Individually dosed omalizumab facilitates peanut oral immunotherapy in peanut allergic adolescents.

BACKGROUND: Peanut oral immunotherapy (pOIT) has showed good short-term outcomes, but allergic reactions may prevent effective up-dosing and is a major cause of stopping OIT. In placebo-controlled trials, omalizumab has been shown to facilitate allergen immunotherapy and increase tolerance to peanut. OBJECTIVE: We hypothesized that by combining omalizumab with pOIT, and monitor treatment effects with basophil allergen threshold sensitivity tests (CD-sens), peanut allergic patients could safely initiate pOIT and thereafter slowly withdraw omalizumab. METHODS: This is the 2nd part of a one-armed open phase-2 study where peanut allergic adolescents (n = 23) started pOIT after an individualized omalizumab treatment. The pOIT dose was increased from 280 to 2800 mg peanut protein in 8 weeks followed by an individualized step-wise withdrawal of omalizumab, based on clinical symptoms and CD-sens levels. pOIT continued for 12 weeks followed by an open peanut challenge. Peanut CD-sens and allergen-binding activity (ABA) and IgE-ab, IgG-ab and IgG4-ab to peanut and its components were measured during the study. RESULTS: All 23 patients successfully reached the 2800 mg maintenance dose. Moderate/systemic allergic reactions were rare while receiving full-dose omalizumab. Eleven of 23 (48%) successfully continued with pOIT after omalizumab was stopped. Compared to treatment failures, median baseline IgE-ab to peanut components Ara h 1-3 and CD-sens to peanut were significantly lower among successfully treated patients and IgG4-ab to peanut, Ara h 2 and 6 increased significantly more during treatment. CONCLUSIONS AND CLINICAL RELEVANCE: This study indicates that omalizumab is an effective adjunctive therapy for initiation and rapid up-dosing of pOIT; however, adverse events from pOIT become more frequent as omalizumab doses are decreased. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov; NCT02402231. EudraCT; 2012-005625-78.

Individually dosed omalizumab: an effective treatment for severe peanut allergy.

BACKGROUND: Treatment with omalizumab has shown a positive effect on food allergies, but no dosages are established. Basophil allergen threshold sensitivity (CD-sens) can be used to objectively measure omalizumab treatment efficacy and correlates with the outcome of double-blind placebo-controlled food challenge to peanut. OBJECTIVE: To evaluate whether individualized omalizumab treatment monitored by CD-sens could be an effective intervention for suppression of allergic reactions to peanut. METHODS: Severely peanut allergic adolescents (n = 23) were treated with omalizumab for 8 weeks, and CD-sens was analysed before and after. Based on whether CD-sens was suppressed after 8 weeks, the patients either were subject to a peanut challenge or received eight more weeks with increased dose of omalizumab, followed by peanut challenge or another 8-week cycle of omalizumab. IgE and IgE-antibodies to peanut and its components were analysed before treatment. RESULTS: After individualized omalizumab treatment (8-24 weeks), all patients continued with an open peanut challenge with no (n = 18) or mild (n = 5) objective allergic symptoms. Patients (n = 15) needing an elevated omalizumab dose (ED) to suppress CD-sens had significantly higher CD-sens values at baseline 1.49 (0.44-20.5) compared to those (n = 8) who managed with normal dose (ND) 0.32 (0.24-5.5) (P < 0.01). Median ratios for Ara h 2 IgE-ab/IgE were significantly higher in the ED group (17%) compared to the ND group (11%). CONCLUSIONS AND CLINICAL RELEVANCE: Individually dosed omalizumab, monitored by CD-sens, is an effective and safe treatment for severe peanut allergy. The ratio of IgE-ab to storage protein Ara h 2/IgE as well as CD-sens to peanut may predict the need of a higher omalizumab dose. Clinical trials numbers: EudraCT; 2012-005625-78, ClinicalTrials.gov; NCT02402231.

Six years without pholcodine; Norwegians are significantly less IgE-sensitized and clinically more tolerant to neuromuscular blocking agents.

