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2.  Galactose-α-1,3-galactose and Delayed Anaphylaxis, Angioedema, and Urticaria in Children 
Pediatrics  2013;131(5):e1545-e1552.
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.
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.
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.
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.
PMCID: PMC3639458  PMID: 23569097
α-Gal; galactose-α-1,3-galactose; delayed anaphylaxis; pediatric urticaria
3.  Pathogenesis of Rhinovirus Infection 
Current Opinion in Virology  2012;2(3):287-293.
Since its discovery in 1956, rhinovirus (RV) has been recognized as the most important virus producing the common cold syndrome. Despite its ubiquity, little is known concerning the pathogenesis of RV infections, and some of the research in this area has led to contradictions regarding the molecular and cellular mechanisms of RV-induced illness. In this article, we discuss the pathogenesis of this virus as it relates to RV-induced illness in the upper and lower airway, an issue of considerable interest in view of the minimal cytopathology associated with RV infection. We endeavor to explain why many infected individuals exhibit minimal symptoms or remain asymptomatic, while others, especially those with asthma, may have severe, even life-threatening, complications (sequelae). Finally, we discuss the immune responses to RV in the normal and asthmatic host focusing on RV infection and epithelial barrier integrity and maintenance as well as the impact of the innate and adaptive immune responses to RV on epithelial function.
PMCID: PMC3378761  PMID: 22542099
Rhinovirus; asthma; pathogenesis; viral-induced asthma exacerbations
4.  The Role of Allergy in Severe Asthma 
Clinical and Experimental Allergy  2012;42(5):659-669.
The classification of asthma to identify forms which have different contributing causes is useful for all cases in which the disease requires regular treatment, but it is essential for the management of severe asthma. Many forms of the disease can occur, and complex mixtures are not uncommon; here we artificially separated the cases into four groups: i) inhalant allergy, ii) fungal sensitization with or without colonization (including ABPA); iii) severe sinusitis with or without aspirin-exacerbated respiratory disease (AERD), and iv) non-inflammatory cases, including those associated with severe obesity and vocal cord dysfunction (VCD). The reason for focusing on these groups is because they illustrate how much the specific management depends upon correct classification. Inhalant allergy can present as chronically severe asthma. However, severe attacks of asthma requiring hospital admission can occur in cases which are generally only mild or moderate. The best recognized and probably the most common cause of these acute episodes is acute infection with a rhinovirus. Recent evidence suggests that high titer IgE, particularly to dust mite, correlates to exacerbations of asthma related to rhinovirus infection. While it is well recognized that the fungus Aspergillus can colonize the lungs and cause severe disease, it is less well recognized that those cases may not have full criteria for diagnosis of ABPA or may involve other fungi. Identifying fungal cases is important, because treatment with imidazole antifungals can provide significant benefit. Taken together, specific treatment using allergen avoidance, immunotherapy, anti-IgE, or antifungal treatment is an important part of the successful management of severe asthma, and each of these requires correctly identifying specific sensitization.
PMCID: PMC3335737  PMID: 22515388
5.  Asthma Outcomes: Exacerbations 
The goals of asthma treatment include preventing recurrent exacerbations. Yet there is no consensus about the terminology for describing or defining “exacerbation,” or about how to characterize an episode’s severity.
National Institutes of Health (NIH) institutes and other federal agencies convened an expert group to propose how asthma exacerbation should be assessed as a standardized asthma outcome in future asthma clinical research studies.
We utilized comprehensive literature reviews and expert opinion to compile a list of asthma exacerbation outcomes, and classified them as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011.
No dominant definition of “exacerbation” was found. The most widely used definitions included 3 components, all related to treatment, rather than symptoms: (1) systemic use of corticosteroids, (2) asthma-specific emergency department visits or hospitalization, and (3) use of short-acting β-agonists (SABAs) as quick-relief (sometimes referred to as “rescue” or “reliever”) medications.
The working group participants propose that the definition of “asthma exacerbation” be “a worsening of asthma requiring the use of systemic corticosteroids to prevent a serious outcome.” As core outcomes, they propose inclusion and separate reporting of several essential variables of an exacerbation. Further, they propose the development of a standardized, component-based definition of “exacerbation” with clear thresholds of severity for each component.
PMCID: PMC3595577  PMID: 22386508
Asthma exacerbations; severity of acute asthma; asthma outcomes; urgent asthma care
6.  Viral Respiratory Infections and Asthma: the Course Ahead 
Inquiries into the relationships between viral respiratory illnesses and the inception and exacerbation of asthma are being facilitated by recent advances in research approaches and technology. In this article, we identify important knowledge gaps and future research questions, and we discuss how new investigational tools, including improved respiratory virus detection techniques, will permit current and future researchers to define these relationships and the host, virus, developmental, and environmental mechanisms that regulate them. A better understanding of these processes should facilitate the development of improved strategies for the prevention and treatment of virus-induced wheezing illnesses and asthma exacerbations and, possibly, the ultimate goal of discovering effective approaches for the primary prevention of asthma.
PMCID: PMC2880817  PMID: 20513518
viral respiratory infections; asthma; wheezing; asthma onset; asthma exacerbations; respiratory viruses; rhinovirus; respiratory syncytial virus; allergy
7.  Risk of Childhood Asthma in Relation to the Timing of Early Child Care Exposures 
The Journal of pediatrics  2009;155(6):781-787.e1.
