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Management of allergic bronchopulmonary : a review and update Mahboobeh Mahdavinia and Leslie C. Grammer Ther Adv Respir Dis 2012 6: 173 originally published online 30 April 2012 DOI: 10.1177/1753465812443094

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Therapeutic Advances in Respiratory Disease Review

Ther Adv Respir Dis

Management of allergic bronchopulmonary (2012) 6(3) 173­–187 DOI: 10.1177/ aspergillosis: a review and update 1753465812443094 © The Author(s), 2012. Reprints and permissions:

Mahboobeh Mahdavinia and Leslie C. Grammer http://www.sagepub.co.uk/ journalsPermissions.nav

Abstract: Since the first description of allergic bronchopulmonary aspergillosis (ABPA) in the 1950s there have been numerous studies that have shed light on the characteristics and immunopathogenesis of this disease. The increased knowledge and awareness have resulted in earlier diagnosis and treatment of patients with this condition. This article aims to provide a summary and updates on ABPA by reviewing the results of recent studies on this disease with a focus on articles published within the last 5 years. A systematic search of PubMed/Medline with keywords of ABPA or allergic bronchopulmonary aspergillosis was performed. All selected articles were reviewed with a focus on findings of articles published from December 2006 to December 2011. The relevant findings are summarized in this paper.

Keywords: ABPA, aspergillosis, , mold, ,

Introduction result in impaction and Correspondence to: Leslie C. Grammer, MD, Allergic bronchopulmonary aspergillosis (ABPA) inflammatory cell infiltration in bronchial wall PhD is a disease that occurs and peribronchial tissues, that can progress to Northwestern University, 676 N St Claire Suite 1400, almost exclusively in patients with asthma and organizing , bronchiectasis and Chicago, IL 60611, USA cystic fibrosis (CF) in the setting of bronchial bronchocentric noncaseating granulomatosis grammer@northwestern. colonization by Aspergillus fumigatus, which is a [Greenberger, 2002; Knutsen et al. 2012]. edu Mahboobeh Mahdavinia, ubiquitous saprophytic mold species that can MD, PhD cause a variety of pathologies in its host [Geiser ABPA is generally more common among severe Northwestern University, et al. 2007]. As depicted in Figure 1, there are five asthmatic patients who are dependent. Chicago, IL 60611, USA major pulmonary caused by A. fumigatus: While the prevalence of ABPA was reported to ABPA, hypersensitivity , , be as low as 1–2% in asthmatic patients in outpa- chronic necrotizing Aspergillus pneumonia, and tient clinics [Donnelly et al. 1991; Novey, 1975], invasive aspergillosis [Soubani and Chandrasekar, this rate was reported as 7–14% among steroid- 2002; Zmeili and Soubani, 2007]. ABPA mani- dependent asthma patients who were referred to fests as recurrent pulmonary infiltrates, bronchi- specialty clinics [Basich et al. 1981], and was ectasis and productive with mucus plugs in even higher (39%) in patients who have been asthmatic and CF patients [Greenberger and admitted to the ICU with severe asthma attacks Patterson, 1988; Rosenberg et al. 1977]. There [Agarwal et al. 2010b]. The prevalence of ABPA are differences in characteristics, prevalence, in CF ranges from 6% to 10% [de Almeida et al. diagnostic criteria and treatment of ABPA in 2006; Chotirmall et al. 2008]. Untreated disease asthmatics versus CF patients. for prolonged periods of time can result in irre- versible pulmonary damage. Therefore early The pathogenesis of ABPA is complex and involves detection and treatment of ABPA is critical in cascades of immunologic reactions including preventing serious lung damage such as bronchi- Aspergillus-specific IgE-mediated (type I) hyper- ectasis [Greenberger, 2003]. sensitivity, IgG-mediated (type III) hypersensitivity, and abnormal cell-mediated Since the first description of ABPA in the 1950s immune responses [Knutsen, 2003, 2011]. In [Hinson et al. 1952], there have been numerous genetically susceptible individuals, these hyper- studies that have shed light on the characteristics sensitivity responses in the bronchi and and immunopathogenesis of this disease. The

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Figure 1. In human hosts with a normal immune system and normal lung architecture, the of Aspergillus spores results in no disease. If the host is immunocompromised, has abnormal lung architecture or develops hypersensitivity responses to Aspergillus, the following five pulmonary diseases may result: invasive aspergillosis; chronic necrotizing aspergillosis; aspergilloma; hypersensitivity pneumonitis; allergic bronchopulmonary aspergillosis (ABPA) in asthma; or cystic fibrosis (CF). Atopic asthma and severe asthma with fungal sensitization (SAFS) are associated with IgE against Aspergillus.

