[Anaphylaxis in children and adults].

In this review, we discuss anaphylaxis, which is a severe allergic condition with potentially life-threatening symptoms from airways or circulation and often associated with skin symptoms. First-line treatment is intramuscular adrenaline given by autoinjector for rapid administration. Initial dose for children less than 25 kg is 0.15 mg and for children ≥ 25 kg and adults 0.3 mg. Repeated smaller doses of adrenaline is to be preferred. Patients with severe anaphylaxis will need an IV access for fluid replacement and supplementary oxygen. Antihistamines and steroids are only second-line treatment after adrenaline administration.

Safety and efficacy of immunotherapy with the recombinant B-cell epitope-based grass pollen vaccine BM32.

BACKGROUND: BM32 is a grass pollen allergy vaccine based on recombinant fusion proteins consisting of nonallergenic peptides from the IgE-binding sites of the 4 major grass pollen allergens and the hepatitis B preS protein. OBJECTIVE: We sought to study the safety and clinical efficacy of immunotherapy (allergen immunotherapy) with BM32 in patients with grass pollen-induced rhinitis and controlled asthma. METHODS: A double-blind, placebo-controlled, multicenter allergen immunotherapy field study was conducted for 2 grass pollen seasons. After a baseline season, subjects (n = 181) were randomized and received 3 preseasonal injections of either placebo (n = 58) or a low dose (80 µg, n = 60) or high dose (160 µg, n = 63) of BM32 in year 1, respectively, followed by a booster injection in autumn. In the second year, all actively treated subjects received 3 preseasonal injections of the BM32 low dose, and placebo-treated subjects continued with placebo. Clinical efficacy was assessed by using combined symptom medication scores, visual analog scales, Rhinoconjunctivitis Quality of Life Questionnaires, and asthma symptom scores. Adverse events were graded according to the European Academy of Allergy and Clinical Immunology. Allergen-specific antibodies were determined by using ELISA, ImmunoCAP, and ImmunoCAP ISAC. RESULTS: Although statistical significance regarding the primary end point was not reached, BM32-treated subjects, when compared with placebo-treated subjects, showed an improvement regarding symptom medication, visual analog scale, Rhinoconjunctivitis Quality of Life Questionnaire, and asthma symptom scores in both treatment years. This was accompanied by an induction of allergen-specific IgG without induction of allergen-specific IgE and a reduction in the seasonally induced increase in allergen-specific IgE levels in year 2. In the first year, more grade 2 reactions were observed in the active (n = 6) versus placebo (n = 1) groups, whereas there was almost no difference in the second year. CONCLUSIONS: Injections of BM32 induced allergen-specific IgG, improved clinical symptoms of seasonal grass pollen allergy, and were well tolerated.

Proficiency testing of skin prick testers as part of a quality assurance system.

BACKGROUND: Skin prick test is an important diagnostic procedure in clinical allergy but documentation of the quality is often missing. METHODS: We describe a proficiency system to evaluate staff members in relation to the international recommended reproducibility in terms of coefficient of variation (CV < 40 %) and the linearity (coefficient of regression >0.85) based on blinded octuplicate histamine testing using histamine 3, 10, 30 and 100 mg/ml. RESULTS: Fourteen trained allergy nurses participated in the proficiency testing. More than 95 % of the nurses, generated coefficient of variation less than 40 %, and for around 35 % of testers the CV were below 20 % based on wheal area. Regarding the linearity (coefficient of regression), only two nurses produced tests with a value below 0.85. On the contrary, 79 % of testers demonstrated a coefficient of regression >0.95. Depending on the gentleness of the prick procedure, the inter-nurse variability in wheal area varied more than twofold corresponding to a 10-doubling of histamine concentration. This would never have been detected without using a proficiency testing system. CONCLUSION: The described histamine testing provides an objective system for the evaluation of basic skin test quality assessment standards especially for documentation in scientific studies.

[Anaphylaxis]. / Anafylaksi.

