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ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
0889-8561 /98 $8.00
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ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS A Historical Perspective Roy Patterson, MD
As we approach the end of this century, we approach the fiftieth anniversary of the initial report of allergic bronchopulmonary aspergillosis (ABPA).3All of the initial clinical and research studies were carried out in Sixteen years after the initial case report from England, the first case was reported in the United state^.^ At first considered a rarity in the United States, increasing numbers of cases were identified.4,l6 However, the relative rarity of ABPA, lack of awareness of the disease, and absence of specific diagnostic criteria did not promote early detection of ABPA in many cases. Cases of ABPA were often labeled the PIE syndrome (pulmonary infiltrates with eosinophilia), and physicians waited for spontaneous improvement, which often occurred, but with a later recurrence. This spontaneous improGement characterizes an important aspect of ABPA: It is often a low-grade, nonacute respiratory syndrome of fluctuating severity that might persist for years without diagnosis. Two to three decades ago, many advanced cases were diagnosed only when patients coughed up golden brown plugs or mucous casts of bronchi, which were colonies of Aspergillus fumigutus growing in mucous in the airway.ll Such cases were usually far advanced ABPA with marked central bronchiectasis and significant fibrotic
Supported by the Ernest S. Bazley Grant to Northwestern Memorial Hospital and Northwestern University Medical School.
From the Division of Allergy-Immunology, Department of Medicine, Northwestem University Medical School, Chicago, Illinois
IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA
-
VOLUME 18 NUMBER 3 AUGUST 1998
471
472
PATTERSON
changes in pulmonary tissue. As awareness of ABPA increased, radiographic diagnosis advanced, serologic assessment improved, and the number of diagnosed cases of ABPA increased. EVOLUTION OF SERODIAGNOSIS Precipitin Reactions
The first major advance in serodiagnosis was the demonstration that patients with ABPA had precipitating antibodies against extracts of A. fumigatus when tested by the Ouchterlony gel double diffusion test." It had already been recognized that all patients with ABPA had immediate-type skin reactivity to A. fumigatus, and the precipitin bands became very useful because not all patients with immediate-type skin reactivity have ABPA. Serodiagnosis of ABPA
Elevated Total Serum IgE
When quantitative immunoassays for immunoglobulins became available, they were used in various immunologic lung diseases? A striking elevation of total serum IgE was found in patients with ABPA, and this elevation became a diagnostic aid in identifying ABPA. The initial assumption was made that the sharp elevations of IgE were IgE antibodies against A. fumigatus, but this assumption was wrong. Extensive studies demonstrated that the majority of the total serum IgE was not anti-A. fumigatus. However, it was found that treatment of ABPA with prednisone and induction of remission of ABPA was accompanied by a significant decline in total serum IgE and that this could be used diagnostically and as a measure of patient respynse to therapy.I3To treat ABPA until serum IgE levels were normal was inappropriate; to treat ABPA until total serum IgE levels reached a plateau level (which varies with each patient) was and is appropriate. Elevated IgG and IgE Antibodies Against A. fumigatus
Initially, using radioimmunoassays and then enzyme-linked immunoassays, elevations of IgG and IgE antibodies were seen in serum samples of patients with ABPA.17This analysis became a useful serodiagnostic test when serum samples of patients with suspected ABPA were compared with a serum pool collected from asthma patients who had immediate-type skin reactivity to A. fumigatus but in whom ABPA had been exc1~ded.I~ It was found that if the IgE and IgG antibodies in serum samples from patients who are skin-test positive to A. ftlrnigatus are compared with pools of serum from normal subjects who are skin-
A HISTORICAL PERSPECTIVE OF ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
473
test negative to A. fumigutus, comparatively higher levels of IgG and IgE anti-A. fumigatus will be found and may lead to a diagnosis of ABPA when it is not present. In summary, positive precipitin bands, elevated levels of IgE and IgG antibodies against A. fumigutus, and elevated total serum IgE with a decline after prednisone therapy have proven to be very useful serologic aids in diagnosing ABPA, in evaluating the course of ABPA, and in considering the mechanisms of lung damage. EVOLUTION OF RADIOGRAPHIC ANALYSIS OF ABPA
