What every physician needs to know:
Aspergillus fumigatus is a ubiquitous mold in the environment. Allergic bronchopulmonary aspergillosis (ABPA) is a disease that results from a hypersensitivity response to aspergillus in the airways. ABPA is part of a spectrum of respiratory disorders that can be caused by Aspergillus. First described by Hinson and colleagues in 1952, ABPA occurs most commonly in immunocompetent patients who have asthma or cystic fibrosis (CF), particularly those with underlying atopy. Although estimates of prevalence vary, ABPA is reported to affect 1-12 percent of patients with asthma and 1-15 percent of patients with CF. Rare cases have been reported among persons without asthma.
The typical presentation of ABPA is one of poorly controlled asthma with symptoms that include wheezing, productive cough, and shortness of breath. Hemoptysis and expectoration of brownish mucus plugs may occur. Low-grade fever, malaise, weight loss, or chest pain, may also be evident. It is important to note that some patients with ABPA may be without symptoms at initial diagnosis if they are on asthma medications. Depending on the stage of the disease, physical examination may be normal or may reveal wheezing and other manifestations of airflow obstruction, crackles, and clubbing. In advanced ABPA, signs of cor pulmonale may be present. Symptoms and physical examination alone are insufficient to establish the diagnosis.
Major diagnostic criteria include the presence of asthma or CF plus immediate skin test reactivity to Aspergillus antigens
elevated IgE levels against Aspergillus fumigatus, and markedly elevated total serum IgE (>1000 IU/mL). Other criteria include serum IgG antibodies against A. fumigatus, serum precipitating antibodies to A. fumigatus, peripheral blood eosinophilia (>500 cell/L in corticosteroid naïve patients, transient pulmonary opacities, and/or central bronchiectasis on chest imaging.
Goals of treatment are to minimize symptoms, control disease activity, maintain normal lung function, and prevent disease progression. Treatment depends on the stage and severity of disease. Heightened awareness of the possibility of disease in persons at risk, as well as early detection and aggressive treatment, is needed to prevent irreversible lung damage. High-dose systemic corticosteroids (usually administered over a period of several months) are the mainstay of treatment. Adjunct treatment with antifungal therapy, such as itraconazole, may be helpful for patients who are corticosteroid-dependent or who experience relapses despite corticosteroid treatment. Case reports suggest a role for monoclonal antibodies directed against IgE in selected patients whose disease has failed to respond to conventional therapy. With early diagnosis, careful patient monitoring, and appropriately aggressive treatment, the prognosis of ABPA is generally favorable, but it is worse for patients who develop corticosteroid-dependent asthma or advanced stage fibrotic lung disease.
ABPA is one of several disorders caused by Aspergillus fumigatus, other types of aspergillus or other fungal species. Historically, the extent of disease was described by a five stage paradigm. However, the definitions and clinical reliability of these stages has proven to be somewhat nebulous. Therefore, an international working group on ABPA has proposed a new clinical staging of ABPA (See Table 1). This new system offers potential benefit for the selection of patients for therapeutic trials. As with the older staging system, patients do not necessarily progress from one stage to the next. The updated staging system includes a stage 0 which is an asymptomatic stage. Patients in stage 0 have controlled asthma and no additional symptoms suggestive of ABPA. These patients are diagnosed with ABPA by routine investigation of asthmatic patients for ABPA. It is recommended that ALL patients with asthma should be investigated for ABPA using A. fumigatus-specific IgE levels or Aspergillus skin testing.
Are you sure your patient has allergic bronchopulmonary aspergillosis? What should you expect to find?
ABPA is present in up to one-fifth of well controlled asthma patients. Evaluation for ABPA should therefore be performed routinely in all patients with asthma. Key symptoms of ABPA include increased wheeze, cough, shortness of breath, and sputum production, with expectoration of brown or black mucus plugs suggestive of ABPA. Other symptoms may include malaise, myalgias, low-grade fever, chest pain, or weight loss. Hemoptysis has also been reported. Failure to improve clinically following antibiotics for a suspected bacterial infection, increased rates of bacterial colonization, and worsening of lung function or nutritional status may also suggest the diagnosis in patients with CF. Coexisting symptoms of atopy, including allergic rhinitis or sinusitis, are common.
The physical examination may be normal, or there may be evidence of wheeze, prolongation of the expiratory phase, crackles on auscultation of the lungs, or hyperresonance to percussion of the chest. Examination findings of consolidated lung (e.g., bronchial breath sounds, egophony) may be present during exacerbations of disease. Clubbing occurs occasionally, and findings of pulmonary hypertension and cor pulmonale (e.g., prominent P2, JVD, peripheral edema) may occur in patients with advanced lung disease.
Symptoms and signs alone are insufficient to establish a diagnosis of ABPA. The typical symptoms and signs of ABPA overlap with otherwise uncomplicated acute exacerbations of asthma and CF. Moreover, exacerbations of ABPA can occur, and ABPA may progress and cause inflammation and lung damage in the absence of acute or new symptoms. Additional radiologic and serologic tests are required to establish the diagnosis and to distinguish ABPA from other disorders caused by Aspergillus, as well as from other disorders with overlapping symptoms.
Beware: there are other diseases that can mimic allergic bronchopulmonary aspergillosis:
The differential diagnosis of ABPA is broad. Several additional disorders have clinical and laboratory features that overlap those found in ABPA. It is important to exclude Aspergillus sensitization among patients with asthma or CF that causes asthma or CF exacerbations but is not ABPA (sometimes termed “mold sensitive asthma,” “asthma with fungal sensitization,” or “allergic asthma with Aspergillus as the antigen trigger”). Symptoms alone are inadequate to make this distinction. Immune sensitivity to Aspergillus is estimated to exist in up to 30 percent of asthmatics and up to 53 percent of patients with CF, both of which are significantly higher than the prevalence of ABPA in these patient groups. A normal serum IgE in a patient who has not received glucocorticoid therapy essentially excludes active ABPA as the cause of the patient’s symptoms.
