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Aspergillosis — Clinical aspects
Zbl. Bakt. Hyg. A 261, 487-495 (1986)
Aspergillosis - Clinical Aspects * 1 PAUL A. GREENBERGER From the Section of Allergy-Immunology, Northwestern University Medical School, Chicago, Illinois 60611, U.S.A.
Accepted December 10, 1985
Abstract Allergic bronchopulmonary aspergillosis (ABPA) is much more common than originally suspected, can have its onset in childhood and remain undiagnosed for years or decades, at which time it presents in a patient with end-stage fibrotic lung disease. In other patients, ABPA may cause a finite number of roentgenographic lesions and not be associated with chronic sputum production or widespread bronchiectasis. Clinical symptoms range from the patient being asymptomatic with a new roentgenographic infiltrate being suspected only by a sharp elevation of total serum 19E to wheezing dyspnea or status asthmaticus. Serologic assays that are of major value in diagnosis of ABPA include 1) elevation of total serum IgEnot all of which is directed against Aspergillus fumigatus, 2) precipitating antibodies to A. fumigatus - unless the patient is in remission, and 3) elevated serum IgE-A. fumigatus and IgG-A. fumigatus compared to serum from patients with asthma with immediate cutaneous reactivity to A. fumigatus but without evidence of ABPA. Five stages have been identified which reflect the time of recognition of ABPAand disease activity. They are Acute, Remission, Recurrent Exacerbation, Corticosteroid-Dependent Asthma, and Fibrotic. Stage I (Acute) patients have the classic clinical, serologic, and radiologic features of ABPA. Stage II (Remission) occurs after prednisone has resulted in resolution of the chest infiltrate and can be tapered and discontinued for 6 months without new infiltrates. Stage III (Exacerbation) occurs when a new roentgenographic infiltrate occurs associated with elevation of total serum 19E. Stage IV (Corticosteroid-Dependent Asthma) is present when repeated attempts to discontinue prednisone results in severe wheezing that cannot be prevented with other therapy. Some Stage IV patients continue to develop new ABPA infiltrates. Stage V (Fibrotic) patients have irreversible obstructive and restrictive pulmonary function abnormalities and may present or progress to respiratory failure and death.
* Presented at the Aspergillosis Symposium conducted by the International Society of Human and Animal Mycology, Atlanta, Georgia, U.S.A., in May 1985, chaired by Drs. Viswanath P. Kurup and Joan 1. Longbottom. 1 Supported by United States Public Health Service Grant 11403, the Ernest S. Bazley Grant, and the Chicago Lung Association. 33 Zbl. Bakt. Hyg. A 261/4
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Zusammenfassung Allergische bronchopulmonare Aspergillose (ABPA) ist verbreiteter als friiher angenommen. Die Erkrankung kann bereits im Kindesalter einsetzen und iiber Jahre und Jahrzehnte unerkannt bleiben; sie zeigr sich dann bei Patienten mit einer fibrotischen Lungenerkrankung im Endstadium. Bei anderen kann ABPA eine begrenzte Zahl rontgenologisch erkennbarer Lasionen hervorrufen und nicht mit chronischer Sputumproduktion oder ausgedehnter Bronchiektase einhergehen. Das klinische Bild reicht von asymptomatischen Patienten mit neuem, r6ntgenologisch erkennbarem Infiltrat und starkem Anstieg des Gesamt-SerurnIgE als einzigem Verdachtsmoment bis zu solchen mit Atemnot oder Status asthmaticus. Fur die ABPA-Diagnose bedeutsam: 1. erhohres Gesamt-Serum-IgE, das nicht in seiner Gesamtheit gegen Aspergillus [umigatus gerichtet ist, 2. prazipitierende A. fumigatus-Antikorper, auBer wenn der Patient sich im Remissionsstadium befindet und 3. erhohte A. fumigatus-IgE und -IgG im Vergleich zum Serum von Asthmapatienten mit unmittelbarer kutaner Reaktion auf A. fumigatus, jedoch ohne APBA-Nachweis. Es wurden funf Stadien erkannt, die den Zeitpunkt der Erkennung der APBA und die Krankheirsaktivitat widerspiegeln: Akutstadium (I), Remission (II), wiederholte Exacerbation (III), Kortikosteroidabhangiges Asthma (IV) und fibrotisches Stadium (V).
Introduction Once considered rare in North America (25), Allergic Bronchopulmonary Aspergillosis (ABPA) is being recognized with much greater frequency than originally suspected. ABPA was initially described in patients with asthma, transient pulmonary infiltrates, peripheral blood and sputum eosinophilia, and sputum containing hyphae of Aspergillus fumigatus (9). The first patient identified in the U.S.A. was a 36-year-old man who is still alive, although his major clinical symptoms relate to corticosteroiddependent asthma some 17 years later (17). The first childhood case (age 9 years) was reported in 1970 (26). ABPA has been confirmed in infants and children who also present with recurrent pulmonary infiltrates, wheezing, peripheral blood eosinophilia, and sputum harboring A. fumigatus (l0, 14). Currently, approximately 55 patients with ABPA are managed by the Northwestern University Allergy Service and we have clinical, radiologic, and serologic data on another 50 patients who are treated elsewhere. Because of increasing awareness of ABPA and serologic parameters that are valuable in confirming the diagnosis, ABPA may be suspected and the diagnosis secured before significant bronchiectasis has occurred. This early recognition has resulted in patients being treated with prednisone before clinical evidence of bronchiectasis has evolved. However, the diagnosis of ABPA may be made in patients with asthma who have symptoms consistent with chronic bronchitis or in patients with substantial sputum production from widespread bronchiectasis. ABPA has been observed to occur in 111 out of 143 patients with "pulmonary eosinophilia" in the U.K. (14), in corticosteroid-dependent asthrnatics.iin patients with previously defined bronchiectasis, in some patients with normal chest roentgenograms and no known history of chest lesions (22), on a familial basis (2), and in patients with cystic fibrosis (12). Patients may not produce sputum because of limited bronchiectasis or demonstrate sputum or peripheral blood eosinophilia at .the time of diagnosis. The necessity of a high index of suspicion for ABPA is emphasized by the case of a woman with mild asthma which usually caused wheezing dyspnea in October and November associated with the high seasonal mold burden who presented because of a lipstick contact der-
