Comparative analysis of the clarus Aspergillus Galactomannan Enzyme Immunoassay for the Diagnosis of Invasive Pulmonary Aspergillosis in Bronchoalveolar Lavage Fluid

doi:10.21203/rs.3.rs-4275634/v1

Background: Galactomannan (GM) testing using Platelia Aspergillus enzyme immunoassay (Platelia GM) from bronchoalveolar lavage fluid (BALF) aids in early diagnosis of invasive pulmonary aspergillosis (IPA). Globally, only a minority of laboratories have the capability to perform on-site GM testing, necessitating accessible and affordable alternatives. Hence, we conducted a comparative evaluation of the new clarus Aspergillus GM enzyme immunoassay (clarus GM) with Platelia GM using BALF samples.

Methods: This is a single-center, prospective, cross-sectional study, where Platelia GM testing was routinely performed followed by clarus GM testing in those with true positive or true negative GM test results according to the 2020 EORTC/MSG and the 2024 FUNDICU consensus definitions. Descriptive statistics, ROC curve analysis, and Spearman’s correlation analysis were used to evaluate analytical performance of the clarus GM assay.

Results: This study enrolled 259 adult patients, of which 53 (20%) were classified as probable IPA, while 206 did not fulfill IPA criteria. Spearman's correlation analysis revealed a strong correlation between the two assays (rho = 0.727, p < 0.001). The clarus GM had a sensitivity of 96% (51/53) and a specificity of 74% (153/206) for differentiating probable versus no IPA when using the manufacturer recommended cut-off. ROC curve analysis showed an AUC of 0.936 (95% CI: 0.901-0.971) for the clarus GM, while the Platelia GM yielded an AUC of 0.918 (95% CI: 0.876-0.959).

Conclusions: Clarus GM demonstrated a strong correlation and promising test performance, comparable to Platelia GM, rendering it a viable alternative in patients at risk of IPA.

invasive pulmonary aspergillosis

galactomannan

BALF

enzyme-linked immunoassay

diagnostics

Invasive aspergillosis is a severe fungal infection caused by Aspergillus spp., with potential life-threatening consequences. Annually, over 2 million people develop invasive aspergillosis, with several hundreds of million individuals considered to live with risk factors for IPA (1-3). Invasive pulmonary aspergillosis (IPA) is the most prevalent manifestation of Aspergillus associated diseases (3), primarily triggered by the inhalation of Aspergillus spores. Aspergillus fumigatus is by far the dominant Aspergillus species causing bronchopulmonary disease in humans (4, 5). With mortality rates ranging from 30% to 60%, IPA predominantly affects immunocompromised individuals, including those with hematological or solid organ malignancies, hematopoietic stem-cell transplant recipients, solid organ transplant recipients, and those experiencing prolonged neutropenia (6, 7). Moreover, IPA can manifest in patients with chronic obstructive pulmonary disease and individuals with substantial corticosteroid exposure (8, 9). Notably, there is an increasing incidence of IPA in intensive care units with severe respiratory viral infections, such as influenza, and more recently, coronavirus disease 2019 (10-12).

Timely and accurate diagnosis of IPA, followed by prompt treatment initiation, is crucial for survival (13, 14). However, early diagnosis remains challenging due to the absence of specific clinical and radiological signs, necessitating additional mycologic diagnostics (15, 16). These include fungal culture from sterile site samples and respiratory specimens (primarily from bronchoalveolar lavage fluid [BALF]), the identification of fungal biomarkers, polymerase chain reaction (PCR)-based techniques and, ideally, histopathological examination of infected tissue. All these modalities come along with certain limitations in terms of diagnostic performance and hard turn-around-times (TATs). The most widely used biomarker for diagnosing IA is galactomannan antigen (GM-Ag), which is typically tested with the Platelia Aspergillus enzyme immunoassay (Platelia GM) (17). The European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) consensus definitions include the detection of Aspergillus GM-Ag from BALF samples as a criterion to establish the diagnosis of probable IPA (18). Despite the effectiveness of GM-Ag testing in BALF, only a minority of laboratories has the option to perform on-site Platelia GM testing (19-22). While more cost-effective tests, including the Euroimmun GM Enzyme Immunoassay (23) as well as point of care tests for GM-Ag or GM-like antigens like the Aspergillus LFA and LFD (24-26), have been shown to be reliable alternatives to the Platelia GM, more alternatives are needed to ensure competitive pricing of the assays. This emphasizes the need for more accessible and cost-effective alternatives to aid in the diagnosis of IPA.

