Chronic pulmonary aspergillosis: Epidemiology, clinical manifestations and diagnosis

INTRODUCTION — The term 'chronic pulmonary aspergillosis' (CPA) encompasses several syndromes caused by the proliferation of Aspergillus organisms in the lungs of individuals with structural lung disease. CPA often remains unrecognized for prolonged periods and results in significant morbidity.

The epidemiology, clinical manifestations, and diagnosis of CPA will be reviewed here. The treatment of CPA is discussed separately. (See "Chronic pulmonary aspergillosis: Treatment".)

Other forms of Aspergillus-associated disease include invasive aspergillosis (IA) and allergic bronchopulmonary aspergillosis (ABPA). Unlike CPA, IA exhibits extensive tissue invasion by the fungus and occurs in severely immunocompromised or critically ill individuals. ABPA is characterized by a chronic allergic response to Aspergillus antigens. Both IA and ABPA are discussed in detail separately. (See "Epidemiology and clinical manifestations of invasive aspergillosis" and "Diagnosis of invasive aspergillosis" and "Treatment and prevention of invasive aspergillosis" and "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis" and "Treatment of allergic bronchopulmonary aspergillosis".)

EPIDEMIOLOGY AND RISK FACTORS — Estimates of prevalence of CPA are inaccurate due to lack of surveillance and underdiagnosis of the disease. Based on modelling, an estimated worldwide prevalence of three million affected individuals has been reported [1]. Prevalence varies substantially by geography, with estimates of <1 case per 100,000 persons in Western Europe and the United States to 43 cases per 100,000 persons in the Democratic Republic of Congo and Nigeria [2]. Because CPA can be a late sequela of tuberculosis (TB), the disease burden is higher in regions with a high incidence of TB [2-8].

All patients with CPA have a history of structural lung disease, often with residual cavities, bullae, or scarring. Specific risk factors include the following:

●Pulmonary TB – Worldwide, previously treated pulmonary TB is the most important risk factor [9-12]. An estimated 370,000 people developed CPA as a sequela of TB in 2007 [2-8]. Observational data suggest that TB accounts for over 85 percent of CPA cases in South and Southeast Asia, compared with 16 percent in the United Kingdom [2].

Approximately 20 to 35 percent of patients with resolved TB have residual pulmonary cavities that predispose to CPA, and the overall risk of developing an aspergilloma in a pulmonary cavity of over 2 cm in diameter has been estimated at 15 to 20 percent [13].

●Chronic obstructive pulmonary disease (COPD), especially bullous disease [12,14].

●Allergic bronchopulmonary aspergillosis (ABPA) – In a United Kingdom series, seven percent of patients with ABPA had CPA in the form of aspergillomas [15].

●Nontuberculous mycobacteria (NTM) lung infection [16].

●History of thoracic surgery, especially for lung cancer [17,18].

●Sarcoidosis [19].

●Hyper-IgE syndrome (ie, Job's syndrome). (See 'Pathology' below.)

●Other conditions, including bronchiectasis, prior pneumothorax, COVID-19 infection, prior severe pneumonia, pneumoconiosis, silicosis, rheumatoid arthritis, ankylosing spondylitis, granulomatosis with polyangiitis, previous pulmonary embolism, and hydatid disease [9,12,14,20-25].

Mild to moderate immunocompromise (eg, low-dose corticosteroids [eg, < equivalent of prednisone 0.3 mg/kg/day for >3 weeks]) predisposes to a specific form of CPA called subacute invasive aspergillosis (SAIA), as discussed below. (See 'Subacute invasive aspergillosis (SAIA)' below.)

MICROBIOLOGY — Aspergillus fumigatus (A. fumigatus) is the most common cause of CPA, although A. flavus, A. niger, A. terreus, and A. nidulans have also been implicated [6,9,26-28].

Aspergillomas may act as a niche for development of resistance, particularly in patients on prolonged antifungal therapy [29]. Resistance mutations vary geographically in patients with CPA; the most prominent mutation in India is the G54 mutation, whereas resistance in the United Kingdom is more commonly due to TR34/L98H and M220 [30-33]. Further details regarding Aspergillus resistance are found separately. (See "Treatment and prevention of invasive aspergillosis", section on 'Consideration of antifungal resistance'.)

PATHOLOGY — Current knowledge of the pathology of CPA comes from case series of surgically resected or post-mortem lesions, usually well-formed aspergillomas. CPA lesions of other types have not been as well characterized.

