Pediatric Pulmonology 43:584593 (2008)

Acute Respiratory Symptoms and General Illness During the First Year of Life: A Population-Based Birth Cohort Study
hler Holst, MSc,2 Karina Larsen, RN,1 Marie-Louise von Linstow, MD, PhD,1* Klaus Ka 3 Anders Koch, MD, PhD, Per Kragh Andersen, PhD, DMSc,2 and Birthe Hgh, MD, DMSc1
Summary. Respiratory symptoms are common in infancy. Most illnesses occurring among children are dealt with by parents and do not require medical attention. Nevertheless, few studies have prospectively and on a community-basis assessed the amount of respiratory symptoms and general illness in normal infants. In this population-based birth cohort study, 228 healthy infants from Copenhagen, Denmark were followed from birth to 1 year of age during 20042006. Symptoms were registered using daily diaries and monthly home visits. Interviews were performed at inclusion and every second month. Risk factor analysis was carried out by multiple logistic regression analysis. On average, children had general symptoms for 3.5 months during their rst year of life, nasal discharge being most frequent followed by cough. Frequency of all symptoms increased steeply after 6 months of age. Each child had on average 6.3 episodes (median: 5.1, inter-quartile range (IQR): 3.37.8) of acute respiratory tract illness (ARTI) (nasal discharge and 1 of the following symptoms: cough, fever, wheezing, tachypnea, malaise, or lost appetite) and 5.6 episodes (median: 4.3, IQR: 2.17.3) of simple rhinitis per 365 days at risk. Determinants for respiratory symptoms were increasing age, winter season, household size, size of residence, day-care attendance, and having siblings aged 13 years attending a day nursery. In conclusion, the present study provides detailed data on the occurrence of disease symptoms during the rst year of life in a general population cohort and emphasizes the impact of increasing age, seasonality, and living conditions on the occurrence of ARTI. Pediatr Pulmonol. 2008; 43:584593. 2008 Wiley-Liss, Inc. Key words: epidemiology; health diaries; infants; respiratory tract infections; risk factors.

INTRODUCTION

Acute respiratory tract illness (ARTI) is the most common disease among young children. A substantial part of respiratory tract infections are associated with viruses and although rarely fatal in industrialized countries, they are a source of signicant morbidity and carry a considerable economic burden. Several risk factors for lower respiratory tract disease and hospitalization in developed countries have been described such as day-care attendance1,2 and lack of breastfeeding.3 Other risk factors such as crowding and siblings, passive smoking, low socioeconomic status, psychosocial factors, male gender, and low birth weight have in many studies also been found to be associated with lower respiratory tract disease, although other studies have not found such associations.4 Not many studies have investigated risk factors for upper respiratory tract disease, which is prevalent among children and has a substantial impact on the disease burden experienced by families. European studies have shown that parents deal with more than 80% of all illnesses occurring among children without requiring medical attention.5,6 The actual amount
2008 Wiley-Liss, Inc.

of childrens general illness is therefore much greater than the fraction seen by the professional health care system. To our knowledge, only one longitudinal community-based
1 Department of Pediatrics, Hvidovre Hospital, University of Copenhagen, Denmark. 2

Department of Biostatistics, University of Copenhagen, Denmark.

Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. Grant sponsor: Pharmacists Foundation; Grant sponsor: Rosalie Petersens Foundation; Grant sponsor: Ebba Celinders Foundation; Grant sponsor: Research Fund of Queen Louises Childrens Hospital. *Correspondence to: Marie-Louise von Linstow, MD, Department of rd Alle Pediatrics, University of Copenhagen, Hvidovre Hospital, Kettega 30, DK-2650 Hvidovre, Denmark. E-mail: linstow@dadlnet.dk Received 20 September 2007; Revised 25 February 2008; Accepted 26 February 2008. DOI 10.1002/ppul.20828 Published online in Wiley InterScience (www.interscience.wiley.com).

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study focusing on infants general symptoms has been carried out,5 and just ve longitudinal population-based studies of respiratory illness in infants from developed countries have been published.7 11 No longitudinal studies of Danish infants general illness have been published. The aim of our study was to obtain reliable data on the incidence and prevalence of respiratory symptoms and overall morbidity in a population-based birth cohort of healthy infants followed up to 1 year of age and to explore possible determinants for respiratory disease.
METHODS Study Population

visits by a pediatrician (MLL), a study nurse (KL) or a study physician. At every home visit the symptom diary from the preceding month was collected and any queries were rectied. At the rst home visit the parents were interviewed about household contacts, parents education and employment, ethnicity, birth weight, breastfeeding, dispositions (hay fever, asthma and atopic dermatitis) and exposures (smoking in homes, smoking during pregnancy, pets, moist, carpets, drying clothes inside). Questions concerning factors that could change over time were repeated every second month and treated as a time-dependent variable in the analyses.
Case Denition