The clarus Aspergillus GM Enzyme Immunoassay (clarus GM (Ref AGM101), IMMY, Norman, Oklahoma) is an IVD-certified sandwich enzyme-linked immunosorbent assay that has been validated for qualitative detection of Aspergillus GM-Ag in BALF samples. In this single-center, prospective, cross-sectional study, the primary objective was to evaluate and compare the analytic performance of the novel clarus GM assay in comparison to the established Platelia GM (Bio-Rad, Marnes-la-Cocquette, France) assay.

A total of 259 BALF samples were collected prospectively from a cohort of 259 patients undergoing bronchoscopy at the Medical University of Graz, Austria, between May 2023 and November 2023. The predefined number of cases (=true GM positives) and controls (=true GM negatives) was 50 and 200, respectively. Thus, the first 50 cases and 200 controls that occurred within the observational period were included in the study.

IPA classifications was performed according to the 2020 EORTC/MSG consensus definitions, as well as the recently published 2024 FUNDICU consensus criteria (18, 27). Cases fulfilling criteria for probable IPA according to EORTC/MSG and/or FUNDICU were considered probable cases for statistical purposes. All samples included in the study were tested for presence of fungi and fungal antigens as part of the routine work-up before being stored at -20°C until subsequent testing by the clarus GM. For extended storage (> four weeks), samples were kept at -80°C until further testing. Collected samples were tested using the clarus GM, within four weeks of the last Platelia GM, following the manufacturer's recommendations (19). In case clarus GM testing was performed four weeks after the routine GM testing by the Platelia GM assay, the Platelia GM test was repeated.

For the clarus GM testing procedure, 100 µl of pre-treatment buffer (4% EDTA solution; 0.2% ProClin) was mixed with 300 µl of each sample and heated in a dry heat block (Grant QBD2, Grant Instruments, Amsterdam, NL) at 120°C for 7 minutes (acceptable range 6 - 8 minutes). After centrifugation at 14,000xg (acceptable range from 10,000 - 14,000 x g) for 5 minutes, 100 µl of each sample was transferred to a microtiter plate, sealed, and incubated at 37°C for 60 minutes. The plate was then washed five times with 300 µl of 1x wash buffer (20x Enzyme Immunoassay wash buffer; contains 0.4% Tween20, 0.2% ProClin) using an automated miroplate washer (HydroFlex microplate washer, TECAN Grödig, Austria), tapping to remove excess buffer. Conjugate (100 µl) was added to each well, sealed, and incubated at 37°C for 60 minutes, followed by another round of washing. Substrate (Tetramethylbenzidine, 100 µl) was added, and after a 30-minute incubation at 37°C, stop solution (<5% methanesulfonic acid, 100 µl) was added to each well. The plate was gently shaken to ensure homogeneous solution distribution, and absorbance was measured at 450 nm and 620/630 nm using a two-wavelength microplate reader (Sunrise microplate reader with Magelan 7.2 sofware, TECAN Grödig, Austria) within 15 minutes after adding stop solution. Corrected optical density values were calculated, and Enzyme Immunoassay units were determined.

The ethical committee of the Medical University of Graz (35-204 ex 22/23) approved the study protocol and all study related procedures. All procedures were performed according to the Declaration of Helsinki. Statistical analyses were performed using IBM SPSS Statistics Version 29 (SPSS Inc., Chicago, IL, USA). Sensitivity and specificity for IPA, defined by criteria for probable versus no IPA, were determined using 2x2 tables. Calculations were based on manufacturer-recommended positivity cutoffs: ≥0.2 optical density index (ODI) for clarus GM and ≥1 ODI for BALF for Platelia GM. Additionally, an assessment for Platelia GM was conducted using a cutoff of ≥0.5 ODI. Receiver operating characteristic (ROC) curve analyses were performed for Platelia GM and clarus GM with area under the curve (AUC) values and 95% confidence intervals (CI) calculated for the outcomes of probable IPA versus no IPA in the study cohort. To minimize confounding factors, additional analysis (sensitivity, specificity, AUCs for both assays) was carried out by reclassifying probable IPA vs. no IPA after excluding GM as a mycological criterion. Optimal cutoff values for clarus GM were determined using Youden’s index. Fisher's Exact and Chi-square tests were employed as appropriate to compare sensitivities and specificities. The significance of the AUC was compared using the Hanley & McNeil method. A two-sided p-value of 0.05 was considered as the threshold for statistical significance.

