The Journal of Allergy and Clinical Immunology - Articles in Press

SQ-standardized sublingual grass immunotherapy: Confirmation of disease modification 2 years after 3 years of treatment in a randomized trial - Corrected Proof

2012-01-30

Background: The main aim of specific immunotherapy is sustained effect due to changes in the immune system that can be demonstrated only in long-term trials.Objective: To investigate sustained efficacy and disease modification in a 5-year double-blind, placebo-controlled trial, including 2 years of blinded follow-up after completion of a 3-year period of treatment, with the SQ-standardized grass allergy immunotherapy tablet, Grazax (Phleum pratense 75,000 SQ-T/2,800 BAU, ALK, Denmark) or placebo.Methods: A randomized, double-blind, placebo-controlled, multinational, phase III trial included adults with a history of moderate-to-severe grass pollen–induced allergic rhinoconjunctivitis, with or without asthma, inadequately controlled by symptomatic medications. Two hundred thirty-eight participants completed the trial. End points included rhinoconjunctivitis symptom and medication scores, combined scores, asthma symptom and medication scores, quality of life, days with severe symptoms, immunologic end points, and safety parameters.Results: The mean rhinoconjunctivitis daily symptom score was reduced by 25% to 36% (P ≤ .004) in the grass allergy immunotherapy tablet group compared with the placebo group over the 5 grass pollen seasons covered by the trial. The rhinoconjunctivitis DMS was reduced by 20% to 45% (P ≤ .022 for seasons 1-4; P = .114 for season 5), and the weighted rhinoconjunctivitis combined score was reduced by 27% to 41% (P ≤ .003) in favor of active treatment. The percentage of days with severe symptoms during the peak grass pollen exposure was in all seasons lower in the active group than in the placebo group, with relative differences of 49% to 63% (P ≤ .0001). Efficacy was supported by long-lasting significant effects on the allergen-specific antibody response. No safety issues were identified.Conclusion: The results confirm disease modification by SQ-standardized grass allergy immunotherapy tablet in addition to effective symptomatic treatment of allergic rhinoconjunctivitis.

Potter Stewart and the definition of anaphylaxis - Corrected Proof

Carlos A. Camargo — 2012-01-30

Potter Stewart was an Associate Justice of the US Supreme Court who might be best known for a snippet from his opinion in the obscenity case of Jacobellis v Ohio (1964). In that case he acknowledged that “hard-core pornography” was difficult to define but then added that “I know it when I see it.”

Clinical relevance of IgE to recombinant Gly m 4 in the diagnosis of adult soybean allergy - Corrected Proof

2012-01-30

Soybean is one of the most important foods causing food allergy in childhood. In addition, studies have shown that allergy to soybean can be caused by IgE cross-reactivity between Bet v 1, a major allergen of birch pollen, and its homologue pathogenesis-related class 10 protein in soybean, Gly m 4. However, the clinical relevance of measuring the level of IgE antibody (IgE-ab) to recombinant Gly m 4 (rGly m 4) is still debated, considering that the concentration of Gly m 4 in soybean extract is quite low and that a considerable proportion of the patients allergic to birch pollen have IgE-ab to Gly m 4 without reporting any symptoms to soybean. Sensitization to the soybean storage proteins Gly m 5 and Gly m 6 have been shown to contribute to more severe soybean allergy. Data from studies on soybean allergy outside Europe, particularly in Asian populations, are still limited.

Laboratory technology for population-based screening for severe combined immunodeficiency in neonates: The winner is T-cell receptor excision circles - Corrected Proof

Jennifer M. Puck — 2012-01-30

The most profound primary immunodeficiency disease, severe combined immunodeficiency (SCID), is fatal in infancy unless affected infants are provided with an adaptive immune system through allogeneic hematopoietic cell transplantation, enzyme replacement, or gene therapy. However, most infants with SCID lack a family history or any clinical clues before the onset of infections, making this serious but treatable disease a candidate for population-based newborn screening. Of several approaches considered for SCID screening, testing for T-cell receptor excision circles (TRECs), a DNA biomarker of normal T-cell development, has proved successful. TREC numbers can be measured in DNA isolated from the dried bloodspots already routinely collected for newborn screening. Infants with low or absent TRECs can thus be identified and referred for confirmatory testing and prompt intervention. TREC testing of newborns is now being performed in several states, indicating that this addition to the newborn screening panel can be successfully integrated into state public health programs.

Remembrance of things past: HLA genes come back on the allergy stage - Corrected Proof

Donata Vercelli — 2012-01-30

Like most other research fields, immunology has witnessed the rise and fall of many paradigms. In the 1970s and early 1980s, the emphasis was on antigen-specific responses and the molecules underpinning them. The leading laboratories focused on the structure of T- and B-cell antigen receptors and the mechanisms underlying their seemingly inexhaustible ability to generate diverse repertoires. In parallel, others dissected the mechanisms restricting antigen-specific responses, thereby placing MHC class I and class II HLA molecules center stage. Allergists were particularly keen on the study of HLA-dependent restriction of immune responsiveness. Allergen by allergen and then epitope by epitope, human and murine models were devised to identify the HLA alleles responsible for presentation to T cells. This intense interest in the role of HLA molecules was motivated by a fundamental (and still largely unanswered) question in our field: Why is an antigen an allergen, or better, why do some, but not all, antigens evoke an IgE response, and why do they do this only in some subjects, even though virtually everyone in the population is exposed?

DNA methylation of TH1/TH2 cytokine genes affects sensitization and progress of experimental asthma - Corrected Proof

2012-01-27

Background: Epigenetic changes in DNA methylation have recently been demonstrated to be involved in effector T-cell polarization, resulting in differential secretion of TH1 and TH2 cytokines. However, the contribution to the development of a chronic inflammatory phenotype remains still unclear.Objective: We sought to investigate changes in DNA methylation in marker genes of T-cell subsets during allergen sensitization/challenge and their influence on the development of an allergic airway inflammatory response.Methods: The relationship between changes in DNA methylation and phenotype development were examined in a well-established model of experimental asthma. DNA methylation was investigated at genomic loci associated with TH1 (IFNG promoter) or TH2 (conserved noncoding sequence 1 [CNS1]) cytokine production by using bisulfite pyrosequencing.Results: Analysis of CD4+ T cells revealed a significant increase in DNA methylation at the IFNG promoter after allergen sensitization/challenge, which correlated with decreased IFN-γ cytokine expression, whereas only minor changes were observed at the CNS1 locus. Furthermore, the increase in DNA methylation at the IFNG promoter could be reversed with a DNA methyltransferase (DNMT) inhibitor in vitro and in vivo with beneficial effects on sensitization status and allergic phenotype. The specific importance of the DNA methylation status in CD4+ T cells could be confirmed by using adoptive transfer experiments.Conclusion: We here report the novel finding that epigenetic regulation in T cells contributes to the development of experimental asthma and can be targeted pharmacologically.

Significance of ovomucoid- and ovalbumin-specific IgE/IgG4 ratios in egg allergy - Corrected Proof

2012-01-27

Background: The role of specific IgG4 antibodies in natural tolerance acquisition remains a matter of debate; the specific IgE/IgG4 ratio might add value to the measurement of absolute amounts of IgE for assessing the ongoing status of egg reactivity.Objective: We sought to determine the significance of IgG4 antibodies to ovalbumin (OVA) and ovomucoid (OVM) in egg-allergic children.Methods: One hundred seven egg-allergic children (mean age 6.9 years; range 1.6-18.6 years) were challenged to baked egg. The outcomes of the challenges were related to the level of specific IgE and IgG4 to OVM and OVA, component IgE/IgG4 ratios, and mediator release in a functional assay based on the rat basophil leukemia cell line.Results: Baked egg–reactive children had significantly higher OVA and OVM ratios of IgE/IgG4 and mediator release in the rat basophil leukemia–based assay than did tolerant children (P < .05 for both). The OVA- and OVM-specific IgE/IgG4 ratios and mediator release were correlated. In the receiver operating characteristic analysis, the areas under the curve for a logistic regression model including specific IgE and IgG4 to OVA and OVM were significantly greater compared with the areas under the curve for egg white–specific IgE and OVM-specific IgE.Conclusions: The balance between IgE and IgG4 to OVA and OVM has functional consequences. A model that includes the interactions between IgE and IgG4 to OVA and OVM accurately predicts reactivity to baked egg and warrants further investigation.

