Original Research

Effect of integrated traditional Chinese medicine and western medicine on the treatment of severe acute respiratory syndrome: A meta-analysis

Yan CHEN, Jeff J. GUO, Daniel P HEALY, Siyan ZHAN.

ABSTRACT Background: Data regarding the treatment efficacy of integrative treatment of Traditional Chinese Medicine (TCM) and Western Medicine (WM) in treating patients with (SARS) are conflicting. The effects of integrative TCM/WM treatment have not been fully quantified. Objectives: To systematically asses the treatment effects of integrated TCM with WM versus WM alone in patients with SARS, incorporating data from recently published studies. Methods: A meta-analysis was conducted, using published randomized and nonrandomized controlled clinical studies that compared the treatment effects of integrative TCM/WM with WM alone from 2002 to 2006.The outcome measurements included mortality rate, cure rate, resolution of pulmonary infiltrate, use of corticosteroid, and time to defervescence. The effect sizes were presented as risk ratio (RR), rate difference (RD), and weighted mean difference (WMD).The pooled effect sizes were calculated by both fixed-effects and random-effects models. Results: A total of 1,678 patients with a diagnosis of SARS were identified, including 866 patients from 16 randomized controlled studies and 812 patients from 8 nonrandomized controlled studies. There were no differences detected in mortality rate or cure rate between treatments. Compared with patients receiving WM treatment alone, patients receiving integrative treatment were more likely to have complete or partial resolution of pulmonary infiltrate (RD=0.18, 95%CI; 0.07 to 0.30), lower average daily dosage (mg) of corticosteroid (WMD=-60.27, 95% CI; -70.58 to -49.96), higher CD4+ counts (cells/uL) (WMD=167.96, 95% CI; 109.68 to 226.24), and shorter time to defervescence (days) (WMD= -1.06, 95%CI;-1.60 to -0.53). ]]> Conclusions: The experience of integrative TCM/WM in the treatment of SARS is encouraging. The use of TCM as an adjunctive therapy in the treatment of SARS should be further investigated. Key words: Severe Acute Respiratory Syndrome. Medicine, Chinese Traditional. Meta-Analysis.

RESUMEN Antecedentes: Los datos sobre la eficacia del tratamiento integrado de medicina tradicional china (MTC) y de tratamiento occidental (TO) para pacientes con SRAS son controvertidos. Los efectos del tratamiento MTC/TO no han sido completamente cuantificados. Objetivos: Evaluar sistemáticamente los efectos del tratamiento integrado de MTC con TO contra el TO solo en pacientes con SRAG, incorporando datos de estudios recientemente publicados. Métodos: se realizó un meta-análisis utilizando los estudios clínicos controlados aleatorizados y no aleatorizados que comparaban la eficacia del tratamiento integrado MTC/TO con el TO solo desde 2002 a 2006. Las medidas de resultados incluían tasa de mortalidad, tasa de cura, resolución de infiltrados pulmonares, uso de corticoides, y tiempo a la recuperación. Los efectos fueron presentados como riesgo relativo (RR), tasa de diferencia (TD) y diferencia media ponderada (DMP). Los efectos combinados se calcularon tanto por efectos fijos como por modelos de efecto aleatorio. Resultados: Se identificaron un total de 1678 pacientes con diagnóstico de SARS, incluyendo 866 pacientes de 16 estudios controlados aleatorizados y 812 pacientes de 8 estudios controlados no aleatorizados. No hubo diferencias detectadas en las tasad e mortalidad o tasa de cura entre los tratamientos. Comparados con los pacientes recibiendo TO solo, los pacientes que recibieron tratamiento integrado tenían más probabilidad de tener una resolución total o parcial del infiltrado pulmonar (TD=0.18, IC 95% 0.07 a 0.30), menor dosis media diaria (mg) de corticoides (DMP=-60.27, IC 95% -70.58 a -49.96), mayor recuento CD4+ (células/uL) (DMP=167.96, IC 95% 109.68 a 226.24), y menor tiempo a recuperación (días) (DMP= -1.06, IC 95% 1.60 a -0.53). Conclusiones: La experiencia del tratamiento integrado MTC/TO para el SRAS anima. El uso de MTC como coadyuvante en tratamiento de SRAS debería ser más investigado. Palabras clave: Síndrome respiratorio agudo severo. Medicina tradicional china. Meta-análisis.