Baseline characteristics

Out of 259 samples obtained, 20% (53/259) were classified as probable IPA according to 2020 EORTC/MSG criteria and 2024 FUNDICU criteria, while the remaining 80% (206/259) were classified as having no IPA. No patient fulfilled the criteria for proven IPA. Demographic breakdown of the patients included 149/259 females (58%) and 110/259 males (42%), with a median age of 65 years, ranging from 20 to 89 years (Table 1). Nine percent (22/259) had hematological diseases, 1% (3/259) were SOT recipients, 30% (77/259) required ICU admission, 29% (75/259) had solid organ malignancies and 31% (82/259) presented with other underlying conditions. Among all samples, 9% (22/259) were collected from patients with ongoing mold-active antifungal prophylaxis at time of BALF sampling.

Table 1 Study cohort characteristics for BALF samples

Baseline characteristics for BALF samples

Probable IPA

(n=53)

No IPA

(n=206)

Total (n=259)

Sex, n (%)

Female
Male

20 (38%)

33 (62%)

90 (44%)

116 (56%)

149 (58%)

110 (42%)

Median age in years (range)

66 (23-82)

65 (20-89)

Underlying diseases/conditions, n (%)

Hematological malignancy

Solid organ transplantation

Need for intensive care treatment

Solid organ malignancy

Other

3 (6%)

2 (4%)

24 (45%)

13 (25%)

11 (21%)

19 (9%)

1 (1%)

53 (26%)

62 (30%)

71 (35%)

22 (9%)

3 (1%)

77 (30%)

75 (29%)

82 (31%)

Antifungal prophylaxis at time of sampling, n (%)

13 (25%)

9 (4%)

22 (9%)

Mycological test results from BALF, n (%)

Aspergillus growth in BALF culture

Aspergillus spp. BALF PCR^§

GM ≥0.5 ODI Platelia

GM ≥1.0 ODI Platelia

GM ≥0.20 ODI clarus

14 (26%)

2/6 (33%)

49 (92 %)

45 (85%)

51 (96%)

13 (6%)

1/47 (2%)

51 (25%)

19 (9%)

53 (26%)

27 (10%)

3/53 (6%)

100 (39%)

64 (25%)

104 (40%)

Abbreviations: GM= Galactomannan; BALF = bronchoalveolar lavage fluid; IPA = invasive pulmonary aspergillosis; PCR = polymerase chain reaction; ODI= optical density index

§ AsperGenius (PathoNostics, Maastricht, The Netherlands)

Analytic performances

Spearman's correlation analysis demonstrated a strong positive correlation between the clarus GM and Platelia GM results (rho = 0. 727, p < 0.001) (Figure 1) in the overall study cohort.

When distinguishing between probable IPA and no IPA, the clarus GM performance (Table 2) with the manufacturer-recommended cutoff of ≥0.20 ODI achieved a sensitivity of 96% (51/53) and a specificity of 74% (153/206). Optimizing diagnostic discriminatory power using Youden’s index resulted in a cutoff value of ≥0.26 ODI for clarus GM. With this adjustment, sensitivity remained 96% (51/53), while specificity increased to 81% (167/206). The specificity of clarus GM with ≥0.26 ODI was significantly lower compared to Platelia GM with ≥1.0 ODI (p=0.003), while the difference in sensitivity was not statistically significant (p=0.09).

For the Platelia GM comparator test (used for IPA classification), sensitivity was 85% (45/53) and specificity was 91% (188/206) when utilizing a cutoff of ≥1.0 ODI, while sensitivity was 92% (49/53) and specificity was 75% (155/206) when using the ≥0.5 ODI cutoff.

