- Email: [email protected]
Filaggrin mutations increase the risk for persistent dry skin and eczema independent of sensitization
LETTERS TO THE EDITOR 1153
J ALLERGY CLIN IMMUNOL VOLUME 129, NUMBER 4
United States and found that nearly one third of prescriptions contained combinations of protease-containing allergen extracts (fungal or insect) and pollen allergen extracts. Cost and patient compliance were cited by prescribers as the most common reason for combining allergen groups. In our study, cost should not be a factor as USACAEL does not place the financial burden for AIT on individual patients, providers, or clinics. Patient compliance may be a driving factor, as one injection can be perceived as less painful and more convenient. Esch found that glycerinated extracts were requested for only about half of these prescriptions, whereas all USACAEL extracts are glycerinated, though the glycerin content of each individual extract formulation is variable. This may also factor into the observed prescribing patterns, as studies have demonstrated that the presence of glycerin in allergen extracts may preserve potency.3 To date, no study has looked at the clinical impact of AIT when mixing mold with pollen. In conclusion, we have observed a significant reduction in AIT prescriptions that contain molds mixed with pollen. There seems to be a strong temporal relationship between the publication of specific mixing recommendations in the AIT Practice Parameters and these observed changes in prescribing patterns. Despite these recommendations, a significant number of prescriptions continue to mix mold with pollen, particularly among SI prescriptions. The reasons behind such prescribing patterns and its clinical impact deserve further study. Satyen Gada, MDa Bret Haymore, MDb Lorne McCoy, BSb Susan Kosisky, MAb Michael Nelson, MD, PhDb From athe Department of Allergy/Immunology, National Naval Medical Center, Bethesda, Md, and bthe Department of Allergy/Immunology, Walter Reed Army Medical Center, Washington, DC. E-mail: [email protected]. Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Departments of the Army, Navy, the Department of Defense, or the US government. Disclosure of potential conflict of interest: R.L. McCoy is an employee of MD Healthcare Management, Inc. The rest of the authors declare that they have no relevant conflicts of interest.
REFERENCES 1. Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol 2011;127:S1-S55. 2. Nelson HS, Ikle D, Buchmeier A. Studies of allergen extract stability: the effects of dilution and mixing. J Allergy Clin Immunol 1996;98:382-8. 3. Grier TJ, LeFevre DM, Duncan EA, Esch RE. Stability of standardized grass, dust mite, cat, and short ragweed allergens after mixing with mold or cockroach extracts. Ann Allergy Asthma Immunol 2007;99:151-60. 4. Kordash TR, Amend MJ, Williamson SL, Jones JK, Plunkett GA. Effect of mixing allergenic extracts containing Helminthosporium, D. farinae, and cockroach with perennial ryegrass. Ann Allergy 1993;71:240-6. 5. Grier TJ, LeFevre DM, Duncan EA, Esch RE. Stability and mixing compatibility of dog epithelia and dog dander allergens. Ann Allergy Asthma Immunol 2009;103:411-7. 6. Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology. Practice parameters for allergen immunotherapy. J Allergy Clin Immunol 1996;98:1001-111. 7. Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology. Allergen immunotherapy: a practice parameter. Ann Allergy Asthma Immunol 2003;90:S1-S40.
8. Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology. Allergen immunotherapy: a practice parameter second update. J Allergy Clin Immunol 2007;120:S25-S85. 9. Esch RE. Formulation of therapeutic allergen mixtures: problems associated with the number, proportion, and enzymatic activities of allergens. Arb Paul Ehrlich Institut 2000;93:57-61. Available online December 9, 2011. doi:10.1016/j.jaci.2011.10.027
Filaggrin mutations increase the risk for persistent dry skin and eczema independent of sensitization
To the Editor: Previous studies have shown that filaggrin gene (FLG) mutations increase the risk for atopic eczema (AE), but data for non–atopic eczema (non-AE) have been scarce.1,2 We used data from a large Swedish prospective birth cohort (BAMSE) to investigate the association between FLG mutations and dry skin and eczema, divided into AE and non-AE, at age 8 years. The population-based BAMSE study included 4089 children, born between 1994 and 1996 in Stockholm. The children were consecutively recruited during their first months of life.3,4 At baseline, the parents answered a questionnaire, focusing on parental allergic disease and environmental factors. Follow-up questionnaires, containing questions on dry skin, symptoms and signs of eczema, and child’s environmental exposures were collected at age 1, 2, 4, and 8 years. Blood samples were collected at age 8 years. DNA was available for 2033 individuals. Genotyping was performed for FLG mutations common in Scandinavia by using TaqMan allelic discrimination assays for R501X and R2447X and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry for 2282del4. Children with a mutation in any of these positions were classified as having a loss-offunction mutation. Eczema during the first 4 years of life was defined as itchy rash for at least 2 weeks with typical distribution and dry skin during the last year at age 1, 2, or 4 years and/or doctor’s diagnosis of eczema sometime during the first 4 years. Eczema at age 8 years was defined as itchy rash for at least 2 weeks with typical distribution and dry skin during the last year and/or doctor’s diagnosis of eczema from the age of 4 years.3 Eczema and dry skin were considered persistent when present sometime during the first 4 years and during the fifth to the eighth year. Sensitization was defined as having IgE antibodies to a mix of common inhalant (Phadiatop, Phadia AB, Uppsala, Sweden) and/or food allergens (fx5; ImmunoCAP System, Phadia AB). Eczema was divided into AE (eczema according to the definition plus sensitization at age 8 years) and non-AE (eczema according to the definition but no sensitization). Statistical analyses were made with the Stata Statistical Software: Release 7.0 (StataCorp, College Station, Tex). Logistic regression models adjusting for established risk factors (parental allergic disease, breast-feeding, furred pets at home, sex, parental education, and parental smoking during child’s first months) and ‘‘one or both parents born outside Scandinavia’’ were used. Since the analyses had 4 levels of outcome (eg, no dry skin and no eczema, dry skin without eczema, eczema without dry skin, and dry skin with eczema), multinomial logistic regression models
1154 LETTERS TO THE EDITOR
J ALLERGY CLIN IMMUNOL APRIL 2012
TABLE I. Risk for dry skin and eczema at age 8 y in relation to filaggrin mutations No filaggrin mutation Dry skin
Filaggrin mutation
Eczema
N
n
Percent
n
Percent
OR*
95% CI
No No Yes Yes
1165 401 21 310
1112 358 19 274
95.4 89.3 90.5 88.4
53 43 2 36
4.6 10.7 9.5 11.6
1.00 2.64 2.42 2.91
1.72-4.04 0.54-10.85 1.85-4.60
No Yes No Yes
*Adjusted for sex, parental allergic disease, breast-feeding, pets at home, parental education, mother and/or father born outside Scandinavia, and parental smoking during child’s first months.
TABLE II. Risk for dry skin over time up to age 8 y in relation to filaggrin mutations in children who never had eczema Dry skin During first 4 y
No Yes No Yes
No filaggrin mutation
Filaggrin mutation
At 8 y
N
n
Percent
n
Percent
OR*
95% CI
No No Yes Yes
540 403 59 151
520 383 56 130
96.3 95.0 94.9 86.1
20 20 3 21
3.7 5.0 5.1 13.9
1.00 1.35 1.47 4.51
0.72-2.55 0.42-5.16 2.35-8.64
*Adjusted for sex, parental allergic disease, breast-feeding, pets at home, parental education, mother and/or father born outside Scandinavia, and parental smoking during child’s first months.
TABLE III. Risk for eczema over time up to age 8 y in relation to filaggrin mutations Eczema During first 4 y
No Yes No Yes
No filaggrin mutation
Filaggrin mutation
At 8 y
N
n
Percent
n
Percent
OR*
95% CI
No No Yes Yes
1154 395 74 253
1090 364 69 220
94.4 92.2 93.2 87.0
64 31 5 33
5.6 7.8 6.8 13.0
1.00 1.39 1.27 2.65
0.89-2.19 0.49-3.28 1.68-4.20
*Adjusted for sex, parental allergic disease, breast-feeding, pets at home, parental education, mother and/or father born outside Scandinavia, and parental smoking during child’s first months.
were used. Proportions and odds ratios (ORs) are shown with 95% CIs. Moreover, tests for gene-environment interactions were performed between FLG mutations and presence of siblings or cat in the household at birth according to the information provided in the questionnaires. The study population consisted of children with available data on sensitization, FLG status, eczema and dry skin as well as complete information on covariates (n 5 1897). There were no differences in the prevalence of covariates between the study population and the cohort (data not shown). In the study population, dry skin was reported in 711 (37%) children at 8 years, with persistence in 623 (33%) children. Of the children with persistent dry skin, 76% had eczema at some point during their first 8 years, 46% reported eczema at age 8 years, and 38% had persistent eczema. Eczema was reported in 331 (17%) at age 8 years, of whom 164 had non-AE and 167 had AE. Persistence was found in 253 (13%) children, of whom 93% reported dry skin at age 8 years and 92% reported persistent dry skin. FLG mutations were found in 134 (7%) children, all heterozygotes. Children with FLG mutations significantly more often had both parents born in Scandinavia than did children without FLG mutations (90% vs 79%, respectively). In addition, they had a tendency toward a higher degree of exclusive breast-feeding for 4 or more months and a parental history of allergic disease. No differences in the prevalence of siblings were seen between the groups.
