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SARS: Clinical Trials on Treatment Using a Combination of Traditional Chinese Medicine and Western Medicine
(2004; 194 pages) View the PDF document
Table of Contents
View the documentAcknowledgements
View the documentIntroduction
View the documentReport of the International Expert Meeting to review and analyse clinical reports on combination treatment for SARS
View the documentReport 1: Clinical research on treatment of SARS with integrated Traditional Chinese medicine and Western Medicine
View the documentReport 2: Clinical efficacy of the treatment of SARS with integrated Traditional Chinese medicine and Western medicine: an analysis of 524 cases
View the documentReport 3: Manifestation of symptoms in patients with SARS and analysis of the curative effect of treatment with integrated Traditional Chinese medicine and Western medicine
View the documentReport 4: Clinical study on 103 inpatients undergoing therapy with integrated Traditional Chinese medicine and Western medicine
View the documentReport 5: Clinical observations of 11 patients with SARS treated with Traditional Chinese medicine
View the documentReport 6: Effects of applying integrated therapy with Traditional Chinese medicine and Western medicine on liver and kidney functions in patients with SARS
View the documentReport 7: Clinical research on 63 patients with SARS treated with integrated Traditional Chinese medicine and Western medicine
View the documentReport 8: Influence of integrated therapy with Traditional Chinese medicine and Western medicine on lymphocytes and T-lymphocyte subpopulations of patients with SARS
View the documentReport 9: Analysis of the clinical curative effects on patients with SARS of treatment with Traditional Chinese medicine and Western medicine
View the documentReport 10: Evaluation of clinical curative effects of Traditional Chinese medicine in treatment of patients convalescing from SARS
View the documentReport A: A herbal formula for the prevention of transmission of SARS during the SARS epidemic in Hong Kong Special Administrative Region - a prospective cohort study
View the documentReport B: Effects of Chinese medicine on patients convalescing from SARS in Hong Kong special administrative region - a prospective non-randomized controlled trial
View the documentReport C: Traditional Chinese medicine in the management of patients with SARS in Hong Kong Special Administrative Region - a case-control study of 24 patients
View the documentAnnex
 

Report 2: Clinical efficacy of the treatment of SARS with integrated Traditional Chinese medicine and Western medicine: an analysis of 524 cases

Liu Baoyan2, Weng Weiliang3, Xie Yanming2, Hu Jingqing2, Wang Rongbing4, Zhang Yanping5, Li Xiuhui6, Ren Aimin7, Li Yun8, Wang Baoguo9, Tang Xudong10, Wang Weidong9, Zhang Jinping11, Wu Hongjin12, Tang Qisheng13, Zhou Wei14, Liang Zhiwei15, Geng Zhi16, Yi Danhui17, Tong Xinyuan18, Li Ping2, Hu Yuling2, Gao Fanzhu2, Peng Jin2 and Fan Weiyu2

2 China Academy of TCM
3 China Academy of TCM: Clinical Evaluation Centre
4 Beijing Ditan Hospital
5 China Academy of TCM: Xiyuan Hospital
6 Beijing You’an Hospital
7 Beijing Friendship Hospital
8 PLA 302 Hospital
9 Beijing Tiantan Hospital
10 China Academy of TCM: Guang’anmen Hospital
11 Beijing Chest Disease Hospital
12 Beijing TCM-WM Hospital
13 Dong Zhi Men Hospital of Beijing TCM University
14 China Academy of TCM: Wangjing Hospital
15 Guangdong Provincial Hospital of TCM
16 Beijing University
17 People’s University of China
18 PLA 301 Hospital


Background

Severe acute respiratory syndrome (SARS) is an acute respiratory infectious disease caused by a corona virus. The drugs used for the treatment of SARS include antivirals, glucocorticoid, antibiotics and immunomodulator. On the basis of the therapeutic experience accumulated in the treatment of similar diseases, most clinical experts consider that these drugs should be helpful in treating SARS, but lack sufficient evidence. The administration of herbal decoctions and injections is the characteristic system of therapeutics adopted in China. An issue of public concern is whether a therapeutic regimen integrating Western medicine with Traditional Chinese medicine (TCM) leads to improved clinical efficacy when compared with treatment of SARS with Western medicine alone. This report presents the results of research on the clinical curative effects by comparing 318 SARS patients who received integrated treatment with 206 patients treated with Western medicine alone.

Method

Design

The study designs were randomized or non-randomized case-control studies.

Grouping of study subjects

Randomized distribution

Patients were grouped randomly by some clinical subcentres. The clinical subcentre represented the unit for the randomized grouping. Random numbers were generated by the application of an SAS software package in an independent data centre, and the clinical subcentres allocated patients randomly to the different treatment groups according to serial number.

Non-randomized grouping

Patients were distributed selectively by some clinical subcentres. When patients were assigned to the different groups, cases and controls were matched on sex, age, time of onset of disease, state of illness and therapeutic conditions.

Study subjects

The observation cases were inpatients admitted to the 11 designated SARS hospitals in the Beijing area from April 2003 to June 2003 who had been clinically diagnosed as having SARS.

Clinical diagnostic criteria for SARS

The diagnosis of SARS was based on the clinical diagnosis criteria of severe acute respiratory syndrome (proposed) promulgated by the Ministry of Health of the People's Republic of China. The diagnostic criteria for SARS promulgated on 3 May 2003 are listed below.

