Abstract
Background
Recurrent wheezing, a common diagnosis after severe bronchiolitis, has multiple phenotypes of uncertain relation to childhood asthma.
Objective
Among infants hospitalized for bronchiolitis, we investigated the relation of three 2020 recurrent wheezing phenotypes by age 4 years to asthma by age 6 years.
Methods
In a 17-center cohort study of infants hospitalized with bronchiolitis, we investigated the National Heart, Lung, and Blood Institute (NHLBI) 2020–defined recurrent wheezing phenotype and 2 additional phenotypes based on this definition: multitrigger and severe. As a sensitivity analysis, we examined the NHLBI 2007 recurrent wheezing phenotype. We calculated the proportion of study subjects who developed asthma by age 6 years and used multivariable logistic regression to examine characteristics associated with the highest-risk 2020 phenotype.
Results
Of 921 infants, 632 (69%) developed NHLBI 2020 recurrent wheezing, 734 (80%) developed multitrigger wheezing, and 165 (18%) developed severe wheezing by age 4 years; in addition, 296 (32%) developed NHLBI 2007–defined recurrent wheezing by age 3 years. Of 862 children with sufficient data (94%), 239 (28%) developed asthma by age 6 years. The proportions of children who progressed to asthma were as follows: 33% of those with NHLBI 2020–defined wheezing, 33% of those with multitrigger wheezing, 54% of those with severe wheezing, and 52% of those with NHLBI 2007–defined recurrent wheezing. The children with the severe phenotype who developed asthma had the associated characteristics preterm birth, child eczema, maternal asthma, and non–respiratory syncytial virus infection.
Conclusion
Most infants with severe bronchiolitis developed the NHLBI 2020–defined recurrent wheezing phenotype by age 4 years. Depending on the phenotype, 33% to 54% will develop asthma by age 6 years. Future research will examine whether earlier treatment of high-risk phenotypes will improve wheezing symptoms and potentially prevent childhood asthma.
Key words: Bronchiolitis, recurrent wheezing, asthma, cohort study, infants
Introduction
Among infants who are hospitalized for bronchiolitis (ie, severe bronchiolitis), between 30% and 40% will develop recurrent wheezing by age 3 years1 and 30% will develop childhood asthma by age 6 years.2 Complicating the interpretation of these incidences are the multiple labels used for and evolving definitions (ie, phenotypes) of recurrent wheezing, including as a result of the National Heart, Lung, and Blood Institute (NHLBI) updating its 2007 recurrent wheezing definition in 2020. Moreover, there is uncertainty about how the different wheezing phenotypes are related to childhood asthma.3 To date, no studies have examined the relationship between different recurrent wheezing phenotypes among infants with a history of severe bronchiolitis and the association of these phenotypes with childhood asthma.
To address this knowledge gap, we analyzed data from a 17-center, prospective cohort study that enrolled 921 of 1016 infants hospitalized for bronchiolitis from 2011 to 2014 into a longitudinal cohort study.1 These infants were followed until age 6 years.
For this analysis, we used clinical data and quantitative PCR virology results from nasopharyngeal aspirates collected at hospitalization.
Results and discussion
Recurrent wheezing phenotypes
We investigated 3 recurrent wheezing phenotypes by age 4 years: (1) NHLBI 2020–defined (ie, ≥3 infection-only–associated wheezing episodes before age 4 years or 2 episodes in 1 year, no symptoms between episodes, and not taking daily asthma treatment)3; (2) multitrigger (NHLBI 2020 definition plus non–infection-associated wheezing)4; and (3) severe (multitrigger wheezing and ≥2 hospitalizations associated with different wheezing episodes [adapted from Belgrave et al5 to include children]). Infection-associated wheezing was identified for each breathing problem by asking families, “Do you think this breathing problem was caused, at least partly, by a cold or other acute respiratory infection?” Of 921 infants with severe bronchiolitis, 632 (69%) developed NHLBI 2020–defined recurrent wheezing, 734 (80%) had multitrigger wheezing, and 165 (18%) had the severe recurrent wheeze phenotype (Fig 1).
Fig 1.
Venn diagram of the 4 phenotypes of recurrent wheeze: NHLBI 2020–defined
281 (n = 632), multitrigger (n = 734), severe (n = 165), and NHLBI 2007–defined (n = 296).
As a sensitivity analysis, we also examined the more restrictive NHLBI 2007–specified definition of recurrent wheezing (ie, ≥4 episodes of a breathing problem lasting at least 1 day and affecting sleep or 2 episodes of breathing problem requiring corticosteroid use within 6 months by age 3 years).6 In this sensitivity analysis, 32% of children met the more restrictive NHLBI 2007 definition of recurrent wheezing (ie, by age 3 years). Furthermore, among children with the NHLBI 2007 phenotype, 39% also had the severe recurrent wheezing phenotype.
