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.
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.
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.
asthma; cats; inhalant allergens; Fel d 1; long-term tolerance
There has been no longitudinal study of the relation between concurrent exposure to dust mite allergen and endotoxin in early life and asthma and atopy at school age.
To examine the relation between exposure to dust mite allergen and endotoxin at age 2 to 3 months and asthma, wheeze, and atopy in high-risk children.
Birth cohort study of 440 children with parental history of atopy in the Boston metropolitan area.
In multivariate analyses, early exposure to high levels of dust mite allergen (≥10 μg/g) was associated with increased risks of asthma at age 7 years (odds ratio [OR], 3.0; 95% CI, 1.1-7.9) and late-onset wheeze (OR, 5.0; 95% CI, 1.5-16.4). Exposure to endotoxin levels above the lowest quartile at age 2 to 3 months was associated with reduced odds of atopy at school age (OR, 0.5; 95% CI, 0.2-0.9). In contrast with its inverse association with atopy, endotoxin exposure in early life was associated with an increased risk of any wheeze between ages 1 and 7 years that did not change significantly with time (hazard ratio for each quartile increment in endotoxin levels, 1.23; 95% CI, 1.07-1.43).
Among children at risk of atopy, early exposure to high levels of dust mite allergen is associated with increased risks of asthma and late-onset wheeze. In these children, endotoxin exposure is associated with a reduced risk of atopy but an increased risk of wheeze.
Early endotoxin exposure may be a protective factor against atopy but a risk factor for wheeze in high-risk children.
Endotoxin; dust mite; wheeze; atopy; asthma
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.
Prenatal exposure to both stress and aeroallergens (dust mite) may modulate the fetal immune system. These exposures may interact to affect the newborn immune response. We examined associations between prenatal maternal stress and cord blood total IgE in 403 predominately low-income minority infants enrolled in the Asthma Coalition on Community, Environment, and Social Stress (ACCESS) project. We also examined potential modifying effects of maternal atopy and maternal dust mite exposure.
The Crisis in Family Systems survey was administered to mothers prenatally and a negative life event domain score was derived to characterize stress. Dust mite allergen was quantified in dust from pregnant mothers’ bedrooms. Cord blood was analyzed for total IgE. Using linear regression, we modeled the relationship of stress with cord blood IgE and interactions of stress with dust mite and/or maternal atopy, adjusting for potential confounders.
Higher prenatal maternal stress (β=0.09; P=0.01) was associated with increased cord blood IgE. The interactive effects between stress and dust mite groups (high vs. low) were significantly different for children of atopic vs. nonatopic mothers (p for three-way interaction =0.005). Among children of atopic mothers, the positive association between stress and IgE was stronger in the high dust mite group. In children of mothers without a history of atopy, the positive association between stress and IgE was most evident in the low allergen group.
Prenatal stress was independently associated with elevated cord blood IgE. Mechanisms underlying stress effects on fetal immunomodulation may differ based on maternal atopic status.
Allergens; cord blood IgE; dust mite; prenatal stress; urban
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.
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.
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.
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.
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.
Anaphylaxis; urticaria; food allergy; galactose-α-1; 3-galactose; cross-reactive carbohydrate determinant
Cat ownership is inversely associated with atopy and asthma in some areas of the world, but the relevance of cat ownership to allergic disease in the inner city is less known.
We sought to evaluate the relationship between cat ownership and the development of early sensitization and wheeze.
By using a prospective birth cohort study, Dominican and African American mothers living in New York City underwent repeated questionnaires about their child from birth to age 5 years. Sera collected from children at ages 2 (n = 323), 3 (n = 336), and 5 (n = 242) years were assayed for anti-cat IgE and anti–Fel d 1 IgG antibodies.
Cat ownership was a significant risk factor for the development of anti-cat IgE by age 2 years (risk ratio [RR], 6.4; 95% CI, 1.9-22) but not for anti-cat IgE development between the ages of 2 and 5 years (RR, 0.88; 95% CI, 0.24-2.3). Current wheeze was significantly more common among those children with anti-cat IgE at ages 3 (RR, 3.5; 95% CI, 2.1-6.0) and 5 (RR, 3.4; 95% CI, 2.3-4.9) years. Cat ownership was inversely associated with current wheeze at age 5 years among children without anti-cat IgE (RR, 0.26; 95% CI, 0.083-0.81). Among children with anti-cat IgE, a similar trend was observed (RR, 0.57; P = .044, Fisher exact test), although one with borderline statistical significance.
