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Preschool rhinovirus wheezing illnesses predict an increased risk of childhood asthma; however, it is not clear how specific viral illnesses in early life relate to lung function later on in childhood.
To determine the relationshipof virus-specific wheezing illnesses and lung function in a longitudinal cohort of children at risk for asthma.
Two hundred thirty-eight children were followed prospectivelyfrom birth to 8 years of age. Early life viral wheezing respiratory illnesses were assessed using standard techniques and lung function was assessed annually by spirometry and impulse oscillometry (IOS). The relationshipsof these virus-specific wheezing illnesses and lung function were assessed by mixed-effect linear regression.
Children who wheezed with rhinovirus (RV) demonstrated significantly decreased spirometry values [FEV1 (p=0.001), FEV0.5 (p<0.001), FEF25–75 (p<0.001)], and also had abnormal IOS measures [more negative Reactance at 5 Hz (p<0.001)] compared to those who did not wheeze with RV. Children who wheezed with RSV or other viral illnesses did not have any significant differences in spirometric or IOS indices when compared to children who did not. Children diagnosed with asthma at ages 6 or 8 years had significantly decreased FEF25–75 (p=0.05) compared to children without asthma.
Among outpatient viral wheezing illnesses in early childhood, those caused by RV infections are the mostsignificant predictors of decreased lung functionup to age 8 years in a high-risk birth cohort. Whether low lung function is a cause and/or effect of RV wheezing illnesses has yet to be determined.
Pediatric asthma remains an important health concern as its prevalence remains at historically high levels1 despite current treatment. Studies evaluating the natural history of asthma have shown that initial asthma-like symptoms and loss in lung function occur early in life2. However, wheezing in infancy is a heterogeneous condition, and the long-term prognosis varies from complete recovery to persistent asthma with demonstrable abnormalities in lung function2. In addition, ongoing longitudinal studies have shown that deficits in lung function are established in school-aged children with persistent asthma and for the most part, are maintained both in magnitude and rate of further loss into adulthood2–4. Genetic and/or environmental factorsunderlie the development of asthma, and viral respiratory tract illnesses caused by respiratory syncytial virus (RSV)5 and rhinovirus (RV)6 in early life have been implicated as contributing to this outcome. However, it is not clear how these illnesses impact lung function in early life.
Reproducible and reliable measurement of lung function in early life is challenging. These challenges relate to developmental maturation and coordination as only children at least 5–6 years of age can be expected to reliably perform reproducible forced respiratory maneuvers by spirometry7. In addition to spirometric evaluations, recent interest has focused on the use of impulse oscillometry (IOS). Given its requirement for minimum cooperation, IOS is very suitable for use in young children. IOS has been used to measure mechanical properties of the respiratory system in children with asthma,8, 9 and has been successfully used in children as young as 2 years10. During IOS, an external pressure impulse signal is applied during tidal breathing. From the resultant flow, total respiratory impedance (Zrs) and its components respiratory resistance (Rrs) and reactance (Xrs) are calculated at various frequencies. IOS may provide additional information than that obtained from spirometry, such as functional assessment of small peripheral airways, and thus has been proposed as a more sensitive measure of abnormal pulmonary processes and airway obstruction11–13.
In a birth cohort of young children at high-risk for developing asthma and/or allergic diseases, we first examined whether these children could successfully perform IOS at an earlier age than spirometry, and if IOS indices correlated with specific spirometric parameters. We then prospectively explored the relationships among early life virus-specific wheezing, childhood lung function, and asthma.
Participants in this study are children enrolled in the Childhood Origin of ASThma (COAST) project at birth and have been followed up to the age of 8 years. Details about the study design and characteristics of its subjects have been previously published14, 15. Briefly, a total of 289 newborns were enrolled from November 1998 through May 2000 in the COAST study. Of these children, 285, 275, 259, and 238 were followed prospectively for 1, 3, 6 and 8 years, respectively. To qualify, at least one parent was required to have respiratory allergies (defined as one or more positive aeroallergen skin tests) and/or a history of physician-diagnosed asthma. The Human Subjects Committee of the University of Wisconsin approved the study, and informed consent was obtained from the parents. Assent was obtained from the children at age 8 years.
Nasopharyngeal mucus samples were collected during scheduled clinic visits (2, 4, 6, 9, 12, 24 and 36 mo) and during times of acute respiratory illnesses15. Parents notified a study coordinator when their child developed a runny nose, cough, or wheeze and a symptom scorecard was completed16. If the symptom score was 5 or greater, classified as a moderate to severe respiratory illness, a nasal lavage was performed and processed as previously described16 for the viral panel outlined under the viral methods below.
Nasal specimens were analyzed for respiratory viruses including RSV, RV, influenza types A and B, parainfluenza virus types 1–4, adenovirus, and enteroviruses using culture16. In addition, samples were also evaluated for RV RNA by seminested reverse transcriptase–polymerase chain reaction (RT-PCR)16, 17, and for the viruses listed above plus coronaviruses (OC143, NL63, and 0229), bocavirus, and metapneumoviruses by multiplex PCR (Respiratory MultiCode PLx Assay; EraGen Biosciences, Madison WI)18.
Allergen-specific IgE was measured at 1, 3 and 6 years of age for dust mite, Alternaria alternata, dog, cat, peanut, milk, egg, and soy, as previously described using a fluorescent enzyme immunoassay (FEIA)19. Allergen-specific IgE values of 0.35 kU/L (class I) or greater were considered positive. The presence of allergic sensitization at age 3 and 6 years was defined by having one or more positive values for allergen-specific IgE.
Spirometry and IOS were performed using the Jaeger MasterScreen system during scheduled annual visits at ages 4, 5, 6, 7 and 8 years. The post-bronchodilator spirometry test was performed at the annual visits starting at age 5 years if the child had reproducible pre-bronchodilator spirometry. The order of the lung function at every annual visit was: IOS, pre-bronchodilator and post-bronchodilator spirometry. The family was instructed to give the child their prescribed asthma medications but to hold albuterol and caffeinated food products for 6 hours prior to the annual visit. If the child was ill or taking albuterol for symptoms, the visit was rescheduled. Two puffs of albuterol given via metered dose inhaler and valved spacer were give 15 minutes prior to the spirometry. Criteria for preschool lung function published by Eigen et al20, similar to that used in CARE Network studies21, 22, were applied in this study (Electronic Table 1). These are similar to those recently recommended by the American Thoracic Society7 (Electronic Table 1). Ten percent of the studies performed in each year were over-read by a blinded reviewer for quality assurance purposes. Only tests that met the modified Eigen/ATS criteria were included.
Spirometric measurements include forced vital capacity (FVC), forced expiratory volume in one second (FEV1), forced vital capacity in 0.5 seconds, (FEV0.5), forced expiratory flow 25–75% (FEF25–75), and peak expiratory flow (PEF). FVC, FEV1, FEV0.5, and PEF were measured in liters; FEF25–75 was measured in liters/sec; and FEV1 and FVC were also expressed as percent predicted values (FEV1 PP and FVC PP)based on the Eigen criteria using family reported ethnicity for the child (Electronic Table 2)20. FEV0.5 was measured since young children often empty their lung volumes in less than one second7, 13.
IOS was attempted before spirometry in the cases where both procedures were performed at the same visit. Further details regarding the spirometry and IOS methods are available in the Electronic Supplement. The IOS indices collected were: resistance at 5 Hz (R5), resistance at 10 Hz (R10), the difference in resistance at 5 Hz and at 10 Hz (R5–R10), resistance at 20 Hz (R20), reactance at 5 Hz (×5) and area of reactance (AX) using criteria similar to that used in CARE Network studies21, 22 (Electronic Table 3). At least 10% of the IOS studies were over read by a blinded reviewer to ensure that tests recorded as acceptable did meet acceptability and reproducibility criteria for quality assurance purposes.
Atopic dermatitis during first three years of life was defined as described6, 15, 19. A wheezing respiratory illness during the first 3 years of life was defined as meeting one or more of the following criteria: (1) physiciandiagnosed wheezing at an office visit; (2) an illness for which the child was prescribed short- or long-acting b-agonists and/or controller medications; or (3) an illness given the following specific diagnoses: bronchiolitis, wheezing illness, reactive airway disease, asthma, or asthma exacerbation6. The severity of RV illnesses were further defined as follows: a severe wheezing RV illness was defined as a wheezing respiratory illness requiring treatment with oral steroids, less severe wheezing RV illness defined as a wheezing respiratory illness with no treatment with oral steroids, non-wheezing RV Illness was defined as a moderate to severe illness which was not a wheezing respiratory illness, and no RV illness was defined as no moderate to severe illness with RV. Race was self-reported by the family at birth. Children were diagnosed as having asthma at 6 and/or 8 years of age if they fulfilled one or more of the following criteria: Physician-diagnosed asthma (e.g. frequent albuterol use for coughing or wheezing episodes prescribed by physician more than 2 times/week or more than 2 nights/month, use of a prescribed daily controller medication, an implemented step-up plan with albuterol or ICS during illness as prescribed by a physician, or used prescribed oral prednisone for an asthma exacerbation). Four separate investigators, blinded to any prior histories regarding viral illnesses or of aeroallergen sensitization, independently evaluated each subject for the presence or absence of asthma based on the above criteria to ensure that the diagnosis was reproducible across multiple providers6.
Spirometric and IOS measurements were obtained from children at yearly visits from age 4 to age 8, with those at age 4 having a relatively low rate of completing maneuvers that met the quality control criteria specified above (24% for spirometry and 21% for IOS). As a result, only data from ages 5, 6, 7, and 8 years were used for analyses. The IOS measurement AX was log-transformed for analysis. A cross sectional analysis was performed at age 8 years. Mixed-effect linear regression models of lung function from childrenobtained atages 5 through 8 (pre-bronchodilator spirometry) and ages 6 through 8 years (post-bronchodilator spirometry) were used to assess associations between lung function measures and lung function and the history (occurrence, severity, and frequency) of viral wheezing illnesses, both overall and for individual ages, while accounting for the repeated outcome measurements over time. Longitudinal analyses were performed separately for each lung function parameter and adjusted for age, race, gender, height, weight, asthma, passive smoke exposure, age at earliest positive FEIA (1–2 years, 3–6 years, no positive FEIA 1–6 years); analyses of percent predicted values (based on age, race, gender, height, and weight) were adjusted for asthma, passive smoke exposure, and FEIA only. Associations between spirometric and demographic variables and successful completion of IOS at each age were assessed using Pearson's chi-square test. Success rates of IOS and spirometry were compared using McNemar's test for paired binary outcomes. A two-sided p-value of 0.05 was regarded as statistically significant. Analyses were performed using SAS version 9.1 (SAS Institute, Inc, Cary, NC) and R version 2.8.1.
A total of 289 children were enrolled in the COAST study; 238 (82%) children completed the follow-up visit at age 8 years. The children started performing spirometry and/or IOS at 4 years of age and these tests were subsequently done on a yearly basis. Overall, the demographic and atopic characteristics of children able to successfully perform IOS or spirometry at 8 years of age were similar to those that could not perform successfully (Table 1). Exceptions were that boys and children without a history of paternal allergy were less likely to successfully perform the maneuvers. At 4 years of age, 21% of children who attempted IOS had acceptable tests compared to 24% with successful spirometry (p=0.7). For ages 5, 6, 7, and 8 years, percentages of acceptable tests of IOS vs. spirometry were 58% vs. 57% (p=0.9), 74% vs. 70% (p=0.4), 79% vs. 88% (p=0.02), and 86% vs. 90% (p=0.3) (Figure 1). In addition, there was no association between the ability to successfully perform IOS and the ability to successfully perform spirometry at ages 5–8 years (data not shown).
In the 259 children with complete follow-up through age 6 years, 454 wheezing respiratory illnesses were documented during the first 3 years of life6. As previously reported, nasopharyngeal wash specimens were obtained during 442 (97%) of these wheezing illnesses. A viral etiology was identified in 398 (90%) of these specimens, and the viruses most commonly detected were RV (48%), RSV (21%), and multiple viruses (48/442=11%)6.
Children with a diagnosis of asthma at 6 or 8 years of age had significantly lower FEF25–75 (1.41 vs. 1.31, p=0.05) and FEV0.5/FVC (0.67 v. 0.64, p=0.01) compared to children without the diagnosis of asthma (Table 2). Post-bronchodilator FEF 25–75 was significantly lower in children who had a diagnosis of asthma than those that did not (p=0.05) (Electronic Table 4). No differences in IOS indices were seen between groups (data not shown). Neither age, race, gender, passive smoke exposure nor allergic sensitization modified the associations between asthma and lung function.
We next evaluated whether a history of wheezing in the first 3 years of life was associated with changes in lung function at age 6–8, and there were no significant relationships (data not shown). We then examined whether viral etiology of wheezing illnesses in the first 3 years impacted lung function at school age. At age 8, children with RV wheezing illnesses had significantly lower FEV1 (1.29 vs. 1.42, p=0.001), FEV1% (96 vs. 102, p=0.03), FEV0.5 (0.98 vs. 1.10, p=0.001), FEF25–75 (1.21 vs. 1.51, p<0.001), FEV1/FVC (0.82 vs. 0.85, p=0.009), and FEV0.5/FVC (0.62 vs. 0.66, p=0.02) compared to children without RV wheezing illnesses (Electronic Table 5). Similar findings were observed using a longitudinal model of lung function obtained from children at ages 5 through 8 years. Children with RV wheezing illnesses had significantly lower FEV1 (1.28 vs. 1.38, p=0.001), FEV1% (97 vs. 103, p=0.01), FEV0.5 (0.96 vs. 1.06, p<0.001), FEF25–75 (1.21 vs. 1.46, p<0.001), FEV1/FVC (0.84 vs. 0.87, p=0.01), and FEV0.5/FVC (0.63 vs. 0.67, p=0.008) compared to children who did not wheeze with RV (Table 3; Figure 2). Similarly, children with RV wheezing illnesses also had a larger R5–R10 difference (0.20 vs. 0.15, p<0.001), a more negative ×5 (0.41 vs. 0.35, p<0.001) and larger AX (3.2 vs. 2.62, p=0.004, Electronic Table 6). Significantly lower post-bronchodilator FEV1 (p=0.01), FEV0.5 (p=0.003), FEF 25–75 (p=0.01) (Table 4) but no differences in IOS indices (Electronic Table 7) were observed in children with a history of RV wheezing illnesses compared to children who did not wheeze with RV. Children with more frequent RV wheezing illnesses did not show significantly lower lung function than children with less frequent RV wheezing illnesses (Electronic Table 8). Both severe and less severe RV wheezing episodes were associated with significantly lower lung function compared to children with non-wheezing RV illnesses and no RV illnesses (Electronic Table 9). These findings persisted after controlling for age, race, gender, height, weight, passive smoke exposure, age at first occurrence of positive aeroallergen FEIA (ages 1–2 or 3–6 years).
In contrast to RV, children with RSV wheezing illnesses did not have significant differences in any of the measured spirometric or IOS indices when compared to children who did not wheeze with RSV (Table 3, electronic), and the same was true for wheezing illnesses caused by other viruses (data not shown).
This study investigated relationships between specific viral wheezing illnesses during the preschool years and lung function between ages 4–8 years in a cohort of children at high risk for developing asthma. The majority of subjects completed technically acceptable maneuvers by age 5. An RV wheezing illness during the first 3 years of life was associated with lower pulmonary function, and notably, this relationship did not hold true for wheezing illnesses caused by RSV or other respiratory viruses. These relationships were less pronounced but were still significantly different after administration of bronchodilator, and thus are not likely explained by increased airway tone alone. We previously reported that RV wheezing illnesses were strong predictors for asthma6; this study underscores and extends these findings by demonstrating that wheezing illnesses with RV and not with other viruses in the first few years are also associated with lower lung function. Children that experience early life viral wheezing episodes are a heterogeneous group with over half outgrowing their wheezing episodes by school age2. It is possible that children that have RV specific wheezing illnesses in early life may be at higher risk to develop asthma and lower lung function as they mature.
Lung function measurement in young children is endorsed by the National Asthma Education and Prevention Program guidelines,23 but is technically challenging. Impulse oscillometry requires minimum cooperation and therefore may have advantages for use in young children. However, success rates for IOS and spirometry were similar in our study in contrast to other studies where children as young as 2 years were able to perform IOS10, 24. This may be due to the fact that in our study spirometry and IOS were performed only once a year and with no further attempts at training the children between visits. Our findings suggest that both IOS and spirometry can be used in a complementary fashion in a clinical setting since 80% of children were able to successfully perform either IOS or spirometry by age 5, and the ability to complete one test was not associated with the ability to complete the other.
IOS may measure respiratory system properties, respiratory system resistance (Rrs) and reactance (Xrs), not directly assessed by spirometry. We observed that children who wheezed with RV had a larger R5–R10 difference and AX which may reflect increased resistance and/or heterogeneity of distal airways13, 25, 26. Children who wheezed with RV also had a more negative ×5 and larger AX compared to those who did not wheeze with RV, results that suggest abnormal small airways. Reactance at 5Hz, R5–10, and AX all may reflect mechanical properties of peripheral airways and their significant change after RV wheezing illnesses in early life suggest RV specific processes in small airways. It should be noted that no differences were found between children with asthma and those without using IOS; in contrast, spirometry was able to detect small differences between groups. This suggests that in our study participants, spirometry was a more sensitive measure of lung function than IOS.
We and others6, 27 have previously demonstrated that RV wheezing illnesses in early life are associated with a subsequent diagnosis of asthma. This study provides additional novel evidence that early RV wheezing illnesses are also related to lower lung function in childhood. The causality of this association is unknown. RSV is a recognized lower airway pathogen and it has also been associated with an increased risk of asthma, the prevalence of which appears to dissipate during the first decade5, 28, 29. Previous studies also have found a relationship between lower lung function and RSV wheezing illnesses30, 31 but these respiratory infections were severe enough to require the child to be hospitalized. Given its role as a lower airway pathogen, we anticipated that RSV illnesses would be more likely to be associated with reduced lung function. Therefore, we were intrigued to find that children who wheezed during early life with RV, as opposed to RSV, were those children who were significantly more likely to have lower lung function at school age. Along these lines, pathways by which RV infection could lead to airway remodeling have recently been identified32, 33. Also, infants born with poor antiviral responses are more prone to repetitive illness. Indeed, recent work has demonstrated that epithelial and/or mononuclear cell innate antiviral responses to infection with RV may be deficient in atopic asthmatic patients34, 35. This deficient immune response may lead to lower lung function after one RV infection. Our data did not show that children with repeated or more severe RV wheezing illnesses had lower lung function than those with less frequent or less severe RV wheezing illnesses. However, it is possible that our study lacked sufficient power to show these associations. Although we did not find evidence that RSV wheezing illnesses were associated with reduced lung function, few of our study participants had severe illnesses requiring hospitalization. It is possible that severe RSV illnesses could lead to significant reductions in lung function.
Unlike the study by Illi and colleagues36, which demonstrated reduced lung function in children with early allergic sensitization and allergen exposure, we did not find that allergic sensitization lead to greater lung function deficits than RV wheezing illnesses alone. However, allergen exposure was not measured in our study. An alternate explanation is that children who wheeze with RV may have congenitally lower lung function, and so RV wheezing illnesses serve only as a marker of antecedent abnormal lung physiology. Children who have lower lung function shortly after birth are more likely to have lower lung function as they age compared to normal children, but not persistent asthma2, 37. However, a study by Håland and colleagues demonstrated that children with lower lung function measured by tidal breathing flow-volume loops shortly after birth are more likely to have lower lung function at age 10 years38 and the diagnosis of asthma at 10 years of age39. Another recent study by van der Zalm40 demonstrates that increased total lung resistance measured at 2 months of age is associated with subsequent RV wheeze; however, the low viral detection rate of other non-RV viruses made it impossible to study an association between neonatal lung function and infection with other types of viruses.We cannot confirm these findings in the COAST study because infant pulmonary function tests were not performed.However, our study does provide unique assessment of numerous respiratory viruses including RV and RSV and their association with childhood lung function. Furthermore, Håland and colleagues39 found that lung function at 10 years of age was not was not affected by a history of at least one or three or more lower respiratory tract illnesses in the first 2 years of life after adjusting for lung function measured at birth. However, this result may have been different if the etiology of the infection was analyzed as was done in this study
Here we demonstrate in a large cohort of children at risk to develop asthma that lung function is reduced in children that wheeze with RV in early life but not with other viruses, and these significant reductions in lung function, while smaller, remain after bronchodilator administration. This association of early RV wheezing illnesses and lower lung function was found using two different methods of lung function measurements, spirometry and IOS, and the findings were consistent across multiple lung function parameters produced by each method. The association was best for the measures of FEV0.5 and FEF25–75 rather than FEV1. This is not an unexpected finding as young children often empty their lung volumes in less than one second7, 13 and FEV1 is often normal in children with asthma41. Other studies have also shown that FEF25–75 rather than FEV1 is often the first lung function measurement that is decreased in children with asthma compared to controls2, 13, 42. However, the children enrolled in COAST also are at high-risk to develop asthma and allergies and mainly Caucasian so these findings may not be generalizable to all children.
In conclusion, RV wheezing illnesses, but not wheezing illnesses caused by other respiratory viruses, were associated with lower lung function in early childhood. This finding, in combination with published data that wheezing with rhinovirus predicts future and persistent wheezing15, 43 and asthma6, suggests that recognizing early RV illnesses could be of prognostic significance. Additional studies confirming that infants that experiencing recurrent RV wheezing illnesses have normal lung function at birth and examining mechanisms by which RV infection in early life may lead to lower lung function in later childhood and beyond are essential. Furthermore, once these disease mechanisms are understood, additional studies could explorenovel interventions such as antiviral or immunosuppressant therapies to interrupt the progression from early childhood wheezing to asthma.
Supported by NIH grants R01 HL61879, P01 HL70831, and M01 RR03186
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Clinical Implications: These findingssuggest that recognizing early RV illnesses could be of prognostic significance. Whether low lung function is a cause and/or effect of RV wheezing illnesses has yet to be determined.