Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study.

BACKGROUND: 3-year subcutaneous specific immunotherapy (SIT) in children with seasonal allergic rhinoconjunctivitis reduced the risk of developing asthma during treatment and 2 years after discontinuation of SIT (5-year follow-up) indicating long-term preventive effect of SIT. OBJECTIVE: We evaluated the long-term clinical effect and the preventive effect of developing asthma 7-years after termination of SIT. METHODS: One hundred and forty-seven subjects, aged 16-25 years with grass and/or birch pollen allergy was investigated 10 years after initiation of a 3-year course of SIT with standardized allergen extracts of grass and/or birch or no SIT respectively. Conjunctival provocations were performed outside the season and methacholine bronchial provocations were performed during the season and winter. Asthma was assessed by clinical evaluation. RESULTS: The significant improvements in rhinoconjunctivitis and conjunctival sensitivity persisted at the 10-year follow-up. Significantly less actively treated subjects had developed asthma at 10-year follow-up as evaluated by clinical symptoms [odds ratio 2.5 (1.1-5.9)]. Patients who developed asthma among controls were 24/53 and in the SIT group 16/64. The longitudinal treatment effect when adjusted for bronchial hyper-responsiveness and asthma status at baseline including all observations at 3, 5 and 10 years follow-up (children with or without asthma at baseline, n = 189; 511 observations) was statistically significant (P = 0.0075). The odds ratio for no-asthma was 4.6 95% CI (1.5-13.7) in favor of SIT. CONCLUSION: A 3-year course of SIT with standardized allergen extracts has shown long-term clinical effects and the potential of preventing development of asthma in children with allergic rhinoconjunctivitis up to 7 years after treatment. CLINICAL IMPLICATION: Specific immunotherapy has long-term clinical effects and the potential of preventing development of asthma in children with allergic rhino conjunctivitis up to 7 years after treatment termination.

Clinical efficacy and safety of sublingual immunotherapy with tree pollen extract in children.

BACKGROUND: Subcutaneous immunotherapy has been the principal approach of immunotherapy in the treatment of allergic diseases. Several clinical studies with birch, alder or hazel pollen extract conducted as subcutaneous immunotherapy have been published suggesting a well-tolerated and clinically effective treatment. Only a few clinical studies of sublingual immunotherapy (SLIT) with these allergens have been published. This study investigated the clinical efficacy, safety and dose-response relationship of SLIT in children suffering from rhinoconjunctivitis with/without asthma. METHODS: Eighty-eight children (5-15 years) with a history of tree pollen-induced allergic rhinoconjunctivitis with/without seasonal asthma for >or=2 years were included. Allergy to tree pollen was confirmed by positive skin-prick test, positive specific IgE and positive conjunctival provocation test. The extract used was a glycerinated mixture of Betula verrucosa, Corylus avellana and Alnus glutinosa 100,000 SQ-U/ml. Children were randomized into three groups receiving SLIT 5 days a week for up to 18 months; dose group 1: accumulated weekly dose of 24,000 SQ-U; dose group 2: accumulated weekly dose of 200,000 SQ-U; and placebo. RESULTS: In the birch pollen season, dose group 2 showed a significant reduction of symptom (P = 0.01) and medication scores (P = 0.04) compared with placebo. Dose group 1 showed a significant reduction of symptom scores (P = 0.03). There were no statistical differences between dose groups 1 and 2. All children tolerated the treatment well. CONCLUSION: SLIT with tree pollen extract provided dose-dependent benefits in tree pollen-allergic children in terms of significantly reduced symptoms and medication use. The treatment was well tolerated.

Five-year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children.

