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Allergic Bronchopulmonary Penicilliosis
286
SAHN, LAKSHMINARAYAN
drome and pleural effusion have been observed.e' The large accumulation of contrast material (Fig 4) around the epicardial implantation site suggests an abscess cavity that burrowed first to the skin and then to the bronchi. The draining cutaneous fistula was present for several years before symptoms of bronchopleural fistula were evident. In recommending surgical removal of the epicardial electrode it was our opinion that removal could be accomplished by exposing the electrode in the subcutaneous position and extracting by gentle traction. It was expected that by removing the infected prostheses and establishing adequate drainage that the fistulous tract to the bronchus would close and thus eliminate the productive purulent coughing. REFERENCES
1 Sowton E: Artificial cardiac pacemaking, with particular reference to cardiac physiology. MD Thesis, University of Cambridge, 1963 2 Siddons H, Sowton E: Cardiac Pacemakers. Springfield, Ill, Charles C Thomas Publishers. 1967 3 Furman S: Complications of pacemaker therapy for heart block. Am J CardioI17:439, 1966 4 Chardack WM: Cardiac pacemakers and heart block. In Surgery of the Chest, (ed 2) Philadelphia, W. B. Saunders Company, 1969
Allergic Bronchopulmonary Penicilliosis* Steven A. Sahn, M.D.,oO and S. Lakshminarayan, M.B.O.
A case of allergic broncbopulmonary disease caused by tbe fungus Penicillium witb intermittent airways obstruction, transient pulmonary infiltrate, blood and sputum eosinopbUia, positive dual skin tests (type I and DI) and precipitating antibodies in tbe serum is described. An Artbus skin reaction was e6cited and supported by bistologic and immunofluorescence studies. Broncbial bygiene alone was effective in treatment. The possibility of otber airborne fungal spores causing a similar disease is empbasized.
T
he importance of airborne fungal spores causing pulmonary disease in man is now established.' This is especially true of the Aspergillus genus which has been reported to cause asthma, allergic bronchopulmonary disease, aspergilloma and disseminated aspergillosis.s-s In view of the proposed pathogenesis of allergic bronchopulmonary aspergillosis, 1 it would be reasonable to postulate a similar entity being caused by other fungi. °From the Division of Pulmonary Diseases, Department of Medicine, University of Colorado Medical Center, Denver. .oFellow in Pulmonary Diseases, University of Colorado Medical Center, Denver. Reprint requests: Steven A. Sahn, M.D., Division of Pulmonary Diseases, Department of Medicine, University of Colorado Medical Center, 4200 East Ninth Avenue, Denver, Colorado 80220.
FIGURE 1. Admission chest x-ray mm (August 10, 1971). Note infiltrate in the right upper zone. Also note right paracardiac density due to severe pectus excavatum. The Penicillium genus has been reported to cause invasive bronchopulmonary and disseminated disease in man." The first case of Penicillium genus causing pulmonary disease in man was reported in 1918. 5 Other authors have also reported this fungus as the etiologic agent of disease in the lung as well as in other organ systems.t-" However, to our knowledge, a disease similar to allergic bronchopulmonary aspergillosis caused by the fungus Penicillium has not yet been reported. We have recently had the opportunity to study a patient with findings compatible with allergic bronchopulmonary disease presumably caused by Penicillium. CASE REPORT
A 76-year-old Caucasian prospector was admitted to the Denver Veterans Administration Hospital on August 10, 1971, with a five-month history of dyspnea on exertion, productive cough and wheezing. The patient had previously been in excellent health with no pulmonary symptoms and was a nonsmoker. He gave no history of atopic disease or aspirin intolerance. In the two months preceding admission, the patient coughed up brownish plugs in his sputum. Physical examination revealed a well-developed man with paroxysms of coughing. The nasal mucosa was normal and no polyps were noted. Examination of the thorax revealed 'marked pectus excavatum. Diffuse rhonchi and wheezes were noted bilaterally. The remainder of the examination was within normal limits. Laboratory data revealed a hematocrit of 45 percent and the leukocyte count was 8700/mm3 with 11 percent eosinophils, 63 percent neutrophils and 22 percent lymphocytes. VDRL, RA latex, LE preparation and antinuclear antibody tests all gave negative results. Stools for ova and parasites were negative on numerous occasions.
