Subclinical HPV Research Articles

Salivary HPV infection in healthy people

Abstract Introduction In recent years, interest in human papillomavirus infections as a causative factor in epithelial cancer development has grown. Literature indicates that HPV involvement in malignant transformations in oral mucosa can vary significantly, from 0 up to 87%. The aim of our study was to detect the prevalence of salivary HPV infection among generally healthy adults. Materials and Methods The examination involved 139 patients, from whom 139 whole, 1.5ml saliva samples were obtained. HPV DNA was detected by the nested PCR technique. To visualize the PCR products electrophoresis reactions were carried out. Results Sample analysis showed that DNA for HPV was detected in 14 patients: 11 positive results were obtained from men, and 3 from women. This yields a high infection rate: 10.07%. Conclusions The HPV prevalence in the male group was more than twice as high as in the female group. Also, subclinical oral HPV infection was detected more frequently in young (19–39 years old) and older (=>60 years old) adults.

Detection of human papillomavirus subtypes harbored in the foreskin of asymptomatic boys: Controlled study

Human papillomavirus infection (HPV) is one of the most common sexually transmitted infections and can cause penile and anal cancer in men, and invasive cervical cancer in women. To evaulate the colonization of 32 HPV subtypes in the foreskin of boys. A prospective analysis was made of the data of 62 healthy boys who had undergone standard circumcision. Deoxyribonucleic acid (DNA) was isolated from the foreskin tissues, and the integrity of DNA was tested. The DNA of each patient was further assessed with real-time polymerase chain reaction (PCR) and the presence of 32 subtypes of HPV was explored. To confirm the results, melting curve analysis and agarose gel electrophoresis (AGE) were performed for all samples. Further analysis was made using LCD-array on six randomly selected samples to confirm the results together with negative and positive controls. The mean age of the boys was 6.8±2years at the time of surgery. All positive controls and samples were positive, all negative controls were negative in the first HPV amplification assay. All positive controls had typical melting curve peaks, whereas all sample amplifications had non-specific, atypical melting curves not fitting with those of the positive controls. Two bands of expected sizes (124 and 405bp) were only observed in positive controls, but not in negative controls or samples on AGE. The same results were observed on the 6 randomly selected samples using LCD-array. Consequently, all the foreskin samples were evaluated as negative for the 32 HPV types investigated in the study. Literature shows a high prevalence of genital HPV in newborns, in early infancy, late adolescence and adulthood. However there is a lack of data in literature on the prevalence in early and late childhood. The negative results of HPV colonization on the foreskin in the current study may be attributed to the conservative and mostly monogamous nature of most family structures in Turkey. The results of the present study have shown that foreskin tissue is not a natural reservoir for HPV and subclinical HPV infection is not likely in the absence of suspected sexual contact.

P521 Infection of the anal canal by human papillomavirus in Crohn’s disease

Abstract Background Compare the frequency of subclinical papillomavirus (HPV) in the anal canal os Crohn′s disease (DC) patients to a control group by smear cytology and polymerase chain reaction (PCR) and hybridisation and to assess whether there is correlation with the presence of immunosuppression and anal manifestations of the disease, besides establishing the agreement between the two diagnostic methods used. Methods Two groups were selected, one with DC and others to be the control population. All the individuals were submitted to smear cytology (two brushes inserted in sequence in the anal canal) and a third one preserved for molecular analysis (PCR and hybridisation). The cytology was classified according to Bethesda criteria as normal, atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL). The molecular analysis was considered with HPV present or absent and types 16 and high-risk HPV group identified. Results During sixteen months, 104 patients underwent anal cytology collection for smear preparation and HPV molecular method detection. The control group consisted of 41 individuals and the DC of 63 patients (32 immunocompetent and 31 immunosuppressed). ASCUS and LSIL represented respectively 26.8% and 22.0% of the control patients and 28.6% and 39.7% of the Crohn′s patients, with no statistically significant difference between the groups. HPV was identified in 17.1% of patients in the control group and 27% of patients with CD by the molecular method, being predominantly high risk in both groups. In a subanalysis considering Crohn’s disease patients with and without immunosuppression and the control group, there was no statistical difference between the frequencies detected by PCR and hybridisation (p = 0.084) as well as the anal manifestation of Crohn’s disease. The Kappa coefficient for agreement between smear anal cytology and HPV identification by PCR and hybridisation was -0.127 in the total sample. Conclusion In this study, is possible to conclude that in the sample studied there was no difference between subclinical HPV anal infection between control patients and Crohn’s disease group evaluated by both cytology and hybridisation and immunosuppression and anal impairment did not influence these results either. Anal cytology and hybridisation did not show agreement represented by the Kappa coefficient in this population.

