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Background: Both sublingual allergen-specific immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) have a documented clinical efficacy, but only few comparative studies have been performed., Objective: To investigate the clinical efficacy of SLIT vs SCIT and secondary to compare SLIT and SCIT with placebo and to evaluate the relative clinical efficacy in relation to systemic side-effects., Methods: A 3-year randomized, placebo-controlled, double-blind, double-dummy study including 71 adult birch pollen hay fever patients treated for two consecutive years after a baseline year. Allocation to treatment groups was based on disease severity in the baseline season, gender and age., Results: Clinical efficacy was estimated in 58 patients completing the first treatment year by subtracting baseline data and by calculating the ratio first treatment season vs baseline. SLIT diminished the median disease severity to one-half and SCIT to one-third of placebo treatment. No statistical significant difference between the two groups was observed. Both for symptoms and medication scores actively treated patients showed statistically significant and clinical relevant efficacy compared with placebo. SLIT treatment only resulted in local mild side-effects, while SCIT resulted in few serious systemic side-effects., Conclusion: Based on the limited number of patients the clinical efficacy of SLIT was not statistically different from SCIT, and both treatments are clinically effective compared with placebo in the treatment of birch pollen rhinoconjunctivitis. The lack of significant difference between the two treatments does not indicate equivalent efficacy, but to detect minor differences necessitates investigation of larger groups. Due to the advantageous safety profile SLIT may be favored.

Background: Long-term reproducibility of the skin-prick test (SPT) has been questioned. The aim of the study was to investigate the clinical relevance of SPT changes., Methods: SPT to 10 common inhalation allergens was performed annually from 1999 to 2001 in 25 nonsensitized and 21 sensitized subjects. An SPT was positive when > or =3 mm, and repeatable if either persistently positive or negative. Clinical sensitivity to birch pollen was used as model for inhalation allergy, and was investigated at inclusion and at study termination by challenge tests, intradermal test, titrated SPT and IgE measurements. Birch pollen symptoms were confirmed in diaries., Results: The repeatability of a positive SPT was 67%, increasing significantly to 100% when supported by the history. When not supported by history, the presence of specific IgE was significantly associated with a repeatable SPT. Allergen sensitivity was significantly lower in subjects loosing SPT positivity. The repeatability of a negative test was 95%, decreasing significantly to 87% by the presence of other sensitization. Development of a positive SPT was clinically relevant. Elevation of SPT cut-off point did not enhance repeatability., Conclusion: SPT changes are clinically relevant. Further studies using other allergens are needed. Long-term repeatability of SPT is high in the presence of a supportive history.

Several studies indicate genetic involvement of Th2 cytokines in allergic diseases. Interleukin (IL)-13 has been mapped to the cytokine cluster on chromosome 5q31-33, which has been associated with atopic conditions. Recently, an association was reported between the T allele in a promoter polymorphism in the IL-13 gene (C to T exchange) at position -1055 and allergic asthma in a population study in the Netherlands. This observation was apparently confirmed in a case-control study using probands and spouses from a Dutch asthma family study, but the polymorphism in that study was reported to occur at position -1111. In the present study, we established that this polymorphism is located at position -1024 relative to the ATG translation initiation codon, and investigated whether it confers a genetic predisposition to atopic conditions and the Th1 condition multiple sclerosis (MS) in Caucasian subjects. We confirmed the association between the IL-13 -1024TT genoype and inhalation allergy (P = 2.4E-02). By combining the data from the three studies, we demonstrated a strong association (P = 1.09E-05) between the IL-13 -1024 marker and inhalation allergy. Furthermore, we showed for the first time that this association also exists in atopic dermatitis (P = 2.0E-02). No association with MS was found.