The primary driver of disease in patients with CPA is the local immune response to Aspergillus colonization of previously damaged lung tissue. Invasion of tissue by the fungus itself is not a major contributor to CPA in immunocompetent individuals.

In patients with CPA, the interplay between the fungal organisms and the patient's immune response determines the clinical and pathological presentation. Variable presentations have led to categorization of CPA into different syndromes.

●Two CPA syndromes (aspergillomas and Aspergillus nodules) are due to localized noninvasive proliferation of Aspergillus spp that do not elicit an extensive inflammatory response:

•Aspergillomas – Aspergillomas are formed when colonizing fungal organisms lining the inner surface of a pre-existing lung cavity spread into the cavity itself; the fungi proliferate in the form of a fungus ball inside the cavity. Microscopically, aspergillomas are composed of fungal hyphae, mucus, and cellular debris. Inflammation, if present, typically does not extend beyond the cavity wall. They are late manifestations of pre-existing persistent cavitary lung lesions. (See 'Aspergilloma' below.)

•Aspergillus nodules – Nodules occur when the fungi replicate in a localized fashion in the lung parenchyma (unlike aspergillomas, which form inside of pre-existing cavities). Histopathologic evaluation reveals fungal hyphae, without evidence of tissue invasion, on a background of necrotic, fibrotic, and chronically inflamed lung tissue; granulomas are present in 25 percent of samples [34,35]. Nodules may have central cavitation due to necrosis. (See 'Aspergillus nodule' below.)

●Two additional forms of CPA are due to extensive tissue inflammation in response to Aspergillus colonization of previously damaged lungs. Actual fungal organisms are uncommonly found in affected lung tissue [36].

•Chronic cavitary pulmonary aspergillosis (CCPA) – This syndrome develops when chronic lung inflammation leads to parenchymal damage and expansion of one or more cavities that may or may not contain aspergillomas (image 1 and image 2). CCPA may begin in pre-existing cavities, and/or cavities may be created as part of the disease process [37]. Histopathologic findings include erosion and granulation tissue in cavity walls with granuloma in some cases; tissue surrounding the cavities reveals florid chronic inflammation, sometimes with organizing pneumonia, bronchiectasis, hypertrophied blood vessels, and/or peri-cavitary fibrosis [36,38]. (See 'Chronic cavitary pulmonary aspergillosis (CCPA)' below.)

•Chronic fibrosing pulmonary aspergillosis (CFPA) – This syndrome occurs in a subset of patients with CCPA. It is characterized by extensive parenchymal fibrosis surrounding CCPA cavities and sometimes in lung tissue distant from the cavities. (See 'Chronic fibrosing pulmonary aspergillosis (CFPA)' below.)

●Subacute invasive aspergillosis (SAIA) – This is a unique form of CPA that has pathologic features that overlap with invasive aspergillosis (IA). Histopathology reveals necrotizing acute and chronic inflammation in combination with fungal hyphae invading lung tissue consistent with IA [39]. Destructive granulomatous destruction of bronchi and bronchioles (ie, bronchocentric granulomatosis) has also been described [39]. (See 'Subacute invasive aspergillosis (SAIA)' below.)

The importance of the immune system on the course of aspergillosis cannot be overstated. In immunocompetent patients with CPA, tissue invasion is absent and the clinical course is prolonged (months to years). For patients with SAIA and IA (all of whom have immunocompromise), tissue invasion is a key factor, and the clinical course is more rapidly progressive (weeks to months for SAIA, and days to weeks for IA). IA is discussed in detail separately. (See "Epidemiology and clinical manifestations of invasive aspergillosis".)

Genetic defects in the Th1 inflammatory cascade have been identified in individuals with CPA, including reduced production of interferon-gamma upon stimulation of peripheral blood by fungal antigens [40]. Genetic analyses have also found other disorders of immune regulation such as polymorphisms in TLR3, TLR4, TLR10, the IL-1 pathway, and IL-15. CPA has also been reported in patients with known abnormalities of the JAK-STAT3 pathway associated with hyper-immunoglobulin (Ig)E syndrome (ie, Job's syndrome) [41-45].

CLINICAL MANIFESTATIONS

Specific syndromes and radiographic features — The term 'chronic pulmonary aspergillosis' (CPA) encompasses several syndromes that occur in individuals with pre-existing structural lung disease. In clinical practice, the syndromes and their radiographic features often overlap, and patients can transition from one form of CPA to another as their disease evolves over time.

Aspergilloma — Patients may have one or more aspergillomas.

