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Home , Allergic rhinitis, Aspergillosis, Atelectasis, Atopy, Fusarium, Mycosis

Allergic Bronchopulmonary

Karen Patterson1 and Mary E. Strek1

1Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, Illinois

Allergic bronchopulmonary aspergillosis (ABPA) is a complex clinical type of pulmonary that may develop in response to entity that results from an allergic immune response to aspergillus exposure (6) (Table 1). ABPA, one of the many fumigatus, most often occurring in a patient with or cystic forms of aspergillus disease, results from a hyperreactive im- fibrosis. Sensitization to aspergillus in the allergic host leads to mune response to A. fumigatus without invasion. activation of T helper 2 lymphocytes, which play a key role in ABPA occurs almost exclusively in patients with asthma or recruiting and other inflammatory mediators. ABPA is CF who have concomitant . The precise incidence of defined by a constellation of clinical, laboratory, and radiographic ABPA in patients with asthma and CF is not known but it is criteria that include active asthma, serum , an elevated not high. Approximately 2% of patients with asthma and 1 to total IgE level, fleeting pulmonary parenchymal opacities, bronchi- 15% of patients with CF develop ABPA (2, 4). Although the ectasis, and evidence for sensitization to by incidence of ABPA has been shown to increase in some areas of skin testing. Specific diagnostic criteria exist and have evolved over the world during months when total counts are high, the past several decades. Staging can be helpful to distinguish active disease from remission or end-stage with ABPA occurs year round, and the incidence has not been progressive destruction of parenchyma and loss of lung definitively shown to correlate with total ambient aspergillus function. Early recognition allows treatment with , counts (1, 7). There is no gender predilection noted. which are effective but may be required indefinitely. There is some evidence to support the use of newer azoles as cortico- -sparing agents. Patients must be followed closely for re- PATHOPHYSIOLOGY current disease. ABPA should be considered in all patients with The pathophysiology of ABPA is complex. In an allergic host, asthma or cystic fibrosis, but especially in those with difficult to the persistence of A. fumigatus in the lung leads to T lympho- control disease. cyte activation, , and immunoglobulin (Ig) release and Keywords: allergic bronchopulmonary aspergillosis; ABPA; asthma; inflammatory cell recruitment. Local inflammation results in cystic fibrosis; aspergillus production, airway hyperreactivity, and ultimately bron- chiectasis. Allergic bronchopulmonary aspergillosis (ABPA) is an indolent A viscous mucus layer in the airway, combined with dys- and potentially progressive disease resulting from a hypersensi- functional clearance in the case of CF, may disrupt the natural tivity response to persistent Aspergillus fumagatus in the airways. process of effective spore removal (2, 8). Aspergillus proteolytic Advances have been made in our understanding of the role of products may also interfere with airway clearance by damage to the allergic response in the pathophysiology of this disease (1, 2). and disruption of the epithelial cell barrier (4, 9). Once resident, ABPA occurs most commonly in patients with asthma or cystic aspergillus germinates and proliferates, and antigen burdens can fibrosis (CF), especially those with coexisting atopy (3, 4). become high. Dendritic cells are local antigen-presenting cells Patients present with symptoms that may be attributed to their that process spore and mycelia antigens. This processing leads underlying disease; therefore, considering ABPA in these patient to the release of specific by antigen-presenting cells populations is important. is directed at mitigating the and to antigen presentation to T lymphocytes (10). In the allergic inflammatory response (5). Early diagnosis and treatment normal host, the response to antigen presentation is activation has been thought to prevent disease progression, parenchymal of nonallergic T helper (Th)1 and allergic (Th2) lymphocytes damage, and loss of lung function. In this review we highlight (10, 11). The Th1 response is marked by and salient clinical features and the current understanding of the cytotoxic action as well as IgG and IgA pathophysiology of ABPA and review treatment options. production, which may protect against aspergillus (12). A frank defect in the Th1 cytotoxic pathway is not present in BACKGROUND AND EPIDEMIOLOGY ABPA, although it is present in immunocompromised patients who are at risk for invasive disease. Activation of the Th2 Aspergillus is a that is found throughout the world. Its pathway results in specific cytokine and immunoglobulin elab- are hardy and ubiquitous, thriving in moist, organic oration that mediate allergic inflammation. Th2 signaling pre- materials. Aspergillus can be cultured from outdoor and indoor dominates in the aspergillus allergic host; the imbalance of the environments and grows optimally at core body temperature Th2 over the Th1 response is thought to drive ABPA (1, 4). (1). Spores are tiny and easily aerosolized and deposit in distal Although the Th2 response predominates in patients with and terminal airways, where they germinate if the airway to aspergillus and in patients with ABPA, the magnitude environment is favorable. Aspergillus is variably pathogenic in of the Th2 immune activation is greatest in ABPA (12). humans. Host characteristics are a major determinant of the Activated Th2 cells release specific cytokines that orches- trate downstream cell signaling and the inflammatory response (11). IL-4 may be especially important. It is linked to B-cell isotype conversion to IgE production, the expression of vascular (Received in original form August 10, 2009; accepted in final form September 8, 2009) cell adhesion molecules on endothelial cells and vascular cell Correspondence and requests for reprints should be addressed to Mary E. Strek, adhesion molecule ligands on eosinophils, and to IgE and IgA M.D., The University of Chicago, Department of Medicine – MC7076, Chicago, Fc expression on eosinophils (7, 12). When bound to IL 60637. E-mail: [email protected] aspergillus antigen, locally produced IgE may activate mast Proc Am Thorac Soc Vol 7. pp 237–244, 2010 DOI: 10.1513/pats.200908-086AL cells. chemokines, in concert with IL-5, recruit Internet address: www.atsjournals.org eosinophils. Eosinophils are the most conspicuous immune cells

