—  SPECIALTY CONFERENCE  —

Pulmonary Pathology

Case 5 - Allergic Bronchopulmonary Aspergillosis

Dani S. Zander
University of Texas
Houston, TX


Click on each slide thumbnail image for an enlarged view
Clinical History
A 50-year-old white female, status post bilateral modified radical mastectomies and chemotherapy 3 years earlier for breast cancer, developed a left upper lobe mass that grew from 2.4 cm to 5.5 cm in maximum dimension over 3 months. Other medical history included probable systemic lupus erythematosus with ocular sicca symptoms, arthralgias, and intermittent mild rash, treated with hydroxychloroquine. Bronchoscopy with bronchial biopsy was negative for malignancy. A PET scan showed increased activity in the left lung and hilar and mediastinal lymph nodes. Left upper lobectomy and thoracic lymphadenectomy were performed. Gross examination of the left upper lobe revealed an ill-defined 6.5 cm zone of tan consolidation with foci of necrosis, and bronchiectasis with thick brown mucus plugs.


Case 5 - Figure 1 - The bronchial wall is inflamed and its lumen is filled with numerous inflammatory cells and mucus.
Case 5 - Figure 2 - The lumen of this inflamed bronchus contains layered mucus and basophilic inflammatory debris.
Case 5 - Figure 3 - A large airway is filled with basophilic mucoid and inflammatory exudate, and shows extensive granulomatous inflammation. An adjacent smaller airway is replaced by a granuloma with focal necrosis.



Case 5 - Figure 4 - This bronchus demonstrates granulomatous bronchitis with superficial ulceration and luminal filling by basophilic material and inflammatory cells.
Case 5 - Figure 5 - Multiple aggregates of eosinophils and Charcot-Leyden crystals are present, in a background of mucus.
Case 5 - Figure 6 - The bronchial mucosa contains dense infiltrates of mixed inflammatory cells including numerous eosinophils. There is superficial loss of epithelial cells.



Case 5 - Figure 7 - This bronchiole is replaced by a necrotizing granuloma with neutrophils.
Case 5 - Figure 8 - Several small airways are filled with necrotic material. Airway walls are replaced by granulomatous inflammation.
Case 5 - Figure 9 - Occasional Aspergillus hyphae lie in the inflammatory exudate (methenamine silver stain).

Diagnosis: Allergic bronchopulmonary aspergillosis (ABPA); cultures yielded A. flavus.

Discussion:
Aspergillus is a genus of fungi that is ubiquitous throughout the world. The organism is found in decomposing organic matter in soil, mulches, and foods, and can be present in fungal cultures from basements and on walls or ceilings where water damage has occurred. [1] Of the approximately 180 officially recognized species of Aspergillus, only a small number cause human disease. [2] The most common human pathogens are A. fumigatus, A. flavus, and A. niger. Pulmonary Aspergillus infection is acquired by inhalation of airborne spores that are small enough (2-3mm) to reach the alveoli. Inhalation of spores is universal, but the consequences vary depending upon host characteristics and predisposing factors.



The figure above outlines the usual host characteristics and predisposing factors for the spectrum of clinicopathologic syndromes associated with Aspergillus. [3] Progression of disease from a less aggressive to a more aggressive form rarely occurs. There are few published reports of pulmonary Aspergillus infections developing in patients with systemic lupus erythematosus, suggesting that it is an uncommon complication of this disease and its treatment. Those reports available describe a necrotizing pneumonia and/or tracheobronchitis. [4, 5, 6, 7]

In ABPA, airway colonization by Aspergillus triggers persistent airway inflammation and mucus hypersecretion, leading to bronchiectasis, airway obstruction and parenchymal changes. The spectrum of pathologic manifestations includes mucoid impaction of bronchi, bronchocentric granulomatosis, eosinophilic pneumonia, and chronic or exudative bronchiolitis. [8, 9, 10] Mucoid impaction of bronchi and bronchocentric granulomatosis are evident in the current case. Mucoid impaction of bronchi refers to dilatation of bronchi with luminal filling by "allergic mucin." Allergic mucin is characterized by a lamellated pattern of cells and debris, including histologically viable and necrotic eosinophils and other cells, cellular debris, Charcot-Leyden crystals, mucus, and fungal hyphae. The fungal hyphae can be difficult to find in the mucin and are often fragmented. Bronchial wall invasion by fungi is usually absent. The bronchial wall, however, usually demonstrates features of asthma including a polymorphous inflammatory infiltrate of eosinophils, lymphocytes and plasma cells; thickening of the basement membrane; and variable degrees of goblet cell hyperplasia, squamous metaplasia and ulceration. Muscular and cartilaginous loss and fibrosis are often present as well, particularly in more advanced cases. In addition to ABPA, mucoid impaction can develop in other settings such as in cystic fibrosis and in association with obstructing bronchial lesions including neoplasms and tuberculosis.

Bronchocentric granulomatosis, also a feature of this case, refers to the replacement of distal airway walls by necrotizing granulomas that are typically centered upon the airway lumens. Aspergillus hyphae can be found in the necrotizing granulomas in the regions corresponding to the airway lumens, but are also usually sparse and fragmented. Bronchioles may also demonstrate infiltration by eosinophils and lymphocytes, allergic mucin, or obliterative bronchiolitis. Bronchocentric granulomatosis is not only found in ABPA, but can also be a manifestation of pulmonary infection with mycobacteria, multiple fungal species, or echinococcus, or may be a component of Wegener's granulomatosis or rheumatoid arthritis. Eosinophilic pneumonia, characterized by alveolar infiltrates of eosinophils and macrophages, is another potential manifestation of ABPA that may occur in association with mucoid impaction and/or bronchocentric granulomatosis, or may be an isolated finding. Finally, aspergilloma can rarely occur in a setting of ABPA. [11] Secondary post-obstructive changes of acute or organizing bacterial pneumonia, abscess formation, lipoid pneumonia, and chronic interstitial pneumonia may also accompany the primary lesions of ABPA.

