Dynamic changes in the respiratory tract and gut antibiotic resistome of patients with COVID-19 and its association with disease severity (preprint)

Background The antibiotic resistome is the collection of all the antibiotic resistance genes (ARGs) present in an individual. Whether an individual’s susceptibility to infection and the eventual severity of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is influenced by their respiratory tract antibiotic resistome is unknown. Additional, whether a relationship exists between the respiratory tract and gut antibiotic resistance genes composition has not been fully explored. Method We recruited 66 patients with COVID-19 at three disease stages (admission, progression and recovery) and conducted a metagenome sequencing analysis of 143 sputum and 97 fecal samples obtained from them. Respiratory tract, gut metagenomes, and peripheral blood mononuclear cell (PBMC) transcriptomes are analyzed to compare the gut and respiratory tract ARGs of intensive care unit (ICU) and non-ICU (nICU) patients and determine relationships between ARGs and immune response. Results Among the respiratory tract ARGs, we found that Aminoglycoside, Multidrugand Vancomycin are increased in ICU patients compared with nICU patients. In the gut, we found that Multidrug, Vancomycin and Fosmidomycinwere increased in ICU patients. Upon further investigation a significantly positive correlation was found between the relative abundance in ARGs (i.e., subtypes of the Aminoglycoside and Tetracyclinetypes) in the respiratory tract and gut. We discovered that the relative abundances of Multidrug were significantly correlated with clinical indices, and there was a significantly positive correlation between ARGs and microbiota in respiratory tract and gut. We found that immune related pathways in PBMC were enhanced, and they were significantly correlated with the relative abundance of Multidrug, Vancomycin and Tetracycline ARGs. Based on the relative abundance of ARG types, we built a respiratory tract-gut ARG combined random-forest classifier to distinguish ICU COVID-19 patients from nICU patients with an AUC of 0.969. The level of Aminoglycoside and Vancomycinin the gut was regarded as the most prominent biomarker. Conclusions Cumulatively, our findings provide some of the first insights into the dynamic alterations of respiratory tract and gut antibiotic resistome in the progression of COVID-19 and disease severity. They also provide a better understanding of how this disease affects different cohorts of patients. As such, these findings should contribute to better diagnosis and treatment scenarios.

Serum Level of Testosterone Predicts Disease Severity of Male COVID-19 Patients and is Related to T-Cell Immune Modulation by Transcriptome Analysis (preprint)

Background: Severe disease of COVID-19 and mortality occur more frequently in male patients than that in female patients may be related to higher level of testosterone. However, the diagnostic value of changes in the level of testosterone in predicting severe disease of male COVID-19 patients has not been determined yet.Methods: Sixty-one male COVID-19 patients admitted to the First Affiliated Hospital of Zhejiang University School of Medicine were enrolled. Serum samples at different stages of the patients after admission were collected and testosterone levels were detected to analyze the correlation between testosterone level and disease severity. Transcriptome analysis of PBMC was performed in 34 patients.Results: Testosterone levels at admission in male COVID-19 patients (4.7 nmol/L, IQR: 2.7~7.7 nmol/L) were significantly lower than those in healthy controls (19.5 nmol/L, IQR: 14.9~22.5). Testosterone levels in the non-ICU group increased gradually during the progression of the disease, while those in the ICU group remained low. In addition, testosterone level of enrolled patients in the second week after onset was significantly correlated with the severity of pneumonia, and ROC curve showed that testosterone level in the second week after onset was highly effective in predicting the severity of COVID-19. Transcriptome studies have found that testosterone levels of COVID-19 patients were associated with immune response, including T cell activation and regulation of lymphocyte activation. In addition, CD28 and Inositol Polyphosphate-4-Phosphatase Type II B (INPP4B) were found positively correlated with testosterone.Conclusions: Serum testosterone is an independent risk factor for predicting the severity of COVID-19 in male patients, and the level of serum testosterone in the second week after onset is valuable for evaluating the severity of COVID-19. Testosterone level is associated with T cell immune activation. The monitoring of serum testosterone should be highlighted in clinical treatment and the related mechanism should be further studied.Funding Information: This work was supported by the the National Natural Science Foundation of China (grant numbers 82072377 and 81971919). Declaration of Interests: All authors: No reported conflicts.Ethics Approval Statement: This study conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Institutional Review Board of the First Affiliated Hospital of Zhejiang University School of Medicine (IIT20210227A).