Defining the Risk and Associated Morbidity and Mortality of Severe Respiratory Syncytial Virus Infection Among Infants with Congenital Heart Disease
verfasst von:
Paul A. Checchia, Bosco Paes, Louis Bont, Paolo Manzoni, Eric A. F. Simões, Brigitte Fauroux, Josep Figueras-Aloy, Xavier Carbonell-Estrany
The REGAL (RSV Evidence—a Geographical Archive of the Literature) series provide a comprehensive review of the published evidence in the field of respiratory syncytial virus (RSV) in Western countries over the last 20 years. This fourth publication covers the risk and burden of RSV infection in infants with congenital heart disease (CHD).
Methods
A systematic review was undertaken for articles published between January 1, 1995 and December 31, 2015 across PubMed, Embase, The Cochrane Library, and Clinicaltrials.gov. Studies reporting data for hospital visits/admissions for RSV infection among children with CHD as well as studies reporting RSV-associated morbidity, mortality, and healthcare costs were included. The focus was on children not receiving RSV prophylaxis. Study quality and strength of evidence (SOE) were graded using recognized criteria.
Results
A total of 1325 studies were identified of which 38 were included. CHD, in particular hemodynamically significant CHD, is an independent predictor for RSV hospitalization (RSVH) (high SOE). RSVH rates were generally high in young children (<4 years) with CHD (various classifications), varying between 14 and 357/1000 (high SOE). Children (<6 years) with RSV infection spent 4.4–14 days in hospital, with up to 53% requiring intensive care (high SOE). Infants (<2 years) with CHD had a more severe course of RSVH than those without CHD (high SOE). Case fatality rates of up to 3% were associated with RSV infection in children with CHD (high SOE). RSV infection in the perioperative period of corrective surgery and nosocomial RSV infection in intensive care units also represent important causes of morbidity (moderate SOE).
Conclusion
CHD poses a significant risk for RSVH and subsequent morbidity and mortality. RSV infection often complicates corrective heart surgery. To reduce the burden and improve outcomes, further research and specific studies are needed to determine the longer-term effects of severe RSV infection in young children with CHD.
Congenital heart disease (CHD) is the most common type of birth defect, accounting for one-third of all major congenital anomalies, and represents a major public health issue [1, 2]. The reported total CHD prevalence has increased substantially over the last century, most likely due to improved diagnostic methods and screening modalities, although prevalence rates vary widely among studies worldwide [2]. It is estimated that CHD affects 9 in 1000 children, although significant geographical differences in prevalence have been reported [2]. A systematic review of the literature found that Europe had the second highest reported total CHD birth prevalence [8.2 per 1000 live births, 95% confidence interval (CI) 8.1–8.3]; this was significantly higher than in North America (6.9 per 1000 live births, 95% CI 6.7–7.1; P < 0.001) [2].
Children with CHD are at risk for increased morbidity from viral lower respiratory tract infection (LRTI) because of anatomical cardiovascular lesions, which can cause pulmonary hypertension leading to increased ventilation–perfusion mismatch and, ultimately, hypoxia [3]. Globally, RSV is the most common cause of childhood acute LRTIs, with at least 3.4 million episodes necessitating admission to hospital each year [4]. CHD limits an infant’s ability to increase cardiac output, and concurrently oxygen delivery can be severely limited [5]. If an infant develops respiratory syncytial virus (RSV) LRTI, oxygen uptake can be further impaired and the work of breathing in these infants with compromised cardiac reserve is increased [5]. Infants and young children with CHD are especially at risk for severe disease and hospitalization and, in some instances, may require admission to the intensive care unit (ICU), supplemental oxygen therapy and prolonged mechanical ventilation [5, 6]. Furthermore, RSV LRTI can cause mortality in the immediate period surrounding either palliative or corrective cardiac surgery employing cardiopulmonary bypass [7]. Hemodynamically significant CHD (HS-CHD) in association with RSV infection can lead to prolonged hospitalization [8] and an increased risk of death [9]. RSV infection may also delay corrective cardiac surgery [10], potentially increasing CHD-associated morbidity.
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Since treatment is largely supportive and there is no effective vaccine for RSV, prevention is critically important in this vulnerable population. Current guidelines focus on infants at high risk for severe RSV infection and recommend RSV immunoprophylaxis in children with HS-CHD aged <12 months at the start of the RSV season [11‐13]. However, since a number of children with residual HS-CHD postoperatively or awaiting cardiac transplant still remain at risk for severe RSV LRTI, some position statements continue to support RSV prophylaxis in the second year of life [14‐17].