Most individuals with ABPA are affected by asthma and/or cystic fibrosis. In patients with persistent asthma, the incidence of ABPA appears to be approximately 1-2%, and approximately 7% (range 1-15%) of patients with cystic fibrosis meet criteria for this disorder. [12, 13, 14, 15] In addition, patients with ABPA show high frequencies of specific HLA-DR2 and –DR5 genotypes. [16] The pathogenesis of ABPA involves a series of cellular and biochemical events that lead to airway injury and fibrosis. The pathophysiologic mechanisms include direct damage to airway epithelial cells by fungal proteases, which facilitates antigen transport across the epithelial cell layer, and interactions of A. fumigatus antigens with airway epithelial cells to prompt release of pro-inflammatory cytokines and chemokines that initiate an immunologic/allergic inflammatory response. [17, 18] The fungus induces a strong Th2-type response with markedly elevated Aspergillus-specific and total serum IgE levels and a strong eosinophilic inflammatory response. [19] Epithelial cell release of growth factors is promoted by Th2-type cytokines (IL-4 and IL-13), and repair and remodeling proceeds to create the bronchiectatic lesions and fibrosis characteristic of ABPA. [17] Therapy for ABPA is geared to reduce inflammation and immunologic activity (corticosteroids are the mainstay) and decrease fungal colonization of airways (itraconazole has shown some benefit). Early institution of therapy is advisable to avert bronchiectasis and parenchymal fibrosis.

Fevers, productive cough, and increased wheezing are common symptoms of ABPA. [20] Patients with mucoid impaction may expectorate brown mucus plugs, providing a clue to the diagnosis as well as a stainable and culturable sample. [3] ABPA often begins in childhood and can smolder for years before the condition is diagnosed. [21] Radiologic findings depend upon the pathologic features present. Computed tomography (CT) frequently shows central (proximal) bronchiectasis involving predominantly the segmental and subsegmental bronchi of the upper lobes. [22] In asthmatic patients, bronchiectasis in three or more lobes was found to be highly suggestive of ABPA. [23] Mucoid impaction and post-obstructive atelectasis may be apparent. In addition, infiltrates are common and may be fleeting. [24] If bronchocentric granulomatosis is present, then the CT may show a focal mass or lobar consolidation with atelectasis. [25]

The classic case of ABPA is diagnosed clinically by the following criteria: presence of asthma, current or previous infiltrates on chest radiograph or CT, immediate cutaneous reactivity to Aspergillus, elevated total serum IgE concentration, serum precipitating antibodies to A. fumigatus, central bronchiectasis, peripheral blood eosinophilia, and elevated serum IgE and/or IgG to A. fumigatus. [15, 21, 26, 27, 28] Not all of these criteria need to be present to diagnose ABPA. If a patient has central bronchiectasis, the essential criteria include asthma, immediate cutaneous reactivity to Aspergillus antigens, and serum IgE level > 417 IU/mL. Patients without central bronchiectasis are labeled as "ABPA-seropositive" if they have asthma, immediate cutaneous reactivity to Aspergillus, serum IgE level > 417 IU/mL, history of radiographically compatible pulmonary infiltrates and elevated levels of serum IgE and IgG antibodies to A. fumigatus. [26] Lung biopsy is usually not needed for diagnosis, but is occasionally important for patients with atypical clinical and laboratory features. In these patients, lung biopsy and cytology specimens showing "allergic" mucin and fungal hyphae can offer further support for a diagnosis of ABPA. [29]

In a setting of cystic fibrosis, the diagnosis of ABPA is often not straightforward due to overlap of many of the diagnostic criteria with common manifestations of cystic fibrosis. [15] Proposed minimal criteria for diagnosis of ABPA in cystic fibrosis include acute or subacute clinical deterioration not attributable to another etiology, total serum IgE concentration of >500 IU/mL, immediate cutaneous reactivity to Aspergillus or presence of serum IgE to A. fumigatus, and one of the following: precipitins to A. fumigatus or IgG to A. fumigatus, or new or recent abnormalities on chest radiography (infiltrates or mucus plugging) or chest CT (bronchiectasis) that have not cleared with antibiotics and standard physiotherapy. [15] A staging system has been applied to patients with asthma and ABPA, but is not often used for patients with ABPA and cystic fibrosis. [30] Five stages of ABPA were described: acute, remission, exacerbation, corticosteroid-dependent asthma, and fibrotic.

Although A. fumigatus is the most common Aspergillus species to trigger ABPA, other Aspergillus species including A. niger, A. flavus, A. nidulans, A. oryzae, and A. terreus are occasionally responsible, and a role for multiple species can also occasionally be demonstrated. [24, 31, 32] If cultures, skin tests, and antibody assays for Aspergillus are negative in the face of clinical and radiographic features suggestive of the disease, then a fungus other than Aspergillus may be responsible. Similar syndromes can be caused by other fungi ("allergic bronchopulmonary fungal disease" or "allergic bronchopulmonary mycosis"), including Candida albicans, Curvularia sp., Helminthosporium sp., Torulopsis glabrata, Bipolaris sp., Cladosporiosis sp., Saccharomyces cerevisiae, Schizophyllum commune, and Tricosporon beigelii, and asthma is not invariably present in these patients. [31, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48] Findings of ABPA also occasionally occur in individuals without clinical symptoms of asthma, [48] and may be more common in patients with the congenital immunodeficiency syndromes of hyper-IgE syndrome (HIE) and chronic granulomatous disease. [49]

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