Screening for Thyroid Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: The incidence of detected thyroid cancer cases has been increasing in the United States since 1975. The majority of thyroid cancers are differentiated cancers with excellent prognosis and long-term survival. Objective: To systematically review the benefits and harms associated with thyroid cancer screening and treatment of early thyroid cancer in asymptomatic adults to inform the US Preventive Services Task Force. Data Sources: Searches of MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials for relevant studies published from January 1966 through January 2016, with active surveillance through December 2016. Study Selection: English-language studies conducted in asymptomatic adult populations. Data Extraction and Synthesis: Two reviewers independently appraised the articles and extracted relevant study data from fair- or good-quality studies. Random-effects meta-analyses were conducted to pool surgical harms. Main Outcomes and Measures: Thyroid cancer morbidity and mortality, test accuracy to detect thyroid nodules or thyroid cancer, and harms resulting from screening (including overdiagnosis) or treatment of thyroid cancer. Results: Of 10 424 abstracts, 707 full-text articles were reviewed, and 67 studies were included for this review. No fair- to good-quality studies directly examined the benefit of thyroid cancer screening. In 2 studies (n = 354), neck palpation was not sensitive to detect thyroid nodules. In 2 methodologically limited studies (n = 243), a combination of selected high-risk sonographic features was specific for thyroid malignancy. Three studies (n = 5894) directly addressed the harms of thyroid cancer screening, none of which suggested any serious harms from screening or ultrasound-guided fine-needle aspiration. No screening studies directly examined the risk of overdiagnosis. Two observational studies (n = 39 211) included cohorts of persons treated for well-differentiated thyroid cancer and persons with no surgery or surveillance; however, these studies did not adjust for confounders and therefore were not designed to determine if earlier or immediate treatment vs delayed or no surgical treatment improves patient outcomes. Based on 36 studies (n = 43 295), the 95% CI for the rate of surgical harm was 2.12 to 5.93 cases of permanent hypoparathyroidism per 100 thyroidectomies and 0.99 to 2.13 cases of recurrent laryngeal nerve palsy per 100 operations. Based on 16 studies (n = 291 796), treatment of differentiated thyroid cancer with radioactive iodine is associated with a small increase in risk of second primary malignancies and with increased risk of permanent adverse effects on the salivary gland, such as dry mouth. Conclusions and Relevance: Although ultrasonography of the neck using high-risk sonographic characteristics plus follow-up cytology from fine-needle aspiration can identify thyroid cancers, it is unclear if population-based or targeted screening can decrease mortality rates or improve important patient health outcomes. Screening that results in the identification of indolent thyroid cancers, and treatment of these overdiagnosed cancers, may increase the risk of patient harms.

Bleeding Risks With Aspirin Use for Primary Prevention in Adults: A Systematic Review for the U.S. Preventive Services Task Force.

BACKGROUND: The balance between potential aspirin-related risks and benefits is critical in primary prevention. PURPOSE: To evaluate the risk for serious bleeding with regular aspirin use in cardiovascular disease (CVD) primary prevention. DATA SOURCES: PubMed, MEDLINE, Cochrane Central Register of Controlled Trials (2010 through 6 January 2015), and relevant references from other reviews. STUDY SELECTION: Randomized, controlled trials; cohort studies; and meta-analyses comparing aspirin with placebo or no treatment to prevent CVD or cancer in adults. DATA EXTRACTION: One investigator abstracted data, another checked for accuracy, and 2 assessed study quality. DATA SYNTHESIS: In CVD primary prevention studies, very-low-dose aspirin use (≤100 mg daily or every other day) increased major gastrointestinal (GI) bleeding risk by 58% (odds ratio [OR], 1.58 [95% CI, 1.29 to 1.95]) and hemorrhagic stroke risk by 27% (OR, 1.27 [CI, 0.96 to 1.68]). Projected excess bleeding events with aspirin depend on baseline assumptions. Estimated excess major bleeding events were 1.39 (CI, 0.70 to 2.28) for GI bleeding and 0.32 (CI, -0.05 to 0.82) for hemorrhagic stroke per 1000 person-years of aspirin exposure using baseline bleeding rates from a community-based observational sample. Such events could be greater among older persons, men, and those with CVD risk factors that also increase bleeding risk. LIMITATIONS: Power to detect effects on hemorrhagic stroke was limited. Harms other than serious bleeding were not examined. CONCLUSION: Consideration of the safety of primary prevention with aspirin requires an individualized assessment of aspirin's effects on bleeding risks and expected benefits because absolute bleeding risk may vary considerably by patient. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Aspirin for the Prevention of Cancer Incidence and Mortality: Systematic Evidence Reviews for the U.S. Preventive Services Task Force.

