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Abstract

Background

Diagnosis of hypersensitivity pneumonitis (HP) or extrinsic allergic alveolitis requires a combination of tests with antibody testing playing a supportive role to identify exposures.

Objectives

We conducted a scoping review on Aspergillus antibody testing in Aspergillus-related HP to identify the utility and diagnostic cutoffs proposed in the literature. We compared these cutoffs with studies of chronic pulmonary aspergillosis (CPA) and manufacturers’ cutoffs.

Eligibility criteria

Only studies addressing the diagnostic value of Aspergillus IgG or precipitins for HP were included. Separately papers defining cutoffs for CPA were tabulated.

Sources of evidence

Published papers were identified in literature searches in Embase, Web of Science, and Medline.

Results

We identified 414 papers, of which 12 were included, all published between 1965 and 2005. Occupational HP linked to Aspergillus spp. exposure included Farmer’s Lung, Malt-Worker’s Lung, Esparto Worker’s Lung, and Woodworker’s lung (Sawmill-workers). No studies directly addressed serological testing in Tobacco Worker’s lung, Compost Lung, or poultry workers. Among Aspergillus species exposure, A. fumigatus was most commonly described; others included A. umbrosus (now A. glaucus), A. clavatus, and A. niger. Antibody tests included ELISA, BALISA, precipitin tests and ImmunoCAP, with a higher sensitivity of ELISA and ImmunoCAP tests compared to precipitin tests. Patients with HP linked to Aspergillus exposures, were positive in 156/290 (53.8%) compared to 96/615 (15.6%) in those with similar occupational exposures without HP. In malt workers with HP 35/53 (66%) had detectable A. clavatus IgG antibody compared to 0/53 A. fumigatus IgG, and 13/74 (18%) exposed but unaffected workers, but are not commercially available.

Conclusions

Improved means of establishing or ruling out Aspergillus exposure are required, given the negative consequences for patients of continued Aspergillus inhalation. Modern studies with commercially available Aspergillus IgG antibody assays are required to define appropriate cutoffs for HP, given numerous studies published for chronic pulmonary aspergillosis.

Keywords

Extrinsic allergic alveolitis ground glass pulmonary fibrosis occupation fungal

Introduction

Hypersensitivity pneumonitis (HP), also called extrinsic allergic alveolitis (EAA), develops when a susceptible individual repeatedly inhales various antigens (e.g. fungi, bacteria, avian proteins, or chemical source) resulting in inflammation of the lung parenchyma and smaller airways.¹ HP was first described in 1713 by Bernardino Ramazzini in his book “Diseases of Workers,” where he described the condition in grain workers, or what is now known as Farmer’s Lung.^2,3 In the UK, in 1932, Munro Campbell wrote the first clinical report of HP, documenting its occurrence in farmers exposed to mouldy hay.³ The first clinical report of HP in pigeon breeders was made in 1965 by Reed et al., which is now known as Pigeon Breeder’s Lung, Bird Fancier’s Lung or Bird Breeder’s Lung.^3,4 Today, more than 300 antigens, including A. fumigatus and various other microorganisms have been identified and found to be associated with HP.^5,6

The ATS and ACCP guidelines (ATS/JRS/ALAT guideline 2020) categorize HP into non-fibrotic and fibrotic categories, based on the presence or absence of fibrosis, determined through radiological and histopathology results, which somewhat aligns with the disease outcome and prognosis.^7,8 The clinical presentation of HP is variable, which complicates the diagnostic process; while some patients experience an acute presentation where symptoms improve within 24–48 h after exposure stops, others progress from non-fibrotic to fibrotic disease due to prolonged and repeated exposures to the inciting antigen.^9,10 High resolution computed tomography scanning (HRCT) of the chest is the cornerstone of diagnosis and usually allows classification into non-fibrotic and fibrotic HP.^8,11 Non-fibrotic HP presents with ground glass opacities, mosaic attenuations, and centrilobular nodules, alongside features like isolated air trapping, airspace consolidation, and lung cysts.^8,9 Fibrotic HP presents additional features such as bronchiolar obstruction and lung fibrosis, sometimes with honeycombing.⁸ The presence of the ‘three density sign’ or ‘headcheese sign’ has a high specificity for fibrotic HP with a specificity of 93%.^10,12 Confirmation and support of the diagnosis of HP comes from lung biopsy and a high lymphocyte count in bronchoalveolar lavage fluid in non-fibrotic HP.

The primary management requires removal of the patient from the source of antigen,^10,13 so identifying the source is important and, given that most identified exposures are occupational, has important economic consequences for the patient. Antigen avoidance leads to improved lung function and longer survival, including transplanted patients.^14,15 Patients with non-fibrotic HP tend to survive longer and have fewer recurrences when they avoid exposure to the antigen causing HP.¹³ However, identification of inciting antigen is not possible in majority of fibrotic HP patients.^8,16 In many instances multiple antigens are responsible, with Aspergillus (if implicated) only one of the responsible exposures.

Numerous occupations and occupational diseases include or are driven by exposure to Aspergillus spp. including Wigmakers, Bird Fancier’s Lung, Compost Lung, Farmer’s Lung Disease, Malt-Worker’s Lung, Esparto Worker’s Lung (stipatosis), Tobacco-worker Lung, and Woodworker’s lung (Sawmill-workers), onion and potato exposure, and poultry workers.^17–32 Home or activity-related Aspergillus exposures include duvets and pillows, air conditioning or humidifiers in homes, offices and vehicles, mould in damp homes or worker places and wind musical instruments.^33–38 Given this wide range of possible exposures and the clinical importance of establishing the inciting antigens, IgG (precipitins) serology should be helpful.

Only some of the assays used in tracing the airborne exposures of patients with HP are commercially available, and in most cases the cutoff between positive and negative is based on 20–40 normal controls.^39,40 Immunoglobulin G assays to A. fumigatus are widely available because of their utility for diagnosing chronic pulmonary aspergillosis and to a lesser extent Aspergillus rhinosinusitis, allergic bronchopulmonary aspergillosis, Aspergillus bronchitis and invasive aspergillosis in non-immunocompromised patients.^41–44 Numerous assays in different formats are available, with different cut-offs, usually based on performance for chronic pulmonary aspergillosis, or a mixture of patients with aspergillosis. The most widely available assay, ImmunoCap^TM, also provides assays for IgG directed against A. niger and A. flavus.⁴⁰ We set out to survey the utility of A. fumigatus IgG assays in the diagnosis of HP and in particular to check if the cutoffs used for CPA diagnosis also may be applied to HP patients.

