Pulmonary Aspergillosis: Pathologic and Pathogenetic FeaturesRichard S. Fraser

Aspergillosis is a disease of w orldw ide distribution caused by species of the dim orphic fungus Aspergillus. A lthough it can occur in virtually any organ, the lungs are by far the m ost com m only affected. W ithin them , the tissue reaction to the presence of fungus and the associated clinical and radiological manifesta­tions are m ore varied than those associated with any o ther infectious agent (Table 1), w ith the possible exception of M ycobacterium tuberculosis. The pur­pose of this review is to docum ent and illustrate these varied pathologic manifes­tations of p leuropulm onary aspergillosis and to briefly discuss their patho­genesis and the m echanism s of clinical and radiographic disease. O ther features of the various disease states and of the fungus itself are discussed in detail in several o th er sources.1-7

THE ORGANISM

Although approxim ately 300 species o f Aspergillus have been described ,5 only a few cause hum an disease. By far the m ost common is A fum igatus; A niger, A flavus, and A glaucis are responsible infrequently and o ther species rarely.

In tissue, the organism typically grows as regular septate hyphae, 2 to 5 p.m in diam eter, w hich often appear to extend from a comm on point in a roughly parallel orientation, resulting in a fan-like appearance (Fig. 1A). Charac­teristically, the hyphae branch dichotomouslv at an angle of 45° (Fig. IB). They are usually easily seen in H & E preparations, although small, fragm ented forms may be difficult or im possible to identify; periodic acid Schiff (PAS) and silver

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TABLE 1. CLINICOPATHOLOGIC FORMS OF PLEUROPULMONARY ASPERGILLOSIS

General Form Specific Disease

Saprophytic aspergillosis Airway colonization Aspergilloma (Fungus ball) Invasion of necrotic tissue

Allergic aspergillosis Hypersensitivity pneumonitisLoeffler’s syndrome (eosinophilic pneumonia)Allergic bronchopulmonary aspergillosis

Invasive aspergillosis Acute bronchopneumonia Angioinvasive aspergillosis Acute tracheobronchitis Miliary aspergillosis Aspergillus pleuritis and empyema Chronic necrotizing aspergillosis

stains dem onstrate them particularly well. Although these histological features are very suggestive of Aspergillus species, they cannot by them selves be consid­ered diagnostic. O ther fungi, such as Pseudoallescheria boydii, resem ble Aspergillus very closely in tissue sections. In addition, degenerated hvphae of Aspergillus may swell and becom e quite irregular in shape, resem bling fungi of the o rder M ucorales (Fig. 2A). T hin hvphae, especially if d isrupted , can be mistaken for the pseudohyphae of Candida species (Fig. 2B).

In the absence of the results of culture or immunologic investigations,8 9 definitive identification or exclusion of Aspergillus as the cause of disease thus m ust be m ade w ith care. However, two specific features seen on routine light microscopy can help make a confident diagnosis. C ertain Aspergillus species, particularly A niger, are associated with the production of calcium oxalate, manifested morphologically as irregularly shaped, angulated, strongly refractile crystals (Fig. 3).1011 These are believed to result from the com bination of oxalic acid produced by the organism and calcium derived from the host and have been seen in both invasive and saprophytic forms of disease. T heir identifica­tion in tissue, pleural fluid, 12 or bronchial secretions13 is good evidence that a fungal infection is truly caused by Aspergillus. The docum entation of oxalic acid in fluid obtained by bronchoalveolar lavage also may aid in specific diagnosis.14

A second histological finding confirming the presence of Aspergillus is the conidiophore. This is the asexual reproductive organ of the fungus and consists of an elongated hvpha that term inates in a swollen vesicle of variable d iam eter from which em anate num erous spore-producing tubes called phialides or sterigm ata (Fig. 4). A variable num ber of more or less round conidia (spores), 1 to 3 /am in diam eter, are usually p resen t adjacent to the sterigm ata. C onidiophores are seen uncommonly, usually w hen the site of infection is exposed to air; thus, they are p resen t most often in aspergillomas and in invasive tracheobronchitis.

Aspergillus organisms are ubiquitous, being found in soil, water, and decay­ing organic m atter throughout the world. As indicated above, asexual reproduc-

Figure 1. Aspergillus hyphae: lypical morpnoiogy. A. lypical radiating tan ap­pearance of aspergillus hyphae in tissue. B. Magnified view showing uniform hyphae with parallel walls, septa, and dichotomous branching at an angle of 45°. (Grocott silver methenamine: A. x45, B. x650) 233

Figure 2. Aspergillus hyphae: Atypical morphology. A. Degenerated hyphae show­ing irregular size and shape and tocal marked swelling, an appearance suggestive of Mucorales. B. Very thin, somewhat beaded forms that might be mistaken for the pseudohyphae of Candida sp. (normal appearing hyphae are present on the bot­tom). (H&E x400)

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PULMONARY ASPERGILLOSIS 235

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Figure 3. Aspergillus abscess with calcium oxalate. High power view of a pulmo­nary abscess showing several irregularly shaped clumps of what appear to be crystalline foreign material (arrows) admixed with neutrophils and necrotic debris. Although hyphae are not visible in the photomicrograph, they were easily demon­strated by silver stain throughout the abscess. (H&E x375)

tion is by means of conidiophores, and it is by inhalation of conidia that the vast majority of infections occur. Conidia are p resen t virtually everyw here in the atm osphere (including hospital w ards),15 although the num ber varies somewhat w ith geographic location and season. Because of this, many infections probably are derived from general atm ospheric “contam ination.” O thers, however, un­doubtedly are related to the p resence of organisms in specific sites, including contam inated m arijuana cigare ttes,16 and such hospital sources as pigeon ex­creta located near a ventilation system 17 and dust created during renovation.18 Some instances of invasive pulm onary aspergillosis also originate in an endoge­nous focus of colonization or saprophytic growth. This is well docum ented in occasional cases o f aspergillom a (see below) and also may occur after coloniza­tion of th e nose or u pper airw ays.19

GENERAL PATHOGENETIC FEATURES

As w ith o th er pulm onary infections, the risk of developing disease after contact with Aspergillus depends on the interplay betw een virulence20 and inoculating

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Figure 4. Aspergillus conidiophores. Typical appearance of conidiophores as seen in tissue sections. V, vesicle; long arrow, sterigmata; short arrows, conidia. (Grocott silver methenamine x640)

dose21 of the organism, and the ability of the host to resist infection,22 The last feature is influenced m ost im portantly by the com petence of local and systemic host defense.

