Randomized controlled trials define shape of dose response for Pollinex Quattro Birch allergoid immunotherapy.

BACKGROUND: The Birch Allergoid, Tyrosine Adsorbate, Monophosphoryl Lipid A (POLLINEX® Quattro Plus 1.0 ml Birch 100%) is an effective, well-tolerated short course subcutaneous immunotherapy. We performed 2 phase II studies to determine its optimal cumulative dose. METHODS: The studies were conducted in Germany, Austria and Poland (EudraCT numbers: 2012-004336-28 PQBirch203 and 2015-000984-15 PQBirch204) using a wide range of cumulative doses. In both studies, subjects were administered 6 therapy injections weekly outside the pollen season. Conjunctival Provocation Tests were performed at screening, baseline and 3-4 weeks after completing treatment, to quantify the reduction in Total Symptom Scores (as the primary endpoint) with each cumulative dose. Multiple Comparison Procedure and Modeling analysis was used to test for the dose response, shape of the curve and estimation of the median effective dose (ED50 ), a measure of potency. RESULTS: Statistically significant dose responses (P < .01 & .001) were seen, respectively. The highest cumulative dose in PQBirch204 (27 300 standardized units [SU]) approached a plateau. Potency of the PQBirch was demonstrated by an ED50 2723 SU, just over half the current dose. Prevalence of treatment-emergent adverse events was similar for active doses, most being short-lived and mild. Compliance was over 85% in all groups. CONCLUSION: Increasing the cumulative dose of PQBirch 5.5-fold from 5100 to 27 300 SU achieved an absolute point difference from placebo of 1.91, a relative difference 32.3% and an increase in efficacy of 50%, without compromising safety. The cumulative dose response was confirmed to be curvilinear in shape.

Determination of sIgE to rPhl p 1 is sufficient to diagnose grass pollen allergy.

BACKGROUND: New diagnostic tools such as the basophil activation test (BAT) and component-resolved diagnosis (CRD) are promising for Hymenoptera venom or food allergy. A clear benefit for inhalant allergens has not yet been shown. Our aim was to compare new and established tests for grass pollen allergy. METHODS: Forty-nine patients with grass pollen allergy and 47 controls were prospectively enrolled in the study. A symptom score was calculated for each patient. Conjunctival provocation tests (CPT), skin prick tests (SPT), BAT, and sIgE determination including CRD were performed. Sensitivity and specificity were compared and results were correlated with the symptom score. RESULTS: Single determination of sIgE to rPhl p 1 showed the best balance between sensitivity (98%) and specificity (92%). Use of additional components, such as rPhl p 2 and 5, did not increase sensitivity. Generally, sensitivity of tests was high: SPT 100%, ISAC-112 100%, sIgE to timothy grass 98%, BAT 98%, ISAC-103 84%, and CPT 83%. Specificity ranged from 79% (SPT) to 96% (CPT). All test results and calculated values (e.g. ratio sIgE/tIgE) did not correlate with symptom severity. Asymptomatic sensitization to timothy grass in controls was rare in the CAP (11%) and predominantly due to Phl p 1 sensitization. CONCLUSION: rPhl p 1 was sufficient to diagnose grass pollen allergy, and sIgE patterns were the same in symptomatically and asymptomatically sensitized subjects. The testing of multiple components was of minor importance, and no test correlated with symptom severity.

Analysis of the antibody responses induced by subcutaneous injection immunotherapy with birch and Fagales pollen extracts adsorbed onto aluminum hydroxide.

