Day Care Attendance, Respiratory Tract Illnesses ...

ARTICLE

Day Care Attendance, Respiratory Tract Illnesses, Wheezing, Asthma, and Total Serum IgE Level in Early Childhood Juan C. Celedoń, MD, DrPH; Augusto A. Litonjua, MD, MPH; Louise Ryan, PhD; Scott T. Weiss, MD, MS; Diane R. Gold, MD, MPH

Background: It has been hypothesized that day care– related infections may explain the inverse relation between day care attendance in early life and asthma in childhood. Objective: To examine the relation between day care attendance or respiratory tract illnesses in the first year of life and wheezing and asthma in the first 4 years of life among children with a parental history of atopy who were followed up from birth. Results: Day care attendance in the first year of life was inversely associated with geometric mean total serum IgE level (12.9 [±1 SD=3.3, 51.4] IU/mL for day care vs 18.5 [±1 SD=5.3, 64.7] IU/mL for no day care; P=.03) at 2 years of age but not significantly associated with wheezing at or after 2 years of age. Having at least 1 physiciandiagnosed lower respiratory tract illness in the first year of life was significantly associated with recurrent wheez-

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From the Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital (Drs Celedoń, Litonjua, Weiss, and Gold), the Division of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center (Drs Celedoń, Litonjua, Weiss, and Gold), Department of Medicine, Harvard Medical School (Drs Celedoń, Litonjua, and Weiss), and the Department of Biostatistics, Harvard School of Public Health (Dr Ryan), Boston, Mass.

ing (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.0-4.1) and asthma (OR, 2.5; 95% CI, 1.1-5.5) at 4 years of age, but not with any wheezing (infrequent and frequent) at 3 years or older. Illnesses of the upper respiratory tract (ⱖ1 physician-diagnosed upper respiratory tract illness or ⱖ3 episodes of nasal catarrh) in the first year of life were associated with any wheezing (frequent and infrequent) between the ages of 1 and 4 years, but not with recurrent wheezing or asthma at 4 years of age. Conclusions: Our results suggest that among children

with a parental history of atopy the protective effect of day care attendance in early life against the development of atopy has begun by 2 years of age, and that a protective effect of day care attendance in early life against wheezing may not be observed until after 4 years of age. Arch Pediatr Adolesc Med. 2002;156:241-245

HE PREVALENCE of asthma in

the United States has increased significantly during the past 30 years, making this respiratory disease a major public health problem.1,2 It has been hypothesized that the asthma epidemic in the United States and other developed countries is due, at least in part, to reduced exposure to other children3 and a decreased risk for infections in early childhood.4 Approximately 60% of children in the United States attended day care in 1995.5 Results of 2 recent studies conducted in Germany6 and the United States7 have demonstrated an inverse association between day care attendance in early life and the development of atopy,6 wheezing,7 and asthma7 later in childhood. Since day care attendance is associated with an increased risk for infectious illnesses of the upper (URI)8 and lower respiratory tract (LRI)9,10 in early life, these infectious illnesses may be partly responsible for the observed protective effect of day care attendance on the development of childhood asthma.

(REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 156, MAR 2002 241

The Home Allergens and Asthma Study is a prospective birth cohort study of children with a parental history of asthma or allergies in the Boston, Mass, metropolitan area. We previously showed that day care attendance among study participants was associated with an increased risk for physician-diagnosed URIs and LRIs in the first year of life.11 In the present report, we examine the association between day care attendance in the first year of life and wheezing and asthma in the first 4 years of life and try to determine whether the observed association is due primarily to day care–related respiratory tract illnesses requiring medical attention. RESULTS

CHARACTERISTICS OF THE COHORT AND DAY CARE EXPERIENCE The characteristics of the 498 study subjects have been described in detail else-

