The Spectrum of Influenza in Children.

BACKGROUND: Children constitute an important component of the influenza burden and community transmission, but the frequency of asymptomatic infection and post-influenza sequelae at the community level is poorly understood. METHODS: Two community-based prospective cohort studies (2011-2020, 2017-2020) and 1 case-ascertained study (2012-2017) were conducted in Managua, Nicaragua. Non-immunocompromised children aged 0-14 years with ≥1 influenza infections, determined by polymerase chain reaction and hemagglutination inhibition assay, were included. RESULTS: A total of 1272 influenza infections occurred in the household-based portion of the study. Influenza infection was asymptomatic in 84 (6.6%) infections, and the asymptomatic fraction increased with age (1.7%, 3.5%, and 9.1% for ages 0-1, 2-4, and 5-14, respectively; P < .001). Of asymptomatic children, 43 (51.2%) shed virus, compared to 1099 (92.5%) symptomatic children (P < .001). Also, 2140 cases of influenza occurred in the primary care portion of the study. Sequelae of influenza were rare, with the most common being pneumonia (52, 2.4%) and acute otitis media (71, 3.3%). A/H1N1 had higher age-adjusted odds of acute otitis media (odds ratio [OR] 1.99, 95% confidence interval [CI]: 1.14-3.48; P = .015) and hospitalization (OR 3.73, 95% CI: 1.68-8.67; P = .002) than A/H3N2. B/Victoria had higher age-adjusted odds of pneumonia (OR 10.99, 95% CI: 1.34-90.28; P = .026) than B/Yamagata. CONCLUSIONS: Asymptomatic influenza infection is much less common in children than adults, although viral shedding still occurs in asymptomatic children. Post-influenza sequelae are rare in children in the community setting, and virus strain may be important in understanding the risk of sequelae.

Association of SARS-CoV-2 Seropositivity and Symptomatic Reinfection in Children in Nicaragua.

Importance: The impact of the SARS-CoV-2 pandemic on children remains unclear. Better understanding of the burden of COVID-19 among children and their risk of reinfection is crucial, as they will be among the last groups vaccinated. Objective: To characterize the burden of COVID-19 and assess how risk of symptomatic reinfection may vary by age among children. Design, Setting, and Participants: In this prospective, community-based pediatric cohort study conducted from March 1, 2020, to October 15, 2021, 1964 nonimmunocompromised children aged 0 to 14 years were enrolled by random selection from the Nicaraguan Pediatric Influenza Cohort, a community-based cohort in District 2 of Managua, Nicaragua. Additional newborn infants aged 4 weeks or younger were randomly selected and enrolled monthly via home visits. Exposures: Prior COVID-19 infection as confirmed by positive anti-SARS-CoV-2 antibodies (receptor binding domain and spike protein) or real-time reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed COVID-19 infection at least 60 days before current COVID-19 infection. Main Outcomes and Measures: Symptomatic COVID-19 cases confirmed by real-time RT-PCR and hospitalization within 28 days of symptom onset of a confirmed COVID-19 case. Results: This cohort study assessed 1964 children (mean [SD] age, 6.9 [4.4] years; 985 [50.2%] male). Of 1824 children who were tested, 908 (49.8%; 95% CI, 47.5%-52.1%) were seropositive during the study. There were also 207 PCR-confirmed COVID-19 cases, 12 (5.8%) of which were severe enough to require hospitalization. Incidence of COVID-19 was highest among children younger than 2 years (16.1 cases per 100 person-years; 95% CI, 12.5-20.5 cases per 100 person-years), which was approximately 3 times the incidence rate in any other child age group assessed. In addition, 41 symptomatic SARS-CoV-2 episodes (19.8%; 95% CI, 14.4%-25.2%) were reinfections. Conclusions and Relevance: In this prospective, community-based pediatric cohort study, rates of symptomatic and severe COVID-19 were highest among the youngest participants, with rates stabilizing at approximately 5 years of age. In addition, symptomatic reinfections represented a large proportion of symptomatic COVID-19 cases.

Prevalence and determinants of oral and cervicogenital HPV infection: Baseline analysis of the Michigan HPV and Oropharyngeal Cancer (MHOC) cohort study.

