1
RSV: The disease, the Pathogen and the unmet Medical Need
Eric A.F. Simões, MB,BS, DCH, MD
Professor of Pediatrics and Epidemiology, University of Colorado, Denver
Co-Director Maternal and Child Health Initiative Center for Global Health
Colorado School of Public Health
The Disease
2
3
RSV disease in children aged <2 years
Glezen WP, et al. Am J Dis Child. 1986;140:543-546. 2. Hall CB. N Engl J Med. 2001;344:1917-1928.
.
% o
f c
hild
ren
(n=34) (n=125)
97.1%
68.0%
21.6%
5.9%
0
20
40
60
80
100
120
0-12 mo 13-24 mo
Primary RSV infections
LRTI
RSV typically enters via the nose and replicates in the upper airways before migrating to lower respiratory tract.2 Most infants recover in 1 to 2 weeks.
Percentages of RSV infection and LRTI
4
Age and risk of severe RSV LRTI
Bont L, et al. Pediatr Infect Dis J 2001; 20: 277-82.
Rietveld E, et al. Pediatr Infect Dis J 2004; 23: 523-9.
0
5
10
15
20
25
0 1 2 3 4 5 6 7 8 9 10 11
Age (months)
Pa
tien
ts (
%)
3
Epidemiology
RSV Infection rates/1000 Children/ Year
0-5 Months 6-11 Months 12-23 Months 24-59
months
Hospitalization 11.7 - 21.7 3.4 - 7.4 1.9 - 3.2 0.2 - 0.4
ER Visits 39 - 69 45 - 68 24 - 38 11 - 15
Practice Visits 108 - 157 160 - 194 53 - 80 31 - 77
Hall CB et al NEJM. 2009;360:588-598
0-5 Months 6-11 Months 12-23 Months 24-59
months
Hospitalization 38.6 13.4 5.0 0.8
Stockman LJ et al PIDJ. 2012;31:5-9
4
RSV Infection rates/1000 Children/ Year
1-11
Months
12-48 Months 1-48 Months 24-59
months
Hospitalization 16.2 - 18.7 3.4 - 7.4 0.23 – 0.26
OP Visits 18 - 28
Hall CB et al NEJM. 2009;360:588-598
0-5 Months 6-11 Months 12-23 Months 24-59
months
Hospitalization 11.7 - 21.7 3.4 - 7.4 1.9 - 3.2 0.2 - 0.4
ER Visits 39 - 69 45 - 68 24 - 38 11 - 15
Practice Visits 108 - 157 160 - 194 53 - 80 31 - 77
Egypt :2009-2012
Rowlison E et al JID. 2013;208 (S3):189-196
RSV Infection rates/1000 Children/ Year
0-5 Months 6-23 Months 24-59 Months
Hospitalization 20.8 5.1 0.5
OP Visits 6.5 18.6 8.9
Hall CB et al NEJM. 2009;360:588-598
0-5 Months 6-11 Months 12-23 Months 24-59
months
Hospitalization 11.7 - 21.7 3.4 - 7.4 1.9 - 3.2 0.2 - 0.4
ER Visits 39 - 69 45 - 68 24 - 38 11 - 15
Practice Visits 108 - 157 160 - 194 53 - 80 31 - 77
Guatemala :2008-2012
McCraken J et al JID. 2013;208 (S3):197-206
5
RSV Infection rates/1000 Children/ Year
0-11 Months
12-58 Months
0-59 Months
SARI 85 -111 17 - 38 27 – 54
ILI 37 - 62 17 -61 21 - 61
Hall CB et al NEJM. 2009;360:588-598
0-5 Months 6-11 Months 12-23 Months 24-59
months
Hospitalization 11.7 - 21.7 3.4 - 7.4 1.9 - 3.2 0.2 - 0.4
ER Visits 39 - 69 45 - 68 24 - 38 11 - 15
Practice Visits 108 - 157 160 - 194 53 - 80 31 - 77
Kenya 2007-2011
Bigogo GM et al JID. 2013;208 (S3):207-216
RSV Infection rates/1000 Children/ Year
