Todd Hulgan

Education of Physicians-in-Training Can Decrease the Risk for Vascular Catheter Infection

Vascular catheter infection is a substantial cause of morbidity and death in hospitalized patients. It has been estimated that 50 000 to 100 000 bloodstream infections related to vascular devices occur yearly in the United States; 90% of these infections originate from central venous catheters (CVCs) (1). The attributable mortality rate for CVC-related bloodstream infections ranges from 14% to 28% (2-6). The attributable cost of such infections has been estimated to be as high as

Mitochondrial haplogroups and peripheral neuropathy during antiretroviral therapy: an adult AIDS clinical trials group study.

29 000 per episode (4). Various interventions, including skin preparation with chlorhexidine (7), use of vascular catheters with anti-infective coatings (8, 9), and use of maximum barrier precautions during catheter insertion, have been shown to reduce risk for catheter-related infections (10, 11). Currently, the optimal strategy for minimizing risk for vascular catheter infection is unclear. In 1993, the infection control committee at Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina, adopted the recommendations of Raad and colleagues (11) and established a policy that called for use of maximum sterile barriers (including a full-size sterile drape, sterile gown, sterile gloves, and a mask) when inserting CVCs. Despite conventional bedside and didactic instruction by critical care medicine faculty over a 2-year period, compliance of physicians-in-training was poor (<20%, according to informal surveys). Unpublished observations during a previous investigation suggested that procedures for CVC insertion varied widely and that a new educational approach was necessary. A multidisciplinary group developed and implemented a 1-day hands-on course to teach basic procedures and infection control practices to physicians completing their first postgraduate year (PGY-1) and third-year medical students. The details of this approach, which nurses call a skills fair, form the substance of our report. Methods Description of the Course The course was organized as follows. Infection control practitioners and a hospital epidemiologist taught 1 hour of basic infection control principles. Content included handwashing, isolation and appropriate use of barrier garments, and handling of patients with resistant organisms and varicella. Occupational Safety and Health Administration (OSHA) considerations for blood and body fluids and tuberculosis were taught in a separate hour-long session on a different day. Thereafter, medical students and PGY-1 physicians rotated through a series of 1-hour stations, at which they received 5 to 15 minutes of didactic instruction followed by hands-on instruction that was overseen by one to three faculty members. Faculty were selected because of their roles in supervising and teaching procedures in patient care settings. The course director observed each instructor for an entire session to ensure that the appropriate content was being delivered. At the hands-on stations, participants received training in 1) blood draws through vascular lines [taught by oncology catheter care nurses], 2) arterial puncture for obtaining an arterial blood gas [taught by respiratory therapists], 3) insertion of arterial catheters and CVCs [taught by critical care medicine faculty and fellows and trauma faculty], 4) urinary catheter insertion [taught by nurse instructors], 5) lumbar puncture [taught by an oncologist], 6) peripheral venous catheter insertion [taught by nurse instructors], and 7) phlebotomy (taught by faculty from the School of Medical Technology at Wake Forest University Baptist Medical Center). At all stations, mannequins were used to simulate patients; urinary catheterization was taught with male and female mannequins. All participants practiced phlebotomy on each other. Participants started peripheral intravenous lines first on mannequins and then on another participant. All of the hands-on sessions employed the same devices and supplies used in the hospital. Fifteen-minute breaks were given in the morning and in the afternoon, and a 1-hour lunch was provided. The PGY-1 physicians were divided into two large groups of approximately 50 persons, each of which was taught on a different day as part of the orientation for new interns. The medical students were taught on a separate day. Each hands-on station had 7 to 16 participants per small group session. In the second year of the course, most of the didactic instruction that preceded the hands-on sessions was done by videotape. A member of our infection control department reviewed the content of each didactic session to ensure its consistency with existing infection control policies. Content of courses on vascular catheters included use of povidone-iodine for skin preparation, avoidance of antibiotic ointment at the insertion site, and use of clear plastic dressings. Participants were also instructed to change dressings and intravenous tubing every 3 days and not to adhere to fixed schedules for changing