Revising the more restrictive NHLBI 2007 definition of recurrent wheezing (ie, ≥4 severe wheezing episodes by age 3 years)6 to a broader definition in 2020 (ie, ≥3 infection-related wheezing episodes by age 4 years)3 increased the prevalence of recurrent wheezing in a prospective multicenter cohort of infants hospitalized for bronchiolitis from 33% by age 3 years to 69% by age 4 years. The present results demonstrate that most children with severe bronchiolitis will develop 2020 NHLBI–defined recurrent wheezing, which equates to a 116% increase from the NHLBI 2007 definition.
Another change from the NHLBI 2007 guideline is the recommendation in 2020 to treat children with recurrent wheezing with 1 week of an inhaled corticosteroid (ICS) at the beginning of an acute respiratory infection for recurrent wheezing.3 Given the broader definition of recurrent wheezing in the NHLBI 2020 guideline and this new treatment recommendation, counseling families during a bronchiolitis hospitalization would help educate them about the diagnosis of recurrent wheezing and prepare them for these new NHLBI treatment recommendations (ie, using an ICS).
Progression from recurrent wheezing to childhood asthma
Although there is heterogeneity among the asthma definitions used in epidemiologic research, we defined asthma by age 6 years, on the basis of a previous analysis,7 as a clinical diagnosis of asthma with either asthma medication use or asthma symptoms during age 5 to 5.9 years by using data from biannual parent interviews.7 We calculated the positive predictive value (PPV) (with 95% CIs) of these 3 phenotypes for asthma by age 6 years.
Of 862 children with sufficient outcome data (94%), 239 (28%) developed asthma by age 6 years. The proportions of children with these 3 phenotypes by age 4 years who progressed to asthma by age 6 years (ie, PPV) were as follows: 33% (95% CI = 30%-37%) of those with NHLBI 2020–defined wheezing; 33% (95% CI = 29%-37%) of those with multitrigger wheezing, and 54% (95% CI = 46%-62%) of those with severe wheezing. In the sensitivity analysis using the NHLBI 2007 phenotype, 52% (95% CI = 46%-58%) developed asthma by age 6 years.
It is notable that among children with NHLBI 2007–defined recurrent wheezing, 52% progressed to asthma by age 6 years compared with 33% of children with 2020 NHLBI–defined recurrent wheezing. Thus, during a bronchiolitis hospitalization, further educating parents that many children will not develop asthma by age 6 years would be welcome news and may help prevent children from being unnecessarily labeled as having asthma.
The diagnosis and treatment (ie, with ICS) for children with recurrent wheezing using the NHLBI 2020 guideline is clear. More complex and uncertain is predicting, treating, and ultimately (we hope) preventing future wheezing and/or childhood asthma, especially among infants with severe bronchiolitis.8 When the NHLBI 2020 based definitions were used, only the severe recurrent wheeze group matched the PPV of the NHLBI 2007 definition for development of asthma by age 6 years (54% vs 52%). Indeed, the NHLBI 2007 definition identifies more children with recurrent wheezing (32% by age 3 years) at an earlier age than with the severe NHLBI 2020 phenotype (18% by age 4 years) and has an equivalent percentage who are diagnosed with asthma by age 6 years (52% vs 54%).
Severe wheezing phenotype
Because the NHLBI updated the definition of recurrent wheezing in 2020 and only the severe recurrent wheeze group matched the PPV of the NHLBI 2007 definition for development of asthma by age 6 years, we focused further analysis on the severe recurrent wheeze phenotype. Among children with this severe phenotype, we estimated odds ratios with 95% CIs by using logistic regression models to examine risk factors associated with asthma by age 6 years. Covariates in the multivariable model were selected a priori (eg, prematurity, child eczema, maternal asthma, and rhinovirus infection).1,2
Some characteristics of infants associated with development of the severe phenotype were child eczema, maternal asthma, and non–respiratory syncytial virus infection during the index hospitalization (specifically, rhinovirus infection) (Table I). In a multivariable model among children with the severe phenotype, those more likely to develop asthma by age 6 years similarly had the characteristics preterm birth, child eczema, maternal asthma, and non–respiratory syncytial virus infection (Table II). These 4 characteristics are similar to the risk factors identified in previous analyses1,2 and in the modified asthma predictive index.9
Table I.
Characteristics of children hospitalized for bronchiolitis during infancy by recurrent wheeze severity at age 4 years (N = 779)
| Characteristic | Severe wheezing (n=165 [21%]) | No severe wheezing (n = 614 [79%]) | P value∗ |
|---|---|---|---|
| Age at enrollment, no. (%) | .07 | ||
| <2 mo | 42 (25) | 201 (33) | |
| ≥2 mo | 123 (75) | 413 (67) | |
| Sex, no. (%) | .06 | ||
| Female | 57 (35) | 263 (43) | |
| Male | 108 (65) | 351 (57) | |
| Race/ethnicity, no. (%) | .02 | ||
| Non-Hispanic White | 62 (38) | 295 (48) | |
| Non-Hispanic Black | 41 (25) | 121 (20) | |
| Hispanic | 59 (36) | 170 (28) | |
| Other | 3 (2) | 28 (5) | |
| Preterm birth (32-37 wk), no. (%) | 36 (21) | 110 (18) | .25 |
| Primarily breast-fed from age 0 mo to 3 mo, no. (%) | 23 (14) | 115 (19) | .16 |
| Child history of eczema, no. (%) | 38 (23) | 73 (12) | <.001 |
| Ever attended day care, no. (%) | 44 (27) | 139 (23) | .28 |
| History of antibiotic use, no. (%) | 71 (44) | 286 (47) | .54 |
| Maternal history of asthma, no. (%) | 53 (32) | 108 (18) | <.001 |
| Intensive care unit admission at enrollment, no. (%) | 30 (18) | 95 (15) | .40 |
| Result of testing for respiratory syncytial virus, no. (%) | <.001 | ||
| Positive | 114 (69) | 530 (86) | |
| Negative | 51 (31) | 84 (14) | |
| Result of testing for rhinovirus, no. (%) | .003 | ||
| Positive | 46 (28) | 108 (18) | |
| Negative | 119 (72) | 506 (82) | |
| Specific IgE to aeroallergen or food, no. (%) | .43 | ||
| Yes | 28 (17) | 121 (20) | |
| No | 137 (83) | 493 (80) | |
| Blood eosinophil concentration, no. (%) | .65 | ||
| <4% | 127 (77) | 473 (77) | |
| ≥4% | 15 (9) | 64 (10) | |
| Missing | 23 (14) | 77 (13) |
Severe wheezing is defined as having multitrigger wheeze and 2 or more hospitalizations by age 4 years (n = 165). No severe wheezing included all other children (ie, those with multitrigger wheeze and fewer than 2 hospitalizations [n=471] and those without multitrigger wheeze [n = 143]). Boldface indicates statistically significant results.
P values were obtained by using the chi-square test for categoric variables or Wilcoxon rank sum test for continuous variables and exclude missing data.
Table II.
Among infants hospitalized for bronchiolitis with severe wheezing phenotype, unadjusted and adjusted models for asthma development by age 6 years (n = 162)
| Characteristics at enrollment | Unadjusted |
Adjusted |
||
|---|---|---|---|---|
| OR (95% CI) | P value | OR (95% CI) | P value | |
| Age at enrollment | ||||
| <2 mo | 0.65 (0.41-1.04) | .07 | 0.70 (0.43-1.12) | .14 |
| ≥2 mo | 1.00 (ref) | — | 1.00 (ref) | — |
| Sex | ||||
| Female | 1.00 (ref) | — | 1.00 (ref) | — |
| Male | 1.30 (0.71-2.41) | .40 | 0.98 (0.48-2.00) | .95 |
| Race/ethnicity | ||||
| Non-Hispanic White | 1.00 (ref) | — | 1.00 (ref) | — |
| Non-Hispanic Black | 2.04 (1.00-4.16) | .05 | 1.41 (0.71-2.82) | .33 |
| Hispanic | 1.74 (0.83-3.65) | .14 | 1.31 (0.64-2.71) | .46 |
| Preterm birth (32 to 37 wk) | 2.15 (1.36-3.38) | .001 | 2.38 (1.43-3.96) | .001 |
| Child history of eczema | 3.00 (1.41-6.34) | .004 | 2.62 (1.13-6.09) | .03 |
| Ever attended day care | 0.74 (0.46-1.20) | .22 | 0.68 (0.42-1.08) | .10 |
| Maternal history of asthma | 2.37 (1.34-4.17) | .003 | 1.92 (1.01-3.64) | .05 |
| Intensive care unit admission | 1.47 (0.77-2.82) | .24 | 1.44 (0.64-3.21) | .38 |
| Result of testing for respiratory syncytial virus | ||||
| Positive | 0.34 (0.15-0.74) | .006 | 0.44 (0.22-0.89) | .02 |
| Negative | 1.00 (ref) | — | 1.00 (ref) | — |
| Result of testing for rhinovirus | ||||
| Positive | 2.14 (0.85-5.40) | .11 | 2.12 (0.92-4.89) | .08 |
| Negative | 1.00 (ref) | — | 1.00 (ref) | — |
| Specific IgE to aeroallergen or food∗ | ||||
| Yes | 1.65 (0.77-3.53) | .20 | — | — |
| No | 1.00 (ref) | — | — | — |
| Blood eosinophil concentration | ||||
| <4% | 1.00 (ref) | — | — | — |
| ≥4% | 1.59 (0.57-4.40) | .38 | — | — |
All results were adjusted for potential clustering by index hospital. Boldface indicates statistically significant results.
OR, Odds ratio; ref, reference.
Serum sIgE to food or aeroallergen measured at the Phadia Immunology Reference Laboratory (Portage, Mich). Any test result that was positive for specific IgE to at least 1 of 5 foods (milk, egg, peanut, cashew, or walnut) defined as at least 0.35 kU/L or specific IgE to any of 112 components on the ImmunoCAP Immuno-solid-phase Allergen Chip from 51 allergen sources (foods, molds, trees, dust mite, cockroach, dog, etc) defined as at least 0.30 Immuno-solid-phase Allergen Chip (ISAC) standardized units (ISU-E).
Wheezing terminology
The different terminology currently used by families, clinicians, and researchers to describe wheezing in preschool age children (eg, wheeze, transient wheeze, wheezy bronchitis, reactive airways disease), may complicate communication.4 Having all stakeholders use consistent terminology (eg, recurrent wheeze) would improve communication and align better with treatment recommendations (ie, using an ICS for recurrent wheezing).
There are potential limitations to this analysis. First, these inferences may not be generalizable beyond children who have had severe bronchiolitis; however, bronchiolitis is the leading cause of infant hospitalizations in the United States.10 Second, it is possible that children without asthma by age 6 years were misclassified or may develop asthma at a later age. To address this potential limitation, we are following these children to age 9 years.
In summary, most infants with severe bronchiolitis developed the NHLBI 2020–defined recurrent wheezing phenotype by 4 years. Depending on the phenotype, 33% to 54% will develop asthma by 6 years. Further research is warranted to examine whether earlier treatment in high-risk groups—possibly geared toward atopy—improves symptoms and potentially prevents childhood asthma.
Clinical implications.
Among infants hospitalized for bronchiolitis, most developed recurrent wheezing by age 4 years. Depending on the recurrent wheezing phenotype, 33% to 54% progressed to asthma by age 6 years.
Acknowledgments
We thank the following principal investigators from the participating medical centers for the collection of patient samples and ongoing dedication to bronchiolitis research: Amy D. Thompson, MD (Alfred I. duPont Hospital for Children, Wilmington, Del); Federico R. Laham, MD, MS (Arnold Palmer Hospital for Children, Orlando, Fla); Jonathan M. Mansbach, MD, MPH (Boston Children's Hospital, Boston, Mass); Vincent J. Wang, MD, MHA, and Susan Wu, MD (Children's Hospital of Los Angeles, Los Angeles, Calif); Michelle B. Dunn, MD, and Jonathan M. Spergel, MD, PhD (Children's Hospital of Philadelphia, Philadelphia, Pa); Juan C. Celedón, MD, DrPH (Children's Hospital of Pittsburgh, Pittsburgh, Pa); Michael R. Gomez, MD, MS-HCA, and Nancy R. Inhofe, MD (Children's Hospital at St. Francis, Tulsa, Okla); Brian M. Pate, MD, and Henry T. Puls, MD (Children's Mercy Hospital and Clinics, Kansas City, Mo); Stephen J. Teach, MD, MPH (Children's National Medical Center, Washington, DC); Stephen C. Porter, MD, MSc, MPH, and Richard T. Strait, MD (Cincinnati Children's Hospital and Medical Center, Cincinnati, Ohio); Ilana Y. Waynik, MD (Connecticut Children's Medical Center, Hartford, Conn); Sujit S. Iyer, MD (Dell Children's Medical Center of Central Texas, Austin, Texas); Ari R. Cohen, MD, Margaret Samuels-Kalow, MD, MPhil, MSHP, and Wayne G. Shreffler, MD, PhD (Massachusetts General Hospital, Boston, Mass); Michelle D. Stevenson, MD, MS (Norton Children’s Hospital and the University of Louisville, Louisville, Ky); Cindy S. Bauer, MD, and Anne K. Beasley, MD (Phoenix Children's Hospital, Phoenix, Ariz); Markus Boos, MD, PhD, and Thida Ong, MD (Seattle Children's Hospital, Seattle, Wash); and Charles G. Macias, MD, MPH, and Sarah Meskill, MD (Texas Children's Hospital, Houston, Texas).
Footnotes
Supported by the National Institute of Allergy and Infectious Diseases (grants U01 AI-087881, R01 AI-114552, and R01 AI-127507 [to J.M.M., K.H., A.F.S., and C.A.C.]) and the Office of the Director at the National Institutes of Health (grant UG3/UH3 OD-023253 [to J.M.M., K.H., A.F.S., and C.A.C.]). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.
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