THE JOURNAL OF PEDIATRICS www.jpeds.

com ORIGINAL
ARTICLES
Cocontribution of Rotavirus and Pneumococcal Conjugate Vaccines to
the Reduction of Pediatric Hospital Visits in Young Children
Shalom Ben-Shimol, MD1,2, Noga Givon-Lavi, PhD1,2, David Greenberg, MD1,2, and Ron Dagan, MD1

Objective To assess rotavirus vaccine and pneumococcal conjugate vaccines (PCVs) cumulative impact on the
pediatric emergency department visits and hospitalization rates in children <2 years of age in southern Israel between
April 2006 and March 2014.
Study design This prospective, population-based observational study calculated the rates of rotavirus gastro-
enteritis (RVGE), non-RVGE, community-acquired alveolar pneumonia (CAAP), nonalveolar lower respiratory tract
infection, and all-cause hospital visits. PCV7, PCV13, and rotavirus vaccination programs were implemented in
Israel in July 2009, November 2010, and January 2011, respectively.
Results From 2006-2009 to 2013-2014, the rates of hospitilizations for RVGE, non-RVGE, CAAP, and nonalveolar
lower respiratory tract infection decreased by 78%, 21%, 46%, and 7%, respectively. In outpatients, the respective
decreases were 80%, 16%, 67%, and 14%. All-cause outpatient pediatric emergency department visits and hos-
pitalization rates were reduced by 12% and 11%, respectively. During the peak season (October through March),
RVGE, non-RVGE, CAAP, and nonalveolar lower respiratory tract infection hospitalization rates decreased signifi-
cantly by 86%, 44.6%, 23.3%, and 10.5%, respectively. In outpatients, the respective decreases were 81.7%, 73.5%,
13.8%, and 10.7%. The proportion of RVGE and CAAP (grouped) of all-cause hospitalizations and outpatient pe-
diatric ED visits decreased from 19.9% to 12.3% and from 6.9% to 1.8%, respectively.
Conclusions Rotavirus vaccine and PCV introduction cocontributed to a rapid, considerable reduction in
hospital burden in children <2 years of age. Because seasonalities of both diseases overlap, this reduction is par-
ticularly helpful in relieving burdens of disease and care during the most cumbersome morbidity season. (J Pediatr
2017;182:253-9).
neumonia and diarrhea are leading causes of morbidity and mortality among children worldwide.1 These infectious

P diseases result in numerous hospitalizations, outpatient visits, and antibiotic prescriptions and lead to productivity loss
for parents and caregivers.2-4 In developed countries, the burden on medical health services resulting from both pneu-
monia and diarrhea in young children peaks in late fall and winter months.5-7 Both pneumonia and diarrhea can be caused by
multiple pathogens, but Streptococcus pneumoniae and rotavirus, respectively, are the leading pathogens,1,4,6,8 and are, in large
part, vaccine preventable. Indeed, the widespread introduction of rotavirus vaccines (RVVs) and pneumococcal conjugate vac-
cines (PCVs) resulted in substantial reductions of diarrhea and respiratory diseases burden.5,6,8,9
The impact of RVVs and PCVs may not be limited to rotavirus gastroenteritis (RVGE) and the classical syndromes usually
reported as pneumonia. In the case of diarrhea, RVVs also may influence the rate of what is perceived as non-RVGE, because
RVVs typically prevent the most severe disease, and thus also may prevent further diarrheal episodes that occur as sequelae of
RVGE.5,10,11 Similarly, radiologically proven pneumonia episodes are shown to be caused frequently by pneumococci.12 However,
PCVs can prevent other lower respiratory tract infections (LRIs), because pneumococci also play a role in these infections.13
Moreover, 1 study suggested that diarrhea may increase the risk of subsequent pneumonia in young children,14 pointing to po-
tential synergistic benefits of RVVs and PCVs.
In Israel, PCVs and RVVs were introduced to the National Immunization Plan
(NIP) within a 1.5-year interval, enabling observation of their cocontribution to
reduction in burden of diseases. Indeed, a substantial reduction of both RVGE and From the 1The Faculty of Health Sciences, Ben-Gurion
University of the Negev, Beer-Sheva, Israel; and 2The
alveolar pneumonia was observed in young children in southern Israel after rapid Pediatric Infectious Disease Unit, Soroka University
uptake of PCV and RVV.5,6 Medical Center, Beer-Sheva, Israel
Supported by Merck Sharpe & Dohme and Pfizer, which
Our current aim was to assess cocontribution introduction of RVV and did not play any role in any of the stages of the
PCV on reduction of hospital burden caused by diarrhea and LRI in children manuscript preparation. R.D., D.G., and S.B.-S. received
speaker fees from Pfizer. R.D. received research support
<2 years of age in southern Israel. Specifically, we examined the following (0887X1-4603) and consulting fees from Pfizer and Merck
Sharpe & Dohme, and received speaker fees from
GlaxoSmithKline. D.G. received research support,
consultant, and speaker fees from Merck Sharpe &
Dohme, and received consulting and speaker fees from
Pfizer. N.G.-L. declares no conflicts of interest.
LRI Lower respiratory tract infection PCV13 13-valent pneumococcal conjugate Portions of the study were presented at the 55th Annual
Interscience Conference on Antimicrobial Agents and
NIP National Immunization Plan vaccine Chemotherapy, September 17-21, 2015, San Diego, CA.
PCV Pneumococcal conjugate vaccine RVGE Rotavirus gastroenteritis
PCV7 7-valent pneumococcal conjugate RVV Rotavirus vaccine 0022-3476/$ - see front matter. 2016 Elsevier Inc. All rights
vaccine SUMC Soroka University Medical Center reserved.
http://dx.doi.org10.1016/j.jpeds.2016.11.041