BACKGROUND: As a strong inducer of IgE antibodies to substituted ammonium ion epitopes (QAI), pholcodine (PHO) is a postulated cause of allergic anaphylaxis to neuromuscular blocking agents (NMBAs). Three years after withdrawal of PHO in Norway, a significant reduction in IgE sensitization and anaphylaxis reporting was seen. OBJECTIVE: Six-year follow-up study on the effects of PHO withdrawal on IgE sensitization and anaphylaxis reporting. METHODS: From 650 acute consecutive reports (2005-2013) to the Norwegian Network for Anaphylaxis under Anaesthesia (NARA), total number of reports on suspected anaphylactic reactions, number of reactions where NMBAs were administered, number of reactions where serum IgE antibodies (≥0.35 kUA /l) to suxamethonium (SUX) and PHO were present at time of reaction and anaphylaxis severity grades were retrieved. In addition, NMBA sales and prevalence of IgE sensitization to PHO and SUX among 'allergics' were monitored. RESULTS: From baseline period P0 (PHO on the market) through the first (P1) and second (P2), three-year periods after withdrawal, significant falls in total reports (P < 0.001) and reports with IgE antibodies to PHO (P = 0.008) and SUX (P = 0.001) at time of reaction were found. Total NMBA sales in P2 were 83% of P0, and SUX and rocuronium (ROC) together made up 86% of sales throughout the study. Five NMBA-related anaphylactic deaths occurred during P0 and P1 and, however, none during P2. Prevalence of IgE sensitization to SUX in 'allergics' fell to 0% at 4 and 5 years after withdrawal. CONCLUSIONS: Six years after PHO withdrawal, the Norwegian population has become significantly less IgE-sensitized and clinically more tolerant to NMBAs.

The discovery of IgE.

In 1919, the search began for the factor, later called reagin, that could mediate an allergy, such as allergic asthma, in sera of allergic subjects. In 1967, the fifth class of immunoglobulins, IgE, was discovered and found to be able to carry reagin activity. This discovery has had immense importance for the understanding, diagnosis, and treatment of allergic diseases.

Evaluation of basophil allergen threshold sensitivity (CD-sens) to peanut and Ara h 8 in children IgE-sensitized to Ara h 8.

BACKGROUND: Diagnosing peanut allergy properly is important and can be achieved by combining clinical history with various diagnostic methods such as IgE-antibody (IgE-ab) measurements, skin-prick test, basophil allergen threshold sensitivity (CD-sens) and food challenge. We aimed to evaluate CD-sens to peanut, Ara h 8 and Gly m 4 in relation to an oral peanut challenge in children IgE-sensitized to birch, peanut and Ara h 8 avoiding peanuts. METHODS: Twenty children IgE-sensitized to birch pollen and Ara h 8, but not to Ara h 1, Ara h 2 or Ara h 3 were challenged orally with roasted peanuts. Blood samples were drawn for IgE-ab and CD-sens analysis. To measure CD-sens, basophils were stimulated in vitro with decreasing doses of allergens until threshold sensitivity was reached. RESULTS: All children passed challenge without objective symptoms, but mild oral allergy syndrome (OAS) symptoms were reported in 6/20 children. Nineteen of twenty children were negative in CD-sens to peanut but 17/20 were positive to rAra h 8. Eleven of twenty children were positive in CD-sens to rGly m 4. CONCLUSION: Positive CD-sens to rAra h 8 show that the Ara h 8 IgE-ab sensitized basophils can be activated by a rAra h 8 allergen and initiate an allergic inflammation despite a negative challenge. Hence, children sensitized to Ara h 8 but not to peanut storage proteins may be at risk for systemic allergic reaction when eating larger amounts of peanuts but most likely don't have to fear smaller amounts.

Basophil allergen threshold sensitivity and component-resolved diagnostics improve hazelnut allergy diagnosis.

BACKGROUND: IgE sensitization to hazelnut is common, especially in birch endemic areas. However, its clinical significance often needs to be confirmed by a food challenge. OBJECTIVE: To evaluate the clinical significance of IgE antibodies to hazelnut components and basophil allergen threshold sensitivity (CD-sens) to hazelnut, in relation to double-blind placebo-controlled food challenge (DBPCFC) in children with a suspected hazelnut allergy. METHODS: Forty children underwent a DBPCFC. CD-sens to hazelnut as well as IgE antibodies to hazelnut and its components Cor a 1, Cor a 8, Cor a 9 and Cor a 14 were analysed. Serum tryptase was measured before, during and after DBPCFC. RESULTS: Eight children had a positive DBPCFC, and all of them had a high CD-sens value to hazelnut. Of the 32 children that passed the DBPCFC, 31 were very low or negative in CD-sens. A positive DBPCFC corresponded with significantly higher CD-sens values (median 8.9, range 3.3-281) compared to children negative in challenge (median 0.05, range 0-34.7, P < 0.0001). Children positive in challenge also had higher levels of IgE-ab to Cor a 9 and Cor a 14 (P < 0.01 and P < 0.001, respectively) compared with those with a negative challenge. In relation to the results from DBPCFC, the sensitivity of CD-sens and IgE-ab to Cor a 14 was excellent (100%) and the specificity was very high (> 97% and > 94%, respectively). Five of the eight patients positive at challenge showed an increase in tryptase > 20% compared to tryptase baseline levels. CONCLUSIONS AND CLINICAL RELEVANCE: CD-sens and component-resolved diagnostics to hazelnut, used separately or in combination, may improve the diagnostic accuracy and safety and reduce overdiagnosis of hazelnut allergy.

