Histology

Histology is not a requirement to diagnose ABPA. If a lung tissue is obtained, histopathological features include bronchocentric granulomatosis, tissue eosinophilia, and bronchial mucoid impaction with the mucin containing large numbers of eosinophils and Charcot–Leyden crystals [61]. Noninvasive fungal hyphae may also be present.

Diagnostic Criteria

Historical Diagnostic Criteria

There is no single test to diagnose ABPA. Rather, the diagnosis is based on a constellation of clinical, serological, and radiographic fndings. The diagnostic criteria for ABPA have evolved over time. ABPA was frst described in a case series of three patients in 1952 in England [62]. The patients had intermittent wheezing, fevers, sputum with brown plugs or ecks, eosinophilia in both the blood and sputum, and pulmonary infltrates noted on chest X-ray. Hinson et al. suggested the following diagnostic criteria: recurrent pyrexial attacks, purulent sputum containing plugs or brownecks, growth of Aspergillus from sputum culture, radiographic evidence of recurrent pulmonary collapse and consolidation in different areas, and peripheral eosinophilia of >1000 per mm3. Following this initial report, Henderson described an additional series of 32 patients in which 22 patients presented with eosinophilia, sputum with abundant hyphae, episodic airway obstruction, and transient pulmonary opacities in multiple sites, which he referred to as allergic aspergillosis [63].

Rosenberg and Patterson Diagnostic Criteria

Rosenberg and Patterson published a case series of 20 patients with ABPA in 1977 in which they proposed a formal diagnosis of ABPA defned by the following seven primary criteria: episodic bronchial obstruction (asthma), peripheral blood eosinophilia, immediate skin reactivity to an Aspergillus antigen, precipitating antibodies against an Aspergillus antigen, elevated serum IgE concentrations, history of transient or fxed pulmonary infltrates, and central bronchiectasis [64]. They proposed that the diagnosis of ABPA is highly likely if six of the seven criteria are met and certain if all seven criteria are present. Secondary criteria of fnding Aspergillus fumigatus in repeated sputum samples

from culture or microscopic examination, history of expectoration of brown ecks or plugs, and Arthus reactivity (late skin reactivity) to the Aspergillus antigen were supportive of a diagnosis of ABPA but were not required.

The Rosenberg–Patterson criteria for ABPA were the generally accepted diagnostic criteria for many years. Critiques of the Rosenberg–Patterson criteria include the equal importance given to each fnding and lack of defned cutoff values for total IgE levels and eosinophil counts. In 1986, it was recognized that limited disease without central bronchiectasis could be present in patients who otherwise met the clinical and serological criteria for a diagnosis [65]. ABPA was subsequently further classifed into allergic bronchopulmonary aspergillosis serological (ABPA-S) and allergic bronchopulmonary aspergillosis with central bronchiectasis (ABPA-CB). The 1977 Rosenberg–Patterson criteria were updated in 1991 by Schwartz and Greenberger [66]. In the updated criteria, elevated levels of Aspergillus fumigatus-­ specifc IgE and Aspergillus fumigatus-specifc IgG were included as the diagnostic criteria.

ISHAM Diagnostic Criteria

More recently, the International Society for Human and Animal Mycology (ISHAM) has formed a working group focused on ABPA in asthma patients to further refne the diagnostic criteria and proposed new diagnostic criteria in 2013 [46]. In these new criteria, a predisposing condition of asthma or CF must be present (Box 4.1). Both obligatory criteria and two of three additional criteria are then needed for a diagnosis of ABPA. Obligatory criteria are an elevated total serum IgE level and either immediate cutaneous hypersensitivity to an Aspergillus antigen or elevated levels of Aspergillus fumigatus-specifc IgE. Additional criteria are the presence of precipitating or IgG-specifc antibodies against Aspergillus fumigatus, radiographic pulmonary opacities consistent with ABPA, and a total eosinophil count >500 cells/μL in glucocorticoid-naïve patients. The elevated total eosinophil count may be a historical abnormality occurring at any point in the patient’s clinical course. The ISHAM group removed the presence of bronchiectasis as a requirement for a diagnosis, given that ABPA may be present without bronchiectasis. The group established a total IgE level of >1000 IU/mL as the cutoff level for a diagnosis in an attempt to differentiate from severe asthma with fungal sensitization (discussed below); however, a diagnosis of ABPA should still be considered in patients with total IgE levels less than 1000 IU/mL if the other diagnostic criteria are met.