An identical clinical syndrome to ABPA can also occur in the absence of demonstrable immune sensitization to Aspergillus. Immune sensitization to several other fungi has been shown to cause an ABPA-like disease termed “Allergic bronchopulmonary mycosis” (ABPM).
The differential diagnosis of ABPA also includes refractory asthma without fungal sensitization, newly identified cystic fibrosis (especially in young adults), non-fungal infectious bronchitis and pneumonia, Aspergillus bronchitis, M. tuberculosis, eosinophilic granulomatosis with polyangiitis, bronchocentric granulomatosis, acute and chronic eosinophilic pneumonia, Loeffler’s syndrome (commonly caused by hypersensitivity to Ascaris lumbricoides), idiopathic hypereosinophilic syndrome, parasitic infections, sarcoidosis, autoimmune disease, other bronchiectasis syndromes, and tropical pulmonary eosinophilia (often caused by filariasis). The laboratory tests used to distinguish ABPA are discussed under “Laboratory and Diagnostic Testing.” The comparative features of ABPA and other disorders in which pulmonary opacities are associated with eosinophilia have been reviewed elsewhere. (See References.)
How and/or why did the patient develop allergic bronchopulmonary aspergillosis?
Aspergillus fumigatus is a soil-growing fungus that is ubiquitous in the environment worldwide. Conidia of Aspergillus, which are 2-3 µm in size and may become airborne, are inhaled readily into the lower respiratory tract. Healthy persons typically clear inhaled Aspergillus from the airways and lungs and do not develop disease. However, in varying clinical settings, Aspergillus can cause a spectrum of respiratory disorders, including asthma, ABPA, semi-invasive or invasive aspergillosis, aspergilloma, and bronchocentric granulomatosis. The contrasting features of these disorders have been reviewed elsewhere.
The pathogenesis of ABPA is incompletely understood. ABPA occurs most commonly in immunocompetent patients who have asthma or cystic fibrosis, particularly those with underlying atopy. ABPA is thought to result from a complex hypersensitivity reaction to persistence of Aspergillus in the bronchial tree, with mixed features of Type I immediate hypersensitivity, Type III antigen-antibody response, and Type IV cellular immune response. The burden of inhaled organisms alone does not correlate well with development of disease. Host factors, fungal virulence factors, and genetic susceptibility factors likely all play a role in development of disease.
Patients with asthma and CF have chronic airway wall inflammation and chronic mucus hypersecretion. Over time, some patients with CF or asthma develop fixed airflow obstruction and worsening pulmonary function. Patients with CF may develop progressive airway damage and diffuse bronchiectasis. The presence of excess mucus in the airways, impaired mucociliary clearance, or airflow obstruction may predispose patients with asthma or CF to have persistence of inhaled Aspergillus spores in the lower respiratory tract, which may create an environment in which Aspergillus spores adhere, germinate, form hyphae, and release antigenic proteins that trigger a hypersensitivity immune response.
Fungal Virulence Factors
Aspergillus organisms produce several products that may contribute to the pathogenesis of ABPA. Organisms damaged by the host immune response may secrete enzymes, including proteases (e.g., collagenase, trypsin, elastase, matrix metalloprotease), phospholipases and superoxide dismutases, and thioredoxins, that may contribute to airway epithelial and extracellular matrix injury and may augment or perpetuate inflammation. Aspergillus may also impair complement activation and phagocytosis of macrophages and neutrophils and further impair mucociliary clearance, enhancing the persistence of Aspergillus in the airways and augmenting the inflammatory response. Fungal expression of adhesin proteins may increase adherence of Aspergillus to the host airways. Patients treated chronically with systemic corticosteroids may also have decreased phagocytic responses to Aspergillus antigens.
The Host Immune Response and Pathogenesis of ABPA:
The sequence of events considered most likely to cause the clinical, physiologic, radiologic, serologic findings in ABPA is as follows:
In the susceptible host, inhaled Aspergillus organisms persist in the tracheobronchial tree and ultimately germinate and form hyphae within airway mucus. The Aspergillus then activates the innate immune system and releases proteases and other antigens (see above) that cause airway epithelial and airway wall injury, worsen mucociliary clearance, and induce an inflammatory response with release of inflammatory cytokines that further induce recruitment of inflammatory cells. Airway dendritic cells process fungal antigens, presenting them to T cells and releasing inflammatory cytokines.
In a healthy person, this process may lead to a mixed Th1-CD4+ and Th2-CD4+ T lymphocyte response wherein fungal organisms may be contained or eliminated. In contrast, an immune response skewed in the direction of a Th2 CD4+ T cell response is thought to occur in patients with ABPA. Th2 CD4+ T cells specific to Aspergillus fumigatus are recruited to the airway and release cytokines, including IL-4, IL-5, and IL-13, which perpetuate or augment airway inflammation. The collective result of fungal activation of the innate immune response and the Aspergillus antigen-specific Th2 cell adaptive immune response is to recruit more T cells and eosinophils, neutrophils, macrophages and mast cells to the airways, and to induce release of additional inflammatory cytokines and growth factors from airway epithelium.
Subsequently, B lymphocytes are activated, and an IL-4-dependent increase in total serum IgE occurs. Increased amounts of Aspergillus-specific IgE, IgG, and IgA are also produced. Airway and systemic eosinophilia occurs, and eosinophils release toxic granule products, such as major basic protein and eosinophilic cationic protein, which can further tissue injury. Airway neutrophils may release gelatinases, including MMP-9. A Type I immediate hypersensitivity response is manifested by development of cutaneous skin reactivity to Aspergillus allergen testing and by IgE-dependent mast cell degranulation with release of mediators like IL-5 (which recruits more eosinophils) and histamine. Mast cell and eosinophil granule products may also promote vasodilation and bronchoconstriction.