The term 'simple aspergilloma' is used in patients with only one aspergilloma that is radiographically stable over time. Patients with a simple aspergilloma usually present with an incidental finding on radiographic imaging that was performed for another reason or for investigation of hemoptysis. Patients typically have no symptoms or have symptoms that are difficult to distinguish from those of their underlying lung disease. The most common symptom is cough. Hemoptysis may occur, including massive hemoptysis in a small subset of patients. Systemic symptoms (eg, fever, weight loss) do not occur in this form of CPA.

On radiographic imaging, an aspergilloma appears as a round, well-formed mass inside a pre-existing cavity, and it is often termed a 'fungus ball' or 'mycetoma' by radiologists (image 3 and image 4). An aspergilloma sometimes has air pockets or calcification inside it, and it may be surrounded by air, have pockets or a crescent of air between them and the cavity wall, or have no surrounding air. An aspergilloma may be gravity dependent (ie, moves as the patient changes position) or immobile with strands connecting it to the wall of the cavity. Images obtained weeks to months prior to the discovery of an aspergilloma may reveal intracavitary fronds attached to the wall and extending into the cavity; subsequent imaging typically reveals that the fronds have coalesced and detached to form an aspergilloma. Imaging findings of aspergillomas are further discussed below. (See 'Imaging suspicious for aspergilloma' below.)

Some patients have multiple aspergillomas, a finding that is indicative of more symptomatic and destructive forms of CPA, as described elsewhere. (See 'Chronic cavitary pulmonary aspergillosis (CCPA)' below.)

Aspergillus nodule — Patients with Aspergillus nodules are typically asymptomatic and have undergone a percutaneous or excisional biopsy of a lung nodule to rule out malignancy. The diagnosis is made when the biopsied tissue reveals fungal hyphae consistent with Aspergillus spp on histology and no other etiology is identified.

The radiological appearance of an Aspergillus nodule cannot be reliably distinguished from nodules of other etiologies, including malignancy (image 5) [46]. In a series of pathologically confirmed Aspergillus nodules, 20 percent were spiculated, 39 percent had calcification, and 61 percent were cavitary; the median long-axis diameter was 22 mm [34]. Patients may have single or multiple Aspergillus nodules.

Chronic cavitary pulmonary aspergillosis (CCPA) — CCPA is the classic form of CPA; in practice, the terms CCPA and CPA are often used interchangeably. A principal feature of this syndrome is slow progression of both symptoms and radiographic findings over months to years.

Patients with CCPA present with symptoms of varying severity; some patients report minimal symptoms if identified early. However, symptoms eventually manifest as the disease progresses. Common symptoms include productive cough, hemoptysis, shortness of breath, chest pain, sweats, anorexia, weight loss, and fatigue; without treatment, weight loss and fatigue may be pronounced [47-49]. Fever is uncommon, except during concurrent bacterial or viral infection. Hemoptysis can range from blood-streaked sputum to massive fatal hemoptysis.

Radiographic imaging reveals one or more thick- or thin-walled cavities that often have irregular walls and intracavitary material; aspergillomas may develop within the cavities as the disease progresses (image 3 and image 4 and image 6 and image 7). The upper lobes are most commonly affected. As the disease progresses, new cavities develop or existing cavities expand, and they may coalesce or perforate into the pleural space (image 4) [36,38].

Infiltrates are common surrounding the cavities. The thickness of cavity walls represents the inflammatory activity of the disease as well as possible adjacent fibrosis. For lesions close to the pleura, pleural thickening is very common. Concomitant findings include bronchiectasis, nodules, ground glass changes, tree-in-bud changes, and organizing pneumonia [48].

Pre-existing cavitary lung lesions are not necessary for the development of CCPA, but when present, these cavities can be the initial site of CCPA.

Chronic fibrosing pulmonary aspergillosis (CFPA) — CFPA occurs in a small subset of patients with CCPA and is characterized by extensive fibrosis and worsening lung function [37].

Patients with CFPA are typically already known to have CCPA, and the onset of CFPA is heralded by complaints of worsening shortness of breath, chest tightness, weight loss, and malnutrition [50-52].

Radiographic imaging typically reveals extensive pulmonary fibrosis in one or both upper lobes near the sites of known cavities and aspergillomas. In many cases, the fibrosis progresses to involve an entire lung, which can result in a 'white-out' of an entire lung or a 'destroyed lung' appearance (image 8) [53].

