4/2/2019 Clinical manifestations and diagnosis of chronic pulmonary aspergillosis - UpToDate

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Clinical manifestations and diagnosis of chronic pulmonary

aspergillosis
Author: David W Denning, MBBS, FRCP, FRCPath, FMedSci
Section Editor: Carol A Kauffman, MD
Deputy Editor: Anna R Thorner, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2019. | This topic last updated: Aug 01, 2018.

INTRODUCTION

Chronic pulmonary aspergillosis includes several disease manifestations, including aspergilloma,

Aspergillus nodules, chronic cavitary pulmonary aspergillosis, and chronic fibrosing pulmonary
aspergillosis. Subacute invasive pulmonary aspergillosis (formerly known as chronic necrotizing
aspergillosis) is on the spectrum between chronic and acute forms of pulmonary aspergillosis (see
'Definitions' below). A duration of disease longer than three months distinguishes chronic pulmonary
aspergillosis from acute and subacute pulmonary aspergillosis.

The pathophysiology, clinical manifestations, and diagnosis of chronic pulmonary aspergillosis will be
reviewed here. The treatment of chronic pulmonary aspergillosis as well as allergic
bronchopulmonary aspergillosis and invasive aspergillosis is discussed separately. (See "Treatment
of chronic pulmonary aspergillosis" and "Clinical manifestations and diagnosis of allergic
bronchopulmonary aspergillosis" and "Epidemiology and clinical manifestations of invasive
aspergillosis".)

DEFINITIONS

Chronic pulmonary aspergillosis describes several patterns of disease. However, the terminology that
has been developed can be difficult to apply to a spectrum of disease entities that have considerable
overlap and variation in severity. The following terminology will be used to describe the spectrum of
disease; each entity is characterized by specific radiographic findings [1,2].

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Aspergilloma — An aspergilloma is a fungus ball composed of Aspergillus hyphae, fibrin, mucus,

and cellular debris found within a pulmonary cavity [3]. Aspergillomas arise in preexisting pulmonary
cavities that have become colonized with Aspergillus spp and are the result of growth of fungus on
the cavity wall that detaches into the cavity, often forming a rounded shape, sometimes with air within
it [1].

If the aspergilloma is single, the cavity stable over months, and the patient has few symptoms (ie, a
mild cough only) and little evidence of systemic inflammation, a simple aspergilloma may be
diagnosed. We will use the term "simple aspergilloma" to distinguish this entity from the more
complex forms of chronic pulmonary aspergillosis. (See 'Diagnosis' below.)

Aspergillus nodule — Aspergillus nodules occur in immunocompetent hosts, may be single or

multiple, and may or may not have cavitation within them [4]. The differential diagnosis includes
carcinoma of the lung, nontuberculous mycobacterial infection, and coccidioidal or other fungal
nodules. Patients are usually asymptomatic, but some have a new minor pulmonary symptom such
as cough, an incidental chest infection, or an exacerbation of asthma or chronic obstructive
pulmonary disease. Using positron emission tomography (PET) scanning, Aspergillus nodules are
fluorodeoxyglucose avid to variable degrees [5] and are usually accompanied by a positive
Aspergillus immunoglobulin (Ig)G titer in the blood. On histopathology, necrosis is surrounded by
granulomatous inflammation with occasional multinucleate giant cells [6]. The center of the necrotic
material contains fungal hyphae.

Chronic cavitary pulmonary aspergillosis — The term "chronic cavitary pulmonary aspergillosis"
describes a pattern of disease in immunocompetent patients in whom there is formation and
expansion of one or more pulmonary cavities over months (image 1 and image 2 and image 3 and
image 4) [1]. This term is preferred over the older term "complex aspergilloma" because more than 50
percent of such patients don't have an aspergilloma visible radiographically. Almost all patients with
chronic cavitary pulmonary aspergillosis have Aspergillus IgG antibodies in the blood. (See
'Radiographic features' below and 'Laboratory findings' below.)

Chronic fibrosing pulmonary aspergillosis — Chronic fibrosing pulmonary aspergillosis is a late-

stage manifestation of chronic cavitary pulmonary aspergillosis in which progression to marked and
extensive fibrosis has occurred, sometimes called "destroyed lung" [1,7].

