Aspergillosis is the collective term used to describe all disease entities caused by any one of ~35 pathogenic and allergenic species of Aspergillosis. Only those species that grow at 37°C can cause invasive infection, although some species without this capability can cause allergic syndromes. 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 some hospitals and causes a higher proportion of cases of sinus and cutaneous infections 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, primarily in patients with chronic granulomatous disease.
Aspergillus has a worldwide distribution, most commonly growing in decomposing plant materials (i.e., compost) 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. Daily exposures vary from a few to many millions of conidia; the latter high numbers of conidia are encountered in hay barns and other very dusty environments. The required size of the infecting inoculum is uncertain; however, only intense exposures (e.g., during construction work, handling of moldy bark or hay, or composting) are sufficient to cause disease in healthy immunocompetent individuals. Allergic syndromes may be exacerbated by continuous antigenic exposure arising from sinus or airway colonization or from nail infection. High-efficiency particulate air (HEPA) filtration is often protective against infection; thus HEPA filters should be installed and monitored for efficiency in operating rooms and in hospital environments that house high-risk patients.
The incubation period of invasive aspergillosis after exposure is highly variable, extending in documented cases from 2 to 90 days. Thus community-acquired acquisition of an infecting strain frequently manifests as invasive infection during hospitalization, although nosocomial acquisition is also common. Outbreaks usually are directly related to a contaminated air source in the hospital.
Risk Factors and Pathogenesis
The primary risk factors for invasive aspergillosis are profound neutropenia and glucocorticoid use; risk increases with longer duration of these conditions. Higher doses of glucocorticoids increase the risk of both acquisition of invasive aspergillosis and death from the infection. Neutrophil and/or phagocyte dysfunction is also an important risk factor, as evidenced by aspergillosis in chronic granulomatous disease, advanced HIV infection, and relapsed leukemia. An increasing incidence of invasive aspergillosis in medical intensive care units suggests that, in patients who are not immunocompromised, temporary abrogation of protective responses as a result of glucocorticoid use or a general anti-inflammatory state is a significant risk factor. Many patients have some evidence of prior pulmonary disease—typically, a history of pneumonia or chronic obstructive pulmonary disease. Glucocorticoid use does not appear to predispose to invasive Aspergillus sinusitis but probably increases the risk of dissemination after pulmonary infection. Anti–tumor necrosis factor therapy also carries an increased risk of infection.
Patients with chronic pulmonary aspergillosis have a wide spectrum of underlying pulmonary disease, often tuberculosis or sarcoidosis. Patients are immunocompetent except for some cytokine regulation defects, most of which are consistent with an inability to mount an inflammatory immune (TH1-like) response. Glucocorticoids accelerate disease progression.
Allergic bronchopulmonary aspergillosis (ABPA) is associated with polymorphisms of interleukin (IL) 4Ra, IL-10, and SPA2 genes (and others) and with heterozygosity of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. These associations suggest a strong genetic basis for the development of a TH2-like and "allergic" response to A. fumigatus.
CD4+CD25+ T (Treg) cells also appear to be pivotal in determining the disease phenotype. Remarkably, high-dose glucocorticoid treatment for exacerbations of ABPA almost never leads to invasive aspergillosis.
Clinical Features and Approach to the Patient
Table 204-1 Major Manifestations of Aspergillosis |Favorite Table|Download (.pdf)
Table 204-1 Major Manifestations of Aspergillosis
|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||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||None||None||None described|
Invasive Pulmonary Aspergillosis
Both the frequency of invasive disease and the pace of its progression increase with greater degrees of immunocompromise (Fig. 204-1). Invasive aspergillosis is arbitrarily divided into acute and subacute forms that have courses of ≤1 month and 1–3 months, respectively. More than 80% of cases of invasive aspergillosis involve the lungs. The most common clinical features are no symptoms at all, fever, cough (sometimes productive), nondescript chest discomfort, trivial hemoptysis, and shortness of breath. Although the fever often responds to glucocorticoids, the disease progresses. The keys to early diagnosis in at-risk patients are a high index of suspicion, screening for circulating antigen (in leukemia), and urgent CT of the thorax.
