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1.  Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-α-1,3-galactose 
Background
Carbohydrate moieties are frequently encountered in food and can elicit IgE responses, the clinical significance of which has been unclear. Recent work, however, has shown that IgE antibodies to galactose-α-1,3-galactose (α-gal), a carbohydrate commonly expressed on nonprimate mammalian proteins, are capable of eliciting serious, even fatal, reactions.
Objective
We sought to determine whether IgE antibodies to α-gal are present in sera from patients who report anaphylaxis or urticaria after eating beef, pork, or lamb.
Methods
Detailed histories were taken from patients presenting to the University of Virginia Allergy Clinic. Skin prick tests (SPTs), intradermal skin tests, and serum IgE antibody analysis were performed for common indoor, outdoor, and food allergens.
Results
Twenty-four patients with IgE antibodies to α-gal were identified. These patients described a similar history of anaphylaxis or urticaria 3 to 6 hours after the ingestion of meat and reported fewer or no episodes when following an avoidance diet. SPTs to mammalian meat produced wheals of usually less than 4 mm, whereas intradermal or fresh-food SPTs provided larger and more consistent wheal responses. CAP-RAST testing revealed specific IgE antibodies to beef, pork, lamb, cow’s milk, cat, and dog but not turkey, chicken, or fish. Absorption experiments indicated that this pattern of sensitivity was explained by an IgE antibody specific for α-gal.
Conclusion
We report a novel and severe food allergy related to IgE antibodies to the carbohydrate epitope α-gal. These patients experience delayed symptoms of anaphylaxis, angioedema, or urticaria associated with eating beef, pork, or lamb.
doi:10.1016/j.jaci.2008.10.052
PMCID: PMC3324851  PMID: 19070355
Anaphylaxis; urticaria; food allergy; galactose-α-1; 3-galactose; cross-reactive carbohydrate determinant
2.  The indoor air and asthma: the role of cat allergens 
Purpose of review
The objective is to discuss recent progress in our understanding of the role of the indoor environment in asthma, focusing on the special role of cat allergens.
Recent findings
Sensitization to Fel d 1 is the dominant event in inhalant responses to cat; however, there are also IgE responses to the lipocalin (Fel d 4), to cat albumin (Fel d 2), and to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) on cat IgA (Fel d 5w) and other molecules. The dose response and routes of sensitization for these allergens are now thought to be diverse. It is important to remember that exposure outside a house with a cat is sufficient to cause sensitization. Furthermore, the only solid evidence about a role in asthma relates to Fel d 1. Recently, it has been shown that tolerance associated with early exposure to cats can persist to age 18 and that IgE to alpha-gal (on cat IgA) is not related to asthma. In addition, a recent study of anti-IgE reinforces the evidence that IgE antibodies to indoor allergens make a major contribution to asthma severity.
Summary
Exposure to Fel d 1 in a home with a cat is far higher than the levels necessary to induce an allergic (IgE antibody) response. In keeping with that, children may develop tolerance, which can be long-lived. In addition, there is increasing evidence that IgE antibodies to an inhalant allergen, such as Fel d 1, dust mite, or cockroach, are causally related to lung inflammation and asthma.
doi:10.1097/MCP.0b013e32834db10d
PMCID: PMC3707607  PMID: 22081090
asthma; cats; inhalant allergens; Fel d 1; long-term tolerance
3.  Galactose-α-1,3-galactose and Delayed Anaphylaxis, Angioedema, and Urticaria in Children 
Pediatrics  2013;131(5):e1545-e1552.
BACKGROUND AND OBJECTIVE:
Despite a thorough history and comprehensive testing, many children who present with recurrent symptoms consistent with allergic reactions elude diagnosis. Recent research has identified a novel cause for “idiopathic” allergic reactions; immunoglobulin E (IgE) antibody specific for the carbohydrate galactose-α-1,3-galactose (α-Gal) has been associated with delayed urticaria and anaphylaxis that occurs 3 to 6 hours after eating beef, pork, or lamb. We sought to determine whether IgE antibody to α-Gal was present in sera of pediatric patients who reported idiopathic anaphylaxis or urticaria.
METHODS:
Patients aged 4 to 17 were enrolled in an institutional review board–approved protocol at the University of Virginia and private practice allergy offices in Lynchburg, VA. Sera was obtained and analyzed by ImmunoCAP for total IgE and specific IgE to α-Gal, beef, pork, cat epithelium and dander, Fel d 1, dog dander, and milk.
RESULTS:
Forty-five pediatric patients were identified who had both clinical histories supporting delayed anaphylaxis or urticaria to mammalian meat and IgE antibody specific for α-Gal. In addition, most of these cases had a history of tick bites within the past year, which itched and persisted.
CONCLUSIONS:
A novel form of anaphylaxis and urticaria that occurs 3 to 6 hours after eating mammalian meat is not uncommon among children in our area. Identification of these cases may not be straightforward and diagnosis is best confirmed by specific testing, which should certainly be considered for children living in the area where the Lone Star tick is common.
doi:10.1542/peds.2012-2585
PMCID: PMC3639458  PMID: 23569097
α-Gal; galactose-α-1,3-galactose; delayed anaphylaxis; pediatric urticaria
4.  Delayed Anaphylaxis to Red Meat in Patients with IgE Specific for Galactose alpha-1,3-Galactose (alpha-gal) 
Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal. In instances where the triggering allergen is not known, establishing the etiology of anaphylaxis is pivotal to long-term risk management. Our recent work has identified a novel IgE antibody (Ab) response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal), that has been associated with two distinct forms of anaphylaxis: (1) immediate onset anaphylaxis during first exposure to intravenous cetuximab, and (2) delayed onset anaphylaxis 3–6 h after ingestion of mammalian food products (e.g., beef and pork). The results of our studies strongly suggest that tick bites are a cause, if not the only significant cause, of IgE Ab responses to alpha-gal in the southern, eastern and central United States. Patients with IgE Ab to alpha-gal continue to emerge and, increasingly, these cases involve children. This IgE Ab response cross-reacts with cat and dog but does not appear to pose a risk for asthma; however, it may impair diagnostic testing in some situations.
doi:10.1007/s11882-012-0315-y
PMCID: PMC3545071  PMID: 23054628
Anaphylaxis; Delayedanaphylaxis; Alpha-gal; Galactose; Food allergy; IgE; Mammalian meat; Tick bites; Asthma; Red meat
5.  Urinary Bromotyrosine Measures Asthma Control and Predicts Asthma Exacerbations in Children 
The Journal of Pediatrics  2011;159(2):248-55.e1.
