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Prof Harish Nair MBBS PhD FRCPE FFPH Chair of Paediatric Infectious Diseases and Global Health
Usher Institute of Population Health Sciences and Informatics
University of Edinburgh E-mail: [email protected]
RSV disease – global burden
WSPID, Shenzen, 5 December 2017
Disclosures • Funding from Bill and Melinda Gates Foundation and Innovative
Medicines Initiative for RSV-related work
• Funding from Sanofi Pasteur for RSV and non-RSV related work
• Honorarium from Medimmune for participating in SAB meeting
• Co-founder of ReSViNET – network has received funding from several pharmaceutical industries to organise high level expert group meetings
2
Outline • Background • Global acute RSV Burden by age and region
• Incidence • Hospitalisation • Mortality
3
Background • Child pneumonia - the leading cause of child mortality in 2000 - 1.68M
(18% of all <5y child deaths)1
• In 2015, estimated 921k child deaths due to pneumonia (15% of all <5y child deaths)1
• In future, as PCV and Hib conjugate vaccine coverage is scaled up, the proportional contribution of viral aetiologies (RSV, flu, hMPV) to pneumonia mortality will be substantial
1. Liu et al., Lancet 2016
Deat
hs p
er 1
000
live
birt
hs
Natural history of RSV infection in young children
6
Updated systematic review
7
15105 records identified through database search
4 records identified through other sources
5198 duplicates removed
9911 records screened
990 full-text articles assessed for eligibility
8921 records excluded because not relevant to topic
250 articles included
740 full-text articles excluded
218 studies reported proportion RSV+ hospitalised - 83 were Chinese data
90 studies reported incidence/hospitalisation data
103 studies reported in-hospital CFR data
76 unpublished studies
Case definitions • Community-based (active) case ascertainment
Cough / difficulty breathing AND RSV positive
RSV-associated ALRI: tachypnoea (IMCI cut-offs)
RSV-associated severe ALRI: chest wall indrawing AND / danger signs
• Hospital-based (passive) case ascertainment Hospitalised RSV-ALRI: Hospitalisation with a physician confirmed diagnosis of ALRI and RSV positive on laboratory confirmation
IMCI: Integrated management of childhood illnesses 8
RSV disease severity- conceptual diagram
9 Shi et al., Lancet 2017
Location of incidence, hospital admission and in-hospital mortality studies (n=157)
10 Shi et al., Lancet 2017
Incidence of RSV-(severe) ALRI in LMIC children <2 years
3 5
7 10
10
3
5
7
7
0
20
40
60
80
100
120
140
160
180
200
0-27 days 28-<3m 3-5m 6-11m 12-23m
Inci
denc
e of
RSV
-ALR
I (pe
r 100
0 pe
r yea
r)
Age group
RSV-ALRI severe RSV-ALRI
Shi et al., Lancet 2017
Estimates of RSV-(severe) ALRI in developing countries in 2015
Incidence (per 1000 children per year) [# studies]
# episodes (millions)
0-5 mo 6-11 mo 0-59 mo 0-5 mo 6-11 mo 0-59 mo
RSV-ALRI 82.5 (50.4, 135.2)
[14]
98.8 (58.8, 166.1)
[10]
50.8 (32.4, 79.7)
[14]
5.1 (3.1, 8.3)
6.1 (3.6, 10.2)
30.5 (19.5, 47.9)
RSV-severe ALRI
36.1 (10.1, 129.1)
[8]
28.7 (9.1, 90.3)
[7]
10.2 (3.5, 29.9)
[8]
2.2 (0.6, 7.8)
1.5 (0.7, 3.3)
6.1 (2.1, 17.9)
12 Shi et al., Lancet 2017
Methods to estimate country-level RSV-ALRI incidence
13
Risk factor Survey Odds ratio
Prematurity (GA<37 wk) Other 1.96 (1.44-2.67)
Low birth weight DHS 1.91 (1.45-2.53)
Siblings DHS 1.6 (1.32-1.95)
Maternal smoking Other 1.36 (1.24-1.5)
Paediatric HIV UNAIDS 3.74 (2.47-5.66)
Crowding DHS 1.94 (1.29-2.93)
Meta-analysis of incidence rates Meta-analysis of risk ratios
Risk factors from survey data
Shi et al., Lancet 2017
National RSV-ALRI incidence estimates
Country Incidence of RSV-ALRI (per 1000 children per year)
No. of episodes of RSV-associated ALRI (millions) (UR)
India 56.7 (35.7-89) 7.0 (4.4-11.0)
China 31 (18.7-50.8) 2.6 (1.6-4.2)
Nigeria 55.6 (34.9-87.3) 1.7 (1.1-2.7)
Pakistan 63.9 (39.4-101.7) 1.6 (1.0-2.5)
Indonesia 50.1 (31.6-78.5) 1.2 (0.8-2.0)
14 Shi et al., Lancet 2017
Hospitalisation rate for RSV-ALRI in children <2 years
Even though peak hospitalisation in children <6 months; substantial burden on hospital in-patient services in 6-11 months
15 Shi et al., Lancet 2017
Global estimates of hospitalised RSV-ALRI Region (% global U-5 pop.)
