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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 4: Clinical study on 103 inpatients undergoing therapy with integrated Traditional Chinese medicine and Western medicine

Lin Lin22, Han Yun22, Yang Zhimin22, Liu Weisheng22, Zhang Minzhou22, Tang Guanghua22 and Xu Yinji22

22 Guangdong Provincial Hospital of Traditional Chinese Medicine 510120, People's Republic of China


Abstract The objective of this study was to investigate the law of dynamic change of the state of patients with atypical pneumonia, also known as severe acute respiratory syndrome (SARS), and the clinical curative effects of therapy with integrated Traditional Chinese medicine (TCM) and Western medicine. The subjects of this study were 103 patients who had been diagnosed with SARS between January and April 2003, who were all treated with a therapeutic regimen of integrated traditional Chinese and Western medicine. In a retrospective study, information was collected on the general conditions, symptoms, results of laboratory examinations, and therapeutic effects, for all the patients when they were admitted to hospital. Emphasis was placed on the dynamic data collected at regular intervals from 77 patients with severe conditions. Data included information on clinical symptoms, body temperatures, results of routine blood tests and chest radiographs. Data were used to establish the database to conduct statistical analyses such as the X2 test, t-test, descriptive analysis and so on. Of the 103 patients, 77 had severe SARS and 26 had normal SARS: 7 (6.97%) died during the course of the study and 96 (93.21%) were cured and discharged. The defervescence time of the 103 patients after treatment in the hospital was 6.72 ± 3.95 days. Of the 77 severe cases, 29 (37.66%) were transferred to the intensive care unit for further treatment, 40 patients (51.95%) underwent non-invasive ventilation, whereas eight patients (10.39%) required invasive ventilation. The defervescence time of the 77 severe cases after treatment in the hospital was 8.34 ± 5.06 days. Unlike the patients with normal SARS, the 29 patients with severe SARS (37.66%) had lesions over the whole lung, and patchy images and a misty image on the chest radiograph were more common in these patients (p < 0.05). There are some recognizable patterns in the changes of clinical symptoms, laboratory examination results and chest radiographs of SARS patients. The patient with serious SARS had a more rapid clinical course and a poorer prognosis. A therapeutic regimen of integrated TCM and Western medicine had obvious curative effects on SARS patients.

Introduction

The World Health Organization (WHO) termed the atypical pneumonia, first seen in 2003, as severe acute respiratory syndrome (SARS) (1). SARS has been reported from 32 countries and regions around the world. From January to April 2003, 103 SARS patients were admitted to the Guangdong Provincial Hospital of Traditional Chinese Medicine, including 77 severe cases. All inpatients were treated with a therapeutic regimen of integrated traditional and Western medicine. A retrospective study was conducted to determine the patterns of dynamic variation in the condition of SARS patients and learn about the clinical curative effect of treatment of SARS patients with integrated Traditional Chinese medicine and Western medicine.

Subjects and methods

Study design

The study was conducted by retrospective research on clinical cases of SARS.

Subjects

One hundred and three patients were included in the study; they were all inpatients at the Guangdong Provincial Hospital of Traditional Chinese Medicine.

Diagnostic criteria

The diagnostic criteria adopted were the “Diagnosis criteria of SARS clinical case” in the Guideline for clinical diagnosis of severe acute respiratory syndrome issued by Health Department of Guangdong Province on 9 March 2003 (2).

Inclusion criteria

Inpatients were eligible for inclusion if their clinical diagnosis was in accordance with the above-mentioned diagnostic criteria for SARS.

Exclusion criteria

Subjects who did not meet the diagnostic criteria were not eligible for inclusion in the study.

Therapeutic regimen

Treatment with Western medicine was based on the Guideline for clinical diagnosis of severe acute respiratory syndrome issued by the Health Department of Guangdong Province (2). Treatment with integrated traditional and Western medicine was based on the clinical stages and types into which SARS is classified by applying the theories of TCM on epidemic febrile disease of the four systems (wei, qi, ying and xue) and differentiation according to the tri-jiao.

Western medicine regimen

The main components of the Western medicine regimen included prescription of medicine specific for the illness, oxygen inhalation or assisted ventilation with breathing apparatus, hormone administration, nutritional support, administration of antibiotics, antiviral treatment and immune regulation.

