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Pediatric Pulmonology 26:113–119 (1998)

One-Year Follow-Up of Young Children Hospitalized for Wheezing: The Influence of Early Anti-Inflammatory Therapy and Risk Factors for Subsequent Wheezing and Asthma

Tiina M. Reijonen, MD,* and Matti Korppi, MD

Summary. We investigated the 1-year outcome of children hospitalized for wheezing, paying

special attention to the effect of early anti-inflammatory therapy. In addition, we identified risk factors for recurrent wheezing and asthma. Eighty-eight children under 2 years old treated in the hospital for wheezing were followed for 1 year. Nebulized anti-inflammatory therapy was given for 16 weeks: 31 patients received budesonide, 29 patients cromolyn sodium, and 28 control patients received no therapy. The number of subsequent physician-diagnosed wheezing epi- sodes was recorded. Four months of anti-inflammatory therapy did not significantly decrease the occurrence of asthma 1 year later; 45% of patients in the cromolyn group, 42% in the budesonide group, and 61% in the control group had asthma, defined as at least two bronchial obstruction episodes during the 1-year period after the original hospitalization for wheezing. An age over 12 months

at the time of the initial bronchial obstructing episode [P = 0.009, risk ratio (RR) = 5.4, 95%

confidence interval (CI) = 1.53–19.31], failure to identify a viral cause (P = 0.0003, RR = 12.0,

CI = 3.16–45.40), history of wheezing (P = 0.02, RR = 14.6, CI = 1.59–132.10), the presence of

atopy (P = 0.01, RR = 5.3, CI = 1.47–19.21), a family history of atopy (P = 0.03, RR = 3.6, CI = 1.15–11.12), and serum eosinophil cationic protein (ECP) 16 µg/L (P = 0.005) were sig- nificant risk factors for asthma. We conclude that early anti-inflammatory therapy for 4 months does not significantly decrease the occurrence of asthma during the period of 1 year following hospitalization for the original episode of wheezing. Young children requiring hospital admission for wheezing during a respiratory tract infection are at increased risk of having subsequent asthma if they have wheezed previously, if they have atopy or a family history of atopy, if they have elevated serum ECP, if they are over 12 months of age at the original bronchial obstructive episode, and especially when viral studies are negative. Pediatr Pulmonol. 1998; 26:113–119.

© 1998 Wiley-Liss, Inc.

Key words: asthma; atopy; bronchiolitis; bronchial obstruction; budesonide; cromolyn sodium; eosinophils; eosinophil cationic protein; immunoglobulin E; wheezing; viral infection; randomized controlled trial.

INTRODUCTION

Infants and young children with wheezing associated respiratory tract infections are frequent patients in pedi- atric departments. Many of these patients have a ten- dency to wheeze after their initial infection. 13 Young wheezing children seem to represent a heterogeneous group of conditions which are often clinically indistin- guishable. Some have narrow airways and their lung function is subnormal before any respiratory illnesses occur, and some, especially atopic children, may have early childhood asthma. 46 Respiratory infections cause edema and mucus production and thus obstruct small airways. 7 The exact role of viral infections in the devel- opment of asthma is not clear. Many studies have shown that bronchiolitis leading to hospitalization is an impor- tant risk factor for asthma. 2,3,8 The identification of

© 1998 Wiley-Liss, Inc.

young children who are at risk of having recurrent wheezing episodes or asthma after acute wheezing has stopped is important. Based on our recent observations,

Department of Pediatrics, Kuopio University Hospital, Finland.

Presented in part at The Annual Meeting of the European Academy of Allergology and Clinical Immunology EAACI ’97, Rhodes, Hellas, Greece June 1–5, 1997.

Contract grant sponsor: Foundation of Pediatric Research in Finland; Contract grant sponsor: North Karelia Cultural Foundation; Contract grant sponsor: University of Kuopio.

*Correspondence to: Dr. Tiina M. Reijonen, Department of Pediatrics, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Fin- land.

Received 17 July 1997; accepted 9 April 1998.

114 Reijonen and Korppi

early anti-inflammatory therapy with cromolyn sodium or budesonide reduces wheezing after bronchiolitis. 9 It is not known, however, whether the early anti-inflam- matory therapy protects the children from recurrent wheezing episodes or decreases the prevalence of later asthma. The aim of this study was to investigate the 1-year follow-up of children hospitalized for wheezing, paying special attention to the influence of early anti-inflam- matory therapy. In addition, we identified risk factors for the recurrence of wheezing episodes and asthma.

