Complementary and alternative medicine for treatment of atopic eczema in children under 14 years old: a systematic review and meta-analysis of randomized controlled trials

Background Due to limitations of conventional medicine for atopic eczema (AE), complementary and alternative medicine (CAM) is widely used as an alternative, maintaining, or simultaneous treatment for AE. We aimed to evaluate the beneficial and harmful effects of CAM for children with AE under 14 years old. Methods We searched for randomized trials on CAM in 12 Chinese and English databases from their inception to May 2018. We included children (< 14 years) diagnosed with AE, who received CAM therapy alone or combined with conventional medicine. We extracted data, and used the Cochrane “Risk of bias” tool to assess methodological quality. Effect was presented as relative risk (RR) or mean difference (MD) with 95% confidence interval (CI) using RevMan 5.3. Results Twenty-four randomized controlled trials involving 2233 children with AE were included. Methodological quality was of unclear or high risk of bias in general. The trials tested 5 different types of CAM therapies, including probiotics, diet, biofilm, borage oil, and swimming. Compared to placebo, probiotics showed improved effect for the SCORAD index (MD 9.01, 95% CI 7.12–10.90; n = 5). For symptoms and signs such as itching, skin lesions, CAM combined with usual care was more effective for symptom relief ≥95% (RR 1.47, 95% CI 1.30–1.68; n = 8), and for ≥50% symptoms improvement (RR 1.34, 1.25–1.45; n = 9) compared to usual care. There was no statistic significant difference between CAM and usual care on ≥95% improvement or ≥ 50% improvement of symptoms. However, swimming, diet and biofilm showed improvement of clinical symptoms compared with usual care. At follow-up of 8 weeks to 3 years, CAM alone or combined with usual care showed lower relapse rate (RR 0.38, 0.28–0.51, n = 2; RR 0.31, 0.24–0.40, n = 7; respectively) compared to usual care. Twelve out of 24 trials reported no occurrence of severe adverse events. Conclusions Low evidence demonstrates that some CAM modalities may improve symptoms of childhood AE and reduce relapse rate. Safety remains unclear due to insufficient reporting. Further well-designed randomized trials are needed to confirm the potential beneficial effect and to establish safety use. Electronic supplementary material The online version of this article (10.1186/s12906-018-2306-6) contains supplementary material, which is available to authorized users.


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Conclusions: Low evidence demonstrates that some CAM modalities may improve symptoms of childhood AE and reduce relapse rate. Safety remains unclear due to insufficient reporting. Further well-designed randomized trials are needed to confirm the potential beneficial effect and to establish safety use.
Keywords: Complementary and alternative medicine, CAM, Atopic eczema, Children, Randomized controlled trials, Systematic review, Meta-analysis, Clinical evidence Background Eczema, as defined by the World Allergy Organization, encompasses both atopic and non-atopic conditions, and is commonly referred to as atopic eczema (AE) or atopic dermatitis (AD) [1]. AE is a chronically relapsing inflammatory skin disease, often found in children under the age of 14 years. It impairs people's quality of life [2] and the prevalence of AE is estimated to be 15-20% in children worldwide [3]. As one of the most common inflammatory skin diseases, AE has a prevalence exceeding 10% of children in some populations [4]. There is an increasing number of studies focusing on AE, such as clinical trials and systematic reviews [5]. AE can be caused by multiple and complex risk factors such as irritants, contact allergens, food, inhaled allergens, stress or infection [6]. The pathogenesis of eczema is a complex interplay of numerous elements including immune, genetic, infection and neuroendocrine factors and their interaction with the environment [2]. Moreover, the diagnosis of AE relies on the assessment of clinical features because there is no definitive/conclusive test to diagnose the condition. The clinical characteristics are itching, skin inflammation, a skin barrier abnormality, and susceptibility to skin infection [7]. Although not always recognized by health-care professionals as being a serious medical condition, AE can have a significant negative impact on quality of life for children and their parents and care takers [8]. Children with AE may suffer from lack of sleep, irritability, daytime tiredness, emotional stress, lowered self-esteem and psychological disturbance [9]. Moreover, many cases of AE clear or improve during childhood, whereas others persist into adulthood [8]. Thus, there is a substantial need for cure and symptom relief as early as possible. However, despite the common claims for curative interventions, there is currently no known cure for AE in allopathic medicine [9].
Therefore, there is an increasing number of trials studying complementary and alternative medicine (CAM) to treat children with AE. There is a growing interest in CAM as a primary, maintenance, or simultaneous treatment for AE [10]. These studies suggest that CAM may improve health related quality of life of children. In fact, many people rely on these treatments as their primary approach to relieve their illness or at least to improve the duration and quality of symptomatic relief [10]. The most frequently used CAM modalities are herbal medicine, vitamins, Ayurveda, naturopathy, homeopathy, traditional healing [6], and probiotics [11]. However, current literature, published protocols and systematic reviews have not involved or included all kinds of CAM modalities. Moreover, we were not able to find any systematic review focusing on CAM with AE in children (< 14 years). Therefore, we conducted a comprehensive literature search involving CAM for AE in children (< 14 years) to add to current available evidence in order to inform clinical practice further.