238 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 7 2010

TABLE 1. PULMONARY MANIFESTATIONS OF ASPERGILLUS ABPA in CF

Disease Host Patients with CF are at risk for developing ABPA (4). The prevalence of ABPA is increased in patients with CF who are Cavity from sarcoid, previous TB, male, are adolescent, have lower lung function, have a history of bullae, or bronchiectasis Allergic bronchopulmonary Asthma, cystic fibrosis wheezing or asthma, or have pseudomonas in the . aspergillosis Atopy is present in up to 60% of patients with CF (4). The Chronic necrotizing COPD, previous TB, corticosteroids, DM impaired airway clearance characteristic of CF may contribute aspergillosis directly to ABPA, although other factors likely play a role as Invasive aspergillosis Immunocompromised, especially well (25, 26). Intense or repeated exposure to aspergillus CLINICAL FEATURES Definition of abbreviations: COPD 5 chronic obstructive pulmonary disease; Symptoms DM 5 mellitus; TB 5 . With the development of ABPA, asthma or CF typically worsens and may manifest with a new or worsening or in airway mucosa in patients with ABPA and are thought to be an increase in sputum production or wheezing. Thick mucus a major effector of inflammation (12, 13). Degranulation of production is common; mucus can be remarkably tenacious and activated mast cells and eosinophils results in the release of resistant to suctioning (27). Patients may cough up well-formed, mediators of and bronchoconstriction (12). tan to brownish-black mucus plugs. Plugs are composed of de- Activated T and B lymphocytes infiltrate lymphatics and generating eosinophils, desquamated epithelial cells, and mucin release cytokines systemically. Circulating IL-4 is thought to (28). may occur secondary to airway inflammation drive total IgE production, and total serum IgE levels are and bronchiectasis; however, massive hemoptysis from ABPA increased out of proportion to aspergillus-specific IgE levels (7). alone is not well described in the literature (5, 29). Systemic IgE and IgG specific for aspergillus circulate system- symptoms of low-grade , , and are ically as well (14). variably part of the clinical spectrum of ABPA (16). These symptoms should trigger an evaluation for ABPA in a patient with asthma or CF. HOST CHARACTERISTICS Susceptibility to ABPA is likely mediated by genetically de- Laboratory Evaluation termined inflammatory responses in atopic patients. Although Total serum IgE levels of at least 1,000 IU/ml are a hallmark of atopy is an inheritable trait, familial occurrence of ABPA, ABPA (2). A. fumigatus–specific IgE levels are also elevated though reported, is rare (15). ABPA occurs most commonly in (30). Laboratory studies may show elevated serum levels of patients with asthma and CF, two conditions strongly associated aspergillus-specific IgG antibodies, precipitins, and eosinophils with atopy. Patients with ABPA also are noted to have higher (2, 14). Corticosteroids may blunt an allergic response; there- rates of other atopic conditions, including allergic and fore, patients on systemic corticosteroids may not have eosin- , atopic , and food hypersensitivity (16). ophilia or a significantly elevated total serum IgE level but may Allergic fungal results from an allergic response to still have ABPA. aspergillus. Initially thought not to be related, allergic and ABPA share a history of atopy and asthma, and Radiographic Imaging several reports document an association of these (17, Chest radiographs that demonstrate fleeting parenchymal opac- 18). The pathophysiology of allergic fungal sinusitis may involve ities or bronchiectasis should trigger a consideration of ABPA. abnormal anatomy, which could explain why only a small Infiltrates are usually eosinophilic in and responsive to fraction of patients with ABPA have concomitant allergic corticosteroids and may be misdiagnosed as infectious pneu- fungal sinusitis. In addition to atopic conditions, ABPA has monia (31). Opacities may also reflect