Saturday 25 February I978 A DOUBLE-BLIND CONTROLLED CROSSOVER TRIAL OF AN ANTIGEN-AVOIDANCE DIET IN
ATOPIC ECZEMA
trolled crossover trial of such
a
diet in children with
atopic eczema. Patients
D.
MARION SEWELL R. S. WELLS
J. ATHERTON
J. F. SOOTHILL Hospital for Sick Children, Great Ormond Street, London WC1, and Institute of Child Health, Guilford Street, London, WC1
CLAIR E. D. CHILVERS
Department of Medical Statistics and Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1
Summary
20
out
years)
of 36 children (aged two to eight with atopic eczema completed a
twelve-week, double-blind, controlled,
crossover
trial of
egg and cows’ milk exclusion diet. During the first and third four-week periods, patients on an egg and cows’ milk exclusion diet received a soya-based milk substitute (trial period) or an egg and cows’ milk preparation (control period). Response was assessed in terms of eczema activity, number of areas affected, pruritus, sleeplessness, and antihistamine usage while on the two diets. During the middle period patients resumed their normal diet to minimise any carry-over effect. 14 patients responded more favourably to the antigen-avoidance diet than to the control diet, whereas only 1 responded more favourably to the control diet than the trial diet. Patients experienced more benefit during the first diet period than the second, whatever the nature of the diet. There was no correlation between a positive prick test to egg and cows’ milk antigen and response to the trial diet.
36 children attending the dermatological clinic with clinically typical atopic eczema were invited to take part in the trial. None was on an egg or cows’ milk exclusion diet. 14 boys and 6 girls, aged two to eight years (median six years) completed the trial. 9 were excluded because of dietary lapses, and 7 withdrew voluntarily, for various reasons. 3 of the 20 patients who completed the study had given a previous history of exacerbation of cutaneous symptoms after ingestion of eggs or cows’ milk; cows’ milk was alleged to provoke pruritus in 1 child and exacerbation of eczema in another, and egg was alleged to exacerbate eczema in the 3rd. Of the 9 excluded for non-adherence, 7 were excluded after the control period and 2 after the trial diet period. Of the 7 who withdrew voluntarily, 4 did so during or after the control period and 3 during or after the trial diet period.
an
Introduction CHILDHOOD eczema usually occurs in atopic children, who show evidence of allergy to many environmental antigens including those found in foods.’ The use of antigen-avoidance diets, though popular in other countries, has found no place in routine management of atopic eczema in the U.K., and there is no objective evidence that it is effective. The finding that exclusive breastfeeding can reduce the incidence of atopic eczema in predisposed infants2 prompted us to evaluate dietary antigen avoidance in the treatment of established atopic eczema. We selected a diet excluding eggs and cows’ milk because we believed that these two foods were likely to be the most important dietary allergens in atopic eczema. We present the results of a double-blind con-
Methods The patients’ parents were instructed by a dietitian (M.S.) a diet which excluded all foods containing egg and cows’ milk. Chicken and beef were also excluded because they have proteins in common with egg and milk. Each patient took part in a twelve-week trial, which was divided into three four-week periods. During the lst and 3rd periods the patients were on the egg and milk elimination diet and were randomly allocated to one of two milk "substitutes". During one period the patients were given a dried soya-based preparation (trial period); during the other they were given a preparation containing a mixture of dried egg and cows’ milk (control period). They were asked to take at least one pint per day of milk "substitute" ; during the control period this was equivalent to one pint of milk and one egg. The patients were unaware of the nature of the difference between the milk "substitutes" and were told that the aim of the study was the comparison of two similar regimens. During the middle period patients resumed their normal diet, to minimise any carry-over effect. Throughout the trial, patients were asked to continue their usual treatment, which normally comprised (i) a daily bath with emulsifying ointment, B.P., (ii) once or twice daily application of 1% hydrocortisone ointment, and (iii) oral trimeprazine tartrate, which most patients were taking as required. Tablets containing trimeprazine tartrate, 10 mg, were provided during the trial, and patients were asked to note the number taken each day on a diary card. They were also asked to note details on the diary card of any dietary lapses and an estimate of the intake of milk "substitute" for the day. The patients’ parents were also asked to record on the diary card a daily score of 0-3 for pruritus during the daytime and lack of sleep during the night. To minimise any carry-over effect, diary-card scores for the first week of each period were discarded at analysis. At the beginning and end of each diet period the patients were seen by D.J.A. and R.S.W. who independently graded in