To examine whether early child care exposure influences the risk of developing asthma.
Study design
Longitudinal data from 939 children and their families from the National Institute of Child Health and Development (NICHD) Study of Early Child Care and Youth Development (SECCYD) were analyzed. Exposure to other children in the primary child care setting as an infant (before 15 months) and as a toddler (16–36 months) were assessed as risk factors for persistent or late-onset asthma by age 15 via logistic regression.
The number of children in the child-care environment when the child was a toddler was significantly associated with odds of asthma, even after adjusting for respiratory illnesses and other risk factors (p<.05). The fewer the children exposed to as toddlers, the higher the probability of persistent or late-onset asthma by age 15.
This study supports the theory of a protective effect of exposure to other children at an early age, especially as a toddler, on the risk of asthma. This effect appears to be independent of the number of reported respiratory tract illnesses, suggesting that other protective mechanisms related to the number of children in the child care environment may be involved.
PMCID: PMC2783908  PMID: 19683726
9.  Lactoferrin and Eosinophilic Cationic Protein in Nasal Secretions of Patients with Experimental Rhinovirus Colds, Natural Colds, and Presumed Acute Community-Acquired Bacterial Sinusitis 
Journal of Clinical Microbiology  2000;38(8):3100-3102.
To distinguish sinusitis from uncomplicated “colds,” we examined lactoferrin and eosinophilic cationic protein (ECP) in nasal secretions. Lactoferrin titers were ≥1:400 in 4% of persons with uncomplicated colds and controls but in 79% of persons with sinusitis or purulent sputa. ECP levels were >200 ng/ml in 61% of persons with colds and >3,000 ng/ml in 62% of persons with sinusitis. Nasal lactoferrin helps distinguish sinusitis from colds.
PMCID: PMC87198  PMID: 10921988
10.  High Titers of IgE Antibody to Dust Mite Allergen and the Risk for Wheezing Among Asthmatic Children Infected with Rhinovirus 
The relevance of allergic sensitization, judged by titers of serum IgE antibodies, to the risk of an asthma exacerbation caused by rhinovirus is unclear.
To examine the prevalence of rhinovirus infections in relation to the atopic status of children treated for wheezing in Costa Rica, a country with an increased asthma burden.
The children enrolled (n=287) were 7 through 12 years old. They included 96 with acute wheezing, 65 with stable asthma, and 126 non-asthmatic controls. PCR methods, including gene sequencing to identify rhinovirus strains, were used to identify viral pathogens in nasal washes. Results were examined in relation to wheezing, total IgE, allergen-specific IgE antibody, and levels of expired nitric oxide (FENO).
Sixty-four percent of wheezing children compared to 13% of children with stable asthma and 17% of the non-asthmatic controls tested positive for rhinovirus (p<0.001 for both comparisons). Among wheezing subjects, 75% of the rhinoviruses detected were Group C strains. High titers of IgE antibodies to dust mite allergen (especially Dermatophagoides sp) were common and correlated significantly with levels of total IgE and FENO. The greatest risk for wheezing was observed among children with titers of IgE antibodies to dust mite ≥17.5 IU/ml who tested positive for rhinovirus (odds ratio for wheezing: 31.5; 95% CI 8.3–108, p<0.001).
High titers of IgE antibody to dust mite allergen were common and significantly increased the risk for acute wheezing provoked by rhinovirus among asthmatic children.
PMCID: PMC3792652  PMID: 22560151
acute asthma; dust mite specific IgE; emergency room visits; viral respiratory tract infections; rhinovirus strain C; total serum IgE; inhaled allergens; exhaled nitric oxide (FENO)
11.  Galactose-α-1,3-Galactose–Specific IgE Is Associated with Anaphylaxis but Not Asthma 
Rationale: IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose (α-gal) are common in the southeastern United States. These antibodies, which are induced by ectoparasitic ticks, can give rise to positive skin tests or serum assays with cat extract.
Objectives: To evaluate the relationship between IgE antibodies to α-gal and asthma, and compare this with the relationship between asthma and IgE antibodies to Fel d 1 and other protein allergens.
Methods: Patients being investigated for recurrent anaphylaxis, angioedema, or acute urticaria underwent spirometry, exhaled nitric oxide, questionnaires, and serum IgE antibody assays. The results were compared with control subjects and cohorts from the emergency department in Virginia (n = 130), northern Sweden (n = 963), and rural Kenya (n = 131).
Measurements and Main Results: Patients in Virginia with high-titer IgE antibodies to α-gal had normal lung function, low levels of exhaled nitric oxide, and low prevalence of asthma symptoms. Among patients in the emergency department and children in Kenya, there was no association between IgE antibodies to α-gal and asthma (odds ratios, 1.04 and 0.75, respectively). In Sweden, IgE antibodies to cat were closely correlated with IgE antibodies to Fel d 1 (r = 0.83) and to asthma (P < 0.001).
Conclusions: These results provide a model of an ectoparasite-induced specific IgE response that can increase total serum IgE without creating a risk for asthma, and further evidence that the main allergens that are causally related to asthma are those that are inhaled.
PMCID: PMC3326422  PMID: 22281828
α-gal; red meat allergy; ticks; total serum IgE; ectoparasite

Results 1-11 (11)