The Duration of Wheezy Episodes in Early Childhood Is Independent of the Microbial Trigger

1 The Duration of Wheezy Episodes in Early Childhood is Independent 2 of the Microbial Trigger3 Christian J Carlsson, medical doctor1; Nadja H Vissing, PhD1; Astrid Sevelsted, MSc1; Sebastian4 L Johnston, professor2; Klaus Bønnelykke, PhD1; Hans Bisgaard, professor15 1 The Copenhagen Prospective Studies on Asthma in Childhood; Faculty of Health and 6 Medical Sciences, University of Copenhagen and The Danish Pediatric Asthma Centre; 7 Copenhagen University Hospital, Gentofte, Ledreborg Allé 34, DK- 2820 Gentofte, 8 Copenhagen, Denmark 9 2Airway Disease Infection Section, National Heart and Lung Institute, MRC and Asthma UK 10 Centre in Allergic Mechanisms of Asthma, Imperial College London, UK 11 Correspondence to: 12 Professor Hans Bisgaard, MD, DMSci 13 Tel: (+45) 39777360 Fax: (+45) 3977712914 E-mail: [email protected] 15 Website: www.copsac.com 1617 Funding: COPSAC is funded by private and public research funds listed on www.copsac.com. 18 The Lundbeck Foundation, the Danish Strategic Research Council, the Pharmacy Foundation 19 of 1991, the Augustinus Foundation, the Danish Medical Research Council, and the Danish 20 Paediatric Asthma Centre provided the core support for COPSAC research centre. The 21 funding agencies had no role in the study design; the conduct of the study; data collection 22 and management; data analysis; or the preparation, review, or approval of the manuscript. 23 All authors are independent of any interests of the funders.24 25 Abstract 26 Background: Wheezy episodes in young children are often triggered by viral and bacterial 27 respiratory infections, but there is little evidence supporting that symptom duration 28 depends on the specific microbial trigger. 29 Objective: To investigate if the duration of wheezy episodes in young children depends on 30 the microbial trigger. 31 Methods: 283 children from the Copenhagen Prospective Study on Asthma in Childhood2000 32 at-risk birth cohort were prospectively examined for common airway pathogenic bacteria 33 and viruses during acute wheezy episodes, in the first 3 years of life. Findings were related to34 symptomatic duration of episodes as monitored in daily diary cards from birth.35 Results: 837 samples were investigated for virus and/or bacteria. In 55% of episodes both 36 virus and bacteria were identified, in 31% bacteria exclusively and in 10% virus exclusively. 37 The median duration of acute symptoms was 9 days (interquartile range 5-16 days). The 38 duration was independent of bacteria or viral species. 39 Conclusions: The duration of wheezy episodes was independent of pathogenic airway 40 bacteria or virus species. This suggests that symptom burden from infections is dependent 41 on other factors, such as environmental exposures or host factors . The common term “viral 42 wheeze” seems inappropriate in view of the finding of pathogenic bacteria in 86% of wheezy43 episodes.44 Word count abstract: 2236 45 Key messages46 - The duration of wheezy episodes in young children is independent of the specific viral47 or bacterial triggers.48 - The common term “viral wheeze” seems inappropriate in view of the finding of 49 pathogenic bacteria in the majority of wheezy episodes.50 Capsule summary51 Viral and bacterial respiratory infections are associated with acute wheezy episodes in young52 children. The duration of wheezy episodes in young children is independent of the specific 53 infecting viral and bacterial species.54 Key words: Respiratory Infections; Wheezy episodes; Pediatrics.55 Word count: 3290 56 Abbreviations 57 95%CI = 95% confidence interval58 COPSAC2000 = Copenhagen Prospective Study on Asthma in Childhood200059 GEE = Generalized estimating equations 60 IQR = Inter Quartile Range61 IRR = Incidence Rate Ratio62 RSV = Respiratory syncytial virus63 RV = Rhinovirus645 65 Background66 Infections with respiratory viruses are known triggers of wheezy episodes in children with 67 reported infection rates of 62% - 95% 1–6 and 40% outside episodes. 5 Rhinoviruses (RV), 68 respiratory syncytial virus (RSV) and coronaviruses seem the most prevalent viruses during 69 wheezy episodes. 1–6 Several other respiratory viruses have been implicated with lesser 70 relative contributions. 