Nej Mo a 1000446

original article

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 365;12 nejm.org september 22, 20111108

Rotavirus Vaccine and Health Care Utilization for Diarrhea in U.S. ChildrenJennifer E. Cortes, M.D., Aaron T. Curns, M.P.H., Jacqueline E. Tate, Ph.D., Margaret M. Cortese, M.D., Manish M. Patel, M.D., Fangjun Zhou, Ph.D.,

and Umesh D. Parashar, M.B., B.S., M.P.H.

From the Epidemic Intelligence Service, Office of Workforce and Career Develop-ment ( J.E.C.), Division of Viral Diseases ( J.E.C., A.T.C., J.E.T., M.M.C., M.M.P., U.D.P.), and Immunization Services Divi-sion (F.Z.), Centers for Disease Control and Prevention, Atlanta. Address reprint requests to Dr. Parashar at the Centers for Disease Control and Prevention, 1600 Clifton Rd., MS A-47, Atlanta, GA 30333, or at [email protected].

N Engl J Med 2011;365:1108-17.Copyright © 2011 Massachusetts Medical Society.

A bs tr ac t

Background

Routine vaccination of U.S. infants with pentavalent rotavirus vaccine (RV5) began in 2006.

Methods

Using MarketScan databases, we assessed RV5 coverage and diarrhea-associated health care use from July 2007 through June 2009 versus July 2001 through June 2006 in children under 5 years of age. We compared the rates of diarrhea-associated health care use in unvaccinated children in the period from January through June (when rotavirus is most prevalent) in 2008 and 2009 with the prevaccine rates to estimate indirect benefits. We estimated national reductions in the number of hospitaliza-tions for diarrhea, and associated costs, by extrapolation.

Results

By December 31, 2008, at least one dose of RV5 had been administered in 73% of children under 1 year of age, 64% of children 1 year of age, and 8% of children 2 to 4 years of age. Among children under 5 years of age, rates of hospitalization for diarrhea in 2001–2006, 2007–2008, and 2008–2009 were 52, 35, and 39 cases per 10,000 person-years, respectively, for relative reductions from 2001–2006 by 33% (95% confidence interval [CI], 31 to 35) in 2007–2008 and by 25% (95% CI, 23 to 27) in 2008–2009; rates of hospitalization specifically coded for rotavirus infection were 14, 4, and 6 cases per 10,000 person-years, respectively, for relative reductions in the rate from 2001–2006 by 75% (95% CI, 72 to 77) in 2007–2008 and by 60% (95% CI, 58 to 63) in 2008–2009. In the January–June periods of 2008 and 2009, the respective relative rate reductions among vaccinated children as compared with unvaccinated children were as follows: hospitalization for diarrhea, 44% (95% CI, 33 to 53) and 58% (95% CI, 52 to 64); rotavirus-coded hospitalization, 89% (95% CI, 79 to 94) and 89% (95% CI, 84 to 93); emergency department visits for diarrhea, 37% (95% CI, 31 to 43) and 48% (95% CI, 44 to 51); and outpatient visits for diar-rhea, 9% (95% CI, 6 to 11) and 12% (95% CI, 10 to 15). Indirect benefits (in unvac-cinated children) were seen in 2007–2008 but not in 2008–2009. Nationally, for the 2007–2009 period, there was an estimated reduction of 64,855 hospitalizations, saving approximately $278 million in treatment costs.

Conclusions

Since the introduction of rotavirus vaccine, diarrhea-associated health care utiliza-tion and medical expenditures for U.S. children have decreased substantially.

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Copyright © 2011 Massachusetts Medical Society. All rights reserved.

Rotavirus Vaccine and Health Care for Diarrhea

n engl j med 365;12 nejm.org september 22, 2011 1109

Before February 2006, when routine vaccination of infants in the United States with pentavalent rotavirus vaccine (RV5)

was recommended, rotavirus diarrhea caused an estimated 400,000 visits to physician’s offices, 200,000 emergency department visits, 55,000 hos-pitalizations, and 20 to 60 deaths annually among children under 5 years of age in the United States, for an annual total medical cost of approximately $300 million.1,2 RV5 is administered orally in chil-dren in three doses, one each given at 2, 4, and 6 months of age.3,4 In trials, use of RV5 reduced the incidence of rotavirus-related hospitalizations or emergency department visits by more than 90% and outpatient visits by 84%.5,6

Severe rotavirus disease has declined substan-tially since the introduction of RV5.7-11 Few reports have correlated declines in disease with popula-tion vaccine coverage. Also, most reports have documented declines in hospitalizations only. Data regarding the effect of RV5 on diarrhea treated in ambulatory settings are limited.