Hospitalisation rate (per 1000 children per year)
# episodes (millions) in 2015
0-5 mo 6-11 mo 12-59 mo 0-5 mo 6-11 mo 12-59 mo
High income (12%)
26.3 (22.6, 30.5)
13.0 (7.2, 23.7)
1.6 (1.1, 2.3)
0.2 (0.2, 0.2)
0.1 (0.05, 0.2)
0.1 (0.07, 0.2)
Upper middle income (26%)
23.0 (16.1, 32.9)
18.5 (9.8, 34.7)
2.2 (1.3, 3.9)
0.4 (0.3, 0.6)
0.3 (0.2, 0.6)
0.3 (0.2, 0.6)
Lower middle income (47%)
22.9 (17.7, 29.7)
11.3 (6.1, 21.0)
1.8 (1.2, 2.8)
0.7 (0.6, 1.0)
0.4 (0.2, 0.7)
0.5 (0.3, 0.7)
Low income (16%)
7.4 (2.4, 22.6)
3.4 (0.6, 19.5)
0.4 (0.1, 1.7)
0.08 (0.03, 0.2)
0.03 (0, 0.2)
0.03 (0, 0.1)
Global 1.4 (1.1, 2.0)
0.8 (0.4, 1.7)
0.9 (0.5, 1.5)
Episodes in 0-59 mo – 3.3M (2.5, 4.5) M
16 Shi et al., Lancet 2017
RSV-ALRI in-hospital CFR in children <5 y
Region (% global U-5 pop.)
# studies
h-CFR [%] (95% CI) 0-5 mo
h-CFR [%] (95% CI) 6-11 mo
h-CFR [%] (95% CI) 12-59 mo
High income (12%) 6 0.2 (0.0, 12.8)
0.9 (0.2, 4.0)
0.7 (0.1, 5.2)
Upper middle income (26%)
12 1.8 (1.2, 2.6)
2.4 (1.1, 5.4)
0.5 (0.1, 3.5)
Lower middle income (47%)
16 2.7 (2.0, 3.6)
2.8 (1.8, 4.4)
2.7 (1.7, 4.3)
Low income (16%) 9 1.7 (0.4, 6.8)
9.3 (3.0, 28.7)
4.7 (0.7, 33.7)
Developing 41 2.2 (1.8, 2.7)
2.4 (1.9, 3.2)
2.2 (1.6, 3.0)
Industrialised 2 0.0 (0.0-0.1) 0.1 (0.0-0.4) 0.1 (0.0-0.3)
17 Shi et al., Lancet 2017
RSV-ALRI in-hospital mortality in children <5y Region #
studies Mortality 0-5 mo (UR)
Mortality 6-11 mo (UR)
Mortality 12-59 mo (UR)
Mortality 0-59 mo (UR)
High income 6 400 (1-228200) 900 (200-4600) 700 (100-5600) 3300 (700-231100)
Upper middle income
12 7200(4200-12300) 8000 (2800-22100)
1500 (200-11700) 17900 (10300-34500)
Lower middle income
16 20000(13500-29500)
10300 (4800-21600)
12300 (6500-23100))
43600 (31400-60400)
Low income 9 1300 (200-7900) 3400 (400-26600) 1400 (100-16100) 8200 (2200-36900)
Developing (A) 41 27100 (20700-35500)
16500 (10400-25800)
15300 (9500-25000)
59600 (47800-74300)
Industrialised (B)
2 <50 (0-2000) <50 (0-300) 100 (0-300) 200 (100-2200)
Global (A+B) 59600 (48000-74500)
18 Shi et al., Lancet 2017
Overall RSV-ALRI mortality in infants: background • ~80% of ALRI deaths in <5 yr children occur outside hospital (Nair et al.,
Lancet 2013)
• Overall mortality can be estimated using modelling - requires data on pneumonia mortality in <5 yr children and RSV transmission
• Data from vital registration incomplete
• Therefore, need to use other data from other sources- verbal autopsy, mortality surveys, medical certification of deaths
• Data for minimum three complete years
• Sufficient number (≥100) of pneumonia deaths
• RSV transmission- clear seasonality, adjust for shared seasonality with influenza
19 Shi et al., Lancet 2017
Approach to RSV-ALRI mortality estimates
20
Overall RSV-ALRI mortality in <5y children : methods