BACKGROUND: A 3-year course of specific immunotherapy (SIT) in children with hay fever to grass and/or birch pollen significantly reduced the risk of developing asthma. To investigate the long-term preventive effect, we performed a follow up--2 years after termination of immunotherapy. METHODS: A total of 183 children, aged 6-14 years with grass and/or birch pollen allergy could be investigated 2 years after discontinuation of SIT or no treatment. Conjunctival provocation tests (CPTs) and methacholine bronchial provocation tests were carried out during the season and winter after 5 years. The development of asthma was assessed by clinical evaluation. RESULTS: The significant improvement in hay fever and CPT results observed after 3 years of SIT persisted at the 5-year follow-up. No difference in bronchial responsiveness to methacholine was found after 5 years because of spontaneous improvement during the follow-up period in the control patients. The immunotherapy-treated children had significantly less asthma after 5 years as evaluated by clinical symptoms [odds ratio 2.68 (1.3-5.7)] in favor of SIT for prevention of development of asthma and significantly less patients reported an increase in asthma scores (P < 0.01). CONCLUSION: Immunotherapy for 3 years with standardized allergen extracts of grass and/or birch shows long-term clinical effect and preventive effect on development of asthma in children with seasonal rhinoconjunctivitis.

Does heredity modify the association between farming and allergy in children?

AIM: It has been suggested that living on a farm decreases the risk of childhood allergy, especially if farming involves livestock. The aim of this study was to examine the association between farming and allergy in children, and the influence of atopic heredity in this association. METHODS: The cross-sectional data of the 7981 children aged 13-14 y who participated in the Finnish ISAAC study between the years 1994 and 1995 were used to evaluate the association between farming and allergy. RESULTS: Living on a farm was associated with a decreased risk of current symptoms of allergic rhinoconjunctivitis among all children (aOR 0.79; 95% CI 0.63, 0.99), and with a decreased risk of hay fever, especially among those children with a parental history of hayfever (aOR 0.60; 95% CI 0.40-0.89, p = 0.072 for interaction). The children of farmers with a history of hay fever also had a decreased risk of current wheeze (aOR 0.38; 95% CI 0.12-1.24, p = 0.040 for interaction). No significant association was found between farming and either asthma or eczema. Children living on a farm with livestock had the lowest risk of allergic rhinoconjunctivitis (aOR 0.69), followed by those living on a farm without livestock (aOR 0.89) compared with the non-farming children (p-value for trend 0.024). CONCLUSION: Our results support the recent findings on a decreased risk of allergy among the children living on farms. A possible differential effect of parental history of hay fever on the relation of farming environment and the risk of allergic symptoms warrant further investigation.

Inpatient resource utilisation in younger (2-5 yrs) and older (6-14 yrs) asthmatic children in Finland.

Asthma is the most common chronic disorder among Finnish children, however, the economic burden of paediatric asthma in Finland has not yet been comprehensively evaluated. The objective of this study was to compare inpatient resource utilisation between younger (2-5 yrs) and older children (6-14 yrs) with asthma in Finland. A national database of inpatient resource utilisation was applied to determine use of hospital services among children with asthma in 1999. Regional estimates of charges were combined with hospitalisation episodes to determine total inpatient cost. The results indicate that younger asthmatic children consume 3-times more inpatient resources per capita. Incidence of first admissions because of asthma was 3-times higher in younger children. Hospitalisation and rehospitalisation rates were also 3- and 4-times higher, respectively. The total annual inpatient cost of asthma in children aged 2-5 and 6-14 yrs was Euro 1.98 million with each group accounting for Euro 1.12 million and Euro 0.86 million, respectively. Regional and age-related differences in hospitalisation rates and costs were likely related to variable clinical practice on the primary level, difficulties with diagnosis and compliance among younger children.

Diagnosis of food allergy in Finland: survey of pediatric practices.

