Mycopathologia DOI 10.1007/s11046-015-9907-0
Acute Invasive Pulmonary Aspergillosis Complicating Allergic Bronchopulmonary Aspergillosis: Case Report and Systematic Review Venkata Nagarjuna Maturu . Ritesh Agarwal
Received: 6 April 2015 / Accepted: 26 May 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Aspergillus fumigatus can cause a variety of pulmonary syndromes including allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis and invasive pulmonary aspergillosis (IPA). Occurrence of IPA and ABPA in the same patient is rare as the risk factors for ABPA and IPA are different. We describe a 45-year-old male with ABPA treated with oral methylprednisolone and itraconazole, who developed acute respiratory failure secondary to IPA, a month later. The patient subsequently improved after systemic antifungal therapy. Presumably, itraconazole by inhibiting CYP3A4 enzyme caused an increase in plasma methylprednisolone levels. This probably led to a profound immunosuppressed state, which predisposed to the development of IPA. We performed a systematic review and identified nine cases of IPA following ABPA. The disease course is fulminant, and only three of the nine patients survived. Physicians treating ABPA patients should be aware of this potentially fatal overlap. Clinical suspicion and early diagnosis are crucial to improve the patient outcomes.
V. N. Maturu R. Agarwal (&) Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh 160012, India e-mail: [email protected]
Keywords ABPA ABPM Bronchial asthma Aspergillus Aspergillosis
Introduction Aspergillus fumigatus can cause a spectrum of pulmonary diseases, which are broadly classified as saprophytic, allergic or invasive [1]. The disease manifestation depends on the immune status (systemic as well as local) of the host as well as the structural integrity of the airways and the lung parenchyma [2]. The saprophytic pulmonary manifestation of Aspergillus is aspergilloma. Invasive forms of pulmonary aspergillosis include acute invasive pulmonary aspergillosis (IPA) or chronic pulmonary aspergillosis (CPA). The most common allergic manifestation of Aspergillus is allergic bronchopulmonary aspergillosis (ABPA) [3]. The disease entities caused by A. fumigatus are usually discrete due to different risk factors for the individual diseases. However, occurrence of Aspergillus overlap syndromes (AOS) is increasingly being recognized [4, 5]. AOS is defined as the occurrence of more than one form of Aspergillus disease in a single individual. This can be simultaneous, in which two syndromes develop from the onset (less common) or sequential (patient with one Aspergillus disease developing another). The most commonly cited examples are the development of saprophytic fungal balls in patients with allergic (ABPA) or invasive (CPA) forms of the
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Mycopathologia
A 45-year-old man presented to our emergency department with history of worsening breathlessness of oneweek duration. He was an asthmatic for the last 25 years, with worsening asthma control over the last 4 years. One month prior to presentation at our hospital, he was evaluated for poorly controlled asthma. Investigations had revealed elevated IgE, both total (3150 IU/mL) and A. fumigatus specific (20.8 kUA/L); peripheral blood eosinophil count was also raised (1420 cells/lL). Chest radiograph and high-resolution computed tomography (HRCT) of the chest showed the presence of central bronchiectasis (Fig. 1). He was diagnosed to have ABPA
with bronchiectasis and was started on oral methylprednisolone 24 mg/day and itraconazole 400 mg/day. There was symptomatic improvement within 2 weeks of starting therapy. However, 1 week prior to presentation, he developed worsening breathlessness, cough and expectoration. In the emergency room, he was hypoxemic with a room air oxygen saturation of 88 %. Auscultation of the chest revealed extensive wheeze. Chest radiograph showed the presence of multiple masslike lesions in both the lungs (Fig. 1). He was shifted to our respiratory intensive care unit, where he was managed with oxygen supplementation, nebulized bronchodilators and injectable antibiotics (meropenem). Serum IgE values had declined to 1250 U/mL (from 3150 IU/mL). CT of chest was performed again; it showed multiple masses, many of them cavitating with irregular inner margins, almost replacing the entire lung parenchyma (Fig. 1). A possibility of invasive fungal pneumonia was considered. Sputum microscopy showed the presence of numerous acute-angled branching septate hyphae conforming to the morphology of Aspergillus; cultures subsequently grew A. fumigatus. Serum galactomannan index was elevated (1.9). Cultures of sputum
Fig. 1 Chest radiograph and high-resolution computed tomography (HRCT) image at diagnosis of allergic bronchopulmonary aspergillosis showing the presence of central bronchiectasis (a,
b); Chest radiograph and HRCT image at admission showing presence of mass lesions replacing the lung parenchyma, many of them cavitating (c, d)
disease [6], and the occurrence of CPA in patients with ABPA [7]. However, development of IPA is distinctly uncommon in patients with ABPA. In this article, we describe a patient of ABPA who developed IPA after treatment with a methylprednisolone and itraconazole. We also systematically review the literature for the overlap of ABPA and IPA.
