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Healthy Late-preterm infants born 33–36 + 6 weeks gestational age have higher risk for respiratory syncytial virus hospitalization
Early Human Development 91 (2015) 541–546
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Healthy Late-preterm infants born 33–36 + 6 weeks gestational age have higher risk for respiratory syncytial virus hospitalization Alison M. Helfrich a,b,⁎, Cade M. Nylund b, Matthew D. Eberly b, Matilda B. Eide b, David R. Stagliano a,b a b
Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, MD, USA Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
a r t i c l e
i n f o
Article history: Received 17 April 2015 Received in revised form 26 June 2015 Accepted 30 June 2015 Keywords: Respiratory syncytial virus Late preterm Lower respiratory tract infection Prematurity Palivizumab Bronchiolitis
a b s t r a c t Background: Respiratory syncytial virus (RSV) is a leading cause of hospitalization for children b1 year old and is more severe in premature infants. Objective: To assess whether late preterm (LPT) birth is an independent risk factor for RSV hospitalization and more severe RSV disease in children less than 24 months old. Methods: We conducted a retrospective cohort study of children enrolled in the military health system. LPT birth was defined as 33 + 0 through 36 + 6 weeks gestation. Patients who received palivizumab or had known risk factors for RSV were excluded. Adjusted hazard ratios (HR) for LPT birth were calculated using a Cox proportional hazard model, while controlling for sex and RSV season. Severity of illness was assessed by comparing the need for respiratory support, length of stay, and age at RSV hospitalization between LPT and term children. Results: A total of 599,535 children for 1,216,382 person-years were studied, of which 7597 children were admitted for RSV infection. LPT infants accounted for 643 (8.5%) of these RSV hospitalizations. The incidence density for RSV hospitalization of LPT infants was higher than term children (12.1 vs 7.8 per 1000 person-years). LPT infants had an increased adjusted risk for RSV hospitalization; specifically, those born 33 + 0 through 34 + 6 weeks (HR 2.45; 95% confidence interval (CI) 1.96–3.07), and 35 + 0 through 36 + 6 weeks (HR, 1.92; 95% CI, 1.66–2.22). LPT infants had longer hospital stays and required more respiratory support than term children. Conclusions: LPT birth is an independent risk factor for severe RSV disease and need for hospitalization. Published by Elsevier Ireland Ltd.
1. Introduction Respiratory syncytial virus (RSV) is one of the leading causes of hospitalizations in children b1 year old and infects nearly all children by age two [1,2]. RSV-related hospitalizations account for 24% of an estimated 5.5 million lower respiratory tract infections (LRTI) in children b5 years of age, which is an estimated 132,000 to 172,000 hospitalized children annually [3]. LRTI may account for up to 55% of pediatric intensive care unit (PICU) admissions, with a significant proportion (30%) of these hospitalizations occurring in premature infants [4]. Overall, RSV disease in children (and particularly in preterm infants) incurs both a significant cost and resource burden on the US health system [5,6].
Abbreviations: AAP, American Academy of Pediatrics; ACOG, American College of Obstetricians and Gynecologists; AHR, Absolute Hospitalization Rate; CHD, Congenital heart disease; CI, Confidence intervals; CLD, Chronic lung disease; ICD-9-CM, International Classification of Disease, 9th revision, Clinical Modification; HR, Adjusted hazard ratio; IDRSV, Incidence density for respiratory syncytial virus hospitalization; IQR, Interquartile range; LPT, Late preterm; LRTI, Lower respiratory tract infection; MHS, Military health system; PICU, Pediatric intensive care unit; RR, Relative risk; RSV, Respiratory syncytial virus; WGA, Weeks gestational age. ⁎ Corresponding author at: Walter Reed National Military Medical Center, Department of Pediatrics, 8901 Wisconsin Avenue, Bethesda, MD, USA, 20889. Tel.: +1 412 874 9476. E-mail address: [email protected] (A.M. Helfrich).
http://dx.doi.org/10.1016/j.earlhumdev.2015.06.009 0378-3782/Published by Elsevier Ireland Ltd.
Palivizumab is a monoclonal antibody that is used for immunoprophylaxis against RSV, specifically to reduce disease severity in high-risk populations. High-risk children are considered those b2 years old who require therapy for chronic lung disease (CLD) or hemodynamically-significant congenital heart disease (CHD), are unable to handle respiratory secretions from neuromuscular disease or anatomical airway abnormalities, are severely immunodeficient, and/or have premature birth [7–13]. A recent study also shows Down syndrome as a risk factor for severe RSV disease with increased risk for hospitalization [14]. In the phase III trial used to support licensure, palivizumab reduced RSV-related hospitalizations by 80% in infants born 32 through 35 weeks gestational age (WGA) [7]. After initial licensure, and until recommendations were revised in 2009, palivizumab was used for premature infants born between 32 and 35 WGA, who were less than six months of age at the beginning of the RSV season with at least two of five additional risk factors. In 2009, in an attempt to reduce overall healthcare cost and better target those born between 32 and 35 WGA at highest risk for severe RSV disease, the American Academy of Pediatrics (AAP) Committee on Infectious Diseases narrowed the guidelines for palivizumab immunoprophylaxis use in these premature infants [15]. The 2009 guidelines re-emphasize that, when prematurity is the only risk factor for severe RSV disease, both gestational and chronological age should
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determine if palivizumab is warranted. However, in 2014 these guidelines were updated and eliminated late preterm infants as a high risk group. The AAP now recommends limiting palivizumab immunoprophylaxis to premature infants born less than or equal to 29 + 0 WGA, unless an additional concomitant risk factor is present [16]. Premature births b37 WGA accounted for 11.4% of all births in the US in 2013, of which 70% were infants born 34 to 36 WGA [17]. Late preterm (LPT) infants, as defined by the AAP and the American College of Obstetricians and Gynecologists (ACOG), are infants born between 34 + 0 and 36 + 6 WGA [18]. When compared to term infants, LPT infants have a three- to five-fold higher rate for overall mortality and are at higher risk of developing medical complications during infancy [19,20]. McLaurin et al. studied different causes of hospitalization for LPT and term infants during the first year of life. Their study demonstrated that LPT infants were almost twice as likely to be hospitalized than term infants, with over 50% of the hospitalizations due to respiratory or gastrointestinal disorders [2]. Although LPT infants were no longer recommended to receive RSV immunoprophylaxis by the 2014 AAP guidelines, the risk of RSV hospitalization and burden of disease in this population may be significantly higher than in term children. Our objective is to assess whether healthy LPT infants born at 33 + 0 to 36 + 6 WGA, who did not receive palivizumab prophylaxis, are at greater risk for RSV hospitalization as compared to healthy term infants. We hypothesized that healthy LPT infants who did not receive palivizumab prophylaxis have increased rates of RSV hospitalization and more severe RSV disease than healthy term infants. 2. Methods 2.1. Study design and source We conducted a retrospective cohort study to compare the risk and rate of RSV hospitalization among healthy LPT infants to those of healthy term infants utilizing the Military Health System (MHS) database. The Department of Defense's health care program, known as TRICARE, provides benefits to members of the uniformed services and their families. TRICARE billing data of all beneficiaries is recorded in the MHS database, and contains inpatient, outpatient, and outpatient pharmacy data from both military and civilian treatment facilities (Fig. 1). This database includes a diversity of socioeonomic classes throughout the United States [21,22]. 2.2. Inclusion and exclusion criteria The MHS database was queried for all children born between 1 October 2005 and 30 April 2011 who were enrolled for more than 90 days of life. Subjects were followed until 24 months of age or healthcare disenrollment, whichever occurred earlier. Subjects were identified as having a hospitalization for RSV and/or risk factors for RSV using their International Classification of Disease, 9th revision, Clinical Modification (ICD-9-CM) diagnostic codes. ICD-9-CM diagnostic codes divide infants by their various gestational ages into the following subcategories: 31– 32 weeks completed gestation (756.26), 33–34 weeks completed gestation (765.27), 35–36 weeks completed gestation (756.28), and 37 or more weeks gestation (756.29), with similar categories for infants born less than 31 weeks gestation. Because we utilized ICD-9-CM codes to define our population, we were unable to remove those infants born 33 WGA from the analysis without also excluding 34 WGA infants. Therefore our study definition of LPT differs from the standard definition by including 33 WGA infants. We defined healthy LPT infants as infants born at 33 + 0 WGA through 36 + 6 WGA without known risk factors for severe RSV disease and who did not receive palivizumab. LPT infants were then divided into two LPT cohorts based on gestational
Fig. 1. Study Profile: military-dependent children b24 months-old born between 1 October 2005 and 30 April 2011.
