Dagan/Rota/2012 Early Effectiveness of the National ... Dagan.pdfSlides prepared by Ron Dagan MD Dagan/Rota2012 Methods •A prospective study since April 1st 2006, still on-going

Dagan/Rota/2012

Ron Dagan, Noga Givon Lavi The Pediatric Infectious Disease Unit

Soroka University Medical Center

Ben-Gurion University

Beer-Sheva, Israel

Early Effectiveness of the National

Immunization Plan with RV5 on

Pediatric Emergency Room Visits

and Hospitalizations in Southern

Israel

Dagan/Rota/2012

This study was sponsored by MSD

My trip to this meeting was partially sponsored by MSD

Dagan/Rota2012 Slides prepared by Ron Dagan MD

Burden of Rotavirus Gastroenteritis on Pediatric ER Visits and Hospitalization in

Southern Israel - a Population-Based Study

(IsraRota Study)

Beer-Sheva

• ~15,000 annual births

• ~50% Jewish children and ~50%

Bedouin children


Methods

• A prospective study since April 1st 2006, still on-going

• All PER visits and hospitalizations of children <5 yrs caused by LRI, URI and GE are recorded daily

• All children <5 yrs with vomiting/diarrhea* are offered participation upon presentation daily (a study person is present at the PER 364/365 d/year 08:00 AM – 09:00 PM)

• Stool/diaper specimens are tested for rotavirus by ELISA**

• RVGE is defined by positive ELISA

• All rotavirus (+) stools are being tested by RT-PCR to determine serotype***

• Complex extrapolation for the missing specimens (next slide)….

* ≥watery or looser-than normal stool within a 24h period and/or forceful vomiting

** IDEIATM rotavirus ELISA kit, DakoCytomation

*** Institute for Medical Research, Katholieke Universiteit of Leuven, Leuven, Belgium


Month 2006 2007 2008

Mo

nth

ly n

um

ber

of

ch

ild

ren

Monthly Figures for the 1

st 2 Yrs of the Study:

All PER Visits (including Hospitalizations) <5 Yrs

105

208

268 263

193 192

233

359

350

164

131 104 113

196

180

142

200

241 232

379

318

174

139 154

6 5 9 11

4 12

37

132

152

34 8

3 0 0 0 4 10

13

44

126 115

46

18 17

0

50

100

150

200

250

300

350

400

4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3

Suitable Enrolled All Samples Rota Pos


Monthly Figures for the 1st

2 Years of the Study:

All Pediatric ER Visits + Hospitalizations), Children <5 Yrs

Extrapolation was done by each ethnic group, and separately for hospitalization and for PER

outpatient visits

Month

0

50

100

150

200

250

300

350

400


Cumulative Age-specific Incidence of Hospital Use (PER and

Hospitalization) for RVGE in Southern Israel

Before Implementation of Any Rotavirus Vaccine

16.2

34.9 36.3

26.4

38.7 39.5

0

5

10

15

20

25

30

35

40

45

<12 m 12-23m 24-59m

Jewish Children Bedouin children

Cu

mu

lati

ve

In

cid

en

ce

of

RV

GE

pe

r 1

,00

0 p

op

ula

tio

n

6.3

12.5 13.4

16.2

23.1 23.7

0

5

10

15

20

25

30

<12 m 12-23m 24-59m

9.9

22.1 22.6

10.3

15.7 15.8

0

5

10

15

20

25

30

<12 m 12-23m 24-59m

Overall incidence – hospital use

In hospital

ER - outpatients

P<0.001 in all points P<0.001

P<0.001 in all points


The Risk to Visit Pediatric ER or to be Hospitalized because of

Rotavirus GE for Jewish and Bedouin Children*

* Using the conservative extrapolation

Event Before Age 2 yrs

Jewish chi ldren Bedouin children

Pediatric Emergency

Room visits (outpatient and in-patients events)

1:29 1:26

Hospitalization 1:78 1:43


RVGE as Proportions of All Yearly Outpatient Pediatric ER Visits

and Hospitalizations Children <2 Years,

Southern Israel*

•Using the conservative extrapolation

Annual

contribution of

RVGE

Outpatients Inpatients

Jewish

children

Bedouin

children

Jewish

children

Bedouin

children

Rota (+)/all patients 337/12,553 220/8320 197/4240 324/5956

% of all patients 2.7% 2.6% 4.6% 5.4%

The denominator is all Pediatric Emergency Room outpatient visits

and all hospitalizations for each ethnic group


Effect of Vaccination on Epidemiology

• Pre-NIP – Both RV1 and RV5 were licensed in Israel in 2007

– Both vaccines were subsidized since mid 2008 by the various HMOs in

Israel • Cost ~US$ 100 for the course

• Reimbursement ~50% for complimentary health insurance

• Different use by different socio-economic classes

• NIP – In January 2011, RV5 was introduced to the National Immunization Plan to

all children born since Nov 2010

• Vaccine uptake….(next slide)


