Epidemiology and Definitions.

An aspergilloma (or fungus ball) develops within a preexisting pulmonary cavity; it is a tangled mass of fungal hyphae, cellular debris, mucus, and fibrin that may or may not adhere to the cavity wall. Aspergillomas were previously most commonly found in cavities caused by tuberculosis, but aspergillomas develop in other cavities such as those caused by bullous emphysema, fibrocavitary sarcoidosis, lung cancer, cystic fibrosis (CF), or other fungal or nonfungal infections. Aspergillomas are most commonly caused by A. fumigatus but can also be seen with non- fumigatus Aspergillus and other molds. Chronic cavitary aspergilloma, also known as chronic cavitary pulmonary aspergillosis, is characterized by multiple cavities with or without intracavitary aspergillomas and with pulmonary and systemic symptoms. Chronic cavitary pulmonary aspergillosis does not invade the surrounding pulmonary parenchyma.

The natural history of aspergillomas is variable. Aspergillomas can remain stable over long periods, regress, spontaneously resolve, or progressively enlarge. Patients with aspergillomas are often asymptomatic, and the lesion may be discovered incidentally on chest radiography. The most common symptoms are cough and hemoptysis. Hemoptysis may develop in up to of 85% of cases and ranges from mild to life-threatening. Proposed mechanisms for the development of hemoptysis include vascular damage by mechanical effects of the fungus ball as well as by fungal toxins.

Imaging is key to the diagnosis of aspergillomas, which are typically found in the upper lung fields and classically appear as a solid rounded mass within a cavity ( Fig. 38-3 ). The mass may be mobile ( eFig. 38-3 ) or adherent to the cavity wall; peripheral lesions may be associated with pleural thickening. Nonradiographic diagnostic support includes positive serum precipitating antibodies to Aspergillus species, which are detectable in approximately 95% of patients. Respiratory cultures may grow Aspergillus species although the sensitivity and specificity are low.

Aspergillomas in sarcoidosis cavities.

A, Frontal chest radiograph in a patient with sarcoidosis demonstrates biapical thin-walled cavities containing rounded intracavitary opacities ( arrows ) that represent aspergillomas. B, Axial chest CT displayed in lung windows performed in another patient with sarcoidosis demonstrates biapical aspergillomas ( arrows ). The background bronchovascular thickening and subpleural nodularity reflects sarcoidosis.

(Modified from Gotway MB, Dawn SK, Caoili EM, et al: The radiologic spectrum of pulmonary Aspergillus infections. J Comput Assist Tomogr 26:159-173, 2002.)

Optimal treatment of aspergillomas depends on the patient’s symptoms, the location of the aspergilloma, and the host status. In patients with hemoptysis, the primary curative intervention is surgical resection. However, surgical resection remains a high-risk intervention in those with lung disease and poor pulmonary reserve. Potential complications from surgical resection include persistent hemorrhage, bronchopleural fistula development with further spread of the infection, and death. Therefore, resection to prevent future complications and disease progression must be approached cautiously. Bronchial artery embolization may be used in the setting of acute bleeding as a temporizing measure in nonsurgical candidates.

Systemic and/or topical (nebulized, or instilled into a cavity) antifungal therapy has been attempted in the management of aspergillomas. Systemic azole therapy is rarely curative and may be used for symptom improvement or stabilization and, in immunocompromised hosts, to prevent dissemination and invasive infection. The preponderance of data supports use of oral itraconazole. An international open-label study of 42 patients with aspergillomas treated with itraconazole at a dose of 100 to 400 mg per day for 18 to 780 days found symptomatic improvement in 62% of evaluable patients ( n = 34) and radiographic improvement in 12 (30%). Although fewer data are available, voriconazole is increasingly used instead of itraconazole. Major concerns with long-term azole administration are the emergence of resistance and toxicities, especially with voriconazole, which has been associated with development of skin cancers including squamous cell carcinoma. Direct intracavitary instillation of antifungal agents such as AmB, nystatin, natamycin, fluconazole, and itraconazole has been used via endobronchial and percutaneous CT-guided approaches and may further reduce fungal burden and the risk of recurrent bleeding, but it is not curative. The optimal management of aspergillomas remains to be defined, and randomized-controlled trials are lacking.

Epidemiology and Pathogenesis.