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PATIENTS AND METHODS The 505 infants with a history of allergy or asthma in at least 1 parent were recruited between September 1, 1994, and August 31, 1996. The screening and recruitment of families have been described elsewhere.12 Every 2 months, beginning when the child was 2 months of age, a telephone questionnaire was administered to the child’s primary caretaker until the child’s second birthday. Afterwards, interviews were conducted every 6 months. Of the 505 children, 7 were excluded because they were followed up for no more than 4 months during their first year of life. The study was approved by the institutional review board of Brigham and Women’s Hospital, Boston. Day care attendance in the first year of life was treated as a binary variable.11 Every 2 months during the child’s first year of life, the caretaker was asked: “Since we last spoke with you on [date given], has your child had a pneumonia diagnosed by a doctor?” Other bimonthly questions included whether a runny or stuffed nose or physician-diagnosed croup, bronchitis, bronchiolitis, ear infection, or sinus trouble had occurred since the previous questionnaire was administered. These variables were then categorized as any vs no physician-diagnosed LRIs (ie, croup, bronchitis, bronchiolitis, or pneumonia), any vs no physician-diagnosed URIs (ie, ear infection and sinus trouble), and at least 3 vs fewer than 3 reports of runny or stuffed nose (nasal catarrh).11 Sociodemographic and familial variables included the child’s race and annual household income,12 type of medical insurance (none, private, and nonprivate), in utero exposure to smoking, breast-feeding (as a binary and a categorical variable [never, exclusively for ⬍4 months, and exclusively for ⱖ4 months]), bottle-feeding in a bed or crib before bedtime, parental history of asthma (ever diagnosed and ever diagnosed with current symptoms),

where.11 Table 1 summarizes the main characteristics of the study participants. Of the 238 children (47.8%) who attended day care in their first year of life, 161 (67.6%) attended in a home setting; 52 (21.8%), a nonresidential setting; and 25 (10.5%), both (mixed day care).11 Among these 238 children, 50 (21.0%) attended day care with at least 10 children. All 238 children attended day care for at least 5 hours per week and for at least 1 month; 109 (45.8%) attended day care for at least 6 months, at least 3 days per week, and at least 4 hours per day. Of the 498 study participants, 461 (92.6%) were followed up to 4 years of age. No statistically significant differences in sex, day care attendance in the first year of life, respiratory tract illnesses in the first year of life, and parental history of asthma were found between those with and without 4-year follow-up. Subjects who dropped out of the study before 4 years of age were significantly more likely to come from low-income families and to not be breastfed in the first year of life than subjects who underwent 4 years of follow-up. Of the 498 participating children, 230 (46.2%) underwent a measurement of total serum IgE level at 2 years of age. No significant differences in day care attendance or respiratory tract illnesses in the first year of life were found between those with and without total serum IgE measurements at 2 years of age.

number of older siblings (as a continuous and as a categorical variable [⬍3 vs ⱖ3]), and average number of cigarettes per day smoked by all adults in the household.11 Wheezing was considered present at any time from 12 to 48 months of age if at least 1 affirmative response was given to the question: “Since we last spoke with you on [date given], has your child had wheezing or whistling in the chest?” Every year—starting at 2 years of age—we also asked: “How many attacks or episodes of wheezing has your child had in the past 12 months?” Recurrent wheezing at 4 years of age was defined as at least 2 episodes of wheezing in the previous 12 months. Asthma at 4 years of age was defined as physician-diagnosed asthma and at least 1 episode of wheezing in the 12 months preceding the interview. Total serum IgE level at 2 years of age was measured by an enzyme-immunoassay based on the sandwich technique (UniCAP; Pharmacia Diagnostics, Kalamazoo, Mich). All values were converted to the log-natural scale for analysis. We conducted the bivariate analysis using ␹2 and 2-tailed t tests. We used stepwise logistic regression to study the relation between day care attendance in the first year of life and the outcomes of interest (total serum IgE level at 2 years of age, and recurrent wheezing and asthma at 4 years of age) while adjusting for potential confounders and examining interactions. In the final models, we included those variables that satisfied a change-in-estimate criterion (ⱖ10% in the odds ratio [OR]) or that were significant at the P⬍.05 level. For the longitudinal analysis of the relation between day care attendance in the first year of life and wheezing in the first 4 years of life, we used proportional hazard models, with repeated events on the same child being handled by the method of Anderson and Gill.13 To examine age-dependent associations, we calculated interaction terms between the age of the children at each survey and the variables in the model.