As patients with ABPA were identified, the abnormalities seen on chest radiographs became extremely important in diagnosis and classification. Transient changes on pulmonary radiographs included ”tramline” shadows, consolidation, perihilar infiltrates, air-fluid levels in bronchi, ”toothpaste” shadows, and “gloved finger” shadows (see Chen’s article elsewhere in this issue).15Of major importance was central br0n~hiectasis.l~ In initial cases of ABPA diagnosed about two decades ago, extensive fibrosis was seen. Fortunately, most cases of ABPA are now diagnosed and treated before extensive fibrosis occurs, and this highly unfavorable outcome is avoidable. CLASSIFICATION AND STAGING OF ABPA
The simultaneous evolution of serologic studies, radiographic studies, and clinical management of patients with ABPA made it obvious that there were different stages of ABPA in different patients. A staging analysis evolved.10These stages were: Stage I, the acute state; Stage 11, the remission stage; Stage 111, the recurrent eyacerbation stage; Stage IV, corticosteroid-dependent asthma; and Stage V, fibrotic, end-stage lung disease.loThis classification system helped in management and in analysis of prognosis. Most of the fibrotic, end-stage lung disease cases are now deceased; very few cases are found now because m q t patients are diagnosed and treated, and evolution of lung destruction is prevented. In the Northwestern University series of ABPA patients, no patient has evolved from stages I to IV to stage V. The final classification that evolved was ABPA-serologic where no central bronchiectasis had occurred, but clinical course and serologic tests were diagnostic of ABPA. PATHOLOGY OF ABPA
The diagnosis of ABPA is based on (1) the occurrence of pulmonary infiltrates with eosinophilia in a patient with asthma, (2) radiographic changes described previously, (3) serologic abnormalities diagnostic or indicative of ABPA, (4) response to clinical therapy with prednisone, and (5) a decline in total serum IgE. These diagnostic features of ABPA
474
PATTERSON
obviate the need for lung biopsy in such patients. The pathologic changes seen in lung tissue of patients with ABPA were often the result of tissue obtained before the currently available diagnostic criteria evolved, and the diagnosis of ABPA was made after lung biopsy. These findings in early historical cases are of great value in defining the gross and histologic changes that occur in pulmonary tissue in ABPA.7 A major gross change is central bronchiectasis, which may be unique for ABPA. The occurrence of bronchocentric granulomatosis in an asthmatic patient is highly suggestive of ABPA, as is mucoid impaction of the bronchi. Eosinophilic pneumonia, eosinophilic bronchitis, and bronchiolitis are suggestive of ABPA but not diagnostic. This summary of pathologic changes illustrates the inflammatory changes in ABPA. The progression of ABPA, if left untreated, is the replacement of the inflamed tissue with fibrous tissue and the resulting end-stage fibrotic lung disease described previously. Fortunately earlier diagnosis and treatment in modern times has prevented the progression to fibrotic end-stage lung disease except in rare cases that are not diagnosed and treated sufficiently early in the course of the disease. IMMUNOPATHOGENESIS OF ABPA
It has been recognized for many years that hyphae of A. fumigutus, spores of A. fumigutus, and antigens eluted from A. fumigutus were in the bronchi of patients with ABPA.*I The host response to these A. fumigutus organisms and their antigens included IgE antibodies, IgG antibodies, and IgA antibodies. According to the Gel1 and Coombs classification of hypersensitivity reactions, the Type 5 (immediate-type, IgE mediated) reaction must occur and the Type I11 antigen-antibody complex reactions must occur because both relevant antigens and antibodies necessary for both reactions are present in bronchi and tissues adjacent to bronchi.' The stage is set for release of bioactive mediators and chemoattraction of inflammatory cells. The result is an inflammatory reaction in the bronchial mucosa and adjacent pulmonary tissue with central bronchiectasis and bronchocentric granulomatosis as the result. The latter inflammatory reaction progresses to fibrosis unless inhibited by treatment. TREATMENT OF ABPA
The treatment for the first case of ABPA in the United States (and for subsequent cases) was initially recommended by an English physician, Dr. Jack Pepys. The first case of ABPA in the United States was treated with prednisone with clearing of pulmonary lesions. At last evaluation, 26 years after diagnosis, the patient had mild corticosteroiddependent asthma managed with low-dose alternate-day prednisone and inhaled corticosteroids. Prednisone has been used in the treatment of all subsequent cases of ABPA in the Northwestern University series.