Identification of risk factors for RSV hospitalization (RSVH) and implementation of targeted prophylaxis are important to reduce the burden of severe RSV disease on inpatient and outpatient services and to improve patient outcomes. A vast amount of literature on RSV has accumulated over the past 20 years, and to review, evaluate and interpret this evidence a panel of experts in RSV from the United States, Canada and Europe formed REGAL (RSV Evidence—a Geographical Archive of the Literature) [18]. REGAL provides a comprehensive understanding on a range of topics on RSV LRTI within Western societies. This, the fourth paper in the REGAL series [18‐20], identifies and evaluates the risks and associated morbidity and mortality of severe RSV LRTI in infants and young children with CHD.
Methods
Study Objective
REGAL encompassed seven specific research questions on RSV related to the following topics: overall epidemiology [18], prematurity [19], chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD) [20], CHD, long-term respiratory morbidity, other high-risk groups (e.g., Down syndrome), and prevention, management and future perspectives. For the purposes of REGAL, Western countries were defined as the United States, Canada, and Europe (including Turkey and the Russian Federation). The overall methodology for REGAL was described in full in the first publication [18]. In summary, to address each question a systematic review of the medical literature electronically indexed in PubMed, EMBASE, and the Cochrane Library was performed. In addition, clinicaltrials.gov was searched for any relevant studies that are currently being conducted.
Literature Search
The specific research question for this review was: “What is the predisposition and associated morbidity, long-term sequelae and mortality of infants and young children with CHD following severe RSV infection?” The target population for this systematic literature review was infants and young children with CHD/HS-CHD who had ‘proven’ or ‘probable’ RSV. CHD as part of syndrome (e.g., Down syndrome) was excluded from this review, as clearly some of the genetic risk factors have an independent impact on RSV acquisition. A separate review on Down syndrome and other special populations will be published in due course. The focus of the current review was children who had not received RSV immunoprophylaxis; however, to avoid the loss of significant studies, all publications were reviewed regardless of whether prophylaxis was given. Where possible, data for children not receiving prophylaxis were reported, or, if this was not possible, the level of prophylaxis was reported alongside the results.
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We performed a literature search in MEDLINE (PubMed), EMBASE and the Cochrane Library from January 1, 1995 to December 31, 2015. The following general terms and limits were used: “RSV” OR “respiratory syncytial virus” AND “congestive heart disease” OR “CHD” AND “hospitalization” OR “predisposition” OR “risk factor” AND “limits: human, infant aged up to 1 year; child (<18 years)’’. ‘‘Bronchiolitis’’ and ‘‘pneumonia’’ were captured as part of the Medical Subject Headings (MeSH) terms. It is recognized that, while some relevant articles might have been missed by the searches, we are confident that the combined Boolean operators ‘‘AND’’ and ‘‘OR’’ of the key text words and index terms precisely captured the vast majority of relevant citations which were pertinent for this evidence-based review. Additional studies identified through review of bibliographies and as abstracts presented at relevant meetings were also included. To ensure that the review was as contemporary as possible, relevant studies published during the drafting of this paper were also included.
Definition of CHD
The working definitions of CHD have evolved over time and may not be consistent between studies. HS-CHD in relation to RSV has been defined as [21‐23]:
Uncorrected or palliated cyanotic or acyanotic CHD with pulmonary hypertension
Systolic pulmonary arterial pressure ≥40 mmHg or mean pulmonary arterial pressure ≥25 mmHg, and/or
Need for medication to manage congestive heart failure.
This definition was not consistently used by all authors and manuscripts, but we suggest that this is a useful definition, and perhaps should be adopted in future manuscripts describing the epidemiology and management of CHD.
For completeness, all reports describing infants with CHD, regardless of definition, were considered for inclusion in this review in order to elucidate the additional risk of RSV infection in children with significant cardiac issues at birth. To facilitate interpretation of the data, the definitions of CHD used in individual studies, where stated, were documented.
Outcomes of Interest
Key outcomes for this review included: hospitalization rates due to severe RSV infection; hospital length of stay (LOS); ICU admission and LOS; oxygen requirement; need for and duration of mechanical ventilation and/or non-invasive ventilation; and case fatality rates.