Anaphylaxis is a potentially life-threatening systemic allergic reaction involving several organ systems. Recognition of the reaction leading to prompt treatment is essential for a good outcome. The lifesaving treatment is intramuscular injection of adrenaline (0.3-0.5 mg for adults and children > 40 kg, 0.3 mg for children 20-40 kg and 0.15 mg for infants < 20 kg). The patient must be placed on the back with elevated lower extremities to improve cerebral and cardiac circulation. High dose oxygen and crystalloid fluid load are needed to improve oxygenation and cardiac output.

Prolonged efficacy of the 300IR 5-grass pollen tablet up to 2 years after treatment cessation, as measured by a recommended daily combined score.

BACKGROUND: The 300IR (index of reactivity) 5-grass pollen tablet has favorable short-term and sustained clinical efficacy in patients with grass pollen-induced allergic rhinoconjunctivitis (ARC). Here, we report maintenance of efficacy and safety over 2 years following treatment discontinuation. METHODS: Randomized, double-blind, placebo-controlled, parallel-group, multicenter Phase 3 trial in patients aged 18-50 years with ARC. During study years 1-3, patients received a daily sublingual tablet containing either 300IR 5-grass pollen extract or placebo, according to a discontinuous pre- and coseasonal protocol. Study years 4 and 5 were treatment-free. In response to health authorities' recommendations, the daily combined score (DCS) was assessed in a post-hoc analysis as the efficacy endpoint. Components of the DCS were daily rhinoconjunctivitis total symptom score (DRTSS) and daily rescue medication score (DRMS). RESULTS: 633 patients with ARC were randomized to placebo (n = 219) or 300IR 5-grass pollen tablet, beginning 4 months (4 M, n = 207) or 2 months (2 M, n = 207) prior to the estimated start of the grass pollen season and continuing until season's end. During the first post-treatment year, a statistically significant difference versus placebo in least squares (LS) mean DCS was noted in patients previously receiving active treatment (300IR (2 M) point estimate: -0.16, 95% confidence interval (CI95%): [-0.26, -0.06], p = 0.0019; -31.1%; 300IR (4 M) point estimate: -0.13, CI95%: [-0.23, -0.03], p = 0.0103, -25.3%). During the second post-treatment year, patients in the 300IR (4 M) group, but not the 300IR (2 M) group, showed a statistically significant difference in LS mean DCS versus placebo (point estimate: -0.11, CI95%: [-0.21; 0.00], p = 0.0478, -28.1%). This significant efficacy seen during the post-treatment years in patients previously treated with 5-grass pollen tablet compared favorably with that during the 3 prior years of active treatment. A statistically significant difference versus placebo was also noted in secondary efficacy measures in both post-treatment years (except for DRTSS in year 5). In the absence of any active treatment, the safety profile was similar in the active groups versus placebo group during either post-treatment year. CONCLUSIONS: In adults with grass pollen-associated ARC, 5-grass pollen tablet therapy beginning 4 months before the pollen season and continuing to season's end demonstrated efficacy across all variables during active treatment, and this effect was prolonged for up to 2 years post-treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00418379.

The effect of a new communication template on anticipated willingness to initiate or resume allergen immunotherapy: an internet-based patient survey.

