Cutaneous infections from viral sources in solid organ transplant recipients.

INTRODUCTION: Solid organ transplant recipients (SOTRs) are susceptible to various dermatological complications caused by long-term immunosuppressive therapy. Of these complications, viral infections are noteworthy because of their high prevalence and the potential morbidity associated with viral carcinogenesis. OBJECTIVES: To evaluate the occurrence of cutaneous viral infections in SOTRs and their correlation with clinical features, transplant type, and the length and intensity of immunosuppressive therapy. METHODS: This retrospective cohort study included SOTRs followed up at the Department of Dermatology in a tertiary hospital. The outcomes analyzed were the occurrence of cutaneous viral infections, including human papillomavirus (HPV) infection, herpes simplex, herpes zoster, molluscum contagiosum, Merkel cell carcinoma, Kaposi's sarcoma, and cytomegalovirus, and the occurrence of HPV-related neoplasms. Clinical variables, such as length and intensity of immunosuppression, type of transplanted organ, and comorbidities, were analyzed as possible risk factors for cutaneous viral infections in SOTRs. RESULTS: A total of 528 SOTRs were included in this study, among which 53.8% had one or more viral infections. Of these, 10% developed a virus-associated malignancy (HPV-associated carcinoma, Merkel cell carcinoma, or Kaposi's sarcoma). The higher risk of viral infections among SOTRs was associated with cyclosporine intake (1.40-fold higher risk) and younger age at transplantation. The use of an immunosuppressive regimen, including additional drugs, was associated with a higher risk of genital HPV infection (1.50-fold higher risk for each incremental drug). CONCLUSIONS: The occurrence of cutaneous viral infections in SOTRs is directly associated with the duration and intensity of immunosuppressive therapy. Patients at higher risk were those taking drugs with a stronger impact on cellular immunity and/or those on an immunosuppressive regimen comprising various drugs.

Imprecision in adverse event reports following immunization against HPV in Japan and COVID-19 in the USA, UK, and Japan-and the effects of vaccine hesitancy and government policy.

INTRODUCTION: Erroneous reports of adverse events following immunization (AEFIs) likely exacerbated the 2013 collapse of Japan's HPV immunization program. A similar phenomenon characterized the first months of COVID-19 immunization programs in the USA, UK, and Japan with high rates of reported anaphylaxis. These reports illustrate the susceptibility of supposedly objective medical judgments to public anxiety. PURPOSE AND METHODS: This study documents inaccuracies in reported AEFIs using three quantitative methods. RESULTS: One of these quantitative methods revealed that false-positive rates for anaphylaxis reports following HPV and later COVID-19 vaccination ranged from 74 to 91 percent. However, unlike HPV vaccinations in Japan, anaphylaxis reports following COVID-19 vaccines fell in Japan, the USA and the UK in the latter months of 2021. Nevertheless, false-positive rates for anaphylaxis reports remained high, suggesting a high degree of imprecision in serious AEFI reports from many countries for many vaccines. Japan's HPV immunization program indicates that media reports, patient hesitancy, healthcare providers' perspectives on vaccine safety, and consistency of government messaging, all influence report number and accuracy. A parallel publication analyzes in depth how such factors affect AEFI reports. CONCLUSION: Confidence in the safety of the COVID-19 vaccines may have been bolstered trough rapid monitoring of AEFI reports and communication of these findings. This may partly explain the different trajectories of serious AEFI following HPV immunizations in Japan and COVID-19 immunizations in the USA, UK, and Japan.

A Nationwide Epidemiological Survey of Adolescent Patients With Diverse Symptoms Similar to Those Following Human Papillomavirus Vaccination: Background Prevalence and Incidence for Considering Vaccine Safety in Japan.

