We report a 35-year-old female receiving natalizumab as monotherapy for multiple sclerosis who subsequently developed severe cytomegalovirus gastritis. As cytomegalovirus gastritis has not been previously described during natalizumab treatment, we discuss the biological plausibility of this potential association and avenues for further study

Hassan, Adil

Hassan, Anjum

Hassan, Tariq

Persaud, Stephen P

ACG Case Reports Journal

English

PubMed

Digital Commons@Becker

Washington University School of MedicineDigital Commons@BeckerOpen Access Publications2017Severe cytomegalovirus gastritis duringnatalizumab-mediated immunosuppressionStephen P. PersaudWashington University School of Medicine in St. LouisAdil HassanUniversity of Missouri-Kansas CityAnjum HassanWashington University School of Medicine in St. LouisTariq HassanEndoscopy and Colonoscopy CenterFollow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubsThis Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in OpenAccess Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact engeszer@wustl.edu.Recommended CitationPersaud, Stephen P.; Hassan, Adil; Hassan, Anjum; and Hassan, Tariq, ,"Severe cytomegalovirus gastritis during natalizumab-mediatedimmunosuppression." ACG Case Reports Journal.4,. e43. (2017).https://digitalcommons.wustl.edu/open_access_pubs/5732Copyright: © 2017 Persaud et al. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 InternationalLicense. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0.ACG Case Reports Journal / Volume 4 acgcasereports.gi.org 1ACG CASE REPORTS JOURNALCASE REPORT | STOMACHSevere Cytomegalovirus Gastritis During Natalizumab-MediatedImmunosuppressionStephen P. Persaud, MD, PhD1, Adil Hassan2, Anjum Hassan, MD3, and  Tariq Hassan, MD41Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO2Combined BA/MD Program, University of Missouri-Kansas City School of Medicine, Kansas City, MO3Department of Pathology and Immunology, Division of Anatomic and Molecular Pathology, Washington University School of Medicine, St. Louis, MO4Endoscopy and Colonoscopy Center, Hazelwood, MOABSTRACTWe report a 35-year-old female receiving natalizumab as monotherapy for multiple sclerosis who subsequently developed severe cytomegalovirus gastritis. As cytomegalovirus gastritis has not been previously described dur-ing natalizumab treatment, we discuss the biological plausibility of this potential association and avenues for fur-ther study.INTRODUCTIONGastrointestinal (GI) infection by cytomegalovirus (CMV) primarily afﬂicts patients who are immunosuppressed, occurring in association with transplantation, malignancy, human immunodeﬁciency virus (HIV) infection, and chronic steroid usage.1,2 T cell–mediated immunity is essential in restraining CMV replication and reactivation; thus, abnormalities of lymphocyte number, function, or tissue distribution may impact patient susceptibility to infection.3 Treatment with natalizumab, which binds a4-integrins, promotes such an immunocompromised state by blocking adhesion interactions required for lymphocyte trafﬁcking, thus perturbing normal immunosurveillance. While numerous studies have discussed natalizumab-associated infections of the central nervous system, fewer studies have addressed infectious sequelae at other anatomic sites.CASE REPORTA 35-year-old woman presented in September 2015 with two weeks of nausea, vomiting, and epigastric pain, with no fevers, chills, or GI bleeding. Her past medical history was notable for multiple sclerosis (MS) diagnosed in 2012, no prior history of GI disease, and no history of recurrent or opportunistic infections that would suggest immuno-deﬁciency. Her medications included ergocalciferol, dosed at 50,000 units per week since October 2013, and nata-lizumab, dosed at 300 mg every 4 weeks since February 2015; she denied use of alcohol and nonsteroidal anti-inﬂammatory drugs. The patient’s only prior MS therapy was a 6-month trial of dimethyl fumarate started December 2013, with no prior treatment with steroids.On physical examination, the patient was in no apparent distress and exhibited normal vital signs. Abdominal exam showed a non-tender, non-distended abdomen with normal bowel sounds and no palpable masses. Complete blood count showed a white blood cell count of 4,900/mL (absolute neutrophil and lymphocyte counts were 1,700/mL and 2,710/mL, respectively), hemoglobin 10.5 g/dL, and platelet count 168,000/mL. Basic chemistry, hepatic function, lipase, and coagulation testing were normal. The patient was HIV-negative, and periodic JohnACG Case Rep J 2017;4:e43. doi:10.14309/crj.2017.43. Published online: March 15, 2017.Correspondence: Stephen P. Persaud, Department of Pathology and Immunology, Washington University School of Medicine, 660 S Euclid Ave, Box 8118,St. Louis, MO 63110 (persaud@wustl.edu).Cunningham (JC) virus serology testing