MATERIALS AND METHODS

One hundred children younger than 24 months old (median age, 10.0 months; range, 1–23 months) and treated in the hospital and the Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland for wheez- ing between January 1, 1992, and November 2, 1993, were enrolled in the study. The clinical criteria for the enrollment were the presence of wheezing and respira- tory distress, leading to hospital admission during an acute respiratory tract infection. The clinical diagnosis of acute bronchiolitis was used. 3 Wheezing and respiratory distress were noted on inspection and auscultation, first by the physician on duty in the emergency room and confirmed within 1 hour by one of the investigators. Pa- tients were excluded when they had a history of chronic cardiorespiratory disease, including doctor-diagnosed asthma, or if they had received regular medication for any pulmonary disease. After an initial clinical evalua- tion, the patients were randomly assigned to three groups by picking an envelope: cromolyn group; budesonide group; or control group. The patients with and without a history of wheezing were randomized separately. To minimize imbalance between groups over time, a prede- termined block randomization scheme was used, with block sizes of 15. The wheezing episode that led to hos- pitalization was the first episode in 87 of the children, and the median duration of tachypnea before admission was 1 day (range, 1–7 days). Nebulized anti-inflammatory therapy was given for 16

days). Nebulized anti-inflammatory therapy was given for 16 weeks: 34 patients received cromolyn sodium, 34 budes-

weeks: 34 patients received cromolyn sodium, 34 budes- onide, and 32 control patients received no anti- inflammatory therapy. The maintenance medication was administered by a foot-pump powered nebulizer with a face mask (Easy-Air Nebuliser, Cameron-Price, Bir- mingham, England), and it was started during the second day of hospitalization. For the first 8 weeks, the dose of cromolyn sodium (Lomudal inhalation liquid, 10 mg/ ml, Fisons Corp., Rochester, NY) was 20 mg four times a day, and that of budesonide (Pulmicort inhalation liq- uid, 250 g/ml, Astra, So¨derta¨lje, Sweden) was 500 g two times a day. For the second 8-week period the doses were reduced: cromolyn sodium to 20 mg three times a day and budesonide to 250 g twice a day. If additional maintenance therapy was needed during the 16-week pe- riod, oral slow-release theophylline was recommended. The outcome from that 4-month period has been recently described in detail. 9 After the termination of the early anti-inflammatory therapy, maintenance therapy for asthma was initiated based on clinical criteria. The study was approved by the Research Ethics Committee of Kuo- pio University Hospital. Before enrollment of the pa- tients, informed oral consent was obtained from the par- ents. If the patients required medical attention and/or treat- ment because of respiratory distress or wheezing, the physicians on duty were asked to record their findings on

diary cards. The patients visited the outpatient clinic 1.5,

4, 8, and 12 months after the index episode of wheezing.

One of the two authors (T.R.) examined the children, interviewed the parents using standard questionnaires, and checked the diaries. The control visits were not per- formed in a blind manner, i.e, the investigator knew to which of the three treatment groups the patient belonged. Ninety-one children (median age, 18.7 months; range, 9.2–32.4 months) attended the 8-month, and 88 children (median age, 22.1 months; range, 13.3–37.4 months) the 1-year follow-up. The baseline characteristics of the sub- jects who were lost from the follow-up did not differ from those of the original study group. A standardized questionnaire was used to interview the parents. It included questions on age, history of wheezing, atopic dermatitis, and family history of asthma and atopic diseases. Only physician diagnoses were con- sidered. Additional information about passive smoking

exposure, pet contacts in the home or at day care, and the number of siblings was recorded. Viral infections were studied by antigen detection in the nasopharyngeal aspirates (NPA) taken at entry and by antibody measurements in paired sera; adeno, influenza

A and B, parainfluenza types 1, 2 and 3, and respiratory

syncytial viruses (RSV) were looked for. 10 Viral antigens were determined by time-resolved fluoroimmuno- assay, and viral antibodies by complement fixation tests. 10 Our test panel did not cover rhinoviruses. Thirty-

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TABLE 1—Characteristics of 88 Young Children Admitted to Hospital for Wheezing a

Characteristic

Cromolyn group (n 29)

Budesonide group (n 31)

Control group (n 28)

P

Median age (range), months Age, <12 mo/ 12 mo (%) Gender, M/F (%)

10.3 (1.0–22.1) 19 (66)/10 (34) 18 (62)/11 (38) 5/29 (17) 9/29 (31) 8/29 (28) 13/29 (45) 14/29 (48) 6/29 (21) 14/29 (48)

