Relevant Information on the Clinical Application of XBJI

Recommended Therapeutic Regimens
XBJI has been recommended in 20 therapeutic regimens of COVID-19 in China (see detailed information in  Tables 1  and  2 ).

Ingredients of XBJI
Carthamus tinctorius L. (Honghua), Paeonia lactiflora Pall. (Chishao), Conioselinum anthriscoides ‘Chuanxiong’ (Chuanxiong), Salvia miltiorrhiza Bunge (Danshen), and Angelica sinensis (Oliv.) Diels (Danggui). Basic information on XBJI is provided in the  Supplementary Table .

Indications for the Treatment of COVID-19 With XBJI
XBJI is used for syndrome of blood-stasis and toxins in the progressive stage of COVID-19 (critical case). Indicative symptoms are fever, dyspnea and tachypnea, palpitations, and dysphoria. It could also be used for treatment of infection-induced systemic inflammatory response syndrome and multiple-organ dysfunction syndrome in the stage of impaired organ function.

Progress of Pharmacological Research on XBJI
Modern pharmacological studies have shown that XBJI is anti-inflammatory, antioxidant, immune-regulatory, and protects against acute lung injury (see  Table 3 ).
Tiantian Li et al. found that in mice with MRSA-induced sepsis, XBJI protected the infected mice by downregulating expression of inflammatory cytokines stimulated by Pam3CSK4, MAPK, PI3K (phosphatidylinositol 3 kinase)/Akt and other pathways, thus, inhibiting the inflammatory response (Li T. T. et al., 2020). Shuwen Zhang et al. and Xi Chen et al. found that XBJI significantly reduced TNF-α, IL-6, and IL-10 levels in mice with sepsis, prevented neutrophil infiltration of lung and kidney, modulated T helper cell (Th) 1/Th2, Th17, and Tregs balance, reduced inflammatory response, and improved survival rate in mice with infectious shock (Zhang et al., 2006; Chen et al., 2018). Mingwei Liu et al. studied rats with paraquat-induced acute lung injury and discovered that XBJI could enhance immunity, reduce expression of inflammatory factors, and protect against acute lung injury by blocking p-38 MAPK and NF-κB p65 pathways, (Liu et al., 2014). Research by Yin Teng et al. found that XBJI in combination with conventional treatment significantly reduced interleukin-1 (IL-1), IL-6, and TNF-α levels, improved CD4+/CD8+ T lymphocyte ratio and NK cell relative activity, reduced inflammatory response, and enhanced cellular immunity in patients with severe pneumonia (Teng et al., 2012). Research by Hui Jin et al. showed that XBJI significantly improved the activity of superoxide dismutase (SOD), reduced reactive oxygen species (ROS) levels and protected against oxidative damage in mice under high-temperature stimulation (Jin et al., 2018). Research by Luo Peng et al. showed that XBJI downregulated MDA levels, upregulated SOD levels, and alleviated LPS-induced acute lung injury in rats (Luo and Zhou, 2017). In a rat model of oleic acid or LPS-induced acute lung injury, XBJI reduced TNF-α levels, alleviated pulmonary tissue edema and inflammatory cell infiltration, and protected against lung injury (Zhang et al., 2014). Research by Yuexia Ma et al. showed that although XBJI had no direct antiviral effect in mice with H1N1 severe pneumonia; it alleviated lung injury and protected against death, which might be due to its regulation of inflammatory cytokine levels in the early stage (Ma et al., 2015).