RELATION BETWEEN DAY CARE ATTENDANCE OR RESPIRATORY TRACT ILLNESSES IN THE FIRST YEAR OF LIFE AND RECURRENT WHEEZING AND ASTHMA AT AGE 4 YEARS As in our previous study,11 the amount of time that the children spent in day care during the first year of life was not associated with the outcomes of interest. Since the estimates of the association between day care attendance in the first year of life and the outcomes of interest were similar, whether the child attended day care in the first or second 6 months of life, we combined attendance in the first and second 6 months of life. Table 2 summarizes the results of the analysis of the relation between day care attendance or respiratory tract illnesses in the first year of life and recurrent wheezing and asthma at 4 years of age. There was no significant association between day care attendance in the first year of life and recurrent wheezing or asthma at 4 years of age. Although children who had at least 1 physiciandiagnosed LRI in the first year of life had increased odds of having recurrent wheezing or asthma at 4 years of age, we found no significant association between URIs (physician-diagnosed URIs or ⱖ3 episodes of nasal catarrh) in the first year of life and recurrent wheezing or asthma




Table 1. Characteristics of Children in the Cohort* % of Patients Variables Female Household yearly income, $† Low (⬍30 000) Medium (30 000-49 999) High (ⱖ50 000) Medical insurance None Private Nonprivate Race White Black Hispanic Other Any cigarette smoking inside the home Ever breastfed Bottle-feeding before nap or sleep time No. of older siblings None 1 2 ⱖ3 Maternal history of asthma, ever-diagnosed Maternal history of asthma with current symptoms Any physician-diagnosed LRI in the first year of life Any physician-diagnosed URI in the first year of life ⱖ3 Episodes of nasal catarrh in the first year of life

Day Care (n = 238)

Total (n = 498)

47.9

46.2

8.0 19.3 68.9

9.0 17.7 70.5

2.1 93.3 4.6

1.8 93.6 4.6

73.5 14.3 5.9 6.3 8.4 73.1 29.4

75.3 12.0 5.6 7.0 7.6 74.7 27.5

50.8 38.2 7.6 3.4 30.7 11.8

45.8 35.3 14.1 4.8 30.5 9.9

29.4

26.5

76.0

65.1

91.1

84.5

at 4 years of age. We found no association between the number of older siblings and recurrent wheezing or asthma at 4 years of age. To examine whether the association between physician-diagnosed LRIs in the first year of life and recurrent wheezing or asthma at 4 years of age was due to reverse causation, we repeated the multivariate analysis after excluding children who wheezed in the first year of life. Among the 280 children who did not have any wheezing episodes in the first year of life, there was no significant association between physician-diagnosed LRIs in the first year of life and recurrent wheezing (OR, 1.7; 95% confidence interval [CI], 0.5-5.8) or asthma (OR, 0.4; 95% CI, 0.1-3.8) at 4 years of age. LONGITUDINAL ANALYSIS OF THE RELATION BETWEEN DAY CARE ATTENDANCE OR RESPIRATORY TRACT ILLNESSES IN THE FIRST YEAR OF LIFE AND ANY WHEEZING IN THE FIRST 4 YEARS OF LIFE

*LRI indicates lower respiratory tract illnesses (croup, bronchitis, bronchiolitis, and pneumonia); URI, upper respiratory tract illnesses (ear infections and sinus trouble). †Information on household income was not available in 14 (2.8%) of the 498 children.

The results of the multivariate longitudinal analysis of the relation between day care attendance or respiratory tract illnesses in the first year of life and the primary caretaker’s report of wheezing (infrequent and frequent) throughout the first 4 years of life are summarized in Table 3. We found a significant interaction between day care attendance or physician-diagnosed LRIs in the first year of life and age. The risk for wheezing associated with day care attendance in the first year of life decreased with increasing age, with no significant day care–related risk for wheezing at 2 years of age. Although the risk for wheezing associated with physiciandiagnosed LRIs in the first year of life decreased significantly with age, the risk for wheezing associated with physician-diagnosed URIs or at least 3 episodes of nasal catarrh in the first year of life was increased throughout the first 4 years of life.

Table 2. Relation Between Day Care Attendance or Physician-Diagnosed Infectious Lower Respiratory Tract Illnesses in the First Year of Life and Recurrent Wheezing and Asthma at 4 Years of Age* Recurrent Wheezing (n = 40)

Asthma (n = 30)

Odds Ratio (95% CI)

Day care attendance, first year of life No Yes Physician-diagnosed LRI, first year of life No Yes Physician-diagnosed URI, first year of life No Yes ⱖ3 Episodes of nasal catarrh (runny nose), first year of life No Yes

Odds Ratio (95% CI)

No. (%)

Unadjusted

Adjusted†

No. (%)

Unadjusted

Adjusted†

21 (52.5) 19 (47.5)

1.0 1.0 (0.5-1.8)

1.0 0.9 (0.5-1.8)

17 (56.7) 13 (43.3)

1.0 0.8 (0.3-1.7)

1.0 0.8 (0.3-1.7)

23 (57.5) 17 (42.5)

1.0 2.2 (1.2-4.4)

1.0 2.0 (1.0-4.1)‡

16 (53.3) 14 (46.7)

1.0 2.6 (1.2-5.5)

1.0 2.5 (1.1-5.5)

11 (27.5) 29 (72.5)

1.0 1.5 (0.7-3.1)

... ...

