Heat‐labile Escherichia coli toxin enhances the induction of allergen‐specific IgG antibodies in epicutaneous patch vaccination

Epicutaneous allergen‐specific immunotherapy (EPIT) is proposed as an alternative route for allergen‐specific immunotherapy (AIT). The induction of allergen‐specific blocking IgG antibodies represents an important mechanism underlying AIT, but has not been investigated for EPIT. Here, we compared the induction of allergen‐specific blocking IgG in outbred guinea pigs which had been immunized with recombinant birch pollen allergen Bet v 1 using patch delivery system (PDS) with or without heat‐labile toxin (LT) from Escherichia coli or subcutaneously with aluminum hydroxide (Alum)‐adsorbed rBet v 1. Only subcutaneous immunization with Alum‐adsorbed rBet v 1 and epicutaneous administration of rBet v 1 with PDS in combination with LT from E. coli induced allergen‐specific IgG antibodies blocking allergic patients' IgE, but not immunization with rBet v 1 via PDS alone. Our results suggest that patch vaccination with rBet v 1 in combination with LT may be a promising strategy for allergen‐specific immunotherapy against birch pollen allergy.     

Intranasal administration of allergen increases specific IgE whereas intranasal omalizumab does not increase serum IgE levels—A pilot study

Background

Administration of the therapeutic anti‐IgE antibody omalizumab to patients induces strong increases in IgE antibody levels.

Objective

To investigate the effect of intranasal administration of major birch pollen allergen Bet v 1, omalizumab or placebo on the levels of total and allergen‐specific IgE in patients with birch pollen allergy.

Methods

Based on the fact that intranasal allergen application induces rises of systemic allergen‐specific IgE, we performed a double‐blind placebo‐controlled pilot trial in which birch pollen allergic subjects were challenged intranasally with omalizumab, placebo or birch pollen allergen Bet v 1. Total and allergen‐specific IgE, IgG and basophil sensitivity were measured before and 8 weeks after challenge. For control purposes, total, allergen‐specific IgE levels and omalizumab‐IgE complexes as well as specific IgG levels were studied in subjects treated subcutaneously with either omalizumab or placebo. Effects of omalizumab on IgE production by IL‐4/anti‐CD40‐treated PBMCs from allergic patients were studied in vitro.

Results

Intranasal challenge with Bet v 1 induced increases in Bet v 1‐specific IgE levels by a median of 59.2%, and this change differed significantly from the other treatment groups (P = .016). No relevant change in allergen‐specific and total IgE levels was observed in subjects challenged with omalizumab. Addition of omalizumab did not enhance IL‐4/anti‐CD40‐induced IgE production in vitro. Significant rises in total IgE (mean IgE before: 131.83 kU/L to mean IgE after: 505.23 kU/L) and the presence of IgE‐omalizumab complexes were observed after subcutaneous administration of omalizumab.

Conclusion

Intranasal administration of allergen induced rises of allergen‐specific IgE levels, whereas intranasal administration of omalizumab did not enhance systemic total or allergen‐specific IgE levels.     

Inhibition of CD23‐dependent facilitated allergen binding to B cells following vaccination with genetically modified hypoallergenic Bet v 1 molecules

