Digestive enzymes of fungal origin as a relevant cause of false positive Aspergillus antigen testing in intensive care unit patients

Abstract

Background Galactomannan antigen (GM) testing is widely used in the diagnosis of invasive aspergillosis (IA). Digestive enzymes play an important role in enzyme substitution therapy in exocrine pancreatic insufficiency. As digestive enzymes of fungal origin like Nortase contain enzymes from Aspergillus, a false-positive result of the test might be possible because of cross-reacting antigens of the cell wall of the producing fungi. We, therefore, asked whether the administration of fungal enzymes is a relevant cause of false-positive GM antigen test results. Methods Patients with a positive GM antigen test between January 2016 and April 2020 were included in the evaluation and divided into two groups: group 1-Nortase-therapy, group 2-no Nortase-therapy. In addition, dissolved Nortase samples were analyzed in vitro for GM and β-1,3-D-glucan. For statistical analysis, the chi-squared and Mann-Whitney U tests were used. Results Sixty-five patients were included in this evaluation (30 patients receiving Nortase and 35 patients not receiving Nortase). The overall false positivity rate of GM testing was 43.1%. Notably, false-positive results were detected significantly more often in the Nortase group (73.3%) than in the control group (17.1%, p < 0.001). While the positive predictive value of GM testing was 0.83 in the control group, there was a dramatic decline to 0.27 in the Nortase group. In vitro analysis proved that the Nortase enzyme preparation was highly positive for the fungal antigens GM and β-1,3-D-glucan. Conclusions Our data demonstrate that the administration of digestive enzymes of fungal origin like Nortase leads to a significantly higher rate of false-positive GM test results compared to that in patients without digestive enzyme treatment. Keywords Invasive aspergillosis • Critical illness • Galactomannan antigen assay • False positive results • Nortase • Digestive enzymes of fungal origin Abbreviations BAL Bronchoalveolar lavage BDG (1,3)-Beta-D-glucan CT Computed tomography DEFO Digestive enzymes of fungal origin ELISA Enzyme-linked immunosorbent assay GM Galactomannan IA Invasive aspergillosis ICU Intensive care unit PPV Positive predictive value

Clinical Value of sTREM-1, PCT, and 1,3-β-D Glucan in Diagnosis of Immune-Associated Pulmonary Interstitial Disease with Fungal Infection

“…The following are the inclusion criteria: (1) diagnostic criteria for connective tissue diseases refer to CTD diagnostic criteria developed by the American College of Rheumatology [ 11 ] and patients with interstitial lung disease confirmed by high resolution CT (HRCT) examination. (2) Patients aged 18–79 years old.…”

An invasive infection caused by the thermophilic mold Talaromyces thermophilus

“…The administered capsulated drug, i.e., Nortase® contains a mixture of lipase, amylase, and protease produced by Rhizopus oryzae and A. oryzae. Very recently, a dramatic increase of false-positive GM-results in patients receiving Nortase® was reported with 75% of treated individuals testing positive for GM [10]. A whole range of fungi is employed in the industrial production of intravenous drugs, so that GM contamination has been observed repeatedly: examples also include the β-lactam antibiotics piperacillin and meropenem as well as the antifungal agent caspofungin [37,38].…”

“…Therefore, powder diluted in 20 mL of water was tested and yielded a strongly positive reaction in the GM ELISA (Platelia Aspergillus GM ELISA, Bio-Rad Laboratories, Hercules, CA, USA). Upon this result, amphotericin B was discontinued, as antigenemia was considered to be a result of Nortase® administration [10].…”