Phytotherapy in paediatric skin disorders – A systematic literature review

A B S T R A C T Objectives: Although skin disorders in children and adolescents are increasingly treated with phytotherapies in practice, there are very few studies investigating this topic, and no systematic review exists that summarizes the current state of research. This review examines which herbal medicines show to be effective to treat atopic dermatitis, diaper dermatitis, and skin lesions or wounds. Methods: Clinical studies were searched according to PRISMA-guidelines in the medical databases of PubMed, EMBASE, and CINAHL and summarised in a systematic review. Results: Among the 429 articles screened, 17 studies with a total of 2358 participants were identified that suited our inclusion criteria. Thereof seven studies each on the treatment of atopic dermatitis and skin lesions or wounds and three on diaper dermatitis. The phytotherapeutics investigated were based on the following herbs: Evening primrose, blackcurrant, polypodium leucotomos, calendula, aloe vera, chamomile, comfrey, hamamelis, olive, hypericum, neem, white oak, and myrrh. They have mainly been analysed in randomized controlled trials, but also in (long-term) observational studies, prospective trials and case series. Conclusions: Based on the application of the Jadad score, eight out of 17 of the studies examined were of low quality. Yet we found some indication that evening primrose oil may be effective for treating atopic dermatitis in children, while comfrey appears to have a positive effect on wound healing. Interestingly, none of the studies found positive effects for treating skin disorders with aloe vera or chamomile.


Background
Skin disorders, like atopic dermatitis, diaper dermatitis, and skin wounds, are common in children and adolescents. 1For atopic dermatitis, the prevalence in children is estimated at 20%, while diaper dermatitis affects about 25% of all children below the age of three. 2 Skin disorders are known to not only affect the physical state of children and adolescents, but they also impact their behaviour and emotion regulation. 3,4Although skin disorders in early childhood and adolescence usually do not influence life expectancy, they can still cause a considerable amount of distress for both children and parents in everyday life. 5his is especially true since the management of skin disorders in children and adolescents, especially atopic dermatitis, can be challenging, and many parents of affected children feel worried related to uncertainties about medication use and available treatment options. 5][8] A high prevalence of complementary and alternative medicine (CAM) use can be observed among children suffering from skin disorders. 9Research shows that over 50% of parents favour CAM products, such as herbal medicine or phytotherapy, in the belief that they are natural and therefore safe. 9Although favoured by many parents, there are only a few studies on the use of herbal medicine (phytotherapy) in children.There are some studies on the use of phytotherapy in adults, but there are only a few studies that provide detailed information on the application of herbal medicines for skin diseases in children. 9However, this research subject is of great importance because there are some specific diseases that mainly affect children, such as diaper dermatitis.This review aims to systematically summarize the available literature on the effectiveness and safety of phytotherapy for skin disorders in children and adolescents and attempts to highlight the gap in the current state of research.

Eligibility criteria 2.1.1. Study selection
For this review, all types of clinical studies were included.Reviews, meta-analyses, case reports, and case series with less than five participants were excluded.Studies were only selected if they were peerreviewed and published as full articles, written in English or German.

Selection of participants
Children and adolescents (aged 0-18) diagnosed with any kind of skin disorder were included.Studies which reported results on both children and adults were excluded.

Types of intervention
Studies that compared herbal medicines with no treatment, placebo, or any pharmaceutical medication, as well as case reports with more than 5 participants, were eligible.Studies were only included if the herbal drug was listed by the European Medicines Agency as an herbal drug to treat skin diseases or wounds.Furthermore, any type of medical outcome, at any type of measurement time was considered.

Search methods
PubMed, EMBASE, and CINAHL were searched by the two first authors from their inception to July 27, 2020.The review was not registered in any database.
The search strategy was constructed around the following search terms: "phytotherapy," "skin disorders," and "injuries," as well as their synonyms, such as "herbal medicine" and "wound healing".In a first step, titles were screened for eligibility, and selected studies were then judged by the abstract.The full text was assessed if inclusion criteria were met.The complete search strategy is depicted in Table 1.

