Sex Differences in Baseline Risk Factors for Asthma Between Early Adolescence and Young Adulthood

Background: Several studies have shown sex differences in the prevalence of asthma and an association with age. The aim of the present study was to prospectively investigate the development of asthma, wheeze, rhinitis, and allergic symptoms in adolescence and adulthood. We also aimed to determine whether sex modifies the association between baseline risk factors and incidence of asthma in early adulthood. Methods: In the Screening Project Asthma in Schools (SPAIS) study, adolescents aged 12-15 years completed a standardized respiratory questionnaire (International Study of Asthma and Allergies in Childhood) and underwent measurements of fractional exhaled nitric oxide (FeNO) and lung function (FEV1) at baseline. Two follow-up assessments with similar questionnaires were performed after 4 and 16 years, with a total of 491 participants in all 3 examinations. Results: The prevalence of asthma and wheeze were unchanged after 4 years but had increased after 16 years. However, the increase was significant only for females. The prevalence of rhinitis and allergy symptoms increased steadily, albeit with no differences between the sexes. The sex interaction analysis showed that higher FeNO (P=.01) and a family history of asthma (P=.02) increased the risk of incident asthma for males but not for females. Conclusions: An increased prevalence of respiratory symptoms was seen primarily between late adolescence and young adulthood; the difference was significant for females but not for males. Allergic risk factors in early adolescence for incident asthma in early adulthood were confirmed in males but not in females. Awareness of these sex differences in the development of symptoms and of the associated risk factors is important in clinical practice (AU)

Antecedentes: Varios estudios han mostrado diferencias por sexo en la prevalencia del asma y una relación de la misma con la edad. El objetivo del presente estudio fue investigar prospectivamente el desarrollo de asma, sibilancias, rinitis y síntomas alérgicos, entre la adolescencia y la edad adulta. Más aún, determinar si el sexo modifica las asociaciones entre los factores de riesgo iniciales y la incidencia de asma en la edad adulta temprana. Métodos: En el estudio "Screening Project Asthma in Schools" (SPAIS), los adolescentes de 12 a 15 años respondieron un cuestionario respiratorio estandarizado (ISAAC) y se sometieron a mediciones de óxido nítrico exhalado (FeNO) y función pulmonar (FEV1) al inicio del estudio. Se realizaron dos seguimientos con cuestionarios similares después de 4 y 16 años, con 491 sujetos que participaron en los tres exámenes. Resultados: La prevalencia de asma y sibilancias se mantuvo sin cambios después de 4 años, pero aumentó a los 16 años. Sin embargo, el aumento fue significativo sólo para las mujeres. Un aumento más continuo de la rinitis y los síntomas alérgicos no mostró diferencias entre los sexos. El análisis de interacción sexual mostró que un FeNO más alto (p=0,01) y los antecedentes familiares de asma (p=0,02) aumentaron el riesgo de asma incidente para los hombres, pero no para las mujeres. Conclusiones: Se observó una mayor prevalencia de síntomas respiratorios principalmente entre la adolescencia tardía y la edad adulta temprana, que fue significativa para las mujeres pero no para los hombres. Los factores de riesgo alérgico en la adolescencia temprana para el asma incidente en la edad adulta temprana se confirmaron en hombres, pero no en mujeres. El conocimiento de estas diferencias por género en el desarrollo de los síntomas y los factores de riesgo asociados son importantes en la práctica clínica (AU)

Sex differences in baseline risk factors for the incidence of asthma between early adolescence and young adulthood.

BACKGROUND: Several studies have shown sex differences in the prevalence of asthma and a relationship to age. The aim of the present study was to prospectively investigate the development of asthma, wheeze, rhinitis and allergic symptoms, between adolescence and adulthood. Furthermore, to determine if sex modifies the associations between baseline risk factors and incidence of asthma in early adulthood. METHODS: In the study Screening Project Asthma in Schools(SPAIS), adolescents aged 12-15 years answered a standardised respiratory questionnaire (ISAAC) and underwent measurements of fractional exhaled nitric oxide (FeNO) and lung function (FEV1) at baseline. Two follow-ups with similar questionnaires were performed after four and 16 years, with 491 subjects participating in all three examinations. RESULTS: The prevalence of asthma and wheeze were unchanged after four years, but had increased after 16 years. However, the increase was significant only for females. A more continuous increasein rhinitis and allergic symptoms showed no difference between the sexes. Sex interaction analysis showed that higher FeNO (p = 0.01) and family asthma (p = 0.02) increased the risk of incident asthma for males but not for females. CONCLUSION: An increased prevalence of respiratory symptoms was seen primarily between late adolescence and young adulthood, and was significant for females but not males. Allergic risk factors in early adolescence for incident asthma in early adulthood were confirmed in males but not in females. Awareness of these sex differences in the development of symptoms, and the associated risk factors, are important in clinical practice.