Invasive aspergillosis: conditions placing patients at elevated risk of acquisition and relatively rapid progression. CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; GVHD, graft-versus-host disease; ICU, intensive care unit.
The sinuses are involved in 5–10% of cases of invasive aspergillosis, especially in patients with leukemia and recipients of hematopoietic stem cell transplants. In addition to fever, the most common features are nasal or facial discomfort, blocked nose, and nasal discharge (sometimes bloody). Endoscopic examination of the nose reveals pale, dusky or necrotic-looking tissue in any location. CT or MRI of the sinuses is essential but does not distinguish invasive Aspergillus sinusitis from preexisting allergic or bacterial sinusitis early in the disease process.
Occasionally, only the airways are infected by Aspergillus. The resulting manifestations range from acute or chronic bronchitis to ulcerative or pseudomembranous tracheobronchitis. These entities are particularly common among lung transplant recipients. Obstruction with mucous plugs occurs in normal individuals, persons with ABPA, and immunocompromised patients.
In the most severely immunocompromised patients, Aspergillus disseminates from the lungs to multiple organs—most often to the brain but also to the skin, thyroid, bone, kidney, liver, gastrointestinal tract, eye (endophthalmitis), and heart valve. Aside from cutaneous lesions, the most common features are gradual clinical deterioration over 1–3 days, with low-grade fever and features of mild sepsis, and nonspecific abnormalities in laboratory tests. In most cases, at least one localization becomes apparent before death occurs. Blood cultures are almost always negative.
Hematogenous dissemination to the brain is a devastating complication of invasive aspergillosis. Single or multiple lesions may develop. In acute disease, hemorrhagic infarction is most typical, and cerebral abscess is common. Rarer manifestations include meningitis, mycotic aneurysm, and cerebral granuloma. Local spread from cranial sinuses also occurs. Postoperative infection occurs rarely and is exacerbated by glucocorticoids, which are often given after neurosurgery. The presentation can be either acute or subacute, with mood changes, focal signs, seizures, and decline in mental status. Cerebral granuloma can mimic a primary or secondary tumor. MRI is the most useful immediate investigation; unenhanced CT of the brain is usually nonspecific, and contrast is often contraindicated because of poor renal function.
Most cases of Aspergillus endocarditis are prosthetic valve infections resulting from contamination during surgery. Native valve disease is reported, especially as a feature of disseminated infection and in persons using illicit IV drugs. Culture-negative endocarditis with large vegetations is the most common presentation, but embolectomy reveals the diagnosis in a few cases.
Dissemination of Aspergillus occasionally results in cutaneous features, usually an erythematous or purplish nontender area that progresses to a necrotic eschar. Direct invasion of the skin occurs in neutropenic patients at the site of IV catheter insertion and in burn patients. Rapidly progressive local aspergillosis of the skin and underlying tissue may follow trauma, and wounds may become infected with Aspergillus (especially A. flavus) after surgery.
Chronic Pulmonary Aspergillosis
The hallmark of chronic cavitary pulmonary aspergillosis (also called semi-invasive aspergillosis, chronic necrotizing aspergillosis, or complex aspergilloma) (Fig. 204-2) 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 (e.g., tuberculosis, atypical mycobacterial infection, sarcoidosis, rheumatoid lung disease, pneumothorax, bullae) or lung surgery. The onset is insidious, and systemic features may be more prominent than pulmonary symptoms. 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. IgG antibodies (usually precipitating) to Aspergillus are almost always detectable in blood. Some patients have concurrent infections—even without a fungal ball—with atypical mycobacteria and/or other bacterial pathogens. 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.