Case Report
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Mycopathologia
and blood for bacterial pathogens were sterile. A fineneedle aspiration cytology from wall of the cavitating mass showed the presence of acute inflammatory infiltrate. Bacterial or fungal organisms could not be demonstrated in the cytology specimen. Antinuclear antibody, anti-neutrophil cytoplasmic antibody and serology for human immunodeficiency virus were all negative. Echocardiography did not reveal any vegetations. A diagnosis of probable IPA was made according to the EORTC-MSG 2008 diagnostic criteria; the patient was started on liposomal amphotericin at 150 mg/day and received a cumulative dose of 2100 mg. There was significant improvement in symptoms, and the patient recovered from respiratory failure. A repeat chest radiograph done 3 weeks after therapy showed near complete resolution of the masses with only residual thin-walled cavities (Fig. 2).
Systematic Review We first searched the PubMed and EmBase databases for any systematic review reporting overlap of IPA with ABPA. No systematic review was found. We then independently searched the PubMed and EmBase databases (till January 2015) using the following free text terms: (‘‘ABPA’’ OR ‘‘allergic bronchopulmonary aspergillosis’’ OR ‘‘allergic broncho pulmonary aspergillosis’’ OR ‘‘allergic aspergillosis’’) AND (‘‘invasive aspergillosis’’ OR ‘‘invasive’’ OR ‘‘invasion’’ OR ‘‘dissemination’’ or ‘‘disseminated’’ OR ‘‘cerebral’’). Editorials, reviews and articles not published in
English language were excluded. Articles reporting chronic/subacute forms of invasive aspergillosis, and those reporting invasion in only extrapulmonary organs were also excluded. Any disagreement between the authors was resolved by consensus. The database created from the electronic searches was compiled in a reference manager package (Endnote X7), and all duplicate citations were eliminated. The citations were first screened by the authors to capture the relevant studies. The full text of each citation was obtained and reviewed in detail. Data were recorded on a standard data extraction sheet. The following items were extracted: (a) publication details (title, authors, and other citation details); (b) patient details (age, sex, final diagnosis obtained); (c) basis for diagnosis of ABPA and the treatment received for ABPA; (d) clinical presentation and the organs involved at the diagnosis of IPA; (e) treatment received for IPA; and (f) the final outcome of the patient. Our initial database search yielded 782 references of which nine studies (excluding the index patient) were included for the final review (Fig. 3) [8–15]. The characteristics of the individual studies are summarized in Table 1. The mean (SD) age of the patients was 44 (15.8) years. The basic disease predisposing to ABPA was asthma in all cases except one patient (cystic fibrosis) [12]. All the patients were on oral steroids for varying durations ranging from 1 month to 5 years. Of the ten cases, the invasion was limited to the lung in five patients and there was disseminated aspergillosis in the rest. The most common extrapulmonary sites involved were the brain, kidneys and the thyroid (three patients each). The clinical presentation was with acute onset of non-specific pulmonary symptoms and respiratory failure in all patients. Two patients had hemoptysis. The diagnosis was suspected antemortem in six of the ten patients. These patients were managed with amphotericin alone (n = 3) or with a combination of amphotericin and surgical resection (n = 3). Only four of the ten patients recovered from the illness.
Discussion
Fig. 2 Chest radiograph (after treatment) showing resolution of the masses which are now replaced by thin-walled cavitary lesions
We describe a patient with an unusual form of AOS, namely acute invasive pulmonary aspergillosis in a patient with ABPA. The pulmonary manifestations of Aspergillus infection usually tend to remain distinct, and occurrence of such overlap syndromes is uncommon.