age and the aforementioned ICD-9-CM codes: 33–34 completed WGA and 35–36 weeks completed WGA. These cohorts are referred to as 33–34 WGA and 35–36 WGA within the statistical analysis, while the overall LPT group included all the patients within both cohorts. The control group consisted of healthy term infants who were within the same age range during the same time frame as the LPT infants, who did not have a risk factor for severe RSV disease and who did not receive palivizumab. (See Table 1.) An event was defined as the first hospitalization of an individual patient with any primary or secondary discharge diagnosis of RSV disease, as defined by the following ICD-9-CM codes: RSV disease (079.6), bronchiolitis due to RSV (466.11), or pneumonia due to RSV (480.1). Each study year was defined broadly as July of the initial year through June the following year, i.e., study year 2 was July 2006 to June 2007. Study year 1 (October 2005 to June 2006) and study year 6 (July 2010 to April 2011) were exceptions because the dataset obtained from the MHS database started in October 2005 and ended in April 2011. From our initial patient population, we then excluded all patients who were considered high-risk for severe RSV disease or received palivizumab in the inpatient or outpatient setting. High-risk patients were defined by the ICD-9-CM codes for the following conditions: premature birth less than or equal to 32 + 6 WGA, hemodynamicallysignificant heart disease, CHD of unknown significance, CLD, congenital airway anomalies, cystic fibrosis, neuromuscular disease, immunodeficiency, and Down syndrome (Table 2). Hemodynamically-significant heart disease was defined by the presence of heart failure and/or pulmonary hypertension. CHD of unknown significance was defined by cardiac conditions that could potentially be hemodynamically significant, but not cardiac and/or vascular conditions that were unlikely to cause hemodynamically-significant heart disease. Palivizumab administration was identified by diagnostic, procedural, and drug codes (Table 2). Data obtained from individual hospitalizations included date of admission, age of the patient at admission, sex, length of stay, or use of respiratory support. Use of respiratory support was defined as use of an airway adjunct, need for respiratory intubation and/or mechanical ventilation as identified by ICD-9-CM clinical procedure codes (Table 2). The study was approved by our Institutional Review Board. All patient data were de-identified.
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Table 1 Study demographics.a
N Male Sexc RSV Hospitalization Males with RSV Hospitalization
33–34 WGA
35–36 WGA
LPTb
Term
Total
5938 3192 (54) 164 84 (51)
19,952 10,581 (53) 479 278 (58)
25,890 13,773 (53) 643 362 (56)
573,645 291,387 (51) 6954 3959 (57)
599,535 305,160 (51) 7597 4321 (57)
Weeks gestational age is abbreviated by WGA. Late preterm is abbreviated by LPT. Respiratory syncytial virus is abbreviated by RSV. a Data are presented as numbers (percent) unless otherwise indicated. b LPT includes both 33–34 WGA and 35–36 WGA cohorts. c Sex was unknown for 2620 patients within the study.
2.3. Statistical analysis Absolute hospitalization rate (AHR) was calculated by dividing the number of patients admitted for RSV by the total number of patients studied in each cohort. The incidence density for RSV hospitalization (IDRSV) was calculated by dividing the number of patients hospitalized for RSV by the person-years at risk. The non-normally distributed variables, length of stay and age at time of RSV hospitalization, were expressed as medians with interquartile ranges (IQR) in days and months. The Mann–Whitney U test was used to compare length of stay and age for LPT versus term infants, while the Kruskal–Wallis test was used to compare across the two independent LPT cohorts and term infants. The chi-squared test and relative risk (RR) were used to
Table 2 International Classification of Disease, 9th revision, Clinical Modification Codes. Used to indicate risk factors for respiratory syncytial virus hospitalization, procedures, and therapeutic interventions. Diagnosis
ICD-9-CM Code
Respiratory Syncytial Virus Disease (including bronchiolitis and pneumonia) Prematurity Term birth Hemodynamically Significant Heart Disease (including pulmonary hypertension, heart failure) Congenital Heart Disease of unknown significance (including cardiomyopathy) Chronic Lung Disease Congenital Pulmonary Anomalies Cystic Fibrosis Neuromuscular disease
079.6, 466.11, 480.1
Immunodeficiency Down Syndrome Palivizumab Airway adjunct, respiratory intubation and mechanical ventilation
765a 765.29 416b, 417b, 428b
425b, 745b, 746c 747d 770.7 748b 277.0b 330.0–330.3, 330.8, 330.9, 331.81, 331.89, 331.9, 333.0–333.7, 333.71, 333.72, 334.0–334.4, 334.8, 334.9, 335.0, 335.1, 335.11, 335.19, 335.20–335.24, 335.29, 335.8, 335.9, 336.1, 336.2, 336.3, 336.8, 336.9 279b 758.0 V04.82; CPT 90378; NDC 605744113, 605744114 93.90e, 93.92e, 96.01e, 96.02e, 96.04e, 96.05e, 96.7–96.72e
American Medical Association Current Procedural Terminology Code is abbreviated by CPT. National Drug Code is abbreviated by NDC. a Includes all diagnostic subcodes with exclusion of 765.27 (37 or more completed weeks gestation). b Includes all diagnostic subcodes. c Includes all diagnostic subcodes with exclusion of 746.86 (congenital heart block). d Includes all diagnostic subcodes with exclusion of 747.0 (patent ductus arteriosus), 747.5 (absence or hypoplasia of umbilical artery), 747.6–747.69 (other congenital anomalies of peripheral vascular system), 747.8–747.89 (other specified anomalies of the circulatory system). e International Classification of Disease, 9th revision, Clinical Modification procedure codes.
