Peter W. Heymann

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

Abstract Background Viral respiratory tract infections and atopy are associated with attacks of wheezing during childhood. However, information about the relationship between viral infections and atopy among children whose attacks of wheezing lead to hospitalization is unclear. Objective To evaluate the prevalence of viral respiratory tract pathogens among infants and children hospitalized for wheezing and to analyze the results in relation to the patients age, atopic characteristics, and season of admission. Methods This was a case-control study of children (age 2 months to 18 years) admitted for wheezing to the University of Virginia Medical Center over a period of 12 months. Children without wheezing were enrolled as controls. Nasal secretions were evaluated for viral pathogens by using cultures, PCR tests, and antigen detection. Total IgE and specific IgE antibody to common aeroallergens was measured in serum. Results Seventy percent of children hospitalized for wheezing before age 3 years (n=79) were admitted between December and March, whereas 46% of children age 3 to 18 years (n=54) were hospitalized between September and November. Among children younger than 3 years, viral pathogens were detected in 84% (66/79) of wheezing children and 55% (42/77) of controls (P < .001). Respiratory syncytial virus was the dominant pathogen during the winter months, but rhinovirus was more common during other months. Total serum IgE levels were generally low, and values from wheezing and control subjects overlapped considerably. Among children 3 years and older, 61% (33/54) of subjects admitted for wheezing tested positive for virus (predominantly rhinovirus), compared with 21% (12/56) of controls (P < .001). The total serum IgE values among wheezing children (geometric mean, 386 IU/mL; 95% CI, 259-573) were substantially elevated compared with those of controls (geometric mean, 38 IU/mL; 95% CI, 26-56; P < .001). A significantly higher percentage of wheezing children compared with controls was sensitized to at least 1 of the inhaled allergens tested: 84% (36/43) compared with 33% (15/45; P < .001). The atopic characteristics of wheezing children who tested positive or negative for virus were similar. Conclusions Viral infections were the dominant risk factor for wheezing among children hospitalized before 3 years of age. By comparison, a large majority of the wheezing children age 3 to 18 years had striking atopic characteristics that may be critical as a risk factor for hospitalization and an adverse response to viral infections, especially infections caused by rhinovirus.

Antigenic and structural analysis of group II allergens (Der f II and Der p II) from house dust mites (Dermatophagoides spp)

Monoclonal antibody affinity chromatography was used to purify two homologous mite allergens, Der f II from Dermatophagoides farinae and Der p II from D. pteronyssinus. They have the same molecular weight (MW) (15 kd) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, they have similar amino acid compositions, and their N-terminal amino acid sequences differ in only four of the first 35 residues. An excellent correlation was observed between IgE antibody to Der f II and Der p II measured in sera from 65 mite-allergic patients (r = 0.94; p less than 0.001) and between quantitative intradermal skin tests to both allergens. A third allergen (Der f III, MW 29 kd) was purified from D. farinae by repeated gel filtration. In sera from 51 mite-allergic patients, IgE antibody to Der f II, Der f III, and previously purified Der f I (MW 24 kd) was detected in 92%, 16%, and 78% of the sera by radioimmunoassay, respectively. Most patients, 41/51 (80%), demonstrated IgE antibody to more than one allergen. With monoclonal antibodies fully cross-reactive with Der f II and Der p II, a two-site immunoassay was developed for measuring absolute quantities (nanograms or micrograms) of these allergens. In extracts rich in mite-fecal material (n = 5), Der f I and Der p I (group I allergens) and Der f II and Der p II (group II allergens) were measured in ratios of 11:1 to 35:1. Lower ratios (1.1:1 to 7:1) were observed in mite body extracts (n = 6). These experiments clearly define a second group of major dust mite allergens that demonstrate extensive structural and antigenic homology.

International consensus on (ICON) pediatric asthma

Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference. The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. To achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with healthcare professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re‐evaluate and fine‐tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent of chronic treatment. There is a trend toward considering phenotype‐specific treatment choices; however, this goal has not yet been achieved.

