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Abstract: Respiratory syncytial virus (RSV) outbreaks in inpatient settings are associated with poor outcomes in cancer patients. The use of molecular epidemiology to document RSV transmission in the outpatient setting has not been well described. We performed a retrospective cohort study of 2 nosocomial outbreaks of RSV at the Seattle Cancer Care Alliance. Subjects included patients seen at the Seattle Cancer Care Alliance with RSV detected in 2 outbreaks in 2007-2008 and 2012 and all employees with respiratory viruses detected in the 2007-2008 outbreak. A subset of samples was sequenced using semi-nested PCR targeting the RSV attachment glycoprotein coding region. Fifty-one cases of RSV were identified in 2007-2008. Clustering of identical viral strains was detected in 10 of 15 patients (67%) with RSV sequenced from 2007 to 2008. As part of a multimodal infection control strategy implemented as a response to the outbreak, symptomatic employees had nasal washes collected. Of 254 employee samples, 91 (34%) tested positive for a respiratory virus, including 14 with RSV. In another RSV outbreak in 2012, 24 cases of RSV were identified; 9 of 10 patients (90%) had the same viral strain, and 1 (10%) had another viral strain. We document spread of clonal strains within an outpatient cancer care setting. Infection control interventions should be implemented in outpatient, as well as inpatient, settings to reduce person-to-person transmission and limit progression of RSV outbreaks. [Copyright &y& Elsevier]

Abstract: Human metapneumovirus (HMPV), a common respiratory virus, can cause severe disease in pre- and post-hematopoietic cell transplantation (HCT) recipients. We conducted a retrospective cohort analysis in HCT patients with HMPV (n = 23) or respiratory syncytial virus (n = 23) detected in bronchoalveolar lavage samples by reverse transcription PCR between 2006 and 2011 to determine disease characteristics and factors associated with outcome. Mortality rates at 100 days were 43% for both HMPV and respiratory syncytial virus lower respiratory tract disease. Steroid therapy, oxygen requirement >2 L or mechanical ventilation, and bone marrow as cell source were significant risk factors for overall and virus-related mortality in multivariable models, whereas the virus type was not. The presence of centrilobular/nodular radiographic infiltrates was a possible protective factor for mechanical ventilation. Thus, HMPV lower respiratory tract disease is associated with high mortality in HCT recipients. Earlier detection in combination with new antiviral therapy is needed to reduce mortality among HCT recipients. [Copyright &y& Elsevier]

Abstract: Background: The epidemiology of respiratory tract infections (RTIs) in a daycare cohort has not been explored using molecular techniques. Objectives: (1) Determine the overall incidence of RTIs in a daycare cohort using real-time reverse transcriptase polymerase chain reaction (RT-PCR). (2) Determine the relative incidence and impact of specific respiratory viruses, and characterize and compare clinical features associated with these pathogens. Study design: In this prospective cohort study conducted from February 2006 to April 2008, nasal swabs were obtained from symptomatic children ages 0–30 months enrolled in fulltime daycare. RT-PCR was performed to detect respiratory syncytial virus (RSV), human metapneumovirus (MPV), influenza (Flu) viruses A and B, parainfluenza (PIV), adenovirus (AdV), human coronaviruses (CoV) and rhinovirus (RhV). Symptom diaries were completed for each illness. Results: We followed 119 children (mean age 10 months; range 2–24 months) for 115 child years. The mean annual incidence of RTI per child was 4.2 the first year and 1.2 the second year of the study. At least 1 virus was identified in 67% RTIs. Co-infections were common (27% RTIs), with RhV, CoV, and AdV the most common co-pathogens. PIV was identified in 12% of RTIs with a high incidence of PIV4. The viruses with the greatest impact on our population were RSV, RhV and AdV. Conclusions: Using molecular techniques, viruses were identified in approximately twice as many RTIs as previously reported in a daycare cohort. Infections with newly identified viruses, such as HMPV and CoV subtypes were less frequent and severe than infections with RSV, AdV and RhV. [ABSTRACT FROM AUTHOR]