1,3–6 In our recent study we highlighted that common pathogenic 71 bacteria and respiratory viruses were equally closely associated with wheezy episodes, 5 72 suggesting that bacteria should also be considered an important trigger.73 The aim of this study was to address the question if the duration of wheezy episodes is 74 attributable specifically to the infecting species. If not, this would suggest host or 75 environmental factors to be responsible for the disease course as suggested by our recent 76 finding of an interaction between 17q21 gene risk variant, exposure to RV and risk of 77 persistent wheeze. 7 Therefore we have compared differences in the duration of wheezy 78 episodes, associated with various respiratory virus and bacteria species, in the Copenhagen 79 Prospective Study on Asthma in Childhood 2000 (COPSAC2000) at-risk birth cohort, followed 80 from birth with daily diary cards and acute visits to our clinic during wheezy episodes. 5,8,9 8182 Methods83 The Copenhagen Prospective Study on Asthma in Childhood 2000 (COPSAC2000) is a single-84 centre, prospective birth cohort study following 411 children of mothers with doctor 6 85 diagnosed asthma. 8 Criteria for inclusion of subjects have been published previously 8,10 and 86 are summarized in the Online Repository. 87 Children in COPSAC2000 attended the research clinic during acute wheezy episodes, at which 88 time airway aspirates for microbiological diagnosis were collected. Wheezy symptoms were 89 recorded in daily diaries from 1 month of age until age 3 years. 8,9 Parents were taught to 90 record their child’s symptoms with emphasis on the lower airways, at comprehensive 91 educational sessions, conducted at planned half-yearly visits. Wheezy symptoms were 92 translated to the parents as any symptom significantly affecting the child’s breathing such as 93 noisy breathing (wheeze or whistling sounds), shortness of breath or persistent troublesome94 cough affecting the sleep or activity of the child. Daily symptoms were recorded as 95 composite dichotomized scores (yes/no) each day; i.e. the parents were taught to make a 96 global assessment. The complexity of symptoms was detailed in a book that was given to the97 parents (www.copsac.com/content/literature-parents). The diary cards were collected and 98 reviewed by the doctors at the planned half-yearly clinic visits.99 Wheezy episodes were defined as three consecutive days on which the child had wheezing 100 symptoms. The parents were requested to bring the child to the clinical research unit for 101 examination by the research physician within 24 hours after every episode (i.e., on the 102 fourth consecutive day of symptoms). For some episodes, wheezy symptoms were not 103 recorded on the day of aspiration. These episodes were still included in the analysis if there 104 had been symptoms up until the day before aspiration. At each acute visit the children were105 examined by physicians trained in paediatrics and clinical research for diagnosis and 106 treatment of wheezy episodes in accordance with predefined standard operating 7 107 procedures. Aspirates from acute respiratory episodes with clinical signs indicative of 108 pneumonia or croup were excluded from this study as described in the Online Repository. 109 Hypopharyngeal aspirates were obtained for routine bacterial cultures without any a priori 110 species selection (we detected Streptococcus pneumoniae, Haemophilus influenza, 111 Moraxella catarrhalis, Staphylococcus aureus and Streptococcus pyogenes) and 112 nasopharyngeal aspirates for PCR virus identification (picornaviruses; RSV; coronaviruses; 113 parainfluenza viruses; influenza viruses; human metapneumoviruses; adenoviruses and 114 bocavirus) at all acute visits as described in the Online Repository. 115 Various baseline host and environmental factors were invesitgated for potential confounding116 effect on the association between microbial triggers and duration of wheezy episodes. 117 Allergic sensitization was determined from specific IgE and skin prick tests at the ages of 6 118 months, 1.5 years and 4 years. Asthma was diagnosed throughout the first three years of life119 in accordance with international guidelines as further detailed in the Online Repository. 120 Allelic discrimination at the ORMDL3 locus rs7216389 at chromosome 17q21 was performed 121 using an Applied Biosystems Custom Taqman SNP Genotyping assay (c/n 4332072) on a 7700122 Sequence Detection System. The variant was in Hardy-Weinberg equilibrium (P > 0.05). We 123 collected occipital hair samples at 1 year of age for determination of trace amounts of 124 nicotine using gas chromatography-mass spectrometry assays as previously described. 