Prevalence and concordance of oral and genital HPV in women positive for cervical HPV infection and in their sexual stable partners: An Italian screening study.

ObjectivesThis cross-sectional study aimed to evaluate the prevalence and type of oral HPV-infection in women with a cervical HPV-lesion and in the oral and genital mucosa of their male partners.MethodsThe study group comprised 44 sexually-active women, 20–45 years with abnormal PAP smear, not more than 6 months prior to referral together with the male partners cohabiting in stable partnerships. A detailed questionnaire was administered concerning the HPV-related risk factors. Oral swabs, oral rinses, cervical swabs and urine samples were collected. HPV DNA was detected using two different polymerase chain reactions (PCRs): MY09-11 and FAP59-64. Positive samples were genotyped by Sanger sequencing and the INNO-LiPA HPV Genotyping Extra II probe assay. The association with risk factors was assessed by fitting a generalized model, using the General Linear Model function in the R-software; correlations were calculated between all data.ResultsHPV was detected in 84% of Cervical Samples, in 24.3% of oral samples and in one urine sample. Only 27% of the HPV-positive results were identical with both PCR DNA assays.8 male had oral HPV-positive samples different from women cervical samples. In one couple the urine-male sample had the same HPV present in the female-cervical sample. A significant association resulted between women/oral sex practices and men/n. of partners.ConclusionsThis study reports that women (20.4%) with a diagnosis of cervical-HPV and their male partners (30,7%) are at high risk for subclinical oral HPV infection.

Cross-sectional study of anal intraepithelial lesions in women with cervical neoplasia without HIV.

To evaluate the prevalence of anal intraepithelial lesions and associated risk factors in women with cervical neoplasia. The present cross-sectional study enrolled patients with intraepithelial or invasive cervical neoplasia who had been referred to the lower genital tract pathology outpatient department of the Instituto de Medicina Integral Prof. Fernando Figueira, Recife, Brazil, between December 1, 2008, and December 31, 2009; patients with HIV infections were excluded. All participants underwent anal cytology and high-resolution anoscopy; sociodemographic and clinical risk factors were identified using multivariate analysis. There were 324 patients included and 37 (11.4%) had anal intraepithelial neoplasia. Factors associated with anal intraepithelial neoplasia in the multivariate analysis were being older than 35years of age (P=0.002), having completed no more than 4years of education (P=0.012), anomalous anal cytology (P=0.003), and anomalous high-resolution anoscopy findings (P<0.001); subclinical HPV lesions on vulvoscopy (P=0.057) were not associated with anal intraepithelial neoplasia. The prevalence of anal intraepithelial neoplasia was high among patients with cervical neoplasia who did not have HIV, particularly patients older than 35years.

Retinol as a micronutrients related to cervical local immunity: The expression of tumor necrosis factor-alpha specifically stimulated with E6 epitope of human papillomavirus type-16 and ratio of CD4+/CD8+ T cell in natural history of cervical cancer