FLG mutations increased the risk for dry skin at 8 years significantly (OR 2.69; 95% CI 1.86-3.88). There was an increased risk for dry skin both with and without eczema (Table I). At 8 years, there was an increased risk both for non-AE and for AE (OR 2.58, CI 1.53-4.37 and OR 1.75, CI 0.97-3.16, respectively). FLG mutations increased the risk for persistent dry skin (OR 3.67, 95% CI 2.21-6.10), also in children who never had eczema (Table II), and for persistent eczema (Table III). For eczema at age 8 years, there was no significant geneenvironment interaction between FLG mutations and siblings or cat in the household at birth. Symptoms were assessed by questionnaires, which may be a limitation. Using a definition of eczema that was slightly different from the UK working party’s definition, though validated,3 makes the prevalence figures less comparable with other studies. The prospective and population-based design is a major strength. Follow-up rates are good in the BAMSE study, and loss to follow-up is unlikely to depend on FLG mutations. There were no differences in the prevalence of dry skin, eczema, or covariates between the study population and the cohort. Thus, the results are likely to be representative for the cohort and probably for the population. Our study confirms that FLG mutations increase the risk for persistent eczema eg.5 Furthermore, we show that this is valid also for persistent dry skin and for both AE and non-AE at age 8 years. We could not confirm an increased risk for
LETTERS TO THE EDITOR 1155
J ALLERGY CLIN IMMUNOL VOLUME 129, NUMBER 4
sensitization only, as reported by Bonnelykke et al.6 This inconsistency could partly be explained by our comparison group of healthy children free from both eczema and sensitization. In addition, we observed no interaction between FLG mutations and siblings at birth. This is contradictory to the results of Cramer et al who reported a higher prevalence of eczema in children with filaggrin deficiency if elder siblings were present.7 Moreover, Bisgaard and coworkers8 found an interaction between FLG mutations and neonatal cat exposure, which could not be confirmed in our study. In conclusion, our prospective study shows that FLG mutations increase the risk for persistent dry skin, persistent eczema, and AE and non-AE at age 8 years, without interactions between FLG mutations and siblings or cat in the household at birth. Maria B€ ohme, MD, PhDa* Cilla S€ oderh€ all, PhDb* Inger Kull, RN, PhDc,d Anna Bergstr€ om, PhDe Marianne van Hage, MD, PhDf Carl-Fredrik Wahlgren, MD, PhDa From athe Department of Dermatology and Venereology, Karolinska University Hospital Solna, and the Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden, bthe Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden, cthe Department of Clinical Science and Education, S€ odersjukhuset, Karolinska Institutet, Stockholm, Sweden, dthe Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden, ethe Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, and fthe Department of Clinical Immunology, Karolinska University Hospital Solna, and the Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. E-mail: [email protected]. *Shared first authorship. This study was funded by the Swedish Asthma and Allergy Association, the WelanderFinsen Foundation, and the Swedish Research Council. Financial support was also provided through regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet. Disclosure of potential conflict of interest: C.-F. Wahlgren received research support from the Swedish Asthma and Allergy Association, the Welander-Finsen Foundation, and the Stockholm County Council (ALF). The rest of the authors declare that they have no relevant conflicts of interest.
