Allergic Bronchopulmonary Aspergillosis (Mycosis) and Severe Asthma with Fungal Sensitivity
INTRODUCTION
Allergic bronchopulmonary aspergillosis (ABPA) is an idiopathic inflammatory disease of the lung, characterized by an allergic inflammatory response to colonization of the airways by Aspergillus fumigatus or other fungi. The entity was first described in 1952 by Hinson et al., and then again in 1967, when Scadding recognized an association between the disease and proximal bronchiectasis in areas previously affected by infiltrates (predominantly in the upper lobes).1,2 The first adult case of ABPA was reported in the United States in 1968.3 Although most cases entail hypersensitivity to Aspergillus spp. (especially A. fumigatus), the finding of a virtually identical clinical syndrome associated with immune sensitivity to Candida albicans (most commonly), Helminthosporium, Alternaria, Curvularia lunata, Drechslera hawaiiensis, Stemphylium languinosum, Saccharomyces cerevisiae, or Pseudallescheria boydii has led some to use the term allergic bronchopulmonary mycosis to describe the syndrome.4 However, since the predominant causative organism is A. fumigatus and the commercially available laboratory testing is for this organism, ABPA is primarily designated as the diagnosis. In addition, a new entity has been recently recognized that appears to be on the continuum between fungal allergy, at one end, and ABPA at the other: severe asthma with fungal sensitivity (SAFS).5
The precise prevalence of ABPA is unknown, in part due to variability in diagnostic criteria used in various studies, the lack of distinction between ABPA and mold-sensitive asthma, and delays in the diagnosis of patients with long-standing disease; however, it is clear that ABPA is a relatively common entity. Estimates are that true ABPA complicates approximately 7% to 14% of cases of chronic steroid–dependent asthma and approximately 7% to 15% of cases of cystic fibrosis (CF).
Most cases of ABPA are recognized in the third to fifth decade of life, but they may present during childhood. In some patients, it is likely that ABPA starts early in life and continues, unrecognized, until adulthood. Interestingly, familial cases have been reported, suggesting that genetic factors underlie development of ABPA.6,7 The spectrum of disease is broad. Patients may be asymptomatic, have mild-to-moderate asthma, or have severe and debilitating disease, leading to lung transplantation. However, if recognized early and managed aggressively, ABPA is treatable and may remit indefinitely; progressive lung damage can be avoided.
For the purposes of this discussion, the focus is on ABPA. However, clinicians should be cognizant that diagnostic testing for other fungi needs to be pursued when organisms other than Aspergillus spp. are suspected. In addition, the newly defined form of asthma noted previously, SAFS, is discussed and differentiated from ABPA.
PATHOGENESIS
Although the pathogenesis of ABPA is poorly understood, it is believed to be the result of an exaggerated immunologic reaction to chronic airway colonization by Aspergillus (or other relevant fungal) species.8 Aspergillus spp. are globally ubiquitous, thermotolerant fungi that reside in decaying organic matter and colonize most domestic environments, including carpets and air duct systems.
In humans, airborn Aspergillus spores or conidia that are inhaled are immunologically inert, and in normal individuals are cleared by innate immune system mechanisms to maintain airway homeostasis. However, in susceptible individuals, conidia colonize airways, germinate into somatic hyphae that stimulate a chronic allergic inflammatory response that results in tissue injury and, ultimately, dictates the clinical features of ABPA. In contrast to a true infection in which fungal hyphae invade the lung parenchyma, colonization of the airways with germinating fungal spores represents an abnormal state that contributes to the exaggerated Th2 inflammatory response without clear tissue invasion. While a detailed understanding of the mechanisms that drive this process remains poorly understood, it appears that susceptibility to Aspergillus colonization and development of clinical disease depend on host factors, such as genetic background, T-cell responsiveness to Aspergillus antigens, the magnitude of tissue response to Aspergillus, and the level of environmental exposure to this ubiquitous fungus.