Subacute invasive pulmonary aspergillosis (chronic necrotizing pulmonary

aspergillosis) — Patients with some degree of immunocompromise who present with progressive
features over one to three months have subacute invasive pulmonary aspergillosis (formerly known
as chronic necrotizing pulmonary aspergillosis). This manifestation typically occurs in patients with
diabetes mellitus, malnutrition, alcoholism, advanced age, prolonged glucocorticoid use or other

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modestly immunosuppressive agents, chronic obstructive pulmonary disease, connective disease,

radiation therapy, nontuberculous mycobacterial infection, or human immunodeficiency virus (HIV)
infection [2]. Hyphal invasion of tissue is observed histologically or can be inferred based upon
radiographic findings, including cavitation [1]. Such patients usually have a single thin-walled cavity or
area of cavitating pneumonia/consolidation and may have detectable Aspergillus antigen
(galactomannan) or Aspergillus IgG antibodies in blood.

PATHOPHYSIOLOGY

The pathogenesis of chronic pulmonary aspergillosis remains incompletely understood. Although

patients with chronic pulmonary aspergillosis are generally immunocompetent, most patients with
chronic pulmonary aspergillosis have either prior pulmonary damage or disease. Aspergillomas
usually always arise in preexisting cavities in the lungs, but the cavity may form initially as a
component of chronic pulmonary aspergillosis. Increasing evidence supports major and complex
genetic factors in patients with chronic cavitary pulmonary aspergillosis, consistent with an inability to
control Aspergillus in the lung, and subsequent persistent inflammation. Low numbers of CD19,
CD56, and/or CD4 cells are common in patients with chronic pulmonary aspergillosis [8].

Mycology — Almost all cases of chronic pulmonary aspergillosis are caused by Aspergillus
fumigatus, although patients have been described with A. niger or A. flavus infection [9,10].
Occasionally, A. fumigatus isolates may be atypical, growing slowly with poor sporulation, delaying
identification.

Underlying diseases — The most common underlying diseases that predispose patients to chronic
pulmonary aspergillosis include pulmonary tuberculosis, nontuberculous mycobacterial infection,
allergic bronchopulmonary aspergillosis, asthma (usually treated by courses of glucocorticoids), lung
cancer (following successful treatment), prior pneumothorax with associated bulla formation, chronic
obstructive pulmonary disease, and fibrocavitary sarcoidosis (table 1) [11,12]. Rarer causes include
rheumatoid arthritis, ankylosing spondylitis, silicosis, pneumoconiosis, and hyperimmunoglobulin E
syndrome. Chronic pulmonary aspergillosis can also evolve from invasive pulmonary aspergillosis
that has not completely resolved.

Patients with classical pulmonary tuberculosis who are left with cavities of ≥2 cm have an
approximately 20 percent chance of subsequently developing aspergillomas and/or chronic
pulmonary aspergillosis [13-15]. In a study that used modeling to estimate the global burden of
chronic pulmonary aspergillosis as a sequela of pulmonary tuberculosis, the prevalence of chronic
pulmonary aspergillosis varied widely, with a lower prevalence in developed countries than in
developing countries [16]. Overall, an estimated 1.2 million people have chronic pulmonary

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aspergillosis following pulmonary tuberculosis, of whom approximately 300,000 live in India [17]. A
cross-sectional study from Nigeria indicates that 8.7 percent of patients with tuberculosis had chronic
pulmonary aspergillosis, whether HIV infected or not, with the highest rate in smear and GeneXpert
negative TB cases (19 percent) [18]. Patients with a history of pulmonary infection caused by
nontuberculous mycobacteria, such as M. xenopi, M. malmoense, or M. avium complex, may have a
higher rate of subsequent chronic pulmonary aspergillosis when compared with patients with a history
of pulmonary tuberculosis [11].

Unlike the other forms of chronic pulmonary aspergillosis, subacute invasive pulmonary aspergillosis
often occurs in immunocompromised patients such as those with diabetes mellitus, alcoholism, and
individuals receiving glucocorticoids [1] (see 'Role of glucocorticoids' below). In contrast, invasive
aspergillosis occurs most commonly in profoundly immunocompromised patients, such as
neutropenic patients with hematologic malignancies, and transplant recipients. (See "Epidemiology
and clinical manifestations of invasive aspergillosis".)