evaluate the proportion of LPT versus term infants requiring respiratory support. Single event analysis was performed utilizing the Cox proportional hazards model including sex and premature gestational groups as independent, time-fixed variables. The hazard ratios were calculated for the entire cohort period of 24 months. In an effort to evaluate and compare differences in the association between LPT birth and RSV disease by chronologic age, four additional models were evaluated by the age groups: 0–3 months, 3–6 months, 6–12 months and 12–24 months. The final models included all of the individual RSV study years as time-dependent, stratification variables. The covariate-adjusted hazard ratios (HR) were reported with 95% confidence intervals (CI). For visualization purposes, we plotted estimated survival curves for each late preterm group and term infants. An alpha of 0.05 was used to determine significance. All analyses were performed using SAS 9.3 (SAS Institute, Cary, NC). 3. Results A total of 599,535 children under 24 months-old and 1,216,382 person-years were studied, of which 25,890 (4.3%) were healthy LPT children (Fig. 1). There was a higher proportion of males who were LPT within the studied cohort than term (53% vs. 51%; P b 0.001). Overall, 7,597 children were admitted for RSV and 8.5% of these hospitalizations occurred in LPT children. LPT infants had an absolute hospitalization rate (AHR) of 2.5%, while term infants had an AHR of 1.3% (P b 0.001). Within the two LPT cohorts, those born 33–34 WGA had the highest AHR at 2.8% (Table 3). The IDRSV of LPT and term infants was 12.1 and 7.8 per 1000 personyears, respectively. Among the LPT infants, the 33–34 WGA cohort also had the highest IDRSV at 18.0 per 1000 person-years. LPT infants had a significantly increased adjusted risk for RSV hospitalization seen within each cohort and consistently higher even when evaluated by chronologic age (Table 4). The estimated percent survival curves also graphically demonstrated that LPT birth was associated with this increased risk of RSV hospitalization (Fig. 2). Males had an increased adjusted risk for RSV hospitalization as compared to females (HR 1.25; 95% CI 1.19–1.31). There was no difference in the median age (IQR) at admission for LPT and term infants, which were 3.2 (1.7–7.8) months and 3.3 (1.6–7.3) months, respectively (P = 0.55). The median (IQR) length of stay for LPT infants was significantly longer at 3 [2–4] days, as compared to 2 [1–3] days (P b 0.001) for term infants. LPT infants had a three-fold higher risk of requiring respiratory support than those born term (RR 3.71; 95% CI 2.36–5.82), as evidenced by the use of an airway adjunct and/or endotracheal intubation and mechanical ventilation. 4. Discussion Our study demonstrates that LPT infants without other risk factors had both a significantly higher risk for RSV hospitalization and requirement for respiratory support than healthy term infants. The IDRSV of
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Table 3 Absolute Hospitalization Rate, Rate Ratio, Incidence Density, length of stay, and age at admission of military-dependent children b24 months-old admitted with RSV. Risk Factor
33–34 WGA n = 164
35–36 WGA n = 479
LPT Infants n = 643
Term Infants n = 6,954
Absolute Hospitalization Rate (%) Incidence Rate Ratio (compared to term) Incidence Density for RSV Hospitalization (per 1000 person-years) Median (IQR) Length of Stay in Days Median (IQR) Age at Admission in Months
2.8 2.25 (1.92–2.62) 18.0 3 (2–4) a 3.4 (1.8–6.7) c
2.4 1.98 (1.81–2.18) 15.7 2 (2–4) a 3.1 (1.6–8.1) c
2.5 2.08 (1.92–2.26) 12.1 3 (2–4) b 3.2 (1.7–7.8) d
1.3 1 7.8 2 (1–3) a,b 3.3 (1.6–7.3) c,d
Respiratory syncytial virus is abbreviated as RSV. Interquartile range is abbreviated as IQR. Late preterm is abbreviated as LPT. Weeks gestational age is abbreviated as WGA. a P-value is b0.001 by Kruskal–Wallis test comparing the cohort group, term infants and the other age cohort. b P-value is b0.001 by Mann–Whitney U test comparing LPT infants to term infants. c P-value is 0.74 by Kruskal–Wallis test comparing the cohort group, term infants and the other age cohort. d P-value is 0.55 by Mann–Whitney U test comparing the cohort group to combined term infants and the other age cohorts.
12.1 per 1000 person-years was one-and-a-half times as high for LPT infants as compared to term infants. We also found that infants in the 33–34 WGA cohort had the highest adjusted hazard ratio for RSV hospitalization at 2.45 (95% CI 1.96–3.07). Prematurity interrupts the development of the immune system and lungs for LPT infants, adversely affecting their ability to cope with the inflammatory response to RSV, allowing for a prolonged infection. While many animal studies provide models for understanding the immunopathology for RSV, the normal human immune response to RSV is still unclear and varies in infants, children, and adults. Studies suggest that cytokines, T-lymphocytes, and neutralizing antibodies play a significant role in human response to RSV infection [23]. Maternally-derived antibodies against RSV are passively acquired during pregnancy but rapidly decline after birth, with a nadir around six months of age [24]. Incomplete transfer of maternal antibody, as well as an immature neonatal immune system, may limit the humoral response to RSV infection, placing premature infants at higher risk during early infancy. Our study showed LPT infants had more severe RSV disease with a higher rate of requiring respiratory support. Intubation with mechanical ventilation usually is utilized only in the PICU; while we did not specifically obtain data regarding PICU stays, increased respiratory support provides a useful marker for more severe RSV disease. LPT infants may require more support than term infants for various reasons. LPT infants have lower functional residual capacity, decreased compliance, and smaller airway diameters than term infants at baseline [20,25,26]. Alveoli are not completely mature until 36 WGA, thus placing LPT infants at higher risk for impaired gas exchange and hypoxia [27]. Lung development interruption from premature birth causes the aforementioned changes and LPT infants are unable to adequately handle the physiological effects of RSV infection. In general, RSV directly injures
the lung epithelium, generating debris from sloughed respiratory epithelial cells, leading to increased mucous production and mucosal edema [28]. Because of their smaller airways and decreased functional residual capacity, LPT infants cannot tolerate the RSV cellular debris and mucous plugs that produce bronchiole obstruction and V–Q mismatch, provoking breathing difficulties and respiratory distress. Impaired gas exchange affects oxygenation and ventilation, resulting in hypoxemia, and requires supplemental oxygen and/or respiratory support. In addition to increased need of respiratory support, we found the length of stay was longer for LPT infants by one day, which contributes to higher medical costs and the potential for increased acquisition and transmission of nosocomial infections among hospitalized children. Palivizumab is a neutralizing monoclonal antibody that prevents severe RSV disease for up to 28 days, and requires high risk populations to receive monthly injections during the RSV season [7]. Multiple health care visits along with medication cost make immunoprophylaxis expensive. Current literature regarding cost-benefit analysis of palivizumab for LPT infants is conflicting. While two retrospective cohort studies have found LPT infants had significantly higher RSV hospitalization costs than term infants [5,6], a literature review by the Cochrane Collaboration found the economic benefit of palivizumab use to be inconsistent [28]. Further cost-assessment studies are needed to assess palivizumab immunoprophylaxis for healthy LPT infants, and further investigate its ability to ameliorate severe RSV disease and prevent hospitalization in this cohort. Previous studies proved that prematurity is a risk factor for severe RSV disease but there are few studies that evaluated the risk in healthy LPT infants. A small prospective study showed LPT infants born 32–36 WGA have a higher RSV hospitalization rate than term infants but risk
Table 4 Adjusted Hazard Ratios for RSV hospitalization based on chronological age groups. Age at admission
Overall (0–24 months) 0–3 monthsa 3–6 monthsa 6–12 monthsa 12–24 monthsa
a
33–34 WGA
35–36 WGA
Term
Male Sex
HR [95% CI]
HR [95% CI]
(reference)
HR [95% CI]
2.45 [1.96 – 3.07] 1.80 [1.43–2.26] 2.37 [1.74–3.23]. 1.74 [1.17–2.58]b 1.96 [1.26–3.05]b
1.92 [1.66 – 2.22] 1.76 [1.44–2.15] 1.71 [1.49–1.95] 1.75 [1.39–2.21] 2.27 [1.79–1.88]
1.00 1.00 1.00 1.00 1.00
1.25 [1.19 – 1.31] 1.15 [1.08–1.23] 1.46 [1.32–1.61] 1.46 [1.31–1.64] 1.12 [0.99–1.27]c
Adjusted hazard ratios were calculated by Cox proportional hazard regression. Respiratory syncytial virus is abbreviated as RSV. Weeks gestational age is abbreviated as WGA. Hazard ratio is abbreviated as HR. Confidence interval is abbreviated as CI. a P b 0.001 for all groups except as indicated. b P b 0.05. c P = 0.07.