Evaluation of Data
All included studies were graded according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence [24, 25] (Supplementary Material 1—REGAL Protocol). Each study was also subject to a risk of bias assessment using the RTI Item Bank (score of 1 = very high risk of bias; score of 12 = very low risk of bias) for observational studies [26]. No quantitative data synthesis was conducted due to heterogeneity between studies in terms of design, patient populations, RSV testing, recording and availability of outcomes, and differences in clinical practice between countries and over time.
Statement of Ethics Compliance
The analysis in this article is based on previously published studies and does not involve any new studies of human subjects performed by any of the authors.
Results
Articles Selected
From a total of 1325 publications, 38 studies were included in the final review: 31 identified from the database searches and a further 7 from reference lists/other sources (Fig. 1). Details of all 36 studies, including evidence grades and risk of bias assessments, can be found in the online supplement.
Fig. 1
PRISMA flow diagram: epidemiology and burden of RSVH in infants with CHD
×
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Incidence of RSVH in Infants and Children with CHD
CHD, irrespective of hemodynamic significance, poses a significant risk for severe RSV infection requiring hospitalization [5, 8, 27‐47]. RSVH rates ranged from 14 to 357 per 1000 (Table 1), although comparison of these studies is difficult as a result of differences in the study populations, some of which were not specifically CHD patients, methods used and inclusion criteria.
Table 1
RSVH rates among children with and without CHD
Study
Country
Study design
Study definition of CHD/HS-CHD
RSVH rate/1000 children
Risk ratio (95% CI)
CHD
Non-CHD
RSVH rates for studies of infants and children with CHD
3-year retrospective study (2004–2008) of 602 children <3 years with HS-CHD or non-hsCHD; RSV immunoprophylaxis recommendation documented in 27.2% with HS-CHD and 2.2% with non-hsCHD
CHD classified as being HS-CHD or non-hsCHD according to definition of authors (pediatric cardiologists)
6-year retrospective study (2004–2009) of 433 infants <12 months hospitalized for RSV (388 [89.6%]) or influenza at tertiary care center; 50 children with CHD
2-year prospective study (1993–1995) of 427 children <3 years (253 complex CHD and 14 heart/lung disease); eight tertiary centers; no data on RSV immunoprophylaxis
Complex CHD defined as congenital heart abnormality needing cardiac surgery or dependence on cardiac medication. Patients who were digoxin-dependent or had not received corrective cardiac surgery were included
7-year retrospective, multicenter study (1996–2003) of 3239 children <2 years with heart disease; no child received RSV immunoprophylaxis
Categorized as HS-CHD in all patients who were cyanotic, decompensated or required anti-congestive therapy. In other patients hemodynamic significance categorized as determined by the attending pediatric cardiologist
4-year prospective, multicenter study (2004–2008) of 2613 children <2 years with HS-CHD hospitalized for ARI (3.8% diagnosed RSV); 90.5% received RSV prophylaxis
Definition of HS-CHD stipulated by the Spanish Society of Pediatric Cardiology
12-year retrospective study (1987–1998) of 1503 episodes of RSVH in children <2 years; infants with cardiac malformation (2.9% catchment area; 13% from other areas); no data on RSV immunoprophylaxis
3-year prospective, multicenter, randomized, controlled study of 416 children <4 years with CHD or cardiomyopathy (214 control group—no RSV immunoprophylaxis)
Not defined
CHD: 150.0 (control group)
<6 months: 240.0 (control group)
>6 months: 90.0 (control group)
NR
NR
RSVH rates for studies with mixed populations of infants and children
6-month retrospective study (1999–2000) of 1214 children <2 years hospitalized for LRTI or developed RSV LRTI whilst hospitalized in 32 tertiary centers (3.5% non-surgically corrected CHD)
6-year retrospective cohort study (2000–2006) of 2407 preterm infants (<36 wGA) followed to 3 years but analyzed at <18 months (34 [1.4%] CHD); 13.5% received ≥1 dose RSV immunoprophylaxis
ICD-9 codes used to classify children. SIO also used to identify infants with diagnosis of CHD
6-month prospective, multicenter, observational study (2008–2009) of 519 children ≤2 years admitted with LRTI (18 [3.5%] high-risk RSV + children, including CHD); No RSV immunoprophylaxis
