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.

Diet in infancy and bronchial hyperreactivity later in childhood.

Sixty-seven atopy-prone children (atopic family group, AFG) and 52 children with no family history of atopy (NAFG) were followed for 10 years. During infancy, the mothers of the newborn AFG children were advised to adjust their infants' diet, with a view toward minimizing the risk of atopy, and not to keep pets. Pulmonary function tests, methacholine inhalation challenge (MIC), and skin prick tests (SPT) were done in order to evaluate the bronchial reactivity and skin reactivity in the two groups. A pathological result in MIC was found in 20 (30%) of the AFG children and in 10 (19%) of the NAFG children. Such results of MIC were more common in the children with positive SPT results than in those without (67% vs. 24%). In regard to the diet consumed in infancy, MIC was pathological in 23% of children with and in 36% without prophylactic diet in infancy. For MIC, using the new, Spira electro 2 dosimeter equipment, the sensitivity was 75% and specificity 97%, but the predictive value for diagnosing bronchial asthma was only 25%. The important advantage of our method is that the degree of bronchial reactivity can be estimated by responses to increasing provocative doses. Our observations confirm that the new method is suitable for detecting bronchial asthma in clinical practice but it seems not to be optimal for epidemiological studies. We concluded that later bronchial hyperreactivity can not be diminished by avoiding home pets or providing a hypoallergenic diet during infancy.

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.

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.

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.

Atopy in children with and without a family history of atopy. I. Clinical manifestations, with special reference to diet in infancy.

The influence of a family history of atopy on atopic morbidity, and relationships between diet in infancy and allergic manifestations at the ages of one and five years were prospectively studied in 91 children. A control group consisted of 72 children with no family history of atopy. At the age of one year, atopic manifestations were found in 19% of 163 children, in 23% of those with a family history of atopy and in 14% of those with no such history. Skin problems were more common in children with a family history of atopy (43%) than in the control children (19%). Of the children with a family history of atopy, 23% had prolonged rhinorrhoea during infancy. The corresponding figure in children with no family history of atopy was 10%. Prolonged rhinorrhoea during infancy correlated with parental smoking only in children with a family history of atopy (47% vs. 18%). At the age of five years, atopic disease was found in 17% of 128 children, 24% of those with a family history of atopy and 9% of those with no such history. Atopic eczema was more common in children with a family history of atopy, irrespective of the diet consumed during infancy. Atopic signs were found in about half of all the children with a family history of atopy. If atopy had been present in the family, the child usually exhibited the same manifestation. Onset of atopic manifestations was not prevented or delayed.

Changes in carbohydrate and lipid metabolism in children with asthma inhaling budesonide.

In a longitudinal study, antiasthmatic and metabolic effects of budesonide inhalations in initially high (800 micrograms/m2/day for 1 month) and subsequently lower (400 micrograms/m2/day for 4 months) dosage were evaluated in nine children with asthma, aged 5 to 10 years. The FEV1 increased significantly after high dosage (median, 96.5% versus 105.5%; p = 0.0339). After lower dosage, FEV1 was still higher than at the baseline (106% versus 96.5%; p = 0.0339). Clinically, no additional beta2-agonist was needed after 2 weeks of treatment. Serum high-density lipoprotein cholesterol increased significantly by 22% after high dosage (medians, 1.18 versus 1.44 mmol/L). A significant decline to 1.31 mmol/L was observed when the dose was reduced (overall, p = 0.0319). The treatment had no significant effect on serum total cholesterol, on serum triglycerides, on the ratio of high-density lipoprotein to total cholesterol, on the body mass index, or on glucose tolerance. The high dosage increased significantly the ratio of serum insulin to blood glucose, calculated from the areas under the incremental 2-hour curves in the glucose tolerance test (medians, 17.3 versus 23.2 mU/mmol). After lower dosage, the ratio declined significantly to 13.5 mU/mmol (overall, p = 0.0164). No significant changes were observed in plasma cortisol in the 2-hour adrenocorticotropic hormone test. The antiasthmatic effect of budesonide inhalations in a dose of 800 micrograms/m2/day for 1 month was accompanied by detectable changes in lipid and carbohydrate metabolism. These metabolic changes were reversible, and the antiasthmatic effect could be maintained by a dose of 400 micrograms/m2 for 4 months without significant systemic effects. This dose is safe and efficient in the maintenance treatment of childhood asthma.

Atopy in childhood and diet in infancy. A nine-year follow-up study. I. Clinical manifestations.

A national program for the prevention of atopy in children has been in progress in Finland since 1979. Its aim is to prevent or at least to reduce atopic symptoms in childhood. Since the start of the program we have followed a group of 119 children with and without a family history of atopy. Half the atopy-prone children kept to the diet intended to prevent atopy, i.e., breast-feeding prolonged up to age 3 months and introduction of solid food and formulae based on cow's milk after age 3 months. All children were examined at ages 5 and 10 years. In addition to clinical examination and interview, skin-prick tests using eight common inhalant allergens were performed. At age 9 to 10 years, 38 of the 119 children (32%) exhibited at least one atopic illness (bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic eczema or food allergy). Forty percent of children with family histories of atopy had atopic illness, independent of diet in infancy. The occurrence of atopic manifestations in the children of nonatopic families was 21%. Only half the children who had atopic symptoms at age 12 months had symptoms 9 years later. Asthma, allergic rhinitis, and positive skin-prick test results at age 5 years, however, correlated well with the subsequent occurrence of respiratory allergy. Our observations indicate that the preventive measures in early infancy intended to reduce the risk of atopy had no influence on atopic manifestations 9 years later.

Follow-up of nutritional status and dietary survey in children with cow's milk allergy.

