Risk Factors for Surgical Site Infections Following Anterior Cruciate Ligament Reconstruction.

OBJECTIVE To determine the effect of graft choice (allograft, bone-patellar tendon-bone autograft, or hamstring autograft) on deep tissue infections following anterior cruciate ligament (ACL) reconstructions. DESIGN Retrospective cohort study. SETTING AND POPULATION Patients from 6 US health plans who underwent ACL reconstruction from January 1, 2000, through December 31, 2008. METHODS We identified ACL reconstructions and potential postoperative infections using claims data. A hierarchical stratified sampling strategy was used to identify patients for medical record review to confirm ACL reconstructions and to determine allograft vs autograft tissue implanted, clinical characteristics, and infection status. We estimated infection rates overall and by graft type. We used logistic regression to assess the association between infections and patients' demographic characteristics, comorbidities, and choice of graft. RESULTS On review of 1,452 medical records, we found 55 deep wound infections. With correction for sampling weights, infection rates varied by graft type: 0.5% (95% CI, 0.3%-0.8%) with allografts, 0.6% (0.1%-1.5%) with bone-patellar tendon-bone autografts, and 2.5% (1.9%-3.1%) with hamstring autograft. After adjusting for potential confounders, we found an increased infection risk with hamstring autografts compared with allografts (odds ratio, 5.9; 95% CI, 2.8-12.8). However, there was no difference in infection risk among bone-patellar tendon-bone autografts vs allografts (odds ratio, 1.2; 95% CI, 0.3-4.8). CONCLUSIONS The overall risk for deep wound infections following ACL reconstruction is low but it does vary by graft type. Infection risk was highest in hamstring autograft recipients compared with allograft recipients and bone-patellar tendon-bone autograft recipients. Infect Control Hosp Epidemiol 2016;37:827-833.

Beyond interferon: rationale and prospects for newer treatment paradigms for chronic hepatitis C.

Hepatitis C virus (HCV) infection results in a chronic carrier state in 80% of individuals infected with the virus and presently affects over 170 million people worldwide. Approximately 20% of those chronically infected will ultimately progress to develop cirrhosis and death due to end-stage liver disease or hepatocellular carcinoma (HCC). Unlike many other chronic viral infections, effective treatments for HCV are available. Cure from the infection is known as a sustained virologic response (SVR). SVR is associated with reversal of the long-term outcomes of chronic liver disease, decrease in incidence of HCC, and decrease HCV attributable mortality. The current FDA approved therapies for hepatitis C virus genotype 1 (GT-1) include pegylated interferon (PEG-IFN) and ribavirin (RBV) in combination with a directly acting antiviral agent (DAA). New therapeutic advances are being made aiming to simplify management, improve the tolerability of treatment, and shorten the duration of therapy. Moreover, treatment regimens that will effectively eradicate hepatitis C without the use of interferon formulations (IFN) are being developed. In this review, we report the transition of HCV therapeutics from an interferon-α based combination therapy to an all-oral, directly acting antiviral therapy.

Current trends in donor testing to detect syphilis infection.

Potential organ and tissue donors are tested to detect infection with T. pallidum, the etiologic agent of syphilis. Important considerations for testing potential donors include available specimen type and volume, turnaround time, and ability to distinguish between past and current infection. Aspects of syphilis infection that inform organ and tissue donor assay selection and interpretation and the principles underlying available assays are described. Serologic assays for syphilis are the methods most commonly used in donor testing. The two categories of serologic assays, treponemal and nontreponemal, have advantages and limitations for testing potential donors. Knowledge of the common syphilis-testing algorithms used in clinical diagnostic testing is useful for assay selection in the organ and tissue donor setting.

The utility of claims data for infection surveillance following anterior cruciate ligament reconstruction.

OBJECTIVE: To explore the feasibility of identifying anterior cruciate ligament (ACL) allograft implantations and infections using claims. DESIGN: Retrospective cohort study. METHODS: We identified ACL reconstructions using procedure codes at 6 health plans from 2000 to 2008. We then identified potential infections using claims-based indicators of infection, including diagnoses, procedures, antibiotic dispensings, specialty consultations, emergency department visits, and hospitalizations. Patients' medical records were reviewed to determine graft type, validate infection status, and calculate sensitivity and positive predictive value (PPV) for indicators of ACL allografts and infections. RESULTS: A total of 11,778 patients with codes for ACL reconstruction were identified. After chart review, PPV for ACL reconstruction was 96% (95% confidence interval [CI], 94%-97%). Of the confirmed ACL reconstructions, 39% (95% CI, 35%-42%) used allograft tissues. The deep infection rate after ACL reconstruction was 1.0% (95% CI, 0.7%-1.4%). The odds ratio of infection for allografts versus autografts was 0.41 (95% CI, 0.19-0.78). Sensitivity of individual claims-based indicators for deep infection after ACL reconstruction ranged from 0% to 75% and PPV from 0% to 100%. Claims-based infection indicators could be combined to enhance sensitivity or PPV but not both. CONCLUSIONS: While claims data accurately identify ACL reconstructions, they poorly distinguish between allografts and autografts and identify infections with variable accuracy. Claims data could be useful to monitor infection trends after ACL reconstruction, with different algorithms optimized for different surveillance goals.