The long quest for neonatal screening for severe combined immunodeficiency - Corrected Proof

Rebecca H. Buckley — 2012-01-27

Early recognition of severe combined immunodeficiency (SCID) is a pediatric emergency because a diagnosis before live vaccines or nonirradiated blood products are given and before development of infections permits lifesaving unfractionated HLA-identical or T cell–depleted haploidentical hematopoietic stem cell transplantation, enzyme replacement therapy, or gene therapy. The need for newborn screening for this condition has been recognized for the past 15 years. However, implementation of screening required development of an assay for T-cell lymphopenia that could be performed on dried bloodspots routinely collected from newborn infants for the past 48 years. This was accomplished 6 years ago, and there have already been 7 successful pilot studies. A recommendation to add SCID to the routine newborn-screening panel was approved by the Secretary’s Advisory Committee on Heritable Disorders of Newborns and Children in 2010 and was soon after approved by the Secretary of Health and Human Services. It is important for allergists, immunologists, and other health care providers to take an active role in promoting newborn screening for SCID and other T-lymphocyte abnormalities in their states. Even more important will be their roles in establishing accurate diagnoses for infants with positive screen results and in ensuring that they are given the best possible treatment.

Activin A and TGF-β promote TH9 cell–mediated pulmonary allergic pathology - Corrected Proof

2012-01-27

Background: IL-9–secreting (TH9) T cells are thought to represent a distinct T-cell subset. However, evidence for their functionality in disease is uncertain.Objective: To define a functional phenotype for TH9-driven pathology in vivo.Methods: We used fluorescence-activated cell sorting to identify circulating TH9 cells in atopic and nonatopic subjects. In mice we utilized a model of allergic airways disease induced by house dust mite to determine TH9 cell function in vivo and the role of activin A in TH9 generation.Results: Allergic patients have elevated TH9 cell numbers in comparison to nonatopic donors, which correlates with elevated IgE levels. In a murine model, allergen challenge with house dust mite leads to rapid TH9 differentiation and proliferation, with much faster kinetics than for TH2 cell differentiation, resulting in the specific recruitment and activation of mast cells. The TGF-β superfamily member activin A replicates the function of TGF-β1 in driving the in vitro generation of TH9 cells. Importantly, the in vivo inhibition of TH9 differentiation induced by allergen was achieved only when activin A and TGF-β were blocked in conjunction but not alone, resulting in reduced airway hyperreactivity and collagen deposition. Conversely, adoptive transfer of TH9 cells results in enhanced pathology.Conclusion: Our data identify a distinct functional role for TH9 cells and outline a novel pathway for their generation in vitro and in vivo. Functionally, TH9 cells promote allergic responses resulting in enhanced pathology mediated by the specific recruitment and activation of mast cells in the lungs.

The relationship between combination inhaled corticosteroid and long-acting β-agonist use and severe asthma exacerbations in a diverse population - Corrected Proof

2012-01-27

Background: Safety concerns surround the use of long-acting β-agonists (LABAs) for the treatment of asthma, even in combination with inhaled corticosteroids (ICSs) and particularly in high-risk subgroups.Objective: To estimate the effect of ICS therapy and fixed-dose ICS/LABA combination therapy on severe asthma exacerbations in a racially diverse population.Methods: ICS and ICS/LABA exposure was estimated from pharmacy data for patients with asthma aged 12 to 56 years who were members of a large health maintenance organization. ICS and ICS/LABA use was estimated for each day of follow-up to create a moving window of exposure. Proportional hazard models were used to assess the relationship between ICS and ICS/LABA combination therapy and severe asthma exacerbations (ie, use of oral corticosteroids, asthma-related emergency department visit, or asthma-related hospitalization).Results: Among the 1828 patients who met the inclusion criteria, 37% were African American, 46% were treated with ICS therapy alone, and 54% were treated with an ICS/LABA combination. Models assessing the risk of severe asthma exacerbations among individuals using ICS treatment alone and ICS/LABA combination therapy suggested that the overall protective effect was as good or better for ICS/LABA combination therapy when compared with ICS treatment alone (hazard ratio, 0.65 vs 0.72, respectively). Analyses in several subgroups, including African American patients, showed a similar statistically significant protective association for combination therapy.Conclusion: Treatment with ICS/LABA fixed-dose combination therapy appeared to perform as well as or better than ICS treatment alone in reducing severe asthma exacerbations; this included multiple high-risk subgroups.

High sensitivity of CAP-FEIA rVes v 5 and rVes v 1 for diagnosis of Vespula venom allergy - Corrected Proof

2012-01-27

Ves v 5 (antigen 5) is a 23-kDa protein from Vespula venom, and it is recognized as the most potent allergen in venoms of the Vespidae family. There is a high sequence similarity of Ves v 5 within species of the same genus, such as yellow jacket, that is, Vespula (>95%); however, when it is compared with other genera such as Dolichovespula or Polistes, the sequence identity is much lower (about 60%). Another potential Vespula allergen is a 37-kDa phospholipase A1, known as Ves v 1. Neither Ves v 5 nor Ves v 1 is found in honeybee venom. Ves v 5 and Ves v 1 recombinant allergen components, both expressed in insect cells, became available in 2010 and 2011, respectively, for analyses on the ImmunoCAP solid-phase IgE assay (CAP-FEIA; Phadia, Uppsala, Sweden).

Specific allergen concentration of WHO and FDA reference preparations measured using a multiple allergen standard - Corrected Proof

2012-01-27

Allergen measurements require well-defined allergen standards. Allergists rely on these measurements for dosing patients on immunotherapy with the aim of achieving maintenance doses of 5 to 20 μg of specific allergen that have been associated with clinical efficacy. Allergists need to know that allergen measurements made by manufacturers are consistent and can reliably be used in clinical practice. Allergen measurements are widely used in the indoor air quality industry to assess exposure in homes, the workplace, schools, and commercial buildings. They are routinely used for assessing health risks associated with allergen exposure, for assessing the efficacy of allergen avoidance procedures, and for developing new allergen control products.

CD21 deficiency, complement, and the development of common variable immunodeficiency - Corrected Proof

Michael M. Frank — 2012-01-27

In this issue, Thiel and colleagues present the first patient identified who lacks the membrane receptor protein CD21. This receptor is mainly present on B cells and follicular dendritic cells. In this 28-year-old man, the deficiency is associated with an immune defect, common variable immunodeficiency (CVID). As such it adds to the growing list of genetic deficiencies associated with the development of CVID. It is not surprising that CD21 deficiency contributes to CVID because CD21 is part of the molecular complex consisting of CD21, CD81, and CD19 present on the membrane of B cells. This molecular complex markedly augments the B-cell receptor response upon triggering by its cognate antigen. Defects in CD19 and CD81 have been previously associated with defects in antibody generation and CVID.

Screening for severe combined immunodeficiency in newborns - Corrected Proof

William T. Shearer — 2012-01-27

This issue of the Journal is devoted to the critical concept of screening for severe combined immunodeficiency (SCID), a long-sought goal of clinical immunologists engaged in hematopoietic stem cell transplantation (HSCT) for SCID, a congenital disease of many causes that is fatal in the first 1 to 2 years of life. The clinical immunologists chosen for the reviews in this thematic issue were selected for their expertise in the diagnosis and management of infants with SCID, their leadership in devising methods of early diagnosis of SCID, and their ability in implementing the current method of detecting a low number of T-cell receptor excision circles (TRECs) in the blood of neonates.

