Elizabeth R. Unger

Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution

BackgroundChronic fatigue syndrome (CFS) is defined by symptoms and disability, has no confirmatory physical signs or characteristic laboratory abnormalities, and the etiology and pathophysiology remain unknown. Difficulties with accurate case ascertainment contribute to this ignorance.MethodsExperienced investigators from around the world who are involved in CFS research met for a series of three day workshops in 2000, 2001 and 2002 intended to identify the problems in application of the current CFS case definition. The investigators were divided into focus groups and each group was charged with a topic. The investigators in each focus group relied on their own clinical and scientific knowledge, brainstorming within each group and with all investigators when focus group summaries were presented. Relevant literature was selected and reviewed independent of the workshops. The relevant literature was circulated via list-serves and resolved as being relevant by group consensus. Focus group reports were analyzed and compiled into the recommendations presented here.ResultsAmbiguities in the current CFS research definition that contribute to inconsistent case identification were identified. Recommendations for use of the definition, standardization of classification instruments and study design issues are presented that are intended to improve the precision of case ascertainment. The International CFS Study Group also identified ambiguities associated with exclusionary and comorbid conditions and reviewed the standardized, internationally applicable instruments used to measure symptoms, fatigue intensity and associated disability.ConclusionThis paper provides an approach to guide systematic, and hopefully reproducible, application of the current case definition, so that case ascertainment would be more uniform across sites. Ultimately, an operational CFS case definition will need to be based on empirical studies designed to delineate the possibly distinct biological pathways that result in chronic fatigue.

Reduction in Human Papillomavirus (HPV) Prevalence Among Young Women Following HPV Vaccine Introduction in the United States, National Health and Nutrition Examination Surveys, 2003–2010

BACKGROUND Human papillomavirus (HPV) vaccination was introduced into the routine immunization schedule in the United States in late 2006 for females aged 11 or 12 years, with catch-up vaccination recommended for those aged 13-26 years. In 2010, 3-dose vaccine coverage was only 32% among 13-17 year-olds. Reduction in the prevalence of HPV types targeted by the quadrivalent vaccine (HPV-6, -11, -16, and -18) will be one of the first measures of vaccine impact. METHODS We analyzed HPV prevalence data from the vaccine era (2007-2010) and the prevaccine era (2003-2006) that were collected during National Health and Nutrition Examination Surveys. HPV prevalence was determined by the Linear Array HPV Assay in cervicovaginal swab samples from females aged 14-59 years; 4150 provided samples in 2003-2006, and 4253 provided samples in 2007-2010. RESULTS Among females aged 14-19 years, the vaccine-type HPV prevalence (HPV-6, -11, -16, or -18) decreased from 11.5% (95% confidence interval [CI], 9.2-14.4) in 2003-2006 to 5.1% (95% CI, 3.8-6.6) in 2007-2010, a decline of 56% (95% CI, 38-69). Among other age groups, the prevalence did not differ significantly between the 2 time periods (P > .05). The vaccine effectiveness of at least 1 dose was 82% (95% CI, 53-93). CONCLUSIONS Within 4 years of vaccine introduction, the vaccine-type HPV prevalence decreased among females aged 14-19 years despite low vaccine uptake. The estimated vaccine effectiveness was high.

Prevalence of Genital Human Papillomavirus Among Females in the United States, the National Health and Nutrition Examination Survey, 2003–2006

BACKGROUND Genital human papillomaviruses (HPV) include >40 sexually transmitted viruses. Most HPV infections do not progress to disease, but infection with certain types of HPV can cause cervical and other anogenital and oropharyngeal cancer, and other types of HPV are associated with anogenital warts. HPV vaccines prevent infection with HPV 16 and 18, which account for 70% of cases of cervical cancer, and HPV 6 and 11, which cause 90% of the cases of anogenital warts. METHODS Using data and self-collected cervicovaginal specimens from 4150 females, 14-59 years of age, from consecutive National Health and Nutrition Examination Surveys (2003-2006), we estimated the prevalence of type-specific HPV DNA and examined sociodemographic and sexual determinants. RESULTS The overall prevalence of HPV was 42.5% in females 14-59 years of age and varied significantly by age, race or ethnicity, and number of sex partners. Individual type prevalence was less than 7%, ranging from <0.5% through 6.5%. The most common type was nononcogenic HPV 62 (found in 6.5% of subjects), followed by HPV 53 and HPV 16 (4.7%), both of which are oncogenic types. The most prevalent species was nononcogenic α3. CONCLUSIONS HPV infection is common among US females, with the highest burden of infection found in young females 20-24 years of age. Monitoring trends in HPV type distribution will contribute to our understanding of the early impact of HPV vaccines.

Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study

BackgroundThe lack of standardized criteria for defining chronic fatigue syndrome (CFS) has constrained research. The objective of this study was to apply the 1994 CFS criteria by standardized reproducible criteria.MethodsThis population-based case control study enrolled 227 adults identified from the population of Wichita with: (1) CFS (n = 58); (2) non-fatigued controls matched to CFS on sex, race, age and body mass index (n = 55); (3) persons with medically unexplained fatigue not CFS, which we term ISF (n = 59); (4) CFS accompanied by melancholic depression (n = 27); and (5) ISF plus melancholic depression (n = 28). Participants were admitted to a hospital for two days and underwent medical history and physical examination, the Diagnostic Interview Schedule, and laboratory testing to identify medical and psychiatric conditions exclusionary for CFS. Illness classification at the time of the clinical study utilized two algorithms: (1) the same criteria as in the surveillance study; (2) a standardized clinically empirical algorithm based on quantitative assessment of the major domains of CFS (impairment, fatigue, and accompanying symptoms).ResultsOne hundred and sixty-four participants had no exclusionary conditions at the time of this study. Clinically empirical classification identified 43 subjects as CFS, 57 as ISF, and 64 as not ill. There was minimal association between the empirical classification and classification by the surveillance criteria. Subjects empirically classified as CFS had significantly worse impairment (evaluated by the SF-36), more severe fatigue (documented by the multidimensional fatigue inventory), more frequent and severe accompanying symptoms than those with ISF, who in turn had significantly worse scores than the not ill; this was not true for classification by the surveillance algorithm.ConclusionThe empirical definition includes all aspects of CFS specified in the 1994 case definition and identifies persons with CFS in a precise manner that can be readily reproduced by both investigators and clinicians.

Seroprevalence of Human Papillomavirus Type 16 Infection in the United States

Infection with human papillomavirus (HPV) type 16 accounts for about half of cervical cancers worldwide. This study investigated the seroepidemiology of HPV-16 infection in the United States by using a population-based survey. Serum samples and questionnaire data were collected from 1991 to 1994 for the National Health and Nutrition Examination Surveys. HPV-16-specific IgG antibody was detected by use of an HPV-16 virus-like particle ELISA. HPV-16 seropositivity in the US population aged 12-59 years was 13.0% (95% confidence interval, 11.5%-14.7%). Seroprevalence was higher in women (17.9%) than in men (7.9%). Age, race/ethnicity, and number of lifetime sex partners were associated with HPV seropositivity in women. Race/ethnicity, age at first intercourse, urban/nonurban residence, years of sexual activity, and having had sex with a man were associated with HPV seropositivity in men. Information on HPV-16 seroepidemiology will be important for designing prevention efforts including vaccine programs.

Seroprevalence of Human Papillomavirus Types 6, 11, 16, and 18 in the United States: National Health and Nutrition Examination Survey 2003–2004

BACKGROUND Human papillomavirus (HPV) seroprevalence data can help define the epidemiology of this common sexually transmitted pathogen. METHODS We determined the seroprevalence of HPV types 6, 11, 16, and 18 (HPV types in the quadrivalent vaccine) among 4303 persons aged 14-59 years who participated in the National Health and Nutrition Examination Survey 2003-2004. RESULTS The seroprevalences of HPV types 6, 11, 16, and 18 among female subjects were 17.0%, 7.1%, 15.6%, and 6.5%, respectively. Among males, the seroprevalences were lower for each type, with 6.3% observed for HPV-6, 2.0% for HPV-11, 5.1% for HPV-16, and 1.5% for HPV-18 (P < .001 for all comparisons). For any HPV vaccine type, the seroprevalence was 32.5% among females and 12.2% among males; the seroprevalence of any HPV vaccine type increased with age, reaching 42.0% among women aged 30-39 years and 18.0% among men aged 50-59 years. Antibodies to all 4 vaccine types were detected in 0.4% of females and 0% of males. Non-Hispanic blacks had a higher seroprevalence of any HPV vaccine type than that observed for non-Hispanic whites or Mexican Americans. Age and lifetime number of sex partners were factors independently associated with seroprevalence of any HPV vaccine type among both females and males, and poverty level was also a factor among females. CONCLUSIONS This is the first population-based seroprevalence study in the United States of all 4 HPV types targeted by the quadrivalent vaccine, and its findings can inform vaccine policy.

