Outcome of oral food challenges in children in relation to symptom-eliciting allergen dose and allergen-specific IgE.

BACKGROUND: Oral food challenge (FC) protocols are discussed with reference to starting doses, dose increments, safety, and predictability of results. The aim of this study was to evaluate the relation of eliciting allergen doses, specific IgE levels and predictive factors to the outcome of FCs in children. METHODS: In 869 children (median age 1.2 years), FCs were performed with cow's milk (n = 633), hen's egg (n = 456), wheat (n = 265) and/or soy (n = 317) starting at 3-5 mg of protein. Each of the seven doses was administered every 30 min using semi-log increases. Severity of symptoms was graded from I to V. IgE was determined prior to challenges. RESULTS: Of the children allergic to egg or milk, 9% and 10%, respectively, experienced reactions already at the first dose. Of these, 14% (egg) and 4% (milk) experienced grade IV reactions. In contrast, few children reacted to the first doses of wheat or soy, and most reactions occurred after the maximum dose. For all allergens, grade V reactions did not occur. However, grade IV reactions were seen at all eliciting doses. Elevated specific IgE level, young age and a history of atopic dermatitis were associated with a positive challenge outcome for milk or egg, and also IgE levels were associated with lower eliciting allergen doses and more severe symptoms. CONCLUSION: Oral FCs bear a risk of severe reactions at all dose levels. Doses of 3-5 mg protein induced symptoms in up to 10% of children allergic to milk or egg. However, food-specific IgE levels are of limited clinical value for the estimation of FC reactions.

Specific IgE serum concentration is associated with symptom severity in children with seasonal allergic rhinitis.

BACKGROUND: The impact of allergen-specific and total IgE serum levels before and during the pollen season on symptom severity as well as efficacy of treatment with anti-IgE requires further delineation. METHODS: Birch and grass pollen allergic patients aged 6-17 years with seasonal allergic rhinitis (SAR) were analyzed for the association of IgE serum concentration with symptom severity and rescue medication use (combination: symptom load, SL) during the grass pollen season. Reference group A (n = 53) received placebo, while group B (n = 54) received Omalizumab (anti-IgE) monotherapy before and during the grass pollen season. RESULTS: Patients on placebo with high baseline specific grass pollen IgE (>50 kU/l) had a significantly higher SL compared with those with low IgE levels (< or =50 kU/l): SL 1.28 vs 0.61, P = 0.015. This association was nonexistent in patients treated with anti-IgE. In contrast, baseline total IgE levels did not correlate with SL in any group. Patients with anti-IgE treatment and high free total IgE levels (>16.7 ng/ml) had a significantly higher SL compared with those with low free total IgE levels (< or =16.7 ng/ml): SL 0.63 vs 0.23, P = 0.031. CONCLUSIONS: Baseline specific IgE, but not total IgE, is associated with symptom severity during the pollen season in children with SAR. Likewise, the symptom load in SAR patients with anti-IgE correlates with free total IgE levels. Although further research in larger populations is needed to confirm our findings, our data suggest that specific IgE can be used as a parameter for patient selection for this kind of treatment.

Specific oral tolerance induction in food allergy in children: efficacy and clinical patterns of reaction.

BACKGROUND: Specific oral tolerance induction (SOTI) seems to be a promising treatment of food allergy. Specific oral tolerance induction and elimination diet were compared with respect to efficacy rate and patterns of clinical reaction. METHODS: Children with challenge proven immunoglobulin E (IgE)-mediated cow's milk (CM) allergy or hen's egg (HE) allergy were randomly assigned to SOTI or elimination diet as a control group. Specific oral tolerance induction treatment was performed at home on a daily basis according to a study protocol with fresh CM or lyophilized HE protein. Re-evaluation of clinically relevant food allergy was performed by food challenge after a median of 21 months. Children in the SOTI group received a secondary elimination diet for 2 months prior to follow-up challenge to evaluate persistence of induced oral tolerance. RESULTS: At follow-up challenge, nine of 25 children (36%) showed permanent tolerance in the SOTI group, three of 25 (12%) were tolerant with regular intake and four of 25 (16%) were partial responders. In the control group, seven of 20 children (35%) were tolerant. Allergen-specific immunoglobulin E decreased significantly both in children who developed natural tolerance during the elimination diet (P < 0.05) and in those with SOTI (P < 0.001). CONCLUSIONS: Specific oral tolerance induction seems a valid treatment option for patients with persistent food allergy. Indications may be given if avoidance cannot be guaranteed or for those who are eager to eat the food in question. Advantages of SOTI are the increased threshold dose for allergic reactions and the substantially reduced risk of severe allergic reactions after inadvertent ingestion of the allergen. However, careful monitoring during SOTI is mandatory.

