Showing papers in "The Journal of Allergy and Clinical Immunology in 2008"

The diagnosis and management of rhinitis: An updated practice parameter

Abstract: These parameters were developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma and Immunology; and the Joint Council of Allergy, Asthma and Immunology. The American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) have jointly accepted responsibility for establishing "The diagnosis and Management of Rhinitis: An Updated Practice Parameter." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma and Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion.

Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy

Abstract: Background Despite guidelines recommending avoidance of peanuts during infancy in the United Kingdom (UK), Australia, and, until recently, North America, peanut allergy (PA) continues to increase in these countries. Objective We sought to determine the prevalence of PA among Israeli and UK Jewish children and evaluate the relationship of PA to infant and maternal peanut consumption. Methods A clinically validated questionnaire determined the prevalence of PA among Jewish schoolchildren (5171 in the UK and 5615 in Israel). A second validated questionnaire assessed peanut consumption and weaning in Jewish infants (77 in the UK and 99 in Israel). Results The prevalence of PA in the UK was 1.85%, and the prevalence in Israel was 0.17% (P Conclusions We demonstrate that Jewish children in the UK have a prevalence of PA that is 10-fold higher than that of Jewish children in Israel. This difference is not accounted for by differences in atopy, social class, genetic background, or peanut allergenicity. Israeli infants consume peanut in high quantities in the first year of life, whereas UK infants avoid peanuts. These findings raise the question of whether early introduction of peanut during infancy, rather than avoidance, will prevent the development of PA.

Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease.

Abstract: Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by the accumulation of inflammatory cells; however, an eosinophil predominance is seen in white (Belgian), but not Asian (south Chinese), patients with polyps. Objective We sought to investigate the association of inflammatory cell predominance with regulatory T-cell and T-effector cell patterns. Methods Nasal mucosal tissue was obtained from 26 consecutive Belgian patients with CRSwNP and 21 Belgian control subjects and 29 south Chinese patients with CRSwNP and 29 south Chinese control subjects, who all underwent phenotyping, including nasal endoscopy and computed tomographic scanning. Tissues were investigated for granulocytes and their products and T-effector/regulatory T cells and related cytokines. Results Both CRSwNP groups were comparable in terms of symptoms, computed tomographic scan results, and nasal endoscopy results, but asthma comorbidity was significantly higher in white patients. Tissue from white patients with CRSwNP was characterized by eosinophilic inflammation (eosinophil cationic protein/myeloperoxidase ratio > 2), whereas samples from Asian patients were biased toward neutrophilic inflammation (eosinophil cationic protein/myeloperoxidase ratio=0.25). Both CRSwNP groups demonstrated significant upregulation of the T-cell activation marker soluble IL-2 receptor α and significant downregulation of Foxp3 expression and TGF-β1 protein content versus their respective control groups. However, whereas white patients displayed a significant increase in T H 2 cytokine and related marker levels versus control subjects and versus Asian patients, the latter showed a T H 1/T H 17 cell pattern versus control tissue. Conclusion Nasal polyps (CRSwNP) from white and Asian patients are both characterized by T-cell activation and impaired regulatory T-cell function; however, T-effector cells in the samples from white patients were T H 2-biased, whereas samples from their Asian counterparts demonstrated a T H 1/T H 17 polarization.

A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow's milk allergy.

Abstract: Background Orally administered, food-specific immunotherapy appears effective in desensitizing and potentially permanently tolerizing allergic individuals. Objective We sought to determine whether milk oral immunotherapy (OIT) is safe and efficacious in desensitizing children with cow's milk allergy. Methods Twenty children were randomized to milk or placebo OIT (2:1 ratio). Dosing included 3 phases: the build-up day (initial dose, 0.4 mg of milk protein; final dose, 50 mg), daily doses with 8 weekly in-office dose increases to a maximum of 500 mg, and continued daily maintenance doses for 3 to 4 months. Double-blind, placebo-controlled food challenges; end-point titration skin prick tests; and milk protein serologic studies were performed before and after OIT. Results Nineteen patients, 6 to 17 years of age, completed treatment: 12 in the active group and 7 in the placebo group. One dropped out because of persistent eczema during dose escalation. Baseline median milk IgE levels in the active (n = 13) versus placebo (n = 7) groups were 34.8 kUa/L (range, 4.86–314 kUa/L) versus 14.6 kUa/L (range, 0.93–133.4 kUa/L). The median milk threshold dose in both groups was 40 mg at the baseline challenge. After OIT, the median cumulative dose inducing a reaction in the active treatment group was 5140 mg (range 2540-8140 mg), whereas all patients in the placebo group reacted at 40 mg ( P = .0003). Among 2437 active OIT doses versus 1193 placebo doses, there were 1107 (45.4%) versus 134 (11.2%) total reactions, with local symptoms being most common. Milk-specific IgE levels did not change significantly in either group. Milk IgG levels increased significantly in the active treatment group, with a predominant milk IgG4 level increase. Conclusions Milk OIT appears to be efficacious in the treatment of cow's milk allergy. The side-effect profile appears acceptable but requires further study.

