Infants and children hospitalized with respiratory syncytial virus

Abstract

Respiratory syncytial virus (RSV) infections are common among young children and represent a significant burden to patients, their families and the Canadian health system. Here we conduct a rapid review of the burden of RSV illness in children 24 months of age or younger. Four databases (Medline, Embase, Cochrane Database of Clinical Trials, ClinicalTrials.gov from 2014 to 2018), grey literature and reference lists were reviewed for studies on the following: children with or without a risk factor, without prophylaxis and with lab-confirmed RSV infection. Of 29 studies identified, 10 provided within-study comparisons and few examined clinical conditions besides prematurity. For infants of 33–36 weeks gestation (wGA) versus term infants, there was low-to-moderate certainty evidence for an increase in RSV-hospitalizations (n=599,535 infants; RR 2.05 [95% CI 1.89–2.22]; 1.3 more per 100 [1.1–1.5 more]) and hospital length of stay (n=7,597 infants; mean difference 1.00 day [95% CI 0.88–1.12]). There was low-to-moderate certainty evidence of little-to-no difference for infants born at 29–32 versus 33–36 wGA for hospitalization (n=12,812 infants; RR 1.20 [95% CI 0.92–1.56]). There was low certainty evidence of increased mechanical ventilation for hospitalized infants born at 29–32 versus 33–35 wGA (n=212 infants; RR 1.58, 95% CI 0.94–2.65). Among infants born at 32–35 wGA, hospitalization for RSV in infancy may be associated with increased wheeze and asthma-medication use across six-year follow-up (RR range 1.3–1.7). Children with versus without Down syndrome may have increased hospital length of stay (n=7,206 children; mean difference 3.00 days, 95% CI 1.95–4.05; low certainty). Evidence for other within-study comparisons was of very low certainty. In summary, prematurity is associated with greater risk for RSV-hospitalization and longer hospital length of stay, and Down syndrome may be associated with longer hospital stay for RSV. Respiratory syncytial virus-hospitalization in infancy may be associated with greater wheeze and asthma-medication use in early childhood. Lack of a comparison group was a major limitation for many studies.

Introduction

Respiratory syncytial virus (RSV) infections are common among young children^{Footnote 1Footnote 2}, presenting as bronchiolitis, pneumonia, or other respiratory morbidity^{Footnote 3}. Hospitalization due to RSV is a significant burden for patients, families and the Canadian health system^{Footnote 4}.

Increased risk for RSV-hospitalization has been associated with age younger than one year. ^{Footnote 3Footnote 5}, prematurity^{Footnote 6}, chronic lung disease^{Footnote 7}, congenital heart disease^{Footnote 8}, other chronic conditions including cystic fibrosis, immunodeficiency^{Footnote 9Footnote 10Footnote 11Footnote 12} and residence in Indigenous, northern or remote communities^{Footnote 13}. These populations may also have higher rates of admission to intensive care units (ICU), requirements for respiratory support, and higher mortality attributable to RSV ^{Footnote 9}. RSV-hospitalization in the first two years of life has also been associated with wheezing in childhood^{Footnote 14Footnote 15Footnote 16}.

While no active vaccines exist for RSV prophylaxis, the monoclonal antibody palivizumab (Synagis^®, AstraZeneca) has demonstrated effectiveness in preventing RSV-hospitalization among some high risk populations^{Footnote 17Footnote 18}. However, while efficacy of palivizumab (PVZ) in clinical trials appears to be high for children with some underlying clinical conditions, real-world evidence from observational studies is less certain^{Footnote 2}, with wide variations in effectiveness. Due to the high numbers needed to treat in order to prevent hospitalization and the relatively high cost of PVZ, most jurisdictions use the intervention sparingly for select groups at highest risk of severe disease. Additionally, RSV vaccine development has been well under way, with some vaccine candidates undergoing phase 3 clinical trials^{Footnote 19}. There is currently no global consensus on RSV risk groups and variable policies exist even within Canada.

The objective of this rapid review is to address the following question: What is the burden of RSV illness including long-term sequelae among children 24 months of age and younger without prophylaxis, and with or without risk factors for severe RSV disease, and for immunocompromised children younger than 18 years of age?

