Aspergillosis

1. Aspergillosis: Introduction
• Aspergillosis is the collective term to describe all
disease entities caused by any one of ~35 pathogenic
and allergenic species of Aspergillus.
• A. fumigatus is responsible for most cases of invasive
aspergillosis, almost all cases of chronic aspergillosis,
and most allergic syndromes.
• A. flavus is more prevalent in hospitals and causes
sinus and cutaneous infection and keratitis than A.
fumigatus.
• A. niger can cause invasive infection but more
commonly colonizes the respiratory tract and causes
external otitis.
• A. terreus causes only invasive disease, usually with a
poor prognosis.
• A. nidulans occasionally causes invasive infection.

2. Epidemiology and Ecology
• Aspergillus most commonly growing in decomposing
plant materials and in bedding. This hyaline
(nonpigmented), septate, branching mold produces
vast numbers of conidia (spores) on stalks above the
surface of mycelial growth.
• Aspergilli are found in indoor and outdoor air, on
surfaces, and in water from surface reservoirs. Allergic
syndromes may be exacerbated by continuous
antigenic exposure arising from sinus or airway
colonization or from nail infection.
• Incubation period of invasive aspergillosis after
exposure is highly variable from 2 to 90 days.
Community-acquired acquisition of an infecting strain
frequently manifests as invasive infection during
hospitalization, although nosocomial acquisition is
also common

3. Risk Factors and Pathogenesis
• For invasive aspergillosis are profound neutropenia
and glucocorticoid use.
• Increasing incidence of invasive aspergillosis in
medical intensive care due to temporary abrogation of
protective responses as a result of glucocorticoid use
or a general anti-inflammatory state is a significant
risk factor.
• Pt with chronic pulmonary aspergillosis have
underlying pulmonary disease, often tuberculosis or
sarcoidosis.
• ABPA is associated with certain HLA class II types;
polymorphisms of interleukin (IL) 4Ra, IL-10, and
SPA2 genes; and heterozygosity of the cystic fibrosis
transmembrane conductance regulator (CFTR) gene.

4. Clinical Features and Approach to the Patient
Major Manifestations in Indicated Type of Disease
Organ Invasive (Acute and
Subacute)
Chronic Saprophytic Allergic
Lung Angioinvasive in
neutropenia, non-
angioinvasive,
granulomatous
Chronic cavitary, chronic
fibrosing
Aspergilloma (single),
airway colonization
Allergic bronchopulmonary,
severe asthma with fungal
sensitization, extrinsic
allergic alveolitis
Sinus Acute invasive Chronic invasive, chronic
granulomatous
Maxillary fungal ball Allergic fungal sinusitis,
eosinophilic fungal
rhinosinusitis
Brain Abscess, hemorrhagic
infarction, meningitis,
mycotic cerebral aneurysm
Granulomatous,
meningitis
None None
Skin Acute disseminated,
locally invasive (trauma,
burns, IV access)
External otitis,
onychomycosis
None None
Heart Endocarditis (native or
prosthetic), pericarditis
None None None
Eye Keratitis, endophthalmitis
(postoperative and
disseminated)
None None None described

5. Aspergilloma
• Aspergilloma (fungal ball) occurs in up to 20% of
residual chest cavities 2 cm in diameter.
• Aspergillomas are often a feature of chronic
pulmonary aspergillosis .
• Signs and symptoms associated with single
(simple) aspergillomas are minor, including a
cough (sometimes productive), hemoptysis,
wheezing, and mild fatigue. More significant signs
and symptoms are associated with chronic cavitary
pulmonary aspergillosis.
• Majority of fungal balls are caused by A. fumigatus,
but A. niger has been implicated, particularly in
diabetic patients.
• Most significant complication of aspergilloma is
life-threatening hemoptysis, which may be the
presenting manifestation.

6. Allergic Bronchopulmonary Aspergillosis
• ABPA represents a hypersensitivity reaction to A.
fumigatus.
• Episodes of bronchial obstruction with mucous
plugs leading to coughing fits, "pneumonia,"
consolidation, and breathlessness are typical.
• Eosinophilia commonly develops before systemic
glucocorticoids are given.
• Cardinal diagnostic tests include an elevated
serum level of total IgE (usually >1000 IU/mL), a
positive skin-prick test to A. fumigatus extract, or
detection of Aspergillus-specific IgE and IgG
(precipitating) antibodies.
• Central bronchiectasis is characteristic, but
patients may present before it becomes apparent.