0-11 Months
12-23 Months
24-59 Months
Hospitalization: HIV+ 73 -157 17 - 44 11 – 34
Hospitalization: HIV - 29 - 34 8 -12 3 - 5
RR (95% CI) 5.4(4.4-6.8) 3.5(2.4-5.0) 5.8(4.8-6.4)
Hall CB et al NEJM. 2009;360:588-598
0-5 Months 6-11 Months 12-23 Months 24-59
months
Hospitalization 11.7 - 21.7 3.4 - 7.4 1.9 - 3.2 0.2 - 0.4
ER Visits 39 - 69 45 - 68 24 - 38 11 - 15
Practice Visits 108 - 157 160 - 194 53 - 80 31 - 77
South Africa 2010-2011
Moyes J et al JID. 2013;208 (S3):217-226
6
RSV Infection rates/1000 Children/ Year
0-2
Months
3-5
Months
0-5
Months
6-11
Months
12-23
Months
24-59
month
s
Hospitaliz
ation
10.6 -18.5
7.8 -13.8
9.6 – 14.3 16.3-21.8 13.5– 16.9 5.7-7.0
Hall CB et al NEJM. 2009;360:588-598
0-5 Months 6-11 Months 12-23 Months 24-59
months
Hospitalization 11.7 - 21.7 3.4 - 7.4 1.9 - 3.2 0.2 - 0.4
ER Visits 39 - 69 45 - 68 24 - 38 11 - 15
Practice Visits 108 - 157 160 - 194 53 - 80 31 - 77
Thailand 2008-2011
Naorat S et al JID. 2013;208 (S3):238-245
RSV SEASONALITY
7
13
RSV Seasonality in NL Positive Results from Registratie virologische laboratoria (1996-98)
0
300
600
900
1200
41-4
4
49-5
25-
8
13-1
6
21-2
4
29-3
2
37-4
0
45-4
81-
49-
12
17-2
0
25-2
8
33-3
6
41-4
4
49-5
25-
8
13-1
6
21-2
4
29-3
2
37-4
0
45-4
81-
4
RS
V C
ases R
ep
ort
ed
RSV Seasonality in UK Cases Reported by UK Centre for Disease Control (1996-98)
0
1000
2000
3000
4000
5000
RS
V C
as
es
Re
po
rte
d
RSV Seasonality in BelgiumCases Reported by Institut Pasteur, Bruxelles (1996-99)
0
300
600
900
1200
1-4
9-12
17-2
0
25-2
8
33-3
6
41-4
4
49-5
25-
8
13-1
6
21-2
4
29-3
2
37-4
0
45-4
81-
49-
12
17-2
0
25-2
8
33-3
6
41-4
4
49-5
25-
8
Ca
se
s R
ep
ort
ed
0
200
400
600
800
1000
RS
V C
ases
Rep
ort
ed
RSV Seasonality in Norway National Institute of Public Health - Dept. of Virology 1996-98)
1996 1997 1998
RSV Seasonality Europe
Seasonality: Temperate Regions
RSV is present in the winter months
Stensballe L, Devasundaram J, Simões EA. PIDJ 2002
8
15
0
20
40
60
80
100
120
Jan Feb Mar Apr May Jun July Aug Sep Oct Nov Dec0
10
20
30
40
50
60
Kuwait, 30°N
cases/temperature rainfall (mm)
Hijazi et al. Pediatr Infect Dis J 1995;14: 322-4
16
Banjul, Gambia 22 0 N
0
20
40
60
80
O D F A J A O D F A J A O D F A J A O D
93 94 95 96
The rainy
season is
indicated
by solid
bars
Weber MW et al. Pediatr infect Dis J 1998:17;224-30
9
17
India, Vellore, 12°N
cases/temperature rainfall (mm)
0
10
20
30
40
Jan FebMarAprMayJun JulyAug SepOct Nov Dec0
50
100
150
200
Cherian, Simões EA et al AJDC 1990;44:1026-30
Seasonality: Northern Tropical
The seasonality appears to be related to a decrease in
temperature associated with an increase in rainfall (the wet-
cool season)
Stensballe L, Devasundaram J, Simões EA. PIDJ 2002