Background: The history of the severity of seasonal allergic symptoms is often obtained post-seasonally as a retrospective assessment. Correct rating is essential when determining the efficacy of pharmaceutical treatment, indications for allergen-specific immunotherapy (SIT), or inclusion into controlled clinical studies., Objectives: To investigate the agreement between in- and post-seasonal ratings of seasonal symptoms, and to investigate whether the effect of SIT could be detected retrospectively., Material and Methods: Thirty-five birch pollen-allergic patients were allocated to SIT or placebo in a double-blind study. Assessment of severity of symptoms from the nose, eyes and lungs were performed daily during the season 2000, and post-seasonally 6 months after the season in 1999 and 2000. A four-point verbal descriptor scale (VDS-4) was used at all occasions. A mean in-seasonal symptom rating was calculated for four periods: the day, the week and the 2 weeks with the highest symptoms score, and the arithmetic season (the period covering the mid-90% of the accumulated pollen count). In- and post-seasonal ratings were compared with Cohen's weighted kappa (kappaw)., Results: Agreement between in-seasonal and retrospective ratings was fair to moderate (kappaw: 0.30-0.60). Post-seasonal ratings were most related to symptoms experienced in the week with the highest symptom scores, and least related to the arithmetic season. The post-seasonal ratings were significantly skewed towards higher symptom scores than the mean of in-seasonal ratings in periods >or= 2 weeks. Despite being comparable before intervention, only in the SIT-treated group was a significant decrease in post-season ratings of severity of rhinoconjunctivitis apparent (P < 0.05). Asthma scores were not reduced but fewer patients in the SIT group reported lung symptoms (P < 0.001)., Conclusion: Post-seasonal assessment of seasonal allergic symptoms generally describes a shorter period than the arithmetic season. Post-season assessment tends to over-rate average symptom severity, but appears sufficiently sensitive to detect treatment efficacy.

CXCR3, known to have four ligands (IFN-gamma inducible protein 10 (gamma IP-10), monokine induced by IFN-gamma (Mig), I-TAC, and 6Ckine), is predominantly expressed on memory/activated T lymphocytes. We recently reported that GM-CSF induces CXCR3 expression on CD34(+) hemopoietic progenitors, in which gamma IP-10 and Mig induce chemotaxis and adhesion. Here we further report that stimulation with GM-CSF causes phosphorylation of Syk protein kinase, but neither Casitas B-lineage lymphoma (Cbl) nor Cbl-b in CD34(+) hemopoietic progenitors can be blocked by anti-CD116 mAb. Specific Syk blocking generated by PNA antisense completely inhibits GM-CSF-induced CXCR3 expression in CD34(+) progenitors at both mRNA and protein as well as at functional levels (chemotaxis and adhesion). Cbl and Cbl-b blocking have no such effects. Thus, GM-CSF binds to its receptor CD116, and consequently activates Syk phosphorylation, which leads to induce CXCR3 expression. gamma IP-10 and Mig can induce Syk, Cbl, and Cbl-b phosphorylation in CD34(+) progenitors by means of CXCR3. gamma IP-10 or Mig has induced neither chemotaxis nor adhesion in GM-CSF-stimulated Cbl-b-blocked CD34(+) hemopoietic progenitors, whereas SDF-1alpha induces both chemotaxis and adhesion in these cells. Interestingly, gamma IP-10 and Mig can induce chemotaxis and adhesion in GM-CSF-stimulated Syk- or Cbl-blocked CD34(+) hemopoietic progenitors. Thus, Cbl-b, but not Syk and Cbl phosphorylation, is essential for gamma IP-10- and Mig-induced chemotaxis and adhesion in CD34(+) hemopoietic progenitors. This study provides a useful insight into novel signaling transduction pathways of the functions of CXCR3/gamma IP-10 and Mig, which may be especially important in the cytokine/chemokine environment for mobilization, homing, and recruitment during proliferation, differentiation, and maturation of hemopoietic progenitor cells.

Background: Allergen-specific immunotherapy (IT) involves the risk of side-effects. Different side-effect profiles have been reported for different allergens, and it would be of great benefit to be able more precisely to predict patient- and allergen-related risk factors., Methods: Fifty-two patients with rhinoconjunctivitis and allergy to birch as well as grass pollen participated in a 3-year IT study, with a baseline year followed by 2 years of treatment. During the first treatment year, the patients received double-blinded IT with either birch (Betula verrucosa) or grass (Phleum pratense) pollen extracts adsorbed to aluminum hydroxide. The following year, the other allergen extract was added. Assessment of systemic reactions (SRs) was performed, and related to patient pretreatment parameters such as seasonal symptoms and medication requirement, skin prick test (SPT), conjunctival provocation test (CPT), nasal provocation test (NPT), total and specific IgE, basophil histamine release (HR), eosinophil count (EOS), eosinophil cationic protein (ECP), and eosinophil protein X (EPX)., Results: In total, 44 and 47 patients started IT with birch- and grass-pollen extracts, respectively. All SRs occurred during the dose-increase phase. No life-threatening SRs were observed. There were a higher number of patients with SRs during IT with grass pollen than IT with birch pollen, 21 vs five patients (P<0.001), with SRs to 3.3% of grass-pollen injections compared to 0.7% of birch-pollen injections (P<0.0001). The SRs of birch-pollen IT were mild, consisting of rhinoconjunctivitis and oral-pharyngeal itching, whereas asthma and urticaria episodes were observed in the grass-pollen IT. No difference was found in sensitivity to birch and grass, when measured by SPT, CPT, NPT, specific IgE, or HR, and no difference was found in age, duration of allergic symptoms, prevalence of asthma, mean seasonal birch/grass symptom score, eye-drop use, or antihistamine or prednisolone intake between the group with and without subsequent SRs to IT. No difference was found in EOS, serum ECP, or EPX, between the group with and without subsequent SRs to IT., Conclusions: IT with grass-pollen extract seems to be associated with a higher number and more severe SRs than birch-pollen IT. Neither demographic data nor diagnostic tests of allergy such as specific IgE, HR, SPT, CPT, and NPT could identify the patients with subsequent SRs.