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and whether additional specific risk factors can be identified. Additional studies are needed to determine if palivizumab immunoprophylaxis would be cost-beneficial for healthy LPT infants. Conflict of Interest Statement The authors have no conflicts of interest to disclose. Disclaimer The views expressed in this article are those of the authors and do not reflect the official policy or position of the United States Armed Forces, Department of Defense, or the U.S. Government. Contributor's Statement
Fig. 2. Estimated percent without RSV Hospitalization stratified by study cohorts.
factors for severe RSV disease were not excluded [29]. Hall et al. found LPT infants had a higher rate of hospitalization for RSV bronchiolitis, regardless of palivizumab use, when compared to infants N35 WGA, but LPT infants were hospitalized significantly less than term infants [30]. Our study shows consistently that healthy LPT infants have higher rates and risk for hospitalization due to severe RSV disease and is novel to the current literature. The design of our study has potential limitations. The MHS database relies on ICD-9-CM billing codes, which allows for misclassification of patient data and prevents chart review; patients may have been excluded for lack of specific diagnosis (for example: bronchiolitis vs. RSV bronchiolitis) or failure to include prematurity as a diagnosis. Without individual chart or laboratory review, we were unable to confirm RSV disease through microbiological lab testing. We also were limited in our definition of LPT birth due to ICD-9-CM codes and had to include infants born 33 WGA, which deviates from the AAP and ACOG definition. The infants born 33 WGA may have more severe RSV disease since they are more premature, which may have contributed to their higher adjusted hazard ratio and IDRSV. Given that the new AAP palivizumab guidelines still exclude these infants from immunoprophylaxis based on prematurity alone, the inclusion of these infants suggests that further study among this cohort is important. One strength of our study is our large patient population, which provides a large demographically and socioeconomically diverse group of children. These patients have universal access to healthcare facilities throughout the United States, making our results applicable to the general population [21,22]. LPT births accounted for 7.99% of all births in the United States in 2013, showing there is a significant population at risk for severe RSV disease [17]. We also evaluated RSV disease severity by the need for respiratory support because the literature had limited data specifically for late preterm infants and RSV hospitalization. We found that healthy LPT infants had a significantly higher risk of requiring respiratory support (RR 3.71, 95% CI 2.36-5.82) when compared to healthy term infants. 5. Conclusions LPT birth is an independent risk factor for severe RSV disease and need for hospitalization. Although LPT infants are often medically managed similarly to term infants, they are at significantly higher risk for severe RSV disease, resulting in a greater risk of hospitalization, longer stay, and higher rate of requirement for respiratory support. Further studies are needed to identify why LPT is a risk factor for severe disease,
Alison M. Helfrich: Dr. Helfrich interpreted the results, drafted and edited the initial manuscript and approved the final manuscript as submitted. Cade M. Nylund: Dr. Nylund carried out the data analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted. Matthew D. Eberly: Dr. Eberly conceptualized and designed the study, reviewed and revised the manuscript, and approved the final manuscript as submitted. Matilda B. Eide: Ms. Eide designed the data collection instruments, collected and organized the data and reviewed and approved the final manuscript as submitted. David R. Stagliano: Dr. Stagliano conceptualized and designed the study, contributed to the data analysis, edited the manuscript, and approved the final manuscript as submitted. Acknowledgements The authors would like to thank Drs. Martin Ottolini, Gregory Gorman, Michael Rajnik and Kathleen Madden for their critical review of the manuscript. References [1] Black CP. Systematic review of the biology and medical management of respiratory syncytial virus infection. Respir Care 2003 Mar;48(3):209–31 [discussion 231–3]. [2] McLaurin KK, Hall CB, Jackson EA, Owens OV, Mahadevia PJ. Persistence of morbidity and cost differences between late-preterm and term infants during the first year of life. Pediatrics 2009 Feb;123(2):653–9. [3] Gunville CF, Sontag MK, Stratton KA, Ranade DJ, Abman SH, Mourani PM. Scope and impact of early and late preterm infants admitted to the PICU with respiratory illness. J Pediatr Aug 2010;157(2) [209-214.e1]. [4] Stockman LJ, Curns AT, Anderson LJ, Fischer-Langley G. Respiratory syncytial virusassociated hospitalizations among infants and young children in the United States, 1997–2006. Pediatr Infect Dis J Jan 2012;31(1):5–9. [5] Stewart DL, Romero JR, Buysman EK, Fernandes AW, Mahadevia PJ. Total healthcare costs in the US for preterm infants with respiratory syncytial virus lower respiratory infection in the first year of life requiring medical attention. Curr Med Res Opin Nov 2009;25(11):2795–804. [6] Forbes ML, Hall CB, Jackson A, Masaquel AS, Mahadevia PJ. Comparative costs of hospitalisation among infants at high risk for respiratory syncytial virus lower respiratory tract infection during the first year of life. J Med Econ Mar 2010;13(1): 136–41. [7] Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. The IMpact-RSV Study Group. Pediatrics Sep 1998;102(3 Pt 1):531–7. [8] Arnold SR, Wang EE, Law BJ, Boucher FD, Stephens D, Robinson JL, et al. Variable morbidity of respiratory syncytial virus infection in patients with underlying lung disease: a review of the PICNIC RSV database. Pediatric Investigators Collaborative Network on Infections in Canada. Pediatr Infect Dis J Oct 1999;18(10):866–9. [9] Purcell K, Fergie J. Driscoll Children's Hospital respiratory syncytial virus database: risk factors, treatment and hospital course in 3308 infants and young children, 1991 to 2002. Pediatr Infect Dis J May 2004;23(5):418–23. [10] Feltes TF, Cabalka AK, Meissner HC, Piazza FM, Carlin DA, Top Jr FH, et al. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease. J Pediatr Oct 2003; 143(4):532–40.
