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Chinese herbal medicines for treatment of hand, foot and mouth disease: A systematic review of randomized clinical trials
Available online at www.sciencedirect.com
European Journal of Integrative Medicine 4 (2012) e85–e111
Review article
Chinese herbal medicines for treatment of hand, foot and mouth disease: A systematic review of randomized clinical trials Huijuan Cao 1 , Zhaolan Liu 1 , Peter Steinmann, Yujie Mu, Hui Luo, Jianping Liu ∗ Beijing University of Chinese Medicine, Centre for Evidence-Based Chinese Medicine, Bei San Huan Dong Lu 11, Chaoyang, Beijing, China Received 31 August 2011; received in revised form 23 November 2011; accepted 23 November 2011
Abstract Background: Chinese herbal medicines are widely used in treating hand, foot and mouth disease (HFMD) in China. Single clinical studies have shown positive results of Chinese herbal medicines on HFMD compared with Western medication. A systematic review was conducted to critically appraise the available evidence on the potential benefits and harms of Chinese herbal medicines’ use in HFMD. Methods: Randomized controlled trials comparing Chinese herbal medicines with no treatment, placebo, or Western medications for HFMD were included. Databases searched included: PubMed, the Cochrane Library, Chinese Biomedical Database, China Network Knowledge Infrastructure, Chinese Scientific Journal Database, and Wan Fang Database. All searches ended in July 2011. Four authors extracted data and assessed the study quality independently. RevMan 5.0.25 software was used for data analysis with effect estimate presented as relative risk and mean difference with a 95% confidence interval. Results: Seventy six trials were included, with generally poor methodological quality. According to the results of each single trial and meta-analysis of 18 trials, herbal medicine with or without active drugs may have effect for reducing fever clearance time, rash subsidence time, oral symptoms healing time and healing time of HFMD. Conclusions: This review suggests herbal medicine, combined with Western medications or used separately might improve symptoms of HMFD. However the current evidence is not of sufficient quality to allow unconditional recommendations to be made about the wider application of any kind of herbal medicine for the treatment of HFMD. © 2011 Elsevier GmbH. All rights reserved. Keywords: Chinese herbal medicine; Hand; Foot; Mouth disease; Systematic review; Meta analysis
Background Hand, Foot and Mouth Disease (HFMD) is a common disease in children. It is caused by an enterovirus, usually coxsackievirus type A 16 (coxA 16) and enterovirus 71 (EV 71) [1]. The diagnosis of HFMD is usually based on the clinical features. The illness typically initially begins with fever, sore throat, poor appetite, tiredness and anorexia, one or two days after the fever begins, vesicles appear on the cheeks, gums, and sides of the tongue. These begin as small red spots that blister and often become ulcers. The skin rash develops over 1–2 days with papulovesicular lesions occurring in 75% of cases. These appear on the palms, fingers, toes, soles, buttocks, genitals and limbs. The
∗ 1
Corresponding author. E-mail address: jianping [email protected] (J. Liu). Both authors contributed equally.
1876-3820/$ – see front matter © 2011 Elsevier GmbH. All rights reserved. doi:10.1016/j.eujim.2011.11.004
lesions may look haemorrhagic and are not itchy. The illness duration usually is 7–10 days, and the viruses can be found in stool for weeks [2]. Humans are thought to be the only natural host of these viruses. The disease mainly spreads by contact with nose and throat discharges, saliva, fluid from vesicles or patients’ stool, or through contaminated objects [3]. A robust immunity develops against the causative agent but a second attack of HFMD may occur following infection with a different member of the enterovirus group. Since the first case of HFMD which occurred in Toronto in 1957 [4], several countries/cities reported the outbreak of this disease. Most of the reported outbreaks of HFMD have occurred in cities in the temperate zones of southern Africa, North America, Australia, Europe and Asia, including Singapore [5] and Taiwan [6]. Many studies have found that infants and children under 5 years of age are commonly susceptible to the virus. Significant risk factors for infection are low socio-economic status and personal hygiene habits such as
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Table 1 Characteristics of included trials. Study ID
Diagnostic criteria
Not reported
Cai JY (2010)
Chinese criteria
Chen ZM (2010)
Age (yr, Rx/C)
Sex (M/F)
I: 26 C: 28 Total: 54 I: 39 C: 39 Total: 78
2/3–5
31/23
I: 3.8 ± 1.6 C: 3.7 ± 1.4
47/31
Chinese criteria
I: 44 C: 42 Total: 86
51/35
Cheng HQ (2009)
Chinese criteria
29/31
Cheng HJ (2010)
Chinese criteria
I: 30 C: 30 Total: 60 I: 41 C: 35 Total: 76
I: < 1y: 12; 1–5y: 24; >5y: 8 C: < 1y: 11; 1–5y: 24; >5 y: 7 2/3–7
3.2 ± 0.6
40/36
Cheng YM (2010)
Chinese criteria
I: 60 C: 60 Total: 120
I: 5.5 C: 4.5
68/52
Deng CL (2010)
Chinese criteria
I: 52 C: 38 Total: 90
I: < 3y 42 3–8y 10 C: < 3y 32 3–8y
66/24
Deng SZ (2010)
Chinese criteria
I1 : 50 I2 : 50 C: 50 Total: 150
I1 : 4.05 ± 1.94 I2 : 3.95 ± 1.34 C: 3.90 ± 1.26
85/65
Intervention group
Control group, administration route, dose
Duration of treatment (days)
Outcomes
Ribavirin injection 10 mg/kg/d 1X/d Ribavirin injection 10 mg/kg 1X/d
Not reported
a FCT/stomatitis
5–7 d
TER/FCT/RST
Route of Ingredients administration, dose
Adverse reaction
Chuanhuning injection 10 mg/kg/d 1X/d Xiyanping injection, 5 mg/kg + 5% glucose 1X/d + ribavirin Xiyanping injection: 5 mg/(kg d) 1X/d + ribarivin
Active extract of Andrographis
None
Water-soluble andrographolide sulfonate
A little rash
Water-soluble andrographolide sulfonate
None
Ribavirin injection 10 mg/(kg d) 1X/d
5d
TER/FCT/OUHT/ RST
Not reported
Ribavirin injection 10–15 mg/kg/d
3d
CK,CK-MB
Not reported
Acyclovir injection: 15 mg/(kg d) + 5% glucose 250 ml
Not reported
TER/HT/RST
Ribavirin 10–20 mg/kg d, 3 X/d
5d
Cure rate/TER
Modified yinqiaosan YINqiaosan oral 200 ml/d + ribavirin Honeysuckle oral: Not reported 1–3y: 1 g 3X/d 4–7Y: 3 g 3X/d + acyclovir
Dazi decoction oral: Indigowoad leaf, Not reported 1X/d gromwell, gypsum fibrosum, isatis root, flos chrysanthemi indici, poison yam, liquorice, pearl powder Potassium sodium None Yanhuning injection: succinate 5–10 mg/(kg d) half-ester salt of + 5%–10% glucose andrographolide 50–100 ml 1X/d I1 : injection Potassium sodium None interferon succinate 50,000–80,000 U/kg, half-ester salt of Yanhuning andrographolide 5–10 mg/kg 1X/d I2 : injection Yanhuning 5–10 mg/kg 1X/d
healing time
Ribavirin injection 5–7 d 10–15 mg/(kg d)2X/d
FCT/RST/time of hospitalization
Injection: interferon 3 d 50,000–80,000 U/kg,
TER/FCT/OUHT/RST
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Cai HW (2001)
Sample size (Rx/C)
Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Intervention group
Control group, administration route, dose
Route of Ingredients administration, dose
Duration of treatment (days)
Outcomes
Adverse reaction
Not reported
I: 40 C: 40 Total: 80
0.6–7
44/36
Modified jidaiyu decoction oral 100 ml/d 3X/d
Jisusan, Daihasan, Not reported Yuquansan, Scutellaria, Forsythia, honeysuckle
Gargling 3 dd chlorhexidine rinse treated with calamine lotion; oral ribavirin
OUHT/RST
Ding S (2011)
Chinese criteria
I: 52 C: 56 Total: 108
I: 2.6 C: 2.5
78/30
Tanreqing injection 0.5 ml/kg plus 5% glucose 100 ml 1X/d
Ribavirin injection 10 mg/kg + 5% glucose 100 ml 1X/d
6 dd
TER/FCT/OUHT/RST
Fan MY (2010)
Chinese criteria
I: 43 C: 42 Total: 85
I: < 1y 12 1–3y 29 >3y 2 C: < 1y 14 1–3y 25 >3y 3
55/30
Injection ribavirin 10–15 ml/kg
7 dd
TER/FCT/RST
Feng FY (2010)
Chinese criteria
I: 300 C: 300 Total: 600
305/295
Guo WZ (2008)
Chinese criteria
I: 37 C: 36 Total: 73
I: < 1y 75; 1– 3 y 180; >3y 45 C: < 1y 80; 1–3 y 176; >3y 44 0.25–8
48/25
Injection ribavirin 10–15 ml/kg Tanreqing 1 ml/kg and 5% glucose 100–200 ml 1X/d Yanhuning injection 5–10 mg/(kg d) and 5% glucose 50–100 ml Ganluxiaodudan oral 1X/d plus ribavirin
Skullcap, bear bile None powder, goat angle, honeysuckle, Forsythia, etc. Skullcap, bear bile None powder, goat angle, honeysuckle, Forsythia, etc.
Guo XY (2009)
Chinese criteria
I: 80 C: 72 Total: 152
Not reported
78/84
A little rash: 3 Acyclovir injection 5 d cases diarrhea: 5–7.5 mg/(kg d) + 5% 5 cases glucose 50–100 ml
TER/FCT/HT/RST
No
Ribavirin injection 10–15 mg/kg 2X/d
3–6 d
FCT/RST/HT
Not reported
Comprehensive treatment
5d
FCT/OUHT/RSR/ appetite improved time/neurological symptoms improved time
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Qingkailing + comprehensive treatment oral <1year old 1/2 × 2X/d; 1–3 years old 1/2 × 3X/d; 3–5 years old 2/3 × 3X/d; > 5 years old 1 × 3X/d
Potassium sodium succinate half-ester salt of andrographolide Talc, Scutellaria, capillary artemisia, Agastache rugosus, Forsythia, Shichangpu, white Kou Yan, mint, Belamcanda, Fritillaria, honeysuckle, Radix isatidis Baicalin, honeysuckle, Radix, buffalo horn, Gardenia, Radix isatidis, pigs deoxycholic acid
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Ding HL (2004)
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Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Intervention group
Control group, administration route, dose
Duration of treatment (days)
Outcomes
Adverse reaction
Qingkailing injection 1 ml/(kg dkg d) + 5% glucose 100 ml 1X/d plus acyclovir
Not reported
Injection acyclovir 30 mg(kg d) + 5% glucose 100 ml 1X/d
Not reported
FCT/RST/time of hospitalization
Not reported
acyclovir Oral 3–6 mg/kg 4X/d
7d
HT/FCT/OUHT/RST
Not reported
Ribavirin injection: 0.1–0.15 mg/kg 1X/d
Not reported
FCT/OUHT
No
Ribavirin injection 10–15 ml/kg 1X/d
7d
Ribavirin injection 10–15 ml/kg 1X/d
7d
FCT/RST/Effect measles back/cough efficacy FCT/RST/effect measles back/cough efficacy
Ribavirin injection 10 mg/(kg d)
Not reported
Hao SL (2011) Chinese criteria
I: 48 C: 48 Total: 96
I: 3.5 C: 3.8
52/44
He YP (2009)
Not reported
I: 96 C: 121 Total: 217
Not reported
136/81
Hu YL (2009)
Chinese criteria
I: 52 C: 49 Total: 101
2/3–7
48/53
Huang RW (2009)
Chinese criteria
I: 103 C: 80 Total: 183
1/3–12
101/82
Huang RW (2009a)
Chinese criteria
I: 110 C: 80 Total: 190
1/3–12
107/83
I: Tanreqing injection 0.3–0.5 ml/kg 1X/d
Huang SP (2010)
Chinese criteria
I: 88 C: 72 Total: 160
I: 3.13 ± 0.62 C: 3.00 ± 0.68
80/80
Injection ribavirin 10 mg/(kg d) + Yanhuning 10 mg/(kg d) 1X/d
Baicalin, honeysuckle, Radix, buffalo horn, Gardenia, Radix isatidis, pigs deoxycholic acid, cholic acid Honeysuckle and Decoction of detoxicating and wild slaking rashes oral chrysanthemum, 1X/d + acyclovir Paris polyphylla, Radix isatidis, Scutellaria, Coptis, Smilax glabra, Gardenia, Anemarrhena, Trichosanthes, Rehmanniae, Scrophulariaceae, paeonol Yanhuning injection Potassium sodium 4–8 mg/kg succinate Half-ester salt of 1X/d + ribavirin andrographolide Artemisia annua, I: Reduning injection 0.6 ml/kg honeysuckle, 1X/d Gardenia
Skullcap, bear bile None powder, goat angle, honeysuckle, Forsythia, etc. Potassium sodium Not reported succinate half-ester salt of andrographolide
TER/FCT/OUHT/ RST/HT
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Route of Ingredients administration, dose
Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Chinese criteria
I: 50 C: 44 Total: 94
I: 3.7 C: 3.5
47/47
Huang ZG (2009)
Not reported
I: 2.3 ± 0.8 C: 2.6 ± 0.7
29/24
Jiang XD (2010)
Chinese criteria
I: 25 C: 28 Total: 53 I: 193 C: 187 Total: 380
Not reported
224/156
Li LJ (2011)
Chinese criteria
I: 43 C: 43 Total: 86
4.5 ± 1.1
51/35
Li P (2010)
Chinese criteria
I: 78 C: 78 Total: 156
I: 2.5 ± 0.7 C: 2.7 ± 0.8
86/70
Li QX (2006)
Chinese criteria
I: 68 C: 64 Total: 132
I: 2.8 C: 2.7
68/64
Control group, administration route, dose
Duration of treatment (days)
Outcomes
Route of Ingredients administration, dose
Adverse reaction
Antelope horn, plaster, Folium isatidis, honeysuckle, Forsythia, dandelion, Scutellaria, radix Paeoniae rubra, licorice Forsythia, Shuanghuanglian honeysuckle, injection 60 mg/kg 1X/d Scutellaria Tanreqing injection: Skullcap, bear bile 0.3–0.5 ml/(kg d) + powder, goat 5% glucose 100 ml angle, 1X/d + ribavirin honeysuckle, Forsythia, etc. Qingrening, Qingrening: goat antiviral oral liquid angle powder, and Reduning + artificial bezoar, adenine arabinoside honeysuckle etc. and ribavirin Antiviral oral liquid: Radix isatidis, gypsum, reed rhizome etc. Reduning: Artemisia annua, honeysuckle, Gardenia Andrographolide Lianbizhi sodium bisulfite 10 mg/(kg d) 1X/d + ribavirin
None
Ribavirin oral 15–30 mg/kg/d
3d
Antipyretic effect/oral ulcers heal rate/effect measles back
None
Ribavirin injection 10–15 mg/kg
Not reported
Time of medication/HT
Not reported
Ribavirin injection
5d
TER/FCT/OUHT/RST
Not reported
Adenine arabinoside Not reported injection 10 mg/kg 1X/d; ribavirin topical 3X/d
Not reported
Ribavirin 10–15 mg/(kg d) + glucose 1X/d Oral ribavirin
Qingrexiehuo decoction oral 2x/d
Yinqiaohuoyin tang oral 2–3X/d
Silver flower, Not reported Forsythia, Agastache rugosa, capillary artemisia, Coix seed, Magnolia, Shichangpu, baicalin, radix isatidis, wild Chrysanthemum
TER/FCT/OUHT/RST
5d
TER/FCT/RST
5d
TER/FCT/relieve oral pain time/RST
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Huang XH (2004)
Intervention group
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Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Chinese criteria
I: 200 C: 200 Total: 400
I: 1.8 ± 0.3 C: 1.9 ± 0.4
234/166
Liang XL (2010)
Chinese criteria
I: 64 C: 62 Total: 126
<1y: 21 1–3y: 76
76/50
Lin YQ (2008) Chinese criteria
I: 70 C: 66 Total: 136 I: 44 C: 40 Total: 84
I: 2.28 ± 1.01 C: 2.18 ± 1.1
68/65
I: 2.8 ± 1.64 C: 2.9 ± 1.45
52/32
Liu M (2006)
Chinese criteria
Liu WD (2008)
Chinese criteria
I: 35 C1: 35 C2: 35 Total: 105
I: 2–11; C1: 3–10, C2: 2.5–11
60/45
Lu N (2009)
Chinese criteria
I: 27 C: 27 Total: 54
0.5–5
39/15
I: 120 C: 120 Total: 240
I: < 1y: 8 1–3y: 90 3–6y: 19 >6y: 3 C: < 1y: 6 1–3y: 92 3–6y: 20 >6y: 2
174/66
Luo XS (2010) Chinese criteria
Control group, administration route, dose
Duration of treatment (days)
Outcomes
Route of Ingredients administration, dose
Adverse reaction
Tanreqing injection: 0.5 ml/kg and 10% glucose 250 ml + ribavirin 1X/d Herbal retention enema, 2–3 ml/kg 1X/d + acyclovir
None
Ribavirin 10 mg/kg and 10% glucose 250 ml 1X/d
Not reported
TER/FCT/OUHT/ RST/HT
Diarrhea: 2 cases. 3–5 times per day
Injection: acyclovir 5–10 mg/(kg d), VitC 150–200 mg/(kg d)
7d
TER/FCT/OUHT/ RST/course of disease
Nausea: 2 cases
Ribavirin injection 15 mg/kg/d
7d
TER/FCT/RST
No
Ribavirin oral 15–30 mg(kg d) 3X/d
3d
TER/FCT/RST
Not reported
Oral: bonner 5–10 mg/kg, 4X/d
Not reported
TER/FCT/HT/RST
None
Ribavirin injection: 7.5 mg/kg; 2X/d
3d
FCT/Herpes scab time/relieve oral pain or salivation time/frequency of ibuprofen use
Ribavirin injection: 10–15 mg/(kg d) 1X/d
Not reported
FCT/RST/ hospitalization time
Xiyanping injection 8 mg/kg/d 1X/d + ribavirin Modified GegenQinlian tang oral 150 ml/d 3–5X/d
Oral: bonner 5–10 mg/kg,4X/d Chimonanthus leaf particles <1year old 1/3X; 1–4 years old 1/2X; > 4 years old 1X; 3X/d Reduning injection: 0.5 ml/kg; 1X/d
Yanhuning injection: 10 mg/(kg d) 1X/d + ribavirin
Skullcap, bear bile powder, goat angle, honeysuckle, Forsythia, etc. Honeysuckle, Forsythia, radix isatidis, patchouli, Scutellaria baicalensis Georgi, duckweed, etc. Water-soluble andrographolide sulfonate Pueraria, Scutellaria, Coptis, licorice, Cimicifuga, red Paeony root, duckweed, Coix seed, couchgrass root, bamboo leaf Flavonoids, alkaloids, inositol, volatile oil
Artemisia annua, honeysuckle, Gardenia
Potassium sodium CK-MB succinate increase: 21 cases half-ester salt of andrographolide
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Li SL (2010)
Intervention group
Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Intervention group
Ingredients Route of administration, dose Ma JH (2010)
Chinese criteria
Not reported
43/39
Tanreqing injection 0.5–1 ml/kg/d 1X/d + ribavirin
Skullcap, bear bile powder, goat angle, honeysuckle, Forsythia, etc.
Ma YP (2010) Chinese criteria
I: 32 C1: 34 C2: 34 Total: 100
Not reported
68/32
Forsythia suspense, honeysuckle, Scutellaria baicalensis Georgi, patchouli, etc.
Mao BR (2009)
Not reported
I: 90 C: 90 Total: 180
I: 2.12 ± 1.04 C: 2.16 ± 1.06
109/71
Chinese medicine compound granules oral: 1–3y half dose + 50–100 ml boiling water per day 3X/d >3y: a dose + 50–100 ml boiling water per day 3X/d Xiyanping injection: 10 mg/kg/d; 1X/d + interferon
Mei P (2010)
According to symptoms
I: 20 C: 20 Total: 40
Not reported
NA
Miao DX (2009)
Chinese criteria
Not reported
108/68
Pan R (2010)
Chinese criteria
I: 130 C: 46 Total: 176 I: 23 C: 23 Total: 46
I: < 1y: 4 1–3y: 14 >3y: 5 C: < 1y: 5 1–3y: 15 >3: 3
30/16
Peng HB (2009)
Chinese criteria
I: 118 C: 117 Total: 235
I: 2.9
Not reported
Water-soluble andrographolide sulfonate
Duration of treatment (days)
Outcomes
CK-MB increased: 11; increased bowel movement frequency: 9 Mild nausea, loss of appetite, gastrointestinal discomfort: 2 cases
Ribavirin injection: ribavirin 10–15 mg/kd/d Vit C 1 g/d 1X/d
Not reported
FCT/RST/OUHT/ myocardial enzymes return to normal time/hospital stay
C1: ribavirin plus Chinese medicine compound granules C2: ribavirin injection: 15 mg/kg + 5% glucose 100 ml 1X/d
3–7 d
Onset of antipyretic action/FCT/fever clearance rate/relieve oral pain time/OUHT/hand foot rash subsidence time
WBC decreased: 3; platelets decreased: 2 None
Injection 50,000 U/kg/d
7d
TER/FCT/OUHT/RST
Ribavirin oral: 10 mg/(kg d) 3X/d
7d
TER/FCT/relief headache time/RST
Adverse reaction
Pudilan oral 1–2y: 1/3 dose 3X/d 2–4y: half dose 3X/d >5y: a dose 3X/d Pudilan oral 0.4–0.8 ml/kg/d 3X/d Yanhuning injection: 10 mg/(kg d) + ribavirin
Dandelion, bitter to the small, radix isatidis, skullcap
Dandelion, bitter None to the small, radix isatidis, skullcap Potassium sodium Not reported succinate half-ester salt of andrographolide
Ribavirin oral 10–15 ml/kg/d; 3X/d Ribavirin
6–10 d
TER/FCT/OUHT/RST
5d
Tanreqing injection: 5–10 ml; 1X/d plus comprehensive treatment
Skullcap, bear bile Rash powder, goat angle, honeysuckle, Forsythia, etc.
