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Recent Advances in Chest Medicine |

Diagnosis and Treatment of Pulmonary Aspergillosis SyndromesAspergillus Pulmonary Syndromes FREE TO VIEW

Karen C. Patterson, MD; Mary E. Strek, MD, FCCP
Author and Funding Information

From the Pulmonary, Allergy and Critical Care Division (Dr Patterson), University of Pennsylvania, Pennsylvania, PA; and the Section of Pulmonary and Critical Care (Dr Strek), University of Chicago, Chicago, IL.

CORRESPONDENCE TO: Karen C. Patterson, MD, Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania, 828 Gates, 3600 Spruce St, Philadelphia, PA 19104; e-mail: karen.patterson@uphs.upenn.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(5):1358-1368. doi:10.1378/chest.14-0917
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Both inherited and acquired immunodeficiency and chronic pulmonary disease predispose to the development of a variety of pulmonary syndromes in response to Aspergillus, a fungus that is ubiquitous in the environment. These syndromes include invasive aspergillosis, which is now recognized to occur in patients with critical illness without neutropenia and in those with mild degrees of immunosuppression, including from corticosteroid use in the setting of COPD. Chronic pulmonary aspergillosis includes simple aspergilloma, which is occasionally complicated by life-threatening hemoptysis, and progressive destructive cavitary disease requiring antifungal therapy. Allergic bronchopulmonary aspergillosis occurs almost exclusively in patients with asthma or cystic fibrosis. Recent advances in each of these syndromes include a greater understanding of the underlying pathophysiology and hosts at risk; improved diagnostic algorithms; and the availability of more effective and well-tolerated therapies. Improvement in outcomes for Aspergillus pulmonary syndromes requires that physicians recognize the varied and sometimes subtle presentations, be aware of populations at risk of illness, and institute potentially life-saving therapies early in the disease course.

Figures in this Article

Pulmonary aspergillosis refers to a spectrum of diseases that result from Aspergillus becoming resident in the lung. These include invasive aspergillosis from angioinvasive disease, simple aspergilloma from inert colonization of pulmonary cavities, and chronic cavitary pulmonary aspergillosis from fungal germination and immune activation (Table 1). Allergic bronchopulmonary aspergillosis (ABPA), driven by allergic responses, has an important place along this spectrum as well.

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TABLE 1 ]  Pulmonary Aspergillosis Syndromes

ABPA = allergic bronchopulmonary aspergillosis.

Aspergillus is a ubiquitous and hardy organism. It grows best in moist environments, although spore aerosolization and dispersion occur most effectively in dry climates. Spores survive harsh external conditions and adapt to a range of internal environments.13 Although there are hundreds of Aspergillus species, Aspergillus fumigatus is by far the most common pathogenic species in humans, where the small size and hydrophobicity of its spores confer a dispersion advantage.46 Although less common, Aspergillus flavus and Aspergillus niger also contribute to the total burden of pulmonary aspergillosis. When inhaled, spores deposit by sedimentation in distal airways and alveolar spaces. In healthy hosts, spores are eliminated by mucociliary clearance and immune defenses. Germination is the conversion of dormant spores into growing hyphal elements.

Aspergillus is an inadvertent human pathogen, and pulmonary aspergillosis is largely the result of impaired airway clearance from a compromised immune function or a chronic lung disease such as COPD and sarcoidosis. Advances in the domains of stem cell transplant and immunosuppressive therapies and an increased prevalence of chronic pulmonary diseases have inadvertently led to a rise in pulmonary aspergillosis syndromes. Now commonly encountered by pulmonologists and intensivists worldwide, these syndromes have a high associated morbidity and can be fatal. In this review, we highlight advances in the diagnosis and treatment of pulmonary aspergillosis relevant to clinical care. These include the recognition of additional hosts at risk of invasive disease, as well as an expanded array of diagnostic and treatment options; a delineation of the features and outcomes of chronic pulmonary aspergillosis; and, updated diagnostic criteria and an evolving understanding of the role of triazole and anti-IgE treatment options in ABPA.

Invasive aspergillosis has been described classically in patients with neutropenia in the setting of hematologic malignancy but is seen increasingly in patients with even milder immune compromise from immunosuppression, chronic pulmonary or liver disease, or critical illness.7 As the portal of entry, the upper and lower respiratory tracts are most commonly infected, although dissemination to any organ may occur. Aspergillus tracheobronchitis and CNS infection are associated with especially poor outcomes. An informative review of the pathogenesis of invasive aspergillosis has been published.8 The diagnosis may be delayed from lack of awareness of the expanded patient populations at risk and because of failure to recognize the significance of positive Aspergillus respiratory cultures or to use available diagnostic tests. Early diagnosis of invasive aspergillosis, along with the use of therapeutic agents with greater tolerability and efficacy, have the potential to decrease mortality, which remains high.

Criteria for the diagnosis of invasive fungal disease were formulated in 2002 and updated in 2008.9 Although intended for research purposes, they serve as a useful conceptual framework for the physician at the bedside. Proven invasive aspergillosis requires histopathologic or cytologic evidence of fungus, or culturing Aspergillus from a sterile site regardless of immune status. The criteria for probable disease include clinical upper or lower respiratory tract involvement with direct (identification of fungus by microscopy, cytology, or culture) or indirect (detection of antigen or cell-wall constituents) mycologic evidence of infection in a predisposed patient. The criteria for possible invasive aspergillosis are similar, but mycologic evidence is not required.