We determined baseline oral and cervicogenital human papillomavirus (HPV) prevalence and determinants of infection in the Michigan HPV and Oropharyngeal Cancer (MHOC) study. We enrolled 394 college-age and older participants of both sexes in Ann Arbor, Michigan and the surrounding area. All participants provided an oral sample at baseline, and 130 females provided a cervicogenital sample. Samples were tested for 18 HPV genotypes using polymerase chain reaction (PCR) MassArray. Participants filled out sociodemographic and behavioral questionnaires. Prevalence ratios for HPV oral or cervicogenital prevalence by predictor variables were estimated in univariable log-binomial models. Analysis was conducted 2018-20. In the full cohort, baseline oral HPV prevalence was 10.0% for any detected genotype (among the 338 valid oral tests at baseline) and 6.5% for high-risk types, and cervicogenital prevalence was 20.0% and 10.8%, respectively (among the 130 first valid cervicogenital tests). Oral HPV prevalence did not vary by sex, with 10.5% of women and 9.0% of men having an infection. We found a high prevalence of oral and cervicogenital HPV infection in college-age participants reporting no lifetime sexual partners. Reporting a single recent partner was associated with a lower oral HPV prevalence (PR 0.39, 95% CI: 0.16, 0.96) than reporting no recent (but at least one ever) partner. No similar protective effect was seen for cervicogenital HPV. Both oral and cervicogenital prevalence increased with the number of recent partners for most sexual behaviors. We observed an ecological fallacy masking the direction of impact of vaccination on HPV prevalence in the full cohort compared to the college-aged and the age 23+ populations considered separately. Substance use was not significantly associated with oral or cervicogenital HPV infection. Many studies report substantially higher oral HPV infection prevalence in men than in women. That difference may not be uniform across populations in the US.

Oral human papillomavirus prevalence, persistence, and risk-factors in HIV-positive and HIV-negative adults.

BACKGROUND: HIV has been shown to increase the likelihood of oral HPV infection. In this study, we evaluated the risk of oral HPV in HIV infected patients compared with HIV-negative controls. METHODS: 101 healthy adult volunteers (HIV-) and 245 adults living with HIV infection (HIV+) were recruited from 5 academic medical centers. Questionnaires and saliva samples were obtained every 3-8 months over a period of 2 years (2015-2017). DNA was isolated from the saliva samples and tested for 18 high- and low-risk genotypes. RESULTS: Oral HPV was detected in 23% of HIV + vs. 10% of HIV- participants (p < 0.0001). Men had a higher oral HPV prevalence than women (27% vs. 15% HIV+, p = 0.03, 16% vs. 5% HIV-, p = 0.01). Risk factors among HIV + participants included more lifetime deep kissing and oral sex partners, and history of AIDS. Persistent oral HPV was detected in 23% of HIV + vs. 5% of HIV- participants (p < 0.001). Among 8 HIV + participants with CD4 counts <200 cell/µL none had cleared their HPV infection during the study. CONCLUSIONS: Risk of oral HPV infection and persistence was significantly higher in HIV + adults with a history of poorly controlled HIV, which may put them at increased risk of HPV-associated cancer.

Burden of SARS-CoV-2 and protection from symptomatic second infection in children.