Methods
The protocol of the review was registered in PROSPERO (CRD42017071267) on 7th of August 2017 (Available from: http://www.crd.york.ac.uk/PROSPERO/). The content of the review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [12].

Type of studies
Randomized controlled trials (RCTs) were included in the systematic review.

Type of participants
Children (< 14 years) diagnosed with AE by defined criteria or validated instruments or tools based on either the UK Working Party, Hanifin and Rajka (Hanifin 1980) or explicitly stated provider based diagnostic criteria [13] were included. Trials without clear diagnostic criteria but with detailed description of clinical features to be diagnosed as AE were also eligible for inclusion in a subgroup analysis. The limited age of < 14 years was set because of the maximum age as younger adolescents defined by WHO. No gender or ethnicity limitations were set.

Type of intervention
CAM modalities used alone or in combination with conventional therapies for children (< 14 years) were included. CAM terms have different concepts: If a non-mainstream practice is used together with conventional medicine, it's considered as "complementary". If a non-mainstream practice is used in place of conventional medicine, it is considered "alternative" [14]. Since a separate review on Traditional Chinese Medicine (TCM) for AE will be prepared due to clinical heterogeneity, we included the following CAM modalities: dietary advices/restriction, dietary supplements, probiotics, prebiotics, psychological interventions, oral evening primrose oil or borage oil, specific allergen immunotherapy, aromatherapy, bath therapy, bioresonance, chromotherapy, homeopathy, hypnotherapy and relaxation techniques in addition to some other CAM modalities that are known to be used for treating AE [10].
However, CAM is different from the new drug to estimate effectiveness, but to focus on its efficacy. So, it is sometimes difficult to to split CAM modalities up into parts to investigate effectiveness and safety of CAM modalities separately, except the placebo-controlled randomized trials [15]. Therefore, from the component level, CAM in the intervention group can be classified as above specific modalities such as probiotics, bath therapy, and so on. And from the system level, CAM can be considered as an integrated "whole system" of intervention.

Type of outcomes
Primary outcomes included clinical disease severity measured by one or more of the following instruments: (1) global improvement in objective AE outcomes as measured by scoring atopic dermatitis index (SCORAD); eczema area and severity index score (EASI); Nottingham eczema severity score (NESS) reported by a clinician; global improvement in subjective AE outcomes as measured by patient oriented eczema measure (POEM); itching visual analogue score (VAS); dermatology life quality index (DLQI) reported by participants or their parents. (2) Frequency of treatment discontinuation due to adverse effects. Secondary outcomes included (1) relapse rate; (2) proportion of participants with ≥50% symptoms and signs improvement in a given outcome as assessed by a clinician; (3) type, frequency, and severity of adverse events.

Search strategy
We conducted systematic literature searches in 12 electronic databases, including 4 Chinese databases (China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Scientific Journal Database (VIP), and SinoMed), and 8 English databases: PubMed, EMBASE via OVID, AMED (Allied and Complementary Medicine Database) via OVID, CINAHL (Cumulative Index to Nursing and Allied Health Literature) via EBSCO, Psy-choInfo, CAM-QUEST, the GREAT database (the Global Resource for Eczema Trials: www.Greatdatabase.org.uk), and the Cochrane Library from their inception date until May 2018. The filters were English and Chinese language (Additional file 1). We also searched in the grey literature such as conference proceedings and dissertations in CNKI and Wanfang for unpublished trials and trial protocols. References of all included studies were hand searched for additional eligible studies.

Study selection and data extraction
Two authors (CL Lu and SB Liang) independently examined the full text to identify the eligible trials. Four authors in pair (CL Lu, XH Liu, X Wang, and X Bai) extracted data independently from the included studies according to a predesigned data sheet. Any disagreement was resolved by discussion with a third author (JP Liu). Following items were extracted: publication year, study type, funding, inclusion/exclusion criteria, diagnostic criteria, study methodology, demographic characteristics of the participants, details of intervention and controls, outcome measures methods, adverse events, and results.

Quality assessment
Two authors (CL Lu and XH Liu) used the risk of bias tool [16] to assess the methodological quality of the included trials. Seven items including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias such as pharmaceutical funding, were used to be judged as "low risk", "high risk", or "unclear risk". Any disagreements were resolved by discussion with a third author (JP Liu).