We used MarketScan databases to correlate RV5 coverage with changes in the rates of diarrhea-associated hospitalizations, emergency department and outpatient visits, and treatment costs after RV5 introduction. We examined both direct and indirect vaccine benefits and estimated the na-tional reduction in hospitalizations for diarrhea and associated costs after the start of RV5 admin-istration.

Me thods

Data Source

Data from the 2001–2009 MarketScan Commer-cial Claims and Encounters database were ana-lyzed.12 MarketScan data are derived from insur-ance claims and contain de-identified information from various public and private health plans, in-cluding health maintenance organizations, fully or partially capitated health plans, preferred-provider organizations, point-of-service plans, indemni-ty plans, and consumer-directed health plans. Medicaid recipients are not included. In 2007, Market Scan databases contained nearly 30 mil-lion enrollees from all 50 U.S. states. Data from approximately 2 million children under 5 years of age were captured during the study period.

Diarrhea-associated health care events were identified with the use of the following Interna-tional Classification of Diseases, 9th Revision, Clinical

Modification (ICD-9-CM) codes: viral enteritis, 008.6–008.8 (including rotavirus, 008.61); bac-terial enteritis, 001.0–005.9 (excluding 003.2) and 008.0–008.5; parasitic intestinal disease, 006.0–007.9 (excluding 006.3–006.6); presumed infec-tious diarrhea, 009.0–009.3; presumed noninfec-tious diarrhea, 558.9; and diarrhea not otherwise specified, 787.91. An event identified as the pri-mary discharge diagnosis or 1 of 15 other possible discharge diagnoses for the inpatient-admissions table was classified as a hospitalization. An event identified in 1 of the 2 diagnosis fields in the outpatient-services table was classified as an out-patient visit. Events were classified as emergency department visits (not hospitalizations or outpa-tient visits) if “urgent care facility” or “emergency room” was specified in either the inpatient-servic-es table or the outpatient-services table. Patients evaluated in more than one setting for the same diarrhea episode may have had multiple encoun-ters recorded in the database for the one episode.

RV5 Coverage

Using data from the January 2006–June 2009 pe-riod, we assessed RV5 coverage (defined as admin-istration of at least one dose of RV5) in a subgroup of children with continuous enrollment in one in-surance plan from birth through at least 3 months of age. The criterion of continuous enrollment en-sured that nearly all vaccinations billed for were captured. Children from 13 states with universal vaccination programs that include RV5 or where RV5 inclusion could not be ascertained (Alaska, Idaho, Massachusetts, Maine, North Dakota, New Hampshire, New Mexico, Oregon, Rhode Island, Vermont, Washington, Wisconsin, and Wyoming) were excluded from the coverage assessment. Vac-cinations in these states were not likely to have been billed to third-party payers and thus would probably not be recorded in this database.

Within the coverage cohort, we identified en-rollees who received RV5 by using the Current Procedural Terminology (CPT) code 90680 and identified those who received the monovalent ro-tavirus vaccine (RV1), recommended in June 2008, by using the CPT code 90681. Coverage on Decem-ber 31, 2007, and on December 31, 2008, was as-sessed on the basis of age group and region. To validate results, we compared coverage with at least one dose of diphtheria–tetanus–acellular per-tussis vaccine (DTaP) by 3 months of age in the MarketScan database with coverage reported by





the National Immunization Survey, considered the U.S. standard for vaccine coverage.13

Trends in Diarrhea-Associated health care Utilization

We examined diarrhea-associated health care utili-zation rates for enrollees under 5 years of age who were seen in inpatient, emergency department, and outpatient settings. We also assessed rates of rotavirus-coded hospitalization (i.e., hospitaliza-tion for diarrhea with the ICD-9-CM code for rota-virus, 008.61); the numbers of emergency depart-ment or outpatient visits for diarrhea that had the rotavirus-specific code were too small to analyze. Data from all states, including those with univer-sal vaccination programs, were included in the analysis of trends. Because the information in the database was restricted to children who were en-rolled in an insurance plan, we used the number of days each child was enrolled per calendar month and year of the study as the follow-up time in cal-culating utilization rates per 10,000 person-years of follow-up.

To compare diarrhea-associated health care uti-lization rates before and after the introduction of RV5, we evaluated rates over each of two 1-year post-vaccine periods (July 2007–June 2008 and July 2008– June 2009) and compared them with the annual mean rates during the 5-year prevaccine baseline period (July 2001–June 2006), according to age group (<1 year, 1 year, and 2 to 4 years) and cen-sus region (Northeast, Midwest, South, and West). Because rotavirus is most prevalent from January through June, we also restricted analyses to this 6-month period, for improved specificity. The period from July 2006 through June 2007 was considered a transition year and was excluded from analyses, since recommendations for RV5 use were not published until August 2006.4

Vaccine Benefits

We restricted analyses of direct and indirect vaccine benefits to children who were age-eligible to re-ceive at least one RV5 dose before the 2008 rotavi-rus season (i.e., who were 3 through 23 months of age by January 2008) and who were continuously enrolled in the same insurance plan from birth through June 2008. We used the same approach for the 2009 rotavirus season. Children from states with universal vaccination programs were exclud-ed. In addition, children who received RV1 were excluded (only approximately 1% of children under

1 year of age had received at least one RV1 dose as of December 31, 2008).

Direct BenefitsTo examine direct vaccine benefits, we compared rates of rotavirus-coded hospitalization and di-arrhea-associated health care utilization rates in the January–June 2008 and 2009 periods among vaccinated versus age-eligible, unvaccinated chil-dren. Since RV5 was recently introduced, vaccine coverage by month of birth was not uniform be-fore the study period. Therefore, risk ratios and 95% confidence intervals were adjusted for month of birth by means of Poisson regression for hospi-talizations and binomial regression for emergency department and outpatient visits. The adjusted es-timates were subtracted from 1 to obtain adjusted rate reductions.

Indirect BenefitsTo examine indirect benefits of the vaccine (i.e., indirect protection of unvaccinated persons be-cause vaccinated persons did not contract and transmit disease), we compared rates of rotavirus-coded hospitalization and diarrhea-associated health care utilization rates among age-eligible, unvaccinated children from January through June in 2008 and in 2009 with prevaccine rates for children under 2 years of age. The relative rate re-ductions and 95% confidence intervals were cal-culated with the use of standardized morbidity ratios, with prevaccine rates as the baseline data.14

Estimation of National Reductions in Hospitalization Rates and Costs

By extrapolating observed diarrhea-associated hos-pitalization rates from July 2007 through June 2009 to the 2009 U.S. population under 5 years of age, we estimated the national burden of diarrhea-associated hospitalizations after the introduction of RV5. We then determined the median total pay-ments for diarrhea-associated hospitalizations and converted them to 2009 constant dollars on the basis of the Bureau of Labor Statistics Consumer Price Index for medical care.15 Median payments were multiplied by the number of diarrhea-asso-ciated hospitalizations to estimate national pay-ments. Baseline payments were derived according to prevaccine rates. The estimated reduction in hos-pitalization costs was calculated as the difference between national payments before and after the introduction of RV5.





R esult s

Rotavirus-Vaccine Coverage

In a cohort of nearly 300,000 children under 5 years of age from 37 states, 32% had received at least one dose of RV5 by December 31, 2008, with the percentage increasing steadily since vaccine licen-sure. At the same time point, coverage was 73% among children under 1 year of age, 64% among 1-year-olds, and 8% among 2-to-4-year-olds; rates were similar across regions (Table 1). In the same cohort, the proportion of children who had re-ceived at least one DTaP dose by 3 months of age was 88%, as compared with 89% according to the National Immunization Survey.13

Trends in Diarrhea-Associated Health Care Utilization

During the 2001–2009 period, a total of 40,574 hospitalizations, 170,082 emergency department visits, and 1,254,613 outpatient visits that were associated with diarrhea were recorded among children under 5 years of age. Baseline monthly diarrhea-associated health care utilization rates peaked in the February–March period of each year in all settings, which is similar to the seasonal

pattern of rotavirus-coded hospitalizations (Fig. 1). In 2007–2008, this winter–spring peak had a de-layed onset and was blunted, as compared with the peak in prevaccine years, in all settings. In 2008–2009, the winter–spring peak was present but was smaller in magnitude than the peak in prevaccine years.