Findings from the review will help inform updated recommendations of Canada's National Advisory Committee on Immunization on the use of PVZ prophylaxis to prevent severe consequences of RSV infection. This evidence base will also be relevant for future deliberations on program design for anticipated RSV vaccines and newer monoclonal antibodies^{Footnote 19}.

Methods

This review was guided by methods for reviews of interventions^{Footnote 20}, overall prognosis^{Footnote 21}, and risk of future event (prognosis)^{Footnote 22}; a protocol was developed a priori (Supplement 1), and reviewed and approved by the National Advisory Committee on Immunization RSV Working Group. In light of the restricted literature search timeframe of interest to the review commissioners, we refer to the undertaken work as a rapid review.

Literature search

Searches were conducted on September 6, 2018, in Medline, Embase, Cochrane Database of Clinical Trials, ClinicalTrials.gov, and websites of international public health authorities (Supplement 2). Limits were applied for date of publication (January 1, 2014 to September 6, 2018) and language (English or French). The date limit was aimed at capturing outcomes just before and after significant changes in clinical practice stemming from the revised recommendations for PVZ prophylaxis by the American Academy of Pediatrics^{Footnote 23} as well as the Canadian Paediatric Society^{Footnote 2}.

Study selection and eligibility criteria

Two reviewers independently screened titles and abstracts followed by full texts. Discrepancies were resolved by discussions.

Studies conducted in Organisation for Economic Co-operation and Development (OECD) countries, including observational studies and placebo groups of controlled trials were eligible for inclusion. Studies reporting on children 24 months of age and younger, with or without a risk factor of interest, or immunocompromised children 18 years of age and younger without PVZ prophylaxis and with lab-confirmed RSV infection were eligible. Children without RSV infection were eligible as a comparator group for long-term outcomes. Short-term outcomes included RSV-hospitalization, hospital length of stay, ICU admission and length of stay, oxygen support and duration, mechanical ventilation and duration, extracorporeal membrane oxygenation and duration, case fatality (death due to RSV), and complications from RSV infection (e.g. secondary infection). Long-term outcomes (minimum one-year follow-up) included self-reported, parent-reported or physician-diagnosed recurrent wheeze, atopic asthma, deterioration of pulmonary or cardiac function, and impaired growth or development. Detailed inclusion and exclusion criteria are in Supplement 3.

Data extraction, synthesis/analysis and risk of bias assessment

One reviewer extracted data with second-reviewer verification.

For dichotomous outcomes, we extracted the number of events and the number analysed in each eligible group, or relative measures (e.g. odds ratio) if crude events were not reported. For continuous outcomes, mean values for each time-point, and change scores, including standard deviations or measures of variability were extracted. Risk ratio (RR) with 95% confidence interval (CI) and mean difference (MD) were used for comparisons between groups.

Our primary interest was using data from studies that reported on two or more groups, either having different risk factors, or a risk group versus healthy term infants (within-study/direct comparisons). For similar comparisons reported by more than one study, data were pooled using the DerSimonian Laird random effects model inverse variance method with Mantel-Haenszel weighting. Risk differences were used when rare or zero events appeared in at least one study group. We also made comparisons between short-term outcomes in risk groups and healthy term infants reported by different studies (between-study/indirect comparisons). We used the double-arc sine transformation to pool single-group proportions across multiple studies. When no comparison was made, we report event proportions for the single group in these studies.

For outcomes where estimates were statistically significant, we calculated the absolute risk difference^{Footnote 24}.

Analyses were performed using Excel, Review Manager (version 5.3) and STATA (version 14.2).

Two reviewers independently assessed the risk of bias for each study, using a modified tool based on the Quality Assessment Tool for Observational Cohort and Cross-sectional Studies and the Quality In Prognosis Studies (QUIPS) tool (Supplement 4). Disagreements were resolved via consensus or third-reviewer consultation.

Certainty of evidence

Two reviewers independently assessed the certainty of evidence for each outcome (as high, moderate, low, or very low) from within-study comparisons (direct evidence), with disagreements resolved through consensus. The approach followed principles of the Grading of Recommendations Assessment, Development and Evaluation working group and considerations for a body of evidence that examines risk of future events (prognosis) (Supplement 5)^{Footnote 21}.