Data extraction and management
Data was extracted independently by the two first authors.For each of the three disorders identified (atopic dermatitis, wound healing, and diaper dermatitis), a separate outcome-table was created.The data extracted involved the following: Year, study design, population, therapeutic agent, intervention, control, measurement, outcome and results of all studies on all three disorders.

Risk of bias assessment
Each study was judged using the Jadad-score. 10The assessment was carried out separately by the two first authors, then compared and in case of disagreement discussed.Criteria rated were randomization, blinding, and patient number.Only nine out of 17 studies reached three or more points.

Literature search
The literature search in PubMed, EMBASE, and CINAHL resulted in 418 hits for the search term mentioned above.Of these, six studies were read as full text and all of them were included in the review.By scanning through their list of literature, 11 more studies could be identified.In total, 17 studies were included in the review.

Studies included
We explicitly searched for studies that investigated the treatment of any kind of skin disease with phytotherapy.However, we only found studies focusing on the following three skin disorders in children: atopic dermatitis, diaper dermatitis, and wound healing.For this reason, we grouped the included studies into these three categories.
Detailed information on the studies, such as study design, intervention, and measurements can be found in Table 2.

Atopic dermatitis (AD)
Seven studies, namely Bordoni et al., 11 Biagi et al., 12 Hederos et al., 13 Chung et al., 14 Giordano et al., 15 Linnamaa et al., 16 and Ramirez-Bosca et al., 17 analysed the treatment of atopic dermatitis with phytotherapy in a total of 630 children, aged from 0 to 17 years.The studies were carried out in Italy, Sweden, South Korea, France, Finland, and Spain.Six studies were randomized controlled clinical trials, only one (Biagi  et  The remaining publications did not mention their diagnostic criteria for AD.To test if there was any improvement regarding AD as compared to no treatment, the placebo, or the control group, the publications used the SCORAD score, EASI score, or a visual analogue scale as comparators.Regarding the Jadad-score only four out of the 7 studies reached three or more points. The first five studies ( Bordoni et al. analysed whether an improvement in the symptoms of atopic dermatitis could be achieved by taking evening primrose oil capsules in addition to standard therapy, such as emollients or weak topical steroids.The results were compared to a placebo-treated group and showed that evening primrose oil indeed substantially improved the clinical symptoms of atopic eczema in two-thirds of the treated children after four weeks of therapy. 11he dosage of the evening primrose capsules and the treatment concept of Biagi et al. were identical to those of Bordoni et al.However, Biagi et al. was not a controlled study but a long-term observation over 20 weeks to assess effectiveness and safety of evening primrose capsules.The results after 4 weeks were almost identical to those of Bordoni et al., namely that the use of evening primrose capsules substantially improved the clinical symptoms of atopic eczema in two-thirds of the treated children after four weeks of therapy.However, after 20 weeks of therapy, no further significant improvement was detectable in the comparison of clinical status between 4 and 20 weeks of treatment. 12ederos et al. conducted a double-blind, placebo controlled, parallel group study with 58 children with a 16-weeks treatment period with either evening primrose oil or placebo capsules.All participants were allowed to continue using their standard therapy, such as steroids or antihistamines.Overall, the symptoms of atopic dermatitis improved during the treatment period of 16 weeks; the study showed no clinical differences between active and placebo treatment. 13hung et al. investigated whether a possible effect of evening primrose oil capsules is dose-related by treating participants with atopic dermatitis with two different dosages.Forty AD patients were randomly divided into two groups.One group received evening primrose oil 160 mg daily for 8 weeks, while the other received 320 mg of evening primrose oil twice a day for 8 weeks.The patients were not allowed to use other drugs such as topical steroids or emollients during the period of treatment.Symptoms improved in both groups after 8 weeks, but only the results of the patients who received a higher dosage were significant. 14mpared to the other studies investigating AD, Giordano et al. administered evening primrose extract in an emollient.Patients were not allowed to use other emollients as therapy, but they were allowed to use dermocorticoids during the study period.Results of this study showed that in AD patients, xerosis and pruritus were significantly improved by a twice-daily application of the emollient, compared to the control group, which solely used dermocorticoids. 15innamaa et al. examined if blackcurrant seed oil processed into capsules has a protective effect on the occurrence of atopic dermatitis and if it has the potential to be used preventively.Three hundred and thirteen pregnant mothers were randomly assigned to receive blackcurrant seed oil capsules or olive oil as a placebo.The first doses were administered at 8-16 weeks of pregnancy and were continued until the cessation of breastfeeding, followed by feeding it to the children until the age of 2 years.Atopic dermatitis and its severity were evaluated with the SCORAD index, and skin tests were performed at the ages of 3, 12, and 24 months.According to SCORAD, atopic dermatitis was less severe in the actively treated group when compared with the placebo group at the age of 12 months (33.0% vs. 47.3%,P = 0.035).SCORAD was also lower in the BCSO group than in the olive oil group at 12 months of age (P = 0.035).No significant differences were observed in the prevalence of atopic dermatitis between the two groups at the age of 24 months (P = 0.18). 16amirez-Bosca et al. investigated whether the administration of orally taken Polypodium leucotomos (PL) extract would lead to a reduction in the use of topical corticosteroids and antihistamines for treating moderate atopic dermatitis.The results of their randomized, double-blind study showed that Polypodium leucotomos extract did not significantly reduce the mean percentage of days on which topical corticosteroids were used (11% [12%] vs 12% [11%] for placebo).However, a significant reduction for oral antihistamine use was observed (median percentage of days, 4.5% in the Polypodium leucotomos group and 13.6% in the placebo group [P = 0.038]). 17ll seven studies investigated safety and tolerance of the active substances.Neither the treatment with evening primrose oil nor the treatment with blackcurrant seed oil, or polypodium leucotomos, caused any serious side effects.