The revised 2008 definition added solid organ transplant, inherited immunodeficiencies, connective tissue diseases, and immunosuppressive therapy to the list of host factors that characterize patients predisposed to invasive disease (Table 2). More recent studies suggest additional populations at risk, including patients with critical illness, COPD, end-stage liver disease, or alcoholic hepatitis.1013 The incidence of invasive aspergillosis among patients without malignancy in the ICU may be as high as 4%.14 In a retrospective multicenter study of 1,209 randomly selected patients with a culture from any body site positive for Aspergillus, 12% had evidence for invasive disease.15 Although patients with hematologic malignancy or transplant or neutropenia accounted for the majority of cases, malnutrition (27%), corticosteroid use (20%), HIV infection (19%), diabetes mellitus (11%), and chronic pulmonary disease (9%) were associated with invasive infection as well. In a single-center retrospective study of 239 patients hospitalized with COPD who had Aspergillus isolated from a lower respiratory tract sample, 22% had probable invasive aspergillosis.12 Multivariate regression identified the following predictors of invasive aspergillosis: ICU admission, heart failure, 3 months of antibiotics use, and > 700 mg cumulative prednisone from admission to Aspergillus isolation. Inhaled corticosteroids may increase the risk of invasive aspergillosis in patients with COPD.16,17 Importantly, mortality may be increased in critically ill patients when Aspergillus is isolated, irrespective of evidence for invasive disease.11,18

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TABLE 2 ]  Populations Predisposed to Invasive Aspergillosis

EORTC/MSG = European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group.

The clinical presentation of invasive aspergillosis includes fever, cough, dyspnea, chest discomfort, and hemoptysis. Chest CT imaging is more sensitive than plain chest radiography.8,9 Signs on CT scans constituting clinical evidence for invasive pulmonary disease by the 2008 criteria include dense, well-circumscribed lesion(s) with or without a surrounding “halo” of ground-glass gray attenuation, air-crescent sign, and cavity formation (Fig 1). A retrospective study of chest CT imaging in 235 patients with invasive aspergillosis demonstrated at presentation one or more macronodules (94%), halo sign (61%), consolidation (30%), infarct shaped nodules (27%), cavitary lesions (20%), and air-crescent signs (10%).19

Figure Jump LinkFigure 1 –  Chest CT scan demonstrating the typical radiographic findings of invasive aspergillosis with both the air crescent sign (arrow) and the cavity formation. This patient had an autoimmune interstitial lung disease treated with low doses of prednisone and azathioprine. The patient presented with fever, right pleuritic chest pain, and an elevated WBC count. Previous respiratory cultures positive for Aspergillus had been presumed to represent “colonization.” Galactomannan antigen was detected in both serum and BAL fluid. Pleural fluid analysis was culture positive for Aspergillus fumigatus. The patient recovered with discontinuation of immunosuppressive therapy and 6 mo of treatment with voriconazole.Grahic Jump Location

Aspergillus tracheobronchitis is a form of invasive aspergillosis recognized increasingly in critically ill patients with a minority having little in the way of formal immunosuppression (Fig 2, Table 1).7,11 The diagnosis requires bronchoscopy, and it is associated with poor outcomes because recognition is often delayed, except in patients undergoing lung transplant who are monitored with periodic surveillance bronchoscopies.11 Characteristic findings on bronchoscopy include tracheobronchial ulceration, nodules, pseudomembranes, plaque, or eschar (Fig 2). Aspergillus tracheobronchitis should be suspected in patients with suggestive imaging and hemoptysis or in patients with lobar atelectasis or unilateral wheeze, which result from thick mucus plugs containing Aspergillus that fill the central airways.

Figure Jump LinkFigure 2 –  Chest CT scan and bronchoscopic images of invasive tracheobronchial aspergillosis. The patient was on immunosuppression for a prior heart transplant. He presented with dyspnea, hemoptysis, and hypoxemia. A, Imaging revealed a dense consolidation in the left upper lobe with peripheral nodular opacities. B, C, Bronchoscopic airway inspection revealed patchy areas of white adherent plaques and airway sloughing in the trachea (B) and left and right bronchial trees (C). Endobronchial biopsy with Grocott stains was positive for septating fungal organisms with tissue invasion. Aspergillus fumigatus grew from BAL cultures. Voriconazole treatment resulted in marked clinical improvement, including resolution of hemoptysis.Grahic Jump Location

Tests that may aid in the diagnosis of invasive infection include an enzyme immunoassay that detects galactomannan antigen, a constituent of the Aspergillus cell wall, and quantitative polymerase chain reaction assay. The sensitivity and specificity of these tests vary depending on the host (immunocompromised vs nonimmunocompromised), the specimen tested (serum or BAL fluid), and the presence of antifungal therapy, which can decrease assay sensitivity.8,20,21 There may be a role for serial tests both in screening high-risk patients and in assessing response to therapy. A meta-analysis evaluating diagnostic serum galactomannan testing in immunocompromised patients demonstrated a sensitivity of 78% and a specificity of 82% at an optical density index cutoff of 0.5. The accuracy of galactomannan testing of BAL fluid in a more recent meta-analysis, in which most patients had a hematologic malignancy, showed a summary estimate sensitivity of 90% and specificity of 94%, when studies had a range of cutoff indexes.22 In a single-center prospective study of 110 patients in the ICU, 26 of whom had proven invasive aspergillosis, the sensitivity of galactomannan in BAL fluid was 88%, with a specificity of 87% using a cutoff index of 0.5.23 The sensitivity of the serum assay was 42% in this same series. However, not all studies have confirmed a high sensitivity of galactomannan testing. In a large, hematologic cohort, the test sensitivity for BAL fluid was 50%, and agreement with the gold standard diagnostic algorithm was only modest.24 False-positive galactomannan tests have been reported in patients receiving piperacillin/tazobactam antibiotics, but this may be less likely to occur with current antibiotic formulations.25 Quantitative polymerase chain reaction assay in BAL fluid has theoretical advantages but is not validated for clinical use.26,27 Testing for serum 1,3-β-D-glucan antigen is not specific, because this antigen is present in other fungi.8,11