A HISTORICAL PERSPECTIVE OF ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
475
Treatment Regimens and Results
In the average case of ABPA, moderate doses of prednisone ( 3 0 4 0 mg daily) for 2 to 4 weeks will result in clearing of the chest radiograph lesions and in the control of asthma. This result is due to the antiinflammatory action of the corticosteroids reversing the inflammation in the bronchi and adjacent tissue. The prednisone reverses the asthma and clears the bronchi of the mucus produced, which is the growth medium for A. fumigatus in the bronchi. After clearing the chest radiograph lesions, the prednisone dose will be converted to an alternate-day regimen. The total serum IgE level will decrease by at least 35% and will not return to normal (less than 1,000 ng/mL), but it will plateau at a level that varies with each patient. The IgE level is used to detect an exacerbation of ABPA. If the total serum IgE level doubles, an exacerbation of ABPA is suggested, a chest radiograph should be obtained, and a further course of prednisone should be initiated. This regimen results in remission and exacerbation of ABPA. After initial treatment of ABPA with prednisone, conversion to alternate-day prednisone, and gradual reduction of prednisone, several outcomes were observed after the first stage (acute ABPA followed by remission) of the initial episode of ABPA: (A) Remission Stage. Prednisone was discontinued, IgE level remained at a lower level, minimal therapy was needed to control asthma, and chest radiographs remained clear. A possible recurrence may occur in the future. (B) Recurrent Exacerbation Stage. After clearing of all signs and symptoms of ABPA, a recurrent exacerbation of ABPA occurred repeatedly. Patients required closer observation, periodic prednisone therapy, and continuous inhaled corticosteroids to control the mucous production of the patient with asthma and to avoid repeated colonization by A. fumigatus of mucus in the bronchi. (C) Corticosteroid-Dependent (CSD) Stage. A group of patients with ABPA was identified who could not have their prednisone discontinued without significant severe exacerbations of asthma in spite of continuous maximal doses of inhaled corticosteroids. Usually, the prednisone dose was modest (15-30 mg on alternate days). It was suspected that the severity of ABPA may have resulted in sufficient damage to the airways to result in increased severity of asthma. Alternatively, the severity of the asthma may have been coincidental with the occurrence of ABPA. Fortunately, the patients in the CSD stage were generally managed with low-to-moderate doses of alternate-day prednisone and inhaled corticosteroids. (D) Fibrotic End-Stage Lung Disease. Treatment of patients in this final stage was and is most difficult. These patients have had long-standing, recurrent ABPA with no early diagnosis and appropriate treatment, resulting in severe central bronchiectasis and severe fibrotic lung disease. Their irreversible pulmonary lesions are not altered by prednisone. Prednisone is used temporarily to reverse the inflammatory lesions that remain, but prolonged high-dose systemic corticosteroids have little value and often have complicated side effects. The prognosis of this end stage is obviously grave. Almost all of the
476
PA'ITERSON
patients initially diagnosed at Northwestern University have died of cardiac or fibrotic pulmonary disease. Fortunately, because of the awareness of and earlier diagnosis of ABPA, progression to this stage rarely occurs now. CYSTIC FIBROSIS AND ABPA
Cystic fibrosis (CF) is a complex disease. The CF patient may have an airway colonized with many organisms, including various Pseudomonas or Klebsiella species, Staphylococcus aureus, Haemophilus influenzae, and
Escherichia coli. A. fumigatus may be one of the colonizing organisms in CF patients, and the result of this colonization can be highly variable. One outcome seen is clearly defined ABPA with positive, immediate-type skin reactivity, pulmonary infiltrates with eosinophilia, high elevations of total serum IgE, precipitins against A . fumigatus, and significant elevations of IgE and IgG antibodies against A. fumigatus. Treatment with prednisone results in clearing of the chest radiograph and the expected decline in total IgE (at least 35% decrease). Approximately 10% of patients with CF may fit the serologic criteria for ABPA.6 Other patients with CF may have immune responses to A. fumigatus due to colonization of the airway with A . fumigutus shown by positive precipitin bands and elevated IgG antibodies against A. fymigatus, but with negative immediate-type skin tests to A. @migatus, no elevated IgE antibodies, and no significant elevation of total serum IgE. This is probably not ABPA, and treatment with prednisone for ABPA is not indicated. Two extremes were just described. Other CF patients may have, serologic results that are intermediate. As reported by Zeaske et al, some * CF patients have positive skin tests to A. fumigatus and elevated IgE or IgG antibodies to A. ftlmigafus.ls These patients may have a variant of ABPA or may have nondiagnostic serologic responses to A. fumigatus without actually having ABPA. In such patients, a trial of therapy with prednisone for ABPA may be warranted because high doses of prednisone are not necessary. Some laboratory and clinical parameters should be evaluated during the prednisone course of therapy, such as the total serum IgE, chest radiograph status, pulmonary function studies, and clinical status of the patient. A very striking case of ABPA in a CF patient was recently identified and demonstrates the complexity of ABPA in CF. A 12-year-old child with CF was diagnosed with ABPA and had a good clinical response with treatment about 16 years ago. Fourteen years later, he had progressive respiratory failure as a result of CF. He received two lower lung lobes from his two brothers, neither of whom had asthma or ABPA. All pulmonary tissue was removed from the recipient. After the lung transplants, the patient did well for approximately one and a half years but then developed asthma, had decreased lung function, and the serologic analyses showed increased total serum IgE, elevated IgE and IgG
A HISTORICAL PERSPECTIVE OF ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
477
antibody indices, and positive precipitins for A. fumigatus. He responded well to prednisone therapy.2This case of ABPA in a child with CF who then developed a recurrence of ABPA after bilateral lung transplants illustrates the need for continuous consideration of ABPA, serodiagnosis, and therapy when ABPA is diagnosed in CF patients.