BACKGROUND: Allergen-specific subcutaneous immunotherapy (SCIT) is an antigen-specific therapy of IgE-mediated allergies. In the present study, we analyze the epitope specificities of antibody responses induced by SCIT with allergen extracts from pollen of trees belonging to the order Fagales (birch, alder, hazel) adsorbed onto aluminum hydroxide. METHODS: The IgE, IgG1-4 and IgA responses to defined recombinant allergens (birch pollen: Bet v 1; alder pollen: Aln g 1; hazel pollen: Cor a 1; apple: Mal d 1) as well as to Bet v 1-derived recombinant fragments and synthetic peptides were analyzed in sera from patients who had undergone SCIT for different periods of time. RESULTS: Long-term SCIT (>1 year; cumulative dose >1,000,000 SQ units) induced more pronounced IgG1, IgG2 and IgG4 responses to Bet v 1 and Bet v 1-related allergens according to the degree of sequence homology (Bet v 1>Aln g 1>Cor a 1>Mal d 1) than short-term SCIT (<1 year; cumulative dose <1,000,000 SQ units). In contrast to patients treated for <1 year, patients treated for >1 year mounted distinct IgG1, IgG2 and IgG4 responses against sequential Bet v 1 epitopes. No relevant allergen-specific IgA or IgG3 responses were induced by short- or long-term SCIT. Using a competitive ELISA assay, it could be shown that serum IgG from patients undergoing long-term SCIT inhibited IgE reactivity to Bet v 1 better than IgG from patients undergoing short-term SCIT. CONCLUSION: SCIT with allergen extracts adsorbed onto aluminum hydroxide induces IgG responses against new epitopes that block IgE binding and cross-react with structurally related allergens depending, among other factors, on duration of treatment and cumulative injected dose.

Immunoglobulin E and G antibody profiles to grass pollen allergens during a short course of sublingual immunotherapy.

BACKGROUND: Various studies have shown the clinical efficacy of sublingual immunotherapy in grass pollen-induced rhinoconjunctivitis. However, even short-term treatment with grass extracts might cause sensitizations to formerly unrecognized antigens. OBJECTIVE: To determine whether the antibody profiles are changing in patients receiving a defined grass pollen extract prior to and during the grass pollen season. METHODS: A randomized, double blind, placebo-controlled, multicenter phase I/I111 trial was started prior to the commencement of the grass pollen season. Patients with grass pollen allergy were randomly allocated to four groups, and received daily a standardized tablet at different doses. Treatment was started 8 weeks prior to the beginning of the pollen season and stopped at the end of the season. Blood samples were taken at the beginning of the study, at the beginning and the end of the pollen season, and one year after commencement of the study. RESULTS: At the beginning of the study, all patients tested positive for the major grass pollen allergens, but negative to the minor antigens. In all patients, the degree of antibody reactivity rose considerably after starting active treatment and fell back to the initial values within one year. Immunoglobulin (Ig) E antibodies to the minor antigens remained negative, independent of treatment and seasonal exposure. In contrast to IgE, specific IgG antibodies to all allergens tested revealed no specific trend. CONCLUSIONS: Immunotherapy with grass allergen tablets was accompanied by an increase in grass-specific IgE antibodies, which further increased during pollen exposure, followed by a post-treatment drop in patient- and disease-specific antibodies. During this short course of treatment, no patient developed any additional sensitizations.

Absence of contact sensitization to Aloe vera (L.) Burm. f.

Aloe vera has been used as a cosmetic and medical remedy since ancient times and has gained increasing popularity in recent years. Despite its widespread use, reports of allergic reactions are rare. We patch tested 702 consecutive patients with an oily extract from the leaves, Aloe pulvis from the entire plant and concentrated Aloe vera gel. A specially designed questionnaire was used for the use of Aloe vera, reasons and location of application, adverse reactions, occupation, hobbies and atopy. None of the subjects showed any reaction to one of the preparations. 2 components of the plant have to be distinguished: the bark of the leaves contains anthrachinones with pro-peristaltic and potential antibiotic and anticancer properties. Constraints have been imposed due to their considerable toxic potential. Today, mostly the Aloe gel from the center of the leaves is processed. It almost exclusively consists of carbohydrates to which also many medical effects have been attributed. Carbohydrates are not likely to induce contact sensitization, which might explain the outcome of our study. However, this does not justify unrestrained promotion of Aloe products, as scientific studies investigating the claims on its constitutional effects are few in number, and the majority of them have been unable to diminish the intuitive scepticism against miracle cures, like Aloe seems to be.

