PEDIATRICS Vol. 106 No. 6 December 2000, pp. 1406-1412

Predictors of Asthma Three Years After Hospital Admission for Wheezing in Infancy

Tiina Marjaana Reijonen, MD, Anne Kotaniemi-Syrjänen, MS, Kaj Korhonen, MD, and Matti Korppi, MD

From the Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland. Presented in part at the European Respiratory Society Annual Congress, Geneva, Switzerland, September 19-23, 1998.

	ABSTRACT

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Objective.  To evaluate the influence of early antiinflammatory therapy in the development of asthma 3 years after hospitalization for wheezing in infancy. In addition, the effects of allergic sensitization and respiratory syncytial virus (RSV) infection on the development of asthma were investigated.

Design and Setting.  A randomized, controlled follow-up study in a university hospital that provides primary hospital care for all pediatric patients in a defined area.

Patients.  Eighty-nine infants under 2 years of age who had been hospitalized for infection associated with wheezing and followed up for 3 years.

Intervention.  Early antiinflammatory therapy was given for 16 weeks; 29 patients received cromolyn sodium and 31 received budesonide. Twenty-nine control patients received no therapy.

Outcome Measures.  Clinical diagnosis of current asthma, defined as having at least 3 episodes of physician-diagnosed wheezing and either a wheezing episode during the preceding year or ongoing antiinflammatory medication for asthma.

Results.  Fourteen (48%) patients in the former cromolyn group, 15 (48%) in the former budesonide group, and 16 (55%) in the control group had current asthma. The significant predictors of asthma were age over 12 months (risk ratio [RR] 4.1; 95% confidence interval [CI] = 1.59-10.35), history of wheezing (RR 6.8; CI = 1.35-34.43), and atopic dermatitis on study entry (RR 3.4; CI = 1.17-9.39). Skin prick test positivity at the age of 16 months significantly predicted asthma (RR 9.5; CI = 2.45-36.72). In addition, all of the 18 (20%) children sensitized with furred pet developed asthma. RSV identification (RR 0.3; CI = 0.08-0.80) and early furred pet contact at home (RR 0.3; CI 0.10-0.79) were associated with the decreased occurrence of asthma.

Conclusions.  Antiinflammatory therapy for 4 months has no influence on the occurrence of asthma 3 years after wheezing in infancy. Early sensitization to indoor allergens, especially to pets, and atopic dermatitis predict subsequent development of asthma. RSV infection in wheezing infants may have a better outcome than other infections.  Key words:  asthma, atopy, budesonide, child, cromlyn sodium, follow-up study, infant, immunoglobulin E, respiratory syncytial virus, risk factors, sensitization, wheezing, virus diseases.

Recurrent bronchial obstructions and asthma are commonly encountered after hospital admission for wheezing.^1-3 Wheezing young children, however, are not a uniform group; some have narrow airways obstructed by mucus and edema during respiratory infection,^4-6 and some, in particular, atopic children, may have eosinophilic inflammation typical of asthma in their airways.⁷ Our previous reports have shown that 4-month antiinflammatory therapy with cromolyn sodium or budesonide reduces the recurrence of wheezing,⁸ but the benefit disappears shortly after termination of the therapy.⁹

There are, to our knowledge, no studies on long-term outcome after early antiinflammatory therapy in wheezing infants. On the other hand, only a few reports exist on the predictive value of allergic sensitization^10,11 in the development of asthma after infantile wheezing.

The aim of our study was to evaluate the 3-year outcome after hospital admission for wheezing in infancy. Special attention was paid to the influence of early antiinflammatory therapy and allergic sensitization in the development of asthma. In addition, factors to predict later asthma in young wheezing children were identified.

	METHODS

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Participants

One hundred children aged under 24 months (median: 10.0; range: 1-23) and treated in the hospital for infection-associated bronchial obstruction between January 1, 1992, and November 2, 1993, in the Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland, were enrolled as previously described.⁸ The inclusion criteria were the presence of wheezing and respiratory distress leading to hospital care during acute respiratory infection. After an initial clinical evaluation, the patients were randomly divided into 3 therapeutic groups: the cromolyn group, the budesonide group, or the control group. The 87 patients without and the 13 patients with a history of wheezing were randomized separately. Patients born prematurely and those with concomitant chronic cardiorespiratory disease were excluded.

