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1.
Moore  PSChang  Y Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without HIV infection. N Engl J Med. 1995;3321181- 1185Article
2.
Boshoff  CSchulz  TFKennedy  MM  et al.  Kaposi's sarcoma associated herpesvirus infects endothelial and spindle cells. Nat Med. 1995;11274- 1278Article
3.
Rady  PLYen  ARollefson  JL  et al.  Herpesvirus-like DNA sequences in non-Kaposi's sarcoma skin lesions of transplant patients. Lancet. 1995;3451339- 1340Article
4.
Sander  CSimon  MPuchta  URaffeld  MKind  P HHV-8 in lymphoproliferative lesions in skin. Lancet. 1996;348475- 476Article
5.
Memar  OMRady  PLGoldblum  RMTyring  SK Human herpesvirus-8 DNA sequences in a patient with pemphigus vulgaris, but without HIV infection or Kaposi's sarcoma. J Invest Dermatol. 1997;108118- 119Article
6.
Nishimoto  SInagi  RYamanishi  KHosokawa  KKakibushi  MYoshikawa  K Prevalence of human herpesvirus-8 in skin lesions. Br J Dermatol. 1997;137179- 184Article
7.
Boshoff  CTalbot  SKennedy  MO'Leary  JSchulz  TChang  Y HHV-8 and skin cancers in immunosuppressed patients. Lancet. 1996;347338- 339Article
8.
Dupin  NGorin  IEscande  J-P  et al.  Lack of evidence of any association between human herpesvirus 8 and various skin tumors from both immunocompetent and immunosuppressed patients [letter]. Arch Dermatol. 1997;133537Article
9.
Pawson  RCatovsky  DSchulz  TF Lack of evidence of HHV-8 in mature T-cell lymphoproliferative disorders. Lancet. 1996;3481450- 1451Article
10.
Henghold  WBPurvis  SFSchaffer  JGiam  CZWood  GS No evidence of KSHV/HHV-8 in mycosis fungoides. J Invest Dermatol. 1997;108920- 922Article
11.
Dupin  NFranck  NCalvez  V  et al.  Detection of human herpesvirus 8 in HIV-negative patients with cutaneous lymphoma. Br J Dermatol. 1997;136827- 830Article
12.
Simpson  GRSchulz  TFWhitby  D  et al.  Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen. Lancet. 1996;3481133- 1138Article
13.
Gao  SJKingsley  LHoover  DR  et al.  Seroconversion of antibodies to Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma. N Engl J Med. 1996;335233- 241Article
14.
Gao  SJKingsley  LLi  M  et al.  KSHV antibodies among North Americans, Italians, and Ugandans with and without Kaposi's sarcoma. Nat Med. 1996;2925- 928Article
15.
Lennette  ETBlackbourn  DJLevy  JA Antibodies to human herpesvirus type 8 in the general population and in Kaposi's sarcoma patients. Lancet. 1996;348858- 861Article
16.
Marcelin  AGDupin  NBouscary  D  et al.  HHV-8 and multiple myeloma in France. Lancet. 1997;3501144Article
17.
Paraviccini  CLauri  EBaldini  L  et al.  Kaposi's sarcoma-associated herpesvirus infection and multiple myeloma. Science. 1997;2781969- 1973Article
18.
Memar  OMRady  PLGoldblum  RMYen  ATyring  SK Human herpesvirus 8 DNA sequences in blistering skin from patients with pemphigus. Arch Dermatol. 1997;1331247- 1251Article
19.
Kedes  DHOperskalski  EBusch  M  et al.  The seroprevalence of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in Kaposi's sarcoma risk group and evidence for sexual transmission. Nat Med. 1996;2918- 924Article
Study
June 1998

Prevalence of Human Herpesvirus 8 Infection Measured by Antibodies to a Latent Nuclear Antigen in Patients With Various Dermatologic Diseases

Author Affiliations

From the Department of Dermatovenereology, Hôpital Tarnier-Cochin (Drs Dupin, Gorin, Franck, and Escande), the Virology Laboratory, Groupe Hospitalier Pitié-Salpétrière (Drs Dupin, Marcelin, Bossi, Huraux, and Calvez), and the Immunology Laboratory, Hôpital Cochin (Dr Weill), Paris, France.

Arch Dermatol. 1998;134(6):700-702. doi:10.1001/archderm.134.6.700
Abstract

Background  Human herpesvirus 8 (HHV-8) has been detected in all epidemiological forms of Kaposi sarcoma (KS). The role of HHV-8 in dermatologic diseases other than KS is controversial. Some studies based on polymerase chain reaction findings suggest an association between HHV-8 and epithelial tumors of the skin, lymphoproliferative disorders, or pemphigus.