Symptomatic treatment

Patients with a body temperature higher than 38.5°C were treated with nonsteroidal anti-inflammatory drugs. Patients with a cough were treated with drugs such as carberapentane citrate or codeine.

Oxygen inhalation or assisted ventilation with breathing apparatus

Oxygen inhalation was supplied through a nasal tube if indicated by the oxygen saturation of haemoglobin, the respiratory rate and the arterial blood gas analysis. Non-invasive inhalation of oxygen through a face mask as well as invasive ventilation was supplied to those patients in whom this was indicated. Non-invasive positive-pressure ventilation was chosen if the patient’s respiratory rate was more than 30 times per minute or the oxygen saturation of haemoglobin was less than 93% even when oxygen was being inhaled at 3-5 litres per minute; nose-cup CPAP was the first option at a pressure level of 4-10 cmH2O, and was administered continuously until the condition of the patient improved. Invasive positive pressure ventilation was chosen if the oxygen saturation of the patient's haemoglobin was still less than 90% even when inhaling oxygen at 5 litres/minute or if the oxygenate index was less than 200 mmHg after treatment with non-invasive positive-pressure ventilation, or if the patient could not tolerate the treatment with non-invasive positive-pressure ventilation.

Administration of glucocorticoids

Glucocorticoids were administered only to patients who had serious toxicity symptoms or to those who met the criteria for severe illness (i.e. those who had had a high fever for more than 3 days or whose chest radiographs had shown a trend of progressive aggravation). The usual dosage of methylprednisolone was in the range from 40 to 240 mg per day, but for the severe cases, a dosage of 500 mg per day could be administered. The dosage was regulated on a case-by-case basis.

Nutritional support

Nutrient mixture, compound amino acids and vitamins were administered through an intravenous drip. A fatty emulsion was also added to the drip fluid if the patient had a poor appetite, and albumin was supplied intravenously when the patient had a low level of albumin.

Administration of antibiotics

Regimen 1 adopted during the early stage of illness: azithromycin plus one type of beta-lactam.

Details of usage: azithromycin 0.5 g per day in intravenous drip on day 1, then azithromycin 0.25 g per day in intravenous drip on days 2-7, plus one type of beta-lactam simultaneously. The main beta-lactams included cefotaxime sodium at a dosage of 2-4 g per day administered twice daily in an intravenous drip, ceftazidime at a dosage of 2-6 g per day, administered twice or three times daily by intravenous drip, ceftriazone, 2-4 g per day once or twice daily by intravenous drip; cefepime, 2-4 g per day administered twice daily by intravenous drip; cefoperazone sodium and sulbactam sodium: 2-4 g per day administered twice daily by intravenous drip.

Regimen 2 adopted during the early stage of illness: levofloxacin 0.3 g per day by intravenous drip, plus tetracycline 2 g per day in four daily doses, administered orally. Vancomycin or norvancomycin was the treatment of choice if the results of sputum culture or the clinical symptoms suggested the presence of infection with drug-resistant cocci. Tienam was administered at a dosage of 1.5 g per day three times a day by intravenous drip.

Administration of antiviral drugs

Oseltamivir, a neuraminidase inhibitor, was administered to 34 patients at a dosage of 150 mg twice per day for the first three days and then 75 mg per day until the end of the course of treatment (a course lasted 7-14 days if begun during the early stage of SARS).

Immunomodulator

Usually, gamma globulin at a dosage of 5 g per day was administered in an intravenous drip for 3 days. When the lymphocyte count was low, thymosin was injected at a dose of 160 mg once per 3 days.

Regimen of traditional Chinese medicine

According to the theories of Traditional Chinese medicine on the four systems (wei, qi, yin and xue) and differentiation according to the tri-jiao, the course of this disease can be divided into four parts: early stage, middle stage, fastigium stage (climax) and convalescent stage.

Early stage

This stage is defined as the period of 1-5 days or so after onset of illness. According to the differentiation of symptoms and signs, it should be treated by drainage of the moist heat and with sanren decoction in combination with shengjiang san powder and other drugs if appropriate. If the disease belongs to the moist heat and damages the defences of the lung, it should be treated by dispelling wind and relieving exterior syndrome (superficial or mild illness chiefly manifested by a chilly sensation, fever, headache, generalized aching and aching limbs) and by facilitating the flow of the lung-qi and clearing away heat with a recipe of yingqiao powder, maxin ganshi decoction in combination with shengjiang san powder and other drugs, if the disease belongs to the exterior cold and interior heat with dampness.

