Pulmonary function following allogeneic stem cell transplantation in childhood: a retrospective cohort study of 51 patients.

HSCT is associated with a high risk of late morbidity. The aim of this study was to evaluate the frequency, time frame, risk factors, and possible etiology of pulmonary dysfunction following allogeneic HSCT in childhood. We evaluated the pulmonary function of 51 HSCT patients (>6 yr), by including FVC and FEV1 values prior to (baseline) and annually up to five yr after HSCT. A Cox proportional hazards model was used to analyze the risk factors for a pulmonary event. Over half (59%) of the patients developed pulmonary dysfunction, mainly consisting of restrictive abnormalities. Acute GvHD (HR 4.31, 95% CI 1.47-12.63), chronic GvHD (HR 10.20, 95% CI 2.42-43.03), and an abnormal baseline pulmonary function (HR 4.82, 95% CI 1.02-22.84) were associated with post-transplant dysfunction. FEV1 (p < 0.001) and FVC (p < 0.001) declined significantly by 12 months after HSCT and both remained below the pre-HSCT level at up to four yr post-transplantation. HSCT in childhood is associated with early and persistent restrictive impairment of pulmonary function. Patients with extensive chronic GvHD are particularly vulnerable to severe pulmonary dysfunction. Scheduled pulmonary function testing is warranted as part of the follow-up of survivors of HSCT in childhood.

Budesonide improves decreased airway conductance in infants with respiratory symptoms.

OBJECTIVE: Inhaled corticosteroids (ICS) are commonly used to treat wheezing disorders in children, but few studies have investigated the effect of ICS on lung function in infants. We evaluated the efficacy of inhaled budesonide for decreased specific airway conductance (sGaw) as an indication of bronchial obstruction in very young children with recurrent cough and/or wheeze. PATIENTS, DESIGN AND INTERVENTIONS: Functional residual capacity (FRC) and sGaw of steroid-naive children aged 3-26 months with respiratory symptoms were measured using an infant whole-body plethysmograph. Clinically indicated bronchoscopy was performed in 79% of the patients to exclude anatomical abnormalities before randomisation. Children with abnormal lung function and respiratory symptoms were randomised into two treatment groups, receiving either inhaled budesonide (400 microg/day) or placebo with NebuChamber for 6 weeks. Inhaled terbutaline 0.25 mg/dose was used as a rescue medication. Lung function measurements were repeated after 6 weeks. MAIN OUTCOME MEASURE: Lung function. RESULTS: 44 children with a median age of 11.3 months (range 3.7-25.9) completed the study. Median sGaw improved from a z score of -3.6 to -1.2 (p<0.001) in the budesonide group and from -3.2 to -2.6 (p = 0.033) in the placebo group; between group difference p = 0.014. Improvement in sGaw was more pronounced in children with atopy (p = 0.017). Symptom-free days increased in both the budesonide and placebo groups with no difference between groups. CONCLUSION: Treatment with inhaled budesonide for 6 weeks improved sGaw in young children with chronic cough or wheeze and bronchial obstruction.

Bronchial response pattern of antigen presenting cells and regulatory T cells in children less than 2 years of age.

BACKGROUND: In early childhood, the ability to mount protective immune responses in the airways is impaired, with increased risk of allergic sensitisation to inhaled allergens. Antigen presenting cells (APC) and regulatory T cells (Treg) are important modifiers of T cell immunity but little is known about their distribution in bronchial mucosa at this age. Here the subset distribution of APC and the appearance of Foxp3(+) Treg and bronchus associated lymphoid tissue (BALT) were examined immunohistochemically in children less than 2 years of age with chronic asthma-like symptoms of the lower airways. METHODS: Immunophenotyping was performed in situ on bronchial biopsy specimens obtained from 45 infants, 4-23 months of age, under investigation for airway disease. RESULTS: A well developed HLA-DR(+) network of APC was present in all samples, approximately 50% of the cells being CD68(+) macrophages and the remainder various subsets of dendritic cells. The density of HLA-DR(+) cells increased significantly with age but was not related to atopy, clinical symptoms or lung function. Comparing the density of APC subsets and clinical parameters, only the number of intraepithelial CD1a(+) dendritic cells was significantly increased in infants who had recently suffered a respiratory infection. BALT structures were identified in 22 children, with no relation to lung function, atopic status or human rhinovirus positivity. Plasmacytoid dendritic cells and Foxp3(+) Treg were located primarily within these isolated lymphoid follicles. CONCLUSION: A bronchial network of dendritic cells and macrophages develops quite rapidly after birth, apparently independent of clinical symptoms or atopy. The high frequency of BALT structures containing putative tolerogenic dendritic cells and Treg suggests that these lymphoid follicles play an important role in bronchial immune homeostasis during infancy.