Retinol is one of the antioxidant micronutrients that plays essential roles in the immune system, by preventing the persistence of modulating CD4+ and CD8+ T cells and cytokines production. Tumor Necrosis Factor-Alpha (TNF-α) is an acute pro-inflammatory cytokine which has many crucial roles in controlling HPV. In contrast, when persistent infection occurs, TNF-α induces carcinogenesis. The ratio of CD4+ cells to CD8+ T cells and adequate TNF-α production in acute HPV infection are key points for clearance. The aim of this research is to analyze the sufficiency level of retinol deposit, the expression of TNF-α, and the ratio of CD4+: CD8+ T cells in a normal cervix, clearance and persistent HPV subclinical infection, and cervical cancer group. The sufficiency level of retinol deposit was analyzed from peripheral blood using the ELISA method. The cervico-vaginal secretions, which were incubated for 24 hours, were stimulated specifically by E6 epitope HPV type-16, measuring TNF-α expression semi-quantitatively by the ELISpot method and CD4+/CD8+ T cells quantitatively by flowcytometry method. The sufficient level of retinol deposit in a normal cervix, clearance HPV subclinical infection, persistent, and cervical cancer group was 85%, 75% (OR 1.89), 33.3% (OR 11.33), and 75% (OR 1.89), respectively. The expression of TNF-α in normal cervix group was 10%, while for cervical cancer it was 75% (OR 27.00; p < 0.001). There was no expression in clearance and persistent HPV subclinical infection groups. A high ratio of CD4+: CD8+ T cells in the normal cervix and cervical cancer group was 10% and 25% (OR 0.33). There was no high ratio of CD4+: CD8+ T cells in clearance (OR 1.22) and persistent (OR 0.95) HPV subclinical infection groups. This study was able to prove that the normal cervix group has the highest retinol deposit sufficiency level and the cervical cancer group has the highest TNF-α expression (OR 27; p < 0.001). The lowest of retinol deposit sufficiency level was not in cervical cancer, but in the persistent HPV subclinical infection group (OR 11.33). There was significant correlation in TNF-α expression between cervical cancer and normal cervix (p < 0.001), cervical cancer and clearance subclinical HPV infection (p = 0.024), and between clearance and persistent group (p = 0.007).

Ethanol and acetaldehyde mediate folic acid and human papillomavirus-induced proliferation of oral squamous cell carcinoma cells in vitro

Background Although great scientific emphasis has been placed upon HPVas the primary cause of cervical cancers and its involvement in carcinogenic progression of other cancers, less attention has been focused on the secondary factors that are associated with progression from subclinical HPV infection to invasive carcinoma. Among the secondary factors that limit virus production and carcinogenic progression is CpG methylation of the HPV genome. Several studies now confirm that CpG site-specific methylation of HPV DNA, mediated in part by folate availability, is sufficient to suppress neoplastic progression. In contrast, demethylation or hypomethylation of HPV-DNA sequences is required for transformation, revealing the importance of preferential DNA methylation at CpG sites in the HPV long control region (LCR) between L1 and E6 HPV genes, in addition to the tumor suppressor sites in p53 exons 248 and 273. Because HPV has the potential to initiate oncogenesis, and also to modulate oral cancer growth and folate plays a central role in mediating the availability of methyl groups for CpG-specific DNA methylation (modulating both p53 and HPV mRNA expression) – an investigation of these inter-connected and inter-related mechanisms in oral cancers must be undertaken. In addition, ethanol and acetaldehyde may also play critical roles in determining folate availability, and are primary risk factors for the development of oral cancers, which makes the evaluation of these interconnected metabolic pathways critically important. Materials and methods Using a comprehensive series of integrated in vitro assays, including proliferation, viability and mRNA analysis using RT-PCR, distinct effects of ethanol and acetaldehyde administration were observed in the oral cancer cell lines, CAL27, SCC15 and SCC25. In addition, the growth modulating effects of HPV infection and FA supplementation were also examined.

