Joseph Caperna

Incidence of and risk factors for clinically significant methicillin-resistant Staphylococcus aureus infection in a cohort of HIV-infected adults.

Objectives:Outbreaks of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) have been noted in multiple sites in the United States. This studys purpose was to estimate trends in the incidence of and risk factors for clinically significant MRSA (CS-MRSA) infection in a cohort of HIV-infected adults. Design:A retrospective clinic-based cohort (January 1, 2000-December 31, 2003) study. Methods:We ascertained all initial episodes of CS-MRSA and categorized them by primary site. Incidence rates were estimated by half year. Risk factors for CA-MRSA infection were identified using Cox modeling. Results:Of 126 potential events, 94 were CS. Their primary sources were 83% skin or soft tissue, 10% blood, 6% respiratory, and 1.0% other sites. Among these, 60% were CA and 40% were nosocomial. Of antibiotics tested, only cotrimoxazole resistance was associated with nosocomial acquisition. The 3455 patients contributed 7003 person-years at risk. The incidence of CS-MRSA infection increased 6.2-fold from the first to the last half year. In multivariate analysis, independent predictors of CA-MRSA infection included HIV transmission by men who have sex with men or by injection drug use, CD4 count <50 cells/μL, log10 HIV plasma viral load, and absence of cotrimoxazole prophylaxis. Conclusions:The incidence of initial CS-MRSA events increased more than 6-fold in a 4-year period. The associations between CA-MRSA infection and HIV severity indicators merit examination in other cohorts.

Measurement characteristics of anal cytology, histopathology, and high-resolution anoscopic visual impression in an anal dysplasia screening program.

Background: The study aims were (1) to estimate agreement between consecutive anal cytologic examinations, between concurrent cytologic examination and histopathology, and between high-resolution anoscopy (HRA) visual impression and histopathology and (2) to estimate the prevalence of severe dysplasia by concurrent cytologic category. Methods: Prospective study of HIV-infected patients receiving anal dysplasia screening as part of routine care. Agreement between measures was estimated by weighted kappa-statistics. Results: Between July 2000 and September 2003, 1864 patients underwent 2947 anal cytology tests. Excluding unsatisfactory tests (6%), 642 patients had repeat cytologic evaluation and 154 had concurrent cytology tests and biopsy. Using 4-category cytology grading, kappa-agreement between the first 2 cytologic measurements was 0.36. Comparing concurrent cytology tests and biopsy, kappa-agreement was 0.36. Comparing the most severe HRA visual impression and biopsy, kappa-agreement was 0.32. The prevalence of anal intraepithelial neoplasia 3 at biopsy by concurrent cytology category was 0 (cytology normal), 21% (atypical squamous cells of uncertain significance), 27% (low-grade squamous intraepithelial lesion), and 54% (high-grade squamous intraepithelial lesion). Conclusions: These data suggest that the reproducibility of key screening measures is moderate at best but of similar magnitude to that of other studies of anal and cervical dysplasia screening. As candidate interventions to treat or prevent precursor lesions enter clinical development, standardization and improvement of measurement methods are essential.

Estimating the accuracy of anal cytology in the presence of an imperfect reference standard.

Background The study aim is to estimate sensitivity and specificity of anal cytology for histologic HSIL in analyses adjusted for the imperfect biopsy reference standard. Methods and Principal Findings Retrospective cohort study of an anal dysplasia screening program for HIV infected adults. We estimated the prevalence of histologic HSIL by concurrent cytology category and the associated cytology ROC area. Cytology operating characteristics for HSIL were estimated and adjusted for the imperfect reference standard by 3 methodologies. The study cohort included 261 patients with 3 available measures: (1) referral cytology; (2) HRA cytology; and (3) HRA directed biopsy. The prevalence of biopsy HSIL varied according to the concurrent HRA cytology result: 64.5% for HSIL or ASC-H, 12.6% for LSIL, 10.9% for ASCUS, and 6.3% for no abnormality. The cytology ROC area was 0.78. The observed prevalence of HSIL was 37% (referral cytology), 24% (HRA cytology), and 24% (HRA biopsy). Unadjusted estimates of sensitivity and specificity of cytology were 0.66 and 0.90, respectively. Adjusted estimates varied from 0.47–0.89 (sensitivity) and 0.89—1.0 (specificity). Conclusions Analysis of a single dataset yields widely different estimates of anal cytology operating characteristics that depend on difficult to verify assumptions regarding the accuracy of the imperfect reference standard.

Early Impact and Performance Characteristics of an Established Anal Dysplasia Screening Program: Program Evaluation Considerations

Background: Screening for invasive anal cancer and its precursors is being increasingly advocated as a response to increasing incidence among HIV-infected persons. We implemented a comprehensive screening program in 2001 and report our early experience to inform monitoring and evaluation of such programs. Our research aims were: (1) to estimate incidence of and mortality from invasive anal cancer (IAC) before (1995-2000) and after (2001-2005) screening program implementation and (2) to examine potential screening program quality indicators. Methods: The study cohort included all patients under care for HIV infection at UCSD Owen Clinic between 1995-2005. Person-time incidence rates (IR) and case survival of IAC were estimated for the pre-screening (1995-2000) and post-screening (2001-2005) periods. High resolution anoscopy (HRA) operator accuracy was estimated by kappa agreement between cyto-histologic comparisons. Program quality indicators included: (1) screening coverage; (2) percent technically unsatisfactory cytology smears; (3) time between 1st abnormal cytology and 1st HRA; and (4) time between last clinic visit and last cytology. Results: 28 cases of IAC and 13,411 person-years were observed between 1995-2005. IRs (95% CI) pre-screening and post-screening were 199 and 216 per 100,000 person-years, respectively. There was no routine treatment of high grade squamous intraepithelial lesions (HSIL) during the study period. The percent of patients with IAC requiring chemoradiation decreased from 90.9% to 70.6% (p=0.36). There was a significant improvement in cyto-histologic agreement at HRA with increasing operator experience (r=0.92, p=0.025). Screening coverage was 73% of the target population. Among 14 providers, the percent unsatisfactory cytology smears averaged 27% but varied from 0 – 62%. The median time from 1st abnormal cytology to 1st HRA was 258 days. The median interval between the last cytology and the last clinic visit was 207 days. Conclusion: (1) The overall IR of IAC did not decline in the screening era and was higher than previous estimates for HIV cohorts; (2) stage shift to IAC of more favorable prognosis is a reasonable screening goal; (3) HRA accuracy varied by provider experience; (4) because of delay in access to HRA, digital rectal exam should be combined with cytology screening to detect palpable disease.

