently oc­
cludes these vessels, thereby stopping the hemorrhage. Immediate
clinical success, defined by cessation of hemoptysis, is attainable in
73%–99% of patient with a variety of lung pathologies ranging from
tuberculosis to malignancy [69,70]. Recurrence of hemoptysis, howev­
er, occur in 10–55% of cases.
Studies on the outcome of BAE in aspergilloma are sparse. He et al.
reported that BAE was effective at treating massive hemoptysis in 84%
(21 of 25) of patients with pulmonary aspergilloma [71]. Beomsu and
colleagues reported immediate success of the procedure in 64% of pa­
tients with CPA and 67% of patients with simple aspergilloma [72].
Unfortunately, 55% of patients with CPA and 33% patients with simple
aspergilloma experienced recurrence of hemoptysis. Interestingly, two
cases of aspergilloma managed initially with BAE for massive
M. Lang et al. Respiratory Medicine 164 (2020) 105903

hemoptysis had disappearance of the fungal ball on radiographic images

2 weeks after treatment [73]. Such positive response to BAE is extremely
rare and embolization as a method to eradicate the aspergilloma cannot
be generalized. Nonetheless, BAE appears to be a safe and effective
procedure for the acute management of life-threatening hemoptysis in
patients with pulmonary aspergillosis.

8.2. Radiotherapy

When BAE is not successful at managing hemoptysis in patients who

are poor surgical candidates, radiotherapy may be considered. Radio­
therapy leads to occlusion of the vessels that line the aspergilloma cavity
without affecting the growth of the fungus. Early effects of radiation on
small vessels include swelling, necrosis, and compression by peri­
vascular edema [74]. Eventually, perivascular and vessel fibrosis
completely occludes the circulation.
The current knowledge on radiotherapy for hemoptysis secondary to
aspergilloma is lacking, with only 8 cases reported in literature by
Shneerson et al., Falkson et al., Glover et al., and Samuelian et al.
[74–77] In all reported cases, hemoptysis was successfully treated
without any signs of toxicity and morbidity up to 6 months
post-treatment. Long-term outcomes of these patients were not avail­
Fig. 4. CT-guided radiofrequency ablation in a case of pulmonary able. There is no consensus on the radiation dose that should be deliv­
aspergilloma. ered for treatment. The most recent report by Samuelian et al. suggested
3.5 Gy per fraction weekly and continuing for 1 fraction after cessation
of hemoptysis [75]. Currently, it remains a second-line option to BAE to
treat hemoptysis secondary to pulmonary aspergilloma. Further studies

Fig. 5. Proposed treatment algorithm for patients with pulmonary aspergilloma.

5
M. Lang et al.
are needed to test the efficacy of radiotherapy before it can be widely
recommended.
8.3. Radiofrequency ablation
Radiofrequency (RF) ablation (Fig. 4) is a minimally invasive ther­
mal technique used predominately for lung cancer treatment. Aspergillus
species can generally grow up to 50 � C and can be killed via heat
exposure beyond 70 � C [78]. The use of RF ablation to treat pulmonary
aspergilloma has only been reported in one case where Hiraki and col­
leagues treated a non-surgical candidate patient with aspergilloma [79].
The team percutaneously placed an electrode into the aspergilloma
under CT fluoroscopic guidance. A RF energy with a maximum power of
73 W was applied for 12 min with the tip of the electrode reaching 79 � C.
Cultures were negative for Aspergillus 7 days after the procedure and
scarring of the ablation zone without disease recurrence was observed at
33 months. Further investigation on the effectiveness of RF ablation for
pulmonary aspergilloma is warranted.
9. Summary
Diagnosis of aspergilloma requires radiographic evidence as well as
serologic or microbiologic evidence of Aspergillus species. While sur­
gery remains the mainstay and the definitive treatment for aspergilloma,
alternative options exist for patients who are poor surgical candidates or
those that refuse surgery.