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Mycopathologia Fig. 3 Citation selection process for the systematic review
Allergic bronchopulmonary aspergillosis has an estimated global burden of 4.8 million patients [7, 16]. The host factors that predispose an individual to develop ABPA are still not clear and include genetic alterations in adaptive and innate immune responses [3]. Patients who develop ABPA are either asthmatic patients or have cystic fibrosis and are not immunosuppressed. Invasive pulmonary aspergillosis, on the other hand, is a disease of the immunosuppressed individuals, the degree of immune compromise determining the clinical course of the disease. The classical risk factors for development of IPA include neutropenia, chemotherapy, post-transplant status, chronic granulomatous disease, hematologic malignancies and high-dose steroid use.
123
Development of chronic pleuropulmonary lesions in patients with long-standing ABPA is well known. Such patients are classified as having ABPA-CPF (chronic pleuropulmonary fibrosis) according to the newly proposed radiologic classification [17]. Development of invasive forms of CPA has also been reported in the literature [18–20]. However, occurrence of acute IPA in a patient with ABPA is distinctly uncommon. Our systematic review yielded only nine cases (excluding the index case) of acute IPA developing in patients with ABPA. Several postulations have been put forth to explain the overlap of IPA with ABPA. The most widely quoted reason is the use of steroids, which suppresses the immunity and leads to invasion by the Aspergilli which are present in the
43/F
21/F
52/M
62/M
15/M
59/F
43/M
60/M
40/M
45/M
Anderson et al. [8]
Starke and Keal [9]
Bodey and Glann [10]
Aquino et al. [11]
Chung et al. [12]
Ganassini and Cazzadori [13]
Chen and Jerome [14]
Gupta et al. [15]
Waldron et al. [26]
Index case
BA, IgE, AfIgE, CXR, Eos
NA
BA, AST, IgE, AfIgE, CXR
NA
BA, IgE, CXR, Eos, AspP, AfIgE
CF, IgE, AfIgE, CXR
NA
BA, AST, IgE, Eos
BA, AST, IgE, AspP, CXR, Eos, AfIgE BA, AST, AspP, CXR, Eos
Basis for the diagnosis of ABPA
Steroids and itraconazole, 1 month
Steroids, 5 weeks
Steroids, NA
Steroids, 5 years
Steroids, NA
Steroids, 5 years
Steroids, NA
Steroids, 2 months
Steroids, 3 years
Steroids, 3 years
Treatment of ABPA, duration
Lung
Lung
Disseminated (lung, heart, kidney, thyroid, colon)
Lung
Lung
Disseminated (lung, brain, kidney, heart, thyroid, bone marrow)
Lung
Disseminated (lungs, brain)
Disseminated (lungs, kidneys, myocardium, thyroid) Disseminated (lungs, brain)
Site of invasion of Aspergillus
Cough and dyspnea for 1 week
Necrotizing pneumonia with bronchopleural fistula
Fever, cough, dyspnea
Cough, hemoptysis, dyspnea, chest pain
Fever and dyspnea for 1 week
Worsening breathlessness and wheeze
NA
Fever, respiratory failure, altered sensorium
Acute exacerbation of asthma
Acute exacerbation of asthma, hemoptysis
Clinical presentation
Antemortem
Antemortem
Postmortem
Antemortem
Antemortem
Antemortem
Postmortem
Antemortem
Postmortem
Postmortem
Time at diagnosis of IA
i.v. amphotericin
Left upper lobectomy
–
Pneumonectomy
i.v. amphotericin
i.v. amphotericin
–
Excision of cerebral aspergilloma, i.v. amphotericin
–
–
Treatment received for IA
Improved
Improved
Died
Improved
Died
Died
Died
Improved
Died
Died
Final outcome
AST Aspergillus skin test type 1 positivity, AfIgE elevated Aspergillus fumigatus specific IgE level, BA bronchial asthma, CF cystic fibrosis, CXR chest radiograph, Eos eosinophilia, F female, IgE elevated total IgE level, i.v. intravenous, M male, NA not available, AspP serum precipitins against Aspergillus, Sp sputum positive for Aspergillus
Age/gender
References
Table 1 Clinical presentation, treatment details and outcomes of the reports describing acute invasive aspergillosis (IA) in patients with allergic bronchopulmonary aspergillosis (ABPA)
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bronchiectatic airways. However, this explanation alone is not sufficient, as most ABPA patients receiving long-term corticosteroids do not develop acute IPA. Although long-term corticosteroid use ([3 weeks) is considered a risk factor for development of IPA, patients with ABPA rarely develop IPA [21]. The reason for such immunity from invasion remains unclear, but is likely due to the net state of immunosuppression, which is not very low in patients with ABPA as they are otherwise healthy individuals. The index patient was on treatment with a combination of oral methylprednisolone and itraconazole. Itraconazole being a CYP3A4 