Effect of neonatal sepsis on the development of allergies and asthma in later childhood

BACKGROUND: Exposure to large amounts of endotoxins and other bacterial products in early childhood may protect against the development of allergic diseases later in childhood. The aim of this study was to investigate the effects of neonatal sepsis on subsequent development of asthma, allergic rhinitis, and atopic dermatitis in children. METHODS: We recruited 85 children (mean age 48.67 +/- 12.88 months) who had been hospitalized for sepsis in their neonatal period and their siblings (n = 85) as controls (mean age 61.81 +/- 21.34 months) to investigate the prevalences of asthma, atopic dermatitis and allergic rhinitis. After asking the questions in the International Study of Asthma and Allergies in Children (ISAAC) questionnaires to the parents, total IgE levels in sera were measured and skin prick tests were performed. RESULTS: Children with neonatal sepsis had lower total IgE levels and less sensitivity to Dermatophagoides pteronyssinus than controls (25.9 vs. 9.4%, p = 0.003). In addition, wheeze ever, wheeze in the last 12 months, physician-diagnosed asthma, and use of asthma drugs were less common in these subjects. Prevalences of allergic rhinitis and atopic dermatitis were equal in both groups. CONCLUSION: Exposure to severe infections such as sepsis in the neonatal period may decrease sensitization to environmental allergens and prevalence of asthma in later childhood.     

Development of serum Dermatophagoides farinae-, ovalbumin- and lactalbumin-specific IgG, IgG1, IgG4, IgA and IgM in children with bronchial asthma/allergic rhinitis or atopic dermatitis

Dermatophagoides farinae-, ovalbumin- and lactalbumin-specific IgG, IgG1, IgG4, IgA and IgM were evaluated in 161 healthy children [Group 1], 84 children with bronchial asthma and/or allergic rhinitis but without atopic dermatitis [Group 2], and 54 children with atopic dermatitis but without bronchial asthma and allergic rhinitis [Group 3]. We also studied D. farinae-, egg-white-, and milk-specific IgE of children with allergic diseases. D. farinae-specific IgG, IgG1, IgG4 and IgA in Groups 2 and 3 increased until 5 years of age and thereafter they remained constant. After 2 years of age, D. farinae-specific IgG, IgG1, IgG4 and IgA in Group 2 were higher than those in Groups 1 and 3. Ovalbumin- and lactalbumin-specific IgG, IgG1, IgG4 and IgA in Groups 2 and 3 increased until 1 year of age and thereafter decreased. Until 1 year of age, ovalbumin- and lactalbumin-specific IgG, IgG1 and IgG4 in Groups 3 were higher than those in Groups 1 and 2. D. farinae-, ovalbumin- and lactalbumin-specific IgM were constant in all ages of all groups. These results suggest that atopic dermatitis in young children is related to food-specific immunoglobulins and that respiratory allergic diseases in older children is related to D. farinae-specific immunoglobulins.     

Tuberculin responses in children with allergic diseases

BACKGROUND: The prevalence of allergic disorders has been increasing over the last 30 years, especially in developed countries. One factor associated with this rise may be the decline of many childhood infections. We investigated tuberculin responses in allergic children in order to see the development of delayed-type hypersensitivity reactions to tubercule bacillus infection. METHODS: The study sample was composed of 106 allergic and 100 nonallergic children vaccinated with bacille Calmette-Guerin (BCG). The standard Mantoux test was applied to all children. The reactions were read after 72 h by measuring the diameter of the wheal. RESULTS: The wheal size was 6.29 +/- 5.09 mm (mean +/- SD) in allergic children, and 2.79 +/- 2.96 mm in nonallergic children. The difference between the two groups was significant (P < 0.001). In children with a single BCG scar, the mean purified protein derivative (PPD) wheal size for allergic children was 4.77 +/- 4.79 mm, and for nonallergic children it was 2.48 +/- 3.19 mm. The mean PPD wheal sizes in allergic and nonallergic children who had been vaccinated twice were 8.35 +/- 4.80 mm and 3.33 +/- 2.44 mm, respectively. This difference was statistically significant (P < 0.05). In 27.35% of the allergic children and 6% of the nonallergic children, the positive tuberculin responses (PPD > or = 10 mm) were recorded. The difference was significant (P < 0.05). CONCLUSIONS: Our results showed that response to tuberculin in BCG-immunized allergic children is higher than in BCG-immunized nonallergic children.     