1. Epidemiological history

1.1 Having had close contact with SARS patients or belonging to one of the affected groups, or having obvious evidence of infecting others;

1.2 Having visited or resided in areas that have been reported to have SARS patients and secondary infection two weeks before being attacked by the disease.

2. Symptoms and signs

The onset of the disease is acute with high fever as the primary symptom, with a body temperature usually higher than 38 °C; sometimes the patients may have chills accompanied by headache, arthralgia, muscular aching, hypodynamia and diarrhoea; usually without catarrh of the upper respiratory tract; may cough, mostly dry cough with little sputum; may have blood-streaked sputum; may experience chest discomfort and patients with severe illness may suffer from accelerated respiration, shortness of breath or obvious respiratory distress. Physical signs in the lung are not obvious, and some patients may have some wet rale or signs of pulmonary consolidation.

Note: A few patients may not have high fever as the primary symptom. This is particularly true for those patients who have recently had an operation or who suffer from underlying diseases.

3. Laboratory tests

The white blood cell count in the peripheral blood is usually unchanged; lymphocyte count (LC) usually goes down.

4. Chest X-ray examination

Patchy and spot-shaped infiltration shadows or reticular change are present in the lung, and develop rapidly in some patients; changes are usually seen in several lung lobes or in both lungs, with shadows being absorbed and dissipated slowly; the lung shadow may not be consistent with the physical symptoms. If the examination result is negative, a re-examination should be done after 1 or 2 days.

5. Effects of treatment with antibacterial drugs

No obvious effects of treatment with antibiotics are seen and clinical diagnostic criteria comply with item 1.1, item 2 and item 4 or more, or items 1.2, 2, 4 and 5, or items 1.2, 2, 3 and 4.

Clinical diagnostic grouping of SARS

A diagnosis of severe disease was made if the following criteria were met:

• general symptoms of toxicity are obvious (persistent high fever for more than 48 hours, or hyperventilation, PaCO2 < 35 mmHg, white blood cell count < 3.0 × 103;

• lesions on several lung lobes or lesions visible on chest radiograph that have increased in size by more than 50% within 48 hours;

• respiratory frequency greater than 28 breaths/minute and hypoxemia;

• patients aged over 50 years; and

• patients who already have underlying disease.


Patients were classified as critical if they met the following criteria:

• acute lung injury (ALI) or acute respiratory distress syndrome (ARDS);

• respiratory frequency > 28/min; arterial partial pressure of oxygen (PaO2)/(fractional concentration of oxygen in inspired air (FiO2) < 300 (for instance, PaO2 < 60 mm Hg when indoor air was inhaled; PaO2 < 150 mm Hg when air with an oxygen level of 50% was inhaled);

• PaO2 < 70 mm Hg or blood oxygen saturation (SpO2) < 93% when oxygen is inhaled at 3-5 l/min;

• diffuse patchy image on chest radiograph of both lungs;

• shock; and

• multiple organ dysfunction syndrome (MODS).


Patients were classified as having normal SARS if they did not meet the criteria listed above for severe or critical disease.

Inclusion criterion

All the cases that met the diagnostic criteria for SARS, with the approval of the patients concerned, were eligible for inclusion.

Exclusion criteria

Patients were not eligible for inclusion in the study if:

• they failed to meet the diagnostic criteria for SARS;
• they were pregnant or lactating; or
• they did not consent to participate in the study.


Therapeutic regimens

For treatment with Western medicine, the therapeutic regimen for SARS recommended by the Ministry of Health was adopted. This consisted of supportive treatment with glucocorticoid, antiviral drugs, antibiotics, immunomodulator and so on. For treatment with TCM, the therapeutic regimen for SARS recommended by the Beijing Municipal Administration for TCM was adopted, and the treatment was based on overall analysis of the disease at different stages (e.g. high-fever stage or coughing and gasping stage). The treatment was based mainly on herbal decoctions with the support of injections or Chinese patent drugs whenever appropriate.

Treatment with Western medicine as recommended by the Ministry of Health, People's Republic of China

Monitoring

Most of the patients were in the progressive stage within 14 days after the onset of disease. The change of the state of the illness therefore had to be observed closely and the factors to be monitored included the symptoms, body temperature, respiratory frequency, SpO2 or arterial blood gas analysis, haemogram, chest radiograph (time interval for early-stage re-examination not exceeding 2-3 days), function of heart, liver and kidneys.

Regular and specific treatment

Treatment included the following:

• bed rest and avoidance of fatigue and physical exertion;

• avoidance of violent coughing; patients with severe cough were treated to relieve the cough, and patients who coughed up sputum were treated with an expectorant;

• patients with a fever and a body temperature exceeding 38.5°C were offered antipyretics and analgesics, and patients with high fever were cooled down physically. Aspirin was not administered to children as it can cause Reye Syndrome;

• appropriate treatment was provided whenever there was any impairment of the functions of the heart, liver, kidneys or other organs; and

• nutritional support was provided and attention paid to the water-electrolyte balance.


Shortness of breath

Patients who were short of breath or who had a PaO2 < 70 mmHg or SpO2 < 93% received continuous oxygen inhalation through a nasal tube or face mask.

