key: cord-0010109-ufgxw9cb authors: Amat, Flore; Plantard, Chloé; Mulliez, Aurélien; Petit, Isabelle; Rochette, Emmanuelle; Verdan, Matthieu; Henquell, Cécile; Labbé, Guillaume; Heraud, Marie Christine; Evrard, Bertrand; Labbé, André title: RSV‐hRV co‐infection is a risk factor for recurrent bronchial obstruction and early sensitization 3 years after bronchiolitis date: 2018-02-15 journal: J Med Virol DOI: 10.1002/jmv.25037 sha: f4b662dc003d0b09c0698b6362460ef8745173d0 doc_id: 10109 cord_uid: ufgxw9cb To assess risk factors of recurrent bronchial obstruction and allergic sensitization 3 years after an episode of acute bronchiolitis, whether after ambulatory care treatment or hospitalization. A monocentric prospective longitudinal study including infants aged under 1 year with acute bronchiolitis was performed, with clinical (severity score), biological (serum Krebs von den Lungen 6 antigen), and viral (14 virus by naso‐pharyngeal suction detection) assessments. Follow‐up included a quaterly telephone interview, and a final clinical examination at 3 years. Biological markers of atopy were also measured in peripheral blood, including specific IgEs towards aero‐ and food allergens. Complete data were available for 154 children. 46.8% of them had recurrent wheezing (RW). No difference was found according to initial severity, care at home or in the hospital, respiratory virus involved, or existence of co‐infection. A familial history of atopy was identified as a risk factor for recurrent bronchial obstruction (60% for RW infants versus 39%, P = 0.02), as living in an apartment (35% versus 15%, P = 0.002). 18.6% of the infants were sensitized, with 48.1% of them sensitized to aeroallergens and 81.5% to food allergens. Multivariate analysis confirmed that a familial history of atopy (P = 0.02) and initial co‐infection RSV‐hRV (P = 0.02) were correlated with the risk of sensitization to aeroallergens at 3 years. Familial history of atopy and RSV‐hRV co‐infection are risk factors for recurrent bronchial obstruction and sensitization. To assess risk factors of recurrent bronchial obstruction and allergic sensitization 3 years after an episode of acute bronchiolitis, whether after ambulatory care treatment or hospitalization. A monocentric prospective longitudinal study including infants aged under 1 year with acute bronchiolitis was performed, with clinical (severity score), biological (serum Krebs von den Lungen 6 antigen), and viral (14 virus by nasopharyngeal suction detection) assessments. Follow-up included a quaterly telephone interview, and a final clinical examination at 3 years. Biological markers of atopy were also measured in peripheral blood, including specific IgEs towards aero-and food allergens. Complete data were available for 154 children. 46.8% of them had recurrent wheezing (RW). No difference was found according to initial severity, care at home or in the hospital, respiratory virus involved, or existence of co-infection. A familial history of atopy was identified as a risk factor for recurrent bronchial obstruction (60% for RW infants versus 39%, P = 0.02), as living in an apartment (35% versus 15%, P = 0.002). 18 .6% of the infants were sensitized, with 48.1% of them sensitized to aeroallergens and 81.5% to food allergens. Multivariate analysis confirmed that a familial history of atopy (P = 0.02) and initial co-infection RSV-hRV (P = 0.02) were correlated with the risk of sensitization to aeroallergens at 3 years. Familial history of atopy and RSV-hRV co-infection are risk factors for recurrent bronchial obstruction and sensitization. bronchiolitis, prospective study, recurrent bronchial obstruction, sensitization, virus Bronchiolitis is the most common cause of lower respiratory infection in the first year of life. Although most children with bronchiolitis have mild disease and are managed at home, infants admitted to hospital for the condition almost always have severe symptoms. 1, 2 The clinical relevance of the identification of the specific pathogens or combination of pathogens infecting a child remains unclear. However, children with human rhinovirus (hRV) may have different short-and long-term outcomes 3-8 compared to children with respiratory syncytial virus (RSV). We showed that clinical severity was not correlated with the level of serum Krebs von den Lungen 6 antigen (KL-6), a biomarker of epithelial dysfunction, in previously healthy children, 9 which indicates that the various clinical outcomes depend more on the adaptive capacities of the host rather than the intensity of epithelial dysfunction. Prediction of the risk of recurrent wheezing or longterm asthma from the first year of life can be challenging. 10 Against this background, we decided to prospectively follow a cohort of infants with an early episode of acute bronchiolitis, either hospitalized or cared for at home. Our main objective was to assess the risk factors for developing symptoms of recurrent bronchial obstruction during a 3-year follow-up after an episode of bronchiolitis in the first year of life. The secondary objective was to identify in this cohort the risk factors associated with allergic sensitization at the age of 3. Consecutive infants with acute bronchiolitis, aged under 1 year, and examined in the Pediatric Emergency Department during one epidemic season, from October 2011 to May 2012, were considered for inclusion. The clinical, biological, and radiological parameters collected at inclusion have been described elsewhere. 9 Briefly, bronchiolitis was diagnosed as recommended in the international guidelines on the diagnosis and management of acute bronchiolitis. 11 . Detailed demographic data were obtained from the parents by a structured questionnaire. Studied variables comprised age, gender, exposure to tobacco smoke, familial (parents or sister or brother), or personal history of atopy, and nursery attendance. Each infant's condition was classified as mild, moderate or severe according to a severity score calculated from SpO2, respiratory rate, and respiratory effort on admission. 12 Patients were admitted to hospital (inpatient group) on the basis of French national guidelines. 13 Infants who did not require hospitalization (outpatient group) were cared for at home. Children were excluded if they had suspected or confirmed underlying chronic diseases (ie, cystic fibrosis, chronic pulmonary disease, congenital heart disease, bronchopulmonary disease, prematurity), or had already had more than one wheezing episode. A nasopharyngeal aspirate was collected either in the emergency room or within the first 24 h following admission to detect respiratory viruses. The methodology of detection of viruses and dosage of KL-6 are detailed in the study by Amat et al 9 After discharge, one of the authors conducted a telephone interview of the parents of each child, every 3 months until the age of 3 years. A standardized questionnaire designed to elicit information on respiratory symptoms was used for the interview. A complete medical check-up by a pediatric pulmonologist was then performed at the Outpatients Department of CHU-Estaing at the age of 3 years. Recurrent bronchial obstruction was defined according to the frequency of the following symptoms: tachypnoea, wheezing, expiratory stridor, respiratory chest retractions, and doctor-diagnosed wheezes. If ≥3 respiratory symptoms were documented ≥2 times, or if such an episode lasted ≥4 weeks, the subject was classified as suffering from recurrent bronchial obstruction. 14 Immunological profile was performed at the age of 3 years at the same time as the medical check-up. Multisensitization was defined if tests were positive for at least two allergens. The primary endpoint was the risk of recurrent bronchial obstruction at the age of 3 years after an early episode of acute bronchiolitis. The secondary endpoint was the risk of sensitization to aeroallergens and/or to food allergens at the age of 3 years. All analyses were performed with Stata software (version 12, StataCorp, College Station, TX). All tests were two-sided and a P-value <5% was considered statistically significant. The study population was described by frequencies and associated percentages for categorical data, and by mean ± standard-deviation (SD) or median and interquartile ranges (IQR) for continuous data, according to the distribution from normality. Univariate analysis of recurrent bronchial obstruction at the age of 3 years was carried out with Chi-squared test for categorical data (or Fisher's exact test when appropriate), Student's t-test for continuous data, or with the Mann-Whitney-test when normality was rejected (using distribution plots and Shapiro-Wilk's test). Multivariable logistic regression was then performed adjusted for clinically relevant and statistically significant factors. Results are shown as adjusted odds ratio (OR) and their 95% interval (95%CI). Sensitization to aeroallergens was analyzed with the same methods as for recurrent bronchial obstruction. All the infants' parents gave written informed consent for their child to participate. The study was approved by the local Ethics Committee (Comité de Protection des Personnes Sud-Est I, Saint-Etienne, France) and was posted on Clinical Trials (www.clinicaltrials.gov) under the ID number NCT01437956. Two hundred and twenty-two children were initially recruited. Complete data after the 3-year follow-up were available for 154 children, aged 3.4 ± 0.3 years. The main reason for drop-out was a change in telephone number. Children lost to follow-up did not differ significantly from others regarding initial hospitalization, gender, type of virus, birth term, serum KL6 level, initial score of severity, and age at inclusion. A total of 46.8% children had a diagnosis of recurrent bronchial obstruction at the age of 3. According to univariate analysis, they did not significantly differ from children who had not, except for familial history of atopy (60% versus 39%, respectively, P = 0.02), and living in an apartment (35% versus 15%, respectively, P = 0.002). No difference was found according to the kind of respiratory virus involved, nor to the existence or not of co-infection. Table 1 According to multivariate analysis, we did not either find any relationship between initial severity (clinical score, level of KL-6, hospitalization or not), the type of viruses and the occurrence of recurrent bronchial obstruction. A familial history of atopy was identified as a risk factor for recurrent bronchial obstruction (OR 2.34, 95%CI [1.09-5.03], P = 0.03). Living in a house seemed to play a protective role compared to living in an apartment (OR 0.22, 95%CI [0.08-0.59], P = 0.003). Additional tests for the 25 patients with positive fx5® using IgE ImmunoCAP showed that 14 (56%) were multisensitized to food allergens. All of them were sensitized to hen's egg and cow's milk, six were sensitized to wheat, two to peanut or hazelnut, and one child was sensitized to fish. However, these sensitizations were quantitatively low, most of them being inferior to 1 kU/L. We feel that our study sample is more closely representative of whole patients population since most infants suffering from acute bronchiolitis are cared for at home and only 1-10% need to be hospitalized. Yet, most other studies have involved infants admitted to hospital, which introduces significant selection bias that we considered important to avoid. This distinction between infants hospitalized or managed at home can partly explain why our results differ from those of other similar studies. The first point to emerge from the results of this prospective study is the high frequency of recurrent bronchial obstruction 3 years after the initial episode, about 50%, which is in line with that in other documented reports. [4] [5] [6] [7] In contrast, unlike in many publications, we did not find any correlation between the risk of recurrent bronchial obstruction, initial severity, virus type, and serum KL-6 level. In the study of Falkenstein-Hagander et al 17 Backman et al 23 The risk of recurrent bronchial obstruction is greater for children living in an apartment than for those living in a house. Those were not living in apartment reside in rural area or in farm. This finding can be explained by protective factors related to the type of farm housing common in our region and by more common concentrations of pollutants of all types in children living in apartments. [29] [30] [31] Parsons et al 32 examined the effect of living in a farm environment on asthma incidence in children. A total of 10 941 children aged 0-11 years who were free of asthma and wheeze at the baseline (1994-1995) were included. The 14-year cumulative incidence of asthma among children living in farming environments was 10.18%, which was significantly lower than that observed for children living in rural non-farming (13.12%) and non-rural environments (16.50%). This cohort study provides further evidence that living in a farming environment during childhood protects against asthma in adolescence and adulthood and provides further support for the hygiene hypothesis. 33, 34 However, we need to analyze our results on the environment carefully, as we analyzed respiratory outcome only after 3 years and throughout childhood or adulthood. 35 current atopy is considered if the child has either allergic rhinitis or atopic dermatitis. Other authors base the diagnosis of atopy on skin prick tests with or without association with physician diagnosis of allergy. 16, 36, 37 ) A co-infection of RSV and rhinovirus associated with an atopic predisposition promotes awareness of sensitization to aeroallergens. This finding is in agreement with a study suggesting that hRV plays a major role in triggering allergy. Two immunologic factors, low interferon responses and indicators of atopy (eosinophilia, allergen-specific IgEs), are closely associated with susceptibility to hRV-bronchiolitis. 38 Perez et al 39 Our study shows that there is significant frequency of recurrent bronchial obstruction 3 years after the initial episode irrespective of its severity or of the type of virus involved. Familial atopy and environmental factors play an important role in the incidence of recurrent episodes. Allergic sensitization is a certain risk factor for asthma in the longer term. This specific infant population should therefore be closely monitored, especially those with RSV-hRV co-infection. Emmanuelle Rochette http://orcid.org/0000-0001-5180-9916 Viral bronchiolitis in children Admission to hospital for bronchiolitis in England: geographical variation and association with perinatal characteristics and subsequent asthma Rhinovirus bronchiolitis and recurrent wheezing: a 1 year follow-up Rhinovirus-associated wheeze during infancy and asthma developement The first wheezing episode, respiratory viral etiology, atopic characteristics and illness severity Rhinovirus wheezing illness in infancy is associated with medically attended third year wheezing in low risk infant results of a healthy birth cohort study The outcome after severe bronchiolitis is related to gender and virus Impact of human rhinovirus types and viral load on the severity of illness in hospitalized children with lower respiratory tract infection The severity of acute bronchiolitis in infants; should we use a clinical score or a biomarker Can we predict which wheezy infants will continue to wheeze? American academy of pediatrics subcommittee on diagnosis and management of bronchiolitis. Diagnosis and management of bronchiolitis A multicenter, randomized double-blind, controlled trial of nebulized epinephrine in infants with acute bronchiolitis Consensus Conference Management of bronchiolitis in infant. Sepember The significance of early recurrent wheezing for asthma outocme in late childhood Viral load in infants hospitalized for respiratory syncitial virus bronchiolitis correlates with recurrent wheezing at thirty-six-month follow-up Prescool asthma after bronchiolitis in infancy Viral aetiology and clinical outcomes in hospitalised infants presenting with respiratory distress A novel group of rhinoviruses is associated with asthma hospitalizations Do rhinoviruses reduce the probability of viral co-detection during acute respiratory tract infections Lopes da Silveira H, et al. human rhinovirus and disease severity in children Respiratory syncytial virus: co-infection and paediatric lower respiratory tract infections The severity-dependent relationship of infant bronchiolitis on the risk and morbidity of early childhood asthma Low eosinophils during bronchiolitis in infancy is associated with lower risk of adulhood asthma Airway secretions micro-RNAome changes during rhinovirus infection in early childhood Infantile respiratory syncitial virus and human rhinovirus infections; respective role in inception and persistence of wheezing Pre-birth cohort study of atopic dermatitis and severe bronchiolitis during infancy Recurrent wheezing 36 months after bronchiolitis is associated with rhinovirus infection and blood eosinophilia Viral infections and atopy in asthma pathogenesis: new rationales for asthma prevention and treatment Housing and child health Volatil organic compounds and risk of asthma and allergy: a systematic review The indoor environment and its effects on childhood asthma Association of living in a farming environment with asthma incidence in Canadian children Environmental microbial exposure and protection againts asthma Farm dust and endotoxin protect againts allergy through A20 production in lung epithelial cells Post-bronchiolitis wheezing is associated with toll-like receptors rs187084 gene polymorphism Following up infant bronchiolitis patients provided new evidence for and against the united airway disease hypothesis Determinants of asthma after severe respiratory syncytial virus bronchiolitis Rhinovirus and the initiation of asthma Rhinovirus-induced airway disease: a model to understand the antiviral and the TH2 epithelial immune dysregulation in childhood asthma RSV-hRV co-infection is a risk factor for recurrent bronchial obstruction and early sensitization 3 years after bronchiolitis