Objective: To determine the prevalence of pathogens that cause sexually transmitted infections (STIs) in semen from asymptomatic male infertility patients with and without leukocytospermia (LCS), and associations between STIs, inflammatory markers, and other semen variables.Design: Retrospective, controlled study.Setting: Academic Medical Center.Patient(s): Two hundred and forty-one male infertility patients undergoing routine semen analysis: 132 with LCS, and 109 without LCS.Intervention(s): None.Main Outcome Measure(s): The DNA from STI pathogens (human papillomavirus [HPV], cytomegalovirus [CMV], herpes simplex virus [HSV], human herpesvirus type 6 [HHV-6], Epstein-Barr virus [EBV], hepatitis B virus [HBV], and Chlamydia trachomatis [CT]), routine semen parameters, and markers of accessory gland and epididymal function and inflammation.Result(s): The DNA from STI pathogens was detected in 45/241 (18.7%) of the samples (CMV, 8.7%; HPV, 4.5%; HHV-6, 3.7%; HSV, 3.7%; CT, 2.5%; EBV, 0.4%; and HBV, 0%), with no difference in prevalence between the LCS and non-LCS groups. The DNA of STI pathogens in semen was associated with a decrease in sperm concentration, motile sperm concentration, total sperm count, and neutral alpha-glucosidase concentration, whereas LCS was associated with a decrease in total sperm count, percent normal forms, and fructose concentration.Conclusion(s): The DNA of STI pathogens was detected in semen from a high percentage of asymptomatic male infertility patients, and was associated with poor semen quality. Efforts to diagnose and treat subclinical genital-tract infections should be intensified. [ABSTRACT FROM AUTHOR]

Previous studies have characterized the prevalence and duration of serum IgG antibodies to human papillomavirus type 16 (HPV 16) in a well-studied cohort of college women, using viruslike particle- (VLP) based ELISAs. In this study IgA antibodies in cervical secretions and sera were examined using a newly developed capsomer-based ELISA and the patterns observed for serum IgG, serum IgA, and cervical IgA antibodies were compared. The median time to antibody detection from the first detection of HPV 16 DNA was 10.5 months for IgA in cervical secretions and 19.1 months for serum IgA. Serum IgA antibody conversion was observed less frequently and occurred later than IgA conversion in cervical secretions (P = 0.011) or serum IgG conversion (P = 0.051). The median time to antibody reversion, following seroconversion, was 12.0 months for IgA in cervical secretions and 13.6 months for serum IgA, whereas approximately 20% of women with serum IgG antibodies reverted within 36 months. Thus, the duration of IgA in cervical secretions and sera was shorter than the duration of serum IgG (P = 0.007 and 0.001). [Copyright &y& Elsevier]

Introduction Bacterial superinfection following moderate to severe respiratory viral infections (RVIs), especially influenza (Flu), is well described in immunocompetent hosts. The clinical impact of preceding RVIs on the development of bacterial superinfection in hematopoietic cell transplant (HCT) recipients may be significant although data are limited. Furthermore, the impact of upper respiratory tract infection (URTI) on this outcome has not been systematically evaluated. Objectives To investigate whether URTI due to specific respiratory viruses was associated with increased risk of developing bacteremia or bacterial pneumonia post-HCT. Methods In a longitudinal surveillance study of RVIs among allogeneic HCT recipients conducted from 2005-10, weekly post-HCT nasal washes were collected through day 100. Nasal and bronchoalveolar lavage samples were tested by multiplex PCR for respiratory syncytial virus, parainfluenza viruses (PIV)1–4, Flu A/B, human metapneumovirus (HMPV), adenovirus, rhinoviruses and coronaviruses. URTI was defined as having respiratory virus detected from nasal samples with respiratory symptoms. Bacteremia and bacterial pneumonia were defined as growth of significant bacteria (e.g., Coagulase-negative staphylococci was defined as insignificant bacteria) from blood and lower respiratory tract samples including bronchoalveolar lavage, respectively. Separate Cox proportional hazards models were used to examine associations between first URTI for individual viruses and the subsequent development of first bacteremia and/or bacterial pneumonia by 100 days post-HCT. Results We identified 471 HCT recipients (median age: 51 years, range 8 months-75 years). Number of patients for each first outcome event by 100 days post-HCT included the following: Gram-positive bacteremia (n=64), Gram-negative bacteremia (n=53), Gram-positive pneumonia (n=46), Gram-negative pneumonia (n=8), and either bacteremia or pneumonia (n=152). After adjusting for pre-transplant factors only and pre- and post-transplant factors, significant URTI variables for outcomes in both models were (1) Flu A for gram-positive bacteremia, (2) HMPV for gram-positive pneumonia, and (3) HMPV for bacteremia or bacterial pneumonia (Figure). The association between PIV URTI and development of bacteremia or pneumonia approached statistical significance. Conclusion In HCT recipients, URTIs due to Flu A and HMPV are significant risk factors for the development of gram-positive bacteremia and pneumonia, respectively. Further studies are needed to assess whether prevention or early diagnostic and treatment strategies for RVIs can reduce the risk of bacterial infection. [ABSTRACT FROM AUTHOR]