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matitis. Six months previously she had an upper lobe infiltrate, temperature of 38°C, and was told she had a viral pneumonia (21). Because of immediate cutaneous reactivity to A. [umigatus, serologic studies were obtained and the chest roentgenogram reviewed. She met all criteria for ABPA including central bronchiectasis. This case illustrates one mode of presentation of ABPA and perhaps how it is possible to not make an early diagnosis of this disease. ABPA may begin in childhood (or even infancy), may remain undiagnosed for years or decades, and cause widespread bronchiectasis, end-stage fibrotic lung disease or fatalities by the third or fourth decades of life. In the agriculture industry, aspergilli (including A. fumigatus) produce avian aspergillosis in practically all groups of birds and results in as high as 5-10% mortality of production flocks (3). Spontaneous abortions are common in sheep infected with aspergilli. Diagnostic Criteria of ABPA ABPA is an immunologic disease that results in lung destruction with defined clinical, serologic, radiologic, and morphologic features. The diagnostic criteria reflect these factors and are as follows: 1. Asthma - which may range from mild to severe 2. Immediate cutaneous reactivity to A. fumigatus or a mixture of Aspergillus species 3. Precipitating antibodies to A. fumigatus in serum that is neat or concentrated 4. Elevated total serum IgE, often dramatically 5. Peripheral blood eosinophilia 6. History of or current chest roentgenographic infiltrate 7. Proximal bronchiectasis 8. Elevated serum IgE-A. fumigatus and IgG-A. fumigatus compared with asthmatic sera from patients without ABPA. These criteria are present in the classic case of ABPA but do not include 1) recovering A. fumigatus from sputum, 2) an immediate and 4-8 hour cutaneous reaction to A. fumigatus, or 3) a "dual" respiratory response following inhalation of A. fumigatus. These three findings are no longer considered necessary for the diagnosis of ABPA. Staging of ABPA A staging system has been developed as an aid in management (15). The five stages are not phases of the disease process but serve to emphasize the indolent nature of ABPA in some patients, failure to recognize the disease in other patients until widespread bronchiectasis has occurred, and potential for lung damage such that end-stage fibrotic lung disease evolves. The stages are I (Acute), II (Remission), III (Exacerbation), IV (Corticosteroid-Dependent Asthma), and V (Fibrotic). Stage I is present when the classic features are present and the patient meets all the diagnostic criteria. Patients may produce sputum that yields A. fumigatus or other Aspergillus species, although some patients will not have any sputum production. Serum IgE-A. fumigatus and IgGA. fumigatus are at least twice that of serum from patients with asthma who do not have ABPA but do exhibit immediate cutaneous reactivity to A. fumigatus (5). Administration of prednisone has a number of salutary effects in that, although it is-flat fungicidal obviously, it causes 1) clearing of the chest roentgenographic lesion usually
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within 4 weeks, 2) decrease of the total serum IgE of at least 35% by 6 weeks, 3) rapid decline of peripheral blood eosinophilia, 4) decrease in severity of respiratory symptoms whether from asthma or from a pulmonary consolidation. Stage II (Remission) is present when there has been resolution of the roentgenographic lesion and decline and stabilization of the total serum 19E for 6 months. Prednisone can be discontinued without appearance of a new roentgenographic lesion or development of severe asthma requiring oral corticosteroids. Some patients appear to have a permanent remission, although in one woman an ABPA exacerbation was documented 7 years after she entered a remission (8). Stage III (Exacerbation) is defined by the development of a new roentgenographic lesion which sharp increase in total serum IgE of at least 100%. Patients may be symptomatic (cough, dyspnea, fever, malaise, wheezing) or asymptomatic in that the only indication for obtaining the chest roentgenogram was a substantial elevation above baseline of the total serum 19E.Prednisone results in resolution of the pulmonary lesion and causes a decrease in total serum IgE as in Stage I. As with Stage I pulmonary lesions, other etiologies such as bacterial or viral infections cannot explain the chest roentgenographic infiltrate. Stage IV ABPA may be present initially (15) or be recognized as prednisone is tapered following administration in Stages I or III. For unclear reasons, following the diagnosis and treatment of ABPA in a definite group of patients, asthma becomes much more severe and indeed corticosteroid-dependent. Inhaled beclomethasone dipropionate and bronchodilators are inadequate to prevent episodes of severe wheezing or status asthmaticus. The total serum IgE ranges from sharply elevated if a new roentgenographic lesion is present to normal if no ABPA exacerbation is present. Stage V ABPA occurs when there is proven ABPA, pulmonary fibrosis on chest roentgenogram, and irreversible obstructive and restrictive pulmonary function changes. Total serum IgE may be elevated or normal, and serum 19E-A. [umigatus, IgG-A. fumigatus, and 19A-A. fumigatus mayor may not be increased. Prednisone is required for management of asthma; in patients with hypoxemia, chronic oxygen administration is indicated. Patients may present with Stage V ABPA in respiratory failure (6). Clinical Symptoms of ABPA McCarthy and Pepys described clinical symptoms during 41 episodes of ABPA exacerbation (14). Eighty-six percent of patients reported malaise and half of the patients had symptoms of such severity that normal activities could not be performed. Five patients had temperature elevation of 39.6-40°C, but most patients had lower elevations. Eight patients were afebrile. ABPA exacerbations may be associated with wheezing dyspnea, no symptoms related to the bronchopulmonary system, pluritic chest pain in a small number of patients, or cough associated with mucopurulent sputum production. ABPA may be recognized because of mucoid impactions on chest roentgenogram in patients admitted with status asthmaticus. Frequently, the consolidation present on the chest roentgenogram attributable to ABPA dotes not produce the constitutional symptoms that would be expected with a similar area of consolidation caused by a bacterial pathogen. Immediate-type allergic diseases in ABPA patients were common and were present whether asthma had its onset before or after age 30 (20). The high degree of allergic symptoms included allergic rhinitis, conjunctivitis, atopic dermatitis, food allergy, drug hypersensitivity. These findings in a group of ABPA subjects identified in the Chicago