Epidemiologic risks for food allergy

Abstract: This article reviews possible risk factors and theories for the development of food allergy. It is noted that previous strategies to prevent food allergy through allergen avoidance during pregnancy, breast-feeding, and infancy have more recently been called into question. Alternative hypotheses are examined with respect to food allergy, namely the hygiene hypothesis, the dietary fat hypothesis, the antioxidant hypothesis, and the vitamin D hypotheses. An alternative hypothesis is proposed, suggesting that sensitization to allergen occurs through environmental exposure to allergen through the skin and that consumption of food allergen induces oral tolerance. This hypothesis provides a possible explanation for the close link between eczema and the development of food allergies. It also suggests novel interventional strategies to prevent the development of food allergies.

The health effects of nonindustrial indoor air pollution

Abstract: Background There is growing public awareness regarding the risk associated with poor indoor air quality in the home and workplace. Because Americans spend approximately 22 hours every day indoors, susceptible individuals are at much greater risk of adverse health effects from chronic low levels of exposure to indoor air pollutants over time. Along with particulate matter, gases such as ozone, nitrogen dioxide, carbon monoxide, and sulfur dioxide; microbial and chemical volatile organic compounds; passive smoke; and outdoor ambient air are the most common types of air pollutants encountered indoors. Objective To provide the allergists with necessary information that will assist them in making useful recommendations to patients seeking advice regarding indoor environmental triggers beyond traditional perennial allergens. Methods Review of the literature pertaining to indoor exposure and health effects of gaseous and particular matter. Results Indoor pollutants act as respiratory irritants, toxicants, and adjuvants or carriers of allergens. Conclusion The allergist should be prepared to evaluate patient exposure to allergic and nonallergic triggers and understand how outdoor air pollution is affecting indoor environments. This requires being familiar with methodologies for monitoring and interpreting indoor air quality and interpreting results in the context of the patients exposure history and advising patients about rational environmental control interventions.

Is eczema really on the increase worldwide

Abstract: Background It is unclear whether eczema prevalence is truly increasing worldwide Objective We sought to investigate worldwide secular trends in childhood eczema Methods Children (n = 302,159) aged 13 to 14 years in 105 centers from 55 countries and children aged 6 to 7 years (n = 187,943) in 64 centers from 35 countries were surveyed from the same study centers taking part in Phase One and Three of the International Study of Asthma and Allergies in Childhood by using identical validated and translated questionnaires Eczema was defined as an itchy, relapsing, flexural skin rash in the last 12 months, and it was termed severe eczema when it was associated with 1 or more disturbed nights per week Results Annual prevalence changes in relation to average prevalence across Phase One and Three were generally small and differed in direction according to the age of the participants and world region For children 13 to 14 years old, eczema symptom prevalence decreased in some previously high-prevalence centers from the developed world, such as the United Kingdom and New Zealand, whereas centers with previously high prevalence rates from developing countries continued to increase In the children 6 to 7 years old, most centers showed an increase in current eczema symptoms Similar patterns to these were present for severe eczema at both ages Conclusion The epidemic of eczema seems to be leveling or decreasing in some countries with previously high prevalence rates The picture elsewhere is mixed, with many formerly low-prevalence developing countries experiencing substantial increases, especially in the younger age group

Tolerance to extensively heated milk in children with cow's milk allergy.

Abstract: Background Cow's milk allergy is the most common childhood food allergy. Previously we noted that children who outgrew their milk allergy had milk-specific IgE antibodies primarily directed against conformational epitopes; those with persistent milk allergy also had IgE antibodies directed against specific sequential epitopes. Objective Because high temperature largely destroys conformational epitopes, we hypothesized that some children with milk allergy would tolerate extensively heated (baked) milk products. Methods Children with milk allergy were challenged with heated milk products; heated milk–tolerant subjects were subsequently challenged with unheated milk. Heated milk–tolerant, unheated milk–reactive subjects ingested heated milk products for 3 months and were then re-evaluated. Immune responses were assessed in all subjects; growth and intestinal permeability were followed in heated milk–tolerant subjects. Results One hundred children (mean age, 7.5 years; range, 2.1-17.3 years) underwent heated milk challenges. Sixty-eight subjects tolerated extensively heated milk only, 23 reacted to heated milk, and 9 tolerated both heated and unheated milk. Heated milk–reactive subjects had significantly larger skin prick test wheals and higher milk-specific and casein-specific IgE levels than other groups. At 3 months, subjects ingesting heated milk products had significantly smaller skin prick test wheals and higher casein-IgG 4 compared with baseline; other immunologic parameters, growth, and intestinal permeability were not significantly different. Heated milk–reactive subjects had more severe symptoms during heated milk challenge than heated milk–tolerant subjects experienced during their unheated milk challenge. Conclusion The majority (75%) of children with milk allergy tolerate heated milk.