ABPA (see also Chapter 48 ), first described in the early 1950s, is an allergic pulmonary disorder caused by hypersensitivity to Aspergillus antigens. It is most often encountered in steroid-dependent asthmatics and in upwards of 15% of patients with CF. ABPA is most commonly associated with A. fumigatus; however, non- fumigatus Aspergillus species as well as non- Aspergillus molds can cause a similar clinical presentation (the latter termed allergic bronchopulmonary mycosis or ABPM). In ABPA, Aspergillus conidia enter the airways, germination ensues, and the hyphae colonize but do not invade. Aspergillus contributes to pathogenesis by producing enzymes such as elastase, collagenase, and trypsin, with airway damage and release of inflammatory cytokines. A marked inflammatory response ensues, resulting in mucoid impaction and granulomatous inflammation, including bronchocentric granulomas. The immune mechanisms associated with ABPA include an exaggerated T-helper 2 CD4 ⁺ T-cell response to Aspergillus antigens, increased Aspergillus -specific and total IgE, and eosinophilia. The primary determinant of dysregulated immune responses in ABPA has not been identified. ABPA is common in patients with CF, and has been linked to polymorphisms in the CF transmembrane conductance regulator (CFTR) and pulmonary surfactant protein-A2 genes.

Epidemiology and Pathogenesis.

IPA is the most severe form of pulmonary aspergillosis and is a major cause of fungal morbidity and mortality, seen most commonly in immunodeficient patients, including HSCT and SOT recipients and those with advanced HIV infection, chronic granulomatous disease, and hematologic malignancies. In a retrospective Italian cohort of nearly 12,000 patients with hematologic malignancies, more than half of the 538 proven or probable IFIs were due to molds, primarily Aspergillus, and patients with acute myelogenous leukemia were most commonly affected. The elevated risk in this population is primarily driven by prolonged neutropenia induced by cytotoxic chemotherapy. Multicenter, prospectively obtained epidemiologic data also confirm Aspergillus as the most common cause of invasive mold infection in both HSCT and SOT recipients. In HSCT recipients, Aspergillus is the most common IFI, predominantly seen during two periods: (1) early after transplantation, during neutropenia, and (2) after engraftment, in the setting of graft-versus-host disease. Of the SOT patients, lung transplant recipients are at highest risk for IPA. IPA is also increasingly reported in patients previously thought to be at low risk for invasive disease, including those with COPD on long-term corticosteroids and critically ill patients in the intensive care unit.

IPA is characterized by tissue invasion, frequently involving blood vessels. Hyphae within the alveoli penetrate the respiratory mucosa and alveolar capillaries into endothelial cells and pulmonary arterioles. Cell injury and inflammation contribute to intravascular thrombosis, local hypoxia, and necrosis. Angioinvasive disease is accompanied by tissue infarction and coagulative necrosis, whereas nonangioinvasive disease is more commonly associated with pyogranulomatous inflammation and inflammatory necrosis.

Clinical Presentation and Diagnosis.

The clinical presentation of IPA typically involves fever, cough, hemoptysis, and pleuritic chest pain. Angioinvasive IPA is seen predominantly in the setting of neutropenia and the course in neutropenic patients can be rapid, with clinical deterioration over hours to days. Patients with disseminated disease may have additional symptoms related to other sites of infection. Aspergillus can extend directly to surrounding areas, including the chest wall (see Fig. 90-27 ), mediastinum, and great vessels.

Early diagnosis of IPA is essential for prompt initiation of therapy, which has been associated with improved survival. However, multiple factors make the diagnosis difficult, including the lack of symptoms early in the course of illness, challenges in obtaining appropriate tissue for histopathology and culture in critically ill or cytopenic hosts, and the variable sensitivity and specificity of many of the available diagnostic tests. Imaging findings associated with IPA are often nonspecific, including nodules (see eFig. 90-27 , eFig. 90-28 , eFig. 91-10 ), consolidation (see eFig. 91-8 ), cavitation (see eFigs. 90-27 and 90-28 ), and effusions (see eFig. 91-10 ). The halo sign, demonstrated by ground-glass opacities surrounding a pulmonary nodule, is the result of alveolar hemorrhage around an infarcted area of the lung ( Fig. 38-4A ; see eFig. 91-10 ) and is typically seen early in the course of infection. The halo sign has a high specificity for IPA in neutropenic patients. The air-crescent sign tends to be seen later in the course of infection (typically with recovery of neutrophils in the neutropenic host) and represents air that has filled the space between necrotic and healthy lung tissue (see Fig. 38-4B ).