If heat pathogen was more serious in the early stage, one of the following injections was chosen and administered during a treatment course of 7 days or so until fever subsided or weakened body resistance was strengthened. The injections were:

• cordate houttuynia; 50-100 ml per day in an intravenous drip.
Qingkailing, 40 ml with 5% glucose; 250 ml per day in an intravenous drip.
• Double coptis root injection, 3.6 g with 5% glucose; 500 ml per day in an intravenous drip.


Middle stage

This stage was defined as the period 3-10 days after onset of illness. If the disease belongs to the moist heat and containing toxin, it should be treated by clearing away heat and the wetness pathogen and by detoxification with or without ganluxiaodu dan. If the disease belongs to pathogenic factor which damages shaoyang, it should be treated by dissipating and discharging shaoyang and by clearing away heat and wetness pathogen with or without a gaocenqingdan tang decoction. If the disease sits in the half-superficies and half-interior position, it should be treated by leading off the pathogen with or without a dayuan drink.

If heat pathogen is serious or if the symptoms presented indicate the state of "containing toxin", one of the injections listed above for the early stage could be used. If fatigue is obvious or if there is a feeble pulse with little strength, shenmai injection can be administered at a dosage of 50-100 ml per day in an intravenous drip until the symptoms abate.

Fastigium stage (climax)

The clinical pathogenesis is characterized by abundant wet heat and toxin that dissipates qi and damages yin, and the stasis of wet heat and toxin in the lung is the main feature. The main manifestations include obvious polypnoea and dyspnoea, which may be accompanied by cyanosis, abdominal distension, constipation or loose stool. It should be treated by clearing away heat and eliminating dampness, facilitating the flow of the lung-qi, regulating the flow of qi, and removing yong, while paying attention to strengthening the body’s resistance.

During the early phase of this stage, the stasis of wet heat and toxin in the lung is the main manifestation, and treatment is directed towards clearing away heat and toxins, regulating qi, invigorating the blood and eliminating dampness, as well as facilitating the flow of the lung-qi and removing yong. Medicine for supplementing qi and nourishing yin can be added when necessary. The treatment can include ganluxiaodu dan and wuhu tang decoction, plus tuber of aromatic turmeric, raw cattail pollen, Leonurus heterophyllus, chuanlian, British inulaflower, seed of peppergrass, balloonflower root, as well as bitter orange. The recipe for supplementing qi and nourishing yin is pseudostellaria root, plus gypsum and powder of antelope horn or buffalo horn if fever is serious.

At the advanced stage, phlegm dampness and toxin exacerbate the stasis of the lung-qi, which decreases the functional activities of the lung; the weakness of spleen-qi and lung-qi are the main manifestations. The patients may suffer from dyspnoea, asthma and feeling of suffocation, thin and white sputum, weakness of limbs, fatigue, loose stools, diarrhoea, a pale, enlarged and dark tongue, white and muddy tai, and slippery and weak pulse.

Treatment of these patients should aim at replenishing qi to invigorate the spleen, regulating qi and invigorating the blood, dispersing phlegm and eliminating dampness, as well as purging the heat accumulated in the lung and eliminating the yong in the lung. The treatment can comprise buzhong yiqi tang and wuhu tang decoction, accompanied by xiefei tang decoction with whitlow grass and Chinese date, plus ercheng tang decoction, sanziyangqing tang decoction, pingwei powder and xiaochengqi tang decoction to enhance the function of regulating the flow of qi and eliminating dampness and clearing away the yong, plus lycopus herb, raw cattail pollen, Leonurus heterophyllus, peach kernel and safflower to stimulate circulation to end stasis.

If the patient presents with ice-cold limbs, pale and enlarged tongue and weak pulse, it means that the patient is in a state of weak qi and yang. Shufuzi, common fennel fruit and cassia twig should be added.

If the patient is suffering from dropsy, wu lin san and zhen wu tang should be added to the prescription.

A few patients can show pathogenic factor in blood, vigorous heat of qi and ying, and exhausted qi and asthma. According to the differentiation of syndromes, symptoms and signs, treatment should be focused on clearing away heat located at yingfen and detoxification, as well as on supplementing qi and nourishing yin, with qingying tang and pulse-activating powder if the patient’s symptoms result from invasion of the ying system by pathogenic heat and from dissipating qi and damaging yin.