enzyme inhibitor decreases the metabolism of steroids, thereby increasing their plasma concentration and half-life [22, 23]. This leads to adrenal suppression and increases the propensity for other steroid-related side effects like secondary infections [24]. Itraconazole has been shown to increase the drug levels of methylprednisolone, while there is only negligible increase in prednisolone levels [25]. We may presume that the use of itraconazole and methylprednisolone combination in the index patient could have led to a potent immunosuppressive state, and thus IPA. Other reasons that have been proposed include an intercurrent viral illness (like influenza) which suppress the local defenses and predisposes to invasion by the preexisting fungi [9]. Use of multiple broad-spectrum antibiotics is known to alter the local microbiologic flora; and, in a patient with structural lung disease and steroid use, this might contribute to development of IPA [12]. However, the exact reason why only a few patients of ABPA go on to develop IPA remains an enigma. In conclusion, development of invasive pulmonary aspergillosis is an uncommon but life-threatening complication in patients with ABPA. Physicians should be aware of this possible overlap syndrome. Early diagnosis is essential so that appropriate antifungal therapy may be instituted. When a combination of itraconazole with steroids is considered essential, prednisolone should always be used in preference to methylprednisolone. Conflict of interest
None.
References 1. Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary aspergillosis. Chest. 2002;121(6):1988–99.
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2. Patterson KC, Strek ME. Diagnosis and treatment of pulmonary aspergillosis syndromes. Chest. 2014;146(5): 1358–68. doi:10.1378/chest.14-0917. 3. Agarwal R. Allergic bronchopulmonary aspergillosis. Chest. 2009;135(3):805–26. doi:10.1378/chest.08-2586. 4. Buckingham SJ, Hansell DM. Aspergillus in the lung: diverse and coincident forms. Eur Radiol. 2003;13(8): 1786–800. doi:10.1007/s00330-002-1813-4. 5. Kousha M, Tadi R, Soubani AO. Pulmonary aspergillosis: a clinical review. Eur Respir Rev. 2011;20(121):156–74. doi:10.1183/09059180.00001011. 6. Agarwal R, Aggarwal AN, Garg M, Saikia B, Gupta D, Chakrabarti A. Allergic bronchopulmonary aspergillosis with aspergilloma: an immunologically severe disease with poor outcome. Mycopathologia. 2012;174(3):193–201. doi:10.1007/s11046-012-9535-x. 7. Denning DW, Pleuvry A, Cole DC. Global burden of allergic bronchopulmonary aspergillosis with asthma and its complication chronic pulmonary aspergillosis in adults. Med Mycol. 2013;51(4):361–70. doi:10.3109/13693786. 2012.738312. 8. Anderson CJ, Craig S, Bardana EJ Jr. Allergic bronchopulmonary aspergillosis and bilateral fungal balls terminating in disseminated aspergillosis. J Allergy Clin Immunol. 1980;65(2):140–4. 9. Starke ID, Keal EE. Cerebral aspergilloma in a patient with allergic bronchopulmonary aspergillosis. Br J Dis Chest. 1980;74(3):301–5. 10. Bodey GP, Glann AS. Central nervous system aspergillosis following steroidal therapy for allergic bronchopulmonary aspergillosis. Chest. 1993;103(1):299–301. 11. Aquino SL, Kee ST, Warnock ML, Gamsu G. Pulmonary aspergillosis: imaging findings with pathologic correlation. AJR Am J Roentgenol. 1994;163(4):811–5. doi:10.2214/ ajr.163.4.8092014. 12. Chung Y, Kraut JR, Stone AM, Valaitis J. Disseminated aspergillosis in a patient with cystic fibrosis and allergic bronchopulmonary aspergillosis. Pediatr Pulmonol. 1994; 17(2):131–4. 13. Ganassini A, Cazzadori A. Invasive pulmonary aspergillosis complicating allergic bronchopulmonary aspergillosis. Respir Med. 1995;89(2):143–5. 14. Chen W, Jerome DC. Invasive aspergillosis from the treatment of allergic bronchopulmonary aspergillosis with high dose oral steroids in an immunocompetent patient. J Allergy Clin Immunol. 2002;109(1):S343. doi:10.1016/S00916749(02)82201-1. 15. Gupta K, Das A, Joshi K, Singh N, Aggarwal R, Prakash M. Aspergillus endocarditis in a known case of allergic bronchopulmonary aspergillosis: an autopsy report. Cardiovasc Pathol. 2010;19(4):e137–9. doi:10.1016/j.carpath.2008.12. 002. 16. Agarwal R, Denning DW, Chakrabarti A. Estimation of the burden of chronic and allergic pulmonary aspergillosis in India. PLoS One. 2014;9(12):e114745. doi:10.1371/journal. pone.0114745. 17. Agarwal R, Chakrabarti A, Shah A, Gupta D, Meis JF, Guleria R, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clin Exp Allergy. 2013;43(8): 850–73. doi:10.1111/cea.12141.