ALLERGIC BRONCHOPULMONARY MYCOSIS
Patients may appear with classic indications of ABPA, including asthma, coughing up mucous plugs, pulmonary infiltrates, and eosinophilia. These patients may respond rapidly to therapy with prednisone, resulting in the clearing of all symptoms, the resolution of the pulmonary infiltrates on chest radiograph, and a decline in eosinophil counts. The expectation is that all serologic results will be consistent with ABPA, but all such tests may be completely normal except for an elevated total serum IgE level. In such cases, the diagnosis is likely to be allergic bronchopulmonary mycosis (ABPM) with the syndrome being caused by a fungus other than A. fumigatus. More than 26 different fungi have been shown to cause ABPM.5The problem for the investigator is to identify the organism and carry out the appropriate serologic tests to show elevated IgE and IgG antibodies and positive precipitin reactions against an extract of the fungus. The fungus may be identified initially by culture of the sputum for fungi, and the serologic assays may be carried out in a research laboratory. The problem for the clinician is that the research facilities for carrying out the seroassays may not be available. A practical approach is to evaluate the patient for central bronchiectasis and treat the patient for ABPM following the guidelines for treatment of ABPA. The clearing of pulmonary infiltrates and a decline in the total serum IgE would be consistent with ABPM. Such an approach is logical in that ABPM, if untreated, can result in progressive bronchiectasis, pulmonary tissue damage, and end-stage pulmonary fibrosis.
References 1. Coombs RRA, Gell PGH: Classification of allergic reactions responsible for clinical hypersensitivity and disease. In Gell PGH, Coombs RRA, Lachmann PJ (eds): Clinical Aspects of Immunology, ed 3. Oxford, Blackwell Scientific Publications, 1975, p 761 2. Fitzsimmons EF, Aris R, Patterson R: Recurrence of ABPA in the post-transplant lungs of a cystic fibrosis patient: A case report. Chest 112:281, 1997 3. Hinson KFW, Moon AJ, Plummer NS, et al: Bronchopulmonary aspergillosis. Thorax 7:317, 1952 4. Hoehe JH, Reed CE, Dickie HA: Allergic bronchopulmonary aspergillosis is not rare. Chest 63:177, 1973 5. Hogan M B Other allergic bronchopulmonary mycoses. In Patterson R, Greenberger PA, Roberts M (eds): Allergic Bronchopulmonary Aspergillosis. Providence, RI, OceanSide Publications, 1995, p 57
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PATTERSON
6. Laufer P, Fink JN, Bruns WT, et al: Allergic bronchopulmonary aspergillosis in cystic fibrosis. J Allergy Clin Immunol 73:44, 1984 7. Myers J L Pathology of allergic bronchopulmonary aspergillosis. In Patterson R, Greenberger PA, Roberts M (eds): Allergic Bronchopulmonary Aspergillosis. Providence, RI, Oceanside Publications, 1995, p 39 8. Patterson R, Fink JN, Pruzansky JJ, et al: Serum immunoglobulin levels in pulmonary allergic aspergillosis and certain other lung diseases, with special reference to immunoglobulin E. Am J Med 54:16, 1973 9. Patterson R, Golbert TM: Hypersensitivity disease of the lung. University of Michigan Medical Center Journal 34:8, 1968 10. Patterson R, Greenberger PA, Radin RC, et al: Allergic bronchopulmonary aspergillosis: Staging as an aid to management. Ann Intern Med 96:286, 1982 11. Pepys J: Pulmonary aspergillosis. In Pepys J (ed): Monographs in Allergy: Hypersensitivity Diseases of the Lungs due to Fungi and Organic Dusts, vol4. London, S. Karger, 1969, p 20 12. Pepys J, Riddell RW, Citron KM, et al: Clinical and immunologic significance of Aspergillus fumigutus in the sputum. American Review of Respiratory Diseases 80:167, 1959 13. Ricketti AJ, Greenberger PA, Patterson R Serum IgE as an important aid in management of allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol74:68, 1984 14. Roberts M, Greenberger PA: Serologic analysis of allergic bronchopulmonary aspergillosis. In Patterson R, Greenberger PA, Roberts M (eds): Allergic Bronchopulmonary Aspergillosis. Providence, Oceanside Publications, Inc., 1995, p 11 15. Sider L: Radiology of ABPA. In Patterson R, Greenberger PA, Roberts M (eds): Allergic Bronchopulmonary Aspergillosis. Providence, RI, OceanSide Publications, 1995, pp 18,22 16. Slavin RG, Stanczyk DJ, Lonigro AJ, et al: Allergic bronchopulmonary aspergillosis: A North American rarity. Am J Med 47306, 1969 17. Wang JLF, Patterson R, Rosenberg M, et al: Serum IgE and IgG antibody activity against Aspergillus fumigutus as a diagnostic aid in allergic bronchopulmonary’ aspergillosis. American Review of Respiratory Diseases 117917, 1978 18. Zeaske R, Bruns WT, Fink JN, et al: Immune responses to Aspergillus in cystic fibrosis. J Allergy Clin Immunol 8273, 1988
Address reprint requests to Roy Patterson, MD Division of Allergy-Immunology, MC 5207 Department of Medicine Northwestern University Medical School 303 East Chicago Avenue Chicago, IL 60611
0889-8561 /98 $8.00
+ .oo
ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS A Historical Perspective Roy Patterson, MD
As we approach the end of this century, we approach the fiftieth anniversary of the initial report of allergic bronchopulmonary aspergillosis (ABPA).3All of the initial clinical and research studies were carried out in Sixteen years after the initial case report from England, the first case was reported in the United state^.^ At first considered a rarity in the United States, increasing numbers of cases were identified.4,l6 However, the relative rarity of ABPA, lack of awareness of the disease, and absence of specific diagnostic criteria did not promote early detection of ABPA in many cases. Cases of ABPA were often labeled the PIE syndrome (pulmonary infiltrates with eosinophilia), and physicians waited for spontaneous improvement, which often occurred, but with a later recurrence. This spontaneous improGement characterizes an important aspect of ABPA: It is often a low-grade, nonacute respiratory syndrome of fluctuating severity that might persist for years without diagnosis. Two to three decades ago, many advanced cases were diagnosed only when patients coughed up golden brown plugs or mucous casts of bronchi, which were colonies of Aspergillus fumigutus growing in mucous in the airway.ll Such cases were usually far advanced ABPA with marked central bronchiectasis and significant fibrotic
Supported by the Ernest S. Bazley Grant to Northwestern Memorial Hospital and Northwestern University Medical School.