bronchoceles, mucus been associated with chronic obstructive pulmonary disease, plugging, , or lobar collapse. The full extent of previous tuberculosis infection, and treatment of sarcoid with radiographic findings is best appreciated on chest CT imaging infliximab (19–21). ABPA has also been reported in hyper-IgE (Figures 1–3). Bronchiectasis, bronchial wall , mucus syndrome, bronchocentric granulomatosis, and chronic granu- plugging, atelectasis, lobar collapse, nodules, and fibrosis also lomatosis disease (6, 17). can be seen (32). Pleural changes may occur but are not common. The presence of central bronchiectasis in multiple ABPA in Asthma lobes is highly suggestive of, and varicose or cystic changes are The relationship between asthma and ABPA is incompletely most specific to ABPA (33). Bronchiectasis is sometimes seen in understood. It is unclear whether having asthma directly increases the peripheral lung fields (34). Although central bronchiectasis the risk for ABPA or whether asthma and ABPA share a common may occur occasionally in patients with asthma who do not have predisposition. As many as 25% of subjects with asthma are ABPA, it is less severe and most often limited to one or two sensitized to aspergillus, yet only a small fraction develop ABPA lobes (35). (22). In the aspergillus-specific, IgE-mediated immune response, Mucus plugging can manifest a ‘‘finger in glove’’ appearance abnormalities of the airway and changes in mucus production and from impacted mucus opacifying an airway and its branches or properties may contribute to the development of ABPA in patients as small nodules from impacted cut on end (2, 31, with asthma. CFTR gene mutations are higher in patients with 36). Airway mucus can have normal or high attenuation. In asthma and ABPA who do not have CF (23). The onset of ABPA high-attenuation mucus, the concentration of ions such as cal- typically occurs many years after the diagnosis of asthma is made cium, iron, and manganese contributes to a Hounsefield density but has been reported in new-onset asthma. Unlike other atopic that can exceed that of surrounding skeletal muscle (33). conditions that are more common in childhood, the incidence of Chemical deposition is a gradual process, and high-attenuation ABPA is highest in adults (5, 24). mucus suggests chronicity. In one report, this was found in 19%

Patterson and Strek: Allergic Bronchopulmonary Aspergillosis 239

Figure 1. Chest CT scan image in a patient with allergic bronchopul- Figure 2. Chest CT scan image in a patient with allergic bronchopul- monary aspergillosis showing nodular and mass-like opacities. monary aspergillosis showing mucus plugging. of cases of ABPA (37). Although not as common as central may also show infiltration of airways by eosinophils and bronchiectasis, high-attenuation mucus is characteristic of lymphocytes, , bronchocentric granulo- ABPA. mas with distal exudative , mucoid impaction, and and cavitation of dilated airways are end-stage fibrotic changes in end-stage disease (1, 42). findings in ABPA. Peribronchiolar fibrosis is thought to be a result of persistent inflammation and progressive broncho- DIAGNOSIS centric (29, 38). Fibrosis predisposes to cor pulmo- nale, and enlarged pulmonary and right ventricular There is not a single test to diagnose ABPA; nor is there may be evident on chest CT scanning (39). a universally recognized set of criteria. However, the diagnostic

Pulmonary Function Testing Airflow obstruction that is at least partially reversible is a common finding on pulmonary function tests, especially in mild or early ABPA. Fixed airflow obstruction and reduced lung volumes due to interstitial changes reflect progressive dis- ease. The may be decreased during an exacerbation and remains low in end-stage ABPA (2, 40). Pulmonary function test findings are not specific to ABPA because most patients typically have underlying lung disease. A more important role for pulmonary function tests is in tracking disease over time.

