Efficient use of longitudinal CD4 counts and viral load measures in survival analysis.

CD4 counts and viral loads are dynamic quantities that change with time in HIV-infected persons. Commonly used single summary measures, such as viral load set point or early CD4 count, do not explicitly account for changes in viral load or CD4 counts or other features of the overall time course of these measures. However, the efficient use of all repeated measurements within each subject is often a challenge made more difficult by sparse and irregular sampling over time. Here, we illustrate how functional principal component (FPC) analysis provides an effective statistical approach for exploiting the patterns in CD4 count and viral load data over time. We demonstrate the method by using data from Kenyan women who acquired HIV-1 during follow-up in a cohort that practices high-risk activities and were subsequently followed up prospectively from early infection. The FPC scores for each woman obtained using this method served as informative summary statistics for the CD4 count and viral load trajectories. Similar to baseline CD4 count or viral set point, the first FPC score can be interpreted as a single-value summary measure of an individual's overall CD4 count or viral load. However, unlike most single-value summaries of CD4 count or viral load trajectories, the first FPC score summarizes the dynamics of these quantities and is seen to reveal specific features of the trajectories associated with mortality in this cohort. Moreover, the FPC scores are shown to be a more powerful prognostic factor than other common summaries when used in survival analysis.

A prospective study of risk factors for herpes simplex virus type 2 acquisition among high-risk HIV-1 seronegative women in Kenya.

OBJECTIVES: Several studies have demonstrated an association between herpes simplex virus type 2 (HSV-2) and HIV-1, but available data on risk factors for HSV-2 acquisition are limited. The objective of this analysis was to determine the incidence and risk factors for HSV-2 acquisition among HIV-1-seronegative female sex workers in Kenya. METHODS: Between February 1993 and December 2006, HIV-1-seronegative women attending a municipal sexually transmitted infection (STI) clinic were invited to enroll in a prospective cohort study. Screening for HIV-1 and STIs were done at monthly follow-up visits. Archived blood samples were tested for HSV-2. RESULTS: Of 1527 HIV-1-seronegative women enrolled, 302 (20%) were HSV-2 seronegative at baseline of whom 297 had at least one follow-up visit. HSV-2 incidence was high (23 cases/100 person-years; 115 cases). In multivariate analysis, HSV-2 was significantly associated with more recent entry into sex work, workplace and higher number of sex partners per week. Condom use was protective, although this was statistically significant only for the intermediate strata (25-75% condom use; HR 0.43; p = 0.05). There were statistical trends for bacterial vaginosis to increase HSV-2 risk (HR 1.56; p = 0.07) and for oral contraceptive use to decrease risk (HR 0.50; p = 0.08). The 23% annual HSV-2 incidence in this study is among the highest reported anywhere in the world. CONCLUSIONS: Women were at increased risk if they had recently entered sex work, had a higher number of sex partners or worked in bars. HSV-2 risk reduction interventions are urgently needed among high-risk African women.

Prospective study of correlates of vaginal Lactobacillus colonisation among high-risk HIV-1 seronegative women.

OBJECTIVE: Vaginal colonisation with Lactobacillus species is characteristic of normal vaginal ecology. The absence of vaginal lactobacilli, particularly hydrogen peroxide (H(2)O(2))-producing isolates, has been associated with symptomatic bacterial vaginosis (BV) and increased risk for HIV-1 acquisition. Identification of factors associated with vaginal Lactobacillus colonisation may suggest interventions to improve vaginal health. METHODS: We conducted a prospective cohort study of correlates of vaginal Lactobacillus colonisation among Kenyan HIV-1 seronegative female sex workers. At monthly follow-up visits, vaginal Lactobacillus cultures were obtained. Generalised estimating equations were used to examine demographic, behavioural and medical correlates of Lactobacillus isolation, including isolation of H(2)O(2)-producing strains. RESULTS: Lactobacillus cultures were obtained from 1020 women who completed a total of 8896 follow-up visits. Vaginal washing, typically with water alone or with soap and water, was associated with an approximately 40% decreased likelihood of Lactobacillus isolation, including isolation of H(2)O(2)-producing strains. Recent antibiotic use, excluding metronidazole and treatments for vaginal candidiasis, reduced Lactobacillus isolation by approximately 30%. H(2)O(2)-producing lactobacilli were significantly less common among women with Trichomonas vaginalis infection and those who were seropositive for herpes simplex virus type 2. In contrast, H(2)O(2)-producing lactobacilli were significantly more common among women with concurrent vaginal candidiasis. CONCLUSIONS: Modifiable biological and behavioural factors are associated with Lactobacillus colonisation in African women. Our results suggest intervention strategies to improve vaginal health in women at high risk for HIV-1.

