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Keywords:

  • acute respiratory illnesses;
  • childhood;
  • epidemiology;
  • management

Abstract

  1. Top of page
  2. Abstract
  3. Key Points
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Aim:  Acute respiratory illnesses (ARI) impose massive economic burden on health services. The growing costs, limited benefits of pharmacotherapeutic agents, and alarming rise in antibiotic resistance poses a major health challenge. Analysis of the nature and burden of ARI through well-designed epidemiologic studies will help in the development of a uniform public health approach to identify methods to reduce disease transmission and maximise prevention strategies. The aim of this study was to analyse the nature and magnitude of the burden of ARI encountered by a cohort of children in the first 5 years of life.

Methods:  This community-based prospective study of ARI followed a cohort of children from birth until 5 years of age. Information on all episodes of ARI encountered, and their management, was collected through daily symptom diary and fortnightly telephone calls.

Results:  Four episodes of ARI/year were reported in the first 2 years and 2–3 episodes/year between 2 and 5 years. The majority were upper respiratory infections. 53% had at least one lower respiratory infection in the first year. For the majority, symptoms lasted 1–2 weeks. 53% were treated with antitussives or cough mixtures, 44% with paracetamol and 23% with antibiotics. A total of 46% of the episodes presented to a family physician, with younger children and those with lower respiratory infection more likely to seek attention.

Conclusion:  ARI are common in childhood and although symptoms may last for 4 weeks, the majority resolve spontaneously. Use of medication does not appear to significantly alter the course or duration of symptoms of ARI.

Acute respiratory illnesses (ARI) are acknowledged as major causes of early childhood morbidity and account for 50% of general practitioner consultations in preschool-aged children in Australia.1 ARI present with a variety of symptoms including nasal congestion, sore throat, cough, wheeze and fever. Families access and utilise considerable health care services in the management of ARI, with subsequent massive economic impact. The world market for cough and cold remedies has been estimated to be of the order of AUD$7 billion/year.2 Inappropriate antibiotic prescription for ARI, the majority of which are viral in aetiology, has led to an alarming increase in antibiotic resistance among respiratory bacteria.

A systematic public health approach in the management of ARI to maximise preventive measures and minimise transmission rates is thus necessary to reduce prevalence rates and economic impact. For this to occur, analysis of the precise nature and magnitude of the disease burden caused by ARI is necessary. As early childhood is a time of particular susceptibility to ARI and the morbidity and mortality related to ARI is concentrated in the very young and the elderly, the best age group to start this endeavour is the first 5 years of life.

Acute respiratory illnesses can be classified as upper respiratory tract illnesses (URI) and lower respiratory tract illnesses (LRI) with the larynx as the site of separation of primary pathology. The impact of a respiratory episode varies greatly with the majority being short-lived and confined to the upper respiratory tract. Little is known about the frequency of URI, as, in the main, they are common, have few complications, resolve spontaneously and medical attention is rarely sought. Studies attempting to quantify the number of ARI experienced by young children have given rates varying from 4 to 9 episodes/year3–6 and these have shown that LRI are more common in infancy with incidence rates falling as children grow older.2–4

Most studies have, however, focused primarily on LRI, in particular, those requiring medical attention or hospitalisation, and there is a paucity of community-based epidemiological studies on ARI.

This community-based prospective study of preschool children investigated the epidemiology and management of ARI encountered in their first 5 years of life.

Key Points

  1. Top of page
  2. Abstract
  3. Key Points
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References
  • 1
    Viruses are major etiological agents for acute respiratory illnesses (ARI).
  • 2
    The majority of ARI, including LRI, resolve spontaneously.
  • 3
    Medications, including antibiotics do not alter course of ARI.