Background Vaccination with hypoallergenic recombinant Bet v 1 derivatives (Bet v 1 fragments and Bet v 1 trimer) is associated with the induction of IgG antibodies specific to natural Bet v 1. Objective To investigate whether IgG antibodies induced following vaccination with genetically modified hypoallergenic Bet v 1 derivatives are able to inhibit IgE‐facilitated binding of allergen‐IgE complexes to B cells. Methods Sera from 46 patients obtained before and after subcutaneous vaccination with Bet v 1 trimer (n=14), Bet v 1 fragments (n=11) or placebo (n=21) were incubated with recombinant (r) Bet v 1 and an indicator serum (IS) from a birch pollen‐allergic patient with high CD23 binding capacity. Bet v 1 immune complexes were added to a CD23‐expressing B cell line and co‐operative binding of Bet v1‐IgE complexes to CD23 was measured with a polyclonal anti‐IgE FITC antibody using a bio‐functional cellular flow cytometric assay. Results When sera from patients vaccinated with rBet v 1 derivatives were incubated with Bet v 1 and the IS, a reduction of IgE binding to CD23 was observed. This effect was not seen when sera from placebo‐treated patients were used. The decrease in CD23/IgE binding was statistically significant in the trimer group [pre‐ vs. post‐specific immunotherapy (SIT): P=0.02; trimer vs. placebo: P<0.04] but not in the Bet v 1 fragments‐treated group. Trimer‐treated patients had higher levels of Bet v 1‐specific IgG than fragment‐treated patients. The degree of inhibitory activity of IgE‐facilitated allergen binding correlated with Bet v 1‐specific IgG levels following SIT (R=0.492; P=0.012). Conclusion Vaccination with both recombinant Bet v 1 derivatives induces Bet v 1‐specific IgG antibodies, which are able to inhibit the co‐operative binding of allergen‐IgE complexes to CD23, and may thereby reduce allergen‐specific T cell responses. Cite this as: I. Pree, M. H. Shamji, I. Kimber, R. Valenta, S. R. Durham and V. Niederberger, Clinical & Experimental Allergy, 2010 (40) 1346–1352.     

Cat allergen‐induced blood basophil reactivity in vitro predicts acute human nasal allergen challenge responses in vivo

Background Basophil histamine release (BHR) to allergen has been used as a confirmatory test to support the clinical diagnosis of allergic disease. Objective Among subjects reporting respiratory cat allergy, we hypothesized that cat‐induced BHR in vitro would predict nasal allergen challenge (NAC) response in that same individual. We therefore compared the magnitude of cat allergen‐induced BHR to NAC outcome and serological measures of cat‐specific IgE and the ratio of cat‐specific IgE to total IgE. Methods Forty‐two subjects with a history of cat allergy, positive cat puncture skin test (PST) and detectable cat‐specific IgE (>0.1 kAU/L, ImmunoCap) participated with consent. Subjects were grouped as positive or negative cat allergen‐induced BHR, with a positive result defined as the release of 20% of the total cellular histamine content. The majority of subjects also underwent a NAC with a positive result defined as 5 total sneezes. Results Subjects with a positive compared with a negative cat allergen BHR had higher cat‐specific IgE levels at 5.40±1.24 kAU/L (n=25) vs. 1.55±0.73 kAU/L (n=17, P=0.01) as well as a higher cat‐specific IgE/total IgE ratio [6.1±1.4% (n=25) vs. 1.6±0.9% (n=17, P=0.01)]. Of the 31 subjects who underwent a NAC, a positive NAC was observed in 78% (18/23) with a positive cat allergen BHR compared with 37% (3/8) with a negative cat allergen BHR, giving a positive predictive value of 78% and a negative predictive value of 63%. The diagnostic sensitivity and specificity of a positive BHR to predict a positive NAC was 86% and 50%, respectively. Conclusions and Clinical Relevance A positive cat allergen‐induced BHR is associated with higher cat‐specific IgE levels, a higher cat‐specific to total IgE ratio and is predictive of a positive cat‐induced NAC [ClinicalTrials.gov NCT00604786]. Cite this as: M. Paterniti, D. C. Kelly, J. A. Eckman, P. M. Sterba, R. G. Hamilton, B. S. Bochner, D. W. MacGlashan Jr. and S. S. Saini, Clinical & Experimental Allergy, 2011 (41) 963–969.     

