Browsing by Subject "infectious diseases"
Now showing 1 - 14 of 14
- Results Per Page
- Sort Options
Item Antibodies Recognizing Protective Pertussis Toxin Epitopes are Preferentially Elicited by Natural Infection Versus Acellular Immunization(2011-06) Sutherland, Jamie N.; Chang, Christine; Yoder, Sandra M.; Rock, Michael T.; Maynard, Jennifer A.; Sutherland, Jamie N.; Chang, Christine; Maynard, Jennifer A.Despite more than 50 years of vaccination, disease caused by the bacterium Bordetella pertussis persists, with rates increasing in industrialized countries over the past decade. This rise may be attributed to several factors, including increased surveillance, emergence of vaccine escape variants, waning immunity in adults, and the introduction of acellular subunit vaccines, which include chemically detoxified pertussis toxin (PTd). Two potently protective epitopes on pertussis toxin (PTx) are recognized by the monoclonal antibodies 1B7 and 11E6, which inhibit catalytic and cell-binding activities, respectively. In order to determine whether the PTx exposure route affects antibody responses to these epitopes, we analyzed sera from 30 adults with confirmed pertussis exposure and from 30 recently vaccinated adults for specific anti-PTx antibody responses and in vitro CHO cell neutralization titers. While overall titers against PTx and the genetically detoxified variant, PTg, containing the R9K and E129G substitutions, were similar in the two groups, titers against specific epitopes depended on the exposure route. Natural infection resulted in significantly higher titers of anti-PTx-subunit 1, 1B7-like, and 11E6-like antibodies, while acellular vaccination resulted in significantly higher titers of antibodies recognizing PTd. We also observed a correlation between in vitro protection and the presence of 1B7-like and 11E6-like antibodies. Notably, chemical detoxification, as opposed to genetic inactivation, alters the PTx tertiary and quaternary structure, thereby affecting conformational epitopes and recognition of PTx by 1B7 and 11E6. The lower levels of serum antibodies recognizing clinically relevant epitopes after vaccination with PTd support inclusion of PTg in future vaccines.Item Application of a Methicillin-Resistant Staphylococcus Aureus Risk Score for Community-Onset Pneumonia Patients and Outcomes with Initial Treatment(2015-09) Teshome, Besu F.; Lee, Grace C.; Reveles, Kelly R.; Attridge, Russell T.; Koeller, Jim; Wang, Chen-Pin; Mortensen, Eric M.; Frei, Christopher R.; Teshome, Besu F.; Lee, Grace C.; Reveles, Kelly R.; Koeller, Jim; Frei, Christopher R.Community-onset (CO) methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is an evolving problem, and there is a great need for a reliable method to assess MRSA risk at hospital admission. A new MRSA prediction score classifies CO-pneumonia patients into low, medium, and high-risk groups based on objective criteria available at baseline. Our objective was to assess the effect of initial MRSA therapy on mortality in these three risk groups. Methods: We conducted a retrospective cohort study using data from the Veterans Health Administration (VHA). Patients were included if they were hospitalized with pneumonia and received antibiotics within the first 48 h of admission. They were stratified into MRSA therapy and no MRSA therapy treatment arms based on antibiotics received in the first 48 h. Multivariable logistic regression was used to adjust for potential confounders. Results: A total of 80,330 patients met inclusion criteria, of which 36 % received MRSA therapy and 64 % did not receive MRSA therapy. The majority of patients were classified as either low (51 %) or medium (47 %) risk, with only 2 % classified as high-risk. Multivariable logistic regression analysis demonstrated that initial MRSA therapy was associated with a lower 30-day mortality in the high-risk group (adjusted odds ratio 0.57; 95 % confidence interval 0.42-0.77). Initial MRSA therapy was not beneficial in the low or medium-risk groups. Conclusions: This study demonstrated improved survival with initial MRSA therapy in high-risk CO-pneumonia patients. The MRSA risk score might help spare MRSA therapy for only those patients who are likely to benefit.Item Black Race as a Predictor of Poor Health Outcomes Among a