Screening for genital and anorectal sexually transmitted infections in HIV prevention trials in Africa.

OBJECTIVES: To demonstrate the value of routine, basic sexually transmitted infection (STI) screening at enrolment into an HIV-1 vaccine feasibility cohort study and to highlight the importance of soliciting a history of receptive anal intercourse (RAI) in adults identified as "high risk". METHODS: Routine STI screening was offered to adults at high risk of HIV-1 upon enrolment into a cohort study in preparation for HIV-1 vaccine trials. Risk behaviours and STI prevalence were summarised and the value of microscopy assessed. Associations between prevalent HIV-1 infection and RAI or prevalent STI were evaluated with multiple logistic regression. RESULTS: Participants had a high burden of untreated STI. Symptom-directed management would have missed 67% of urethritis cases in men and 59% of cervicitis cases in women. RAI was reported by 36% of male and 18% of female participants. RAI was strongly associated with HIV-1 in men (adjusted odds ratio (aOR) 3.8; 95% CI 2.0 to 6.9) and independently associated with syphilis in women (aOR 12.9; 95% CI 3.4 to 48.7). CONCLUSIONS: High-risk adults recruited for HIV-1 prevention trials carry a high STI burden. Symptom-directed treatment may miss many cases and simple laboratory-based screening can be done with little cost. Risk assessment should include questions about anal intercourse and whether condoms were used. STI screening, including specific assessment for anorectal disease, should be offered in African research settings recruiting participants at high risk of HIV-1 acquisition.

The effect of treatment of vaginal infections on shedding of human immunodeficiency virus type 1.

To assess the effect of treatment of vaginal infections on vaginal shedding of cell-free human immunodeficiency virus type 1 (HIV-1) and HIV-1-infected cells, HIV-1-seropositive women were examined before and after treatment of Candida vulvovaginitis, Trichomonas vaginitis, and bacterial vaginosis. For Candida (n=98), vaginal HIV-1 RNA decreased from 3.36 to 2.86 log(10) copies/swab (P<.001), as did the prevalence of HIV-1 DNA (36% to 17%; odds ratio [OR], 2.8; 95% confidence interval [CI], 1.3-6.5). For Trichomonas vaginitis (n=55), HIV-1 RNA decreased from 3.67 to 3.05 log(10) copies/swab (P<.001), but the prevalence of HIV-1 DNA remained unchanged (22%-25%; OR, 0.8; 95% CI, 0.3-2.2). For bacterial vaginosis (n=73), neither the shedding of HIV-1 RNA (from 3.11 to 2.90 log(10) copies/swab; P=.14) nor the prevalence of DNA (from 21% to 23%; OR, 0.8; 95% CI, 0.3-2.0) changed. Vaginal HIV-1 decreased 3.2- and 4.2-fold after treating Candida and Trichomonas, respectively. These data suggest that HIV-1 transmission intervention strategies that incorporate diagnosis and treatment of these prevalent infections warrant evaluation.

Treatment of cervicitis is associated with decreased cervical shedding of HIV-1.