Injections

According to the differentiation of syndromes, symptoms and signs, patients whose symptoms result from excessive pathogenic factor and weakened body resistance, or from loss of consciousness and collapse could be grouped into five categories.

For patients deficient in yin-qi and who exhibit prostration syndrome: Shenmai injection at a dosage of 100 ml to 200 ml per day was administered intravenously or in an intravenous drip in several daily doses in addition to a decoction of American ginseng and pulp of dogwood fruit.

For patients deficient in yang-qi: Shenfu injection at a dosage of 20-100 ml per day intravenously or in an intravenous drip in several daily doses in addition to a decoction of red ginseng and Paofuzi.

For patients with heat blockage: half pill of cow-bezoar bolus once or twice a day.

For those suffering from impairment by turbid pathogen: a half pill of storax should be taken once or twice a day. If the patient has no obvious haemorrhagic tendency, 30 ml xiangdan injection with 250 ml 5% glucose can be administered once a day in an intravenous drip. Patients with digestive problems received huoxiangzhengqi water at a dosage of 30 ml three times per day and berberine at a dosage of 0.9 g/day three times daily.

Convalescent stage

This stage is usually defined as the period 10-14 days after the onset of illness, with the main pathogenesis of weakened body resistance and invasive pathogenic factor as well as an inclination towards dampness and stasis. The treatment of patients at this stage should focus on eliminating the pathogenic factor and strengthening the body resistance with attention being paid to eliminating dampness and to activating blood circulation. According to the differentiation of syndromes, symptoms and signs, if the patient’s symptoms result from weakness of qi and yin, the treatment should focus on supplementing qi and nourishing yin with a shenmai powder or shashengmaidong tang decoction. If the patient’s symptoms result from weakened qi with dampness and stasis, the treatment should focus on supplementing qi and clearing away the wetness-pathogen, as well as on activating blood circulation and expelling the obstruction from the branches of the meridians, with lishiqingshuyiqi tang decoction, shenlinbaishu powder or xuefuzhuyu tang decoction adjusted according to the needs of the individual patient.

The patients at this stage of the illness who had suffered from deficiency of qi and yin were treated with shenmai injection at a dosage of 50 ml in an intravenous drip for one or two 7-day courses. Alternatively, a solution of pulse-activation decoction was given orally, at a dosage of 30 ml three times per day for two or three 7-days courses. Patients at this stage of illness who had suffered from obvious deficiency of qi were treated with a 30-ml injection of astragalus root added to 250 ml 5% glucose or 0.9% normal saline in an intravenous drip once a day for one or two courses of 7 days. For those patients who had stasis of blood, a 30-ml injection of xiangdan was added to 250 ml 5% glucose or 0.9% normal saline once a day for one or two courses of 7 days, accompanied by an orally administered solution of xuefuzhuyu at a dosage of 10 ml three times a day and for one or two courses of 7 days.

Observations

Clinical symptoms such as fever, cough, panting, joint and muscular aching, nausea and vomiting, diarrhoea, as well as the appearance of the tongue and the strength of the pulse; signs such as body temperature and respiration; results of routine blood tests, tests of renal function and liver function, chest X-ray and chest spiral CT.

Quality control

The following quality control measures were implemented.

• All doctors who worked with SARS patients in isolation wards were trained in the diagnosis and treatment of SARS.

• The 103 patients were all confirmed as clinically diagnosed cases after consultation with the Guangdong group of SARS experts.

• Data management protocols were implemented and original material checked.

• All herbal decoction pieces to be used had to comply with the requirements specified in the Chinese Pharmacopoeia (2000 Edition, Part I) and the patent medicines used were prescription drugs for which market approval had been obtained from the Chinese drug administration.


Statistical treatment

The database was set up and statistical analysis carried out using the SPSS10.0 statistical package. Tests for normality and homogeneity were followed by the X2 test, rank-sum test and t-test, ∝ = 0.05.

