He-Jie-Shen-Shi Decoction as an Adjuvant Therapy on Severe Coronavirus Disease 2019: A Retrospective Cohort and Potential Mechanistic Study

Abstract

Combination therapy using Western and traditional Chinese medicines has shown notable effects on coronavirus disease 2019 (COVID-19). The He-Jie-Shen-Shi decoction (HJSS), composed of Bupleurum chinense DC., Scutellaria baicalensis Georgi, Pinellia ternata (Thunb.) Makino, Glycyrrhiza uralensis Fisch. ex DC., and nine other herbs, has been used to treat severe COVID-19 in clinical practice. The aim of this study was to compare the clinical efficacies of HJSS combination therapy and Western monotherapy against severe COVID-19 and to study the potential action mechanism of HJSS. From February 2020 to March 2020, 81 patients with severe COVID-19 in Wuhan Tongji Hospital were selected for retrospective cohort study. Network pharmacology was conducted to predict the possible mechanism of HJSS on COVID-19-related acute respiratory distress syndrome (ARDS). Targets of active components in HJSS were screened using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and PharmMapper databases. The targets of COVID-19 and ARDS were obtained from GeneCards and Online Mendelian Inheritance in Man databases. The key targets of HJSS in COVID-19 and ARDS were obtained based on the protein-protein interaction network (PPI). Kyoto Encyclopedia of Genes and Genomes analysis (KEGG) was conducted to predict the pathways related to the targets of HJSS in COVID-19 and ARDS. A "herb-ingredient-target-pathway" network was established using Cytoscape 3.2.7. Results showed that the duration of the negative conversion time of nucleic acid was shorter in patients who received HJSS combination therapy. HJSS combination therapy also relieved fever in patients with severe COVID-19. Network pharmacology analysis identified interleukin (IL) 6, tumor necrosis factor (TNF), vascular endothelial growth factor A (VEGFA), catalase (CAT), mitogen-activated protein kinase (MAPK) 1, tumor protein p53 (TP53), CC-chemokine ligand (CCL2), MAPK3, prostaglandin-endoperoxide synthase 2 (PTGS2), and IL1B as the key targets of HJSS in COVID-19-related ARDS. KEGG analysis suggested that HJSS improved COVID-19-related ARDS by regulating hypoxia-inducible factor (HIF)-1, NOD-like receptor, TNF, T cell receptor, sphingolipid, PI3K-Akt, toll-like receptor, VEGF, FoxO, and MAPK signaling pathways. In conclusion, HJSS can be used as an adjuvant therapy on severe COVID-19. The therapeutic mechanisms may be involved in inhibiting viral replication, inflammatory response, and oxidative stress and alleviating lung injury. Further studies are required to confirm its clinical efficacies and action mechanisms.

Keywords: acute respiratory distress syndrome; coronavirus disease 2019; he-jie-shen-shi decoction; network pharmacology; retrospective cohort study.

FIGURE 1

Data collection of clinical efficacy study.

FIGURE 2

Absolute standardized differences comparing characteristics of patients in GT and HJSS + GT groups before matching and after 1:1 propensity score matching. The absolute standardized differences <0.1 show adequate matching. Y axis represented the selected characteristics. X axis of the scatterplot represented whether the status was before matching or after matching.

FIGURE 3

Chest CT scan before and after GT and HJSS treatment. Bilateral pulmonary infiltrate was clearly absorbed after GT and HJSS treatment. (A–D) represent different slices. GT group: A 66-year-old female received GT for 15 days. HJSS + GT group: A 59-year-old female received HJSS and GT for 12 days.

FIGURE 4

The number of active ingredients of each herb in HJSS obtained from TCMSP (OB ≥ 30%, DL ≥ 0.18).

FIGURE 5

After intersecting the targets of HJSS, COVID-19 and ARDS, 28 potential targets of HJSS on COVID-19-related ARDS were obtained (Venn diagram).

FIGURE 6

PPI network of 28 potential targets obtained from venn diagram. Nodes in red indicate more interactions with other targets, while nodes in yellow indicate less interactions with other targets.

FIGURE 7

KEGG pathway analysis of 28 potential targets. The size of bubbles indicates the numbers of associated genes, the larger bubble indicates more gene counts. Color coding scale indicates the significance of KEGG terms, the deeper red indicates lower p values [higher -log10 (p value)].

FIGURE 8

“Herb-ingredient-target-pathway” network of HJSS on COVID-19-related ARDS.