Skip Navigation



NDT Advance Access published online on March 12, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm056
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
22/6/1757    most recent
gfm056v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Bergallo, M.
Right arrow Articles by Cavallo, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bergallo, M.
Right arrow Articles by Cavallo, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Human herpes virus 8 infection in kidney transplant patients from an area of northwestern Italy (Piemonte region)

Massimiliano Bergallo1, Cristina Costa1, Samuela Margio1, Francesca Sidoti1, Daniela Re1, Giuseppe P. Segoloni2 and Rossana Cavallo1

1Dipartimento di Sanità Pubblica e Microbiologia, Laboratorio di Virologia, Università di Torino, Italy and 2Dipartimento di Medicina Interna, Unità Trapianto Rene, Ospedale Molinette, Torino, Italy

Correspondence and offprint requests to: Prof. Rossana Cavallo, Dipartimento di Sanità Pubblica e Microbiologia, Laboratorio di Virologia, Università di Torino, Italy, Università di Torino, Via Santena 9 - 10126 Torino, Italy. Email: rossana.cavallo{at}unito.it



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Human herpes virus 8 (HHV-8) infection is associated with Kaposi sarcoma (KS) and other neoplastic and non-neoplastic manifestations. A strong association between HHV-8 and KS has been evidenced in transplant recipients, particularly kidney recipients.

Methods. We have investigated the HHV-8 seroprevalence by an immunoenzymatic assay in 408 patients awaiting kidney transplantation and in the corresponding 356 donors; moreover, we have tested for the presence of HHV-8 DNA by nested PCR in available serum samples of the same graft recipients at 6, 12 and >18 months post-transplantation (overall 156 specimens). Associated factors, such as age, sex, area of residence, potential for HHV-8 transmission via organ transplantation and development of KS were also investigated.

Results. Twenty (4.9%) of 408 patients and 7 (1.9%) of 356 donors were seropositive. HHV-8 seropositive patients were on average about 6 years older than seronegative individuals. No difference in prevalence by gender was found. Considering the area of residence of seropositive patients, 4/161 (2.48%) were resident in Piemonte vs 16/247 (6.47%) in other areas of Italy (P = n.s.). During the follow-up post-transplantation, HHV-8 DNA was found only in four patients who were seropositive before transplantation, in three cases the corresponding donor was seronegative, in one the corresponding donor was also seropositive and the recipient developed KS. At >18 months post-transplantation, two patients were HHV-8 DNA positive, both were seronegative pre-transplantation and their corresponding donors were seronegative.

Conclusions. HHV-8 seroprevalence in the Piemonte region seems to be low, also in a population of kidney transplant recipients. Based on our data, it does not seem that the immunosuppressive regimen favours the reactivation of HHV-8. Our results do not suggest the possibility of HHV-8 transmission via organ transplantation. Incidence of KS among HHV-8 seropositive patients was very low.

Keywords: human herpes virus 8; kidney transplantation; seroprevalence



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Human herpes virus 8 (HHV-8) is a member of the Herpesviridae family, Gammaherpesvirinae subfamily, and was first identified in 1994 by Chang et al. from the skin lesions of human immunodeficiency virus (HIV)-infected patients with Kaposi sarcoma (KS) [1]. Beside KS, HHV-8 has been associated with primary effusion lymphoma, a rare lymphoma occurring mainly, but not exclusively, in AIDS patients, and with the plasma cell variant of multicentric Castleman's disease, a localized lymphoproliferative condition occurring in AIDS patients and transplant recipients frequently, but not invariably, associated with HHV-8. Moreover, HHV-8 has recently been linked to non-neoplastic manifestations such as haemophagocytic syndrome, cytopenia in renal graft recipients and acute bone marrow failure. Like other herpes viruses, HHV-8 establishes a lifelong relationship with its host, remaining latent in CD19+ B lymphocytes. Human herpes virus 8 is not as ubiquitous as most herpes viruses as its seroprevalence varies in different areas, mirroring the rates of the geographic distribution of KS before the AIDS epidemic [2]. In the adult general population, the seroprevalence of HHV-8 ranges from <5% in North America, northern Europe and Southeastern Asia to 10–20% in certain Mediterranean countries to more than 50% in sub-Saharan regions [3]. In areas at low seroprevalence (non-endemic countries), transmission is primarily sexual and risk groups are represented by homosexual men, persons with promiscuous sexual contacts and transplant recipients. In endemic areas, transmission occurs prevalently in childhood, with seroprevalence continuously rising during adulthood and in the presence of lower socioeconomic conditions. In this setting, although sexual transmission can occur, non-sexual modes of transmission may be important [2,4,5].