CHEST, VOL. 63, NO.2, FEBRUARY, 1973
ALLERGIC BRONCHOPULMONARY PENICILLIOSIS Pulmonary function tests on admission revealed a vital capacity of 3.7 liters (4.2 predicted), a FEV! of 2.2 liters (3.0 predicted), a MMEF of 1.2 liters per second (3.1 predicted), and a MVV of 115 liters per minute (125 predicted). Arterial blood gases breathing room air were P02 66 mm Hg, PC02 31 mm Hg, and pH 7.45. 0 Multiple sputum collections were negative on both smear and culture for AFB and sterile for bacteria on culture. Microscopy of the sputum revealed numerous leukocytes, 98 percent of which were eosinophils. Six sputum specimens revealed the genus Penicillium on culture; these were divaricate and asymmetrical in morphology. Based on morphologic characteristics of the mycelial phase, the Penicillium was speciated as P rubrum. However, as the speciation is based solely on morphology it may not be consistently reproducible." Chest fllm on admission revealed an inflltrate in the right upper lung field (Fig 1). A repeat chest film done 13 days later demonstrated complete clearing of the right upper zone infiltrate. During the interim, the patient had coughed up a large brown plug which on sectioning and silver staining revealed numerous mycelia, and on culture grew Penicillium. A bronchogram performed on August 25, 1971 revealed proximal saccular bronchiectasis of the medium-sized bronchi of the right upper lobe (Fig 2), but normal peripheral filling was not demonstrated. Skin tests were applied by the intracutaneous technique to both the patient and a control. Mixed Penicillium extract 0.02 ml of 200 PNU/ml was used.t " The intracutaneous test in the patient revealed a 9 mm immediate wheal with surrounding flare and 15 mm of induration at five hours. No reaction was noted at 48 and 72 hours. The control subject showed a 2 mm immediate wheal and no reaction at 5, 48 and 72 hours.
Special Studies
287
FIGURE 2. Bronchogram (August 25, 1971) showing saccular bronchiectasis of the medium-sized bronchi in the anterior segment of the upper right lobe. ulized isoetharine and water followed by steam and postural drainage four times daily. Under this regimen, large amounts of brownish sputum, including numerous plugs, were expec-
Three mm punch biopsies were taken from the site of the skin test from both the patient and the control at five hours. The patient's biopsy revealed perivascular infiltration with neutrophils, mononuclears and eosinophils compatible with an Arthus reaction. The control biopsy revealed minimal nonspecific changes. The biopsy material from the patient was also stained for immunofluorescence with an anti-IgG and an anti-Cs complement after pretreatment of the sections with whole goat serum to minimize nonspecific fluorescence. The sections demonstrated perivascular fluorescence which was suggestive of an Arthus reaction. s The patient's undiluted serum was studied by double immunodiffusion employing the standard Ouchterlony technique.v It was diffused against extracts of six different species of Penicilliumt (P claviforme, P ienseni, P digitatum, P chrysogenus, P rubrum and P glaucum) at a concentration of 20 mg/ml. Precipitin arcs were demonstrable against P digitatum and P rubrum only (Fig 3). The patient's serum was also diffused against an extract of Aspergillus fumigatus and no precipitation arc was demonstrable. Control serum from a normal subject did not reveal any precipitation arcs.
Clinical Course During the patient's 29 day hospital stay, he was treated with bronchial hygiene, consisting of the inhalation of neb°Normal values for Denver, P02 70 to 75 mm Hg; Pco233 to 37 mm Hg. oOCenter Laboratories, Port Washington, New York. tMeridian Laboratories, Denver, Colorado.
CHEST, VOL. 63, NO.2, FEBRUARY, 1973
FIGURE 3. Double diffusion tests of patient's undiluted serum against extracts of six species of penicillium: 1) P. calviforme, 2) P ienseni, 3) P digitatum, 4) P chrueogenum, 5) P rubrum, 6) P glaucom. Note precipitation arcs to P digitatum and Prubrum.