Introduction Respiratory infections after HCT lead to significant morbidity, mortality, and health care costs due to pulmonary complications. In up to a third of patients following allogeneic HCT, infection can progress from an upper to a lower respiratory tract infection. Without vaccines or effective therapeutics for most viruses, very little can be done beyond supportive care. Objectives There is a need to identify risk factors for virus acquisition in HCT recipients in order to develop and implement better preventative interventions. Methods In a prospective study, 471 HCT patients enrolled between 2005 and 2010 underwent weekly PCR-based surveillance for RSV, metapneumovirus, parainfluenza virus 1-4, influenza A and B, rhinovirus, coronavirus, and adenovirus. Detailed weekly surveys were collected from subjects for up to 1 year post-transplant on symptoms and exposures to children under 10 years or sick contacts (within 3 feet for more than 1 hour total in the past week). We performed multivariable Cox regression analysis to identify risk factors associated with the time to first positive respiratory viral detection by PCR (asymptomatic and symptomatic) within the first 100 days HCT. Results In this cohort, 211 patients (45%) acquired a respiratory virus in the first 100 days after transplant. Of those infected, 88 (42%) were symptomatic with at least 2 respiratory symptoms. We found significantly higher risk of acquiring any respiratory viral infection for patients with underlying chronic leukemia compared with other hematologic malignancies [hazard ratio (HR) 1.79 (1.16 – 2.77)], exposure to children under or over 4 years [HR 1.84 (1.36 – 2.48)], exposure to contacts with cold symptoms [HR 1.47 (1.02 – 2.12)], exposure to systemic steroids [HR 1.49 (1.07 – 2.08)], and absolute monocyte counts < 100/µL [HR 1.81 (1.12 – 2.94)]. Age, age of child exposure, gender, smoking history, season, conditioning regimen, donor relationship, cell source, presence of acute GVHD, albumin level, total IgG level, lymphocyte counts, and neutrophil counts were not associated with risk for acquisition. We also analyzed the association of these same variables with the time to first positive respiratory viral detection with symptomatic respiratory disease. We found that exposure to children [HR 1.56 (1.03 – 2.35)] and exposure to steroids [HR 1.59 (1.01 – 2.52)] remained associated with acquisition of symptomatic respiratory viral infection. Conclusions These data support the contribution of both exposure and immunologic determinants to the risk of respiratory viral acquisition with and without development of symptoms. Although many infections were asymptomatic, patients receiving steroids and those in close proximity to children may benefit from closer monitoring and counseling in the early post-transplant period. [ABSTRACT FROM AUTHOR]

We report herein a fatal case of acute human orthopneumovirus (formerly respiratory syncytial virus) infection in a captive white-handed gibbon ( Hylobates lar ). Other members of the housing group had mild respiratory signs. Gross examination revealed bilateral pulmonary congestion and froth in the bronchi. Microscopically, the lungs had lymphocytic, neutrophilic infiltration of the interstitium and alveolar walls. There was necrosis of terminal bronchiolar epithelium and terminal bronchioles, and surrounding alveoli contained necrotic and exfoliated epithelial cells admixed with histiocytes and syncytial cells. Additional lesions included nonsuppurative meningoencephalitis, and epidermal hyperkeratosis and hyperplasia with syncytial cell formation. PCR screening for 12 human respiratory viruses was positive for orthopneumovirus in multiple tissues, including lung, and immunohistochemical staining for human orthopneumovirus detected viral antigen within bronchial epithelial cells. IHC and PCR for measles virus on preserved sections were negative. White-handed gibbons have not been previously reported as hosts for human orthopneumovirus, an important respiratory pathogen of both primates and humans.

Problem: Rhinoviruses (RVs), the most common causes of acute respiratory infections in young children and infants, are highly diverse genetically., Objective: To characterize the RV types detected with respiratory illness episodes in infants in Nepal., Study Methods: Infants born to women enrolled in a randomized trial of maternal influenza immunization in rural, southern Nepal were followed with household-based weekly surveillance until 180 days of age. Infants with respiratory symptoms had nasal swabs tested for twelve respiratory viruses. A subset with RV alone was selected for sequencing of the VP4/2 gene to identify RV types., Results: Among 547 RV-only positive illnesses detected from December 2012 to April 2014, 285 samples (52%) were sequenced. RV-A, B, and C species were detected in 193 (68%), 18 (6%), and 74 (26%) specimens, respectively. A total of 94 unique types were identified from the sequenced samples, including 52 RV-A, 11 RV-B, and 31 RV-C. Multiple species and types circulated simultaneously throughout the study period. No seasonality was observed. The median ages at illness onset were 88, 104, and 88 days for RV-A, B, and C, respectively. The median polymerase chain reaction cycle threshold values did not differ between RV species. No differences between RV species were observed for reported respiratory symptoms, including pneumonia, or for medical care-seeking., Conclusions: Among very young, symptomatic infants in rural Nepal, all three species and many types of RV were identified; RV-A was detected most frequently. There was no association between RV species and disease severity., (© 2019 Wiley Periodicals, Inc.)