Reduction of total IgE by targeted coengagement of IgE B-cell receptor and FcγRIIb with Fc-engineered antibody - Corrected Proof

2012-01-18

Background: Sequestration of IgE to prevent its binding to high-affinity IgE receptor FcεRI on basophils and mast cells is an effective therapy for allergic asthma. IgE production requires differentiation of activated IgE+ B cells into plasma cells upon allergen sensitization. B-cell receptor signaling is suppressed by the inhibitory IgG Fc receptor FcγRIIb; therefore, we reasoned that a therapeutic antibody that coengages FcγRIIb and IgE B-cell receptor would not only sequester IgE but also suppress its production by blocking IgE+ B-cell activation and differentiation to IgE-secreting plasma cells.Objective: To explore the effects of IgE sequestration versus IgE suppression by comparing omalizumab to FcγRIIb-optimized anti-IgE antibodies in humanized mouse models of immunoglobulin production.Methods: By using a murine anti-IgE antibody as a template, we humanized, increased IgE binding, and modified its Fc domain to increase affinity for FcγRIIb. We next compared effects of this antibody (XmAb7195) versus omalizumab on the secretion of IgE and other isotypes in human PBMC cultures and in PBMC-engrafted severe combined immunodeficiency mice.Results: Relative to omalizumab, XmAb7195 has a 5-fold higher affinity for human IgE and more than 400-fold higher affinity for FcγRIIb. In addition to sequestering soluble IgE, XmAb7195 inhibited plasma cell differentiation and consequent human IgE production through coengagement of IgE B-cell receptor with FcγRIIb. In PBMC-engrafted mice, XmAb7195 reduced total human IgE (but not IgG or IgM) levels by up to 40-fold relative to omalizumab.Conclusion: XmAb7195 acts by IgE sequestration coupled with an FcγRIIb-mediated inhibitory mechanism to suppress the formation of IgE-secreting plasma cells and reduce both free and total IgE levels.

Multiple-allergen and single-allergen immunotherapy strategies in polysensitized patients: Looking at the published evidence - Corrected Proof

2012-01-13

In allergen immunotherapy there is debate as to whether polysensitized patients are best treated with many allergens simultaneously (chosen according to the sensitization profile, a predominantly North American approach) or a single allergen (chosen according to the most clinically problematic allergy, a predominantly European approach). In patients seeking treatment for moderate-to-severe respiratory allergies, polysensitization is more prevalent (range, 50% to 80%) than monosensitization in both the United States and Europe. Safe, effective, single-allergen preparations will most likely have been tested in polysensitized patients. In robust, large-scale clinical trials of grass pollen sublingual tablets, polysensitized patients benefited at least as much from allergen immunotherapy as monosensitized patients. A recent review of multiallergen immunotherapy concluded that simultaneous delivery of multiple unrelated allergens can be clinically effective but that there was a need for additional investigation of therapy with more than 2 allergen extracts (particularly in sublingual allergen immunotherapy). More work is also required to determine whether single-allergen and multiallergen immunotherapy protocols elicit distinct immune responses in monosensitized and polysensitized patients. Sublingual and subcutaneous multiallergen immunotherapy in polysensitized patients requires more supporting data to validate its efficacy in practice.

The Wisconsin approach to newborn screening for severe combined immunodeficiency - Corrected Proof

James Verbsky, Monica Thakar, John Routes — 2012-01-13

Severe combined immunodeficiency (SCID) is a life-threatening disease of infants that is curable with hematopoietic cell transplantation if detected early. Population-based screening for SCID using the T-cell receptor excision circle (TREC) assay began in Wisconsin in 2008; 5 infants with SCID or other forms of severe T-cell lymphopenia (TCL) have been detected, and no infants with SCID have been missed. This review will provide an overview of the TREC screening assay and an update of the findings from Wisconsin on all infants screened from January 1, 2008, until December 31, 2010. Importantly, we give practical recommendations regarding newborn population-based screening using the TREC assay, including the evaluation and care of infants detected.

The risk of allergic reactions to allergen extracts in personnel - Corrected Proof

Sten Dreborg — 2012-01-13

I would like to comment on the interesting letter to the Editor by Bandino and Tankersley. First, I will address the risk of handling stock solutions. Thirty years ago, I was clinically responsible for developing a series of freeze-dried allergenic extracts/stock solutions (1:10 wt/vol) for the US market. The potency of the timothy extract was 5000 μg of Phl p 1/mL. Thus 1 drop contained 250 μg of Phl p 1, which was approximately 10 times more than the top dose of timothy extract for subcutaneous immunotherapy marketed by ALK-Abelló (Hørsholm, Denmark) on the European market. Given as a first shot, that dose is definitely capable of inducing anaphylaxis.

Reply - Corrected Proof

Michelle L. Bandino, Michael S. Tankersley — 2012-01-13

In response to our recent report of a case of anaphylaxis in an allergy immunotherapy extract-compounding technician after an extract needle stick, we want to thank Dr Dreborg for sharing his own similar clinical experience with both allergen stock solutions and allergen bronchial provocation. Of special interest is his survey among 20 pediatric nurses, with the majority reporting possible sensitization or new allergic symptoms coinciding with occupational exposure. Although this might have been merely temporally related to natural nonoccupational exposure responsible for the sensitization, this survey highlights an occurrence that has not been well described or investigated in the allergy community. Regarding bronchial provocation tests, the American Thoracic Society has reported precautions for technician safety and ventilation requirements during methacholine challenges, which would be similar for aerosolized allergen challenge. More practical and of greater clinical importance are the issues of compounding personnel and also those who deliver immunotherapy in the clinics around the world, the development of new allergen sensitivities to the allergen mixing compounds through either natural or occupational exposure, and the potential risk to such personnel should an accidental stick, mucosal splash, or allergen entry into a broken cutaneous surface result in subsequent anaphylaxis, as described in our recent report.

Obesity is not linked to increased whole-body mast cell burden in children - Corrected Proof

Brant R. Ward, Silva A. Arslanian, Elisa Andreatta, Lawrence B. Schwartz — 2012-01-13

Obesity is clearly associated with insulin resistance and chronic low-grade inflammation. Macrophages appear to be especially important in this relationship because they infiltrate adipose tissue and produce a variety of inflammatory cytokines. Exploring the contribution of other immune cells to the development of obesity, Liu et al described a role for mast cells in the development of obesity and diabetes in mice. Using genetically modified mice and pharmacologic stabilizers of mast cells, they demonstrated that mast cells and mast cell–mediated protease expression can promote the growth of white adipose tissue. Importantly, the idea that mast cells might function in a similar manner in human obesity was suggested by the finding of increased numbers of mast cells in human white adipose tissue from obese compared with lean subjects in their study. Furthermore, mean serum tryptase levels were higher in obese (13.1 ng/mL) than lean (7.7 ng/mL) subjects, as determined by using an in-house tryptase assay. We attempted to replicate these data by comparing serum tryptase levels in obese, overweight, and lean subjects from a pediatric population.

Nationwide cohort study of the leukotriene receptor antagonist montelukast and incident or recurrent cardiovascular disease - Corrected Proof

Erik Ingelsson, Li Yin, Magnus Bäck — 2012-01-13

Background: The leukotriene pathway has been associated with an increased cardiovascular risk. However, the effects of the antileukotriene treatment used in asthmatic patients on cardiovascular outcomes have remained largely unexplored.Objective: We sought to examine a potential protective role of the leukotriene receptor antagonist montelukast on future risk of incident and recurrent myocardial infarction and ischemic stroke.Methods: A nationwide population-based cohort of approximately 7 million persons integrating data from the Prescribed Drug, Patient, Cause of Death, Income, Educational, and Emigration Registers was followed from July 1, 2005, to December 31, 2008. Analyses were performed in the whole population after exclusion of subjects with a prior cardiovascular diagnosis (incident events; sample size, n = 6,910,923 for myocardial infarction and n = 6,932,578 for stroke) and in subjects with a prior diagnosis (recurrent events; n = 153,937 and n = 132,291 for stroke and myocardial infarction, respectively).Results: Cox proportional hazard ratios (HRs) did not reveal an association of montelukast use with incident events. In contrast to these findings, montelukast use was associated with a lower risk for recurrent stroke (HR, 0.62; 95% CI, 0.38-0.99) accounting for age, sex, education level, and yearly income. Adjusting the latter finding also for respiratory and cardiovascular medications and diagnoses revealed similar point estimates (HR, 0.62; 95% CI, 0.39-1.0). Post hoc analyses revealed a significant association of montelukast use with a lower risk for recurrent myocardial infarction in male subjects (HR, 0.65; 95% CI, 0.43-0.99).Conclusion: These data provide a first indication for a potential role of the antiasthma drug montelukast for secondary prevention of cardiovascular disease.

Development and validation of the Composite Asthma Severity Index—an outcome measure for use in children and adolescents - Corrected Proof

2012-01-13

Background: Asthma severity is reflected in many aspects of the disease, including impairment and future risks, particularly for exacerbations. According to the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma, however, to assess more comprehensively the severity of asthma the level of current treatment needed to maintain a level of control should be included.Objective: Development and validation of a new instrument, the Composite Asthma Severity Index (CASI), which can quantify disease severity by taking into account impairment, risk, and the amount of medication needed to maintain control. At present, there is no instrument available to measure and assess the multidimensional nature of asthma.Methods: Twenty-six established asthma investigators, who are part of the National Institutes of Health–supported Inner City Asthma Consortium, participated in a modified Delphi consensus process to identify and weight the dimensions of asthma. Factor analysis was performed to identify independent domains of asthma by using the Asthma Control Evaluation trial. CASI was validated by using the Inner City Anti-IgE Therapy for Asthma trial.Results: CASI scores include 5 domains: day symptoms and albuterol use, night symptoms and albuterol use, controller treatment, lung function measures, and exacerbations. At Asthma Control Evaluation trial enrollment, CASI ranged from 0 to 17, with a mean of 6.2. CASI was stable, with minimal change in variance after 1 year of treatment. In external validation, CASI detected a 32% larger improvement than did symptoms alone.Conclusion: CASI retained its discriminatory ability even with low levels of symptoms reported after months of guidelines-directed care. Thus, CASI has the ability to determine the level of asthma severity and provide a composite clinical characterization of asthma.

Allergen-induced IgE-dependent gut inflammation in a human PBMC–engrafted murine model of allergy - Corrected Proof

2012-01-11

Background: Humanized murine models comprise a new tool to analyze novel therapeutic strategies for allergic diseases of the intestine.Objective: In this study we developed a human PBMC–engrafted murine model of allergen-driven gut inflammation and analyzed the underlying immunologic mechanisms.Methods: Nonobese diabetic (NOD)–scid-γc−/− mice were injected intraperitoneally with human PBMCs from allergic donors together with the respective allergen or not. Three weeks later, mice were challenged with the allergen orally or rectally, and gut inflammation was monitored with a high-resolution video miniendoscopic system, as well as histologically.Results: Using the aeroallergens birch or grass pollen as model allergens and, for some donors, also hazelnut allergen, we show that allergen-specific human IgE in murine sera and allergen-specific proliferation and cytokine production of human CD4+ T cells recovered from spleens after 3 weeks could only be measured in mice treated with PBMCs plus allergen. Importantly, these mice had the highest endoscopic scores evaluating translucent structure, granularity, fibrin, vascularity, and stool after oral or rectal allergen challenge and a strong histologic inflammation of the colon. Analyzing the underlying mechanisms, we demonstrate that allergen-associated colitis was dependent on IgE, human IgE receptor–expressing effector cells, and the mediators histamine and platelet-activating factor.Conclusion: These results demonstrate that allergic gut inflammation can be induced in human PBMC–engrafted mice, allowing the investigation of pathophysiologic mechanisms of allergic diseases of the intestine and evaluation of therapeutic interventions.

Administration of influenza vaccine to pediatric patients with egg-induced anaphylaxis - Corrected Proof

Irene Fung, Jonathan M. Spergel — 2012-01-11

Administration of egg-containing influenza vaccine to subjects with egg allergy continues to generate discourse. From a public health perspective, vaccination offers clear benefits. However, the potential for egg-induced anaphylaxis remains a concern. For those with a history of a severe reaction to egg ingestion, there is understandable unease by both health care providers and patients’ families regarding vaccination. Current Joint Task Force on Practice Parameter guidelines suggest that most patients with egg allergy can safely receive influenza vaccination. Indeed, studies show a reaction rate to vaccination ranging from 0% to 6.2% in cohorts with egg allergy. However, these studies reported on relatively small numbers of patients with egg-induced anaphylaxis.

Usefulness of PBMCs to predict clinical response to corticosteroids in asthmatic patients - Corrected Proof

Elena Goleva, Leisa P. Jackson, Melanie Gleason, Donald Y.M. Leung — 2012-01-11

Background: Blood tests are needed to identify steroid-resistant (SR) asthmatic patients early so that they can be managed with alternative anti-inflammatory therapy.Objective: We sought to assess the usefulness of peripheral blood to predict steroid response in asthmatic patients.Methods: Nineteen asthmatic patients with FEV1 of less than 80% of predicted value were classified as SR or steroid sensitive (SS) based on change in lung FEV1 percentage after 7 days of oral prednisone. Blood was collected at baseline (visit 1) and 30 days after prednisone administration (visit 3). PBMCs were cultured for 4 hours with or without 10−7 mol/L dexamethasone, and cellular response to dexamethasone was determined by using real-time PCR based on expression analysis of steroid-regulated genes. Suppression of PHA-induced T-cell proliferation by dexamethasone was assessed.Results: Prednisone significantly improved FEV1 percentages in SS asthmatic patients (mean ± SE: 17.5% ± 2.4%) but not SR asthmatic patients (0.8% ± 2.0%, P < .001). Before prednisone treatment, mitogen-induced kinase phosphatase 1 (P = .01) and IL-8 mRNA (P < .05) levels were significantly higher in PBMCs from SR asthmatic patients. TNF-α (P < .05) and IL-8 fold suppression by dexamethasone (P < .05) were significantly reduced in PBMCs from SR asthmatic patients. The expression of glucocorticoid receptor (GCR) β, but not GCR-α, was significantly increased in PBMCs of SR asthmatic patients (P = .01). The dexamethasone inhibitory concentration of 50% for PBMC proliferation was significantly higher for SR asthmatic patients (P < .05). These markers no longer differed between groups in PBMCs 30 days after prednisone administration. The composite score of assays at baseline before prednisone was significantly different between SR and SS asthmatic patients (P < .001).Conclusions: PBMCs from SR asthmatic patients have higher baseline mitogen-induced kinase phosphatase 1, IL-8, and GCR-β mRNA levels; have a lower GCR-α/GCR-β mRNA ratio; are less responsive to suppression of TNF-α and IL-8 by dexamethasone; and require more dexamethasone to suppress T-cell proliferation compared with SS asthmatic patients.

Possible eosinophilic esophagitis induced by milk oral immunotherapy - Corrected Proof

2012-01-11

New therapeutic strategies to treat food allergy have emerged in recent years. At present, oral immunotherapy (OIT) with food is one of the most widely researched treatments for food allergy. Immediate adverse reactions during therapy have been widely described, and most of them were mild. However, long-term effects of OIT have been barely reported. We describe 3 cases of esophageal eosinophilia in 110 patients treated with milk OIT at our outpatient clinic during the last 5 years.

Age-related differences in the pathogenesis of chronic rhinosinusitis - Corrected Proof

2012-01-11

Chronic rhinosinusitis (CRS) significantly affects the quality of life of elderly people. However, the inflammatory mechanisms of CRS in the elderly have not been well studied. CRS is commonly divided into 2 subtypes: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). The inflammatory response in patients with CRSsNP has been shown to have a tendency toward TH1 polarization, whereas CRSwNP inflammatory responses are characterized by eosinophilia with a TH2 skewing. Recently, there has been increasing evidence that CRS and some allergic diseases might be linked to deficiencies in the barrier function of the skin or airway mucosal epithelium. The objective of the present study was to evaluate whether there are age-related differences in clinical presentation and/or immunologic markers in patients with CRS.