CVCs. Of note, the hospitals infection control policy on vascular catheters did not change substantially during the study period, with the exception of the educational intervention; in particular, antibiotic-coated catheters were not used. Data Collection Previous Experience with Procedures During each hands-on session, PGY-1 physicians were asked to estimate the number of previous procedures that they had performed during medical school. Course Evaluation At the end of each 1-day course, an evaluation was given to each participant. Participants were asked to rate various factors, including each instructor, on a scale of 1 to 5 (1=poor; 5=excellent). Use of Full-Size Sterile Drapes The purchasing department provided data on the use of full-size sterile drapes. During the baseline year, a locally prepared sterile sheet was used. After the first course, a commercially available, full-size sterile drape (Kimberly-Clark, Roswell, Georgia) was used in all areas of the hospital in which CVCs were inserted. The purchasing department also monitored the number of CVCs inserted before and after each course was taught. Full-size sterile drapes were separate from the CVC kits during the preintervention and postintervention periods. Eight months before the first course (4 months into the baseline period), 140 physicians at all levels of training completed an anonymous survey of the perceived need for use of full-size sterile drapes. Before the first course, immediately after the first course, and 6 months after the first course, the participating group of PGY-1 physicians completed subsequent anonymous surveys. The same PGY-1 physicians were also surveyed about whether CVC insertion required povidone-iodine skin preparation, sterile gowns, sterile towels, and sterile gloves. Catheter-Related Infection To determine whether improved compliance with use of full-size sterile drapes or improvements in other areas of vascular catheter insertion were associated with reduced risk for catheter-related infection, precourse and postcourse surveillance for such infection was performed in six general medicine-surgery intensive care units and the associated step-down unit. We focused on insertion of CVCs and arterial catheters because at our institution, physicians-in-training perform essentially all of these procedures. In addition, we examined primary bloodstream infections because more than 90% of such infections in intensive care units probably originate from CVCs (12-14). Nosocomial primary bloodstream infections were identified on the basis of Centers for Disease Control and Prevention (CDC) surveillance definitions (15). In a primary bloodstream infection, a pathogen is isolated from a blood culture or cultures and is not related to infection at another site, unless that site is a vascular catheter (15). Catheter-related infections were defined as meeting definition three of the CDC Cardiovascular System Infection criteria for arterial or venous infection (15). Fulfillment of this definition required the presence of fever (temperature>38 C), pain, erythema, or heat at the catheter site plus the presence of a negative blood culture or absence of any blood cultures and the presence of a positive roll-plate culture of the catheter. For the positive roll-plate culture, we substituted a positive sonication culture ( 100 colony-forming units/mL) (16). Blood cultures were done by using the Wampole Isolator (Wampole Laboratories, Cranbury, New Jersey) and were predominately drawn only through a peripheral vein or as paired cultures through a peripheral vein and through a catheter. Catheter and bloodstream isolates were not molecularly typed. In the seven study units, use of CVCs was high ([central line days/patient days] 100%=73%). Because of this, we concluded that patient-days could serve as a surrogate of device-days, even though the latter would probably be more accurate under other circumstances (12). Other Procedure Considerations The frequency of blood and body fluid exposures among PGY-1 physicians was evaluated during the year before and the year after the first course. These data were obtained from our employee health service, which has had a formalized reporting program for 6 years. We did not measure changes in practice or outcomes related to lumbar punctures because the number of procedures performed was small and the complication rate is low; this made our sample size inadequate for demonstrating differences. In addition, we did not monitor procedures that are not performed primarily by physicians (that is, arterial punctures, urinary catheter insertions, blood draws through lines, peripheral line insertions, and phlebotomy). Statistical Analysis Proportions were compared by using the two-tailed chi-square test or the Fisher exact test. The rates of catheter-related infection were compared by using the incidence density ratio of the preintervention and postintervention periods, which were obtained by using the z test statistic (17). A P value less than 0.05 was consid

Race and Sex Differences in Antiretroviral Therapy Use and Mortality among HIV-Infected Persons in Care