Is the hygiene hypothesis still a viable explanation for the increased prevalence of asthma

The hygiene hypothesis states that a reduced exposure to allergens in early life is solely implicated in the growing propensity for allergy sensitization. Important elements of the hypothesis include helminth infection, exposure to endotoxins, exposure to pets and growing up on a farm. However, the hygiene hypothesis alone does not provide an adequate explanation for the observed increase in allergic disease. For example, in North American inner cities, asthma is increasing among children who live in very poor housing, which might be assumed to be somewhat dirty. In order to explain the increase in asthma, we need to take a broader view and also consider alterations related to the adoption of a western lifestyle. It has been suggested that lifestyle changes related to obesity (e.g. a change in diet) are associated with asthma. Other changes include a progressive decrease in physical activity. This lifestyle factor seems to correlate best with the recent increase in asthma. Clearly, the link between physical activity and asthma needs to be investigated in more detail.

Airborne dust mite allergens : Comparison of group II allergens with group I mite allergen and cat-allergen Fel d I

The form in which allergens become airborne is important because it may influence both symptoms caused by allergen exposure and methods used to reduce exposure. The group I allergens from dust mites only become airborne during disturbance and fall rapidly, which is in keeping with their being carried on fecal pellets. Their mean size is approximately 20 microns in diameter. By contrast, the cat-allergen Fel d I is airborne on particles varying from greater than 10 to less than 2 microns in diameter, some of which remain airborne even without disturbance. A second group of mite allergens, molecular weight 14,000, are equally important and are associated predominantly with mite bodies. With a monoclonal antibody-based assay and a cascade impactor, we have investigated the form in which group II mite allergens become airborne. The results reveal that these allergens only become airborne during disturbance and that they fall within 15 minutes. However, the mean size of particles carrying group II allergens appears to be slightly smaller than the mean size of particles carrying group I allergens. In addition, the quantities of group II allergen becoming airborne during disturbance (mean, 26 ng/m3) could not be explained by the quantity found in fecal particles. Thus, group II mite allergens become airborne in a form quite distinct from cat allergens and very similar to group I mite allergens; however, it appears unlikely that fecal particles are the main form in which group II allergens become airborne.

Airborne allergens associated with asthma: Particle sizes carrying dust mite and rat allergens measured with a cascade impactor

Patients with asthma may develop acute symptoms after exposure to domestic or laboratory animal allergens; however, they are usually not aware of a direct relationship between their acute attacks and exposure to pollen or dust mite allergens. The present experiments were designed to study whether the differences in symptoms could be explained by differences in the number or size of particles carrying airborne allergens. Airborne particles were collected with a filter or on the stages of a cascade impactor, and allergens were measured by use of inhibition radioimmunoassays. In rat rooms and during disturbance of rat litter, a large proportion of rat urinary allergen (45.9%) was collected on the second stage of the impactor (mean size approximately 7 microns diameter). When sampled 15 to 35 minutes after disturbance, 16% of these medium-sized particles were still airborne. By contrast, during disturbance of house dust, a significantly larger proportion of dust mite, antigen P1 (80.6 +/- 11.8%; p less than 0.001) was collected on the first stage of the impactor, and in keeping with the apparent size of these particles (diameter greater than 10 microns), very little of this allergen (less than 4%) was still airborne when sampled 15 to 35 minutes after disturbance. With nebulized diluted rat urine, approximately 75% of the allergen was collected on the fourth and final stages of the cascade impactor in keeping with the expected size, 0.5 to 3 microns in diameter. These results demonstrate that natural exposure to both allergens is strikingly different from the conditions used for bronchial provocation.(ABSTRACT TRUNCATED AT 250 WORDS)

The relevance of allergen exposure to the development of asthma in childhood

Abstract Sensitization to 1 or more of the common indoor allergens has been consistently associated with asthma among children and young adults (odds ratios for asthma, 3-18). For dust mite and cockroach allergens, there is a dose response relationship between domestic exposure and sensitization. Given that allergen provocation can induce many of the features of asthma, the findings strongly suggest that there is a causal relationship between allergen exposure in the home and asthma. However, it remains unclear at what time the critical exposure occurs (ie, in infancy or later) and what role allergen exposure has played in the increasing prevalence and severity of asthma. Objective evidence of an immune response to allergens is generally not present until after 2 years of age. Viral infections play several different roles in asthma in childhood. In infancy, respiratory syncytial virus infection can induce bronchiolitis and set up recurrent wheezing over the next few years. However, the risk factors for this are maternal smoking and small lungs at birth, rather than allergy. By contrast, the role of rhinovirus in precipitating attacks in children and young adults is strongly associated with allergy. Thus the likely scenario is that allergen exposure over the first few years of life induces sensitization (ie, TH2 cells and IgE antibodies). Continuing exposure can maintain inflammation in the nose and lungs. However, many other factors contribute to wheezing such that there is no simple relationship between allergen exposure and asthma. Nonetheless, it is clear that the changes that have increased asthma have acted on allergic children. (J Allergy Clin Immunol 2000;105:S503-8.)

