Bronchiolitis is the leading cause for hospitalization in infants in developed countries. In the United States, up to 3% of infants are hospitalized yearly for bronchiolitis.1 Children <6 months of age are at the highest risk for bronchiolitis hospitalization. Respiratory syncytial virus (RSV) is the most common cause of hospitalized bronchiolitis, followed by rhinoviruses. Although data are limited, up to 11% of the children hospitalized for bronchiolitis have a relapse event during the first weeks after hospital discharge; these relapses lead to the further use of healthcare services, additional treatments and rehospitalizations.2,3 Previously, patient and clinical characteristics such as male sex, age <2 months, family history of asthma, shorter hospital length of stay and RSV/rhinovirus coinfection have been associated with an increased risk for bronchiolitis relapse.2,3 There are, however, limited data outside the United States on bronchiolitis relapse rates or characteristics of the children with relapse.
MATERIALS AND METHODS
As part of the Multicenter Airway Research Collaboration, a program of the Emergency Medicine Network (www.emnet-usa.org), this prospective, multicenter cohort study was conducted during the 2008 to 2010 winter seasons. The study was performed in the Departments of Pediatrics of Turku, Tampere and Kuopio University Hospitals in Finland. As in its U.S. counterpart study,4 a standardized protocol was used to enroll a target number of consecutive patients from the inpatient wards and the intensive care unit. Inclusion criteria were an attending physician’s diagnosis of bronchiolitis, informed consent from the guardian and age <2 years. The exclusion criteria were previous enrollment, or transfer to a participating hospital >48 hours after the original admission time. The institutional review board of Turku University Hospital approved the study and covered all 3 participating hospitals.
At enrollment, investigators conducted a structured interview on patients’ demographic and clinical characteristics.4 Medical records were used to collect clinical data from the prehospitalization evaluation as well as the hospitalization course, including vital signs and medical management. Follow-up data were collected by telephone interviews conducted 2 weeks after hospital discharge. The interview included questions regarding any unscheduled visits, follow-up visits and hospital readmissions since discharge. Data were manually reviewed at the Emergency Medicine Network Coordinating Center, and site investigators were queried about missing or discrepant data. Nasopharyngeal aspirates were collected during enrollment using a standardized protocol4 and stored at –80°C until analyzed at Baylor College of Medicine. Polymerase chain reaction assays were used for the detection of RSV types A and B; rhinovirus; parainfluenza virus types 1, 2 and 3; influenza virus types A and B and 2009 novel H1N1; human metapneumovirus; coronaviruses NL-63, HKU1, OC43 and 229E; enteroviruses, adenovirus, Mycoplasma pneumoniae and Bordetella pertussis as described previously.2,4
Similar to the U.S. counterpart study,2 we identified children with bronchiolitis relapse during the 2 weeks after hospital discharge using a previously validated classification method.3 Relapse was defined as either (1) an urgent (unscheduled) bronchiolitis visit or (2) routine check-up, follow-up visit or visit for another health problem during which changes to the child’s bronchiolitis medications were made (eg, adding bronchodilator or corticosteroid). All analyses were performed using Stata 14.1 (Stata Corp, College Station, TX). Data are presented as proportions or medians with interquartile ranges (IQRs). The associations between subject characteristics and bronchiolitis relapse were tested using χ2, Fisher exact test and Wilcoxon-Mann-Whitney U test, as appropriate. All P values were 2-tailed, with P < 0.05 considered statistically significant.
We enrolled 408 children who were hospitalized for bronchiolitis at 1 of 3 Finnish hospitals. Of them, 391 (96%) children completed the follow-up telephone interview after discharge. Bronchiolitis relapse was identified in 22 (6%; 95% confidence interval: 4%–8%) children. Among relapse cases, 11 (50%) children had an urgent visit after the discharge and 11 had a nonurgent visit at which changes to a child’s bronchiolitis medications were made. Eight (36%) of the 22 children were rehospitalized.
Median time to relapse was 2 (IQR, 1–7) days. Children’s demographic and clinical characteristics, stratified by relapse status, are shown in Table 1. Relapse was more often documented in children admitted to the hospital C (P = 0.01) and occurred more often in males (P = 0.04). Maternal smoking during pregnancy and tobacco smoke exposure in the home were also associated with relapse (P = 0.008 and P = 0.02, respectively). Moderate-to-severe retractions were less often documented in children who relapsed (P = 0.03). The median age in children with relapse was 7.6 (IQR, 3.4–14.9) months and in children without relapse 8.0 (IQR, 3.2–14.8) months (P = 0.88). Relapse was not significantly associated with family history of asthma (P = 0.78), nor were history of wheezing (P = 0.08) or eczema (P = 0.26). Clinical presentation (other than severity of retractions) and hospital length of stay were not associated with bronchiolitis relapse (all P > 0.05). Likewise, RSV or rhinovirus etiology of bronchiolitis was not associated with relapse (P = 0.82 for RSV and P = 0.65 for rhinovirus). There were only 2 RSV/rhinovirus coinfections and neither child experienced relapse.
In this prospective multicenter study, we report that the bronchiolitis relapse rate was 6% among Finnish children hospitalized for bronchiolitis. In its large counterpart multicenter prospective cohort study conducted in 16 U.S. centers, using a similar protocol and involving 1836 children, a similar relapse rate of 8% after bronchiolitis hospitalization was reported.2 Similarly, a relapse rate of 11% was documented in a prospective multicenter study involving 722 U.S. children discharged from the emergency department with bronchiolitis.3 In a retrospective single-center study of 555 U.S. children hospitalized for bronchiolitis, 4% had rehospitalization.5 These relatively minor differences in relapse rates (4%–11%) may be explained by different study populations, settings, definitions used and differences in healthcare systems. In the current study (6%) and the U.S. counterpart study (8%), the bronchiolitis relapse was defined similarly, with evidence of clinical worsening or prolonging of the bronchiolitis symptoms during the 2 weeks after hospital discharge.
In this Finnish cohort, children with bronchiolitis relapse were more often males and exposed to maternal smoking during pregnancy or to tobacco smoke in the home. Consistent with our observations, in the emergency department-based cohort study, male sex was a risk factor for an unscheduled visit after discharge with bronchiolitis.3 Some studies have also indicated that boys may be at a higher risk for severe RSV lower respiratory tract infection.6,7 Genetic factors and differences in the development of airways have been suggested to explain the possible sex differences in susceptibility to respiratory infections.1 Additionally, although data are inconsistent, both prenatal and postnatal smoke exposure have been linked to an increased risk for bronchiolitis hospitalization,7,8 and similar mechanisms, such as modified airway inflammation, could lead to the increased risk of relapse. Interestingly, in the U.S. counterpart cohort, sex or smoke exposure was not associated with relapse.2 These apparent discrepancies may be explained by the different patient populations with different genetic background and possible differences in viral etiology of bronchiolitis, such as the predominance of rhinovirus in hospitalized bronchiolitis in Finland (30%–32%)9,10 when compared with the United States (up to 26%).1,4 Our results suggest that male sex and exposure to smoke may predispose to bronchiolitis relapse in certain populations.
Children with relapse also had less severe retractions at the primary hospitalization, which may indicate that they were at an earlier stage of the disease. Other clinical features such as oxygen saturation were not associated with relapse. In a previous study, children who did not require supplemental oxygen were at higher risk for readmission after bronchiolitis hospitalization.5 These findings suggest that the parents of the children whose clinical presentation at primary hospitalization is less severe should be informed of the risk and signs of relapse as they may be progressing in their disease. Several other potential risk factors for relapse (eg, family history of asthma, history of wheezing or eczema, or shorter duration of hospitalization) were not associated with bronchiolitis relapse.
Parallel to previous studies, RSV was the most common virus detected in hospitalized bronchiolitis, followed by rhinovirus.1,4 Neither RSV nor rhinovirus etiology was associated with relapse. However, in the larger U.S. counterpart study, RSV/rhinovirus coinfection was associated with increased risk for bronchiolitis relapse, while there were no differences in the likelihood of relapse in children with a sole RSV infection when compared with children with a sole rhinovirus infection.2 In the current study, there were only 2 children with RSV/rhinovirus coinfection and neither led to relapse. Because of the low number of coinfections, no further conclusions could be made on the role they play in relapse.
Because there were only 22 relapse cases, we were not able to perform multivariable analyses on risk factors for bronchiolitis relapse. However, the relapse rate in this Finnish cohort was similar to that found in its U.S. counterpart study, and most findings were consistent with those reported in the larger U.S. study.
In conclusion, bronchiolitis relapse was identified in 6% of children shortly after hospital discharge in this Finnish multicenter cohort study. Relapse occurred more often in males and in children exposed to tobacco smoke.
1. Meissner HCViral bronchiolitis
in children. N Engl J Med. 2016;374:62–72.
2. Hasegawa K, Mansbach JM, Teach SJ, et alMulticenter study of viral etiology and relapse
in hospitalized children with bronchiolitis
. Pediatr Infect Dis J. 2014;33:809–813.
3. Norwood A, Mansbach JM, Clark S, et alProspective multicenter study of bronchiolitis
: predictors of an unscheduled visit after discharge from the emergency department. Acad Emerg Med. 2010;17:376–382.
4. Mansbach JM, Piedra PA, Teach SJ, et alMARC-30 Investigators. Prospective multicenter study of viral etiology and hospital length of stay in children with severe bronchiolitis
. Arch Pediatr Adolesc Med. 2012;166:700–706.
5. Kemper AR, Kennedy EJ, Dechert RE, et alHospital readmission for bronchiolitis
. Clin Pediatr (Phila). 2005;44:509–513.
6. Stockman LJ, Curns AT, Anderson LJ, et alRespiratory syncytial virus-associated hospitalizations among infants and young children in the United States, 1997-2006. Pediatr Infect Dis J. 2012;31:5–9.
7. Simoes EAEnvironmental and demographic risk factors for respiratory syncytial virus
lower respiratory tract disease. J Pediatr. 2003;143(5 suppl):S118–S126.
8. Lanari M, Vandini S, Adorni F, et alStudy Group of Italian Society of Neonatology on Risk Factors for RSV Hospitalization. Prenatal tobacco smoke exposure increases hospitalizations for bronchiolitis
in infants. Respir Res. 2015;16:152.
9. Jartti T, Lehtinen P, Vuorinen T, et alBronchiolitis: age and previous wheezing episodes are linked to viral etiology and atopic characteristics. Pediatr Infect Dis J. 2009;28:311–317.
10. Jartti T, Aakula M, Mansbach JM, et alHospital length-of-stay is associated with rhinovirus
etiology of bronchiolitis
. Pediatr Infect Dis J. 2014;33:829–834.