Infection with human herpesvirus type 8 and Kaposi's sarcoma in Sardinia.

BACKGROUND: A cross-sectional study was conducted in the provinces of Sassari (northern Sardinia, covered by a population-based cancer registry), and of Cagliari (southern Sardinia) to estimate the prevalence of infection with human herpesvirus type 8 (HHV8) and the incidence of classic Kaposi's sarcoma (KS) among HHV8-infected individuals. PATIENTS AND METHODS: Sera from 297 hospitalized persons potentially at risk of developing classic KS (i. e., those aged 50 years or older) were tested for antibodies against HHV8. HHV8 seroprevalence rates (with 95% confidence intervals-CI) and yearly incidence rates (IR/100,000) of KS were calculated according to age and sex. RESULTS: Of tested individuals, 32.0% had antibodies against HHV8 in Sassari and 30.0% in Cagliari. Estimated IR of KS among HHV8-positive persons and KS:HHV8 ratio were two times higher in Sassari (1:3,891) than in Cagliari (1:8,114), and higher in men (1:2,846 in Sassari; 1:5,483 in Cagliari) as compared to women (1:6,827 in Sassari; 1:12,489 in Cagliari). CONCLUSIONS: Although the overall prevalence of HHV8 seemed similar in Sassari and in Cagliari, the risk of KS was higher in Sassari, suggesting that different cofactor(s), or different distribution of the same cofactor(s) between the two provinces of Sardinia, might have played a role in KS development.

Pityriasis rotunda in childhood.

Pityriasis rotunda is a rare disease characterized by round or oval patches, localized mainly on the trunk, arms, and legs. The patches are usually lighter than the surrounding skin, but sometimes may be darker, and are covered by fine, adherent scales. Two types of pityriasis rotunda have been described. Type I has been observed mainly in oriental and black patients older than 60 years of age, and is often associated with systemic disease or malignancy. Type II has been observed in white patients younger than 40 years of age, is often familial, and has never been observed in association with malignancy or internal disease. On Sardinia, a cluster of patients with type II pityriasis rotunda has been described. From 1981 until 1998, 51 cases of this disease have been observed in the Department of Dermatology, University of Sassari; 32 of them were children. The great prevalence of pityriasis rotunda on Sardinia, an island which until 40 years ago had limited contact with the Italian mainland, and the presence of a large number of familial cases suggest that type II pityriasis rotunda should be considered a genetically determined disease. The trend toward spontaneous resolution after the age of 20 years suggests that pityriasis rotunda should be considered a genodermatosis with a temporary phenotypic expression.

Direct correlation between human herpesvirus-8 seroprevalence and classic Kaposi's sarcoma incidence in Northern Sardinia.

The human herpesvirus-8 (HHV-8) has been associated with the development of Kaposi's sarcoma. A high incidence of classic Kaposi's sarcoma has been described in Sardinia, an island West of Italy's mainland. Different seroepidemiological analyses have reported that prevalence of HHV-8 infection varies worldwide: a high HHV-8 seroprevalence has been shown in Italy. The present survey was carried out to evaluate the correlation between HHV-8 infection and classic Kaposi's sarcoma incidence in northern Sardinia. Blood samples were collected from 226 healthy donors born and resident in five different areas of North Sardinia. Seroprevalence to HHV-8 was determined searching antibodies to viral lytic proteins by immunofluorescence in sera diluted at 1:10. Classic Kaposi's sarcoma incidence data spanning a period of 23 years were examined in the areas studied. The present screening revealed that seroprevalence was 35%, within a range of 15.3-46.3% in the five areas, although it should be considered that the seroprevalence to HHV-8 can be established more accurately by the combined use of different assays. Age emerged as an important risk factor. Indeed, subjects aged > 50 years showed a higher seroprevalence to HHV-8 as compared with younger individuals. A strong direct correlation between HHV-8 prevalence and classic Kaposi's sarcoma incidence has been also observed. The wide diffusion of HHV-8 in Sardinia appears to represent an important factor in the high incidence of classic Kaposi's sarcoma reported in the island. However, additional co-factors, such as age, sex, genetic traits, or viral strain pathogenicity, are likely to play a role in the development of the disease.

Urocanic acid isomers in patients with non-melanoma skin cancer.

