- Email: [email protected]
Non-surgical treatment options for pulmonary aspergilloma
Journal Pre-proof Non-surgical treatment options for pulmonary aspergilloma Min Lang, Lu Dai, Nikunj Chauhan, Amanjit Gill PII:
S0954-6111(20)30043-3
DOI:
https://doi.org/10.1016/j.rmed.2020.105903
Reference:
YRMED 105903
To appear in:
Respiratory Medicine
Received Date: 7 October 2019 Accepted Date: 17 February 2020
Please cite this article as: Lang M, Dai L, Chauhan N, Gill A, Non-surgical treatment options for pulmonary aspergilloma, Respiratory Medicine (2020), doi: https://doi.org/10.1016/j.rmed.2020.105903. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd.
Author information: Min Lang MD, MSc1, Lu Dai MD, MSc2, Nikunj Chauhan MD3, Amanjit Gill MD3 1
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston,
Massachusetts 2
Department of Anesthesia, Massachusetts General Hospital, Harvard Medical School, Boston,
Massachusetts 3
Department of Interventional Radiology, Cleveland Clinic Foundation, Cleveland, OH
Corresponding author: Min Lang, MD, MSc Department of Radiology Massachusetts General Hospital, Harvard Medical School Boston, MA Cleveland, OH 44195 Tel: 216-924-8862 Email: [email protected]
Key words: aspergilloma, aspergillosis, intracavitary, endobronchial, radiotherapy, bronchial artery embolization
Contributions: ML – writing of manuscript, literature search, generation of tables; LD – writing of manuscript, literature search; NC – writing of manuscript, generation of figures; AG – writing of manuscript, generation of tables and figures. Funding: none Conflict of Interest: None
Non-surgical treatment options for pulmonary aspergilloma
Abstract Aspergilloma, also known as mycetoma or fungus ball, is the most common manifestation of pulmonary involvement by Aspergillus species. The fungal ball typically forms within preexisting cavities of the lungs. Diagnosis requires both radiographic evidence along with serologic or microbiologic evidence of Aspergillus species involvement. While clinical features such as hemoptysis, chest pain, shortness of breath, cough, and fever are helpful in diagnosis, they are non-specific symptoms. Surgery is currently the mainstay of treatment for 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 5080% of patients. Potential alternatives to surgery include intracavitary instillation or endobronchial 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.
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 pulmonary 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 surrounded 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 asymptomatic aspergilloma remains controversial.12 Some authors advocate 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 approximately 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 and may be an option for primarily asymptomatic aspergilloma patients.
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 underlying 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 (Figure 1B, 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 (CPA), regardless 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 Aspergillus species can be seen in chronic lung conditions including tuberculosis, chronic obstructive pulmonary disease (COPD), non-tuberculous mycobacteriosis, lung cancer, and interstitial lung disease.29
Non-surgical treatments While surgical resection is currently considered the gold standard of treatment for symptomatic aspergilloma, many patients have contraindications to surgery including poor respiratory reserve, multiple or bilateral aspergilloma, and patient preference. The morbidity associated with surgery is considerable and potential complications include hemorrhage, empyema, wound infection, tracheobronchitis, bronchopleural fistula formation, and seeding of Aspergillus infection.30-32 Fortunately, 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 approximately 5% over 3 years, or 7%-10% of all cases6,33,34; but the natural history of aspergilloma has not been extensively studied. For inoperable patients that require treatment, there are several alternatives.
Systemic administration of antifungal medication Amphoterocin B Systemic administration of amphotericin B has a reported cure rate of approximately 10%, which is similar to the spontaneous rate of resolution.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 postsurgical patients.36 Furthermore, the potential complications associated with amphoterocin
B, particularly nephrotoxicity, makes this option unfavorable.37 Within recent years, aerosolized 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.
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, treatment with 50-400mg itraconazole daily led to symptomatic improvement in 62% of cases with minor gastrointestinal side effects.44 A multicenter clinical trial demonstrated that daily dose of 200mg of itraconazole for a duration of six months is effective at treating aspergilloma, with a cure rate of 63.4%.45 In a more recent prospective study, Gupta et al. found patients treated with 200mg of itraconazole twice daily and those who received weight-based dosing had good 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 200mg orally every 12 hours, similar to treatment of invasive pulmonary aspergillosis, with the total duration of treatment dependent on the individual’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 voriconazole 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 voriconazole 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 6mg/kg IV every 12 hours for one day, and 4mg/kg IV every 12 hours thereafter; oral therapy can be 200-300mg every 12 hours.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, prolonged 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.