10 (33.3) 20 (66.7)

1.0 1.1 (0.5-2.4)

... ...

0 40 (100.0)

. . .§ . . .§

... ...

2 (6.7) 28 (93.3)

1.0 2.6 (0.6-11.2)

... ...

*CI indicates confidence interval. Other abbreviations and definitions are given in the first footnote to Table 1. †Adjusted also for sex, household income, bottle-feeding in the bed or crib before bedtime in the first year of life, maternal history of asthma with current symptoms, maternal cigarette smoking during pregnancy, and either day care attendance or physician-diagnosed LRIs in the first year of life. ‡P⬍.05. §No odds ratio was calculated since none of the subjects without recurrent nasal catarrh had recurrent wheezing.




Table 3. Multivariate Longitudinal Analysis of the Relation Between Day Care Attendance in the First Year Life and Wheezing in the First 4 Years of Life* Risk Ratio (95% CI) for Any Wheezing, by Age, y

Physician-diagnosed LRI in the first year of life Day care attendance in the first year of life Physician-diagnosed URI in the first year of life ⱖ3 Episodes of nasal catarrh in the first year of life

1

2

3

4

1-4

P Value for Interaction With Age†

2.6 (2.2-3.1) 1.3 (1.1-1.5) ... ...

1.7 (1.5-2.0) 1.1 (0.9-1.3) ... ...

1.1 (0.9-1.4) 0.9 (0.7-1.1) ... ...

0.7 (0.5-1.1) 0.8 (0.5-1.1) ... ...

... ... 1.4 (1.2-1.7) 1.7 (1.3-2.2)

⬍.01 ⬍.01 ⬎.05 ⬎.05

*We adjusted for sex, household income, in utero exposure to smoking, number of older siblings (⬍3 vs ⱖ3), and maternal history of asthma with current symptoms, in addition to all of the variables in the table. The risk for wheezing associated with either physician-diagnosed URIs or 3 or more episodes of nasal catarrh in the first year of life did not change significantly between the ages of 1 and 4 years. Abbreviations are given in the first footnotes to Tables 1 and 2. †Indicates whether the risk for wheezing associated with any of the variables in the model decreased significantly with age.

DAY CARE ATTENDANCE IN THE FIRST YEAR OF LIFE AND TOTAL SERUM IgE LEVEL AT 2 YEARS OF AGE The geometric mean (± 1 SD) total serum IgE level at 2 years of age was significantly lower in children who attended day care in their first year of life than that in children who did not (12.9 [3.3, 51.4] IU/mL vs 18.5 [5.3, 64.7] IU/mL; P = .03). This difference was not significantly changed after adjusting for sex and household income. There was no significant association between physician-diagnosed respiratory tract illnesses or at least 3 episodes of nasal catarrh in the first year of life and the children’s total serum IgE level at 2 years of age. COMMENT

Our study is unique in that we included detailed information on exposure to day care and URIs and LRIs in the first year of life, a time when exposure to day care or respiratory tract infections may influence the development of the immune system.6,7,14 Among children with parental history of atopy, the risk for wheezing associated with day care attendance in the first year of life decreased significantly with age. At 2 years of age, day care attendance in the first year of life was inversely associated with total serum IgE level, but not significantly associated with wheezing. In a longitudinal birth cohort study, children with greater exposure to older siblings at home or day care were more likely to have frequent wheezing at 2 years of age, but significantly less likely to have frequent wheezing or a high total serum IgE level at 6 years of age than those with less exposure to other children.7 Cross-sectional studies of German6 and Italian15 children also showed an inverse association between day care attendance in early life and atopy6 and persistent wheezing at school age.15 Our longitudinal finding of an inverse association between day care attendance in the first year of life and total serum IgE level among children with a parental history of atopy suggests that the protective effect of day care attendance in early life on the development of atopy has begun by 2 years of age. The lack of a significant inverse association between day care attendance in the first year of life and asthma or wheezing at 4 years of age in our study is likely because wheezing in early childhood may be related to infections in children with small airways or to allergic inflammation of the airways.15 Since day care attendance in