253
THE JOURNAL OF PEDIATRICS www.jpeds.com
community-acquired entities: RVGE, gastroenteritis not caused
by rotavirus (non-RVGE), alveolar pneumonia, and nonalveolar
LRI. We studied the associated reduction in burden on rates
of both outpatient pediatric emergency department visits and
hospitalizations.
Methods
This prospective, population-based observational study was con-
ducted over an 8-year period (April 2006 to March 2014). The
study was approved by the Institutional Ethics Committees of
the Soroka University Medical Center (SUMC). The SUMC is
the only hospital in the Negev district of southern Israel, pro-
viding primary and referral health services to the entire popu-
lation of the region (>640 000 inhabitants and approximately
30 000 children under 2 years of age in 2012).5,6,15 More than
95% of the children living in the region are served by the SUMC,
enabling incidence rate calculations. Similarly, even though pa-
tients from other regions are treated in our hospital, this is the
case in <5% of all pediatric ED and hospitalization cases.
Two distinct ethnic populations reside side by side in south-
ern Israel: The Bedouin Muslim population, similar to a de-
veloping population, and the Jewish population, whose lifestyle
is similar to that of a developed population.5,6 The socioeco-
nomic conditions and lifestyles of the 2 populations differ and
social contacts between them, especially between children, are
uncommon. However, both have access to the same medical
services (both clinic and hospitalization services). The pro-
portion of children of each ethnic group born at the SUMC
during the study period was similar; approximately 7500 Jewish
children and approximately 7200 Bedouin children.6,15 Hos-
pitalization rates for respiratory infections and gastroenteri-
tis were reported previously to be higher among the Bedouin
population.5,6
PCV and RVV Introduction to the Israeli NIP
and Uptake
The 7- and 13-valent PCVs (PCV7 and PCV13) and RVV were
introduced into the Israeli NIP in July 2009, November 2010,
and January 2011, respectively.
The PCV7 was licensed in Israel in mid 2007, and was used
sporadically until 2009. In July 2009, the PCV7 was intro-
duced to the NIP (administered at 2, 4, and 12 months of age)
with a catch-up campaign in children <2 years of age. In
November 2010, PCV13 gradually replaced PCV7, without a
further catch-up program.16 It was estimated that in 2007-
2008, the proportion of 12- to 23-month-old Jewish and
Bedouin children with 2 PCV doses was approximately 25%
and <5%, respectively.16
In June 2010, 2011, 2012, and 2013, the proportion of
7- to 11-month-old children who had received 2 doses of any
PCV was 81%, 90%, 89%, and 89%, respectively. The respec-
tive figures for PCV13 were 3%, 30%, 86%, and 89%.6 These
rates were similar in the Jewish and Bedouin populations.
Two RVVs (a monovalent vaccine, Rotarix, and a pentava-
lent vaccine, Rotateq) were licensed in Israel in 2007 but ini-
tially were used scarcely. From mid-2008 to December 2010,
254
Volume 182
they were distributed at reduced costs by the health mainte-
nance organizations, covering approximately 25% of the Jewish
children with 1 doses. In contrast, the Bedouin population
did not use any RVV during that period.5 In January 2011, the
pentavalent RVV was introduced into the Israeli NIP, and
offered free of charge to all infants born after September 1, 2010;
it was administered at 2, 4, and 6 months of age.5
RVV uptake was rapid and by the end of 2012, approxi-
mately 95% and approximately 85% of the Jewish children 7-11
months of age received 2 and full 3 doses, respectively. The
respective rates among Bedouin infants were approximately 90%
and approximately 65%.5
Alveolar Pneumonia. A child was diagnosed radiologically as
having alveolar pneumonia according to the World Health Or-
ganizations Standardization of Interpretation of Chest Ra-
diographs working group, as described previously.6 Briefly,
alveolar pneumonia was defined as a dense opacity that may
be a fluffy consolidation of a portion, whole of a lobe, or the
entire lung, often containing air bronchogram(s) and some-
times associated with pleural effusion. All chest radiographs
were collected daily and were evaluated separately by 2 pedi-
atric infectious disease specialists who read all the chest ra-
diographs independently. Further analysis was performed by
an independent pediatric radiologist who was unaware of the
clinical data and the pediatricians analysis. The presence of
radiologically diagnosed alveolar pneumonia was confirmed
by agreement between 1 of the study pediatric infectious
disease specialists and the study pediatric radiologist.
LRI (Other Than Alveolar Pneumonia). LRI was diagnosed
clinically by the treating physician. Diagnoses compatible with
LRI (eg, bronchiolitis, respiratory distress, hypoxemia, pneu-
monia) were made by International Classification of Diseases,
9th edition codes, and radiologically confirmed alveolar pneu-
monia was excluded from these cases. For pediatric ED visits
and hospitalized cases, a study member went over all medical
charts and determined (coded) the diagnosis. If the coding for
the pediatric ED patient did not include LRI, but the study co-
ordinator coded it as LRI, it was counted as LRI. For double
coding (both ER and hospitalized patient), cases were only
counted once, as hospitalized LRI.
RVGE. Episodes were defined as acute diarrhea lasting <7 days
before enrollment, with a positive stool enzyme immunoas-
say for rotavirus antigen, as previously described.5 Briefly, study
staff located at the pediatric ED identified all eligible chil-
dren daily, year round. All children <5 years with a history of
diarrhea/vomiting (3 watery or looser-than-normal stool
within a 24-hour period and/or forceful vomiting) were offered
participation in the study upon presentation to the pediatric
ED. A stool sample was collected from the diaper or directly
from the child within 48 hours of admission. All samples were
tested by enzyme immunoassay for rotavirus.5
Non-RVGE. Episode was defined as a diarrheal disease lasting
from <7 days before enrollment with a negative stool enzyme
Ben-Shimol et al
March 2017 ORIGINAL ARTICLES