• Overall RSV-ALRI mortality for <5y children using an excess mortality model (data from 3 sites – Bangladesh, Indonesia and Argentina)
• Attributing all excess ALRI mortality during RSV season to RSV overestimates RSV mortality
• Exclusion of secondary bacterial infection post RSV-ALRI underestimates RSV mortality
• Inflation factor ranged from 1.5 (Argentina) to 2.9 (Indonesia) – applied mean inflation factor (2.2)
• Adjusted for shared seasonality with influenza (90% of excess mortality during RSV season attributable to RSV)
21 Shi et al., Lancet 2017
Overall RSV-ALRI mortality in <5y children: modelled estimates
• Overall RSV mortality in <5 children in 2015 – 118 (95-149)k
• >99% mortality in developing countries
• 73% of in-hospital RSV-ALRI mortality in infants; 46% in infants <6 months
• No national ALRI mortality estimates for infants; so not possible to directly model overall RSV-ALRI mortality estimates for this age group
• However, if proportional RSV-ALRI mortality (by age group) outwith hospital were same as in-hospital, then overall RSV mortality in infants could be as high as 86k (69k to 109k)
22
How can we improve global mortality estimates?
Community mortality data Site-specific mortality multiplier – need site-specific overall and in-hospital RSV mortality PREREQUISITE
• Community mortality surveillance with hospital arm
POSSIBLE DATA SOURCES • Gates funded RSV mortality studies- Argentina, India, Pakistan and Zambia • CHAMPS
ADVANTAGES • Hospital and community mortality are from same site and are from true deaths
– reliable multiplier • Data on 30-day post RSV mortality for post-RSV secondary bacterial infection
(CHAMPS)
23
24
Summary
• RSV associated with about 25% of ALRI episodes in children <5 years • 37% of RSV-severe ALRI and 42% of RSV hospitalisations in infants 0-5
months • Overall RSV-ALRI mortality in children <5 years - 118 (95-149)k (13%
of global ALRI mortality) 50% (~60 k) occurs in hospital
43k (73%) RSV-ALRI in-hospital deaths in infants; 63% in infants <6 months
• Relatively robust in-hospital RSV mortality estimates • Overall RSV mortality estimates limited by number of data points and
lack of national level pneumonia mortality estimates in infants
25
Acknowledgements • RSV Global Epidemiology Network
S Madhi, K O’Brien, E Simoes, B Gessner, F Polack, J Nokes, A Brooks,
D Feikin, M Venter, J Moyes, E Azziz-Baumgartner, A Gordon, G Bacalla,
J Montgomery, S Broor, M Chadha, S Hirve, A Krishnan, R Singleton,
S Thamtithiwat, M Oliveira, M Echhavaria, R Fasce, Y Hongjie, M Lucero,
C Kartasasmita, C Lupisan, S Howie, H Oshitani, L Yoshida, C Turner,
K Strum-Ramirez, J McCracken, A Ali, H Zar, Z Rasmussen, L Bont,
W Clara, J Jara, P Byass, A Scott, D Thea, C Romero, P Buchy, A Gentile, Q Bassat, A Ali
• Bill and Melinda Gates Foundation
• Innovative Medicines Initiative
27