Risk of Rotavirus Nosocomial Spread After Inpatient Pentavalent Rotavirus Vaccination
BACKGROUND: Infants born prematurely or with underlying conditions are at increased risk of severe rotavirus disease and associated complications. Given the theoretical risk of nosocomial transmission of vaccine-type rotavirus, rotavirus vaccination is recommended for infants at or after discharge from neonatal care settings. Because the first dose should be administered by 104 days of age, some infants may be age-ineligible for vaccination if delayed until discharge.
METHODS: This prospective cohort included infants admitted to an urban academic medical center between birth and 104 days who received care in intensive care settings. Pentavalent human-bovine reassortant rotavirus vaccine (RV5) was used, per routine clinical care. Stool specimens were collected weekly (February 2013–April 2014) and analyzed for rotavirus strains using real-time reverse transcription–polymerase chain reaction. Demographic and vaccine data were collected. RV5 safety was not assessed.
RESULTS: Of 385 study infants, 127 were age-eligible for routine vaccinations during hospitalization. At discharge, 32.7% were up-to-date for rotavirus vaccination, compared with 82.7% for other vaccinations. Of rotavirus-unvaccinated infants, 42.6% were discharged at age >104 days and thus vaccination-ineligible. Of 1192 stool specimens collected, rotavirus was detected in 13 (1.1%): 1 wild-type strain from an unvaccinated infant; 12 vaccine-type strains from 9 RV5-vaccinated infants. No vaccine-type rotavirus cases were observed among unvaccinated infants (incidence rate: 0.0 [95% confidence interval: 0.0–1.5] cases per 1000 patient days at risk).
CONCLUSIONS: These data suggest that delaying rotavirus vaccination until discharge from the hospital could lead to missed vaccination opportunities and may be unnecessary in institutions using RV5 with comparable infection control standards.
- ACIP —
- Advisory Committee on Immunization Practices
- CDC —
- Centers for Disease Control and Prevention
- DTaP —
- diphtheria-tetanus-acellular pertussis
- Hib —
- Haemophilus influenzae type b
- IPV —
- inactivated poliovirus vaccine
- IQR —
- interquartile range
- RT-PCR —
- reverse transcription–polymerase chain reaction
- RV5 —
- pentavalent human-bovine reassortant rotavirus vaccine
What’s Known on This Subject:
Rotavirus vaccination is considered generally safe for infants born prematurely or with underlying conditions. It is recommended at or after discharge from neonatal care units, given the potential spread of vaccine-type rotavirus, despite the lack of data demonstrating hospital transmission.
What This Study Adds:
Many hospitalized infants did not receive rotavirus vaccination before discharge and were no longer age-eligible for vaccination after discharge from the hospital. Although vaccine-type rotavirus shedding occurred in patients who received the pentavalent rotavirus vaccine, no vaccine-type rotavirus was detected in any unvaccinated infant.
Infants born prematurely, with low birth weight, or with other high-risk medical conditions are at increased risk of severe rotavirus disease that may necessitate hospitalization.1–3 Data reveal that rotavirus vaccine is well tolerated in these infants.4–8 Thus, the US Advisory Committee on Immunization Practices (ACIP) recommends rotavirus vaccination of clinically stable preterm infants without contraindications who fulfill chronological age requirements (ie, 42–104 days of age for dose 1). ACIP specifies that administration should occur at or after discharge from the NICU or nursery because of a theoretical risk of shedding and transmission to vulnerable infants or infants who are age-ineligible for vaccination.9–11 The authors of a previous study found that 63% of very low birth weight infants failed to receive rotavirus vaccine at the time of NICU discharge, often because they exceeded the upper age limit for vaccine receipt.12
Data describing vaccine-type rotavirus shedding and transmission in the NICU are scarce. In a recent study, researchers were unable to detect any rotavirus infections among unvaccinated infants who neighbored vaccinated infants in the NICU; <1% had nonspecific gastrointestinal symptoms or fever that were attributed to concomitant medical conditions.5 Because of the serious consequences of rotavirus infection in high-risk infants,1–3 understanding shedding and the nosocomial spread of vaccine-type rotavirus in a large sample of hospitalized infants is important. Greater knowledge of other gastrointestinal pathogens shed in this population, which may cause symptoms similar to those associated with rotavirus, may also be valuable in the diagnosis and management of these high-risk patients.
This study evaluated infection, vaccination, and the potential nosocomial spread of wild-type and vaccine-type rotavirus strains among hospitalized infants in a regional tertiary care children’s hospital. Pentavalent human-bovine reassortant rotavirus vaccine (RV5) was administered under a standard hospital-wide protocol during this period.
Study Design, Setting, and Population
We conducted prospective surveillance, funded by the Centers for Disease Control and Prevention (CDC), between February 2013 and April 2014 at an urban academic pediatric hospital. This hospital is the main regional referral center for pediatric care, including care of infants born prematurely and/or with major congenital anomalies at other institutions. All infants in the cardiac or pediatric ICU, half of those in the NICU, and three-quarters of those in non-ICU settings have single-room assignments; the remaining infants have double-room assignments. All are screened for vaccination status as part of routine clinical care. During the study period, the hospital policy was to administer RV5 (RotaTeq; Merck, Kenilworth Station, NJ), irrespective of hospital setting (ICU or non-ICU), to infants without a history of intussusception, without moderate-to-severe acute illnesses, on no more than a maintenance dose of steroids, and not otherwise immunocompromised. An additional institution-specific criterion of ≥37 weeks postmenstrual age was used to indicate clinical stability for simplified vaccine decision-making. Minimum and maximum ages for vaccine administration and dosing intervals followed ACIP recommendations. During the study period, population-based surveillance for rotavirus disease was also conducted in this hospital.13,14
Infants were eligible for inclusion if they were admitted to the study hospital between 0 and 104 postnatal days of life and had received care in an ICU setting, including the NICU, cardiac ICU, or pediatric ICU. Infants who were wards of the state, were transferred from another institution at or after 60 postnatal days of life, or required extracorporeal membrane oxygenation at the time of eligibility assessment were excluded. A waiver of consent was obtained. The study was approved by the Seattle Children’s Hospital and CDC institutional review boards.
Research staff reviewed ICU census lists twice weekly to identify potentially eligible subjects. Those who fulfilled eligibility criteria and had a stool specimen available for collection were enrolled. Participants were observed throughout their hospitalization, including after transfer to a non-ICU setting, or until 245 days of age for those with prolonged hospitalization. Demographic (age, sex, race, ethnicity, insurance status), visit (admission and discharge dates), and vaccine (types, administration dates) information were obtained from the electronic health records by using a standardized abstraction form. Clinical data were not abstracted; thus, RV5 safety was not assessed. Nonclinical surveillance stool specimens were collected during a fixed 24-hour period each week. Specimens were sent to the CDC for rotavirus laboratory confirmation and genotypic analyses by using qualitative real-time reverse transcription–polymerase chain reaction (RT-PCR) and RT-PCR assays, as described previously.15–17 Four samples yielded an invalid qualitative real-time RT-PCR result (internal process control was not detected). These samples were subsequently tested and determined to be negative for rotavirus by using an enzyme immunoassay (Premier Rotaclone Rotavirus Detection Kit; Meridian Diagnostics, Cincinnati, OH). A subset of systematically sampled stool specimens (median: 9 specimens per observation month) was also analyzed for other gastrointestinal pathogens (Campylobacter, Clostridium difficile toxin A/B, Escherichia coli O157, enterotoxigenic E coli, Shiga-like toxin-producing E coli, Salmonella, Shigella, Vibrio cholerae, Yersinia enterocolitica, adenovirus 40/41, norovirus GI/GII, Cryptosporidium, Entamoeba histolytica, and Giardia) by using the xTAG Gastrointestinal Pathogen Panel (Luminex, Austin, TX).