BACKGROUND: A patient's knowledge of his/her allergic condition and treatment is a key factor in adherence and effectiveness. METHODS: To assess patients' understanding of allergy and acceptance of allergen immunotherapy on the basis of (i) information given by their physician at the time of prescription and (ii) a new communication template viewed some months later, we performed an Internet-based survey of patient panels in France, Germany, Spain, the USA and Russia. The survey participants were either recent "early abandoners" (having discontinued allergen immunotherapy before the end of the prescribed course) or "non-starters" (having decided not to initiate a course of allergen immunotherapy recommended by their physician). All participants completed an on-line questionnaire immediately before and immediately after viewing the new communication template. The study's main objectives were to validate the new communication template and to assess its impact on anticipated willingness to initiate or resume allergen immunotherapy. RESULTS: We surveyed a total of 261 patients (France: 57; Germany: 51; Spain: 52; USA: 51; Russia: 50), comprising 127 "early abandoners" and 134 "non-starters". The mean time since symptom onset and selection for the study was 14.5 years. Subcutaneous allergen immunotherapy had been prescribed in 60 % of cases. Twenty-eight percent of the participants did not know for which allergy they were being treated. Early abandoners reported a perception of low effectiveness (39 %) and complained about expense (39 %) and practical constraints (32 %). Twenty-two percent of the non-starters feared side effects. The communication template was considered to be clear (by 92 % of the patients), convincing (by 75 %) and reassuring (by 89 %); 80 % of the participants felt better informed afterwards, and 67 % stated that viewing the communication template would have made them more likely to continue or initiate allergen immunotherapy (overall willingness score: 5.65 out of 10 before viewing and 7.1 out of 10 afterwards). CONCLUSIONS: After viewing a new communication template on allergy and allergen immunotherapy, patients participating in the survey felt better informed and more likely to initiate or complete this therapy. It now remains to investigate the communication template's effect on actual acceptance of and adherence to allergen immunotherapy.

"The value of pre- and co-seasonal sublingual immunotherapy in pollen-induced allergic rhinoconjunctivitis".

Allergen immunotherapy (AIT) is a guidelines-approved, disease-modifying treatment option for respiratory allergies, including allergic rhinitis (AR) induced by pollen. The various AIT regimens employed to date in pollen-induced AR can be classified as continuous (i.e. year-round) or discontinuous (i.e. pre-seasonal alone, co-seasonal alone or pre- and co-seasonal). Pre-and co-seasonal regimens are typically used for sublingual allergen immunotherapy (SLIT) and have economic and compliance advantages over perennial (year-round) regimens. However, these advantages must not come at the expensive of poor efficacy or safety. The results of recent double-blind, placebo-controlled, randomized clinical trials show that pre- and co-seasonal SLIT is safe and effective in patients with AR induced by grass pollen (treated with a tablet formulation) or by birch pollen (treated with a liquid formulation). Progress in SLIT has been made in defining the optimal dose of major allergen, the administration frequency (daily), the duration of pre-seasonal treatment (four months) and the number of treatment seasons (at least three). Post-marketing, "real-life" trials of pre- and co-seasonal birch or grass pollen SLIT regimens have confirmed the efficacy and safety observed in the clinical trials. In the treatment of pollen-induced AR, pre- and co-seasonal SLIT regimens appear to be at least as effective and safe as perennial SLIT regimens, and are associated with lower costs and good compliance. Good compliance may mean that pre- and co-seasonal SLIT regimens are inherently more effective and safer than perennial SLIT regimens. When considering the pre- and co-seasonal discontinuous regimen in particular, a 300 IR five-grass-pollen formulation is the only SLIT tablet with a clinical development programme having provided evidence of short-term, sustained and post-treatment efficacy.

[Anaphylaxis].

Anaphylaxis is a potentially life-threatening systemic allergic reaction involving several organ systems. Recognition of the reaction leading to prompt treatment is essential for a good outcome. The lifesaving treatment is intramuscular injection of adrenaline (0.3-0.5 mg for adults and children > 40 kg, 0.3 mg for children 20-40 kg and 0.15 mg for infants < 20 kg). The patient must be placed on the back with elevated lower extremities to improve cerebral and cardiac circulation. High dose oxygen and crystalloid fluid load are needed to improve oxygenation and cardiac output.

Sustained efficacy and safety of a 300IR daily dose of a sublingual solution of birch pollen allergen extract in adults with allergic rhinoconjunctivitis: results of a double-blind, placebo-controlled study.