Yan CHEN. MPH, Division of Pharmacy Practice and Administrative Sciences, College of Pharmacy, University of Cincinnati Medical Center, Cincinnati, OH (USA). ]]> Jeff J. GUO. PhD, Pharmacoepidemiology and Pharmacoeconoomics, Division of Pharmacy Practice and Administrative Sciences, College of Pharmacy, University of Cincinnati Medical Center, Cincinnati, OH (USA).
Daniel P HEALY. PharmD, Division of Pharmacy Practice and Administrative Sciences, College of Pharmacy, University of Cincinnati Medical Center, Cincinnati, OH (USA).
Siyan ZHAN. MPH, PhD, Department of Biostatics and Epidemiology, School of Public Health, Peking University Health Science Center, Beijing, PR.(China).

INTRODUCTION

Severe acute respiratory syndrome (SARS), caused by the SARS-associated coronavirus (SARS-CoV),¹ is a newly emerged infectious disease associated with significant morbidity and mortality. Even now, much about this disease still remains poorly understood. As of April 21, 2004, a cumulative number of 8,096 cases with SARS and 774 SARS-related deaths were recorded from 29 countries and regions.

The urgency of a global outbreak did not allow sufficient time for conducting well-designed efficacy studies. As a result, there is currently no consensus on the optimal treatment of SARS. Many management strategies, including antiviral agents, immune-modulating agents, convalescent plasma, had been employed based on different rationales, and remained largely empiric.

In China, at the time of SARS epidemic, Traditional Chinese Medicine (TCM), as an auxiliary therapy to Western Medicine (WM), was extensively employed for the treatment of SARS. In April, 2003, several anti-SARS formulae were recommended by Ministry of Health (MOH) of China to use with WM, which consisted of more than twenty different herbal medicines (Table 1). In China, 3,104 of 5,327 clinically confirmed patients with SARS (58.27%) received TCM treatment. According to the official reports, the mortality rate in China was approximately 6.5%, which was apparently lower than that reported worldwide (9.6 %).²

In parallel with the TCM use, a series of studies were conducted to evaluate the effectiveness of integrative TCM/WM treatment versus WM alone. To date, a few randomized controlled (RC) studies have investigated the beneficial effects of integrated TCM/WM treatments in the reduction of case-fatality rate, improvement of clinical symptoms, and shortening the course of illness. However, the findings have largely been inconsistent due to differences in study design and outcome measures. Meanwhile, the limited number of RC studies and inherent limitations (e.g. limited sample size, inadequate statistical analyses) prevented a critical assessment of efficacy. Although there have been three published meta-analyses evaluating the effectiveness of integrative TCM/WM treatments,^3-5 no firm conclusion can be drawn due to the methodological limitations. Those three studies do not include updated data. The literature included in the Zhang MM et al. study³ and Liu et al.⁴ study was limited information available through 2003, excluding a number of more recent studies. None of them presented the sensitivity and subgroup analyses to test the robustness of findings.

With these considerations in mind, we conducted a meta-analysis using updated literature searches to asses the treatment effects of integrated TCM with WM in patients with SARS and to determine whether integrative treatment was more efficacious than WM alone in reducing mortality rate, increasing cure rate, and improving other clinical outcomes.