Genetic defects — Many patients with chronic pulmonary aspergillosis appear to have genetic
defects in one or more innate immune functions, such as toll-like receptor (TLR) 4, interleukin 15,
TLR3, TLR10, triggering receptor expressed on myeloid cells (TREM1), vascular endothelial growth
factor A (VEGFA), DENND1B (a gene expressed by natural killer cells and dendritic cells), and/or
plasminogen activator gene (PLAT) [19-21]. The interrelationship of these defects with disease
expression is complex. Cytokine production profiles are most consistent with a Th2 profile in these
patients [22]. Macrophages from patients with chronic cavitary pulmonary aspergillosis produce large
amounts of the neutrophil chemoattractant pro-platelet basic protein (CXCL7), suggesting low
interleukin 10 levels or activity [23]. (See "The adaptive cellular immune response: T cells and
cytokines", section on 'Th2'.)

Patients with chronic pulmonary aspergillosis frequently have poor antibody responses to
polysaccharide antigens [24]. Many have a diminished interferon-gamma response. (See "Treatment
of chronic pulmonary aspergillosis", section on 'Clinical failure'.)

Role of glucocorticoids — Glucocorticoids given without antifungal therapy in patients with chronic
pulmonary aspergillosis may accelerate lung destruction, especially in patients with sarcoidosis or
rheumatoid arthritis. Presumably, cavities expand because the Aspergillus growing on the interior
surface of the cavity secretes proteins (eg, proteases, phospholipases, catalases, and others) or
secondary metabolic products (eg, gliotoxin), which lead to ongoing inflammation and progressive
localized lung tissue damage. It is not clear why new cavities form without tissue invasion being
demonstrable, why fungal balls are present in some cavities and not others, and why abnormal
bronchial arterial vasculature forms, resulting in hemoptysis. Glucocorticoids may be helpful in
resolving inflammation in those receiving adequate antifungal therapy.

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Pathology — Aspergillomas in the lung are rounded conglomerates of hyphae, mucus, and cellular
debris that may be loosely attached to the wall of a pulmonary cavity [3]. On histologic section, a
pulmonary aspergilloma has a lamellar appearance due to the accumulation of sequential layers of
fungal hyphae combined with fungal extracellular matrix that have grown on the interior surface of the
cavity and sloughed off. Oxalate crystals may be visible in tissue, especially in patients with A. niger
infection [9].

Chronic cavitary pulmonary aspergillosis is characterized pathologically by chronic inflammation with

localized fibrosis, usually without granulomas, necrosis, or eosinophilic infiltrates. Cavity walls may be
composed of three layers: necrotic, granulation, and fibrotic tissue [25]. Hyphae do not invade tissue
unless the patient becomes immunocompromised, when localized invasive disease supervenes. The
distinction between chronic cavitary pulmonary aspergillosis and subacute invasive pulmonary
aspergillosis is particularly difficult in patients with rheumatoid arthritis receiving modest doses of
immunosuppressants.

Chronic fibrosing pulmonary aspergillosis is characterized by extensive fibrosis and some chronic
inflammation distant from a cavity and involving large sections of lung [1].

CLINICAL FEATURES

Patients with chronic pulmonary aspergillosis vary in age from 20 to over 80 years old but are
typically in their middle years. In a series of 18 patients with chronic pulmonary aspergillosis, the
median age was 59 [1]. The cavitary and fibrosing forms of chronic pulmonary aspergillosis usually
progress slowly over months or years, but the subacute invasive form usually progresses more
rapidly over weeks.

Signs and symptoms — Patients with chronic pulmonary aspergillosis present most commonly with
a several month history of weight loss, chronic productive cough, hemoptysis of variable severity,
fatigue, and/or shortness of breath [1,26-28]. Fever and night sweats occur occasionally. The
systemic symptoms of chronic cavitary pulmonary aspergillosis are an important point of distinction
from a simple aspergilloma, in which these do not occur.

In a series of 18 patients with chronic pulmonary aspergillosis, the various signs and symptoms were
present with the following frequencies [1]:

● Weight loss – 17 patients (94 percent)

● Cough, which is usually productive – 14 patients (78 percent)
● Shortness of breath – 9 patients (50 percent)
● Hemoptysis – 10 patients (58 percent)

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● Moderate to severe fatigue/malaise – 5 patients (28 percent)

● Chest pain – 3 patients (17 percent)
● Substantial sputum production – 2 patients (11 percent)
● Fever – 2 patients (11 percent)

It is likely that the patients with fever had subacute invasive pulmonary aspergillosis or a coexistent
bacterial infection, as patients with the other forms of chronic aspergillosis rarely have fever.