Cost‐effectiveness of specific immunotherapy with Grazax in allergic rhinitis co‐existing with asthma

Background: In the United Kingdom, approximately 10.8 million people suffer from asthma, placing an economic burden on the society of more than £2 billion per year. For allergic asthma, treatment options consist of allergen avoidance, symptomatic treatment and allergen‐specific immunotherapy (SIT). Only SIT addresses the underlying cause of the disease, reducing symptoms and offering the potential for long‐term improvement. Grazax – the first tablet‐based SIT – is indicated for the treatment of patients with grass pollen‐induced rhinoconjunctivitis, including those with co‐existing asthma. Objective: To assess the cost‐effectiveness of Grazax in patients with rhinoconjunctivitis and co‐existing asthma. Methods: A prospective pharmacoeconomic analysis was carried out as part of a multinational clinical trial assessing the efficacy of Grazax (n = 79) compared with placebo (n = 72). Both groups had access to symptomatic medication; thus the placebo group represented current standard care. Pooled data on health resource use, productivity loss because of absence from work and quality of life (Quality Adjusted Life Years, QALYs) were collected in the trial. Reduced productivity at work was estimated from the literature. A societal perspective was adopted with a 9‐year time horizon. The NHS price of Grazax of £2.25 per tablet was used. Results: The QALY gain was significantly higher for patients treated with Grazax than the placebo group receiving symptomatic medication alone (0.197 discounted QALYs gained 9 years into the future – equal to an extra 72 days of perfect health over 9 years). The levels of resource use and productivity loss were higher for the placebo group. As a result, the cost per QALY gained with Grazax was £4319, which is highly cost‐effective. Price sensitivity analyses demonstrated that Grazax remained cost‐effective up to a tablet price of £5.07. Conclusion: SIT with Grazax is a cost‐effective strategy compared with standard management of patients with rhinoconjunctivitis and co‐existing asthma.     

Sublingual grass pollen immunotherapy is associated with increases in sublingual Foxp3‐expressing cells and elevated allergen‐specific immunoglobulin G4, immunoglobulin A and serum inhibitory activity for immunoglobulin E‐facilitated allergen binding to B cells

Background The mechanisms of sublingual immunotherapy (SLIT) are less well understood than those of subcutaneous immunotherapy (SCIT). Objectives To determine the effects of grass‐pollen SLIT on oral mucosal immune cells, local regulatory cytokines, serum allergen‐specific antibody subclasses and B cell IgE‐facilitated allergen binding (IgE‐FAB). Methods Biopsies from the sublingual mucosa of up to 14 SLIT‐treated atopics, nine placebo‐treated atopics and eight normal controls were examined for myeloid dendritic cells (mDCs) (CD1c), plasmacytoid dendritic cells (CD303), mast cells (AA1), T cells (CD3) and Foxp3 using immunofluorescence microscopy. IL‐10 and TGF‐β mRNA expression were identified by in situ hybridization. Allergen‐specific IgG and IgA subclasses and serum inhibitory activity for binding of allergen‐IgE complexes to B cells (IgE‐FAB) were measured before, during and on the completion of SLIT. Results Foxp3⁺ cells were increased in the oral epithelium of SLIT‐ vs. placebo‐treated atopics (P=0.04). Greater numbers of subepithelial mDCs were present in placebo‐treated, but not in SLIT‐treated, atopics compared with normal controls (P=0.05). There were fewer subepithelial mast cells and greater epithelial T cells in SLIT‐ compared with placebo‐treated atopics (P=0.1 for both). IgG₁ and IgG₄ were increased following SLIT (P<0.001). Peak seasonal IgA₁ and IgA₂ were increased during SLIT (P<0.05). There was a time‐dependent increase in serum inhibitory activity for IgE‐FAB in SLIT‐treated atopics. Conclusions SLIT with grass pollen extract is associated with increased Foxp3⁺ cells in the sublingual epithelium and systemic humoral changes as observed previously for SCIT. Cite this as: G. W. Scadding, M. H. Shamji, M. R. Jacobson, D. I. Lee, D. Wilson, M. T. Lima, L. Pitkin, C. Pilette, K. Nouri‐Aria and S. R. Durham, Clinical & Experimental Allergy, 2010 (40) 598–606.     

