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Fungal Pneumonias
REVIEW
Fungal Pneumonias• Part 3. Allergic Bronchopulmonary Aspergillosis Richtwd A. Glimp, M.D., t and Amold S. 'BayM, M.D., F.C.C.P.*
ADerafc
broncbopulmolllll'f Mperllllolll (ABPA) Is re-
ceivina lncreued recoplCion • a anm of respiratory
dllwe. 11ae .........., lnuaaolotkt radJolo&lc features of tldl . . . _ me reTlewed wltb a dllcmllon of pwlllle ....,,..Jllolollc .............. One .......... to Che ............ of ..... dilonler lncorponda tlae criteria of ~ pulmonary ........, Ilda-felt rwtitlty to 8Dd precipltadaa antibodies 11pinst Asper-
Allergic bronchopulmonary aspergillosis ( ABPA) is a disorder characterized by bronchospasm, pulmonary infiltrates, esosinophilia, and immunologic evidence of allergy to the antigens of Aspergillus species. The occurrence of asthma in patients with aspergillosis was noted as early as 1897,1 but it was not until the 1900s that an association between the two was recognized. In 1952 Hinson et al1 first described the entity of ABPA in three patients with wheezing, recurrent febrile episodes, roentgenograpbic evidence of pulmonary consolidation, blood eosinophilia, and sputum •plugs" containing the fungus, mucus, polymorphonuclear leukocytes, eosinophils, and Curschmann's spirals. Subsequent studies have elaborated on the immunologic aspects of this disease, including the demonstration of precipitating serum antibodies to Aapergalua antigens and an elevation of serum IgE levels. Only recently have long-term studies of this disorder appeared, and better agreement reached regarding the criteria for the diagnosis of ABPA and the methods of its treatment. It is now becoming clear that ABPA is not a rare disorder but rather a significant cause of respiratory disease. •From the Department of Medicine, Harbor-UCLA Medical Center, Torrance, and the UCLA School of Medicine ' Los Angeles, CA. tFellow, Infectious Disease, Harbor-UCLA Medical Center. Ussociate Professor of Medicine-Infectious Disease UCLA School of Medicine. ' Parts I and 2 have appeared in the May and June issues of Chen. Part 4 wfll appear in August Chert. &,nint requedl: Dr. Baller: Dfoialon of lnfect;fow DiletlHI Tommce, California soso9 Htll''bor-UCLA Medical
c.:..r,
CHEST, 80: 1, JULY, 1981
gillas •tipn, eoslnopldllll, eletlded IaE levels, clwlc brondlopapldc ....... Steroids . . . . . to be the drus of cbolce In ABPA, bat specl8c Cbe111peat1c ......... will require flUClaer ................... Tiie 11E levels may pnwe fo be mefnl In fo11ow1q the ~of ..... . . . _ ... In ..... dedslom ~ duntlon of therapy.
EPIDEMIOLOGY
The most common sources of exposure to Aapergillus spores are decaying vegetation and birds. Due to the ubiquitous distribution of the fungus, however, a failure to elicit a definitive history of exposure is not uncommon in patients with ABPA. The incidence of new cases of this disease, as well as the frequency of symptoms in previously diagnosed patients, is increased during the fall and winter months (September to March) when spore counts are highest Nosocomial outbreaks of ABPA have been linked to elevated spore counts in ventilation systems and have been controlled with air filtration techniques.1 The most common species of Aspergillus associated with ABPA is A 'fumigatus, though other species such as A 'flawa, A niger, and A nidulans have occasionally been implicated. The use of species-speciflc antigenic extracts of varius Aspergillus strains as skin-test reagents may, at times, document ABPA related to other species.1 No significant sexual predilection has been cited in ABP A, and the disorder has been seen in all age groups, including the pediatric population;• however, the majority of patients do present with clinically-evident ABPA at less than 35 years of age. INCIDENCE
Hinson's' original 1952 description was followed by several hundred reported cases of ABPA in the United Kingdom, but it was not until 1968 that the &rst case was described in the United States. Early
FUNUL PNEUMONIAS (PUT 3) 85
investigators suggested a failure of recognition of this disorder rather than a true difference in prevalence between the two countries,1 and by 1978, over 100 cases had been described in this country. A recent four-year survey disclosed 44 cases of ABPA in California alone. 7 Aocorate incidence figures are difficult to obtain. Henderson et al's8 1968 review of the incidence of ABPA in patients with chronic lung disease revealed that 11 percent of 46 asthmatics met his stricter criteria for the diagnosis of ABPA, suggesting that it is an underdiagnosed syndrome in most centers. PATHOPHYSIOLOGY
It is now accepted that the basic underlying pathologic process in ABPA is a hypersensitivity reaction to the presence of the fungus in the bronchial tree. Tissue invasion by the fungus is not thought to occur. The exact mechanism( s) involved in the pathogenesis of this syndrome are unknown, but evidence exists to support the presence of a number of immunologic reactions, most notably the type I (immediate) and type III (antigen-antibody, immune complex) hypersensitivity reactions. A simplified schematic diagram, incorporating the more widely accepted theories of the pathophysiology of this disorder, is shown in Figure 1. Asperg111us In bronchi of •susceptible" host
Chronic lung
Type Ill rHCtlon
Type I rHctlon
cllonges. e.g.
(medhted tllrougll
fibrosis,
1 - CC1111Pl•xes)
(med1atlld through lg£)
brondllectes1s
I
rf sustelned
Pol1110rph aggregation In lung; lnfl-tlon of bronchial 1nd peribronch111 tissues
R1dlogroph1c pulmnary lnflltrotlon
1
The factors favoring the initial Aspergillus colonization of the bronchi are unclear, but the changes brought about by the ensuing local immunologic reactions are believed to favor trapping of fungal spores and further colonization. The immediate hypersensitivity reaction is believed to be IgE-mediated and probably accounts for the bronchospastic symptoms that are the hallmark of this disorder. The type III reaction is probably responsible for the roentgenographic features of ABPA, as well as the more destructive changes in the bronchi.1 Recently, a possible role for a cell-mediated (delayed) hypersensitivity (type IV) reaction has been inferred from the demonstration of in vitro lymphocyte transformation to Aspergillus antigens in patients with ABPA10 and the presence of parenchymal granulomata and mononuclear cellular infiltration seen on lung histopathology. 11 Alternate pathway complement activation may also be involved in the inilammatory response of ABPA.11 The pathophysiology of this disorder is complex and far from being well understood. Long-standing involvement of the bronchial tree with these immunologic processes is felt to lead to the chronic sequelae of ABPA such as fibrosis, bronchiectasis, lung contraction, and lobar shrinkage. These complications have been documented since the earliest reports of this disease and probably account for most of the morbidity associated with ABPA Histopathologi.c confirmations of tissue invasion by the fungus are uncommon, 11-11 and may be related to other factors such as steroid therapy. 18 Aspergillomas (pulmonary mycetoma) have been cited as rare complications of ABPA.14.11 The development of the syndrome of ABPA is only one of a number of possible clinical manifestations of hypersensitivity to this fungus. Katzenstein et al, 17 in reviewing the pathologic features of ABPA, found overlap between this disorder and the entities of eosinophilic pneumonia, bronchocentric granu-
MIB
I
Cllnlcol
..,..zing
BCG
EP hrou I. Propoeed interrelationships between aDergic bronchopu]mmwy upergillosis ( ABPA), bnmcbocentric granulomatolis ( BCG), mucoid impaction of bronchi (Mm) and eosinoplillic pneumonia ( EP)-(Reprocluced with permUsioD &om Friedman PJ: Am Rev Respir Dis; 3:497-537.
•
GUMP, IAYU
FICllu i. Proposed pathogenetic mechanisms iDYolved in induction and propeptioD of ABPA.
CHEST, 80: 1, JULY, 1981
lomatosis, and mucoid impaction of bronchi. The suggested interrelationships are shown in Figure 2, with an open circle being used to denote the lack of a defined pathologic lesion in ABPA. The ultimate manifestation of hypersensitivity to Aspergillus in a given individual cannot be predicted and is probably dependent on a multiplicity of host factors yet to be defined. CllNicALFEATURES
Symptomatology and Physical Emmination An episodic, recurrent disorder, ABPA bas a wide spectrum of clinical presentations depending upon the severity of the disease. Milder episodes may be mistaken for "extrinsic" asthma and may remit without therapy. Chronic cases can present with symptoms more compatible with bronchiectasis. Patients may exhibit minimal symptoms, yet demonstrate extensive pulmonary consolidation on chest roentgenographs.11 Universal to this disease are symptoms of bronchospasm, with wheezing and dyspnea most commonly reported. Cough was present in 98 percent of 111 patients reviewed in detail by McCarthy and Pepys,1 with an approximately equal distribution between continuous and intermittent cough at time of presentation. Productive cough is common, with mucopurulent to purulent sputum reported The presence of sputum "plugs,.. one of the original reported findings, ranges in frequency from 5 percent10 to 54 percent' of cases in recent reviews. Of clinical-diagnostic importance, expectoration of plugs is often accompanied by improvement in bronchospastic symptoms and a marked increase in sputum production. Hemoptysis bas been reported in 34 percentH to 85 percent' of cases and is usually minimal. Pleuritic chest pain is noted in 50 percent of ABPA cases' and is usually localized to the side involved on chest x-ray film. Generalized constitutional symptoms, such as malaise, anorexia, and headache have also been reported. Most of the patients with ABPA in one series• lost four to eight weeks per year from their normal activities because of their disease. Fever is present in 34 to 68 percent of patients.1·1' The most notable finding on physical examination is evidence of wheezing, found in almost all cases of active ABPA. Also, rales are commonly heard, especially over lung segments involved roentgenographically by pulmonary infiltrates. Of interest, nasal mucus plugs are seen in 10 percent of cases'•11 and may be the sole presenting feature of ABPA. LAB<>BATORY AND IMMUNOLOGIC FEATURES
Eosinophaia Peripheral blood eosinophilia is recognized as a
CHEST, 80: l, JULY, 1981 .
