Early Human Development 87S (2011) S47–S49
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Are late preterm infants as susceptible to RSV infection as full term infants? Bernhard Resch a,⁎, Bosco Paes b a b
Research Unit for Neonatal Infectious Diseases and Epidemiology, Division of Neonatology, Department of Pediatrics, Medical University of Graz, Austria Division of Neonatology, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
a r t i c l e
i n f o
Keywords: Late preterm infants Respiratory syncytial virus Infection
a b s t r a c t Preterm infants are at increased risk of being rehospitalised during the first few months of life with severe respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) that usually manifests as apnea and hypoxemia. This occurs more commonly in preterm infants b 33 weeks gestational age (GA), but recent studies demonstrate that late preterm infants (those born between 34 weeks and 0 days to 36 weeks and 6 days GA) are equally susceptible to RSV LRTI as those with lower GA. Factors associated with severe LRTI include immaturity of both the humoral and cell-mediated immune system and interrupted lung development prior to 36 weeks GA which results in lower functional residual capacity, reduced compliance, diminished forced expiratory air flow and impaired gas exchange. Morbidity and mortality are significantly increased in late preterms compared to their term counterparts. Prophylaxis with palivizumab against RSV infection seems to be crucial. Due to the large number of infants in this age group, additional risk factors have been identified in order to tailor palivizumab prophylaxis effectively to those at highest risk for severe RSV LRTI. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Late preterm infants account for approximately three-quarters of all preterm births, and there is an increasing body of evidence that they experience increased morbidity and even higher neonatal mortality compared to near-term or full-term infants [1–4]. A large retrospective multicenter analysis of late preterms across the United States revealed a 36.5% rate of NICU-admissions with 28.8% having respiratory compromise compared with a 7.2% admission rate in term infants with a corresponding respiratory morbidity of 15.6% [1]. The odds of respiratory distress syndrome decreased with each advancing week of gestation until 38 weeks compared with 39 to 40 weeks (40.1; 95% confidence interval (CI), 32.0–50.3 at 34 weeks vs. 1.1; 95% CI, 0.9–1.4 at 38 weeks). Interestingly, this study and others indicate that there are important differences between each week of gestational age (GA) [1–4]. In essence, late preterm infants have higher frequencies of respiratory distress, temperature instability, hypoglycemia, kernicterus, apnea, seizures, and feeding problems, as well as higher rates of rehospitalisation, compared with term infants [5]. Identified risk factors for readmission include firstborn infant, infant being breastfed at discharge, jaundice, proven or suspected infections, feeding difficulties, and failure to thrive [5]. Long-term outcomes of this population are also of concern. Although ⁎ Corresponding author. Division of Neonatology, Pediatric Department, Medical University of Graz, Auenbruggerplatz 30, 8036 Graz, Austria. Tel.: +43 316 385 81134; fax: +43 316 385 2678. E-mail address:
[email protected] (B. Resch). 0378-3782/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2011.01.010
few studies have evaluated neurodevelopmental outcome of late preterms, 20% are reported to have clinically significant behavior problems at 8 years of age that is higher than term infants [6]. 2. Susceptibility to RSV infection Two factors are principally involved in the increased susceptibility of late preterm infants to respiratory tract infections including severe respiratory syncytial virus (RSV) illness. First, the rate of lung maturation is greatest during the third trimester of pregnancy. During this period bronchi increase in number, saccules invaginate to form alveoli, capillaries approach and surround the air spaces, alveolar interstitium thins and surfactant is produced by type II pneumocytes, resulting in a rapid increase in lung volume and surface area. Interrupted pulmonary development prior to 36 weeks gestational age results in lower functional residual capacity, reduced compliance, diminished forced expiratory air flow, and impaired gas exchange in preterm infants over the first two