Results

Status of patients admitted to hospital

General data

Of the 103 patients who participated in this study, 44 were male and 59 were female. The oldest patient was 79 years old and the youngest was 19 years old. The mean age was 34.64 ± 12.69 years. Ninety-three patients (90.29%) had a history of contact with SARS, whereas 10 had an unknown contact history. The average age of the 77 patients with severe SARS was 35.52 ± 13.38. Of these, 92.21% patients had a history of contact with SARS. The time between onset of illness and admission to hospital was 3.56 ± 2.67 days.

Symptoms, signs and appearance of tongue and characteristics of pulse at the time of admission

Fever was the common symptom of onset in all 103 patients. The major symptoms included: fever, muscular stiffness, aversion to cold, diarrhoea, fatigue, shortness of breath, chest distress, headache, cough, blood-streaked sputum, nausea and vomiting, red tongue, thin and yellowish tongue fur, yellowish and greasy tongue fur, and white and greasy tongue fur (Fig. 1).


Fig. 1. Clinical symptoms of 103 patients with SARS

Body temperature at the time of admission

The highest temperature in the 103 patients was 39.11°C ± 0.98. Eighty-one patients (78.64%) had a body temperature higher than 39°C. The period of time for which body temperature was higher than 39°C ranged from 1 day to 11 days with a mean value of 3.05 ± 2.21 days (Fig. 2).


Fig. 2. The highest body temperature measured in 103 patients with severe acute respiratory syndrome

Results of laboratory tests at the time of admission

The results of peripheral blood tests and major indices of liver and kidney functions of the 103 SARS patients at the time of their admission to hospital are summarized in Fig. 3.


Fig. 3. Results of laboratory tests on 103 patients with severe acute respiratory syndrome at the time of their admission to hospital

Evaluation and classification of severity

Seventy-seven cases met the standard of “Clinical diagnostic criteria of infectious SARS”; the others were all normal cases. Patients with severe SARS all had lesions in multiple lung lobes, sometimes accompanied by underlying disease. The lesions progressed relatively rapidly and there were sometimes complications such as hypoxaemia, acute respiratory distress syndrome (ARDS) or multiple organ dysfunction syndrome (MODS). Of the patients with severe SARS, 40 received non-invasive ventilation, eight received invasive ventilation and 29 were transferred to the intensive care unit (Fig. 4).


Fig. 4. Evaluation of severity and major complications in 77 patients with severe cases of disease

ARDS, Acute respiratory distress syndrome; MODS, multiple organ dysfunction syndrome.

(a) Hypoxaemia was defined as SaO2 < 93% or oxygenation index < 300 mmHg when 3-5L/min oxygen was supplied.

(b) Underlying diseases: these included three patients with diabetes mellitus, one of whom had undergone amputation because of diabetic gangrene; three patients with coronary heart disease, one of whom had had a mitral valve replacement because of rheumatic heart disease; two patients with chronic renal failure; one patient with Crohn disease complicated by partial resection of the jejunum because of intestinal obstruction; and five patients with hypertensive disease.


Dynamic course of patient’s condition

Changes in body temperature

The dynamic variations of body temperature in the patients after their admission to hospital are shown in Fig. 5.


Fig. 5. Day-by-day changes of body temperature (median) in patients with serious and normal severe acute respiratory syndrome

Dynamic course of clinical symptoms of 77 patients with severe SARS

Symptoms such as aversion to cold, chills, headache, arthralgia and muscular aching, nausea and vomiting and diarrhoea were seen more frequently in the early stages of the illness. Symptoms in the respiratory tract such as cough, chest distress, and shortness of breath were aggravated between the seventh and ninth days after onset of illness, and general symptoms such as fatigue and inertia were also aggravated between the seventh and ninth days (Fig. 6a and Fig. 6b).

Results of dynamic routine blood tests of 77 patients with severe disease

At the onset of SARS, 46 patients (75.41%) had a normal white blood cell count and 13 patients had a decreased white blood cell count. The proportion of patients with an increased white blood cell count increased from the seventh day after onset and reached 29 cases (59.18%) on the twenty-first day. At the onset of illness, 23 patients (37.7%) had a decreased lymphocyte count. On the fourteenth day, the number of patients with a decreased lymphocyte count reached its peak (32 cases, 47.76%). During the initial stages of SARS, 58 cases (95.08%) had a normal or decreased neutrophilic granulocyte count. Seven days later the proportion of patients with an elevated neutrophilic granulocyte count increased significantly and reached 32 cases (65.30%) on the twenty-first day. During the early stages of SARS, 64 cases (84.21%) had a normal blood platelet count, and the proportion of patients with an increased platelet count rose from the fourteenth day. Only 2-6 patients (3.94-7.89%) had a decreased blood platelet count. All these counts had returned to a normal level by the time of follow-up (Figs 7 and 8).