9.9 (1.6–23.1) 20 (65)/11 (35) 21 (68)/10 (32) 5/31 (16) 6/31 (19) 6/31 (21) 10/31 (32) 20/31 (65) 9/31 (29) 16/31 (51) 10/31 (32) 17/31 (55)* 13/31 (42) 11/29 (38) 3/31 (10) 14/29 (14)

10.5 (2.1–23.2) 19 (68)/9 (32) 24 (86)/4 (14) 3/28 (11) 10/28 (36) 6/27 (22) 11/28 (39) 13/28 (46) 5/28 (18) 11/28 (39) 10/28 (36) 6/28 (21) 10/28 (36) 13/27 (48) 10/28 (29) 11/27 (41)

0.97

0.96

0.31

History of wheezing (%) Atopic dermatitis at entry (%) Serum IgE > 60 kU/L (%) Atopy (%) Family history of atopy (%) Family history of asthma (%) Passive smoking (%)

0.76

0.35

0.83

0.60

0.30

0.56

0.62

A

pet at home or at day care (%)

8/29 (28) 10/29 (34) 11/29 (38) 4/29 (14)* 3/29 (10) 6/28 (21)

0.80

Two or more siblings (%) Positive viral identification (%) Blood eosinophils 0.45 × 10 9 /L (%)

0.03

0.88

0.02

Serum ECP 16 g/L (%) Nasopharyngeal ECP 870 ng/g (%)

0.09

0.06

a Median age determined by Kruskall-Wallis one-way analysis of variance. , atopic dermatitis or serum IgE 60 KU/L

at entry; , atopic dermatitis or allergic rhinitis diagnosed by physician; , positive identification of viral antigen or

significant rise in antibodies. The viruses searched for were respiratory syncytial viruses, influenza A and B, parainfluenza

types 1,2,3, and adenoviruses. IgE, immunoglobulin E; ECP, eosinophil cationic protein. *P < 0.05 compared with the control group. P values determined by Chi-squared test.

four (39%) of the 88 patients were virus positive; RSV was found in 24 patients, adenoviruses in 5 patients, and parainfluenza 3 in 9, parainfluenza 2 in one, and parain- fluenza 1 virus in one patient. Five patients had two or three viral findings. Viruses were evenly distributed among the therapy groups (Table 1). During the primary hospitalization a venous blood sample was obtained to determine blood eosinophils, serum eosinophil cationic protein (ECP), and immunoglobulin E (IgE). Values of greater than 0.45 cells × 10 9 /L for blood eosinophils, 11 >16 g/L for serum ECP, 10,12 >60 kU/L (144 g/L) for serum IgE were considered significantly elevated. 13 The ECP concentrations in the NPA were determined accord- ing to the instructions of the manufacturer (Pharmacia ECP RIA, Pharmacia, Uppsala, Sweden). The result was expressed as nanograms of ECP per gram of NPA; values of >870 ng/g were considered abnormally elevated. 14

Clinical Definitions

One or more consecutive days of wheezing followed or preceded by a healthy period of at least 1 week con- stituted one wheezing episode. Recurrent wheezing epi- sodes were defined as one physician-diagnosed episode of bronchial obstruction after the index episode. Patients having at least two episodes of physician-diagnosed wheezing after the index episode of wheezing were con- sidered as having asthma. 8 Children with a history of atopic dermatitis or an elevated level of IgE at entry were defined as having atopy. Only physician-diagnosed cases were included.

Statistical Analysis

Data were analyzed with the use of SPSS/PC + 5.0.1 software (SPSS Inc., Chicago, IL). Comparability among the groups was assessed with the Chi-squared test for proportions. The proportional differences between the three groups were analyzed first, with the use of an over- all Chi-square test. If the P value was <0.05, further paired analyses were made. Two-tailed tests and a Bon- ferroni correction 15 were used in all paired analysis. As the distribution of age was not normal, Kruskal-Wallis one-way analysis of variance was used in comparison of age among the three groups. The results are expressed as medians and ranges. The logistic regression model was used to calculate the adjusted risk ratios (RR) with 95% confidence intervals (CI) for estimating the associations between potential risk factors and asthma.