In 2007–2008, annual rates of hospitalization for rotavirus-coded diarrhea among children under 5 years of age declined by 75% (calculated accord-ing to numbers before rounding), from a baseline of 14 hospitalizations per 10,000 person-years to 4 per 10,000 person-years (Table 1). Declines were similar across age groups despite variations in vac-cine coverage, including negligible coverage among 2-to-4-year-olds. In 2008–2009, annual rates of hospitalization for rotavirus-coded diarrhea de-clined by 60% from baseline rates, and the de-clines by age group were proportional to vaccine coverage; rates declined by 26% among children 2 to 4 years of age (with 8% coverage [defined as administration of at least one dose of RV5] in this age group), whereas the rate declined by 76% among children 1 year of age or younger (approxi-mately 68% coverage). The Northeast, Midwest, and South had rates that decreased by 75% or

Table 1. Mean Annual Rates of Hospitalization for Rotavirus-Coded Diarrhea among Children under 5 Years of Age before and after Rotavirus-Vaccine Introduction in 2006 and Vaccine Coverage in December 2007 and 2008, According to Age Group and Region.

Variable 2001–2006* 2007–2008 2008–2009

Hospitalization Rate


Rate Reduction (95% CI)

Coverage on December 31,

2007†Hospitalization

RateRate Reduction

(95% CI)

Coverage on December 31,

2008†

no./10,000 person-yr percent no/10,000 person-yr percent

Age group

<5 yr 14 4 75 (72–77) 17 6 60 (58–63) 32

<1 yr 16 3 81 (77–84) 64 4 78 (74–81) 73

1 yr 33 9 72 (69–76) 23 9 74 (71–77) 64

2–4 yr 8 2 72 (67–76) 0 6 26 (19–32) 8

Region‡

Northeast 10 2 82 (74–88) 16 4 63 (53–71) 30

Midwest 15 4 75 (71–78) 17 7 50 (44–56) 31

South 19 4 80 (78–82) 19 6 66 (63–69) 34

West 8 4 45 (33–54) 15 2 71 (64–77) 29

* For 2001–2006, the mean of the annual rates is shown.† Coverage was defined as receipt of at least 1 dose of RV5 by December 31, 2007, or December 31, 2008, in children who had been in the data-

base since birth and for at least 3 months continuously. Coverage for children under 1 year of age was restricted to those who were eligible for vaccination (i.e., those 3 through 11 months of age).

‡ Regional estimates are for children under 5 years of age.





more in 2007–2008 and by 50% or more in 2008–2009. In contrast, the West had a 45% decrease in 2007–2008 but a 71% decrease in 2008–2009.

After RV5 was introduced, annual rates of di-arrhea-associated hospitalization among all chil-dren under 5 years of age were 33% and 25% lower in 2007–2008 and 2008–2009, respectively, than in 2001–2006 (Table 2). Annual rates of emergency department and outpatient visits declined by 9% and 3%, respectively, in 2007–2008. The annual rates in 2008–2009 in both settings were similar to the prevaccine rates. In both periods, 1-year-old children had the largest decreases in rates of diar-rhea-associated hospitalization. Although the hos-pitalization rate in 2007–2008 was reduced by 34% among children 2 to 4 years of age, the reduction in 2008–2009 was a modest 9%. Rates of emer-gency department and outpatient visits were re-duced among children under 1 year of age and among 1-year-old children in each postvaccine year. Children 2 to 4 years of age had higher rates of emergency department and outpatient visits in 2008–2009 than in the prevaccine years.

Overall, for children under 5 years of age, all regions had significant reductions in the rates of hospitalization for diarrhea, with the South hav-ing the largest decreases over the 2-year period after vaccine introduction (Table 1 in the Supple-mentary Appendix, available with the full text of this article at NEJM.org). The Northeast and Mid-west rates decreased from 34% each in 2007–2008 to 13% and 20%, respectively, in 2008–2009. In contrast, reductions in the West increased from 17% in 2007–2008 to 30% in 2008–2009. In 2007–2008, emergency department and outpatient visits declined in all regions except the West, but to a lesser extent than hospitalizations. Although declines were not maintained in 2008–2009 in the other regions, emergency department and out-patient visits for diarrhea did decline in the West.