BACKGROUND: Allergic rhinoconjunctivitis (ARC) due to birch pollen is a growing health concern in Europe. Here, we report the efficacy and safety of 300IR birch pollen sublingual solution administered discontinuously for 2 consecutive years to patients with birch-associated allergic rhinoconjunctivitis. METHODS: Birch pollen-allergic adults were randomized in this double blind study to 300IR birch pollen sublingual solution or placebo, daily, starting 4 months before and continuing through the pollen season for two pollen seasons. Randomization was stratified according to the presence or absence of oral allergy syndrome (OAS). The primary efficacy endpoint was the Average Adjusted Symptom Score (AAdSS) over the second pollen season and was analyzed by ANCOVA. Secondary efficacy endpoints included the AAdSS over the first pollen period. Safety was evaluated by means of adverse event monitoring. RESULTS: 574 patients (284 in the active group and 290 in the placebo group) were randomized and 496 completed the study. Over the second pollen period, the least square (LS) mean AAdSS was significantly lower in the 300IR group than in the placebo group (LS mean difference -2.04, 95% CI [-2.69, -1.40], (p <0.0001) with a relative reduction of 30.6%. Results were consistent in patients with and without OAS (-33.6% and -28.4%, respectively). A significant reduction in LS mean AAdSS was also observed over the first pollen season. The most frequently reported adverse events were application site reactions: oral pruritus, throat irritation, and mouth edema. There were no reports of anaphylaxis. CONCLUSIONS: Pre- and co-seasonal treatment with 300IR birch pollen sublingual solution demonstrated sustained clinical efficacy over 2 pollen seasons and was well tolerated in adults with birch pollen-associated allergic rhinoconjunctivitis. Efficacy results were consistent in patients with and without oral allergy syndrome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01731249.

[Indication for adrenalin autoinjector after anaphylaxis]. / Indikation for adrenalinautoinjektor efter anafylaksi.

Anaphylaxis is a potentially fatal hypersensitivity reaction, which should be treated with adrenaline. Patients at risk of recurrent anaphylaxis after the initial episode should be prescribed an adrenalin autoinjector. The patients include persons, who are allergic to insect venom, before they reach the maintenance dose of allergen-specific immunotherapy, persons with food allergy who are at risk of accidental intakes, persons with anaphylaxis induced by low-intensity physical activity, and idiopathic anaphylaxis. The recommended dose of adrenaline is 0.15 mg for children up to 20 kg and 0.30 mg for larger children and adults.

Sustained 3-year efficacy of pre- and coseasonal 5-grass-pollen sublingual immunotherapy tablets in patients with grass pollen-induced rhinoconjunctivitis.

BACKGROUND: Seasonal allergic rhinoconjunctivitis affects millions of persons. The efficacy of allergen sublingual immunotherapy (SLIT) was demonstrated in previous short-term studies. OBJECTIVES: We sought to evaluate the sustained efficacy of 2 dosing regimens of a pre- and coseasonal treatment with 300 IR (index of reactivity) 5-grass-pollen SLIT tablets (Oralair) compared with placebo assessed by using the average adjusted symptom score (AAdSS) at season 3 in adults with grass pollen-induced rhinoconjunctivitis. METHODS: Six hundred thirty-three patients were treated for either 2 or 4 months before and then during the grass pollen season with active or placebo treatment for 3 consecutive seasons. The primary outcome was the AAdSS, a symptom score adjusted for rescue medication use, after 3 consecutive treatment seasons. Secondary outcomes were symptoms and rescue medication score, quality-of-life, and safety assessments. RESULTS: The mean AAdSS was reduced by 36.0% and 34.5% at season 3 in the 2- and 4-month pre- and coseasonal active treatment groups, respectively, compared with that in the placebo group (P < .0001 for both). Reductions were observed in total symptom scores and ISSs and the medication score, with a marked improvement in quality of life for both active groups compared with the placebo group at season 3. Most treatment-emergent adverse events were local reactions expected with SLIT, decreasing in number and intensity in each treatment season. CONCLUSIONS: Sustained efficacy of 2- and 4-month pre- and coseasonal treatment with the 300 IR tablet over 3 pollen seasons was demonstrated, with reduction in symptoms and rescue medication use. The treatment was well tolerated. Adverse events decreased in number and intensity over the 3 seasons.

Treatment with epinephrine (adrenaline) in suspected anaphylaxis during anesthesia in Denmark.

