CHAPTER 116: ASPERGILLOSIS

Aspergillosis is the collective term used to describe all disease entities caused by any one of ~50 pathogenic and allergenic species of Aspergillus. Only those species that grow at 37°C can cause invasive infection, although some species without this ability 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 infections, 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 areas of the hospital 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 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.

Global aspergillosis incidence and prevalence have been estimated (Table 116-1). However, given the inadequate diagnostic capability in almost all low- and middle-income countries, the accuracy of these estimates is uncertain. The frequency of different manifestations of aspergillosis varies considerably with geographic location; most notably, chronic granulomatous sinusitis is rare outside the Middle East and India, and fungal keratitis is particularly common in Nepal, Myanmar, Bhutan, and India (800 and 113 cases/100,000 population, respectively). The potential effects of chronic pulmonary aspergillosis after pulmonary tuberculosis have only recently been appreciated and include life-threatening hemoptysis, misdiagnosis of smear-negative tuberculosis, and general exacerbation of posttuberculosis morbidity.

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 also is 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. Therapy with infliximab, adalimumab, alemtuzumab, daclizumab, rituximab, and possibly bevacizumab therapy also carries an increased risk of invasive aspergillosis, as do severe liver disease and high levels of stored iron in bone marrow.

Patients with chronic pulmonary aspergillosis have a wide spectrum of underlying pulmonary disease, including tuberculosis, prior pneumothorax, or chronic obstructive pulmonary disease. These patients are immunocompetent except for some cytokine regulation defects, most of which are consistent with an inability to mount an inflammatory immune (T_H1-like) response or to control it adequately. 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 T_H2-like and “allergic” response to A. fumigatus.

CD4+CD25+ T (T_reg) cells also appear to be pivotal in determining disease phenotype. Remarkably, high-dose glucocorticoid treatment for exacerbations of ABPA almost never leads to invasive aspergillosis.

See Table 116-2.

Invasive pulmonary aspergillosis

Both the frequency of invasive disease and the pace of its progression increase with greater degrees of immunocompromise. Invasive aspergillosis is arbitrarily classified as acute and subacute, with 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 is one of the most common diagnostic errors revealed at autopsy.

Invasive sinusitis

The sinuses are involved in 5–10% of cases of invasive aspergillosis, especially affecting 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.

Tracheobronchitis

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; in persons with ABPA, cystic fibrosis, and/or bronchiectasis; and in immunocompromised patients.

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 (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. Blood cultures 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 (mimicking a brain tumor). Local spread from cranial sinuses also occurs. Postoperative infection develops rarely and is exacerbated by glucocorticoids, often given after neurosurgery. The presentation can be either acute or subacute, with mood changes, focal signs, seizures, and decline in mental status. 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.

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; embolectomy occasionally reveals the diagnosis.

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; such invasion may also follow trauma. 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. 116-1) 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. An irregular internal cavity surface and thickened cavity walls are indicative of disease activity. IgG antibodies (usually precipitating) to Aspergillus are almost always detectable in blood, and levels fall slowly with successful therapy. Some patients have concurrent infections—even without a fungal ball—with atypical mycobacteria and/or other bacterial pathogens. One or more Aspergillus nodules that resemble early lung carcinoma and may cavitate have been recognized. 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 pulmonary cavities ≥2.5 cm in diameter. Signs and symptoms associated with single (simple) aspergillomas are minor, including 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.

Chronic Aspergillus sinusitis

Three entities are subsumed under this broad designation: fungal ball of the sinus, chronic invasive sinusitis, and chronic granulomatous sinusitis. Fungal ball of the sinus is limited to the maxillary sinus (except in rare cases involving the sphenoid sinus) and consists of a chronic saprophytic entity in which the sinus cavity is filled with a fungal ball. Maxillary 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, including infections caused by numerous other fungi; 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. IgG antibodies to A. flavus are usually detectable.

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 ~2.5% of patients with asthma who are referred to secondary care and in up to 15% of adults with cystic fibrosis. 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. 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 in response to A. fumigatus extract, or detection of Aspergillus-specific IgE and IgG antibodies. The presence of hyperattenuated mucus in airways is highly specific. Central bronchiectasis is characteristic, and some patients develop chronic cavitary pulmonary aspergillosis.

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 species) are implicated by skin-prick testing and/or specific IgE radioallergosorbent testing. Serum total IgE concentrations are <1000 IU/mL, and bronchiectasis is moderately common.

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 that is relatively unresponsive to antibiotics. Many of these patients have nasal polyps, and all have congested nasal mucosae and sinuses full of mucoid material. The histologic hallmarks of allergic fungal sinusitis are local eosinophilia and 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. Recurrence is common, often after another bacterial or viral infection.

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 intensive 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 (Table 116-1). 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 fewer 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 species 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. Both antigen detection and real-time polymerase chain reaction (PCR) 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 organisms during growth. Positive serum antigen results usually precede clinical or radiologic features by several days. The sensitivity of antigen detection is reduced by antifungal prophylaxis and empirical therapy.

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 species 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, reflecting an early diagnosis. 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 nodules and pleural-based infarction or cavitation, with pleural fluid apparent in 10% of patients.

For chronic invasive aspergillosis, Aspergillus antibody testing is invaluable although relatively imprecise. Biopsy of new nodules reveals hyphae surrounded by cells of chronic inflammation and sometimes granulomas. Antibody titers fall with successful therapy. Cultures are infrequently positive but are important in checking for azole resistance. Real-time PCR of sputum is often strongly 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 also may be useful.

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 species. Itraconazole capsules are ineffective, and itraconazole solution offers only modest efficacy. Posaconazole solution is more effective. Some data support the use of IV micafungin. No prophylactic regimen is completely successful.

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 treated but is 100% if the diagnosis is missed. Infection with a voriconazole-resistant strain carries a mortality rate of 88%. Cerebral aspergillosis, Aspergillus endocarditis, and bilateral extensive invasive pulmonary aspergillosis have very poor outcomes, as does invasive infection in persons with late-stage AIDS or relapsed uncontrolled leukemia and in recipients of allogeneic hematopoietic stem cell transplants.

The mortality rate for chronic cavitary pulmonary aspergillosis is ~30% 6 months after presentation, falling to ~15% annually thereafter. After 12 months with no antifungal therapy, 70% of patients have deteriorated and 30% are stable (Fig. 116-2). Therapy fails in ~30% of recipients of antifungal therapy and still more often if azole resistance is present.

Both ABPA and SAFS patients respond to antifungal therapy; ~60% respond to itraconazole and ~80% to voriconazole and posaconazole (if tolerated). If the severity of asthma declines, the inhaled glucocorticoid dose can be reduced and oral glucocorticoids can be stopped.