++
Aspergillosis, caused by any of several species of Aspergillus, usually
manifests in immunocompromised or debilitated hosts as necrotizing
cavitary pulmonary lesions or as hematogenously disseminated foci
in multiple organs. Aspergillus can also cause
a hypersensitivity or allergic pneumonitis in immunocompetent hosts
and in patients with chronic pulmonary diseases. This is referred
to as allergic bronchopulmonary aspergillosis (ABPA) (eFig.
295.1).
++
Ubiquitous in nature, Aspergillus spp are commonly
found in soil, water, and on decaying vegetation. Human exposure
to the spores of potentially pathogenic species, particularly A fumigatus, is
unavoidable. Aspergillus fumigatus has been implicated
in most of the disseminated and pulmonary infections, but A flavus and A
niger, among others, have also been recovered as pathogens. Transmission
occurs by inhalation of airborne spores that regularly contaminate
the environment; human-to-human transmission or zoonotic transmission has
not been documented. Patients with immunosuppression are at greatest
risk, especially those who are being treated for lymphoreticular
disorders and other hematologic malignancies. Because the phagocytic
functions of neutrophils and mononuclear cells are the primary immune
defense against invasive aspergillosis, Aspergillus is
a common infectious cause of death in bone marrow transplant recipients. Outbreaks
in transplant units have been epidemiologically linked to building
demolition and construction, which releases fungal spores into the
environment. There has been a significant increase in the incidence
of invasive aspergillosis over the past few decades owing to the
increasing numbers of patients undergoing transplantation, specifically
for hematologic malignancies, as well an increase in the intensity
of treatment regimens. Invasive aspergillosis in a patient without
underlying disease is infrequent, and intensive investigation for
a predisposing disorder should be undertaken.
+++
Clinical Manifestations
++
Infection with Aspergillus can manifest as three
distinct syndromes; two types of noninvasive aspergillosis; pulmonary
aspergilloma and allergic bronchopulmonary aspergillosis (ABPA),
as well as invasive aspergillosis, either locally invasive or disseminated
disease.1
++
Aspergilloma is the most common form of pulmonary aspergillosis2 and
occurs when the fungus grows as a dense mass of hyphae and tissue
debris within a preexistent pulmonary cavity caused by a concomitant
pulmonary disease such as tuberculosis, lung abscess, or bronchiectasis.
A patient with an aspergilloma may be asymptomatic and the lesion
noted on incidental radiographic examination; however, there may
be significant and life-threatening hemoptysis as a result of invasion
of local bronchial blood vessels lining the cavity.
++
ABPA is a hypersensitivity reaction to fungal antigens and is
most commonly caused by A fumagatis. ABPA is seen
in patients with chronic pulmonary disease such as asthma or cystic
fibrosis. Some studies suggest that ABPA occurs in up to 15% of
patients with cystic fibrosis3 and in 7% to
14% of patients with corticosteroid dependent asthma.4 Inhalation
of fungal spores leads to hyphal colonization of the bronchopulmonary
tree resulting in mucus plugging, dyspnea, wheezing, and cough.
ABPA may eventually lead to large areas of bronchiectasis and systemic
inflammation. The pathogenesis of ABPA is incompletely understood,
but most likely results from Aspergillus-specific
IgE mediated type I hypersensitivity. The sputum of patients with
ABPA commonly reveals Aspergillus species and eosinophils
and pathological specimens reveal mucoid plugs and granulomatous
inflammation, without evidence of tissue invasion.5 Criteria
have been developed to diagnose and classify ABPA.6,7 These
include the presence of wheezing, peripheral blood eosinophilia,
elevated serum IgE levels, specific antibodies to A fumagatis,
immediate cutaneous reactivity to Aspergillus species, changing
pulmonary infiltrates, bronchiectasis, and peripheral eosinophilia.
All criteria need not be present to make the diagnosis of ABPA,
but for the diagnosis of ABPA in asthma, at least 5 criteria must
be present.
