Inflammatory Bowel Disease Presenting With Concurrent COVID-19 Multisystem Inflammatory Syndrome Katherine F. Sweeny, MD,a,p Yanjia J. Zhang, MD, PhD,a,p Bonnie Crume, MD,b Colin A. Martz, MD, PhD,b Melissa M. Blessing, DO,c Stacy A. Kahn, MDa

Coronavirus disease 2019 is associated with a postinfectious multisystem abstract inflammatory syndrome in children (MIS-C). This syndrome is marked by cytokine storm and multiorgan dysfunction, often affecting the , the heart, and the hematopoietic system. We describe the case of a 16-year-old boy with an initial presentation of severe inflammatory bowel disease and concurrent MIS-C. He presented with , , and hematochezia and met criteria for the systemic inflammatory response syndrome. Laboratory inflammatory profiling aDivision of , and Nutrition and bDepartments of Medicine, and cPathology, Boston revealed markedly elevated ferritin, D-dimer, C-reactive protein, soluble Children’s Hospital, Boston, Massachusetts interleukin 2, and interleukin 6 levels. Endoscopy and colonoscopy revealed pContributed equally as co-first authors severe active gastroduodenitis, patchy , and a normal-appearing terminal . The patient was treated with a combination of steroids, Drs Zhang, Sweeny, and Kahn conceptualized the report and drafted the initial manuscript; Drs Crume intravenous immunoglobulin, and infliximab, and his symptoms slowly and Martz collected patient data and analyzed data resolved over a 3-week period. In this case, we describe coincident MIS-C with trends; Dr Blessing collected and analyzed a remarkably severe and difficult-to-treat initial presentation of inflammatory histopathologic data; and all authors reviewed and revised the manuscript and approved the final bowel disease and highlight the need to investigate the effect of coronavirus manuscript as submitted. fl disease 2019 and MIS-C on in ammatory disorders. DOI: https://doi.org/10.1542/peds.2020-027763 Accepted for publication Dec 14, 2020 Address correspondence to Stacy A Kahn, MD, fl Coronavirus disease 2019 (COVID-19) is complaint of 3 weeks of hematochezia In ammatory Bowel Disease Center, Division of Gastroenterology, Hepatology and Nutrition, Boston increasingly associated with multisystem and worsening abdominal pain. He was Children’s Hospital, 300 Longwood Ave, Boston, MA inflammatorysyndromeinchildren(MIS- in his usual state of good health until 6 02115. E-mail: [email protected] C). MIS-C is a serious postinfectious weeks before, when he developed mild PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, syndrome resulting in cytokine storm rhinorrhea. The rhinorrhea resolved, 1098-4275). ∼ and multiorgan dysfunction often and 2 weeks later, he developed Copyright © 2021 by the American Academy of affecting the heart, the hematopoietic intermittent abdominal discomfort and Pediatrics system, and the gastrointestinal (GI) diarrhea, which progressed to 6 bloody FINANCIAL DISCLOSURE: The authors have indicated 1 tract. Here, we describe a novel and stools per day with severe generalized they have no financial relationships relevant to this timely case of an adolescent boy with an abdominal pain. He denied fevers, oral article to disclose. initial presentation of severe ulcers, myalgia, arthralgia, respiratory FUNDING: Dr Zhang is supported by the National inflammatory bowel disease (IBD) and symptoms, rash or headaches. Family Institutes of Health (T32 DK007477). Funded by the concurrent MIS-C. history was remarkable for a father National Institutes of Health (NIH). diagnosed with colonic cancer at age POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest CASE 43, currently in remission. There was no history of travel, trauma, or sick to disclose. A 16-year-old African American boy of contacts. Family history was negative Cape Verdean descent with no for autoimmune diseases or COVID-19. To cite: Sweeny KF, Zhang YJ, Crume B, et al. significant past medical history Inflammatory Bowel Disease Presenting With fl presented to an outside hospital On physical examination, the patient Concurrent COVID-19 Multisystem In ammatory Syndrome. Pediatrics. 2021;147(4):e2020027763 emergency department with a chief was thin, ill appearing, and met clinical

