Showing papers in "Clinical & Experimental Allergy in 2009"

Immunoglobulin G4: an odd antibody

Abstract: Despite its well-known association with IgE-mediated allergy, IgG4 antibodies still have several poorly understood characteristics. IgG4 is a very dynamic antibody: the antibody is involved in a continuous process of half-molecules (i.e. a heavy and attached light-chain) exchange. This process, also referred to as 'Fab-arm exchange', results usually in asymmetric antibodies with two different antigen-combining sites. While these antibodies are hetero- bivalent, they will behave as monovalent antibodies in most situations. Another aspect of IgG4, still poorly understood, is its tendency to mimic IgG rheumatoid factor (RF) activity by interacting with IgG on a solid support. In contrast to conventional RF, which binds via its variable domains, the activity of IgG4 is located in its constant domains. This is potentially a source of false positives in IgG4 antibody assay results. Because regulation of IgG4 production is dependent on help by T-helper type 2 (Th2) cells, the IgG4 response is largely restricted to non-microbial antigens. This Th2-dependency associates the IgG4 and IgE responses. Another typical feature in the immune regulation of IgG4 is its tendency to appear only after prolonged immunization. In the context of IgE-mediated allergy, the appearance of IgG4 antibodies is usually associated with a decrease in symptoms. This is likely to be due, at least in part, to an allergen-blocking effect at the mast cell level and/or at the level of the antigen-presenting cell (preventing IgE-facilitated activation of T cells). In addition, the favourable association reflects the enhanced production of IL-10 and other anti-inflammatory cytokines, which drive the production of IgG4. While in general, IgG4 is being associated with non-activating characteristics, in some situations IgG4 antibodies have an association with pathology. Two striking examples are pemphigoid diseases and sclerosing diseases such as autoimmune pancreatitis. The mechanistic basis for the association of IgG4 with these diseases is still enigmatic. However, the association with sclerosing diseases may reflect an excessive production of anti-inflammatory cytokines triggering an overwhelming expansion of IgG4-producing plasma cells. The bottom line for allergy diagnosis: IgG4 by itself is unlikely to be a cause of allergic symptoms. In general, the presence of allergen-specific IgG4 indicates that anti-inflammatory, tolerance-inducing mechanisms have been activated. The existence of the IgG4 subclass, its up-regulation by anti-inflammatory factors and its own anti-inflammatory characteristics may help the immune system to dampen inappropriate inflammatory reactions.

Maternal vitamin D intake during pregnancy is inversely associated with asthma and allergic rhinitis in 5-year-old children

Abstract: Summary Background Vitamin D is known to have a number of immunological effects and it may play a role in preventing allergic diseases. Objectives To study the effect of maternal intake of vitamin D during pregnancy on the emergence of asthma, allergic rhinitis (AR), and atopic eczema by the age of 5 years in children with HLA-DQB1-conferred susceptibility for type 1 diabetes. Methods Children (1669) participating in the population-based birth cohort study were followed for asthma, AR, and atopic eczema assessed by validated questionnaire at 5 years. Maternal diet was assessed by a food-frequency questionnaire. Results The mean maternal intake of vitamin D was 5.1 (SD 2.6) μg from food and 1.4 (2.6) μg from supplements. Only 32% of the women were taking vitamin D supplements. When adjusted for potential confounders, maternal intake of vitamin D from food was negatively related to risk of asthma [hazard ratio (HR) 0.80; 95% confidence interval (CI) 0.64–0.99] and AR [HR 0.85; 95% CI 0.75–0.97]. Vitamin D supplements alone were not associated with any outcome. Adjustment for maternal intake of other dietary factors did not change the results. Conclusion Maternal vitamin D intake from foods during pregnancy may be negatively associated with risk of asthma and AR in childhood.

Altered early infant gut microbiota in children developing allergy up to 5 years of age

Abstract: BACKGROUND: Early colonization with bifidobacteria and lactobacilli is postulated to protect children from allergy, while Clostridium (C.) difficile colonization might be associated with allergic d ...

Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype.

Abstract: Asthma is a highly prevalent chronic respiratory disease affecting 300 million people world-wide. A significant fraction of the cost and morbidity of asthma derives from acute care for asthma exacerbations. In the United States alone, there are approximately 15 million outpatient visits, 2 million emergency room visits, and 500,000 hospitalizations each year for management of acute asthma. Common respiratory viruses, especially rhinoviruses, cause the majority of exacerbations in children and adults. Infection of airway epithelial cells with rhinovirus causes the release of pro-inflammatory cytokines and chemokines, as well as recruitment of inflammatory cells, particularly neutrophils, lymphocytes, and eosinophils. The host response to viral infection is likely to influence susceptibility to asthma exacerbation. Having had at least one exacerbation is an important risk factor for recurrent exacerbations suggesting an 'exacerbation-prone' subset of asthmatics. Factors underlying the 'exacerbation-prone' phenotype are incompletely understood but include extrinsic factors: cigarette smoking, medication non-compliance, psychosocial factors, and co-morbidities such as gastroesophageal reflux disease, rhinosinusitis, obesity, and intolerance to non-steroidal anti-inflammatory medications; as well as intrinsic factors such as deficient epithelial cell production of the anti-viral type I interferons (IFN-alpha and IFN-beta). A better understanding of the biologic mechanisms of host susceptibility to recurrent exacerbations will be important for developing more effective preventions and treatments aimed at reducing the significant cost and morbidity associated with this important global health problem.

Clinical effects of sulphite additives.