Methods

In this study, a scoping review was conducted using the five-stage framework proposed by Hilary Arksey & Lisa O’Malley.^45,46 Ethical approval was not required, as this scoping review examined existing published studies. A thorough literature search was performed using the databases Embase (Ovid), Web of Science, and Medline (Ovid). This search employed specific keywords (i.e. HP, extrinsic allergic alveolitis and the individual occupational disease terms) and subject-headings as listed in supplemental materials, with no restrictions on publication date to make sure all relevant studies are included; the searches were conducted on 11th July 2024 (see supplement for full search terms). Inclusion and exclusion criteria were established to select relevant studies. The inclusion criteria required that papers must (1) include a suitable control group for comparison; (2) include Aspergillus spp. in antibody test findings; and (3) be primary/original studies. The exclusion criteria were (1) lack of full text availability; (2) books, letters, poster/conference abstracts, case reports, reviews, meta-analyses, or conference papers; (3) animal studies; (4) non-English papers; (5) follow-up studies and (6) undefined or unspecific HP antigen exposure types. All studies from each database were exported to EndNote 20 for management and selection. The established eligibility criteria were applied to select relevant papers using the PRISMA flowchart guidelines Figure S1, by both authors (Supplemental material).⁴⁷

A second thorough literature search in Medline and the Aspergillus Web site (https://www.aspergillus.org.uk/) was done to identify all the published cutoffs of Aspergillus IgG used for different commercial assays and different forms of aspergillosis, mostly chronic pulmonary aspergillosis.

The characteristics of the 12 included studies were individually tabulated. The characteristics of each study was analyzed using descriptive statistics, summarizing the major characteristic of the studies in the form of percentages. The studies were organized and reviewed according to different HP exposure types, and data from those with A. fumigatus or A. clavatus IgG cutoffs summed. No-meta analysis was conducted due to the different nature of the studies, including variations in diagnostic tests, antigens, environmental conditions, exposure types and control groups. Separately all studies describing a cutoff of A. fumigatus IgG for currently commercially available assays were tabulated.

Results

Database searches resulted in a total of 779 papers of which 365 were duplicates leaving 414 papers for screening. Following title and abstract screening, 355 papers were excluded, resulting in 59 papers being selected for full-text review. After full-text review, 47 papers were excluded, resulting in 12 studies with original data utilising Aspergillus IgG testing for the diagnosis of HP (Figure S1).

The 12 studies included were cross-sectional studies published from 1965 to 2005. Collectively they reported on 554 patients with suspected or confirmed HP and 2576 controls without HP, including exposed and unexposed subjects, with or without other respiratory conditions (Table 1). Likely exposures for all HP cases included different bacteria and fungi; concerning Aspergillus spp., A. fumigatus was most commonly described and other species included A. umbrosus (now synonomised with A. glaucus),⁴⁸ A. clavatus and A. niger. These studies tested for Aspergillus IgG and other antigens using different antibody testing methods including ELISA, BALISA, precipitation tests and ImmunoCAP. Of these assays, only ImmunoCap is currently commercially available, although other Aspergillus IgG assays are sold, including immunoprecipitation assays (different from those published).

Table 1.

Data chart depicting characteristics of included cross-sectional studies (n = 12).