BACKGROUND: Since June 2013, Japan has suspended proactive recommendation of human papillomavirus (HPV) vaccination due to self-reported diverse symptoms, including pain and motor dysfunction, as possible serious adverse events following immunization. Although these symptoms may be seen in adolescents without HPV vaccination, their frequency, taking into account disease severity, has not been examined. METHODS: A two-stage, descriptive, nationwide epidemiological survey was conducted in 2016, with a 6-month target period from July 1 to December 31, 2015, to estimate the prevalence and incidence of diverse symptoms among Japanese adolescents without HPV vaccination. Participants were 11,037 medical departments in hospitals selected nationwide by stratified random sampling. Eligible patients had to satisfy four criteria: (1) aged 12-18 years upon visiting hospital; (2) having at least one of four symptoms/disorders (pain or sensory dysfunction, motor dysfunction, autonomic dysfunction, or cognitive impairment); (3) symptoms/disorders persisting for at least 3 months; and (4) both criteria (2) and (3) influence attendance at school or work. We then extracted data of patients with diverse symptoms similar to those after HPV vaccination while considering opinions of doctors in charge. RESULTS: Estimated 6-month period prevalence of diverse symptoms among girls aged 12-18 years without HPV vaccination was 20.2 per 100,000. Annual incidence was estimated to be 7.3 per 100,000. CONCLUSION: Adolescent Japanese girls without HPV vaccination also visited hospitals with diverse symptoms similar to those following HPV vaccination. Our findings predict the medical demands for coincident diverse symptoms, which are temporally associated with but not caused by HPV vaccination of Japanese adolescents.

The relationship between hormonal contraception and cervical dysplasia/cancer controlling for human papillomavirus infection: A systematic review.

OBJECTIVE: Studies on the effect of long-term use of combined oral contraceptives (COCs) on cervical dysplasia and/or cancer risk have been inconsistent. Less is known about the effects of other forms of hormonal contraception (HC). We examine whether HC use increases the risk of incident cervical intraepithelial neoplasia (CIN) 2, 3 and/or cancer after accounting for preexisting human papillomavirus (HPV) infection. STUDY DESIGN: Systematic review of prospective studies on HC use as risk factor for cervical dysplasia with HPV infection documented prior to outcome assessment including PubMed and EMBASE records between January 2000 and February 2020 (Prospero #CRD42019130725). RESULTS: Among nine eligible studies, seven described recency and type of HC use and therefore comprise the primary analysis; two studies limit comparisons to ever versus never use and are summarized separately. All seven studies explored the relationship between oral contraceptive (OC) use and cervical dysplasia/cancer incidence: two found increased risk (adjusted odds ratio, aOR = 1.5-2.7), one found no association but decreased risk when restricted to women with persistent HPV (adjusted hazard ratio = 0.5), and four found no association. None of the seven studies differentiated between COC and progestin-only pills (POPs) by use recency or duration. The only study that included injectable progestin-only contraception (DMPA) found increased CIN3 incidence among current versus never users (aOR = 1.6). The one study that included Norplant found no association. Two studies included intrauterine device (IUD) use, but did not differentiate between hormonal and copper IUDs, and found no association. CONCLUSION: We found no consistent evidence that OC use is associated with increased risk for cervical dysplasia/cancer after controlling for HPV infection. There were too few studies of progestin-only injectables, implants or IUDs to assess their effect on cervical dysplasia/cancer risk. IMPLICATIONS: Use of single self-reported HC measures and insufficient distinction by hormonal constituent cloud our understanding of whether some HCs increase risk for cervical cancer. Methodologically rigorous studies with distinct HCs measured as time-varying exposures are needed to inform cervical cancer prevention efforts and improve our understanding of cervical cancer etiology.

Prevalence of Human Papillomavirus Infection in the Head and Neck Area of Patients After Kidney Transplantation Treated With Immunosuppressive Therapy.

The introduction of new and stronger immunosuppressive agents has significantly improved the overall survival rate of patients with transplanted organs; however, prolonged use of immunosuppressive agents has led to severe complications, such as the development of de novo malignant cancers. The incidence of malignant tumors is 3 to 5 times greater among renal transplant recipients than that of the overall population. Traditional neoplasms of the head and neck region are associated with the addiction to smoking and drinking alcohol. However, recent studies indicate that cancers of the throat, tongue, and tonsils are primarily associated with the human papillomavirus (HPV) infection. At present, approximately 25% of the head and neck squamous cell carcinomas are associated with HPV infection. Therefore, we aimed to determine the incidence of oropharyngeal HPV infection in recipients with kidney transplants treated with immunosuppressive therapy and to determine the factors that may favor the contraction of infectious diseases. Furthermore, we considered the purpose of vaccination against HPV among transplant recipients. A total of 32 recipients with kidney transplants were included in this study. Medical history was obtained and a throat swab was collected from each patient. The presence of the HPV DNA in the throat was determined using the GP5+/GP6+ primers. According to our results, 28% of the recipients with kidney transplants were positive for oropharyngeal HPV infection. In addition, among the investigated risk factors, early commencement of the sexual life (below the age of 16 years) was significantly correlated with the development of oropharyngeal HPV infection.