Objectives
To determine the usefulness of urinary bromotyrosine, a noninvasive marker of eosinophil-catalyzed protein oxidation, in tracking with indexes of asthma control and in predicting future asthma exacerbations in children.
Study design
Children with asthma were recruited consecutively at the time of clinic visit. Urine was obtained, along with spirometry, exhaled nitric oxide, and Asthma Control Questionnaire data. Follow-up phone calls were made 6 weeks after enrollment.
Results
Fifty-seven participants were enrolled. Urinary bromotyrosine levels tracked significantly with indexes of asthma control as assessed by Asthma Control Questionnaire scores at baseline (R = 0.38, P = .004) and follow-up (R = 0.39, P = .008). Participants with high baseline levels of bromotyrosine were 18.1-fold (95% CI 2.1–153.1, P = .0004) more likely to have inadequately controlled asthma and 4.0-fold more likely (95% CI 1.1–14.7, P = .03) to have an asthma exacerbation (unexpected emergency department visit; doctor’s appointment or phone call; oral or parenteral corticosteroid burst; acute asthma-related respiratory symptoms) over the ensuing 6 weeks. Exhaled nitric oxide levels did not track with Asthma Control Questionnaire data; and immunoglobulin E, eosinophil count, spirometry, and exhaled nitric oxide levels failed to predict asthma exacerbations.
Conclusions
Urinary bromotyrosine tracks with asthma control and predicts the risk of future asthma exacerbations in children.
doi:10.1016/j.jpeds.2011.01.029
PMCID: PMC3354913  PMID: 21392781
6.  Sensitization to Food and Inhalant Allergens in Relation to Age and Wheeze Among Children with Atopic Dermatitis 
Background
Atopic dermatitis (AD) is common in children; however, persistence of AD with or without asthma, is less common. Longitudinal studies remain limited in their ability to characterize how IgE antibody responses evolve in AD, and their relationship to asthma.
Objective
To use a cross-sectional study design of children with active AD to analyze age-related differences in IgE antibodies and relation to wheeze.
Methods
IgE antibodies to food and inhalant allergens were measured in children with active AD (5 months to 15 years of age, n=66), with and without history of wheeze.
Results
Whereas IgE antibodies to foods persisted at a similar prevalence and titer throughout childhood, IgE antibodies to all aeroallergens rose sharply into adolescence. From birth, the chance of sensitization for any aeroallergen increased for each 12-month increment in age (OR≥1.21, p≤0.01), with the largest effect observed for dust mite (OR=1.56, p<0.001). A steeper age-related rise in IgE antibody titer to dust mite, but no other allergen, was associated with more severe disease. Despite this, sensitization to cat was more strongly associated with wheeze (OR=4.5, p<0.01), and linked to Fel d 1 and Fel d 4, but not Fel d 2. Comparison of cat allergic children with AD to those without, revealed higher titers to Fel d 2 and Fel d 4 (p<0.05), but not Fel d 1.
Conclusions and Clinical Relevance
Differences in sensitization to cat and dust mite among young children with AD may aid in identifying those at increased risk for disease progression and development of asthma. Early sensitization to cat and risk for wheeze among children with AD may be linked to an increased risk for sensitization to a broader spectrum of allergen components from early life. Collectively, our findings argue for early intervention strategies designed to mitigate skin inflammation in children with AD.
doi:10.1111/cea.12169
PMCID: PMC3801418  PMID: 24074334
Atopic dermatitis; asthma; wheeze; IgE antibodies; age; food allergy; aeroallergens; cat; dust mite
7.  31 Nasal Nitric Oxide and Nasal Polyposis as Determinants of Asthma Control 
Background
The relationship between asthma control, its comorbidities and noninvasive markers of airway inflammation has been investigated with controversial results. The aim of this study was to analyze the relationship between level of asthma control (evaluated by ACT and ACQ questionnaires), its main comorbidities (rhinitis, chronic rhinosinusitis - CRS, obesity), exhaled nitric oxide (FENO) and nasal nitric oxide (nNO).
Methods
Forty-one consecutive asthmatic patients (mean age: 50 years, range: 21–80; 21 females; 2 smokers) were enrolled into the study. All patients were investigated to assess diagnosis of rhinitis, CRS (with or without nasal polyps) and obesity (by measuring the BMI). All patients underwent skin prick tests for a panel of common inhalant allergens, spirometry, FENO and nNO, and completed ACT and ACQ questionnaires. An univariate analysis was performed to identify determinants of asthma control (defined by means of ACT and ACQ values).
Results
Twenty-seven (65.9%) patients had ACQ values indicating asthma control (ACQ ≤1), while, according to ACT, only 14.6% of patients were completely controlled (ACT = 25), 48.8% partially controlled (20≥ ACT <25) and 36.6% uncontrolled (ACT <20). ACT and ACQ values were negatively correlated with nNO levels (R2 = −0.175 and R2 = 0.013 respectively). The univariate analysis showed that the the only significant determinants of lack of asthma control were nNO and the diagnosis of CRS with nasal polyps (P = 0.020 and 0.018 respectively).
