Regularity of syndrome differentiation and treatment of traditional Chinese medicine for Henoch-Schonlein purpura based on data mining techniques

Shuai Zhang ,Yinglin Qin ,Jiaqi Yang ,Jie Guo ,Xueshuai Dai ,Xiaoming Jin*

1College of Chinese Medicine,Hebei University,Baoding,Hebei province,071000,China.

Abstract Objective:This study aims to explore the regularity of syndrome differentiation and treatment of traditional Chinese medicine (TCM)for allergic purpura.Methods:CNKI,Weipu Chinese science and technology database,wanfang medical network database,and Chinese biomedical literature database were searched for eligible studies.Medical records including complete patient personal information,patient symptoms,TCM syndromes,treatment,and medication were included.The data was analyzed using the Chinese medicine heritage support platform provided by the Chinese Academy of Chinese medicine (V2.5).Results:Differentiation of health gas camp blood was the most commonly used method of differentiation of symptoms and signs in famous veteran TCM.The treatment included cooling blood,activating blood circulation,clearing heat and detoxifying toxins,removing blood stasis and stopping bleeding.Honeysuckle,Forsythia suspensa,cicada slough and other drugs were interrelated.Potential drug pair combinations and drug networks showed the basic drug composition of Qingying Decoction.According to the entropy cluster analysis,28 core drug combination and 12 new formulations were obtained.Conclusion:The regularity of syndrome differentiation and treatment of traditional Chinese medicine for Henoch-Schonlein purpura based on the famous and old TCM doctors was complex.Further researches are still needed.

Keywords:syndrome differentiation and treatment;traditional Chinese medicine;Henoch-Schonlein purpura;data mining;

Introduction

Henoch-Schonlein purpura (HSP)is a comprehensive systemic inflammation mediated by immune complex.Its clinical manifestation is characterized by skin rash,often accompanied by joint,digestive tract,kidney and other organ damage.The pathogenesis of HSP is still unclear [1-3].At present,glucocorticoids and immunosuppressants are mostly used in the treatment of this disease,which belongs to symptomatic treatment.The use of glucocorticoids in children with HSP is still controversial.Some studies believe that glucocorticoids can not prevent the occurrence of kidney disease in HSP patients,and the recurrence of HSP [4].The overall prognosis of HSP is good.However,some researchers find that 67% of HSP children have the tendency of relapse,some of them turn to purpura nephritis.If the disease continues repeatedly,it can eventually develop to end-stage renal failure [5].Traditional Chinese medicine or the combination of Chinese and Western medicine in the treatment of HSP has incomparable efficacy and advantages,and has gradually become the basic consensus of many domestic experts.This study aimed to use data mining to explore the regularity of syndrome differentiation and treatment of traditional Chinese medicine (TCM)for allergic purpura.

1 Materials and methods

1.1 Literature search

(1)keywords:“allergic purpura”and“ traditional Chinese medicine”;

(2)Publication year:from 2000 to 2018;

(3)Databases:CNKI,,Weipu Chinese science and technology database,wanfang medical network database,and Chinese biomedical literature database.

1.2 Inclusion criteria

(1)Henoch-Schonlein purpura without any other underlying diseases and complications.

(2)The patient's attending physician was a master of Chinese medicine promulgated by the Ministry of Health,a national expert of traditional Chinese medicine,an instructor of academic experience inheritance,an expert enjoying special allowances from the State Council,a famous veteran Chinese medicine of provinces and municipalities,a tutor of doctoral students of traditional Chinese medicine,and an associate of all three-level comprehensive hospitals and hospitals of traditional Chinese medicine.

(3)Medical records include complete patient personal information,patient symptoms,TCM syndromes,treatment,and medication.

(4)There are clear criteria for evaluating the effect.

1.3 Exclusion criteria

(1)The literature is nonclinical experience or report,such as summary,animal experiment and TCM nursing.

(2)The treatment plan is mainly western medicine,and Chinese medicine is subsidiary.

(3)The curative effect is not clear or short time relapse.

