Background The patient is an 11-year-old male with pre-B acute lymphoblastic leukemia (ALL) in second relapse 15 months after a hematopoietic stem cell transplant (HSCT) who presented for anti-CD19 CAR T-cell therapy with tisagenlecleucel. Tumor burden prior to therapy revealed ~60% bone marrow involvement by leukemia without CNS disease. He received Fludarabine/Cyclophosphamide for lymphodepletion followed by CAR T-cell infusion on D0 (Image 1). He developed grade 1 CRS, grade 1 neurotoxicity for which he received Tocilizumab and 10 days of dexamethasone, and carHLH (grade 3 transaminitis, hyperferritinemia, coagulopathy) for which he received 5 days of Anakinra (figure 1). He developed abdominal pain and tenesmus that progressed to hematochezia on D+12. CT abdomen revealed bowel wall thickening and mucosal hyperenhancement suggestive of pancolitis. Stool viral panel and Clostridium difficile were negative. He was empirically treated for typhlitis with Zosyn and switched to Cefepime/Flagyl without improvement. Fecal Adenovirus resulted positive while CMV and enterovirus were negative. Blood Adenovirus was detected at <190 copies/mL. Endoscopy showed crypt epithelial apoptosis with scattered atrophy and loss. Colonic biopsy was positive for Adenovirus. The patient slowly improved and discharged on D+36.
Methods Adenovirus infection leads to significant morbidity and mortality among pediatric HSCT patients.1–3 After infection, adenovirus persists in mucosal lymphocytes but competent host immunity prevents viral expansion in gut epithelial cells . When host immunity is compromised, viral reactivation can lead to adenoviremia resulting in enteritis, hepatitis, and death.2,5 Historically, supportive care has been used with cidofovir reserved for fulminant disease. Recently, viral specific T-cells (VSTs) have shown promise.6
A recent study noted that adenovirus was the most common identifiable pathogen in a cohort of pediatric patients receiving CAR T-cells.7 However, previous studies have not identified it as a common cause of post-CAR infections.8 Pre-infusion disease burden, lymphodepleting regimens, carHLH, neutropenia duration, hypogammaglobulinemia, high grade CRS, and previous HSCT have been identified as risk factors for infections.7–9
We propose three contributors to adenoviral reactivation in the gut during CAR T-cell treatment (Image 2):
Pre-infusion lymphodepletion destroys gut mucosal lymphocytes, spreading viral particles to host epithelial cells and reactivating infection.
CAR T-cell expansion leads to generalized immune dysregulation/contraction during CRS and HLH/MAS
Immune blockade blunts immune regulation.
Conclusions Adenovirus should be considered in patients who develop gastrointestinal symptoms (abdominal pain, diarrhea, tenesmus, hematochezia) after CAR infusion. Further research is needed to identify those at risk for severe disease who may warrant additional treatment.
Ali S, Krueger J, Richardson SE, Sung L, Waespe N, Renzi S, et al. The yield of monitoring adenovirus in pediatric hematopoietic stem cell transplant patients. Pediatric Hematology and Oncology. 2019 Apr 3;36(3):161–72.
Fisher BT, Boge CLK, Petersen H, Seif AE, Bryan M, Hodinka RL, et al. Outcomes of human adenovirus infection and disease in a retrospective cohort of pediatric hematopoietic cell transplant recipients. J Pediatric Infect Dis Soc. 2019 Sep 25;8(4):317–24.
Feghoul L, Chevret S, Cuinet A, Dalle JH, Ouachée M, Yacouben K, et al. Adenovirus infection and disease in paediatric haematopoietic stem cell transplant patients: clues for antiviral pre-emptive treatment. Clinical Microbiology and Infection. 2015 Jul;21(7):701–9.
Lion T. Adenovirus persistence, reactivation, and clinical management. FEBS Letters. 2019 Dec 8;593(24):3571–82.
Lion T. Adenovirus infections in immunocompetent and immunocompromised patients. Clinical Microbiology Reviews. 2014 Jul;27(3):441–62.
Rubinstein JD, Zhu X, Leemhuis T, Pham G, Ray L, Emberesh S, et al. Virus-specific T cells for adenovirus infection after stem cell transplantation are highly effective and class II HLA restricted. Blood Advances. 2021 Sep 14;5(17):3309–21.
Maron GM, Hijano DR, Epperly R, Su Y, Tang L, Hayden RT, et al. Infectious complications in pediatric, adolescent and young adult patients undergoing CD19-CAR T cell therapy. Frontiers in Oncology. 2022 Mar 9;12.
Vora SB, Waghmare A, Englund JA, Qu P, Gardner RA, Hill JA. Infectious complications following cd19 chimeric antigen receptor T-cell therapy for children, adolescents, and young adults. Open Forum Infect Dis. 2020 May;7(5):ofaa121.
Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. New England Journal of Medicine. 2018 Feb;378(5):439–48.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.