Conclusions
Nasal nitric oxide was the only biomarker, amongst those evaluated, which was correlated to asthma control. This finding suggests that nNO may reflect particular aspects of airway inflammation which may be more strictly correlated with asthma, underlying the importance of CRS with nasal polyps in loosing asthma control.
doi:10.1097/01.WOX.0000411776.36849.46
PMCID: PMC3512849
8.  Synergism between allergens and viruses and risk of hospital admission with asthma: case-control study 
BMJ : British Medical Journal  2002;324(7340):763.
Objective
To investigate the importance of sensitisation and exposure to allergens and viral infection in precipitating acute asthma in adults resulting in admission to hospital.
Design
Case-control study.
Setting
Large district general hospital.
Participants
60 patients aged 17-50 admitted to hospital over a year with acute asthma, matched with two controls: patients with stable asthma recruited from the outpatient department and patients admitted to hospital with non-respiratory conditions (inpatient controls).
Main outcome measures
Atopic status (skin testing and total and specific IgE), presence of common respiratory viruses and atypical bacteria (polymerase chain reaction), dust samples from homes, and exposure to allergens (enzyme linked immunosorbent assay (ELISA): Der p 1, Fel d 1, Can f 1, and Bla g 2).
Results
Viruses were detected in 31 of 177 patients. The difference in the frequency of viruses detected between the groups was significant (admitted with asthma 26%, stable asthma 18%, inpatient controls 9%; P=0.04). A significantly higher proportion of patients admitted with asthma (66%) were sensitised and exposed to either mite, cat, or dog allergen than patients with stable asthma (37%) and inpatient controls (15%; P<0.001). Being sensitised and exposed to allergens was an independent associate of the group admitted to hospital (odds ratio 2.3, 95% confidence interval 1.0 to 5.4; P=0.05), whereas the combination of sensitisation, high exposure to one or more allergens, and viral detection considerably increased the risk of being admitted with asthma (8.4, 2.1 to 32.8; P=0.002).
Conclusions
Allergens and viruses may act together to exacerbate asthma.
What is already known on this topicStudies on segmental allergen challenge of the lung and experimental rhinovirus infection show synergistic effects between allergens and respiratory virus infectionNo studies have investigated an interaction between sensitisation, exposure to allergens, and virus infections in real life exacerbations of asthmaWhat this study addsAllergens and viruses may act together to exacerbate asthma, indicating that domestic exposure to allergens acts synergistically with viruses in sensitised patients, increasing the risk of hospital admissionStrategies to reduce the impact of asthma exacerbations in adults should include interventions directed at both viruses and reducing exposure to allergens
PMCID: PMC100316  PMID: 11923159
9.  Mouse allergen is the major allergen of public health relevance in Baltimore City 
Background
Cockroach and mouse allergens have both been implicated as causes in inner-city asthma morbidity in multicenter studies, but whether both allergens are clinically relevant within specific inner-city communities is unclear. Objective: Our study aimed to identify relevant allergens in Baltimore City.
Methods
One hundred forty-four children (5–17 years old) with asthma underwent skin prick tests at baseline and had clinical data collected at baseline and 3, 6, 9, and 12 months. Home settled dust samples were collected at the same time points for quantification of indoor allergens. Participants were grouped based on their sensitization and exposure status to each allergen. All analyses were adjusted for age, sex, and serum total IgE level.
Results
Forty-one percent were mouse sensitized/exposed, and 41% were cockroach sensitized/exposed based on bedroom floor exposure data. Mouse sensitization/exposure was associated with acute care visits, decreased FEV1/forced vital capacity percentage values, fraction of exhaled nitric oxide levels, and bronchodilator reversibility. Cockroach sensitization/exposure was only associated with acute care visits and bronchodilator reversibility when exposure was defined by using bedroom floor allergen levels. Mouse-specific IgE levels were associated with poor asthma health across a range of outcomes, whereas cockroach-specific IgE levels were not. The relationships between asthma outcomes and mouse allergen were independent of cockroach allergen. Although sensitization/exposure to both mouse and cockroach was generally associated with worse asthma, mouse sensitization/exposure was the primary contributor to these relationships.
Conclusions
In a community with high levels of both mouse and cockroach allergens, mouse allergen appears to be more strongly and consistently associated with poor asthma outcomes than cockroach allergen. Community-level asthma interventions in Baltimore should prioritize reducing mouse allergen exposure.
doi:10.1016/j.jaci.2013.05.005
PMCID: PMC3800085  PMID: 23810154
Inner-city asthma; childhood asthma; mouse allergen; cockroach allergen; indoor allergens
10.  Use of Exhaled Nitric Oxide Measurement to Identify a Reactive, at-Risk Phenotype among Patients with Asthma 
Rationale: Exhaled nitric oxide (FeNO) is a biomarker of airway inflammation in mild to moderate asthma. However, whether FeNO levels are informative regarding airway inflammation in patients with severe asthma, who are refractory to conventional treatment, is unknown. Here, we hypothesized that classification of severe asthma based on airway inflammation as defined by FeNO levels would identify a more reactive, at-risk asthma phenotype.
Methods: FeNO and major features of asthma, including airway inflammation, airflow limitation, hyperinflation, hyperresponsiveness, and atopy, were determined in 446 individuals with various degrees of asthma severity (175 severe, 271 nonsevere) and 49 healthy subjects enrolled in the Severe Asthma Research Program.
Measurements and Main Results: FeNO levels were similar among patients with severe and nonsevere asthma. The proportion of individuals with high FeNO levels (>35 ppb) was the same (40%) among groups despite greater corticosteroid therapy in severe asthma. All patients with asthma and high FeNO had more airway reactivity (maximal reversal in response to bronchodilator administration and by methacholine challenge), more evidence of allergic airway inflammation (sputum eosinophils), more evidence of atopy (positive skin tests, higher serum IgE and blood eosinophils), and more hyperinflation, but decreased awareness of their symptoms. High FeNO identified those patients with severe asthma characterized by the greatest airflow obstruction and hyperinflation and most frequent use of emergency care.