BACKGROUND: Cancer is the second leading cause of death in the United States. PURPOSE: To conduct systematic reviews of aspirin and 1) total cancer mortality and incidence in persons eligible for primary prevention of cardiovascular disease (CVD) and 2) colorectal cancer (CRC) mortality and incidence in persons at average CRC risk. DATA SOURCES: MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials through January 2015 and relevant references from other reviews. STUDY SELECTION: Trials comparing oral aspirin versus placebo or no treatment in adults aged 40 years or older were included. Two investigators independently reviewed abstracts and articles against inclusion and quality criteria. DATA EXTRACTION: Data from 20 good- or fair-quality trials were abstracted by one reviewer and checked by another. DATA SYNTHESIS: In CVD primary prevention trials, cancer mortality (relative risk [RR], 0.96 [95% CI, 0.87 to 1.06]) (10 trials; n = 103 787) and incidence (RR, 0.98 [CI, 0.93 to 1.04]) (6 trials; n = 72 926) were similar in aspirin and control groups over 3.6 to 10.1 years. In CVD primary and secondary prevention trials, 20-year CRC mortality was reduced among persons assigned to aspirin therapy (RR, 0.67 [CI, 0.52 to 0.86]) (4 trials; n = 14 033). Aspirin appeared to reduce CRC incidence beginning 10 to 19 years after initiation (RR, 0.60 [CI, 0.47 to 0.76]) (3 trials; n = 47 464). LIMITATIONS: Most data were from clinically and methodologically heterogeneous CVD prevention trials. Outcome assessment and follow-up length varied across studies. Data on non-CRC cancer types and subgroups were limited. CONCLUSION: In CVD primary prevention populations, aspirin's effect on total cancer mortality and incidence was not clearly established. Evidence from CVD primary and secondary prevention studies suggested that aspirin therapy reduces CRC incidence and perhaps mortality approximately 10 years after initiation. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Validity of diabetes self-reports in the Women's Health Initiative.

OBJECTIVE: This study aims to determine the positive and negative predictive values of self-reported diabetes during the Women's Health Initiative (WHI) clinical trials. METHODS: All WHI trial participants from four field centers who self-reported diabetes at baseline or during follow-up, as well as a random sample of women who did not self-report diabetes, were identified. Women were surveyed regarding diagnosis and treatment. Medical records were obtained and reviewed for documented treatment with antidiabetes medications or for physician diagnosis of diabetes supported by laboratory measurements of glucose. RESULTS: We identified 1,275 eligible participants; 732 consented and provided survey data. Medical records were obtained for 715 women (prevalent diabetes, 207; incident diabetes, 325; no diabetes, 183). Records confirmed 91.8% (95% CI, 87.0-95.0) of self-reported prevalent diabetes cases and 82.2% (95% CI, 77.5-86.1) of incident diabetes cases. Among those who never self-reported diabetes, there was no medical record or laboratory evidence for diabetes in 94.5% (95% CI, 89.9-97.2). Women with higher body mass index were more likely to accurately self-report incident diabetes. In a subgroup of participants enrolled in fee-for-service Medicare, a claims algorithm correctly classified nearly all diabetes cases and noncases. CONCLUSIONS: Among WHI clinical trial participants, there are high positive predictive values of self-reported prevalent diabetes (91.8%) and incident diabetes (82.2%) and a high negative predictive value (94.5%) when diabetes is not reported. For participants enrolled in fee-for-service Medicare, a claims algorithm has high positive and negative predictive values.

