Showing papers in "The Journal of Allergy and Clinical Immunology in 2004"

Development of the asthma control test: A survey for assessing asthma control

Abstract: Background Asthma guidelines indicate that the goal of treatment should be optimum asthma control In a busy clinic practice with limited time and resources, there is need for a simple method for assessing asthma control with or without lung function testing Objectives The objective of this article was to describe the development of the Asthma Control Test (ACT), a patient-based tool for identifying patients with poorly controlled asthma Methods A 22-item survey was administered to 471 patients with asthma in the offices of asthma specialists The specialist's rating of asthma control after spirometry was also collected Stepwise regression methods were used to select a subset of items that showed the greatest discriminant validity in relation to the specialist's rating of asthma control Internal consistency reliability was computed, and discriminant validity tests were conducted for ACT scale scores The performance of ACT was investigated by using logistic regression methods and receiver operating characteristic analyses Results Five items were selected from regression analyses The internal consistency reliability of the 5-item ACT scale was 084 ACT scale scores discriminated between groups of patients differing in the specialist's rating of asthma control (F = 345, P P 1 (F = 43, P = 0052) As a screening tool, the overall agreement between ACT and the specialist's rating ranged from 71% to 78% depending on the cut points used, and the area under the receiver operating characteristic curve was 077 Conclusion Results reinforce the usefulness of a brief, easy to administer, patient-based index of asthma control

Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003.

Abstract: The nomenclature proposed in the October 2003 report of the Nomenclature Review Committee of the World Allergy Organization is an update of the European Academy of Allergology and Clinical Immunology Revised Nomenclature for Allergy Position Statement published in 2001. The nomenclature can be used independently of target organ or patient age group and is based on the mechanisms that initiate and mediate allergic reactions. It is assumed that as knowledge about basic causes and mechanisms improves, the nomenclature will need further review.

Update on food allergy

Abstract: Tremendous progress has been made in our understanding of food-based allergic disorders over the past 5 years. Recent epidemiologic studies suggest that nearly 4% of Americans are afflicted with food allergies, a prevalence much higher than appreciated in the past. In addition, the prevalence of peanut allergy was found to have doubled in American children less than 5 years of age in the past 5 years. Many food allergens have been characterized at the molecular level, which has contributed to our increased understanding of the immunopathogenesis of many allergic disorders and might soon lead to novel diagnostic and immunotherapeutic approaches. The management of food allergies continues to consist of educating patients on how to avoid relevant allergens, to recognize early symptoms of an allergic reaction in case of an accidental ingestion, and to initiate the appropriate emergency therapy. However, the recent successful clinical trial of anti-IgE therapy in patients with peanut allergy and the number of immunomodulatory therapies in the pipeline provide real hope that we will soon be able to treat patients with food allergy.

Worldwide severity and control of asthma in children and adults : the global asthma insights and reality surveys

Abstract: Background In 1995, the Global Initiative for Asthma (GINA) guidelines recommended goals for the management of asthma, which were updated in 2002. However, there are no recent international surveys on the real management of asthma. Objective The Asthma Insights and Reality surveys are the first large-scale surveys aimed at determining international variations in the severity, control, and management of asthma in children and adults. Methods A cross-section of households in 29 countries in North America, Europe, and Asia were surveyed to identify from the general population asthmatic patients with symptoms within the last year or who were taking current asthma medication. A standard questionnaire was administered to 7786 adults, and, through a proxy, to 3153 children with asthma. Objective and subjective patient perception of asthma control and severity were assessed, including access to medical care, health care use, missed work-school, and medication use. Results Despite variations at a country level, a substantial effect of asthma on patients' lives was observed, with considerable loss of schooldays and workdays. The current level of asthma control worldwide falls far short of the goals for long-term management in international guidelines. A significant proportion of patients continue to have symptoms and lifestyle restrictions and to require emergency care. The proportion of adult asthmatic patients who were current smokers was also high. However, the use of anti-inflammatory preventative medication, even in patients with severe persistent asthma, was low, ranging from 26% in Western Europe to 9% in Japan, as was the use of objective lung function testing. The correlation between self-perceived severity of asthma and objective assessment of severity on the basis of GINA criteria was consistently poor in all areas. Conclusion We conclude that there is direct evidence for suboptimal asthma control in many patients worldwide, despite the availability of effective therapies, with long-term management falling far short of the goals set in the GINA guidelines.

Rhinosinusitis: Establishing definitions for clinical research and patient care

Abstract: Background There is a need for more research on all forms of rhinosinusitis. Progress in this area has been hampered by a lack of consensus definitions and the limited number of published clinical trials. Objectives To develop consensus definitions for rhinosinusitis and outline strategies useful in clinical trials. Methods Five national societies, The American Academy of Allergy, Asthma and Immunology; The American Academy of Otolaryngic Allergy; The American Academy of Otolaryngology Head and Neck Surgery; The American College of Allergy, Asthma and Immunology; and the American Rhinologic Society formed an expert panel from multiple disciplines. Over two days, the panel developed definitions for rhinosinusitis and outlined strategies for design of clinical trials. Results Committee members agreed to adopt the term "rhinosinusitis" and reached consensus on definitions and strategies for clinical research on acute presumed bacterial rhinosinusitis, chronic rhinosinusitis without polyposis, chronic rhinosinusitis with polyposis, and classic allergic fungal rhinosinusitis. Symptom and objective criteria, measures for monitoring research progress, and use of symptom scoring tools, quality-of-life instruments, radiologic studies, and rhinoscopic assessment were outlined for each condition. Conclusion The recommendations from this conference should improve accuracy of clinical diagnosis and serve as a starting point for design of rhinosinusitis clinical trials.

Eosinophilic gastrointestinal disorders (EGID)

Abstract: Primary eosinophilic gastrointestinal disorders are defined as disorders that selectively affect the gastrointestinal tract with eosinophil-rich inflammation in the absence of known causes for eosinophilia (eg, drug reactions, parasitic infections, and malignancy). These disorders include eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic enteritis, and eosinophilic colitis and are occurring with increasing frequency. Significant progress has been made in elucidating that eosinophils are integral members of the gastrointestinal mucosal immune system and that eosinophilic gastrointestinal disorders are primarily polygenic allergic disorders that involve mechanisms that fall between pure IgE-mediated and delayed T(H)2-type responses. Preclinical studies have identified a contributory role for the cytokine IL-5 and the eotaxin chemokines, providing a rationale for specific disease therapy. An essential question is to determine the cellular and molecular basis for each of these clinical problems and the best treatment regimen, which is the main subject of this review.

Clinical features and severity grading of anaphylaxis

Abstract: Background Existing grading systems for acute systemic hypersensitivity reactions vary considerably, have a number of deficiencies, and lack a consistent definition of anaphylaxis. Objective The aims of this study were to develop a simple grading system and definition of anaphylaxis and to identify predictors of reaction severity. Methods Case records from 1149 systemic hypersensitivity reactions presenting to an emergency department were analyzed retrospectively. Logistic regression analyses of the associations between individual reaction features and hypotension and hypoxia were used to construct a grading system. Epinephrine use, etiology, age, sex, comorbidities, and concurrent medications were then assessed for their association with reaction grade. Results Confusion, collapse, unconsciousness, and incontinence were strongly associated with hypotension and hypoxia and were used to define severe reactions. Diaphoresis, vomiting, presyncope, dyspnea, stridor, wheeze, chest/throat tightness, nausea, vomiting, and abdominal pain had weaker, albeit significant, associations and were used to define moderate reactions. Reactions limited to the skin (urticaria, erythema, and angioedema) were defined as mild. These grades correlated well with epinephrine usage. Older age, insect venom, and iatrogenic causes were independent predictors of severity. Preexisting lung disease was associated with an increased risk of hypoxia. Conclusion This simple grading system has potential value for defining reaction severity in clinical practice and research settings. The moderate and severe grades provide a workable definition of anaphylaxis. Age, reaction precipitant, and preexisting lung disease appear to be the major determinants of reaction severity.

The natural course of atopic dermatitis from birth to age 7 years and the association with asthma.

Abstract: Background Atopic dermatitis (AD) is considered to be one of the first manifestations in the atopic march. However, few prospective studies on AD and its association with childhood asthma exist. Objective The aim of this study was to prospectively investigate the natural course of AD to determine factors influencing its prognosis and to analyze the relationship of AD with childhood asthma. Methods The Multicenter Allergy Study, a German birth cohort, followed 1314 children from birth to age 7 years. Physical examinations, parental interviews on atopic symptoms and diagnoses, and determination of specific IgE levels were performed regularly. Results The cumulative prevalence of AD in the first 2 years of life was 21.5%. Of these children with early AD, 43.2% were in complete remission by age 3 years, 38.3% had an intermittent pattern of disease, and 18.7% had symptoms of AD every year. Severity (adjusted cumulative odds ratio, 5.86; 95% CI, 3.04-11.29) and atopic sensitization (adjusted cumulative odds ratio, 2.76; 95% CI, 1.29-5.91) were major determinants of prognosis. Early wheeze and a specific sensitization pattern were significant predictors for wheezing at school age, irrespective of AD. Early AD without these cofactors constituted no increased risk of subsequent wheeze (adjusted odds ratio, 1.11; 95% CI, 0.56-2.20) or bronchial hyperreactivity. Conclusion AD is a common condition in infancy but disappears around age 3 years in a significant proportion of children. The prognosis is mostly determined by the severity and the presence of atopic sensitization. Early AD is associated with asthma at school age, but in many of these asthmatic children, wheezing manifests before or with the onset of AD. Children with AD and wheeze have a marked loss in lung function, suggesting a distinct phenotype rather than a progressive development from AD to asthma.

Health effects of air pollution

Abstract: The general public, especially patients with upper or lower respiratory symptoms, is aware from media reports that adverse respiratory effects can occur from air pollution. It is important for the allergist to have a current knowledge of the potential health effects of air pollution and how they might affect their patients to advise them accordingly. Specifically, the allergist–clinical immunologist should be keenly aware that both gaseous and particulate outdoor pollutants might aggravate or enhance the underlying pathophysiology of both the upper and lower airways. Epidemiologic and laboratory exposure research studies investigating the health effects of outdoor air pollution each have advantages and disadvantages. Epidemiologic studies can show statistical associations between levels of individual or combined air pollutants and outcomes, such as rates of asthma, emergency visits for asthma, or hospital admissions, but cannot prove a causative role. Human exposure studies, animal models, and tissue or cellular studies provide further information on mechanisms of response but also have inherent limitations. The aim of this rostrum is to review the relevant publications that provide the appropriate context for assessing the risks of air pollution relative to other more modifiable environmental factors in patients with allergic airways disease.

Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond.

Abstract: Hereditary angioedema (HAE), a rare but life-threatening condition, manifests as acute attacks of facial, laryngeal, genital, or peripheral swelling or abdominal pain secondary to intra-abdominal edema. Resulting from mutations affecting C1 esterase inhibitor (C1-INH), inhibitor of the first complement system component, attacks are not histamine-mediated and do not respond to antihistamines or corticosteroids. Low awareness and resemblance to other disorders often delay diagnosis; despite availability of C1-INH replacement in some countries, no approved, safe acute attack therapy exists in the United States. The biennial C1 Esterase Inhibitor Deficiency Workshops resulted from a European initiative for better knowledge and treatment of HAE and related diseases. This supplement contains work presented at the third workshop and expanded content toward a definitive picture of angioedema in the absence of allergy. Most notably, it includes cumulative genetic investigations; multinational laboratory diagnosis recommendations; current pathogenesis hypotheses; suggested prophylaxis and acute attack treatment, including home treatment; future treatment options; and analysis of patient subpopulations, including pediatric patients and patients whose angioedema worsened during pregnancy or hormone administration. Causes and management of acquired angioedema and a new type of angioedema with normal C1-INH are also discussed. Collaborative patient and physician efforts, crucial in rare diseases, are emphasized. This supplement seeks to raise awareness and aid diagnosis of HAE, optimize treatment for all patients, and provide a platform for further research in this rare, partially understood disorder.

Distinguishing severe asthma phenotypes: Role of age at onset and eosinophilic inflammation

Abstract: Background Asthma is a heterogeneous process, yet little is understood regarding phenotypes. Objective To determine whether phenotypic differences exist between early-onset, severe asthma as compared with late-onset disease and whether the presence or absence of eosinophilia influences the phenotypes. Methods Cross-sectional analysis of integrated clinical, physiologic, and pathologic data collected from 80 subjects with severe asthma. Subjects were divided into those with asthma onset before age 12 years (n = 50) versus after age 12 (n = 30) and by the presence or absence of lung eosinophils. Results Subjects with early-onset, severe asthma had significantly more allergen sensitivity (skin test positivity, 98% vs 76%, P P values all ≤ .02) than subjects with late-onset asthma. In contrast, subjects with late-onset asthma had lower lung function ( P values=.05 to .07) than early-onset, despite a shorter ( P P values P ≤ .02). Although late-onset asthma was associated with the highest numbers of lung eosinophils ( P Conclusions Differentiating severe asthma by age at onset and presence or absence of eosinophils identifies phenotypes of asthma, which could benefit subsequent genetic and therapeutic studies.

Prevalence of seafood allergy in the United States determined by a random telephone survey

Abstract: Background Seafood allergy is potentially severe, but the prevalence of this group of food allergies in the US population has not been determined. Objective To estimate the prevalence of seafood (fish, shellfish) allergy in the United States. Methods We performed a nationwide, cross-sectional, random telephone survey by using a standardized questionnaire. Criteria were established in advance to define seafood allergy by report of convincing symptoms and physician evaluation. Results A total of 5529 households completed the survey (67.3% participation rate), representing a census of 14,948 individuals. Fish or shellfish allergy defined by established criteria was reported in 5.9% (95% CI, 5.3%-6.6%) of households and among individuals as follows: 2.3% (95% CI, 2%-2.5%) for any seafood allergy, 2% for shellfish, 0.4% for fish, and 0.2% for both types. Seafood allergy was more common in adults compared with children (2.8% vs 0.6%; P P Conclusions Physician-diagnosed and/or convincing seafood allergy is reported by 2.3% of the general population, or approximately 6.6 million Americans. Affected individuals typically report recurrent and sometimes severe reactions, indicating that seafood allergy represents a significant health concern.

A classification of plant food allergens.

Abstract: Plant food allergens can be classified into families and superfamilies on the basis of their structural and functional properties. The most widespread groups of plant proteins that contain allergens are the cupin and prolamin superfamilies and the protein families of the plant defense system. The cupin superfamily includes allergenic seed storage proteins of the vicilin and legumin type present in soybeans, peanuts, and tree nuts. The prolamin superfamily includes several important types of allergens of legumes, tree nuts, cereals, fruits, and vegetables, such as the 2S albumin seed storage proteins, the nonspecific lipid transfer proteins, and the cereal α-amylase and protease inhibitors. Plant food allergens are also found among the various groups of defense proteins that enable plants to resist biotic and abiotic stress, such as the pathogenesis-related proteins, certain proteases, and protease inhibitors. This review focuses on a classification system of plant food allergens that is emerging from the synopsis of allergology and protein evolution.

Toll-like receptor 2 as a major gene for asthma in children of European farmers

Abstract: Background The finding that the prevalence of asthma and allergies is less frequent in children raised on animal farms has led to the conjecture that exposure to microbial products modifies immune responses. The toll-like receptors (TLRs) represent an evolutionarily conserved family of innate immunity receptors with microbial molecules as ligands. Objectives We reasoned that polymorphisms in genes encoding TLRs might modulate the protective effects observed in farming populations. Methods Farmers' and nonfarmers' children living in rural areas in Austria and Germany and who were enrolled in the cross-sectional ALEX study were genotyped for single nucleotide polymorphisms in the TLR2 and TLR4 genes. The frequencies of asthma, allergic rhinitis, and atopic sensitization were compared between the genotypes in relation to exposure to farming and endotoxin. Results Among farmers' children, those carrying a T allele in TLR2/−16934 compared with children with genotype AA were significantly less likely to have a diagnosis of asthma (3% vs 13%, P = .012), current asthma symptoms (3% vs 16%, P = .004), atopic sensitization (14% vs 27%, P = .023), and current hay fever symptoms (3% vs 14%, P = .01). The association between TLR2/−16934 and asthma among children of farmers was independent of atopy. No such association was found among children from the same rural communities but not living on farms. Conclusion Our results suggest that genetic variation in TLR2 is a major determinant of the susceptibility to asthma and allergies in children of farmers.

Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma

Abstract: Background Regular use of inhaled corticosteroids (ICSs) can improve asthma symptoms and prevent exacerbations. However, overall adherence is poor among patients with asthma. Objective To estimate the proportion of poor asthma-related outcomes attributable to ICS nonadherence. Methods We retrospectively identified 405 adults age 18 to 50 years who had asthma and were members of a large health maintenance organization in southeast Michigan between January 1, 1999, and December 31, 2001. Adherence indices were calculated by using medical records and pharmacy claims. The main outcomes were the number of asthma-related outpatient visits, emergency department visits, and hospitalizations, as well as the frequency of oral steroid use. Results Overall adherence to ICS was approximately 50%. Adherence to ICS was significantly and negatively correlated with the number of emergency department visits (correlation coefficient [ R ]=−0.159), the number of fills of an oral steroid ( R =−0.179), and the total days' supply of oral steroid ( R =−0.154). After adjusting for potential confounders, including the prescribed amount of ICS, each 25% increase in the proportion of time without ICS medication resulted in a doubling of the rate of asthma-related hospitalization (relative rate, 2.01; 95% CI, 1.06-3.79). During the study period, there were 80 asthma-related hospitalizations; an estimated 32 hospitalizations would have occurred were there no gaps in medication use (60% reduction). Conclusions Adherence to ICS is poor among adult patients with asthma and is correlated with several poor asthma-related outcomes. Less than perfect adherence to ICS appears to account for the majority of asthma-related hospitalizations.

Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma

Abstract: Background T regulatory (T reg ) cells are characterized by expression of suppressive cytokines and the transcription factor FOXP3. They play a key role in balancing immune responses and maintain peripheral tolerance against antigens and allergens. The loss of peripheral tolerance against allergens causes diseases that can be therapeutically controlled with glucocorticoids. Objective The present study investigates whether glucocorticoids affect the activity of T reg cells on the basis of FOXP3 and cytokine expression. Methods CD4 + T cells from healthy donors and glucocorticoid-treated asthmatic patients were isolated, and expression of FOXP3, along with IL-10 and TGF-β1, was determined. The effect of glucocorticoids on T reg cells was measured in vivo before and after GC treatment and in in vitro cultures. Results FOXP3 mRNA expression was significantly increased in asthmatic patients receiving inhaled glucocorticoid treatment, systemic glucocorticoid treatment, or both. FOXP3 tightly correlated with IL10 mRNA expression. No correlation of FOXP3 mRNA expression was observed in relation to a (GT)n microsatellite promoter polymorphism on chromosome Xp11.23 or total IgE level. The frequency of CD25 + memory CD4 + T cells and transient FOXP3 mRNA expression by CD4 + T cells significantly increased after systemic glucocorticoid treatment, whereas TGFB1 expression did not change. Furthermore, glucocorticoids induced IL10 and FOXP3 expression in short-term and long-term cultures in vitro . Conclusion These findings demonstrate that glucocorticoid treatment is not only immunosuppressive and anti-inflammatory but also promotes or initiates differentiation toward T R 1 cells by a FOXP3-dependent mechanism. Strategies that convert transient glucocorticoid-induced T reg activity into a stable phenotype might improve allergy and asthma therapy.

Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis

Abstract: Background We wondered whether short-term coseasonal sublingual immunotherapy (SLIT) can reduce the development of asthma in children with hay fever in an open randomized study. Objective We sought to determine whether SLIT is as effective as subcutaneous immunotherapy in reducing hay fever symptoms and the development of asthma in children with hay fever. Methods One hundred thirteen children aged 5 to 14 years (mean age, 7.7 years) with hay fever limited to grass pollen and no other clinically important allergies were randomized in an open study involving 6 Italian pediatric allergy centers to receive specific SLIT for 3 years or standard symptomatic therapy. All of the subjects had hay fever symptoms, but at the time of study entry, none reported seasonal asthma with more than 3 episodes per season. Symptomatic treatment was limited to cetirizine, loratadine, nasal budesonide, and salbutamol on demand. The hay fever and asthma symptoms were quantified clinically. Results The actively treated children used less medication in the second and third years of therapy, and their symptom scores tended to be lower. From the second year of immunotherapy, subjective evaluation of overall allergy symptoms was favorable in the actively treated children. Development of asthma after 3 years was 3.8 times more frequent (95% confidence limits, 1.5-10.0) in the control subjects. Conclusions Three years of coseasonal SLIT improves seasonal allergic rhinitis symptoms and reduces the development of seasonal asthma in children with hay fever.

Immunologic influences on allergy and the TH1/TH2 balance

Abstract: TH2 cell-mediated immune responses against "innocuous" antigens play a triggering role in atopic allergy. Several epidemiologic studies have clearly shown that the reduced microbial exposure of children caused by the westernized lifestyle is responsible for the increased prevalence of allergy that has occurred in the last decades in developed countries ("hygiene hypothesis"). The immunologic changes caused by the reduced exposure to pathogenic and nonpathogenic microbes during childhood are still controversial. The initial interpretation has been a lack of shift of allergen-specific responses from the TH2 to the TH1 phenotype. This is because of reduced production of IL-12 and IFNs by cells of the natural immunity stimulated by bacterial products through their Toll-like receptors (missing immune deviation). Another interpretation emphasizes the importance of reduced activity of T-regulatory cells (reduced immune suppression). However, although there are impressive amounts of data in favor of the missing immune deviation, experimental evidence supporting the role of reduced immune suppression in explaining the increased prevalence of allergy is currently weak or even contradictory. The solution to this question is very important not only from a theoretic point of view but also because of its therapeutic implications.

Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001.

Abstract: Background Fatal reactions associated with skin testing and injection immunotherapy have not been surveyed in North America since 1989. Objective A survey of fatal reactions related to skin testing and immunotherapy and of near-fatal immunotherapy reactions that transpired from 1990 through 2001 was conducted among member practices of the American Academy of Allergy, Asthma and Immunology. Methods A short survey of fatal reactions was sent to all American Academy of Allergy, Asthma and Immunology physicians, and an 87-item follow-up detailed questionnaire was sent to those reporting fatal reactions. Results Of 2404 members, 646 (25%) responded to the short survey. There were 20 fatal immunotherapy reactions that were directly reported and 21 indirectly reported cases by local physicians. There were 273 (42% of the responding sample) reports of near-fatal reactions. It was estimated that fatal reactions occurred every 1 per 2.5 million injections, with an average of 3.4 deaths per year. One fatality was confirmed after skin prick testing with multiple food allergens. Of 17 fatal deaths described in long questionnaires, 15 were in asthmatic patients, the majority of whose symptoms were not optimally controlled. Three reactions occurred in a medically unsupervised setting. None were receiving β-blockers, and one was taking an angiotensin-converting enzyme inhibitor. Most fatal reactions (59%) occurred with maintenance allergen doses. The onset of 3 reactions began more than 30 minutes after injections, with a significant delay in starting epinephrine. Epinephrine was not administered in 3 other fatal reactors. Conclusions Fatal reactions to immunotherapy injections occurred at similar rates reported in previous surveys. Certain clinical practices have improved (ie, exclusion of β-blockers), and dosing errors were infrequent. Fatal reactions to immunotherapy often occur in settings inappropriate for optimal treatment of anaphylaxis. Strict adherence to practice guidelines might prevent or minimize future fatal reactions.