BACKGROUND: Literature on the use of epinephrine in the treatment of anaphylaxis during anesthesia is very limited. The objective of this study was to investigate how often epinephrine is used in the treatment of suspected anaphylaxis during anesthesia in Denmark and whether timing of treatment is important. METHODS: A retrospective study of 270 patients investigated at the Danish Anaesthesia Allergy Centre after referral due to suspected anaphylaxis during anesthesia was performed. Reactions had been graded by severity: C1, mild reactions; C2, moderate reactions; C3, anaphylactic shock with circulatory instability; C4, cardiac arrest. Use of epinephrine, dosage, route of administration, and time between onset of circulatory instability and epinephrine administration were noted. RESULTS: A total of 122 (45.2%) of referred patients had C3 or C4 reactions; of those, 101 (82.8%) received epinephrine. Route of administration was intravenous in 95 (94%) patients. Median time from onset of reported hypotension to treatment with epinephrine was 10 min (range, 1-70 min). Defining epinephrine treatment less than or equal to 10 min after onset of hypotension as early, and more than 10 min as late, infusion was needed in 12 of 60 patients (20%) treated early versus 12 of 35 patients (34%) treated late (odds ratio, 2.09) (95% confidence interval, 0.81-5.35). CONCLUSION: Anaphylaxis may be difficult to diagnose during anesthesia, and treatment with epinephrine can be delayed as a consequence. Anaphylaxis should be considered and treated in patients with circulatory instability during anesthesia of no apparent cause who do not respond to the usual treatments.

Allergen-specific immunotherapy with recombinant allergens.

Subcutaneous immunotherapy is a well-documented treatment of allergic rhinitis and asthma. The major limitation is the risk of anaphylactic side effects. The documentation of clinical efficacy is based on crude allergenic extracts sometimes containing varying amounts of individual allergens including allergens to which the patient may not be sensitized. The introduction of recombinant allergens offer a possibility to use well-defined molecules with consistent pharmaceutical quality defined in mass units. The proof-of-concept of the clinical efficacy of recombinant allergens is based on two studies published as full articles. One study applied a mixture of five Phleum pratense major allergens in a maximum dose of 40 µg protein. The clinical efficacy showed a significant efficacy with about 40% reduction in disease severity. The second study compared a commercial birch extract with both recombinant Bet v 1 and purified Bet v 1 in dosages of 15 µg allergen. The clinical effect was around 60% additional efficacy. Systemic side effects occurred more frequently with grass allergens. A third study used hypoallergenic fragments and a trimer of Bet v 1. The study did not show efficacy and a rather high frequency of systemic side effects. The advantages of using recombinant allergens for immunotherapy are obvious but more large-scale clinical studies are needed before the overall value in terms of efficacy and safety can be determined.

Sensitization to cereals and peanut evidenced by skin prick test and specific IgE in food-tolerant, grass pollen allergic patients.

BACKGROUND: The botanical relation between grass and cereal grains may be relevant when diagnosing food allergy to cereals. The aim was to investigate the diagnostic specificity of skin prick test (SPT) and specific immunoglobulin E (sIgE) tests to cereals and peanut in grass pollen allergic subjects without history of, and clinically reactions to foods botanically related to grass. METHODS: 70 subjects (41 females; mean age 32 years) and 20 healthy controls (13 females; mean age 24 years) were tested by open food challenge (OFC) with cereals and peanut. SPT and sIgE both with Immulite® (Siemens) and ImmunoCAP® (Phadia) to grass and birch pollen, cereals, peanut and bromelain were performed. RESULTS: Of the 65 OFC-negative subjects 29-46% (SPT, depending on cut-off), 20% (Immulite) and 38% (ImmunoCAP) had positive results to one or more of the foods tested. Controls were negative in all tests. Cross-reactive carbohydrate determinants (CCD) as evidenced by reaction to bromelain could explain only a minority of the measured IgE-sensitizations. CONCLUSION: Grass pollen allergic patients with documented food tolerance to cereals and peanut may express significant sensitization. False-positive cereal or peanut allergy diagnoses may be a quantitatively important problem both in routine clinical work and epidemiological studies.

[The influence of allergic rhinitis on asthma]. / Allergisk rinitis' indflydelse på astma.

