Aspergillus Lung Disease

Judd W. Landsberg

Aspergillus species are responsible for a diverse spectrum of human pulmonary diseases, ranging from hypersensitivity reactions to necrotizing angioinvasive infection. Overall, the incidence of Aspergillus lung disease is on the rise, largely as a result of increased numbers of immunosuppressed patients. Worldwide, Aspergillus is the most common cause of invasive mold infection. Although the host immune status influences disease susceptibility (e.g., allergic reaction with atopy vs. invasive aspergillosis with neutropenia), the notion that invasive disease is seen exclusively in neutropenic individuals is incorrect. Only 31% of patients with invasive pulmonary aspergillosis (IPA) are neutropenic when diagnosed. Increasingly, IPA has been recognized to occur in solid organ transplant patients, HIV infected individuals, and those receiving systemic glucocorticoid therapy for chronic inflammatory disease.

There are more than 200 species of Aspergillus, but Aspergillus fumigatus is responsible for more than 90% of human disease; the remainder is mostly caused by A. flavus (5%–10%), A. terreus (2%–5%), or A. niger (1%–2%). Aspergillus is ubiquitous and found worldwide in organic debris and soil. It commonly contaminates sputum and laboratory specimens exposed to unfiltered air. Aspergillus can be isolated from sputum in 1% to 6% of healthy individuals; higher rates of asymptomatic colonization are found in cigarette smokers and patients with chronic lung disease or HIV infection.

In the environment, the fungi produce small spores that are routinely inhaled and rapidly cleared from the normal host. However, inhalation in patients with underlying lung disease, immunologic sensitization, or immunocompromised status, may result in saprophytic colonization, hypersensitivity, or invasive disease. Person-to-person transmission has not been reported, but clustered mini-outbreaks of aspergillosis in immunocompromised patients have been reported from environmental exposure.

Aspergillus can cause at least seven distinct pulmonary syndromes, depending on host susceptibility and immune response, leading to colonization, allergy, or invasive disease. Patients with parenchymal lung disease are susceptible to (1) aspergilloma and (2) chronic pulmonary aspergillosis (CPA). Individuals with immune sensitization are vulnerable to (3) immunoglobulin E (IgE)-mediated asthma, (4) hypersensitivity pneumonitis (HP), and (5) allergic bronchopulmonary aspergillosis (ABPA). Patients with even minor degrees of immune suppression are at risk of (6) IPA ranging from bronchopneumonia to vessel invasive disseminated disease and, less commonly, (7) tracheobronchial aspergillosis. Although each syndrome has a unique pathogenesis, there is significant overlap between these syndromes in individual patients (e.g., an individual with ABPA developing tracheobronchial aspergillosis after high-dose prednisone therapy for a systemic inflammatory disease).

ASPERGILLOMA AND CHRONIC PULMONARY ASPERGILLOSIS

Aspergilloma (mycetoma or fungus ball) refers to a mass of fungal mycelia, inflammatory cells, and tissue debris, typically occurring in a preexisting, poorly draining lung cavity. Cavities occur most commonly in association with tuberculosis (TB), emphysematous bullae, treated lung cancer, ABPA-associated bronchiectasis, sarcoidosis, endemic fungal infection, chronic Pneumocystis carinii (PCP) infection (in HIV disease), and bronchial cysts.

An aspergilloma may be discovered on routine chest imaging in asymptomatic individuals or may be associated with recurrent mild hemoptysis. Most aspergillomas remain stable and up to 10% regress spontaneously. Typical imaging reveals an upper-lobe cavity with an intraluminal irregularity. Fluoroscopy may demonstrate mobility of the irregularity with positional changes. Sputum culture for Aspergillus may be negative in 50% of cases. Serum IgG Aspergillus-specific antibodies are present in over 90% of patients with associated cavitation and fibrosis, but may be falsely negative in patients on systemic corticosteroids, or in patients infected with non-Aspergillus species. Aspergillus skin testing is uniformly negative in patients with aspergilloma. Lesions tend to be solitary, but bilateral disease occurs in 5% to 10%. Asymptomatic patients with stable chest imaging require no antifungal therapy.

