Efficacy of Oral Supplementation of Probiotics in Children With Atopic Dermatitis
Condition: Atopic Dermatitis
MeSH terms: Dermatitis, Atopic; Dermatitis; Eczema
Study type: Interventional

Summary: 
      Various clinical studies have evaluated the role of probiotics in children with atopic
      dermatitis, with some studies showing improvement in clinical outcome after supplementation
      of probiotics and others showing no additional benefit. This study is to provide clinical
      evidence of effect of a mixture of probiotics in Atopic Dermatitis (AD) patients based on
      improvement in SCORAD (SCORing Atopic Dermatitis) index.
    

Detailed description: 
      Atopic dermatitis (AD) is the common chronic inflammatory skin disease with relapsing courses
      that often start in infancy and childhood. It is characterized by erythema, itchy papules,
      occasionally vesicles (in infants), which may become excoriated and lichenified and have a
      typical flexural distribution. Atopy is defined as a "personal or familial tendency to
      produce immunoglobulin antibodies in response to even low doses of allergen, and associated
      with development of AD, asthma and rhinoconjunctivitis.The worldwide prevalence of AD is
      estimated to be 20% in children and 2-10% in adults. The incidence of AD has increased by 2
      to 3 folds in past 3 decades in the industrialized countries and represents a major public
      health burden. According to the International Study of Asthma and Allergies in Childhood
      (ISAAC) phase 3, the prevalence of AD among the age group of 13 to 14 in Africa and Latin
      America was at 12-14% and 6-10% respectively. The Asian Pacific countries, the Eastern
      Mediterranean region and the Indian subcontinent, it was 3-6% among the same age groups
      (13-14 years). Whereas among 6 to 7 years children, for Asian Pacific countries, Africa and
      Latin America the prevalence of AD was around 10% and in Indian subcontinent and Eastern
      Mediterranean region, value was lower at 3-5%

      In Nepal the frequency of AD in all age group was 2% as per a year hospital based study done
      by Singh S and Agrawal S et.al in 2012. (Unpublished data, on personal communication)

      The pathogenesis of AD appears to result from interaction between various genetic and
      environmental factors. It is associated with skin barrier dysfunction and immune
      dysregulation. The barrier dysfunction is early feature of AD which may be a primary but may
      also be a secondary to skin inflammation. Lack of exposure to microbial stimuli in early life
      programs the immune system towards Th2-type allergic response as described by 'hygiene
      hypothesis'.In allergic disorders there is shift of the Th1/Th2 cytokine balance towards a
      Th2 response, and causes the release of Interleukin-4, interleukin-5 and interleukin-13 as
      well as Immunoglobulin E production.

      The diagnosis of AD is mainly clinical as there is no specific test for AD. Diagnosis of AD
      is based on specific a criterion which includes patient's history, clinical presentations as
      well as family history. In 1980 Hanifin and Rajka proposed major and minor diagnostic
      criteria based on clinical symptoms of AD. Williams coordinated a UK working party to attempt
      to simplify and refine the criteria given by Hanifin and Rajka in 1994. Severity of disease
      is evaluated by using widely accepted SCORing Atopic Dermatitis (SCORAD), based on extent of
      area involved, severity of symptoms and intensity of the subjective symptoms of pruritus and
      sleep disturbances.The chronic and recurrent nature of AD negatively impacts the quality of
      life (QOL) of patients as well as their family members. The symptoms of AD limit patient's
      physical, psychosocial development and quality of sleep.

      The main goals of treatment are to improve the skin barrier function and hydration, to
      suppress inflammation and to control microbial colonization. It can be achieved through
      emollients, topical corticosteroids and topical calcineurin inhibitor like tacrolimus. Oral
      drugs like corticosteroids, methotrexate and cyclosporine are reserved for severe cases.

      Probiotics are defined by World Health Orgnization as "live microorganisms, which when
      consumed in adequate amounts, confer a health effect on the host."Under the hypothesis that
      probiotics have global allergy protective effect, they have been extensively used for several
      conditions like inflammatory bowel disease, bronchial asthma and other allergic diseases. If
      children who are genetically predisposed to AD are supplemented with probiotics early in
      their life, series of events like antigenic competition, immune regulation and stimulation of
      innate immunity will occur, all of which might minimize their susceptibility to allergic
      disorders. Hence, investigators planned this study to see its role in AD.

      Statement of problem and rationale:

      The rationale for this therapeutic option is based on well-established effects of bacteria on
      cellular immune responses. The probiotics has an immunomodulatory property that plays an
      essential role in the development of normal immune tolerance. Early life exposure to these
      microbial agents plays an important role in maturation of Type 1 helper cell (Th1) immune
      responses and could inhibit development of allergic Type 2 helper cell (Th2) responses and
      IgE antibody production. Therefore the onset of AD could be prevented by probiotics and this
      treatment strategy could also be effective even when AD is already established.

      In a meta-analysis conducted in 2017, involving 13 randomized controlled trials (RCT) with
      1,070 children, significant difference in SCORAD values favoring probiotics over the control
      group was observed. Though, a high degree of heterogeneity was observed across these 13
      trials.

      Cochrane review, 2018 which included 39 RCTs found that probiotic treatment may slightly
      reduce SCORAD value. However the researcher concluded that the differences were not
      clinically significant. Recent review in 2019 on "prebiotics and probiotics in atopic
      dermatitis" based on various RCT and meta-analysis support the supplementation of probiotics
      for at least 8 weeks in improving severity score of AD.

