Introduction
Methods
Outcomes of Interest
Evaluation of Data
Compliance with Ethics Guidelines
Results
Articles Selected
Incidence of RSV Infection and Outcomes
Down Syndrome
Study | Country | Design/study population | Incidence RSVH (per 1000) | Hospital LOS, median days (IQR) | Admission to ICU/PICU (%) | Supplemental oxygen (%) | Intubation and/or mechanical ventilation (%) | Case fatality rate (%) |
---|---|---|---|---|---|---|---|---|
Studies specifically assessing children with Down syndrome
| ||||||||
Sánchez Luna 2017 [29] | Spain | Prospective multicenter study (2012–2013) of 93 term infants aged <12 months with Down syndrome and no risk factors for RSV and 68 matched control infants with no risk factors for RSV; 35.5% Down syndrome cohort received RSV immunoprophylaxis | 97a (108b) | 7.3 | 14.3 | 53.6 | 3.6 | 0 |
Stagliano 2015 [22] | US | Retrospective cohort study of 633 200 children born 2005–2011, 842 of whom had Down syndrome; for children with Down syndrome, 64 of 81 (79%) hospitalized for RSV had ≥1 concomitant risk factor and CHD was present in 50%. Excluded children receiving RSV immunoprophylaxis | 96c
| 4 (2–7) | NR | NR | 9.3 | NR |
Zachariah 2012 [27] | US | Population-based study of 630 children aged <2 years with Down syndrome hospitalized for RSV in 2000–2006 [580 (92%) had concurrent underlying conditions]. CHD present (<1 year 31.8%; 1–2 years 15.4%). One child with CLD received RSV immunoprophylaxis | 135 | <1 year: 4 1–2 years: 5 | NR | NR | <1 year: 8.2 1–2 years: 9.6 | NR |
Gooch 2011 [15] | US | Retrospective study (2001–2007) of 196 children aged <2 years with Down syndrome without concurrent CHD or BPD and 784 matched term controls. Excluded children receiving RSV immunoprophylaxis | 36a
| 4.4 (2.7)d
| NR | NR | NR | NR |
Medrano Lopez 2009 [30] | Spain | Prospective study (2006–2007) of 1085 children aged <2 years of whom 279 (25.7%) had Down syndrome (48% with significant CHD). 39.9% of Down syndrome cohort received RSV immunoprophylaxis | 78 | 7e
| 28.4e
| NR | 14.7e
| NR |
Bloemers 2007 [31] | Netherlands | Three groups studied (1) Retrospective observational study of 206 children with Down syndrome born between 1976 and 2005 (2) Prospective birth-cohort study of 241 children with Down syndrome born between 2003 and 2005 followed until 2 years old (45.6% had ≥1 risk factor for severe RSV); (3) unmatched control group of 276 siblings of birth cohort. 36% had hemodynamically significant CHD. No information on RSV immunoprophylaxis | 99f
| 10 | NR | 79.5 | 12.8 | NR |
Studies that included a subset of children with Down syndrome
| ||||||||
Pisesky 2016 [28] | Canada | Retrospective chart review that identified (using ICD10 codes) 19 815 children (<3 years) hospitalized for RSV from 2005 to 2013. 145 RSVHs for children with Down syndrome. No information on RSV immunoprophylaxis | 70 | NRg
| NRg
| NRg
| NRg
| NRg
|
Murray 2014 [7] | UK | Retrospective multicenter study (2007–2008) of 7189 children aged <12 months admitted to hospital with bronchiolitis [28 (0.4%) with Down syndrome]. No information on RSV immunoprophylaxis | 154 | 3 (0–9) | NR | NR | NR | NR |