Abstract: Sulphites are widely used as preservative and antioxidant additives in the food and pharmaceutical industries. Topical, oral or parenteral exposure to sulphites has been reported to induce a range of adverse clinical effects in sensitive individuals, ranging from dermatitis, urticaria, flushing, hypotension, abdominal pain and diarrhoea to life-threatening anaphylactic and asthmatic reactions. Exposure to the sulphites arises mainly from the consumption of foods and drinks that contain these additives; however, exposure may also occur through the use of pharmaceutical products, as well as in occupational settings. While contact sensitivity to sulphite additives in topical medications is increasingly being recognized, skin reactions also occur after ingestion of or parenteral exposure to sulphites. Most studies report a 3-10% prevalence of sulphite sensitivity among asthmatic subjects following ingestion of these additives. However, the severity of these reactions varies, and steroid-dependent asthmatics, those with marked airway hyperresponsiveness, and children with chronic asthma, appear to be at greater risk. In addition to episodic and acute symptoms, sulphites may also contribute to chronic skin and respiratory symptoms. To date, the mechanisms underlying sulphite sensitivity remain unclear, although a number of potential mechanisms have been proposed. Physicians should be aware of the range of clinical manifestations of sulphite sensitivity, as well as the potential sources of exposure. Minor modifications to diet or behaviour lead to excellent clinical outcomes for sulphite-sensitive individuals.

Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses

Abstract: Introduction: Among sensitized infants those with high, as compared with low levels, of salivary secretory IgA (SIgA) are less likely to develop allergic symptoms. Also, early colonization with cer ...

Pathogenesis of chronic urticaria

Abstract: Summary Chronic urticaria is defined as the presence of urticaria (hives) for at least 6 weeks with the assumption that it occurs daily or close to it. If we eliminate physical urticarias and urticarial vasculitis from consideration, the remainder can be divided into autoimmune chronic urticaria (45%) and idiopathic chronic urticaria (55%). The autoimmune subgroup is associated with the IgG anti-IgE receptor α subunit in 35–40% of patients and IgG anti-IgE in an additional 5–10%. These autoantibodies have been shown to activate blood basophils and cutaneous mast cells in vitro with augmentation of basophil activation by complement and release of C5a, in particular. Binding methods (immunoblot and ELISA) yield positives in many autoimmune diseases as well as occasional normal subjects or patients with other forms of urticaria but most such sera are non-functional. Activation of basophils or mast cells causing histamine release is quite specific for chronic urticaria and defines the autoimmune subgroup. Although pathogenicity is not formally proven, the antibodies cause wealing upon intradermal injection, and removal of the autoantibody leads to remission. A cellular infiltrate is seen to be characterized by mast cell degranulation and infiltration of CD4+ T lymphocytes, monocytes, neutrophils, eosinophils, and basophils. The intensity of the infiltrate and clinical severity of the disease (including accompanying angio-oedema) is more severe in the autoimmune subpopulation. This latter group also has a higher evidence of human leucocyte antigen DR alleles associated with autoimmunity and a 25% incidence of antithyroid antibodies with diagnosed hypothyroidism in some. Hypo-responsiveness of patients' basophils to anti-IgE and hyperresponsiveness to serum defines another subpopulation (at least 50%) that overlaps the idiopathic and autoimmune subgroups. Hypo-responsiveness to anti-IgE has been shown to be associated with elevated levels of cytoplasmic phosphatases that inhibit degranulation. Reversal of the abnormality is seen with disease remission. Further work will be needed to distinguish whether this is a cause or a consequence of persistent urticaria and to further assess the relationship (or lack thereof) of altered responsiveness (decreased or increased) with the presence or absence of activating autoantibodies.

Histamine, histamine receptors and their role in immune pathology

Abstract: Summary The important roles of histamine in body physiology and various pathologic events have been well established, whereas new and exciting findings are still being uncovered. Histamine is not only the major mediator of the acute inflammatory and immediate hypersensitivity responses, but has also been demonstrated to affect chronic inflammation and regulate several essential events in the immune response. The diverse effects of histamine on immune regulation are due to the differential expression and regulation of four histamine receptors (HR) and their distinct intracellular signals. Differences in the affinities of these receptors are highly decisive on the biological effects of histamine and agents that target HRs. In particular, the discovery of reciprocal regulation of T cell activity by H1 and H2 receptor activation indicating histamine-cytokine cross-talk, as well as the characterization of the fourth histamine receptor (HR4) and its expression on numerous immune and inflammatory cells have prompted a re-evaluation of the actions of histamine. This accounts for a new potential for HR antagonists and agonists in targeting various immunopathologic conditions.

Regulatory T cells and asthma.

Abstract: Airway inflammation in asthma is characterized by activation of T helper type-2 (Th2) T cells, IgE production and eosinophilia. In many cases, this process is related to an inappropriate T cell response to environmental allergens, and other T cell-dependent pathways may also be involved (such as Th17). Regulatory T cells (Tregs) are T cells that suppress potentially harmful immune responses. Two major subsets of Treg are CD25hi, Foxp3+Tregs and IL-10-producing Tregs. There is evidence that the numbers or function of both subsets may be deficient in patients with atopic allergic disease. Recent work has extended these findings into the airway in asthma where Foxp3 expression was reduced and CD25hi Treg-suppressive function was deficient. In animal models of allergic airways disease, Tregs can suppress established airway inflammation and airway hyperresponsiveness, and protocols to enhance the development, recruitment and function of Tregs have been described. Together with studies of patients and in vitro studies of human T cells, these investigations are defining potential interventions to enhance Treg function in the airway in asthma. Existing therapies including corticosteroids and allergen immunotherapy act on Tregs, in part to increase IL-10 production, while vitamin D3 and long-acting β-agonists enhance IL-10 Treg function. Other possibilities may be enhancement of Treg function via histamine or prostanoid receptors, or by blocking pro-inflammatory pathways that prevent suppression by Tregs (activation of Toll-like receptors, or production of cytokines such as IL-6 and TNF-α). As Tregs can also suppress the potentially beneficial immune response important for controlling infections and cancer, a therapeutic intervention should target allergen- or site-specific regulation.