Characterization of a subgroup of non-type 2 asthma with cow's milk hypersensitivity in young subjects.

BACKGROUND: Asthma with atopy is often characterized by type 2 inflammation but less progress has been made in defining non-type 2 asthma. We have previously identified a subgroup of young non-atopic asthmatics with perceived food hypersensitivity and poor asthma control. OBJECTIVE: Our aim was to further characterize this subgroup of non-type 2 asthmatics, including the use of a broad panel of inflammation-related proteins. METHODS: Sex- and age-matched subjects (10-35 years old) were divided into three groups with regard to history of asthma and atopy: non-atopic asthmatics with perceived cow's milk hypersensitivity but with IgE antibodies < 0.35 kUA/L (NAA; n = 24), non-atopic controls with IgE < 0.35 kUA/L (NAC; n = 24), and atopic asthmatics with IgE ≥ 0.35 kUA/L (AA; n = 29). Serum or plasma were analysed using the multi-allergen tests Phadiatop and fx5 (ImmunoCAP), a multiplex immunoassay comprising 92 inflammation-related proteins (Proseek Inflammation), and an ELISA for human neutrophil lipocalin (S-HNL). Fraction of exhaled nitric oxide (FeNO), blood eosinophil (B-Eos) count, C-reactive protein (CRP), airway responsiveness to methacholine (PD20), and asthma-related quality of life (mAQLQ) were also measured. RESULTS: NAA had lower FeNO (p < 0.001) and B-Eos count (p < 0.001), but scored worse on mAQLQ (p = 0.045) compared with AA. NAA displayed higher levels of matrix metalloproteinase-1 (MMP-1) compared with both NAC (p = 0.011) and AA (p = 0.001), and lower PD20 compared with NAC (p < 0.001). In NAA, S-HNL correlated negatively with PD20 (rho = - 0.048, p < 0.05) and CRP correlated negatively with mAQLQ (rho = - 0.439, p < 0.05). CONCLUSION: In a subgroup of non-atopic young asthmatics with perceived cow's milk hypersensitivity we observed poor asthma-related quality of life, airway hyperresponsiveness, and clinically relevant non-type 2 inflammation. MMP-1 was elevated in this group, which deserves further studies.

Elevated Exhaled Nitric Oxide in Adolescents Is Associated With Incident Allergic Symptoms: A Prospective Cohort Study.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is a marker of type-2 inflammation in the airways. Elevated FeNO may precede the development of allergic disease. The aim of the present study was to investigate the association between elevated FeNO and the development of allergic symptoms. METHODS: A total of 959 adolescents from the general population and their parents completed a standardized questionnaire. Lung function and FeNO were assessed at baseline. Four years later, 921 of these individuals (96%) completed the same version of the baseline questionnaire. RESULTS: Adolescents with self-reported incident allergic symptoms to cat (n=50) or dog (n=33) had higher baseline FeNO (P<.001) than those without allergic symptoms to cat and dog at both time points (n=776 and n=838, respectively). Adolescents with incident allergic symptoms to pollen did not have elevated baseline FeNO. The adjusted odds ratio (aOR [95%CI]) for incident allergic symptoms to cat was 4.2 (2.2-8.0) times higher if FeNO was >75th percentile (vs <75th percentile) at baseline. This was consistent after exclusion of individuals with reported asthma, wheeze, or rhinitis at baseline (8.6 [3.0-24.1]). CONCLUSION: Elevated FeNO in adolescents was associated with an increased risk of developing allergic symptoms to cat and dog allergens, but not to pollen allergens, after 4 years.

Elevated exhaled nitric oxide in adolescents is associated with incident allergic symptoms: a prospective cohort study

Background: Fractional exhaled nitric oxide (FeNO) is a marker of type-2 inflammation in the airways. Elevated FeNO may precede the development of allergic disease. The aim of the present study was to investigate the association between elevated FeNO and the development of allergic symptoms. Methods: A total of 959 adolescents from the general population and their parents completed a standardized questionnaire. Lung function and FeNO were assessed at baseline. Four years later, 921 of these individuals (96%) completed the same version of the baseline questionnaire. Results: Adolescents with self-reported incident allergic symptoms to cat (n=50) or dog (n=33) had higher baseline FeNO (P<.001) than those without allergic symptoms to cat and dog at both time points (n=776 and n=838, respectively). Adolescents with incident allergic symptoms to pollen did not have elevated baseline FeNO. The adjusted odds ratio (aOR [95%CI]) for incident allergic symptoms to cat was 4.2 (2.2-8.0) times higher if FeNO was >75th percentile (vs <75th percentile) at baseline. This was consistent after exclusion of individuals with reported asthma, wheeze, or rhinitis at baseline (8.6 [3.0-24.1]). Conclusion: Elevated FeNO in adolescents was associated with an increased risk of developing allergic symptoms to cat and dog allergens, but not to pollen allergens, after 4 years