Despite a positive association with sensitization, cat ownership in this inner-city cohort was inversely associated with wheeze, potentially suggesting an IgE-independent protective mechanism in this community.
Cat; asthma; allergy; wheeze; inner-city; rhinitis; IgE; IgG; Fel d 1
The IgE response to pollen allergens often includes IgE antibodies specific for glycosylation motifs on the pollen proteins. These oligosaccharides are present on many different species and are known as cross-reactive carbohydrate determinants. However, IgE antibodies to plant-derived cross-reactive carbohydrate determinants seem to have only minor clinical significance and have not been related to anaphylaxis. Recently, two novel forms of anaphylaxis have become apparent in the southeastern United States: 1) reactions during the first infusion of the monoclonal antibody cetuximab and 2) adult-onset delayed anaphylaxis to red meat. Detailed investigation of serum antibodies established that in both cases, the patients had IgE antibodies specific for the mammalian oligosaccharide galactose alpha-1, 3-galactose. Identification of these cases is helpful in avoiding infusion reactions to cetuximab or recommending specific avoidance of meat derived from mammals. However, the current evidence does not fully resolve why these IgE antibodies are so common in the Southeast or why the anaphylactic or urticarial reactions to red meat are delayed.
Anaphylaxis; Oligosaccharides; Cross-reactive Carbohydrate Determinants; Red Meat; IgE to Alpha-Gal
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).
anaphylaxis; cross-reactive carbohydrate determinant (CCD); alpha-gal; glycosylation
Why are the prevalence and severity of asthma increasing? Platts-Mills looks at the key studies that can help to anwer this important question
In an area with high exposure, grass pollen specific IgE can contribute to total IgE. This allergen specific characteristic is relevant to understanding relationships between the immune response and clinical allergic disease.
inhalant allergens; specific antibodies; total IgE; wheezing
The inappropriate closure of the vocal cords is characteristic of vocal cord dysfunction (VCD). These patients present with wheezing and frequently receive a misdiagnosis of asthma.
To demonstrate the ability of computed tomography (CT) scored for the presence and extent of sinus disease and markers of inflammation to distinguish patients with VCD from patients with asthma.
Comparisons of 13 patients with VCD were made to 77 patients presenting to the emergency room with acute asthma, 31 non-acute asthmatic patients, and 65 nonasthmatic controls. Evaluation consisted of exhaled nitric oxide gas (eNO), circulating eosinophils, and total serum immunoglobulin (Ig)E, as well as the sinus CT scan.
Extensive sinus CT changes were present in 23 of 74 acute asthmatic patients, 5 of 29 non-acute asthmatic patients, and 2 of 59 nonasthmatic controls. In addition, absolute eosinophil counts, eNO, and total IgE were significantly elevated among the asthmatic patients. Sinus symptoms reported by questionnaire did not predict sinus CT findings. Among the patients with VCD, none had extensive sinus disease. They also had normal eNO, low IgE, and normal eosinophil count. Five of the patients presenting to the emergency room who were identified as acute asthmatic were identified with VCD by laryngoscopy and were all characterized by the absence of significant inflammation on their sinus CT scan, low IgE, and normal eosinophil count.
Among patients presenting with intermittent or reversible airway obstruction, patients with VCD can be distinguished from asthma by minimum or absence of inflammation in their sinuses as shown by CT scan. Clinical symptom scores are not predictive of presence or extent of sinus disease in most cases.
We have observed patients clinically allergic to red meat and meat-derived gelatin.
We describe a prospective evaluation of the clinical significance of gelatin sensitization, the predictive value of a positive test and an examination of the relationship between allergic reactions to red meat and sensitization to gelatin and alpha-Gal.
Adult patients evaluated 1997-2011 for suspected allergy/anaphylaxis to medication, insect venom or food were skin tested with gelatin colloid. In vitro (ImmunoCap) testing was undertaken where possible.
