Retrospective Clinical Analysis on Treatment of Novel Coronavirus-infected Pneumonia with Traditional Chinese Medicine Lianhua Qingwen

YAO Kai-tao1, LIU Ming-yu1, LI Xin2, HUANG Ji-han 3, CAI Hong-bin1*

(1.The Ninth Hospital of Wuhan, Wuhan 430081, China; 2.CR&WISCO General Hospital, Wuhan 430080, China; 3.Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China)

[Abstract] Objective:To analyze the clinical effect of traditional Chinese medicine Lianhua Qingwen in the treatment of novel coronavirus-infected pneumonia (NCIP) and provide the basis for medication guides through a retrospective study in a cohort of NCIP confirmed patients. Method: A retrospective analysis of clinical records was conducted in NCIP confirmed patients at The Ninth Hospital of Wuhan and CR&WISCO General Hospital including the treatment group (21 patients, basic treatment in combination with Lianhua Qingwen Granules, 1 packet/time, 3 times/day) and the control group (21 patients, basic treatment). Comparison between the two groups was made in terms of the disappearance rates of cardinal symptoms (fever, cough and asthenia), duration of fever, and disappearance rates of other symptoms (muscle pain, expectoration, nasal obstruction, running nose, dry throat, pharyngalgia, shortness of breath, chest distress, dyspnea, dizziness, headache, nausea, vomiting, loss of appetite and diarrhea). Result: The baseline data were similar between the two groups. When compared with the control group, patients in the treatment group had the higher clinical effect, including the disappearance rate of fever (85.7% vs 57.1%, Χ2=4.200, P=0.040), the disappearance rate of cough (46.7% vs 5.6%, P=0.012), the disappearance rate expectoration (64.3% vs 9.1%, P=0.012), the disappearance rate of shortness of breath (77.8% vs 0, P=0.021), and the duration of fever [(4.6±3.2) d vs (6.1±3.1) d, P=0.218]. Conclusion: Lianhua Qingwen can significantly relieve cardinal symptoms in NCIP confirmed patients by inhibiting fever and cough, reducing their duration, as well as improving individual symptoms. All these results provide preliminary clinical evidence for Lianhua Qingwen Granules in the NCIP treatment. 

[Key words] Lianhua Qingwen; novel coronavirus-infected pneumonia (NCIP); 2019-nCoV; confirmed patients; clinical research; fever; cough

Unknown pneumonia epidemic broke out recently in Wuhan City, Hubei Province. On January 12, 2020, the World Health Organization officially named the new coronavirus which caused the pneumonia in Wuhan as “2019 – nCov” [1]. <Prevention and Control Plan of the Pneumonia Caused by the Novel Coronavirus> issued by National Health Commission of the People’s Republic of China (hereinafter referred to as NHC) named it novel coronavirus-infected pneumonia (NCIP). It is reported that the coronavirus is envelope single-strand positive-strand RNA virus[2], 2019-nCoV pathogens and their genome sequence has been identified[3], laid the important foundation for epidemic prevention. Clinical symptom manifestations are mainly fever, asthenia, dry cough, a few patients are with nasal congestion, runny nose, sore throat and diarrhea and other symptoms, dyspnea occurs in severe patients and can cause life-threatening [4]. The disease is highly contagious, researchers have used a model to evaluate the “Basic Reproductive Number” of this epidemic (R0), the R0 is as high as 2.682[2]. According to the open data of NHC, until 24:00 of February 4, 24324 confirmed patients has been reported and 490 patients died across the country, it can be speculated that the mortality is 2.01%. Since the outbreak of the epidemic, number of confirmed and suspected cases climbed, the NHC has defined the disease as Class B infectious diseases regulated as the <Law of the People’s Republic of China on the prevention and treatment of infectious diseases>, prevention and control measures as Class A infectious diseases should be taken. On January 31, 2020, the disease is treated as a public health emergency of international concern by the World Health Organization, which is one of the major outbreaks caused serious damage to people’s health and public safety after severe acute respiratory ensemble Syndrome (SARS) in 2003. Currently there is no confirmed effective antiviral drugs on NCIP, clinical symptomatic support treatment based comprehensive intervention is taken[4]. Reference is made to the important role of the therapy of combination of Chinese traditional and western medicine for SARS and Class A H1N1flu, based on the overall treatment advantages of TCM combined with improving clinical symptoms, traditional Chinese medicine is significant in NCIP treatment.