Estimation of the effect of neutropenia on rates of clinical bacteraemia in HIV-infected patients

A retrospective cohort study was conducted to quantitate the relationship between neutropenia and rates of clinical bacteraemia among adults with HIV infection receiving medical care at one institution between 1991-5. The primary exposure, absolute neutrophil count (ANC), was summarized as mean ANC within a given week, using a five-level stratification (reference > 1000/microl). ANC stratum-specific rates of bacteraemia were calculated, by organism type. Linear trend tests were performed to assess dose-response relationship between neutropenia and rates of bacteraemia. The cohort included 1645 patients contributing 26,785 patients-weeks and 191 episodes of bacteraemia. The unadjusted effect of neutropenia was most evident for bacteraemia due to E. coli (RR 3.4), Klebsiella pneumoniae (RR 16.7), and P. aeruginosa (RR 10.4). For bacteraemia due to any of these three organisms (47 episodes), with reference ANC > 1000/microl, relative rates were: 751-1000/microl, 1.12; 501-750/microl, 2.11; 251-500/microl, 13.58; 0-250/microl, 21.89.

Denial of Risk Behavior Does Not Exclude Asymptomatic Anorectal Sexually Transmitted Infection in HIV-Infected Men

Background The Centers for Disease Control recommend screening for asymptomatic sexually transmitted infection (STI) among HIV-infected men when there is self-report of unprotected anal-receptive exposure. The study goals were: (1) to estimate the validity and usefulness for screening policies of self-reported unprotected anal-receptive exposure as a risk indicator for asymptomatic anorectal infection with Neisseria gonorrhoeae (GC) and/or Chlamydia trachomatis (CT). (2) to estimate the number of infections that would be missed if anal diagnostic assays were not performed among patients who denied unprotected anorectal exposure in the preceding month. Methods and Findings Retrospective analysis in HIV primary care and high resolution anoscopy (HRA) clinics. HIV-infected adult men were screened for self-reported exposure during the previous month at all primary care and HRA appointments. Four sub-cohorts were defined based on microbiology methodology (GC culture and CT direct fluorescent antibody vs. GC/CT nucleic acid amplification test) and clinical setting (primary care vs. HRA). Screening question operating characteristics were estimated using contingency table methods and then pooled across subcohorts. Among 803 patients, the prevalence of anorectal GC/CT varied from 3.5–20.1% in the 4 sub-cohorts. The sensitivity of the screening question for self-reported exposure to predict anorectal STI was higher in the primary care than in the HRA clinic, 86–100% vs. 12–35%, respectively. The negative predictive value of the screening question to predict asymptomatic anorectal STI was ≥90% in all sub-cohorts. In sensitivity analyses, the probability of being an unidentified case among those denying exposure increased from 0.4–8.1% in the primary care setting, and from 0.9–18.8% in the HRA setting as the prevalence varied from 1–20%. Conclusion As STI prevalence increases, denial of unprotected anal-receptive exposure leads to an increasingly unacceptable proportion of unidentified asymptomatic anorectal STI if used as a criterion not to obtain microbiologic assays.

Utility of clinical assessment, imaging, and cryptococcal antigen titer to predict AIDS-related complicated forms of cryptococcal meningitis

BackgroundThis study aimed to evaluate the prevalence and predictors of AIDS-related complicated cryptococcal meningitis. The outcome was complicated cryptococcal meningitis: prolonged (≥ 14 days) altered mental status, persistent (≥ 14 days) focal neurologic findings, cerebrospinal fluid (CSF) shunt placement or death. Predictor variable operating characteristics were estimated using receiver operating characteristic curve (ROC) analysis. Multivariate analysis identified independent predictors of the outcome.ResultsFrom 1990-2009, 82 patients with first episode of cryptococcal meningitis were identified. Of these, 14 (17%) met criteria for complicated forms of cryptococcal meningitis (prolonged altered mental status 6, persistent focal neurologic findings 7, CSF surgical shunt placement 8, and death 5). Patients with complicated cryptococcal meningitis had higher frequency of baseline focal neurological findings, head computed tomography (CT) abnormalities, mean CSF opening pressure, and cryptococcal antigen (CRAG) titers in serum and CSF. ROC area of log2 serum and CSF CRAG titers to predict complicated forms of cryptococcal meningitis were comparable, 0.78 (95%CI: 0.66 to 0.90) vs. 0.78 (95% CI: 0.67 to 0.89), respectively (χ2, p = 0.95). The ROC areas to predict the outcomes were similar for CSF pressure and CSF CRAG titers. In a multiple logistic regression model, the following were significant predictors of the outcome: baseline focal neurologic findings, head CT abnormalities and log2 CSF CRAG titer.ConclusionsDuring initial clinical evaluation, a focal neurologic exam, abnormal head CT and large cryptococcal burden measured by CRAG titer are associated with the outcome of complicated cryptococcal meningitis following 2 weeks from antifungal therapy initiation.