From the Division of Allergy-Immunology, Department of Medicine, Northwestem University Medical School, Chicago, Illinois
IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA
-
VOLUME 18 NUMBER 3 AUGUST 1998
471
472
PATTERSON
changes in pulmonary tissue. As awareness of ABPA increased, radiographic diagnosis advanced, serologic assessment improved, and the number of diagnosed cases of ABPA increased. EVOLUTION OF SERODIAGNOSIS Precipitin Reactions
The first major advance in serodiagnosis was the demonstration that patients with ABPA had precipitating antibodies against extracts of A. fumigatus when tested by the Ouchterlony gel double diffusion test." It had already been recognized that all patients with ABPA had immediate-type skin reactivity to A. fumigatus, and the precipitin bands became very useful because not all patients with immediate-type skin reactivity have ABPA. Serodiagnosis of ABPA
Elevated Total Serum IgE
When quantitative immunoassays for immunoglobulins became available, they were used in various immunologic lung diseases? A striking elevation of total serum IgE was found in patients with ABPA, and this elevation became a diagnostic aid in identifying ABPA. The initial assumption was made that the sharp elevations of IgE were IgE antibodies against A. fumigatus, but this assumption was wrong. Extensive studies demonstrated that the majority of the total serum IgE was not anti-A. fumigatus. However, it was found that treatment of ABPA with prednisone and induction of remission of ABPA was accompanied by a significant decline in total serum IgE and that this could be used diagnostically and as a measure of patient respynse to therapy.I3To treat ABPA until serum IgE levels were normal was inappropriate; to treat ABPA until total serum IgE levels reached a plateau level (which varies with each patient) was and is appropriate. Elevated IgG and IgE Antibodies Against A. fumigatus
Initially, using radioimmunoassays and then enzyme-linked immunoassays, elevations of IgG and IgE antibodies were seen in serum samples of patients with ABPA.17This analysis became a useful serodiagnostic test when serum samples of patients with suspected ABPA were compared with a serum pool collected from asthma patients who had immediate-type skin reactivity to A. fumigatus but in whom ABPA had been exc1~ded.I~ It was found that if the IgE and IgG antibodies in serum samples from patients who are skin-test positive to A. ftlrnigatus are compared with pools of serum from normal subjects who are skin-
A HISTORICAL PERSPECTIVE OF ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
473
test negative to A. fumigutus, comparatively higher levels of IgG and IgE anti-A. fumigatus will be found and may lead to a diagnosis of ABPA when it is not present. In summary, positive precipitin bands, elevated levels of IgE and IgG antibodies against A. fumigutus, and elevated total serum IgE with a decline after prednisone therapy have proven to be very useful serologic aids in diagnosing ABPA, in evaluating the course of ABPA, and in considering the mechanisms of lung damage. EVOLUTION OF RADIOGRAPHIC ANALYSIS OF ABPA
As patients with ABPA were identified, the abnormalities seen on chest radiographs became extremely important in diagnosis and classification. Transient changes on pulmonary radiographs included ”tramline” shadows, consolidation, perihilar infiltrates, air-fluid levels in bronchi, ”toothpaste” shadows, and “gloved finger” shadows (see Chen’s article elsewhere in this issue).15Of major importance was central br0n~hiectasis.l~ In initial cases of ABPA diagnosed about two decades ago, extensive fibrosis was seen. Fortunately, most cases of ABPA are now diagnosed and treated before extensive fibrosis occurs, and this highly unfavorable outcome is avoidable. CLASSIFICATION AND STAGING OF ABPA
