RSV disease – global [email protected] RSV disease – global burden WSPID, Shenzen, 5...

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

mailto:[email protected]

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

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Outline • Background • Global acute RSV Burden by age and region

• Incidence • Hospitalisation • Mortality

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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

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Natural history of RSV infection in young children

Updated systematic review

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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76 unpublished studies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)


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

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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)


Methods to estimate country-level RSV-ALRI incidence

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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)


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


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


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)


RSV-ALRI in-hospital mortality in children <5y Region #

studies Mortality 0-5 mo (UR)

Mortality 6-11 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)


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


Approach to RSV-ALRI mortality estimates

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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)


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)

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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)

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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

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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

RSV disease – global [email protected] RSV disease – global burden WSPID, Shenzen, 5...

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