nearly universal feature of ABPA and is included as one of the diagnostic criteria in all major reviews. Absolute eosinophil counts greater than 500/cu mm are the rule, with counts exceeding 1,000 documented in 50 to 100 percent1UO of patients at some time during their illness. Sputum eosinophilia has also been found to occur commonly. Blood eosinophil counts appear to parallel the activity of pulmonary involvement and usually decrease with steroid therapy. Total white blood cell counts are normal to mildly elevated in most series. Skin Teats Skin test reactivity to Aspergillus antigenic extracts was documented in asthmatics as early as the 1930s and is now widely employed in the screening of patients with suspected ABPA. Two types of reactions have been described in ABPA: the type I (immediate) reaction consisting of cutaneous "wheal and flare'" within 15 to 20 minutes of skin-test challenge; and the type III ( Aithus) reaction seen as a hemorrhagic cutaneous lesion 4 to 10 hours after skin-test inoculation. lntracutaneous tests can yield both types, the "dual reaction." McCarthy and Pepys' described the dual reaction in almost all of their ABPA patients, though more recent figures have ranged from 33 percent10 to 81 percent7 of patients. Problems are encountered with using Aspergillus skin tests in the screening of suspected ABPA patients. Standardization of antigenic extracts used for testing bas not yet been performed, with most commercial preparations consisting of a mixture of extracts from a variety of Aapergilltu species in different concentrations. While these are probably adequate for screening purposes, the use of extracts of lower potency may lead to false-negative reactions, a problem which may have contributed to early failures of diagnosis of this disease in the United States. 8 Also, the lack of specificity of skin tests is well documented. Henderson et al' found positive immediate skin test reactivity in 36 percent of asthmatics without other evidence of ABPA, and in 1 percent of patients with other chronic pulmonary diseases. Hoehne et al8 reported similar figures, and additionally found positive tests in 4 percent of healthy normal controls. Others have reported a 10 to 15 percent incidence of positivity in patients with typical extrinsic asthma. 11 Also, patients with aspergillomas can have positive skin tests. 8· • Finally, it should be noted that corticosteroid therapy will inhibit the type III (but not the type I) skin reaction, while antihistaminics may inhibit the type I reaction.
FUllUL PllEUMOlllAS (PART 3) 81
Setvm Precipitins Serum precipitating antibodies to Aspergillus extracts were first described in patients with ABPA in
1959,12 and are now also used in the diagnosis of this disorder. Two major techniques, double gel immunodiffusion and counterimmunoelectrophoresis ( CIE), are employed in their detection. It has been shown that techniques to concentrate serum will increase the sensitivity of the immunodiffusion assay without reducing speciflcity,11 and thus, should be performed in suspected cases. Serum precipitins by immunodiHusion were demonstrated in 92 percent of patients thought to have ABPA by McCarthy and Pepys,• when concentration of samples was performed, versus 72 percent positivity in samples of unconcentrated sera. Malo et al18 also reported a 20 percent increase in serum precipitin positivity by concentration techniques in this assay. The CIE test, in contrast, is generally more sensitive when using unconcentrated serum.11 Because the precipitin tests also rely on unstandardized Aspergillus antigenic extracts, many of the same problems of false-positive reactions mentioned above with skin-testing are also encountered with these assays. Precipitins have been found in 1 percent of normals, 2.5 percent of a general hospital population, and 25 percent of extrinsic asthmatics. 8 Henderson et al8 also found precipitins in 8 percent of patients with chronic lung diseases and no evidence of asthma. Additionally, precipitins are found in almost all patients with aspergillomas. s,IO Steroid therapy will inhibit the precipitin reactions. The "strength" or "grade" of the precipitin reaction roughly correlates with ABPA disease activity but may remain elevated for many weeks after clinical resolution of an acute bronchospastic episode.
IgE Levels The association between elevated serum IgE levels and ABPA was &rst reported in 1972." Both total IgE and IgE specific for Aspergillus antigens have been found to be elevated in ABPA.11 This &nding is not unique to ABPA and can be present in patients with other pulmonary diseases, especially extrinsic asthma. 25 In studies comparing total IgE levels and Aspergillus-specific IgE levels in patients with classic ABPA versus extrinsic asthma, the following has been noted:U.• ( 1) total lgE levels tend to be signiftcantly higher in ABPA than in extrinsic asthma; however, the individual overlapping between these two groups greatly limits its value in individual patients. Based on the studies of Wang et al,25 levels of IgE must reach > 15,000 ng/ ml to be discriminatory in ABPA vs extrinsic asthma; ( 2) Aspergillus-
a
GLIMP, BAYER
specific IgE levels are also signiJicantly higher in patients with ABPA vs extrinsic asthma, ari.d in addition offer more distinct separation between ~ two groups of patients, especially when the Aspergillus skin-test is positive in a patient with bronchospasm; ( 3) it now appears that IgE levels are the best correlates of ABPA disease activity,• with levels often rising prior to clinical exacerbations. The IgE levels willdecrease with remission, with or without steroid therapy.• As will be disctissed below, most investigators now recommend using speciflc and/ or total IgE levels to follow the course of ABPA and to aid decisions regarding initiation of therapy.
Fungal Cultures Sputum cultures yield Aspergillus in approximately two-thirds of patients with ABPA,9•18 but because of the ubiquitous distribution of this fungus and its occasional presence as a culture contaminant, cultural evidence of Aspergillus is poor diagnostic indicator of ABPA. Henderson et al8 found positive, cultures in 24 percent of asthmatics and in 6 percent of patients with other lung diseases. The presence of Aspergillus in multiple sputum cultures may suggest the diagnosis of ABPA, but immunologic and roentgenographic evidence is required for con&rmation. Pulmonary Function Tests Abnormalities of pulmonary function tests in patients with ABPA have been reported in a number of earlier reviews. 9•11•18 In general, these tests reflect the underlying pathologic processes in this diseasea spectrum from pure bronchospasm (obstructive physiologic profile) to such irreversible lung disease as bronchiectasis and fl.brosis (restrictive physiologic profile). Test values for pulmonary function will vary according to the degree to which each of these processes contributes to the overall disease. McCarthy and Pepys' found decreased FEV1 and Fv:C values in almost all of 86 patients reported to be at their "'baseline'" level, with most cases having an FEV1/FVC ratio less than 70 percent. As opposed to classic extrinsic asthmatics, reversibility with bronchodilators was found to be generally minimal, though some reversibility was documented even in patients with the most severe disease, a &nding which suggests the possibility of symptomatic improvement with these drugs in ABPA. The lack of reversibility of bronchospastic factors in ABPA vs extrinsic asthma has suggested that the airway "lesion" in ABPA is in smaller bronchi than in extrinsic asthma; this small airways bronchospasm may be exaggerated by the associated bronchiectasis. Diffusion capacity was found to be decreased
CHEST, 80: 1, JULY, 1981
h:rou 3. A (kft), Acllle inSltrate in left upper lobe in patient with ABPA; B (rlcM). Magnified view shows massive consolidation, "parallel line shadows.. (amall tltfOIDheatl.) and •ring shadows" (large """'*'1tl). (Reproduced with permillion &om Pattenon R: RadJology
1978; 127:302-07.
below 85 percent predicted in 24 or 35 patients in that study. Malo et al• have found that impairments in diffusion capacity correlate with the duration of the disease in their patients and suggest that this measurement can be used to gauge the severity of involvement in ABPA. Also, there is a statistically significant correJation between the reduction of FVC and FEV 1 with the age of the patient at time of study and the later in life the diagnosis of ABPA is made.