Conclusions: Grouping of asthma by FeNO provides an independent classification of asthma severity, and among patients with severe asthma identifies the most reactive and worrisome asthma phenotype.
doi:10.1164/rccm.200905-0695OC
PMCID: PMC2874447  PMID: 20133930
nitric oxide; severe asthma; phenotype; airway reactivity; exhaled breath
11.  Anaphylaxis syndromes related to a new mammalian cross-reactive carbohydrate determinant 
Anaphylaxis is a severe allergic reaction that can be rapidly progressing and occasionally fatal. In instances where the triggering allergen is not obvious, establishing the etiology of anaphylaxis is pivotal to long-term management. Assigning etiology is limited, however, by the number of known exposures associated with anaphylaxis. Therefore, identification of novel causative agents can provide an important step forward in facilitating new, allergen specific approaches to management. In contrast to the view that carbohydrate-directed IgE has minimal, if any, clinical significance, recent data suggests that IgE antibodies to carbohydrate epitopes can be an important factor in anaphylaxis that may otherwise appear to be idiopathic. Specifically, IgE antibodies to the carbohydrate galactose-α-1,3-galactose (alpha-gal) were found to be capable of eliciting serious, even fatal, reactions to the monoclonal antibody (ab) cetuximab.1 Moreover, alpha-gal has recently been identified as a novel food allergen.2 Patients who have IgE to alpha-gal report delayed anaphylaxis or urticaria occurring 3-6 hours after eating beef, pork or lamb. Here, we review the evidence relating to carbohydrates in food allergy and anaphylaxis and discuss the implications of a new mammalian cross-reactive carbohydrate determinant (CCD).
doi:10.1016/j.jaci.2009.08.026
PMCID: PMC2774206  PMID: 19815111
anaphylaxis; cross-reactive carbohydrate determinant (CCD); alpha-gal; glycosylation
12.  Allergen-specific IgE as a biomarker of exposure plus sensitization in inner-city adolescents with asthma 
Allergy  2010;65(11):1414-1422.
Background
Relationships among allergen-specific IgE levels, allergen exposure and asthma severity are poorly understood since sensitization has previously been evaluated as a dichotomous, rather than continuous characteristic.
Methods
Five hundred and forty-six inner-city adolescents enrolled in the Asthma Control Evaluation study underwent exhaled nitric oxide (FENO) measurement, lung function testing, and completion of a questionnaire. Allergen-specific IgE levels and blood eosinophils were quantified. Dust samples were collected from the participants’ bedrooms for quantification of allergen concentrations. Participants were followed for 12 months and clinical outcomes were tracked.
Results
Among sensitized participants, allergen-specific IgE levels were correlated with the corresponding settled dust allergen levels for cockroach, dust mite, and mouse (r = 0.38, 0.34, 0.19, respectively; P < 0.0001 for cockroach and dust mite and P = 0.03 for mouse), but not cat (r = )0.02, P = 0.71). Higher cockroach-, mite-, mouse-, and cat-specific IgE levels were associated with higher FENO concentrations, poorer lung function, and higher blood eosinophils. Higher cat, dust mite, and mouse allergen-specific IgE levels were also associated with an increasing risk of exacerbations or hospitalization.
Conclusions
Allergen-specific IgE levels were correlated with allergen exposure among sensitized participants, except for cat. Allergen-specific IgE levels were also associated with more severe asthma across a range of clinical and biologic markers. Adjusting for exposure did not provide additional predictive value, suggesting that higher allergen-specific IgE levels may be indicative of both higher exposure and a greater degree of sensitization, which in turn may result in greater asthma severity.
doi:10.1111/j.1398-9995.2010.02412.x
PMCID: PMC3345161  PMID: 20560910
allergen exposure; allergen-specific IgE; biomarker; childhood asthma; Inner-city Asthma Consortium
13.  Allergen exposure modifies the relation of sensitization to FENO levels in children at risk for allergy and asthma 
Background
Studies on airway inflammation, measured as fraction exhaled nitric oxide (FENO), have focused on its relation to control of asthma, but the contribution of allergen exposure to elevation of FENO is unknown.
Objective
We evaluated (1) whether FENO was elevated in children with allergic sensitization or asthma; (2) whether specific allergen exposure increased FENO levels in sensitized, but not in unsensitized children; and (3) whether sedentary behavior increased FENO, independent of allergen exposures.
Methods
At age 12, in a birth cohort of children with parental history of allergy or asthma, we measured bed dust allergen (dust mite, cat, cockroach) by ELISA; specific allergic sensitization primarily by specific IgE ; and respiratory disease (current asthma, rhinitis, and wheeze) and hours of TV viewing/video game playing by questionnaire. Children performed spirometry maneuvers before and after bronchodilator responses, and had FENO measured using electrochemical detection methods (NIOX MINO).
Results
FENO was elevated in children with current asthma (32.2 ppb), wheeze (27.0 ppb), or rhinitis (23.2ppb) as compared to individuals without these respective symptoms/diagnoses (16.4 ppb to 16.6 ppb, p< 0.005 for all comparisons). Allergic sensitization to indoor allergens (cat, dog, dust mite) predicted higher levels of FENO, and explained one third of the variability of FENO. FENO levels were highest in children both sensitized and exposed to dust mite. Greater than 10 hours of weekday TV viewing was associated with a 0.64 log increase in FENO, after controlling indoor allergen exposure, BMI and allergic sensitization.
Conclusion
Allergen exposures and sedentary behavior (TV viewing/ video game playing), may increase airway inflammation, measured as FENO.
doi:10.1016/j.jaci.2011.01.066
PMCID: PMC3137133  PMID: 21463890
Asthma; dust mite; cat; allergens; exhaled NO; allergic sensitization; home environment
14.  The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose 
Background
In 2009, we reported a novel form of delayed anaphylaxis to red meat, which is related to serum IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Most of these patients had tolerated meat for many years previously. The implication is that some exposure in adult life had stimulated the production of these IgE antibodies.