The simultaneous evolution of serologic studies, radiographic studies, and clinical management of patients with ABPA made it obvious that there were different stages of ABPA in different patients. A staging analysis evolved.10These stages were: Stage I, the acute state; Stage 11, the remission stage; Stage 111, the recurrent eyacerbation stage; Stage IV, corticosteroid-dependent asthma; and Stage V, fibrotic, end-stage lung disease.loThis classification system helped in management and in analysis of prognosis. Most of the fibrotic, end-stage lung disease cases are now deceased; very few cases are found now because m q t patients are diagnosed and treated, and evolution of lung destruction is prevented. In the Northwestern University series of ABPA patients, no patient has evolved from stages I to IV to stage V. The final classification that evolved was ABPA-serologic where no central bronchiectasis had occurred, but clinical course and serologic tests were diagnostic of ABPA. PATHOLOGY OF ABPA
The diagnosis of ABPA is based on (1) the occurrence of pulmonary infiltrates with eosinophilia in a patient with asthma, (2) radiographic changes described previously, (3) serologic abnormalities diagnostic or indicative of ABPA, (4) response to clinical therapy with prednisone, and (5) a decline in total serum IgE. These diagnostic features of ABPA
474
PATTERSON
obviate the need for lung biopsy in such patients. The pathologic changes seen in lung tissue of patients with ABPA were often the result of tissue obtained before the currently available diagnostic criteria evolved, and the diagnosis of ABPA was made after lung biopsy. These findings in early historical cases are of great value in defining the gross and histologic changes that occur in pulmonary tissue in ABPA.7 A major gross change is central bronchiectasis, which may be unique for ABPA. The occurrence of bronchocentric granulomatosis in an asthmatic patient is highly suggestive of ABPA, as is mucoid impaction of the bronchi. Eosinophilic pneumonia, eosinophilic bronchitis, and bronchiolitis are suggestive of ABPA but not diagnostic. This summary of pathologic changes illustrates the inflammatory changes in ABPA. The progression of ABPA, if left untreated, is the replacement of the inflamed tissue with fibrous tissue and the resulting end-stage fibrotic lung disease described previously. Fortunately earlier diagnosis and treatment in modern times has prevented the progression to fibrotic end-stage lung disease except in rare cases that are not diagnosed and treated sufficiently early in the course of the disease. IMMUNOPATHOGENESIS OF ABPA
It has been recognized for many years that hyphae of A. fumigutus, spores of A. fumigutus, and antigens eluted from A. fumigutus were in the bronchi of patients with ABPA.*I The host response to these A. fumigutus organisms and their antigens included IgE antibodies, IgG antibodies, and IgA antibodies. According to the Gel1 and Coombs classification of hypersensitivity reactions, the Type 5 (immediate-type, IgE mediated) reaction must occur and the Type I11 antigen-antibody complex reactions must occur because both relevant antigens and antibodies necessary for both reactions are present in bronchi and tissues adjacent to bronchi.' The stage is set for release of bioactive mediators and chemoattraction of inflammatory cells. The result is an inflammatory reaction in the bronchial mucosa and adjacent pulmonary tissue with central bronchiectasis and bronchocentric granulomatosis as the result. The latter inflammatory reaction progresses to fibrosis unless inhibited by treatment. TREATMENT OF ABPA
The treatment for the first case of ABPA in the United States (and for subsequent cases) was initially recommended by an English physician, Dr. Jack Pepys. The first case of ABPA in the United States was treated with prednisone with clearing of pulmonary lesions. At last evaluation, 26 years after diagnosis, the patient had mild corticosteroiddependent asthma managed with low-dose alternate-day prednisone and inhaled corticosteroids. Prednisone has been used in the treatment of all subsequent cases of ABPA in the Northwestern University series.