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 147, number 4, April 2021:e2020027763 CASE REPORT criteria for systemic inflammatory ferritin level at 1116.0 ng/mL (range heterozygous ECMI and STAT3 single- response syndrome. He had a fever 10.0–320.0 ng/mL), a significantly nucleotide polymorphisms. with a maximum temperature of 38.0° elevated D-dimer level of 9.14 mg/mL C and remained febrile on the first day or fibrinogen-equivalent units (FEU) Immune workup revealed an elevated of hospitalization; he had a heart rate (range #0.50m g/mL),andanelevated interleukin 2 receptor level at 1550 , of 165 beats per minute, a blood procalcitonin level of 0.65 ng/mL pg/mL (normal low level of 1033 pressure of 110/60 mm Hg, (range #0.09 ng/mL). The patient was pg/mL) and interleukin 6 level at 8 pg/mL (normal range ,5 pg/mL). a respiratory rate of 22, and an oxygen admitted to the gastroenterology Subsequently, SARS-CoV-2 saturation of 98% on room air. He service for further evaluation and immunoglobulin G testing results received 3 L of normal saline boluses treatment. Infectious diseases, returned positive, with a titer of 12 but remained tachycardic with a heart rheumatology, and immunology were (upper limit of normal 9), with repeat rate of ∼120 beats per minute. He had consulted. He received vitamin K and testing resulting in a titer of 16 and severe diffuse abdominal tenderness was started on 40 mg of intravenous a negative immunoglobulin M result. to palpation with involuntary guarding methylprednisolone daily. but no rebound or focal tenderness Because of concern for MIS-C, an and no hepatosplenomegaly. He had The patient was stabilized, and on electrocardiogram, an no cough, shortness of breath, rashes, hospital day 5, he underwent echocardiogram, troponin testing, and lymphadenopathy, icterus, esophagogastroduodenoscopy and N-terminal-pro-hormone brain conjunctivitis, joint tenderness or colonoscopy with biopsies. natriuretic peptide testing were swelling, and a normal perianal Esophagogastroduodenoscopy revealed performed, and results were all examination. severe and . within normal limits. Colonoscopy revealed patchy moderate On hospital day 7, the patient had acute Laboratory evaluation was significant to severe colitis with a normal- worsening, with increasing large- for leukocytosis to 21 660 cells/mL appearing terminal ileum (Fig 1A). volume bloody stools, and the (range 5240–9740 cells/mL), Pathology from the upper GI tract methylprednisolone was increased to neutrophilia with an absolute revealed severe, chronic active 60 mg intravenous daily. Exclusive neutrophil count of 20 530 cells/mL duodenitis as well as chronic active enteral nutrition (EEN) was initiated. (range 2730–66 680 cells/mL) and gastritis. Notably, in the , On hospital day 10, because of severe lymphopenia with an absolute fl fi there was an in ammatory in ltrate ongoing symptoms unresponsive to lymphocyte count of 560 cells/mL focally involving medium-sized blood parenteral corticosteroids and EEN in – m (range 1030 2180 cells/ L). His was vessels. Although the computed the setting of MIS-C, he was given 1 mildly anemic, with a hemoglobin level tomography revealed mild , the g/kg of intravenous immunoglobin – of 10.4 g/dL, (range 11.0 14.3 g/dL) terminal ileum histopathology was (IVIg). Within 24 hours, his serum and a mean corpuscle volume of 83.4 normal. There was moderately to inflammatory markers and coagulation – fL (range 80.8 86.6 fL). His C-reactive severely active colitis in the ascending, laboratories began to downtrend (Fig protein (CRP) level was 22.14 mg/dL transverse, descending, and sigmoid 1C). Two days after receiving IVIg, he , (range 0.50 mg/dL) and his colon and mildly active colitis in the developed chest pain,afeverof40.0°C, erythrocyte sedimentation rate was 21 (Fig 1B). Immunostaining and hypotension (blood pressure of – Helicobacter mm/hour (range 0 30 mm/hour). His results for cytomegalovirus, 95/36 mm Hg) and was transferred to albumin was normal at 4.0 g/dL. He (stomach), and SARS-CoV-2 were theICU.Hereceivedapackedred was mildly coagulopathic with an negative. Features of chronicity were blood cell transfusion for a hemoglobin international normalized ratio (INR) of seen in the duodenum, antrum and level that had dropped from 11.5 to 8.8 1.45 seconds. An abdominal computed corpus, and in several colon biopsies; g/dL and additional crystalloid fi tomography scan revealed trace free granulomata were not identi ed. The resuscitation. Within 24 hours, he had fl fi uid, mild ileitis, and signi cant diagnostic possibilities included IBD, stabilized and was transferred back to ascending and descending colitis with MIS-C, infection, or a combination the gastroenterology service. relative sparing of the transverse and thereof. The Prometheus IBD sgi and rectum. Results of Diagnostic test was sent, and results The patient’sseruminflammatory infectious studies, including stool were consistent with Crohn disease, markers improved significantly on cultures, Clostridium difficile testing, with serology revealing an elevated steroids and IVIg; His CRP level blood cultures, and nasal swab for anti–Saccharomyces cerevisiae antibody decreased from 22.14 to 2.9 mg/dL, severe acute respiratory syndrome immunoglobulin A enzyme-linked and his D-dimer level decreased from coronavirus 2 (SARS-CoV-2) antigen immunosorbent assay level of 13.5 EU/ 9.14 to 1.62 mg/mL or FEU, but he testing were negative. Additional mL (reference ,9.2 EU/mL), continued to have significant diarrhea laboratory tests revealed an elevated homozygous ATG16L1 and NKX2-3,and and hematochezia (Fig 1C). Magnetic

Downloaded from www.aappublications.org/news by guest on September 30, 2021 2 SWEENY et al FIGURE 1 A, Severe gastritis in the body of the stomach (left), severe duodenitis in the duodenal bulb (middle), and severe colitis in the sigmoid colon (right) noted on endoscopy. B, Corpus mucosa with active gastritis and expansile lamina propria lymphoplasmacytic infiltrate (left, arrow), ulcerated duodenal mucosa with vasculitis-like involvement of a blood vessel (middle), and severe active colitis with mucosal ulceration (right) (original magnification 3400). C, Course of laboratory inflammatory markers (green: ferritin, blue: D-dimer, yellow: CRP), stool output (maroon bars), and treatment (gray bars and arrows). IV, intravenous. resonance enterography performed at on day 24 and has continued to features of MIS-C related to COVID-19 that time revealed colonic wall improve in the outpatient setting on in an adolescent boy. In several MIS-C thickening with a normal-appearing infliximab monotherapy. case series, researchers now describe small bowel. With ongoing input from significant GI symptoms in many the immunology, infectious diseases, children, especially older children, DISCUSSION andIBDservices,onhospitalday17he but endoscopic and histologic was treated with infliximab 10 mg/kg, In this case, we describe an unusual features consistent with IBD appear whichresultedinrapidimprovement presentation of new-onset IBD, likely to be rare.1,2 The overlap in our in his GI symptoms. He was discharged Crohn disease, with overlapping patient of new-onset IBD and MIS-C

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 147, number 4, April 2021 3 represents an important and novel severe ongoing inflammation despite coagulopathy and GI symptoms), and pediatric presentation during the typically effective treatment of IBD with (3) positive SARS-CoV-2 serology still-unfolding COVID-19 pandemic. steroids, bowel rest, and EEN. He had results.7 The case definitions include biochemical improvement in his different exclusion criteria. The WHO The successful evaluation and systemic inflammation after receiving and RCPCH exclude patients with other management of this patient was