pediatrics 2006 lynch e827 32

DOI: 10.1542/peds.2005-1556 2006;117;e827Pediatrics

Zaki and Roger I. GlassTara Jones, Baoming Jiang, Erik Hummelman, Christopher M. Zimmerman, Sherif R. Maureen Lynch, Wun-Ju Shieh, Joseph S. Bresee, Kathleen M. Tatti, Jon R. Gentsch,

Vaccine (Rotashield): The Search for a Pathogenic MechanismIntussusception After Administration of the Rhesus Tetravalent Rotavirus

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of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2006 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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ARTICLE

Intussusception After Administration of the RhesusTetravalent Rotavirus Vaccine (Rotashield): TheSearch for a Pathogenic MechanismMaureen Lynch, MD, MRCPatha, Wun-Ju Shieh, MD, PhDb, Joseph S. Bresee, MDa, Kathleen M. Tatti, PhDb, Jon R. Gentsch, PhDa,

Tara Jones, MAb, Baoming Jiang, DVM, PhDa, Erik Hummelman, MPHa, Christopher M. Zimmerman, MDa, Sherif R. Zaki, MD, PhDb,

Roger I. Glass, MD, PhDa

aViral Gastroenteritis Section, Division of Viral and Rickettsial Diseases, and bInfectious Disease Pathology Activity, National Center for Infectious Diseases, Centers forDisease Control and Prevention, Atlanta, Georgia

The authors have indicated they have no nancial relationships relevant to this article to disclose.

ABSTRACT

OBJECTIVES. The rhesus tetravalent rotavirus vaccine (RRV) was withdrawn from theroutine program for childhood immunization in the United States because of therare and unexpected occurrence of intussusception in the 2-week period afteradministration of the first dose.

METHODS. To search for the pathogenesis of this association, we compared thepathology of surgical specimens from infants who had surgical reduction of theirintussusceptions within 2 weeks of receiving the vaccine (case patients; n 8)with the pathology of specimens from children who had surgery 2 weeks afterimmunization (n 6) or who had never been immunized (n 26). Tissue wasexamined for evidence of the vaccine strain of rotavirus by reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridization, and immunohisto-chemical staining.

RESULTS.RRV was identified by RT-PCR in tissue samples from 7 of the 8 casepatients and in 2 of the 6 children who received the vaccine at a more distant time(29 and 58 days before surgery), but it was not identified in samples from any ofthe nonvaccinated children. No evidence of rotavirus tissue involvement wasdetected in any of the children by in situ hybridization or immunohistochemicalstaining. Pathologic evidence (for example, inclusion bodies, smudge cells) ofadenovirus infection was present in 35% of the 37 specimens examined by routinestaining and immunohistochemistry.

CONCLUSIONS. The fact that RRV was detected by RT-PCR but not by either of theother assays could be explained by RRV being present in the lumen of the gut butnot in the tissues of appendix, ileum, or Peyers patches. The Peyers patches werenot hyperplastic, and we could not establish the pathogenic mechanism for thisassociation.

www.pediatrics.org/cgi/doi/10.1542/peds.2005-1556

doi:10.1542/peds.2005-1556

The ndings and conclusions in this articleare those of the authors and do notnecessarily represent the views of thefunding agency.

KeyWordsrotavirus, intussusception, vaccines,adverse events

AbbreviationsRRVrhesus tetravalent rotavirusRT-PCRreverse transcriptase-polymerasechain reactionIHCimmunohistochemistryISHin situ hybridizationCDCCenters for Disease Control andPreventionH&Ehematoxylin and eosinHRVhuman rotavirus

Accepted for publication Nov 17, 2005

Address correspondence to Roger I. Glass, MD,PhD, Viral Gastroenteritis Section, MS G04,Centers for Disease Control and Prevention,1600 Clifton Rd, Atlanta, GA 30333. E-mail:[email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005;Online, 1098-4275); published in the publicdomain by the American Academy ofPediatrics

