Allergic Bronchopulmonary Aspergillosis

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Allergic Bronchopulmonary Aspergillosis· Anthony]. Ricketti, M. D., F. C. C. P.; Paul A Greenberger, M. D.; Richard A Mintzer, M.D., F.C.C.P.; and Roy Patterson, M.D.

he first three cases of allergic bronchopulmonary T aspergillosis (ABPA) were diagnosed in England in

1952. 1 These patients were described as having recurrent episodes of "wheezy" bronchitis, peripheral blood eosinophilia, fever, sputum production, roentgenographic infiltrates, and bronchial plugging by secretions containing Aspergillus fumigatus (Af) hyphae. By 1969, Pepys" and Henderson et al" reported series of cases of ABPA, and the interest in this disease increased. In fact, Henderson et al noted that up to 20 percent of asthmatic patients admitted to the hospital for chronic pulmonary disease in England may have ABPA. The first case of ABPA in the United States was found in 1968,4 and the first childhood case in the United States was reported in 1970.5 Although at first considered rare in the United States," over the next 15 years, numerous cases of ABPA have been reported in both the adult and pediatric population, and interest has grown in the United States. ;.8 The marked increase in proven cases can be attributed to increased awareness by physicians of ABPA, improved diagnostic criteria for identifying the disease, and serologic techniques to help confirm the diagnosis. CLINICAL FINDINGS

Diagnostic Criteria

The clinical diagnostic features of ABPA include the following: (1) asthma; (2) blood eosinophilia (> 1,000/ cu mm); (3) immediate cutaneous reactivity to Af antigen; (4) precipitating antibodies against Afantigen; (5) elevated serum IgE concentration; (6) history of roentgenographic infiltrates (transient or fixed); (7) central bronchiectasis; and (8) elevated serum IgE and IgG antibodies to Af(compared with asthmatic patients with immediate cutaneous reactivity to Af).9.10 Other features may include positive result of sputum culture of AI: a history of expectoration of golden-brown plugs, *From the Section of Allergy-Immunology, Department of Medicine and the Department of Radiology, Northwestern University Medical School, Chicago. Supported by NIH Grant AI 11403, Ernest S. Bazley Grant and the Chicago Lung Association. Reprint requests: Dr. Greenberger, 303 East Chicago Avenue, Chicago 60611

and late (arthus-type) skin reactivity to intracutaneous testing with Af antigen. Another diagnostic aid is the fall in total IgE after institution of prednisone. 11 The total IgE should fall at least 35 percent by two months. Some patients, often children, with ABPA may not demonstrate peripheral blood eosinophilia or have a history of roentgenographic infiltrates because of the recent onset of ABPA. In these patients, bronchiectasis may be minimal. Mycology

Aspergillus species are ubiquitous in nature and large numbers of conidia or spores are dispersed in the air so that inhalation is inescapable. Aspergillus species multiply by growth of bunching hyphae or by bud formation with production of spore-forming conidiophores. The spores can be captured simply by exposing Sabarouds culture plates to air. Although Aspergillus can be identified in tissue by routine hematoxylin and eosin staining, identification and morphology are better appreciated using periodic acid-Schiff and silver staining. The hyphae are 7 to 10 urn in diameter, septate, branch at 450 angles, and often assume a radial arrangement when found in free spaces. The Aspergillus species, particularly Aspergillus flavus and AI: produce a number of toxic metabolites of which aflatoxin is the most widely known. Other toxic substances still poorly understood include a bacteriostatic exotoxin and an endotoxin thought to produce local disturbances in hemostasis. 12 Aspergillosis is common in turkey poults and can cause mortality of 5-10 percent in production flocks. 13 Aspergillus flavus and Aspergillus fumigatus have been incriminated in avian aspergillosis. Description of Patients

Patients with ABPAcommonly demonstrate marked immediate skin reactivity to AI: other molds, and inhalant antigens. They also commonly have other clinical allergic features such as allergic rhinitis, allergic conjunctivitis, atopic eczema, urticaria, anaphyCHEST / 86 / 5 / NOVEMBER. 1984