Treatment with glucocorticoid

Indications for glucocorticoid treatment included:

• patients with severe symptoms of toxicity and with high fever that could not be allayed after 3 days of treatment;

• an increase in the size of the lung shadow of more than 50% in 48 hours;

• acute lung lesion or appearance of acute respiratory distress syndrome (ARDS). The usual dose for an adult was equal to 80-320 mg/day of methylprednisolone: the dose was increased if necessary, bearing in mind that it is advisable not to take a high dose for too long a period. The exact dose and the course of treatment were adjusted according to the state of the illness, and the dose was gradually reduced and stopped when the condition of the patient improved or once the shadow on the chest radiograph had been absorbed to certain extent. Hormones with a short half-life were recommended.


Prevention and treatment of secondary bacterial infection

Appropriate antibiotics such as quinolones were used as appropriate, depending on the clinical situation.

Treatment with antivirals

The use of antiviral drugs could be considered in the earlier stage of the illness.

Drugs to enhance immunological function

Drugs enhancing immunological functions could be considered for the treatment of severe cases.

Treatment for SARS with Traditional Chinese medicine

This treatment was developed by experts authorized by the Beijing Municipal Administration for TCM, and is recommended by this body.

For patients whose major symptom is high fever

Main symptoms: fever, dry cough, headache, muscular stiffness, inertia, thirst, thin white or white greasy fur on the margin and tip of the tongue, slippery pulse (a pulse coming and going smoothly, feeling slick to the finger like beads rolling on a plate, indicating excess heat syndrome, phlegm and dyspepsia as well as pregnancy).

Principles of treatment: to clear away heat and toxic materials; dispel the “wind” and ventilate the lung

Prescription:

Parched ephedra 5 g, almond 12 g, fossilia chitonis 45 g, Rhizoma Anemarrhenae 10 g, honeysuckle flower 15 g, Fructus Forsythiae 12 g, parched Fructus Gardeniae 12 g, Fructus Scutellariae 12 g, perilla leaf 10 g, Herba Artemisiae 15 g, Radices Puerarire 15 g, pseudostellaria root 15 g.


To be decocted for oral administration; each prescription is decocted into two bags (150 ml/bag); to be taken three times a day, one bag each time.

With the exception of the first, the preparations listed below are prepared with the above herbs to treat patients with the following specific symptoms:

• For patients with persistent high fever: angongniuhuangwan with water.

• For patients with nausea and vomiting: plus 10 g of bamboo shavings, 10 g of Rhizoma Pinelliae and 10 g of ginger.

• For patients with diarrhoea: remove fossilia chitonis and add 12 g of Herba Pogostemi, 12 g of Herba Eupatorii and 10 g of Rhizoma Atractylodis.

• For patients with poor appetite: plus 30 g of three scorched herbs (scorched germinating barley, hawthorn fruit and medicated leaven).

• For patients with severe cough: plus 12 g of Folia Eriobotryae and 12 g of Radix Asteris


Houttuynia injection, qingkailing or xingnaojing injection and shenmai injection can be administered by intravenous drip.

For patients whose major symptoms are cough and shortness of breath

Main symptoms: cough, shortness of breath, chest distress, asthma, thirst, sweating, feeling listless and inert, may or may not be accompanied by fever, cyanosis, flaccid tongue with decreased saliva, feeble pulse.

Principles of treatment: to supplement qi and nourish the yin, remove pathogenic heat and promote blood circulation, relieve cough and asthma.

Prescription:

Radix Panacis Quinquefolii 15 g (to be decocted separately and mixed with other decoction before use), lilyturf root 10 g, Fructus Schizandrae 10 g, and Fructus Corni 12 g, Semen Lepidii 15 g, Radix Asteris 15 g, Folia Eriobotryae 12 g, and Guangdong earthworm 12 g, Radix Salviae Miltiorrhizae 12 g, Radix Paeoniae Rubra 12 g, Chinese globeflower 8 g, Fructus Scutellariae 10 g, Trichosanthes kirilowii Maxim 15 g.


To be decocted for oral administration; each prescription is decocted into two bags (150 ml/bag); to be taken three times a day, one bag each time. The following may be taken in addition to the decoction described above.

• For patients with symptoms accompanied by high fever: plus 30-60 g of unprepared gypsum, 15 g of abrotanum, 0.6-1.2 g of cornu saigae tatariace talcum; or the above decoction may be taken with angongniuhuangwan.

• For patients with poor appetite: plus 30 g of three scorched herbs (scorched germinating barley, hawthorn fruit and medicated leaven) and 10 g of ventriculi galli mucosa.

• For patients with bradycardia: plus shenfu injection for intravenous injection; or plus 10 g of processed Radix Aconiti Carmichaeli, 6 g of Rhizoma Zingiberis and 3 g of asarum herb.

• For patients with copious sputum: plus 30 g of herba nouttuyniae, 30 g of golden buckwheat rhizome and 10 g of Radix Platycodi.

Shenmai injection or shengmai injection can be used selectively in an intravenous drip.


For patients at the convalescent stage

Main symptoms: chest distress, shortness of breath, sweating, palpitations, fatigue, occasional cough, loss of appetite, abdominal distension or loose stool, flaccid tongue with white or greasy fur, slippery and thready pulse.

Principles of treatment: to supplement qi, nourish the yin and strengthen the spleen and stomach.