The primary outcome was a stool specimen positive for rotavirus. Secondary outcomes included rotavirus genotype, potential exposure to vaccine-type rotavirus, the presence of other gastrointestinal pathogens, and up-to-date vaccination status at the time of hospital discharge. Potential exposure was defined as a temporal overlap between hospitalization of an unvaccinated infant and the 14-day postvaccination interval of a vaccinated infant who shed vaccine-type rotavirus (interval onset: day of RV5 administration [day 0]6; interval offset: postvaccination day 14 or discharge date, whichever occurred first). One vaccinated infant was discharged to an outside facility on postvaccination day 5 and readmitted on postvaccination day 6; the entire 14-day interval was included. Geotemporal proximity was defined as concurrent hospitalization in the same hospital area (eg, closely located rooms with similar nursing assignments) within the 14-day postvaccination interval. Up-to-date vaccination at hospital discharge was defined as receipt of 1, 2, or 3 doses of recommended vaccines (diphtheria-tetanus-acellular pertussis [DTaP] vaccine, Haemophilus influenzae type b [Hib] vaccine, inactivated poliovirus vaccine [IPV], pneumococcal conjugate vaccine, hepatitis B vaccine, and RV5) among those hospitalized beyond 3, 5, or 7 months of age (ie, 1-month grace period), respectively.18 To minimize missing vaccine information, up-to-date vaccination was calculated only among infants admitted at <2 days of age for hepatitis B vaccine and at <42 days of age for all other vaccines.
The associations between demographic or visit characteristics and up-to-date vaccination status were assessed by using χ2 and Fisher’s exact tests. Patient days of potential exposure to vaccine-type rotavirus were calculated among unvaccinated infants with ≥1 stool specimen collected during a potential exposure interval, excluding the first 2 days after hospital admission (to limit detection of community-acquired rotavirus infection) and any days preceding the first specimen collection. A sensitivity analysis included only days of specimen collection. Geotemporal proximity was assessed among infants with stool specimens positive for rotavirus. To generate a 95% confidence interval for the incidence rate of vaccine-type rotavirus detections among unvaccinated infants, we assumed that observed cases followed a Poisson distribution. Analyses were performed by using SAS version 9.4 (SAS Institute, Inc, Cary, NC).
Screening was performed for 838 hospitalizations of 775 unique infants. Of these, 248 hospitalizations (29.6%) were ineligible because the infant was a ward of the state (n = 8), was admitted at an age >104 days (n = 191), was transferred at an age ≥60 days (n = 47), or required extracorporeal membrane oxygenation (n = 9) (>1 reason, n = 7). For another 200 hospitalizations (23.9%), the infant did not produce a stool specimen within the observation period. The remaining 390 hospitalizations (46.5%) of 385 unique infants (49.7%) were included (Table 1, Fig 1). Infants were primarily male, non-Hispanic, white, and publicly insured. Most (93.1%) were hospitalized ≥7 days (median hospitalization: 27 days). The infants were typically enrolled on day 8 of hospitalization, at 16 days of age, and were observed for 14 days (median values). No infant was hospitalized for rotavirus gastroenteritis. There were 16 deaths during the study period (all RV5-unvaccinated patients; none had stool specimens positive for rotavirus).
Of the 385 study infants, 127 (33.0%) were age-eligible for routine vaccinations during their hospitalization. At hospital discharge, the proportion of infants who were up-to-date was high for DTaP vaccine (86.5%, n = 45/52), Hib vaccine (86.5%, n = 45/52), IPV vaccine (84.6%, n = 44/52), pneumococcal conjugate vaccine (84.6%, n = 44/52), and hepatitis B vaccine (82.1%, n = 23/28), but not for rotavirus vaccine (32.7%, n = 17/52). In total, 47 RV5 doses were administered (19 in ICU settings, 28 in non-ICU settings); 33 infants received dose 1 (median age: 78 days; interquartile range [IQR]: 29 days), 10 of the 33 received dose 2 (median age: 131 days; IQR: 11 days), and 4 of the 10 received dose 3 (median age: 188 days; IQR: 28 days). Three infants initiated rotavirus vaccination after 104 days of age, contrary to ACIP and hospital recommendations. Sex, race, ethnicity, insurance, and hospitalization duration were not associated with up-to-date rotavirus vaccination at discharge. Of eligible infants who did not receive their first rotavirus vaccine dose during hospitalization (n = 61), 26 (42.6%) were discharged after 104 days of age and were no longer vaccine-eligible.