++
Invasive aspergillosis can range from locally invasive disease
to a disseminated form of disease that occurs in severely immunocompromised
patients and is almost always fatal. The most commonly recognized
risk factors for invasive pulmonary aspergillosis include prolonged
neutropenia, hematopoietic stem cell and organ transplantation,
high-dose corticosteroid administration, graft versus host disease,
advanced AIDS, and chronic granulomatous disease. The disease presents
as a necrotizing bronchopneumonia, with invasion of the pulmonary
vessels often accompanied by thrombosis. Widespread embolization
to the heart, gastrointestinal tract, skin, kidneys, and liver occurs
in about one-third of patients. The clinical presentation of invasive
aspergillosis is variable, but patients may have prolonged fever
and respiratory symptoms, including hemoptysis.8 Invasion
of the central nervous system with occlusion of cerebral vessels
may lead to cerebral infarction resulting in seizures or stupor.
The mortality of invasive aspergillosis approaches 50% to
90% when the central nervous system is affected.2
++
The paranasal sinuses, especially the maxillary sinuses, as well
as the external auditory meatus can become colonized by various
species of Aspergillus. If the individual is immunocompetent,
drainage or curettage usually is sufficient to cure the patient.9 Occasionally,
in immunocompromised individuals the fungus becomes invasive, erodes
bone, and extends into adjoining structures such as the orbit or brain.
This complication of Aspergillus sinusitis is most
common in patients experiencing a relapse of acute leukemia, or
in the setting of hematopoietic stem cell transplantation.
++
Cutaneous aspergillosis may result from either hematogenous seeding
in a highly immunocompromised patient, or it may be caused by direct
invasion of aspergillus spores in contaminated occlusive dressings
associated with central venous catheter sites (eFig.
295.2). This direct route of skin infection has been seen in immunocompetent
hosts such as burn and trauma patients. It may initially manifest
as erythematous macules that develop progressive necrosis or as
a cluster of hemorrhagic bullae at sites of intravenous access.10,11
++
++
Sputum
can be directly examined for hyphal elements; however, a positive
examination must be viewed with caution and interpreted in the context
of clinical presentation. The
diagnosis of invasive Aspergillus in immunocompromised
patients is difficult as the hallmark of disease is tissue invasion
and thus a biopsy is required for definitive diagnosis. A high index of
suspicion in severely immunocompromised patients is critical to
making a timely diagnosis. Even repeated positive sputum cultures may
reflect colonization. Bronchoalveolar lavage (BAL) cultures have
approximately 50% sensitivity for focal disease, but are
highly predictive of invasive disease when Aspergillus is
isolated in an immunocompromised patient.12 In
the areas of necrotizing pneumonia, hyphae often can be identified
by hematoxylin-and-eosin stain, but Gomori methenamine silver stain
may be necessary to identify typical mycelial structures. The hyphae
of Aspergillus are 3 to 4 μ in
diameter, septate, and reveal asymmetric dichotomous branching that
may be morphologically indistinguishable from other fungi such as Pseudallescheria
boydii or Alternaria species. Sputum and
bronchial aspirates should be cultured on Sabouraud dextrose agar.
++
Chest-computed tomography
may show a “halo sign” or an “air crescent”:
a haziness around an area of infiltrate or nodule. This represents
areas of hemorrhagic infarction as the infection progresses to invade
small vessels and is most frequently present early in the course
of disease.13 These signs may be absent in non-neutropenic
hosts, and studies have shown that these classic signs of invasive
pulmonary aspergillosis maybe be less frequently present in younger
children.14 More extensive disease may appear as
a cavitary lesion, or as an area of pulmonary hemorrhage. Radiographic
evidence along with evidence from direct sputum or BAL examination
may provide stronger support for the diagnosis, but lung biopsy
remains the diagnostic gold standard for invasive pulmonary aspergillosis. Because
invasive aspergillosis is often rapidly fatal, the finding of hyphal
elements or positive cultures from superficial sites such as nasal
mucous membranes should lead to a more aggressive search for deep-seated
infection (eg, transtracheal aspiration, bronchopulmonary washings,
bronchial brush biopsy, and lung biopsy).