We used RT-PCR-electrospray ionization-mass spectrometry to identify subtypes and strains of influenza viruses detected during a maternal influenza immunization study in Nepal from May 2011 to April 2014. Hemagglutinin (HA) gene amino acid (aa) sequences of inferred reference strains were compared to those of the vaccines to determine impact of aa relatedness on vaccine efficacy (VE) and disease severity. Three influenza subtypes and many strains were identified. A(H3N2) strains with less than 13 aa differences in HA compared to vaccine strains (matched) showed higher VE than strains with 13 or more differences (mismatched). Yamagata lineage B strains, which were mismatched to the Victoria strain in the vaccine, demonstrated lower VE compared to Victoria strains. Differences in VE were not statistically significant. All A(H1N1pdm) matched the vaccine strain, with 10 or fewer aa differences. Except for women infected with vaccine-matched strains of influenza A, clinical signs and symptoms did not differ between vaccinated and unvaccinated participants., (Copyright © 2018. Published by Elsevier Inc.)

Background: Despite the frequency of human rhinovirus (HRV), data describing the molecular epidemiology of HRV in the community are limited. Childcare centers are optimal settings to characterize heterotypic HRV cocirculation., Methods: HRV specimens were prospectively obtained from a cohort of childcare attendees at enrollment and weekly during respiratory illness. The 5' noncoding region sequences were used to determine HRV species (A, B, C) and genotypes., Results: Among 225 children followed, sequence data were available for 92 HRV infections: HRV-A (n = 80; 59%) was most common, followed by HRV-C (n = 52, 39%), and HRV-B (n = 3, 2%). Forty-one genotypes were identified and cocirculation was common. Frequent spread between classrooms occurred with 2 HRV-A genotypes. Repeated detections within single illnesses were a combination of persistent (n = 7) and distinct (n = 7) genotypes. Prevalence of HRV among asymptomatic children was 41%. HRV-C was clinically similar to HRV-A and HRV-B., Conclusions: HRV epidemiology in childcare consists of heterotypic cocirculation of genotypes with periodic spread within and among classrooms. Based on our finding of multiple genotypes evident during the course of single illnesses, the use of sequence-based HRV type determination is critical in longitudinal studies of HRV epidemiology and transmission.

Objectives: Respiratory syncytial virus (RSV) pneumonia is a leading cause of infant mortality worldwide. The risk of RSV infection associated with preterm birth is not well-characterized in resource-limited settings. We aimed to obtain precise estimates of risk factors and disease burden of RSV in infants in rural southern Nepal., Methods: Pregnant women were enrolled, and along with their infants, followed to six months after birth with active weekly home-based surveillance for acute respiratory illness (ARI). Mid-nasal swabs were obtained and tested for RSV by PCR for all illness episodes. Birth outcomes were assessed at a postpartum home visit., Results: 311 (9%) of 3509 infants had an RSV ARI. RSV ARI incidence decreased from 551/1000 person-years in infants born between 28 and 31 weeks to 195/1000 person-years in infants born full-term (p = 0.017). Of 220 infants (71%) evaluated in the health system, 41 (19%) visited a hospital or physician. Of 287 infants with an assessment performed, 203 (71%) had a lower respiratory tract infection., Conclusions: In a rural south Asian setting with intensive home-based surveillance, RSV caused a significant burden of respiratory illness. Preterm infants had the highest incidence of RSV ARI, and should be considered a priority group for RSV preventive interventions in resource-limited settings., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Human metapneumovirus (HMPV) is a newly identified pulmonary pathogen that can cause fatal lower respiratory tract disease (LRD) in hematopoietic cell transplantation (HCT) recipients. Little is known about progression rates from upper respiratory tract infection (URI) to LRD and risk factors associated with progression., Methods: A total of 118 HCT recipients receiving transplantation between 2004 and 2014 who had HMPV detected in nasopharyngeal, bronchoalveolar lavage, or lung biopsy samples by real-time reverse transcription polymerase chain reaction were retrospectively analyzed., Results: More than 90% of the cases were identified between December and May. Among the 118 HCT patients, 88 and 30 had URI alone and LRD, respectively. Among 30 patients with LRD, 17 patients progressed from URI to LRD after a median of 7 days (range, 2-63 days). The probability of progression to LRD within 40 days after URI was 16%. In Cox regression analysis, steroid use ≥1 mg/kg prior to URI diagnosis (hazard ratio [HR], 5.10; P = .004), low lymphocyte count (HR, 3.43; P = .011), and early onset of HMPV infection after HCT (before day 30 after HCT; HR, 3.54; P = .013) were associated with higher progression to LRD. The median viral load in nasal wash samples was 1.1 × 10(6) copies/mL (range, 3.3 × 10(2)-1.7 × 10(9)) with no correlation between the viral load and progression., Conclusions: Progression from URI to LRD occurred in up to 60% of HCT recipients with risk factors such as systemic corticosteroid use or low lymphocyte counts. Further studies are needed to define the role of viral load in the pathogenesis of progressive disease., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Rapid PCR-based influenza tests are increasingly used as point-of-care diagnostics in hospitals and clinics. To our knowledge, no prior studies have described clinical outcomes with implementation of rapid PCR-based influenza tests in hospitalized adult inpatients. Electronic medical records were used to assess differences in laboratory testing time and antiviral use among a subset of 175 consecutive adult inpatients tested for influenza in two respiratory seasons before and after implementation of rapid PCR-based influenza testing at an academic medical center. Of the 350 hospitalized inpatients included in this analysis, 96 (27%) were over 65 years of age and 308 (88%) had a comorbid condition. The overall time to result decreased significantly from 25.2 to 1.7 hr (P < 0.001) after implementation of rapid PCR-based influenza testing. Among influenza-negative patients, the frequency of oseltamivir initiation remained unchanged (before: 43% vs. after: 45%; P = 0.60), though the median duration of oseltamivir was significantly decreased from 1.1 to 0.0 days (P < 0.001). By providing an earlier result to clinicians, rapid PCR-based influenza tests may decrease unnecessary antiviral use among adult inpatients who test negative for influenza., (© 2015 Wiley Periodicals, Inc.)