Although the 2008 criteria provide a useful and partially validated diagnostic algorithm, in practice therapy for invasive aspergillosis is often started empirically in patients in whom invasive aspergillosis is suspected on clinical grounds. Management requires a multipronged approach that includes reversal of immunosuppression when possible. Immunomodulatory therapy with granulocyte colony stimulating factor may be useful in neutropenic patients. A single-center retrospective study demonstrated that surgical excision of an isolated pulmonary site of infection can be carried out safely in neutropenic and thrombocytopenic patients who have progressive disease despite antifungal therapy.28

Agents with efficacy against invasive aspergillosis include amphotericin B and its lipid formulations; the triazoles itraconazole, voricanozole, and posaconazole; and caspofungin and micafungin.29,30 Guidelines favor voriconazole as the initial treatment of invasive aspergillosis based on its greater activity in vitro and a randomized trial showing improved outcomes and a lower rate of adverse reactions compared with amphotericin B.29,30 Voriconazole is started IV, then switched to oral therapy when clinical improvement occurs (Table 3). According to expert opinion, monitoring serum trough levels to adjust dosing to achieve a therapeutic serum concentration may improve efficacy and decrease toxicity. Monitoring for liver toxicity and recognizing the potential for drug interactions is necessary. In particular, visual changes and hallucinations may occur. If required, salvage therapy consists of IV caspofungin or micafungin or oral posaconazole, which is highly active against Aspergillus. Combination therapy may be of benefit, but data to support this are limited.

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TABLE 3 ]  Management of Pulmonary Aspergillosis Syndromes

sq = subcutaneous injection. See Table 1 for expansion of other abbreviation.

Medical therapy is often prolonged, with duration dependent on response, which includes assessment of clinical and radiographic resolution, microbiologic clearance, and improvement in immune function. Therapy may need to be restarted if immunosuppression, chemotherapy, or stem cell transplant is required. Several studies suggest that survival (64% at 12 weeks in one prospective study) may be higher than in the past.31 In a retrospective cohort study of patents in the ICU without traditional risk factors for invasive aspergillosis, a delay in initiating antifungal therapy was associated with a longer hospital stay.32

Chronic pulmonary aspergillosis refers to a spectrum of diseases, from simple aspergilloma to progressive cavitary aspergillosis (Table 1). Simple aspergillomas form in preexisting cavities, which sequester spores from clearance and the resulting fungus ball from immune responses (Fig 3). Positive precipitins or elevated serum IgG titers to Aspergillus are often observed.7,33 Except when hemoptysis occurs, the clinical course is typically benign with long-term radiographic stability. Patients generally do not require or benefit from medical therapy, although the instillation of intracavitary antifungal treatment may lead to a short-term benefit in patients with hemoptysis.34

Figure Jump LinkFigure 3 –  Chest CT scan of a patient with biapical scarring from previous infection with Mycobacterium tuberculosis who developed a simple aspergilloma in the left upper lobe scar. Hemoptysis was initially treated with bronchial artery embolization, but, at recurrence some years later, resection of the left upper lobe was performed after pretreatment with voriconazole to reduce the risk of local postoperative Aspergillus infection.Grahic Jump Location

In contrast to simple aspergilloma, syndromes of progressive cavitary aspergillosis are highly morbid (Fig 4). Over 30 years ago, Gefter and colleagues35 coined the term “semi-invasive aspergillosis” for this clinical entity. Since then, it has been variably referred to as “complex aspergilloma,” “chronic cavitary pulmonary aspergillosis,” “chronic necrotizing pulmonary aspergillosis,” and “subacute invasive disease.”30,3638 “Chronic cavitary pulmonary aspergillosis” and “chronic necrotizing pulmonary aspergillosis” have been the more commonly used terms in recent years, and many authors distinguish the two entities by cavity features, host immune status, and the degree of suspected tissue invasion.37,39 Specifically, the term “chronic necrotizing pulmonary aspergillosis” is often reserved for quickly progressing disease in patients with compromised immune function, in whom local tissue invasion is suspected. However, the terms continue to be used interchangeably in the literature, the clinical features demonstrate significant overlap, and parenchymal invasion is rarely demonstrated. Although a consensus on terminology is still lacking, we refer to this syndrome as “chronic cavitary pulmonary aspergillosis.”37 Cavities may be single or multiple, thin-walled or thick-walled, and progress in a dramatic or indolent fashion (Fig 4). Discrete mycetomas were observed in only 25% of patients in one study.40 Pleural thickening is common. Progressive pulmonary fibrosis develops in a subset of patients.37 Symptoms include dyspnea, cough, hemoptysis, chest pain, weight loss, fever, and malaise. Nonspecific serum inflammatory markers such as C-reactive protein and the erythrocyte sedimentation rate are often elevated.

Figure Jump LinkFigure 4 –  A, Chest CT scan demonstrating chronic cavitary pulmonary aspergillosis in the setting of underlying fibrocystic sarcoidosis. After years of stable sarcoidosis, this patient developed dyspnea, hemoptysis, and hypoxemia. Sputum cultures grew Aspergillus niger. Serum IgG for Aspergillus was positive. Imaging revealed extensive right-sided consolidation with discrete areas of cavitation and mycetoma. B, Extensive tissue destruction ensued in the following year. Hemoptysis has not recurred since itraconazole was started.Grahic Jump Location

In the largest published review of comorbidities, all patients with chronic cavitary pulmonary aspergillosis had at least one underlying pulmonary disease, of which COPD was the most common.41 A history of mycobacterial disease, split between TB and non-TB infection, was present in one-third of patients. Fibrotic sarcoidosis and ABPA were other important comorbidities. The nature of these underlying lung diseases suggests that mechanical impediments to Aspergillus elimination are an important element of disease. Defects in innate immunity and exogenous immunosuppression likely also contribute to increased susceptibility.33 Specific polymorphisms in Toll-like receptors and mannose-binding lectin, both involved in pathogen pattern recognition and innate immune responses, continue to be explored.4245 However, the mechanisms of tissue destruction, where local tissue invasion is rarely observed, remain poorly understood.