Fig. 6. Dynamic course of clinical symptoms of 77 patients with severe disease (a)


Fig. 6. Dynamic course of clinical symptoms of 77 patients with severe disease (b)


Fig 7. Dynamic course of white cell count of peripheral blood for 77 patients with severe illness (x ± s)

A pair-matching t-test was used.
**Comparison with the first day p < 0.01.


Fig. 8. Dynamic course of platelet count of peripheral blood for 77 patients with severe illness (x ± s)

A pair-matching t-test was used.
**Comparison with the first day, p < 0.01.


Features of chest radiograph at image fastigium stage

All 77 patients with severe SARS underwent chest radiography and 29 of them had lesions over the whole lung. The main manifestations of severe SARS seen on radiographs were patchy shadow, large patches of shadow and misty images. The images of large patches of shadow and misty appearance were more common on the chest radiographs of patients with severe SARS than in patients with normal SARS and the difference was statistically significant (p < 0.05) (see Table 1). (Note: image fastigium stage was defined as the time when the maximum focus was steady and would not expand any further.)

The results indicated that patients with severe SARS had a significantly higher proportion of large patches and misty images of parenchyma and mesenchyma than patients with normal SARS.

Table 1. Comparison of features of chest radiograph on image fastigium stage between patients with severe and normal SARS

Severity of illness

Small patch image

Patchy shadow

Large patches

Misty image

Exudation

Consolidation

Alteration of parenchyma

Mixed alteration of parenchyma and mesenchyma

Severe
n = 77

2

47

24

14

41

42

38

36

Normal
n = 26

6

16

2

0

17

9

15

4

Outcome of treatment

Gross effect

Of 103 patients, 96 (93.21%) were clinically cured and discharged and seven patients (6.79%) died. Two patients had a focus of fibrosis on their chest radiographs and one patient had diminution of eyesight after discharge. After admission and treatment, defervescence time was 6.72 ± 3.95 days and few patients relapsed.

Of the 77 patients with severe SARS, two had infective shock, three had disseminated intravascular coagulation, seven had impaired renal function, eight had impaired liver function, eight had arrhythmia, six had haemorrhage of upper digestive tract, 18 had ARDS, eight had MODS, and one suffered from pneumothorax after endotracheal intubation. After the treatment, 70 (90.91%) of the patients who had had severe illness were clinically cured and discharged and seven (9.09%) had died. After admission and treatment, defervescence time was 8.34 ± 5.06 days. Twenty-nine patients were transferred to the intensive care unit. During their treatment, 40 patients (51.95%) received non-invasive ventilation and eight patients (10.39%) received invasive ventilation.

Results of examination of further chest radiographs

In 94 out of 96 patients (97.91%) the lung focus had completely disappeared. The time taken for focus absorption was 18.13 ± 8.99 days. Two patients had a focus of fibrosis on their chest radiographs.

Analysis of patients who died

The average age of the seven patients who died, all of whom had severe SARS, was 51.57 ± 13.36 years; the oldest was 75 years old and the youngest was 35 years old. Three of the patients who died had serious underlying cardiovascular disease. One patient's condition deteriorated quickly and this patient died within 72 hours after admission to hospital. All these patients developed ARDS and progressed to MODS and death.

Results of sputum culture

Secondary bacterial infection was detected in 38 SARS patients and 55 separate bacterial strains were identified, including 25 strains of Gram-negative bacillus (20 strains of non-zymogen), 20 strains of Gram-positive cocci (13 strains of staphylococci with negative coagulase) and 10 strains of Candida albicans.

Administration of glucocorticoids

Of the 103 SARS patients, 69 had been administered glucocorticoids whereas 34 had not. The intravenous glucocorticoid used was generally methylprednisolone except for three cases in which decasterolone (5-10 mg/day, 1-3 days) was administered in the initial stages of illness. In the later stages of the disease, the doses of glucocorticoid were decreased and oral preparations of prednisone and methylprednisolone were chosen (all dosages were converted to equivalent dosages of methylprednisolone). Those patients who had not been treated with glucocorticoids all recovered and were subsequently discharged (Table 2).