The presence of a Type III hypersensitivity reaction is manifested by the presence of IgG precipitins, complement activation, and antigen-antibody complexes. A Type IV cellular immune response is suggested by the finding of dual (immediate and delayed) cutaneous reactions and in vitro lymphocyte transformation to Aspergillus antigen stimulation in some patients. T and B lymphocytes also release cytokines into the systemic circulation. Increased levels of total IgE and Aspergillus-specific IgE and IgG are also present in the systemic circulation.
This combination of immune responses is thought to be ultimately responsible for the airway inflammation, mucus plugging, airway damage, central bronchiectasis, airway remodeling, worsening pulmonary function, and ultimately, in some patients, permanent pulmonary fibrosis. The laboratory tests used in diagnosis of ABPA reflect this mixed and complex immune hypersensitivity response. Murine models suggest that several additional inflammatory cytokines, including eotaxin, IL-8, MIP-1-alpha, and T cell-derived RANTES, contribute to airway inflammation in ABPA.
Genetic Susceptibility Factors:
Genetic susceptibility likely impacts the patient’s risk of developing ABPA. Several genetic factors that lead to alterations in the innate or adaptive immune response have been implicated. Persons with human leukocyte antigen (HLA) phenotypes DR2 or DR5 may be at risk for the disease, perhaps because of impaired host ability to clear Aspergillus from the airway, increased sensitivity of dendritic cells to interleukin-4 (IL-4), or increased production of more IL-10, which may exaggerate the MHC-Class II restricted Th2 immune response. In contrast, the HLA-DQ phenotype may protect patients from developing ABPA.
Mutations in the cystic fibrosis trans-membrane receptor (CFTR) are identified commonly in asthmatic patients with ABPA, independent of CF. One study demonstrated the presence of at least one CFTR gene mutation in 28.5 percent of patients with ABPA, compared with only 4.6 percent of asthmatics without ABPA. Patients with ABPA also have a higher rate of mutations in CFTR than the overall population does. However, CFTR mutations are not the sole or principal factor in ABPA pathogenesis, as they are identified in a minority of persons with the disease. However, when they are present, CFTR mutations may contribute to pathogenesis by leading to formation of thick, viscous mucus and impaired mucociliary clearance.
Toll-like receptors (TLR) are trans-membrane proteins that contribute to prompt recognition of infectious pathogens and initiation of an inflammatory response by activation of pro-inflammatory intracellular signaling pathways. TLR-2 and TLR-4 are particularly important in the initial immune response to fungi. A polymorphism in the TLR-9 gene has been associated with an increased risk of ABPA.
Collectins are antimicrobial proteins that serve as another component of the innate immune response by enhancing neutrophil and macrophage phagocytosis and killing of organisms. Examples of collectins include surfactant proteins A and D and mannose-binding lectin. Murine models have suggested an important role for these proteins in the host defense against Aspergillus. Polymorphisms in the SP-A protein and mannose-binding lectin have been associated with increased risk of ABPA.
Cytokines play an important role in initiating and perpetuating the immune response to fungal and other pathogens. As noted above, ABPA is thought to develop in the setting of an exaggerated Th2-subtype CD4+ T cell immune response. Polymorphisms in several Th2 (IL-4, IL-10 and IL-13) and Th-1 (TNF-alpha) cytokine genes have also been reported in association with ABPA. The precise mechanisms by which these polymorphisms may contribute to ABPA pathogenesis remain unclear.
Which individuals are at greatest risk of developing allergic bronchopulmonary aspergillosis?
Immunocompetent patients with asthma or CF, particularly those with a history of atopy, are at greatest risk of developing ABPA. ABPA occurs in 1-12 percent of patients who have asthma and in 1-15 percent of patients who have CF. Patients with asthma who develop ABPA range from those with mild asthma to those with severe corticosteroid-dependent disease. ABPA may be particularly likely in: (1) patients who require hospitalization for acute severe asthma exacerbations, (2) adolescent males with CF with reduced lung function or whose airways are colonized by Pseudomonas aeruginosa or Stenotrophomonas maltophilia, (3) those with low BMI, (4) individuals with concurrent sensitization to other fungi, and (5) those who are receiving treatment with recombinant human DNAse. Approximately 10 percent of acute exacerbations of respiratory symptoms in CF requiring hospitalization may be associated with ABPA.
Rare cases of ABPA have been reported in persons who do not have asthma or CF. ABPA commonly occurs in persons with allergic fungal sinusitis and may occasionally be seen in combination with aspergilloma or in association with other disorders, including sarcoidosis following treatment with infliximab, as well as COPD, diffuse bronchiectasis syndromes, and hyper IgE syndrome. Familial cases of ABPA have also been reported, so a higher index of suspicion and more intense monitoring for the disease are appropriate for family members of affected persons.
ABPA is recognized typically among asthmatic patients in their third to fourth decade and among CF patients during their teenage years. Among patients with asthma, women and men are affected equally. Patients are often recognized as having ABPA many years after their initial diagnosis of asthma.
What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?
The diagnosis of ABPA cannot be made based on symptoms and physical findings alone, even among those at greatest risk of developing the disease. The diagnosis of ABPA depends on the coexistence of suggestive clinical features, relevant radiologic findings, pulmonary function, and other laboratory testing. Laboratory studies reflect the underlying disease pathogenesis, as discussed previously. No single test is diagnostic for the disease. ABPA should be particularly considered among patients with asthma or CF with recurrent exacerbations and among family members of patients with the disease.