our study was positively associated with an increased risk for infectious respiratory tract illnesses in the first year of life11 but inversely associated with a marker of atopy at 2 years (total serum IgE level), it may not be possible to observe a protective effect of day care attendance in early life on wheezing until the children are older. In our study, having at least 1 physician-diagnosed LRI in the first year of life was associated with increased odds of recurrent wheezing and asthma at 4 years of age. Reverse causation is a plausible explanation for our findings, as the observed association between physiciandiagnosed LRIs in the first year of life and recurrent wheezing or asthma at 4 years of age was no longer significant once children who wheezed in the first year of life were excluded from the analysis. Thus, children who are true asthmatic patients may be predisposed to infectious LRIs in early life. An alternative explanation for our findings is that some of the LRIs in our study may have been due to respiratory syncytial virus, an infectious illness that is associated with wheezing in early life16 and up to 11 years of age.17 Our findings are in agreement with those of 2 longitudinal birth cohort studies of Norwegian18 and German14 children. In the Norwegian study, a strong association was found between parental report of infectious LRIs in infancy and asthma at 4 years of age.18 The German investigators found a strong association between infectious LRIs in the first 3 years of life and asthma and current wheezing at 7 years of age.14 This association was no longer significant, however, when wheezing LRIs were excluded from the analysis. We found that having at least 1 physician-diagnosed LRI in the first year of life was associated with an increased risk for wheezing (infrequent and frequent wheeze) at 1 and 2 years of age but not at 3 or 4 years of age. This finding is likely explained by airway growth resulting in a decreased risk for wheezing related to infectious LRIs in early life, particularly among children with infrequent wheezing and no maternal history of asthma.19 We found that URIs (physician-diagnosed URIs or ⱖ3 episodes of nasal catarrh) in the first year of life were significantly associated with wheezing (infrequent and frequent) from 1 to 4 years of age, but not with asthma at 4 years of age. However, we found a nonstatistically significant trend for an association between at least 3 episodes of nasal catarrh in the first year of life and recurrent wheezing at 4 years of age, as none of the children who had fewer than 3 episodes of nasal catarrh in the first year of life had




What This Study Adds Day care attendance in early life is inversely related to atopy and asthma among children of school age. Little is known about the relation between day care attendance or respiratory tract illnesses in early life and wheezing and asthma in early childhood, particularly among children with a parental history of atopy. Our findings among children with parental history of atopy suggest that an inverse relation exists between day care attendance in early life and atopy by 2 years of age, but that any inverse association between day care attendance in early life and wheezing may not be evident until after 4 years of age. In children at high risk for atopy, the positive association between illnesses of the upper and lower respiratory tract and wheezing in the first 4 years of life may be due to infections and/or be the early manifestation of an atopic predisposition.

recurrent wheezing at 4 years of age. Among children with parental history of atopy, URIs may be due to infection or allergic inflammation. Inflammation of the nasal mucosa due to allergy or infection could lead to recurrent nasal catarrh, physician-diagnosed sinus trouble, or eustachian tube dysfunction with persistent middle ear effusions20 and, perhaps, otitis media. Thus, the association between URIs and wheezing in the first 4 years of life in our study may be due to concurrent infectious or allergic inflammation of the lower airways. Nafstad and colleagues18 found a positive association between having otitis media in the first year of life or the common cold in the first 6 months of life and asthma at 4 years of age. We recognize several limitations to our findings. First, since most of the subjects participating in our study attended day care in home settings with a relatively small number of children, they may have been exposed to a more modest burden of infectious and noninfectious illnesses than children attending nonresidential day care centers. This could have resulted in limited statistical power to detect an association between day care attendance in the first year of life and asthma or recurrent wheezing at 4 years of age. However, the predilection of study participants for home-based day care reflects the general experience in the greater Boston area, where approximately 76% of licensed day care is provided in a home setting.11 Second, we assessed the presence of respiratory tract illnesses in early life by means of parental report and did not make an attempt to measure asymptomatic infections. As previously mentioned, illnesses of the respiratory tract among children with a parental history of atopy may be due to moderate to severe infection, allergy, or both. Third, other investigators have found an inverse association between recurrent nasal catarrh and asthma at 7 years of age.14 Since we have followed up children to 4 years of age, we do not yet know what the relation between URIs and asthma will be when the children reach school age. CONCLUSIONS