Invasive pulmonary aspergillosis.

A, Axial chest CT displayed in lung windows performed in a hematopoietic stem cell transplant recipient during profound neutropenia demonstrates a poorly defined nodule with surrounding ground-glass opacity ( arrows ) representing the “halo sign.” B, Following engraftment, the nodule has become cavitary ( arrowheads ), representing the “air-crescent” sign.

(Courtesy Michael Gotway, MD.)

Direct microscopy of sputum or BAL lacks both sensitivity (reported ranges from 0% to 90%) and specificity. Histopathologic evaluation of tissue specimens using standard hematoxylin and eosin, periodic acid–Schiff, and/or Gomori’s methenamine silver staining with demonstration of characteristic hyphae supports the diagnosis of IPA, but culture or sequence data are required to confirm the identity of the pathogen (see Fig. 38-2 ). Furthermore, 48% to 70% of tissues with evidence of invasive septate hyphae fail to grow in culture. When positive, cultures for most Aspergillus species typically grow within 48 to 72 hours on standard mycologic media.

Noninvasive tests are increasingly used for patients at risk for IPA. These include assays for fungal galactomannan (GM) and β-D-glucan. GM is a heteropolysaccharide component of the cell wall of Aspergillus and other fungi that is released during hyphal growth. Platelia Aspergillus EIA (Bio-Rad Laboratories) is an FDA-approved, commercially available diagnostic for detecting GM in neutropenic and HSCT patients with invasive Aspergillus, including IPA. The positive cutoff value is an optical density (OD) index of 0.5. A meta-analysis of 27 studies from 1966 to 2005 using surveillance GM in immunocompromised hosts with invasive Aspergillus reported an overall sensitivity and specificity of 71% and 89%, respectively. Subgroup analysis showed that test performance was higher in patients with hematologic malignancy (sensitivity, 70%; specificity, 92%) and HSCT recipients (sensitivity, 82%; specificity, 86%) compared to SOT recipients (sensitivity, 22%; specificity, 84%). One potential explanation for the improved performance in patients with hematologic malignancies or HSCT recipients was gained from an in vitro model of the human alveolus showing that detection of GM correlated with its release into the circulation following angioinvasion, which is more common in neutropenic patients.

Assaying BAL specimens for GM by the same enzyme immunoassay may complement assays of serum. A meta-analysis of 30 studies evaluating BAL GM using a cutoff OD index of 0.5 for proven and probable invasive aspergillosis found a sensitivity of 87% and specificity of 89%. Compared to serum GM, BAL GM had a higher sensitivity but a lower specificity. By increasing the positive cutoff value to an OD index of 1, specificity was increased without decreasing sensitivity. This is particularly important in lung transplant patients in whom high rates of colonization with molds such as Aspergillus and Penicillium can result in false-positive tests for GM. In one study, lung transplant recipients (16 of 81) accounted for more than 40% of false-positive BAL test results for GM. Other factors that compromise the utility of the GM assay include cross-reactivity with other fungi (e.g., Alternaria, Fusarium, Geotrichum, Histoplasma, Paecilomyces, and Penicillium ) and false-positive results secondary to the presence of GM in antimicrobials, such as piperacillin-tazobactam, in nutritional supplements, and in Plasmalyte. However, the magnitude of serum GM was shown to have prognostic utility in a single-center study of invasive aspergillosis in allogeneic HSCT recipients, with higher values correlated with higher all-cause mortality. Use of the GM assay to monitor response to treatment and to detect relapse is under investigation.

β-D-glucan, another fungal cell wall component, is used in the diagnosis of invasive aspergillosis as well as other IFIs, including Candida and Pneumocystis . The FDA approved and commercially licensed assay in the United States is the Fungitell assay, which has a positive cutoff value of 80 pg/mL or greater (sensitivity, 64%; specificity, 92%) for patients with proven or probable invasive aspergillosis. β-D-glucan may be detectable earlier in the course of invasive aspergillosis than is GM. False-positive β-D-glucan results may be associated with hemodialysis using cellulose membranes, intravenous immunoglobulin, and bacterial bloodstream infections. In a study to assess the utility of serially monitoring lung transplant recipients with the β-D-glucan assay, 90% of subjects without an IFI had at least one positive β-D-glucan result (≥80 pg/mL), leading to a low positive predictive value (9%). Similar issues were encountered in a study using β-D-glucan to monitor for invasive candidiasis in an intensive care unit; 45% of subjects had false-positive results, which were ultimately attributed to receipt of intravenous immunoglobulin and hemodialysis.