Effectiveness of weight management interventions in children: a targeted systematic review for the USPSTF.

CONTEXT: Targeted systematic review to support the updated US Preventive Services Task Force (USPSTF) recommendation on screening for obesity in children and adolescents. OBJECTIVES: To examine the benefits and harms of behavioral and pharmacologic weight-management interventions for overweight and obese children and adolescents. METHODS: Our data sources were Ovid Medline, PsycINFO, the Education Resources Information Center, the Database of Abstracts of Reviews of Effects, the Cochrane databases, reference lists of other reviews and trials, and expert recommendations. After 2 investigators reviewed 2786 abstracts and 369 articles against inclusion/exclusion criteria, we included 15 fair- to good-quality trials in which the effects of treatment on weight, weight-related comorbidities, and harms were evaluated. Studies were quality rated by 2 investigators using established criteria. Investigators abstracted data into standard evidence tables. RESULTS: In the available research, obese (or overweight) children and adolescents aged 4 to 18 years were enrolled, and no studies targeted those younger than 4 years. Comprehensive behavioral interventions of medium-to-high intensity were the most effective behavioral approach with 1.9 to 3.3 kg/m(2) difference favoring intervention groups at 12 months. More limited evidence suggests that these improvements can be maintained over the 12 months after the end of treatments and that there are few harms with behavioral interventions. Two medications combined with behavioral interventions resulted in small (0.85 kg/m(2) for orlistat) or moderate (2.6 kg/m(2) for sibutramine) BMI reduction in obese adolescents on active medication; however, no studies followed weight changes after medication use ended. Potential adverse effects were greater than for behavioral interventions alone and varied in severity. Only 1 medication (orlistat) has been approved by the US Food and Drug Administration for prescription use in those aged > or =12 years. CONCLUSIONS: Over the past several years, research into weight management in obese children and adolescents has improved in quality and quantity. Despite important gaps, available research supports at least short-term benefits of comprehensive medium- to high-intensity behavioral interventions in obese children and adolescents.

Screening for child and adolescent depression in primary care settings: a systematic evidence review for the US Preventive Services Task Force.

CONTEXT: Depression among youth is a disabling condition that is associated with serious long-term morbidities and suicide. OBJECTIVE: To assess the health effects of routine primary care screening for major depressive disorder among children and adolescents aged 7 to 18 years. METHODS: Medline, the Cochrane Central Registry of Controlled Trials, PsycInfo, the Cochrane Database of Systematic Reviews, recent systematic reviews, experts, and bibliographies from selected studies were the data sources. The studies selected were fair- and good-quality (on the basis of US Preventive Services Task Force criteria) controlled trials of screening and treatment (selective serotonin reuptake inhibitor and/or psychotherapy), diagnostic accuracy studies, and large observational studies that reported adverse events. Two reviewers quality-graded each article. One reviewer abstracted relevant information into standardized evidence tables, and a second reviewer checked key elements. RESULTS: We found no data describing health outcomes among screened and unscreened populations. Although the literature on diagnostic screening test accuracy is small and methodologically limited, it indicates that several screening instruments have performed fairly well among adolescents. The literature on treatment efficacy of selective serotonin reuptake inhibitors and/or psychotherapy is also small but includes good-quality randomized, controlled trials. Available data indicate that selective serotonin reuptake inhibitors, psychotherapy, and combined treatment are effective in increasing response rates and reducing depressive symptoms. Not all specific selective serotonin reuptake inhibitors, however, seem to be efficacious. Selective serotonin reuptake inhibitor treatment was associated with a small absolute increase in risk of suicidality (ie, suicidal ideation, preparatory acts, or attempts). No suicide deaths occurred in any of the trials. CONCLUSIONS. Limited available data suggest that primary care-feasible screening tools may accurately identify depressed adolescents and treatment can improve depression outcomes. Treating depressed youth with selective serotonin reuptake inhibitors may be associated with a small increased risk of suicidality and should only be considered if judicious clinical monitoring is possible.