BACKGROUND: Cis-urocanic acid (cis-UCA), formed from the naturally occurring trans-isomer in the epidermis on ultraviolet (UV) radiation, initiates some of the changes leading to UV-induced immunosuppression, but its role in cutaneous carcinogenesis has not been fully investigated. OBJECTIVES: To measure the concentration of UCA isomers in the photoexposed and non-photoexposed skin of patients with multiple non-melanoma skin cancer (NMSC), enrolled in different periods of the year, in comparison with control subjects. PATIENTS/METHODS: UCA isomers were determined by high-performance liquid chromatography analysis in samples from the outer arm (photoexposed site) and buttock (non-photoexposed site) obtained from 20 patients and 19 controls during the winter period (October to April), and from five patients and 11 controls during the summer period (June to September). RESULTS: In the winter months, no difference was found between patients and controls in the concentration of UCA or the percentage of cis-UCA in either site. In the summer months, the percentage of cis-UCA in the buttock of patients and controls was similar but it was significantly higher in the arm of the controls (42%) than in the patients (17%). CONCLUSIONS: We conclude that different behaviour regarding sun exposure is the most likely explanation for these results, and that the concentration of UCA and its isomers does not reflect a tendency for individuals to develop NMSC.

Kaposi's sarcoma associated with previous human herpesvirus 8 infection in kidney transplant recipients.

This study investigates the prevalence of human herpesvirus 8 (HHV-8) infection in kidney transplant patients, evaluating the risk of HHV-8 transmission via transplantation and the association between pre- and posttransplantation HHV-8 infection and the subsequent development of Kaposi's sarcoma (KS). Immunofluorescence and an enzyme immunoassay were used to determine HHV-8 seroprevalence in 175 patients awaiting kidney transplantation and 215 controls who were attending our clinic for other reasons. All patients in the study came from central or southern Italy. Seroprevalence was similar in both groups (14.8 versus 14.9%), with no significant difference between the rates for male and female patients. Of the 175 patients, 100 were tested for anti-HHV-8 antibodies at various times during follow-up. During follow-up, seroprevalence increased from 12% on the date of transplantation to 26%. This increase was paralleled by an age-related increase in seroprevalence in the control group. During follow-up from 3 months to 10 years after transplantation, KS was diagnosed in seven patients (4.0%). Six of these patients were positive for HHV-8 prior to transplantation. Overall, 23.0% of patients who were HHV-8 positive before transplantation developed KS, whereas only 0.7% of seronegative patients developed the disease (relative risk, 34.4; 95% confidence interval, 4.31 to 274.0). This finding suggests that the key risk factor for KS is infection prior to transplantation and that antibody detection in patients awaiting transplantation could be useful in identifying patients at high risk for KS. In patients from geographic areas with a high prevalence of HHV-8, serological tests on donors may be less important.

HHV8 in renal transplant recipients.

Human herpevirus 8 (HHV8) DNA sequences have been found in lesions from patients with Kaposi's sarcoma (KS) in several forms including immunosuppressed transplant patients. We wanted to study the transmission of HHV8 in kidney transplant recipients and to assess the risk of development of KS related to the viral infection in this group of patients. We tested sera of 120 renal transplant recipients with serological assay for antibodies to HHV8 antigens before transplantation and then we tested sera of 66 patients of the same group after transplantation. Antibodies were detectable in 27.5% of the patients before transplantation. In the seropositive population 15.1% developed KS and in the negative group 1.1%. Analysing 66 posttransplant sera we noticed that 24% of the seronegative patients became positive after transplantation. Our data suggest that being positive for HHV8 before transplantation could be an important risk factor for the development of KS.

Antibodies against human herpesvirus 8 in subjects with non-venereal dermatological conditions.

BACKGROUND: Human herpesvirus 8 (HHV8) is considered as the infectious cofactor involved in the pathogenesis of Kaposi's sarcoma (KS). Its seroprevalence and modes of transmission in the general population are still undetermined. OBJECTIVES: We aimed to estimate the prevalence of HHV8 infection in a population at low risk for sexually transmitted diseases. METHODS: We conducted a seroepidemiological survey on randomly selected individuals attending the dermatology department of a teaching hospital in Rome. Of 257 patients, 248 had their blood analysed for anti-HHV8 antibodies and 201 completed a standardized interview. Serological analysis was performed by an immunofluorescence assay able to detect antilytic antibodies. RESULTS: We found an overall seroprevalence of 15.7% (95% confidence interval, CI 11.4-20.9%), similar in men and women (15.1% vs. 16.3%) and higher at older ages. Seropositivity was not related to sexual habits, while it was significantly associated with a history of hepatitis (seroprevalence 34.6%, adjusted odds ratio, OR 4.08, 95% CI 1.52-11.00) and with a diagnosis of non-melanoma skin cancer (42.9%, OR 4.20, 95% CI 1.26-14.02) or atypical naevi (35.3%, OR 6.21, 95% CI 1.85-20.86). CONCLUSIONS: Our data suggest that a non-sexual mode of transmission of HHV8 infection is plausible in an Italian population at low risk for sexually transmitted diseases and that other factors, besides differences in prevalence of HHV8 infection, may be involved in the epidemiology of classical KS. The unexpectedly high seropositivity rates in subjects with non-melanoma skin cancer and atypical naevi should be viewed with caution and require confirmation.

