Introduction

Bronchiolitis is the most common seasonal viral respiratory disorder and the leading cause of hospital admission due to viral infection in the first 12 months of life [1–4]. Respiratory syncytial virus (RSV) represents the most common cause of bronchiolitis, followed by other viruses, such as rhinovirus, influenza, or metapneumovirus [1,3,4]. It is well-established that premature infants and those with bronchopulmonary dysplasia (BPD) or congenital heart disease (CHD) are at high-risk for severe bronchiolitis requiring hospital admission during epidemic season [5–7]. Recently, D. Verhoeven notes that although some of the morbidity associated with RSV in neonates is due to immunological maturation, the rapid development of the immune system right after birth suggests that each age group of infants may respond to the virus in different ways [8]. Infants with chronic conditions, such as Down syndrome, congenital malformations, especially pulmonary and airway anomalies, cystic fibrosis, and neuromuscular diseases, may also be associated with an increased vulnerability to severe bronchiolitis [9]. However, a recent systematic review has highlighted the need for large studies to better identify, update, and estimate risk factors associated with hospital admission for bronchiolitis, especially those including infants with rare underlying medical disorders in a real-life setting [5–7,9]. In the area of innovative therapies for RSV infection bronchiolitis, it is also crucial to have solid data on risk factors and susceptible populations for an optimal use of new resources.

The aims of the present study were to 1) perform a nationwide analysis of the hospitalization rate for bronchiolitis in infants over four consecutive seasons using nationwide hospital discharge data, and 2) identify independent risk factors for bronchiolitis hospitalization in this large cohort.

Methods

The present study was a retrospective cohort study over four consecutive bronchiolitis seasons.

Study population

All infants discharged alive from maternity wards from January 1, 2008, to December 31, 2013, in metropolitan France were initially included in the study. Infants discharged with missing birth weight or discharged after March 31, 2013, were excluded.

The study population was structured into four consecutive cohorts at risk of bronchiolitis during the seasons of 2009–2010 to 2012–2013 (Fig 1). The bronchiolitis season usually lasts from early October to late March of the following year in France [3]. Accordingly, each cohort was composed of all infants <2 years of age on October 1, as well as all newborns discharged until March 31. In theory, all infants could be consecutively exposed to 2 or 3 seasons depending on their birthdate in April to September or October to March, respectively. Because hospital discharge data were left-truncated on January 1, 2008 and right-truncated on March 31, 2013, infants could be followed at different ages in 1, 2, or 3 consecutive cohorts. In particular, infants older than 12 months at October 1, 2009, and infants born after March 31, 2012, were followed over a single season, while infants born during the season of 2009–2010 or 2010–2011 were followed at different ages in three consecutive cohorts.

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Fig 1. Flow chart of sample selection.

Abbreviations: RSV, respiratory syncytial virus.

https://doi.org/10.1371/journal.pone.0229766.g001

Results

Characteristics of the study population

The study population comprised 3,884,791 infants (Fig 1) after excluding 13,885 (0.31%) infants with missing birth weight. Boys and girls were almost evenly distributed across bronchiolitis seasons (Table 1).

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Table 1. Characteristics of infants and children <2 years at-risk over four consecutive bronchiolitis seasons (N = 7,211,571).

https://doi.org/10.1371/journal.pone.0229766.t001

Preterm infants accounted for about 6.0% of live-born infants on October 1 each year: 0.1% extremely preterm, 0.8% very preterm, and 5.1% moderate preterm. Infants with ≥1 diagnosis out of nineteen chronic conditions under study represented approximately 2.0% of the study population. Approximately 0.2% of live-born infants on October 1 of each year had BPD and HS–CHD. Hemodynamically non-significant CHD and other underlying medical disorders were present in 0.6% and 1.1% of infants, respectively. A history of bronchiolitis and LRTI, respectively, was noted in 2.0% and 0.4% of the infants on October 1. Maternal smoking during pregnancy was reported for 2.1% of the infants.