Background: Evaluation of the efficacy of allergen-specific immunotherapy (IT) with pollen extracts is complicated by annual variation in pollen intensity. Our study aimed to evaluate the efficacy of birch and grass IT, taking into consideration these variations., Methods: After 1 year of observation, 52 patients with rhinoconjunctivitis and allergy to birch as well as grass pollen were allocated to double-blinded clustered IT with aluminum-adsorbed extract produced from either birch (Betula verrucosa) pollen or grass (PIleum pratense) pollen. After 1 year of treatment, the patients continued IT with their original extract and also received the other extract. During the three consecutive pollen seasons, the rhinoconjunctivitis symptom score and the use of antihistamines, eye-drops, and oral prednisolone were recorded. Longitudinal data analysis was used to investigate the relation between different pollen counts and the magnitude of clinical efficacy., Results: An effect of IT was found on symptom score, antihistamine intake, and eye-drop use for both birch and grass (P values <0.05). The mean reduction in symptom score/medication by IT ranged from 24% to 95%, depending on mean seasonal pollen counts. A minimum mean seasonal grass-pollen count of 20-30 pollen grains m3 was required for the efficacy of grass IT to emerge., Conclusions: A model was developed for evaluation of efficacy in longitudinal IT studies, taking the differences in annual pollen counts into consideration. The model showed a significant beneficial role of pollen IT in rhinoconjunctivitis patients allergic to birch and grass pollen.

CXC chemokine receptor 3 (CXCR3), which is known to be expressed predominately on memory and activated T lymphocytes, is a receptor for both interferon gamma (IFN-gamma)-inducible protein 10 (gamma IP-10) and monokine induced by IFN-gamma (Mig). We report the novel finding that CXCR3 is also expressed on CD34(+) hematopoietic progenitors from human cord blood stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) but not on freshly isolated CD34(+) progenitors. Freshly isolated CD34(+) progenitors expressed low levels of CXCR3 messenger RNA, but this expression was highly up-regulated by GM-CSF, as indicated by a real-time quantitative reverse transcriptase-polymerase chain reaction technique. gamma IP-10 and Mig induced chemotaxis of GM-CSF-stimulated CD34(+) progenitors by means of CXCR3, since an anti-CXCR3 monoclonal antibody (mAb) was found to block gamma IP-10-induced and Mig-induced CD34(+) progenitor chemotaxis. These chemotactic attracted CD34(+) progenitors are colony-forming units-granulocyte-macrophage. gamma IP-10 and Mig also induced GM-CSF-stimulated CD34(+) progenitor adhesion and aggregation by means of CXCR3, a finding confirmed by the observation that anti-CXCR3 mAb blocked these functions of gammaIP-10 and Mig but not of chemokine stromal cell-derived factor 1 alpha. gamma IP-10-induced and Mig-induced up-regulation of integrins (CD49a and CD49b) was found to play a crucial role in adhesion of GM-CSF-stimulated CD34(+) progenitors. Moreover, gamma IP-10 and Mig stimulated CXCR3 redistribution and cellular polarization in GM-CSF-stimulated CD34(+) progenitors. These results indicate that CXCR3-gamma IP-10 and CXCR3-Mig receptor-ligand pairs, as well as the effects of GM-CSF on them, may be especially important in the cytokine/chemokine environment for the physiologic and pathophysiologic events of differentiation of CD34(+) hematopoietic progenitors into lymphoid and myeloid stem cells, subsequently immune and inflammatory cells. These processes include transmigration, relocation, differentiation, and maturation of CD34(+) hematopoietic progenitors. (Blood. 2000;96:1230-1238)

