Viral infections in immunosuppressed patients with hematological malignancies

Acute or reactivated viral infections are common in patients who are immunosuppressed because of hematopoietic stem cell transplantation (HSCT) or chemotherapy due to hematological malignancies. The severity of the immunosuppression, the type of immune functions that are affected by various therapeutic interventions, as well as underlying hematological malignancy contributes to viral susceptibility and clinical outcome of the infection. Furthermore, in patients undergoing HSCT, the serostatus of viruses with reactivation capacity in both the recipient and the donor must be considered, as well as the sociodemographic and genetic characteristics.

Here we have studied DNA viruses that can cause clinical events in patients with malignant hematological diseases. Foremost, we evaluated whether it is advisable to continuously screen for the presence of these viruses during illness or chemotherapy in children and adults. In papers I and II we studied the presence of human adenovirus (HAdV) in the blood of patients undergoing HSCT. In papers III and IV, the presence of parvovirus B19 (B19V) in the bone marrow of children with various malignancies was studied, while paper V focused on the presence of B19V in the blood of adults and children undergoing HSCT. Paper VI focused on human herpesvirus 6 (HHV-6), polyoma BK virus (BKV) and B19V in the blood of adult patients undergoing chemotherapy for non-transplanted hematological malignancies. In these retrospective studies, blood and/or bone marrow samples were analyzed by quantitative real-time PCR for DNA representing HAdV, B19V, HHV-6 and BKV. Clinical and laboratory data were obtained from medical records. The proportion of patients with HAdV infection was relatively small, and asymptomatic infections did not occur. On the other hand, HAdV DNA loads >15,000 copies/mL in blood were associated with morbidity and mortality. Furthermore, findings of B19V in bone marrow of children undergoing treatment for acute lymphoblastic leukemia (ALL), were associated with prolonged chemotherapy. Neither B19V, HHV-6A, 6B nor BKV was common in the blood of adult patients with hematological malignancies who were immunosuppressed due to chemotherapy.

In general, screening for these viruses in the patient groups presented may not be indicated at the current state. However, testing for HAdV should be performed generously when unexpected symptoms occur, even if they are not typical for the virus. B19V infection is almost always linked with some degree of cytopenia, and if unexpected cytopenia occurs in children undergoing chemotherapy, B19V infection should be tested for. Patients with primary infections normally suffer from more severe clinical disease as compared to those with reactivated infections. Thus, knowledge of viral serostatus in HSCT recipients and donors should be taken into account in diagnostic considerations.

Overall, the diagnostic value of direct viral detection in blood and/or bone marrow samples of immunosuppressed patients with hematological malignancies is of considerable importance. Hopefully, a broad spectrum of novel antiviral compounds as well as novel procedures for adoptive cell therapy will be developed for these viral infections. Whether novel interventions will be used as pre-emptive therapy, or as symptomatic treatment, there will be an urgent need to monitor viral load. The present thesis can thus inform the field of clinically relevant viral infections and how to monitor these in selected patient categories that can be targeted for future therapeutic clinical interventions.

List of scientific papers

I. Igge Gustafson, Anna Lindblom, Zhibing Yun, Hamdy Omar, Liselotte Engström, Ilona Lewensohn-Fuchs, Per Ljungman, Kristina Broliden. Quantification of adenovirus DNA in unrelated donor hematopoietic stem cell transplant recipients. Journal of Clinical Virology. 2008; 43: 79–85.
https://doi.org/10.1016/j.jcv.2008.04.014

II. Lars Öhrmalm, Anna Lindblom, Hamdy Omar, Oscar Norbeck, Igge Gustafson, Ilona Lewensohn-Fuchs, Jan-Erik Johansson, Mats Brune, Per Ljungman and Kristina Broliden. Evaluation of a surveillance strategy for early detection of adenovirus by PCR of peripheral blood in hematopoietic SCT recipients: incidence and outcome. Bone Marrow Transplantation. 2011; 46, 267–72.
https://doi.org/10.1038/bmt.2010.86

III. Anna Lindblom, Mats Heyman, Igge Gustafsson, Oscar Norbeck, Tove Kaldensjö, Åsa Vernby, Jan-Inge Henter, Thomas Tolfvenstam and Kristina Broliden. Parvovirus B19 infection in children with acute lymphoblastic leukemia is associated with cytopenia resulting in prolonged interruptions of chemotherapy. Clinical Infectious Diseases. 2008; 46: 528-36.
https://doi.org/10.1086/526522

IV. Igge Gustafsson, Tove Kaldensjö, Anna Lindblom, Oscar Norbeck, Jan-Inge Henter, Thomas Tolfvenstam and Kristina Broliden. Evaluation of parvovirus B19 infection in children with malignant or hematological disorders. Clinical Infectious Diseases. 2010; 50(10): 1425-26.
https://doi.org/10.1086/652286

V. Lars Öhrmalm, Igge Gustafson, Anna Lindblom, Oscar Norbeck, Jan-Erik Johansson, Mats Brune, Per Ljungman and Kristina Broliden. Human parvovirus B19 in pediatric and adult recipients of allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplantation. 2013; 48, 1366–67.
https://doi.org/10.1038/bmt.2013.110

VI. Igge Gustafsson, Carl Aust, Zhibing Yun, Kristina Broliden, Lars Öhrmalm. Presence of human herpesvirus type 6, polyoma BK virus and parvovirus B19V in non-transplanted patients with hematological malignancies and neutropenic fever. [Manuscript]