Diagnosing chronic cavitary pulmonary aspergillosis can be challenging. Imaging abnormalities may be mistaken for underlying parenchymal disease, and cavitation may not be evident early in the disease course. Serum IgG testing by quantitative or precipitins assays establishes sensitization and is positive in most patients.46 Total IgE and Aspergillus-specific IgE levels are often, although not consistently, elevated.37,39 Cultures of expectorated sputum or BAL fluid are often positive for Aspergillus, but negative cultures do not rule out disease when it is suspected on clinical grounds.47 Because Aspergillus antigens may access the circulation, serum galactomannan testing is positive in some patients. Reported sensitivities have increased with the liberalization of the cutoff index in recent years.48 Serum 1,3 β-D glucan testing is unreliable and in one study was positive in only 21% of patients with chronic progressive pulmonary aspergillosis.48 Histology reveals chronic inflammation; granulomas are a variable finding. Fungal hyphae are more commonly observed within cavities than in surrounding parenchyma.35,49 Ultimately, the diagnosis rests in the combination of clinical features, imaging, serologies, and cultures, with consideration of predisposing patient factors (Table 1).

With a high attributable morbidity, outcomes in chronic cavitary pulmonary aspergillosis are generally poor.50,51 Survival likely increases with treatment, although mortality is also high, even among treated patients.52 Several retrospective and prospective case series, and limited data from randomized controlled studies, support a protracted course of treatment in patients with symptomatic disease (Table 3).40,5355 IV amphotericin or voriconazole are options for severe disease, and oral voriconazole or itraconazole is typically used in stable patients. Radiographic and clinical improvements typically accompany decreases in fungal burden, but serum Aspergillus-IgG levels may remain elevated, and serologic normalization is not a reliable end point of treatment.56 Not all patients improve with treatment; in patients with progressive disease, a positive response to therapy may be reflected in stabilization rather than in radiographic improvement.55 Azole resistance is of increasing concern and has been associated with treatment failure.57 In addition to antifungals, a therapeutic role for interferon γ (IFN-γ), an important cytokine in the containment of fungal infections, has been explored. Similar to the results observed in a small series of patients with invasive aspergillosis, a positive response to exogenous IFN-γ therapy was noted in a report of two patients with chronic cavitary pulmonary aspergillosis.58,59 Notably, these patients had demonstrated reduced IFN-γ production and had failed antifungal therapy alone.59

Subacute or massive hemoptysis can complicate both simple aspergilloma and chronic cavitary pulmonary aspergillosis. Bronchial artery embolization is an important treatment option for short-term control of hemoptysis that threatens clinical stability. However, long-term recurrence is common. Intracavitary instillation of amphotericin has been tried in some patients. Although typically delivered via bronchoscopic technique, in a recently published series of patients with simple aspergilloma or chronic cavitary pulmonary aspergillosis, percutaneous installation of intracavitary treatment was associated with good short-term control of hemoptysis in 25% of patients.34 Surgical resection is generally reserved for fit patients who fail medical management and/or bronchial artery embolization and who have disease favorable to resection.60,61 Concomitant antifungal treatment is not recommended universally but should be considered for patients with contamination of the pleural space during resection or with residual disease postoperatively.61,62 Recurrent disease is not uncommon, even in those with a good initial response to medical and/or surgical treatment.60,63 Schweer and colleagues39 recently published an elegant treatment algorithm emphasizing the need for careful long-term follow-up.

ABPA is the result of immune-mediated damage to, and dysfunction of, the airways triggered by Aspergillus (Fig 5). Modifications to diagnostic criteria developed decades ago have been proposed in recent years (Table 4).64,65Aspergillus-specific IgE levels may be more sensitive than skin testing for establishing sensitization. In a recent evaluation of diagnostic criteria, Aspergillus-specific IgE levels were increased in 100% of patients with ABPA.66 This was the most sensitive finding for ABPA. Although asthma is the most common comorbidity, patients with cystic fibrosis have a higher rate of Aspergillus colonization, and up to 15% of patients develop ABPA.67 For patients with asthma, spirometry may be normal and ABPA should be considered even in mild disease when serologies and imaging are otherwise suggestive.64,68 The usefulness of bronchiectasis as a diagnostic criterion has been questioned recently.53 The possibility of ABPA should not be dismissed in patients without bronchiectasis, which can be a late-stage event, who otherwise have suggestive clinical findings. Although typically central, peripheral bronchiectasis may be evident.64 High-attenuation mucous, when present, is highly suggestive of ABPA over other causes of bronchiectasis and predicts relapse among patients with ABPA (Fig 5B).64,69 Finally, positive respiratory cultures are supportive but are not a formal diagnostic criterion. Even when stains or cultures are negative, Aspergillus DNA may be detected in respiratory samples.70

Figure Jump LinkFigure 5 –  Chest CT scan demonstrating typical features of allergic bronchopulmonary aspergillosis. A, Central bronchiectasis. B, Plugging of airways with mucus.Grahic Jump Location
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TABLE 4 ]  Diagnosing ABPA

See Table 1 for expansion of abbreviation.

