Bacterial Lysate Treatment in Allergic Disease: A Systematic Review and Meta-Analysis 2021 PDF

Received: 28 December 2020 | Revised: 29 April 2021 | Accepted: 31 May 2021 DOI: 10.1111/pai.13572 ORIGINAL ARTICLE Bacterial lysate treatment in allergic disease: A systematic review and meta-­analysis Chengmei Li | Hua Zhou | Wei Zhang | Datian Che International Medical...

Received: 28 December 2020 | Revised: 29 April 2021 | Accepted: 31 May 2021 DOI: 10.1111/pai.13572 ORIGINAL ARTICLE Bacterial lysate treatment in allergic disease: A systematic review and meta-­analysis Chengmei Li | Hua Zhou | Wei Zhang | Datian Che International Medical Department, Shanghai Children's Hospital, Shanghai Abstract Jiao Tong University, Shanghai, China Objective: The aim of this review was to assess the efficacy of bacterial lysate treat- Correspondence ment in patients with allergic disease. Datian Che, International Medical Method: Randomized controlled trials (RCTs) of bacterial lysate therapy for patients Department, Shanghai Children's Hospital, Shanghai Jiao Tong University, Lu Ding with allergic diseases (asthma, atopic dermatitis, and allergic rhinitis) were searched Road No. 355, Shanghai 200062 China. using PubMed, EMBASE, Cochrane, China National Knowledge Infrastructure, Email: [email protected] Chinese Biomedical literature, and Wanfang databases up to March 2020. Based on Editor: Rachel Peters the guidelines of the Cochrane collaboration, risk of bias was assessed. Results: This meta-­analysis based on 19 studies comparing bacterial lysate-­treated patients with a control group showed a 24% (RR: 1.24, 95% CI [1.19, 1.30]) increase in improvement of allergy symptom control. In addition, the improvement of asthma symptom control was 22% (RR: 1.22, 95% CI [1.14, 1.26]) higher in the bacterial lysate treatment group. Moreover, the levels of immunoglobulin (IgA and IgG), T lymphocyte subtype (CD3+, CD4+, CD4+/CD8+, Th1), and cytokines (IFN-­γ, IL-­2, and IL-­12) were increased in the treated group compared with controls. There was no significant dif- ference in adverse event rate between the two groups. Conclusion: Treatment with bacterial lysate improves symptom control in patients with allergic diseases on the basis of routine therapy. No adverse risk was found in this meta-­analysis. KEYWORDS asthma, bacterial lysate, dermatitis, rhinitis, treatment 1 | I NTRO D U C TI O N survey in 2014 reported that the prevalence of AD among children from 1 to 7 years old was 12.94% and the trend declined when they Currently, allergic diseases have a great impact on the health of chil- are growing up. Its etiology is related to heredity, immunity, and skin dren. The childhood incidence rates of asthma, eczema or dermatitis, barrier function. and allergic rhinitis are increasing gradually, and this increase is even According to reports from the World Health Organization, the evident in adults. number of asthma sufferers worldwide has reached 235 million, Atopic dermatitis (AD) is a chronic recurrent inflammatory skin and as such, asthma represents one of the most common diseases disease characterized by severe itching and eczema-­like lesions. It in children. WHO also released the report that the number of deaths usually occurs in infancy and childhood. A Chinese epidemiology caused by asthma was 383,000 in 2015. In 2010, a large-­ scale This is an open access article under the terms of the Creative Commons Attribution-­NonCommercial-­NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-­commercial and no modifications or adaptations are made. © 2021 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd. Pediatr Allergy Immunol. 2021;32:1813–1823.  