Cutaneous sarcoma: a review and practical approach to management.

Sarcomas arising in the skin are rare but potentially fatal. These tumours originate from mesenchymal cells and can be divided between those that arise in soft tissue and those arising from bone. General guidelines exist for the management of soft-tissue sarcomas; however, there are no specific guidelines for cutaneous sarcomas. Current literature was reviewed for management of seven cutaneous sarcomas including atypical fibroxanthoma, pleomorphic dermal sarcoma, dermal and subcutaneous leiomyosarcoma, dermatofibroma sarcoma protuberans, Kaposi sarcoma, cutaneous angiosarcoma and malignant peripheral nerve sheath tumour. All suspected sarcomas should be discussed in a sarcoma multidisciplinary team meeting. This article is not a clinical guideline but should serve as a practical summary of how these tumours present, how they are recognized histologically, and how best to manage and follow-up patients. The aim is to support clinicians and facilitate the best and most evidence-based standard of care available.

Evidence for Placental HPV Infection in Both HIV Positive and Negative Women.

Human papillomaviruses (HPVs) have previously been reported to infect epithelial trophoblast cells of the placenta. To investigate this possibility, 200 placental samples from Zambian women were separated into HIV+ and HIV- groups and tested for HPV by redundant primer PCR, using GP5+/GP6+ and CPI/CPII primer sets. Three HPV genotypes (HPV6, 16 and 90) were detected in placental samples. Whereas, 20 different HPV genotypes were detected in vaginal sampling of the same patients, suggesting that compartment specific sub-populations of HPV may exist. The incidence of HPV16 in placental samples was almost 2-fold greater in HIV+ women compared to HIV- (p = 0.0241). HPV16 L1 expression, detected by immunochemistry, was significantly higher in HIV+ than HIV- samples (p = 0.0231). HPV16 DNA was detected in the nuclei of trophoblast cells by in situ hybridization. Overall, these results suggest that HPVs infect the placenta and that HIV significantly influences these infections.

Risk factors for early childhood infection of human herpesvirus-8 in Zambian children: the role of early childhood feeding practices.

BACKGROUND: Human herpesvirus-8 (HHV-8) infection in early childhood is common throughout sub-Saharan Africa with prevalence increasing throughout childhood. Specific routes of transmission have not been clearly delineated, though HHV-8 is present in high concentrations in saliva. METHODS: To understand the horizontal transmission of HHV-8 within households to children, we enrolled for cross-sectional analysis, 251 households including 254 children, age two and under, in Lusaka, Zambia. For all children, plasma was screened for HHV-8 and HIV type I (HIV-1) and health and behavioral questionnaires were completed. Multilevel logistic regression analysis was conducted to assess independent factors for HHV-8 infection in children. RESULTS: Risk factors for HHV-8 infection included increasing number of HHV-8-positive household members [OR = 2.5; 95% confidence interval (CI), 1.9-3.3; P < 0.01] and having a primary caregiver who tested the temperature of food with their tongue before feeding the child (OR = 2.4; 95% CI, 1.93-3.30; P = 0.01). Breastfeeding was protective against infection with HHV-8 for children (OR = 0.3; 95% CI, 0.16-0.72; P < 0.01). CONCLUSIONS: These results indicate that exposure to HHV-8 in the household increases risk for early childhood infection, with specific feeding behaviors likely playing a role in transmission. IMPACT: Interventions to protect children from infection should emphasize the possibility of infection through sharing of foods.

Chronic kidney disease associated with perinatal HIV infection in children and adolescents.