11 125126 Statistical analyses8 127 Microbial findings in wheezy episodes were summarized in frequency tables across all 128 episodes with available microbial data. Co-infection was defined as identification of at least 129 one respiratory virus and at least one of the investigated bacteria (S. pneumonia, H. 130 influenzae and M. catarrhalis). 131 The main outcome was duration of acute wheezy episodes where microbial sampling was 132 performed. The effect of various infectious agents on duration of episodes was investigated, 133 using generalized estimating equation (GEE), to adjust for inter-observational correlations, 134 due to multiple sampling from the same child. We assumed negative binomial distribution of135 duration of episodes. Each infectious agent was investigated separately as a dichotomous 136 variable (present/not present) independent of other findings in sample. Results are shown 137 unadjusted and adjusted for confounders.138 Distribution of potentially confounding environmental and host risk factors (sex; age at 139 episode; fathers asthma; mothers educational level; nicotine in hair age 1 year; sensitization 140 at ages 6 months, 18 months, 4 years; asthma during age 0-3 years; chromosome 17q21 141 variant) were summarized for the study base of wheezy episodes, and investigated for their 142 independent effect on duration of wheezy episodes, also using GEE.143144 The effect of infection with virus only, bacteria only or co-infection compared to no infection145 was investigated in a sub-analysis. A significance level of 0.05 was used in all analyses. All 146 analyses were conducted in SAS statistical software (version 9.3).9 147 To visualize the effect of various agents on symptom duration, not limiting the analyses to 148 consecutive days with symptoms, we plotted the percentage of diaries on which symptoms 149 were recorded on the day of sampling and for each day 30 days before and after sampling. 150 Results151 The clinical follow-up rate of the COPSAC cohort was 95% at age 1 year; 90% at age 2 years 152 and 85% at age 3 years. 153 The study base (Figure 1) included 837 samples taken at wheezy episodes from 283 children 154 in the first three years of life. Cultures were excluded if antibiotics had been taken within the155 previous week of sampling (N=74). Samples taken in relation to a clinical diagnosis of 156 pneumonia (N=163) were excluded and samples taken in relation to a clinical diagnosis of 157 croup (N=8) were also excluded leaving 592 eligible samples from 240 children. Of these, 540158 samples were investigated for virus; 483 were investigated for bacterial findings and 431 159 were investigated for both. 160 During the first 3 years of life 96 children contributed 1 aspirate, 112 contributed 2-4 161 aspirates and 32 children contributed 5 or more aspirates with either virus or bacteria. 171 162 of 411 children (42%) had no eligible aspirates performed during wheezy episodes. Details 163 on numbers of eligible bacterial and viral aspirates per child are displayed in Figure E1 in the 164 Online Repository. 165 While we encouraged the parents to bring their child to the research clinic after three 166 consecutive days of wheezy symptoms this was not always the case. If parents and children 10 167 attended the clinic after only 1-2 days of troublesome lung symptoms (N=23), aspirates were168 still obtained according to standard operating procedures described above. 169 Table 1 shows the distribution of viruses and bacteria in the samples taken during wheezy 170 episodes. Picornaviruses (of which 84% was RV), RSV and coronaviruses were the most 171 prevalent viral agents present in 29%, 17% and 13% of samples with lesser relative 172 contributions of other viruses. S. pneumonia, M. catarrhalis and H. influenzae were found in 173 47%, 49% and 41% of the samples while S. aureus and S. pyogenes were found in an 174 insignificant proportion of samples and were excluded from further analyses In 55% of 175 wheezy episodes co-infection with both virus and bacteria was identified. Exclusively 176 bacterial or viral infection was found in 31% and 10% of episodes respectively. In 5% of 177 samples no pathogen was identified. There were no increased risk of co-infection with any 178 type of pathogen i.e., infection with virus did not cause greater risk of bacterial infection and179 vice versa (Chi square p=0.59).180 There were no apparent difference in age at first infection between investigated viruses and 181 bacteria, and there were no obvious age-dependent differences in prevalence of any of the 182 pathogens (details in Figure E2 and E3). 