Effectiveness of weight management programs in children and adolescents.

OBJECTIVES: To examine available behavioral, pharmacological, and surgical weight management interventions for overweight (defined as BMI > 85th to 94th percentile of age and sex-specific norms) and/or obese (BMI > 95th percentile) children and adolescents in clinical and nonclinical community settings. DATA SOURCES: We identified two good quality recent systematic reviews that addressed our research questions. We searched Ovid MEDLINE, PsycINFO, Database of Abstracts of Reviews of Effects, the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Education Resources Information Center from 2005 (2003 for pharmacological studies) to December 11, 2007, to identify literature that was published after the search dates of prior relevant systematic reviews; we also examined reference lists of five other good-quality systematic reviews and of included trials, and considered experts' recommendations. We identified two good quality systematic reviews and 2,355 abstracts from which we identified 45 primary studies and trials that addressed our research questions. REVIEW METHODS: After review by two investigators against pre-determined inclusion/exclusion criteria, we included existing good-quality systematic reviews, fair-to-good quality trials, and case series (for bariatric surgeries only) to evaluate the effects of treatment on weight and weight-related co-morbidities; we would have included large comparative cohort studies to evaluate longer term followup and harms of behavioral and pharmaceutical treatment and noncomparative cohort studies for surgical treatments if they had been available. Investigators abstracted data into standard evidence tables with abstraction checked by a second investigator. Studies were quality-rated by two investigators using established criteria. RESULTS: Available research primarily enrolled obese (but not overweight) children and adolescents aged 5 to 18 years and no studies targeted those less than 5 years of age. Behavioral interventions in schools or specialty health care settings can result in small to moderate short-term improvements. Absolute or relative weight change associated with behavioral interventions in these settings is generally modest and varies by treatment intensity and setting. More limited evidence suggests that these improvements can be maintained completely (or somewhat) over the 12 months following the end of treatments and that there are few harms with behavioral interventions. Two medications (sibutramine, orlistat) combined with behavioral interventions can result in small to moderate short-term weight loss in obese adolescents with potential side effects that range in severity. Among highly selected morbidly obese adolescents, very limited data from case series suggest bariatric surgical interventions can lead to moderate to substantial weight loss in the short term and to some immediate health benefits through resolution of comorbidities, such as sleep apnea or asthma. Harms vary by procedure. Short-term severe complications are reported in about 5 percent and less severe short-term complications occur in 10 to 39 percent. Very few cases provide data to determine either beneficial or harmful consequences more than 12 months after surgery. CONCLUSIONS: The research evaluating the treatment of obese children and adolescents has improved in terms of quality and quantity in the past several years. While there are still significant gaps in our understanding of obesity treatment in children and adolescents, the current body of research points the way to further improvements needed to inform robust policy development. Publication of additional research and policy activities by others, including the U.S. Preventive Services Task Force, is expected in the near future. And, in considering this important public health issue, policymakers should not ignore the importance of obesity prevention efforts as well as treatment.

Clinically identified maternal depression before, during, and after pregnancies ending in live births.