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[21] US Department of Defense. Demographics 2010: Profile of the military community. Office of the Deputy Under Secretary of Defense (Military Community and Family Policy); 2010 1–185. [22] Barrett JP, Sevick CJ, Conlin AM, Gumbs GR, Lee S, Martin DP, et al. Validating the use of ICD-9-CM codes to evaluate gestational age and birth weight. J Registry Manag Summer 2012;39(2):69–75. [23] Borchers AT, Chang C, Gershwin ME, Gershwin LJ. Respiratory syncytial virus—a comprehensive review. Clin Rev Allergy Immunol Dec 2013;45(3):331–79. [24] Ochola R, Sande C, Fegan G, Scott PD, Medley GF, Cane PA, et al. The level and duration of RSV-specific maternal IgG in infants in Kilifi Kenya. PLoS One Dec 2 2009; 4(12):e8088. [25] 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 Dec 15 2007; 176(12):1269–73. [26] Manzoni P, Paes B, Resch B, Carbonell-Estrany X, Bont L. High risk for RSV bronchiolitis in late preterms and selected infants affected by rare disorders: a dilemma of specific prevention. Early Hum Dev May 2012;88(Suppl. 2):S34–41. [27] Maritz GS, Morley CJ, Harding R. Early developmental origins of impaired lung structure and function. Early Hum Dev Sep 2005;81(9):763–71. [28] Andabaka T, Nickerson JW, Rojas-Reyes MX, Rueda JD, Bacic Vrca V, Barsic B. Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children. Cochrane Database Syst Rev Apr 30 2013;4:CD006602. [29] Olabarrieta I, Gonzalez-Carrasco E, Calvo C, Pozo F, Casas I, Garcia-Garcia ML. Hospital admission due to respiratory viral infections in moderate preterm, late preterm and term infants during their first year of life. Allergol Immunopathol (Madr) Nov 2014;8. [30] Hall CB, Weinberg GA, Blumkin AK, Edwards KM, Staat MA, Schultz AF, et al. Respiratory syncytial virus-associated hospitalizations among children less than 24 months of age. Pediatrics Aug 2013;132(2):e341–8.
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Healthy Late-preterm infants born 33–36 + 6 weeks gestational age have higher risk for respiratory syncytial virus hospitalization Alison M. Helfrich a,b,⁎, Cade M. Nylund b, Matthew D. Eberly b, Matilda B. Eide b, David R. Stagliano a,b a b
Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, MD, USA Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
a r t i c l e
i n f o
Article history: Received 17 April 2015 Received in revised form 26 June 2015 Accepted 30 June 2015 Keywords: Respiratory syncytial virus Late preterm Lower respiratory tract infection Prematurity Palivizumab Bronchiolitis
a b s t r a c t Background: Respiratory syncytial virus (RSV) is a leading cause of hospitalization for children b1 year old and is more severe in premature infants. Objective: To assess whether late preterm (LPT) birth is an independent risk factor for RSV hospitalization and more severe RSV disease in children less than 24 months old. Methods: We conducted a retrospective cohort study of children enrolled in the military health system. LPT birth was defined as 33 + 0 through 36 + 6 weeks gestation. Patients who received palivizumab or had known risk factors for RSV were excluded. Adjusted hazard ratios (HR) for LPT birth were calculated using a Cox proportional hazard model, while controlling for sex and RSV season. Severity of illness was assessed by comparing the need for respiratory support, length of stay, and age at RSV hospitalization between LPT and term children. Results: A total of 599,535 children for 1,216,382 person-years were studied, of which 7597 children were admitted for RSV infection. LPT infants accounted for 643 (8.5%) of these RSV hospitalizations. The incidence density for RSV hospitalization of LPT infants was higher than term children (12.1 vs 7.8 per 1000 person-years). LPT infants had an increased adjusted risk for RSV hospitalization; specifically, those born 33 + 0 through 34 + 6 weeks (HR 2.45; 95% confidence interval (CI) 1.96–3.07), and 35 + 0 through 36 + 6 weeks (HR, 1.92; 95% CI, 1.66–2.22). LPT infants had longer hospital stays and required more respiratory support than term children. Conclusions: LPT birth is an independent risk factor for severe RSV disease and need for hospitalization. Published by Elsevier Ireland Ltd.
1. Introduction Respiratory syncytial virus (RSV) is one of the leading causes of hospitalizations in children b1 year old and infects nearly all children by age two [1,2]. RSV-related hospitalizations account for 24% of an estimated 5.5 million lower respiratory tract infections (LRTI) in children b5 years of age, which is an estimated 132,000 to 172,000 hospitalized children annually [3]. LRTI may account for up to 55% of pediatric intensive care unit (PICU) admissions, with a significant proportion (30%) of these hospitalizations occurring in premature infants [4]. Overall, RSV disease in children (and particularly in preterm infants) incurs both a significant cost and resource burden on the US health system [5,6].
Abbreviations: AAP, American Academy of Pediatrics; ACOG, American College of Obstetricians and Gynecologists; AHR, Absolute Hospitalization Rate; CHD, Congenital heart disease; CI, Confidence intervals; CLD, Chronic lung disease; ICD-9-CM, International Classification of Disease, 9th revision, Clinical Modification; HR, Adjusted hazard ratio; IDRSV, Incidence density for respiratory syncytial virus hospitalization; IQR, Interquartile range; LPT, Late preterm; LRTI, Lower respiratory tract infection; MHS, Military health system; PICU, Pediatric intensive care unit; RR, Relative risk; RSV, Respiratory syncytial virus; WGA, Weeks gestational age. ⁎ Corresponding author at: Walter Reed National Military Medical Center, Department of Pediatrics, 8901 Wisconsin Avenue, Bethesda, MD, USA, 20889. Tel.: +1 412 874 9476. E-mail address: [email protected] (A.M. Helfrich).
http://dx.doi.org/10.1016/j.earlhumdev.2015.06.009 0378-3782/Published by Elsevier Ireland Ltd.
Palivizumab is a monoclonal antibody that is used for immunoprophylaxis against RSV, specifically to reduce disease severity in high-risk populations. High-risk children are considered those b2 years old who require therapy for chronic lung disease (CLD) or hemodynamically-significant congenital heart disease (CHD), are unable to handle respiratory secretions from neuromuscular disease or anatomical airway abnormalities, are severely immunodeficient, and/or have premature birth [7–13]. A recent study also shows Down syndrome as a risk factor for severe RSV disease with increased risk for hospitalization [14]. In the phase III trial used to support licensure, palivizumab reduced RSV-related hospitalizations by 80% in infants born 32 through 35 weeks gestational age (WGA) [7]. After initial licensure, and until recommendations were revised in 2009, palivizumab was used for premature infants born between 32 and 35 WGA, who were less than six months of age at the beginning of the RSV season with at least two of five additional risk factors. In 2009, in an attempt to reduce overall healthcare cost and better target those born between 32 and 35 WGA at highest risk for severe RSV disease, the American Academy of Pediatrics (AAP) Committee on Infectious Diseases narrowed the guidelines for palivizumab immunoprophylaxis use in these premature infants [15]. The 2009 guidelines re-emphasize that, when prematurity is the only risk factor for severe RSV disease, both gestational and chronological age should
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determine if palivizumab is warranted. However, in 2014 these guidelines were updated and eliminated late preterm infants as a high risk group. The AAP now recommends limiting palivizumab immunoprophylaxis to premature infants born less than or equal to 29 + 0 WGA, unless an additional concomitant risk factor is present [16]. Premature births b37 WGA accounted for 11.4% of all births in the US in 2013, of which 70% were infants born 34 to 36 WGA [17]. Late preterm (LPT) infants, as defined by the AAP and the American College of Obstetricians and Gynecologists (ACOG), are infants born between 34 + 0 and 36 + 6 WGA [18]. When compared to term infants, LPT infants have a three- to five-fold higher rate for overall mortality and are at higher risk of developing medical complications during infancy [19,20]. McLaurin et al. studied different causes of hospitalization for LPT and term infants during the first year of life. Their study demonstrated that LPT infants were almost twice as likely to be hospitalized than term infants, with over 50% of the hospitalizations due to respiratory or gastrointestinal disorders [2]. Although LPT infants were no longer recommended to receive RSV immunoprophylaxis by the 2014 AAP guidelines, the risk of RSV hospitalization and burden of disease in this population may be significantly higher than in term children. Our objective is to assess whether healthy LPT infants born at 33 + 0 to 36 + 6 WGA, who did not receive palivizumab prophylaxis, are at greater risk for RSV hospitalization as compared to healthy term infants. We hypothesized that healthy LPT infants who did not receive palivizumab prophylaxis have increased rates of RSV hospitalization and more severe RSV disease than healthy term infants. 2. Methods 2.1. Study design and source We conducted a retrospective cohort study to compare the risk and rate of RSV hospitalization among healthy LPT infants to those of healthy term infants utilizing the Military Health System (MHS) database. The Department of Defense's health care program, known as TRICARE, provides benefits to members of the uniformed services and their families. TRICARE billing data of all beneficiaries is recorded in the MHS database, and contains inpatient, outpatient, and outpatient pharmacy data from both military and civilian treatment facilities (Fig. 1). This database includes a diversity of socioeonomic classes throughout the United States [21,22]. 2.2. Inclusion and exclusion criteria The MHS database was queried for all children born between 1 October 2005 and 30 April 2011 who were enrolled for more than 90 days of life. Subjects were followed until 24 months of age or healthcare disenrollment, whichever occurred earlier. Subjects were identified as having a hospitalization for RSV and/or risk factors for RSV using their International Classification of Disease, 9th revision, Clinical Modification (ICD-9-CM) diagnostic codes. ICD-9-CM diagnostic codes divide infants by their various gestational ages into the following subcategories: 31– 32 weeks completed gestation (756.26), 33–34 weeks completed gestation (765.27), 35–36 weeks completed gestation (756.28), and 37 or more weeks gestation (756.29), with similar categories for infants born less than 31 weeks gestation. Because we utilized ICD-9-CM codes to define our population, we were unable to remove those infants born 33 WGA from the analysis without also excluding 34 WGA infants. Therefore our study definition of LPT differs from the standard definition by including 33 WGA infants. We defined healthy LPT infants as infants born at 33 + 0 WGA through 36 + 6 WGA without known risk factors for severe RSV disease and who did not receive palivizumab. LPT infants were then divided into two LPT cohorts based on gestational
Fig. 1. Study Profile: military-dependent children b24 months-old born between 1 October 2005 and 30 April 2011.
