Eczema in young children : aspects of clinical investigation and treatment

Bakgrund: Eksem förekommer hos 10-20% av barn i hela världen. En tredjedel av barnen med eksem har födoämnesallergi. Hos de flesta växer födoämnesallergin bort innan skolåldern. Förbättrat kliniskt omhändertagande och bättre förståelse av hur klinisk tolerans uppkommer är viktiga mål för forskning inom barnmedicin. Studieupplägg: Denna doktorsavhandling baseras på studier av två grupper av barn. Den första är en stor grupp med misstänkt allergi som undersökts med pricktest vid ett tillfälle. Den andra gruppen består av små barn med eksem och misstänkt födoämnesallergi. Barnen påbörjade studien innan två års ålder och har sedan följts över tid till fyra och ett halvt års ålder. Säkerhet vid pricktest: 5908 barn med en medelålder på 6 år och 5 månader, undersöktes med pricktest (SPT). Sju barn (0,12 %) reagerade med generaliserad allergisk reaktion (GAR), och behövde antiallergisk medicinering. Sju barn reagerade vasovagalt (VVR) med svimning eller ”nära-svimning”. Riskfaktorer för GAR var ålder <1 år (RR 6,28) och aktivt eksem (RR 16,98). Risken för VVR var högst hos tonårsflickor och barn/ungdomar undersökta med många allergen (många prickar) samtidigt, oavsett om de var positiva eller inte. Effekt av lokalbehandling och födoämneselimination hos spädbarn med eksem: 123 barn, 52 flickor och 71 pojkar deltog i studien. Åldern varierade mellan 1-24 månader, med en medelålder på 8,4 månader vid studiens början. Kraven för att få delta var eksem och/eller misstänkt födoämnesallergi. Diagnos av eksem gjordes med stöd av Hanifin och Rajkas kriterier. Eksemgrad bedömdes med instrumentet SCORAD. Barnen bedömdes vid två tillfällen med ca sex veckors mellanrum. 62 % av barnen hade positiv pricktest för födoämnen. SCORAD-värdena i gruppen med positiv pricktest var högre än i gruppen med negativ pricktest, barnen som var födoämnessensibiliserade hade alltså svårare eksem. Efter sex veckors behandling; födoämneselimination+ lokalbehandling hos SPTpositiva barn; endast lokalbehandling hos SPT-negativa barn; var det ingen skillnad i eksemens svårighetsgrad mellan de två grupperna. Både födoämnessensibiliserade och icke födoämnessensibiliserade förbättrades signifikant av behandling. En grupp med negativ pricktest, men med påvisade antikroppar mot födoämnen i blodet (analyserade först i efterhand), som behandlades enbart med lokalbehandling förbättrade sina eksem lika mycket som de barn som också ställts på eliminationskost. Antikroppar i blod och saliv i relation till toleransutveckling: Serumnivåer av total- samt ägg- och mjölkspecifika antikroppar av IgE, IgG1 och IgG4 analyserades. I saliv analyserades totalnivåer av sekretoriskt IgA samt specifikt IgA mot mjölk och ägg. Prover togs vid studiens början, efter sex veckor samt vid 4,5 års ålder. Barn som var sensibiliserade mot mjölk och/eller ägg, men som tålde dessa födoämnen vid 4,5 års ålder hade högre IgG4 nivåer och högre IgG4/IgE-kvot vid studiens början, än de barn som ej uppnått tolerans. De högsta IgG4/IgE-kvoterna sågs hos barnen med negativt pricktest men positivt specifikt IgE i blod. Under den första korta observationsperioden på sex veckor sågs ingen påverkan på barnens antikroppsnivåer. Recept/metodutvecklande och resultat av öppna och dubbel-blinda placebokontrollerade födoämnesprovokationer: Efter recept och metodutveckling för födoämnesprovokationer med mjölk och ägg, utfördes 52 provokationer på 39 barn. Fyra barn, alla provocerade blint, reagerade på provokationen. Generella slutsatser: Risken för generaliserade allergiska reaktioner vid pricktest är liten hos barn och tonåringar, men den finns. Riskfaktorer är låg ålder och aktivt eksem. Vasovagala reaktioner är lika vanliga som generaliserade allergiska reaktioner. Lokalbehandling/smörjning ger signifikant förbättring av eksem. Elimination av födoämnen kanske inte är nödvändigt hos eksembarn med sensibilisering för mjölk och ägg under förutsättning att hudvården sköts noga. Höga IgG4/IgE-kvoter av specifika antikroppar mot födoämnen kan vara associerat med snabbare toleransutveckling, och kan stödja idén med fortsatt allergenexponering hos födoämnessensibiliserade barn. Recept på beredningar som väl maskerar komjölk och ägg, vid öppna och blindade födoämnesprovokationer, är en god hjälp vid provokationer av små barn som ofta är misstänksamma mot nya smaker och konsistenser av mat.Background: Eczema affects at least 20 % of children worldwide, and 1/3 of them also have food allergy. In most children, the food allergy is temporary. Improved clinical management and better understanding of etiological mechanisms underlying the tolerance development are target issues in paediatric research. Study design: The thesis is based on two study groups. The first is a large group of children with suspected allergy investigated with skin prick test in a cross-sectional study. The second group is a cohort of infants with eczema and/or suspected food allergy before 2 years of age, investigated prospectively with follow-up to 4.5 years of age. Safety of skin prick test (SPT): 5908 children with a mean age of 6.4 years (range: 1 month – 18 years) were investigated with SPT. Seven children, i.e. 0.12%, displayed a generalized allergic reaction (GAR), necessitating pharmacological treatment. Seven children showed a vasovagal reaction (VVR). Risk factors for GAR were age < 1 year (RR 6.28) and eczema (RR 16.98). The risk for VVR was highest among female adolescents, and children investigated with multiple skin pricks. The effect of skin care and food elimination on eczema in infants: 123 children, 52 girls and 71 boys, with a mean age of 8.4 months (range: 1-24 months) were recruited due to eczema and/or suspected food allergy. For diagnosis of eczema, the Hanifin and Rajka criteria were used, and for scoring of eczema severity SCORAD. The infants were investigated twice with an interval of 6 weeks. 62% showed positive SPTs. The SCORAD was higher among the sensitized children before treatment compared to not sensitized children. After treatment, i.e. skin care for all and elimination diet for sensitized children, there was no difference regarding eczema severity. Both SPT-positive and SPT-negative children decreased their SCORAD values significantly after treatment. A SPT-negative subgroup, with circulating specific IgE to milk/egg, was only treated with skin care, but these children improved their eczema to the same extent as those also treated with an elimination diet. Serum and salivary antibodies and achievement of tolerance Analyses were performed regarding: serum levels of total and egg- and milk-specific IgE antibodies, IgG1 and IgG4 antibodies to β-lactoglobulin (BLG) and ovalbumin (OVA); and salivary levels of total IgA, total SIgA and salivary IgA antibodies to OVA and BLG. Samples were drawn at inclusion, after 6 weeks of intervention (skin care, elimination diet), and at 4.5 years of age. Children sensitized to egg and/or milk who had developed tolerance at 4 ½ years of age had higher levels of IgG4 antibodies to OVA and BLG and also higher IgG4/IgE ratios on inclusion in the study, than those who remained non-tolerant. The highest IgG4/IgE ratios were found in children with circulating IgE antibodies to egg and/or milk but negative SPT on inclusion. The six-week treatment period did not significantly affect the levels of serum and salivary antibodies. Recipes and outcomes of open and double-blinded food challenges in children: After development of recipes for open and blinded challenge with cow’s milk and egg, 52 challenges were performed in 39 children. 4 children, challenged blindly, had a positive outcome of the challenge. General conclusions: The risk for generalized allergic reactions at SPT is low among children and teenagers, but allergic reactions do occur, and low age and eczema are risk factors. Vasovagal reactions occur as often as allergic reactions. Skin care gives significant improvement of eczema severity. Elimination diet may not be needed in infants with sensitization to milk and/or egg, provided that the skin care is adequate. High ratios of serum IgG4/IgE antibodies to food allergens may be associated with faster achievement of clinical tolerance, and may support the concept of benefit from continuing allergen exposure in sensitized children. Recipes for masking of cow’s milk and egg in open or blinded food challenges may help to accomplish challenges in young children, often suspicious to unfamiliar tastes or textures