National Cohort of HIV/AIDS Patients Admitted to US Hospitals: A Cohort Study(2009-08) Oramasionwu, Christine U.; Hunter, Jonathan M.; Skinner, Jeff; Ryan, Laurajo; Lawson, Kenneth A.; Brown, Carolyn M.; Makos, Brittany R.; Frei, Christopher R.; Oramasionwu, Christine U.; Skinner, Jeff; Ryan, Laurajo; Lawson, Kenneth A.; Brown, Carolyn M.; Makos, Brittany R.; Frei, Christopher R.In general, the Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) population has begun to experience the benefits of highly active antiretroviral therapy (HAART); unfortunately, these benefits have not extended equally to Blacks in the United States, possibly due to differences in patient comorbidities and demographics. These differences include rates of hepatitis B and C infection, substance use, and socioeconomic status. To investigate the impact of these factors, we compared hospital mortality and length of stay (LOS) between Blacks and Whites with HIV/AIDS while adjusting for differences in these key characteristics. Methods: The 1996-2006 National Hospital Discharge Surveys were used to identify HIV/AIDS patients admitted to US hospitals. Survey weights were incorporated to provide national estimates. Patients < 18 years of age, those who left against medical advice, those with an unknown discharge disposition and those with a LOS < 1 day were excluded. Patients were stratified into subgroups by race (Black or White). Two multivariable logistic regression models were constructed with race as the independent variable and outcomes (mortality and LOS > 10 days) as the dependent variables. Factors that were significantly different between Blacks and Whites at baseline via bivariable statistical tests were included as covariates. Results: In the general US population, there are approximately 5 times fewer Blacks than Whites. In the present study, 1.5 million HIV/AIDS hospital discharges were identified and Blacks were 6 times more likely to be hospitalized than Whites. Notably, Blacks had higher rates of substance use (30% vs. 24%; P < 0.001), opportunistic infections (27% vs. 26%; P < 0.001) and cocaine use (13% vs. 5%; P < 0.001). Conversely, fewer Blacks were co-infected with hepatitis C virus (8% vs. 12%; P < 0.001). Hepatitis B virus was relatively infrequent (3% for both groups). Crude mortality rates were similar for both cohorts (5%); however, a greater proportion of Blacks had a LOS > 10 days (21% vs. 19%; P < 0.001). Black race, in the presence of comorbidities, was correlated with a higher odds of LOS > 10 days (OR, 95% CI = 1.20 [1.10-1.30]), but was not significantly correlated with a higher odds of mortality (OR, 95% CI = 1.07 [0.93-1.25]). Conclusion: Black race is a predictor of LOS > 10 days, but not mortality, among HIV/AIDS patients admitted to US hospitals. It is possible that racial disparities in hospital outcomes may be closing with time.Item A Clinical Pathway for Community-Acquired Pneumonia: An Observational Cohort Study(2011-07) Frei, Christopher R.; Bell, Allison M.; Traugott, Kristi A.; Jaso, Terry C.; Daniels, Kelly R.; Mortensen, Eric M.; Restrepo, Marcos I.; Oramasionwu, Christine U.; Ruiz, Andres D.; Mylchreest, William R.; Sikirica, Vanja; Raut, Monika R.; Fisher, Alan; Schein, Jeff R.; Frei, Christopher R.; Bell, Allison M.; Traugott, Kristi A.; Jaso, Terry C.; Daniels, Kelly R.; Oramasionwu, Christine U.Six hospitals instituted a voluntary, system-wide, pathway for community acquired pneumonia (CAP). We proposed this study to determine the impact of pathway antibiotics on patient survival, hospital length of stay (LOS), and total hospital cost. Methods: Data were collected for adults from six U. S. hospitals with a principal CAP discharge diagnosis code, a chest infiltrate, and medical notes indicative of CAP from 2005-2007. Pathway and non-pathway cohorts were assigned according to antibiotics received within 48 hours of admission. Pathway antibiotics included levofloxacin 750 mg monotherapy or ceftriaxone 1000 mg plus azithromycin 500 mg daily. Multivariable regression models assessed 90-day mortality, hospital LOS, total hospital cost, and total pharmacy cost. Results: Overall, 792 patients met study criteria. Of these, 505 (64%) received pathway antibiotics and 287 (36%) received non-pathway antibiotics. Adjusted means and