RESULTS

The demographic, laboratory, and clinical characteris- tics were similar in the three treatment groups with the exceptions of family size and blood eosinophils (Table 1). In the budesonide group, there were more frequently two or more siblings compared with the control group. In addition, the cromolyn group had less frequently elevated blood eosinophils than the other two groups. The total follow-up period after the index episodes of wheezing was 12 months; randomized regular early anti- inflammatory therapy was given during the first 4 months, and anti-inflammatory therapy for asthma was offered on the basis of clinical indications during the

116 Reijonen and Korppi

116 Reijonen and Korppi Fig. 1. The outcome of 88 young children in three therapy groups

Fig. 1. The outcome of 88 young children in three therapy groups 1 year after hospitalization for wheezing. The differ- ences among the groups were not significant.

subsequent 8 months. During the total follow-up period, 27 of 88 patients (31%) had no subsequent physician- diagnosed bronchial obstruction, 18 patients (21%) had one (recurrent wheezing group), and 43 patients (49%) had two or more bronchial obstructions (asthma group). The proportions of children with asthma, recurrent wheezing, or with no wheezing did not differ signifi- cantly in the original therapy groups (Fig. 1). At the end of the follow-up period, 8 children (28%) in the former cromolyn group, 9 (29%) in the former budesonide group, and 13 (48%) in the control group received main- tenance therapy for asthma (P 0.24). Of these 30 children, 11 were given cromolyn, 12 were given budes- onide, and 2 were given oral theophylline. Five children received combination therapy: two patients received cro- molyn and theophylline; two patients budesonide and theophylline; and one patient budesonide and salmeterol. All but two children with asthma had experienced at least one subsequent episode of wheezing after the first 4- month period. Of the 88 children, 34 (39%) who completed the 1- year follow-up had positive viral identification during the index episode of wheezing. These 34 children had sig- nificantly less asthma and were significantly more often without symptoms during the follow-up than the 54 pa- tients with no viral identification (Fig. 2). We evaluated the potential risk factors for subsequent wheezing by comparing the characteristics of patients with no subsequent bronchial obstruction to the charac- teristics of those with recurrent wheezing episode and to those with asthma. An age of more than 12 months at the time of the original (baseline) airway obstructive episode was a significant risk factor for asthma (P 0.009, risk ratio, RR 5.4, 95% confidence interval CI 1.53– 19.31). Only 4 of 27 children (15%) with no subsequent episodes of wheezing were older than 12 months of age at the start of the study. The 4 months of anti-

of age at the start of the study. The 4 months of anti- Fig. 2. The

Fig. 2. The outcome of 88 young children according to viral identification at entry 1 year after hospitalization for wheezing *** P = 0.0002 compared with the virus-negative children with asthma, ****P = 0.00001 compared with the virus-negative chil- dren with no wheezing (Chi-squared test).

inflammatory therapy either with cromolyn sodium or with budesonide did not significantly diminish the risk of asthma (Fig. 1) When calculating the effects of other risk factors, both of these factors (age as a significant and anti-inflammatory therapy as a possible confounding fac- tor) were adjusted for. The absence of viral identification was the dominant risk factor for asthma (Table 2). The result was the same for the patients with negative RSV identification (P 0.001, RR 11.9, CI 2.72– 52.30). Other significant risk factors for asthma were history of wheezing, the presence of atopy at entry, and family history of atopy. The following factors did not predict the development of asthma: male gender, atopic dermatitis, family history of asthma, passive smoking, or pet contacts at home or at day care, having two or more siblings, or the presence of elevated blood eosinophils, serum IgE, or nasopharyngeal ECP. The significant risk factors for the recurrence of wheezing were atopic der- matitis (P 0.04, RR 5.8, 95% CI 1.06– 2.0), atopy (P 0.047, RR 5.3, 95% CI 1.02–27.92 ), family history of atopy (P 0.02, RR 7.4, 95% CI 1.45–37.56), and having two or more siblings (P 0.007, RR 10.2, 95% CI 1.87–55.55). No other risk factor was significant in relation to the recurrence of wheezing. Because none of the 27 subsequently non- wheezing patients had serum ECP 16 g/L, the risk ratios for asthma and recurrent wheezing were incalcu- lable. As many as 11 of 43 patients (26%) in the asthma group (P 0.005 vs. nonwheezing children) and 3 of 18 patients (17%) in the recurrent wheezing group (P 0.06 vs. nonwheezing children) had serum ECP 16 g/L. Thus, serum ECP 16 g/L is considered as a significant risk factor for asthma.

