Treatment of Herpangina Patients with Xiyanping Injection:A Retrospective Study Based on the Hospital Electronic Medical Record System

Background: Although we have made tremendous medical advances in recent decades in vaccine and supportive therapies, the treatment of herpangina has not experienced such rapid advancement. Xiyanping injection(XYP) is a Chinese prescription with andrographolide as the main components.XYP shows strong inhibitory effects against enterovirus 71 virus,and existence of dose-response relationships in pharmacology studies.However, herpangina still lack specific therapeutics.The present study aimed to demonstrate the “real-world” experiences of herpangina in China using XYP therapy,to provide a basis for treatment of herpangina in children. Methods: We analyzed data of patients (≤70 years) diagnosed with herpangina and used XYP between October 2006 to October 2016 from the large electronic data warehouse (EDW), a multiple sources including hospital information system （ HIS ） data of “tertiary grade A hospitals” in China. Statistical analyses were performed by SAS9.2 and R.25 software.We present the following article in accordance with the STROBE Statement reporting checklist. Results: A total of 3423 patients of herpangina were retrieved for the analysis in this study.The mean age of the patient population was 2.66 years.Herpangina patients are often with multiple diagnosis, of which hand-foot-and-mouth disease(HFMD), bronchopneumonia and febrile seizure present a higher probability. Antibiotics were the most prescribed (17.61%) except for XYP, followed by ascorbate (10.40%). Conclusions: This study is the first comprehensive retrospective review of herpangina for XYP that has been used in a medication use of herpangina were basically in accordance with Expert Consensus of Herpangina in China(2019).Meanwhile,there are abuse problems of antibiotics and antivirals.Despite the underlying mechanisms in antibacterial and antiviral of XYP, the exact clinical efficacy is yet to be revealed.The efficacy and safety of XYP with Western medicines has not been studied.


Introduction
Herpangina is one of the multimorbidity and Common Diseases of the Pediatrics,which is a special type of upper respiratory infections.Herpangina caused by enterovirus(EVs) and coxsackievirus presenting as fever,sore throat,oropharyngeal herpes and superficial ulcers [1].Most herpangina patients have mild symptoms,but some may occur serious complications,even fatal [2][3].
Xiyanping injection(XYP),with andrographolide( Fig.1)as the main components,shows strong inhibitory effects against enterovirus 71 and respiratory syncytial virus,and existence of dose-response relationships in pharmacology studies [4][5].XYP is the Consensus/Guideline-Recommended medication for hand-foot-and-mouth disease(HFMD) and viral pneumonia in children,et al [6],also used in the treatment of herpangina clinically.
The current status of the disease caused by enterovirus 71 infections: epidemiology, molecular epidemiology, vaccine development and pathogenesis [7][8].Although a commercial EV-A71 vaccine was available in mainland China in 2016 [9],but it has 3 no cross-protective immunity in other enterovirus serotypes [10].Herpangina still lack specific therapeutics [11].The present study aimed to demonstrate the "real-world" experiences of herpangina in China using XYP therapy,to provide a basis for treatment of herpangina in children.We present the following article in accordance with the STROBE Statement reporting checklist.

Data Source
This is a retrospective study based on HIS data. This analysis is based on a large electronic data warehouse (EDW), which was extracted from multiple sources The key was engineered in the data extraction process, and the data were normalized and standardized. To overcome the heterogeneous data integration challenges of HIS data, we proposed (extract, transform, load) ETL technology. The HIS data were centralized and standardized [12].

Study design
This study was established in departments of 14  was showed in Fig. 2.

Data Standardization
Before the statistical analysis, the original HIS data must be standardized. The Western medicine diagnosis was standardized in reference to ICD-10 [13]. Western medicine was standardized according to the drug code of the Anatomical Therapeutic Chemical (ATC), and Chinese patent medicine was standardized according to China National Medical Insurance Directory.

Inclusion criteria for participants
Data were collected from patients whose discharge diagnoses were classified coded 'B00.202', referred to herpangina.Meanwhile,they were prescribed and took XYP and aged less than 70 years.

Study Variables
Study variables were characteristics of herpangina patients and the combined diagnosis,characteristics of XYP medication use,combination drugs and intercorrelations among drugs.

Statistical analysis
The data were imported into SAS 9.2 (SAS Inc., Renmin University of China version).
Descriptive analysis, including numbers and percentages, was performed for every item.Associations were analyzed using the apriori function in the arules package in R.25. 5 A total of 3423 patients in the EDW database were retrieved for the analysis in this study.Characteristics of all patients are displayed in Tables 1.

Combined diagnosis
Combined diagnosis of patients were analyzed.The result of the analysis indicates that,except for herpangina, HFMD, bronchopneumonia and febrile seizure present a higher probability. The detailed disease distribution was illustrated in Fig.3.

Characteristics of XYP medication use
A total of 38788 medical advice records were extracted.There were 4238 XYP records in the database.Characteristics of XYP medication use are displayed in Table 2.
Set age of patients as the independent variable x.Regression analysis was ).Curves were drawn according to the equation.A curvilinear relationship was shown between age of patients and single doses (Fig.4).

Combination drugs
Other combination drugs were also analysed.The results are shown in the Table3.

Association analysis of drugs
In this study,we used the Apriori algorithm to analyze the association rules of XYP and combination drugs in all prescriptions.The terms confidence, support, and lift are metrics used in the rule selection to be described next.Support and confidence are measures of the interestingness of a rule.Support reflects the probability that drug A 6 and drug B appear at the same time.It is used to measure of the importance of an association rule, which indicates the frequency of this rule.Confidence is to use drug B on the basis of drug A,which is a measure of the accuracy of association rules and indicates the strength of the rules [14].
Analyze the application of XYP combined with two or three drugs.Extract drug combinations with support greater than 10%.The detailed values are given in Table 4.

Clinical characteristics of herpangina
According to the results of this study,the most commonly used dosage of XYP was less than 100 mg one time(84.2%).Single dose of an adult should be 250-500mg,and children 5-10mg/kg,according to the specification from the seller. Because of,the data about the participants' weight were unavailable in this study, we referenced in "The WHO Child Growth Standards" [29],to explore the actual dosage of infection [20],antibiotics were more often prescribed in clinical.Based on prior biological principles studies, there is increasing interest regarding the use of vitamin C for acute inflammatory disease prevention and therapy.Administering vitamin C is seen to increase generation of IFN-α and IFN-β,the production of pro-inflammatory cytokines and oxidative killing， lymphopoiesis proliferation and function， to modulate immune function [30][31][32][33].As a potent antioxidant ， vitamin C is capable of scavenging oxygen radicals and other cellular antioxidant ， reducing oxidative damages caused by virus [34][35].Despite vitamin C may be effective on virus infections in biologically,current evidence-based options for treatment remain limited.We were unable to obtain consistent findings to support this view [36]. Riboflavin(Vitamin B2) as a coenzyme of multiple oxidoreductases of body,is a key regulator of cellular respiration,and 10 involved in the oxidation of the human body [37].