Bronchoscopy and Bronchoscopic evaluation, fungal culture, and histology are not required to make a diagnosis of ABPA. may be performed in patients with ABPA when the diagnosis is un- clear. On , counts and levels of IgA, IgG, IgM, and IgE are elevated (41). Aspergillus is not reliably cultured, even in active disease, and the sensitivity of staining bronchoalveolar lavage washes or sputum samples for aspergillus is poor (17). Conversely, the recovery of aspergillus in culture may reflect colonization alone and is not specific for active disease. Given the lack of sensitivity or specificity of aspergillus culture, we agree with recent diagnostic algorithms that do not require culture for diagnosis. Finding aspergillus on Figure 3. Chest CT scan image in a patient with allergic bronchopul- lung , however, is diagnostically helpful. Lung monary aspergillosis showing bronchiectasis in the central or proximal is not necessary for diagnosis but, when performed in ABPA, two thirds of the lung fields.

240 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 7 2010

TABLE 2. EVOLUTION OF DIAGNOSTIC APPROACH

1977 Diagnostic 1986 Recognition of 1991 Diagnostic Criteria: 1952 First Case Series (79) Criteria (43) Limited Disease (47) Revised (44)

Clinical features described Asthma ABPA-CB ABPA-CB Total IgE elevated ABPA with central bronchiectasis Asthma Immediate skin test positive Immediate skin test positive ABPA-S Serum eosinophilia Total IgE elevated Clinical and serologic features without central Precipitins Specific IgE and IgG elevated bronchiectasis Parenchymal infiltrates Central bronchiectasis Central bronchiectasis ABPA-S Asthma Immediate skin test positive Total IgE elevated Specific IgE & IgG elevated Additional findings Mucus plugs Sputum 1 aspergillus Precipitins Parenchymal infiltrates Delayed skin test positive

Definition of abbreviations: ABPA-CB 5 allergic bronchopulmonary aspergillosis–central bronchiectasis; ABPA-S 5 Allergic bronchopulmonary aspergillosis–serological. criteria articulated by Rosenberg, and later revised by Green- The diagnosis of ABPA in patients with CF may be particu- berger, are widely accepted (27, 43, 44) (Table 2). A simple larly challenging (4). Bronchiectasis, thick mucus, and mucus approach to diagnosis is limited by the facts that many of the plugging are often present at baseline in CF. Development of diagnostic markers are continuously variable, and most are not ABPA is suggested by worsening baseline cough, dyspnea, or highly specific or sensitive. Integration of clinical, radiographic, ; increased or colored sputum; the onset of new or and serologic features and clinical judgment is used to make the weight loss; or a decline in pulmonary function tests. This should diagnosis of ABPA. prompt skin testing and measurement of total serum IgE levels. When ABPA is suspected, a serum total IgE level and skin Serial CT scanning may be helpful to distinguish infiltrates due to testing for hypersensitivity to A. fumigatus should be performed. ABPA over an active infectious process (32) (Table 3). The A positive skin test in the form of an immediate IgE-mediated diagnostic criteria in CF are reviewed extensively in the CF response is highly sensitive for aspergillus sensitization but not Foundation Consensus Conference statement (4). Annual specific for ABPA (2). IgG-mediated late skin test responses are screening with serum total IgE levels is advised. The degree to variably positive and not usually assessed (16). A wheal di- which development of ABPA results in accelerated decline in ameter of at least 3 mm is required; smaller wheal formation lung function in patients with CF requires further study (4, 50). may occur in patients sensitized to aspergillus or in patients with non-ABPA aspergillus diseases (16). Intradermally placed skin tests are more sensitive than the epicutaneous prick test. If skin testing is positive and total IgE is elevated, A. The differential diagnosis for ABPA includes refractory asthma, fumigatus–specific antibody levels help to distinguish ABPA newly diagnosed CF, tuberculosis, , infectious pneu- from other conditions, such as asthma with aspergillus sensitiv- monia, , aspergillus sensitive asthma, ity (1, 2). Historically, precipitin antibodies were useful to make Churg-Strauss syndrome, and bronchocentric granulomatosis this distinction in cases of positive skin tests. Precipitins are not (2, 24). In addition, fungi other than aspergillus have caused as commonly used for the initial diagnostic evaluation as the allergic bronchopulmonary , a clinical condition identi- ability to detect aspergillus IgE, and IgG antibody levels are cal to ABPA but with antibody and skin test reflecting allergy to more easily obtained and are quantitative (27, 29). Although the implicated mold (51). specific antibody levels are quantifiable, there is a lack of standardization of laboratory testing to permit precise labora- NATURAL HISTORY tory to laboratory comparison of values (44). The clinical course of ABPA is variable. There are five Elevated eosinophil levels were a primary diagnostic feature, recognized stages of ABPA, and they are useful to appreciate but recent criteria do not incorporate serum eosinophilia (Table the status and trajectory of a given patient (5, 48). Stage I 2). Serum eosinophilia is not sensitive or specific but if present defines new, active ABPA. Stage II is marked by clinical and supports a diagnosis of ABPA (45, 46). Central bronchiectasis is a hallmark finding, although ABPA TABLE 3. CLUES TO THE PRESENCE OF ALLERGIC without bronchiectasis is also recognized (47). ABPA-S refers BRONCHOPULMONARY ASPERGILLOSIS to ABPA diagnosed serologically, whereas ABPA-CB refers to patients with central bronchiectasis. This distinction does not Asthma correlate well with severity of asthma or degree of serologic Mucus production New, brown-black Increased, Brown-Black abnormalities (34). Distinguishing between ABPA-S and Total IgE . 1,000 IU/mL 11 ABPA-CB may have prognostic implications: The frequency Bronchiectasis Central Predominantly central, of exacerbations and the likelihood of permanent lung damage extensive are believed to be lower in patients with ABPA-S (48, 49). Fleeting pulmonary opacities 11 ABPA-S may be a more benign phenotype of ABPA, but most High attenuation mucus plugs 11 on chest CT experts consider it a precursor of ABPA-CB.