183 Figure 2 shows the seasonal variation of viruses and bacteria found during acute respiratory 184 episodes. RSV exhibited a marked peak during winter months while the all other viruses and 185 bacteria were found in stable proportions throughout the year. For both viruses and bacteria186 a larger percentage of aspirates were without pathogen findings during summer months.187 During the first three years of follow-up, symptom diary data was completed for 387 188 children in a total of 374,264 days of the potential 450,867 days of observation i.e. a 11 189 coverage rate of 83%. The median age for starting the diary recordings was 19 days 190 (Interquartile range 13-29). Wheezy symptoms were recorded on 6.6% (24,708) of the days. 191 Twenty-four children had no dairy data for the first three years of life. Forty-five children 192 never recorded any symptom days throughout the first three years of follow-up. 193 515 (91%) of the 592 eligible aspirates were taken from episodes with complete diary data 194 one month before and one month after the sample collection. Thus we analysed a total of 195 515 samples in 216 children (Figure 1). 196 The median duration of the 515 wheezy episodes was 9 days (IQR 5 to 16). The effect of 197 various environmental and host factors on duration of episodes are shown in Table 2. A 198 diagnosis of asthma during age 0-3 years was associated with significantly longer duration of 199 wheezy episodes (IRR 1.74, [1.32-2.30], p=<0.001) while there was no evidence of 200 association with the other risk factors.201 There was no significant difference in duration of wheezy episodes associated with any 202 specific viral or bacterial trigger (Table 3). Similarly, symptom duration was independent of 203 the presence of solely viral or bacterial infection or co-infection compared to episodes with 204 no pathogens detected (Table E1). Adjusting the analyses for potential confounding effect of 205 various environmental and host factors did not change the results (Table 3 and E1). 206 Figure 2A shows the proportion of diaries on which symptoms were recorded for each day 207 during the 30-day period before and after an aspirate with positive findings for respiratory 208 viruses. In the immediate period surrounding positive viral aspirates, there were no 209 discernible differences in the portion of children with wheezy symptoms between different 210 virus species; i.e. all virus triggered wheezy episodes of similar symptom profile. The level of 12 211 baseline respiratory symptoms before and after the wheezy episodes was also similar among212 the investigated viruses, i.e. no species caused more sustained symptoms than others. It was213 evident that the majority of families attended the research clinic for clinical examination and214 airway aspiration (day 0) after a period of a few symptom days in accordance with our 215 protocol. Again this was true for all the most common respiratory viruses. 216 Figure 2B shows the proportion of diaries on which symptoms were recorded for each day 217 during the 30 day period before and after an aspirate with positive findings for the 218 pathogenic respiratory bacteria. There were no differences in the course of disease and 219 remission between bacterial species. The level of baseline respiratory symptoms before and 220 after the wheezy episode was similar among the investigated bacteria.221 Figure 2C shows the proportion of diaries on which symptoms were recorded for each day 222 during the 30 day period before and after an aspirate with positive findings for only virus, 223 only bacteria, co-infection or no identified pathogens. Symptom duration was similar for the 224 three groups with positive microbiological findings. Symptomatic episodes with no identified225 pathogens were rare and thus appeared to have a more erratic course with fewer baseline 226 symptoms before the wheezy episode. 227228 Discussion229 Pathogenic bacteria were a more common finding than virus during wheezy episodes, hence 230 the common term “viral wheeze” should be abandoned. Duration of wheezy episodes was 231 independent of specific pathogenic respiratory bacteria or virus species. This suggests that 13 232 symptom burden from infections in terms of duration of wheezy episodes is dependent on 233 other factors than the specific triggering agent. . 234 Strengths and weaknesses of the study235 The intense clinical surveillance of the COPSAC2000 birth cohort is a major strength of this 236 study. All children attended the COPSAC research clinic instead of other healthcare facilities. 