Kristensen 2012 [10] | Denmark | Register-based cohort study of 452 205 children aged <2 years of whom 12 498 (2.8%) were hospitalized for RSV from 1997 to 2003. 78/399 RSVHs for children with Down syndrome. During the study period, 118 of total population received RSV immunoprophylaxis | 195 | 1.9 (1.5–2.4)h
| NRg
| NRg
| NRg
| NRg
|
Fjaerli 2004 [32] | Norway | Population-based retrospective study of 764 children aged ≤2 years hospitalized for RSV between 1993 and 2000 [4 of 7 (57%) children with Down syndrome had CHD]. No information on RSV immunoprophylaxis | 135 (154b) | 7.5 (range 2–34) | NR | NR | 28.6 | 14.3i
|
Outcome | Number of studies | Number of countries | Population age range and timeframe of studies | Value |
---|---|---|---|---|
Summary | ||||
Incidence of RSVH | 10 | 7 | <3 years; 1976–2013 | 36–195 per 1000 children |
LOS | 7j
| 5 | <3 years; 1976–2013 | 3–10 days |
Admission to ICU/PICU | 1j
| 1 | <1 year; 2012–2013 | 14.3% |
Supplemental oxygen | 2 | 2 | ≤2 years; 1976–2013 | 53.6–79.5% |
Intubation and/or mechanical ventilation | 3j
| 3 | ≤2 years; 1976–2013 | 3.6–28.6% |
Case fatality rate | 2 | 2 | ≤2 years; 1993–2013 | 0–14.3% |
Immunocompromised Children
Study | Country | Design/study population | Incidence RSV (per 1000) | Incidence RSVH (per 1000) | LOS, median days (range) | Admitted to ICU/PICU (%) | Supplemental oxygen (%) | Intubation and/or mechanical ventilation (%) | Case fatality rate (%) |
---|---|---|---|---|---|---|---|---|---|
Studies of children ≤2 years
| |||||||||
Murray 2014 [7] | UK | Retrospective multicenter study (2007–2008) of 7189 children aged <12 months admitted to hospital with bronchiolitis [7 (0.1%) were immunocompromised]. No information on RSV immunoprophylaxis | NA | 117 | 8 (1–58) | NR | NR | NR | NR |
Kristensen 2012 [10] | Denmark | Register-based cohort study of 452 205 children aged <2 years of whom 12 498 (2.8%) were hospitalized for RSV from 1997 to 2003. 7/83 RSVHs for children with cancer. During the study period, 118 of total population received RSV immunoprophylaxis | NR | 187 | 1.1 (0.4–2.9)a
| NRb
| NRb
| NRb
| NRb
|
Germany | Prospective, multicenter study of 39 hospitalized infants (<1 year) with cancer who had an RSV infection between 1999 and 2005; no information on RSV immunoprophylaxis | NA (study population) | NA (study population) | 7 (2–35) | 13 | 44 | 3 | 0 | |
Wang 1995 [42] | US | Multicenter, prospective cohort study of 689 children aged <2 years hospitalized with an RSV infection in 1993 (21 immunocompromised childrenc); no information on RSV immunoprophylaxis | NA (study population) | NA (study population) | 10d
| 19.1d
| NRd
| 14.3d
| 4.8d
|
Studies of children ≤18 years
| |||||||||
Feldman 2015 [35] | US | Retrospective cohort study of 2554 children aged <18 years who had a liver transplant between 2004 and 2013; no information on RSV immunoprophylaxis | 72 | 40e
| NR | 20.9 | NR | 9.3 | 4.9e
|
Hutspardol 2015 [9] | Canada | Retrospective study of 844 children [median age 7.5 years (range 1 month–17.8 years)] who underwent HSCT (allogeneic 491, autologous 353) between 2000 and 2012; 1 child (0.1%) received RSV immunoprophylaxis | 18 | NR | NR | NR | NR | 0.2 | 6.7 |
Robinson 2015 [8] | Canada | Surveillance study of 24 inpatients and outpatients aged <17 years who had received HSCT or SOT and had an RSV infection within 2 years post-transplant (2010–2013); 2 children (8.3%) had/possibly received RSV immunoprophylaxis | NA (study population) | NAf