Other lmmunologjc Features Elevated levels of IgG against Aspergillus have also been demonstrated in patients with ABPA.10,11,211 Lymphocyte transformation to Aspergillus antigen has been described, 10 raising the possibility of the additional presence of a type IV allergic response in ABPA. The HLA antigen studies have failed to reveal an increased frequency of a specific HLA antigen in this disease. ao Bacterial precipitins, especially those to Haemophil,ua influenzae, Streptococcu8 pneumoniae, and Staphylococcua aureus, were elevated in 60 percent of patients in one series,• though the interpretation of these results is subject to some debate. Nasal and bronchial challenge tests with Aspergillus antigen in patients with ABPA result in both immediate and delayed re-
CHEST, 80: 1, JULY, 1981
F'lGlJBB 4. "Gloved-&nger shadows;" two of these join promnally to form Ul inverted abapecl shadow. ( Reproduced with pemUaioD of the Faca)ty of RadJologisb, London. England: Clin RadJol 1970; il:388-75
-v-
FUllUL PllEUMOllAS (PAIT S) •
sponses, analogous to the dual reaction seen with cutaneous tests. 81 RoENTCENOGRAPHIC FEATUBES Although roentgenographic abnormalities (Fig 35) have been reported in association with ABPA since its original description,1 these abnormalities were not described in detail until 1970 when McCarthy et al18 reported their findings in 111 patients with this disorder. The acute infiltrates of ABPA are the most commonly described features and probably indicate active disease. These take the form of homogeneous densities ranging in size from patchy infiltrates to lobar consolidation. The infiltrates generally have ill-defined margins, and those of smaller size often have very low density. 18 An Upper' lobe predilection has been cited in all major reviews, iua,as with occasional confusion with tuberculosis. McCarthy et al 18 found these infiltrates to be bilateral in 72 of their 111 patients. As previously mentioned, these infiltrates are probably secondary to type III reactions in the lung,9 and patients may be relatively free of symptoms with extensive involvement seen on roentgenograms.18 Another arute finding which has been reported is the presence of tram-line shadows, transient hairlike densities approximately the width of a normal bronchus apart. These probably represent edema of the bronchial wall and can also be seen in extrinsic asthma, cystic fibrosis, and states of elevated pulmonary venous pressure.18 Once bronchiectasis has occurred, numerous other roentgenographic abnormalities may be present. Parallel line shadows may be noted in areas where a previous homogenous infiltrate was present. These are like tram-line shadows, only wider apart, and
indicate that bronchial dilatation has occurred. These are permanent densities and were seen in 77 of the 111 cases previously cited. 18 When secretions fill the dilated brondll, band like shadows can be seen, .and when the distal end of the bronchus is additionally occluded, the density has a rounded distal end and is called a gloved-&nger shadow. These latter two findings may revert back to parallel line shadows after secretions and obstructions are cleared. Dilated bronchi seen on end, called ring shadows, may also be seen. Large numbers of these give rise to a "'honeycomb" appearance which may be confused with &brosing alveolitis, though these shadows are much more numerous in the latter condition. Other findings reported in APBA (with their incidence as cited by McCarthy et al18 in parentheses) : cavitation ( 14 percent), atelectasis ( 17 percent), local emphysema ( 25 percent), and lobar shrinkage ( 36 percent). Mintzer et alas have also described perihilaf' pseudoadenopathy believed to be the result of dilated perihilar bronchi filled with 8uid Air 8uid levels have also been described in this perihilar area. Bronchography has been additionally employed as a diagnostic tool in ABPA. Scadding38 originally reported the presence of sacculat- proximal bronchiectaais in this disorder with normal tapering of the bronchi distal to these lesions. This &nding is in contrast to the distal changes commonly described in asthma and infectious bronchiectasis and is considered by some investigators to be unique to ABPA. Rosenberg et al10 have suggested that this &nding be used to confirm the diagnosis of ABPA in patients meeting certain speci.6c clinical and immunologic criteria (see below). Proximal bronchiectasis was also recently found in three patients with clinical
F'Jcou 5. A (left), "Tram-line shadow;" B (cenlSr), "Parallel line shadow;" and C (right), °'Band" or "toothpaste shadow." (Reproduced with permission of the Faculty of Radiologists, London, Eog)aod: Clin Radiol 1970; .B1:386-75.
90 GUMP, BAYER
CHEST, 80: l, JULY, 1981
Flemm 6. Bronchogram m patient with ABPA showing proximal saccaJar bronchiectasisA ('fsfl), Dilated proximal bronchi with proximal ooclmion; and B (right), Focal brondllal dilations. (Reproduced with permission of the Faculty of Radiologists, London, England: Clio Radiol 1970; 21:366-75.
and immunologic features suggestive of ABPA but with normal chest x-ray films and no prior history of roentgenographic infiltrates, thus confirming the diagnosis" (Fig 6). DIAGNOSIS
As is apparent from the preceding sections, ABPA
is a syndrome-complex with few specific, pathologic,
or roentgenographic features unique to itself. The major exception, proximal saccular broncbiectasis, can be diagnosed only by broochography, a procedure which is impractical to employ as a routine screening study. Throughout the brief history of this disorder, no universal agreement has existed as to which features should constitute the clinical syndrome of ABPA. Criteria for diagnosis have varied among investigators and have been revised to accommodate new immunologic discoveries. Rosenberg et al 10 have recently proposed the most complete listing of criteria for diagnosis which now appears to be gaining acceptance in the United States. This list is shown in Table 1. The diagnosis of ABPA is considered likely if the 6rst six primary criteria are present, certain if all seven are present A suggested. approach to the diagnosis of ABPA is presented in Figure 7. In most cases, the patient
CHEST, 80: l, JULY, 1981
will present with a history of broncbospasm and recurrent pulmonary infiltrates. This obviously would include a large number of asthmatics with bacterial pneumonias, but in the presence of an elevated blood eosinophil count, positive sputum cultures for the fungus, or a history of expectoration of sputum plugs, the diagnosis of ABPA becomes auapect. Intracutaneous testing with Aspergillus antigenic extracts is the best screening procedure for patients with suspected disease. If positive, serum IgE and serum precipitin assays can be used to further support the diagnosis. Bronchogniphy could then be Table I-Criteria for dae Diapoa• of .4BP..4* Primary 1. Episodic bronchial obstruction 2. Peripheral blood eosinophilia 3. Immediate skin reactivity to Affpergillus antigens 4. Precipitating antibodies vs Aspergillus antigens
5. Elevat.ed serum lgE 6. History of infiltrates 7. Central bronchiectasis Secondary 1. Aspergillus in sputum 2. History of mucus plug expectoration 3. Late skin (Arthus) reactivity to Aspergillus antigens •Modified from Roeenberg et al."
FUllCAL PIEUllOlllAS (PAIT 3) 91
Is-- of brondlospasll/astt..j +
of rl!Curn!nce History of sput,.
Elevated peripheral
p1ug expectol'lt1 on
eos1noph11
l
Pos1t1Ye 1-hte (and + dtl~)react1on
SERUll PRECl:ITlllS
Sput• culture evidence of Asee111mus
coW1t
Negathe
~
.
lbs~nt ----~1::::1 Elev~ated
;evated
Repeat later or w1th
'
•••:11:Q
IDIA&llOSIS CERTAIN I 7. Algorithmic approach to the diagnosis of allergj.c broncbopulmonary upergilbis. F:IG11BB
additionally employed jf the diagnmis was still in doubt or if there were any hesitations regarding initiation of therapy. The problems encountered with using each of these criteria for the diagnosis of ABPA were discussed under their respective sections, and should be kept in mind when pursuing the diagnosis of this disorder. Differential DiagnoaiB
TREATMENT AND CouBsE Therapeutic modalities in ABPA have been directed toward two separate goals as follows: ( 1) removing the source of antigenic stimulation by eliminating the fungus from the bronchial tree,. or ( 2) suppressing the bronchial hypersensitivity reactions and their associated local parenchymal changes. Methods to accomplish the former, largely . _ . employing, inhalation of aeR>som.ed . anti£ungal agents such as amphotericin,11 nystatin,• natamycin,11 and clotrimazole,40 have now been largely abandoned. Recurrences were common with these drugs, with effective response requiring frequent repetitive treatments. Coreico8teroid therapy has now emerged as the treatment of choice in ABPA. These drugs appear to be effective by virtue of their suppressive effect on allergic inflammatory reactions as well as decreasTahle 1---0Mer Edolosia al EN•.,,,.,.
A number of disorders may be confused with ABPA. Tuberculo&U, because of the similar upper lobe involvement on roentgenographs, may be the initial diagnosis. This was the case in 32 percent of the patients reviewed by McCarthy and Pepys,• despite the fact that 89 percent of these patients had negative tuberculin skin tests. Cystic fibroai8 patients have been found to have a number of features in common with ABPA. Nelson et al81 reviewed 46 patients with cystic fibrosis and found that four of these also met the criteria for ABPA. Positive spupertum cultures for Aspergillus were found in cent of their group, with 39 percent manifesting immediate skin test reactivity to .Aspergillus antigens. Additionally, 33 percent had elevated precipitins (a figure similar to other studies),• 46 percent had evidence of bronchospasm, and 22 percent had elevated serum IgE levels. Eosinophilia, however, was seen in only one patient. The importance of distinguishing between these two entities lies in the
rn
92 CUllP, IAYD
risks of treating cystic fibrosis patients, who are prone to bacterial pneumonias, with steroids (the treatment of choice in ABPA). Such features as elevated sweat chloride levels, exocrine pancreatic insuftlciency, positive family history, relatively young age of onset, and lack of eosinophilia, when present, aid in the differentiation of cystic flb.rosis from ABPA. The diagnosis of carcinoma of the lung is occasionally confused with ABPA in elderly patients. The many etiologies of eosinophilic pneumonia, a partial list of which appears in Table 2, can usually be distinguished from ABPA on clinical and immunologic grounds. Atelectasis and bronchiectasis of other etiologies have also been confused with ABPA.
r...rraon1a•
Helminth infections
Anculottoma duodenale
Strongyloidiasis Trichinosis
Schist.oeomiaais Filariasis
Aacariasia Dirofilariasis
Cutaneous larva migrana
Vmceral larva migrana Loemer's syndrome Drugs penicillin
hydra.luine para-aminosalicylic acid
nitrofurantoin mecamylamine chlorpropamide
Unknown
•Modified from Liebow AA, Carrington CB: The eoeinophilic pneumonias. Medicine 1969; 48:251-85.