When combining clarus GM ≥0.26 with Platelia GM ≥1.0, test performance sensitivity remained unchanged with 96% (51/53) with either/or both tests resulting positive, while specificity increased to 94% (194/206) when positive results of both tests were required.

ROC curve analysis demonstrated an AUC of 0.936 (95% CI of 0.901-0.971) for clarus GM and 0.918 (95% CI of 0.876-0.959) for the Platelia GM assay (Figure 2a).

Nine percent (22/259) of the samples were obtained from patients undergoing mold-active antifungal prophylaxis. Among these, 13 had probable IPA. Using for clarus GM a cutoff value of ≥0.2 ODI, the sensitivity was 92% (12/13), with a specificity of 56% (5/9). Increasing the cutoff value to ≥0.26 ODI maintained the sensitivity at 92%, while the specificity increased to 67% (6/9). The AUC for clarus GM was numerically but not significantly lower with antifungal prophylaxis (0.863 (95% CI: 0.711 – 1) compared to patients without prophylaxis 0.951 (95% CI: 0.920 – 0.981; p=0.27). The AUC for the Platelia GM in patients with ongoing mold-active antifungals was 0.940 (95%CI 0.835 – 1), and not significantly different from the performance of the clarus GM in this cohort (p=0.42).

When classifying probable IPA vs. no IPA based solely on Aspergillus culture and PCR (Table 2), only 19/53 probable IPA cases remained probable IPA cases. The AUCs for Platelia GM and clarus GM were 0.948 (95% CI: 0.882-1) and 0.945 (95% CI: 0.884-1), respectively (Figure 2b).

The Platelia GM had a sensitivity of 93% (14/15) and a specificity of 92% (190/206) at a cutoff value of ODI ≥1.0. Lowering the cutoff to ≥0.5 ODI maintained sensitivity at 93% (14/15), with specificity decreasing to 76% (157/206). At the manufacturer-recommended cutoff of ODI ≥0.2, the clarus GM had a sensitivity of 93% (14/15) and specificity of 74% (152/206). Using the calculated optimal cutoff of ODI ≥0.26, sensitivity remained 93% (14/15), while specificity increased to 81% (167/206).

Table 2 Sensitivity and specificity comparison of Platelia GM and clarus GM for diagnosing probable IPA in BALF, with and without Platelia GM test results as a mycological criterion

Probable IPA vs. no IPA classification
	Sensitivity (n=53)	Specificity (n=206)
GM ≥0.2 ODI Clarus	96% (51)	74 % (153)
GM ≥0.26 corrected ODI Clarus	96% (51)	81% (167)
GM ≥0.5 ODI Platelia	92% (49)	75% (155)
GM ≥1.0 ODI Platelia	85% (45)	91% (188)
Probable IPA vs. no IPA classification after exclusion of GM as mycological criterion
	Sensitivity (n=15)	Specificity (n=206)
GM ≥0.2 ODI Clarus	93% (14)	74 % (152)
GM ≥0.26 ODI Clarus	93% (14)	81% (167)
GM ≥0.5 ODI Platelia	93% (14)	76% (157)
GM ≥1.0 ODI Platelia	93% (14)	92% (190)
Abbreviations: GM= Galactomannan; BALF = bronchoalveolar lavage fluid; IPA = invasive pulmonary aspergillosis; ODI= optical density index

In this study, we compared the clarus GM assay with the Platelia GM assay in BALF samples in a prospective enriched patient cohort. Findings revealed a strong correlation between the two assays, with clarus GM demonstrating comparable sensitivity and specificity to Platelia GM. Notably, clarus GM showed promising diagnostic accuracy, suggesting its potential as an accessible and affordable alternative for early detection of IPA.

Here, we conducted a comparative analysis of the clarus GM performed on BALF samples, in relation to the validated Platelia GM. The clarus GM assay utilizes a monoclonal antibody targeting a proprietary mix of two different antibodies: the ME-A5 human immunoglobulin G monoclonal antibody (mouse derived), and an undisclosed proprietary antibody with an unreleased GM-Ag target (28). On the other hand, the Platelia GM assay employs the rat monoclonal immunoglobulin M antibody EB-A2, specifically directed against Aspergillus GM-Ag(29).It is worth noting that different antigens may dominate in different stages of IPA, as indicated in previous studies (30). Therefore, tests targeting different antigens may have their advantages and disadvantages at different stages of the disease. This also explains why, despite an overall strong correlation, Platelia GM and clarus GM results differed in some cases, as they may recognize similar but not identical antigens. The challenge of immunological assays lies in the variability of antibodies. Consequently, consideration of the antibody's species of origin becomes imperative, as it can significantly impact the test's specificity and sensitivity. A combination of tests might be beneficial in capturing the complexities of IPA progression, as shown in our cohort where sensitivity and specificity could be increased by using different combination scenarios.