IL-17 cytokine family

Abstract: A new family of cytokines, IL-17, has recently been defined that reveals a distinct ligand-receptor signaling system. Functional studies have provided evidence for its importance in the regulation of immune responses. Notably, 3 members, IL-17A, IL-17E (IL-25), and IL-17F, have been best characterized both in vitro and in vivo, and have been shown to be proinflammatory in nature. This proinflammatory activity is exemplified by their involvement in pulmonary inflammatory responses, in which both IL-17A and IL-17F are involved in the recruitment of neutrophils, and IL-17E is able to induce TH2 cytokine production and eosinophilia. Although the elucidation of a detailed mechanism of action continues to be an active area of research, the potent inflammatory activity and its association with various human disease states suggest this new cytokine family as an important contributor to the pathophysiology of human disease conditions, in particular the pulmonary diseases.

The role of eosinophils in host defense against helminth parasites

Abstract: The precise function of eosinophils in parasitic infection in vivo remains poorly understood despite eosinophils having been shown to be potent effectors in killing parasites in vitro. Although it has long been held that the primary function of the eosinophil is protection against helminth parasites, there are little data to prove this unequivocally. Moreover, eosinophils are responsible for a considerable amount of inflammatory pathology accompanying helminth infections. This article will provide an overview of our current knowledge about eosinophils and their role, both protective and pathogenetic, in parasitic helminth infections.

Omalizumab-induced reductions in mast cell FcεRI expression and function

Abstract: Background By design, omalizumab binds free IgE in the circulation and prevents its attachment to the surface of mast cells and basophils, thereby preventing them from responding to allergens. Previously, omalizumab rapidly reduced free IgE levels, as well as basophil high-affinity IgE receptors, leading to significant reductions in basophil mediator response to allergen. It is assumed that tissue mast cells are similarly altered in their FceRI density and function. Objective We examined the phenotypic shift of skin mast cells in parallel to that of blood basophils in 3 subjects infused with omalizumab. Methods Three subjects with allergic rhinitis underwent intradermal skin test titration with house dust mite antigen at days 0, 7, 70, and 196 of omalizumab treatment. As control subjects, 5 untreated subjects with allergic rhinitis were evaluated at similar time points. All subjects underwent skin biopsy 18 to 24 hours later at the site of allergen injection. Biopsy specimens were characterized by means of immunohistochemisty for tryptase and FceRIα immunoreactivity, as well other markers (CD3, CD45RO, CD68, cutaneous lymphocyte antigen, and major basic protein). Results Omalizumab recipients, but not control subjects, demonstrated reductions in FceRIα immunoreactivity at days 70 and 196 in parallel with reductions in the acute wheal response to allergen. However, no reductions in tryptase-positive cells were noted at these time points. Conclusion Reductions in free IgE levels by omalizumab leads to a rapid reduction in basophil FceRI receptor expression. In contrast, the time course for the decrease of FceRI expression in skin mast cells is slower and associated with decreased acute allergen wheal size.

Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing.

Abstract: Background Viral respiratory tract infections and atopy are associated with attacks of wheezing during childhood. However, information about the relationship between viral infections and atopy among children whose attacks of wheezing lead to hospitalization is unclear. Objective To evaluate the prevalence of viral respiratory tract pathogens among infants and children hospitalized for wheezing and to analyze the results in relation to the patient's age, atopic characteristics, and season of admission. Methods This was a case-control study of children (age 2 months to 18 years) admitted for wheezing to the University of Virginia Medical Center over a period of 12 months. Children without wheezing were enrolled as controls. Nasal secretions were evaluated for viral pathogens by using cultures, PCR tests, and antigen detection. Total IgE and specific IgE antibody to common aeroallergens was measured in serum. Results Seventy percent of children hospitalized for wheezing before age 3 years (n=79) were admitted between December and March, whereas 46% of children age 3 to 18 years (n=54) were hospitalized between September and November. Among children younger than 3 years, viral pathogens were detected in 84% (66/79) of wheezing children and 55% (42/77) of controls ( P P P P Conclusions Viral infections were the dominant risk factor for wheezing among children hospitalized before 3 years of age. By comparison, a large majority of the wheezing children age 3 to 18 years had striking atopic characteristics that may be critical as a risk factor for hospitalization and an adverse response to viral infections, especially infections caused by rhinovirus.

Mechanisms of immunotherapy.