3-year retrospective study (1989–1993) of all children <3 years (enrolled in Medicaid program; included children with CHD)
ICD-9 codes used to classify children
CHD: 50.0
0–6 months: 120.8
6–<12 months: 63.5
12–24 months: 18.2
24–36 months: 4.8
0–6 months: 44.1g
6 to <12 months: 15.0g
12–24 months: 3.7g
24–36 months: 1.0g
≤12 months: 2.8 (2.3–3.3)
Summary
Number of studies
Number of countries
Population age range and timeframe of studies
RSVH per 1000 (all CHD)
15
11
<4 years; 1979–2009
14–357
ARI acute respiratory infection, CHD congenital heart disease, CI confidence interval, HS-CHD hemodynamically significant congenital heart disease, ICD International Classification of Diseases, Clinical Modification codes, LRTI lower respiratory tract infection, non-hsCHD non-hemodynamically significant congenital heart disease, NR not recorded, OR odds ratio, RSVH respiratory syncytial virus hospitalization, SIO Sistema Informativo Ospedaliero della Regione Laziow, wGA weeks’ gestational age
aChildren with heart disease (any cardiac diagnosis)
bPer 1000 child–person years
cAdjusted OR for HS-CHD
dRSVH rate depending on ‘early’ or ‘late’ season
eP = 0.002 vs. non-CHD cases
fP = 0.01 vs. remaining CHDs
gLow risk group
Several studies reported a higher RSVH rate in infants aged <12 months [29, 30, 36, 38]. In a retrospective study by Boyce et al. [29], the estimated number of hospitalizations per 1000 children with CHD aged 6 to <12 months and 12 to <24 months were 63.5 and 18.2, respectively. In another retrospective study performed in Switzerland [30], RSVH rates (per 100 child–years) in CHD patients aged <6, <12, 12–24, and <24 months of age were 2.5 (95% CI: 0.8–5.6), 2.0 (0.8–3.8), 0.5 (0.1–1.8), and 1.3 (0.6–2.3), respectively. The relative risk in comparison with non-CHD patients was 1.4 (0.6–3.1), 1.6 (0.8–3.2), 2.7 (0.7–9.7), and 1.8 (1.0-3.3), respectively [30]. A significant decrease in frequency of RSV LRTI and RSVH was also observed with increasing age in the Canadian PICNIC study [36]. The RSVH rates in children with CHD aged 0–3, 3–6, 6–12 and 12–24 months were 360, 60, 0 and 10 per 1000, respectively [36]. In contrast, Altman et al. [10] found that RSV disease necessitating hospitalization occurred in children with CHD well into the second year of life. The average age at admission for RSV infection in children with CHD was 16 ± 12 months, with children >12 months of age accounting for 61% (34/56) of the cohort [10]. The aforementioned studies included data from 1989–2003 [10, 29, 30, 36, 38]. It might be expected that, with corrective surgery now mostly occurring in the first few months of life, rates of RSVH in the second year of life would be lower than what has been reported here. However, we were unable to identify any data to support this assertion. There is recently published evidence from the US and Canada which indicates that infants with complex cardiac conditions remain at substantial risk of RSVH in the second year of life [48, 49].
In multivariate analyses, CHD has been found to be an independent risk factor for RSVH [27, 34, 38, 50]. Data on a population of Danish children with heart disease revealed that cardiomyopathy [odds ratio (OR) 5.84, 95% CI 1.26–27.16] and HS-CHD (OR 1.53, 95% CI 1.04–2.26) were both significant predictors of RSVH [38]. In a retrospective study by Boyce et al. [29], CHD was found to be an independent risk factor for RSVH in the first year of life with an incidence rate ratio of 2.8 (95% CI 2.3–3.3) versus children born at term with no underlying medical condition (low-risk group). While HS-CHD has been shown to have a significantly higher RSVH rate compared to other CHDs (92 vs. 33 per 1000; P = 0.01) [8], recent data from the PONI study [50] suggest that children diagnosed with CHD that is not hemodynamically significant (non-hsCHD) suffer a substantial burden of RSV disease that seems to be underestimated and underreported in the literature. During the 2013–2014 RSV season, 2390 preterm infants (33 weeks + 0 days to 35 weeks + 6 days) aged ≤6 months were prospectively followed across 23 countries in Western Europe. RSVH rates (per 1000 infant–years) for the study cohort were 41 and 61 during the study period and RSV season, respectively. Non-hsCHD diagnosis in this premature population was associated with an increased risk of RSV-related LRTI hospitalization in multivariable analyses (P = 0.0077) [50]. Verification of non-hsCHD as an independently significant risk factor for RSVH in non-premature populations is required.