Authors, year	Country	Aims	HP exposure type	Serological technique	Subject groups
⁶⁷	U.K.	To investigate precipitin reactions in Farmer’s Lung patients, identify relevant antigens, compare serological techniques, and contrast results with other control groups, including other lung diseases	Farmer’s Lung	Double diffusion; Immuno-electrophoresis⁶⁷	Study group: 1. Farmer’s Lung Disease - exposed to mouldy hay: n = 205 Control group: 2. Exposed to mouldy hay but do not have Farmer’s Lung Disease: n = 122 3. Non-farmers: n = 134
⁶⁸	USA	To investigate serological reactivity and cross-reaction patterns observed in patients with various types of HP (including Farmer’s Lung Disease) and aspergillosis to different strains of A. fumigatus, 9 common fungi (Mucor, Rhizopus, Cephalosporium, Fusarium, Penicillium, Alternaria, Hormodendrum, Candida albicans, Trichoderma) and dusts	Farmer’s Lung; Pigeon breeder's disease; textile worker pneumonitis	Double diffusion agar gel, antigen production⁶⁹	Study group: 1. Farmer’s Lung Disease: n = 20 2. Pigeon breeders disease: n = 19 3. Textile worker pneumonitis: n = 10 Control group: 4. Aspergillosis: n = 36 5. Healthy controls: n = 42 6. Asthma: n = 29
⁷⁰	Finland	To investigate prevalence of antibodies to the antigens of A. fumigatus, M. faeni, and T. vulgaris in farmers, non-farmers, and respiratory patients (including those with Farmer’s Lung Disease)	Farmer’s Lung	Immunoprecipitation with modification⁷¹	Study group: 1. Patients (suspected of fungal allergy): n = 48; 1.1. Patients (Farmer’s Lung Disease): n = 22 Control group: 2. Farmers: n = 325 3. Non-farmers: n = 80
⁷²	Finland	To investigate antibody levels to A. fumigatus among patients with Farmer’s Lung Disease, different pulmonary diseases, and healthy controls and to study the correlation between precipitin and ELISA tests	Farmer’s Lung	ELISA IgG	Study group: 1. Farmer’s Lung Disease: n = 31 Control group: 2. Miscellaneous respiratory diseases: n = 41 3. Bronchial asthma: n = 24 4. Non-allergic respiratory diseases: n = 16 5. Controls (healthy non-farmers: n = 63
⁷³	Finland	To investigate role of antibody testing using ELISA in Farmer’s Lung Disease patients for the antigens of A. fumigatus, T. vulgaris, and M. faeni	Farmer’s Lung	ELISA IgG⁷⁴	Study group: 1. Farmers’ Lung Disease patients: n = 17 Control group: 2. Bronchitis patients: n = 18 3. Controls (non-farmers, no respiratory symptoms): n = 20
⁷⁵	Finland and USA (with contributions from Switzerland and Canada)	To measure the antibody levels against various HP antigens and strains (including A. fumigatus, M. faeni, T. vulgaris, Penicillium, T. candidus, S. viridis, and A. umbrosus) in patients with Farmer’s Lung Disease and control subjects from different countries	Farmer’s Lung	ELISA IgG^{76 ^,}⁷⁷	Study group: 1. Farmer’s Lung Disease patients: n = 69 Control group: 2. Healthy lab employees: n = 28
⁷⁸	Finland	To determine appropriate immunoglobulin class (IgG, IgA, IgM, and IgE) for diagnosing Farmer’s Lung Disease using ELISA focusing on antibodies against A. umbrosus, A. fumigatus, T. vulgaris, and M. faeni	Farmer’s Lung	ELISA IgG, IgA, IgM, and IgE⁷³	Study group: 1. Farmer’s Lung Disease: n = 24 Control group: 2. Spouses of Farmer’s Lung Disease patients (exposed): n = 24;
⁷⁹	Scotland	To investigate respiratory syndromes and the presence of precipitating antibodies against P. granulatum, P. citrinum, R. stolonifer, and A. clavatus in maltworkers	Malt-workers	Double diffusion agar gel⁸⁰	Study group: 1. Maltmen (exposed): n = 114 Control group: 2. Carpet workers (dusty work): n = 25 3. Paper workers: n = 100
⁸¹	Scotland	To investigate maltworkers through environmental samples, sputum samples, prick tests and precipitins for fungal antigens. Precipitin test included antigens of C. herbarum, A. niger, R. stolonifer, A. fumigatus, T. viride, A. clavatus Also, relation between HP and antigens of A. clavatus was investigated	Malt-worker	Double diffusion agar gel, IE, immunoelectro-osmophoresis^{67 ^,}⁸²	Part 1: Study group: 1. Maltworkers (exposed): n = 711 Control group: 2. Control sera: n = 50 Part 2: Study group: 1. Maltworkers suspected of having HP: n = 127
⁸³	Spain	To investigate esparto grass exposure in symptomatic patients and measure antibody levels to A. fumigatus, M. faeni, and T. vulgaris	Esparto grass	Double diffusion, ELISA IgG^{84 ^,}⁸⁵	Study group: 1. Esparto grass workers with suspected HP: (n = 5) Control group: 2. Healthy control sera: (n = 10)
⁸⁶	Spain	To investigate IgG levels in workers with HP from esparto grass exposure and in healthy workers exposed to esparto, in response to A. fumigatus, M. faeni, and T. vulgaris	Esparto grass	Double diffusion and CAP IgG (Pharmacia, Upsala, Sweden)	Study group: 1. Esparto-grass HP workers : n = 5, Control group: 2. Healthy workers exposed to esparto: n = 45, 3. Unexposed controls n = 20
²²	Norway	To investigate and compare exposure level, symptoms and IgG antibodies in two populations that each include wood-trimmers and planning operators	Wood-trimmer disease (Sawmill workers)	ELISA IgG⁸⁷	Suspected wood trimmer disease cases): (total = 170) Wood trimmer: n = 99 Planning operator (control): n = 71 No disease control: Wood trimmers: n = 113 Planning operators (control): n = 190

ELISA: Enzyme-linked immunosorbent assay; IE: lmmunoelectrophoresis. CAP: ImmunoCap.

The studies included four from Finland all on Farmer’s Lung, two from Scotland on malt workers, two from Spain on Esparto grass workers, one from USA, one from both Finland and the USA with contributions from Switzerland and Canada, one from UK and one from Norway on sawmill workers (Table 1). Various occupational exposures were addressed, including six studies focused solely on Farmer’s Lung, one study addressing Farmer’s Lung along with other HP exposure types (textile worker pneumonitis and Pigeon Breeder’s disease), Malt Worker’s Lung, sawmill workers and stipatosis (esparto grass workers). No studies directly addressed serological testing in Tobacco Worker’s lung, Compost Lung, or poultry workers.

Exposures were usually to multiple antigens, including A. fumigatus, A. umbrosus, A. clavatus and A. niger. We know from more recent studies that detection of precipitating antibodies using the original Ouchterlony gel method, and its adaptations is less sensitive than the best ELISA and automated methods. The proportions of patients with HP, exposed but unaffected patients and non-diseased and unexposed controls are shown in Table 2.

Table 2.

Aspergillus fumigatus antibody data from the HP studies where the positive and negative proportions are presented.

Occupation	Antibody detected/antibody negative (%)			Method	Reference
Occupation	HP	Exposed without HP	Other controls	Method	Reference
Farmers	63/166 (38%)	Healthy farmers 1/27 (4%)		Immunodiffusion	Pepys, 1965⁶⁷
		Lung diseases 12/87 (14%)
Farmers	13/20 (65%)	4/19 (19%)	Healthy 2/42 (4%)	Immunodiffusion	Flaherty, 1974⁸⁸
		–	Asthma: 2/29 (7%)
			Aspergillosis 30/36 (86%)^a
Farmers	18/22 (82%)	36/325 (11%)	3/80 (4%)	Immunoprecipitation	Katila, 1978⁸⁹
Farmers	25/31 (81%)	19/41 (46%)	6/63 (10%)	ELISA	Mäntyjärvi, 1980¹⁸
Farmers	13/17 (76%)	4/18 (22%)	9/20 (45%)	ELISA	Ojanen, 1980⁹⁰
Farmers	16/24 (67%)	4/24 (17%)		ELISA	Ojanen, 1992⁹¹
Malt-worker	0/53^b	16/74 (22%)^c	0/50	Immunoelectrophoresis	Blyth, 1977⁸¹
Esparto grass	5/5 (100%)		0/10	ELISA	Hinojosa, 1996²⁰
Esparto grass	3/5 (60%)		7/20 (35%)	ImmunoCap	Gamboa, 2005⁸⁶
Totals ^d	156/290 (53.8%)	96/615 (15.6%)	36/314 (11.1%)

^aOmitted from total as a ‘positive control’

^bPositives to A. clavatus antigen in those with HP was 35/53 (66%).

^cPatients with other respiratory conditions, not HP.

^dOmitting maltworker, given the lack of cross reactivity between A, clavatus and A. fumigatus.