Children were enrolled from the post-natal ward at Hvidovre Hospital, Denmark, which serves an area of Copenhagen with 396,228 persons (35% of the total population of Greater Copenhagen) and had 5,541 births in 2005. Approximately 20 children were recruited each month to ensure that children at all ages were represented in all seasons. All newborn children whose mothers were available during our presence at the postnatal ward were approached on predesignated weeks. Children without siblings were over-represented on the ward, and after inclusion of 10 such children each month, only children with siblings were approached. The inclusion criteria for participation in the study were: Infants free of obvious health problems and for practical purposes living within a radius of 11 km from Hvidovre Hospital. Exclusion criteria were: infants whose parents did not understand or speak Danish or English; infants whose mothers had a serious psychiatric disorder; infants with any congenital diseases; and if change of address to outside the area of Hvidovre Hospital was planned within 12 months of enrollment. Written informed consent was obtained from the parents of the infant after they had been informed about the study and before performance of any study procedure. The study was conducted in accordance with the Helsinki Declaration II for human clinical studies. Study approval was obtained from The Ethics Committee of Frederiksberg, Copenhagen, Denmark.
Clinical Data

An episode of ARTI was dened as a period with nasal discharge together with one or more of the following symptoms: cough, fever/feels hot, wheezing, tachypnea, malaise, or lost appetite. Episodes with nasal discharge only were assigned as simple rhinitis. Children with an episode of simple rhinitis were at risk of acquiring ARTI, whereas children with an episode of ARTI were not at risk of acquiring simple rhinitis. If a child for example had nasal discharge without any other symptoms for 2 days and then developed fever/felt hot on the third day, then the rst 2 days were considered as an episode of simple rhinitis and the ARTI episode was regarded to begin at day 3. A new episode was dened as an episode commencing after 6 days free of symptoms to the previous same type of episode. This episode-free interval was chosen to ensure that the same sickness was not counted as two illnesses and is in accordance with another study of similar design.8 Incidence rates for the two outcomes ARTI and simple rhinitis were calculated as number of episodes divided by person time at risk. Time at risk was dened as the number of days with no recorded symptoms excluding the 6 consecutive days without symptoms following an episode. To evaluate all episodes, we performed risk factor analysis for both ARTI and simple rhinitis.
Statistical Methods

Parents were provided monthly with a health diary displaying 12 different symptoms and clinical signs: nasal discharge, cough, fever/feels hot, conjunctivitis, fast breathing, wheezing, hoarseness, skin rash, reduced appetite, vomiting, diarrhea (>3 watery stools/day), general malaise, in addition to information on doctors visits, hospital admissions, and medicine. Parents were encouraged to complete the diary every day. To reduce the risk of dropouts and to ensure the quality of the health diaries, children were monitored through monthly home

Outcome data for each child consist of a time-series of daily episode recordings (yes or no to each dened type of episode). We dened prevalence at day t as the probability of having an episode recorded at that day. Similarly, we dened incidence at day t as the probability of having a new episode recorded at day t given that the child was at risk for having a new episode at that day. For both analyses, time-dependent explanatory variables were included, i.e. when analyzing the outcome of day t, covariate information available at the previous day, t 1, was used. For the analysis of prevalence the daily episode status was modeled using logistic regression. For the
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incidence we used a similar approach but only days under risk were modeled. To account for the possible correlation between episodes from the same child, odds ratio (OR) and condence intervals (CI) were estimated using generalized estimating equations.12 Both an independence working correlation and an autoregressive correlation structure (AR(1)) (taking into account missing data and exclusion of days not at risk) were used and showed good agreement. P-values were calculated using Walds test. All regression analyses were adjusted for sex, age and calendar period. The calendar effect was modeled as a periodic function with period of 1 year by inclusion of a sine and a cosine term in the models. The parameters for these two terms were transformed into parameters giving the time of maximum incidence/prevalence and the OR for December versus July, respectively. Standard errors of the transformed estimates were calculated using the delta method. All models showed good agreement with similar models including a categorical calendar period. The multiple logistic regression models for ARTI and simple rhinitis episodes included the following variables: age, season, gender, gestational age, mothers age, ethnicity, mother having had a cold<2 weeks prior to delivery, day-care attendance, and smoking in pregnancy. Relevant information from interview schemes was carried forward 2 months. Breastfeeding status was revised every 2 weeks. To reduce problems with co-linearity, one to three variables from each group of covariates (social variables, smoking parameters, atopic dispositions, breastfeeding, siblings in institution, crowding factors, and indoor environment) were included based on the results of analyses of combinations of covariates from each group adjusted for age, gender, and season, selecting only the most signicant variables. Finally, multiple logistic regression analyses were performed by including all the selected predictor variables in a model and successively removing the variable with the highest P-value, continuing until all predictors had a P-value below 0.1. Sub-analyses excluding the rst twin from each twinpair and sub-analyses with longer and shorter duration of the symptom-free intervals (incidence analyses) were examined and showed no particular deviation from the original models. All analyses were performed in R using the geepack library.13,14
RESULTS Study Population