Comprehensive treatment
5–7 d
FCT/RST/neurological symptoms improved time/tremble disappearance time/time of hospitalization FCT/RST/hospital stay
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
I: 41 C: 41 Total: 82
Control group, administration route, dose
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Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
I: 65 C: 60 Total: 125
I: 2.5 ± 0.9 C: 2.7 ± 0.6
66/59
Sun QK (2011)
Chinese criteria
I: 38 C: 32 Total: 70
I: 1–3y: 25 3–5y: 13 C: 1–3y: 21 3–5y: 11
41/29
Sun YF (2010) Chinese criteria
I: 36 C: 32 Total: 68
Not reported
41/27
Tian ZL (2008)
Chinese criteria
I: 34 C: 33 Total: 67
I: 3.1 ± 0.5 C: 3.2 ± 0.3
34/33
Wang L (2010)
Chinese criteria
I: 75 C: 75 Total: 150
0.5y–5y
85/65
I: 30 C: 30 Total: 60
I: 3.93 ± 1.29 C: 3.79 ± 1.47
35/25
Wang P (2010) Not reported
Control group, administration route, dose
Duration of treatment (days)
Outcomes
5d
TER/FCT/OUHT/RST
Ingredients Route of administration, dose
Adverse reaction
Oral: chaihuang < = 3y: 4 g/X >3y: 6 g/X bid kangfuxin < = 3y: 5 ml/X >3y: 10 ml/X bid
Mild diarrhea: 3 cases Nausea: 5 cases
Oral: ribavirin 10 mg/(kg d) 3X/d
Not reported
Ribavirin: injection Not reported 10–15 mg/kg/d, 1–2X/d Oral: 10–15 mg/kg/d 3X/d
TER/FCT/OUHT/RST
Not reported
Antiviral therapy
Not reported
Time of hospitalization/symptomatic improvement time
Not reported
Acyclovir injection 10 mg/kg 1X/d
5d
TER/FCT/OUHT/ RST/HT
None
Ribavirin injection: 7–10 d 10–15 mg/kg, 5% glucose 100–200 ml
FCT/RST
Not reported
Ribavirin oral: 10–15 mg/kg d, 3X/d
FCT/OUHT/hands and feet rash subsidence time/HT
Chuaihuang granule: Bupleurum, Scutellaria. Kangfuxing: American cockroach ethanol extract Injection: xuebijing Honeysuckle, radix scutellariae, 1–2 ml/kg/d, 1–2X/d; oral: Water Artemisia annua, decoction, burdock, ganluxiaodu dan patchouli, Perrin, 1X/d coix seed, talc, cogongrass rhizome Tanreqing injection: Skullcap, bear bile 0.3–0.5 ml/kg/d and powder, goat 5% glucose 1X/d + angle, antiviral therapy honeysuckle, Forsythia, etc. Jieduxiaozhen oral, Honeysuckle, Forsythia, Dan, 90 ml, nX/d + acyclovir Leptospermum, Poria, Coix seed, rhizoma imperatae, pale leaves, bellflower, Rehmanniae, Arctium, raw licorice Chiqiao qingre Forsythia, granule oral: fermented 0.5–1y: 1–2 g/X soybean 1–3y: 2–3 g/X 4–6y: 3–4 g/X 3X/d + ribavirin Kanggan granules Not reported oral: 2-4y: 5 g/X 5-7y: 10 g/X 3X/d + ribavirin
Not reported
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Shi YP (2011) Chinese criteria
Intervention group
Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Intervention group
Duration of treatment (days)
Outcomes
Adverse reaction Diarrhea: 3 cases Nausea: 2 cases
Ribavirin oral: 10 mg/kg/d, 3X/d
7d
FCT/RST/virus RNA negative time
Not reported
Conventional therapy
6d
TER/FCT/OUHT/ hospital stay
Ribavirin
7d
TER/FCT/OUHT/ RST/cough healing time
Ribavirin oral 0.25–0.5X 4X/d
Not reported
FCT/relieve oral pain time/OUHT/RST/HT
Symptoms pattern Not reported therapy decoction: modified yinqiaosan; honeysuckle flower, Forsythia, Comfrey, Gardenia, mint, etc.; wild Chrysanthemum, Dandelion, radix isatidis,etc. Artemisia annua, None honeysuckle, Gardenia
Acyclovir injection: 20 mg/(kg d) and 5% glucose 250 ml 1X/d
Not reported
TER/FCT/OUHT/ RST/course of disease
Ribavirin injection 10 mg/(kg d) 1X/d
5d
Average body temperature/RSR
Scutellaria, Gardenia, honeysuckle etc.
Ribavirin oral: 10–15 mg/(kg d) 3X/d
3–5 d
TER/FCT/OUHT/ RST/course of disease/course of fever/course of fever treatment
Chinese criteria
I: 68 C: 68 Total: 136
I: 1.46 C: 1.39
89/47
Lianhuanqingwen oral: 1–2y: 4.5 g/d 3X/d 2–5y: 9 g/d 3X/d
Wang YP (2009)
Chinese criteria
I: 90 C: 90 Total: 180
I: 2.4 C: 2.7
108/72
Wei XL (2010)
Chinese criteria
I: 34 C: 34 Total: 68
Total: 3.5
36/32
Symptoms pattern therapy oral 1X/d plus conventional therapy Tanreqing injection: 0.3–0.5 mg/(kg d) and 5% glucose 100 ml + ribavirin
Wu YH (2009) Chinese criteria
I: 50 C: 50 Total: 100
0.6–6
58/42
Xi RH (2010)
Chinese criteria
I: 104 C: 104 Total: 208
I: 5.26 ± 1.76 C: 5.13 ± 1.89
127/81
1 xiefufeiwei; 2 weiqitongbing; 3 shireneiyun; 4 xinhuokangsheng modified daochisan 5 qiyinliangxu Si jun zi tang and modified sha shen mai dong tang: one dose per day + acyclovir
Xin SX (2009) Chinese criteria
I1 : 31 I2 : 38 C: 34 Total: 103
0.6–7
53/50
Xin YN (2010)
I: 115 C: 110 Total: 225
I: 2–5y C: 1–5y
112/113
I1 : Reduning injection, 0.6 ml/kg/d I2 : Reduning + ribavirin 1X/d Huangzhihua oral liquid 5–20 ml 2X/d
Honeysuckle flower, Forsythia, Ephedra, mint, almond, gypsum,etc. Not reported
Skullcap, bear bile Not reported powder, goat angle, honeysuckle, Forsythia, etc. Pudilan oral 3–5 ml; Dandelion, bitter None 3X/d + Ribavirin to the small, radix isatidis, skullcap
Not reported
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Ingredients Route of administration, dose Wang XG (2010)
Chinese criteria
Control group, administration route, dose
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Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Chinese criteria
I: 48 C: 47 Total: 95
I: 3.2 ± 0.5 C: 3.1 ± 0.4
50/45
Xu ZF (2009)
Not reported
I: 70 C: 60 Total: 130
0.5–5
Not reported
Xu H (2011)
Chinese criteria
I: 96 C: 90 Total: 186
I: 0.5–7y C: 0.5–7y
103/83
Xu R (2010)
Chinese criteria
I: 278 C: 278 Total: 556
I: 34.58 ± 1.39 m 361/195 C: 32.36 ± 1.17 m
Yang PY (2010)
Chinese criteria
I: 110 C: 100 Total: 210
Yang ZJ (2009)
Not reported
I: 72 C: 69 Total: 141
I: <1: 19; 1–4: 60; 125/85 >4: 31 C: < 1: 11; 1–4: 59; >4: 30 77/64 1/3–8
Yao BY (2011)
Chinese criteria
I: 33 C: 32 Total: 65
I: 0.5–7 C: 5 m–8y
35/30
Yuan BB (2010)
Chinese criteria
I: 39 C: 39 Total: 78
I: 2.3 ± 0.5 C: 2.7 ± 0.6
43/35
Control group, administration route, dose
Duration of treatment (days)
Outcomes
Route of Ingredients administration, dose
Adverse reaction
Liangxuejiedu tang oral 1X/d + acyclovir
Not reported
Acyclovir injection 10 mg/kg 1X/d
5d
TER/FCT/OUHT/ RST/HT
None
Ribavirin injection 10–15 mg/kg/d 2X/d
3–5 d
TER/FCT/OUHT/RST
None
Ribavirin spray inhalation: 1X/4–5 h
3–7 d
TER/FCT/OUHT/ RST/HT
Not reported
Injection: ribavirin 10 mg/kg Oral: ibuprofen 5 mg/kg
7d
TER/FCT/OUHT/ RST/HT
None
Interferon 8–10 g
5d
TER, symptoms subsidence time
Not reported
Ribavirin injection 10–15 mg/dk/d; 1X/d
7d
TER/FCT/OUHT/RST
Not reported
Ganciclovir injection
>6 d
TER, body temperature/hospitalization time/RST
None
Ribavirin 10 –15 mg/kg and 5% glucose 1X/d
Not reported
Symptoms and signs clearance time, TER
Honeysuckle, Forsythia, folium isatidis, cortex moutan, Lithospermum, cicada skin, Coix seed, rhizoma imperatae, pale leaves, bellflower, Rehmanniae, etc. Yanhuning injection Potassium sodium 4–8 mg/kg/d succinate half-ester salt of 1X/d andrographolide Jinzhen oral liquid: Antelope horn, 1–2y: 5 ml, 3X/d rhubarb, radix 2–3y: 10 ml, 2X/d scutellariae, gypsum, artificial 4–7y: 10 ml, 3X/d bezoar, etc. 1st HFMD herbal Dyers woad leaf, decoction: Chrysanthemum, 150 ml*2; oral: < 3y: honeysuckle, puerarin, comfrey, 10–40 ml/X, 3X/d >3y: 50 ml/X, 3X/d mint, etc. + ribavirin Lianzitang 20 ml Lithospermum, flavescens, honeysuckle, Forsythia Yanhuning injection Potassium sodium 10–15 mg/kg/d; succinate half-ester salt of 1X/d andrographolide Andrographis Chuanhuning paniculata injection 10 mg/kg with 250 ml 5% glucose 1X/d Tanreqing injection: Skullcap, bear bile 0.3–0.5 ml/kg and powder, goat 5% glucose angle, 2X/d + ribavirin honeysuckle, Forsythia, etc.
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Xing HZ (2009)
Intervention group
Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Intervention group
Route of Ingredients administration, dose
Adverse reaction
Duration of treatment (days)
Outcomes
Not reported
Total effective rate, body temperature/hospitalization time/RST TER, body temperature/RSR
Zeng QS (2010)
Chinese criteria
I: 62 C: 62 Total: 126 (2 excluded)
0.75–9y
68/58
Curcuma oil injection: 10 mg/kg and ribavirin
Curcuma
None
Ribavirin 10 mg/kg
Zhan GY (2010)
Chinese criteria
I: 61 C: 60 Total: 121
Not reported
NA
Artemisia annua, honeysuckle, Gardenia
None
Ribavirin10 mg/kg + 7 d 100 ml glucose 1X/d
Zhang H (2010)
Chinese criteria
I: 88 C: 84 Total: 172
0.6–6Y
102/70
Reduning injection: 0.5 ml/kg and 100 ml glucose; 1X/d Xiyanping injection, 5–10 mg/kg(I) and 10–15 mg/kg 5(C)
Water-soluble andrographolide sulfonate
Not reported
7d
Symptoms and signs clearance time, TER
Zhang JW (2009)
Chinese criteria
I: 2 ± 0.4 C1: 2.1 ± 0.7 C2: 1.9 ± 0.5
61/47
Xiyanping injection 5–10 mg/kg 1X/d + ribavirin
Water-soluble andrographolide sulfonate
None
4d
TER/FCT/OUHT/RST
Zhang N (2003)
Not reported
I: 2.8 C: 2.5
67/57
Jinlan mixture oral 1X/d
4d
TER/FCT/OUHT/RST
Chinese criteria
I: 2.42 ± 1.18 C: 2.13 ± 1.65
31/22
Detoxication No. 1 oral, 2X/d plus routine Western medicine
Formosanus, radix Not reported isatidis, daqingye, dandelion etc. None Not reported (Herbal medicine)
Oral ribavirin
Zhang QP (2009)
I: 36 C1: 36 C2: 36 Total: 108 I: 68 C: 56 Total: 124 I: 29 C: 24 Total: 53
Ribavirin water-soluble andrographolide sulfonate Ribavirin injection 5 mg/kg 2X/d
Routine Western medicine injection 0.1–0.3 g, 1–2X/d
5–7 d
Zhang W (2008)
Chinese criteria
I: 39 C: 40 Total: 79
Not reported
40/39
Qingkailing oral <1 years old: 3 g/d; 1–3 years old: 4.5 g/d; > 3 years old: 9 g/d
Ribavirin oral 10–15 mg/(kg·X) 1X/d
1 day
Zhang WH (2009)
Not reported
I: 36 C: 36 Total: 72
I: 2.5 ± 0.4 C: 2.3 ± 0.5
39/33
Pudilan oral 1 years old: 1/3X/d; 1–3 years old: 0.5X/d; 3–6 years old: 1X/d; >6 years old: 1X/d + ribavirin
Baicalin, No honeysuckle, radix, buffalo horn, Gardenia, radix isatidis, pigs deoxycholic acid, cholic acid Dandelion, bitter No to the small, radix isatidis, skullcap
TER/FCT/OUHT/RST/ fading duration of constipation or loose stools/fading duration of indigestion and anorexia/fading duration of sore throat/HT TER/FCT/OUHT/RST
Ribavirin spray 1st day: 4 or 8X/d; 2nd day: 10X/d 3–5d: 4X/d
5d
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Control group, administration route, dose
TER/FCT/OUHT/ RST/HT
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Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Intervention group
Adverse reaction Nausea, vomit: 1 case dizziness: 1 case exanthems: 1 case
Zhang X (2011)
Chinese criteria
I1 : 50 I2 : 46 C: 48 Total: 144
I1 : 3.17 ± 1.17 I2 : 3.14 ± 1.22 C: 3.13 ± 1.24
80/64
I1 : anti-viral oral liquid: 5 ml/X 3X/d Injection: 0.6 ml/kg d + Reduning injection I2 : I1 + C
Radix, plaster, reed rhizome, radix rehmanniae, etc.
Zhang Y (2007)
Chinese criteria
I: 36 C: 24 Total: 60
I: 3.1 C: 3.4
36/24
Xiehuangsan oral 1X/d shuijianbi
Zhao JW (2009)
Chinese criteria
I: 158 C: 155 Total: 313
I: 2.1 C: 2.2
166/147
Reduning injection 0.6 mg (kg d), 1X d plus conventional
Wrinkled giant Not reported hyssop, fangfeng, licorice, gypsum, Rehmanniae, rushes, Achyranthes, light bamboo, Gardenia Artemisia annua, None honeysuckle, Gardenia
Zheng H (2010)
Chinese criteria
I: 125 C: 110 Total: 235
I: 2.53 C: 2.76
149/86
Qingre guanchang liquid enema therapy: 200 ml
Zhi ZQ (2008) Chinese criteria
I: 65 C: 60 Total: 125
Not reported
62/63
Zhong ZW (2007)
Chinese criteria
I: 59 C: 56 Total: 115
Not reported
62/53
Zhu XL (2009)
Chinese criteria
I: 76 C: 58 Total: 134
Not reported
Not reported
a TER:
Gypsum, Anemarrhena, raw licorice, honeysuckle, giant knotweed, skullcap, rhubarb, silkworm, cicada Yanhunin injection Potassium sodium 4–8 mg/kg/d succinate 1X/d half-ester salt of andrographolide Yanhuning injection Potassium sodium 10 mg (kg d), 1X d + succinate ribavirin half-ester salt of andrographolide Yanhuning injection Potassium sodium 10 mg(kg d), 1X d + succinate ribavirin half-ester salt of andrographolide
Duration of treatment (days)
Outcomes
Ribavirin: 10 mg/(kg d)
7d
Symptoms and signs clearance time, TER
Ribavirin oral
3d
TER/FCT/OUHT/RST
Conventional therapy
3d
Antipyretic effect/RSR/OUHT/ myocardial enzymes decreased rate/neurological symptoms improved rate TER, body temperature/other symptoms/RSR
None
Nimesulide granules 2 d 100 ml with 200 ml physiological saline
None
Ribavirin injection 10–15 mg/kg/d, 1X/d
5d
TER/FCT/OUHT/RST
None
Ribavirin injection 5 d 10 mg–15 mg (kg d), 1X d
TER/FCT/OUHT/RST
Rash: 3 cases Diarrhea: 5 cases
Ribavirin injection 10 mg (kg d), 1X d
TER/FCT/OUHT/RST
total effective rate; FCT: fever clearance time; OUHT: oral ulcers healing time; RST: rash subsidence time; HT: healing time; RSR: rash subsidence rate.
5d
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Route of Ingredients administration, dose
Control group, administration route, dose
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
residence in rural areas, being member of a migrant population, not washing hands before eating [7], toy sucking [8], and low family income [9]. Incidence is also closely correlated with population density. In China, a total of 1,774,669 cases were reported in 2010, with a case fatality rate of 0.51/1000 [10]. HFMD is a generally self-limiting illness, and there are no specific drug treatments. However, symptomatic treatment often is required. Commonly used drugs include antiviral agents, antibiotics, and immunopotentiators, although there are few studies showing a clear improvement in outcome [11]. According to the plague theory of Traditional Chinese Medicine (TCM) etiology, HFMD should be classified as an infectious disease caused by dampness-heat, accumulation of heart and spleen and invasion of mouth and extremities through the meridians [12]. Consequently, TCM clinical treatment refers to the law of eliminating dampness and clearing heat. Herbal medicines, including herbal decoctions, patents, and injections, are popularly used as treatment for HFMD in China. Many clinical studies indicated that herbal medicine were superior to controls (antiviral treatment or usual care) [13–16], but the findings have not yet been systematically summarized. The objective of the present review is to critically appraise the available evidence on the potential benefits and harms of Chinese herbal medicines’ use in HFMD to enrich the body of evidence. Methods Inclusion criteria Parallel randomized controlled trials (RCTs) of Chinese herbal medicines compared with no treatment, placebo, nonpharmaceutical therapy or Western medications in patients with HFMD were included. Combination therapy of Chinese herbal medicines and other interventions compared with the same other interventions alone was also included. Participants could be of any age, sex or ethnic origin, and HFMD had to be diagnosed according to recognized criteria. Outcome measures included mortality and morbidity due to HFMD-related complications, death from all causes, hospital admissions and stay (directly related to HFMD), time to cure (fever clearance time, disappearance of rash and other symptoms), time to fever reduction, time to symptom disappearance (rash, angina), and adverse events (related to treatment). Duplicate publications and companion papers of a primary study were excluded. Publications in all languages were eligible for inclusion. Study identification and selection We searched the China Network Knowledge Infrastructure (CNKI; 1979–2011), Chinese VIP Information (1989–2011), Wan Fang Database (1985–2011), Chinese Biomedicine (CBM) database (1978–2011), PubMed (1966–2011) and Cochrane Library (Issue 7, 2011). All searches ended in July 2011. The search terms included “enterovirus 71 infection”, “Herpangina”, “Coxsackievirus infections”, or “Hand, Foot and Mouth Disease” combined with “traditional Chinese medicine”, “TCM”, “herbal”, “complementary”, “alternative”, or “Phytotherapy”.
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Two authors (Ma LX and Mu YJ) independently assessed studies for eligibility against the inclusion criteria. Data extraction and quality assessment Four authors (Liu ZL, Mu YJ, Cao HJ and Luo H) independently extracted relevant population and intervention characteristics using self-designed data extraction templates. All disagreements were resolved through discussion, or if required by a fifth party (Liu JP). The methodological quality of RCTs was assessed using criteria from the Cochrane Handbook for Systematic Reviews of Interventions, Version 5.0.2 [17]. The quality of trials was categorized into low risk of bias, unclear risk of bias, or high risk of bias according to the risk for each important outcome of included trials, including adequacy of generation of the allocation sequence, allocation concealment, blinding, whether there was incomplete outcome data, selective outcome reporting, or other sources of bias. Data analysis Dichotomous data were expressed as risk ratios (RR) with 95% confidence interval (CI). Continuous data were expressed as mean differences (MD) with 95% CI. Statistical heterogeneity was tested by the I2 [17]. We used the Revman 5.0.2 software from the Cochrane Collaboration for data analyses. Meta-analysis was used if the trials had acceptable homogeneity (I2 < 85%) of study design, participants, interventions, controls, and outcome measures. We performed meta-analyses using fixed-effect models (I2 < 25%) for homogeneous studies and using random-effects methods prior to fixed-effect models when there was substantial heterogeneity (25% < I2 < 85%). Results Description of studies Results of the search The initial search identified 9433 publications. After duplicates had been removed, potentially relevant articles were further assessed. A total of 9041 manuscripts were excluded because they were non-clinical studies, or irrelevant to HFMD, and 392 articles were highlighted for further evaluation. After full text reading, 310 publications were excluded because they did not meet our inclusion criteria. Of the remaining, 76 trials [18–93] were included, a further 5 [94–98] studies were excluded due to insufficient data and 1 study [99] was excluded due to an inappropriate randomization method (Fig. 1). All 76 trials were published in scientific journals, no unpublished dissertations or conference papers were included. Characteristics of included trials The 76 RCTs included a total of 10,664 participants. All RCTs were conducted in China. Only 1 was published in English [84], the remaining trials were all published in Chinese. There were 6 three-arm trials [25,48,52,69,82,87] and 70 with a parallel two-arm design. Detailed information of included studies is shown in Table 1.
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H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Fig. 1. Flow-chart of study selection.
The average sample size of the trials was 141 participants (ranging from 40 to 600 participants per trial). The age of the participants ranged from 0.3 to 16 years. Except 5 trials [54,57,74,80,93] which failed to report the sex ratio of participants, the percentage of female participants was 73.8%. Ten included trials did not report the diagnostic criteria for HFMD, 65 trials diagnosed HFMD according to Chinese national criteria and 1 trial [54] only mentioned that HFMD was diagnosed based on the subjects’ symptoms. Twenty-three different herbal medicines were employed as main interventions in the included trials (Table 1). Their formulations included capsules, tablets, injections and decoctions. No trials reported quality standards of the herbal preparations. The control interventions included usual care, acyclovir, ribavirin, and other conventional Western medications. The duration of treatment varied from 1 to 10 days. The outcomes included time of hospital stay, time until cure (defervescence, disappearance of rash and other symptoms), time to bring down the fever, time until symptoms disappeared (rash, angina, gastritis, mucous ulcer), creatine kinase (CK), creatine kinase muscle and brain (CK-MB), time to appetite return, time to psychiatric symptoms disappearance, and adverse events. Risk of bias in included trials According to our pre-defined methodological quality criteria, all included trials should be evaluated as unclear risk of bias. Only 9 trials described randomization procedures (random number table), but only 1 of them [87] reported allocation
concealment (sealed envelope). One trial [87] mentioned single blinding, but did not provide details. One trial [87] reported the number of dropouts, but intention-to-treat analysis was not employed. None of the included trial could be considered as a low risk of bias study. Effect of intervention Among the 76 included trials, 47 used herbal medicine plus active drugs compared with active drugs alone, and 32 trials compared herbal medicine with Western medications (3 trials involved both above comparisons). Results of each single trial are summarized in Table 2. Due to different intervention or control treatment, or high potential of heterogeneity between trials, only 18 trials [19,20,26,31,32,35,36,46,49,57,60,67,74,76,80,82,86,91] could be included in the meta-analysis (Table 3). Cure rate “Cure” was defined as disappearance of the clinical symptoms, and normal results in laboratory tests and X-ray examinations. Ten trials which used herbal medicine plus active drugs versus active drugs alone reported the cure rate after treatment. Only 4 of them showed that a combination of herbal medicine and active drugs was superior to active drugs alone in increasing the cure rate of patients with HFMD.