Totalling all the patients described in papers with A. fumigatus serology with a defined cutoff (Table 2), 156/290 (53.8%) had a positive result. This contrasts with 96/615 (15.6%) exposed patients with evidence of HP in the same studies, and 36/314 (11.1%) apparently healthy, unexposed controls (although some controls were farmers). None of the malt workers with HP had a positive A. fumigatus IgG but 35 of 53 (66%) were positive to A. clavatus antigen, along with 13/74 (18%) exposed but unaffected workers. Only one of these studies used a commercial assay, ImmunoCap, and only five affected patients were included, all esparto grass workers.

In Table 3 are shown the published A. fumigatus antibody cutoffs, for all forms of aspergillosis, notably chronic pulmonary aspergillosis which has the highest fungal load in the lung for months or years. Fifteen studies addressed the cutoff for ImmunoCap, including two explicitly for HP patients. The cutoff values recommended for clinical reporting vary from 22 to 83mgA/mL, mostly derived from chronic pulmonary aspergillosis cases or healthy controls only, and conducted in several countries. Two studies from Germany focussed on HP patients utilising normal control sera recommended a cutoff of 65 mgA/L⁴⁰ or 39 mgA/L (75% centile) or 78 mgA/L (90% centile)³⁹ and one from Singapore reported a median A. fumigatus IgG of 31 mgA/L.⁴⁹ Five studies recommended a cutoff for the Immulite 2000 assay of 10–20 mg/L, including one addressing HP patients, and A. niger IgG.^50–54 The two studies with the Bordier Aspergillus IgG assay derived an optical density index of 0.82 or 0.9.^55,56 The three Dynamiker studies derived cutoffs of 65-107AU/L.^50,53,57 Only one study with data supporting a cutoff has been published for the BioRad Platelia assay,⁵⁸ the Serion assay⁵⁰ and the Omega (Genesis) assay.⁵⁰

Table 3.

Aspergillus fumigatus IgG cutoffs determined in the literature (2006 onwards).

Authors, year	Country	Assay	Patient group	Controls	Cutoff
Kranke, 2001⁹²	Austria	ImmunoCap^a	None	Healthy	39 mgA/L
Hoeyveld, 2006⁶⁰	Belgium	Immunocap	None with HP	Healthy	35, 70^a mgA/L
Barton, 2008⁹³	UK	ImmunoCap	Cystic fibrosis, ABPA, sensitised	Cystic fibrosis	90 mgA/L
Watkins, 2012⁹⁴	South Africa	ImmunoCap	None	Healthy	67 mgA/L
Fujiuchi, 2016⁹⁵	Japan	ImmunoCap	Untreated CPA	Chronic lung disease	50 mgA/L
Page, 2016⁵⁰	UK	ImmunoCap	CPA	Healthy (Uganda)	20 mgA/L
Agarwal, 2017⁴¹	India	Immunocap	ABPA and allergic asthma	Healthy	27 mgA/L
Sehgal, 2018⁶²	India	ImmunoCap	CPA	TB patients with CPA excluded	27 mgA/L
Al-Rahman, 2018⁹⁶	Oman	ImmunoCap	None	Healthy	69 mgA/L^a
Raulf, 2019³⁹	Germany	ImmunoCap	None	Unexposed, healthy	78^b, 97^c mgA/L
Tan, 2019⁴⁹	Singapore	ImmunoCap	None	Healthy	31^d mgA/L
Huang, 2020⁹⁷	Taiwan	ImmunoCap	CPA	Chronic lung disease	22 mgA/L
Lee, 2021⁹⁸	Taiwan	ImmunoCap	CPA	Chronic lung disease, CPA excluded	40 mgA/L
Sennekamp, 2022⁴⁰	Germany	ImmunoCap	Suspected HP	Healthy	64 mgA/L^e
Hsiao, 2022⁹⁹	Taiwan	ImmunoCap	CPA, IA and ABPA	Healthy	42 mgA/L
Salzer, 2023⁶³	Multiple	ImmunoCap	Histologically proven CPA	Lung disease (including possible CPA) and healthy	83 mgA/L
Page, 2016⁵⁰	UK	Immulite	CPA	Healthy (Uganda)	10 mg/L
Page, 2019⁵¹	Uganda	Immulite	TB and CPA patients	Healthy and screened controls with TB	20 mg/L
Jabeen, 2020⁵²	Pakistan	Immulite	CPA	Chronic lung disease and healthy	20 mg/L
Setiangingrum, 2020⁵³	Indonesia	Immulite	CPA	TB without CPA	11.5 mg/L
Intra, 2024⁵⁴	italy	Immulite	HP	Healthy	10.2 mg/L
Shinfuku, 2023⁵⁸	Japan	Platelia	CPA and ABPA	Colonised with A. fumigatus	16 AU/mL
Wilopo, 2020⁵⁵	UK	Bordier	CPA	Healthy	0.9 ODI
Oladele, 2021⁵⁶	Nigeria	Bordier	CPA	Healthy	0.82 ODI
Page, 2016⁵⁰	UK	Serion	CPA	Healthy (Uganda)	35 U/L
Page, 2016⁵⁰	UK	Dynamiker	CPA	Healthy (Uganda)	65 AU/L
Ma, 2019⁵⁷	China	Dynamiker	IA and CPA	Healthy	89 AU/L
Setiangingrum, 2020⁵³	Indonesia	Dynamiker	CPA	TB without CPA	107 AU/mL
Page, 2016⁵⁰	UK	Genesis (Omega)	CPA	Healthy (Uganda)	20 U/L

CPA: chronic pulmonary aspergillosis; IA: invasive aspergillosis; ABPA: allergic bronchopulmonary aspergillosis; ODI: optical density index.

^a97.5% centile.

^b90% centile.

^c95% centile.

^dMedian (SD = 31.7)

^eThe 90% centil was 146 mgA/L and the cutoff used in clinical work is derived from a prior paper.⁵⁹

Discussion

The first serum assays for exposure to Aspergillus and other antigens causing HP were precipitins assays. By diluting serum, a rough quantification of antibody titre could be determined. It was soon realised that not only was the titre variable in clear cut cases of HP, but also that some patients with HP did not have detectable precipitating antibody and that conversely that other exposed workers did without manifesting HP. Some laboratories do still run precipitins assays, often using double-diffusion immunoelectrophoresis procedures, but more automated assays have been adopted by most immunology laboratories these days, partly because of improved sensitivity.⁶⁰ Themofisher/Phadia has a range of IgG assays in their ImmunoCap range including Aspergillus fumigatus, A. flavus, A. niger, budgerigar (GE90), pigeon (GE91) and Micropolyspora faeni (Gm22) (reclassified in 1989 as Saccharopolyspora rectivirgula). They do not offer a normal range for reporting A. fumigatus IgG declaring: “There is no common cut-off value for above normal levels of circulating specific IgG antibodies, as these are markers for allergen exposure, which may not be directly related to the disease and will depend on the local environment and levels of exposure”. Individual laboratories therefore have to decide their ‘normal’ range for the ImmunoCap assay, to issue reports to clinicians, based on internal validation or published work. Other manufacturers do recommend cutoffs for their assays.