BACKGROUND: This study describes the incidence, clinical and demographic characteristics, and spectrum of chronic kidney disease (CKD) in youths with perinatal HIV-1 infection. METHODS: Retrospective analysis between May 1993 and December 2006 of subjects with renal disease followed in the Pediatric AIDS Clinical Trials Group 219/219C multicenter study examining the long-term consequences of perinatal HIV infection. Diagnosis confirmation was made utilizing a questionnaire mailed to research sites. Participants with CKD of other etiology than HIV were excluded. Outcome measures were biopsy-diagnosed CKD and, in the absence of biopsy, HIV-associated nephropathy (HIVAN) using established clinical criteria. RESULTS: Questionnaires on 191 out of 2,102 participants identified 27 cases of CKD: 14 biopsy-diagnosed and 6 clinical cases of HIVAN, and 7 biopsy-diagnosed cases of immune complex-mediated kidney disease (lupus-like nephritis, 3; IgA nephropathy, 2; membranous nephropathy, 2). Incidence rates for CKD associated with HIV in pre-highly active antiretroviral therapy (HAART) (1993-1997) and HAART (1998-2002, 2003-2006) eras were 0.43, 2.84, and 2.79 events per 1,000 person years respectively. In multivariate analysis, black race and viral load ≥100,000 copies/mL (rate ratios 3.28 and 5.05, p ≤ 0.02) were associated with CKD. CONCLUSIONS: A variety of immune complex-mediated glomerulonephritides and HIVAN occurs in this population. Black race and uncontrolled viral replication are risk factors for CKD associated with HIV.

The Zambia Children's KS-HHV8 Study: rationale, study design, and study methods.

The epidemic of human immunodeficiency virus in Zambia has led to a dramatic rise in the incidence of human herpesvirus-8 (HHV-8)-associated Kaposi's sarcoma in both adults and children. However, there is a paucity of knowledge about the routes of HHV-8 transmission to young children. The Zambia Children's KS-HHV8 Study, a large, prospective cohort study in Lusaka, Zambia, was launched in 2004 to investigate the role of household members as a source of HHV-8 infection in young children and social behaviors that may modify the risk of HHV-8 acquisition. This cohort is distinct from other epidemiologic studies designed to investigate HHV-8 incidence and transmission because it recruited and followed complete households in the urban central African context. Between July 2004 and March 2007, 1,600 households were screened; 368 households comprising 464 children and 1,335 caregivers and household members were enrolled. Follow-up of this population continued for 48 months postrecruitment, affording a unique opportunity to study horizontal transmission of HHV-8 and understand the routes and sources of transmission to young children in Zambia. The authors describe the study rationale, design, execution, and characteristics of this cohort, which provides critical data on the epidemiology and transmission of HHV-8 to young children in Zambia.

Primary gamma-herpesviral infection in Zambian children.

BACKGROUND: HHV-8 is closely related to Epstein-Barr virus (EBV), but the clinical presentations of these two infections in early childhood are not well understood. Also, it is not known whether infection by one virus correlates with another. Here, we compare the natural history of infection by these two viruses along with the clinical manifestations and risk factors that are associated with early childhood infection in Zambia, which is an endemic area for HHV-8. METHODS: This study was conducted in a cohort of 12 month old Zambian children (N = 677). Data on socio-economic status and a wide range of clinical manifestations were collected. Logistic regression was used to test for significant associations between the collected variables and HHV-8 or EBV serostatus at 12 months of age. RESULTS: We observed a significantly higher seroprevalence for EBV (58.9%) as compared to HHV-8 (13.4%). HIV-1 infected children had at a significantly higher risk of being infected with HHV-8 (Odds ratio [OR] 3.69, 95% confidence interval [CI] 1.64 - 8.32). HIV-1 infection of the mothers was a significant risk factor for increased acquisition of EBV but not HHV-8 by children (OR 1.86, 05% CI 1.20 - 2.87). Self reported rash was marginally associated with primary infection for HHV-8 and EBV. CONCLUSIONS: These results suggest that there is no correlation between EBV and HHV-8 infections. Infection by one does not increase the susceptibility for the second virus. Primary HHV-8 and EBV infection in early childhood may clinically present as rash but remains largely asymptomatic and may remain undetected in this population. HIV infection in the mother or child are important risk factors that contribute to EBV or HHV-8 infection.

Practice of feeding premasticated food to infants: a potential risk factor for HIV transmission.