CHEST, 80: 1, JULY, 1981
ing sputum production and thereby making the bronchus less favorable to further fungal colonization. Resolution of infiltrates on roentgenogram.ad improvement in symptoms have been widely reported with their use.1•10,17 Inhaled therapy has shown some promise as a therapeutic adjunct but iS limited in its eflici.ency by the degree of obstruction and mucus plugging which is so common in this
disease.'•
Other forms of therapy should also be mentioned. Results with cromolyn sodium have been largely disappointing, possibly because of the same reasons cited for inhaled steroids. 17 Immunotherapy through intradermal hyposensitization has not been found . to be effective.. Conventional methods of treating asthma (such as bronchodilator therapy), while generally effective only in milder cases of ABPA, should nonetheless be employed in this disease to improve symptoms and possibly aid in the resolution of bronchial obstruction. Chest physiotherapy may aid in removal of mucus plugging. Antibiotics should be used if bacterial superinfections complicate the clinical picture. Long-term studies of patients with ABPA are few, making it difficult both to predict the course of this disease in a given patient and to de&ne treatment regimens. As Saftrstein et al11 have pointed out, clinical symptoms often do not correlate well with the activity of this disease, and unrecognized pulmonary involvement, as documented With acute infiltrates incidentally found on roentgenographs, is not uncommon. Because of the potential for asymptomatic pulmonary involvement to progress to irreversible lung damage, long-term corticosteroid therapy would seem warranted. McCarthy and Pepys' showed that recurrence of pulmonary in8ltrates occurred in their patients receiving less than 7.5 mg of prednisone per day, a Snding confirmed by Sa&rstein et al. 11 Rosenberg et al10 have recommended a prednisone regimen of 0.5 mg/kg body weight every other day, but later reported recurrences on that dose, which responded to daily dose steroid therapy.41 Thus, the prevention of recurrence of disease in this disorder would appear to require longterm corticosteroid therapy at doses which could potentially produce serious side-effects, possibly even local tissue invasion by the fungus. 11 A possible solution to this problem may come from the use of IgE levels to monitor disease activity. As previously mentioned, total IgE levels are elevated in active disease and diminish with remission, presumably independent of steroid therapy.• Imbeau et al" have advocated measuring IgE levels every two to three months in this disease and adjusting corticosteroid dosages accordingly, discon-
CHEST, 80: 1, JULY, 1981
tinuing them altogether whenever posn"ble. Further studies are needed to con8rm this approach, as well as to better deflne other therapeutic regimens in this
disease.
REnaEN'CES 1 Hinson KFW, Moon AJ, Plummer NS: Bronchopu)monary aspergillosis. 'Iboru 195!; 7:317-33 i Bose H, Hirsch SR: Filtming hospital air decreases Aaperglllw spore count& Am Rev Bespir Dis 1979; 114:511-13 3 Novey H, Wells I: Allergic broncbopulmonary aspergillosis caused by Aapergfllt.u oc1araceua. Am J Clin Path U178; 70:840-43 4 Wang JLF, Patterson R, Mintzer R, et al: Allergic bronchopu]monary aspergillosia in pediatric practice. J Pediatr 1979; 94:37~1 5 Pattenon R, Colbert TM: Hypersensitivity disease of the lung. U Mich Med Center J 1968; 34:8-11 6 Hoehne JH, Reed CE, l)jckie BA: Allergic broncbopulmoD&I)' aspergillosis is not rare. Chest 1973; 63:177-81 1 Novey HS, Wells ID: Allergic bronchopu1monary aspergillosis. West J Med 1979; 130: 1-S 8 Henderson AH, English MP, Vecht RJ: Puhnonary aspergillosis: a survey of its occurrence in patients with chronic lung disease and disa111ion of the significance of diagnostic tests. Thorax 1968; 23:513-18 9 McCarthy DS, Pepys J: Allergic broncho-pulmoD&I)' aspergillosis: clinical immunology: \ 1) clinical featmes. Clin Allerg 1971; 1:261-86 10 Rosenberg M, Pattenon R, MiDber I\: Clinical and immunologic criteria for the diagnosis of allergic bronchopuhnoD&I)' aspergil)osfs. Ann Intern Med 1977; 88:40514 11 Chan-Yeung M, Chue WH, Trapp W, et al: A1lergic bronchopulmonary aspergillosis: clinical and pathologic study of three cues. Cheat 1971; 59:33-39 12 Man: JJ Jr, Flaherty DK: Activation of the complement sequence by extracts of bacleria and fungi llllOCiated with hypersensitivity pneumonitfs. J Allerg C1in Immunol 1976; 51 :328 13 Riley DJ, Madrenzie JW, UhJman WE, et al: Allergic bronchopulmonary aspergl]losis: evidence of limited tissue invasion. Am Rev Bespir Dis 1975; lll:m-36 14 Henderson AH: Allergic upergillosis: review of 32 cases. Thoru: 1968; 23:501-12 15 Wahner HW, Hepper NGG, Andersen HA, et al: Pulmonary aspergdlosis. Ann Intern Med 1963; 58:472-85 16 Sa&rstein BH: Aspergilloma comequent to allergic bronchopulmonary aspergillosis. Am Rev Bespir Dia 1973; 108:940-43 17 Kat:zemtein AL, Liebow AA, Friedman PJ: Bronchocentric granulomatosis, mucoid impaction and hypeneasitivity reactions to fungi. Am Rev Bespir Dis 1975; 111:497537 18 McCarthy DS, Simon G, Hargreave FE: 'lbe radiological appearances in allergic broocho-pulmonary aspergillolis. Clin Radi~l 1970; 21:366-75 19 Sa8ntein BH: Allergic bronchopulmonary aspergillolis with obstruction Of the upper respiratory tract. Ciest 1976; 70:788-90 00 Campbell MJ, Clayton YM: Bronchopulmonary aspergillosis: a correlation of the clinical and laboratory 8ndiDp in 272 patients investigated for 1mmchopulmonary upergillosis. Am Rev Respir Dis 1964; 89:186-96 i i Turner-Warnick M, Citron KM, Carroll KB, et al: Im-
FUllUL PIEUllOllAS (PART 3) 13
22 23
24
25
26
27
28 29 30
31 32
munologic lung disease due to Aapergillw. Chest 1975: 68( 3) :346-55 Pepys J, Riddell RW, Citron KM, et al: Clinical and immunological significance of Aspergfllw fum'gau in the sputum. Am Rev Respir Dis 1959; 80:167-80 Malo JL, Longbottom J, Mitchell J, et al: Studies in chronic allergic bronchopulmonary aspergillosis: ( 3) Immunological findings. Thorax 1977; 32:269-74 Patterson R, Fink JN, Pruzansky JJ, et al: Serum immunoglobulin levels in pulmonary allergic aspergillosis and certain other lung diseases, with special reference to immunoglobulin. E Am J Med 1973; 54:16-22 Wang JLF, Patterson R, Rosenburg M, et al: Serum lgE and IgG antibody activity against Asperglllua fum'gau as a diagnostic aid in allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 1978; 117:917-27 Rosenberg M, Patterson R, Roberts M: Immunologic responses to therapy in allergic bronchopulmonary aspergillosis: serum 1gE value as an indicator and prediction of disease activity. J Pediatr 1977; 91:914-17 Saflrstein BH, D'Souza M, Simon G, et al: Five-year follow-up of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 1973; 108:450-59 Malo JL, Hawkins R, Pepys J: Studies in chronic allergic bronchopulmonary aspergillosis: ( 1) Clinical and physiological findings. Thorax 1977; 32:254-61 Bardana EJ, Gerber JD, Craig S, et al: The general and specific humoral immune response to pulmonary aspergillosis. Am Rev Respir Dis 1975; 112:799-805 Flaherty DK, Surfus JE, Geller M, et al: HI.A antigen frequencies in allergic bronchopulmonary aspergillosis. Clin Allerg 1978; 8:73-76 McCarthy DS, Pepys J: Allergic bronchopulmonary aspergillosis: clinical immunology: (2) Skin, nasal and bronchial test Clin Allerg 1971; 1:415-32 Mint7.er RA, Rogers LF, Kruglik GD, et al: The specbwn
14 IUllP, BAYER
of radiologic &ndings in allergic bronchopulmonar asper-
gillosis. Radiology 1978; 127:301-07 33 Scadding JG: The bronchi in allergic aspergillosis. Scand J Respir Dis 1967; 48:372-77 34 Rosenberg M, Mint7.er R, Aaronson DW, et al: Allergic bronchopulmonary aspergillosis in three patients with normal chest x-ray films. Oiest 1977; 72:597-800 35 Nelson L, Callerame ML, Schwartz R: Aspergiilosis and atopy in cystic ftbrons. Am Rev Respir Dis 1979; 120:86373 36 Mearus M, Longbottom J, Batten J: Precipitating antibodies to Aapergillt1$ fum'gatva in cystic flbrosfs. Lancet 1967; 1:538-39 ~ Slavin RG, Stanczyk DJ, Lonigro AJ, et al: Allergic bronchopulmonary aspergillosis-a North American rarity. AmJ Med 1969; 47:306-13 38 Stark JE: Allergic pulmonary aspergillosis successfuDy treated with inhalations of nystatin. Dis Chest 1967; 51:96-99 39 Henderson AH, Pearson JEG: Treabnent of bronchopulmonary aspergillosis with observations on the Wl8 of natamycin. Thorax 1968; 23:519-23 40 Cromptom GK, Milne LJR: Treatment of bronchopulmonary aspergillosis with clotrimazole. Br J Dis Chest 1973; 67 :301-07 41 Pingleton WW, Hiller FC, Bone RC, et al: Treatment of allergic aspergillosis with triamcinclone acetonide aerosol Cliest 1977; 71:782-84 42 Rosenberg M, Patterson R, Roberts M, et al: The assessment of immunologic and clinical changes occurring during corticosteroid therapy for allergic bronchopulmonary aspergillosis. Am J Med 1978; 64:599-606 43 lmbeau S, Nichols D, Flaherty D, et al: Relationships . between prednisone therapy, disease activity and the total serum lgE level in allergic bronchopulmonary aspergillosis. J Allerg Clin Immunol 1978; 62:91-95
CHEST, 80: 1, JULY, 1981
Fungal Pneumonias• Part 3. Allergic Bronchopulmonary Aspergillosis Richtwd A. Glimp, M.D., t and Amold S. 'BayM, M.D., F.C.C.P.*
ADerafc
broncbopulmolllll'f Mperllllolll (ABPA) Is re-
ceivina lncreued recoplCion • a anm of respiratory
dllwe. 11ae .........., lnuaaolotkt radJolo&lc features of tldl . . . _ me reTlewed wltb a dllcmllon of pwlllle ....,,..Jllolollc .............. One .......... to Che ............ of ..... dilonler lncorponda tlae criteria of ~ pulmonary ........, Ilda-felt rwtitlty to 8Dd precipltadaa antibodies 11pinst Asper-
Allergic bronchopulmonary aspergillosis ( ABPA) is a disorder characterized by bronchospasm, pulmonary infiltrates, esosinophilia, and immunologic evidence of allergy to the antigens of Aspergillus species. The occurrence of asthma in patients with aspergillosis was noted as early as 1897,1 but it was not until the 1900s that an association between the two was recognized. In 1952 Hinson et al1 first described the entity of ABPA in three patients with wheezing, recurrent febrile episodes, roentgenograpbic evidence of pulmonary consolidation, blood eosinophilia, and sputum •plugs" containing the fungus, mucus, polymorphonuclear leukocytes, eosinophils, and Curschmann's spirals. Subsequent studies have elaborated on the immunologic aspects of this disease, including the demonstration of precipitating serum antibodies to Aapergalua antigens and an elevation of serum IgE levels. Only recently have long-term studies of this disorder appeared, and better agreement reached regarding the criteria for the diagnosis of ABPA and the methods of its treatment. It is now becoming clear that ABPA is not a rare disorder but rather a significant cause of respiratory disease. •From the Department of Medicine, Harbor-UCLA Medical Center, Torrance, and the UCLA School of Medicine ' Los Angeles, CA. tFellow, Infectious Disease, Harbor-UCLA Medical Center. Ussociate Professor of Medicine-Infectious Disease UCLA School of Medicine. ' Parts I and 2 have appeared in the May and June issues of Chen. Part 4 wfll appear in August Chert. &,nint requedl: Dr. Baller: Dfoialon of lnfect;fow DiletlHI Tommce, California soso9 Htll''bor-UCLA Medical
c.:..r,
CHEST, 80: 1, JULY, 1981
gillas •tipn, eoslnopldllll, eletlded IaE levels, clwlc brondlopapldc ....... Steroids . . . . . to be the drus of cbolce In ABPA, bat specl8c Cbe111peat1c ......... will require flUClaer ................... Tiie 11E levels may pnwe fo be mefnl In fo11ow1q the ~of ..... . . . _ ... In ..... dedslom ~ duntlon of therapy.