Specific oral tolerance induction in food allergy.

Specific oral tolerance in food allergy can be induced by oral administration of the offending food, starting with very low dosages, gradually increasing the daily dosage up to an amount equivalent to a usually relevant dose for daily intake, followed up by a daily maintenance dose. Unfortunately, the body of scientific evidence concerning specific oral tolerance induction (SOTI) is still rather poor. Following a couple of case reports, only a few studies on a limited number of patients including different allergens are available. So far, no placebo-controlled, long-term study has been published. Concerning the underlying immunological mechanism, a limited number of studies have reported on changes in antibody production, and more recently on the role of different T-cell populations. The individual pattern of clinical reaction during SOTI seems to vary considerably between patients and from allergen to allergen. Arguments in favour of SOTI are the safety for an inadvertent intake of the offending food and the increased quality of life. Arguments against SOTI are the necessity for a regular intake and possible long-term compliance problems. Indications to consider SOTI in the future might be (i) importance of the incriminated food for the individual nutritional regimen, (ii) avoidance of the corresponding food cannot be assured and (iii) persistent severe food allergy. However, before SOTI can be recommended for the daily praxis, more studies are warranted to clarify whether certain patients may profit from SOTI and to understand the underlying mechanism.

Controlled oral food challenges in children--when indicated, when superfluous?

The diagnostic work-up of suspected food allergy includes the skin prick test (SPT), the measurement of food specific immunoglobulin E (IgE) antibodies using serologic assays, and more recently the atopy patch test (APT). For specific serum IgE and the SPT, decision points have been established for some foods allowing prediction of clinical relevance in selected cases. The APT may be helpful, especially when considered in combination with defined levels of specific IgE. Controlled oral food challenges still remain the gold standard in the diagnostic work-up of children with suspected food allergy. Most food allergic children will lose their allergy over time. As there is no laboratory parameter, which can accurately predict when clinical tolerance has been developed, controlled oral food challenges are the measure of choice. In this article, the current knowledge of predictors for the outcome of oral food challenges is reviewed and proposals for the daily practical work-up in the case of suspected food related clinical symptoms are presented.

Specific oral tolerance induction with food in children: transient or persistent effect on food allergy?

BACKGROUND: The standard treatment of food allergy is elimination of the incriminated food from the diet. Specific oral tolerance induction (SOTI) seems to be a promising approach for a causal treatment; however, it is unclear whether the tolerance achieved is transient or persistent. We report on a subset of three patients of a larger ongoing study who were treated successfully with SOTI treatment, but experienced a secondary loss of tolerance after a period of allergen avoidance. METHODS: The patients suffered from IgE-mediated allergy either to cow's milk (CM) (patient A) or hen's egg (HE) (patients B and C), confirmed by double-blind, placebo-controlled food challenge (DBPCFC). SOTI treatment was performed at home on a daily basis until tolerance to a maximum of 250 ml CM or 4.5 g lyophilized HE protein was achieved. The daily maintenance dose was 100 ml CM or 2.5 g HE protein. RESULTS: Patients A, B and C reached tolerance to the maximum dose after 37, 41 and 52 weeks, respectively. According to the protocol, patients A and B performed a strict secondary elimination diet for 2 months prior to a follow-up DBPCFC after a maintenance phase of 27 and 39 weeks, respectively. Patient C discontinued treatment for 2 days after 4 weeks on the maintenance dose. Despite previous tolerance, on re-exposure to the allergen all patients experienced moderate systemic allergic reactions. CONCLUSIONS: We conclude that SOTI can induce transient tolerance in food allergy, but does not necessarily lead to its permanent abrogation. Regular allergen intake seems necessary to maintain the established tolerance.