Several studies on the Italian general population have reported HHV-8 seroprevalence ranging from <3% in areas of northern Italy to >30% in central and southern Italy corresponding to areas of relatively high prevalence of KS [6,7].

Since many people infected with HHV-8 never develop KS, this is likely to result from a disequilibrium between the virus and the immune system. The role of HHV-8 in the pathogenesis of KS is not completely clear, but it probably involves a transcriptional re-programming of endothelial cells by HHV-8 [8–11].

A strong association between HHV-8 and KS has been evidenced in transplant recipients, particularly kidney allograft recipients [12,13]. It is still unknown whether this results from the reactivation of HHV-8 or to HHV-8 transmission via organ transplantation [12,14–16].

In our study, we investigated the prevalence of HHV-8 antibodies in a group of patients awaiting kidney transplantation and in corresponding donors immediately before transplantation; moreover, we tested for the presence of HHV-8 DNA in available serum samples of the same graft recipients at 6, 12 and >18 months after transplantation. A comparison of seroprevalence rates between patients awaiting kidney transplantation (patients with end-stage renal disease on haemodialysis) and organ donors (considered as healthy subjects) was done. We also looked for associated factors, such as age, sex and area of residence among graft recipients. Furthermore, the potential for a HHV-8 transmission via organ transplantation and the correlation between HHV-8 infection and the development of KS was investigated.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Between December 2001 and February 2006, serum samples were collected from 408 patients (male/female, 260/148; mean age ± SD, 51.7 ± 12.14 years; range 19–75 years) awaiting kidney transplantation at the Renal Transplant Unit of the Molinette Hospital, Turin, Italy, and from the corresponding donors (356 subjects, male/female, 181/175; mean age ± SD, 51.12 ± 16.45; range 15–79) considered as a comparison group of subjects without renal disease, immediately before transplantation and tested for HHV-8 antibodies. Considering the area of residence, 161 patients (39.5%) were from the Piemonte region or other areas of north western Italy, while more than 85% of the donors were resident in the Piemonte region north-western for more than 10 years.

Serum samples were tested with two commercially available immunoenzymatic assays: the first assay (HHV-8 ORF-73 IgG ELISA; Advanced Biotechnologies Inc., Columbia, MD) utilizes a recombined protein fragment of the major latent nuclear antigen, encoded by open reading frame (ORF) 73, therefore detecting antibodies to HHV-8 Latent Nuclear Antigen-1 (LNA-1). The second assay (HHV-8 IgG bi-peptide Enzyme Immunoassay; Biotrin International GmbH, Heidelberg, Germany) is based on a synthetic peptide mix which allows for the detection of antibodies to lytic HHV-8 viral proteins. The tests were performed according to the manufacturer's instructions.

Subsequently, during the follow-up post-transplantation, 156 specimens obtained from 104 patients were investigated for the presence of HHV-8 DNA: 57, 54 and 45 samples obtained from the corresponding number of patients at 6, 12 and >18 months (mean ± SD, 19.9 ± 4.8 months; range, 17.1–23.4) post-transplantation, respectively. Clinical follow-up was as follows: all the sera of the pre-transplantation seropositive recipients and of the seronegative recipients whose donors were seropositive were tested for HHV-8 DNA at 6 months, while evaluation at 12 and >18 months was based on clinician's decision; moreover, additional serum samples of seronegative recipients were tested based on the availability of the specimens. HHV-8 DNA was tested by nested PCR, as previously described [17].