Background: Human bocavirus 1 (HBoV-1) is frequently detected in young children. The role of HBoV-1 in respiratory illness is unclear, owing to frequent detection in asymptomatic children., Methods: Weekly oral fluid samples from a longitudinal cohort of infants were tested by quantitative polymerase chain reaction for HBoV-1 DNA. Symptoms during HBoV-1 primary shedding events were compared to those during 14-day control periods occurring 1 month prior to and following the primary event. Eight single-nucleotide polymorphisms were analyzed to assess HBoV-1 variants., Results: Sixty-six of 87 children (76%), followed for at least 18 months from birth, had a primary HBoV-1 infection. HBoV-1 was consistently detected for >1 month (maximum duration, 402 days) following 42 of 66 primary shedding events. Children were more likely to experience new cough symptoms (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.4-5.5) and to visit a healthcare provider (OR, 2.8; 95% CI, 1.02-7.7) during the 14 days surrounding the time of initial detection of HBoV-1. Recurrent HBoV-1 shedding events were found in 33 children (50%). Twelve of 48 children with HBoV-1 variant data had multiple viral allelic patterns over time., Conclusions: HBoV-1 primary shedding events are associated with mild respiratory illness with subsequent prolonged detection of HBoV-1 DNA for up to a year. HBoV-1 reinfection contributes to long-term shedding., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Zoonotic disease transmission and infections are of particular concern for humans and closely related great apes. In 2009, an outbreak of human metapneumovirus infection was associated with the death of a captive chimpanzee in Chicago, Illinois, USA. Biosecurity and surveillance for this virus in captive great ape populations should be considered.

Adeno-associated virus (AAV) is widely considered to be nonpathogenic, but the clinical epidemiology of this virus is limited. By use of polymerase chain reaction assays, we investigated the incidence and clinical significance of AAV viremia in a population of consecutive recipients of a hematopoietic cell transplant (HCT). Four (2.8%) of 145 patients developed AAV viremia after HCT. Viremia was low level and transient in all patients. Two patients were admitted to the hospital and died in proximity to AAV viremia (<7 weeks between diagnosis and death); however, AAV was not detected in tissue specimens obtained at autopsy. Thus, AAV does not appear to play a pathogenic role in organ-specific illness, even in a highly immunocompromised population.

Background: Women infected with human immunodeficiency virus type 1 (HIV-1) and -2 may be at higher risk of developing cervical cancer than uninfected women. We assessed the relationships among human papillomavirus (HPV) types and persistence, HIV-1 and/or HIV-2 infection, and the development of high-grade cervical squamous intraepithelial lesions (HSILs) in a prospective study., Methods: We studied 627 women with and without HIV-1 and/or HIV-2 infection and high-risk HPV infection in Senegal, West Africa, who were assessed every 4 months for HSIL and HPV DNA over a mean follow-up of 2.2 years. Cox regression modeling was used to assess risks associated with development of HSIL., Results: During follow-up, 71 (11%) of 627 women developed HSIL as detected by cytology. HIV-infected women with high-risk HPV types were at greatest risk for development of HSIL. In multivariable modeling, infection with oncogenic HPV types--both persistent (hazard ratio [HR] = 47.1, 95% confidence interval [CI] = 16.3 to 136) and transient (HR = 14.0, 95% CI = 3.7 to 54)--was strongly associated with HSIL risk. In univariate analyses, HIV-positive women infected with HIV-2 were less likely to develop HSIL (HR = 0.3, 95% CI = 0.1 to 0.9) than HIV-positive women infected with HIV-1. HIV-positive women with CD4+ cell counts between 200 and 500 cells per microliter (HR = 2.2, 95% CI = 0.8 to 6.3) or fewer than 200 cells per milliliter (HR = 5.5, 95% CI = 2.0 to 15.2) were at greater risk of HSIL than HIV-positive women with CD4 counts of more than 500 cells per milliliter. High plasma HIV RNA levels were associated with increased HSIL risk (HR for each order of magnitude increase in the level of plasma HIV RNA = 1.4, 95% CI = 1.1 to 1.7; P = .005). After adjustment for HPV types and persistence, however, HIV type, plasma HIV RNA level, and CD4 count were no longer statistically significantly associated with increased risk of HSIL., Conclusions: HIV-1 and HIV-2 are associated with increased risk for development of HSIL. This risk appears to be associated primarily with increased HPV persistence that may result from immunosuppression related to HIV-1 and/or HIV-2 infection.

