Chapter 295. Aspergillosis

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

Diagnosis

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

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.