Skin warts during fingolimod treatment in patients with multiple sclerosis.

BACKGROUND: Fingolimod is associated with different infections including lower respiratory tract, herpes virus, cryptococcal meningitis, histoplasmosis, progressive multifocal leukoencephalopathy, atypical mycobacterial infections, kaposi sarcoma and reactivation of hepatitis c. OBJECTIVES: To describe five cases of skin warts in MS patients treated with fingolimod at the American University of Beirut Medical Center (AUBMC) MS center (MSC). METHODS: We reviewed all MS patients treated with fingolimod at our MSC and identified patients who developed skin warts during treatment. We also reviewed a control group of patients treated with different interferons matched for age and sex. RESULTS: Of 220 patients treated with fingolimod at our MSC, 5 (2.2%) developed skin warts. In 220 patients treated with different interferons and matched for age and sex, no cases of skin warts could be detected. CONCLUSIONS: In conclusion, we report five patients who developed skin warts during fingolimod therapy, especially HPV-related, for an overall incidence of 2.2%. Larger cohorts are needed to confirm this proposed higher susceptibility of fingolimod-treated patients to HPV infections.

Association of DFNA5, SYK, and NELL1 variants along with HPV infection in oral cancer among the prolonged tobacco-chewers.

Southeast Asia, especially India, is well known for the highest use of smokeless tobacco. These products are known to induce oral squamous cell carcinoma. However, not all long-term tobacco-chewers develop oral squamous cell carcinoma. In addition, germline variants play a crucial role in susceptibility, prognosis, development, and progression of the disease. These prompted us to study the genetic susceptibility to oral squamous cell carcinoma among the long-term tobacco-chewers. Here, we presented a retrospective study on prolonged tobacco-chewers of Northeast India to identify the potential protective or risk-associated germline variants in tobacco-related oral squamous cell carcinoma along with HPV infection. Targeted re-sequencing (n = 60) of 170 genetic regions from 75 genes was carried out in Ion-PGM™ and validation (n = 116) of the observed variants was done using Sequenom iPLEX MassARRAY™ platform followed by polymerase chain reaction-based HPV genotyping and p16-immunohistochemistry study. Subsequently, estimation of population structure, different statistical and in silico approaches were undertaken. We identified one nonsense-mediated mRNA decay transcript variant in the DFNA5 region (rs2237306), associated with Benzo(a)pyrene, as a protective factor (odds ratio = 0.33; p = 0.009) and four harmful (odds ratio > 2.5; p < 0.05) intronic variants, rs182361, rs290974, and rs169724 in SYK and rs1670661 in NELL1 region, involved in genetic susceptibility to tobacco- and HPV-mediated oral oncogenesis. Among the oral squamous cell carcinoma patients, 12.6% (11/87) were HPV positive, out of which 45.5% (5/11) were HPV16-infected, 27.3% (3/11) were HPV18-infected, and 27.3% (3/11) had an infection of both subtypes. Multifactor dimensionality reduction analysis showed that the interactions among HPV and NELL1 variant rs1670661 with age and gender augmented the risk of both non-tobacco- and tobacco-related oral squamous cell carcinoma, respectively. These suggest that HPV infection may be one of the important risk factors for oral squamous cell carcinoma in this population. Finally, we newly report a DFNA5 variant probably conferring protection via nonsense-mediated mRNA decay pathway against tobacco-related oral squamous cell carcinoma. Thus, the analytical approach used here can be useful in predicting the population-specific significant variants associated with oral squamous cell carcinoma in any heterogeneous population.

Glucocorticosteroids and ciclosporin do not significantly impact canine cutaneous microbiota.