Methods

  1. Top of page
  2. Abstract
  3. Key Points
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

This longitudinal prospective study on ARI episodes was carried out in Perth, Western Australia, a city with a population of 1.38 million inhabitants. Perth enjoys a temperate climate with average temperatures between 18°C and 31°C. The maximum rainfall occurs in the colder winter months of June–August. Two hundred and sixty-three (263) infants at high risk of atopy (that is, at least one parent with a doctor-diagnosed history of asthma, hay fever or eczema) were recruited prenatally between 1996 and 1998 as part of a cohort study to look at the role of ARI on development of the immune system. Parents kept a daily diary of their child’s health from birth and contacted the study centre within 24 h of their children exhibiting any symptoms of a respiratory illness, which included fever, runny/blocked nose or cough. Home visits were arranged (within 48 h) to collect postnasal aspirate samples of mucous for viral identification and details of specimen analysis for viruses has previously been described.5

Detailed information about each episode of ARI was collected by fortnightly follow-up telephone calls until resolution of the child’s symptoms. The information sought included duration of symptoms, doctor diagnosis, if the child was seen by a doctor, medications the child was given during the course of the illness (prescribed as well as over the counter medications), hospitalisation and investigations performed, if any, during the illness.

We tried to limit information bias by prospective, frequent and standardised surveillance of all subjects and we ascertained the status of the child’s health through daily recording with a symptom diary.

Analysis of data was performed using SPSS (Version 11.0 for Windows). Fully informed written consent was obtained from the parents prior to recruitment into the study and approval for the study was obtained from the ethics committee of King Edward Memorial and Princess Margaret Hospitals.

Classification of ARI

Any episode with runny/blocked nose or dry cough was classified as an URI. Episodes that were associated with wheeze, or cough and rattly chest were considered to be LRI. Rattle/rattly chest was described as moist, wet noisy breath sounds from the child’s chest. Wheeze was defined as a high-pitched whistling sound heard coming from the chest, on expiration. LRI were further classified into wheezy LRI and non-wheezy LRI based on the presence of any wheeze reported by the parent or family doctor.

Results

  1. Top of page
  2. Abstract
  3. Key Points
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Characteristics of the cohort

A total of 263 children were recruited into the study. There were more boys than girls (137:126). The children were from smaller families of higher socio-economic class than average and the majority (58.6%) lived in a household with a pet (Table 1). More than 74% of the infants were breastfed for more than 6 months, less than half attended day care in early infancy, only 4% were exposed to maternal antenatal smoking and 11.4% to postnatal environmental tobacco smoke (Table 1). The parents had a high prevalence of atopic disease with 63.8% of the mothers (46.2% of fathers) having a history of hay fever, 47.1% of mothers (33.0% of fathers) with asthma and 31.2% of mothers (11.3% of fathers) with eczema.

Table 1.  Characteristics of cohort
 n (%)
  • A total of 263 children were recruited into the study;

  • ‡A total of 236 children remained in the first year of the study.

Characteristic (= 263)
Male137 (52.1)
Number of older sibs
 Nil143 (54.4)
 One 76 (28.9)
 Two 35 (13.3)
 Three or more  9 (3.4)
Maternal education level
 Completed 10 years of schooling 60 (22.9)
 Completed 12 years of schooling 69 (26.2)
 Completed tertiary education134 (51.0)
Paternal education level
 Completed 10 years of schooling 56 (21.3)
 Completed 12 years of schooling 64 (24.3)
 Completed tertiary education143 (54.4)
Pet ownership
 Any pet154 (58.6)
 Dog 78 (29.7)
 Cat 69 (26.2)
Antenatal smoking 11 (4.2)
Characteristic (n = 236)
Childcare attendance in 1st year of life
 Nil160 (67.8)
 First 6 months of age 23 (9.7)
 7–12 months of age 53 (22.5)
Postnatal tobacco smoke exposure 0–12 months of age
 Maternal smoking 23 (9.7)
 Paternal smoking 27 (11.4)
Duration of breastfeeding
 Never breastfed  3 (1.3)
 0–6 weeks 16 (6.8)
 7–12 weeks 17 (7.2)
 13–20 weeks 11 (4.7)
 21–26 weeks 13 (5.4)
 >26 weeks176 (74.6)

Withdrawals/exclusions

A total of 236 children remained in the first year of the study. Of the 27 children who were excluded or withdrew in this first year, the most common reasons were migration interstate (33.3%), and prematurity/malformations (22.0%). A total of 198 children (75.3%) completed the full 5 years of the study. The majority of children who withdrew after the first year (55.3%) were because of migration interstate or overseas. No significant differences were seen in the number of ARI encountered in the first year between those who remained in the study for the full 5 years and those who withdrew after the first year.