Mothers of very low birth weight infants have less atopy than mothers of full-term infants.

BACKGROUND: Studies on the pregnancy outcome of asthmatic mothers have suggested an increased rate of preterm deliveries. In contrast, our earlier study suggests that mothers of very low birth weight (VLBW) (<1500 g) infants less frequently had atopy than did mothers of full-term infants. METHODS: We inquired about symptoms of atopy and doctor-diagnosed atopy in parents of 370 infants of VLBW (<1500 g) and 544 parents of full-term infants. Odds ratios for atopic symptoms and diagnosed atopy were calculated, and groups were compared with a trend test. RESULTS: Mothers of preterm infants of birth weight (BW) <1000 g significantly less often had physician-diagnosed allergic rhinitis (AR) (P=0.02). Among all the mothers, a trend test showed that maternal AR was significantly (P=0.03) higher in parallel with a higher infant BW. Fathers of infants with different BWs showed no differences in prevalence of atopic symptoms. CONCLUSION: We thus infer that maternal balance between T-helper type 1 (Th1) and Th2 cells, shifted towards Th2 in those with AR, may have a favourable effect on maintenance of pregnancy before gestational week 30.

A dual long-term effect of breastfeeding on atopy in relation to heredity in children at 4 years of age.

BACKGROUND: The long-term effect of early feeding on atopic sensitization is still unsolved. The aim of this study was to evaluate the long-term effect of breastfeeding on atopy in groups of 4-year-old children stratified by atopic heredity. METHODS: We collected four groups of 4-year-old children from a birth cohort: two groups with differing backgrounds of atopic heredity, all exclusively breast-fed for at least 3 months; and two groups with differing atopic heredity, but all fed with cow's milk-based formula during their first weeks. The data were collected with a questionnaire, skin prick testing, and measurement of serum total and allergen-specific IgE levels. RESULTS: Breastfeeding significantly decreased the risk of allergic rhino-conjunctivitis [odds ratio (OR) 0.41, 95% confidence interval (CI) 0.18-0.95] and sensitization to furred pets, as measured by skin prick results, in children with atopic heredity, whereas in children without atopic heredity, breastfeeding was related to an increased risk of symptomatic atopy (OR 2.57, 95% CI 1.16-5.70), and high serum IgE values. A significant interaction was found between heredity and breastfeeding. CONCLUSIONS: The long-term effect of breastfeeding was dual: in children with atopic heredity, breastfeeding protected against atopy, whereas in children without atopic heredity, it increased the risk of atopy.

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.

Prematurity at birth reduces the long-term risk of atopy.

BACKGROUND: Antigen exposure in early life has long-lasting effects on atopic sensitization. Thus the predisposition to atopy of children born preterm can be assumed to differ from that of children born at term. OBJECTIVE: The aim of this study was to evaluate the association between premature birth and atopy. METHODS: At an outpatient clinic, we examined 2 groups of 10-year-old children, 72 who were born preterm (birth weight < 1500 g) and 65 who were born at term (birth weight > 2500 g). The atopy data were collected with a questionnaire, by performing skin prick testing, and by measuring the serum total IgE level, 3 allergen-specific IgE levels, the eosinophil cationic protein level, and the blood eosinophil level. The data on perinatal and neonatal events affecting the preterm children were collected from the hospital records. RESULTS: By the age of 10 years, the children born preterm had significantly less atopy than the children born at term: 15% versus 31% of children in the 2 groups were defined as having had obvious atopy (P = .03, odds ratio 0.41, 95% CI 0.18-0.93). The mean value of total IgE level was significantly higher in the term group, 74 kU/L versus 41 kU/L (P = .02). By skin prick testing, the children born at term had positive reactions 2 to 3 times more often; 37% versus 17% of children in the groups had at least 1 positive reaction (P = .007). CONCLUSION: Our data show that prematurity at birth is linked with a decreased long-term risk of atopic sensitization.