Subacute invasive aspergillosis (SAIA) — This term is reserved for patients who present with a subacute form of invasive aspergillosis (IA); SAIA progresses over one to three months as opposed to the more rapid presentation seen in patients with IA. Because of the slower nature of SAIA, it is categorized as a form of CPA instead of IA.

The features of SAIA straddle the line between IA and CPA. Symptoms are similar to those of CCPA except constitutional symptoms, including fever, are more prominent. Radiographic findings may include infiltrates, nodules, and consolidation with or without cavitation; the most common finding is a single area of consolidation (image 9) [37,50]. Unlike other forms of CPA, pre-existing structural lung disease or cavitation is not necessary for the development of SAIA.

Because SAIA involves tissue invasion by the fungus and has a more rapid course than other forms of CPA, patients with SAIA are presumed to have some form of immunocompromise. In most patients, mild to moderate immunocompromise is known to be present (eg, poorly-controlled diabetes mellitus, prolonged low-dose corticosteroid therapy [eg,< equivalent of prednisone 0.3 mg/kg/day for >3 weeks], advanced HIV disease, malnutrition) [54]. In a minority, underlying immunocompromising conditions are not identified but are presumed to be present. Patients with more severe underlying immunosuppression (eg, neutropenia, prolonged high-dose corticosteroid therapy) typically have IA as opposed to SAIA. Detailed discussion of IA is found separately. (See "Epidemiology and clinical manifestations of invasive aspergillosis".)

Immunocompromised patients can also develop the other forms of CPA, characterized by a more chronic course and lack of tissue invasion (eg, aspergilloma, aspergillus nodule, CCPA). Furthermore, SAIA may evolve into other less progressive forms of CPA (eg, residual aspergilloma after treatment) over time.

SAIA was previously termed 'chronic necrotizing pulmonary aspergillosis' (CNPA) or 'semi-invasive pulmonary aspergillosis' (SIPA).

Laboratory findings — Routine laboratory tests in patients with CPA often reflect the presence of chronic inflammation, with anemia of chronic disease, lymphopenia, hypoalbuminemia, elevated inflammatory markers (erythrocyte sedimentation rate [ESR] and C-reactive protein), and polyclonal hypergammaglobulinemia. Laboratory findings are usually normal in patients with simple aspergillomas or Aspergillus nodules.

Microbiologic findings and diagnostic blood tests are discussed in detail below. (See 'Diagnosis' below.)

DIAGNOSIS — The method of diagnosis of CPA depends on the specific syndrome suspected.

Limited value of microbiologic tests (eg, culture) — Identification of Aspergillus spp (eg, by culture, visualization of hyphae, polymerase chain reaction [PCR]) from a respiratory specimen (eg, sputum, bronchial lavage fluid) is not diagnostic of any form of CPA, even in patients with compatible clinical and radiographic findings.

Aspergillus spp are known to colonize the airways, and the majority of positive respiratory cultures in hospitalized patients represent colonization [55-57]. In patients with underlying lung pathology, differentiating colonization from CPA can be challenging because worsening of the underlying lung process can mimic symptoms and signs of CPA. Other processes, such as bacterial or mycobacterial infection, can also mimic CPA and be associated with Aspergillus colonization.

When Aspergillus spp are identified from a respiratory specimen, we clinically and radiographically evaluate the patient for signs of CPA. We send additional tests if we suspect CPA, as described below. (See 'Diagnostic evaluation' below.)

Patients with no or minimal symptoms — Patients with CPA who have no or minimal symptoms, such as isolated hemoptysis, typically have a simple aspergilloma or an Aspergillus nodule.

Imaging suspicious for aspergilloma — Characteristic radiographic findings of an aspergilloma inside a pre-existing cavitary lung lesion allows for a presumptive diagnosis of an aspergilloma; it is rare for such radiographic findings to be due to any other cause. Details regarding imaging appearance of aspergillomas are found above. (See 'Aspergilloma' above.)

Patients with radiographic findings consistent with aspergilloma are characterized into one of two categories based on the number of cavities with an aspergilloma:

●Simple aspergilloma – A presumptive diagnosis of a simple aspergilloma is made when radiography reveals a single aspergilloma inside a pre-existing cavitary lung lesion in a patient who has minimal symptoms (or any amount of hemoptysis). The cavity is usually thin-walled, round, and stable on serial imaging (image 10).

The diagnosis is confirmed with a positive serum Aspergillus IgG and documentation of stable or improved follow-up imaging obtained at least three months after the initial imaging [37]. (See 'When to suspect chronic pulmonary aspergillosis' below.)

