- Email: [email protected]
Xiyanping Injection in Treatment of Viral Pneumonia in Children: A Meta-analysis of Random Control Trials
Sun SG et al. Chinese Herbal Medicines, 2015, 7(2): 173-178
173
Available online at SciVarse ScienceDirect
ChineseHerbalMedicines(CHM) ISSN 1674-6384 Journal homepage: www.tiprpress.com
E-mail: [email protected]
Originalarticle
Xiyanping Injection in Treatment of Viral Pneumonia in Children: A Meta-analysis of Random Control Trials Shi-guang Sun1†*, Ya-fei Shi1†, Hui Yan1, Yang Li1, Rui Wang2, Su-hui Wang2, Xiao-di Sun2 1.
The Second Out-Patient Department, General Hospital of Beijing Military Region, Chinese People's Liberation Army, Beijing 100700, China
2. Department of Pharmacy, General Hospital of Beijing Military Region, Chinese People's Liberation Army, Beijing 100700, China
ARTICLEINFO Article history Received: August 31, 2014 Revised: November 3, 2014 Accepted: March 23, 2015 Available online: May 6, 2015
DOI: 10.1016/S1674-6384(15)60035-1
ABSTRACT Objective To evaluate the efficacy and safety of Xiyanping Injection in the treatment of
viral pneumonia in children. Methods
We searched several databases, including
PubMed, CNKI, VIP and Wanfang Data (Januaryü June, 2014). The references of all
selected studies were also retrieved to collect the relevantly randomized controlled trials (RCTs) on Xiyanping Injection for viral pneumonia in children. Two authors
screened the literatures in accordance with the inclusive criteria, extracted the data and
assessed the methodological quality of the included studies. We used RevMan 5.2 software for meta-analysis. Results
Meta-analysis on the 10 included RCTs showed
that the effective rates of defervescing and vanishing of the rashes and cough in the Xiyanping Injection group were better than those in the Ribavirin Injection group. There
was no significant difference between the two groups in the incidence of adverse drug reaction. Conclusion The existing research indicated that Xiyanping Injection is a
secure and efficient scheme for viral pneumonia in children. Because of the poor quality
of present researches, these results should be verified by strictly-designed and large-scale sample RCTs.
Key words
children; meta-analysis; viral pneumonia; Xiyanping Injection
© 2015 published by TIPR Press. All rights reserved.
1. Introduction Viral pneumonia is inflammation (irritation and swelling) of the lungs due to infection with a virus which occurs more often in children and accounts for approximate 50 percent of pediatric pneumonia (Ruuskanen et al, 2011). Specific treatments for the viral pneumonia were not yet determined. Ribavirin was generally included in combination with
supportive care in the treatment. However, the clinical use of Ribavirin is controversial for its efficiency and safety, which has been found to be teratogenic, carcinogenic, and mutagenic (Hebert and Guglielmo 1990; Ceylan et al, 2013). Therefore, the development of a more effective treatment for viral pneumonia is a major goal. The herb-derived compound Xiyanping Injection, obtained from a popular Chinese herb Andrographis paniculata (Burm) Nees, which is used to low
* Corresponding author: Sun SG E-mail: [email protected] † These authors contributed equally to this work Fund: Public Health Cultivation Program of the capital of China (No.z131100004013007)
174
Sun SG et al. Chinese Herbal Medicines, 2015, 7(2): 173-178
body temperature and for the detoxification in Chinese medicine. Xiyanping Injection has various potential benefits, such as antivirus, anti-inflammatory, and antimicrobial effects (Li et al, 2013) et al. Many randomized trials have compared the curative effect of treating viral pneumonia by using Xiyanping Injection to take place Ribavirin Injection in children. However, the evidence supporting or disproving the curative effect of Xiyanping Injection for children suffering from viral pneumonia is not robust. Our goal was to observe the efficacy and safety of Xiyanping Injection in the treatment of viral pneumonia in children by a meta-analysis, so as to provide the reference for rational use of drug in clinic.
2. Materialsandmethods 2.1 Searchstrategies Major bibliographical databases including Medline, PubMed, Cochrane Library, Science Direct, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Data, Chinese Scientific Journal Database (VIP) were searched between the inception dates of databases and 2014 (last search on 30 June 2014). The online clinical trial registry websites were also searched for published and unpublished randomized controlled trials (RCTs) of Xiyanping Injection for viral pneumonia up to June 30 2013 with no language restrictions. The following terms were used in the search strategies included the following terms: “Xiyanping” and “viral pneumonia”. The reference lists of review articles and included studies were also checked. The languages of publications were restricted to English and Chinese.