The allergen profile of beech and oak pollen

Background Beech and oak pollen are potential allergen sources with a world‐wide distribution. Objective We aimed to characterize the allergen profile of beech and oak pollen and to study cross‐reactivities with birch and grass pollen allergens. Methods Sera from tree pollen‐allergic patients with evidence for beech and oak pollen sensitization from Basel, Switzerland, (n=23) and sera from birch pollen‐allergic patients from Vienna, Austria, (n=26) were compared in immunoblot experiments for IgE reactivity to birch (Betula pendula syn. verrucosa), beech (Fagus sylvatica) and oak (Quercus alba) pollen allergens. Subsequently, beech and oak pollen allergens were characterized by IgE inhibition experiments with purified recombinant and natural allergens and with allergen‐specific antibody probes. Birch‐, beech‐ and oak pollen‐specific IgE levels were determined by ELISA. Results Beech and oak pollen contain allergens that cross‐react with the birch pollen allergens Bet v 1, Bet v 2 and Bet v 4 and with the berberine bridge enzyme‐like allergen Phl p 4 from timothy grass pollen. Sera from Swiss and Austrian patients exhibited similar IgE reactivity profiles to birch, beech and oak pollen extracts. IgE levels to beech and oak pollen allergens were lower than those to birch pollen allergens. Conclusion IgE reactivity to beech pollen is mainly due to cross‐reactivity with birch pollen allergens, and a Phl p 4‐like molecule represented another predominant IgE‐reactive structure in oak pollen. The characterization of beech and oak pollen allergens and their cross‐reactivity is important for the diagnosis and treatment of beech and oak pollen allergy.     

Epicutaneous immunotherapy on intact skin using a new delivery system in a murine model of allergy

Background Allergen‐specific immunotherapy, subcutaneous immunotherapy (SCIT) or oral, has been used for almost a century to redirect inappropriate immune responses in atopic patients. A new mode of administration through the intact skin [epicutaneous immunotherapy (EPIT)], using an original epicutaneous delivery system, may represent an alternative to these classical methods. Objective Proof of concept of efficacy of EPIT on intact skin in mice sensitized to aeroallergens or food allergens. Methods Mice were sensitized to pollen (n=18), house dust mite (HDM, n=24), ovalbumin (OVA, n=18) or peanut (n=18), and allocated to four groups: EPIT, SCIT, not treated (NT) and control. Specific Ig (sIg)E, sIgG1 and sIgG2a were monitored. After 8 weeks of treatment, plethysmography was performed after aerosol provocation with appropriate allergens. Results At the highest doses of methacholine, pause enhancement (Penh) values were significantly decreased in the EPIT group vs. the sensitized NT groups (7.5 vs. 12.3 – pollen, 7.6 vs. 8.9 – HDM, 11.5 vs. 14.5 – OVA, 7.6 vs. 12.8 – peanut, respectively) (P<0.05). With all the allergens tested, Penh values were similar in SCIT, EPIT and control. IgG2a for pollen, HDM, OVA and peanuts were significantly increased in the EPIT group vs. NT: 0.97 vs. 0.42 μg/mL, 2.5 vs. 0.46 μg/mL, 0.39 vs. 0.05 μg/mL and 15.0 vs. 5.5 μg/mL, respectively (P<0.05). There were no significant differences between EPIT and SCIT groups. The IgE/IgG2a ratio decreased significantly in the EPIT group for the four allergens from 70 to 58 (pollen), 175 to 26 (HDM), 5433 to 120 (OVA) and 49 to 6 (peanut), respectively (P<0.05). Conclusion In mice sensitized to the four allergens tested, EPIT was as efficacious as SCIT, considered as the reference immunotherapy. These first results have to be confirmed by clinical studies. Cite this as: L. Mondoulet, V. Dioszeghy, M. Ligouis, V. Dhelft, C. Dupont and P.‐H. Benhamou, Clinical & Experimental Allergy, 2010 (40) 659–667.     