Clinical management of HIV drug resistance.

Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. Management of clinical drug resistance requires in depth evaluation, and includes extensive history, physical examination and laboratory studies. Appropriate use of resistance testing provides valuable information useful in constructing regimens for treatment-experienced individuals with viremia during therapy. This review outlines the emergence of drug resistance in vivo, and describes clinical evaluation and therapeutic options of the individual with rebound viremia during therapy.

HIV/Hepatitis C virus-coinfected virologic responders to pegylated interferon and ribavirin therapy more frequently incur interferon-related adverse events than nonresponders do.

BACKGROUND: This study aimed to assess the relationship between interferon (IFN)-related adverse effects and Hepatitis C virus (HCV) virologic response in HIV/HCV-coinfected individuals treated with pegylated interferon and ribavirin. METHODS: We conducted 2 prospective, open-label trials treating HIV/HCV-coinfected individuals with pegylated interferon alpha-2b or alpha-2a and ribavirin for 48 weeks. Safety laboratories, HCV RNA, psychiatric, and ophthalmologic evaluations were performed at baseline and monthly until week 72. RESULTS: Responders were defined as those with HCV RNA decline of > or = 2-log drop from baseline and nonresponders were those who did not. Remarkably, of the 27 patients (50%) who developed psychiatric toxicities, 26 patients were responders, although only 1 of 14 virologic nonresponders experienced psychiatric toxicity. Other adverse effects, such as anemia and ophthalmologic toxicities, were also more frequent in responders compared with nonresponders. Decline in CD4 T-cell counts strongly correlated with HCV viral decline. CONCLUSIONS: Our study demonstrates coupling of antiviral effect and occurrence of adverse events in HIV/HCV-coinfected patients. These patients with IFN-related adverse effects need a multidisciplinary treatment approach, hence, they are more likely to achieve sustained virologic response. Future studies are needed to evaluate the factors that predict the development of IFN-alpha-dependent adverse events before therapy.

Altered regulation of extrinsic apoptosis pathway in HCV-infected HCC cells enhances susceptibility to mapatumumab-induced apoptosis.

BACKGROUND: Hepatitis C virus (HCV)-infected patients, including those co-infected with human immunodeficiency virus (HIV), are at increased risk of developing hepatocellular carcinoma (HCC). We evaluated the ability of agonistic human monoclonal antibodies to tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors, mapatumumab and lexatumumab, respectively, to induce TRAIL-receptor mediated apoptosis (TRMA) in HCC (HCV-infected and -uninfected) cells and in peripheral blood cells (HIV-infected and -uninfected). METHODS: Susceptibility to antibody-mediated TRMA was measured by caspase 3/7 activity and by confocal microscopy. Surface expression of receptors on HCV-uninfected and -infected Huh7.5 cells was measured by flow cytometry and confocal microscopy. Inhibitor of Apoptosis Protein (IAP) RNA levels were quantified by RT-PCR. DNA Microarray was performed using RNA isolated from Huh7.5 cells (HCV-infected and uninfected) using Affymetrix U133A chips. RESULTS: Mapatumumab preferentially induces TRMA of HCV-infected Huh7.5 cells by binding to TRAIL-R1. Higher basal expression of TRAIL-R2 compared to that of TRAIL-R1 on HCV-uninfected Huh7.5 cells were observed. Lexatumumab induces TRMA of both HCV-infected and -uninfected cells by binding to TRAIL-R2. IFN-alpha has minimal effect on mapatumumab- and lexatumumab-induced TRMA. HCV infection of Huh7.5 cells up-regulates TRAIL-R1 expression and X-linked Inhibitor of apoptosis protein and survivin gene expression. Neither antibody had a pro-apoptotic effect on PBMCs from patients with HIV infection ex vivo. CONCLUSION: Both mapatumumab and lexatumumab are excellent candidates for therapy of HCC. HCV infection of Huh7.5 cells selectively up-regulates TRAIL-R1 receptor, associated with increased susceptibility to mapatumumab-mediated TRMA. HCV infection up-regulated IAP genes, offering promise for future combination therapy using TRAIL agonists and IAP inhibitors.