Intervention

Nebulized antiinflammatory therapy was given for 16 weeks: 34 patients received cromolyn sodium, 34 received budesonide, and 32 control patients received no antiinflammatory medication. The maintenance medication, administered by a foot pump with a face mask (Easy-Air Nebuliser, Cameron-Price, Birmingham, England), 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 Corporation, Rochester, NY) was 20 mg 4 times a day, and the dose of budesonide (Pulmicort inhalation liquid, 0.25 mg/mL, Astra, Södertälje, Sweden) was 500 µg twice a day. For the subsequent 8 weeks the doses were reduced; cromolyn sodium to 20 mg 3 times a day and budesonide to 250 µg twice a day. All but 1 child in both medication groups received the therapy regularly.⁸ After the termination of early antiinflammatory therapy, maintenance medication for asthma was started on a clinical basis. The study was approved by the Research Ethics Committee of Kuopio University Hospital. Before enrollment of the patients, an informed consent was obtained from the parents.

If the patients required medical treatment or hospital care 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 at 6 and 16 weeks, 8 and 12 months, and 3 years after the index episode of wheezing. One of the authors (T.R. or M.K.) examined the children, interviewed the parents, and checked the diaries. If the notes by physicians on any wheezing episode were missing, photocopies of the medical reports were obtained and checked. Eighty-nine children who attended the 3-year follow-up constitute the participants in the present study.

Data

Standardized questionnaires were used to interview the parents. At entry this included questions on day of birth, history of wheezing, and atopic dermatitis, as well as family history of asthma and atopic diseases. Only diagnoses made by a physician were considered. Additional information about passive smoking during the pregnancy and in the vicinity of the study entry, pet contacts at home, the number of siblings, and the type of living area, urban or rural, was recorded. On the 3-year follow-up visit the questionnaire included questions on the occurrence of physician-diagnosed atopic dermatitis, allergic rhinitis, allergic conjunctivitis, and bronchial obstructions during the preceding year. The use of maintenance medication for asthma was also recorded. One or more consecutive days of wheezing followed or preceded by a healthy period of at least 1 week constituted 1 wheezing episode. A recurrent wheezing episode was defined as 1 physician-diagnosed episode of bronchial obstruction after the index episode. Patients having at least 2 episodes of physician-diagnosed bronchial obstructions after the index episode of wheezing were considered as having asthma.¹² If the patient with asthma had had at least 1 physician-diagnosed episode of wheezing during the year preceding the 3-year visit, or if he/she still received maintenance therapy for asthma, he/she was defined as having current asthma.

Viral infections at study entry were studied by antigen detection in the nasopharyngeal aspirates taken at entry and by antibody measurements in paired sera; adeno group, influenza A and B, parainfluenza types 1, 2, and 3, and respiratory syncytial viruses (RSVs) were assayed.¹³ Viral antigens were determined by time-resolved fluoroimmunoassay and viral antibodies were determined by a complement fixation test.¹³ Thirty-four (38%) of the 89 patients had positive viral identification; RSV was found in 23 patients, adenoviruses were found in 4 patients, parainfluenza 3 was found in 10 patients, parainfluenza 2 was found in 2 patients, and parainfluenza 1 virus was found in 1 patient. Four patients had 2 viral findings and 1 patient 3 viral findings.

During the primary hospitalization, a venous blood sample was obtained to determine serum immunoglobulin E (IgE). The value of 60 kU/l (144 µg/l) was used as the pathologic limit.¹⁴ On the 8-month and 3-year control visits, skin prick tests (SPTs) were performed by a trained nurse using the ALK SPT extracts (ALK Laboratories, Copenhagen, Denmark). The allergens tested on both visits were birch pollen, timothy grass pollen, mugwort pollen, cat and dog epithelial danders, and house dust mites Dermatophagoides farinae and Dermatophagoides pteronyssimus. In addition, the food allergens egg white, cows' milk, fish, and wheat were tested on the 8-month visit, and common alder, meadow grass pollen, horse and cow epithelial danders, and spores of mold Cladosporium herbarum were tested on the 3-year visit. The concentrations of nonstandardized allergen extracts such as cows' milk, fish, wheat, and C herbarum spores were 1:20 (w/v), and those of egg white and cow epithelial dander were1:100 (w/v). Ten other extracts, with a concentration of 10 histamine equivalent points, were standardized. Histamine dihydrochloride (10 mg/mL) was used as a positive control and 50% glycerol was used as a negative control. The SPT was regarded as positive when the mean diameter of the wheal (half the sum of the largest diameter and its perpendicular measurement) was 3 mm. No reactions were allowed in negative controls.¹⁵