IMPORTANCE: The impact of the SARS-CoV-2 pandemic on children remains unclear. Better understanding of the burden of COVID-19 among children and their protection against re-infection is crucial as they will be among the last groups vaccinated. OBJECTIVE: To characterize the burden of COVID-19 and assess how protection from symptomatic re-infection among children may vary by age. DESIGN: A prospective, community-based pediatric cohort study conducted from March 1, 2020 through October 15, 2021. SETTING: The Nicaraguan Pediatric Influenza Cohort is a community-based cohort in District 2 of Managua, Nicaragua. PARTICIPANTS: A total of 1964 children aged 0-14 years participated in the cohort. Non-immunocompromised children were enrolled by random selection from a previous pediatric influenza cohort. Additional newborn infants aged ≤4 weeks were randomly selected and enrolled monthly, via home visits. EXPOSURES: Prior COVID-19 infection as confirmed by positive anti SARS-CoV-2 antibodies (receptor binding domain [RBD] and spike protein) or real time RT-PCR confirmed COVID-19 infection ≥60 days prior to current COVID-19. MAIN OUTCOMES AND MEASURES: Symptomatic COVID-19 cases confirmed by real time RT-PCR and hospitalization within 28 days of symptom onset of confirmed COVID-19 case. RESULTS: Overall, 49.8% of children tested were seropositive over the course of the study. There were also 207 PCR-confirmed COVID-19 cases, 12 (6.4%) of which were severe enough to require hospitalization. Incidence of COVID-19 was highest among children aged <2 years-16.1 per 100 person-years (95% Confidence Interval [CI]: 12.5, 20.5)-approximately three times that of children in any other age group assessed. Additionally, 41 (19.8%) symptomatic SARS-CoV-2 episodes were re-infections, with younger children slightly more protected against symptomatic reinfection. Among children aged 6-59 months, protection was 61% (Rate Ratio [RR]:0.39, 95% CI:0.2,0.8), while protection among children aged 5-9 and 10-14 years was 64% (RR:0.36,0.2,0.7), and 49% (RR:0.51,0.3-0.9), respectively. CONCLUSIONS AND RELEVANCE: In this prospective community-based pediatric cohort rates of symptomatic and severe COVID-19 were highest among the youngest participants, with rates stabilizing around age 5. Reinfections represent a large proportion of PCR-positive cases, with children <10 years displaying greater protection from symptomatic reinfection. A vaccine for children <5 years is urgently needed. KEY POINTS: Question: What is the burden of COVID-19 among young children and how does protection from re-infection vary with age?Findings: In this study of 1964 children aged 0-14 years children <5 years had the highest rates of symptomatic and severe COVID-19 while also displaying greater protection against re-infection compared to children ≥10 years.Meaning: Given their greater risk of infection and severe disease compared to older children, effective vaccines against COVID-19 are urgently needed for children under 5.

Incidence and clearance of oral and cervicogenital HPV infection: longitudinal analysis of the MHOC cohort study.

OBJECTIVES: The Michigan HPV and Oropharyngeal Cancer study aimed to evaluate patterns of oral and cervicogenital human papillomavirus (HPV) infection prevalence, incidence, and clearance as well as their relationship to sexual behaviours. DESIGN: Cohort SETTING: General public in and around Ann Arbor, Michigan. PARTICIPANTS: 394 college-age and older-adult participants of both sexes provided oral samples, and 325 completed at least 2 visits. 130 who provided a cervicogenital samples, and 127 completed at least 2 visits. OUTCOMES: Incidence and clearance rates as well as HRs for oral and cervicogenital HPV. RESULTS: Oral HPV infections were transient, with only 16% of genotypes persisting to the next visit. The mean time to clearance of a genotype was 46 days (95% CI 37 to 58). In contrast, cervicogenital infections were more persistent, with 56% of genotypes persisting to the next visit. The mean time to clearance of a genotype was 87 days (95% CI 74 to 102). HPV vaccination was associated with reduced incidence of cervicogenital HPV infection (HR 0.63; 95% CI 0.47 to 0.83) but not oral HPV infection. Incidence of oral HPV infection was associated with 2+ recent deep kissing partners (HR 2.00; 95% CI 1.13 to 3.56). Incidence of both oral (HR: 1.70; 95% CI 1.08 to 2.68) and cervicogenital (HR 2.46; 95% CI 1.69 to 3.59) was associated with 2+ recent sexual partners. CONCLUSIONS: Detection of oral HPV was highly transient, but incidence was associated with recent deep kissing and sexual partners. Detection of cervicogenital HPV was more persistent, and incidence was positively associated with recent sexual partners and negatively associated with HPV vaccination.

Characteristics of head and neck squamous cell carcinoma cell Lines reflect human tumor biology independent of primary etiologies and HPV status.

Explanations for the differences in clinical outcomes in head and neck squamous cell carcinomas (HNSCCs) when compared by similar tumor location, stage, nodal status, human papillomavirus (HPV) status, and patient history remain elusive. Cell lines are an excellent tool of study for understanding the in vitro properties of cancers. However, HNSCC cell lines from progression-free and/or HPV-positive tumors are very rare. Here we studied HPV-positive and HPV-negative University of Michigan squamous cell carcinoma cell lines (2 HPV-, 2 HPV16+, 1 HPV18+) coming from donors with nonoropharyngeal sites and variant clinical outcomes. Cell morphology and proliferation were assessed, and immunofluorescence and Western blotting evaluated tumor biomarkers (TP53, RB1, p16, HPV E6 and E7, EGFR, Cyclin D1, Ki-67, and beta-catenin). Slow in vitro proliferation, long lag phase before exponential proliferation, lower maximal cell density, and higher wild-type TP53 expression were common to cell lines from patients who experienced long-term disease-free survival. In contrast, shorter lag phases, rapid proliferation, and high maximal cell density were observed in cell lines from patients who experienced aggressive tumor progression leading to death. Membrane-bound beta-catenin was present in all cell lines, but nuclear beta-catenin was associated with the more lethal cancers. In summary, the HNSCC cell lines present key characteristics, independent of primary etiologies and HPV infection, that mirror the behavior of the tumors from which they were derived.

