Epidemiology: Rotavirus is the most common cause of severe diarrhea in children in the United States. Virtually all children have one or more rotavirus infections in the first 5 years of life. Each year in the United States, rotavirus is responsible for more than 3 million episodes of diarrhea, 500,000 physician visits, 50,000 hospitalizations and 20-40 deaths(1,2,3,4). Children between the ages of 3 and 24 months have the greatest rates of severe disease and infection. It is also a major cause of morbidity and mortality worldwide (more than 125 million cases of diarrhea annually in children <5 years of age with approximately 800,000 deaths per year)(5,6). In addition, rotavirus accounts for an estimated $264 million in health care costs and approximately $1 billion in total medical and non-medical costs in the U.S. annually(14).
Etiology: Rotavirus disease is caused by the group A rotaviruses which are wheel-shaped RNA viruses. Human strains occur worldwide and there are known animal strains but animal-to-human transmission has not been documented. Rotavirus is present in high concentrations in stools of infected children two days before to 10 days after onset of symptoms. It may persist on fomites thus making it an important pathogen in settings such as day care centers. It is transmitted through the fecal-oral route but person-to-person transmission has been reported.
Since 1991, rotavirus activity in the United States has been prospectively monitored by the National Respiratory and Enteric Virus Surveillance System. The report from 1997-1998 showed seasonal peaks similar to those seen in the past 5 years with increases in rotavirus detection throughout the United States varying with geographic location. Activity peaked first in the Southwest during November-December 1997 and last in the North and Northeast during April-May. The only variation from the previous 5 years was a late-season peak reported in the Western United States(15). This trend in temperate climates is unlike that found in tropical countries where the seasonal patterns are less pronounced.
Clinical Manifestations: Rotavirus infection most commonly causes diarrhea usually preceded by emesis and low grade fever, but in some cases, it may cause severe dehydration with electrolyte imbalance and acidosis leading to neurologic signs and sometimes even death, mostly in premature infants. In immunocompromised children, including those infected with HIV, rotavirus disease can cause persistent infection with multisystem involvement particularly hepatic and renal.
Diagnosis: The most common way to detect rotavirus is with "rotazyme" which is an enzyme immunoassay (EIA) but it can also be detected by latex agglutination assays for group A rotavirus antigen. Both are performed on stool samples and are commercially available. Both are useful in detecting rotavirus antigen during the diarrhea phase, however EIA is more sensitive late in the illness course. Both assays have high specificity but may have some false positive results in neonates and those patients with other underlying conditions. Direct viral identification in stools can be performed in some research labs.
Treatment: The treatment of rotavirus is mostly supportive and consists of correction of dehydration and any electrolyte imbalance.
Rotavirus vaccine: "Rotashield"
The vaccine was FDA approved for use in the U.S. on August 31, 1998. It is a live attenuated orally administered vaccine. It is tetravalent, that is, containing four strains, three of which have genes from human rotavirus serotypes (G1, G2 and G4) and one with genes from rhesus rotavirus serotype (G3) which is antigenically similar to human G3.
In most trials the vaccine was administered orally in the first 6 months of life in three doses separated at least by 3 weeks. Each dose is 2.5 ml corresponding to approximately 1x105 plaque forming unit (PFU) of each of the four strains. Because the vaccine strains were acid labile, they were administered with 2.5 ml of citrate-bicarbonate buffer to neutralize stomach acidity.
Immunogenicity & Efficacy
More than 88% of children respond to the three doses of the vaccine as indicated by a fourfold or more increase in serum IgA titers as compared to 4% to 29% of the placebo group, the latter indicating the rate of natural infection.
Seven large studies have been completed using the rotavirus vaccine, four with the 4x105 PFU dose and three with the lower dose of 4x104 PFU. The first 4 studies yielded similar results with the vaccine demonstrating significant protection against any rotavirus diarrhea in 49% - 68% and even greater protection against severe rotavirus diarrhea 61%-91% and 50%-100% efficacy in preventing doctor visits for diarrhea (6,8,9,10,11,12).
The efficacy of the vaccine in developing countries has been variable, but in a recent trial involving more than 2,200 underprivileged urban children in Venezuela, vaccine efficacy approached levels seen in industrialized countries (9). This large study is the first to clearly show the potential usefulness of the rotavirus vaccine in developing countries, where they are most needed. Duration of protection is not really known, but seems to wane with age.
Adverse Effects:
The major side effects reported were increased temp > 38oC (occurring in 7-29% of immunized children versus 4-7% in the placebo group), increased temp >39oC, decreased appetite, irritability and decreased activity in the first 3-5 days after the first dose. Also increases in temp > 38oC occurred after the 2nd dose.
In the studies of rotavirus vaccine with almost 10,000 children, 5 cases of intussusception occurred after receiving the vaccine on day 6-51 after doses 2 or 3. One case occurred in the placebo group. However, this was neither significant nor exceeded the expected rate in the community (12). Of 23 premature infants < 35 weeks gestation who received the vaccine, one developed fever of 38.6oC and 2 developed diarrhea (12).
Serious adverse events to rotavirus vaccine should be described in the patient's medical record and reported to the vaccine adverse events reporting system by calling 800-822-7967 or via the world wide web at http://www.cdc.gov/nip/vaers.htm.
Cost Effectiveness:
A model proposed by Tucker and Associates(14) demonstrated cost effectiveness of rotavirus vaccine administration when compared with the expenses of hospitalization, physician visits and lost work days, however, this type of analysis would yield varying results depending on the actual immunization, health care and societal costs.
AAP Recommendations:
The following summarizes the most recent AAP recommendations on the administration of rotavirus vaccine as presented in the December 1998 issue of Pediatrics:
1. Based on safety and efficacy data, rotavirus vaccine is recommended for use in infants at 2, 4, and 6 months of age for prevention of rotavirus disease; routine implementation of this recommendation will require reconciliation of related economic issues.
2. The first dose of rotavirus vaccine may be given to infants as early as 6 weeks of age. For children in whom initiation of vaccine has been delayed, the first dose may be given as late as 6 months of age. Each subsequent dose should be given at an interval of at least 3 weeks. Special efforts should be made to immunize infants before the anticipated annual onset of rotavirus disease activity in their local communities.
3. Increased rates of fever have been reported in vaccine recipients after the first and second doses, but fevers generally are mild and last less than 24 hours. Initiation of immunization after 6 months of age is not recommended because of the age-related occurrence of fever after receipt of the first dose of vaccine. All three doses of vaccine should be administered during the first 12 months of age because data regarding the safety and efficacy of vaccine administration to older children are not available.
4. The rotavirus vaccine can be administered at the same time as DtaP, Hib, hepatitis B, or IPV/OPV vaccines as recommended in the routine immunization schedule. Modification of timing of administration of rotavirus vaccine is not necessary after administration of antibody-containing blood products, including blood, plasma, and immune globulin.
5. To ensure maximum immunity, the recommended three-dose rotavirus immunization schedule should be completed even if a child has had a documented episode of wild-type rotavirus gastroenteritis.
6. Contraindications to rotavirus vaccine include the following:
Infants with hypersensitivity to aminoglycoside antibiotics, amphotericin B or monosodium glutamate that are components of the vaccine, should not receive this vaccine. In addition, rotavirus vaccine should not be administered to persons who have experienced an anaphylactic reaction to a previous dose of rotavirus vaccine.
Infants with moderate or severe febrile illness should not receive the rotavirus vaccine during the illness, but should be immunized as soon as they have recovered from the acute phase of their illness. The rotavirus vaccine, like other vaccines, can be given to infants with a low-grade fever.
Until further data are available, children who are known or suspected to be immunosuppressed or immunodeficient should not receive this live-attenuated virus vaccine. The vaccine should not be administered to infants born to women known to be HIV-infected until tests for HIV infection in the infant are negative at 2 months or older by PCR or culture. Infants living in household with persons known or suspected to be immunocompromised should be immunized.
7. Breastfeeding is not a contraindication to administration of rotavirus vaccine(13).
8. This rotavirus vaccine is not recommended for children with acute vomiting or diarrhea because vaccine efficacy in these circumstances has not been established. Consideration should be given to immunizing children with chronic gastrointestinal tract disease until further data are available to make definitive recommendations for this group.
9. Although data are limited, premature infants may receive rotavirus vaccine at or after discharge from the hospital nursery if they have achieved a chronologic age of at least 6 weeks.
10. If a child is hospitalized after administration of rotavirus vaccine, he/she can be managed by standard precautions and does not need to be placed in contact precautions unless diarrhea, vomiting, or both occur. Children may attend their child care facilities after administration of rotavirus vaccine.