Positive gelatin tests were observed in 40/1335 individuals; 30/40 patients with red meat allergy (12 also clinically allergic to gelatin); 2/2 with gelatin colloid anaphylaxis; 4/172 with idiopathic anaphylaxis (all responded to intravenous gelatin challenge of 0.02 to 0.4g); 4/368 with drug allergy. Testing was negative in all patients with venom allergy (n=241), non-meat food allergy (n=222), and miscellaneous disorders (n=290). ImmunoCap was positive to alpha-Gal in 20/24 meat allergics and in 20/22 with positive gelatin skin tests. The results of gelatin skin testing and anti-alpha-Gal IgE were strongly correlated (r=0.46; P<0.01). Alpha-Gal was detected in bovine gelatin colloids at concentrations of ~ 0.44 to 0.52ug/gm gelatin by inhibition radioimmunoassay.
Most patients allergic to red meat were sensitized to gelatin and a subset was clinically allergic to both. The detection of alpha-Gal in gelatin and correlation between the results of alpha-Gal and gelatin testing raises the possibility that alpha-Gal IgE may be the target of reactivity to gelatin. The pathogenic relationship between tick bites and sensitization to red meat, alpha-Gal and gelatin (with or without clinical reactivity) remains uncertain.
food allergy; anaphylaxis; red meat; alpha-galactose; gelatin; colloid
We assessed the accuracy of questionnaire reports of cat and dog ownership and presence of cockroaches in predicting measured allergen concentrations in house dust. We collected dust samples in the homes of 932 newborns living in New England. Dust samples were taken from the main living area and the infant's bedding. Allergen content of house dust was measured by enzyme-linked immunosorbent assays (ELISA) and related to questionnaire information on past and current cat and dog ownership and presence of cockroaches. Allergen levels were dichotomized using the limit of detection and the following cut points: 1.0 microg/g and 8.0 microg/g for cat, 2.0 microg/g and 10.0 microg/g for dog, and 2 U/g and 8 U/g for cockroach allergen. For the upper cut point, both specificity and sensitivity of questionnaire-reported cat and dog ownership and presence of cockroaches were high. For the limit of detection and lower cut point, specificity was high (> 80%), whereas sensitivity was low, particularly for current cat and dog ownership (21-60%). Taking pet ownership during the preceding 2 years into account increased the sensitivity by 10%, but it remained relatively poor. In conclusion, questionnaire-reported pet ownership and presence of cockroaches predicts allergen levels above the upper cut point but is a relatively poor measure of allergen exposure above the limit of detection and the lower cut point. Knowledge of past pet ownership can improve pet allergen exposure assessment by means of questionnaire. However, for epidemiologic purposes, measured concentrations of allergens are necessary.
Home exposures to aeroallergens are an important environmental factor in allergic sensitization and in the development and exacerbation of asthma. We assessed variations in home concentrations of dust mite, cockroach, cat, and dog allergens in dust collected in the main living areas of asthmatics' homes by family income, mother's education, dwelling type, population density, household population density, and ethnicity in Connecticut and south-central Massachusetts. Dust samples were collected at the time of home interview in 999 homes as part of an ongoing longitudinal birth cohort study of 1,002 infants and their asthmatic siblings. The analysis employed lower and upper cut points for group 1 dust mite (> or = 2.0 microg/g and > or = 10 microg/g), cockroach (> or = 1.0 U/g and > or = 4.0 U/g), cat (> or = 1.0 microg/g and > or = 8.0 ug/g), and dog (> or = 2.0 microg/g and > or = 10.0 microg/g) allergens. Subject residences were geocoded to assess population density from the U.S. Census, and multiple logistic regression was used to control for confounding. The portion of homes at the lower cut point for dust mite, cockroach, cat, and dog allergens were 46.9%, 24.9%, 42.2%, and 35.6%, respectively; the upper cut point for each of the allergens was reached in 22.4%, 13.4%, 21.0%, and 22.9% of the homes, respectively. In all, 86.0% of the homes had at least one allergen at the lower cut point, and 58.0% had at least one allergen at the upper cut point. Forty-nine percent of the homes had two or more allergens at the lower cut point, and 19.7% had two or more allergens at the upper cut point. Higher education of the mother, higher household income, living in a single-family home in a less densely populated area with fewer people per room, and being a white household were associated with elevated dust mite, cat, and dog allergens and low cockroach allergen. In contrast, low income, living in a multifamily home in a high population density area with a higher occupancy rate per room, and being a Hispanic or black household were associated with elevated cockroach allergens and low concentrations of dust mite, cat, and dog allergens. Although the presence of an individual allergen is more likely associated with one or more socioeconomic or ethnic factors, most homes typically have multiple allergen burdens in excess of concentrations thought to be associated with sensitization and exacerbation of asthma. Mite and cockroach allergens have distinct and opposite associations with socioeconomic factors and population density.