Seroprevalence was expressed as percentage. Categorical variables were assessed with {chi}2-test with Yates’ correction and continuous variables with Student's t test for unpaired data.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Results obtained in renal transplant recipients are summarized in Table 1. Before renal transplantation, 20 (4.9%) of 408 recipients and 7 (1.9%) of 356 donors were seropositive, being the difference of seroprevalence significant (P = 0.046). In particular, 16 of the recipients and all the donors showed antibodies to both HHV-8 lytic and LNA-1 antigens, while four recipients showed antibodies only to lytic HHV-8 viral proteins. We also investigated possible differences in HHV-8 seroprevalence associated with sex, age, or area of residence. No difference in antibody prevalence by gender was found. HHV-8 seropositive patients were on average about 6 years older than seronegative individuals (59.1 ± 9.684 vs 53.1 ± 11.68; 95% CI: –11.29 to –0.64; P = 0.028). Considering the area of residence of recipients, among the 161 patients resident in the Piemonte region or other areas of Northwestern Italy (i.e. including Valle d’Aosta, Lombardia and Liguria regions), four (2.48%) were seropositive vs 16 seropositive patients of 247 (6.47%) living in other areas, however the difference of seroprevalence did not reach the significance.


View this table:
[in this window]
[in a new window]

  		Table 1. HHV-8 seroprevalence rates in renal transplant recipients according to gender, area of residence and stratified in different age groups

 
Results of follow-up post-transplantation are reported in Table 2. Six months post-transplantation HHV-8 DNA was found in 4 (20%) of the 20 patients seropositive before transplantation: in three cases, the corresponding donor was seronegative, in one the corresponding donor was also seropositive and the recipient developed KS. All the 37 seronegative recipients who were tested, including the seven whose corresponding donors were seropositive, resulted HHV-8 DNA-negative.


View this table:
[in this window]
[in a new window]

  		Table 2. Serum HHV-8 DNA in renal transplant recipients: post-transplantation follow-up at 6, 12 and >18 months of pre-transplantation seropositive recipients and pre-transplantation seronegative recipients whose donor was seropositive

 
After 12 months post-transplantation, HHV-8 DNA was negative in all the 54 patients whose sera were available, including seven seropositive patients before transplantation whose corresponding donors were seronegative; HHV-8 DNA was negative also in five patients whose corresponding donors were seropositive. None of these patients developed KS over this period.

At >18 months post-transplantation, HHV-8 DNA was found in two patients seronegative before transplantation and whose corresponding donors were seronegative and in none of 10 patients seropositive before transplantation. Also, five seronegative patients whose donors were seropositive resulted HHV-8 DNA negative. None of these patients developed KS in >18 months following transplantation.



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
The results of our study allow some general and circumstantial conclusions. Pre-transplant prevalence of HHV-8 antibodies among graft recipients was 4.9%. Considering the area of residence, the prevalence was 2.48% and 6.47% in Piemonte and in other areas of Italy (mainly Central and Southern Italy), respectively. The observed rates are similar to those previously reported in different regions of Italy [6,7], although, to our knowledge, this is the first study on HHV-8 seroprevalence in renal transplant recipients in Piemonte. Overall, based on these data, the Piemonte region and northwestern Italy seem to be areas at low HHV-8 seroprevalence. The difference of prevalence between recipients and donors could be attributable to the different area of residence or, alternatively, to the clinical conditions, i.e. end-stage renal subjects vs individuals without renal disease. In a similar study on HHV-8 seroprevalence among patients with end-stage renal disease in Saudi Arabian patients, the authors concluded that these patients seem to have at most a small increased risk of HHV-8 infection compared with subjects without renal disease. Considering our data, no definitive conclusions on the possibility of an increased HHV-8 seroprevalence in this category of patients can be made [18].