Safety and tolerability of omalizumab

Abstract: Summary Background Omalizumab (Xolair®) is a recombinant humanized monoclonal anti-IgE antibody with proven efficacy in patients with moderate-to-severe and severe persistent allergic (IgE-mediated) asthma. Objective To review clinical study data to assess the safety profile of omalizumab. Methods We analysed the safety of omalizumab using data from completed clinical studies (up to 1 year) involving more than 7500 patients with asthma, rhinitis or related conditions and up to 4 years in one study of patients with severe allergic asthma, as well as post-marketing safety data. Analysis focuses on the risk of immune-system effects, hypersensitivity reactions, malignant neoplasia, parasitic infections and thrombocytopenia. Results Omalizumab exhibited a good safety and tolerability profile that was maintained up to 4 years in one study. The incidence of anaphylaxis was 0.14% in omalizumab-treated patients and 0.07% in control patients. No omalizumab-treated patient developed measurable anti-omalizumab antibodies. Post-marketing, based on estimated exposure of 57 300 patients (June 2003–December 2006), the frequency of anaphylaxis attributed to omalizumab use was estimated to be at least 0.2% of patients. Current clinical trial data do not support an increased risk of malignant neoplasia or thrombocytopenia with omalizumab. Conclusion Data indicate that the proven efficacy of add-on omalizumab in patients with moderate-to-severe or severe allergic asthma is accompanied by a favourable safety and tolerability profile.

Use of A-type CpG oligodeoxynucleotides as an adjuvant in allergen-specific immunotherapy in humans: a phase I/IIa clinical trial.

Abstract: Summary Background B-type CpG oligodeoxynucleotides (ODN) is currently used in clinical trials because of its prolonged half–life, which is due to its phosphorothioate backbone. A-type CpG ODN is a stronger inducer of IFN but has an unstable phosphodiester backbone that has so far prohibited its clinical use. However, upon association with virus-like particles (VLP) consisting of the bacteriophage Qβ coat protein, A-type CpG ODN can be stabilized and can become an efficient adjuvant in mice. Therefore, the phase I/IIa study presented represents the first test of A-type CpGs in humans. Objective To test the safety, tolerability and clinical efficacy of QbG10 as an adjuvant for subcutaneous immunotherapy with a house dust mite (HDM) allergen extract in allergic patients. Methods A single centre, open-label phase I/IIa study evaluated the safety, tolerability and clinical efficacy of QbG10 as an adjuvant to immunotherapy with a subcutaneous HMD allergen extract in 20 patients suffering from HDM allergy. Twenty-one patients were enrolled between March and July 2005. Individual immunotherapy lasted 10 weeks. Clinical end-points included questionnaires, conjunctival provocation, skin prick tests and the measurement of allergen-specific IgG and IgE. Results QbG10 was well tolerated. Almost complete tolerance to the allergen was observed in conjunctival provocation testing after treatment with QbG10, and symptoms of rhinitis and allergic asthma were significantly reduced. Within 10 weeks of therapy, patients were nearly symptom-free and this amelioration lasted for at least 38 weeks post-treatment. Following injections of QbG10 and HDM allergen extract, allergen-specific IgG increased, while there was a transient increase in allergen-specific IgE titres. Skin reactivity to HDM was reduced. Conclusion The subcutaneous application of HDM allergen, together with A-type CpG ODN packaged into VLP, was safe. All patients achieved practically complete alleviation of allergy symptoms after 10 weeks of immunotherapy. This promising clinical outcome calls for larger placebo-controlled phase II studies.

BSACI guidelines for the management of drug allergy

Abstract: These guidelines have been prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI) and are intended for allergists and others with a special interest in allergy. As routine or validated tests are not available for the majority of drugs, considerable experience is required for the investigation of allergic drug reactions and to undertake specific drug challenge. A missed or incorrect diagnosis of drug allergy can have serious consequences. Therefore, investigation and management of drug allergy is best carried out in specialist centres with large patient numbers and adequate competence and resources to manage complex cases. The recommendations are evidence-based but where evidence was lacking consensus was reached by the panel of specialists on the committee. The document encompasses epidemiology, risk factors, clinical patterns of drug allergy, diagnosis and treatment procedures. In order to achieve a correct diagnosis we have placed particular emphasis on obtaining an accurate clinical history and on the physical examination, as these are critical to the choice of skin tests and subsequent drug provocation. After the diagnosis of drug allergy has been established, communication of results and patient education are vital components of overall patient management.

