Barn med tarmsvikt och rotavirusvaccin

Fråga: Vi fungerar som tertiärt centrum för barn med tarmsvikt av olika anledningar, vanligast orsak till tarmsvikt är kort tarmsyndrom som vanligen debuterar i nyföddhetsperioden, antingen på grund av medfödda missbildningar (tunntarmsatresi, gastroschisis, hirschsprung, mm) eller efter tarmresektion vid NEC (nekrotiserande enterocolit) eller volvulus orsakad av malrotation.

En obesvarad fråga är om dessa barn får vaccineras mot rotavirusinfektion. Det är i sig angeläget eftersom de löper ökad risk för allvarlig komplikation av viral gastroenterit, dock står det som kontraindikation i FASS.

Vi ber om er hjälp med att reda ut om det går att finna stöd i litteraturen för att ge barnen med tarmsvikt av ovan orsaker rotavirusvaccin.

Svar: SAMMANFATTNING

The current published data to assess the safety and efficacy of rotavirus vaccine for infants with pre-existing gastrointestinal conditions such as intestinal failure secondary to short bowel syndrom are very scarce. Clinical trials of rotavirus vaccine have not investigated the possibility of using the vaccines in infants with underlying conditions.

The Advisory Committee on Immunization Practices (ACIP) from the Centers for Disease Control and Prevention (CDC), USA, and the Australian Technical Advisory Group on Immunisation (ATAGI) recommends that pre-existing chronic gastrointestinal disease (e.g., short-gut syndrome, Hirschsprung's disease, or congenital malabsorption syndromes), who are not undergoing immunosuppressive therapy is not a contraindication to rotavirus vaccination. Because of the greater risk of serious rotavirus disease, ACIP and ATAGI consider the benefits from vaccination are expected to outweigh the risk in these infants. The exceptions are conditions that may predispose to intussusception (ATAGI). This is largely in agreement with the current contraindication in the Swedish product information, stating “Individer med obehandlad medfödd missbildning av gastrointestinalkanalen som kan vara predisponerade för intussusception.”

SVAR

The pathophysiology inherent to intestinal failure may complicate the safety and immunogenicity of an oral vaccine. Children with intestinal failure are prone to have a decreased small bowel absorptive capacity, intense alterations in gut motility, and frequent episodes of bacterial overgrowth (1). The gut-associated lymphatic tissue in children with intestinal failure may be disordered from resection or anatomic variation.

The Advisory Committee on Immunization Practices (ACIP) from the Centers for Disease Control and Prevention (CDC), USA, 2009 (2), and the Australian Technical Advisory Group on Immunisation (ATAGI) (3) recommends that pre-existing chronic gastrointestinal disease, (e.g., congenital malabsorption syndromes, Hirschsprung's disease, or short-gut syndrome) who are not undergoing immunosuppressive therapy is not a contraindication to rotavirus vaccination. Because of the greater risk of serious rotavirus disease, ACIP and ATAGI consider the benefits from vaccination are expected to outweigh the risk in these infants. The exceptions are conditions that may predispose to intussusception (ATAGI). However, the recommendation is listed as a precaution because of the lack of information regarding safety and efficacy of rotavirus vaccine for infants with preexisting chronic gastrointestinal conditions. The ATAGI refers to the safety data from Fang AY et al 2012 (8). The recommendation from ACIP and ATAGI is largely in agreement with the current contraindication in the Swedish product information, stating “Individer med obehandlad medfödd missbildning av gastrointestinalkanalen som kan vara predisponerade för intussusception.” (5)

The European Society for Paediatric Infectious Diseases consensus recommendations made no specific recommendation for rotavirus vaccination of infants with underlying conditions of pre-existing chronic gastrointestinal disease because of insufficient evidence at present (4).

The rotavirus vaccines are available in two forms; pentavalent (RV5; RotaTeq); the vaccination course consists of three doses, and monovalent (RV1; Rotarix); the vaccination course consists of two doses, and are administered orally to infants starting at 6 weeks of age (5).

The most commonly reported adverse reactions that occurred in healthy infants more frequently with vaccine than with placebo were fever (RotaTeq: 20.9 %), diarrhoea (17.6 %, Rotrix: common (=1/100 till <1/10)) and vomiting (10.1 %) (5, 6). The American SPC for RotaTeq vaccine (7) and the ACIP (2) reported higher incidences; fever (RotaTeq 42%, Rotarix 39,8%), diarrhea (RotaTeq 24%, Rotarix 6,8%) and vomiting of (RotaTeq 15%, Rotarix 17,6%). Irritability was reported as common for Rotarix (5) as 62% (2).

