David H. Adler

The Impact of HAART on HPV-Related Cervical Disease

PURPOSE OF REVIEW highly active antiretroviral therapy (HAART) has had an unequivocally positive impact on morbidity and mortality in HIV-infected individuals. These benefits have clearly extended to some HIV-related malignancies, including Kaposis sarcoma and non-Hodgkins lymphoma. The impact of HAART on cervical cancer, however, remains uncertain. The objective of this review is to summarize the last ten years of registry-based and clinical research into the impact of HAART on human papillomavirus (HPV) related cervical disease. RELEVANT FINDINGS compared to their HIV-uninfected counterparts, HIV-infected women have an increased prevalence of HPV infection, increased risk of progression of HPV-related cervical disease, and an increased risk of invasive cervical cancer. While the partial immune reconstitution afforded by HAART might be expected to decrease susceptibility to HPV infection and cervical disease, the local effects of improved immunosurveillance on the cervix are uncertain and the increased longevity of patients on HAART may increase risk of exposure to HPV and provide the time required for progression of cervical disease. Registry-based evidence has been consistent in identifying the lack of decrease in cervical cancer incidence in the HAART era. Clinical research on the subject, however, has produced conflicting evidence with regards to both the effect of HAART on HPV infection and its impact on cervical disease progression/regression. SUMMARY the incidence of cervical cancer has not decreased in the HAART-era. Furthermore, clinical research has not shown a clear benefit of HAART in decreasing HPV-related cervical disease in HIV-infected women. A better understanding of this subject will have an impact on cervical disease surveillance practices.

Increased regression and decreased incidence of human papillomavirus-related cervical lesions among HIV-infected women on HAART.

Objective:To determine the impact of HAART on incidence, regression, and progression of cytopathological abnormalities in HIV-infected women. Design:Prospective cohort. Methods:HIV-infected women (N = 1123) from Soweto, South Africa underwent serial cervical smears that were analyzed and reported using the Bethesda System. The results of HAART and non-HAART users were compared using two statistical approaches: a survival analysis assessing risk of incident smear abnormality among women with baseline normal smear results; and analysis with marginal models assessing for an association between HAART use and likelihood of regression/progression in consecutive smears. Results:After multivariate survival analysis, women using HAART with a normal baseline smear were 38% less likely to have an incident smear abnormality during follow-up than nonusers [confidence interval (CI) 0.42–0.91; P = 0.01]. Multivariate marginal models analysis identified a significantly increased likelihood (odds ratio 2.61; CI 1.75–3.89; P < 0.0001) of regression of cervical lesions among women on HAART. Conclusion:Our large prospective cohort study adds significant weight to the side of the balance of clinical research supporting the positive impact of HAART on the natural history of human papillomavirus-related cervical disease in HIV-infected women.

Blunt diaphragmatic injury in a 7-year-old girl.

Blunt diaphragmatic injury is notoriously difficult to diagnose. There is no gold standard for radiologic diagnosis of this disease entity. This article reports a case of traumatic diaphragmatic rupture in a 7-year-old girl whose injury was identified on hospital day 2. The discussion includes a review of the physiology of this injury and the utility of radiologic modalities in making a timely diagnosis.

Cervical Dysplasia and High-Risk Human Papillomavirus Infections among HIV-Infected and HIV-Uninfected Adolescent Females in South Africa

Background. HIV-infected adolescents may be at higher risk for high-grade cervical lesions than HIV-uninfected adolescents. The purpose of this study was to compare the prevalence of high-risk HPV (HR-HPV) infections and Pap smear abnormalities between these two groups. Methods. In this cross-sectional study, we compared the HPV DNA and Pap smear results between 35 HIV-infected and 50 HIV-uninfected adolescents in order to determine the prevalence of HR-HPV genotypes and cervical cytological abnormalities. Comparisons were made using Pearson χ 2 and independent-samples t-tests analyses, and associations between demographic and behavioral characteristics and HPV infections were examined. Results. HIV-infected participants were more likely to be infected with any HPV (88.6% versus 48.0%; P < 0.001) and with at least one HR-HPV (60.0% versus 24.0%; P = 0.001), and to have multiple concurrent HPV infections (68.6% versus 22.0%; P < 0.001). HPV 16 and 18 were relatively underrepresented among HR-HPV infections. Abnormal Pap test results were more common among HIV-infected participants (28.8% versus 12.0%; P = 0.054). A history of smoking was associated with HR-HPV infection. Conclusions. HIV-infected adolescents have an increased risk of infection with HR-HPV and of Pap test abnormalities. The majority of HR-HPV infections among our participants would not be prevented by the currently available vaccinations against HPV.