Do helminth parasites protect against atopy and allergic disease

Abstract: Summary Allergic diseases are rare in areas with high helminth parasite exposure and common where helminth exposure is lacking or significantly reduced, such as urban areas of developing countries and industrialized nations. Studies suggest that helminths induce a systemic immuno-modulatory network, including regulatory T cells and anti-inflammatory IL-10, which might play a key role in the protection against the allergic phenotype. Here, we review the current cross-sectional, birth cohort, and intervention study evidence for a protective effect of helminth infection on allergy. There is increasing evidence for a causal relationship between helminth infection and reduced skin prick test responsiveness to allergens. Cross-sectional studies have shown a consistent negative relationship, and these results have been confirmed in several, although not all, intervention studies. The immunological basis for this protective effect is less clear. Recent studies do not support the mast-cell IgE saturation hypothesis, but suggest that protection is associated with IL-10 production. As for allergic disease, cross-sectional studies support a negative relationship between clinical asthma and infection with some helminth species, particularly hookworm, but more studies are required to draw conclusions for eczema and rhinitis. In addition, none of the few intervention studies to date have demonstrated an increase in clinical allergy after helminth treatment, and further studies are needed. Furthermore, we are only beginning to understand the host genetic factors that are potentially involved. A genetically predetermined T-helper type 2 cell-dominated cytokine milieu reduces parasite burden and may enhance host survival in an environment where helminth parasites are prevalent. Lack of parasite exposure in such hosts might lead to hypersensitivity to seemingly minor environmental allergen stimuli. Large birth cohort studies in helminth-endemic areas that use epidemiological, genetic, and immunological tools are required to further examine how helminth parasites affect the development of atopy and allergic disease. Intervention studies with hookworm in parasite-naive allergic individuals are currently ongoing in the United Kingdom to test the above hypotheses further.

Development and validation of a self‐administered Food Allergy Quality of Life Questionnaire for children

Abstract: Summary Background Having a food allergy may affect health-related quality of life (HRQL). Currently, no validated, self-administered, disease-specific HRQL questionnaire exists for children with food allergy. Objective The aim of this study was to develop and validate the Food Allergy Quality of Life Questionnaire – Child Form (FAQLQ-CF) in the Dutch language. Methods Interviews with food-allergic children (n=13, 8–12 years) generated 139 HRQL items. The most important items were identified by 51 food-allergic children using the clinical impact method. This resulted in the FAQLQ-CF containing 24 items (total score range 1 ‘not troubled’ to 7 ‘extremely troubled’). The FAQLQ-CF, the Food Allergy Independent Measure (FAIM) and a generic HRQL questionnaire (CHQ-CF87) were sent to 115 food-allergic children for cross-sectional validation of the FAQLQ-CF. Results Construct validity was demonstrated by the correlation between the FAQLQ-CF and the FAIM (rho=0.60, P 2 food allergies vs. 2 food allergies; total FAQLQ-CF score, 4.3 vs. 3.6; P=0.036), but did not discriminate between reported anaphylaxis or not. The total FAQLQ-CF score correlated with 8 of the 11 CHQ-CF87 sub-scales which demonstrated convergent/discriminant validity. Conclusion The FAQLQ-CF is the first self-administered disease-specific HRQL questionnaire for food-allergic children. This questionnaire has a strong internal consistency and cross-sectional validity. It discriminates between children who differ in number of food allergies, and it was short and easy to use in the population studied. Therefore, the FAQLQ-CF may be a useful tool in clinical research.

Probiotic supplementation in the first 6 months of life in at risk Asian infants--effects on eczema and atopic sensitization at the age of 1 year.

Abstract: Background The role of probiotics in allergy prevention remains uncertain but has been shown in some studies to have a possible protective effect on eczema Objective We aimed to assess the effect of probiotic supplementation in the first 6 months of life on eczema and allergic sensitization at 1 year of age in Asian infants at risk of allergic disease Methods A double-blind, placebo-controlled randomized clinical trial involving 253 infants with a family history of allergic disease was carried out Infants received at least 60 mL of commercially available cow's milk formula with or without probiotic supplementation [Bifidobacterium longum (BL999) 1 x 10(7) colony forming unit (CFU)/g and Lactobacillus rhamnosus (LPR) 2 x 10(7) CFU/g] daily for the first 6 months Clinical evaluation was performed at 1, 3, 6 and 12 months of age, with serum total IgE measurement and skin prick tests conducted at the 12-month visit The primary and secondary end-points were eczema and allergen sensitization, respectively Results The incidence of eczema in the probiotic (22%) group was similar to that in the placebo group (25%) (P=053) The median Scoring Atopic Dermatitis score at 12 months was 1710 (974) in the probiotic group and 1160 (840) in the placebo group (P=017) The prevalence of allergen sensitization showed no difference (probiotic=24% vs placebo=19%, P=026) The total IgE geometric mean (95% confidence interval) was 1876 (1254-2498) kU/L in the probiotic group and 2313 (1601-3024) kU/L in the placebo group (P=015) Atopic eczema (with sensitization) in the probiotic (73%) group was comparable to the placebo group (58%) (P=086) Conclusion Early life administration of a cow's milk formula supplemented with probiotics showed no effect on prevention of eczema or allergen sensitization in the first year of life in Asian infants at risk of allergic disease Further work is needed to determine whether timing of supplementation, dose and probiotic strain are important considerations

The natural history and epidemiology of insect venom allergy: clinical implications