2.2 Studyselection Studies with following pre-determined criteria were included: (a) The study was claimed as a RCT; (b) Children were diagnosed with viral pneumonia by recognized criterion; (c) The study on the efficiency of Xiyanping Injection in the treatment of viral pneumonia versus Ribavirin injection; (d) Outcomes must contain one of the following: Clinical curative effect, adverse reactions, disappearance time to defervesce, cough, and pulmonary rales. Exclusion criteria were included: (a) The study used or compared with other Chinese medicine; (b) The study used different baseline-treatment in the treatment group and control group; (c) The study had unclear criteria of evaluating the clinical curative effect or data error; (d) The study was a duplicated or redundant publication. Two authors (Y.F. Shi and S.G. Sun) independently searched the databases and selected studies according to the inclusion and exclusion criteria. Potentially relevant studies were retrieved as full articles and then again independently searched by the two authors. Disagreements were resolved by discussion, or consulting a third author (H. Yan).
2.3 Dataextraction Data were extracted from eligible studies by the first author (Y.F. Shi) and checked by the second author (S.G. Sun). Extracted information included (if available) demographic data, detailed description in the treatment and control groups (ie, dose given, study duration), outcome measures, and information on adverse drug reactions.
2.4 Qualityassessmentofincludedstudies The two authors independently assessed the study quality using criteria from the Cochrane Handbook for Systematic Review of Interventions, Version 5.1.0. The items of the criteria include random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias. The quality of all the included trials was categorized to low/unclear/high risk of bias (“yes” for a low of bias, “no” for a high risk of bias, “unclear” otherwise). Then studies were categorized into three levels: low risk of bias (all the items were in low risk of bias), high risk of bias (at least one item was in high risk of bias), unclear risk of bias (at least one item was in unclear) (Higgins and Green, 2009). Disagreements were resolved by consulting the third author (H. Yan).
2.5 Datasynthesis The software package Revman 5.2 provided by the Cochrane Collaboration was used for data analysis. Dichotomous outcome will be presented as risk ratio (RR) and continuous outcomes as standardized mean difference (SMD), with their 95% confidence intervals (CI), respectively. Heterogeneity across studies was examined using the I2 parameter. A value for I2 > 50% was considered to represent significant heterogeneity (Lukas and Georg, 2013). Where no significant heterogeneity was identified, the fixed-effects model was used as the summary measure. Random-effects model was used if significant heterogeneity existed (I2 > 50%). Publication bias would be assessed by funnel plot analysis if sufficient studies were found.
3. Results 3.1 Studyselection The search of bibliographical databases found 83 records, after reading the titles and abstracts, 10 RCTs —16 were included in meta-analysis. All 10 RCTs were conducted in China and published in Chinese. The total number of participants with viral pneumonia was 1004, of which 530 in the treatment group, 474 in the control group. Xiyanping Injection was administered 5—10 mg/kg/d for iv infusion (in
Sun SG et al. Chinese Herbal Medicines, 2015, 7(2): 173-178 5% Dextrose) in the treatment group. Ribavirin Injection was administered 5—10 mg/kg/d in the same manner for the control Table 1
Studies
Sample
Gender
Sizes
(M/F)
(T/C) Han et al, 2004 Huang, 2013 Li, 2009 Lan, 2013 Pan, 2011 Li, 2006 Huang, 2005 Zhang and Lan, 2005 Wang, 2013 Wang, 2011
group. The main characteristics of the included trials were listed in Table 1.
Characteristics of included studies Drug doses
Ages
Xiyanping
Injection
(T)
Treatment
Ribavirin Injection
80/40
6 months to 6 years
10 mg/kg/d, iv gtt
15 mg/kg/d, iv gtt
44/43
45/42
3 months to 2 years
10 mg/kg/d, iv gtt
10 mg/kg/d, iv gtt
60/38
63/35
2 years
5ü10 mg/kg/d, iv gtt
63/63
–
–
10 mg/kg/d, ivgtt
15 mg/kg/d, iv gtt
35/35
40/30
1 to 3 years
10 mg/kg/d, iv gtt
10 mg/kg/d, iv gtt
32/30
32/30
3 months to 3 years
5~10 mg/kg/d, iv gtt
10 mg/kg/d,
30/30
33/27
2 months to 3 years
5 mg/kg/d, iv gtt
10 mg/kg/d, iv gtt
120/90
114/96
2 months to 13 years
5~10 mg/kg/d, iv gtt
42/42 44/43
43/41 48/39
months 2 months to 3 years
10 mg/kg/d, iv gtt 1 ü 15 mg/kg/d, iv gtt
duration
Outcomes
/d
(C)
60/60
14.3 months / 15.2
175
10 ü 20 mg/kg/d, iv gtt
iv gtt
10 ü 15 mg/kg/d, iv gtt 10 ü 15 mg/kg/d, iv gtt 15 mg/kg/d, iv gtt
7 ü10
CCE, ADR
_
CCE
10
CCE
7 7 ü10 14 5 ü7 7 7 7
CCE, DT, CDT, PRDT CE, ADR, DT, CDT, PRDT CE, ADR, DT, CDT, RDT CE, ADR, DT CE, ADR, DT, CDT, RDT CE, ADR, DT, CDT, PRDT CE, ADR, DT, CDT, PRDT
CCE: clinical curative effect, ADR: adverse drug reactions, DT: defervescence time, CDT : cough disappearance time, PRDT: pulmonary rales disappearance time, –: unclear
3.2 Methodologicalqualityofincludedtrials Most of the studies’ methodological quality was unclear due to the insufficient information. The evaluation of the methodological quality of the included trials were listed in Table 2.