Hypersensitivity reactions to chemotherapy: Outcomes and safety of rapid desensitization in 413 cases

Abstract: Background Hypersensitivity reactions (HSRs) to chemotherapeutic drugs, including mAbs, often require that the provoking medication be discontinued, thus raising a dilemma for the caregiver: further use could precipitate a severe, even fatal, allergic reaction on re-exposure, but alternative drugs might be poorly tolerated or much less effective compared with the preferred agent. Objective We have developed a standardized rapid desensitization protocol for achieving temporary tolerization to drug allergens. In this study we evaluate the safety and efficacy of this protocol. Methods Ninety-eight patients who had HSRs in response to treatment with carboplatin, cisplatin, oxaliplatin, paclitaxel, liposomal doxorubicin, doxorubicin, or rituximab received rapid desensitization to these agents. A standardized 12-step protocol was used, with treatment given intravenously or intraperitoneally. Initial desensitizations occurred in the medical intensive care unit, whereas most subsequent infusions took place in an outpatient setting. Safety and efficacy of the protocol were assessed by review of treatment records. Results Of the 413 desensitizations performed, 94% induced mild or no reactions. No life-threatening HSRs or deaths occurred during the procedure, and all patients received their full target dose. Most reactions occurred during the first desensitization. Reactions were most commonly reported at the last step of the protocol. Desensitizations through the intravenous and intraperitoneal routes were equally effective. Conclusions Our standardized 12-step protocol for rapid drug desensitization is safe and effective and has been adopted as the standard of care at our institutions in treating patients with HSRs to chemotherapeutic drugs, including mAbs.

The prevalence of plant food allergies: a systematic review.

Abstract: Background There is uncertainty regarding the prevalence of allergies to plant food. Objective To assess the prevalence of allergies to plant food according to the different subjective and objective assessment methods. Methods Our systematic search of population-based studies (since 1990) in the literature database MEDLINE focused on fruits, vegetables/legumes, tree nuts, wheat, soy, cereals, and seeds. Prevalence estimates were categorized by food item and method used (food challenges, skin prick test, serum IgE, parent/self-reported symptoms), complemented by appropriate meta-analyses. Results We included 36 studies with data from a total of over 250,000 children and adults. Only 6 studies included food challenge tests with prevalences ranging from 0.1% to 4.3% each for fruits and tree nuts, 0.1% to 1.4% for vegetables, and Conclusion Population-based prevalence estimates for allergies to plant products determined by the diagnostic gold standard are scarce. There was considerable heterogeneity in the prevalence estimates of sensitization or perceived allergic reactions to plant food.

Specific oral tolerance induction in children with very severe cow's milk–induced reactions

Abstract: Background Some children allergic to cow's milk proteins (CMPs) experience exceptionally severe reactions after ingesting only trace amounts of antigen. Avoiding the food and carrying self-injectable epinephrine are the current strategies for their management. Objective The aim of this study was to evaluate the safety and efficacy of specific oral tolerance induction (SOTI) for children with severe CMP-induced systemic reactions. Methods Ninety-seven children aged 5 years or older with a history of severe allergic reactions and very high CMP-specific IgE levels were selected for a double-blind, placebo-controlled food challenge. Sixty had positive test results to very small amounts of milk and were randomly divided in 2 different groups. Thirty children (group A) immediately began SOTI, whereas the remaining 30 (group B) were kept on a milk-free diet and followed for 1 year. Results After 1 year, 11 (36%) of 30 children in group A had become completely tolerant, 16 (54%) could take limited amounts of milk (5-150 mL), and 3 (10%) were not able to complete the protocol because of persistent respiratory or abdominal complaints. In group B the result of the double-blind, placebo-controlled food challenge performed after a year was positive in all 30 cases (P Conclusions In this study SOTI was effective in a significant percentage of cases.

A novel IL-1 family cytokine, IL-33, potently activates human eosinophils.

Abstract: Background Eosinophils are likely key cells involved in the pathogenesis of asthma and allergic diseases; however, the mechanisms that regulate eosinophil dynamics and functions in mucosal tissues are incompletely understood. IL-33, which is produced by mucosal cells, is a new member of the IL-1 cytokine family. Mice injected with IL-33 display profound mucosal eosinophilia with associated pathologic changes. Although mast cells and T H 2 cells express the IL-33 receptor, ST2, the roles of IL-33 and ST2 in eosinophil biology are unknown. Objectives We investigated the effects of IL-33 on human eosinophils in vitro . Methods Eosinophils and neutrophils were isolated from blood of normal individuals and mildly atopic patients. Real-time RT-PCR and flow cytometry were used to detect ST2. Granulocyte responses to IL-33 were monitored by superoxide anion production and by degranulation; IL-5, IL-1β, and TNF-α served as controls. Eosinophil survival and cytokine production were assessed by flow cytometry and ELISA, respectively. Results ST2 mRNA and protein were detected on eosinophils. IL-33 induced eosinophil superoxide anion production and degranulation as potently as IL-5. IL-33 also increased eosinophil survival and induced production of IL-8. Anti-ST2 inhibited eosinophil responses to IL-33. Neutrophils did not express ST2, nor did they respond to IL-33. Conclusion IL-33 and its receptor, ST2, may play important roles in eosinophil-mediated inflammation; they may provide new therapeutic targets for controlling mucosal eosinophilic inflammation.