Prescription:

Pseudostellaria root 15 g, lilyturf root 15 g, Radix Adenophorae 15 g, parched Atractyloides macrocephala 15 g, honey-fried loquat leaf 15 g, Semen Amomi 6 g, three scorched herbs (scorched germinating barley, hawthorn fruit and medicated leaven) 30 g, Radix Astragli 15 g, Radix Puerarire 15 g, Radix Salviae Miltiorrhizae 15 g, Pericarpium Citri Reticulatae 6 g, Rhizoma Polygonati 15 g.


To be decocted for oral administration; each prescription is decocted into two bags (150 ml/bag); to be taken twice a day, one bag each time.

For patients with abdominal distension: replace Radix Adenophorae with 6-10 g of Radix Saussureae and 5g of round cardamon seed.

Chinese caterpillar fungus mycelium preparation or rhodiola root preparation can be administered.

Physicians should tailor the treatment with TCM to fit the specific needs of the individual patient and the different stages of the disease.

Patients characteristics and duration of observations

Records included demographic characteristics (age and sex distribution), basic clinical features of the onset of disease (symptoms, physical signs and results of laboratory examinations), treatment (e.g. administration of hormone, antibiotics, immunomodulator and TCM, and use of a respirator), recent clinical outcome (discharged from hospital, transferred to another hospital or died) and so on. The observation started from the time when the patients were included in the group and continued until they were discharged from the hospital or had died.

Quality control

The following measures were taken to strengthen the quality control of the research process:

• selection of suitable clinical centres and appropriately qualified researchers and clinicians to participate in the studies;

• centralized training of personnel in charge of the clinical centres prior to the start of the studies;

• coordination and settlement of relevant data collection issues through numerous teleconferences;

• appointment of a central coordinator, designated by each clinical centre, and under the leadership of the centre manager, with responsibility for coordinating and handling issues relating to data collection at that centre; and

• strengthening of data management and the verification of original data.


Data management and statistical analysis

The head physicians in the designated hospital filled in a case report form (CRF) for each patient and the details were sent to an independent data centre. After the data in the CRF had been verified, they were entered into the central database. The data were then "locked" (i.e. made read-only) for statistical analysis. ACCESS and SQL Server 2000 were used to set up the database and the SAS6.12 statistical software package was used for the analysis. The data on rates were analysed by X2 testing; the mean value between different groups was tested by t-testing or analysis of variance, and the frequency of classified data was calculated with the rank-sum test. Symptom persistence time was analysed by the LIFETEST procedure, and the mixed effects model used for data from replicate measurements.

Ethical approval

The research project was approved by the State Ministry of Science and Technology, and the research programme was approved by the Independent Ethics Committee of Guang’anmen Hospital affiliated to the China Academy of Traditional Chinese Medicine.

Basic information on the cases

Altogether 549 inpatients clinically diagnosed with SARS, were included in the observation. During the observation period, 14 patients diagnosed with SARS and 11 patients for whom the observation time was shorter than 6 days, due to factors such as hospital transfer, were excluded. The number of SARS patients finally included in the statistical analysis was 524. Patients in both the treatment groups were comparable in terms of age, sex and the state of the illness (Table 1).

Results

Influence on lung inflammation shown in chest radiographs

Digitized scanning of the chest radiographs was conducted for all the patients included in the study. The data were used to set up a SARS chest radiograph library. A team of experts for reviewing and commenting on chest radiographs from SARS patients was organized to discuss and establish the quantitative criteria for assessing chest radiographs, and to conduct quantitative evaluations of the lung inflammation seen on the chest radiographs.

The scores were assigned as follows:

• A high-density consolidation image (similar to mediastinum) scored 3.

• A low-density image (similar to hilar density image) indicating pathological changes due to exudation scored 2.

• A fibrosis image indicating the change in the ultra-early stage of disease or after incomplete absorption scored 1.


The left and right lungs were divided into 12 areas in the upper, middle and lower lobes and the inner and outer zones. Any enlargement or pleural lesions were given a score of 1 for each.

The total possible number of accumulated points was 38. Each chest radiograph was studied by a team consisting of three experienced radiological and respiratory experts who were not informed of the identity of the patient, to determine the pathological areas and the classification of the shadow density on the chest radiographs.

Table 1. Basic information on the cases

Parameter

Case load (percentage)

No of days after disease onset (n = 524)

 

1-7

142 (27.1)

8-14

182 (34.7)

≥ 15

200 (38.3)

   

Onset time (n = 522)a

 

14-31 March

28 (5.4)

01-15 April

183 (35.1)

16-30 April

250 (47.9)

01-15 May

58 (11.1)

16-27 May

3 (0.6)

   

Sex (n = 524)

 

Male

247 (47.1)

Female

277 (52.9)

Age (years) (n = 524)

 

≥ 20

47 (9.0)

21-30

162 (30.9)

31-40

138 (26.3)

41-50

106 (20.2)

> 50

71 (13.5)

   

Occupation (n = 503)b

 

Manual labourers (except farmers)

84 (16.7)

Farmers

12 (2.4)

Students and teachers

58 (11.5)

Hospital staff

113 (22.5)

Employees and cadres

93 (18.5)

Army personnel and armed police officers

18 (3.6)

Restaurant workers

29 (5.8)

Retired people

21 (4.2)

Others

15 (3.0)

Unemployed people

60 (11.9)

   

Classification of illness (n = 524)

 

Normal

360 (68.7)

Severe

153 (29.2)

Critical

11 (2.1)

   

Underlying diseases (n = 493)c

 

Yes

64 (13.0)

No

429 (87.0)

   

Treatment group (n = 524)

 

Integrated (Traditional Chinese medicine + Western medicine)

318 (60.7)

Western medicine

206 (39.3)

 

a Time of onset of disease in two patients was not known. b Twenty-one patients did not state their profession. c No records were available for 31 patients.