REFERENCES 1. Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A. Loss-offunction variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol 2006;118:214-9. 2. Irvine AD. Fleshing out filaggrin phenotypes. J Invest Dermatol 2007;127:504-7. 3. B€ohme M, Lanner€ o E, Wickman M, Nordvall SL, Wahlgren CF. Atopic dermatitis and concomitant disease patterns in children up to two years of age. Acta Derm Venereol 2002;82:98-103. 4. Wickman M, Kull I, Pershagen G, Nordvall SL. The BAMSE project: presentation of a prospective longitudinal birth cohort study. Pediatr Allergy Immunol 2002;13: 11-3. 5. Weidinger S, Rodriguez E, Stahl C, Wagenpfeil S, Klopp N, Illig T, et al. Filaggrin mutations strongly predispose to early-onset and extrinsic atopic dermatitis. J Invest Dermatol 2007;127:724-6. 6. Bonnelykke K, Pipper CB, Tavendale R, Palmer CNA, Bisgaard H. Filaggrin gene variants and atopic diseases in early childhood assessed longitudinally from birth. Pediatr Allergy Immunol 2010;21:954-61. 7. Cramer C, Link E, Horster M, Koletzko S, Bauer CP, Berdel D, et al. Elder siblings enhance the effect of filaggrin mutations on childhood eczema: results from the 2 birth cohort studies LISAplus and GINIplus. J Allergy Clin Immunol 2010;125: 1254-60. 8. Bisgaard H, Simpson A, Palmer CNA, Bonnelykke K, Mclean I, Mukhopadhyay S, et al. Gene-environment interaction in the onset of eczema in infancy: Filaggrin loss-of-function mutations enhanced by neonatal cat exposure. PLoS Med 2008;5: e131 doi:10.1371/journal.pmed.0050131. Available online February 22, 2012. doi:10.1016/j.jaci.2011.11.032
Possible eosinophilic esophagitis induced by milk oral immunotherapy To the Editor: New therapeutic strategies to treat food allergy have emerged in recent years.1 At present, oral immunotherapy (OIT) with food is one of the most widely researched treatments for food allergy.2 Immediate adverse reactions during therapy have been widely described,3,4 and most of them were mild. However, long-term effects of OIT have been barely reported.5 We describe 3 cases of esophageal eosinophilia in 110 patients treated with milk OIT at our outpatient clinic during the last 5 years. Our milk OIT protocol consisted of increasing weekly doses of milk in the hospital and daily maintenance of the tolerated dose at home. Once a dose of 200 mL/d was achieved, continued daily intake of this dose at home was compulsory and consumption of dairy products was allowed.4 OIT was performed in 110 milk-allergic children aged 2 to 16 years (mean, 6.8 years) who were followed up for 5 years. IgE-mediated allergy was previously confirmed by using skin prick tests, specific IgE (sIgE) levels, and oral food challenges. After successfully achieving a daily intake of 200 mL of milk, 3 children who were previously asymptomatic developed malaise and gastrointestinal symptoms. Case 1: An asthmatic boy had been diagnosed with milk allergy at age 6 months because of vomiting immediately after drinking milk. He was treated with an elimination diet. He had an egg allergy that resolved spontaneously when he was 2 years old. Endoscopy and biopsy performed at 26 months revealed cardia insufficiency and no inflammatory signs with no eosinophils, leading to a diagnosis of gastroesophageal reflux disease (GERD). He was treated with cycles of omeprazole. At the age of 3 years and 9 months, milk and casein sIgE levels were 55.6 and 67.3 kUA/L, respectively, and an oral challenge with milk was positive. The patient underwent an OIT protocol. After 29 weeks of treatment, he had successfully achieved a 200 mL milk intake, with milk and casein sIgE levels of 23.2 and 25.8 kUA/L, respectively. After 14 months of daily milk intake and dairy products consumption, he began to eat slowly and experienced general weakness, low physical activity, sleep disturbances, and slow growth for 5 months. Markers for celiac disease and Helicobacter pylori were negative. A complete blood cell count revealed 420 eosinophils/mm3, and esophageal endoscopy showed rings and white mucosal exudates with a peak of 35, 35, and 40 eosinophils/hpf in mucosa from the upper, middle, and lower esophagus, respectively. After treatment with omeprazole and oral fluticasone (250 mg/12 h) for 