Abstract
Despite available diagnostic tests and recent advances, diagnosis of pulmonary invasive aspergillosis (IPA) remains challenging. We performed a longitudinal case-control pilot study to identify host-specific, novel, and immune-relevant molecular candidates indicating IPA in patients post allogeneic stem cell transplantation (alloSCT). Supported by differential gene expression analysis of six relevant in vitro studies, we conducted RNA sequencing of three alloSCT patients categorized as probable IPA cases and their matched controls without Aspergillus infection (66 samples in total). We additionally performed immunoassay analysis for all patient samples to gain a multi-omics perspective. Profiling analysis suggested LGALS2, MMP1, IL-8, and caspase-3 as potential host molecular candidates indicating IPA in investigated alloSCT patients. MMP1, IL-8, and caspase-3 were evaluated further in alloSCT patients for their potential to differentiate possible IPA cases and patients suffering from COVID-19-associated pulmonary aspergillosis (CAPA) and appropriate control patients. Possible IPA cases showed differences in IL-8 and caspase-3 serum levels compared with matched controls. Furthermore, we observed significant differences in IL-8 and caspase-3 levels among CAPA patients compared with control patients. With our conceptual work, we demonstrate the potential value of considering the human immune response during Aspergillus infection to identify immune-relevant molecular candidates indicating IPA in alloSCT patients. These human host candidates together with already established fungal biomarkers might improve the accuracy of IPA diagnostic tools.
Highlights
Invasive pulmonary aspergillosis (IPA) is often associated with a high mortality rate as a result of late diagnosis due to frequent, nonspecific symptoms and the limitations of currently used diagnostic tools including fungal biomarkers
We report a characteristic signature (LGALS2-MMP1-Caspase-3) identified by an integrated approach based on differential gene expression analysis of seven relevant gene expression datasets, combined with transcriptome and protein profiling of three selected IPA cases and their three matched controls with no evidence of Aspergillus infection
Protein levels of potential molecular candidates indicating IPA in the investigated allogeneic stem cell transplantation (alloSCT) patients were assessed in an independent cohort consisting of COVID-19 patients suffering from aspergillosis as a secondary indicating IPA in the investigated alloSCT patients were assessed in an independent cohort infection
Summary
Invasive pulmonary aspergillosis (IPA) is often associated with a high mortality rate as a result of late diagnosis due to frequent, nonspecific symptoms and the limitations of currently used diagnostic tools including fungal biomarkers. Diagnosis of IPA is based on the integration of radiological, clinical, and microbiological data [1]. Detection of the cell wall component galactomannan with a commercially available enzyme-linked immunosorbent assay (ELISA) and detection of Aspergillus-specific DNA by polymerase chain reaction (PCR) are essential tools for IPA diagnosis [1,2,3]. Despite these advances and different available assays, diagnostic tools for identifying IPA provide variable sensitivity and specificity. Given the frequency that these cases are encountered in the clinic, there is a clear need for an unambiguous diagnosis of aspergillosis
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