The chest radiographs of 231 patients in the integrated treatment group and 130 patients in the group treated with Western medicine, comprising a total of 1561 sheets of chest radiographs, were included in the evaluation. There was no significant difference between the treatment groups in terms of age, sex, hormone administration and time at which chest radiographs were taken. Comparison of the degree of illness between the two groups showed that the illness of patients in the integrated treatment group was more severe than that of those in the group treated with Western medicine.

Overall comparison of lung inflammation scores between the two treatment groups

The Wilcox rank-sum test was not statistically significant, which indicates that there was no significant difference between the overall curative effects in terms of inflammation absorption in the two treatment groups. Comparison of the scores from the chest radiographs of the two treatment groups (Figs. 1 and 2) showed that in terms of the overall efficacy of treatment, the scores on the chest radiographs from the integrated treatment group were lower than those from the group treated with Western medicine. In the patients with severe disease, the total scores from the chest radiographs of the integrated treatment group were clearly lower than that of the group treated with Western medicine (Fig. 3), but showed better curative effects.

Table 2. Comparison of lung inflammation scores between SARS patients treated with traditional Chinese medicine plus Western medicine and with Western medicine alone

Treatment group

No of subjects

Number of chest radiographs

Mean ± SD

Median

Z value

p

All patients

           

Western medicine

130

523

5.85 ± 6.59

4

-0.81

0.21

Integrated treatment
(TCM + Western medicine)

231

1017

6.67 ± 7.61

4

   

Patients with normal type SARS

           

Western medicine

105

396

4.79 ± 5.60

3

0.18

0.43

Integrated treatment
(TCM + Western medicine)

153

635

5.40 ± 6.86

     

Patients with severe type SARS

           

Western medicine

23

115

7.67 ± 6.34

6

- 0.03

0.488

Integrated treatment
(TCM + Western medicine)

72

350

8.16 ± 7.60

6

   

 

SD, Standard deviation; TCM, Traditional Chinese medicine.


Fig. 1. Dynamic comparison between total scores from chest radiographs of all SARS patients in the two treatment groups (traditional Chinese medicine plus Western medicine and Western medicine alone


Fig. 2. Dynamic comparison between total scores of patients with normal SARS in the two treatment groups (traditional Chinese medicine plus Western medicine and Western medicine alone)


Fig. 3. Dynamic comparison between total scores of patients with severe SARS in the two treatment groups (traditional Chinese medicine plus Western medicine and Western medicine alone)

Figures 1, 2 and 3 show that, in the early stage of the disease, the scores of chest radiographs from patients in the integrated treatment group were higher than those of the group treated with Western medicine alone, which indicates that the degree of illness of the SARS patients in the integrated treatment group, at the earlier stage, was more severe than that of the patients in the Western medicine-treated group. This may be the reason why no significant difference was found when the curative effects were compared between the two groups. The results of further analyses at different intervention time-points are described below.

Comparison between scores for lung inflammation in the two treatment groups following early intervention (within 7 days of the onset of disease)

Generally, the total scores from the chest radiographs were obviously lower in the integrated treatment group than in the group treated with Western medicine, and the difference was statistically significant (Z = 3.32, p = 0.0004) (Table 3). This indicates that when intervention begins within 7 days after the onset of disease, the curative effects of the integrated therapy in promoting the absorption of lung inflammation will be better than those of treatment with Western medicine alone (Figs 3 and 4).

For patients with normal-type SARS, the effects of intervention with integrated treatment within 7 days after disease onset on the absorption of lung inflammation were not significantly different from those in the group treated with Western medicine alone (Z = 1.17, p = 0.12).

A comparison of the total scores, before and after the treatment, from the chest radiographs of patients with severe SARS in whom intervention took place within 7 days after the onset of disease, showed that the scores of the integrated treatment group were obviously lower than those of the group treated with Western medicine alone, and the statistical test showed that the difference was significant (p = 0.034; Table 4, Fig. 6), which indicates that if intervention with integrated treatment begins within 7 days after the onset of disease, the absorption of lung inflammation is better than that in the group treated with Western medicine alone.

Table 3. Comparison between scores for lung inflammation in the two treatment groups following intervention within 7 days of the onset of disease

Treatment group

No of patients

Number of chest radiographs

Mean ± SD

Median

Z value

p

All patients

           

Western medicine

36

144

6.39 ± 6.48

4.5

3.32

0.000

Integrated treatment
(TCM + Western medicine)

51

228

4.40 ± 4.97

3

   

Patients with normal-type SARS

           

Western medicine

27

87

4.59 ± 5.22

4

1.17

0.12

Integrated treatment
(TCM + Western medicine)

37

156

3.99 ± 4.67

3

   

Patients with severe-type SARS

           

Western medicine

9

57

9.14 ± 7.24

6

3.45

0.034

Integrated treatment
(TCM + Western medicine)

14

72

5.30 ± 5.48

4

   

 

SD, Standard deviation; TCM, Traditional Chinese medicine.


