A total of 454 wheezing respiratory illnesses were documented during the first 3 years of life: 153 illnesses in 76 children ages 0–1 year, 155 illnesses in 72 children ages 1–2 years, and 146 illnesses in 63 children in the third year of life. Nasopharyngeal wash specimens were obtained during 442 (97%) of these wheezing illnesses. A viral etiology was identified in 398 (90%) of these specimens. The types of viruses detected during the first 3 years of life included RV (212; 48%), RSV (93; 21%), PIV (51; 12%), MPV (33; 7%), CV (20; 5%), AdV (17; 4%), flu (16; 4%), and EnV (10; 2%). Multiple viruses were identified for 48 wheezing illnesses. The following viruses were recovered from these multiple-virus infections: RV (29; 60%), RSV (20; 42%), MPV (15; 31%), AdV (10; 21%), flu (9; 19%), PIV (8; 17%), CV (7; 15%), and EnV (5; 10%). The pattern of early-life infections was distinct in children diagnosed with asthma at age 6 years (). Notably, the frequency of RV-induced wheezing episodes increased over the first 3 years of life for children diagnosed with asthma at age 6 years (P = 0.05), and decreased during the same time period in children without asthma (P = 0.0004) ().
Figure 1. Viral etiology of wheezing illnesses in the first 3 years of life in children with and without asthma at age 6 years. Frequency of rhinovirus (RV) wheezing illnesses during the first 3 years of life increased in children with asthma (n = 73) and (more ...)
Viral Illnesses in Early Childhood and Asthma in the Sixth Year of Life
In the sixth year of life, 73 of 259 (28%) children had asthma based on predefined clinical criteria. On the basis of National Asthma Education and Prevention Program (NAEPP) guideline criteria, 35 (48%) of these children had intermittent asthma, 25 (34%) had mild persistent asthma, and 13 (18%) had moderate persistent asthma. Of these 73 children with asthma, 46 (63%) were boys and 27 (37%) were girls. Skin prick testing was performed at age 5 years on 64 of 73 children with asthma; 37 (58%) were positive to at least one allergen. This compares to a sensitization rate of 46% (69 of 149) for the children without asthma at age 6 years (P = 0.12).
The relationship between the viral etiology of wheezing illnesses in each of the first 3 years of life and the diagnosis of asthma at age 6 years was analyzed. Because RV and RSV were most frequently identified as the cause of wheezing illnesses, the analysis focused on these two viruses. Children who wheezed with RV during infancy were at greater risk of asthma at age 6 than children who did not wheeze with RV or RSV, regardless of whether they wheezed only with RV (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.1, 7.5) or had additional wheezing illnesses with RSV (OR, 2.7; 95% CI, 1.2, 6.3) during this same time period (). In contrast, children who wheezed only with RSV during infancy developed asthma at age 6 at a rate similar to those who did not wheeze with RV or RSV (OR, 1.2; 95% CI, 0.4, 3.2) ().
RHINOVIRUS AND RESPIRATORY SYNCYTIAL VIRUS WHEEZING ILLNESSES IN YEARS 1, 2, AND 3, AND RISK OF ASTHMA AT AGE 6 YEARS
In the second year of life, RV wheezing illnesses continued to be strongly associated with asthma at age 6 years whether children also wheezed with RSV (OR, 12.7; 95% CI, 2.5, 63.1) or did not (OR, 5.6; 95% CI, 2.4, 12.8) (). Children who wheezed only with RSV during Year 2 were not at increased risk of asthma at age 6 years (OR, 1.3; 95% CI, 0.4, 3.8) (). In contrast to the first 2 years of life, children who wheezed only with RSV in Year 3 had a significantly increased risk of asthma at age 6 years (OR, 13.6; 95% CI, 3.4, 54.0) (). Year 3 RV wheezing illnesses were associated with a dramatically increased risk of Year 6 asthma (OR, 31.7; 95% CI, 10.6, 94.9). Among children with one to two wheezing illnesses, RV wheezing was associated with significantly greater asthma risk than non-RV wheezing (89% [16/18] vs. 55% [16/29], P = 0.02). All children who wheezed three or more times in Year 3 wheezed at least once with RV.
When wheezing history during the entire first 3 years of life was considered, wheezing with RSV alone was associated with an increased risk of asthma at age 6 years compared with children who did not wheeze with RV or RSV (OR, 2.6; 95% CI, 1.0, 6.3) (). Wheezing with RV, regardless of RSV wheezing history, was associated with a substantially increased risk of asthma at age 6 years compared with children who did not wheeze with either RV or RSV (RV only: OR, 9.8; 95% CI, 4.3, 22.0; and RV and RSV: OR. 10.0; 95% CI. 4.5, 22.2) () Furthermore, wheezing with RV alone or in addition to RSV was associated with significantly greater asthma risk compared with wheezing with RSV alone (RV only: OR, 3.8; 95% CI, 1.4, 10.4; and RV and RSV: OR, 3.9; 95% CI, 1.5, 10.5).
Figure 2. Risk of asthma at age 6 years in children who wheezed during the first 3 years of life with rhinovirus (RV), respiratory syncytial virus (RSV), or both (*P < 0.05 vs. Neither; +P < 0.05 vs. RSV only). OR = odds (more ...)
We next compared rates of asthma for children who wheezed during the first 3 years of life with RV with those who wheezed with any other viruses (including RSV). Rates of Year 6 asthma were 9% for nonwheezing children and 31% for children who wheezed only with viruses other than RV (OR, 4.2; 95% CI, 1.8, 9.9). Wheezing with RV, either alone or in addition to other viruses, was associated with a significantly greater asthma risk (58%) compared with children who did not wheeze (OR, 13.1; 95% CI, 6.3, 27). Asthma risk was similar for children who wheezed only with RV (53%) and children who wheezed with RV and other viruses (60%) (P = 0.57).
There were no differences between rates of infection as determined by viral recovery from nasal lavage samples performed during scheduled clinic visits during Year 1 for children with and without asthma at age 6 years (asthma, 1.2 ± 1.1, and no asthma, 1.2 ± 1.0 infections/y; P = 0.91). Moreover, RV moderate to severe illnesses (MSI) without wheeze were not associated with increased asthma risk at age 6 (no RV MSI Years 1–3, 12% asthma risk; RV MSI without wheeze Years 1–3, 16% asthma risk; RV MSI with wheeze Years 1–3, 59% asthma risk).
Nonviral Risk Factors and Asthma
The associations between environmental factors and the development of asthma by age 6 years were analyzed. In univariate and stepwise multivariate analyses, allergic sensitization to either aeroallergen or food at age 1 year (aeroallergen: OR, 2.7; 95% CI, 1.2, 6.2; food: OR, 2.0; 95% CI, 1.0, 3.9) and older siblings in the home during infancy (OR, 1.9; 95% CI, 1.0, 3.5) were associated with increased risk for asthma at age 6 years. The presence of a dog in the home at the time of birth was associated with reduced asthma risk by univariate analyses (OR, 0.5; 95% CI, 0.3, 0.9), but this did not reach statistical significance in a stepwise multivariate model (OR, 0.6; 95% CI, 0.3, 1.1) ().
RISK FACTORS FOR ASTHMA AT AGE 6 YEARS
Allergic Sensitization, RV Wheezing, and Asthma
Aeroallergen sensitization without RV wheezing in Year 1 and RV wheezing without concomitant aeroallergen sensitization were each associated with increased rates of asthma at age 6 years (45 and 39%, respectively; ). Infants with both RV wheezing and aeroallergen sensitization by age 1 year had the highest incidence (86%) of subsequent asthma. Sensitization to aeroallergens did not alter the impact of RV wheezing on subsequent asthma development (interaction P = 0.61).
RELATIVE CONTRIBUTION OF RHINOVIRUS WHEEZING ILLNESSES AND AEROALLERGEN SENSITIZATION TO RISK OF ASTHMA AT AGE 6 YEARS
In the third year of life, RV wheezing illnesses had a more prominent effect on asthma risk (OR, 25.6), whereas aeroallergen sensitization was associated with a smaller, but still significant increase in asthma risk (OR, 3.4) (). Again, aeroallergen sensitization did not modify the relationship between RV wheezing illnesses and asthma development (interaction P = 0.99).