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Rotavirus Overview
David I. Bernstein, MD, MA
Abstract: Rotaviral gastroenteritis is a serious public health problem in
both developed and developing countries. The disease is ubiquitous,
affecting nearly all children by the age of 5 years. It is the most common
cause of hospitalizations for gastroenteritis among children in the United
States (30%–70% depending on the season) and is associated with direct
and indirect costs of approximately $1 billion per year. Symptoms of
rotaviral gastroenteritis are nonspecific (ie, diarrhea, vomiting, and fever),
with disease severity varying considerably. Diagnostic confirmation of
rotaviral gastroenteritis requires laboratory tests (most commonly enzyme
immunoassay or latex agglutination); however, because specific diagnosis
is costly and does not affect treatment, laboratory tests are generally not
performed. Because no antiviral therapies are currently available, treatment
of rotavirus infection is supportive and primarily aimed at the replacement
of fluid and electrolyte losses. Based on the observations that improved
sanitation does not decrease disease prevalence and that hospitalizations
remain high despite the availability and use of oral rehydrating solutions,
the primary public health intervention for rotavirus infection is vaccination.
Current vaccines (ie, RotaTeq, Merck and Company; Rotarix, GlaxoSmithKline) are effective for reducing rotaviral gastroenteritis (particularly
severe disease), emergency department visits, and hospitalizations. Rotavirus vaccination is now included as part of the routine vaccination
schedule for all infants in the United States.
Key Words: rotavirus, gastroenteritis, rotavirus vaccine, diagnosis,
treatment, epidemiology
(Pediatr Infect Dis J 2009;28: S50 –S53)
R
otavirus is the most common cause of severe diarrhea in infants
and young children in both the United States and around the
world.1 Rotavirus infection is nearly universal, with approximately
95% of children experiencing rotavirus gastroenteritis by age 5
years.2 There is no difference in the incidence of rotavirus infection between developed and developing countries, indicating that
improved sanitation does not decrease the transmissibility of the
virus.2 In the United States, rotavirus is responsible for 5% to 10%
of cases of gastroenteritis among children ⬍5 years of age, but it
is responsible for a much higher proportion of severe episodes.2
Compared with other causes of gastroenteritis, rotavirus is more
frequently associated with severe symptoms (eg, fever, vomiting,
combined diarrhea/vomiting).3 Rotaviral gastroenteritis has been
shown to cause approximately 40% of all outpatient visits for acute
gastroenteritis in infants and young children to pediatric primary
care practices.3 Furthermore, between 30% and 50% of all hospitalizations for gastroenteritis among US children aged ⬍5 years
are due to rotavirus infection. This value increases to approxi-
From the Cincinnati Children’s Hospital Medical Center; University of Cincinnati, Cincinnati, OH.
Disclosure: Dr. Bernstein receives royalties for his work in the development of
Rotarix and the patent for 89-12. He is also a consultant for GlaxoSmithKline.
Address for correspondence: David I. Bernstein, MD, MA, Cincinnati Children’s Hospital Medical Center; University of Cincinnati, 3333 Burnet
Avenue, Cincinnati, OH 45229. E-mail: [email protected].