HPV vaccination has not increased sexual activity or accelerated sexual debut in a college-aged cohort of men and women.

BACKGROUND: The human papillomavirus (HPV) is the most common sexually transmitted infection and is linked to several types of cancer. HPV vaccination uptake in the U.S. is relatively low, despite the vaccine's high efficacy. Some parents of adolescents have concerns that vaccination will encourage sexual behavior and therefore choose not to vaccinate. Previous studies investigating vaccination and sexual behavior have included only young women and girls. METHODS: The objective of this study is to assess associations between HPV-vaccination and sexual behavior in a college-age cohort of both men and women. We analyzed questionnaire data collected from the Michigan HPV and Oropharyngeal Cancer Study, a cohort study designed to investigate HPV infection and its association with sexual behavior (data collected 2015-17, Ann Arbor, MI). Here, we consider vaccination status, sexual behavior, and substance use among 241 college-aged men and women. Logistic, Poisson, and Cox regression were used to determine the relationship between probability of sexual debut, number of sexual partners, and HPV vaccination status at baseline as well as between age at sexual debut and vaccination status at debut. RESULTS: HPV vaccination status was not significantly associated with an increased likelihood of sexual debut (odds ratio: 0.80 (95% CI: 0.41-1.58), decreased age of sexual debut (hazard ratio: 0.81 (95% CI: 0.65-1.00), nor an increased number of sexual partners (per year sexually active; incidence rate ratio: 1.27 (95% CI: 0.86-1.87)) in this cohort, after controlling for age, race, sex, and substance use. Instead, race or alcohol use were independent predictors of sexual behavior. CONCLUSIONS: Concerns about the influence of the HPV vaccine on sexual behavior are likely unfounded for both men and women. These results can aid in increasing vaccine acceptability, inform and strengthen physician recommendations, and ultimately reduce the burden of HPV and HPV-related cancers in the U.S.

Dynamics and Determinants of HPV Infection: The Michigan HPV and Oropharyngeal Cancer (M-HOC) Study.

INTRODUCTION: Human papillomavirus (HPV) is the primary cause of cervical and other anogenital cancers and is also associated with head and neck cancers. Incidence of HPV-related oropharyngeal squamous cell cancers (OPSCCs) is increasing, and HPV-related OPSCCs have surpassed cervical cancer as the most common HPV-related cancer in the USA. Given the multisite nature of HPV, there is strong interest in collecting data from both genital and oral sites, as well as associated data on social and sexual behaviours. The overarching goal of this study is to evaluate patterns of oral HPV infection incidence, clearance and persistence and their relationship to sexual behaviour history. METHODS AND ANALYSIS: Participants are recruited from two populations: college students at a large public university and general population from the surrounding area. At the first study visit, participants complete a detailed sexual history, health and behaviour questionnaire. Follow-up visits occur every 3-4 months over 3 years, when participants complete an abbreviated questionnaire. All participants provide a saliva sample at each visit, and eligible participants may provide a cervicovaginal self-swab. Genetic material isolated from specimens is tested for 15 high-risk and 3 low-risk HPV types. Statistical analyses will examine outcome variables including HPV prevalence, incidence, persistence and clearance. Logistic regression models will be used to estimate odds ratios and 95% confidence intervals for associations between the outcomes of interest and demographic/behavioural variables collected in the questionnaires. The longitudinal HPV infection data and detailed sexual history data collected in the questionnaires will allow us to develop individual-based network models of HPV transmission and will be used to parameterise multiscale models of HPV-related OPSC carcinogenesis. ETHICS AND DISSEMINATION: This study has been approved by the University of Michigan Institutional Review Board. All participants are consented in person by trained study staff. Study results will be disseminated through peer-reviewed publications.