Food-related symptoms are common in the first years of life, and food allergy should be diagnosed using an elimination challenge test. We surveyed Finnish hospital-based pediatricians using a self-completion questionnaire to ascertain the current clinical practice: 24 of the 25 pediatricians (representing 24 of 25 hospitals) so approached gave evaluable responses. Food allergies were diagnosed using a clinical elimination challenge test in patients with suspected allergy to cow's milk or cereals (wheat, rye, barley, oats). Of the 24 departments, four reported that they performed challenge in all patients before diagnosis was confirmed, and 14 performed challenge in most patients before diagnosis was confirmed. The duration of the challenge varied from 0.5 to 7 days (median 4 days). A 1-week challenge was used in eight hospitals. The double-blind placebo-controlled challenge was used in seven of the hospitals, and in none routinely. Altogether, 16 of the respondents agreed that there is a need to establish clinical guidelines for the diagnosis of food allergy. In conclusion, despite a long tradition of medical education on the subject of food allergy, practices vary for its diagnosis. There is therefore a requirement for appropriate clinical guidelines.

Prevalence of allergic rhinitis and atopic dermatitis among children in four regions of Finland.

The primary aim of the study was to evaluate the prevalences of allergic rhinitis and atopic dermatitis and their regional differences among Finnish children. The secondary objective was to determine whether the responses to the questions used are affected by the pollen season if asked during such a season. In 1994-5, the self-reported prevalence of allergic symptoms in four regions of Finland was studied among 11,607 schoolchildren aged 13-14 years, as part of the International Study of Asthma and Allergies in Childhood (ISAAC). The prevalence of rhinoconjunctivitis during the preceding year was 16% in eastern Finland (Kuopio County, n=2821), 23% in southern Finland (Helsinki area, n=2771), 15% in southwestern Finland (Turku and Pori County, n=2983), and 16% in northern Finland (Lapland, n=3032). The respective prevalences of flexural dermatitis were 15%, 19%, 16%, and 18%. The surveys were performed in winter, except in the Helsinki area where the survey was carried out mainly in the spring pollen season. Among the children studied in autumn in Helsinki, the prevalence of rhinoconjunctivitis was 19% and that of flexural dermatitis 17%. In multivariate analysis, flexural dermatitis was slightly more common in Lapland than in all other areas. In contrast, no significant differences were found in rhinoconjunctivitis. The prevalences of both disorders were twice as high in girls as in boys. In conclusion, regional differences in the prevalence of allergic rhinitis and atopic dermatitis were small in our country, and the prevalence figures were rather similar to those reported from other European countries. Almost half of the children had suffered from at least one atopic disorder, and over one-third had had symptoms in the past year. A clear season-of-response effect was observed; the prevalence of rhinoconjunctivitis was 25% when studied during the pollen seasons in the Helsinki area.

IgE, IgA, and IgG responses to common yeasts in atopic patients.

This study was undertaken to analyze the differences in exposure and sensitization to five common environmental yeasts. The responses of IgG, IgA, and IgE to Candida albicans, C. utilis, Cryptococcus albidus, Rhodotorula rubra, and Saccharomyces cerevisiae and purified S. cerevisiae enolase were analyzed by immunoblotting (IgE-IB), and the cross-reactivity of their IgE-binding components by IgE-IB inhibition. Twenty atopic subjects, with asthma, allergic rhinitis, or atopic dermatitis were included. In skin prick tests (SPT), 12 of the patients showed simultaneous reactivity to at least two of the five yeasts, four reacted to one of the yeasts, and four had no responses. Antigens run in SDS-PAGE and transferred to nitrocellulose were probed with enzyme-labeled IgA-, IgG-, and IgE-specific antibodies. The IgE immunoblotting revealed most IgE-binding bands in C. albicans (11 bands) followed by C. utilis (eight bands), S. cerevisiae (five bands), R. rubra (five bands), and Cr. albidus (four bands). Six of the IgE-binding bands of C. albicans and C. utilis shared molecular weight, and only two bands shared molecular weight with other yeasts. These were the 46-kDa band, shared by all five yeasts, and a 13-kDa band shared by four yeasts. Prominent IgE binding was seen to a 46-kDa band of C. albicans (seven patients), C. utilis (five patients), and S. cerevisiae (one patient) and to corresponding weak bands of Cr. albidus and R. rubra (one patient). The possible cross-reactivity of the 46-kDa band was analyzed by IgE-IB inhibition and densitometry, revealing clear C. albicans inhibition of C. utilis (80%) and enolase (98%) (autoinhibition 100%). The strongest IgG responses were seen against S. cerevisiae and C. albicans. The responses were mainly against mannans of C. albicans and S. cerevisiae, suggesting that most of the exposure is to these yeasts. Yeasts with different types of exposure, from saprophytic growth on human mucous membranes to exposure by air and food, were shown to cross-react at the allergenic level. Atopic patients primarily sensitized by C. albicans and S. cerevisiae may develop allergic symptoms by exposure to other environmental yeasts due to cross-reacting IgE antibodies.