Clinical effects of immunotherapy with genetically modified recombinant birch pollen Bet v 1 derivatives

Background Birch pollen and pollen from related trees of the Fagales order are a major cause of allergic rhinitis, conjunctivitis, and asthma through the spring season in northern and central Europe. Objective To investigate the clinical effects of injection immunotherapy with genetically modified derivatives of major birch pollen allergen Bet v 1 on pollen‐induced allergic symptoms. Methods A three‐arm double‐blind placebo‐controlled immunotherapy study was conducted with one pre‐seasonal course of treatment using two derivatives of Bet v 1, namely a recombinant Bet v 1 trimer and an equimolar mixture of two recombinant Bet v 1 fragments together representing the whole protein sequence. Analysis of local and systemic adverse events was performed for 124 patients who had received at least one dose of medication. Clinical efficacy was monitored by symptom medication scores and interval scoring in the per protocol‐treated population (n=84). In addition, skin and nasal provocation responses and allergen‐specific antibodies were assessed. Results There were trends towards improvement in the subjects' well‐being and clinical symptoms (nasal scores), although comparisons with a placebo group did not show statistical significance in the main end‐point, the combined symptom medication score. Reductions in skin and nasal sensitivity were observed for some subjects with a trend for the Bet v 1 trimer to be more effective than the fragments. Treatment induced strong IgG1 and IgG4 allergen‐specific antibody responses. Local injection‐site reactions were most frequent in the trimer group affecting 59.5% of patients as opposed to 37.8% and 30.6% in the fragment and placebo groups, respectively. Systemic reactions were elicited more frequently by fragments. A large proportion of adverse side‐effects appeared hours following injections, and might be attributable to concurrent exposure to related pollens. Conclusion Single courses of injection immunotherapy with Bet v 1 allergen derivatives showed trends towards improved well‐being and reduced reactivity to specific allergen provocation, but did not yield significant improvement in the combined symptom medication score in this study.     

Efficacy,safety, and immunological effects of a 2‐year immunotherapy with Depigoid® birch pollen extract: a randomized,double‐blind,placebo‐controlled study

Background Rhinoconjunctivitis due to birch pollen sensitization is common in Northern Europe. A depigmented polymerized birch pollen extract – Depigoid^® has been developed for immunotherapy. Objective To evaluate its clinical efficacy, safety, and effects on immunological parameters. Methods Sixty‐one patients aged 7–69 years were included in a randomized, double‐blind, placebo‐controlled trial of subcutaneous immunotherapy (SCIT) using depigmented polymerized birch pollen extract. SCIT consisted of four increasing doses at 7‐day intervals, followed by maintenance injections of 500 DPP (corresponding to 30 μg Bet v1 before depigmentation) at 6‐week intervals for 18 months. The primary outcome was the combined symptom and medication score during the 2006 birch pollen season. The frequency of peripheral blood mononuclear cells (PBMC)producing IL‐4, IL‐10, IL‐12, and IL‐13 was assessed in a subgroup of patients by ELISPOT assay. Results After 18 months of treatment, the median combined symptom and medication score (upper/lower quartile) of treated patients was significantly lower than those on placebo: 8.0 (5.8–10.3) and 12.6 (8.6–16.2), respectively (P=0.004). Systemic reactions occurred in 29 patients (12 active, 17 placebo), were grades 1 or 2, and none required specific treatment. After 18 months of treatment, mean serum concentrations of specific IgE increased significantly in both groups (P<0.0001) whereas serum concentrations of both specific IgG1 and IgG4 only increased significantly in the SCIT group (P=0.002) and not in the placebo group. The seasonal increase in numbers of IL‐4‐ and IL‐13‐producing PBMC was blunted by immunotherapy. Conclusions SCIT with depigmented polymerized birch pollen extract significantly reduced symptom and medication scores when compared with the placebo, was well tolerated, and resulted in immunological changes comparable with those of native pollen extracts. Cite this as: A.‐S. Höiby, V. Strand, D.S. Robinson, A. Sager and S. Rak, Clinical & Experimental Allergy, 2010 (40) 1062–1070.     