Radiographic features — Radiographic examination usually reveals one or more cavities, typically
within the upper lobes, which may or may not contain fungus balls (image 1 and image 2 and image 3
and image 4) [1,29].

A simple aspergilloma is a fungus ball in a single pulmonary cavity with limited surrounding
inflammation, pleural thickening, or fibrosis. The radiographic appearance remains stable over
several months, unlike in chronic cavitary pulmonary aspergillosis, in which cavities may expand or
coalesce. It develops from detachment of layers of growth of fungus on the inner cavity wall over
weeks or months, with several intermediate appearances before being seen as a typical fungal ball
[30].

Chronic cavitary pulmonary aspergillosis usually begins as ill-defined regions of consolidation that
progress to form clearly defined cavities [1]. Cavities may contain fungus balls, debris, or fluid. There
are often multiple cavities of different sizes. It is most common for the cavities to be thin-walled and to
lack associated pleural thickening, although both thick cavity walls and pleural thickening occur in
some cases. If pericavitary infiltrates and pleural thickening adjacent to cavities are present, they
generally improve very slowly with appropriate therapy, leaving residual thin-walled empty cavities.
New cavity formation or expansion of one or more existing cavities over time is highly characteristic
and typically occurs over months in the absence of treatment.

Single or multiple nodules are also seen in chronic pulmonary aspergillosis [5]. They are not usually
spiculated and are therefore not typical of lung carcinoma; nevertheless, carcinoma should always be
considered in the differential diagnosis. These may or may not cavitate, forming a small air crescent,
and may develop into larger cavities over time. Such nodules have been noted to be moderately or
strongly positive on positron emission tomography (PET) scanning, mimicking carcinoma of the lung
[5].

Chronic fibrosing pulmonary aspergillosis is characterized by the same radiographic findings that
occur with chronic cavitary pulmonary aspergillosis in combination with significant fibrosis.

In contrast with chronic cavitary pulmonary aspergillosis, thin-walled cavities or consolidation with
cavitation associated with subacute invasive pulmonary aspergillosis usually worsen over weeks to a

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few months [1].

Although the diagnosis of chronic pulmonary aspergillosis can be inferred from a single chest
radiograph, detailed and sequentially acquired radiographic data may be required to observe both the
typical radiographic features and the very slow progression (over months or years) that is
characteristic of the cavitary and fibrotic forms of this disease. Computed tomography (CT) scans are
useful to define the precise pattern and extent of involvement. PET scans are usually positive at
varying levels of intensity but do not discriminate between different causes [5,31].

Serial imaging is useful not only for following the progression of disease prior to starting therapy but
also for evaluating the response to therapy, although it improves very slowly. (See 'Monitoring during
therapy' below.)

Laboratory findings — The cardinal test for chronic pulmonary aspergillosis is a positive Aspergillus
immunoglobulin (Ig)G antibody test from the serum [32-35]. Previously, Aspergillus precipitins were
done but appear to be less sensitive [32]. Most patients with chronic cavitary pulmonary aspergillosis,
including those with simple aspergillomas and Aspergillus nodules, have positive Aspergillus IgG
antibodies in the blood [36-39]. Patients with a negative test but highly suspicious findings should
have an alternative Aspergillus IgG test performed. Very few centers offer Aspergillus IgG testing for
non-fumigatus species. These tests may be useful in those with negative A. fumigatus IgG tests but
are not standardized or validated.

The differential diagnosis of a positive Aspergillus IgG test if there is radiologic or clinical uncertainty
about the diagnosis of CPA includes Aspergillus bronchitis, allergic bronchopulmonary aspergillosis,
chronic or allergic Aspergillus rhinosinusitis, invasive pulmonary aspergillosis (acute or resolved), and
subacute invasive pulmonary aspergillosis.

More than 50 percent of patients with chronic pulmonary aspergillosis have positive Aspergillus IgE
tests, and some have slightly elevated total serum IgE levels without having allergic
bronchopulmonary aspergillosis (ABPA) [1]. Patients with ABPA as their underlying diagnosis usually
have very high total IgE and Aspergillus IgE results. (See "Clinical manifestations and diagnosis of
allergic bronchopulmonary aspergillosis".)