OBJECTIVE: To determine whether cervical mucosal shedding of HIV-1 RNA and HIV-1 infected cells decreases following successful treatment of cervicitis. DESIGN: Prospective interventional study. SETTING: Sexually Transmitted Infections Clinic, Coast Provincial General Hospital, Mombasa, Kenya. PARTICIPANTS: Thirty-six HIV-1 seropositive women with cervicitis: 16 with Neisseria gonorrhoeae, seven with Chlamydia trachomatis, and 13 with non-specific cervicitis. INTERVENTIONS: Treatment of cervicitis. MAIN OUTCOME MEASURES: Levels of total (cell-free and cell-associated) HIV-1 RNA and presence of HIV-1 DNA (a marker for infected cells) in cervical secretions before and after resolution of cervicitis. RESULTS: After treatment of cervicitis, the median HIV-1 RNA concentration in cervical secretions was reduced from 4.05 to 3.24 log10 copies/swab (P = 0.001). Significant decreases in cervical HIV-1 RNA occurred in the subgroups with N. gonorrhoeae (3.94 to 3.28 log10 copies/swab; P = 0.02) and C. trachomatis (4.21 to 3.19 log10 copies/swab; P = 0.02). Overall, the prevalence of HIV-1 infected cells in cervical secretions also decreased after treatment, from 67% to 42% (odds ratio, 2.8; 95% confidence interval, 1.3-6.0; P = 0.009). Detection of infected cells was associated with higher mean HIV-1 RNA levels (4.04 versus 2.99 log10 copies/swab; P< 0.0001). CONCLUSIONS: Effective treatment of cervicitis resulted in significant decreases in shedding of HIV-1 virus and infected cells in cervical secretions. Treatment of sexually transmitted diseases may be an important means of decreasing the infectivity of HIV-1 seropositive women by reducing exposure to HIV-1 in genital secretions.

Prospective analysis of Staphylococcus aureus bacteremia in nonneutropenic adults with malignancy.

PURPOSE: To determine the primary sources and secondary complications of Staphylococcus aureus bacteremia (SAB) in cancer patients, as well as predictors of outcome in cancer patients with SAB. PATIENTS AND METHODS: Fifty-two patients at Duke University Medical Center met entry criteria between September 1994 and December 1996 for this prospective cohort study involving hospitalized nonneutropenic adult cancer patients with SAB. All subjects were observed throughout initial hospitalization and were evaluated again at 6 and 12 weeks or until death. RESULTS: SAB was intravascular device-related in 42%, tissue infection-related (TIR) in 44%, and unidentifiable focus-related (UFR) in 13%. Seventeen patients (33%) were found to have metastatic infections or conditions, with eight (15%) developing infectious endocarditis (IE). Patients with TIR bacteremia were less likely than other patients to develop IE (4% v 24%, P =.06). The overall mortality rate was 38%, the SAB-related mortality rate was 15%, and the rate of SAB relapse was 12%. Methicillin resistance was not associated with adverse outcome. Inability to identify a point of entry (UFR bacteremia), however, was associated with a higher overall mortality rate (100% v 24%, P =.0006). Furthermore, a 72-hour surveillance blood culture positive for organisms was associated with an increased incidence of IE (P =.0006), metastatic infections or conditions (P =.0002), SAB relapse (P =.038), and SAB-related death (P =.038). CONCLUSION: SAB in cancer patients is associated with significant morbidity from frequent metastatic infections or conditions including IE, as well as considerable mortality. Unknown initial infection site and 72-hour surveillance cultures positive for organisms were predictive of a complicated course and poor final outcome.

Staphylococcus aureus bacteremia in the surgical patient: a prospective analysis of 73 postoperative patients who developed Staphylococcus aureus bacteremia at a tertiary care facility.