CT scan image of the chest in a patient with longstanding bilateral chronic cavitary pulmonary aspergillosis. He had a prior history of several bilateral pneumothoraces and required bilateral pleurodesis (1990). CT scan then demonstrated multiple bullae, and sputum cultures grew A. fumigatus. The patient had initially weakly and later strongly positive serum Aspergillus antibody tests (precipitins). This scan (2003) shows a mixture of thick- and thin-walled cavities in both lungs (each marked with C), with a probable fungal ball (black arrow) protruding into the large cavity on the patient's right side (R). There is also considerable pleural thickening bilaterally.
Aspergilloma (fungal ball) occurs in up to 20% of residual pulmonary cavities ≥2.5 cm in diameter. 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 and should be treated as such. The vast majority of fungal balls are caused by A. fumigatus, but A. niger has been implicated, particularly in diabetic patients; aspergillomas due to A. niger can lead to oxalosis with renal dysfunction. The most significant complication of aspergilloma is life-threatening hemoptysis, which may be the presenting manifestation. Some fungal balls resolve spontaneously, but the cavity may still be infected.
Three entities are subsumed under this broad label: sinus aspergilloma, chronic invasive sinusitis, and chronic granulomatous sinusitis. Sinus aspergilloma is limited to the maxillary sinus and consists of a chronic saprophytic entity in which the sinus cavity is filled with a fungal ball. This form of disease is associated with prior upper-jaw root canal work and chronic (bacterial) sinusitis. About 90% of CT scans show focal hyperattenuation related to concretions; on MRI scans, the T2-weighted signal is decreased, whereas it is increased in bacterial sinusitis. Removal of the fungal ball is curative. No tissue invasion is demonstrable histologically or radiologically.
In contrast, chronic invasive sinusitis is a slowly destructive process that most commonly affects the ethmoid and sphenoid sinuses but can involve any sinus. Patients are usually but not always immunocompromised to some degree (e.g., as a result of diabetes or HIV infection). Imaging of the cranial sinuses shows opacification of one or more sinuses, local bone destruction, and invasion of local structures. The differential diagnosis is wide, as numerous other fungi may cause a similar disease and sphenoid sinusitis is often caused by bacteria. Apart from a history of chronic nasal discharge and blockage, loss of the sense of smell, and persistent headache, the usual presenting features are related to local involvement of critical structures. The orbital apex syndrome (blindness and proptosis) is characteristic. Facial swelling, cavernous sinus thrombosis, carotid artery occlusion, pituitary fossa, and brain and skull base invasion have been described.
Chronic granulomatous sinusitis due to Aspergillus is most commonly seen in the Middle East and India and is often caused by A. flavus. It typically presents late, with facial swelling and unilateral proptosis. The prominent granulomatous reaction histologically distinguishes this disease from chronic invasive sinusitis, in which tissue necrosis with a low-grade mixed-cell infiltrate is typical.
Allergic Bronchopulmonary Aspergillosis
In almost all cases, ABPA represents a hypersensitivity reaction to A. fumigatus; rare cases are due to other aspergilli and other fungi. ABPA occurs in ~1% of patients with asthma and in up to 15% of adults with cystic fibrosis; occasional cases are reported in patients with neither of the latter. Episodes of bronchial obstruction with mucous plugs leading to coughing fits, "pneumonia," consolidation, and breathlessness are typical. Many patients report coughing up thick sputum casts, usually brown or clear. Eosinophilia commonly develops before systemic glucocorticoids are given. The 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.
Severe Asthma with Fungal Sensitization
Many adults with severe asthma do not fulfill the criteria for ABPA and yet are allergic to fungi. Although A. fumigatus is a common allergen, numerous other fungi (e.g., Cladosporium and Alternaria spp.) are implicated by skin-prick testing and/or specific IgE radioallergosorbent testing.