Evolução dos doentes com citologia oncótica alterada e colposcopia anal normal

A citologia anal vem sendo usada para rastreamento do carcinoma anal e suas lesões precursoras nas populações de risco. Quando o raspado do canal anal mostra alterações citológicas está indicada o exame com colposcópio e ácido acético para identificar e realizar biópsia para confirmar o achado. Poucos estudos mostram o seguimento dos doentes tratados de condilomas acuminados perianais. Temos usado os métodos em associação e encontrado lesões subclínicas em metade dos doentes, cujo exame proctológico não revelava doença HPV induzida. Essas lesões são tratadas com tópicos. Entretanto, algumas citologias estavam alteradas e a colposcopia anal não revelou doença HPV induzida. O objetivo deste estudo foi observar o comportamento dessas lesões no seguimento semestral, durante 12 meses, e avaliar se a periodicidade da reavaliação foi suficiente para evitar o aparecimento das lesões de alto grau ou superior. Encontramos 58 (21%) entre 273 doentes nessas condições. As reavaliações de 22 deles após um ano mostraram que as colposcopias permaneceram normais em 17 (74%), sendo que em cinco (22%) a citologia voltou aos padrões normais e 12 (52%) persistiram com alterações. Os outros seis (26%) desenvolveram lesões clínicas ou subclínicas provocadas pelo HPV. As contagens de linfócitos T CD4 dos doentes HIV-positivos foram inferiores nos doentes cujas lesões progrediram. Os resultados permitiram concluir que as alterações podem progredir ou regredir neste grupo distinto de doentes, sendo relacionada à imunidade, e que o intervalo de seis meses é suficiente para cada reavaliação.

Aminolevulinic acid (ALA)-assisted photodynamic diagnosis of subclinical and latent HPV infection of external genital region

The relatively high recurrence rate of genital warts can be attributed to the unsuccessful elimination of viruses in areas of subclinical and latent infection. Therefore, the identification and treatment of the subclinical and latent infection is a key to reduce the recurrence. The goal of this study is to investigate the usefulness of 5-aminolevulinic acid (ALA)-assisted in situ fluorescence diagnosis of subclinical lesion and latent HPV infection. A total of 30 patients with histologically confirmed genital warts (condylomata acuminata) were subjected to topical application of ALA, acetic acid test, histopathologic examination and HPV DNA subtyping. Topical application of ALA was performed by applying 20% ALA cream to the lesion plus 2-cm margin for 2h followed by fluorescence examination. Correlations between histopathologic examination, aceto-whitening test, HPV DNA subtyping and fluorescence were examined. All warty lesions and subclinical lesions (n=25) showed red fluorescence and harbored HPV DNA (HPV6 or 11). Latent HPV infections at 0.5-2 cm away from the warty lesion also showed red fluorescence. Nonspecific fluorescence was associated with mucosa, inflammatory infiltration and erosive lesion. ALA-assisted photodynamic diagnosis could be employed for the detection of the lesion and subclinical lesion of genital warts. It is also useful in detecting latent HPV infection.

Editorial Comment on: Photodynamic Diagnosis in Urology: State-of-the-Art

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Resultados do exame anátomo-patológico e "Polymerase Chain Reaction (PCR)" na forma clinica e subclinica da infecção anal pelo Papilomavirus Humano (HPV): estudo em quatro grupos de pacientes

O Papilomavírus Humano tem alta incidência na população. O objetivo deste trabalho é o estudo dos resultados encontrados no exame anatomo-patológico e no PCR das formas clínica e subclínica da infecção anal por HPV em quatro grupos de pacientes. MÉTODO: Foram estudados 10 pacientes com prurido anal idiopático, seis com infecção genital pelo HPV, tratada, seis com condiloma anal tratado e oito com condiloma anal. As verrugas foram biopsiadas nos oito pacientes com condiloma e feito exame de anuscopia de alta resolução com biópsia dirigida nos outros 22 pacientes. O material foi encaminhado para exame anátomo-patológico e depois, a partir do mesmo bloco de parafina, foi feito o exame de PCR. Resultados: O anátomo-patológico foi positivo para HPV em todos os pacientes, sendo que nos oito com condiloma confirmou-se a forma clínica e em 22 diagnosticou-se a subclínica com 13 casos de neoplasia intraepitelial associada. O PCR foi positivo em 91,9% dos 22 pacientes da forma subclínica ao anátomo-patológico e em 87,5% dos oito pacientes da forma clínica. O tipo predominante nos casos de HPV anal subclínico foi o 16 e o predominante nas verrugas foi o 11. CONCLUSÕES: O exame anátomo-patológico foi positivo para HPV em todos os pacientes, propiciando também o diagnóstico de 13 casos de neoplasia intraepitelial, sendo dois de carcinoma "in situ". O PCR foi positivo em 91,9% dos pacientes da forma subclínica ao anátomo-patológico e em 87,5% da forma clínica ao anátomo-patológico. O tipo predominante da forma subclinica foi o 16 e das verrugas foi o 11.

