Agudas respiratorias síntomas y malestar general durante 6 a 12 meses, 2008

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Pediatric Pulmonology 43:584593 (2008)

Acute Respiratory Symptoms and General IllnessDuring the First Year of Life:

A Population-Based Birth Cohort Study

Marie-Louise von Linstow, MD, PhD,1* Klaus Kahler Holst, MSc,2 Karina Larsen, RN,1

Anders Koch, MD, PhD,3 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 diariesand 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

firstyearof life,nasal discharge being most frequentfollowedby cough. Frequencyof allsymptoms

increased steeply after 6 months of age. Each child had on average 6.3 episodes (median: 5.1,

inter-quartile range (IQR): 3.3 7.8) 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 1 3 years attending a day nursery. In

conclusion, the present study provides detailed data on the occurrence of disease symptoms

during the first 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 mostcommondisease among young children.A substantial partof respiratory tract infections are associated with virusesand although rarely fatal in industrialized countries,they are a source of significant morbidity and carry aconsiderable economic burden.

Several risk factors for lower respiratory tract diseaseand hospitalization in developed countries have beendescribed such as day-care attendance1,2 and lack of

breastfeeding.3

Other risk factors such as crowding andsiblings, passive smoking, low socioeconomic status,psychosocial factors, male gender, and low birth weighthave in many studies also been found to be associated withlower respiratory tractdisease, although other studies havenot found such associations.4 Not many studies haveinvestigated risk factors for upper respiratory tractdisease,which is prevalent among children and has a substantialimpact on the disease burden experienced by families.

European studies have shown that parents deal withmore than 80% of all illnesses occurring among childrenwithout requiring medical attention.5,6 The actual amount

of childrens general illness is therefore much greater thanthefraction seen by the professionalhealthcare system. Toour knowledge, only one longitudinal community-based

2008 Wiley-Liss, Inc.

1Department of Pediatrics, Hvidovre Hospital, University of Copenhagen,

Denmark.

2Department of Biostatistics, University of Copenhagen, Denmark.

3Department of Epidemiology Research, Statens Serum Institut, Copenha-

gen, Denmark.

Grant sponsor: Pharmacists Foundation; Grant sponsor: Rosalie PetersensFoundation; Grant sponsor: Ebba Celinders Foundation; Grant sponsor:

Research Fund of Queen Louises Childrens Hospital.

*Correspondence to: Marie-Louise von Linstow, MD, Department of

Pediatrics, University of Copenhagen, Hvidovre Hospital, Kettegard Alle

30, DK-2650 Hvidovre, Denmark. E-mail: [email protected]

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 beencarried out,5 and just five longitudinal population-basedstudies of respiratory illness in infants from developed

countries have been published.711 No longitudinal

studies of Danish infants general illness have beenpublished.

The aim of our study was to obtain reliable data on theincidence 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

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 birthsin 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 post-

natal 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; infantswhose 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

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 doctorsvisits, 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

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 rectified.At the first home visit the parents were interviewed

about household contacts, parents education and employ-

ment, 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 concern-

ing factors that could change over time were repeated

every second month and treated as a time-dependent

variable in the analyses.

Case Definition

An episode of ARTI was defined as a period with nasaldischarge together with one or more of the following

symptoms: cough, fever/feels hot, wheezing, tachypnea,

malaise, or lost appetite. Episodes with nasal dischargeonly were assigned assimple rhinitis. Children with anepisode 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

first 2 days were considered as an episode of simplerhinitis and the ARTI episode was regarded to beginat day 3. A new episode was defined as an episodecommencing 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 notcounted as two illnesses and is in accordance with another

study of similar design.8 Incidence rates for the two

outcomesARTIandsimple rhinitiswere calculatedas number of episodes divided by person time at risk. Time

at risk was defined as the number of days with no recordedsymptoms excluding the 6 consecutive days without

symptoms following an episode. To evaluate all episodes,

we performed risk factor analysis for both ARTI andsimple rhinitis.

Statistical Methods

Outcome data for each child consist of atime-seriesof daily episode recordings (yes or no to each definedtype of episode). We defined prevalence at day t as theprobability of having an episode recorded at that day.

Similarly, we defined incidence at day t as the probabilityof 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

Pediatric Pulmonology

Respiratory and General Symptoms in Infancy 585


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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

confidence intervals (CI) were estimated using genera-lized estimating equations.12 Both an independencework-

ing 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 timeof maximum incidence/prevalenceand 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 similarmodels including a categorical calendar period.

The multiple logistic regression models for ARTIand simple rhinitis episodes included the followingvariables: age, season, gender, gestational age, mothersage, ethnicity, mother having had a cold


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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

first 6 months of life, increasing to 30% from 6 to 9 monthsand 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 121),

whereof 17 (9%) children saw a doctor10 times. A childhad 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): 3.37.8) ofARTI and 5.6 episodes (median: 4.3, IQR: 2.1 7.3) ofsimple 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:

5.211.2) per 365 days at risk. The incidence ofARTI 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 fromrespiratory 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, contactswith the health system and drug use in 228 children during their first year of life,Copenhagen, 20042006

Symptom by age

% of children with one or more days of the specific symptom (% of days

observed)

090 days 91180 days 181270 days >270 days Total

General malaise 48 (4.3) 58 (3.6) 67 (5.2) 70 (6.4) 92 (4.9)

Nasal discharge 62 (9.4) 75 (11.5) 89 (19.3) 89 (23.6) 99 (16.1)

Cough 34 (3.3) 52 (5.9) 65 (9.7) 68 (12.3) 94 (7.9)

Cough nasal discharge 26 (2.0) 40 (3.1) 58 (7.3) 62 (8.7) 90 (5.3)

Cough nasal discharge 20 (1.3) 33 (2.8) 36 (2.4) 38 (3.6) 70 (2.6)

Fever 22 (0.6) 50 (1.8) 64 (3.5) 78 (5.2) 91 (2.8)

Hoarseness 14 (0.6) 9 (0.5) 14 (0.9) 22 (1.4) 45 (0.8)

Conjunctivitis 30 (3.7) 15 (1.3) 14 (1.2) 27 (1.7) 61 (2.0)

Wheezing 8 (0.6) 8 (1.3) 20 (2.2) 17 (2.0) 35 (1.5)

Fast breathing 7 (0.4) 6 (0.3) 8 (0.6) 14 (0.8) 25 (0.5)

Vomiting 14 (0.4) 17 (0.5) 26 (0.8) 35 (0.9) 61 (0.7)

Diarrhea 25 (1.1) 26 (2.3) 28 (1.8) 38 (2.3) 70 (1.9)

Lost appetite 19 (0.9) 25 (1.5) 42 (3.1) 55 (4.2) 77 (2.5)

Skin rash/eczema 17 (2.8) 17 (4.1) 24 (3.8) 32 (4.8) 52 (3.9)

1 of the above symptoms 88 (21.6) 95 (24.6) 96 (31.1) 94 (38.8) 100 (29.2)2 of the above symptoms 72 81 87 92 100

3 of the above symptoms 52 64 79 88 98

4 of the above symptoms 33 47 69 77 97

Simple rhinitis episodes 41 (6.5) 43 (7.4) 50 (10.3) 59 (12.3) 91 (9.2)

ARTI episodes1 45 (2.9) 56 (4.1) 72 (9.0) 79 (11.4) 97 (6.9)

Doctors visit 40 (1.0) 39 (0.8) 50 (1.2) 57 (1.5) 83 (1.1)

Hospital admission 6 (0.3) 4 (0.1) 3 (0.1) 5 (0.1) 16 (0.1)

Medicine 25 (3.6) 27 (3.6) 34 (3.9) 48 (6.5) 74 (4.4)

*Period prevalence defined asthe total number of persons known to have had the disease or attribute at

any time during a specified period.34

1ARTI episodes aredefinedas nasal discharge together with one or more of thefollowing symptoms:cough,

fever, wheezing, tachypnea, malaise, lost appetite.




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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 symptomsincreased significantly from 6 months of age, and childrenhad relatively more respiratory symptoms during the

winter months (P< 0.001). Other factors significantly

associated with increased risk of ARTI and simple rhinitisin univariate analyses are shown in Table 3 and include

household size, number of children sharing bedroom,

siblings in day nursery, defined as a day-care institutionwith 1015 children in the age range 1/23 years, day-careattendance, size of residence, and if the mother had had a

cold


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2.7%, and fever on 0.8% of days observed. Most of these

numbers are equal to our findings, although we reporthigher 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

managed care of 66.899%5 and 94%19 of symptomswithout 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, definitions and classifications of

TABLE 4 Multiple risk factor regression analysis of incidence of acute respiratory tract illness (ARTI) and simple rhinitisepisodes in 228 children during their first year of life, Copenhagen, 20042006*

ARTI Simple rhinitis

Variable OR 95% CI P OR 95% CI P

Age (days)


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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 first year of life found in mostother 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 (6.1246.925).

Children suffered from nasal discharge for approxi-

mately 2 months and cough for 1 month during the

first year of life, showing that the amount of minorrespiratory illness was substantial in this cohort of healthy

children. The reported prevalence of respiratory symp-

toms 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


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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 optimalway, 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 difficult for the parents to judge.Instead, we chose the definitions simple rhinitis andARTI, 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 almostimpossible to judge without doing otoscopy.

In conclusion, this prospective birth cohort study

provides detailed data on the occurrence of disease

symptoms during the first year of life and affirms thatnasal 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, day-

care attendance, and having young siblings are major

determinants for the occurrence of respiratory symptoms

in infancy.

ACKNOWLEDGMENTS

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.

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Agudas respiratorias síntomas y malestar general durante 6 a 12 meses, 2008

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