Like the lungs, the sinuses manifest allergic responses to Aspergillus and other fungi. The affected patients present with chronic (i.e., perennial) sinusitis typically requiring multiple courses of antibiotics that are of only limited benefit. Many of these patients have nasal polyps, and all have congested nasal mucosae and sinuses full of mucoid material. The histologic hallmark of allergic fungal sinusitis is local eosinophilia and Charcot-Leyden crystals (the breakdown products of eosinophils). Removal of abnormal mucus and polyps, with local and occasionally systemic administration of glucocorticoids, usually leads to resolution. Persistent or recurrent signs and symptoms may require more extensive surgery (ethmoidectomy) and possibly local antifungal therapy.
Aspergillus can cause keratitis and otitis externa. The former may be difficult to diagnose early enough to save the patient's sight. Treatment requires local surgical debridement as well as both systemic and topical antifungal therapy. Otitis externa usually resolves with debridement and local application of antifungal agents.
Several techniques are required to establish the diagnosis of any form of aspergillosis with confidence. Patients with acute invasive aspergillosis have a relatively heavy load of fungus in the affected organ; thus culture, molecular diagnosis, antigen detection, and histopathology usually confirm the diagnosis. However, the pace of progression leaves only a narrow window for making the diagnosis without losing the patient, and some invasive procedures are not possible because of coagulopathy, respiratory compromise, and other factors. Currently, ~40% of cases of invasive aspergillosis are missed clinically and are diagnosed only at autopsy. Histologic examination of affected tissue reveals either infarction, with invasion of blood vessels by many fungal hyphae, or acute necrosis, with limited inflammation and hyphae. Aspergillus hyphae are hyaline, narrow, and septate, with branching at 45°; no yeast forms are present in infected tissue. Hyphae can be seen in cytology or microscopy preparations, which therefore provide a rapid means of presumptive diagnosis.
Culture is important in confirming the diagnosis, given that multiple other (rarer) fungi can mimic Aspergillus spp. histologically. Bacterial agar is less sensitive than fungal media for culture. Thus, if physicians do not request fungal culture, the diagnosis may be missed. Culture may be falsely positive (e.g., in patients whose airways are colonized by Aspergillus) or falsely negative. Only 10–30% of patients with invasive aspergillosis have a positive culture at any time. Molecular diagnostic techniques are faster and much more sensitive than culture of respiratory samples and blood.
The Aspergillus antigen test relies on detection of galactomannan release from Aspergillus spp. during growth. Antigen testing in high-risk patients is best done prospectively, as positive results usually precede clinical or radiologic features by several days. Antigen testing may be falsely positive in patients receiving certain β-lactam/β-lactamase inhibitor antibiotic combinations. Antigen and molecular testing on bronchoalveolar lavage fluid and cerebrospinal fluid are useful if performed before antifungal therapy has been given for more than a few days. The sensitivity of antigen detection is reduced by antifungal prophylaxis.
Definitive confirmation of the diagnosis requires (1) a positive culture of a sample taken directly from an ordinarily sterile site (e.g., a brain abscess) or (2) positive results of both histologic testing and culture of a sample taken from an affected organ (e.g., sinuses or skin). Most diagnoses of invasive aspergillosis are inferred from fewer data, including the presence of the halo sign on a high-resolution thoracic CT scan, in which a localized ground-glass appearance representing hemorrhagic infarction surrounds a nodule. While a halo sign may be produced by other fungi, Aspergillus spp. are by far the most common cause. Halo signs are present for ~7 days early in the course of infection in neutropenic patients and are a good prognostic feature. Thick CT sections can give the false appearance of a halo sign, as can other technical factors. Other common radiologic features of invasive pulmonary aspergillosis include pleural-based infarction or cavitation.
For chronic invasive aspergillosis, Aspergillus antibody testing is invaluable although relatively imprecise. Titers fall with successful therapy. Cultures are infrequently positive. Some patients with chronic pulmonary aspergillosis also have elevated titers of total serum IgE and Aspergillus-specific IgE.