Mother to child transfer of IgG and IgA antibodies against Dermatophagoides pteronyssinus

There is strong evidence from animal models that placental and/or breast milk-mediated transfer of maternal allergen-specific IgG prevents allergic immune responses in the progeny. Both human and animal data also point to IgA as having an important regulatory role. In contrast, little is known about maternal transfer of IgG and IgA specific for respiratory allergens in humans. Dermatophagoides pteronyssinus (Der p) is an indoor allergen that is a major cause of asthma worldwide. We analysed maternal to child Der p-specific IgG and IgA transfer in a cohort of 77 paired maternal and child samples. We found Der p-specific IgG and its IgG1, IgG2 and IgG4 subclasses in all cord blood samples. Except for IgG1, cord levels were higher in newborns from atopic mothers (n = 29) compared to non-atopic mothers (n = 48). Der p-specific IgA was found in all colostrum samples and levels were independent of maternal atopic status. Notably, anti-Der p IgG was also found in colostrum and levels were higher in atopic mothers. We believe that our work is a critical first step in the identification of early factors that may impact asthma development and should guide the development of clinical studies that assess whether Der p-specific IgG and IgA protect children from allergy as demonstrated in animal models.     

Serum thymic hormone thymulin activity is normal in children with asthma

In asthma, it has been hypothesized that suppressor T-lymphocytes play a protective role and have been reported to be functionally abnormal. Thymic hormone thymulin plays a role in the differentiation of T-lymphocytes and plasmatic thymulin concentration and is related to the functional state of the thymus. To assess the participation of the thymus in the impairment of T-lymphocyte function, we measured plasma thymulin activity in children with allergic asthma (N = 40). The plasma thymulin activity was compared with plasma thymulin activity of children with nonallergic asthma (N = 6), children with atopic dermatitis (N = 9) or allergic rhinitis (N = 7), and in age-matched healthy control children (N = 18) (age range of children studied, 2 to 19 years). Thymulin activity was found within the normal range (1/16 to 1/64) in all control children and in all children with allergic asthma and allergic rhinitis, as well as in all children with intrinsic asthma and atopic dermatitis. Our findings are at variance with the low thymulin activity previously reported in allergic asthma, and we could not explain these discrepancies. (Both studies used the same bioassay, and the population studied did not appear to be different.) T-lymphocyte abnormalities in subjects with asthma must be assessed by other means than measurement of thymic function.     

Allergic vs nonallergic asthma: what makes the difference?

BACKGROUND: The aim of this work was to describe clinical similarities and differences between allergic and nonallergic asthmatics, notably concerning the nasosinusal involvement. METHODS: A total of 165 asthmatics (122 allergics and 43 nonallergics) and 193 controls (40 allergics and 153 nonallergics), recruited in the frame of EGEA study (Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy), were included. Asthmatics were included on the basis of positive answer to four standardized items. To establish differences and similarities between allergic and nonallergic asthmatics, general characteristics (age, sex, smoking habits, history of hay fever and allergic dermatitis), history of asthma, severity and nasosinusal involvement were examined. Clinical assessment was based on the answers to a detailed questionnaire, and spirometry. RESULTS: Greater age, female sex, sinusal polyposis, and FEV1 below 80% of the predicted value increased the risk of displaying a nonallergic type of asthma, whereas history of hay fever, seasonal exacerbation of asthma, and asthma duration lowered this risk. Unexpectedly, we found no difference in terms of rhinitic symptoms between both groups, probably resulting from distinct causes. CONCLUSION: These results give new insights into the contrasts between clinical features of allergic and nonallergic asthma. The terminology of extrinsic asthma was first introduced by Rackeman in 1947 (1) and referred to the triggering role of allergens in asthma. By symmetry, he described intrinsic asthma as a disease characterized by later onset in life, female predominance, higher degree of severity, and more frequent association to nasosinusal polyposis. As these asthmatics were not improved by conventional treatment, this author considered their disease as caused by a nonallergic, unknown phenomenon. It is now widely admitted that nonallergic asthma can be objectively distinguished from allergic asthma based on negative skin tests to usual aeroallergens. On the other hand, positive skin test shows a tendency to produce IgE antibodies in response to low doses of allergens. "Atopy" and "atopic" are the terms used to describe this clinical trait and predisposition (2). Allergic clinical manifestations of atopy are of various types, for example rhinitis and asthma. Nowadays the terminology of "extrinsic" and "intrinsic" asthma should no longer be used, and should be replaced by the terminology of "allergic" or "nonallergic" asthma (2).     