Abstract: Specific allergen injection immunotherapy is highly effective in IgE-mediated diseases, such as allergic rhinitis and venom anaphylaxis. Immunotherapy inhibits both early and late responses to allergen exposure. Immunotherapy is accompanied by increases in allergen-specific IgG, particularly the IgG4 isotype, which blocks not only IgE-dependent histamine release from basophils but also IgE-mediated antigen presentation to T cells. Immunotherapy acts on T cells to modify peripheral and mucosal T H 2 responses to allergen in favor of T H 1 responses. Recent studies have identified increased IL-10 production in peripheral blood and mucosal surfaces after immunotherapy. IL-10 has numerous potential antiallergic properties, including suppression of mast cell, eosinophil, and T-cell responses, as well as acting on B cells to favor heavy chain class switching to IgG4. These IL-10–producing cells might be so-called regulatory T cells and appear to be identified by the CD4 + CD25 + phenotype. Studies in mice suggest that dendritic cells play a vital role in induction of regulatory T cells. Novel approaches to immunotherapy currently being explored include the use of adjuvants, such as monophosphoryl lipid A or nucleotide immunostimulatory sequences derived from bacteria that potentiate T H 1 responses. Alternative strategies include the use of allergen-derived peptides or modified recombinant allergen vaccines that act on T cells while minimizing the IgE-dependent mast cell activation that is dependent on the native allergen conformation.

The role of protease activation of inflammation in allergic respiratory diseases.

Abstract: Extracellular endogenous proteases, as well as exogenous proteases from mites and molds, react with cell-surface receptors in the airways to generate leukocyte infiltration and to amplify the response to allergens. Stimulation leads to increased intracellular Ca ++ and gene transcription. The most thoroughly investigated receptors, protease-activated receptors (PARs), are 7-transmembrane proteins coupled to G proteins. PARs are widely distributed on the cells of the airways, where they contribute to the inflammation characteristic of allergic diseases. PAR stimulation of epithelial cells opens tight junctions, causes desquamation, and produces cytokines, chemokines, and growth factors. They degranulate eosinophils and mast cells. Proteases contract bronchial smooth muscle and cause it to proliferate. PARs also promote maturation, proliferation, and collagen production of fibroblast precursors and mature fibroblasts. PAR-2, apparently the most important of the 4 PARs that have been characterized, is increased on the epithelium of patients with asthma. Trypsin, a product of injured epithelial cells, and mast cell tryptase are potent activators of PAR-2. Mast cell chymase activates PAR-1. Proteases from mites and molds appear to act through similar receptors. They amplify IgE production to allergens, degranulate eosinophils, and can generate inflammation, even in the absence of IgE. Proteases produced by Aspergillus species to support its growth are presumably responsible for the exuberant IgE, IgG, and granulomatous response of allergic bronchopulmonary aspergillosis. Similar proteases from molds germinating on the respiratory mucosa have been recently been implicated in the pathogenesis of chronic hyperplastic rhinitis and polyps and, by extension, of intrinsic asthma. Finally, proteases from mites and fungi growing in damp, water-damaged buildings might be the basis for the increased prevalence in these buildings of rhinitis, asthma, and other respiratory diseases. Future research promises to promote our understanding of the pathogenesis of allergic respiratory diseases and point the way to new therapies.

Toxic epidermal necrolysis: Effector cells are drug-specific cytotoxic T cells

Abstract: Background Toxic epidermal necrolysis (TEN) is a very rare but extremely severe drug reaction characterized by widespread apoptosis of epidermis with extensive blisters. We previously found drug-specific cytotoxic CD8 T lymphocytes in the blisters of a single patient. Objective To confirm the role of drug specific cytotoxic lymphocytes in a larger series, to test the cytotoxicity on keratinocytes, and to look for cross-reactivity between chemically related drugs. Methods The phenotype of lymphocytes present in the blister fluids of 6 patients with TEN was analyzed by flow cytometry. Cytotoxic functions were tested by chromium release assay on a variety of target cells (autologous or MHC class I–matched EBV-transformed lymphocytes, autologous keratinocytes) after nonspecific (CD3 monoclonal antibody) or specific (suspected and potentially cross-reactive drugs) activation. Results Blister lymphocytes were CD8 + HLA-DR + CLA + CD56 + . In all 6 cases, they were cytotoxic after nonspecific activation. A drug-specific cytotoxicity was observed in 4 cases (3 related to cotrimoxazole and 1 to carbamazepine) toward lymphocytes. Blister cells also killed IFN-γ–activated autologous keratinocytes in the presence of drug in the 2 patients tested. Blister cells showed a strong immunoreactivity for granzyme B, and cytotoxicity was abolished by EGTA, but not by anti-Fas/CD95, suggesting perforin/granzyme–mediated killing. By using several sulfonamides for testing the specificity of the drug T-cell receptor interaction, we observed cross-reactivity only between 4 structurally closely related medications. Conclusion These results strongly suggest that drug-specific, MHC class I–restricted, perforin/granzyme–mediated cytotoxicity probably has a primary role in TEN.

Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma

Abstract: Background Few studies have characterized the atopic profile of toddler-aged children with recurrent wheezing at high risk of the development of persistent asthma. Objective We sought to determine the atopic profile of toddler-aged children with frequent wheeze at high risk for the development of persistent asthma who either had a parental history of asthma, a personal history of atopic dermatitis, or both. Methods Participants enrolled in the Prevention of Early Asthma in Kids study (n=285) on the basis of a modified Asthma Predictive Index were characterized on the basis of allergy and asthma questionnaire responses and allergy skin puncture test results. Results The majority of the children (60.7%, n=148) were sensitized to either food or aeroallergens. Male children were significantly more likely to be sensitized to aeroallergens ( P =.03) and to have a blood eosinophil level of 4% or greater ( P =.03) and a total serum IgE level of greater than 100 IU/mL ( P =.0004). Additionally, eosinophilia and total serum IgE level had the strongest correlation with aeroallergen sensitization. Conclusion The high prevalence of aeroallergen sensitization in this high-risk cohort suggests that aeroallergens might have an important role in the early development of asthma. As such, the Prevention of Early Asthma in Kids cohort appears to be an appropriate cohort in which to test whether early intervention with an inhaled corticosteroid can significantly attenuate, or perhaps even prevent, the allergic march from the initial stages of allergic sensitization to the subsequent development of asthma in toddlers with episodic wheezing.

Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3

Abstract: Background Although mast cells (MCs) have been clearly implicated in innate immune responses involving bacteria, their ability to respond to viral infection is less clear. Objective Given that MCs increase at sites of inflammation and are located at surfaces where exposure to invading viruses may occur, we explored the ability of MCs to produce cytokines including type I IFNs after exposure to viruses and to polyinosine-polycytidylic acid (polyI:C), a synthetic mimic of viral double-stranded RNA, and characterized the receptors involved, if any. Methods Human peripheral blood-derived cultured MCs and 2 MC lines, Laboratory of Allergic Disease MC line and human MC line 1, were stimulated with viruses and polyI:C, and cytokine production, degranulation, and signaling pathway activation were examined. Because polyI:C is a ligand for Toll-like receptor (TLR)–3, human MCs were also analyzed for TLR expression. Results Viruses and polyI:C induced IFN-α and IFN-β production. PolyI:C did not induce TNF, IL-1β, IL-5, or GM-CSF production, in contrast with other TLR ligands (LPS, peptidoglycan, CpG-A, or flagellin). IFN-α production involved nuclear factor–κB, p38, and C-Jun NH2-terminal kinase and mitogen-activated protein kinase. RT-PCR and Western blot analysis confirmed expression of TLR-3 by all MCs. Human cultured MCs also expressed TLR-1, TLR-2, TLR-4, TLR-5, TLR-6, TLR-7 and TLR-9. Antibodies to TLR-3 significantly decreased IFN-α production. Bone marrow–derived MCs from TLR-3 knockout mice showed an ablated response to polyI:C. Conclusions Murine and human MCs produce type I IFNs after exposure to double-stranded RNA and/or virus, the former via specific interactions with TLR-3. These data suggest that MCs contribute to innate immune responses to viral infection via the production of type I IFNs.

Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes.

Abstract: Background IL-5 is a cytokine critically involved in regulating several aspects of eosinophils including their production, activation, and tissue recruitment. As such, IL-5 may be involved in the pathogenesis of hypereosinophilic syndromes, a group of poorly treated diverse disorders characterized by sustained peripheral blood and/or tissue eosinophilia. Objective We aimed to assess the safety and efficacy of a humanized blocking monoclonal antibody against IL-5 (mepolizumab) in patients with several forms of hyper-eosinophilic syndromes. Methods We performed an open-label trial of anti–IL-5 in which 3 intravenous doses (10 mg/kg, maximum 750 mg) were administered at 4-week intervals to 4 patients with hypereosinophilic syndromes (defined by peripheral blood and/or tissue eosinophilia). The effects of treatment on safety, eosinophil levels (in peripheral blood and/or diseased tissue), pulmonary function, and quality of life were measured over a 28-week period. Results Anti–IL-5 was well tolerated in all patients and lowered peripheral blood eosinophil counts despite ongoing systemic glucocorticoid therapy. The decline in circulating eosinophil counts was sustained for at least 12 weeks after the last dose of anti–IL-5. In addition, anti–IL-5 improved clinical and quality of life measurements. In one patient with striking tissue eosinophilia (eosinophilic esophagitis), anti–IL-5 resulted in a 10-fold reduction in tissue eosinophil levels. Conclusions These results suggest that anti–IL-5 is safe, effective in lowering eosinophil levels, and has potential glucocorticoid-sparing effects in patients with a variety of hyper-eosinophilic syndromes. As such, anti–IL-5 may have significant therapeutic potential for hypereosinophilic syndromes.