Increased peanut-specific IgA levels in saliva correlate with food challenge outcomes after peanut sublingual immunotherapy - Corrected Proof

2012-01-11

Antigen-specific immunotherapy has been practiced for 100 years and is the only known therapy that modulates IgE-mediated allergy. Immunotherapy is commonly administered through the subcutaneous (SCIT) or sublingual (SLIT) routes, with clinical benefits demonstrated for each. Although immunotherapy can readily be given to patients with aeroallergen sensitivity (ie, pollen, grass, and pet dander) and Hymenoptera venom allergy, no such treatment is offered for food allergies. The lack of a proactive therapeutic approach for food allergies has left millions of affected subjects to rely solely on avoiding the allergen triggers, which has been associated with a decreased quality of life. Both antigen-specific and nonspecific approaches for food allergies are being investigated.

Pancreatitis as a novel complication of aspirin therapy in patients with aspirin-exacerbated respiratory disease - Corrected Proof

Flavia C.L. Hoyte, Richard W. Weber, Rohit K. Katial — 2012-01-11

Aspirin-exacerbated respiratory disease (AERD), previously termed Samter triad, is an adult-onset disease characterized by asthma, hyperplastic chronic sinusitis, nasal polyposis, and hypersensitivity to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Although the upper and lower airway inflammation seen in patients with AERD is exacerbated by the ingestion of aspirin and other NSAIDs, the disease progresses independently of exposure to these medications. Since 1922, when this syndrome was originally identified by Widal, and 1967, when it was further described by Samter and Beers, the clinical efficacy of aspirin desensitization and ongoing aspirin therapy has been well established. Aspirin desensitization is a procedure whereby patients receive increasing doses of aspirin, usually to a dose of 650 mg, over 2 to 3 days. If these patients continue to take aspirin on a daily basis after the desensitization procedure, many of them demonstrate improved control of their asthma and sinus disease.

Recurrent severe exacerbations in early life and reduced lung function at school age - Corrected Proof

2012-01-11

Asthma exacerbations have been linked to progressive loss of lung function in school-age children and adults. Previous longitudinal studies have suggested that lung function deficits in children with persistent wheezing are established by school age, and these deficits can persist into adulthood. Because the first several years of life are a critical time in lung growth and development, we hypothesized that recurrent severe wheezing exacerbations during early life could lead to airway remodeling and be associated with reductions in lung function at school age.

The airway epithelium nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome is activated by urban particulate matter - Corrected Proof

2012-01-10

Background: The airway epithelium is the first line of defense against inhaled insults and therefore must be capable of coordinating appropriate inflammatory and immune responses.Objective: We sought to test the hypothesis that the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome, an intracellular danger-sensing complex, plays a critical role in airway epithelium–mediated immune responses to urban particulate matter (PM) exposure.Methods: In this study we (1) identified NLRP3 and caspase-1 expression in human airway epithelium bronchus and primary cells, (2) characterized NLRP3 inflammasome–mediated IL-1β production from human airway epithelium in response to PM, and (3) performed in vivo PM exposure experiments with wild-type and Nlrp3−/− mice.Results: Our results demonstrate that human airway epithelium contains a functional NLRP3 inflammasome that responds to PM exposure with caspase-1 cleavage and production of IL-1β. Exposure of Nlrp3−/− and wild-type mice to PM in vivo demonstrates NLRP3-dependent production of IL-1β in the lung, airway neutrophilia, and increases in CD11c+hi/MHC class II+hi cell numbers in intrathoracic lymph nodes.Conclusion: Our study is the first to characterize airway epithelial NLRP3 inflammasome–mediated immune responses to PM exposure, which might have implications in patients with asthma and other lung diseases.

Airway epithelial cells from asthmatic children differentially express proremodeling factors - Corrected Proof

2012-01-10

Background: The airway epithelium can express factors that drive subepithelial airway remodeling. TGF-β2, vascular epithelial growth factor (VEGF), a disintegrin and metalloprotease 33 (ADAM33), and periostin are hypothesized to be involved in subepithelial remodeling and are overexpressed in adult asthmatic airways. Epidemiologic data suggest that lung function deficits in asthmatic patients are acquired in childhood.Objectives: We sought to determine whether airway epithelial cells (AECs) from asthmatic children differentially express TGF-β2, VEGF, ADAM33, or periostin compared with cells from atopic nonasthmatic and healthy children intrinsically or in response to IL-4/IL-13 stimulation.Methods: Bronchial and nasal epithelial cells were obtained from brushings from well-characterized asthmatic (n = 16), atopic nonasthmatic (n = 9), and healthy (n = 15) children after achievement of anesthesia for elective procedures. After differentiation at an air-liquid interface (ALI) for 3 weeks, conditioned media were sampled and RNA was extracted from unstimulated and IL-4/IL-13–stimulated cultures. TGF-β2 and VEGF levels were measured with ELISA. ADAM33 and periostin expression was assessed by using real-time PCR.Results: TGF-β2 and VEGF production was significantly greater in bronchial and nasal ALI cultures from asthmatic children than in cultures from atopic nonasthmatic and healthy children. TGF-β2 levels increased significantly in asthmatic cultures after IL-4/IL-13 stimulation. Within-subject correlation between nasal and bronchial ALI production of TGF-β2 (r = 0.64, P = .001) and VEGF (r = 0.73, P < .001) was good. Periostin expression was 3.7-fold higher in bronchial cells (P < .001) and 3.9-fold higher in nasal cells (P < .004) from asthmatic children than in cells from atopic nonasthmatic or healthy children. ADAM33 was not differentially expressed by AECs from asthmatic patients compared with that from cells from atopic nonasthmatic or healthy children.Conclusion: AECs from asthmatic children differentially express TGF-β2, VEGF, and periostin compared with cells from atopic nonasthmatic and healthy children. Nasal epithelial cells might be a suitable surrogate for bronchial cells that could facilitate investigation of the airway epithelium in future longitudinal pediatric studies.

Endocannabinoids limit excessive mast cell maturation and activation in human skin - Corrected Proof

2012-01-09

Background: Mast cells (MCs) crucially contribute to many inflammatory diseases. However, the physiological controls preventing excessive activities of MCs in human skin are incompletely understood.Objective: Since endocannabinoids are important neuroendocrine MC modifiers, we investigated how stimulation/inhibition of cannabinoid 1 (CB1) receptors affect the biology of human skin MCs in situ.Methods: This was investigated in the MC-rich connective tissue sheath of organ-cultured human scalp hair follicles by quantitative (immuno)histomorphometry, ultrastructural, and quantitative PCR techniques with the use of CB1 agonists or antagonists, CB1 knockdown, or CB1 knockout mice.Results: Kit+ MCs within the connective tissue sheath of human hair follicles express functional CB1 receptors, whose pharmacological blockade or gene silencing significantly stimulated both the degranulation and the maturation of MCs from resident progenitor cells in situ (ie, enhanced the number of tryptase+, FcεRIα, or chymase+ connective tissue sheath-MCs). This was, at least in part, stem cell factor–dependent. CB1 agonists counteracted the MC-activating effects of classical MC secretagogues. Similar phenomena were observed in CB1 knockout mice, attesting to the in vivo relevance of this novel MC-inhibitory mechanism.Conclusion: By using human hair follicle organ culture as an unconventional, but clinically relevant model system for studying the biology of MCs in situ, we show that normal skin MCs are tightly controlled by the endocannabinoid system. This limits excessive activation and maturation of MCs from resident progenitors via “tonic” CB1 stimulation by locally synthesized endocannabinoids. The excessive numbers and activation of MCs in allergic and other chronic inflammatory skin diseases may partially arise from resident intracutaneous MC progenitors, for example, because of insufficient CB1 stimulation. Therefore, CB1 stimulation is a promising strategy for the future management of allergy and MC-dependent skin diseases.

