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• W2891843538 abstract "Early lower respiratory tract infections are associated with an increased risk of developing childhood asthma.1van Meel E.R. den Dekker H.T. Elbert N.J. Jansen P.W. Moll H.A. Reiss I.K. et al.A population-based prospective cohort study examining the influence of early-life respiratory tract infections on school-age lung function and asthma.Thorax. 2018; 73: 167-173Crossref PubMed Scopus (39) Google Scholar Young children experience frequent acute respiratory infections (ARIs) of which the vast majority are upper respiratory tract infections. Although the research has mainly focused on lower respiratory tract infections, limited data exist on the association of all early ARIs and development of asthma. Results from previous studies are inconsistent1van Meel E.R. den Dekker H.T. Elbert N.J. Jansen P.W. Moll H.A. Reiss I.K. et al.A population-based prospective cohort study examining the influence of early-life respiratory tract infections on school-age lung function and asthma.Thorax. 2018; 73: 167-173Crossref PubMed Scopus (39) Google Scholar, 2Rantala A.K. Jaakkola M.S. Makikyro E.M. Hugg T.T. Jaakkola J.J. Early respiratory infections and the development of asthma in the first 27 years of life.Am J Epidemiol. 2015; 182: 615-623Crossref PubMed Scopus (26) Google Scholar, 3Bonnelykke K. Vissing N.H. Sevelsted A. Johnston S.L. Bisgaard H. Association between respiratory infections in early life and later asthma is independent of virus type.J Allergy Clin Immunol. 2015; 136: 81-86.e4Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 4Kusel M.M. Kebadze T. Johnston S.L. Holt P.G. Sly P.D. Febrile respiratory illnesses in infancy and atopy are risk factors for persistent asthma and wheeze.Eur Respir J. 2012; 39: 876-882Crossref PubMed Scopus (85) Google Scholar, 5Nafstad P. Brunekreef B. Skrondal A. Nystad W. Early respiratory infections, asthma, and allergy: 10-year follow-up of the Oslo Birth Cohort.Pediatrics. 2005; 116: e255-e262Crossref PubMed Scopus (85) Google Scholar, 6Illi S. von Mutius E. Lau S. Bergmann R. Niggemann B. Sommerfeld C. et al.Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study.BMJ. 2001; 322: 390-395Crossref PubMed Scopus (466) Google Scholar and population-based data are sparse. We conducted a prospective, population-based birth cohort study to investigate the association between ARIs during the first 24 months of life and asthma at age 7 years. Details of the methods and data analysis are present in this article's Online Repository at www.jacionline.org. Briefly, in the Steps to the Healthy Development and Well-being of Children (STEPS) Study, 923 Finnish children were followed intensively for upper and lower ARIs from birth to age 24 months.7Toivonen L. Schuez-Havupalo L. Karppinen S. Teros-Jaakkola T. Rulli M. Mertsola J. et al.Rhinovirus infections in the first 2 years of life.Pediatrics. 2016; 138: e20161309Crossref PubMed Scopus (14) Google Scholar Data were collected with daily symptom diaries, study clinic visits, and medical records. Nasal swab samples for respiratory viruses were taken at the onset of respiratory symptoms. Asthma diagnoses and medications were retrieved from medical records and electronic prescriptions at age 7 years. Parents of participating children gave their written, informed consent. The primary outcome was physician-diagnosed asthma at age 7 years, based on a diagnosis of asthma in the medical records or an electronic prescription of inhaled corticosteroids for asthma when the child was aged 6.5 to 7.5 years. Children who completed the follow-up on ARIs for 12 months or more were included in the analyses. Risk of asthma at age 7 years was analyzed by binary logistic regression analysis. Thirteen children withdrew from the study. Medical records and electronic prescriptions were reviewed for 910 (99%) children. Characteristics of the children are presented in Table E1 in this article's Online Repository at www.jacionline.org. Altogether 781 (86%) children completed the follow-up on ARIs for 12 months or more and the median completed follow-up time was 24.0 months (interquartile range [IQR], 20.2-24.0). A total of 8795 ARIs were recorded, with a mean frequency of 6.2 (95% CI, 6.0-6.4) per child per year. Altogether 273 doctor-diagnosed wheezing illnesses were documented in 135 (17%) children and 46 (17%) led to hospitalization. Diagnosis of asthma was documented in 75 (8%) of 910 children at age 7 years. A prescription for inhaled corticosteroids for asthma was documented in 70 (93%) of these children. Children with asthma at age 7 years had higher annual numbers of days with ARI symptoms, lower respiratory tract