Results

Study selection and characteristics

Twenty-nine cohort studies were included (Figure 1, Table 1, and Supplements 6 and 7)^{Footnote 13Footnote 25Footnote 26Footnote 27Footnote 28Footnote 29Footnote 30Footnote 31Footnote 32Footnote 33Footnote 34Footnote 35Footnote 36Footnote 37Footnote 38Footnote 39Footnote 40Footnote 41Footnote 42Footnote 43Footnote 44Footnote 45Footnote 46Footnote 47Footnote 48Footnote 49Footnote 50Footnote 51Footnote 52}; of these, 10 reported at least one within-study comparison ^{Footnote 26Footnote 27Footnote 28Footnote 31Footnote 32Footnote 36Footnote 37Footnote 42Footnote 50Footnote 52}. Twelve studies were conducted in the United States^{Footnote 25Footnote 26Footnote 33Footnote 34Footnote 36Footnote 38Footnote 42Footnote 45Footnote 46Footnote 47Footnote 49Footnote 50}, three each, in Canada^{Footnote 13Footnote 29Footnote 48} and the Netherlands^{Footnote 30Footnote 43Footnote 52}, two each, in Finland^{Footnote 27Footnote 28}, France^{Footnote 35Footnote 37} and Japan^{Footnote 40Footnote 41} and one each in Chile^{Footnote 44}, Denmark^{Footnote 31}, Ireland^{Footnote 39}, Spain^{Footnote 32} and multiple countries^{Footnote 51}. Thirteen^{Footnote 13Footnote 25Footnote 26Footnote 29Footnote 30Footnote 31Footnote 32Footnote 37Footnote 43Footnote 45Footnote 46Footnote 51Footnote 52} studies had some form of industry funding. Three papers reported on the same study: primary publication by Ambrose et al.^{Footnote 25}, with associated publications by Franklin et al.^{Footnote 53} and Simões et al.^{Footnote 54}.

Eighteen studies^{Footnote 25Footnote 26Footnote 29Footnote 30Footnote 33Footnote 34Footnote 35Footnote 36Footnote 37Footnote 39Footnote 40Footnote 41Footnote 42Footnote 43Footnote 45Footnote 48Footnote 50Footnote 51} included children either not given or not considered for PVZ prophylaxis prior to RSV-hospitalization; four studies^{Footnote 13Footnote 32Footnote 46Footnote 47} reported prophylaxis among less than 5% of the applicable population with RSV, and seven studies^{Footnote 27Footnote 28Footnote 31Footnote 38Footnote 44Footnote 49Footnote 52} were considered by clinical judgement to not have included children who received prophylaxis. One study included some children who may have received prophylaxis^{Footnote 34}.

We included three studies of children with RSV older than 24 months of age to capture evidence for immunocompromised populations: children three years old or younger with Down syndrome with or without known risk factors for RSV^{Footnote 50}, and younger than 18 years old with liver transplantation^{Footnote 38} and sickle cell disease^{Footnote 49}.

Studies of at-risk populations reporting short-term outcomes included the following: infants with premature birth (eleven studies)^{Footnote 25Footnote 26Footnote 30Footnote 32Footnote 36Footnote 37Footnote 42Footnote 43Footnote 47Footnote 48Footnote 51}; cystic fibrosis (two studies)^{Footnote 29Footnote 39}; one study each for congenital cystic lung disease^{Footnote 40}, childhood interstitial lung disease^{Footnote 35}, Down syndrome^{Footnote 50}, sickle cell disease^{Footnote 49}, acute leukemia^{Footnote 41} and prior liver transplant^{Footnote 38}; and children residing in remote geographic locations (two studies)^{Footnote 13Footnote 46}.

Seven studies reporting short-term outcomes included data on healthy term infants hospitalized for RSV^{Footnote 33Footnote 37Footnote 42Footnote 44Footnote 45Footnote 50Footnote 52}.

Six studies reported on long-term outcomes: healthy term infants with versus without RSV in infancy^{Footnote 27Footnote 28Footnote 31Footnote 52}, premature infants with versus without RSV-hospitalization in infancy^{Footnote 32}, and premature versus term infants hospitalized for RSV in their first RSV season^{Footnote 37}.