Patterson and Strek: Allergic Bronchopulmonary Aspergillosis 241 serological remission. Stage III is recurrent active ABPA. nal antibody directed against IgE (2, 27). None of these Patients with chronic, steroid-dependent asthma secondary to have been shown to be of benefit in large, ABPA are stage IV. Fibro-cavitary disease secondary to pro- randomized, double-blind, -controlled trials, but there gressive inflammation and airway dilation defines stage V, which is considerable support based on case series and expert opinion may lead to progressive and death. ABPA for the benefit of oral corticosteroids to induce remission and does not necessarily evolve through these stages in a sequential prevent progression of disease (Table 4). Corticosteroids de- manner. At presentation, it is not always clear who will enter crease the inflammatory response to aspergillus in the lung but remission, who will have recurrent disease, or who will progress. at considerable cost in terms of side effects if used chronically. Early diagnosis and treatment is thought to be associated with Corticosteroids do not inhibit the growth of aspergillus. Anti- a lower risk of advanced disease in the future (5, 7, 27, 47). fungal agents decrease the antigen burden and subsequent Changes in serum total IgE level or pulmonary function tests immune response but cannot be recommended as monotherapy. are useful for objectively assessing remission or recurrence of The benefit of environmental evaluation and remediation of ABPA (5, 52). Establishing a patient’s total IgE level during ongoing exposure to aspergillus has been debated. Failure to remission is important to be able to interpret serial values respond to therapy should prompt consideration of comorbid- because levels even in remission are typically above normal (1). ities such as or sinusitis or alternate diagnoses. A common approach is to use a sustained decrease of 25 to 35% Treatment of ABPA in patients with CF is similar, although to identify remission and an increase of 100% to identify higher doses of are recommended initially (4). recurrent disease (2, 27, 52, 53). Changes in total IgE levels may precede the onset of symptoms or new radiographic Corticosteroids infiltrates, and regular monitoring in high-risk patients can be Systemic corticosteroids are the mainstay of therapy for ABPA. useful to screen for the recurrence or development of ABPA. They are associated with decreased wheezing, serum total IgE levels, and eosinophilia, and with resolution of parenchymal TREATMENT opacities (54, 55). A number of dosing regimens have been recommended. Some experts think a more aggressive regimen The goal of therapy is to induce remission by suppressing the with higher doses of systemic corticosteroids at disease onset inflammatory pathway so that further lung destruction does not results in the best long-term outcomes, but the evidence for this occur while minimizing side effects. Remission is defined by is limited (Table 4). This aggressive regimen involves prednis- improvement in clinical symptoms, decrease in total serum IgE olone 0.75 mg/kg daily for 6 weeks, then 0.5 mg/kg daily for 6 level, resolution of radiographic opacities, and improvement in weeks, then tapered by 5 mg daily every 6 weeks, for a total of 6 lung function. A number of medications have been tried in the to 12 months (5, 34). A more conservative approach is to treat treatment of ABPA. These include systemic and inhaled with prednisone 0.5 mg/kg daily for 1 to 2 weeks, then on corticosteroids, antifungal agents, and , a monoclo- alternate days for 6 to 8 weeks, then tapered by 5 to 10 mg daily