area or insufcient language qualities. The remaining 68 families were not interested in participating. Mothers from these 68 families did not differ from participating mothers according to mean age and method of delivery (data not shown). Of non-participating children, 75% had siblings compared with 47% of participating children (P < 0.0001). Fourteen children dropped out within one month. Of the remaining 228 children who were included in the analyses, 217 children were followed throughout 1 year. Participating infants included eight pairs of twins. Median age interval to an older sibling was 41 months (range 9 184 months). Of 2,655 possible contacts, we went on 1,992 home visits and had 298 appointments at the hospital. Characteristics of the study population are given in Table 1. Breastfeeding was initiated by 95% of the mothers. At age 1 month, 77% of the children were exclusively breastfed, dropping to 54% at 4 months, and 14% at 6 months of age. Only 5% of the infants attended day-care outside the home by the age of 8 months, and 22% did so by the age of 10 months.
TABLE 1 Demographic characteristics of 228 healthy infants followed from birth to 1 year of age, Copenhagen, 2004 2006 Sex (%) Boys Girls Gestational age (week) Median (IQR) Range Birth weight (g) Median (IQR) Range Mothers age (year) Median (IQR) Range Fathers age (year) Median (IQR) Range Ethnicity Western (%) Non-Western (%) Socioeconomic status (%) 12 35 Out of classication (students) No. of siblings (%) 0 1 2 3 Current smoking (at birth) (%) Mother Father Two adult smokers No. of parents with asthma/hay-fever (%) 0 1 2 121 (53) 107 (47) 40 (39 41) 30 43 3,502 (3,200 3,800) 1,700 4,700 30 (28 33) 19 44 32 (29 36) 20 53 214 (94) 14 (6) 165 (72) 58 (25) 5 (2) 123 (54) 81 (36) 16 (7) 8 (4) 19 (8) 49 (21) 14 (6) 123 (55) 92 (41) 10 (4)

Of 336 children whose parents were invited to participate in the study, 242 accepted. Each month 12 30 children (mean 20) were included, except for December, where only 5 children were included. Twenty-six families were excluded due to plans of moving away from the study
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General Symptoms

Of 80,013 days of observation, one or more symptoms were recorded on 23,345 days (29.2%), corresponding to 3.5 months with symptoms for each child. Roughly, the children had symptoms on 20% of all days during the rst 6 months of life, increasing to 30% from 6 to 9 months and 40% from 9 to 12 months (Table 2). Nasal discharge and cough were the far most prevalent comprising 59 and 29 days per year, respectively. Even though cough was most often seen in addition to nasal discharge, especially among children older than six months of age, it also appeared as a single symptom without signs of rhinitis. Eighteen percent of the children had atopic dermatitis. Parents of 9.3% of the children reported that their child had suffered from colic (weaning/ crying > 3 h/day > 3 days/week > 3 week). Parents of 190 (83%) infants went to a physician with their child on 904 occasions (median 3, range 1 21), whereof 17 (9%) children saw a doctor 10 times. A child had symptoms for averagely 26 days per doctors visit, which corresponds to a visit on 3.9% of the days with symptoms. Medicine was administered to 168 (74%) children for a median of 12 days during 1 year. Thirty-six

(16%) children were admitted to hospital 45 times for a variety of reasons during the study period.
Frequency of Respiratory Symptoms

Children had ARTI on 5,518 (6.9%) days and simple rhinitis on 7,338 (9.2%) days of 80,013 days of observation. Each child had on average 6.3 episodes (median: 5.1, inter-quartile range (IQR): 3.3 7.8) of ARTI and 5.6 episodes (median: 4.3, IQR: 2.1 7.3) of simple rhinitis per 365 days at risk. Forty percent of simple rhinitis episodes proceeded into an ARTI episode, so if both types of episodes were considered, each child had in total 9.7 respiratory episodes (median: 7.9, IQR: 5.2 11.2) per 365 days at risk. The incidence of ARTI episodes is illustrated in Figure 1. An average ARTI episode lasted for 4.7 days (median: 3, IQR: 2 6). Duration was not related to age. Diarrhea was reported to occur in 11% of respiratory episodes, and in 51% of diarrhea episodes, children were reported to suffer from respiratory symptoms. One hundred forty-nine (65%) children were seen by a physician due to respiratory symptoms, and 87 (38%) children received antibiotics (penicillins in 95% of cases)