Mycopathologia 18. Henderson AH. Allergic aspergillosis: review of 32 cases. Thorax. 1968;23(5):501–12. 19. Riley DJ, Mackenzie JW, Uhlman WE, Edelman NH. Allergic bronchopulmonary aspergillosis: evidence of limited tissue invasion. Am Rev Respir Dis. 1975;111(2): 232–6. 20. Fagbami O, Platt AB. A unique case of coexisting ABPA and semi-invasive aspergillosis in an immunocompetent patient. J Gen Intern Med. 2012;27:S376–7. 21. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46(12):1813–21. doi:10.1086/588660. 22. Varis T, Kaukonen KM, Kivisto KT, Neuvonen PJ. Plasma concentrations and effects of oral methylprednisolone are
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considerably increased by itraconazole. Clin Pharmacol Ther. 1998;64(4):363–8. doi:10.1016/s0009-9236(98)90066-2. Varis T, Kivisto KT, Neuvonen PJ. The effect of itraconazole on the pharmacokinetics and pharmacodynamics of oral prednisolone. Eur J Clin Pharmacol. 2000;56(1):57–60. Linthoudt H, Van Raemdonck D, Lerut T, Demedts M, Verleden G. The association of itraconazole and methylprednisolone may give rise to important steroid-related side effects. J Heart Lung Transplant. 1996;15(11):1165. Lebrun-Vignes B, Archer VC, Diquet B, Levron JC, Chosidow O, Puech AJ, et al. Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects. Br J Clin Pharmacol. 2001;51(5):443–50. Waldron RM, Cushen B, Gilmartin JJ, Rutherford R. A complicated case of ABPA. Ir J Med Sci. 2012;181:S391.
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Acute Invasive Pulmonary Aspergillosis Complicating Allergic Bronchopulmonary Aspergillosis: Case Report and Systematic Review Venkata Nagarjuna Maturu . Ritesh Agarwal
Received: 6 April 2015 / Accepted: 26 May 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Aspergillus fumigatus can cause a variety of pulmonary syndromes including allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis and invasive pulmonary aspergillosis (IPA). Occurrence of IPA and ABPA in the same patient is rare as the risk factors for ABPA and IPA are different. We describe a 45-year-old male with ABPA treated with oral methylprednisolone and itraconazole, who developed acute respiratory failure secondary to IPA, a month later. The patient subsequently improved after systemic antifungal therapy. Presumably, itraconazole by inhibiting CYP3A4 enzyme caused an increase in plasma methylprednisolone levels. This probably led to a profound immunosuppressed state, which predisposed to the development of IPA. We performed a systematic review and identified nine cases of IPA following ABPA. The disease course is fulminant, and only three of the nine patients survived. Physicians treating ABPA patients should be aware of this potentially fatal overlap. Clinical suspicion and early diagnosis are crucial to improve the patient outcomes.