8061
402 their eczema according to both area involved and activity; neither patient, parent, nor dermatologist knew which diet was being given. Lichenification or ichthyosis alone were ignored. The body surface was divided into 20 separate zones, each of which was recorded as affected or unaffected; this gave an area score of up to 20. The activity of a patient’s eczema was recorded and, on completion of each diet period, a score reflecting any change was given, as follows: major improvement +2; minor improvement +1; no change 0; minor deterioration -1; major deterioration -2. At the end of each diet period, the patients’ parents were seen again by the dietitian who assessed the degree of adherence to the diet. A "lapse" was defined as either (i) taking less than 2pint of milk substitute in any one day, or (ii) eating any excluded food. Insufficient intake of soya milk was ignored, though the patients’ were unaware of this. Any patient found to have had more than 5 such lapses in either four-week period was excluded from the trial. Prick tests were performed in all patients at the start of the second period with 10 allergen solutions (Bencard): Dermato-
CLINICAL AND SYMPTOMATIC EFFECTS OF DIETS AND ORDER OF ADMINISTRATION
,
phagoides pteronyssinus, Timothy-grass pollen, cat fur, Aspergillus fumigatus, whole egg, egg white, cereals (A3), egg yolk, ot-lactalbumin, whole cows’ milk and a control solution. The results were analysed by a paired t test as described by Smart.3 Results 3
patients experienced a severe exacerbation of within a few days of starting their final diet per-
eczema
iod ; in all 3 this was the control diet. The diet was stopped and these patients were allocated, by protocol, the highest activity score (-4) for that diet period. They were, however, unable to complete their diary cards and could not be given a final area score for the period; they are therefore omitted from these analyses. Activity scores.-13 of the 20 patients showed improvement during the trial diet period, 6 showed no
Fig. I-Activity
scores
(sum of
scores
given by
2
observers)
at
end nf each diet nerind.
Positive scores indicate improvement. Lines join scores for individual patients. A positive slope indicates a relatively greater improvement on
trial diet.
Fig. 2-Area scores (mean) at each visit. Lines join scores for individual patients. improvement.
A
negative slope
indicates
change, and
1 showed deterioration, whereas during the control diet period only 3 showed improvement, 11 showed no change, and 6 showed deterioration (fig. 1). The activity scores, which record change of activity during each diet period, showed significantly more improvement after the trial diet than after the control diet (P
ATOPIC ECZEMA
trolled crossover trial of such
a
diet in children with
atopic eczema. Patients
D.
MARION SEWELL R. S. WELLS
J. ATHERTON
J. F. SOOTHILL Hospital for Sick Children, Great Ormond Street, London WC1, and Institute of Child Health, Guilford Street, London, WC1
CLAIR E. D. CHILVERS
Department of Medical Statistics and Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1
Summary
20
out
years)
of 36 children (aged two to eight with atopic eczema completed a
twelve-week, double-blind, controlled,
crossover
trial of
egg and cows’ milk exclusion diet. During the first and third four-week periods, patients on an egg and cows’ milk exclusion diet received a soya-based milk substitute (trial period) or an egg and cows’ milk preparation (control period). Response was assessed in terms of eczema activity, number of areas affected, pruritus, sleeplessness, and antihistamine usage while on the two diets. During the middle period patients resumed their normal diet to minimise any carry-over effect. 14 patients responded more favourably to the antigen-avoidance diet than to the control diet, whereas only 1 responded more favourably to the control diet than the trial diet. Patients experienced more benefit during the first diet period than the second, whatever the nature of the diet. There was no correlation between a positive prick test to egg and cows’ milk antigen and response to the trial diet.
36 children attending the dermatological clinic with clinically typical atopic eczema were invited to take part in the trial. None was on an egg or cows’ milk exclusion diet. 14 boys and 6 girls, aged two to eight years (median six years) completed the trial. 9 were excluded because of dietary lapses, and 7 withdrew voluntarily, for various reasons. 3 of the 20 patients who completed the study had given a previous history of exacerbation of cutaneous symptoms after ingestion of eggs or cows’ milk; cows’ milk was alleged to provoke pruritus in 1 child and exacerbation of eczema in another, and egg was alleged to exacerbate eczema in the 3rd. Of the 9 excluded for non-adherence, 7 were excluded after the control period and 2 after the trial diet period. Of the 7 who withdrew voluntarily, 4 did so during or after the control period and 3 during or after the trial diet period.