Rota Vaccine Status

All Children Age 8-11 Months

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100% ≥1 dose ≥2 doses 3 doses*

07-09

2009

10-12

2009

01-03

2010

04-06

2010

07-09

2010

10-12

2010

01-03

2011 04-06

2011

07-09

2011

10-12

2011

01-03

2012

04-06

2012

All

children 62 67 70 60 61 86 80 59 73 65 66 60

Initiation of NIP

1/1/11

* Since before NIP both RV1 and

RV5 were used, we considered for

the pre-NIP period 2 doses of RV1

as equivalent to 3 doses RV5 for

the purpose of dosing

measurement


Rota Vaccine Status

Jewish Children Age 8-11 Months

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%


07-09

2009

10-12

2009

01-03

2010

04-06

2010

07-09

2010

10-12

2010

01-03

2011 04-06

2011

07-09

2011

10-12

2011

01-03

2012

04-06

2012

Jewish

children 33 29 34 24 32 47 41 29 34 27 32 19

Initiation of NIP

1/1/11






measurement


Rota Vaccine Status

Bedouin Children Age 8-11 Months

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%


07-09

2009

10-12

2009

01-03

2010

04-06

2010

07-09

2010

10-12

2010

01-03

2011 04-06

2011

07-09

2011

10-12

2011

01-03

2012

04-06

2012

Bedouin

children 29 38 36 36 29 39 39 30 39 38 34 41

Initiation of NIP

1/1/11






measurement


0

50

100

150

200

250

Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar

2006-2007

2007-2008

2008-2009

2009-2010

2010-2011

2011-2012

2009-2010 extrapolated

2012-2013

Remark: Due to technical issues (“week 53” in 2011, the report of week 1 2012 is an additive of “week 53”, 2011 and week 1, 2012

Yearl

y c

um

ula

tive n

um

ber

of

cases

Week number

Yearly Cumulative Number of Rota-positive Samples,

<12 Months

0

10

20

30

40

50

60

70

80

90


2006-2007

2007-2008

2008-2009

2009-2010

2010-2011

2011-2012


2012-2013

Bedouin Children Jewish Children


0

20

40

60

80

100

120


2006-2007

2007-2008

2008-2009

2009-2010

2010-2011

2011-2012


2012-2013


Week number


12-23 Months

0

10

20

30

40

50

60

70

80

90


2006-2007

2007-2008

2008-2009

2009-2010

2010-2011

2011-2012


2012-2013


Yearl

y c

um

ula

tive n

um

ber

of

ca

se

s


0

2

4

6

8

10

12

14

16

18

20


2006-2007

2007-2008

2008-2009

2009-2010

2010-2011

2011-2012


2012-2013


Week number


24-59 Months

0

5

10

15

20

25

30

35


2006-2007

2007-2008

2008-2009

2009-2010

2010-2011

2011-2012


2012-2013


Yearl

y c

um

ula

tive n

um

ber

of

ca

se

s


RVGE Age-specific Incidence (PER + Hospitalization ) in

Southern Israel

Incid

en

ce o

f R

VG

E p

er

1,0

00 p

op

ula

tio

n

Apr 06 - Mar 08 Apr 08 - Mar 11 Apr 11 - Mar 12

16.2

26.4

10.3

27.3

3.0

8.1

0

5

10

15

20

25

30

35

Jewish children Bedouin children

1st

year of life

P<0.001

P<0.001

P<0.001

* *

* P<0.001

Jewish vs.

Bedouin children

P<0.001 -81%

-70%

18.7

12.3 13.3 14.8

5.7

9.9

0

5

10

15

20

25

30

35


2nd

year of life

P<0.001

P<0.001

P<0.001

** **

** P=0.110

Jewish vs.

Bedouin children

P<0.001 -70%

-27%

1.4 0.7 1.5 0.9 0.9 0.6 0

5

10

15

20

25

30

35


3rd

– 5th

years of life

P=0.019

P<0.066

-36%


RVGE as Proportions of All Yearly Outpatient Pediatric ER

Visits and Hospitalizations

Children <2 Years in Southern Israel*

Pro

po

rtio

n o

f all o

utp

ati

en

t E

R v

isit

s

Apr 06 - Mar 08 Apr 08 - Mar 11 Apr 11 - Mar 12

2.7 2.6

1.5 2.1

0.5

1.2

0

1

2

3

4

5

6

7

8


Outpatients

ER visits

* *

P<0.001

*P<0.001

Jewish vs.