IVIg, a treatment that has revealed microbial causes of inflammation, delivered via a multidisciplinary team efficacy for MIS-C.2 After our patient’s whereas the CDC excludes patients with involving the gastroenterology, hospital course, a case was reported of other plausible alternative diagnoses. infectious diseases, immunology, and a patient who had features of both IBD Thus, despite our hesitancy to ascribe all critical care physicians. This allowed and MIS-C that resolved following our findings to IBD, our patient for a comprehensive evaluation of the treatment with infliximab. Infliximab is technically meets the WHO and RCPCH ’ patient s GI illness as well as his typically reserved for cases of but not the CDC definition of MIS-C. fl systemic in ammatory response established IBD, which was not true for Because this pandemic is now entering syndrome physiology in the setting of our patient when IVIg was initially its third and most severe wave, it is fl severe in ammation and immune administered. Multiple providers likely that we will see more cases of dysregulation. This team approach thoughtthathisGIfindings could be MIS-C and further refine our definitions facilitated the development of explained by MIS-C alone. His and inclusion and exclusion criteria. a treatment plan that included lymphopenia, elevated ferritin level, medical therapies not commonly used elevated D-dimer level, and cytokine Our understanding of the to treat IBD, which may not have profile were suggestive of MIS-C.4 pathophysiology of MIS-C related to otherwise been considered. Fourth, it is unusual for a case of COVID-19 is rapidly evolving; however, pediatric IBD to present with its relationship to triggering predisposed Many features of this case are autoimmune conditions has not been consistent with IBD. These include coagulopathy. Studies of coagulation factors during active IBD exacerbations established. It may be that the predominant GI symptoms for 4 fl have revealed elevations in fibrinogen in ammatory dysregulation of the weeks with associated laboratory, immune system triggered by viral imaging, biomarker, and ultimately, levels but normal D-dimer and INR 5,6 infection of immune cells led to the histologic evidence of chronic GI levels. Even in studies in which a statistically significant difference was presentation of IBD in a genetically inflammation. Histologically, the 8 9 found in D-dimer and INR levels susceptible host. Dolinger et al presence of chronic changes supports described a case of a patient with known ’ between patients with Crohn disease IBD. The patient s GI symptoms Crohn disease who had – and controls, the D-dimer and INR levels ultimately responded to anti tumor contemporaneous IBD exacerbation and necrosis factor therapy, the mainstay of patients with Crohn disease were 6 MIS-C. The virus-as-trigger hypothesis treatment of moderate to severe IBD. within normal ranges. Fifth, it is uncommon for children with IBD could apply to that case as well, although, However, several aspects of the patient’s without fulminant colitis to present in notably, our patient did not have course were unusual for new-onset IBD compensated shock as our patient did a previous diagnosis of IBD. Alternatively, and were more consistent with our on admission. Finally, our patient had no it may be that this patient presented with – growing understanding of MIS-C. First, personal or family history of IBD or GI symptom predominant MIS-C related the finding of submucosal vasculitis on other autoimmune conditions. On the to previous SARS-CoV-2 infection the biopsy is not expected in IBD and is contrary, his familial background may because of a genetic predisposition to GI fl rather a finding consistent with MIS-C. confer higher MIS-C risk because early in ammation, but he will not continue to Sahn et al3 describe vascular case series of MIS-C note an have chronic GI disease suggestive of inflammation in patients with MIS-C. overrepresentation of children of Afro- a primary diagnosis of