Intracavitary instillation of antifungal medication Direct intracavitary delivery of antifungal medication has been reported 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 (Figure 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 antifungals can be done on an outpatient basis.
The efficacy of intracavitary instillation amphotericin B varies between studies. Early case series on this technique by Brouet et al., Krakowka et al., Shapiro et al. and Hargis et al., showed that 66.6% to 100% of patients exhibited clinical improvement such as cessation of
hemoptysis.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 improvement 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 CTguided 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 201362 demonstrated that hemoptysis ceased in 85% of cases, however, recurrence 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 50mg daily for 10 days, Giron et al. treated the patients with 50mg daily for at least 15 days, and Lee et al. used 50mg for 15 days.57,61,62 The total dose of amphotericin B used in Yamada et al. ranged from 250mg to 1085mg.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 placement, or missing the cavity containing the fungal ball during amphotericin 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.
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 improvement 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, ketoconazole, 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. administered 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 treatment 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.
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 preprocedural planning, flexible bronchoscope through either a rigid bronchoscope or doublelumen endotracheal tube for access, 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 technique 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.
Treatment for hemoptysis 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, hemoptysis arises from the bronchial arteries due to changes in the terminal vascular bed, but collateral or variant supply can arise from other systemic arteries including intercostal, subclavian, or internal mammary arteries (Figure 3).69 Successful embolization semi-permanently occludes 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, however, 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 patients 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 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.
Radiotherapy When BAE is not successful at managing hemoptysis in patients who are poor surgical candidates, radiotherapy may be considered. Radiotherapy 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 perivascular 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 available. There is no consensus on the radiation dose that should be delivered 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 are needed to test the efficacy of radiotherapy before it can be widely recommended.
Radiofrequency Ablation Radiofrequency (RF) ablation (Figure 4) is a minimally invasive thermal 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 colleagues 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 minutes 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.
Summary Diagnosis of aspergilloma requires radiographic evidence as well as serologic or microbiologic evidence of Aspergillus species. While surgery 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 reported 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 requires 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, Figure 5 illustrates a proposed treatment algorithm for patients with aspergilloma.
Acknowledgements: We would like to thank Amanda Mendelsohn, medical illustrator at Cleveland Clinic, for providing us with illustrations used in Figures 1 and 2.
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Chow L, Brown NE, Kunimoto D. An unusual case of pulmonary invasive aspergillosis and aspergilloma cured with voriconazole in a patient with cystic fibrosis. Clin Infect Dis. 2002;35(9):e106-110. Freymond N, Le Loch JB, Devouassoux G, Harf R, Rakotomalala A, Pacheco Y. [Aspergillus bronchitis and aspergilloma treated successfully with voriconazole]. Rev Mal Respir. 2005;22(5 Pt 1):811-814. Campbell JH, Winter JH, Richardson MD, Shankland GS, Banham SW. Treatment of pulmonary aspergilloma with itraconazole. Thorax. 1991;46(11):839-841. Brouet G, Liot F, Demange J, Nevot P. [Local Treatment of Pulmonary Aspergilloma with Transparietal Injections of Amphotericin B]. Journal francais de medecine et chirurgie thoraciques. 1964;18:789-798. Klein JS, Fang K, Chang MC. Percutaneous transcatheter treatment of an intracavitary aspergilloma. Cardiovascular and interventional radiology. 