TABLE 2 Period prevalence* of parent-reported symptoms and clinical signs, contacts with the health system and drug use in 228 children during their rst year of life, Copenhagen, 2004 2006 % of children with one or more days of the specic symptom (% of days observed) Symptom by age General malaise Nasal discharge Cough Cough nasal discharge Cough nasal discharge Fever Hoarseness Conjunctivitis Wheezing Fast breathing Vomiting Diarrhea Lost appetite Skin rash/eczema 1 of the above symptoms 2 of the above symptoms 3 of the above symptoms 4 of the above symptoms Simple rhinitis episodes ARTI episodes1 Doctors visit Hospital admission Medicine 0 90 days 48 (4.3) 62 (9.4) 34 (3.3) 26 (2.0) 20 (1.3) 22 (0.6) 14 (0.6) 30 (3.7) 8 (0.6) 7 (0.4) 14 (0.4) 25 (1.1) 19 (0.9) 17 (2.8) 88 (21.6) 72 52 33 41 (6.5) 45 (2.9) 40 (1.0) 6 (0.3) 25 (3.6) 91 180 days 58 (3.6) 75 (11.5) 52 (5.9) 40 (3.1) 33 (2.8) 50 (1.8) 9 (0.5) 15 (1.3) 8 (1.3) 6 (0.3) 17 (0.5) 26 (2.3) 25 (1.5) 17 (4.1) 95 (24.6) 81 64 47 43 (7.4) 56 (4.1) 39 (0.8) 4 (0.1) 27 (3.6) 181 270 days 67 (5.2) 89 (19.3) 65 (9.7) 58 (7.3) 36 (2.4) 64 (3.5) 14 (0.9) 14 (1.2) 20 (2.2) 8 (0.6) 26 (0.8) 28 (1.8) 42 (3.1) 24 (3.8) 96 (31.1) 87 79 69 50 (10.3) 72 (9.0) 50 (1.2) 3 (0.1) 34 (3.9) >270 days 70 (6.4) 89 (23.6) 68 (12.3) 62 (8.7) 38 (3.6) 78 (5.2) 22 (1.4) 27 (1.7) 17 (2.0) 14 (0.8) 35 (0.9) 38 (2.3) 55 (4.2) 32 (4.8) 94 (38.8) 92 88 77 59 (12.3) 79 (11.4) 57 (1.5) 5 (0.1) 48 (6.5) Total 92 (4.9) 99 (16.1) 94 (7.9) 90 (5.3) 70 (2.6) 91 (2.8) 45 (0.8) 61 (2.0) 35 (1.5) 25 (0.5) 61 (0.7) 70 (1.9) 77 (2.5) 52 (3.9) 100 (29.2) 100 98 97 91 (9.2) 97 (6.9) 83 (1.1) 16 (0.1) 74 (4.4)

*Period prevalence dened as the total number of persons known to have had the disease or attribute at any time during a specied period.34 1 ARTI episodes are dened as nasal discharge together with one or more of the following symptoms: cough, fever, wheezing, tachypnea, malaise, lost appetite.

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Fig. 1. Distribution of number of episodes with acute respiratory tract illness (ARTI) per 365 days at risk in 228 children, Copenhagen, 2004 2006. ARTI is dened by nasal discharge together with one or more of the following symptoms: cough, fever/feels hot, wheezing, tachypnea, malaise, or lost appetite.

for their respiratory tract infection, including otitis media. Thirty-nine (17%) children were treated with beta-2 agonists, and 14 (6%) children were hospitalized due to respiratory symptoms.
Determinants of Respiratory Symptoms

The incidence and prevalence of ARTI and simple rhinitis episodes greatly depended upon age and season: childrens risk of acquiring respiratory symptoms increased signicantly from 6 months of age, and children had relatively more respiratory symptoms during the winter months (P < 0.001). Other factors signicantly associated with increased risk of ARTI and simple rhinitis in univariate analyses are shown in Table 3 and include household size, number of children sharing bedroom, siblings in day nursery, dened as a day-care institution with 10 15 children in the age range 1/2 3 years, day-care attendance, size of residence, and if the mother had had a cold <2 weeks prior to delivery. The father being a student had a protective effect on prevalence of simple rhinitis. In contrast, sex, gestational age, birth weight, mothers age, ethnicity, socioeconomic status, breastfeeding, passive smoking, smoking in pregnancy, asthma and hay fever in the family, furred pets, moisture in the home, and carpets were not associated with respiratory symptoms. The nal multiple regression models for incidences of ARTI and simples rhinitis are shown in Table 4. In both models increasing age, winter season, and having siblings aged 1 3 years in a day nursery were consistently associated with increasing odds of respiratory symptoms. Children in large day-care centers comprising 10 15 children per room had higher incidence of ARTI than children in home care. Large household size and a small residence, dened as total m2/number of rooms <30 m2, were associated with simple rhinitis. Similar results were observed for prevalence analyses (data not shown).
Pediatric Pulmonology

To further elucidate the effect of breastfeeding among the youngest children, interaction variables between breastfeeding and age and breastfeeding and siblings were entered into the nal multiple regression models. Analyses for ARTI showed a non-signicant trend towards a protective effect of exclusive breastfeeding in the youngest children from 0 to 4 months of age (OR: 0.54 0.68 depending on the monthly age of the child. All 95% CIs were included in the interval 0.27 1.39). On the other hand, analyses for simple rhinitis showed a nonsignicant tendency of a protective effect of exclusive breastfeeding for rstborn children (OR: 0.74, 95% CI: 0.5 1.1).
DISCUSSION

The present study is the rst prospective birth cohort study of acute respiratory symptoms and general illness in a general population cohort of healthy infants from Denmark. We have shown that children had general symptoms on average 3.5 months during their rst year of life, and that the frequency of all symptoms increased with age. Respiratory symptoms were far most prevalent and were related to increasing age, winter season, large household size, day-care attendance, and having siblings aged 1 3 years attending a day nursery.
General Symptoms

Most published studies on general illness in infancy are either cross-sectional,16,17 retrospective,15 focus mainly on older children,7,17,18 or follow children for a short period of time,7,18,19 and are not directly comparable with our study. A British longitudinal birth cohort study of infants general symptoms using diary cards followed children up to 2 years of age.5 In this study, cold, snufes or sneezing were found on 9.5% of days observed, wheezing on 2.0%, cough on 4.8%, vomiting on 0.8%, diarrhea on 1.2%, rash on