Introducción: La fracción de óxido nítrico exhalado (FeNO) es un marcador de inflamación de tipo 2 en las vías respiratorias y un valor de FeNO elevado puede preceder al desarrollo de enfermedad alérgica. El objetivo del presente estudio fue investigar la asociación entre FeNO elevado y el desarrollo posterior de síntomas alérgicos. Métodos: Un total de 959 adolescentes, procedentes de población general, respondieron, junto con sus padres, a un cuestionario estandarizado, realizaron una prueba de función pulmonar y una medición de FeNO en una visita basal. Cuatro años después, 921 de estos sujetos (96%) completaron, la misma versión, en gran medida, del cuestionario de referencia. Resultados: Los adolescentes con síntomas alérgicos incidentes autoinformados por gato (n=50) o perro (n=33) tenían mayor FeNO inicial (p <0,001) que los sujetos sin síntomas alérgicos por estos alérgenos, en cualquier momento del estudio (n=776 y n=838, respectivamente). Por el contrario, los adolescentes con síntomas alérgicos incidentes por polen no presentaban un FeNO inicial elevado. La razón de riesgo ajustada [aOR (intervalo de confianza del 95%)] para síntomas alérgicos incidentes por gato fue 4,2 (2,2, 8,0) veces mayor si el FeNO fue mayor que percentil 75 de la muestra (vs. menor del percentil 75) al inicio del estudio. Este resultado se mantuvo también después de la exclusión de los sujetos con asma, sibilancias o rinitis notificados al inicio del estudio [aOR (IC 95%) 8,6 (3,0, 24,1)].Conclusiones: El FeNO elevado en adolescentes se relacionó con un mayor riesgo de desarrollar en los cuatro años siguientes síntomas alérgicos inducidos por gatos y perros, pero no por los alérgenos del polen

Sensitization to minor cat allergen components is associated with type-2 biomarkers in young asthmatics.

BACKGROUND: Cat allergy is a major trigger of asthma world-wide. Molecular patterns of cat sensitization vary between individuals, but their relationship to inflammation in asthmatics has not been extensively studied. OBJECTIVE: To investigate the prevalence and levels of IgE antibodies against different cat allergen components and their relationship to type-2 inflammation and total IgE among young asthmatic subjects sensitized to furry animals. METHODS: Patients with asthma (age 10-35 years; n = 266) and IgE sensitization to cat, dog or horse extract (ImmunoCAP), were analysed for IgE to the cat allergen components Fel d 1 (secretoglobin), Fel d 2 (serum albumin), Fel d 4 and Fel d 7 (lipocalins). Independent associations between IgE-antibody concentrations, and fraction of exhaled nitric oxide (FeNO), blood eosinophil (B-Eos) count, and total IgE were analysed by multiple linear regression after adjustment for possible confounders. RESULTS: The level of IgE against Fel d 2 was independently related to FeNO (P = .012) and total IgE (P < .001), and IgE against Fel d 4 associated with Β-Eos count (P = .009) and total IgE (P < .001). IgE antibodies against Fel d 1 or cat extract did not independently relate to these inflammatory markers (P = .23-.51). CONCLUSIONS: Levels of IgE to lipocalin (Fel d 4) and serum albumin (Fel d 2), but not to secretoglobin (Fel d 1) or cat extract, were independently associated with type-2 biomarkers and total IgE in young asthmatics. CLINICAL RELEVANCE: We suggest that measurement of IgE to minor cat allergen components may be useful when investigating asthma morbidity in cat allergic subjects.

The absence of serum IgE antibodies indicates non-type 2 disease in young asthmatics.