immunoassay for rotavirus. For both RVGE and non-RVGE,

(0.15-0.26)

(0.78-0.91)

(0.26-0.41)

(0.80-0.93)

(0.71-0.78)

(0.92-0.96)

(0.86-0.89)
Table I. Annual rates per 1000 children <2 years of age and incidence rate ratios of RVGE, non-RVGE, alveolar pneumonia, and nonalveolar lower respiratory hos-
episodes were separated by >28 days from a previous diar-

(95% CI)
IRR
rheal episode. Extrapolation for children enrolled in the study,

0.20

0.84

0.33

0.86

0.74

0.94

0.88
but who failed to provide samples (both those with diarrheal
episodes who were not approached and cases with no paren-

pitalization and pediatric ED outpatient visits in southern Israel, comparing the periods between April 2013-March 2014 with April 2006-March 2009

2013-

1.7

24.2

2.4

27.9

56.1

230.2

286.3
2014
tal consent) was conducted separately for each ethnic group
and each age group, by calendar year and month, and sepa-

Outpatient pediatric ED visit (annual rates)

rately for children who were hospitalized and for outpatient

2012-

2.0

24.6

2.0

31.4

59.9

232.8

292.7
2013
pediatric ED visits, as described.5 We conducted these extrapo-
lations using the assumption that the missing samples had the

2011-

2.4

20.5

2.8

30.8

56.5

223.8

280.3
2012
same proportion of rota-negative and rota-positive samples as
the tested samples. For missed samples (refusals or episodes
outside the study hours), diagnoses compatible with GE

2010-

5.9

24.2

4.0

42.7

76.9

236.5

313.4
2011
(eg, diarrhea, gastroenteritis) were made by International
Classification of Diseases, 9th edition codes, similar to the coding

2009-
of LRI.