Obesity and asthma: Possible mechanisms

Abstract: Epidemiologic data indicate that obesity increases the prevalence and incidence of asthma and reduces asthma control. Obese mice exhibit innate airway hyperresponsiveness and augmented responses to certain asthma triggers, further supporting a relationship between obesity and asthma. Here I discuss several mechanisms that may explain this relationship. In obesity, lung volume and tidal volume are reduced, events that promote airway narrowing. Obesity also leads to a state of low-grade systemic inflammation that may act on the lung to exacerbate asthma. Obesity-related changes in adipose-derived hormones, including leptin and adiponectin, may participate in these events. Comorbidities of obesity, such as dyslipidemia, gastroesophageal reflux, sleep-disordered breathing, type 2 diabetes, or hypertension may provoke or worsen asthma. Finally, obesity and asthma may share a common etiology, such as common genetics, common in utero conditions, or common predisposing dietary factors. Novel therapeutic strategies for treatment of the obese patient with asthma may result from an increased understanding of the mechanisms underlying this relationship.

Immunologic changes in children with egg allergy ingesting extensively heated egg.

Abstract: Background Prior studies have suggested that heated egg might be tolerated by some children with egg allergy. Objective We sought to confirm tolerance of heated egg in a subset of children with egg allergy, to evaluate clinical and immunologic predictors of heated egg tolerance, to characterize immunologic changes associated with continued ingestion of heated egg, and to determine whether a diet incorporating heated egg is well tolerated. Methods Subjects with documented IgE-mediated egg allergy underwent physician-supervised oral food challenges to extensively heated egg (in the form of a muffin and a waffle), with tolerant subjects also undergoing regular egg challenges (in a form of scrambled egg or French toast). Heated egg–tolerant subjects incorporated heated egg into their diets. Skin prick test wheal diameters and egg white, ovalbumin, and ovomucoid IgE levels, as well as ovalbumin and ovomucoid IgG4 levels, were measured at baseline for all subjects and at 3, 6, and 12 months for those tolerant of heated egg. Results Sixty-four of 117 subjects tolerated heated egg, 23 tolerated regular egg, and 27 reacted to heated egg. Heated egg–reactive subjects had larger skin test wheals and greater egg white–specific, ovalbumin-specific, and ovomucoid-specific IgE levels compared with heated egg– and egg-tolerant subjects. Continued ingestion of heated egg was associated with decreased skin test wheal diameters and ovalbumin-specific IgE levels and increased ovalbumin-specific and ovomucoid-specific IgG4 levels. Conclusions The majority of subjects with egg allergy were tolerant of heated egg. Continued ingestion of heated egg was well tolerated and associated with immunologic changes that paralleled the changes observed with the development of clinical tolerance to regular egg.

Allergens are distributed into few protein families and possess a restricted number of biochemical functions.

Abstract: Background Existing allergen databases classify their entries by source and route of exposure, thus lacking an evolutionary, structural, and functional classification of allergens. Objective We sought to build AllFam, a database of allergen families, and use it to extract common structural and functional properties of allergens. Methods Allergen data from the Allergome database and protein family definitions from the Pfam database were merged into AllFam, a database that is freely accessible on the Internet at http://www.meduniwien.ac.at/allergens/allfam/. A structural classification of allergens was established by matching Pfam families with families from the Structural Classification of Proteins database. Biochemical functions of allergens were extracted from the Gene Ontology Annotation database. Results Seven hundred seven allergens were classified by sequence into 134 AllFam families containing 184 Pfam domains (2% of 9318 Pfam families). A random set of 707 sequences with the same taxonomic distribution contained a significantly higher number of different Pfam domains (479 ± 17). Classifying allergens by structure revealed that 5% of 3012 Structural Classification of Proteins families contained allergens. The biochemical functions of allergens most frequently found were limited to hydrolysis of proteins, polysaccharides, and lipids; binding of metal ions and lipids; storage; and cytoskeleton association. Conclusion The small number of protein families that contain allergens and the narrow functional distribution of most allergens confirm the existence of yet unknown factors that render proteins allergenic.

Filaggrin in atopic dermatitis

Abstract: The recent identification of loss-of-function mutations in the structural protein filaggrin as a widely replicated major risk factor for eczema sheds new light on disease mechanisms in eczema, a disease that had heretofore largely been considered to have a primarily immunologic etiopathogenesis. The filaggrin gene (FLG) mutation findings are consistent with a recently proposed unifying hypothesis that offers a mechanistic understanding of eczema pathogenesis synthesizing a heritable epithelial barrier defect and resultant diminished epidermal defense mechanisms to allergens and microbes, followed by polarized TH2 lymphocyte responses with resultant chronic inflammation, including autoimmune mechanisms. Although compelling evidence from genetic studies on FLG implicates perturbed barrier function as a key player in the pathogenesis of eczema in many patients, much is still unknown about the sequence of biologic, physicochemical, and aberrant regulatory events that constitute the transition from an inherited barrier defect to clinical manifestations of inflammatory eczematous lesions and susceptibility to related atopic disorders. The exact contribution of FLG to the wider atopic story, factors modifying FLG expression, and the role of other barrier proteins remain to be delineated. In this review we highlight recent advances in our understanding of the FLG genetics in the cause of eczema and related complex diseases.