| NR | 29 | NR | 21 | 8.3 |
Chemaly 2014 [37] | US | Retrospective study of 59 children aged <18 years with cancer (solid tumor 15%; hematologic malignancy 53%; HSCT 32%) with RSV between 1998 and 2009; no information on RSV immunoprophylaxis | NA (study population) | NAg (study population) | 6 (2–9) | 10 | NR | 5 | 5 |
Lo 2013 [39] | US | Retrospective study of 2375 children who received HSCT or SOT or had cancer at a tertiary center (1993–2006); median age 6.1 and 4.3 years, respectively; no information on RSV immunoprophylaxis | 37h
| NRi
| NRi
| NRi
| NRi
| NRi
| NRi
|
Asner 2013 [47] | Canada | Single-center observational study of 117 immunocompromised children aged <18 years (HSCT 13.7%; SOT 16.2%; solid tumors 16.2%; leukemia/lymphoma 28.2%; immunosuppression for chronic condition 1.7%) with positive RSV infection from 2006 to 2011; 15 (12.8%) children received RSV immunoprophylaxis | NA (study population) | NAj (study population) | 9 (5–24.5) | 23.9 | NR | 17.1 | 4.3 |
Tran 2013 [38] | US | Retrospective study of 30 children aged ≤18 years who received an abdominal organ transplant, hospitalized with a positive respiratory illness in 2008–2011; 5 patients (16.7%) with RSV; children <24 months old received immunoprophylaxis | NA (study population) | NA (study population) | NR | NR | NRi
| NR | 40 |
Anak 2010 [50] | Turkey | Retrospective survey of two RSV outbreaks (2006; 2009) among 30 pediatric patients hospitalized for hemato-oncological diseases treated with or without HSCT; no information on RSV immunoprophylaxis | 200 | NA | NR | NR | NRi
| 0 | 0 |
Sung 2008 [40] | US | Retrospective review of 3 Children’s Oncology Group AML trials (2003–2005); 2078 children with de novo AML (median age 8.7 years); no information on RSV immunoprophylaxis | 0–22k
| NR | NR | NR | NR | NR | 0.2 |
Mendoza Sánchez 2006 [17] | Spain | Retrospective study of 347 children aged ≤14 years diagnosed with cancer and receiving anticancer therapy (n = 218) or HIV infection (n = 129) (1989–2003) | 101 (HIV); 46 (cancer) | NRi
| NRi
| NRi
| NRi
| NRi
| 0 (HIV); 20.0 (cancer) |
Small 2002 [45] | US | Single center, retrospective study of 548 allogenic HSCT (including 154 children <19 years) and 394 autologous HSCT recipients from 1994 to 1999; no information on RSV immunoprophylaxis | 175l
| NR | NR | NR | NR | NR | 12m
|
Miller 1996 [41] | US | Retrospective study of 173 pediatric recipients of renal transplantation between 1985 and 1993; no information on RSV immunoprophylaxis | 30 | NR | NR | NR | NR | 0 | 0 |
Studies of mixed populations of children and adults
| |||||||||
Chu 2016 [33] | US | Single-center retrospective cohort study of 15 children and young adults aged <21 years with HSCT, SOT or hematologic malignancy with RSV diagnosed as an outpatient between 2008 and 2013; no patient received RSV immunoprophylaxis | NA (study population) | NAn
| NR | 2 | 6 | 0 | 0 |
Campbell 2015 [34] | US | Prospective study of 458 patients (52 children aged <18 years) who underwent allogeneic HSCT between 2005 and 2010; no information on RSV immunoprophylaxis | 19o
| NA | NR | NR | NR | NR | 0o
|