Aspergillus species produce a variety of toxic substances that undoubtedly are of im portance in the pathogenesis of disease. Both A fum igatus and A fla vu s have been shown to produce an endotoxin that is lethal after injection in several anim als.23 A variety of proteases, including elastase, also are produced; the presence o f the la tte r enzym e has been shown to be related to the developm ent of invasive disease in m ice.24 The ability of different species and strains to produce these toxic substances may at least partially explain their variable pathogenicity.24

The conidial d iam eter also may be a factor influencing the risk of disease. For example, conidia o f A fum iga tus m easure 2 to 3 yum in diam eter, a size ideal for inhalation and deposition in th e distal respiratory tract. By contrast, conidia of the relatively less comm on pathogens A niger and A flavus are 4 to 5 /xm in diam eter, a size m ore likely to be associated with proximal airway deposition and, possibly, m ore rapid mucociliary clearance. This, however, cannot be the sole explanation for variation in species pathogenicity, as some species that are rare causes of hum an disease have a conidial d iam eter similar to that of A fum igatus.

PULMONARY ASPERGILLOSIS 2 3 7

The precise m echanism s of host defense against Aspergillus species are not well understood. It is likely that clearance of inhaled conidia by alveolar m acrophages and the tracheobronchial mucociliary escalator is im portant as a local defense. In situations in w hich such clearance appears to be deranged, as in bronchiectasis or th e cavities of chronic tuberculosis, the likelihood of fungal colonization and growth is greatly increased. Although efficient pulm onary clearance also may be im portant in p reventing invasive disease, a variety of observations suggest that adequate inflam matory and im munologic reactions are of even greater significance. The m ost convincing of these observations is clinical: healthy individuals rarely acquire invasive aspergillosis, whereas indi­viduals w ith an im m une or inflam m atory deficiency are clearly at increased risk for the disease. T here are several experim ental findings that help to explain this. For example, th e re is evidence that alveolar macrophages can prevent germ ination of conidia by phagocytosing and killing them , and that defense against invasion is dep en d en t on this m echanism .25 26 (D espite this, some investi­gators27 have suggested that spores can be phagocvtosed bu t not effectively killed by alveolar m acrophages.) In addition, although neutrophils may be inca­pable of killing “resting” conidia, it appears that they can kill conidia that are swollen in a pregerm inative stage, as well as hyphae.28

T here are several substances produced by Aspergillus organisms that are capable of decreasing the effectiveness of host defense. Both A flavus and A fum igatus produce a com pound that appears to interfere w ith the activation of the alternate com plem ent pathw ay and by so doing inhibits the opsonization of conidia and, possibly, the production of chem otactic factors.29 In addition, there is evidence that the conidia of A fum iga tu s secrete substances that are capable of im peding both phagocytosis30 and the production of reactive oxygen in term e­diaries31 by monocytes and polym orphonuclear leukocytes. Gliotoxin, a m etabo­lite of A fum igatus, also is capable of inhibiting phagocytosis and the develop­m ent of T cell cytotoxicity.32

Pulm onary aspergillosis is traditionally considered to com prise th ree gen­eral forms of disease: (1) saprophytic, in which there is fungal growth w ithout invasion of viable tissue; (2) allergic, characterized by the presence of a hyper­sensitivity reaction to fungal hyphae or conidia; and (3) invasive, in which there is extension of the fungus into viable pulm onary tissue. These th ree varieties are not m utually exclusive. Occasional cases of saprophytic33 or allergic34 dis­ease progress to invasive disease and allergic bronchopulm onary aspergillosis som etimes is associated with an aspergillom a,35 N evertheless, as a rule, each form tends to rem ain true and is associated with significantly different patho­genetic, pathologic, and clinical features.

SAPROPHYTIC ASPERGILLOSIS

Saprophytic growth of A spergillus species in the lungs occurs in th ree clinico- pathologic- forms: (1) colonization of the tracheobronchial tree w ithout formation

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of macroscopic fungal colonies; (2) formation of a grossly visible colony within an ectatic bronchus or pulm onary cavity (fungus ball or aspergilloma); and (3) invasion of necrotic lung tissue. A lthough often not associated w ith evidence of clinical disease, such grow th occasionally results in local tissue damage and subsequent sym ptom s (usually hemoptysis); in addition, the fungal colonies can serve as the source o f serious disease w hen local or systemic defenses are com prom ised (see below).

Airway ColonizationColonization of the tracheobronchial tree usually occurs in the presence of chronic airway disease such as asthm a, bronchiectasis, and chronic bronchitis. In these conditions, the organism can be cultured from sputum or bronchial washings in as many as 2 to 3 percen t of patien ts .36 Colonization probably is even m ore com m on in patients w ith cystic fibrosis, in whom positive sputum cultures have been reported in 10 to 57 percen t of individuals.37 Some of these patients also have clinical and radiological features of allergic bronchopulm o­nary aspergillosis, bu t in others it is not possible to identify a specific disease state caused by the fungus. In these individuals, microscopic fungal colonies appear to be able to survive in m ucopurulent exudate w ithin ectatic airways and, possibly, in alveolar airspaces them selves, w ithout causing pulm onary injury.38

Aspergilloma (Fungus Ball)A fungus ball consists of a grossly identifiable cluster of in tertw ined hyphae m atted together with a variable am ount of mucus and cellular debris. It is most often identified radiographically as a roughly spherical nodule or mass sepa­rated by a crescent-shaped lucencv from an adjacent cavity wall (Fig. 5). Al­though the abnorm ality can be caused by many fungal species,7 Aspergillus is by far the most comm on and the term '‘aspergilloma” often is used synony­mously for “fungus ball,” even in the absence of cultural proof. (The term "m ycetom a” also is used frequently to refer to this lesion; strictly speaking, however, this refers to a chronic sinus-forming infection of the skin and subcuta­neous tissue and its use in saprophytic pulm onary disease probably should be avoided.)

Typically, an aspergillom a develops in a parenchym al cavity or ectatic bronchus of long duration. Occasionally, in abnorm alities such as carcinoma39 or lung abscess,40 it begins at m ore or less the same tim e as the cavity forms (Fig. 6). It is also likely that some aspergillomas create their own “cavity” as they develop. In one series of five patients reported as “semi-invasive aspergil­losis,”41 radiologically and pathologically typical aspergillomas developed in lungs previously shown to have no or m inim al disease. Pathologic examination of some of these cases showed non-invasive colonies of Aspergillus surrounded by a fibrous wall and a chronic inflam matory infiltrate. All bu t one of the patients had clinical evidence or a history com patible with a mild immunologic abnormality, such as alcoholism or sarcoidosis. The authors speculated that

PULMONARY ASPERGILLOSIS 239

Figure 5. Pulmonary aspergil- loma: Radiological appearance. A. A postero-anterior roentgen­ogram shows patchy opacities and loss of volume of the left up­per lobe (representing chronic tu­berculosis). In the apical portion of the right lung is a large cavity, most of which appears to be occupied by a solid mass. B. A tomogram in AP projection reveals a crescent-shaped lu- cency surrounding the mass, an appearance characteristic of an intracavitary aspergilloma.

these cases rep resen t a form of disease interm ediate betw een typical aspergil­loma and true invasive aspergillosis.