Linköping University Post Print Urinary nitric oxide excretion in infants with eczema

N.B.: When citing this work, cite the original article. This is the authors ’ version of the following article: which has been published in final form at

Urinary nitric oxide excretion in infants with eczema

Eczema is characterized by inflammation of the skin and is commonly associated with food allergy. It has been suggested that nitric oxide (NO) is an important player in eczema, food allergy and intestinal inflammation. The aim of this study was to assess the levels of urinary NO breakdown products in infants with eczema and the effect of eczema treatment on NO levels. Ninety-four infants with eczema, 58 boys and 36 girls, with a mean age of 7.5 ± 5.2 months (mean ± s.d.) at inclusion were examined twice with an interval of 6 wk. The sum of nitrite and nitrate was measured colorimetrically in urinary samples from both visits and compared with clinical data concerning eczema severity, nutrition, gastrointestinal symptoms, asthma and skin prick positivity. The levels of NO products increased significantly from the first to the second visit: 289; 374 μm (median; IQR) vs. 457; 678 μm (median; IQR) (p &lt; 0.001) in parallel with a significant improvement of the eczema. After eczema treatment consisting of skin care and elimination diet during the 6-wk interval between evaluations, the NO levels approached the values previously found in healthy children. The results support previous studies indicating that the homeostasis of nitrogen radicals is disturbed in childhood eczema.Tidigare titel: Nitric oxide urinary products in infants with eczema This is the authors’ version of the following article: which has been published in final form at:Irene Devenney, Gunilla Norrman, Tony Forslund, Karin Fälth-Magnusson and Tommy Sundqvist, Urinary nitric oxide excretion in infants with eczema., 2010, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, (21), 1, E229-E234which has been published in final form at: http://dx.doi.org/10.1111/j.1399-3038.2009.00892.xCopyright: Wiley-Blackwell</p