Rotavirus Shedding and Nosocomial Spread
Two-thirds (67.2%) of infants eligible for stool specimen collection in a given week had a specimen collected, resulting in 1192 stool specimens (Figs 1 and 2). Overall, 57% had >1 specimen collected (mean: 3.1; range: 1–24). Unvaccinated infants provided 976 specimens. Vaccinated infants provided 216 specimens, 75 of which were collected postvaccination (52 within 28 days after vaccination; Fig 3). Fourteen vaccinated infants had >1 postvaccination specimen (8 had between 2–4 consecutive postvaccination specimens); the mean number of postvaccination specimens (total and consecutive) did not differ between those who did and did not shed vaccine-type virus.
Of the 1192 specimens, 13 (1.1%) were positive for rotavirus and 1179 (98.9%) were negative for rotavirus. Of the specimens positive for rotavirus, 1 specimen was genotyped as wild-type and 12 specimens were vaccine-type. The single wild-type genotype, G3P, was observed in an unvaccinated infant (64 days of age) in April 2014, a time when rotavirus infection with a similar strain was observed in surrounding clinical settings through active surveillance (data not shown). The 12 vaccine-type specimens from 9 RV5-vaccinated infants included G4P, G6P, and 10 unspecified strains (no reassortants identified). They typically occurred after dose 1 and within 7 days after vaccination (Fig 3). One infant had 4 specimens positive for rotavirus: day 12 after dose 1, day 2 after dose 2, and days 6 and 27 after dose 3; specimens negative for the virus were collected on day 19 after dose 1; days 9 and 30 after dose 2; and days 13, 48, 55, and 62 after dose 3. The 24 RV5-vaccinated infants without detectable vaccine-type rotavirus shedding had 43 specimens collected postvaccination and were observed for a median of 12 days after the last dose (range: 1–117 days).
We observed no vaccine-type rotavirus strains in any unvaccinated study infant. Of the 357 hospitalizations of unvaccinated infants, 301 overlapped temporally with a 14-day postvaccination interval of an RV5-vaccinated infant, 202 occurred during a potential exposure interval, and 155 had specimens collected from an unvaccinated infant during a potential exposure interval (45.2% with >1 specimen; range: 1–7 specimens; 275 total specimens). The latter resulted in 1952 patient days of potential exposure. Given that no vaccine-type rotavirus cases were observed among these unvaccinated infants, the incidence rate (95% confidence interval) was 0.0 (0.0–1.5) cases per 1000 patient days at risk (0.0 [0–10.9] when using only days of specimen collection). There was no geotemporal proximity between the unvaccinated infant who shed wild-type virus and the RV5-vaccinated infants who shed vaccine-type rotavirus strains.
Other Gastrointestinal Pathogens
In total, 299 (25.1%) stool specimens were tested for other gastrointestinal pathogens. One specimen (0.3%) had a positive result (C difficile, toxin B positive). No other results were positive.
In this prospective weekly surveillance of high-risk, medically complex infants during hospitalization, no transmission of vaccine-type rotavirus from an RV5-vaccinated to unvaccinated infant was detected, including in those with geotemporal overlap. Vaccine-type rotavirus strains were detected only among infants who had received RV5 vaccination.
As in earlier studies examining rotavirus vaccination in preterm and other high-risk infants,5–8 our data suggest that delaying rotavirus vaccination until hospital discharge may be unnecessary in institutions with comparable infection control standards. Our observed incidence rate empirically supports this assessment, although it does not preclude the possibility of transmission.