p-values were derived from Least Squares regression models that included Pneumonia Severity Index risk class, patient age, heart failure, chronic obstructive pulmonary disease, and admitting hospital as covariates. After adjustment, patients who received pathway antibiotics experienced lower adjusted 90-day mortality (p = 0.02), shorter mean hospital LOS (3.9 vs. 5.0 days, p < 0.01), lower mean hospital costs ($2,485 vs. $3,281, p = 0.02), and similar mean pharmacy costs ($356 vs. $442, p = 0.11). Conclusions: Pathway antibiotics were associated with improved patient survival, hospital LOS, and total hospital cost for patients admitted to the hospital with CAP.Item Comparison of Lateral Flow Technology and Galactomannan and (1 -> 3)-Beta-D-Glucan Assays for Detection of Invasive Pulmonary Aspergillosis(2009-12) Wiederhold, Nathan P.; Thornton, Christopher R.; Najvar, Laura K.; Kirkpatrick, William R.; Bocanegra, Rosie; Patterson, Thomas F.; Wiederhold, Nathan P.We compared a lateral flow device to galactomannan and (1 -> 3)-beta-D-glucan assays to detect invasive aspergillosis in an established guinea pig model of pulmonary disease. The lateral flow device became positive earlier ( =day 3) than the (1 -> 3)-beta-D-glucan and galactomannan assays ( day 5), with all samples positive by each assay on day 7.Item The Dynamics of Risk Perceptions and Precautionary Behavior in Response to 2009 (H1N1) Pandemic Influenza(2010-10) Ibuka, Yoko; Chapman, Gretchen B.; Meyers, Lauren A.; Li, Meng; Galvani, Alison P.; Meyers, Lauren A.The trajectory of an infectious disease outbreak is affected by the behavior of individuals, and the behavior is often related to individuals' risk perception. We assessed temporal changes and geographical differences in risk perceptions and precautionary behaviors in response to H1N1 influenza. Methods: 1,290 US adults completed an online survey on risk perceptions, interests in pharmaceutical interventions (preventive intervention and curative intervention), and engagement in precautionary activities (information seeking activities and taking quarantine measures) in response to H1N1 influenza between April 28 and May 27 2009. Associations of risk perceptions and precautionary behaviors with respondents' sex, age, and household size were analyzed. Linear and quadratic time trends were assessed by regression analyses. Geographic differences in risk perception and precautionary behaviors were evaluated. Predictors of willingness to take pharmaceutical intervention were analyzed. Results: Respondents from larger households reported stronger interest in taking medications and engaged in more precautionary activities, as would be normatively predicted. Perceived risk increased over time, whereas interest in pharmaceutical preventive interventions and the engagement in some precautionary activities decreased over time. Respondents who live in states with higher H1N1 incidence per population perceived a higher likelihood of influenza infection, but did not express greater interests in pharmaceutical interventions, nor did they engage in a higher degree of precautionary activities. Perceived likelihood of influenza infection, willingness to take medications and engagement in information seeking activities were higher for women than men. Conclusions: Perceived risk of infection and precautionary behavior can be dynamic in time, and differ by demographic characteristics and geographical locations. These patterns will likely influence the effectiveness of disease control measures.Item The Effect of Sexually Transmitted Co-Infections on HIV Viral Load Amongst Individuals on Antiretroviral Therapy: A Systematic Review and Meta-Analysis(2015-06) Champredon, David; Bellan, Steven E.; Delva, Wim; Hunt, Spencer; Shi, Chyun-Fung; Smieja, Marek; Dushoff, Jonathan; Bellan, Steven E.Antiretroviral therapy (ART) markedly reduces HIV transmission, and testing and treatment programs have been advocated as a method for decreasing transmission at the population level. Little is known, however, about the extent to which sexually transmitted infections (STIs), which increase the HIV infectiousness of untreated individuals, may decrease the effectiveness of treatment as prevention. Methods: We searched major bibliographic databases to August 12th, 2014 and