We studied the patterns of linkage disequilibrium (LD) in the human genome among three populations: African Americans, Caucasians and Ashkenazi Jews. These three populations represent admixed, outbred and isolated populations, respectively. The study examined defined chromosomal regions across the whole genome. We found that SNP allele frequencies are highly correlated between Ashkenazi Jews and Caucasians and somewhat distinct in African Americans. In addition, Ashkenazi Jews have a modest increase in LD compared with Caucasians, and both have greater LD than African Americans. The three populations differed more significantly with regard to haplotype heterogeneity. We found, as expected, that Ashkenazi Jews display the greatest extent of homogeneity and African Americans the greatest extent of heterogeneity. We found that most of the variance in LD can be attributed to the difference between regions and markers rather than to that between different population types. The average recombination rates estimated by low-resolution genetic maps can only explain a small fraction of the variance between regions. We found that LD (in terms of r(2)) decreases as a function of distance even within the so-called 'haplotype blocks'. This has significant consequences when using LD mapping for the genetic dissection of complex traits, as higher density SNP maps will be required to scan the genome.

Objective: The purpose of this study was to identify clinical signs and symptoms associated with detection of human papillomavirus (HPV) DNA in the female genital tract., Study Design: A total of 516 university students (18 to 24 years old) enrolled in a cohort study that included the collection of genital specimens for HPV DNA testing every 4 months for up to 4 years. Reported symptoms and objective clinical findings of women with and without HPV DNA were compared by multivariate analysis., Results: Acute and persisting HPV infections were not associated with discharge, itching, burning, soreness, or fissures. Clinical evidence of genital warts was statistically associated only with HPV types 6 and 11. Detection of any HPV DNA was associated with bacterial vaginosis (BV). Furthermore, a time lag analysis suggests that HPV infection usually precedes detection of BV., Conclusion: Most women who acquire genital HPV infection are asymptomatic; some, however, are at increased risk for BV.

Context: Human papillomavirus (HPV) DNA testing of women having Papanicolaou (Pap) smears showing atypical squamous cells of undetermined significance (ASCUS) has clinical usefulness. Whether HPV DNA testing alone is useful in primary screening remains to be determined., Objective: To determine the accuracy of HPV DNA testing for detecting cervical intraepithelial neoplasia (CIN) grade 3 or cancer (the criterion standard)., Design, Setting, and Participants: Between December 1997 and October 2000, 4075 women who attended Planned Parenthood clinics in Washington State were screened simultaneously using thin-layer Pap and HPV DNA testing by a polymerase chain reaction (PCR)-based method and by a liquid-based RNA-DNA hybridization capture with signal amplification assay (signal amplification). Women who were positive for high-risk HPV types, or had Pap results of ASCUS or higher, were considered to have positive screening test results and were referred for colposcopy and biopsy. Additionally, a random sample of women with negative screening test results was referred for colposcopy. Based on individual and combined thin-layer Pap, HPV PCR, and HPV signal amplification test results from the screening and the colposcopy visits, 7 colposcopy triage strategies were defined and evaluated., Main Outcome Measure: Sensitivity and specificity for detecting cervical lesions graded CIN 3 or higher for each of the 7 triage strategies., Results: The estimated prevalence of CIN 3 or higher was 3.2%. The sensitivity (95% confidence interval) of thin-layer Pap (with a result of > or = ASCUS) for identifying women with CIN 3 or higher was only 61.3% (48.5%-70.9%) compared with 88.2% (78.9%-93.8%) for HPV testing by PCR and 90.8% (83.1%-95.8%) by signal amplification. Differences in specificities were also observed: 82.4% (81.8%-83.1%) for thin-layer Pap (with a result of > or = ASCUS), 78.8% (77.9%-79.7%) for PCR, and 72.6% (69.4%-75.0%) for signal amplification. Compared with referral for colposcopy of all women with ASCUS or higher, signal amplification testing of women with ASCUS and referral of those with a positive result was about as sensitive (61.3% vs 60.3%, respectively) and significantly more specific (82.4% vs 88.9%, respectively). The strategy requiring repeat positive PCR tests on 2 visits had a sensitivity of 84.2% (75.3%-91.0%) and a specificity of 86.2% (85.1%-87.3%). All tests were more specific and less sensitive in older (> or = 30 years) vs younger women., Conclusions: Testing for HPV has higher sensitivity but lower specificity than thin-layer Pap screening. In some settings, particularly where screening intervals are long or haphazard, screening for HPV DNA may be a reasonable alternative to cytology-based screening of reproductive-age women.