Copyright © 2009 by Lippincott Williams & Wilkins
ISSN: 0891-3668/09/2803-0050
DOI: 10.1097/INF.0b013e3181967bee
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mately 70% during seasonal peaks of the disease.1 Figure 14
illustrates the very large importance of rotavirus as an etiologic
agent in severe diarrhea requiring hospitalization compared with
other pathogens in both developing and developed countries.4
Several epidemiologic and clinical characteristics associated with rotavirus argue for use of vaccination as the primary
public health intervention for rotavirus.1 This includes the observations that the rates of rotavirus illness are similar in developed
and less-developed countries, indicating that improved sanitation
will not decrease disease prevalence and the continued high rates
of hospitalization despite the widespread availability and use of
oral rehydration solutions.1 In addition, natural history studies
suggest that mild, asymptomatic infection effectively protects
against subsequent severe rotavirus gastroenteritis. Thus, the development of a vaccine that mimics a mild asymptomatic infection
has the potential to prevent the morbidity and mortality associated
with severe rotavirus disease.1
DISEASE BURDEN
Rotavirus gastroenteritis inflicts a devastating impact on
infants and young children, particularly in developing countries. It
is estimated that the disease is associated with the deaths of more
than 600,000 children per year worldwide, with the majority of
deaths occurring in Africa and Asia.5 Yearly death tolls are high in
India (146,000), Nigeria (47,500), China (41,000), Pakistan
(36,500), Congo (29,000), and Ethiopia (29,000).5 Bangladesh has
the highest per capita death rate from the disease.5 Although
mortality rates in the United States are much lower (20 – 60
deaths/yr), the disease is still associated with substantial disease
burden. It is estimated that rotavirus gastroenteritis is associated
with 410,000 physician visits, 205,000 to 272,000 emergency
department visits, and 55,000 to 70,000 hospitalizations each year
in the United States.1 Thus, between 1 in 67 and 1 in 85 children
in the United States will be hospitalized with rotavirus by the age
of 5 years.6 Risk factors for rotavirus-induced hospitalization
include no breastfeeding, low birth weight, being in child care, no
insurance or having Medicaid, and the presence of another child
⬍24 months in the house.7
The direct and indirect costs associated with the disease are
estimated to be approximately $1 billion in the United States.1,2 A
study in 1993 calculated that the average total cost per episode of
diarrhea presenting to a primary care physician was $289, with time
missed from work by the parent/caretaker responsible for half of the
total cost (Fig. 2).8 The majority of parents missed at least 1 day of
work (average 1.3 days).8 As expected, costs are much higher when
hospitalization is required. A study analyzing medical claims between
1993 and 1996 found that the cost of hospitalization (in 1998 dollars)
was in excess of $2300, with a range of $648 to $79,886.9 Other
studies of rotavirus-related hospitalizations have estimated median
charges per hospitalization of $2999 to $3399.6,10 Notably, because
these analyses included only charges for medical services, these
values did not include indirect costs (eg, lost time from work).
One large prospective study11 examined these indirect costs
between November 1997 and December 1999 at 3 pediatric medical centers. The average nonmedical cost per case of severe
rotavirus disease that required hospitalization was approximately
$450 – 80% of which ($359) was attributed to missed work and
The Pediatric Infectious Disease Journal • Volume 28, Number 3, March 2009
The Pediatric Infectious Disease Journal • Volume 28, Number 3, March 2009
Rotavirus Overview
EPIDEMIOLOGY
FIGURE 1. Role of etiologic agents in the pathogenesis of
severe diarrheal illness requiring hospitalization in developed and developing countries. Reproduced with permission from JAMA. 1993;269:627– 629. Copyright 1993,
American Medical Association.4
FIGURE 2. Cost of a rotavirus episode by category.8 ORS
indicates oral rehydration therapy.
more than half of which (53%) occurred before or after hospitalization. The remaining costs included approximately $57 for transportation, $10 for diapers, $7 for child care changes, and $17 for
special foods, oral rehydration solutions, and formula changes. In
the current economic climate, these costs would obviously be
much higher.
Further, the prevalence of rotavirus disease may be underreported. Current estimates of disease activity are based on surveys, cohort studies, and hospital discharge data.2 However, only
a small proportion of diarrhea-related hospitalizations that are
caused by rotavirus are correctly classified as rotavirus specific.12,13 It has been estimated that only 47% of hospital discharge
records were correctly coded as rotavirus infections. Furthermore, the sensitivity decreased to 25% when detection rates
from active surveillance were extrapolated to the number of
acute gastroenteritis hospitalizations.12 A major reason for
underreporting is that laboratory identification of the pathogen
increases costs but does not affect treatment.13 Furthermore,
there are no specific guidelines for the diagnostic testing of
rotavirus.12 In addition, there is substantial variation between
institutions in testing and coding practices for rotavirus-specific
disease.6 Therefore, many cases of rotavirus may be attributed
to unspecified viral gastroenteritis.