Lianhua Qinwen Capsules (Granules) is one innovative patent Chinese medicine developed during the period of SARS in 2003 and approved through fast review of new drug, and effects for viral respiratory infectious on broad spectrum antiviral, antibacterial, anti-inflammatory fever, relieving cough resolving phlegm, regulating immune system interfere [5-14], especially has significant inhibition and killing effect for respiratory syndrome SARS coronavirus and the Middle East (MERS). The drug has been listed as recommended drugs for 20 times in respiratory infectious disease prevention and control plan issued by NHC and the State Administration of Traditional Medicine of China. The drug has been treated as representative Chinesed medicine responsing to respiratory public health events. And the drug has been listed as recommended drug in < Prevention and Control Plan of the Pneumonia Caused by the Novel Coronavirus (Trail Fourth Edition) >. Since the outbreak, the method of traditional Chinese and western medicine is applied, basic treatment in combination with Lianhua Qingwen Granules has good effect for common NCIP patients, clinical data of these patients are summarized as follows.

1 Document and Method

1.1    Clinical Data Collect the clinical data of patients who were in treatment at The Ninth Hospital of Wuhan and CR&WISCO General Hospital from the date January 11, 2020 to January 30, 2020 and then confirmed as novel coronavirus-infected pneumonia (NCIP) patients by positive nucleic acid detection of sputum, throat swab and secretion of lower respiratory tracts etc.

1.2    Inclusion Criteria Common inpatients aged over 18 years and met the diagnostic criteria of ordinary[4] NCIP.

1.3    Exclusion Criteria (1)Severe and critically severe NCIP patients; (2)Acute respiratory diseases not caused by 2019-nCoV; (3)any other chronic respiratory diseases, respiratory bacterial infections such as suppurative tonsillitis, acute tracheal-bronchitis, sinusitis, otitis media and other respiratory diseases that affect clinical trial evaluation; (4)for asthma patients requiring daily treatment, chest X-ray computed tomography (CT) confirmed the existence of serious pulmonary interstitial lesions, bronchiectasis and other basic pulmonary diseases; (5)Accompanied by basic diseases such as serious primary immunodeficiency disease, acquired immunodeficiency syndrome, congenital respiratory tract malformation, congenital heart disease, lung dysplasia and so on.

1.4    Grouping Method Inpatients meeting the diagnostic criteria of NCIP are divided into basic treatment (recommended treatment of <Prevention and Control Plan of the Pneumonia Caused by the Novel Coronavirus (Trial)> issued by NHC) and basic treatment in combination with Lianhua Qingwen Granules (1 packet/time, 3 times/day). Among the patients of basic treatment in combination with Lianhua Qingwen Granules, patients meeting the inclusion criteria and exclusion criteria and whose body temperature was >37.2 ℃ were selected as the treatment group. Then age and body temperature were taken as covariates and the propensity score was calculated using Logistic regression model, 21 patients of basic treatment were matched at a 1:1 ratio as the control group.

1.5    Evaluation Index Compare the disappearance rate of main symptoms (fever, asthenia and cough), disappearance time of fever and disappearance rate of other individual symptoms between the treatment group and the control group.

1.6    Statistical Method SAS 9.4 software was used for statistical analysis. All statistical tests were double-sided, and P≤0.05 indicated difference has statistically significant. The counting data of descriptive analysis were described by the number of cases and composition ratio, and the measurement data were described by ±s. Quantitative data were compared by t test, and classified data were tested by chi-square test or exact probability method.

2          Result

2.1    Baseline Data Collect total of 42 ordinary NCIP patients, including 16 males (76.2%) and 5 females (23.8%) in the treatment group, with an average age of 57.1±14.0 years; and including 12 males (57.1%) and 9 females (42.9%) in the control group, with an average age of 62.4±12.3 years. The baseline data had no statistically significant differences between the two groups in terms of age, gender, temperature, blood pressure, heart rate, respiration, previous medical history, time from onset to diagnosis etc. and had omparability. Detailed data are shown in table 1.

Table 1 Baseline data of treatment group and control group (±s, n=21)

Group

Age

Male/Subject

Body Temperature/℃

Systolic Blood Pressure/mmHg

Diastolic Blood Pressure/mmHg

Heat Rate/BPM

Respiratory Rates/min

Patients with Previous Medical History/Subject

Time from Onsert to Diagnosis/d

Treatment Group

57.1±14.0

16

38.56±0.68

123.9±12.9

75.3±10.2

88.5±10.8

20.0±2.3

10

12.8±3.8

Control Group

62.4±12.3

12

38.38±0.63

119.3±14.4

72.4±9.8

88.4±11.6

19.8±1.3

10

12.9±3.3

Statistics

1.2981)

1.7142)