increased knowledge and awareness have resulted (HRCT) of the chest is the imaging modality of in earlier diagnosis and treatment of patients with choice for the diagnosis of ABPA. There are this condition. This article aims to provide a sum- patients with ABPA who fulfill diagnostic criteria mary and updates on ABPA by reviewing the but do not have the CT chest finding consistent results of recent studies on this disease with focus with proximal or central bronchiectasis; this on articles published within the last 5 years. A sys- group of patients is labeled as serological ABPA tematic search of PubMed/Medline with key- (ABPA-S). In contrast, ABPA-CB refers to patients words of ABPA or allergic bronchopulmonary with central bronchiectasis [Greenberger et al. aspergillosis was performed. All selected articles 1993]. were reviewed with focus on findings of articles published from December 2006 to December More recently another phenotype of severe 2011. The relevant findings are summarized in asthma has been defined. These asthma patients this paper. have positive skin prick test to Aspergillus but their levels to A. fumigatus is below the thresh- old for diagnosis of ABPA and thus do not fulfill Diagnostic criteria the minimal criteria; this group of patients are The diagnosis of ABPA in asthma is based on classified as severe asthma with fungal sensitiza- clinical features and immunologic sensitivity to A. tion (SAFS) [Agarwal et al. 2011; Denning et al. fumigatus. The Rosenberg–Patterson criteria was 2006]. It should be noted that patients with ABPA described in 1977 for diagnosis of this disease might not fulfill serologic criteria except when [Rosenberg et al. 1977]. According to the authors, they are in or exacerbation stages of the the presence of six of the seven major criteria disease. Therefore, it is recommended to repeat made the diagnosis likely, and the presence of all the serologic tests in this group of patients during seven made it certain. recurrent exacerbation.

The criteria were further modified to the minimal There is controversy on the threshold for total IgE essential criteria as detailed in Table 1 [Greenberger, level used for diagnosis with some centers using 2003; Schwartz and Greenberger, 1991] which 1000 ng/ml (equivalent to 417 IU/ml) [Greenberger, is currently widely used. High-resolution CT 2003] and others using 1000 IU/ mL [Agarwal

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Table 1. The minimal essential criteria for allergic bronchopulmonary aspergillosis (ABPA) diagnosis.

Minimal essential criteria for ABPA-central bronchiectasis (ABPA-CB) 1. Asthma 2. Immediate cutaneous reactivity on skin-prick testing (1000 protein units/ml of A. fumigatus); 3. Elevated total serum IgE (more than 417 kU/l) 4. Elevated serum IgE and IgG to A. fumigatus ( IgG and/or IgE above twice the pooled serum samples from patients with asthma) 5. Proximal (central) bronchiectasis on radiograph (inner two-thirds of lung on computed tomography scan) Other criteria (not minimal essential criteria) Chest roentgenographic infiltrates Serum precipitating to A. fumigatus Minimal essential criteria for the diagnosis of ABPA-seropositive (ABPA-S) 1. Asthma 2. Immediate cutaneous reactivity on skin-prick testing (1000 protein nitrogen units/ml of A. fumigatus); 3. Elevated total serum IgE (more than 417 kU/l) 4. Elevated serum IgE and IgG to A. fumigatus (IgG and/or IgE above twice the pooled serum samples from patients with asthma) Other criteria (not minimal essential criteria) Chest roentgenographic infiltrates

et al. 2006; Pa, 2003]. There are no studies com- et al. 2010]. New serological tests such as specific paring these levels with respect to response to IgE to recombinant A. fumigatus , or treatment or in cohorts of asthmatics. thymus and activation regulated chemokine (TARC/CCL17), have been identified as potential Agarwal and colleagues proposed an algorithm diagnostic markers for ABPA in CF [Delhaes for the diagnosis of ABPA starting with screening et al. 2010]. of all asthmatic patients for Aspergillus sensitiza- tion using skin testing [Agarwal et al. 2006; Agarwal, 2009]. Patients who demonstrate imme- Clinical features diate hyperreactivity to Aspergillus antigen would ABPA usually presents with increased cough, spu- be further tested for total IgE level. Depending tum production or wheezing [Safirstein et al. upon the result, additional tests such as eosino- 1973]. may consist of tan to brownish– phil count, Aspergillus precipitins and HRCT black mucus plugs [de Almeida et al. 2006]. The would be obtained. The diagnosis of ABPA in CF dark mucus plugs are due to increased production is more controversial due to overlap between clin- of tenacious mucus in the and ical and radiological features of ABPA and CF. consist of inflammatory cells including eosino- Traditionally the Nelson criteria was the most phils, desquamated epithelial cells, and mucin commonly used; the most recent diagnostic crite- [Kradin and Mark, 2008]. These mucus plugs have ria proposed by the Cystic Fibrosis Foundation been reported in up to 69% of patients in different Consensus Conference was published in 2003 ABPA series [Agarwal et al. 2006; Agarwal, 2009]. (Table 2) [Greenberger, 2002, 2003; Stevens et al. 2003]. may occur in late-stage disease (stage V) and is primarily due to severe airway inflam- As many CF patients demonstrate a spontaneous mation and bronchiectasis [Kumar, 2003]. decline in immunologic parameters, such as IgE levels, it has been proposed that the diagnosis of Systemic symptoms including low-grade , ABPA in CF patients should not be based only on , and are seen in up to 26% of serology and skin test results. Instead, prolonged ABPA patients [Prasad et al. 2009]. The presence longitudinal testing with newer markers might be of these symptoms in a patient with asthma or CF required to make a definite diagnosis [Antunes should prompt an evaluation for ABPA; prior to

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Table 2. Criteria for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis. Classic case criteria Clinical deterioration (increased cough, wheezing, exercise intolerance, increased sputum, decrease in pulmonary function) Immediate cutaneous reactivity to Aspergillus or presence of serum IgE–A. fumigatus Total serum IgE concentration >1000 kU/l precipitating antibodies to A. fumigatus or serum IgG–A. fumigatus Abnormal chest roentgenogram (infiltrates, mucus plugging, or a change from earlier films) Suggestions for screening on annual phlebotomy for ABPA Maintain clinical suspicion for ABPA Annual total serum IgE determination: if it is >500 kU/l, test for immediate cutaneous reactivity to Aspergillus or by an in vitro test for serum IgE–A. fumigatus If the total serum IgE is <500 kU/l, repeat if clinical suspicion is high

(From the ABPA Consensus Conference of the Cystic Fibrosis Foundation [Stevens et al. 2003].)