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
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Table 2 Effect estimates of herbal medicine for hand, foot and mouth disease in 76 trials. Outcomes or subgroups 1. Fever clearance time (days) 1.1 Herbal medicine versus active drugs 1.1.1 Herbal patent drug versus active drugs 1.1.1.1 Chinese medicine compound granules versus ribavirin 1.1.1.2 Pudilan versus ribavirin 1.1.1.3 Chaihuang granules plus kangfuxin oral liquid versus ribavirin 1.1.1.4 Lianghuaqingwen granules versus ribavirin 1.1.1.5 Huangzhihua oral liquid versus ribavirin 1.1.1.6 Jinzhen oral liquid versus ribavirin 1.1.1.7 Jinlan mixture versus supportive therapy 1.1.1.8 Kangbingdu and Reduning versus ribavirin 1.1.1.9 Xiehuangsan versus ribavirin 1.1.2 Herbal injection versus active drugs 1.1.2.1 Chuanhuning versus ribavirin 1.1.2.2 Yanhuning versus interferon 1.1.2.3 Tanreqing versus ribavirin
No. of studies
Study ID
Participants
27
3784
10
1138
Effect estimate
66
−0.04 [−0.28, 0.20]
216
−1.21 [−2.97, 0.56]
1
Mei P (2010) Miao DX (2009) Shi YP (2011)
125
−0.92 [−1.33, −0.51]
1
Wang XG (2010)
136
0.04 [−0.18, 0.26]
1
Xin YN (2010)
225
−2.20 [−2.47, −1.93]
1
Xu H (2011)
186
−1.15 [−1.45, −0.85]
1
Zhang N (2003)
124
−1.59 [−1.70, −1.48]
1
Zhang X (2011)
98
−0.62 [−0.91, −0.33]
1 14
Zhang Y (2007)
60 2122
−0.41 [−0.48, −0.34]
54 100 298
−0.47 [−0.80, −0.14] 0.00 [−0.28, 0.28] −1.26 [−2.07, −0.44]
600 358
−0.54 [−0.71, −0.37] −0.89 [−0.99, −0.79]
396
−2.53 [−2.80, −2.27]
1
Ma YP (2010)
2
1 1 2
1.1.2.4 Yanhuning versus ganciclovir 1.1.2.5 Reduning versus ribavirin
1 3
1.1.2.6 Yanhuning versus ribavirin
3
1.1.2.7 Chuanhuning injection versus ganciclovir 1.1.2.8 Qingkailing versus ribavirin 1.1.2.9 Xiyanping versus ribavirin 1.1.3 Herbal decoction versus active drugs 1.1.3.1 Yinqiaohuoyin decoction versus ribavirin 1.1.3.2 Modified gegen qinlian decoction versus ribavirin 1.1.3.3 Lianzitang decoction versus interferon 1.2 Herbal medicine plus active drugs versus active drugs alone 1.2.1 Herbal patent drug plus active drugs versus active drugs alone 1.2.1.1 Jinyinhua plus acyclovir versus acyclovir alone 1.2.1.2 Ganluxiaodu pill plus ribavirin versus ribavirin 1.2.1.3 Qingrening, Reduning and kangbingdu oral liquid plus ribavirin versus ribavirin alone 1.2.1.4 Bonner plus Chimonanthus leaf particles treatment versus bonner alone
1
Cai HW (2001) Deng SZ (2010) Ding S (2011) Huang RW (2009a) Feng FY (2010) Huang RW (2009) Lu N (2009) Zhan GY (2010) Xu ZF (2009) Yang ZJ (2009) Zhi ZQ (2008) Yao BY (2011)
65
−0.44 [−1.02, 0.14]
1 1 3
Zhang W (2008) Zhang H (2010)
79 172 426
0.20 [−0.35, 0.75] −2.70 [−3.00, −2.40]
1
Li QX (2006)
132
−1.51 [−1.72, −1.30]
1
Liu M (2006)
84
−0.78 [−0.91, −0.65]
1
Yang PY (2010)
210
−1.17 [−1.41, −0.93]
43
5815
9
781
1
Cheng HJ (2010)
76
−1.50 [−2.08, −0.92]
1
Guo WZ (2008)
73
−0.68 [−1.01, −0.35]
1
Li LJ (2011)
86
−2.00 [−2.80, −1.20]
1
Liu WD (2008)
70
−1.63 [−1.81, −1.45]
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H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Table 2 (Continued) Outcomes or subgroups 1.2.1.5 Chiqiaoqingre granules plus ribavirin versus ribavirin alone 1.2.1.6 Kanggan granules plus ribavirin versus ribavirin 1.2.1.7 Pudilan plus ribavirin versus ribavirin alone 1.2.1.8 Kangbingdu and Reduning plus ribavirin versus ribavirin alone 1.2.2 Herbal injection plus active drugs versus active drugs alone 1.2.2.1 Yanxiping plus ribavirin versus ribavirin alone
No. of studies
Participants
Effect estimate
1
Wang L (2010)
150
−1.20 [−1.65, −0.75]
1
Wang P (2010)
60
−1.57 [−1.84, −1.30]
2
Wu YH (2009) Zhang WH (2009) Zhang X (2011)
172
−1.81 [−2.33, −1.29]
94
−1.15 [−1.37, −0.93]
1
25 4
1.2.2.2 Yanhuning plus ribavirin versus ribavirin alone
7
1.2.2.3 Yanhuning plus interferon versus interferon alone 1.2.2.4 Tanreqing plus ribavirin versus ribavirin alone
1
1.2.2.5 Qingkailing plus comprehensive treatment versus comprehensive treatment alone 1.2.2.6 Lianbizhi plus ribavirin versus ribavirin alone 1.2.2.7 Xiyanping plus interferon versus interferon alone 1.2.2.8 Tanreqing plus comprehensive treatment versus comprehensive treatment alone 1.2.2.9 Xuebijing injection and ganluxiaodu pill plus ribavirin versus ribavirin alone 1.2.2.10 Ezhuyou injection plus ribavirin versus ribavirin 1.2.3 Herbal decoction plus active drugs versus active drugs alone 1.2.3.1 Decoction of qingrejiedu plus acyclovir versus acyclovir alone 1.2.3.2 Chinese medicine compound decoction plus ribavirin versus ribavirin alone 1.2.3.3 Soup of detoxicating and slaking rashes plus acyclovir versus acyclovir alone 1.2.3.4 Symptoms pattern therapy plus conventional therapy versus conventional therapy alone 1.2.3.5 Herbal decoction plus acyclovir versus acyclovir 1.2.3.6 Liangxuejiedu tang plus acyclovir versus acyclovir 1.2.3.7 HFMD no. 1 decoction plus ribavirin versus ribavirin alone
Study ID
6
2
3464 Cai JY (2010) Chen JM (2010) Lin YQ (2008) Zhang JW (2009) Deng CL (2010) Hu YL (2009) Huang SP (2010) Luo XS (2010) Pan R (2010) Zhong (2007) Zhu XL (2009) Deng SZ (2010)
372
−1.59 [−2.50, −0.67]
886
−1.19 [−1.81, −0.57]
100
−0.76 [−1.01, −0.51]
Fan MY (2010) Jiang XD (2010) Li SL (2010) Ma JH (2010) Wei XL (2010) Yuan BB (2010) Guo XY (2009) Hao SL (2011)
1093
−1.18 [−1.97, −0.40]
248
−0.95 [−1.56, −0.34]
1
Li P (2010)
156
−1.70 [−2.15, −1.25]
1
Mao BR (2009)
180
−1.23 [−1.67, −0.79]
1
Peng HB (2009)
235
−1.03 [−1.63, −0.97]
1
Sun QK (2011)
70
−0.70 [−1.07, −0.33]
1
Zeng QS (2010)
124
−1.80 [−2.03, −1.57]
8
1444 −1.24 [−1.33, −1.15]
1
He YP (2009)
217
1
Ma YP (2010)
68
−0.04 [−0.26, 0.18]
1
Tian ZL (2008)
67
−0.62 [−0.95, −, −0.29]
1
Wang YP (2009)
180
−1.30 [−1.63, −0.97]
1
Xi RH (2010)
208
−0.59 [−0.69, −0.49]
1
Xing HZ (2009)
95
−0.78 [−0.98, −0.58]
1
Xu R (2010)
556
−0.24 [−0.29, −0.19]
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
e101
Table 2 (Continued) Outcomes or subgroups 1.2.3.8 Detoxication no. 1 plus routine Western medicine versus routine Western medicine alone 1.2.4 Herbal coloclyster plus active drugs versus active drugs alone 2. Cure rate 2.1 Herbal medicine versus active drugs 2.1.1 Herbal patent drug versus active drugs 2.1.1.1 Pudilan versus ribavirin 2.1.1.2 Chaihuang granules plus kangfuxin oral liquid versus ribavirin 2.1.1.3 Jinlan mixture versus supportive therapy 2.1.2 Herbal injection versus active drugs 2.1.2.1 Yanhuning versus ribavirin 2.1.2.2 Reduning versus ribavirin 2.1.3 Herbal decoction versus active drugs 2.1.3.1 Dazi decoction versus ribavirin 2.1.3.2 Qingrexiehuo decoction versus ribavirin 2.1.3.3 Modified gegen qinlian decoction versus ribavirin 2.1.4 Herbal coloclyster versus active drugs 2.1.4.1 Qingreguanchang versus nimesulid 2.2 Herbal medicine plus active drugs versus active drugs alone 2.2.1 Herbal injection plus active drugs versus active drugs alone 2.2.1.1 Yanhuning plus ribavirin versus ribavirin alone 2.2.1.2 Tanreqing plus ribavirin versus ribavirin alone 2.2.2 Herbal coloclyster plus active drugs versus active drugs alone 2.2.3 Herbal patent drug plus active drugs versus active drugs alone 2.2.4 Herbal decoction plus active drugs versus active drugs alone 2.2.4.1 Herbal decoction plus vidarabine versus vidarabine 2.2.4.2 Soup of detoxicating and slaking rashes plus acyclovir versus acyclovir alone 2.2.4.3 Herbal decoction plus acyclovir versus acyclovir 2.2.4.4 Liangxuejiedu decoction plus acyclovir versus acyclovir alone 2.2.4.5 HFMD no. 1 decoction plus ribavirin versus ribavirin 3. Rash subsidence time (days) 3.1 Herbal medicine versus active drugs 3.1.1 Herbal patent drug versus active drugs 3.1.1.1 Chinese medicine compound granules versus ribavirin
No. of studies
Study ID
Participants
Effect estimate
1
Zhang QP (2009)
53
−0.12 [−1.03, 0.79]
1
Liang XL (2010)
126
−0.22 [−0.46, 0.02]
10
1209
3
289
1 1
Mei P (2010) Shi YP (2011)
40 125
1.83 [0.84, 3.99] 1.15 [1.00, 1.33]
1
Zhang N (2003)
124
1.62 [1.28, 2.05]
3 2 1 3
387 Yang ZJ (2009) Zhi ZQ (2008) Zhan GY (2010)
266
1.35 [1.08, 1.66]
121 298
1.39 [1.10, 1.76]
1
Cheng YM (2010)
120
1.53 [1.20, 1.95]
1
Huang XH (2004)
94
1.52 [1.20, 1.95]
1
Liu M (2006)
84
1.46 [1.09, 1.97]
235
1 1
Zheng H (2010)
235
10
2010
3
674
2.85 [1.97, 4.12]
294
1.71 [0.75, 3.93]
1
Huang SP (2010) Zhu XL (2009) Jiang XD (2009)
380
1.30 [1.14, 1.47]
1
Liang XL (2010)
126
1.00 [0.90, 1.12]
1
Li LJ (2011)
86
1.44 [0.89, 2.32]
2
5
1124
1
Li CX (2009)
1
Tian ZL (2008)
1
Xi RH (2010)
1
Xing HZ (2009)
1
Xu R (2010)
198
1.27 [1.05, 1.54]
67
1.33 [0.94, 1.88]
208
1.37 [1.05, 1.79]
95
0.77 [0.57, 1.03]
556
1.02 [1.00, 1.04]
26
3731
10
1236
1
Ma YP (2010)
66
−2.55 [−2.92, −2.18]
e102
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Table 2 (Continued) Outcomes or subgroups
No. of studies
Study ID
Participants
Effect estimate
216
−1.17 [−2.82, 0.48]
1
Mei P (2010) Miao DX (2009) Shi YP (2011)
125
−1.45 [−1.81, −1.09]
1
Wang XG (2010)
136
0.10 [−0.58, 0.78]
1
Xin YN (2010)
225
−1.80 [−2.20, −1.40]
1
Xu H (2011)
186
−2.41 [−3.06, −1.76]
1
Zhang N (2003)
124
−0.86 [−1.02, −0.70]
1
Zhang X (2011)
98
0.02 [−0.30, 0.34]
1 12
Zhang Y (2007)
60 1989
−0.21 [−0.37, −0.05]
Deng SZ (2010) Ding S (2011) Huang RW (2009a) Feng FY (2010) Xu ZF (2009) Yang ZJ (2009) Zhi ZQ (2008) Huang RW (2009) Lu N (2009) Zhang GY (2010) Yao BY (2011)
100 298
0.01 [−0.21, 0.23] −0.85 [−1.45, −0.25]
600 396
−0.25 [−0.42, −0.08] −2.21 [−2.96, −1.46]
358
−1.45 [−2.12, −0.78]
65
0.06 [−0.65, 0.77]
1 4
Zhang H (2010)
172 506
−1.33 [−1.60, −1.06]
1
Ding HL (2004)
80
−1.84 [−2.38, −1.30]
1
Li QX (2006)
132
−1.44 [−1.67, −1.21]
1
Liu M (2006)
84
−0.42 [−0.48, −0.36]
1
Yang PY (2010)
210
−2.00 [−2.60, −1.40]
3.1.1.2 Pudilan versus ribavirin
2
3.1.1.3 Chaihuang granules plus kangfuxin oral liquid versus ribavirin 3.1.1.4 Lianghuaqingwen granules versus ribavirin 3.1.1.5 Huangzhihua oral liquid versus ribavirin 3.1.1.6 Jinzhen oral liquid versus ribavirin 3.1.1.7 Jinlan mixture versus supportive therapy 3.1.1.8 Kangbingdu and reduning versus ribavirin 3.1.1.9 Xiehuangsan versus ribavirin 3.1.2 Herbal injection versus active drugs 3.1.2.1 Yanhuning versus interferon 3.1.2.2 Tanreqing versus ribavirin
1 2
3.1.2.3 Yanhuning versus ganciclovir 3.1.2.4 Yanhuning versus ribavirin
1 3
3.1.2.5 Reduning versus ribavirin
3
3.1.2.6 Chuanhuning injection versus ganciclovir 3.1.2.7 Xiyanping versus ribavirin 3.1.3 Herbal decoction versus active drugs 3.1.3.1 Modified jidaiyu decoction versus ribavirin 3.1.3.2 Yinqiaohuoyin decoction versus ribavirin 3.1.3.3 Modified gegen qinlian decoction versus ribavirin 3.1.3.4 Lianzitang decoction versus interferon 3.2 Herbal medicine plus active drugs versus active drugs alone 3.2.1 Herbal patent drug plus active drugs versus active drugs alone 3.2.1.1 Jinyinhua plus acyclovir versus acyclovir alone 3.2.1.2 Ganluxiaodu dan plus ribavirin versus ribavirin alone 3.2.1.3 Qingrening, Reduning and kangbingdu oral liquid plus ribavirin versus ribavirin alone 3.2.1.4 Bonner plus Chimonanthus leaf particles treatment versus bonner alone 3.2.1.5 Chiqiaoqingre granules plus ribavirin versus ribavirin alone 3.2.1.6 Kanggan granules plus ribavirin versus ribavirin 3.2.1.7 Pudilan plus ribavirin versus ribavirin alone 3.2.1.8 Kangbingdu and reduning plus ribavirin versus ribavirin alone
1
43
5924
9
781
1
Cheng HJ (2010)
76
−2.10 [−2.94, −1.26]
1
Guo WZ (2008)
73
−1.14 [−1.39, −0.89]
1
Li LJ (2011)
156
−0.95 [−1.29, −0.61]
1
Liu WD (2008)
70
−2.24 [−2.43, −2.05]
1
Wang L (2010)
150
−1.10 [−1.64, −0.56]
1
Wang P (2010)
60
−2.71 [−3.05, −2.37]
2
Wu YH (2009) Zhang WH (2009) Zhang X (2011)
172
−2.56 [−3.03, −2.08]
94
−1.25 [−1.71, −0.79]
1
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
e103
Table 2 (Continued) Outcomes or subgroups
No. of studies
3.2.2 Herbal injection plus active drugs versus active drugs alone 3.2.2.1 Xiyanping plus ribavirin versus ribavirin alone
25 4
3.2.2.2 Yanhuning plus ribavirin versus ribavirin alone
6
3.2.2.3 Yanhuning plus interferon versus interferon alone 3.2.2.4 Tanreqing plus ribavirin versus ribavirin alone
1
3.2.2.5 Qingkailing plus comprehensive treatment versus comprehensive treatment alone 3.2.2.6 Lianbizhi plus ribavirin versus ribavirin alone 3.2.2.7 Xiyanping plus interferon versus interferon 3.2.2.8 Tanreqing plus comprehensive treatment versus comprehensive treatment alone 3.2.2.9 Xuebijing injection and ganluxiaodu pill plus ribavirin versus ribavirin alone 3.2.2.10 Ezhuyou injection plus ribavirin versus ribavirin 3.2.3 Herbal decoction plus active drugs versus active drugs alone 3.2.3.1 Decoction of qingrejiedu plus acyclovir versus acyclovir alone 3.2.3.2 Chinese medicine compound decoction plus ribavirin versus ribavirin alone 3.2.3.3 Soup of detoxicating and slaking rashes plus acyclovir versus acyclovir alone 3.2.3.4 Symptoms pattern therapy plus conventional therapy versus conventional therapy 3.2.3.5 Herbal decoction plus acyclovir versus acyclovir 3.2.3.6 Liangxuejiedu decoction plus acyclovir versus acyclovir alone 3.2.3.7 HFMD no. 1 decoction plus ribavirin versus ribavirin alone 3.2.3.8 Detoxication no. 1 plus routine Western medicine versus routine Western medicine alone 3.2.4 Herbal coloclyster plus active drugs versus active drugs alone 4. Oral ulcer heal time (days) 4.1 Herbal medicine versus active drugs 4.1.1 Herbal decoction versus active drugs
6
2
Study ID
Participants
Effect estimate
3573 Cai JY (2010) Chen ZM (2010) Lin YQ (2008) Zhang JW (2009) Deng CL (2010) Huang SP (2010) Luo XS (2010) Pan R (2010) Zhong (2007) Zhu XL (2009) Deng SZ (2010)
372
−1.54 [−2.31, −0.76]
785
−1.58 [−2.28, −0.89]
1
−0.76 [−1.00, −0.52]
Fan MY (2010) Jiang XD (2010) Li SL (2010) Ma JH (2010) Wei XL (2010) Yuan BB (2010) Guo XY (2009) Hao SL (2011)
1093
−1.29 [−2.05, −0.54]
248
−1.31 [−2.58, −0.04]
1
Li P (2010)
208
−2.03 [−3.01, −1.05]
1
Mao BR (2009)
180
−2.45 [−2.99, −1.91]
1
Peng HB (2009)
235
−1.03 [−1.58, −0.48]
1
Sun QK (2011)
70
−0.80 [−1.08, −0.52]
1
Zeng QS (2010)
124
−2.50 [−2.96, −2.04]
1444
8 1
He YP (2009)
217
−1.89 [−2.10, −1.68]
1
Ma YP (2010)
68
−2.35 [−2.72, −1.98]
1
Tian ZL (2008)
67
−2.38 [−2.64, −2.12]
1
Wang YP (2009)
180
−2.00 [−2.35, −1.65]
1
Xi RH (2010)
208
−1.37 [−1.53, −1.21]
1
Xing HZ (2009)
95
−2.40 [−2.65, −2.15]
1
Xu R (2010)
556
−0.94 [−0.95, −0.93]
1
Zhang QP (2009)
53
1
Liang XL (2010)
126
14
1590
3
422
−0.11 [−1.05, 0.83] −0.22 [−0.41, −0.03]
e104
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Table 2 (Continued) Outcomes or subgroups 4.1.1.1 Modified jidaiyu decoction versus ribavirin 4.1.1.2 Yinqiaohuoyin decoction versus ribavirin 4.1.1.3 Lianzitang decoction versus interferon 4.1.2 Herbal patent drug versus active drugs 4.1.2.1 Chinese medicine compound granules versus ribavirin 4.1.2.2 Pudilan versus ribavirin 4.1.2.3 Chaihuang granules plus kangfuxin oral liquid versus ribavirin 4.1.2.4 Huangzhihua oral liquid versus ribavirin 4.1.2.5 Xiehuangsan versus ribavirin 4.1.3 Herbal injection versus active drugs 4.1.3.1 Chuanhuning versus ribavirin 4.1.3.2 Yanhuning versus interferon 4.1.3.3 Tanreqing versus ribavirin 4.1.3.4 Reduning versus ribavirin 4.1.3.5 Qingkailing versus ribavirin 4.2 Herbal medicine plus active drugs versus active drugs alone 4.2.1 Herbal patent drug plus active drugs versus active drugs alone 4.2.1.1 Qingrening, Reduning and kangbingdu oral liquid plus ribavirin versus ribavirin alone 4.2.1.2 Kanggan granules plus ribavirin versus ribairin 4.2.1.3 Pudilan plus ribavirin versus ribavirin alone 4.2.2 Herbal injection plus active drugs versus active drugs alone 4.2.2.1 Xiyanping plus ribavirin versus ribavirin alone 4.2.2.2 Yanhuning plus interferon versus interferon alone 4.2.2.3 Qingkailing plus comprehensive treatment versus comprehensive treatment alone 4.2.2.4 Yanhuning plus ribavirin versus ribavirin alone 4.2.2.5 Tanreqing plus comprehensive treatment versus comprehensive treatment alone 4.2.2.6 Xuebijing injection and ganluxiaodu pill plus ribavirin versus ribavirin alone 4.2.2.7 Ezhuyou injection plus ribavirin versus ribavirin 4.2.3 Herbal coloclyster plus active drugs versus active drugs alone 4.2.4 Herbal decoction plus active drugs versus active drugs alone 4.2.4.1 Decoction of qingrejiedu plus acyclovir versus acyclovir alone 4.2.4.2 Chinese medicine compound decoction plus ribavirin versus ribavirin alone
No. of studies
Study ID
Participants
Effect estimate
80
−0.92 [−1.28, −0.56]
Li QX (2006)
132
−0.27 [−0.51, −0.03]
Yang PY (2010)
210
−1.34 [−2.01, −0.67]
1
Ding HL (2004)
1 1 5
652 66
−1.70 [−2.07, −1.33]
Miao DX (2009) Shi YP (2011)
176 125
−1.10 [−1.28, −0.92] −1.42 [−1.73, −1.11]
1
Xin YN (2010)
225
−1.00 [−1.41, −0.59]
1 6
Zhang Y (2007)
60 516
−0.70 [−0.90, −0.50]
1 1 1 2
Cai HW (2001) Deng SZ (2010) Ding S (2011) Lu N (2009) Zhang GY (2010) Zhang W (2008)
54 100 108 175
−1.54 [−1.96, −1.12] −0.01 [−0.19, 0.17] −0.64 [−1.19, −0.09] −1.42 [−2.76, −0.08]
1
Ma YP (2010)
1 1
1 22 4
79 2674
−0.40 [−0.94, 0.14]
318
1
Li LJ (2011)
86
−1.30 [−1.51, −1.09]
1
Wang P (2010)
60
−1.20 [−1.50, −0.90]
2
Wu YH (2009) Zhang WH (2009)
172
−1.62 [−2.56, −0.68]
11
1522 158
−1.28 [−1.81, −0.75]
1
Chen ZM (2010) Zhang JW (2009) Deng SZ (2010)
100
−0.64 [−0.81, −0.47]
1
Guo XY (2009)
152
−1.29 [−1.81, −0.77]
2
235
−1.67 [−3.19, −0.15]
683
−1.22 [−1.81, −0.64]
1
Hu YL (2009) Zhu XL (2009) Jiang XD (2010) Peng HB (2009) Wei XL (2010) Sun QK (2011)
70
−0.35 [−0.64, −0.06]
1
Zeng QS (2010)
124
−2.20 [−2.58, −1.82]
1
Liang XL (2010)
126
−0.20 [−0.39, −0.01]
2
3
708
6 1
He YP (2009)
217
−1.98 [−2.18, −1.78]
1
Ma YP (2010)
68
−1.52 [−1.87, −1.17]
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
e105
Table 2 (Continued) Outcomes or subgroups 4.2.4.3 Soup of detoxicating and slaking rashes plus acyclovir versus acyclovir alone 4.2.4.4 Herbal decoction plus acyclovir versus acyclovir 4.2.4.5 Liangxuejiedu decoction plus acyclovir versus acyclovir alone 4.2.4.6 Detoxication no. 1 plus routine Western medicine versus routine Western medicine alone 5. Healing time (days) 5.1 Herbal medicine versus active drugs 5.1.1 Herbal decoction versus active drugs 5.1.1.1 Lianzitang decoction versus interferon 5.1.2 Herbal patent drug versus active drugs 5.1.2.1 Shuanghuanglian versus ribavirin 5.1.2.2 Pudilan versus ribavirin 5.1.2.3 Huangzhihua oral liquid versus ribavirin 5.1.2.4 Jinzhen oral liquid versus ribavirin 5.1.3 Herbal injection versus active drugs 5.1.3.1 Yanhuning versus ganciclovir 5.1.3.2 Qingkailing versus ribavirin 5.1.3.3 Xiyanping versus ribavirin 5.2 Herbal medicine plus active drugs versus active drugs alone 5.2.1 Herbal injection plus active drugs versus active drugs alone 5.2.1.1 Tanreqing plus ribavirin versus ribavirin alone 5.2.1.2 Yanhuning plus ribavirin versus ribavirin alone 5.2.1.3 Tanreqing plus comprehensive treatment versus comprehensive treatment alone 5.2.1.4 Xiyanping plus ribavirin versus ribavirin alone 5.2.2 Herbal patent drug plus active drugs versus active drugs alone 5.2.2.1 Jinyinhua plus acyclovir versus acyclovir alone 5.2.2.2 Ganluxiaodu dan plus ribavirin versus ribavirin 5.2.2.3 Bonner plus Chimonanthus leaf particles treatment versus bonner alone 5.2.2.4 Kanggan granules plus ribavirin versus ribavirin 5.2.2.5 Pudilan plus ribavirin versus ribavirin alone 5.2.2.6 Kanggan granules plus ribavirin versus ribavirin 5.2.3 Herbal decoction plus active drugs versus active drugs alone 5.2.3.1 Modified yinqiaosan plus ribavirin versus ribavirin