METHODS

Literature Search and Inclusion Criteria

A literature search was performed using MEDLINE (2002-August 2006), PubMed (2002- August 2006), EMBASE (2002 to August 2006),Cochrane library (2002 to August 2006) in English by 2 reviewers (YC and JJG) and using Chinese National Knowledge Infrastructure (CNKI) (2002- August 2006), and Chinese Biomedical Database (2002 to August 2006) in Chinese by 2 reviewers (YC and SZ). Key words used in the search were SARS or severe acute respiratory syndrome, treatment, effectiveness, Traditional Chinese Medicine, Chinese Herbal medicines, and Western Medicine. Various combinations of the search terms were used depending on the database searched. The type of publication searched was clinical study. The retrieved articles were also searched for additional references.

Two reviewers of the English literature and Chinese literature independently reviewed the studies for inclusion. Any disagreements on inclusion were resolved through discussion. Qualified studies were selected if they met the following inclusion criteria: (1) patients with a diagnosis of SARS, (2) studies had either RC design or nonrandomized controlled (NRC) design, (3) studies compared the treatment effects between integrated TCM/WM treatments and WM alone. The studied TCM included either raw herbs or refined herbal products. They could be single herb, mixtures of different herbs, or herbal extraction. The integrative TCM/WM treatment was defined as combined use of any type of TCM with WM. There was no restriction of inclusion on patients' and study characteristics, such as age, sex, medications and duration of study.

During outbreak period, there was no validated, or widely available rapid test for diagnosis of SARS Cov infection. Therefore, the diagnosis of SARS in China mainly relied on the clinical and epidemiological basis as suggested by the WHO.⁶

Data Extraction

For the included studies, data were extracted by 2 reviewers (YC and SZ). Once completed, any disagreements on data extraction and study evaluation were resolved through discussion. Recorded data included study design, patient characteristics, and medication use.

The Jadad scale was used to assess the quality of the included RC studies, including method of randomization, double blinding, and reporting of withdrawal and dropouts.⁷ One point is given for each 'yes' and 0 point for each 'no'. Besides, other individual markers, including estimation of sample size, Intention-To-Treat (ITT) analysis, were also examined for each included study.

The measurements of outcomes in this study included mortality rate, cure rate, resolution of lung infiltrates, dosage of corticosteroid (the average daily dosage, cumulative dosage of corticosteroid and course of corticosteroid treatment), CD4+ counts, and time to defervescence. The mortality rate was defined as the proportion of death among the patients with SARS who received the treatments. The cure rate was defined as the proportion of patients who simultaneously satisfied all three following conditions⁶: (1) patient's fever remained normal (37.5°C) for at least seven days without using any anti-fever medications, (2) symptoms of respiratory systems disappeared, (3) partial or complete resolution of the pulmonary infiltrates as demonstrated by chest radiographs. The time to defervescence was defined as the time period from the day of hospital admission to the date when the temperature of patients recovered to the normal range and stayed normal for at least seven days.

Data were analyzed using RevMan 4.27 (Cochrane Collaboration, Oxford, UK). Statistical significant level was predetermined at the 0.05 level. The effects of integrative treatments were presented as risk ratio (RR), rate difference (RD) for dichotomous outcomes, and weighted mean difference (WMD) for continuous outcomes. The RD was defined as the difference of occurrence rate of events between integrative treatment group and WM alone group.

The computations of RR, RD and WMD were given by the following standard formulas:

with standard error

and

with standard error,

with standard error

where m1_i and m2_i are the mean response, sd1_i and sd2_i are the standard deviation, for the two studied group in the study i, respectively.

The pooled RR, RD and WMD were calculated by using both fixed-effects⁸ and random-effects model.⁹ If the test of heterogeneity (chi square statistic) was significant (p<0.05), we presented the results of the random-effect models; otherwise, estimated results of fixed-effect models were presented.

In order to exclude the bias brought by those nonrandomized controlled clinical studies (NRC), sensitivity analysis was performed to reassess the treatment effects by including randomized controlled clinical studies (RC) only. In addition, subset analyses were performed, where the robustness of the pooled estimates were further assessed by repeating the meta-analysis on the basis of sample sizes and the presence of adequate information about randomization.