Basis for the barrier abnormality in atopic dermatitis: Outside-inside-outside pathogenic mechanisms

Abstract: Until quite recently, the pathogenesis of atopic dermatitis (AD) has been attributed to primary abnormalities of the immune system. Intensive study revealed the key roles played by TH1/TH2 cell dysregulation, IgE production, mast cell hyperactivity, and dendritic cell signaling in the evolution of the chronic, pruritic, inflammatory dermatosis that characterizes AD. Accordingly, current therapy has been largely directed toward ameliorating TH2-mediated inflammation and pruritus. In this review we will assess emerging evidence that inflammation in AD results from inherited and acquired insults to the barrier and the therapeutic implications of this paradigm.

A differential effect of 2 probiotics in the prevention of eczema and atopy: a double-blind, randomized, placebo-controlled trial.

Abstract: Background The role of probiotics in prevention of allergic disease is still not clearly established, although early reports suggested Lactobacillus GG halved the risk of eczema at 2 years. Objective To determine whether probiotic supplementation in early life could prevent development of eczema and atopy at 2 years. Methods Double-blind, randomized placebo-controlled trial of infants at risk of allergic disease. Pregnant women were randomized to take Lactobacillus rhamnosus HN001 (L rhamnosus), Bifidobacterium animalis subsp lactis strain HN019 or placebo daily from 35 weeks gestation until 6 months if breast-feeding, and their infants were randomized to receive the same treatment from birth to 2 years (n = 474). The infant's cumulative prevalence of eczema and point prevalence of atopy, using skin prick tests to common allergens, was assessed at 2 years. Results Infants receiving L rhamnosus had a significantly (P = .01) reduced risk of eczema (hazard ratio [HR], 0.51; 95% CI, 0.30-0.85) compared with placebo, but this was not the case for B animalis subsp lactis (HR, 0.90; 95% CI, 0.58-1.41). There was no significant effect of L rhamnosus (HR, 0.74; 95% CI, 0.46-1.18) or B animalis subsp lactis (HR, 0.82; 95% CI, 0.52-1.28) on atopy. L rhamnosus (71.5%) was more likely than B animalis subsp lactis (22.6%) to be present in the feces at 3 months, although detection rates were similar by 24 months. Conclusion We found that supplementation with L rhamnosus, but not B animalis subsp lactis, substantially reduced the cumulative prevalence of eczema, but not atopy, by 2 years. Understanding how Lactobacilli act to prevent eczema requires further investigation.

Antimicrobial peptides and the skin immune defense system

Abstract: Our skin is constantly challenged by microbes but is rarely infected. Cutaneous production of antimicrobial peptides (AMPs) is a primary system for protection, and expression of some AMPs further increases in response to microbial invasion. Cathelicidins are unique AMPs that protect the skin through 2 distinct pathways: (1) direct antimicrobial activity and (2) initiation of a host response resulting in cytokine release, inflammation, angiogenesis, and reepithelialization. Cathelicidin dysfunction emerges as a central factor in the pathogenesis of several cutaneous diseases, including atopic dermatitis, in which cathelicidin is suppressed; rosacea, in which cathelicidin peptides are abnormally processed to forms that induce inflammation; and psoriasis, in which cathelicidin peptide converts self-DNA to a potent stimulus in an autoinflammatory cascade. Recent work identified vitamin D3 as a major factor involved in the regulation of cathelicidin. Therapies targeting control of cathelicidin and other AMPs might provide new approaches in the management of infectious and inflammatory skin diseases.

Reduced diversity in the early fecal microbiota of infants with atopic eczema

Abstract: Background It might be that early intestinal colonization by bacteria in westernized infants fails to give rise to sufficient immune stimulation to support maturation of regulatory immune mechanisms. Objective The purpose of the present study was to characterize the very early infantile microbiota by using a culture-independent approach and to relate the colonization pattern to development of atopic eczema in the first 18 months of life. Methods Fecal samples were collected from 35 infants at 1 week of age. Twenty infants were healthy, and 15 infants were given diagnoses of atopic eczema at the age of 18 months. The fecal microbiota of the infants was compared by means of terminal restriction fragment length polymorphism (T-RFLP) and temporal temperature gradient gel electrophoresis (TTGE) analysis of amplified 16S rRNA genes. Results By means of T-RFLP analysis, the median number of peaks, Shannon-Wiener index, and Simpson index of diversity were significantly less for infants with atopic eczema than for infants remaining healthy in the whole group and for the Swedish infants when Alu I was used for digestion. The same was found when TTGE patterns were compared. In addition, TTGE analysis showed significantly less bands and lower diversity indices for the British atopic infants compared with those of the control subjects. Conclusion There is a reduced diversity in the early fecal microbiota of infants with atopic eczema during the first 18 months of life.