BACKGROUND: Atopic asthma is associated with elevated type-2 biomarkers such as fraction of exhaled nitric oxide (FeNO) and blood eosinophil (B-Eos) count. However, increased type 2 markers have also been reported in traditionally defined non-atopic asthma. OBJECTIVE: To determine a clinically useful level of IgE sensitization for ruling out type 2 asthma. METHODS: Asthmatics (N = 408; age 10-35 years) were analysed using the multi-allergen tests Phadiatop and fx5 (ImmunoCAP). Subjects were grouped based on IgE-antibody concentrations: ≥0.35 kUA /L for at least one test (n = 326) or <0.35 kUA /L for both tests (n = 82). Τhe latter group was subsequently divided into 2 groups: IgE 0.10-0.34 kUA /L (n = 34) and IgE < 0.10 kUA /L (n = 48). The relationships between type 2 biomarkers, and inadequate asthma control (ACT < 20), reduced lung function (FEV1  < 80%), recent asthma attacks and airway hyperresponsiveness (AHR) to methacholine were determined. RESULTS: In univariate analyses, at least one type 2 marker related to each asthma outcome in subjects with IgE ≥0.35 kUA /L. In subjects with IgE 0.10-0.34 kUA /L, elevated FeNO related to reduced lung function (P = .008) and B-Eos to AHR (P = .03). No associations were found in subjects with IgE < 0.10 kUA /L. In multivariate analysis, a relationship between FeNO and reduced lung function remained in subjects with IgE < 0.35 kUA /L (P = .03). CONCLUSION AND CLINICAL RELEVANCE: Clinically relevant elevation of type 2 biomarkers was seen in young asthmatics with IgE antibodies <0.35 kUA /L, but not those with IgE < 0.10 kUA /L. It seems possible to define non-type 2 asthma through sensitive IgE-antibody measurement.

Overall and peripheral lung function assessment by spirometry and forced oscillation technique in relation to asthma diagnosis and control.

BACKGROUND: Classic spirometry is effort dependent and of limited value in assessing small airways. Peripheral airway involvement, and relation to poor control, in asthma, has been highlighted recently. Forced oscillation technique (FOT) offers an effort-independent assessment of overall and peripheral lung mechanics. We studied the association between lung function variables, obtained either by spirometry or multifrequency (5, 11 and 19 Hz) FOT, and asthma diagnosis and control. METHODS: Spirometry measures, resistance at 5 (R5) and 19 Hz (R19), reactance at 5 Hz (X5), resonant frequency (fres ), resistance difference between 5-19 Hz (R5-R19) and Asthma Control Test scores were determined in 234 asthmatic and 60 healthy subjects (aged 13-39 years). We used standardized lung function variables in logistic regression analyses, unadjusted and adjusted for age, height, gender and weight. RESULTS: Lower FEV1 /FVC (OR [95% CI] 0.47 [0.32, 0.69]) and FEF50 (0.62 [0.46, 0.85]) per standard deviation increase, and higher R5 (3.31 [1.95, 5.62]) and R19 (2.54 [1.65, 3.91]) were associated with asthma diagnosis. Independent predictive effects of FEV1 /FVC and R5 or R19, respectively, were found for asthma diagnosis. Lower FEV1 /FVC and altered peripheral FOT measures (X5, fres and R5-R19) were associated with uncontrolled asthma (P-values < .05). CONCLUSIONS: Resistance FOT measures were equally informative as spirometry, related to asthma diagnosis, and, furthermore, offered additive information to FEV1 /FVC, supporting a complementary role for FOT. Asthma control was related to FOT measures of peripheral airways, suggesting a potential use in identifying such involvement. Further studies are needed to determine a clinical value and relevant reference values in children, for the multifrequency FOT measurements.

Alveolar and exhaled NO in relation to asthma characteristics--effects of correction for axial diffusion.

BACKGROUND: Inflammation in the small airways might contribute to incomplete asthma disease control despite intensive treatment in some subgroups of patients. Exhaled NO (FeNO) is a marker of inflammation in asthma and the estimated NO contribution from small airways (CalvNO ) is believed to reflect distal inflammation. Recent studies recommend adjustments of CalvNO for trumpet model and axial diffusion (TMAD-adj). This study aimed to investigate the clinical correlates of CalvNO , both TMAD-adjusted and unadjusted. METHODS: Asthma symptoms, asthma control, lung function, bronchial responsiveness, blood eosinophils, atopy and treatment level were assessed in 410 subjects, aged 10-35 years. Exhaled NO was measured at different flow-rates and CalvNO calculated, with TMAD-adjustment according to Condorelli. RESULTS: Trumpet model and axial diffusion-adjusted CalvNO was not related to daytime wheeze (P = 0.27), FEF50 (P = 0.23) or bronchial responsiveness (P = 0.52). On the other hand, unadjusted CalvNO was increased in subjects with daytime wheeze (P < 0.001), decreased FEF50 (P = 0.02) and with moderate-to-severe compared to normal bronchial responsiveness (P < 0.001). All these characteristics correlated with increased FeNO (all P < 0.05). Unadjusted CalvNO was positively related to bronchial NO flux (J'awNO ) (r = 0.22, P < 0.001) while TMAD-adjCalvNO was negatively related to J'awNO (r = -0.38, P < 0.001). CONCLUSIONS: Adjusted CalvNO was not associated with any asthma characteristics studied in this large asthma cohort. However, both FeNO and unadjusted CalvNO related to asthma symptoms, lung function and bronchial responsiveness. We suggest a potential overadjustment by current TMAD-corrections, validated in healthy or unobstructed asthmatics. Further studies assessing axial diffusion in asthmatics with different degrees of airway obstruction and the validity of proposed TMAD-corrections are warranted.