In the last 10 years, many publications have emerged defining cut-offs for A. fumigatus IgG in the diagnosis of chronic pulmonary aspergillosis (CPA) specifically. In this condition, the majority of patients have a positive A. fumigatus IgG, given the chronicity of the infection and huge microbial load of fungus in the lung. A key element of the design of these studies has been the control group, sometimes blood donors or surgical patients without lung disease, sometimes patients with other respiratory disorders, and sometimes both. Two German studies and one from Singapore, addressed the cutoff for possible HP using the ImmunoCap method. Monika Raulf and colleagues in Germany (2019) examined cutoffs for 32 antibody assays of possible antigens causing HP, using 121 sera from unexposed persons.³⁹ For A. fumigatus, 75% of sera had antibody levels <39 mgA/L (90% centile was 78 mgA/L), and they proposed using an online calculator to define the cutoff. In Singapore, Yi Hern Tan et al found the median ImmunoCap A. fumigatus IgG antibody level in 120 healthy donors to be 30.9 +/− 31.7 mgA/L.⁴⁹ Joachim Sennekamp and colleagues assessed 20 healthy persons and found 64 mgA/L to be the 95% in sera from 20 healthy donors and all 100 selected sera from possible HP patients to be above this.⁴⁰ These cutoffs are higher than the cutoff value (40 mgA/L) currently used in the UK and other countries for diagnosing CPA,⁶¹ and higher than that recommended in India at 27 mgA/L.^62,63 Jari Intra and colleagues in Italy (2024) compared 1850 sera from patients without HP to 54 with the disease linked to many different exposures using the Siemens Immulite 2000 assay for 6 antibodies including A. fumigatus and A. niger.⁵⁴ The median and 95% centile of A. fumigatus IgG for controls and HP patients were 10.2 and 38.0 mg/L compared to 42.0 and 142.0 mg/L (p < 0.001). They also examined sera for antibody to A. niger with markedly different levels between controls and HP patients.

Some environmental exposures leading to HP are highly specific, including some chemicals and bird antigens. Others are more common, as for microorganisms found in hay (for many people an occasional exposure) or Alternaria linked to thunderstorms and wheat fields,^64–66 as one example. But Aspergillus exposure is continuous of varying levels; for example compost and older pillows and bedding contain billions of spores. Occupational Aspergillus exposures clearly can lead to HP but may not; what is less clear is whether other non-occupational exposures may drive the onset of HP and/or pulmonary fibrosis. A combination of a clearcut diagnosis of HP, historical information (including occupation) indicating substantial fungal exposures and a positive Aspergillus IgG, is sufficient to infer (monovalent or polyvalent) causality. Unfortunately, pulmonary fibrosis may present without evidence of prior HP, specific exposure history is lacking and Aspergillus (or other fungal) IgG testing is negative. And this situation is further confounded by positive IgG antibody results in exposed persons without HP and several other forms of aspergillosis including allergic bronchopulmonary aspergillosis, with or without asthma, Aspergillus bronchitis or rhinosinusitis, Aspergillus nodules or chronic pulmonary aspergillosis. Additional work is required to address these uncertainties, especially better measures of exposure to specific antigens in those with lung fibrosis of uncertain aetiology. Given that antigen avoidance allows lung function to improve^14,15 and that HP patients without pulmonary fibrosis survive longer and have fewer recurrences,¹³ redoubled efforts to address this area are required.

However, this scoping review has several limitations. A systematic quality appraisal of the selected studies was not conducted. Furthermore, due to variability in diagnostic methods and patient populations, a meta-analysis was not considered appropriate for these studies. As HP is not a commonly diagnosed disease, the data is limited to smaller studies, making it challenging for some studies to draw definite conclusions. Diagnostic criteria have been updated and changed, and previously differed between countries, which introduces inconsistency and complicates interpretation and comparison of older and newer study findings together. Some studies failed to mention HP exposure types or include appropriate controls for comparison, causing these to be excluded. The majority of studies on Farmer’s Lung Disease were from Finland, which may limit the findings to that country. No studies directly addressed serological testing in Tobacco Worker’s lung, Compost Lung, or poultry workers in which exposure to Aspergillus spp. is implicated. Our review was also limited to studies in English, which may have excluded additional findings.

In conclusion, we review the current understanding of how Aspergillus antibody testing could aid in the diagnosis of HP, with significant repeated exposure to Aspergillus spp. and contrast the cutoffs for A. fumigatus IgG antibody with other forms of aspergillosis. Unlike other HP exposures, which reflect antigens unrelated to other disorders, Aspergillus spp. is responsible for several different disease entities, with a corresponding rise in detectable A. fumigatus IgG. We highlight the difficulties in establishing cut-off values to differentiate between prior infection or exposure and disease. Recent studies have been published which aim to define cut-off values for specific IgG to A. fumigatus but further standardization is required to accommodate HP sera.

Supplemental Material

Supplemental Material -Aspergillus IgG antibody testing in the diagnosis of hypersensitivity pneumonitis: A scoping review

Supplemental Material for Aspergillus IgG antibody testing in the diagnosis of hypersensitivity pneumonitis: A scoping review by Lana Hatim and David W Denning in Chronic Respiratory Disease.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

David W Denning

Supplemental Material

Supplemental material for this article is available online.

References

Pereira

Gimenez

Kuranishi

, et al. Chronic hypersensitivity pneumonitis. J Asthma Allergy 2016; 9: 171–181.

Berlinski

Carroll

. Chapter 45 - Eosinophilic lung diseases and hypersensitivity pneumonitis. In: Taussig

Landau

(eds). Pediatric Respiratory Medicine. 2nd ed. Philadelphia: Mosby, 2008, pp. 671–680.

Barnes

Jones

Blanc

. The hidden history of hypersensitivity pneumonitis. Eur Respir J 2022; 59: 2100252.