Bedouin children

•Using the conservative extrapolation

P<0.001

P<0.001

P<0.001

P<0.001

P<0.001

4.6

5.4 5.0

7.3

2.4

3.5

0

1

2

3

4

5

6

7

8


Inpatients

P<0.001

** **

**P=0.023

Jewish vs.

Bedouin children

P<0.001

P<0.001

Pro

po

rtio

n o

f all h

osp

italizati

on

s

-81%

-54%

-48%

-45%

Dagan/Rota/2012

Case-control

study

Nov 1st 2011 through March 31st 2012


Determination of Cases and Controls

• Initial selection

– All patients <24m that visited the PER from November 1st 2011 through March 31st 2012

with ≥3 diarrhea stools in last 24h (but <7 days) – both hospitalized and non-hospitalized

– Stool samples obtained and tested for Rota

– Information on vaccination recorded (through active surveillance)

• Cases: were children with stool sample positive for Rota (EILSA)

• Controls: were children with negative Rota ELISA stool

• Selection of children for inclusion in the analysis by age-windows

was according to vaccination status in the controls (≥1 dose, ≥2

doses, 3 doses)*

* No interval between dose or after doses was required to be included


Selection of Age Windows for the Analysis

(according to distribution among controls)

Nu

mb

er

of

co

ntr

ols

Age (weeks)

≥1 doses

≥2 doses

3 doses


Effectiveness Analysis

• Odds ratios for RVGE in vaccinated vs. non-vaccinated children in

each vaccine status (≥1 dose, ≥2 doses, 3 doses) and their 95% CIs,

were calculated

• Effectiveness was defined as (1.0 –OR) x 100

• Analysis was conducted

– Separately

• Jewish vs. Bedouin children (adjusted for age and hospitalization)

• Hospitalized vs. non hospitalized children (adjusted for age and ethnic group)

– Jointly all children (adjusted for age, ethnic group and hospitalization)

– Jointly for scoring (adjusted for age and ethnic group)


Effectiveness of RV5 Against RVGE Visits

62.4 60.3 64.4

0

10

20

30

40

50

60

70

80

90

≥1 ≥2 3

*Adjusted for age, ethnic group and hospitalization

Number of doses

Eff

ecti

ven

ess (

95%

CI)

9-69

weeks old

18-69

weeks old

28-69

weeks old


Effectiveness of RV5 Against RVGE Visits

Children 9-69 Weeks Old*

75.3 78.8

54.3

0

10

20

30

40

50

60

70

80

90

100

≥1 ≥2 3

*Adjusted for age and hospitalization

57.4 57.4

68.7

0

10

20

30

40

50

60

70

80

90

100

≥1 ≥2 3

P=0.009

P=0.004

Two-sample test for binomial proportions (Normal-Theory test)

Number of doses

Eff

ecti

ven

ess (

95%

CI)


9-69

weeks old

18-69

weeks old

28-69

weeks old

9-69

weeks old

18-69

weeks old

28-69

weeks old


Effectiveness of ≥1 RV5 Dose Against RVGE Visits

Children 9-69 Weeks Old*

*Adjusted for age and ethnic group

40.8

86.1

0

10

20

30

40

50

60

70

80

90

100

9-16 (n=91) >16 (n=78)

23.1

80.1

0

10

20

30

40

50

60

70

80

90

100

11-15 (n=43) 16-20 (n=113)

Two-sample test for binomial proportions (Normal-Theory test)

P<0.001 P<0.001

Eff

ecti

ven

ess (

95%

CI)

Clarck score Vesikari score

There were too few cases scored <9 and <11 in the Clarck and Vesikari scores, respectively to be analyzed


Conclusions

• Pre-vaccine RVGE was common in both Jewish and Bedouin populations in

southern Israel, and was responsible for high rate of ER visits and hospitalization

in children <2 yrs

• The Bedouin population, with similarities to developing populations, had a higher

rate of hospitalization

• Partial introduction of RV vaccines to the Jewish but not to the Bedouin

population pre-NIP, created inequity in reduction of disease

• Introduction of RV5 to the NIP in January 2011 resulted within 1 year in a 81% and

70% reduction of hospital use because of RVGE during 1st year of life in the

Jewish and Bedouin populations, respectively; the respective figures during 2nd

year of life were 70% and 27%

• The reduction in incidence was associated with the relative reduction of RVGE

burden compared to other diagnoses, despite the introduction of PCV7/13

vaccines in 2009

• The overall effectiveness after ≥2 doses was 60% (79% and 57% for Jewish and

Bedouin children, respectively)

• Effectiveness for severe disease was high (86% - Clarck score >16; 80% Vesikari

score >15)

Documents

Dagan/Rota/2012 Early Effectiveness of the National ... Dagan.pdfSlides prepared by Ron Dagan MD Dagan/Rota2012 Methods •A prospective study since April 1st 2006, still on-going