Taking into account the different areas of residence, our results suggest that HHV-8 seroprevalence is unaffected by pre-transplant therapeutic regimens and/or dialysis.

As generally reported, our study found that seroprevalence was similar in men and women. The observed 1.4–7.9% increase in rates of seropositivity according to age group reflects the age-related increased possibility of infection, due to sexual and possibly non-sexual transmission [12] or an age-associated decline in immune competence determining an increased risk of either primary infection or reactivation of latent infection.

The discordance between the results obtained with the two types of serological assays could be due to the different sensitivity, as the lytic antigen-based assays result more sensitive in identifying seropositivity than the latent antigen-based assays, as reported by many studies. Therefore, a combination of assays may be the best way to achieve the best detection rates [19].

The fact that HHV-8 DNAemia was negative in 16 of the 20 pre-transplantation seropositive patients could suggest that the level of immunosuppression at 6 months post-transplantation did not favour viral reactivation, as further evidenced at 12 and >18 month follow-up (Table 2).

Regarding the possibility of HHV-8 transmission via organ transplantation, our results do not seem to support this hypothesis, as none of the seronegative patients whose donor was anti-HHV-8-positive resulted HHV-8 DNA-positive at the follow-up post-transplantation. These data differ from those reported by Sheldon et al. [14]: in a study on kidney transplant patients in Belgium, the authors found a 2.1% of seroconversion following transplantation that could be due to acquisition through the transplanted organ or through transfusion. However, the lack of positive PCR at the follow-up post-transplantation in seronegative recipients whose donors were seropositive does not exclude an, albeit clinically not relevant, HHV-8 infection during the follow-up.

Finally, the overall incidence of KS after renal transplantation showed very low results (1/408 patients, 0.25%), as only one patient who was seropositive before transplantation and whose donor was also seropositive developed KS in 6 months. In this regard, it has been hypothesized that the risk of KS could be exceedingly high when the organ donor and recipient are both HHV-8 positive [20]. It is to be noted that this patient (a 64-year-old male) was resident in Piemonte, but originated from Albania. In the view of the small number, no definitive conclusion can be drawn, although this could suggest that in an area at low HHV-8 seroprevalence other factors contribute to KS development. However, our study clearly evidences patients with an increased risk for KS of about 3.7% (1/27) in the presence of seropositivity of either donor or recipient and 25% (1/4) in transplant recipients with a positive PCR within the first 6 months following transplantation.