RESULTS

Identified Studies and Characteristics

Of the 24 included studies, WM treatment mainly consisted of empiric antibiotics (e.g. azithromycin: 0.5g/d, Levofloxacin: 0.4g/d, Ceftriaxone: 2-4g/d), antiviral drugs (e.g. ribavirin: 0.5-1g/d), corticosteroid (e.g. Methylprednisolone: 80-320mg/d), and/or thymosin (50-200 mg/d). The use of TCM is shown in Table 1, where anti-SARS formulae were evaluated in ten studies, herb extracts were evaluated in three studies, and other combinations of herbal medicines were evaluated in eleven studies.

Of the 24 studies, only three studies reported the outcomes based on the severity of diseases^14,27,33 Of the 16 RC studies, most of them did not provide adequate information about the methods of blinding, and ITT. According to the Jadad scoring method, of the 16 RC studies, 7 studies scored 2 points^{11,12,17,18,21,23,24} and the remaining studies each scored 1 point.

Mortality Rate

Ten of 24 studies reported the mortality rate.^{11,13,14,21,23,25,27,29,32,33} The pooled mortality rates attributed to SARS in the integrated TCM/WM group and WM alone group were 3.7% (16/430) and 10.9% (44/403), respectively (RR=0.38, 95%CI:0.22 to 0.63). Based on the sensitivity analysis, when NRC studies were excluded^27,29,32,33, the conclusion was not affected (RR=0.33, 95%CI: 0.14 to 0.77) (Figure 1). However, no significant difference in mortality rate between treatments was detected in further subset analysis (RR=0.35, 95%CI: 0.12 to 1.10), where only those RC studies with larger sample sizes and adequate information of randomization were included (Table 2).

Cure Rate

Nine studies reported the cure rate^{13,14,20,21,23,25,27,28,33}, of which three were NRC studies.^27,28,33 Positive effects in improving cure rate were noted with integrative treatment regardless of the inclusion of NRC studies (Figure 2), however, no significant difference was found in further subset analysis (RD=0.10 , 95%CI: -0.02 to 0.22, Table 2).

Resolution of pulmonary Infiltrate

Resolution of lung infiltrate were reported in eight studies.^{11,15,17,21,23,24,26,32} As shown in Figure 3, 80.9% (292/361) patients receiving the integrative treatments had partial or complete resolution of pulmonary infiltrate, which was significantly higher than patients in WM alone group (67.8%,202/298) (RD=0.18, 95%CI: 0.07 to 0.30). Consistent findings were noted in sensitivity and subset analyses.

Use of Corticosteroids

CD4+ Counts

Four studies reported CD4+ counts (cell/uL).^21,25,27,30 Prior to any treatments, there were no significant differences in CD4+ counts between two groups (WMD=-11.00, 95%CI: -56.02 to 34.01). After the treatments, the pooled WMD between the two groups was 167.96 (95%CI; 109.68 to 226.24) .indicating a significant difference in the recovery of CD4+ counts between integrative treatment group and WM alone group.

Time to Defervescence

Eight studies reported the time in days to fever resolution.^{13,14,18,20,23,28,29,32} The pooled WMD between integrative TCM/WM treatment group and WM alone group was -1.06 (95%CI : -1.60 to -0.53, Figure 4). It suggested that integrative treatment could significantly reduce the time to defervescence in patients with SARS. Consistent findings were found in sensitivity and subset analyses.

Sensitive and Subgroup analysis

Based on the sensitivity analysis, the results were not affected with the exclusion of NRC studies (Figures 1-4). Additional subset analyses found that the previously observed differences in mortality rate and cure rate became insignificant when only RC studies with larger sample sizes and adequate randomization information were included (Table 2).