Fluorescence Guided Laser Therapy of Urethral Warts

Summary Depending on the sensitivity of the various methods of detection, HPV infections of the urethra are found in up to 50% of the sexually active population, mainly in a latent, not virulent form. On the other hand, clinical and subclinical HPV lesions of the urethra are known to be infectious and therefore have to be treated. It was fluorescence urethroscopy that first allowed clinical marking as well as specifically targeted biopsy and treatment of subclinical urethral HPV lesions. These can be found in just under 30% of patients in whom urethral warts can be readily detected by conventional endoscopy. Fluorescence guided laser therapy is more effective than laser treatment under white-light conditions. Fluorescence diagnostics is thus a valuable complement to the HPV diagnostics and to the established Nd:YAG laser therapy of urethral HPV infections.

HUMAN PAPILLOMAVIRUS: Subclinical and Atypical Manifestations

Subclinical HPV infections, together with latent infections, are probably the most likely outcome after exposure to HPV. Subclinical infection is associated with symptoms such as burning, fissuring, and dyspareunia in some patients. Only these patients should be offered treatment. Diagnosing and treating asymptomatic HPV infection cannot be recommended until better knowledge about the infectious potential of the infection in that phase is obtained. Recently, results have been presented showing a median duration of HPV infection of only 8 months, and after 24 months, only 9% of the women studied continued to be infected. This provides the possibility to reassure patients with HPV infection that it is most likely a transient infection, and one should not worry unduly. In light of this knowledge, it seems unwise to diagnose an asymptomatic infection for which no effective treatment is available and for which the natural history and consequences remain unclear; however, if these lesions were found to have the potential to transmit HPV, the patient should be so counseled.

Treatment of anogenital warts

AbstractThis article critically reviews both established and experimental treatment modalities for anogenital (AG) warts. Efficacy, cost, safety, advantages and disadvantages of each therapy are directly compared and treatment algorithms are suggested. Treatment of AG warts in pregnant women and prepubertal children is discussed. As AG warts are a sexually transmitted disease (STD) prevention of infection and the need to screen and treat patients and their sexual partners for other concurrent infections is stressed. The majority of patients with AG warts also have subclinical or latent HPV infection/associated disease of the AG tract. In this regard alt such women should be screened for the presence of cervical intraepithelial neoplasia (CIN).

Anal intercourse: a risk factor for anal papillomavirus infection in women?

To determine whether anal intercourse is a risk factor for anal HPV infection in women. Results derived from clinical examination, anal cytology and HPV DNA hybridisation were correlated with data obtained from a questionnaire administered to the patients at the time of their clinical examination. A sexually transmitted diseases (STD) clinic in Sydney, Australia. 31 women attending the clinic for HPV related problems. A thorough history was elicited from each woman followed by physical examination of the anogenital region. Cervical and anal scrapes were collected for cytology and HPV DNA hybridisation. Of the 15 women who practised anal intercourse, a total of 12 (80%) had either clinical or subclinical HPV infection. Seven had overt anal warts, situated either internally or externally in the anal canal; and further 5 women had evidence of subclinical HPV infection as determined by positive cytological and/or HPV DNA hybridisation results on their anal scrapes. The women who did not have a history of anal intercourse had a lower (7/16, 43%), but not statistically significant, rate of anal HPV infection: five had anal warts and two had subclinical evidence of infection. No correlations were found between anal HPV infection and genital (cervical, vulval or vaginal) HPV infection; nor between the HPV typing patterns of women in either group. The results obtained from these women do not indicate a close relationship between anal intercourse and the presence of detectable anal HPV infection.