While some evidence suggests that antigen sensitization may begin prenatally, the influence of maternal allergen exposure during pregnancy has not been fully elucidated.
We examined the relationship between prenatal maternal aeroallergen exposure and cord blood total immunoglobulin E (IgE) and the potential mediating/indirect effect of maternal immune response.
This study was performed in 301 mother-infant pairs enrolled in the Asthma Coalition on Community, Environment, and Social Stress (ACCESS) project, a study examining the effects of prenatal and early life social and physical environmental exposures on urban asthma risk. Dust samples collected prenatally from mothers’ bedrooms were analyzed for cockroach and dust mite allergens. Cord blood was analyzed for total IgE and maternal serum collected during pregnancy for total and specific IgE. We assessed the relationship between prenatal exposure and cord blood total IgE and the potential mediation effect adjusting for maternal age, race, education, smoking status and dust collection season; and child’s gender and season of birth.
In multivariate models, elevated prenatal dust mite levels (> 0.2 µg/g) increased cord blood IgE concentrations by 29% (p=0.08) and continuous dust mite concentration was associated with a significant non-linear increase in cord blood IgE (p=0.02). Elevated prenatal exposure to cockroach allergen (> 2 U/g) was not associated with cord blood IgE, but showed a significant indirect relationship through maternal total IgE (β=0.23; 95% CI: 0.08, 0.41).
These results demonstrate that maternal prenatal exposure to household allergens may impact cord blood IgE albeit the underlying mechanism may be allergen-specific.
Maternal prenatal inhalant allergen exposure may precipitate infant immune response although the pathway of the effect may differ by allergen.
Prenatal exposure to dust mite was associated with increased cord blood total IgE whereas the relationship between prenatal cockroach exposure and total cord blood IgE was only observed through the indirect effect of maternal allergic response.
Allergen; Dust Mite; Cockroach; Maternal; Prenatal; Cord Blood; Immunoglobulin E; IgE; Urban
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.
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.
α-gal; red meat allergy; ticks; total serum IgE; ectoparasite
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.
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.
Serum assays were carried out using biotinylated proteins and extracts bound to a streptavidin ImmunoCAP.
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).
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.
ticks; anaphylaxis; oligosaccharide; alpha-gal; IgE antibody to CCD
Cetuximab, a chimeric mouse–human IgG1 monoclonal antibody against the epidermal growth factor receptor, is approved for use in colorectal cancer and squamous-cell carcinoma of the head and neck. A high prevalence of hypersensitivity reactions to cetuximab has been reported in some areas of the United States.
We analyzed serum samples from four groups of subjects for IgE antibodies against cetuximab: pretreatment samples from 76 case subjects who had been treated with cetuximab at multiple centers, predominantly in Tennessee, Arkansas, and North Carolina; samples from 72 control subjects in Tennessee; samples from 49 control subjects with cancer in northern California; and samples from 341 female control subjects in Boston.
Among 76 cetuximab-treated subjects, 25 had a hypersensitivity reaction to the drug. IgE antibodies against cetuximab were found in pretreatment samples from 17 of these subjects; only 1 of 51 subjects who did not have a hypersensitivity reaction had such antibodies (P<0.001). IgE antibodies against cetuximab were found in 15 of 72 samples (20.8%) from control subjects in Tennessee, in 3 of 49 samples (6.1%) from northern California, and in 2 of 341 samples (0.6%) from Boston. The IgE antibodies were shown to be specific for an oligosaccharide, galactose-α-1,3-galactose, which is present on the Fab portion of the cetuximab heavy chain.
In most subjects who had a hypersensitivity reaction to cetuximab, IgE antibodies against cetuximab were present in serum before therapy. The antibodies were specific for galactose-α-1,3-galactose.