Frequency, type of ARI and viruses associated with ARI

The majority of the episodes of ARI occurred in the first 2 years (Table 2), with the children having on average four episodes of ARI/year in the first 2 years and 2–3 episodes/year between 2 and 5 years of age (Table 2).

Table 2.  Number of acute respiratory illnesses (ARI) in first 5 years
Age (years)No. childrenNo. ARI (%)No. infections (per child/year)
0–1 236 986 (26.7)4.2
1–2 223 926 (25.1)4.2
2–3 216 795 (21.5)3.7
3–4 204 604 (16.4)3
4–5 198 380 (10.3)2
Total child-years107736913.4

More than 53% of the infants reported at least one episode of LRI in the first year (Table 3). The majority (70.9%) of the ARI were classified as URI (Table 3). Approximately 30% of the ARI involved the lower respiratory tract, with a higher incidence occurring in the first 2 years. Just under half of these LRI episodes were associated with wheeze (Table 3).

Table 3.  Characteristics of ARI
Age of child (years)URI n (%)Total LRI n (%)Non-wheezy LRI n (%)Wheezy LRI n (%)Decongestants, antitussives n (%)Visit to doctor n (%)Antibiotics n (%)
  1. The per cent in parentheses are % within year. ARI, acute respiratory illnesses; LRI, lower respiratory tract illnesses; URI, upper respiratory tract illnesses.

0–1 656 (66.5) 330 (33.5)235 (23.9) 95 (9.6) 394 (40.0) 479 (48.6)223 (22.6)
1–2 630 (68.0) 296 (32.0)163 (17.6)133 (14.4) 534 (57.7) 443 (47.8)253 (27.3)
2–3 599 (75.3) 196 (24.7) 81 (10.2)115 (14.5) 466 (58.6) 324 (40.8)180 (22.6)
3–4 441 (73.0) 163 (27.0) 47 (7.8)116 (19.2) 333 (55.1) 246 (40.7)131 (21.7)
4–5 291 (76.6)  89 (23.4) 26 (6.8) 63 (16.6) 213 (56.1) 164 (43.2) 85 (22.4)
Total (% of Total)2617 (70.9)1074 (29.1)552 (15.0)522 (14.1)1940 (52.6)1656 (44.9)872 (23.6)

The majority of the ARI occurred during the colder winter months of June to August, with all types of ARI occurring most often during these months (Fig. 1).

image

Figure 1. Monthly distribution of ARI. Type of ARI: (bsl00077) wheezy LRI, (▪) non-wheezy LRI, (bsl00036) URI. ARI, acute respiratory illnesses; LRI, lower respiratory tract illnesses; URI, upper respiratory tract illnesses.

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Of the nasopharyngeal aspirate specimens collected during ARI episodes occurring in the first year of life, viruses were detected in almost 70% of the specimens; with rhinoviruses being the most commonly identified, followed by respiratory syncytial virus (RSV). These results have previously been published but have been included here to demonstrate the viral aetiology of the majority of ARI.5

Duration of symptoms of ARI

Runny/blocked nose was the most common presenting symptom with the majority (68.8%) lasting between 4 days to 2 weeks. Over three quarters (76.7%) of the ARI were associated with cough lasting mainly between 4 days to 2 weeks (61.7%), but 15.5% lasted 2–4 weeks (Table 4).

Table 4.  Duration of symptoms of acute respiratory illnesses
Symptoms1–3 days n (%)4–7 days n (%)1–2 weeks n (%)2–4 weeks n (%)4–6 weeks n (%)6–8 weeks n (%)>8 weeks n (%)
Fever (n = 997)862 (86.5) 129 (12.9)   6 (0.6)  0  0 0 0
Runny/Blocked nose (n = 3526)307 (8.7)1128 (32.0)1298 (36.8)568 (16.1)144 (4.1)67 (1.9)14 (0.4)
Cough (n = 2832)473 (16.7) 891 (31.5) 855 (30.2)440 (15.5)106 (3.7)47 (1.7)22 (0.7)
Rattly/wheezy chest (n = 1074)635 (59.1) 238 (22.2) 124 (11.5) 56 (5.2)  5 (0.5) 2 (0.1)14 (1.3)

A total of 27.0% of the ARI were associated with a temperature of >38°C with the majority lasting between 1 and 3 days (86.5%) (Table 4).