Eyckmans

Gyselen

Lauwerijns

, et al. Pigeon breeder's lung. Report of three cases. Dis Chest 1968; 53: 358–364.

Singh

Collins

Sharma

, et al. Hypersensitivity pneumonitis: clinical manifestations – Prospective data from the interstitial lung disease-India registry. Lung India 2019; 36: 476–482.

Sabino

Veríssimo

Viegas

, et al. The role of occupational Aspergillus exposure in the development of diseases. Med Mycol 2019; 57: S196–S205.

Churg

. Hypersensitivity pneumonitis: new concepts and classifications. Mod Pathol 2022; 35: 15–27.

Raghu

Remy-Jardin

Ryerson

, et al. Diagnosis of hypersensitivity pneumonitis in adults: an official ATS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med 2020; 202: e36–e69.

Barnes

Troy

Lee

, et al. Hypersensitivity pneumonitis: current concepts in pathogenesis, diagnosis, and treatment. Allergy 2022; 77: 442–453.

10.

Calaras

David

Vasarmidi

, et al. Hypersensitivity pneumonitis: challenges of a complex disease. Can Respir J 2024; 2024: 1–14.

11.

Dabiri

Jehangir

Khoshpouri

, et al. Hypersensitivity pneumonitis: a pictorial review based on the new ATS/JRS/ALAT clinical practice guideline for radiologists and pulmonologists. Diagnostics 2022; 12: 2874.

12.

Walsh

SLF

Richeldi

. Demystifying fibrotic hypersensitivity pneumonitis diagnosis: it's all about shades of grey. Eur Respir J 2019; 54: 1900906.

13.

Nishida

Kawate

Ishiguro

, et al. Antigen avoidance and outcome of nonfibrotic and fibrotic hypersensitivity pneumonitis. ERJ Open Res 2022; 8: 00474–02021.

14.

De Sadeleer

Hermans

De Dycker

, et al. Effects of corticosteroid treatment and antigen avoidance in a large hypersensitivity pneumonitis cohort: a single-centre cohort study. J Clin Med 2018; 8: 14.

15.

Robertshaw

Gorman

Glazer

, et al. Effect of antigen removal in hypersensitivity pneumonitis. BMC Pulm Med 2024; 24: 398.

16.

Fernández Pérez

Travis

Lynch

, et al. Diagnosis and evaluation of hypersensitivity pneumonitis: CHEST guideline and expert panel report. Chest 2021; 160: e97–e156.

17.

Bünger

Schappler-Scheele

Hilgers

, et al. A 5-year follow-up study on respiratory disorders and lung function in workers exposed to organic dust from composting plants. Int Arch Occup Environ Health 2007; 80: 306–312.

18.

Mantyjärvi

Jousilahti

Katila

. Antibodies to Aspergillus fumigatus in farmers’ lung patients measured by enzyme-linked immunosorbent assay (ELISA). Clin Allergy. 1980; 10: 187–194.

19.

Grant

Blackadder

Greenberg

, et al. Extrinsic allergic alveolitis in Scottish maltworkers. Br Med J 1976; 1: 490–493.

20.

Hinojosa

Fraj

De la Hoz

, et al. Hypersensitivity pneumonitis in workers exposed to esparto grass (Stipa tenacissima) fibers. J Allergy Clin Immunol 1996; 98: 985–991.

21.

Huuskonen

Husman

Järvisalo

, et al. Extrinsic allergic alveolitis in the tobacco industry. Br J Ind Med 1984; 41: 77–83.

22.

Eduard

Sandven

Levy

. Serum IgG antibodies to mold spores in two Norwegian sawmill populations: relationship to respiratory and other work-related symptoms. Am J Ind Med 1993; 24: 207–222.

23.

Miller

. Fungal bioaerosols as an occupational hazard. Curr Opin Allergy Clin Immunol 2023; 23: 92-97.

24.

Rénon

Etude sur les aspergilloses chez les animaux et chez l’homme. Paris, Masson et Cie: British Medical Association, 1897, pp. 22–23.

25.

Scribner

Barboriak

Fink

. Prevalence of precipitins in groups at risk of developing hypersensitivity pneumonitis. Clin Allergy 1980; 10: 91–95.

26.

Müller

de Haller

Grob

. Serological investigations in 15 cases of bird fanciers disease. Int Arch Allergy Appl Immunol 1976; 50: 341–358.

27.

Sennekamp

Juergens

L-J

Sturm

, et al. Extrinsic allergic alveolitis due to inhaled molds in occupational onion and potato processing: onion- and potato-sorter alveolitis. Allergo J Int 2016; 25: 138–143.

28.

Sakamoto

Yamasaki

Funaki

, et al. An onion farmer with a case of hypersensitivity pneumonitis caused by Aspergillus niger. Respir Med Case Rep. 2018; 23: 60–62.

29.

Lugauskas

Krikstaponis

Sveistyte

. Airborne fungi in industrial environments--potential agents of respiratory diseases. Ann Agric Environ Med 2004; 11: 19–25.

30.

Lal

Akhtar

Pinto

, et al. Recurrent pulmonary embolism and hypersensitivity pneumonitis secondary to Aspergillus, in a compost plant worker: case report and review of literature. Lung. 2018; 196: 553–560.

31.

Vincken

Roels

. Hypersensitivity pneumonitis due to Aspergillus fumigatus in compost. Thorax. 1984; 39: 74–75.

32.

Hagemeyer

Bünger

van Kampen

, et al. Occupational allergic respiratory diseases in garbage workers: relevance of molds and actinomycetes. Adv Exp Med Biol 2013; 788: 313–320.

33.

Woodcock

Steel

Moore

, et al. Fungal contamination of bedding. Allergy 2006; 61: 140–142.

34.

Brewer

Thrasher

Straus

, et al. Detection of mycotoxins in patients with chronic fatigue syndrome. Toxins 2013; 5: 605–617.

35.

Thrasher

Crawley

. The biocontaminants and complexity of damp indoor spaces: more than what meets the eyes. Toxicol Ind Health 2009; 25: 583–615.

36.

Soumagne

Reboux

Metzger

, et al. Fungal contamination of wind instruments: immunological and clinical consequences for musicians. Sci Total Environ 2019; 646: 727–734.

37.

Pertegal

Riquelme

Lozano-Serra

, et al. Cleaning technologies integrated in duct flows for the inactivation of pathogenic microorganisms in indoor environments: a critical review of recent innovations and future challenges. J Environ Manage 2023; 345: 118798.