1993;16(5):321-324. Shapiro MJ, Albelda SM, Mayock RL, McLean GK. Severe hemoptysis associated with pulmonary aspergilloma. Percutaneous intracavitary treatment. Chest. 1988;94(6):1225-1231. Krakowka P, Traczyk K, Walczak J, Halweg H, Elsner Z, Pawlicka L. Local treatment of aspergilloma of the lung with a paste containing nystatin or amphotericin B. Tubercle. 1970;51(2):184-191. Hargis JL, Bone RC, Stewart J, Rector N, Hiller FC. Intracavitary amphotereicin B in the treatment of symptomatic pulmonary aspergillomas. The American journal of medicine. 1980;68(3):389-394. Lee KS, Kim HT, Kim YH, Choe KO. Treatment of hemoptysis in patients with cavitary aspergilloma of the lung: value of percutaneous instillation of amphotericin B. AJR. American journal of roentgenology. 1993;161(4):727-731. Jackson M, Flower CD, Shneerson JM. Treatment of symptomatic pulmonary aspergillomas with intracavitary instillation of amphotericin B through an indwelling catheter. Thorax. 1993;48(9):928-930. Munk PL, Vellet AD, Rankin RN, Muller NL, Ahmad D. Intracavitary aspergilloma: transthoracic percutaneous injection of amphotericin gelatin solution. Radiology. 1993;188(3):821-823. Ryan PJ, Stableforth DE, Reynolds J, Muhdi KM. Treatment of pulmonary aspergilloma in cystic fibrosis by percutaneous instillation of amphotericin B via indwelling catheter. Thorax. 1995;50(7):809-810. Giron J, Poey C, Fajadet P, et al. CT-guided percutaneous treatment of inoperable pulmonary aspergillomas: a study of 40 cases. European journal of radiology. 1998;28(3):235-242. Kravitz JN, Berry MW, Schabel SI, Judson MA. A modern series of percutaneous intracavitary instillation of amphotericin B for the treatment of severe hemoptysis from pulmonary aspergilloma. Chest. 2013;143(5):1414-1421. Yamada H, Kohno S, Koga H, Maesaki S, Kaku M. Topical treatment of pulmonary aspergilloma by antifungals. Relationship between duration of the disease and efficacy of therapy. Chest. 1993;103(5):1421-1425. Ramirez J. Pulmonary Aspergilloma: Endobronchial Treatment. The New England journal of medicine. 1964;271:1281-1285.
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Rachel Hinerman FA, Ashish Singh, and Cesar Keller. Treatment of Endobronchial Mucormycosis with Amphotericin B Via Flexible Bronchoscopy. Journal of Bronchology. 2002;9(4):294-297. Hamamoto T, Watanabe K, Ikemoto H. Endobronchial miconazole for pulmonary aspergilloma. Annals of internal medicine. 1983;98(6):1030. Stather DR, Tremblay A, Dumoulin E, et al. A Series of Transbronchial Removal of Intracavitary Pulmonary Aspergilloma. Ann Thorac Surg. 2017;103(3):945-950. Tani S, Tomioka H, Tsuchimoto K, et al. [A case of pulmonary aspergilloma successfully treated with transbronchial intracavitary itraconazole]. Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society. 2008;46(12):9971002. Sopko DR, Smith TP. Bronchial artery embolization for hemoptysis. Seminars in interventional radiology. 2011;28(1):48-62. Serasli E, Kalpakidis V, Iatrou K, Tsara V, Siopi D, Christaki P. Percutaneous bronchial artery embolization in the management of massive hemoptysis in chronic lung diseases. Immediate and long-term outcomes. International angiology : a journal of the International Union of Angiology. 2008;27(4):319-328. He G, Liu W, Gao Z, Gao Z, Gao H, Wang Y. Intervention treatment on massive hemoptysis of pulmonary aspergilloma. Experimental and therapeutic medicine. 2017;13(5):2259-2262. Shin B, Koh WJ, Shin SW, et al. Outcomes of Bronchial Artery Embolization for LifeThreatening Hemoptysis in Patients with Chronic Pulmonary Aspergillosis. PloS one. 2016;11(12):e0168373. Prasad BPK, Ray B. Singular observation of a desirable change after bronchial artery embolization for hemoptysis in intracavitary aspergilloma. The Indian journal of radiology & imaging. 2017;27(2):225-228. Shneerson JM, Emerson PA, Phillips RH. Radiotherapy for massive haemoptysis from an aspergilloma. Thorax. 1980;35(12):953-954. Samuelian JM, Attia AA, Jensen CA, Monjazeb AM, Blackstock AW. Treatment of hemoptysis associated with aspergilloma using external beam radiotherapy: A case report and literature review. Practical radiation oncology. 2011;1(4):279-281. Falkson C, Sur R, Pacella J. External beam radiotherapy: a treatment option for massive haemoptysis caused by mycetoma. Clinical oncology. 2002;14(3):233-235. Glover S, Holt SG, Newman GH, Kingdon EJ. Radiotherapy for a pulmonary aspergilloma complicating p-ANCA positive small vessel vasculitis. The Journal of infection. 2007;54(4):e215-217. Latge JP. Aspergillus fumigatus and aspergillosis. Clin Microbiol Rev. 1999;12(2):310-350. Hiraki T, Gobara H, Kato K, et al. A case of pulmonary aspergilloma treated with radiofrequency ablation. Cardiovasc Intervent Radiol. 2014;37(2):554-557.