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IN AUGUST 1998, the US Food and Drug Administrationlicensed the first rotavirus vaccine, Rotashield, a live,orally administrated, tetravalent rhesus-human reassor-tant (RRV-TV) vaccine. The vaccine was subsequentlyrecommended by the Advisory Committee on Immuni-zation Practices and the American Academy of Pediatricsfor the routine immunization of children on a 2-, 4-, and6-month schedule.1,2 Between November 1998 and July1999, an estimated 600 000 children received 1 dosesof the vaccine. In July 1999, reports of intussusceptionafter administration of RRV-TV3 led to a suspension ofthe recommendation. An investigation was conducted todetermine if the vaccine was causally associated withintussusception.4 When results from a series of epidemi-ologic studies confirmed the association,59 The AdvisoryCommittee on Immunization Practices and AmericanAcademy of Pediatrics withdrew their recommendationsfor use of the vaccine in November 1999,10 and themanufacturer, Wyeth Lederle Vaccines and Pediatrics(Pearl River, NY), withdrew the vaccine from the mar-ket.

Although the statistical association between RRV andintussusception was documented in epidemiologic stud-ies, the mechanism of this relationship remains unclear.Lack of understanding of the mechanism could impededevelopment of other live oral rotavirus vaccines11,12 andraise doubts about licensed oral vaccines against typhoid,cholera, and polio.13 For instance, concerns were imme-diately raised that oral poliovirus vaccine might also beassociated with intussusception, but this was not sup-ported by an international consultation on the issue.13

The pathogenesis of intussusception is not well under-stood, but the presence of mesenteric lymphadenopathyor inflamed Peyers patches supports an infectious orinflammatory process, and viruses such as adenovirus,human herpesvirus 6 and 7, Epstein-Barr virus, cyto-megalovirus, and wild-type human rotavirus (HRV)have been implicated.14

We examined the putative role of RRV-TV as a specificetiologic agent of intussusception and wanted to examinetissue to determine if we could identify a pathologic basis forthis association. We developed assays to detect and type ro-taviruses in formalin-fixed tissues by immunohistochemistry(IHC), in situ hybridization (ISH), and reverse transcriptase-polymerase chain reaction (RT-PCR).15 Tissues from childrenwho underwent surgery for intussusception in the 2 weeksafter receipt of RRV-TV (case patients) were compared withsurgical specimens from children who had received RRV-TVat a time more distant from the intussusception and withspecimens from children who had never been vaccinatedwith RRV-TV (controls).

METHODS

Tissue SourcesWe obtained surgical specimens of intestinal or lymphnode tissues from patients with intussusception after

RRV-TV and from children with intussusception identi-fied in the multistate case-control study who did notreceive the vaccine.5 We obtained tissue from intussus-ception patients who were reported to Vaccine AdverseEvents Reporting System (11 vaccinees) and from chil-dren investigated as part of the Centers for Disease Con-trol and Prevention (CDC) case-control study (4 vacci-nees, 25 controls). The study was approved by theInstitutional Review Boards of the CDC and of 14participating states (California, Florida, Georgia, Illinois,Indiana, Minnesota, New Jersey, New York, Ohio, Penn-sylvania, South Carolina, Tennessee, Texas, and Wash-ington). For cases identified through Vaccine AdverseEvents Reporting System, the CDC used the contactinformation on the report form to contact the childsphysician or parents. The CDC then contacted the ap-propriate department of pathology to request the speci-men. Informed consent was obtained from parents orguardians of infants in the case-control study to releaseto the CDC the name of their child, to obtain all infor-mation and data collected from the original study, and tosecure tissues specimens from the pathologists involvedfor additional analysis.

Acceptable TissuesAny available surgical specimens were acceptable for thisstudy (for example, tissue from resected bowel, appen-dix, and mesenteric lymph nodes). Preferred specimenswere tissues that were formalin-fixed, paraffin-embed-ded, or fresh-frozen. Unstained slides were also acceptedfor limited examination. Tissue specimens were collectedon the basis of 2 criteria: (1) the child had a radiologi-cally or surgically confirmed case of intussusception andunderwent surgery to reduce the intussusception and(2) the child was 2 to 11 months of age at the onset ofintussusception.