3.3 Effectivenessandsafety 3.3.1 Efficientivenessanalysis Statistical heterogeneity was found among these 10 studies in the clinical curative effect˄CCE, P = 0.005, I2 = 62%,) Random-effects model was used as the summary measure. Significant improvement of the CCE was seen in the Xiyanping Injection group compared to the Ribavirin Injection group (RR = 1.23, 95% CI[1.13, 1.34], P < 0.000 01) (Figure 1). The funnel plot of the comparison on CCE was asymmetric. There would be some publication bias of the included studies (Figure 2). Six studies reported the defervescence time. Metaanalysis using random-effect model revealed that children taking Xiyanping Injection could defervesce with more less time than those taking Ribavirin Injection (MD = -1.08, 95% CI[-1.34, -0.81], P < 0.000 01) (Figure 3). The cough disappearance time was measured in five studies. The data were pooled by using random-effect model.
Result showed that cough disappearance time in the Xiyanping Injection group was significantly less than that of Ribavirin Injection group (MD = -2.24, 95% CI[-3.09, -1.39], P < 0.000 01) (Figure 4). 3.3.2 Safetyanalysis Of the 10 trials, six reported adverse events. including allergic reaction in the Xiyanping Injection group (seven cases); gastrointestinal reaction (10 cases), anemia (five cases), elevating of ALT levels (seven cases) in the Ribavirin Injection group. In total, adverse events were no significant difference in the Xiyanping Injection group compared to Ribavirin Injection group. (RD = -0.04, 95% CI [-0.09, 0.02], P = 0.19) Severe adverse events were seen in the Xiyanping Injection group that one child developed paroxysmal cough and chest distress following single dose of iv Xiyanping Injection. The symptom was relieved by using Dexamethasone and Promethazine. The pulmonary rales disappearance time alone with the cough disappearance timewas also seen in the five studies. Random-effect model was also used for pooling the data. As a result, the disappearance of pulmonary rales in the Xiyanping Injection group was sooner than that in the Ribavirin Injection group (MD = -1.48, 95%CI[-1.96, -1.00], P < 0.000 01) (Figure 5).
Sun SG et al. Chinese Herbal Medicines, 2015, 7(2): 173-178
176
Table 2
Studies
Evaluation on methodological quality of included trials Allocation
Random methods
concealment
Blind methods Patients
Outcome
and doctors
measurer
Integrity
of
Selective
outcome data
reporting
Other bias
Han et al, 2004
unclear
unclear
unclear
unclear
yes
no
Huang, 2013
unclear
unclear
unclear
unclear
yes
unclear
unclear unclear
Li, 2009
unclear
unclear
unclear
unclear
yes
unclear
unclear unclear
Lan YY, 2013
unclear
unclear
unclear
unclear
yes
unclear
Pan, 2011
Random number table method
unclear
unclear
unclear
yes
no
unclear
Li, 2006
no
unclear
unclear
unclear
yes
no
unclear
Huang, 2005
unclear
unclear
unclear
unclear
yes
no
unclear
Zhang and Lan, 2005
no
unclear
unclear
unclear
yes
no
unclear
Wang, 2013
unclear
unclear
unclear
unclear
yes
no
unclear
Wang, 2011
unclear
unclear
unclear
unclear
no
unclear
unclear
Figure 1
0.00
Forest plot: Comparison on CCE
SE (log[RR])
0.05
0.10 0.15 RR 0.20 0.2
0.5 Figure 2
1
2
5
Funnel plot: Comparison on CCE
4. Discussion According to our results, Xiyanping Injection appeared to be an effective and safe treatment option for the treatment of viral pneumonia in children, and Xiyanping Injection appeared to be more effective than Ribavirin Injection. Compared with Ribavirin Injection the cure rate was much higher in Xiyanping Injection group. The other objective measurements, such as
defervescence time, cough disappearance time, pulmonary rales disappearance time, also provided evidences. However, these advantages were associated with low methodological quality of studies collected so far. The following limitations should be considered before accepting the findings of this paper. Firstly, five databases have been searched up to June 2014 including the Cochrane Library, EM Database PubMed, Wanfang Database, CNKI, and VIP. In addition, the online clinical trial registry websites were also searched. However, all included studies were conducted in China. Most of the studies are small size with positive findings. No multicenter and large-scale RCTs were identified. The potential publication bias can not be excluded. Secondly, as the insufficient information reported from the included studies the methodological quality of most included studies can not be sure. All studies claimed randomization, but only two studies described the detailed method. One trial is at high risk of bias that they allocated the participants according the number of their hospital records. All the included studies did not report the information on the allocation concealment. None of the included studies mentioned blind. So researchers follow the basic guidelines for reporting clinical studies such as the Consolidated Standards of Reporting Trials (CONSORT)
Sun SG et al. Chinese Herbal Medicines, 2015, 7(2): 173-178
Figure 3
Figure 4
Figure 5
177
Forest plot: Comparison of defervescence time
Forest plot: Comparison of cough disappearance time
Forest plot: Comparison of pulmonary rales disappearance time
statement is quite necessary. The adverse effects of Xiyanping Injection included seven cases of headache 1.53% (7/456) only. Of which one case of serious allergic reaction was seen. A recent notification from the State Food and Drug
Administration prompted that serious allergic reaction was related to Xiyanping Injection, cases were more seen in children under 14 years old than adults (Lin and Zhang, 2012). So confirming the patient family history of allergies is
178
Sun SG et al. Chinese Herbal Medicines, 2015, 7(2): 173-178
recommended when using this kind of therapy, emergency medications is also needed to prevention the serious adverse events.