wileyonlinelibrary.com/journal/pai | 1813 1814 | LI et al. asthma epidemiology survey of Chinese children aged 0–­14 years revealed the overall prevalence of asthma was 3.02% and around Key Message one third of children with asthma did not receive a timely diagnosis.1 Our study showed the effective extent of bacterial lysate Allergic rhinitis is usually caused by allergens, and the prevalence 2 therapy on allergic diseases. As three allergic diseases rate for children may be as high as 40%. Allergic rhinitis and sinusitis (asthma, allergic rhinitis, and dermatitis) were included in are linked to each other, because allergic rhinitis causes the nose to our study, the degree of influence of bacterial lysate on become blocked and in turn blocks the sinuses.3 each disease could be assessed. In addition, our research Allergic symptoms vary and differ among individuals and age includes not only an evaluation of clinical symptoms but groups. Some common preventive methods were usually used in also some serum markers of immunity as well as indicators allergic diseases such as reduction in exposure to the sensitizing al- of lung function. lergen, targeted pharmacotherapy, and some immunotherapies. All of these are very important for the prevention of allergic disease.4 Pathogenesis of allergic diseases was proven to involve immune imbalance so that it is believed that some bacterial lysates promote observed in the group of infants with single heredity for atopy.13 immune responses by increasing immunoglobulin and cellular im- Feeding bacterial lysate early in life is likely to reduce the occurrence munity. 5 Bacterial lysates consist of inactivated bacterial extracts of AD in infants with single atopic family history. from pathogenic respiratory bacteria. Most of them are divided Therefore, the aim of our study was to investigate the clinical into two types, either PCBL (polyvalent chemical bacterial lysate) efficiency of bacterial lysate treatment on allergic disease as well as or PMBL (polyvalent mechanical bacterial lysate (PMBL). OM-­85 assess the extent of its influence. is the most common PCBL used in current studies. It is a lysate of 21 strains of eight bacteria which may boost immunologic re- sponses.6 Ismigen was the PMBL used in the included studies. This 2 | M E TH O D S orally/or sublingually administered immunomodulator can activate immunologic defense reactions by increasing IgA and IgG, elevating 2.1 | Data sources levels of the Th-­1-­specific cytokine IFN-­γ, and reducing the Th2-­ specific cytokine IL-­4.7,8 We conducted a systematic literature search to identify potential ar- Some studies have shown that administration of bacterial lysate ticles from PubMed, EMBASE, Cochrane, China National Knowledge could reduce episodes in patients with recurrent respiratory infec- Infrastructure(CNKI), Chinese Biomedical database (CBM), and tions. According to the result of a double-­blind, placebo-­controlled, Wanfang databases. The search was performed using key terms, multicenter clinical trial, bacterial lysate treatment could reduce the “broncho-­vaxom,” “asthma,” “dermatitis, atopic,” “eczema, atopic,” number of infectious episodes in patients with recurrent respiratory “rhinitis” as well as key words “bacterial lysate,” “bacterial extract,” tract infections.9 The placebo group experienced a mean of 1.43 “OM-­85.” All identified articles were imported in Endnote, and selec- (95% CI [1.01, 1.86]) episodes in the 8-­month study period, while tion was based on a three-­step procedure, first screening by title, 0.86 (95% CI [0.54, 1.19]) episodes were recorded in the bacterial then by abstract, and finally by assessing full texts. antigen-­treated group. The mean days of antibiotic usage in the Two reviewers (LCM and CDT) conducted article screening in- treated group was 1.24 compared with 2.83 in the placebo group. dependently, and any disagreements were resolved by discussion. Another meta-­analysis included 53 studies to assess the efficacy of OM-­85 in pediatric patients with recurrent respiratory tract in- fection found that bacterial lysates could reduce the frequency of 2.2 | Inclusion and exclusion criteria respiratory infection.10 However, the effect of bacterial antigen treatment on allergic In order to be included in this review, studies had to meet all of disease remains controversial. Some studies have shown bacterial the following criteria: (1) study design: RCTs without language re- lysate treatment could reduce asthma attack in terms of duration of striction; (2) participants: children and adults receiving