Case 5 -
Allergic Bronchopulmonary Aspergillosis
Dani S. Zander
University of Texas
Click on each slide thumbnail image for an enlarged view
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.
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.  Of
the approximately 180 officially recognized species of Aspergillus, only a
small number cause human disease.  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. 
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
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.
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.  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.
In addition, patients with
ABPA show high frequencies of specific HLA-DR2 and –DR5 genotypes.  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
The fungus induces a strong Th2-type response with markedly elevated Aspergillus-specific and total serum IgE levels and a strong eosinophilic
inflammatory response.  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.  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.  Patients
with mucoid impaction may expectorate brown mucus plugs, providing a clue to the diagnosis as well as a
stainable and culturable sample.  ABPA often begins in childhood and can smolder for years
before the condition is diagnosed.  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.  In asthmatic
patients, bronchiectasis in three or more lobes was found to be highly suggestive of ABPA. 
Mucoid impaction and post-obstructive atelectasis may be apparent. In addition, infiltrates are common
and may be fleeting.  If bronchocentric granulomatosis is present, then the CT may show a
focal mass or lobar consolidation with atelectasis. 
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.
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.  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. 
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.  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.  A staging system has been applied
to patients with asthma and ABPA, but is not often used for patients with ABPA and cystic
fibrosis.  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.
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.
Findings of ABPA also
occasionally occur in individuals without clinical symptoms of asthma,  and may be more
common in patients with the congenital immunodeficiency syndromes of hyper-IgE syndrome (HIE) and chronic
granulomatous disease. 
- Greenberger PA. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 2002; 110:685-92.
- Marr KA, Patterson T, Denning D. Aspergillosis. Pathogenesis, clinical manifestations, and therapy. Infect Dis Clin North Am 2002; 16:875-94.
- Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary aspergillosis. Chest 2002; 121:1988-99.
- Angelotti T, Krishna G, Scott J, Berry G, Weinacker A. Nodular invasive tracheobronchitis due to Aspergillus in a patient with systemic lupus erythematosus. Lupus 2002; 11:325-8.
- Gonzalez-Crespo MR, Gomez-Reino JJ. Invasive aspergillosis in systemic lupus erythematosus. Semin Arthritis Rheum 1995; 24:304-14.
- Collazos J, Martinez E, Flores M, Mayo J. Aspergillus pneumonia successfully treated with itraconazole in a patient with systemic lupus erythematosus. Clin Investig 1994; 72:920-1.
- Pillay VK, Wilson DM, Ing TS, Kark RM. Fungus infection in steroid-treated systemic lupus erythematosus. JAMA 1968; 205:261-5.
- Sulavik SB. Bronchocentric granulomatosis and allergic bronchopulmonary aspergillosis. Clin Chest Med 1988; 9:609-21.
- Bosken CH, Myers JL, Greenberger PA, Katzenstein AL. Pathologic features of allergic bronchopulmonary aspergillosis. Am J Surg Pathol 1988; 12:216-22.
- Katzenstein AL, Liebow AA, Friedman PJ. Bronchocentric granulomatosis, mucoid impaction, and hypersensitivity reactions to fungi. Am Rev Respir Dis 1975; 111:497-537.
- Rosenberg IL, Greenberger PA. Allergic bronchopulmonary aspergillosis and aspergilloma. Long-term follow-up without enlargement of a large multiloculated cavity. Chest 1984; 85:123-5.
- Greenberger PA. Clinical aspects of allergic bronchopulmonary aspergillosis. Front Biosci 2003; 8:s119-27.
- Geller DE, Kaplowitz H, Light MJ, Colin AA. Allergic bronchopulmonary aspergillosis in cystic fibrosis: reported prevalence, regional distribution, and patient characteristics. Scientific Advisory Group, Investigators, and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Chest 1999; 116:639-46.
- Moss RB. Allergic bronchopulmonary aspergillosis. Clin Rev Allergy Immunol 2002; 23:87-104.
- Stevens DA, Moss RB, Kurup VP, Knutsen AP, Greenberger P, Judson MA, et al. Allergic bronchopulmonary aspergillosis in cystic fibrosis--state of the art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis 2003; 37 Suppl 3:S225-64.
- Chauhan B, Santiago L, Kirschmann DA, Hauptfeld V, Knutsen AP, Hutcheson PS, et al. The association of HLA-DR alleles and T cell activation with allergic bronchopulmonary aspergillosis. J Immunol 1997; 159:4072-6.
- Kauffman HF. Immunopathogenesis of allergic bronchopulmonary aspergillosis and airway remodeling. Front Biosci 2003; 8:e190-6.
- Knutsen AP, Bellone C, Kauffman H. Immunopathogenesis of allergic bronchopulmonary aspergillosis in cystic fibrosis. J Cyst Fibros 2002; 1:76-89.
- Chauhan B, Knutsen A, Hutcheson PS, Slavin RG, Bellone CJ. T cell subsets, epitope mapping, and HLA-restriction in patients with allergic bronchopulmonary aspergillosis. J Clin Invest 1996; 97:2324-31.
- Fink JN. Allergic bronchopulmonary aspergillosis. Chest 1985; 87:81S-84S.
- Rosenberg M, Patterson R, Mintzer R, Cooper BJ, Roberts M, Harris KE. Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med 1977; 86:405-14.
- Franquet T, Muller NL, Gimenez A, Guembe P, de La Torre J, Bague S. Spectrum of pulmonary aspergillosis: histologic, clinical, and radiologic findings. Radiographics 2001; 21:825-37.