No. of studies
Study ID
Participants 67
−0.90 [−1.29, −0.51]
208
−1.07 [−1.25, −0.89]
Xing HZ (2009)
95
−0.86 [−1.14, −0.58]
Zhang QP (2009)
53
−0.11 [−1.05, 0.83]
1
Tian ZL (2009)
1
Xi RH (2010)
1 1
8
1701
1
210
1
Effect estimate
Yang PY (2010)
210
−2.00 [−2.53, −1.47]
640
4 1
Huang ZG (2009)
53
−0.90 [−1.69, −0.11]
1 1
Miao DX (2009) Xin YN (2010)
176 225
−2.50 [−2.94, −2.06] −1.40 [−1.75, −1.05]
1
Xu H (2011)
186
−1.03 [−1.26, −0.80]
3 1 1 1 21
851 Feng FY (2010) Zhang W (2008) Zhang H (2010)
7
600 79 172 2982
−1.20 [−1.40, −1.00] −0.30 [−1.01, 0.41] −2.42 [−2.84, −2.00]
1095 Li SL (2010) Ma JH (2010) Yuan BB (2010) Huang SP (2010)
560
−1.28 [−1.99, −0.57]
160
−1.53 [−1.86, −1.20]
2
Peng HB (2009) Sun YF (2010)
303
−1.46 [−1.93, −0.98]
1
Zhang JW (2009)
72
−1.01 [−1.46, −0.56]
3
1
6
451
1
Cheng HJ (2010)
76
−1.20 [−2.10, −0.30]
1
Guo WZ (2008)
73
−1.13 [−1.43, −0.83]
1
Liu WD (2008)
70
−2.29 [−2.49, −2.09]
1
Wang P (2010)
60
−2.97 [−3.35, −2.59]
2
Wu YH (2009) Zhang WH (2009) Wang P (2010)
172
−2.36 [−3.62, −1.10]
60
−2.97 [−3.35, −2.59]
1
1436
8 1
Cheng HQ (2009)
60
−0.63 [−1.19, −0.07]
e106
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Table 2 (Continued) Outcomes or subgroups 5.2.3.2 Decoction of qingrejiedu plus acyclovir versus acyclovir alone 5.2.3.3 Soup of detoxicating and slaking rashes plus acyclovir versus acyclovir alone 5.2.3.4 Symptoms pattern therapy plus conventional therapy versus conventional therapy 5.2.3.5 Herbal decoction plus acyclovir versus acyclovir 5.2.3.6 Liangxuejiedu decoction plus acyclovir versus acyclovir alone 5.2.3.7 HFMD no. 1 decoction plus ribavirin versus ribavirin alone 5.2.3.8 Detoxication no. 1 plus routine Western medicine versus routine Western medicine alone 6. Rash subsidence rate 6.1 Herbal medicine plus other treatment versus active drugs 6.1.1 Tanreqing plus ribavirin versus ribavirin alone 6.1.2 Reduning plus ribavirin versus ribavirin alone 7. Oral symptoms heal rate 7.1 Herbal medicine versus active drugs 7.1.1 Qingrexiehuo decoction versus ribavirin 7.1.2 Reduning versus ribavirin 7.2 Herbal medicine plus active drugs versus active drugs alone 7.2.1 Reduning plus ribavirin versus ribavirin alone
No. of studies
Study ID
Participants
Effect estimate
1
He YP (2009)
217
−1.57 [−1.76, −1.38]
1
Tian ZL (2009)
67
−2.56 [−2.89, −2.23]
1
Wang YP (2009)
180
−2.00 [−2.36, −1.64]
1
Xi RH (2010)
208
−2.26 [−2.70, −1.82]
1
Xing HZ (2009)
95
−2.46 [−2.71, −2.21]
1
Xu R (2010)
556
−1.07 [−1.12, −1.02]
1
Zhang QP (2009)
53
−0.66 [−1.63, 0.31]
157
2 1
Fan MY (2010)
85
1.00 [0.96, 1.05]
1
Xin SX (2009)
72
1.79 [1.03, 3.12]
2
277
1
Huang XH (2004)
94
1.52 [1.17, 1.98]
1 1
Huang RW (2009)
183 287
1.00 [0.98, 1.02]
1
Zhao JW (2009)
287
1.13 [0.75, 1.68]
Another 10 trials employed herbal medicine as the main intervention compared to active drugs, only one trial showed no difference between Pudilan and ribavirin injection on increasing cure rate in patients with HFMD, the remaining 9 trials all showed significant difference between herbal medicine and active drugs regarding this outcome.
Rash subsidence time/rate A total of 43 trials comparing herbal medicine plus active drugs and active drugs alone reported symptom changes after treatment which were relevant to rash subsidence. Results of 41 trials showed positive effect of combination treatment compared to active drugs. Meta-analysis showed that compared to ribavirin alone, both pudilan (MD −2.56, 95% CI −3.03 to −2.08, random model, 2 trials) or xiyanping (MD −1.54, 95% CI −2.31 to −0.76, random model, 4 trials) plus ribavirin had better effect in reducing rash subsidence time for patients with HFMD. However, 1 trials showed Tanreqing injection plus ribavirin was not significant different from ribavirin alone on increasing rash subsidence rate for HFMD patients, and another trial showed no difference between herbal decoction plus routine Western medicine and routine Western medicine alone on increasing rash subsidence rate.
Twenty six trials compared herbal medicine and active drugs, and meta-analysis showed Tanreqing injection (MD −0.85, 95% CI −2.96 to −1.46, random model, 2 trials), Yanhuning injection (MD −2.21, 95% CI −1.53 to −0.86, random model, 3 trials) and Reduning injection (MD −1.45, 95% CI −2.21 to −0.78, random model, 3 trials) were significantly better than ribavirin in reducing rash subsidence time of HFMD. With the exception of 4 trials, other trials results were all consistent to the results of meta-analysis that herbal medicines were superior to active drugs in reducing rash subsidence time. Oral ulcers healing time/rate Totally 36 trials reported oral ulcers healing time or oral symptoms healing rate during the treatment. Twenty two of them used combination therapy compared to active drugs alone, the meta-analysis of 4 trials showed a combination of pudilan (MD −1.62, 95% CI −2.56 to −0.68, random model, 2 trials) or xiyanping (MD −1.28, 95% CI −1.81 to −0.75, fixed model, 2 trials) and ribavirin could significantly reduce the oral ulcers healing time compared to ribavirin alone and all the other 18 trials’ results supported that herbal medicine plus active drugs were better in reducing the oral ulcers healing time. Another 14 trials compared herbal medicine with active drugs, and results of them showed a significant difference between these
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
e107
Table 3 Results of meta-analysis of 18 included trials. Outcomes or subgroups
No. of studies
Study ID
Participants
Statistical method
Effect estimate
P Value
Huang RW (2009) Lu N (2009) Zhan GY (2010) 3 Xu ZF (2009) 1.1.2 Yanhuning injection versus ribavirin Yang ZJ (2009) Zhi ZQ (2008) 1.2 Herbal medicine plus active drugs versus active drugs alone Wu YH (2009) 1.2.1 Pudilan plus ribavirin versus 2 ribavirin alone Zhang WH (2009)
358
Mean Difference (IV, fixed, I2 = 0%, 95% CI) Mean Difference (IV, fixed, I2 = 0%, 95% CI)
−0.89 [−0.99, −0.79]
<0.00001
−2.53 [−2.80, −2.27]
<0.00001
−1.81 [−2.33, −1.29]
<0.00001
1.2.2 Qingkailing plus 2 comprehensive treatment versus comprehensive treatment alone 2. Rash subsidence time (days) 2.1 Herbal medicine versus active drugs 2 2.1.1 Tanreqing versus ribavirin
248
Mean Difference (IV, Random, I2 = 83%, 95% CI) Mean Difference (IV, Random, I2 = 83%, 95% CI)
−0.95 [−1.56, −0.34]
0.002
Mean Difference (IV, Random, I2 = 27%, 95% CI) Mean Difference (IV, Random, I2 = 81%, 95% CI) Mean Difference (IV, Random, I2 = 76%, 95% CI)
−0.85 [−1.45, −0.25]
0.007
−2.21 [−2.96, −1.46]
<0.00001
−1.45 [−2.12, −0.78]
<0.0001
Mean Difference (IV, Random, I2 = 45%, 95% CI) Mean Difference (IV, Random, I2 = 78%, 95% CI)
−2.56 [−3.03, −2.08]
<0.00001
−1.54 [−2.31, −0.76]
<0.0001
Mean Difference (IV, Random, I2 = 83%, 95% CI) Mean Difference (IV, fixed, I2 = 0%, 95% CI)
−1.62 [−2.56, −0.68]
0.0008
−1.28 [−1.81, −0.75]
<0.00001
−1.46 [−1.93, −0.98]
<0.00001
1. Fever clearance time (days) 1.1 Herbal medicine versus active drugs 1.1.1Reduning injection versus 3 ribavirin
Guo XY (2009) Hao SL (2011)
396
172
Ding S (2011) Huang RW (2009a) 3 Xu ZF (2009) 2.1.2 Yanhuning versus ribavirin Yang ZJ (2009) Zhi ZQ (2008) 2.1.3 Reduning versus ribavirin 3 Huang RW (2009) Lu N (2009) Zhan GY (2010) 2.2 Herbal medicine plus active drugs versus active drugs alone Wu YH (2009) 2.2.1 Pudilan plus ribavirin versus 2 ribavirin alone Zhang WH (2009)
298
2.2.2 Xiyanping plus ribavirin versus ribavirin alone
372
4
Cai JY (2010) Chen ZM (2010) Lin YQ (2008) Zhang JW (2009)
3. Oral ulcer healing time (days) 3.1 Herbal medicine plus active drugs versus active drugs alone 2 Wu YH (2009) 3.1.1 Pudilan plus ribavirin versus ribavirin alone Zhang WH (2009) 3.1.2 Xiyanping plus ribavirin versus ribavirin alone
2
Chen ZM (2010) Zhang JW (2009)
4. Healing time (days) 4.1 Herbal medicine plus active drugs versus active drugs alone Peng HB (2009) 4.1.1 Tanreqing plus comprehensive 2 treatment versus comprehensive Sun YF (2010) treatment alone
two therapies in reducing oral ulcer healing time except 2 trials which employed Qingkailing versus ribavirin, and Yanhuning versus interferon. Two trials showed no difference in increasing oral ulcers healing rate neither between Reduning and ribavirin nor between combination of Reduning and ribavirin and ribavirin alone on patients with HFMD. Fever clearance time/antipyretic effect Sixty eight trials reported fever clearance time during treatments, 4 meta-analyses of 10 trials showed Reduning (MD −0.89, 95% CI −0.99 to −0.79, fixed model, 3 trials) and Yanhuning injection (MD −2.53, 95% CI −2.80 to −2.27, fixed
396
358
172
172
158
303
Mean Difference (IV, fixed, I2 = 0%, 95% CI)
model, 3 trials) alone or a combination with Pudilan (MD −1.81, 95% CI −2.33 to −1.29, random model, 2 trials) or Qingkailing (MD −0.95, 95% CI −1.56 to −0.34, random model, 2 trials) and active drugs were all significantly superior to active drugs alone in reducing fever clearance time of HFMD patients. For the remaining 58 trials, only 9 showed no difference between herbal medicine (alone or combined with active drugs) and active drugs, in reducing fever clearance time. One trial [89] showed herbal medicine plus conventional therapy was better than conventional therapy alone in antipyretic effect for HFMD patients (RR 1.19, 95% CI 1.09 to 1.30, 1 trial). Another trial [69] showed herbal medicine combined with
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ribavirin was superior to ribavirin alone in reducing average body temperature of patients with HFMD (MD −0.32, 95% CI −0.52 to −0.12, 1 trial). Healing time Twenty nine trials reported the healing time or length of hospital stay for HFMD patients. Twenty one of them compared combination therapy to active drugs alone, and the meta-analysis of 2 trials showed combination of Tanreqing and active drugs significantly reduced the healing time of HFMD (MD −1.46, 95% CI −1.93 to −0.98, fixed model, 2 trials). With the exception of 1 trial, the remaining 26 trials showed that herbal medicine (alone or combined with active drugs) was superior to active drugs in reducing healing time. Creatine kinase (CK) and creatine kinase muscle and brain (CK-MB) Only one trial [21] reported CK and CK-MB after treatment, it showed herbal medicine plus ribavirin significantly reduce CK (MD −10.60, 95% CI −18.09 to −3.11, 1 trial) and CKMB (MD −3.40, 95% CI −5.50 to −1.30, 1 trial) compared to ribavirin alone. Adverse events Forty six of the 76 trials reported adverse events. Amonst these, 33 trials reported no adverse events in both groups. Details of adverse events in the Chinese herbal medicine group were reported in the remaining 13 trials. Only mild adverse events were found in the herbal medicine group, i.e., rash, diarrhea, slightly increased CK-MB, increased bowel movement frequency, and nausea. In the control groups as well as all the above events, some studies indicated that ribavirin may cause reduction in WBC or platelets, but no detailed information was reported. All trials measured outcomes at the end of treatment, no trials reported long-term follow-up after the treatment. Funnel plot analysis Funnel plot analysis could not be conducted due to the insufficient number of trials in the meta-analysis. Discussion This review provided indications that herbal patents, herbal injections or herbal decoctions with or without active drugs had an effect of reducing fever clearance time, rash subsidence time, oral symptoms healing time and healing time of HFMD. However, the majority of the included trials had a high risk of bias. Consequently, only poor quality, provisional evidence could be provided by this systematic review. There are limitations to the significance of the findings of this review. First of all, the methodological quality of the included studies was generally poor. According to the analysis of their methodological reporting, only 11.8% of the included studies mentioned the method of randomization, and only 1 trial report referred to the method of allocation concealment. Almost all
studies had not used placebo as comparison, so blinding methods could not be used for patients and doctors. Intention-to-treat analysis was not used in any of the studies. Further, the experimental group included several kinds of herbal medicine, such as herbal patent drug, herbal injection, herbal decoction, and herbal coloclyster. Several studies used two or more drugs as a combination therapy to do the treatment. Equally, control groups were made up of many different interventions, such as antiviral drugs, antibiotics, usual care, and immunopotentiators. This non-uniform approach also reduced the comparability of the included studies. Most of the included trials used composite outcome measures which categorized the effect of the treatment into four grades. The classification of “cure”, “markedly effective”, “effective” or “ineffective” is not internationally recognized and highly subjective. According to the low quality of studies, the variety of interventions and the variance of outcome measures, studies were highly heterogeneous. We finally included 18 trials in subgroup meta-analysis and the results showed that compared to ribavirin, several kinds of herbal injections (such as Reduning, Yanhuning, Tanreqing and Qingkailing, etc.) may have significantly better effects in reducing the time of healing, time of fever clearance and time of rash subsidence. Using these herbal injections alone or combined with other active drugs (such as ribavirin) may accelerate the improvement of symptoms of HMFD; on average 1 day could be gained for healing the disease during treatment. On the other hand, all included trials had treatment duration for less than 7 days, so that due to the lack of long-term follow up, its hard to conclude the safety of herbal medicine on HFMD. We suggest that at least two weeks after treatment should be included as follow up in future studies in order to observe whether herbal medicines have a long-term effect for shortening the disease’s duration. Although this review suggests that the evidence on the use of herbal medicine for HMFD is of insufficient quality, the available data indicated that herbal medicine, especially herbal injections, and even more so the combination of herbal medicine with Western medication, might improve symptoms of HMFD. Further high quality studies of sufficient sample size are needed to assess the effectiveness of herbal medicine in treating HFMD. Randomization methods need to be more rigorous. By using the appropriate placebo, blinding of the patients, the other care providers or at least the outcome assessors will minimize performance and assessment biases. Herbal injections or herbal patents could be paid more attention according to the potential effect shown in this research. As the disease is diagnosed according to symptoms, and the patients are almost all children/infants which means patient report outcome (PRO) may be difficult to obtain the main outcome measurements could include symptom improvement, such as fever clearance time and rash total subsidence time. Analysis of outcomes based on intention-to-treat principle is important. Currently many researchers are aware of using adequate study designs, but they lack knowledge of the implementation of clinical studies, and also the appropriate way for reporting research. Researchers should adhere to the standards of CONSORT [100] for trial reporting, details of methods and results should be fully addressed.
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Potential conflict of interest None known. Acknowledgements This review was supported by a grant of the international cooperation project (no. 2009DFA311460) from China and by the research capacity establishment grant of Beijing University of Chinese Medicine. Jianping Liu was in part supported by the grant number R24 AT001293 from the National Center for Complementary and Alternative Medicine (NCCAM) of the US National Institutes of Health. References [1] Frydenberg A, Starr M. Hand: foot and mouth disease. Australian Family Physician 2003;32(8):594–5. [2] Emond RTD, Welsby PD, Rowland HAK. Colour atlas of infectious disease. Elsevier Science Limited; 2003. pp. 194–195. [3] Kushner D, Caldwell BD. Hand, foot and mouth disease. Journal of the American Podiatric Medical Association 1996;86(6):257–9. [4] Robinson CR. Report of an outbreak of febrile illness with pharyngeal lesions and exanthema, Toronto, summer 1957 – Isolation of Group A Coxsackievirus. Canadian Medical Association Journal 1958;79:615–21. [5] Goh KT, Doraisingham S, Tan JL, Lim GN, Chew SE. An outbreak of hand, foot, and mouth disease in Singapore. Bulletin of the World Health Organization 1982;60(6):965–9. [6] Chang LY, Lin TY, Hsu KH, Huang YC, Lin KL, Hsueh C, et al. Clinical features and risk factors of pulmonary oedema after enterovirus-71related hand, foot, and mouth disease. The Lancet 1999;354:1682–6. [7] Yao XJ, Hao C, Xu H, Chen C, Zhang HL, Deng YM. Investigation of the risk factors of hand, foot and mouth disease in Changzhou. Acta Universitatis Medicinalis Nanjing (Natural Science) 2010;30(9):1275–8. [8] Li ST. Analysis of HFMD epidemiology and risk factors in Hebei district of Tianjin from 2008 to 2009. Port Health Control 2010;15(4):26–8. [9] Cao MH, Liu H, Wan JF, Zhu LY. A case–control study of severe case of hand, foot and mouth disease (EV71) in Fuyang City, Anhui Province. Anhui Journal of Preventive Medicine 2010;16(1):19–20. [10] Ministry of Health of The People’s Republic of China. Report of epidemic situation of infectious disease in China from January of 2010 to January of 2011. http://www.moh.gov.cn/publicfiles/business/htmlfiles/ mohjbyfkzj/s3578/201102/50646.htm. [11] Lighton L. Hand, foot and mouth disease. British Journal of Infection Control 2001;2(2):28. [12] Yang HS, Yang W, Li N, Tian YM, Zhang JY, Li XH. Analysis of characteristics of the cause of hand, foot and mouth disease based on traditional Chinese medicine theory [in Chinese]. Global Traditional Chinese Medicine 2010;3(6):413–5. [13] Li BQ. Development of the medical treatment for hand, foot and mouth disease. PJCCPVD 2011;19(6):1064–5. [14] Jiang XJ, Zhang Y. Clinical observation of Qingkailing for hand, foot and mouth disease [in Chinese]. Journal of Clinical and Experimental Medicine 2006;5(10):1610. [15] Chen YH. Clinical observation of therapeutic effect of Shuanghuanglian Injection on treatment of infantile hand, foot and mouth disease [in Chinese]. Chinese Journal of Integrated Traditional and Western Medicine in Intensive Critical Care 2006;13(1):47. [16] Gong ZA. Observation of Yinqiao Daochi San on treatment for 76 children with hand, foot and mouth disease. Clinical Journal of Traditional Chinese Medicine 2007;19(5):463. [17] Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions version 5.0.2 [updated September 2009]. The Cochrane Collaboration; 2009 [Available from www.cochrane-handbook.org].