10
19
0
5
10
15
20
25
30
35
Jan FebMarAprMayJun JulyAug SepOct Nov Dec0
50
100
150
200
250
300
350
Singapore, 4°N
cases/temperature rainfall (mm)
Doraisingham et al Ann Acad Med Singapore 1986;15:14-19
20
Colombia, Cali, 4°N
cases/temperature rainfall (mm)
0
7
14
21
28
35
Jan FebMarAprMayJun JulyAug SepOct Nov Dec0
35
70
105
140
175
Borrero I, et al. Rev Infect Dis. 1990;105:S950-956
11
Seasonality: Equatorial
RSV appears to be present year round with some
increase during the dry months
Stensballe L, Devasundaram J, Simões EA. PIDJ 2002
22
0
10
20
30
40
50
60
70
80
JanFebMarAprMayJun JulyAugSepOct NovDec0
50
100
150
200
Argentina, Buenos Aires, 35°S
cases/temperature rainfall (mm)
Weisenbacher M et al Rev Infect Dis 1990;12:S889-98
12
23
0
10
20
30
40
50
Jan FebMarAprMayJun JulyAug SepOct Nov Dec
month
0
30
60
90
120
150
South Africa, Johannesburg 26°S
cases/temperature rainfall (mm)
Seasonality: Southern Tropical
The seasonality appears to be related to a
decrease in temperature associated with a
decrease in rainfall (the dry-cool season)
Stensballe L, Devasundaram J, Simões EA. PIDJ 2002
13
25
0
.05
.1.1
5.2
.25
De
nsity
0 5 10 15titre
RSV neutralising antibodies in cord blood
26
RSV-MNabs in Cord Blood and RSV Isolations
0
100
200
300
No.
RSV-pos
itive t
est
s in
Denm
ark
per
week
6
7
8
9
Mean
RSV-ne
utra
lizing
ant
ibod
y t
iter
01 Jul 1998
01 Jul 1999
01 Jul 2000
01 Jul 2001
01 Jul 2002
Date of birth
Mean RSV antibody titer RSV seasonality
RSV-MNabs = Maternally-derived RSV neutralising antibodies
Stensballe L, et al . J Pediatrics 2009;154:296-8
14
27
Titre of RSV-Mabs in Cord Blood and Incidence Rate Ratio of RSV Hospitalization Among Children Below 1.5 Years of Age
RSV-Mabs
titre
Age
0-5 months 6-11 months 12-18 months
N IRR (95% CI) N IRR (95% CI) N IRR (95% CI)
0-6 48 reference 10 reference 8 reference
6.5 25 0.40 (0.18-0.92) 2 0.27 (0.05-1.55) 7 0.94 (0.23-3.89)
7.0-7.5 57 0.57 (0.29-1.10) 25 1.45 (0.52-4.06) 8 0.58 (0.16-2.03)
8-8.5 35 0.41 (0.20-0.85) 31 1.91 (0.73-5.02) 10 0.69 (0.22-2.21)
9 + 32 0.27 (0.13-0.57) 22 0.69 (0.25-1.92) 12 0.79 (0.25-2.51)
All 19
7 0.74 (0.62-0.87) 90 0.98 (0.82-1.16) 45 1.00 (0.78-1.29)
Healthy RSV
Stensballe LG, et al. J Allergy Clin Immunol. 2009;123:398-403.
28
Conclusions: RSV Antibodies protect against RSV Hospitalization
• The seasonality of RSV in infants may depend on the decline and increase in levels of RSV-MNabs
• When the titer doubled, the risk of RSV hospitalization decreased by 26% (13–38%) in infants <6 months
• RSV-MNabs protect against RSV hospitalization in the first 6 months of life
15
29
Protecting the Family to Protect the Child
Munyoki et al. JID 2014;209:1685-1692; Graham B JID 2014;209:1679-1681 .