DISCUSSION

In this present study, we summarized the results of the findings from both RC studies and NPC studies using the meta-analysis. There is no convincing evidence to support that integrative TCM/WM treatment could significantly decrease the mortality rate, which contrasted from the findings from Liu et al. study.⁴ Although we first noted a significant reduction in mortality rate with the integrative treatment when ten studies were included, further subgroup analyses failed to consistently find a significant difference in mortality rate in those RC studies with larger sample sizes and adequate information of randomization. This suggests that the previously observed positive effects of integrative treatment were likely due to the inclusion of those studies of poor quality.

It has been found that a large percent of patients with SARS presented with lymphopenia.^34,35 Low counts of CD4+ and CD8+ are often associated with adverse outcome.³⁶ How to recover the lymphocyte cells became a critical treatment issue. In this present study, patients receiving integrative TCM/WM treatment had significantly higher CD4+ counts (uL) at the end of study (WMD=167.96, 95%CI; 109.68 to 226.24). With the limited follow-up, how well such effects could be translated into clinical outcomes were unknown. This aspect of benefits certainly warrants further investigation.

Our study suggests that adjunctive use of TCM with WM could significantly reduce the average daily use of corticosteroids. To date, use of corticosteroids for patients with SARS remains controversial. One important concern is the occurrence of adverse events associated with the use of corticosteroids, such as the development of Aspergillus, fungal infection.^37,38 Recent literature reported that some Chinese SARS survivors who had received high-dose corticosteroids treatment suffered the femoral head necrosis following therapy.^39,40 In the 24 identified studies used in this analysis, no long-term outcomes were reported. The questions of how clinically relevant the observed benefit of integrative treatment in reducing the average daily dose of corticosteroids were, and whether it could lead to a lower risk of developing corticosteroids-related adverse events, have not been answered yet in this study.

The findings of this study should be considered within the context of limitations. First, due to the limited number of published RCT studies, our analysis also included some NRC studies. However, the sudden outbreak of this new and serious disease precluded well controlled clinical studies during the epidemic. Despite twenty-four clinical studies, most of them had low methodological quality according to the Jadad scores. Second, the variation in treatment regimens, particularly the wide range of TCM in concoction constituents, dose, route of administration, and duration of therapy, became a major obstacle to a clear interpretation of the results. Third, there were only three studies that reported the outcomes on the basis of severity of disease. The data were insufficient for conducting an effective subset analysis on the severity of disease. Fourth, diagnoses of SARS during the outbreak were not confirmed by laboratory evidence of the SARS-Cov infection. As a recent study indicated, out of 28 patients, only 24 (85.71%) were eventually confirmed as having SARS according to the T-PCT detection of SARS-Cov RNA.⁴¹ Fifth, because of the variety of TCM and WM under study, it would have been difficult to meaningfully measure the rate of adverse events related to treatments. Therefore, such an analysis of adverse events was not conducted as part of this present study.

CONCLUSION

The experience of integrative TCM/WM in the treatment of SARS is encouraging. This study demonstrated the possibility that integrated TCM/WM treatments might be a beneficial modality for the treatment of SARS, especially on quickening the resolution of lung infiltrate, increasing the CD4+ counts, and reducing the time to defervescence. Clearly, further studies are needed with any future outbreak of SARS, and the quality of studies evaluating TCM needs to be improved. Further studies should aim to standardize the TCM treatment and include long-term follow-up on major outcomes in order to strengthen the rationale of using TCM.

1. Rota PA, Oberste MS, Monroe SS et al. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science. 2003;300:1394-1399.         [ Links ]

2. Jia W,Gao WY. Is Traditional Chinese Medicine (TCM) Useful in the Treatment of SARS? Phytother Res.2003;17:840-1.         [ Links ]

3. Zhang MM, Liu XM, Lin H. Effect of integrated traditional Chinese and Western Medicine on SARS: A review of clinical evidence. World J Gastroenterol. 2004; 10:3500-5.         [ Links ]

4. Liu JP, Manheimer E, Yi S, Gluud C. Chinese herbs medicine for SARS: A systematic review and Meta-analysis. J Altern Complement Med. 2004;10:1041-51.         [ Links ]