Objective: Although human papillomavirus (HPV) may be a necessary cause of cervical cancer, most women with HPV infections do not develop this disease. This study was conducted to evaluate the possible effects of specific dietary factors on cervical carcinogenesis., Methods: Fifty hospitalized in-situ cases and 125 controls were identified from family planning or gynecologic clinics associated with Siriraj hospital in Bangkok, Thailand, and 134 hospitalized invasive cases and 384 hospitalized controls from the public wards of Siriraj Hospital were administered a food-frequency questionnaire and tested for HPV DNA in exfoliated cervical cells. Odds ratios in relation to intake of foods high in vitamin C, folate, vitamin E, vitamin A, beta-carotene, retinol, and cruciferous vegetables were estimated using logistic regression in case-control comparisons and in case-case comparisons adjusted for HPV status., Results: High intake of foods rich in vitamin A, and particularly high-retinol foods, were associated with a reduced risk of in-situ disease and less strongly also with a reduced risk of invasive as compared to in-situ disease. No association was found between intake of cruciferous vegetables, foods high in vitamin C, folate, vitamin E, and beta-carotene and risk of either in-situ or invasive cervical cancer., Conclusions: Increasing intake of foods rich in total vitamin A, and particularly high-retinol foods, may reduce risk of in-situ cervical cancer, and at the highest level of intake may inhibit progression to invasion. If others confirm these results they suggest means of reducing the risk of cervical cancer that are amenable to public health action.

Objective: To evaluate whether ThinPrep smears without versus those with a transformation zone component were more likely to have falsely negative cytology findings., Methods: Women aged 18-50 (N = 4389) attended one of three Planned Parenthood clinics between 1997 and 2001 for screening by ThinPrep Papanicolaou and polymerase chain reaction-based human papillomavirus (HPV) DNA testing. Women with 1) any cytologic abnormality, 2) high-risk HPV types, and 3) a random sample with normal Papanicolaou and negative HPV tests were offered repeat cytology, colposcopy, and biopsy. Cytology and biopsy diagnoses at the colposcopy visit were reviewed according to the presence (n = 3689) or absence (n = 700) of a transformation zone component at screening., Results: Among women with normal cytology at screening, histologic detection of at least cervical intraepithelial neoplasia grade 2 (odds ratio 1.3, 95% confidence interval 0.5, 3.3) at colposcopy did not differ significantly between transformation zone-positive and zone-negative smears. Histologically confirmed cervical intraepithelial neoplasia grade 1 was detected more often among smears lacking a transformation zone component (odds ratio 2.0, confidence interval 1.0, 3.8). Transformation zone-negative smears were more common among older women, current oral contraceptive users, those past the 14th day of their last menstrual period, and those negative for high-risk HPV types., Conclusion: Absence of a transformation zone component in a screening ThinPrep Papanicolaou test was not associated with missed high-grade lesions. Based upon our data, we do not recommend repeat screening of reproductive-aged women with negative liquid-based tests and no cytologic evidence of a transformation zone component.

Analogous to the epidemiology of different types of human papillomaviruses (HPVs), variants of a single type such as HPV16 may differ in the natural course of infection. A prospective study was conducted in a cohort of female university students who did not have HPV16 DNA or antibody at enrollment. Subjects were followed every 4 months with Pap smear and colposcopic examinations and tests for HPV DNA and antibody. Of 528 women, 62 acquired HPV16 infection during follow-up. The 5-year cumulative incidence was 12.6% for infection with HPV16 prototype-like variants and 3.1% for infection with non-prototype-like (NPL) variants. Among those with incident HPV16 infection, the adjusted odds ratio of detecting NPL variants was 6.0 [95% confidence interval (CI), 1.3-27.5)] for nonwhite women or white women who had had nonwhite sex partners compared with white women who had not had nonwhite sex partners. As compared with women who had not used hormonal contraceptives in the 8 months prior to the first HPV16-positive detection, the adjusted odds ratio of detecting NPL variants increased from 1.6 (95% CI, 0.3-9.1) for those who had used hormonal contraceptives for 1-4 months to 5.4 (95% CI, 1.0-28.3) for those who had used hormonal contraceptives for 5-8 months (P for trend = 0.04). There was no difference in HPV16 seroconversion rates between women with prototype-like variants and women with NPL variants. The increased risk for biopsy-confirmed cervical intraepithelial neoplasia grades 2 or 3 associated with detection of incident infection by NPL variants was not explained by differences in persistence between the two variant groups, indicating that biological mechanisms other than viral persistence may be responsible for the observed difference in risk for cervical intraepithelial neoplasia grades 2 or 3.