BACKGROUND: As prednisone and ciclosporin can have immunosuppressive effects and have been considered potential predisposing factors for skin infections, we investigated the impact of these drugs on the diversity of the cutaneous microbiota, the abundance of Malassezia and infection with Papillomaviruses. RESULTS: Six atopic, asymptomatic Maltese-beagle dogs were treated with ciclosporin for one month and then with prednisone for another month, with a one-month wash-out between treatments. The dogs were sampled on the abdomen and pinna before and after each treatment using a swab. Samples for Papillomavirus detection were obtained with cytobrush sticks. The bacterial microbiota was characterized using 16S amplicon high-throughput sequencing. Malassezia populations were quantified with nested real-time PCR targeting the ribosomal internal transcribed spacer 1. The diversity and composition of cutaneous microbiota was not impacted in a detectable manner by any of the treatments. As observed for the bacterial microbiota, Malassezia populations were not affected by treatment. Three dogs were positive for Papillomavirus at more than one timepoint, but an association with treatment was not apparent. CONCLUSIONS: Ciclosporin and prednisone at doses used for the treatment of atopic dermatitis do not impact the canine cutaneous microbiota in a detectable manner.

Human Papillomavirus in Kidney Transplant Recipients.

Human papillomavirus (HPV) is a common infection in kidney transplant recipients. HPV causes cervical, anal, vulvar, vaginal, penile and head and neck cancers. Kidney transplant recipients have a disproportionate burden of disease given prolonged immunosuppression. Given the long pre-invasive state of precancer lesions such as cervical intraepithelial neoplasia (CIN) and anal intraepithelial neoplasia (AIN) most HPV-cancers are preventable with screening and targeted treatment of disease. Pre-transplant vaccination of age-eligible kidney transplant recipients is otherwise ideal.

mRNA expression in cervical specimens for determination of severe dysplasia or worse in HPV-16/18-positive squamous lesions.

OBJECTIVES: The objective of current study was to determine the p16 mRNA level in cervical cells by relative quantification (RQ) and to test viral E6 expression in human papillomavirus (HPV) -16 or -18-positive specimens by widely used methods. We targeted the pivotal mRNA level associated with severe dysplasia or worse. MATERIALS AND METHODS: Cervical specimens were taken from 134 women with cervical disease and 132 women with normal cytologic results. The presence of HPV was analyzed by sequencing. The results of p16 and E6 analyses were statistically processed in receiver operating characteristic curve analysis to predict severe dysplasia or worse. RESULTS: The HPV DNA was detected in 81.4% (109/134) of women with cervical disease and in 27.3% (36/132) of women with normal cytologic results. HPV-16 or -18 were present in 59.7% (80/134) of abnormal specimens. p16 and E6 mRNA expression was increasing with severity of cervical dysplasia. p16 mRNA expression was found 4.35-fold and 13.15-fold increased in high-grade squamous intraepithelial lesions and squamous cell carcinomas, respectively. E6 mRNA expression was significantly increased (p = .0038) in severe dysplasias or worse. The RQ method achieved better sensitivity (82.6%), and E6 mRNA got better specificity (80.6%) for the prediction of severe dysplasia or worse. CONCLUSIONS: An increasing level of p16 and E6 mRNA transcripts could mean the potential of cervical dysplasia progression to cancer, but further studies should be done to confirm this proposition. Nevertheless, we consider using both tests to improve the sensitivity and specificity for prediction of severe dysplasia or worse.

The impact of glucocorticoids and anti-cd20 therapy on cervical human papillomavirus infection risk in women with systemic lupus erythematosus

OBJECTIVE: To identify the prevalence and factors associated with cervical human papillomavirus infection in women with systemic lupus erythematosus METHODS: This cross-sectional study collected traditional and systemic lupus erythematosus-related disease risk factors, including conventional and biologic therapies. A gynecological evaluation and cervical cytology screen were performed. Human papillomavirus detection and genotyping were undertaken by PCR and linear array assay. RESULTS: A total of 148 patients were included, with a mean age and disease duration of 42.5±11.8 years and 9.7±5.3 years, respectively. The prevalence of squamous intraepithelial lesions was 6.8%. The prevalence of human papillomavirus infection was 29%, with human papillomavirus subtype 59 being the most frequent. Patients with human papillomavirus were younger than those without the infection (38.2±11.2 vs. 44.2±11.5 years, respectively; p = 0.05), and patients with the virus had higher daily prednisone doses (12.8±6.8 vs. 9.7±6.7 mg, respectively; p = 0.01) and cumulative glucocorticoid doses (14.2±9.8 vs. 9.7±7.3 g, respectively; p = 0.005) compared with patients without. Patients with human papillomavirus infection more frequently received rituximab than those without (20.9% vs. 8.5%, respectively; p = 0.03). In the multivariate analysis, only the cumulative glucocorticoid dose was associated with human papillomavirus infection. CONCLUSIONS: The cumulative glucocorticoid dose may increase the risk of human papillomavirus infection. Although rituximab administration was more frequent in patients with human papillomavirus infection, no association was found. Screening for human papillomavirus infection is recommended in women with systemic lupus erythematosus. .