Survey of human papilloma virus infection in the cervix of pregnant females in Hong Kong

Information about clinical and subclinical HPV infection in the local population is scanty. Cytologlcal evidence of condyloma is only found in about 0.5% (359/70,000) of routine cervical smears in Hong Kong. Thus a very large survey would be necessary to gain significant epidemiological Information, even with the aid of the usual 3-fold increase seen with nucleic acid hybridization techniques. Pregnant Western females have been found to have an increased incidence of HPV infection of the cervix compared to non-pregnant females. Using Southern blot analysis this ranges as high as 28%. Thus a sequential series of 215 pregnant females attending an antenatal clinic of the University Obstetrical Unit were studied. After a cervical PAP smear was performed, cells were collected with a swab from the endocervlcal canal and transformation zone. The DNA dot-blot procedure utilised the specific binding of a mixture of complementary ³²P_labelled RNA probes to membrane-bound target HPV DNA types 6,11,16,18, 31,33. Positive and negative controls were used and the presence of DNA was confirmed in representative samples from the series. Of the cases studied, 6% (12/215) were positive for HPV DNA; specific subtyplng is in progress. A cytologlcal diagnosis of condyloma was made in 1.5% (3/215) of cervical smears. No examples of CIN were present. This Information provides baseline data for subsequent studies of cervical neoplasia.

Genital Papillomavirus Infections:: Current Knowledge and Future Prospects

Although much has been learned about the biology of HPV during the last decade, little progress has been made in the development of rational and effective patient management strategies. Without stronger evidence supporting a causal role for HPV in the development of genital tract and anal cancers, and without the availability of effective therapies, it is premature to recommend widespread screening for detection of HPV DNA or RNA with the molecular hybridization tests soon to be available commercially. Papanicolaou smear screening for detection of early precancerous changes of the cervix and referral for colposcopy and biopsy of areas of epithelium that are suspicious for intraepithelial neoplasia of the cervix, vagina, vulva, penis, or anus remain the cornerstones of genital tract and anal cancer prevention. The patient care implications of subclinical persistent HPV infection of the genital tract are not well understood. For this reason, and because none of the available therapies are curative, treatment of large areas of normal-appearing genital tract epithelium also cannot be recommended at this time. It is hoped that, with the growing research focus on therapies that have the potential for virologic cure, some day effective treatment for subclinical infection will be available. Until that time, patients with recalcitrant or recurring genital warts may benefit most by the sequential application of different treatment modalities.

Genital Human Papillomavirus Infections

In summary, the development of new techniques to identify HPV DNA in genital secretions and tissue, the recognition of subclinical HPV infection, and the remarkable association between HPV and genital neoplasia have markedly increased the concern of both patients and physicians about genital wart virus infections. The prevalence of this viral STD appears to be increasing and the clinical spectrum of disease appears to be expanding. New methods to diagnose genital HPV infection and techniques to treat these infections more effectively are under development. It is hoped that these techniques will provide the tools to understand and more effectively control this important infection.

Accuracy of Pap Smear and Colposcopy in the Detection of Condyloma of the Cervix

ABSTRACT Because of a perceived failure to detect many cases of cervical condyloma, the cervical cytologic and colposcopic findings were retrospectively reviewed in 150 patients referred for colposcopy to evaluate abnormal cytology. Colposcopic findings, cytology slides, and histologic specimens were reviewed in concert. Pap smear and colposcopy were equally effective in detecting the presence of cervical condyloma (58% and 57%, respectively). The inability of the colposcope consistently to distinguish between mild dysplasia and flat condyloma, and the paucity of koilocytes on many Pap smear specimens accounted for the relatively high percentage of patients with condyloma on biopsy not detected previously. Biopsy thus remains the cornerstone in the diagnosis of subclinical HPV infection of the cervix, and Pap smear is equally as effective as colposcopy in screening for this disease.