The following additional laboratory tests should be ordered to support or exclude the diagnosis:
Chest radiograph (CXR):
A variety of abnormalities may be present on the CXR (discussed further in Radiologic Features). Hallmark features of ABPA are the presence of transient pulmonary opacities, evidence of mucus plugging, airway wall thickening and inflammation, and centrally-distributed bronchiectasis. These findings are supportive but not sufficient to establish the diagnosis.
High-resolution chest CT (HRCT) scan:
HRCT scans characteristically show centrally distributed bronchiectasis but may also show pulmonary consolidation, atelectasis, or mucus plugging. HRCT should be performed when clinical features, CXR findings, skin testing, serologic tests, and other blood tests suggest the diagnosis.
Complete blood count (CBC) with differential:
A CBC should be performed to determine the presence of peripheral blood eosinophilia. Blood eosinophils in those with ABPA are typically elevated to a level higher than 500/mm3 or higher than 1000 cells/microliter. However, peripheral blood eosinophilia may be seen in several disorders other than ABPA, and counts of less than 1000 cells/microliter are also common. Moreover, absence of eosinophilia does not rule out the disease. The presence of eosinophilia supports the diagnosis of ABPA, especially among persons who are receiving systemic corticosteroid treatment. The CBC can also be helpful in evaluating possible alternate processes, such as bacterial infection.
Cutaneous skin testing for Aspergillus sensitivity:
Patients with asthma or CF should be evaluated with either cutaneous skin prick test to assess reactivity to Aspergillus antigens or measurement of Aspergillus specific IgE levels (see below). A positive skin test indicates immune sensitization to Aspergillus. However, this finding is not specific for ABPA since an estimated 20-30 percent of patients with Aspergillus-sensitive asthma or CF without ABPA have positive skin tests to Aspergillus. If the skin prick test is negative, an intradermal skin test should be done, as this test is more sensitive in detecting Aspergillus sensitization. The combination of negative skin prick and intradermal skin testing for Aspergillus excludes the diagnosis of ABPA. In patients with negative skin tests in whom the diagnosis is still suspected clinically, skin testing with other fungal antigens should be considered in pursuit of a possible diagnosis of non-aspergillus ABPM. In such cases, skin testing with the relevant fungal antigen is crucial to establishing the diagnosis.
Aspergillus-specific IgE measurement is a more sensitive indicator for the diagnosis of ABPA and is now recommended as an alternative first step in the diagnostic work up. Blood should be tested by enzyme-linked immunoassay for titers of Aspergillus-specific IgE. Titers that are at least twice reference values for asthmatics who are sensitive to Aspergillus but lack ABPA strongly suggest the presence of disease and help to differentiate persons with ABPA from those with fungal sensitization and resultant allergic asthma without ABPA. Experts have proposed that >0.35 kUA/L could be used for a cut-off value.
Serum total IgE levels:
If the skin test to Aspergillus is positive, serum total IgE should be measured. A normal IgE level virtually excludes the diagnosis. Levels of total IgE are typically greater than 1000 IU/ml during exacerbations of ABPA; greater than two-fold increases in the level indicate relapses of disease. As is true for peripheral blood eosinophilia, elevated serum IgE is not specific for ABPA. However, total IgE levels are currently the best available test to follow disease activity over time and are the most useful guides to titrating anti-inflammatory therapy. Total IgE levels rarely normalize even with intensive or prolonged corticosteroid treatment; 35 to 50 percent reduction in IgE levels compared with levels seen during exacerbations can be expected.
Serum precipitins to Aspergillus:
If skin testing is positive, serum-precipitating IgG antibodies to Aspergillus should also be measured. Their presence is supportive of but not specific for the diagnosis of ABPA; an estimated 10 percent of asthmatics with sensitivity to Aspergillus without ABPA have positive precipitating antibodies.Sputum culture (for fungal, bacterial or other pathogens):
Sputum cultures may be helpful in excluding alternate microbial pathogens that may be contributing to symptom exacerbations, radiographic abnormalities, or worsening lung function, particularly among patients with CF. Aspergillus is commonly found in the mucus plugs of patients with ABPA (approximately 50% of patients). Its presence is supportive of the diagnosis but is by no means specific. Organisms such as pseudomonas can be seen in culture as occurs in patients with other forms of bronchiectasis.
Serologic testing for the presence of immune sensitivity or reactivity to recombinant Aspergillus antigens:
Since most testing for Aspergillus sensitivity has been done using crude extracts of Aspergillus, research has been conducted to test the utility of recombinant Aspergillus antigens derived from both secreted (e.g., Asp-f 1, Asp-f 3, Asp-f 5) and cytoplasmic proteins (e.g., Asp-f 6) in establishing the diagnosis of ABPA. The hope has been that these antigens will help to standardize the diagnosis. While such antigens may ultimately prove to be useful, they are currently not widely available, they are comparatively expensive, and they are not yet available for routine clinical use.
What imaging studies will be helpful in making or excluding the diagnosis of allergic bronchopulmonary aspergillosis?
Routine chest radiographs (CXR) and high resolution chest CT scans (HRCT) are both helpful in establishing the diagnosis of ABPA. The radiographic findings reflect the underlying disease pathogenesis and typically include findings suggestive of airway wall thickening or inflammation, mucus plugging, inflammatory pneumonitis, bronchiectasis, or severe destruction of lung architecture with fibrosis. Accordingly, the radiographic features vary among patients and depend on activity and stage of the disease, as well as the presence or absence of underlying CF or other concurrent lung disease.
