Viral gastrointestinal infections in allogeneic hematopoietic stem cell transplant patients

Gastrointestinal symptoms, and elevated liver enzymes, are common after HSCT, often due to drug toxicity, graft-versus-host disease (GVHD) or infections. It is essential to distinguish between GVHD and infection, since both conditions may progress to lethal disease, but require opposite strategies for the immunosuppressive treatment. Several of the viral gastrointestinal infections are easily transmitted and can cause outbreaks in health care facilities. In this thesis I studied viral gastrointestinal infections in HSCT patients, with focus on human adenovirus (HAdV), norovirus and hepatitis E virus (HEV), addressing transmission within health care, clinical importance, risk factors for severe/prolonged disease and the importance of secretor-status.

In paper I we analyzed an outbreak of HAdV at the Center for Allogeneic Hematopoietic Stem Cell transplantation (CAST), Karolinska University Hospital. We identified nine patients with HAdV A31. Hygiene measures were implemented, but the outbreak continued for a prolonged time. High strain on the staff during the early part of the outbreak, possible contamination of the facilities of the ward, and unidentified cases with sparse symptoms, may have contributed to the prolonged outbreak. The clinical consequences were significant, although no patient developed severe HAdV disease. Paper II was a retrospective study of the clinical importance, and risk factors for long-term symptoms, in 63 HSCT patients with norovirus infection. In paper III, we analyzed if secretor-status influenced the clinical course of norovirus infection in 89 HSCT patients with norovirus infection, of whom 63 also had been included in paper II. we found chronic symptoms of norovirus (>30 days) in 18/89 (20%) of the patients. Severe combined immunodeficiency (SCID) diagnosis was associated with chronic norovirus symptoms in both paper II and III, which may be due to the delayed immune reconstitution in many of these patients. The number of secretor-negative patients was low compared to the general population, indicating that secretor-negative genotype may protect against norovirus even when the patient is severely immunocompromised. Paper IV was a retrospective study of the frequency and clinical importance of HEV infection in a cohort of 236 HSCT recipients. HEV RNA was detected in 8/236 (3.4%) patients 6 months after HSCT. We found that elevated alanine aminotransferase (ALT) at six months after HSCT was associated with HEV infection. Spontaneous clearance was common, but one patient died of multiorgan failure where HEV infection may have contributed.

In conclusion, we found that an outbreak of HAdV can be difficult to control and may have serious consequences. Norovirus causes chronic symptoms (> 30 days) in 20% of HSCT patients, and SCID as indication for HSCT is associated with a chronic course of norovirus infection. We found that problems discriminating symptoms of HAdV, or norovirus, from symptoms of gastrointestinal GVHD, are a significant clinical challenge. HEV infection is an infrequent, but potentially severe, differential diagnosis in patients with elevated ALT six months after HSCT.

List of scientific papers

I. Prolonged outbreak of adenovirus A31 in allogeneic stem cell transplant recipients. Swartling L, Allard A, Törlen J, Ljungman P, Mattsson J, Sparrelid E. Transpl Infect Dis. 2015 Dec;17(6):785-94.
https://doi.org/10.1111/tid.12443

II. Norovirus causing severe gastrointestinal disease following allogeneic hematopoietic stem cell transplantation: A retrospective analysis. Swartling L, Ljungman P, Remberger M, Sundin M, Tiveljung A, Mattsson J, Sparrelid E. Transpl Infect Dis. 2018 Apr;20(2).
https://doi.org/10.1111/tid.12847

III. The Importance of Secretor-status in Norovirus Infection Following Allogeneic Hematopoietic Stem Cell Transplantation. Swartling L, Sparrelid E, Ljungman P, Boriskina K, Valentini D, Sharma S, Svensson L, Nordgren J. [Manuscript]

IV. Hepatitis E virus is an infrequent but potentially serious infection in allogeneic hematopoietic stem cell transplant recipients. Swartling L, Nordén R, Samuelsson E, Boriskina K, Valentini D, Westin J, Norder H, Sparrelid E, Ljungman P. Bone Marrow Transplant. 2020 Jul;55(7):1255-1263.
https://doi.org/10.1038/s41409-020-0823-7