years of life even in those without significant respiratory disease [7,8]. Infants born during the critical period of saccular development appear to have major differences in lung maturation compared to full-term infants and exposure to mechanical ventilation further impairs optimal alveolar development. In addition to the decreased capacity for oxygenation and ventilation, the small diameter of the airways in 33 to 35 week GA infants infected with RSV are further reduced by sloughing of the necrotic respiratory epithelium, increased mucus production and mucus plug formation that enhances breathing difficulties and respiratory distress [9]. Second, the immaturity of the immune system also contributes to
S48
B. Resch, B. Paes / Early Human Development 87S (2011) S47–S49
the heightened risk of severe RSV infection in late preterm infants. Premature birth interrupts the transfer of maternal antibodies, and the foetal immune system does not fully develop until approximately six months postnatal age. In the absence of mature IgG levels, postnatal exposure to viruses results in increased susceptibility to lower respiratory tract infections. Both immature humoral and cellmediated immunity may compromise the immune system of 33 to 35 week GA infants. Data have shown that age at first exposure to infection is a strong determinant of the type of immune response stimulated upon subsequent re-infections, and earlier exposure has been linked to immune-driven disease augmentation and a strong inflammatory response [9]. A cumulative analysis of 24 studies demonstrated that overall, late preterm infants experience significant respiratory morbidity in infancy compared to term infants which may impact pulmonary development, influence susceptibility to respiratory infections and ultimately affect lung function in adulthood [10]. 3. Prematurity and RSV infection One of the first studies reporting on a more severe course of respiratory syncytial virus (RSV) disease in premature infants (mean GA 33.6 weeks) compared to full-term babies, [11] found that preterms were more likely to present with apnoea (p b 0.01), have a higher incidence of atelectasis/infiltrate and hyperinflation in chest roentgenograms (p b 0.05), and experience longer hospital stays as well as higher PSI (Physiologic Stability Index) and TIS (Therapeutic Intervention Scores) (p b 0,01). They were also more likely to receive supplemental oxygen, intensive care unit (ICU) admission, mechanical ventilation, and nothing by mouth (p b 0,001). A prospective study of infants aged b2 years hospitalised for viral upper and lower respiratory tract infection over a two-year period [12] revealed that RSV was associated with younger age, higher lower respiratory illness scores, more days of hospitalisation, oxygen requirement and respiratory support, and prolonged hospitalisation in preterm vs. term infants (mean 14 vs. 8.9 days, p = 0.007). The incidence of RSV hospitalisation was 7/1000 child years among term vs. 28/1000 in preterm infants (p b 0.001). 4. RSV and late preterm birth A retrospective study evaluating rehospitalisation rates due to respiratory illness in preterm infants of 29 to 36 weeks gestation without chronic lung disease reported a 14% rate of one or more readmissions during follow-up [13]. The overall RSV attack rate was 4.4% over two consecutive RSV seasons for infants aged b6 months at onset of the RSV season (7.7% and 1.1%, respectively, p = 0.015), with significant differences between infants of 29 to 32 and 33 to 36 weeks GA (10.5% vs. 2.3%, p = 0.008). The RSV related rehospitalisation rate for late preterm infants b3 months chronological age was 5.3%. Infants with RSV infection were of younger age (mean 4.2 vs. 8.2 months; p = 0.015), had longer hospital stays (11.5 vs. 7.0 days; p = 0.006), and more severe courses of disease (score 3.0 vs. 1.8; p b 0.001). Additional risk factors for RSV infection were multiple gestation (Odds Ratio (OR) 5.5; 95% Confidence Interval (CI), 1.439–21.028) and congenital heart disease (OR 4.2; 95%CI, 1.005–17.669). Additionally, risk factors for rehospitalisation due to any respiratory illness in infants 33 to 36 weeks GA included younger maternal age and a history of intra-periventricular haemorrhage. Data on resource use and outcomes associated with RSV hospitalisation found significant differences for rates of intubation (P= .002); intensive care unit (ICU) and hospital length of stay (P= .021 and P b .0001), respectively in preterm infants, with the highest resource use being in 33 to 35 weeks GA infants, which remained significant in multiple regression analyses [14]. These results were similarly replicated in a study by Willson et al. who additionally reported higher