identified studies reporting differences in HIV transmission rate or in viral load between individuals on ART who either were or were not co-infected with another STI. We used hierarchical Bayesian models to estimate viral load differences between individuals with and without STI co-infections. Results: The search strategy retrieved 1630 unique citations of which 14 studies (reporting on 4607 HIV viral load measurements from 2835 unique individuals) met the inclusion criteria. We did not find any suitable studies that estimated transmission rates directly in both groups. Our meta-analysis of HIV viral load measurements among treated individuals did not find a statistically significant effect of STI co-infection; viral loads were, on average, 0.11 log10 (95 % CI -0.62 to 0.83) higher among co-infected versus non-co-infected individuals. Conclusions: Direct evidence about the effects of STI co-infection on transmission from individuals on ART is very limited. Available data suggests that the average effect of STI co-infection on HIV viral load in individuals on ART is less than 1 log10 difference, and thus unlikely to decrease the effectiveness of treatment as prevention. However, there is not enough data to rule out the possibility that particular STIs pose a larger threat.Item Empiric Guideline-Recommended Weight-Based Vancomycin Dosing and Mortality in Methicillin-Resistant Staphylococcus Aureus Bacteremia: A Retrospective Cohort Study(2012-04) Hall, Ronald G., II; Giuliano, Christopher A.; Haase, Krystal K.; Hazlewood, Kathleen A.; Frei, Chistopher R.; Forcade, Nicolas A.; Brouse, Sara D.; Bell, Todd; Bedimo, Roger J.; Alvarez, Carlos A.; Frei, Chistopher R.; Forcade, Nicolas A.No studies have evaluated the effect of guideline-recommended weight-based dosing on in-hospital mortality of patients with methicillin-resistant Staphylococcus aureus bacteremia. Methods: This was a multicenter, retrospective, cohort study of patients with methicillin-resistant Staphylococcus aureus bacteremia receiving at least 48 hours of empiric vancomycin therapy between 01/07/2002 and 30/06/2008. We compared in-hospital mortality for patients treated empirically with weight-based, guideline-recommended vancomycin doses (at least 15 mg/kg/dose) to those treated with less than 15 mg/kg/dose. We used a general linear mixed multivariable model analysis with variables identified a priori through a conceptual framework based on the literature. Results: A total of 337 patients who were admitted to the three hospitals were included in the cohort. One-third of patients received vancomycin empirically at the guideline-recommended dose. Guideline-recommended dosing was not associated with in-hospital mortality in the univariable (16% vs. 13%, OR 1.26 [95% CI 0.67-2.39]) or multivariable (OR 0.71, 95% CI 0.33-1.55) analysis. Independent predictors of in-hospital mortality were ICU admission, Pitt bacteremia score of 4 or greater, age 53 years or greater, and nephrotoxicity. Conclusions: Empiric use of weight-based, guideline-recommended empiric vancomycin dosing was not associated with reduced mortality in this multicenter study.Item Impaired Function of Antibodies to Pneumococcal Surface Protein A but not to Capsular Polysaccharide in Mexican American Adults with Type 2 Diabetes Mellitus(2012-09) Mathews, Christine E.; Brown, Eric L.; Martinez, Perla J.; Bagaria, Upasana; Nahm, Moon H.; Burton, Robert L.; Fisher-Hoch, Susan P.; McCormick, Joseph B.; Mirza, Sharper; Nahm, Moon H.The goal of the study was to determine baseline protective titers of antibodies to Streptococcus pneumoniae surface protein A (PspA) and capsular polysaccharide in individuals with and individuals without type 2 diabetes mellitus. A total of 561 individuals (131 individuals with diabetes and 491 without) were screened for antibodies to PspA using a standard enzyme-linked immunosorbent assay (ELISA). A subset of participants with antibodies to PspA were retested using a WHO ELISA to determine titers of antibodies to capsular polysaccharide (CPS) (serotypes 4, 6B, 9V, 14, 18C, 19A, 19F, and 23F). Functional activity of antibodies was measured by assessing their ability to enhance complement (C3) deposition on pneumococci and promote killing of opsonized pneumococci. Titers of antibodies to protein antigens (PspA) were significantly lower in individuals with diabetes than controls without diabetes (P = 0.01), and antibodies showed a significantly reduced complement deposition ability (P = 0.02). Both antibody titers and complement deposition were negatively associated with hyperglycemia. Conversely, titers of antibodies to capsular polysaccharides were either comparable between the two groups or were significantly higher in individuals with diabetes, as was observed for CPS 14 (P = 0.05). The plasma specimens from individuals with diabetes also demonstrated a higher opsonophagocytic index against CPS serotype 14. Although we demonstrate comparable protective titers of antibodies to CPS in individuals with and individuals without diabetes, those with diabetes had lower PspA titers and poor opsonic activity strongly associated with hyperglycemia. These results suggest a link between diabetes and impairment of antibody response.Item Long-Term Control Of Viral Replication In A Group O, Human Immunodeficiency Virus Type 1-Infected Individual(2014-06) Buckheit, R. W.; Sexauer, S. B.; Sedaghat, A. R.; Wilke, C. O.; Laeyendecker, O.; Basseth, C. R.; Blankson, J. N.; Wilke, Claus O.Item Low-Level HIV-I Replication and the Dynamics of the Resting CD4(+) T Cell Reservoir for HIV-I in the Setting of HAART(2008-01) Sedaghat, Ahmad R.; Siliciano, Robert F.; Wilke, Claus O.; Wilke, Claus O.In the setting of highly active antiretroviral therapy (HAART), plasma levels of human immunodeficiency type-I (HIV-I) rapidly decay to below the limit of detection of standard clinical assays. However, reactivation of remaining latently infected memory CD4(+) T cells is a source of continued virus production, forcing patients to remain on HAART despite clinically undetectable viral loads. Unfortunately, the latent reservoir decays slowly, with a half-life of up to 44 months, making it the major known obstacle to the eradication of HIV-I infection. However, the mechanism underlying the long half-life of the latent reservoir is unknown. The most likely potential mechanisms are low-level viral replication and the intrinsic stability of latently infected cells. Methods: Here we use a mathematical model of T cell dynamics in the setting of HIV-I infection to probe the decay characteristics of the latent reservoir upon initiation of HAART. We compare the behavior of this model to patient derived data in order to gain insight into the role of low-level viral replication in the setting of HAART. Results: By comparing the behavior of our model to patient derived data, we find that the viral dynamics observed in patients on HAART could be consistent with low-level viral replication but that this replication would not significantly affect the decay rate of the latent reservoir. Rather than low-level replication, the intrinsic stability of latently infected cells and the rate at which they are reactivated primarily determine the observed reservoir decay rate according to the predictions of our model. Conclusion: The intrinsic stability of the latent reservoir has important implications for efforts to eradicate HIV-I infection and suggests that intensified HAART would not accelerate the decay of the latent reservoir.Item An Open-Label, Pragmatic, Randomized Controlled Clinical Trial to Evaluate the Comparative Effectiveness of Daptomycin Versus Vancomycin for the Treatment of Complicated Skin and Skin Structure Infection(2015-11) Kauf, Teresa L.; McKinnon, Peggy; Corey, G. Ralph; Bedolla, John; Riska, Paul F.; Sims, Matthew; Jauregui-Peredo, Luis; Friedman, Bruce; Hoehns, James D.; Mercier, Renee-Claude; Garcia-Diaz, Julia; Brenneman, Susan K.; Ng, David; Lodise, Thomas; Bedolla, JohnTreatment of complicated skin and skin structure infection (cSSSI) places a tremendous burden on the health care system. Understanding relative resource utilization associated with different antimicrobials is important for decision making by patients, health care providers, and payers. Methods: The authors conducted an open-label, pragmatic, randomized (1:1) clinical study (N = 250) to compare the effectiveness of daptomycin with that of vancomycin for treatment of patients hospitalized with cSSSI caused by suspected or documented methicillin-resistant Staphylococcus aureus infection. The primary study end