Nucleic acid-based tests including PCR have been explored in the diagnosis of invasive aspergillosis, although none of these have been incorporated into formal diagnostic criteria. A meta-analysis of PCR testing of blood, plasma, or serum reported a sensitivity and specificity of 75% and 87%, respectively. Avni and associates found comparable performance of BAL-PCR versus BAL GM testing (using an OD index of 0.5) as well as improved sensitivity with stable specificity when used together, suggesting a possible advantage to combination testing. To date there is no FDA-approved nucleic acid assay for Aspergillus in the United States. Attempts at standardization and the availability of a commercial PCR platform are necessary steps toward validation and routine clinical use. Newer diagnostics, including a lateral flow device incorporating a monoclonal antibody, JF5, to detect an Aspergillus extracellular glycoprotein antigen may provide rapid and inexpensive point-of-care testing.

Diagnostic criteria for IPA have been proposed by the Mycoses Study Group/European Organization for Research and Treatment of Cancer and include proven, probable, and possible invasive aspergillosis. A diagnosis of proven IFI requires microscopic evidence of Aspergillus tissue invasion or a positive culture from a normally sterile site. A diagnosis of probable IPA requires an at-risk host, corroborating radiographic findings, and direct (e.g., culture) or indirect mycologic evidence (e.g., positive serum, plasma, or BAL GM, or positive serum β-D-glucan). Other clinical algorithms continue to be introduced to assist in differentiating Aspergillus colonization from true invasive aspergillosis in critically ill intensive care unit patients without clear predisposing host factors but with positive respiratory specimens and/or clinical concern for invasive aspergillosis.

Treatment.

As with other IFIs, management of IPA may involve a combination of surgical, pharmacologic, and other adjunctive interventions. Attempts to restore host immunity should be made wherever feasible, being mindful of the risk for IRIS. Indications for surgical intervention include life-threatening hemoptysis, lesions contiguous to the great vessels and/or pericardium, and invasion of the chest wall, as well as isolated lesions in patients about to undergo intensive chemotherapy or HSCT. The drug of choice for IPA is voriconazole, based on recommendations from both the IDSA and American Thoracic Society and data from a large prospective randomized trial of invasive aspergillosis that demonstrated significantly better response and overall survival in those treated with voriconazole than those treated with AmB-d. The dose of voriconazole for IPA is 6 mg/kg intravenously every 12 hours on day 1, followed by 4 mg/kg every 12 hours thereafter. Therapy can be transitioned to the oral route once the patient is stable and tolerating oral medications. While most patients are treated for a minimum of 6 to 12 weeks, the total duration of pharmacologic therapy for IPA is not clearly defined and is dependent upon the immune status of the host and clinical response to treatment ( eFig. 38-5 ).

Posaconazole may be an effective alternative to voriconazole, although it is most often used as salvage therapy because it has not been studied as primary treatment. In patients with invasive aspergillosis refractory or intolerant to other antifungal therapies, response to posaconazole was superior (45/107, 42%) compared with the external control group (22/86, 26%), primarily treated with AmB or itraconazole. Other researchers have also shown success with posaconazole as salvage therapy.

Azole resistance in Aspergillus was first reported with A. fumigatus in 1997 and appears to be increasing in frequency. The known mechanism of resistance is due to sequence variation in the fungal cyp51A gene, which encodes the drug target, 14-α-demethylase. Many of these sequence variants result in cross-resistance between the azole compounds, namely itraconazole, voriconazole, and posaconazole. Although interpretive breakpoints defining clinical resistance have yet to be established for molds, standard methods for testing filamentous fungi have been validated, and epidemiologic cutoff values (which define susceptibility using the MIC distribution of wild-type Aspergillus strains lacking known azole resistance mechanisms) have been proposed. While epidemiologic cutoff values do not predict outcomes, they may aid in detecting isolates with potential resistance mutations, including those in cyp51A. Some experts advocate MIC testing as a screen for the presence of resistance mutations in patients with invasive aspergillosis that fail to respond to azole therapy.