Objective:HIV nucleoside reverse transcriptase inhibitors (NRTI) can cause peripheral neuropathy that is a result of mitochondrial injury. Polymorphisms in the mitochondrial genome define haplogroups that may have functional implications. The objective of this study was to determine if NRTI-associated peripheral neuropathy is associated with European mitochondrial haplogroups. Design:Case–control study of Adult AIDS Clinical Trials Group (ACTG) study 384 and ACTG Human DNA Repository participants. Methods:ACTG study 384 was a treatment strategy trial of antiretroviral therapy with didanosine (ddI) plus stavudine (d4T) or zidovudine plus lamivudine given with efavirenz, nelfinavir, or both. Subjects were followed for up to 3 years. Peripheral neuropathy was ascertained based on signs and symptoms. For this analysis, polymorphisms that define European mitochondrial haplogroups were characterized in a majority of ACTG 384 participants, and associations with peripheral neuropathy were assessed using logistic regression. Results:A total of 509 subjects were included in this analysis of whom 250 (49%) were self-identified as white, non-Hispanic. Mitochondrial haplogroup T was more frequent in subjects who developed peripheral neuropathy. Among 137 white subjects randomized to receive ddI plus d4T, 20.8% of those who developed peripheral neuropathy belonged to mitochondrial haplogroup T compared to 4.5% of control subjects (odds ratio, 5.4; 95% confidence interval, 1.4–25.1; P = 0.009). Independent predictors of peripheral neuropathy were randomization to receive ddI plus d4T, older age, and mitochondrial haplogroup T. Conclusions:A common European mitochondrial haplogroup may predict NRTI-associated peripheral neuropathy. Future studies should validate this relationship, and evaluate non-European mitochondrial haplogroups and other NRTI toxicities.

Oxidant Stress Is Increased during Treatment of Human Immunodeficiency Virus Infection

BACKGROUND There are conflicting data regarding race, sex, and mortality among persons infected with human immunodeficiency virus (HIV). We studied all-cause mortality among persons in care during the highly-active antiretroviral therapy (HAART) era. METHODS This retrospective cohort study included patients who made>or=1 clinic visit from January 1998 through December 2005. RESULTS Of 2605 patients (with 6657 person-years of follow-up), 38% were black and 24% were female. The percentage of time in care while receiving HAART was lower for blacks than for nonblacks (47% vs. 76%; P<.001) and for females than for males (57% vs. 71%; P=.01). There were 253 deaths (38 per 1000 person-years). After adjustment for characteristics at baseline, death was associated with black race (hazard ratio [HR], 1.33; P .04), female sex (HR, 1.53; P .007), injection drug use (IDU) as a risk factor for HIV infection (HR, 1.61; P .009), older age (HR, 1.45 per 10 years; P<.001), a lower CD4 cell count (HR, 0.59 for 200 vs. 350 cells/mm3; P<.001) and a higher HIV type 1 RNA level (HR, 1.35; P<.001). After adjustment for the length of time that HAART was received, black race (HR, 1.00; P .99) and IDU (HR, 1.37; P .09) were no longer associated with death, but female sex was (HR, 1.62; P=.002). CONCLUSIONS Race-associated differences in mortality likely resulted from HAART use. Women had an increased risk of death even after adjustment for HAART use. Addressing racial disparities will require improved HAART utilization. Increased mortality among women requires further study.

Absolute Count and Percentage of CD4+ Lymphocytes Are Independent Predictors of Disease Progression in HIV-Infected Persons Initiating Highly Active Antiretroviral Therapy

Some diseases and environmental exposures, including those that are risk factors for atherosclerosis, are associated with increased oxidant stress. The objective of this cross-sectional, observational study was to determine whether oxidant stress is increased during human immunodeficiency virus type 1 (HIV-1) infection or its therapy. To quantify oxidant stress, plasma F2 isoprostane (F2-IsoP) concentrations were determined by gas chromatography/mass spectroscopy. A total of 120 subjects were enrolled during routine primary care visits. The median CD4+ T cell count was 341 cells/mm3, the median HIV-1 RNA level was 3.4 log10 copies/mL, and 74% of patients were receiving antiretroviral therapy. Plasma F2-IsoP concentrations were 12-149 pg/mL (median, 31 pg/mL). In univariate analysis, higher F2-IsoP concentrations were associated with lower log10 plasma HIV-1 RNA levels (P=.009) and with efavirenz use (P=.02). Both factors remained associated with plasma F2-IsoP concentrations in multivariate analysis. Oxidant stress associated with therapeutic control of viral replication may have important implications for long-term complications of antiretroviral therapy.

Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy

BACKGROUND Highly active antiretroviral therapy (HAART) is recommended when the absolute CD4(+) T lymphocyte count is <200 cells/mm(3), and it should be considered when that count is > or =200, although the optimal timing when it is > or =200 is unclear. Because preliminary data had suggested that a low CD4(+) T lymphocyte percentage (%CD4) is associated with disease progression in persons initiating HAART who have a higher absolute CD4, we sought to further characterize the predictive utility of %CD4. METHODS We conducted an observational study of persons in Collaborations in HIV Outcomes Research/US cohort who initiated their first HAART regimen between 1997 and 2004, received > or =30 days of therapy, and had baseline values of absolute CD4, %CD4, and HIV-1 RNA. Cox proportional-hazards models determined associations between %CD4 and disease progression (to either a new AIDS-defining event [ADE] or death). RESULTS Of 1891 persons, 11% were female and 18% were African American; the median age was 38 years. Median follow-up was 55 months (interquartile range, 23-83 months), and 468 (25%) had disease progression. Multivariable analysis including age, race, sex, HIV-1 RNA, prior antiretroviral therapy, probable route of infection, prior ADE, absolute CD4, and %CD4 was performed; prior ART (P<.0001), injection-drug use (P=.04), lower absolute CD4 (P=.002), and lower %CD4 (P=.002) predicted disease progression. CONCLUSIONS %CD4 at initiation of the first HAART regimen predicted disease progression independent of absolute CD4; %CD4 may be used to determine the timing of HAART.

Hemochromatosis Gene Polymorphisms, Mitochondrial Haplogroups, and Peripheral Lipoatrophy during Antiretroviral Therapy

Objective:Peripheral neuropathy (PN) often complicates nucleoside reverse transcriptase inhibitor (NRTI) therapy of HIV infection and may involve mitochondrial dysfunction. Since iron deficiency is associated with some types of PN, and iron is essential for mitochondrial function, we tested the hypothesis that hemochromatosis (HFE) gene mutations influence susceptibility to NRTI-induced PN. Design:Case-control study involving multicenter, AIDS Clinical Trials Group (ACTG) protocol 384 and ACTG Human DNA Repository specimens. Methods:Study participants were randomized to receive three- or four-drug antiretroviral therapy with didanosine (ddI) plus stavudine (d4T) or zidovudine plus lamivudine, given with efavirenz, nelfinavir, or both, with up to three years of follow-up. PN was ascertained based on signs and symptoms. HFE C282Y and H63D genotypes were determined, and associations with PN were assessed using logistic regression. Results:Of 509 participants, 147 (29%) developed PN, 73% of whom had been randomized to receive ddI plus d4T. Among ddI/d4T-ever-treated individuals, HFE C282Y heterozygotes developed PN on ddI/d4T significantly less often than C282Y non-carriers, adjusting for age, CD4 lymphocyte count and viral load at baseline, and concomitant antiretroviral drugs [6% vs. 35%, respectively, in whites; adjusted odds ratio (OR), 0.17; 95% confidence interval (CI) 0.03-0.83; P = 0.021]. Regardless of race/ethnicity, ddI/d4T-associated PN was uncommon in C282Y heterozygotes [race-adjusted OR, 0.30; 95% CI 0.09–0.96); P = 0.042]. Conclusions:Iron-loading HFE mutations such as C282Y are associated with a decreased risk of PN during antiretroviral therapy. This finding has potential implications for the prediction and prevention of NRTI-associated PN, particularly in populations at risk of iron deficiency.