Fewer than half of infants receiving routine childhood immunizations also received rotavirus vaccine before discharge, illustrating the extent of missed opportunities for rotavirus vaccination among infants at high risk for severe rotavirus infection. Only one-third of vaccine-eligible infants received rotavirus vaccine before discharge. This finding is striking, given that the study took place in a hospital with a permissive policy toward rotavirus vaccination and in which vaccination is strongly supported, which is demonstrated by the high proportion of infants who were up-to-date for other routine vaccines at discharge. Another institution reported up-to-date levels for DTaP (58%), Hib (58%), IPV (58%), and hepatitis B (62%) vaccines at NICU discharge19 that were lower than observed here, even without the 1-month grace period (data not shown). It is noteworthy that nearly half of infants unvaccinated against rotavirus in our study were no longer eligible for vaccination after hospital discharge. These data are similar to those reported in a 2013 cohort, in which only 37% of very low birth weight infants were vaccinated against rotavirus before NICU discharge and in which 36% of unvaccinated infants were age-ineligible at discharge.12 Data describing rotavirus vaccination rates in high-risk infants after hospital discharge are limited, although these rates likely fall below Healthy People 2020 target levels (80%)20 given the lower vaccination rates for rotavirus than for other routine vaccines in general.21,22
Nine RV5-vaccinated infants in our study had ≥1 stool specimen positive for vaccine-type rotavirus strains after rotavirus vaccination. Some shedding of vaccine-type virus after RV5 vaccination is expected.23–26 In a previous study of 15 preterm infants with 6 stool specimens collected during the 2 weeks after vaccination, 87% of infants shed a vaccine-type strain, and 77% of specimens were positive for a vaccine-type strain.6 In another study of infants with intestinal failure who had stool specimens collected at 1, 2, and 4 weeks postvaccination, 47% shed rotavirus.8 In the current study, most vaccine-type rotavirus shedding occurred within 1 week after vaccination, which is consistent with data in the general infant population, in whom peak shedding occurs at 4 to 7 days after dose 1 and at 1 to 3 days after doses 2 and 3.26
Although vaccine-type rotavirus shedding did occur, no vaccine-type strains were detected in stool specimens collected during the 155 hospitalizations of unvaccinated infants with potential exposure. This could be due, in part, to the small number of RV5-vaccinated infants with shedding during hospitalization. It could also reflect reduced exposure due to hospital infection control measures. The findings are consistent with those of studies in which only 10 of 801 “neighboring” unvaccinated infants in the NICU had gastrointestinal symptoms or fever postvaccination5 and no household contacts (n = 53) of infants vaccinated at NICU discharge developed symptoms suggestive of rotavirus infection.6
During this 14-month study, 1 wild-type rotavirus specimen was detected, which was collected from an unvaccinated infant. This finding is consistent with the findings of another study in which nosocomial cases of rotavirus gastroenteritis in the NICU were rare (ie, 4.9 per 10 000 patient days in the prevaccination period at 1 hospital).7 Similarly, 1 of 299 specimens tested for other common gastrointestinal pathogens was positive. This reveals surprisingly low rates of colonization with other viral pathogens and C difficile in this hospital. Limited data describing gastrointestinal shedding, regardless of symptoms, among hospitalized infants are available. One study from Australia found that 6% of stool specimens from preterm infants were colonized with viruses.27 Our data, obtained by using sensitive molecular techniques with prospective surveillance, indicate that common gastrointestinal pathogens in infants may not be frequent in ICUs today.