TABLE 4. SELECTED STUDIES OF THE TREATMENT OF ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS

Medication Reference Study Description Outcome

Prednisone 0.5 mg/kg Rosenberg 1977 (43) Case series of 20 patients ‘‘Complete remission’’ in all cases QD 3 1 wk then QOD Prednisone 0.5 mg/kg Patterson 1986 (47) Case series of 84 patients 38 (45%) dependent QD 3 2wkthen QOD 3 3mo 0.75 mg/kg Agarwal 2006 (34) Case series of 126 patients 126 ‘‘remission’’ at 6 wk, QD 3 6 wk, 0.5 mg/kg 25 (20%) ‘‘relapse,’’ 17 (13.5%) QD 3 6 wk then taper corticosteroid dependent by 5 mg Q 6 wk Prednisone 2 mg/kg Nepomuceno 1999 (68) Case series of 16 patients with CF; 1: Decreased wheezing, serum eos, QD 3 1 wk then 1 mg/kg 12 on dual therapy, 2 on radiographic infiltrates, and IgE QD 3 1wkthen prednisone alone 2: Fewer episodes QOD and intraconazole with intraconazole IV Thompson 2006 (56) Case series of 4 patients with CF Disease ‘‘control’’ 3 (75%) 15–20 mg/kg QD 3 3dQ4wk

Budesonide inhaled 400 mg Chest 1977 (59) Double-blind trial in 32 patients No benefit asthma score or FEV1 daily vs. placebo Nebulized Laoudi 2008 (58) Case series of 3 patients with CF Decreased serum eos, and total and

and specific IgE and improved FEV1 200 mg BID vs. Stevens 2000 (66) Randomized double-blind Decreased prednisone dose and total placebo 3 16 wk; trial in 55 patients IgE 13/28 (46%), itraconazole vs. 5/27 prednisone . 10 mg daily (19%) placebo Itraconazole 400 mg QD vs. Wark 2003 (67) Randomized double-blind Decreased IgE and fewer exacerbations placebo 3 16 wk trial in 29 patients requiring prednisone with itraconazole

Itraconazole/prednisone vs. Skov 2002 (69) Retrospective study in patients with Decreased precipitins, increased FEV1 intraconazole 200–600 mg CF (9 both, 12 intraconazole alone) in all; IgE decreased in 56% on QD both vs. in 42% on itraconazole 3 1 yr Erwin 2007 (71) Case report, 1 patient Improved symptoms, tapered prednisone off

Omalizumab Kanu 2008 (75) Case report, 1 patient Improved symptoms and FEV1

Definition of abbreviations:CF5 cystic fibrosis; Eos 5 eosinophils; Q 5 every; QD 5 daily; QOD 5 every other day.