CXC chemokine receptor 3 (CXCR3), predominately expressed on memory/activated T lymphocytes, is a receptor for both IFN-gamma-inducible protein-10 (gamma IP-10) and monokine induced by IFN-gamma (Mig). We report a novel finding that CXCR3 is also expressed on eosinophils. gamma IP-10 and Mig induce eosinophil chemotaxis via CXCR3, as documented by the fact that anti-CXCR3 mAb blocks gamma IP-10- and Mig-induced eosinophil chemotaxis. gamma IP-10- and Mig-induced eosinophil chemotaxis are up- and down-regulated by IL-2 and IL-10, respectively. Correspondingly, CXCR3 protein and mRNA expressions in eosinophils are up- and down-regulated by IL-2 and IL-10, respectively, as detected using flow cytometry, immunocytochemical assay, and a real-time quantitative RT-PCR technique. gamma IP-10 and Mig act eosinophils to induce chemotaxis via the cAMP-dependent protein kinase A signaling pathways. The fact that gamma IP-10 and Mig induce an increase in intracellular calcium in eosinophils confirms that CXCR3 exists on eosinophils. Besides induction to chemotaxis, gamma IP-10 and Mig also activate eosinophils to eosinophil cationic protein release. These results indicate that CXCR3-gamma IP-10 and -Mig receptor-ligand pairs as well as the effects of IL-2 and IL-10 on them may be especially important in the cytokine/chemokine environment for the pathophysiologic events of allergic inflammation, including initiation, progression, and termination in the processes.

We report that interleukin (IL)-4 and IL-10 can significantly up- or down-regulate CXC chemokine receptor 4 (CXCR4) expression on CD4+ T lymphocytes, respectively. Stromal cell-derived factor-1alpha (SDF-1alpha)-induced CD4+ T-lymphocyte chemotaxis was also correspondingly regulated by IL-4 and IL-10. IL-4 and IL-10 up- or down-regulated CXCR4 mRNA expression in CD4+ T lymphocytes, respectively, as detected by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). Scatchard analysis revealed a type of CXCR4 with affinity (Kd approximately 6.3 nM), and approximately 70,000 SDF-1alpha-binding sites per cell, among freshly isolated CD4+ T lymphocytes, and two types of CXCR4 with different affinities (Kd1 approximately 4.4 nM and Kd2 approximately 14.6 nM), and a total of approximately 130,000 SDF-1alpha-binding sites per cell, among IL-4-stimulated CD4+ T lymphocytes. The regulation of CXCR4 expression in CD4+ T lymphocytes by IL-4 and IL-10 could be blocked by a selective inhibitor of protein kinase (staurosporine) or by a selective inhibitor of cAMP- and cGMP-dependent protein kinase (H-8), indicating that these cytokines regulate CXCR4 on CD4+ T lymphocytes via both cAMP and cGMP signalling pathways. The fact that cyclosporin A or ionomycin were able to independently change the CXCR4 expression and block the effects of IL-4 and IL-10 on CXCR4 expression implied that the capacity of IL-4 and IL-10 to regulate CXCR4 on CD4+ T lymphocytes is not linked to calcium-mobilization stimulation. These results indicate that the effects of IL-4 and IL-10 on the CXCR4-SDF-1 receptor-ligand pair may be of particular importance in the cytokine/chemokine environment concerning the inflammatory processes and in the progression of human immunodeficiency virus (HIV) infection.