Objectives
To investigate possible causes of this IgE antibody response, focusing on evidence related to tick bites, which are common in the region where these reactions occur.
Methods
Serum assays were carried out using biotinylated proteins and extracts bound to a streptavidin ImmunoCAP.
Results
Prospective studies on IgE antibodies in three subjects following tick bites showed an increase in IgE to alpha-gal of twenty-fold or greater. Other evidence included i) a strong correlation between histories of tick bites and IgE to alpha-gal (χ2=26.8, p<0.001), ii) evidence that these IgE antibodies are common in areas where the tick Amblyomma americanum is common, and iii) a significant correlation between IgE antibodies to alpha-gal and IgE antibodies to proteins derived from A. americanum (rs=0.75, p<0.001).
Conclusion
The results presented here provide evidence that tick bites are a cause, or possibly the only cause, of IgE specific for alpha-gal in this area of the United States. Both the number of subjects becoming sensitized and the titer of IgE antibodies to alpha-gal are striking. Here we report the first example of a response to an ectoparasite giving rise to an important form of food allergy.
doi:10.1016/j.jaci.2011.02.019
PMCID: PMC3085643  PMID: 21453959
ticks; anaphylaxis; oligosaccharide; alpha-gal; IgE antibody to CCD
15.  Alterations of the Arginine Metabolome in Asthma 
Rationale: As the sole nitrogen donor in nitric oxide (NO) synthesis and key intermediate in the urea cycle, arginine and its metabolic pathways are integrally linked to cellular respiration, metabolism, and inflammation.
Objectives: We hypothesized that arginine (Arg) bioavailability would be associated with airflow abnormalities and inflammation in subjects with asthma, and would be informative for asthma severity.
Methods: Arg bioavailability was assessed in subjects with severe and nonsevere asthma and healthy control subjects by determination of plasma Arg relative to its metabolic products, ornithine and citrulline, and relative to methylarginine inhibitors of NO synthases, and by serum arginase activity. Inflammatory parameters, including fraction of exhaled NO (FeNO), IgE, skin test positivity to allergens, bronchoalveolar lavage, and blood eosinophils, were also evaluated.
Measurements and Main Results: Subjects with asthma had greater Arg bioavailability, but also increased Arg catabolism compared with healthy control subjects, as evidenced by higher levels of FeNO and serum arginase activity. However, Arg bioavailability was positively associated with FeNO only in healthy control subjects; Arg bioavailability was unrelated to FeNO or other inflammatory parameters in severe or nonsevere asthma. Inflammatory parameters were related to airflow obstruction and reactivity in nonsevere asthma, but not in severe asthma. Conversely, Arg bioavailability was related to airflow obstruction in severe asthma, but not in nonsevere asthma. Modeling confirmed that measures of Arg bioavailabilty predict airflow obstruction only in severe asthma.
Conclusions: Unlike FeNO, Arg bioavailability is not a surrogate measure of inflammation; however, Arg bioavailability is strongly associated with airflow abnormalities in severe asthma.
doi:10.1164/rccm.200710-1542OC
PMCID: PMC2556449  PMID: 18635886
asthma; arginine; arginase; nitric oxide; methylarginine
16.  Severe asthma and the omalizumab option 
Atopic diseases and asthma are increasing at a remarkable rate on a global scale. It is now well recognized that asthma is a chronic inflammatory disease of the airways. The inflammatory process in many patients is driven by an immunoglobulin E (IgE)-dependent process. Mast cell activation and release of mediators, in response to allergen and IgE, results in a cascade response, culminating in B lymphocyte, T lymphocyte, eosinophil, fibroblast, smooth muscle cell and endothelial activation. This complex cellular interaction, release of cytokines, chemokines and growth factors and inflammatory remodeling of the airways leads to chronic asthma. A subset of patients develops severe airway disease which can be extremely morbid and even fatal. While many treatments are available for asthma, it is still a chronic and incurable disease, characterized by exacerbation, hospitalizations and associated adverse effects of medications. Omalizumab is a new option for chronic asthma that acts by binding to and inhibiting the effects of IgE, thereby interfering with one aspect of the asthma cascade reviewed earlier. This is a humanized monoclonal antibody against IgE that has been shown to have many beneficial effects in asthma. Use of omalizumab may be influenced by the cost of the medication and some reported adverse effects including the rare possibility of anaphylaxis. When used in selected cases and carefully, omalizumab provides a very important tool in disease management. It has been shown to have additional effects in urticaria, angioedema, latex allergy and food allergy, but the data is limited and the indications far from clear. In addition to decreasing exacerbations, it has a steroid sparing role and hence may decrease adverse effects in some patients on high-dose glucocorticoids. Studies have shown improvement in quality of life measures in asthma following the administration of omalizumab, but the effects on pulmonary function are surprisingly small, suggesting a disconnect between pulmonary function, exacerbations and quality of life. Anaphylaxis may occur rarely with this agent and appropriate precautions have been recommended by the Food and Drug Administration (FDA). As currently practiced and as suggested by the new asthma guidelines, this biological agent is indicated in moderate or severe persistent allergic asthma (steps 5 and 6).
doi:10.1186/1476-7961-6-4
PMCID: PMC2478654  PMID: 18489791
17.  Non-invasive testing of lung function and inflammation in pediatric patients with acute asthma exacerbations 
Objective
There is limited information on performance rates for tests of lung function and inflammation in pediatric patients with acute asthma exacerbations. We sought to examine how frequently pediatric patients with acute asthma exacerbations could perform non-invasive lung function and exhaled nitric oxide testing and participant characteristics associated with successful performance.