V. N. Maturu R. Agarwal (&) Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh 160012, India e-mail: [email protected]
Keywords ABPA ABPM Bronchial asthma Aspergillus Aspergillosis
Introduction Aspergillus fumigatus can cause a spectrum of pulmonary diseases, which are broadly classified as saprophytic, allergic or invasive [1]. The disease manifestation depends on the immune status (systemic as well as local) of the host as well as the structural integrity of the airways and the lung parenchyma [2]. The saprophytic pulmonary manifestation of Aspergillus is aspergilloma. Invasive forms of pulmonary aspergillosis include acute invasive pulmonary aspergillosis (IPA) or chronic pulmonary aspergillosis (CPA). The most common allergic manifestation of Aspergillus is allergic bronchopulmonary aspergillosis (ABPA) [3]. The disease entities caused by A. fumigatus are usually discrete due to different risk factors for the individual diseases. However, occurrence of Aspergillus overlap syndromes (AOS) is increasingly being recognized [4, 5]. AOS is defined as the occurrence of more than one form of Aspergillus disease in a single individual. This can be simultaneous, in which two syndromes develop from the onset (less common) or sequential (patient with one Aspergillus disease developing another). The most commonly cited examples are the development of saprophytic fungal balls in patients with allergic (ABPA) or invasive (CPA) forms of the
123
Mycopathologia
A 45-year-old man presented to our emergency department with history of worsening breathlessness of oneweek duration. He was an asthmatic for the last 25 years, with worsening asthma control over the last 4 years. One month prior to presentation at our hospital, he was evaluated for poorly controlled asthma. Investigations had revealed elevated IgE, both total (3150 IU/mL) and A. fumigatus specific (20.8 kUA/L); peripheral blood eosinophil count was also raised (1420 cells/lL). Chest radiograph and high-resolution computed tomography (HRCT) of the chest showed the presence of central bronchiectasis (Fig. 1). He was diagnosed to have ABPA
with bronchiectasis and was started on oral methylprednisolone 24 mg/day and itraconazole 400 mg/day. There was symptomatic improvement within 2 weeks of starting therapy. However, 1 week prior to presentation, he developed worsening breathlessness, cough and expectoration. In the emergency room, he was hypoxemic with a room air oxygen saturation of 88 %. Auscultation of the chest revealed extensive wheeze. Chest radiograph showed the presence of multiple masslike lesions in both the lungs (Fig. 1). He was shifted to our respiratory intensive care unit, where he was managed with oxygen supplementation, nebulized bronchodilators and injectable antibiotics (meropenem). Serum IgE values had declined to 1250 U/mL (from 3150 IU/mL). CT of chest was performed again; it showed multiple masses, many of them cavitating with irregular inner margins, almost replacing the entire lung parenchyma (Fig. 1). A possibility of invasive fungal pneumonia was considered. Sputum microscopy showed the presence of numerous acute-angled branching septate hyphae conforming to the morphology of Aspergillus; cultures subsequently grew A. fumigatus. Serum galactomannan index was elevated (1.9). Cultures of sputum
Fig. 1 Chest radiograph and high-resolution computed tomography (HRCT) image at diagnosis of allergic bronchopulmonary aspergillosis showing the presence of central bronchiectasis (a,
b); Chest radiograph and HRCT image at admission showing presence of mass lesions replacing the lung parenchyma, many of them cavitating (c, d)
disease [6], and the occurrence of CPA in patients with ABPA [7]. However, development of IPA is distinctly uncommon in patients with ABPA. In this article, we describe a patient of ABPA who developed IPA after treatment with a methylprednisolone and itraconazole. We also systematically review the literature for the overlap of ABPA and IPA.
Case Report
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Mycopathologia
and blood for bacterial pathogens were sterile. A fineneedle aspiration cytology from wall of the cavitating mass showed the presence of acute inflammatory infiltrate. Bacterial or fungal organisms could not be demonstrated in the cytology specimen. Antinuclear antibody, anti-neutrophil cytoplasmic antibody and serology for human immunodeficiency virus were all negative. Echocardiography did not reveal any vegetations. A diagnosis of probable IPA was made according to the EORTC-MSG 2008 diagnostic criteria; the patient was started on liposomal amphotericin at 150 mg/day and received a cumulative dose of 2100 mg. There was significant improvement in symptoms, and the patient recovered from respiratory failure. A repeat chest radiograph done 3 weeks after therapy showed near complete resolution of the masses with only residual thin-walled cavities (Fig. 2).