When analyses were restricted to the rotavirus season, January through June, in both 2008 and 2009, declines in rates of diarrhea-associated hos-pitalizations among children under 1 year of age

Figure 1. Diarrhea-Associated Health Care Utilization among Children under 5 Years of Age According to Month and Setting, January 2001–June 2009.

Rates per 10,000 person-years are shown for hospitaliza-tions (Panel A), emergency department visits (Pa nel B), and outpatient visits (Panel C).

Hos

pita

lizat

ions

per

10,

000

Pers

on-Y

r

200

160

120

80

40

02001 2003 20052002 2004 2006 2007 2008 2009

B Emergency Department Visits

A Hospitalizations

Diarrhea

Rotavirus-codeddiarrhea

Vis

its p

er 1

0,00

0 Pe

rson

-Yr

500

400

300

200

100

02001 2003 20052002 2004 2006 2007 2008 2009

C Outpatient Visits

Vis

its p

er 1

0,00

0 Pe

rson

-Yr

3000

2500

2000

1500

500

1000

02001 2003 20052002 2004 2006 2007 2008 2009





Tabl

e 2.

Mea

n A

nnua

l Rat

es o

f Dia

rrhe

a-A

ssoc

iate

d H

ealth

Car

e U

tiliz

atio

n am

ong

Chi

ldre

n un

der

5 Ye

ars

of A

ge b

efor

e an

d af

ter

Rot

avir

us-V

acci

ne In

trod

uctio

n, A

ccor

ding

to A

ge

Gro

up a

nd H

ealth

Car

e Se

ttin

g.*

Age

Gro

upJu

ly–J

une

Janu

ary–

June

Hea

lth C

are

Util

izat

ion

Rat

eR

ate

Red

uctio

n (9

5% C

I)H

ealth

Car

e U

tiliz

atio

n R

ate

Rat

e R

educ

tion

(95%

CI)

2001

–200

6†20

07–2

008

2008

–200

920

07–2

008

2008

–200

920

02–2

006†

2008

2009

2008

2009

no./

10,0

00 p

erso

n-yr

perc

ent

no./

10,0

00 p

erso

n-yr

perc

ent

Hos

pita

lizat

ions

<5 y

r52

3539

33 (

31 to

35)

25 (

23 to

27)

78

41

51

47 (

45 to

49)

34 (

32 to

36)

<1 y

r65

5045

24 (

20 to

27)

30 (

27 to

34)

103

61

60

41 (

37 to

45)

41 (

37 to

45)

1 yr

9656

6041

(38

to 4

4)38

(35

to 4

1) 1

50

70

7653

(50

to 5

6)49

(46

to 5

2)

2–4

yr32

2129

34 (

31 to

37)

9 (5

to 1

3)

46

25

4046

(42

to 4

9)12

(8

to 1

6)

Emer

genc

y de

part

men

t vi

sits

<5 y

r18

516

918

89

(7 to

10)

−2 (

−3 to

0)

254

195

240

23 (

22 to

25)

6 (4

to 7

)

<1 y

r21

220

418

54

(1 to

6)

13 (

11 to

15)

320

244

243

24 (

21 to

26)

24 (

22 to

26)

1 yr

324

282

298

13 (

11 to

15)

8 (6

to 1

0) 4

62 3

32 3

6928

(26

to 3

0)20

(18

to 2

2)

2–4

yr13

011

915

59

(7 to

11)

−19

(−21

to −

17)

166

134

198

19 (

16 to

21)

−20

(−22

to −

17)

Out

patie

nt v

isits

<5 y

r13

4813

0313

603

(3 to

4)

−1 (

−1 to

0)

1659

1404

1530

15 (

15 to

16)

8 (7

to 8

)

<1 y

r17

1316

0814

996

(5 to

7)

13 (

12 to

13)

2377

1870

1816

21 (

20 to

22)

24 (

23 to

24)

1 yr

2376

2264

2355

5 (4

to 5

)1

(0 to

2)

2926

2393

2547

18 (

17 to

19)

13 (

12 to

14)

2–4

yr87

187

198

40

(−1

to 1

)−1

3 (−

14 to

−12

)10

02 9

2211

048

(7 to

9)

−10

(−11

to −

9)

* R

egio

nal d

ata

are

prov

ided

in T

able

1 in

the

Sup

plem

enta

ry A

ppen

dix.