Objective  To assess the prevalence of antibodies against a latent nuclear antigen of HHV-8 in patients with various dermatologic diseases.

Design  An indirect immunofluorescence assay was used to search for HHV-8 antibodies.

Setting  Ambulatory or hospitalized patients from a university hospital associated with a research laboratory.

Patients  Eighty-three patients with various non-KS dermatologic diseases and 16 patients with KS who were seronegative for the human immunodeficiency virus. Controls were 100 healthy subjects living in the same area.

Results  Antibodies to HHV-8 were found in 100% (16/16) of the patients with KS and 3.6% (3/83) of the patients with non-KS dermatologic diseases: 1 patient with pemphigus vulgaris, 1 with discoid lupus erythematosus, and 1 with bullous pemphigoid. The prevalence of antibodies to HHV-8 in controls was 2% (2/100) and was not significantly different than the prevalence in patients with dermatologic diseases other than KS (P=.28).

Conclusions  Our serologic study confirms the higher prevalence of HHV-8 antibodies in patients with KS and demonstrates that contrary to other human herpesviruses, HHV-8 is not a ubiquitous virus in France. We could not determine any causal association between HHV-8 and pemphigus or lymphoproliferative disorders of the skin.

KAPOSI sarcoma (KS)–associated herpesvirus, also known as human herpesvirus 8 (HHV-8), is consistently found in all epidemiological forms of KS.1 Human herpesvirus 8 genomes are present in endothelial and spindle cells, the histological hallmark of KS.2 The frequency of detection of HHV-8 in other dermatologic diseases is controversial. Some authors report that HHV-8 may be found in other dermatologic diseases, such as epithelial tumors, cutaneous T-cell lymphoma, or pemphigus vulgaris, and that HHV-8 could be a widespread virus reactivated in some tumoral or immunological conditions.36 However, we and others711 have not confirmed the presence of HHV-8 in lymphoproliferative disorders of the skin or in epithelial tumors either in immunocompetent or immunosuppressed patients. Such discrepancies could reflect the variation of the distribution of HHV-8 infection by geographical area. Some serologic study results suggest that, at least in western countries, HHV-8 infection is largely confined to individuals with or at risk for KS.1214 However, one study of antilytic HHV-8 antibodies suggests that the prevalence of HHV-8 could be as high as 25% in the general population in the United States.15 Nevertheless, using an antilytic assay cross-reactive against other human herpesviruses, notably Epstein-Barr virus (HHV-4), could lead to an overestimation of the prevalence of HHV-8 antibodies. The aim of our study was to assess the prevalence of antibodies against a latent nuclear antigen of HHV-8 in patients with various cutaneous diseases and to compare it with the prevalence in patients with KS and in healthy control subjects.

PATIENTS AND METHODS

Serum samples were collected from 83 patients with various dermatologic diseases: cutaneous T-cell lymphoma (n=17), pseudolymphoma (n=4), B-cell lymphoma (n=1), anaplastic T-cell lymphoma (n=1), malignant melanoma (n=5), discoid lupus erythematosus (n=6), psoriasis (n=8), pemphigus (n=13, including 4 with pemphigus foliaceus and 9 with pemphigus vulgaris), vasculitis (n=5), erythema multiforme (n=4), bullous pemphigoid (n=11), and other dermatologic diseases (urticaria [n=2], pruritus [n=2], erythema nodosum [n=2], cutaneous sarcoidosis [n=1], and morphea [n=1]). We also studied serum samples from 14 patients with classic KS, including 2 homosexual patients with KS who were seronegative for the human immunodeficiency virus (HIV) and 3 partners of 3 patients with KS: 1 HIV-negative homosexual man whose partner was an HIV-negative homosexual man with stage I KS and 2 HIV-negative partners of 2 patients with stage I classic KS. Serum samples were collected at the patient's first visit or before the initiation of immunosuppressive therapy, except in 4 patients with autoimmune bullous diseases who were undergoing therapy with prednisone at a low level (5-20 mg/d). The samples were stored at −80°C until needed for processing. Serum samples from 100 healthy subjects served as controls.

Antibodies to a latent nuclear antigen (LNA-1) of HHV-8 were searched for using an immunofluorescence assay on a primary effusion cell line (BCP-1) latently infected with HHV-8 but not with the Epstein-Barr virus. The immunofluorescence assay was performed as previously described.10 Briefly, BCP-1 cells were fixed in 4% paraformaldehyde, rendered permeable with detergent (0.2% Triton × 100, Sigma-Aldrich, Dorset, England), incubated with human sera (1:100) for 30 minutes at room temperature, washed in a combined solution of phosphate-buffered saline and 3% fetal calf serum, incubated for 30 minutes with anti-human IgG–fluorescein isothiocyanate conjugate (Dako, Carpinteria, Calif), and then washed again and examined using fluorescence microscopy.