2 months and a milk-free diet for 3 months, he was asymptomatic and endoscopy and biopsy findings were normal. The child remains symptom free after 20 months. Case 2: A boy with atopic dermatitis and asthma vomited after drinking milk. He was diagnosed with milk allergy and GERD at age 7 months, and he was treated with milk-free diet and omeprazole. When he was 11 years old, his milk and casein sIgE levels were 35.1 and 46 kUA/L, respectively, a persistent milk allergy was confirmed by oral challenge, and the patient was included in a milk OIT protocol. He successfully achieved a daily intake of 200 mL in 19 weeks, with no gastrointestinal symptoms and milk and casein sIgE levels of 32.3 and 32.1 kUA/L, respectively. Three months later, he began to experience retrosternal pain and dysphagia related to food ingestion. Markers for celiac disease and H pylori were negative. A complete blood
J ALLERGY CLIN IMMUNOL VOLUME 129, NUMBER 4
United States and found that nearly one third of prescriptions contained combinations of protease-containing allergen extracts (fungal or insect) and pollen allergen extracts. Cost and patient compliance were cited by prescribers as the most common reason for combining allergen groups. In our study, cost should not be a factor as USACAEL does not place the financial burden for AIT on individual patients, providers, or clinics. Patient compliance may be a driving factor, as one injection can be perceived as less painful and more convenient. Esch found that glycerinated extracts were requested for only about half of these prescriptions, whereas all USACAEL extracts are glycerinated, though the glycerin content of each individual extract formulation is variable. This may also factor into the observed prescribing patterns, as studies have demonstrated that the presence of glycerin in allergen extracts may preserve potency.3 To date, no study has looked at the clinical impact of AIT when mixing mold with pollen. In conclusion, we have observed a significant reduction in AIT prescriptions that contain molds mixed with pollen. There seems to be a strong temporal relationship between the publication of specific mixing recommendations in the AIT Practice Parameters and these observed changes in prescribing patterns. Despite these recommendations, a significant number of prescriptions continue to mix mold with pollen, particularly among SI prescriptions. The reasons behind such prescribing patterns and its clinical impact deserve further study. Satyen Gada, MDa Bret Haymore, MDb Lorne McCoy, BSb Susan Kosisky, MAb Michael Nelson, MD, PhDb From athe Department of Allergy/Immunology, National Naval Medical Center, Bethesda, Md, and bthe Department of Allergy/Immunology, Walter Reed Army Medical Center, Washington, DC. E-mail: [email protected]. Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Departments of the Army, Navy, the Department of Defense, or the US government. Disclosure of potential conflict of interest: R.L. McCoy is an employee of MD Healthcare Management, Inc. The rest of the authors declare that they have no relevant conflicts of interest.
REFERENCES 1. Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol 2011;127:S1-S55. 2. Nelson HS, Ikle D, Buchmeier A. Studies of allergen extract stability: the effects of dilution and mixing. J Allergy Clin Immunol 1996;98:382-8. 3. Grier TJ, LeFevre DM, Duncan EA, Esch RE. Stability of standardized grass, dust mite, cat, and short ragweed allergens after mixing with mold or cockroach extracts. Ann Allergy Asthma Immunol 2007;99:151-60. 4. Kordash TR, Amend MJ, Williamson SL, Jones JK, Plunkett GA. Effect of mixing allergenic extracts containing Helminthosporium, D. farinae, and cockroach with perennial ryegrass. Ann Allergy 1993;71:240-6. 5. Grier TJ, LeFevre DM, Duncan EA, Esch RE. Stability and mixing compatibility of dog epithelia and dog dander allergens. Ann Allergy Asthma Immunol 2009;103:411-7. 6. Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology. Practice parameters for allergen immunotherapy. J Allergy Clin Immunol 1996;98:1001-111. 7. Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology. Allergen immunotherapy: a practice parameter. Ann Allergy Asthma Immunol 2003;90:S1-S40.
8. Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology. Allergen immunotherapy: a practice parameter second update. J Allergy Clin Immunol 2007;120:S25-S85. 9. Esch RE. Formulation of therapeutic allergen mixtures: problems associated with the number, proportion, and enzymatic activities of allergens. Arb Paul Ehrlich Institut 2000;93:57-61. Available online December 9, 2011. doi:10.1016/j.jaci.2011.10.027
Filaggrin mutations increase the risk for persistent dry skin and eczema independent of sensitization
To the Editor: Previous studies have shown that filaggrin gene (FLG) mutations increase the risk for atopic eczema (AE), but data for non–atopic eczema (non-AE) have been scarce.1,2 We used data from a large Swedish prospective birth cohort (BAMSE) to investigate the association between FLG mutations and dry skin and eczema, divided into AE and non-AE, at age 8 years. The population-based BAMSE study included 4089 children, born between 1994 and 1996 in Stockholm. The children were consecutively recruited during their first months of life.3,4 At baseline, the parents answered a questionnaire, focusing on parental allergic disease and environmental factors. Follow-up questionnaires, containing questions on dry skin, symptoms and signs of eczema, and child’s environmental exposures were collected at age 1, 2, 4, and 8 years. Blood samples were collected at age 8 years. DNA was available for 2033 individuals. Genotyping was performed for FLG mutations common in Scandinavia by using TaqMan allelic discrimination assays for R501X and R2447X and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry for 2282del4. Children with a mutation in any of these positions were classified as having a loss-offunction mutation. Eczema during the first 4 years of life was defined as itchy rash for at least 2 weeks with typical distribution and dry skin during the last year at age 1, 2, or 4 years and/or doctor’s diagnosis of eczema sometime during the first 4 years. Eczema at age 8 years was defined as itchy rash for at least 2 weeks with typical distribution and dry skin during the last year and/or doctor’s diagnosis of eczema from the age of 4 years.3 Eczema and dry skin were considered persistent when present sometime during the first 4 years and during the fifth to the eighth year. Sensitization was defined as having IgE antibodies to a mix of common inhalant (Phadiatop, Phadia AB, Uppsala, Sweden) and/or food allergens (fx5; ImmunoCAP System, Phadia AB). Eczema was divided into AE (eczema according to the definition plus sensitization at age 8 years) and non-AE (eczema according to the definition but no sensitization). Statistical analyses were made with the Stata Statistical Software: Release 7.0 (StataCorp, College Station, Tex). Logistic regression models adjusting for established risk factors (parental allergic disease, breast-feeding, furred pets at home, sex, parental education, and parental smoking during child’s first months) and ‘‘one or both parents born outside Scandinavia’’ were used. Since the analyses had 4 levels of outcome (eg, no dry skin and no eczema, dry skin without eczema, eczema without dry skin, and dry skin with eczema), multinomial logistic regression models
1154 LETTERS TO THE EDITOR
J ALLERGY CLIN IMMUNOL APRIL 2012
TABLE I. Risk for dry skin and eczema at age 8 y in relation to filaggrin mutations No filaggrin mutation Dry skin
Filaggrin mutation
Eczema
N
n
Percent
n
Percent
OR*
95% CI
No No Yes Yes
1165 401 21 310
1112 358 19 274
95.4 89.3 90.5 88.4
53 43 2 36
4.6 10.7 9.5 11.6
1.00 2.64 2.42 2.91
1.72-4.04 0.54-10.85 1.85-4.60
No Yes No Yes
*Adjusted for sex, parental allergic disease, breast-feeding, pets at home, parental education, mother and/or father born outside Scandinavia, and parental smoking during child’s first months.
TABLE II. Risk for dry skin over time up to age 8 y in relation to filaggrin mutations in children who never had eczema Dry skin During first 4 y
No Yes No Yes
No filaggrin mutation
Filaggrin mutation
At 8 y
N
n
Percent
n
Percent
OR*
95% CI
No No Yes Yes
540 403 59 151
520 383 56 130
96.3 95.0 94.9 86.1
20 20 3 21
3.7 5.0 5.1 13.9
1.00 1.35 1.47 4.51
0.72-2.55 0.42-5.16 2.35-8.64
*Adjusted for sex, parental allergic disease, breast-feeding, pets at home, parental education, mother and/or father born outside Scandinavia, and parental smoking during child’s first months.
TABLE III. Risk for eczema over time up to age 8 y in relation to filaggrin mutations Eczema During first 4 y
No Yes No Yes
No filaggrin mutation
Filaggrin mutation
At 8 y
N
n
Percent
n
Percent
OR*
95% CI
No No Yes Yes
1154 395 74 253
1090 364 69 220
94.4 92.2 93.2 87.0
64 31 5 33
5.6 7.8 6.8 13.0
1.00 1.39 1.27 2.65
0.89-2.19 0.49-3.28 1.68-4.20
*Adjusted for sex, parental allergic disease, breast-feeding, pets at home, parental education, mother and/or father born outside Scandinavia, and parental smoking during child’s first months.
were used. Proportions and odds ratios (ORs) are shown with 95% CIs. Moreover, tests for gene-environment interactions were performed between FLG mutations and presence of siblings or cat in the household at birth according to the information provided in the questionnaires. The study population consisted of children with available data on sensitization, FLG status, eczema and dry skin as well as complete information on covariates (n 5 1897). There were no differences in the prevalence of covariates between the study population and the cohort (data not shown). In the study population, dry skin was reported in 711 (37%) children at 8 years, with persistence in 623 (33%) children. Of the children with persistent dry skin, 76% had eczema at some point during their first 8 years, 46% reported eczema at age 8 years, and 38% had persistent eczema. Eczema was reported in 331 (17%) at age 8 years, of whom 164 had non-AE and 167 had AE. Persistence was found in 253 (13%) children, of whom 93% reported dry skin at age 8 years and 92% reported persistent dry skin. FLG mutations were found in 134 (7%) children, all heterozygotes. Children with FLG mutations significantly more often had both parents born in Scandinavia than did children without FLG mutations (90% vs 79%, respectively). In addition, they had a tendency toward a higher degree of exclusive breast-feeding for 4 or more months and a parental history of allergic disease. No differences in the prevalence of siblings were seen between the groups.