5.9

25.9

5.8

72.3

109.8

192.8

302.7
2010
Statistical Analyses. Only children residing in the Negev region

2008-

6.0

25.8

5.8

32.3

69.8

234.6

304.4
2009
were included in the study.
The incidence of all pediatric ED visits for RVGE, non-
RVGE, alveolar pneumonia, and nonalveolar LRI were calcu-

2007-

9.0

29.1

8.1

30.5

76.7

249.4

326.0
2008
lated for the period between April 2006 and March 2014. Rates
per 1000 population <2 years of age were calculated annually

2006-

10.6

31.3

7.9

34.6

84.4

265.0

349.4
2007
(April through March, each year) as the number of cases divided
by the total population at risk during each year of the study.
Because the H1N1 influenza outbreak occurred in the year

(0.17-0.28)

(0.72-0.87)

(0.47-0.61)

(0.87-0.99)

(0.73-0.80)

(0.99-1.07)

(0.86-0.92)
(95% CI)
between April 2009 and March 2010, incidence rate ratios and IRR

0.22

0.79

0.54

0.93

0.77

1.03

0.89
95% CI of RVGE, non-RVGE, alveolar pneumonia, and
nonalveolar LRI were calculated comparing rates in the 3 years
between April 2006 and March 2009 (pre-vaccines period) with
2013-

2.1

15.1

8.3

39.9

65.3

87.2

152.5
2014

the last study year, namely, April 2013 through March 2014
(when both vaccine uptakes were approximately 90%).
2012-

Additionally, proportions (percentage) and ORs, with 95%

3.0

16.4

9.4

33.5

62.3

103.2

165.5
2013

CIs were calculated for RVGE, non-RVGE, alveolar pneumo-

nia, and nonalveolar LRI out of all-cause pediatric ED visits
Inpatients (annual rates)
2011-

4.4

13.7

9.3

39.9

67.4

82.6

150.0
2012

in the peak respiratory and diarrhea season (October through

March). The mean annual duration of hospitalization was cal-
culated for RVGE, non-RVGE, and alveolar pneumonia, but
2010-

12.1

17.7

15.3

45.2

90.3

85.4

175.8
2011

not for nonalveolar LRI (missing data).

2009-

Results
9.5

18.5

16.3

43.2

87.5

71.1

158.7
2010

Throughout the study, 3092, 10 591, 4383, 19 525, and 116 321
2008-

10.2

19.2

16.3

39.7

85.4

75.5

160.9
2009

episodes in children <24 months of age of community-

acquired RVGE, non-RVGE, alveolar pneumonia, nonalveolar
LRI, and all-cause hospital visits were recorded, respectively.
ED, emergency department; IRR, incidence rate ratio.
2007-

9.2

18.6

14.3

40.9

82.9

86.7

169.6
2008

Of the overall 37 591 children with 1 of the diagnoses listed,

19 466 (51.8%) and 18 125 (48.2%) were in children who were
2006-

8.4

19.2

15.8

48.7

92.1

91.7

183.8
2007

hospitalized and children who visited the pediatric ED as out-

patients, respectively.
All-cause hospital visits

Bold values indicate P < .05.

Other entities (non-4)

Dynamics of RVGE, Non-RVGE, Alveolar

Alveolar pneumonia

Grouped 4 entities

Pneumonia, and Nonalveolar LRI Rates

Nonalveolar LRI

Throughout the study, RVGE, non-RVGE, alveolar pneumo-

Non-RVGE

nia, and nonalveolar LRI rates (per 1000 children <2 years of
RVGE

age) all were reduced significantly by 78%, 21%, 46%, and 7%,
respectively, in children who were hospitalized (Table I and
Cocontribution of Rotavirus and Pneumococcal Conjugate Vaccines to the Reduction of Pediatric Hospital Visits 255
in Young Children
THE JOURNAL OF PEDIATRICS www.jpeds.com Volume 182

Incidence per 1000 children <2 years of age (Non-RVGE GE and LRI)

Incidence per 1000 children <2 years of age (Non-RVGE GE and LRI)
Incidence per 1000 children <2 years of age (RVGEand pneumonia)

Incidence per 1000 children <2 years of age (RVGEand pneumonia)