Morbidity and Healthcare Resource Utilization
The disease burden associated with RSVH in infants and young children (<6 years) with CHD is considerable (Table 2). Length of stay in hospital and ICU admissions vary among studies, but, on average, children with CHD and severe RSV infection spent an average of 4.4–14 days in hospital [5, 6, 8, 10, 27, 30, 33, 38‐40, 42, 45, 47, 48, 52]. Up to 53% were admitted to ICU with a median stay of 9.5–11 days [5, 6, 10, 27, 30, 44]. A retrospective, single-center study of 30 children with CHD and severe RSV infection reported that more than half (53.3%) were admitted to PICU for treatment [6]. The majority (87.5%) of PICU admissions were in infants ≤2 years of age and the median number of days spent in PICU was 11 days (range 1–43 days). The majority (87.7%) of these children had not received RSV immunoprophylaxis. During hospitalization, 15 children (50%) required respiratory support: 9 required mechanical ventilation and 6 required continuous positive airway pressure (CPAP) or non-invasive positive pressure ventilation. In addition, a third (33.3%) of the children required supplemental oxygen. Of the 24 infants in the study aged ≤2 years, 14 had non-hsCHD. The overall hospital LOS for all patients was 10 days (range: 1–65 days). Hospitalized children were susceptible to major complications following RSV infection: 20% were found to have concurrent bacterial sepsis, 16.7% electrolyte abnormalities, and 13.3% worsening of pulmonary hypertension [6].
Table 2
Hospital/ICU LOS for severe RSV infection among infants and children with and without CHD
Study
Country
Study participants
Hospital LOS (days)
Admitted intensive care (%)
ICU LOS (days)
Mechanical ventilation or respiratory support (%)
Oxygen therapy (%)
Case fatality rate (%)
Rates for studies of infants and children with CHD
684 infants ≤1 year hospitalized for bronchiolitis or RSV pneumonia
6.0 (median)
NR
4.1 (median)
31.7
NR
0.15
Summary for studies infants and children with CHD
Outcome
Number of studies
Number of countries
Population age range and timeframe of studies
Value
Hospital LOS
7
5
<6 years; 1994–2012
4.4–14j
ICU admission
5
4
<6 years; 1992–2009
5–53.3 k
ICU LOS
4
4
<6 years; 1994–2009
9.5–11i
Oxygen therapy
3
3
<6 years; 1996–2009
27.5–64k
Invasive mechanical ventilation
5
3
<6 years; 1992–2012
3–30k
CPAP or non-invasive positive pressure ventilation
2
2
<6 years; 1996–2003
20–25.8k
Case fatality rate
8
5
<6 years; 1992–2009
0–3.3k
CHD congenital heart disease, CLD/BPD chronic lung disease/bronchopulmonary dysplasia, CHF congestive heart failure, CPAP continuous positive airway pressure, HS-CHD hemodynamically significant congenital heart disease, ICD International Classification of Diseases, Clinical Modification codes, ICU intensive care unit, IQR interquartile range, LOS length of stay, LRTI lower respiratory tract infection, non-hsCHD non-hemodynamically significant congenital heart disease, NR not reported, NSCHD non-surgically corrected congenital heart disease, RSVH respiratory syncytial virus hospitalization
a2366 children received RSV immunoprophylaxis
bCase fatality rate due to respiratory infection
cData for control group (n = 214) who did not receive RSV immunoprophylaxis
dGroup of children with only CHD as risk factor
eData for all high-risk children in study, defined as prematurity, CLD/BPD or CHD
fCase fatality rate for all children enrolled
gOne patient
hPercentage of children admitted to hospital due to RSV
iMedian days
jAverage (mean/median) days
kPercentage
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Duppenthaler et al. [30] observed that complications leading to ICU admission, supplemental oxygen and ventilation appear to be more common in infants aged <2 years with CHD than in those without CHD. In addition, infants with CHD were significantly more often admitted to the ICU than infants with BPD or prematurity ≤35 weeks gestational age (50% vs. 6.7% and 20%, respectively), but not in comparison with otherwise healthy infants <1 month of age (32%) (Table 3) [30]. Baysal et al. [42] also reported that PICU admission and mechanical ventilation rates were significantly higher for infants with CHD aged <2 years as compared to infants without CHD infected with RSV (P = 0.01). In a further study by Kristensen et al. [38], cardiac decompensation (including the need for anticongestive therapy) was identified as a predictor for respiratory support (supplemental oxygen, nasal CPAP or mechanical ventilation) during RSVH [relative risk (RR): 1.81, 95% CI 1.02–3.23].