since starting natali-zumab was negative. Immunoglobulin and cortisol levels, aswell as counts of CD4þ and CD8þ T lymphocytes, were notassessed. Barium upper GI ﬂuoroscopy demonstrated noesophageal dilatation or stricture, hiatal hernia, reﬂux, orulceration of the esophagus or duodenum. Helical computedtomography scans of abdomen and pelvis with intravenouscontrast were unremarkable.Upper GI endoscopy revealed severe inﬂammation of theentire examined stomach, with mucosal erosions and ery-thema and without ulceration or mass lesions (Figure 1). Coldforceps biopsies of the gastric antral mucosa were obtainedfor histopathologic analysis. Microscopic examination of he-matoxylin and eosin-stained tissue showed a chronic inﬂam-matory inﬁltrate and nuclear enlargement of the glandularepithelial cells consistent with reactive changes (Figure 2).Occasional epithelial cell nuclei showed prominent nucleoliand possible intranuclear inclusions. Immunostaining for CMVwas positive, while it was negative for herpes simplex virusand Helicobacter pylori (Figure 3). Rapid urease testing of thebiopsy tissue was negative. On the basis of these ﬁndings, aﬁnal diagnosis of severe chronic active CMV gastritis wasrendered.The patient completed a 3-week course of valganciclovir,dosed at 900 mg twice per day. She reported complete re-solution of her symptoms on follow-up with her infectiousdisease physician 1 week after ﬁnishing treatment. Due toher clinical improvement, the patient declined repeat en-doscopy. Natalizumab was continued as her MS symptomswere well-controlled; she has continued follow-up with herneurologist approximately every 3 months and has deniedrecurrence of her GI symptoms.DISCUSSIONCMV has a broad cellular tropism and can cause disease innearly any organ; within the GI tract, the colon and stomachare the most commonly affected sites.1,4 Deﬁnitive diagnosisof CMV gastritis relies on endoscopy and biopsy. Grossly,mucosal erosion and ulceration may be observed, with hemor-rhage, obstruction, or perforation seen in more severe cases.Unusual tissue morphologies of CMV gastritis, with polypoidor pseudotumoral appearance on endoscopy, have beendescribed.5,6 Microscopically, infected cells may show cyto-megaly and intracellular viral inclusions with a surroundingclear zone ("owl’s eye" inclusions).2,7CMV gastritis is a rare condition, with approximately 110 casesdescribed in the literature. Presenting symptoms are gener-ally nonspeciﬁc, including nausea, vomiting, and epigastricpain, although several unique presentations have beendescribed, including protein-losing gastropathy with general-ized edema, postural epigastric pain, chronic dysmotility, andFigure 1. Upper GI endoscopy demonstrating severe inﬂammation of the(A) body and (B) antrum of the stomach, with signiﬁcant erythema, ero-sions, and friability of the involvedmucosa.Figure 2. Hematoxylin and eosin staining of gastric antrum tissue demon-strating severe chronic mucosal inﬂammation and occasional enlargedcells with prominent intracellular inclusions (arrowheads).Figure 3. Immunohistochemical staining for CMV shows strong nuclearreactivity among the enlarged cells.Persaud et al Severe CMV Gastritis During Natalizumab TreatmentACG Case Reports Journal / Volume 4 acgcasereports.gi.org 2gastrocolic ﬁstula formation.8-11 The majority of reportedpatients were immunocompromised, although several casesin immunocompetent patients have been described.8,12 CMVgastritis is typically self-limited and can be managed suppor-tively in healthy patients, but antiviral treatment was fre-quently initiated in the reported cases if patients wereimmunosuppressed or had severe or persistent disease.2Complete recovery was often achieved with resolution of thepathologic endoscopic ﬁndings, though notably adult casesof protein-losing gastropathy showed poorer prognosis thantheir pediatric counterparts.8Natalizumab has primarily been associated with progressivemultifocal leukoencephalopathy secondary to JC virus reacti-vation.13 Consequently, clinical and laboratory assessment ofpatient immune status, including total leukocyte and T-lym-phocyte counts, history of opportunistic infection and priorimmunosuppressive therapy, and periodic JC virus serologicscreening have been recommended for patients taking thismedication.14,15 Other atypical infections, including herpessimplex and varicella zoster virus encephalitis and meningitis,as well as CMV colitis, have also been described.16,17 Notably,CMV colitis has also been reported with the use of vedolizu-mab, an a4b 7-integrin speciﬁc antibody used to treat inﬂam-matory bowel disease.18We hypothesize that CMV gastritis and colitis in patients tak-ing natalizumab or vedolizumab share a common pathogene-sis, whereby lymphocyte a4-integrin blockade disruptsnormal mucosal immunosurveillance. Consistently, the cell ad-hesion molecule MAdCAM-1, which