Systemic azoles, such as itraconazole and voriconazle, have a re­
ported treatment success rate of 53%–85%, and is recommended as an
alternative to surgery by the IDSA [43–50]. If systemic azole treatment
fails, endobronchial and direct intracavitary instillation of antifungal
medication as well as direct transbronchial removal of the aspergilloma
are possible salvage treatments to consider. The effectiveness of these
methods, however, have only been shown through case series and re­
quires further investigation. Finally, BAE and radiotherapy are options
to manage life-threatening hemoptysis and bridge to definite treatment
for the fungal ball. Based on available data, Fig. 5 illustrates a proposed
treatment algorithm for patients with aspergilloma.
Author contribution section
ML: Writing - original draft, literature search, generation of tables.
LD: Writing - original draft, literature search. NC: Writing - original
draft, generation of figures. AG: writing of manuscript, generation of
tables and figures.
Funding
None.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
We would like to thank Amanda Mendelsohn, medical illustrator at
Cleveland Clinic, for providing us with illustrations used in Figs. 1 and 2.
References
[1] S.H. Lee, B.J. Lee, D.Y. Jung, et al., Clinical manifestations and treatment outcomes
of pulmonary aspergilloma, Kor. J. Intern. Med. 19 (1) (2004) 38–42.
[2] A.O. Soubani, P.H. Chandrasekar, The clinical spectrum of pulmonary aspergillosis,
Chest 121 (6) (2002) 1988–1999.
6
Respiratory Medicine 164 (2020) 105903
[3] K.J. Kwon-Chung, J.A. Sugui, Aspergillus fumigatus–what makes the species a
ubiquitous human fungal pathogen? PLoS Pathog. 9 (12) (2013) e1003743.
[4] H. Ohba, S. Miwa, M. Shirai, et al., Clinical characteristics and prognosis of chronic
pulmonary aspergillosis, Respir. Med. 106 (5) (2012) 724–729.
[5] A. Al-Alawi, C.F. Ryan, J.D. Flint, N.L. Muller, Aspergillus-related lung disease,
Can. Respir. J. J. Can. Thorac. Soc. 12 (7) (2005) 377–387.
[6] J.C. Chen, Y.L. Chang, S.P. Luh, J.M. Lee, Y.C. Lee, Surgical treatment for
pulmonary aspergilloma: a 28 year experience, Thorax 52 (9) (1997) 810–813.
[7] M.M. El Hammoumi, O. Slaoui, F. El Oueriachi, H. Kabiri el, Lung resection in
pulmonary aspergilloma: experience of a Moroccan center, BMC Surg. 15 (2015)
114.
[8] J.P.N. Belcher, Surgery in broncho-pulmonary aspergillosis, Br. J. Dis. Chest 54
(1960) 335–341.
[9] D. Gossot, P. Validire, R. Vaillancourt, et al., Full thoracoscopic approach for
surgical management of invasive pulmonary aspergillosis, Ann. Thorac. Surg. 73
(1) (2002) 240–244.
[10] A. Lejay, P.E. Falcoz, N. Santelmo, et al., Surgery for aspergilloma: time trend
towards improved results? Interact. Cardiovasc. Thorac. Surg. 13 (4) (2011)
392–395.
[11] C. Pohl, L. Jugheli, F. Haraka, E. Mfinanga, K. Said, K. Reither, Pulmonary
aspergilloma: a treatment challenge in sub-Saharan Africa, PLoS Neglected Trop.
Dis. 7 (10) (2013) e2352.
[12] L. Moodley, J. Pillay, K. Dheda, Aspergilloma and the surgeon, J. Thorac. Dis. 6 (3)
(2014) 202–209.
[13] B. Hirshberg, I. Biran, M. Glazer, M.R. Kramer, Hemoptysis: etiology, evaluation,
and outcome in a tertiary referral hospital, Chest 112 (2) (1997) 440–444.
[14] J.F. Regnard, P. Icard, M. Nicolosi, et al., Aspergilloma: a series of 89 surgical
cases, Ann. Thorac. Surg. 69 (3) (2000) 898–903.