Airborne olive pollen counts are not representative of exposure to the major olive allergen Ole e 1

Pollen is routinely monitored, but it is unknown whether pollen counts represent allergen exposure. We therefore simultaneously determined olive pollen and Ole e 1 in ambient air in Córdoba, Spain, and Évora, Portugal, using Hirst‐type traps for pollen and high‐volume cascade impactors for allergen. Pollen from different days released 12‐fold different amounts of Ole e 1 per pollen (both locations P < 0.001). Average allergen release from pollen (pollen potency) was much higher in Córdoba (3.9 pg Ole e 1/pollen) than in Évora (0.8 pg Ole e 1/pollen, P = 0.004). Indeed, yearly olive pollen counts in Córdoba were 2.4 times higher than in Évora, but Ole e 1 concentrations were 7.6 times higher. When modeling the origin of the pollen, >40% of Ole e 1 exposure in Évora was explained by high‐potency pollen originating from the south of Spain. Thus, olive pollen can vary substantially in allergen release, even though they are morphologically identical.     

Evaluation of desloratadine on conjunctival allergen challenge-induced ocular symptoms

Background Allergic conjunctivitis (AC) is frequently associated with allergic rhinitis (AR) and affects up to 91% of patients with AR. Desloratadine, an orally administered, non‐sedating second‐generation antihistamine, has proven efficacy and safety in the control of nasal and non‐nasal – including ocular – symptoms of AR. This randomized‐controlled trial is the first to evaluate the effects of continuous oral desloratadine treatment on ocular symptoms after conjunctival allergen challenge. Objective To evaluate the impact of administering oral desloratadine 5 mg daily for 7 days on ocular symptoms in conjunctival allergen‐challenged subjects. Methods In this crossover study, adults with a history of seasonal AC and a minimal threshold response to allergen challenge were randomized to receive desloratadine 5 mg daily (n=20) or placebo (n=21) for 7 days after which they underwent a second ocular allergen challenge. After a 2‐week washout period, subjects crossed over to the other treatment. The primary efficacy parameter was the intra‐subject difference from baseline at end‐point in the post‐challenge mean composite ocular redness score (the sum of redness scores in ciliary, conjunctival, or episcleral vessel beds). Secondary efficacy parameters included the intra‐subject and inter‐subject differences in individual symptom scores for ciliary, conjunctival, or episcleral redness; pruritus; chemosis; eyelid swelling; and tearing. Results The mean composite ocular redness score was reduced at 10, 15, and 20 min post‐challenge with desloratadine treatment compared with placebo, though these differences were not statistically significant (P=NS). Desloratadine was significantly more effective than placebo in preventing post‐challenge ocular pruritus (P<0.001). Significant improvements post‐challenge were also seen in ciliary and episcleral redness, chemosis, eyelid swelling, and tearing (P<0.05 vs. placebo for all comparisons). Desloratadine was well tolerated. Conclusion Treatment with desloratadine 5 mg daily for 7 days reduced allergic ocular symptoms following allergen challenge.     

Clinico-immunologic Study on Immunotherapy with Mixed and Single Insect Allergens

Background  Immunotherapy (IT) is practiced mainly with mixed and single allergen vaccines. But studies are rare with mixed allergen preparations. Objective  The objective of this study is to study mix and single insect allergen IT in patients of allergic rhinitis and asthma. Methods  We performed a double-blind placebo-controlled trial of mix and single allergen IT for 1 year in 99 patients of asthma or rhinitis or both. There were two groups, (1) active allergen IT (n = 61) with three subgroups single insect extract (cockroach, housefly, or mosquito) and mix allergen IT (two or three insect extracts) and (2) placebo (n = 38). Clinical (skin reactivity, airway reactivity, and symptom score) and immunological (IgE/IgG4 and IgG1/IgG4 ratio) parameters were assessed at baseline and after 1 year of IT. Results  Eighty-five patients completed 1 year of IT. The active allergen IT group patients showed a significant improvement compared to baseline values (p < 0.05) and placebo group patients (p < 0.05) with regard to symptom scores, FEV1 values, and immunological parameters (IgG4). No significant difference was found between mixed and single IT group patients for changes in clinical and immunological parameters. Positive correlation was observed between increase in IgG4 and clinical improvement. The changes in above parameters in placebo group were nonsignificant after 1 year of treatment. Conclusion  IT with two to three mix extract from the same allergen group is effective for insect hypersensitivity.     