5. Liu X, Zhang M, He L et al. Chinese herbs combined with Western medicine for severe acute respiratory syndrome (SARS). Cochrane Databases Systematic Reviews.2006: CD004882.         [ Links ]

6. Zhong NS. Consensus of the management of severe acute respiratory syndrome. Natl Med J China. 2003;83:1731-52.         [ Links ]

7. Jaded AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1-12.         [ Links ]

8. Robins J, Breslow NE, Greenland S. Estimators of the Mantel-Haenszel variance consistent in both sparse data and large strata limiting models. Biometric. 1986;42:311-23.         [ Links ]

9. Dersimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177-88.         [ Links ]

10. Jiang ZY, Tong XD, Qi WS. Efficacy of Chinese herbs in the treatment of SARS convalescents In: China Academy of Traditional Chinese Medicine, eds. SARS Research. China Academy of Traditional Chinese Medicine Press: Beijing, PR.China,2003:67-81.         [ Links ]

11. Ren AM, Zhang SW, Wang BE et al. Clinical study on treatment of SARS by integrative Chinese and Western Medicine. Chin J Integr Trad West Med. 2004; 24:112-14.         [ Links ]

12. Bian YJ, Qi WS, Son QQ et al. Evaluation on effect of integrative medical treatment on quality of life of rehabilitation stage in 85 patients with SARS. Chin J Integr Trad West Med. 2003;23:658-60.         [ Links ]

13. Huang XB, Li ZX, Li B et al. Clinic studies on the patients with SARS with integrative TCM with WM. Chin J Inform Trad Med. 2004;11:144-6.         [ Links ]

14. Huang XB, Li ZX, Li B et al. Clinic studies on the elder patients with SARS with integrative TCM with WM. Chin J Gerontol. 2004;24:223-5.         [ Links ]

15. Kang J, Chen HW, Liu ZY. Clinical observation of 43 cases with SARS treated by integrated Chinese and Western Medicine. Shanxi J Trad Chin Med. 2003;19:34-5.         [ Links ]

16. Lei CL, Wang J, Chen YQ. Clinical observation on Qiankunning for treatment of SARS. Available at: Http://www.enwei.com.cn/ . Accessed Sep 22, 2006.         [ Links ]

17. Li H, Lu CZ,Tang KC et al. Clinical observation on treatment of SARS with combination of Chaihu Droplet Pill and Huoxiang Zhengqi Droplet Pill. Chin J Integr Trad West Med. 2004; 24:321-4.         [ Links ]

18. Li J, Li SD, Du N et al. Clinical study on treatment of SARS with integrative TCM and WM. Chin J Integr Trad West Med. 2004;24:28-31.         [ Links ]

19. Li X, Sun J, Zhang YY et al. Clinical study on the patients with SARS at the recovery stage with integrative TCM with WM. J Beijing Trad Chin Med. 2004;23:26-8.         [ Links ]

20. Li ZJ, Bao FH, Li Q et al. Clinical study on treatment of SARS with integrative TCM with WM. Chin. J Integr Trad West Med Crit Care. 2003;10:214-6.         [ Links ]

21. Wang RB, Liu JM, Jang YY et al. Preliminary study on clinical efficacy of integrative Chinese and Western Medicine in treating SARS. Chin J Integr Trad West Med. 2003; 23:492-93.         [ Links ]

22. Zhang SN. Effects of integrative Traditional Chinese Medicine and Western Medicine on the lung fibrosis of patients with SARS. Chin Gen Practice. 2003;6:576-7.         [ Links ]

23. Zhang XM, Zhang YL, Yang ZF et al. Clinical Observation of Effect of Series of Recipes 1, 2, 3 on SARS. Chin J Trad Chin Med Pharm. 2003;18:323-5.         [ Links ]

24. Zhang YL, Zhang XM, Jin YW et al. Clinical observation of 65 patients with SARS treated with integrative Traditional Chinese Medicine and Western Medicine. J Beijing Trad Chin Med. 2003; 26:60-4.         [ Links ]