The CXR may be normal in early or dormant stages of the disease. Common CXR findings include:
Transient (“fleeting”) airspace opacities, especially those that involve the upper or middle lobes
Focal areas of atelectasis (lobar or segmental)
Mucus-impacted bronchi (“toothpaste” or “finger-in-glove” shadows or nodules (mucus-impacted bronchi seen on end)
Evidence of bronchial wall thickening (“tram-line shadows”) or bronchial dilatation (“parallel line” or “ring” shadows)
Bronchiectasis with a central distribution
Pulmonary fibrosis (especially in the upper lobes), with or without cavitation: this is a manifestation of advanced disease
Other features that have been reported, but are less common on routine CXR, include peri-hilar opacities, pleural effusions or thickening, air-fluid levels, mediastinal or hilar adenopathy, mass-like areas of consolidation, and aspergilloma.
High-Resolution CT Scan
The most characteristic feature of ABPA on HRCT is the presence of central, cylindrical bronchiectasis with tapering of the bronchi in the lung periphery, predominantly affecting the upper lobes. Intermittent mucoid impaction of bronchiectatic airways is common, and bronchiectasis may also be seen in the periphery of the lung. However, the presence of bronchiectasis is neither sensitive nor specific for the diagnosis of ABPA.
Localized or diffuse bronchiectasis may be seen in many other pulmonary disorders (including post-infectious disorders, those associated with immunoglobulin deficiency, ciliary dysfunction, recurrent aspiration, autoimmune, and inherited disorders). Patients with CF without ABPA develop diffuse bronchiectasis over time as a result of chronic airway inflammation, impaired mucus clearance, and recurrent pulmonary infections. Patients with asthma without ABPA can also develop bronchiectasis. Moreover, bronchiectasis in ABPA (and other disorders) typically results from longstanding airway inflammation and injury. As such, bronchiectasis is seldom present among patients early in the course of ABPA.
Patients with ABPA may be divided into two subgroups: those with central bronchiectasis on radiologic imaging (ABPA-CB) and those without (ABPA-S). Patients in the latter group have clinical and serologic or immunologic manifestations of the disease in the absence of evident central bronchiectasis. (See additional discussion under Diagnosis of ABPA.) There is uncertainty concerning whether patients with ABPA-S have an earlier stage or milder form of the disease.
Other common findings on HRCT in ABPA include airspace consolidation, atelectasis, ground glass opacities, mosaic appearance with regional air trapping, centrilobular nodules with tree-in-bud appearance, and fibrosis. Less common HRCT findings include peribronchial fibrosis, pleural effusion or thickening, and randomly scattered nodules.
Some patients have evidence of “high-attenuation mucus” on CT imaging, that is, mucus that is visibly denser than paraspinal skeletal muscle. Such high-attenuation mucus may represent deposition of salts and metals and drying of mucus, and is thought to imply disease chronicity. Studies have demonstrated that high-attenuation mucus may be an adjunct characteristic radiologic finding supportive of the diagnosis of ABPA. Its presence may suggest an amplified inflammatory response and an increased risk of disease relapse. Additional studies are needed to investigate this finding.
What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of allergic bronchopulmonary aspergillosis?
Pulmonary function testing does not assist in confirmation or exclusion of the diagnosis of ABPA. However, pulmonary function testing can be used to measure the impact of the disease on lung function and to monitor patients for changes, especially worsening of pulmonary function over time. Pulmonary function test findings may vary, depending on the stage and severity of ABPA, as well as on the presence of coexisting underlying lung disease, such as CF.
Pulmonary function testing may be normal when patients are early in the course of disease or during periods of remission. Patients with CF or severe or chronic asthma, may have a component of fixed, irreversible airflow obstruction. During exacerbations of ABPA, or with progressive disease, patients typically have varying degrees of airflow obstruction (reduced FEV1 and FEV1/FVC) with at least partial bronchodilator reversibility (improvement in FEV1 or FVC following inhalation of bronchodilator).
Varying degrees of air trapping (increased RV or RV/TLC) and hyperinflation (elevated FRC or TLC) may be seen. More severe airflow obstruction with less bronchodilator reversibility tends to occur with advancing disease. If advanced stage fibrotic lung disease occurs, a restrictive ventilatory defect (with reduced TLC) and impaired diffusing capacity are seen.
What diagnostic procedures will be helpful in making or excluding the diagnosis of allergic bronchopulmonary aspergillosis?
The constellation of clinical features, radiologic findings, pulmonary function abnormalities, and laboratory studies useful in establishing the diagnosis of ABPA are discussed above in the relevant sections for these topics. The diagnosis of ABPA can be difficult to establish since:
Symptoms of the acute stage and the exacerbation stage and physical findings during these periods may be similar or identical to acute exacerbations of asthma or CF without ABPA.
Symptoms and signs of ABPA and some of its laboratory features overlap with several other respiratory disorders, including Aspergillus-sensitive asthma and CF without ABPA.
The disease (and its associated symptoms and radiographic and laboratory studies) fluctuates over time, disease activity is not always manifested by obvious symptoms, and radiographic images that may suggest the diagnosis are not performed during otherwise uncomplicated exacerbations of asthma.
As a result, patients may have ABPA for many years before the diagnosis is considered, and some patients are not diagnosed until later stages, when irreversible lung damage is present. Therefore, routine investigation should be performed in all at risk patients (asthma and CF), and a high degree of vigilance for the diagnosis must be maintained over time among persons at risk for the disease, and a systematic approach to establishing or excluding the diagnosis is needed in an effort to determine proper treatment and prevent occurrence of irreversible lung disease. Accurate and early diagnosis is believed to be important in prevention of advanced lung disease.