FLG mutations increased the risk for dry skin at 8 years significantly (OR 2.69; 95% CI 1.86-3.88). There was an increased risk for dry skin both with and without eczema (Table I). At 8 years, there was an increased risk both for non-AE and for AE (OR 2.58, CI 1.53-4.37 and OR 1.75, CI 0.97-3.16, respectively). FLG mutations increased the risk for persistent dry skin (OR 3.67, 95% CI 2.21-6.10), also in children who never had eczema (Table II), and for persistent eczema (Table III). For eczema at age 8 years, there was no significant geneenvironment interaction between FLG mutations and siblings or cat in the household at birth. Symptoms were assessed by questionnaires, which may be a limitation. Using a definition of eczema that was slightly different from the UK working party’s definition, though validated,3 makes the prevalence figures less comparable with other studies. The prospective and population-based design is a major strength. Follow-up rates are good in the BAMSE study, and loss to follow-up is unlikely to depend on FLG mutations. There were no differences in the prevalence of dry skin, eczema, or covariates between the study population and the cohort. Thus, the results are likely to be representative for the cohort and probably for the population. Our study confirms that FLG mutations increase the risk for persistent eczema eg.5 Furthermore, we show that this is valid also for persistent dry skin and for both AE and non-AE at age 8 years. We could not confirm an increased risk for
LETTERS TO THE EDITOR 1155
J ALLERGY CLIN IMMUNOL VOLUME 129, NUMBER 4
sensitization only, as reported by Bonnelykke et al.6 This inconsistency could partly be explained by our comparison group of healthy children free from both eczema and sensitization. In addition, we observed no interaction between FLG mutations and siblings at birth. This is contradictory to the results of Cramer et al who reported a higher prevalence of eczema in children with filaggrin deficiency if elder siblings were present.7 Moreover, Bisgaard and coworkers8 found an interaction between FLG mutations and neonatal cat exposure, which could not be confirmed in our study. In conclusion, our prospective study shows that FLG mutations increase the risk for persistent dry skin, persistent eczema, and AE and non-AE at age 8 years, without interactions between FLG mutations and siblings or cat in the household at birth. Maria B€ ohme, MD, PhDa* Cilla S€ oderh€ all, PhDb* Inger Kull, RN, PhDc,d Anna Bergstr€ om, PhDe Marianne van Hage, MD, PhDf Carl-Fredrik Wahlgren, MD, PhDa From athe Department of Dermatology and Venereology, Karolinska University Hospital Solna, and the Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden, bthe Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden, cthe Department of Clinical Science and Education, S€ odersjukhuset, Karolinska Institutet, Stockholm, Sweden, dthe Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden, ethe Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, and fthe Department of Clinical Immunology, Karolinska University Hospital Solna, and the Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. E-mail: [email protected]. *Shared first authorship. This study was funded by the Swedish Asthma and Allergy Association, the WelanderFinsen Foundation, and the Swedish Research Council. Financial support was also provided through regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet. Disclosure of potential conflict of interest: C.-F. Wahlgren received research support from the Swedish Asthma and Allergy Association, the Welander-Finsen Foundation, and the Stockholm County Council (ALF). The rest of the authors declare that they have no relevant conflicts of interest.