TABLE 3 Univariate analysis of factors associated with incidence and prevalence of episodes with acute respiratory tract illness (ARTI) and simple rhinitis in 228 children less than 1 year of age, Copenhagen, 2004 2006* ARTI episodes1 Simple rhinitis episodes Prevalence P value 0.57 1.00 0.97 0.99 0.77 0.89 0.08 1.00 1.17 0.03 1.00 1.22 0.01 1.00 1.42 0.41 1.00 1.09 0.02 1.00 1.40 1.50 1.04 1.04 0.45 0.41 0.51 1.00 1.13 0.67 1.00 1.04 1.14 1.00 1.13 Reference (0.91 1.40) Reference (0.82 1.32) (0.85 1.54) 0.27 1.00 1.03 Reference (0.79 1.34) 1.00 1.09 1.01 Reference (0.81 1.48) (0.67 1.51) 0.83 1.00 1.31 1.00 0.92 Reference (0.72 1.18) Reference (0.78 2.51) (1.12 2.02) (0.94 1.16) (0.95 1.15) 1.00 1.61 1.72 0.99 1.07 Reference (0.84 3.09) (1.10 2.71) (0.87 1.12) (0.96 1.20) Reference (0.87 1.45) 0.80 1.00 1.13 1.72 Reference (0.89 1.34) 1.00 0.94 Reference (0.75 1.20) 0.03 1.00 0.39 1.34 1.33 1.16 0.84 0.21 0.36 1.00 1.29 0.64 1.00 1.20 Reference (0.90 1.59) Reference (1.07 1.87) 1.00 1.52 Reference (1.04 2.21) 1.00 2.30 0.03 Reference (1.75 3.03) 0.21 1.00 1.08 1.00 0.83 1.55 1.26 1.13 1.00 1.56 1.00 1.24 1.76 1.00 1.44 0.16 Reference (0.11 1.34) (0.81 2.23) (1.20 1.47) <0.001 (1.02 1.31) 0.02 0.07 Reference (0.98 1.69) <0.001 Reference (0.87 1.46) (1.27 2.32) 0.04 Reference (1.01 1.68) Reference (0.79 1.48) 0.23 Reference (0.39 1.81) (0.91 2.62) (1.12 1.41) <0.001 (0.98 1.29) 0.09 <0.01 Reference (1.12 2.16) <0.01 Reference (0.92 1.67) (1.22 2.54) 0.03 Reference (1.04 1.99) Reference (1.02 1.46) 1.00 1.16 Reference (0.89 1.50) 1.00 1.77 0.28 Reference (1.43 2.18) <0.001 1.00 2.04 Reference (1.42 2.92) 0.63 Reference (0.98 1.39) 1.00 1.13 Reference (0.87 1.45) 1.00 1.68 Reference (1.37 2.08) <0.001 1.00 1.61 Reference (1.27 2.04) <0.001 0.36 <0.001 1.00 1.56 Reference (1.25 1.97) <0.001 Reference (0.75 1.26) (0.78 1.27) (0.55 1.08) (0.68 1.17) 1.00 1.01 0.91 0.76 0.92 Reference (0.70 1.46) (0.63 1.33) (0.50 1.14) (0.62 1.36) 1.00 1.13 1.15 0.96 0.92 Reference (0.81 1.58) (0.85 1.55) (0.64 1.45) (0.67 1.27) 1.00 1.09 1.23 0.73 0.71 0.66 0.68 Reference (0.74 1.59) (0.88 1.71) (0.50 1.05) (0.51 0.98) <0.001 OR 95% CI P value OR 95% CI P value OR Incidence Prevalence 95% CI P value <0.001 Incidence OR 95% CI

Variable

Education, father (n 225) 1 (n 73) 2 (n 41) 3 (n 55) 4 (n 24) 5 (n 30) Siblings No (n 123) Yes (n 105) Siblings in institution3 No (n 135) Yes (n 93) Siblings in day nursery3 (1/2 3 years) No (n 191) Yes (n 36) Siblings in day-care center3 (3 6 years) No (n 184) Yes (n 43) Day-care attendance No Family day-care home (2 4 children) Day-care center (10 15 children) Each additional person in household Each additional person sleeping in the same room as the child Sharing bedroom with a sibling No Yes Size of residence 1 2 rooms 3 4 rooms >4 rooms Mother had a cold <2 weeks prior to delivery No (n 186) Yes (n 42)

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OR, odds ratio; CI, condence interval. *All variables adjusted for age, gender and season. P value test for homogeneity. 1 ARTI episodes are dened as nasal discharge together with one or more of the following symptoms: cough, fever, wheezing, tachypnea, malaise, lost appetite. 2 Education: (1) long theoretical education 5 years; (2) education of medium length 3 4 years; (3) short education 1 3 years or skilled worker; (4) none or short courses; (5) studying. 3 Numbers when the child was 1 month old.