age and the aforementioned ICD-9-CM codes: 33–34 completed WGA and 35–36 weeks completed WGA. These cohorts are referred to as 33–34 WGA and 35–36 WGA within the statistical analysis, while the overall LPT group included all the patients within both cohorts. The control group consisted of healthy term infants who were within the same age range during the same time frame as the LPT infants, who did not have a risk factor for severe RSV disease and who did not receive palivizumab. (See Table 1.) An event was defined as the first hospitalization of an individual patient with any primary or secondary discharge diagnosis of RSV disease, as defined by the following ICD-9-CM codes: RSV disease (079.6), bronchiolitis due to RSV (466.11), or pneumonia due to RSV (480.1). Each study year was defined broadly as July of the initial year through June the following year, i.e., study year 2 was July 2006 to June 2007. Study year 1 (October 2005 to June 2006) and study year 6 (July 2010 to April 2011) were exceptions because the dataset obtained from the MHS database started in October 2005 and ended in April 2011. From our initial patient population, we then excluded all patients who were considered high-risk for severe RSV disease or received palivizumab in the inpatient or outpatient setting. High-risk patients were defined by the ICD-9-CM codes for the following conditions: premature birth less than or equal to 32 + 6 WGA, hemodynamicallysignificant heart disease, CHD of unknown significance, CLD, congenital airway anomalies, cystic fibrosis, neuromuscular disease, immunodeficiency, and Down syndrome (Table 2). Hemodynamically-significant heart disease was defined by the presence of heart failure and/or pulmonary hypertension. CHD of unknown significance was defined by cardiac conditions that could potentially be hemodynamically significant, but not cardiac and/or vascular conditions that were unlikely to cause hemodynamically-significant heart disease. Palivizumab administration was identified by diagnostic, procedural, and drug codes (Table 2). Data obtained from individual hospitalizations included date of admission, age of the patient at admission, sex, length of stay, or use of respiratory support. Use of respiratory support was defined as use of an airway adjunct, need for respiratory intubation and/or mechanical ventilation as identified by ICD-9-CM clinical procedure codes (Table 2). The study was approved by our Institutional Review Board. All patient data were de-identified.
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Table 1 Study demographics.a
N Male Sexc RSV Hospitalization Males with RSV Hospitalization
33–34 WGA
35–36 WGA
LPTb
Term
Total
5938 3192 (54) 164 84 (51)
19,952 10,581 (53) 479 278 (58)
25,890 13,773 (53) 643 362 (56)
573,645 291,387 (51) 6954 3959 (57)
599,535 305,160 (51) 7597 4321 (57)
Weeks gestational age is abbreviated by WGA. Late preterm is abbreviated by LPT. Respiratory syncytial virus is abbreviated by RSV. a Data are presented as numbers (percent) unless otherwise indicated. b LPT includes both 33–34 WGA and 35–36 WGA cohorts. c Sex was unknown for 2620 patients within the study.
2.3. Statistical analysis Absolute hospitalization rate (AHR) was calculated by dividing the number of patients admitted for RSV by the total number of patients studied in each cohort. The incidence density for RSV hospitalization (IDRSV) was calculated by dividing the number of patients hospitalized for RSV by the person-years at risk. The non-normally distributed variables, length of stay and age at time of RSV hospitalization, were expressed as medians with interquartile ranges (IQR) in days and months. The Mann–Whitney U test was used to compare length of stay and age for LPT versus term infants, while the Kruskal–Wallis test was used to compare across the two independent LPT cohorts and term infants. The chi-squared test and relative risk (RR) were used to
Table 2 International Classification of Disease, 9th revision, Clinical Modification Codes. Used to indicate risk factors for respiratory syncytial virus hospitalization, procedures, and therapeutic interventions. Diagnosis
ICD-9-CM Code
Respiratory Syncytial Virus Disease (including bronchiolitis and pneumonia) Prematurity Term birth Hemodynamically Significant Heart Disease (including pulmonary hypertension, heart failure) Congenital Heart Disease of unknown significance (including cardiomyopathy) Chronic Lung Disease Congenital Pulmonary Anomalies Cystic Fibrosis Neuromuscular disease
079.6, 466.11, 480.1
Immunodeficiency Down Syndrome Palivizumab Airway adjunct, respiratory intubation and mechanical ventilation
765a 765.29 416b, 417b, 428b
425b, 745b, 746c 747d 770.7 748b 277.0b 330.0–330.3, 330.8, 330.9, 331.81, 331.89, 331.9, 333.0–333.7, 333.71, 333.72, 334.0–334.4, 334.8, 334.9, 335.0, 335.1, 335.11, 335.19, 335.20–335.24, 335.29, 335.8, 335.9, 336.1, 336.2, 336.3, 336.8, 336.9 279b 758.0 V04.82; CPT 90378; NDC 605744113, 605744114 93.90e, 93.92e, 96.01e, 96.02e, 96.04e, 96.05e, 96.7–96.72e
American Medical Association Current Procedural Terminology Code is abbreviated by CPT. National Drug Code is abbreviated by NDC. a Includes all diagnostic subcodes with exclusion of 765.27 (37 or more completed weeks gestation). b Includes all diagnostic subcodes. c Includes all diagnostic subcodes with exclusion of 746.86 (congenital heart block). d Includes all diagnostic subcodes with exclusion of 747.0 (patent ductus arteriosus), 747.5 (absence or hypoplasia of umbilical artery), 747.6–747.69 (other congenital anomalies of peripheral vascular system), 747.8–747.89 (other specified anomalies of the circulatory system). e International Classification of Disease, 9th revision, Clinical Modification procedure codes.