In-house reference (IHR) preparation of Candida albicans allergen extract. A standardized extraction procedure.

A standardized, controlled procedure for preparation of an in-house reference (IHR) preparation of an allergen extract of Candida albicans is described. The procedure, based on previous studies of allergens of C. albicans, is designed to yield a maximum of allergens in optimum extraction conditions and to provide a reference preparation for further extract production. The SDS-PAGE, IgE-immunoblotting, and crossed radioimmunoelectrophoresis (CRIE) analyses showed that the procedure is reproducible with acceptable batch-to-batch variation. The variation in the content of the most important allergens, namely, proteins with molecular weights of 46, 29, and 27 kDa in the pooled final batches, is acceptable (coeff. of variation < 15%), although in the intermediate batches of different strains, the coefficient of variation may occasionally exceed 20%. A comparison with other C. albicans allergen preparations used in our previous studies is also presented. The resulting extract can be used as a reference in further extract production and also in experimental in vitro and in vivo studies.

Prevalence of asthma symptoms in video and written questionnaires among children in four regions of Finland.

The aim of this study was to determine whether there are regional differences in the prevalence of childhood asthma in Finland. A secondary objective was to assess the concordance between a written and a video questionnaire on asthma symptoms. In 1994-1995, the self-reported prevalence of asthma symptoms in four regions of Finland was studied among 11,607 schoolchildren aged 13-14 yrs, as part of the International Study of Asthma and Allergies in Childhood (ISAAC). The ISAAC written and video (AVQ 3,0) questionnaires were administered in the school setting. The prevalences of any wheezing during the previous 12 months in the ISAAC video questionnaire were 10% in East Finland (Kuopio County, n=2,821), 12% in South Finland (Helsinki area, n=2,771), 12% in Southwest Finland (Turku and Pori County, n=2,983), and 11% in North Finland (Lapland, n=3,032). The prevalences in the ISAAC written questionnaire were 13, 20, 15, and 16%, respectively. The surveys were performed during winter, except in Helsinki where the survey was carried out mainly during the spring pollen season. During autumn, the prevalence in the written questionnaire in Helsinki was 16%. In multivariate analysis, boys had a lower prevalence than girls, and smokers a threefold higher prevalence than nonsmokers. In conclusion, the prevalence of childhood asthma is lower in Finland than in other European countries, and may be even lower in the eastern part of the country. In contrast to the results from some other European countries, prevalences were lower in the video than in the written questionnaire, which suggests that translating the word "wheezing" into other languages, including Finnish, may produce results that cannot be compared. The strong association of smoking with wheeze both in the video and written questionnaires should be considered in further analysis of the ISAAC study.

Cardiovascular autonomic regulation in asthmatic children evidenced by spectral analysis of heart rate and blood pressure variability.

The objective of the study was to investigate the features of cardiovascular and respiratory autonomic nervous regulation in asthmatic and control children. Cardiorespiratory reactivity was studied by continuous and non-invasive recording of the electrocardiogram, finger systolic arterial pressure (SAP) and flow-volume spirometry in supine and upright positions and during a deep breathing test in 19 children with bronchial asthma and 10 healthy control children (age 8-11 years). The periodic variability components of R-R intervals (the time between successive heart beats) and SAP in relation to respiration were assessed using spectral analysis techniques. Nine asthmatic children without beta2-agonist medication had a lower respiratory rate and larger high frequency (HF) variability of SAP than the controls, and 10 asthmatic children with beta2-agonist medication had greater low-frequency (LF) variability of SAP and LF/HF ratio of R-R intervals, but their respiratory rate did not differ from the controls. No intergroup differences were found in the postural change of variables. Stable bronchial asthma appears to increase respiratory-induced alterations in systolic blood pressure in children. Beta2-agonist medication, on the other hand, increases sympathetic cardiovascular activity in children with asthma.