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TABLE 4 Multiple risk factor regression analysis of incidence of acute respiratory tract illness (ARTI) and simple rhinitis episodes in 228 children during their rst year of life, Copenhagen, 2004 2006* ARTI Variable Age (days) 0 30 31 60 61 90 91 120 121 150 151 180 181 210 211 240 241 270 271 300 301 330 >330 Season1 July January Siblings in day nursery (1/2 3 years) No Yes Each additional person in household Size of residence Total m2/no. of rooms >30 m2 Total m2/no. of rooms <30 m2 Socioeconomic status 1 2 3 45 Out of classication (students) Day-care attendance No Family day-care home (2 4 children) Day-care center (10 15 children) Sex Female Male OR 1.00 1.19 1.19 1.30 1.60 1.69 2.83 3.33 2.48 3.40 3.43 3.79 1.00 2.47 1.00 1.41 1.00 1.46 1.49 1.00 1.13 95% CI Reference (0.81 1.73) (0.80 1.77) (0.89 1.91) (1.10 2.34) (1.15 2.49) (2.00 4.02) (2.34 4.74) (1.71 3.59) (2.39 4.84) (2.43 4.85) (2.71 5.29) <0.001 Reference (2.03 2.99) 0.01 Reference (1.08 1.84) 0.02 Reference (0.81 2.61) (1.10 2.02) 0.17 Reference (0.95 1.35) 1.00 1.02 Reference (0.83 1.26) 0.89 1.00 1.22 1.04 0.78 1.07 Reference (0.96 1.56) (0.68 1.60) (0.58 1.05) (0.52 2.21) 1.00 1.99 1.23 1.00 1.26 Reference (1.50 2.64) (1.10 1.38) Reference (1.02 1.56) 0.07 1.00 1.95 Reference (1.53 2.47) <0.001 P <0.001 1.00 1.30 0.88 1.30 1.33 1.21 1.51 2.18 2.08 2.27 2.53 2.90 Reference (0.89 1.90) (0.57 1.37) (0.85 1.98) (0.87 2.05) (0.80 1.85) (1.02 2.23) (1.50 3.18) (1.39 3.11) (1.52 3.40) (1.71 3.76) (1.92 4.39) <0.001 OR Simple rhinitis 95% CI P <0.001

<0.001 0.03

OR, odds ratio; CI, condence interval. *ARTI is dened as nasal discharge together with one or more of the following symptoms: cough, fever/feels hot, wheezing, tachypnea, malaise, lost appetite. Variables included in analyses are age, gender, season, gestational age, mothers age, ethnicity, socioeconomic status, mother had a cold<2 weeks prior to delivery, smoking in pregnancy, siblings in day nursery, siblings in day-care center, day-care attendance, and carpets. In ARTI analysis is in addition included: smoking inside, maternal smoking, breastfeeding, number of adults in the household, siblings, and atopy in siblings. In simple rhinitis analysis is in addition included: smoking in household, paternal education, exclusive breastfeeding, household size, atopy in the family, moisture in home, and size of residence. 1 The dates with the highest amplitude of symptoms were: ARTI: January 11 (95% CI: December 28 January 24). Simple rhinitis: December 12 (95% CI: November 22 January 1).

2.7%, and fever on 0.8% of days observed. Most of these numbers are equal to our ndings, although we report higher prevalence of nasal symptoms, fever, and cough. This might be explained by a more precise registration of minor symptoms in our study due to closer contact with the families through regular home visits. In our study, 83% of children were seen by a physician for a median of three times and 96% of days with symptoms were dealt with by parents only. This is in accordance with two British studies, where parents
Pediatric Pulmonology

managed care of 66.8 99%5 and 94%19 of symptoms without seeking professional advice. Factors encouraging and discouraging a decision to see the doctor were not assessed in this study, but are well described in another recent Danish study.20
Incidence and Prevalence of Respiratory Illness

Despite differences in design, climate, demographics of the populations studied, denitions and classications of

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respiratory illness, the period required between episodes, and the methods of surveillance employed, the average number of 6.3 episodes of ARTI per 365 days at risk in the present study correlated well with reported mean numbers of ARTIs during the rst year of life found in most other prospective birth cohort studies in both developed and developing countries (5.1,21 5.8,22 6.2,7 and 6.623) and even in early family and community studies (6.124 6.925). Children suffered from nasal discharge for approximately 2 months and cough for 1 month during the rst year of life, showing that the amount of minor respiratory illness was substantial in this cohort of healthy children. The reported prevalence of respiratory symptoms in our study is higher than for most studies,5,7,11 except studies from Greenland reporting respiratory symptoms on 41.6% of days of observation for children <2 years of age.8 Thirty-eight percent of the children received antibiotics due to respiratory symptoms. We did not evaluate the effect of antibiotic treatment, but in a recent Australian study, antibiotics did not alter the course or duration of respiratory illness in early childhood, suggesting that routine use of antibiotics should be avoided in young children to limit potential side effects and to reduce development of antibiotic resistance.10
Risk Factors for Respiratory Symptoms

The most substantial risk factors for respiratory symptoms in our study were increasing age, winter season, and exposure to infections reected by having siblings in a day nursery, number of household members, living in small average rooms, and day-care attendance. The amount of disease was relatively low in children less than 6 months of age, after which a steep rise in incidence and prevalence of respiratory symptoms occurred. With increasing age, several factors arise, inuencing on the childs susceptibility to infections, such as degradation of maternal antibodies, cessation of breastfeeding, coming into more contact with others, and start at day-care centers at a time when the adaptive immune system is still immature. Both ARTI and simple rhinitis were more frequent during the winter season, which is similar to ndings in an Australian birth cohort study of respiratory symptoms in early childhood.10 Many respiratory viruses peak in the winter period and families tend to spend more time inside on cold days, increasing the crowding factor. A population-based study from Greenland, where the climate is distinct from and colder than in Denmark, did not nd any seasonal variation in the incidence of respiratory episodes8. Most other studies either fail to include season in their analyses or report an association between month at birth and respiratory symptoms.7,9,11

