Aspergillus fumigatus Antibody, IgG

Serum

0.6 mL

0.4 mL (Note: This volume does not allow for repeat testing.)

Red-top tube or gel-barrier tube

Measurement of Aspergillus fumigatus IgG levels

This test was developed and its performance characteristics determined by Labcorp. It has not been cleared or approved by the Food and Drug Administration.

• Although ABPA and CPA represent distinct manifestations of Aspergillus-related lung disease, a patient's status can evolve over time from one category to the other, making the specific diagnosis challenging, particularly in the context of chronic lung disease.^1-6 The cutoffs reported for diagnosing ABPA are often similar to those used for CPA, and there is no value of A. fumigatus IgG that can discriminate between the two disorders.^2,4,6

• In some patients with ABPA or CPA, the Aspergillus IgG may remain negative even in the presence of symptoms, radiology and laboratory diagnostics.^4,7

• It is common for patients with active chronic lung disease to have measurable Aspergillus-specific IgG levels in the absence of CPA. Consequently, the diagnosis of CPA requires clinical and radiological evidence in addition to serological evidence.

• Non-fumigatus strains account a significant proportion of CPA in some populations⁸ and IgG to these strains may not be detected by the ImmunoCAP® A. fumigatus IgG assay. The Labcorp Aspergillus Precipitating Antibodies, IgG [606846] assay includes most species associated with Aspergillus-related lung disease in the United States.

• Studies have not consistently revealed a strong correlation between A. fumigatus IgG levels and clinical and/or radiological response to treatment.^4,9

• Aspergillus IgG testing is generally not useful in the diagnosis of IPA due to the lack of antibody production in severely immunocompromised patients.^10-12

Thermo Fisher ImmunoCAP®

See table.

Aspergillus species are ubiquitous environmental molds that grow on organic matter and aerosolize conidia.^13-15 Humans inhale hundreds of conidia per day without adverse consequences except for a small minority of people for whom infection with Aspergillus causes significant morbidity. The clinical manifestations of aspergillosis are determined by the host immune response to exposure with the spectrum ranging from a simple allergic response to local lung disease with mycelial balls to catastrophic systemic Aspergillus infection.^13,15

Aspergillus is a genus of molds that includes several hundred species that grow in nutrient-depleted environments.^13,15 These obligate aerobes are ubiquitous and can be found in virtually every oxygen-rich setting. Aspergillus molds are saprophytes that thrive on decaying organic matter. They are often found as contaminants of starchy foods and other carbon-rich substrates. They are commonly found in soil and marine habitats as well as indoor environments and in drinking water.¹⁴ Of the hundred species identified, only a few have been associated with pathology in humans.^14-16 Aspergillus fumigatus is the species most commonly associated with disease.¹⁷ Other species that have been linked to disease include A. flavus, A. glaucus, A. niger, A. nidulans and A. terreus.^1,17-25

Aspergillus molds continuously disseminate spores (conidia) into the environment.¹⁴ Humans are constantly exposed to airborne Aspergillus spores, which once inhaled can access the most distal airways of the lungs due to their size and durability.¹ In immunocompetent individuals with healthy lungs, inhaled conidia are eliminated by the neutrophils and macrophages of the innate immune system and do not lead to disease.^1,14 Illness only develops in a small proportion of patients with altered immune systems or underlying lung pathology.^{1,2,10,13,15,26} Non-invasive forms of Aspergillus-induced lung disease include Allergic Bronchopulmonary Aspergillosis (ABPA) and Chronic Pulmonary Aspergillosis (CPA).^3,16 In severely immunocompromised individuals, Aspergillus infection of the respiratory system can spread to other organs in a condition referred to as Invasive Pulmonary Aspergillosis (IPA).^10,14,15 Antibody testing is central to diagnosis of these conditions, with raised Aspergillus-specific IgG often seen in patients with ABPA and CPA. Antibody levels are also used to monitor treatment response in these syndromes.

Allergic Bronchopulmonary Aspergillosis (ABPA)

ABPA is a relatively uncommon allergic reaction to Aspergilli that almost exclusively affects individuals with asthma or cystic fibrosis.^1,10,16,27 ABPA typically causes bronchospasm and mucus buildup, resulting in coughing, breathing difficulty and airway obstruction. Bronchiectasis can develop, resulting in worsening lung function and increased risk of infection. ABPA in patients with poorly controlled asthma has also been referred to as Severe Asthma with Fungal Sensitization (SAFS).²⁸

The diagnostic criteria for ABPA include the presence of a predisposing condition (asthma or cystic fibrosis) and positive allergen specific IgE to aspergillus species, a total IgE >1000 IU/mL and blood eosinophil count >500 cells/L (in corticosteroid-naïve patients).^29-31 An elevated serum aspergillus IgG also supports the diagnosis of ABPA.^4,29,31-34