Clinical Research on XBJI
Modern clinical studies have shown that XBJI in combination with conventional treatment has therapeutic effects in relevant diseases, such as MERS, human infection with H7N9 avian influenza, CAP, severe pneumonia, systemic inflammatory response syndrome, COPD and sepsis (see  Table 3 ). XBJI has been recommended in MERS Diagnosis and Treatment Scheme (Version 2015) and Diagnosis and Treatment Scheme for Human Infection with H7N9 Avian Influenza (Version 1, 2017).
Clinical research by Wen Long et al. randomly divided 60 severe COVID-19 patients into routine treatment (n = 20), XBJI 50 ml (n = 20), and XBJI 100 ml (n = 20) groups. On the basis of conventional treatment, XBJI (50 ml) was injected twice a day for 7 days in the XBJI 50 ml group, or 100 ml twice a day for 7 days in the XBJI 100 ml group. After treatment, the white blood cell count (WBC) and lymphocyte count (LYM) of the three groups increased, while CRP and ESR decreased. Compared with the routine treatment group, the WBC count in the XBJI 100 ml group after treatment significantly increased (×109/L: 7.12 ± 0.55 vs. 5.67 ± 0.51, p < 0.05), and the levels of CRP and ESR in the XBJI 50 ml and 100 ml groups significantly decreased [CRP (mg/L): 32.3 ± 4.6, 28.0 ± 6.2 vs. 37.3 ± 5.9; ESR (mm/h): 45.9 ± 5.7, 40.5 ± 7.4 vs. 55.3 ± 6.6, all p < 0.05]. Compared with the XBJI 50 ml group, the increase of WBC, and the decrease of CRP and ESR were more significant in the XBJI 100 ml group [WBC (×109/L): 7.12 ± 0.55 vs. 5.82 ± 0.49; CRP (mg/L): 28.0 ± 6.2 vs. 32.3 ± 4.6; ESR (mm/h): 40.5 ± 7.4 vs. 45.9 ± 5.7, all p < 0.05]. The APACHE II score of three groups decreased. In the XBJI 100 ml group, the APACHE II score after treatment was significantly lower than those in the routine treatment and XBJI 50 ml groups (12.3 ± 1.5 vs. 16.5 ± 1.6, 15.9 ± 1.4, both p < 0.05). After treatment, the 2019-nCoV nucleic acid test in the three groups partly turned negative: nine cases in the routine treatment group, eight cases in the XBJI 50 ml group and nine cases in the XBJI 100 ml group, with no significant differences (p > 0.05). The conditions of patients in the three groups were improved after treatment. Eight cases in the routine treatment group were transformed into common type and one case into critical type; nine cases and 12 cases in the XBJI 50 ml and 100 ml groups, respectively, were transformed into the common type. Patients in the XBJI 100 ml group improved more obviously than in the XBJI 50 ml and routine treatment groups (both p < 0.05). The XBJI injection can effectively improve the inflammatory markers and prognosis of severe COVID-19 patients (Wen et al., 2020).
Clinical research by Qi Fei et al. showed that, of 80 patients with severe pneumonia, those receiving a combination of XBJI and conventional treatment exhibited reduced levels of blood LDH, α1-acid glycoprotein (α1-AG) and α1-antitrypsin (α1-AT). Body temperature was reduced significantly and secretion of TNF-α, IL-6, IL-8, and other cytokines was inhibited. The total treatment efficiency was up to 80%, compared to 67.5% in the control group (Qi et al., 2011). An RCT study comprised of 33 centers and 710 patients conducted by Yuanlin Song et al. showed that XBJI in combination with conventional treatment significantly improved the primary endpoint, pneumonia severity index, in patients with severe CAP (the control group vs XBJI Group, 46.33% vs 60.78%, p < 0.001). There was also significantly reduced mortality in 28 days (24.65% vs 15.87%, p = 0.006), the duration of mechanical ventilation was shortened (11 vs 16.5 d, p = 0.012) and length of stay in ICU was reduced (12 vs 16 d, p = 0.004) (Song et al., 2019). Mingjin Zhu et al. conducted a meta-analysis of 12 studies with a total of 860 patients and showed that XBJI in combination with conventional treatment was superior to the treatment group in improving total response rate in patients with severe pneumonia. Infectious indicators (WBC, CRP, CPIS) and inflammatory cytokine (IL-6, IL-8, TNF-α) levels were reduced, and the average length of stay in hospital was reduced (Zhu et al., 2014). Wei Zhao et al. studied 56 patients with systemic inflammatory response syndrome (SIRS) and found that after 7 d treatment with XBJI in combination with conventional treatment, body temperature, WBC, and acute physiology and chronic health evaluation II (APACHE-II) score improved more significantly compared to the control group (p < 0.05). Expression of CD4+, CD4+/CD8+, CD14+/HLA-DR (human leukocyte antigen-DR) increased significantly, and the combination regulated the SIRS immune state and improved systemic status of the patients (Zhao W. et al., 2014). Clinical research found that XBJI in combination with conventional treatment lowered TNF-α, CRP, and other inflammatory indicators in AECOPD patients and had a certain therapeutic effect. In patients with accompanying SIRS, the combination significantly improved cough, expectoration, shortness of breath, and other clinical symptoms, and shortened hospital stay (Chen et al., 2011; Zhu et al., 2019). Meta-analysis by Chengyu Li et al. included sepsis patients from 16 RCTs (total 1,144 cases), and evidence of moderate intensity showed that XBJI in combination with conventional treatment effectively reduced the mortality rate of sepsis patients over 28 d (934/1144, p < 0.00001), APACHE-II score (792/1144, p < 0.00001) and body temperature (362/1144, p < 0.00001) (Li et al., 2018).

Usage and Dosage of XBJI
Intravenous injection. 1) Systemic inflammatory response syndrome: 50 ml plus 100 ml 0.9% sodium chloride injection for intravenous drip, completed in 30–40 min, twice a day. Three times a day for severe patients. 2) Multiple-organ dysfunction syndrome: 100 ml plus 100 ml 0.9% sodium chloride injection for intravenous drip, completed in 30–40 min, twice a day. Three or four times a day for severe patients.

Adverse Reactions of XBJI
Allergic reactions: skin flush, rash, itching, palpitations, cyanosis, laryngeal edema, allergic shock, etc. Cardiovascular system: palpitations, cyanosis, increase, or decrease of blood pressure, arrhythmia. Nervous system: dizziness, headache. Respiratory system: difficulty breathing, chest distress, labored breathing, shortness of breath, and cough. Digestive system: nausea, vomiting, stomach ache, diarrhea, and abnormal liver function. Others: facial edema, conjunctival congestion, abnormal tears, phlebitis, lumbago, backache, and local numbness.

XBJI Precautions
1) Not for use in pregnant women and children under 14 (inclusive) years of age. 2) The product must not be mixed with others, and must be used with caution in combination with others. When used in combination with other drugs, 50 ml 0.9% sodium chloride injection must be used between doses. 3) Allergic history, family allergic history and patient history of medications should be queried before administration. 4) During administration, special attention should be given to the initial 30 min of intravenous drip. In case of abnormality, the drug should be discontinued immediately and symptomatic treatment administered. 5) Monitoring of administration should be enhanced in older patients and in patients receiving TCM injection for the first time.