A minority of patients (10 to 40 percent) with chronic pulmonary aspergillosis have positive cultures of
A. fumigatus (or rarely other Aspergillus species) in their sputum [26]. Multiple samples increase the
recovery rate. A higher proportion has a positive Aspergillus polymerase chain reaction (PCR) from
the sputum or bronchoalveolar lavage (BAL) fluid. Among 42 patients with chronic pulmonary
aspergillosis, 71 percent had a positive PCR from the sputum but only 17 percent had a positive
culture [40]. However, 4 of 11 normal volunteers had a positive PCR from BAL, so false-positive
results can occur and are likely due to transient colonization or contamination of samples.

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Galactomannan is also detectable in BAL fluid in about 50 to 90 percent of patients [41,42].

Galactomannan in sputum is not a useful test as it is so frequently positive and cut-offs have not been
established for chronic pulmonary aspergillosis [43].

Elevated galactomannan and 1,3-beta-D-glucan levels have been reported in serum in some patients
with chronic pulmonary aspergillosis [31,42,44,45]. In a retrospective cohort study that included 48
patients with pulmonary aspergilloma, the galactomannan assay had a sensitivity of 38 percent for
serum and 92 percent for BAL fluid [41]. Galactomannan detection from serum was higher in patients
with hemoptysis compared with those without hemoptysis (52 versus 9 percent). (See "Diagnosis of
invasive aspergillosis", section on 'Galactomannan antigen detection'.)

Elevated inflammatory markers, such as C-reactive protein and/or erythrocyte sedimentation rate, are
very common in patients with chronic pulmonary aspergillosis but are not specific [1].

Pulmonary function testing — Most patients have significant reduction in pulmonary function, with
the character and degree of abnormalities reflecting their underlying pulmonary disease. Chronic
fibrosing pulmonary aspergillosis leads to major reductions in vital and diffusing capacity, often with
abnormally low oxygen saturations. Hypoxic respiratory failure with either hypocapnia or hypercapnia
may occur, typically during an acute bacterial infection.

A flight assessment is useful to determine the need for supplemental oxygen for air travel. (See
"Traveling with oxygen aboard commercial air carriers".)

DIAGNOSIS

Once chronic pulmonary aspergillosis is considered, usually on the basis of general symptoms of
fatigue and weight loss with one or more cavities in one or both lung apices with negative tests for
tuberculosis, the diagnosis is established by a positive Aspergillus immunoglobulin (Ig)G serology.
Some patients have a positive culture of Aspergillus spp from the lungs, but this alone is insufficient
to make the diagnosis of chronic pulmonary aspergillosis if Aspergillus IgG antibodies are negative or
pending.

In patients with negative fungal cultures, bronchoscopy should be considered to collect samples for
fungal and mycobacterial stains and cultures and to exclude malignancy. Nontuberculous
mycobacterial disease can precede, occur concurrently with, or follow chronic pulmonary
aspergillosis. Concurrent bacterial infection (often an exacerbation of bronchiectasis) is common and
occasionally occurs in a cavity, resulting in a fluid level. Ultrasound- or computed tomography (CT)-
guided aspiration may be required to document the pathogen, such as methicillin-resistant
Staphylococcus aureus or Pseudomonas aeruginosa.

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Aspergilloma — The criteria for the diagnosis of aspergilloma are radiologic evidence of a rounded
mass in a pulmonary cavity combined with microbiologic evidence of Aspergillus as the causative
agent, usually a positive culture from sputum or detectable Aspergillus IgG [46]. Since aspergillomas
may occur in the context of chronic cavitary pulmonary aspergillosis, the distinction between a simple
aspergilloma and chronic cavitary pulmonary aspergillosis relies on symptomatology, evidence of
inflammation, the radiologic appearance, and change over time. If the aspergilloma is single, the
cavity stable over months, and the patient has few symptoms (ie, a mild cough only) and little
evidence of systemic inflammation, a simple aspergilloma may be diagnosed.

Aspergillus nodule — The diagnosis of an Aspergillus nodule can be made in an immunocompetent

patient in whom lung carcinoma has been excluded by the combination of one or more lung nodules
on lung imaging and either a percutaneous or surgical biopsy (eg, by video-assisted thorascopic
surgery) showing Aspergillus in tissue or a positive Aspergillus IgG titer in blood [2,4].