288
SAHN, LAKSHMINARAYAN
torated. The patient had improved symptomatically by the time of discharge with diappearance of dyspnea, productive cough and wheezing. His chest had become clear on physical examination and the chest film had returned to normal. Pulmonary function tests had improved slightly: the vital capacity was 3.9 liters, the FEV 1 was 2.8 liters, the MMEF 2.4 liters per second and the MVV 120 liters per minute. Penicillium could no longer be cultured from the sputum after 20 days. In view of the patient's significant improvement and asymptomatic state, it was decided not to use corticosteroids or antifungal agents. He was discharged on a regimen of bronchial hygiene. DISCUSSION
Aspergillus can cause both an al1ergic type I and IIp·I0 reaction in the lung. We believe that our case represents both types of reaction caused by the fungus Penicillium, The features observed in this case-I) intermittent airways obstruction, 2) transient pulmonary infiltrate, 3) blood and sputum eosinophilia, 4) positive dual skin tests (type I and III), and 5) precipitins to the fungus in the serum-clearly fit the diagnostic criteria established for al1ergic bronchopulmonary aspergillosis," In al1ergic aspergillosis, due to A fumigatus, the precipitins have been shown to cross react with other species of Aspergillus. 1 Furthermore, gel filtration of the Aspergillus extract has been shown to consist of three separate fractions, each with different capacities to form precipitation arcs.' Our patient demonstrated precipitating antibodies to two species of Penicillium, which may represent cross reactivity between the various species. Scadding!' has described proximal saccular bronchiectasis as being characteristic of allergic bronchopulmonary aspergil1osis. This was noted in our patient in the' same segment that had contained the infiltrate. It has been suggested that this is due to an Arthus reaction in the bronchial wall causing local irreversible tissue darnage.!' Corticosteroids have been used with success in the treatment of allergic bronchopulmonary aspergtllosis.P the effect being a reduction in the purulent eosinophilcontaining sputum from which the fungus is usually easily cultured. The frequent swift disappearance of the fungus from the sputum in steroid treated patients lends credence to the concept that an allergic reaction is responsible for the retention of the spores in the bronchial tree with resultant bronchial wall damage. Corticosteroids are also capable of inhibiting the Arthus reaction in the skin 1 8 and have been effective in resolving pulmonary infiltrates. 12 , 14 These facts suggest that one of the pathogenetic mechanisms in allergic aspergillosis in the bronchial walls is analagous to the mechanism in the skin-the Arthus reaction. The possibility of a type IV reaction operating in the pathogenesis of allergic aspergillosis has been suggested.P but in the present case, no evidence of a delayed hypersensitivity reaction was found to the skin test. Antifungal therapy has been primarily used for invasive aspergillosis and aspergillomas." Intravenous
amphotericin B, local instillation of amphotericin B and inhalation of nystatin and amphotericin B have not been very encouraging in the treatment of various forms of aspergillosis except for isolated reports.> In our patient, bronchial hygiene without the use of corticosteroids or antifungal agents was effective in abating all manifestations of the disease. In light of our experience with a previously unreported fungus causing allergic bronchopulmonary disease in man, we suggest that the possibility of other airborne fungal spores causing similar disease should be borne in mind. ACKNOWLEDGMENTS: We thank Thomas L. Petty, M.D., Roger S. Mitchell, M.D. and Richard S. Farr, M.D., for reviewing the manuscript. We also thank George Ward, M.D. for help with the immunologic studies. REFERENCES