OBJECTIVE: This study estimated the prevalence of diagnosed depression and treatment among women before, during, and after pregnancies ending in live births. METHOD: A previously validated algorithm identified health plan members with at least one pregnancy between Jan. 1, 1998, and Dec. 31, 2001. Women with a pregnancy ending in one or more live births and continuously enrolled from 39 weeks before pregnancy through 39 weeks after pregnancy were eligible. Maternal depression was identified from the medical records. Depression treatment included antidepressant medication and/or mental health visits. The authors examined the prevalence of depression and treatments received. RESULTS: Among 4,398 continuously enrolled women with eligible pregnancies ending in live births, 678 (15.4%) had depression identified during at least one pregnancy phase; 8.7%, 6.9%, and 10.4% had depression identified before, during, and/or after pregnancy, respectively. Among women with identified depression during the 39 weeks before pregnancy, 56.4% also had a depression diagnosis during pregnancy. Of women identified with depression during the 39 weeks following pregnancy, 54.2% had depression diagnoses either during or preceding pregnancy. Most women diagnosed with depression received antidepressant medications and/or had at least one mental health visit. Having at least one mental health visit did not vary before, during, or after pregnancy; however, antidepressant use was lower during pregnancy than before or after pregnancy. CONCLUSIONS: Approximately one in seven women was identified with and treated for depression during 39 weeks before through 39 weeks after pregnancy, and more than half of these women had recurring indicators for depression.

Counseling about proper use of motor vehicle occupant restraints and avoidance of alcohol use while driving: a systematic evidence review for the U.S. Preventive Services Task Force.

BACKGROUND: Motor vehicle-related injuries are the leading cause of death among children, adolescents, and young adults. PURPOSE: To systematically review evidence of the effectiveness of counseling people of any age in primary care settings about occupant restraints or alcohol-related driving to prevent injuries. DATA SOURCES: MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PsycINFO, CINAHL, and Traffic Research Information Service; published systematic evidence reviews; experts; and bibliographies of selected trials. STUDY SELECTION: Randomized, controlled trials (RCTs); controlled clinical trials (CCTs); or comparative observational research studies that evaluated behavioral counseling interventions feasible to conduct in primary care or referral from primary care. DATA EXTRACTION: Investigators abstracted data on study design, setting, patients, interventions, outcomes, and quality-related study details. DATA SYNTHESIS: Trials report that counseling to increase the use of child safety seats leads to increased short-term restraint use (7 CCTs, 6 RCTs). Interventions that included a demonstration of correct use or distribution of a free or reduced-cost child safety seat reported larger effects. Few trials described the effect of counseling children 4 to 8 years of age to use booster seats (1 RCT); counseling older children, adolescents, or adults to use seat belts (1 CCT, 2 RCTs); or counseling unselected primary care patients to reduce alcohol-related driving behaviors (no trials). LIMITATIONS: Most of the relevant trials were published before the widespread enactment of child safety seat legislation and had methodological flaws. CONCLUSIONS: The incremental effect of primary care counseling to increase the correct use of child safety seats in the current regulatory environment is not established. The effectiveness of primary care counseling to reduce alcohol-related driving has not been tested. Studies are needed.

Development of an algorithm to identify pregnancy episodes in an integrated health care delivery system.

OBJECTIVE: To develop and validate a software algorithm to detect pregnancy episodes and maternal morbidities using automated data. DATA SOURCES/STUDY SETTING: Automated records from a large integrated health care delivery system (IHDS), 1998-2001. STUDY DESIGN: Through complex linkages of multiple automated information sources, the algorithm estimated pregnancy histories. We evaluated the algorithm's accuracy by comparing selected elements of the pregnancy history obtained by the algorithm with the same elements manually abstracted from medical records by trained research staff. DATA COLLECTION/EXTRACTION METHODS: The algorithm searched for potential pregnancy indicators within diagnosis and procedure codes, as well as laboratory tests, pharmacy dispensings, and imaging procedures associated with pregnancy. PRINCIPAL FINDINGS: Among 32,847 women with potential pregnancy indicators, we identified 24,680 pregnancies occuring to 21,001 women. Percent agreement between the algorithm and medical records review on pregnancy outcome, gestational age, and pregnancy outcome date ranged from 91 percent to 98 percent. The validation results were used to refine the algorithm. CONCLUSIONS: This pregnancy episode grouper algorithm takes advantage of databases readily available in IHDS, and has important applications for health system management and clinical care. It can be used in other settings for ongoing surveillance and research on pregnancy outcomes, pregnancy-related morbidities, costs, and care patterns.