Association of interleukin-15-induced peripheral immune activation with hepatic stellate cell activation in persons coinfected with hepatitis C virus and HIV.

Hepatic stellate cells (HSCs) mediate hepatitis C virus (HCV)-related liver fibrosis, and increased HSC activation in human immunodeficiency virus (HIV)/HCV coinfection may be associated with accelerated fibrosis. We examined the level of HSC activation in HIV/HCV-coinfected and HCV-monoinfected subjects and its relationship to the level of activation and gene expression of peripheral immune cells in coinfected subjects. HSC activation levels positively correlated with peripheral CD4+ and CD8+ T cell immune activation and were associated with enhanced interleukin-15 (IL-15) gene expression, suggesting a pathogenic role for IL-15-driven immunomediated hepatic fibrosis. Future strategies that reduce immune activation and HSC activation may delay progression of liver fibrosis.

Human immunodeficiency virus and hepatitis C infections induce distinct immunologic imprints in peripheral mononuclear cells.

UNLABELLED: Coinfection with hepatitis C virus (HCV) is present in one-third of all human immunodeficiency virus (HIV)-infected individuals in the United States and is associated with rapid progression of liver fibrosis and poor response to pegylated interferon (IFN) and ribavirin. In this study we examined gene expression profiles in peripheral blood mononuclear cells (PBMCs) from different groups of individuals who are monoinfected or coinfected with HIV and HCV. Data showed that HIV and HCV viremia up-regulate genes associated with immune activation and immunoregulatory pathways. HCV viremia is also associated with abnormalities in all peripheral immune cells, suggesting a global effect of HCV on the immune system. Interferon-alpha-induced genes were expressed at a higher level in PBMCs from HIV-infected individuals. HCV and HIV infections leave distinct profiles or gene expression of immune activation in PBMCs. HIV viremia induces an immune activated state; by comparison, HCV infection induces immunoregulatory and proinflammatory pathways that may contribute to progression of liver fibrosis. CONCLUSION: An aberrant type-I IFN response seen exclusively in HIV-infected individuals could be responsible for the poor therapeutic response experienced by HIV/HCV coinfected individuals receiving interferon-alpha-based current standard of care.

Infections caused by Scedosporium spp.

Scedosporium spp. are increasingly recognized as causes of resistant life-threatening infections in immunocompromised patients. Scedosporium spp. also cause a wide spectrum of conditions, including mycetoma, saprobic involvement and colonization of the airways, sinopulmonary infections, extrapulmonary localized infections, and disseminated infections. Invasive scedosporium infections are also associated with central nervous infection following near-drowning accidents. The most common sites of infection are the lungs, sinuses, bones, joints, eyes, and brain. Scedosporium apiospermum and Scedosporium prolificans are the two principal medically important species of this genus. Pseudallescheria boydii, the teleomorph of S. apiospermum, is recognized by the presence of cleistothecia. Recent advances in molecular taxonomy have advanced the understanding of the genus Scedosporium and have demonstrated a wider range of species than heretofore recognized. Studies of the pathogenesis of and immune response to Scedosporium spp. underscore the importance of innate host defenses in protection against these organisms. Microbiological diagnosis of Scedosporium spp. currently depends upon culture and morphological characterization. Molecular tools for clinical microbiological detection of Scedosporium spp. are currently investigational. Infections caused by S. apiospermum and P. boydii in patients and animals may respond to antifungal triazoles. By comparison, infections caused by S. prolificans seldom respond to medical therapy alone. Surgery and reversal of immunosuppression may be the only effective therapeutic options for infections caused by S. prolificans.

Galactomannan antigen detection in the diagnosis of invasive aspergillosis.

Invasive aspergillosis is a serious and lethal infection among immunocompromised patients, with reported mortality rates as high as 74-92%. The high mortality is related to the severe immunosuppression experienced by these patients as well as the difficulties for physicians in arriving at a timely diagnosis. Definitive diagnostic procedures (tissue biopsy for histopathology and culture) are often precluded by severe cytopenias and coagulation abnormalities. The development of minimally invasive, nonculture diagnostic methods is a major advance in the early diagnosis of invasive aspergillosis. Galactomannan is a heteropolysaccharide (mannan core and side residues of galactofuranosyl units) present in the cell wall of Aspergillus spp. The double sandwich enzyme immunoassay, which detects galactomannan in serum samples, has been available in Europe for almost a decade and in the USA since May 2003, for the diagnosis of invasive aspergillosis. However, availability of the double galactomannan enzyme immunoassay is center variable in the USA and, although its analytical performance in the diagnosis of invasive aspergillosis is well documented, its routine use in clinical practice is limited. As an adjunct in the diagnosis and management of invasive aspergillosis, incorporation of the galactomannan enzyme immunoassay into clinical trials will help to further define its role.