RESULTS

Antibodies to HHV-8 were found in the serum samples of all 14 patients with classic KS and in the 2 HIV-negative homosexual patients with KS. Antibodies to HHV-8 were also found in the serum samples of 3 tested partners of patients with KS. Serum samples of 2 (2%) of the 100 controls were found to be positive for HHV-8. Among the patients with dermatologic diseases, the prevalence of antibodies to HHV-8 was as follows: 0 (0%) of 23 patients with lymphoproliferative disorders of the skin, 0 (0%) of 5 patients with malignant melanoma, 1 (16%) of 6 patients with discoid lupus erythematosus, 0 (0%) of 8 patients with psoriasis, 1 (7%) of 13 patients with pemphigus, 0 (0%) of 5 patients with vasculitis, 0 (0%) of 4 patients with erythema multiforme, 1 (9%) of 11 patients with bullous pemphigoid, and 0 (0%) of the 8 patients with other dermatologic diseases. The prevalence of antibodies to HHV-8 in patients with dermatologic diseases other than KS was not statistically different than the prevalence in controls (3.6 % vs 2%, respectively; Fisher exact test, P=.28).

COMMENT

Our study was based on results of an immunofluorescence assay that detects antibodies against a latent nuclear antigen of HHV-8. This is the most sensitive and specific serologic assay available for determining past or present infection with this virus. The same serologic assay has enabled researchers to establish a strong correlation between HHV-8 infection and KS, to identify populations at risk for KS, and to question the pathogenic role of HHV-8 in multiple myeloma.16,17 Our results confirm that, in the area of Paris, France, HHV-8 is not a ubiquitous virus and is largely confined to patients with KS. The prevalence of antibodies to HHV-8 that we found in patients with KS is similar to the prevalence previously reported in such patients.1215 Moreover, serologic studies provide explicit and confirmatory epidemiological data about HHV-8: the link between all epidemiological forms of KS and HHV-8; the preferential sexual transmission of this agent as suggested by a high prevalence in populations exposed to sexually transmitted diseases (eg, syphilis or HIV); and the restricted distribution in the general population in western countries and a higher prevalence in African countries.1215 Thus, serologic assays give the best indication of prevalence of HHV-8. According to the findings of our serologic assay, the implication of HHV-8 in dermatologic diseases other than KS, such as cutaneous lymphoma or pemphigus, is uncommon. Previous studies based on findings of polymerase chain reaction suggest that HHV-8 could be implicated in the pathogenesis of epithelial tumors of the skin.3,6 However, these results have not been confirmed by other reports.7,8 Concerning the role of HHV-8 in lymphoproliferative disorders of the skin, one study reported the presence of HHV-8 DNA sequences in 7 of 48 cutaneous T-cell lymphomas, including 2 cases of mycosis fungoides, 2 peripheral T-cell lymphomas, 2 cases of parapsoriasis en plaque, and 1 lymphomatoid papulosis.4 These results were not confirmed in following studies, suggesting that HHV-8 is not directly implicated in the pathogenesis of either cutaneous T-cell or B-cell lymphoma.911 Results of our serologic study confirm the absence of any direct or indirect role of HHV-8 in the pathogenesis of lymphoproliferative disorders of the skin.

The role of HHV-8 in pemphigus vulgaris has been suspected in one case.5 Recently, HHV-8 DNA sequences were detected in 4 of 6 skin lesions from patients with pemphigus vulgaris and in all 6 skin lesions from patients with pemphigus foliaceus.18 These findings could not be explained by a cross-contamination of DNA according to the DNA sequencing analysis, and these results contrast with our own, which suggest that there is no link between HHV-8 and pemphigus. However, some argue that such discrepancies could result from the variation of the geographical distribution of HHV-8 infection. However, contrary to KS, which is associated with HHV-8 regardless of the patient's geographical origin, we could not determine any causative role of HHV-8 in pemphigus. Moreover, the presence of HHV-8 DNA sequences does not unambiguously signify that HHV-8 is directly implicated in the pathogenesis of pemphigus. In fact, this result could be explained by the presence of these sequences in the patients' peripheral blood mononuclear cells, which could have contaminated the skin samples. This hypothesis needs to be explored by further studies that compare HHV-8 DNA load in both lesional skin and normal skin in the same patient and include an evaluation of the presence of HHV-8 viremia.