Table 3
Clinical course of RSVH in children aged <2 years with CHD compared to other risk populations [30]
Parameter
CHD (n = 10)
BPD (n = 15)
Prematurity ≤35 wGA (n = 60)
Age <1 month (n = 90)
No risk factor (n = 554)
Hospital LOSa
6.5 (2–41)
11 (4–23)
6 (2–23)
8 (1–27)
5 (1–30)
Supplemental oxygenb
100
80
73
86
66
ICU admissionb,c
50
6.7
20
32
7.0
ICU LOSa
1.5 (0–25)
0 (0–5)
0 (0–16)
0 (0–17)
0 (0–18)
Mechanical ventilationb
20
0
1.7
5.6
1.3
BPD bronchopulmonary dysplasia, CHD congenital heart disease, ICU intensive care unit, LOS length of stay, wGA weeks’ gestational age
aMedian days (range)
bPercentage
cCHD vs. BPD, P = 0.01; CHD vs. prematurity, P = 0.045; CHD vs. age <1 month, P = 0.144; CHD vs. no risk factor, P < 0.001
Recently published data from the US specifically examined the risk of RSVH in the second year of life in infants with CHD [48]. In total, 4468 RSVHs among infants 12–23 months of age with CHD were identified over a 16-year period (1997–2012). The mean LOS for RSVH was 4.4 days, with 11.4% requiring mechanical ventilation. For those without CHD, the comparative rates were 2.3 days and 2.3%, respectively. Several specific CHD diagnoses were associated with a longer LOS and higher rates of mechanical ventilation, with congestive heart failure having the worst overall morbidity (LOS: 8.2 days; mechanical ventilation: 31%) [48].
Nosocomial outbreaks of RSV infection in ICUs also represent an important cause of morbidity in this specific, high-risk population [53, 54]. Children on long-term mechanical ventilation may acquire RSV infection by transmission through droplets or caregivers and face an increased risk of a severe course of RSV infection [53]. A German study prospectively documented 1568 RSV infections in 1541 pediatric patients of whom 20 (1.3%) had acquired the RSV infection while being treated by mechanical intervention for other reasons. Thirty-five percent of the children (median age 4.2 months, range 0.5–97 months) who acquired the RSV infection whilst mechanically ventilated had CHD [53]. In a UK study reporting on a RSV outbreak in a PICU, 27.8% (15/54) of the children acquired the RSV infection whilst in the PICU [54]. In this study, PICU-acquired RSV infection was defined as having occurred when a child admitted to the PICU was RSV-negative or from whom no samples were taken because they did not exhibit signs of bronchiolitis, and who then was found to be RSV-positive ≥5 days after the admission [54]. Nosocomially-acquired RSV infection has also been documented during hospitalization in infants aged <2 years in an Italian study [45]. These data confirm the high risk of infants and children developing a severe RSV infection during hospitalization and the importance of adhering to strict infection control measures to prevent further spread of RSV in clinical settings.
Further data from a retrospective study in Canada demonstrated that children with CHD hospitalized for LRTI (0.6% RSV) in infancy had an almost two-fold increase in risk of childhood chronic respiratory morbidity (asthma, chronic bronchitis or chronic lung disease) by age 10 compared to CHD children not hospitalized for LRTI [58.5% (244/417) vs. 31.5% (884/2805), respectively] [55]. Among CHD children, LRTI hospitalization was associated with a 3-fold increase in the risk of childhood chronic respiratory morbidity [adjusted OR 3.0 (2.3–3.9)] and a 6-fold increased risk of hospitalization for chronic respiratory morbidity [adjusted OR 5.7 (4.0–8.1)] [55]. The nature, incidence and impact of long-term respiratory morbidity associated with RSVH in infancy in Western countries will be covered in more detail in a subsequent publication in the REGAL series.