EPIDEMIOLOGY
The most common sources of exposure to Aapergillus spores are decaying vegetation and birds. Due to the ubiquitous distribution of the fungus, however, a failure to elicit a definitive history of exposure is not uncommon in patients with ABPA. The incidence of new cases of this disease, as well as the frequency of symptoms in previously diagnosed patients, is increased during the fall and winter months (September to March) when spore counts are highest Nosocomial outbreaks of ABPA have been linked to elevated spore counts in ventilation systems and have been controlled with air filtration techniques.1 The most common species of Aspergillus associated with ABPA is A 'fumigatus, though other species such as A 'flawa, A niger, and A nidulans have occasionally been implicated. The use of species-speciflc antigenic extracts of varius Aspergillus strains as skin-test reagents may, at times, document ABPA related to other species.1 No significant sexual predilection has been cited in ABP A, and the disorder has been seen in all age groups, including the pediatric population;• however, the majority of patients do present with clinically-evident ABPA at less than 35 years of age. INCIDENCE
Hinson's' original 1952 description was followed by several hundred reported cases of ABPA in the United Kingdom, but it was not until 1968 that the &rst case was described in the United States. Early
FUNUL PNEUMONIAS (PUT 3) 85
investigators suggested a failure of recognition of this disorder rather than a true difference in prevalence between the two countries,1 and by 1978, over 100 cases had been described in this country. A recent four-year survey disclosed 44 cases of ABPA in California alone. 7 Aocorate incidence figures are difficult to obtain. Henderson et al's8 1968 review of the incidence of ABPA in patients with chronic lung disease revealed that 11 percent of 46 asthmatics met his stricter criteria for the diagnosis of ABPA, suggesting that it is an underdiagnosed syndrome in most centers. PATHOPHYSIOLOGY
It is now accepted that the basic underlying pathologic process in ABPA is a hypersensitivity reaction to the presence of the fungus in the bronchial tree. Tissue invasion by the fungus is not thought to occur. The exact mechanism( s) involved in the pathogenesis of this syndrome are unknown, but evidence exists to support the presence of a number of immunologic reactions, most notably the type I (immediate) and type III (antigen-antibody, immune complex) hypersensitivity reactions. A simplified schematic diagram, incorporating the more widely accepted theories of the pathophysiology of this disorder, is shown in Figure 1. Asperg111us In bronchi of •susceptible" host
Chronic lung
Type Ill rHCtlon
Type I rHctlon
cllonges. e.g.
(medhted tllrougll
fibrosis,
1 - CC1111Pl•xes)
(med1atlld through lg£)
brondllectes1s
I
rf sustelned
Pol1110rph aggregation In lung; lnfl-tlon of bronchial 1nd peribronch111 tissues
R1dlogroph1c pulmnary lnflltrotlon
1
The factors favoring the initial Aspergillus colonization of the bronchi are unclear, but the changes brought about by the ensuing local immunologic reactions are believed to favor trapping of fungal spores and further colonization. The immediate hypersensitivity reaction is believed to be IgE-mediated and probably accounts for the bronchospastic symptoms that are the hallmark of this disorder. The type III reaction is probably responsible for the roentgenographic features of ABPA, as well as the more destructive changes in the bronchi.1 Recently, a possible role for a cell-mediated (delayed) hypersensitivity (type IV) reaction has been inferred from the demonstration of in vitro lymphocyte transformation to Aspergillus antigens in patients with ABPA10 and the presence of parenchymal granulomata and mononuclear cellular infiltration seen on lung histopathology. 11 Alternate pathway complement activation may also be involved in the inilammatory response of ABPA.11 The pathophysiology of this disorder is complex and far from being well understood. Long-standing involvement of the bronchial tree with these immunologic processes is felt to lead to the chronic sequelae of ABPA such as fibrosis, bronchiectasis, lung contraction, and lobar shrinkage. These complications have been documented since the earliest reports of this disease and probably account for most of the morbidity associated with ABPA Histopathologi.c confirmations of tissue invasion by the fungus are uncommon, 11-11 and may be related to other factors such as steroid therapy. 18 Aspergillomas (pulmonary mycetoma) have been cited as rare complications of ABPA.14.11 The development of the syndrome of ABPA is only one of a number of possible clinical manifestations of hypersensitivity to this fungus. Katzenstein et al, 17 in reviewing the pathologic features of ABPA, found overlap between this disorder and the entities of eosinophilic pneumonia, bronchocentric granu-
MIB
I
Cllnlcol
..,..zing
BCG
EP hrou I. Propoeed interrelationships between aDergic bronchopu]mmwy upergillosis ( ABPA), bnmcbocentric granulomatolis ( BCG), mucoid impaction of bronchi (Mm) and eosinoplillic pneumonia ( EP)-(Reprocluced with permUsioD &om Friedman PJ: Am Rev Respir Dis; 3:497-537.
•
GUMP, IAYU
FICllu i. Proposed pathogenetic mechanisms iDYolved in induction and propeptioD of ABPA.
CHEST, 80: 1, JULY, 1981
lomatosis, and mucoid impaction of bronchi. The suggested interrelationships are shown in Figure 2, with an open circle being used to denote the lack of a defined pathologic lesion in ABPA. The ultimate manifestation of hypersensitivity to Aspergillus in a given individual cannot be predicted and is probably dependent on a multiplicity of host factors yet to be defined. CllNicALFEATURES
Symptomatology and Physical Emmination An episodic, recurrent disorder, ABPA bas a wide spectrum of clinical presentations depending upon the severity of the disease. Milder episodes may be mistaken for "extrinsic" asthma and may remit without therapy. Chronic cases can present with symptoms more compatible with bronchiectasis. Patients may exhibit minimal symptoms, yet demonstrate extensive pulmonary consolidation on chest roentgenographs.11 Universal to this disease are symptoms of bronchospasm, with wheezing and dyspnea most commonly reported. Cough was present in 98 percent of 111 patients reviewed in detail by McCarthy and Pepys,1 with an approximately equal distribution between continuous and intermittent cough at time of presentation. Productive cough is common, with mucopurulent to purulent sputum reported The presence of sputum "plugs,.. one of the original reported findings, ranges in frequency from 5 percent10 to 54 percent' of cases in recent reviews. Of clinical-diagnostic importance, expectoration of plugs is often accompanied by improvement in bronchospastic symptoms and a marked increase in sputum production. Hemoptysis bas been reported in 34 percentH to 85 percent' of cases and is usually minimal. Pleuritic chest pain is noted in 50 percent of ABPA cases' and is usually localized to the side involved on chest x-ray film. Generalized constitutional symptoms, such as malaise, anorexia, and headache have also been reported. Most of the patients with ABPA in one series• lost four to eight weeks per year from their normal activities because of their disease. Fever is present in 34 to 68 percent of patients.1·1' The most notable finding on physical examination is evidence of wheezing, found in almost all cases of active ABPA. Also, rales are commonly heard, especially over lung segments involved roentgenographically by pulmonary infiltrates. Of interest, nasal mucus plugs are seen in 10 percent of cases'•11 and may be the sole presenting feature of ABPA. LAB<>BATORY AND IMMUNOLOGIC FEATURES
Eosinophaia Peripheral blood eosinophilia is recognized as a
CHEST, 80: l, JULY, 1981 .