The prevalence of antibodies to HHV-8 reported herein in healthy controls and in patients with non-KS dermatologic diseases is similar to the prevalence previously reported in the general population in western countries.1214 Thus, our study reinforces the hypothesis of a link between HHV-8 and KS. Moreover, the fact that 3 partners of 3 different patients with KS were found to be seropositive for HHV-8 suggests that this virus could be sexually transmitted, as recently reported.19

In conclusion, using an immunofluorescence assay, we detected antibodies to a latent nuclear antigen of HHV-8, suggesting that contrary to other human herpesviruses, HHV-8 is not a widespread virus in France and that HHV-8 infection is limited to patients with or at risk for KS. Thus, we maintain that, HHV-8 is not involved in the pathogenesis of lymphoproliferative disorders of the skin or pemphigus.

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Article Information

Accepted for publication February 24, 1998.

This work was supported by grant 97020 from the Fondation Cancer et Solidarité and the Agence Nationale de Recherche Sur le Sida.

The primary effusion cell line BCP-1 was kindly provided by P. S. Moore, MD, School of Public Health, Columbia, NY. In addition, Irina Bournerias, MD, provided samples for our study.

We thank the nurses from Tarnier Hospital and Françoise Lamy, laboratory technician, for technical assistance.

Corresponding author: Nicolas Dupin, MD, Institute of Cancer Research, Virology Team, 237 Fulham Rd, London SW3 6JB, England.

References
1.
Moore  PSChang  Y Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without HIV infection. N Engl J Med. 1995;3321181- 1185Article
2.
Boshoff  CSchulz  TFKennedy  MM  et al.  Kaposi's sarcoma associated herpesvirus infects endothelial and spindle cells. Nat Med. 1995;11274- 1278Article
3.
Rady  PLYen  ARollefson  JL  et al.  Herpesvirus-like DNA sequences in non-Kaposi's sarcoma skin lesions of transplant patients. Lancet. 1995;3451339- 1340Article
4.
Sander  CSimon  MPuchta  URaffeld  MKind  P HHV-8 in lymphoproliferative lesions in skin. Lancet. 1996;348475- 476Article
5.
Memar  OMRady  PLGoldblum  RMTyring  SK Human herpesvirus-8 DNA sequences in a patient with pemphigus vulgaris, but without HIV infection or Kaposi's sarcoma. J Invest Dermatol. 1997;108118- 119Article
6.
Nishimoto  SInagi  RYamanishi  KHosokawa  KKakibushi  MYoshikawa  K Prevalence of human herpesvirus-8 in skin lesions. Br J Dermatol. 1997;137179- 184Article
7.
Boshoff  CTalbot  SKennedy  MO'Leary  JSchulz  TChang  Y HHV-8 and skin cancers in immunosuppressed patients. Lancet. 1996;347338- 339Article
8.
Dupin  NGorin  IEscande  J-P  et al.  Lack of evidence of any association between human herpesvirus 8 and various skin tumors from both immunocompetent and immunosuppressed patients [letter]. Arch Dermatol. 1997;133537Article
9.
Pawson  RCatovsky  DSchulz  TF Lack of evidence of HHV-8 in mature T-cell lymphoproliferative disorders. Lancet. 1996;3481450- 1451Article
10.
Henghold  WBPurvis  SFSchaffer  JGiam  CZWood  GS No evidence of KSHV/HHV-8 in mycosis fungoides. J Invest Dermatol. 1997;108920- 922Article
11.
Dupin  NFranck  NCalvez  V  et al.  Detection of human herpesvirus 8 in HIV-negative patients with cutaneous lymphoma. Br J Dermatol. 1997;136827- 830Article
12.
Simpson  GRSchulz  TFWhitby  D  et al.  Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen. Lancet. 1996;3481133- 1138Article
13.
Gao  SJKingsley  LHoover  DR  et al.  Seroconversion of antibodies to Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma. N Engl J Med. 1996;335233- 241Article
14.
Gao  SJKingsley  LLi  M  et al.  KSHV antibodies among North Americans, Italians, and Ugandans with and without Kaposi's sarcoma. Nat Med. 1996;2925- 928Article
15.
Lennette  ETBlackbourn  DJLevy  JA Antibodies to human herpesvirus type 8 in the general population and in Kaposi's sarcoma patients. Lancet. 1996;348858- 861Article
16.
Marcelin  AGDupin  NBouscary  D  et al.  HHV-8 and multiple myeloma in France. Lancet. 1997;3501144Article
17.
Paraviccini  CLauri  EBaldini  L  et al.  Kaposi's sarcoma-associated herpesvirus infection and multiple myeloma. Science. 1997;2781969- 1973Article
18.
Memar  OMRady  PLGoldblum  RMYen  ATyring  SK Human herpesvirus 8 DNA sequences in blistering skin from patients with pemphigus. Arch Dermatol. 1997;1331247- 1251Article
19.
Kedes  DHOperskalski  EBusch  M  et al.  The seroprevalence of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in Kaposi's sarcoma risk group and evidence for sexual transmission. Nat Med. 1996;2918- 924Article
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