The pathogenesis of ABPA is complex. In basic terms it involves (1) noninvasive growth of Aspergillus aided by poor airway clearance, and (2) a hypersensitive response in predisposed individuals. The activation of lymphocytes occurs along a T-helper (Th) 2 pathway, rather than the Th1 pathway for sensitization in patients without ABPA.53 Th2 cells recruit eosinophils, which, along with fungal enzymes, contribute to epithelial damage. A more detailed unifying model of the essential immunologic events in ABPA across cystic fibrosis and asthma subtypes is still evolving. In patients with cystic fibrosis, human leukocyte antigen alleles have been associated with the development of ABPA.71 In addition, in patients with cystic fibrosis, regulatory T cells were reduced in patients with ABPA compared with patients with asymptomatic colonization.72 In this same study, vitamin D levels were also lower in patients with ABPA.72 Vitamin D attenuates innate immune responses and enhances regulatory T cells, and research on Vitamin D and ABPA is ongoing.73

Corticosteroids are the mainstay of treatment (Table 3). However, therapies that attenuate fungal burden are used increasingly for augmentation or second-line therapy.53,7476 In ABPA due to asthma or cystic fibrosis, the addition of a triazole antifungal agent has been associated with improvements in lung function, serologic markers, rates of exacerbation, and corticosteroid requirements. Although important for combination regimens, the role of antifungals as a sole, first-line treatment remains to be determined. A placebo-controlled study is underway, and case reports and series suggest that omalizumab, a monoclonal antibody to IgE, may be effective in some patients.53 Treatment end points in ABPA remain a reduction in, although not normalization of, total IgE levels associated with clinical and radiographic improvement. Following a treatment course, patients may remain in remission, relapse and require long-term treatment, and/or progress to end-stage lung disease. Therefore, close long-term follow-up with serial assessments of total serum IgE is advised for all patients.

Aspergillus sensitization can cause hypersensitivity pneumonitis or can complicate asthma. The features of hypersensitivity pneumonitis have been reviewed elsewhere.77 Severe asthma with fungal sensitization (SAFS) is an emerging disease concept. Although fungal sensitization can be associated with severe asthma, a direct role of sensitization in the disease process remains unclear. Unlike the syndromes described earlier, Aspergillus germination is not thought to be a feature of SAFS. SAFS is distinguished from ABPA by sensitization to an array of fungal species, a lower total IgE, normal Aspergillus-IgG levels, and a lack of bronchiectasis and other radiographic changes of ABPA.78,79 It has been suggested that SAFS and ABPA occur along a spectrum, with a more pronounced inflammatory response in ABPA, but it remains to be established that patients with SAFS are at predictable risk of progressing to ABPA. A role for antifungal therapy in SAFS has not been established, and an aggressive asthma regimen remains the mainstay of treatment.78

Aspergillus is a ubiquitous organism that is encountered regularly in the environment. Although preexisting lung disease or immune dysfunction have long been recognized as prerequisites for the development of pulmonary disease in response to Aspergillus, recent studies demonstrate that even a modest degree of immunosuppression increases this risk, where the type of pulmonary response is often a function of host factors. Invasive pulmonary aspergillosis is encountered in patients with chronic lung disease exposed to oral or inhaled corticosteroids and in critically ill patients. The diagnosis of invasive aspergillosis is aided by an understanding of the populations and settings that predispose to infection, the recognition that positive cultures may indicate invasive disease; the use of noninvasive galactomannan testing may be helpful, although test sensitivity is variable across studies and the clinical utility remains unclear. Chronic cavitary pulmonary aspergillosis occurs most often in patients with preexisting lung disease. Outcomes are generally poor, particularly without antifungal treatment. Patients with asthma or cystic fibrosis may develop ABPA from a Th2 response to germinated Aspergillus in the airway. For invasive and chronic cavitary pulmonary aspergillosis, and potentially for ABPA, patients benefit from antifungal therapy, most often with triazole medications. Future work to further identify the immune alterations that mediate the inflammatory responses to Aspergillus, or the lack thereof, will advance our understanding of the pathogeneses of these syndromes.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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Avni T, Levy I, Sprecher H, Yahav D, Leibovici L, Paul M. Diagnostic accuracy of PCR alone compared to galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive pulmonary aspergillosis: a systematic review. J Clin Microbiol. 2012;50(11):3652-3658. [CrossRef] [PubMed]
 
Buess M, Cathomas G, Halter J, et al. Aspergillus-PCR in bronchoalveolar lavage for detection of invasive pulmonary aspergillosis in immunocompromised patients. BMC Infect Dis. 2012;12:237. [CrossRef] [PubMed]
 
Nebiker CA, Lardinois D, Junker L, et al. Lung resection in hematologic patients with pulmonary invasive fungal disease. Chest. 2012;142(4):988-995. [CrossRef] [PubMed]
 
Walsh TJ, Anaissie EJ, Denning DW, et al; Infectious Diseases Society of America. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(3):327-360. [CrossRef] [PubMed]
 
Limper AH, Knox KS, Sarosi GA, et al; American Thoracic Society Fungal Working Group. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011;183(1):96-128. [CrossRef] [PubMed]
 
Steinbach WJ, Marr KA, Anaissie EJ, et al. Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry. J Infect. 2012;65(5):453-464. [CrossRef] [PubMed]
 
Baddley JW, Stephens JM, Ji X, Gao X, Schlamm HT, Tarallo M. Aspergillosis in Intensive Care Unit (ICU) patients: epidemiology and economic outcomes. BMC Infect Dis. 2013;13:29. [CrossRef] [PubMed]
 
Riscili BP, Wood KL. Noninvasive pulmonaryAspergillusinfections. Clin Chest Med. 2009;30(2):315-335. [CrossRef] [PubMed]
 
Kravitz JN, Berry MW, Schabel SI, Judson MA. A modern series of percutaneous intracavitary instillation of amphotericin B for the treatment of severe hemoptysis from pulmonary aspergilloma. Chest. 2013;143(5):1414-1421. [CrossRef] [PubMed]
 
Gefter WB, Weingrad TR, Epstein DM, Ochs RH, Miller WT. “Semi-invasive” pulmonary aspergillosis: a new look at the spectrum of aspergillus infections of the lung. Radiology. 1981;140(2):313-321. [CrossRef] [PubMed]
 
Binder RE, Faling LJ, Pugatch RD, Mahasaen C, Snider GL. Chronic necrotizing pulmonary aspergillosis: a discrete clinical entity. Medicine (Baltimore). 1982;61(2):109-124. [CrossRef] [PubMed]
 
Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature change, and review. Clin Infect Dis. 2003;37(suppl 3):S265-S280. [CrossRef] [PubMed]
 
Nam HS, Jeon K, Um SW, et al. Clinical characteristics and treatment outcomes of chronic necrotizing pulmonary aspergillosis: a review of 43 cases. Int J Infect Dis. 2010;14(6):e479-e482. [CrossRef] [PubMed]
 
Schweer KE, Bangard C, Hekmat K, Cornely OA. Chronic pulmonary aspergillosis. Mycoses. 2014;57(5):257-270. [CrossRef] [PubMed]
 
Felton TW, Baxter C, Moore CB, Roberts SA, Hope WW, Denning DW. Efficacy and safety of posaconazole for chronic pulmonary aspergillosis. Clin Infect Dis. 2010;51(12):1383-1391. [CrossRef] [PubMed]
 
Smith NL, Denning DW. Underlying conditions in chronic pulmonary aspergillosis including simple aspergilloma. Eur Respir J. 2011;37(4):865-872. [CrossRef] [PubMed]
 
Carvalho A, Pasqualotto AC, Pitzurra L, Romani L, Denning DW, Rodrigues F. Polymorphisms in toll-like receptor genes and susceptibility to pulmonary aspergillosis. J Infect Dis. 2008;197(4):618-621. [CrossRef] [PubMed]
 
Vaid M, Kaur S, Sambatakou H, Madan T, Denning DW, Sarma PU. Distinct alleles of mannose-binding lectin (MBL) and surfactant proteins A (SP-A) in patients with chronic cavitary pulmonary aspergillosis and allergic bronchopulmonary aspergillosis. Clin Chem Lab Med. 2007;45(2):183-186. [CrossRef] [PubMed]
 
Saxena S, Madan T, Shah A, Muralidhar K, Sarma PU. Association of polymorphisms in the collagen region of SP-A2 with increased levels of total IgE antibodies and eosinophilia in patients with allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 2003;111(5):1001-1007. [CrossRef] [PubMed]
 
Kaur S, Gupta VK, Shah A, Thiel S, Sarma PU, Madan T. Plasma mannan-binding lectin levels and activity are increased in allergic patients. J Allergy Clin Immunol. 2005;116(6):1381-1383. [CrossRef] [PubMed]
 
Baxter CG, Denning DW, Jones AM, Todd A, Moore CB, Richardson MD. Performance of twoAspergillusIgG EIA assays compared with the precipitin test in chronic and allergic aspergillosis. Clin Microbiol Infect. 2013;19(4):E197-E204. [CrossRef] [PubMed]
 
Denning DW. Chronic forms of pulmonary aspergillosis. Clin Microbiol Infect. 2001;7(suppl 2):25-31. [CrossRef] [PubMed]
 
Kitasato Y, Tao Y, Hoshino T, et al. Comparison of Aspergillus galactomannan antigen testing with a new cut-off index andAspergillusprecipitating antibody testing for the diagnosis of chronic pulmonary aspergillosis. Respirology. 2009;14(5):701-708. [CrossRef] [PubMed]
 
Tashiro T, Izumikawa K, Tashiro M, et al. A case series of chronic necrotizing pulmonary aspergillosis and a new proposal. Jpn J Infect Dis. 2013;66(4):312-316. [PubMed]
 
Denning DW, Pleuvry A, Cole DC. Global burden of chronic pulmonary aspergillosis complicating sarcoidosis. Eur Respir J. 2013;41(3):621-626. [CrossRef] [PubMed]
 
Denning DW, Pleuvry A, Cole DC. Global burden of allergic bronchopulmonary aspergillosis with asthma and its complication chronic pulmonary aspergillosis in adults. Med Mycol. 2013;51(4):361-370. [CrossRef] [PubMed]
 
Nakamoto K, Takayanagi N, Kanauchi T, Ishiguro T, Yanagisawa T, Sugita Y. Prognostic factors in 194 patients with chronic necrotizing pulmonary aspergillosis. Intern Med. 2013;52(7):727-734. [CrossRef] [PubMed]
 
Agarwal R, Chakrabarti A, Shah A, et al; ABPA complicating asthma ISHAM working group. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clin Exp Allergy. 2013;43(8):850-873. [CrossRef] [PubMed]
 
Saito T, Fujiuchi S, Tao Y, et al; NHO Pulmonary Fungosis Research Group. Efficacy and safety of voriconazole in the treatment of chronic pulmonary aspergillosis: experience in Japan. Infection. 2012;40(6):661-667. [CrossRef] [PubMed]
 
Agarwal R, Vishwanath G, Aggarwal AN, Garg M, Gupta D, Chakrabarti A. Itraconazole in chronic cavitary pulmonary aspergillosis: a randomised controlled trial and systematic review of literature. Mycoses. 2013;56(5):559-570. [CrossRef] [PubMed]
 
Camuset J, Nunes H, Dombret MC, et al. Treatment of chronic pulmonary aspergillosis by voriconazole in nonimmunocompromised patients. Chest. 2007;131(5):1435-1441. [CrossRef] [PubMed]
 
Lelièvre L, Groh M, Angebault C, Maherault AC, Didier E, Bougnoux ME. Azole resistantAspergillus fumigatus: an emerging problem. Med Mal Infect. 2013;43(4):139-145. [CrossRef] [PubMed]
 
Bandera A, Trabattoni D, Ferrario G, et al. Interferon-gamma and granulocyte-macrophage colony stimulating factor therapy in three patients with pulmonary aspergillosis. Infection. 2008;36(4):368-373. [CrossRef] [PubMed]
 
Kelleher P, Goodsall A, Mulgirigama A, et al. Interferon-gamma therapy in two patients with progressive chronic pulmonary aspergillosis. Eur Respir J. 2006;27(6):1307-1310. [CrossRef] [PubMed]
 