237 Experienced research physicians did clinical diagnosis and sampling at the clinic in 238 accordance with standard procedures. This approach reduced the risk of misclassification of 239 illness and variation in sampling quality. The physicians at the clinic distinguished clinical 240 pneumonia from wheezy episodes on the basis of the presence of tachypnoea, fever, and 241 crepitation on auscultation without wheeze in accordance with standard operating 242 procedures. This clinical differentiation between wheeze and pneumonia can be debated. 243 However, the children were assessed by the same doctors in accordance with standard 244 operating procedures; the sampling for viruses and bacteria was independent of such a 245 distinction, and the clinical diagnosis was independent of microbiological results. 246 Another strength of this study is the prospective monitoring of lung symptoms in daily 247 diaries since neonatal age. This assured reliable monitoring of episode duration. The validity 248 of mother’s symptom observation and recording was probably improved from the fact that 249 they all had a history of asthma.250 The incidence of viruses in wheezy episodes in this study is comparable to other recent 251 studies of viral infections in wheezy episodes of infants and preschool children. 2–4,614 252 It is a limitation of this study that we do not have data on symptom severity. It is our 253 interpretation that symptom duration is a surrogate marker of symptom severity, but this 254 needs to be studied. 255 According to the study protocol we instructed the parents to bring their child to the research256 clinic after three consecutive days of symptoms. This potentially hampers our ability to 257 analyse duration of episodes. As some parents brought their child to the research clinic after 258 only 1-2 days of symptoms we do have some samples (N=23) from episodes of shorter 259 duration and these are included in the analysis. Comparison of the microbial spectrum for 260 the lower and upper quartile of duration of wheezy episodes included (1-5 days vs. 17-28+ 261 days) did not reveal any differences (data not shown). 262 The use of traditional culturing methods is a limitation. Unfortunately, bacterial DNA 263 sequencing data were not available in the current study.264 Another limitation of our findings is that the investigations were carried out in a high-risk 265 population. The selection for maternal asthma and exclusion of premature newborns limit 266 the generalizability of the findings, which need replication in unselected cohorts.267268 Meaning of this study269 Viral and bacterial infections are triggers of wheezy episodes in young children. 1,5 This study 270 shows similar symptom duration of acute wheezy episodes from the most common 271 respiratory bacteria and viruses. These findings suggest that the particular pathogenic 272 species is not important for the course of such episodes. This conclusion is supported by our 15 273 recent findings of similar relative distributions of specific bacterial and viral species in 274 symptomatic and asymptomatic children. 5 The notion that different species cause different 275 clinical outcomes might be confounded by prevalence and there is little evidence to signify 276 that the role of the infectious agent among pathogenic respiratory bacteria and virus is 277 dependent on species.278 Previous reports have been conflicting as to whether the presence of viral infection 279 augments severity and duration of lower respiratory tract symptoms, and differential 280 symptom burden for specific viruses has been reported in some studies. 1,12,13 School children281 were reported to have a lesser fall in peak expiratory flow and a lower subjective symptom 282 score when infected with coronaviruses than with other respiratory viruses. 1 Others 283 reported picornaviruses and adenoviruses to be more prevalent in near-fatal adult asthma 284 than in less severe exacerbations. 12 One important difference from our study is that these 285 phenotypes are much different from the wheezy episodes in young children. 286 Wheezy episodes are a much debated diagnosis to the point that the debate often confuse 287 the need to understand, prevent and treat this entity. Wheeze is the most common reason 288 for acute hospitalization, healthcare utilization and use of medicine in the young children in 289 westernized countries. 