ABPA and severe asthma with fungal sensitization are diagnosed serologically with elevated total and specific serum IgE levels and with skin-prick tests. Allergic Aspergillus sinusitis is usually diagnosed histologically, although precipitating antibodies in blood may also be useful.
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. Current recommendations are shown in Table 204-2. Voriconazole is the preferred agent for invasive aspergillosis; caspofungin, posaconazole, and lipid-associated amphotericin B are second-line agents. Amphotericin B is not active against A. terreus or A. nidulans. An infectious disease consultation is advised for patients with invasive disease, given the complexity of management. It is not clear whether combination therapy for acute invasive aspergillosis is beneficial, but it is widely used for very ill patients and for those with a poor prognosis. Commonly used combinations include an azole with either caspofungin or micafungin. The interactions of voriconazole and itraconazole with many drugs must be considered before these agents are prescribed. In addition, the plasma concentrations of both drugs vary substantially from one patient to another, and many authorities recommend monitoring to ensure that drug concentrations are adequate but not excessive. 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.
Table 204-2 Treatment of Aspergillosis |Favorite Table|Download (.pdf)
Table 204-2 Treatment of Aspergillosis
|Indication||Primary Treatment||Evidence Levela||Precautions||Secondary Treatment||Comments|
|Invasiveb||Voriconazole||AI||Drug interactions (especially with rifampin), renal failure (IV only)||AmB, caspofungin, posaconazole, micafungin||As primary therapy, voriconazole carries 20% more responses than AmB. If azole prophylaxis fails, it is unclear whether a class change is required for therapy.|
|Prophylaxis||Posaconazole, itraconazole solution||AI||Diarrhea and vomiting with itraconazole, vincristine interaction||Micafungin, aerosolized AmB||Some centers monitor plasma levels of itraconazole and posaconazole.|
|ABPA||Itraconazole||AI||Some glucocorticoid interactions, including with inhaled formulations||Voriconazole, posaconazole||Long-term therapy is helpful in most patients. No evidence indicates whether therapy modifies progression to bronchiectasis/fibrosis.|
|Single aspergilloma||Surgery||BII||Multicavity disease: poor outcome of surgery; medical therapy preferable||Itraconazole, voriconazole, intracavity AmB||Single large cavities with an aspergilloma are best resected.|
|Chronic pulmonaryb||Itraconazole, voriconazole||BII||Poor absorption of capsules with proton pump inhibitors or H2 blockers||Posaconazole, IV AmB, IV micafungin||Resistance may emerge during treatment, especially if plasma drug levels are subtherapeutic.|
Itraconazole is the preferred oral agent for chronic and allergic forms of aspergillosis. Voriconazole or posaconazole can be substituted when failure, emergence of resistance, or adverse events occur. An itraconazole dose of 200 mg twice daily is recommended, with monitoring of drug concentrations in the blood. Chronic cavitary pulmonary aspergillosis probably requires life-long therapy, whereas the duration of treatment for other forms of chronic and allergic aspergillosis requires case-by-case evaluation.
Resistance to one or more azoles, although uncommon, may develop during long-term treatment, and a positive culture during antifungal therapy is an indication for susceptibility testing. Glucocorticoids should be used with caution in chronic cavitary pulmonary aspergillosis.
Surgical treatment is important in several forms of aspergillosis, including maxillary fungal ball and single aspergillomas, in which surgery is curative; invasive aspergillosis involving bone, heart valve, sinuses, and proximal areas of the lung; brain abscess; keratitis; and endophthalmitis. In allergic fungal sinusitis, removal of abnormal mucus and polyps, with local and occasionally systemic glucocorticoid treatment, usually leads to resolution. Persistent or recurrent signs and symptoms may require more extensive surgery (ethmoidectomy) and possibly local antifungal therapy. Surgery is problematic in chronic pulmonary aspergillosis, usually resulting in serious complications. Bronchial artery embolization is preferred for problematic hemoptysis.