Human immunodeficiency virus (HIV) type 2 infection is characterized by slower disease progression to acquired immunodeficiency syndrome than results from HIV-1 infection. To better understand the biological factors underlying the different natural histories of infection with these 2 retroviruses, we examined the relationship between HIV RNA and DNA levels and the rate of CD4(+) T cell decline among 472 HIV-1- and 114 HIV-2-infected individuals from Senegal. The annual rate of CD4(+) T cell decline in the HIV-2 cohort was approximately one-fourth that seen in the HIV-1 cohort. However, when the analysis was adjusted for baseline plasma HIV RNA level, the rates of CD4(+) T cell decline per year for the HIV-1 and HIV-2 cohorts were similar (a rate increase of approximately 4% per year for each increase in viral load of 1 log(10) copies/mL). Therefore, plasma HIV load is predictive of the rate of CD4(+) T cell decline over time, and the correlation between viral load and the rate of decline appears to be similar among all HIV-infected individuals, regardless of whether they harbor HIV-1 or HIV-2.

Little is known about factors that favor the development of cervical atypical squamous cells of undetermined significance (ASCUS), nor how these factors might affect the pathogenesis of cervical neoplasia. The primary focus of this case-control study among the multiethnic population of Hawaii was to identify biomarkers of diet in the recent past that may influence the risk of ASCUS, after carefully accounting for the presence of HPV DNA. Cases included 185 women with ASCUS and 191 cytologically-normal controls diagnosed between 1992 and 1996 from three clinics in Honolulu, Hawaii. In-person interviews were conducted in the subjects' homes, a fasting blood sample was drawn to measure plasma levels of various micronutrients, and the presence and type of HPV was determined in exfoliated cell samples using Polymerase Chain Reaction (PCR) dot blot hybridization. As results, we found an inverse dose-response gradient with increasing plasma concentrations of &mgr;-cryptoxanthin and &mgr;-tocopherol for the development of ASCUS. The odds ratio for ASCUS among women in the highest quartile compared with women in the lowest quartile of total cryptoxanthin was 0.5 (95% confidence interval (CI): 0.3-1.0), &mgr;-cryptoxanthin was 0.4 (0.2-0.8), total tocopherol was 0.5 (0.2-1.0), &mgr;-tocopherol was 0.5 (0.2-1.0), and &mgr;-tocopherol was 0.4 (0.2-0.8). Little association of plasma levels of lutein/zeaxanthin, lycopene, &mgr;- or &mgr;-carotene, retinol, vitamin C, or cholesterol, with disease risk was evident. Our findings suggest that women with high circulating concentrations of cryptoxanthin and tocopherol may be at a reduced risk of ASCUS.

Little is known about factors that favor the development of cervical atypical squamous cells of undetermined significance (ASCUS), nor how these factors might affect the pathogenesis of cervical neoplasia. The primary focus of this case-control study among the multiethnic population of Hawaii was to identify biomarkers of diet in the recent past that may influence the risk of ASCUS, after carefully accounting for the presence of HPV DNA. Cases included 185 women with ASCUS and 191 cytologically-normal controls diagnosed between 1992 and 1996 from three clinics in Honolulu, Hawaii. In-person interviews were conducted in the subjects' homes, a fasting blood sample was drawn to measure plasma levels of various micronutrients, and the presence and type of HPV was determined in exfoliated cell samples using Polymerase Chain Reaction (PCR) dot blot hybridization. As results, we found an inverse dose-response gradient with increasing plasma concentrations of &mgr;-cryptoxanthin and &mgr;-tocopherol for the development of ASCUS. The odds ratio for ASCUS among women in the highest quartile compared with women in the lowest quartile of total cryptoxanthin was 0.5 (95% confidence interval (CI): 0.3-1.0), &mgr;-cryptoxanthin was 0.4 (0.2-0.8), total tocopherol was 0.5 (0.2-1.0), &mgr;-tocopherol was 0.5 (0.2-1.0), and &mgr;-tocopherol was 0.4 (0.2-0.8). Little association of plasma levels of lutein/zeaxanthin, lycopene, &mgr;- or &mgr;-carotene, retinol, vitamin C, or cholesterol, with disease risk was evident. Our findings suggest that women with high circulating concentrations of cryptoxanthin and tocopherol may be at a reduced risk of ASCUS.