Successful management of severe cow's milk allergy with omalizumab treatment and CD-sens monitoring.

Food allergy is common in children and young adults and may be difficult to diagnose and is at present treated with avoidance of the food in question. The aim of this report is to share our clinical experiences monitoring omalizumab treatment by basophil allergen threshold sensitivity, CD-sens. Five children, 6-16 years of age, with a severe milk allergy including episodes of anaphylaxis and IgE-antibodies, between 30 and 160 kUA/L to casein and alpha-lactalbumin (milk proteins), were treated with omalizumab. CD-sens, was tested prior to and after 4 months of omalizumab and if turned negative, it was followed by an oral milk challenge. All children became negative in CD-sens and had a negative milk challenge, but one child required doubling of the omalizumab dose to achieve a negative CD-sens before a challenge was done. Omalizumab appears useful in treatment of severe food allergy, e.g., anaphylaxis to milk, and CD-sens monitoring may decide when and how to perform a food challenge.

The discovery of immunoglobulin e and its role in allergy.

Immunoglobulin E (IgE) was discovered in 1967. Today, more than 40 years after the discovery, the normal beneficial function in the body of this enigmatic immunoglobulin still remains unclear. However, ever since the discovery new knowledge about allergic diseases and allergens, new treatments and new diagnostic tools have continued to emerge as a direct result of our ability to identify and measure IgE and IgE antibodies.

Combining analyses of basophil allergen threshold sensitivity, CD-sens, and IgE antibodies to hydrolyzed wheat, ω-5 gliadin and timothy grass enhances the prediction of wheat challenge outcome.

BACKGROUND: Wheat is a common food causing allergy which has implications on the quality of life. The diagnosis of IgE-mediated wheat allergy is based on the clinical history and presence of IgE antibodies (IgE-Ab) in skin or blood, and the results of an oral food challenge which is time consuming and associated with risks. An improved diagnostic workup is needed for wheat allergy. The objective was to examine the relationship between wheat challenge, CD-sens and IgE-Ab to related allergens in wheat-allergic children and investigate if a combination of different markers could enhance the prediction of challenge outcome. METHOD: Twenty-four children (aged 1-15 years) with a wheat allergy diagnosis underwent an open wheat challenge. CD-sens and IgE-Ab to wheat, hydrolyzed wheat protein (HWP), ω-5 gliadin and timothy grass were analyzed and related to the challenge outcome. RESULTS: A positive challenge was seen in 12/24 children. Children reacting to the challenge had higher IgE-Ab concentrations to wheat, ω-5 gliadin and HWP (p < 0.01) and a tendency to higher wheat CD-sens values (p = 0.08) than nonreacting children. Combining wheat CD-sens >150 and IgE-Ab to wheat >20 kUA/l, or ω-5 gliadin >0.1 kUA/l predicted the challenge outcome in 83% of the patients. Most children with IgE-Ab to wheat also had IgE-Ab to timothy. Seven of 9 challenge-positive children had a positive CD-sens to HWP and IgE-Ab to HWP >8 kUA/l. CONCLUSION: Combining CD-sens and IgE-Ab to wheat or wheat components could be useful in the diagnosis and follow-up of wheat-allergic children.

Oral peanut challenge identifies an allergy but the peanut allergen threshold sensitivity is not reproducible.