point was infection-related length of stay (IRLOS). Secondary end points included health care resource utilization, cost, clinical response, and patient-reported outcomes. Patient assessments were performed daily until the end of antibiotic therapy or until hospital discharge, and at 14 days and 30 days after discharge. Results: No difference was found for IRLOS, total LOS, and total inpatient cost between cohorts. Hospital LOS contributed 85.9 % to the total hospitalization cost, compared with 6.4 % for drug costs. Daptomycin showed a nonsignificant trend toward a higher clinical success rate, compared with vancomycin, at treatment days 2 and 3. In the multivariate analyses, vancomycin was associated with a lower likelihood of day 2 clinical success (odds ratio [OR] = 0.498, 95 % confidence interval [CI], 0.249-0.997; P < 0.05). Conclusion: This study did not provide conclusive evidence of the superiority of one treatment over the other in terms of clinical, economic, or patient outcomes. The data suggest that physician and patient preference, rather than drug acquisition cost, should be the primary driver of initial antibiotic selection for hospitalized patients with cSSSI.Item Optimized Adenovirus-Antibody Complexes Stimulate Strong Cellular and Humoral Immune Responses Against an Encoded Antigen in Naive Mice and Those with Preexisting Immunity(2012-01) Choi, Jin Huk; Dekker, Joe; Schafer, Stephen C.; John, Jobby; Whitfill, Craig E.; Petty, Christopher S.; Haddad, Eid E.; Croyle, Maria A.; Choi, Jin Huk; Dekker, Joe; Schafer, Stephen C.; John, Jobby; Whitfill, Craig E.; Petty, Christopher S.; Haddad, Eid E.; Croyle, Maria A.The immune response to recombinant adenoviruses is the most significant impediment to their clinical use for immunization. We test the hypothesis that specific virus-antibody combinations dictate the type of immune response generated against the adenovirus and its transgene cassette under certain physiological conditions while minimizing vector-induced toxicity. In vitro and in vivo assays were used to characterize the transduction efficiency, the T and B cell responses to the encoded transgene, and the toxicity of 1 x 10(11) adenovirus particles mixed with different concentrations of neutralizing antibodies. Complexes formed at concentrations of 500 to 0.05 times the 50% neutralizing dose (ND(50)) elicited strong virus-and transgene-specific T cell responses. The 0.05-ND(50) formulation elicited measurable anti-transgene antibodies that were similar to those of virus alone (P = 0.07). This preparation also elicited very strong transgene-specific memory T cell responses (28.6 +/- 5.2% proliferation versus 7.7 +/- 1.4% for virus alone). Preexisting immunity significantly reduced all responses elicited by these formulations. Although lower concentrations (0.005 and 0.0005 ND(50)) of antibody did not improve cellular and humoral responses in naive animals, they did promote strong cellular (0.005 ND(50)) and humoral (0.0005 ND(50)) responses in mice with preexisting immunity. Some virus-antibody complexes may improve the potency of adenovirus-based vaccines in naive individuals, while others can sway the immune response in those with preexisting immunity. Additional studies with these and other virus-antibody ratios may be useful to predict and model the type of immune responses generated against a transgene in those with different levels of exposure to adenovirus.Item Short Communication: Dynamic Constraints On The Second Phase Compartment Of Hiv-Infected Cells(2011-07) Spivak, A. M.; Rabi, S. A.; McMahon, M. A.; Shan, L.; Sedaghat, A. R.; Wilke, C. O.; Siliciano, R. F.; Wilke, Claus O.The cells responsible for the second phase decay of HIV-1 viremia following the initiation of antiretroviral therapy have yet to be identified. A dynamic model that considers where drugs act in the virus life cycle places constraints on candidate cell types. In this regard, the rapid drop in viremia in patients starting regimens containing the integrase inhibitor raltegravir is of particular interest. We show here that the time delay between reverse transcription and integration is short in differentiated macrophages, making these cells poor candidates for the second phase compartment under the assumptions of standard models of viral dynamics.