[Sensitization to tea tree oil in Germany and Austria. A multicenter study of the German Contact Dermatitis Group]. / Sensibilisierung auf Teebaumöl in Deutschland und Osterreich--Eine multizentrische Studie der Deutschen Kontaktallergiegruppe.

BACKGROUND AND AIM: Tea tree oil, a distillation product of the Australian tea tree (Melalence alternitolia) is increasingly used as an alternative remedy for various dermatological diseases. Tea tree oil contains several allergenic monoterpenes and sesquiterpenes. In this multicenter study it was evaluated, whether the increasing use of tea tree oil has lead to an increased frequency of sensitization in Germany and Austria which would justify its inclusion into the standard series. PATIENTS AND METHOD: For patch testing a standardized tea tree oil was used, dissolved 5% in diethylphtalate (DEP). Consecutive patients of 11 dermatological departments in Germany and Austria were tested. Readings were taken on day 2 and 3 according to the guidelines of the German Contact Dermatitis Research Group (DKG). RESULTS: 5% tea tree oil was positive in 36/3375 patients (1.1%). Sensitization frequencies showed great regional variations and ranged from 2.3% (Dortmund), 1.7% (Buxtehude), 1.1% (Essen), 0.7% (Graz), to 0% (Berlin, Vienna). 14/36 patients (38.9%) also showed a positive patch test reaction to oil of turpentine. CONCLUSION: Our results show that tea tree oil is an important contact allergen for some centers. It should be tested, if medical history suggests its previous use. Considering the great regional differences in frequencies of sensitization its inclusion into the standard series is not recommended yet.

The seamy side of natural medicines: contact sensitization to arnica (Arnica montana L.) and marigold (Calendula officinalis L.).

Medical remedies of plant origin have gained increasing popularity in recent years. Both anaphylactic and eczematous allergic reactions are on the rise, accordingly. Arnica and marigold, both of the Compositae family, are in widespread use, but only limited data are available on their allergenic potential. We tested 443 consecutive patients, in addition to the European standard and other series, with Compositae mix, sesquiterpene lactone mix, arnica, marigold, and propolis. 5 subjects ( approximately 1.13%) reacted to arnica, 9 ( approximately 2.03%) to marigold. The Compositae mix was positive in 18 cases ( approximately 4.06%). Among them were 3 out of 5 individuals with a sensitization to arnica, and 4 out of 9 who reacted to marigold. Sensitization to arnica and marigold was often accompanied by reactions to nickel, Myroxylon Pereirae resin, fragrance mix, propolis, and colophonium. We conclude that Compositae allergy contributes significantly to the epidemiology of contact dermatitis and that sensitization to arnica and marigold cannot be assessed by testing with the Compositae or sesquiterpene mix alone. As extracts of these plants are frequently used in occupational and cosmetic products, patch testing with additional plant extracts or adjustment of the commercial Compositae mix to regional conditions is recommended.

Cross-reacting allergens in tree pollen and pollen-related food allergy: implications for diagnosis of specific IgE.

BACKGROUND: A number of recombinant allergens are by now constituents of devices that can be routinely used for the detection of specific IgE. Therefore, the results of diagnostic procedures using conventional allergen extracts can be compared with those employing selected recombinant allergens. METHODS: Thirty-four sera from patients allergic to birch pollen were tested with the standard t3-CAP and rBet v 1a- and rBet v 2-CAP. cDNA was prepared by RT-PCR using primers according to the N terminus of purified allergens. Expression cDNA libraries were screened with IgE from selected patients. RESULTS: Twenty-four patients allergic to birch pollen showed the same RAST class with t3 as with rBet v 1a; 8 patients differed within 1 RAST class. In addition, 3 patients showed RAST class 3 with rBet v 2. Besides Bet v 1 and Bet v 2, 3 allergens from celery and avocado belonging to highly conserved protein families were cloned and sequenced. CONCLUSIONS: rBet v 1a can be expected to represent an excellent tool for the diagnosis of patients allergic to birch pollen in Central, Northern, and Eastern Europe. Still, a much higher number of patients has to be tested. For their high degree of conservation, further protein families have to be identified to explain cross-reactivities of birch pollen allergens other than Bet v 1 and Bet v 2 with, e.g., allergens from vegetable food.