5. Conclusion In conclusion, compared with Ribavirin Injection, Xiyanping Injection is of more benefits for children with viral pneumonia while non-significant side effects are found in the Xiyanping Injection group. However, concerning methodological quality of included studies, it is difficult to draw a definitive conclusion. Higher quality, longer follow-up periods, larger sample sizes, and multi-centers RCT need to be warranted to confirm the results.
Acknowledgments Yafei Shi and Shiguang Sun contributed equally to this paper. The current work was partially supported by the Public Health Cultivation Program of the capital of China (No. z131100004013007). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.
References Ceylan B, Calıca A, Ak O, Akkoyunlu Y, Turhan V, 2013. Ribavirin is not effective against Crimean-Congo hemorrhagic fever: Observations from the Turkish experience. Int J Infect Dis 17(10): e799-801. Han YG, Liu HP, Cui M, 2004. Clinical observation of 60 children with viral pneumonia treated by Xiyanping Injection. Mod J Integr Tradit Chin West Med 13(19): 2562-2563. Hebert MF, Guglielmo BJ, 1990. What is the clinical role of aerosolized ribavirin. DICP 24(7-8): 735-738. Higgins JPT, Green S, 2009. Cochrane Handbook for Systematic Reviews of Interventions, Version 5. 1. 0, The Cochrane
Collaboration. Huang H, 2005. Clinical observation of Xiyanping Injection on treatment of 30 cases of infantile viral pneumonia. Jilin J Tradit Chin Med, 25(06): 29. Huang W, 2013. Effect observation of Xiyanping in treatment of viral pneumonia for children. Med J Chin People's Health 25(19): 25-26. Lan YY, 2013. Effect observation of Xiyanping in treatment of viral pneumonia for children. China Pract Med 8(25): 179-180. Li QY, 2009. Clinical observation of Xiyanping Injection on treatment of 60 cases of infantile viral pneumonia. J Pediatr Tradit Chin Med 5(6): 13-15. Li XH, Zhang C, Shi QS, Yang T, 2013. Improving the Efficacy of Conventional Therapy by Adding Andrographolide Sulfonate in the Treatment of Severe Hand, Foot, and Mouth Disease: A Randomized Controlled Trial. Evid Based Complement Alternat Med 2013: 316250. Li YJ, 2006. Effect observation of Xiyanping in treatment of viral pneumonia for children. Qingdao Med J 38(03): 176-177. Lin Q, Zhang S, 2012. Analysis of 270 Cases of Adverse Drug Reactions/Events Reports Caused by Xiyanping Injection. Chin J Pharmacovigil 9(12):751-754. Schwingshackl L, Hoffmann G, 2013. Long-term effects of low-fat diets either low or high in protein on cardiovascular and metabolic risk factors: a systematic review and meta-analysis. Nut J doi:10.1186/1475-2891-12-48. Pan YL, 2011. Clinical observation of Xiyanping Injection on treatment of 35 cases of infantile viral pneumonia. Chin Pediatr Integr Tradit West Med 3(05): 415-416. Ruuskanen O, Lahti E, Jennings LC, Murdoch DR, 2011. Viral pneumonia. Lancet 377(9773): 1264-1275. Wang BQ, 2011. Curative effect observation of Xiyanping Injection in the treatment of children viral pneumonia. Med Informat 24(5): 154-155. Wang ZX, 2013. Effect observation of Xiyanping in treatment of viral pneumonia for children. Med Aesthet Cosmetol 21(1): 83. Zhang JH, Lan ZJ, 2005. 60 cases of infantile viral pneumonia treated by Xiyanping Injection. Zhejiang J Tradit Chin Med (10): 455.