The most com m on pathologic condition predisposing to aspergilloma forma­tion is chronic cavitary tuberculosis; approximately 25 percen t of all patients with the abnorm ality have a history of this disease.42 Stated another way, the risk of developing an aspergillom a w ith cavitary tuberculosis is appreciable. In one study of 544 patients w ith healed open tuberculous cavities, 59 (11 percent) w ere considered to have definitive radiographic evidence of aspergilloma forma­tion43; after 3 years follow-up, th e frequency had increased to 17 percen t.44 The second most comm on condition associated with aspergillom a is sarcoidosis; in

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Figure 6. Acute lung abscess with early aspergilloma. Section from an ill-defined area of pneumonia shows parenchymal consolidation by an acute inflammatory infiltrate associated with an area of necrosis and early cavity formation. Fungal hyphae are seen along the wall of the cavity (arrows) and within the necrotic debris. They were not identified in viable tissue. The patient was a 75-year-old man with a cerebral infarct; the pneumonia was considered to be related to aspiration and anaerobic infection and the fungus most likely to represent early colonization of the resulting cavity. (H&E x30)

one prospective study of 100 patients with this disease, 10 developed a fungus ball.45

Many o ther abnorm alities can predispose to aspergilloma formation," includ­ing bronchiectasis of any etiology; chronic abscess; cavities related to chronic fungal infection, such as cocidioidomycosis; bullae associated with em physem a or connective tissue disease such as ankylosing spondylitis; congenital abnorm ali­ties, such as bronchogenic cysts and intralobar sequestration; and bronchial stum ps rem aining after pneum onectom y. The common feature of all these condi­tions is the p resence of an enlarged cystic space within the lung parenchym a or airways in w hich the norm al clearance mechanisms are im paired or altogether absent. Although many conidia inhaled within such a space are probably de­stroyed by local inflam matory cells, defective clearance may favor the establish­m ent of occasional colonies that can then enlarge and form a grossly visible fungus ball.

PULMONARY ASPERGILLOSIS 241

Pathologically, a pulm onary aspergilloma usually is a w ell-circum scribed mass, that on cut section is round to oval in shape, som etim es with nodular expansions or depressions conform ing to the shape of the surrounding cavity (Fig, 7). Serpiginous lam inations may be seen within its substance, correspond­ing to variably dense zones of hyphae and possibly represen ting the effect of different rates of fungal grow th. The space betw een the cavity wall and the fungus ball so characteristic o f the chest roentgenogram may not be apparent, probably because of collapse of the lung and cavity around the aspergilloma. The fungus ball may be relatively solid and fragment only w ith force, bu t m ore often it is friable and partially disintegrates w hen an a ttem pt is m ade to cut it. Frequently, it has a pale tan color, although intracavitary hem orrhage may result in a darker appearance and can even obscure the presence of the fungal mass itself (Fig. 8).

Microscopically, the lesion is composed of num erous intertw ined hyphae, many of which show degenerative changes or frank necrosis, particularly in the central portion. D istinct lam inations, corresponding to those seen grossly, may be apparen t (Fig. 9). Polym orphonuclear leukocytes are not infrequently clus­tered at the periphery of th e fungal mass, bu t the rem ainder is usually acellular. The surrounding cavity wall is com posed of a layer o f fibrous tissue in which there is a variable num ber of m ononuclear inflammatory cells and small blood vessels (Fig. 10); granulom atous inflammation is rare. In ectatic airways and in some pulm onary parenchym al cavities, there is frequently an epithelial lining

Figure 7. Pulmonary aspergil­loma. Typical appearance of an un­complicated aspergilloma show­ing a sharply circumscribed, tan- colored nodule with distinct lamina­tions within a fibrous walled cavity. (Bar = 0.5 cm.) (Reprinted from Fraser RG, et ai, 1989, with per­mission.7)

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AFigure 8. Pulmonary aspergilloma with hemorrhage. A. An upper lobe cavity (actu­ally a markedly ectatic bronchus) is filled with a friable mass composed of blood clot and fragments of aspergilloma. Indistinct laminations are present in some of the fragments (arrow). The patient was a young woman with chronic sarcoidosis who died after an episode of severe hemoptysis, (bar = 1 cm.) continued

(respiratory or squam ous in type) that separates the aspergilloma from the fibrous tissue. In such circum stances, there are often foci of epithelial ulcera­tion (Fig. 10). The pathogenesis of this epithelial damage is not clear, bu t may be related to the presence of toxins secreted or released from viable or degener­ated fungus, or to enzym es or inflam matory m ediators derived from the in- tercavitarv inflam matory reaction. It has also been speculated that physical

PULMONARY ASPERGILLOSIS 243

BFigure 8. (cont’d) B. The source of hemorrhage was a large pulmonary artery located adjacent to the ectatic bronchial wall. (H8E x30)

traum a caused by friction of the aspergillom a on the cavity wall46 or the toxic effect of calcium oxalate1011 may be responsible. D irect invasion of viable tissue cannot be invoked: fungal hyphae are identified only rarely in the cavity wall, usually in an autopsy specim en. In this circum stance, some derangem ent of systemic im munologic com petence is probably involved.

W hatever the cause of the local tissue damage, it is undoubtedly related to hem optysis. This is the most im portant clinical consequence of aspergilloma, occurring in 50 to 70 percen t of patien ts and causing death in as many as 5 percen t.47 48 The source of b leed ing in most cases is probably small vessels derived from the bronchial circulation ,46 which are invariably present in the cavity wall and w hich can be num erous (Fig. 10). Occasionally, hem orrhage occurs from a pulm onary artery (Fig. 8). This is particularly likely to develop in bronchiectatic cavities, in w hich a branch of the pulm onary artery, often of relatively large size, is in close proxim ity to the cavity wall. This difference in bleeding source is im portant, since bronchial artery embolization, a procedure not uncom m only used in an a ttem pt to stop hemoptysis, clearly is of no benefit in cases of pulm onary artery rup tu re .

The natural history of aspergillom a is variable. As discussed above, those that come to clinical attention do so most often as a result of hemoptysis. However, there are undoubted ly cases in which this complication does not

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Figure 9. Pulmonary aspergilloma. Section through an ectatic bronchus shows an aspergilloma with distinct laminations. The surrounding bronchial wall shows an intact epithelium and moderate fibrosis and chronic inflammation. (H&E x40)

occur, the lesion being identified and followed for years by roentgenography or being discovered incidentally at autopsy. Lysis and com plete resolution w ithout therapeutic intervention are said to occur in 7 to 10 percen t of cases.44 49 There is evidence that aspergillomas that develop in recently formed lung cavities (such as abscesses) may have an increased likelihood of such spontaneous resolution.40 Rarely, an aspergillom a can serve as a source for invasive aspergillosis (see below ).33

Invasion of Necrotic TissueThe th ird variety of saprophytic aspergillosis is the least common and consists of invasion and colonization of necrotic tissue, usually infarcted lung50 and occa­sionally a m alignant tum or.51 In m ost cases, there is radiologic evidence of cavitation and the pathogenesis of the initial phase of fungal growth is probably similar to that of an aspergilloma. In the la tter condition, however, the cavity is lined entirely by viable tissue and norm al host defenses appear to be sufficient to p reven t fungal invasion; such defenses are presum ably deficient w ithin the necrotic tissue, enabling colonization and growth of fungus w ithin it.