7. Invasive Pulmonary Aspergillosis
• Frequency and pace of invasive pulmonary
progression increase with degrees of
immunocompromise.
• Invasive aspergillosis is arbitrarily divided into acute
and subacute forms that have courses of 1 month and
1–3 months, respectively.
• Most common clinical features are no symptoms at
all, fever, cough (sometimes productive), nondescript
chest discomfort, trivial hemoptysis, and shortness of
breath.
• Keys to early diagnosis in at-risk patients are a high
index of suspicion, screening for circulating antigen,
and urgent CT of the thorax.

8. Chronic Pulmonary Aspergillosis
• Hallmark of chronic cavitary pulmonary aspergillosis
(semi-invasive aspergillosis, chronic necrotizing
aspergillosis, or complex aspergilloma) is one or more
pulmonary cavities expanding over a period of months
or years in association with pulmonary symptoms and
systemic manifestations such as fatigue and weight
loss.
• Pulmonary aspergillosis developing over <3 months is
better classified as subacute invasive aspergillosis.
• Often mistaken initially for tuberculosis, almost all
cases occur in patients with prior pulmonary disease .
• Onset is insidious, and systemic features are
sometimes more prominent than pulmonary
symptoms.

9. • Cavities may have a fluid level or a well-formed fungal
ball, but pericavitary infiltrates and multiple
cavities—with or without pleural thickening—are
typical.
• Antibodies to Aspergillus are almost always detectable
in blood, usually as precipitating antibody and
sometimes at high titers.
• Some patients have concurrent infections—even
without a fungal ball—with atypical mycobacteria
and/or other bacterial pathogens, such as
Staphylococcus aureus or Pseudomonas aeruginosa.
• If untreated, chronic pulmonary aspergillosis typically
progresses (sometimes relatively rapidly) to unilateral
or upper-lobe fibrosis.
• This end-stage entity is termed chronic fibrosing
pulmonary aspergillosis.

10. Aspergillosis: Treatment
• Antifungal drugs active against Aspergillus include voriconazole,
itraconazole, posaconazole, caspofungin, micafungin, and
amphotericin B.
• Initial IV administration is preferred for acute invasive aspergillosis
and oral administration for all other disease that requires
antifungal therapy.
• Voriconazole is the preferred agent for invasive aspergillosis;
caspofungin, posaconazole, and lipid-associated amphotericin B are
second-line agents.
• Commonly used combinations include an azole with either
caspofungin or micafungin.
• The duration of therapy for invasive aspergillosis varies from ~3
months to several years, depending on the patient's immune status
and response to therapy.
• Relapse occurs if the response is suboptimal and immune
reconstitution is not complete.

11. Treatment of Aspergillosis
Indication Primary Treatment Evidence Levela Precautions Secondary Treatment Comments
Invasivea Voriconazole AI Drug interactions
(especially with
rifampin), renal failure
(IV only)
Amphotericin B,
caspofungin,
posaconazole,
micafungin
As primary therapy,
voriconazole carries
20% more responses
than amphotericin B.
If azole prophylaxis
fails, it is unclear
whether a class change
is required for therapy.
Prophylaxis Itraconazole solution,
posaconazole
AI Diarrhea and vomiting
with itraconazole,
vincristine interaction
Micafungin,
aerosolized
amphotericin B
Some centers monitor
plasma levels of
itraconazole.
ABPA Itraconazole AI Some glucocorticoid
interactions, including
with inhaled
formulations
Voriconazole Long-term therapy is
helpful in most
patients..
Single aspergilloma Surgery BII Multicavity disease:
poor outcome of
surgery; medical
therapy preferable
Itraconazole,
voriconazole,
intracavity
amphotericin B
Single large cavities
with an aspergilloma
are best resected.
Chronic pulmonaryb Itraconazole BII Poor absorption of
capsules with proton
pump inhibitors or H2
blockers
Voriconazole, IV
amphotericin B
Resistance may
emerge during
treatment, especially if
plasma drug levels are
subtherapeutic.