© 2009 Lippincott Williams & Wilkins
The severity of rotavirus infection is age dependent. Although the disease can occur at any age, the disease most commonly causes clinically significant disease in young infants and
children.14,15 The first infection after 3 months of age is generally
the most significant, with severe, dehydrating rotaviral gastroenteritis primarily occurring among infants and children aged 3
to 35 months.1,2 The reasons for the reduced severity of disease
in neonates are not completely understood, but because the
onset of rotavirus disease corresponds with the decline of
maternal antibody levels, early protection may be related to
transplacental antibodies that persist for the first months of
life.14,15
Transmission of rotavirus is primarily via fecal-to-oral
spread, both through close person-to-person contact and contact
with contaminated environmental surfaces.2,16 The virus is also
probably transmitted via fecally contaminated food and water
and/or respiratory droplets.2,16 Once established within the small
intestine, the virus replicates in the villous epithelium, resulting in
decreased intestinal absorption of sodium, glucose, and water, and
decreased levels of intestinal lactase, alkaline phosphatase, and
sucrase activity that may result in isotonic diarrhea.2
Rotavirus outbreaks exhibit a seasonal pattern. In temperate
climates, rotavirus infections peak in winter months.1,2,17 In 1
study,18 the proportion of patients hospitalized with gastroenteritis
who had confirmed rotavirus infection ranged from 25% during the
off season to more than 70% during peak season. In the United
States, annual epidemics begin in the Southwest during November
and December, progressing north and east and reaching the Northeast by April or May.14 A similar pattern has been identified in
Europe, with the seasonal peak beginning in Spain in January,
spreading to northern countries by March.14 Seasonality is less
marked closer to the equator but the disease is more pronounced
during drier and cooler months. The reason for this seasonality
remains unknown.14,15 Recent data from the Centers for Disease
Control and Prevention suggest that the seasonality of rotavirus
could be changed by the introduction of rotavirus vaccines.
According to a recent interim report rotavirus activity in the
2007 to 2008 season began in February, 3 months later than the
previous 15 years.19
Rotavirus is characterized by substantial genetic diversity,
as evidenced by the presence of multiple serotypes. The most
common circulating strains associated with rotaviral gastroenteritis
worldwide are serotype G1 through G4 and G9. These strains are
responsible for 95% of pediatric rotavirus diarrhea worldwide.2 G1
is particularly prevalent in North America, Australia, and Europe
(70% of infections) but less so in South America, Asia, and Africa
(20%–30%).20,21 In addition, G9 has emerged in recent years as an
important strain, with the highest rates in South America and
Australia.20 Other serotypes continue to emerge including G5, G8,
and G12 strains.20
COURSE OF THE DISEASE
After an incubation period of 1 to 3 days, the illness can
begin abruptly with a variable presentation.1 The clinical features
of rotavirus illness are nonspecific and similar to those caused by
other gastrointestinal pathogens, although they tend to be more
severe.2 Fever, diarrhea, and vomiting are the most common
symptoms, which can occur either alone or in combination.18 In a
study of children admitted with diarrhea, vomiting, and unexplained fever, the most common presentation was diarrhea, vomiting, and fever in combination (63%) (Fig. 3).18 Ninety-seven
percent presented with diarrhea and/or vomiting and 91% had
diarrhea (with or without vomiting and/or fever).18
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The Pediatric Infectious Disease Journal • Volume 28, Number 3, March 2009
Bernstein
TREATMENT
Treatment of rotavirus is supportive and primarily aimed at
the replacement of fluid and electrolyte losses.14 Rehydration can
be accomplished using the World Health Organization formulation
or any of a number of commercial formulations.22,24 Studies have
shown that these formulations are effective for children who are
mildly to moderately dehydrated.22,24 Intravenous fluids should be
used for those with severe diarrhea, intractable vomiting, altered
consciousness, or if the child cannot or will not drink.22 Nutritional
therapy is also important and can reduce the morbidity and mortality of rotaviral gastroenteritis.22 Early initiation of refeeding is
important because oral rehydration therapy is low in calories.22
There are no antiviral agents available for the treatment of rotavirus infection.
PREVENTION
FIGURE 3. Rotavirus detection in hospitalized children
according to presenting symptoms.18
The severity of symptoms is variable with the spectrum of
illness, ranging from mild, watery diarrhea of limited duration to
severe diarrhea with vomiting and fever.2 Clinical presentation can
vary by age group. In general, the first infection after 3 months of
age is the most severe.2 Infants may be asymptomatic or only have
mild symptoms with a lower likelihood of diarrhea and vomiting
compared with other children.10,22 However, infants can experience a wide range of symptoms, including frank necrotizing
enterocolitis.22 Indeed, it has been proposed that 30% to 40% of
cases of necrotizing enterocolitis may be related to rotavirus
infection.22 Adults with rotavirus infection are usually asymptomatic or have mild disease—presumably because of protection from
previous infections—although 3% to 5% of admissions for gastroenteritis in adults are due to rotavirus.22,23
Rotaviral gastroenteritis is more severe than other causes of
gastroenteritis and more often results in dehydration, hospitalization, and if not treated, shock, electrolyte imbalance, and death.
Temperature of ⬎102°F can occur in up to a third of patients.