OBJECTIVES: Although some caregivers are known to premasticate food for infants, usually during the weaning period, HIV transmission has not been linked to this practice. We describe 3 cases of HIV transmission in the United States possibly related to this practice. PATIENTS AND METHODS: Three cases of HIV infection were diagnosed in children at ages 9, 15, and 39 months; clinical symptomatology prompted the testing. A thorough investigation to rule out alternative modes of transmission was conducted. In addition, phylogenetic comparisons of virus from cases and suspected sources were performed by using the C2V3C3 or gp41 region of env and the p17 coding region of gag. RESULTS: In 2 cases, the mothers were known to be infected with HIV, had not breastfed their children, and perinatal transmission of HIV had previously been ruled out following US HIV testing guidelines. In the third case, a great aunt who helped care for the child was infected with HIV, but the child's mother was not. All 3 children were fed food on multiple occasions that had been premasticated by a care provider infected with HIV; in 2 cases concurrent oral bleeding in the premasticating adult was described. Phylogenetic analyses supported the epidemiologic conclusion that the children were infected through exposure to premasticated food from a caregiver infected with HIV in 2 of the 3 cases. CONCLUSIONS: The reported cases provide compelling evidence linking premastication to HIV infection, a route of transmission not previously reported that has important global implications including being a possible explanation for some of the reported cases of "late" HIV transmission in infants, so far attributed to breastfeeding. Until the risk of premastication and modifying factors (eg, periodontal disease) are better understood, we recommend that health care providers routinely query children's caregivers and expecting parents who are infected with HIV or at risk of HIV infection about this feeding practice and direct them to safer, locally available, feeding options.

Mortality among HIV-1- and human herpesvirus type 8-affected mother-infant pairs in Zambia.

OBJECTIVE: To determine the respective trends in mortality of Zambian mother-infant pairs based on maternal infection with HIV-1 and human herpesvirus type 8 (HHV-8). METHODS: A prospective cohort study was done on Zambian mother-infant pairs, stratified by maternal serologic status and followed from 6 weeks postdelivery for 48 months. Statistical analysis of the differences in the calculated mortality rates among the four groups was done using Stata 7.0. Kaplan-Meier analysis and Cox proportional hazard models were used to measure subject survival time. RESULTS: Between September 1998 and March 2002, a total of 1,425 mother-infant pairs were enrolled. The crude mortality rate among children born to dually infected mothers was approximately 9 times higher (245.90 deaths per 1,000 live births) when compared with the death ratio of children born to seronegative mothers (24.63 deaths per 1,000 live births). The incidence rate for death was 0.34/1,000 in infants of co-infected mothers in comparison with 0.32/1,000 among HIV-1-infected mothers, 0.0336/1,000 among uninfected mothers, and 0.0403/1,000 among HHV-8-infected mothers (chi(2) = 154.56; P < 0.01). Infants of co-infected mothers had a comparable risk of death in comparison with infants infected with HIV-1 alone [hazard ratio, 9.91 [95% confidence interval (95% CI), 5.08-19.37] for co-infected versus 9.26 [95% CI, 4.75-18.07] for HIV-1-infected alone]. Infants of mothers infected only with HHV-8 also had comparable survival in comparison with uninfected infants (hazard ratio, 1.21; 95% CI, 0.56-2.61). CONCLUSION: Infants born to mothers dually infected with both HIV-1 and HHV-8 have comparable survival with infants exposed to HIV-1 alone. Infants born to mothers infected only with HHV-8 have comparable survival with uninfected infants.

Early childhood infection by human herpesvirus 8 in Zambia and the role of human immunodeficiency virus type 1 coinfection in a highly endemic area.