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Impact of RSV Infection on Cardiac Surgery for CHD
Surgical outcomes in children with CHD have improved over the past two decades. However, a significant number of children are exposed to RSV, which can result in substantial morbidity and mortality [10, 56‐58]. In a post hoc analysis of a multicenter, randomized trial [59], Tulloh et al. [57] included all children who underwent cardiac surgery comparing outcomes for those who acquired RSV infection with those who did not (controls), matched for demographics (age and weight at operation) and physiology of cardiac morphology. It was found that RSV infection more than 6 weeks before cardiopulmonary bypass caused significant morbidity, but there was no indirect evidence of pulmonary hypertension after RSVH. This analysis also found that the duration of heart failure medication tended to be longer (by 6 months in >50% of children) if the children were hospitalized for RSV than if not [57]. Khongphatthanayothin et al. [56] reported on 25 children with CHD who had cardiac surgery within 6 months after RSV infection. Surgery for CHD performed during the symptomatic period of RSV infection was associated with a higher risk of postoperative complications (particularly pulmonary hypertension) than if surgery was undertaken electively after being discharged following RSV infection [56]. Altman et al. [10] reported that post-operative RSV infection in children with CHD can cause significant morbidity, resulting in prolonged hospital stays (2.1 times longer vs. historical, age-matched controls with comparable cardiac lesions) and time spent in ICU. RSV infection also resulted in delayed cardiac surgery in 35% (12/34) of patients in need of surgery during the RSV season [10]. Any delays in corrective surgery caused by RSV infection may increase cardiac-associated morbidity in children with CHD, though no evidence is available to adequately quantify this impact.
Case Fatality Rates
Few studies have specifically investigated mortality due to RSV in young children with CHD. Available data from the published literature suggest that the case fatality rate for RSV is relatively low among infants and children with CHD in Western countries, ranging from 0 to 3.3% [5, 6, 8, 10, 30, 38‐40, 42, 44, 47, 48, 52]. In a retrospective, single-center study of 30 children with CHD by Butt et al. [6], conducted over a period of 7 years, only one death (3.3%) was attributed to RSV. Meberg et al. [8] reported one death related to RSV infection among 500 RSVH children with CHD; a 4-month-old premature, male infant with Down syndrome, suffering from CLD, atrioventricular septal defect and heart failure. In a US study of 4486 RSVHs among infants 12–23 months of age with various CHD diagnoses, the overall case fatality rate was 1.6%; however, certain diagnoses were associated with substantially higher rates (transposition of great vessels: 10.6%; congestive heart failure: 9.6%; cardiomyopathy: 9.5%; Ebstein’s anomaly: 8.8%) [48]. A study published in 2009, undertaken to determine the mortality rate and risk factors for death in children with severe RSV infection, found that pre-existing disease/comorbidity, in particular multiple pre-existing diseases and cardiac anomaly, was associated with a significantly higher risk of death from severe RSV infection [9]. All the RSV deaths had pre-existing medical conditions/comorbidity (27% cardiac lesions) [9]. Similar data come from a recently published US study which reported that the majority (76–79%) of RSV-associated deaths occurred in infants with complex chronic conditions [60]. Cardiovascular conditions were the most frequent single chronic condition identified, being associated with 37–45% of all RSV-related deaths [60].
Limitations
It should be recognised that the evolving definitions of CHD over time may have affected comparisons between studies and interpretation of results. Additionally, it is difficult to measure the impact of improved surgical practice in this population on the subsequent outcome of RSV infection. There were also few studies identified specifically addressing children with CHD, with the majority of studies including mixed populations of children. Other factors, such as improvements over time in both medical and surgical practice and RSV surveillance, will also have influenced interpretation of the results. Future studies should use the current, accepted definition of CHD, as described in “Methods”. Research areas of particular interest include studies investigating how delays in surgery caused by RSV impact CHD-related morbidity and studies on the epidemiology and associated morbidity of severe RSV LRTI in infants with CHD in the second year of life.