Filaggrin mutations, atopic eczema, hay fever, and asthma in children

Abstract: Background Mutations in the filaggrin gene (FLG) have been shown to play a significant role in ichthyosis vulgaris and eczema, 2 common chronic skin diseases. However, their role in the development of other atopic diseases such as asthma and rhinitis has not yet been clarified in large population-based studies. Objectives To study the effect of FLG mutations at the population level and their effect on other atopic phenotypes. Methods Association analysis of the 2 common FLG-null mutations R501X and 2282del4 and 3 recently identified rare FLG variants (R2447X, S3247X, 3702delG) was performed on our cross-sectional population of German children (n = 3099) recruited as part of the International Study of Asthma and Allergies in Childhood II in Munich (n = 1159) and Dresden (n = 1940). Results FLG variants increased the risk for eczema more than 3-fold (odds ratio [OR], 3.12; 95% CI, 2.33-4.173; P = 2.5 × 10−14; population-attributable risk, 13.5%). Independent of eczema, FLG mutations conferred a substantial risk for allergic rhinitis (OR, 2.64; 95% CI, 1.76-4.00; P = 2.5 × 10−6; population-attributable risk, 10.8%). Nasal biopsies demonstrated strong filaggrin expression in the cornified epithelium of the nasal vestibular lining, but not the transitional and respiratory nasal epithelia. In contrast, the association with asthma (OR, 1.79; 95% CI, 1.19-2.68; P = .0048) was restricted to asthma occurring in the context of eczema, and there was a strong association with the complex phenotype eczema plus asthma (OR, 3.49; 95% CI, 2.00-6.08; P = 1.0 × 10−5). Conclusion Our results suggest that FLG mutations are key organ specific factors predominantly affecting the development of eczema and confer significant risks of allergic sensitization and allergic rhinitis as well as asthma in the context of eczema.

Adiponectin and inflammation: Consensus and controversy

Abstract: Circulating levels of adiponectin decrease with increasing visceral obesity and are lower in patients with type 2 diabetes, the metabolic syndrome, and cardiovascular disease compared with controls matched by body mass index. Several reports demonstrated anti-inflammatory effects of adiponectin. Because increased adipose tissue is associated with low-grade chronic inflammation and proinflammatory factors inhibit adiponectin production, the current hypothesis states that chronic inflammation associated with visceral obesity inhibits production of adiponectin, perpetuating inflammation. The negative correlation between adiponectin and markers of inflammation in the aforementioned conditions supports this hypothesis. In contrast with disorders typically associated with excess adiposity and positive energy balance, adiponectin levels are elevated—rather than decreased—in classic chronic inflammatory/autoimmune diseases that are unrelated to increased adipose tissue, such as rheumatoid arthritis, SLE, inflammatory bowel disease, type 1 diabetes, and cystic fibrosis. In these patients, adiponectin levels positively—rather than negatively—correlate with inflammatory markers. Furthermore, proinflammatory effects of adiponectin have been reported in tissues such as joint synovium and colonic epithelium. Thus, adiponectin is regulated in the opposite direction and may exert differential functions in classic versus obesity-associated inflammatory conditions. This article discusses this apparent paradox and presents possible alternative and/or complementary explanations.

The etiology and incidence of anaphylaxis in Rochester, Minnesota: A report from the Rochester Epidemiology Project

Abstract: Background Reported incidences of anaphylaxis range from 3.2 to 20 per 100,000 population. The incidence and trend over time has meaningful public health implications but has not been well characterized because of a lack of a standard definition and deficiencies in reporting of events. Objective We sought to determine the incidence and cause of anaphylaxis over a 10-year period. Methods We performed a population-based incidence study that was conducted in Rochester, Minnesota, from 1990 through 2000. Anaphylaxis episodes were identified on the basis of symptoms and signs of mast cell and basophil mediator release plus mucocutaneous, gastrointestinal tract, respiratory tract, or cardiovascular system involvement. Results Two hundred eleven cases of anaphylaxis were identified (55.9% in female subjects). The mean age was 29.3 years (SD, 18.2 years; range, 0.8-78.2 years). The overall age- and sex-adjusted incidence rate was 49.8 (95% CI, 45.0-54.5) per 100,000 person-years. Age-specific rates were highest for ages 0 to 19 years (70 per 100,000 person-years). Ingested foods accounted for 33.2% (70 cases), insect stings accounted for 18.5% (39 cases), medication accounted for 13.7% (29 cases), radiologic contrast agent accounted for 0.5% (1 case), "other" causes accounted for 9% (19 cases), and "unknown" causes accounted for 25.1% (53 cases). The "other" group included cats, latex, cleaning agents, environmental allergens, and exercise. There was an increase in the annual incidence rate during the study period from 46.9 per 100,000 persons in 1990 to 58.9 per 100,000 persons in 2000 ( P = .03). Conclusion The overall incidence rate is 49.8 per 100,000 person-years, which is higher than previously reported. The annual incidence rate is also increasing. Food and insect stings continue to be major inciting agents for anaphylaxis.