Functional genomics of innate host defense molecules in normal human monocytes in response to Aspergillus fumigatus.

Aspergillus fumigatus induces the release of innate immune-related molecules from phagocytic cells early in the course of infection. Little is known, however, about the complex expression profiles of the multiple genes involved in this response. We therefore investigated the kinetics of early gene expression in human monocytes (HMCs) infected with conidia of A. fumigatus using DNA microarray analysis. Total RNA from HMCs at 0, 2, 4, and 6 h was extracted, linearly amplified, hybridized onto Affymetrix HG133 Plus 2.0 gene chips, and analyzed with an Affymetrix scanner. Changes in gene expression were calculated as a ratio of those expressed by infected versus control HMCs. Aspergillus fumigatus induced differential regulation of expression in 1,827 genes (P < 0.05). Genes encoding cytokines and chemokines involved in host defense against A. fumigatus, including interleukin-1beta (IL-1beta), IL-8, CXCL2, CCL4, CCL3, and CCL20, as well as the opsonin long pentraxin 3, were up-regulated during the first 2 to 6 h, coinciding with an increase in phagocytosis. Simultaneously, genes encoding CD14, ficolin1, and MARCO were down-regulated, and genes encoding IL-10 and matrix metalloproteinase 1 were up-regulated. Up-regulation of the genes encoding heat shock proteins 40 and 110 and connexins 26 and 30 may point to novel molecules whose role in the pathogenesis of aspergillosis has not been previously reported. Verification of the transcriptional profiling was obtained for selected genes by reverse transcription-PCR and enzyme immunoassay. Thus, A. fumigatus conidia induced a coordinated expression of genes important in host defense and immunomodulation.

Resources for medical mycology on the World Wide Web.

Searching the World Wide Web for information on medical mycology can be challenging. We provide the reader with an organized overview of the available resources on the Internet, including authoritative sites from academic institutions, professional societies, government agencies, and personal sites. This article reviews clinically relevant Internet resource directories, comprehensive sites of interest to clinicians, clinical trials in medical mycology, clinically relevant Web sites devoted to specific fungal pathogens and their infections, genomic resources in medical mycology, culture collections, images of fungi on the World Wide Web, medical mycology lecture and teaching materials, environmental health and safety information, and a listing of Web sites of medical mycology professional societies.

Clinical trial of quantitative real-time polymerase chain reaction for detection of cytomegalovirus in peripheral blood of allogeneic hematopoietic stem-cell transplant recipients.

The preemptive therapy of cytomegalovirus (CMV) reactivation is useful for the prevention of CMV disease in allogeneic hematopoietic stem-cell transplant (HSCT) recipients. We compared results of the pp65 CMV antigenemia test with quantitative touch-down polymerase chain reaction (Q-PCR) on unfractionated whole blood for the detection of CMV reactivation in 51 HSCT recipients. Forty episodes of reactivation in 28 patients were detected by antigenemia and treated by antiviral drugs. Q-PCR detected CMV DNA in 39 (97.5%) of 40 reactivation episodes. False-positive results occurred in 3% of tests, of which 63% were borderline positive. Q-PCR results were positive earlier than antigenemia results in 30 (77%) of 39 episodes detected by antigenemia. Q-PCR remained positive after treatment was discontinued in 14 (36%) of 39 episodes and predicted the return of CMV reactivation in 4 (31%) of 13 episodes. Q-PCR was more sensitive than the antigenemia test and had sufficient specificity for clinical use.

Successful treatment of coccidioidal meningitis with voriconazole.

A previously healthy 47-year-old man with coccidioidal meningitis had fluconazole treatment failure and developed severe symptoms, multiple cranial nerve palsies, and brain-stem inflammation visible on magnetic resonance imaging (MRI). High-dose voriconazole therapy resulted in gradual resolution of almost all signs and symptoms, normalization of cerebrospinal fluid, and clearing of brain-stem edema seen on MRI. The patient had photosensitivity after 10 weeks of treatment, but this improved when the voriconazole dose was lowered. Continuous voriconazole therapy kept coccidioidal meningitis in complete remission in this patient for >2 years.