A HISTORICAL PERSPECTIVE OF ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
475
Treatment Regimens and Results
In the average case of ABPA, moderate doses of prednisone ( 3 0 4 0 mg daily) for 2 to 4 weeks will result in clearing of the chest radiograph lesions and in the control of asthma. This result is due to the antiinflammatory action of the corticosteroids reversing the inflammation in the bronchi and adjacent tissue. The prednisone reverses the asthma and clears the bronchi of the mucus produced, which is the growth medium for A. fumigatus in the bronchi. After clearing the chest radiograph lesions, the prednisone dose will be converted to an alternate-day regimen. The total serum IgE level will decrease by at least 35% and will not return to normal (less than 1,000 ng/mL), but it will plateau at a level that varies with each patient. The IgE level is used to detect an exacerbation of ABPA. If the total serum IgE level doubles, an exacerbation of ABPA is suggested, a chest radiograph should be obtained, and a further course of prednisone should be initiated. This regimen results in remission and exacerbation of ABPA. After initial treatment of ABPA with prednisone, conversion to alternate-day prednisone, and gradual reduction of prednisone, several outcomes were observed after the first stage (acute ABPA followed by remission) of the initial episode of ABPA: (A) Remission Stage. Prednisone was discontinued, IgE level remained at a lower level, minimal therapy was needed to control asthma, and chest radiographs remained clear. A possible recurrence may occur in the future. (B) Recurrent Exacerbation Stage. After clearing of all signs and symptoms of ABPA, a recurrent exacerbation of ABPA occurred repeatedly. Patients required closer observation, periodic prednisone therapy, and continuous inhaled corticosteroids to control the mucous production of the patient with asthma and to avoid repeated colonization by A. fumigatus of mucus in the bronchi. (C) Corticosteroid-Dependent (CSD) Stage. A group of patients with ABPA was identified who could not have their prednisone discontinued without significant severe exacerbations of asthma in spite of continuous maximal doses of inhaled corticosteroids. Usually, the prednisone dose was modest (15-30 mg on alternate days). It was suspected that the severity of ABPA may have resulted in sufficient damage to the airways to result in increased severity of asthma. Alternatively, the severity of the asthma may have been coincidental with the occurrence of ABPA. Fortunately, the patients in the CSD stage were generally managed with low-to-moderate doses of alternate-day prednisone and inhaled corticosteroids. (D) Fibrotic End-Stage Lung Disease. Treatment of patients in this final stage was and is most difficult. These patients have had long-standing, recurrent ABPA with no early diagnosis and appropriate treatment, resulting in severe central bronchiectasis and severe fibrotic lung disease. Their irreversible pulmonary lesions are not altered by prednisone. Prednisone is used temporarily to reverse the inflammatory lesions that remain, but prolonged high-dose systemic corticosteroids have little value and often have complicated side effects. The prognosis of this end stage is obviously grave. Almost all of the
476
PA'ITERSON
patients initially diagnosed at Northwestern University have died of cardiac or fibrotic pulmonary disease. Fortunately, because of the awareness of and earlier diagnosis of ABPA, progression to this stage rarely occurs now. CYSTIC FIBROSIS AND ABPA
Cystic fibrosis (CF) is a complex disease. The CF patient may have an airway colonized with many organisms, including various Pseudomonas or Klebsiella species, Staphylococcus aureus, Haemophilus influenzae, and
Escherichia coli. A. fumigatus may be one of the colonizing organisms in CF patients, and the result of this colonization can be highly variable. One outcome seen is clearly defined ABPA with positive, immediate-type skin reactivity, pulmonary infiltrates with eosinophilia, high elevations of total serum IgE, precipitins against A . fumigatus, and significant elevations of IgE and IgG antibodies against A. fumigatus. Treatment with prednisone results in clearing of the chest radiograph and the expected decline in total IgE (at least 35% decrease). Approximately 10% of patients with CF may fit the serologic criteria for ABPA.6 Other patients with CF may have immune responses to A. fumigatus due to colonization of the airway with A . fumigutus shown by positive precipitin bands and elevated IgG antibodies against A. fymigatus, but with negative immediate-type skin tests to A. @migatus, no elevated IgE antibodies, and no significant elevation of total serum IgE. This is probably not ABPA, and treatment with prednisone for ABPA is not indicated. Two extremes were just described. Other CF patients may have, serologic results that are intermediate. As reported by Zeaske et al, some * CF patients have positive skin tests to A. fumigatus and elevated IgE or IgG antibodies to A. ftlmigafus.ls These patients may have a variant of ABPA or may have nondiagnostic serologic responses to A. fumigatus without actually having ABPA. In such patients, a trial of therapy with prednisone for ABPA may be warranted because high doses of prednisone are not necessary. Some laboratory and clinical parameters should be evaluated during the prednisone course of therapy, such as the total serum IgE, chest radiograph status, pulmonary function studies, and clinical status of the patient. A very striking case of ABPA in a CF patient was recently identified and demonstrates the complexity of ABPA in CF. A 12-year-old child with CF was diagnosed with ABPA and had a good clinical response with treatment about 16 years ago. Fourteen years later, he had progressive respiratory failure as a result of CF. He received two lower lung lobes from his two brothers, neither of whom had asthma or ABPA. All pulmonary tissue was removed from the recipient. After the lung transplants, the patient did well for approximately one and a half years but then developed asthma, had decreased lung function, and the serologic analyses showed increased total serum IgE, elevated IgE and IgG
A HISTORICAL PERSPECTIVE OF ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
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antibody indices, and positive precipitins for A. fumigatus. He responded well to prednisone therapy.2This case of ABPA in a child with CF who then developed a recurrence of ABPA after bilateral lung transplants illustrates the need for continuous consideration of ABPA, serodiagnosis, and therapy when ABPA is diagnosed in CF patients.