Table 3. Allergic bronchopulmonary aspergillosis (ABPA) stages and serologic diagnosis.

Stage Total Precipitins IgE–A. IgG–A. Lung IgE fumigatus fumigatus infiltrates I: Acute +++ + + + + + II: Remission + ± - ± ± - III: Exacerbation +++ + + + + + IV:  ++ ± ± ± ± - dependent V: Fibrotic + ± - ± ± -

the diagnosis of ABPA, the combination of fever guide the management of the disease [Patterson and productive coughing can be misinterpreted as et al. 1986]. It is important to note that ABPA pneumonia or , especially in context serology is most likely to be positive in stage I of pulmonary infiltrates on chest X-rays [Agarwal and III (Table 3). The ideal time to send ABPA et al. 2006; Ragosta et al. 2004]. serology is prior to initiation of for acute or exacerbation stages (stage I or III). In a recently reported cohort of ABPA patients, it was shown that the disease can be present in Stage I (acute stage) is defined as the initial symp- asthmatics, these patients were tomatic stage of ABPA with radiographic infiltrates, diagnosed on routine screening of asthmatics raised IgE levels, and elevated A. fumigatus-spe- showing that screening can lead to earlier diag- cific IgG/IgE. Stage II (remission stage) is the nosis of ABPA and possibly better prognosis clinical and serologic remission; and is defined as [Agarwal et al. 2007]. 35–75% decline in IgE levels by 6 weeks, clearing of the chest infiltrates and symptomatic improve- Aspergillus can also cause hypersensitivity in para- ment. In stage II, serology may be negative. Stage nasal sinuses manifesting as allergic Aspergillus III (exacerbation stage) is the recurrence of the (AAS). It has been proposed that ABPA initial symptoms and up to a twofold increase must be excluded in all patients with AAS and in serum IgE levels. Stage IV (corticosteroid- vice versa [Panjabi and Shah, 2011]. dependent asthma stage) is the uncontrolled symptomatic phase and patients in this stage need continuous to control their asthma Staging and prevent recurrence of ABPA symptoms. Patterson and colleagues have classified the clin- Serology is often negative in stage IV. Stage V ical course of ABPA into five stages that helps to (fibrotic stage) is the fibrocavity disease due to

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Downloaded from tar.sagepub.com at NORTHWESTERN UNIV LIBRARY on January 3, 2014 LC Grammer and M Mahdavinia prolonged ; it is diagnosed with lobes, caused by bronchial obstruction with presence of upper lobe fibrosis on the chest imag- mucus plugs. The filled with mucus ing. If the patient reaches stage V, the fibrotic results in a band shadow or glove-finger shadow lesions will not be improved by treatment with on the plain radiographs that may be relieved by corticosteroids, although are often neces- coughing up a mucus plug [McCarthy et al. 1970]. sary to maintain a bronchodilator response and prevent severe asthma symptoms. ABPA serology The impacted mucus in the airways can manifest may be negative in Stage V. is as the ‘tree-in-bud pattern’ on HRCT scan and an advanced complication that can result in can have normal or high attenuation. In HAM, pulmonary , right , and the higher concentration of ions such as calcium, death [Patterson et al. 1986]. iron, and manganese results in higher Hounsfield density when compared with surrounding normal It worth mentioning that ABPA does not always skeletal muscle [Ward et al. 1999]. evolve sequentially through all of these stages. Early diagnosis and treatment is thought to be associated with a lower risk of advanced disease in Classification the future [Patterson et al. 1986; Tillie-Leblond Classically ABPA is categorized based on pres- and Tonnel, 2005]. ence of the radiographic finding of central bron- chiectasis. Imaging modalities in this way are major tools to predict the outcome and guide Imaging studies treatment. Greenberger and colleagues classified ABPA can have a wide spectrum of radiographic patients as ABPA-S, who otherwise fulfill all diag- appearances. nostic criteria, but lack demonstrable abnormali- ties on CT chest, and ABPA-CB, who have central HRCT of chest with thin (1–2 mm) sections is bronchiectasis in the imaging [Greenberger et al. considered the imaging modality of choice for the 1993]. Another CT classification categorizes diagnosis of ABPA [Lynch, 1998]. ABPA into mild (ABPA-S), moderate (ABPA-CB) and severe (ABPA-CB with other radiologic find- The major findings on HRCT chest are central ings; ABPA-CB-ORF) [Kumar, 2003]. bronchiectasis (CB), (mosaic atten- uation), and high-attenuation mucus (HAM) Multiple studies have shown that patients with caused by mucus plugs or mucoid impactions. ABPA-S developed fewer exacerbations and Some of the other findings include bronchial do not progress to irreversible lung disease wall thickening, , lobar or whole lung [Greenberger et al. 1993; Kumar and Chopra, collapse, pulmonary fibrosis, centrilobular nod- 2002]. ules, and cavities with or without air-fluid levels [Logan and Muller, 1996]. A recent study correlated the chest HRCT find- ings with the immunological severity in ABPA. Central bronchiectasis manifests as dilated bron- Results of this study showed that presence of chi that have a larger caliber (1.5 to >3 times) HAM was the most consistent marker of sero- than the adjacent bronchial artery in the central logical severity in ABPA. Agarwal and colleagues two thirds of the lung field. Bronchiectasis is fur- proposed this finding as an alternate method of ther classified to cylindrical, varicose or cystic. classifying ABPA [Agarwal et al. 2010a]. The Patients with ABPA can have any type of bronchi- presence of HAM in HRCT of has been ectasis involving multiple bronchi; upper lobes shown to be associated with recurrent relapses of are more likely to be involved. Of note asthma ABPA [Agarwal et al. 2007]. patients can also have bronchial wall thickening or localized areas of cylindrical bronchiectasis. However, the extent of lung involvement is much Laboratory studies less in asthma patients mostly limited to one or ABPA is characterized by a Th2 immune response two lobes [Mitchell et al. 2000; Ward et al. 1999]. with increased serum IgE, and eosinophilia [Chauhan et al. 1996; Kauffman, 2003]. Most of The transient areas of consolidation seen fre- the laboratory findings in ABPA are based on this quently in ABPA are predominately in the upper hypersensitivity response.