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TABLE 2—Age- and Anti-inflammatory Therapy-Adjusted Risk Factors for Asthma in 70 Children 1 Year after Bronchiolitis a

 

Asthma (n 43)

No wheezing (n 27)

 

Significance

Risk Factor

P

RR

95% CI

No viral identification History of wheezing

35/43 (81%)

8/27 (30%)

0.0003

12.0

3.16–45.40

12/43 (28%)

1/27 (4%)

0.02

14.6

1.59–132.10

Atopic dermatitis at entry Serum IgE 60 kU/L)

16/43 (37%)

3/27 (11%)

0.09

3.5

0.84–14.70

14/42 (33%)

2/25 (8%)

0.06

5.0

0.92–27.93

Atopy

23/43 (53%)

4/27 (15%)

0.01

5.3

1.47–19.21

Family history of atopy Family history of asthma Male gender

26/43 (60%)

9/27 (33%)

0.03

3.6

1.15–11.12

9/43 (21%)

7/27 (26%)

0.29

0.5

0.13–1.84

35/43 (81%)

18/27 (67%)

0.23

2.3

0.60–8.56

Passive smoking 22/43 (51%)

14/27 (52%)

0.82

1.1

0.39–3.25

A pet at home or at day care At least two siblings Blood eosinophils 0.45 × 10 9 /L

11/43 (26%)

9/27 (33%)

0.67

0.8

0.25–2.46

13/43 (30%)

8/27 (30%)

0.71

1.3

0.38–4.15

17/42 (40%)

4/26 (15%)

0.23

2.3

0.58–9.17

Nasopharyngeal ECP 870 ng/g

12/39 (31%)

4/27 (15%)

0.56

1.5

0.37–6.29

a P values, RR (risk ratio), and 95% CI (confidence interval) were determined by logistic regression adjusted for age and anti-inflammatory therapy. Analyses have been done separately for each risk factor. , positive identification of viral antigen or significant rise in antibodies. The viruses searched for were respiratory syncytial viruses, influenza A and B, parainfluenza types 1,2,3, and adenoviruses. , atopic dermatitis or serum IgE 60 KU/L at entry; , atopic dermatitis or allergic rhinitis diagnosed by physician; IgE, immunoglobulin E; ECP, eosinophil cationic protein.

DISCUSSION

This prospective, controlled study in children treated in hospital for wheezing shows that early anti-inflam- matory therapy for 4 months does not significantly de- crease the occurrence of asthma 1 year later. Asthma was defined in a very strict way as two physician-diagnosed episodes of wheezing after the index episode. The other purpose of this study was to find clinically useful criteria for predicting which children are at risk to have recurrent episodes of wheezing or asthma. Only a minority (about 1%) of young children need hospital treatment for bron- chial obstruction. 16 This study was hospital-based, and thus the patients represented severe cases. In the present study, age over 12 months at the time of the initial (in- dex) episode of wheezing, absence of viral identification, history of wheezing, presence of atopy, family history of atopy, and elevated serum ECP were identified as sig- nificant risk factors for asthma. A recent study by Young and colleagues showed that lower respiratory illness la- beled as bronchiolitis in the second year is likely to be asthma. 6 Our observation that wheezing children older than 12 months had a significantly higher risk for asthma than the younger ones supports that view. In fact, only 15% of patients with no subsequent wheezing episodes were at entry older than 12 months. Our recent study showed that early anti-inflammatory therapy of bronchiolitis with nebulized cromolyn sodium or budesonide for 4 months reduced wheezing after bron- chiolitis. 9 The present study showed that this initial ben- eficial effect did not persist when therapy was stopped and recurrent wheezing episodes or asthma did not differ significantly among the patients who had received early

anti-inflammatory therapy and those who had not. Only 18% of the patients who had not received early anti- inflammatory therapy did not wheeze during the follow- up period of 1 year. The respective figure was 41% in patients who had received cromolyn sodium and 32% in the patients who had received budesonide as early anti- inflammatory therapy. These findings suggest that early anti-inflammatory therapy may have some prolonged ef- fect in protecting subsequent bronchial obstructions. Be- cause the occurrence of asthma was significantly depen- dent on the age of the children, and because the early anti-inflammatory therapy was a possible confounding factor, both of these factors were controlled in the analy- sis of the other risk factors. The significantly lower risk for asthma in patients with

a demonstrable viral identification compared with those with no established viral identification was one of the most interesting findings of this study. The outcome did not depend on the type of viral infection looked for; the

risk for asthma was the same in patients with RSV as in those with other viral infections. This result is different from a previous study with a rather similar patient group. 17 In that study, the outcome of children with ob- structive bronchitis did not differ in patients with and without established RSV infection. Despite negative vi- rologic results, all our wheezing patients with a high probability for asthma had an infection; the presence of symptoms consistent with acute respiratory tract infec- tion was one of the inclusion criteria of the study. Thus,

it is likely that the virus-negative children had the first

manifestation of asthma and started to wheeze as a result of mild upper respiratory tract infection or as a result of