1 Pepys J: Hypersensitivity Diseases of the Lung Due to Fungi and Organic Dusts. New York, S. Karger, 1969, pp 20-131 2 Pepys J, Ridell RW, Citron KM, et al: Clinical and immunologic significance of Aspergillus fumigatus in the sputum. Am Rev Resp Dis 80:167-180,1959 3 Young RC, Bennett JE, Vogel CL, et al: Aspergillosis-the spectrum of the disease in 98 patients. Medicine 49: 147173, 1970 4 Huang S, Harris LS: Acute disseminated penicilliosis. Am J Clin Path 39:167-174,1963 5 Ciodano M: Un cas die micosi polmonare da "penicillium glaucum." Ann Med Nav Roma 2:912-917, 1918 6 Delore P, Coudert J, Lambert R, et al: Un cas de mycose bronchique avec localisation musculaires septicemiques. Presse Med 63:1580-1582,1955 7 Raper KB, Thorn C: Manual of the Penicillia. Baltimore, Williams and Wilkins Co, 1949 8 Pepys J, Turner-Warwick M, Dawson PL, et al: Arthus (type II' skin test reactions in man. Clinical and immunopathological features. Excerpta Medica Foundation, No. 162, pp 221-235, 1968 9 Ouchterlony 0: Diffusion-in-gel methods for immunologic analysis. II. Progr Allergy vol 6, pp 30-154 (Karger, Basel, Switzerland) 1962 10 Coombs RRA, Cell PGH: Classification of allergic reactions responsible for clinical hypersensitivity and disease. In Clinical Aspects of Immunology. Second edition. Cell PGH, Coombs RRA (eds ). Philadelphia, FA Davis, 1968, pp575-596 11 Scadding JG: The bronchi in allergic aspergillosis. Scand J Resp Dis 48: 372-377, 1967 12 McCarthy DS, Pepys J: Allergic bronchopulmonary aspergillosis. Clin Allergy 1:261-286, 1971 13 Goldstein GB, Yokoyama M: Studies on the dual antibody response in allergic bronchopulmonary asperigillosis. J Allergy 46:34-351, 1970 14 Slavin RG, Million L, Cherry J: Allergic bronchopulmonary aspergillosis: Characterization of antibodies and results of treatment. J Allergy 46: 150-155, 1970 15 Chan Yeung M, Chase WH, Trapp W, et al: Allergic bronchopulmonary aspergillosis. Chest 59:33-39, 1971
CHEST, VOL. 63, NO.2, FEBRUARY, 1973
SAHN, LAKSHMINARAYAN
drome and pleural effusion have been observed.e' The large accumulation of contrast material (Fig 4) around the epicardial implantation site suggests an abscess cavity that burrowed first to the skin and then to the bronchi. The draining cutaneous fistula was present for several years before symptoms of bronchopleural fistula were evident. In recommending surgical removal of the epicardial electrode it was our opinion that removal could be accomplished by exposing the electrode in the subcutaneous position and extracting by gentle traction. It was expected that by removing the infected prostheses and establishing adequate drainage that the fistulous tract to the bronchus would close and thus eliminate the productive purulent coughing. REFERENCES
1 Sowton E: Artificial cardiac pacemaking, with particular reference to cardiac physiology. MD Thesis, University of Cambridge, 1963 2 Siddons H, Sowton E: Cardiac Pacemakers. Springfield, Ill, Charles C Thomas Publishers. 1967 3 Furman S: Complications of pacemaker therapy for heart block. Am J CardioI17:439, 1966 4 Chardack WM: Cardiac pacemakers and heart block. In Surgery of the Chest, (ed 2) Philadelphia, W. B. Saunders Company, 1969
Allergic Bronchopulmonary Penicilliosis* Steven A. Sahn, M.D.,oO and S. Lakshminarayan, M.B.O.
A case of allergic broncbopulmonary disease caused by tbe fungus Penicillium witb intermittent airways obstruction, transient pulmonary infiltrate, blood and sputum eosinopbUia, positive dual skin tests (type I and DI) and precipitating antibodies in tbe serum is described. An Artbus skin reaction was e6cited and supported by bistologic and immunofluorescence studies. Broncbial bygiene alone was effective in treatment. The possibility of otber airborne fungal spores causing a similar disease is empbasized.