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area were different from that reported in the U. K. in that, when asthma had its onset after age 30, patients did not exhibit an arra y of allergic diseases and were considered as "low atopic status " (14). ABPA may occur in a subset of highly atopic individuals who develop many of the classic allergic diseases (20). ABPApatients usually demonstrate widespread immediate cutaneous reactivity to common inhalant allergens. In contrast to experience in the U. K. (14), none of our patients has isolated reactivity to A. [umigatus and nonreactive cutaneous tests otherwise (20). It should be noted that, while many patients describe respiratory symptoms upon exposure to moldy areas, a small number of patients report respiratory symptoms only with "nonimmunologic" stimuli such as cold air, infection, change in weather, or emotions (20). If ABPAwere not excluded in all asthmatics with an immediate wheal and erythema reaction to A. [umigatus seen by our service, the diagnosis may not have been made. Laboratory Findings From the diagnostic criteria, all patients demonstrate immediate cutaneous reactivity to Aspergillus antigens. The immediate wheal and erythema reaction can be elicited by prick testing with reagents of 1: 20 weight/volume. Only rarely is it necessary to perform an intradermal test to demonstrate IgE-A. [umigatus, and some patients have had anaphylactic reactions from intradermal skin testing. Negative skin tests could be attributable to poorly standardized or potent reagents utilized for testing. Another explanation for negative skin tests is that the patient has another allergic bronchopulmonary mycosis or has IgE antibodies directed to Aspergillus antigens not present in the material utilized for testing. Because we use prick testing and introduce a small quanritiy of antigen into the skin, Arthus-type reactions rarely occur. When these late cutaneous reactions occur, biopsy specimens have demonstrated IgG, IgM, IgA, and C3 (14). Precipitating antibodies are almost always present at the time of an ABPAinfiltrate, although serum may require fivefold concentration. The spectrum of precipitin reactions at the time of an ABPAexacerbation included 26 of 27 (96.3 %) sera positive with A. [umigatus, 14 of 27 positive with A. terreus, 7 of 27 reactive with A. niger, and 4 reactive with A. nidulans (3). Precipitin reactions may be absent after admin istration of oral corticosteroids results in resolution of the chest roentgenographic infiltrate or if the patient enters a remission. The absence of detectable precipitins to A. [umigatus or other aspergilli should not be considered evidence against the diagnosis of ABPA. In a study using similar antigenic material for testing, approximately 10% of patients with asthma (either in London or Cleveland) without ABPA demonstrated precipitins to A. [umigatus (24). Immediate cutaneous reactivtiy to A. [umigatus was about 25% in the same patients. Measurement of total serum IgE is of major value in confirming the diagnosis of ABPA, detecting exacerbations, and in monitoring the response to prednisone administration (3). At the time of diagnosis, total serum IgE is elevated markedly in nearly all pat ients in Stages I and III (15). In patients in the other stages of ABPA, the total serum IgE may be normal to moderately elevated. Much of the elevation in total serum IgE is not directed against A. fumigatus (16). This observation is consistent with A . fumigatus stimulating "nonspecific" IgE formtion or IgE to antigens different from A. [umigatus. When IgE is determined on a serial (preferably monthly) basis, at least 100% elevations occur when ABPA exacerbations occur.
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Measurement of serum IgE-A. [umigatus, IgG-A. [umigatus, and IgA-A. fumigatus by radioimmunoassay or ELISAhas demonstrated elevations compared to serum from patients with asthma and immediate cutaneous reactivity to A. fumigatus but not ABPA (5). The differentiation of patients with mold-induced asthma from patients with ABPA may be difficult in that both patients may have had a prior pulmonary infiltrate for example. Serum antibodies to A. fumigatus are valuable in making this distinction. ABPA sera has at least twice the amount of antibody that is present in a pool of asthmatic sera (5). Serum IgE-A. fumigatus does not peak at the time of the chest roentgenographic lesion in contrast to total serum IgE; rather, the peak may occur 'several months later (3). Serum IgG-A. fumigatus peaks at the time of the ABPA exacerbation (3). Bronchoalveolar lavage (BAL) of patients with stable ABPA and no current chest roentgenographic infiltrate has revealed a divergent antibody response in terms of isotypic antibodies to A. fumigatus and total IgE (4). The ratio of BAL IgE-A. fumigatus/albumin to serum IgE-A. fumigatus/albumin was 44 and for IgA-A. fumigatus was 165 compared with an IgG-A. fumigatus ratio of 0.8 (4). These results suggest that in ABPA there is local pulmonary production of isotypic antibodies to A. fumigatus as one might expect. The low ratio for IgG-A. fumigatus could reflect the poor sampling of peripheral bronchi which contain IgG by BAL or absence of pulmonary function. In contrast, the ratio of BAL total IgE/serum IgE corrected for albumin was near unity, suggesting that the marked elevations in total serum IgE may not originate in the lung (4). ABPA patients have an array of clinical allergic diseases in most cases. ABPA serum has isotypic antibodies to A. fumigatus and may well have elevated concentrations of antibodies to other antigens as well. This is specultive now however. When in vitro basophil histamine release to A. fumigatus and other molds was determined, basophils from ABPA patients have marked hyperreactivity compared with basophils from patients with mold-sensitive asthma (19). Further, basophils from patients with Stages IV and V ABPA (more advanced disease) released a significantly greater amount of histamine to A. fumigatus than cells from patients in Stages, I, II and III. This observation was the first cellular abnormality in ABPA, and raises the question whether certain patients may be at risk of developing more advanced disease. This observation needs prospective evaluation. By use of crossed-radioimmunoelectrophoresis with ABPApatient sera, Longbottom has reported serum to serum variability in reactivity (13). Two main antigenic components were detected: 1) poorly precipitating antigens that have high IgE binding, and 2) strongly precipitating antigens that have weak IgE binding. The former were considered to be major antigens. Piechura et al. have described preparation of a cell sap antigen from three strains of A. fumigatus which has been useful as a diagnostic reagent (18). The molecular weight of the major component of this preparation was approximately 150,000. From a clinical perspective, the lack of standardization of commercial extracts used for skin testing continues to be a dilemma. Negative immediate cutaneous reactivity with presumed relevant antigens can virtually exclude the diagnosis, and in only rare cases would further serologic tests be obtained such as total serum IgE and precipitins. Immune complexes were described in one patient with an ABPA exacerbation (1) but, although local pulmonary immune complexes may contribute to lung destruction, ABPA cannot be considered a disease of circulating immune complexes analogous to