Levels of immunoglobulin G, M, A, and E at various ages in allergic and nonallergic black and white individuals

Studies were conducted to detect major differences in immunoglobulin levels between allergic and nonallergic individuals. Immunoglobulins G, M, A, and E were quantitated in members of 63 families selected for the presence of children with asthma or allergic rhinitis and compared with a larger group of healthy individuals and families. Mean IgE levels were significantly higher in healthy black than in white individuals. No significant difference was found in IgE levels between healthy parents with and without allergic children. Mean IgE levels were significantly higher in asthmatic children than in healthy children and also much higher in asthmatic children than in their healthy siblings. Asthma occurred more frequently in boys than in girls. IgE levels in healthy children increased rapidly early in childhood, reached a peak before 10 yr of age, and decreased during the teens. This decrease in IgE during the teens may provide the immunologic mechanism by which some children can "outgrow" certain childhood allergies. IgA levels were very low in young children and not significantly different between allergic and healthy individuals. The low IgA level in young children may be of importance in the development of childhood allergies.     

Prevalence and subclass distribution of IgG-anti-IgE autoantibodies in atopy and parasitosis.

Using immunoblotting, we investigated sera of 60 patients with atopic dermatitis, 12 patients with helminth infections and 36 nonallergic controls, for anti-IgE autoantibodies. We found IgG anti-IgE autoantibodies in 62% of the atopics, 42% of the patients with parasitosis and 11% of the controls. IgG anti-IgE occurred most often (94%) in patients with atopic dermatitis plus additional atopic disorder, such as allergic asthma and rhinoconjunctivitis. In parallel, we found a significantly higher occurrence of IgG anti-IgE in the patients with high IgE levels compared to patients with low IgE levels (p less than 0.0005). The predominant subclasses of anti-IgE autoantibodies were IgG1 and IgG3 in atopy and parasitosis. In the controls, we found IgG4 and IgG3 anti-IgE, but no IgG1 autoantibodies. The frequency of IgG2 anti-IgE was very low; it occurred in 2 patients only. Prevalence and IgG subclass distribution of anti-IgE autoantibodies was found to be different for patients with atopic dermatitis, parasitic infection and for controls.     

Variant in promoter region of platelet-derived growth factor receptor-alpha (PDGFRalpha) gene is associated with the severity and allergic status of childhood asthma

BACKGROUND: Upregulation of the platelet-derived growth factor receptor-alpha (PDGFRalpha) in airway myofibroblast cells is one of the mechanisms of airway remodeling. The genetic association between PDGFRalpha promoter polymorphism and severity of childhood asthma was examined. METHODS: Five single nucleotide polymorphisms (SNPs) at the promoter regions of the PDGFRalpha gene were genotyped in 277 unrelated allergic and nonallergic asthmatic children and 93 age-matched controls. Promoter haplotypes were constructed using SNP genotyping data. The serum level of PDGF-AA, the ligand for PDGFRalpha, was assayed by ELISA kits. RESULTS: The genotype distribution of SNP rs1800810 (-1171G/C) in nonallergic asthma was significantly different from controls (p=0.038), as well as its allele distribution (p=0.028). Using haplotype analysis, the combination frequency of the low expression of H1 homozygous and heterozygous genotype (H1/H1+H1/H2) was significantly higher in nonallergic asthma as compared to controls (OR=1.94, CI=1.11-3.39, p<0.02). The frequency of H2/H2 homozygous was higher in persistent asthma than in intermittent asthma (p=0.008, OR=2.625). In addition, the PDGF-AA serum level in H2/H2 homozygous haplotype was significantly lower as compared to non-H2/H2 homozygous haplotype both in asthmatic (138.1+/-62.9 vs. 249.7+/-97.1 ng/ml, p<0.05) and nonallergic asthmatic children (113.8+/-38.0 vs. 256.6+/-58.3 ng/ml, p<0.05). CONCLUSIONS: The developmental deficiency due to the low expression of PDGFRalpha may be one of the susceptible factors for nonallergic asthmatic children. There was also an autocrine effect of lower PDGF-AA and higher PDGFRalpha expression that might lead to airway remodeling causing the severity of asthma.     