1.4 Research Tools and Data Mining

This data was analyszed using the Chinese medicine heritage support platform provided by the Chinese Academy of Chinese medicine (V2.5).Because of the large number of medical cases,the“support”was set to“40”and the“confidence”was set to“0.7”.By the“rule analysis”function,the frequency of frequently used drug pairs,association rules and network between main drugs presented more than 40 times in medical cases were analyzed.According to the results,“correlation degree”was set to 8,and“punishment degree”was set to 4.The new prescriptions were clustered by entropy clustering analysis.

2 Results

2.1 Frequency of main symptoms in patients

We identified 649 relevant literatures.The frequency of concurrent syndromes except skin rash in this study is shown in Table 1.In addition to skin rash manifestations such as blood stasis and ecchymosis,Henoch-Schonlein purpura often involves the kidney,gastrointestinal tract and joints,causes a series of concurrent syndromes such as hematuria,celiagia,constipation,joint swelling and pain.

2.2 Methods of identifing different syndromes

The methods of identifing different syndromes used by famous and old TCM doctors are shown in Table 2.

2.3 Frequency of Main Syndromes

There are 39 syndromes involved in this study.The frequency of main syndromes is shown in Table 3.

2.4 Analysis of Association Rules for Important Drugs

The distribution of high-frequency drug pairs showsd that high-frequency drug pairs were the combination of many dozens of important drugs.We used association rules to explore the combination rule.Confidence was set to 0.7.The results are shown in table 4 and figure 1.

2.5 New Formula Mining

According to the results,the correlation degree was set to 8,the confidence level was set to 4,and eight new prescriptions were obtained,which reflected the experience of famous and veteran TCM prescriptions.The results are shown in Table 5.

3 Discussion

3.1 Syndrome Differentiation and Treatment

In this study,blood-heat rampancy,heat poison incandescence syndrome is the most common,such as the two syndromes as the main syndrome,should belong to the extreme stage of the development of the disease.The disease is mainly characterized by solid symptoms,heat syndrome,and blood syndrome[6].Ye Tianshi's“On Warming Heat”holds that“the heart governs the blood and belongs to the camp”,“those who are spotted and pyretic do not understand,and the stomach dies in yin.”It can be seen that the location of the disease is in the heart and stomach.Secondary symptoms may be hyperactivity of heart fire or gastric heat.They may be accompanied by fever,sore throat,excessive drinking,hematuria,abdominal distension and constipation.The spots are dense and bright compared with the initial and final stages.Wind-heat damaging collaterals syndrome is exogenous syndrome,when it is aimed at the initial stage of the disease or when the disease recurs.Because wind heat invades the lung and affects the lung collateral,the subcutaneous hemorrhage is seen.The location of the disease is in the lung,and the spots are not obvious,such as the tip of the needle,which is hidden.The location of the disease is Lung Wei,which can be accompanied by cold,fever,sore throat and other symptoms.Blood stasis,spleen deficiency and dampness accumulation,phlegm and blood stasis,and spleen and kidney deficiency are the late syndrome differentiation of the disease.At this time,the course of the disease is long,fever is not more,spots recede,and the disease is also developed from exogenous disease to internal injury syndrome,deficiency and excess are mixed,involving the heart,spleen and kidney.

It can be concluded that this disease belongs to exogenous febrile disease.First of all,it has the characteristics of offending the lungs,and has the law of transformation ofhealth gas camp blood.In the initial stage of treatment,the method of clearing heat and dredging wind was adopted,followed by the method of clearing heat and detoxifying toxins and cooling blood to stop bleeding,which blocked the progress of the disease,while the method of clearing heat and nourishing Yin was obvious.With the development of the disease,the fever declines gradually,affecting the dysfunction of many viscera such as the spleen and kidney of middle and lower Jiao [7].Spleen deficiency is damp,dampness accumulates phlegm,phlegm and blood stasis are blocked each other.Kidney essence,essence and blood are homologous,blood fever bleeding for a long time,will inevitably injure the essence of kidney,the use of invigorating the spleen and dampness,promoting blood circulation and phlegm,invigorating the spleen and kidney and other treatment methods.