T
he importance of airborne fungal spores causing pulmonary disease in man is now established.' This is especially true of the Aspergillus genus which has been reported to cause asthma, allergic bronchopulmonary disease, aspergilloma and disseminated aspergillosis.s-s In view of the proposed pathogenesis of allergic bronchopulmonary aspergillosis, 1 it would be reasonable to postulate a similar entity being caused by other fungi. °From the Division of Pulmonary Diseases, Department of Medicine, University of Colorado Medical Center, Denver. .oFellow in Pulmonary Diseases, University of Colorado Medical Center, Denver. Reprint requests: Steven A. Sahn, M.D., Division of Pulmonary Diseases, Department of Medicine, University of Colorado Medical Center, 4200 East Ninth Avenue, Denver, Colorado 80220.
FIGURE 1. Admission chest x-ray mm (August 10, 1971). Note infiltrate in the right upper zone. Also note right paracardiac density due to severe pectus excavatum. The Penicillium genus has been reported to cause invasive bronchopulmonary and disseminated disease in man." The first case of Penicillium genus causing pulmonary disease in man was reported in 1918. 5 Other authors have also reported this fungus as the etiologic agent of disease in the lung as well as in other organ systems.t-" However, to our knowledge, a disease similar to allergic bronchopulmonary aspergillosis caused by the fungus Penicillium has not yet been reported. We have recently had the opportunity to study a patient with findings compatible with allergic bronchopulmonary disease presumably caused by Penicillium. CASE REPORT
A 76-year-old Caucasian prospector was admitted to the Denver Veterans Administration Hospital on August 10, 1971, with a five-month history of dyspnea on exertion, productive cough and wheezing. The patient had previously been in excellent health with no pulmonary symptoms and was a nonsmoker. He gave no history of atopic disease or aspirin intolerance. In the two months preceding admission, the patient coughed up brownish plugs in his sputum. Physical examination revealed a well-developed man with paroxysms of coughing. The nasal mucosa was normal and no polyps were noted. Examination of the thorax revealed 'marked pectus excavatum. Diffuse rhonchi and wheezes were noted bilaterally. The remainder of the examination was within normal limits. Laboratory data revealed a hematocrit of 45 percent and the leukocyte count was 8700/mm3 with 11 percent eosinophils, 63 percent neutrophils and 22 percent lymphocytes. VDRL, RA latex, LE preparation and antinuclear antibody tests all gave negative results. Stools for ova and parasites were negative on numerous occasions.
CHEST, VOL. 63, NO.2, FEBRUARY, 1973
ALLERGIC BRONCHOPULMONARY PENICILLIOSIS Pulmonary function tests on admission revealed a vital capacity of 3.7 liters (4.2 predicted), a FEV! of 2.2 liters (3.0 predicted), a MMEF of 1.2 liters per second (3.1 predicted), and a MVV of 115 liters per minute (125 predicted). Arterial blood gases breathing room air were P02 66 mm Hg, PC02 31 mm Hg, and pH 7.45. 0 Multiple sputum collections were negative on both smear and culture for AFB and sterile for bacteria on culture. Microscopy of the sputum revealed numerous leukocytes, 98 percent of which were eosinophils. Six sputum specimens revealed the genus Penicillium on culture; these were divaricate and asymmetrical in morphology. Based on morphologic characteristics of the mycelial phase, the Penicillium was speciated as P rubrum. However, as the speciation is based solely on morphology it may not be consistently reproducible." Chest fllm on admission revealed an inflltrate in the right upper lung field (Fig 1). A repeat chest film done 13 days later demonstrated complete clearing of the right upper zone infiltrate. During the interim, the patient had coughed up a large brown plug which on sectioning and silver staining revealed numerous mycelia, and on culture grew Penicillium. A bronchogram performed on August 25, 1971 revealed proximal saccular bronchiectasis of the medium-sized bronchi of the right upper lobe (Fig 2), but normal peripheral filling was not demonstrated. Skin tests were applied by the intracutaneous technique to both the patient and a control. Mixed Penicillium extract 0.02 ml of 200 PNU/ml was used.t " The intracutaneous test in the patient revealed a 9 mm immediate wheal with surrounding flare and 15 mm of induration at five hours. No reaction was noted at 48 and 72 hours. The control subject showed a 2 mm immediate wheal and no reaction at 5, 48 and 72 hours.