Allergic and nonallergic forms of atopic diseases

Atopic dermatitis, allergic rhinitis, and asthma are atopic diseases that develop on a complex genetic background, the so-called atopic diathesis. Although they target different organs, in most patients they are characterized by the presence of elevated total serum IgE levels. However, a subgroup of atopic patients exhibits normal IgE levels and mechanisms contributing to the so-called "intrinsic" or "nonallergic form" have been the matter of intensive research work in the last years. Because of the rapid advancements in the research field of atopic diseases, it now becomes possible for the first time to delineate a new disease classification of allergic and nonallergic subtypes of atopic diseases, thereby bringing hope to the clinician for a more specific treatment approach for each subgroup of these patients.     

Humoral and cellular immunity in asthma

Parameters of humoral and cellular immunity have been measured in 91 asthmatic patients. Mean serum levels of IgG and IgE were raised. IgG levels were higher in those with a family history of asthma. IgE levels were higher in those with a past history of atopic eczema, but intrinsic and extrinsic asthma could not be differentiated on the basis of IgE levels. Thirteen of 74 patients failed to respond to tetanus immunization, while only 1 failed to respond to Salmonella typhi H antigen. Tetanus nonresponders had a raised mean serum IgA level, reduced spontaneous lymphocyte tritiated thymidine uptake, and reduced thymidine uptake in fetal calf serum. Eight of 87 patients failed to mount delayed hypersensitivity reactions to a battery of five intradermal antigens. The tritiated thymidine uptake of lymphocytes stimulated with phytohemagglutinin was normal in autologous serum, but reduced in fetal calf serum. The data support the hypothesis that asthma may be associated with immunodeficiency states.     

Elevated IgG immune complexes in children with atopic eczema

The levels of serum IgG complement-fixing immune complexes were studied in 20 children with atopic eczema and in 10 children with allergic rhinitis as control subjects with the use of a Raji cell assay. Immune-complex levels were strikingly elevated in those with eczema, 50 +/- 10 SE micrograms/ml, compared to control subjects 11 +/- 9 micrograms/ml (p less than 0.0047), the latter falling within the range for nonallergic subjects. Levels tended to be higher in those subjects with more severe eczema, but there was no statistically significant correlation, nor were levels correlated with serum IgE. Sucrose-density gradient analysis demonstrated the immune complexes to be present in two peaks, 8 to 10S and 21S or higher. High-molecular-weight IgG immune complexes that are complement-fixing may promote the characteristic pruritus of eczema by formation of anaphylactic complement fragments and the release of inflammatory substances from cutaneous mast cells, as well as contributing to the impaired cell-mediated immunity associated with the disease.     

Measurement of histamine-releasing factor activity in individual nasal washings: relationship with atopy, basophil response, and membrane-bound IgE.

We collected individual pools of nasal washings (NWs) from 15 allergic and 15 nonallergic subjects to determine histamine-releasing factor (HRF) activity and to ascertain the relationship of these cytokines with atopic status, basophil releasability, and cell membrane-bound IgE. NWs were concentrated, dialyzed, and assayed with basophils from a single donor. Samples from 12 of 15 allergic subjects and from all the nonallergic subjects revealed greater than or equal to 15% histamine release (HR), 33.5% +/- 21.3% (mean +/- SD) and 38.6% +/- 19.6%, respectively (p greater than 0.05). When we assayed the same samples with autologous basophils, the allergic group demonstrated higher HR than the nonallergic group (31.9% +/- 19.7% versus 4.8% +/- 4.3%; p less than 0.001). A standard lot of mononuclear cell-derived HRFs was also screened with basophils from both groups. Means for HR from basophils of allergic and nonallergic subjects were 51.9% +/- 16.7% versus 26.3% +/- 8.2%, respectively (p less than 0.001). Pretreatment of basophils with lactic acid led to abrogation of sensitivity to HRF. Acid-stripped cells incubated with sera from patients with asthma regained their capacity to release histamine. We found that HRF activity can be detected in NWs of most donors, and there is no difference among allergic and nonallergic subjects. Our results suggest that the capacity of these cytokines to induce HR depends on several factors: atopic status, basophil releasability, and membrane-bound IgE.     