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laxis, and in particular, food allergy." In the United States, these clinical allergic diseases have been recognized regardless of the age of onset of asthma. However, in England, McCarthy and Pepys" reported two subsets of ABPA patients based on the patient's age of onset of asthma or eosinophilia. They were able to show that patients with the onset of asthma before the age of 30 had greater skin reactivity to other common allergens and showed additional features of allergic disease such as eczema and allergic rhinitis. However, patients with the onset of asthma after age 30 generally had less cutaneous skin reactivity to common allergens and no other clinical symptom suggesting allergic disease. They identified patients with ABPA who had isolated skin reactivity to At: At present, it is unknown why these discrepancies exist between England and the United States. Natural History Five stages have been identified in patients with ABPA. The stages are acute, remission, recurrent exacerbation, corticosteroid-dependent asthma, and fibrosis." The acute stage is characterized by the classic signs, symptoms, and laboratory findings present at diagnosis. The remission stage is characterized by a clearing of roentgenographic lesions, a decline in total serum IgE, control of respiratory symptoms, and a discontinuation of corticosteroid therapy over a sixmonth period without recurrence of ABPA. Prolonged and permanent remissions may occur after treatment of the acute stage with corticosteroids, and maintenance oral corticosteroids are not required in these patients. In some patients asthma may become refractory to theophylline, beta agonists and cromolyn and beclomethasone dipropionate by inhalation may be necessary. A prolonged remission does not imply a permanent remission, as an exacerbation has been documented after a remission of 7Y2 years. 17 The exacerbation stage occurs when patients demonstrate all characteristics of the acute stage or when patients experience a twofold rise in the total serum IgE level in association with a new roentgenographic infiltrate in the absence of other causes of the infiltrate (bacterial, viral pneumonia, etc). Remission after an exacerbation is induced with corticosteroids; prolonged corticosteroid therapy is not required in these patients. The corticosteroid-dependent asthma stage is present when patients require oral corticosteroids to control either asthma or to prevent recurrent exacerbations of ABPAor both. The dose of oral corticosteroids needed to control asthma usually is insufficient for preventing exacerbations of ABPA. At times, it may be difficult to distinguish between an exacerbation of asthma, a flare in ABPA, or the occurrence of both. In one patient observed by us for ten years, pro774

gression through four stages has been observed: acute, remission, recurrent exacerbation, and corticosteroiddependent asthma. Despite roentgenographic lesions during exacerbations, this patient has a normal chest roentgenogram, pulmonary function, and exercise tolerance. The fibrotic lung disease stage of ABPA is present when there are extensive fibrotic changes on chest roentgenograms with irreversible obstructive lung disease by pulmonary testing. Neither the pulmonary lesions nor the pulmonary function abnormalities reverse completely with high-dose prednisone therapy. In some patients, a reversible obstructive component may be present, and in these patients, high-dose corticosteroid therapy often is required. Cor pulmonale, respiratory failure, and death may occur in some patients from ABPA. 18 ABPA may precede the clinical recognition of the disease for many years. In many patients, a history of asthma and peripheral eosinophilia with documented roentgenographic infiltrates started in childhood or adolescence and preceded the diagnosis of ABPA by ten to 30 years. Irreversible lung damage from ABPA may have occurred before patients sought medical attention. Because of the indolent nature of this disease, it is not unusual to diagnose ABPAduring the corticosteroid-dependent asthma stage of ABPA. In a retrospective analysis of 42 corticosteroid-dependent asthmatic patients, Basich et al" found three cases of definite and three of probable ABPA. These patients were atopic, young, and required high doses of corticosteroids to control their asthma. However, some patients may have ABPA and have minimal asthma controlled by intermittent or daily administration of bronchodilators. Therefore, we have routinely performed further immunologic studies in all patients with asthma and immediate cutaneous reactivity to Af in an attempt to identify patients with ABPA in an early stage and possibly prevent the progression of ABPA to corticosteroid-dependent asthma and/or fibrosis. Radiology The roentgenographic changes in ABPA may be transient or permanent. iO Transient roentgenographic changes, which may clear with or without corticosteroid therapy, appear to be the result of parenchymal infiltrates, mucoid impactions, or secretions in damaged bronchi. These transient findings include the following: (1) perihilar infiltrates simulating adenopathy; (2) air-fluid levels from dilated central bronchi filled with fluid and debris; (3) massive homogenous consolidation that may be unilateral or bilateral; (4) roentgenographic in6ltrates; (5) "toothpaste" shadows that result from mucoid impactions in damaged bronchi; (6)"gloved-finger" shadows from distally occluded bronchi filled with secretions; and (7) tramline shadAllergIc8IonchopuImonary Aspergillosis (Riclcetfi et 1M)