3.2 Causes of Symptoms and Evolution of Febrile Diseases

In this study,pharyngalgia occurred in 14.25% of patients.The cause of the symptoms was that windheat evil Qi violated Wei Fen,Wei Yang vigorously resisted evil Qi,and the superficial evil caused by the confrontation between right and evil [8].The patient may be accompanied by symptoms such as fever,tonsillar swelling,thirst and so on.The tongue is red and fur is white or has no obvious change,only the tongue surface is dry,the number of pulses floating or has no obvious change.Because wind and heat are easy to carry out and change rapidly,the simple Wei Fen is rare in this disease.Once it occurs,it often has Taiyin internal injury,damp and heat connotation,spleen and stomach qi dysfunction.Although the location of the disease is in the lung,it has spread to the spleen and stomach.Although the pathogen is divided into Wei,it has spread to Qi.At this time,the evil mainly lies in the surface,and the healthy qi is not fading [9].We should clear the heat and dredge the wind in time,and select Forsythia suspensa,cicada slough,burdock and other medicines to prevent the evil gas from penetrating into the gas.Celiagia,constipation,and anorexia often occur at the same time.They are caused by pharyngalgia.The pathogenic factors of wind and heat go deep into qi,heat enters Yangming,the Qi of spleen and stomach goes up and down imbalance,heat damaging intestines and collaterals.Therefore,celiagia can be seen,such as hemorrhage between intestines,even hematemesis and hematochezia [10].But at this time,the hemorrhage is still not caused by heat evil,which can be cured after clearing away heat and purging fire.Therefore,it is different from the blood-moving,blood-consuming and blood-stasis-heat internal obstruction of blood component,and should be emphasized on differential diagnosis.Constipation is the combination of intestinal evil heat and drugs,which consume body fluid,intestinal conduction loss,can be accompanied by belching,vomiting and anorexia,red tongue coating yellow dry,red spots or burrs on the tongue,patients with severe thirst,strong pulse counts.The treatment should be focused on clearing away heat and purging fire.Baihu Decoction is the first choice.Damp-heat pathogens directly offend the spleen and stomach,damp-heat pathogenic airflow is connected with qi,which invades the spleen,gastrointestinal tract,and may be accompanied by symptoms such as fecal stickiness,chest tightness and so on.The patient's tongue is yellow,thick and greasy,pulse slippery,slow onset and transmission,difficult to cure quickly,and is treated by clearing away heat and dampness,fragrance and rubella.Although the treatment of symptoms caused by two different reasons is different,they belong to Qi syndrome.The pathological changes of Qi syndrome are nothing more than the changes of human"Qi",which is the extreme stage of the disease.If healed in time,the positive Qi is not injured,the patient is only the loss of body fluid,if not cured in time,the positive Qi is depleted,the patient can see the fatigue of God,is a sign of the transition to camp.Insomnia can be seen in febrile disease and febrile disease syndrome of Weifen and Yingfen.Insomnia can be caused by wind-heat evil gas retrogressing pericardium,or by warming evil,Ying-heat injuring Yin and heat disturbing mind.The key of identification is whether the patient's tongue is red.Because the insomnia of patients is caused by heat disturbing the mind,it is often accompanied by restlessness.At the same time,because Yin-Fen Yin fluid injury is more serious,whether thirsty for drinking water is also an important sign of the division of patients who belong to the Wei-Fen syndrome or Ying-Fen syndrome [11].Urine blood,stool blood,hematemesis,back pain,and edema are all found in Yingxue.Warming pathogen goes deep into Yingxue.The substantial damage of organs and tissues is more obvious,and the related dysfunction is more serious.Urine blood,stool blood and hematemesis are the manifestations of the further deterioration of the disease.Patient's macula also develops from vague macula to bright red in color.Lumbago is caused by heat entering Yingxue,Yin drainage and liver and kidney manifestations,liver and kidney yin deficiency,so lumbago is sore.Edema is caused by the heat evil going deep into the lower coke,the disadvantage ofbladder gasification,the blood stasis of the lower coke,the water-heat junction and the obstruction of blood circulation.The occurrence of the above symptoms(except Yang Ming Qi and blood in stool)can indicate that the disease has developed to the late stage of febrile disease,the condition is mixed with deficiency and reality,and it is difficult to recover.On the basis of symptomatic treatment,we should focus on nourishing liver and kidney,clearing waste heat,and restoring the normal physiological function of the viscera.