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Aspergillus skin test ABPA patients. In reports of testing Asp f1, Asp Cutaneous reactivity on skin-prick testing is the f2, Asp f3, Asp f4, and Asp f6, it has been shown first step for diagnosis of ABPA and is a marker of that Asp f 2, Asp f 4, and Asp f 6 have the highest immediate IgE-mediated response. A negative specificity for measurement of specific IgE and skin prick test should be followed by an intrader- diagnosis of ABPA [Crameri, 1998; Crameri et al. mal test, which is more sensitive. The test is posi- 1998; Kurup et al. 2000]. A recent study showed tive if a wheal and is observed within 20 that measuring the rAspf4 IgE with both anti- min [Ricketti et al. 1984]. Up to 28% of patients Aspergillus enzyme-linked immunosorbent assay with asthma have positive skin test to Aspergillus (ELISA) and precipitin has sensitivity of 100% but as mentioned before this is the initial screening for detection of ABPA in CF patients [Fricker- and patients need to fulfill the minimal criteria for Hidalgo et al. 2010]. diagnosis of ABPA [Agarwal, 2011].

TARC Total serum IgE levels Chemokine (C-C motif) ligand 17 (CCL17) is a The IgE level is a useful marker for both diagnosis small cytokine belonging to the CC chemokine and follow up of disease activity. The values may family that is also known as TARC. It was found reach to 30,000 IU/ml but the cut off needed for that CF patients with ABPA have significantly diagnosis of ABPA is greater than 417 IU/ml higher serum levels of TARC compared with the [Ricketti et al. 1984]. Much of the IgE is the result rest of CF patients [Hartl et al. 2006]. Another of polyclonal B-cell activation and not specific to study by Latzin and colleagues longitudinally fol- Aspergillus [Knutsen, 2011]. lowed 48 CF patients, of whom 12 had a diagno- sis of ABPA according to Nelson's criteria. They performed repeated measurements of serum total Peripheral eosinophilia immunoglobulin IgE, specific A. fumigatus IgE An elevated blood eosinophil count of more than and IgG, and specific IgE against recombinant A. 1000 cells/ml is another potentially useful test for fumigatus for 1–8 years. They reported that TARC the diagnosis of ABPA. However, a recent cohort was a more accurate marker for the diagnosis of study has shown that a considerable percentage of ABPA with an accuracy of (93%) for TARC com- ABPA patients fail to show eosinophilia to this pared with total IgE (74%), or specific IgE against extent [Agarwal et al. 2006]. recombinant A. fumigatus-4 (75%) and specific IgE against recombinant A. fumigatus-6 (79%) [Latzin et al. 2008]. A. fumigates-specific serum IgE and IgG antibodies An elevated level of A. fumigatus-specific antibod- Histopathology ies measured by fluorescent enzyme immuno- Histopathologic findings in patients with allergic assay is another important diagnostic test for bronchopulmonary aspergillosis can be varied. ABPA. Patient’s serum IgG and IgE antibodies to The common findings include mucin filled bron- A. fumigatus are compared to the pooled serum chioles, bronchial lumen containing allergic samples from patients with asthma and a positive mucin, necrotic eosinophils, Charcot–Leyden Aspergillus skin test. An index higher than two is crystals, and at times septate fungal hyphae. The considered a positive test [Wang et al. 1978]. alveolar spaces might be filled by eosinophils admixed with variable number of . The other finding is bronchocentric - Precipitating antibodies against A. fumigatus tosis, which is manifested by partial replacement Using the double gel immunodiffusion technique, of bronchial epithelium by palisading histiocytes precipitating antibodies can be detected in uncon- [Kradin and Mark, 2008; Chan-Yeung et al. 1971; centrated sera of 70–100% of ABPA patients. Slavin et al. 1988].