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serum sickness. An area of investigation would be the detection of Aspergillus antigens in immune complexes in the lung. McCarthy and Pepys have described that, at the time of an ABPAexacerbation, 56% of patients produced sputum plugs containing A. fumigatus (14). The repeated recovery of A. fumigatus or other Aspergillus species from sputum of asthmatic patients should raise the possibility of ABPA. Colonization of bronchi by Mycobacterium chelonei in a young woman with extensive bronchiectasis from ABPA has not resulted in dissemination over a 5-year period to date (7). It is possible that other uncommon organisms may be recovered from sputum from other ABPA patients and a decision will be necessary regarding colonization or pathogenesis when there is an associated roentgenographic lesion. In patients whose ABPA is recognized early, sputum plugs may not occur because bronchiectasis is limited. Even at times of ABPA exacerbations, there may be no sputum production of any type in these patients. T and B cell subsets in selected patients with ABPA has demonstrated normal numbers of T4 and T8 cells as well as B cells. These findings are similar to reports in patients with asthma in which no definite abnormalities have been identified. Pathologic Findings Bronchiectasis classically affects the upper lobes but we have seen lower lobe and middle lobe involvement by ABPA. The pattern of bronchiectasis is that of proximal saccular dilation in contrast to obliterative changes or distal bronchiectasis that follows bacterial pneumonias. In spite of colonization of bronchial mucus by A. [umigatus, tissue invasion does not occur. The doses of prednisone used for treatment of ABPAare not great and do not result in serious infections. Although daily prednisone has been shown to result in resolution of the roentgenographic lesion (23), alternate day prednisone has proven useful and has been recommended for patients with ABPA (3). Some of the morphologic diagnoses that have been made in ABPA and which should raise the possibility of ABPA in undiagnosed patients include eosinophilic pneumonia, mucoid impaction syndrome, granulomatous bronchiolitis, lipid pneumonia, desquamative or lymphocytic interstitial pneumonia, vasculitis, and end-stage fibrotic lung disease (3). From a clinical perspective, patients with these diagnoses may satisfy all the diagnostic criteria for ABPA and should be treated as such. In patients who do not have ABPA, a recently recognized syndrome called "allergic Aspergillus sinusitis" has been described (11). Patients have a history of asthma but present with complaints from chronic sinusitis and nasal polyposis. The mucinous material recovered during sinus drainage procedures resembled mucoid impactions that occur in the bronchi of patients with ABPA. The mucin contained eosinophils, Charcot-Leyden crytals, and fungal hyphae resembling Aspergillus species. Tissue invasion did not occur. Serum precipitins were identified in six of seven patients, but elevated IgE-A. fumigatus and IgG-A. fumigatus as in ABPA were not present. The serologic pattern was analogous to that of aspergilloma. The optimal approach for management of this syndrome has yet to be established but may be that of surgical drainage and topical nasal corticosteroids. It is speculative whether any of these patients will evolve into ABPA.
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References
1. Geha, R. S.: Circulating immune complexes and activation of the complement sequence in acute allergic bronchopulmonary aspergillosis. J. Allergy Clin. Immunol. 60 (1977) 357-359 2. Graves, T. S., ]. N. Fink, R. Patterson, V. P. Kurup, and G. T. Scanlon: A familial occurrence of allergic bronchopulmonary aspergillosis. Ann. Intern. Med. 91 (1978) 378-382 3. Greenberger, P. A.: Allergic bronchopulmonary aspergillosis. J. Allergy Clin. Immunol. 74 (1984) 645-653 4. Greenberger, P. A., L. ]. Smith, C. C. S. Hsu, M. Roberts, and]. L. Liotta: Analysis of bronchoalveolar lavage in allergic bronchopulmonary aspergillosis: divergent responses of antigen specific antibodies and total IgE (submitted for publication) 5. Greenberger, P. A. and R. Patterson: Application of enzyme-linked immunosorbent assay (ELISA) in diagnosis of allergic bronchopulmonary aspergillosis. J. Lab. Clin. Med. 99 (1982) 288-293 6. Greenberger, P. A., R. Patterson, A. C. Ghory,]. A. Arkins, T. Walsh, T. Graves, and]. Saker: Late sequelae of allergic bronchopulmonary aspergillosis. J. Allergy Clin. Immunol. 66 (1980) 327-335 7. Greenberger, P. A. and A.-L. A. Katzenstein: Lipoid pneumonia with atypical mycobacterial colonization in allergic bronchopulmonary aspergillosis: a complication of bronchography and a therapeutic dilemma. Arch. Intern. Med. 143 (1983) 2003-2005 8. Halwig, ]. M., P. A. Greenberger, M. Levine, and R. Patterson: Recurrence of allergic bronchopulmonary aspergillosis after 7 years of remission. ]. Allergy Clin. Immunol. 74