Rotavirus Vaccine
References
1.Jin S, Kilgore PE, Holman RC, et al, Trends in hospitalizations for diarrhea in United States Children from 1979 through 1992: Estimates of the morbidity associated with rotavirus. Pediatr Infect Dis J 1986;15:397-404
2. Parashar UD, Holman RC, Clarke MJ, Bresee JS, Glass RI. 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;177:13-19
3. Matson DO, Estes MK. Impact of rotavirus at a large pediatric hospital. J Infect Dis. 1990;162:598-604
4. Kilgore PE, Holman RC, Clarke MJ, Glass RI. Trends of diarrheal disease-associated mortality in US children, 1968 through 1991. JAMA 1995;274:1143-1148
5. Bern C, Martinez J, deZoysa I, Glass RI. The magnitude of the global problem of diarrheal disease: a ten year update. Bull WHO 1992;70:705-714
6. Umesh D Parashar, Joseph S Bresee, Jon R Gentsh & Roger I. Glass. CDC, Rotavirus Synopses
7. Bernstein DI, Glass RI, Rodgers G, Davidson BL, Sack DA. US Rotavirus vaccine efficacy group. Evaluation of rhesus rotavirus monovalent and tetravalent reassortment vaccines in US children. JAMA 1995;273:1191-1196
8. Joensuu J, Koskenniemi E, Pang XL, Vesikari T. Randomized placebo-controlled trial of rhesus human reassortment rotavirus vaccine for prevention of sever rotavirus gastroenteritis. Lancet. 1997;350:1205-1209
9. Perez-Schael I, Guntinas MJ, Perez M, Pagone V, Rojas AM, Gonzalez R, et al. Efficacy of the rhesus rotavirus-based quadrivalent vaccine in infants and young children in Venezuela. N Engl J Med. 1997;337:1181-7
10. Rennels MB, Glass RI, Dennehy PH, Bernstein DI, Pichichero ME, Zito PT, et al. Safety and efficacy of high-dose rhesus-human reassortment rotavirus vaccines-report of the national multicenter trial. Pediatrics. 1996;97:7-13
11. Sautosham M, Moulton LH, Reid R, Croll J, Weatherholt R, Ward R, et al. Efficacy and safety of high-dose rhesus-human reassortment rotavirus vaccine in Native American populations. J. Pediatr. 1997;131:632-8
12. American Academy of Pediatrics, Committee on Infectious Diseases. Prevention of rotavirus disease: guidelines for use of rotavirus vaccine. Pediatrics. 1998; 102:1483-91
13. Rennels MB, Wasserman SS, Glass RI, Keane VA, US rotavirus vaccine efficacy group. Comparison of immunogenicity and efficacy of rhesus rotavirus reassortment vaccine in breastfed and nonbreastfed children. Pediatrics. 1995; 96:1132-1136
14. Tucker AW, Bresee JS, Haddix AC, Holman RC, Glass RI. Cost-effectiveness analysis of a rotavirus vaccine program in the United States. JAMA. 1998; 279:1371-1376
15. MMWR Vol 47/No. 45:978-980.
Enteroviral disease continued to effect CNY children through October with four children admitted with rule out sepsis/meningitis. Recent identification of our enterovirus subtypes revealed equal distribution of coxsackie B2, B5 and echoviruses. A few CNY children were admitted with fever and their viral cultures yielded rhinovirus.
November was an active month for both adenovirus and parainfluenza. Many infants and toddlers admitted with fever, pneumonia and rule out sepsis had positive cultures for these viruses.
You know it's winter when RSV strikes. Our first positive RSV culture was identified on 12/2/98 from a 2 month old admitted with rule out sepsis and bronchiolitis. This was the latest initial occurrence of RSV in several years.
Influenza activity has not been reported in CNY, although influenza A (H3N2) has been documented in other areas of New York State. Influenza B has also been reported in NYS with no local outbreaks as yet.
We are participating in two Influenza clinical research studies. One is for children over age 10 through adulthood, admitted to the hospital with influenza pneumonia. The other is for children, ages 1-12 years with fever and respiratory symptoms, randomized to receive either a new oral neuraminidase inhibitor or placebo x 5 days. If you have potential candidates for either of these studies, please let us know.
Beginning this month, the Pediatric Infectious Disease Newsletter is available via the Department of Pediatrics' Web Page, online at www.hscsyr.edu/peds/. If this is more convenient for you, please let us know so we can remove your name from our mailing list.
We would like to acknowledge the Pediatric Society of Onondaga County for their contribution in support of this newsletter