Human herpesvirus 8 seroprevalence and evaluation of nonsexual transmission routes by detection of DNA in clinical specimens from human immunodeficiency virus-seronegative patients from central and southern Italy, with and without Kaposi's sarcoma.

In order to investigate the seroprevalence of human herpesvirus 8 (HHV-8) infection in central and southern Italy, sera from human immunodeficiency virus (HIV)-seronegative subjects, with and without Kaposi's sarcoma (KS), were analyzed by immunofluorescence assay, using BC-3, a cell line latently infected with HHV-8. High titers of antibody against HHV-8 lytic and latent antigens were detected in all 50 KS patients studied, while in 50 HIV-seronegative subjects without KS, 32 (64%) were found positive for HHV-8 antibodies. Titers in the sera of these patients were lower than those for KS patients. This data suggests that HHV-8 infection is not restricted to KS patients and that the prevalence of HHV-8 infection in the general population may be correlated with differing rates of prevalence of KS in different parts of the world. In view of these findings, possible nonsexual transmission routes were evaluated. Nested PCR was used to test for the presence of HHV-8 DNA in saliva, urine, and tonsillar swabs from KS and non-KS patients. In KS patients, 14 out of 32 tonsillar swabs (43.7%), 11 out of 24 saliva samples (45.8%), and just 2 out of 24 urine samples (8.3%) tested positive for HHV-8 DNA. In the control group, on the contrary, none of the 20 saliva and 20 urine specimens was positive for HHV-8 DNA; only 1 out of 22 tonsillar swabs gave a positive result. This data supports the hypothesis that HHV-8 infects the general population in a latent form. The reactivation of viral infection may result in salivary shedding of HHV-8, contributing to viral spread by nonsexual transmission routes.

Immunohistochemical study of the early histopathologic changes occurring in trauma-injured skin of psoriatic patients.

In the present study we have investigated the early histopathologic as changes occurring in the Koebner reaction induced by traumatic injury in uninvolved skin of 23 psoriatic and 7 non-psoriatic control patients. A punch biopsy of the injured area was performed after 2-3 (15 cases) or 7 days (8 cases). As a trauma, instead of the classic sellotape stripping, needle scarification was used. A peculiar histological feature of the skin biopsies of 13/23 psoriatic patients (56%) was a keratinocyte hyperplasia leading to a "papillary" projection into the upper dermis, just beneath the scarification. The papillary projection was associated with the expression of intercellular adhesion molecule-1 (ICAM-1) in the keratinocytes of 9/13 cases (70%) and with the presence of peri-papillary aggregates of CD68+ cells in 10/13 cases. In the upper dermis, tenascin was markedly expressed in 12/13 cases. Moreover, in one third of the cases, just beneath the scarification, there was reabsorption of the epidermal basal membrane as documented by a marked reduction of collagen type IV and laminin content. These histopathological alterations were detected in 6/15 psoriatic patients whose skin biopsy was taken 2-3 days after scarification, in 7/8 after 7 days, and in only 1/7 non psoriatic controls. Our results indicate that needle scarification can be a suitable method to study the early events occurring in trauma injured psoriatic skin.

Human herpesvirus 8 in Italian HIV-seronegative patients with Kaposi sarcoma.

OBJECTIVE: To evaluate the prevalence of human herpesvirus 8 (HHV-8) DNA detection in a large series of human immunodeficiency virus-seronegative patients with and without Kaposi sarcoma (KS) from the central and southern regions of Italy where classic KS is prevalent. DESIGN: Samples of lesional, peripheral unaffected, and distant normal skin and peripheral blood mononuclear cells (PBMCs) from 33 patients with KS and PBMCs from 42 control subjects were analyzed using single and nested polymerase chain reaction techniques for the presence of HHV-8 DNA. PATIENTS: A total of 33 patients with KS not related to acquired immunodeficiency syndrome (26 patients with classic KS and 7 patients with iatrogenic KS) were studied. Furthermore, 2 control groups were enrolled. The first group consisted of 13 healthy volunteers, the second of 29 patients affected by different dermatological diseases. RESULTS: Human herpesvirus 8 sequences were found in 100% of lesional and perilesional specimens, in 33% of the distant normal skin samples, and in 69.6% of the PBMCs from patients with KS. A possible correlation between HHV-8 DNA in PBMCs and the clinical stage of the disease was observed. Moreover, the prevalence of viral DNA in PBMCs from the total control group was 23.8%. No viral DNA was detected in tissue biopsy specimens taken from the control group. CONCLUSIONS: Our data suggest that HHV-8 could be a widespread virus, at least in Mediterranean regions where KS is more prevalent, such as southern and central Italy. As with other herpesviruses, it may be present lifelong in latent form somewhere in the body and may contribute to the pathogenesis of KS when other predisposing conditions are present.