infections, physician visits, and antibiotics for ARIs at age 0 to 23 months as compared with children without asthma, and were more frequently hospitalized for ARI at age 0 to 23 months (Table I). The median duration of ARIs at age 0 to 23 months was longer in children with asthma at age 7 years than in those without later asthma (8.0 [IQR, 5.0-12.0] vs 7.0 [IQR, 4.0-12.0] days; P = .04) and ARIs in children with later asthma were more severe, but the virus etiology did not differ (see Table E2 in this article's Online Repository at www.jacionline.org).Table INumber of ARIs at age 0-23 months in children with and without asthma at age 7 years∗In children with ≥12-months follow-up data on ARIs. Categorical data were compared by using the χ2 test or Fisher exact test. Number of ARIs and associated outcomes were compared by using negative binomial regression with the natural logarithm of follow-up time as an offset variable.ARIs at age 0-23 moChildren with asthma at age 7 y (n = 63)Children without asthma at age 7 y (n = 718)P valueNo. of ARIs per year, mean (95% CI)6.8 (6.1-7.7)6.1 (5.9-6.3).07No. of ARIs per year, n (%).009 <514 (22.2)261 (36.4) 5-831 (49.2)347 (48.3) ≥918 (28.6)110 (15.3)No. of days with ARI symptoms per year, mean (95% CI)64.8 (53.4-78.7)50.2 (47.5-53.0).01No. of days with wheezing per year, mean (95% CI)5.2 (3.0-9.2)1.6 (1.4-1.9)<.001No. of RV infections per year, mean (95% CI)2.0 (1.6-2.4)2.0 (1.9-2.1).94RSV infection, n (%)21 of 60 (35)201 of 676 (30).39No. of physician visits for ARIs per year, mean (95% CI)4.7 (3.8-5.8)3.0 (2.8-3.2)<.001Hospitalization for an ARI, n (%)15 (23.8)41 (5.7)<.001No. of acute otitis media per year, mean (95% CI)1.3 (1.0-1.7)1.0 (0.9-1.0).05No. of LRTIs per year, mean (95% CI)0.3 (0.2-0.3)0.0 (0.0-0.1)<.001No. of wheezing illnesses, n (%)<.001 029 (46)617 (86) 111 (18)66 (9) ≥223 (37)35 (5)RV wheezing illness, n (%)15 of 60 (25)34 of 676 (5)<.001RSV wheezing illness, n (%)10 of 60 (17)32 of 676 (5)<.001Pneumonia, n (%)10 (15.9)26 (3.6)<.001No. of antibiotic treatments for ARIs per year, mean (95% CI)1.8 (1.4-2.4)1.2 (1.1-1.3).008LRTI, Lower respiratory tract infection; RSV, respiratory syncytial virus; RV, rhinovirus.∗ In children with ≥12-months follow-up data on ARIs. Categorical data were compared by using the χ2 test or Fisher exact test. Number of ARIs and associated outcomes were compared by using negative binomial regression with the natural logarithm of follow-up time as an offset variable. Open table in a new tab LRTI, Lower respiratory tract infection; RSV, respiratory syncytial virus; RV, rhinovirus. Number of ARIs and days with ARI symptoms per year at age 0 to 23 months were associated with an increased risk of asthma at age 7 years (Table II). Compared with children with less than 5 ARIs/y at age 0 to 23 months, children with 9 or more ARIs/y had a higher risk of asthma at age 7 years (adjusted odds ratio, 7.20; 95% CI, 2.49-20.88). Recurrent doctor-diagnosed wheezing illnesses, hospitalization for wheezing, and wheezing caused by either rhinovirus or respiratory syncytial virus at age 0 to 23 months were associated with an increased risk of asthma. Association of background variables with asthma is presented in Table E3 in this article's Online Repository at www.jacionline.org.Table IIARIs at age 0-23 months and risk of asthma at age 7 years∗Risk of asthma was calculated by using multivariable binomial logistic regression analysis in children with ≥12-months follow-up data on ARIs. Sex, birth by cesarean section, child's atopy at age 13 months, parental asthma, and parental smoking were used as covariates. Results of unadjusted analyses are presented in Table E4. Association between ARIs at age 0-11 months and risk of asthma is presented in Table E5.ARIs at age 0-23 moAll children (n = 781), nChildren with asthma at age 7 y (n = 63), n (%)Adjusted OR (95% CI)No. of ARI episodes per year1.17 (1.04-1.31)No. of ARI episodes per year <527514 (5.1)1.00 5-837831 (8.2)2.80 (1.06-7.42) ≥912818 (14.1)7.20 (2.49-20.88)No. of days with ARI symptoms per year, per 10 d1.12 (1.04-1.22)No. of RV infections per year <245538 (8.4)1.00 ≥228122 (7.8)0.78 (0.40-1.52)RSV infection 051439 (7.6)1.00 ≥122221 (9.5)1.32 (0.68-2.58)No. of LRTIs2.03 (1.62-2.53) No. of doctor-diagnosed wheezing illnessesNone64629 (4.5)1.0017711 (14.3)2.55 (0.95-6.87)≥25823 (39.7)16.91 (7.21-39.67) Age at first wheezing episode, mo0-117617 (22.4)1.0012-235917 (28.8)1.33 (0.51-3.46) Etiology of wheezing illnesses†Virus diagnostics was performed during 164 (60.1%) episodes of the total of 273 doctor-diagnosed wheezing illness. RV was detected in 77 (47.0%) episodes of doctor-diagnosed wheezing illness, RSV in 47 (28.7%), and other virus in 9 (5.5%) episodes.No wheezing60327 (4.5)1.00Wheezing, no detected RV or RSV4413 (29.5)6.89 (2.45-19.32)At least 1 RSV+ wheezing, no RV325 (15.6)4.90 (1.53-15.69)At least 1 RV+ wheezing, no RSV429 (21.4)5.13 (1.76-14.94)Both RSV+ and RV+ wheezing156 (40.0)13.93 (3.88-50.08) Severity of wheezing illnessesNo wheezing64629 (4.5)1.00Wheezing illness without hospitalization10421 (20.2)5.29 (2.46-11.38)Hospitalized for a wheezing illness3113 (41.9)14.93 (4.99-44.63)Hospitalization for an ARI No72548 (6.6%)1.00 Yes5615 (26.8%)5.46 (2.27-13.14)No. of antibiotics for ARIs1.20 (1.09-1.34)LRTI, Lower respiratory tract infection; OR, odds ratio; RSV, respiratory syncytial virus; RV, rhinovirus.