Table 2. Administration of glucocorticoids

Severity of illness

No glucocorticoids administered

Glucocorticoid administered

Maximum dosage per day (mg)

Minimum dosage per day (mg)

Mean dosage
(mg) ± standard deviation

Course of treatment (days) ± standard deviation

Normal
n = 26

14 (54)

12 (46)

160

40

83.33 ± 39.85

8.83 ± 5.69

Severe
n = 77

20 (26)

57 (74)

500

10

166.83 ± 116.06

18.80 ± 2.23

Discussion and conclusion

Dynamic analysis of clinical data from patients with severe illness

All 103 patients had a rapid onset of illness. The majority of them were adults with a mean age of 35.52 ± 13.38 years and 92.21% of patients had a history of contact with the disease. Fever was the common symptom of onset, and 66 patients had a body temperature exceeding 39 °C. Patients with severe SARS had a higher body temperature and longer duration of fever than patients with normal SARS. Fluctuation of body temperature was noted in the course of defervescence, but body temperature returned to normal rapidly when it was lower than 38 °C. During the early stage of SARS, common symptoms included fever, aversion to cold, chills, headache, muscle and joint pain, nausea and vomiting, and diarrhoea. These symptoms were considered to be the presentation of viraemia. As the illness progressed, respiratory tract symptoms such as cough, chest distress and shortness of breath, and general symptoms such as fatigue were gradually aggravated during days 7-12 of the illness; this period coincided with radiological manifestation at the image fastigium stage (9.91 ± 3.58 days) of severe SARS. Autopsy of patients who had died from SARS revealed acute diffuse whole-lobule interstitial pneumonia and formation of transparent membrane in the alveoli that could lead to hypoxaemia or to ARDS and was the main reason for aggravation of symptoms at the fastigium stage.

Patients with severe SARS usually had a normal or lowered white blood cell count at the onset of illness and an increased white blood cell count during the middle and final stages of the disease which peaked on day 21. Twenty-five patients (32.46%) still had an increased white blood cell count when they were discharged from hospital. At the onset of SARS, 23 patients (37.7%) had a decreased lymphocyte count. On the fourteenth day, the number of patients with a decreased lymphocyte count reached its peak (32 cases, 47.76%) and the lymphocyte count decreased to its lowest point (1.11 ± 0.66 × 109/l). Few patients had a decreased blood platelet count; of these three suffered from disseminated intravascular coagulation and died. Twenty-six patients (38.80%) had an increased platelet count during the middle and last stages of the disease. Abnormal blood counts had returned to the normal level by the time the patients were followed up. These results indicated that the SARS virus could impair immunological function at the onset of illness, and caused lymphocytopenia. The serious decrease in the number of lymphocytes at the middle stage of the disease could be the result of double immunosuppression caused by glucocorticoids; this was a reversible impairment and the count was restored to normal when the patient's condition improved. The results of autopsies of SARS patients revealed that the lymphatic and haematopoietic system outside the lungs was impaired, particularly the production of T lymphocytes. Visceral bleeding, necrosis and vasculitis constituted the morphological features of acute SARS (4). The observations noted from the autopsies were in accordance with changes in the numbers of lymphocytes and platelets noted in our patients. The increased blood platelet count that occurred in the middle and final stages of SARS was considered to be the result of the administration of high doses of glucocorticoids, and its influence on the condition of the patients was unclear. During the middle and final stages of the disease, immunological function was depressed because of virus infection and administration of glucocorticoids, which led to secondary infections that accounted for the significant increases in the counts of white blood cells and neutrophils. Non-zymogen bacteria were responsible for most of the secondary bacterial infections, and infections caused by staphylococci with negative coagulase were second most common. Infection with Candida albicans or simultaneous infections with two or three different types of bacteria were seen in patients with serious SARS. Candida albicans infection was seen in those who had a flora imbalance.

The chest radiographs of patients with severe SARS presented a large focus that progressed rapidly. Twenty-nine patients had lesions over the whole lung. At the fastigium stage, large patchy shadow and misty shadow were the main manifestations of lung lesions. Relative to the radiographs of patients with normal SARS, serious SARS had a larger focus and longer absorption time, and residual lung lesions were seen in some patients who had severe SARS.