† F

or 2

001–

2006

and

200

2–20

06, t

he m

ean

of t

he a

nnua

l rat

es is

sho

wn.





and those 1 year old were greater than but similar in pattern to those observed annually (Table 2, and Table 1 in the Supplementary Appendix). Rates of hospitalization for diarrhea among 2-to-4-year-olds were reduced in both years, although to a lesser extent in 2009. The rates of emergency de-partment and outpatient visits for diarrhea were reduced in 2007–2008, but they were increased in 2008–2009. According to region, rates of diarrhea-associated hospitalization in 2007–2008 decreased by approximately 50% each in the Northeast, Mid-west, and South and by 25% in the West. In 2008– 2009, the rate reductions were approximately 25% in the Northeast and Midwest, 43% in the South, and 31% in the West.

Direct Benefits of Vaccine

Vaccinated children had 89% fewer rotavirus-coded hospitalizations than unvaccinated children in each of the two postvaccine rotavirus seasons (Ta-ble 3, and Table 2 in the Supplementary Appendix). The magnitude of direct vaccine benefits was sim-ilar across regions, but because of the small num-ber of rotavirus-coded hospitalizations in the Northeast in 2008 and in the West in 2009, esti-mates were unreliable. Rates were also significant-ly reduced among vaccinated children as compared with unvaccinated children for both 2007–2008 and 2008–2009 for hospitalization for diarrhea of any cause (44% and 58%, respectively), emer-gency department visits (37% and 48%), and out-patient visits (9% and 12%).

Indirect Benefits of Vaccine

Substantial reductions occurred in rates of health care utilization for diarrhea of any cause and for rotavirus-coded diarrhea among age-eligible, un-vaccinated children in all settings during the Janu-ary–June period of 2008, as compared with pre-vaccine rates, with the exception of rates in the West (Table 4, and Table 3 in the Supplementary Appendix). Such reductions did not occur during the January–June period of 2009 in most regions in the inpatient and emergency department set-tings, but substantial reductions did occur in the outpatient setting.

Estimated National Reduction in Hospitalizations and Associated Costs

We estimated that, nationally, 64,855 hospitaliza-tions for diarrhea were averted among children un-der 5 years of age during the 2 postvaccine years studied. By applying this reduction to the median

payment for a diarrhea-associated hospitaliza-tion in the MarketScan database in 2008–2009, we estimated that hospitalization costs were reduced by $278 million for the 2-year period (Table 5).

Discussion

Rates of diarrhea-associated hospitalizations and ambulatory visits among U.S. children under 5 years of age declined during both rotavirus sea-sons (in 2007–2008 and 2008–2009) after the intro-duction of RV5. The findings that reductions were greater during the months when rotavirus was prevalent and that rates of rotavirus-coded hospi-talization declined by 60% to 75% support the suggestion that the observed changes were largely attributable to declines in the rate of rotavirus dis-ease. Nationally, we estimated that approximately 65,000 diarrhea-associated hospitalizations were prevented during the 2007–2009 period, resulting in a reduction of $278 million in treatment costs.

Our findings confirm other reports of a decline in rotavirus activity in the United States after the introduction of rotavirus vaccine.7-11,16,17 They also show the effect of the vaccine on emergency de-partment and outpatient visits for diarrhea. The observed 89% reduction in the most specific outcome, rotavirus-coded hospitalizations, in vac-cinated children as compared with unvaccinated children is consistent with the efficacy of the vac-cine in prelicensure trials.5 Although the reduc-tion in hospitalizations for diarrhea from any cause (by 44%) in vaccinated versus unvaccinated children in 2007–2008 was somewhat lower than the 59% reduction seen in prelicensure trials,5 the reduction in 2008–2009 (by 59%) was virtually identical.18 The smaller reduction in 2007–2008 may be attributable, in part, to the marked de-cline in rotavirus activity in that season, which probably diminished the proportion of hospital-izations for diarrhea from any cause that were attributable to rotavirus.

Although the direct benefits of vaccination were similar in 2007–2008 and 2008–2009, the indirect benefits differed. In 2007–2008, indirect benefits were evidenced by declines in rotavirus disease that greatly exceeded expected declines, given the level of RV5 coverage, and that were also substantial among unvaccinated 2-to-4-year-olds. In addition, in all regions except the West, diarrhea-associated rates of health care utilization among age-eligible, unvaccinated children during the 2007–2008 pe-riod were lower than baseline prevaccine rates, a





finding that supports indirect benefits. In 2008–2009, however, the indirect benefits were smaller and were inconsistent across settings.