PCV7 PCV7
PCV13 PCV13
RV5 RV5
80 18 80 18
16.3 16.3
15.8 72.3
15.3 16 16
70 70
14.3
14 14
60 60
12.1
12 12
50 50 10.6
10.2
9.5 9.3 9.4
48.7 9.2 10 9.0 10
8.4 45.2 8.3 40
40 43.2 7.9 8.1 42.7
40.9 39.9
39.7 8 32.3
8
39.9 34.6
30 33.5 30 6.0 5.9
5.8 5.8 5.9
6 31.3 30.5 30.8 31.4 6
27.9
4.4 29.1 24.2
25.8 25.9 24.6
20 20 24.2
3.0 15.1 4 4.0 20.5 4
19.2 18.6 19.2 2.8
18.5 17.7 2.4 2.4
16.4 2.0
10 13.7 10
2.1
2 2
1.7

0 0 0 0
Apr 06- Apr 07 - Apr 08 - Apr 09 - Apr 10 - Apr 11 - Apr 12 - Apr 13 - Apr 06- Apr 07 - Apr 08 - Apr 09 - Apr 10 - Apr 11 - Apr 12 - Apr 13 -
Mar 07 Mar 08 Mar 09 Mar 10 Mar 11 Mar 12 Mar 13 Mar 14 Mar 07 Mar 08 Mar 09 Mar 10 Mar 11 Mar 12 Mar 13 Mar 14

Inpatients Outpatient pediatric

(annual rates) emergency department visits
(annual rates)

Figure 1. Rates of hospitalization and outpatient visits for respiratory and gastrointestinal disease in children <2 years of age
in Southern Israel. GE, gastroenteritis; RV5, rotavirus 5.

Figure 1). This could be translated to overall reductions of 7.2, This could be translated into overall reductions of 19.0 and
4.0, 7.1, and 3.2 episodes per 1000 population <2 years of age 40.3 episodes per 1000 population <2 years of age for hospi-
in hospitalizations owing to RVGE, non-RVGE, alveolar pneu- talization and outpatient pediatric ED visits, respectively (a total
monia, and nonalveolar LRI, respectively. The respective de- of 59.3 hospital visits per 1000 population <2 years of age).
creased in outpatient pediatric ED visits were 80%, 16%, 67%, These overall reductions were derived mainly from 23% and
and 13%. This could be translated to overall reductions of 6.8, 26% reductions in the 4 clinical entities (RVGE, non-RVGE,
4.6, 4.9, and 4.5 episodes per 1000 population <2 years of age alveolar pneumonia, and nonalveolar LRI grouped) in hospi-
of outpatient pediatric ED visits owing to RVGE, non-RVGE, talization and outpatient pediatric ED visits, respectively
alveolar pneumonia, and nonalveolar LRI, respectively. (Table I and Figure 2) In contrast, hospitalizations rates owing
These decreases resulted in overall respective reductions in to other diseases (nonrespiratory, nondiarrhea) were not
hospital visits by 79%, 18%, 53%, and 10% (all P < .05). reduced. Additionally, although outpatient visit rates owing to
Although RVGE and alveolar pneumonia rates decreased other diseases were slightly but significantly reduced by 6%
constantly in each year after the introduction of RVV and PCVs, when the 2013-2014 was compared with the 3 prevaccination
the rates of non-RVGE and nonalveolar LRI showed fluctua- years, the rates and dynamics of this group exhibited consid-
tions. This was most apparent in 2009-2010 and 2010-2011, erable fluctuations throughout the study.
when nonalveolar LRI rates peaked during the H1N1 outbreak.
Mean Annual Hospitalization Duration (Days) of
Dynamics of Overall (All-Cause) Hospitalization RVGE, Non-RVGE, and Alveolar Pneumonia
and Outpatients Pediatric ED Visit Rates The hospitalization duration (days) for non-RVGE and alveo-
Overall, rates of hospitalization and outpatient pediatric ED lar pneumonia decreased significantly by 23.9% (from 4.6 to
visits were reduced significantly by 11% and 12%, respec- 3.5) and 36.4% (from 4.4 to 2.8), respectively, and nonsignifi-
tively, throughout the study (Table I and Figure 2; Figure 2 cantly by 10.8% (from 3.7 to 2.3) for RVGE, comparing the
available at www.jpeds.com). prevaccines period with the last study year (Table II).
256 Ben-Shimol et al
March 2017 ORIGINAL ARTICLES