Just under a third (29.1%) of the ARI were associated with a rattly or wheezy chest and thus considered to be LRI. More than 81% of these resolved within the first 7 days of onset of symptoms (Table 4).

Management of ARI

Paracetamol was used in 43.9% of the ARI with similar patterns of use between URI (42.9%) and wheezy LRI (42.5%) and higher use in episodes of non-wheezy LRI (49.6%) (Table 5).

Table 5.  Management by type of ARI
 All ARI n (%)URI n (%)Non-wheezy LRI n (%)Wheezy LRI n (%)
  1. ARI, acute respiratory illnesses; LRI, lower respiratory tract illnesses; URI, upper respiratory tract illnesses.

Paracetamol1620 (43.9)1124 (42.9)274 (49.6)222 (42.5)
Antibiotics 872 (23.6) 543 (20.7)172 (31.2)157 (30.1)
Oral decongestants or antitussives1940 (52.6)1328 (50.7)326 (59.1)286 (54.8)
Doctor visit1656 (44.9)1011 (38.6)325 (58.9)320 (61.3)
Hospitalised  46 (1.2)  21(0.8) 11 (2.0) 14 (2.7)

Cough mixtures, including decongestants and antitussive medications were used in more than half (52.6%) of the episodes (Table 5), with a larger percentage (59.1%) being used if the child was reported to have a non-wheezy LRI (Table 5).

A total of 45.0% of the ARI presented to their family physician, with a slightly higher percentage presenting in the first 2 years (Table 3), or if they had a LRI (61.3% and 58.9% for wheezy and non-wheezy LRI respectively) (Table 5).

Antibiotics were prescribed for 23.6% of the episodes and no trends were found in antibiotic prescription between the different age groups (Table 3). More antibiotics were prescribed for non-wheezy LRI (31.2%) and wheezy LRI (30.1%) than URI (20.7%) (Table 5). Antibiotic use was associated with longer duration of symptoms such as fever, persisting cough and symptoms of LRI (Fig. 2). The most common antibiotics prescribed were penicillins (56.0%) (amoxycillin – 42.9%, other penicillins, e.g. phenoxymethylpenicillin 13.1%), cephalosporins (31.0%) and macrolides (8.6%).

image

Figure 2. Relationship between antibiotic use and duration of cough, LRI and fever. (bsl00077) Cough, (bsl00036) LRI, (□) fever. LRI, lower respiratory tract illnesses.

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Only 1.2% of the episodes were hospitalised, with wheezy LRI having the highest proportion requiring hospitalisation (2.7%), compared with URI (0.8%) or non-wheezy LRI (2.0%) (Table 5).

Use of medication including antibiotics did not appear to shorten or alter the course of illness.

Risk factors for ARI

Male children were found to have significantly more ARI in the first 5 years (Fig. 3). Exposure to other children, either by having older sibs or attending day care were risk factors for ARI and LRI in the first year of life (Fig. 4). This relationship was significant for those children with older sibs, and day care attendance in the first year had an additive effect. For wheezy LRI, the combination of older sibs and only day care attendance was found to be significant (Fig. 5).

image

Figure 3. Relationship between gender and total number of acute respiratory illnesses in first 5 years.

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image

Figure 4. Relationship between exposure to children and number of acute respiratory illnesses in first year.

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image

Figure 5. Relationship between exposure to children and wheezy lower respiratory tract illnesses in first year of life.

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Discussion

  1. Top of page
  2. Abstract
  3. Key Points
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

This is the first community-based study to provide close follow-up of all ARI that children suffer in the first 5 years of life. There was a good retention rate of study subjects and accurate data collection on respiratory infections has been achieved through regular telephone calls and validation with daily diaries. This cohort at high genetic risk of atopy, however, represents infants from small families of higher socio-economic group. More than half the cohort was first born, 74% were breastfed for more than 6 months, only 32.2% attended day care in early infancy, only 4% were exposed to maternal antenatal smoking and 11.4% to postnatal environmental tobacco smoke. Thus the findings may not reflect the findings in a general population. However, to counterbalance the shortcomings of this study, early childhood is a time of particular susceptibility for ARI and asthmatics have recently been demonstrated to have a profound deficiency in innate antiviral immunity.7 Thus infants at high-risk of developing allergic diseases, such as the children in this study, are the population most likely to become ill with respiratory viral infections and are therefore the best group to study aspects of ARI.