173
Available online at SciVarse ScienceDirect
ChineseHerbalMedicines(CHM) ISSN 1674-6384 Journal homepage: www.tiprpress.com
E-mail: [email protected]
Originalarticle
Xiyanping Injection in Treatment of Viral Pneumonia in Children: A Meta-analysis of Random Control Trials Shi-guang Sun1†*, Ya-fei Shi1†, Hui Yan1, Yang Li1, Rui Wang2, Su-hui Wang2, Xiao-di Sun2 1.
The Second Out-Patient Department, General Hospital of Beijing Military Region, Chinese People's Liberation Army, Beijing 100700, China
2. Department of Pharmacy, General Hospital of Beijing Military Region, Chinese People's Liberation Army, Beijing 100700, China
ARTICLEINFO Article history Received: August 31, 2014 Revised: November 3, 2014 Accepted: March 23, 2015 Available online: May 6, 2015
DOI: 10.1016/S1674-6384(15)60035-1
ABSTRACT Objective To evaluate the efficacy and safety of Xiyanping Injection in the treatment of
viral pneumonia in children. Methods
We searched several databases, including
PubMed, CNKI, VIP and Wanfang Data (Januaryü June, 2014). The references of all
selected studies were also retrieved to collect the relevantly randomized controlled trials (RCTs) on Xiyanping Injection for viral pneumonia in children. Two authors
screened the literatures in accordance with the inclusive criteria, extracted the data and
assessed the methodological quality of the included studies. We used RevMan 5.2 software for meta-analysis. Results
Meta-analysis on the 10 included RCTs showed
that the effective rates of defervescing and vanishing of the rashes and cough in the Xiyanping Injection group were better than those in the Ribavirin Injection group. There
was no significant difference between the two groups in the incidence of adverse drug reaction. Conclusion The existing research indicated that Xiyanping Injection is a
secure and efficient scheme for viral pneumonia in children. Because of the poor quality
of present researches, these results should be verified by strictly-designed and large-scale sample RCTs.
Key words
children; meta-analysis; viral pneumonia; Xiyanping Injection
© 2015 published by TIPR Press. All rights reserved.
1. Introduction Viral pneumonia is inflammation (irritation and swelling) of the lungs due to infection with a virus which occurs more often in children and accounts for approximate 50 percent of pediatric pneumonia (Ruuskanen et al, 2011). Specific treatments for the viral pneumonia were not yet determined. Ribavirin was generally included in combination with
supportive care in the treatment. However, the clinical use of Ribavirin is controversial for its efficiency and safety, which has been found to be teratogenic, carcinogenic, and mutagenic (Hebert and Guglielmo 1990; Ceylan et al, 2013). Therefore, the development of a more effective treatment for viral pneumonia is a major goal. The herb-derived compound Xiyanping Injection, obtained from a popular Chinese herb Andrographis paniculata (Burm) Nees, which is used to low
* Corresponding author: Sun SG E-mail: [email protected] † These authors contributed equally to this work Fund: Public Health Cultivation Program of the capital of China (No.z131100004013007)
174
Sun SG et al. Chinese Herbal Medicines, 2015, 7(2): 173-178
body temperature and for the detoxification in Chinese medicine. Xiyanping Injection has various potential benefits, such as antivirus, anti-inflammatory, and antimicrobial effects (Li et al, 2013) et al. Many randomized trials have compared the curative effect of treating viral pneumonia by using Xiyanping Injection to take place Ribavirin Injection in children. However, the evidence supporting or disproving the curative effect of Xiyanping Injection for children suffering from viral pneumonia is not robust. Our goal was to observe the efficacy and safety of Xiyanping Injection in the treatment of viral pneumonia in children by a meta-analysis, so as to provide the reference for rational use of drug in clinic.
2. Materialsandmethods 2.1 Searchstrategies Major bibliographical databases including Medline, PubMed, Cochrane Library, Science Direct, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Data, Chinese Scientific Journal Database (VIP) were searched between the inception dates of databases and 2014 (last search on 30 June 2014). The online clinical trial registry websites were also searched for published and unpublished randomized controlled trials (RCTs) of Xiyanping Injection for viral pneumonia up to June 30 2013 with no language restrictions. The following terms were used in the search strategies included the following terms: “Xiyanping” and “viral pneumonia”. The reference lists of review articles and included studies were also checked. The languages of publications were restricted to English and Chinese.
