Rotavirus Overview

SUPPLEMENT

Rotavirus Overview

David I. Bernstein, MD, MA

mately 70% during seasonal peaks of the disease.1 Figure 14 Abstract: Rotaviral gastroenteritis is a serious public health problem in illustrates the very large importance of rotavirus as an etiologic both developed and developing countries. The disease is ubiquitous, agent in severe diarrhea requiring hospitalization compared with affecting nearly all children by the age of 5 years. It is the most common other pathogens in both developing and developed countries.4 cause of hospitalizations for gastroenteritis among children in the United Several epidemiologic and clinical characteristics associ- States (30%–70% depending on the season) and is associated with direct ated with rotavirus argue for use of vaccination as the primary and indirect costs of approximately $1 billion per year. Symptoms of public health intervention for rotavirus.1 This includes the obser- rotaviral gastroenteritis are nonspecific (ie, diarrhea, vomiting, and fever), vations that the rates of rotavirus illness are similar in developed with disease severity varying considerably. Diagnostic confirmation of and less-developed countries, indicating that improved sanitation rotaviral gastroenteritis requires laboratory tests (most commonly enzyme will not decrease disease prevalence and the continued high rates immunoassay or latex agglutination); however, because specific diagnosis of hospitalization despite the widespread availability and use of is costly and does not affect treatment, laboratory tests are generally not oral rehydration solutions.1 In addition, natural history studies performed. Because no antiviral therapies are currently available, treatment suggest that mild, asymptomatic infection effectively protects of rotavirus infection is supportive and primarily aimed at the replacement against subsequent severe rotavirus gastroenteritis. Thus, the de- of fluid and electrolyte losses. Based on the observations that improved velopment of a vaccine that mimics a mild asymptomatic infection sanitation does not decrease disease prevalence and that hospitalizations has the potential to prevent the morbidity and mortality associated remain high despite the availability and use of oral rehydrating solutions, with severe rotavirus disease.1 the primary public health intervention for rotavirus infection is vaccination. Current vaccines (ie, RotaTeq, Merck and Company; Rotarix, GlaxoSmith- Kline) are effective for reducing rotaviral gastroenteritis (particularly DISEASE BURDEN severe disease), emergency department visits, and hospitalizations. Rota- Rotavirus gastroenteritis inflicts a devastating impact on virus vaccination is now included as part of the routine vaccination infants and young children, particularly in developing countries. It schedule for all infants in the United States. is estimated that the disease is associated with the deaths of more Key Words: rotavirus, gastroenteritis, rotavirus vaccine, diagnosis, than 600,000 children per year worldwide, with the majority of 5 treatment, epidemiology deaths occurring in Africa and Asia. Yearly death tolls are high in India (146,000), Nigeria (47,500), China (41,000), Pakistan (Pediatr Infect Dis J 2009;28: S50–S53) (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 otavirus is the most common cause of severe diarrhea in infants burden. It is estimated that rotavirus gastroenteritis is associated Rand young children in both the United States and around the with 410,000 physician visits, 205,000 to 272,000 emergency 1 world. Rotavirus infection is nearly universal, with approximately department visits, and 55,000 to 70,000 hospitalizations each year 95% of children experiencing rotavirus gastroenteritis by age 5 1 2 in the United States. Thus, between 1 in 67 and 1 in 85 children years. There is no difference in the incidence of rotavirus infec- in the United States will be hospitalized with rotavirus by the age tion between developed and developing countries, indicating that of 5 years.6 Risk factors for rotavirus-induced hospitalization improved sanitation does not decrease the transmissibility of the 2 include no breastfeeding, low birth weight, being in child care, no virus. In the United States, rotavirus is responsible for 5% to 10% insurance or having Medicaid, and the presence of another child of cases of gastroenteritis among children Ͻ5 years of age, but it Ͻ 7 2 24 months in the house. is responsible for a much higher proportion of severe episodes. The direct and indirect costs associated with the disease are Compared with other causes of gastroenteritis, rotavirus is more estimated to be approximately $1 billion in the United States.1,2 A frequently associated with severe symptoms (eg, fever, vomiting, 3 study in 1993 calculated that the average total cost per episode of combined diarrhea/vomiting). Rotaviral gastroenteritis has been diarrhea presenting to a primary care physician was $289, with time shown to cause approximately 40% of all outpatient visits for acute missed from work by the parent/caretaker responsible for half of the gastroenteritis in infants and young children to pediatric primary 8 3 total cost (Fig. 2). The majority of parents missed at least 1 day of care practices. Furthermore, between 30% and 50% of all hospi- work (average 1.3 days).8 As expected, costs are much higher when Ͻ talizations for gastroenteritis among US children aged 5 years hospitalization is required. A study analyzing medical claims between are due to rotavirus infection. This value increases to approxi- 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 From the Cincinnati Children’s Hospital Medical Center; University of Cincin- charges per hospitalization of $2999 to $3399.6,10 Notably, because nati, Cincinnati, OH. Disclosure: Dr. Bernstein receives royalties for his work in the development of these analyses included only charges for medical services, these Rotarix and the patent for 89-12. He is also a consultant for GlaxoSmithKline. values did not include indirect costs (eg, lost time from work). Address for correspondence: David I. Bernstein, MD, MA, Cincinnati Chil- One large prospective study11 examined these indirect costs dren’s Hospital Medical Center; University of Cincinnati, 3333 Burnet between November 1997 and December 1999 at 3 pediatric med- Avenue, Cincinnati, OH 45229. E-mail: [email protected]. Copyright © 2009 by Lippincott Williams & Wilkins ical centers. The average nonmedical cost per case of severe ISSN: 0891-3668/09/2803-0050 rotavirus disease that required hospitalization was approximately DOI: 10.1097/INF.0b013e3181967bee $450–80% of which ($359) was attributed to missed work and