complication rates and median costs of hospital stay for infants 33– 35 weeks GA compared to infants N37 weeks [15]. In a retrospective study of RSV hospitalisations in infants aged b6 months between 1989 and 1993, Boyce et al. reported rates of 159.6 vs. 88.2/1000 child years for infants 33–35 completed weeks GA compared to those born at term [16]. Another retrospective cohort study from a national claims database which included preterm and full term infants b6 months of age, born between April 2004 and April 2006 and continuously enrolled through their first RSV season, revealed rates of outpatient RSV LRTI ranging from 183.3 to 245.7/ 1000 among late preterms (33–36 weeks GA), which was higher than full term infants (128.8 to 171.3/1000) [17]. During 1996 through 1998 there were 229 bronchiolitis related infant deaths, resulting in an average annual infant mortality rate of 2.0 per 100 000 live births in the United States [18]. The majority (55%) of infant deaths occurred among those aged between 1 and 3 months. The bronchiolitis mortality rate was highest among infants weighing b1500 g at birth as compared with infants 1500 to 2499 g and those N2500 g (29.8, 6.4 and 1.3 per 100,000 live births, respectively). Sixty-three percent of bronchiolitis deaths occurred in infants N2500 g. Other risk factors included increasing birth order, low 5-min Apgar score, young maternal age, unmarried mothers and tobacco use during pregnancy. In a matched, control study Sampalis [19] evaluated the impact of RSV infections on subsequent health care resource utilisation in preterm infants of 32–35 weeks GA hospitalised for proven or probable RSV, and reported significant increases in all hospital utilisation parameters with an overall mortality rate of 8.1% for the RSV cohort and 1.6% for the controls (p b 0.001). 5. Risk factors for RSV hospitalisation in late preterm infants Two studies [20,21] quantitatively assessed specific risk factors that contributed to RSV hospitalisation in infants born between 33 and 35 weeks GA and found consistent similarities despite different methodologies; birth before or during the first half of the RSV season, crowding, breast feeding ≤ 2 months, preschool or school age siblings, male gender, low birth weight, day care attendance, family history of wheezing, and smoking in the home [22]. Across Europe and Canada several tools were developed to identify infants at highest risk for severe RSV infection and hospitalisation in this particular age group because they comprise a significant percentage of the birth population [23–25]. Preliminary data suggest robustness of the European and Canadian RSV risk score models demonstrating correct prediction in 62, 66% and 64% of the French, Danish and Spanish populations respectively [26–28]. The utility and costeffectiveness of these multiple risk factor models in 32–35 week GA infants have been demonstrated in clinical practice and the recommendations have been adopted by international, paediatric advisory statements [23,29–33]. In 2009 the AAP [34] revised their recommendations for infants 32 to 35 weeks gestation in the USA to include only those younger than 3 months of age at the start of or born during the RSV season with at least one of two risk factors; day care attendance or presence of siblings aged younger than five years. 6. Palivizumab prophylaxis The IMpact Study [35] reported a 10% RSV hospitalisation rate in preterm infants aged 32 to 35 weeks GA that was reduced to 1.8% (82% reduction) by monthly injections of palivizumab. Despite these impressive data, palivizumab was restricted to infants b32 weeks GA and those with bronchopulmonary dysplasia [34] mostly due to economic considerations regarding universal prophylaxis of late preterm infants. Data from the American Palivizumab Outcomes Registry provide the largest data set (n = 9317) available on infants born between 32
B. Resch, B. Paes / Early Human Development 87S (2011) S47–S49
and 35 weeks GA who received palivizumab prophylaxis. The incidence of RSV hospitalisation steadily declined from 1.6% during the 2000/2001 RSV season to 0.2 in the 2003/2004 season [36]. 7. Conclusion Late preterm infants are at greater risk of infection and subsequent hospitalisation than term infants and they incur more morbidities following admission to hospital. The burden of illness in this cohort of infants significantly impacts costs from the payer and societal perspective and is fraught with the risk of increased complications which may potentially influence downstream costs and long term outcomes. Prophylaxis against RSV infection is highly efficacious in this sub-population but should be used cost-effectively in those at highest risk in accordance with country-specific guidelines. Conflict of interest statement Dr Paes is currently Co-Principal Investigator of a multicenter investigator initiated research study entitled “CARESS” (Canadian Registry of Synagis). The Principal Investigators are supported by a grant in aid of research by Abbott Laboratories Ltd. The investigators for the CARESS study maintain control over any abstracts and presentations arising from the data and the rights to publish. Dr Paes is also co-investigator on a research study funded by Abbott International entitled “Surveillance and cost analysis for Respiratory Syncytial Virus hospital admissions in the Arctic communities in Canada.” Dr. Resch has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript including employment, consultancies, stock ownership or options, expert testimony, patents received or pending, or royalties. He received honoraria for national and international presentations on the subject of RSV infection and RSV prophylaxis with palivizumab from several Abbott Companies. Dr. Resch is the principal Investigator of the AIR-NID study (Austrian–Italian multicenter study on RSV infection in neuromuscular disease and immune deficiency syndromes) that is funded by a grant from Abbott Company Austria. No writing assistance was utilised in the production of this manuscript. References [1] Hibbard JU, Wilkins I, Sun L, Gregory K, Haberman S, Hoffman M, et al. Respiratory morbidity in late preterm births. Consortium on safe labor. JAMA 2010;304: 419–25. [2] Pulver LS, Denny JM, Silver RM, Young PC. Morbidity and discharge timing of late preterm newborns. Clin Pediatr Phila 2010;49:1061–7. [3] Bird TM, Bronstein JM, Hall RW, Lowery CL, Nugent R, Mays GP. Late preterm infants: birth outcomes and health care utilization in the first year. Pediatrics 2010;126:e311–9. [4] Kitsommart R, Janes M, Mahajan V, Rahman A, Seidlitz W, Wilson J, et al. Outcomes of late-preterm infants: a retrospective, single-center, Canadian study. Clin Pediatr Phila 2009;48:844–50. [5] Raju TNK, Higgins RD, Stark AR, Leveno KJ. Optimizing care and outcome for latepreterm (near-term) infants: a summary of the workshop sponsored by the National Institute of Child Health and Human Development. Pediatrics 2006;118: 1207–14. [6] Gray RF, Indurkhya A, McCormick MC. Prevalence, stability, and predictors of clinically significant behaviour problems in low birth weight children at 3, 5, and 8 years of age. Pediatrics 2004;114:736–43. [7] Friedrich L, Stein RT, Pitrez PM, Corso AL, Jones MH. Reduced lung function in healthy preterm infants in the first months of life. Am J Respir Crit Care Med 2006;173:442–7. [8] Friedrich L, Pitrez PM, Stein RT, Goldani M, Tepper R, Jones MH. Growth rate of lung function in healthy preterm infants. Am J Respir Crit Care Med 2007;176: 1269–73. [9] Carbonell-Estrany X, Bont L, Dorering G, Gouyon J-B, Lanari M. Clinical relevance of prevention of respiratory syncytial virus lower respiratory tract infection in preterm infants born between 33 and 35 weeks gestational age. Pediatr Infect Dis J 2008;27:891–9.
S49
[10] Colin AA, McEvoy C, Castile RG. Respiratory morbidity and lung function in preterm infants of 32 to 36 weeks gestational age. Pediatrics 2010;126:115–28. [11] Meert K, Heidemann S, Abella B, Saeniak A. Does prematurity alter the course of respiratory syncytial virus infection? Crit Care Med 1990;18:1357–9. [12] Resch B, Gusenleitner W, Müller W. The impact of respiratory syncytial virus infection: a prospective study in hospitalized infants younger than 2 years. Infection 2002;30:193–7. [13] Resch B, Pasnocht A, Gusenleitner W, Müller W. Rehospitalisations for respiratory disease and respiratory syncytial virus infection in preterm infants of 29– 36 weeks gestational age. J Infect 2005;50:397–403. [14] Horn SD, Smout RJ. Effect of prematurity on respiratory syncytial virus hospital resource use and outcomes. J Pediatr 2003;143:S133–41. [15] Willson DF, Landrigan