BACKGROUND: Double-blind placebo-controlled food challenge, DBPCFC, the gold standard for diagnosing food allergy, is time-consuming and potentially dangerous. A basophil allergen threshold sensitivity test, CD-sens, has shown promising results as a diagnostic tool in food allergy. OBJECTIVES: To evaluate the reproducibility of oral peanut challenge and compare the outcome to CD-sens in peanut-sensitized children. METHODS: Twenty-seven children (4-19 years) underwent a DBPCFC followed by a single-blind oral food-challenge. The peanut challenges (1 mg to 5 g) were evaluated by severity scoring. Blood samples were drawn for CD-sens before the two first challenges. RESULTS: Thirteen children (48%) did not react at any of the challenges. Fourteen reacted at both peanut challenges but not to placebo. Only two of these children reacted at the same threshold dose and with the same severity score. All other children scored differently or reacted at different doses. For children with a positive challenge the geometric mean of the ratio of the doses was 1.834 (p = 0.307) and the arithmetic mean of the difference between the severity scores was 0.143 (p = 0.952). No association was obtained between the two peanut challenges regarding severity score (r(s) = 0.11, p = 0.71) or threshold dose (r(s) = 0.35, p = 0.22). Among the children positive in peanut challenge, 12 were positive in CD-sens. Two were low-responders and could not be evaluated. Geometric mean of the ratio of CD-sens values in children with a positive challenge was 1.035 (p = 0.505) but unlike for the severity score and the threshold dose the association between the two CD-sens values was strong (r(s) = 0.94, P<0.001). CONCLUSIONS: For a positive/negative test the reproducibility is 100% for both peanut challenge and CD-sens. However, a comparison of the degree of allergen threshold sensitivity between the two tests is not possible since the threshold dose and severity scoring is not reproducible.

CD-sens can be a reliable and easy-to-use complement in the diagnosis of allergic rhinitis.

BACKGROUND: A reproducible standard for a graded allergen response in allergic rhinitis is lacking. The aim was to evaluate basophil allergen threshold sensitivity, CD-sens, as a diagnostic complement to nasal allergen challenge. METHODS: Twenty-six patients with a history of allergic rhinitis due to grass pollen were intranasally challenged and nasal symptom score and peak nasal inspiratory flow (PNIF) changes were determined after 15 min. A 20% decrease in PNIF or a symptom score ≥2 were considered a positive test. A blood sample for CD-sens was drawn before each challenge. Eighteen patients were tested twice. RESULTS: CD-sens agreed with the positive or negative nasal symptom score in 22/26 and PNIF in 24/26 patients. After the second challenge, 14/18 patients had the same symptom, 17/18 the same PNIF, while all had identical CD-sens classification. CONCLUSION: CD-sens appears to be a reproducible test for diagnosis of allergic rhinitis with great advantages also for follow-up of disease development and treatment effects.

IgE sensitization to the fish parasite Anisakis simplex in a Norwegian population: a pilot study.

The reports on fish parasite Anisakis simplex allergy have increased in countries with high fish consumption in the last decade. In Norway, a high consumption country, the prevalence of immunoglobulin E (IgE) sensitization to A. simplex was still unknown. Thus, our objective was to investigate the sensitization prevalence in this country. At the Haukeland University Hospital, Bergen, Norway, two main groups of surplus serum samples were collected: one from newly recruited blood donors (BDO) and the other from the Allergy laboratory (ALL) after analysing IgE and IgE antibodies. The latter was divided into three series: one containing unsorted sera and two sorted by either Phadiatop(®) ≥0.35 kU(A)/l or total IgE ≥1000 kU/l. The sera were analysed for total IgE and IgE antibodies against A. simplex, shrimp, house dust mite (HDM), cod and cross-reactive carbohydrates (CCDs). The prevalence of IgE sensitization to A. simplex was 2.0%, 2.2% and 6.6% in BDO, the unsorted and Phadiatop(®) positive serum groups, respectively. A considerable degree of cross-sensitization to shrimp and HDM is further suggested. Unspecific binding because of high total IgE or by binding to CCDs seemed to play a minor role. The prevalence of IgE sensitization to A. simplex appears to be lower in a Norwegian population than in other high fish-consuming countries, but might still be overestimated owing to cross-sensitization.

The Pholcodine Case. Cough Medicines, IgE-Sensitization, and Anaphylaxis: A Devious Connection.