Data Analysis

Data were analyzed with the use of SPSS/PC + 5.0.1 software (SPSS Inc, Chicago, IL). Comparability between the groups was assessed with the ² test for proportions. When analyzing the proportional differences among the 3 groups, an overall ² test was analyzed first, and if the P value was < 0.05, further paired analyses were made applying the so-called Bonferoni correction.¹⁶ Two-tailed t tests were used in all analyses. The logistic regression model was used to calculate the adjusted risk ratios (RR) with 95% confidence intervals for estimating the association between different factors and asthma.

	RESULTS

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Effect of Early Antiinflammatory Therapy

The basic characteristics of the 89 children who completed the 3-year follow-up are presented in Table 1. These children did not differ from the 11 participants who were lost during the follow-up. No differences were noted in the basic characteristics between the 3 original therapy groups. At the 3-year follow-up visit the median age of the children was 4.0 years (range 3.2-5.1 years); 45 (51%) of those had current asthma. A total of 36 (40%) children received inhaled maintenance medication: 27 received cromolyn sodium and 9 received budesonide. The early antiinflammatory therapy had no influence on the occurrence of asthma or on the need for the maintenance medication 3 years later (Table 2). The result did not differ among the patients with and without atopic dermatitis at entry.

Age and Allergic Sensitization and the Development of Asthma

We evaluated which factors predicted the presence of asthma 3 years after the primary hospital admission for wheezing. An age more than 12 months at study entry increased significantly the occurrence of asthma (Table 3). Thus, the age was adjusted in further analyses when the effects of the other factors were calculated. SPT positivity 8 months after the index episode of wheezing was a dominant predictor for asthma. It was found in 24 (27%) patients, 21 of whom had asthma at the median age of 4 years (Table 4). Positive reactions to indoor allergens, especially to cat or dog epithelial danders, were very prognostic; all 18 (20%) patients with a positive reaction developed asthma. Positive reactions to food or to outdoor allergens were rare and did not differentiate the children who developed asthma from those who did not. The only exception was reactivity to fish. Seven of 45 (16%) children who later developed asthma and none of those who did not were reactive (P = .0049). In the whole study group, no significant association was noted between having a furred pet at home during infancy and SPT reactivity to animal dander.

Other Factors and Asthma

Identification of RSV at entry as well as the presence of furred pet at home during infancy seemed to decrease the risk of later asthma (Table 3). The negative association between furred pet ownership at entry and later asthma remained after adjustment for atopic dermatitis at entry and family history of atopy or asthma. Only 22% of patients with RSV infection on entry compared with 61% of patients without RSV (P = .0013) developed asthma by the age of 4 years (Fig 1). History of wheezing and atopic dermatitis on study entry were also significant predictors of asthma (Table 3). Family history of atopy or asthma, male sex, passive smoking during pregnancy or in infancy, number of siblings, living area in early childhood, and elevated IgE in serum were not predictive of asthma 3 years after hospital admission for wheezing.

View larger version (18K): [in this window] [in a new window]   Fig. 1.   RSV infection and the development of asthma 3 years after hospitalization for wheezing in early childhood.

Progression of Wheezing and Asthma

The progression of wheezing and asthma between 1 and 3 years after the study entry is presented in Fig 2. A total of 84 patients participated in both 1- and 3-year visits. Thirty-four of 43 (79%) children who had had asthma in the 1-year follow-up still had asthma 2 years later. The 9 children who had recovered from asthma differed statistically from those with current asthma only with respect to SPT findings and furred animal contacts in early life. None of them had had any positive SPT findings either on the 8-month or 3-year visit. The respective figures for the 36 children who still had asthma were 16 (44%, P = .016) and 19 (53%, P = .010). Five of the 9 (56%) recovered patients compared with 6 of the 36 (16%) not-recovered patients had contacted furred pet at home in infancy (P = .027). On the other hand, 5 of the 9 (56%) children whose asthma began after the 1-year follow-up had positive SPT findings at the 8-month follow-up and 8 (89%) had positive SPT findings at the 3-year follow-up.

View larger version (27K): [in this window] [in a new window]   Fig. 2.   The progression of wheezing and asthma in 84 patients who attended both 1-year and 3-year follow-up visits.