nearly universal feature of ABPA and is included as one of the diagnostic criteria in all major reviews. Absolute eosinophil counts greater than 500/cu mm are the rule, with counts exceeding 1,000 documented in 50 to 100 percent1UO of patients at some time during their illness. Sputum eosinophilia has also been found to occur commonly. Blood eosinophil counts appear to parallel the activity of pulmonary involvement and usually decrease with steroid therapy. Total white blood cell counts are normal to mildly elevated in most series. Skin Teats Skin test reactivity to Aspergillus antigenic extracts was documented in asthmatics as early as the 1930s and is now widely employed in the screening of patients with suspected ABPA. Two types of reactions have been described in ABPA: the type I (immediate) reaction consisting of cutaneous "wheal and flare'" within 15 to 20 minutes of skin-test challenge; and the type III ( Aithus) reaction seen as a hemorrhagic cutaneous lesion 4 to 10 hours after skin-test inoculation. lntracutaneous tests can yield both types, the "dual reaction." McCarthy and Pepys' described the dual reaction in almost all of their ABPA patients, though more recent figures have ranged from 33 percent10 to 81 percent7 of patients. Problems are encountered with using Aspergillus skin tests in the screening of suspected ABPA patients. Standardization of antigenic extracts used for testing bas not yet been performed, with most commercial preparations consisting of a mixture of extracts from a variety of Aapergilltu species in different concentrations. While these are probably adequate for screening purposes, the use of extracts of lower potency may lead to false-negative reactions, a problem which may have contributed to early failures of diagnosis of this disease in the United States. 8 Also, the lack of specificity of skin tests is well documented. Henderson et al' found positive immediate skin test reactivity in 36 percent of asthmatics without other evidence of ABPA, and in 1 percent of patients with other chronic pulmonary diseases. Hoehne et al8 reported similar figures, and additionally found positive tests in 4 percent of healthy normal controls. Others have reported a 10 to 15 percent incidence of positivity in patients with typical extrinsic asthma. 11 Also, patients with aspergillomas can have positive skin tests. 8· • Finally, it should be noted that corticosteroid therapy will inhibit the type III (but not the type I) skin reaction, while antihistaminics may inhibit the type I reaction.
FUllUL PllEUMOlllAS (PART 3) 81
Setvm Precipitins Serum precipitating antibodies to Aspergillus extracts were first described in patients with ABPA in
1959,12 and are now also used in the diagnosis of this disorder. Two major techniques, double gel immunodiffusion and counterimmunoelectrophoresis ( CIE), are employed in their detection. It has been shown that techniques to concentrate serum will increase the sensitivity of the immunodiffusion assay without reducing speciflcity,11 and thus, should be performed in suspected cases. Serum precipitins by immunodiHusion were demonstrated in 92 percent of patients thought to have ABPA by McCarthy and Pepys,• when concentration of samples was performed, versus 72 percent positivity in samples of unconcentrated sera. Malo et al18 also reported a 20 percent increase in serum precipitin positivity by concentration techniques in this assay. The CIE test, in contrast, is generally more sensitive when using unconcentrated serum.11 Because the precipitin tests also rely on unstandardized Aspergillus antigenic extracts, many of the same problems of false-positive reactions mentioned above with skin-testing are also encountered with these assays. Precipitins have been found in 1 percent of normals, 2.5 percent of a general hospital population, and 25 percent of extrinsic asthmatics. 8 Henderson et al8 also found precipitins in 8 percent of patients with chronic lung diseases and no evidence of asthma. Additionally, precipitins are found in almost all patients with aspergillomas. s,IO Steroid therapy will inhibit the precipitin reactions. The "strength" or "grade" of the precipitin reaction roughly correlates with ABPA disease activity but may remain elevated for many weeks after clinical resolution of an acute bronchospastic episode.
IgE Levels The association between elevated serum IgE levels and ABPA was &rst reported in 1972." Both total IgE and IgE specific for Aspergillus antigens have been found to be elevated in ABPA.11 This &nding is not unique to ABPA and can be present in patients with other pulmonary diseases, especially extrinsic asthma. 25 In studies comparing total IgE levels and Aspergillus-specific IgE levels in patients with classic ABPA versus extrinsic asthma, the following has been noted:U.• ( 1) total lgE levels tend to be signiftcantly higher in ABPA than in extrinsic asthma; however, the individual overlapping between these two groups greatly limits its value in individual patients. Based on the studies of Wang et al,25 levels of IgE must reach > 15,000 ng/ ml to be discriminatory in ABPA vs extrinsic asthma; ( 2) Aspergillus-
a
GLIMP, BAYER
specific IgE levels are also signiJicantly higher in patients with ABPA vs extrinsic asthma, ari.d in addition offer more distinct separation between ~ two groups of patients, especially when the Aspergillus skin-test is positive in a patient with bronchospasm; ( 3) it now appears that IgE levels are the best correlates of ABPA disease activity,• with levels often rising prior to clinical exacerbations. The IgE levels willdecrease with remission, with or without steroid therapy.• As will be disctissed below, most investigators now recommend using speciflc and/ or total IgE levels to follow the course of ABPA and to aid decisions regarding initiation of therapy.
Fungal Cultures Sputum cultures yield Aspergillus in approximately two-thirds of patients with ABPA,9•18 but because of the ubiquitous distribution of this fungus and its occasional presence as a culture contaminant, cultural evidence of Aspergillus is poor diagnostic indicator of ABPA. Henderson et al8 found positive, cultures in 24 percent of asthmatics and in 6 percent of patients with other lung diseases. The presence of Aspergillus in multiple sputum cultures may suggest the diagnosis of ABPA, but immunologic and roentgenographic evidence is required for con&rmation. Pulmonary Function Tests Abnormalities of pulmonary function tests in patients with ABPA have been reported in a number of earlier reviews. 9•11•18 In general, these tests reflect the underlying pathologic processes in this diseasea spectrum from pure bronchospasm (obstructive physiologic profile) to such irreversible lung disease as bronchiectasis and fl.brosis (restrictive physiologic profile). Test values for pulmonary function will vary according to the degree to which each of these processes contributes to the overall disease. McCarthy and Pepys' found decreased FEV1 and Fv:C values in almost all of 86 patients reported to be at their "'baseline'" level, with most cases having an FEV1/FVC ratio less than 70 percent. As opposed to classic extrinsic asthmatics, reversibility with bronchodilators was found to be generally minimal, though some reversibility was documented even in patients with the most severe disease, a &nding which suggests the possibility of symptomatic improvement with these drugs in ABPA. The lack of reversibility of bronchospastic factors in ABPA vs extrinsic asthma has suggested that the airway "lesion" in ABPA is in smaller bronchi than in extrinsic asthma; this small airways bronchospasm may be exaggerated by the associated bronchiectasis. Diffusion capacity was found to be decreased
CHEST, 80: 1, JULY, 1981
h:rou 3. A (kft), Acllle inSltrate in left upper lobe in patient with ABPA; B (rlcM). Magnified view shows massive consolidation, "parallel line shadows.. (amall tltfOIDheatl.) and •ring shadows" (large """'*'1tl). (Reproduced with permillion &om Pattenon R: RadJology
1978; 127:302-07.
below 85 percent predicted in 24 or 35 patients in that study. Malo et al• have found that impairments in diffusion capacity correlate with the duration of the disease in their patients and suggest that this measurement can be used to gauge the severity of involvement in ABPA. Also, there is a statistically significant correJation between the reduction of FVC and FEV 1 with the age of the patient at time of study and the later in life the diagnosis of ABPA is made.