38.

Gołofit-Szymczak

Wójcik-Fatla

Stobnicka-Kupiec

, et al. Filters of automobile air conditioning systems as in-car source of exposure to infections and toxic moulds. Environ Sci Pollut Res Int 2023; 30: 108188–108200.

39.

Raulf

Joest

Sander

, et al. Update of reference values for IgG antibodies against typical antigens of hypersensitivity pneumonitis. Allergo J Int 2019; 28: 192–203.

40.

Sennekamp

Lehmann

Joest

. Improved IgG antibody diagnostics of hypersensitivity pneumonitis and pulmonary mycoses by means of newly evaluated serum antibody ranges and frequencies using IgG ImmunoCAP™. Allergo J Int 2022; 31: 172–182.

41.

Agarwal

Dua

Choudhary

, et al. Role of Aspergillus fumigatus-specific IgG in diagnosis and monitoring treatment response in allergic bronchopulmonary aspergillosis. Mycoses. 2017; 60: 33–39.

42.

Chakrabarti

Rudramurthy

Panda

, et al. Epidemiology of chronic fungal rhinosinusitis in rural India. Mycoses 2015; 58: 294–302.

43.

Denning

. Aspergillus & Aspergillosis: community acquired Aspergillus pneumonia and/or pneumonitis.

44.

Prats

JAGG

Denning

. Aspergillus & Aspergillosis: Aspergillus bronchitis.

45.

Arksey

O'Malley

. Scoping studies: towards a methodological framework. Int J Soc Res Methodol 2005; 8: 19–32.

46.

Levac

Colquhoun

O'Brien

. Scoping studies: advancing the methodology. Implementation Sci 2010; 5: 69.

47.

Page

McKenzie

Bossuyt

, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71.

48.

Chen

Hubka

Frisvad

, et al. Polyphasic taxonomy of Aspergillus section Aspergillus (formerly Eurotium), and its occurrence in indoor environments and food. Stud Mycol. 2017; 88: 37–135.

49.

Tan

Ngan

Huang

, et al. Specific serum immunoglobulin G (IgG) levels against antigens implicated in hypersensitivity pneumonitis in asymptomatic individuals. Ann Acad Med Singap 2019; 48: 36–38.

50.

Page

Richardson

Denning

. Comparison of six Aspergillus-specific IgG assays for the diagnosis of chronic pulmonary aspergillosis (CPA). J Infect. 2016; 72: 240–249.

51.

Page

Richardson

Denning

. Siemens Immulite Aspergillus-specific IgG assay for chronic pulmonary aspergillosis diagnosis. Med Mycol. 2019; 57: 300–307.

52.

Jabeen

Farooqi

Iqbal

, et al. Aspergillus fumigatus and Aspergillus flavus-specific IgG cut-offs for the diagnosis of chronic pulmonary aspergillosis in Pakistan. J Fungi (Basel). 2020; 6: 20201026.

53.

Setianingrum

Rozaliyani

Syam

, et al. Evaluation and comparison of automated and manual ELISA for diagnosis of chronic pulmonary aspergillosis (CPA) in Indonesia. Diagn Microbiol Infect Dis 2020; 98: 115124.

54.

Intra

Biffi

Basta

, et al. The role of serum IgG precipitins against six typical organic antigens involved in hypersensitivity pneumonitis: a 10-year retrospective study of a referral interstitial lung disease centre. Int J Transl Med (Basel) 2024; 4: 381–386.

55.

Wilopo

BAP

Hunter

Richardson

, et al. Optimising the cut-off of the bordier Aspergillus IgG ELISA for the diagnosis of chronic pulmonary aspergillosis. J Microbiol Methods. 2020; 176: 106021.

56.

Oladele

Otu

Balogun

, et al. Standardization of Aspergillus IgG diagnostic cutoff in Nigerians. Ther Adv Infect Dis. 2021; 8: 20499361211050158.

57.

Wang

Zhao

, et al. Prospective study of the serum Aspergillus-specific IgG, IgA and IgM assays for chronic pulmonary aspergillosis diagnosis. BMC Infect Dis. 2019; 19: 694.

58.

Shinfuku

Suzuki

Takeda

, et al. Validity of Platelia Aspergillus IgG and Aspergillus precipitin test to distinguish pulmonary aspergillosis from colonization. Microbiol Spectr. 2023; 11: e0343522.

59.

Sennekamp

Lehmann

Joest

. Work related extrinsic allergic alveolitis. ASU Int 2015; 50: 38–52.

60.

Van Hoeyveld

Dupont

Bossuyt

. Quantification of IgG antibodies to Aspergillus fumigatus and pigeon antigens by ImmunoCAP technology: an alternative to the precipitation technique? Clin Chem. 2006; 52: 1785–1793.

61.

Hunter

Wilopo

Richardson

, et al. Effect of patient immunodeficiencies on the diagnostic performance of serological assays to detect Aspergillus-specific antibodies in chronic pulmonary aspergillosis. Respir Med. 2021; 178: 106290.

62.

Sehgal

Choudhary

Dhooria

, et al. Diagnostic cut-off of Aspergillus fumigatus-specific IgG in the diagnosis of chronic pulmonary aspergillosis. Mycoses. 2018; 61: 770–776.

63.

Salzer

HJF

Reimann

Oertel

, et al. Aspergillus-specific IgG antibodies for diagnosing chronic pulmonary aspergillosis compared to the reference standard. Clin Microbiol Infect. 2023; 29: 1605.e1-1605.e4.

64.

D'Amato

Annesi-Maesano

Urrutia-Pereira

, et al. Thunderstorm allergy and asthma: state of the art. Multidiscip Respir Med 2021; 16: 806.

65.

Hughes

Price

Torriero

AAJ

, et al. Impact of fungal spores on asthma prevalence and hospitalization. Int J Mol Sci 2022; 23: 4313.

66.

The Impact of Climate Change on Fungal Diseases 2022. DOI: 10.1007/978-3-030-89664-5.

67.

Pepys

Jenkins

. Precipitin (F.L.H.) test in farmer’s lung. Thorax. 1965; 20: 21–35.

68.

Flaherty

Murray

Reed

. Cross reactions to antigens causing hypersensitivity pneumonitis. J Allergy Clin Immunol 1974; 53: 329–335.

69.