The distinction betw een colonization of infarcted pulm onary tissue and true invasive aspergillosis may be difficult. Obviously, the clinical context is im portant. For example, if there are significant risk factors for the developm ent

PULMONARY ASPERGILLOSIS 2 45

Figure 10. Pulmonary aspergilloma: Cavity wall. Sections from the walls of two cavities of undetermined etiology, each of which contained a typical aspergilloma. In A., there is an intact respiratory epithelium lining the wall, which itself shows moderate chronic inflammation and numerous somewhat dilated vascular chan­nels. In B., the lining squamous epithelium is ulcerated and there is an intense acute inflammatory reaction; there is no evidence of fungal invasion. (H&E x80)

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of invasive aspergillosis, such as granulocytopenia, then the presence of sapro­phytic disease m ust be seriously questioned. However, the observation of a w edge-shaped, p leural-based area of necrosis (as opposed to nodular, intra- parenchym al disease) and the finding of pulm onary artery throm bosis proximal to and separate from the area of tissue necrosis should strongly suggest the possibility of saprophytic colonization of an infarct.

ALLERGIC ASPERGILLOSIS

As w ith saprophytic disease, allergic aspergillosis has three distinct clinico- pathologic m anifestations: (1) hypersensitivity pneum onitis (extrinsic allergic alveolitis), w hich is felt to rep resen t a reaction to inhaled conidia, usually in an occupational setting such as the production of m alt52; (2) Loeffler’s syndrom e (transient pulm onary opacities, blood eosinophilia, fever, and cough), corre­sponding pathologically to eosinophilic pneum onia; and (3) allergic bronchopul­m onary aspergillosis (ABPA), the m ost comm on form, characterized by asthma, peripheral eosinophilia, bronchial mucoid im paction, and serological evidence of sensitization to Aspergillus organisms. Although this last form of disease is infrequently seen by pathologists, it is by far the most common of the th ree types of allergic aspergillosis and the rem ainder of this section is concerned with it.

Clinically, patients w ith ABPA may have recu rren t acute episodes of cough, dyspnea, hem optysis, and fever or may be asymptomatic. Many have allergic m anifestations in addition to asthma, including rhinitis, eczema, and drug and food hypersensitivity.53 C hest roentgenogram s characteristically show hom ogeneous, elongated, and often branched opacities represen ting mucous plugging (mucoid im paction) of proximal bronchi (Fig. 11). These may be tran ­sient (if the patien t coughs up the plugs) or persisten t (in which case irreversible bronchiectasis often is present). A lthough the condition is sporadic and uncom ­mon in the general population, it has been estim ated that as many as 10 percen t of patients w ith cystic fibrosis54 and, in some studies, as many as 25 percen t of patients w ith asthm a55 are affected.

The pathogenesis of ABPA is no t well understood and probably complex. The fungus clearly is able to survive and replicate in the mucous plugs in the proximal airways. W hether the asthm atic com ponent of the disease plays a pathogenetic role in the developm ent of these plugs or w hether these are produced solely as a reaction to the presence of fungus is unclear. Similarly, it is uncertain w hether im munologic abnorm alities such as precipitins to Aspergillus and a dual (im m ediate and late) skin hypersensitivity reaction to the fungus, are simply m arkers of disease or are involved in the pathogenesis of the pulm onary abnorm alities. As w ith aspergillomas, it is possible that toxins derived from viable or degenerating hyphae or enzym es or mediators released from host inflam matory cells are capable of injuring the adjacent airway wall, eventually resulting in bronchiectasis. W hatever the pathogenesis, at the tim e they are

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AFigure 11. Allergic bronchopulmonary aspergillosis: Radiographic appearance. A.A posteroanterior roentgenogram from a 42-year-old man with fever, cough, blood eosinophilia, and a history of asthma shows patchy airspace consolidation and atelectasis involving predominantly the left lung and the right middle lobe, continued

seen by pathologists, proximal airways containing the mucous plugs are typi­cally ectatic and inflamed; eosinophils and plasma cells predom inate. The air­way epithelium usually is intact, although there may be focal squamous metaplasia or ulceration; how ever, fungal invasion of the bronchial wall is al­most never seen.

T he diagnosis of ABPA is m ade most often on the basis of clinical, serologi­cal, and radiological findings, and it is uncom m on for m aterial to be examined pathologically. D espite this, occasional cases have atypical features and are first recognized by identification of a characteristic histological abnormality. Mucous plugs may be expectorated or washed from the airways during bronchoscopic examination. Typically, they contain num erous eosinophils and have a lami­nated, som ewhat geom etric appearance, caused by alternating bands of eosino­phils and mucus (Fig, 12).56 Fungal hyphae, often fragm ented and sometimes swollen and degenerated in appearance, are difficult to identify on H&E sec­tions bu t usually can be readily seen w ith silver stain. Nasal mucous plugs histologically identical to those in the bronchi57 have been described in 10

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BFigure 11. (cont’d) B. A full lung tomogram shows several broad, more or less linear band shadows in a distribution compatible with the normal bronchovascular bundles; one (arrow) appears to branch, (Reprinted from Fraser R.G., et a/., 7989, with permission.7)

percen t of patients w ith ABPA58 and occasionally may be a diagnostic clue to the nature of pulm onary disease.

A nother histological abnorm ality not uncom m only seen in ABPA is bron- chocentric granulom atosis.56-59'60 In fact, this tissue reaction is probably most frequently identified in association w ith ABPA and its presence, even on biopsy specim ens in w hich larger airways are not presen t, should suggest this diagno­sis. The abnorm ality may be seen in an open lung biopsy perform ed in cases of recu rren t or pers isten t radiographic abnorm alities or in lobectom y or pneum o­nectom y specim ens excised for presum ed carcinoma. As the name implies, the most p rom inen t histological feature of bronchocentric granulomatosis is necro­tizing granulom atous inflammation cen te red about small bronchi and b ron­chioles. Recognizing this localization of the inflam matory process is essential for diagnosis. Som etim es, residual airway epithelium may be presen t, indicating the bronchocentric nature of the process; w hen this is not seen, the location of

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Figure 12. Allergic bronchopulmonary aspergillosis: Mucous plug. Section of a mucous plug removed at bronchoscopy from a patient with typical ABPA shows vague lamination due to the presence of alternating bands of eosinophils and of mucus. No fungus was visible with H&E stain; however, silver stain showed fairly numerous but fragmented hyphae consistent with Aspergillus species. (H&E x40)

the disease can be inferred by the apparent absence of small airways on the tissue section, the presence of pulm onary arteries adjacent to the foci of inflam­mation, or the dem onstration of residual airway elastic tissue by appropriate stain. L ung parenchym a betw een the affected airways is variably affected and may be norm al or show obstructive pneum onitis or eosinophilic pneum onia.61