Aspergillus IgG is positive in over 90 percent of cases. If IgG is negative in a patient with high clinical suspicion who resides in an area where non-fumigatus strains are common (eg, Pakistan), additional testing should be performed which may include IgG testing for other species of Aspergillus [58]. Respiratory fluid (sputum or bronchoalveolar lavage [BAL]) and biopsy are not necessary to make this diagnosis.

●Multiple cavities each containing an aspergilloma – Patients with this finding are typically symptomatic and are classified as having chronic cavitary pulmonary aspergillosis (CCPA), which is discussed in further detail elsewhere. (See 'Chronic cavitary pulmonary aspergillosis (CCPA)' above and 'Symptomatic patients' below.)

Resected or biopsied Aspergillus nodule — Definitive diagnosis of an Aspergillus nodule is made when lung tissue from a biopsy of a nodule is found to have fungal hyphae suggestive of Aspergillus on microscopic examination (see 'Pathology' above) [37]. A biopsy with histologic confirmation is always necessary because cancer may have a similar radiologic appearance.

In patients with multiple lung nodules including one that is a biopsy-confirmed Aspergillus nodule, the other nodules cannot be assumed to be Aspergillus nodules. Management of these patients varies on a case-by-case basis. Serial imaging is often helpful; follow-up with a pulmonologist, particularly for patients with risk factors for cancer (eg, smokers), may be beneficial.

Serum Aspergillus IgG may be positive or negative in patients with Aspergillus nodules; in a study of 24 patients with biopsy-confirmed Aspergillus nodules who had Aspergillus serology performed, 10 (42 percent) had negative serology [34]. Nonetheless, we typically obtain serology in our patients with Aspergillus nodules to establish a baseline value which may be helpful in situations where the nodule grows after biopsy.

In some cases, fungal organisms are not seen on histopathology but Aspergillus grows from tissue culture. These situations are challenging because the positive culture may represent contamination or colonization. We often follow these patients with serial imaging, and we repeat evaluation for malignancy, CPA, or other processes if changes occur.

Symptomatic patients — In contrast with patients who have a simple aspergilloma or Aspergillus nodule, patients with other forms of CPA (ie, CCPA, CFPA, subacute invasive aspergillosis [SAIA]) have chronic progressive symptoms.

When to suspect chronic pulmonary aspergillosis — CCPA or CFPA should be suspected in individuals with a history of structural lung disease who have pulmonary and/or systemic symptoms and compatible radiographic findings (particularly lung cavities) that progress over months to years. (See 'Chronic cavitary pulmonary aspergillosis (CCPA)' above and 'Chronic fibrosing pulmonary aspergillosis (CFPA)' above.)

SAIA should be suspected if symptoms and radiologic findings progress over weeks to months in an individual with mild to moderate immunosuppression. (See 'Subacute invasive aspergillosis (SAIA)' above.)

In patients with hemoptysis, any form of CPA can be suspected, including simple aspergilloma, as noted above. (See 'Aspergilloma' above.)

Diagnostic evaluation — For patients suspected of CCPA, CFPA, or SAIA, we obtain a computed tomography (CT) scan of the chest along with serologic testing. Microbiologic tests can play a supportive role.

●Serum Aspergillus IgG – Although IgG is highly sensitive for the diagnosis of CCPA, IgG cannot confirm the diagnosis if radiologic and clinical findings are equivocal; alternative diagnoses may be present or coexist in a patient with a positive Aspergillus serology.

When this test is ordered for patients who reside in areas where non-fumigatus strains are common (eg, Pakistan), separate IgG tests should be sent for A. fumigatus species and for the species predominant to the locale, if available [58].

●We also perform the following tests, even though the sensitivity of these tests for these syndromes has not been systematically evaluated:

•Sputum for fungal stains and cultures, bacterial stains and cultures, and mycobacterial stains and cultures. Although Aspergillus spp can grow on standard bacterial culture plates, requesting the microbiology lab to perform dedicated fungal cultures increases the yield [59].

•Bronchoscopy with BAL for galactomannan testing, fungal stains and cultures, and PCR. We also send BAL fluid for bacterial stains and cultures, and mycobacterial stains and cultures, to assess for concomitant or alternative diagnoses. Biopsy is performed when a lesion that is suitable for biopsy is noted on a CT scan.

•Serum for galactomannan testing. We do not send serum beta-D-glucan due to lack of data in patients with CPA and challenges with interpreting results [27,60].