0.8831)

1.0721)

0.9241)

0.0271)

0.4071)

02)

0.0701)

P

0.202

0.190

0.383

0.290

0.361

0.978

0.687

1.000

0.944

Note: 1mmHg ≈0.133kPa. 1) t test; 2) chi-square test

2.2    Comparison of Main Symptom Disappearance Rate (1)Baseline data: Among the 21 patients in the treatment group, 21 patients had fever (100%), 15 patients had cough (71.4%), and 12 patients were asthenia (57.1%); Among the 21 patients in the control group, 21 patients had fever (100%), 18 patients had cough (85.7%) and 13 patients were asthenia (61.9%).There was no significant difference between the two groups.(2) treatment outcome: when compared with the control group, fever disappeared in 18 patients in the treatment group(85.7%), which is significantly better than the 57.1% in control group (X2=4.200, P=0.040); and cough symptom disappeared in 7 patient(46.7%), which is significantly better than the 5.6% in control group (P=0.012); The differences of the two index between the two groups have statistically significant(P<0.05). There was no significant difference in the disappearance rate of asthenia symptoms between the two groups (P=0.688). Detailed data are shown in table 2.

Table 2 Main symptom disappearance rates of treatment group and control group

Symptom

Treatment Group

Control Group

Χ2

P

n

Disappeared Number

Disappeared

Rate %

n

Disappeared Number

Disappeared

Rate %

Fever1)

21

18

85.7

21

12

57.1

4.200

0.040

Cough2)

15

7

46.7

18

1

5.6

-

0.012

Asthenia2)

12

5

41.7

13

4

30.8

-

0.688

Note: 1) chi-square test; 2) exact probability method

2.3    Comparison of fever duration There were 21 patients in the treatment group, and the duration time of fever was (4.6 ± 3.2) days. There were 21 patients in the control group,the duration time of fever was (6.1 ± 3.1) days, There was no statistically significant difference between the groups (P = 0.218).

2.4    Comparison of the disappearance rate of other symptoms The expectoration and shortness of breath symptoms in the treatment group were 64.3% and 77.8%, respectively. Compared with the control group, the differences were statistically significant (P <0.05); There was no significant difference in the disappearance rate of other symptoms between the two groups. See Table 3 for detailed data.

Table 3   Other symptom disappearance rates of treatment group and controlgroup

Object

treatment group

control group

P

n

number of disappearance

disappearance rates%

n

number of disappearance

disappearance rates%

muscle pain

6

4

66.7

7

2

28.6

0.286

expectoration

14

9

64.3

11

1

9.1

0.012

rhinobyon

3

1

33.3

0

0

0

-

running nose

3

1

33.3

0

0

0

-

pharyngalgia

3

1

33.3

3

1

33.3

1.000

anhelation

9

7

77.8

5

0

0

0.021

chest distress

7

5

71.4

9

2

22.2

0.126

dyspnea

2

1

50.0

2

1

50.0

1.000

headache

4

2

50.0

1

0

0

1.000

nausea

4

2

50.0

3

2

66.7

1.000

vomit

4

3

75.0

0

0

0

-

appetite

11

4

36.4

12

2

16.7

0.371

diarrhea

5

3

60.0

3

2

66.7

1.000

Note: The data are processed using exact probability method.

3 Discussion

According to reports, the main clinical symptoms of NCIP are fever, muscle pain, asthenia, expectoration, shortness of breath, headache, and pharyngalgia, running nose, diarrhea, nausea and vomiting, etc. [2,15]. According to the<Diagnosis and treatment plan for pneumonia caused by novel coronavirus > (Trial Fifth Edition) [4] issued by the National Health Commission, the mainly symptoms of disease is fever, asthenia, and dry cough, few patients have symptoms such as nasal obstruction, running nose, pharyngalgia, diarrhea. Academician Zhong Nanshan of the Chinese Academy of Engineering also pointed out in an exclusive interview with Xinhua News Agency that fever is still the most important and typical symptom among NCIP-diagnosed patients [16], so this study selects confirmed patients with fever as the main clinical manifestation to evaluate the efficacy of traditional Chinese medicine. At the same time, in view of the lack of effective antiviral therapies identified by NCIP, improving clinical symptoms related to diseases such as fever, cough, and asthenia has important clinical significance for relieving the severity of the disease and shortening the duration of the disease.