This study has several limitations. First, approval from institutional review boards to passively enroll infants in this study facilitated stool specimen collection but limited our ability to acquire and review additional data (ie, assigned medical providers; clinical status of RV5-vaccinated infants or infants with rotavirus-positive specimens). Second, we likely underestimated the shedding rate in this study because specimens were collected on a weekly basis during hospitalization, and shedding can be intermittent.6,8 However, the authors of other studies have shown shedding of >1 week’s duration.24–26 The use of sensitive molecular laboratory methods potentially increased viral detection overall, and shedding in sequential stool specimens from RV5-vaccinated patients was detected. Only 1 study infant had intermittent RV5 shedding documented. Third, this study was not designed to include all hospitalized infants, and we therefore could not determine actual exposure in all unvaccinated infants and may have also underestimated RV5 transmission. Our ability to detect transmission in this study depended on the observation of vaccine-type rotavirus strains in unvaccinated patients within the time period when vaccine-type rotavirus strains were most likely to be shed.24–26 It is worth noting that polymerase chain reaction detection of vaccine-type rotavirus among RV5-vaccinated infants does not necessarily mean that there is enough viable virus to transmit to unvaccinated infants, as suggested by comparatively lower rates of culture positivity.6,25 Fourth, this study included a diverse population of high-risk hospitalized infants in ICU and non-ICU settings, all with single and double-room assignments, at 1 academic medical center. This could impact generalizability to other populations and settings. Because all vaccinated infants received RV5, the findings also should not be generalized to the monovalent human rotavirus vaccine. Evidence suggests that the monovalent human rotavirus vaccine has a comparable shedding rate, but a significantly higher viral load, than RV5.26 Lastly, vaccines administered before or after hospitalization and reasons for missed vaccination opportunities were not captured.
The timing of rotavirus vaccination is somewhat controversial worldwide. Recognizing the programmatic challenges and potential risk/benefit ratio in certain developing countries, the World Health Organization expanded the acceptable maximum age of rotavirus vaccination to 24 months.28 Although this recommendation has been poorly adopted worldwide, many preterm and high-risk infants may be potentially eligible for rotavirus vaccination after hospital discharge. Given available data,5,7 however, RV5 vaccination during hospitalization could still be considered for optimal protection of these vulnerable infants.
Since the introduction of rotavirus vaccines, the disease burden and cost of rotavirus gastroenteritis has decreased substantially.29 Our study found that two-thirds of eligible high-risk infants failed to receive rotavirus vaccine during their hospitalization, and nearly half (43%) were no longer age-eligible for vaccination after hospital discharge. No vaccine-type rotavirus transmission to unvaccinated study infants in this hospital environment was observed, despite documented shedding of vaccine-type rotavirus strains in RV5-vaccinated infants. Delaying rotavirus vaccination until the time of hospital discharge may be unnecessary in institutions where RV5 is used and with comparable infection control standards. Such delays may leave medically-vulnerable infants unprotected and susceptible to severe rotavirus infection and associated complications.
We thank the nurses and medical staff at Seattle Children’s Hospital who facilitated stool specimen collection, as well as our research staff who participated in the conduct of this study, especially Diane Kinnunen, Catherine Bull, and Kristin Follmer. In addition, we thank Anne Cent and staff in the University of Washington Clinical Virology Laboratory. All individuals listed here have provided written permission to be acknowledged.
- Accepted September 20, 2017.
- Address correspondence to Annika M. Hofstetter, MD, PhD, MPH, Department of Pediatrics, University of Washington, 1900 Ninth Ave, M/S JMB-9, Seattle, WA 98101. E-mail:
The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
FINANCIAL DISCLOSURE: Other than those listed in the Conflict of Interest, the authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Supported by the New Vaccine Surveillance Network of the Centers for Disease Control and Prevention (U01IP000457).
POTENTIAL CONFLICT OF INTEREST: Dr Hofstetter previously received research support from Pfizer Independent Grants for Learning and Change. Dr Englund receives research support from Pfizer, Gilead, and GlaxoSmithKline. Dr Englund was a consultant for Pfizer and Gilead and served on a data safety monitoring board for GlaxoSmithKline; the other authors have indicated they have no potential conflicts of interest to disclose.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2017-3499.
- Cortese MM,
- Parashar UD; Centers for Disease Control and Prevention
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- Tam KI,
- Kerin TK, et al
- US Department of Health and Human Services
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- Tate JE,
- Steiner CA,
- Curns AT,
- Lopman BA,
- Parashar UD
- Copyright © 2018 by the American Academy of Pediatrics