Box 4.1 ISHAM Group Diagnostic Criteria

Predisposing conditions

Asthma, cystic fbrosis

Obligatory criteria (both must be present)

 Immediate cutaneous hypersensitivity to the Aspergillus antigen or elevated Aspergillus fumigatus-specifc IgE levels

 Elevated total IgE levels (>1000 IU/mL)

Additional criteria (at least two of the following)

 Total eosinophil count >500 cells/μL in a steroid-naïve patient, may be historical

Positive precipitating antibodies or Aspergillus fumigatus- specifc IgG antibodies

 Radiographic pulmonary opacities consistent with ABPA

ISHAM International Society for Human and Animal Mycology, IgE immunoglobulin E, IgG immunoglobulin G

Box 4.2 Cystic Fibrosis Foundation Consensus Criteria

Obligatory criteria (all must be present)

 Acute or subacute clinical deterioration not attributable to another cause

 Elevated total serum IgE levels (>500 IU/mL, >1200 ng/ mL)

 Immediate cutaneous reactivity to the Aspergillus antigen or presence of Aspergillus fumigatus-specifc IgE antibodies

Additional criteria (at least one of the following)

 Demonstration of precipitins to Aspergillus fumigatus Presence of Aspergillus fumigatus-specifc IgG antibodies

 New or recent chest imaging abnormalities that have not resolved with standard

 Chest physiotherapy or antibiotics

IgE immunoglobulin E, IgG immunoglobulin G

Cystic Fibrosis Foundation Diagnostic Criteria

The diagnosis of ABPA presents unique challenges in patients with CF. The clinical manifestations of CF overlap with those seen in ABPA with many patients with CF demonstrating thick mucus, mucus plugging, and bronchiectasis at baseline. Diagnosing ABPA in patients with CF requires a high index of suspicion and often relies on serological testing to differentiate ABPA from a CF exacerbation. It is recommended to check annual serum IgE levels in patients with CF to screen for ABPA [20]. In 2003, the Cystic Fibrosis Foundation published consensus criteria for diagnosing ABPA in patients with CF [20]. According to this statement, the minimal diagnostic criteria for ABPA in CF require evidence of acute or subacute clinical deterioration not attributable to an alternative etiology, demonstration of Aspergillus fumigatus-specifc IgE antibodies or immediate cutaneous reactivity to Aspergillus antigens, total serum IgE level > 500 IU/mL (1200 ng/mL) while off corticosteroids, and one of the following: serum precipitins to Aspergillus fumigatus, Aspergillus fumigatus-specifc IgG antibodies, or new abnormalities on chest imaging that do not respond to antibiotics and chest physiotherapy (Box 4.2). The CF Foundation recommends repeating a total serum IgE level in 1–3 months in patients for whom there is a high suspicion for ABPA but prior total serum IgE levels were not suffciently elevated to meet the diagnostic criteria.

Baxter ABPA in Cystic Fibrosis Diagnostic

Criteria

Baxter et al. suggested new diagnostic criteria for ABPA complicating CF with incorporation of real-time quantitative polymerase chain reaction (PCR) (RT-PCR) for Aspergillus DNA and the galactomannan antigen [67]. In these criteria,

four classes are proposed, with each class representing a diagnostic group. Class 1 consists of non-diseased CF patients with or without Aspergillus growth in sputum cultures but without a measurable immunological response and negative galactomannan. Class 2 represents serological ABPA with all immunological markers high as well as positive RT-PCR and positive galactomannan. Patients in class 3 are Aspergillus IgE-sensitized with or without Aspergillus noted in sputum but test negative for Aspergillus fumigatus-­ specifc IgG and galactomannan. Patients in class 4 have Aspergillus bronchitis with negative IgE markers but positive Aspergillus fumigatus-specifc IgG, RT-PCR, and galactomannan. Although this proposed class system addresses the potential confounders of Aspergillus sensitization and Aspergillus bronchitis, the RT-PCR and galactomannan testing may be impractical in non-tertiary care centers.

General Diagnostic Recommendations

In summary, when a diagnosis of ABPA is suspected in a patient with asthma or CF, a total serum IgE level and Aspergillus fumigatus-specifc IgE levels should be obtained. If the total serum IgE level is >1000 IU/mL and the Aspergillus fumigatus-specifc IgE levels are positive, then Aspergillus fumigatus-specifc IgG or serum precipitins to Aspergillus and absolute eosinophil count should be measured and a CT of the chest performed to look for radiographic signs of ABPA.