Fig. 4. Dynamic comparison of overall curative effects between patients in the integrated treatment group and the group treated with Western medicine within 7 days after onset of SARS


Fig. 5. Comparison of curative effects on patients with normal SARS of intervention (within 7 days after onset of SARS) with integrated treatment and treatment with Western medicine alone


Fig. 6. Dynamic comparison of curative effects on patients with severe SARS of intervention (within 7 days after onset of disease) with integrated treatment and treatment with Western medicine alone

The above results indicate that intervention with integrated treatment during the early stage of the disease can alleviate inflammation in the lung, and the effect is more marked in the patients with severe SARS.

Influence on clinical symptoms

An analysis of the changes in the symptoms of the 524 SARS patients indicated that the integrated treatment (i.e. TCM plus Western medicine) was better than the treatment with Western medicine alone at alleviating symptoms such as inertia, tachypnoea and shortness of breath.

Dynamic changes in the main symptoms of both treatment groups during the course of the treatment

Hypodynamia

Two hundred and nine patients (65.9%) in the integrated treatment group and 124 patients (60.8%) in the group treated with Western medicine had hypodynamia at the time when they were assigned to a treatment group. After 14 days of treatment, the number of patients suffering from hypodynamia in the integrated treatment group had dropped by 33.0% to 58 (33.0%), while that in the group treated with Western medicine had dropped by 26.5% to 36 (34.3%), a difference in percentage decrease between the two groups of 6.5%. After 14 days, the curative effects in the integrated treatment group were therefore better than those of the treatment with Western medicine alone (Fig. 7).


Fig. 7. Comparison of symptoms of hypodynamia between the two treatment groups

Shortness of breath

One hundred and fifty-seven patients (49.5%) in the integrated treatment group and 99 patients (48.5%) in the group treated with Western medicine had shortness of breath at the time they were assigned to the treatment groups. After 14 days of treatment, the number of patients with shortness of breath in the integrated treatment group had dropped by 26.2% to 41 (23.3%), whereas that in the group treated with Western medicine had dropped by 25.67% to 24 (22.86%). After 14 days, the curative effects of the integrated treatment were therefore greater than those of the treatment with Western medicine (Fig. 8).


Fig. 8. Comparison of changes in symptoms of shortness of breath between the two treatment groups

Tachypnoea

One hundred and thirty patients (41.0%) in the integrated treatment group and 78 patients (60.8%) in the group treated with Western medicine showed tachypnoea at the time when they were assigned to the treatment groups. After 14 days of treatment, the number of patients with tachypnoea in the integrated treatment group had dropped by 22.3% to 33 (18.8%), whereas that in the group treated with Western medicine decreased by 23.0% to 16 (15.2%). After 14 days, the curative effects of the integrated treatment were therefore greater than those of the treatment with Western medicine alone (Fig. 9).

When decreases in the severity of symptoms such as dry cough, muscular pain and headache were compared between the two treatment groups, no significant difference was found (p < 0.05).

Statistical model analysis

In order to analyse the improvement of hypodynamia resulting from integrated treatment and treatment with Western medicine alone, over time, and to exclude the influence of age, severity of illness, duration of disease, course of treatment and dosage of hormone on the analytical results of curative effects, the accumulative logistic model, known as the MIXED statistical process in SAS software was adopted. Variables for the two therapeutic methods, age, severity of illness, duration of disease, course of treatment, dosage of hormone as well as the interactive influence between therapies and the severity of illness were used to set up the model, which was adjusted for different parameters. The results are shown in Table 4.


Fig. 9. Change in the occurrence of tachypnoea after treatment with traditional Chinese medicine plus Western medicine or with Western medicine alone

Table 4. Improvement of hypodynamia after integrated treatment in a multifactor accumulative logistic model analysis

Effect (parameters of model)

Standard

 

Estimate

error

DF

t-value

p > |t|

Intercept

2.5709

0.2057

3518

12.50

< 0.0001

Group

-0.2640

0.1247

3246

-2.12

0.0343

Typing of Western medicine

-0.7977

0.09548

3223

8.35

< 0.0001

Age

-0.4659

0.1006

3242

4.63

< 0.0001

Duration of disease

-0.007139

0.003971

3273

1.80

0.0723

Group* typing of Western medicine

0.3406

0.1545

3259

2.21

0.0275

Course of treatment

0.1022

0.006232

4817

16.39

< 0.0001

Hormone accumulation

0.000011

0.000034

3560

0.31

0.7534

 

DF, degrees of freedom.


The results show that the influence of factors such as age, type of Western medicine, duration of disease and course of treatment on the improvement of hypodynamia was significant (p < 0.05): the older the patient, the less satisfactory the effects; the more severe the disease, the less satisfactory the effects. The dosage of hormone had no significant influence on the improvement of hypodynamia. After adjustment for the influence of age, course of treatment, severity of illness, duration of disease and the dosage of hormone, the influence of both therapeutic regimens on the improvement of hypodynamia was significant (p < 0.05). In combination with the above analysis on the occurrence of hypodynamia, we conclude that the integrated treatment was more effective than treatment with Western medicine alone in improving hypodynamia.

The same procedure was used to analyse the improvement of shortness of breath by integrated treatment and treatment with Western medicine alone as that described above for the analysis of the effects on hypodynamia, and the results are given in Table 5.

