The current diagnosis and medicines approach in coronavirus disease 2019 (COVID-19) does not reflect the heterogeneous characteristics of this disease. This study aims to find a new antiviral combination regimen by investigating the frequency of clinically relevant and objectively identified comorbidities, and the clustering of these clinical syndromes and varying results of treatment with antiviral drugs in patients hospitalized with severe COVID-19. Methods: This study recruited 151 severe COVID-19 infection cases diagnosed in our hospital examination and illustrated the clinical potential during a consecutive 25-day medication period. Potential differences in disease severity and clinical characteristics, hematological profile, and current pharmacologic treatments (single agent, double or triple combinations, and the combined antiviral drugs plus Lianhua Qingwen) among comorbidity clusters were explored. Results: Although disease severity was comparable among three clusters, it was markedly different in terms of laboratory test status. Coagulable abnormality was mainly present in cluster 1 and cluster 2. Other indicators were normal, except for a significant increase of neutrophils presented in cluster 2. Patients showed the most complicated haematological results in cluster 3, including severe coagulation abnormalities, leukocytosis, neutrophilic granulocytosis, and lymphopenia. Our results for the first time suggest that a quadruple combination therapy (Ribavirin, Lopinavir/ritonavir, Umifenovir, and Lianhua Qingwen) can be considered as a preferred treatment approach to severe COVID-19 patients. After treatment, abnormal coagulation and leukocyte had markedly improved with a better prognosis. Conclusion: This study expands the understanding of the co-occurrence of combination therapy in patients with COVID-19, which provides the probability of developing novel combined therapy. Furthermore, explore clinical trials of variable antivirus treatments based on subgroup analyses or on using subgroups in the selection criteria would be the next step.

Highlights: The pernicious global impact of COVID-19 is still growing, no medications or vaccines have been verified for the treatment or prevention of COVID-19. Thymosin alpha-1 (Tα1) intervention has been recommended for adjuvant immunoregulation therapy in COVID-19 patients, but the efficiency and security of Tα1 cannot be determined due to the influence of many factors on curative effect. This work observed the efficiency and safety of thymosin-α1 treatment in patients with COVID-19 infection and identifies more characteristics and features of COVID-19. The present study represents the first examination of the relationship between gender and Tα1 treatment outcomes for a population with COVID-19 infection. A high degree of gender differences-related variability was observed in the C-reactive protein, procalcitonin and cell counts of many lymphocyte subpopulations levels in the COVID-19 patients after Tα1 intervention. The results suggest that gender differences may be a factor in sustaining COVID-19 immunity responded to Tα1, that clinical indicators of gender differences in Tα1 interventions must be closely monitored and treatment regimens adjusted accordingly. Our findings support the hypothesis that men and women show statistically significant differences in relevance to cytokine production associated with the development of a greater number of symptoms. Although an early cytokine response appears to be crucial to control infection, successful immunity may require a modest response that is maintained during therapy. We believed that this evidence may help in the precision treatment of COVID-19 patients in the clinical and deserves further exploration.

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Urine is the most appropriate body fluid for analysis because it is easily and less-invasively obtained than blood; thus, urinary miRNAs can better represent the local stage of the disease and might grow up to be a new class of noninvasive biomarkers of postmyocardial infarction (MI). Monofunctionalized Au nanoparticles (AuNPs) with only one selective DNA at a specific location are more promising in nanotechnology. This study developed a urinary miRNA ultratrace detection strategy based on single-target DNA-functionalized AuNPs for the noninvasive prognosis of post-MI. The AuNPs were designed with only single-stranded biotinylated DNA complementary to the target miRNA through a ratio-optimized stoichiometric method for the first time. Combined with the duplex specific nuclease-assisted target recycling amplification, the single-target DNA-functionalized AuNPs for the first time were used in inductively coupled plasma–mass spectrometry for the determination of urinary miRNA with high sensitivity. After optimizing the reaction conditions, a linear detection range between 1 fM and 10 pM for miR-155 and a detection limit of 0.47 fM were obtained. Finally, the target miR-155 in urine samples collected from MI rats was quantified and the level of miR-155 in MI groups was 30 times higher than in the control groups. The results suggest that urinary miR-155 could be a novel biomarker for the noninvasive diagnosis of MI.