Diaper dermatitis
Three studies (Adib-Hajbaghery et al., 18 Panahi et al., 19 and Badelbuu et al. 20 ) analysed the treatment of diaper dermatitis with phytotherapy in a total of 215 children, aged from 0 to 3 years.All three studies were conducted in Iran, and all of them were randomized-controlled, double-blind trials.Diaper dermatitis was diagnosed either in the hospital or by a paediatrician or general practitioner.The researchers investigated the impact of calendula, aloe vera, and chamomile in the treatment of diaper dermatitis.To evaluate the severity of complaints before and after treatment, a checklist and a 0-4 visual analogue scale were used.Regarding the Jadad-score all three studies reached three or more points.
Adib-Hajbaghery et al. compared the therapeutic effect of two different creams, one containing calendula and one containing bentonite for the treatment of diaper dermatitis.The findings of the study showed that the onset of improvement in the first six hours was significantly higher in the bentonite group than in the calendula group.Also, the total improvement in the first three days was significantly higher in the bentonite group. 18anahi et al. compared the therapeutic efficacy of topical aloe vera and calendula officinalis on diaper dermatitis in children.Although the severity of diaper dermatitis was significantly decreased in both groups by the end of the trial, the reduction rate was found to be significantly greater in the group treated with calendula officinalis. 19he third study by Badelbuu et al. again compared the effect of two different ointments-one containing chamomile, the other one aloe vera-to each other and also to routine treatment.According to the results, there was an improvement in the severity of dermatitis during        the six-day study in all three groups, but no group was superior to another. 20n all three studies, the treatments were described as safe without describing the process of side effect assessment in more detail.