Figure Legend Figure 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) Figure 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. Figure 3. (A) Computed tomography image demonstrating pulmonary aspergilloma in the right lower lobe. (B) Digital subtraction angiogram of the left intercostobronchial trunk demonstrating hyperplastic bronchial artery (arrow) with significant hypervascularity around the aspergilloma cavity. Figure 4. CT-guided radiofrequency ablation in a case of pulmonary aspergilloma. Figure 5. Proposed treatment algorithm for patients with pulmonary aspergilloma.
Declaration of interests ☒ 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. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
S0954-6111(20)30043-3
DOI:
https://doi.org/10.1016/j.rmed.2020.105903
Reference:
YRMED 105903
To appear in:
Respiratory Medicine
Received Date: 7 October 2019 Accepted Date: 17 February 2020
Please cite this article as: Lang M, Dai L, Chauhan N, Gill A, Non-surgical treatment options for pulmonary aspergilloma, Respiratory Medicine (2020), doi: https://doi.org/10.1016/j.rmed.2020.105903. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd.
Author information: Min Lang MD, MSc1, Lu Dai MD, MSc2, Nikunj Chauhan MD3, Amanjit Gill MD3 1
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston,
Massachusetts 2
Department of Anesthesia, Massachusetts General Hospital, Harvard Medical School, Boston,
Massachusetts 3
Department of Interventional Radiology, Cleveland Clinic Foundation, Cleveland, OH
Corresponding author: Min Lang, MD, MSc Department of Radiology Massachusetts General Hospital, Harvard Medical School Boston, MA Cleveland, OH 44195 Tel: 216-924-8862 Email: [email protected]
Key words: aspergilloma, aspergillosis, intracavitary, endobronchial, radiotherapy, bronchial artery embolization
Contributions: ML – writing of manuscript, literature search, generation of tables; LD – writing of manuscript, literature search; NC – writing of manuscript, generation of figures; AG – writing of manuscript, generation of tables and figures. Funding: none Conflict of Interest: None
Non-surgical treatment options for pulmonary aspergilloma
Abstract Aspergilloma, also known as mycetoma or fungus ball, is the most common manifestation of pulmonary involvement by Aspergillus species. The fungal ball typically forms within preexisting cavities of the lungs. Diagnosis requires both radiographic evidence along with serologic or microbiologic evidence of Aspergillus species involvement. While clinical features such as hemoptysis, chest pain, shortness of breath, cough, and fever are helpful in diagnosis, they are non-specific symptoms. Surgery is currently the mainstay of treatment for 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 5080% of patients. Potential alternatives to surgery include intracavitary instillation or endobronchial 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.
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 pulmonary 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 surrounded 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 asymptomatic aspergilloma remains controversial.12 Some authors advocate 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 approximately 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 and may be an option for primarily asymptomatic aspergilloma patients.
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 underlying 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 (Figure 1B, 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 (CPA), regardless 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 Aspergillus species can be seen in chronic lung conditions including tuberculosis, chronic obstructive pulmonary disease (COPD), non-tuberculous mycobacteriosis, lung cancer, and interstitial lung disease.29
Non-surgical treatments While surgical resection is currently considered the gold standard of treatment for symptomatic aspergilloma, many patients have contraindications to surgery including poor respiratory reserve, multiple or bilateral aspergilloma, and patient preference. The morbidity associated with surgery is considerable and potential complications include hemorrhage, empyema, wound infection, tracheobronchitis, bronchopleural fistula formation, and seeding of Aspergillus infection.30-32 Fortunately, 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 approximately 5% over 3 years, or 7%-10% of all cases6,33,34; but the natural history of aspergilloma has not been extensively studied. For inoperable patients that require treatment, there are several alternatives.