Gastrointestinal symptoms typically resolve within 3 to 7 days.1
DIAGNOSIS
Rotavirus cannot be diagnosed solely on clinical grounds;
however, findings suggestive of rotavirus infection include a
mildly febrile illness accompanied by vomiting and watery diarrhea.14 Although there are differences between rotaviral gastroenteritis and other forms of acute gastroenteritis, it is not possible to
distinguish rotavirus-induced disease solely on clinical presentation.22 Nevertheless, fever, acid-reducing substance-positive stool,
and low serum bicarbonate are more likely in rotaviral gastroenteritis, whereas the presence of gross bloody diarrhea is more
common in acute gastroenteritis caused by other organisms.22
Disease occurrence during peak rotavirus season in temperate
climates in appropriate age groups can also suggest the presence of
rotavirus.
Although laboratory testing is generally not performed, it is
the only way to confirm the diagnosis.14 The most widely available
methods for disease confirmation are enzyme immunoassay (eg,
Rotaclone) and latex agglutination.2,22 These tests are easy to
perform, provide rapid results, and are highly sensitive (70%–
98%) and specific (71%–100%).1,14,22 Other techniques include
electron microscopy, culture, and polymerase chain reaction.1,2
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The goal of rotavirus vaccine development is to duplicate
the protection produced by natural infection.15 At present, 2
vaccines are licensed for use in the United States: RotaTeq and
Rotarix. These vaccines use somewhat different principles to
achieve immunity against a broad range of diverse strains of
rotavirus.15,16 RotaTeq, approved in February 2006 by the US
Food and Drug Administration, is a live, oral vaccine that contains
a combination of 5 human/bovine reassortant rotaviruses that
replicate poorly in the gut.2,15,16 Three doses at 2, 4, and 6 months
of age are recommended. In contrast, Rotarix is a live-attenuated
human rotavirus vaccine prepared from a single human strain
(P1A关8兴G1) that replicates well in the gut.2,15,16 Two doses,
administered at 2 and 4 months are recommended.
In clinical trials, the 3-dose regimen of RotaTeq was associated with 74% efficacy against rotaviral gastroenteritis of any
severity and 98% efficacy against severe disease.1 RotaTeq was
associated with substantial reductions in office visits (86%), emergency department visits (94%), and hospitalizations (96%).15
Similarly, in a clinical study conducted in Europe, the
2-dose regimen of Rotarix was associated with 79% efficacy
against rotavirus of any severity and 96% efficacy against severe
disease in the first season. Efficacy was sustained through 2
rotavirus seasons. Rotarix reduced hospitalizations for rotaviral
gastroenteritis by 100% and medically attended visits by 92% in
the first rotavirus season, and reduced hospitalizations by 96%
through 2 seasons.25
It seems that vaccination against rotavirus disease may
already have had an effect on disease rates. An interim report on
the 2007 to 2008 rotavirus season in the United States, when only
RotaTeq was available, suggests that rotavirus vaccination may
have contributed to a decreased magnitude of rotavirus activity
during this season.19 Reductions were greater than expected based
on the protective effects of the vaccine alone, suggesting that a
herd effect may also be contributing to these reduced rates.19
SUMMARY AND CONCLUSIONS
Rotaviral gastroenteritis is associated with a substantial
clinical and economic burden in both developed and developing
countries. The disease burden is particularly considerable in infants and young children, producing infections that range from
mild diarrhea to severe diarrhea, vomiting, and fever that result in
hospitalization and death. The prevalence of the disease may be
under-reported because laboratory confirmation is not typically
performed. Because there are currently no specific treatments for
rotaviral infection, vaccination is the primary public health intervention for rotavirus infection. At present, approved vaccines
(RotaTeq and Rotarix) produce effective protection against disease
(particularly severe disease), and decrease emergency room visits
© 2009 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 28, Number 3, March 2009
Rotavirus Overview
and hospitalizations. Rotaviral vaccination is included in the routine vaccination schedule of all infants in the United States.
13. Hsu VP, Staat MA, Roberts N, et al. Use of active surveillance to validate
international classification of diseases code estimates of rotavirus hospitalizations in children. Pediatrics. 2005;115:78 – 82.
REFERENCES
14. Bernstein DI, Ward RL. Rotaviruses. In: Feigin RD, Cherry JD, eds.
Textbook of Pediatric Infectious Diseases. 5th ed. Vol 2. Philadelphia, PA:
Saunders; 2004:2110 –2133.