evaluate the proportion of LPT versus term infants requiring respiratory support. Single event analysis was performed utilizing the Cox proportional hazards model including sex and premature gestational groups as independent, time-fixed variables. The hazard ratios were calculated for the entire cohort period of 24 months. In an effort to evaluate and compare differences in the association between LPT birth and RSV disease by chronologic age, four additional models were evaluated by the age groups: 0–3 months, 3–6 months, 6–12 months and 12–24 months. The final models included all of the individual RSV study years as time-dependent, stratification variables. The covariate-adjusted hazard ratios (HR) were reported with 95% confidence intervals (CI). For visualization purposes, we plotted estimated survival curves for each late preterm group and term infants. An alpha of 0.05 was used to determine significance. All analyses were performed using SAS 9.3 (SAS Institute, Cary, NC). 3. Results A total of 599,535 children under 24 months-old and 1,216,382 person-years were studied, of which 25,890 (4.3%) were healthy LPT children (Fig. 1). There was a higher proportion of males who were LPT within the studied cohort than term (53% vs. 51%; P b 0.001). Overall, 7,597 children were admitted for RSV and 8.5% of these hospitalizations occurred in LPT children. LPT infants had an absolute hospitalization rate (AHR) of 2.5%, while term infants had an AHR of 1.3% (P b 0.001). Within the two LPT cohorts, those born 33–34 WGA had the highest AHR at 2.8% (Table 3). The IDRSV of LPT and term infants was 12.1 and 7.8 per 1000 personyears, respectively. Among the LPT infants, the 33–34 WGA cohort also had the highest IDRSV at 18.0 per 1000 person-years. LPT infants had a significantly increased adjusted risk for RSV hospitalization seen within each cohort and consistently higher even when evaluated by chronologic age (Table 4). The estimated percent survival curves also graphically demonstrated that LPT birth was associated with this increased risk of RSV hospitalization (Fig. 2). Males had an increased adjusted risk for RSV hospitalization as compared to females (HR 1.25; 95% CI 1.19–1.31). There was no difference in the median age (IQR) at admission for LPT and term infants, which were 3.2 (1.7–7.8) months and 3.3 (1.6–7.3) months, respectively (P = 0.55). The median (IQR) length of stay for LPT infants was significantly longer at 3 [2–4] days, as compared to 2 [1–3] days (P b 0.001) for term infants. LPT infants had a three-fold higher risk of requiring respiratory support than those born term (RR 3.71; 95% CI 2.36–5.82), as evidenced by the use of an airway adjunct and/or endotracheal intubation and mechanical ventilation. 4. Discussion Our study demonstrates that LPT infants without other risk factors had both a significantly higher risk for RSV hospitalization and requirement for respiratory support than healthy term infants. The IDRSV of
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Table 3 Absolute Hospitalization Rate, Rate Ratio, Incidence Density, length of stay, and age at admission of military-dependent children b24 months-old admitted with RSV. Risk Factor
33–34 WGA n = 164
35–36 WGA n = 479
LPT Infants n = 643
Term Infants n = 6,954
Absolute Hospitalization Rate (%) Incidence Rate Ratio (compared to term) Incidence Density for RSV Hospitalization (per 1000 person-years) Median (IQR) Length of Stay in Days Median (IQR) Age at Admission in Months
2.8 2.25 (1.92–2.62) 18.0 3 (2–4) a 3.4 (1.8–6.7) c
2.4 1.98 (1.81–2.18) 15.7 2 (2–4) a 3.1 (1.6–8.1) c
2.5 2.08 (1.92–2.26) 12.1 3 (2–4) b 3.2 (1.7–7.8) d
1.3 1 7.8 2 (1–3) a,b 3.3 (1.6–7.3) c,d
Respiratory syncytial virus is abbreviated as RSV. Interquartile range is abbreviated as IQR. Late preterm is abbreviated as LPT. Weeks gestational age is abbreviated as WGA. a P-value is b0.001 by Kruskal–Wallis test comparing the cohort group, term infants and the other age cohort. b P-value is b0.001 by Mann–Whitney U test comparing LPT infants to term infants. c P-value is 0.74 by Kruskal–Wallis test comparing the cohort group, term infants and the other age cohort. d P-value is 0.55 by Mann–Whitney U test comparing the cohort group to combined term infants and the other age cohorts.
12.1 per 1000 person-years was one-and-a-half times as high for LPT infants as compared to term infants. We also found that infants in the 33–34 WGA cohort had the highest adjusted hazard ratio for RSV hospitalization at 2.45 (95% CI 1.96–3.07). Prematurity interrupts the development of the immune system and lungs for LPT infants, adversely affecting their ability to cope with the inflammatory response to RSV, allowing for a prolonged infection. While many animal studies provide models for understanding the immunopathology for RSV, the normal human immune response to RSV is still unclear and varies in infants, children, and adults. Studies suggest that cytokines, T-lymphocytes, and neutralizing antibodies play a significant role in human response to RSV infection [23]. Maternally-derived antibodies against RSV are passively acquired during pregnancy but rapidly decline after birth, with a nadir around six months of age [24]. Incomplete transfer of maternal antibody, as well as an immature neonatal immune system, may limit the humoral response to RSV infection, placing premature infants at higher risk during early infancy. Our study showed LPT infants had more severe RSV disease with a higher rate of requiring respiratory support. Intubation with mechanical ventilation usually is utilized only in the PICU; while we did not specifically obtain data regarding PICU stays, increased respiratory support provides a useful marker for more severe RSV disease. LPT infants may require more support than term infants for various reasons. LPT infants have lower functional residual capacity, decreased compliance, and smaller airway diameters than term infants at baseline [20,25,26]. Alveoli are not completely mature until 36 WGA, thus placing LPT infants at higher risk for impaired gas exchange and hypoxia [27]. Lung development interruption from premature birth causes the aforementioned changes and LPT infants are unable to adequately handle the physiological effects of RSV infection. In general, RSV directly injures
the lung epithelium, generating debris from sloughed respiratory epithelial cells, leading to increased mucous production and mucosal edema [28]. Because of their smaller airways and decreased functional residual capacity, LPT infants cannot tolerate the RSV cellular debris and mucous plugs that produce bronchiole obstruction and V–Q mismatch, provoking breathing difficulties and respiratory distress. Impaired gas exchange affects oxygenation and ventilation, resulting in hypoxemia, and requires supplemental oxygen and/or respiratory support. In addition to increased need of respiratory support, we found the length of stay was longer for LPT infants by one day, which contributes to higher medical costs and the potential for increased acquisition and transmission of nosocomial infections among hospitalized children. Palivizumab is a neutralizing monoclonal antibody that prevents severe RSV disease for up to 28 days, and requires high risk populations to receive monthly injections during the RSV season [7]. Multiple health care visits along with medication cost make immunoprophylaxis expensive. Current literature regarding cost-benefit analysis of palivizumab for LPT infants is conflicting. While two retrospective cohort studies have found LPT infants had significantly higher RSV hospitalization costs than term infants [5,6], a literature review by the Cochrane Collaboration found the economic benefit of palivizumab use to be inconsistent [28]. Further cost-assessment studies are needed to assess palivizumab immunoprophylaxis for healthy LPT infants, and further investigate its ability to ameliorate severe RSV disease and prevent hospitalization in this cohort. Previous studies proved that prematurity is a risk factor for severe RSV disease but there are few studies that evaluated the risk in healthy LPT infants. A small prospective study showed LPT infants born 32–36 WGA have a higher RSV hospitalization rate than term infants but risk
Table 4 Adjusted Hazard Ratios for RSV hospitalization based on chronological age groups. Age at admission
Overall (0–24 months) 0–3 monthsa 3–6 monthsa 6–12 monthsa 12–24 monthsa
a
33–34 WGA
35–36 WGA
Term
Male Sex
HR [95% CI]
HR [95% CI]
(reference)
HR [95% CI]
2.45 [1.96 – 3.07] 1.80 [1.43–2.26] 2.37 [1.74–3.23]. 1.74 [1.17–2.58]b 1.96 [1.26–3.05]b
1.92 [1.66 – 2.22] 1.76 [1.44–2.15] 1.71 [1.49–1.95] 1.75 [1.39–2.21] 2.27 [1.79–1.88]
1.00 1.00 1.00 1.00 1.00
1.25 [1.19 – 1.31] 1.15 [1.08–1.23] 1.46 [1.32–1.61] 1.46 [1.31–1.64] 1.12 [0.99–1.27]c
Adjusted hazard ratios were calculated by Cox proportional hazard regression. Respiratory syncytial virus is abbreviated as RSV. Weeks gestational age is abbreviated as WGA. Hazard ratio is abbreviated as HR. Confidence interval is abbreviated as CI. a P b 0.001 for all groups except as indicated. b P b 0.05. c P = 0.07.