We observed a strong correlation between the clarus GM and the Platelia GM test results, indicating that the clarus GM exhibits similar reliability as the Platelia GM for the detection of GM. This particularly noteworthy as the diagnosis of IPA was initially established using the Platelia GM assay. The clarus GM yielded a trend towards a higher sensitivity (96% vs. 85%) while specificity was markedly lower (74% vs 91%) for differentiating between probable IPA vs no IPA versus Platelia GM with cutoff of ≥1.0 ODI. Using a cutoff of ODI≥0.26 identified by Youden´s index, specificity of the clarus GM increased to 81% with preserved sensitivity. These findings are comparable with data of a systematic review evaluating the value of BALF-GM in the diagnosis of IPA in hematological patients, which found a pooled sensitivity of 82% (70%-91%) and a specificity of 92% (85%-96%) (31).

The preselection of true positive and true negative samples was based on clinical classification, informed in part by Platelia GM test results. To further investigate the diagnostic performance of both the Platelia GM and the clarus GM assays, we performed a subanalysis excluding GM-Ag results as a mycological criterion for clinical classification. In this subanalysis, where Aspergillus culture and PCR were exclusively used as mycological evidence for the classification of IPA, the diagnostic performance of both assays in discriminating between probable IPA and non-IPA cases remained robust. Notably, in this subanalysis, both the Clarus GM and Platelia GM showed a sensitivity of 93%, with Clarus exhibiting 81% specificity at ≥0.26 ODI cutoff and Platelia showing 92% specificity at ≥1.0 ODI cutoff.

Our study has several limitations. First, caution is warranted when interpreting clinical performance data and AUC values due to the study design involving a cohort enriched with IPA cases that mostly also had positive Platelia GM test results, which correlated strongly with the results of the clarus GM test. As the results of the Platelia GM were used in the classification of most IPA cases, its performance may be overestimated.

In conclusion, our study indicates that the clarus GM could serve as a viable alternative in GM-Ag testing of BALF samples of patients at risk of IPA. As our study suggests a cutoff of an ODI ≥0.26 potentially leading to an increased specificity by preserved sensitivity, more studies are needed to exploit the full potential of this test. On a global scale, there is a pressing need for more widely accessible and dependable antigen-based assays to enhance our diagnostic capabilities for IPA.

Acknowledgements

Funding

This study was funded by an Investigator-Sponsored Research Grant with IMMY, titled ’’Evaluation of the IMMY Aspergillus Galactomannan Enzyme Immunoassay and its ability to detect Aspergillus in Serum and Bronchoalveolar Lavage Fluid from patients at risk for invasive aspergillosis (IMMY-AGM)’’.

The manufacturers had no role in the study design, data collection, analysis, interpretation, decision to publish, writing of the manuscript, or decision to submit the manuscript for publication.

Conflicts of Interest

M.H. received research funding from Gilead, Astellas, MSD, IMMY, Pulmocide, Shionogi, Melinta, Mundipharma, Scynexis, F2G and Pfizer. J.P. holds the position of President at the Austrian Society of Medical Mycology, received speaker fees from Gilead, Pfizer, Swedish Orphan BioVitrum, Associates of Cape Cod and is stockholder of AbbVie Inc. and Novo Nordisk – all outside of the submitted work. K.D. received research funding from Euroimmun Medizinische Labordiagnostika and FUJUFILM Wako Chemicals Europe outside of the submitted work.

All other authors declare no conflict of interest for this study.

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Comparative analysis of the clarus Aspergillus Galactomannan Enzyme Immunoassay for the Diagnosis of Invasive Pulmonary Aspergillosis in Bronchoalveolar Lavage Fluid

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Abstract

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Introduction

Material and Methods

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Supplementary Files

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