Allergens on desktop surfaces in preschools and elementary schools of urban children with asthma

Desktop dust has been studied as a source of food allergen, but not as a source of potential aeroallergen exposure. Thirty‐six wiped samples from desktop surfaces were collected from preschools and schools. Samples were analyzed for detectable levels of common aeroallergens including Alternaria, cockroach, dog, dust mite, cat, mouse, and rat allergens by immunoassay. Mouse allergen was the most prevalent, detectable in 97.2% of samples. Cat allergen was detectable in 80.6% of samples, and dog allergen was detectable in 77.8% of samples. Other allergens were not as prevalent. Mouse was the only allergen that was highly correlated with settled floor dust collected from the same rooms (r = 0.721, P < 0.001). This is the first study to detect aeroallergens on desktop surfaces by using moist wipes. Allergens for mouse, cat, and dog were highly detectable in wipes with mouse desktop surface levels correlating with levels in vacuumed floor dust.     

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 PD₂₀ (provocative dose causing a 20% drop in forced expiratory volume in 1 s) and allergen PD₂₀. 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 PD₂₀ (P=0.01; r=0.49; n=26) as well as between CD‐sens and the ratio of allergen PD₂₀ to methacholine PD₂₀ (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 PD₂₀ 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. Cite this as: B. Dahlén, A. Nopp, S. G. O. Johansson, M. Eduards, M. Skedinger and J. Adédoyin, Clinical & Experimental Allergy, 2011 (41) 1091–1097.     

Efficacy and safety of the SQ‐standardized grass allergy immunotherapy tablet in mono‐ and polysensitized subjects

The efficacy of single‐allergen‐specific immunotherapy in polysensitized subjects is a matter of debate. We therefore performed a post hoc analysis of pooled data from six randomized, double‐blind, placebo‐controlled trials (N = 1871) comparing the efficacy and safety of the SQ‐standardized grass allergy immunotherapy tablet (AIT), Grazax (Phleum pratense 75 000 SQ‐T/2800 BAU, ALK, Denmark), in mono‐ and polysensitized subjects. A statistically significant reduction in the mean total combined symptom/medication score (TCS) of 27% was demonstrated in actively treated subjects compared with placebo (P < 0.0001). This was not dependent on sensitization status (P = 0.5772), suggesting a similar treatment effect in mono‐ and polysensitized subjects (i.e. reductions of the TCSs of 28% and 26%, respectively, both P < 0.0001). Finally, a comparable and favourable safety profile of grass AIT was demonstrated in the two subgroups. Thus, no difference in efficacy and safety of single‐allergen grass AIT was observed between mono‐ and polysensitized subjects.     

Immunotherapy with a modified birch pollen extract in allergic rhinoconjunctivitis: clinical and immunological effects

Background Modification of allergens by glutaraldehyde in extracts used for immunotherapy reduces the risk for side‐effects, but the therapeutic efficacy of such extracts still requires further evaluation. The aim of this study was to show the efficacy and safety of immunotherapy with a single‐strength glutaraldehyde‐modified aluminium hydroxide‐adsorbed extract of birch pollen. Methods In a multi‐centre, randomized, placebo‐controlled double‐blind setting, starting in 2001 between 1 August and 15 December, birch pollen‐allergic subjects (n=62) were injected subcutaneously with increasing doses of the allergen extract or placebo at weekly intervals over a 6‐week period (or longer if adverse reactions occurred). Maintenance dose was given monthly for at least 18 months till June 2003. Efficacy was evaluated on the basis of the clinical index score (CIS), a combined symptom and medication score. Results Fifty‐eight patients could be evaluated for clinical efficacy. Treatment with the birch pollen extract resulted in a lower CIS for the eye and nose during the peak birch pollen season of 2003, compared with placebo (reductions of 42% and 31%, respectively) (P=0.017 and 0.039). Active treatment induced IgG and IgG4 antibodies reacting with Bet v 1 (P<0.001). Sera from treated patients had a blocking effect on Bet v 1‐induced basophil activation (P<0.04). No major adverse reactions occurred, and local reactions, if occurring, were mild. Conclusion Immunotherapy with a modified slow‐release birch pollen extract, administered in a single‐strength preparation with a rapid dose increase, is safe and efficacious. IgG and IgG4 antibodies against native Bet v 1 are induced, which block basophil activation.     