Wound healing
Seven studies (Grünwald et al., 21 , Barna et al., 22 , Kucera et al., 23 Wolff et al., 24 , Kiechel-Kohlendorfer et al., 25 Flurry et al. 26 and Mainetti et al. 27 ) analysed the effect of phytotherapy in treating blunt trauma and wounds on a total of 1513 children, aged from 25 weeks of gestation to 11 years.The studies were carried out in Germany, Czech republic, Austria, USA, and Bolivia.Among them were randomized controlled trials, open, non-interventional prospective trials, observational studies, and case series.
The studies investigated the impact of comfrey cream, hamamelis ointment, olive oil cream, hypericum and neem oil, as well as burn and wound ointment containing aloe vera, comfrey, white oak bark, and myrrh on wound healing.Regarding the Jadad-score only two out of the 7 studies reached three or more points.
Grünwald et al. examined the influence of traumaplant cream containing comfrey on wound healing.According to the results, comfrey can be regarded as a good and safe therapeutic option for the treatment of blunt traumas like strains, contusions or sprains in children, since the effect of the comfrey cream was judged by over 80% of parents and doctors to be good or very good. 21arna et al. examined the effect of a cream containing comfrey on the wound healing in children.The control group received a cream containing 1% of the active agent instead of no treatment or a placebo due to ethical concerns, while the intervention group received a cream containing 10% of the active agent.The collected data shows an acceleration of the wound healing process for the intervention group and the effect was found to be good or very good in over 90%. 22ucera et al. investigated the safety and tolerance of a comfrey cream as well.Their results support the findings of Barna et al., in that comfrey seems to be effective in the treatment of intact or broken skin in children. 23In all three studies that focused on comfrey, possible side effects were investigated, but none were found.
Wolff et al. compared the effect of hamamelis ointment to dexpanthenol ointment for the following skin diseases in children: minor skin injuries, diaper dermatitis, and localized inflammation of skin or mucous membranes.The results showed that the effect of both treatments was similar, by leading to clinically relevant and significant improvements in the conditions. 24The researchers also investigated safety and tolerance and found hamamelis to be safe for application in children.
Kiechl-Kohlendorfer et al. treated 173 neonates between 25 and 36 weeks of gestational age admitted to a neonatal intensive care unit.Infants were randomly assigned to daily topical treatment with water-inoil emollient cream ("Bepanthen"), olive oil cream (70% lanoline, 30% olive oil), or to a control group (no treatment).Each neonate was continuously treated for a maximum of four weeks.Skin condition (skin score reflecting degree of dermatitis) in the three groups was compared at weeks 1, 2, 3, and 4. Findings revealed that neonates treated with olive oil cream showed statistically less dermatitis than did neonates treated with emollient cream, and both had a better outcome than neonates in the control group (p < 0.001 in weeks 2-4). 25lurry et al. studied an ointment called "Burn & Wound ointment" used by the Amish.It contains, among others, honey, aloe vera, comfrey, white oak bark, and myrrh.The treatment also included the application of burdock leaves.Since this explorative study was a non-controlled case series with only five children, no general statements can be made about the effectiveness of the treatment.Results showed that the treatment had no harmful side effects.In the conclusion, it was stated that supervised applications of these wound dressings could allow healthcare providers to ensure a low-cost treatment and to foster trust with members of the Amish community. 26ainetti et al. examined the impact of hypericum and neem oil called "1 Primary Wound Dressing" on the time of complete wound healing and the extent of pain in burnt soft tissue.As this study was a case series, no conclusive statements can be made about treatment effectiveness.However, the results of the nine children examined suggest that the plant-derived wound spray "1 Primary Wound Dressing" is potentially effective in treating burnt soft tissue. 27