2.2 Studyselection Studies with following pre-determined criteria were included: (a) The study was claimed as a RCT; (b) Children were diagnosed with viral pneumonia by recognized criterion; (c) The study on the efficiency of Xiyanping Injection in the treatment of viral pneumonia versus Ribavirin injection; (d) Outcomes must contain one of the following: Clinical curative effect, adverse reactions, disappearance time to defervesce, cough, and pulmonary rales. Exclusion criteria were included: (a) The study used or compared with other Chinese medicine; (b) The study used different baseline-treatment in the treatment group and control group; (c) The study had unclear criteria of evaluating the clinical curative effect or data error; (d) The study was a duplicated or redundant publication. Two authors (Y.F. Shi and S.G. Sun) independently searched the databases and selected studies according to the inclusion and exclusion criteria. Potentially relevant studies were retrieved as full articles and then again independently searched by the two authors. Disagreements were resolved by discussion, or consulting a third author (H. Yan).
2.3 Dataextraction Data were extracted from eligible studies by the first author (Y.F. Shi) and checked by the second author (S.G. Sun). Extracted information included (if available) demographic data, detailed description in the treatment and control groups (ie, dose given, study duration), outcome measures, and information on adverse drug reactions.
2.4 Qualityassessmentofincludedstudies The two authors independently assessed the study quality using criteria from the Cochrane Handbook for Systematic Review of Interventions, Version 5.1.0. The items of the criteria include random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias. The quality of all the included trials was categorized to low/unclear/high risk of bias (“yes” for a low of bias, “no” for a high risk of bias, “unclear” otherwise). Then studies were categorized into three levels: low risk of bias (all the items were in low risk of bias), high risk of bias (at least one item was in high risk of bias), unclear risk of bias (at least one item was in unclear) (Higgins and Green, 2009). Disagreements were resolved by consulting the third author (H. Yan).
2.5 Datasynthesis The software package Revman 5.2 provided by the Cochrane Collaboration was used for data analysis. Dichotomous outcome will be presented as risk ratio (RR) and continuous outcomes as standardized mean difference (SMD), with their 95% confidence intervals (CI), respectively. Heterogeneity across studies was examined using the I2 parameter. A value for I2 > 50% was considered to represent significant heterogeneity (Lukas and Georg, 2013). Where no significant heterogeneity was identified, the fixed-effects model was used as the summary measure. Random-effects model was used if significant heterogeneity existed (I2 > 50%). Publication bias would be assessed by funnel plot analysis if sufficient studies were found.
3. Results 3.1 Studyselection The search of bibliographical databases found 83 records, after reading the titles and abstracts, 10 RCTs —16 were included in meta-analysis. All 10 RCTs were conducted in China and published in Chinese. The total number of participants with viral pneumonia was 1004, of which 530 in the treatment group, 474 in the control group. Xiyanping Injection was administered 5—10 mg/kg/d for iv infusion (in
Sun SG et al. Chinese Herbal Medicines, 2015, 7(2): 173-178 5% Dextrose) in the treatment group. Ribavirin Injection was administered 5—10 mg/kg/d in the same manner for the control Table 1
Studies
Sample
Gender
Sizes
(M/F)
(T/C) Han et al, 2004 Huang, 2013 Li, 2009 Lan, 2013 Pan, 2011 Li, 2006 Huang, 2005 Zhang and Lan, 2005 Wang, 2013 Wang, 2011
group. The main characteristics of the included trials were listed in Table 1.
Characteristics of included studies Drug doses
Ages
Xiyanping
Injection
(T)
Treatment
Ribavirin Injection
80/40
6 months to 6 years
10 mg/kg/d, iv gtt
15 mg/kg/d, iv gtt
44/43
45/42
3 months to 2 years
10 mg/kg/d, iv gtt
10 mg/kg/d, iv gtt
60/38
63/35
2 years
5ü10 mg/kg/d, iv gtt
63/63
–
–
10 mg/kg/d, ivgtt
15 mg/kg/d, iv gtt
35/35
40/30
1 to 3 years
10 mg/kg/d, iv gtt
10 mg/kg/d, iv gtt
32/30
32/30
3 months to 3 years
5~10 mg/kg/d, iv gtt
10 mg/kg/d,
30/30
33/27
2 months to 3 years
5 mg/kg/d, iv gtt
10 mg/kg/d, iv gtt
120/90
114/96
2 months to 13 years
5~10 mg/kg/d, iv gtt
42/42 44/43
43/41 48/39
months 2 months to 3 years
10 mg/kg/d, iv gtt 1 ü 15 mg/kg/d, iv gtt
duration
Outcomes
/d
(C)
60/60
14.3 months / 15.2
175
10 ü 20 mg/kg/d, iv gtt
iv gtt
10 ü 15 mg/kg/d, iv gtt 10 ü 15 mg/kg/d, iv gtt 15 mg/kg/d, iv gtt
7 ü10
CCE, ADR
_
CCE
10
CCE
7 7 ü10 14 5 ü7 7 7 7
CCE, DT, CDT, PRDT CE, ADR, DT, CDT, PRDT CE, ADR, DT, CDT, RDT CE, ADR, DT CE, ADR, DT, CDT, RDT CE, ADR, DT, CDT, PRDT CE, ADR, DT, CDT, PRDT
CCE: clinical curative effect, ADR: adverse drug reactions, DT: defervescence time, CDT : cough disappearance time, PRDT: pulmonary rales disappearance time, –: unclear
3.2 Methodologicalqualityofincludedtrials Most of the studies’ methodological quality was unclear due to the insufficient information. The evaluation of the methodological quality of the included trials were listed in Table 2.