∗ Risk of asthma was calculated by using multivariable binomial logistic regression analysis in children with ≥12-months follow-up data on ARIs. Sex, birth by cesarean section, child's atopy at age 13 months, parental asthma, and parental smoking were used as covariates. Results of unadjusted analyses are presented in Table E4. Association between ARIs at age 0-11 months and risk of asthma is presented in Table E5.† Virus diagnostics was performed during 164 (60.1%) episodes of the total of 273 doctor-diagnosed wheezing illness. RV was detected in 77 (47.0%) episodes of doctor-diagnosed wheezing illness, RSV in 47 (28.7%), and other virus in 9 (5.5%) episodes. Open table in a new tab LRTI, Lower respiratory tract infection; OR, odds ratio; RSV, respiratory syncytial virus; RV, rhinovirus. In this population-based child cohort, we report that children with a high frequency of early ARIs had an increased risk for asthma at age 7 years. There are limited earlier data about the association of all ARIs—including also upper ARIs—at early age and later asthma in a population-based setting and earlier results are inconsistent.1van Meel E.R. den Dekker H.T. Elbert N.J. Jansen P.W. Moll H.A. Reiss I.K. et al.A population-based prospective cohort study examining the influence of early-life respiratory tract infections on school-age lung function and asthma.Thorax. 2018; 73: 167-173Crossref PubMed Scopus (39) Google Scholar, 2Rantala A.K. Jaakkola M.S. Makikyro E.M. Hugg T.T. Jaakkola J.J. Early respiratory infections and the development of asthma in the first 27 years of life.Am J Epidemiol. 2015; 182: 615-623Crossref PubMed Scopus (26) Google Scholar, 3Bonnelykke K. Vissing N.H. Sevelsted A. Johnston S.L. Bisgaard H. Association between respiratory infections in early life and later asthma is independent of virus type.J Allergy Clin Immunol. 2015; 136: 81-86.e4Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 4Kusel M.M. Kebadze T. Johnston S.L. Holt P.G. Sly P.D. Febrile respiratory illnesses in infancy and atopy are risk factors for persistent asthma and wheeze.Eur Respir J. 2012; 39: 876-882Crossref PubMed Scopus (85) Google Scholar, 5Nafstad P. Brunekreef B. Skrondal A. Nystad W. Early respiratory infections, asthma, and allergy: 10-year follow-up of the Oslo Birth Cohort.Pediatrics. 2005; 116: e255-e262Crossref PubMed Scopus (85) Google Scholar, 6Illi S. von Mutius E. Lau S. Bergmann R. Niggemann B. Sommerfeld C. et al.Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study.BMJ. 2001; 322: 390-395Crossref PubMed Scopus (466) Google Scholar In line with our results, some earlier prospective studies have found that an increased number of all ARIs associate with the development of asthma.2Rantala A.K. Jaakkola M.S. Makikyro E.M. Hugg T.T. Jaakkola J.J. Early respiratory infections and the development of asthma in the first 27 years of life.Am J Epidemiol. 2015; 182: 615-623Crossref PubMed Scopus (26) Google Scholar, 3Bonnelykke K. Vissing N.H. Sevelsted A. Johnston S.L. Bisgaard H. Association between respiratory infections in early life and later asthma is independent of virus type.J Allergy Clin Immunol. 2015; 136: 81-86.e4Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar Some previous studies have found no1van Meel E.R. den Dekker H.T. Elbert N.J. Jansen P.W. Moll H.A. Reiss I.K. et al.A population-based prospective cohort study examining the influence of early-life respiratory tract infections on school-age lung function and asthma.Thorax. 2018; 73: 167-173Crossref PubMed Scopus (39) Google Scholar, 4Kusel M.M. Kebadze T. Johnston S.L. Holt P.G. Sly P.D. Febrile respiratory illnesses in infancy and atopy are risk factors for persistent asthma and wheeze.Eur Respir J. 2012; 39: 876-882Crossref PubMed Scopus (85) Google Scholar, 5Nafstad P. Brunekreef B. Skrondal A. Nystad W. Early respiratory infections, asthma, and allergy: 10-year follow-up of the Oslo Birth Cohort.Pediatrics. 2005; 116: e255-e262Crossref PubMed Scopus (85) Google Scholar or even negative6Illi S. von Mutius E. Lau S. Bergmann R. Niggemann B. Sommerfeld C. et al.Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study.BMJ. 2001; 322: 390-395Crossref PubMed Scopus (466) Google Scholar association between early upper ARIs and later asthma. However, many previous studies have assessed ARIs as a dichotomous variable, and frequently recurring infections, which in our study were associated with the development of asthma, have not been investigated.1van Meel E.R. den Dekker H.T. Elbert N.J. Jansen P.W. Moll H.A. Reiss I.K. et al.A population-based prospective cohort study examining the influence of early-life respiratory tract infections on school-age lung function and asthma.Thorax. 2018; 73: 167-173Crossref PubMed Scopus (39) Google Scholar, 4Kusel M.M. Kebadze T. Johnston S.L. Holt P.G. Sly P.D. Febrile respiratory illnesses in infancy and atopy are risk factors for persistent asthma and wheeze.Eur Respir J. 2012; 39: 876-882Crossref PubMed Scopus (85) Google Scholar, 5Nafstad P. Brunekreef B. Skrondal A. Nystad W. Early respiratory infections, asthma, and allergy: 10-year follow-up of the Oslo Birth Cohort.Pediatrics. 2005; 116: e255-e262Crossref PubMed Scopus (85) Google Scholar In some studies, data have been collected by questionnaires, which makes it difficult for parents to recall all past ARIs.1van Meel E.R. den Dekker H.T. Elbert N.J. Jansen P.W. Moll H.A. Reiss I.K. et al.A population-based prospective cohort study examining the influence of early-life respiratory tract infections on school-age lung function and asthma.Thorax. 2018; 73: 167-173Crossref PubMed Scopus (39) Google Scholar, 2Rantala A.K. Jaakkola M.S. Makikyro E.M. Hugg T.T. Jaakkola J.J. Early respiratory infections and the development of asthma in the first 27 years of life.Am J Epidemiol. 2015; 182: 615-623Crossref PubMed Scopus (26) Google Scholar, 5Nafstad P. Brunekreef B. Skrondal A. Nystad W. Early respiratory infections, asthma, and allergy: 10-year follow-up of the Oslo Birth Cohort.Pediatrics. 2005; 116: e255-e262Crossref PubMed Scopus (85) Google Scholar, 6Illi S. von Mutius E. Lau S. Bergmann R. Niggemann B. Sommerfeld C. et al.Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study.BMJ. 2001; 322: 390-395Crossref PubMed Scopus (466) Google Scholar These data collection methods may have underestimated the effect of recurrent ARIs on asthma risk. In this study, use of symptom diaries allowed a more precise exposure-response-analysis, which showed a clear increase in the risk of asthma as both the number of ARI episodes and days with ARI symptoms increased. The mean duration of ARIs was longer and measures of severity were higher in children with asthma at age 7 years compared with those without asthma. These findings may reflect poorer immunological responses in children who later develop asthma. Although part of this morbidity is probably caused by wheezing illnesses, it is notable that the vast majority of ARIs presented without wheezing. Similar virus etiology of ARIs in children with and without later asthma is in line with an earlier report3Bonnelykke K. Vissing N.H. Sevelsted A. Johnston S.L. Bisgaard H. Association between respiratory infections in early life and later asthma is independent of virus type.J Allergy Clin Immunol. 2015; 136: 81-86.e4Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar and suggests that there is no pathogen-specific immunologic weakness. Our findings suggest common mechanisms behind susceptibility to ARIs and asthma. Airway hyperreactivity in children who later develop asthma may contribute to prolonging symptoms during ARIs. Altered cytokine responses to respiratory viruses have been detected in children with asthma8Feldman A.S. He Y. Moore M.L. Hershenson M.B. Hartert T.V. Toward primary prevention of asthma: reviewing the evidence for early-life respiratory viral infections as modifiable risk factors to prevent childhood asthma.Am J Respir Crit Care Med. 2015; 191: 34-44Crossref PubMed Scopus (140) Google Scholar and could predispose to ARIs. Genetic factors or, as recent data suggest, airway microbiome9Teo S.M. Mok D. Pham K. Kusel M. Serralha M. Troy N. et al.The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development.Cell Host Microbe. 