We found that attending a day-care center increased the incidence of ARTI, which is in accordance with other studies.1,2,10 As most of the children who attended a daycare center in this study had turned 10 months before starting, this nding reects increased illness when introduced to a day-care center and does not say for how long the higher amount of symptoms would continue after the introduction period. Household size and size of residence were in our study only associated with risk of simple rhinitis, indicating that crowding in the home, however important, is mainly related to mild symptoms while day-care attendance has a much higher impact on the severity of respiratory illness. ARTI developed in continuation of 40% of episodes with simple rhinitis, emphasizing the importance of identifying risk factors for simple rhinitis as well as for ARTI. An important risk factor for respiratory symptoms was having siblings aged 1 3 years attending a day nursery. As we did not have a control group of 1 3-year-old siblings not attending a day nursery, the effect of having siblings in a day nursery might as well be an age effect of the sibling. Many studies nd that the number and age of siblings predict the incidence of lower respiratory illness and wheezing in infancy, but do not divide siblings into subgroups according to nursery care.7,11,26,27 A Norwegian birth cohort study looking specically at lower respiratory tract infections among infants with siblings in day-care found an increased OR for children with siblings in day-care, especially if the children shared bedroom. However, the type of day-care was not dened, and differences in risk attributed to different kinds of day-care settings were not assessed.28 In contrast to developing countries, the association between breastfeeding and illness in industrialized nations has not been consistently demonstrated.3,15,29,30 Our results are in accordance with the ndings by other groups that breastfeeding is protective against illness for the rstborn child only31 and in the rst four months of life.29 This indicates that the increased exposure to pathogens of infants living with other children may override the protective effects of breastfeeding and that breastfeeding must be exclusive to confer a benet.
Strengths and Limitations

The present study has some strengths and limitations that need to be taken into account when interpreting the ndings. The prospective design of the study with parentreported infant health and illness using diary cards gives a comprehensive picture of the infants health problems, including all minor symptoms, which are often forgotten or neglected by the parents when they have to recall symptoms retrospectively.32,33 The active surveillance by monthly home visits helped maintain a high compliance by parents and resulted in a low dropout rate of
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general practitioner consultation rates. Br J Gen Pract 1998;48: 880 884. Douglas RM, Woodward A, Miles H, Buetow S, Morris D. A prospective study of proneness to acute respiratory illness in the rst two years of life. Int J Epidemiol 1994;23:818 826. Koch A, Sorensen P, Homoe P, Molbak K, Pedersen FK, Mortensen T, Elberling H, Eriksen AM, Olsen OR, Melbye M. Population-based study of acute respiratory infections in children. Greenland Emerg Infect Dis 2002;8:586 593. Wright AL, Taussig LM, Ray CG, Harrison HR, Holberg CJ. The Tucson Childrens Respiratory Study. II. Lower respiratory tract illness in the rst year of life. Am J Epidemiol 1989;129:1232 1246. Kusel MM, de Klerk NH, Holt PG, Landau LI, Sly PD. Occurrence and management of acute respiratory illnesses in early childhood. J Paediatr Child Health 2007;43:139 146. Latzin P, Frey U, Roiha HL, Baldwin DN, Regamey N, Strippoli MP, Zwahlen M, Kuehni CE. Prospectively assessed incidence, severity, and determinants of respiratory symptoms in the rst year of life. Pediatric Pulmonol 2007;42:41 50. Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986;42:121 130. R Development Core Team, R: A language and environment for statistical computing http://www.R-project.org. 2006. Geepack YanJ. Yet another package for generalized estimating equations. R-News 2002;2/3:12 14. Nielsen AM, Rasmussen S, Christoffersen MN. Morbidity of Danish infants during their rst months of life. Incidence and risk factors (Danish). Ugeskr Laeger 2002;164:5644 5648. Nielsen AM, Koefoed BG, Moller R, Laursen B. Prevalence rates of recent illnesses in Danish children, 1994 and 2000 (Danish). Ugeskr Laeger 2006;168:373 378. brns almindelige sygelighed - forekomst Uldall P. Spd- og sma og sociale konsekvenser (Acute illness in preschool children) (Danish). Thesis, University of Copenhagen 1986. Hansen BW. Acute illnesses in children. A. description and analysis of the cumulative incidence proportion. Scand J Prim Health Care 1993;11:202 206. Pattison CJ, Drinkwater CK, Downham MA. Mothers appreciation of their childrens symptoms. J R Coll Gen Pract 1982;32: 149 162. derstro m M, Reventlow S. Parents motivation Ertmann RK, So for seeing a physician. Scand J Prim Health Care 2005;23:154 158. Lopez BI, Sepulveda H, Valdes I. Acute respiratory illnesses in the rst 18 months of life. Rev Panam Salud Publica 1997;1:9 17. Hortal M, Benitez A, Contera M, Etorena P, Montano A, Meny M. A community-based study of acute respiratory tract infections in children in Uruguay. Rev Infect Dis 1990;12:S966 S973. Borrero I, Fajardo L, Bedoya A, Zea A, Carmona F, de Borrero MF. Acute respiratory tract infections among a birth cohort of children from Cali, Colombia, who were studied through 17 months of age. Rev Infect Dis 1990;12:S950 S956. Monto AS, Ullman BM. Acute respiratory illness in an American community. The Tecumseh study. JAMA 1974;227:164 169. Badger GF, Dingle JH, Feller AE, Hodges RG, Jordan WS Jr, Rammelkamp CH Jr. A study of illness in a group of Cleveland families. II. Incidence of the common respiratory diseases. Am J Hyg 1953;58:31 40. Sherriff A, Peters TJ, Henderson J, Strachan D. Risk factor associations with wheezing patterns in children followed longitudinally from birth to 31/2 years. Int J Epidemiol 2001;30: 1473 1484. Leeder SR, Corkhill R, Irwig LM, Holland WW, Colley JR. Inuence of family factors on the incidence of lower respiratory