CD4 Lymphocyte Percentage Predicts Disease Progression in HIV-Infected Patients Initiating Highly Active Antiretroviral Therapy with CD4 Lymphocyte Counts >350 Lymphocytes/mm3

BACKGROUND Antiretroviral therapy (ART)-associated lipoatrophy involves mitochondrial dysfunction. Iron metabolism impacts mitochondrial function and oxidative stress. Mitochondrial haplogroups and hemochromatosis gene (HFE) polymorphisms have been associated with ART-induced neuropathy. We assessed relationships between these variants and lipoatrophy. METHODS The AIDS Clinical Trials Group 384 study randomized ART-naive individuals to receive didanosine-stavudine or zidovudine-lamivudine, combined with efavirenz and/or nelfinavir. Substudy A5005s evaluated fat distribution by dual-energy X-ray absorptiometry (DEXA). We characterized HFE polymorphisms 845G>A and 187C>G and European mitochondrial haplogroups in A5005s participants who consented to genetic analyses. RESULTS Among 96 participants (58% were white, and 10% were female) with baseline and 48 or 64 week DEXA data, the median limb fat change was -8.8% (interquartile range, -28.7% to +15.6%). HFE 187C/G heterozygotes (n = 23) had less limb fat loss than 187C/C homozygotes (n = 71) (+6.1% vs. -12.5%; P = .02) and were less likely to develop lipoatrophy after adjustment for age, sex, race, and ART randomization (odds ratio, 0.31; 95% confidence interval, 0.10-0.95; P = .04). Among non-Hispanic white participants, median limb fat change was +26.1% among 5 participants with mitochondrial haplogroup J, compared with -9.7% among 49 participants with other mitochondrial haplogroups (P = .07). CONCLUSIONS HFE 187C>G and, possibly, mitochondrial haplogroup J gave relative protection against lipoatrophy during ART in A5005s. These associations should be replicated in other studies.

The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy

BACKGROUND The optimal timing of highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV)-infected patients with > or = 200 absolute CD4 lymphocytes/mm3 is unknown. CD4 lymphocyte percentage could add prognostic information. METHODS Persons who initiated HAART between 1 January 1998 and 1 January 2003, received > or = 30 days of therapy, and had baseline CD4 lymphocyte data available were included in the study. The log-rank test for time to event and Cox proportional hazards models were used to determine predictors of a new acquired immunodeficiency syndrome-defining illness or death. RESULTS A total of 788 patients met the inclusion criteria. At baseline, subjects had a median of 225 CD4 lymphocytes/mm3 and 17% CD4 lymphocytes. Subjects with < 17% CD4 lymphocytes had earlier disease progression, compared with subjects with > or = 17%, both in the entire cohort (P<.0001) and of those subjects with > 350 absolute CD4 lymphocytes/mm3 at baseline (P=.03). CD4 lymphocyte percentage < 17% was the strongest predictor of disease progression among subjects in this latter group (hazard ratio, 3.57; P=.045). CONCLUSIONS In this cohort, CD4 lymphocyte percentage predicted disease progression in HIV-infected subjects who initiated therapy with > 350 CD4 lymphocytes/mm3. This information may help identify persons who will derive the greatest benefit from initiation of HAART.

Identification of a CCR5-Expressing T Cell Subset That Is Resistant to R5-Tropic HIV Infection

Peripheral neuropathy (PN) due to mitochondrial injury complicates HIV therapy with some nucleoside reverse transcriptase inhibitors (NRTIs). Variation in the mitochondrial genome may influence susceptibility to NRTI toxicities. Two non-synonymous mitochondrial DNA polymorphisms, MTND1*LHON4216C (4216C) and MTND2*LHON4917G (4917G) were characterized in HIV-infected participants exposed to NRTIs in a randomized clinical trial. Among 250 self-identified white, non-Hispanic participants, symptomatic PN (⩾ grade 1) developed in 70 (28%). Both 4216C (odds ratio (OR)=1.98 (95% confidence interval (CI) 1.05–3.75); P=0.04) and 4917G (OR=2.93 (95% CI 1.25–6.89); P=0.01) were more frequent in PN cases. These two polymorphisms remained independently associated with PN after adjusting for age, baseline CD4 count, plasma HIV RNA level, and NRTI randomization arm; 4216C (OR=2.0 (95% CI 1.1–4.0) P=0.04) and 4917G (OR=5.5 (95% CI 1.6–18.7) P<0.01). When 4917G individuals were excluded from the analysis, the association with 4216C was no longer seen. The mitochondrial 4917G polymorphism may increase susceptibility to NRTI-associated PN.