Participants

Fifty six children aged from 6 to 18 months with moderate or severe AD were recruited between April and November 2003 from the general community and from outpatient clinics. All children met the Hanafin and Raijka criteria for AD and had a modified SCORAD score ⩾25.^20,21 Children were ineligible for the study if they had prior exposure to probiotics, were currently taking a course of antibiotics, or had other major medical problems.

Protocol

The study design is a randomised double blind placebo controlled trial. To detect a 50% reduction in SCORAD index scores at the 5% significance level with 80% power, 23 children per group are required. We recruited a larger number to allow for an estimated 10% withdrawal rate. A computerised randomisation schedule was prepared by the hospital biostatistician with allocation and dispensing of sachets by the pharmacy department. The probiotic and placebo sachets were matched for size, shape, and volume of contents.

Assignment

The groups were stratified and block randomised according to the following criteria: (a) modified SCORAD (25–50; 50 and over), (b) current topical corticosteroid potency (none; mild or moderate; potent or very potent),²² and (c) age (6 to 12 months; 12 months and over).

Participants in the probiotic group received 1 billion cfu of L fermentum VRI-003 PCC (Probiomics, Eveleigh, NSW, Australia) freeze dried powder twice daily for 8 weeks. The control group received maltodextran without probiotics twice daily for the same duration. Both supplements were dispensed as a stable powder in identical individual 1 g sachets, reconstituted by parents with 5–10 ml of water and administered orally as a suspension. Compliance was monitored by use of a sachet chart (completed by parents) and sachet counts.

Participant flow and follow up

Participants were first seen at baseline (week 0) when they were assessed for eligibility, provided parental written informed consent, and commenced intervention (fig 1⇓). All patients who met eligibility criteria were randomised. Participants had clinical assessments at week 2, week 4, and at the end of intervention week 8, and final assessment at week 16. Topical corticosteroid use was continued under the guidance of the patient’s own physician. Three participants withdrew from the study within the first 4 weeks (fig 1⇓). One child experienced vomiting on day 5 as part of an intercurrent illness and after commencing antibiotic therapy the parents found multiple drug administration difficult and withdrew. Two children (one in each group) withdrew due to refusal of the suspension. Fifty three patients were available for analysis.

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Figure 1

 Consort statement: progress of participants through the trial.

Clinical outcomes

A detailed history was obtained at baseline with follow up questionnaires at each of the other visits. A SCORAD assessment was also performed at each visit by a clinician who was blind to the intervention. The primary outcome measure was change in the severity of AD as assessed by the SCORAD index. Other outcomes included: (a) change in family quality of life as reported in the Dermatitis Family Impact Questionnaire (DFIQ), (b) change in reported topical corticosteroid usage, and (c) parental impression of the intervention. The SCORAD index¹⁹ is a tool used to assess the severity of AD by combining evaluation of extent, intensity of lesions, and subjective symptoms (pruritus and sleep loss). A modified SCORAD is obtained by using only the assessment of extent and intensity, omitting subjective criteria.²¹ To ensure consistency, a single investigator performed all SCORAD assessments at weeks 0, 8, and 16. The DFIQ is a tool to measure the impact of AD on family function.²³ Parents reported topical corticosteroid usage as frequency of use and potency required, prospectively in a diary. A steroid score was calculated from number of applications per week multiplied by potency used. At completion of intervention parents were asked if their child’s AD was better, worse, or unchanged since commencing supplementation. At week 16 they were similarly questioned about any change during the follow up phase.

Laboratory measures

A 5–10 ml sample of blood was collected from each participant at baseline. Plasma was frozen and then stored for analysis at completion of the study. Levels of total IgE and radioallergosorbent test (RAST) results were obtained using standardised commercial fluoroimmunoassays (Pharmacia CAPSystem for specific IgE and the Pharmacia ImmunoCAP for total IgE; Pharmacia, Uppsala, Sweden). Antigen specific IgE to food allergen mix (egg white, milk, cod, wheat, peanut, and soya bean), grass allergen mix (couch, rye, timothy, meadow, johnson, and bahia) and house dust mite were determined from the baseline plasma sample. Specific IgE >0.35 kU/l were considered positive.

Analysis

Differences between the probiotic and placebo groups were assessed using the χ² test for nominal data. The differences in SCORAD index scores from baseline were non-parametric and analysed using Mann-Whitney U test to compare groups at each time point and Freidman’s one way analysis of variance to compare change over time in each group. Total IgE data were log natural transformed to describe the geometric mean. Statistic analyses were performed using SPSS software (Version 10 and 11 for Macintosh; SPSS, Chicago, IL). A p value <0.05 was considered statistically significant for all analyses.