Other lmmunologjc Features Elevated levels of IgG against Aspergillus have also been demonstrated in patients with ABPA.10,11,211 Lymphocyte transformation to Aspergillus antigen has been described, 10 raising the possibility of the additional presence of a type IV allergic response in ABPA. The HLA antigen studies have failed to reveal an increased frequency of a specific HLA antigen in this disease. ao Bacterial precipitins, especially those to Haemophil,ua influenzae, Streptococcu8 pneumoniae, and Staphylococcua aureus, were elevated in 60 percent of patients in one series,• though the interpretation of these results is subject to some debate. Nasal and bronchial challenge tests with Aspergillus antigen in patients with ABPA result in both immediate and delayed re-
CHEST, 80: 1, JULY, 1981
F'lGlJBB 4. "Gloved-&nger shadows;" two of these join promnally to form Ul inverted abapecl shadow. ( Reproduced with pemUaioD of the Faca)ty of RadJologisb, London. England: Clin RadJol 1970; il:388-75
-v-
FUllUL PllEUMOllAS (PAIT S) •
sponses, analogous to the dual reaction seen with cutaneous tests. 81 RoENTCENOGRAPHIC FEATUBES Although roentgenographic abnormalities (Fig 35) have been reported in association with ABPA since its original description,1 these abnormalities were not described in detail until 1970 when McCarthy et al18 reported their findings in 111 patients with this disorder. The acute infiltrates of ABPA are the most commonly described features and probably indicate active disease. These take the form of homogeneous densities ranging in size from patchy infiltrates to lobar consolidation. The infiltrates generally have ill-defined margins, and those of smaller size often have very low density. 18 An Upper' lobe predilection has been cited in all major reviews, iua,as with occasional confusion with tuberculosis. McCarthy et al 18 found these infiltrates to be bilateral in 72 of their 111 patients. As previously mentioned, these infiltrates are probably secondary to type III reactions in the lung,9 and patients may be relatively free of symptoms with extensive involvement seen on roentgenograms.18 Another arute finding which has been reported is the presence of tram-line shadows, transient hairlike densities approximately the width of a normal bronchus apart. These probably represent edema of the bronchial wall and can also be seen in extrinsic asthma, cystic fibrosis, and states of elevated pulmonary venous pressure.18 Once bronchiectasis has occurred, numerous other roentgenographic abnormalities may be present. Parallel line shadows may be noted in areas where a previous homogenous infiltrate was present. These are like tram-line shadows, only wider apart, and
indicate that bronchial dilatation has occurred. These are permanent densities and were seen in 77 of the 111 cases previously cited. 18 When secretions fill the dilated brondll, band like shadows can be seen, .and when the distal end of the bronchus is additionally occluded, the density has a rounded distal end and is called a gloved-&nger shadow. These latter two findings may revert back to parallel line shadows after secretions and obstructions are cleared. Dilated bronchi seen on end, called ring shadows, may also be seen. Large numbers of these give rise to a "'honeycomb" appearance which may be confused with &brosing alveolitis, though these shadows are much more numerous in the latter condition. Other findings reported in APBA (with their incidence as cited by McCarthy et al18 in parentheses) : cavitation ( 14 percent), atelectasis ( 17 percent), local emphysema ( 25 percent), and lobar shrinkage ( 36 percent). Mintzer et alas have also described perihilaf' pseudoadenopathy believed to be the result of dilated perihilar bronchi filled with 8uid Air 8uid levels have also been described in this perihilar area. Bronchography has been additionally employed as a diagnostic tool in ABPA. Scadding38 originally reported the presence of sacculat- proximal bronchiectaais in this disorder with normal tapering of the bronchi distal to these lesions. This &nding is in contrast to the distal changes commonly described in asthma and infectious bronchiectasis and is considered by some investigators to be unique to ABPA. Rosenberg et al10 have suggested that this &nding be used to confirm the diagnosis of ABPA in patients meeting certain speci.6c clinical and immunologic criteria (see below). Proximal bronchiectasis was also recently found in three patients with clinical
F'Jcou 5. A (left), "Tram-line shadow;" B (cenlSr), "Parallel line shadow;" and C (right), °'Band" or "toothpaste shadow." (Reproduced with permission of the Faculty of Radiologists, London, Eog)aod: Clin Radiol 1970; .B1:386-75.
90 GUMP, BAYER
CHEST, 80: l, JULY, 1981
Flemm 6. Bronchogram m patient with ABPA showing proximal saccaJar bronchiectasisA ('fsfl), Dilated proximal bronchi with proximal ooclmion; and B (right), Focal brondllal dilations. (Reproduced with permission of the Faculty of Radiologists, London, England: Clio Radiol 1970; 21:366-75.
and immunologic features suggestive of ABPA but with normal chest x-ray films and no prior history of roentgenographic infiltrates, thus confirming the diagnosis" (Fig 6). DIAGNOSIS
As is apparent from the preceding sections, ABPA
is a syndrome-complex with few specific, pathologic,
or roentgenographic features unique to itself. The major exception, proximal saccular broncbiectasis, can be diagnosed only by broochography, a procedure which is impractical to employ as a routine screening study. Throughout the brief history of this disorder, no universal agreement has existed as to which features should constitute the clinical syndrome of ABPA. Criteria for diagnosis have varied among investigators and have been revised to accommodate new immunologic discoveries. Rosenberg et al 10 have recently proposed the most complete listing of criteria for diagnosis which now appears to be gaining acceptance in the United States. This list is shown in Table 1. The diagnosis of ABPA is considered likely if the 6rst six primary criteria are present, certain if all seven are present A suggested. approach to the diagnosis of ABPA is presented in Figure 7. In most cases, the patient
CHEST, 80: l, JULY, 1981
will present with a history of broncbospasm and recurrent pulmonary infiltrates. This obviously would include a large number of asthmatics with bacterial pneumonias, but in the presence of an elevated blood eosinophil count, positive sputum cultures for the fungus, or a history of expectoration of sputum plugs, the diagnosis of ABPA becomes auapect. Intracutaneous testing with Aspergillus antigenic extracts is the best screening procedure for patients with suspected disease. If positive, serum IgE and serum precipitin assays can be used to further support the diagnosis. Bronchogniphy could then be Table I-Criteria for dae Diapoa• of .4BP..4* Primary 1. Episodic bronchial obstruction 2. Peripheral blood eosinophilia 3. Immediate skin reactivity to Affpergillus antigens 4. Precipitating antibodies vs Aspergillus antigens
5. Elevat.ed serum lgE 6. History of infiltrates 7. Central bronchiectasis Secondary 1. Aspergillus in sputum 2. History of mucus plug expectoration 3. Late skin (Arthus) reactivity to Aspergillus antigens •Modified from Roeenberg et al."
FUllCAL PIEUllOlllAS (PAIT 3) 91
Is-- of brondlospasll/astt..j +
of rl!Curn!nce History of sput,.
Elevated peripheral
p1ug expectol'lt1 on
eos1noph11
l
Pos1t1Ye 1-hte (and + dtl~)react1on
SERUll PRECl:ITlllS
Sput• culture evidence of Asee111mus
coW1t
Negathe
~
.
lbs~nt ----~1::::1 Elev~ated
;evated
Repeat later or w1th
'
•••:11:Q
IDIA&llOSIS CERTAIN I 7. Algorithmic approach to the diagnosis of allergj.c broncbopulmonary upergilbis. F:IG11BB
additionally employed jf the diagnmis was still in doubt or if there were any hesitations regarding initiation of therapy. The problems encountered with using each of these criteria for the diagnosis of ABPA were discussed under their respective sections, and should be kept in mind when pursuing the diagnosis of this disorder. Differential DiagnoaiB
TREATMENT AND CouBsE Therapeutic modalities in ABPA have been directed toward two separate goals as follows: ( 1) removing the source of antigenic stimulation by eliminating the fungus from the bronchial tree,. or ( 2) suppressing the bronchial hypersensitivity reactions and their associated local parenchymal changes. Methods to accomplish the former, largely . _ . employing, inhalation of aeR>som.ed . anti£ungal agents such as amphotericin,11 nystatin,• natamycin,11 and clotrimazole,40 have now been largely abandoned. Recurrences were common with these drugs, with effective response requiring frequent repetitive treatments. Coreico8teroid therapy has now emerged as the treatment of choice in ABPA. These drugs appear to be effective by virtue of their suppressive effect on allergic inflammatory reactions as well as decreasTahle 1---0Mer Edolosia al EN•.,,,.,.
A number of disorders may be confused with ABPA. Tuberculo&U, because of the similar upper lobe involvement on roentgenographs, may be the initial diagnosis. This was the case in 32 percent of the patients reviewed by McCarthy and Pepys,• despite the fact that 89 percent of these patients had negative tuberculin skin tests. Cystic fibroai8 patients have been found to have a number of features in common with ABPA. Nelson et al81 reviewed 46 patients with cystic fibrosis and found that four of these also met the criteria for ABPA. Positive spupertum cultures for Aspergillus were found in cent of their group, with 39 percent manifesting immediate skin test reactivity to .Aspergillus antigens. Additionally, 33 percent had elevated precipitins (a figure similar to other studies),• 46 percent had evidence of bronchospasm, and 22 percent had elevated serum IgE levels. Eosinophilia, however, was seen in only one patient. The importance of distinguishing between these two entities lies in the
rn
92 CUllP, IAYD
risks of treating cystic fibrosis patients, who are prone to bacterial pneumonias, with steroids (the treatment of choice in ABPA). Such features as elevated sweat chloride levels, exocrine pancreatic insuftlciency, positive family history, relatively young age of onset, and lack of eosinophilia, when present, aid in the differentiation of cystic flb.rosis from ABPA. The diagnosis of carcinoma of the lung is occasionally confused with ABPA in elderly patients. The many etiologies of eosinophilic pneumonia, a partial list of which appears in Table 2, can usually be distinguished from ABPA on clinical and immunologic grounds. Atelectasis and bronchiectasis of other etiologies have also been confused with ABPA.
r...rraon1a•
Helminth infections
Anculottoma duodenale
Strongyloidiasis Trichinosis
Schist.oeomiaais Filariasis
Aacariasia Dirofilariasis
Cutaneous larva migrana
Vmceral larva migrana Loemer's syndrome Drugs penicillin
hydra.luine para-aminosalicylic acid
nitrofurantoin mecamylamine chlorpropamide
Unknown
•Modified from Liebow AA, Carrington CB: The eoeinophilic pneumonias. Medicine 1969; 48:251-85.