IBD. Further study Second, the patient’ssymptomsonly Caribbean descent. These features, in of the impact of COVID-19 infection and began 1 month before admission with the setting of a positive SARS-CoV-2 MIS-C on the presentation of mild rhinorrhea amid the COVID-19 immunoglobulin G antibody titer, autoimmune diseases is indicated. outbreak in his community, rather than support the hypothesis that this patient prolonged GI symptoms, growth failure, had concurrent MIS-C related to COVID- ACKNOWLEDGMENTS anemia, or other common 19 and new-onset IBD. Altogether, he extraintestinal manifestation of IBD. His meets the positive criteria in the Centers We thank Drs Pui Lee and Craig Platt mean corpuscular volume and albumin for Disease Control and Prevention for their discussions and suggestions, levels were normal, which is unusual in (CDC), Royal College of Pediatrics and particularly with the immunologic the setting of chronic GI inflammation Child Health (RCPCH), and WHO case and rheumatologic aspects of this and GI . Third, his evolving definitions of MIS-C, including (1) fever, case. We also thank Dr Lisa Teot for biochemical laboratory profile revealed (2) multisystem involvement (including her discussions and suggestions of

Downloaded from www.aappublications.org/news by guest on September 30, 2021 4 SWEENY et al the pathologic findings presented in REFERENCES and fibrinolysis in children, adolescents, and young adults with this article. 1. Verdoni L, Mazza A, Gervasoni A, et al. inflammatory bowel disease. J Pediatr An outbreak of severe Kawasaki-like – disease at the Italian epicentre of the Gastroenterol Nutr. 1999;28(4):418 422 ABBREVIATIONS SARS-CoV-2 epidemic: an observational 6. Zhang J, Guo Z, Yang W, et al. D-Dimer cohort study. Lancet. 2020;395(10239): CDC: Centers for Disease Control levels are correlated with disease 1771–1778 ’ and Prevention activity in Crohns patients. Oncotarget. 2017;8(38):63971–63977 COVID-19: coronavirus disease 2. Riphagen S, Gomez X, Gonzalez-Martinez 2019 C, Wilkinson N, Theocharis P. 7. Jiang L, Tang K, Levin M, et al. COVID-19 fl CRP: C-reactive protein Hyperin ammatory shock in children and multisystem inflammatory during COVID-19 pandemic. Lancet. EEN: exclusive enteral nutrition syndrome in children and adolescents. 2020;395(10237):1607–1608 FEU: fibrinogen-equivalent units Lancet Infect Dis. 2020;20(11): – GI: gastrointestinal 3. Sahn B, Eze OP, Edelman MC, et al. e276 e288 IBD: inflammatory bowel disease Features of intestinal disease 8. Pain CE, Felsenstein S, Cleary G, et al. INR: international normalized associated with COVID-related Novel paediatric presentation of COVID- fl ratio multisystem in ammatory syndrome in 19 with ARDS and cytokine storm children. J Pediatric Gastroenterology IVIg: intravenous immunoglobulin syndrome without respiratory Nutr. 2021;72(3):384–387 MIS-C: multisystem inflammatory symptoms. Lancet Rheumatol. 2020; syndrome in children 4. Chiotos K, Bassiri H, Behrens EM, et al. 2(7):e376–e379 Multisystem inflammatory syndrome in RCPCH: Royal College of Pediatrics 9. Dolinger MT, Person H, Smith R, et al. children during the coronavirus 2019 and Child Health Pediatric Crohn disease and pandemic: a case series. J Pediatric SARS-CoV-2: severe acute respira- multisystem inflammatory syndrome in Infect Dis Soc. 2020;9(3):393–398 tory syndrome coro- children (MIS-C) and COVID-19 treated navirus 2 5. Weber P, Husemann S, Vielhaber H, with infliximab. J Pediatr Gastr Nutr. Zimmer K-P, Nowak-Göttl U. Coagulation 2020;71(2):153–155

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Downloaded from www.aappublications.org/news by guest on September 30, 2021 Inflammatory Bowel Disease Presenting With Concurrent COVID-19 Multisystem Inflammatory Syndrome Katherine F. Sweeny, Yanjia J. Zhang, Bonnie Crume, Colin A. Martz, Melissa M. Blessing and Stacy A. Kahn Pediatrics 2021;147; DOI: 10.1542/peds.2020-027763 originally published online January 7, 2021;

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