30
Background
1. Children who have RSV LRTI at <3 years of age have recurrent wheezing rates 25-80% greater than controls 11-13 years later.
Stein RT, et al. Lancet. 1999;354:5415;
Sigurs et al. Am J Resp Crit Care Med. 2005; 171:137;
Henderson et al Pediatr Allergy Immunol 2005;16:386
2. Preterm infants, even those without chronic lung disease (CLD), have higher risk of severe RSV disease.
Groothuis et al Pediatrics 1988;82:199;
Navas L, et al. J Pediatr 1992;121:348\
Brooks et al. Arch Ped Adolesc Med 2001;155:401
16
31
Hypothesis
That palivizumab prophylaxis in preterm infants
would decrease the rate of recurrent wheezing in
early childhood
Simões EA, Groothuis JR, Carbonell XC et al J Pediatrics2007;151:34-42
32
Point Estimates of Relative Risk of Respiratory Outcomes (Multivariate analysis)
Palivizumab
treated
Palivizumab
untreated P RR (95% CI)
Subjects with any event
Recurrent wheezing
Combined untreated groups
Non-hospitalized untreated group
Physician-diagnosed recurrent
wheezing
Combined untreated groups
Non-hospitalized untreated group
25/191 (13%)
25/191 (13%)
15/191 (8%)
15/191 (8%)
59/230 (26%)
35/154 (23%)
37/230 (16%)
24/154 (16%)
0.001
0.022
0.011
0.027
0.51 (0.33, 0.78)
0.58 (0.36, 0.92)
0.49 (0.28, 0.86)
0.50 (0.27, 0.93)
0.1 1 10
Simões EA, Groothuis JR, Carbonell XC et al J Pediatrics2007;151:34-42
17
33
Summary of Primary Results
• At the 24-month follow-up in palivizumab-treated children
compared with untreated children:
– Recurrent wheezing:
• There was a 51% reduction in the number of subjects (13% versus 26%) and
– Physician-documented recurrent wheezing
• There was a 49% reduction in the number of subjects (8% versus 16%) and
• Similar effects were seen in time to event analyses for both
outcomes
Simões EA, Groothuis JR, Carbonell XC et al J Pediatrics2007;151:34-42
RSV disease: Unmet medical need
18
Adapted from Rudan, et al Bull World Health Org 2008; 86: 408–16
Incidence of pneumonia is highest in South Asia and Sub-Saharan Africa
East Asia and Pacific
South Asia
Middle East and North Africa
Africa
Latin America and Caribbean CEE/CIS
156 million cases of pneumonia occur in children <5 years of age
globally annually
19
RSV incidence studies: by GBD region
RSV incidence
RSV-
ALRI 0-<5
incidence/
1000/
year
(95% CI)
No. of new
cases of
RSV-ALRI
0-<5
annually (millions)
RSV-severe
ALRI 0-<5
incidence/
1000/ year (95% CI)
No. of new
cases of RSV-
severe ALRI 0-
<5 annually (millions)
Developing 59
(40,88)
32.5 6 (4,7) 3.1
Industrialized 24
(19,30)
1.3 6 (4,7) 0.3
Global 49
(31,75)
33.8
(22% of all
ALRI)
6 (4,7) 3.4
(22% of all
severe-ALRI)
20
RSV Mortality: approaches to estimation
– Boundaries estimated using 3 approaches
Approach 1: using RSV-ALRI CFR reports and severe RSV-ALRI
incidence measures. Lower boundary
Approach 2: estimated proportion of severe RSV cases with
hypoxemia and assumed 14% CFR based on published data from
developing countries
Approach 3: assumed excess mortality due to ALRI in <5 year
children during RSV season is due to RSV. Upper boundary. Data
available only for Indonesia
RSV Mortality estimation
– 25 papers: CFR data on RSV-ALRI in hospitalised children
Also from 6 unpublished studies