Simple aspergillomas and asthmatics with ABPA may progress to CPA. Classically called chronic invasive aspergillosis or chronic necrotizing aspergillosis, CPA encompasses a spectrum of indolent Aspergillus infections occurring in patients with underlying lung disease and often mild degrees of immunosuppression in which saprophytic colonization of abnormal parenchyma progresses to local invasion, often in a fibrocavitary pattern. CPA typically occurs in middle-aged and elderly patients with chronic obstructive pulmonary disease (COPD), late-stage ABPA, prior granulomatous disease (both mycobacterial and fungal), cystic fibrosis (CF), and other diseases involving parenchymal distortion. Patients may be immunocompetent but typically have varying degrees of mild immunosuppression secondary to diabetes mellitus, low-dose oral glucocorticoid therapy, alcoholism, poor nutrition, or connective tissue disease. Some patients with CPA appear to have an immune predisposition involving both a poor antibody response to polysaccharide antigens and a failure to produce interferon-γ (IFN-γ) (a recent therapeutic target). Clinically, patients complain of weight loss (94%), dry cough (78%), recurrent hemoptysis (58%), and dyspnea (50%). Fever and sputum production are less common and should prompt consideration for bacterial infection. Imaging typically demonstrates multiple upper-lobe, often confluent thick-walled, cavities with intraluminal irregularities, associated fibrosis, and adjacent pleural thickening. Up to 70% of these patients do not have a clearly discernible fungus ball. Given the presence of underlying lung disease, old imaging studies are essential to look for subtle changes surrounding preexisting areas of parenchymal scar, cavity, or aspergilloma. The presence of a significant air fluid level suggests bacterial superinfection more than CPA.

Biopsy is the diagnostic gold standard. However, given the poor yield from transbronchial biopsy and complications associated with transthoracic, thoracoscopic or open-lung biopsy in patients with severe underlying lung disease, diagnosis is usually made on clinical grounds. Diagnostic criteria include (1) compatible clinical and radiographic features; (2) isolation of Aspergillus species in sputum or bronchoalveolar lavage (BAL) fluid. If cultures are negative but suspicion is high, the presence of a positive galactomannan test (BAL more sensitive than serum) and/or IgG-specific Aspergillus antibodies can further suggest the diagnosis; and (3) exclusion of other conditions with similar presentations (e.g., active TB, atypical mycobacterial infection, bacterial superinfection, endemic fungal infection, and lung cancer), often through combined BAL, serology results, and close clinical and radiographic follow-up. Patients with ongoing parenchymal destruction (increased cavity size, wall thickness, and fibrosis) are at risk of worsening lung function, recurrent bacterial superinfection, and massive hemoptysis.

Bronchial artery embolization is an appropriate initial step in the management of massive, life-threatening, hemoptysis, though recurrent bleeding from collateral blood vessels is very common. Although surgical resection of the cavity provides definitive treatment, mortality (7%) and morbidity (23%) can be very high in the presence of coexisting lung disease. Younger patients without significant underlying lung disease have significantly lower rates of morbidity (18%) and mortality (1.5%). In general, surgery is reserved for patients with massive hemoptysis who have adequate pulmonary reserve and fail embolization.

Clinically symptomatic and or radiographically progressive CPA requires antifungal therapy. Immunocompetent patients, with subacute disease can typically be treated with oral itraconazole (more data) or voriconazole (better absorption and tissue penetration). The duration of therapy ranges from 6 months to lifelong chronic suppressive therapy for patients with substantial immunosuppression. Imaging improves gradually with cavity walls thinning and intraluminal irregularities resolving. Surgical resection is rarely an option, reserved for the young patient with focal disease and good pulmonary reserve. Treatment failures should prompt consideration for drug-level testing and possible IV therapy as well as the possibility of common disease mimics (e.g., bacterial superinfection or lung cancer). The long-term prognosis for patients with CPA has not been well studied, but 2-year survival is reported to be 70%, with the majority of deaths attributed to underlying lung disease or comorbidities, rather than Aspergillus infection.