Regional variation in the effect of vaccination was also observed. In 2007–2008, the West had a smaller decline in the rate of diarrhea-associated hospitalizations than other regions, and the rate of emergency department visits for diarrhea increased as compared with prevaccine rates. Furthermore, in the January–June period in 2008, among age-eligible, unvaccinated children under 2 years of age, rates of hospitalization for rotavirus-coded diarrhea, as well as rates of health care utilization for any diarrhea, exceeded prevaccine rates in the West but declined in all other regions. RV5 cov-erage and direct vaccine benefits were similar in the West and in other regions, suggesting that the discrepant data cannot be attributed to these factors. A recent mathematical-modeling study revealed a correlation between the traditional ear-lier onset of rotavirus activity in the West, as com-pared with other U.S. regions, and the birth rate

in Western states, which is approximately 10% higher than in other regions19,20; this relationship may be the result of faster growth of the popula-tion of susceptible infants through new births. Similarly, greater vaccine coverage may be needed in the West to reduce rotavirus transmission to the same extent as that seen in other regions with lower coverage. The finding that in 2008–2009 re-ductions in the West were more marked than in other regions supports this hypothesis.

Some limitations of our study should be con-sidered. First, we lacked data on uninsured and Medicaid populations, as well as information on race or ethnic group and on socioeconomic status, all of which affect extrapolation to the general U.S. population.

Second, no reliable, timely data on RV5 cover-age were available to validate our estimates; how-ever, concordance between our DTaP coverage data and the National Immunization Survey data are reassuring.

Third, states with universal vaccination pro-

Table 3. Reduction in Rates of Diarrhea-Associated Hospitalization among Children Who Received at Least One Dose of RV5 versus Unvaccinated Children Who Were Age-Eligible for RV5, According to Study Period and Region.*

Region January–June 2008 January–June 2009


Rate Reduction (95% CI)†


Rate Reduction (95% CI)†

Vaccinated Unvaccinated Vaccinated Unvaccinated

no./10,000 person-yr percent no./10,000 person-yr percent

Rotavirus-coded diarrhea

All 3 24 89 (79 to 94) 5 42 89 (84 to 93)

Northeast 0 5 — 5 17 75 (−35 to 96)

Midwest 1 25 90 (68 to 97) 4 51 92 (83 to 96)

South 5 24 88 (73 to 94) 6 46 88 (80 to 93)

West 1 35 94 (39 to 99) 0 16 —

Any diarrhea

All 57 91 44 (33 to 53) 53 131 58 (52 to 64)

Northeast 51 65 — 50 124 57 (25 to 76)

Midwest 30 82 52 (33 to 66) 46 131 64 (53 to 73)

South 71 96 43 (28 to 55) 59 137 56 (46 to 63)

West 64 113 51 (19 to 71) 43 106 61 (38 to 76)

* Children who were age-eligible for vaccine were 3 through 23 months old at the start of each study period (January 1, 2008, and January 1, 2009) and were continuously enrolled in their insurance plan from birth through the end of each study period (June 30, 2008, and June 30, 2009). Vaccination status was determined by the presence or absence of a current procedural terminology code for receipt of at least one dose of RV5. Children who had received one or more doses of RV1 (<1% of age-eligible children) were excluded. Rates were adjusted for month of birth. For rates of health care utili-zation in emergency department and outpatient settings, see Table 2 in the Supplementary Appendix.

† Rate reductions for rotavirus-coded diarrhea and any diarrhea events in the Northeast and rotavirus-coded diarrhea in the West became unreliable owing to small numbers of events.





grams were excluded from analyses of vaccine coverage and direct and indirect benefits. As a con-sequence, for the Northeast, where 5 of the 13 ex-cluded states are located, we were unable to gener-ate reliable estimates for direct vaccine benefits in inpatient settings.

Fourth, although we adjusted for age-related variation in the risk of rotavirus disease and chang-es in vaccine coverage over time by controlling for month of birth, we may not have accounted for all confounders.

Fifth, we examined data from only two post-vaccine rotavirus seasons and cannot be certain that observed changes were due solely to RV5 use. Secular trends in the incidence of rotavirus and other diarrheal pathogens could affect our find-ings,9 particularly for emergency department and outpatient settings, where rotavirus accounts for a smaller proportion of all diarrhea events than it does in hospitals.