In conclusion, the current study evidences that Piemonte and northwestern Italy are areas at low HHV-8 seroprevalence and supports the hypothesis that age- and environmentally-related differences may be involved both in primary infection and in immunological control of HHV-8 replication.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Chang Y, Cesarman E, Pessin MS, et al. (1994) Identification of herpes-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266:1865–1869.[Abstract/Free Full Text]
  2. Moore PS. (2000) The emergence of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8). N Engl J Med 343:1411–1413.[Free Full Text]
  3. Plancoulaine S and Gessain A. (2005) Epidemiological aspects of Human Herpesvirus 8 infection and of Kaposi's sarcoma. Med Mal Infect 35:314–321.[Web of Science][Medline]
  4. Moore PS and Chang Y. (2001) Kaposi's sarcoma-associated herpesvirus. In Howley P, Griffin D, Martin M, Lamb R, Roizman B, Straus S (Eds.). Field's Virology(Lippincott, Williams & Wilkins, Philadelphia, PA) pp. 2803–2833.
  5. Vitale F, Viviano E, Perna AM, et al. (2000) Serological and virological evidence of non-sexual transmission of human herpesvirus type 8 (HHV8). Epidemiol Infect 125:671–675.[CrossRef][Medline]
  6. Dal Maso L, Polesel J, Ascoli V, et al. (2005) Classic Kaposi's sarcoma in Italy, 1985–1998. Br J Cancer 92:188–193.[CrossRef][Web of Science][Medline]
  7. Tanzi E, Zappa A, Caramaschi F, et al. (2005) Human herpesvirus type 8 infection in an area of northern Italy with high incidence of classical Kaposi's sarcoma. J Med Virol 76:571–575.[CrossRef][Web of Science][Medline]
  8. Naranatt PP, Krishnan HH, Svojanovsky SR, Bloomer C, Mathur S, Chandran B. (2004) Host gene induction and transcriptional reprogramming in Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8)-infected endothelial, fibroblast, and B cells: insights into modulation events early during infection. Cancer Res 64:72–84.[Abstract/Free Full Text]
  9. Raggo C, Ruhl R, McAllister S, et al. (2005) Novel cellular genes essential for transformation of endothelial cells by Kaposi's sarcoma-associated herpesvirus. Cancer Res 65:5084–5095.[Abstract/Free Full Text]
  10. Wang HW, Trotter MW, Lagos D, et al. (2004) Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nature Genet 36:687–693.[CrossRef][Web of Science][Medline]
  11. Schulz TF. (2006) The pleiotropic effects of Kaposi's sarcoma herpesvirus. J Pathol 208:187–198.[CrossRef][Web of Science][Medline]
  12. Cattani P, Capuano M, Graffeo R, et al. (2001) Kaposi's sarcoma associated with previous human herpesvirus 8 infection in kidney transplant recipients. J Clin Microbiol 39:506–508.[Abstract/Free Full Text]
  13. Sarid R, Pizov G, Rubinger D, et al. (2001) Detection of human herpesvirus-8 DNA in kidney allografts prior to the development of Kaposi's sarcoma. Clin Infect Dis 33:1502–1505.[CrossRef][Web of Science][Medline]
  14. Luppi M, Barozzi P, Santagostino G, et al. (2000) Molecular evidence of organ-related transmission of Kaposi sarcoma associated herpesvirus or human-herpesvirus-8 in transplant patients. Blood 96:3279–3281.[Abstract/Free Full Text]
  15. Regamey N, Tamm M, Wernli M, et al. (1998) Transmission of human herpesvirus 8 infection from renal-transplant donors to recipients. N Engl J Med 339:1358–1363.[Abstract/Free Full Text]
  16. Sheldon J, Henry S, Mourad M, et al. (2000) Human herpes virus 8 infection in kidney transplant patients in Belgium. Nephrol Dial Transplant 15:1443–1445.[Abstract/Free Full Text]
  17. Tasaka T, Said JW, Morosetti R, et al. (1997) Is Kaposi's sarcoma-associated herpesvirus ubiquitous in urogenital and prostate tissues? Blood 89:1686–1689.[Abstract/Free Full Text]
  18. Almuneef M, Nimjee S, Khoshnood K, Miller G, Rigsby MO. (2001) Prevalence of antibodies to human herpesvirus 8 (HHV-8) in Saudi Arabian patients with and without renal failure. Transplantation 71:1120–1124.[CrossRef][Web of Science][Medline]
  19. Corchero JL, Mar EC, Spira TJ, Pellet PE, Inoue N. (2001) Comparison of serologic assays for detection of antibodies against Human Herpesvirus 8. Clin Diag Laboratory Immunol 8:913–921.[Abstract/Free Full Text]
  20. Parravicini C, Poli F, Bestetti G, et al. Risk of Kaposi's sarcoma development in renal transplant patients from Northern Italy. The second International Workshop on KSHV/HHV-8 and related agents. , Oxford, UK.
Received for publication: 12. 9.06
Accepted in revised form: 18. 1.07


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Virol.Home page
R. Wells, L. Stensland, and J. Vieira
The Human Cytomegalovirus UL112-113 Locus Can Activate the Full Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication Cycle
J. Virol., May 1, 2009; 83(9): 4695 - 4699.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
22/6/1757    most recent
gfm056v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Bergallo, M.
Right arrow Articles by Cavallo, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bergallo, M.
Right arrow Articles by Cavallo, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?