Risk of bias

Risk of bias ratings are in Table 1 and Supplements 4 and 6. Studies that reported incidence of RSV-hospitalization were at moderate-to-high risk of bias, mainly due to lack of blinding to childrens’ risk status by healthcare providers that may have influenced admission to hospital. For other short-term outcomes, studies were mostly at moderate risk of bias^{Footnote 25Footnote 26Footnote 29Footnote 33Footnote 35Footnote 39Footnote 45Footnote 46Footnote 47}. Two studies were at high risk of bias due to concerns in more than one domain^{Footnote 41Footnote 44}. Nearly all reported long-term outcomes^{Footnote 27Footnote 28Footnote 32Footnote 37Footnote 52} were at moderate risk of bias, arising from lack of blinding for patient or parent-reported outcomes and/or potential selection biases.

Short-term outcomes from within-study comparisons

Table 2 summarizes evidence for short-term outcomes from within-study comparisons. Here we do not report further on findings having very low certainty of evidence.

Different degrees of prematurity: One study found little-to-no difference in RSV-hospitalization during their first RSV season for infants born at 29–32 compared with 33–36 weeks’ gestation (wGA)^{Footnote 36}. This study found little-to-no difference for hospital stay of less than one day versus one day or more between infants born at 29–32 or 33–36 wGA^{Footnote 36}.

Another study of infants born at 29–32 versus 33–35 wGA who were hospitalized for RSV in the first year of life found little-to-no difference for ICU admission, but longer (although not statistically significant) ICU length of stay among the infants born at 29–32 wGA^{Footnote 26}. There was a greater need for mechanical ventilation for hospitalized infants born at 29–32 wGA versus 33–35 wGA^{Footnote 26}.

There were no studies of premature infants born before 29 wGA.

Premature versus term infants: One study found that being born late-premature (33–36 wGA) versus at term was associated with increased RSV-hospitalization in the first two years of life^{Footnote 42}. The same study found slightly longer hospitalization for the preterm group^{Footnote 42}.

Down syndrome: One study comparing children with Down syndrome without additional risk factors for RSV versus healthy children, all followed to three years of age, reported a higher hospitalization rate in those with Down syndrome^{Footnote 50}. There was a discrepancy between the text and tables for RSV-hospitalization rates in these groups that could not be resolved due to unsuccessful attempts to contact the study authors^{Footnote 50}. This study also found that RSV was associated with longer hospital length of stay among children with Down syndrome without other risk factors versus children without Down syndrome^{Footnote 50}. For all cases of Down syndrome, including those with known risk factors for RSV, the authors conclude that Down syndrome is independently associated, after adjusting for known risk factors for RSV disease, with an increased risk for RSV-hospitalization^{Footnote 50}. Of note, data on children younger than 24 months of age without risk factors were not isolated from those with additional risk factors, and therefore, were not used in our analysis.

Select short-term outcome comparisons: Other data

Supplement 8 contains single risk group data and pooled analyses (when appropriate). Data for between-study comparisons are in Supplement 9. Findings for select outcomes are reported below; data on other short-term outcomes are in Supplement 8.

Single group proportions for RSV-hospitalizations were 5.1% in the first six months of life and 3.3% in the first two years of life for infants 29 to younger than 33 wGA^{Footnote 36Footnote 37} and 32/33 to 35 wGA^{Footnote 25Footnote 30Footnote 32Footnote 36Footnote 42Footnote 43Footnote 48Footnote 51}, respectively; 5.3% two years post-transplantation, 8.3% in the first two years of life, 12.3% in the first two years of life and 30.0% in the first or second RSV season for liver transplant^{Footnote 38}, congenital cystic lung disease^{Footnote 40}, cystic fibrosis^{Footnote 29Footnote 39} and childhood interstitial lung disease^{Footnote 35}, respectively. The 95% confidence intervals for the latter three conditions were very wide. The pooled proportion for healthy term infants was 1.2% in the first two years of life^{Footnote 37Footnote 42Footnote 45Footnote 52}.