IGE-MEDIATED ASTHMA

Patients with severe extrinsic IgE-mediated asthma attributable to environmental Aspergillus antigens (a.k.a. severe asthma with fungal sensitization) must be differentiated from those with asthma and ABPA. Immediate skin test reactivity to Aspergillus is present in as many as 25% to 40% of patients in asthma clinics. The absence of bronchiectasis, mucus plugging, and elevated IgE levels (<2,400 ng/mL or <1,000 IU/mL) argues against ABPA in this group. As in all allergic asthma, both avoidance of antigen (e.g., gardening, moldy environments) and antiinflammatory therapy are mainstays.

HYPERSENSITIVITY PNEUMONITIS

Inhalation of organic matter contaminated with Aspergillus species has been associated with HP. Aspergillus antigens are associated with malt worker’s lung, paper mill worker’s lung, and, more recently, a cluster of hypersensitivity pneumonitis cases in plaster workers exposed to Aspergillus-contaminated esparto fibers.

ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS

ABPA refers to a clinical syndrome involving a hypersensitivity to A. fumigatus which complicates asthma and CF. It is characterized by episodic chest radiograph infiltrates, IgE elevations, and poorly controlled asthma (20% of the time, asthma is well controlled on medications). The peak incidence is in the fourth to fifth decades. The clinical course is characterized by a cough productive of golden-brown sputum plugs (containing Aspergillus hyphae), hemoptysis, intermittent fever, chest pain, and recurrent pneumonias. Often, there is a discrepancy between significant chest radiograph consolidation and muted clinical findings. During disease flares, serum IgE levels are typically elevated greater than 1,000 ng/mL. After disease is established, exacerbations may be clinically silent, requiring vigilant chest radiograph and serum IgE surveillance. While ABPA may remain quiescent for many years, it rarely (if ever) resolves.

The pathogenesis of ABPA involves both failures in innate and adaptive immunity which allow persistence of Aspergillus spores in the tracheobronchial tree, which in turn germinate leading to hyphal growth. In the predisposed (HLA DR2/DR5) hyphal antigen, presentation leads to a Th2 predominant phenotype and increased total IgE, Aspergillus-specific IgE, pulmonary eosinophilic inflammation, and tissue damage. Radiographic findings include fleeting upper-lobe infiltrates, branching homogeneous (gloved finger) shadows of mucoid impaction, and tramline and ring shadows indicative of thickened bronchial walls. Computed tomographic (CT) scans may identify central bronchiectasis (medial two-thirds of the chest) that classically terminates abruptly, leaving distal airways uninvolved. More recent imaging series suggest ABPA bronchiectasis may involve distal airways up to 40% of the time. Recurrent episodes of ABPA with mucus plugging and airway inflammation can lead to end-stage bronchiectasis, mixed obstructive–restrictive lung disease, and respiratory failure. ABPA has been historically classified by the presence or absence of bronchiectasis and clinically staged according to disease activity. Recently, the International Society of Human and Animal Mycology (ISHAM) convened a working group of experts entitled “ABPA in asthmatics” to refine the classification and staging of ABPA. Though not yet widely adopted, the refinements address some the most significant misconceptions and vagaries in the previous classification and staging scheme, and thus will be discussed here. Additionally, they suggest the concept that central bronchiectasis is a sine qua non for the diagnosis of ABPA should be replaced by the CT finding of high attenuation mucus (HAM) impaction, a finding purported to be pathognomonic for ABPA, as well as predicting relapsing progressive disease. Typical mucus impaction is low attenuation. In general, treatment focuses on both control of inflammation with steroids and decreasing organism burden with antifungals.

Traditionally, the essential features required for the diagnosis of ABPA are (1) asthma, (2) immediate cutaneous reactivity to Aspergillus and, in patients not on systemic glucocorticoids, (3) total serum (IgE) greater than 1,000 ng/mL, (4) elevated serum IgE-Af, and/or (5) IgG-Af specific to Aspergillus. Common, but not required features include (6) episodic chest radiograph infiltrates and (7) peripheral eosinophilia. During flares, sputum stains may be positive for fungal elements and cultures positive for Aspergillus

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