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Review article
Chinese herbal medicines for treatment of hand, foot and mouth disease: A systematic review of randomized clinical trials Huijuan Cao 1 , Zhaolan Liu 1 , Peter Steinmann, Yujie Mu, Hui Luo, Jianping Liu ∗ Beijing University of Chinese Medicine, Centre for Evidence-Based Chinese Medicine, Bei San Huan Dong Lu 11, Chaoyang, Beijing, China Received 31 August 2011; received in revised form 23 November 2011; accepted 23 November 2011
Abstract Background: Chinese herbal medicines are widely used in treating hand, foot and mouth disease (HFMD) in China. Single clinical studies have shown positive results of Chinese herbal medicines on HFMD compared with Western medication. A systematic review was conducted to critically appraise the available evidence on the potential benefits and harms of Chinese herbal medicines’ use in HFMD. Methods: Randomized controlled trials comparing Chinese herbal medicines with no treatment, placebo, or Western medications for HFMD were included. Databases searched included: PubMed, the Cochrane Library, Chinese Biomedical Database, China Network Knowledge Infrastructure, Chinese Scientific Journal Database, and Wan Fang Database. All searches ended in July 2011. Four authors extracted data and assessed the study quality independently. RevMan 5.0.25 software was used for data analysis with effect estimate presented as relative risk and mean difference with a 95% confidence interval. Results: Seventy six trials were included, with generally poor methodological quality. According to the results of each single trial and meta-analysis of 18 trials, herbal medicine with or without active drugs may have effect for reducing fever clearance time, rash subsidence time, oral symptoms healing time and healing time of HFMD. Conclusions: This review suggests herbal medicine, combined with Western medications or used separately might improve symptoms of HMFD. However the current evidence is not of sufficient quality to allow unconditional recommendations to be made about the wider application of any kind of herbal medicine for the treatment of HFMD. © 2011 Elsevier GmbH. All rights reserved. Keywords: Chinese herbal medicine; Hand; Foot; Mouth disease; Systematic review; Meta analysis
Background Hand, Foot and Mouth Disease (HFMD) is a common disease in children. It is caused by an enterovirus, usually coxsackievirus type A 16 (coxA 16) and enterovirus 71 (EV 71) [1]. The diagnosis of HFMD is usually based on the clinical features. The illness typically initially begins with fever, sore throat, poor appetite, tiredness and anorexia, one or two days after the fever begins, vesicles appear on the cheeks, gums, and sides of the tongue. These begin as small red spots that blister and often become ulcers. The skin rash develops over 1–2 days with papulovesicular lesions occurring in 75% of cases. These appear on the palms, fingers, toes, soles, buttocks, genitals and limbs. The
∗ 1
Corresponding author. E-mail address: jianping [email protected] (J. Liu). Both authors contributed equally.
1876-3820/$ – see front matter © 2011 Elsevier GmbH. All rights reserved. doi:10.1016/j.eujim.2011.11.004
lesions may look haemorrhagic and are not itchy. The illness duration usually is 7–10 days, and the viruses can be found in stool for weeks [2]. Humans are thought to be the only natural host of these viruses. The disease mainly spreads by contact with nose and throat discharges, saliva, fluid from vesicles or patients’ stool, or through contaminated objects [3]. A robust immunity develops against the causative agent but a second attack of HFMD may occur following infection with a different member of the enterovirus group. Since the first case of HFMD which occurred in Toronto in 1957 [4], several countries/cities reported the outbreak of this disease. Most of the reported outbreaks of HFMD have occurred in cities in the temperate zones of southern Africa, North America, Australia, Europe and Asia, including Singapore [5] and Taiwan [6]. Many studies have found that infants and children under 5 years of age are commonly susceptible to the virus. Significant risk factors for infection are low socio-economic status and personal hygiene habits such as
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Table 1 Characteristics of included trials. Study ID
Diagnostic criteria
Not reported
Cai JY (2010)
Chinese criteria
Chen ZM (2010)
Age (yr, Rx/C)
Sex (M/F)
I: 26 C: 28 Total: 54 I: 39 C: 39 Total: 78
2/3–5
31/23
I: 3.8 ± 1.6 C: 3.7 ± 1.4
47/31
Chinese criteria
I: 44 C: 42 Total: 86
51/35
Cheng HQ (2009)
Chinese criteria
29/31
Cheng HJ (2010)
Chinese criteria
I: 30 C: 30 Total: 60 I: 41 C: 35 Total: 76
I: < 1y: 12; 1–5y: 24; >5y: 8 C: < 1y: 11; 1–5y: 24; >5 y: 7 2/3–7
3.2 ± 0.6
40/36
Cheng YM (2010)
Chinese criteria
I: 60 C: 60 Total: 120
I: 5.5 C: 4.5
68/52
Deng CL (2010)
Chinese criteria
I: 52 C: 38 Total: 90
I: < 3y 42 3–8y 10 C: < 3y 32 3–8y
66/24
Deng SZ (2010)
Chinese criteria
I1 : 50 I2 : 50 C: 50 Total: 150
I1 : 4.05 ± 1.94 I2 : 3.95 ± 1.34 C: 3.90 ± 1.26
85/65
Intervention group
Control group, administration route, dose
Duration of treatment (days)
Outcomes
Ribavirin injection 10 mg/kg/d 1X/d Ribavirin injection 10 mg/kg 1X/d
Not reported
a FCT/stomatitis
5–7 d
TER/FCT/RST
Route of Ingredients administration, dose
Adverse reaction
Chuanhuning injection 10 mg/kg/d 1X/d Xiyanping injection, 5 mg/kg + 5% glucose 1X/d + ribavirin Xiyanping injection: 5 mg/(kg d) 1X/d + ribarivin
Active extract of Andrographis
None
Water-soluble andrographolide sulfonate
A little rash
Water-soluble andrographolide sulfonate
None
Ribavirin injection 10 mg/(kg d) 1X/d
5d
TER/FCT/OUHT/ RST
Not reported
Ribavirin injection 10–15 mg/kg/d
3d
CK,CK-MB
Not reported
Acyclovir injection: 15 mg/(kg d) + 5% glucose 250 ml
Not reported
TER/HT/RST
Ribavirin 10–20 mg/kg d, 3 X/d
5d
Cure rate/TER
Modified yinqiaosan YINqiaosan oral 200 ml/d + ribavirin Honeysuckle oral: Not reported 1–3y: 1 g 3X/d 4–7Y: 3 g 3X/d + acyclovir
Dazi decoction oral: Indigowoad leaf, Not reported 1X/d gromwell, gypsum fibrosum, isatis root, flos chrysanthemi indici, poison yam, liquorice, pearl powder Potassium sodium None Yanhuning injection: succinate 5–10 mg/(kg d) half-ester salt of + 5%–10% glucose andrographolide 50–100 ml 1X/d I1 : injection Potassium sodium None interferon succinate 50,000–80,000 U/kg, half-ester salt of Yanhuning andrographolide 5–10 mg/kg 1X/d I2 : injection Yanhuning 5–10 mg/kg 1X/d
healing time
Ribavirin injection 5–7 d 10–15 mg/(kg d)2X/d
FCT/RST/time of hospitalization
Injection: interferon 3 d 50,000–80,000 U/kg,
TER/FCT/OUHT/RST
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Cai HW (2001)
Sample size (Rx/C)
Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Intervention group
Control group, administration route, dose
Route of Ingredients administration, dose
Duration of treatment (days)
Outcomes
Adverse reaction
Not reported
I: 40 C: 40 Total: 80
0.6–7
44/36
Modified jidaiyu decoction oral 100 ml/d 3X/d
Jisusan, Daihasan, Not reported Yuquansan, Scutellaria, Forsythia, honeysuckle
Gargling 3 dd chlorhexidine rinse treated with calamine lotion; oral ribavirin
OUHT/RST
Ding S (2011)
Chinese criteria
I: 52 C: 56 Total: 108
I: 2.6 C: 2.5
78/30
Tanreqing injection 0.5 ml/kg plus 5% glucose 100 ml 1X/d
Ribavirin injection 10 mg/kg + 5% glucose 100 ml 1X/d
6 dd
TER/FCT/OUHT/RST
Fan MY (2010)
Chinese criteria
I: 43 C: 42 Total: 85
I: < 1y 12 1–3y 29 >3y 2 C: < 1y 14 1–3y 25 >3y 3
55/30
Injection ribavirin 10–15 ml/kg
7 dd
TER/FCT/RST
Feng FY (2010)
Chinese criteria
I: 300 C: 300 Total: 600
305/295
Guo WZ (2008)
Chinese criteria
I: 37 C: 36 Total: 73
I: < 1y 75; 1– 3 y 180; >3y 45 C: < 1y 80; 1–3 y 176; >3y 44 0.25–8
48/25
Injection ribavirin 10–15 ml/kg Tanreqing 1 ml/kg and 5% glucose 100–200 ml 1X/d Yanhuning injection 5–10 mg/(kg d) and 5% glucose 50–100 ml Ganluxiaodudan oral 1X/d plus ribavirin
Skullcap, bear bile None powder, goat angle, honeysuckle, Forsythia, etc. Skullcap, bear bile None powder, goat angle, honeysuckle, Forsythia, etc.
Guo XY (2009)
Chinese criteria
I: 80 C: 72 Total: 152
Not reported
78/84
A little rash: 3 Acyclovir injection 5 d cases diarrhea: 5–7.5 mg/(kg d) + 5% 5 cases glucose 50–100 ml
TER/FCT/HT/RST
No
Ribavirin injection 10–15 mg/kg 2X/d
3–6 d
FCT/RST/HT
Not reported
Comprehensive treatment
5d
FCT/OUHT/RSR/ appetite improved time/neurological symptoms improved time
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Qingkailing + comprehensive treatment oral <1year old 1/2 × 2X/d; 1–3 years old 1/2 × 3X/d; 3–5 years old 2/3 × 3X/d; > 5 years old 1 × 3X/d
Potassium sodium succinate half-ester salt of andrographolide Talc, Scutellaria, capillary artemisia, Agastache rugosus, Forsythia, Shichangpu, white Kou Yan, mint, Belamcanda, Fritillaria, honeysuckle, Radix isatidis Baicalin, honeysuckle, Radix, buffalo horn, Gardenia, Radix isatidis, pigs deoxycholic acid
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Ding HL (2004)
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Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Intervention group
Control group, administration route, dose
Duration of treatment (days)
Outcomes
Adverse reaction
Qingkailing injection 1 ml/(kg dkg d) + 5% glucose 100 ml 1X/d plus acyclovir
Not reported
Injection acyclovir 30 mg(kg d) + 5% glucose 100 ml 1X/d
Not reported
FCT/RST/time of hospitalization
Not reported
acyclovir Oral 3–6 mg/kg 4X/d
7d
HT/FCT/OUHT/RST
Not reported
Ribavirin injection: 0.1–0.15 mg/kg 1X/d
Not reported
FCT/OUHT
No
Ribavirin injection 10–15 ml/kg 1X/d
7d
Ribavirin injection 10–15 ml/kg 1X/d
7d
FCT/RST/Effect measles back/cough efficacy FCT/RST/effect measles back/cough efficacy
Ribavirin injection 10 mg/(kg d)
Not reported
Hao SL (2011) Chinese criteria
I: 48 C: 48 Total: 96
I: 3.5 C: 3.8
52/44
He YP (2009)
Not reported
I: 96 C: 121 Total: 217
Not reported
136/81
Hu YL (2009)
Chinese criteria
I: 52 C: 49 Total: 101
2/3–7
48/53
Huang RW (2009)
Chinese criteria
I: 103 C: 80 Total: 183
1/3–12
101/82
Huang RW (2009a)
Chinese criteria
I: 110 C: 80 Total: 190
1/3–12
107/83
I: Tanreqing injection 0.3–0.5 ml/kg 1X/d
Huang SP (2010)
Chinese criteria
I: 88 C: 72 Total: 160
I: 3.13 ± 0.62 C: 3.00 ± 0.68
80/80
Injection ribavirin 10 mg/(kg d) + Yanhuning 10 mg/(kg d) 1X/d
Baicalin, honeysuckle, Radix, buffalo horn, Gardenia, Radix isatidis, pigs deoxycholic acid, cholic acid Honeysuckle and Decoction of detoxicating and wild slaking rashes oral chrysanthemum, 1X/d + acyclovir Paris polyphylla, Radix isatidis, Scutellaria, Coptis, Smilax glabra, Gardenia, Anemarrhena, Trichosanthes, Rehmanniae, Scrophulariaceae, paeonol Yanhuning injection Potassium sodium 4–8 mg/kg succinate Half-ester salt of 1X/d + ribavirin andrographolide Artemisia annua, I: Reduning injection 0.6 ml/kg honeysuckle, 1X/d Gardenia
Skullcap, bear bile None powder, goat angle, honeysuckle, Forsythia, etc. Potassium sodium Not reported succinate half-ester salt of andrographolide
TER/FCT/OUHT/ RST/HT
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Route of Ingredients administration, dose
Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Chinese criteria
I: 50 C: 44 Total: 94
I: 3.7 C: 3.5
47/47
Huang ZG (2009)
Not reported
I: 2.3 ± 0.8 C: 2.6 ± 0.7
29/24
Jiang XD (2010)
Chinese criteria
I: 25 C: 28 Total: 53 I: 193 C: 187 Total: 380
Not reported
224/156
Li LJ (2011)
Chinese criteria
I: 43 C: 43 Total: 86
4.5 ± 1.1
51/35
Li P (2010)
Chinese criteria
I: 78 C: 78 Total: 156
I: 2.5 ± 0.7 C: 2.7 ± 0.8
86/70
Li QX (2006)
Chinese criteria
I: 68 C: 64 Total: 132
I: 2.8 C: 2.7
68/64
Control group, administration route, dose
Duration of treatment (days)
Outcomes
Route of Ingredients administration, dose
Adverse reaction
Antelope horn, plaster, Folium isatidis, honeysuckle, Forsythia, dandelion, Scutellaria, radix Paeoniae rubra, licorice Forsythia, Shuanghuanglian honeysuckle, injection 60 mg/kg 1X/d Scutellaria Tanreqing injection: Skullcap, bear bile 0.3–0.5 ml/(kg d) + powder, goat 5% glucose 100 ml angle, 1X/d + ribavirin honeysuckle, Forsythia, etc. Qingrening, Qingrening: goat antiviral oral liquid angle powder, and Reduning + artificial bezoar, adenine arabinoside honeysuckle etc. and ribavirin Antiviral oral liquid: Radix isatidis, gypsum, reed rhizome etc. Reduning: Artemisia annua, honeysuckle, Gardenia Andrographolide Lianbizhi sodium bisulfite 10 mg/(kg d) 1X/d + ribavirin
None
Ribavirin oral 15–30 mg/kg/d
3d
Antipyretic effect/oral ulcers heal rate/effect measles back
None
Ribavirin injection 10–15 mg/kg
Not reported
Time of medication/HT
Not reported
Ribavirin injection
5d
TER/FCT/OUHT/RST
Not reported
Adenine arabinoside Not reported injection 10 mg/kg 1X/d; ribavirin topical 3X/d
Not reported
Ribavirin 10–15 mg/(kg d) + glucose 1X/d Oral ribavirin
Qingrexiehuo decoction oral 2x/d
Yinqiaohuoyin tang oral 2–3X/d
Silver flower, Not reported Forsythia, Agastache rugosa, capillary artemisia, Coix seed, Magnolia, Shichangpu, baicalin, radix isatidis, wild Chrysanthemum
TER/FCT/OUHT/RST
5d
TER/FCT/RST
5d
TER/FCT/relieve oral pain time/RST
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Huang XH (2004)
Intervention group
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Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Chinese criteria
I: 200 C: 200 Total: 400
I: 1.8 ± 0.3 C: 1.9 ± 0.4
234/166
Liang XL (2010)
Chinese criteria
I: 64 C: 62 Total: 126
<1y: 21 1–3y: 76
76/50
Lin YQ (2008) Chinese criteria
I: 70 C: 66 Total: 136 I: 44 C: 40 Total: 84
I: 2.28 ± 1.01 C: 2.18 ± 1.1
68/65
I: 2.8 ± 1.64 C: 2.9 ± 1.45
52/32
Liu M (2006)
Chinese criteria
Liu WD (2008)
Chinese criteria
I: 35 C1: 35 C2: 35 Total: 105
I: 2–11; C1: 3–10, C2: 2.5–11
60/45
Lu N (2009)
Chinese criteria
I: 27 C: 27 Total: 54
0.5–5
39/15
I: 120 C: 120 Total: 240
I: < 1y: 8 1–3y: 90 3–6y: 19 >6y: 3 C: < 1y: 6 1–3y: 92 3–6y: 20 >6y: 2
174/66
Luo XS (2010) Chinese criteria
Control group, administration route, dose
Duration of treatment (days)
Outcomes
Route of Ingredients administration, dose
Adverse reaction
Tanreqing injection: 0.5 ml/kg and 10% glucose 250 ml + ribavirin 1X/d Herbal retention enema, 2–3 ml/kg 1X/d + acyclovir
None
Ribavirin 10 mg/kg and 10% glucose 250 ml 1X/d
Not reported
TER/FCT/OUHT/ RST/HT
Diarrhea: 2 cases. 3–5 times per day
Injection: acyclovir 5–10 mg/(kg d), VitC 150–200 mg/(kg d)
7d
TER/FCT/OUHT/ RST/course of disease
Nausea: 2 cases
Ribavirin injection 15 mg/kg/d
7d
TER/FCT/RST
No
Ribavirin oral 15–30 mg(kg d) 3X/d
3d
TER/FCT/RST
Not reported
Oral: bonner 5–10 mg/kg, 4X/d
Not reported
TER/FCT/HT/RST
None
Ribavirin injection: 7.5 mg/kg; 2X/d
3d
FCT/Herpes scab time/relieve oral pain or salivation time/frequency of ibuprofen use
Ribavirin injection: 10–15 mg/(kg d) 1X/d
Not reported
FCT/RST/ hospitalization time
Xiyanping injection 8 mg/kg/d 1X/d + ribavirin Modified GegenQinlian tang oral 150 ml/d 3–5X/d
Oral: bonner 5–10 mg/kg,4X/d Chimonanthus leaf particles <1year old 1/3X; 1–4 years old 1/2X; > 4 years old 1X; 3X/d Reduning injection: 0.5 ml/kg; 1X/d
Yanhuning injection: 10 mg/(kg d) 1X/d + ribavirin
Skullcap, bear bile powder, goat angle, honeysuckle, Forsythia, etc. Honeysuckle, Forsythia, radix isatidis, patchouli, Scutellaria baicalensis Georgi, duckweed, etc. Water-soluble andrographolide sulfonate Pueraria, Scutellaria, Coptis, licorice, Cimicifuga, red Paeony root, duckweed, Coix seed, couchgrass root, bamboo leaf Flavonoids, alkaloids, inositol, volatile oil
Artemisia annua, honeysuckle, Gardenia
Potassium sodium CK-MB succinate increase: 21 cases half-ester salt of andrographolide
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Li SL (2010)
Intervention group
Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Intervention group
Ingredients Route of administration, dose Ma JH (2010)
Chinese criteria
Not reported
43/39
Tanreqing injection 0.5–1 ml/kg/d 1X/d + ribavirin
Skullcap, bear bile powder, goat angle, honeysuckle, Forsythia, etc.
Ma YP (2010) Chinese criteria
I: 32 C1: 34 C2: 34 Total: 100
Not reported
68/32
Forsythia suspense, honeysuckle, Scutellaria baicalensis Georgi, patchouli, etc.
Mao BR (2009)
Not reported
I: 90 C: 90 Total: 180
I: 2.12 ± 1.04 C: 2.16 ± 1.06
109/71
Chinese medicine compound granules oral: 1–3y half dose + 50–100 ml boiling water per day 3X/d >3y: a dose + 50–100 ml boiling water per day 3X/d Xiyanping injection: 10 mg/kg/d; 1X/d + interferon
Mei P (2010)
According to symptoms
I: 20 C: 20 Total: 40
Not reported
NA
Miao DX (2009)
Chinese criteria
Not reported
108/68
Pan R (2010)
Chinese criteria
I: 130 C: 46 Total: 176 I: 23 C: 23 Total: 46
I: < 1y: 4 1–3y: 14 >3y: 5 C: < 1y: 5 1–3y: 15 >3: 3
30/16
Peng HB (2009)
Chinese criteria
I: 118 C: 117 Total: 235
I: 2.9
Not reported
Water-soluble andrographolide sulfonate
Duration of treatment (days)
Outcomes
CK-MB increased: 11; increased bowel movement frequency: 9 Mild nausea, loss of appetite, gastrointestinal discomfort: 2 cases
Ribavirin injection: ribavirin 10–15 mg/kd/d Vit C 1 g/d 1X/d
Not reported
FCT/RST/OUHT/ myocardial enzymes return to normal time/hospital stay
C1: ribavirin plus Chinese medicine compound granules C2: ribavirin injection: 15 mg/kg + 5% glucose 100 ml 1X/d
3–7 d
Onset of antipyretic action/FCT/fever clearance rate/relieve oral pain time/OUHT/hand foot rash subsidence time
WBC decreased: 3; platelets decreased: 2 None
Injection 50,000 U/kg/d
7d
TER/FCT/OUHT/RST
Ribavirin oral: 10 mg/(kg d) 3X/d
7d
TER/FCT/relief headache time/RST
Adverse reaction
Pudilan oral 1–2y: 1/3 dose 3X/d 2–4y: half dose 3X/d >5y: a dose 3X/d Pudilan oral 0.4–0.8 ml/kg/d 3X/d Yanhuning injection: 10 mg/(kg d) + ribavirin
Dandelion, bitter to the small, radix isatidis, skullcap
Dandelion, bitter None to the small, radix isatidis, skullcap Potassium sodium Not reported succinate half-ester salt of andrographolide
Ribavirin oral 10–15 ml/kg/d; 3X/d Ribavirin
6–10 d
TER/FCT/OUHT/RST
5d
Tanreqing injection: 5–10 ml; 1X/d plus comprehensive treatment
Skullcap, bear bile Rash powder, goat angle, honeysuckle, Forsythia, etc.