Methods
We studied a prospective convenience sample aged 5–17 years with acute asthma exacerbations in a pediatric emergency department. Participants attempted spirometry for percent predicted forced expiratory volume in 1-second (%FEV1), airway resistance (Rint) and exhaled nitric oxide (FENO) testing before treatment. We examined overall performance rates and the associations of age, gender, race, and baseline acute asthma severity score with successful test performance.
Results
Among 573 participants, age was (median [IQR]) 8.8 [6.8, 11.5] years, male 60%, African-American 57%, and Medicaid insurance 58%. Tests were performed successfully by [n (%)]: full ATS/ERS-criteria spirometry, 331 (58%); Rint, 561 (98%); and FENO, 354 (70% of 505 attempting test). Sixty-percent with mild-moderate exacerbations performed spirometry compared to 17% with severe exacerbations (P=0.0001). Participants ages 8–12 years (67%) were more likely to perform spirometry than those 5–7 years (48%) (OR=2.23, 95% CI: 1.45–3.11) or 13–17 years (58%) (OR=1.61, 95%CI: 1.00–2.59).
Conclusions
There is clinically important variability in performance of these tests during acute asthma exacerbations. The proportion of patients with severe exacerbations able to perform spirometry (17%) limits its utility. Almost all children with acute asthma can perform airway resistance testing, and further development and validation of this technology is warranted.
doi:10.3109/02770903.2011.637599
PMCID: PMC3813959  PMID: 22133263
Asthma; asthma exacerbation; spirometry; airway resistance; respiratory function testing
18.  Comparison of orally exhaled nitric oxide in allergic versus nonallergic rhinitis 
Background:
Fractional exhaled nitric oxide (FeNO), a well-known marker of airway inflammation, is rarely evaluated in rhinitis of different etiology. We aimed to compare the eNO levels in allergic rhinitis (AR) and nonallergic rhinitis (NAR) with/without asthma, as well as the contributing factors that interfere with elevated FeNO.
Methods:
Patients were enrolled based on chronic nasal symptoms. Orally exhaled NO was measured with the single exhalation method at 50 mL/s. All subjects underwent a panel of tests: skin-prick tests, asthma control test, blood sampling, spirometry, and health-related quality-of-life questionnaires.
Results:
The study group consisted of mainly women (130 women/41 men), with a mean age of 32.6 ± 13.2 years. AR was diagnosed in 122 (78.2%), NAR in 34 (21.8%), and 15 subjects were healthy controls. FeNO was insignificantly higher in patients with AR compared with patients with NAR and controls (32.2 parts per billion [ppb] versus 27 and 19.4 ppb), with no difference between genders. NAR + asthma had higher FeNO than those without asthma (40.5 ppb versus 14.9 ppb; p < 0.03), whereas accompanying asthma did not affect FeNO levels in the AR group. AR ± asthma had significantly higher FeNO levels than the NAR-only group (p < 0.01). Among AR + asthma, perennial sensitization caused higher FeNO levels than did seasonal allergens (48.5 ± 33.9 and 19.5 ± 13.6′ p = 0.003), whereas FeNO was significantly higher during the allergen season. Nasally inhaled corticosteroids insignificantly reduced FeNO levels in all groups. Severity and seasonality of rhinitis, asthma, and ocular symptoms, but not gender, age, body mass index, Total IgE, forced expiratory volume in 1 second, and smoking, were associated with FeNO.
Conclusion:
Rhinitis and comorbid asthma are responsible for increased FeNO, irrespective of atopy. However, NAR without asthma may not be considered as a strong risk factor for airway inflammation.
doi:10.2500/ajra.2012.26.3717
PMCID: PMC3906508  PMID: 22487277
Airway inflammation; allergic rhinitis; asthma; atopy; exhaled nitric oxide; inhaled corticosteroids; nonallergic rhinitis
19.  Eastern Carolina Asthma Prevention Program (ECAPP): An Environmental Intervention Study Among Rural and Underserved Children with Asthma in Eastern North Carolina 
OBJECTIVE
Asthma is the most common chronic childhood condition affecting 6.3 million (US) children aged less than 18 years. Home-based, multi-component, environmental intervention studies among children with asthma have demonstrated to be effective in reducing asthma symptoms. In this study, a local hospital and university developed an environmental intervention research pilot project, Eastern Carolina Asthma Prevention Program (ECAPP), to evaluate self-reported asthma symptoms, breathing measurements, and number of asthma-related emergency department (ED) visits among low-income, minority children with asthma living in rural, eastern North Carolina. Our goal was to develop a conceptual model and demonstrate any asthma respiratory improvements in children associated with our home-based, environmental intervention.
METHODS
This project used a single cohort, intervention design approach to compare self-reported asthma-related symptoms, breathing tests, and ED visits over a 6 month period between children with asthma in an intervention study group (n = 12) and children with asthma in a control study group (n = 7). The intervention study group received intense asthma education, three home visits, 2 week follow-up telephone calls, and environmental intervention products for reducing asthma triggers in the home. The control group received education at baseline and 2 week calls, but no intervention products.
RESULTS
At the end of the study period, significant improvements were observed in the intervention group compared with the control group. Overall, the intervention group experienced a 58% (46 ± SD 26.9) reduction in self-reported asthma symptoms; 76% (34 ± SD 29.7) decrease in rescue medicine; 12% (145 ± SD 11.3) increase in controller medicine; 37% decrease in mean exhaled nitric oxide levels and 33% fewer ED asthma-related visits.