Special Studies
287
FIGURE 2. Bronchogram (August 25, 1971) showing saccular bronchiectasis of the medium-sized bronchi in the anterior segment of the upper right lobe. ulized isoetharine and water followed by steam and postural drainage four times daily. Under this regimen, large amounts of brownish sputum, including numerous plugs, were expec-
Three mm punch biopsies were taken from the site of the skin test from both the patient and the control at five hours. The patient's biopsy revealed perivascular infiltration with neutrophils, mononuclears and eosinophils compatible with an Arthus reaction. The control biopsy revealed minimal nonspecific changes. The biopsy material from the patient was also stained for immunofluorescence with an anti-IgG and an anti-Cs complement after pretreatment of the sections with whole goat serum to minimize nonspecific fluorescence. The sections demonstrated perivascular fluorescence which was suggestive of an Arthus reaction. s The patient's undiluted serum was studied by double immunodiffusion employing the standard Ouchterlony technique.v It was diffused against extracts of six different species of Penicilliumt (P claviforme, P ienseni, P digitatum, P chrysogenus, P rubrum and P glaucum) at a concentration of 20 mg/ml. Precipitin arcs were demonstrable against P digitatum and P rubrum only (Fig 3). The patient's serum was also diffused against an extract of Aspergillus fumigatus and no precipitation arc was demonstrable. Control serum from a normal subject did not reveal any precipitation arcs.
Clinical Course During the patient's 29 day hospital stay, he was treated with bronchial hygiene, consisting of the inhalation of neb°Normal values for Denver, P02 70 to 75 mm Hg; Pco233 to 37 mm Hg. oOCenter Laboratories, Port Washington, New York. tMeridian Laboratories, Denver, Colorado.
CHEST, VOL. 63, NO.2, FEBRUARY, 1973
FIGURE 3. Double diffusion tests of patient's undiluted serum against extracts of six species of penicillium: 1) P. calviforme, 2) P ienseni, 3) P digitatum, 4) P chrueogenum, 5) P rubrum, 6) P glaucom. Note precipitation arcs to P digitatum and Prubrum.
288
SAHN, LAKSHMINARAYAN
torated. The patient had improved symptomatically by the time of discharge with diappearance of dyspnea, productive cough and wheezing. His chest had become clear on physical examination and the chest film had returned to normal. Pulmonary function tests had improved slightly: the vital capacity was 3.9 liters, the FEV 1 was 2.8 liters, the MMEF 2.4 liters per second and the MVV 120 liters per minute. Penicillium could no longer be cultured from the sputum after 20 days. In view of the patient's significant improvement and asymptomatic state, it was decided not to use corticosteroids or antifungal agents. He was discharged on a regimen of bronchial hygiene. DISCUSSION
Aspergillus can cause both an al1ergic type I and IIp·I0 reaction in the lung. We believe that our case represents both types of reaction caused by the fungus Penicillium, The features observed in this case-I) intermittent airways obstruction, 2) transient pulmonary infiltrate, 3) blood and sputum eosinophilia, 4) positive dual skin tests (type I and III), and 5) precipitins to the fungus in the serum-clearly fit the diagnostic criteria established for al1ergic bronchopulmonary aspergillosis," In al1ergic aspergillosis, due to A fumigatus, the precipitins have been shown to cross react with other species of Aspergillus. 