The COVID-2019 belongs to the category of “Epidemic Disease” Chinese Medicine. The main pathogenic factor is attacked by the evil of pestilence, and then entered the interior to lead to an inflammatory response is the important pathogenesis. This is consistent with the clinical symptoms of fever as the main manifestation of NCIP. The formula of Lianhua Qingwen is an innovative Chinese Patent Medicine, which is based on the theory of collateral disease of traditional Chinese medicine to reveal the law of transmission of respiratory system infectious diseases caused by viruses and the method of “clearing away distemper and detoxication, dispersing lung and relieving heat”. The formula is based on Maxing Shigan decoction in Zhang Zhongjing’s treatise on Febrile Diseases of the Han Dynasty and Yinqiao powder in Wu Jutong’s treatise on epidemic febrile diseases of the Qing Dynasty, and drawing on Wu Youke’s experience in treating epidemic diseases with rhubarb in the treatise on Epidemic Febrile Diseases of the Ming Dynasty, and combining with Rhodiola rosea to clear the lung, remove blood stasis and regulating immune function. The formula represents 2,000 years of experience in the use of traditional Chinese medicine in the prevention and treatment of such diseases. It is clinically applicable to respiratory system infectious diseases with fever, chills, cough, muscle soreness and so on. Previous pharmacodynamic studies have confirmed that the Chinese medicine Lianhua Qingwen significantly inhibits SARS-CoV virus activity in vitro culture [17], and at the same time has a certain inhibitory effect on MERS-CoV activity, which was listed in the “Middle East Respiratory Syndrome Case Diagnosis and Treatment Scheme ( 2015 version) [18]“, multi-stage anti-influenza virus of Class A H1N1 and H3N2[19-20], significantly inhibit the avian influenza virus H7N9[21], and also have antibacterial, anti-inflammatory, antipyretic, cough, phlegm, and regulation Immunity and other effects [5-14]. The pharmacodynamic research results above confirm that the traditional Chinese medicine Lianhua Qingbing has the characteristics of “overall regulation and multi-target therapy”, and also confirms the scientificity of its theory and formula.

This study included 42 confirmed NCIP patients with fever symptoms, accompanied by different levels of cough, asthenia, expectoration, muscle pain, anhelation, pharyngalgia, nausea, vomiting, loss of appetite, and diarrhea. The results showed that the conventional treatment combined with Lianhua Qingwen Granules could significantly relieve clinical symptoms such as fever, cough, expectoration and anhelation, although there was no statistical difference in the disappearance time of fever, it was 1.5 days shorter than the control group. It has also been shown to have clinical advantages in improving fever symptoms. At the same time, the drug also shows a positive trend in improving the symptoms of asthenia, muscle pain, rhinobyon and headache. Compound Chinese Medicine have an important clinical application value for improving the symptoms, relieving the disease and shortening the duration of the disease in the absence of effective antiviral drugs for the disease by playing the characteristics advantages of “overall regulation, multi-target therapy”.

The preliminary results of this study are consistent with the previously reported clinical studies of traditional Chinese medicine Lianhua Qingwen, such as the 2009 random, double-blind, multi-center clinical trial of Lianhua Qingwen Capsule for the treatment of Class A H1N1 flu [22], indicating that the drug have no difference with Oseltamivir Phosphate from reducing the duration of viral nucleic acid changing to negative and duration of all influenza symptoms, and be better than oseltamivir phosphate at relief of cough, muscle soreness, asthenia and other symptoms. Another randomized, controlled clinical study of Lianhua Qingwen Capsule for the treatment of Class A H1N1 flu found that the drug is basically consistent with the above results [23]. In addition, a retrospective analysis of Lianhua Qingwen medication at the designated hospital for influenza A H1N1 flu—Beijing Ditan Hospital [24] also confirmed the application of Lianhua Qingwen Capsule’s antipyretic time, viral nucleic acid changing to negative time is same with oseltamivir. The above research results are clinical evidence obtained during the 2009 H1N1 flu outbreak, indicating that the Chinese medicine Lianhua Qingwen has played an important role in preventing and controlling respiratory public health events caused by the virus. Combined with the results of this study, this drug is suggested it has certain clinical application value for the treatment of NCIP.

It should be pointed out that this study is based on the general diagnostic criteria for<Diagnosis and treatment plan for pneumonia caused by novel coronavirus> issued by the NHC. Patients were collected and included in retrospective clinical studies. Traditional Chinese Medicine dialectics has not yet been performed. And the sample quantity is small, the lack of viral nucleic acid changing into negative and serological examination data support,is a deficiency of research. The sample quantity will be expanded in the future, and a prospective, randomized controlled clinical study will be conducted to further evaluate the clinical efficacy of Chinese medicine Lianhua Qingwen in treating NCIP.

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[Responsible editor Dewen Liu]

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