Exercise-induced dyspnea is a problem among the general adolescent population.

RATIONALE: Respiratory symptoms during exercise are common and might limit adolescents' ability to take part in physical activity. OBJECTIVE: To estimate the prevalence, determinants and consequences of exercise-induced dyspnea (EID) on daily life in a general population of 12-13 year old adolescents. METHODS: A letter was sent to the parents of all 12-13 year old adolescents in the city of Uppsala (n = 3838). Parents were asked to complete a questionnaire together with their child on EID, asthma and allergy, consequences for daily life (wheeze, day time- and nocturnal dyspnea) and physical activity. The response rate was 60% (n = 2309). RESULTS: Fourteen percent (n = 330) reported EID, i.e. had experienced an attack of shortness of breath that occurred after strenuous activity within the last 12 months. Female gender, ever-asthma and rhinitis were independently associated with an increased risk of EID. Ever-asthma was reported by 14.6% (n = 338), and 5.4% (n = 128) had both EID and ever-asthma. Sixty-one percent (n = 202) of the participants with EID did not have a diagnosis of asthma. In addition to rhinitis, participants with EID reported current wheeze and day-time as well as nocturnal dyspnea more often than the group without EID. No difference was found in the level of physical activity between participants with and without EID. CONCLUSION: Adolescents with undiagnosed exercise-induced dyspnea have respiratory symptoms and are affected in daily life but have the same level of physical activity as adolescents without exercise-induced respiratory symptoms.

Nasal nitric oxide is associated with exhaled NO, bronchial responsiveness and poor asthma control.

The fraction of exhaled nitric oxide (FeNO) is an established marker of airway inflammation in asthma. Nasal nitric oxide (nNO) has initially been regarded as a promising marker of inflammation of nasal mucosa. However, due to its dual origins, paranasal sinuses and nasal mucosa, the clinical use of nNO is controversial. There is an inflammatory link between inflammation in the upper and lower airways within the united airways' paradigm, but the study of the clinical value of nNO in asthma has been limited. The objective of this study is to analyse nNO in asthmatics and its relationship to FeNO, bronchial hyperresponsiveness, allergic sensitization and asthma control. A total of 371 children and young adults from an asthma cohort were included in this study, which performed measurements of nNO (through aspiration at 5 mL s(-1)), FeNO, bronchial responsiveness to methacholine, blood eosinophil count (B-Eos) and IgE sensitization. The asthma control test (ACT) and a questionnaire regarding medical treatment, symptoms of asthma, rhinitis and chronic rhinosinusitis were completed by all subjects. An association was found between higher nNO levels and increased bronchial responsiveness (p < 0.001), FeNO (p < 0.001) and B-Eos (p = 0.002). Sensitization to furry animals related to higher levels of nNO (p < 0.001). Subjects with poorly controlled asthma (ACT < 15) had lower levels of nNO than subjects with a higher ACT score (619 ± 278 ppb, versus 807 ± 274 ppb, p = 0.002). Loss of smell showed the strongest association with lower nNO levels among the upper airway symptoms recorded. In patients with asthma, nNO was positively correlated with exhaled NO, bronchial responsiveness and asthma control. This study suggests clinical utility of nNO in subjects with asthma, but in order to get better understanding of the nNO determinants, simultaneous mapping of upper airway comorbidities by clinical examination is appropriate.

Aeroallergen and food IgE sensitization and local and systemic inflammation in asthma.

BACKGROUND: We recently reported an independent association between IgE sensitization to food allergens and increased airway inflammation, assessed by fraction of exhaled nitric oxide (FeNO), in a population-based study (J Allergy Clin Immunol, 130, 2012, 397). Similar studies have not been performed in populations with asthma. The aim of the present study was to investigate the allergic sensitization profile in asthmatics and examine FeNO, airway responsiveness and blood eosinophilia in relation to type and degree of IgE sensitization. METHOD: FeNO, airway responsiveness, blood eosinophil count (B-Eos) and IgE sensitization to food allergens and aeroallergens were determined in 408 subjects with asthma, aged 10-34 years. RESULTS: Asthmatics had higher prevalence of IgE sensitization against all allergens than controls (P < 0.001). Mite, pollen, furry animal, mould and food sensitizations were each associated with increased FeNO, airway responsiveness and B-Eos in asthmatics. IgE sensitization to mould, furry animals and food allergens was independently related to FeNO (all P < 0.05) after adjustment for age, sex, height, smoking history and medication. IgE sensitization to mould (P < 0.001) and furry animals (P = 0.02) was related to airway responsiveness in a similar model. Finally, IgE sensitization to mould (P = 0.001), furry animals (P < 0.001) and food allergens (P < 0.001) was independently related to B-Eos. CONCLUSION: Independent effects of IgE sensitization to aeroallergens (furry animals and mould) and food allergens were found on both local and systemic markers of inflammation in asthma. The finding regarding food IgE sensitization is novel, and a clinical implication might be that even food sensitization must be assessed to fully understand inflammation patterns in asthma.