1 Furthermore, gel filtration of the Aspergillus extract has been shown to consist of three separate fractions, each with different capacities to form precipitation arcs.' Our patient demonstrated precipitating antibodies to two species of Penicillium, which may represent cross reactivity between the various species. Scadding!' has described proximal saccular bronchiectasis as being characteristic of allergic bronchopulmonary aspergil1osis. This was noted in our patient in the' same segment that had contained the infiltrate. It has been suggested that this is due to an Arthus reaction in the bronchial wall causing local irreversible tissue darnage.!' Corticosteroids have been used with success in the treatment of allergic bronchopulmonary aspergtllosis.P the effect being a reduction in the purulent eosinophilcontaining sputum from which the fungus is usually easily cultured. The frequent swift disappearance of the fungus from the sputum in steroid treated patients lends credence to the concept that an allergic reaction is responsible for the retention of the spores in the bronchial tree with resultant bronchial wall damage. Corticosteroids are also capable of inhibiting the Arthus reaction in the skin 1 8 and have been effective in resolving pulmonary infiltrates. 12 , 14 These facts suggest that one of the pathogenetic mechanisms in allergic aspergillosis in the bronchial walls is analagous to the mechanism in the skin-the Arthus reaction. The possibility of a type IV reaction operating in the pathogenesis of allergic aspergillosis has been suggested.P but in the present case, no evidence of a delayed hypersensitivity reaction was found to the skin test. Antifungal therapy has been primarily used for invasive aspergillosis and aspergillomas." Intravenous
amphotericin B, local instillation of amphotericin B and inhalation of nystatin and amphotericin B have not been very encouraging in the treatment of various forms of aspergillosis except for isolated reports.> In our patient, bronchial hygiene without the use of corticosteroids or antifungal agents was effective in abating all manifestations of the disease. In light of our experience with a previously unreported fungus causing allergic bronchopulmonary disease in man, we suggest that the possibility of other airborne fungal spores causing similar disease should be borne in mind. ACKNOWLEDGMENTS: We thank Thomas L. Petty, M.D., Roger S. Mitchell, M.D. and Richard S. Farr, M.D., for reviewing the manuscript. We also thank George Ward, M.D. for help with the immunologic studies. REFERENCES
1 Pepys J: Hypersensitivity Diseases of the Lung Due to Fungi and Organic Dusts. New York, S. Karger, 1969, pp 20-131 2 Pepys J, Ridell RW, Citron KM, et al: Clinical and immunologic significance of Aspergillus fumigatus in the sputum. Am Rev Resp Dis 80:167-180,1959 3 Young RC, Bennett JE, Vogel CL, et al: Aspergillosis-the spectrum of the disease in 98 patients. Medicine 49: 147173, 1970 4 Huang S, Harris LS: Acute disseminated penicilliosis. Am J Clin Path 39:167-174,1963 5 Ciodano M: Un cas die micosi polmonare da "penicillium glaucum." Ann Med Nav Roma 2:912-917, 1918 6 Delore P, Coudert J, Lambert R, et al: Un cas de mycose bronchique avec localisation musculaires septicemiques. Presse Med 63:1580-1582,1955 7 Raper KB, Thorn C: Manual of the Penicillia. Baltimore, Williams and Wilkins Co, 1949 8 Pepys J, Turner-Warwick M, Dawson PL, et al: Arthus (type II' skin test reactions in man. Clinical and immunopathological features. Excerpta Medica Foundation, No. 162, pp 221-235, 1968 9 Ouchterlony 0: Diffusion-in-gel methods for immunologic analysis. II. Progr Allergy vol 6, pp 30-154 (Karger, Basel, Switzerland) 1962 10 Coombs RRA, Cell PGH: Classification of allergic reactions responsible for clinical hypersensitivity and disease. In Clinical Aspects of Immunology. Second edition. Cell PGH, Coombs RRA (eds ). Philadelphia, FA Davis, 1968, pp575-596 11 Scadding JG: The bronchi in allergic aspergillosis. Scand J Resp Dis 48: 372-377, 1967 12 McCarthy DS, Pepys J: Allergic bronchopulmonary aspergillosis. Clin Allergy 1:261-286, 1971 13 Goldstein GB, Yokoyama M: Studies on the dual antibody response in allergic bronchopulmonary asperigillosis. J Allergy 46:34-351, 1970 14 Slavin RG, Million L, Cherry J: Allergic bronchopulmonary aspergillosis: Characterization of antibodies and results of treatment. J Allergy 46: 150-155, 1970 15 Chan Yeung M, Chase WH, Trapp W, et al: Allergic bronchopulmonary aspergillosis. Chest 59:33-39, 1971
CHEST, VOL. 63, NO.2, FEBRUARY, 1973