ows, which are two parallel hairline shadows extending out from the hilum. Permanent roentgenographic findings include proximal bronchiectasis, parallel line shadows, and ring shadows. Parallel line shadows are dilated tramline shadows resulting from bronchiectasis. The ring shadows are dilated bronchi en face. Normal findings on chest roentgenogram do not exclude the diagnosis of ABPA,21 and tomography or bronchography of the lungs should be performed when the suspicion of ABPAis high. Bronchography must be done with very great caution in patients suspected of having ABPA. Some late roentgenographic findings in ABPAinclude cavitation, local emphysema, contracted upper lobes, and honeycomb fibrosis." Occasionally one may see total lung collapse secondary to mucoid impaction of the major bronchi. 23 Rarely, spontaneous pneumothorax may be seen in far-advanced ABPA, especially when bullous changes in the lungs are present. 24

Pathologic Findings With improved diagnostic criteria for identifying the disease, the need for lung biopsy specimens to confirm ABPA has become less important. Lung biopsy is not necessary because the diagnosis is now made on clinical, serologic and roentgenographic findings. Histologically, bronchi contain tenacious mucus, fibrin, Curschmanns spirals, Charcot-Leyden crystals, eosinophils, and mononuclear cells. Fungal hyphae may be seen in the bronchial lumen, and Aspergillus can be isolated in culture. Despite numerous hyphae in the lumen, there is no invasion of the bronchial wall. Other morphologic lesions described in patients with ABPA are eosinophilic pneumonia, lipid pneumonia, pulmonary vasculitis, pulmonary fibrosis, and bronchocentric granulomatosis. 2S

Laboratory Findings Patients with ABPA exhibit immediate cutaneous reactivity (wheal and flare) to Af antigen, and approximately one third of patients will have biphasic skin reactivity. Biopsy of the late reaction (four to eight hours) reveals presence of IgG, IgM, IgA, and C 3 , suggesting an Arthus (type 3) immune reaction. Patients usually have precipitating antibodies to Af during the acute stage of ABPA. It has been demonstrated that 25 percent of asthmatic patients have immediate skin reactivity to Af and 10 percent demonstrate positive precipitating antibody to Af, 25 Thus, neither of these parameters is specific for ABPA. Repeated positive sputum cultures for Af are helpful, although not a pathognomonic feature of ABPA. Peripheral blood eosinophilia is typically seen in untreated patients, but may not be elevated in patients requiring use of corticosteroids to control asthma.