El-Bietar 2015 [36] | US | Prospective study of 349 consecutive patients aged 6 months–25 years who underwent BMT between 2008 and 2013; no information on RSV immunoprophylaxis | 52p
| NR | NR | NR | NR | NR | 0 |
Liu 2009 [44] | US and Europeq
| Multicenter, retrospective study of 576 lung transplant recipients (≤21 years) from 1988 to 2005; no information on RSV immunoprophylaxis | 36e,h
| NR | NR | NR | NR | NR | NR |
El Saleeby 2008 [20] | US | Retrospective study of 58 cases of RSV in immunocompromised pediatric patients aged <21 years (40% ALL, 19% solid tumors, 41% HSCT recipients, AML, or SCID) between 1997 and 2005; no information on RSV immunoprophylaxis | NA (study population) | NA (study population)p,r
| 7 (3–51)p
| NR | 22p
| 9p
| 8.6p,s
|
Luján-Zilbermann 2001 [43] | US | Single center, retrospective review of 281 HSCT recipients (including hematological malignancies, solid tumors, sickle cell disease, metabolic disorders, primary immunodeficiencies) from 1994 to 1997; mean age 9.28 (0.2–22) years; no information on RSV immunoprophylaxis | 17e
| 11 | NR | NR | NR | NR | 0 |
McCarthy 1999 [51] | UK | Single-center retrospective study of 336 patients [median age 10.6 years (range 0.5–31.1)] who received BMT between 1993 and 1998; no information on RSV immunoprophylaxis | 63t
| NA | NR | NR | NR | NR | 19.2 |
Outcome | Number of studies | Number of countries | Population age and timeframe of studiesu
| Value |
---|---|---|---|---|
Summary | ||||
Incidence of RSV infection | 13 | 7 | ≤31 years; 1985–2013 | 0–200 per 1000 population |
Incidence of RSVH | 4 | 3 | ≤22 years; 1994–2013 | 11–187 per 1000 population |
LOS, median | 6 | 4 | <21 years; 1993–2011 | 6–10 days |
Admission to ICU/PICU | 7 | 3 | <21 years; 1993–2013 | 2–29% |
Supplemental oxygen | 4 | 2 | <21 years; 1993–2013 | 6–44% |
Intubation and/or mechanical ventilation | 10 | 4 | <21 years; 1993–2013 | 0–21% |
Case fatality rate | 17 | 6 | ≤31 years; 1985–2013 | 0–40% |
Cystic Fibrosis
Study | Country | Design/study population | Incidence RSV (per 1000) | Incidence RSVH (per 1000) | LOS, median days (range) | Admitted to ICU/PICU (%) | Supplemental oxygen (%) | Intubation and/or mechanical ventilation (%) | Case fatality rate (%) |
---|---|---|---|---|---|---|---|---|---|
Deschamp 2015 [61] | US | Interim analysis of multicenter, prospective study estimated to enroll 90 infants (<4 months at recruitment) with CF. Analysis included 13 infants with CF who had 59 nasopharyngeal samples collected and tested using viral PCR analysis over 11 months. No information on RSV immunoprophylaxis | 77a
| NR | NR | NR | NR | NR | NR |
Murray 2014 [7] | UK | Retrospective, multicenter study (2007–2008) of 7189 children aged <12 months admitted to hospital with bronchiolitis [11 (0.2%) with CF]. No information on RSV immunoprophylaxis | NA | 64 | 2 (0–14) | NR | NR | NR | NR |
Kristensen 2012 [10] | Denmark | Register-based cohort study of 452 205 children aged <2 years of whom 12 498 (2.8%) were hospitalized for RSV from 1997 to 2003. Included 72 children with CF of whom 13 were hospitalized for RSV infection. During the study period, 118 of the total population received RSV immunoprophylaxis | NR | 181 | 1.3 (0.8–2.1)b
| NRc
| NRc
| NRc
| NRc
|