Increased exhaled nitric oxide predicts new-onset rhinitis and persistent rhinitis in adolescents without allergic symptoms.

BACKGROUND: The fraction of nitric oxide in exhaled air (FE(NO)) is increased in rhinitis and asthma. We have previously suggested that elevated FE(NO) levels in the absence of asthma symptoms may be a sign of 'early asthma'. In the present study, we hypothesize that elevated exhaled NO levels may also precede rhinitis symptoms. OBJECTIVE: To investigate in a cohort of adolescents whether or not increased exhaled NO levels at the age of 13-14 years predicted new-onset or persistent rhinitis within a 4-year period. METHODS: A total of 959 randomly selected adolescents (13-14 years) completed a questionnaire on respiratory symptoms at baseline and follow-up, 4 years later. Exhaled NO was measured at baseline. After exclusion of subjects with asthma diagnosis or asthma symptoms at baseline, 657 participants were eligible for the present study. RESULTS: Higher FE(NO) levels at baseline were associated with increased risk for new-onset (P = 0.009) and persistent rhinitis (P = 0.03) within a 4-year period. The risk of new-onset rhinitis was 2.32 (1.23, 4.37) [OR (95% CI)] times higher if FE(NO) > 90th percentile of the group without rhinitis at baseline. This increased risk for new-onset rhinitis was significant [2.49 (1.24, 5.01)] after excluding subjects with allergic symptoms. The risk of persistent rhinitis was 5.11 (1.34, 19.57) times higher if FE(NO) > 90th percentile of the group without rhinitis at baseline. CONCLUSION: Elevated exhaled nitric oxide levels predicted incident and persistent rhinitis in this population-based study of adolescents. Moreover, these findings were consistent after excluding subjects with allergic symptoms. Thus, it appears that elevation of exhaled NO precedes airway symptoms and predicts development of rhinitis in subjects without allergic symptoms or family history of allergic disease.

Symptoms to pollen and fruits early in life and allergic disease at 4 years of age.

BACKGROUND: The predictive value of reported early symptoms to pollen or fruits on later allergic disease is unclear. Our aim is to evaluate if symptoms to pollen and/or to fruits early in life are associated with allergic disease and sensitization to pollen at 4 years. METHODS: The study included 3619 children from the Barn (Children), Allergy, Milieu, Stockholm, Epidemiology project (BAMSE) birth cohort. Reported symptoms of wheeze, sneeze or rash to birch, grass or weed, symptoms (vomiting, diarrhea, rash, facial edema, sneeze, or wheeze) to fruits including tree-nuts at 1 or 2 years of age, and definitions of asthma, rhinitis and eczema at 4 years were derived from questionnaire data. Sensitization to pollen allergens was defined as allergen-specific IgE-antibodies to any pollen (birch/timothy/mugwort) > or =0.35 kU(A)/l. RESULTS: At 1 or 2 years of age, 6% of the children were reported to have pollen-related symptoms, 6% had symptoms to fruits, and 1.4% to both pollen and fruits. Children with symptoms to both pollen and fruits at 1 or 2 years of age had an increased risk for sensitization to any pollen allergen at age 4 (OR(adj) = 4.4, 95% CI = 2.1-9.2). This group of children also had a substantially elevated risk for developing any allergic disease (asthma, rhinitis, or eczema) at 4 years irrespective of sensitization to pollen (OR(adj) = 8.6, 95% CI = 4.5-16.4). CONCLUSIONS: The prevalence of reported symptoms to pollen and fruits is very low in early childhood. However, children with early symptoms to both pollen and fruits appear to have a markedly elevated risk for allergic disease.

Exposure to environmental tobacco smoke and sensitisation in children.