The impact of glucocorticoids and anti-cd20 therapy on cervical human papillomavirus infection risk in women with systemic lupus erythematosus.

OBJECTIVE: To identify the prevalence and factors associated with cervical human papillomavirus infection in women with systemic lupus erythematosus METHODS: This cross-sectional study collected traditional and systemic lupus erythematosus-related disease risk factors, including conventional and biologic therapies. A gynecological evaluation and cervical cytology screen were performed. Human papillomavirus detection and genotyping were undertaken by PCR and linear array assay. RESULTS: A total of 148 patients were included, with a mean age and disease duration of 42.5±11.8 years and 9.7±5.3 years, respectively. The prevalence of squamous intraepithelial lesions was 6.8%. The prevalence of human papillomavirus infection was 29%, with human papillomavirus subtype 59 being the most frequent. Patients with human papillomavirus were younger than those without the infection (38.2±11.2 vs. 44.2±11.5 years, respectively; p = 0.05), and patients with the virus had higher daily prednisone doses (12.8±6.8 vs. 9.7±6.7 mg, respectively; p = 0.01) and cumulative glucocorticoid doses (14.2±9.8 vs. 9.7±7.3 g, respectively; p = 0.005) compared with patients without. Patients with human papillomavirus infection more frequently received rituximab than those without (20.9% vs. 8.5%, respectively; p = 0.03). In the multivariate analysis, only the cumulative glucocorticoid dose was associated with human papillomavirus infection. CONCLUSIONS: The cumulative glucocorticoid dose may increase the risk of human papillomavirus infection. Although rituximab administration was more frequent in patients with human papillomavirus infection, no association was found. Screening for human papillomavirus infection is recommended in women with systemic lupus erythematosus.

Long-lasting immunoprotective and therapeutic effects of a hyperstable E7 oligomer based vaccine in a murine human papillomavirus tumor model.

Cervical cancer and many other anogenital and oropharyngeal carcinomas are strongly associated with high-risk human papillomavirus (HPV) persistent infections. HPV E7 oncoprotein is the major viral transforming factor, emerging as a natural candidate for immunotherapy, since it is constitutively expressed in HPV-induced cancer cells. We have previously shown that E7 can self-assemble into soluble and homogeneous spherical oligomers, named E7 soluble oligomers (E7SOs). These are highly resistant to thermal denaturation, providing an additional advantage given the demand for highly stable vaccine formulations. Here, we present a new chemically stabilized form of the E7SOs (E7SOx) and analyzed its effect in a murine HPV-tumor model. Vaccination of female mice with low doses of E7SOx combined with a CpG-rich oligonucleotide (ODN) as adjuvant elicits a strong long-lasting protection against E7-expressing tumor cells, preventing tumor outgrowth after rechallenge 90-days later. Therapeutic experiments showed that E7SOx/ODN vaccination significantly delays tumor growth and extends the time of survival of the treated mice in a dose-dependent manner. These proof-of-principle preclinical experiments denote the potential applicability of our E7SOx-based vaccine to the treatment of cervical cancer and other mucosal HPV-related neoplastic lesions. In addition to thermal, chemical and proteolysis stability, the combined recombinant and chemical modification nature of the E7SOx vaccine candidate, results in low-cost, of particular interest in developing countries, where most of the cervical cancer cases occur and the most affected population is at reproductive age.

Combined oral contraceptive use increases HPV persistence but not new HPV detection in a cohort of women from Thailand.