Abstract: Hymenoptera stings can cause severe systemic allergic reactions and occasionally fatal anaphylaxis, which contribute significantly to morbidity and deterioration in health-related quality of life. The latest epidemiological data confirm the importance of insect sting allergy as a cause of anaphylaxis. Despite the high prevalence of asymptomatic sensitization, the prevalence of sting-induced systemic reactions (SRs) is low. However, to date, no parameter has been identified that can predict who will have a future reaction and whether it will be a large local reaction or anaphylactic. The combination of several concomitant factors, which include environmental, genetics and individual factors, may account for the occurrence of a system reaction in individual patients. Several not completely known factors may be associated with the severity of systemic re-stings. As about 50% of subjects with fatal sting reactions had no documented history of a previous SR, greater insight of the natural history and risk factors is required, especially in asymptomatic sensitized subjects. For patients with SRs, prevention of future severe allergic reactions starts with referral to an emergency department, correct administration of epinephrine by medical staff, referral to an allergist and coaching for the self-administration of epinephrine. However, most insect sting victims failed to seek medical advice and hospital attendance does not always correlate with the severity of the allergic reaction. Moreover, only about one-third of patients received a prescription for self-injectable epinephrine and were officially referred to an allergist after being discharged, causing the non- or delayed prescription of specific immunotherapy. Significantly, this means that at least half of the sting fatalities in patients with a positive history could have been avoided through the timely administration of specific immunotherapy. These findings indicate the urgent need to educate the general population and doctors on the management of venom-allergic patients.

BSACI guidelines for the investigation of suspected anaphylaxis during general anaesthesia.

Abstract: Investigation of anaphylaxis during general anaesthesia requires an accurate record of events including information on timing of drug administration provided by the anaesthetist, as well as timed acute tryptase measurements. Referrals should be made to a centre with the experience and ability to investigate reactions to a range of drug classes/substances including neuromuscular blocking agents (NMBAs) intravenous (i.v.) anaesthetics, antibiotics, opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), local anaesthetics, colloids, latex and other agents. About a third of cases are due to allergy to NMBAs. Therefore, investigation should be carried out in a dedicated drug allergy clinic to allow seamless investigation of all suspected drug classes as a single day-case. This will often require skin prick tests, intra-dermal testing and/or drug challenge. Investigation must cover the agents administered, but should also include most other commonly used NMBAs and i.v. anaesthetics. The outcome should be to identify the cause and a range of drugs/agents likely to be safe for future use. The allergist is responsible for a detailed report to the referring anaesthetist and to the patient's GP as well as the surgeon/obstetrician. A shorter report should be provided to the patient, adding an allergy alert to the case notes and providing an application form for an alert-bracelet indicating the wording to be inscribed. The MHRA should be notified. Investigation of anaphylaxis during general anaesthesia should be focussed in major allergy centres with a high throughput of cases and with experience and ability as described above. We suggest this focus since there is a distinct lack of validated data for testing, thus requiring experience in interpreting tests and because of the serious consequences of diagnostic error.

Combination of omalizumab and specific immunotherapy is superior to immunotherapy in patients with seasonal allergic rhinoconjunctivitis and co-morbid seasonal allergic asthma

Abstract: Summary Background The treatment of allergic asthma by specific immunotherapy (SIT) is hampered by potential side-effects. Objective The aim of this study was to study the effect of omalizumab, a monoclonal anti-IgE antibody, in combination with SIT in patients with seasonal allergic rhinoconjunctivitis (SAR) and co-morbid seasonal allergic asthma (SAA) incompletely controlled by conventional pharmacotherapy. Methods A randomized, double-blind, placebo-controlled, multi-centre trial was performed to assess the efficacy and safety of omalizumab (Xolair®) vs. placebo in combination with depigmented SIT (Depigoid®) during the grass pollen season. Omalizumab or placebo was started 2 weeks before SIT; the whole treatment lasted 18 weeks. Primary endpoint was daily ‘symptom load’, the sum of daily scores for symptom severity and rescue medication use. Results A total of 140 patients (age 11–46 years) were randomized; and a total of 130 finished the study. Combination therapy reduced the symptom load by 39% (P=0.0464, Wilcoxon test) over SIT monotherapy. This difference was mainly due to reduced symptom severity (P=0.0044), while rescue medication use did not change significantly. Combination therapy also improved asthma control (Asthma Control Questionnaire, P=0.0295) and quality of life in the case of asthma (Asthma Quality of Life Questionnaire, P=0.0293) and rhinoconjunctivitis (Rhinoconjunctivitis Quality of Life Questionnaire, P=0.0537). Numbers of patients with ‘excellent or good’ treatment efficacy according to ratings of investigators (75.0% vs. 36.9%) or patients (78.5% vs. 46.1%) were markedly higher in the combination group than under SIT alone. Conclusion Combination of omalizumab with SIT for treatment of patients with SAR and co-morbid SAA was safe and reduced the symptom load in a statistically significant and clinically meaningful manner.

The danger within: endogenous danger signals, atopy and asthma.

Abstract: Summary In allergic asthmatics, airway inflammation is triggered by specific (inhalation of allergen such as house dust mite allergen and pollen spores) or non-specific triggers (such as air pollutants and viral infection). Most of these inhaled particles are immunologically inert. Dendritic cells (DCs) are essential for priming and T helper-2 differentiation of naive T cells towards aeroallergens. Contamination of antigens with pattern-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS), is required to activate DCs to mount an immune response. Damage-associated molecular patterns (DAMPs), such as uric acid and adenosine triphosphate (ATP), also contribute to the induction of inflammation by activation and recruitment of various inflammatory cells. Compelling evidence suggests that a tight collaboration between PAMPs and DAMPs is needed to start an immune response to allergens. Several studies have recently demonstrated an important role of endogenous danger signals at the inception and maintenance phase of allergic disease. Further research into this area should focus on the possible role of these factors in maintenance of chronic disease and induction of airway remodelling.

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

Abstract: Summary 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.

