Jay B. Varkey

Gene Expression Signatures Diagnose Influenza and Other Symptomatic Respiratory Viral Infections in Humans

Acute respiratory infections (ARIs) are a common reason for seeking medical attention, and the threat of pandemic influenza will likely add to these numbers. Using human viral challenge studies with live rhinovirus, respiratory syncytial virus, and influenza A, we developed peripheral blood gene expression signatures that distinguish individuals with symptomatic ARIs from uninfected individuals with >95% accuracy. We validated this acute respiratory viral signature-encompassing genes with a known role in host defense against viral infections-across each viral challenge. We also validated the signature in an independently acquired data set for influenza A and classified infected individuals from healthy controls with 100% accuracy. In the same data set, we could also distinguish viral from bacterial ARIs (93% accuracy). These results demonstrate that ARIs induce changes in human peripheral blood gene expression that can be used to diagnose a viral etiology of respiratory infection and triage symptomatic individuals.

A host transcriptional signature for presymptomatic detection of infection in humans exposed to influenza H1N1 or H3N2.

There is great potential for host-based gene expression analysis to impact the early diagnosis of infectious diseases. In particular, the influenza pandemic of 2009 highlighted the challenges and limitations of traditional pathogen-based testing for suspected upper respiratory viral infection. We inoculated human volunteers with either influenza A (A/Brisbane/59/2007 (H1N1) or A/Wisconsin/67/2005 (H3N2)), and assayed the peripheral blood transcriptome every 8 hours for 7 days. Of 41 inoculated volunteers, 18 (44%) developed symptomatic infection. Using unbiased sparse latent factor regression analysis, we generated a gene signature (or factor) for symptomatic influenza capable of detecting 94% of infected cases. This gene signature is detectable as early as 29 hours post-exposure and achieves maximal accuracy on average 43 hours (pu200a=u200a0.003, H1N1) and 38 hours (p-valueu200a=u200a0.005, H3N2) before peak clinical symptoms. In order to test the relevance of these findings in naturally acquired disease, a composite influenza A signature built from these challenge studies was applied to Emergency Department patients where it discriminates between swine-origin influenza A/H1N1 (2009) infected and non-infected individuals with 92% accuracy. The host genomic response to Influenza infection is robust and may provide the means for detection before typical clinical symptoms are apparent.

Viral infections in patients with chronic obstructive pulmonary disease

Purpose of review Chronic obstructive pulmonary disease is a major cause of morbidity and mortality worldwide. There is increasing evidence that implicates viral infections as a major risk factor for exacerbations of chronic obstructive pulmonary disease. Recent studies have attempted to better characterize the epidemiology of viral infections in chronic obstructive pulmonary disease, identify unique clinical manifestations of virus-associated exacerbations, and develop new diagnostic tools and treatments. Recent findings Rhinovirus, the organism most often responsible for causing the common cold, is also the most common infectious cause of chronic obstructive pulmonary disease exacerbations. Coronavirus, influenza, respiratory syncytial virus, parainfluenza, adenovirus, and metapneumovirus are other important viral causes of chronic obstructive pulmonary disease exacerbations. These exacerbations can be severe with prolonged recovery times. Although PCR technology has dramatically increased the detection rate of viruses in patients with chronic obstructive pulmonary disease, it does not differentiate infection from colonization. The use of biomarkers represents an exciting new potential diagnostic tool that may lend new insights into the pathogenesis of viral infections in patients with chronic obstructive pulmonary disease. Summary Despite strong epidemiologic evidence linking respiratory virus infection to exacerbations of chronic obstructive pulmonary disease, many of the cellular and molecular mechanisms by which viruses cause exacerbations remain undetermined. Future research efforts to understand these mechanisms would aid the development of novel therapeutics to reduce the morbidity and mortality of this disease.

Postoperative joint infections due to propionibacterium species: A case-control study

We compared 40 patients with Propionibacterium acnes postoperative joint infection to a cohort of uninfected patients. Infection manifested a median of 210 days after surgery. Most patients with joint prostheses underwent hardware removal. Prior joint surgery (odds ratio [OR], 28.2) and male sex (OR, 7.2) were independent risk factors for infection.