Analysis of results of treatment with integrated Traditional Chinese medicine

All 103 patients with SARS in this study had a rapid onset of illness and most had a history of contact with the disease and were seriously ill. Of the 103 cases, 77 met the diagnostic criteria for severe SARS. After treatment with integrated Chinese medicine and Western medicine, 96 (93.21%) of the 103 SARS patients had been cured clinically and seven had died (6.79%). Those who were cured had a defervescence time of 6.72 ± 3.95 days after admission and no relapse of fever. The chest radiographs of ninety-four of the patients showed complete absorption. Of the patients with severe SARS, 70 (90.91%) had been clinically cured and discharged and seven had died (9.09%), a rate lower than that for patients with severe "typical" pneumonia. In addition, the absorption of lung focus in these patients was good. Therapy with integrated traditional and Western medicine was adopted to treat this group of SARS patients, and emphasis was put on strengthening the body resistance to eliminate pathogenic factors in combination with reinforcement of protection and elimination of disease. Modern medicine places emphasis on support and monitoring. The results of the combination of support and monitoring indicate that therapy with integrated Chinese medicine and Western medicine has a good curative effect on SARS.

Administration of hormone

A major symptom of SARS was hypoxaemia, and patients with severe SARS were liable to progress to ARDS. SARS virus and administration of glucocorticoids inhibited immunological function, especially cellular immunity, making SARS patients susceptible to secondary bacterial infections during the last stage of disease. Certain "modern" medical treatments, notably effective oxygen therapy and assisted ventilation with breathing apparatus had an important impact on prognosis. For patients with severe SARS, timely administration of glucocorticoids was helpful in ameliorating toxicity symptoms and alleviating inflammation of the lung. But it must be noted that glucocorticoids were a double-edged sword in the treatment of SARS. In this study, 54% of patients with normal SARS and 26% of the patients with severe SARS had not been treated with glucocorticoids, and in other patients the dosage of glucocorticoids was low, which might be the result of the treatment with TCM. Further research is needed to determine whether there was a difference in prognosis between patients who were not given glucocorticoids and those who were. Previous studies have shown that a lower dosage of glucocorticoids leading to fewer side-effects could be used if TCM was added to the treatment regime. The interaction of glucocorticoids and TCM in SARS patients merits further research.

In conclusion, for the management of SARS, treatment that integrates traditional Chinese and Western medicine can incorporate the merits of both. Modern medicine is excellent for supporting, monitoring, reducing inflammation and so on, whereas Traditional Chinese medicine can ameliorate symptoms and improve curative effect by strengthening the body's resistance enabling it to eliminate pathogenic factors, and by adjusting body condition through individual diagnosis and treatment on the basis of an overall analysis of the illness and the patient's condition. Further research will be needed to clarify the mechanism of action of TCM on SARS and the interaction between TCM and Western medicine, as well as the impact of TCM on prognosis of SARS.

Acknowledgements

In the process of developing the TCM regimen for SARS control, the following experts in TCM gave us useful guidance: Professor Deng Tietao and Professor Peng Shengquan, Guangzhou University of Traditional Chinese Medicine; Professor Ren Jixue, Changchun College of Traditional Chinese Medicine; Professor Jiao Shude and Professor Chao Enxiang, Beijing China-Japan Friendship Hospital; Professor Lu Zhizheng and Professor Lu Guangshen, China Academy of TCM; Professor Yan Dexin, Medical College of Shanghai Tongji University and Professor Zhou Zhongying, Nanjing, University of Traditional Chinese Medicine. We hereby express our thanks.

We are grateful for funding received from Special Funds for SARS of the State Administration of Traditional Chinese Medicine, People's Republic of China (GZYKFDZX No. 08).

References

1. Update: outbreak of severe acute respiratory syndrome - Worldwide, 2003. Morbidity and Mortality Weekly Report, 2003, 52:241-248.

2. Guangdong Provincial Hospital’s guideline to clinic work of severe acute respiratory syndrome. Guangdong Province, Health Bureau of Guangdong province, 2003.

3. Lai Riquan et al. Autopsy tissue’s clinical pathology and ultrastructure of SARS patients. Chinese Journal of Pathology, 2003, 32:201-204.

4. Lang Zhengwei, et al. Autopsy tissue’s pathological analysis for 3 cases of SARS patients. Chinese Journal of Pathology, 2003, 32:205-208.

 

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