Systematic Review We first searched the PubMed and EmBase databases for any systematic review reporting overlap of IPA with ABPA. No systematic review was found. We then independently searched the PubMed and EmBase databases (till January 2015) using the following free text terms: (‘‘ABPA’’ OR ‘‘allergic bronchopulmonary aspergillosis’’ OR ‘‘allergic broncho pulmonary aspergillosis’’ OR ‘‘allergic aspergillosis’’) AND (‘‘invasive aspergillosis’’ OR ‘‘invasive’’ OR ‘‘invasion’’ OR ‘‘dissemination’’ or ‘‘disseminated’’ OR ‘‘cerebral’’). Editorials, reviews and articles not published in
English language were excluded. Articles reporting chronic/subacute forms of invasive aspergillosis, and those reporting invasion in only extrapulmonary organs were also excluded. Any disagreement between the authors was resolved by consensus. The database created from the electronic searches was compiled in a reference manager package (Endnote X7), and all duplicate citations were eliminated. The citations were first screened by the authors to capture the relevant studies. The full text of each citation was obtained and reviewed in detail. Data were recorded on a standard data extraction sheet. The following items were extracted: (a) publication details (title, authors, and other citation details); (b) patient details (age, sex, final diagnosis obtained); (c) basis for diagnosis of ABPA and the treatment received for ABPA; (d) clinical presentation and the organs involved at the diagnosis of IPA; (e) treatment received for IPA; and (f) the final outcome of the patient. Our initial database search yielded 782 references of which nine studies (excluding the index patient) were included for the final review (Fig. 3) [8–15]. The characteristics of the individual studies are summarized in Table 1. The mean (SD) age of the patients was 44 (15.8) years. The basic disease predisposing to ABPA was asthma in all cases except one patient (cystic fibrosis) [12]. All the patients were on oral steroids for varying durations ranging from 1 month to 5 years. Of the ten cases, the invasion was limited to the lung in five patients and there was disseminated aspergillosis in the rest. The most common extrapulmonary sites involved were the brain, kidneys and the thyroid (three patients each). The clinical presentation was with acute onset of non-specific pulmonary symptoms and respiratory failure in all patients. Two patients had hemoptysis. The diagnosis was suspected antemortem in six of the ten patients. These patients were managed with amphotericin alone (n = 3) or with a combination of amphotericin and surgical resection (n = 3). Only four of the ten patients recovered from the illness.
Discussion
Fig. 2 Chest radiograph (after treatment) showing resolution of the masses which are now replaced by thin-walled cavitary lesions
We describe a patient with an unusual form of AOS, namely acute invasive pulmonary aspergillosis in a patient with ABPA. The pulmonary manifestations of Aspergillus infection usually tend to remain distinct, and occurrence of such overlap syndromes is uncommon.
123
Mycopathologia Fig. 3 Citation selection process for the systematic review
Allergic bronchopulmonary aspergillosis has an estimated global burden of 4.8 million patients [7, 16]. The host factors that predispose an individual to develop ABPA are still not clear and include genetic alterations in adaptive and innate immune responses [3]. Patients who develop ABPA are either asthmatic patients or have cystic fibrosis and are not immunosuppressed. Invasive pulmonary aspergillosis, on the other hand, is a disease of the immunosuppressed individuals, the degree of immune compromise determining the clinical course of the disease. The classical risk factors for development of IPA include neutropenia, chemotherapy, post-transplant status, chronic granulomatous disease, hematologic malignancies and high-dose steroid use.