CONCLUSION
As demonstrated, a combination of efforts appeared effective for improving asthma respiratory symptoms among children in the intervention group. ECAPP is a low cost pilot project that could readily be adapted and expanded into other communities throughout eastern North Carolina. Future efforts could include enhanced partnerships between environmental health professionals at local health departments and pediatric asthma programs at hospitals to carry out ECAPP.
doi:10.4137/EHI.S16430
PMCID: PMC4077872  PMID: 25057240
exhaled nitric oxide; environmental health; airway inflammation
20.  Establishing IMMULITE® 2000 cut-off values for serum allergen-specific immunoglobulin and exploring their relationship to exhaled nitric oxide 
Aim
Paediatric cut-off values for serum allergen-specific IgE (sIgE) using the Siemens IMMULITE® 2000 system to diagnose allergic rhinoconjunctivitis have not been established. We aimed to determine cut-off levels for sIgE for 10 common inhalant allergens and to study the relationship between sIgE, total IgE and fractional exhaled nitric oxide (FENO).
Methods
We enrolled 243 schoolchildren, including 164 with allergic rhinoconjunctivitis. Parental interviews, skin prick tests, sIgE, total IgE, FENO measurements, spirometry and exercise tests were performed.
Results
Cut-off values with the best combined sensitivity and specificity were above the detection limit of the assay for seven of the ten allergens (0.23–1.1 kU/L). The overall accuracy of the IMMULITE® in detecting allergic rhinoconjunctivitis was good. sIgE was superior to total IgE and FENO in predicting allergic rhinoconjunctivitis to timothy, birch, mugwort, cat, dog and house dust mite. FENO was elevated in children with allergic rhinoconjunctivitis, irrespective of asthma.
Conclusion
Cut-off values for sIgE were dependent on the allergic phenotype and were above the IMMULITE® detection limit for seven of ten inhalant allergens. Consequently, using the detection limit for sIgE as the decision point would result in over-diagnosing allergic rhinoconjunctivitis. When measuring elevated FENO in children, allergic rhinoconjunctivitis should be suspected.
doi:10.1111/apa.12631
PMCID: PMC4320778  PMID: 24628428
Allergic rhinoconjunctivitis; Children; Exhaled nitric oxide; Skin prick test; Specific IgE
21.  Differences in both prevalence and titre of specific immunoglobulin E among children with asthma in affluent and poor communities within a large town in Ghana 
Clinical and Experimental Allergy  2011;41(11):1587-1594.
Background
Reports from several African countries have noted an increasing prevalence of asthma in areas of extensive urbanization.
Objective
To investigate the relevance of allergen-specific sensitization and body mass index (BMI) to asthma/wheezing and exercise-induced bronchospasm (EIB) among children from affluent and poorer communities within a large town in Ghana.
Methods
Children with physician-diagnosed asthma and/or current wheezing aged 9–16 years (n=99; cases) from three schools with differing socio-economic backgrounds [urban affluent (UA), urban poor (UP) or suburban/rural (SR)] were recruited from a cross-sectional study (n=1848) in Kumasi, Ghana, and matched according to age, sex and area of residence with non-asthmatic/non-wheezy controls. We assayed sera for IgE antibodies to mite, cat, dog, cockroach, Ascaris and galactose-α-1,3-galactose.
Results
Children from the UA school had the lowest total serum IgE. However, cases from the UA school had a higher prevalence and mean titre of sIgE to mite (71.4%, 21.2 IU/mL) when compared with controls (14.3%, 0.8 IU/mL) or cases from UP (30%, 0.8 IU/mL) and SR community (47.8%, 1.6 IU/mL). While similar findings were observed with EIB in the whole population, among cases there was no difference in IgE antibody prevalence or titre between children with or without EIB. BMI was higher among UA children with and without asthma; in UP and SR communities, children with EIB (n=14) had a significantly higher BMI compared with children with asthma/wheezing without EIB (n=38) (18.2 vs. 16.4, respectively, P<0.01).
Conclusions and Clinical Relevance
In the relatively affluent school, asthma/wheezing and EIB were associated with high titre IgE antibodies to mite, decreased total IgE, and increased BMI. This contrasted with children in the urban poor school and suggests that changes relevant to a Western model of childhood asthma can occur within a short geographical distance within a large city in Africa.
Cite this as: W. Stevens, E. Addo-Yobo, J. Roper, A. Woodcock, H. James, T. Platts-Mills and A. Custovic, Clinical & Experimental Allergy, 2011 (41) 1587–1594.
doi:10.1111/j.1365-2222.2011.03832.x
PMCID: PMC3505371  PMID: 21810123
Africa; asthma; body mass index; exercise-induced bronchospasm; specific IgE; total IgE
22.  Longitudinal study of grass pollen exposure, symptoms, and exhaled nitric oxide in childhood seasonal allergic asthma 
Thorax  2004;59(9):752-756.
Background: Exhaled nitric oxide (NO) has been proposed as a marker of airway eosinophilic inflammation in asthma. There is currently a paucity of longitudinal data relating it to allergen exposure and asthma symptoms.
Methods: Forty four children (6–16 years) with seasonal allergic asthma were sequentially followed before and during the grass pollen season. Asthma symptoms, lung function, NO levels, and pollen counts were recorded. The relationship between exhaled NO and both the pollen levels and asthma control were assessed longitudinally, comparing a subject's measurements with their previous ones.
Results: The median exhaled NO concentration was significantly increased during the pollen season (6.2 v 9.2 parts per billion (ppb), p<0.002; median change 2.9 ppb, 95% confidence interval 1.5 to 5.4). Exhaled NO was best associated with the mean pollen count in the week before measurement. It was also significantly associated with asthma control.
Conclusions: The results suggest that, within a longitudinal model, the exhaled NO concentration is related to preceding allergen exposure and asthma control. It may be clinically more useful to compare exhaled NO values with a subject's previous values than to compare them with a population based normal range.
doi:10.1136/thx.2003.008722
PMCID: PMC1747120  PMID: 15333850
23.  Fractional Exhaled Nitric Oxide (FeNO) Measurements are Most Closely Associated with Allergic Sensitization in School Aged Children 
Background
Factors affecting fractional exhaled nitric oxide (FeNO) in early childhood are incompletely understood.