Chronic Pulmonary Aspergillosis (CPA)

CPA is an uncommon, slowly destructive pulmonary disease characterized by progressive lung cavitation, fibrosis, and pleural thickening caused by Aspergillus infection of the pulmonary parenchyma in subjects with normal or mildly suppressed immunity and underlying structural lung disease.^{1,2,4,7,10,18,26,30-33} Predisposing conditions include pulmonary tuberculosis, nontuberculous mycobacterial infection, sarcoidosis, pneumothorax, chronic obstructive pulmonary disease, surgically treated lung cancer and other cavitating or bullous lung conditions. Patients with allergic bronchopulmonary aspergillosis sometimes proceed to CPA. Patients with CPA can present with chronic productive cough, weight loss and hemoptysis with nodules, cavities or fungal balls (aspergilloma) on chest imaging. The most common form of CPA is chronic cavitary pulmonary aspergillosis (CCPA), defined as one or more pulmonary cavities that may or may not contain solid or liquid material or a fungal ball with significant pulmonary or systemic symptoms and overt radiographic progression.^14,31 Untreated, CCPA can progress to chronic fibrosing pulmonary aspergillosis (CFPA).⁴ A less common manifestation of CPA is the simple aspergilloma, a fungal ball consisting of Aspergillus hyphae, fibrin and other debris, formed within a pre-existing area of pulmonary scar or cavity that has been colonized by Aspergillus.^4,10,30

Guidelines for the diagnosis and management of CPA were published in 2016 jointly by the European Society for Clinical Microbiology and Infectious Diseases (ESCMID), the European Respiratory Society (ERS), and the European Confederation of Medical Mycology (ECMM).⁴ Also, the Infectious Diseases Society of America (IDSA) established recommendations for the diagnosis of CPA in the same year.³¹ According to these guidelines, the diagnosis of CPA requires (i) one or more cavities with or without a fungal ball or nodules present on thoracic imaging for ≥3 months, (ii) direct evidence of Aspergillus infection (microscopy or culture from biopsy) or an immunological response to Aspergillus specie(s), and (iii) exclusion of alternative diagnoses.⁴ Numerous studies support the utility of measuring Aspergillus IgG for diagnosing CPA.^{2,5,8,9,12,17,33,35-44}

Invasive Pulmonary Aspergillosis (IPA)

Chronic and allergic forms of aspergillosis are much more common than IPA .^44,45 Patients with diminished cell-mediated immunity, including those with neutropenia due to cytotoxic chemotherapy, or T-cell dysfunction due to corticosteroid or other immunosuppressive therapy, are at risk of developing IPA.⁸ Aspergillus infection in severely immunocompromised patients, such as individuals with hematological cancers or organ/stem cell transplant recipients can lead to IPA, the most serious entity on the spectrum of pulmonary aspergillosis.^11,26 This life threatening disease is characterized by invasion of lung tissue by Aspergillus hyphae and subsequent spread into the lung parenchyma and associated vasculature.¹ IPA can lead to intravascular thrombosis and hemorrhagic pulmonary infarction¹⁰ and has a relatively rapid progression, over days to a few weeks, with a very high mortality rate.^1,11,26,36 Aspergillus IgG testing is generally not useful in the diagnosis of IPA due to the lack of antibody production in severely immunocompromised patients.^10-12

Clinical Application of Aspergillus fumigatus IgG Test

The assignment of diagnostic cut-offs for A. fumigatus IgG is challenging^9,42 and depends on the geographic region and the comorbidities of the population tested.^4,7,41 In many other types of infections, the presence of any antibody reflects evidence of current or past infection because clinically inconsequential exposure to the causative organism is uncommon. However, humans are continuously exposed to Aspergillus but rarely develop illness if they have structurally normal lungs and an intact, innate immune system. Most healthy individuals have some level of Aspergillus-specific IgG.^9,41 The median of A. fumigatus IgG measured by ImmunoCAP® in several European healthy control populations ranged from 6 to 13.75 mg/L.^46-49 The reported upper limit of the reference intervals for healthy controls in a number of countries range between 65 and 70 mg/L.^34,46,50,51 The reference ranges reported by Labcorp were derived from an extensive reference range study of individuals from across the United States.

Increased susceptibility to colonization by A. fumigatus growth that occurs in patients with chronic lung diseases is reflected in raised levels of A. fumigatus-specific IgG seen in these populations. Higher levels of Aspergillus-specific IgG, relative to controls, have been found in patients with chronic obstructive pulmonary disease (COPD),⁴⁸ sarcoidosis,⁵² cystic fibrosis³² and tuberculosis.^2,5,33