Investigations into the genetic risk factors associated with ABPA have identified several candidate genes, suggesting that the pathogenesis of ABPA requires both host and environmental factors.9 Best characterized is the association between gene mutations in the CF transmembrane conductance regulator (CFTR) and the pathogenesis of ABPA.10,11 CFTR mutations are more common among patients with ABPA compared with the general population or with individuals with severe asthma without sensitivity to A. fumigatus. Another genetic link to ABPA is that Th2-type T-cell reactivity to selected Aspergillus antigens is determined by the presence of MHC Class II DR2 or DR5 alleles, which may predispose patients to the disease, whereas the MHC DQ2 allele may be protective.12,13 In addition, investigators have determined that there is an increased prevalence of polymorphisms in the promoter region of the pathogen associated molecular pattern receptor, Toll (TLR) 9, in individuals with ABPA compared with controls or patients with SAFS.14 We recently determined that children with severe asthma and ABPA are more likely to carry the Chitotriosidase 1 (CHIT1) exon 10 mutation.15,16 Individuals with the exon 10 mutation have lower levels of, or lack, chitinase activity in serum and are unable to degrade chitin, a structural polysaccharide in the cell wall of lower life forms such as A. fumigatus.17–19
At the microscopic level, ABPA is characterized by an intense eosinophilic and mononuclear cell inflammatory response, leading into areas of parenchymal scarring, airway remodeling, and bronchiectasis.20,21 Immunologic studies demonstrate the presence of a type I hypersensitivity reaction, with elevated serum levels of total IgE and A. fumigatus-specific IgE in individuals with ABPA. In addition, patients have evidence of an exaggerated Type III hypersensitivity reaction, indicated by the presence of A. fumigatus-specific IgG antibodies (classically called “precipitins” or precipitating antibodies) and circulating immune complexes during disease exacerbations. A type IV cell-mediated immune reaction may also be at work, based on the finding of dual (immediate and delayed) cutaneous reactions and in vitro lymphocyte transformation to A. fumigatus antigen stimulation in some patients.22,23
A substantial amount of work has been done on the immune response in ABPA, demonstrating that several cell types and pathways are involved in the pathogenesis of this destructive variant of asthma.17,18 A pathogenetic role for helper T lymphocytes is suggested by a number of findings, including the presence of increased numbers of airway Th2 cells and elevated levels of soluble interleukin 2 receptors (suggesting T-cell activation) in the circulation of persons with active ABPA24; the derivation of A. fumigatus-specific T-cell clones with T helper–2 (Th2) patterns of cytokine production from the blood of patients with ABPA25,26; positive correlations between activated T-cell number, levels of the T-cell–derived cytokines IL-4 and IL-5, and number of airway eosinophils in the disease; the critical role IL-5 plays in murine models of ABPA27–34; and increased reactivity of Th2 cells to A. fumigatus antigens among patients with ABPA as compared with patients with asthma and skin reactivity to Aspergillus.
In addition to lymphocytes, eosinophils and basophils may contribute to local airway injury, and neutrophils likely play a role in airway inflammation and tissue damage in ABPA, as evidenced by the fact that sputum IL-8 levels correlate with sputum neutrophilia, matrix metalloproteinase levels, and FEV1 among patients with ABPA.35,36
It is also clear that the fungus itself contributes substantially to the pathogenesis of disease. A. fumigatus-derived proteases likely cause epithelial cell injury and protective barrier disruption, triggering immune hypersensitivity by inducing inflammation or by allowing increased penetration of fungal antigens into the airway wall.37 Aspergillus-derived proteases may also stimulate proinflammatory cytokines, such as IL-8, and release of growth factors; proteases may also cause tissue damage, leading to bronchiectasis.36
A variety of other Aspergillus-derived antigens (including cytotoxins and heat shock proteins) with demonstrated ability to bind IgE and IgG derived from the blood of patients with ABPA have also been shown to drive both the IgE (hypersensitivity) and IgG immune responses. A. fumigatus-derived proteases with antibody-binding capacity may also amplify the inflammatory response. A. fumigatus antigens, such as Aspf1 (a cytotoxic protein), Aspf2 (a fibrinogen binding protein), Aspf5 (a metalloprotease), Aspf6 (manganese superoxide dismutase), Aspf8 (a ribosomal protein), Aspf13 and Aspf18 (serine proteases), as well as Aspf3 and Aspf4, have all been implicated in these processes. Finally, host response to Aspergillus fumigatus antigens includes surfactant proteins (SP) A and D, which may play a protective role against ABPA by interfering with binding between A. fumigatus antigens and IgE. Notably, however, SPD levels do not correlate with acute exacerbations of ABPA in humans.38–40