Airborne birch pollen antigens in different particle sizes.

Two particle samplers for ambient air, situated together: a static size-selective bio-aerosol sampler (SSBAS) and a Burkard pollen and spore trap were compared in sampling intact birch pollen grains through one flowering period of Betula (a total of 44 days). The SSBAS trapped pollen grains three times more efficiently than the Burkard trap, but the variations in pollen counts were significantly correlated. In contrast, birch pollen antigenic activity and the pollen count in the Burkard samples were not closely correlated. The antigenic concentration was occasionally high both before and after the pollination period. There was a high birch pollen antigenic activity in particle size classes where intact pollen grains were absent, even on days when the pollen count was very low. Correspondingly, on days with high birch pollen counts in the air, pollen antigenic activity was on several occasions low, indicating that pollen grains were empty of antigenic material. The small particle size classes are especially important to allergic patients because they are able to penetrate immediately into the alveoli and provoke asthmatic reactions. Therefore, aerobiological information systems based on pollen and spore counts should be supplemented with information concerning antigenic activities in the air.

Stability of Candida albicans allergens during storage.

Stability of Candida albicans allergens was studied under various storage conditions. Lyophilized extract was reconstituted with human serum albumin (NSA) diluent, glycerol-free and in the presence of 10% or 50% glycerol and stored at various temperatures for different time periods. All extracts were tested at the same time with immunoblotting using C. albicans allergic patient sera and galactosidase-labelled anti-IgE. The highest number of detected allergens in the immunoblotting pattern was found in the presence of 50% glycerol at +6 degrees C. The most important allergen of C. albicans, the 46 kD protein allergen was stable up to 10 weeks at +6 degrees C in the presence of 50% glycerol but thereafter began to lose its IgE-binding capacity. After 30 weeks more than 50% of the IgE binding had disappeared. The 27 kD protein, another important allergen, was also labile but retained the allergenicity better than the 46 kD one. The 29 kD protein allergen was stable at all storage conditions, except +37 degrees C tested even after one year. More than 6 months storage at +6 degrees C or higher temperature is, however, unacceptable even in the presence of the 50% glycerol. These findings have particular importance in the diagnosis and treatment of allergic diseases.

Use of the extended Phadebas RAST panel in the diagnosis of mould allergy in asthmatic children.

The clinical significance of mould allergens in Phadebas RAST panel was investigated in 121 asthmatic children. They were selected from a total population of 1649 patients. The patients were distributed into four groups, based on the combination of positive or negative skin prick tests (SPT) together with symptoms suggestive or not of mould sensitivity. Mould-specific IgE antibodies were investigated using the original RAST panel (Alternaria, Aspergillus, Candida, Cladosporium, Mucor and Penicillium) and a set of 10 additional mould-allergen discs (Aureobasidium, Botrytis, Curvularia, Epicoccum, Fusarium, Helminthosporium, Phoma, Rhizopus, Stemphylium and Trichoderma). The set of additional RAST discs revealed patients with mould-reaginic antibodies not found with the original RAST panel. This occurred in four of 49 (8.2%) RAST positive (class greater than or equal to 2) patients. The allergens most frequently positive were Cladosporium (in 28% of the patients), Candida (28%) and Helminthosporium (26%). A remarkable degree of simultaneous reactivity to almost all moulds tested was observed. Patients with multiple (greater than or equal to 7) mould sensitization were effectively pinpointed using any duplicate combination of Aureobasidium, Botrytis, Candida, Cladosporium, Helminthosporium, Penicillium and Stemphylium.