Histopathologic EvaluationPathologists were blinded to the vaccination status ofinfants whose tissues were tested, and the clinical andvaccine data were combined with the pathology resultsonly after examination. Routine histopathologic evalu-ation was performed on hematoxylin and eosin (H&E)-stained slides, and specimens were tested by using 3diagnostic techniques: IHC, ISH, and RT-PCR.15 The an-tibody used in the IHC assays was a polyclonal rabbitantibody directed against HRV Wa strain, which cross-reacts with RRV. The positive controls used in the IHCassays included cells infected with HRV and RRV, respec-tively, and small intestinal tissues from experimentallyinfected piglets (provided by Linda Saif, MD, Ohio StateUniversity, Worster, OH). The negative control antibodywas preimmune serum from the same rabbit from whichthe polyclonal antibody was generated. Uninfected cellswere used as negative controls. A monoclonal antiade-novirus antibody was used in the IHC assay for adeno-

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virus.16 For ISH, the RNA probes were generated from PCRproducts amplified from the rotaviral genes encoding VP4,NSP4, and NSP1 and tailored with the T7 promoter.17 ForRT-PCR, RNAwas isolated from formalin-fixed tissue usinga commercial RNaid Plus kit (Bio101, Vista, CA) as de-scribed previously.15 RNA extracts were analyzed with a1-step procedure followed by confirmation of the PCRproducts by probe hybridization using type-specific primersand an oligonucleotide probe to detect the RRV VP4 gene.The HRV VP4 gene was detected with degenerate primerpair con1/con2 (spanning nucleotides 676887) anddigoxigenin-labeled oligonucleotide probe A VP4-c1(nucleotides 743763), which is homologous to com-mon HRV P[8] and P[4] strains (J.R.G., unpublisheddata). Negative controls included extracts from rotavi-rus-negative tissues. Positive controls were RNAs ex-tracted from Wa (P1A[8], G1) or DS-1 (P1B [4], G2)rotavirus-infected cell lysates.

RESULTS

Study PopulationInfants had to be 7 months old to receive the first doseof vaccine, and most had received only 1 dose; conse-quently, case patients (ie, those who developed intus-susception in the 2-week period after vaccination withRRV-TV) were younger than controls (P .007) anddeveloped intussusception only after the first vaccinedose (Table 1). No other significant differences werenoted between cases and controls.

Specimen EvaluationWe received tissue specimens or slides from 41 infantswith intussusception. Of these, 37 were suitable for test-ing by IHC and ISH, whereas no additional testing couldbe performed on 4 samples submitted with H&E slidesonly. Of the 37 patients with suitable specimens, 19 had

TABLE 1 Characteristics of Vaccinated and Unvaccinated Infants With Intussusception

Variable Vaccinated Infants,RRV-TV Vaccine/Intussusception Timing

Unvaccinated Infants, NoRRV-TV Vaccine (N 26)

14 d (N 9) 14 d (N 6)

Age, mean (range), mo 3.7 (27)a 5.3 (48) 6.5 (311)Gender, n (%)

Male 5 (55) 3 (50) 15 (58)Female 4 (45) 3 (50) 11 (42)

Type of health insurance, n (%)Medicaid or subsidized 1 (11) 4 (15)Private, military, self-paid 7 (77) 1 (17) 20 (77)Unknown 1 (11) 5 (83) 2 (8)

Vaccine doseFirst 9 (100) 3 (50) Second 3 (50)

Onset of symptoms to surgery,mean, d (range)

0.75 (02) 1.7 (13) 0.8 (05)

Blood in stool, n (%) 4 (44) 1 (17) 9 (35)Diagnosis, n (%)

Radiograph 2 (22) 1 (17) Ultrasound 1 (17) 2 (8)Enema 5 (56) 1 (17) 23 (88)Laparotomy 1 (17) 1 (4)Autopsy 1 (11) 2 (8)Unknown 1 (11) 2 (33)

Location, n (%)Ileocecal 6 (66) 2 (33) 19 (73)Ileoileal 1 (17) 4 (15)Unknown 3 (33) 3 (50) 3 (12)

Tissue type, n (%)Intestine 6 (66) 2 (33) 10 (38)Appendix 2 (22) 3 (50) 14 (54)Lymph node 1 (11) Unknown 1 (17) 2 (8)

Management, n (%)Medical 1 (12) 2 (33) 8 (31)Surgical reduction 4 (44) 1 (16) 10 (38)Surgical resection 4 (44) 2 (33) 12 (46)Spontaneous resolution 2 (8)

Outcome, n (%)Recovered 8 (88) 6 (100) 24 (92)Death 1 (12) 2 (8)

a Using the paired t test for cases14 days versus controls; t value 2.89, P .007.