CLINICAL FEATURES
Although ABPA typically presents in patients with a history of difficult-to-control asthma, the spectrum of presentation is highly variable and should be considered in any patient with difficult-to-control asthma and hypersensitivity to A. fumigatus (Table 48-1).40 Typical presenting complaints are often nonspecific and include dyspnea, wheezing, poor asthma control, cough (sometimes productive of thick, brown mucus plugs), malaise, low-grade fever, and occasionally, hemoptysis. There may be an antecedent history of recurrent asthma exacerbations in conjunction with pneumonias without a culture-identified bacterial source. In addition, atopy with rhinitis, drug allergy, and/or allergic conjunctivitis are also common. It is often not until a patient has been repeatedly ill over weeks to months and unresponsive to standard treatments that the diagnosis is considered.41 As patients with SAFS have the same clinical presentation, differentiation from ABPA is based on interpretation of laboratory testing and radiographic studies.40
DIAGNOSTIC GUIDELINES
In general, the diagnosis of ABPA is based on appropriate clinical features in combination with supporting radiologic and serologic findings. While there are no absolutely specific diagnostic criteria, similar guidelines have been proposed by multiple expert panels to aid clinicians in the diagnosis of ABPA (Table 48-1).20,42 These guidelines have evolved over time and have been recently updated by several societies. Although there is no agreement on clinical criteria that should trigger screening for ABPA, in most asthma centers, all asthmatics with difficult-to-control asthma are screened by checking an eosinophil count, total IgE, and radioallergosorbent test for 22 aeroallergens, including A. fumigatus and Alternaria.
Using the Patterson criteria (Table 48-1), ABPA may be considered to exist in two different forms: ABPA-seropositive (S) and ABPA-central bronchiectasis (CB).
Patients with ABPA-S usually display all of the following diagnostic criteria proposed by Greenberger and Patterson: (1) history of asthma; (2) total IgE >1000 IU/mL; (3) elevated serum anti-AF IgE and IgG (twofold higher than A. fumigatus allergic asthma controls); (4) positive immediate hypersensitivity skin test to A. fumigatus; and/or (5) serum anti-A. fumigatus IgG antibodies to A. fumigatus. The last criterion is considered positive when either the double gel diffusion, enzyme-linked immunoassay (ELISA), or fluorescent enzyme immunoassay (FEIA) are positive for anti-AF IgG antibodies.43
Patients with ABPA-S have normal chest radiographic studies, with no evidence of bronchiectasis. In contrast, patients with ABPA-CB have the classic features of advanced disease (expectoration of mucus plugs or sputum culture positive for A. fumigatus) and are positive for all of the criteria of ABPA-S listed earlier. Patients with ABPA-CB also have central bronchiectasis on high-resolution CT scanning or chest X-ray.44,45 Patients with ABPA-S tend to have fewer symptoms, lower IgE levels, less severe airflow obstruction, and fewer exacerbations than do persons with ABPA-CB. Although IgE levels fluctuate with disease activity, a normal IgE level in a symptomatic, untreated patient with asthma virtually excludes the diagnosis.46 It remains unclear whether ABPA-S is a milder form of the disease (e.g., representing a different host response) or an earlier stage of illness. Identification of Aspergillus (or other relevant fungus) in the sputum and dual (immediate and delayed) cutaneous reactions to challenge with Aspergillus (by prick test or intradermal) are also common clinical features of ABPA. Rare cases lacking a history of asthma, but meeting the other major diagnostic criteria, have been reported.41
SEVERE ASTHMA WITH FUNGAL SENSITIVITY
The broad spectrum of clinical, laboratory, and radiographic abnormalities evident in patients with asthma with fungal allergy has led to the description of additional diagnostic categories of allergic fungal disease. The most relevant of these diagnoses is based on studies that demonstrate that antifungal therapies are effective in patients with poorly controlled asthma that have some of the criteria for ABPA-S, but do not reach the threshold for diagnosis. These patients have been designated as having SAFS.