BACKGROUND: Staphylococcus aureus is a frequent cause of infection and bacteremia in the postoperative patient. Unfortunately, there have been no prospective studies evaluating these patients, so the incidence of complications, subsequent treatment algorithms, and prognosis remain undefined. The objectives of this prospective study of postoperative Staphylococcus aureus bacteremia (SAB) were to define the primary sources of bacteremia and to identify the common complications of SAB in the postoperative setting. METHODS: A registry was developed into which 309 consecutive adult patients with SAB were prospectively enrolled between September 1994 and December 1996. Seventy-three of these patients (23.6%) developed SAB in the postoperative setting. RESULTS: Analysis of the clinical features of these 73 postoperative patients revealed three important results. First, infective endocarditis is surprisingly common in postoperative patients with SAB and the classical stigmata of endocarditis are often absent. Transesophageal echocardiography was performed in 31 of 73 patients; 10 of these patients (32.3%) met Duke Criteria for definite endocarditis, but only 3 of these patients had vegetations detected by transthoracic echocardiography, and only 2 patients had peripheral stigmata of infective endocarditis. Second, the development of SAB after cardiothoracic surgery was strongly associated with underlying S. aureus mediastinitis. Twenty-one of the 23 patients who developed SAB after median sternotomy had mediastinitis (positive predictive value 91.3%). In many cases, the diagnosis of mediastinitis was not apparent when SAB was detected. Third, complications, relapses, and mortality were high in postoperative patients with SAB. Fourteen of 73 patients (19.2%) developed multiple noncardiac metastatic complications, including metastatic abscesses (5), septic emboli (3), pneumonia or empyema (2), septic arthritis (1), epidural abscess (1), and other metastatic foci (7). Twelve of 73 patients (16.4%) had recurrent staphylococcal infection after treatment of their first episode of SAB, including 8 patients (11.0%) with recurrent bacteremia. Of patients who survived, those with recurrent staphylococcal infection were more likely to have an infected surgical wound than were patients who were cured of infection (p = 0.05). Finally, mortality attributable to SAB (11.0%), and all-cause mortality (21.9%), was high. CONCLUSIONS: SAB in the postoperative setting is often a severe disease with high morbidity and mortality. A thorough diagnostic evaluation is indicated in surgical patients with S. aureus bacteremia to ensure the early detection of metastatic infections such as infective endocarditis and to define foci such as mediastinitis re quiring surgical intervention.

Staphylococcus aureus bacteremia among elderly vs younger adult patients: comparison of clinical features and mortality.

BACKGROUND: Previous studies give conflicting results regarding the effect of age on outcomes in Staphylococcus aureus bacteremia (SAB). These studies have been limited by retrospective design or small sample size. METHODS: We conducted a prospective cohort study of 385 patients with SAB aged 18 to 90 years. The setting was a large academic medical center. We observed patients from diagnosis of SAB to discharge or death. Discharged patients were contacted 12 weeks after their first positive culture findings. Data were collected on demographics, comorbid conditions, focus of infection, length of stay, and outcome. Primary outcomes were total mortality and death due to SAB. RESULTS: Comparisons were made between 145 patients, aged 66 to 90 years, and 240 patients, aged 18 to 60 years. Forty-three (29.7%) of the elderly patients and 36 (15%) of the younger patients died. Death directly attributable to SAB occurred in 21 (14.5%) older and 15 (6.3%) younger patients. After adjusting for confounding variables, older patients continued to have higher total mortality (odds ratio, 2.21; 95% confidence interval, 1.32-3.70), and higher mortality from SAB (odds ratio, 2.30; 95% confidence interval, 1.13-4.69). Infection with methicillin-resistant S aureus was associated with higher total mortality in the elderly (odds ratio, 2.59; 95% confidence interval, 1.23-5.43). CONCLUSIONS: Staphylococcus aureus bacteremia among the elderly is associated with high mortality. Both total mortality and mortality directly attributable to SAB are more than twice as likely in older patients. Infection with methicillin-resistant S aureus carries a worse prognosis than infection with methicillin-sensitive S aureus in the elderly.

Recurrent Staphylococcus aureus bacteremia: pulsed-field gel electrophoresis findings in 29 patients.

To identify risk factors for relapse among 309 prospectively identified cases of Staphylococcus aureus bacteremia, patients with recurrent S. aureus bacteremia were identified, and pulsed-field gel electrophoresis (PFGE) was performed on isolates from both episodes. PFGE banding patterns from both isolates were identical in 23 patients, consistent with relapsed infection. Patients with PFGE-confirmed relapse were more likely by both univariate and multivariate analyses to have an indwelling foreign body (odds ratio [OR]=18.2, 95% confidence interval [CI]=7. 6-43.6; P<.001), to have received vancomycin therapy (OR=4.1, 95% CI=1.5-11.6; P=.008), or be hemodialysis-dependent (OR=4.1, 95% CI=1. 8-9.3; P=.002) than patients who did not develop recurrent bacteremia. These results suggest that recurrent episodes of S. aureus bacteremia are primarily relapses and are associated with an indwelling foreign body, receiving vancomycin therapy, and hemodialysis dependence.

Infective endocarditis due to Staphylococcus aureus: 59 prospectively identified cases with follow-up.