For patients suspected of having an aspergilloma or Aspergillus nodule, the evaluation is discussed elsewhere. (See 'Imaging suspicious for aspergilloma' above and 'Resected or biopsied Aspergillus nodule' above.)

Confirming the diagnosis — Definitive diagnosis of CPA cannot be established by a single test. Depending on the suspected syndrome, the diagnosis typically requires some combination of compatible clinical, radiographic, serologic, and microbiologic tests [37].

Each CPA syndrome has specific diagnostic criteria [37]:

●Aspergillomas and Aspergillus nodules – The diagnostic criteria for these forms of CPA are discussed elsewhere. Most patients with these syndromes have no or minimal symptoms, although patients with a simple aspergilloma may have hemoptysis. (See 'Imaging suspicious for aspergilloma' above and 'Resected or biopsied Aspergillus nodule' above.)

●Chronic cavitary pulmonary aspergillosis (CCPA) – Definitive diagnosis of CCPA requires at least three months of compatible symptoms, characteristic radiographic findings with progression over at least three months, and positive serologic testing (ie, serum Aspergillus IgG) in the absence of an alternative diagnosis (image 3 and image 4 and image 6 and image 7) [37]. Microbiologic tests can support the diagnosis. (See 'Chronic cavitary pulmonary aspergillosis (CCPA)' above.)

The contribution of various tests to the diagnosis of CCPA depends on the type of test:

•Blood tests

-Serum Aspergillus IgG – Serum IgG by enzyme immunoassay (EIA) is the lab test for diagnosing CCPA, and it is highly sensitive and specific in patients with characteristic clinical and radiographic findings. It can be very high in high-burden disease, such as CCPA with multiple or large aspergillomas. False-negative results may occur in patients with CCPA who reside in areas where non-fumigatus Aspergillus species are prevalent; in such patients, IgG tests that target the suspected non-fumigatus spp can be helpful, if available. Some institutions have developed in-house serologic tests using Aspergillus precipitin detection methods, but these tests may not be as sensitive or specific as IgG testing [61].

-Serum galactomannan Aspergillus antigen – This test can be helpful, but its sensitivity and specificity are suboptimal. In studies of CPA patients (most of whom had CCPA), sensitivity ranged from 40 to 64 percent using an index cut-off of >0.5, and false-positive results occurred in substantial numbers of control patients [27,28,60].

•Tests performed on respiratory fluids (eg, sputum, BAL fluid)

-Microbiologic tests – Fungal stains, fungal cultures, and molecular tests (eg, PCR) of respiratory fluid can provide supportive evidence of CCPA. Cultures are positive in 20 to 80 percent of respiratory samples (sputum or BAL fluid) from patients with CCPA, and positive cultures from BAL fluid are more likely to represent infection compared with positive sputum cultures [37,60,62]. Visualization of fungal hyphae in BAL fluid has been found to be highly suggestive of CCPA in patients with the appropriate clinical picture [55]. Available data suggest that PCR is more sensitive than culture, with sensitivities ranging from 71 to 87 percent when performed on BAL fluid, but this test is not standardized or available in all clinical settings [33,60,63].

-Galactomannan Aspergillus antigen – This test can be performed on BAL fluid. In case-control studies of patients with CPA (mostly CCPA), the positive predictive value ranged from 64 to 67 percent and the negative predictive value from 72 to 95 percent using a cut-off index of 0.5 [27,60]. The test should only be used on BAL fluid because it cannot differentiate colonization from infection in sputum samples from patients with CPA [64].

•Tissue biopsy – Biopsy is rarely performed to diagnose CCPA. Occasionally, CCPA diagnosis is made histologically with a transbronchial, CT-guided, or excisional biopsy in patients with severe hemoptysis or concern for cancer. Biopsied tissue, if obtained, should be sent for fungal stains, fungal cultures, and histopathology.

●Chronic fibrosing pulmonary aspergillosis (CFPA) – CFPA is confirmed in patients who have known CCPA and develop extensive lung fibrosis on imaging, as described elsewhere (image 8) (see 'Chronic fibrosing pulmonary aspergillosis (CFPA)' above). CFPA patients may have very high Aspergillus IgG titers [53].

●Subacute invasive aspergillosis (SAIA) – SAIA is confirmed in patients with evidence of invasive fungal disease on lung biopsy and a subacute course that lasts weeks to months, as opposed to the shorter course of acute invasive aspergillosis (IA). Mild to moderate immunocompromise is usually present and is presumed in patients with no known immunocompromising condition.

