Lori L. Hudson

Immunosenescence of ageing

Ageing is a complex process that negatively impacts the development of the immune system and its ability to function. The mechanisms that underlie these age‐related defects are broad and range from defects in the haematopoietic bone marrow to defects in peripheral lymphocyte migration, maturation and function. The thymus is a central lymphoid organ responsible for production of naïve T cells, which play a vital role in mediating both cellular and humoral immunity. Chronic involution of the thymus gland is thought to be one of the major contributing factors to loss of immune function with increasing age. It has recently been demonstrated that thymic atrophy is mediated by a shift from a stimulatory to a suppressive cytokine microenvironment. In this review we present an overview of the morphological, cellular and biochemical changes that have been implicated in the decline of thymic and peripheral immune function with ageing. We conclude with the clinical implications of age‐associated immunosenescence to vaccine development for tumours and infectious disease. A fundamental understanding of the complex mechanisms by which ageing attenuates immune function will enable translational research teams to develop new therapies and vaccines specifically aimed at overcoming these defects in immunological function in the aged. Copyright

Host gene expression classifiers diagnose acute respiratory illness etiology.

Pathogen-specific host gene expression changes may combat inappropriate antibiotic use and emerging antibiotic resistance. Resisting antibiotics No matter the cause, acute respiratory infections can be miserable. Indeed, these infections are one of the most common reasons for seeking medical care. A clear diagnostic can help medical practitioners resist the patient-induced pressure to prescribe antibiotics as a catch-all therapy, which increases the risk of bacteria developing antibiotic resistance. Now, Tsalik et al. report clear differences in host gene expression induced by bacterial and viral infection as well as by noninfectious illness. These differences can be used to discriminate between these groups, and a host gene expression classifier may be a helpful diagnostic platform to curb unnecessary antibiotic use. Acute respiratory infections caused by bacterial or viral pathogens are among the most common reasons for seeking medical care. Despite improvements in pathogen-based diagnostics, most patients receive inappropriate antibiotics. Host response biomarkers offer an alternative diagnostic approach to direct antimicrobial use. This observational cohort study determined whether host gene expression patterns discriminate noninfectious from infectious illness and bacterial from viral causes of acute respiratory infection in the acute care setting. Peripheral whole blood gene expression from 273 subjects with community-onset acute respiratory infection (ARI) or noninfectious illness, as well as 44 healthy controls, was measured using microarrays. Sparse logistic regression was used to develop classifiers for bacterial ARI (71 probes), viral ARI (33 probes), or a noninfectious cause of illness (26 probes). Overall accuracy was 87% (238 of 273 concordant with clinical adjudication), which was more accurate than procalcitonin (78%, P < 0.03) and three published classifiers of bacterial versus viral infection (78 to 83%). The classifiers developed here externally validated in five publicly available data sets (AUC, 0.90 to 0.99). A sixth publicly available data set included 25 patients with co-identification of bacterial and viral pathogens. Applying the ARI classifiers defined four distinct groups: a host response to bacterial ARI, viral ARI, coinfection, and neither a bacterial nor a viral response. These findings create an opportunity to develop and use host gene expression classifiers as diagnostic platforms to combat inappropriate antibiotic use and emerging antibiotic resistance.

Differential evolution of peripheral cytokine levels in symptomatic and asymptomatic responses to experimental influenza virus challenge.