S50 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 The severity of rotavirus infection is age dependent. Al- though 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 FIGURE 1. Role of etiologic agents in the pathogenesis of maternal antibody levels, early protection may be related to severe diarrheal illness requiring hospitalization in devel- transplacental antibodies that persist for the first months of 14,15 oped and developing countries. Reproduced with permis- life. sion from JAMA. 1993;269:627–629. Copyright 1993, Transmission of rotavirus is primarily via fecal-to-oral American Medical Association.4 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 North- east 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 FIGURE 2. Cost of a rotavirus episode by category.8 ORS could be changed by the introduction of rotavirus vaccines. indicates oral rehydration therapy. 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, more than half of which (53%) occurred before or after hospital- as evidenced by the presence of multiple serotypes. The most ization. The remaining costs included approximately $57 for trans- common circulating strains associated with rotaviral gastroenteritis portation, $10 for diapers, $7 for child care changes, and $17 for worldwide are serotype G1 through G4 and G9. These strains are 2 special foods, oral rehydration solutions, and formula changes. In responsible for 95% of pediatric rotavirus diarrhea worldwide. G1 the current economic climate, these costs would obviously be is particularly prevalent in North America, Australia, and Europe (70% of infections) but less so in South America, Asia, and Africa much higher. 20,21 Further, the prevalence of rotavirus disease may be under- (20%–30%). In addition, G9 has emerged in recent years as an important strain, with the highest rates in South America and reported. Current estimates of disease activity are based on sur- 20 2 Australia. Other serotypes continue to emerge including G5, G8, veys, cohort studies, and hospital discharge data. However, only 20 a small proportion of diarrhea-related hospitalizations that are and G12 strains. caused by rotavirus are correctly classified as rotavirus specific.12,13 It has been estimated that only 47% of hospital discharge COURSE OF THE DISEASE records were correctly coded as rotavirus infections. Further- After an incubation period of 1 to 3 days, the illness can more, the sensitivity decreased to 25% when detection rates begin abruptly with a variable presentation.1 The clinical features from active surveillance were extrapolated to the number of of rotavirus illness are nonspecific and similar to those caused by acute gastroenteritis hospitalizations.12 A major reason for other gastrointestinal pathogens, although they tend to be more underreporting is that laboratory identification of the pathogen severe.2 Fever, diarrhea, and vomiting are the most common increases costs but does not affect treatment.13 Furthermore, symptoms, which can occur either alone or in combination.18 In a there are no specific guidelines for the diagnostic testing of study of children admitted with diarrhea, vomiting, and unex- rotavirus.12 In addition, there is substantial variation between plained fever, the most common presentation was diarrhea, vom- institutions in testing and coding practices for rotavirus-specific iting, and fever in combination (63%) (Fig. 3).18 Ninety-seven disease.6 Therefore, many cases of rotavirus may be attributed percent presented with diarrhea and/or vomiting and 91% had to unspecified viral gastroenteritis. diarrhea (with or without vomiting and/or fever).18