However, in most patients with SAIA, biopsy is not performed. In these cases, a presumptive diagnosis of SAIA is based on:

•A subacute presentation over one to three months (as opposed to the more acute presentation of IA)

•Radiological findings compatible with SAIA: infiltrates, nodules, and consolidation with or without cavitation

•Mild to moderate degree of immunocompromise

•Evidence for the presence of Aspergillus in respiratory secretions (eg, positive fungal culture, galactomannan or Aspergillus PCR in BAL)

•Exclusion of alternative diagnoses

Serum galactomannan and Aspergillus IgG are rarely positive in patients with SAIA [34].

The diagnostic criteria for acute IA are discussed in detail separately. (See "Diagnosis of invasive aspergillosis".)

Diagnosis in low-resource settings — Because CPA can be a sequela of tuberculosis (TB), disproportionately more cases occur in low- to middle-income countries. Diagnostic capabilities may be limited, including lack of access to CT scan or Aspergillus IgG tests. In addition, the condition may not be suspected; it is often misdiagnosed as a TB relapse.

In these settings, a presumptive diagnosis can be made based on the presence of compatible symptoms for longer than three months, negative microbiologic TB tests, positive Aspergillus IgG, and the presence of cavitation on chest x-ray [65]. A point of care test for serum Aspergillus IgG is available and appears to be helpful in this setting [3,66].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for CPA is broad and varies by syndrome. CPA must also be differentiated from invasive aspergillosis (IA) and allergic bronchopulmonary aspergillosis (ABPA).

●Invasive aspergillosis (IA) – IA has specific diagnostic criteria and involves patients who are severely immunocompromised (eg, neutropenia, high-dose corticosteroid therapy) or debilitated. (See "Diagnosis of invasive aspergillosis".)

●Allergic bronchopulmonary aspergillosis (ABPA) – ABPA is associated with asthma and has a chronic waxing and waning course. Specific criteria exist for the diagnosis of ABPA. (See "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis".)

The differential diagnosis for specific CPA syndromes includes the following:

●Aspergilloma – Characteristic clinical and radiographic findings are highly specific for aspergillomas, so the differential diagnosis is limited. The primary concern in a patient with an aspergilloma is the existence of an active concomitant process causing the underlying cavity. Such conditions include cavitary lung cancer, tuberculous (TB) and non-TB mycobacterial infections, and other fungal infections (eg, histoplasmosis, blastomycosis, coccidioidomycosis, paracoccidioidomycosis, cryptococcosis). (See "Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer" and "Diagnosis of pulmonary tuberculosis in adults" and "Nontuberculous mycobacterial pulmonary infections in children".)

●Aspergillus nodule – Any cause of lung nodules can mimic Aspergillus nodules, including carcinoma (eg, primary lung cancer, metastatic cancer). Tissue biopsy is necessary to differentiate these conditions. (See "Diagnostic evaluation of the incidental pulmonary nodule", section on 'Differential diagnosis'.)

●Chronic cavitary pulmonary aspergillosis (CCPA), CFPA, and subacute invasive aspergillosis (SAIA) – Subacute progressive lung processes can mimic these forms of CPA. Infectious mimics include TB and non-TB mycobacterial infection, other fungal infection (eg, histoplasmosis, blastomycosis, coccidioidomycosis, paracoccidioidomycosis, cryptococcosis), bacterial infection (eg, anaerobic infection, nocardiosis, Rhodococcus infection), and protozoal infection (eg, toxoplasmosis). Microbiologic and laboratory studies can confirm these diagnoses, and biopsy is necessary in some cases. (See "Diagnosis of pulmonary tuberculosis in adults" and "Nontuberculous mycobacterial pulmonary infections in children" and "Primary pulmonary coccidioidal infection" and "Aspiration pneumonia in adults".)

Noninfectious possibilities include sarcoidosis, pulmonary infarction, and ANCA-associated vasculitides and other autoimmune diseases (eg, rheumatoid arthritis). Tissue biopsy is often necessary to make these diagnoses, and serologic tests can be of value for the vasculitides and autoimmune diseases. (See "Clinical manifestations and diagnosis of sarcoidosis" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and "Overview of pleuropulmonary diseases associated with rheumatoid arthritis".)

SUMMARY AND RECOMMENDATIONS

●Terminology and risk factors – The term 'chronic pulmonary aspergillosis' (CPA) encompasses several syndromes (described below) caused by the proliferation of Aspergillus organisms in the lungs of individuals with structural lung disease. The most common risk factor is prior pulmonary tuberculosis (TB). (See 'Introduction' above and 'Epidemiology and risk factors' above.)