intestinal tissue, 17 had appendices (4 with lymphnodes), and 1 had a lymph node only. Of these, 8 tissueswere obtained from case patients immunized in the 2weeks preceding the onset of intussusception, the periodof highest estimated relative risk for intussusception as-sociated with receipt of RRV-TV.5

Virus DetectionThe presence of a virus (rotavirus or adenovirus) wasdetected in 23 (62%) of 37 specimens. Adenovirus wasthe most commonly detected (13 of 37 [35%] samples),and it was associated with distinct histopathologic find-ings, including Cowdry type A inclusion bodies andsmudge cells, on H&E staining of the mucosal epithelialcells. RRV-TV was detected in 9 (36%) of 25 specimenstested, and a wild-type HRV was detected in 1 (4%) of25 specimens.

RotavirusA total of 25 specimens were tested by RT-PCR forrotavirus. Of these, 8 were from case patients vaccinatedin the 2 weeks preceding onset of intussusception, 7were from children vaccinated 2 weeks before onsetand whose intussusception was believed to be unrelatedto the vaccine, and 10 were from controls chosen fromthe entire group on the basis of the quality of the spec-imens available. Of the 25 specimens, 10 were positivefor rotavirus; a natural rotavirus strain was detected in asample from a nonvaccinated control, and RRV-TVstrains were detected in samples from 9 vaccinees. Of thelatter, 7 were detected in the 8 case patients who hadreceived the vaccine in the previous 2 weeks, and theremaining 2 were detected in children who had receivedthe vaccine 29 and 58 days before the onset of intussus-ception. For these 2 late cases, virus was present in smallquantity because specimens were positive only on probehybridization of the RT-PCR product. None of the tis-sues, including those positive for RV by RT-PCR, waspositive by ISH or IHC. By H&E staining, none of thelymph nodes or Peyers patches from infants who hadbeen recently vaccinated showed definitive evidence oflymphoid hyperplasia.

AdenovirusAdenovirus was the most common virus detected byhistopathologic evaluation and IHC testing in 13 (35%)of the 37 specimens examined (Fig 1). These specimenshad distinct histopathologic features, including smudgecells and Cowdry type A inclusion bodies. The frequencyof detection did not differ significantly between controls(9 of 22 [41%]) and vaccinees (4 of 15 [27%]).

DISCUSSIONThis study was done to gain greater understanding of thepossible role of RRV-TV in the pathogenesis of RRV-TV-associated intussusception. We identified RRV-TV RNA

by RT-PCR in tissue from 7 of 8 vaccinees who receivedRRV-TV in the 2 weeks before surgery but found noevidence of RRV in the same tissues by IHC or ISH. Thesefindings can be explained in several ways. First, thesensitivity of RT-PCR allows for detection of as few as 10viral particles,15 and in a child recently vaccinated with alive oral rotavirus vaccine, a positive test result is not

FIGURE 1A, Smudge cells (arrowhead) and Cowdry type A inclusion (arrow) in intestinal epithelialcells suggestive of adenovirus infection. (H&E stain; original magnication: 100.) B,Abundant adenovirus antigens are present in epithelial cells and intestinal mucosa. (Im-munoalkaline phosphatase staining, naphthol fast red substrate with light hematoxylincounterstain; original magnication: 100.) C, Intestinal section of an intussusceptioncase showing hemorrhage, prominent lymphoid follicles, inammatory inltrates inmu-cosa and lamina propria, and focal epithelial damage. No smudge cells or viral inclusionsare present. (H&E stain; original magnication:25.)


unexpected. This finding confirms the high sensitivity ofthe assay to detect a small quantity of virus whenpresent in pathology specimens. In fact, in 2 vaccinees,RRV-TV RNA was detected at 29 and 58 days aftervaccination by probe testing of the RT-PCR product, afinding that indicates how long an attenuated rotaviruscan remain in the gastrointestinal tract even at a lowlevel of detection and that because of this extra probingof the PCR product is required. Second, tissues availablefor testing in this study were mostly from the ileocecaljunction, appendiceal or lymph node tissues. The pri-mary site of natural rotavirus infection is in the smallintestine,18 but tissues from these sites were not availablefor testing. Last, as PCR testing does not localize RRVRNA to a particular tissue or cell type, the positive PCRresults could only represent virus in the intestinal lu-men, whereas the negative IHC and ISH results suggestno direct tissue invasion. In addition, by direct staining,no evidence of hyperplasia was noted in the Peyerspatches, a finding that in the past has been associatedwith intussusception.