Data analysis
We used RevMan 5.3 software for data analysis. For continuous data, we used mean difference (MD) with 95% confidence intervals (CI), and for dichotomous data we used relative risk (RR) with 95% CI. We performed meta-analyses for trials if the study design, participants, interventions, control, and outcome measures were similar. Bulk data were synthesized quantitatively by descriptive counting. Other data not suitable for pooling analysis were synthesized qualitatively.
We used I-square (I 2 ) to test the statistical heterogeneity as recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We considered I 2 statistic value greater than 50% as a suggestion that there might be substantial heterogeneity [16]. We used random effects model for data pooling with significant heterogeneity (I 2 ≥ 50%), otherwise a fixed effect model was applied. If the data were available, we did subgroup analyses for subcategories of CAM modalities.
A sensitivity analysis was conducted to explore the influence of the type of randomized trials (parallel or cross-over randomized) and the quality of trials (high or low) if the data were available. A funnel plot was generated to explore possible publication bias if more than ten trials were included in a meta-analysis.

Study characteristics
The details of the 24 trials are presented in Table 1. The sample size of these studies ranged from 15 to 298 participants. The age ranged from 2 months to 13 years. We defined the conventional therapy with more than two modalities (e.g. topical and systemic anti-allergic, and immunomodulatory therapy) as "usual care" in 24 trials [9]. Every trial had more than two modalities of conventional therapy except placebo. Therefore, from the component level, CAM modalities of 22 trials [21, in the intervention group could be classified as   Table 2). Moreover, two trials [20,22] had their main modality referring to swimming and biofilm while accompanying other modalities. So, we considered for three different comparisons in the two-arm trials from system level: CAM versus usual care [20][21][22], CAM plus usual care versus usual care [23][24][25][26][27][28][29][30][31][32], and CAM (probiotics) versus placebo [33][34][35][36][37][38][39][40][41]. For the two trials with three or more arms [42,43], probiotics was compared with other formula of probiotics, placebo, usual care, or observation with no intervention.

Risk of bias of included trials
The trials only reporting that the study was "randomized" were defined as "unclear" risk of bias, while the trials describing a specific method of randomized sequences generation, allocation concealment, and blinding as "low" risk of bias. Other bias accessed the funding scheme. Trials supported by non-commercial funding were defined as "low" risk of bias, trials funded by pharmaceutical companies were classified as "high" risk of bias, no information as "unclear" risk of bias. Eight trials [22,24,29,31,33,34,37,41] reported the random allocation by random number table or computer generated-list. Only five trials [33,34,37,38,40,41] reported the allocation concealment by using computer-generated random numbers or randomization software, which can conceal the allocation automatically. Ten trials [33,34,[36][37][38][39][40][41][42][43] reported double blinding. Eight trials [33-37, 39, 41, 43] reported the drop out in both intervention group and control group, and only four trials [33,39,41,43] used intention-to-treat (ITT) to analyze for all outcome [33,39,41] and primary outcome [43], and the other four trials [34][35][36][37] analyzed data by per-protocol (PP) and reported the data of available participants. Besides, two trials [39,41] analyzed by both ITT and PP. We considered one trial [34] as high risk of incomplete data for loss to follow up without ITT analysis because of 13 withdrawals in intervention group and 16 withdrawals in control group among the 100 participants in the trial. Four trials [33,39,41,43] were considered as low risk of bias and the others as unclear. Eleven trials [21,25,29,33,[35][36][37][40][41][42][43] mentioned non-commercial funding. Three trials [33,39,43] reported that probiotic manufacturers produced the drugs used. We considered these three trials [33,39,43] as high risk of bias for conflict of interest (Fig. 2). Sample size calculation was reported in five trials [33,35,37,41,43] according to disease prevalence [33], symptoms and signs reduction in treatment group by 30% [34,41], 34% [37] and in placebo group by 15% [34], 17% [37], 10% [41], and symptoms and signs scale of SCORAD for a standard deviation increments of 7.65 [43]. The other trials did not report any detail of sample size calculation. We considered the other bias of power calculation as unclear.
Apart from statistical heterogeneity, the interventions in three trials [20][21][22] were totally different, including swimming [20], diet [21], biofilm [22], and one trial [20] investigated swimming in combination with Chinese herbal medicine lotion and tuina (Chinese massage for children). We conducted a qualitative description on these three trials. One trial [20] tested swimming, Chinese herbal medicine lotion and tuina compared to usual care. The intervention group showed more symptom reduction than the control group, however, not at a significant level. One trial [21] compared fasting and rotation diet with Pevisone paste, and reported beneficial effects of diet on symptom improvement. Another trial [22] showed statistically significant effects of Velvetfeeling Lotion (biofilm) on symptom improvement when compared with usual care.