Pharmacokinetics of Posaconazole Administered Orally or by Nasogastric Tube in Healthy Volunteers

ABSTRACT The use of a nasogastric tube is one means of administering antifungal therapy to critically ill patients unable to receive medication via the oral route. This was a phase 1, open-label, single-center, randomized, crossover study of posaconazole administered via nasogastric tube in healthy volunteers. Each subject received two 400-mg single doses of posaconazole, one administered orally and one administered by nasogastric tube, with a 7-day washout period between each dose. Posaconazole was administered 5 to 10 min after subjects received a nutritional supplement. Blood samples for pharmacokinetic analysis were obtained up to 120 h postdose. The analysis of variance estimate of the study population suggests that the posaconazole nasogastric tube administration least-square mean values of observed maximum concentration (Cmax), area under the plasma concentration-time curve (AUC) to the last measurable concentration, and AUC to time infinity were 81%, 76%, and 77%, respectively, of the corresponding oral administration values. The reason for lower Cmax and AUC values when posaconazole is administered via the nasogastric tube route is not known. Oral and nasogastric tube administration of a single 400-mg dose of posaconazole suspension was safe and well tolerated in healthy adult subjects. The incidence and nature of treatment-emergent adverse events were similar with both administration routes, and no serious adverse events or clinically significant laboratory test or vital sign abnormalities were reported. Obtaining plasma posaconazole concentrations may be warranted when posaconazole is given to patients via a nasogastric tube to ensure adequate posaconazole exposure. Strategies that have been shown to enhance posaconazole exposure (such as splitting the dose and minimizing the use of proton pump inhibitors) may also be used.

Prophylactic vaccinations in chronic obstructive pulmonary disease: current status

Purpose of review Acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of morbidity and mortality worldwide. Most acute exacerbations are triggered by community-acquired respiratory infections. Medications to treat COPD exacerbations are limited; therefore, identifying effective ways to prevent exacerbations are needed. Influenza and pneumococcal vaccines are currently recommended for all persons with COPD. However, current immunization rates are far lower than the Healthy People 2010 Goals. The reasons for nonadherence are multifactorial and strategies for overcoming these barriers are discussed. Recent findings Influenza vaccine clearly reduces the number of acute exacerbations that occur in persons with COPD. Influenza vaccine may reduce hospitalizations and mortality from COPD, but the evidence is not conclusive. Pneumococcal vaccine reduces the incidence of invasive pneumococcal disease. However, there is not enough evidence to conclude that pneumococcal vaccination in persons with COPD has a significant impact on reducing morbidity or mortality. Vaccination with both influenza and pneumococcal vaccine may produce an additive effect that reduces exacerbations more effectively than either vaccine alone. Whole genome sequencing of bacteria and genome mining may represent a powerful way to identify novel potential vaccine antigens for future vaccine development. Summary Although clinical trial data are limited, vaccinations can prevent some of the infections that cause COPD exacerbations and should be administered to all patients with COPD. Vaccines do not cause exacerbations of COPD. Patient and physician barriers to vaccination can be overcome with targeted education and system-wide interventions. Further research efforts should focus on improving current vaccines and identifying novel targets for future vaccine development.

Rare and Emerging Fungal Pulmonary Infections

The frequency and diversity of serious fungal infections are increasing. Persons who are severely immunocompromised are particularly vulnerable to infection from unusual molds and yeasts that are often found naturally in the environment. Clinical manifestations from these unusual fungal infections range from colonization of airways to chronic localized lesions to acute invasive or disseminated disease. When present, rare and emerging fungi are often isolated from the respiratory tract during a severely immunosuppressed state, and diagnosis requires isolation and identification of the infecting organism. Histopathology is often required to differentiate tissue invasion from airway colonization. There are no diagnostic serologies, and radiological exams are not specific. Furthermore, many emerging opportunistic molds demonstrate in vitro resistance to the older azoles and amphotericin B. As a result, successful treatment may require adjunct surgical debridement and, when possible, reconstitution of the host immune system. Also, the newer triazoles such as voriconazole and posaconazole may be useful to treat some of these infections caused by rare and emerging molds.

Analysis of two- and three-year trends in antimicrobial resistance in intensive care units using unit-specific antibiograms.

Unit-specific antibiograms serve as useful guides to clinicians and infection control personnel. We compared trends in antimicrobial resistance in intensive care units using traditional 2-y unit-specific antibiogram data and 3 y of data. Three-y unit-specific antibiogram data may provide increased statistical power to detect changes in antimicrobial resistance.