Inhaled corticosteroids during and after respiratory syncytial virus-bronchiolitis may decrease subsequent asthma.

Respiratory syncytial virus (RSV) bronchiolitis in infancy can lead to bronchial hyper-reactivity or recurrent obstructive bronchitis. The aim of the present study was to determine whether the type of treatment has an influence on respiratory status after RSV bronchiolitis. The study involved 117 infants (mean age 2.6 months), who needed hospital treatment because of RSV bronchiolitis. The patients were divided randomly into three groups. All received the same symptomatic treatment. Group I children received symptomatic treatment only, group II children were treated for 7 days with inhaled budesonide, 500 microg three times per day, administered via a nebulizer. Group III children received nebulized budesonide, 500 microg twice per day for two months. Follow-up consisted of out-patient check-ups 2 and 6 months after the infection, and telephone contact two years after the infection. Statistically significant differences were seen between the groups. In group I 37% of the children had asthma, in group II 18%, and in group III 12%. According to the present study it seems that inhaled corticosteroid treatment during and after the acute phase of infant RSV bronchiolitis may have a beneficial effect on subsequent bronchial wheezing tendency.

Infections in early childhood and risk of atopic disease.

Having more siblings has been shown to be associated with lower risk of atopic diseases. This might be due to the higher number of infections in larger families. Because children attending day care centres have more respiratory infections, we analysed the association of number of siblings and day care attendance in children aged 1-3 y with atopic disease in a cross sectional survey of 8387 schoolchildren aged 13-14 y and their parents in four regions of Finland. Having no siblings, compared to three or more siblings, was associated with significantly higher risk of lifetime history of hay fever (odds ratios (OR) 1.53, 95% confidence interval (CI) 1.25-1.86) and atopic eczema (OR 1.28, 95%CI 1.04-1.56), and higher risk (ns) of doctor-diagnosed asthma ever (OR 1.26, 95%CI 0.85-1.88). Less strong associations were observed with the number of older siblings (birth order). No associations were observed with current symptoms of these diseases during the last 12 mo. Attending a day care centre at the age of 1-3 y was not associated with decreased risk of any of the atopic diseases studied, but, in contrast to the hypothesis, was associated with slightly increased risk of current symptoms of hay fever (OR 1.34, 95%CI 1.12-1.60). The present results suggest that other factors than early childhood respiratory infections explain the association between number of siblings and future risk of atopic disease.

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.

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.

Breastfeeding as prophylaxis against atopic disease: prospective follow-up study until 17 years old.

Atopic diseases constitute a common health problem. For infants at hereditary risk, prophylaxis of atopy has been sought in elimination diets and other preventive measures. We followed up healthy infants during their first year, and then at ages 1, 3, 5, 10, and 17 years to determine the effect on atopic disease of breastfeeding. Of the initial 236 infants, 150 completed the follow-up, which included history taking, physical examination, and laboratory tests for allergy. The subjects were divided into three groups: prolonged (> 6 months), intermediate (1-6 months), and short or no (< 1 month) breastfeeding. The prevalence of manifest atopy throughout follow-up was highest in the group who had little or no breastfeeding (p < 0.05, analysis of variance and covariance with repeated measures [ANOVA]). Prevalence of eczema at ages 1 and 3 years was lowest (p = 0.03, ANOVA) in the prolonged breastfeeding group, prevalence of food allergy was highest in the little or no groups (p = 0.02, ANOVA) at 1-3 years, and respiratory allergy was also most prevalent in the latter group (p = 0.01, ANOVA) having risen to 65% at 17 years of age. Prevalences in the prolonged, intermediate, and little or no groups at age 17 were 42 (95% CI 31-52)%, 36 (28-44)%, and 65 (56-74)% (p = 0.02, trend test) for atopy, respectively, and 8 (6-10)%, 23 (21-25)%, and 54 (52-56)% (p = 0.0001, trend test) for substantial atopy. We conclude that breastfeeding is prophylactic against atopic disease--including atopic eczema, food allergy, and respiratory allergy--throughout childhood and adolescence.