Objectives: 1. To identify all published randomised controlled trials of allergen specific immunotherapy in asthma. 2. To estimate the overall efficacy of allergen specific immunotherapy upon asthmatic symptoms, medication requirements, lung function, nonspecific bronchial hyperreactivity (BHR) and allergen specific BHR., Search Strategy: A search of the asthma database by the Cochrane Airways Group at St. Georges Hospital Medical School, London identified 660 nonunique citations with the keywords Immunotherapy* or Hyposensitive or Desensiti*. This database included all studies published up to 1997 with the keywords Asthma or Wheez* from the Medline, Embase and Cinahl databases, together with other studies identified by handsearching., Selection Criteria: The review was restricted to randomised controlled trials (RCT). Only studies which focussed upon asthma were included. Allergen specific immunotherapy was defined as the subcutaneous administration of extracts of house dust mites, pollens, animal danders or moulds, chemically modified allergoids or antigen-antibody complexes. Although placebo controlled trials were methodologically stronger, studies which administered house dust or other relatively antigenically inactive preparations to the control group were also considered. Double blinded trials were preferred, but single blind and open studies were also reviewed for possible inclusion. At least one of the following clinical outcomes had to be reported: asthmatic symptoms, asthma medication requirements, lung function, nonspecific BHR or allergen specific BHR. Inclusion of studies in the review was decided by a simple majority of all three reviewers, who independently read the methods sections of papers identified by the search strategy and applied the stated criteria. Quality assessment was performed by 2 reviewers, who independently assessed the concealment of allocation., Data Collection and Analysis: The comparisons were: Allergen immunotherapy v placebo, Allergen immunotherapy v antigenically inactive control, House dust v placebo and Allergen immunotherapy v untreated control. These comparisons were performed separately for each outcome, whenever these results were reported. Outcome data were extracted and entered into RevMan 3.0.1 for statistical analysis. Categorical outcomes were analysed as odds ratios (OR) and 95% confidence intervals (95% CI) calculated by Peto's method. Continuous outcomes were analysed as standardised mean differences (SMD). Fixed effects models were used to obtain summary statistics for the overall efficacy of allergen immunotherapy and x2 tests were performed to assess heterogeneity between studies., Main Results: Fifty four randomised controlled trials published between 1954 and 1997 satisfied the inclusion criteria. There were 25 studies reporting immunotherapy for mite allergy, 13 studies of pollen allergy, eight studies of animal dander allergy, two studies of allergy to the mould Cladosporium and six studies which attempted simultaneous immunotherapy for multiple aeroallergens. Concealment of allocation was assessed as clearly adequate in only 11 studies. The adequacy or otherwise of 40 studies could not be determined from the details published in the papers. Only three studies used a clearly inadequate method for concealment of allocation. There was a significant overall improvement in asthma symptom scores following immunotherapy (combined SMD -0.52; 95% -0.70 to -0.35). Patients randomised to immunotherapy were also significantly less likely to report a deterioration in asthma symptoms than those randomised to placebo (OR 0.27; 95% CI 0.21 to 0.35). Asthma medication requirements were significantly reduced (SMD -0.51; 95% CI -0.74 to -0.28). Patients randomized to immunotherapy were also significantly less likely to require medication than those randomised to placebo (OR 0.28; 95% CI 0.19 to 0.42). There was no overall improvement in lung function following immunotherapy and marked hete

We report that NF-AT1 and NF-AT4 are expressed cytoplasmically in resting eosinophils, whereas NF-AT2 and NF-AT3 have not been seen. Likewise, NF-AT1 mRNA and NF-AT4 mRNA have been detected in resting eosinophils, and their levels can be significantly up-regulated by the Th2-associated cytokines IL-4 and IL-5. There is no detectable NF-AT protein expression in the nuclei of resting eosinophils. However NF-ATs appear in the nuclei of IL-4-, IL-5-, or ionomycin-stimulated eosinophils. Only NF-AT1 and NF-AT4, but not NF-AT2 and NF-AT3, have translocated into the nuclei in IL-4- or IL-5-stimulated eosinophils. These findings delineate a novel pathway in the cytokine network in which Th2 lymphocytes "control" eosinophils via the release of IL-4 and IL-5, and activation of NF-AT in eosinophils. The findings also suggest that a later feedback "talking" may exist between eosinophils and Th2 lymphocytes.

Background: Specific immunotherapy (SIT) of allergic disorders as introduced by Freeman and Noon involves the application of gradually increasing doses of extracts of the material to which the individual is sensitive. SIT represents the only specific treatment that can be offered to allergic patients besides allergen avoidance. SIT has been widely used in patients with pollen allergic rhinitis and its clinical efficacy has been demonstrated in several controlled clinical trials. The underlying mechanism of this treatment is still not understood. Previous studies have focused on changes in serum antibodies, including blunting of seasonal rises in specific IgE and increases in specific IgG antibodies, especially of the IgG4 isotype. Recent studies have suggested an effect on T-lymphocytes, leading to a switch from a predominant Th2 response--that is, interleukin (IL)-4 and IL-5--to a Th1 response involving interferon (IFN)-gamma. The switch of a cytokine profile to a predominant IFN-gamma response results in inhibition of IL-4 dependent IgE production, which is reinforced by a decrease in the production of IL-4 by Th2 cells., Methods: In the present study a meta-analysis was performed to evaluate all double-blind placebo-controlled studies investigating the effect of SIT on clinical and immunological treatment used in patients with allergic rhinoconjunctivitis., Results: SIT was shown to be an effective treatment modality in allergic rhinoconjunctivitis, decreasing symptoms, the need for medication and reactivity in specific nasal and conjunctival provocation tests, as well as inflammatory markers. Histologically, a switch might be induced from a predominant Th2 cell profile to that of a Th1., Conclusions: In general, the efficacy of SIT is dependent on the allergen the individual patient is sensitive to, the quality and total amount of the allergen applied and the SIT schedule.