Table 5. Improvement of shortness of breath after integrated treatment in a multi-factor accumulative logistic model analysis

Effect (parameters of model)

Standard

 

Estimate

error

DF

t-value

p> |t|

Intercept

4.1079

0.2164

4357

18.98

< 0.0001

Group

- 0.2418

0.1210

3593

- 2.00

0.0457

Typing of Western medicine

0.6796

0.09527

3608

7.13

< 0.0001

Age

- 0.6617

0.09681

3600

6.84

< 0.0001

Group* typing of Western medicine

0.2385

0.1537

3621

1.55

0.1207

Course of treatment (first 3 days)

1.0692

0.09441

1533

- 11.32

< 0.0001

Course of treatment (first 14 days)

0.6818

0.08084

1433

- 8.43

< 0.0001

Hormone accumulation

0.000115

0.000033

4808

3.51

0.0005

 

DF, degrees of freedom.


Table 6. Improvement of tachypnoea after integrated treatment in multi-factor accumulative logistic model analysis

Effect (parameters of model)

Standard

 

Estimate

error

DF

t-value

p > |t|

Intercept

2.5709

0.2057

3518

12.50

< 0.0001

Group

-0.2413

0.1269

3892

-1.90

0.0573

Typing of Western medicine

-0.9766

0.1050

3919

9.30

< 0.0001

Age

-0.8314

0.1020

3911

8.15

< 0.0001

Course of disease

-0.004211

0.004373

3961

0.96

0.3356

Group* typing of Western medicine

0.1365

0.1651

3938

0.83

0.4086

Course of treatment

0.1167

0.007812

5411

14.94

< 0.0001

Hormone accumulation

-0.00013

0.000038

4168

-3.37

0.000

 

DF, degrees of freedom.


The results of the analysis were essentially similar to those obtained for hypodynamia. The influence of both therapeutic regimens on the improvement of shortness of breath was significant (p < 0.05). However, in combination with the above analysis on shortness of breath, the researchers concluded that the integrated treatment was more effective than treatment with Western medicine alone in improving the symptom of shortness of breath.

The improvements of tachypnoea using integrated treatment and treatment with Western medicine alone were compared using the same procedure as that described above for hypodynamia, and the results are given in Table 6.

The results of the analysis were essentially similar to those obtained for hypodynamia and shortness of breath. The influence of both therapeutic regimens on the improvement of tachypnoea was significant (p < 0.05). However, in combination with the above analysis on tachypnoea, the researchers concluded that the integrated treatment was more effective than Western medicine alone in improving the symptom of tachypnoea.

Table 7. Comparison of the average dosages of hormone used and duration of usage in the two treatment groups

Treatment group

Total dosage of hormones (mg)

Daily dosage (mg)

No of days of hormone use

 

Mean

(SD)

Median

Mean

(SD)

Median

Mean

(SD)

Median

Integrated (traditional Chinese + Western)
(n = 272)

1884.51

(1834.19)

1277.00

115.78

(87.51)

84.40

15.16

(5.77)

15.00

Western medicine alone
(n = 189)

1992.55

(1586.65)

1680.00

130.78

(85.63)

115.33

14.56

(4.50)

15.00

Z

 

3.000

   

5.026

   

0.696

 

p

 

0.0833

   

0.0250

   

0.4041

 

The analysis showed that the integrated treatment had certain advantages over that with Western medicine alone in improving the symptoms of dry cough, muscular pain and headache. However, after adjustment for the influence of age, severity of illness, duration of disease, course of treatment and dosage of hormone on the analytical results of curative effects, the two therapeutic regimens were not significantly different in their ability to improve the symptoms of dry cough, muscular pain and headache.

Influence on the dosage of glucocorticoid

Analysis of the dosage of glucocorticoid used to treat 461 (out of 524) patients with SARS showed that, if there was no significant difference in the time required for the absorption of lung inflammation between the integrated treatment group (272 patients, 18.8 ± 9.7 days) and the group treated with Western medicine (189 cases, 20.8 ± 10.5 days), the daily average dosage of hormone (calculated on the basis of methylprednisolone) for the integrated treatment group was 115.78 ± 87.51 mg/day with a median of 84.40 mg/day, and that for the group treated with Western medicine was 130.78 ± 85.63mg/day with a median of 115.33 mg/day.

Of the 524 patients, 244 (76.7%) in the integrated treatment group and 117 (85.9%) in the group treated with Western medicine had received antiviral drugs, whereas 286 (89.9%) and 190 (92.2%), respectively, had been treated with antibiotics. Two hundred and seventy-two patients (82.9%) and 189 (96.4%), respectively, had been treated with glucocorticoid, and 222 (69.8%) and 174 (84.5%), respectively, had received immunomodulator. After all treatments, except for that with antibiotics (X2 = 0.712, p = 0.374), statistically significant differences were seen between the two treatment groups: antiviral drugs; X2 = 6.690, p = 0.01: hormone; X2 = 4.529, p = 0.033: immunomodulator; X2 = 15.544, p = 0.00).

Influence on the degree of blood oxygen saturation

The dynamic change of blood oxygen saturation of 447 (out of 524) SARS patients was analysed. Of these patients, 276 were in the integrated treatment group and the remainder (171) were in the group treated with Western medicine. The results of the analysis found no significant difference in terms of age, sex or severity of the disease.

After adjustment for the difference in age, severity of disease and the duration of treatment, the general effects on oxygen saturation in the two groups during the entire course of treatment were not significantly different (p = 0.088).

To take into account the influence of different durations of treatment and the severity of illness on blood oxygen saturation, we conducted further stratified analyses and the results, after adjustment for age, are shown in Tables 8 and 9.