Our results suggest that the protective effect of day care attendance in early life against the development of atopy

has begun by 2 years of age, and that a protective effect of day care attendance in early life against wheezing may not be observed until after 4 years of age. Among children with a parental history of atopy, the association between illnesses of the respiratory tract in the first year of life and wheezing in the first 4 years of life may be due to infections and/or may be the early manifestation of an atopic predisposition. Further follow-up of our study cohort should help us to clarify the relation between day care attendance or respiratory tract illnesses in early life and childhood asthma and atopy. Accepted for publication November 14, 2001. This study was supported by grant AI35786 from the National Institutes of Health, Bethesda, Md. Dr Celedo´ n is supported by a Charles A. King Trust Fellowship Award, Boston. We thank Jaylyn Olivo, MS, for her editorial assistance and Diane Sredl, MPH, for her assistance with computer programming. Corresponding author and reprints: Juan C. Celedo´ n, MD, DrPH, Channing Laboratory, 181 Longwood Ave, Boston, MA 02115 (e-mail: [email protected]). REFERENCES 1. Mannino DM, Homa DM, Pertowski CA, et al. Surveillance for asthma—United States, 1960-1995. Mor Mortal Wkly Rep CDC Surveill Summ. 1998;47:1-27. 2. Centers for Disease Control and Prevention. Asthma—United States, 19821992. MMWR Morb Mortal Wkly Rep. 1995;3:952-955. 3. Strachan DP. Hay fever, hygiene, and household size. BMJ. 1989;299:12591260. 4. Martinez FD. Maturation of immune responses at the beginning of asthma. J Allergy Clin Immunol. 1999;103:355-361. 5. West J, Wright D, Hausken EG. Child Care and Early Education Program Participation for Infants, Toddlers, and Preschoolers. Washington, DC: Dept of Health, Education, and Welfare; 1995. Dept of Health, Education, and Welfare publication (NCES) 95-824. 6. Kra¨ mer U, Heinrich J, Wjst M, Wichmann H-E. Age of entry to day nursery and allergy in later childhood. Lancet. 1998;353:450-454. 7. Ball TM, Castro-Rodriguez JA, Griffith KA, Holberg CJ, Martinez FD, Wright AL. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med. 2000;343:538-543. 8. Nafstad P, Hagen JA, Oie L, Magnus P, Jaakkola JJ. Day care centers and respiratory health. Pediatrics. 1999;103:753-758. 9. Holberg CJ, Wright AL, Martinez FD, Morgan WJ, Taussig LM, and Group Health Medical Associates. Child day care, smoking by caregivers, and lower respiratory tract illness in the first 3 years of life. Pediatrics. 1993;91:885-892. 10. Marbury MC, Maldonado G, Waller L. Lower respiratory illness, recurrent wheezing, and day care attendance. Am J Respir Crit Care Med. 1997;155:156-161. 11. Celedon JC, Litonjua AA, Weiss ST, Gold DR. Day care attendance in the first year of life and illnesses of the upper and lower respiratory tract in children with a familial history of atopy. Pediatrics. 1999;104:495-500. 12. Litonjua AA, Carey VJ, Burge HA, Weiss ST, Gold DR. Parental history and the risk for childhood asthma. Am J Respir Crit Care Med. 1998;158:176-181. 13. Therneau TM, Grambsch J. Extending the Cox model. In: Modeling Survival Data: Extending the Cox Model. New York: Springer-Verlag NY Inc; 2000:185-186. 14. Illi S, von Mutius E, Lau S, et al, and the MAS Group. Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. BMJ. 2001;322:390-395. 15. Rusconi F, Galassi C, Corbo GM, et al, for the SIDRIA Collaborative Group. Risk factors for early, persistent, and late-onset wheezing in young children. Am J Respir Crit Care Med. 1999;160:1617-1622. 16. Wright AL, Taussig LM, Ray CG, Harrison HR, Holberg CJ. The Tucson Children’s Respiratory Study, II. Am J Epidemiol. 1989;129:1232-1246. 17. Stein RT, Sherrill D, Morgan WJ, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet. 1999;354:541-545. 18. Nafstad P, Magnus P, Jaakkola J, Jouni JK. Early respiratory infections and childhood asthma. Pediatrics [serial online]. 2000;106:doc e38. 19. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ, for the Group Health Medical Associates. Asthma and wheezing in the first six years of life. N Engl J Med. 1995;332:133-138. 20. Kraemer MS, Richardson MA, Weiss NS, et al. Risk factors for persistent middleear effusions. JAMA. 1983;249:1022-1025.