Chronic cavitary pulmonary aspergillosis — The specific criteria we suggest for the diagnosis of
chronic cavitary pulmonary aspergillosis are [1,2,26]:

● One large cavity or two or more cavities on chest imaging with or without a fungal ball
(aspergilloma) in one or more of the cavities

and

● At least one of the following symptoms for at least three months: fever, weight loss, fatigue,
cough, sputum production, hemoptysis, or shortness of breath

and

● A positive Aspergillus IgG with or without culture of Aspergillus spp from the lungs

Some patients may have concurrent infection with nontuberculous mycobacteria or other bacteria.
Coccidioidomycosis, chronic cavitary pulmonary histoplasmosis, and paracoccidioidomycosis should
be excluded.

Chronic fibrosing pulmonary aspergillosis — The criteria for the diagnosis of chronic fibrosing
pulmonary aspergillosis are similar to those for chronic cavitary pulmonary aspergillosis. In addition,
substantial areas of fibrosis (determined by biopsy or inferred from CT scanning of the thorax) in
immediate proximity to an area of chronic cavitary pulmonary aspergillosis are seen, and there is
major impairment of respiratory function.

Subacute invasive pulmonary aspergillosis (chronic necrotizing pulmonary

aspergillosis) — As noted above, most patients with subacute invasive pulmonary aspergillosis
(formerly known as chronic necrotizing pulmonary aspergillosis) have some evidence of
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immunosuppression. The criteria for the diagnosis of subacute invasive pulmonary aspergillosis are
similar to those for invasive pulmonary aspergillosis, but the subacute form progresses more slowly
than the acute form (over 1 to 3 months versus over 0 to 4 weeks) [2]. Patients may have detectable
Aspergillus antigen (galactomannan) or Aspergillus IgG antibody in the blood [39,46]. Confirmation
requires a biopsy of the pulmonary lesion. (See "Diagnosis of invasive aspergillosis", section on
'Diagnostic modalities'.)

MONITORING DURING THERAPY

Aspergillus immunoglobulin (Ig)G and inflammatory markers (C-reactive protein, plasma viscosity,
and/or erythrocyte sedimentation rate) should be repeated approximately every 3 months during
therapy and chest radiographs every 6 to 12 months, depending on clinical status (ie, earlier if
deterioration occurs). Computed tomography (CT) scans of the thorax are indicated if there is a major
change in clinical status not attributable to a concurrent bacterial infection, new chest radiographic
findings despite apparent clinical improvement, and for follow-up evaluation every 12 to 24 months,
until clinical stability on therapy is achieved. If the patient does not have hemoptysis, contrast is not
required. Low-dose CT is a useful means of minimizing the radiation dose. The expected changes in
laboratory and radiographic findings following the initiation of therapy are discussed separately. (See
"Treatment of chronic pulmonary aspergillosis", section on 'Assessing treatment response'.)

Apparent exacerbations must be distinguished from concurrent bacterial respiratory infections,

exacerbations of asthma and/or allergic bronchopulmonary aspergillosis, recurrence or development
of tuberculosis or nontuberculous mycobacterial infection, and tumor development or recurrence in
those at risk. (See "Treatment of chronic pulmonary aspergillosis", section on 'Clinical failure'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Aspergillosis".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The
Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
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detailed. These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-
mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on “patient info” and the keyword(s) of interest.)

● Basics topic (see "Patient education: Chronic pulmonary aspergillosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Chronic pulmonary aspergillosis includes several disease manifestations, including aspergilloma,

Aspergillus nodules, chronic cavitary pulmonary aspergillosis, and chronic fibrosing pulmonary
aspergillosis. Subacute invasive pulmonary aspergillosis (formerly known as chronic necrotizing
aspergillosis) is on the spectrum between chronic and acute forms of pulmonary aspergillosis. A
duration of disease longer than three months distinguishes chronic pulmonary aspergillosis from
acute and subacute pulmonary aspergillosis. (See 'Introduction' above and 'Definitions' above.)

● Almost all cases of chronic pulmonary aspergillosis are caused by Aspergillus fumigatus,
although patients have been described with A. niger or A. flavus infection. (See 'Mycology'
above.)

● Almost all patients with chronic pulmonary aspergillosis have either prior pulmonary damage or
disease. The most common underlying diseases that predispose patients to chronic pulmonary
aspergillosis include pulmonary tuberculosis, nontuberculous mycobacterial infection, allergic
bronchopulmonary aspergillosis, lung cancer (following successful treatment), prior
pneumothorax with associated bulla formation, chronic obstructive pulmonary disease, and
fibrocavitary sarcoidosis (table 1). (See 'Underlying diseases' above.)