BACKGROUND: Exposure to environmental tobacco smoke (ETS) increases the risk of respiratory illness in children but data are inconclusive regarding the risk of IgE sensitisation. OBJECTIVE: To elucidate whether exposure to smoking prenatally and/or postnatally is related to IgE sensitisation in children at 4 years of age. METHODS: As part of a prospective birth cohort study (BAMSE), a total of 4089 families with children answered questionnaires when the child was 2 months, 1, 2 and 4 years old on environmental factors and symptoms of allergic disease. Blood collected at age 4 years from 2614 children was analysed for IgE antibodies to common inhalant and food allergens. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression with adjustments for potential confounders. RESULTS: There was no evident association between maternal smoking during pregnancy and risk of IgE sensitisation. In contrast, a dose-response effect was found for exposure to ETS from parental smoking during the first few months of life and IgE sensitisation. There was an increased risk of sensitisation to inhalant and/or food allergens (OR(adj) 1.28 (95% CI 1.01 to 1.62)) among children exposed to ETS at 2 months of age. The risk appeared particularly elevated for indoor inhalant allergens, such as cat (OR(adj) 1.96 (95% CI 1.28 to 2.99)) and for food allergens (OR(adj) 1.46 (95% CI 1.11 to 1.93)). The IgE sensitising effect of ETS seemed to be confined to infants of parents without allergic diseases and to ETS exposure during early infancy. CONCLUSIONS: Our data indicate that exposure in early infancy to ETS increases the risk of IgE sensitisation to indoor inhalant and food allergens.

Determinants of lung function and airway hyperresponsiveness in asthmatic children.

BACKGROUND: Asthma patients exhibit an increased rate of loss of lung function. Determinants to such decline are largely unknown and the modifying effect of steroid therapy is disputed. This cross-sectional study aimed to elucidate factors contributing to such decline and the possible modifying effect of steroid treatment. METHODS: We analyzed determinants of lung function and airway hyperresponsiveness (AHR) in a Scandinavian study of 2390 subjects from 550 families. Families were selected for the presence of two or more asthmatic children as part of a genetic study, Scandinavian Asthma Genetic Study (SAGA). RESULTS: The primary analysis studied the association between the lung function and delay of inhaled corticosteroids (ICS) after asthma diagnosis among asthmatic children and young adults with a history of regular ICS treatment (N=919). FEV(1) percent predicted (FEV(1)% pred) was 0.25% lower per year of delay from diagnosis until treatment (p=0.039). This association was significantly greater in allergy skin prick test negative children. There was no significant influence of gender, age at asthma onset, or smoking. In the secondary analysis of the whole population of 2390 asthmatics and non-asthmatics, FEV(1)% pred was inversely related to having asthmatic siblings (-7.9%; p<0.0001), asthma diagnosis (-2.7%; p=0.0007), smoking (-3.5%; p=0.0027), and positive allergy skin prick test (-0.47% per test; p=0.012), while positively related to being of female gender (1.8%; p=0.0029). Risk of AHR was higher by having asthmatic siblings (OR 2.7; p<0.0001), being of female gender (OR 2.0; p<0.0001), and having asthma (OR 2.0; p<0.0001). CONCLUSIONS: These data suggest that lung function is lower in asthmatics with delayed introduction of ICS therapy, smoking, and positive allergy skin prick test. Lung function is lower and AHR higher in female asthmatics and subjects with asthmatic siblings or established asthma.

Association between Chlamydia pneumoniae antibodies and wheezing in young children and the influence of sex.

BACKGROUND: The proposed association between Chlamydia pneumoniae (Cpn) infection and wheezing needs further clarification. METHODS: Serum samples obtained from 1581 children aged 4 years in a population based cohort were tested for antibodies to Cpn and IgE antibodies to common allergens. Data on environmental factors and disease were collected prospectively from birth. RESULTS: The occurrence of IgG antibodies to Cpn at 4 years of age was associated with reported wheezing at different ages; however, these findings were most often not significant. In girls, the occurrence of anti-Cpn IgG was associated with wheezing at the ages of 1, 2, and 4 years (odds ratios (ORs) 3.41 (95% confidence interval (CI) 1.46 to 7.96), 2.13 (95% CI 1.02 to 4.44), and 2.01 (95% CI 1.14 to 3.54), respectively), and even higher ORs were observed for each age category when only high level antibody responses to Cpn were analysed. At the time of blood sampling the association between anti-Cpn IgG and wheezing was restricted to girls without atopic sensitisation (OR 2.39 (95% CI 1.25 to 4.57). No associations with wheezing were detected in boys, in whom IgE sensitisation was inversely associated with the presence of anti-Cpn IgG (OR 0.49 (95% CI 0.26 to 0.90)). CONCLUSIONS: This study suggests an association between evidence of earlier Cpn infection and a history of wheezing in young girls. Infection with Cpn may be an important risk factor for wheezing and possibly for non-atopic asthma, predominantly in girls.

Performance of a new hand-held device for exhaled nitric oxide measurement in adults and children.