a diagnosis coughing and wheezing compared with the control group,4,11 but oth- of any type of allergic disease (asthma, dermatitis, allergy rhinitis); ers have reported that no significant difference was observed in the (3) intervention group: patients treated with at least one course of 9 number of allergic episodes between treated and placebo groups. bacterial lysate alone, or participants received treatments of bac- For AD, a study by Bodemer and colleagues12 demonstrated that a terial lysate combined with routine allergic disease treatment; (4) 20% reduction in occurrence of repeated events was observed in comparison group: patients treated with routine therapy for allergic the OM-­85-­treated group compared with placebo. Conversely, the disease or placebo only; and (5) outcome assessment: each study result from a randomized placebo-­ controlled trial including 606 must provide the effective or invalid number. The primary outcome newborns revealed that the prevalence of AD was no difference refers to effective/invalid numbers in the bacterial lysate and con- between the bacterial lysate and placebo groups after 3 years' trol groups individually. According to the guide for management and follow-­up. However, it was noted that a significant difference was prevention of asthma,14,15 asthma symptoms could be assessed as LI et al. | 1815 well controlled, partly controlled, or not controlled, by frequency of 3 | R E S U LT S asthma attack during the day, the efficiency of treatment, activity limitation, or night waking due to asthma. Partly controlled and well 3.1 | Study characteristics controlled were regarded as effective outcomes, and not controlled was defined as an invalid outcome. The effectiveness of treatment A total of 231 references were searched, and after three-­step selec- on dermatitis and rhinitis was assessed as improvement or no im- tion, 19 articles16–­34 were finally included, of which 15 studies16–­30 provement by questionnaire or clinical observation. Secondary out- were published in Chinese and four in English31–­34 (Figure 1). One comes included serum immunoglobulin levels (IgG, IgA, or IgM), or thousand seven hundred and twenty-­eight patients were recruited T lymphocyte subtypes (CD3+, CD4+, or CD8+). FEV1 levels or side in this study, of which 881 and 841 belonged to the bacterial lysate effects of treatment would be analyzed if mentioned by at least two treatment and control groups, respectively. Out of those 19 articles, articles. 17 studies used OM-­85 treatment as intervention therapy. The re- Trials were excluded if (1) the study design was not an RCT; maining two studies used polyvalent bacterial lysate (PBL) and killed (2) no primary outcome number was available; (3) bacterial ly- mycobacterium vaccae as their intervention treatment. Twelve RCTs sate and other treatments were administered to the experiment described results in asthma, four for dermatitis, and three for rhini- group while giving conventional treatment to the control group; tis. All 19 studies reported the number of symptom improvement. and (4) external use of bacterial lysate was applied rather than Five studies and six studies analyzed the level change of T-­cell sub- oral or injected. groups and interleukins, respectively. Two studies showed the level of serum immunoglobulin and four studies involved the change of FEV1. Only two studies reported the adverse events. Four RCTs 2.3 | Statistical analysis included adults, while the remaining 15 studies concerned children (Table 1). In the meta-­a nalysis of RCTs, dichotomous data were expressed as a relative ratio (RR) with 95% confidence intervals (CI). Continuous data were expressed as mean difference (MD) with 3.2 | Assessing the risk of bias in included studies 95% CI. Subgroup analysis was performed when at least two stud- ies were concerned. The I 2 statistic was used to assess heteroge- Randomization methods were reported in 19 studies. Results of neity. When I 2 was between 25% and 50%, it was regarded as low some studies were assessed by questionnaire, whereby the non-­ heterogeneity. Moderate heterogeneity and high