Case fatality rate attributable to RSV for those hospitalized were 1.1 % (n=89), 2.5% (n=80), 4.4% (n=135) and 40.0% (n=10) for infants of 29–32 wGA^{Footnote 26}, children residing in remote geographic area^{Footnote 46}, children with liver transplant^{Footnote 38} and with leukemia^{Footnote 41}, respectively. Most studies reported no attributable deaths. Many studies of clinical conditions contained very small sample sizes.

Complications

One study reported on complications associated with RSV-hospitalization (Supplement 10).

Long-term outcome comparisons from within-study comparisons

Table 3, Table 4 and Table 5 summarize evidence for long-term outcomes from within-study comparisons. No study reported on growth or impaired development. Here we do not report on findings having very low certainty evidence.

Prematurity: One study enrolled premature (32–35 wGA) infants with or without hospitalization for RSV infection before 12 months of age to examine several long-term outcomes^{Footnote 32}. Data were collected through telephone calls every four months and annual visits until the 6^th year of life. The authors analysed data both across the five years and only within the 6^th year. All findings offered low certainty evidence.

Across years two through six, associations were found between RSV-hospitalization and increased risk for parent or physician-reported simple wheeze, recurrent wheeze, severe wheeze and any/all wheeze^{Footnote 32}. When examining the 6th year only, there was little-to-no difference in parent or physician-reported simple wheeze, recurrent wheeze, severe wheeze and any/all wheeze^{Footnote 32}. This study also compared groups for parent-reported asthma-associated medication use across years two through six. There were associations with increased risk from RSV-hospitalization for use of bronchodilators, inhaled corticosteroids, oral corticosteroids and leukotriene antagonists^{Footnote 32}. Through lung function testing using spirometry, there was little-to-no difference in severe respiratory morbidity at six years of age between groups^{Footnote 32}.

RSV without risk factors: Pooled data from two studies of children with versus without RSV-hospitalization at younger than 24 months of age found low certainty of an increase in self-reported asthma in adulthood^{Footnote 27Footnote 28}. Of note, there was no difference in physician-diagnosed asthma (considered more reliable than patient-reported asthma)^{Footnote 28}, but certainty of evidence was very low for this outcome. An association was also found between RSV and lower pre-bronchodilation mean percent of predicted forced expiratory volume in one second (FEV₁), but there was little-to-no difference in change in FEV1 from pre to post-bronchodilation^{Footnote 27Footnote 28}. The RSV was associated with lower predicted forced vital capacity, but not fractional exhaled nitric oxide^{Footnote 27Footnote 28}.

Long-term outcome comparisons: Other data

Supplement 11 contains single group data and pooled analyses (when appropriate). We did not conduct analyses for between-study comparator groups, since single studies that contributed to each long-term outcome were represented among within-study comparisons.

Discussion

Summary of findings and limitations

Few studies contributed data for within-study comparisons of outcomes of interest. There was moderate-to-low certainty that RSV is associated with a small increase in hospitalization and length of stay among moderate-to-late preterm (33–36 wGA) compared with term infants. There was moderate-to-low certainty evidence for no significant differences in hospitalizations between infants born at 29–32 wGA versus 33–36 wGA. Low certainty of evidence was found for a slight increase in mechanical ventilation among those born at 29–32 wGA versus 33–35 wGA and hospitalized for RSV prior to 12 months of age. Low certainty evidence was found for increased hospital length of stay among children younger than three years of age with versus without Down syndrome. There was low certainty evidence for increased wheezing and asthma medication use from two to six years of age among RSV-hospitalized versus non-hospitalized premature (32–35 wGA) infants, although there was little-to-no difference for these outcomes in the 6^th year of follow-up. Low certainty evidence was found for decreased lung function measurements before bronchodilation but changes in measurements after bronchodilation did not differ between groups. Very low certainty evidence was found for other long-term outcomes comparing different risk groups.

Single studies contributed data for most outcomes, where populations with rare conditions (e.g. cystic fibrosis) often represent small/under-powered sample sizes, precluding investigation of heterogeneity among studies for important population and RSV characteristics, or consistency in findings. The paucity of studies on clinical conditions other than prematurity is a limitation of the evidence base. We also did not find studies of premature infants born before 29–30 weeks gestation, or of children with chronic lung disease of prematurity or congenital heart disease, groups for whom prophylaxis is now recommended in the United States and in Canada^{Footnote 2Footnote 23}.