[15] C.A. Kauffman, Quandary about treatment of aspergillomas persists, Lancet 347
(9016) (1996) 1640.
[16] J.G. Lee, C.Y. Lee, I.K. Park, et al., Pulmonary aspergilloma: analysis of prognosis in
relation to symptoms and treatment, J. Thorac. Cardiovasc. Surg. 138 (4) (2009)
820–825.
[17] C.K. Park, S. Jheon, Results of surgical treatment for pulmonary aspergilloma, Eur.
J. Cardio. Thorac. Surg. 21 (5) (2002) 918–923, official journal of the European
Association for Cardio-thoracic Surgery.
[18] Y.T. Kim, M.C. Kang, S.W. Sung, J.H. Kim, Good long-term outcomes after surgical
treatment of simple and complex pulmonary aspergilloma, Ann. Thorac. Surg. 79
(1) (2005) 294–298.
[19] J.G. Akbari, P.K. Varma, P.K. Neema, M.U. Menon, K.S. Neelakandhan, Clinical
profile and surgical outcome for pulmonary aspergilloma: a single center
experience, Ann. Thorac. Surg. 80 (3) (2005) 1067–1072.
[20] G. Babatasi, M. Massetti, A. Chapelier, et al., Surgical treatment of pulmonary
aspergilloma: current outcome, J. Thorac. Cardiovasc. Surg. 119 (5) (2000)
906–912.
[21] S. Sharma, S.K. Dubey, N. Kumar, D. Sundriyal, ’Monod’ and ’air crescent’ sign in
aspergilloma, BMJ Case Rep. 2013 (2013).
[22] H.I. Libshitz, G.W. Atkinson, H.L. Israel, Pleural thickening as a manifestation of
aspergillus superinfection, Am. J. Roentgenol. Radium Ther. Nucl. Med. 120 (4)
(1974) 883–886.
[23] I.D. Page, M.D. Richardson, D.W. Denning, Comparison of six Aspergillus-specific
IgG assays for the diagnosis of chronic pulmonary aspergillosis (CPA), J. Infect. 72
(2) (2016) 240–249.
[24] C. Dumollard, S. Bailly, S. Perriot, et al., Prospective evaluation of a new
Aspergillus IgG enzyme immunoassay kit for diagnosis of chronic and allergic
pulmonary aspergillosis, J. Clin. Microbiol. 54 (5) (2016) 1236–1242.
[25] I.D. Page, M. Richardson, D.W. Denning, Antibody testing in aspergillosis–quo
vadis? Med. Mycol. 53 (5) (2015) 417–439.
[26] B.W. Jhun, K. Jeon, J.S. Eom, et al., Clinical characteristics and treatment
outcomes of chronic pulmonary aspergillosis, Med. Mycol. 51 (8) (2013) 811–817.
[27] K. Izumikawa, Y. Yamamoto, T. Mihara, et al., Bronchoalveolar lavage
galactomannan for the diagnosis of chronic pulmonary aspergillosis, Med. Mycol.
50 (8) (2012) 811–817.
[28] N. Urabe, S. Sakamoto, G. Sano, et al., Usefulness of two Aspergillus PCR assays
and Aspergillus galactomannan and beta-d-Glucan testing of bronchoalveolar
lavage fluid for diagnosis of chronic pulmonary aspergillosis, J. Clin. Microbiol. 55
(6) (2017) 1738–1746.
[29] T. Tashiro, K. Izumikawa, M. Tashiro, et al., Diagnostic significance of Aspergillus
species isolated from respiratory samples in an adult pneumology ward, Med.
Mycol. 49 (6) (2011) 581–587.
[30] B. Mohapatra, P. Sivakumar, S. Bhattacharya, S. Dutta, Surgical treatment of
pulmonary aspergillosis: a single center experience, Lung India 33 (1) (2016) 9–13,
official organ of Indian Chest Society.
[31] P. Rummens, M. Bruyneel, M. Lungarella, V. Ninane, Aspergillus tracheobronchitis,
bronchopleural fistula and empyema after lobectomy for aspergilloma, Med.