REFERENCES 1. Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A. Loss-offunction variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol 2006;118:214-9. 2. Irvine AD. Fleshing out filaggrin phenotypes. J Invest Dermatol 2007;127:504-7. 3. B€ohme M, Lanner€ o E, Wickman M, Nordvall SL, Wahlgren CF. Atopic dermatitis and concomitant disease patterns in children up to two years of age. Acta Derm Venereol 2002;82:98-103. 4. Wickman M, Kull I, Pershagen G, Nordvall SL. The BAMSE project: presentation of a prospective longitudinal birth cohort study. Pediatr Allergy Immunol 2002;13: 11-3. 5. Weidinger S, Rodriguez E, Stahl C, Wagenpfeil S, Klopp N, Illig T, et al. Filaggrin mutations strongly predispose to early-onset and extrinsic atopic dermatitis. J Invest Dermatol 2007;127:724-6. 6. Bonnelykke K, Pipper CB, Tavendale R, Palmer CNA, Bisgaard H. Filaggrin gene variants and atopic diseases in early childhood assessed longitudinally from birth. Pediatr Allergy Immunol 2010;21:954-61. 7. Cramer C, Link E, Horster M, Koletzko S, Bauer CP, Berdel D, et al. Elder siblings enhance the effect of filaggrin mutations on childhood eczema: results from the 2 birth cohort studies LISAplus and GINIplus. J Allergy Clin Immunol 2010;125: 1254-60. 8. Bisgaard H, Simpson A, Palmer CNA, Bonnelykke K, Mclean I, Mukhopadhyay S, et al. Gene-environment interaction in the onset of eczema in infancy: Filaggrin loss-of-function mutations enhanced by neonatal cat exposure. PLoS Med 2008;5: e131 doi:10.1371/journal.pmed.0050131. Available online February 22, 2012. doi:10.1016/j.jaci.2011.11.032
Possible eosinophilic esophagitis induced by milk oral immunotherapy To the Editor: New therapeutic strategies to treat food allergy have emerged in recent years.1 At present, oral immunotherapy (OIT) with food is one of the most widely researched treatments for food allergy.2 Immediate adverse reactions during therapy have been widely described,3,4 and most of them were mild. However, long-term effects of OIT have been barely reported.5 We describe 3 cases of esophageal eosinophilia in 110 patients treated with milk OIT at our outpatient clinic during the last 5 years. Our milk OIT protocol consisted of increasing weekly doses of milk in the hospital and daily maintenance of the tolerated dose at home. Once a dose of 200 mL/d was achieved, continued daily intake of this dose at home was compulsory and consumption of dairy products was allowed.4 OIT was performed in 110 milk-allergic children aged 2 to 16 years (mean, 6.8 years) who were followed up for 5 years. IgE-mediated allergy was previously confirmed by using skin prick tests, specific IgE (sIgE) levels, and oral food challenges. After successfully achieving a daily intake of 200 mL of milk, 3 children who were previously asymptomatic developed malaise and gastrointestinal symptoms. Case 1: An asthmatic boy had been diagnosed with milk allergy at age 6 months because of vomiting immediately after drinking milk. He was treated with an elimination diet. He had an egg allergy that resolved spontaneously when he was 2 years old. Endoscopy and biopsy performed at 26 months revealed cardia insufficiency and no inflammatory signs with no eosinophils, leading to a diagnosis of gastroesophageal reflux disease (GERD). He was treated with cycles of omeprazole. At the age of 3 years and 9 months, milk and casein sIgE levels were 55.6 and 67.3 kUA/L, respectively, and an oral challenge with milk was positive. The patient underwent an OIT protocol. After 29 weeks of treatment, he had successfully achieved a 200 mL milk intake, with milk and casein sIgE levels of 23.2 and 25.8 kUA/L, respectively. After 14 months of daily milk intake and dairy products consumption, he began to eat slowly and experienced general weakness, low physical activity, sleep disturbances, and slow growth for 5 months. Markers for celiac disease and Helicobacter pylori were negative. A complete blood cell count revealed 420 eosinophils/mm3, and esophageal endoscopy showed rings and white mucosal exudates with a peak of 35, 35, and 40 eosinophils/hpf in mucosa from the upper, middle, and lower esophagus, respectively. After treatment with omeprazole and oral fluticasone (250 mg/12 h) for 2 months and a milk-free diet for 3 months, he was asymptomatic and endoscopy and biopsy findings were normal. The child remains symptom free after 20 months. Case 2: A boy with atopic dermatitis and asthma vomited after drinking milk. He was diagnosed with milk allergy and GERD at age 7 months, and he was treated with milk-free diet and omeprazole. When he was 11 years old, his milk and casein sIgE levels were 35.1 and 46 kUA/L, respectively, a persistent milk allergy was confirmed by oral challenge, and the patient was included in a milk OIT protocol. He successfully achieved a daily intake of 200 mL in 19 weeks, with no gastrointestinal symptoms and milk and casein sIgE levels of 32.3 and 32.1 kUA/L, respectively. Three months later, he began to experience retrosternal pain and dysphagia related to food ingestion. Markers for celiac disease and H pylori were negative. A complete blood