T regulatory cells and their counterparts: masters of immune regulation

Abstract: The interaction of environmental and genetic factors with the immune system can lead to the development of allergic diseases. The essential step in this progress is the generation of allergen-specific CD4(+) T-helper (Th) type 2 cells that mediate several effector functions. The influence of Th2 cytokines leads to the production of allergen-specific IgE antibodies by B cells, development and recruitment of eosinophils, mucus production and bronchial hyperreactivity, as well as tissue homing of other Th2 cells and eosinophils. Meanwhile, Th1 cells may contribute to chronicity and the effector phases. T cells termed T regulatory (Treg) cells, which have immunosuppressive functions and cytokine profiles distinct from that of either Th1 or Th2 cells, have been intensely investigated during the last 13 years. Treg cell response is characterized by an abolished allergen-specific T cell proliferation and the suppressed secretion of Th1 and Th2-type cytokines. Treg cells are able to inhibit the development of allergen-specific Th2 and Th1 cell responses and therefore play an important role in a healthy immune response to allergens. In addition, Treg cells potently suppress IgE production and directly or indirectly suppress the activity of effector cells of allergic inflammation, such as eosinophils, basophils and mast cells. Currently, Treg cells represent an exciting area of research, where understanding the mechanisms of peripheral tolerance to allergens may soon lead to more rational and safer approaches for the prevention and cure of allergic diseases.

Volatile organic compounds in exhaled breath as a diagnostic tool for asthma in children.

Abstract: Summary Background The correct diagnosis of asthma in young children is often hard to achieve, resulting in undertreatment of asthmatic children and overtreatment in transient wheezers. Objectives To develop a new diagnostic tool that better discriminates between asthma and transient wheezing and that leads to a more accurate diagnosis and hence less undertreatment and overtreatment. A first stage in the development of such a tool is the ability to discriminate between asthmatic children and healthy controls. The integrative analysis of large numbers of volatile organic compounds (VOC) in exhaled breath has the potential to discriminate between various inflammatory conditions of the respiratory tract. Methods Breath samples were obtained and analysed for VOC by gas chromatography–mass spectrometry from asthmatic children (n=63) and healthy controls (n=57). A total of 945 determined compounds were subjected to discriminant analysis to find those that could discriminate diseased from healthy children. A set of samples from both asthmatic and healthy children was selected to construct a model that was subsequently used to predict the asthma or the healthy status of a test group. In this way, the predictive value of the model could be tested. Measurements and main results The discriminant analyses demonstrated that asthma and healthy groups are distinct from one another. A total of eight components discriminated between asthmatic and healthy children with a 92% correct classification, achieving a sensitivity of 89% and a specificity of 95%. Conclusion The results show that a limited number of VOC in exhaled air can well be used to distinguish children with asthma from healthy children. Cite this as: J. W. Dallinga, C. M. H. H. T. Robroeks, J. J. B. N. van Berkel, E. J. C. Moonen, R. W. L. Godschalk, Q. Jobsis, E. Dompeling, E. F. M. Wouters and F. J. van Schooten, Clinical & Experimental Allergy, 2010 (40) 68–76.

Siglec‐8 on human eosinophils and mast cells, and Siglec‐F on murine eosinophils, are functionally related inhibitory receptors

Abstract: Siglecs (sialic acid-binding, Ig-like lectins) are a family of single-pass transmembrane cell surface proteins found predominantly on leucocytes. Their unique structural characteristics include an N-terminal carbohydrate-binding ('lectin') domain that binds sialic acid, followed by a variable number of Ig-like domains, hence these structures are a subset of the Ig gene superfamily. Another unique feature of Siglecs is that most, but not all, possess so-called immunoreceptor tyrosine-based inhibitory motifs in their cytoplasmic domains, suggesting that these molecules function in an inhibitory capacity. Siglec-8, the eighth member identified at the time, was discovered as part of an effort initiated almost a decade ago to identify novel human eosinophil and mast cell proteins. Since that time, its selective expression on human eosinophils and mast cells has been confirmed. On eosinophils, Siglec-8 engagement results in apoptosis, whereas on mast cells, inhibition of FcepsilonRI-dependent mediator release, without apoptosis, is seen. It has subsequently been determined that the closest functional paralog in the mouse is Siglec-F, selectively expressed by eosinophils but not expressed on mast cells. Despite only modest homology, both Siglec-8 and Siglec-F preferentially recognize a sulphated glycan ligand closely related to sialyl Lewis X, a common ligand for the selectin family of adhesion molecules. Murine experiments in normal, Siglec-F-deficient mice and hypereosinophilic mice have resulted in similar conclusions that Siglec-F, like Siglec-8, plays a distinctive and important role in regulating eosinophil accumulation and survival in vivo. Given the resurgent interest in eosinophil-directed therapies for a variety of disorders, plus its unique additional ability to also target the mast cell, therapies focusing on Siglec-8 could some day prove to be a useful adjunct to our current armamentarium for the treatment of asthma, allergies and related disorders where overproduction and overactivity of eosinophils and mast cells is occurring.