2015; 17: 704-715Abstract Full Text Full Text PDF PubMed Scopus (557) Google Scholar may play a role in susceptibility to ARIs and asthma. Frequent early ARIs may also play a causative role in the development of asthma by adversely affecting the developing lungs.8Feldman A.S. He Y. Moore M.L. Hershenson M.B. Hartert T.V. Toward primary prevention of asthma: reviewing the evidence for early-life respiratory viral infections as modifiable risk factors to prevent childhood asthma.Am J Respir Crit Care Med. 2015; 191: 34-44Crossref PubMed Scopus (140) Google Scholar There are limitations in this study. Outcome definition based partly on electronic prescriptions of inhaled corticosteroids enabled efficient data collection, but it may have led to overreporting or underreporting of asthma. To avoid overreporting, we included only corticosteroid prescriptions with asthma as the indication of treatment. The follow-up time of early ARIs varied. However, we included in the analyses only children with follow-up of ARIs for 12 months or more. In conclusion, we found that increased number of ARIs in the first 24 months of life was associated with an increased risk of asthma at age 7 years. Children who later developed asthma had more prolonged and severe ARIs in the first 24 months of life than other children. These results suggest that susceptibility to ARIs and asthma may share common pathophysiologic mechanisms, or recurrent ARIs in early childhood may predispose the child to the development of asthma. We thank all the families who participated in this study, the midwives for their help in recruiting the families, and the whole STEPS Study team for assistance with data collection, study nurses Niina Lukkarla, Petra Rajala, and Mira Katajamäki for their assistance in the study clinic, Tiina Ylinen for her technical assistance in virus detection, and Anne Kaljonen for her assistance with statistical analyses. In this observational prospective birth cohort study, STEPS Study, 1827 children born in the period 2008 to 2010 in the Hospital District of Southwest Finland are followed from pregnancy or birth to early adulthood.E1Lagstrom H. Rautava P. Kaljonen A. Raiha H. Pihlaja P. Korpilahti P. et al.Cohort profile: steps to the healthy development and well-being of children (the STEPS Study).Int J Epidemiol. 2013; 42: 1273-1284Crossref PubMed Scopus (87) Google Scholar An intensive follow-up of ARIs from birth to age 24 months of the child was offered to these families, and 923 children were enrolled.E2Toivonen L. Schuez-Havupalo L. Karppinen S. Teros-Jaakkola T. Rulli M. Mertsola J. et al.Rhinovirus infections in the first 2 years of life.Pediatrics. 2016; 138: e20161309Crossref PubMed Scopus (40) Google Scholar The children were followed for ARIs through daily symptom diaries, and the families were encouraged to visit the study clinic if they felt that an evaluation by a physician was needed. At the onset of respiratory symptoms, nasal swab samples were taken at the study clinic by a study physician, or at home by the parents and sent to the study clinic as previously described.E2Toivonen L. Schuez-Havupalo L. Karppinen S. Teros-Jaakkola T. Rulli M. Mertsola J. et al.Rhinovirus infections in the first 2 years of life.Pediatrics. 2016; 138: e20161309Crossref PubMed Scopus (40) Google Scholar, E3Waris M. Österback R. Lahti E. Vuorinen T. Ruuskanen O. Peltola V. Comparison of sampling methods for the detection of human rhinovirus RNA.J Clin Virol. 2013; 58: 200-204Crossref PubMed Scopus (26) Google Scholar Background data were collected by structured questionnaires. Data on emergency room visits, hospitalizations, and outpatient visits at the hospitals for ARIs at age 0 to 23 months and asthma diagnoses until age 7.5 years were retrieved from medical records of the Hospital District of Southwest Finland. Asthma medications until age 7.5 years were retrieved from electronic prescriptions. All asthma diagnoses and prescriptions were made by attending physicians (not the study physicians). The electronic prescription was introduced in Finland in 2010, and all public health care providers had taken it in use latest in 2013 and private health care providers by 2015. All pharmacies have been able to deliver electronic prescriptions since 2011. Electronic prescription became the main form of prescription in the beginning of 2017, and paper or phone prescriptions have been allowed only in exceptional situations. The Ministry of Social Affairs and Health and the Ethics Committee of the Hospital District of Southwest Finland approved the STEPS Study. Parents of participating children gave their written, informed consent. The nasal swab samples were stored at −80°C before analysis. Swabs were suspended in PBS and nucleic acids were extracted by NucliSense easyMag (BioMerieux, Boxtel, The Netherlands) or MagnaPure 96 (Roche, Penzberg, Germany) automated extractor. Extracted RNA was reverse transcribed and the cDNA was amplified using real-time, quantitative PCR for rhinovirus, human enteroviruses, and respiratory syncytial virus as described earlier.E4Osterback R. Tevaluoto T. Ylinen T. Peltola V. Susi P. Hyypiä T. et al.Simultaneous detection and differentiation of human rhino- and enteroviruses in clinical specimens by real-time PCR with locked nucleic acid probes.J Clin Microbiol. 