●Aspergilloma – An aspergilloma is a ball of Aspergillus fungi inside a pre-existing lung cavity. The term 'simple aspergilloma' is used in patients with only one aspergilloma that is radiographically stable over time. Most patients with simple aspergillomas are asymptomatic, although serious hemoptysis occurs in some cases. (See 'Aspergilloma' above.)

•Diagnosis – A presumptive diagnosis of an aspergilloma is made when radiography reveals a fungus ball inside a pre-existing cavitary lung lesion. The diagnosis is confirmed with a positive serum Aspergillus IgG and documentation of stable or improved follow-up imaging obtained at least three months after the initial imaging. (See 'Imaging suspicious for aspergilloma' above.)

●Aspergillus nodule – An Aspergillus nodule is a lung nodule that reveals fungal hyphae consistent with Aspergillus on histology. Most Aspergillus nodules are initially biopsied or resected due to suspicion of malignancy. (See 'Aspergillus nodule' above.)

•Diagnosis – Definitive diagnosis of an Aspergillus nodule is made when lung tissue from a biopsy of a nodule is found to have fungal hyphae suggestive of Aspergillus on microscopic examination. (See 'Resected or biopsied Aspergillus nodule' above.)

●Chronic cavitary pulmonary aspergillosis (CCPA) – This is the classic form of CPA and is characterized by slow progression of both symptoms and radiographic findings over months to years. A typical patient has a history of structural lung disease and productive cough, hemoptysis, shortness of breath, fatigue, and weight loss. (See 'Chronic cavitary pulmonary aspergillosis (CCPA)' above.)

Radiographic findings include one or more cavities (that may or may not contain aspergillomas), infiltrates, and pleural thickening.

•Diagnosis – Definitive diagnosis of CCPA requires at least three months of compatible symptoms, characteristic radiographic findings with progression over at least three months, and positive serologic testing (ie, serum Aspergillus IgG) in the absence of an alternative diagnosis. Microbiologic tests (eg, fungal culture or Aspergillus galactomannan tests) can support the diagnosis but are not definitive tests. (See 'Confirming the diagnosis' above.)

●Chronic fibrosing pulmonary aspergillosis (CFPA) – CFPA occurs in a small subset of patients with CCPA and is characterized by extensive fibrosis and worsening lung function that may eventually involve an entire lung. (See 'Chronic fibrosing pulmonary aspergillosis (CFPA)' above.)

•Diagnosis – CFPA is confirmed in patients who have known CCPA and develop extensive lung fibrosis on imaging. (See 'Confirming the diagnosis' above.)

●Subacute invasive aspergillosis (SAIA) – This term is reserved for patients who present with a subacute form of invasive aspergillosis (IA) that progresses over one to three months as opposed to the more rapid presentation seen in patients with acute IA.

Most patients with SAIA have mild to moderate immunocompromise (eg, poorly-controlled diabetes mellitus, prolonged low-dose corticosteroid therapy). Unlike other forms of CPA, pre-existing structural lung disease or cavitation is not necessary. (See 'Subacute invasive aspergillosis (SAIA)' above.)

Symptoms are similar to those of CCPA except constitutional symptoms, including fever, are more prominent. Radiographic findings may include infiltrates, nodules, and consolidation with or without cavitation.

•Diagnosis – SAIA is confirmed in patients with evidence of invasive fungal disease on lung biopsy and a subacute course that lasts weeks to months. (See 'Confirming the diagnosis' above.)

However, in most patients with SAIA, biopsy is not performed. In these cases, a presumptive diagnosis of SAIA is based on:

-A subacute presentation over one to three months

-Radiological findings compatible with SAIA

-Mild to moderate immunocompromise

-Evidence for the presence of Aspergillus in respiratory secretions (eg, positive fungal culture, galactomannan or Aspergillus polymerase chain reaction [PCR] in bronchoalveolar lavage [BAL])

-Exclusion of alternative diagnoses

Serum galactomannan and Aspergillus IgG are rarely positive in patients with SAIA.

●Differential diagnosis – The differential diagnosis for CPA is broad and varies by syndrome. CPA must also be differentiated from IA and allergic bronchopulmonary aspergillosis (ABPA). (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David Denning, MBBS, FRCP, FRCPath, FMedSci, who contributed to earlier versions of this topic review.