the disease - who.int · rsv seasonality in uk rsv seasonality in norway cases reported by uk...

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


months

Hospitalization 38.6 13.4 5.0 0.8

Stockman LJ et al PIDJ. 2012;31:5-9

4


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


months


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


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


months


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


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


months


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


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


months


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


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


months


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


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)


10

19

0

5

10

15

20

25

30

35


50

100

150

200

250

300

350

Singapore, 4°N


Doraisingham et al Ann Acad Med Singapore 1986;15:14-19

20

Colombia, Cali, 4°N


0

7

14

21

28

35


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


22

0

10

20

30

40

50

60

70

80

JanFebMarAprMayJun JulyAugSepOct NovDec0

50

100

150

200

Argentina, Buenos Aires, 35°S


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


Seasonality: Southern Tropical

The seasonality appears to be related to a

decrease in temperature associated with a

decrease in rainfall (the dry-cool season)


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


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


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

the disease - who.int · rsv seasonality in uk rsv seasonality in norway cases reported by uk...

Documents