Specific Aspergillus antigens Pathogenesis Few studies have evaluated the role of recombi- The pathogenesis of ABPA starts with inhalation nant Aspergillus allergens in diagnosing ABPA of A. fumigatus and deep colonization of . based on their specific binding to IgE in sera of The germination and production of hyphae will

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Downloaded from tar.sagepub.com at NORTHWESTERN UNIV LIBRARY on January 3, 2014 LC Grammer and M Mahdavinia result in high concentrations of Aspergillus allergens a Th2 response. It was proposed that the APCs on the respiratory epithelium [Slavin et al. 1988]. such as and dendritic cells bearing Aspergillus produces multiple proteases that can HLA-DR2 and/or HLA-DR5 and increased sen- disrupt the epithelial integrity and induce an sitivity to IL-4 stimulation may play an important inflammatory response that will result in enhancing role in skewing A. fumigatus-specific Th2 responses the exposure to the bronchoalveolar in ABPA [Slavin et al. 1987]. lymphoid [Knutsen, 2011].

A. fumigatus detection in sputum was found to be Genetics of ABPA associated not only with A. fumigatus-IgE sensiti- Studies have identified multiple genetic altera- zation but also with neutrophilic airway inflam- tions in the patients with ABPA and proposed mation and reduced lung function in asthmatics the idea that ABPA patients are genetically at [Fairs et al. 2010]. risk to develop hypersensitivity to A. fumigatus due to the exaggerated Th2 responses to its anti- Aspergillus allergens are processed by antigen- gens. These genetic risks include IL-4 receptor presenting cells (APCs) and presented to CD4+ T alpha chain (IL-4Ra) polymorphisms, HLA-DR cells. The T-cell response is skewed toward Th2 and HLA-DQ polymorphisms, IL-10 promoter and therefore production of IL- 4, IL-5, and polymorphisms, surfactant protein A2 (SP-A2) IL-13 [Kumar, 2003]. In a murine model, sensi- polymorphisms, cystic fibrosis transmembrane tized mice when challenged by A. fumigatus conductance regulator gene (CFTR) mutations, showed a strong allergic response with accumula- and TLR-9 polymorphisms. The genetic altera- tion of pulmonary Th2 cells [Chu et al. 1996]. tions in these genes attributed to ABPA are briefly discussed here. It is proposed that ABPA develops in susceptible patients because of increased frequency and/ or activity of A. fumigatus-specific Th2 CD4+. HLA- DR Furthermore peripheral blood mononuclear cells The expression of HLA-DR2 and/or DR5 par- captured from ABPA patients were found to have ticularly DRB1-1501 and DRB1-1503 geno- an increased sensitivity to IL-4 [Khan et al. 2000]. types in asthmatic and CF patients is associated IL-4 produced by Th2 lymphocytes binds to the with increased risk for ABPA after exposure to IL- 4 receptor (IL-4R) on B cells and results in A. fumigatus. On the other hand, the presence of B-cell proliferation and isotype switching to IgE HLA-DQ2, especially DQB-0201, provided [Bacharier and Geha, 2000]. This receptor bind- protection from the development of ABPA [Aron ing can also increase the expression of HLA-DR et al. 1999; Chauhan et al. 1996, 1997]. class II, and CD23 on B-cells. CD23 is the low affinity IgE receptor (FcεRII), which is an activa- tion marker present on multiple immune cells IL-4Ra including B cells, monocytes, eosinophils, and There is a high prevalence of gain of function activated T cells. Of note CD23 interacts with IL-4 receptor polymorphisms in ABPA patients. CD21 and plays a major role in inducing IgE syn- The single nucleotide polymorphisms (SNPs) of thesis by B cells [Bonnefoy et al. 1995, 1996]. IL-4Ra (ile75val) were seen with significantly higher prevalence in ABPA cases. It was shown IL-4 can also increase the expression of VCAM-1 that copresence of ile75val with another SNP, on endothelial cells and result in recruitment of gln576arg, resulted in elevated IL-4-dependent other immune cells, such as eosinophils and baso- CD23 expression in ABPA [Knutsen et al. 2004, phils, and enhance the proliferation of fibroblasts, 2006; Hershey et al. 1997]. which have a major role in airway remodeling [Moser et al. 1992; Schleimer et al. 1992]. IL-10 promoter polymorphisms It has also been reported that ABPA patients have The -1082GG genotype is associated with higher an increased expression of CD86 on - risk for Aspergillus colonization and ABPA in derived dendritic cells [Knutsen, 2011]. CD86 is CF patients. This polymorphism is associated found on dendritic cells that have the with increased IL-10 synthesis [Brouard et al. receptor 2, which skews antigen-specific T cells to 2005].