heterogeneity blinding of outcome assessment may lead to overestimation of re- were reflected by I 2 between 50% and 75%, and 75% and 100%, sults. In addition, as bacterial lysate usually took at least 3 months 2 respectively. When I was below 25%, it was regarded as no het- to show its effect, some studies with shorter follow-­up times may erogeneity. All analyses were performed using StataMP-­6 4. The mask the real effect which leads to underestimated results. And, in risk of bias was also assessed by the Cochrane risk bias assess- some studies, the methodology was described in insufficient detail ment tool. to assess the risk of bias (Figure 2A,B). Records idenfied through Records idenfied through Chinese databases :PubMed, Embase, databases: WanFang, CNKI,CBM Cochrane (n=152) (n=127) Records aer duplicates removed (n=231) Records excluded with Records screen (n=231) tle and abstract (n= 159) Full-text arcles excluded with reasons: not related ,reviews ,not Full-text arcles assessed for eligibility randomly design, different outcome (n=72) no crude result number available (n =53 ) Studies included in qualitave synthesis (n =19 ) Studies included in quantave synthesis F I G U R E 1 The literature search and (meta-analysis) (n =19 ) selection process TA B L E 1 Characteristics of included studies 1816 | Intervention Publisher Study year Type T/C T C Followed Age (year) Endpoint Yang Xing 2017 Asthma 44/44 OM-­85 Budesonide Aerosol 21 days T:6.28 + 1.31 1, 2, 3, C:6.35 + 1.17 5, 6 Cao Jian 2016 Asthma 36/36 OM-­85 Terbutaline 10 days T:35.4 + 8.7 1, 4 C:39.9 + 10.4 Zhang Tian 2018 Asthma 48/47 OM-­85 placebo, 3 months T:6.2 ± 0.5 1, 3 routine therapies C:5.8 ± 0.7 Cheng Yang 2015 Asthma 67/54 OM-­85 Pulmicort Respules 21 days T:5.2 ± 2.2 1, 2, 3 C:5.4 ± 1.3 Yang F 2017 Asthma 43/43 OM-­85 Pulmicort Respules 3 weeks T:5.3 ± 2.06 1, 2 C:5.02 ± 1.82 Jiang Yuan 2012 Dermatitis 20/20 OM-­85 Loratadine tablets 3 months 3–­12 1 Jiang Yuan 2013 Dermatitis 46/45 OM-­85 Ebastine tablets 4 weeks T:40 ± 3 1, 6 C:39 ± 3 Su Huixia 2017 Asthma 65/65 OM-­85 placebo 12 months T:8.59 ± 1.38 1, 3 C:8.64 ± 1.40 Zhang Hua 2019 Asthma 44/44 OM-­85 Pulmicort Respules 1 month T:6.73 ± 0.82 1, 5 C:6.45 ± 0.74 Tang Yuqi 2017 Asthma 44/43 OM-­85 Dipropionate powder 4 months T:7.8 ± 2 1, 3, 5 inhalation Aerosol C:7.6 ± 1.9 Wu Huanting 2019 Asthma 49/49 OM-­85 Pulmicort Respules 3 months T:7.43 ± 2.62 1, 3 C:7.31 ± 2.71 Cai Jierong 2020 Asthma 37/37 OM-­85 Pulmicort Respules 6 months T:2.13 ± 0.46 1, 4 C:2.21 ± 0.57 Cai Weiwei 2019 Asthma 44/44 OM-­85 Laboratoire GlaxoSmithKline 3 months T:46.52 ± 3.2 1, 2, 5 C:47.62 ± 4.1 Hou Jie 2019 Asthma 45/45 OM-­85 Terbutaline 2 weeks T:7.72 ± 2.16 1, 2 C:7.13 ± 1.86 Xu Huai Yuan 2016 Dermatitis 72/72 OM-­85 Ebastine tablets 3 months T:13–­58 1 C:14–­61 Chen J 2017 Rhinitis 48/48 OM-­85 intranasal saline 3 months 4–­12 1 G. Banche 2006 Rhinitis 26/15 PMBL placebo treatment 3 months T:7–­76 1 C:5–­78 Berth-­Jones J 2006 Dermatitis 54/49 Killed mycobacterium vaccae Phosphate-­buffered saline 6 months 5–­16 1 Zagar S 1988 Rhinitis 29/22 OM-­85 placebo treatment 6 months T:6.52 ± 0.96 1 C:6.81 ± 0.80 Note: Endpoints: 1. Improvement of symptoms; 2. the level of T-­cell subgroup; 3. the level of interleukins; 4. the level of serum immunoglobulin; 5. the level of FEV1; 6. adverse event. LI et al. LI et al. | 1817 (A) (B) F I G U R E 2 (A) The summary of risk of bias. (B) Each risk of bias item for each included study 3.3 | Allergy symptom improvement 3.4 | Level of T-­cell subgroup A total of 19 RCTs reported improvement of allergic symptoms by After bacterial lysate treatment, the experimental group showed assessing symptom control. There were 881 patients in the bacte- significantly increased CD3+ (SMD = 1.47, 95% CI [1.2, 1.74]), rial lysate-­treated group and 847 children in the control group. As CD4+ (SMD = 1.57, 95% CI [1.33,1.81]), CD4/CD8 (SMD = 0.91, shown in Figure 3, allergic symptom improvement was 24% higher in 95% CI [0.67, 1.15]), and Th1 (SMD = 0.48, 95% CI [0.22, 0.74]) the bacterial lysate group than in the control group. Asthma symp- cells and significantly