In classic cases of bronchocentric granulomatosis, a layer of palisaded epithelioid histiocytes replaces the airway epithelium and m ore or less com­pletely surrounds intralum inal necrotic debris (Fig. 13). Occasionally, however, a w ell-developed granulom atous reaction is not apparent, the inflammatory infiltrate consisting of a m ixture of lym phocytes, histiocytes, plasm a cells, neu ­trophils, and relatively num erous eosinophils (Fig. 14). In such cases, recogniz­ing the true nature of the disease can be difficult, especially w ith small tissue fragments. However, identification of the inflammatory process as bronchocen­tric should prom pt silver staining. As in the m ore typical granulomatous dis­ease, this usually shows fungal hyphae in the necrotic m aterial within the airway lum en; like th e m ore proximal mucous plugs, however, such hyphae are few in num ber and often fragm ented and degenerated.

BFigure 13. Allergic bronchopulmonary aspergillosis: Bronchocentric granulomato­sis. A. A focus of inflammation and necrosis is present adjacent to a pulmonary artery. B. Although no airway is evident on H&E stain, residual elastic tissue is focally evident with Verhoeff-van-Gieson (arrows), continued

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Figure 13. (cont’d) C. Higher magnification shows a layer of palisaded epithelioid histiocytes at the junction of viable and necrotic tissue. D. Silver stain shows several fragmented hyphae consistent with Aspergillus within the necrotic material (A. x40, B. x141, C. x250, D. x325) (Reprinted from Fraser RG, etal, 1989, with permission.7)

251

Figure 14. Allergic bronchopulmonary aspergillosis: Bronchocentric granulomato­sis. A. Low power photomicrograph shows a somewhat nodular inflammatory infil­trate situated adjacent to pulmonary arteries (arrows). Despite the absence of a rec­ognizable airway, this location indicates a bronchiolocentric process. B. Magnified view shows the inflammatory infiltrate to consist of a mixture of histiocytes, lympho- ctyes, eosinophils, and polymorphonuclear leukocytes; well-defined granulomatous inflammation is not present. Proximal bronchi were ectatic and contained mucous plugs with fragmented fungai hyphae typical of ABPA. (H&E: A. x30, B. x150)

PULMONARY ASPERGILLOSIS 2 5 3

Rarely, the histological reaction of bronchocentric granulomatosis is associ­ated w ith relatively num erous hyphae that are clustered together in colonies similar to those of invasive aspergillosis (Fig. 15). In the few reported cases62 63 and the single one that we have seen with this appearance, there has been no history of asthm a and no significant tissue or blood eosinophilia. Such findings, in addition to the presence of fungal colonies as opposed to small hvphal frag­ments, suggest that the pathogenesis of disease is related to true infection rather than an allergic reaction (see below).

INVASIVE ASPERGILLOSIS

This category includes cases in which there is extension of fungus into viable tissue. As m entioned previously, such invasion occasionally is seen in allergic and saprophytic forms of aspergillosis; usually, however, this is focal and m ini­mal in extent and does not lead to significant clinicopathologic effects. Thus, these two varieties are conceptually different from necrotizing invasive disease (in which there is invariably tissue necrosis and often im portant pathologic and clinical consequences) and are not considered under this heading. D espite these statem ents, it should be rem em bered that both aspergilloma33 and the mucous plugs of ABPA34 occasionally are the source of fungus in true invasive aspergillosis (Fig. 16). Som etim es this occurs in the setting of a previously im m unocom petent individual who develops immunodeficiency. In o ther cases, however, a clear-cut cause of im m unodeficiency is not apparent.

It is likely that most cases of invasive aspergillosis develop by inhalation of conidia normally p resen t in th e atm osphere. Sometim es, infection occurs by hem atogenous spread from a focus of aspergillosis elsew here in the body and, rarely, there is direct extension from the site of saprophytic or allergic disease as m entioned above. Some degree of im pairm ent in host defense is almost invari­able and is often due to a com bination of pre-existing disease and its therapy. The most common predisposing condition process is neoplasia, particularly acute or chronic myelogenous leukem ia, in patients who are neutropenic .64-66 Patients w ith lym phom a are also at risk, although som ewhat less so, and the disease is a relatively uncom m on complication of visceral or soft tissue malignan­cies. Cases also are seen following organ transplantation,67 viral infection (par­ticularly influenza),68 diabetes m ellitus,69 and in association with renal or h e ­patic failure.70 It is a relatively uncom m on infection in individuals with the acquired im m unodeficiency syndrom e.71 In addition to these underlying dis­eases, a history of previous therapy w ith antineoplastic drugs, corticosteroids, and/or antibiotics is common.

Rare cases of invasive aspergillosis have been reported in apparently healthy individuals w ithout the predisposing factors described above.72 It is not known w hether these are caused by particularly virulent strains of Aspergillus or are related to undetec ted im munologic abnorm alities.

Although there is overlap, invasive pleuropulm onary aspergillosis is mani-

Figure 15. Bronchocentric granulomatosis in invasive aspergillosis. A. A low power photomicrograph again shows a focus of inflammation near a pulmonary artery where a bronchus might be expected. B. Magnified view shows destruction of the air­way wall and its replacement by a granulomatous inflammatory infiltrate. This ap­pearance would be consistent with bronchocentric granulomatosus in ABPA; how­ever, fungal hyphae are present in a large colony and not as fragments, indicating a true infectious (invasive) rather than allergic pathogenesis. (H&E: A. x15, B. x130)

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Figure 16. Pulmonary aspergilloma with pleural invasion. A. An upper lobe shows marked collapse and fibrosis associated with several small foci of calcified material (short arrows), all indicative of remote tuberculosis. An aspergilloma completely fills a residual cavity (long arrow).

fested by several fairly distinct clinicopathologic forms of disease, which can conveniently be considered under six headings: acute bronchopneum onia, angioinvasive aspergillosis, acute tracheobronchitis, miliary aspergillosis, p leu ­ral aspergillosis, and chronic necrotizing aspergillosis. The first two forms are the most comm on; in one review of 92 patients with pulm onary aspergillosis (of whom 84 had invasive aspergillosis as defined in this review), they accounted for 30 and 29 cases, respectively.73

Acute BronchopneumoniaAcute Aspergillus bronchopneum onia occurs w hen there is fungal proliferation and invasion prim arily in relation to small m em branous and proximal respira-

Figure 16. (cont’d) B. Section through the area of pleural fibrosis shows patchy but extensive necrosis and granulomatous inflammation in relation to fungal hyphae. C. Hyphae are seen to better advantage with PAS stain. (B. H&E x56; C.