Significance of sampling height of airborne particles for aerobiological information.

Pollen and spore counts from Burkard traps for routine pollen and spore sampling placed at 15 m above ground and at ground level were compared. Daily counts of most pollen types were higher on the ground than at roof level, but the counts were significantly correlated. The ratios of pollen frequencies at high and low levels varied between 1.0 and 11.5. The most prominent differences were recorded for herbaceous pollen (e.g. Artemisia counts 11.5 and Poaccae counts 4.4 times higher at ground level) and in Botrytis and Ustilaginales spores. Tree pollen grains and basidiomycetous spores were more equally distributed. Wind speed did not affect the variation of pollen frequencies at either height. Large spores are not so unevenly distributed as previously supposed. Artemisia and grass pollen was detected 1 to 2 weeks earlier at ground level than on the roof. It is therefore concluded that especially the beginning of flowering should be monitored at a low level.

Recurrent wheezy bronchitis and viral respiratory infections.

Fifty four patients aged from 1 to 6 years who had had recurrent attacks of wheezy bronchitis were prospectively followed up for three months to find out if there was an association between different viral respiratory infections and episodes of wheezing. Of the 115 episodes of upper or lower respiratory tract symptoms, virus or Mycoplasma pneumoniae infection were diagnosed in 52 (45%). Thirty four of rhinoviruses. The patients had an average of 2.1 episodes of respiratory tract symptoms the total mean (SD) duration of which was 30 (2) days of the 92 days that followed. Wheezing occurred during 76 (66%) of the 115 episodes and during a third of these the patient was admitted to hospital because of severe dyspnoea. Wheezing started a mean (SD) of 43 (7) hours after the first symptoms of respiratory infection and persisted for 3.8 (4.2) days in patients in whom virus infection was diagnosed. The incidence of wheezing was not associated with IgE mediated atopy, with positive virological tests, or with fever during virus infection, but was associated with parental smoking and more than one sibling.

IgE, IgA and IgG antibodies and delayed skin response towards Candida albicans antigens in atopics with and without saprophytic growth.

Immunoblotting and RAST were used to analyse IgE, IgA and IgG responses to antigens of Candida albicans. These were compared with the delayed skin response and C. albicans carriage in 40 atopic subjects. The majority of the atopic patients showed a strong IgG and IgA antibody response towards mannan, a carbohydrate, but only occasionally to proteins. Altogether 22 of the 40 patients showed specific IgE towards C. albicans by immunoblotting. The IgE response was mainly towards proteins, particularly to ones with molecular weights of 29 kD and 46 kD, and only in eight out of 22 IgE-positive subjects towards mannan. The IgG and IgA responses to mannan and the total IgE response towards C. albicans assessed by RAST showed an association with C. albicans carriage, whereas the delayed skin response showed an inverse relationship. The immunological parameters characteristic of C. albicans carriage were found to be C. albicans-specific depressed delayed skin response and elevated IgE, IgA and IgG responses. This situation in the atopics presenting such parameters may favour simultaneous sensitization and exposure by colonization. The degree of sensitization may be sufficiently high to produce symptomatic allergy, such as asthma, in some individuals during occasional overgrowth of C. albicans, e.g. due to antibiotic therapy.

Immunoblotting analysis of concanavalin A-isolated allergens of Candida albicans.

The carbohydrate-containing fraction of Candida albicans was isolated from the crude extract with ConA Sepharose affinity chromatography and studied by IgE-immunoblotting with individual and pooled sera from C. albicans-allergic subjects. In the ConA-bound fraction there was a diffuse IgE binding in the high molecular weight area which also gave a carbohydrate stain (PAS). A distinct band corresponding to a molecular weight of 70 kD bound specific IgE antibodies. This glycoprotein, presumably a mannoprotein, gave a weak carbohydrate staining and a strong protein staining. Further biochemical studies are needed to reveal the exact nature of the epitopes in the ConA-bound mannose-containing fraction of C. albicans.