1. Centers for Disease Control and Prevention. Prevention of rotavirus
gastroenteritis among infants and children. Recommendations of the
Advisory Committee on Immunization Practices (ACIP). MMWR. 2006;
55(RR-12):1–16.
2. Centers for Disease Control and Prevention. Epidemiology and Prevention
of Vaccine-Preventable Diseases. Atkinson W, Hamborsky J, McIntyre L,
et al, eds. 10th ed. Washington, DC: Public Health Foundation; 2007:295–
306.
3. Coffin SE, Elser J, Marchant C, et al. Impact of acute rotavirus gastroenteritis on pediatric outpatient practices in the United States. Pediatr Infect
Dis J. 2006;25:584 –589.
4. Kapikian AZ. Viral gastroenteritis. JAMA. 1993;269:627– 629.
5. Glass RI. New hope for defeating rotavirus. Sci Am. 2006;294:46 –51,
54 –55.
6. Malek MA, Curns AT, Holman RC, et al. Diarrhea- and rotavirus-associated hospitalizations among children less than 5 years of age: United States,
1997 and 2000. Pediatrics. 2006;117:1887–1892.
7. Dennehy PH, Cortese MM, Bégué RE, et al. A case-control study to
determine risk factors for hospitalization for rotavirus gastroenteritis in U.S.
children. Pediatr Infect Dis J. 2006;25:1123–1131.
8. Avendaño P, Matson DO, Long J, et al. Costs associated with office visits
for diarrhea in infants and toddlers. Pediatr Infect Dis J. 1993;12:897–902.
9. Zimmerman CM, Bresee JS, Parashar UD, et al. Cost of diarrhea-associated
hospitalizations and outpatient visits in an insured population of young
children in the United States. Pediatr Infect Dis J. 2001;20:14 –19.
10. Chang HG, Glass RI, Smith PF, et al. Disease burden and risk factors for
hospitalizations associated with rotavirus infection among children in New
York State, 1989 through 2000. Pediatr Infect Dis J. 2003;22:808 – 814.
11. Lee BP, Azimi PH, Staat MA, et al. Nonmedical costs associated with rotavirus
disease requiring hospitalization. Pediatr Infect Dis J. 2005;24:984–988.
12. Fischer TK, Viboud C, Parashar U, et al. Hospitalizations and deaths from
diarrhea and rotavirus among children ⬍5 years of age in the United States,
1993–2003. J Infect Dis. 2007;195:1117–1125.
© 2009 Lippincott Williams & Wilkins
15. Dennehy PH. Rotavirus vaccines: an overview. Clin Microbiol Rev. 2008;
21:198 –208.
16. Glass RI, Parashar UD, Bresee JS, et al. Rotavirus vaccines: current
prospects and future challenges. Lancet. 2006;368:323–332.
17. Parashar UD, Holman RC, Clarke MJ, et al. Hospitalizations associated
with rotavirus diarrhea in the United States, 1993 through 1995: surveillance based on the new ICD-9-CM rotavirus-specific diagnostic code.
J Infect Dis. 1998;177:13–17.
18. Staat MA, Azimi PH, Berke T, et al. Clinical presentations of rotavirus
infection among hospitalized children. Pediatr Infect Dis J. 2002;21:221–
227.
19. Centers for Disease Control and Prevention. Delayed onset and diminished
magnitude of rotavirus activity—United States, November 2007–May
2008. MMWR. 2008;57:1– 4.
20. Santos N, Hosino Y. Global distribution of rotavirus serotypes/genotypes
and its implication for the development and implementation of an effective
rotavirus vaccine. Rev Med Virol. 2005;15:29 –56.
21. Griffin DD, Kirkwood CD, Parashar UD, et al. Surveillance of rotavirus
strains in the United States: identification of unusual strains. The National
Rotavirus Strain Surveillance System collaborating laboratories. J Clin
Microbiol. 2000;38:2784 –2787.
22. Bass ES, Pappano DA, Humiston SG. Rotavirus. Pediatr Rev. 2007;28:
183–191.
23. Anderson EJ, Weber SG. Rotavirus infection in adults. Lancet Infect Dis.
2004;4:91–99.
24. World Health Organization. Oral rehydration salts (ORS): a new reduced
osmolarity formulation. Available at: http://www.who.int/child-adolescenthealth/New_Publications/NEWS/Statement.htm. Accessed May 24, 2006.
25. Rotarix (live, attenuated human rotavirus 关HRV兴 vaccine, oral) Prescribing
Information. Research Triangle Park, NC: GlaxoSmithKline; 2008.
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