118 Reijonen and Korppi

viruses we did not study, such as rhino- or corona vi- ruses. The influence of rhinoviruses on the outcome after early childhood wheezing need further studies. Our re- sults support the theory that viral or other infections, or the airway damage caused by them, have a minor role in the development of asthma. 18 Our observation that a history of wheezing is an im- portant risk factor for asthma is consistent with previous findings. 8,19 In our 1-year follow-up, 12 of the 13 chil- dren (92%) with a history of wheezing developed asthma, and only one (8%) had no subsequent wheezing. In accordance with some previous studies, children who have atopy 5,9,19 or family history of atopy 20,21 were prone to recurrent wheezing and asthma. Contrary to pre- vious observations of population based studies, male gender 21,22 family history of asthma 5,23 or passive smok- ing 2124 were not significant risk factors for recurrent wheezing or asthma. The result that there was no rela- tionship between passive smoking and asthma was sur- prising; this observation may be true, because many par- ents now smoke outdoors. It is also possible that smoking did not emerge as a risk factor because it was so frequent in the population as a whole. Likewise, the development of asthma did not depend on contact with pets. 8 The observation that having two or more siblings was a sig- nificant risk factor for recurrent wheezing can be ex- plained by increased number of contacts with infections in these families. In this study, 20 elevated blood eosinophil counts were not a risk factor for recurrent wheezing or asthma, which is consistent with previous observations. Our recent re- ports showed that high concentrations of serum 10 and nasopharyngeal ECP 14 were predictive of bronchial ob- structions, and especially of episodes requiring hospital treatment. This study confirmed that elevated concentra- tion of serum ECP significantly predicted asthma. In fact, all of the 14 patients with elevated serum ECP at entry had at least one subsequent physician-diagnosed bron- chial obstruction, and 11 (79%) had asthma 1 year later. The high concentration of ECP in respiratory secretions did not, however, associate with the occurrence of recur- rent wheezing or asthma in this follow-up. The term ‘‘asthma’’ has been rarely used to describe recurrent or persistent wheezing in the very young. The reasons for this are the differences in outcome, and pos- sibly differences in pathophysiology between young chil- dren and those at school age. 46,25 Although the majority of children with early childhood wheezing will grow out of their symptoms, 5,19 an important problem remains how to reduce bronchial obstructions and hospital admis- sions in early childhood. The avoidance of the term ‘‘asthma’’ will lead to inappropriate treatment with an- tibiotics 26 instead of bronchodilator 2729 and anti- inflammatory agents. 9,30,31 On the basis of previous stud- ies, the persistence of asthma in late childhood can be

decreased by diminishing exposure to inhaled allergens 32 and to tobacco smoke. 33 The influence of an early intro- duction of anti-inflammatory therapy on the posttreat- ment outcome in wheezing children needs further stud- ies. Such therapy did not provide protection for 1 year in the present study. There are three possible explanations for the negative results. First, the number of children in this study was too small to detect small difference (17%) between the therapy and the control groups. The power was calculated after the study, and it was only 0.44 at the significance level of 0.05. Second, the treatment period may have been too short. Third, although anti- inflammatory therapy lessens bronchial obstruc- tions, 9,30,31 it probably has little long-term posttreatment effects on the lungs. In conclusion, early anti-inflammatory therapy for 4 months does not significantly decrease the occurrence of asthma 1 year after hospital admission for wheezing. Age over 12 months, history of wheezing, elevated serum ECP concentrations, atopy, or family history of atopy increased the risk for asthma. The outcome was much worse in the children with negative than in those with positive viral identifications. We suggest that young chil- dren admitted to hospital for wheezing should be re- garded as having asthma if they have wheezed previ- ously, if they have atopy, have a family history of atopy, or have elevated serum ECP levels, especially if viral identifications are negative. An age over 12 months at the time of the original index episode supports the diagnosis.

ACKNOWLEDGMENTS

The authors thank Pirjo Halonen, PhD, for her advice with the statistical analyses, and the Foundation of Pe- diatric Research in Finland, the North Karelia Cultural Foundation, and the University of Kuopio for financial support.

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