Table II. Mean hospitalization duration for RVGE, non-RVGE, and alveolar pneumonia in children <2 years of age in
southern Israel, April-March, 2006-2014
Change %
(2013-14
2006-2007 2007-2008 2008-2009 2006-2009 2009-2010 2010-2011 2011-2012 2012-2013 2013-2014 vs 2006-09) P
RVGE 3.6 1.7 3.7 2.6 3.8 2.1 3.7 2.2 3.2 1.3 3.4 1.5 3.3 1.8 3.3 1.3 3.3 1.9 10.8% .203
Non-RVGE 4.5 3.4 4.7 5.6 4.8 5.5 4.6 3.5 4.5 6.4 4.1 4.2 2.8 4.5 3.8 4.6 3.5 2.4 23.9% <.001
Alveolar 5.0 12.1 3.9 7.1 4.3 6.9 4.4 9.0 4.0 7.5 4.3 5.4 3.8 6.8 3.2 4.9 2.8 4.2 36.4% <.001
pneumonia

Bold values indicate P < .05.

Dynamics of RVGE, Non-RVGE, Alveolar
Pneumonia, Nonalveolar LRI, and Other Diagnoses
during the Peak Season (October Through March)
Hospitalization rates during the peak seasons (October through
March) in children <2 years of age with RVGE, non-RVGE,
alveolar pneumonia, and nonalveolar LRI decreased signifi-
cantly by 86%, 23.3%, 44.6%, and 10.5%, respectively, when
comparing the prevaccines period with the season in between
October 2013 through March 2014 (Table III and Figure 3;
Table III available at www.jpeds.com) The respective reduc-
tions for outpatients pediatric ED visits were 81.7%, 10.7%,
73.5%, and 13.8%.
The rates of all other diagnoses increased significantly by
7.2% in children who were hospitalized, and decreased sig-
nificantly by 13.6% for outpatients pediatric ED visits, when
2013-2014 was compared with 2006-2009. However, consid-
erable fluctuations in these rates were observed throughout the
study, unlike the 4 study endpoints (Table III). Furthermore,
the most remarkable reductions in pediatric ED visits for the
other diagnoses occurred in the years before the introduc-
tion of PCVs and RVV.
The proportions of RVGE and community-acquired alveo-
lar pneumonia (grouped) of all-cause hospitalizations during
the peak season decreased from 19.9% to 12.3%, when the

Figure 3. Rates of pediatric ED visits for RVGE, non-RVGE, alveolar pneumonia, nonalveolar lower respiratory infections, and
other diseases, during peak season (October to March) 2006-2014. Incidence rate ratios are compared for the prevaccine period
(2006-2009) and the postvaccine period (2013-2014).