- Ward S, Heyneman L, Lee MJ, Leung AN, Hansell DM, Muller NL. Accuracy of CT in the diagnosis of allergic bronchopulmonary aspergillosis in asthmatic patients. AJR Am J Roentgenol 1999; 173:937-42.
- Chakrabarti A, Sethi S, Raman DS, Behera D. Eight-year study of allergic bronchopulmonary aspergillosis in an Indian teaching hospital. Mycoses 2002; 45:295-9.
- Ward S, Heyneman LE, Flint JD, Leung AN, Kazerooni EA, Muller NL. Bronchocentric granulomatosis: computed tomographic findings in five patients. Clin Radiol 2000; 55:296-300.
- Greenberger PA. Immunologic aspects of lung diseases and cystic fibrosis. JAMA 1997; 278:1924-30.
- Greenberger PA, Patterson R. Diagnosis and management of allergic bronchopulmonary aspergillosis. Ann Allergy 1986; 56:444-8.
- Latge JP. Aspergillus fumigatus and aspergillosis. Clin Microbiol Rev 1999; 12:310-50.
- Aubry MC, Fraser R. The role of bronchial biopsy and washing in the diagnosis of allergic bronchopulmonary aspergillosis. Mod Pathol 1998; 11:607-11.
- Patterson R, Greenberger PA, Radin RC, Roberts M. Allergic bronchopulmonary aspergillosis: staging as an aid to management. Ann Intern Med 1982; 96:286-91.
- Sandhu RS, Mehta SK, Khan ZU, Singh MM. Role of Aspergillus and Candida species in allergic bronchopulmonary mycoses. A comparative study. Scand J Respir Dis 1979; 60:235-42.
- Akiyama K, Takizawa H, Suzuki M, Miyachi S, Ichinohe M, Yanagihara Y. Allergic bronchopulmonary aspergillosis due to Aspergillus oryzae. Chest 1987; 91:285-6.
- Gondor M, Michaels MG, Finder JD. Non-aspergillus allergic bronchopulmonary mycosis in a pediatric patient with cystic fibrosis. Pediatrics 1998; 102:1480-2.
- Akiyama K, Mathison DA, Riker JB, Greenberger PA, Patterson R. Allergic bronchopulmonary candidiasis. Chest 1984; 85:699-701.
- Moreno-Ancillo A, Diaz-Pena JM, Ferrer A, Martin-Munoz F, Martin-Barroso JA, Martin-Esteban M, et al. Allergic bronchopulmonary cladosporiosis in a child. J Allergy Clin Immunol 1996; 97:714-5.
- Mroueh S, Spock A. Allergic bronchopulmonary disease caused by Curvularia in a child. Pediatr Pulmonol 1992; 12:123-6.
- Lake FR, Froudist JH, McAleer R, Gillon RL, Tribe AE, Thompson PJ. Allergic bronchopulmonary fungal disease caused by Bipolaris and Curvularia. Aust N Z J Med 1991; 21:871-4.
- Travis WD, Kwon-Chung KJ, Kleiner DE, Geber A, Lawson W, Pass HI, et al. Unusual aspects of allergic bronchopulmonary fungal disease: report of two cases due to Curvularia organisms associated with allergic fungal sinusitis. Hum Pathol 1991; 22:1240-8.
- Halwig JM, Brueske DA, Greenberger PA, Dreisin RB, Sommers HM. Allergic bronchopulmonary curvulariosis. Am Rev Respir Dis 1985; 132:186-8.
- McAleer R, Kroenert DB, Elder JL, Froudist JH. Allergic bronchopulmonary disease caused by Curvularia lunata and Drechslera hawaiiensis. Thorax 1981; 36:338-44.
- Halloran TJ. Allergic bronchopulmonary helminthosporiosis. Am Rev Respir Dis 1983; 128:578.
- Hendrick DJ, Ellithorpe DB, Lyon F, Hattier P, Salvaggio JE. Allergic bronchopulmonary helminthosporiosis. Am Rev Respir Dis 1982; 126:935-8.
- Patterson R, Samuels BS, Phair JJ, Roberts M. Bronchopulmonary torulopsosis. Int Arch Allergy Appl Immunol 1982; 69:30-3.
- Ogawa H, Fujimura M, Tofuku Y. Allergic bronchopulmonary fungal disease caused by Saccharomyces cerevisiae. J Asthma 2004; 41:223-8.
- Ikushima S. Case of allergic bronchopulmonary mycosis caused by Schizophyllum commune. Jpn J Antibiot 1997; 50:47-9; discussion 50,75-6.
- Tomita K, Hashizume I, Kasamatsu N, Nakamura A, Hanzawa S, Momiki S, et al. Allergic bronchopulmonary mycosis caused by Schizophyllum commune. Nihon Kyobu Shikkan Gakkai Zasshi 1996; 34:804-9.
- Matthiesson AM. Allergic bronchopulmonary disease caused by fungi other than Aspergillus. Thorax 1981; 36:719.
- Glancy JJ, Elder JL, McAleer R. Allergic bronchopulmonary fungal disease without clinical asthma. Thorax 1981; 36:345-9.
- Eppinger TM, Greenberger PA, White DA, Brown AE, Cunningham-Rundles C. Sensitization to Aspergillus species in the congenital neutrophil disorders chronic granulomatous disease and hyper-IgE syndrome. J Allergy Clin Immunol 1999; 104:1265-72.