3.3 Effectivenessandsafety 3.3.1 Efficientivenessanalysis Statistical heterogeneity was found among these 10 studies in the clinical curative effect˄CCE, P = 0.005, I2 = 62%,) Random-effects model was used as the summary measure. Significant improvement of the CCE was seen in the Xiyanping Injection group compared to the Ribavirin Injection group (RR = 1.23, 95% CI[1.13, 1.34], P < 0.000 01) (Figure 1). The funnel plot of the comparison on CCE was asymmetric. There would be some publication bias of the included studies (Figure 2). Six studies reported the defervescence time. Metaanalysis using random-effect model revealed that children taking Xiyanping Injection could defervesce with more less time than those taking Ribavirin Injection (MD = -1.08, 95% CI[-1.34, -0.81], P < 0.000 01) (Figure 3). The cough disappearance time was measured in five studies. The data were pooled by using random-effect model.
Result showed that cough disappearance time in the Xiyanping Injection group was significantly less than that of Ribavirin Injection group (MD = -2.24, 95% CI[-3.09, -1.39], P < 0.000 01) (Figure 4). 3.3.2 Safetyanalysis Of the 10 trials, six reported adverse events. including allergic reaction in the Xiyanping Injection group (seven cases); gastrointestinal reaction (10 cases), anemia (five cases), elevating of ALT levels (seven cases) in the Ribavirin Injection group. In total, adverse events were no significant difference in the Xiyanping Injection group compared to Ribavirin Injection group. (RD = -0.04, 95% CI [-0.09, 0.02], P = 0.19) Severe adverse events were seen in the Xiyanping Injection group that one child developed paroxysmal cough and chest distress following single dose of iv Xiyanping Injection. The symptom was relieved by using Dexamethasone and Promethazine. The pulmonary rales disappearance time alone with the cough disappearance timewas also seen in the five studies. Random-effect model was also used for pooling the data. As a result, the disappearance of pulmonary rales in the Xiyanping Injection group was sooner than that in the Ribavirin Injection group (MD = -1.48, 95%CI[-1.96, -1.00], P < 0.000 01) (Figure 5).
Sun SG et al. Chinese Herbal Medicines, 2015, 7(2): 173-178
176
Table 2
Studies
Evaluation on methodological quality of included trials Allocation
Random methods
concealment
Blind methods Patients
Outcome
and doctors
measurer
Integrity
of
Selective
outcome data
reporting
Other bias
Han et al, 2004
unclear
unclear
unclear
unclear
yes
no
Huang, 2013
unclear
unclear
unclear
unclear
yes
unclear
unclear unclear
Li, 2009
unclear
unclear
unclear
unclear
yes
unclear
unclear unclear
Lan YY, 2013
unclear
unclear
unclear
unclear
yes
unclear
Pan, 2011
Random number table method
unclear
unclear
unclear
yes
no
unclear
Li, 2006
no
unclear
unclear
unclear
yes
no
unclear
Huang, 2005
unclear
unclear
unclear
unclear
yes
no
unclear
Zhang and Lan, 2005
no
unclear
unclear
unclear
yes
no
unclear
Wang, 2013
unclear
unclear
unclear
unclear
yes
no
unclear
Wang, 2011
unclear
unclear
unclear
unclear
no
unclear
unclear
Figure 1
0.00
Forest plot: Comparison on CCE
SE (log[RR])
0.05
0.10 0.15 RR 0.20 0.2
0.5 Figure 2
1
2
5
Funnel plot: Comparison on CCE
4. Discussion According to our results, Xiyanping Injection appeared to be an effective and safe treatment option for the treatment of viral pneumonia in children, and Xiyanping Injection appeared to be more effective than Ribavirin Injection. Compared with Ribavirin Injection the cure rate was much higher in Xiyanping Injection group. The other objective measurements, such as
defervescence time, cough disappearance time, pulmonary rales disappearance time, also provided evidences. However, these advantages were associated with low methodological quality of studies collected so far. The following limitations should be considered before accepting the findings of this paper. Firstly, five databases have been searched up to June 2014 including the Cochrane Library, EM Database PubMed, Wanfang Database, CNKI, and VIP. In addition, the online clinical trial registry websites were also searched. However, all included studies were conducted in China. Most of the studies are small size with positive findings. No multicenter and large-scale RCTs were identified. The potential publication bias can not be excluded. Secondly, as the insufficient information reported from the included studies the methodological quality of most included studies can not be sure. All studies claimed randomization, but only two studies described the detailed method. One trial is at high risk of bias that they allocated the participants according the number of their hospital records. All the included studies did not report the information on the allocation concealment. None of the included studies mentioned blind. So researchers follow the basic guidelines for reporting clinical studies such as the Consolidated Standards of Reporting Trials (CONSORT)
Sun SG et al. Chinese Herbal Medicines, 2015, 7(2): 173-178
Figure 3
Figure 4
Figure 5
177
Forest plot: Comparison of defervescence time
Forest plot: Comparison of cough disappearance time
Forest plot: Comparison of pulmonary rales disappearance time
statement is quite necessary. The adverse effects of Xiyanping Injection included seven cases of headache 1.53% (7/456) only. Of which one case of serious allergic reaction was seen. A recent notification from the State Food and Drug
Administration prompted that serious allergic reaction was related to Xiyanping Injection, cases were more seen in children under 14 years old than adults (Lin and Zhang, 2012). So confirming the patient family history of allergies is
178
Sun SG et al. Chinese Herbal Medicines, 2015, 7(2): 173-178
recommended when using this kind of therapy, emergency medications is also needed to prevention the serious adverse events.