Frequency, type of ARI and viruses associated with ARI

The frequency of four episodes/year in the first 2 years and 2–3 episodes/year between 2 and 5 years is lower than that reported in some other studies that have described rates of 6–9 episodes/year.2,6,8 Data on ARI incidence in community studies are scarce and the majority of studies have involved older children or been observational studies in day care settings.7,9,10 Environmental factors associated with ARI include young age, environmental tobacco smoke (ETS) exposure, poverty, lack of breastfeeding, day care attendance and overcrowding.2,11–15 The lower incidence rate in this study could have arisen because the cohort were from small families of higher socio-economic status, the majority were ‘only’ children, most of them were breastfed for more than 6 months, and only 11% exposed to ETS. While these factors may limit the generalisability of our findings, they do not compromise the validity of the results.

More than two-thirds of the ARI involved only the upper respiratory tract. The majority of the infants had two episodes of URI in the first year and 53% reported at least one episode of LRI. Schwartz et al. found infants in their study had nine ARI/year with only 13% involving the lower respiratory tract.10 Fergusson and Horwood,6 in a prospective study in Christchurch, New Zealand, found 64.1% of children under the age of 2 years experienced at least one LRI. The definition of LRI was ambiguous and based on parental recall. Other studies2,4 found higher incidences of 250 episodes per 100 child-years. These rates were drawn from studies of close populations such as private paediatric clinic and day care facilities. Studies relying on medical attendance to draw conclusions on LRI incidence would be unreliable as many episodes of LRI resolve spontaneously without requiring medical attention.

In this study, as expected, most of the ARI occurred during the colder winter months of June to August. Clear seasonal trends in ARI rates have been demonstrated with relatively fewer infections in the summer months.16

The majority of ARI in the first year of life, including wheezy LRI, were found to have viral aetiology, with rhinoviruses and RSV the most common pathogens identified, supporting reports by other studies that viruses are the primary respiratory pathogens in ARI in early childhood.17,18

Duration and management of symptoms

Runny/blocked nose was the most common presenting symptom, followed by cough. In the majority of episodes, both these symptoms resolved within 2 weeks of onset. A total of 27.0% of the ARI episodes were associated with a fever of >38°C, which resolved in the majority of cases within the first 3 days.

Ray et al. reported on URI respondents at a walk-in clinic, and found 84% had phlegm, 95% cough, and 38% reported associated fever.19 With that pattern of symptoms, paracetamol was used in half of the ARI, while cough mixtures, antitussives and other cold medications were used in 53% of ARI, particularly if the child had a ‘moist, wet’ cough. Jhaj et al. found 88% of episodes of URI in children were treated with cough mixtures and other cold medications.20

Forty-five per cent of all episodes of ARI in this study presented to their family physicians, with a slightly higher percentage presenting in the first 2 years, or if the child had symptoms of a LRI. As the majority of children from this cohort are ‘only’ children, their parents may have felt less experienced in managing ARI symptoms and may thus be more likely to seek medical attention, especially when the child is younger, or when their child had a rattly or wheezy chest, which they may have considered a more serious illness.

Antibiotics were used in 23.6% of all episodes of ARI, with more LRI being treated with antibiotics than URI. This rate is markedly lower than that found in comparable studies in other countries. Antibiotic prescriptions for ARI in the primary care setting show markedly differing rates from 74% to 79% in the UK, Canada and Mexico,21–23 56% to 67% in the USA, Italy and Sweden,24–26 with the lowest rate of 26% in Malaysia.27 These studies also show higher rate of antibiotic prescription for LRI compared with URI (75% and 46%),28 (90% and 76%),29 (91% and 58%),22 (81% and 44%).25 The rate of antibiotic prescription for ARI in Australia has dropped from 42.1% in 1998–1999 to 35.1% in 2002–2003 reflecting the effectiveness of ongoing education strategies to reduce the use of antibiotics in the primary care setting.21,30

An association was found between antibiotic use and the duration of symptoms, perhaps reflecting parental concern over the length of their child’s illness and physicians’ perception of parental expectations of the need for antibiotic treatment.