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Surfactant protein A gene polymorphisms not always clear whether the patient will enter Multiple SNPs in SP-A2 collagen region is asso- remission or have recurrent disease. Following ciated with ABPA; for instance a significantly adequate therapy most patients in stage I and III higher percentage of AGA allele (A1660G) was can go to complete remission (stage II), but a found in patients with ABPA. Some of these pol- complete remission is not necessarily permanent ymorphisms were associated with increased lev- as exacerbations can occur several years later. els of total IgE and eosinophilia in ABPA patients. About 25–50% of patients may relapse, defined by It is also proposed that changes in conformation doubling of the baseline IgE levels. However, early or affinity of SP-A2 based on these polymor- diagnosis and treatment is thought to be associ- phisms in the collagen region may affect the ated with a lower risk of advancement to stage IV function of alveolar macrophages and compro- and V [Agarwal et al. 2006; Agarwal, 2009]. mise host defense [Knutsen, 2011; Saxena et al. 2003; Vaid et al. 2007]. Patients diagnosed in stage IV and V require oral for longer period of time and patients in stage V with widespread bronchiecta- CFTR gene mutation sis, pulmonary dysfunction and/or corpulmonale An increased frequency of CFTR mutations is may never improve clinically and immunologically seen in patients with ABPA compared with other despite long-term therapy [Lee asthma patients [Lebecque et al. 2011; Marchand et al. 1987]. et al. 2001; Miller et al. 1996].

Treatment Toll-like receptor gene polymorphisms The goals of therapy in ABPA are to treat acute ABPA patients are shown to have increased asthmatic exacerbations, control the inflamma- frequency of allele C for the TLR9 (T-1237C) tion, and limit progressive end-stage fibrotic polymorphism compared with control patients disease. Patients should also be advised to avoid [Carvalho et al. 2008]. TLR-9 is involved in rec- and clear the sources of fungi such as moldy ognition of CpG motifs in bacterial and viral basements. It is of utmost importance to opti- DNA. Of note on murine neutrophils, Aspergillus mally control the asthma or CF, and the other hyphae and conidia signal through TLR-9 comorbid conditions patients might have like [Bellocchio et al. 2004]. sinusitis or .

Differential diagnosis Steroids There are multiple pulmonary conditions that Oral corticosteroid is the mainstay treatment of have similar characteristic and can mimic ABPA ABPA [Stevens et al. 2000a]. Corticosteroids These diseases include infectious pneumonia, target the inflammatory response triggered by severe asthma, nondiagnosed CF, pulmonary A. fumigatus, which, as detailed above is the cor- tuberculosis, , eosinophilic pneumo- nerstone in pathophysiology of ABPA. nia, Churg–Strauss syndrome, and bronchocen- tric granulomatosis. The most accepted treatment dose for oral pred- nisone is 0.5 mg/kg/day [Greenberger, 2002]. The It is very important to differentiate ABPA from duration of steroid therapy should be individual- these conditions and start treatment before ized in each patient based on the clinical course. development of bronchiectasis and potential The most commonly used strategy is 2 weeks of subsequent and respir- daily therapy with 0.5 mg/kg/day followed by atory failure. alternate days for 6–8 weeks, then tapered by 5–10 mg every 2 weeks [Greenberger, 2002].

Natural history Most patients require prolonged low-dose corti- As described above ABPA is categorized to five costeroid therapy to control their symptoms and different stages. However, the disease does not decrease the rate of relapse [Capewell et al. 1989; necessarily progress from stage one to five and it Stevens et al. 2000a]. Close follow up is needed can have a different natural history in different during the first year, patients are considered to be individuals. Upon presentation and diagnosis, it is in complete remission if no exacerbations happen