The serum IgE level in patients with ABPA is elevated, and Af growing in the respiratory tract in patients with ABPA appears to provide a potent stimulus for the elevation of total serum IgE. 27 The total serum IgE may be very high and interestingly the elevation of IgE is not all directed against Af. 27 With corticosteroid therapy, the total serum IgE level should decrease substantially within four-eight weeks. is Increased serum IgE and IgG antibodies against At: as measured by the polystyrene tube radioimmunoassay, are seen in patients with ABPA.10The level of this IgE and IgG antibody to Af is at least twice that of mold-sensitive asthmatic patients who demonstrate immediate skin reactivity to At: but do not have ABPA. These antibodies should be measured in all patients suspected of having ABPA. Although lymphocyte transformation, an in vitro test of cell-mediated immunity, is seen in some patients with ABPA, delayed hypersensitivity (type 4) reactions to intradermal Aspergillus antigens are not seen in ABPA. It has been demonstrated that basophils of patients with ABPA have greater histamine release to Af and other molds than patients with mold-sensitive asthma. 29 Also, basophils of patients with stage 4 and 5 ABPA have greater histamine release to Af than patients in stages 1, 2 or 3 ABPA.29 Bronchial challenges with Afcharacteristically show a dual response in patients with ABPA.15 One commonly sees an immediate reduction in 8o~ which is followed in some patients with a recurrence of obstruction in four to ten hours. The immediate reaction may be prevented by betas-agonists, and the late reaction may be prevented by administration of corticosteroids. Cromolyn sodium may prevent both the immediate and late reaction. Bronchial inhalational challenges with Afare not required to confirm a diagnosis of ABPA and may be of risk, in that patients with ABPA may have prolonged (48 to 72 hours) and severe bronchial obstruction from an Af challenge. Circulating immune complexes have been described during an acute flare of ABPA with activation of the classic pathway. Other evidence for the role of the complement system in this disease is that Af can convert C 3 proactivator to C 3 activator. 30 ABPAdoes not resemble serum sickness though as a prototype immune complex disease. Lung damage could result from immune complexes in bronchi. PATHOGENESIS

It is believed that Af mycelia are either trapped in the tenacious mucus of asthmatic patients or colonize the bronchial tree of asthmatic patients. Antigenic material from Af stimulates production of IgE, IgG, 19A antibodies and possibly sensitizes lymphocytes. The biphasic skin reaction seen in patients with ABPA CHEST I 88 I 5 I NOVEMBER, 1984

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and increased physician awareness, the identification of other fungi causing this type of lung reaction is likely.

requires both IgE and IgG, and it is believed that a similar mechanism occurs in the lung. Passive transfer of IgE and IgG antibodies for a patient with ABPA to a monkey, followed by bronchial challenge with At: was associated with pulmonary lesions in the monkey.4 Slavinet al" immunized monkeys with Afand detected IgG antibodies in gel. Normal human serum was infused into immunized and non-immunized monkeys, and human serum (without precipitating antibody) was infused into other monkeys, immunized and nonimmunized. All animals were challenged with aerosolized At: and lung biopsy specimens were taken on day five. Only the monkey with precipitating antibody (IgG) to Af who received human ABPA serum (IgE) showed changes on the biopsy specimen consistent with ABPA. Mononuclear and eosinophilic infiltrates were seen, with thickening of alveolar septa, but without evidence of vasculitis. .

Pulmonary Function Tests Pulmonary function tests may not clearly define the extent of ABPA-inducedlung damage. Patients studied long-term for ABPA demonstrated marked variability in total lung capacity (TLC), vital capacity (VC), forced expiratory volume at 1 s (FEV J, forced vital capacity (FEVl %), and diffusing capacity (Dco), these measurements did not correlate with duration of ABPA or asthma." Pulmonary function testing during acute exacerbations of ABPA may demonstrate a substantial reduction in TLC, VC, FEV b and Dco, which return to baseline with corticosteroid therapy. However, in some cases no change in volumes or Bowrates may be detected during an exacerbation.