A Viable and Simple Self-Sampling Method for Human Papillomavirus Detection among South African Adolescents

BACKGROUND Self-sampling for Human Papillomavirus (HPV) testing may offer improved patient acceptability, decreased cost, and greater practicality than clinician collection of specimens. HPV testing among adolescents is necessary to conduct vaccine surveillance and may play a role in cervical cancer screening among some populations. METHODS A cross-sectional prevalence study was conducted to compare the results of self-collected and clinician-collected specimens for Human papillomavirus (HPV) testing among South African adolescent females. All participants provided self-sampled vaginal swabs and underwent clinician-collection of cervical swabs for HPV DNA analysis. The level of agreement between HPV DNA results from the two specimen collection methods was measured. RESULTS The level of agreement between HPV DNA results from self-collected and clinician-collected specimens was high (κ=86.7; p<0.001). A high prevalence of HPV overall was found by both specimen collection methods (57%; 95% CI 0.37-0.75). Low-risk HPV (LR-HPV) types were found slightly more frequently in self-collected specimens. CONCLUSION There is a high level of agreement between the HPV DNA results from self-collected and clinician-collected specimens. Self-collection of specimens for HPV testing is a viable alternative among adolescents.

Minimizing Attrition for Multisite Emergency Care Research

Loss to follow-up of enrolled patients (a.k.a. attrition) is a major threat to study validity and power. Minimizing attrition can be challenging even under ideal research conditions, including the presence of adequate funding, experienced study personnel, and a refined research infrastructure. Emergency care research is shifting toward enrollment through multisite networks, but there have been limited descriptions of approaches to minimize attrition for these multicenter emergency care studies. This concept paper describes a stepwise approach to minimize attrition, using a case example of a multisite emergency department prospective cohort of over 3,000 patients that has achieved a 30-day direct phone follow-up attrition rate of <3%. The seven areas of approach to minimize attrition in this study focused on patient selection, baseline contact data collection, patient incentives, patient tracking, central phone banks, local enrollment site assistance, and continuous performance monitoring. Appropriate study design, including consideration of these methods to reduce attrition, will be time well spent and may improve study validity.

Reliability of clinical assessments in older adults with syncope or near syncope

OBJECTIVES Clinical prediction models for risk stratification of older adults with syncope or near syncope may improve resource utilization and management. Predictors considered for inclusion into such models must be reliable. Our primary objective was to evaluate the inter-rater agreement of historical, physical examination, and electrocardiogram (ECG) findings in older adults undergoing emergency department (ED) evaluation for syncope or near syncope. Our secondary objective was to assess the level of agreement between clinicians on the patients overall risk for death or serious cardiac outcomes. METHODS We conducted a cross-sectional study at 11 EDs in adults 60 years of age or older who presented with unexplained syncope or near syncope. We excluded patients with a presumptive cause of syncope (e.g., seizure) or if they were unable or unwilling to follow-up. Evaluations of the patients past medical history and current medication use were completed by treating provider and trained research associate pairs. Evaluations of the patients physical examination and ECG interpretation were completed by attending/resident, attending/advanced practice provider, or attending/attending pairs. All evaluations were blinded to the responses from the other rater. We calculated the percent agreement and kappa statistic for binary variables. Inter-rater agreement was considered acceptable if the kappa statistic was 0.6 or higher. RESULTS We obtained paired observations from 255 patients; mean (±SD) age was 73 (±9) years, 137 (54%) were male, and 204 (80%) were admitted to the hospital. Acceptable agreement was achieved in 18 of the 21 (86%) past medical history and current medication findings, none of the 10 physical examination variables, and three of the 13 (23%) ECG interpretation variables. There was moderate agreement (Spearman correlation coefficient, r = 0.40) between clinicians on the patients probability of 30-day death or serious cardiac outcome, although as the probability increased, there was less agreement. CONCLUSIONS Acceptable agreement between raters was more commonly achieved with historical rather than physical examination or ECG interpretation variables. Clinicians had moderate agreement in assessing the patients overall risk for a serious outcome at 30 days. Future development of clinical prediction models in older adults with syncope should account for variability of assessments between raters and consider the use of objective clinical variables.