● Many patients with chronic pulmonary aspergillosis have genetic defects in one or more innate
immune functions and have a diminished interferon-gamma response. (See 'Genetic defects'
above.)

● Patients with chronic cavitary pulmonary aspergillosis present most commonly with weight loss,
chronic productive cough, hemoptysis of variable severity, fatigue, and/or shortness of breath.
Fever and night sweats occur occasionally. The systemic symptoms of chronic cavitary
pulmonary aspergillosis are an important point of distinction from a simple aspergilloma, in which
these do not occur. (See 'Signs and symptoms' above.)

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● Radiographic examination usually reveals one or more cavities, typically within the upper lobes,
which may or may not contain fungus balls. New cavity formation or expansion of one or more
existing cavities over time is highly characteristic of chronic cavitary pulmonary aspergillosis.
(See 'Radiographic features' above.)

● The cardinal test for chronic pulmonary aspergillosis is a positive Aspergillus immunoglobulin
(Ig)G antibody test from the serum. Serum galactomannan is usually negative, and 1,3-betaD-
glucan is often positive. However, standardization of this testing is not well established for this
indication. A minority of patients with chronic pulmonary aspergillosis has positive cultures of A.
fumigatus (or rarely other Aspergillus species) in their sputum, but Aspergillus polymerase chain
reaction from the sputum is usually positive. More than 50 percent of patients have positive
Aspergillus IgE tests, and some have slightly elevated total serum IgE levels without having
allergic bronchopulmonary aspergillosis. (See 'Laboratory findings' above.)

● Elevated inflammatory markers, such as C-reactive protein and/or erythrocyte sedimentation

rate, are very common in patients with chronic pulmonary aspergillosis but are not specific. (See
'Laboratory findings' above.)

● Once chronic pulmonary aspergillosis is considered, usually on the basis of general symptoms of
fatigue and weight loss with one or more cavities in one or both lung apices with negative tests
for tuberculosis, the diagnosis is established by a positive Aspergillus IgG. Some patients have a
positive culture of Aspergillus spp from the lungs, but this alone is insufficient to make the
diagnosis of chronic pulmonary aspergillosis if Aspergillus IgG antibodies are negative or
pending. (See 'Diagnosis' above.)

● Aspergillus IgG and inflammatory markers (C-reactive protein and erythrocyte sedimentation
rate) should be repeated approximately every 3 months during therapy and chest radiographs
every 6 to 12 months, depending on clinical status (ie, earlier if deterioration occurs). (See
'Monitoring during therapy' above.)

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GRAPHICS

Chronic pulmonary aspergillosis

(A) Chest radiograph showing a large left upper lobe cavity, with some pleural thickening
and minor pericavitary infiltrates inferiorly, with no evidence of an aspergilloma. Otherwise,
the lung fields are abnormal, with subtle infiltrates most consistent with sarcoidosis. He
presented with significant hemoptysis, weight loss, cough, and fatigue over several months.
(B) Bronchial artery angiogram in the same patient, showing a extensive network of
additional vessels surrounding the empty cavity, which were successfully embolized.

Reproduced with permission from: Denning DW. Chronic aspergillosis. In: Aspergillus fumigatus
and aspergillosis, Latge JP, Steinbach WJ (Eds). ASM Press, Washington, DC 2009. Copyright ©
2009 ASM Press.

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Chronic pulmonary aspergillosis

(A) Chest radiograph showing several left upper lobe cavities, tracheal deviation
indicating collapse due to contraction and fibrosis, as well as marked pleural
thickening. There are marked infiltrates inferior to the largest cavity and a linear
opacity extending inferiorly from there. No overt aspergilloma is visible.
(B) Computed tomography scan of the same patient, showing multi-cavity
disease on the left and some emphysema on the right. There is gross
mediastinal shift to the left. The cavities in the left are of variable size and at
least one contains an aspergilloma. The pleural thickening is variable in
thickness, and some fibrosis is visible between the cavities.

Reproduced with permission from: Denning DW. Chronic aspergillosis. In: Aspergillus
fumigatus and aspergillosis, Latge JP, Steinbach WJ (Eds). ASM Press, Washington,
DC 2009. Copyright © 2009 ASM Press.