Establishing the diagnosis requires documentation of the presence of appropriate clinical, radiographic, and immunologic manifestations in the absence of other demonstrable causes. Diagnostic criteria have been updated by an international ABPA working group and include the following:
Predisposing Conditions: asthma or cystic fibrosis
Obligatory Criteria (both should be present)
Immediate skin test reactivity to Aspergillus antigens
elevated IgE levels against Aspergillus fumigatus
Elevated total serum IgE (>1000 IU/mL)
Other Criteria (at least two of three)
Presence of serum precipitating or IgG antibodies against A. fumigatus
Radiographic pulmonary opacities consistent with ABPA
Total eosinophil count >500 cells/L in a corticosteroid naïve patient
(Adapted from Agarwal et al. Clinical & Experimental Allergy 2013 (43) 850.)
In addition, the international ABPA working group has suggested four major radiographic classifications of ABPA: (1) Serological ABPA in which criteria for diagnosis of ABPA are met but without evidence of bronchiectasis, (2) ABPA with bronchiectasis, in which criteria for diagnosis of ABPA are met and bronchiectasis is present, (3) ABPA with high-attenuation mucus, in which all diagnostic criteria are met including the presence of high attenuation mucus, (4) ABPA with chronic pleuropulmonary fibrosis in which two of three additional radiographic features are present, such as pulmonary fibrosis, parenchymal scarring, fibro-cavitary lesions, aspergilloma, and pleural thickening without presence of mucoid impaction or high-attenuation mucus.
The following stepwise approach has been put forward by the international ABPA working group:
Screen with A. fumigatus specific IgE levels.
If A. fumigatus IgE specific levels are positive, measure total IgE levels.
If IgE levels are >1000 IU/mL, proceed with Aspergillus skin test, measurement of serum eosinophils, and A. fumigatus precipitins or A. fumigatus specific IgG.
If two of the four tests in #3 are positive (skin test, elevated eosinophils, Aspergillus precipitins, or specific IgG) proceed with HRCT.
Radiographic category can be assigned based on the result of the HRCT (see above).
Establishing the diagnosis of ABPA in patients with CF requires special consideration. The diagnosis may be particularly difficult in these patients because, in addition to having many overlapping clinical features (e.g., symptoms and signs), they often already have or will develop diffuse bronchiectasis in the absence of ABPA. Moreover, they are prone to infectious exacerbations that are due to bacterial pathogens; furthermore, colonization with Aspergillus fumigatus may occur in up to 60 percent of patients with CF.
In 2003, the Cystic Fibrosis Consensus Conference proposed diagnostic criteria for ABPA in patients with CF. The criteria include:
Acute or subacute deterioration in symptoms and pulmonary function in the absence of an alternate identifiable cause (especially if the patient does not improve after one week of antibiotics)
Immediate skin test reactivity to Aspergillus OR serologic presence of serum anti-Aspergillus IgE
Total serum IgE > 1200 ng/ml or > 500 IU/L.
plus one of the following:
Positive serum precipitins or anti-Aspergillus-specific serum IgG
New or recent abnormalities (e.g., infiltrates, mucus plugs) on CXR or HRCT that do not clear or improve with antibiotics or secretion mobilization techniques
Repeat IgE testing is recommended in three months if total IgE is 480-1200ng/ml or 200-500 IU/L initially, or if the initial IgE is measured while the patient is taking systemic corticosteroids.
The conference guidelines also suggest the following approach to screening or monitoring for ABPA in patients with CF:
Maintain high level of suspicion in patients over age six.
Measure total serum IgE annually: if the level is greater than 1200 ng/ml or greater than 500 IU/L, check for skin test reactivity or presence of serum Aspergillus-specific IgE.
If total IgE is 480-1200 ng/ml (200-500 IU/L), repeat the measurement or perform other diagnostic tests (e.g., skin testing, anti-Aspergillus-specific IgE, IgG, Aspergillus precipitins, CXR).
Others have recommended that total IgE be measured every two months for one year and that spirometry be performed at least annually in CF patients. CXR should be performed if there is a two-fold or greater increase in IgE, regardless of whether there is an escalation or exacerbation of symptoms.
Recent work has shown that blood levels of thymus- and activation-regulated chemokine (TARC) are higher in CF patients with ABPA than in those without the disease. TARC levels correlated directly with Aspergillus-specific IgE and inversely with lung function. Increased TARC levels may be found during exacerbations before marked elevations in total IgE occur; TARC levels are reduced with corticosteroid treatment, so serum TARC levels may prove useful in identifying ABPA in patients with CF, as well as in monitoring disease activity over time.
What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of allergic bronchopulmonary aspergillosis?
Bronchoscopy and Bronchoalveolar Lavage
Bronchoscopy is not necessary for establishing the diagnosis of ABPA so it is not routinely performed. Bronchoscopy with washings and bronchoalveolar lavage may be considered in selected patients in whom the diagnosis remains uncertain, and alternate diagnoses (e.g., other infectious pathogens, bronchiolitis obliterans organizing pneumonia (BOOP), eosinophilic pneumonia, parasitic infection) are being entertained. If performed, bronchoscopy may produce specimens that contain Aspergillus organisms and increased numbers of eosinophils.
ABPA is not typically diagnosed via tissue sampling. Nevertheless, histologic findings among patients with ABPA (e.g., if lung biopsy is performed to exclude an alternate diagnosis) typically include:
Mucus-impacted bronchi and central bronchiectasis
Charcot-Leiden crystals and Curschmans spirals
Bronchial wall eosinophilic and lymphocytic inflammation
Eosinophilic infiltration of lung parenchyma
Bronchocentric granulomatosis (non-caseating granulomas with multinucleated giant cells and eosinophils)
Fungal hyphae in mucus plugs, without bronchial tissue invasion
Pulmonary fibrosis, with or without cavitation, in Stage V disease
Less common findings include obstructive bronchiolitis or bronchiolitis obliterans organizing pneumonia, interstitial pneumonitis, vasculitis, and microabscesses that contain fungal hyphae. Histopathologic findings may vary in differing parts of the lung and in different stages of the disease. When available, histologic findings may be useful in helping to distinguish ABPA from other disorders in which pulmonary infiltrates are associated with eosinophilia, such as Churg-Strauss syndrome, acute or chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, and idiopathic hypereosinophilic syndrome.