The results shown in Table 8 indicate that there was no significant difference at the baseline (0-2 days after being included in the groups), but that the difference between the two groups after a treatment period of 3-14 days, and after more than 15 days was significant, and that the integrated treatment could reduce the risk of an abnormal level of blood oxygen saturation. After a treatment period of 3-14 days, the odds ratio (OR) of the two groups was exp (-0.6582) = 0.5178, and after 15 days, OR = exp(-1.4164) = 0.2426. After adjustment for age, for the patients with normal SARS, there was no significant difference (p = 0.4745) in reduction in the risk of abnormal blood oxygen concentration between the integrated treatment group and the group treated with Western medicine; for patients with severe SARS, the integrated treatment was more effective than the treatment with Western medicine in lowering the risk of abnormal blood oxygen concentration, OR = exp(-1.7173) = 0.18; p = 0.0001.

A stratified analysis of the blood oxygen concentration of patients included in the groups at different stages of illness (early, mid and later stages) was conducted. The results indicated that the difference between the two treatment groups in blood oxygen concentration measured in patients included in the early stage of illness (after 0-2 days) was not significantly different, whereas there was a significant difference between the two groups after 3-14 days of illness. After 15 days the difference was again nonsignificant. Blood oxygen concentration in patients included in the mid and later stages tended to be better in the integrated group than in the group treated with Western medicine, but the difference between the two groups was not statistically significant.

Table 8. Comparison of curative effects on the two groups after different durations of treatment

Duration of treatment (days)

Estimate of difference

Estimated standard deviation

t-value

p-value

0-2

-0.1982

0.2602

-0.76

0.4464

3-14

-0.6582

0.2271

-2.90

0.0038

> 15

-1.4164

0.4156

-3.41

0.0007

Table 9. Comparison of curative effects of both groups according to severity of illness

Disease severity

Estimate of difference

Estimated standard deviation

t-value

p-value

Normal

0.2021

0.2825

0.72

0.4745

Severe

-1.7173

0.3390

5.07

0.0001

A stratified analysis of the blood oxygen concentration of patients included in the groups at different stages of illness (early, mid and later stages) was conducted. The results indicated that the difference between the two treatment groups in blood oxygen concentration measured in patients included in the early stage of illness (after 0-2 days) was not significantly different, whereas there was a significant difference between the two groups after 3-14 days of illness. After 15 days the difference was again non-significant. Blood oxygen concentration in patients included in the mid and later stages tended to be better in the integrated group than in the group treated with Western medicine, but the difference between the two groups was not statistically significant.

Influence on case fatality rate and complications

During our observation of the clinical outcome of the 524 cases of SARS, no patients in the integrated treatment group (318 cases) died, but seven of the patients (3.4%) in the group treated with Western medicine alone (206 cases) died.

The number of patients who experienced complications such as fungal infection, ARDS, disseminated intravascular coagulation and multiple organ dysfunction syndrome and the incidence rates are shown in Table 10. The incidence of complications in the group treated with Western medicine tended to be higher than that in the integrated treatment group.

Table 10. Summary of complications experienced by the 524 patients with SARS

 

Fungal infection

ARDS

MODS

DIC

No of cases (incidence rate)

20 (3.8)

11 (2.1)

6 (1.1)

2 (0.4)

Treatment group

       

Integrated (Chinese traditional + Western)

11 (3.5)

7 (2.2)

1 (0.3)

0

Western medicine alone

9 (4.4)

4 (1.9)

5 (2.4)

2 (1.0

x2

0.416

Precision
Probability

Precision
Probability

Precision
Probability

p

0.519

1.000

0.037

0.522

 

ARDS, acute respiratory distress syndrome; DIC, disseminated intravascular coagulation; MODS, multiple organ dysfunction syndrome.


Table 11. Number of patients with abnormally high levels of alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and blood urea nitrogen (BUN)

 

ALT
(> 40 µ/l)

LDH
(> 240 µ/l)

BUN
(> 8.2 µmol/l)

No of cases (incidence rate)

436 (83.2)

376 (71.8)

291 (55.5)

Treatment group

     

Integrated (Chinese traditional + Western)

260 (81.8)

214 (67.3)

150 (47.2)

Western medicine alone

176 (85.4)

162 (78.6)

141 (68.4)

x2

1.209

7.940

22.916

P

0.272

0.005

0.000

Change of alanine aminotransferase, lactate dehydrogenase and blood urea nitrogen

The numbers of patients in the two treatment groups whose alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and blood urea nitrogen (BUN) were above the normal range and the incidence rate throughout the period of observation are given in Table 11. The results indicate that the incidence of abnormal rises in ALT, LDH and BUN in the group treated with Western medicine tended to be higher than in the integrated treatment group, which suggests that the integrated treatment does not increase the incidence of abnormal rises of ALT, LDH or BUN.

Conclusions

Our initial research results showed that the integrated treatment (TCM in combination with Western medicine) may have advantages over treatment with Western medicine alone, and the advantages are reflected in the following findings: the integrated treatment can help alleviate lung inflammation caused by SARS, improve the level of blood oxygen saturation, alleviate symptoms of hypodynamia, tachypnoea and shortness of breath, and reduce the required dose of Western medicines such as glucocorticoid. Our initial safety evaluation also suggested that the integrated treatment is safe.

 

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