Polyenes are used for the treatment of IPA in the setting where mucormycosis remains in the differential diagnosis or in patients intolerant or refractory to azoles. The lipid formulations of AmB are currently preferred because of their reduced nephrotoxicity compared with that of AmB-d. Currently, the IDSA recommends ABLC 5 mg/kg/day or LAmB 3 to 5 mg/kg/day for the treatment of IPA. LAmB 3 mg/kg/day was compared with LAmB 10 mg/kg/day in a double-blind trial of patients with proven or probable invasive aspergillosis to assess whether higher doses would improve response; there was no clinical advantage with the higher dose but there was significantly more hypokalemia and nephrotoxicity.

Echinocandins may be used in patients who are refractory or intolerant to other therapies, although randomized controlled trials evaluating echinocandins as primary therapy for invasive aspergillosis have not been performed. In one study, 83 adults with probable/proven invasive aspergillosis, including 64 with IPA were treated with caspofungin; 45% (50% of those with IPA) obtained a complete or partial response. Based on these data, caspofungin was cleared by the FDA as salvage therapy for invasive aspergillosis. For micafungin, a large report from Japan indicated a 71% (90 of 130) clinical response rate in patients with invasive aspergillosis treated with micafungin monotherapy (doses ranged from 50 to 300 mg/day) as first-line therapy.

Given the high mortality associated with IPA, combination therapy is often considered. While in vitro and in vivo data support a role for combination therapy, the IDSA does not recommend using combination therapy as first-line therapy for invasive aspergillosis, due to the lack of data from a randomized controlled trial. When combination therapy is used, echinocandins are most often paired with polyenes or azoles based on their activity at a different site (fungal cell wall) compared with the azoles and polyenes (fungal membrane). A randomized controlled trial comparing voriconazole monotherapy with voriconazole plus anidulafungin in patients with invasive aspergillosis is underway. Other adjunctive measures used to optimize outcomes of IPA include granulocyte or granulocyte-macrophage colony stimulating factor, interferon-gamma, and granulocyte infusions.

Epidemiology and Pathogenesis.

Tracheobronchial aspergillosis (TBA) should be considered as a spectrum, including mild tracheobronchitis and obstructive, ulcerative, and pseudomembranous TBA, often with more than one form present concurrently. Mild tracheobronchitis demonstrates only superficial mucosal inflammation; obstructive, ulcerative, and pseudomembranous forms may be superficial or progress to involve the entire bronchial wall with necrotizing tracheobronchitis and invasion of the surrounding tissue. A rare form of IPA, TBA is most commonly encountered in lung and heart-lung transplant recipients, although it has been reported in patients with advanced HIV and hematologic malignancies, including patients undergoing HSCT.

Clinical Manifestations, Diagnosis and Treatment.

In lung and heart-lung transplant recipients, TBA is often discovered early in the posttransplant period when patients may have ulceration and/or pseudomembrane formation at the bronchial anastomotic site visible by bronchoscopy ( Fig. 38-5 ), even without symptoms. In contrast, patients with hematologic malignancies are typically symptomatic at the time of discovery of TBA with productive cough, dyspnea, fever, wheezing, stridor, hemoptysis, and respiratory failure. Early diagnosis is crucial given the potential for progressive symptoms and disseminated infection and complications including bronchial obstruction, anastomotic rupture, and bronchopleural or bronchoarterial fistulas. While chest imaging may demonstrate bronchial wall thickening, luminal narrowing, and/or endobronchial lesions ( eFig. 38-6 ), it cannot make the diagnosis. Serum GM is of limited value for tracheobronchial aspergillosis. Diagnosis is made via bronchoscopy with visualization of plaques, ulceration, pseudomembranes, and obstructive mucous plugs and/or masses ( Fig. 38-6 ) together with pathologic and microbiologic findings.

Tracheobronchial aspergillosis.

Bronchoscopic visualization of the right mainstem bronchus in a lung transplant recipient demonstrates tracheobronchial aspergillosis with Aspergillus fumigatus . Stenosis and extensive necrotic pseudomembranes and debris are seen at the anastomotic site.

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