Mycol. Case Rep. 6 (2014) 25–28.
[32] A. Brik, A.M. Salem, A.R. Kamal, et al., Surgical outcome of pulmonary
aspergilloma, Eur. J. Cardio. Thorac. Surg. 34 (4) (2008) 882–885, official journal
of the European Association for Cardio-thoracic Surgery.
[33] Aspergilloma and residual tuberculous cavities–the results of a resurvey, Tubercle
51 (3) (1970) 227–245.
[34] C.E. Eastridge, J.M. Young, F. Cole, R. Gourley, J.W. Pate, Pulmonary aspergillosis,
Ann. Thorac. Surg. 13 (4) (1972) 397–403.
[35] K.J. Hammerman, G.A. Sarosi, F.E. Tosh, Amphotericin B in the treatment of
saprophytic forms of pulmonary aspergillosis, Am. Rev. Respir. Dis. 109 (1) (1974)
57–62.
M. Lang et al.
[36] L. Benhamed, D. Woelffle, Adjuvant antifungal therapy after pulmonary surgery for
aspergilloma: is it useful? Interact. Cardiovasc. Thorac. Surg. 18 (6) (2014)
835–837.
[37] H. Ikemoto, Treatment of pulmonary aspergilloma with amphotericin B, Arch.
Intern. Med. 115 (1965) 598–601.
[38] D. Xia, W.K. Sun, M.M. Tan, et al., Aerosolized amphotericin B as prophylaxis for
invasive pulmonary aspergillosis: a meta-analysis, Int. J. Infect. Dis. 30 (2015)
78–84. IJID : official publication of the International Society for Infectious
Diseases.
[39] B.J. Rijnders, J.J. Cornelissen, L. Slobbe, et al., Aerosolized liposomal amphotericin
B for the prevention of invasive pulmonary aspergillosis during prolonged
neutropenia: a randomized, placebo-controlled trial, Clin. Infect. Dis. 46 (9) (2008)
1401–1408, an official publication of the Infectious Diseases Society of America.
[40] S. Schwartz, G. Behre, V. Heinemann, et al., Aerosolized amphotericin B
inhalations as prophylaxis of invasive aspergillus infections during prolonged
neutropenia: results of a prospective randomized multicenter trial, Blood 93 (11)
(1999) 3654–3661.
[41] S. Hanada, H. Uruga, H. Takaya, et al., Nebulized liposomal amphotericin B for
treating Aspergillus empyema with bronchopleural fistula, Am. J. Respir. Crit. Care
Med. 189 (5) (2014) 607–608.
[42] P. Diot, B. Rivoire, A. Le Pape, et al., Deposition of amphotericin B aerosols in
pulmonary aspergilloma, Eur. Respir. J. 8 (8) (1995) 1263–1268.
[43] P.R. Gupta, S. Jain, J.P. Kewlani, A comparative study of itraconazole in various
dose schedules in the treatment of pulmonary aspergilloma in treated patients of
pulmonary tuberculosis, Lung India 32 (4) (2015) 342–346.
[44] K. De Beule, P. De Doncker, G. Cauwenbergh, et al., The treatment of aspergillosis
and aspergilloma with itraconazole, clinical results of an open international study
(1982-1987), Mycoses 31 (9) (1988) 476–485.
[45] E. Tsubura, [Multicenter clinical trial of itraconazole in the treatment of pulmonary
aspergilloma. Pulmonary Aspergilloma Study Group], Kekkaku 72 (10) (1997)
557–564.
[46] T.F. Patterson, G.R. Thompson 3rd, D.W. Denning, et al., Practice guidelines for the
diagnosis and management of aspergillosis: 2016 update by the infectious diseases
society of America, Clin. Infect. Dis. 63 (4) (2016) e1–e60.
[47] R. Herbrecht, D.W. Denning, T.F. Patterson, et al., Voriconazole versus
amphotericin B for primary therapy of invasive aspergillosis, N. Engl. J. Med. 347
(6) (2002) 408–415.