Prevalence of HPV After Introduction of the Vaccination Program in the United States

BACKGROUND: Since mid-2006, human papillomavirus (HPV) vaccination has been recommended for females aged 11 to 12 years and through 26 years if not previously vaccinated. METHODS: HPV DNA prevalence was analyzed in cervicovaginal specimens from females aged 14 to 34 years in NHANES in the prevaccine era (2003–2006) and 4 years of the vaccine era (2009–2012) according to age group. Prevalence of quadrivalent HPV vaccine (4vHPV) types (HPV-6, -11, -16, and -18) and other HPV type categories were compared between eras. Prevalence among sexually active females aged 14 to 24 years was also analyzed according to vaccination history. RESULTS: Between the prevacccine and vaccine eras, 4vHPV type prevalence declined from 11.5% to 4.3% (adjusted prevalence ratio [aPR]: 0.36 [95% confidence interval (CI): 0.21–0.61]) among females aged 14 to 19 years and from 18.5% to 12.1% (aPR: 0.66 [95% CI: 0.47–0.93]) among females aged 20 to 24 years. There was no decrease in 4vHPV type prevalence in older age groups. Within the vaccine era, among sexually active females aged 14 to 24 years, 4vHPV type prevalence was lower in vaccinated (≥1 dose) compared with unvaccinated females: 2.1% vs 16.9% (aPR: 0.11 [95% CI: 0.05–0.24]). There were no statistically significant changes in other HPV type categories that indicate cross-protection. CONCLUSIONS: Within 6 years of vaccine introduction, there was a 64% decrease in 4vHPV type prevalence among females aged 14 to 19 years and a 34% decrease among those aged 20 to 24 years. This finding extends previous observations of population impact in the United States and demonstrates the first national evidence of impact among females in their 20s.

US Assessment of HPV Types in Cancers: Implications for Current and 9-Valent HPV Vaccines

BACKGROUND This study sought to determine the prevaccine type-specific prevalence of human papillomavirus (HPV)-associated cancers in the United States to evaluate the potential impact of the HPV types in the current and newly approved 9-valent HPV vaccines. METHODS The Centers for Disease Control and Prevention partnered with seven US population-based cancer registries to obtain archival tissue for cancers diagnosed from 1993 to 2005. HPV testing was performed on 2670 case patients that were fairly representative of all participating cancer registry cases by age and sex. Demographic and clinical data were evaluated by anatomic site and HPV status. Current US cancer registry data and the detection of HPV types were used to estimate the number of cancers potentially preventable through vaccination. RESULTS HPV DNA was detected in 90.6% of cervical, 91.1% of anal, 75.0% of vaginal, 70.1% of oropharyngeal, 68.8% of vulvar, 63.3% of penile, 32.0% of oral cavity, and 20.9% of laryngeal cancers, as well as in 98.8% of cervical cancer in situ (CCIS). A vaccine targeting HPV 16/18 potentially prevents the majority of invasive cervical (66.2%), anal (79.4%), oropharyngeal (60.2%), and vaginal (55.1%) cancers, as well as many penile (47.9%), vulvar (48.6%) cancers: 24 858 cases annually. The 9-valent vaccine also targeting HPV 31/33/45/52/58 may prevent an additional 4.2% to 18.3% of cancers: 3944 cases annually. For most cancers, younger age at diagnosis was associated with higher HPV 16/18 prevalence. With the exception of oropharyngeal cancers and CCIS, HPV 16/18 prevalence was similar across racial/ethnic groups. CONCLUSIONS In the United States, current vaccines will reduce most HPV-associated cancers; a smaller additional reduction would be contributed by the new 9-valent vaccine.

Human Papillomavirus Infection and Cervical Cytology in Women Screened for Cervical Cancer in the United States, 2003–2005

Some cervical cancer screening programs test for human papillomavirus (HPV) only after abnormal Papanicolaou (Pap) test results, whereas others perform both tests routinely and repeat testing if ei...

Epidemiology of Human Papillomavirus Infection and Abnormal Cytologic Test Results in an Urban Adolescent Population

We determined the prevalence of and the risk factors for human papillomavirus (HPV) infection and abnormal cytologic test results in 312 adolescent girls (mean age, 16.1 years). Subjects had a median of 2 years of sexual activity and 4 lifetime sex partners. Cervical HPV was detected by use of L1-consensus polymerase chain reaction in 64% of subjects; half of those with HPV had >1 type, and 77% had >/=1 high-risk type. Independent risk factors for HPV were lifetime number of sex partners, age of partner, and douching. Cytologic abnormalities were common (20.9% of subjects had atypical squamous cells of uncertain significance, and 17.0% had high- or low-grade squamous intraepithelial lesions) and were significantly associated with detection of HPV (P=.0001); however, most (51.6%) subjects with HPV had normal cytologic test results.