Olive oil--contact sensitizer or irritant?

Adverse cutaneous reactions to topically applied olive oil are seldom reported, and positive patch tests to it are mostly regarded as allergic. To evaluate such "positive" patch test reactions, 77 female (mean age: 44 years) and 23 male eczema patients (mean age: 46 years) were prospectively patch tested with freshly prepared olive oil. Tests were performed openly (including ROAT) as well as using Al-tests and Finn Chambers on Scanpor. 5 patients (2 male) showed "positive" test reactions (all patients at the Al-test site, 3 at the Finn Chamber site, 1 with ROAT). In only 1 patient could the reaction be classified as probably allergic, in contrast to previous reports. In conclusion, olive oil is very weakly irritant in general, but bears relevant irritant capacity when applied under occlusive conditions. Therefore, olive oil appears to be less than suitable for the topical therapy of patients with venous insufficiency and associated eczema of the lower extremities.

Allergy to colophony acquired backstage.

The masseur of a famous ballet company developed severe contact dermatitis of his hands. Skin testing yielded a surprising result: not one of the suspected 23 different massage creams that the members of the ballet made him use gave a positive reaction. Only colophony, which was included in the standard test series, was positive. Colophony is regularly used on the shoes of dancers on wooden stages to prevent slipping. The masseur had to change his place of employment.

Effects of physicochemical agents on murine epidermal Langerhans cells and Thy-1-positive dendritic epidermal cells.

The possibility that Thy-1-positive dendritic epidermal cells (Thy-1+DEC) may contribute to the immunologic functions of murine epidermal cells (EC) prompted us to simultaneously assess the effects of certain immunomodulating physicochemical agents on both Thy-1+DEC and Ia-bearing Langerhans cells (LC). C3H/He mice received one of the following treatment modalities: UV-B irradiation (four consecutive days); psoralen plus UV-A (PUVA; three times a week for three consecutive weeks); topically and systemically applied glucocorticosteroids (GCS). Beginning 2 days after the last treatment, animals were sacrificed and the structure and surface marker expression of Ia+EC and Thy-1+DEC were assessed by immunohistologic means on epidermal sheet preparations from ear skin by using appropriate monoclonal antibodies. Whereas low-dose UV-B irradiation (4 X 100 or 200 J/m2) had little, if any, effect on either Ia+EC or Thy-1+DEC, high-dose UV-B (4 X 700 or 1000 J/m2) or PUVA treatment led to an almost complete disappearance of both surface characteristics. Immunoelectron microscopic studies revealed that in the case of LC, high-dose UV-B or PUVA treatment results in the disappearance of their anti-Ia reactivity but leaves their ultrastructural morphology intact. In sharp contrast, Thy-1+DEC escape ultrastructural detection after PUVA treatment and are greatly reduced in number after high-dose UV-B. Ia+EC continuously reappeared with both treatment modalities over a course of 4 to 6 wk, whereas even after 14 to 22 wk Thy-1+DEC were present only in negligible numbers. Similar to high-dose UV-B or PUVA therapy, administration of GCS resulted in the disappearance of both anti-Thy-1- and anti-Ia-reactive cells. Ultrastructural studies disclosed, however, that these steroid-induced alterations in the surface characteristics were accompanied by a dramatic reduction of the LC population but were not paralleled by morphologic changes of Thy-1+DEC. In the course of 7 wk after cessation of steroid treatment, the number of both Ia+EC and Thy-1+DEC had returned to normal values. The selective removal of either of these two dendritic epidermal cell populations by physicochemical agents may provide an excellent strategy to further clarify the functional properties of both LC and Thy-1+DEC.