[48] E. Dannaoui, D. Garcia-Hermoso, J.M. Naccache, et al., Use of voriconazole in a
patient with aspergilloma caused by an itraconazole-resistant strain of Aspergillus
fumigatus, J. Med. Microbiol. 55 (Pt 10) (2006) 1457–1459.
[49] L. Chow, N.E. Brown, D. Kunimoto, An unusual case of pulmonary invasive
aspergillosis and aspergilloma cured with voriconazole in a patient with cystic
fibrosis, Clin. Infect. Dis. 35 (9) (2002) e106–110.
[50] N. Freymond, J.B. Le Loch, G. Devouassoux, R. Harf, A. Rakotomalala, Y. Pacheco,
[Aspergillus bronchitis and aspergilloma treated successfully with voriconazole],
Rev. Mal. Respir. 22 (5 Pt 1) (2005) 811–814.
[51] J.H. Campbell, J.H. Winter, M.D. Richardson, G.S. Shankland, S.W. Banham,
Treatment of pulmonary aspergilloma with itraconazole, Thorax 46 (11) (1991)
839–841.
[52] G. Brouet, F. Liot, J. Demange, P. Nevot, [Local treatment of pulmonary
aspergilloma with transparietal injections of amphotericin B], J. Fr. Med. Chir.
Thoraciques 18 (1964) 789–798.
[53] J.S. Klein, K. Fang, M.C. Chang, Percutaneous transcatheter treatment of an
intracavitary aspergilloma, Cardiovasc. Intervent. Radiol. 16 (5) (1993) 321–324.
[54] M.J. Shapiro, S.M. Albelda, R.L. Mayock, G.K. McLean, Severe hemoptysis
associated with pulmonary aspergilloma. Percutaneous intracavitary treatment,
Chest 94 (6) (1988) 1225–1231.
[55] P. Krakowka, K. Traczyk, J. Walczak, H. Halweg, Z. Elsner, L. Pawlicka, Local
treatment of aspergilloma of the lung with a paste containing nystatin or
amphotericin B, Tubercle 51 (2) (1970) 184–191.
[56] J.L. Hargis, R.C. Bone, J. Stewart, N. Rector, F.C. Hiller, Intracavitary
amphotereicin B in the treatment of symptomatic pulmonary aspergillomas, Am. J.
Med. 68 (3) (1980) 389–394.
Respiratory Medicine 164 (2020) 105903
[57] K.S. Lee, H.T. Kim, Y.H. Kim, K.O. Choe, Treatment of hemoptysis in patients with
cavitary aspergilloma of the lung: value of percutaneous instillation of
amphotericin B, Am. J. Roentgenol. 161 (4) (1993) 727–731.
[58] M. Jackson, C.D. Flower, J.M. Shneerson, Treatment of symptomatic pulmonary
aspergillomas with intracavitary instillation of amphotericin B through an
indwelling catheter, Thorax 48 (9) (1993) 928–930.
[59] P.L. Munk, A.D. Vellet, R.N. Rankin, N.L. Muller, D. Ahmad, Intracavitary
aspergilloma: transthoracic percutaneous injection of amphotericin gelatin
solution, Radiology 188 (3) (1993) 821–823.
[60] P.J. Ryan, D.E. Stableforth, J. Reynolds, K.M. Muhdi, Treatment of pulmonary
aspergilloma in cystic fibrosis by percutaneous instillation of amphotericin B via
indwelling catheter, Thorax 50 (7) (1995) 809–810.
[61] J. Giron, C. Poey, P. Fajadet, et al., CT-guided percutaneous treatment of
inoperable pulmonary aspergillomas: a study of 40 cases, Eur. J. Radiol. 28 (3)
(1998) 235–242.
[62] J.N. Kravitz, M.W. Berry, S.I. Schabel, M.A. Judson, A modern series of
percutaneous intracavitary instillation of amphotericin B for the treatment of
severe hemoptysis from pulmonary aspergilloma, Chest 143 (5) (2013)
1414–1421.