Kaposi's sarcoma occurs at high incidence among Zambian adults and children, but there is a paucity of data on human herpesvirus 8 (HHV-8) incidence and routes of infection, especially in children. Between 1998 and 2004, the authors conducted a prospective study of viral transmission in a cohort of 684 children in Lusaka, Zambia, to estimate the annual incidence of HHV-8 from birth through 48 months of age. Maternal and pediatric human immunodeficiency virus type 1 (HIV-1) infection status was also determined. The results, based on 1,532 child-years of follow-up, showed that HHV-8 seroconversion occurs early in life. The incidence rate of HHV-8 seroconversion was 13.8 infections per 100 child-years by 48 months of age. HIV-1-infected children were at substantially higher risk for HHV-8 seroconversion (adjusted hazard ratio = 4.60, 95% confidence interval: 2.93, 7.22). Maternal HIV-1 and HHV-8 infection status were not independently associated with risk of HHV-8 seroconversion in the child. HHV-8 antibody titers in children followed at all consecutive time points revealed sero-reversion of HHV-8 antibodies, with undetectable titers in some children at one or more time points after seroconversion. These results demonstrate that cross-sectional serologic screening probably underestimates true HHV-8 seroprevalence in young Zambian children because of fluctuations in detectable antibody titers.

Development of an immunofluorescence assay using recombinant proteins expressed in insect cells to screen and confirm presence of human herpesvirus 8-specific antibodies.

Human herpesvirus 8 (HHV-8), or Kaposi's sarcoma (KS)-associated herpesvirus, has been linked to all forms of KS. The results of most current serological assays for the detection of HHV-8-specific antibodies have low levels of concordance among themselves. To establish a sensitive and specific testing strategy that can be used to screen for HHV-8-specific antibodies, three HHV-8 proteins, ORF65, ORF73, and K8.1A, were expressed by using baculoviral vectors in insect cells and incorporated into a monoclonal antibody-enhanced immunofluorescence assay (mIFA) termed the Sf9 three-antigen mIFA. The results obtained by this mIFA were compared to those obtained by a standard mIFA with an HHV-8-infected B-cell line (BC3 mIFA). Test sera were obtained from patients diagnosed with KS, human immunodeficiency virus type 1-infected patients at high risk for HHV-8 infection, and healthy controls from a local blood bank. The combined use of both assays had a sensitivity of 94% and a specificity of 96%. The performance of these two assays when they were used together indicates that they may be useful for the reliable detection of HHV-8-specific immunoglobulin G antibodies in a population.

Characterization of HIV-1 subtype C envelope glycoproteins from perinatally infected children with different courses of disease.

BACKGROUND: The causal mechanisms of differential disease progression in HIV-1 infected children remain poorly defined, and much of the accumulated knowledge comes from studies of subtype B infected individuals. The applicability of such findings to other subtypes, such as subtype C, remains to be substantiated. In this study, we longitudinally characterized the evolution of the Env V1-V5 region from seven subtype C HIV-1 perinatally infected children with different clinical outcomes. We investigated the possible influence of viral genotype and humoral immune response on disease progression in infants. RESULTS: Genetic analyses revealed that rapid progressors (infants that died in the first year of life) received and maintained a genetically homogeneous viral population throughout the disease course. In contrast, slow progressors (infants that remained clinically asymptomatic for up to four years) also exhibited low levels variation initially, but attained higher levels of diversity over time. Genetic assessment of variation, as indicated by dN/dS, showed that particular regions of Env undergo selective changes. Nevertheless, the magnitude and distribution of these changes did not segregate slow and rapid progressors. Longitudinal trends in Env V1-V5 length and the number of potential N-glycosylation sites varied among patients but also failed to discriminate between fast and slow progressors. Viral isolates from rapid progressors and slow progressors displayed no significant growth properties differences in vitro. The neutralizing activity in maternal and infant baseline plasma also varied in its effectiveness against the initial virus from the infants but did not differentiate rapid from slow progressors. Quantification of the neutralization susceptibility of the initial infant viral isolates to maternal baseline plasma indicated that both sensitive and resistant viruses were transmitted, irrespective of disease course. We showed that humoral immunity, whether passively acquired or developed de novo in the infected children, varied but was not predictive of disease progression. CONCLUSION: Our data suggest that neither genetic variation in env, or initial maternal neutralizing activity, or the level of passively acquired neutralizing antibody, or the level of the de novo neutralization response appear to be linked to differences in disease progression in subtype C HIV-1 infected children.

Distribution of Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 in maternal saliva and breast milk in Zambia: implications for transmission.