(1984) 738-740 9. Hinson, K. F. W., A. ]. Moon, and N. S. Plummer: Bronchopulmonary aspergillosis. Thorax 7 (1952) 317-333 10. Imbeau, S. A., M. Cohen, and C. E. Reed: Allergic bronchopulmonary aspergillosis in infants. Amer. J. Dis. Child. 131 (1977) 1127-1130 11. Katzenstein, A.-L. A., S. R. Sale, and P. A. Greenberger: Allergic Aspergillus sinusitis: a newly recognized form of sinusitis. ]. Allergy Clin. Immunol. 72 (1983) 89-93 12. Laufer, P.,]. N. Fink, W. T. Bruns, G. F. Unger,]. H. Kalbfleisch, P. A. Greenberger, and R. Patterson: Allergic bronchopulmonary aspergillosis in cystic fibrosis. ]. Allergy Clin. Immunol. 73 (1984) 44-48 13. Longbottom, ].: Allergic bronchopulmonary aspergillosis: reactivity of IgE and IgG antibodies with antigen components of Aspergillus fumigatus (IgE-IgG antigen complexes). J. Allergy Clin. Immunol. 72 (1983) 668-675 14. McCarthy, D. S. and]. Pepys: Allergic bronchopulmonary aspergillosis. Clin. Allergy 1 (1971) 261-286 15. Patterson, R., P. A. Greenberger, R. A. Radin, and M. Roberts: Allergic bronchopulmonary aspergillosis: staging as an aid to management. Ann. Intern. Med. 96 (1982) 286-291 16. Patterson, R., M. Rosenberg, and M. Roberts: Evidence that Aspergillus fumigatus growing in the airway of man can be a potent stimulus of specific and nonspecific IgE formation. Amer. J. Med. 63 (1977) 257-262 17. Patterson, R. and T. Golbert: Hypersensitivity disease of the lung. Univ. Michigan Med. Ctr. J. 34 (1968) 8-11 18. Piechura, ]. E., ]. H. Caecilia, S. H. Cohen, ]. M. Kidd, V. P. Kurup, and N. ]. Calvanico: Antigens of Aspergillus fumigatus. Clin. Exp. Immunol. 49 (1983) 657-665 19. Ricketti, A.]., P. A. Greenberger.].], Pruzansky, and R. Patterson: Hyperreactivity of mediator releasing cells from patients with allergic bronchopulmonary aspergillosis as evidenced by basophil histamine release. J. Allergy Clin. Immunol. 72 (1983) 386-392 20. Ricketti, A. J., P. A. Greenberger, and R. Patterson: Immediate-type reactions in pa-
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tients with allergic bronchopulmonary aspergillosis. J. Allergy Clin, Immunol. 71 (1983) 541-545 21. Ricketti, A. j., P. A. Greenberger, and R. Patterson: Varying presentations of allergic bronchopulmonary aspergillosis. Int. Arch. Allergy Appl. Immunol. 73 (1984) 283-285 22. Rosenberg, M., R. Mintzer, D. W. Aaronson, and R. Patterson: Allergic bronchopulmonary aspergillosis in three patients with normal chest X-ray films. Chest 72 (1977) 597-600 23. Safirstein, B. H., M. F. D'Souza, G. Simon, E. H.-C. Tai, and]. Pepys: Five-yearfollowup of allergic bronchopulmonary aspergillosis. Amer. Rev. resp. Dis. 108 (1973) 450-459 24. Schwartz, H.]., K. M. Atron, E. H. Chester,]. Kaimal, P. B. Barlow, G. L. Baum, and M. R. Schuyler: A comparison of sensitization to Aspergillus antigens among asthmatics in Cleveland and London. J. Allergy Clin. Immunol. 62 (1978) 9-14 25. Slavin, R. G., D.]. Stanczyk, A.]. Lonigro, and G. D. Brown: Allergic bronchopulmonary aspergillosis: A North American rarity. Amer. J. Med. 47 (1969) 306-313 26. Slavin, R. G., T. S. Laird, and I. D. Cherry: Allergic bronchopulmonary aspergillosis in a child. J. Pediat. 76 (1970) 416-421
Paul A. Greenberger, M. D., 303 East Chicago Avenue, Chicago, Illinois 60611, U.S.A.
Aspergillosis - Clinical Aspects * 1 PAUL A. GREENBERGER From the Section of Allergy-Immunology, Northwestern University Medical School, Chicago, Illinois 60611, U.S.A.
Accepted December 10, 1985
Abstract Allergic bronchopulmonary aspergillosis (ABPA) is much more common than originally suspected, can have its onset in childhood and remain undiagnosed for years or decades, at which time it presents in a patient with end-stage fibrotic lung disease. In other patients, ABPA may cause a finite number of roentgenographic lesions and not be associated with chronic sputum production or widespread bronchiectasis. Clinical symptoms range from the patient being asymptomatic with a new roentgenographic infiltrate being suspected only by a sharp elevation of total serum 19E to wheezing dyspnea or status asthmaticus. Serologic assays that are of major value in diagnosis of ABPA include 1) elevation of total serum IgEnot all of which is directed against Aspergillus fumigatus, 2) precipitating antibodies to A. fumigatus - unless the patient is in remission, and 3) elevated serum IgE-A. fumigatus and IgG-A. fumigatus compared to serum from patients with asthma with immediate cutaneous reactivity to A. fumigatus but without evidence of ABPA. Five stages have been identified which reflect the time of recognition of ABPAand disease activity. They are Acute, Remission, Recurrent Exacerbation, Corticosteroid-Dependent Asthma, and Fibrotic. Stage I (Acute) patients have the classic clinical, serologic, and radiologic features of ABPA. Stage II (Remission) occurs after prednisone has resulted in resolution of the chest infiltrate and can be tapered and discontinued for 6 months without new infiltrates. Stage III (Exacerbation) occurs when a new roentgenographic infiltrate occurs associated with elevation of total serum 19E. Stage IV (Corticosteroid-Dependent Asthma) is present when repeated attempts to discontinue prednisone results in severe wheezing that cannot be prevented with other therapy. Some Stage IV patients continue to develop new ABPA infiltrates. Stage V (Fibrotic) patients have irreversible obstructive and restrictive pulmonary function abnormalities and may present or progress to respiratory failure and death.
* Presented at the Aspergillosis Symposium conducted by the International Society of Human and Animal Mycology, Atlanta, Georgia, U.S.A., in May 1985, chaired by Drs. Viswanath P. Kurup and Joan 1. Longbottom. 1 Supported by United States Public Health Service Grant 11403, the Ernest S. Bazley Grant, and the Chicago Lung Association. 33 Zbl. Bakt. Hyg. A 261/4
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P.A. Greenberger
Zusammenfassung Allergische bronchopulmonare Aspergillose (ABPA) ist verbreiteter als friiher angenommen. Die Erkrankung kann bereits im Kindesalter einsetzen und iiber Jahre und Jahrzehnte unerkannt bleiben; sie zeigr sich dann bei Patienten mit einer fibrotischen Lungenerkrankung im Endstadium. Bei anderen kann ABPA eine begrenzte Zahl rontgenologisch erkennbarer Lasionen hervorrufen und nicht mit chronischer Sputumproduktion oder ausgedehnter Bronchiektase einhergehen. Das klinische Bild reicht von asymptomatischen Patienten mit neuem, r6ntgenologisch erkennbarem Infiltrat und starkem Anstieg des Gesamt-SerurnIgE als einzigem Verdachtsmoment bis zu solchen mit Atemnot oder Status asthmaticus. Fur die ABPA-Diagnose bedeutsam: 1. erhohres Gesamt-Serum-IgE, das nicht in seiner Gesamtheit gegen Aspergillus [umigatus gerichtet ist, 2. prazipitierende A. fumigatus-Antikorper, auBer wenn der Patient sich im Remissionsstadium befindet und 3. erhohte A. fumigatus-IgE und -IgG im Vergleich zum Serum von Asthmapatienten mit unmittelbarer kutaner Reaktion auf A. fumigatus, jedoch ohne APBA-Nachweis. Es wurden funf Stadien erkannt, die den Zeitpunkt der Erkennung der APBA und die Krankheirsaktivitat widerspiegeln: Akutstadium (I), Remission (II), wiederholte Exacerbation (III), Kortikosteroidabhangiges Asthma (IV) und fibrotisches Stadium (V).