256 PAS x2 5 °) RePnn(ed from Fraser RG, et al, 1989, with permission.7)

PULMONARY ASPERGILLOSIS 2 5 7

tory bronchioles. It shows many of the pathologic characteristics of broncho­pneum onia of bacterial etiology. Typically, there are m ultiple foci of disease that, in the early stages, have a branching or finely nodular appearance due to involvem ent of contiguous airways (Fig. 17A). As disease progresses, infection extends from the airway lum en to the adjacent lung parenchym a w here it tends to appear as a m ore or less spherical, w ell-circum scribed area of consolidation, not infrequently distinctly w hite, and with one or m ore small foci of central cavitation or necrosis (Fig. 17B). Microscopically, there is usually an intense polym orphonuclear leukocyte reaction associated w ith necrosis of airway wall and adjacent pulm onary parenchym al tissue (Fig. 18). Fungal colonies tend to

Figure 17. Aspergillus bronchopneumonia. A. A slice of lower lobe shows numer­ous foci of white consolidation; some appear to branch (arrows) and others have a nodular shape. (Bar = 1 cm.) continued

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BFigure 17. (cont’d) B. A magnified view of lung from another patient again shows multiple discrete white nodules, some of which are associated with a central cavity (short arrow) or necrosis (long arrow).

be confined to the necrotic m aterial that appears to liquefy and drain via the involved airway, resulting in the cavities noted grossly. F u rther progression of disease can resu lt in m ore or less com plete consolidation of a portion of a lobe (confluent bronchopneum onia); however, the nodular appearance is often p re ­served, at least focally. Sometim es, such confluent disease is associated with pulm onary vascular invasion and secondary hem orrhage, in which case this typical gross appearance is obscured. Instead, the lobe or portion of a lobe is m ore or less uniformly consolidated by blood, fungal colonies, and inflam ma­tory exudate, grossly resem bling lobar (acute airspace) pneum onia (Fig. 19).74 Rarely, bronchopneum onia is lim ited in extent and appears to be relatively well controlled by host defenses, in which case the appearance is best described as an abscess.

Angioinvasive AspergillosisSince vascular infiltration can be seen in any form of invasive aspergillosis, it m ight be considered inappropriate to discuss this manifestation u nder a sepa­rate heading. However, in this variety, it is e ither clearly or (as discussed below) erroneously believed to be related to the pathologic manifestations of disease.

BFigure 18. Aspergillus bronchopneumonia. A. Early stage showing inflamed bron­chiole (B) and limited extension of fungus into adjacent parenchyma forming a well- circumscribed nodule. B. Later stage showing fungal colonies (F) and necrotic material (N) representing an early stage of the cavities illustrated in Figure 17. (H&E x25). ("A. Reprinted from Fraser RG, et al, 1989, with permission.7) 259

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AFigure 19. Aspergillus "lobar" pneumonia. A. A slice of a lower lobe shows consoli­dation of almost the entire parenchyma, only a small area at the bottom right remaining unaffected. The superior portion of the lobe appears necrotic and the inferior portion hemorrhagic, continued

In addition, the nodular form of angioinvasive disease has both radiological and pathologic appearances quite different from those of o ther types of pulm onary aspergillosis. For these reasons, a separate discussion is w arranted.

T here are two fairly distinct pathologic variants of angioinvasive aspergil­losis. In the first, affected lung appears as a w ell-circum scribed, m ore or less spherical nodule, usually 0.5 to 3 cm in diam eter. Typically, the nodule has a

Figure 19. (cont’d). Section through the latter area (B. and C.) shows alveolar airspace consolidation by blood and multiple foci of polymorphonuclear leukocytes containing fungal hyphae. (Bar = 1 cm.) (H&E: B. x40, C. x300)

A

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pale cen te r and a peripheral hem orrhagic rim (forming the so-called “target lesion”) (Fig. 20A); less commonly, it has a uniform hem orrhagic appearance (Fig. 21). Histologically, the pale area consists of lung parenchym a that shows coagulative necrosis and extensive perm eation by fungal hyphae (Fig. 20B); hem orrhage and an inflam matory reaction are absent. Vascular infiltration is usually prom inent, comm only in a relatively large vessel in the cen ter of the lesion. Not infrequently, the fungus appears to transgress the vesssel wall and fill the lum en w ithout any tissue reaction; however, in some instances, there is associated throm bosis or vasculitis. The peripheral rim of the “target lesion” consists of a zone of congested and hem orrhagic lung parenchym a, often w ith no or m inim al inflam matory cellular reaction. As might be anticipated, the central necrotic portion of the m ore uniformly hem orrhagic nodules contains abundant blood.

Because of th e presence of coagulative necrosis and vascular infiltration and apparen t occlusion by fungal hyphae, the term “infarct” is frequently used to describe these nodular lesions. However, several observations suggest that it is unlikely that ischem ia is the sole or even principle pathogenetic mechanism:

1. The areas of necrosis are characteristically spherical, a shape unlike that of the typical w edge or triangular appearance of pulm onary infarcts and difficult to explain by occlusion of a pulm onary artery.

2. Most lesions are entirely surrounded by lung parenchym a and have no relationship with the pleura, a feature most unusual for an infarct; when there is a pleural association, the nodule often retains its spherical shape, forming acute ra ther than obtuse angles w ith the p leura (Fig. 2 i ) .

3. Occasionally, two foci of disease are p resen t in lung on both sides of a fissure, the two together forming a roughly spherical nodule (Fig. 22). In this situation, it is unlikely that there are two independent sites of disease, each causing an infarct that approximates the o ther perfectly. Similarly, it is unlikely that infection originating on one side of the p leura crosses the fissure, extends to involve a relatively large vessel, and causes an infarct of the precise size and shape to match the initial lesion.

4. Coagulative necrosis identical to that of angioinvasive aspergillosis is also seen in o ther forms of disease, such as bronchitis, in w hich vascular invasion has not occurred.

Bather than ischem ic necrosis, therefore, it seems likely that these foci of nodular disease rep resen t coagulative necrosis of lung parenchym a caused by toxins or enzym es secreted by viable fungal hyphae or released by degenerating or dead ones. The abnorm ality most likely begins as a small focus of bronchitis, bronchopneum onia, or hem atogenously dissem inated pneum onitis. H yphae then proliferate and expand centrifugally in a relatively uniform fashion, killing the lung as they infiltrate it and resulting in a macroscopically visible spherical

PULMONARY ASPERGILLOSIS 263

B

Figure 20. Angioinvasive asper­gillosis: The "target lesion." Typi­cal gross (A.) and histological (B.) appearance of the “target lesion” of angioinvasive aspergillosis, con­sisting of a more or less round fo­cus of pale, necrotic lung paren­chyma surrounded by a rim of hemorrhagic tissue. (Bar = 0.5 cm.) (B. H&E x25)

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llll llll llll llll llll llll llll llll llll llll llll llll4 5 6 7 8 9

Figure 21. Angioinvasive aspergillosis. A well-circumscribed focus of necrotic lung is present adjacent to the visceral pleura. Unlike the pale central portion of the “target lesion," this has a distinct hemorrhagic appearance and resembles a true infarct. In contrast to this abnormality, however, the nodule is oval in shape and has acute rather than obtuse angles with the pleura.

nodule. The reason for the paucity of hem orrhage in some nodules and not others is unclear.