Comprehensive treatment
5–7 d
FCT/RST/neurological symptoms improved time/tremble disappearance time/time of hospitalization FCT/RST/hospital stay
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I: 41 C: 41 Total: 82
Control group, administration route, dose
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Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
I: 65 C: 60 Total: 125
I: 2.5 ± 0.9 C: 2.7 ± 0.6
66/59
Sun QK (2011)
Chinese criteria
I: 38 C: 32 Total: 70
I: 1–3y: 25 3–5y: 13 C: 1–3y: 21 3–5y: 11
41/29
Sun YF (2010) Chinese criteria
I: 36 C: 32 Total: 68
Not reported
41/27
Tian ZL (2008)
Chinese criteria
I: 34 C: 33 Total: 67
I: 3.1 ± 0.5 C: 3.2 ± 0.3
34/33
Wang L (2010)
Chinese criteria
I: 75 C: 75 Total: 150
0.5y–5y
85/65
I: 30 C: 30 Total: 60
I: 3.93 ± 1.29 C: 3.79 ± 1.47
35/25
Wang P (2010) Not reported
Control group, administration route, dose
Duration of treatment (days)
Outcomes
5d
TER/FCT/OUHT/RST
Ingredients Route of administration, dose
Adverse reaction
Oral: chaihuang < = 3y: 4 g/X >3y: 6 g/X bid kangfuxin < = 3y: 5 ml/X >3y: 10 ml/X bid
Mild diarrhea: 3 cases Nausea: 5 cases
Oral: ribavirin 10 mg/(kg d) 3X/d
Not reported
Ribavirin: injection Not reported 10–15 mg/kg/d, 1–2X/d Oral: 10–15 mg/kg/d 3X/d
TER/FCT/OUHT/RST
Not reported
Antiviral therapy
Not reported
Time of hospitalization/symptomatic improvement time
Not reported
Acyclovir injection 10 mg/kg 1X/d
5d
TER/FCT/OUHT/ RST/HT
None
Ribavirin injection: 7–10 d 10–15 mg/kg, 5% glucose 100–200 ml
FCT/RST
Not reported
Ribavirin oral: 10–15 mg/kg d, 3X/d
FCT/OUHT/hands and feet rash subsidence time/HT
Chuaihuang granule: Bupleurum, Scutellaria. Kangfuxing: American cockroach ethanol extract Injection: xuebijing Honeysuckle, radix scutellariae, 1–2 ml/kg/d, 1–2X/d; oral: Water Artemisia annua, decoction, burdock, ganluxiaodu dan patchouli, Perrin, 1X/d coix seed, talc, cogongrass rhizome Tanreqing injection: Skullcap, bear bile 0.3–0.5 ml/kg/d and powder, goat 5% glucose 1X/d + angle, antiviral therapy honeysuckle, Forsythia, etc. Jieduxiaozhen oral, Honeysuckle, Forsythia, Dan, 90 ml, nX/d + acyclovir Leptospermum, Poria, Coix seed, rhizoma imperatae, pale leaves, bellflower, Rehmanniae, Arctium, raw licorice Chiqiao qingre Forsythia, granule oral: fermented 0.5–1y: 1–2 g/X soybean 1–3y: 2–3 g/X 4–6y: 3–4 g/X 3X/d + ribavirin Kanggan granules Not reported oral: 2-4y: 5 g/X 5-7y: 10 g/X 3X/d + ribavirin
Not reported
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Shi YP (2011) Chinese criteria
Intervention group
Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Intervention group
Duration of treatment (days)
Outcomes
Adverse reaction Diarrhea: 3 cases Nausea: 2 cases
Ribavirin oral: 10 mg/kg/d, 3X/d
7d
FCT/RST/virus RNA negative time
Not reported
Conventional therapy
6d
TER/FCT/OUHT/ hospital stay
Ribavirin
7d
TER/FCT/OUHT/ RST/cough healing time
Ribavirin oral 0.25–0.5X 4X/d
Not reported
FCT/relieve oral pain time/OUHT/RST/HT
Symptoms pattern Not reported therapy decoction: modified yinqiaosan; honeysuckle flower, Forsythia, Comfrey, Gardenia, mint, etc.; wild Chrysanthemum, Dandelion, radix isatidis,etc. Artemisia annua, None honeysuckle, Gardenia
Acyclovir injection: 20 mg/(kg d) and 5% glucose 250 ml 1X/d
Not reported
TER/FCT/OUHT/ RST/course of disease
Ribavirin injection 10 mg/(kg d) 1X/d
5d
Average body temperature/RSR
Scutellaria, Gardenia, honeysuckle etc.
Ribavirin oral: 10–15 mg/(kg d) 3X/d
3–5 d
TER/FCT/OUHT/ RST/course of disease/course of fever/course of fever treatment
Chinese criteria
I: 68 C: 68 Total: 136
I: 1.46 C: 1.39
89/47
Lianhuanqingwen oral: 1–2y: 4.5 g/d 3X/d 2–5y: 9 g/d 3X/d
Wang YP (2009)
Chinese criteria
I: 90 C: 90 Total: 180
I: 2.4 C: 2.7
108/72
Wei XL (2010)
Chinese criteria
I: 34 C: 34 Total: 68
Total: 3.5
36/32
Symptoms pattern therapy oral 1X/d plus conventional therapy Tanreqing injection: 0.3–0.5 mg/(kg d) and 5% glucose 100 ml + ribavirin
Wu YH (2009) Chinese criteria
I: 50 C: 50 Total: 100
0.6–6
58/42
Xi RH (2010)
Chinese criteria
I: 104 C: 104 Total: 208
I: 5.26 ± 1.76 C: 5.13 ± 1.89
127/81
1 xiefufeiwei; 2 weiqitongbing; 3 shireneiyun; 4 xinhuokangsheng modified daochisan 5 qiyinliangxu Si jun zi tang and modified sha shen mai dong tang: one dose per day + acyclovir
Xin SX (2009) Chinese criteria
I1 : 31 I2 : 38 C: 34 Total: 103
0.6–7
53/50
Xin YN (2010)
I: 115 C: 110 Total: 225
I: 2–5y C: 1–5y
112/113
I1 : Reduning injection, 0.6 ml/kg/d I2 : Reduning + ribavirin 1X/d Huangzhihua oral liquid 5–20 ml 2X/d
Honeysuckle flower, Forsythia, Ephedra, mint, almond, gypsum,etc. Not reported
Skullcap, bear bile Not reported powder, goat angle, honeysuckle, Forsythia, etc. Pudilan oral 3–5 ml; Dandelion, bitter None 3X/d + Ribavirin to the small, radix isatidis, skullcap
Not reported
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Ingredients Route of administration, dose Wang XG (2010)
Chinese criteria
Control group, administration route, dose
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Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Chinese criteria
I: 48 C: 47 Total: 95
I: 3.2 ± 0.5 C: 3.1 ± 0.4
50/45
Xu ZF (2009)
Not reported
I: 70 C: 60 Total: 130
0.5–5
Not reported
Xu H (2011)
Chinese criteria
I: 96 C: 90 Total: 186
I: 0.5–7y C: 0.5–7y
103/83
Xu R (2010)
Chinese criteria
I: 278 C: 278 Total: 556
I: 34.58 ± 1.39 m 361/195 C: 32.36 ± 1.17 m
Yang PY (2010)
Chinese criteria
I: 110 C: 100 Total: 210
Yang ZJ (2009)
Not reported
I: 72 C: 69 Total: 141
I: <1: 19; 1–4: 60; 125/85 >4: 31 C: < 1: 11; 1–4: 59; >4: 30 77/64 1/3–8
Yao BY (2011)
Chinese criteria
I: 33 C: 32 Total: 65
I: 0.5–7 C: 5 m–8y
35/30
Yuan BB (2010)
Chinese criteria
I: 39 C: 39 Total: 78
I: 2.3 ± 0.5 C: 2.7 ± 0.6
43/35
Control group, administration route, dose
Duration of treatment (days)
Outcomes
Route of Ingredients administration, dose
Adverse reaction
Liangxuejiedu tang oral 1X/d + acyclovir
Not reported
Acyclovir injection 10 mg/kg 1X/d
5d
TER/FCT/OUHT/ RST/HT
None
Ribavirin injection 10–15 mg/kg/d 2X/d
3–5 d
TER/FCT/OUHT/RST
None
Ribavirin spray inhalation: 1X/4–5 h
3–7 d
TER/FCT/OUHT/ RST/HT
Not reported
Injection: ribavirin 10 mg/kg Oral: ibuprofen 5 mg/kg
7d
TER/FCT/OUHT/ RST/HT
None
Interferon 8–10 g
5d
TER, symptoms subsidence time
Not reported
Ribavirin injection 10–15 mg/dk/d; 1X/d
7d
TER/FCT/OUHT/RST
Not reported
Ganciclovir injection
>6 d
TER, body temperature/hospitalization time/RST
None
Ribavirin 10 –15 mg/kg and 5% glucose 1X/d
Not reported
Symptoms and signs clearance time, TER
Honeysuckle, Forsythia, folium isatidis, cortex moutan, Lithospermum, cicada skin, Coix seed, rhizoma imperatae, pale leaves, bellflower, Rehmanniae, etc. Yanhuning injection Potassium sodium 4–8 mg/kg/d succinate half-ester salt of 1X/d andrographolide Jinzhen oral liquid: Antelope horn, 1–2y: 5 ml, 3X/d rhubarb, radix 2–3y: 10 ml, 2X/d scutellariae, gypsum, artificial 4–7y: 10 ml, 3X/d bezoar, etc. 1st HFMD herbal Dyers woad leaf, decoction: Chrysanthemum, 150 ml*2; oral: < 3y: honeysuckle, puerarin, comfrey, 10–40 ml/X, 3X/d >3y: 50 ml/X, 3X/d mint, etc. + ribavirin Lianzitang 20 ml Lithospermum, flavescens, honeysuckle, Forsythia Yanhuning injection Potassium sodium 10–15 mg/kg/d; succinate half-ester salt of 1X/d andrographolide Andrographis Chuanhuning paniculata injection 10 mg/kg with 250 ml 5% glucose 1X/d Tanreqing injection: Skullcap, bear bile 0.3–0.5 ml/kg and powder, goat 5% glucose angle, 2X/d + ribavirin honeysuckle, Forsythia, etc.
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Xing HZ (2009)
Intervention group
Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Intervention group
Route of Ingredients administration, dose
Adverse reaction
Duration of treatment (days)
Outcomes
Not reported
Total effective rate, body temperature/hospitalization time/RST TER, body temperature/RSR
Zeng QS (2010)
Chinese criteria
I: 62 C: 62 Total: 126 (2 excluded)
0.75–9y
68/58
Curcuma oil injection: 10 mg/kg and ribavirin
Curcuma
None
Ribavirin 10 mg/kg
Zhan GY (2010)
Chinese criteria
I: 61 C: 60 Total: 121
Not reported
NA
Artemisia annua, honeysuckle, Gardenia
None
Ribavirin10 mg/kg + 7 d 100 ml glucose 1X/d
Zhang H (2010)
Chinese criteria
I: 88 C: 84 Total: 172
0.6–6Y
102/70
Reduning injection: 0.5 ml/kg and 100 ml glucose; 1X/d Xiyanping injection, 5–10 mg/kg(I) and 10–15 mg/kg 5(C)
Water-soluble andrographolide sulfonate
Not reported
7d
Symptoms and signs clearance time, TER
Zhang JW (2009)
Chinese criteria
I: 2 ± 0.4 C1: 2.1 ± 0.7 C2: 1.9 ± 0.5
61/47
Xiyanping injection 5–10 mg/kg 1X/d + ribavirin
Water-soluble andrographolide sulfonate
None
4d
TER/FCT/OUHT/RST
Zhang N (2003)
Not reported
I: 2.8 C: 2.5
67/57
Jinlan mixture oral 1X/d
4d
TER/FCT/OUHT/RST
Chinese criteria
I: 2.42 ± 1.18 C: 2.13 ± 1.65
31/22
Detoxication No. 1 oral, 2X/d plus routine Western medicine
Formosanus, radix Not reported isatidis, daqingye, dandelion etc. None Not reported (Herbal medicine)
Oral ribavirin
Zhang QP (2009)
I: 36 C1: 36 C2: 36 Total: 108 I: 68 C: 56 Total: 124 I: 29 C: 24 Total: 53
Ribavirin water-soluble andrographolide sulfonate Ribavirin injection 5 mg/kg 2X/d
Routine Western medicine injection 0.1–0.3 g, 1–2X/d
5–7 d
Zhang W (2008)
Chinese criteria
I: 39 C: 40 Total: 79
Not reported
40/39
Qingkailing oral <1 years old: 3 g/d; 1–3 years old: 4.5 g/d; > 3 years old: 9 g/d
Ribavirin oral 10–15 mg/(kg·X) 1X/d
1 day
Zhang WH (2009)
Not reported
I: 36 C: 36 Total: 72
I: 2.5 ± 0.4 C: 2.3 ± 0.5
39/33
Pudilan oral 1 years old: 1/3X/d; 1–3 years old: 0.5X/d; 3–6 years old: 1X/d; >6 years old: 1X/d + ribavirin
Baicalin, No honeysuckle, radix, buffalo horn, Gardenia, radix isatidis, pigs deoxycholic acid, cholic acid Dandelion, bitter No to the small, radix isatidis, skullcap
TER/FCT/OUHT/RST/ fading duration of constipation or loose stools/fading duration of indigestion and anorexia/fading duration of sore throat/HT TER/FCT/OUHT/RST
Ribavirin spray 1st day: 4 or 8X/d; 2nd day: 10X/d 3–5d: 4X/d
5d
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Control group, administration route, dose
TER/FCT/OUHT/ RST/HT
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Table 1 (Continued) Study ID
Diagnostic criteria
Sample size (Rx/C)
Age (yr, Rx/C)
Sex (M/F)
Intervention group
Adverse reaction Nausea, vomit: 1 case dizziness: 1 case exanthems: 1 case
Zhang X (2011)
Chinese criteria
I1 : 50 I2 : 46 C: 48 Total: 144
I1 : 3.17 ± 1.17 I2 : 3.14 ± 1.22 C: 3.13 ± 1.24
80/64
I1 : anti-viral oral liquid: 5 ml/X 3X/d Injection: 0.6 ml/kg d + Reduning injection I2 : I1 + C
Radix, plaster, reed rhizome, radix rehmanniae, etc.
Zhang Y (2007)
Chinese criteria
I: 36 C: 24 Total: 60
I: 3.1 C: 3.4
36/24
Xiehuangsan oral 1X/d shuijianbi
Zhao JW (2009)
Chinese criteria
I: 158 C: 155 Total: 313
I: 2.1 C: 2.2
166/147
Reduning injection 0.6 mg (kg d), 1X d plus conventional
Wrinkled giant Not reported hyssop, fangfeng, licorice, gypsum, Rehmanniae, rushes, Achyranthes, light bamboo, Gardenia Artemisia annua, None honeysuckle, Gardenia
Zheng H (2010)
Chinese criteria
I: 125 C: 110 Total: 235
I: 2.53 C: 2.76
149/86
Qingre guanchang liquid enema therapy: 200 ml
Zhi ZQ (2008) Chinese criteria
I: 65 C: 60 Total: 125
Not reported
62/63
Zhong ZW (2007)
Chinese criteria
I: 59 C: 56 Total: 115
Not reported
62/53
Zhu XL (2009)
Chinese criteria
I: 76 C: 58 Total: 134
Not reported
Not reported
a TER:
Gypsum, Anemarrhena, raw licorice, honeysuckle, giant knotweed, skullcap, rhubarb, silkworm, cicada Yanhunin injection Potassium sodium 4–8 mg/kg/d succinate 1X/d half-ester salt of andrographolide Yanhuning injection Potassium sodium 10 mg (kg d), 1X d + succinate ribavirin half-ester salt of andrographolide Yanhuning injection Potassium sodium 10 mg(kg d), 1X d + succinate ribavirin half-ester salt of andrographolide
Duration of treatment (days)
Outcomes
Ribavirin: 10 mg/(kg d)
7d
Symptoms and signs clearance time, TER
Ribavirin oral
3d
TER/FCT/OUHT/RST
Conventional therapy
3d
Antipyretic effect/RSR/OUHT/ myocardial enzymes decreased rate/neurological symptoms improved rate TER, body temperature/other symptoms/RSR
None
Nimesulide granules 2 d 100 ml with 200 ml physiological saline
None
Ribavirin injection 10–15 mg/kg/d, 1X/d
5d
TER/FCT/OUHT/RST
None
Ribavirin injection 5 d 10 mg–15 mg (kg d), 1X d
TER/FCT/OUHT/RST
Rash: 3 cases Diarrhea: 5 cases
Ribavirin injection 10 mg (kg d), 1X d
TER/FCT/OUHT/RST
total effective rate; FCT: fever clearance time; OUHT: oral ulcers healing time; RST: rash subsidence time; HT: healing time; RSR: rash subsidence rate.
5d
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Route of Ingredients administration, dose
Control group, administration route, dose
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
residence in rural areas, being member of a migrant population, not washing hands before eating [7], toy sucking [8], and low family income [9]. Incidence is also closely correlated with population density. In China, a total of 1,774,669 cases were reported in 2010, with a case fatality rate of 0.51/1000 [10]. HFMD is a generally self-limiting illness, and there are no specific drug treatments. However, symptomatic treatment often is required. Commonly used drugs include antiviral agents, antibiotics, and immunopotentiators, although there are few studies showing a clear improvement in outcome [11]. According to the plague theory of Traditional Chinese Medicine (TCM) etiology, HFMD should be classified as an infectious disease caused by dampness-heat, accumulation of heart and spleen and invasion of mouth and extremities through the meridians [12]. Consequently, TCM clinical treatment refers to the law of eliminating dampness and clearing heat. Herbal medicines, including herbal decoctions, patents, and injections, are popularly used as treatment for HFMD in China. Many clinical studies indicated that herbal medicine were superior to controls (antiviral treatment or usual care) [13–16], but the findings have not yet been systematically summarized. The objective of the present review is to critically appraise the available evidence on the potential benefits and harms of Chinese herbal medicines’ use in HFMD to enrich the body of evidence. Methods Inclusion criteria Parallel randomized controlled trials (RCTs) of Chinese herbal medicines compared with no treatment, placebo, nonpharmaceutical therapy or Western medications in patients with HFMD were included. Combination therapy of Chinese herbal medicines and other interventions compared with the same other interventions alone was also included. Participants could be of any age, sex or ethnic origin, and HFMD had to be diagnosed according to recognized criteria. Outcome measures included mortality and morbidity due to HFMD-related complications, death from all causes, hospital admissions and stay (directly related to HFMD), time to cure (fever clearance time, disappearance of rash and other symptoms), time to fever reduction, time to symptom disappearance (rash, angina), and adverse events (related to treatment). Duplicate publications and companion papers of a primary study were excluded. Publications in all languages were eligible for inclusion. Study identification and selection We searched the China Network Knowledge Infrastructure (CNKI; 1979–2011), Chinese VIP Information (1989–2011), Wan Fang Database (1985–2011), Chinese Biomedicine (CBM) database (1978–2011), PubMed (1966–2011) and Cochrane Library (Issue 7, 2011). All searches ended in July 2011. The search terms included “enterovirus 71 infection”, “Herpangina”, “Coxsackievirus infections”, or “Hand, Foot and Mouth Disease” combined with “traditional Chinese medicine”, “TCM”, “herbal”, “complementary”, “alternative”, or “Phytotherapy”.
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Two authors (Ma LX and Mu YJ) independently assessed studies for eligibility against the inclusion criteria. Data extraction and quality assessment Four authors (Liu ZL, Mu YJ, Cao HJ and Luo H) independently extracted relevant population and intervention characteristics using self-designed data extraction templates. All disagreements were resolved through discussion, or if required by a fifth party (Liu JP). The methodological quality of RCTs was assessed using criteria from the Cochrane Handbook for Systematic Reviews of Interventions, Version 5.0.2 [17]. The quality of trials was categorized into low risk of bias, unclear risk of bias, or high risk of bias according to the risk for each important outcome of included trials, including adequacy of generation of the allocation sequence, allocation concealment, blinding, whether there was incomplete outcome data, selective outcome reporting, or other sources of bias. Data analysis Dichotomous data were expressed as risk ratios (RR) with 95% confidence interval (CI). Continuous data were expressed as mean differences (MD) with 95% CI. Statistical heterogeneity was tested by the I2 [17]. We used the Revman 5.0.2 software from the Cochrane Collaboration for data analyses. Meta-analysis was used if the trials had acceptable homogeneity (I2 < 85%) of study design, participants, interventions, controls, and outcome measures. We performed meta-analyses using fixed-effect models (I2 < 25%) for homogeneous studies and using random-effects methods prior to fixed-effect models when there was substantial heterogeneity (25% < I2 < 85%). Results Description of studies Results of the search The initial search identified 9433 publications. After duplicates had been removed, potentially relevant articles were further assessed. A total of 9041 manuscripts were excluded because they were non-clinical studies, or irrelevant to HFMD, and 392 articles were highlighted for further evaluation. After full text reading, 310 publications were excluded because they did not meet our inclusion criteria. Of the remaining, 76 trials [18–93] were included, a further 5 [94–98] studies were excluded due to insufficient data and 1 study [99] was excluded due to an inappropriate randomization method (Fig. 1). All 76 trials were published in scientific journals, no unpublished dissertations or conference papers were included. Characteristics of included trials The 76 RCTs included a total of 10,664 participants. All RCTs were conducted in China. Only 1 was published in English [84], the remaining trials were all published in Chinese. There were 6 three-arm trials [25,48,52,69,82,87] and 70 with a parallel two-arm design. Detailed information of included studies is shown in Table 1.