Screening and interventions for childhood overweight: a summary of evidence for the US Preventive Services Task Force.

BACKGROUND: Childhood and adolescent overweight and obesity are related to health risks, medical conditions, and increased risk of adult obesity, with its attendant effects on morbidity and mortality rates. The prevalence of childhood overweight and obesity has more than doubled in the past 25 years. Purpose. This evidence synthesis examines the evidence for the benefits and harms of screening and early treatment of overweight among children and adolescents in clinical settings. METHODS: We developed an analytic framework and 7 key questions representing the logical evidence connecting screening and weight control interventions with changes in overweight and behavioral, physiologic, and health outcomes in childhood or adulthood. We searched the Cochrane Library from 1996 to April 2004. We searched Medline, PsycINFO, DARE, and CINAHL from 1966 to April 2004. One reviewer abstracted relevant information from each included article into standardized evidence tables, and a second reviewer checked key elements. Two reviewers quality-graded each article with US Preventive Services Task Force criteria. RESULTS: Although BMI is a measure of relative weight rather than adiposity, it is recommended widely for use among children and adolescents to determine overweight and is the currently preferred measure. The risk of adult overweight from childhood overweight provides the best available evidence to judge the clinical validity of BMI as an overweight criterion for children and adolescents. BMI measures in childhood track to adulthood moderately or very well, with stronger tracking seen for children with >or=1 obese parent and children who are more overweight or older. The probability of adult obesity (BMI of >30 kg/m(2)) is >or=50% among children >13 years of age whose BMI percentiles meet or exceed the 95th percentile for age and gender. BMI-based overweight categorization for individuals, particularly for racial/ethnic minorities with differences in body composition, may have limited validity because BMI measures cannot differentiate between increased weight for height attributable to relatively greater fat-free mass (muscle, bone, and fluids) and that attributable to greater fat. No trials of screening programs to identify and to treat childhood overweight have been reported. Limited research is available on effective, generalizable interventions for overweight children and adolescents that can be conducted in primary care settings or through primary care referrals. CONCLUSIONS: BMI measurements of overweight among older adolescents identify those at increased risk of developing adult obesity. Interventions to treat overweight adolescents in clinical settings have not been shown to have clinically significant benefits, and they are not widely available. Screening to categorize overweight among children under age 12 or 13 who are not clearly overweight may not provide reliable risk categorization for adult obesity. Screening in this age group is compromised by the fact that there is little generalizable evidence for primary care interventions. Because existing trials report modest short- to medium-term improvements (approximately 10-20% decrease in percentage of overweight or a few units of change in BMI), however, overweight improvements among children and adolescents seem possible.

The primary prevention of heart disease in women through health behavior change promotion in primary care.