In contrast to the nodules described above, pulm onary disease in the second variety of angioinvasive aspergillosis is not spherical in shape and is clearly and consistently related to vascular damage. This variety can be a com pli­cation of any form of invasive aspergillosis and appears grossly as a well or poorly defined area of parenchym al hem orrhage or clear-cut infarction (Fig. 23). As w ith infarcts associated w ith bland throm boem boli, those associated with Aspergillus most often are located adjacent to the p leura and have a more or less triangular shape. H em orrhage alone may occur anyw here, its gross appearance depend ing on the quantity of blood extravasating into the paren­chyma and the presence of norm al anatom ic boundaries such as interlobular septa and bronchovascular bundles. As w ith the relationship betw een pulm o­nary infarcts and noninfected throm boem boli, it is unclear why some instances of pulm onary vascular occlusion lead to tissue death and others do not. Histological examination of the vessels in cases of hem orrhage usually does not reveal the source of b leeding; how ever, some disruption of the vessel wall is

PULMONARY ASPERGILLOSIS 265

Figure 22. Angioinvasive aspergillosis: transpleural spread. A more or less circu­lar focus of necrotic lung parenchyma is present in the superior segment of a lower lobe. A smaller portion of similarly necrotic lung can be seen in the adjacent upper lung. Although separated by a space on this cut, the two regions were contiguous in an adjacent slice. The appearance suggests that the two foci represent a single necrotizing process that began in the lower lobe and extended across the pleura to affect the upper lobe.

undoubtedly responsible and again may be caused by secreted fungal toxins or, possibly, th e ensuing inflam m atory reaction.

O ne uncom m on m anifestation of aspergillosis, which probably occurs most often w ith the nodular form of angioinvasive disease, is acute “m ycetom a” form ation.75 76 This com plication usually is identified radiologicallv as one or m ore foci of parenchym al consolidation that develop cavities containing roughly spherical opacities resem bling typical aspergillomas. T here is often a history of recently trea ted acute myelogenous leukem ia associated w ith neutropenia; in at

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Figure 23. Aspergillus bronchopneumonia with vascular invasion. Small portion of lung showing several well-circumscribed foci of consolidation, some of which are cavitated and others necrotic. The lung parenchyma between one of these foci and the adjacent interlobular septa is markedly hemorrhagic. Sections of this region showed Aspergillus bronchopneumonia complicated by extension of fungus from the bronchial lumen into the adjacent pulmonary artery. The lung showed airspace hemorrhage without infarction. (Bar = 0.5 cm.)

least some cases, the developm ent of the abnorm ality appears to coincide w ith clinical rem ission and the re tu rn of a normal or near-norm al granulocyte coun t.75 The gross appearance corresponds to that seen radiologically: one or m ore parenchym al cavities, each containing a fragm ent of necrotic tissue whose shape is similar to that of the cavity itself (Fig. 24). Histological examination shows the “m ycetom a” to consist o f necrotic lung within which are num erous adm ixed hyphae; the la tter do not extend into viable tissue. The cavity wall consists o f organization tissue whose inner aspect is som etimes lined by a layer

PULMONARY ASPERGILLOSIS 2 6 7

AFigure 24. Angioinvasive aspergillosis with lung sequestrum. A. The lower portion of an upper lobe shows a poorly defined area of consolidation within which is a cavity containing a fragment of necrotic material. The central portion of this resem­bles lung parenchyma, continued

of polym orphonuclear leukocytes. On the basis of this latter feature and the observation that the cavity often develops at the same tim e as the re tu rn of a normal leukocyte count, it has been suggested that the necrotic lung becomes separated from viable tissue by the action of proteolytic enzym es derived from neutrophils newly recruited to th e site of infection.75 Because the designation “m ycetom a” traditionally (although som ewhat erroneously) implies saprophytic disease, it seem s preferable to use a term such as “mycotic lung sequestrum ”76 to refer to this abnormality.

Acute TracheobronchitisThis is a distinctive manifestation of invasive aspergillosis in which infection is lim ited com pletely or predom inantly to the tracheobronchial tre e .77 It accounts

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BFigure 24. (cont’d) B. Sections of this region confirmed the presence of necrotic lung containing numerous Aspergillus hyphae. The parenchyma surrounding the consolidated area contained an interstitial leukemic infiltrate. (H&E x97)

for about 5 p ercen t of cases of invasive disease and again has several m orphologi­cal forms. The first consists of intralum inal growth of fungus involving m ore or less the en tire circum ference of the airway wall. Although infection may be lim ited to only a short segm ent of the tracheobronchial tree, not uncom m only it involves several airway branches continuously. In some cases, most bronchi in a lobe or lobes may be affected. Grossly, such disease may take the form of pseudom em branes lining and partly obstructing the airway lum en or com pletely occlusive mucous/fungus plugs (Fig. 25). Microscopically, the superficial portion of the airway wall is necrotic and acutely inflamed and contains fungal hyphae; however, extension beyond the bronchial wall is unusual and infection is often confined to the mucosa (Fig. 26). D epending on the extent and location of airway disease, affected patients may be asym ptom atic or complain of a variable degree of dyspnea and hem optysis. In severe cases, respiratory failure and death may occur.78 Since infection is lim ited predom inantly to the tracheobronchial mucosa, the cause of the disease in sym ptom atic patients can be easily overlooked during life because of the paucity of roentgenographic abnorm alities.

It is not certain why these cases are characterized by such extensive in­tralum inal growth of fungus w ith so little tissue invasion. In one rep o rt,73 the degree and duration of neu tropenia and the historyof im m unosuppressive ther-

PULMONARY ASPERGILLOSIS 2 6 9

Figure 25. Aspergillus bronchitis. A. A longitudinal section of a mainstem bron­chus shows necrotic material lining the airway wall in the form of a pseudomem­brane. The adjacent interstitial tissue is infiltrated by renal cell carcinoma. Similar pseudomembranous bronchitis was present in lobar and segmental airways; inva­sive fungus was limited to the mucosa. B. A lung slice from another patient shows occlusion of numerous medium-sized bronchi by thick gelatinous material: many segmental bronchi were similarly affected. (A. bar = 0.5 cm; B. bar = 1 cm.) (Reprinted from Clarke A, et al 1991, with permission.77)

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Figure 26. Aspergillus bronchitis. Section of plugged airway illustrated in Figure 25B shows layers of fungal hyphae and mucus within the lumen. There is necrosis and inflammation of the superficial mucosa, but the underlying cartilage and adi­pose tissue are unaffected. (H&E x i 10) (Reprinted from Clarke A, etal, 7997, with permission.77)

apy w ere less in patients w ith tracheobronchitis than in patients w ith broncho­pneum onia or angioinvasive disease. This suggested that a lesser degree of host im pairm ent may have contributed to a m ore localized form of disease. However, additional studies of this possible relationship have not been docum ented.