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 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 FIGURE 3. Rotavirus detection in hospitalized children 18 Rotarix. These vaccines use somewhat different principles to according to presenting symptoms. 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 The severity of symptoms is variable with the spectrum of a combination of 5 human/bovine reassortant rotaviruses that illness, ranging from mild, watery diarrhea of limited duration to replicate poorly in the gut.2,15,16 Three doses at 2, 4, and 6 months severe diarrhea with vomiting and fever.2 Clinical presentation can of age are recommended. In contrast, Rotarix is a live-attenuated vary by age group. In general, the first infection after 3 months of human rotavirus vaccine prepared from a single human strain age is the most severe.2 Infants may be asymptomatic or only have (P1A͓8͔G1) that replicates well in the gut.2,15,16 Two doses, mild symptoms with a lower likelihood of diarrhea and vomiting administered at 2 and 4 months are recommended. compared with other children.10,22 However, infants can experi- In clinical trials, the 3-dose regimen of RotaTeq was asso- ence a wide range of symptoms, including frank necrotizing ciated with 74% efficacy against rotaviral gastroenteritis of any enterocolitis.22 Indeed, it has been proposed that 30% to 40% of severity and 98% efficacy against severe disease.1 RotaTeq was cases of necrotizing enterocolitis may be related to rotavirus associated with substantial reductions in office visits (86%), emer- infection.22 Adults with rotavirus infection are usually asymptom- gency department visits (94%), and hospitalizations (96%).15 atic or have mild disease—presumably because of protection from Similarly, in a clinical study conducted in Europe, the previous infections—although 3% to 5% of admissions for gastro- 2-dose regimen of Rotarix was associated with 79% efficacy enteritis in adults are due to rotavirus.22,23 against rotavirus of any severity and 96% efficacy against severe Rotaviral gastroenteritis is more severe than other causes of disease in the first season. Efficacy was sustained through 2 gastroenteritis and more often results in dehydration, hospitaliza- rotavirus seasons. Rotarix reduced hospitalizations for rotaviral tion, and if not treated, shock, electrolyte imbalance, and death. gastroenteritis by 100% and medically attended visits by 92% in Temperature of Ͼ102°F can occur in up to a third of patients. the first rotavirus season, and reduced hospitalizations by 96% Gastrointestinal symptoms typically resolve within 3 to 7 days.1 through 2 seasons.25 It seems that vaccination against rotavirus disease may DIAGNOSIS already have had an effect on disease rates. An interim report on Rotavirus cannot be diagnosed solely on clinical grounds; the 2007 to 2008 rotavirus season in the United States, when only however, findings suggestive of rotavirus infection include a RotaTeq was available, suggests that rotavirus vaccination may have contributed to a decreased magnitude of rotavirus activity mildly febrile illness accompanied by vomiting and watery diar- 19 rhea.14 Although there are differences between rotaviral gastroen- during this season. Reductions were greater than expected based on the protective effects of the vaccine alone, suggesting that a teritis and other forms of acute gastroenteritis, it is not possible to 19 distinguish rotavirus-induced disease solely on clinical presenta- herd effect may also be contributing to these reduced rates. tion.22 Nevertheless, fever, acid-reducing substance-positive stool, and low serum bicarbonate are more likely in rotaviral gastroen- SUMMARY AND CONCLUSIONS teritis, whereas the presence of gross bloody diarrhea is more Rotaviral gastroenteritis is associated with a substantial common in acute gastroenteritis caused by other organisms.22 clinical and economic burden in both developed and developing Disease occurrence during peak rotavirus season in temperate countries. The disease burden is particularly considerable in in- climates in appropriate age groups can also suggest the presence of fants and young children, producing infections that range from rotavirus. mild diarrhea to severe diarrhea, vomiting, and fever that result in Although laboratory testing is generally not performed, it is hospitalization and death. The prevalence of the disease may be the only way to confirm the diagnosis.14 The most widely available under-reported because laboratory confirmation is not typically methods for disease confirmation are enzyme immunoassay (eg, performed. Because there are currently no specific treatments for Rotaclone) and latex agglutination.2,22 These tests are easy to rotaviral infection, vaccination is the primary public health inter- perform, provide rapid results, and are highly sensitive (70%– vention for rotavirus infection. At present, approved vaccines 98%) and specific (71%–100%).1,14,22 Other techniques include (RotaTeq and Rotarix) produce effective protection against disease electron microscopy, culture, and polymerase chain reaction.1,2 (particularly severe disease), and decrease emergency room visits