      Investigators have observed conflicting results of different studies with some showing
      significant advantages while some studies revealing no benefit. Almost all of the studies
      have suggested further research in different populations. Therefore, we are conducting this
      study to find out the effect of probiotics in AD in our institute.

      OBJECTIVES

        1. Primary objective: To investigate the efficacy of oral probiotics in the clinical
           outcome of Atopic dermatitis based on the SCORAD index

        2. Secondary objectives: To find out the total duration of topical corticosteroid use in
           the interventional and conventional group.

      To assess the impact of AD in children's family members based on FDLQI (Family Dermatology
      Life Quality Index)

      MATERIALS AND METHODS Type of study design: Assessor blinded, randomized controlled trial.
      Setting: Hospital (Dermatology Outpatient Department, BPKIHS, Dharan). The probable duration
      of the study will be one year after approval from the Institutional Review Committee and
      Nepal Health Research Council (NHRC). Ethical Clearance: taken from the Institutional Review
      Committee (IRC), BPKIHS, and Nepal Health Research Council (NHRC).

      Calculation of the sample size: According to a study done by Ekaputri et.al, it is reported
      that mean± SD of SCORAD index after intervention in probiotic group and control group was
      (18.09 ± 8.59) and (23.21± 8.71) respectively. Considering the least difference, 5.12 and
      pooled SD- 8.65, the sample size has been calculated at 95% CI and 80% power, using two means
      formula.

      n = 44.56, adding 10% in calculated value for lost to follow-up, final sample size is 45 in
      each group. Thus a total of 98 patients will be enrolled.

      n = 2σ2 (Z α/2 + Z β) 2 (μ1- μ2) 2

      n= sample size of each group. σ = standard deviation 8.65 Z = reliability coefficient. 1.96 α
      = significance level. 0.05 Zβ= at 20% power 0.84 μ1 = mean (Probiotic) 18.09 μ2 = mean
      (Control) 23.21 d = mean difference 5.12

      Randomization and allocation concealment:

      A block randomization list will be generated with the block sizes 4, 6 and 8. Two parallel
      groups (1:1 ratio) of patients following computerized randomization will be produced. Prior
      to the enrollment of the patients a sequentially generated number with the treatment group
      will be written in sealed envelope, which will be prepared by independent dermatologist.

      Interventional and conventional groups:

      Interventional group: Children with AD meeting eligibility criteria receiving probiotics and
      conventional treatment (topical corticosteroid, topical tacrolimus, an oral antihistamine and
      emollients) Conventional group: Children with AD meeting eligibility criteria, under
      conventional treatment only.

      Follow up:

      Each patient will be asked for their follow up at 2, 4, 6, 8, 10 and 12 weeks of commencing
      treatment. In each follow up, every patient will be evaluated for the side effects and
      compliance to treatment. SCORAD index will be measured at baseline and at 4, 8, 10 and 12
      weeks. FDLQI will be measured at baseline and at 8 weeks. Parents will be provided a card to
      record for flare of symptoms; total days of steroid use for the same and total flare episode
      will be recorded during 12 weeks follow up. Flare is defined as worsening of clinical
      features leading to use of corticosteroids for at least 3 consecutive days.

      Family dermatology life quality index:

      Parents or guardian of each children will be asked to fill the questionnaire intended to
      measure quality of life of family members whose relative have dermatological conditions. The
      standardized nepali version of FDLQI (MKA Basra, AY Finlay. Cardiff University 2005) will be
      used. Questions concern the influence of disease on parents QOL in the last month. Each
      question can be answered by selecting 1 out of 4 answers scored 0-3. The maximum score is 30
      points and minimum 0 point. The higher the score lower the parents QOL.

      Severity Index (SCORAD) It uses the rule of nine to assess extent of disease and evaluates
      five clinical characteristics to determine disease severity: i) erythema, ii) edema/
      papulation, iii) oozing/crusts, iv) excoriation and v) lichenification. It also assesses
      subjective symptoms of pruritus and sleep loss with Visual Analogue Scales (VAS).

      Based on SCORAD score, AD is categorized as

        -  Mild AD (SCORAD <25)

        -  Moderate (SCORAD 25-50)

        -  Severe (SCORAD >50)

      Statistical Analysis:

      Statistical analysis will be conducted both per protocol and intention to treat population
      (defined as all enrolled children to whom study drug will be given; with the last observation
      carried forward) basis using two sided tests.

      Statistical methods proposed:

        1. Descriptive statistics will be summarized as mean, median, percentage, standard
           deviation (SD) and interquartile range along with appropriate graphical and tabular
           presentation.

        2. Intragroup SCORAD index and FDLQI score will be compared by paired t-test and between
           the groups by independent t- test.

        3. In case of nonparametric data Mann- Whitney U test for independent groups and Wilcoxon
           signed- rank test for paired group will be used.

        4. Chi-square test will be used to compare the categorical data. All statistical tests will
           be carried out at a significance level P<0.05.
    

Intervention name(s): Probiotic sachet containing mixture of four strains i.e.Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium longum, and Saccharomyces boulardii; Conventional treatment
Intervention type(s): Drug; Drug
Intervention description(s): Interventional group: Children with AD meeting eligibility criteria receiving probiotics and conventional treatment (topical corticosteroid, topical tacrolimus, an oral antihistamine and emollients).; topical corticosteroid, topical tacrolimus, an oral antihistamine and emollients as per atopic dermatitis treatment guidelines.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Assessor blinded, randomized controlled trial.
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment