Daily versus as-needed inhaled corticosteroid for mild persistent asthma (The Helsinki early intervention childhood asthma study).

OBJECTIVE: To compare the effect of inhaled budesonide given daily or as-needed on mild persistent childhood asthma. Patients, design and INTERVENTIONS: 176 children aged 5-10 years with newly detected asthma were randomly assigned to three treatment groups: (1) continuous budesonide (400 microg twice daily for 1 month, 200 microg twice daily for months 2-6, 100 microg twice daily for months 7-18); (2) budesonide, identical treatment to group 1 during months 1-6, then budesonide for exacerbations as needed for months 7-18; and (3) disodium cromoglycate (DSCG) 10 mg three times daily for months 1-18. Exacerbations were treated with budesonide 400 microg twice daily for 2 weeks. MAIN OUTCOME MEASURES: Lung function, the number of exacerbations and growth. RESULTS: Compared with DSCG the initial regular budesonide treatment resulted in a significantly improved lung function, fewer exacerbations and a small but significant decline in growth velocity. After 18 months, however, the lung function improvements did not differ between the groups. During months 7-18, patients receiving continuous budesonide treatment had significantly fewer exacerbations (mean 0.97), compared with 1.69 in group 2 and 1.58 in group 3. The number of asthma-free days did not differ between regular and intermittent budesonide treatment. Growth velocity was normalised during continuous low-dose budesonide and budesonide therapy given as needed. The latter was associated with catch-up growth. CONCLUSIONS: Regular use of budesonide afforded better asthma control but had a more systemic effect than did use of budesonide as needed. The dose of ICS could be reduced as soon as asthma is controlled. Some children do not seem to need continuous ICS treatment.

Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a double-blind placebo-controlled trial.

BACKGROUND: Probiotic bacteria are suggested to reduce symptoms of the atopic eczema/dermatitis syndrome (AEDS) in food-allergic infants. We aimed to investigate whether probiotic bacteria have any beneficial effect on AEDS. METHODS: Follow-up of severity of AEDS by the Severity Scoring of Atopic Dermatitis (SCORAD) index in 230 infants with suspected cow's milk allergy (CMA) receiving, in a randomized double-blinded manner, concomitant with elimination diet and skin treatment, Lactobacillus GG (LGG), a mixture of four probiotic strains, or placebo for 4 weeks. Four weeks after the treatment, CMA was diagnosed with a double-blind placebo-controlled (DBPC) milk challenge in 120 infants. RESULTS: In the whole group, mean SCORAD (at baseline 32.5) decreased by 65%, but with no differences between treatment groups immediately or 4 weeks after the treatment. No treatment differences were observed in infants with CMA either. In IgE-sensitized infants, however, the LGG group showed a greater reduction in SCORAD than did the placebo group, -26.1 vs-19.8 (P=0.036), from baseline to 4 weeks after the treatment. Exclusion of infants who had received antibiotics during the study reinforced the findings in the IgE-sensitized subgroup. CONCLUSION: Treatment with LGG may alleviate AEDS symptoms in IgE-sensitized infants but not in non-IgE-sensitized infants.

Mechanical ventilation in children with severe asthma.

Hospital admissions for childhood asthma have increased during the past few decades. The aim of this study was to describe the need for mechanical ventilation for severe asthma exacerbation in children in Finland from 1976 to 1995. We reviewed medical records and collected data retrospectively from all 5 university hospitals in Finland, thus covering the entire population of about 5 million. The endpoints selected were the number of admissions and readmissions leading to mechanical ventilation, duration of stay in the hospital, and mortality. Moreover, asthma medications prescribed prior to admission and administered in the intensive care unit (ICU), as well as the etiology of the exacerbation associated with mechanical ventilation were examined. Mechanical ventilation was required in 66 ICU admissions (59 patients). This constituted approximately 10% of all 632 admissions for acute asthma to an ICU. The number of admissions decreased from 1976 to 1995: 41 admissions between 1976 and 1985 vs. 25 admissions during the next 10-year period. The mean age at admission to the ICU was 3.6 years, and 46% of the patients were boys. Prior to the index admission, 70% of the patients had used asthma medication such as oral bronchodilator (50%), inhaled bronchodilator (20%), theophylline (38%), inhaled glucocorticoid (18%), oral glucocorticoid (5%), and cromoglycate (7%). Respiratory infection was by far the most common cause of all the exacerbations (61%), followed by food allergy (8%) and gastroesophageal reflux (3%). In 28% of cases the cause of the severe asthma exacerbation could not be identified. In the mechanically ventilated patients readmissions occurred 38 times between 1976 and 1985 vs. 5 times between 1986 and 1995. Five of the patients who received mechanical ventilation died, and in 3 of these patients asthma was the event causing death. In conclusion, there has been decrease in the number of first and repeat ICU admission for asthma requiring mechanical ventilation between 1970 and 1995. This trend occurred despite a simultaneous 5% yearly increase in hospital admissions for childhood asthma during these 2 decades.

Acute childhood asthma in Finland: a retrospective review of hospital admissions from 1976 to 1995.

The prevalence of childhood asthma has increased markedly in many Western societies during recent decades. We wanted to study whether the incidence and severity of childhood asthma in Finland had changed during the time-period 1976-95. Hospital admission rates from 1976 to 1995 were obtained from the National Hospital Discharge Register and the individual intensive care unit (ICU) registers of the five university hospitals in Finland. The number and length of treatment periods for childhood asthma in all Finnish hospitals and at the ICUs of the five university hospitals were analyzed. The number of children receiving special reimbursement for asthma medication costs was obtained from the central register of the Social Insurance Institution. The data showed that during the time-period investigated, hospital admissions as a result of asthma had increased by 2.8-fold, but the mean length of hospital stay had more than halved (from 7.3 to 2.6 days). The increase in hospital admissions showed greatest significance in the 0-4-year age-group among both sexes (p <0.001). In contrast, a significant reduction in hospital admissions was found among the 10-14-year age-group (p <0.001). No discernible change in admission to ICUs was seen. During the same time-period, the number of children receiving special reimbursement for asthma medication costs increased 7.5-fold. Hence, a major increase has occurred in the number of children diagnosed with asthma that has not been paralleled by a proportionate increase in the number of hospital admissions. While the prevalence of mild and moderate asthma has increased, the occurrence of severe asthma has remained essentially unchanged.

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

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

Breast-feeding and the development of cows' milk protein allergy.

Early feeding with cows' milk (CM) may cause cows' milk allergy (CMA). Breast milk contains many immune factors which compensate for the undeveloped defence mechanisms of the gut of the newborn infant. We studied the effect of supplementary CM feeding at the maternity hospital on the subsequent incidence of CMA, the effects of formula and breast feeding on the subsequent immunologic types of CMA, and the importance of immune factors present in colostrum in the immune responses of infants with CMA. In a cohort of 6209 infants, 824 were exclusively breast-fed and 87% required supplementary milk while in the maternity hospital: 1789 received CM formula, 1859 pasteurized human milk, and 1737 whey hydrolysate formula. The cumulative incidence of CMA, verified by a CM elimination-challenge test, was 2.4% in the CM, 1.7% in the pasteurized human milk and 1.5% in the whey hydrolysate group. Among these infants, exposure to CM at hospital and a positive atopic heredity increased the risk of CMA. Of the exclusively breast-fed infants, 2.1% had CMA. Risk factors for the development of IgE-mediated CMA were: exposure to CM at hospital, breast-feeding during the first 8 weeks at home either exclusively or combined with infrequent exposure to small amounts of CM and long breast-feeding. The content of transforming growth factor-beta1 (TGF-beta1) in colostrum from mothers of infants with IgE-mediated CMA was lower than from mothers of infants with non-IgE-mediated CMA. In infants with CMA, TGF-beta1 in colostrum negatively correlated with the result of skin prick test and the stimulation of peripheral blood mononuclear cells to CM, but positively with infants' IgA and IgG antibodies to CM proteins. Feeding of CM formula at maternity hospital increases the risk of CMA, but exclusive breast-feeding does not eliminate the risk. Prolonged breast-feeding exclusively or combined with infrequent exposure to small amounts of CM during the first 8 weeks induces the development of IgE-mediated CMA. Colostral TGF-beta1 may inhibit IgE- and cell mediated reactions and promote IgG-IgA antibody production to CM in infants prone to developing CMA.

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.

Supplementary feeding in maternity hospitals and the risk of cow's milk allergy: A prospective study of 6209 infants.

BACKGROUND: Early feeding with cow's milk (CM) may increase the risk of cow's milk allergy (CMA). OBJECTIVE: We sought to examine prospectively whether supplementary feeding of CM at the maternity hospital would increase the risk when compared with feeding with pasteurized human milk or hydrolyzed formula. METHODS: We studied 6209 unselected healthy, full-term infants, of whom 5385 (87%) required supplementary milk while in the hospital. The infants were randomly assigned to receive CM formula (1789 infants), pasteurized human milk (1859 infants), or whey hydrolysate formula (1737 infants). The comparison group (824 infants) was composed of infants who were exclusively breast-fed. The infants were followed for 18 to 34 months for symptoms suggestive of CMA. The primary endpoint was a challenge-proven adverse reaction to CM after a successful CM elimination diet. RESULTS: The cumulative incidence of CMA in the infants fed CM was 2.4% compared with 1.7% in the pasteurized human milk group (odds ratio [OR], 0.70; 95% confidence interval [CI], 0. 44-1.12) and 1.5% in the whey hydrolysate group (OR, 0.61; 95% CI, 0. 38-1.00). In the comparison group, CMA developed in 2.1% of the infants. Among the infants who required supplementary feeding at hospital, both exposure to CM while in the hospital (OR, 1.54; 95% CI, 1.04-2.30; P =.03) and obvious parental atopy (OR, 2.32; 95% CI, 1.53-3.52; P <.001) increased the risk of CMA. CONCLUSIONS: Our data indicate that feeding of CM at maternity hospitals increases the risk of CMA when compared with feeding of other supplements, but exclusive breast-feeding does not eliminate the risk.

Relation between weak HLA-DR expression on human breast milk macrophages and cow milk allergy (CMA) in suckling infants.

The precise role of breast milk leukocytes is unknown. We therefore studied the cellular composition of breast milk and the activation of breast milk macrophages in mothers with a cow milk-allergic infant and in those with a healthy infant. Further, we sought to determine the influence of the cellular composition of mother's milk on the infant's risk of developing cow milk allergy. Thirty-six asymptomatic mothers (26 with atopic constitution) whose babies had challenge-proven cow milk allergy and 24 asymptomatic mothers (17 with atopic constitution) with healthy infants were recruited. Geometric mean ages of the infants were 3.2 mo (95% confidence interval [CI], 2.3 to 4.4) and 2.4 mo (95% CI, 1.6 to 3.7), respectively. After separation of the fat layer, breast milk cells were incubated with fluorescein-labeled MAb to CD antigens (CD14, 45, 3, 4, 8, 19, 23, and HLA-DR) and analyzed by flow cytometry. Breast milk samples, collected with a breast pump, were processed immediately. Cytospin preparations of milk samples, made after separation of the fat layer, were stained with May-Grunwald-Giemsa and examined with a light microscope. HLA-DR expression on breast milk macrophages was significantly lower in the mothers whose infant was allergic to cow milk, 58.3% (95% CI, 44.9 to 75.6), than in the mothers of a healthy infant, 86.9% (95% CI, 78.7 to 96.1), p=0.012 (ANOVA). There was also a significant difference in the total number of breast milk leukocytes between the mothers with an allergic child, 0.17 x 10(6)/mL (95% CI, 0.12 to 0.25), and those with a healthy child, 0.08 x 10(6)/mL (95% CI, 0.05 to 0.14), p=0.019 (Mann-Whitney U test). These results suggest impaired function of breast milk macrophages in mothers whose infants had cow milk allergy. They may also reflect decreased antigen presentation to the inexperienced T cells in the gut or on other mucosal surfaces of the suckling infant, leading to subsequent development of food or respiratory allergies, e.g. asthma.

Large number of CD19+/CD23+ B cells and small number of CD8+ T cells as early markers for cow's milk allergy (CMA).

Assessment of activation of immune mechanisms is valuable in the early diagnosis of cow's milk allergy (CMA). The purpose of this study was to evaluate peripheral blood lymphocyte subclasses in children suspected of having CMA and healthy infants in order to detect an early marker for food allergy. Altogether 47 breast-fed infants, aged from 0.4 to 10 months were followed-up prospectively from birth because of atopic heredity. Twenty-three of the infants were healthy and 24 infants had a strong suspicion of and later challenge-proven cow's milk allergy. Leucocyte subsets were determined from peripheral blood mononuclear cells by flow cytometry. In response to a clinical cow's milk challenge, seven infants developed urticaria, 11 infants had eczema, three patients had loose stools, diarrhoea or vomiting and three infants had eczema and diarrhoea, loose stools or vomiting. The total percentage of B cells and also the proportion of B cells bearing a low-affinity IgE receptor as a marker for activation were significantly higher, whereas the percentage of CD8+ T cells was significantly lower in infants with challenge-proven CMA than in healthy controls. These results imply that infants with active CMA have a defect in regulation of B-cell function. Further, they suggest that imbalance of the ratio of suppressor and helper T cells might be an important factor in the etiopathogenesis of CMA. Our results show that large numbers of activated CD19+ B cells and low numbers of CD8+ T cells could be considered as early markers for food allergy since they are already detectable in peripheral blood during the earliest symptoms of CMA.

Eosinophil cationic protein in induced sputum as a marker of inflammation in asthmatic children.

We evaluated the usefulness of eosinophil cationic protein (ECP) in induced sputum and in serum as markers of asthmatic inflammation in children. We measured ECP in serum and in total induced sputum samples from 14 children (7-11 years) with newly detected asthma before and after treatment, and from ten healthy non atopic controls of the same age. The patients inhaled budesonide, 800 micrograms/m2/day for the first month and 400 micrograms/ m2/day for the next 5 months, both divided into two doses, and nedocromil, 4 mg three times daily for the following 6 months. In both sputum and serum, ECP levels were higher in the patients than in the controls, but the difference was more distinct in sputum. Significant clinical improvement during the treatment was accompanied by a decrease in sputum ECP, whereas serum ECP did not change. The results suggest that induced sputum is useful as a non invasive source material for evaluating asthmatic inflammation in children, total sputum ECP being more sensitive than serum ECP for diagnosing and monitoring asthma.

Changes in bone markers in children with asthma during inhaled budesonide and nedocromil treatments.

We evaluated serum and urinary markers of bone turnover in 14 children with asthma during inhaled budesonide and nedocromil treatments. Both the markers of formation (serum carboxy- and amino-terminal propeptides of type I procollagen and serum osteocalcin) and the markers of degradation (serum carboxy-terminal telopeptide of type I collagen and urinary pyridinium cross-links) decreased (p < 0.05) during budesonide treatment for 6 months. During inhaled nedocromil treatment (for the following 6 months), the markers returned to the normal levels. These transient decreases in the markers of both formation and degradation of bone suggest that inhaled budesonide may slightly decrease the bone turnover rate. However, normal "coupling" between formation and degradation seemed to operate, e.g. a change in one resulted in a corresponding change in the other, so that net bone loss did not necessarily occur.

Skin-prick test and RAST responses to cereals in children with atopic dermatitis. Characterization of IgE-binding components in wheat and oats by an immunoblotting method.

BACKGROUND: Hypersensitivity to cereals may occur via inhalation or ingestion. Although cereals are essential in the daily nutrition, only little information is available of the allergens causing symptoms in patients with atopic dermatitis (AD). OBJECTIVE: The purpose of the present study was to analyse the IgE immune-response to various cereals and specific cereal fractions of wheat and oats in children with severe AD and correlate the results with challenge studies. METHODS: Skin-prick tests (SPT) with a NaCl suspension of wheat, oats, rice, corn, millet and buckwheat and the ethanol soluble gliadin fraction of wheat were performed to 34 wheat/oats challenge positive or negative children with AD. Simultaneously serum total IgE and specific IgE antibody radioallergosorbent test (RAST), levels to wheat, oats and gluten were determined. In addition serum samples of these 34 AD patients and five age matched controls were analysed with IgE immunoblotting using neutral and acidic protein extracts of wheat and oats. RESULTS: From the 34 AD children 33 were SPT positive with wheat and 18 with oats. Positive RAST to wheat and oats could be detected in 32 and 30 samples respectively. From the oral wheat challenge positive children 12/14 appeared positive with gliadin SPT and revealed positive RAST to gluten, but each of the wheat challenge negative were negative in SPT with gliadin. In immunoblotting using neutral and acidic fractions of cereals the IgE binding with sera of challenge positive children showed the most intensive staining, but no correlation was found between different staining patterns and the clinical wheat sensitivity. The 26, 38 and 69 kDa bands in wheat and the 46 and 66 kDa in oats could be classified as major IgE binding proteins of these cereals (> 50% of the sera were positive). SPT with rice, corn, millet or buckwheat was positive in 16/34 patients. CONCLUSIONS: Intensive IgE staining to neutral/acidic soluble proteins in wheat and oats was seen, with major IgE binding to 26, 38 and 69 kDa proteins in wheat and 46 and 66 kDa in oats, but no specific IgE staining patterns correlating with clinical cereal sensitivity were found. The strong association between the positive oral wheat challenge and the positive SPT with the ethanol soluble gliadin suggests that also gliadin is an important allergen in wheat-allergic children with AD. The allergens in rice, corn, millet and buckwheat should be better studied before they can be recommended as alternatives for cereal allergic children.

Latex allergy in children with no known risk factor for latex sensitization.

We describe latex allergy in 11 atopic children, aged 0.7-11.1 years, without any known risk factor. A skin prick-test (SPT) for latex was positive in 8/11, and latex specific IgE was found in all. Latex glove challenge was positive in 9 assessed. These patients demonstrate that latex allergy should be looked for not only in children who have had several operations or those children reporting symptoms from rubber, but also in children with severe atopic eczema, banana allergy, or urticaria or anaphylaxis for which the cause is unknown.

Bronchial asthma and hyperreactivity after early childhood bronchiolitis or pneumonia. An 8-year follow-up study.

OBJECTIVE: To determine the infantile risk factors and long-term outcome up to 8 to 10 years of age for bronchial asthma and hyperreactivity in children with early-childhood bronchiolitis or pneumonia. DESIGN: Prospective follow-up of three groups of children. SETTING: University hospital providing primary hospital care and outpatient consultations for all pediatric patients in a defined area. INTERVENTIONS: None. PATIENTS: The study groups consisted of 62 children with early-childhood bronchiolitis, 29 children with early-childhood pneumonia with no wheezing, and 52 control children. METHODS: Infantile risk factors were prospectively registered until 2 years of age. Clinical examination, performed 7 to 8 years later, included recording of atopic and asthmatic symptoms from the preceding 12 months. The methacholine inhalation challenge test was used to assess bronchial hyperreactivity, and mean midexpiratory flow results were used to assess bronchial obstruction. MAIN RESULTS: Bronchial asthma was present in nine (15%) of the 62 children from the bronchiolitis group, compared with 7% in the pneumonia group and 2% in the control group. Bronchial hyperreactivity indicated by methacholine inhalation challenge was far more common; it was present in 62% of the bronchiolitis group and in 45% of the pneumonia group. Both groups differed significantly from the control group. Decreased mean midexpiratory flow values were observed in 29% and 21% of the bronchiolitis and pneumonia groups, respectively. All 10 asthmatic patients had bronchial hyperreactivity, but only 20% of hyperreactive children had asthma. An analysis of infantile risk factors disclosed only one, an early onset of wheezing, with a significant effect on bronchial hyperreactivity at school age. Elevated IgE values measured during infancy were associated with the development of clinical asthma. CONCLUSIONS: The risk of bronchial asthma was increased after infantile bronchiolitis. Moreover, bronchial hyperreactivity was increased after both infantile bronchiolitis and pneumonia. Methacholine inhalation challenge was a sensitive but nonspecific test for diagnosing bronchial asthma. Both bronchiolitis and pneumonia resulting in hospitalization in early childhood distinguish a group of children with an increased risk for long-term lung function abnormalities and pulmonary illnesses.