Table 1 Frequency of main symptoms in patients with HSP

Table 2 Methods of identifing different syndromes

Table 3 Frequency of main syndromes

3.3 Relevance analysis of commonly used drugs

Association rules were used to analyze the relationship among commonly used drugs.We found that rhizomz were associated with other drugs [12].They were related to Rhizoma Glycyrrhizae,Radix Glycyrrhizae,Radix Scutellariae,radix paeoniae rubra,radix rehmanniae,Radix Scutellariae and Scutellaria baicalensis Georgi.The commonly used combination of drugs is based on the prototype of Qingying Decoction,reducing bamboo leaves,Ophiopogon japonicus,Salvia miltiorrhiza,Coptis chinensis and cicada slough,Saposhnikovia divaricata,Radix Paeoniae Rubra,Angelica sinensis,Paeonia Alba root and Lithospermum.Combination of water ox horn,Rehmannia glutinosa extract,heat toxin,Radix et Rhizoma,Radix et Rhizoma,Radix et Rhizoma,radix paeoniae rubra,Rhizoma Coicis rhizome,clearing away heat and cooling blood,honeysuckle flower,forsythia diathermy and transforming Qi [13].All drugs are used together for playing the role of clearing away heat and cooling blood.Qingying Decoction is the representative prescription for treating fever in Yingfen syndrome.Modern pharmacological studies show that Qingying Decoction has obvious cooling and antipyretic effects on various febrile models,which can reduce the permeability of capillaries.In addition,it has anti-virus,anti-inflammation,changes

in blood rheology and thrombolytic effects [4-6].So it has become the basic prescription for old Chinese medicine to treat this disease.Among the new medicines,Saposhnikovia divaricata has significant anti-allergic effect,and Lithospermum has inhibitory effect on specific allergic reaction.When using the two medicines we should not only consider the mechanism of TCM syndrome differentiation and treatment of the disease,but also the modern medical pharmacological research of the disease.

Table 4 Analysis of Association Rules for Important Drugs

Figure 1 Network of commonly used drugs

Table 5 Core drug combinations in modern Chinese medicine prescriptions for seborrheic dermatitis

3.4 Analysis of Four New Formulas

Combination 1 is composed of Bamboo Leaf,RadiScrophulariae,Bupleurum chinense,Ulmus pumila,Typha.Bamboo leaf cold,return to heart,stomach meridian,clear heat and purge fire,relieve irritation and cough.Radix Scrophulariae is bitter and slight cold,return to heart,liver and kidney meridians,clear heat and cool blood,strong detoxification and dissolution of knots,used for eye swelling and pain,throat swelling and pain;[14]Bupleurum Bupleurum has strong antipyretic effect,which is used to disperse heart,stomach stagnation fire,heat stagnation in clearing,heat and breathing effect.Ulmus pumila and Typha are both good drugs for hemostasis and promoting blood circulation.It can induce blood to meridian and eliminate skin rash.According to the prescription,it is suitable for the extreme blood-heat delusion syndrome or heat-poisoning incandescence syndrome.The location of the disease is in the heart and stomach,the spots are bright,and may be accompanied by pharyngalgia,fever and other symptoms,such as pharyngalgia can be added to Daqingye as appropriate.Composition 3 is composed of Salvia miltiorrhiza,Phellodendron amurense,Leonurus japonicus and Sophora flavescens.Salvia miltiorrhiza is slightly cold,bitter and belongs to the heart and liver meridian.It has the functions of activating blood circulation,removing blood stasis,clearing heart and removing trouble.The modern pharmacological study of "good treatment of blood,eliminating stagnation and generating new,regulating meridians and collaterals" in the Commentary on Materia Medica shows that paeonol can significantly inhibit platelet aggregation caused by various factors [7].Phellodendron Phellodendri bitter cold,returning to kidney and bladder meridian can not only clear heat and dry dampness,but also be used for damp.It can clear the deficiency fire of liver and kidney;motherwort is bitter,slightly cold,belongs to liver,pericardium and bladder meridians,clears heat and activates blood circulation,has strong diuresis and detumescence effect,and is beneficial to the syndromes of water and heat.Sophora flavescens is bitter cold,belongs to heart and liver meridians,and has strong heat and dampness clearing force.For the late stage of this disease,liver and kidney deficiency,dampheat injection syndrome,may be accompanied by the emergence of urinary protein,the condition is lingering and repeated,and it is difficult to recover for a long time.