Farid S, Mohamed S, Devbhandari M, et al. Results of surgery for chronic pulmonary Aspergillosis, optimal antifungal therapy and proposed high risk factors for recurrence - a National Centre’s experience. J Cardiothorac Surg. 2013;8(1):180. [CrossRef] [PubMed]
 
Kim YT, Kang MC, Sung SW, Kim JH. Good long-term outcomes after surgical treatment of simple and complex pulmonary aspergilloma. Ann Thorac Surg. 2005;79(1):294-298. [CrossRef] [PubMed]
 
Sagan D, Goździuk K. Surgery for pulmonary aspergilloma in immunocompetent patients: no benefit from adjuvant antifungal pharmacotherapy. Ann Thorac Surg. 2010;89(5):1603-1610. [CrossRef] [PubMed]
 
Cadranel J, Philippe B, Hennequin C, et al. Voriconazole for chronic pulmonary aspergillosis: a prospective multicenter trial. Eur J Clin Microbiol Infect Dis. 2012;31(11):3231-3239. [CrossRef] [PubMed]
 
Agarwal R, Gupta D, Aggarwal AN, Saxena AK, Chakrabarti A, Jindal SK. Clinical significance of hyperattenuating mucoid impaction in allergic bronchopulmonary aspergillosis: an analysis of 155 patients. Chest. 2007;132(4):1183-1190. [CrossRef] [PubMed]
 
Greenberger PA. When to suspect and work up allergic bronchopulmonary aspergillosis. Ann Allergy Asthma Immunol. 2013;111(1):1-4. [CrossRef] [PubMed]
 
Agarwal R, Maskey D, Aggarwal AN, et al. Diagnostic performance of various tests and criteria employed in allergic bronchopulmonary aspergillosis: a latent class analysis. PLoS ONE. 2013;8(4):e61105. [CrossRef] [PubMed]
 
Knutsen AP, Bush RK, Demain JG, et al. Fungi and allergic lower respiratory tract diseases. J Allergy Clin Immunol. 2012;129(2):280-291. [CrossRef] [PubMed]
 
Agarwal R, Gupta D, Aggarwal AN, Behera D, Jindal SK. Allergic bronchopulmonary aspergillosis: lessons from 126 patients attending a chest clinic in north India. Chest. 2006;130(2):442-448. [CrossRef] [PubMed]
 
Agarwal R, Khan A, Garg M, Aggarwal AN, Gupta D. Chest radiographic and computed tomographic manifestations in allergic bronchopulmonary aspergillosis. World J Radiol. 2012;4(4):141-150. [CrossRef] [PubMed]
 
Denning DW, Park S, Lass-Florl C, et al. High-frequency triazole resistance found In nonculturableAspergillus fumigatusfrom lungs of patients with chronic fungal disease. Clin Infect Dis. 2011;52(9):1123-1129. [CrossRef] [PubMed]
 
Muro M, Mondejar-López P, Moya-Quiles MR, et al. HLA-DRB1 and HLA-DQB1 genes on susceptibility to and protection from allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. Microbiol Immunol. 2013;57(3):193-197. [CrossRef] [PubMed]
 
Kreindler JL, Steele C, Nguyen N, et al. Vitamin D3 attenuates Th2 responses toAspergillus fumigatusmounted by CD4+ T cells from cystic fibrosis patients with allergic bronchopulmonary aspergillosis. J Clin Invest. 2010;120(9):3242-3254. [CrossRef] [PubMed]
 
Chambers ES, Hawrylowicz CM. The impact of vitamin D on regulatory T cells. Curr Allergy Asthma Rep. 2011;11(1):29-36. [CrossRef] [PubMed]
 
Elphick HE, Southern KW. Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. Cochrane Database Syst Rev. 2012;6:CD002204. [PubMed]
 
Wark P. Pathogenesis of allergic bronchopulmonary aspergillosis and an evidence-based review of azoles in treatment. Respir Med. 2004;98(10):915-923. [CrossRef] [PubMed]
 
Wark PA, Gibson PG, Wilson AJ. Azoles for allergic bronchopulmonary aspergillosis associated with asthma. Cochrane Database Syst Rev. 2004;;(3):CD001108.
 
Selman M, Pardo A, King TE Jr. Hypersensitivity pneumonitis: insights in diagnosis and pathobiology. Am J Respir Crit Care Med. 2012;186(4):314-324. [CrossRef] [PubMed]
 
Denning DW, O’Driscoll BR, Powell G, et al. Randomized controlled trial of oral antifungal treatment for severe asthma with fungal sensitization: The Fungal Asthma Sensitization Trial (FAST) study. Am J Respir Crit Care Med. 2009;179(1):11-18. [CrossRef] [PubMed]
 
