Functional Gastrointestinal Symptoms Are Associated with Higher Serum Total IgE Levels, but Less Atopic Sensitization.

BACKGROUND: The relation of gastrointestinal (GI) complaints to IgE-mediated allergy is not well understood. Increased numbers of "IgE-armed" mast cells have been observed in duodenal mucosa of patients with functional GI complaints. AIMS: To explore whether total IgE and atopic sensitization were associated with functional GI complaints. METHODS: Levels of serum total and specific IgE and GI complaints were measured in 161 patients and in a general population sample of 478 persons. Standard inhalant allergens were measured in the patient group, and selected inhalant allergens in the general population. GI complaints were assessed by two standardized questionnaires. The associations between GI complaints and total IgE were analyzed in multiple regression models. RESULTS: GI complaints were positively associated with higher total IgE levels (all: b = 0.028, p = 0.012; patient group: b = 0.038, p = 0.072; general population: b = 0.038, p = 0.005), but negatively associated with atopic sensitization (all: b = -11.256, p = 0.181; patient group: b = -85.667, p < 0.001; general population: b = -14.394, p = 0.083). The relationship between total IgE and GI complaints was consistent among sensitized and non-sensitized persons, among men and women, and across age groups. CONCLUSION: Serum total IgE was positively associated with GI complaints, while atopic sensitization was inversely associated with GI complaints. This suggests that IgE-mediated immunology plays a role in the pathophysiology of functional GI complaints. The biological mechanisms reflected in higher total IgE levels, but less atopic sensitization, warrant further studies.

Design and recruitment for the GAP trial, investigating the preventive effect on asthma development of an SQ-standardized grass allergy immunotherapy tablet in children with grass pollen-induced allergic rhinoconjunctivitis.

BACKGROUND: Allergic rhinoconjunctivitis is a risk factor for asthma development. Treating the underlying allergy may represent an attractive method of asthma prevention. No regulatory guidance exists in this area, and, to our knowledge, no clinical investigations meeting modern regulatory standards have been published. OBJECTIVE: The objective of this publication is to describe the rationale behind the design of and report on the recruitment for the ongoing pediatric Grazax Asthma Prevention (GAP) trial. METHODS: The trial was designed for assessment of the preventive effect of an SQ-standardized grass allergy immunotherapy tablet (AIT) on asthma development, both during treatment and after the end of treatment. (The standardized quality [SQ] procedure is a standardization procedure comprising 3 components: total potency, major allergen content, and assessment of extract complexity.) The trial design was discussed with several European Competent Authorities. RESULTS: The GAP trial is a multinational, parallel-group, double-blind, placebo-controlled randomized trial. Main eligibility criteria were age of 5 to 12 years, grass pollen-induced allergic rhinoconjunctivitis, no asthma, and no overlapping symptomatic allergies. The children have been randomized 1:1 to receive the grass AIT or placebo once daily for 3 years, followed by a blinded observational period of 2 years. Asthma is assessed by the investigators according to specific diagnostic criteria, used at screening visits before randomization to exclude children with existing asthma, and evaluated at least half-yearly during the trial. Seven months of screening resulted in 812 randomized children at 101 centers in 11 countries. CONCLUSIONS: To our knowledge, the GAP trial represents the first double-blind, placebo-controlled randomized trial to assess the preventive effect of allergen-specific immunotherapy on asthma development. A total of 812 children were successfully recruited into the trial. EudraCT number: 2009-011235-12.

Economic evaluation of second generation pneumococcal conjugate vaccines in Norway.

BACKGROUND: A seven valent pneumococcal conjugate vaccine (PCV7) was introduced in the Norwegian childhood immunization programme in 2006, and since then the incidence of invasive pneumococcal disease has declined substantially. Recently, two new second generation pneumococcal conjugate vaccines have become available, and an update of the economic evidence is needed. The aim of this study was to estimate incremental costs, health effects and cost-effectiveness of the pneumococcal conjugate vaccines PCV7, PCV13 and PHiD-CV in Norway. METHODS: We used a Markov model to estimate costs and epidemiological burden of pneumococcal- and NTHi-related diseases (invasive pneumococcal disease (IPD), Community Acquired Pneumonia (CAP) and acute otitis media (AOM)) for a specific birth cohort. Using the most relevant evidence and assumptions for a Norwegian setting, we calculated incremental costs, health effects and cost-effectiveness for different vaccination strategies. In addition we performed sensitivity analyses for key parameters, tested key assumptions in scenario analyses and explored overall model uncertainty using probabilistic sensitivity analysis. RESULTS: The model predicts that both PCV13 and PHiD-CV provide more health gains at a lower cost than PCV7. Differences in health gains between the two second generation vaccines are small for invasive pneumococcal disease but larger for acute otitis media and myringotomy procedures. Consequently, PHiD-CV saves more disease treatment costs and indirect costs than PCV13. CONCLUSION: This study predicts that, compared to PVC13, PHiD-CV entails lower costs and greater benefits if the latter is measured in terms of quality adjusted life years. PVC13 entails more life years gained than PHiD-CV, but those come at a cost of NOK 3.1 million (∼€0.4 million) per life year. The results indicate that PHiD-CV is cost-effective compared to PCV13 in the Norwegian setting.

Clinical characteristics of patients with drug hypersensitivity in Norway: a single-centre study.