BACKGROUND: Women diagnosed with cervical cancer report longer duration and more recent use of combined oral contraceptives (COCs). It is unclear how COC use impacts risk of cervical carcinogenesis. METHODS: We estimated the risk of new human papillomavirus (HPV) DNA detection and persistence among 1135 human immunodeficiency virus (HIV)-negative women aged 20-37 years from Thailand who were followed for 18 months at 6-month intervals. Type-specific HPV DNA, demographic information, hormonal contraceptive use, sexual behavior, genital tract coinfection, and Papanicolaou test results were assessed at baseline and each follow-up. RESULTS: Women who reported current COC use during follow-up were less likely to clear HPV infection compared with nonusers, independent of sexual behavior, and Papanicolaou test diagnosis (AHR: 0.67 [95% CI: .49-.93]). Similar associations were not observed among women reporting current use of depomedroxyprogesterone acetate (DMPA). Neither COC nor DMPA use was significantly associated with new HPV DNA detection. CONCLUSIONS: These data do not support the hypothesis that contraceptive use is associated with cervical cancer risk via increased risk of HPV acquisition. The increased risk of HPV persistence observed among current COC users suggests a possible influence of female sex hormones on host response to HPV infection.

The association of current hormonal contraceptive use with type-specific HPV detection.

BACKGROUND: Increased duration of hormonal contraceptive (HC) use may be positively associated with the risk of invasive cervical cancer. METHODS: This is a secondary analysis from the HPV Sentinel Surveillance Study. The authors examined the association between type-specific human papillomavirus (HPV) detection and current HC use among 7718 women attending 26 sexually transmitted disease, family planning and primary care clinics in the USA. RESULTS: There was an association between HC use and HPV-16 detection (adjusted prevalence rate ratio 1.34 (95% CI 1.05 to 1.71) for oral contraceptive users and 1.41 (1.01 to 2.04) for depot-medroxyprogesterone acetate users); there was no association between HC use and detection of other HPV types or any HPV overall. CONCLUSIONS: Longitudinal studies are needed to better define this type-specific association and its clinical significance.

Hormonal contraceptives and the length of their use are not independent risk factors for high-risk HPV infections or high-grade CIN.

AIMS: To evaluate the role of hormonal contraceptives as a risk factor of high-risk human papillomavirus (HR-HPV), cervical intraepithelial lesions (CIN) and cervical cancer in our multi-center population-based LAMS (Latin American Screening) study. METHODS: A cohort study with >12,000 women from Brazil and Argentina using logistic regression to analyze the covariates of hormonal contraception (HOC - oral, injections, patches, implants, vaginal ring and progesterone intrauterine system) use followed by multivariate modeling for predictors of HR-HPV and CIN2+. RESULTS: HR-HPV infection was a consistent risk factor of high-grade CIN in all three groups of women. The length of HOC use was not significantly related to high-grade squamous intraepithelial lesions (HSIL)+ Pap (p = 0.069), LSIL+ Pap (p = 0.781) or ASCUS+ (p = 0.231). The same was true with the length of HOC use and histology CIN3+ (p = 0.115) and CIN2+ (p = 0.515). Frequently, HOC users have previously shown more HPV-related lesions, as well as lower HPV prevalence if they were current smokers. But HOC use and time of usage were not independent risk factors of either HR-HPV infection or high-grade CIN using multiple logistic regressions. CONCLUSIONS: No evidence was found for an association between the use of HOC with an increased risk for HR-HPV infection or high-grade CIN in this cohort.

Skin infections in HIV-infected individuals in the era of HAART.

PURPOSE OF REVIEW: Clinicians should be aware of the shift in the cutaneous infectious disease burden in human immunodeficiency virus-infected individuals as a reflection of immune restoration in the era of highly active antiretroviral therapy (HAART). RECENT FINDINGS: As in the general population but to greater extent, methicillin-resistant Staphylococcus aureus (MRSA) soft-tissue infection is a rising problem among those with human immunodeficiency virus (HIV). Human papilloma virus (HPV) is exceedingly prevalent and persistent despite HAART, and HPV-associated malignancy is increasing as those with HIV live longer. Herpes, syphilis, and Kaposi's sarcoma continue to plague individuals with HIV. Immune reconstitution inflammatory syndrome (IRIS) is common and often presents with infectious cutaneous manifestations. SUMMARY: This review implicates the importance of the acknowledgment of MRSA infections risk factors, screening for HPV-related neoplasia, continuance of trials to establish the efficacy of herpes vaccines, and awareness of prevalent cutaneous infections presenting with IRIS in those with HIV.