21
RSV Case Fatality Rate
Region
No. of studies
included RSV-LRI Case fatality rate%
<1 year <5 years <1 year <5 years
Industrialized
countries 5 7 0.7 (0.3;4.8) 0.3 (0.2;0.4)
Developing
countries 3 12 2.1 (1.6;2.2) 2.1 (1.3;3.4)
RSV Mortality
– Using these methods RSV-ALRI mortality in 0-<5 years
appears to be between 66,000 and 199,000
– 99% mortality occurs in developing countries
– Indonesia data reveal considerable annual variation in
magnitude of annual RSV epidemic activity and associated
RSV-ALRI deaths
22
Acute lower respiratory infections: Cases
• RSV is the most common cause of LRI1
1O’Brien, et al. Lancet 2009; 374: 893–902; 2Watt et al. Lancet 2009; 374: 903–11; 3Nair, et al. Lancet 2010; 375: 1545–55; 4 Nair, et al Lancet 2011;378:1917
Acute lower respiratory infections: Deaths
• Mortality is higher from S. pneumoniae and Haemophilus influenzae type b (Hib) infections
1O’Brien, et al. Lancet 2009; 374: 893–902; 2Watt et al. Lancet 2009; 374: 903–11; 3Nair, et al. Lancet 2010; 375: 1545–55; 4 Nair, et al Lancet 2011;378:1917
23
Effectiveness of an 11-valent pneumococcal conjugate vaccine (11PCV) in preventing radiographically confirmed pneumonia in children < 2 years of age: a randomized, double-blind, placebo-controlled trial in Philippines Lucero et al. Pediatr Infect Dis J 2009;28: 455–462
Vaccine effectiveness (VE) against first episode of radiographically-confirmed pneumonia (PP)
Endpoint
Event-based 11PCV Placebo
VE
(95% CI) p
Cases
prevented
/100,000
N Rate** N Rate**
Children <12m 47 1,264 71 1,917
34.0
(4.8;54.3) 0.03
653
Children 12-
23m 50 957 51 982 2.7
(-43.5;34.0) 0.89
25
* Per protocol analysis; **per 100,000 child-years
24
Organism Hospitalization
Rate/ 100,000
PY
5wk-5mo
Hospitalization
Rate/ 100,000
PY
6mo-11 mo
Hospitalization
Rate/ 100,000
PY
12-23mo
RSV 4839 3257 1645
PIV 3 1142 467 186
Influenza virus 521 489 542
hMPV 635 734 277
Adenovirus 357 549 314
Coronavirus 562 266 171
11 PCV Vaccine
Preventable Radiographic
Pneumonia
-234 612
-54
No Virus Identified 723 894 893
Adjusted rates of Hospitalization
Philippines 2000-2004 6wks-24 mo.
Entity LRTI Rate
per 100,000
PY
Placebo
Group
LRTI Rate per
100,000 PY
VAR
RSV: Bohol 5227 -
Influenza: Bohol 985 -
Clinical LRTI: SA- VAR 3565 336
Clinical LRTI: Bohol- VAR 10,454 6
Clinical LRTI: Gambia- VAR (PCV) 24,800 1770
Clinical LRTI: Gambia- VAR (HiB) 3,640 130
Radiographic Pneumonia: SA- VAR (PCV) 927 155
Radiographic Pneumonia: Bohol – VAR
(PCV)
1349 309
Radiographic Pneumonia: Gambia- VAR
(PCV)
5100 2200
Comparison of various rates of LRTI
25
Conclusions: RSV-The Disease
• RSV causes severe disease in infants under 3
months of age
• Seasonality varies even within countries
• Maternal immunization and sibling immunization
might be strategies to protect the very young
infants
• RSV may be associated with long term outcomes
till at least 13 years of age.
Conclusions: RSV- Unmet Medical Need
• Globally: RSV is the most important single
pathogen causing respiratory hospitalizations
• RSV causes about 33 million cases of LRTI
• RSV causes between 66,000 – 234,000 deaths
• Population based studies allow for the
comparison of the burden of disease in that
population