Molecular profiles of IgE to Phleum pratense in children with grass pollen allergy: Implications for specific immunotherapy - Corrected Proof

2011-12-30

Background: The so-called component-resolved immunotherapy of allergies proposes an immunization tailored to the molecular sensitization profiles of individual patients.Objectives: We sought (1) to investigate the profiles of IgE sensitization to Phleum pratense in children with grass pollen allergy and (2) to define the compatibility of these profiles with a mixture of recombinant allergenic molecules of P pratense previously proposed for specific immunotherapy.Methods: We examined 200 children (age, 4-18 years; 126 boys) with allergic rhinitis, asthma, or both ascertained through validated questionnaires. Each child underwent skin prick testing (ALK-Abelló) and serum IgE assays (ImmunoCAP, Phadia) with 9 pollen extracts. Sera reacting against P pratense were tested for the individual molecules (rPhl p 1, rPhl p 2, rPhl p 4, nPhl p 4, rPhl p 5b, rPhl p 6, rPhl p 7, rPhl p 11, and Phl p 12). Through a combinatorial approach, the IgE individual sensitization profiles were matched against an experimental allergen-specific immunotherapy (SIT) preparation containing Phl p 1, Phl p 2, Phl p 5, and Phl p 6.Results: Among the 176 of 200 children with IgE sensitization to P pratense extract, 39 profiles of sensitization to the 8 allergenic molecules tested (cutoff, 0.35 kU/L) were identified. This high heterogeneity was reduced by considering only 6 or 4 P pratense molecules but not by increasing the cutoff levels of IgE positivity. The molecular profile of the experimental SIT preparation matched that of 7 (4%) of 176 patients only; the remaining 169 patients were classified in 4 mismatch categories: underpowered (29%), overpowered (32%), underpowered/overpowered (32%), and unrelated (3%).Conclusions: IgE sensitization profiles to P pratense are highly heterogeneous. Molecularly designed SIT preparations tailored to patients’ needs should consider this high heterogeneity and be driven by locally performed population studies.

Increased risk of pertussis in patients with asthma - Corrected Proof

2011-12-30

Background: The recent pertussis outbreak in California highlights the effect of pertussis on public health. In 2004, a pertussis outbreak occurred in Olmsted County, Minnesota, despite a high vaccine uptake. This outbreak provided a natural experiment to assess the relationship between asthma and pertussis.Objective: We sought to determine whether asthmatic subjects have a higher risk of pertussis than nonasthmatic subjects.Methods: We conducted a population-based case-control study. There were 223 pertussis cases identified by means of PCR in 2004 and 2005. We identified age- and sex-matched control subjects from 5537 patients with negative test results for pertussis. We conducted a comprehensive medical record review and applied predetermined criteria to ascertain asthma status. Conditional logistic regression was fit to assess the effect of asthma status on the risk of pertussis.Results: Of the 223 subjects, 164 were eligible for the study, and 328 matched control subjects (1:2 matching) were enrolled. Of these 164 subjects, 50% were male, and 82% were white. The median age at the index date of pertussis was 14 years. Sixty-two (38%) of the 164 cases had asthma before the index date of pertussis compared with 85 (26%) of the 328 control subjects (odds ratio, 1.73; 95% CI, 1.12-2.67; P = .013). The population attributable risk percentage of asthma for risk of pertussis was 17%.Conclusions: Given the high prevalence of asthma and the ongoing risk of pertussis throughout the United States, consideration of defining asthmatic subjects as a target group for pertussis vaccination (eg, replacing decennial tetanus-diphtheria booster with tetanus, diphtheria, and acellular pertussis vaccine for adolescents and adults) should be given.

CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia - Corrected Proof

2011-12-26

Background: CD27 is a lymphocyte costimulatory molecule that regulates T-cell, natural killer (NK) cell, B-cell, and plasma cell function, survival, and differentiation. On the basis of its function and expression pattern, we considered CD27 a candidate gene in patients with hypogammaglobulinemia.Objective: We sought to describe the clinical and immunologic phenotypes of patients with genetic CD27 deficiency.Methods: A molecular and extended immunologic analysis was performed on 2 patients lacking CD27 expression.Results: We identified 2 brothers with a homozygous mutation in CD27 leading to absence of CD27 expression. Both patients had persistent symptomatic EBV viremia. The index patient was hypogammaglobulinemic, and immunoglobulin replacement therapy was initiated. His brother had aplastic anemia in the course of his EBV infection and died from fulminant gram-positive bacterial sepsis. Immunologically, lack of CD27 expression was associated with impaired T cell–dependent B-cell responses and T-cell dysfunction.Conclusion: Our findings identify a role for CD27 in human subjects and suggest that this deficiency can explain particular cases of persistent symptomatic EBV viremia with hypogammaglobulinemia and impaired T cell–dependent antibody generation.

Tolerance-like mediated suppression by mesenchymal stem cells in patients with dust mite allergy–induced asthma - Corrected Proof

2011-12-26

Background: Mesenchymal stem cells (MSCs) can suppress and enhance immune functions. MSCs show promise as off-the-shelf cellular therapy for several disorders, including inflammation.Objective: We investigated the effects of MSCs on the proliferation of PBMCs to allergic subjects (dust mite [DM]), allergic asthmatic subjects, or both.Methods: Proliferation was studied by using tritiated thymidine uptake with or without MSCs. The refractoriness of PBMCs to DM was examined after preconditioning with MSCs and after repeated challenge with low-dose DM. Flow cytometry was used to study regulatory T cells and dendritic cells (DCs), and ELISA was used to study cytokine production.Results: Seven subjects with allergic asthma met the inclusion/exclusion criteria. MSCs significantly (P < .05) reduced the proliferation of 6 subjects with allergic asthma but not those with allergy alone. The effect was specific to the allergen because MSCs did not affect challenges to tetanus toxoid. There was no change in CD4/CD25/forkhead box protein 3–positive cells, although there were decreased IFN-γ and increased IL-10 levels. Numbers of mature DCs were increased 6-fold. Refractoriness to DM was achieved by means of repeated exposure to low-dose DM and MSCs and also MSC- preconditioned MSC.Conclusion: MSCs suppressed the proliferation of DM-challenged PBMCs from allergic asthmatic subjects but not from allergic subjects without asthma. MSCs blunted the maturation of DCs but not regulatory T cells. Repeated exposure to low-dose DM and MSCs, as well as preconditioning of PBMCs with MSCs, caused refractoriness to DM. These findings have implications for the use of MSCs in attenuation of the inflammatory responses to allergic triggers in asthmatic patients with off-the-shelf MSCs.

Relating small airways to asthma control by using impulse oscillometry in children - Corrected Proof

2011-12-19

Background: Previous reports suggest that the peripheral airways are associated with asthma control. Patient history, although subjective, is used largely to assess asthma control in children because spirometric results are many times normal values. Impulse oscillometry (IOS) is an objective and noninvasive measurement of lung function that has the potential to examine independently both small- and large-airway obstruction.Objective: We sought to determine the utility of IOS in assessing asthma control in children.Methods: Asthmatic and healthy children (6-17 years) were enrolled in the study. Spirometric and IOS (resistance of the respiratory system at 5 Hz [R5] and 20 Hz [R20], reactance of the respiratory system at 5 Hz [X5], resonant frequency of reactance [Fres], and area under the reactance curve between 5 Hz and Fres [reactance area {AX}]) values were collected in triplicate before and after a bronchodilator was administered. The physicians were blinded to the IOS measurements and assessed asthma control using American Thoracic Society guidelines.Results: Small-airway IOS measurements, including the difference of R5 and R20 [R5-20], X5, Fres, and AX, of children with uncontrolled asthma (n = 44) were significantly different from those of children with controlled asthma (n = 57) and healthy children (n = 14), especially before the administration of a bronchodilator. However, there was no difference in large-airway IOS values (R20). No differences were found between children with controlled asthma and healthy children in any of the end points. Receiver operating characteristic analysis showed cut points for baseline R5-20 (1.5 cm H2O · L−1 · s) and AX (9.5 cm H2O · L−1) that effectively discriminated controlled versus uncontrolled asthma (area under the curve, 0.86 and 0.84) and correctly classified more than 80% of the population.Conclusion: Uncontrolled asthma is associated with small-airways dysfunction, and IOS might be a reliable and noninvasive method to assess asthma control in children.