High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in life

Children with eczema and sensitization to foods are recommended skin care and, if food allergy is proven by challenge, an elimination diet. For most children the diet period is transient, but the process behind tolerance development and the influence of decreased allergen exposure is not fully known. The aim of the study was to investigate the effect of elimination diet on serum and salivary antibodies and to identify immunological parameters related to the ability to tolerate foods. Eighty-nine children, below 2 yr of age, with eczema and suspected food allergy were included. Recommended treatment was skin care to all children, and 60 children had a period of elimination diet. At 4½ yr of age, the children were divided into two groups, based on if they had been able to introduce the eliminated foods, or not. Serum and salivary antibodies were analyzed with enzyme-linked immunosorbent assay and UniCAP® before and after a 6-wk treatment period and at 4½ yr of age. Children sensitized to egg and/or milk that could eat and drink the offending foods at 4½ yr of age, had higher levels of Immunoglobulin G4 antibodies to ovalbumin and β-lactoglobulin and also higher IgG4/Immunoglobulin E ratios on inclusion in the study, than those who had to eliminate egg and/or milk from their diet, beyond 4½ yr of age. The highest IgG4/IgE ratios were found in children with circulating IgE antibodies to egg and/or milk but negative skin prick test on inclusion. The 6-wk treatment period did not significantly affect the levels of serum and salivary antibodies. In conclusion, eczematous, food sensitized infants with high levels of IgG4 and high ratios of IgG4/IgE antibodies to food allergens are more likely to consume these foods at 4½ yr than infants with low levels and ratios.The fulltext of this work is available at Blackwell-Syergy:Sara Tomičić, Gunilla Norrman, Karin Fälth-Magnusson, Maria C. Jenmalm, Irene Devenney and Malin Fagerås Böttcher, High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in life, 2008, Pediatric Allergy and Immunology, (5), 1, 35-41.http://dx.doi.org/10.1111/j.1399-3038.2008.00738.xCopyright: Blackwell-Synergyhttp://www.blackwellpublishing.com

Intestinal bacteria and permeability during experimental acute pancreatitis in rats

Background: An increase in intestinal permeability and subsequent bacterial translocation has been demonstrated in critical illness. Cellulose derivatives have in the past been shown to reduce gut leakage following liver resection. Aims: The aim of the present study was to evaluate changes in microbial counts in experimental acute pancreatitis and the effect of pre-treatment with cellulose derivatives and N-acetyl cysteine. Subjects: 92 male Sprague Dawley rats. Methods: Acute pancreatitis was induced by intraductal taurodeoxycholic acid infusion. Animals received oral pretreatment and were randomized to either sham operation or the pancreatitis groups, with or without pre-treatment with cellulose derivatives, the antioxidant or their combinations. Intestinal bacterial populations and permeability were evaluated using bacterial counts and Ussing chamber, respectively. Results: The number of E. coli increased in the luminal content and ileal and colonic mucosa, but levels were restored to almost those seen in controls in all pre-treatment groups except for N-acetyl cysteine. When intestinal permeability was measured, none of the treatment groups showed significant differences compared to challenge, except for Nacetyl cysteine, which significantly increased permeability. Conclusion: Pre-treatment with cellulose derivatives was more efficient against disturbances in intestinal permeability and microbial populations than the antioxidant Nacetyl cysteine

Running title: IgG4 and elimination diet Corresponding Author:

High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in lif

Percentage of children who had allergic rhinoconjunctivitis at 4.5 years among the groups with no airway symptoms, allergic rhinoconjunctivitis and asthma at 10 years.

<p>Percentage of children who had allergic rhinoconjunctivitis at 4.5 years among the groups with no airway symptoms, allergic rhinoconjunctivitis and asthma at 10 years.</p

Percentage of children who had had at least one episode of wheezing before inclusion in the groups who had no airway symptoms, allergic rhinoconjunctivitis and asthma at 10 years.

<p>Percentage of children who had had at least one episode of wheezing before inclusion in the groups who had no airway symptoms, allergic rhinoconjunctivitis and asthma at 10 years.</p

Average SCORAD points on inclusion for children with no airway symptoms, allergic rhinoconjunctivitis or asthma at 10 years.

<p>Average SCORAD points on inclusion for children with no airway symptoms, allergic rhinoconjunctivitis or asthma at 10 years.</p

Percentage of children who were diagnosed with asthma at 4.5 years in the groups with no airway symptoms, allergic rhinoconjunctivitis and asthma at 10 years.

<p>Percentage of children who were diagnosed with asthma at 4.5 years in the groups with no airway symptoms, allergic rhinoconjunctivitis and asthma at 10 years.</p