Graphic 65409 Version 6.0

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Chronic pulmonary aspergillosis

(A) Chest radiograph in 1969 in a patient aged 24 with asthma with bronchiectasis
showing mild left mid-zone shadows consistent with bronchiectasis and a small area of
opacification in the left base, with left apical scarring. New streaky shadowing is
projected over the left heart border.
(B) Chest radiograph in same patient in 1981 (aged 36) following first radiological
feature of allergic bronchopulmonary aspergillosis (ABPA; clearance of the left upper
lobe shadowing after physiotherapy and corticosteroids). Compared with 1969, there
is now extensive bronchiectasis in the left lower and right lower lobes.
(C) Chest radiograph in same patient in 1985 (aged 40), with first clue of chronic
cavitary pulmonary aspergillosis. The chest radiograph shows development of right
upper pleural thickening with further volume loss, without extensive fibrotic disease.
There is more obvious new cavity formation in the left upper lobe with unchanged
thickened bronchi in the left mid zone. A mild scoliosis has developed.
(D) Chest radiograph in same patient in 1995 (aged 50), showing interval
development of scoliosis with bilateral upper lobe pleural thickening, worse on the
right, with cavities in the left upper lobe and fullness of the right upper mediastinum.
The features of central bronchiectasis, so characteristic of ABPA, are very prominent.
She is significantly disabled by her disease now.

Reproduced with permission from: The Aspergillus Website

(http://www.aspergillus.org.uk/). Copyright © 2010.

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Chronic cavitary aspergillosis transformed from allergic

bronchopulmonary aspergillosis (ABPA)

Longstanding asthma, ABPA with chronic cavitary pulmonary aspergillosis. The

patient suffered a long history of severe steroid-dependent asthma with
recurrent infective exacerbations culture positive for Aspergillus fumigatus and
Pseudomonas aeruginosa. An Aspergillus precipitins test was positive with an
elevated total IgE level. Despite initial treatment with oral itraconazole, chest
radiograph deteriorated, showing cystic cavities in both apices and a computed
tomography scan showing a right upper lobe mycetoma (fungal ball). She
developed respiratory failure and was established on long-term oxygen therapy
of 2 L/min via an oxygen concentrator at home and oxygen conserver when
mobile. Systemic steroids, nebulizers, and long-term itraconazole did not
prevent disease progression of ABPA to chronic cavitary aspergillosis. She was
treated with voriconazole for >5 years with some benefit, although very slow
deterioration requiring 4 L/min oxygen 24 hours a day.

Reproduced with permission from: The Aspergillus Website

(http://www.aspergillus.org.uk/). Copyright © 2010.

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Underlying diseases in patients with chronic pulmonary aspergillosis

Common underlying diseases

Pulmonary tuberculosis

Nontuberculous mycobacterial infection

Allergic bronchopulmonary aspergillosis

Treated lung cancer

Pneumothorax (often related to a bulla)

Chronic obstructive pulmonary disease

Sarcoidosis (stage II/III)

Uncommon underlying diseases

Rheumatoid arthritis with pulmonary nodules

Ankylosing spondylitis

Thoracic surgery

Asthma

Radiotherapy to the thorax or chest wall

Community-acquired pneumonia

Invasive pulmonary aspergillosis

Cannabis lung

Pneumoconiosis

Histoplasmosis

Silicosis

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Contributor Disclosures
David W Denning, MBBS, FRCP, FRCPath, FMedSci Grant/Research/Clinical Trial Support: Pfizer; Gilead;
MSD; Dynamiker; Mayne Pharma [Aspergillus]. Speaker’s Bureau: Pfizer [Fungal diseases (Voriconazole,
anidulafungin)]; Gilead [Fungal diseases (Liposomal amphotericin B)]; Astellas [Fungal diseases (Micafungin)];
Merck [Fungal diseases (Caspofungin, posaconazole)]; Dynamiker [Fungal disease (Diagnostic products)];
Mylan [Fungal diseases (Liposomal amphotericin B)], Hikma [Fungal disease (Isavuconazole)].
Consultant/Advisory Boards: Scynexis; Cidara; Pulmatrix; Pulmocide; Zambon; Roivant; Fujifilm; iCo
Therapeutics [Fungal disease (New antifungal developments)]. Equity Ownership/Stock Options: F2G Ltd [New
antifungals (Product in development)]. Carol A Kauffman, MD Consultant/Advisory Boards: Cidara Therapeutics
[Treatment of candidiasis (Rezafungin)]. Anna R Thorner, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.

Conflict of interest policy

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