High prevalence of antibodies to human herpesvirus 8 in relatives of patients with classic Kaposi's sarcoma from Sardinia.

A survey for antibodies to a recombinant small viral capsid antigen (sVCA) of human herpesvirus type 8 (HHV-8) was conducted in Sardinia, one of the world's highest incidence areas for classic Kaposi's sarcoma (KS). Prevalence of antibodies to HHV-8 sVCA was greatest in patients with KS (95%), followed by family members (39%) and a Sardinian control population age- and sex-matched to the relatives (11%). Within families, prevalence of antibodies was about equal among spouses, children, and siblings of KS patients, a finding that raises the possibilities of intrafamilial person-to-person or vertical transmission. Antibodies were detected 2-3 times more frequently in males than in females. The data show that prevalence of antibodies to HHV-8 sVCA correlates with the distribution of classic KS in a high- incidence area. Clustering of seroprevalence within some families suggests the presence of familial risk factors for active HHV-8 infection.

Estimation of the effect of increasing UVB exposure on the human immune system and related resistance to infectious diseases and tumours.

Exposure to UV light has, besides some beneficial effects (vitamin D production), many harmful effects on human health. UVB irradiation has been shown to suppress both systemic and local immune responses to a variety of antigens, including some microorganisms. However, it is still not known whether such immunomodulating effects may lead to an increase in the number and severity of certain tumours and/or infections in humans. We report herein the data provided by a project that was funded by the European Union (Programme Environment), and that was aimed at the estimation of the risk associated with increased UVB exposure due to ozone depletion regarding the deleterious effects on the immune system and related resistance to tumours and infections in humans. The data, obtained by the different research groups involved, were assembled and used to calculate for the first time a risk assessment for increased environmental exposure to UVB in human subjects.

gamma-Interferon production in peripheral blood mononuclear cells and tumor infiltrating lymphocytes from Kaposi's sarcoma patients: correlation with the presence of human herpesvirus-8 in peripheral blood mononuclear cells and lesional macrophages.

Evidence indicates that, at least in the early stage, Kaposi's sarcoma (KS) is a cytokine-mediated disease and that it is consistently associated with a novel herpesvirus termed human herpesvirus-8 (HHV-8). To gain insights into the mechanisms by which cytokines and HHV-8 may cooperate in disease pathogenesis, we examined the phenotype, the Th1 (gamma-interferon [gamma IFN]) and Th2 (interleukin-4 [IL-4] cytokine profile and the presence of HHV-8 in peripheral blood mononuclear cells (PBMC), tumor-infiltrating lymphocytes (TIL), and spindle cell cultures derived from skin lesions of patients affected by classical KS (C-KS) and acquired immunodeficiency syndrome (AIDS)-associated KS (AIDS-KS). TIL and spindle cell cultures were examined at day 0 or after culture in conditioned media from activated T cells (TCM) that contain the same cytokines increased in KS tissues. No differences were found in the immunophenotype of PBMC from C-KS patients versus controls, except for AIDS-KS patients who showed a T-CD8+ expansion. However, a preferential infiltration of T-CD8+ cells was found in all KS lesions examined, which was maintained after culture of TIL in TCM. gamma IFN production was found in both PBMC and cultures derived from all KS examined; some IL-4 positive supernatants were found only in three AIDS-KS cases. Uninvolved skin did not show appreciable lymphocyte infiltration or cytokine production. The culture conditions of the lesional skin allowed also the appearance of adherent, spindle-like cells bearing markers of tissue macrophages. Finally, most or all of the PBMC, lesions, and macrophagic cell cultures from the skin lesions were found to be positive for HHV-8 infection by nested polymerase chain reaction (PCR). These findings indicate that patients with KS express a Th1 phenotype with a prevalent gamma IFN production, likely accounted for by the local T-CD8+ infiltration. By analogy with other viral infections (i.e., Epstein-Barr virus), this suggests that in loco recruitment of lymphoid cells and the subsequent gamma IFN production may be in response to or elicited by HHV-8 that was found in both PBMC and macrophagic cell cultures from the lesions of the same patients.