2013; 51: 3960-3967Crossref PubMed Scopus (41) Google Scholar, E5Toivonen L. Schuez-Havupalo L. Rulli M. Ilonen J. Pelkonen J. Melen K. et al.Blood MxA protein as a marker for respiratory virus infections in young children.J Clin Virol. 2015; 62: 8-13Crossref PubMed Scopus (33) Google Scholar All specimens collected during influenza seasons were analyzed by reverse transcription PCR for influenza A and B viruses.E6Jokela P. Vuorinen T. Waris M. Manninen R. Performance of the Alere i influenza A&B assay and mariPOC test for the rapid detection of influenza A and B viruses.J Clin Virol. 2015; 70: 72-76Crossref PubMed Scopus (33) Google Scholar For samples collected in January 2009 or later, laboratory-developed antigen detection tests were performed for influenza A and B viruses, parainfluenza type 1, 2, and 3 viruses, respiratory syncytial virus, adenovirus, and human metapneumovirus (89% of samples). The primary outcome was physician-diagnosed asthma at age 7 years, based on a diagnosis of asthma in the medical records, or a prescription of inhaled corticosteroids for asthma, when the child was aged 6.5 to 7.5 years. All asthma diagnoses and corticosteroid prescriptions were made by physicians. An ARI was defined as the presence of rhinitis or cough, with or without fever or wheezing, documented in the symptom diary by the parents, or as an ARI diagnosed by a physician. The duration of 97.2% of ARIs was 30 days or less. To account for overlapping infections, the length of an ARI was limited to 30 days and longer ARIs (2.8%) were calculated as separate episodes with a maximum duration of 30 days. Wheezing illnesses (eg, bronchiolitis, recurrent wheezing, or acute exacerbation of asthma) were diagnosed by a physician on the basis of expiratory wheezing and other signs and symptoms. If there were repeated diagnoses of acute otitis media, wheezing illness, pneumonia, or laryngitis during continuous respiratory symptoms, diagnoses within 14 days were calculated as 1 episode. Recurrent wheezing was defined as 2 or more doctor-diagnosed wheezing illnesses at age 0 to 23 months. Children who completed the follow-up on respiratory infections until at least age 12 months were included in analyses on the association between ARIs at age 0 to 23 months and asthma at age 7 years. Categorical data were compared by using the χ2 test or Fisher exact test. Continuous data were described by using means and 95% CIs or medians and IQRs as appropriate. Skewed data were compared by using Mann-Whitney U test. Generalized linear models were used for describing and analyzing the number of ARIs and associated outcomes. Outcome counts were analyzed by using negative binomial distribution and log link with natural logarithm of follow-up time as an offset variable. Number of ARIs and associated outcomes was compared by using negative binomial regression. Risk of asthma at age 7 years was first analyzed by unadjusted binary logistic regression analysis. Adjusted binary logistic regression analyses were performed with background variables based on clinical plausibility and with P values of less than .10 in univariate analyses included in the final model (sex, birth by cesarean section, child's atopy at age 13 months, parental asthma, and parental smoking at child's age of 24 months). Unadjusted and adjusted odds ratios with 95% CIs were determined. P values of less than .05 were considered statistically significant. The data were analyzed with the use of SPSS software, version 24.0 (IBM SPSS Statistics for Macintosh, Armonk, NY), and SAS software for Windows, version 9.4 (SAS Institute Inc, Cary, NC).Table E1Characteristics of the study childrenCharacteristicAll children (N = 910), n (%)Sex: female430 (47.3)Premature (gestational age <37 wk)37 (4.1)Birth by cesarean section121 (13.3)Birth weight (kg) <2.525 (2.7) 2.5-4.5866 (95.2) >4.519 (2.1)Older siblings373 (41.0)Maternal asthma71 of 909 (7.8)Paternal asthma57 of 853 (6.7)Parental asthma120 of 909 (13.2)Maternal atopic eczema, allergy, or allergic rhinitis320 of 879 (36.4)Paternal atopic eczema, allergy, or allergic rhinitis201 of 853 (23.6)Parental atopic eczema, allergy, or allergic rhinitis411 of 884 (46.5)Maternal smoking during pregnancy after first trimester47 of 906 (5.2)Parental smoking at child's age of 24 mo102 of 628 (16.2)Maternal educational level at least professional569 of 882 (64.5)Indoor pets at age 3 or 24 mo223 of 567 (39.3)Breast-fed for at least 6 mo427 of 708 (60.3)At outside-home day care, age 13 mo184 of 775 (23.7) 18 mo279 of 676 (41.3) 24 mo366 of 674 (54.3)Atopic eczema