Allergic rhinitis presents as intermittent or persistent nasal symptoms with sneeze, blockage and secretions. Rhinitis affects more that 20% of the population and is more frequent in younger persons. Allergic rhinitis influences all aspects of quality of life, school performance and work. Most asthmatics suffer from rhinitis and many rhinitis patients suffer from asthma. Patients with rhinitis should be evaluated for asthma and patients with asthma should be evaluated for rhinitis. A combined strategy should be applied in the treatment of upper and lower airways.

Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis.

BACKGROUND: Recombinant DNA technology has the potential to produce allergen-specific immunotherapy vaccines with defined composition. OBJECTIVE: To evaluate the effectiveness of a new recombinant birch pollen allergen vaccine in patients with birch pollen allergy. METHODS: A multicenter, randomized, double-blind, placebo-controlled trial was undertaken to compare the following 3 vaccines in 134 adults with birch pollen allergy: recombinant birch pollen allergen vaccine (rBet v 1a), licensed birch pollen extract, natural purified birch pollen allergen (nBet v 1), and placebo. Patients received 12 weekly injections followed by monthly injections of the maintenance dose containing 15 microg Bet v 1 for 2 years. RESULTS: Significant reductions (about 50%) in rhinoconjunctivitis symptoms (rBet v 1, P = .0002; nBet v 1, P = .0006; birch extract, P = .0024), rescue medication (rBet v 1, P = .0011; nBet v 1, P = .0025; birch extract, P = .0063), and skin sensitivities (P < .0001) were observed in the 3 actively treated groups compared with placebo during 2 consecutive pollen seasons. Clinical improvement was accompanied by marked increases in Bet v 1-specific IgG levels, which were higher in the rBet v 1-treated group than in the birch and nBet v 1-treated groups. New IgE specificities were induced in 3 of 29 patients treated with birch pollen extract, but in none of the 32 rBet v 1-treated or 29 nBet v 1-treated patients. No severe systemic adverse events were observed in the rBet v 1-treated group. CONCLUSION: The rBet v 1-based vaccine was safe and effective in treating birch pollen allergy, and induced a highly specific immune response.

Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis.

BACKGROUND: Sublingual immunotherapy is well tolerated and data suggest its effectiveness for the treatment of allergic rhinitis in adults, but it lacks optimum dose definition. OBJECTIVE: To assess the efficacy, safety, and optimal dose of grass pollen tablets for immunotherapy of patients with allergic rhinoconjunctivitis. METHODS: In this multinational, randomized, double-blind, placebo-controlled study, 628 adults with grass pollen rhinoconjunctivitis (confirmed by positive skin prick test and serum-specific IgE) received 1 of 3 doses of a standardized 5-grass pollen extract, or placebo, administered sublingually using a once-daily tablet formulation. The treatment was initiated 4 months before the estimated pollen season and continued throughout the season. The primary outcome was Rhinoconjunctivitis Total Symptom Score; secondary outcomes included 6 individual symptom scores, rescue medication use, quality of life, and safety assessments. RESULTS: Both the 300-index of reactivity (IR) and 500-IR doses significantly reduced mean Rhinoconjunctivitis Total Symptom Score (3.58 +/- 3.0, P = .0001; and 3.74 +/- 3.1, P = .0006, respectively) compared with placebo (4.93 +/- 3.2) in the intent-to-treat and per-protocol analyses. The 100-IR group (4.70 +/- 3.1) score was not significantly different from placebo. Analysis of all secondary efficacy variables (sneezing, runny nose, itchy nose, nasal congestion, watery eyes, itchy eyes, rescue medication usage, and quality of life) confirmed the efficacy of the 300-IR and 500-IR doses. No serious side effects were reported. CONCLUSION: In the first pollen season, the efficacy and safety of sublingual immunotherapy with grass tablets was confirmed. The 300-IR and 500-IR doses both demonstrated significant efficacy compared with placebo. CLINICAL IMPLICATIONS: The risk-benefit ratio favors the use of 300-IR tablets for clinical practice.