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Canada Communicable Disease Report

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Volume: 27S3 • September 2001

Viral Hepatitis and Emerging Bloodborne Pathogens in Canada

SEN Virus and the Rapid Response Surveillance System

Leslie Forrester, Shimian Zou, Antonio Giulivi


Between 80% and 90% of all community-acquired or transfusion-associated viral hepatitis is caused by hepatitis viruses A, B, C, D, and E, leaving 10% to 20% currently unaccounted for. Hepatitis of unknown etiologic origin is typically referred to as non-A non-E, or NANE hepatitis, and researchers in the field are working to identify the cause(s). Recent advances in molecular biology have led to the discovery of several new viruses. In the past 5 years, three candidate viruses for NANE hepatitis have been discovered, namely, GB virus-C/hepatitis G virus (GBV-C/HGV), TT virus, and the more recently discovered SEN virus (SEN-V). The present article summarizes what is currently known about SEN-V and describes the surveillance system that HC has put in place to address new and re-emerging bloodborne pathogens.

The discovery of SEN-V by an Italian research group, led by Dr. Daniele Primi, was announced at a press conference in July 1999 without the support of any published empirical data(1). To date, there is only one known published, peer-reviewed article on SEN-V(2). Besides that, the only information available to the scientific community has been in the form of a few press releases and conference abstracts, and the supporting documentation for a patent application for the identification of SEN-V genotypes. Until such time as more data are published in the peer-reviewed scientific literature, the information on SEN-V contained in this and other reports should be considered preliminary.

SEN-V is named after the initials of the patient from whom the virus was isolated. SEN-V is a circular, single stranded DNA virus with an average length of 3,900 nucleotides(2). Sequence and physical studies suggest that it is an unenveloped virus(3). To date, standard sequencing procedures have revealed eight, highly divergent genotypes: SEN-V A through H. All eight members of the SEN-V family are encoded for at least three open reading frames (ORFs) that code for one protein each(4). The length of the ORFs can vary with each SEN V genotype(4). In terms of diagnostic methodology, general PCR primers able to detect the presence of any member of the SEN-V family as well as specific primers for each subtype have been developed(2-5). Further to this, a specific PCR serum assay has been developed to obtain epidemiologic information on the prevalence and distribution of SEN-V in the general population as well as in specific patient population groups(2). Studies employing PCR DNA detection indicate that SEN-V exists in the blood and is transmitted parenterally(2,3,6,7).

SEN-V and hepatitis

Preliminary results suggest that SEN-V is associated with transfusion-associated non-A to non-E hepatitis. In the first peer-reviewed publication on SEN-V, Umemura et al.(2) reported a significantly higher incidence of SEN-V infection among transfused (30%; 86 of 286) than non-transfused controls (3%; 3 of 97). Moreover, a significant association was observed between the number of units transfused and transfusion risk, and donor-recipient linkage was confirmed by sequence homology(2). In collaboration with the National Institutes of Health and others, the Italian research group has also tested blood samples from normal blood donors and patients, with or without hepatitis, followed prospectively after open-heart surgery(6). The results showed a prevalence of 2.1% (5 of 243) among normal blood donors from the United States, and 3.8% (10 of 262) in patients prior to transfusion or surgery. Excluding those with prior infection, a significantly higher proportion of transfused (40.0%) than non-transfused patients (3.1%) developed SEN-V infection following surgery (p < 0.0001). Among transfused patients without pre-existing viremia, newly acquired SEN-V infection was detected in 83% of patients (10 of 12) who developed NANE hepatitis, 41% of patients (20 of 49) with chronic hepatitis C and 34% of patients (32 of 94) who did not develop hepatitis(6). Although the incidence of SEN-V infection was significantly higher in the NANE patient group than among those patients who did not develop hepatitis (p < 0.003), this does not necessarily imply that SEN-V causes hepatitis. The fact remains that 34% of individuals who did not develop hepatitis were SEN-V positive. As a first step towards establishing causality, studies demonstrating intrahepatic replication are required(6).

In a study examining the incidence of SEN-V infection among 143 HIV positive and 80 HCV/HBV positive patients, Pirovano et al.(7) found a similar incidence of SEN-V in the two patient groups, with rates of 45% and 47% respectively. However, when examined closer, it was found that the prevalence of SEN-V was significantly higher (p < 0.0001) among injection drug users (IDUs) (68.6%) than homo/heterosexual HIV positive individuals (28.9%), suggesting the possibility of effective transmission through contaminated needles or syringes. It is still not known whether the virus can be spread through ways other than blood and injections, such as through nosocomial or sexual transmission.

Finally, in a cross-sectional study examining the seroprevalence of SEN-V in a sample of liver transplant recipients, Yoshida et al. found that SEN-V infection was common, with 51.7% or 30 of 58 patients testing positive(8). No significant differences were observed with regard to the primary indication for transplantation. Further to this, no biochemical differences attributed to SEN-V were detected. The authors concluded that although SEN-V was highly prevalent among liver transplant recipients it did not appear to be associated with graft dysfunction(8).