Background: Antihistamines (H1-receptor antagonists) act by competitive antagonism of histamine at H1-receptors. In addition, high concentrations of some antihistamines inhibit allergen-induced histamine release from mast cells in vitro., Objective: The purpose of this study was to determine the effect of intranasal azelastine or systemic cetirizine (both potent antihistamines) on the allergen-induced release of mast-cell mediators from the human nasal mucosa in vivo., Methods: Patients allergic to birch pollen (n = 11) and control subjects not allergic to birch pollen (n = 5) were included in a randomized, double-blind, placebo-controlled, 3-way crossover study outside the pollen season. Each subject was treated with azelastine nasal spray 0.14 mg per nostril twice daily, cetirizine tablets 10 mg every day, or placebo for 1 week using a double-dummy design. At the end of each treatment period, nasal allergen challenges were performed, and the number of sneezes were counted. In addition, nasal lavage fluid was collected, and the levels of mast-cell mediators (histamine and tryptase) were measured., Results: The allergen challenge of patients allergic to pollen produced sneezing and a significant increase in the levels of histamine and tryptase. The challenge of subjects not allergic to pollen produced no such response. Azelastine and cetirizine significantly reduced allergen-induced sneezing and the associated increase in histamine and tryptase levels. No significant differences were found between the azelastine and cetirizine treatments., Conclusion: Pretreatment with azelastine or cetirizine inhibits the allergen-induced release of mast-cell mediators from the human nasal mucosa. Our results are consistent with the hypothesis that both antihistamines reduce mediator release from nasal mucosa mast cells in vivo. However, further studies are necessary to test this hypothesis.

Efficacy monitoring of immunotherapy (IT) is performed to adjust the therapy according to the patient's reactions, to collect data for scientific studies and to evaluate the efficacy of IT. A decrease of allergy symptoms and of drug use are the main parameters. For this, allergy diaries are most suitable. Pollen exposition should be monitored with Burkhard traps. Wheal and flare reactions in skin tests can be measured by visual inspection with quantification of the diameter on transparent foils or by means of laser scanners. Nasal provocation testing leads to subjective and objective (rhinomanometry, acoustic rhinometry) results. A change in the threshold concentration of allergen, which is needed to provoke a positive test reaction, can be used to evaluate the success of an IT. Additionally, systemic or local side-effects should be carefully revealed. Cytologic measures can be achieved by nasal lavages. Cotton samplers, cytology brushes and suction techniques are used to collect cells and nasal secretions. Early and late allergic reactions can be evaluated. Specific cell activation markers like ECP or tryptase are useful parameters in nasal secretions. T-lymphocyte subpopulations and T-cell-lymphokine-profiles can be detected. During IT, a change from a dominating TH2-cytokine-profile to a dominating TH1-cytokine-profile can be seen. For the reason of their expense, those methods are restricted to scientific investigations and only rarely used for routine diagnostics.

From January 27 to 29, 1997, experts on allergen immunotherapy from various geographic locations throughout the world met at the headquarter of the World Health Organization (WHO) in Geneva, Switzerland to reach a consensus on international guidelines. Guidelines or indications for immunotherapy with inhalant allergens and venoms have been published before by the WHO, the European Academy of Allergy and Clinical Immunology (EAACI), the International Consensus Report on Asthma, the Global Strategy for Asthma Management and Prevention, the International Consensus Report on Rhinitis, the British Society for Allergy and Clinical Immunology, the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI). The committee wrote a position paper based on scientific articles reviewed for data before April 1, 1997. These guidelines should result in a better understanding of the science and rationale for using allergen immunotherapy as well as improve the safety of such therapy. The document also defines new techniques being developed which may result in better efficacy and less risk for allergen immunotherapy as well as recommends areas of additional and necessary research.

The World Health Organization and various allergy, asthma, and immunology societies throughout the world met on January 27 through 29, 1997, in Geneva, Switzerland to write guidelines for allergen immunotherapy. Over the ensuing year, the editors and panel members reached a consensus about the information to include in the WHO position paper "Allergen immunotherapy: Therapeutic vaccines for allergic diseases." The historical term allergen extract was changed to allergen vaccine to reflect the fact that allergen vaccines are used in medicine as immune modifiers. The document summarizes the scientific literature and rationale for the appropriate use of such therapy to treat allergic rhinoconjunctivitis, allergic asthma, and Hymenoptera hypersensitivity. It also includes recommendations to improve safety, discusses new techniques being developed that may result in better efficacy and less risk, and offers recommendations for areas of additional and necessary research.