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H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Fig. 1. Flow-chart of study selection.
The average sample size of the trials was 141 participants (ranging from 40 to 600 participants per trial). The age of the participants ranged from 0.3 to 16 years. Except 5 trials [54,57,74,80,93] which failed to report the sex ratio of participants, the percentage of female participants was 73.8%. Ten included trials did not report the diagnostic criteria for HFMD, 65 trials diagnosed HFMD according to Chinese national criteria and 1 trial [54] only mentioned that HFMD was diagnosed based on the subjects’ symptoms. Twenty-three different herbal medicines were employed as main interventions in the included trials (Table 1). Their formulations included capsules, tablets, injections and decoctions. No trials reported quality standards of the herbal preparations. The control interventions included usual care, acyclovir, ribavirin, and other conventional Western medications. The duration of treatment varied from 1 to 10 days. The outcomes included time of hospital stay, time until cure (defervescence, disappearance of rash and other symptoms), time to bring down the fever, time until symptoms disappeared (rash, angina, gastritis, mucous ulcer), creatine kinase (CK), creatine kinase muscle and brain (CK-MB), time to appetite return, time to psychiatric symptoms disappearance, and adverse events. Risk of bias in included trials According to our pre-defined methodological quality criteria, all included trials should be evaluated as unclear risk of bias. Only 9 trials described randomization procedures (random number table), but only 1 of them [87] reported allocation
concealment (sealed envelope). One trial [87] mentioned single blinding, but did not provide details. One trial [87] reported the number of dropouts, but intention-to-treat analysis was not employed. None of the included trial could be considered as a low risk of bias study. Effect of intervention Among the 76 included trials, 47 used herbal medicine plus active drugs compared with active drugs alone, and 32 trials compared herbal medicine with Western medications (3 trials involved both above comparisons). Results of each single trial are summarized in Table 2. Due to different intervention or control treatment, or high potential of heterogeneity between trials, only 18 trials [19,20,26,31,32,35,36,46,49,57,60,67,74,76,80,82,86,91] could be included in the meta-analysis (Table 3). Cure rate “Cure” was defined as disappearance of the clinical symptoms, and normal results in laboratory tests and X-ray examinations. Ten trials which used herbal medicine plus active drugs versus active drugs alone reported the cure rate after treatment. Only 4 of them showed that a combination of herbal medicine and active drugs was superior to active drugs alone in increasing the cure rate of patients with HFMD.
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
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Table 2 Effect estimates of herbal medicine for hand, foot and mouth disease in 76 trials. Outcomes or subgroups 1. Fever clearance time (days) 1.1 Herbal medicine versus active drugs 1.1.1 Herbal patent drug versus active drugs 1.1.1.1 Chinese medicine compound granules versus ribavirin 1.1.1.2 Pudilan versus ribavirin 1.1.1.3 Chaihuang granules plus kangfuxin oral liquid versus ribavirin 1.1.1.4 Lianghuaqingwen granules versus ribavirin 1.1.1.5 Huangzhihua oral liquid versus ribavirin 1.1.1.6 Jinzhen oral liquid versus ribavirin 1.1.1.7 Jinlan mixture versus supportive therapy 1.1.1.8 Kangbingdu and Reduning versus ribavirin 1.1.1.9 Xiehuangsan versus ribavirin 1.1.2 Herbal injection versus active drugs 1.1.2.1 Chuanhuning versus ribavirin 1.1.2.2 Yanhuning versus interferon 1.1.2.3 Tanreqing versus ribavirin
No. of studies
Study ID
Participants
27
3784
10
1138
Effect estimate
66
−0.04 [−0.28, 0.20]
216
−1.21 [−2.97, 0.56]
1
Mei P (2010) Miao DX (2009) Shi YP (2011)
125
−0.92 [−1.33, −0.51]
1
Wang XG (2010)
136
0.04 [−0.18, 0.26]
1
Xin YN (2010)
225
−2.20 [−2.47, −1.93]
1
Xu H (2011)
186
−1.15 [−1.45, −0.85]
1
Zhang N (2003)
124
−1.59 [−1.70, −1.48]
1
Zhang X (2011)
98
−0.62 [−0.91, −0.33]
1 14
Zhang Y (2007)
60 2122
−0.41 [−0.48, −0.34]
54 100 298
−0.47 [−0.80, −0.14] 0.00 [−0.28, 0.28] −1.26 [−2.07, −0.44]
600 358
−0.54 [−0.71, −0.37] −0.89 [−0.99, −0.79]
396
−2.53 [−2.80, −2.27]
1
Ma YP (2010)
2
1 1 2
1.1.2.4 Yanhuning versus ganciclovir 1.1.2.5 Reduning versus ribavirin
1 3
1.1.2.6 Yanhuning versus ribavirin
3
1.1.2.7 Chuanhuning injection versus ganciclovir 1.1.2.8 Qingkailing versus ribavirin 1.1.2.9 Xiyanping versus ribavirin 1.1.3 Herbal decoction versus active drugs 1.1.3.1 Yinqiaohuoyin decoction versus ribavirin 1.1.3.2 Modified gegen qinlian decoction versus ribavirin 1.1.3.3 Lianzitang decoction versus interferon 1.2 Herbal medicine plus active drugs versus active drugs alone 1.2.1 Herbal patent drug plus active drugs versus active drugs alone 1.2.1.1 Jinyinhua plus acyclovir versus acyclovir alone 1.2.1.2 Ganluxiaodu pill plus ribavirin versus ribavirin 1.2.1.3 Qingrening, Reduning and kangbingdu oral liquid plus ribavirin versus ribavirin alone 1.2.1.4 Bonner plus Chimonanthus leaf particles treatment versus bonner alone
1
Cai HW (2001) Deng SZ (2010) Ding S (2011) Huang RW (2009a) Feng FY (2010) Huang RW (2009) Lu N (2009) Zhan GY (2010) Xu ZF (2009) Yang ZJ (2009) Zhi ZQ (2008) Yao BY (2011)
65
−0.44 [−1.02, 0.14]
1 1 3
Zhang W (2008) Zhang H (2010)
79 172 426
0.20 [−0.35, 0.75] −2.70 [−3.00, −2.40]
1
Li QX (2006)
132
−1.51 [−1.72, −1.30]
1
Liu M (2006)
84
−0.78 [−0.91, −0.65]
1
Yang PY (2010)
210
−1.17 [−1.41, −0.93]
43
5815
9
781
1
Cheng HJ (2010)
76
−1.50 [−2.08, −0.92]
1
Guo WZ (2008)
73
−0.68 [−1.01, −0.35]
1
Li LJ (2011)
86
−2.00 [−2.80, −1.20]
1
Liu WD (2008)
70
−1.63 [−1.81, −1.45]
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H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Table 2 (Continued) Outcomes or subgroups 1.2.1.5 Chiqiaoqingre granules plus ribavirin versus ribavirin alone 1.2.1.6 Kanggan granules plus ribavirin versus ribavirin 1.2.1.7 Pudilan plus ribavirin versus ribavirin alone 1.2.1.8 Kangbingdu and Reduning plus ribavirin versus ribavirin alone 1.2.2 Herbal injection plus active drugs versus active drugs alone 1.2.2.1 Yanxiping plus ribavirin versus ribavirin alone
No. of studies
Participants
Effect estimate
1
Wang L (2010)
150
−1.20 [−1.65, −0.75]
1
Wang P (2010)
60
−1.57 [−1.84, −1.30]
2
Wu YH (2009) Zhang WH (2009) Zhang X (2011)
172
−1.81 [−2.33, −1.29]
94
−1.15 [−1.37, −0.93]
1
25 4
1.2.2.2 Yanhuning plus ribavirin versus ribavirin alone
7
1.2.2.3 Yanhuning plus interferon versus interferon alone 1.2.2.4 Tanreqing plus ribavirin versus ribavirin alone
1
1.2.2.5 Qingkailing plus comprehensive treatment versus comprehensive treatment alone 1.2.2.6 Lianbizhi plus ribavirin versus ribavirin alone 1.2.2.7 Xiyanping plus interferon versus interferon alone 1.2.2.8 Tanreqing plus comprehensive treatment versus comprehensive treatment alone 1.2.2.9 Xuebijing injection and ganluxiaodu pill plus ribavirin versus ribavirin alone 1.2.2.10 Ezhuyou injection plus ribavirin versus ribavirin 1.2.3 Herbal decoction plus active drugs versus active drugs alone 1.2.3.1 Decoction of qingrejiedu plus acyclovir versus acyclovir alone 1.2.3.2 Chinese medicine compound decoction plus ribavirin versus ribavirin alone 1.2.3.3 Soup of detoxicating and slaking rashes plus acyclovir versus acyclovir alone 1.2.3.4 Symptoms pattern therapy plus conventional therapy versus conventional therapy alone 1.2.3.5 Herbal decoction plus acyclovir versus acyclovir 1.2.3.6 Liangxuejiedu tang plus acyclovir versus acyclovir 1.2.3.7 HFMD no. 1 decoction plus ribavirin versus ribavirin alone
Study ID
6
2
3464 Cai JY (2010) Chen JM (2010) Lin YQ (2008) Zhang JW (2009) Deng CL (2010) Hu YL (2009) Huang SP (2010) Luo XS (2010) Pan R (2010) Zhong (2007) Zhu XL (2009) Deng SZ (2010)
372
−1.59 [−2.50, −0.67]
886
−1.19 [−1.81, −0.57]
100
−0.76 [−1.01, −0.51]
Fan MY (2010) Jiang XD (2010) Li SL (2010) Ma JH (2010) Wei XL (2010) Yuan BB (2010) Guo XY (2009) Hao SL (2011)
1093
−1.18 [−1.97, −0.40]
248
−0.95 [−1.56, −0.34]
1
Li P (2010)
156
−1.70 [−2.15, −1.25]
1
Mao BR (2009)
180
−1.23 [−1.67, −0.79]
1
Peng HB (2009)
235
−1.03 [−1.63, −0.97]
1
Sun QK (2011)
70
−0.70 [−1.07, −0.33]
1
Zeng QS (2010)
124
−1.80 [−2.03, −1.57]
8
1444 −1.24 [−1.33, −1.15]
1
He YP (2009)
217
1
Ma YP (2010)
68
−0.04 [−0.26, 0.18]
1
Tian ZL (2008)
67
−0.62 [−0.95, −, −0.29]
1
Wang YP (2009)
180
−1.30 [−1.63, −0.97]
1
Xi RH (2010)
208
−0.59 [−0.69, −0.49]
1
Xing HZ (2009)
95
−0.78 [−0.98, −0.58]
1
Xu R (2010)
556
−0.24 [−0.29, −0.19]
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
e101
Table 2 (Continued) Outcomes or subgroups 1.2.3.8 Detoxication no. 1 plus routine Western medicine versus routine Western medicine alone 1.2.4 Herbal coloclyster plus active drugs versus active drugs alone 2. Cure rate 2.1 Herbal medicine versus active drugs 2.1.1 Herbal patent drug versus active drugs 2.1.1.1 Pudilan versus ribavirin 2.1.1.2 Chaihuang granules plus kangfuxin oral liquid versus ribavirin 2.1.1.3 Jinlan mixture versus supportive therapy 2.1.2 Herbal injection versus active drugs 2.1.2.1 Yanhuning versus ribavirin 2.1.2.2 Reduning versus ribavirin 2.1.3 Herbal decoction versus active drugs 2.1.3.1 Dazi decoction versus ribavirin 2.1.3.2 Qingrexiehuo decoction versus ribavirin 2.1.3.3 Modified gegen qinlian decoction versus ribavirin 2.1.4 Herbal coloclyster versus active drugs 2.1.4.1 Qingreguanchang versus nimesulid 2.2 Herbal medicine plus active drugs versus active drugs alone 2.2.1 Herbal injection plus active drugs versus active drugs alone 2.2.1.1 Yanhuning plus ribavirin versus ribavirin alone 2.2.1.2 Tanreqing plus ribavirin versus ribavirin alone 2.2.2 Herbal coloclyster plus active drugs versus active drugs alone 2.2.3 Herbal patent drug plus active drugs versus active drugs alone 2.2.4 Herbal decoction plus active drugs versus active drugs alone 2.2.4.1 Herbal decoction plus vidarabine versus vidarabine 2.2.4.2 Soup of detoxicating and slaking rashes plus acyclovir versus acyclovir alone 2.2.4.3 Herbal decoction plus acyclovir versus acyclovir 2.2.4.4 Liangxuejiedu decoction plus acyclovir versus acyclovir alone 2.2.4.5 HFMD no. 1 decoction plus ribavirin versus ribavirin 3. Rash subsidence time (days) 3.1 Herbal medicine versus active drugs 3.1.1 Herbal patent drug versus active drugs 3.1.1.1 Chinese medicine compound granules versus ribavirin
No. of studies
Study ID
Participants
Effect estimate
1
Zhang QP (2009)
53
−0.12 [−1.03, 0.79]
1
Liang XL (2010)
126
−0.22 [−0.46, 0.02]
10
1209
3
289
1 1
Mei P (2010) Shi YP (2011)
40 125
1.83 [0.84, 3.99] 1.15 [1.00, 1.33]
1
Zhang N (2003)
124
1.62 [1.28, 2.05]
3 2 1 3
387 Yang ZJ (2009) Zhi ZQ (2008) Zhan GY (2010)
266
1.35 [1.08, 1.66]
121 298
1.39 [1.10, 1.76]
1
Cheng YM (2010)
120
1.53 [1.20, 1.95]
1
Huang XH (2004)
94
1.52 [1.20, 1.95]
1
Liu M (2006)
84
1.46 [1.09, 1.97]
235
1 1
Zheng H (2010)
235
10
2010
3
674
2.85 [1.97, 4.12]
294
1.71 [0.75, 3.93]
1
Huang SP (2010) Zhu XL (2009) Jiang XD (2009)
380
1.30 [1.14, 1.47]
1
Liang XL (2010)
126
1.00 [0.90, 1.12]
1
Li LJ (2011)
86
1.44 [0.89, 2.32]
2
5
1124
1
Li CX (2009)
1
Tian ZL (2008)
1
Xi RH (2010)
1
Xing HZ (2009)
1
Xu R (2010)
198
1.27 [1.05, 1.54]
67
1.33 [0.94, 1.88]
208
1.37 [1.05, 1.79]
95
0.77 [0.57, 1.03]
556
1.02 [1.00, 1.04]
26
3731
10
1236
1
Ma YP (2010)
66
−2.55 [−2.92, −2.18]
e102
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Table 2 (Continued) Outcomes or subgroups
No. of studies
Study ID
Participants
Effect estimate
216
−1.17 [−2.82, 0.48]
1
Mei P (2010) Miao DX (2009) Shi YP (2011)
125
−1.45 [−1.81, −1.09]
1
Wang XG (2010)
136
0.10 [−0.58, 0.78]
1
Xin YN (2010)
225
−1.80 [−2.20, −1.40]
1
Xu H (2011)
186
−2.41 [−3.06, −1.76]
1
Zhang N (2003)
124
−0.86 [−1.02, −0.70]
1
Zhang X (2011)
98
0.02 [−0.30, 0.34]
1 12
Zhang Y (2007)
60 1989
−0.21 [−0.37, −0.05]
Deng SZ (2010) Ding S (2011) Huang RW (2009a) Feng FY (2010) Xu ZF (2009) Yang ZJ (2009) Zhi ZQ (2008) Huang RW (2009) Lu N (2009) Zhang GY (2010) Yao BY (2011)
100 298
0.01 [−0.21, 0.23] −0.85 [−1.45, −0.25]
600 396
−0.25 [−0.42, −0.08] −2.21 [−2.96, −1.46]
358
−1.45 [−2.12, −0.78]
65
0.06 [−0.65, 0.77]
1 4
Zhang H (2010)
172 506
−1.33 [−1.60, −1.06]
1
Ding HL (2004)
80
−1.84 [−2.38, −1.30]
1
Li QX (2006)
132
−1.44 [−1.67, −1.21]
1
Liu M (2006)
84
−0.42 [−0.48, −0.36]
1
Yang PY (2010)
210
−2.00 [−2.60, −1.40]
3.1.1.2 Pudilan versus ribavirin
2
3.1.1.3 Chaihuang granules plus kangfuxin oral liquid versus ribavirin 3.1.1.4 Lianghuaqingwen granules versus ribavirin 3.1.1.5 Huangzhihua oral liquid versus ribavirin 3.1.1.6 Jinzhen oral liquid versus ribavirin 3.1.1.7 Jinlan mixture versus supportive therapy 3.1.1.8 Kangbingdu and reduning versus ribavirin 3.1.1.9 Xiehuangsan versus ribavirin 3.1.2 Herbal injection versus active drugs 3.1.2.1 Yanhuning versus interferon 3.1.2.2 Tanreqing versus ribavirin
1 2
3.1.2.3 Yanhuning versus ganciclovir 3.1.2.4 Yanhuning versus ribavirin
1 3
3.1.2.5 Reduning versus ribavirin
3
3.1.2.6 Chuanhuning injection versus ganciclovir 3.1.2.7 Xiyanping versus ribavirin 3.1.3 Herbal decoction versus active drugs 3.1.3.1 Modified jidaiyu decoction versus ribavirin 3.1.3.2 Yinqiaohuoyin decoction versus ribavirin 3.1.3.3 Modified gegen qinlian decoction versus ribavirin 3.1.3.4 Lianzitang decoction versus interferon 3.2 Herbal medicine plus active drugs versus active drugs alone 3.2.1 Herbal patent drug plus active drugs versus active drugs alone 3.2.1.1 Jinyinhua plus acyclovir versus acyclovir alone 3.2.1.2 Ganluxiaodu dan plus ribavirin versus ribavirin alone 3.2.1.3 Qingrening, Reduning and kangbingdu oral liquid plus ribavirin versus ribavirin alone 3.2.1.4 Bonner plus Chimonanthus leaf particles treatment versus bonner alone 3.2.1.5 Chiqiaoqingre granules plus ribavirin versus ribavirin alone 3.2.1.6 Kanggan granules plus ribavirin versus ribavirin 3.2.1.7 Pudilan plus ribavirin versus ribavirin alone 3.2.1.8 Kangbingdu and reduning plus ribavirin versus ribavirin alone
1
43
5924
9
781
1
Cheng HJ (2010)
76
−2.10 [−2.94, −1.26]
1
Guo WZ (2008)
73
−1.14 [−1.39, −0.89]
1
Li LJ (2011)
156
−0.95 [−1.29, −0.61]
1
Liu WD (2008)
70
−2.24 [−2.43, −2.05]
1
Wang L (2010)
150
−1.10 [−1.64, −0.56]
1
Wang P (2010)
60
−2.71 [−3.05, −2.37]
2
Wu YH (2009) Zhang WH (2009) Zhang X (2011)
172
−2.56 [−3.03, −2.08]
94
−1.25 [−1.71, −0.79]
1
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
e103
Table 2 (Continued) Outcomes or subgroups
No. of studies
3.2.2 Herbal injection plus active drugs versus active drugs alone 3.2.2.1 Xiyanping plus ribavirin versus ribavirin alone
25 4
3.2.2.2 Yanhuning plus ribavirin versus ribavirin alone
6
3.2.2.3 Yanhuning plus interferon versus interferon alone 3.2.2.4 Tanreqing plus ribavirin versus ribavirin alone
1
3.2.2.5 Qingkailing plus comprehensive treatment versus comprehensive treatment alone 3.2.2.6 Lianbizhi plus ribavirin versus ribavirin alone 3.2.2.7 Xiyanping plus interferon versus interferon 3.2.2.8 Tanreqing plus comprehensive treatment versus comprehensive treatment alone 3.2.2.9 Xuebijing injection and ganluxiaodu pill plus ribavirin versus ribavirin alone 3.2.2.10 Ezhuyou injection plus ribavirin versus ribavirin 3.2.3 Herbal decoction plus active drugs versus active drugs alone 3.2.3.1 Decoction of qingrejiedu plus acyclovir versus acyclovir alone 3.2.3.2 Chinese medicine compound decoction plus ribavirin versus ribavirin alone 3.2.3.3 Soup of detoxicating and slaking rashes plus acyclovir versus acyclovir alone 3.2.3.4 Symptoms pattern therapy plus conventional therapy versus conventional therapy 3.2.3.5 Herbal decoction plus acyclovir versus acyclovir 3.2.3.6 Liangxuejiedu decoction plus acyclovir versus acyclovir alone 3.2.3.7 HFMD no. 1 decoction plus ribavirin versus ribavirin alone 3.2.3.8 Detoxication no. 1 plus routine Western medicine versus routine Western medicine alone 3.2.4 Herbal coloclyster plus active drugs versus active drugs alone 4. Oral ulcer heal time (days) 4.1 Herbal medicine versus active drugs 4.1.1 Herbal decoction versus active drugs
6
2
Study ID
Participants
Effect estimate
3573 Cai JY (2010) Chen ZM (2010) Lin YQ (2008) Zhang JW (2009) Deng CL (2010) Huang SP (2010) Luo XS (2010) Pan R (2010) Zhong (2007) Zhu XL (2009) Deng SZ (2010)
372
−1.54 [−2.31, −0.76]
785
−1.58 [−2.28, −0.89]
1
−0.76 [−1.00, −0.52]
Fan MY (2010) Jiang XD (2010) Li SL (2010) Ma JH (2010) Wei XL (2010) Yuan BB (2010) Guo XY (2009) Hao SL (2011)
1093
−1.29 [−2.05, −0.54]
248
−1.31 [−2.58, −0.04]
1
Li P (2010)
208
−2.03 [−3.01, −1.05]
1
Mao BR (2009)
180
−2.45 [−2.99, −1.91]
1
Peng HB (2009)
235
−1.03 [−1.58, −0.48]
1
Sun QK (2011)
70
−0.80 [−1.08, −0.52]
1
Zeng QS (2010)
124
−2.50 [−2.96, −2.04]
1444
8 1
He YP (2009)
217
−1.89 [−2.10, −1.68]
1
Ma YP (2010)
68
−2.35 [−2.72, −1.98]
1
Tian ZL (2008)
67
−2.38 [−2.64, −2.12]
1
Wang YP (2009)
180
−2.00 [−2.35, −1.65]
1
Xi RH (2010)
208
−1.37 [−1.53, −1.21]
1
Xing HZ (2009)
95
−2.40 [−2.65, −2.15]
1
Xu R (2010)
556
−0.94 [−0.95, −0.93]
1
Zhang QP (2009)
53
1
Liang XL (2010)
126
14
1590
3
422
−0.11 [−1.05, 0.83] −0.22 [−0.41, −0.03]
e104
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Table 2 (Continued) Outcomes or subgroups 4.1.1.1 Modified jidaiyu decoction versus ribavirin 4.1.1.2 Yinqiaohuoyin decoction versus ribavirin 4.1.1.3 Lianzitang decoction versus interferon 4.1.2 Herbal patent drug versus active drugs 4.1.2.1 Chinese medicine compound granules versus ribavirin 4.1.2.2 Pudilan versus ribavirin 4.1.2.3 Chaihuang granules plus kangfuxin oral liquid versus ribavirin 4.1.2.4 Huangzhihua oral liquid versus ribavirin 4.1.2.5 Xiehuangsan versus ribavirin 4.1.3 Herbal injection versus active drugs 4.1.3.1 Chuanhuning versus ribavirin 4.1.3.2 Yanhuning versus interferon 4.1.3.3 Tanreqing versus ribavirin 4.1.3.4 Reduning versus ribavirin 4.1.3.5 Qingkailing versus ribavirin 4.2 Herbal medicine plus active drugs versus active drugs alone 4.2.1 Herbal patent drug plus active drugs versus active drugs alone 4.2.1.1 Qingrening, Reduning and kangbingdu oral liquid plus ribavirin versus ribavirin alone 4.2.1.2 Kanggan granules plus ribavirin versus ribairin 4.2.1.3 Pudilan plus ribavirin versus ribavirin alone 4.2.2 Herbal injection plus active drugs versus active drugs alone 4.2.2.1 Xiyanping plus ribavirin versus ribavirin alone 4.2.2.2 Yanhuning plus interferon versus interferon alone 4.2.2.3 Qingkailing plus comprehensive treatment versus comprehensive treatment alone 4.2.2.4 Yanhuning plus ribavirin versus ribavirin alone 4.2.2.5 Tanreqing plus comprehensive treatment versus comprehensive treatment alone 4.2.2.6 Xuebijing injection and ganluxiaodu pill plus ribavirin versus ribavirin alone 4.2.2.7 Ezhuyou injection plus ribavirin versus ribavirin 4.2.3 Herbal coloclyster plus active drugs versus active drugs alone 4.2.4 Herbal decoction plus active drugs versus active drugs alone 4.2.4.1 Decoction of qingrejiedu plus acyclovir versus acyclovir alone 4.2.4.2 Chinese medicine compound decoction plus ribavirin versus ribavirin alone