Dynamic features of placebo effects addressing persistent insomnia disorder: A meta‐analysis of placebo‐controlled randomized clinical trials

It has been accepted knowledge that placebo effects have been significant in insomnia clinical trials. However, the dynamic features of placebo effects have not been clarified. Our aim was therefore to conduct a meta‐analysis of placebo‐controlled randomized clinical trials to characterize the dynamic features of placebo effects addressing persistent insomnia disorder. We performed a comprehensive literature search for randomized, placebo‐controlled, double‐blind clinical trials evaluating the efficacy of therapeutic regimens addressing persistent insomnia disorder. We pooled separate effect size estimates (Hedge's g) of placebo and regimen conditions across trials for outcome measures, and multilevel mixed‐effects models were used to explore potential sources of heterogeneity. The placebo effects were significant and robust to improve the symptoms of insomnia, and subjective measures were significantly smaller than objective measures (p < .001), but placebo response rates were nearly identical between subjective and objective measures. The overall placebo effects were influenced by publication year (p = .015), treatment duration (p = .010), sample size (p < .001) and therapeutic regimen (p < .001). Placebo effects showed a diphasic feature within treatment duration: initially a decrease and subsequently being stable; a sustained decline trend after withdrawals; and a steady‐to‐upward trend for a mixed therapeutic regimens in a large‐scale period over decades. The dynamic features of placebo effects addressing persistent insomnia disorder may lead to the development and validation of dosing strategies that require less medication exposure to maintain clinical effects.     

Monogenic diabetes syndromes: Locus‐specific databases for Alström,Wolfram, and Thiamine‐responsive megaloblastic anemia

We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease‐associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine‐responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype–phenotype relations for the WFS1 gene. The presence of biallelic loss‐of‐function variants predicted Wolfram syndrome defined by insulin‐dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%–83%) and specificity of 92% (83%–97%). The presence of minor loss‐of‐function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%–100%]; specificity 78% [73%–82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next‐generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org .     

Increase of allergen‐specific immunoglobulin E antibodies from 1973 to 1994 in a Finnish population and a possible relationship to Helicobacter pylori infections1

Background The prevalence of atopic diseases – hayfever, asthma and eczema – has increased over the past decades. The increase may be associated with decreased rates of infections such as measles, hepatitis A, tuberculosis, toxoplasmosis, and, as recently suggested, Helicobacter pylori gastritis. Objective Since the increase of atopy has been mainly based on clinical studies, we wanted to study the prevalence of allergen‐specific Immunoglobulin (Ig)E antibodies in two cross‐sectional, adult population‐based serum samples two decades apart. Since the sera had been tested for H. pylori antibodies, we also had a chance to look for a possible relationship between these two findings. Methods We determined the prevalence rate of allergen‐specific serum IgE antibodies against birch and timothy pollen, and cat and dog epithelium allergens by the radioallergosorbent test in a 15–54‐years‐old Finnish population using 326 sera collected in 1973 and 319 sera collected in 1994 from randomly selected subjects. Results From 1973 to 1994 allergen‐specific IgE prevalence rates and IgE antibody levels rose. In 1994, the prevalence rate of positive findings in 15–24‐year‐old population had increased from 11 to 38% (3.5‐fold increase, P = 0.0001, OR 5.12, CI 95% 2.32–11.3). In older 10‐year age groups similar trends did not reach significance, but the overall change was significant with all three cut‐off levels of allergen‐specific IgE analysed. The percentage of IgE‐positive persons rose mainly in the subgroup with no H. pylori antibodies. In 1994 21% of the H. pylori‐negative subjects had IgE antibodies compared with 5% of the H. pylori‐positive subjects (in 1973 11% in both subgroups). Conclusions IgE‐based evidence for an increase in IgE‐mediated allergy was uncovered. The increase occurred mainly in the subgroup with no antibodies to H. pylori, which support the hypothesis that H. pylori could be one of the microbes counteracting atopy.