decreased CD8+ (SMD = −0.71, 95% CI tom control (RR: 1.22, 95% CI [1.14, 1.26]) was 22% higher in the [−0.95, −0.47]) and Th2 (SMD = −0.61, 95% CI [−0.88, −0.35]) cells bacterial lysate-­treated group compared with controls. In addition, (Figure 4). the effect size of dermatitis was 1.08 (95% CI 1.0–­1.17) which seems to be a small improvement. However, there are only four stud- ies concerned dermatitis treatment. None of the analyses reached 3.5 | Levels of interleukins statistical significance. Therefore, there was insufficient evidence to conclude that bacterial lysate treatment benefits for dermatitis This subgroup analysis showed (Figure 5) that after bacterial lysate patients. treatment, IFN-­γ (SMD = 1.0, 95% CI [0.81, 1.19]), IL-­2 (SMD = 1.07, On the other side, the total I2 was 68.7%, which was regarded as 95% CI [0.73, 1.4]), and IL-­12 (SMD = 2.4, 95% CI [2.04, 2.76]) were moderate heterogeneity. After subgroup analysis by disease type, significantly increased, while other factors such as IL-­4 (SMD = −0.87, moderate heterogeneity was found in rhinitis studies. Conversely, 95% CI [−1.07, −0.68]) and IL-­5 (SMD = −2.63, 95% CI [−3.14, −2.13]) lower heterogeneity was observed in asthma and dermatitis studies. were decreased. 1818 | LI et al. F I G U R E 3 The allergy symptom improvement rate in bacterial lysate and control group 3.6 | Level of serum immunoglobulin 3.8 | Adverse events The studies regarding IgA and IgM showed high heterogeneity-­and Only two RCTs reported the rate of adverse events. Dizziness, all used random-­effects models to analyze the data. After bacte- lethargy, nausea, and diarrhea were reported during treatment rial lysate treatment, IgA (SMD = 1.67, 95% CI [1.33, 2.01] and IgG in both groups, with the results showing that the adverse event (SMD = 1.00, 95% CI [0.69, 1.31]) were significantly increased, but rate was not significantly different in the bacterial lysate-­ there were no differences in IgM levels (SMD = 0.05, 95% CI [−0.25, treated group compared with controls (RR = 1.27, 95% CI [0.51, 0.36]) between the two groups (Figure 6). 3.09]). 3.7 | FEV1 3.9 | Funnel plot of study The studies regarding FEV1 showed no heterogeneity. The bacterial From the funnel plot (Figure 8), small-­study effect was evident in lysate treatment significantly improved the FEV1 (SMD = 0.53, 95% this study. CI [0.32, 0.74]) (Figure 7). There was small-­study effect in this study. LI et al. | 1819 F I G U R E 4 The level of T-­cell subgroup in bacterial lysate and control group 4 | DISCUSSION in dermatitis patients. Moreover, the levels of immunoglobulin (IgA and IgG) were higher in the treated group compared with This meta-­a nalysis based on 19 studies comparing bacterial lysate the control group. Bacterial lysate treatment improved the levels treatment with a control group showed a 24% improvement in al- of T lymphocyte subtypes (CD3+, CD4+, CD4+/CD8+, Th1) and lergy symptom control. Additionally, the improvement of asthma decreased CD8+ and Th2 T-­cell numbers. Similarly, the bacterial symptoms was 22% higher following bacterial lysate treatment, lysate also elevated the levels of IFN-­γ, IL-­2 , and IL-­12 while de- while rhinitis improvement was three times higher in the bacte- creasing the levels of IL-­4 and IL-­5. It was noted that the FEV1 rial lysate-­t reated group compared with controls. However, there also increased after bacterial lysate treatment, indicating im- was no difference between bacterial lysate and control groups proved lung function. 