PURPOSE: To summarize recent evidence-based recommendations for physical activity promotion, dietary improvement, and tobacco cessation from the U.S. Preventive Services Task Force (USPSTF) and the Task Force on Community Preventive Services (CTF), and examine their applicability to the primary prevention of cardiovascular disease (CVD) in women through primary care interventions. METHODS: For the behaviors cited, USPSTF and CTF recommendations and their associated systematic evidence reviews (SERs) were retrieved. Individual articles from the USPSTF healthy diet and physical activity SERs that met our inclusion criteria were systematically examined to determine the applicability of this research to women. We supplemented findings from these sources with comprehensive federal research summaries and SERs from focused searches of systematic review databases relevant to primary CVD prevention in women through healthy behavior change. MAIN FINDINGS: The USPSTF strongly recommends primary care interventions for tobacco cessation. Strong CTF recommendations for multicomponent systems supports for clinicians, telephone support for quitters, and reduced patient costs for effective cessation therapies guide complementary approaches to assist clinicians. The USPSTF recommends intensive behavioral dietary counseling by specialists for high-risk CVD patients, but found insufficient evidence to recommend for routine healthy diet or physical activity promotion in primary care. The evidence base for these recommendations generally applies to women. Better reporting of gender and minority subgroup outcomes will assist more in-depth understanding of potential differences in either the processes or outcomes of behavior change interventions. CONCLUSIONS: Primary care clinicians, including obstetrician-gynecologists, can contribute to preventing CVD in women through implementing credible evidence-based recommendations for clinical interventions in tobacco and healthy diet. Researchers can further our understanding of gender-specific issues in healthy behavior interventions by reporting process and outcome data for gender and minority subgroups.

Human immunodeficiency virus (HIV)-specific antibody in cervicovaginal lavage specimens obtained from women infected with HIV type 1.

To evaluate correlates of anti-human immunodeficiency virus (HIV) type 1 (HIV-1) immunoglobulin (Ig) in the genital tract, anti-HIV-gp120 IgA and IgG titers in cervicovaginal lavage specimens obtained from 104 HIV-1-infected women were measured by enzyme-linked immunosorbent assay. Overall, 24% and 94% of women had detectable anti-gp120 IgA and IgG, respectively. CD4 cell count correlated negatively with total IgA concentration (r=-0.301; P=.0027) and positively with specific IgA activity (anti-gp120 IgA titer/total IgA concentration, r=0.306; P=.0023). Women with bacterial vaginosis had 5-fold lower anti-gp120 IgG titer (P=.0042), 5-fold lower total IgG concentration (P< or =.0001), and 4-fold higher specific IgG activity (P=.0474) compared with women who did not have bacterial vaginosis. Enhanced understanding of correlates of mucosal immunity to HIV-1 may assist in the design of vaccine strategies or in the prevention of vertical transmission of HIV-1.

Differential induction of mucosal and systemic antibody responses in women after nasal, rectal, or vaginal immunization: influence of the menstrual cycle.

A cholera vaccine containing killed vibrios and cholera toxin B subunit (CTB) was used to compare mucosal immunization routes for induction of systemic and mucosal Ab. Four groups of women were given three monthly immunizations by the rectal immunization (R(imm)) route, nasal immunization (N(imm)) route, or vaginal immunization route during either the follicular (V-FP(imm)) or luteal (V-LP(imm)) menstrual cycle phase. N(imm) was performed with 10-fold less vaccine to determine if administration of less Ag by this route can, as in rodents, produce mucosal Ab responses comparable to those induced by higher dose R(imm) or vaginal immunization. Concentrations of Ab induced in sera and secretions were measured by ELISA. None of these routes produced durable salivary Ab responses. N(imm) induced greatest levels of CTB-specific IgG in sera. R(imm) failed to generate CTB-specific IgA in genital tract secretions. N(imm), V-FP(imm), and V-LP(imm) all produced cervical CTB-specific IgA responses comparable in magnitude and frequency. However, only V-FP(imm) induced cervical IgA2-restricted Ab to the bacterial LPS vaccine component. V-FP(imm), but not V-LP(imm), also induced CTB-specific IgA in rectal secretions. N(imm) was superior to V-FP(imm) for producing rectal CTB-specific IgA, but the greatest amounts of CTB-specific IgA and LPS-specific IgA, IgG, and IgM Ab were found in rectal secretions of R(imm) women. These data suggest that in women, N(imm) alone could induce specific Ab in serum, the genital tract, and rectum. However, induction of genital tract and rectal Ab responses of the magnitude generated by local V-FP(imm) or R(imm) will likely require administration of comparably high nasal vaccine dosages.