Background: A growing body of evidence suggests that proinflammatory cytokines play a role in allergic inflammation by attracting and activating inflammatory cells. In this study, we have investigated the relationship between interleukin-8 (IL-8) in nasal lavage fluid and the local activation of eosinophils and neutrophils following nasal allergen challenge of allergic patients., Methods: Nasal challenges were performed with grass pollen extract in 14 allergic patients and 5 nonallergic controls. Nasal lavage fluid was collected repeatedly for 10 h, and the levels of eosinophil cationic protein (ECP) and myeloperoxidase (MPO) were used as markers of eosinophil and neutrophil activation, respectively. The levels of these molecules were compared with that of IL-8 in nasal lavage fluid., Results: Allergen challenge of allergic patients produced a significant late-phase increase in the levels of ECP and MPO. Furthermore, the level of MPO showed a highly significant correlation with the level of IL-8 in lavage fluid (r = 0.8, p< 0.0001), whereas there was no significant relationship between the levels of ECP and IL-8., Conclusion: Interestingly, our findings suggest that both eosinophils and neutrophils are activated following nasal allergen challenge. In addition, our results are consistent with the hypothesis that IL-8 acts as a chemoattractant/activator of neutrophils during the late phase of the allergic inflammation. In contrast, we were not able to demonstrate any significant relationship between the level of IL-8 in lavage fluid and the activation of eosinophils.

Background: The level of histamine in nasal lavage fluid has been used as an index of mast cell/basophil activation in a number of studies. Obviously, such an index can only be valid if changes in the secretory activity of nasal glands do not affect the level of histamine in lavage fluid (i.e. hypersecretion, without a simultaneous activation of mast cells/basophils in the nasal mucosa, must not increase the level of histamine)., Objectives: To asses the effect of nasal hypersecretion on histamine levels in lavage fluid., Methods: Nasal challenges were performed with methacholine and allergen in grass pollen-allergic patients and non-allergic controls. Nasal lavage fluid was collected before and repeatedly for nine hours after nasal challenge, and the level of histamine was compared with that of a specific mast cell-derived enzyme, tryptase. In addition, the effect of methacholine on basophils was examined in vitro., Results: Allergen challenge of allergic patients produced sneezing and a significant increase in histamine and tryptase levels, whereas challenge of non-allergic subjects produced no such response. Interestingly, challenge with methacholine also induced a significant increase in histamine levels. This increase was seen in both allergic and non-allergic subjects and it was not associated with any sneezing or increase in tryptase levels, indicating that mast cells were not activated. Furthermore, stimulation of basophils with methacholine did not induce any histamine release in vitro., Conclusions: Apparently, there exists a pool of histamine in the human nose that can be transferred to lavage fluid during glandular hypersecretion. The source of this histamine is yet to be identified. As the level of histamine seems to be affected by the secretory activity of nasal glands, we question the use of this single mediator as an index of mast cell/basophil activation in nasal lavage studies.

Adrenaline is the drug of choice for the treatment of anaphylaxis. The indications, available formulations, and rules for prescribing adrenaline for self treatment of anaphylactic reactions in allergic subjects are summarized in this paper. Emergency kits containing adrenaline must be prescribed only to patients with a definite history of anaphylactic reactions or laryngeal oedema. A kit containing Adrenaline DAK 1 mg/ml in a traditional glass ampoule together with a 1 ml syringe and an i.m. cannula is the cheapest solution, and a usable alternative in the patient who after sufficient training feels safe to prepare his own injection. Ana-guard injector is recommended for the allergic adult due to its easy handling and the fact that it contains two doses of adrenaline 0.3 mg. For both children and adults with a low bodyweight, the Epi-Pen automatic injector is recommended. It contains one dose of adrenaline (0.15 or 0.30 mg) and requires no preparation before use. The Adrenalin Medihaler is recommended for the treatment of laryngeal oedema and threatened airway obstruction. Due to the low and unpredictable absorption after inhalation, adrenaline injection is recommended for the treatment of systemic symptoms. Prescribing adrenaline in semi-or automatic injectors requires special permission from the Danish Health Authorities.

Background: Specific immunotherapy treatment in allergic diseases involves a risk of systemic side effects. A double-blind, placebo-controlled study was performed in 45 patients allergic to pollen to determine whether pretreatment with loratadine could reduce the number and severity of systemic reactions during the dose-increase phase of cluster immunotherapy., Methods: The patients received cluster immunotherapy with a standardized birch (Betula verrucosa) or grass (Phleum pratense) pollen extract adsorbed to aluminum hydroxide. The immunotherapy schedule involved seven visits and 14 injections to reach a maintenance dose of 100,000 standardized quality units. Loratadine, 10 mg, or placebo tablets were administered 2 hours before the first injection at each visit., Results: A total of 720 injections were given (309 injections in 21 patients receiving loratadine and 411 injections in 24 patients receiving placebo). The median numbers of injections to reach maintenance dose were 15 (range, 14 to 18) in the loratadine group and 16 (range, 14 to 23) in the placebo group (p = 0.037). The numbers of patients with systemic reactions were seven (33%) and 19 (79%) in the loratadine and placebo groups, respectively (p = 0.002). Twenty-five reductions caused by systemic reactions were observed in the placebo group in contrast to nine in the loratadine group (p = 0.047). No life-threatening systemic reactions were observed in either group. Systemic reactions were, however, more severe in the placebo group, mainly because of a significantly higher incidence of urticaria (10 vs 1, p = 0.022)., Conclusion: Pretreatment with loratadine seems to reduce both the number and severity of systemic reactions in specific cluster immunotherapy.