5. Conclusion In conclusion, compared with Ribavirin Injection, Xiyanping Injection is of more benefits for children with viral pneumonia while non-significant side effects are found in the Xiyanping Injection group. However, concerning methodological quality of included studies, it is difficult to draw a definitive conclusion. Higher quality, longer follow-up periods, larger sample sizes, and multi-centers RCT need to be warranted to confirm the results.
Acknowledgments Yafei Shi and Shiguang Sun contributed equally to this paper. The current work was partially supported by the Public Health Cultivation Program of the capital of China (No. z131100004013007). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.
References Ceylan B, Calıca A, Ak O, Akkoyunlu Y, Turhan V, 2013. Ribavirin is not effective against Crimean-Congo hemorrhagic fever: Observations from the Turkish experience. Int J Infect Dis 17(10): e799-801. Han YG, Liu HP, Cui M, 2004. Clinical observation of 60 children with viral pneumonia treated by Xiyanping Injection. Mod J Integr Tradit Chin West Med 13(19): 2562-2563. Hebert MF, Guglielmo BJ, 1990. What is the clinical role of aerosolized ribavirin. DICP 24(7-8): 735-738. Higgins JPT, Green S, 2009. Cochrane Handbook for Systematic Reviews of Interventions, Version 5. 1. 0, The Cochrane
Collaboration. Huang H, 2005. Clinical observation of Xiyanping Injection on treatment of 30 cases of infantile viral pneumonia. Jilin J Tradit Chin Med, 25(06): 29. Huang W, 2013. Effect observation of Xiyanping in treatment of viral pneumonia for children. Med J Chin People's Health 25(19): 25-26. Lan YY, 2013. Effect observation of Xiyanping in treatment of viral pneumonia for children. China Pract Med 8(25): 179-180. Li QY, 2009. Clinical observation of Xiyanping Injection on treatment of 60 cases of infantile viral pneumonia. J Pediatr Tradit Chin Med 5(6): 13-15. Li XH, Zhang C, Shi QS, Yang T, 2013. Improving the Efficacy of Conventional Therapy by Adding Andrographolide Sulfonate in the Treatment of Severe Hand, Foot, and Mouth Disease: A Randomized Controlled Trial. Evid Based Complement Alternat Med 2013: 316250. Li YJ, 2006. Effect observation of Xiyanping in treatment of viral pneumonia for children. Qingdao Med J 38(03): 176-177. Lin Q, Zhang S, 2012. Analysis of 270 Cases of Adverse Drug Reactions/Events Reports Caused by Xiyanping Injection. Chin J Pharmacovigil 9(12):751-754. Schwingshackl L, Hoffmann G, 2013. Long-term effects of low-fat diets either low or high in protein on cardiovascular and metabolic risk factors: a systematic review and meta-analysis. Nut J doi:10.1186/1475-2891-12-48. Pan YL, 2011. Clinical observation of Xiyanping Injection on treatment of 35 cases of infantile viral pneumonia. Chin Pediatr Integr Tradit West Med 3(05): 415-416. Ruuskanen O, Lahti E, Jennings LC, Murdoch DR, 2011. Viral pneumonia. Lancet 377(9773): 1264-1275. Wang BQ, 2011. Curative effect observation of Xiyanping Injection in the treatment of children viral pneumonia. Med Informat 24(5): 154-155. Wang ZX, 2013. Effect observation of Xiyanping in treatment of viral pneumonia for children. Med Aesthet Cosmetol 21(1): 83. Zhang JH, Lan ZJ, 2005. 60 cases of infantile viral pneumonia treated by Xiyanping Injection. Zhejiang J Tradit Chin Med (10): 455.