CP, Horn SD, Smout RJ. Complications in infants hospitalized for bronchiolitis or respiratory syncytial virus pneumonia. J Pediatr 2003 Nov;143:S142–9. [16] Boyce TG, Mellen BG, Mitchel Jr EF, Wright PF, Griffin MR. Rates of hospitalisation for respiratory syncytial virus infection among children in Medicaid. J Pediatr 2000;137:865–70. [17] Paramore LC, Mahadevia PJ, Piedra PA. Outpatient RSV Lower respiratory infections among high-risk Infants and other pediatric populations. Pediatr Pulmonol 2010;45:578–84. [18] Holman RC, Shay DK, Curns AT, Lingappa JR, Anderson LJ. Risk factors for bronchiolitis-associated deaths among infants in the United States. Pediatr Infect Dis J 2003;22:483–9. [19] Sampalis JS. Morbidity and mortality after RSV-associated hospitalizations among premature Canadian infants. J Pediatr 2003;143:S150–6. [20] Law BJ, Langley JM, Allen U, Paes B, Lee DS, Mitchell I, et al. The pediatric investigators collaborative network on infections in Canada study of predictors of hospitalization for respiratory syncytial virus infection for infants born at 33 through 35 completed weeks of gestation. Pediatr Infect Dis J 2004;23:806–14. [21] Figueras-Aloy J, Carbonell-Estrany X, IRIS Study Group. Case–control study of the risk factors linked to respiratory syncytial virus infection requiring hospitalization in premature infants born at a gestational age of 33–35 weeks in Spain. Pediatr Infect Dis J 2004;23:815–20. [22] Carbonell-Estrany X, Figueras-Aloy J, Infección 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:S193–201. [23] Resch B, Berger A, Bernert G, Eber E, Frischer T, Simma B, et al. Konsensuspapier zur Prophylaxe der RSV-Infektion mit Palivizumab und Post-RSV-Atemwegserkrankung. Monatsschr Kinderheilkd 2008;156:381–3. [24] Döring G, Gusenleitner W, Belohradsky BH, Burdach S, Resch B, Liese JG. The risk of respiratory syncytial virus-related hospitalizations in preterm infants of 29 to 35 weeks gestational age. Pediatr Infect Dis J 2006;25:1188–90. [25] Simoes EA, Carbonell-Estrany X, Fullarton JR, Liese JG, Figueras-Aloy J, Doering G, et al. 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;9:78–88. [26] Carbonell-Estrany X, Simões EA, Fullarton JR, Ferdynus C, Risk Factor Study Group. Validation of a model to predict hospitalization due to RSV of infants born at 33– 35 weeks gestation. J Perinat Med 2010;38:411–7. [27] Stensballe LG, Fullarton JR, Carbonell-Estrany X, Simões EA. Population based external validation of a European predictive model for respiratory syncytial virus hospitalization of premature infants born 33 to 35 weeks of gestational age. Pediatr Infect Dis J 2010;29:374–6. [28] Sampalis JS, Langley J, Carbonell-Estrany X, Paes B, O'Brien K, Allen U, 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 Mak 2008;28(4):471–80. [29] Paes B, Steele S, Janes M, Pinelli J. Risk-scoring tool for respiratory syncytial virus prophylaxis in premature infants born at 33–35 completed weeks' gestational age in Canada. Curr Med Res Opin 2009;25:1585–91. [30] Carbonell-Estrany X, Lázaro y de Mercado P. Health economics and RSV. Paediatr Resp Rev 2009;10(Suppl 1):12–3. [31] Lanctôt KL, Masoud ST, Paes BA, Tarride JE, Chiu A, Hui C, et al. The costeffectiveness of palivizumab for respiratory syncytial virus prophylaxis in premature infants with a gestational age of 32–35 weeks: a Canadian-based analysis. Curr Med Res Opin 2008;24:3223–37. [32] Figueras Aloy J, Carbonell Estrany X, Comité de Estándares de la Sociedad Española de Neonatología. Recommendations for the use of palivizumab in the prevention of respiratory syncytial virus infection in late preterm infants (32(1) to 35(0) weeks of gestation)]. An Paediatr (Barc) 2010;73:98.e1-4. [33] Samson L. The Canadian Paediatric Society, Infectious Diseases and Immunization Committee. Paediatr Child Health 2009;14:521–6. [34] Committee on Infectious Diseases. From the American Academy of Pediatrics: Policy statements — modified recommendations for use of palivizumab for prevention of respiratory syncytial virus infections. Pediatrics 2009;124: 1694–701. [35] The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalisation from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998;102:531–7. [36] Frogel M, Nerwen C, Boron M, Cohen A, VanVeldhuisen P, Harrington M, et al. Improved outcomes with home-based administration of palivizumab: results from the 2000–2004 palivizumab outcomes registry. Pediatr Infect Dis J 2008;27:870–3.