The nutritional status of children with cow's milk allergy was followed during an elimination diet in 19 children (9 boys and 10 girls) beginning at the mean age of two years (range 0.6-4.1 years). The cow's milk allergy had been verified in hospital by a challenge test at a mean age of 0.9 years (range 0.2-1.9 years). Weight, height and laboratory indices to test protein, mineral and vitamin status were measured at three follow-up visits at three-month intervals. In addition to cow's milk allergy all these children had some other food allergies, and six of the 19 children were allergic to soy protein. Only two of the 19 children were given a soy-based formula. In the diets of the other children, cow's milk was replaced by increasing amounts of other foodstuffs and supplementary calcium. At the beginning of the study the relative heights of the children were slightly retarded (-0.6 SD) and remained unchanged during follow-up (-0.8 SD at the end of the study). The relative weights were found to be decreased during follow-up (p less than 0.05). There was a significant reduction in serum prealbumin values; eight of the 19 children showed abnormally low values. Low serum zinc values were seen in 12 children. Serum iron concentration was low in two children and two had high serum alkaline phosphatase values. Seven-day food recording indicated that dietary intake of energy was below the recommendation in some children, but protein intake was high. Some children had low intakes of riboflavin.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Beta-lactoglobulin secretion in human milk varies widely after cow's milk ingestion in mothers of infants with cow's milk allergy.

BACKGROUND: Cow's milk proteins secreted in human milk may cause cow's milk allergy (CMA) even during exclusive breast-feeding. We studied beta-lactoglobulin levels in human milk of mothers of infants with CMA. We also studied intestinal absorption of macromolecules in the same mothers to see whether it is related to the secretion of beta-lactoglobulin in human milk. METHODS: CMA was verified with oral challenge in 46 of 55 infants assessed. beta-Lactoglobulin levels were assessed in human milk from 53 of 55 mothers of the infants before (basal sample) and 1 and 2 hours after an oral cow's milk load, which was given after a 24-hour milk-free diet. beta-Lactoglobulin was determined by an ELISA with a detection limit of 0.002 microgram/L. The 6-hour urine recovery of a high-molecular-weight polyethylene glycol (PEG) 3000 was assessed after an oral load of PEG in 45 of 55 mothers. RESULTS: beta-Lactoglobulin was found in the 1- or 2-hour samples in 75% of the mothers. beta-Lactoglobulin levels were increased in the 1- or 2-hour samples as compared with the basal levels in about half of the mothers. The respective levels were decreased in one third of the mothers whose basal beta-lactoglobulin levels were higher than in the others. beta-Lactoglobulin was found in none of the three human milk samples in 15% of the mothers. After an oral load of a high-molecular-weight PEG 3000, the 6-hour urine recovery of PEG was similar in the mothers of the infants with CMA and the mothers of infants without CMA. Neither was the urinary recovery of PEG related to the beta-lactoglobulin levels in human milk. CONCLUSIONS: The results support the view that beta-lactoglobulin in human milk may contribute to, but does not alone explain, the development of CMA in breast-fed infants.

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.

Serum eosinophil cationic protein during treatment of asthma in children.

BACKGROUND: Serum eosinophil cationic protein (ECP) is suggested to reflect the degree of bronchial inflammation and hyperreactivity in patients with asthma. We measured serum ECP levels before and 1 and 5 months after treatment with inhaled budesonide (n = 10) or sodium cromoglycate (SCG) (n = 7) in children with asthma. METHODS: The daily dose of budesonide was 800 micrograms/m2 during the first month and 400 micrograms/m2 during the next 4 months. ECP levels were determined by radioimmunoassay. RESULTS: ECP decreased during the 5 months of treatment (p = 0.020 for treatment groups combined; p = 0.049 for the budesonide group; p = NS for the SCG group). The higher the serum ECP level at entry, the more it decreased during treatment, both in the budesonide group (r = -0.697, p < 0.05) and in the SCG group (r = -0.893, p < 0.05). No correlation was found between the ECP level and the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1%) or between changes in these. However, basal pulmonary function was reduced in 8 of 16 subjects only, and FEV1% did not change significantly in either group. Thus the absence of a correlation is understandable. CONCLUSIONS: The clinical value of the sensitive decrease in serum ECP remains to be established.

A 2- to 3-year outcome after bronchiolitis.

OBJECTIVE: To determine the risk factors and short-term outcome until 3 years of age for subsequent wheezing in children with early childhood bronchiolitis or pneumonia. DESIGN: Prospective follow-up of a patient group. SETTING: University hospital providing primary care for all pediatric patients of a defined area. PATIENTS: One hundred twenty-seven children under 2 years of age hospitalized owing to wheezing (n = 83) or pneumonia (n = 44) during 12 months in 1981 to 1982. One hundred eight children completed the prospective follow-up until 3 years of age. INTERVENTIONS: None. MAIN RESULTS: The wheezing and pneumonia groups had equal viral and bacterial etiologic findings. History of wheezing, atopic eczema, and elevated serum IgE levels were more common in patients with wheezing than with pneumonia. Subsequent wheezing was seen after bronchiolitis in 76% (61 of 80) of the children at 1 to 2 years of age and in 58% (44 of 76) at 2 to 3 years of age. The respective figures were significantly lower, 9% (three of 33) and 16% (five of 32), in patients with pneumonia. An analysis of risk factors did not reveal any with a significant effect on subsequent wheezing. CONCLUSIONS: Subsequent wheezing is common after bronchiolitis, but rare after early childhood pneumonia, although caused by the same viruses or bacteria. Atopic diathesis is the host factor associated with initial wheezing. No genetic or environmental risk factor had significant association with later wheezing.