Meta-analysis of clinical trials of probiotics for prevention and treatment of pediatric atopic dermatitis

Abstract: Background Prenatal and postnatal probiotic supplementation for prevention and treatment of pediatric atopic dermatitis (PAD) has been studied in clinical trials, but results have been mixed and hindered by heterogeneity of study design. Objectives To summarize and interpret quantitatively clinical trial findings on the efficacy of probiotics for PAD and to define key trial features correlating with high methodologic quality. Methods PubMed and Cochrane database searches yielded 21 trials (n = 1898; age 0-13 y) published between February 1997 and May 2007 for review and quality assessment. Ten double-blind randomized controlled clinical trials were meta-analyzed by using RevMan. Data from the 6 prevention studies (n = 1581) and 4 treatment trials (n = 299) were pooled by using fixed-effects and random-effects models of relative risk ratios and of weighted mean difference, respectively. Results Prevention corresponded with summary effect sizes of 0.69 (0.57, 0.83) and 0.66 (0.49, 0.89), respectively, supporting probiotics' PAD prevention potential, which decreased further to 0.61 after exclusion of the 1 trial of postnatal-only probiotics. The clinical significance of the treatment trial findings of intergroup Scoring Atopic Dermatitis (quantification of PAD severity) score reduction by –6.64 points (–9.78, –3.49) and –8.56 (–18.39, 1.28), and intragroup change of –1.06 (–3.86, 1.73) and –1.37 (–4.81, 2.07), is questionable. Conclusion Current evidence is more convincing for probiotics' efficacy in prevention than treatment of PAD.

Oxidants and the pathogenesis of lung diseases

Abstract: The increasing number of population-based and epidemiologic associations between oxidant pollutant exposures and cardiopulmonary disease exacerbation, decrements in pulmonary function, and mortality underscores the important detrimental effects of oxidants on public health. Because inhaled oxidants initiate a number of pathologic processes, including inflammation of the airways, which may contribute to the pathogenesis and/or exacerbation of airways disease, it is critical to understand the mechanisms through which exogenous and endogenous oxidants interact with molecules in the cells, tissues, and epithelial lining fluid of the lung. Furthermore, it is clear that interindividual variation in response to a given exposure also exists across an individual lifetime. Because of the potential impact that oxidant exposures may have on reproductive outcomes and infant, child, and adult health, identification of the intrinsic and extrinsic factors that may influence susceptibility to oxidants remains an important issue. In this review, we discuss mechanisms of oxidant stress in the lung, the role of oxidants in lung disease pathogenesis and exacerbation (eg, asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome), and the potential risk factors (eg, age, genetics) for enhanced susceptibility to oxidant-induced disease.

Targeting TNF-α: A novel therapeutic approach for asthma

Abstract: Approximately 5% to 10% of patients with asthma have severe disease that is refractory or poorly responsive to inhaled corticosteroid therapy. These patients represent an important unmet clinical need because they experience considerable morbidity and mortality and consume a disproportionately large amount of health care resources. TNF-α is a proinflammatory cytokine that has been implicated in many aspects of the airway pathology in asthma. Evidence is emerging to suggest that it might play an important role in severe refractory disease. The development of novel TNF-α antagonists has allowed us to test the role of this cytokine in vivo . Preliminary studies have demonstrated an improvement in asthma quality of life, lung function, and airway hyperresponsiveness and a reduction in exacerbation frequency in patients treated with anti–TNF-α therapy. However, there is marked heterogeneity in response, suggesting that benefit is likely to be reserved to a small subgroup. Importantly, where efficacy is reported, this also needs to be considered in the context of concerns about the safety of anti–TNF-α therapies. Therefore the challenge for clinicians is to evaluate the risk/benefit ratio of these therapies in individual patients with asthma.

The burden of disease associated with filaggrin mutations: A population-based, longitudinal birth cohort study

Abstract: Background Atopic disease is a major health problem. Mutations in the filaggrin gene (FLG) confer major susceptibility to eczema and related asthma. Objective We sought to determine the natural history and burden of atopic disease conferred by the 2 most common FLG mutations in a large, population-based birth cohort study. Methods We analyzed the effect of the most common null alleles (R501X and 2282del4) on several atopic phenotypes in a cohort of approximately 7000 English children born in 1990-1991. Results FLG null alleles associated strongly with eczema; eczema associated with these mutations presents in early life and is more persistent (hazard ratio for eczema resolution for those with FLG mutations to FLG wild type, 0.67; 95% CI, 0.58-0.77; P = 5 × 10 −8 ). FLG mutations conferred a population asthma risk of 1.80 (95% CI, 1.34-2.41; P = .00019); asthma risk was especially high in the context of eczema (odds ratio, 3.16; 95% CI, 2.25-4.43; P = 1.4 × 10 −11 ). Strong associations were identified with sensitization to grass, house dust mite, and cat dander and sensitization to multiple allergens (odds ratio, 2.12; 95% CI, 1.03-4.37; P = 5.42 × 10 −27 ). Conclusion FLG mutations are strong genetic determinants of eczema, early wheeze, asthma in the context of eczema, and atopic sensitization. They confer risk of a particular trajectory for eczema, with increased duration of disease and greater risk of asthma and multiple allergic sensitizations. FLG alleles help define the risk profile of children with eczema and help define the "eczema plus early wheeze" and "eczema plus asthma" phenotypes.