A second morphological variety of Aspergillus tracheobronchitis consists of one or m ore discrete plaques lim ited to a relatively small area of the airway wall. Such infection can rem ain localized to this site and grow within the lum en to form an obstructing mass that, if located in the trachea or a main bronchus, can cause acute respiratory failure .79 More commonly, however, fungus invades the tracheal or bronchial wall and extends into adjacent tissue. The ensuing disease depends largely on the site o f the original airway plaque. If it is situated in the trachea or a m ainstem bronchus, complications include fistula formation betw een the airway and the m ediastinum , esophagus, or pleura80 and pulm o­nary artery invasion w ith pleural hem orrhage. W hen it is located in m ore distal bronchi, extension can cause pneum onia, abscess, and parenchym al hem or­rhage or infarction.

The final form of tracheobronchial aspergillosis is the least comm on and is seen predom inantly in the sm aller bronchi and bronchioles.62-63 It may be local­ized to one lobe or d istribu ted m ore or less diffusely throughout the lung, patients p resen ting w ith productive cough in the form er situation and progres­

PULMONARY ASPERGILLOSIS 271

sive dyspnea in the latter. Histologically, the abnorm ality is characterized by bronchocentric granulom atosis, w ith necrosis of airway mucosa and its replace­m ent by palisaded epithelioid histiocytes and granulation tissue (see Fig. 15). Although similar to distal airway disease in ABPA, there are two im portant differences: the virtual absence of eosinophils and the presence of fungal hyphae in dense colonies ra ther than as scattered fragments. This variant has been described in clearly im m unocom prom ised individuals in whom it has progressed fairly rapidly and has eventually led to invasive parenchym al dis­ease.81 However, it also has been reported in apparently im m unocom petent individuals62 and we have seen it progress slowly over a period of months.

Miliary AspergillosisMiliary aspergillosis occurred in 9 (12 percent) of the 84 cases of invasive aspergillosis in one large review m entioned73; however, our own experience and that in the rem aining lite ra tu re suggests that it is less common than this. As with the m ore frequen t tuberculous infection, this form of aspergillosis rep re ­sents w idespread hem atogenous dissem ination to all parts of the lung. H isto­logically, m inute colonies of A spergillus are d istributed random ly w ithin the lung parenchym a, w hich is itself consolidated by a variable am ount of edem a and hem orrhage.

Pleural AspergillosisPleural disease is an uncom m on complication of pulm onary Aspergillus infec­tion that can develop by several mechanisms. As noted above, invasion of fungus from a localized p laque in a main bronchus can result in a broncho­pleural fistula w ith associated pneum othorax, pleural effusion, and/or Aspergil­lus p leuritis. Similarly, extension from the same site into a main pulm onary artery can cause sudden and massive hemothorax. P leural invasion w ith local­ized pleuritis and a small p leural effusion is not uncom m on in association with extensive bronchopneum onia; however, such disease is usually an incidental finding of little clinical im portance. Infrequently, fungi derived from an aspergil- loma invade the p leural space or adjacent fibrotic p leura (see Fig. 16). In one report of six such patients, most had a rem ote history of therapeutic pneum o­thorax for tuberculosis.82 Rare cases also have been reported of pleural aspergil­losis following aspergillom a resection com plicated by intraoperative rup tu re83 and after pneum onectom y.84 In the la tter situation, the fungus first forms an aspergillom a in the bronchial stum p and then extends from that site into the residual pleural cavity.

Chronic Necrotizing AspergillosisThis is a rare m anifestation of invasive aspergillosis whose pathologic features and pathogenesis are poorly understood .85 As the nam e suggests, the disease has a relatively indolent clinical course, with a history of fever, cough, and sputum production occurring over a period of m onths (and occasionally years) prior to diagnosis. Radiographic changes are seen most often in the upper lobes

Figure 27. Chronic necrotizing aspergillosis. A. The upper portion ot a right lung shows extensive fibrosis, focal necrosis, and cavity formation, an appearance resembling chronic fibrocaseous tuberculosis. B. Histological section of affected lung shows a focus of necrotizing granulomatous inflammation within which were fungi consistent with Aspergillus. No acid-fast organisms were identified. The pa­tient was a middle-aged alcoholic man with bilateral upper lobe disease that pro­gressed over a period of about 4 months, (H&E x43)

PULMONARY ASPERGILLOSIS 2 7 3

or superior segm ents of th e low er lobes and resem ble those of chronic fibrocaseous tuberculosis. Many patients have an underlying pulm onary abnor­mality such as long-standing infarct, inactive tuberculosis, or fibrosis related to radiation, prior lobectomy, or pneumoconiosis. Some derangem ent of systemic host defense may be presen t, b u t typically is not of the degree seen w ith the more comm on forms of invasive aspergillosis. U nderlying abnorm alities include diabetes m ellitus, connective tissue disorders, and poor nutrition. Some pa­tients have undergone a course of low-dose steroid therapy before the onset of disease; however, a history of in tensive im m unosuppressive therapy is invari­ably absent.

Pathologic findings in these cases rarely have been described. In some, there is a com bination of fibrosis, cavitation (sometimes with the presence of lung sequestra as described in angioinvasive disease), and necrotizing granulo­matous inflammation (Fig. 27), the w hole resem bling the appearance of chronic fibrocaseous tuberculosis.85 Since Aspergillus can colonize the cavities of tu b e r­culosis, the m ere p resence of fungus in these cases does not establish the diagnosis; in o rder to do this, hyphae m ust be identified in tissue and in direct relation to foci of granulom atous inflammation. In addition to necrotizing paren­chymal disease, it has been suggested that bronchocentric granulomatosis (as described in the section on invasive tracheobronchial disease) may be a tissue reaction in some cases.63

SUMMARY

Pulm onary aspergillosis is a relatively common fungal infection in individuals who are im m unocom prom ised or have intrinsic lung disease. Clinical, radio­logical, and pathologic m anifestations are quite varied and depend to a large extent on the type and severity of local or systemic host defense abnorm ali­ties. In individuals w ith only structural lung damage, saprophytic growth alone is the rule. Patients w ith atopy or o ther hypersensitivity state typically develop allergic disease, most often allergic bronchopulm onary aspergillosis. Individuals with o ther im m unologic abnorm alities, particularly im m unodefi­ciency, and with granulocytopenia characteristically develop invasive disease, which may take several m orphological forms. Identification of Aspergillus as the cause of all these disease variants is usually not a problem . However, recognition of the different pa tterns of disease is useful in understanding the pathogenesis of disease and in in terp re ting prem ortem clinical and radio- graphic abnorm alities.

Acknowledgments. The au thor gratefully acknowledges A nthony Graham and Joseph D onohue for photographic help and D onna O ’Connor for preparing the m anuscript.

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