Current Atopic Findings

Children with asthma more often had current atopic manifestations than those with no asthma: 17 (38%, P = .0093) had atopic eczema, 9 (20%, P = .029) had allergic rhinitis, and 9 had (20%, P = .068) allergic conjunctivitis. The respective figures in children without asthma were 6 (14%), 2 (5%), and 3 (7%). The proportion of children with SPT reactivity increased from 27% to 39% between the 2 tests; only 2 children lost their reactivity during the follow-up. Current skin test reactivity, mainly to indoor allergens, and especially to cat or dog epithelial dander, occurred significantly more often in the patients with asthma (Table 5). SPT reactions to house dust mites, in contrast, were very rare irrespective of whether asthma developed or not. Current reactivity to outdoor allergens was present in one third of the patients with asthma and only in one tenth in those without, reactions to birch and alder pollens being the most common ones. Only 1 child with asthma reacted to mold spores.

	DISCUSSION

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This prospective 3-year follow-up study in infants treated in hospital for wheezing shows that early antiinflammatory therapy for 4 months has no influence on the occurrence of asthma 3 years later. Our results involve previously healthy term children without underlying comorbidities. About 50% of all patients, regardless of the early therapy, had asthma at the median age of 4 years. Furthermore, physician-diagnosed asthma continued in 80% of children who had asthma in the 1-year follow-up. The factor that best predicted the outcome was SPT reactivity to indoor allergens, especially to animal danders. Other significant predictors of asthma were age over 12 months, history of wheezing, and atopic dermatitis during the primary hospitalization. The outcome in wheezing children with RSV infection or early furred pet contact was much better than in those without.

Our result that early maintenance medication with cromolyn or budesonide did not prevent the development of asthma is analogous with 2 recent 1-year reports on wheezing infants.^9,17 We found a both clinically and statistically insignificant 7% difference in the occurrence of asthma among the medication and control groups. There was a 16% decrease in the current use of maintenance therapy in the budesonide group compared with the control group. Our material was, however, far too small to prove this difference significant. For that purpose, the sample size should have been ~400 patients. The medication was effective as long as it was given,⁸ but the benefit was gradually lost within 4 months after termination of the therapy.¹⁸ This result indicates that the development of asthma after early childhood wheezing cannot be prevented by early introduction of 4-month antiinflammatory therapy. Whether the result would be different if the therapy had continued longer remains to be resolved.

The increased prevalence of asthma after hospital admission for wheezing in early childhood is well documented in many studies.^1,19,20 This study in a population of young wheezing children suggests that later outcome may be dependent on the type of viral infection present during bronchial obstruction. The wheezing patients with RSV infection had a much better prognosis than those without. This favorable outcome was perceived already in the 1-year follow-up.⁹ This finding contradicts the results of Sigurs et al,¹² who showed in a case-control study that RSV bronchiolitis was a major risk factor for later asthma. In that study, all infants with RSV infection wheezed, but the control infants had neither RSV nor wheezing. The increased risk for asthma in wheezing infants may have been attributed to RSV infection²¹ or conditions related to wheezing, such as preexisting small airways,⁵ bronchial hyperreactivity,²² or atopy.^3,5 Early childhood wheezing with other than RSV etiology seems to carry the highest risk for asthma, followed by early childhood wheezing with RSV etiology³, and early childhood lower respiratory tract illnesses with no wheezing.²¹ Furthermore, our thus far unproved hypothesis is that the outcome after infantile wheezing is partly dependent on the invasiveness of the causative virus. Invasive viruses like RSV are able to induce wheezing and transient but reversible impairment in pulmonary function also in children with no susceptibility to asthma.²³ The majority of these infants have diminished pre-illness lung function,^4,6 and their predisposition to wheezing will have decreased with age²¹ and growth of the airways.⁵ Noninvasive viruses like rhinoviruses, which were not searched for in the present study, have been shown to induce lower airway responsiveness in allergic but not in nonallergic participants.²⁴ According to a very recent study, rhinoviruses may cover up to 40% of viral findings in wheezing infants.²⁵

Consistent with few previous findings in wheezing infants, SPT sensitivity to indoor allergens,¹⁰ unlike the reactivity to food allergens,¹¹ is strongly associated with the development of asthma. Sensitization, however, seemed to be fairly rare among young children.¹⁰ It was present only in 27% at the median age of 16 months, and the proportion rose to 40% by the age of 4 years. Most responses were seen in children with asthma. On the average, positive SPT predicted an ~10-fold risk for the development of asthma compared with negative SPT. Our results emphasize the role of early sensitization to indoor allergens, especially to animal dander, in the development of asthma after wheezing in early childhood. Reactions to cat or dog represented 75% of the SPT findings, and asthma developed invariably if either allergen gave the response. When skin test reactions were compared 2 years apart, reactivity to animal danders further increased, but sensitivity to house dust mites remained low, as is typical for children in the northern climate.²⁶ This increase was observed only in children having or developing asthma, stressing again the connection between atopic sensitization and asthma.