Exposure to influenza virus triggers a complex cascade of events in the human host. In order to understand more clearly the evolution of this intricate response over time, human volunteers were inoculated with influenza A/Wisconsin/67/2005 (H3N2), and then had serial peripheral blood samples drawn and tested for the presence of 25 major human cytokines. Nine of 17 (53%) inoculated subjects developed symptomatic influenza infection. Individuals who will go on to become symptomatic demonstrate increased circulating levels of interleukin (IL)‐6, IL‐8, IL‐15, monocyte chemotactic protein (MCP)‐1 and interferon (IFN) gamma‐induced protein (IP)‐10 as early as 12–29 h post‐inoculation (during the presymptomatic phase), whereas challenged patients who remain asymptomatic do not. Overall, the immunological pathways of leucocyte recruitment, Toll‐like receptor (TLR)‐signalling, innate anti‐viral immunity and fever production are all over‐represented in symptomatic individuals very early in disease, but are also dynamic and evolve continuously over time. Comparison with simultaneous peripheral blood genomics demonstrates that some inflammatory mediators (MCP‐1, IP‐10, IL‐15) are being expressed actively in circulating cells, while others (IL‐6, IL‐8, IFN‐α and IFN‐γ) are probable effectors produced locally at the site of infection. Interestingly, asymptomatic exposed subjects are not quiescent either immunologically or genomically, but instead exhibit early and persistent down‐regulation of important inflammatory mediators in the periphery. The host inflammatory response to influenza infection is variable but robust, and evolves over time. These results offer critical insight into pathways driving influenza‐related symptomatology and offer the potential to contribute to early detection and differentiation of infected hosts.

A Genomic Signature of Influenza Infection Shows Potential for Presymptomatic Detection, Guiding Early Therapy, and Monitoring Clinical Responses

Early, presymptomatic intervention with oseltamivir (corresponding to the onset of a published host-based genomic signature of influenza infection) resulted in decreased overall influenza symptoms (aggregate symptom scores of 23.5 vs 46.3), more rapid resolution of clinical disease (20 hours earlier), reduced viral shedding (total median tissue culture infectious dose [TCID50] 7.4 vs 9.7), and significantly reduced expression of several inflammatory cytokines (interferon-γ, tumor necrosis factor-α, interleukin-6, and others). The host genomic response to influenza infection is robust and may provide the means for early detection, more timely therapeutic interventions, a meaningful reduction in clinical disease, and an effective molecular means to track response to therapy.

Potential Cost-effectiveness of Early Identification of Hospital-acquired Infection in Critically Ill Patients.

RATIONALE Limitations in methods for the rapid diagnosis of hospital-acquired infections often delay initiation of effective antimicrobial therapy. New diagnostic approaches offer potential clinical and cost-related improvements in the management of these infections. OBJECTIVES We developed a decision modeling framework to assess the potential cost-effectiveness of a rapid biomarker assay to identify hospital-acquired infection in high-risk patients earlier than standard diagnostic testing. METHODS The framework includes parameters representing rates of infection, rates of delayed appropriate therapy, and impact of delayed therapy on mortality, along with assumptions about diagnostic test characteristics and their impact on delayed therapy and length of stay. Parameter estimates were based on contemporary, published studies and supplemented with data from a four-site, observational, clinical study. Extensive sensitivity analyses were performed. The base-case analysis assumed 17.6% of ventilated patients and 11.2% of nonventilated patients develop hospital-acquired infection and that 28.7% of patients with hospital-acquired infection experience delays in appropriate antibiotic therapy with standard care. We assumed this percentage decreased by 50% (to 14.4%) among patients with true-positive results and increased by 50% (to 43.1%) among patients with false-negative results using a hypothetical biomarker assay. Cost of testing was set at

Bayesian modeling of temporal properties of infectious disease in a college student population

110/d. MEASUREMENTS AND MAIN RESULTS In the base-case analysis, among ventilated patients, daily diagnostic testing starting on admission reduced inpatient mortality from 12.3 to 11.9% and increased mean costs by

A novel diagnostic approach may reduce inappropriate antibiotic use for acute respiratory infections

1,640 per patient, resulting in an incremental cost-effectiveness ratio of

Abstract A42: ALK and cMET expression in glioblastoma multiforme: Implications for therapeutic targeting.

21,389 per life-year saved. Among nonventilated patients, inpatient mortality decreased from 7.3 to 7.1% and costs increased by

Software for Administering the National Cancer Institute’s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events: Usability Study

1,381 with diagnostic testing. The resulting incremental cost-effectiveness ratio was

Human T cell reconstitution in DiGeorge syndrome and HIV-1 infection

42,325 per life-year saved. Threshold analyses revealed the probabilities of developing hospital-acquired infection in ventilated and nonventilated patients could be as low as 8.4 and 9.8%, respectively, to maintain incremental cost-effectiveness ratios less than