Sixth, rotavirus testing and coding are not con-sistently performed in health care settings and could be influenced by knowledge of the child’s vaccination status. Thus, the effect of RV5 admin-istration cannot be measured by means of data-base evaluations alone, and other study designs, which include laboratory testing for rotavirus in patients with diarrhea, should be considered.

Seventh, although we estimated the postvac-cination reduction in the costs of hospitalization for diarrhea nationally, a formal cost–benefit analy-sis that includes other key factors (e.g., the cost of the vaccine program) is required to fully assess the economic effect of vaccination.

Finally, we did not include information reflect-ing either the health or economic effects of ad-verse events related to rotavirus vaccination in our analysis. A small increase in the risk of intussus-ception (by 1 to 2 cases per 100,000 vaccinated infants) has recently been reported in association with rotavirus vaccination in Latin America and Australia.21,22 Although this risk has not been documented in the United States, if it is present, it would translate into an excess of approximately 50 intussusceptions in a fully vaccinated national birth cohort.23 Multiplying this number by the median payment for visits in the MarketScan data-base with an ICD-9-CM code for intussusception (560.0) in inpatient, emergency department, and outpatient settings results in an estimated total health care cost of approximately $532,000. Thus, this level of risk and its economic impact would be far outweighed by the health and economic benefits of vaccination reported in this study.

In conclusion, since the implementation of rou-tine rotavirus vaccination of infants in the United

Table 4. Rates and Rate Reductions for Diarrhea-Associated Hospitalization among Unvaccinated Children after RV5 Introduction, According to Study Period and Region.*

Region Hospitalization Rate Rate Reduction (95% CI)

2002–2006 2008 2009 2008 2009

number/10,000 person-yr percent

Rotavirus-coded diarrhea

All 45 24 42 46 (37 to 54) 6 (−6 to 17)

Northeast 31 5 17 83 (48 to 94) 45 (−10 to 73)

Midwest 49 25 51 50 (35 to 61) −4 (−26 to 14)

South 60 25 46 60 (49 to 68) 24 (9 to 36)

West 21 35 16 −65 (−134 to −17) 21 (−38 to 55)

Any diarrhea

All 125 91 131 27 (21 to 32) −5 (−12 to 2)

Northeast 109 65 124 40 (18 to 56) −14 (−48 to 12)

Midwest 122 82 131 33 (23 to 42) −7 (−21 to 5)

South 155 96 137 38 (31 to 45) 12 (3 to 20)

West 81 113 106 −39 (−69 to −15) −30 (−63 to −4)

* Data for 2002–2006 were averaged among children under 2 years of age during the January–June period of each year. Data for 2008 and 2009 were averaged among unvaccinated children who were age-eligible for the vaccine: those 3 through 23 months of age by January 1, 2008, and January 1, 2009. Rate reductions for diarrhea-associated emergency department and outpatient visits are provided in Table 3 in the Supplementary Appendix.





States, diarrhea-associated health care utilization and medical expenditures have declined. Direct vaccine benefits were consistent across the two postvaccine seasons studied and were similar to the benefits in prelicensure trials. Although in-direct benefits were seen in 2007–2008, they were smaller in 2008–2009. Continued surveillance is needed to further characterize direct and indi-

rect vaccine effects, including those of the re-cently approved rotavirus vaccine RV1, on diar-rhea-associated health care utilization among U.S. children.

The findings and conclusions of this report are those of the authors and do not necessarily represent the views of the Cen-ters for Disease Control and Prevention.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Table 5. Estimated Reductions in the Number and Cost of Diarrhea-Associated Hospitalizations among Children under 5 Years of Age, after the Introduction of Rotavirus Vaccine.

Variable* Number and Cost Reduction

2001–2006 2007–2008 2008–2009 2007–2008 2008–2009 2007–2009

No. of hospitalizations 110,688 73,778 82,703 36,890 27,965 64,855

Cost of hospitalizations ($) 473,770,195 315,842,541 354,051,300 157,927,653 119,718,894 277,646,547

* Numbers of hospitalizations were derived by applying average rates of hospitalization for July 2001–June 2006, July 2007–June 2008, and July 2008–June 2009 to the 2009 U.S. Census population estimate for children under 5 years of age. Treatment costs were calculated by multiplying the number of hospitalizations by the inflation-adjusted median payment per hospitalization during the July 2008–June 2009 period ($4,281).

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