and hospitalizations. Rotaviral vaccination is included in the rou- 13. Hsu VP, Staat MA, Roberts N, et al. Use of active surveillance to validate tine vaccination schedule of all infants in the United States. 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. 1. Centers for Disease Control and Prevention. Prevention of rotavirus Textbook of Pediatric Infectious Diseases. 5th ed. Vol 2. Philadelphia, PA: gastroenteritis among infants and children. Recommendations of the Saunders; 2004:2110–2133. Advisory Committee on Immunization Practices (ACIP). MMWR. 2006; 15. Dennehy PH. Rotavirus vaccines: an overview. Clin Microbiol Rev. 2008; 55(RR-12):1–16. 21:198–208. 2. Centers for Disease Control and Prevention. Epidemiology and Prevention 16. Glass RI, Parashar UD, Bresee JS, et al. Rotavirus vaccines: current of Vaccine-Preventable Diseases. Atkinson W, Hamborsky J, McIntyre L, prospects and future challenges. Lancet. 2006;368:323–332. et al, eds. 10th ed. Washington, DC: Public Health Foundation; 2007:295– 306. 17. Parashar UD, Holman RC, Clarke MJ, et al. Hospitalizations associated with rotavirus diarrhea in the United States, 1993 through 1995: surveil- 3. Coffin SE, Elser J, Marchant C, et al. Impact of acute rotavirus gastroen- lance based on the new ICD-9-CM rotavirus-specific diagnostic code. teritis on pediatric outpatient practices in the United States. Pediatr Infect J Infect Dis. 1998;177:13–17. Dis J. 2006;25:584–589. 4. Kapikian AZ. Viral gastroenteritis. JAMA. 1993;269:627–629. 18. Staat MA, Azimi PH, Berke T, et al. Clinical presentations of rotavirus infection among hospitalized children. Pediatr Infect Dis J. 2002;21:221– 5. Glass RI. New hope for defeating rotavirus. Sci Am. 2006;294:46–51, 227. 54–55. 19. Centers for Disease Control and Prevention. Delayed onset and diminished 6. Malek MA, Curns AT, Holman RC, et al. Diarrhea- and rotavirus-associ- magnitude of rotavirus activity—United States, November 2007–May ated hospitalizations among children less than 5 years of age: United States, 2008. MMWR. 2008;57:1–4. 1997 and 2000. Pediatrics. 2006;117:1887–1892. 20. Santos N, Hosino Y. Global distribution of rotavirus serotypes/genotypes 7. Dennehy PH, Cortese MM, Be´gue´ RE, et al. A case-control study to and its implication for the development and implementation of an effective determine risk factors for hospitalization for rotavirus gastroenteritis in U.S. rotavirus vaccine. Rev Med Virol. 2005;15:29–56. children. Pediatr Infect Dis J. 2006;25:1123–1131. 8. Avendanõ P, Matson DO, Long J, et al. Costs associated with office visits 21. Griffin DD, Kirkwood CD, Parashar UD, et al. Surveillance of rotavirus for diarrhea in infants and toddlers. Pediatr Infect Dis J. 1993;12:897–902. strains in the United States: identification of unusual strains. The National Rotavirus Strain Surveillance System collaborating laboratories. J Clin 9. Zimmerman CM, Bresee JS, Parashar UD, et al. Cost of diarrhea-associated Microbiol. 2000;38:2784–2787. hospitalizations and outpatient visits in an insured population of young children in the United States. Pediatr Infect Dis J. 2001;20:14–19. 22. Bass ES, Pappano DA, Humiston SG. Rotavirus. Pediatr Rev. 2007;28: 183–191. 10. Chang HG, Glass RI, Smith PF, et al. Disease burden and risk factors for hospitalizations associated with rotavirus infection among children in New 23. Anderson EJ, Weber SG. Rotavirus infection in adults. Lancet Infect Dis. York State, 1989 through 2000. Pediatr Infect Dis J. 2003;22:808–814. 2004;4:91–99. 11. Lee BP, Azimi PH, Staat MA, et al. Nonmedical costs associated with rotavirus 24. World Health Organization. Oral rehydration salts (ORS): a new reduced disease requiring hospitalization. Pediatr Infect Dis J. 2005;24:984–988. osmolarity formulation. Available at: http://www.who.int/child-adolescent- 12. Fischer TK, Viboud C, Parashar U, et al. Hospitalizations and deaths from health/New_Publications/NEWS/Statement.htm. Accessed May 24, 2006. diarrhea and rotavirus among children Ͻ5 years of age in the United States, 25. Rotarix (live, attenuated human rotavirus ͓HRV͔ vaccine, oral) Prescribing 1993–2003. J Infect Dis. 2007;195:1117–1125. Information. Research Triangle Park, NC: GlaxoSmithKline; 2008.