CHEST, 80: 1, JULY, 1981
ing sputum production and thereby making the bronchus less favorable to further fungal colonization. Resolution of infiltrates on roentgenogram.ad improvement in symptoms have been widely reported with their use.1•10,17 Inhaled therapy has shown some promise as a therapeutic adjunct but iS limited in its eflici.ency by the degree of obstruction and mucus plugging which is so common in this
disease.'•
Other forms of therapy should also be mentioned. Results with cromolyn sodium have been largely disappointing, possibly because of the same reasons cited for inhaled steroids. 17 Immunotherapy through intradermal hyposensitization has not been found . to be effective.. Conventional methods of treating asthma (such as bronchodilator therapy), while generally effective only in milder cases of ABPA, should nonetheless be employed in this disease to improve symptoms and possibly aid in the resolution of bronchial obstruction. Chest physiotherapy may aid in removal of mucus plugging. Antibiotics should be used if bacterial superinfections complicate the clinical picture. Long-term studies of patients with ABPA are few, making it difficult both to predict the course of this disease in a given patient and to de&ne treatment regimens. As Saftrstein et al11 have pointed out, clinical symptoms often do not correlate well with the activity of this disease, and unrecognized pulmonary involvement, as documented With acute infiltrates incidentally found on roentgenographs, is not uncommon. Because of the potential for asymptomatic pulmonary involvement to progress to irreversible lung damage, long-term corticosteroid therapy would seem warranted. McCarthy and Pepys' showed that recurrence of pulmonary in8ltrates occurred in their patients receiving less than 7.5 mg of prednisone per day, a Snding confirmed by Sa&rstein et al. 11 Rosenberg et al10 have recommended a prednisone regimen of 0.5 mg/kg body weight every other day, but later reported recurrences on that dose, which responded to daily dose steroid therapy.41 Thus, the prevention of recurrence of disease in this disorder would appear to require longterm corticosteroid therapy at doses which could potentially produce serious side-effects, possibly even local tissue invasion by the fungus. 11 A possible solution to this problem may come from the use of IgE levels to monitor disease activity. As previously mentioned, total IgE levels are elevated in active disease and diminish with remission, presumably independent of steroid therapy.• Imbeau et al" have advocated measuring IgE levels every two to three months in this disease and adjusting corticosteroid dosages accordingly, discon-
CHEST, 80: 1, JULY, 1981
tinuing them altogether whenever posn"ble. Further studies are needed to con8rm this approach, as well as to better deflne other therapeutic regimens in this
disease.
REnaEN'CES 1 Hinson KFW, Moon AJ, Plummer NS: Bronchopu)monary aspergillosis. 'Iboru 195!; 7:317-33 i Bose H, Hirsch SR: Filtming hospital air decreases Aaperglllw spore count& Am Rev Bespir Dis 1979; 114:511-13 3 Novey H, Wells I: Allergic broncbopulmonary aspergillosis caused by Aapergfllt.u oc1araceua. Am J Clin Path U178; 70:840-43 4 Wang JLF, Patterson R, Mintzer R, et al: Allergic bronchopu]monary aspergillosia in pediatric practice. J Pediatr 1979; 94:37~1 5 Pattenon R, Colbert TM: Hypersensitivity disease of the lung. U Mich Med Center J 1968; 34:8-11 6 Hoehne JH, Reed CE, l)jckie BA: Allergic broncbopulmoD&I)' aspergillosis is not rare. Chest 1973; 63:177-81 1 Novey HS, Wells ID: Allergic bronchopu1monary aspergillosis. West J Med 1979; 130: 1-S 8 Henderson AH, English MP, Vecht RJ: Puhnonary aspergillosis: a survey of its occurrence in patients with chronic lung disease and disa111ion of the significance of diagnostic tests. Thorax 1968; 23:513-18 9 McCarthy DS, Pepys J: Allergic broncho-pulmoD&I)' aspergillosis: clinical immunology: \ 1) clinical featmes. Clin Allerg 1971; 1:261-86 10 Rosenberg M, Pattenon R, MiDber I\: Clinical and immunologic criteria for the diagnosis of allergic bronchopuhnoD&I)' aspergil)osfs. Ann Intern Med 1977; 88:40514 11 Chan-Yeung M, Chue WH, Trapp W, et al: A1lergic bronchopulmonary aspergillosis: clinical and pathologic study of three cues. Cheat 1971; 59:33-39 12 Man: JJ Jr, Flaherty DK: Activation of the complement sequence by extracts of bacleria and fungi llllOCiated with hypersensitivity pneumonitfs. J Allerg C1in Immunol 1976; 51 :328 13 Riley DJ, Madrenzie JW, UhJman WE, et al: Allergic bronchopulmonary aspergl]losis: evidence of limited tissue invasion. Am Rev Bespir Dis 1975; lll:m-36 14 Henderson AH: Allergic upergillosis: review of 32 cases. Thoru: 1968; 23:501-12 15 Wahner HW, Hepper NGG, Andersen HA, et al: Pulmonary aspergdlosis. Ann Intern Med 1963; 58:472-85 16 Sa&rstein BH: Aspergilloma comequent to allergic bronchopulmonary aspergillosis. Am Rev Bespir Dia 1973; 108:940-43 17 Kat:zemtein AL, Liebow AA, Friedman PJ: Bronchocentric granulomatosis, mucoid impaction and hypeneasitivity reactions to fungi. Am Rev Bespir Dis 1975; 111:497537 18 McCarthy DS, Simon G, Hargreave FE: 'lbe radiological appearances in allergic broocho-pulmonary aspergillolis. Clin Radi~l 1970; 21:366-75 19 Sa8ntein BH: Allergic bronchopulmonary aspergillolis with obstruction Of the upper respiratory tract. Ciest 1976; 70:788-90 00 Campbell MJ, Clayton YM: Bronchopulmonary aspergillosis: a correlation of the clinical and laboratory 8ndiDp in 272 patients investigated for 1mmchopulmonary upergillosis. Am Rev Respir Dis 1964; 89:186-96 i i Turner-Warnick M, Citron KM, Carroll KB, et al: Im-
FUllUL PIEUllOllAS (PART 3) 13
22 23
24
25
26
27
28 29 30
31 32
munologic lung disease due to Aapergillw. Chest 1975: 68( 3) :346-55 Pepys J, Riddell RW, Citron KM, et al: Clinical and immunological significance of Aspergfllw fum'gau in the sputum. Am Rev Respir Dis 1959; 80:167-80 Malo JL, Longbottom J, Mitchell J, et al: Studies in chronic allergic bronchopulmonary aspergillosis: ( 3) Immunological findings. Thorax 1977; 32:269-74 Patterson R, Fink JN, Pruzansky JJ, et al: Serum immunoglobulin levels in pulmonary allergic aspergillosis and certain other lung diseases, with special reference to immunoglobulin. E Am J Med 1973; 54:16-22 Wang JLF, Patterson R, Rosenburg M, et al: Serum lgE and IgG antibody activity against Asperglllua fum'gau as a diagnostic aid in allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 1978; 117:917-27 Rosenberg M, Patterson R, Roberts M: Immunologic responses to therapy in allergic bronchopulmonary aspergillosis: serum 1gE value as an indicator and prediction of disease activity. J Pediatr 1977; 91:914-17 Saflrstein BH, D'Souza M, Simon G, et al: Five-year follow-up of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 1973; 108:450-59 Malo JL, Hawkins R, Pepys J: Studies in chronic allergic bronchopulmonary aspergillosis: ( 1) Clinical and physiological findings. Thorax 1977; 32:254-61 Bardana EJ, Gerber JD, Craig S, et al: The general and specific humoral immune response to pulmonary aspergillosis. Am Rev Respir Dis 1975; 112:799-805 Flaherty DK, Surfus JE, Geller M, et al: HI.A antigen frequencies in allergic bronchopulmonary aspergillosis. Clin Allerg 1978; 8:73-76 McCarthy DS, Pepys J: Allergic bronchopulmonary aspergillosis: clinical immunology: (2) Skin, nasal and bronchial test Clin Allerg 1971; 1:415-32 Mint7.er RA, Rogers LF, Kruglik GD, et al: The specbwn
14 IUllP, BAYER
of radiologic &ndings in allergic bronchopulmonar asper-
gillosis. Radiology 1978; 127:301-07 33 Scadding JG: The bronchi in allergic aspergillosis. Scand J Respir Dis 1967; 48:372-77 34 Rosenberg M, Mint7.er R, Aaronson DW, et al: Allergic bronchopulmonary aspergillosis in three patients with normal chest x-ray films. Oiest 1977; 72:597-800 35 Nelson L, Callerame ML, Schwartz R: Aspergiilosis and atopy in cystic ftbrons. Am Rev Respir Dis 1979; 120:86373 36 Mearus M, Longbottom J, Batten J: Precipitating antibodies to Aapergillt1$ fum'gatva in cystic flbrosfs. Lancet 1967; 1:538-39 ~ Slavin RG, Stanczyk DJ, Lonigro AJ, et al: Allergic bronchopulmonary aspergillosis-a North American rarity. AmJ Med 1969; 47:306-13 38 Stark JE: Allergic pulmonary aspergillosis successfuDy treated with inhalations of nystatin. Dis Chest 1967; 51:96-99 39 Henderson AH, Pearson JEG: Treabnent of bronchopulmonary aspergillosis with observations on the Wl8 of natamycin. Thorax 1968; 23:519-23 40 Cromptom GK, Milne LJR: Treatment of bronchopulmonary aspergillosis with clotrimazole. Br J Dis Chest 1973; 67 :301-07 41 Pingleton WW, Hiller FC, Bone RC, et al: Treatment of allergic aspergillosis with triamcinclone acetonide aerosol Cliest 1977; 71:782-84 42 Rosenberg M, Patterson R, Roberts M, et al: The assessment of immunologic and clinical changes occurring during corticosteroid therapy for allergic bronchopulmonary aspergillosis. Am J Med 1978; 64:599-606 43 lmbeau S, Nichols D, Flaherty D, et al: Relationships . between prednisone therapy, disease activity and the total serum lgE level in allergic bronchopulmonary aspergillosis. J Allerg Clin Immunol 1978; 62:91-95
CHEST, 80: 1, JULY, 1981