at age 13 mo128 of 748 (17.1)Asthma at age 7 y75 (8.2)ARIs at age 0-23 mo∗In children with ≥12-months follow-up data on ARIs (n = 781). Mean number of ARIs per child per y (95% CI)6.2 (6.0-6.4) Mean number of days with ARI symptoms per child per y (95% CI)51.3 (48.6-54.1) Mean number of LRTIs per child per y (95% CI)0.1 (0.1-0.1) Wheezing illness135 of 781 (17.3) Recurrent wheezing illness (≥2)58 of 781 (7.4) No. of wheezing illnesses0646 of 781 (82.7)177 of 781 (9.9)2-336 of 781 (4.6)≥422 of 781 (2.8) RV wheezing illness49 of 736 (6.7)Recurrent RV wheeze (≥2)15 of 736 (2.0) RSV wheezing illness42 of 736 (5.7) Age at first wheezing episode (mo)0-1176 of 781 (9.7)12-2359 of 781 (7.6)LRTI, Lower respiratory tract infection; RSV, respiratory syncytial virus; RV, rhinovirus.∗ In children with ≥12-months follow-up data on ARIs (n = 781). Open table in a new tab Table E2Characteristics of ARIs at age 0-23 months in children with and without asthma at age 7 years∗In children with ≥12-months follow-up data on ARIs. Categorical data were compared by using the χ2 test or Fisher exact test. Median durations of ARIs were compared by using Mann-Whitney U test.VariableARIs in children with asthma at age 7 y (n = 800)ARIs in children without asthma at age 7 y (n = 7995)P valueMedian duration of an ARI (d) (IQR)8.0 (5.0-12.0)7.0 (4.0-12.0).04Symptoms during an ARI, n (%) Fever253 of 705 (35.9)2268 of 6979 (32.5).07 Cough469 of 705 (66.5)3935 of 6979 (56.4)<.001 Wheezing158 of 705 (22.4)580 of 6979 (8.3)<.001 Rhinorrhea642 of 705 (91.1)6448 of 6979 (92.4).21Child absent from day care during an ARI, n (%)†Calculated among children at outside-home day care at the time of ARI.60 of 116 (51.7)647 of 1783 (36.3).001Parent absent from work during child's ARI, n (%)†Calculated among children at outside-home day care at the time of ARI.49 of 116 (42.2)529 of 1783 (29.7).004Physician visit during an ARI, n (%)387 of 800 (48.4)3178 of 6979 (39.7)<.001Hospitalization during an ARI, n (%)26 of 800 (3.3)52 of 6979 (0.7)<.001Diagnoses during an ARI, n (%) Acute otitis media157 of 800 (19.6)1249 of 6979 (15.6).003 Wheezing illness97 of 800 (12.1)174 of 6979 (2.2)<.001 Laryngitis19 of 800 (2.4)125 of 6979 (1.6).09 Pneumonia10 of 800 (1.3)26 of 6979 (0.3).001Antibiotic treatment during an ARI, n (%)200 of 800 (25.0)1530 of 6979 (19.1)<.001Virus detections during an ARI, n (%) Virus positive269 of 384 (70.1)2945 of 4151 (70.9).71 RV219 of 384 (57.0)2452 of 4151 (59.1).47 RSV23 of 384 (6.0)228 of 4151 (5.5) Other virus24 of 384 (6.3)199 of 4151 (4.8) Codetection3 of 384 (0.8)66 of 4151 (1.6)RSV, Respiratory syncytial virus; RV, rhinovirus.∗ In children with ≥12-months follow-up data on ARIs. Categorical data were compared by using the χ2 test or Fisher exact test. Median durations of ARIs were compared by using Mann-Whitney U test.† Calculated among children at outside-home day care at the time of ARI. Open table in a new tab Table E3Baseline risk factors for asthma at age 7 yearsCharacteristicAll children (n = 910), nChildren with asthma at age 7 y, n (%)Univariate, OR (95% CI)∗Risk of asthma was calculated by using binomial logistic regression analysis.Multivariate, OR (95% CI)†Sex, birth by cesarean section, child's atopy at age 13 months, parental asthma, and parental smoking as covariates.Sex Female43027 (6.3)1.01.0 Male48048 (10.0)1.66 (1.02-2.71)2.28 (1.17-4.41)Birth by cesarean section No78960 (7.6)1.01.00 Yes12115 (12.4)1.72 (0.94-3.14)1.10 (0.47-2.59)Older siblings No53746 (8.6)1.0 Yes37329 (7.8)0.90 (0.55-1.46)Child's atopy at age 13 mo No62037 (6.0)1.01.0 Yes12823 (18.0)3.45 (1.97-6.05)3.24 (1.66-6.33)Indoor pets No34431 (9.0)1.0 Yes22316 (7.2)0.78 (0.42-1.46)Maternal asthma No83856 (6.7)1.0 Yes7119 (26.8)5.10 (2.83-9.22)Paternal asthma No79660 (7.5)1.0 Yes5713 (22.8)3.62 (1.85-7.10)Parental asthma No78947 (6.0)1.01.0 Yes12028 (23.3)4.81 (2.87-8.05)6.49 (3.31-12.76)Maternal smoking during pregnancy No85970 (8.1)1.0 Yes475 (10.6)1.34 (0.51-3.50)Parental smoking at child's age of 24 mo No52639 (7.4)1.01.0 Yes10214 (13.7)1.99 (1.04-3.81)2.06 (0.99-4.29)OR, Odds ratio.∗ Risk of asthma was calculated by using binomial logistic regression analysis.