Modulation of basophil activity: A novel function of the neuropeptide α-melanocyte–stimulating hormone - Corrected Proof

2011-12-19

Background: Little is known about the effect of neuropeptides on basophils, which are important effector cells in immune and allergic responses.Objective: This study aimed at revealing the role of α-melanocyte–stimulating hormone (α-MSH) on basophil function.Methods: Expression of melanocortin receptors and proopiomelanocortin (POMC) was analyzed by means of RT-PCR, Western immunoblotting, fluorescence-activated cell sorting, and double-immunofluorescence analysis. Signal transduction studies included cyclic AMP and Ca2+ mobilization assays. Basophil activity was assessed based on CD63 surface expression and cytokine release.Results: MC-1R expression was detectable in basophils isolated from human peripheral blood, as well as in basophils within nasal tissue. In isolated basophils from human blood, truncated POMC transcripts were present, but there was no POMC protein. Treatment of basophils with α-MSH increased intracellular Ca2+ but not cyclic AMP levels. α-MSH at physiologic doses potently suppressed basophil activation induced by N-formyl-methionyl-leucyl-phenylalanine, phorbol 12-myristate 13-acetate, or grass pollen allergen in whole blood of healthy or allergic subjects, respectively. The effect of α-MSH on basophil activation was MC-1R mediated (as shown by blockade with a peptide analogue of agouti-signaling protein) and imitated by adrenocorticotropic hormone but not elicited by the tripeptides KPV and KdPT, both of which lack the central pharmacophore of α-MSH. Moreover, α-MSH at physiologic doses significantly suppressed secretion of 3 proallergic cytokines, IL-4, IL-6, and IL-13, in basophils stimulated with anti-IgE, N-formyl-methionyl-leucyl-phenylalanine, or phorbol 12-myristate 13-acetate.Conclusion: Our findings highlight a novel functional activity of α-MSH, which acts as a natural antiallergic basophil-response modifier. These findings might point to novel therapeutic strategies in treating allergic diseases.

The course of asthma activity: A population study - Corrected Proof

Andrea Gershon, Jun Guan, J. Charles Victor, Chengning Wang, Teresa To — 2011-12-19

Background: Unlike most chronic diseases, which tend to progress over time, asthma is known to persist, possibly resolve, and/or present with any combination of remissions and relapses. As a result, its course has been difficult to characterize and its prognosis difficult to predict.Objective: To quantify the proportion of individuals with asthma who have active disease and, of those, the proportion who experience significant gaps in their asthma activity; and to determine factors associated with asthma activity.Methods: Universal population health administrative databases were used to identify all individuals with asthma living in Ontario, Canada, in 1993 and follow them for 15 years. Active asthma was indicated by 1 or more physician claims for asthma.Results: Of 613,394 individuals with asthma in 1993, 504,851 (82.3%) had active disease in subsequent years. Of those who had complete follow-up, 74.6% experienced a gap of 2 or more years in their asthma activity. Previous asthma claims, older and younger age, and a codiagnosis of chronic obstructive pulmonary disease correlated with greater asthma activity.Conclusion: Over 15 years, most individuals with asthma in Ontario, Canada, had active disease that was interspersed by periods of inactivity when they did not require medical attention and were likely in remission. These analyses offer insight into the natural course of asthma activity that may help improve the ability to predict an individual’s course of disease.

Asthma diagnosis and airway bronchodilator response in HIV-infected patients - Corrected Proof

2011-12-19

Background: Despite the high prevalence of respiratory symptoms and obstructive lung disease in HIV-infected subjects, the prevalence of bronchodilator reversibility (BDR) and asthma has not been systematically studied during the era of combination antiretroviral therapy (ART).Objective: We sought to determine the prevalence of asthma diagnosis and related pulmonary function abnormalities in an HIV-infected cohort and to identify potential mechanisms.Methods: We performed a cross-sectional analysis of 223 HIV-infected subjects with data on respiratory symptoms and diagnoses, pulmonary function, sputum cell counts, and asthma-related cytokines and chemokines in serum/sputum.Results: Doctor-diagnosed asthma was present in 46 (20.6%), and BDR (≥200 mL and ≥12% increase in FEV1 or forced vital capacity) was present in 20 (9.0%) participants. Pulmonary symptoms and function were worse in those with doctor-diagnosed asthma. Doctor-diagnosed asthma was independently associated with female sex (P = .04), body mass index of greater than 29.6 kg/m2 (vs <29.6 kg/m2, P = .03), history of bacterial or Pneumocystis pneumonia (P = .01), and not currently taking ART (P = .04) and in univariate analysis with parental history of asthma (n = 180, P = .004). High sputum eosinophil percentages (>2.3% based on the highest decile) were more likely in those with doctor-diagnosed asthma (P = .02) or BDR (P = .02). Doctor-diagnosed asthma tended to be more common with high sputum IL-4 (P = .02) and RANTES (P = .02) levels, whereas BDR was associated with high plasma macrophage inflammatory protein 1α (P = .002) and sputum macrophage inflammatory protein 1β (P = .001) levels.Conclusion: Asthma diagnosis and BDR are prevalent in an HIV-infected outpatient cohort, and associations with family history, obesity, allergic inflammation, prior infection, absence of ART, and increased HIV-stimulated cytokines suggest possible mechanisms of HIV-associated asthma.

Dendritic cells from X-linked hyper-IgM patients present impaired responses to Candida albicans and Paracoccidioides brasiliensis - Corrected Proof

2011-12-12

Background: Patients with X-linked hyper-IgM syndrome (X-HIGM) due to CD40 ligand (CD40L) mutations are susceptible to fungal pathogens; however, the underlying susceptibility mechanisms remain poorly understood.Objective: To determine whether monocyte-derived dendritic cells (DCs) from patients with X-HIGM exhibit normal responses to fungal pathogens.Methods: DCs from patients and controls were evaluated for the expression of costimulatory (CD80 and CD86) and MHC class II molecules and for their ability to produce IL-12 and IL-10 in response to Candida albicans and Paracoccidioides brasiliensis. We also evaluated the ability of C albicans– and P brasiliensis–pulsed mature DCs to induce autologous T-cell proliferation, generation of T helper (TH) 17 cells, and production of IFN-γ, TGF-β, IL-4, IL-5, and IL-17.Results: Immature DCs from patients with X-HIGM showed reduced expression of CD80, CD86, and HLA-DR, which could be reversed by exogenous trimeric soluble CD40L. Most important, mature DCs from patients with X-HIGM differentiated by coculturing DCs with fungi secreted minimal amounts of IL-12 but substantial amounts of IL-10 compared with mature DCs from normal individuals. Coculture of mature DCs from X-HIGM patients with autologous T cells led to low IFN-γ production, whereas IL-4 and IL-5 production was increased. T-cell proliferation and IL-17 secretion were normal. Finally, in vitro incubation with soluble CD40L reversed the decreased IL-12 production and the skewed TH2 pattern response.Conclusion: Absence of CD40L during monocyte/DC differentiation leads to functional DC abnormalities, which may contribute to the susceptibility to fungal infections in patients with X-HIGM.

Frequency of mold and pollen mixing in allergen immunotherapy prescriptions within a large health care system, 1990-2010 - Corrected Proof

Satyen Gada, Bret Haymore, Lorne McCoy, Susan Kosisky, Michael Nelson — 2011-12-12

Proteolytic enzymes can be found in extracts produced from insects, mites, and molds. Loss of allergen extract potency over time may be attributed to several factors including the activity of proteolytic enzymes. Nelson et al demonstrated deleterious effects on the potency of pollen extracts when mixed with mold, with the exception of ragweed. Similarly, Grier et al also reported a decrease in extract recovery when combining high-protease- and low-protease–containing extracts. The most deleterious effects were seen when cockroach or mold was mixed with trees, grasses, and weeds, again with the exception of ragweed. However, the results of these and other studies are somewhat conflicting.

The who, where, and when of IgE in allergic airway disease - Corrected Proof

2011-12-12

Allergic asthma and allergic rhinitis/conjunctivitis are characterized by a TH2-dominated immune response associated with increased serum IgE levels in response to inhaled allergens. Because IgE is a key player in the induction and maintenance of allergic inflammation, it represents a prime target for therapeutic intervention. However, our understanding of IgE biology remains fragmentary. This article puts together our current knowledge on IgE in allergic airway diseases with a special focus on the identity of IgE-secreting cells (“who”), their location (“where”), and the circumstances in which they are induced (“when”). We further consider the therapeutic implications of the insights gained.