Lack of detectable alterations in immune responses during sublingual immunotherapy in children with seasonal allergic rhinoconjunctivitis to grass pollen.

BACKGROUND: Recent work indicates that subcutaneous specific immunotherapy induces specific T-cell anergy, a shift in the TH1/TH2 ratio, and antibody production in favor of IgG4. There are few data on sublingual immunotherapy (SLIT), especially in children. METHODS: We assessed the proliferation of peripheral blood mononuclear cells ((3)H-thymidine incorporation) and secretion of interleukin (IL)-4, interferon (IFN)gamma and IL-5 (ELISA) after in vitro stimulation with allergen or phytohemagglutinin (PHA) in 29 children with allergic rhinoconjunctivitis receiving SLIT with grass pollen before, and after 1 and 2 years of treatment in a multicenter placebo-controlled study on the efficacy of the treatment. Further, non-specific intracellular production of IL-4, IL-13, IFNgamma, IL-2, IL-10 and IL-5 (FACS) and serum total and specific IgE and IgG4 (ELISA) were analyzed. RESULTS: Proliferation and IL-4 and IL-5 secretion after stimulation with allergen or PHA did not differ between the groups. In addition, we observed no effect of SLIT on intracellular cytokine production. IFNgamma secretion after allergen coculture was comparable between the groups. Following PHA stimulation, IFNgamma secretion was significantly higher in the SLIT group after 1 year, and a trend was observable already before and after 2 years of treatment, probably due to the inhomogeneity in the groups despite randomization (for age and asthma). No significant changes were observed for sIgE/sIgG4 ratios over time either in or between the groups. CONCLUSION: During 2 years of SLIT in children with a positive effect on rescue medication use, we observed no significant effects on in vitro T-cell immune responses or immunoglobulins. So far, pediatric studies demonstrating stable effects of SLIT on such reactions are missing, probably due to limited effects of SLIT on systemic immunologic reactions.

The predictive value of the skin prick test weal size for the outcome of oral food challenges.

BACKGROUND: The skin prick test (SPT) is regarded as an important diagnostic measure in the diagnostic work-up of food allergy. Objective To evaluate the diagnostic capacity of the SPT in predicting the outcome of oral food challenges, and to determine decision points for the weal size and the skin index (SI) that could render double-blind, placebo-controlled food challenges unnecessary. METHODS: In 385 children (median age 22 months), 735 controlled oral challenges were performed with cow's milk (CM), hen's egg (HE), wheat and soy. Three hundred and thirty-six of 385 (87%) children suffered from atopic dermatitis. SPT was performed in all children. Diagnostic capacity, receiver-operator characteristics (ROC) curves and predictive decision points were calculated for the mean weal size and the calculated SI. RESULTS: Three hundred and twelve of 735 (43%) oral food challenges were assessed to be positive. Calculation of 95% and 99% predicted probabilities using logistic regression revealed predictive decision points of 13.0 and 17.8 mm for HE, and 12.5 and 17.3 mm for CM, respectively. However, using the SI, the corresponding cut-off levels were 2.6 and 3.7, respectively, for HE, and 2.7 and 3.7 for CM. For wheat, 95% and 99% decision points of 2.2 and 3.0 were found in children below 1 year of age. CONCLUSION: Predictive decision points for a positive outcome of food challenges can be calculated for HE and CM using weal size and SI. They may help to avoid oral food challenges.

Late clinical manifestation of cerebral tuberculomas in two children with tuberculous meningoencephalitis.