Grass pollen immunotherapy induces Foxp3-expressing CD4(+)CD25(+) cells in the nasal mucosa

Abstract: Background Regulatory T (Treg) cells play an important role in controlling allergic inflammation. The transcription factor Foxp3 regulates the development and function of natural and adaptive CD4 + CD25 + Treg cells. Objectives We sought to examine the effect of grass pollen injection immunotherapy on the numbers of Foxp3 + CD4 + and Foxp3 + CD25 + T cells in and out of season and their expression of IL-10 in the nasal mucosa of patients with hay fever. Methods Nasal biopsy specimens were obtained from untreated patients with hay fever, participants with grass pollen allergy who had received 2 years of immunotherapy, and healthy control subjects. Dual-immunofluorescence microscopy was used to enumerate and colocalize Foxp3 expression to CD4 + and CD25 + T cells in the nasal mucosa. Triple staining was performed to colocalize Foxp3 + cells to CD3 + CD25 + and CD3 + IL-10–expressing cells. Results At peak season, numbers of Foxp3 + CD25 + ( P = .02) and Foxp3 + CD4 + ( P = .03) cells were significantly increased in the nasal mucosa of immunotherapy-treated patients compared with numbers before treatment. Foxp3 + CD25 + ( P = .03) and Foxp3 + CD4 + ( P = .04) cells were also greater in immunotherapy-treated patients out of season compared with those in untreated patients with hay fever. Within the immunotherapy-treated group, 20% of CD3 + CD25 + cells expressed Foxp3, and 18% of Foxp3 + CD3 + cells were IL-10 positive. Conclusion The presence of local Foxp3 + CD25 + CD3 + cells in the nasal mucosa, their increased numbers after immunotherapy, and their association with clinical efficacy and suppression of seasonal allergic inflammation support a putative role for Treg cells in the induction of allergen-specific tolerance in human subjects.

T-cell regulation in chronic paranasal sinus disease

Abstract: Background Chronic rhinosinusitis is an inflammatory disease with distinct cytokine and remodeling patterns. Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a T H 2-skewed eosinophilic inflammation, whereas chronic rhinosinusitis without nasal polyps (CRSsNP) represents a predominant T H 1 milieu. Objective We aimed to study the direct tissue expression of transcription factors for T-cell subpopulations, including T regulatory cells, in relation to the cytokine expression patterns in the different disease subgroups. Methods The expression of forkhead box P3 (FOXP3), T-box transcription factor (T-bet), GATA-3, retinoid acid-related orphan receptor C (RORc), the suppressive cytokines TGF-β1 and IL-10, and T H 1/ T H 2/ T H 17 cytokines (IFN-γ, IL-4, IL-5, IL-13, IL-17) were analyzed by means of RT-PCR in 13 CRSsNP, 16 CRSwNP, and 10 control samples. Additional protein measurements were performed for TGF-β1 and IFN-γ. Results In CRSwNP, we observed a significantly lower FOXP3 mRNA and TGF-β1 protein expression, but a significantly higher T-bet, GATA-3, IL-5, and IL-13 mRNA expression compared with controls, whereas RORc was not significantly different compared with controls. In CRSsNP, FOXP3, T-bet, GATA-3, and RORc expression was not significantly different from controls, whereas TGF-β1 mRNA, IFN-γ mRNA, and protein were significantly higher in CRSsNP compared with controls. For IL-17, no significant differences were noted among all groups. Conclusion We demonstrate for the first time a decreased FOXP3 expression accompanied by an upregulation of T-bet and GATA-3 and a downregulation of TGF-β1 in CRSwNP versus controls and CRSsNP.

8. Hereditary angioedema.

Abstract: Hereditary angioedema is an episodic swelling disorder with autosomal dominant inheritance. Attacks are characterized by brawny, self-limited, nonpruritic edema of the deep dermal layers of the skin that most often involve the hands and feet. They usually begin in childhood and become more severe after puberty. Patients also have episodic attacks of severe abdominal pain caused by edema of the gastrointestinal mucosa. Swelling attacks are life threatening when they involve the airway. Estrogens exacerbate attacks, and in some patients attacks are precipitated by trauma or psychologic stress. The disease is caused by a mutation in one of the 2 copies of the gene for the plasma protein C1 inhibitor, with the product of 1 gene unable to control generation of bradykinin. Eighty-five percent of patients have low antigenic levels of C1 inhibitor, and 15% have normal levels of poorly functioning protein. Most patients have decreased plasma complement protein C4 levels. Impeded androgens and, less frequently, ɛ-aminocaproic acid are currently the mainstays of chronic treatment. These agents or fresh frozen plasma are also used for prophylaxis. At this time, acute therapy is mostly supportive. There are currently ongoing multiple trials of new therapeutic agents. In half a century, a life-threatening disease has become one that is manageable and rarely causes death.