Association of asthma with serum IgE levels and skin-test reactivity to allergens

We investigated the association of self-reported asthma or allergic rhinitis with serum IgE levels and skin-test reactivity to allergens in 2657 subjects in a general-population study. Regardless of the subjects' status with respect to atopy or their age group, the prevalence of asthma was closely related to the serum IgE level standardized for age and sex (P less than 0.0001), and no asthma was present in the 177 subjects with the lowest IgE levels for their age and sex (greater than 1.46 SD below the mean). The log odds ratio increased linearly with the serum IgE level after we controlled for possible confounders and the degree of reactivity to skin tests. In contrast, allergic rhinitis appeared to be associated primarily with skin-test reactions to common aeroallergens, independently of the serum IgE level. We conclude that asthma is almost always associated with some type of IgE-related reaction and therefore has an allergic basis, although not all the allergic stimuli that cause asthma appear to have been included in the battery of common aeroallergens we used to assess atopic status. These findings challenge the concept that there are basic differences between so-called allergic ("extrinsic") and nonallergic ("intrinsic") forms of asthma.     

Predictable clinical disorders related to serum and saliva Ig-levels and the number of circulating T cells in asthmatic children

An examination was made of 221 children with bronchial asthma, who were divided into six groups according to serum and saliva Ig levels and the number of circulating T cells. Absence or small amounts of IgA and low or low-normal numbers of T cells were associated with (1) atopic dermatitis, (2) hypersensitivity to house dust mite and animal danders, (3) previous hospital admissions due to respiratory tract infections with pathogenic bacteria and (4) a high family incidence of allergic diseases. In a group of patients with IgA deficiency and elevated serum and saliva IgM, respiratory tract infections were not common, and furthermore, in another group of IgA-deficient patients with normal numbers of circulating T cells, atopic dermatitis was rare. In the latter patients, allergic rhinitis occurred very frequently, and in that respect they resembled a group of patients with combined high IgM/high IgE levels. Another group of asthmatic children with normal Ig levels represented an intermediate type of patient with regard to hypersensitivity to different allergens and family incidence of allergy on the one hand, and the occurrence of atopic dermatitis and allergic rhinitis on the other. Investigations on Ig levels and circulating T cells in asthmatic children may provide important clues into disease classification and mechanisms of such patients.     

Rare mutations in TNFRSF13B increase the risk of asthma symptoms in Swedish children

TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) mutations seem to be associated with autoimmunity and common variable immunodeficiency in humans. Because of its role in immune responses, we investigated the association between TACI mutations and infection proneness/asthma symptoms in children. A total of 2372 children were genotyped for TACI mutations (I87N, C104R, S144X, A181E, R202H and ins204A). Serum IgA, IgG and specific IgE levels were determined in children with mutations. Data on parentally reported allergic diseases and infections were collected. In all, 55 individuals with TACI mutations were identified. Children with TACI mutations had a 2-fold increased risk of wheeze at 2 and 4 years of age and a 2.5-fold increased risk of asthma was seen at 4 years of age. None of the children with mutations suffered from IgA deficiency (<0.07?g?l(-1)). No significant differences in serum IgG levels or specific IgE were found. Common variants in asthma susceptibility genes may account for up to 40% of cases of childhood-onset asthma, indicating a high contribution, compared with other common disorders. The role of rare variants/mutations in the pathogenesis of asthma is less clear. We conclude that mutations in TACI are the contributing factors for asthma symptoms in Swedish children, although the mechanisms still remain elusive.     

Expression of CD23 antigen and its ligands in children with intrinsic and extrinsic asthma

