Viral infections in children with cancer

Viral infections are the most common cause of infection morbidity in children. Nevertheless, few studies have been devoted to exploring the viral panorama in children receiving chemotherapy for cancer. The present thesis aims to study viral infections in children with cancer with special focus on Parvovirus B19 (B19) and viral infections during episodes of neutropenic fever.

B19 was for many years, believed to be a lytic virus cleared by the humoral response. However, subsequent studies in our laboratory led to the discovery of a B19-specific CD8+ T-cell response persisting for up to two years indicating persistence of antigen. To learn more about the kinetics of B19 viral load and with the aim of developing a more sensitive method, we applied a Taqman-based quantitative PCR with a sensitivity of 2 geq/mL. With this assay we reassessed consecutive collected samples from five acutely infected patients and found a persistent viral load of 103 - 105geq/mL, not detected with the less sensitive qualitative PCR. This challenges our current understanding about the virus pathogenesis and suggests that B19 frequently causes persistent infection.

As long as twenty years ago, complications from B19 infection were found in children undergoing anti cancer treatment. To further study the pathogenesis of B19 in a group of children with proven or suspected malignant disorders, bone marrow aspirates obtained were supplemented with testing for parvovirus B19 DNA. Here we could confirm results from other studies in which severe cytopenia led to multiple transfusions, withdrawal or postponed chemotherapy and B19 infection mimicking a relapse. Moreover, for the first time, we were also able to include a control group of B19-negative patients and compare them with the B19 DNA-positive patients during maintenance therapy for acute lymphoblastic leukemia. Particularly striking was the number of treatment days lost in the B19 DNA-positive group, strongly indicating the potential of this factor to affect treatment outcome.

Furthermore, we did a one year prospective study on children presenting with neutropenic fever at two pediatric oncology units in Stockholm, Sweden and Sydney, Australia, focusing on viral infections. Little is known about the etiology behind neutropenic fever and the microbial detection in 15-30% of the cases corresponds mostly to bacterial findings. In this study we showed that respiratory virus RNA/DNA are a common finding in nasopharyngeal aspirates from children presenting with neutropenic fever. Moreover, the addition of PCR-based viral diagnostic tools to the routinely performed bacterial blood culture increased the detection rate of a possible etiological agent to two thirds of the cases.

In conclusion, this thesis provides support for viral infections as a common cause of morbidity also in children receiving treatment for cancer. Neglect of viral diagnostic efforts may lead to inappropriate clinical management or suboptimal therapy intensity.

List of scientific papers

I. Lindblom A, Isa A, Norbeck O, Wolf S, Johansson B, Broliden K, Tolfvenstam T (2005). Slow clearance of human parvovirus B19 viremia following acute infection. Clin Infect Dis. 41(8): 1201-3. Epub 2005 Sep 2
https://pubmed.ncbi.nlm.nih.gov/16163641

II. Lindblom A, Heyman M, Gustafsson I, Norbeck O, Kaldensjö T, Vernby A, Henter JI, Tolfvenstam T, Broliden K (2008). Parvovirus B19 infection in children with acute lymphoblastic leukemia is associated with cytopenia resulting in prolonged interruptions of chemotherapy. Clin Infect Dis. 46(4): 528-36
https://pubmed.ncbi.nlm.nih.gov/18194100

III. Gustafsson I, Kaldensjö T, Lindblom A, Norbeck O, Henter JI, Tolfvenstam T, Broliden K (2008). Detection of Parvovirus B19 infection in children with malignant or hematological disorders. [Submitted]

IV. Lindblom A, Bhadri V, Söderhäll S, Öhrmalm L, Wong M, Lindau C, Rotzen-Östlund M, Allander T, Catchpoole D, Dalla-Pozza L, Broliden K, Tolfvenstam T (2008). Respiratory viral infections are the most common findings employing PCR-based diagnostics in children with neutropenia. [Manuscript]