Retrospective study designs utilizing older data (i.e. pre-2014) were included, and may reflect different practices (e.g. prophylaxis, RSV-testing, standard of care) over time and across countries and settings. Detection of RSV infection may be impacted by variation in testing methods, including types of tests and indications for testing, and seasonal and geographic variability. Among tested individuals, the proportion of patients with viral or bacterial co-infections may be an important confounder in etiology of outcome severity. Lack of blinding of healthcare providers to risk status may influence rates of hospitalization and possibly other care parameters, particularly among children with known RSV risk factors.

Comparison with other reviews

A series of systematic reviews of publications from 1995 to 2015 found that RSV-hospitalization is associated with significant morbidity among children younger than 18 years old in Western countries (Canada, United States, Europe), particularly for young children with prematurity, chronic lung disease of prematurity and congenital heart disease^{Footnote 6Footnote 7Footnote 8Footnote 9}. Whereas the current work focused on children younger than two years of age with a single risk factor, these reviews also included studies of children up to 18 years of age. Our review scope searched comparatively more recent publications (2014–2018) and covered a broader geographic area by including high-income (OECD) countries.

Future research

Based on current evidence, there is a need for studies to focus on the burden of RSV disease among children with underlying chronic conditions, for some of which data on risk are contradictory or non-existing. Assessments of current RSV surveillance activities in Canada have identified data gaps for particular populations, including children with underlying medical conditions and those living in Indigenous, northern or remote communities^{Footnote 19}. Gaps will need to be filled in preparation for monitoring of RSV vaccine effectiveness in the future.

Conclusion

Prematurity is associated with increased risk for RSV-hospitalization in infancy and increased hospital length of stay, and may be associated with increased wheeze and asthma-medication use at up to six years of age. Down syndrome may be associated with longer hospital length of stay. We are very uncertain about evidence from other within-study comparisons. Very few studies included a comparison group.

Authors’ statement

• AW — Conceptualization, methodology, analysis, writing–original draft, review and editing
• JP — Conceptualization, methodology, analysis, writing–review and editing
• DLM — Conceptualization, methodology, analysis, writing–review and editing
• SG — Analysis, writing–review and editing
• BV — Analysis, writing–review and editing
• MPD — Conceptualization, methodology, analysis
• AS — Conceptualization, methodology, analysis, writing–review and editing
• MT — Conceptualization, methodology, writing–review and editing
• LH — Conceptualization, methodology, writing–review and editing

Competing interests

AW, JP, SG, BV, MPD and LH report grants from the Public Health Agency of Canada during the conduct of the study.

Acknowledgments

The authors would like to thank Canada’s National Advisory Committee on Immunization RSV Working Group (Drs. D Moore, J Papenburg, J Robinson, M Salvadori, W Vaudry, R Stirling, A Sinilaité, and R Pless) for their advice during initial study conception on strategic framing of the risk groups and for reviewing the search parameters. The authors thank Ms. L Gamble, librarian (Health Library of Health Canada and Public Health Agency of Canada), for conducting the literature search; Mr. S Duchesne-Belanger for assistance with title/abstract screening; and Dr. A Gates and Ms. S Rahman for assistance with data verification. The authors gratefully acknowledge Drs. K Backman and K Bønnelykke for providing study data.

Funding

This work was conducted for the National Advisory Committee for Immunization, under contract to the Public Health Agency of Canada (contract #4600001536). The views of the funding body have not influenced the content of the review. The views expressed are those of the authors and do not necessarily represent those of the Public Health Agency of Canada. LH is supported by a Tier 1 Canada Research Chair in Knowledge Synthesis and Translation.

Supplemental material

These documents can be accessed on the Supplemental material file.

Supplement 1: Methods

Supplement 2: Search strategy

Supplement 3: Inclusion/exclusion criteria

Supplement 4: Methodological quality assessments

Supplement 5: Certainty of evidence assessments

Supplement 6: Characteristics of included studies

Supplement 7: Outcomes of included studies

Supplement 8: Single group proportions for short-term outcomes

Supplement 9: Summary of evidence for short-term outcomes—between-study

Supplement 10: Complications

Supplement 11: Single group proportions for long-term outcomes