Rapid Response Surveillance System

Since SEN-V exists in the blood and preliminary evidence indicates that it is prevalent in patients with liver diseases, the virus was determined to pose a potential threat to the health of Canadians. In response, HC formed a special working group to assess the risk of SEN-V in Canada. To assess the level of risk associated with a virus such as SEN-V, it is necessary to determine the level of infection in different population groups, to follow up the outcomes of infection, and to explore factors that may put Canadians at risk of infection. Timely risk assessment, however, usually requires the testing of blood specimens as soon as possible. Since it is not possible to test stored specimens for this purpose because of a lack of consent for the testing of any new pathogen, it became imperative to establish a Rapid Response Surveillance System for new and re-emerging bloodborne pathogens. Specifically, the system was designed to collect blood specimens for the identification of SEN-V as well as relevant clinical and epidemiologic information for the assessment of risk associated with the virus(9). To ensure the confidentiality and anonymity of the information collected, HC does not receive any personal information on the patients recruited into the system through participating physicians. Rather, blood specimens are coded with a personal identification (PID) number, permitting specimens to be linked anonymously to the clinical and epidemiologic data collected by way of a questionnaire.

Two categories of individuals are the target population for the system: patients visiting family physicians for routine check-ups and/or the treatment of common conditions, and patients in special groups, such as those with viral hepatitis of unknown cause, patients with hemophilia, and other groups with risk factors that potentially put them at higher risk for bloodborne infection. Surveillance results from the first category of patients will be used to assess the risk of the new pathogen in the general Canadian population, whereas results from the latter category will be important for assessing the clinical relevance of the pathogen as well as the risk associated with specific subgroups.

The Rapid Response Surveillance System is composed of the Division of Blood-Borne Pathogens as the national coordinator, health care professional groups as collaborators and facilitators, members of these groups as investigators and recruiters, and provincial/territorial public health agencies as consultants. Currently, the surveillance network includes the Canadian Science Centre for Human and Animal Health in Winnipeg; the Liver Diseases Unit of the University of Manitoba; the Cadham Provincial Laboratory of Manitoba; the British Columbia Transplant Society; the Canadian Association of Hepatologists (Canadian Association for Study of the Liver); the College of Family Physicians of Canada; and the Canadian Hemophiliac Physicians Association.

Although initiated in response to SEN-V, once fully established the system will be able to respond rapidly to determine the risk associated with any new or re-emerging bloodborne pathogen: in addition to the collection and testing of blood specimens (with specific consent for SEN-V) as well as the collection of relevant information, aliquots of the blood specimens are being stored in centralized laboratories (with consent) for future testing. Should a new bloodborne pathogen be identified, the individuals whose blood is in storage will be contacted through their physicians for specific consent for testing. If granted, their specimens will be tested immediately for the new pathogen.

To date, over 1,000 blood specimens have been collected. The collection of relevant clinical and epidemiologic data is ongoing. Of the specimens tested so far, preliminary Canadian results indicate that SEN-V is prevalent in patients with chronic hepatitis of unknown cause (31.3%), patients infected with hepatitis B (50.0%) and, as reported above, among liver transplant recipients (51.7%). It should be noted, however, that 18% of a sample of 50 community controls were also found to be SEN-V positive. The preliminary results also suggest that SEN-V positivity may be associated with a history of blood transfusion among those patients tested. However, more research, especially longitudinal epidemiologic studies following both SEN-V positive and negative individuals over time, are needed to clarify the clinical relevance of SEN-V. More specifically, evidence needs to be obtained to show that SEN-V positive individuals are more likely to develop a certain disease than are comparable control (SEN-V negative) individuals.

Acknowledgement

The authors wish to acknowledge Dr. Magdy Dawood, of the Cadham Provincial Laboratory of Manitoba, Dr. Gerry Minuk, of the Liver Diseases Unit of the University of Manitoba, and Dr. Eric Yoshida, of the British Columbia Transplant Society, for their past and ongoing contributions to the Rapid Response Surveillance System.

References

  1. Allain J-P. Emerging viruses in blood transfusion. Vox Sanguinis 2000;78(suppl 2):243-48.

  2. Umemura T, Yeo AET, Sottini A et al. SEN virus infection and its
    relationship to transfusion-associated hepatitis    . Hepatology 2001;33(5):1303-11.

  3. Primi D, Sottini A. Identification and characterization of SEN virus, a family of novel DNA viruses. Antiviral Therapy 2000;5(Suppl. 1):G.7.

  4. Fiordalisi G, Bonelli M, Olivero P et al. Identification of SENV Genotypes. Requested Patent WO0028039, 18 May 2000.

  5. Chan I, Diaz-Mitoma F. SEN virus. Report prepared for the Division of Bloodborne Pathogens, Health Canada, 2000.

  6. Umemura T, Donahue P, Sottini A et al. The incidence of SEN virus infection in transfusion-associated hepatitis. Antiviral Therapy 2000;5(Suppl. 1):Abstract G.11.

  7. Pirovano S, Sottini A, Bianchi V et al. Incidence of the SENV-A subtype in different cohorts of patients. Antiviral Therapy 2000;5(Suppl. 1):Abstract 81.

  8. Yoshida EM, Buczkowski AK, Giulivi A et al. A cross-sectional study of SEN virus in liver transplant recipients. Liver Transplantation (in press).

  9. Zou S, Forrester L, Giulivi A, and the Working Group on Emerging Bloodborne Agents. Surveillance and risk assessment for emerging bloodborne agents in Canada. Presented at the 10th International Symposium on Viral Hepatitis and Liver Disease in Atlanta, Georgia, and in Antiviral Therapy 2000;5(Suppl 1):G.5.

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