Garcia 2007 [62] | US | Single center, prospective study of 44 children with CF (7–18 years) during the 1998–1999 RSV season. No information on RSV immunoprophylaxis | 364d
| NRe
| NR | NR | NR | NR | NR |
Arnold 1999 [60] | Canada | Secondary analysis of a prospective cohort (1993–1995) including 159 children with underlying lung disease, 8 of whom had CF (mean age 33 weeks). No information on RSV immunoprophylaxis | NR | NA (study population) | 11 (4–13) | 12.5 | NR | 0 | 0 |
Outcome | Number of studies | Number of countries | Population age and timeframe of studies | Value |
---|---|---|---|---|
Summary | ||||
Incidence of RSV infection | 2 | 1 | ≤18 years; 1998–2015 | 77–364 per 1000 children |
Incidence of RSVH | 2 | 2 | <2 years; 1997–2008 | 64–181 per 1000 children |
LOS, median | 2 | 2 | <1 year; 1993–2008 | 2–11 days |
Admission to ICU/PICU | 1 | 1 | <2 years; 1993–1995 | 12.5% |
Supplemental oxygen | – | – | – | – |
Intubation and/or mechanical ventilation | – | – | – | – |
Case fatality rate | 1 | 1 | <1 years; 1993–1995 | 0% |
Neurological and Neuromuscular Disorders, Congenital Malformations, and Other Chronic Conditions
Conditiona
| RSV/Total (%) | IRR (95% CI); P value | GMR for LOSb (95% CI); P value |
---|---|---|---|
Congenital
| |||
Malformations of respiratory system
| |||
Cleft lip and palate | 50/855 (6.4) | 1.5 (1.1–2.0); 0.004 | 1.0 (0.8–1.3); NS |
Malformations of the larynx; trachea and bronchi | 41/440 (9.3) | 1.5 (1.1–2.1); 0.009 | 1.1 (0.8–1.5); NS |
Malformation of the lungs | 7/51 (13.7) | 2.2 (1.0–4.8); 0.049 | 1.5 (0.7–3.2); NS |
Other conditions associated with respiratory symptoms
| |||
Esophageal atresia | 26/115 (22.6) | 2.8 (1.6–4.9); <0.001 | 1.8 (1.1–3.1); 0.022 |
Neuromuscular disease
| |||
Encephalocele | 58/542 (10.7) | 1.5 (1.1–2.1); 0.005 | 1.1 (0.8–1.4); NS |
Spina bifida and malformations of the spinal cord | 17/172 (9.9) | 2.2 (1.3–3.6); 0.002 | 2.1 (1.3–3.3); 0.003 |
Muscular dystrophy | 13/82 (15.9) | 2.5 (1.4–4.6); 0.003 | 1.5 (0.9–2.4); NS |
Cerebral palsy | 93/905 (10.3) | 1.6 (1.3–2.0); <0.001 | 1.3 (1.1–1.6); 0.005 |
Congenital diseases, chromosomal abnormalities, and others
| |||
Malformations of the urinary systemc
| 82/1232 (6.7) | 1.5 (1.2–1.9); <0.001 | 1.0 (0.8–1.2); NS |
Other chromosomal abnormalities | 4/17 (23.5) | 5.1 (1.7–15.5); 0.004 | 1.6 (0.7–3.8); NS |
Malformations of the GI tract, liver, biliary system, pancreas, and abdominal wall | 94/1078 (8.7) | 1.6 (1.3–2.0); <0.001 | 1.2 (1.0–1.5); NS |
Congenital immunodeficiencies | 26/122 (21.3) | 2.4 (1.6–3.5); <0.001 | 1.2 (0.9–1.8); NS |
Inborn errors of metabolism | 29/276 (10.5) | 2.4 (1.6–3.5); <0.001 | 1.1 (0.8–1.5); NS |
Acquired
| |||
Interstitial lung disease | 3/11 (27.3) | 6.5 (1.7–23.9); 0.005 | 1.3 (0.4–4.1); NS |
Gastroesophageal reflux | 40/610 (6.6) | 1.5 (1.1–2.1); 0.019 | 1.0 (0.7–1.3); NS |
Epilepsy | 75/713 (10.5) | 2.6 (2.1–3.4); <0.001 | 1.6 (1.3–2.0); <0.001 |
Acquired heart disease | 53/427 (12.4) | 2.0 (1.5–2.7); <0.001 | 1.1 (0.8–1.4); NS |
Liver disease | 9/48 (18.7) | 4.0 (2.0–8.2); <0.001 | 1.0 (0.6–1.9); NS |
Incidence of RSVH Over Time in Children Affected by Underlying Comorbidities
Case Fatality Rates
Limitations
Key statements/findings | Level of evidencea
|
---|---|