Combination 4 consists of Poria cocos,Codonopsis pilosula,Ziziphus jujuba seed and Leonurus heterophyllus.Poria cocos are mild and mild,and can be used to soothe the dampness and strengthen the spleen and heart.It is used for the spleen deficiency and dampness;the dangshen Gan Ping,the spleen and lung meridian,the spleen and the lung,the Qi replenishing qi,the nourishing qi and blood,the Zizyphus jujube kernel acid,the Ningxin calming mind,and the compatibility of water and swelling.It is used for spleen deficiency,dampness,and excessive syndrome.All drugs are peaceful,tonifying deficiency and tonifying injury and strengthening qi.

Composition 5 is composed of Gardenia jasminoides,Pogostemon vulgaris,Rehmannia glutinosa and Prunella vulgaris.Gardenia jasminoides and herbs are the ingredients of Xiehuang powder.Xiehuang powder is found in Zhizhi of Pediatric Medicine Syndrome.It is a good prescription for the treatment of spleen and stomach fire.[15]It can be combined with Rehmannia glutinosa with heat-cooling blood and Prunella vulgaris with heat-clearing and fire-clearing,which can strengthen the function of clearing fire in stomach,clearing heat in blood and nourishing yin and protecting liquid.For this disease,the location of the disease is mainly in the stomach,which may be accompanied by halitosis,celiagia,constipation and other symptoms.According to the severity of symptoms,we can add Yuzhu,Ophiopogon japonicus and other antipyretic and Yin-nourishing drugs as appropriate.

Composition 8 consists of Angelica sinensis,cicada slough,thistle,Typha and Saposhnikovia divaricata.Small thistle and cattail are good at stopping urine and bleeding,cooperating with Angelica sinensis,quite similar to small thistle drinks,can play the role of blood induction and meridian tropism.Cicada slough and Saposhnikovia divaricata can make the heat of lower coke blood permeate outside.At the same time,modern pharmacological studies show that cicada slough and Saposhnikovia divaricata can play an immunoregulatory role to a certain extent.In addition,Angelica sinensis,which nourishes blood and promotes blood circulation,is suitable for the later stage of the disease.It has a long course of disease,insufficient Yin and blood,and blood-heat has not fallen into the syndrome of lower burning liver and kidney.Its pathogenesis is more complex.The main symptoms are liver and kidney.It can be seen that Urine-Blood and Deficiency-heat do not fade.It can be added with Artemisia annua,turtle shell and other heat-clearing and Yin-nourishing drugs as appropriate.Because of the long course and deep position of the disease,it is especially suitable for the use of visible products of flesh and blood.

Conclusion

This study searched a large number of literature on Chinese medicine treatment for allergic purpura.By the data mining techniques,It formed a more systematic medicine theory of syndrome differentation and treatment variation and used Traditional Chinese Medicine auxiliary system platform to identify a number of new prescriptions with characteristics for the development of clinical drugs and new drugs.There may be some unique therapeutic ideas.However,due to the small number of medical records collected,the efficacy of the new prescription has not been clinically evaluated.Further researches are still needed.