Cocontribution of Rotavirus and Pneumococcal Conjugate Vaccines to the Reduction of Pediatric Hospital Visits 257
in Young Children
THE JOURNAL OF PEDIATRICS www.jpeds.com
periods of October and March were compared between 2006-
2009 and 2013-2014. The respective reduction for outpatient
pediatric ED visits was from 6.9% to 1.8%.
Discussion
In the current study, the successive introduction, within 1.5
years, of RVV and PCV to the Israeli NIP, resulted in rapid and
considerable reductions in diarrhea and LRI in children <2 years
of age, treated at the SUMC. Furthermore, both vaccines
cocontributed to a significant reduction in overall hospital
burden in the pediatric population.
The decreases observed in gastrointestinal and lower respi-
ratory tract diseases varied. Although RVGE rates declined by
approximately 80% for both inpatients and outpatient pedi-
atric ED visits, the respective decrease in alveolar pneumonia
rates were by 46% and 67%. For non-RVGE and nonalveolar
LRI, the rates of overall hospital burden were reduced by ap-
proximately 20% and 10%, respectively.
As expected, the most dramatic decrease was observed in
RVGE. Rotavirus is the most common cause of diarrhea in
young children5 and RVGE is a well-defined disease, caused
by a single pathogen. RVGE is detected early in the course of
disease and is preventable by RVV, as demonstrated in this
study and in many others studies worldwide evaluating its
efficacy.11
For alveolar pneumonia, the expectations were somewhat
less obvious, because the etiology of pneumonia is difficult to
determine.13,17 Nevertheless, in this regard, the impressive impact
of PCV7/PCV13 on alveolar pneumonia serves as a vaccine
probe, suggesting that a major portion of alveolar pneumo-
nia episodes are bacterial, and are caused by pneumococcal se-
rotypes included in PCV13. This was especially pronounced
for outpatient pediatric ED visits for alveolar pneumonia, where
67% reduction was observed.
Non-RVGE and nonalveolar LRI are less well-defined in
terms of the causative pathogens, but some proportion is caused
directly or indirectly by the pathogens covered by the 2 vac-
cines. Specifically, nonalveolar LRI episodes were expected to
be reduced, especially in inpatients, because, among others, S
pneumoniae is a collaborator with viruses.17 However, the de-
crease is not as marked as is evident in episodes of alveolar
pneumonia. The roles of vaccines in the reduction observed
in non-RVGE is an intriguing question. Several speculations
can be made. First, the test may have missed true RVGE epi-
sodes owing to imperfect sensitivity. However, the test used in
the current study has been shown to have high sensitivity in
most cases, and can detect small amounts of rotavirus.5 Second,
RVVs may reduce non-RVGE by reducing RVGE sequelae, often
manifesting as secondary diarrhea, which could account for
some proportion of cases.
Considerable fluctuation was noted for all other diagnoses
(nonrespiratory, nondiarrheal). Specifically, for inpatients, no
decreases were observed. For outpatients, although a reduc-
tion in other diagnoses rates were observed, these were docu-
mented even before vaccines were introduced and fluctuated
subsequently, with no further decrease observed. This empha-
258
Volume 182
sizes the importance of observing multiyear dynamics from
both before and after the introduction of vaccines.
The impact of RVV and PCV may not be limited to pre-
vention of diarrhea and respiratory disease, respectively. In 1
study, it was suggested that diarrhea may increase the risk of
subsequent pneumonia in young children,14 pointing to po-
tential synergistic benefits of RVV and PCV.
Vaccine impact was not limited to decreases in hospital visits,
but also led to a reduced mean hospitalization duration of al-
veolar pneumonia and non-RVGE. This was especially pro-
nounced in alveolar pneumonia, increasing vaccines impact
in terms of overall reduction in hospital burden. These re-
ductions may be attributed, at least in part, to the prevention
of nosocomial infections caused by S pneumoniae and rota-
virus. Indeed, in the prevaccines era, it was estimated that a
substantial portion of all rotavirus hospitalizations was due to
infection acquired in the hospital.10
The impact observed in the current study on diarrhea and
respiratory infections is similar to that found in other reports
from different countries introducing RVV11 or PCV.9 Those
reports focused on the impact of a single vaccine. In the US,
rates of all-cause acute gastroenteritis hospitalization among
children younger than 5 years of age declined by 31%-55% in
the postvaccine years,8 and a 15%-20% decline of severe (as-
sociated with hospitalization) all-cause diarrhea cases was ob-
served in developing countries, similar to figures reported from
Malawi and South Africa.11 Similarly, a 43% decrease in rates
of pneumonia hospitalization was observed in US children <2
years of age after PCV7 implementation.9 Our study was pos-
sible because PCV and RVV were introduced to the NIP in
Israel within a 1.5-year interval, enabling observation of their
cocontribution to the reduction in the burden of diseases.
This resulted in a reduction in all-cause hospital visits at a
magnitude of approximately 12%. Because both diarrhea and
respiratory diseases are seasonal, the observed reduction in all-
cause hospital visits was especially notable in the winter season,
with approximately a 15% reduction observed. These ben-
efits have substantial impact, in terms of public health, finan-
cial costs, and relieving the burden of hospital visits during
the most cumbersome seasons.
Despite the impressive reduction seen after PCVs and RVV
implementation to date, future prevention measures may allow
further reduction in hospital burden. In Israel, as in many
other countries, influenza vaccination coverage is relatively
poor (Israeli health ministry data). Efforts have been made
to increase vaccination rates by vaccinating children attend-
ing primary schools, starting in the 2016-2017 school
year (http://www.health.gov.il/English/News_and_Events/
Spokespersons_Messages/Pages/15042015_1.aspx). In the UK,
a school vaccination program resulted in decreases in respi-
ratory disease burden in all ages.18 In addition, it is hoped
that in the next decade, one or more vaccines against the
respiratory syncytial virus will be licensed and implemented.
Because the respiratory syncytial virus is the most common
pathogen responsible for hospitalization owing to LRIs in
young children, respiratory syncytial virus vaccines may further
decrease burden of LRI.
Ben-Shimol et al
March 2017
Theoretically, the reductions observed in the 4 clinical di-
arrhea and respiratory diseases rates could be unrelated to the
introduction of these vaccines. However, the fact that hospi-
talization rates for other diseases increased throughout the study,
as well as the observed fluctuations of those entities in pedi-
atric ED outpatient visits rates, suggests that reductions in the
4 clinical entities evaluated were in fact driven by the intro-
duction of both RVV and PCV.
Submitted for publication Aug 8, 2016; last revision received Oct 10, 2016;
accepted Nov 9, 2016
Reprint requests: Ron Dagan, MD, The Pediatric Infectious Disease Unit,
Soroka University Medical Center, Beer-Sheva, Israel. E-mail: rdagan
@bgu.ac.il
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259
THE JOURNAL OF PEDIATRICS www.jpeds.com Volume 182