A number of conditions, diseases, and disorders are associated with an increased risk of severe RSV disease and related morbidity and mortality | |
Down syndrome
| |
Down syndrome is a significant risk factor for RSVH in early (<3 years) childhood (rate ratiob: 2.5–12.6), even when excluding co-existing risk factors for severe RSV disease, such as CHD and prematurity (rate ratiob: 3.5–10.5) [moderate SOEc] RSVH rate of 70–195 per 1000 children [moderate SOEc] Average of 3–10 days hospitalization [moderate SOEc] Irrespective of other risk factors, increased severity of disease, longer duration of hospital stay, and greater risk of respiratory support, including intubation and/or mechanical ventilation, versus otherwise healthy children [moderate/low SOEc] | Level 1 studies: n = 1; Level 2 studies: n = 8; Level 3 studies: n = 1d
Risk of biase: very low |
Immunocompromised children (including HSCT/BMT recipients, SOT recipients, cancer patients on chemotherapy, children with SCID/DiGeorge syndrome, and those with HIV)
| |
RSVH rate of 11–187 per 1000 children and young adults [low SOEc] Average of 6–10 days hospitalization with ≤29% admitted to ICU and ≤21% requiring intubation and/or mechanical intervention [low SOEc] Independent predictors of prolonged hospital stay: nosocomial RSV infection (P < 0.001) and presence of HSCT, SOT or congenital immunodeficiencies (P = 0.008) [low SOEc] | Level 1 studies: n = 1 Level 2 studies: n = 5 Level 3/4 studies: n = 21f
Risk of biase: lowg
|
Cystic fibrosis
| |
Cystic fibrosis is a significant risk factor for RSVH in early (<2 years) childhood (rate ratiob: 2.5–4.3) [low SOEc] RSVH rate of 64–181 per 1000 children [low SOEc] Average of 2–11 days hospitalization [low SOEc] Morbidity (LOS, ICU, mechanical ventilation) of RSV in children with various forms of underlying lung disease (including cystic fibrosis) similar to those with CLD [low SOEc] | Level 1 studies: n = 0 Level 2 studies: n = 5 Level 3 studies: n = 1h
Risk of biase: very low |
Neurological and neuromuscular disorders, congenital malformations, and other chronic conditions
| |
Neurological and neuromuscular conditions (including spina bifida, cerebral palsy, and muscular dystrophyi) are associated with a significantly (P < 0.05) increased risk of RSVH and increased morbidity [low SOEc] A number of other congenital malformations and chronic conditionsk are also associated with a significantly (P < 0.05) increased risk of RSVH [low SOE] | Level 1 studies: n = 0 Level 2 studies: n = 8 Level 3 studies: n = 1j
Risk of biase: very low |
RSV-attributable mortality
| |
Immunocompromised children, case fatality rates: 0–40% (7/18 studies with 0%) [low SOEc] Underlying medical conditions, case fatality rates: <1%, with pre-existing disease (RR 2.4, 95% CI 2.0–2.8) a significant risk factor for mortality [low SOEc] | Level 1 studies: n = 1 Level 2 studies: n = 6 Level 3/4 studies: n = 17 Risk of biase: very lowl
|
Key areas for research
| |
Where feasible, larger, prospective, well-designed studies are needed to more fully define the risk and outcomes of RSV infection in these populations More data are needed on fatality rates in children with underlying medical conditions or chronic diseases to determine how much is directly attributable to RSV and the true burden of disease |