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and whether additional specific risk factors can be identified. Additional studies are needed to determine if palivizumab immunoprophylaxis would be cost-beneficial for healthy LPT infants. Conflict of Interest Statement The authors have no conflicts of interest to disclose. Disclaimer The views expressed in this article are those of the authors and do not reflect the official policy or position of the United States Armed Forces, Department of Defense, or the U.S. Government. Contributor's Statement
Fig. 2. Estimated percent without RSV Hospitalization stratified by study cohorts.
factors for severe RSV disease were not excluded [29]. Hall et al. found LPT infants had a higher rate of hospitalization for RSV bronchiolitis, regardless of palivizumab use, when compared to infants N35 WGA, but LPT infants were hospitalized significantly less than term infants [30]. Our study shows consistently that healthy LPT infants have higher rates and risk for hospitalization due to severe RSV disease and is novel to the current literature. The design of our study has potential limitations. The MHS database relies on ICD-9-CM billing codes, which allows for misclassification of patient data and prevents chart review; patients may have been excluded for lack of specific diagnosis (for example: bronchiolitis vs. RSV bronchiolitis) or failure to include prematurity as a diagnosis. Without individual chart or laboratory review, we were unable to confirm RSV disease through microbiological lab testing. We also were limited in our definition of LPT birth due to ICD-9-CM codes and had to include infants born 33 WGA, which deviates from the AAP and ACOG definition. The infants born 33 WGA may have more severe RSV disease since they are more premature, which may have contributed to their higher adjusted hazard ratio and IDRSV. Given that the new AAP palivizumab guidelines still exclude these infants from immunoprophylaxis based on prematurity alone, the inclusion of these infants suggests that further study among this cohort is important. One strength of our study is our large patient population, which provides a large demographically and socioeconomically diverse group of children. These patients have universal access to healthcare facilities throughout the United States, making our results applicable to the general population [21,22]. LPT births accounted for 7.99% of all births in the United States in 2013, showing there is a significant population at risk for severe RSV disease [17]. We also evaluated RSV disease severity by the need for respiratory support because the literature had limited data specifically for late preterm infants and RSV hospitalization. We found that healthy LPT infants had a significantly higher risk of requiring respiratory support (RR 3.71, 95% CI 2.36-5.82) when compared to healthy term infants. 5. Conclusions LPT birth is an independent risk factor for severe RSV disease and need for hospitalization. Although LPT infants are often medically managed similarly to term infants, they are at significantly higher risk for severe RSV disease, resulting in a greater risk of hospitalization, longer stay, and higher rate of requirement for respiratory support. Further studies are needed to identify why LPT is a risk factor for severe disease,
Alison M. Helfrich: Dr. Helfrich interpreted the results, drafted and edited the initial manuscript and approved the final manuscript as submitted. Cade M. Nylund: Dr. Nylund carried out the data analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted. Matthew D. Eberly: Dr. Eberly conceptualized and designed the study, reviewed and revised the manuscript, and approved the final manuscript as submitted. Matilda B. Eide: Ms. Eide designed the data collection instruments, collected and organized the data and reviewed and approved the final manuscript as submitted. David R. Stagliano: Dr. Stagliano conceptualized and designed the study, contributed to the data analysis, edited the manuscript, and approved the final manuscript as submitted. Acknowledgements The authors would like to thank Drs. Martin Ottolini, Gregory Gorman, Michael Rajnik and Kathleen Madden for their critical review of the manuscript. References [1] Black CP. Systematic review of the biology and medical management of respiratory syncytial virus infection. Respir Care 2003 Mar;48(3):209–31 [discussion 231–3]. [2] McLaurin KK, Hall CB, Jackson EA, Owens OV, Mahadevia PJ. Persistence of morbidity and cost differences between late-preterm and term infants during the first year of life. Pediatrics 2009 Feb;123(2):653–9. [3] Gunville CF, Sontag MK, Stratton KA, Ranade DJ, Abman SH, Mourani PM. Scope and impact of early and late preterm infants admitted to the PICU with respiratory illness. J Pediatr Aug 2010;157(2) [209-214.e1]. [4] Stockman LJ, Curns AT, Anderson LJ, Fischer-Langley G. Respiratory syncytial virusassociated hospitalizations among infants and young children in the United States, 1997–2006. Pediatr Infect Dis J Jan 2012;31(1):5–9. [5] Stewart DL, Romero JR, Buysman EK, Fernandes AW, Mahadevia PJ. Total healthcare costs in the US for preterm infants with respiratory syncytial virus lower respiratory infection in the first year of life requiring medical attention. Curr Med Res Opin Nov 2009;25(11):2795–804. [6] Forbes ML, Hall CB, Jackson A, Masaquel AS, Mahadevia PJ. Comparative costs of hospitalisation among infants at high risk for respiratory syncytial virus lower respiratory tract infection during the first year of life. J Med Econ Mar 2010;13(1): 136–41. [7] Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. The IMpact-RSV Study Group. Pediatrics Sep 1998;102(3 Pt 1):531–7. [8] Arnold SR, Wang EE, Law BJ, Boucher FD, Stephens D, Robinson JL, et al. Variable morbidity of respiratory syncytial virus infection in patients with underlying lung disease: a review of the PICNIC RSV database. Pediatric Investigators Collaborative Network on Infections in Canada. Pediatr Infect Dis J Oct 1999;18(10):866–9. [9] Purcell K, Fergie J. Driscoll Children's Hospital respiratory syncytial virus database: risk factors, treatment and hospital course in 3308 infants and young children, 1991 to 2002. Pediatr Infect Dis J May 2004;23(5):418–23. [10] Feltes TF, Cabalka AK, Meissner HC, Piazza FM, Carlin DA, Top Jr FH, et al. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease. J Pediatr Oct 2003; 143(4):532–40.
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