123
Development of chronic pleuropulmonary lesions in patients with long-standing ABPA is well known. Such patients are classified as having ABPA-CPF (chronic pleuropulmonary fibrosis) according to the newly proposed radiologic classification [17]. Development of invasive forms of CPA has also been reported in the literature [18–20]. However, occurrence of acute IPA in a patient with ABPA is distinctly uncommon. Our systematic review yielded only nine cases (excluding the index case) of acute IPA developing in patients with ABPA. Several postulations have been put forth to explain the overlap of IPA with ABPA. The most widely quoted reason is the use of steroids, which suppresses the immunity and leads to invasion by the Aspergilli which are present in the
43/F
21/F
52/M
62/M
15/M
59/F
43/M
60/M
40/M
45/M
Anderson et al. [8]
Starke and Keal [9]
Bodey and Glann [10]
Aquino et al. [11]
Chung et al. [12]
Ganassini and Cazzadori [13]
Chen and Jerome [14]
Gupta et al. [15]
Waldron et al. [26]
Index case
BA, IgE, AfIgE, CXR, Eos
NA
BA, AST, IgE, AfIgE, CXR
NA
BA, IgE, CXR, Eos, AspP, AfIgE
CF, IgE, AfIgE, CXR
NA
BA, AST, IgE, Eos
BA, AST, IgE, AspP, CXR, Eos, AfIgE BA, AST, AspP, CXR, Eos
Basis for the diagnosis of ABPA
Steroids and itraconazole, 1 month
Steroids, 5 weeks
Steroids, NA
Steroids, 5 years
Steroids, NA
Steroids, 5 years
Steroids, NA
Steroids, 2 months
Steroids, 3 years
Steroids, 3 years
Treatment of ABPA, duration
Lung
Lung
Disseminated (lung, heart, kidney, thyroid, colon)
Lung
Lung
Disseminated (lung, brain, kidney, heart, thyroid, bone marrow)
Lung
Disseminated (lungs, brain)
Disseminated (lungs, kidneys, myocardium, thyroid) Disseminated (lungs, brain)
Site of invasion of Aspergillus
Cough and dyspnea for 1 week
Necrotizing pneumonia with bronchopleural fistula
Fever, cough, dyspnea
Cough, hemoptysis, dyspnea, chest pain
Fever and dyspnea for 1 week
Worsening breathlessness and wheeze
NA
Fever, respiratory failure, altered sensorium
Acute exacerbation of asthma
Acute exacerbation of asthma, hemoptysis
Clinical presentation
Antemortem
Antemortem
Postmortem
Antemortem
Antemortem
Antemortem
Postmortem
Antemortem
Postmortem
Postmortem
Time at diagnosis of IA
i.v. amphotericin
Left upper lobectomy
–
Pneumonectomy
i.v. amphotericin
i.v. amphotericin
–
Excision of cerebral aspergilloma, i.v. amphotericin
–
–
Treatment received for IA
Improved
Improved
Died
Improved
Died
Died
Died
Improved
Died
Died
Final outcome
AST Aspergillus skin test type 1 positivity, AfIgE elevated Aspergillus fumigatus specific IgE level, BA bronchial asthma, CF cystic fibrosis, CXR chest radiograph, Eos eosinophilia, F female, IgE elevated total IgE level, i.v. intravenous, M male, NA not available, AspP serum precipitins against Aspergillus, Sp sputum positive for Aspergillus
Age/gender
References
Table 1 Clinical presentation, treatment details and outcomes of the reports describing acute invasive aspergillosis (IA) in patients with allergic bronchopulmonary aspergillosis (ABPA)
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bronchiectatic airways. However, this explanation alone is not sufficient, as most ABPA patients receiving long-term corticosteroids do not develop acute IPA. Although long-term corticosteroid use ([3 weeks) is considered a risk factor for development of IPA, patients with ABPA rarely develop IPA [21]. The reason for such immunity from invasion remains unclear, but is likely due to the net state of immunosuppression, which is not very low in patients with ABPA as they are otherwise healthy individuals. The index patient was on treatment with a combination of oral methylprednisolone and itraconazole. Itraconazole being a CYP3A4 enzyme inhibitor decreases the metabolism of steroids, thereby increasing their plasma concentration and half-life [22, 23]. This leads to adrenal suppression and increases the propensity for other steroid-related side effects like secondary infections [24]. Itraconazole has been shown to increase the drug levels of methylprednisolone, while there is only negligible increase in prednisolone levels [25]. We may presume that the use of itraconazole and methylprednisolone combination in the index patient could have led to a potent immunosuppressive state, and thus IPA. Other reasons that have been proposed include an intercurrent viral illness (like influenza) which suppress the local defenses and predisposes to invasion by the preexisting fungi [9]. Use of multiple broad-spectrum antibiotics is known to alter the local microbiologic flora; and, in a patient with structural lung disease and steroid use, this might contribute to development of IPA [12]. However, the exact reason why only a few patients of ABPA go on to develop IPA remains an enigma. In conclusion, development of invasive pulmonary aspergillosis is an uncommon but life-threatening complication in patients with ABPA. Physicians should be aware of this possible overlap syndrome. Early diagnosis is essential so that appropriate antifungal therapy may be instituted. When a combination of itraconazole with steroids is considered essential, prednisolone should always be used in preference to methylprednisolone. Conflict of interest
None.
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