Complete remission in 3 of 3 anti-IL-6–treated patients with Schnitzler syndrome - Corrected Proof

Karoline Krause, Eugen Feist, Michael Fiene, Tilmann Kallinich, Marcus Maurer — 2011-12-12

Schnitzler syndrome (SchS) is a rare chronic inflammatory disease that usually occurs in patients older than 50 years and is characterized by urticarial rash and monoclonal gammopathy, usually of the IgM class. Further clinical symptoms include episodes of fever, arthralgia or arthritis, lymphadenopathy, and bone and muscle pain. SchS is severely debilitating and notoriously hard to treat.

Advanced glycation end products contribute to the immunogenicity of IFN-β pharmaceuticals - Corrected Proof

2011-12-12

Human IFN-β proved to be efficient for the treatment of relapsing-remitting multiple sclerosis. There are 2 forms of recombinant human IFN-β on the market, IFN-β1a (Avonex [Biogen Idec Inc, Weston, Mass] and Rebif [Merck Serono S.A., Geneva, Switzerland]) and IFN-β1b (Betaferon and Betaseron [Bayer HealthCare Pharmaceuticals Inc, Berlin, Germany]). IFN-β1a is produced in Chinese hamster ovary cells, whereas IFN-β1b is derived from Escherichia coli. The latter is a nonglycosylated form with a C17S substitution. Formation of neutralizing antibodies against human IFN-β has been reported for all IFN-β therapeutics, with the percentage of neutralizing antibody–positive patients varying between 3% (Avonex) and 35% (Betaferon). The most frequent side effects observed with IFN-β are injection-site reactions and flu-like symptoms. Cases of type 1 hypersensitivity reactions, including urticaria and severe anaphylaxis, have also been reported.

Application of cultured human regulatory T cells requires preclinical in vivo evaluation - Corrected Proof

2011-12-12

To the Editor: Application of CD4+CD25+ forkhead box protein 3 (FOXP3)–positive regulatory T (Treg) cells is considered a promising treatment or prevention strategy for human inflammatory diseases, such as allergy, graft-versus-host disease (GvHD), and autoimmunity. In a first-in-human clinical trial, CD4+CD25+FOXP3+ Treg cells suppressed GvHD, indicating a crucial role for Treg cells in suppressing inflammation. Several methods have been developed for either in vitro expansion of natural Treg (nTreg) cells or induction of Treg cells from CD4+CD25− conventional T cells to enable Treg cell application in clinical trials. These methods include T-cell receptor stimulation; costimulation through CD28; addition of IL-2, which is required for FOXP3 induction, and Treg survival, proliferation, and function. Nonetheless, differences between these Treg cell populations exist. For example, although expanded nTreg cells are suppressive in in vitro suppression assays, human induced FOXP3+ T cells are not consistently suppressive in vitro. Moreover, although the reliability of in vitro assays has been criticized, these assays are still considered the gold standard to determine T cell–suppressive capacity. Importantly, there are indications that murine induced FOXP3+ T cells are not always suppressive in vivo. In our view preclinical testing of in vitro–expanded or in vitro–generated human Treg cells in a reliable in vivo model is crucial for estimating the suitability of Treg cells for therapy. To this end, we tested cultured human Treg cells in a previously developed preclinical model for xenogeneic GvHD (x-GvHD) in recombination-activating gene (Rag) 2−/− common γ-chain−/− mice.

Home treatment of hereditary angioedema with icatibant administered by health care professionals - Corrected Proof

2011-12-12

Hereditary angioedema caused by C1-inhibitor deficiency (HAE-C1-INH) is a rare autosomal dominant disorder that manifests as recurrent unpredictable attacks of nonurticarial angioedema. Attacks are typically localized to the skin or submucosal tissues, cause temporary disablement, and resolve within 48 to 96 hours. Gastrointestinal edema can mimic an acute abdominal emergency, prompting unnecessary surgical exploration during attacks; critically, upper airway edema can potentially lead to suffocation. In addition to living with an unpredictable and potentially life-threatening disease, the need to attend hospital for acute treatment imposes further burdens on patients.

IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor–associated kinase M - Corrected Proof

2011-12-12

Background: Impaired airway mucosal immunity can contribute to increased respiratory tract infections in asthmatic patients, but the involved molecular mechanisms have not been fully clarified. Airway epithelial cells serve as the first line of respiratory mucosal defense to eliminate inhaled pathogens through various mechanisms, including Toll-like receptor (TLR) pathways. Our previous studies suggest that impaired TLR2 function in TH2 cytokine–exposed airways might decrease immune responses to pathogens and subsequently exacerbate allergic inflammation. IL-1 receptor–associated kinase M (IRAK-M) negatively regulates TLR signaling. However, IRAK-M expression in airway epithelium from asthmatic patients and its functions under a TH2 cytokine milieu remain unclear.Objectives: We sought to evaluate the role of IRAK-M in IL-13–inhibited TLR2 signaling in human airway epithelial cells.Methods: We examined IRAK-M protein expression in epithelia from asthmatic patients versus that in normal airway epithelia. Moreover, IRAK-M regulation and function in modulating innate immunity (eg, TLR2 signaling) were investigated in cultured human airway epithelial cells with or without IL-13 stimulation.Results: IRAK-M protein levels were increased in asthmatic airway epithelium. Furthermore, in primary human airway epithelial cells, IL-13 consistently upregulated IRAK-M expression, largely through activation of phosphoinositide 3-kinase pathway. Specifically, phosphoinositide 3-kinase activation led to c-Jun binding to human IRAK-M gene promoter and IRAK-M upregulation. Functionally, IL-13–induced IRAK-M suppressed airway epithelial TLR2 signaling activation (eg, TLR2 and human β-defensin 2), partly through inhibiting activation of nuclear factor κB.Conclusions: Our data indicate that epithelial IRAK-M overexpression in TH2 cytokine–exposed airways inhibits TLR2 signaling, providing a novel mechanism for the increased susceptibility of infections in asthmatic patients.

Protective effect of IgM against colonization of the respiratory tract by nontypeable Haemophilus influenzae in patients with hypogammaglobulinemia - Corrected Proof

2011-12-08

Background: Primary immunoglobulin deficiencies lead to recurrent bacterial infections of the respiratory tract and bronchiectasis, even with adequate immunoglobulin replacement therapy. It is not known whether patients able to secrete IgM (eg, those with hyper-IgM [HIgM] syndrome) are as susceptible to these infections as patients who lack IgM production (eg, those with panhypogammaglobulinemia [PHG]).Objective: This study is aimed at identifying specific microbiological and clinical (infections) characteristics that distinguish immunoglobulin-substituted patients with PHG from patients with HIgM syndrome.Methods: A cohort of patients with HIgM syndrome (n = 25) and a cohort of patients with PHG (n = 86) were monitored prospectively for 2 years while receiving similar polyvalent immunoglobulin replacement therapies. Regular bacterial analyses of nasal swabs and sputum were performed, and clinical events were recorded. In parallel, serum and saliva IgM antibody concentrations were measured.Results: When compared with patients with PHG, patients with HIgM syndrome were found to have a significantly lower risk of nontypeable Haemophilus influenzae carriage in particular (relative risk, 0.39; 95% CI, 0.21-0.63). Moreover, patients with HIgM syndrome (including those unable to generate somatic hypermutations of immunoglobulin genes) displayed anti–nontypeable H influenzae IgM antibodies in their serum and saliva. Also, patients with HIgM syndrome had a lower incidence of acute respiratory tract infections.Conclusions: IgM antibodies appear to be microbiologically and clinically protective and might thus attenuate the infectious consequences of a lack of production of other immunoglobulin isotypes in patients with HIgM syndrome. Polyvalent IgG replacement therapy might not fully compensate for IgM deficiency. It might thus be worth adapting long-term antimicrobial prophylactic regimens according to the underlying B-cell immunodeficiency phenotype.