an
Introduction CHILDHOOD eczema usually occurs in atopic children, who show evidence of allergy to many environmental antigens including those found in foods.’ The use of antigen-avoidance diets, though popular in other countries, has found no place in routine management of atopic eczema in the U.K., and there is no objective evidence that it is effective. The finding that exclusive breastfeeding can reduce the incidence of atopic eczema in predisposed infants2 prompted us to evaluate dietary antigen avoidance in the treatment of established atopic eczema. We selected a diet excluding eggs and cows’ milk because we believed that these two foods were likely to be the most important dietary allergens in atopic eczema. We present the results of a double-blind con-
Methods The patients’ parents were instructed by a dietitian (M.S.) a diet which excluded all foods containing egg and cows’ milk. Chicken and beef were also excluded because they have proteins in common with egg and milk. Each patient took part in a twelve-week trial, which was divided into three four-week periods. During the lst and 3rd periods the patients were on the egg and milk elimination diet and were randomly allocated to one of two milk "substitutes". During one period the patients were given a dried soya-based preparation (trial period); during the other they were given a preparation containing a mixture of dried egg and cows’ milk (control period). They were asked to take at least one pint per day of milk "substitute" ; during the control period this was equivalent to one pint of milk and one egg. The patients were unaware of the nature of the difference between the milk "substitutes" and were told that the aim of the study was the comparison of two similar regimens. During the middle period patients resumed their normal diet, to minimise any carry-over effect. Throughout the trial, patients were asked to continue their usual treatment, which normally comprised (i) a daily bath with emulsifying ointment, B.P., (ii) once or twice daily application of 1% hydrocortisone ointment, and (iii) oral trimeprazine tartrate, which most patients were taking as required. Tablets containing trimeprazine tartrate, 10 mg, were provided during the trial, and patients were asked to note the number taken each day on a diary card. They were also asked to note details on the diary card of any dietary lapses and an estimate of the intake of milk "substitute" for the day. The patients’ parents were also asked to record on the diary card a daily score of 0-3 for pruritus during the daytime and lack of sleep during the night. To minimise any carry-over effect, diary-card scores for the first week of each period were discarded at analysis. At the beginning and end of each diet period the patients were seen by D.J.A. and R.S.W. who independently graded in
8061
402 their eczema according to both area involved and activity; neither patient, parent, nor dermatologist knew which diet was being given. Lichenification or ichthyosis alone were ignored. The body surface was divided into 20 separate zones, each of which was recorded as affected or unaffected; this gave an area score of up to 20. The activity of a patient’s eczema was recorded and, on completion of each diet period, a score reflecting any change was given, as follows: major improvement +2; minor improvement +1; no change 0; minor deterioration -1; major deterioration -2. At the end of each diet period, the patients’ parents were seen again by the dietitian who assessed the degree of adherence to the diet. A "lapse" was defined as either (i) taking less than 2pint of milk substitute in any one day, or (ii) eating any excluded food. Insufficient intake of soya milk was ignored, though the patients’ were unaware of this. Any patient found to have had more than 5 such lapses in either four-week period was excluded from the trial. Prick tests were performed in all patients at the start of the second period with 10 allergen solutions (Bencard): Dermato-
CLINICAL AND SYMPTOMATIC EFFECTS OF DIETS AND ORDER OF ADMINISTRATION
,
phagoides pteronyssinus, Timothy-grass pollen, cat fur, Aspergillus fumigatus, whole egg, egg white, cereals (A3), egg yolk, ot-lactalbumin, whole cows’ milk and a control solution. The results were analysed by a paired t test as described by Smart.3 Results 3
patients experienced a severe exacerbation of within a few days of starting their final diet per-
eczema
iod ; in all 3 this was the control diet. The diet was stopped and these patients were allocated, by protocol, the highest activity score (-4) for that diet period. They were, however, unable to complete their diary cards and could not be given a final area score for the period; they are therefore omitted from these analyses. Activity scores.-13 of the 20 patients showed improvement during the trial diet period, 6 showed no
Fig. I-Activity
scores
(sum of
scores
given by
2
observers)
at
end nf each diet nerind.
Positive scores indicate improvement. Lines join scores for individual patients. A positive slope indicates a relatively greater improvement on
trial diet.
Fig. 2-Area scores (mean) at each visit. Lines join scores for individual patients. improvement.
A
negative slope
indicates
change, and
1 showed deterioration, whereas during the control diet period only 3 showed improvement, 11 showed no change, and 6 showed deterioration (fig. 1). The activity scores, which record change of activity during each diet period, showed significantly more improvement after the trial diet than after the control diet (P