Summary of evidence
This systematic review aimed to examine the efficacy of herbal medicines for children affected by skin disorders, such as atopic dermatitis, diaper dermatitis, or skin wounds.
In total, 17 studies were included, seven each examined atopic dermatitis or wound healing, three investigated diaper dermatitis.For the treatment of atopic dermatitis, evening primrose capsules were found to be the most safe and effective phytotherapeutical treatment, based on the evidence of one double-blind randomized and placebocontrolled trial, 11 one randomized trial investigating dose-dependent effects, 14 and one longitudinal observation study over 20 weeks.Interestingly, the study of Hederos et al. 13 could not replicate the positive effect of evening primrose capsules as seen in the other studies, although the same dosage of evening primrose capsules was used.Likewise, the extract of polypodium leucotomos was found to be safe and effective in treating atopic dermatitis. 17However, as this is the only study that exists on polypodium leucotomos that was eligible for this review, the positive results await replication by further studies.The prevention of atopic dermatitis with blackcurrant seed oil did not provide clear evidence. 16ontrary to atopic dermatitis, no clear recommendation can be provided for the best phytotherapeutical treatment of diaper dermatitis in young children.Findings of Kiechl-Kohlendorfer et al. revealed that neonates treated with olive oil cream showed statistically less dermatitis; however, the results of this controlled clinical trial would benefit from replication. 25Panahi et al. 19 also found that calendula has a significant impact on the symptoms of diaper dermatitis, however, Adib-Hajbaghery et al. 18 disproved this results in their study.For Aloe vera and chamomile, none of the publications found significant results.To accelerate wound healing in children, comfrey was found to be effective and safe in both a randomized controlled trial by Barna et al.,  as well as in an open, non-interventional, prospective trial with children by Kucera et al. 23 A third study, by Grünwald et al., 21 investigated comfrey for treating internal injuries, and showed positive results for it as well.In all studies, comfrey-based treatments showed no or only mild side effects.Finally, the use of hamamelis ointment was found to be effective in the treatment of minor skin injuries, local inflammation and diaper dermatitis. 24Since the results await replication, no final conclusions can be made on this agent.

Limitations
We searched for studies that investigated the treatment of any kind of skin disease in children by phytotherapy.However, we only found studies on the following three skin disorders that met our inclusion criteria: atopic dermatitis, diaper dermatitis, and wound healing.The children affected by these disorders had typically already been treated with standard therapies before the studies started.In some studies, this initial treatment was continued during the trial, and it was not always clarified what kind of drugs the standard therapy was composed of.Therefore, it remains unclear what confounding effects the initial treatments might have had on the final study outcomes.
Moreover, the length of the treatment period in the studies varied greatly depending on the disorder.For disorders requiring a longer treatment period, such as atopic dermatitis, all studies were designed for at least four weeks, so that long-term effects could be observed.For disorders requiring shorter treatment periods, such as diaper dermatitis, the studies lasted for a maximum of ten days, which renders comparisons difficult.Furthermore, all examined phytotherapeutics were classified as low-risk treatments, even if recordings of side effects/adverse events were not provided.
Our quality rating showed that most of the included studies were of poor quality, with only nine out of 17 studies reaching three or more points on the Jadad-score.
Another limitation results from the data collected on the populations in each study.For the studies, children with skin diseases in Asian, European, North, and South American countries were examined.Based on the origin of the cited studies, it only can be assumed, that BIPoC were included in the studies.However, the studies did not provide detailed information.Future studies, that provide detailed information on effectiveness, safety, and dosage of herbal medicine to treat skin diseases in the form of randomized controlled trials will be of great importance.

Conclusion
Based on the application of the Jadad score, eight out of 17 of the studies examined were of low quality.Yet we found some indication that evening primrose oil processed in capsules may be effective for the treatment of atopic dermatitis in children.To accelerate wound healing in children, comfrey processed in an ointment appears to have a positive effect.Since no or only mild side effects have been reported, both primrose oil capsules and treatments containing comfrey can be considered as low-risk treatment for skin disorders in children and adolescents.For Aloe vera and chamomile, none of the studies found positive results.
al.) was a longitudinal observation study.In the studies of Hederos et al., Chung et al., and Ramirez-Bosca et al., the diagnosis of AD was based on the Hanifin-Rajka diagnostic criteria for atopic dermatitis.

Table 1
Prisma-flowchart of study selection.
Bordoni et al., Biagi et al., Hederos et al., Chung et al., Giordano et al.) focused on the effect of evening primrose oil, taken as capsules or applied as an emollient to relieve the symptoms of atopic dermatitis.The remaining two studies (Linnamaa et al. and Ramirez-Bosca et al.) examined the effect of blackcurrant seed oil and Polypodium leucotomos.

Table 2
Characteristics of the studies included for the systematic literature review "Phytotherapy in paediatric skin disorders".
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