Agarwal R. Severe asthma with fungal sensitization. Curr Allergy Asthma Rep. 2011;11(5):403-413. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Chest CT scan demonstrating the typical radiographic findings of invasive aspergillosis with both the air crescent sign (arrow) and the cavity formation. This patient had an autoimmune interstitial lung disease treated with low doses of prednisone and azathioprine. The patient presented with fever, right pleuritic chest pain, and an elevated WBC count. Previous respiratory cultures positive for Aspergillus had been presumed to represent “colonization.” Galactomannan antigen was detected in both serum and BAL fluid. Pleural fluid analysis was culture positive for Aspergillus fumigatus. The patient recovered with discontinuation of immunosuppressive therapy and 6 mo of treatment with voriconazole.Grahic Jump Location
Figure Jump LinkFigure 2 –  Chest CT scan and bronchoscopic images of invasive tracheobronchial aspergillosis. The patient was on immunosuppression for a prior heart transplant. He presented with dyspnea, hemoptysis, and hypoxemia. A, Imaging revealed a dense consolidation in the left upper lobe with peripheral nodular opacities. B, C, Bronchoscopic airway inspection revealed patchy areas of white adherent plaques and airway sloughing in the trachea (B) and left and right bronchial trees (C). Endobronchial biopsy with Grocott stains was positive for septating fungal organisms with tissue invasion. Aspergillus fumigatus grew from BAL cultures. Voriconazole treatment resulted in marked clinical improvement, including resolution of hemoptysis.Grahic Jump Location
Figure Jump LinkFigure 3 –  Chest CT scan of a patient with biapical scarring from previous infection with Mycobacterium tuberculosis who developed a simple aspergilloma in the left upper lobe scar. Hemoptysis was initially treated with bronchial artery embolization, but, at recurrence some years later, resection of the left upper lobe was performed after pretreatment with voriconazole to reduce the risk of local postoperative Aspergillus infection.Grahic Jump Location
Figure Jump LinkFigure 4 –  A, Chest CT scan demonstrating chronic cavitary pulmonary aspergillosis in the setting of underlying fibrocystic sarcoidosis. After years of stable sarcoidosis, this patient developed dyspnea, hemoptysis, and hypoxemia. Sputum cultures grew Aspergillus niger. Serum IgG for Aspergillus was positive. Imaging revealed extensive right-sided consolidation with discrete areas of cavitation and mycetoma. B, Extensive tissue destruction ensued in the following year. Hemoptysis has not recurred since itraconazole was started.Grahic Jump Location
Figure Jump LinkFigure 5 –  Chest CT scan demonstrating typical features of allergic bronchopulmonary aspergillosis. A, Central bronchiectasis. B, Plugging of airways with mucus.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Pulmonary Aspergillosis Syndromes

ABPA = allergic bronchopulmonary aspergillosis.

Table Graphic Jump Location
TABLE 2 ]  Populations Predisposed to Invasive Aspergillosis

EORTC/MSG = European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group.

Table Graphic Jump Location
TABLE 3 ]  Management of Pulmonary Aspergillosis Syndromes

sq = subcutaneous injection. See Table 1 for expansion of other abbreviation.

Table Graphic Jump Location
TABLE 4 ]  Diagnosing ABPA

See Table 1 for expansion of abbreviation.

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Mikulska M, Furfaro E, Del Bono V, et al. Piperacillin/tazobactam (Tazocin™) seems to be no longer responsible for false-positive results of the galactomannan assay. J Antimicrob Chemother. 2012;67(7):1746-1748. [CrossRef] [PubMed]
 
Avni T, Levy I, Sprecher H, Yahav D, Leibovici L, Paul M. Diagnostic accuracy of PCR alone compared to galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive pulmonary aspergillosis: a systematic review. J Clin Microbiol. 2012;50(11):3652-3658. [CrossRef] [PubMed]
 
Buess M, Cathomas G, Halter J, et al. Aspergillus-PCR in bronchoalveolar lavage for detection of invasive pulmonary aspergillosis in immunocompromised patients. BMC Infect Dis. 2012;12:237. [CrossRef] [PubMed]
 
Nebiker CA, Lardinois D, Junker L, et al. Lung resection in hematologic patients with pulmonary invasive fungal disease. Chest. 2012;142(4):988-995. [CrossRef] [PubMed]
 
Walsh TJ, Anaissie EJ, Denning DW, et al; Infectious Diseases Society of America. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(3):327-360. [CrossRef] [PubMed]
 
Limper AH, Knox KS, Sarosi GA, et al; American Thoracic Society Fungal Working Group. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011;183(1):96-128. [CrossRef] [PubMed]
 
Steinbach WJ, Marr KA, Anaissie EJ, et al. Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry. J Infect. 2012;65(5):453-464. [CrossRef] [PubMed]
 
Baddley JW, Stephens JM, Ji X, Gao X, Schlamm HT, Tarallo M. Aspergillosis in Intensive Care Unit (ICU) patients: epidemiology and economic outcomes. BMC Infect Dis. 2013;13:29. [CrossRef] [PubMed]
 
Riscili BP, Wood KL. Noninvasive pulmonaryAspergillusinfections. Clin Chest Med. 2009;30(2):315-335. [CrossRef] [PubMed]
 
Kravitz JN, Berry MW, Schabel SI, Judson MA. A modern series of percutaneous intracavitary instillation of amphotericin B for the treatment of severe hemoptysis from pulmonary aspergilloma. Chest. 2013;143(5):1414-1421. [CrossRef] [PubMed]
 
Gefter WB, Weingrad TR, Epstein DM, Ochs RH, Miller WT. “Semi-invasive” pulmonary aspergillosis: a new look at the spectrum of aspergillus infections of the lung. Radiology. 1981;140(2):313-321. [CrossRef] [PubMed]
 
Binder RE, Faling LJ, Pugatch RD, Mahasaen C, Snider GL. Chronic necrotizing pulmonary aspergillosis: a discrete clinical entity. Medicine (Baltimore). 1982;61(2):109-124. [CrossRef] [PubMed]
 
Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature change, and review. Clin Infect Dis. 2003;37(suppl 3):S265-S280. [CrossRef] [PubMed]
 
Nam HS, Jeon K, Um SW, et al. Clinical characteristics and treatment outcomes of chronic necrotizing pulmonary aspergillosis: a review of 43 cases. Int J Infect Dis. 2010;14(6):e479-e482. [CrossRef] [PubMed]
 
Schweer KE, Bangard C, Hekmat K, Cornely OA. Chronic pulmonary aspergillosis. Mycoses. 2014;57(5):257-270. [CrossRef] [PubMed]
 
Felton TW, Baxter C, Moore CB, Roberts SA, Hope WW, Denning DW. Efficacy and safety of posaconazole for chronic pulmonary aspergillosis. Clin Infect Dis. 2010;51(12):1383-1391. [CrossRef] [PubMed]
 
Smith NL, Denning DW. Underlying conditions in chronic pulmonary aspergillosis including simple aspergilloma. Eur Respir J. 2011;37(4):865-872. [CrossRef] [PubMed]
 
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