While findings in animal models of and patients with ABPA suggest some genetic predisposition to developing the disease (see How and Why Did My Patient Develop ABPA), such testing is investigational at present, and genetic studies are currently not used routinely in establishing the diagnosis of ABPA.
If you decide the patient has allergic bronchopulmonary aspergillosis, how should the patient be managed?
The goals of management of ABPA are to minimize symptoms, control disease activity, maintain normal lung structure and function, and prevent disease progression. Consequently, early detection and aggressive treatment of the acute stage of disease and disease exacerbations are essential in preventing development of permanent airway remodeling, bronchiectasis, and pulmonary fibrosis.
Treatment of ABPA depends on the stage and severity of disease:
Systemic corticosteroids (prednisone) are the mainstay of treatment of ABPA for both the acute and exacerbation stages. The goals of systemic corticosteroid treatment are to suppress the immune hypersensitivity and inflammatory response to Aspergillus, thus reducing IgE and eosinophil levels, improving radiographic infiltrates, and improving symptoms and pulmonary function. Retrospective studies and case series confirm the efficacy of systemic corticosteroids in controlling symptoms, improving radiographic opacities, reducing serum IgE levels, improving pulmonary function, and preventing disease progression. A recently published randomized controlled trial of systemic corticosteroid treatment in ABPA suggests medium rather than high dose corticosteroid therapy results in similar improvement in lung function and time to first exacerbation with lower cumulative corticosteroid dose and adverse effects.
Based on this study the recommended initial dose of prednisone is 0.5 mg/kg/day for two weeks, followed by every-other-day dosing for eight (six to twelve) weeks, and then a gradual tapering of 5 mg every two weeks until therapy is stopped after three to five months. Children who have CF may require higher doses or longer duration of treatment: An initial dose of 2 mg/kg/day is recommended for one week, followed by one mg/kg/day for one week, and subsequent alternate-day dosing at 0.5 mg/kg/day for three months; the dose is tapered further thereafter, as tolerated. The duration of treatment is determined by the patient’s symptoms AND by demonstration of disease control.
Patients should be monitored with total serum IgE levels every six to eight weeks and with serial CXRs during treatment. A 25-50 percent reduction in IgE and radiographic improvement are expected in six to eight weeks with successful treatment. IgE levels typically do not return to normal; the patient’s lowest achievable baseline should be noted to guide diagnosis of and to use as a target for treatment of subsequent exacerbations. Prolonged treatment with systemic corticosteroids may be needed to induce remission, control the disease, and prevent recurrence (exacerbation).
Once in remission, the patient should be monitored with medical history, physical examinations, intermittent CXRs, and pulmonary function testing, as well as IgE levels every six to eight weeks for a year. IgE levels can then be followed yearly, unless an increase in symptoms or new radiographic findings prompt earlier reassessment. A two-fold or greater rise in IgE level or recurrence of radiographic infiltrates are indications of the need to return to high-dose corticosteroid treatment, as noted above for the acute phase of the disease.
Case reports have also indicated improvement in pulmonary function, serum IgE levels, and eosinophil counts following monthly intravenous pulse methylprednisolone therapy (e.g., doses of 10-20 mg/kg/day for three days/month) for patients with CF and ABPA who fail to improve with standard glucocorticoid dosing and antifungal therapy.
Late stage disease is defined by chronic dependence on systemic corticosteroid treatment; variable dosing is required to maintain optimal symptom and disease control. Alternate-day dosing with the lowest possible dose is suggested. Patients with advanced disease may still require chronic or intermittent systemic corticosteroid treatment to control asthma symptoms, despite the presence of end-stage pulmonary fibrosis.
Patients should be monitored closely for adverse effects of systemic corticosteroid treatment, such as osteoporosis, hyperglycemia, hypertension, muscle weakness, cataracts, and opportunistic infections. Children and adolescents with CF must also be monitored for evidence of growth retardation. Prophylaxis to prevent osteoporosis should be considered.
Some patients fail to achieve adequate symptom and disease control despite high-dose corticosteroid treatment, and many develop adverse effects of corticosteroids that make ongoing treatment difficult. Antifungal therapy is an alternate or adjunct strategy to achieve or improve control of ABPA. The rationale for antifungal treatment is that reduction of the burden of Aspergillus organisms in the airways may reduce antigenic stimulation, thereby reducing the immune and inflammatory responses. Antifungal agents may also have some direct anti-inflammatory effects.
Several azoles have been used in the treatment of ABPA. Itraconazole, which has a more favorable side effect profile (including less hepatotoxicity) than ketoconazole, has been the best studied of these agents. To date, two randomized, controlled trials have demonstrated benefits of itraconazole as an adjunct to systemic corticosteroids among patients who remain glucocorticoid-dependent or who relapse, despite corticosteroid treatment. In such patients, itraconazole leads to more rapid improvement in symptoms, exercise tolerance, and reduction in IgE levels compared with placebo; its use often enables reduction of the systemic corticosteroid dose.
Patients who are treated with itraconazole plus corticosteroids may also experience greater radiographic improvement, faster reduction in sputum eosinophils, and fewer disease exacerbations. No definite effect on pulmonary function has been shown thus far. Whether itraconazole treatment is helpful in all stages of the disease is unclear, and the long-term effects on disease progression are unknown. In addition, although similar promising results of itraconazole treatment for patients with CF and ABPA have been reported in uncontrolled studies, no randomized trials of ABPA and azole treatment have been conducted in patients with ABPA and CF.