Introduction Once considered rare in North America (25), Allergic Bronchopulmonary Aspergillosis (ABPA) is being recognized with much greater frequency than originally suspected. ABPA was initially described in patients with asthma, transient pulmonary infiltrates, peripheral blood and sputum eosinophilia, and sputum containing hyphae of Aspergillus fumigatus (9). The first patient identified in the U.S.A. was a 36-year-old man who is still alive, although his major clinical symptoms relate to corticosteroiddependent asthma some 17 years later (17). The first childhood case (age 9 years) was reported in 1970 (26). ABPA has been confirmed in infants and children who also present with recurrent pulmonary infiltrates, wheezing, peripheral blood eosinophilia, and sputum harboring A. fumigatus (l0, 14). Currently, approximately 55 patients with ABPA are managed by the Northwestern University Allergy Service and we have clinical, radiologic, and serologic data on another 50 patients who are treated elsewhere. Because of increasing awareness of ABPA and serologic parameters that are valuable in confirming the diagnosis, ABPA may be suspected and the diagnosis secured before significant bronchiectasis has occurred. This early recognition has resulted in patients being treated with prednisone before clinical evidence of bronchiectasis has evolved. However, the diagnosis of ABPA may be made in patients with asthma who have symptoms consistent with chronic bronchitis or in patients with substantial sputum production from widespread bronchiectasis. ABPA has been observed to occur in 111 out of 143 patients with "pulmonary eosinophilia" in the U.K. (14), in corticosteroid-dependent asthrnatics.iin patients with previously defined bronchiectasis, in some patients with normal chest roentgenograms and no known history of chest lesions (22), on a familial basis (2), and in patients with cystic fibrosis (12). Patients may not produce sputum because of limited bronchiectasis or demonstrate sputum or peripheral blood eosinophilia at .the time of diagnosis. The necessity of a high index of suspicion for ABPA is emphasized by the case of a woman with mild asthma which usually caused wheezing dyspnea in October and November associated with the high seasonal mold burden who presented because of a lipstick contact der-
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matitis. Six months previously she had an upper lobe infiltrate, temperature of 38°C, and was told she had a viral pneumonia (21). Because of immediate cutaneous reactivity to A. [umigatus, serologic studies were obtained and the chest roentgenogram reviewed. She met all criteria for ABPA including central bronchiectasis. This case illustrates one mode of presentation of ABPA and perhaps how it is possible to not make an early diagnosis of this disease. ABPA may begin in childhood (or even infancy), may remain undiagnosed for years or decades, and cause widespread bronchiectasis, end-stage fibrotic lung disease or fatalities by the third or fourth decades of life. In the agriculture industry, aspergilli (including A. fumigatus) produce avian aspergillosis in practically all groups of birds and results in as high as 5-10% mortality of production flocks (3). Spontaneous abortions are common in sheep infected with aspergilli. Diagnostic Criteria of ABPA ABPA is an immunologic disease that results in lung destruction with defined clinical, serologic, radiologic, and morphologic features. The diagnostic criteria reflect these factors and are as follows: 1. Asthma - which may range from mild to severe 2. Immediate cutaneous reactivity to A. fumigatus or a mixture of Aspergillus species 3. Precipitating antibodies to A. fumigatus in serum that is neat or concentrated 4. Elevated total serum IgE, often dramatically 5. Peripheral blood eosinophilia 6. History of or current chest roentgenographic infiltrate 7. Proximal bronchiectasis 8. Elevated serum IgE-A. fumigatus and IgG-A. fumigatus compared with asthmatic sera from patients without ABPA. These criteria are present in the classic case of ABPA but do not include 1) recovering A. fumigatus from sputum, 2) an immediate and 4-8 hour cutaneous reaction to A. fumigatus, or 3) a "dual" respiratory response following inhalation of A. fumigatus. These three findings are no longer considered necessary for the diagnosis of ABPA. Staging of ABPA A staging system has been developed as an aid in management (15). The five stages are not phases of the disease process but serve to emphasize the indolent nature of ABPA in some patients, failure to recognize the disease in other patients until widespread bronchiectasis has occurred, and potential for lung damage such that end-stage fibrotic lung disease evolves. The stages are I (Acute), II (Remission), III (Exacerbation), IV (Corticosteroid-Dependent Asthma), and V (Fibrotic). Stage I is present when the classic features are present and the patient meets all the diagnostic criteria. Patients may produce sputum that yields A. fumigatus or other Aspergillus species, although some patients will not have any sputum production. Serum IgE-A. fumigatus and IgGA. fumigatus are at least twice that of serum from patients with asthma who do not have ABPA but do exhibit immediate cutaneous reactivity to A. fumigatus (5). Administration of prednisone has a number of salutary effects in that, although it is-flat fungicidal obviously, it causes 1) clearing of the chest roentgenographic lesion usually
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within 4 weeks, 2) decrease of the total serum IgE of at least 35% by 6 weeks, 3) rapid decline of peripheral blood eosinophilia, 4) decrease in severity of respiratory symptoms whether from asthma or from a pulmonary consolidation. Stage II (Remission) is present when there has been resolution of the roentgenographic lesion and decline and stabilization of the total serum 19E for 6 months. Prednisone can be discontinued without appearance of a new roentgenographic lesion or development of severe asthma requiring oral corticosteroids. Some patients appear to have a permanent remission, although in one woman an ABPA exacerbation was documented 7 years after she entered a remission (8). Stage III (Exacerbation) is defined by the development of a new roentgenographic lesion which sharp increase in total serum IgE of at least 100%. Patients may be symptomatic (cough, dyspnea, fever, malaise, wheezing) or