The result that furred pet exposure in early life seemed to protect from the development of asthma was an unexpected finding not reported in previous studies in wheezing infants.^12,20 The result was, however, analogous in the subgroup of children whose asthma symptoms ceased between the age of 2 and 4 years. Parallel results have been presented recently in school-aged children.²⁷ Our result was not explained by selection bias, meaning the avoidance of pets in families predisposed to allergy. In our whole study group, opposite to the results of the above-mentioned Swedish study,²⁷ no significant negative association was noted between early pet contact and SPT reactivity to animal dander. We are unable to explain this discrepancy.

The age at onset of wheezing was associated with later asthma; the children older than 12 months had a significantly greater risk than the younger ones.⁶ In accordance with previous findings, a history of wheezing^3,12 and atopic dermatitis^3,28 predicted the development of asthma after hospital admission for wheezing. Contrary to previous findings, a family history of atopy²⁹ or asthma,³⁰ male sex,³¹ passive smoking,^30,31 urban living area during infancy,³² or number of siblings³³ did not predict the occurrence of asthma 3 years after infantile wheezing. Furthermore, elevated serum IgE on entry was not predictive of later asthma.²⁸

Between the 1- and the 3-year follow-up, the asthma status remained rather stable, although the frequency of wheezing should have a decreasing trend at the age of 3 to 5 years.³⁴ Approximately 80% of children with asthma remained asthmatic, and the same proportion of children remained without symptoms 2 years apart. Furthermore, over 75% of the children with recurrent wheezing but with no asthma did not continue to have symptoms. The progress of the status depended on the development of atopy.

The strength of our study was that it was strictly prospective and represented wheezing infants in a defined area. All basic data were collected at enrollment during the index episode of wheezing, and the great majority attended the follow-up visits: 88% were followed up for 12 months⁹ and 89% were followed up for 3 years. The principal weakness was that the follow-up study was not blinded; the investigators knew the clinical data of each patient including atopic findings and the early maintenance medication when making decisions at follow-up visits. In addition, the diagnosis of asthma was entirely clinical. The patients with current asthma had had at least 3 episodes of wheezing and they consisted of 2 subgroups: those with physician-diagnosed wheezing during the preceding year and, regardless of symptoms, patients with ongoing antiinflammatory medication for asthma. In our area, the need for continuing maintenance medication for asthma in young children is checked at 3- to 6-month intervals by the pediatric allergists of the university hospital, and a symptom-free period of 6 to 12 months is usually demanded for discontinuing the medication.³⁵ Thus, the need for maintenance therapy was assessed independently of the present study. Our study was hospital-based and thus offers information about only the severe form of wheezing in early childhood. The results should not be extrapolated to infants who have underlying comorbidity such as prematurity or cardiopulmonary disease.

In summary, our findings indicate that antiinflammatory therapy for 4 months has no influence on the occurrence of asthma 3 years after hospitalization for wheezing. Early sensitization to indoor allergens, especially to pets, history of wheezing, atopic dermatitis, and age over 12 months in a wheezing infant predict the occurrence of asthma at the age of 4 years. Our results also suggest that RSV infection in wheezing infants may have a better outcome than other infections.

	ACKNOWLEDGMENTS

This study was supported by grants from the Foundation of Pediatric Research in Finland and the North Karelia Cultural Foundation.

	FOOTNOTES

Received for publication Sept 20, 1999; accepted Feb 14, 2000.

Reprint requests to (T.M.S.) Department of Pediatrics, Kuopio University Hospital, Box 1777, FIN-70211 Kuopio, Finland. E-mail: tiina.reijonen{at}iobox.fi

	ABBREVIATIONS

IgE, immunoglobulin E; RR, risk ratio; RSV, respiratory syncytial virus; SPT, skin prick test.

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