ECG Predictors of Cardiac Arrhythmias in Older Adults With Syncope

Study objective: Cardiac arrhythmia is a life‐threatening condition in older adults who present to the emergency department (ED) with syncope. Previous work suggests the initial ED ECG can predict arrhythmia risk; however, specific ECG predictors have been variably specified. Our objective is to identify specific ECG abnormalities predictive of 30‐day serious cardiac arrhythmias in older adults presenting to the ED with syncope. Methods: We conducted a prospective, observational study at 11 EDs in adults aged 60 years or older who presented with syncope or near syncope. We excluded patients with a serious cardiac arrhythmia diagnosed during the ED evaluation from the primary analysis. The outcome was occurrence of 30‐day serous cardiac arrhythmia. The exposure variables were predefined ECG abnormalities. Independent predictors were identified through multivariate logistic regression. The sensitivities and specificities of any predefined ECG abnormality and any ECG abnormality identified on adjusted analysis to predict 30‐day serious cardiac arrhythmia were also calculated. Results: After exclusion of 197 patients (5.5%; 95% confidence interval [CI] 4.7% to 6.2%) with serious cardiac arrhythmias in the ED, the study cohort included 3,416 patients. Of these, 104 patients (3.0%; 95% CI 2.5% to 3.7%) had a serious cardiac arrhythmia within 30 days from the index ED visit (median time to diagnosis 2 days [interquartile range 1 to 5 days]). The presence of nonsinus rhythm, multiple premature ventricular conductions, short PR interval, first‐degree atrioventricular block, complete left bundle branch block, and Q wave/T wave/ST‐segment abnormalities consistent with acute or chronic ischemia on the initial ED ECG increased the risk for a 30‐day serious cardiac arrhythmia. This combination of ECG abnormalities had a similar sensitivity in predicting 30‐day serious cardiac arrhythmia compared with any ECG abnormality (76.9% [95% CI 67.6% to 84.6%] versus 77.9% [95% CI 68.7% to 85.4%]) and was more specific (55.1% [95% CI 53.4% to 56.8%] versus 46.6% [95% CI 44.9% to 48.3%]). Conclusion: In older ED adults with syncope, approximately 3% receive a diagnosis of a serious cardiac arrhythmia not recognized on initial ED evaluation. The presence of specific abnormalities on the initial ED ECG increased the risk for 30‐day serious cardiac arrhythmias.

High Level of Agreement between Clinician-Collected and Self-Collected Samples for HPV Detection among South African Adolescents

To the Editor, A number of investigators have reported reasonably high concordance between clinician-collected and self-collected specimens for detection of human papillomaviruses (HPV),1–6 and meta-analyses have concurred that self-sampling may be a viable alternative under some circumstances.7,8 Potential advantages of self-sampling for HPV testing include greater acceptability,2 inexpensiveness, and practicality in low-resource settings.7 However, inadequate agreement between these methods for high-risk HPV (HR-HPV) has also been reported.9 Several investigators have noted increased detection of low-risk HPV (LR-HPV) among self-collected samples,3,5,7 which may reflect a greater tropism for vaginal over cervical epithelium of some phylogenetic species. There has been significant variability in self-sampling methods among studies of this subject as well as variability in the ages of study subjects. We conducted a pilot study of clinician-collected versus self-collected genital samples for HPV testing among a notably young age group (16- and 17-year-old South African females) using a simple self-sampling method. In our small cohort of South African adolescents (N = 15), samples from self-collected vaginal Dacron swabs were collected during the same visit as clinician-collected cervical specimens. Patients were instructed to insert the swab high into the vagina and twirl it for 10 seconds. Human papillomavirus genotyping was performed using the Roche Linear Array kit, which uses polymerase chain reaction (PCR) to detect 37 human genital HPV genotypes, including all 18 HR-HPV types.10 All specimens were β-globin positive. We found a high prevalence of HPV, with good agreement between clinician-collected and self-collected samples (Table 1). The κ statistic for HR-HPV was 0.73 (P = .009, SE = 0.18), and for LR-HPV it was 0.59 (P = .03, SE = 0.19). Sixty percent of samples obtained from both methods were positive for any HPV, and 53% of samples from both methods were positive for any HR-HPV. A greater prevalence of LR-HPV was found among self-collected samples (47% vs 27%, P = .45). All participants had cervical smears performed; 1 showed atypical squamous cells of uncertain significance, and all others were normal. Table 1 Comparison of Human Papillomavirus DNA Test Results of Clinician-Collected and Self-collected Samplesa Our new data are limited in their precision as a result of the small sample size, but they support prior suggestions that agreement between clinician-collected and self-collected samples for HR-HPV is high and that LR-HPV is more frequently detected among self-collected vaginal specimens. For epidemiologic and research purposes, clinician-collected and self-collected specimens may be complimentary. Human papillomavirus testing is not currently recommended for adolescents and does not have a well-established clinical application. Although some comparisons among self-collection techniques have been reported,11,12 there is a dearth of data comparing vaginal lavage to the simpler swab method. Although overall patient acceptance of self-sampling has been reported to be high,2,6,11 in the only reported evaluation of preference between lavage and swab techniques, swabs were overwhelmingly preferred.13 The simple self-collection technique used in our study and others may be most appropriate. Our self-sampling cohort is among the youngest reported on the subject and supports the extension of evidence for reasonably high agreement between clinician-collected and self-collected samples for HPV detection to this age group.

Inclusion of South African adolescents in HIV vaccine trials

South Africa has more people living with HIV than any other nation. The HIV epidemic in South Africa is being driven by new infections among adolescents. Inclusion of adolescents in HIV vaccine trials is essential for successful vaccine development, however, recruitment and retention of at-risk South African adolescents into these trials poses a number of legal, ethical and operational challenges. This article discusses the South African ethico-legal context in which future adolescent HIV vaccine trials would be conducted followed by a review of available data regarding strategies for recruitment into these trials and retention of trial participants.