Comparison of skin prick tests with specific serum immunoglobulin E in the diagnosis of fungal sensitization in patients with severe asthma

Abstract: Summary Background It has been shown that patients with allergic bronchopulmonary aspergillosis (ABPA) and patients with severe asthma with fungal sensitization (SAFS) can benefit from antifungal therapy. It is not known whether allergy skin prick tests (SPT) or specific IgE tests are more sensitive in the identification of patients who are sensitized to fungi and who are therefore candidates for antifungal therapy. Objectives To compare SPT and specific serum IgE tests for fungal sensitization in patients with severe asthma. Methods We have undertaken SPT and specific serum IgE tests to six fungi (Aspergillus fumigatus, Candida albicans, Penicillium notatum, Cladosporium herbarum, Alternaria alternata and Botrytis cineria) and specific serum IgE test for Trichophyton in 121 patients with severe asthma (British Thoracic Society/SIGN steps 4 and 5). Results Sixty-six percent of patients were sensitized to one or more fungi based on SPT and/or specific serum IgE results. Positivity to SPT and/or specific serum IgE was as follows: A. fumigatus 45%, C. albicans 36%, P. notatum 29%, C. herbarum 24%, A. alternata 22%, B. cineria 18%, Trichophyton 17% (specific serum IgE only). Concordance between the tests was 77% overall but only 14–56% for individual fungi. Twenty-nine (24%) patients were sensitized to a single fungus and seven (6%) were sensitized to all seven fungal species. Fifty percent of patients were sensitized to fungal and non-fungal extracts, 21% were sensitized only to non-fungal extracts, 16% were sensitized only to fungal extracts and 13% had no positive tests. Conclusion This study is consistent with previous reports that fungal sensitization is common in patients with severe asthma. At present, it remains necessary to undertake both SPT and specific serum IgE testing to identify all cases of fungal sensitization. This may be important in the identification of patients with ABPA and SAFS who may benefit from antifungal therapy.

The definition and diagnosis of asthma.

Abstract: Summary The diagnosis of asthma depends on what we mean by the word. Its definition continues to be controversial because there is no single genetic or environmental cause. Addressed from a descriptive point of view, the disease components include airway inflammation, symptoms, variable airflow limitation and chronic airflow limitation. The essentialist definition conveys the message that asthma is a separate disease entity, fails to identify a primary defining characteristic which separates it from other diseases and is long winded. These disadvantages are overcome by the nominalist definition of asthma in which the word ‘asthma’refers to an abnormality of airway function, specifically to wide variations in airflow limitation over short periods of time. In patients with asthma the other components of airway disease need to be considered. These have separate nominalist definitions and especially include different types of bronchitis for airway inflammation and chronic obstructive pulmonary disease for chronic airflow limitation. What is present will vary between and within patients. The accurate diagnosis of asthma and of other components of disease all require objective measurements. Currently spirometry and airway responsiveness should be available to the general practitioner, who sees milder disease, and additional quantitative sputum cell counts in specialist practice, where moderate to severe disease is more prevalent. Such measurements characterize the patient, identify heterogeneity and allow treatment to be personalized.

Basophil activation tests for the diagnosis of food allergy in children.

Abstract: Summary Background Positive skin prick tests (SPT) for food allergens and specific IgE (sIgE) in serum indicate sensitization but do not enable distinction between sensitized but tolerant and clinically allergic patients. Objective Herein, we evaluate the clinical relevance of basophil activation tests (BATs) for peanut or egg allergy diagnosis. Methods Thirty-two peanut-allergic, 14 peanut-sensitized (sIgE+ and/or SPT+ to peanuts) but tolerant children and 29 controls with no history of an adverse reaction to peanuts were included. Similarly, 31 egg-allergic, 14 egg-sensitized children (sIgE+ and/or SPT+ to egg white) and 22 controls were studied. Flow cytometric analysis of CD63 expression or CD203c upregulation on basophils and the production of leukotrienes (LT) were performed in response to an in vitro crude peanut extract or ovalbumin (OVA) challenge. Results After in vitro peanut challenge, the basophils from peanut-allergic children showed significantly higher levels of activation than those from controls (P<0.001). After OVA challenge, a similar distinction (P<0.001) was observed between egg-allergics and controls. Interestingly, the majority of egg- or peanut-sensitized children failed to activate basophils, respectively, in response to OVA and peanut challenge. The sensitivity of the CD63, CD203c and LT assay was 86.7%, 89.5% and 76.0% with a specificity of 94.1%, 97.1% and 94.6% for peanut allergy diagnosis. The corresponding performances of BATs applied to egg allergy diagnosis were 88.9%, 62.5% and 77.8% for the sensitivity and 100%, 96.4% and 96.4% for the specificity. Conclusion Neither conventional tests nor BATs are sensitive and specific enough to predict food allergy accurately. However, BATs may helpfully complete conventional tests, especially SPT, allowing improved discrimination between allergic and non-allergic individuals.

Thymic stromal lymphopoietin, OX40-ligand, and interleukin-25 in allergic responses.

Abstract: Allergic diseases are often triggered by environmental allergens that induce dominant type 2 immune responses, characterized by the infiltrated T-helper type 2 (TH2) lymphocytes, eosinophils, and elevated TH2 cytokines. In addition to TH2 type immune responses, epithelial stress and injury linked to tissue remodelling are often observed, suggesting that epithelial cells may play important role in regulating allergic responses. Dendritic cells (DCs), the professional antigen-presenting cells with the capabilities of sampling allergens, are considered as the key player on instructing TH2 immune responses. Whether inflamed epithelium can regulate innate immunity, such as macrophages and DCs, which in turn instructs adaptive immunity has long been hypothesized. Studies of thymic stromal lymphopoietin (TSLP), an epithelial cells-derived cytokine, that can strongly activate DCs, provide important evidences that the epithelial barrier can trigger allergic diseases by regulating immune responses. The finding that OX40/OX40Ligand (OX40L) interactions are the molecular trigger responsible for the induction and maintenance of TH2 responses by TSLP-activated DCs provides a plausible molecular explanation for TSLP-mediated allergy. Recent progresses in characterizing the pro-inflammatory IL-17 cytokine family have added an additional layer of complexity on the regulation of allergic inflammation. TSLP-DCs can induce a robust expansion of TH2 memory cells and strengthen functional attributes by up-regulating their surface expression of IL-17RB (IL-25R), the receptor for cytokine IL-17E (IL-25), a distinct member of IL-17 cytokine family. IL-17E (also known as IL-25) produced by epithelial cells, and other innate cells, such as eosinphils, basophils, and mast cells, are shown to regulate adaptive immunity by enhancing TH2 cytokine productions. These exciting findings expand our knowledge of the complex immunological cascades that result in allergic inflammation and may provide novel therapeutic approaches for the treatment of allergic diseases.