BACKGROUND: The seroprevalence of Kaposi sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8) in sub-Saharan Africa suggests that multiple routes of transmission exist. In the present study, we examined 2 possible routes of mother-to-child transmission, through breast milk and saliva, during the first 6 months after delivery. METHODS: The prevalence of HHV-8 DNA in the breast-milk cells (n=75), milk supernatant (n=56), colostrum (n=2), and saliva cells (n=65) of HHV-8-seropositive mothers who recently gave birth was examined. Polymerase chain reaction analysis was performed for the detection of HHV-8 in cross-sectional samples isolated at 2, 4, and 6 months after delivery. RESULTS: None of the 75 breast-milk samples but 2 of the colostrum samples that were analyzed contained HHV-8 DNA at a limit of detection of approximately 1 HHV-8 copy/10(4) cellular genomes, whereas Epstein-Barr virus DNA and HIV-1 DNA were detected in 16 and 22 samples, respectively. Analysis of 65 saliva cell samples, which were obtained from mothers who also provided milk samples, revealed that 19 of the samples had detectable HHV-8 DNA. Viral DNA was found at all time points, but the presence of viral DNA in saliva was independent of maternal HIV-1 serostatus (chi 2=0.33; P=.57). CONCLUSIONS: Our findings demonstrate the lack of HHV-8 DNA in the breast milk of seropositive mothers, and they suggest that contact with breast milk is not a likely source of horizontal transmission of virus to infants in sub-Saharan Africa.

Avaliação do InstantScreen na rotina, um ensaio ultra rápido para detecção de anticorpos anti-HIV-1/2 / Evaluation of InstantScreen under routine, an ultra rapid HIV-1/2 assay for the detection of HIV antibodies

Objetivo: Avaliar o InstantScreen Rapid HIV-1/2(GAIFAR GmbH, Alemanha), em condições de rotina em Caxias do Sul, RS, Brasil. Métodos: 781 amostras de soro coletadas de doadores de sangue, de pacientes com síndrome da imunodeficiência adquirida (SIDA), de gestantes e de crianças (<12 meses de idade) atendidas em instituições de saúde locais. Os testes foram realizados entre o dia 1 de abril até 20 de dezembro de 2001. O soro foi pesquisado para a presença de anticorpos anti HIV pelo InstantScreen assim como por testes de referência (Genscreen HIV 1/2 Vrsion 2, sanofi Pasteur; ICE HIV 1.0.2, Murex Diagnostics e Abbott Axsym HIV-1/HIV-2, Abbott Diagnostics. Resultados: 780 amostras testadas obtiveram os seguintes dados de desempenho: sensibilidade (IC = 95%) 160/160 = 100% (98-100%), especificidade (IC = 95%) 620/620 = 100% (99-100%). conclusão: O teste se mostrou de alta confiabilidade. As membranas do teste podem ser removidas, servindo de opção para a documentação permanente. Devido à facilidade de execução, o teste é adequado para ser utilizado nas mais variadas condições de trabalho.

Postnatal human herpesvirus 8 and human immunodeficiency virus type 1 infection in mothers and infants from Zambia.

The specific route and timing of human herpesvirus (HHV) 8 infection in regions where Kaposi sarcoma is endemic are not known. HHV-8 infection and any risk factors that may be associated with HHV-8, including human immunodeficiency virus (HIV) type 1 infection, were monitored during the 12-month postdelivery period for 416 mothers and 485 infants from Lusaka, Zambia. HHV-8 incident infection rates during this period were 3.2 and 5.3 infections/100 person-years for infants and mothers, respectively. HHV-8 infection among infants was not associated with HHV-8 or HIV-1 infection in the mother. Among the HHV-8-positive infants, 2 of 12 tested were found to have HHV-8 DNA in their peripheral blood mononuclear cells at birth, which suggests that in utero infection is possible. However, most HHV-8-positive infants appeared to have acquired infection either intrapartum or postpartum. The present study indicates that transmission of HHV-8 to infants can occur early and is likely via multiple routes.