Aspergillosis

Aspergillosis is the collective term used to describe all disease entities caused by any one of ~35 pathogenic and allergenic species of Aspergillus. 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 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, primarily in patients with chronic granulomatous disease. 

EPIDEMIOLOGY AND ECOLOGY 

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 very–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. Patients with chronic pulmonary aspergillosis have a wide spectrum of underlying pulmonary disease, often tuberculosis or sarcoidosis. Patients are immunocompetent except that a genetic defect in mannose-binding protein is common, as are 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 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.These associations suggest a strong genetic basis for the development of a TH2-like and “allergic” response to A. fumigatus; this response probably is also protective against invasive disease, since highdose glucocorticoid treatment for exacerbations of ABPA almost never leads to invasive aspergillosis. 

CLINICAL FEATURES AND APPROACH TO THE PATIENT (Table 108-1) 

Invasive Pulmonary Aspergillosis Both the frequency of invasive disease and the pace of its progression increase with greater degrees of immunocompromise (Fig. 108-1). 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, and urgent CT of the thorax. Invasive Sinusitis 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). Direct examination of the interior of the nose reveals dusky or necrotic-looking tissue in any location. CT or MRI of the sinuses is essential but does not distinguish invasive Aspergillus sinusitis from pre-existing allergic sinusitis, bacterial sinusitis, or other fungal sinusitis early in the disease process. Disseminated Aspergillosis 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, 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 multiple nonspecific abnormalities in laboratory tests. In most cases, at least one localization becomes apparent. Blood cultures are not helpful since they are almost always negative. 

Cerebral Aspergillosis 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 also occurs, resulting in a single abscess. Postoperative infection from cranial sinuses is occasionally recorded and is exacerbated by glucocorticoid use 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 in the affected patients because of poor renal function. Endocarditis 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. Cutaneous Aspergillosis 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 after surgery. 

Chronic Pulmonary Aspergillosis The hallmark of chronic cavitary pulmonary aspergillosis (also called semi-invasive aspergillosis, chronic necrotizing aspergillosis, or complex aspergilloma) (Fig. 108-2) 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, ankylosing spondylitis, rheumatoid lung disease, pneumothorax, bullae) or prior lung surgery. The onset is insidious, and systemic features are sometimes 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. 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. Aspergilloma Aspergilloma (fungal ball) occurs in up to 20% of residual chest cavities ≥2 cm in diameter. Some fungal balls remain stable in a single cavity for many years, and 10% resolve spontaneously. However, aspergillomas are often a feature of chronic pulmonary aspergillosis with its associated features. 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.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 lifethreatening hemoptysis, which may be the presenting manifestation. Chronic Sinusitis 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 that of bacterial sinusitis is increased. 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, and occasional cases are reported in patients without either of these diseases. 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 (SAFS) 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 (RAST) testing. Allergic Sinusitis 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 course of antibiotics that are of only limited benefit. Many of these patients have nasal polyps, and all have congested nasal mucosa and sinuses full of mucoid material. The histologic hallmark of allergic fungal sinusitis is local eosinophilia and the breakdown products of eosinophils, Charcot-Leyden crystals. 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. Superficial Aspergillosis 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 is a common problem for which local debridement and local application of antifungal agents constitute the most common approach to treatment. 

DIAGNOSIS 

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 promise to be both faster and more sensitive than culture. 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 -lactam/-lactamase inhibitor antibiotic combinations, such as tazocillin/sulbactam and amoxicillin/ clavulanic acid; in these cases, a second test is required for confirmation. 

Antigen testing 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 Aspergillusspecific IgE. ABPA and SAFS are diagnosed serologically or with skin-prick tests.Allergic Aspergillus sinusitis is usually diagnosed histologically, although precipitating antibodies in blood may also be useful.  Treatment: 

ASPERGILLOSIS 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 108-2. 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 effects 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. Itraconazole is the preferred oral agent for chronic and allergic forms of aspergillosis. Voriconazole and 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 lifelong 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, proximal areas of the lung, and areas impinging on the great vessels; 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.  

PROPHYLAXIS 

In situations in which moderate or high risk is predicted (e.g., after induction therapy for acute myeloid leukemia), the need for antifungal prophylaxis for superficial and systemic candidiasis and for invasive aspergillosis is generally accepted. Fluconazole is commonly used in these situations but has no activity against Aspergillus spp. Itraconazole capsules are ineffective, and itraconazole solution offers only modest efficacy. Posaconazole solution is probably more effective. Some data support the use of IV lowdose micafungin. No prophylactic regimen is completely successful. OUTCOME Invasive aspergillosis is curable if immune reconstitution occurs, whereas allergic and chronic forms are not.The mortality rate for invasive aspergillosis is ∼50% if the infection is diagnosed and treated but is 100% if the diagnosis is missed. Cerebral aspergillosis, Aspergillus endocarditis, and bilateral extensive invasive pulmonary aspergillosis have very poor outcomes, as does invasive infection in patients with late-stage AIDS, patients with relapsed uncontrolled leukemia, and recipients of allogeneic hematopoietic stem cell transplants.