Inpatients Outpatient PER visit

(annual rates) (annual rates)

SUM 4 (RVGE+OTHER GE+PNEUMONIA+LRI) SUM 4 (RVGE+OTHER GE+PNEUMONIA+LRI)

non-4 non-4
All visits All visits
240 480
PCV7 PCV7
220 PCV13 440 PCV13
RV5 RV5
200 400

Incidence per 1000 children <2 years of age

Incidence per 1000 children <2 years of age

180 360

160 320

140 280

120 240

100 200

80 160

60 120

40 80

20 40

0 0
Apr 06 - Apr 07 - Apr 08 - Apr 09 - Apr 10 - Apr 11 - Apr 12 - Apr 13 - Apr 06 - Apr 07 - Apr 08 - Apr 09 - Apr 10 - Apr 11 - Apr 12 - Apr 13 -
Mar 07 Mar 08 Mar 09 Mar 10 Mar 11 Mar 12 Mar 13 Mar 14 Mar 07 Mar 08 Mar 09 Mar 10 Mar 11 Mar 12 Mar 13 Mar 14

Figure 2. Rates of hospitalization and outpatient pediatric emergency department visits for all-causes, respiratory and diar-
rheal diseases (grouped) and other causes in children <2 years of age in Southern Israel. GE, gastroenteritis; RV5, rotavirus 5.

259.e1 Ben-Shimol et al
in Young Children
Cocontribution of Rotavirus and Pneumococcal Conjugate Vaccines to the Reduction of Pediatric Hospital Visits

March 2017
Table III. Rates (per 1000 children <2 years of age) during peak disease season (October through March) and incidence rate ratios of RVGE, non-RVGE, alveolar
pneumonia, and nonalveolar lower respiratory hospitalization and pediatric ED outpatient visits in Southern Israel
Inpatients (seasonal rates) Outpatient pediatric ED visit (seasonal rates)
2006- 2007- 2008- 2009- 2010- 2011- 2012- 2013- IRR 2006- 2007- 2008- 2009- 2010- 2011- 2012- 2013- IRR*
2007 2008 2009 2010 2011 2012 2013 2014 (95% CI) 2007 2008 2009 2010 2011 2012 2013 2014 (95% CI)
RVGE 7.5 8.6 8.7 8.0 9.4 4.3 2.6 1.2 0.14 9.1 8.3 5.2 4.7 4.6 2.3 1.6 1.4 0.18
(0.10-0.20) (0.14-0.25)
Non-RVGE 8.0 8.3 8.7 8.4 8.2 5.7 7.6 6.4 0.77 13.2 12.4 11.4 11.2 12.2 9.2 12.1 11.0 0.89
(0.66-0.89) (0.80-1.01)
Alveolar pneumonia 11.9 10.8 12.6 12.3 11.8 7.0 7.1 6.5 0.56 5.6 5.4 3.6 3.3 3.0 1.8 1.0 1.3 0.27
(0.48-0.64) (0.19-0.36)
Nonalveolar LRI 32.7 27.2 26.3 27.7 31.0 26.5 19.1 25.7 0.90 25.2 21.7 24.0 51.9 27.3 21.1 21.0 20.4 0.87
(0.83-0.97) (0.79-0.94)
Grouped 4 entities 60.1 54.9 56.3 56.4 60.5 43.5 36.4 39.8 0.71 53.1 47.9 44.2 71.1 47.1 34.5 35.8 34.1 0.71
(0.67-0.75) (0.67-0.76)
Other entities (non-4) 49.5 43.9 37.8 40.3 41.8 42.6 59.3 46.9 1.07 142.9 131.1 118.4 94.1 126.3 111.3 122.8 113.0 0.88
(1.01-1.13) (0.85-0.91)
All-cause hospital visits 109.6 98.8 94.1 96.7 102.3 86.1 95.7 86.7 0.87 196.0 179.0 162.6 165.1 173.4 145.8 158.5 147.1 0.84
(0.84-0.91) (0.82-0.87)

ED, emergency department; IRR, incidence rate ratio.

Bold values indicate P < .05.
*Comparing the periods between October-March, 2013-2014 and 2006-2009.

ORIGINAL ARTICLES
259.e2