asymptomatic in that the only indication for obtaining the chest roentgenogram was a substantial elevation above baseline of the total serum 19E.Prednisone results in resolution of the pulmonary lesion and causes a decrease in total serum IgE as in Stage I. As with Stage I pulmonary lesions, other etiologies such as bacterial or viral infections cannot explain the chest roentgenographic infiltrate. Stage IV ABPA may be present initially (15) or be recognized as prednisone is tapered following administration in Stages I or III. For unclear reasons, following the diagnosis and treatment of ABPA in a definite group of patients, asthma becomes much more severe and indeed corticosteroid-dependent. Inhaled beclomethasone dipropionate and bronchodilators are inadequate to prevent episodes of severe wheezing or status asthmaticus. The total serum IgE ranges from sharply elevated if a new roentgenographic lesion is present to normal if no ABPA exacerbation is present. Stage V ABPA occurs when there is proven ABPA, pulmonary fibrosis on chest roentgenogram, and irreversible obstructive and restrictive pulmonary function changes. Total serum IgE may be elevated or normal, and serum 19E-A. [umigatus, IgG-A. fumigatus, and 19A-A. fumigatus mayor may not be increased. Prednisone is required for management of asthma; in patients with hypoxemia, chronic oxygen administration is indicated. Patients may present with Stage V ABPA in respiratory failure (6). Clinical Symptoms of ABPA McCarthy and Pepys described clinical symptoms during 41 episodes of ABPA exacerbation (14). Eighty-six percent of patients reported malaise and half of the patients had symptoms of such severity that normal activities could not be performed. Five patients had temperature elevation of 39.6-40°C, but most patients had lower elevations. Eight patients were afebrile. ABPA exacerbations may be associated with wheezing dyspnea, no symptoms related to the bronchopulmonary system, pluritic chest pain in a small number of patients, or cough associated with mucopurulent sputum production. ABPA may be recognized because of mucoid impactions on chest roentgenogram in patients admitted with status asthmaticus. Frequently, the consolidation present on the chest roentgenogram attributable to ABPA dotes not produce the constitutional symptoms that would be expected with a similar area of consolidation caused by a bacterial pathogen. Immediate-type allergic diseases in ABPA patients were common and were present whether asthma had its onset before or after age 30 (20). The high degree of allergic symptoms included allergic rhinitis, conjunctivitis, atopic dermatitis, food allergy, drug hypersensitivity. These findings in a group of ABPA subjects identified in the Chicago
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area were different from that reported in the U. K. in that, when asthma had its onset after age 30, patients did not exhibit an arra y of allergic diseases and were considered as "low atopic status " (14). ABPA may occur in a subset of highly atopic individuals who develop many of the classic allergic diseases (20). ABPApatients usually demonstrate widespread immediate cutaneous reactivity to common inhalant allergens. In contrast to experience in the U. K. (14), none of our patients has isolated reactivity to A. [umigatus and nonreactive cutaneous tests otherwise (20). It should be noted that, while many patients describe respiratory symptoms upon exposure to moldy areas, a small number of patients report respiratory symptoms only with "nonimmunologic" stimuli such as cold air, infection, change in weather, or emotions (20). If ABPAwere not excluded in all asthmatics with an immediate wheal and erythema reaction to A. [umigatus seen by our service, the diagnosis may not have been made. Laboratory Findings From the diagnostic criteria, all patients demonstrate immediate cutaneous reactivity to Aspergillus antigens. The immediate wheal and erythema reaction can be elicited by prick testing with reagents of 1: 20 weight/volume. Only rarely is it necessary to perform an intradermal test to demonstrate IgE-A. [umigatus, and some patients have had anaphylactic reactions from intradermal skin testing. Negative skin tests could be attributable to poorly standardized or potent reagents utilized for testing. Another explanation for negative skin tests is that the patient has another allergic bronchopulmonary mycosis or has IgE antibodies directed to Aspergillus antigens not present in the material utilized for testing. Because we use prick testing and introduce a small quanritiy of antigen into the skin, Arthus-type reactions rarely occur. When these late cutaneous reactions occur, biopsy specimens have demonstrated IgG, IgM, IgA, and C3 (14). Precipitating antibodies are almost always present at the time of an ABPAinfiltrate, although serum may require fivefold concentration. The spectrum of precipitin reactions at the time of an ABPAexacerbation included 26 of 27 (96.3 %) sera positive with A. [umigatus, 14 of 27 positive with A. terreus, 7 of 27 reactive with A. niger, and 4 reactive with A. nidulans (3). Precipitin reactions may be absent after admin istration of oral corticosteroids results in resolution of the chest roentgenographic infiltrate or if the patient enters a remission. The absence of detectable precipitins to A. [umigatus or other aspergilli should not be considered evidence against the diagnosis of ABPA. In a study using similar antigenic material for testing, approximately 10% of patients with asthma (either in London or Cleveland) without ABPA demonstrated precipitins to A. [umigatus (24). Immediate cutaneous reactivtiy to A. [umigatus was about 25% in the same patients. Measurement of total serum IgE is of major value in confirming the diagnosis of ABPA, detecting exacerbations, and in monitoring the response to prednisone administration (3). At the time of diagnosis, total serum IgE is elevated markedly in nearly all pat ients in Stages I and III (15). In patients in the other stages of ABPA, the total serum IgE may be normal to moderately elevated. Much of the elevation in total serum IgE is not directed against A. fumigatus (16). This observation is consistent with A . fumigatus stimulating "nonspecific" IgE formtion or IgE to antigens different from A. [umigatus. When IgE is determined on a serial (preferably monthly) basis, at least 100% elevations occur when ABPA exacerbations occur.