Edwards

. The double dialysis method of producing farmer's lung antigens. J Lab Clin Med 1972; 79: 683–688.

70.

Katila

Mäntyjärvi

. The diagnostic value of antibodies to the traditional antigens of farmer's lung in Finland. Clin Experimental Allergy 1978; 8: 581–587.

71.

Flaherty

Barboriak

Emanuel

, et al. Multilaboratory comparison of three immunodiffusion methods used for the detection of precipitating antibodies in hypersensitivity pneumonitis. J Lab Clin Med 1974; 84: 298–306.

72.

Mäntyjärvi

Jousilahti

Katila

. Antibodies to Aspergillus fumigatus in farmers' lung patients measured by enzyme-linked immunosorbent assay (ELISA). Clin Allergy 1980; 10: 187–194.

73.

Ojanen

Katila

Mäntyjärvi

. The use of enzyme-linked immunosorbent assay (ELISA) in the diagnosis of farmer's lung. Allergy 1980; 35: 537–542.

74.

Voller

. Microplate enzyme immunoassays for the immunodiagnosis of virus infections. Manual of Clinical Immunology. Washington. DC: American Society for Microbiology, 1976, pp. 506–512.

75.

Kurup

Mäntyjärvi

Terho

, et al. Circulating IgG antibodies against fungal and actinomycete antigens in the sera of farmer's lung patients from different countries. Mycopathologia 1987; 98: 91–99.

76.

Kendall

Ionescu-Matiu

Dreesman

. Utilization of the biotin/avidin system to amplify the sensitivity of the enzyme-linked immunosorbent assay (ELISA). J Immunol Methods 1983; 56: 329–339.

77.

Shamsuddin

Harris

. Improved enzyme immunoassays using biotin-avidin-enzyme complex. Arch Pathol Lab Med 1983; 107: 514–517.

78.

Ojanen

. Class specific antibodies in serodiagnosis of farmer's lung. Br J Ind Med 1992; 49: 332–336.

79.

Riddle

. Prevalence of respiratory symptoms and sensitization by mould antigens among a group of maltworkers. Br J Ind Med 1974; 31: 31–35.

80.

Longbottom

Pepys

. Pulmonary aspergillosis: diagnostic and immunological significance of antigens and C-substance in Aspergillus fumigatus. J Pathol Bacteriol. 1964; 88: 141–151.

81.

Blyth

Grant

Blackadder

, et al. Fungal antigens as a source of sensitization and respiratory disease in Scottish maltworkers. Clin Allergy 1977; 7: 549–562.

82.

Gordon

Almy

Greene

, et al. Diagnostic mycoserology by immunoelectroosmophoresis: a general, rapid, and sensitive microtechnic. Am J Clin Pathol 1971; 56: 471–474.

83.

Hinojosa

Fraj

De La Hoz

, et al. Hypersensitivity pneumonitis in workers exposed to esparto grass (Stipa tenacissima) fibers. J Allergy Clin Immunol 1996; 98: 985–991.

84.

Voller

Bidwell

Bartlett

. Enzyme immunoassays in diagnostic medicine. Theory and practice. Bull World Health Organ 1976; 53: 55–65.

85.

Sepulveda

Longbottom

Pepys

. Enzyme linked immunosorbent assay (ELISA) for IgG and IgE antibodies to protein and polysaccharide antigens of Aspergillus fumigatus. Clin Allergy. 1979; 9: 359–371.

86.

Gamboa

Urbaneja

Olaizola

, et al. Specific IgG to Thermoactynomices vulgaris, Micropolyspora faeni and Aspergillus fumigatus in building workers exposed to esparto grass (plasterers) and in patients with esparto-induced hypersensitivity pneumonitis. J Investig Allergol Clin Immunol. 2005; 15: 17–21.

87.

Sandven

Eduard

. Detection and quantitation of antibodies against Rhizopus by enzyme-linked immunosorbent assay. Apmis 1992; 100: 981–987.

88.

Flaherty

Murray

Reed

. Cross reactions to antigens causing hypersensitivity pneumonitis. J Allergy Clin Immunol 1974; 53: 329–335.

89.

Katila

Mäntyjärvi

. The diagnostic value of antibodies to the traditional antigens of farmer's lung in Finland. Clin Exp Allergy 1978; 8: 581–587.

90.

Ojanen

Katila

Mäntyjärvi

. The use of enzyme-linked immunosorbent assay (ELISA) in the diagnosis of farmer's lung. Allergy 1980; 35: 537–542.

91.

Ojanen

. Class specific antibodies in serodiagnosis of farmer's lung. Br J Ind Med 1992; 49: 332–336.

92.

Kränke

MWB

Woltsche-Kahr

Aberer

. IgG-Antikörper gegen “EAA-spezifische” Umweltantigene: Die Problematik der Normalwertdefinition. Allergologie, Jahrgang 2001; 24: 145–154.

93.

Barton

Hobson

Denton

, et al. Serologic diagnosis of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis through the detection of immunoglobulin G to Aspergillus fumigatus. Diagn Microbiol Infect Dis. 2008; 62: 287–291.

94.

Watkins

Benjamin

Kotze

, et al. Reference range for specific IgG antibodies to Aspergillus fumigatus in the South African adult population. Curr Allergy Clin Immunol. 2012; 25: 212–214.

95.

Fujiuchi

Fujita

Suzuki

, et al. Evaluation of a quantitative serological assay for diagnosing chronic pulmonary aspergillosis. J Clin Microbiol 2016; 54: 1496–1499.

96.

Al-Rahman

Al Kindi

Kutty

, et al. Determination of an Aspergillus fumigatus-specific immunoglobulin G reference range in an adult Omani population. Sultan Qaboos Univ Med J. 2018; 18: e43–e46.

97.

Huang

Chan

, et al. Diagnostic cut-off value for Aspergillus fumigatus- and flavus-specific IgG with clinical relevance in chronic pulmonary Aspergillus infection: a pilot study in Taiwan. Mycoses. 2020; 63: 1083–1093.

98.

Lee

Huang

Keng

, et al. Establishing Aspergillus-specific IgG cut-off level for chronic pulmonary aspergillosis diagnosis: multicenter prospective cohort study. J Fungi (Basel). 2021; 7: 480.

99.

Hsiao

Yen

, et al. Comparison of Aspergillus-specific antibody cut-offs for the diagnosis of aspergillosis. Front Microbiol. 2022; 13: 1060727.

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