Bronchiolitis hospitalization rates

Hospitalization rates for bronchiolitis varied significantly between seasons, with a higher rate in 2012–2013 (1.48%) compared with 2010–2011 (1.26%; p < .001; Table 2).

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Table 2. Hospital admissions for bronchiolitis, severe bronchiolitis, RSV infection, and acute LRTI over four consecutive bronchiolitis seasons (N = 7,211,571).

https://doi.org/10.1371/journal.pone.0229766.t002

Similar seasonal trends were found when strengthening the definition of bronchiolitis to severe bronchiolitis or RSV infection (mostly (96.3%) recorded as bronchiolitis due to RSV). A seasonal peak was observed in 2009–2010 when broadening the definition of bronchiolitis to all 121,969 admissions for acute LRTI.

Risk factors for bronchiolitis hospitalization

All potential risk factors were associated with the risk for bronchiolitis hospitalization by season (S2 Table) and integrated along season into the multivariate analysis (Table 3).

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Table 3. Risk factors of hospital admission for bronchiolitis–multivariate analyses of 99,494 hospital admissions for bronchiolitis (N = 7,211,571).

https://doi.org/10.1371/journal.pone.0229766.t003

All risk factors except omphalocele were independent risk factors for hospital admission for bronchiolitis. Boys had a 27% increased risk of admission for bronchiolitis compared with girls. Multiple birth, lower GA, a lower birth weight for GA, and birth during or close to the onset of the bronchiolitis season were associated with an increased risk of admission for bronchiolitis. Tobacco exposure during pregnancy, but also maternal cardiovascular and respiratory diseases, and maternal diabetes mellitus were associated with an increased risk of bronchiolitis hospitalization. A history of bronchiolitis and/or LRTI was associated with an increased risk of bronchiolitis hospitalization.

Regarding chronic conditions under study, an increased risk of hospitalization for bronchiolitis was observed for (by decreasing order of adjusted OR): solid organ and stem cell transplants, muscular dystrophy, cardiomyopathy, HS-CHD, congenital lung disease and/or bronchial abnormalities, Down syndrome, diaphragmatic hernia, congenital tracheoesophageal fistula, pulmonary hypertension, chromosomal abnormalities other than Down syndrome, hemodynamically non-significant CHD, cystic fibrosis, HIV infection, congenital abnormalities of the nervous system, cleft palate, cardiovascular disease occurring during the perinatal period, and BPD (Table 3). Fig 2 displays number of cases with underlying medical disorders at risk per season (panel A) and related adjusted OR depending on case definition (panel B).

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Fig 2.

Panel A: Number of cases with underlying medical disorders per season- Panel B: Underlying medical disorders as risk factors of hospital admission for bronchiolitis, severe bronchiolitis, RSV infection and acute LRTI (respective OR). Abbreviations: CHD: congenital heart disease; HS: hemodynamically significant; LRTI: lower respiratory tract infection; NS: nervous system (1) Congenital lung disease and/or bronchial abnormalities (2) Other than Down syndrome.

https://doi.org/10.1371/journal.pone.0229766.g002

All associations with bronchiolitis were also found when sensitivity analyses were performed on case definition using hospitalization risk for severe bronchiolitis, RSV infection, and acute LRTI (Fig 2, panel B and S3 Table). The strength of the association with age at season onset decreased significantly with a broadened definition from RSV infection to acute LRTI. Conversely, the strength of the association of extremely preterm, BPD, and HS–CHD increased significantly with a broadened definition of bronchiolitis. Finally, all associations with bronchiolitis were also found when infants and children were selected at first bronchiolitis season exposure (S4 Table).

Discussion

This study is the first assessing the hospitalization rates for bronchiolitis in a recent, large, nationwide cohort of all newborns and infants <2 years of age at risk over four bronchiolitis seasons. Our results show that hospitalization rates range between 1 and 1.5% (from 1.26% to 1.48%), but are significantly higher in infants with well-known risk factors such as prematurity, BPD, and HS–CHD, and those with a large range of underlying medical disorders. The risk assessment of these various medical disorders in a nationwide study represents one of the major interests of our study, in particular, with regard to treatment strategies.

The present study identifies a large range of medical disorders that are independent risk factors for bronchiolitis hospitalization (Table 3). Besides BPD and HS–CHD, these disorders comprise other cardiothoracic diseases, congenital malformations, neuromuscular diseases, chromosomal abnormalities, HIV infection, and solid organ or stem cell transplants. Although the frequency of each disorder is low, the total number of affected infants is about six-fold that of BPD and HS–CHD at each season onset (Table 1). Moreover, in most cases, the ORs for bronchiolitis hospitalization in these diseases exceed those for BPD (Table 3).

Pulmonary hypertension, congenital lung disease and/or bronchial abnormalities, and congenital tracheoesophageal fistula are conditions that are associated with a high respiratory morbidity at any age. It is thus easily understandable that these conditions are associated with an increased risk of bronchiolitis hospitalization. These infants have a reduced respiratory reserve, which explains the increased risk of hypoxemia in case of respiratory injury or aggression. RSV mortality has been noted to be higher in infants with cyanotic cardiac lesions and pulmonary hypertension than in healthy peers [21]. In pulmonary hypertension, relatively unoxygenated blood bypasses the lung and enters the systemic circulation [21]. Thus, hypoxia is already present in infants with cyanotic heart defects and/or pulmonary hypertension before RSV infection [21]. As a result, these infants are likely to have hypoxia during acute LRTI. Cystic fibrosis has been found to be a significant risk factor for RSV infection hospitalization in numerous studies [9,16]. We have recently shown that infants with congenital diaphragmatic hernia repair present diaphragmatic weakness and dysfunction during the first 2 years of life, which normalizes by 5 to 6 years of age [22]. This respiratory muscle dysfunction underlies the respiratory vulnerability of these infants during the first 2 years of life. Conversely, omphalocele was not identified as a risk factor for bronchiolitis hospitalization. Differences in the abdominal size defect and the consequent neonatal respiratory morbidity may explain why this diagnosis did not emerge as a risk factor in the present study.

Respiratory muscles are rarely spared in neuromuscular diseases. Respiratory muscle weakness and/or dysfunction may explain the increased risk of respiratory failure during acute LRTI in infants with neuromuscular disorders. Muscular dystrophy was indeed associated with a four–fold increased risk for bronchiolitis hospitalization (Table 3).

Congenital malformations of the nervous system were also associated with an increased risk for bronchiolitis hospitalization. Similar findings have been observed in other studies [9,16]. In a nationwide study in Denmark, encephalocele, spina bifida, and malformations of the spinal cord, as well as cerebral palsy, were identified as risk factors for RSV infection hospitalization [16]. Despite the fact that these diseases do not directly affect the cardiorespiratory system, ineffective cough and breathing, sleep-disordered breathing, and false passages may predispose these infants to an increased risk of bronchiolitis hospitalization.

Numerous worldwide studies have demonstrated that infants with Down syndrome are at increased risk of severe bronchiolitis and resultant morbidity, independent of concomitant CHD [9]. Infants with Down syndrome are predisposed to upper airway obstruction and obstructive sleep apnea due to altered craniofacial anatomy with midfacial and mandibular hypoplasia, glossoptosis with relative macroglossia, frequent adenotonsillar hypertrophy, muscle hypotonia with an increased prevalence of pharyngo-laryngomalacia, and subglottic and/or tracheal stenosis [23]. These anatomical predisposing factors for obstructive sleep apnea are aggravated by obesity, hypothyroidism, and gastroesophageal reflux disease [23]. Infections are associated with an increased morbidity due to immune dysfunction. All these factors explain why Down syndrome was associated with a three-fold increased risk for bronchiolitis hospitalization (Table 3).

Any type of congenital or acquired immunodepression has been shown to be associated with an increased risk for bronchiolitis hospitalization. In our study, infants with solid organ transplant or stem cell transplant had the highest OR for bronchiolitis hospitalization (Table 3). Improvements in the treatment of HIV infection may explain why this condition is a less serious risk factor for bronchiolitis hospitalization.

Regarding the conditions discussed previously, recurrent or prolonged hospital visits expose these infants to a nosocomial risk of microbiologic infection, in particular, bronchiolitis, during the winter season. This may explain, in part, the increased risk of bronchiolitis hospitalization in infants with disorders that do not affect the cardiorespiratory or immune system, such as malformations of the urinary system or the gastrointestinal tract [16]. The risk of RSV infection is a major argument for restricting hospital visits during the bronchiolitis season in these vulnerable infants.

Overall, bronchiolitis hospitalization rates found in this nationwide study in France were comparable to those observed in other West European countries [24] as well as some well-recognized risk factors for bronchiolitis hospitalization, such as male sex, multiple birth, prematurity, growth restriction, maternal smoking, and age at the onset of the RSV season [5,25,26]. BPD and HS–CHD, representing about 0.20 and 0.17% of the total population exposed each season, respectively, were also confirmed as significant risk factors for bronchiolitis hospitalization, supporting the validity of preventive strategies [6,7,27–29].

Our study has both strengths and limitations. The study is based on a nationwide sample of hospital births retrieved from the French National Hospital Discharge database, representing more than 95% of all births in France from 2008–2013 [10]. However, because of left-truncation of hospital discharge data, we could not identify hospital births before January 1, 2008, and therefore children aged 22 to 24 months at risk during the season 2009–2010. These children should represent less than 10% of all infants (Table 1) and had the lowest adjusted risk of hospitalization for bronchiolitis (Table 3) suggesting that the raw hospitalization rate for bronchiolitis may be overestimated during the season of 2009–2010 (Table 2). Also, risk factors and outcomes were identified from administrative records and may have introduced misclassification bias. Several validation studies conducted in teaching hospitals suggest that risk factors and bronchiolitis hospitalizations are correctly recorded in the French Hospital Discharge database [12,19,20]. At the national level, we identified several administrative recording problems for perinatal care that concerned a minority of hospitals and greatly improved over the study period: multiple births with the same anonymous identifier (0.79%), missing data on birth weight (0.31%), or GA (11.9%). In the main analysis, multiple births with the same anonymous identifier and infants with missing birth weight were excluded (Fig 1), and GA was imputed for missing data. Similar results were found in a complete-case analysis after excluding infants with missing data on GA. Regarding outcomes, RSV testing is not recommended in routine practice in France as in other high-income countries [19,30,31]. Reassuringly, we found that all associations with bronchiolitis hospitalization were similarly identified in sensitivity analyses with case definitions that were either more specific (severe bronchiolitis or RSV infection) or were more sensitive (acute LRTI). Moreover, our results are globally comparable to those of the nation-wide study of RSV-hospitalization in Denmark. Interestingly, we found that the influenza pandemic (H1N1) was associated with an increased risk of hospital admission in 2009–2010 for acute LRTI that did not affect other risk factors. Also, a history of bronchiolitis was strongly associated with the risk for bronchiolitis hospitalization suggesting an individual susceptibility to bronchiolitis. Finally, this is a retrospective cohort study and causation cannot be claimed.

Conclusions

This large nationwide study confirms a list of eighteen chronic conditions that are independent risk factors for bronchiolitis hospitalization and represent approximately 2.0% of live-borns. Recognition of these disorders besides prematurity, BPD, and HS–CHD as priority targets for preventative and curative treatment strategies is warranted. Indeed, preventative and curative therapeutic options are becoming available for RSV infection and bronchiolitis. Within a global health perspective, information on updated risk factors and susceptible populations is necessary for an optimal use of new resources.

Supporting information

Acknowledgments

The authors acknowledge the contribution of Sylvain Baillot, MSc, of Translational Health Economics (THEN). They would like to thank the French Scientific and Medical Information AbbVie Team for the literature search and Brigitte Bourdillat, PhD, for support in writing the manuscript.