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Downloaded from tar.sagepub.com at NORTHWESTERN UNIV LIBRARY on January 3, 2014 LC Grammer and M Mahdavinia in the 3 months after discontinuing steroid therapy. counts [Cohen-Cymberknoh et al. 2009]. Larger Patients who have evolved to stage IV cannot be randomized controlled studies are needed to taken off prednisone as it will cause exacerba- evaluate the role of this treatment in ABPA. tions, and should be managed with continuous daily or alternate-day corticosteroid therapy if possible [Agarwal, 2009; Greenberger, 2002]. Antifungals Antifungals have an adjunctive role in treatment Total serum IgE is a useful marker to guide treat- of ABPA by decreasing the burden of fungal ment as it is correlated with disease activity, the organisms and antigenic stimulation (Table 4). level should be checked every 6–8 weeks after the initiation of corticosteroid treatment, then every A number of antifungals have been tried to treat 8 weeks for 1 year [Ricketti et al. 1984]. During the ABPA. The most highly accepted agent is itra- this prolonged follow up, one can determine the conazole that has been proved to have significant lowest level as a baseline for each patient. In therapeutic benefit in randomized, controlled tri- many patients, the IgE levels do not decrease to als [Stevens et al. 2000a; Wark et al. 2003]. The normal values. addition of itraconazole for 16 weeks resulted in a significant increase in the likelihood of a clinical A repeated chest roentgenogram or CT of the response (46% versus 19%). In this trial, response lung after 4–8 weeks of treatment is needed to was defined as at least 50% reduction in the ster- demonstrate that infiltrates have cleared. Also oid dose, at least 25% reduction in the serum pulmonary function tests should be monitored IgE, and one of the following: at least 25% to check the lung function during treatment improvement in exercise tolerance or pulmonary [Greenberger, 2003]. function tests, or resolution of pulmonary infil- trates. The rate of adverse events was similar in the two groups [Stevens et al. 2000b]. Another Inhaled corticosteroids randomized controlled trial showed that subjects Inhaled corticosteroids (ICSs) are usually needed receiving itraconazole had a decrease in sputum to control the symptoms of asthma, but studies eosinophils of 35% per week, with no decrease have failed to demonstrate a role for inhaled seen in the placebo arm. Itraconazole also signifi- corticosteroids in preventing the progression of cantly reduced the serum IgE. There were fewer lung damage in patients with ABPA [Research exacerbations requiring oral corticosteroids in Committee of the British Thoracic Association, those treated with itraconazole compared with 1979; Heinig et al. 1988]. A recent study fol- the placebo group [Wark et al. 2003]. The recom- lowed a group of ABPA-S patients treated with mended dose for itraconazole is 200 mg twice formoterol/ (24–1600 µg/day) for a daily for 4–6 months, and then tapered over 4–6 period of 6 months. Results showed symptomatic months. Further pooled analysis of studies con- deterioration and rise of 99.3% in the median firmed that itraconazole could decrease the IgE IgE level in this group. Nineteen out of 21 of levels but could not significantly improve the lung those same patients were treated with oral corti- function [Agarwal, 2009]. Of note, the levels of costeroids afterwards and had resolution of drug might be altered in some patients due to symptoms and significant decline in serum IgE potential interaction with multiple other medica- [Agarwal, 2011]. These results confirmed that tions. Owing to the higher cost, side effects, and inhaled steroids alone should not be used for potential toxicity of this drug, the use of itracona- treatment of ABPA. zole is recommended only after trial of steroids is proven to be insufficient [Elphick and Southern, 2000; Greenberger, 2002; Camuset et al. 2007; Intravenous Glackin et al. 2009; Patterson and Strek, 2010]. A few small studies have used intravenous meth- ylprednisolone in patients with CF and ABPA A few case reports have shown acceptable benefit [Thomson et al. 2006]. Patients who received from using voriconazole, which is a newer anti- high-dose intravenous methylprednisolone (10– fungal azole with higher bioavailability [Glackin 15 mg/kg/day) plus itraconazole showed clinical et al. 2009; Patterson and Strek, 2010]. A recent and laboratory improvement with increase in review has reported that 70–80% of patients forced expiratory volume in 1 second FEV1 and who tolerated either voriconazole or posacona- decrease in serum IgE levels and total eosinophil zole have responded to this treatment [Hogan and

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Table 4. Antifungals and in treament of ABPA Treatment Study Nature of study # of Brief results patients Itraconazole Wark RCT 29 Decreased IgE and fewer et al., 2003 exacerbations requiring prednisone . Stevens et al., RCT 55 Decreased prednisone dose and 2000 total IgE in 13/28 (46%) with itraconazole vs. 5/27 (19%) with placebo. Skov et al., retrospective: 21 Decreased IgE levels in 42% of 2002 Itraconazole/prednisone patients on monotherapy and vs. intraconazole in 56% on combination therapy. Specific IgE decreased in 6 of 21 patients. Eleven patients had transient increased ALT. Voriconazole Erwin GE, 2008 case report 1 Clinical improvement, taperd prednisone. Glackin et al., retrospective Decreased IgE levels and 2009 decrease in steroid dosing, but no improvement in FEV1. Patterson and repost of a case in the 1 Resolution of ABPA-related Strek, 2010 review radiographic abnormalities, and reduction in total IgE. Inhaled Hayes et al., case report 1 Decreased hospitalizations, Oral amphotericin 2010 corticosteroids and anti-fungal therapy were stopped. Proesmans case series 7 CF Six out of seven patients could et al., 2010 patients be withdrawn from steroids, five out of six had improved lung function Omalizumab Tillie-Leblond case series 16 Three out of nine patients were et al., 2011 able to discontinue steroidst, five reduced the dose to 50% of the initial dose or less. Lebecque et al., case series 2 Improved lung function , 2009 steroids could be withdrawn in both Kanu et al., case report 1 Improved lung function, steroids 2008 could be withdrawn van der Ent case report 1 Improved lung function, steroids et al., 2007 could be withdrawn

Denning, 2011]. No prospective controlled trials There are no prospective controlled trials of have been conducted to evaluate this drug in amphotericin for the treatment of ABPA. ABPA.

Case studies have reported successful use of aero- Anti-IgE monoclonal antibody solized amphotericin B for the treatment of ABPA Omalizumab has been shown beneficial in few in CF [Hayes et al. 2010]. Another small study reports. A recent small trial of omalizumab in 16 showed improve in lung function and decreased patients with ABPA showed a reduction in num- steroid need in six out of seven CF patients with ber of exacerbations and systemic steroid need, recurrent or difficult to treat ABPA treated with but no improvement of the respiratory function nebulized amphotericin B [Proesmans et al. 2010]. [Tillie-Leblond et al. 2011]. A randomized,