Prophylaxis of atopic disease by six months' total solid food elimination. Evaluation of 135 exclusively breast-fed infants of atopic families.

One hundred and thirty-five infants of atopic parents were exclusively breast-fed for 6 months without any cow's milk based supplements. Of these infants 70 received no nourishment except breast milk during the 6 months, and 65 were started on solid foods at the age of 3 months. The diet of all the infants was similar during 6 to 12 months of age. The children were examined at the age of one year. In the exclusive breast milk group atopic eczema and food allergy were less frequent than in the solid food group. The results suggest that total solid food elimination for the first 6 months of life, in addition to exclusive breast milk feeding, is prophylactic for atopic disease in children who are at hereditary risk.

Immunoglobulin E and immunoglobulin G4 antibodies to cow's milk in children with cow's milk allergy.

The presence of cow's milk specific antibodies of immunoglobulin E and G4 classes were studied in 47 children with a positive clinical history of cow's milk allergy. The children were challenged with cow's milk orally. The clinical diagnosis was verified by immediate reactions in 25 patients while 22 had late reactions or were provocation test negative in spite of the clinical history. There was no relation between levels of cow's milk specific IgG4 antibodies and provocation test results, i.e. neither with immediate or late reactions. Total IgE was elevated above +1 SD for age in 31 of 41 tested patients. Of these, 29 had immediate type reactions to cow's milk, wheat flour and/or egg white, while only two of 10 children with IgE of less than +1 SD had a demonstrable allergy to any of these foods. The sensitivity of the total IgE determinations for the diagnosis of food allergy was 94% and the specificity was 80%. Specific IgE antibodies to cow's milk were demonstrated in 11 of 14 children with immediate reactions and in three of 15 who were provocation test negative or had only late reactions. This means a sensitivity of 79% and a specificity of 80%. At least one of the four patients with specific IgE but negative provocation test results had earlier shown an immediate reaction when challenged with cow's milk, indicating that the specific IgE antibodies were not truly "false" positive reactions but a consequence of previous allergy. Our results confirm an association between elevated total serum IgE and food allergy and an association between positive RAST to cow's milk and positive provocations in young children. We did not find any evidence for specific IgG4 antibodies playing a role in these patients.

Food allergy in Finnish children aged 1 to 6 years.

Food allergy was studied in a total of 866 Finnish children aged 1, 2, 3 and 6 years in the Helsinki region. The diagnosis was based on history as well as on elimination and challenge performed at home concerning fish, citrus fruit and eggs. The prevalence of food allergy was 19% at one year of age, increased to a peak of 27% at three years, and thereafter decreased to 8% at six years of age. The most common allergenic foods were citrus fruit, tomato, eggs, strawberry and fish. A positive history of food allergy could be confirmed by challenge in about half of the cases in the younger age groups and in 100% at six years of age. The data indicate that food allergy is common in Finnish children.

Birch pollen allergy in children. Role of milk feeding during the first birch season of life.

The effect of exclusive breast-feeding throughout the first birch pollen season of life was examined in 59 children compared to 67 children on cow milk formula and to 27 children weaned to cow milk-based formula during their first birch season. The infants were about 3 months of age in their first birch season, and allergy to birch pollen was evaluated at 5 years of age by history and prick and provocation tests. Breast-feeding throughout the first birch season did not prevent birch pollen allergy; a similar birch allergy prevalence of about 10% was found in children initially fed on human or cow milk. Instead, weaning to cow milk-based formula during the first birch season seemed to protect from subsequent development of birch pollen allergy. Analogous results were obtained regarding allergy to grass pollen. This unexpected finding may be related to the immunologic stress on the young infant provided by introduction of cow milk proteins at an early age.