Itraconazole should be considered for patients who experience disease relapse despite glucocorticoid treatment, who remain glucocorticoid-dependent, or who have adverse effects from corticosteroid treatment. Although optimal duration of treatment is not known, the recommended dose for adults is 200 mg by mouth twice daily for sixteen weeks, during which time monitoring for disease activity similar to that described previously should be undertaken. The dose of itraconazole for children with CF and ABPA is 5 mg/kg/day, administered either once daily, or in divided doses (twice daily) for persons who require more than 200 mg/day. Itraconazole doses should be taken with food, and concurrent antacid treatment should be avoided, as the drug is not well absorbed under conditions of high gastric pH.
Patients should be monitored closely for adverse effects while taking itraconazole; gastrointestinal upset is the most frequent complaint. Elevation of liver enzymes is common, especially among persons with preexisting hepatic dysfunction. Liver function tests should be monitored every one to three months. Other, less common adverse effects include edema, quadriparesis, and tremor.
Concurrent use of itraconazole and corticosteroids may inhibit corticosteroid metabolism and potentiate the steroid effect. Therefore, patients are at increased risk of adverse systemic effects, such as adrenal insufficiency. Itraconazole affects the metabolism of other drugs and vice versa. Patients with intestinal disorders may not absorb the medication well so regular monitoring of serum itraconazole levels is advised during treatment. Sputum cultures should also be obtained and followed in order to ensure that the Aspergillus is susceptible to the antifungal agent used.
Case reports have suggested successful adjunct treatment of ABPA using other antifungal agents, such as voriconazole, posiconazole, and inhaled amphotericin B, including among patients with CF. The combination of nebulized budesonide plus nebulized amphotericin B was shown in a small randomized trial to significantly reduce the number of exacerbations in patients with ABPA. Case studies suggest a possible steroid spacing effect for nebulized anti-fungal therapy, although reports are inconsistent. [PUBMED:26666774 and 24809846]
Additional studies are needed to confirm the efficacy and safety of these treatments.
Monoclonal Antibody Targeted Against IgE
Omalizumab is a monoclonal antibody directed against IgE that binds to circulating IgE, prevents its binding to effector cells, and downregulates IgE receptors. Therefore, Its effect is to reduce the inflammatory response. Omalizumab has proven to be effective in improving disease control in selected asthmatic patients without ABPA. Several, although not all, case reports have demonstrated that omalizumab treatment may be effective in reducing symptoms, IgE levels, corticosteroid dose requirements, and exacerbations; omalizumab may also improve lung function among corticosteroid-dependent patients with ABPA who have also failed itraconazole therapy, including adults with asthma and children with CF. Omalizumab may have synergistic effects when combined with other monoclonal antibody therapies. The addition of mepolizumab, a monoclonal antibody to IL-5 was described in a case report to allow for the discontinuation of steroids in a patient with severe, treatment refractory ABPA. [PUBMED:28279664] Larger and longer-term studies are needed to confirm efficacy, safety and to justify the cost of monoclonal antibody treatment in ABPA.
Other Aspects of Patient Management
Bronchodilator treatment is indicated for management of asthma symptoms, bronchoconstriction, and airflow obstruction, as it is for patients with asthma or CF without ABPA. While inhaled corticosteroids are, in general, a core component of the treatment of asthma, and they may help to control asthma symptoms in persons with ABPA as well, case series and one small placebo-controlled trial suggest that inhaled corticosteroids alone are insufficient for inducing and maintaining disease control in ABPA. It is reasonable to use inhaled corticosteroids when patients are taking 10 mg or less prednisone per day.
Training of patients with proper inhaler and bronchial hygiene techniques is essential. It is also prudent to optimize management of other conditions that may exacerbate asthma symptoms, such as gastroesophageal reflux, allergic rhinitis, and sinusitis. In addition, since inhaled Aspergillus is thought to cause ABPA, it may be helpful to avoid areas with high spore counts, such as compost piles, barns, and damp basements. Patients should receive influenza and pneumococcal vaccines according to standard guidelines. Patients with Stage V fibrotic lung may require supplemental oxygen therapy or referral for lung transplantation.
What is the prognosis for patients managed in the recommended ways?
Although the pathogenesis of ABPA and the factors that determine progression of disease are incompletely understood, achieving disease remission and minimization of recurrence are common when the disease is detected early and treated appropriately. Patients should be followed long-term since late relapses may occur.
Unfortunately, if the disease goes unrecognized, is untreated, or is treated insufficiently, progression of the inflammatory response leads to worsening lung function, bronchiectasis, and, ultimately, to development of fibrotic lung. Overall, few patients develop advanced stage fibrotic disease, but the prognosis is poor for those who do. Patients with end-stage disease can be transplanted successfully, although ABPA recurrence in transplanted lung has been reported.
What other considerations exist for patients with allergic bronchopulmonary aspergillosis?
All of the relevant considerations for ABPA have been considered elsewhere.
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- What every physician needs to know:
- Are you sure your patient has allergic bronchopulmonary aspergillosis? What should you expect to find?
- Beware: there are other diseases that can mimic allergic bronchopulmonary aspergillosis:
- How and/or why did the patient develop allergic bronchopulmonary aspergillosis?
- Which individuals are at greatest risk of developing allergic bronchopulmonary aspergillosis?
- What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?
- What imaging studies will be helpful in making or excluding the diagnosis of allergic bronchopulmonary aspergillosis?
- What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of allergic bronchopulmonary aspergillosis?
- What diagnostic procedures will be helpful in making or excluding the diagnosis of allergic bronchopulmonary aspergillosis?
- What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of allergic bronchopulmonary aspergillosis?
- If you decide the patient has allergic bronchopulmonary aspergillosis, how should the patient be managed?
- What is the prognosis for patients managed in the recommended ways?
- What other considerations exist for patients with allergic bronchopulmonary aspergillosis?