Objective
To examine the relationships between FeNO and allergic sensitization, total IgE, atopic dermatitis, rhinitis, asthma, and lung function (spirometry) in children.
Methods
Children at high-risk of asthma and other allergic diseases due to parental history were enrolled at birth and followed prospectively. FeNO was measured by online technique at ages 6 and 8 years. Relationships among FeNO, various atopic characteristics, and asthma were evaluated.
Results
Reproducible FeNO measurements were obtained in 64% (135 of 210) of 6 year old and 93% (180 of 194) of 8 year old children. There was seasonal variability in FeNO. Children with aeroallergen sensitization at age 6 and 8 years had increased levels of FeNO compared to those not sensitized [geometric mean (6 years, 10.9 vs. 6.7 ppb, p<0.0001; 8 years, 14.6 vs. 7.1 ppb, p<0.0001)]. FeNO was higher in children with asthma than in those without asthma at 8 years, but not 6 years of age (6 years, 9.2 vs. 8.3 ppb, p = 0.48; 8 years, 11.5 vs. 9.2 ppb, p = 0.03). At 8 years of age, this difference was no longer significant in a multivariate model that included aeroallergen sensitization (p=0.33). There were no correlations between FeNO and spirometric indices at 6 or 8 years of age.
Conclusion
These findings underscore the importance of evaluating allergen sensitization status when FeNO is used as a potential biomarker in the diagnosis and/or monitoring of atopic diseases, particularly asthma.
Clinical Implications
When FeNO is utilized as a biomarker for the diagnosis and/or monitoring of atopic diseases such as asthma, the presence or absence of allergic sensitization should be carefully considered.
Capsule Summary
This pediatric cohort study evaluates the relationships between FeNO and various atopic characteristics. The results suggest that allergic sensitization should be evaluated when FeNO is used as a biomarker in clinical or research settings.
doi:10.1016/j.jaci.2009.07.024
PMCID: PMC2784153  PMID: 19748661
fractional exhaled nitric oxide (FeNO); asthma; allergic sensitization; atopic dermatitis; lung function; children; seasonality; atopy
24.  Relationship between exposure to domestic allergens and bronchial hyperresponsiveness in non-sensitised, atopic asthmatic subjects 
Thorax  2005;60(1):17-21.
Background: The effect of exposure to allergens not causing sensitisation in atopic asthmatic subjects has not previously been studied. A study was undertaken to assess the degree of asthma severity (measured by spirometry, airway reactivity and exhaled nitric oxide) in atopic asthmatic patients not sensitised to the domestic allergen to which they were exposed.
Methods: Dust samples were collected from the living room carpet and mattress in the homes of 248 subjects and dust mite, cat and dog allergen concentrations were measured. Spirometry, non-specific bronchial reactivity (BR), and exhaled nitric oxide (eNO) were ascertained. Patients' sensitisation status was assessed by skin prick testing.
Results: Adult atopic asthmatics not sensitised to mite but exposed to high levels of mite allergen had significantly more severe BR than subjects not exposed to high levels of mite (PD20, geometric mean (GM) 0.21 mg (95% CI 0.09 to 0.47) v 0.86 mg (95% CI 0.44 to 1.67), mean ratio difference 4.1 (95% CI 1.5 to 11.4), p = 0.008). Subjects not sensitised but exposed to high levels of dog allergen also had significantly more severe BR than subjects not exposed (PD20 GM 0.16 v 0.52 mg, mean ratio difference 3.3 (95% CI 1.2 to 9.2), p = 0.01). The differences in BR between these groups were still significant after adjusting for confounding factors. This effect of greater airway reactivity was not seen in subjects exposed but not sensitised to cat allergens.
Conclusion: Atopic asthmatic subjects who are exposed to high levels of dust mite or dog allergens but not sensitised to these allergens have evidence of increased airway reactivity.
doi:10.1136/thx.2004.027839
PMCID: PMC1747172  PMID: 15618577
25.  Tick-induced allergies: mammalian meat allergy, tick anaphylaxis and their significance 
Asia Pacific Allergy  2015;5(1):3-16.
Serious tick-induced allergies comprise mammalian meat allergy following tick bites and tick anaphylaxis. Mammalian meat allergy is an emergent allergy, increasingly prevalent in tick-endemic areas of Australia and the United States, occurring worldwide where ticks are endemic. Sensitisation to galactose-α-1,3-galactose (α-Gal) has been shown to be the mechanism of allergic reaction in mammalian meat allergy following tick bite. Whilst other carbohydrate allergens have been identified, this allergen is unique amongst carbohydrate food allergens in provoking anaphylaxis. Treatment of mammalian meat anaphylaxis involves avoidance of mammalian meat and mammalian derived products in those who also react to gelatine and mammalian milks. Before initiating treatment with certain therapeutic agents (e.g., cetuximab, gelatine-containing substances), a careful assessment of the risk of anaphylaxis, including serological analysis for α-Gal specific-IgE, should be undertaken in any individual who works, lives, volunteers or recreates in a tick endemic area. Prevention of tick bites may ameliorate mammalian meat allergy. Tick anaphylaxis is rare in countries other than Australia. Tick anaphylaxis is secondarily preventable by prevention and appropriate management of tick bites. Analysis of tick removal techniques in tick anaphylaxis sufferers offers insights into primary prevention of both tick and mammalian meat anaphylaxis. Recognition of the association between mammalian meat allergy and tick bites has established a novel cause and effect relationship between an environmental exposure and subsequent development of a food allergy, directing us towards examining environmental exposures as provoking factors pivotal to the development of other food allergies and refocusing our attention upon causation of allergy in general.
doi:10.5415/apallergy.2015.5.1.3
PMCID: PMC4313755  PMID: 25653915
Mammalian meat; Ticks; Anaphylaxis; Alpha-gal; Cetuximab

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