The role of the low-affinity IgE receptor CD23 in immune reactions has been further emphasized by recent discoveries of novel surface ligands for CD23: CD21, CD11b, and CD11c. We previously observed the difference between the expression of CD23 and CD21 antigens in children suffering from extrinsic asthma when compared to healthy controls. In the present study, we investigated the expression of CD23 and its ligand CD21 on CD20⁺B cells in 44 asthmatic children (23 allergic and 21 nonallergic) using three-color immunofluorescence analysis. In addition, the expression of two other ligands for CD23, CD11b, and CD11c, on T cells (CD3⁺), a subpopulation of T cells (CD4⁺ and CD8⁺), natural killer cells (CD56⁺), and monocytes (CD14⁺) was tested by two-color immunofluorescence analysis in 12 allergic and 14 nonallergic children. We found that children with extrinsic asthma had higher levels of CD23⁺ B cells than those with intrinsic asthma. No difference was observed in the percentage of either CD23⁺CD21⁺ or CD23^- CD21⁺ B cells. The CD11b antigen was expressed on each tested population, but only on CD4⁺ T cells was CD11b significantly increased in children with extrinsic asthma. CD11c was expressed mainly on monocytes, and no difference was observed between tested groups. The increased percentage of CD11b antigen on CD4⁺ T cells and the increased percentage of CD23 antigen on B cells in children with extrinsic asthma provide further evidence of the immunologic differences between intrinsic and extrinsic asthma.     

Immunoglobulin E- (IgE) and non-IgE-mediated reactions in the pathogenesis of atopic eczema/dermatitis syndrome (AEDS)

AEDS is a chronic, relapsing, highly pruritic inflammatory skin disease that commonly begins in childhood. Two forms of this disorder exist, i.e. an allergic (extrinsic) form and a nonallergic (intrinsic) form. There are clear genetic, humoral and cellular differences between the allergic and nonallergic forms of AEDS. The allergic variants express local IgE production in affected tissue and both allergic and nonallergic triggers play a major role in the expression of disease. The role of allergens is very important in the immunopathogenesis of AEDS. Nonimmunological triggers play a secondary modulatory role often hampering treatment effort and optimal response to therapeutic efforts.     

Prevalence of allergy in children in relation to prior BCG vaccination and infection with atypical mycobacteria

By influence on the Thl/Th2 cell balance, infectious agents may affect development of atopic allergy. In this study, we investigated whether previous BCG vaccination or infection with atypical mycobacteria might related lo the development of atopic disease. The study, which involved skin testing with mycobaeteria and answers to a questionnaire for more than 6000 children in Sweden, revealed a low prevalence of allergy among BCG-vaccinated children who were immigrants or adopted from other countries. Vaccinated children bom in Sweden, however, did not have significantly lower allergy prevalence than age-matched, unvaccinated children. Furthermore, the overall frequencies of skin-test reactivity to atypical mycobacteria M. avlum and M. scrofulaceum were higher rather than lower in allergic than in nonallergic children. By contrast, there was tendency toward a lower frequency of more strongly positive skin reactions (>10mm) to mycobacteria in allergic than in nonallergic children. These findings do not support the hypothesis that early mycobacterial infections have a suppressive effect on the development of atopic disease. Earlier findings of an apparent association between atopy and lack of previous mycobacterial infection may possibly be explained by a relatively decreased ability of atopic patients to mount strong Thl cell-mediated immune responses.     

Asthma and allergy in Russian and Norwegian schoolchildren: results from two questionnaire-based studies in the Kola Peninsula, Russia, and northern Norway

BACKGROUND: Previous studies have shown that the prevalence of asthma and allergy in children is lower in Eastern than Western Europe. METHODS: We have compared the prevalence of asthma, respiratory symptoms, allergic rhinoconjunctivitis, and atopic dermatitis in schoolchildren aged 7-13 years in a questionnaire-based study conducted in the city of Nikel on the Kola Peninsula, Russia, in 1994 (n = 1143) and another conducted in northern Norway in 1995 (n = 8676). RESULTS: The prevalence of diagnosed asthma was 5.1% in Russian children and 8.6% in Norwegian children; RR =0.58 (95% CI: 0.44-0.76). The prevalence of all respiratory symptoms was higher in Russian children. The prevalence of allergic rhinoconjunctivitis was 16.9%, in Russian children and 22.1%, in Norwegian children: RR =0.74 (95% CI: 0.65-0.85). The prevalence of atopic dermatitis was 7.4% in Russian children and 19.7% in Norwegian children; RR=0.38 (95% CI: 0.31-0.46). CONCLUSIONS: We conclude that the prevalence of diagnosed asthma, allergic rhinoconjunctivitis, and atopic dermatitis was higher in Norwegian than Russian schoolchildren. The higher prevalence of respiratory symptoms in Russian children probably reflects a higher prevalence of undiagnosed, nonallergic asthma.