Diferential Diagnosis

“ABPA” is the diagnostic term associated with allergic bronchopulmonary diseases driven by the Aspergillus species; however, a range of other fungi, including the

Penicillium and Curvularia species, can cause a nearly identical clinical course and are described by the diagnostic term “allergic bronchopulmonary mycosis (ABPM)” [68]. When Aspergillus-specific testing is negative, but clinical features otherwise suggest ABPA, testing for allergic responses to other fungal agents may be helpful. Although Candida albicans has been implicated in a few case reports of ABPM, coexisting Aspergillus growth and allergic responses are often present and definitive evidence for Candida-driven disease is lacking.

Severe asthma with fungal sensitization (SAFS) is another disease that may be confused with ABPA, particularly in patients with ABPA without bronchiectasis. The diagnostic criteria of SAFS include the presence of asthma severe enough to warrant high-dose inhaled corticosteroids and frequent systemic corticosteroid use (which are not requirements for the diagnosis of ABPA) and a positive skin prick test for individual fungi, which does not have to be specifc to the Aspergillus species [68]. The total IgE level may be elevated but is less than the threshold for ABPA, and serum precipitins testing should be negative. An important distinction from ABPA is the absence of radiographic fndings suggestive of ABPA in SAFS.

Beyond ABPA and SAFS, a range of other serious pulmonary diseases are caused by the Aspergillus species, including chronic necrotizing aspergillosis, and should be considered in the differential diagnosis, given the potential overlap in clinical features. In contrast to ABPA, in which fungal growth does not violate the epithelial airway barrier, local tissue invasion is a feature of chronic necrotizing aspergillosis, which often leads to progressive tissue damage and parenchymal destruction if untreated. Progressive peribronchial opacities on serial chest imaging in patients with evidence of immune responses to Aspergillus should raise a strong suspicion for chronic necrotizing aspergillosis, particularly in the setting of systemic symptoms such as weight loss or fevers. Rather than elevated total and Aspergillus-­ specifc IgE levels, anti-Aspergillus IgG immune responses are the hallmark serological fnding. Moreover, rather than asthma, the underlying pulmonary conditions associated with an increased risk of chronic necrotizing aspergillosis include chronic obstructive pulmonary disease, sarcoidosis, a history of pulmonary tuberculosis, and prior radiation treatment.

Less frequently, other Aspergillus pulmonary diseases, such as aspergilloma, Aspergillus tracheobronchitis, or invasive pulmonary aspergillosis, may be confused with ABPA. Consideration of the underlying immune status of the

patient and radiographic fndings on HRCT imaging of the chest are often instrumental in directing the differential toward the most likely disease.

Allergic Aspergillus Sinusitis (AAS)

Allergic Aspergillus sinusitis is a noninvasive fungal rhinosinusitis that can sometimes be seen in patients with ABPA [69]. Similar to ABPA, allergic Aspergillus sinusitis is believed to be secondary to a hypersensitivity response to fungal hyphae in the sinus and is often found in patients with atopy and asthma [70]. The diagnostic criteria for allergic Aspergillus sinusitis include demonstration of sinusitis of one or more paranasal sinuses on imaging and nasal polyps in a patient with histopathological confrmation of a characteristic, eosinophil-rich, viscous sinus material called “allergic mucin” and the presence of fungal elements without an invasive fungal disease. Patients may also have peripheral blood eosinophilia, elevated total serum and Aspergillus fumigatus-specifc IgE levels, and precipitating antibodies to Aspergillus antigens [71]. Potential treatments for AAS are systemic corticosteroids in combination with topical intranasal corticosteroid instillations and sinus surgery [72]. The use of systemic or topical antifungal therapy in the treatment of allergic Aspergillus sinusitis has unclear beneft [73, 74]. Referral to a specialist in otolaryngology is recommended.

Natural History

The natural history of ABPA is not well-defned, and the clinical course varies among patients [48, 65, 75]. ABPA may be quiescent and asymptomatic for long periods of time interspersed with episodes of relapsed symptoms and increased in ammation. The percentage of patients with ABPA that relapse ranges from 19% to 49% [48, 76, 77]. If untreated, the in ammatory process in the airways may result in irreversible tissue damage including development of bronchiectasis and pulmonary fbrosis in long-standing diseases. The latter, in turn, can lead to serious complications such as respiratory failure and cor pulmonale.

Previously, ABPA had been classifed into fve stages: acute, remission, exacerbation, corticosteroid-dependent asthma, and fbrotic [78]. The acute stage is defned by the presence of classic symptoms and signature laboratory fndings at the time of diagnosis. Remission is defned as the period of time after diagnosis and treatment in which decreasing levels of total serum IgE and clearing of pulmo-