: The Scandinavian data on pholcodine (PHO) strongly indicates that there is a biological chain from PHO exposure through IgE-sensitization to IgE-mediated anaphylaxis to neuromuscular blocking agents (NMBA). PHO is probably one of the strongest inducer of an IgE antibody response known. Of individuals taking PHO in cough medicines, over-the-counter accessibility to large populations, as many as 20 to 25% may become IgE sensitized. Once sensitized, PHO re-exposure will booster IgE antibody levels and IgE by around 100-fold. PHO is monovalent for 2 non-cross-reacting epitopes the quaternary ammonium ion (QAI), the main allergenic epitope of NMBA, and a non-QAI epitope. Thus, PHO most unlikely would initiate an allergic inflammatory response. Consequently, IgE sensitization is not revealed by obvious clinical signs, neither through tests based on IgE-sensitized effector cells. Therefore, it will escape detection if not assayed serologically. However, when subjected to general anesthesia, and thus the IgE-sensitized individual is administered a bivalent NMBA intravenously, the unrecognized presence of serum IgE antibodies to QAI may increase the risk of anaphylaxis 200- to 300-fold. Severe damages to patient's health can result, and mortality rates of 3 to 10% are reported. The Scandinavian experience indicates that the chain of events can efficiently be avoided by stopping PHO exposure: Within 1 year, the prevalence of IgE sensitization to PHO and QAI decreases significantly, and after 2 to 3 years, the numbers of reported anaphylactic reactions decreases equally so.

Basophil allergen threshold sensitivity, CD-sens, IgE-sensitization and DBPCFC in peanut-sensitized children.

BACKGROUND: Immunoglobulin E (IgE)-sensitization to peanut is common and can indicate an allergy. A positive test needs to be confirmed by a double-blind, placebo-controlled food challenge (DBPCFC), which is regarded as 'the gold standard'. The aim of the study was to evaluate the basophil allergen threshold sensitivity (CD-sens) and antibodies to peanut allergen components in relation to DBPCFC in the diagnoses of peanut allergy in children. METHODS: Thirty-eight children with suspected peanut allergy underwent a DBPCFC. CD-sens to peanut and Ara h 2 were analysed as well as IgE-antibody to peanut and some of its allergen components (Ara h 1, 2, 3, 8 and 9). RESULTS: Twenty-five children had a positive DBPCFC, and 92% of these were positive in CD-sens to peanut and Ara h 2. Two children with a positive DBPCFC were classified as 'low-responders' and were not further evaluated. Children positive in DBPCFC had higher CD-sens values to peanut (median 1.3; range 0.4-29, n = 21) compared with children negative in DBPCFC (median 0; range 0-0.5, n = 13) (P < 0.0001). A positive DBPCFC correspond with increased levels of IgE-antibody to Ara h 1, 2 and 3 compared with those with a negative challenge (P < 0.0001 for all). All children with a negative CD-sens were negative in DBPCFC. CONCLUSION: In this study, a negative CD-sens to peanut excluded peanut allergy. Both tests, CD-sens to peanut and immunoassay for IgE-antibody to the peanut components, appear to be safe, time saving and cost-effective complements to DBPCFC.

Basophil allergen threshold sensitivity, CD-sens, is a measure of allergen sensitivity in asthma.

BACKGROUND: Allergic asthma is IgE-mediated and the IgE-sensitisation is usually demonstrated by skin prick tests (SPT) and IgE antibody determinations in serum. The SPT and IgE-antibody values do not directly predict if the allergy clinically contributes to the asthma. There is therefore a need for new objective tests that may indicate the clinical importance of an IgE-sensitisation. OBJECTIVE: To evaluate basophil allergen threshold sensitivity (CD-sens) as a measure of allergen sensitivity in allergic asthma. METHODS: Twenty-six subjects with stable, intermittent allergic asthma were tested with SPT and spirometry, and methacholine and allergen inhalation challenges to determine methacholine PD(20) (provocative dose causing a 20% drop in forced expiratory volume in 1 s) and allergen PD(20) . The results were compared with CD-sens and serological parameters, i.e. IgE- and IgG4 antibodies to the relevant allergens. RESULTS: A significant correlation was found between CD-sens and allergen PD(20) (P = 0.01; r = 0.49; n = 26) as well as between CD-sens and the ratio of allergen PD(20) to methacholine PD(20) (P = 0.007; r = 0.52; n = 26). In patients with a moderate to low degree of bronchial hyperresponsiveness there was an excellent correlation (P = 0.0001; r = 0.88, n = 13) between CD-sens and allergen sensitivity. No relation to either allergen PD(20) or the ratio was found for basophil allergen reactivity measured as CD63 up-regulation at high concentrations of the respective allergen. CONCLUSIONS AND CLINICAL RELEVANCE: CD-sens was found to be an objective marker of airway allergen sensitivity in stable allergic asthmatics, that may be used to predict airway responsiveness when bronchial challenge tests cannot be performed.