Fifty-nine consecutive patients with definite Staphylococcus aureus infective endocarditis (IE) by the Duke criteria were prospectively identified at our hospital over a 3-year period. Twenty-seven (45.8%) of the 59 patients had hospital-acquired S. aureus bacteremia. The presumed source of infection was an intravascular device in 50.8% of patients. Transthoracic echocardiography (TTE) revealed evidence of IE in 20 patients (33.9%), whereas transesophageal echocardiography (TEE) revealed evidence of IE in 48 patients (81.4%). The outcome for patients was strongly associated with echocardiographic findings: 13 (68.4%) of 19 patients with vegetations visualized by TTE had an embolic event or died of their infection vs. five (16.7%) of 30 patients whose vegetations were visualized only by TEE (P < .01). Most patients with S. aureus IE developed their infection as a consequence of a nosocomial or intravascular device-related infection. TEE established the diagnosis of S. aureus IE in many instances when TTE was nondiagnostic. Visualization of vegetations by TTE may provide prognostic information for patients with S. aureus IE.

In vitro resistance to thrombin-induced platelet microbicidal protein among clinical bacteremic isolates of Staphylococcus aureus correlates with an endovascular infectious source.

Platelet microbicidal proteins (PMPs), small cationic peptides released at sites of endovascular damage, kill common bloodstream pathogens in vitro. Our group previously showed that in vitro resistance of clinical staphylococcal and viridans group streptococcal bacteremic strains to PMPs correlated with the diagnosis of infective endocarditis (IE) (Wu et al., Antimicrob. Agents Chemother. 38:729-732, 1994). However, that study was limited by (i) the small number of Staphylococcus aureus isolates from IE patients, (ii) the retrospective nature of the case definitions, and (iii) the diverse geographic sources of strains. The present study evaluated the in vitro PMP susceptibility phenotype of a large number of staphylococcemic isolates (n = 60), collected at a single medical center and categorized by defined and validated clinical criteria. A significantly higher proportion of staphylococcemic strains from patients with IE was PMP resistant in vitro than the proportion of strains from patients with soft tissue sepsis (83% and 33%, respectively; P < 0.01). Moreover, the levels of PMP resistance (mean percent survival of strains after 2-h exposure to PMP in vitro) were significantly higher for isolates from patients with IE and with vascular catheter sepsis than for strains from patients with abscess sepsis (P < 0.005 and P < 0.01, respectively). These data further support the concept that bloodstream pathogens that exhibit innate or acquired PMP resistance have a survival advantage with respect to either the induction or progression of endovascular infections.

Outcome of Staphylococcus aureus bacteremia according to compliance with recommendations of infectious diseases specialists: experience with 244 patients.

To determine whether recommendations of infectious diseases specialists affect outcome for patients, we evaluated 244 hospitalized patients with Staphylococcus aureus bacteremia. We offered our management recommendations to each patient's physicians and then assessed the clinical outcome for both patients for whom our consultative advice was followed and those for whom our advice was not heeded. All patients were followed up for 12 weeks after their first positive blood culture. Our management advice was followed for 112 patients (45.9%) and partially or completely ignored for 132 patients (54.1%). Patients for whom our recommendations were followed were more likely to be cured of their S. aureus infection and less likely to relapse (P < .01), despite having significantly more metastatic infections (P < .01) at the outset of therapy, than were those for whom our recommendations were not followed. Failure to follow recommendations to remove an infected intravascular device was the most important risk for treatment failure. After controlling for other factors, logistic regression analysis revealed that patients whose intravascular device was not removed were 6.5 times more likely to relapse or die of their infection than were those whose device was removed. Our findings suggest that patient-specific management advice by infectious diseases consultants can improve the clinical outcome for patients with S. aureus bacteremia.

Report of spores of Henneguya salminicola (Myxozoa) in human stool specimens: possible source of confusion with human spermatozoa.

The spores of Henneguya salminicola, a common tissue parasite of salmonid fishes in the northern hemisphere, were observed in stool specimens from two different patients with diarrhea. The spores' superficial resemblance to human spermatozoa resulted, in one instance, in an incorrect report, leading to suspicion of sexual abuse. H. salminicola spores and human spermatozoa can be differentiated on the basis of size, morphology, and staining characteristics. Laboratory personnel who perform microscopic examinations of stool specimens for ova and parasites should be aware that spores of H. salminicola may be seen from time to time.