Summary Box
Key statements/findings
Level of evidencea
CHD, in particular HS-CHD, is a significant risk factor for severe RSV infection with RSVH rates ranging from 14–357 per 1000
Level 1
(Level 1 studies: n = 9;
Risk of biasb: very low)
Children with CHD spend an average of 4.4–14 days in hospital for RSV infection, with up to 53% requiring admission to the ICU
Level 1
(Level 1 studies: n = 8;
Risk of biasb: very low)
Children with CHD have a more severe disease course (increased ICU admission and ventilation) than children without CHD
Level 1
(Level 1 studies: n = 2;
Risk of biasb: very low)
RSV infection can delay and impact surgery for CHD, increasing post-operative complications, such that the timing of surgery is an important consideration
Level 2
(Level 1 studies: n = 1; Level 2 studies: n = 1; Level 3 studies: n = 2
Risk of biasb: very low)
Case fatality rates associated with RSVH in children with CHD are reported to range from 0–3.3%
Level 1
(Level 1 studies: n = 6; Risk of biasb: very low)
Key areas for research
Further research and specific studies are needed to determine the longer-term effects of severe RSV infection in infants and young children with HS-CHD as well as those with CHD that is not hemodynamically significant. Additional data are also required to assess outcomes of HS-CHD and non-hsCHD in children, independent of chromosomal/non-chromosomal anomalies and other serious pre-existing medical disorders
CHD congenital heart disease, HS-CHD hemodynamically significant congenital heart disease, ICU intensive care unit, LOS length of stay, non-hsCHD non-hemodynamically significant congenital heart disease, RSVH respiratory syncytial virus hospitalization, OR odds ratio, RR risk ratio
aLevel 1: local and current random sample surveys (or censuses); Level 2: systematic review of surveys that allow matching to local circumstances; Level 3: local non-random sample; Level 4: case-series [24]
bAverage RTI Item Bank Score [26], where ≤2 = very high risk of bias and 10–12 = very low risk of bias
Conclusions
Infants and children with CHD are at high risk for severe RSV infection, particularly in the first year of life. Available data from the published literature suggest that, while the case fatality rate for RSV in this vulnerable population is relatively low, the burden of RSV in terms of hospitalization and the need for ICU admission is high. Nosocomially acquired RSV-infection in CHD children results in substantial morbidity. In addition, cardiac surgery performed during the symptomatic period of RSV infection has been associated with a high risk of postoperative complications, particularly postoperative pulmonary hypertension. Data suggest that early surgery significantly reduces the risk of RSVH during the first RSV season. Conversely, RSV infection may delay corrective cardiac surgery.
Most studies have focussed on HS-CHD, but the definition across the reviewed studies is not standardized. Recent data suggest that infants with CHD that is not hemodynamically significant are also at increased risk of RSVH and suffer a substantial burden of RSV disease. Moreover, infants with CHD seem to remain at risk for RSVH during their second year of life, particularly those with complex cardiac conditions, although this risk may be diminishing with earlier surgical intervention and improving outcomes. Further research and specific studies are needed to determine the longer-term effects of severe RSV infection in infants and young children with HS-CHD, as well as those with CHD that is not hemodynamically significant, in order to reduce the burden and improve outcomes in this patient population.
Acknowledgements
Sponsorship and article processing charges for this study were funded by AbbVie. Dr Joanne Smith, Julie Blake (Reviewers 1 and 2) and Dr Barry Rodgers-Gray (Reviewer 3), from Strategen Limited, undertook the systematic review following the protocol approved by the authors. AbbVie provided funding to Strategen to undertake the systematic review. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Editorial assistance in the preparation of this manuscript was provided by Julie Blake and Dr Barry Rodgers-Gray. Julie Blake and Barry Rodgers-Gray developed a first draft of the manuscript, based on the results of the systematic review and input/approval from all authors, which was initially edited by Xavier Carbonell-Estrany and Paul Checchia and then circulated among the other authors for input, further edits and subsequent approval. Support for this assistance was funded by AbbVie. AbbVie had the opportunity to review and comment on the completed manuscript but final editorial control rested fully with the authors.
Disclosures
The institute of Louis Bont received money for investigator-initiated studies by MeMed, AstraZeneca, AbbVie, and Janssen. The institute of Louis Bont received money for consultancy by Astra Zeneca, AbbVie, MedImmune, Janssen, Gilead and Novavax. Paul Checchia has acted as an expert advisor and speaker for AbbVie and has received honoraria in this regard. He has also received research grant funding from AstraZeneca. Brigitte Fauroux has received compensation as a neonatology board member from AbbVie. Josep Figueras-Aloy has acted as an expert advisor and speaker for AbbVie and has received honoraria in this regard. Paolo Manzoni has acted as a speaker for AbbVie, and as an expert advisor for AbbVie, TEVA, MedImmune, AstraZeneca, Janssen, and has received honoraria in this regard. Bosco Paes has received research funding from AbbVie Corporation and compensation as an advisor or lecturer from AbbVie and MedImmune. Eric Simões has received grant funding to his institution from MedImmune Inc, Glaxo Smith Kline Inc, and received consultancy fees to the institution, from AbbVie. Xavier Carbonell-Estrany has acted as an expert advisor and speaker for AbbVie and has received honoraria in this regard.
Compliance with Ethics Guidelines
The analysis in this review article is based on previously published studies and does not involve any new studies of human subjects performed by any of the authors.
Data Availability
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Open Access
This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