Systemic administration of antifungal medication Amphoterocin B Systemic administration of amphotericin B has a reported cure rate of approximately 10%, which is similar to the spontaneous rate of resolution.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 postsurgical patients.36 Furthermore, the potential complications associated with amphoterocin
B, particularly nephrotoxicity, makes this option unfavorable.37 Within recent years, aerosolized 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.
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, treatment with 50-400mg itraconazole daily led to symptomatic improvement in 62% of cases with minor gastrointestinal side effects.44 A multicenter clinical trial demonstrated that daily dose of 200mg of itraconazole for a duration of six months is effective at treating aspergilloma, with a cure rate of 63.4%.45 In a more recent prospective study, Gupta et al. found patients treated with 200mg of itraconazole twice daily and those who received weight-based dosing had good 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 200mg orally every 12 hours, similar to treatment of invasive pulmonary aspergillosis, with the total duration of treatment dependent on the individual’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 voriconazole 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 voriconazole 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 6mg/kg IV every 12 hours for one day, and 4mg/kg IV every 12 hours thereafter; oral therapy can be 200-300mg every 12 hours.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, prolonged 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.
Intracavitary instillation of antifungal medication Direct intracavitary delivery of antifungal medication has been reported 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 (Figure 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 antifungals can be done on an outpatient basis.
The efficacy of intracavitary instillation amphotericin B varies between studies. Early case series on this technique by Brouet et al., Krakowka et al., Shapiro et al. and Hargis et al., showed that 66.6% to 100% of patients exhibited clinical improvement such as cessation of
hemoptysis.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 improvement 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 CTguided 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 201362 demonstrated that hemoptysis ceased in 85% of cases, however, recurrence 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 50mg daily for 10 days, Giron et al. treated the patients with 50mg daily for at least 15 days, and Lee et al. used 50mg for 15 days.57,61,62 The total dose of amphotericin B used in Yamada et al. ranged from 250mg to 1085mg.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 placement, or missing the cavity containing the fungal ball during amphotericin 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.
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 improvement 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, ketoconazole, 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. administered 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 treatment 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.
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 preprocedural planning, flexible bronchoscope through either a rigid bronchoscope or doublelumen endotracheal tube for access, 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 technique 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.
Treatment for hemoptysis 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, hemoptysis arises from the bronchial arteries due to changes in the terminal vascular bed, but collateral or variant supply can arise from other systemic arteries including intercostal, subclavian, or internal mammary arteries (Figure 3).69 Successful embolization semi-permanently occludes 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, however, 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 patients 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 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.
Radiotherapy When BAE is not successful at managing hemoptysis in patients who are poor surgical candidates, radiotherapy may be considered. Radiotherapy 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 perivascular 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 available. There is no consensus on the radiation dose that should be delivered 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 are needed to test the efficacy of radiotherapy before it can be widely recommended.
Radiofrequency Ablation Radiofrequency (RF) ablation (Figure 4) is a minimally invasive thermal 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 colleagues 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 minutes 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.
Summary Diagnosis of aspergilloma requires radiographic evidence as well as serologic or microbiologic evidence of Aspergillus species. While surgery 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 reported 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 requires 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, Figure 5 illustrates a proposed treatment algorithm for patients with aspergilloma.
Acknowledgements: We would like to thank Amanda Mendelsohn, medical illustrator at Cleveland Clinic, for providing us with illustrations used in Figures 1 and 2.
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Figure Legend Figure 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) Figure 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. Figure 3. (A) Computed tomography image demonstrating pulmonary aspergilloma in the right lower lobe. (B) Digital subtraction angiogram of the left intercostobronchial trunk demonstrating hyperplastic bronchial artery (arrow) with significant hypervascularity around the aspergilloma cavity. Figure 4. CT-guided radiofrequency ablation in a case of pulmonary aspergilloma. Figure 5. Proposed treatment algorithm for patients with pulmonary aspergilloma.
Declaration of interests ☒ 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. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: