Respiratory syncytial virus (RSV) is the most common cause of infection of the upper and lower respiratory tract in infants and young children worldwide, and by the age of 2 years, 90% of all children have been infected.1 The majority of children experience only mild upper respiratory tract infection, but in 1%–3% of children, the infection is severe enough to lead to hospitalization.2,3 Management of children hospitalized with RSV infection is essentially supportive with treatment directed toward ensuring adequate oxygenation and optimizing fluid and nutrition intake.
Currently, no effective vaccine against RSV exists, but passive immunoprophylaxis with a humanized monoclonal antibody, palivizumab, is available and has been approved for use in preterm infants with and without chronic lung disease and in children with hemodynamically significant heart disease, who are all at an increased risk of severe RSV infection.4,5 Recent studies have furthermore recognized other chronic conditions in children such as Down syndrome, neuromuscular disease, malformations, chromosomal abnormalities, congenital immunodeficiencies, inborn errors of metabolism and interstitial lung disease to be associated with an increased risk of severe RSV infection.6,7
To further explore how other circumstances such as previous asthma hospitalization, the presence of siblings, day care and maternal smoking, which can be regarded as add-on risk factors to underlying chronic conditions, affect the risk of hospitalization for RSV infection, we performed this population-based cohort study. We furthermore wanted to assess the effect of these factors according to 5 groups of children separated by their gestational ages (GAs).
MATERIALS AND METHODS
We applied data from 6 Danish national registries: The Medical Birth Register,8 The National Patient Register,9 The National Prescription Register,10 The RSV Database,11 The Childcare Database12 and Statistics Denmark.13 The Medical Birth Register includes data on maternal characteristics, pregnancy, delivery and the neonatal period. Data on birth, GA and neonatal outcome are registered by the attending midwife or physician after birth. GA is calculated from either the date of last menstrual period or where available ultrasound-based estimates. The National Patient Register records information on hospital contacts, including all diagnoses coded according to International Classification of Diseases version 10 (ICD-10). Statistics Denmark holds the Danish National Prescription Register that includes data on dispensed medication, including formulations and date of dispensing. All drugs are classified according to the World Health Organization Anatomical Therapeutic Chemical classification. The childcare database contains information on day care attendance in Danish children aged 0–5 years of age. The RSV database contains results from all Danish laboratories testing hospitalized children for RSV from January 1997 through June 2003. During the study period, the presence of RSV in nasopharyngeal aspirate was detected by enzyme-linked immunosorbent assay. Data were linked by using the Central Personal Registration number allocated to each individual residing in Denmark.14
Exposure and Confounding Variables
For all children in the study population, the following data were extracted from the registries: maternal age at delivery (<25, 25–29, 30–34 and ≥35 years), maternal history of asthma hospitalization (yes/no), single parenthood at birth (yes/no), maternal smoking during pregnancy (yes/no/missing), plurality (singleton/multiple), GA at birth, size for GA [small for gestational age (SGA), appropriate, or large for GA), mode of delivery (vaginal/caesarean section), sex (male/female), chronic disease (yes/no), previous asthma hospitalization(s) of the child (yes/no), number of children living in the household at time of birth (1, 2 and ≥3) and enrollment in day care facilities (yes/no).
The criteria described by Marsál et al15 was used to calculate the size for GA at birth. The definition of any congenital or acquired chronic diseases was based on the ICD-10 codes and included as a binary variable. Chronic diseases included conditions such as congenital malformations, intestinal lung disease, neuromuscular disease, chromosomal abnormalities, congenital immunodeficiencies and inborn errors of metabolism. The selection procedure has been described in detail elsewhere.6 Previous asthma hospitalization was defined as a hospitalization with the ICD-10 diagnosis J45.0–J45.9 and J46.9. Because asthma and RSV infection may present with same clinical picture, we included only cases of asthma diagnosed ≥30 days before hospitalization for RSV infection. Siblings were defined as number of other children living in the household at time of birth. Enrollment in day care facility was defined as enrollment in any day care facility (age-integrated facility, crèche and day care) before hospitalization for RSV infection.
The study outcome was hospitalization because of RSV infection defined by the first positive sample recorded in the RSV database during the first 2 years of living.
Incidence rates (IRs) of hospitalization for RSV infection were calculated by the number of children who experienced hospitalization for RSV infection per 1000 child years at risk for 5 groups of children separated by GA. The associations between potential risk factors for hospitalization for RSV infection were analyzed using a Cox regression model. Children were followed up from birth to 24 month of age, first hospitalization for RSV infection, death, emigration or June 2003, whichever came first. Age was used as the underlying time variable. The variables chronic disease, previous asthma hospitalization of the child and enrollment in day care facility were entered into the model as time-varying covariates, whereas all other variables were fixed. The analyses were stratified by date of birth. By stratifying by date of birth, the model was controlled for the seasonality of RSV infection. All variables were entered in 1 final model with no variable selection procedure; by that all estimates presented were adjusted for all the other potential risk factors. The estimated associations were presented as hazard ratios with 95 % confidence intervals. Data management and analysis were carried out using Stata version 13.
Study Cohort and Hospitalization for RSV Infection
In the Medical Birth Register, we identified 428,117 children born during the study period from January 1997 through June 2003, which is the 7-year period covered by the RSV database. A total of 6175 (1.4%) children were excluded because of missing information on GA (n = 2157), unlikely birth weight for GA (n = 3731), inactive Central Personal Registration number (n = 235) or exposure to palivizumab (n = 52) leaving a final study cohort of 421,942 children for statistical analysis. A total of 5200 (1.2%) were born between 23 and 32 weeks of GA, 11,193 (2.7%) between 33 and 35 weeks of GA, 9815 (2.3%) at 36 weeks of GA, 360,484 (85.4%) between 37 and 41 weeks of GA and 35,250 (8.3%) between 42 and 45 weeks of GA. A total of 12,200 children (2.9%) had at least 1 hospitalization for RSV infection during their first 24 months of life. The overall IR of hospitalization for RSV infection in children aged 0–24 months was 14.9 per 1000 years at risk. The IRs of hospitalization for RSV infection per 1000 years of risk in children born at 23–32, 33–35, 36, 37–41 and 42–45 weeks of GA were 50.8, 28.0, 22.6, 14.1 and 11.5, respectively (Tables, Supplemental Digital Content 1, https://links.lww.com/INF/C283).
Risk Factors According to GA
In the adjusted Cox regression model chronic disease, asthma hospitalization before RSV infection and siblings were associated with increased risk of hospitalization for RSV infection in children born between 23 and 32 weeks of GA. Similar findings were found for children born between 33 and 35 weeks of GA, where smoking and day care were also associated with an increased risk of hospitalization for RSV infection. Multiple pregnancy was associated with a decreased risk of hospitalization for RSV infection both among children born between 33 and 35 and at 36 weeks of gestation (Fig. 1).
In term children (37–41 weeks of GA), young maternal age, maternal smoking, maternal asthma, single parenthood, caesarean section, SGA, male sex, chronic disease, asthma hospitalization before the RSV infection in the case child, siblings and day care were associated with an increased risk of hospitalization for RSV (Fig. 1). In postterm children (42–45 weeks of GA), young maternal age, maternal smoking, being SGA, male gender, chronic disease, asthma hospitalization before the RSV infection in the case child, siblings and day care were associated with an increased risk of hospitalization for RSV infection (Fig. 1).
To date, this is the largest study on risk factors for hospitalization for RSV infection. We provide estimates of the effects of a total of 12 factors, which can be regarded as add-on risk factors to factors already known to increase the risk of hospitalization for RSV infection, and we present the effect both as IRs and adjusted hazard ratios, and by 5 groups of GAs.
The highest hospitalizations rates for RSV infection were found in the group of very preterm children with GAs between 23 and 32 weeks, which is in line with earlier studies showing that low GA is a strong independent risk factor for RSV infection.16–18 However, only few studies on risk factors for hospitalization because of RSV infection have been performed in extremely preterm children, and to our knowledge, this study is the first to provide precise estimates of IRs of hospitalization for RSV in these highly susceptible children. We further identified chronic disease, asthma hospitalization before the RSV infection, older siblings, and day care as risk factors for hospitalization for RSV infection independent on GA although the effect of day care was not significant in the smallest preterm children with GAs between 23 and 32 weeks.
Asthma hospitalization before hospitalization for RSV was by far the most important risk factor for all children under study. However, it is important to emphasize that although asthma and severe RSV infection may present with a similar clinical picture, this finding was not based on the inability to discriminate between asthma and hospitalization for RSV, because only asthma hospitalizations that occurred more than 30 days before hospitalization for RSV were included in the analysis. Therefore, our study supports other studies showing that there is a tight link between hospitalization for RSV infection and asthma.19–23 Currently, however, it is still unclear to what extent this represents a genetic predisposition and/or a common environmental exposure in individuals with hospitalization for RSV and later asthma or whether the severe RSV infection in itself leads to hyperreactive airways. It is also possible that both are true. Hence, studies on the causal direction of the association between hospitalization for RSV and asthma have suggested that a common predisposition exist.24–26 Conversely, 3 studies found that passive immunoprophylaxis against RSV with palivizumab in moderately preterm infants reduced not only the risk of hospitalization for RSV infection but also the risk of subsequent wheezing episodes.27–29
The protective effect of multiple gestation against hospitalization for RSV infection in preterm children has previously been described and has been suggested to reflect behavioral changes in parents to twins.30 However, we believe that this effect is rather mediated by the fact that besides being twins as the explanation of the preterm birth, the twins are otherwise healthy preterm babies, whereas other preterm children are often diseased or influenced by maternal disease as the reason for the preterm birth.
Other studies have identified low birth weight to be an independent risk factor for hospitalization because of RSV infection,31,32 but birth weight alone cannot separate low birth weight as a result of prematurity from impaired fetal growth. Using size for GA made it possible for us to make this discrimination, and this enabled us to identify SGA in term children as an independent risk factor for hospitalization because of RSV, which is in line with earlier studies showing that SGA is associated with both increased the risk of respiratory tract infection and asthma.33,34
Single parenthood at time of birth and young maternal age have previously been associated with an increased risk of hospitalization for RSV,31 and these findings were confirmed in our study in both term and postterm children. Both factors may be associated with lower socioeconomic status that is known to be associated with an increased risk of RSV infection,35 and we speculate that exposure to smoking may be a part of the explanation.36 Thus, other studies have shown an increased risk of hospitalization for RSV infection in families with household smoking,31,37 and in line with this, our study demonstrated an increased risk of hospitalization for RSV infection in children exposed to smoking during pregnancy.
Risk assessment tools for hospitalization for RSV infection in children born between 32 and 35 weeks of GA have been developed in both Europe38 and Canada17 and have demonstrated ability to predict hospitalization for RSV infection in late preterm infants. However, a recent study failed to demonstrate reliability of risk scoring among children born at term both with respect to severity of RSV disease and risk of hospitalization.39 We believe that including add-on risk factors as those presented in this study in risk scoring systems will make these more reliable. Thus, risk factors are likely to have additive effects, and for instance, a child who is moderately preterm, has siblings and has been born by caesarian section by a young mother with asthma have a highly increased risk of hospitalization for RSV infection. This has been recognized by the American Academy of Pediatrics, who in their latest guidance regarding the use of Palivizumab has included the most consistent factors such as month of birth, siblings and day care.40
The major strengths of this study are the population-based design and the large sample size, which enhanced the generalizability of the findings and allowed us to stratify by GA and to adjust for multiple confounders. Furthermore, very few children had been exposed to palivizumab, and these were excluded from the analysis.
Limitations of the study include the risk of misclassification of exposure data, because data in the National Patient Register and Statistics Denmark are not collected primarily for research purposes. However, misclassification is likely to be nondifferentially distributed and, therefore, should not affect the relative estimates presented here. Because of the lack of data, we could not adjust for socioeconomic status, household smoking and breastfeeding, and we can, therefore, not rule out confounding from these factors. However, it is worth mentioning that a protective effect of breastfeeding on the risk of hospitalization for RSV has not been convincingly demonstrated.16
Although the laboratory-verified RSV test gave strength to this study, the sensitivity of the enzyme-linked immunosorbent assay used at the time of the study is lower than the polymerase chain reaction commonly used today.41 However, it is unlikely that the lower sensitivity of the enzyme-linked immunosorbent assay tests for detection of RSV should affect the relative estimates reported here, although the absolute numbers of RSV cases and therefore the IRs may well be underestimated.
Author Contributions: No persons other than the listed authors have contributed to the study.
1. Simoes EA.. Respiratory syncytial virus
infection. Lancet. 1999;354:847–852
2. Boyce TG, Mellen BG, Mitchel EF Jr, et al. Rates of hospitalization for respiratory syncytial virus
infection among children in medicaid. J Pediatr. 2000;137:865–870
3. Eriksson M, Bennet R, Rotzén-Ostlund M, et al. Population-based rates of severe respiratory syncytial virus
infection in children with and without risk factors, and outcome in a tertiary care setting. Acta Paediatr. 2002;91:593–598
4. Bonnet D, Schmaltz AA, Feltes TF.. Infection by the respiratory syncytial virus
in infants and young children at high risk. Cardiol Young. 2005;15:256–265
5. Meissner HC, Rennels MB, Pickering LK, et al. Risk of severe respiratory syncytial virus
disease, identification of high risk infants and recommendations for prophylaxis with palivizumab. Pediatr Infect Dis J. 2004;23:284–285
6. Kristensen K, Hjuler T, Ravn H, et al. Chronic diseases, chromosomal abnormalities, and congenital malformations as risk factors for respiratory syncytial virus
hospitalization: a population-based cohort study. Clin Infect Dis. 2012;54:810–817
7. Murray J, Bottle A, Sharland M, et al.Medicines for Neonates Investigator Group. Risk factors for hospital admission with RSV bronchiolitis in England: a population-based birth cohort study. PLoS One. 2014;9:e89186
8. Knudsen LB, Olsen J.. The Danish Medical Birth Registry. Dan Med Bull. 1998;45:320–323
9. Andersen TF, Madsen M, Jørgensen J, et al. The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull. 1999;46:263–268
10. Kildemoes HW, Sørensen HT, Hallas J.. The Danish National Prescription Registry. Scand J Public Health. 2011;39(7 suppl):38–41
11. Stensballe LG, Kristensen K, Nielsen J, et al. Diagnosis coding in the Danish National Patient Registry for respiratory syncytial virus
infections. Scand J Infect Dis. 2005;37:747–752
12. Kamper-Jørgensen M, Wohlfahrt J, Simonsen J, et al. The Childcare Database: a valuable register linkage. Scand J Public Health. 2007;35:323–329
13. Thygesen L.. The register-based system of demographic and social statistics in Denmark. Stat J UN Econ Comm Eur. 1995;12:49–55
14. Pedersen CB, Gøtzsche H, Møller JO, et al. The Danish Civil Registration System. A cohort of eight million persons. Dan Med Bull. 2006;53:441–449
15. Marsál K, Persson PH, Larsen T, et al. Intrauterine growth curves based on ultrasonically estimated foetal weights. Acta Paediatr. 1996;85:843–848
16. Sommer C, Resch B, Simões EA.. Risk factors for severe respiratory syncytial virus
lower respiratory tract infection. Open Microbiol J. 2011;5:144–154
17. Sampalis JS, Langley J, Carbonell-Estrany X, et al. Development and validation of a risk scoring tool to predict respiratory syncytial virus
hospitalization in premature infants born at 33 through 35 completed weeks of gestation. Med Decis Making. 2008;28:471–480
18. Carbonell-Estrany X, Figueras-Aloy J, Law BJInfección Respiratoria Infantil por Virus Respiratorio Sincitial Study Group; Pediatric Investigators Collaborative Network on Infections in Canada Study Group. . Identifying risk factors for severe respiratory syncytial virus
among infants born after 33 through 35 completed weeks of gestation: different methodologies yield consistent findings. Pediatr Infect Dis J. 2004;23(11 suppl):S193–S201
19. Escobar GJ, Masaquel AS, Li SX, et al. Persistent recurring wheezing in the fifth year of life after laboratory-confirmed, medically attended respiratory syncytial virus
infection in infancy. BMC Pediatr. 2013;13:97
20. Henderson J, Hilliard TN, Sherriff A, et al. Hospitalization for RSV bronchiolitis before 12 months of age and subsequent asthma, atopy and wheeze: a longitudinal birth cohort study. Pediatr Allergy Immunol. 2005;16:386–392
21. Pedraz C, Carbonell-Estrany X, Figueras-Aloy J, et al.IRIS Study Group. Effect of palivizumab prophylaxis in decreasing respiratory syncytial virus
hospitalizations in premature infants. Pediatr Infect Dis J. 2003;22:823–827
22. Sigurs N, Aljassim F, Kjellman B, et al. Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life. Thorax. 2010;65:1045–1052
23. Stein RT, Sherrill D, Morgan WJ, et al. Respiratory syncytial virus
in early life and risk of wheeze and allergy by age 13 years. Lancet. 1999;354:541–545
24. Poorisrisak P, Halkjaer LB, Thomsen SF, et al. Causal direction between respiratory syncytial virus
bronchiolitis and asthma studied in monozygotic twins. Chest. 2010;138:338–344
25. Stensballe LG, Simonsen JB, Thomsen SF, et al. The causal direction in the association between respiratory syncytial virus
hospitalization and asthma. J Allergy Clin Immunol. 2009;123:131–137.e1
26. Thomsen SF, van der Sluis S, Stensballe LG, et al. Exploring the association between severe respiratory syncytial virus
infection and asthma: a registry-based twin study. Am J Respir Crit Care Med. 2009;179:1091–1097
27. Blanken MO, Rovers MM, Molenaar JM, et al.Dutch RSV Neonatal Network. Respiratory syncytial virus
and recurrent wheeze in healthy preterm infants. N Engl J Med. 2013;368:1791–1799
28. Simoes EA, Groothuis JR, Carbonell-Estrany X, et al.Palivizumab Long-Term Respiratory Outcomes Study Group. Palivizumab prophylaxis, respiratory syncytial virus
, and subsequent recurrent wheezing. J Pediatr. 2007;151:34–42, 42.e1
29. Yoshihara S, Kusuda S, Mochizuki H, et al.C-CREW Investigators. Effect of palivizumab prophylaxis on subsequent recurrent wheezing in preterm infants. Pediatrics. 2013;132:811–818
30. Ambrose CS, Anderson EJ, Simões EA, et al. Respiratory syncytial virus
disease in preterm infants in the U.S. born at 32-35 weeks gestation not receiving immunoprophylaxis. Pediatr Infect Dis J. 2014;33:576–582
31. Cilla G, Sarasua A, Montes M, et al. Risk factors for hospitalization due to respiratory syncytial virus
infection among infants in the Basque Country, Spain. Epidemiol Infect. 2006;134:506–513
32. Nielsen HE, Siersma V, Andersen S, et al. Respiratory syncytial virus
infection—risk factors for hospital admission: a case-control study. Acta Paediatr. 2003;92:1314–1321
33. Liu X, Olsen J, Agerbo E, et al. Birth weight, gestational age, fetal growth and childhood asthma hospitalization. Allergy Asthma Clin Immunol. 2014;10:13
34. Paranjothy S, Dunstan F, Watkins WJ, et al. Gestational age, birth weight, and risk of respiratory hospital admission in childhood. Pediatrics. 2013;132:e1562–e1569
35. Simoes EA.. Respiratory syncytial virus
infection. Lancet. 1999;354:847–852
36. Corsi DJ, Boyle MH, Lear SA, et al. Trends in smoking in Canada from 1950 to 2011: progression of the tobacco epidemic according to socioeconomic status and geography. Cancer Causes Control. 2014;25:45–57
37. Figueras-Aloy J, Carbonell-Estrany X, Quero-Jiménez J, et al.IRIS Study Group. FLIP-2 Study: risk factors linked to respiratory syncytial virus
infection requiring hospitalization in premature infants born in Spain at a gestational age of 32 to 35 weeks. Pediatr Infect Dis J. 2008;27:788–793
38. Simões EA, Carbonell-Estrany X, Fullarton JR, et al.European RSV Risk Factor Study Group. A predictive model for respiratory syncytial virus
(RSV) hospitalisation of premature infants born at 33-35 weeks of gestational age, based on data from the Spanish FLIP Study. Respir Res. 2008;9:78
39. Mosalli R, Abdul Moez AM, Janish M, et al. Value of a risk scoring tool to predict respiratory syncytial virus
disease severity and need for hospitalization in term infants. J Med Virol. 2015;87:1285–1291
40. American Academy of Pediatrics Committee on Infectious Diseases; American Academy of Pediatrics Bronchiolitis Guidelines Committee.. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus
infection. Pediatrics. 2014;134:415–420
41. Schützle H, Weigl J, Puppe W, et al. Diagnostic performance of a rapid antigen test for RSV in comparison with a 19-valent multiplex RT-PCR ELISA in children with acute respiratory tract infections. Eur J Pediatr. 2008;167:745–749