14 The terminology is misleading since evidence shows wheeze is an 290 unusual symptom for parents to report even prior to severe exacerbations, 15 and that the 291 quantitative global assessment of significant troublesome lung symptoms in the first 3 years 292 of life is a better predictor of asthma than assessment of wheeze alone 16. The common term293 viral wheeze is further obsolete given the fact that bacteria seem more prevalent in such 294 episodes than virus.16 295 In the COPSAC birth cohort studies we have instead educated the parents to record the 296 global respiratory distress being it wheeze, breathlessness, cough or what others terms lay-297 people relate to this. Symptoms severely affecting the well-being of the child is the key to 298 the recordings in the diary cards. Though we find “wheezy episodes” a misnomer, we need 299 to use the term to be able to communicate our research.300 Our results suggest that while microbiological pathogens act as instigators of respiratory 301 distress in children, other factors determines duration of the symptomatic episode. The 302 mechanisms by which viruses and bacteria provoke exacerbations are yet unclear but 303 current evidence suggests that allergic sensitization and altered immune response may be 304 more important than the virulence of the specific agent. 24 It has been suggested that 305 deficiencies in antiviral activity and the integrity of the airway epithelial barrier may make 306 individuals with asthma more likely to have severe viral respiratory infections of the lower 307 airway. 24 In this study we found asthma at age three years to be associated with episodes of 308 longer duration. This finding was not unexpected since persistent symptoms is one of the 309 diagnostic criteria for asthma. None of the other host factors investigated had any 310 confounding effect on duration of episodes.311 RSV showed a peak in winter, with no other species-specific variation with respect to season 312 or age. There was however a general decrease in the proportion of infections per wheezy 313 episode during summer. The latter is an unexpected and interesting observation, but the 314 interpretation uncertain.It is a common notion that virus is the predominant microbial agent 315 responsible for acute respiratory symptoms in young children. However, we recently found 316 bacterial infections to be significantly associated with acute wheezy episodes in children up 17 317 to three years of age, similar to but independent of the well known association with viral 318 infections. 5 In this study we showed a high prevalence of concurrent infection with both 319 virus and bacteria (55%) and of exclusively bacterial infection (31%) in acute symptomatic 320 episodes. Surprisingly only few aspirates were found with only virus species (10%). This is of 321 apparent clinical interest as acute episodes with bacteria may be amendable to antibiotic 322 therapy or prophylaxis. 323 Conclusion324 We found no significant differences in duration of wheezy episodes from the most common 325 pathogenic respiratory virus and bacteria. While triggered by virus and bacteria, the course 326 of wheezy episodes seems independent of infecting species and may therefore be controlled327 by other factors such as intrinsic host factors or environmental exposures.328 Acknowledgements329 We gratefully express our gratitude to the children and families of the COPSAC2000 cohort 330 study for all their support and commitment. We acknowledge and appreciate the unique 331 efforts of the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) research 332 team, and T. Kebadze and J. Aniscenko for the virologic analyses. COPSAC is funded by 333 private and public research funds listed on www.copsac.com. The Lundbeck Foundation, the 334 Danish Strategic Research Council, the Pharmacy Foundation of 1991, the Augustinus 335 Foundation, the Danish Medical Research Council, and the Danish Paediatric Asthma Centre 336 provided the core support for COPSAC research centre.33718 338 References339 1. Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs L, et al. Community 340 study of role of viral infections in exacerbations of asthma in 9-11 year old children. 341 BMJ. 1995 May 13;310(6989):1225–9. 342 2. Rakes GP, Arruda E, Ingram JM, Hoover GE, Zambrano JC, Hayden FG, et al. Rhinovirus 343 and respiratory syncytial virus in wheezing children requiring emergency care. IgE and 344 eosinophil analyses. Am J Respir Crit Care Med. 1999 Mar;159(3):785–90. 345 3. Kusel MMH, de Klerk NH, Holt PG, Kebadze T, Johnston SL, Sly PD. 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N Engl J Med. 2006 Apr 409 13;354(15):1589–600. 410 26. Hahn DL, Plane MB, Mahdi OS, Byrne GI. Secondary outcomes of a pilot randomized 411 trial of azithromycin treatment for asthma. PLoS Clin Trials. 