Ethics

The Princess Margaret Hospital for Children Ethics Committee approved the trial.

Baseline clinical characteristics of participants

Fifty six children were recruited into the trial, 30 males and 26 females. There was no significant difference between the probiotic and placebo group in any of the baseline characteristics displayed in table 1⇓. The majority of participants (n = 49; 88%) were using topical corticosteroids, 54% of participants had been exposed to antibiotics in the past, and half were regularly consuming yogurt at the commencement of the study. The majority (95%) of children had been breastfed and 38% were still being breastfed. Fifty three participants (95%) had at least one parent with a history of allergy (asthma, allergic rhinitis, or AD). Only three (5%) children had doctor-diagnosed asthma, although 13 (23%) were reported by parents to have had at least one episode of wheeze. Clinical food allergy was common, with 16 (29%) cases having had a reported immediate-type allergic reaction to food. Total IgE was elevated in 43 (77%), and RAST testing for specific IgE was positive to food mix in 40 (71%) and to house dust mite allergen in 12 (21%). No children had elevated specific IgE to grass mix.

Compliance

Compliance, as reported by parents, was good with 94% of doses administered and no difference between the groups (p = 0.87).

Effects of probiotics on the extent and severity of AD

The differences in the SCORAD index from baseline at each time point are presented in table 2⇓, with greater improvement in the probiotic group compared to the placebo group. Firstly, the reduction in the SCORAD index over time was significant in the probiotic group, but not in the placebo group (p = 0.03 and p = 0.83, respectively, using Friedman’s analysis of variance). Secondly, this change was manifest in a difference between the two groups that approached the conventional level of statistical significance at week 16 (p = 0.06) as shown in fig 2A⇓. The same pattern was apparent for the components of the SCORAD index as indicated in table 2⇓. To determine if these effects were also apparent within individuals, a further analysis was undertaken. Week 16 SCORAD index scores were categorised as better than baseline versus worse than baseline for each group (individual data in fig 2B⇓). Using a χ² test of independence on the frequencies, the probiotic group was significantly more likely than the placebo group to be better than baseline at the end of the study (n = 24; 92% and n = 17; 63%, respectively; p = 0.01). Finally, more children in the probiotic group had mild AD at the end of the study (n = 14, 54%) compared with the placebo group (n = 8, 30%), although this did not reach statistical significance using Fisher’s exact test (p = 0.066) (fig 2C⇓).

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Figure 2

 Change in extent and severity of AD during the study. (A) The differences in the SCORAD index from baseline (box plot) are shown for the probiotic L fermentum VRI-003 PCC group (shaded boxes) and the placebo group (white boxes) at each follow up visit. (B) Baseline and follow up (week 16) SCORAD index scores are shown for each participant in the placebo and probiotic groups. (C) The proportion of children in the mild, moderate, and severe categories of AD at baseline, end of supplementation (week 8), and at follow up are presented for the placebo and probiotic groups.

Effect of probiotics on parental perceptions

The median differences in DFIQ scores at end of intervention and at follow up are presented for each group in table 3⇓. There was an improvement in the quality of life score over time in both groups. In response to questioning about whether their child’s AD, was better, worse, or unchanged during intervention and during the follow up period, parental perceptions of severity were similar for both groups (table 3⇓). Overall, 62% of parents in the probiotic group and 73% in the placebo group reported they would continue the supplement their child was on after conclusion of the trial.

Effect of probiotics on medications

The amount of topical corticosteroid applied was derived from the potency and number of applications reported per week. The differences from baseline at each time point are shown in table 3⇑. The change in topical corticosteroid use over time was not significant in either group (probiotic group, p = 0.2; placebo, p = 0.6). The correlations between change in corticosteroid use and change in the SCORAD index in each group were small. Twenty one (40%) children received antibiotics during the trial, with similar numbers in both groups.

Effects of probiotics on other clinical symptoms

Significantly less children in the probiotic group had lower respiratory tract infections as reported by parents, compared to the placebo group (12/26, 46% and 20/27, 74%, respectively; p = 0.04). There were no significant differences between the groups in number of children having episodes of vomiting, diarrhoea, gastroenteritis, fever, wheezing, coughing, or ear infections. No specific adverse events were recorded, although, as previously described, one child experienced vomiting of concern to the parents.