There is little doubt that antibiotic resistance is a direct consequence of antibiotic use. People who had recently received antibiotics have been demonstrated to be more likely to be infected by antibiotic-resistant bacteria,29,31,32 while bacterial resistance to one drug or drug class increases the likelihood of developing resistance to unrelated antibiotics.

In Australia, Streptococcus pneumoniae resistance to antibiotics typically used to treat URTI has increased dramatically in the preceding few years.33 An Australian study that followed 484 preschool children for 25 months in the community setting found that rates of pneumococcal resistance are higher among children who had used more antibiotics and that the likelihood of carrying penicillin-resistant pneumococci was doubled in children who had received a beta-lactam (i.e. a penicillin or a cephalosporin) antibiotic in the preceding 2 months.34

Imprudent prescribing of antibiotics for ARI, particularly URI, which are, in the main viral in origin, has no doubt contributed to the rising trend of antibiotic resistance world-wide. Just under a quarter (23.6%) of the ARI in the present study were treated with antibiotics and although no trends were found between age groups, children with LRI were more likely to be treated with antibiotics. The majority of wheezy LRI episodes in hospitalized preschool children are caused by viruses, particularly RSV.35 In this study, more than two-thirds of the episodes of ARI, including wheezy LRI in the first year of life had viral aetiology5 and education of parents and physicians on the viral nature of the majority of ARI could thus contribute an effective strategy for changing therapeutic behaviour.

Risk factors to ARI

The finding that male children have more ARI in the first 3 years is similar to other studies.36,37

Children who were exposed to other children either at home or at day care had significantly more ARI, LRI and wheezy LRI in the first year. These findings are consistent with the literature,2,14,38 and can be explained by the increased exposure through contact with other children and the spread of respiratory pathogens.

The low prevalence of ETS exposure, prolonged breastfeeding and low rate of day care attendance were felt to have contributed to the lower incidence of ARI in this study. A systematic public health approach in the management of ARI to maximise preventive measures such as increased public education to raise awareness about the detrimental effects of ETS, protective effects of breastfeeding, reduced exposure to other children through delaying child care attendance would help to minimise transmission rates to reduce prevalence rates and economic impact. Clinicians can promote and reinforce these public health messages through parental education during consultations. Governments should ban all tobacco advertisements, legislate to stop smoking in public places as well as private vehicles, impose higher levies on cigarettes and tobacco products; and use revenue raised from these sources for further public education.

Conclusion

  1. Top of page
  2. Abstract
  3. Key Points
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

This prospective community study of ARI in early childhood provides valuable information for the physician on the epidemiology of respiratory tract illnesses in early childhood. It demonstrates that ARI are common causes of morbidity in early childhood, with the majority of episodes involving only the upper respiratory tract. Viruses are the major aetiological agents responsible, and although symptoms are usually present for 1–2 weeks, symptom persistence beyond 2 weeks is not uncommon and even in this cohort at high atopic risk, the majority resolve spontaneously with only 1.2% requiring hospitalisation. Antihistamines, decongestants and antibiotics were not found to alter the course or duration of illness, and routine use of these medications should be avoided to limit potential adverse effects and to reduce development of antibiotic resistant bacteria both in the individual as well as in the community.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Key Points
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

The authors acknowledge the tremendous support of the study families and their children throughout the duration of the study, and the study nurses and personnel for the recruitment and follow-up of the families. This study was supported by a National Health and Medical Research Council (Australia) grant.

References

  1. Top of page
  2. Abstract
  3. Key Points
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References
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    Chanarin N, Corne J, Holgate ST. Viral infections. In: BarnesPJ, et al., eds. Asthma. New York: Lippincott-Raven Publishers, 1997; 1193205.
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    Chauhan A, Johnston S. Advances in the diagnosis of respiratory virus infections. In: SkonerDP ed. Asthma and Respiratory Infections. New York: Marcel Dekker, 2000; 22144.
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