Our finding of adenovirus in 35% of the patient tissuesamples supports the results of previous studies thathave found these viruses in 30% to 50% of tissue sam-ples from children with intussusception.14,1923

This study was limited by the availability of tissues inpathology departments and by the types and quality oftissue submitted. For infants who did not have surgicalresection of intussusception, only appendices or lymphnodes were available for testing. Intestinal tissues wereobtained from infants who had surgical resections; how-ever, the quality and quantity of tissues varied, and insome cases, small quantities of tissues may not havebeen representative of the ongoing pathologic process.Rotavirus normally infects the small intestine, but intus-susception occurs distant, at the ileal-cecal junction, soepithelial invasion is not anticipated. The sensitivity andspecificity of the 3 test methods was also an issue ininterpretation of results, because the most specificmethod, ISH, did not confirm the results of the mostsensitive method, RT-PCR.15 Last, although we originallyestimated that 30 specimens would be available, giventhe initially large risk of intussusception estimated as aconsequence of RRV-TV administration, a reassessmentof and lowering of this risk during our study6 led to asubstantially smaller number of specimens being avail-able. In fact, we were successful in obtaining specimensfrom all recently vaccinated children for whom intussus-ception and resection could be documented.3,5

CONCLUSIONSDespite pathologic studies, the mechanism of intussus-ception in infants who received RRV-TV still eludes us.The detection of RRV-TV RNA indicates the presence ofvirus in the gastrointestinal tract, but the absence ofRRV-TV antigen and RNA in tissue and the lack of

representative intestinal tissues for extensive his-topathologic examination precluded us from reachingmore definitive conclusions. The molecular and immu-nologic methods developed in this study can be used infuture studies of formalin-fixed tissues to explore furtherthe role of adenovirus and HRV in the etiology of intus-susception and the pathogenesis of gastroenteritis andthe investigation of deaths associated with these agents.Such methods could also be used in future vaccine eval-uation studies.

ACKNOWLEDGMENTSWe thank Paul Gargiullo, Trudy Murphy, and DavidNelson for providing the information gathered in thecase-control study and Claudia Chesley for editorial as-sistance in preparing the manuscript. We also acknowl-edge the initial consultation from the Rotavirus Pathol-ogy Study Group (Dennis Lang [National Institute ofAllergy and Infectious Diseases]; Diane Griffin [Bloom-berg School of Public Health, Johns Hopkins University];Richard Ward [Cincinnati Childrens Hospital]; Harry B.Greenberg [Stanford University Medical School]; AlbertZ. Kapikian [National Institute of Allergy and InfectiousDiseases]; Amir Kende, Lena A. Kombo, and Mary Estes[Baylor College of Medicine]; David O. Matson [EasternVirginia Medical School]; Melinda Wharton [NationalImmunization Program, Centers for Disease Control andPrevention]; Scott Campbell, Mitchell Wolfe, and PaulOffit [Childrens Hospital of Pennsylvania]; PennyHeaton and Alan Shaw [Merck Vaccines]; RobertBreiman [National Vaccine Program Office]; and SteveUdem, Frederick E. Varricchio, and William Gruber[Wyeth Lederle Vaccines and Pediatrics]) and statehealth department investigators (Jerry Narramore [Ten-nessee], Natalie Smith [California], John Talarico [NewYork], Eddy A. Bresnitz [New Jersey], Charles E. Jen-nings [Illinois], Wayne Staggs [Indiana], Dennis Perrottaand Maggie Kownaski [Texas], John Iskander [SouthCarolina], Peter Lurie [Pennsylvania], and Kris Erismin[Minnesota]).

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DOI: 10.1542/peds.2005-1556 2006;117;e827Pediatrics

Zaki and Roger I. GlassTara Jones, Baoming Jiang, Erik Hummelman, Christopher M. Zimmerman, Sherif R. Maureen Lynch, Wun-Ju Shieh, Joseph S. Bresee, Kathleen M. Tatti, Jon R. Gentsch,

Vaccine (Rotashield): The Search for a Pathogenic MechanismIntussusception After Administration of the Rhesus Tetravalent Rotavirus

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