1820 | LI et al. F I G U R E 5 The change of IL-­4, IFN-­γ, IL-­5, IL-­2, IL-­12 in bacterial lysate and control group Some studies showed the ability of bacterial lysate to prevent exacerbations (mean difference −0.9 (−1.23–­0.57)).35 The result was respiratory tract infection and asthma exacerbations. One meta-­ similar to our study. analysis of OM-­85 in pediatric recurrent respiratory tract infections Two further meta-­analysis studies investigated the effect of OM-­ showed that OM-­85 could not only reduce the frequency of respi- 85 on respiratory infection36,37 and showed that bacterial lysate was ratory infections (MD = −2.22, 95% CI [−2.75, −1.90]) but also re- beneficial in the prevention of infection in children but presented no duce the duration of wheezing (MD = −3.37 days, 96% CI [−4.52, data regarding wheezing or allergic disease. Nevertheless, some re- −2.22]).13 The trends identified in the present study for IgA, IgG, CD3, searches proposed that the decrease in upper respiratory infection and CD4 were similar with this meta-­analysis. Another meta-­analysis may lead to the reduction in asthma exacerbations. included 5 studies showed the use of bacterial lysate decreased both The occurrence of allergic diseases is usually accompanied by an wheezing episodes (mean difference −2.35 (−3.03–­1.67)) and asthma imbalance of the immune system, with skewing away from Th1 and LI et al. | 1821 Study % ID SMD (95% CI) Weight IgA Cao jian (2016) 1.35 (0.90, 1.80) 57.82 caijierong (2020) 2.10 (1.58, 2.63) 42.18 Subtotal (I-squared = 78.3%, p = 0.032) 1.67 (1.33, 2.01) 100.00 IgM Cao jian (2016) 0.86 (0.44, 1.28) 51.66 caijierong (2020) -0.80 (-1.24, -0.37) 48.34 Subtotal (I-squared = 96.5%, p = 0.000) 0.05 (-0.25, 0.36) 100.00 IgG Cao jian (2016) 1.05 (0.62, 1.48) 51.32 caijierong (2020) 0.95 (0.51, 1.39) 48.68 Subtotal (I-squared = 0.0%, p = 0.738) 1.00 (0.69, 1.31) 100.00 -3 0 3 F I G U R E 6 The change of IgA, IgM, IgG in bacterial lysate and control group F I G U R E 7 The change of FEV1 in bacterial lysate and control group 1822 | LI et al. Funnel plot with pseudo 95% confidence limits 0 5 | CO N C LU S I O N Our study showed improvement of allergic disease symptoms when.2 bacterial lysate combined with routine treatment was administered. Standard error of RR However, because of some high-­risk bias and unclear methodolo-.4 gies, these results still require confirmation by high-­quality and large sample size studies in the future..6 AC K N OW L E D G M E N T.8 We thank Gillian Campbell, PhD, from Liwen Bianji, Edanz Group China, for editing the English text of a draft of this manuscript. 1 -2 -1 0 1 2 The Risk ratio of allergy symptoms improvement rate C O N FL I C T O F I N T E R E S T The authors declare no conflict of interests. F I G U R E 8 Funnel plot of studies AU T H O R C O N T R I B U T I O N S toward Th2. Therefore, many treatments are expected to increase Chengmei Li: Formal analysis (lead); Methodology (lead); Software (lead); levels of Th1 effectors and reduce Th2 to achieve an immune re- Writing-­original draft (lead). Hua Zhou: Conceptualization (equal). Wei sponse that is more Th1-­prone. Consistent with this, increased levels Zhang: Resources (equal). Datian Che: Supervision (lead). of Th1-­t ype cytokines (IFN-­γ and IL-­2) and decreased levels of Th2-­ type cytokines (IL-­4, IL-­5, IL-­10) were observed in our study. It could E T H I C A L A P P R OVA L be concluded that bacterial lysate regulates the immune response All analyses were based on previously published studies; thus, no by altering T-­cell subgroups and immune cells. This finding was con- ethical approval and patient consent are required. sistent with other studies8,38,39 which claimed that OM-­85 could induce an immune response shift from Th1/Th2 to Th1. The mech- PEER REVIEW anism by which bacterial lysates stimulate immune responses may The peer review history for this article is available at https://publo​ concern pathogen recognition receptor ligands containing common ns.com/publo​n/10.1111/pai.13572. motifs shared by pathogenic and commensal bacteria. Furthermore, the changes in gut microbiome diversity following oral administra- ORCID tion of bacterial lysates may contribute to immune interactions and Chengmei Li https://orcid.org/0000-0003-4677-1719 influence the immune response.40–­42 A major strength of our study is the identification of the effec- REFERENCES tive extent of bacterial lysate therapy on allergic diseases. As three 1. The National Cooperative Group on Childhood Asthma. Third na- allergic diseases (asthma, allergic rhinitis, and dermatitis) were in- tionwide survey of childhood asthma in urban areas of China. 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