25. Zhao CH, Li XH, Zhang K et al. Randomized controlled study of integrated traditional Chinese medicine and Western medicine in treatment of 77 patients with SARS. Chin J Integr Trad West Med Crit Care. 2003;10:197-200.         [ Links ]

26. Zhang YP, Miao Q, Huang YZ. A study of clinical effect of integrated traditional Chinese medicine and Western medicine in treatment of SARS. In: China Academy of Traditional Chinese Medicine, eds. SARS research. China Academy of Traditional Chinese Medicine Press: Beijing, PR.China, 2003:62-66.         [ Links ]

27. Li XH, Zhang K, Hu JH et al. Clinical observations of effects from integrative traditional Chinese medicine and Western medicine on the patients with SARS. Chin J Trad Chin Med Pharm.2003;18:326-28.         [ Links ]

28. Zhang RL, Jiao Q, Wang BG et al. Controlled study on 49 patients with SARS treated by integrative Chinese Medicine and Western Medicine. Chin J Integr Trad West Med. 2003;23:654-6.         [ Links ]

29. Sun ZJ, Li YM, Jie JL et al. . Observation on therapeutic effects of Traditional Chinese Medicine and Western Medicine in 26 patients with SARS. Chin J Integr Trad West Med Crit Care.2003;10:217-9.         [ Links ]

30. Wang YY, Wang RB, Liu JM et al. Effect of integrative Chinese and Western medicine on T-lymphocyte subsets in treating patients with SARS. Chin J Integr Trad West Med. 2004;24:514-6.         [ Links ]

31. Li Hui, Hua JB, Wang WD et al. Clinical observations of 40 cases with SARS in the restoration stage treated by integrative Traditional Chinese Medicine and Western Medicine. J Beijing Trad Chin Med.2003; 26:74-6.         [ Links ]

32. Tong XL, Chen XG, Zhao D et al. Effect assessment for Traditional Chinese Medicine integrated with Western Medicine in the treatment of patients with SARS. Chin J Trad Chin Med Pharm. 2003;18:603-8.         [ Links ]

33. He XY, Hou YJ, Zhang YL et al. Analysis on treatment of patients with SARS by integrative traditional Chinese and Western Medicine. Chin J Integr Trad West Med Crit Care. 2003;10:271-4.         [ Links ]

34. Booth CM, Matukas LM, Tomlinson GA et al. Clinical features and short-term outcomes of 144 patients with SARS in the Greater Toronto Area. JAMA. 2003;289:2801-9.         [ Links ]

35. Lee N, Hui D, Wu A et al. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Eng J Med. 2003;348:1986-94.         [ Links ]

36. Wong RS, Wu A, To KF et al. Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis. BMJ. 2003;326:1358-62.         [ Links ]

37. Griffith JF, Antonio GE, Kumta SM et al. Osteonecrosis of hip and knee in patients with severe acute respiratory syndrome treated with steroids. Radiology. 2005;235:168-75.         [ Links ]

38. Wang H, Ding Y, Li X et al. Fatal asperigilosis in a patien with SARS who was treated with cortiocteroids. N Engl J Med. 2003;349:507-8.         [ Links ]

39. Hong N, Du XK, Nie ZS et al. Diffusion-weighted MR study of femoral head avascular necrosis in severe acute respiratory syndrome patients. J Magn Reson Imaging. 2005; 22:661-4.         [ Links ]

40. Shen J, Liang BL, Zhan QS et al. Report on the investigation of lower extremity osteonecrosis with magnetic resonance imaging in recovered severe acute respiratory syndrome in Guangzhou. Natl Med J China. 2004:84:1814-7.         [ Links ]

41. Ren Y, Ding HG, Wu QF et al. Discussion on the pathogenic diagnosis of 28 patients with SARS. Theory and Practice of Chinese Medicnie. 2004;14:165-8.         [ Links ]