† Sex, birth by cesarean section, child's atopy at age 13 months, parental asthma, and parental smoking as covariates. Open table in a new tab Table E4Full results of analysis of association between ARIs at age 0-23 months and risk of asthma at age 7 years∗Risk of asthma was calculated by using unadjusted and multivariable binomial logistic regression analysis in children with ≥12-months follow-up data on ARIs. In multivariable analyses, sex, birth by cesarean section, child's atopy at age 13 months, parental asthma, and parental smoking were used as covariates.ARIs at age 0-23 moAll children (n = 781), nChildren with asthma at age 7 y (n = 63), n (%)Univariate, OR (95% CI)Multivariate, OR (95% CI)No. of ARI episodes per year1.09 (0.99-1.19)1.17 (1.04-1.31)No. of ARI episodes per year <527514 (5.1)1.01.0 5-837831 (8.2)1.67 (0.87-3.19)2.80 (1.06-7.42) ≥912818 (14.1)3.05 (1.47-6.35)7.20 (2.49-20.88)No. of days with ARI symptoms per year, per 10 d1.11 (1.03-1.18)1.12 (1.04-1.22)No. of RV infections per year <245538 (8.4)1.001.00 ≥228122 (7.8)0.93 (0.54-1.61)0.78 (0.40-1.52)RSV infection 051439 (7.6)1.001.00 ≥122221 (9.5)1.27 (0.73-2.22)1.32 (0.68-2.58)No. of LRTIs1.90 (1.60-2.25)2.03 (1.62-2.53) Doctor-diagnosed wheezing illnessesNone64629 (4.5)1.001.0017711 (14.3)3.55 (1.69-7.43)2.55 (0.95-6.87)≥25823 (39.7)13.98 (7.34-26.64)16.91 (7.21-39.67) Age at first wheezing episode (mo)0-117617 (22.4)1.001.0012-235917 (28.8)1.41 (0.64-3.07)1.33 (0.51-3.46) Etiology of wheezing illnesses†Virus diagnostics was performed during 164 (60.1%) episodes of the total of 273 doctor-diagnosed wheezing illness. RV was detected in 77 (47.0%) episodes of doctor-diagnosed wheezing illness, RSV in 47 (28.7%), and other virus in 9 (5.5%) episodes.No wheezing60327 (4.5)1.001.00Wheezing, no detected RV or RSV4413 (29.5)8.95 (4.21-19.01)6.89 (2.45-19.32)At least 1 RSV+ wheezing, no RV325 (15.6)3.95 (1.41-11.06)4.90 (1.53-15.69)At least 1 RV+ wheezing, no RSV429 (21.4)5.82 (2.53-13.37)5.13 (1.76-14.94)Both RSV+ and RV+ wheezing156 (40.0)14.22 (4.72-42.84)13.93 (3.88-50.08) Severity of wheezing illnessesNo wheezing64629 (4.5)1.001.00Wheezing illness without hospitalization10421 (20.2)5.38 (2.94-9.87)5.29 (2.46-11.38)Hospitalized for a wheezing illness3113 (41.9)15.37 (6.87-34.36)14.93 (4.99-44.63)Hospitalization for an ARI No72548 (6.6%)1.001.00 Yes5615 (26.8%)5.16 (2.67-9.98)5.46 (2.27-13.14)No. of antibiotics for ARIs1.14 (1.06-1.24)1.20 (1.09-1.34)LRTI, Lower respiratory tract infection; OR, odds ratio; RSV, respiratory syncytial virus; RV, rhinovirus.∗ Risk of asthma was calculated by using unadjusted and multivariable binomial logistic regression analysis in children with ≥12-months follow-up data on ARIs. In multivariable analyses, sex, birth by cesarean section, child's atopy at age 13 months, parental asthma, and parental smoking were used as covariates.† Virus diagnostics was performed during 164 (60.1%) episodes of the total of 273 doctor-diagnosed wheezing illness. RV was detected in 77 (47.0%) episodes of doctor-diagnosed wheezing illness, RSV in 47 (28.7%), and other virus in 9 (5.5%) episodes. Open table in a new tab Table E5ARIs at age 0-11 months and risk of asthma at age 7 years∗Risk of asthma was calculated by using multivariable binomial logistic regression analysis in children with ≥12-months follow-up data on ARIs. Sex, birth by cesarean section, child's atopy at age 13 months, parental asthma, and parental smoking were used as covariates.ARIs at age 0-11 moAll children (n = 781), nChildren with asthma at age 7 y (n = 63), n (%)Univariate, OR (95% CI)Multivariate, OR (95% CI)No. of ARI episodes1.07 (0.99-1.16)1.10 (1.00-1.22)No. of days with ARI symptoms, per 10 d1.08 (1.01-1.16)1.10 (1.02-1.19)No. of RV infections <233624 (7.1)1.001.00 ≥240036 (9.0)1.29 (0.75-2.20)1.29 (0.65-2.53)RSV infection 058846 (7.8)1.001.00 ≥114814 (9.5)1.23 (0.66-2.31)1.22 (0.58-2.58)No. of LRTIs2.12 (1.56-2.87)2.12 (1.46-3.08)No. of doctor-diagnosed wheezing illnesses None70546 (6.5)1.001.00 15110 (19.6)3.49 (1.65-7.42)3.33 (1.33-8.38) ≥2257 (28.0)5.57 (2.21-14.02)4.70 (1.37-16.15)Hospitalization for an ARI No74554 (7.2)1.001.00 Yes369 (25.0)4.27 (1.91-9.53)6.72 (2.36-19.16)No. of antibiotics for ARIs1.21 (1.03-1.41)1.25 (1.04-1.50)LRTI, Lower respiratory tract infection; OR, odds ratio; RSV, respiratory syncytial virus; RV, rhinovirus.∗ Risk of asthma was calculated by using multivariable binomial logistic regression analysis in children with ≥12-months follow-up data on ARIs. Sex, birth by cesarean section, child's atopy at age 13 months, parental asthma, and parental smoking were used as covariates. Open table in a new tab LRTI, Lower respiratory tract infection; RSV, respiratory syncytial virus; RV, rhinovirus. RSV, Respiratory syncytial virus; RV, rhinovirus. OR, Odds ratio. LRTI, Lower respiratory tract infection; OR, odds ratio; RSV, respiratory syncytial virus; RV, rhinovirus. LRTI, Lower respiratory tract infection; OR, odds ratio; RSV, respiratory syncytial virus; RV, rhinovirus." @default.
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• W2891843538 title "Acute respiratory infections in early childhood and risk of asthma at age 7 years" @default.
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