In a double-blind, placebo-controlled, randomized, multinational trial which inrolled 34,837 vaccine recipients and 34,788 placebo recipients, cases of intussusception occurring within 42 days of any dose, were 6 cases among RotaTeq recipients and 5 cases among placeborecipients (7). However, data from observational safety studies performed in several countries indicate that rotavirus vaccines carry an increased risk of intussusception, with up to 6 additional cases per 100,000 infants within 7 days of vaccination in countries with a background incidence of 25–101 per 100,000 infants per year (6).

Clinical trials of rotavirus vaccine have been performed in healthy infants and have not investigated the possibility of using the vaccines in infants with underlying conditions of, malformations of the gastrointestinal tract, those having undergone abdominal surgery, chronic diseases or those with food intolerance. Theoretically, there may be an increased risk of diarrhoea, vomiting and intussusception associated with live-attenuated oral rotavirus vaccination in this population.

The current published data to assess the safety and efficacy of rotavirus vaccine for infants with pre-existing gastrointestinal conditions such as intestinal failure secondary to short bowel syndrome are very scarce (8-11).

The first clinical report, case series, of rotavirus vaccination in infants with non-Hirschsprung’s disease-related functional short gut syndrome (8) found that the rotavirus vaccination was well tolerated in most, but not all vaccinated infants. The study aimed to describe the short-term effects of rotavirus vaccination (RotaTeq) on weight gain and gastrointestinal losses in infants with functional short gut syndrome secondary to anileostomy. A retrospective review of 9 infants (7 with necrotising enterocolitis (NEC); 1 with meconium ileus(MI); 1 with malrotation (MR) + microcolon (MC), age 61–99 days) with an ileostomy that caused short gut syndrome who received RotaTeq was performed in Australia. Daily data included type and volume of feeds, ileostomy losses, need for fluid replacement of ileostomy losses, weight, temperature, urine sodium, stool culture, suspected and confirmed sepsis were collected from 1 week before to 2 weeks after vaccination. In this case series, ileostomy losses were highly variable throughout the study period and did not appear to be associated with vaccination in most infants according to the judgement of the investigators. One infant developed severe stomal losses after vaccination. Overall, rotavirus vaccination did not alter weight gain, temperature or urinary sodium. The authors suggest that infants with functional short gut syndrome should be closely monitored for early signs of malabsorption.

In a prospective, open-label, case-controlled clinical trial of eight infants (5 with surgical gastrointestinal disease matched by gestational age and chronological age to 3 control) (9,), the outcome evaluated was the safety and immunogenicity of the pentavalent rotavirus vaccine RotaTeq. The surgical indications for the patients were gastroschisis with intestinal infarction, total colonic Hirschsprung disease, NEC, MI, MR + midgut volvulus. All infants were monitored for adverse events (AEs) during the first 42 days after each dose and monthly thereafter for 12 months. Serum anti-rotavirus immunoglobulin A (IgA) titers were measured pre-vaccination and 2 weeks after dose 3. All participants (100%) results showed a 3-fold increase in serum anti-rotavirus IgA geometric mean titer postvaccination. According to the authors this indicates that RotaTeq is immunogenic in infants with a history of bowel resection, despite varying lengths of residual bowel. RotaTeq administration to surgical infants was well tolerated with few vaccine-related AEs which were similar to those previously reported in healthy infants with the exception of stoma site bleeding after RotaTeq dose 1 in 2 of surgical participants. There were no instances of intussusception, and no AE was deemed life threatening. In 1 surgical infant, diarrhea symptoms increased above participant baseline: stool antigen was negative for rotavirus. The majority of AEs being attributed to the underlying medical condition.