10.3% during 1 year. We analyzed the repeated recordings of symptoms using logistic regression. Both prevalence (probability of having the symptom at day t) and incidence (probability of having a new episode at day t given that the child was at risk for a new episode) were studied because these two measures focus on different aspects of the disease. This analytic approach utilizes, in an optimal way, the available information from the diaries and it allows the inclusion of time-dependent explanatory variables. As we did not perform medical examinations of the children at the time of symptoms, we chose not to divide respiratory illnesses into upper and lower respiratory illness, which can be difcult for the parents to judge. Instead, we chose the denitions simple rhinitis and ARTI, which can easily be made by the parents and are independent of a physical examination. In addition, we did not obtain information about otitis media, as symptoms of middle ear involvement in this age group are almost impossible to judge without doing otoscopy. In conclusion, this prospective birth cohort study provides detailed data on the occurrence of disease symptoms during the rst year of life and afrms that nasal discharge and cough are major contributors to this illness. The majority of illness resolves spontaneously and does not come to light of the professional health care system. Increasing age, seasonality, household size, daycare attendance, and having young siblings are major determinants for the occurrence of respiratory symptoms in infancy.
ACKNOWLEDGMENTS

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12. 13. 14. 15.

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We are grateful to the participating children and parents. We thank Nanna Lietmann who performed a number of home visits, Niels Steen Krogh for design of the MySQL database, and Yoshio Suzuki for computerizing data.
REFERENCES
1. Koch A, Molbak K, Homoe P, Sorensen P, Hjuler T, Olesen ME, Pejl J, Pedersen FK, Olsen OR, Melbye M. Risk factors for acute respiratory tract infections in young Greenlandic children. Am J Epidemiol 2003;158:374 384. 2. Kamper-Jorgensen M, Wohlfahrt J, Simonsen J, Gronbaek M, Benn CS. Population-based study of the impact of childcare attendance on hospitalizations for acute respiratory infections. Pediatrics 2006;118:1439 1446. 3. Cushing AH, Samet JM, Lambert WE, Skipper BJ, Hunt WC, Young SA, McLaren JC. Breastfeeding reduces risk of respiratory illness in infants. Am J Epidemiol 1998;147:863 870. 4. Graham NM. The epidemiology of acute respiratory infections in children and adults: A global perspective. Epidemiol Rev 1990; 12:149 178. 5. Holme CO. Incidence and prevalence of non-specic symptoms and behavioural changes in infants under the age of two years. Br J Gen Pract 1995;45:65 69. 6. Bruijnzeels MA, Foets M, van der Wouden JC, van den Heuvel WJ, Prins A. Everyday symptoms in childhood: Occurrence and

20.

21.

22.

23.

24. 25.

26.

27.

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Respiratory and General Symptoms in Infancy

illness during the rst year of life. Br J Prev Soc Med 1976;30: 203 212. 28. Nafstad P, Hagen JA, Botten G, Jaakkola JJ. Lower respiratory tract infections among Norwegian infants with siblings in daycare. Am J Public Health 1996;86:1456 1459. 29. Wright AL, Holberg CJ, Martinez FD, Morgan WJ, Taussig LM. Breast feeding and lower respiratory tract illness in the rst year of life. Group Health Medical Associates Br Med J 1989;299: 946 949. 30. Rubin DH, Leventhal JM, Krasilnikoff PA, Kuo HS, Jekel JF, Weile B, Levee A, Kurzon M, Berget A. Relationship between

593

31.

32. 33. 34.

infant feeding and infectious illness: A prospective study of infants during the rst year of life. Pediatrics 1990;85:464 471. Pettigrew MM, Khodaee M, Gillespie B, Schwartz K, Bobo JK, Foxman B. Duration of breastfeeding, day-care, and physician visits among infants 6 months and younger. Ann Epidemiol 2003; 13:431 435. Butz A. Use of health diaries in pediatric research. J Pediatr Health Care 2004;18:262 263. Verbrugge LM. Health diaries. Med Care 1980;18:73 95. Last JM, ass. editors. A dictionary of epidemiology, 4th edition. Thuriaux: Oxford University Press 2001. p. 141.

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