Components in the insect venom and probably also in their saliva may have direct toxic effects or may cause sensitization and may result in allergic reactions to subsequent stings. In Denmark, only the stings of honey bees and wasps (yellow jackets) are of clinical significance and it is important to be aware that these insects contain separate allergenic components. Clinical manifestations following stings are observed from all of the organ systems on the whole. The commonest are itching of the skin, urticaria, possibly angioedema and slight generalized symptoms with vertigo, headache and fatigue. Life-threatening reactions may also occur and one or two fatal cases are registered annually in Denmark. It may be difficult to decide whether an allergic or a toxic reaction is involved on the basis of the symptoms. Possible IgE-sensitization must therefore be assessed by means of a prick test and measurement of specific IgE. The main treatment in cases of acute systemic reactions is adrenaline which may possibly be supplemented with antihistamine and corticosteroid. In cases of massive local reactions and urticaria, antihistamines will, as a rule, prove sufficient. Hyposensitization with insect venom preparations eliminates the future risk for systemic insect sting reactions practically entirely and this must be recommended for patients with demonstrated IgE-sensitizing and generalized reactions. At present, treatment should be continued for three to five years and protection lasts for a series of years after cessation of treatment.

Sera from 33 patients with mold allergy proven by bronchial provocation were analyzed for specific IgE against six mold species comparing an improved Phadebas RAST with four other techniques. The new method was more sensitive and gave significantly higher IgE antibody concentrations for all tested molds except Cladosporium herbarum.

A placebo-controlled, double-blind study of immunotherapy with the mould species Cladosporium was performed in 22 adult asthmatics. The diagnosis of Cladosporium allergy was based on a combination of bronchial provocation test and daily symptom score in the Cladosporium season. An aqueous preparation of a potent, biologically standardized and purified extract was used in a clustered dose-increase regimen. The clinical efficacy was evaluated by a combination of symptoms (asthma score + peak flow) and consumption of antiasthmatic medication. The mean changes in symptoms and medication consumption over a 10-week registration period (peak Cladosporium season) in 1982 after 5-7 months of immunotherapy were compared with the corresponding 1981 pretreatment 10-week period. A significant (P = 0.03) difference in terms of "improved", "unchanged" and "deteriorated" patients in favour of Cladosporium treatment was found. Approximately 80% in the Cladosporium group showed improved/unchanged symptoms contrary to 30% of the placebo treated. Side effects were observed frequently but only in the Cladosporium-treated. About 70% experienced a large local reaction and 100% had episodes of asthma during dose-increase phase. Only a few severe systemic reactions occurred. Based on the clinical efficacy of the treatment we consider immunotherapy with Cladosporium feasible for highly specialized clinics.

Skin prick test has advantages over other diagnostic tests in allergy, and attempts to increase the reproducibility are warranted. A standardised disposable precision needle with a needle point of 1.0 mm has recently become available. Based on 960 tests with histamine and grass pollen (Phleum pratense) the reproducibility of the skin prick weal area was calculated. Using histamine 10 mg/ml and grass pollen (1000 and 5000 PNU) a significantly lower coefficient of variation was found compared with a standard blood lancet with a point of 4 mm. The mean weal reaction is reduced to about 80% of the size obtained with the blood lancet. Testing with the precision needle resulted in a significantly reduced incidence of bleedings. The precision needle simplifies the skin test and does not require as much skill as other needles, and is recommended for both routine tests and the biological standardization of allergen extracts.

Sera from 73 grass pollen allergic patients in two double blind studies on hyposensitization were investigated for IgE response towards one major timothy allergen-antigen 19 (Ag 19) by means of crossed radioimmunoelectrophoresis (CRIE). The clinical efficacy of hyposensitization after initial preseasonal treatment was positively correlated with increase in specific IgE binding to Ag 19. It was possible to predict the clinical efficacy by comparing CRIE performed on sera before and after 3 months of treatment.