UNLABELLED: We report on two children with cerebral tuberculomas leading to late dramatic clinical exacerbation after appropriate antituberculous chemotherapy and high-dose corticosteroids. A 6-year-old girl with tuberculous meningoencephalitis initially fully recovered. However, after 9 months of continuous therapy she presented with acute increased intracranial pressure caused by tuberculomas requiring rapid drainage of CSF. A 16-year-old boy with miliary pulmonary tuberculosis and severe meningoencephalitis had reached a stable condition for more than 10 months although still suffering from a left-dominant spasticity and motor dysphasia. Fifteen months after initiation of therapy he presented with an acute central paralysis of the left facial nerve, progressive hemiplegia, severe ataxia and increasing lethargy caused by a cerebral tuberculoma with a perifocal oedema. Prolonged treatment with antituberculous chemotherapy and high-dose corticosteroids led to complete recovery in the younger patient and marked improvement in the older patient who remains severely handicapped. CONCLUSION: Patients with initially successful treatment of central nervous system tuberculosis should undergo an alert follow-up for the development of late cerebral tuberculomas. Treatment should consist of prolonged courses of antituberculous chemotherapy and high-dose corticosteroids.

A prospective, randomized, double-blind, placebo-controlled multi-centre study on the efficacy and safety of sublingual immunotherapy (SLIT) in children with seasonal allergic rhinoconjunctivitis to grass pollen.

BACKGROUND: Especially in childhood, sublingual immunotherapy (SLIT) could offer advantages over subcutaneous therapy. However, limited data on its efficacy is available. METHODS: In four German centres 97 children (age 3-14 years) with allergic rhinoconjunctivitis to grass pollen were enrolled in a prospective, double-blind trial comparing SLIT (Pangramin SLIT; ALK-SCHERAX, 0.5 microg major allergens, three times per week, 32 months) with placebo. Primary endpoint was a multiple symptom-medication score for changes in seasonal diary entries between the first and third year of the study (SLIT n=39; placebo n=38). RESULTS: The multiple symptom-medication score was significantly reduced by SLIT to 77.3% of the placebo group (P=0.0498). The subsequent analysis of the single endpoints did not reveal significant differences for symptom scores in favour of SLIT (85.1% of placebo group; P=0.22). However, the medication score improved significantly (67.1% of placebo group; P=0.0025). Furthermore, secondary endpoints assessing in vivo immune responses did not differ significantly between the groups. However, retrospective analysis showed some inhomogeneity for clinical and in vitro parameters at the beginning of the study. Allergic side effects with possible relation to the study drug were reported in both groups (SLIT 49%, placebo 27%, P=0.026). CONCLUSION: Our study indicates that SLIT had a positive effect on the reduction of a multiple symptom-medication score, mainly by significantly reducing rescue medication use, but had no significant effect on symptoms alone in children with rhinoconjunctivitis to grass pollen compared with a placebo.

The co-seasonal application of anti-IgE after preseasonal specific immunotherapy decreases ocular and nasal symptom scores and rescue medication use in grass pollen allergic children.

BACKGROUND: Specific immunotherapy (SIT) and treatment with anti-immunoglobulin (Ig)E antibody are complementary approaches to treat allergic rhinoconjunctivitis, which may be used for single or combined treatment. OBJECTIVE: A randomized, double-blind, placebo-controlled trial was conducted to compare the efficacy of single and combined treatment with SIT and anti-IgE (Omalizumab) in reducing symptom severity and rescue medication use. METHODS: A total of 221 subjects with birch and grass pollen allergic rhinoconjunctivitis aged 6-17 years were analysed during the grass pollen season. Group A (SITbirch + placebo) served as a reference group obtaining no effective treatment for grass pollen allergy. Group B received anti-IgE monotherapy during grass pollen season, group C SIT grass pollen monotherapy, and group D the combined treatment of SIT and Omalizumab. RESULTS: Preseasonal treatment with grass pollen SIT alone compared with SIT with the nonrelated allergen did not reduce symptoms or rescue medication use. Anti-IgE monotherapy significantly diminished rescue medication use and number of symptomatic days. The combined treatment with SIT and anti-IgE showed superior efficacy on symptom severity compared with anti-IgE alone. CONCLUSIONS: Co-seasonal Omalizumab therapy showed considerable effects in children with seasonal allergic rhinitis. The combination of SIT plus Omalizumab was clinically superior to each treatment alone during the first year of observation.