binds a4b 7-integrins, isexpressed by gut endothelial cells, particularly during inﬂam-mation.19 Human studies and mouse models of H. pylori gastri-tis have demonstrated dense lymphocytic inﬁltration ofMAdCAM-1–positive tissue foci, implicating this receptor inrecruiting circulating lymphocytes into the gastric mucosa.19,20More studies, however, are necessary to solidify the connec-tion between CMV gastritis and natalizumab; given the rarityof this condition, accrual of greater numbers of natalizumab-treated patients will likely be necessary. Detailed immuno-logic workup will be particularly helpful in excluding othercauses of immunodeﬁciency. Finally, animal models of viral GIinfection in the setting of integrin blockade may provide im-portant proof-of-principle and pathophysiologic insights tohow natalizumab impacts susceptibility to CMVGI infection.DISCLOSURESAuthor contributions: SP Persaud wrote the manuscript andis the article guarantor. T. Hassan provided the images. Allauthors edited the manuscript and approved the ﬁnal version.Financial disclosure: None to report.Informed consent was obtained for this case report.ReceivedSeptember24, 2016;AcceptedJanuary 17, 2017REFERENCES1. Hokama A, Taira K, Yamamoto Y, et al. Cytomegalovirus gastritis.WorldJ Gastrointest Endosc. 2010;2:379–80.2. Goodgame RW. Gastrointestinal cytomegalovirus disease. Ann InternMed. 1993;119:924–35.3. Gandhi MK, Khanna R. Human cytomegalovirus: Clinical aspects,immune regulation, and emerging treatments. Lancet Infect Dis.2004;4:725–38.4. Scrivano L, Sinzger C, Nitschko H, Koszinowski UH, Adler B. HCMVspread and cell tropism are determined by distinct virus populations.PLoS Pathog. 2011;7:e1001256.5. Laguna F, Garcia-Samaniego J, Alonso MJ, Alvarez I, Gonzalez-LahozJM. Pseudotumoral appearance of cytomegalovirus esophagitis andgastritis in AIDS patients.Am J Gastroenterol. 1993;88:1108–11.6. Tsujii Y, Nishida T, Takehara T. Polypoid change in cytomegalovirus gas-tritis following treatment.Dig Endosc. 2013;25(3):342.7. Sepulveda AR, Patil M. Practical approach to the pathologic diagnosis ofgastritis. Arch Pathol LabMed. 2008;132:1586–93.8. Setakhr V, Muller G, Hoang P, Lambert AS, Geubel A. Cytomegalovirus-associated protein losing gastropathy in an immunocompetent adult: Acase report.Acta Gastroenterol Belg. 2007;70:296–9.9. Moustafellos P, Hadjianastasiou V, Gray D. Postural epigastric pain as asign of CMVgastritis: A case report. Transplant Proc. 2006;38:1357–8.10. Nowak TV, Goddard M, Batteiger B, Cummings OW. Evolution of acutecytomegalovirus gastritis to chronic gastrointestinal dysmotility in a non-immunocompromised adult.Gastroenterology. 1999;116:953–8.11. Aqel NM, Tanner P, Drury A, Francis ND, Henry K. Cytomegalovirus gas-tritis with perforation and gastrocolic ﬁstula formation. Histopathology.1991;18:165–8.12. Crespo P, Dias N, Marques N, Saraiva da Cunha J. Gastritis as a manifes-tation of primary CMV infection in an immunocompetent host. BMJCase Rep 2015. 2015;2015:pii:bcr2014206991.13. Warnke C, Olsson T, Hartung HP. PML: The dark side of immunotherapyin multiple sclerosis. Trends Pharmocol Sci. 2015;36:799–801.14. Gold R, Jawad A, Miller DH, et al. Expert opinion: Guidelines for the useof natalizumab in multiple sclerosis patients previously treated withimmunomodulating therapies. J Neuroimmunol. 2007;187:156–8.15. Fernandez O. Best practice in the use of natalizumab in multiple sclero-sis. Ther Adv Neurol Disord. 2013;6:69–79.16. Center for Drug Evaluation and Research (CDER). Tysabri(Natalizumab) biologic license application 125104/15: In: Proceedings ofthe Peripheral and Central Nervous System Drugs Advisory Committee;March 7–8, 2006; Gaithersburg, Maryland. http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4208S1-Slide-Index.htm. Accessed January9, 2017.17. Fine AJ, Sorbello A, Kortepeter C, Scarazzini L. Central nervous systemherpes simplex and varicella zoster virus infections in natalizumab-treated patients.Clin Infect Dis. 2013;57:849–52.18. Vivio EE, Kanuri N, Gilbertsen JJ, et al. Vedolizumab effectiveness andsafety over the ﬁrst year of use in an IBD clinical practice. J CrohnsColitis. 2016;10:402–9.19. Hatanaka K, Hokari R, Matsuzaki K, et al. Increased expression of muco-sal addressin cell adhesion molecule-1 (MAdCAM-1) and lymphocyterecruitment in murine gastritis induced by Helicobacter pylori. Clin ExpImmunol. 2002;130:183–9.20. Ohara H, Isomoto H, Wen CY, et al. Expression of mucosal addressincell adhesion molecule 1 on vascular endothelium of gastric mucosa inpatients with nodular gastritis.World J Gastroenterol. 2003;9:2701–5.Persaud et al Severe CMV Gastritis During Natalizumab TreatmentACG Case Reports Journal / Volume 4 acgcasereports.gi.org 3

Severe cytomegalovirus gastritis during natalizumab-mediated immunosuppression

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