++
Because
the patients most at risk for invasive aspergillosis are the ones
in whom invasive procedures are most commonly contraindicated, the
detection of Aspergillus antigens in serum and
bronchial fluid can be a useful diagnostic modality. Galactomannan
is a cell wall polysaccharide that is released by the mold during
hyphal growth. The assay has proven helpful because it can become
positive in patients with invasive aspergillosis prior to radiographic
changes.15,16 There are several commercial methodologies for
detection of Galactomannan, but the most sensitive test is an ELISA-based
method, with sensitivity and specificity of 80.7% and 89.2%,
respectively.17 Lower sensitivity and specificity
have been noted in pediatric populations and false-positive results
have been seen in patients receiving piperacillin-tazobactam18 and
false-negative results have been noted in patients on antifungal
therapy.19 There have also been false-positive
results reported in newborns, possibly owing to cross-reactivity
with of organisms in the neonatal gastrointestinal tract.17 In
some specific patient populations, such as high risk hematopoietic
stem cell recipients, biweekly screening for Galactomannan by ELISA
has been shown to be useful for early diagnosis of invasive disease.15
++
Serologic diagnosis of aspergillosis by immunodiffusion and complement
fixation tests can be helpful in immunocompetent patients. Precipitins
are reported in more than 90% of aspergillomas and in approximately
70% of allergic bronchopulmonary aspergillosis. Polymerase
chain reaction (PCR) has been used to diagnose invasive pulmonary
aspergillosis in immunocompromised patients, but this technique
remains investigational.
++
Treatment guidelines have been developed for the treatment of
diseases caused by Aspergillus.9 Treatment
of aspergilloma usually requires surgical excision for definitive treatment,
but often the risks of surgical intervention outweigh the clinical
benefit. A combination of surgical excision and antifungal therapy
has been used to manage life-threatening hemoptysis in patients
with aspergilloma. Intracavitary instillation of antifungal agents has
also been used successfully.
++
Treatment of patients with allergic bronchopulmonary aspergillosis
involves treating the immunological response to the Aspergillus antigens.
Corticosteroids have been the mainstay of treatment, but a randomized
trial of patients with steroid-dependent allergic bronchopulmonary
aspergillosis (ABPA) showed improvement of symptoms in patients treated
with the antifungal itraconazole.20 Prednisone
is usually initiated at a dose of 0.5 mg/kg/day
for 1 to 2 weeks and then given on alternate days for the next 8
weeks. The steroids can then be tapered as symptoms and IgE levels
are monitored.7 It is not uncommon for symptoms to
improve with treatment but then recur.
++
A
recent study showed that voriconazole may be preferable to amphotericin
B for initial treatment of invasive pulmonary aspergillosis.21 The mortality
of aspergillosis in immunocompromised patients is high, and empiric
treatment upon suspicion for invasive fungal disease is imperative.
For treatment of invasive aspergillosis, parenteral amphotericin
B in high doses of 1.0 to 1.5 mg/kg/day has been
standard therapy. Because of intolerance to amphotericin B, especially
in older individuals, lipid-based preparations, which can be given in
high doses, have been developed to reduce side effects. Newer antifungal
agents such as voriconazole and posaconazole have also shown excellent
efficacy in invasive aspergillosis and have fewer side effects.
Both of these agents can be given orally, making prolonged outpatient
therapy more feasible. Echinocandin derivatives such as caspofungin,
micafungin, and anidulafungin also have anti-aspergillus efficacy
and are considered second-line therapeutic agents.22 Echinocandins
act as a noncompetitive inhibitor of an enzyme required for fungal
cell wall assembly. This unique mechanism of action makes this new
class attractive for synergistic use. Combination antifungal therapy
has been suggested for treatment of refractory invasive pulmonary
aspergillosis and combinations of liposomal amphotericin with either
voriconazole or with an echinocandin have been explored in limited
case series and anecdotal clinical reports. Duration of therapy
and total optimal dose is not clear, but practice guidelines recommend
a period of initial induction therapy during disease stabilization,
followed by a period of maintenance therapy until resolution of
radiographic changes and completion of immune reconstitution. Surgical
resection, in combination with antifungal therapy, is usually necessary
in patients with localized aspergillomas or cutaneous aspergillosis
who fail to respond to amphotericin B.
++
Given the high morbidity associated with invasive aspergillosis,
an effective prophylactic strategy would be desirable. Highly immunocompromised
patients should avoid areas of construction, and the use of high-efficiency
air (HEPA) filters has been instituted in many transplantation units.
Chemoprophylaxis with antifungal agents is currently an area of
investigation. A high index of suspicion for invasive Aspergillus infection,
Galactomannan antigen screening, and empiric antifungal therapy
in high-risk patients are all key components to successful identification
and treatment of patients with invasive disease.