ALLERGIC BRONCHOPULMONARY MYCOSIS
Patients may appear with classic indications of ABPA, including asthma, coughing up mucous plugs, pulmonary infiltrates, and eosinophilia. These patients may respond rapidly to therapy with prednisone, resulting in the clearing of all symptoms, the resolution of the pulmonary infiltrates on chest radiograph, and a decline in eosinophil counts. The expectation is that all serologic results will be consistent with ABPA, but all such tests may be completely normal except for an elevated total serum IgE level. In such cases, the diagnosis is likely to be allergic bronchopulmonary mycosis (ABPM) with the syndrome being caused by a fungus other than A. fumigatus. More than 26 different fungi have been shown to cause ABPM.5The problem for the investigator is to identify the organism and carry out the appropriate serologic tests to show elevated IgE and IgG antibodies and positive precipitin reactions against an extract of the fungus. The fungus may be identified initially by culture of the sputum for fungi, and the serologic assays may be carried out in a research laboratory. The problem for the clinician is that the research facilities for carrying out the seroassays may not be available. A practical approach is to evaluate the patient for central bronchiectasis and treat the patient for ABPM following the guidelines for treatment of ABPA. The clearing of pulmonary infiltrates and a decline in the total serum IgE would be consistent with ABPM. Such an approach is logical in that ABPM, if untreated, can result in progressive bronchiectasis, pulmonary tissue damage, and end-stage pulmonary fibrosis.
References 1. Coombs RRA, Gell PGH: Classification of allergic reactions responsible for clinical hypersensitivity and disease. In Gell PGH, Coombs RRA, Lachmann PJ (eds): Clinical Aspects of Immunology, ed 3. Oxford, Blackwell Scientific Publications, 1975, p 761 2. Fitzsimmons EF, Aris R, Patterson R: Recurrence of ABPA in the post-transplant lungs of a cystic fibrosis patient: A case report. Chest 112:281, 1997 3. Hinson KFW, Moon AJ, Plummer NS, et al: Bronchopulmonary aspergillosis. Thorax 7:317, 1952 4. Hoehe JH, Reed CE, Dickie HA: Allergic bronchopulmonary aspergillosis is not rare. Chest 63:177, 1973 5. Hogan M B Other allergic bronchopulmonary mycoses. In Patterson R, Greenberger PA, Roberts M (eds): Allergic Bronchopulmonary Aspergillosis. Providence, RI, OceanSide Publications, 1995, p 57
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6. Laufer P, Fink JN, Bruns WT, et al: Allergic bronchopulmonary aspergillosis in cystic fibrosis. J Allergy Clin Immunol 73:44, 1984 7. Myers J L Pathology of allergic bronchopulmonary aspergillosis. In Patterson R, Greenberger PA, Roberts M (eds): Allergic Bronchopulmonary Aspergillosis. Providence, RI, Oceanside Publications, 1995, p 39 8. Patterson R, Fink JN, Pruzansky JJ, et al: Serum immunoglobulin levels in pulmonary allergic aspergillosis and certain other lung diseases, with special reference to immunoglobulin E. Am J Med 54:16, 1973 9. Patterson R, Golbert TM: Hypersensitivity disease of the lung. University of Michigan Medical Center Journal 34:8, 1968 10. Patterson R, Greenberger PA, Radin RC, et al: Allergic bronchopulmonary aspergillosis: Staging as an aid to management. Ann Intern Med 96:286, 1982 11. Pepys J: Pulmonary aspergillosis. In Pepys J (ed): Monographs in Allergy: Hypersensitivity Diseases of the Lungs due to Fungi and Organic Dusts, vol4. London, S. Karger, 1969, p 20 12. Pepys J, Riddell RW, Citron KM, et al: Clinical and immunologic significance of Aspergillus fumigutus in the sputum. American Review of Respiratory Diseases 80:167, 1959 13. Ricketti AJ, Greenberger PA, Patterson R Serum IgE as an important aid in management of allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol74:68, 1984 14. Roberts M, Greenberger PA: Serologic analysis of allergic bronchopulmonary aspergillosis. In Patterson R, Greenberger PA, Roberts M (eds): Allergic Bronchopulmonary Aspergillosis. Providence, Oceanside Publications, Inc., 1995, p 11 15. Sider L: Radiology of ABPA. In Patterson R, Greenberger PA, Roberts M (eds): Allergic Bronchopulmonary Aspergillosis. Providence, RI, OceanSide Publications, 1995, pp 18,22 16. Slavin RG, Stanczyk DJ, Lonigro AJ, et al: Allergic bronchopulmonary aspergillosis: A North American rarity. Am J Med 47306, 1969 17. Wang JLF, Patterson R, Rosenberg M, et al: Serum IgE and IgG antibody activity against Aspergillus fumigutus as a diagnostic aid in allergic bronchopulmonary’ aspergillosis. American Review of Respiratory Diseases 117917, 1978 18. Zeaske R, Bruns WT, Fink JN, et al: Immune responses to Aspergillus in cystic fibrosis. J Allergy Clin Immunol 8273, 1988
Address reprint requests to Roy Patterson, MD Division of Allergy-Immunology, MC 5207 Department of Medicine Northwestern University Medical School 303 East Chicago Avenue Chicago, IL 60611