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Measurement of serum IgE-A. [umigatus, IgG-A. [umigatus, and IgA-A. fumigatus by radioimmunoassay or ELISAhas demonstrated elevations compared to serum from patients with asthma and immediate cutaneous reactivity to A. fumigatus but not ABPA (5). The differentiation of patients with mold-induced asthma from patients with ABPA may be difficult in that both patients may have had a prior pulmonary infiltrate for example. Serum antibodies to A. fumigatus are valuable in making this distinction. ABPA sera has at least twice the amount of antibody that is present in a pool of asthmatic sera (5). Serum IgE-A. fumigatus does not peak at the time of the chest roentgenographic lesion in contrast to total serum IgE; rather, the peak may occur 'several months later (3). Serum IgG-A. fumigatus peaks at the time of the ABPA exacerbation (3). Bronchoalveolar lavage (BAL) of patients with stable ABPA and no current chest roentgenographic infiltrate has revealed a divergent antibody response in terms of isotypic antibodies to A. fumigatus and total IgE (4). The ratio of BAL IgE-A. fumigatus/albumin to serum IgE-A. fumigatus/albumin was 44 and for IgA-A. fumigatus was 165 compared with an IgG-A. fumigatus ratio of 0.8 (4). These results suggest that in ABPA there is local pulmonary production of isotypic antibodies to A. fumigatus as one might expect. The low ratio for IgG-A. fumigatus could reflect the poor sampling of peripheral bronchi which contain IgG by BAL or absence of pulmonary function. In contrast, the ratio of BAL total IgE/serum IgE corrected for albumin was near unity, suggesting that the marked elevations in total serum IgE may not originate in the lung (4). ABPA patients have an array of clinical allergic diseases in most cases. ABPA serum has isotypic antibodies to A. fumigatus and may well have elevated concentrations of antibodies to other antigens as well. This is specultive now however. When in vitro basophil histamine release to A. fumigatus and other molds was determined, basophils from ABPA patients have marked hyperreactivity compared with basophils from patients with mold-sensitive asthma (19). Further, basophils from patients with Stages IV and V ABPA (more advanced disease) released a significantly greater amount of histamine to A. fumigatus than cells from patients in Stages, I, II and III. This observation was the first cellular abnormality in ABPA, and raises the question whether certain patients may be at risk of developing more advanced disease. This observation needs prospective evaluation. By use of crossed-radioimmunoelectrophoresis with ABPApatient sera, Longbottom has reported serum to serum variability in reactivity (13). Two main antigenic components were detected: 1) poorly precipitating antigens that have high IgE binding, and 2) strongly precipitating antigens that have weak IgE binding. The former were considered to be major antigens. Piechura et al. have described preparation of a cell sap antigen from three strains of A. fumigatus which has been useful as a diagnostic reagent (18). The molecular weight of the major component of this preparation was approximately 150,000. From a clinical perspective, the lack of standardization of commercial extracts used for skin testing continues to be a dilemma. Negative immediate cutaneous reactivity with presumed relevant antigens can virtually exclude the diagnosis, and in only rare cases would further serologic tests be obtained such as total serum IgE and precipitins. Immune complexes were described in one patient with an ABPA exacerbation (1) but, although local pulmonary immune complexes may contribute to lung destruction, ABPA cannot be considered a disease of circulating immune complexes analogous to
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serum sickness. An area of investigation would be the detection of Aspergillus antigens in immune complexes in the lung. McCarthy and Pepys have described that, at the time of an ABPAexacerbation, 56% of patients produced sputum plugs containing A. fumigatus (14). The repeated recovery of A. fumigatus or other Aspergillus species from sputum of asthmatic patients should raise the possibility of ABPA. Colonization of bronchi by Mycobacterium chelonei in a young woman with extensive bronchiectasis from ABPA has not resulted in dissemination over a 5-year period to date (7). It is possible that other uncommon organisms may be recovered from sputum from other ABPA patients and a decision will be necessary regarding colonization or pathogenesis when there is an associated roentgenographic lesion. In patients whose ABPA is recognized early, sputum plugs may not occur because bronchiectasis is limited. Even at times of ABPA exacerbations, there may be no sputum production of any type in these patients. T and B cell subsets in selected patients with ABPA has demonstrated normal numbers of T4 and T8 cells as well as B cells. These findings are similar to reports in patients with asthma in which no definite abnormalities have been identified. Pathologic Findings Bronchiectasis classically affects the upper lobes but we have seen lower lobe and middle lobe involvement by ABPA. The pattern of bronchiectasis is that of proximal saccular dilation in contrast to obliterative changes or distal bronchiectasis that follows bacterial pneumonias. In spite of colonization of bronchial mucus by A. [umigatus, tissue invasion does not occur. The doses of prednisone used for treatment of ABPAare not great and do not result in serious infections. Although daily prednisone has been shown to result in resolution of the roentgenographic lesion (23), alternate day prednisone has proven useful and has been recommended for patients with ABPA (3). Some of the morphologic diagnoses that have been made in ABPA and which should raise the possibility of ABPA in undiagnosed patients include eosinophilic pneumonia, mucoid impaction syndrome, granulomatous bronchiolitis, lipid pneumonia, desquamative or lymphocytic interstitial pneumonia, vasculitis, and end-stage fibrotic lung disease (3). From a clinical perspective, patients with these diagnoses may satisfy all the diagnostic criteria for ABPA and should be treated as such. In patients who do not have ABPA, a recently recognized syndrome called "allergic Aspergillus sinusitis" has been described (11). Patients have a history of asthma but present with complaints from chronic sinusitis and nasal polyposis. The mucinous material recovered during sinus drainage procedures resembled mucoid impactions that occur in the bronchi of patients with ABPA. The mucin contained eosinophils, Charcot-Leyden crytals, and fungal hyphae resembling Aspergillus species. Tissue invasion did not occur. Serum precipitins were identified in six of seven patients, but elevated IgE-A. fumigatus and IgG-A. fumigatus as in ABPA were not present. The serologic pattern was analogous to that of aspergilloma. The optimal approach for management of this syndrome has yet to be established but may be that of surgical drainage and topical nasal corticosteroids. It is speculative whether any of these patients will evolve into ABPA.
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References
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Paul A. Greenberger, M. D., 303 East Chicago Avenue, Chicago, Illinois 60611, U.S.A.