Adverse events
Only 12 trials (50%) [20, 22, 24, 25, 29, 30, 32, 35-37, 39, 43] reported the outcome of adverse events. Among these, four trials [27,29,35,36] reported no occurrence of adverse events in either groups, and one trial [39] reported no relation between adverse events and the tested product without any details about adverse events, while seven trials [20,22,24,30,32,37,43] reported that children (< 14 years) with adverse events gradually adapted to treatments without extra treatment or that the adverse events was not related to the medications under investigation (Table 4). No severe adverse event such as death or hospitalization were reported. The reported adverse events included crying, irritability, and worsening of skin lesions (reddening) ( Table 4).

Additional analysis
Since the fact that each comparison did not include more than 10 trials, we were not able to conduct meaningful funnel plot analysis in order to identify the publication bias. Due to the same quality and the type of randomized trials, we could not conduct sensitivity analysis in this aspect. Besides, significant heterogeneity in two outcomes with two comparisons was more than 50% (I 2 ≥ 50%), so we conducted a subgroup meta-analysis or a meaningful sensitivity analysis.

Summary of findings
This review identified 24 RCTs involving 2233 children (< 14 years) with AE. The findings suggest that some of the CAM modalities used alone or in combination with usual care may relieve the symptoms and signs of AE with ≥95% and ≥ 50% improvement, such as itchiness, skin lesions, swelling, and papula, in addition to reduce relapse of eczema. Moreover, some CAM modalities (such as probiotics) showed significant effect compared with placebo. The evaluated modalities appear to be safe and tolerated for lower relapse rate in CAM modality group. In spite of unclear pathogenesis of AE, CAM modalities may reduce symptoms and signs, and relapse of AE compared to conventional therapies.
The majority of trials had unclear risk of bias in many domains such as allocation concealment, blinding, missing data, and sample size calculation. Due to the unclear risk of bias of included trials, we could not come to firm   Without any treatment, to ease soon and symptoms disappearance.
T treatment group, NR not report conclusions from the evidence of the included trials in this review.

Comparison with previous studies
By searching the Cochrane Library with "AE", "AD", and "CAM", there are 19 Cochrane reviews and 11 other reviews published, and after scanning, 9 reviews [13,[44][45][46][47][48][49][50][51] with CAM related to children (< 14 years) for treating or preventing. These reviews or protocols included both children and adults, and even pregnant women to prevent, cure and explore the pathogenesis of AE. We found only one protocol [44] similar to our review, but was withdrawn as the author gave up the title "Complementary and alternative medicine treatments for AE". In addition, the previous studies did not exclude the allergic diseases (such as asthma, and intestinal diseases) to focus on AE. Our review included children (< 14 years) suffering only from AE. Moreover, most reviews investigated the specific treatment like probiotics, based on pathological mechanisms but ignoring the complex and unclear pathogenesis of AE. The findings of our review are based on the symptom relief of AE and we included more comprehensive trials involving CAM for children (< 14 years).

Strengths and limitations
Although great effort was made to retrieve all trials, we still cannot confirm that we were able to cover all the evidence due to non identified unpublished data. Besides, selecting and extracting data may also lead to some bias. We included only children under the age of 14 as this is the maximum age as younger adolescents defined by WHO, which may exclude some studies due to unavailable data for their participants over the age of 14 years. In addition, due to the various treatment for AE with an integrated "whole system" of care approach, we considered the control group with usual care as the system effect. The intervention group with CAM for a specific modality as the component efficacy, which cannot be used to document or disprove the effectiveness of a "whole system" treatment approach [15]. Additionally, in terms of the statistical heterogeneity and the variability in the CAM modalities, we were not able to conduct a subgroup meta-analysis, meaningful sensitivity analysis and funnel plot analysis. These factors limit the conclusiveness and robustness of this systematic review.

Implications for research
In fact of the limitations of this review, future trials should be designed as multi-center, double-blind placebo controlled trials with sufficient power, and reported according to the CONSORT (Consolidated Standards for Reporting Trials) Statement [52]. In addition, trials should record the relapse with sufficient length of follow-up. Besides, it is important to provide the definite safe treatments to the patients. Thus, adverse events in each group should be reported respectively so that we could retrospect the reason of different modalities and be easy to estimate the safety of CAM modalities.

Conclusion
Based on evidence from this systematic review we found some promising effect of CAM modalities on reducing symptoms and signs, and relapse of AE. However, it is still premature to recommend the therapy in clinical practice due to the limited number of trials and general low methodological quality of the included trials. Further rigorously double-blind, placebo-controlled trials are warranted to confirm efficacy of the CAM modalities for AE.