Whether SAFS is a unique disease or is on the continuum from asthma to ABPA remains unclear. However, the primary distinction is that patients with SAFS have a milder allergic reaction and lack the exaggerated IgG response that is typical of patients with ABPA. Therefore, patients with SAFS are difficult to distinguish from patients with ABPA, and especially ABPA-S, as the clinical features are identical between the two entities and both lack radiographic abnormalities.
The diagnosis of SAFS is based on the interpretation of Aspergillus-specific immunologic studies. The diagnostic criteria for SAFS (Table 48-2) overlap substantially with ABPA-S and include: (1) severe uncontrolled asthma (treatment requirement of >500 μg/d of fluticasone or the equivalent, need for near continuous oral corticosteroids for 6 months or >2 oral steroid tapers per year); (2) positive skin prick test or RAST for A. fumigatus or other fungi; (3) total serum IgE (<417 IU/mL or <1000 ng/mL)); and (4) absence of IgG against A. fumigatus (by ELISA, gel diffusion, or FEIA).
In general, patients with SAFS typically have normal radiographic studies and a milder immunologic response that may be identified in patients with milder asthma. Although it remains unclear whether these patients are on the continuum from asthma to ABPA or are at risk of progressing to frank ABPA, the importance of identifying such patients is based on several studies indicating that antifungal therapies may significantly improve asthma control and reduce oral corticosteroid exposure.47–49
The differential diagnosis of ABPA is broad and includes corticosteroid-dependent asthma without ABPA, SAFS, chronic obstructive pulmonary disease (COPD), chronic necrotizing aspergillosis, tuberculosis, parasitic infections, hypersensitivity pneumonitis, Churg–Strauss syndrome, acute eosinophilic pneumonia (including drug-induced pneumonitis), chronic eosinophilic pneumonia, lymphoma, idiopathic hypereosinophilic syndrome, autoimmune disease, crack cocaine use, CF, and other causes of bronchiectasis. In addition, the diagnosis of ABPA in patients with mold-sensitive asthma and CF poses particular diagnostic challenge. This is especially true in asthmatics, since, by definition, bronchiectasis is absent; furthermore, serum precipitins to Aspergillus spp. may be present in up to 10% of patients with positive immediate skin tests to Aspergillus and in up to 25% of asthmatics, making distinction from ABPA-S difficult.
Persons with mold-sensitive asthma or ABPA may have peripheral blood eosinophilia and/or elevated serum total IgE levels. However, most persons with ABPA have 2- to 20-fold higher serum levels of Aspergillus-specific IgE and total IgE than do mold-sensitive asthmatics without ABPA. A more confusing diagnostic conundrum occurs when considering the diagnosis of ABPA in patients with CF, because patients with CF alone may manifest chronic airflow obstruction, recurrent exacerbations with infections and/or bronchoconstriction, underlying bronchiectasis, pulmonary infiltrates, chronic sputum production, Aspergillus colonization of the airways, and positive serum precipitins.
Distinguishing ABPA in patients with CF is critical, because infectious CF exacerbations and the presence of ABPA require different treatments. The steroid treatment required for ABPA may be detrimental in the setting of infection, yet antibiotics alone given for infection may be inadequate to control the inflammation associated with ABPA. Among patients with CF, factors associated with the risk of ABPA include adolescent age, atopy, severe lung disease, and colonization with Pseudomonas aeruginosa. ABPA should be suspected in patients with CF who develop clinical deterioration, exhibit a greater than fourfold increase in total serum IgE (especially >1000 IU/mL), have immediate cutaneous reactivity to Aspergillus or increased Aspergillus-specific IgE or IgG, and show a change in baseline CXR. Annual screening of total serum IgE is recommended; if the level rises >500 IU/mL, immediate cutaneous hypersensitivity testing for reactivity to A. fumigatus or testing for serum anti-A. fumigatus IgE is recommended.11,50 The presence of IgE reactive against the purified Aspergillus allergens Aspf3 and Aspf4 may be useful in distinguishing patients with ABPA and CF or Aspergillus-sensitive asthma from patients without ABPA.10
CLINICAL STAGING OF ABPA
Five clinical stages of ABPA have been recognized, based on clinical, serologic, and radiographic characteristics (Table 48-3). A modified version proposed by the International Society for Human and Animal Mycology (ISHAM) has not been widely adopted.20,51