BACKGROUND: Drug hypersensitivity reactions (DHRs) represent an important public health problem. Knowledge of their clinical characteristics will provide improved diagnostic approaches to this topic. OBJECTIVES: The aim of the present study was to describe the clinical characteristics of patients with suspected DHRs. METHODS: The medical records of 206 outpatients with suspected DHRs, who consulted a Norwegian allergy centre from January 2005 to December 2009, were investigated in a retrospective study. RESULTS: Mean age (range) was 44.3 (11-84) years, and 72% of the patients were women. The most common underlying diseases justifying the use of drugs were infections (49%) and pain-related diseases (23%). Antibiotics (53%), non-steroidal anti-inflammatory drugs (NSAIDs) (32%), paracetamol (15%) and other drugs (46%), used as monotherapy or combinations, were the most often suspected drugs. Cutaneous symptoms were the most frequently reported symptoms (83%). Hospitalisation or prolonged hospitalisation was needed in 38% of the cases, and anaphylaxis was reported in 28% of all the patients. Skin prick tests were performed in 185 patients, of which 14 patients had positive test results. Drug provocation tests (DPTs) were performed in only 86 patients, six of which had positive reactions. DHRs were confirmed in 24 and rejected in 81 patients. Unsettled cases (39%) were mainly due to not performing DPTs. CONCLUSIONS: Suspected DHRs occur predominantly in women. The most common manifestations are cutaneous symptoms, but life-threatening reactions justifying hospitalisation may occur. Antibiotics and NSAIDs are the two drug families most frequently suspected. DPTs need to be included in diagnostic protocols in order to evaluate suspected DHRs.

A non-living nasal influenza vaccine can induce major humoral and cellular immune responses in humans without the need for adjuvants.

Twenty-eight healthy adult volunteers were immunized intranasally with an inactivated whole-virus influenza vaccine based on the strain A/New Caledonia/20/99 (H1N1), either in saline or mixed with formaldehyde-inactivated Bordetella pertussis as a mucosal adjuvant, or in a thixotropic vehicle with mucoadhesive properties. After four doses, all groups of vaccinees developed significant IgG- and IgA-antibody responses, measured by ELISA, in respectively serum and nasal secretions. None of the volunteers had demonstrable hemagglutination inhibition (HAI) antibodies in serum before being immunized, whereas more than 80% of them reached HAI titers>or=40, considered protective, after immunizations. In addition, cellular immune responses, measured as significant increases in CD4+ T-cell proliferation and granzyme B-producing cytotoxic T-cells, were detected against the vaccine strain as well as against heterologous virus strains (H3N2). However, no additive effect on these responses could be demonstrated with use of B. pertussis or the thixotropic substance in the present vaccines. It appeared, actually, that the mucoadhesive vehicle containing the thixotropic substance was less efficient than were the two other formulations. An influenza vaccine made as a simple particulate formulation of inactivated virus, and given repeatedly onto the nasal mucosa, may thus be an attractive alternative to currently available vaccines.

Bordetella pertussis can act as adjuvant as well as inhibitor of immune responses to non-replicating nasal vaccines.

In mice immunised intranasally with an inactivated whole-virus influenza (INV) vaccine, or ovalbumin (OVA), formalin-inactivated Bordetella pertussis (Bp) augmented antibody responses to the same degree as did cholera toxin (CT) when simply being mixed with INV or OVA. In order to study possible non-carrier effects of mucosal adjuvants, mice were given Bp or CT intranasally 1 day before or 1 day after the INV vaccines. At high antigen doses, both Bp and CT had an adjuvant effect on antibodies in serum also when given 1 day after the vaccine. However, Bp and CT inhibited such antibody responses in serum and saliva when given 1 day ahead of the vaccine. This inhibitory effect was most marked at low antigen doses, i.e. when the adjuvant effect was less obvious. In that event, Bp also inhibited responses in serum and saliva when given 1 day after the INV vaccine. The inhibition of these responses may thus depend on Bp and CT themselves being strongly immunogenic, and competing with INV for the functional capacity of the mucosal immune system.

Influence of intravenous anesthesia on mucosal and systemic antibody responses to nasal vaccines.

Inhalation of antigens may stimulate the immune system by way of the upper as well as the lower airways. We have shown that at least 1,000 times more live pneumococci were recovered from pulmonary tissue after being presented as drops of a liquid suspension onto the nares of anesthetized mice compared to the number of bacteria recovered from animals that were not anesthetized in the course of the challenge. Mice that were similarly immunized intranasally by inhalation of three different nonreplicating particulate vaccine formulations, i.e., a meningococcal outer membrane vesicle (OMV) vaccine, a formalin-inactivated whole-virus influenza (INV) vaccine, and the INV vaccine with OMVs as a mucosal adjuvant, during general intravenous anesthesia developed concentrations of vaccine-specific serum immunoglobulin G (IgG) antibodies that were four to nine times higher than in mice that were fully awake during immunizations. The concentrations of IgA antibodies in serum were also higher in anesthetized than in nonanesthetized mice and correlated positively with the corresponding levels of serum IgG antibodies in the anesthetized but not in the nonanesthetized mice. In saliva and feces, however, the concentrations of IgA antibodies were equally high whether or not the animals were dormant during immunizations. The results indicate that intrapulmonary antigen presentation, as a part of an intranasal immunization strategy, is of importance for systemic but not for mucosal antibody responses. A major portion of IgA antibodies in serum may thus be derived from nonmucosal sites.