242 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 7 2010 every 2 weeks (27, 54). With either regimen, serum total IgE Adverse effects of azole therapy include nausea, , concentration is followed closely until clinical and radiographic , fever, , , , and decreased libido. remission is achieved. Serum total IgE is repeated every 8 to Elevations in transaminase levels occur and are usually tran- 12 weeks for 1 year, then annually (5). An increase of greater sient, but has been reported, and monitoring liver than 100% over baseline suggests recurrent disease and may enzymes is advised. Drug interactions have been reported with precede the development of active clinical disease. The chest numerous agents including midozolam, cyclosporine, tacroli- roentgenogram or CT scan should be repeated in 4 to 8 weeks to mus, oral hypoglycemic agents, and methylprednisolone but not look for resolution of pulmonary opacities. Pulmonary function prednisone (4, 74). Agents that lower gastric acid may decrease tests are monitored and should improve on therapy. Patients the effectiveness of these agents. Response to therapy is who cannot be tapered off systemic corticosteroids have evolved assessed by the criteria outlined above. to Stage IV disease and should be managed with alternate-day corticosteroid therapy if possible and are candidates for anti- MONOCLONAL ANTIBODY AGAINST IgE fungal therapy. In a small series, intravenous methylpred- nisolone was given to children with CF and severe ABPA Case reports of improvement with omalizumab suggest that because of relapse or intolerance to high-dose oral corticoste- anti-IgE therapy may be of benefit (75, 76). In addition to the roids, with disease control achieved in three of the four patients risk of , a recent FDA advisory suggests that cardiac (56) (Table 4). Patients with CF may have incomplete absorp- and thromboembolic events may occur with increased fre- tion of enteric-coated prednisolone (4). quency in patients using omalizimab (77). We do not recom- Inhaled corticosteroids have been studied in the treatment of mend this therapy based on the limited evidence for benefit and ABPA (57, 58). A case series of three children with CF and potential toxicity. ABPA showed improvement with nebulized budesonide and amphotericin B. However, a double-blind, placebo-controlled AVOIDANCE study in patients with non-CF ABPA failed to demonstrate the benefit of beclomethasone 400 mg daily (59). Although aspergillus is ubiquitous, identification of environ- The side-effects of systemic corticosteroids are numerous mental sources that are particularly high in or support the active and include weight gain, , , hypokalemia, growth of aspergillus is advised but may not be possible. gastric ulcers, thinning and bruising of skin, , de- Remediation should be considered, although definite evidence velopment or worsening of diabetes, aseptic joint , of benefit is lacking. Theoretically, this may reduce the ongoing cataracts, glaucoma, and immune, adrenal, and growth suppres- antigen exposure. Marijuana use may be an unidentified risk sion and in most cases preclude long-term use. Patients treated factor, with case reports attesting to an association of marijuana with corticosteroids should receive vaccination for pneumococcus smoking and aspergillus exposure (78). and influenza as well as calcium plus with monitoring for osteoporosis. Cases of invasive pulmonary aspergillosis and central disease have been reported in patients receiving CONCLUSIONS systemic corticosteroids for the treatment of ABPA (60–62). ABPA is a complex hypersensitivity response to A. fumigatus in atopic patients with CF or asthma. It is characterized by ANTIFUNGAL AGENTS worsening symptoms, serum eosinophilia, and fleeting pulmonary opacities on radiographs. An elevated serum total IgE, central To decrease the burden of fungal organisms and prevent bronchiectasis, and hyperattenuating mucus on chest CT scan continued antigenic stimulation and subsequent inflammation, heightens the suspicion for ABPA. The pathophysiology of antifungal such as nystatin, amphotericin B, natamy- ABPA is allergic in nature, characterized by activation of cin, and have been tried (2, 27). Ketoconazole eosinophils and elaboration of IgE. Immune suppression there- showed some benefit but was associated with significant side fore is the mainstay of treatment. Early identification allows effects. Itraconazole has been used with greater success and treatment with corticosteroids with a potential role for newer tolerability (5, 63–69). A number of case reports and a few antifungal azole medications as corticosteroid-sparing agents, randomized studies attest to its beneficial effects (Table 4). which may improve the long-term outcome in this potentially Current recommendations are to consider it as a corticosteroid- relapsing condition. sparing agent or if corticosteroids alone are ineffective (2, 62). Itraconazole is administered at a dose of 200 mg twice daily for Conflict of Interest Statement: K.P. does not have a financial relationship with 4 to 6 months, then tapered over 4 to 6 months. Serum levels a commercial entity that has an interest in the subject of this manuscript. M.E.S. received grant support from AstraZeneca, GlaxoSmithKline, and Novartis. drawn 4 hours after a dose after 1 to 2 weeks of therapy should be checked in patients with severe disease or not responding to therapy or in those on medications that might interact with References itraconazole. 1. Cockrill BA, Hales CA. Allergic bronchopulmonary aspergillosis. Annu Voriconazole, a newer antifungal azole with greater bio- Rev Med 1999;50:303–316. availability, has the potential to be more effective, with case 2. Agarwal R. Allergic bronchopulmonary aspergillosis. Chest 2009;135: reports attesting to its benefit (70–73). It is given at a dose of 805–826. 3. Eaton T, Garrett J, Milne D, Frankel A, Wells AU. Allergic bron- 200 mg twice daily. The authors have personal experience with chopulmonary aspergillosis in the asthma clinic. Chest 2000;118: its use in a patient with long-standing asthma who was treated 66–72. with voriconazole for presumed invasive aspergillosis. By the 4. 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