BACKGROUND: Exhaled nitric oxide (NO) measurement has been shown to be a valuable tool in the management of patients with asthma. Up to now, most measurements have been done with stationary, chemiluminescence-based NO analysers, which are not suitable for the primary health care setting. A hand-held NO analyser which simplifies the measurement would be of value both in specialized and primary health care. In this study, the performance of a new electrochemical hand-held device for exhaled NO measurements (NIOX MINO) was compared with a standard stationary chemiluminescence unit (NIOX). METHODS: A total of 71 subjects (6-60 years; 36 males), both healthy controls and atopic patients with and without asthma were included. The mean of three approved exhalations (50 ml/s) in each device, and the first approved measurement in the hand-held device, were compared with regard to NO readings (Bland-Altman plots), measurement feasibility (success rate with 6 attempts) and repeatability (intrasubject SD). RESULTS: Success rate was high (> or = 84%) in both devices for both adults and children. The subjects represented a FENO range of 8-147 parts per billion (ppb). When comparing the mean of three measurements (n = 61), the median of the intrasubject difference in exhaled NO for the two devices was -1.2 ppb; thus generally the hand-held device gave slightly higher readings. The Bland-Altman plot shows that the 95% limits of agreement were -9.8 and 8.0 ppb. The intrasubject median difference between the NIOX and the first approved measurement in the NIOX MINO was -2.0 ppb, and limits of agreement were -13.2 and 10.2 ppb. The median repeatability for NIOX and NIOX MINO were 1.1 and 1.2 ppb, respectively. CONCLUSION: The hand-held device (NIOX MINO) and the stationary system (NIOX) are in clinically acceptable agreement both when the mean of three measurements and the first approved measurement (NIOX MINO) is used. The hand-held device shows good repeatability, and it can be used successfully on adults and most children. The new hand-held device will enable the introduction of exhaled NO measurements into the primary health care.

Indoor exposures and recurrent wheezing in infants: a study in the BAMSE cohort.

AIM: The aim of this study was to examine the relationship between indoor exposures and the home environment, and the development of recurrent wheezing during infancy. METHODS: A birth cohort, comprising 4089 children, was followed. Information on exposures was obtained shortly after birth, and episodes of wheezing were recorded when the infants were 1 and 2 y of age. In a nested case-control study, 181 infants were enrolled, who had three or more reported episodes of wheezing after 3 mo of age combined with either use of inhaled steroids or symptoms of bronchial hyper-reactivity, and 359 age-matched controls. Home inspections were performed during the winter following enrolment, and indoor conditions were measured. RESULTS: Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated. The OR for recurrent infant wheezing associated with signs of dampness reported prospectively by parents was 1.4 (0.9-2.2), and the OR for observed signs of dampness at home inspections was 1.6 (1.0-2.5). A trend was found in the risk of recurrent wheezing in relation to the number of indicators of dampness: OR 1.3 (0.8-2.2) for one sign of dampness and OR 2.7 (1.3-5.4) for three or more signs of dampness. Newly painted surfaces in the child's bedroom was associated with an increased OR for recurrent wheezing: 1.7 (1.3-2.6). CONCLUSION: Indicators of dampness, as well as recently repainted interior surfaces, appear to be associated with recurrent infant wheezing, with a strengthened effect of combined indoor exposures.

Building characteristics, indoor air quality and recurrent wheezing in very young children (BAMSE).

This study was conducted to examine the impact of building characteristics and indoor air quality on recurrent wheezing in infants. We followed a birth cohort (BAMSE) comprising 4089 children, born in predefined areas of Stockholm, during their first 2 years of life. Information on exposures was obtained from parental questionnaires when the children were 2 months and on symptoms and diseases when the children were 1 and 2 years old. Children with recurrent wheezing, and two age-matched controls per case, were identified and enrolled in a nested case-control study. The homes were investigated and ventilation rate, humidity, temperature and NO2 measured. We found that living in an apartment erected after 1939, or in a private home with crawl space/concrete slab foundation were associated with an increased risk of recurrent wheezing, odds ratio (OR) 2.5 (1.3-4.8) and 2.5 (1.1-5.4), respectively. The same was true for living in homes with absolute indoor humidity >5.8 g/kg, OR 1.7 (1.0-2.9) and in homes where windowpane condensation was consistently reported over several years, OR 2.2 (1.1-4.5). However, air change rate and type of ventilation system did not seem to affect the risk. In conclusion, relatively new apartment buildings, single-family homes with crawl space/concrete slab foundation, elevated indoor humidity, and reported wintertime windowpane condensation were associated with recurrent wheezing in infants. Thus, improvements of the building quality may have potential to prevent infant wheezing.