Javid and colleagues (10) reported the results of a trial of Rotarix rotavirus vaccine in infants with intestinal failure. The authors examined the safety and immunogenicity of rotavirus vaccination in a cohort of infants 6-14 weeks of age with early intestinal failure who underwent surgery. Infants received two doses of monovalent rotavirus vaccine Rotarix, with the exception of 2 infants who completed the series with pentavalent rotavirus vaccine RotaTeq. Of 15 infants (who had undergone surgical treatment for gastroschisis, NEC, jejuno-ileal atresia, total colonic Hirschsprung’s disease, midgut volvulus, or complicated meconium peritonitis) enrolled in the study, 14 completed the vaccine series and 6-month follow-up data were available for 12. Irritability in the first 5 days after vaccination was the most common adverse event, in 9 (60%) infants. Vomiting in 6 (40%), diarrhea in 5 (33%), and diaper rash in 2 (13%) infants. None of these adverse events required alteration in a patient's feeding regimen. No case of intussusception was reported during the study period. One infant (7%) developed a fever of 38.7°C after the second dose of the vaccine. the incidence of fever in this cohort, according to the authors, was much less than expected from previously published data. Phase III trials of the currently approved vaccines have reported an incidence of postvaccine diarrhea and emesis of up to 24% and 18%, respectively (2). Results of serum anti-rotavirus IgA antibody measurement demonstrated seroconversion in 12 infants (86%) despite clear impairments in the bowel function. The remaining 2 infants had an elevated baseline IgA antibody to rotavirus prior to vaccination and did not demonstrate a 3-fold increase in antibody levels after vaccination. Overall, postvaccine stool shedding of rotavirus was seen in 7 (47%) infants, which, according to the authors, was similar to previously published data in healthy infants (50.0%-80.0% with Rotarix (2)), with 1 infant shedding virus for more than 2 weeks following vaccination. Rotavirus antigen was not detected in the serum of any subjects. The authors concluded that, in infants with intestinal failure, rotavirus vaccination appears to be safe and immunogenic.

Lopez RN (11) presented a case report of a nearly 3-month-old infant with short bowel syndrome (SBS) who developed enteritis with pneumatosis intestinalis following administration of the Rotarix vaccine. An 11-week-old boy had SBS with an ileostomy secondary to long-segment Hirschsprung’s disease. Three days following Rotarix immunisation, the patient developed increased stoma losses of >70?mL/kg/day. The increased losses persisted for 3?days and on the fifth day following Rotarix immunisation, the patient developed bloody stomal output and became lethargic. The patient had clinical and sonographic evidence consistent with necrotizing enterocolitis (NEC), with increased and bloody stomal outputs, bowel wall thickening suggestive of an inflammatory reaction as well as compromised mucosal integrity allowing entry of pathogenic organisms into the bowel wall leading to the development of pneumatosis intestinalis. The alternative diagnosis considered was Hirschsprung’s-associated enterocolitis potentially triggered by administration of rotavirus vaccine. According to the authors, direct causality as a result of rotavirus immunisation cannot be proven, although the temporal relationship with the patient’s illness, and biological plausibility, raise the possibility of a cause–effect relationship particularly as a similar event occurred neither prior to nor since the immediate aftermath of rotavirus immunisation.

1. Peterson J, Kerner JA Jr. Review New advances in the management of children with intestinal failure. JPEN J Parenter Enteral Nutr. 2012 Jan; 36(1 Suppl):36S-42S.
2. Centers for Disease Control and Prevention. Prevention of Rotavirus Gastroenteritis Among Infants and Children: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2009; 58(No. RR-2): 1-24. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5802a1.htm
3. Australian Technical Advisory Group on Immunisation (ATAGI). Australian Immunisation Handbook, Australian Government Department of Health, Canberra, 2018, immunisationhandbook.health.gov.au. https://immunisationhandbook.health.gov.au/vaccine-preventable-diseases/rotavirus
4. Vesikari T, Van Damme P, Giaquinto C, Dagan R, Guarino A, Szajewska H, Usonis V. European society for paediatric infectious diseases consensus recommendations for rotavirus vaccination in Europe: update 2014. Pediatr Infect Dis J, 34 (2015), pp. 635-643
5. Produktresuméer. www.FASS.se
6. https://www.ema.europa.eu/en/documents/product-information/rotateq-epar-product-information_en.pdf
7. https://www.merck.com/product/usa/pi_circulars/r/rotateq/rotateq_pi.pdf
8. Fang AY, Tingay DG. Early observations in the use of oral rotavirus vaccination in infants with functional short gut syndrome. J Paediatr Child Health. 2012;48(6):512-516. doi:10.1111/j.1440-1754.2011.02227.x
9. McGrath EJ, Thomas R, Duggan C, et al. . Pentavalent rotavirus vaccine in infants with surgical gastrointestinal disease. J Pediatr Gastroenterol Nutr 2014;59:44–8.
10. Javid PJ, Sanchez SE, Jacob S, McNeal MM, Horslen SP, Englund JA. The Safety and Immunogenicity of Rotavirus Vaccination in Infants With Intestinal Failure. J Pediatric Infect Dis Soc. 2014 Mar;3(1):57-65
11. Lopez RN, Krishnan U, Ooi CY.Lopez RN, et al. Enteritis with pneumatosis intestinalis following rotavirus immunisation in an infant with short bowel syndrome. BMJ Case Rep. 2017 Apr 26;2017:bcr2017219482. doi: 10.1136/bcr-2017-219482.BMJ Case Rep. 2017. PMID: 28446443.