Epidemiology of the Relationship between Exposure to Indoor Allergens and Asthma

A very high prevalence of immediate hypersensitivity to common indoor allergens can be demonstrated among children and young adults, with asthma. Recent progress in the immunochemistry of cat, dust mite and cockroach allergens has made it possible to measure exposure to these allergens and to start to define threshold levels of exposure which increase the risk of sensitization and symptomatic asthma. Indeed, it is already clear that exposure to greater than 2 micrograms group I dust mite allergen (or 100 mites) per gram of dust increases the risk of children developing sensitization and asthma. Furthermore, from studies on patients presenting to emergency rooms with asthma, it is clear that the risk of sensitization to allergens derived from cats or cockroaches or grass pollen is restricted to patients who are exposed to high levels of these allergens. Given the increasing morbidity and mortality of asthma it is clear that therapeutic efforts should be focused on identifying relevant allergens and advising patients about techniques for reducing exposure.

Natural exposure and serum antibodies to house dust mite of mite-allergic children with asthma in Atlanta

Pyroglyphid mites in house dust are important allergens associated with asthma in Europe, but comparable studies of house dust mites in the homes of patients with asthma have not been done in the United States. We examined the distribution of mites and mite allergen in the houses of 20 mite-sensitive children with asthma in Atlanta and measured IgE antibodies to mite allergens in their sera. One or more dust samples from bedding, bedroom floor, television room floor, or television room furniture from 17/20 houses contained greater than 10,000 ng of antigen P1 equivalent per gram of fine dust; amounts ranged from 280 to 230,400 ng/gm. Allergen levels were higher in dust samples from furniture and bedding than from floors. Dust samples obtained from houses in June to September had more mites and mite allergen than those houses sampled in March to April; relative humidity in the room also was higher in June to September. Mite numbers and allergen in floor and furniture samples were correlated with relative humidity in the room and were high when relative humidity was greater than 50%; antigen P1 equivalent was greater than 10,000 ng/gm in 21/39 such samples. Dermatophagoides pteronyssinus was present in all houses and dominant in 11/20. D. farinae was found in 17 houses and was dominant in six. All children studied had high IgE antibody with either D. farinae or D. pteronyssinus RAST; 16 of the 20 children also had IgE to antigen P1. It is likely that the IgE antibody responses in these 20 children with asthma were a direct result of exposure to high levels of mite allergen.(ABSTRACT TRUNCATED AT 250 WORDS)

Monoclonal antibodies to group II Dermatophagoides spp. allergens: Murine immune response, epitope analysis, and development of a two-site ELISA

BACKGROUND Group II allergens are a major cause of sensitization in patients allergic to mites. To facilitate the antigenic analysis of group II allergens and to develop improved methods of allergen detection, we compared IgG anti-group II antibody responses in inbred mouse strains and raised a panel of monoclonal antibodies (mAbs). METHODS IgE antibody responses were compared by antigen-binding radioimmunoassay. Epitope specificity of the mAbs was analyzed by two-site binding assays and by cross-inhibition radioimmunoassays. RESULTS Comparison of polyclonal IgG antibody responses in five BALB congenic strains showed that H-2d mice had poor responses, whereas H-2b and H-2k mice had strong, cross-reactive, IgG anti-group II responses. The specificities of nine anti-Der p II IgE mAbs raised in A/J mice were compared with specificities of seven mAbs produced previously. Most mAbs (11 of 16) recognized common epitopes on Der p II and Der f II: three were specific to Der p II, and two showed high binding to Der f II. Epitope analysis showed that the mAbs defined four cross-reactive, nonoverlapping sites on the group II allergens. Binding of several combinations of mAbs was compared, and a two-site ELISA for group II antigens was developed. Linear regression analysis showed an excellent correlation between results of this assay and group II radioimmunoassay of house dust samples (n = 40, r = 0.85, p < 0.001). CONCLUSIONS There are multiple cross-reactive B-cell epitopes on group II allergens. The group II ELISA has several important applications, including assessment of environmental allergen exposure, monitoring of the efficacy of avoidance procedures, and standardization of commercial mite allergen extracts.