No. of studies
Study ID
Participants
Effect estimate
80
−0.92 [−1.28, −0.56]
Li QX (2006)
132
−0.27 [−0.51, −0.03]
Yang PY (2010)
210
−1.34 [−2.01, −0.67]
1
Ding HL (2004)
1 1 5
652 66
−1.70 [−2.07, −1.33]
Miao DX (2009) Shi YP (2011)
176 125
−1.10 [−1.28, −0.92] −1.42 [−1.73, −1.11]
1
Xin YN (2010)
225
−1.00 [−1.41, −0.59]
1 6
Zhang Y (2007)
60 516
−0.70 [−0.90, −0.50]
1 1 1 2
Cai HW (2001) Deng SZ (2010) Ding S (2011) Lu N (2009) Zhang GY (2010) Zhang W (2008)
54 100 108 175
−1.54 [−1.96, −1.12] −0.01 [−0.19, 0.17] −0.64 [−1.19, −0.09] −1.42 [−2.76, −0.08]
1
Ma YP (2010)
1 1
1 22 4
79 2674
−0.40 [−0.94, 0.14]
318
1
Li LJ (2011)
86
−1.30 [−1.51, −1.09]
1
Wang P (2010)
60
−1.20 [−1.50, −0.90]
2
Wu YH (2009) Zhang WH (2009)
172
−1.62 [−2.56, −0.68]
11
1522 158
−1.28 [−1.81, −0.75]
1
Chen ZM (2010) Zhang JW (2009) Deng SZ (2010)
100
−0.64 [−0.81, −0.47]
1
Guo XY (2009)
152
−1.29 [−1.81, −0.77]
2
235
−1.67 [−3.19, −0.15]
683
−1.22 [−1.81, −0.64]
1
Hu YL (2009) Zhu XL (2009) Jiang XD (2010) Peng HB (2009) Wei XL (2010) Sun QK (2011)
70
−0.35 [−0.64, −0.06]
1
Zeng QS (2010)
124
−2.20 [−2.58, −1.82]
1
Liang XL (2010)
126
−0.20 [−0.39, −0.01]
2
3
708
6 1
He YP (2009)
217
−1.98 [−2.18, −1.78]
1
Ma YP (2010)
68
−1.52 [−1.87, −1.17]
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
e105
Table 2 (Continued) Outcomes or subgroups 4.2.4.3 Soup of detoxicating and slaking rashes plus acyclovir versus acyclovir alone 4.2.4.4 Herbal decoction plus acyclovir versus acyclovir 4.2.4.5 Liangxuejiedu decoction plus acyclovir versus acyclovir alone 4.2.4.6 Detoxication no. 1 plus routine Western medicine versus routine Western medicine alone 5. Healing time (days) 5.1 Herbal medicine versus active drugs 5.1.1 Herbal decoction versus active drugs 5.1.1.1 Lianzitang decoction versus interferon 5.1.2 Herbal patent drug versus active drugs 5.1.2.1 Shuanghuanglian versus ribavirin 5.1.2.2 Pudilan versus ribavirin 5.1.2.3 Huangzhihua oral liquid versus ribavirin 5.1.2.4 Jinzhen oral liquid versus ribavirin 5.1.3 Herbal injection versus active drugs 5.1.3.1 Yanhuning versus ganciclovir 5.1.3.2 Qingkailing versus ribavirin 5.1.3.3 Xiyanping versus ribavirin 5.2 Herbal medicine plus active drugs versus active drugs alone 5.2.1 Herbal injection plus active drugs versus active drugs alone 5.2.1.1 Tanreqing plus ribavirin versus ribavirin alone 5.2.1.2 Yanhuning plus ribavirin versus ribavirin alone 5.2.1.3 Tanreqing plus comprehensive treatment versus comprehensive treatment alone 5.2.1.4 Xiyanping plus ribavirin versus ribavirin alone 5.2.2 Herbal patent drug plus active drugs versus active drugs alone 5.2.2.1 Jinyinhua plus acyclovir versus acyclovir alone 5.2.2.2 Ganluxiaodu dan plus ribavirin versus ribavirin 5.2.2.3 Bonner plus Chimonanthus leaf particles treatment versus bonner alone 5.2.2.4 Kanggan granules plus ribavirin versus ribavirin 5.2.2.5 Pudilan plus ribavirin versus ribavirin alone 5.2.2.6 Kanggan granules plus ribavirin versus ribavirin 5.2.3 Herbal decoction plus active drugs versus active drugs alone 5.2.3.1 Modified yinqiaosan plus ribavirin versus ribavirin
No. of studies
Study ID
Participants 67
−0.90 [−1.29, −0.51]
208
−1.07 [−1.25, −0.89]
Xing HZ (2009)
95
−0.86 [−1.14, −0.58]
Zhang QP (2009)
53
−0.11 [−1.05, 0.83]
1
Tian ZL (2009)
1
Xi RH (2010)
1 1
8
1701
1
210
1
Effect estimate
Yang PY (2010)
210
−2.00 [−2.53, −1.47]
640
4 1
Huang ZG (2009)
53
−0.90 [−1.69, −0.11]
1 1
Miao DX (2009) Xin YN (2010)
176 225
−2.50 [−2.94, −2.06] −1.40 [−1.75, −1.05]
1
Xu H (2011)
186
−1.03 [−1.26, −0.80]
3 1 1 1 21
851 Feng FY (2010) Zhang W (2008) Zhang H (2010)
7
600 79 172 2982
−1.20 [−1.40, −1.00] −0.30 [−1.01, 0.41] −2.42 [−2.84, −2.00]
1095 Li SL (2010) Ma JH (2010) Yuan BB (2010) Huang SP (2010)
560
−1.28 [−1.99, −0.57]
160
−1.53 [−1.86, −1.20]
2
Peng HB (2009) Sun YF (2010)
303
−1.46 [−1.93, −0.98]
1
Zhang JW (2009)
72
−1.01 [−1.46, −0.56]
3
1
6
451
1
Cheng HJ (2010)
76
−1.20 [−2.10, −0.30]
1
Guo WZ (2008)
73
−1.13 [−1.43, −0.83]
1
Liu WD (2008)
70
−2.29 [−2.49, −2.09]
1
Wang P (2010)
60
−2.97 [−3.35, −2.59]
2
Wu YH (2009) Zhang WH (2009) Wang P (2010)
172
−2.36 [−3.62, −1.10]
60
−2.97 [−3.35, −2.59]
1
1436
8 1
Cheng HQ (2009)
60
−0.63 [−1.19, −0.07]
e106
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
Table 2 (Continued) Outcomes or subgroups 5.2.3.2 Decoction of qingrejiedu plus acyclovir versus acyclovir alone 5.2.3.3 Soup of detoxicating and slaking rashes plus acyclovir versus acyclovir alone 5.2.3.4 Symptoms pattern therapy plus conventional therapy versus conventional therapy 5.2.3.5 Herbal decoction plus acyclovir versus acyclovir 5.2.3.6 Liangxuejiedu decoction plus acyclovir versus acyclovir alone 5.2.3.7 HFMD no. 1 decoction plus ribavirin versus ribavirin alone 5.2.3.8 Detoxication no. 1 plus routine Western medicine versus routine Western medicine alone 6. Rash subsidence rate 6.1 Herbal medicine plus other treatment versus active drugs 6.1.1 Tanreqing plus ribavirin versus ribavirin alone 6.1.2 Reduning plus ribavirin versus ribavirin alone 7. Oral symptoms heal rate 7.1 Herbal medicine versus active drugs 7.1.1 Qingrexiehuo decoction versus ribavirin 7.1.2 Reduning versus ribavirin 7.2 Herbal medicine plus active drugs versus active drugs alone 7.2.1 Reduning plus ribavirin versus ribavirin alone
No. of studies
Study ID
Participants
Effect estimate
1
He YP (2009)
217
−1.57 [−1.76, −1.38]
1
Tian ZL (2009)
67
−2.56 [−2.89, −2.23]
1
Wang YP (2009)
180
−2.00 [−2.36, −1.64]
1
Xi RH (2010)
208
−2.26 [−2.70, −1.82]
1
Xing HZ (2009)
95
−2.46 [−2.71, −2.21]
1
Xu R (2010)
556
−1.07 [−1.12, −1.02]
1
Zhang QP (2009)
53
−0.66 [−1.63, 0.31]
157
2 1
Fan MY (2010)
85
1.00 [0.96, 1.05]
1
Xin SX (2009)
72
1.79 [1.03, 3.12]
2
277
1
Huang XH (2004)
94
1.52 [1.17, 1.98]
1 1
Huang RW (2009)
183 287
1.00 [0.98, 1.02]
1
Zhao JW (2009)
287
1.13 [0.75, 1.68]
Another 10 trials employed herbal medicine as the main intervention compared to active drugs, only one trial showed no difference between Pudilan and ribavirin injection on increasing cure rate in patients with HFMD, the remaining 9 trials all showed significant difference between herbal medicine and active drugs regarding this outcome.
Rash subsidence time/rate A total of 43 trials comparing herbal medicine plus active drugs and active drugs alone reported symptom changes after treatment which were relevant to rash subsidence. Results of 41 trials showed positive effect of combination treatment compared to active drugs. Meta-analysis showed that compared to ribavirin alone, both pudilan (MD −2.56, 95% CI −3.03 to −2.08, random model, 2 trials) or xiyanping (MD −1.54, 95% CI −2.31 to −0.76, random model, 4 trials) plus ribavirin had better effect in reducing rash subsidence time for patients with HFMD. However, 1 trials showed Tanreqing injection plus ribavirin was not significant different from ribavirin alone on increasing rash subsidence rate for HFMD patients, and another trial showed no difference between herbal decoction plus routine Western medicine and routine Western medicine alone on increasing rash subsidence rate.
Twenty six trials compared herbal medicine and active drugs, and meta-analysis showed Tanreqing injection (MD −0.85, 95% CI −2.96 to −1.46, random model, 2 trials), Yanhuning injection (MD −2.21, 95% CI −1.53 to −0.86, random model, 3 trials) and Reduning injection (MD −1.45, 95% CI −2.21 to −0.78, random model, 3 trials) were significantly better than ribavirin in reducing rash subsidence time of HFMD. With the exception of 4 trials, other trials results were all consistent to the results of meta-analysis that herbal medicines were superior to active drugs in reducing rash subsidence time. Oral ulcers healing time/rate Totally 36 trials reported oral ulcers healing time or oral symptoms healing rate during the treatment. Twenty two of them used combination therapy compared to active drugs alone, the meta-analysis of 4 trials showed a combination of pudilan (MD −1.62, 95% CI −2.56 to −0.68, random model, 2 trials) or xiyanping (MD −1.28, 95% CI −1.81 to −0.75, fixed model, 2 trials) and ribavirin could significantly reduce the oral ulcers healing time compared to ribavirin alone and all the other 18 trials’ results supported that herbal medicine plus active drugs were better in reducing the oral ulcers healing time. Another 14 trials compared herbal medicine with active drugs, and results of them showed a significant difference between these
H. Cao et al. / European Journal of Integrative Medicine 4 (2012) e85–e111
e107
Table 3 Results of meta-analysis of 18 included trials. Outcomes or subgroups
No. of studies
Study ID
Participants
Statistical method
Effect estimate
P Value
Huang RW (2009) Lu N (2009) Zhan GY (2010) 3 Xu ZF (2009) 1.1.2 Yanhuning injection versus ribavirin Yang ZJ (2009) Zhi ZQ (2008) 1.2 Herbal medicine plus active drugs versus active drugs alone Wu YH (2009) 1.2.1 Pudilan plus ribavirin versus 2 ribavirin alone Zhang WH (2009)
358
Mean Difference (IV, fixed, I2 = 0%, 95% CI) Mean Difference (IV, fixed, I2 = 0%, 95% CI)
−0.89 [−0.99, −0.79]
<0.00001
−2.53 [−2.80, −2.27]
<0.00001
−1.81 [−2.33, −1.29]
<0.00001
1.2.2 Qingkailing plus 2 comprehensive treatment versus comprehensive treatment alone 2. Rash subsidence time (days) 2.1 Herbal medicine versus active drugs 2 2.1.1 Tanreqing versus ribavirin
248
Mean Difference (IV, Random, I2 = 83%, 95% CI) Mean Difference (IV, Random, I2 = 83%, 95% CI)
−0.95 [−1.56, −0.34]
0.002
Mean Difference (IV, Random, I2 = 27%, 95% CI) Mean Difference (IV, Random, I2 = 81%, 95% CI) Mean Difference (IV, Random, I2 = 76%, 95% CI)
−0.85 [−1.45, −0.25]
0.007
−2.21 [−2.96, −1.46]
<0.00001
−1.45 [−2.12, −0.78]
<0.0001
Mean Difference (IV, Random, I2 = 45%, 95% CI) Mean Difference (IV, Random, I2 = 78%, 95% CI)
−2.56 [−3.03, −2.08]
<0.00001
−1.54 [−2.31, −0.76]
<0.0001
Mean Difference (IV, Random, I2 = 83%, 95% CI) Mean Difference (IV, fixed, I2 = 0%, 95% CI)
−1.62 [−2.56, −0.68]
0.0008
−1.28 [−1.81, −0.75]
<0.00001
−1.46 [−1.93, −0.98]
<0.00001
1. Fever clearance time (days) 1.1 Herbal medicine versus active drugs 1.1.1Reduning injection versus 3 ribavirin
Guo XY (2009) Hao SL (2011)
396
172
Ding S (2011) Huang RW (2009a) 3 Xu ZF (2009) 2.1.2 Yanhuning versus ribavirin Yang ZJ (2009) Zhi ZQ (2008) 2.1.3 Reduning versus ribavirin 3 Huang RW (2009) Lu N (2009) Zhan GY (2010) 2.2 Herbal medicine plus active drugs versus active drugs alone Wu YH (2009) 2.2.1 Pudilan plus ribavirin versus 2 ribavirin alone Zhang WH (2009)
298
2.2.2 Xiyanping plus ribavirin versus ribavirin alone
372
4
Cai JY (2010) Chen ZM (2010) Lin YQ (2008) Zhang JW (2009)
3. Oral ulcer healing time (days) 3.1 Herbal medicine plus active drugs versus active drugs alone 2 Wu YH (2009) 3.1.1 Pudilan plus ribavirin versus ribavirin alone Zhang WH (2009) 3.1.2 Xiyanping plus ribavirin versus ribavirin alone
2
Chen ZM (2010) Zhang JW (2009)
4. Healing time (days) 4.1 Herbal medicine plus active drugs versus active drugs alone Peng HB (2009) 4.1.1 Tanreqing plus comprehensive 2 treatment versus comprehensive Sun YF (2010) treatment alone
two therapies in reducing oral ulcer healing time except 2 trials which employed Qingkailing versus ribavirin, and Yanhuning versus interferon. Two trials showed no difference in increasing oral ulcers healing rate neither between Reduning and ribavirin nor between combination of Reduning and ribavirin and ribavirin alone on patients with HFMD. Fever clearance time/antipyretic effect Sixty eight trials reported fever clearance time during treatments, 4 meta-analyses of 10 trials showed Reduning (MD −0.89, 95% CI −0.99 to −0.79, fixed model, 3 trials) and Yanhuning injection (MD −2.53, 95% CI −2.80 to −2.27, fixed
396
358
172
172
158
303
Mean Difference (IV, fixed, I2 = 0%, 95% CI)
model, 3 trials) alone or a combination with Pudilan (MD −1.81, 95% CI −2.33 to −1.29, random model, 2 trials) or Qingkailing (MD −0.95, 95% CI −1.56 to −0.34, random model, 2 trials) and active drugs were all significantly superior to active drugs alone in reducing fever clearance time of HFMD patients. For the remaining 58 trials, only 9 showed no difference between herbal medicine (alone or combined with active drugs) and active drugs, in reducing fever clearance time. One trial [89] showed herbal medicine plus conventional therapy was better than conventional therapy alone in antipyretic effect for HFMD patients (RR 1.19, 95% CI 1.09 to 1.30, 1 trial). Another trial [69] showed herbal medicine combined with
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ribavirin was superior to ribavirin alone in reducing average body temperature of patients with HFMD (MD −0.32, 95% CI −0.52 to −0.12, 1 trial). Healing time Twenty nine trials reported the healing time or length of hospital stay for HFMD patients. Twenty one of them compared combination therapy to active drugs alone, and the meta-analysis of 2 trials showed combination of Tanreqing and active drugs significantly reduced the healing time of HFMD (MD −1.46, 95% CI −1.93 to −0.98, fixed model, 2 trials). With the exception of 1 trial, the remaining 26 trials showed that herbal medicine (alone or combined with active drugs) was superior to active drugs in reducing healing time. Creatine kinase (CK) and creatine kinase muscle and brain (CK-MB) Only one trial [21] reported CK and CK-MB after treatment, it showed herbal medicine plus ribavirin significantly reduce CK (MD −10.60, 95% CI −18.09 to −3.11, 1 trial) and CKMB (MD −3.40, 95% CI −5.50 to −1.30, 1 trial) compared to ribavirin alone. Adverse events Forty six of the 76 trials reported adverse events. Amonst these, 33 trials reported no adverse events in both groups. Details of adverse events in the Chinese herbal medicine group were reported in the remaining 13 trials. Only mild adverse events were found in the herbal medicine group, i.e., rash, diarrhea, slightly increased CK-MB, increased bowel movement frequency, and nausea. In the control groups as well as all the above events, some studies indicated that ribavirin may cause reduction in WBC or platelets, but no detailed information was reported. All trials measured outcomes at the end of treatment, no trials reported long-term follow-up after the treatment. Funnel plot analysis Funnel plot analysis could not be conducted due to the insufficient number of trials in the meta-analysis. Discussion This review provided indications that herbal patents, herbal injections or herbal decoctions with or without active drugs had an effect of reducing fever clearance time, rash subsidence time, oral symptoms healing time and healing time of HFMD. However, the majority of the included trials had a high risk of bias. Consequently, only poor quality, provisional evidence could be provided by this systematic review. There are limitations to the significance of the findings of this review. First of all, the methodological quality of the included studies was generally poor. According to the analysis of their methodological reporting, only 11.8% of the included studies mentioned the method of randomization, and only 1 trial report referred to the method of allocation concealment. Almost all
studies had not used placebo as comparison, so blinding methods could not be used for patients and doctors. Intention-to-treat analysis was not used in any of the studies. Further, the experimental group included several kinds of herbal medicine, such as herbal patent drug, herbal injection, herbal decoction, and herbal coloclyster. Several studies used two or more drugs as a combination therapy to do the treatment. Equally, control groups were made up of many different interventions, such as antiviral drugs, antibiotics, usual care, and immunopotentiators. This non-uniform approach also reduced the comparability of the included studies. Most of the included trials used composite outcome measures which categorized the effect of the treatment into four grades. The classification of “cure”, “markedly effective”, “effective” or “ineffective” is not internationally recognized and highly subjective. According to the low quality of studies, the variety of interventions and the variance of outcome measures, studies were highly heterogeneous. We finally included 18 trials in subgroup meta-analysis and the results showed that compared to ribavirin, several kinds of herbal injections (such as Reduning, Yanhuning, Tanreqing and Qingkailing, etc.) may have significantly better effects in reducing the time of healing, time of fever clearance and time of rash subsidence. Using these herbal injections alone or combined with other active drugs (such as ribavirin) may accelerate the improvement of symptoms of HMFD; on average 1 day could be gained for healing the disease during treatment. On the other hand, all included trials had treatment duration for less than 7 days, so that due to the lack of long-term follow up, its hard to conclude the safety of herbal medicine on HFMD. We suggest that at least two weeks after treatment should be included as follow up in future studies in order to observe whether herbal medicines have a long-term effect for shortening the disease’s duration. Although this review suggests that the evidence on the use of herbal medicine for HMFD is of insufficient quality, the available data indicated that herbal medicine, especially herbal injections, and even more so the combination of herbal medicine with Western medication, might improve symptoms of HMFD. Further high quality studies of sufficient sample size are needed to assess the effectiveness of herbal medicine in treating HFMD. Randomization methods need to be more rigorous. By using the appropriate placebo, blinding of the patients, the other care providers or at least the outcome assessors will minimize performance and assessment biases. Herbal injections or herbal patents could be paid more attention according to the potential effect shown in this research. As the disease is diagnosed according to symptoms, and the patients are almost all children/infants which means patient report outcome (PRO) may be difficult to obtain the main outcome measurements could include symptom improvement, such as fever clearance time and rash total subsidence time. Analysis of outcomes based on intention-to-treat principle is important. Currently many researchers are aware of using adequate study designs, but they lack knowledge of the implementation of clinical studies, and also the appropriate way for reporting research. Researchers should adhere to the standards of CONSORT [100] for trial reporting, details of methods and results should be fully addressed.
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