2006 Jun;1(2):e11. 41241321 414 Table 1: Viral and bacterial findings in pharyngeal aspirates obtained during wheezy episodes415 in young children.Numbers Percentage Viruses Picornaviruses 159/540 29% Respiratory syncytial virus 89/540 17% Coronaviruses 69/540 13% Other virus (5 below) 129/540 24% Parainfluenza viruses 42/540 8% Influenza viruses 36/540 7% Human metapneumoviruses 17/540 3% Adenoviruses 5/540 1% Bocavirus 43/540 8% Any virus (of above) 350/540 65% Multiple virus (of above) 183/540 34% Bacteria S. pneumoniae 229/483 47% H. influenzae 200/483 41% M. catarrhalis 238/483 49% Any bact (of above) 412/483 85% Multiple bacteria (of above) 205/483 42% Tested for Only virus 42/431 10% both Only bacteria 132/431 31% Both 237/431 55% No pathogens 20/431 5% 41641741841942022 421 Table 2. Effect of environmental and host factors on duration of wheezy episodes in young 422 children.N N children IRR [CI 95]; p-value episodesGender 515 216 Female 288 115 0.97 [0.72- 1.30]; 0.85 Male 227 101 reference Age 515 216 0--1 years 227 136 1.22 [0.82- 1.81]; 0.33 1--2 years 205 139 1.13 [0.75- 1.70]; 0.56 2--3 years 83 62 reference Farther with a diagnosis of asthma 485 205 Yes 100 33 0.93 [0.70- 1.25]; 0.65 No 385 172 reference Maternal educational level 505 210 At most college 333 137 1.01 [0.73- 1.41]; 0.94 Medium duration 127 50 0.99 [0.60- 1.62]; 0.963 University 45 23 reference Environmental tobacco exposure (nicotine 491 207 in hair age 1 year above 1 ng/mg vs. below) Yes 206 90 1.16 [0.86- 1.56]; 0.34 No 285 117 reference Sensitization at any point (6 months, 18 512 214 months, 4 years) Yes 183 52 0.82 [0.64- 1.04]; 0.10 No 329 162 reference Asthma during age 0-3 years (yes vs. no) 478 198 Yes 183 52 1.74 [1.32- 2.30]; <0.001 No 295 146 reference Chromsome 17q21 gene variant 509 211 TT 170 72 1.05 [0.67- 1.66]; 0.83 TC 227 88 0.87 [0.56- 1.35]; 0.54 CC 112 51 reference IRR: Incidence rate ratio.23 423 Table 3: Duration of wheezy episodes in young children, in relation to various viral and bacterial triggers.Negative Positive Results from GEE models Median days No. of No. of Median days No. of No. of Unadjusted IRR [95% CI]; p- Confounder* (IQR) episodes children (IQR) episodes children value N=483 episodes adjusted IRR (N) (n) (N) (n) [95% CI]; p- value N=403 episodes Virus Picornaviruses 10 (6-16) 345 184 9 (6-17) 138 101 0.91 [0.74- 1.13]; 0.40 0.88 [0.71- 1.08]; 0.22 RSV 9 (6-17) 402 192 11 (7-15) 81 73 0.94 [0.76- 1.16]; 0.54 0.99 [0.78- 1.26]; 0.95 Coronaviruses 10 (6-17) 422 202 9 (5-13) 61 47 1.04 [0.68- 1.58]; 0.85 1.00 [0.70- 1.42]; 0.99 Other virus 10 (6-16) 366 182 10 (6-17) 117 88 1.05 [0.86- 1.29]; 0.61 1.06 [0.87- 1.3]; 0.55 Any virus 9 (6- 17) 171 117 10 (6- 17) 312 171 0.97 [0.78- 1.22]; 0.81 0.95 [0.74- 1.21]; 0.67 Bacteria S. pneumoniae 9 (6-16) 224 134 11 (6-19) 196 130 1.22 [0.99- 1.49]; 0.058 1.18 [0.94- 1.48]; 0.16 H. influenzae 10 (6-18) 243 154 11 (6-17) 177 113 0.98 [0.79- 1.22]; 0.88 1.00 [0.78- 1.27]; 0.99 M. catarrhalis 11 (6-18) 215 128 10 (6-17) 205 135 1.02 [0.82- 1.27]; 0.85 1.03 [0.84- 1.27]; 0.76 Any bacteria 9 (5- 16) 62 47 11 (6- 17) 358 180 1.22 [0.99- 1.51]; 0.059 1.17 [0.94- 1.45]; 0.15 424 * Sex; age at episode; fathers asthma; mothers educational level; nicotine in hair age 1 year; sensitization at ages 6 months, 18 months, 4 425 years; asthma during age 0-3 years; chromosome 17q21 variant. IRR: Incidence rate ratio; GEE: generalized estimating equations24 426 Figure legends427 Figure 1: Study base selection of samples from young children with wheezy episodes, 428 analyzed for viruses and bacteria.429 Figure 2: Seasonal variation in prevalence of viruses and bacteria found during wheezy 430 episodes in young children. The y-axis gives the proportion of aspirates with relevant 431 findings within each month while the x-axis represents calendar months. RSV: respiratory 432 syncytial virus.433 Figure 3A: Days with wheezy symptoms before and after pharyngeal sampling (day 0) with 434 positive findings of various respiratory viruses. RSV: respiratory syncytial virus.435 Figure 3B: Days with wheezy symptoms before and after pharyngeal sampling (day 0) with 436 positive findings of various respiratory bacteria.437 Figure 3C: Days wheezy symptoms before and after pharyngeal sampling (day 0) with no 438 microbial findings, only viral findings, only bacterial findings or both virus and bacteria 439 detected. 25

The Duration of Wheezy Episodes in Early Childhood Is Independent of the Microbial Trigger

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