[63] H. Yamada, S. Kohno, H. Koga, S. Maesaki, M. Kaku, Topical treatment of
pulmonary aspergilloma by antifungals. Relationship between duration of the
disease and efficacy of therapy, Chest 103 (5) (1993) 1421–1425.
[64] J. Ramirez, Pulmonary aspergilloma: endobronchial treatment, N. Engl. J. Med.
271 (1964) 1281–1285.
[65] F.A. Rachel Hinerman, Ashish Singh, Cesar Keller, Treatment of endobronchial
mucormycosis with amphotericin B via flexible bronchoscopy, J. Bronchol. 9 (4)
(2002) 294–297.
[66] T. Hamamoto, K. Watanabe, H. Ikemoto, Endobronchial miconazole for pulmonary
aspergilloma, Ann. Intern. Med. 98 (6) (1983) 1030.
[67] D.R. Stather, A. Tremblay, E. Dumoulin, et al., A series of transbronchial removal
of intracavitary pulmonary aspergilloma, Ann. Thorac. Surg. 103 (3) (2017)
945–950.
[68] S. Tani, H. Tomioka, K. Tsuchimoto, et al., [A case of pulmonary aspergilloma
successfully treated with transbronchial intracavitary itraconazole], J. Jpn. Respir.
Soc. 46 (12) (2008) 997–1002.
[69] D.R. Sopko, T.P. Smith, Bronchial artery embolization for hemoptysis, Semin.
Intervent. Radiol. 28 (1) (2011) 48–62.
[70] E. Serasli, V. Kalpakidis, K. Iatrou, V. Tsara, D. Siopi, P. Christaki, Percutaneous
bronchial artery embolization in the management of massive hemoptysis in chronic
lung diseases. Immediate and long-term outcomes, Int. Angiol. 27 (4) (2008)
319–328, a journal of the International Union of Angiology.
[71] G. He, W. Liu, Z. Gao, Z. Gao, H. Gao, Y. Wang, Intervention treatment on massive
hemoptysis of pulmonary aspergilloma, Exp. Therapeut. Med. 13 (5) (2017)
2259–2262.
[72] B. Shin, W.J. Koh, S.W. Shin, et al., Outcomes of bronchial artery embolization for
life-threatening hemoptysis in patients with chronic pulmonary aspergillosis, PloS
One 11 (12) (2016) e0168373.
[73] B.P.K. Prasad, B. Ray, Singular observation of a desirable change after bronchial
artery embolization for hemoptysis in intracavitary aspergilloma, Indian J. Radiol.
Imag. 27 (2) (2017) 225–228.
[74] J.M. Shneerson, P.A. Emerson, R.H. Phillips, Radiotherapy for massive
haemoptysis from an aspergilloma, Thorax 35 (12) (1980) 953–954.
[75] J.M. Samuelian, A.A. Attia, C.A. Jensen, A.M. Monjazeb, A.W. Blackstock,
Treatment of hemoptysis associated with aspergilloma using external beam
radiotherapy: a case report and literature review, Pract. Radiat. Oncol. 1 (4) (2011)
279–281.
[76] C. Falkson, R. Sur, J. Pacella, External beam radiotherapy: a treatment option for
massive haemoptysis caused by mycetoma, Clin. Oncol. 14 (3) (2002) 233–235.
[77] S. Glover, S.G. Holt, G.H. Newman, E.J. Kingdon, Radiotherapy for a pulmonary
aspergilloma complicating p-ANCA positive small vessel vasculitis, J. Infect. 54 (4)
(2007) e215–217.
[78] J.P. Latge, Aspergillus fumigatus and aspergillosis, Clin. Microbiol. Rev. 12 (2)
(1999) 310–350.
[79] T. Hiraki, H. Gobara, K. Kato, et al., A case of pulmonary aspergilloma treated with
radiofrequency ablation, Cardiovasc. Intervent. Radiol. 37 (2) (2014) 554–557.