EpidemAAITO: features of food allergy in Italian adults attending allergy clinics: a multi-centre study.

Abstract: Summary Background Studies of the prevalence of different types of food allergy in adults are lacking. Objective To define the prevalence of IgE-mediated food allergies in Italian adults attending allergy clinics and to assess possible differences associated with geographical position and/or dietary habits. Methods Seventeen allergy outpatient clinics scattered throughout Italy participated to a multi-centre study in 2007. The number of atopic subjects and of food allergic patients along with clinical features were recorded by pre-defined criteria. Patients with unequivocal history of food allergy confirmed by positive skin prick test were included as cases. Results Twenty five thousand six hundred and one subjects were screened; 12 739 (50%) were atopic, and 1079 (8,5%) had IgE-mediated food allergy. Sixty four percent of patients were females. Overall, the most frequent food allergy was the pollen–food allergy syndrome (55%), which was associated with oral allergy syndrome in 95% of cases and whose frequency decreased southbound. Forty-five percent of patients had a type 1 food allergy, in most cases (72%) caused by fruits and vegetables, and generally associated with a history of systemic symptoms. Type 1 food allergies represented 96% of food allergies in the South. Lipid transfer protein (LTP) accounted for 60% of sensitizations and caused most primary food allergies in all areas. Conclusion Plant-derived foods cause most food allergies in Italian adults. The pollen–food allergy syndrome is the most frequent type of food allergy followed by allergy to LTP whose frequency increases southbound. The pattern of allergy to certain foods is clearly influenced by specific geographic features such as pollen exposure and dietary habits.

Intrinsic asthma: not so different from allergic asthma but driven by superantigens?

Abstract: Summary The mechanisms of intrinsic or non-allergic asthma remain uncertain as allergens have no obvious role in driving the inflammatory process in the airways. However, IgE synthesis occurs in the airways, despite negative skin prick tests and serum-specific IgE. Furthermore, the inflammatory process in the airways is very similar between allergic and non-allergic asthma, with increased T-helper type 2 (Th2) cells, mast cell activation and infiltration of eosinophils. This pattern of inflammation is associated with a similar expression of inflammatory mediators, including Th2 cytokines and eosinophilotactic chemokines. There is increasing evidence that microbial superantigens, particularly Staphylococcal enterotoxins are important in amplifying inflammation in atopic dermatitis and chronic rhinosinusitis, in atopic and non-atopic patients. Superantigens may also be important in intrinsic asthma as airway epithelial cells may be colonized by Staphylococci and other superantigen-producing microbes. Superantigens produced locally in the airways may lead to class switching of local B cells, resulting in polyclonal IgE production in the airways and also specific IgE against the superantigen (which functions as a ‘superallergen’). This leads to sensitization of mast cells, which can be activated by the usual asthma triggers, such as exercise. Superantigens also cause clonal expansion of T cells, resulting in increased Th2 cells and CD8 1 cells, while suppressing regulatory T cells. Superantigens may also reduce responsiveness to corticosteroids, resulting in more severe asthma. Finally, cytotoxic autoantibodies may also be implicated as IgG antibodies directed against epithelial proteins, such as cytokeratin-18, have been detected in intrinsic asthma, possibly as a result of epithelial damage and this may make epithelial cells more susceptible to microbial colonization. The therapeutic implications are that antibodies against local IgE and microbial superantigens or antibiotic therapy to eradicate the relevant superantigen-producing microorganisms may improve the efficacy of conventional therapy with corticosteroids.

Probiotics for the treatment of eczema: a systematic review

Abstract: Summary Background Probiotics have been proposed as a treatment for eczema, but the results of intervention trials have been mixed. Objective To evaluate the efficacy of probiotics for treating eczema by performing a systematic review of randomized-controlled trials (RCTs). Design We searched the Cochrane Skin Group Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO, AMED, LILACS, ISI Web of Science, the reference lists of articles, ongoing clinical trial registers and conference proceedings. RCTs of live orally ingested microorganisms for the treatment of eczema were eligible for inclusion. Results Twelve trials (781 participants) were identified. Meta-analysis of data from five of these trials showed that there was no significant reduction in eczema symptoms with probiotic treatment compared with placebo (mean difference −0.90 points on a 20-point visual analogue scale; 95% confidence interval −2.84, 1.04). Meta-analysis of data from seven trials showed no significant difference in investigator rated eczema severity between probiotic and placebo treatments. Subgroup analysis by eczema severity or presence of atopy did not identify a specific population in which probiotic treatment was effective. There was significant heterogeneity between studies; however, the results of three studies that used the same probiotic strain were concordant. The adverse events search identified case reports of sepsis and bowel ischaemia caused by probiotics. Conclusions Currently, probiotics cannot be recommended for treating eczema. The heterogeneity between studies may be attributable to probiotic strain-specific effects, which means that novel probiotic strains may still have a role in eczema management.