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Downloaded from tar.sagepub.com at NORTHWESTERN UNIV LIBRARY on January 3, 2014 LC Grammer and M Mahdavinia controlled trial is needed to better investigate the Bacharier, L.B. and Geha, R.S. (2000) Molecular role of omalizumab in treating ABPA. mechanisms of IgE regulation. J Clin Immunol 105: S547–S558. Funding Basich, J.E., Graves, T.S., Baz, M.N., Scanlon, G., This work was supported by the Ernest S. Bazley Hoffmann, R.G., Patterson, R., et al. (1981) Allergic Grant to Northwestern Memorial Hospital and bronchopulmonary aspergillosis in corticosteroid- Northwestern University dependent asthmatics. J Allergy Clin Immunol 68: 98–102. Conflict of interest statement Bellocchio, S., Moretti, S., Perruccio, K., Fallarino, LCG is the Co-Director of the Northwestern F., Bozza, S., Montagnoli, C., et al. (2004) TLRs University Allergy- Laboratory which govern neutrophil activity in aspergillosis. J Immunol analyzes sera for allergic bronchopulmonary 173: 7406–7415. aspergillosis. Bonnefoy, J.Y., Gauchat, J.F., Life, P., Graber, P., Aubry, J.P. and Lecoanet-Henchoz, S. (1995) Regulation of IgE synthesis by CD23/CD21 interaction. Int Arch Allergy Immunol 107: 40–42. References Agarwal, R. (2009) Allergic bronchopulmonary Bonnefoy, J.Y., Gauchat, J.F., Life, P., Graber, aspergillosis. Chest 135: 805–826. P., Mazzei, G. and Aubry, J.P. (1996) Pairs of surface molecules involved in human IgE regulation: Agarwal, R. (2011) Severe asthma with fungal CD23-CD21 and CD40-CD40L. Eur Respir J Suppl sensitization. Curr Allergy Asthma Rep 11: 403–413. 22: 63s–66s. Agarwal, R., Gupta, D., Aggarwal, A.N., Behera, D. Brouard, J., Knauer, N., Boelle, P.Y., Corvol, H., and Jindal, S.K. (2006) Allergic bronchopulmonary Henrion-Caude, A., Flamant, C., et al. (2005) aspergillosis: lessons from 126 patients attending a Influence of interleukin-10 on Aspergillus fumigatus chest clinic in north India. Chest 130: 442–448. in patients with cystic fibrosis. J Infect Dis Agarwal, R., Gupta, D., Aggarwal, A.N., Saxena, 191: 1988–1991. A.K., Chakrabarti, A. and Jindal, S.K. (2007) Clinical significance of hyperattenuating mucoid impaction in Camuset, J., Lavolé, A., Wislez, M., Khalil, A., Bellocq, allergic bronchopulmonary aspergillosis: an analysis A., Bazelly, B., et al. (2007) Bronchopulmonary of 155 patients. Chest 132: 1183–1190. aspergillosis in the non-immunocompromised patient. Rev Pneumol Clin 63: 155–166. Agarwal, R., Khan, A., Aggarwal, A.N., Saikia, B., Gupta, D. and Chakrabarti, A. (2011) Role of inhaled Capewell, S., Chapman, B.J., Alexander, F., corticosteroids in the management of serological Greening, A.P. and Crompton, G.K. (1989) allergic bronchopulmonary aspergillosis (ABPA). Corticosteroid treatment and prognosis in pulmonary Intern Med 50: 855–860. eosinophilia. Thorax 44: 925–929. Agarwal, R., Khan, A., Gupta, D., Aggarwal, Carvalho, A., Pasqualotto, A.C., Pitzurra, L., A.N., Saxena, A.K. and Chakrabarti, A. (2010a) Romani, L., Denning, D.W., and Rodriques, An alternate method of classifying allergic F.(2008) Polymorphisms in toll-like receptor genes bronchopulmonary aspergillosis based on high- and susceptibility to pulmonary aspergillosis. J Infect attenuation mucus. PLoS One 5: e15346. Dis 197: 618–621. Agarwal, R., Nath, A., Aggarwal, A.N., Gupta, Chan-Yeung, M., Chase, W. H., Trapp, W. and D. and Chakrabarti, A. (2010b) Aspergillus Grzybowski, S. (1971) Allergic bronchopulmonary hypersensitivity and allergic bronchopulmonary aspergillosis. Clinical and pathologic study of three aspergillosis in patients with cases. Chest 59: 33–39. in a respiratory intensive care unit in North India. Chauhan, B., Knutsen, A., Hutcheson, P.S., Slavin, Mycoses 53: 138–143. R.G. and Bellone, C.J. (1996) subsets, epitope Antunes, J., Fernandes, A., Borrego, L.M., Leiria- mapping, and HLA-restriction in patients with allergic Pinto, P. and Cavaco, J. (2010) Cystic fibrosis, , bronchopulmonary aspergillosis. J Clin Invest asthma and ABPA. Allergol Immunopathol (Madr) 97: 2324–2331. 38: 278–284. Chauhan, B., Santiago, L., Kirschmann, D.A., Aron, Y., Bienvenu, T., Hubert, D., Dusser, D., Hauptfeld, V., Knutsen, A.P., Hutcheson, P.S., Dall’Ava, J. and Polla, B.S. (1999) HLA-DR et al. (1997) The association of HLA-DR alleles polymorphism in allergic bronchopulmonary and T cell activation with allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 104: 891–892. aspergillosis. J Immunol 159: 4072–4076.

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