DIFFERENTIAL DIAGNOSIS

TREATMENT

The differential diagnosis of ABPA includes diseases that cause roentgenographic infiltrates and those associated with bronchospasm. Patients with inadequately controlled asthma may have mucoid impaction and atelectasis. Infiltrates may occur in asthmatic patients secondary to bacterial or viral infections. Peripheral blood eosinophilia may also be seen with tuberculosis, sarcoidosis, parasitism, Churg-Strauss vasculitis, neoplasm, extrinsic allergic alveolitis, and eosinophilic pneumonia. These conditions should be excluded carefully. Patients with cystic fibrosis may have asthma, and their bronchi may be colonized with At: Since these patients may demonstrate bronchiectasis on chest roentgenogram, differentiation from ABPA may be difficult. Nevertheless, ABPA may occur in patients with cystic fibrosis.32 Bronchocentric granulomatosis is associated with asthma, presence of non-invasive fungi, and in some cases, mucoid impaction. Histologically, granulomatous replacement of bronchial mucous membrane is seen with eosinophilic infiltration of bronchi." Some cases of bronchocentric granulomatosis likely satisfy criteria of ABPA such that such a biopsy report should raise the suspicion of ABPA. Although classically ABPA is caused by At: some cases of ABPA have been reported from other species of Aspergillus. In recent years, allergic bronchopulmonary reactions have been observed where the causative organism was a mold or bacterium other than Aspergillus. Stemphylum Sp,34 Helminthosporium Sp,35 Pseudomonas aeruginosa," Curoularia lunata,37 Candida albicans,38 Dreschslera hawaiiensis, 37 and Torulopsis globata38 are examples of organisms which have been shown to cause allergic bronchopulmonary reactions in the lung. With improved serologic testing

Many agents have been used in the treatment of ABPA. Some of these include amphotericin B, mycostatin, cromolyn sodium, and beclomethasone dipropionate. However; none of these agents is currently recommended. At present, prednisone is the drug of choice in the therapy of ABPA. Prednisone will improve lesions seen on the chest roentgenogram, reduce clinical symptoms, decrease total serum IgE levels, and decrease the incidence of positive sputum cultures of Ai:28 Corticosteroids may exert their effect by decreasing sputum volume, by making the bronchi less suitable for At: and by inhibiting toxic antigen-antibody immunologic reactions. Safirstein et al," in a fiveyear follow-up of ABPA, reported the efficacy of prednisone therapy in maintaining clinical improvement in 80 percent of patients. The current treatment of exacerbations of ABPA is daily administration of prednisone, usually 0.5 rug/kg/day given as a single morning dose. This dosage is usually sufficient to improve pulmonary lesions in two weeks, at which time the same dosage is changed to a single alternate-day regimen. This dosage is maintained for a minimum of three months. If the chest roentgenogram remains improved and there is a substantial reduction in the level of total serum IgE, slow reduction in prednisone, at no faster than 5 mg/mo may be attempted. Treatment must be individualized for patients depending upon the stage of ABPA, frequency of exacerbations, and severity of asthma. Monthly total serum IgE levels are obtained, and when a twofold increase in the total serum IgE level is present, a chest roentgenogram should be obtained to rule out exacerbation of ABPA. It was noted that the majority of exacerbations of ABPA in Chicago occurred during the period of March through November; correlating with the higher atmospheric mold counts." Reduction of

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corticosteroids during this period should be done with caution in selected patients. This may vary with geographic location and individual disease activity. The frequency with which chest roentgenograms should be obtained in patients with ABPA is unknown, but chest roentgenograms should be obtained every three to six months during the first year of follow-up and on a yearly basis thereafter to avoid missing intercurrent pulmonary damage. Further; a rise in IgE levels should be evaluated by chest roentgenograms to exclude an infiltrate occurring during an exacerbation. This emphasizes the necessity to obtain serial total serum IgE levels. Pulmonary function tests should be obtained on a yearly basis. Immunotherapy with Af probably should not be administered to patients with ABPA, in view of the possible pathogenetic roles of immune complexes in the disease. In terms of prophylaxis, it might be wise to discourage the exposure of patients with ABPA to materials containing high concentrations of At: such as compost heaps, delayed organic matter; and stored grain. 43 FAMILIAL

ABPA

Three family pairs of ABPA cases have been identified. These are in two pairs of siblings and in a father and daughter: At this time, no genetic or environmental explanation for this familial relationship has been documented. REFERENCES

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Allergic Bronchopulmonary AIpergIIoeis (RIcIcetI at til)