Division of Allergy Pulmonary amp Critical Care Medicine Newsletter

New Fellows for 2015 - 2016June 2015

ATS Highlights

Josh Fessel MD PhD is the winner of the first ATS BEAR (Building Education to Advance Research) Cage competition for his research proposal for ldquoA Novel System to Detect and Prevent Impending AspirationmdashAspirGard IT-NGTrdquo

Vanderbilt PCCMPulmonary amp Critical Care Casey Jonathan Dale (12326327) Photograph - (Page 1)

Jonathan Casey MDPulmonaryCCM FellowMed School LouisvilleResidency Brigham amp Womenrsquos

A new class of fellows will be joining the division on July 1 Join us in welcoming them to the division The new fellows are

Vanderbilt AIAllergy amp Immunology Derrick Michael Ian (12363920) Photograph - (Page 1)

Michael Derrick MDAllergy FellowMed School ETSUResidency MUSC

Vanderbilt AIAllergy amp Immunology Garon Sarah (12153643) Photograph - (Page 1)

Sarah Garon MDAllergy FellowMed School Sackler Residency Jacobi Medi-cal Center

Vanderbilt PCCMPulmonary amp Critical Care Halliday Stephen James (12615187) Photograph - (Page 1)

Steve Halliday MDPulmonaryCCM FellowMed School UT San AntonioResidency Vanderbilt

Vanderbilt PCCMPulmonary amp Critical Care Kerchberger Vern Eric (12648035) Photograph - (Page 1)

Eric Kerchberger MDPulmonaryCCM FellowMed School EmoryResidency NY Pres-byterian (Columbia Campus)

Vanderbilt PCCMPulmonary amp Critical Care Merrick Christopher Michael (12695712) Photograph - (Page 1)

Christopher Merrick MDPulmonaryCCM FellowMed School Univ of ArkansasResidency Duke

Vanderbilt AIAllergy amp Immunology Ortiz Christina Funari (12332394) Photograph - (Page 1)

Christina Ortiz MDAllergy FellowMed School E VirginiaResidency Univ of Virginia(Will begin January 1)

The Division was very well representedat this yearrsquos ATS meeting Some highlights and accomplishments

Tim Blackwell MD was the annual Parker B Francis lecturer This is awarded to former PBF Fellows who are internationally recognized for their outstanding con-tributions to scientific research and teaching

Lorraine Ware MD received the Recognition Award for Scientific Accomplishments which is given to ATS members for outstanding scientific contributions in ba-sic or clinical research to the understanding prevention and treatment of acute or chronic lung diseases

Carla Sevin MD and Jim Jackson PsyD chaired a symposium on ICU survivor clinics Pictured here with Dr Sevin are Millie and Woody Camp Millie was a patient speaker for the Symposium

Congratulations to the Graduating Fellows

Benjamin Ferrell MDwill be joining The Nash-ville Medical Group at St Thomas Midtown

Parties to honor the fellowship class will be held on Jun 23 (Pulmonary 530 at The Boundrsquory) and Jun 26 (Allergy 500 Maggianorsquos) Join us in congratulating

Kali Gerace MD will be joining Allergy Partners in Lexington KY

Raj Keriwala MD MPHwill be joining Pulmo-nary and Critical Care Consultants of Austin in Austin TX

Yasmin Khan MD will join the Pediatric Allergy faculty at Vanderbilt as an Asssitant Professor

Jon Kropski MD will join the division faculty as an Asssitant Profes-sor Jon is the recipient of multiple grants too numerous to list here

Hector Rodriguez MD will join Allergy Partners in Columbia SC

Ciara Shaver MD PhD will join the division faculty as an Instructor in Medicine Ciara is a re-ciepient of the Vanderbilt Faculty Researc Scholar Award

Anna Hemnes MD participated in this yearrsquos Boston Marathon Anna pictured here on the rainy race day finished with a time of 335 qualifying her to participate again next year

Abstract Travel Scholarship Recipients

The Sepsis Definitions Task Force with representatives from the ATS SCCM ESICM and Chest have been working together for the past year and met for the last time at the SCCM national meeting in Phoenix Gordon Bernard MD is serving on this task force with Jean Louis Vincent Mitch Levy Derek Angus Djalli Annane Gordon Rubenfeld John Marshall and others The committee is working on revising sepsis definitions and a final paper detailing the work which all will find very interest-ing will be out soon

Eric Austin MD MSCI (Pediatric Pulmonary) received the Robert B Mellins MD Outstanding Achievement Award which is given to a junior faculty member for their contribu-tions in child lung health

Thomas Atwater MD (Medicine Resident) had his poster featured in the 4 best abstracts of the Thoracic Oncology as-sembly

Tufik Assad MD from Pulmonary Circulation Assembly

Dru Claar MD from Respiratory Cell amp Molecular Biology As-sembly

Ben Ferrell MD from Critical Care Assembly

Brett Norman MD from Critical Care Assembly

Matt Semler MD from Critical Care Assembly

Jon Kropski MD from Respiratory Cell amp Molecular BiologyAssembly

Bradley Richmond MD from the National Emphysema Foundation

Chelsi Short (RA Young lab)from Respiratory Cell amp Molecular Biology As-

Ciara Shaver MD PhD from the Respiratory Structure amp Func-tion Assembly

Recent PublicationsOR I G I N A L R E S E A R CH

Use of pulmonary arterial hypertensionndashapproved therapy

in the treatment of nonndashgroup 1 pulmonary hypertension

at US referral centers

Aaron W Trammell Meredith E Pugh John H Newman Anna R Hemnes Ivan M Robbins

Division of Pulmonary and Critical Care Medicine Vanderbilt University Medical Center Nashville Tennessee USA

Abstract Pulmonary hypertension (PH) is a frequent complication of left heart disease and parenchymal lung disease and it portendsincreased mortality A growing number of medications are approved for the treatment of World Health Organization (WHO) group 1pulmonary arterial hypertension (PAH) However they are not well studied in PH of other etiologies (WHO groups 2ndash5) We sought toassess treatment approaches used by PAH referral centers in this diverse group of patients We developed a semiquantitative online surveydesigned to evaluate the use of PAH-approved therapy by pulmonary vascular disease centers in the United States for management of nonndashgroup 1 PH Thirty of 50 centers completed the survey Almost all centers (93) reported using PAH therapy for patients with nonndashgroup 1PH including 77 with group 2 PH and 80 with group 3 PH Elevated transpulmonary gradient or pulmonary vascular resistance and thepresence of right ventricular (RV) dysfunction were commonly cited as supporting use of PAH therapy in patients with PH secondary to leftheart disease For patients with PH and concomitant parenchymal lung disease degree of pulmonary function impairment and RV dysfunc-tion were most important in influencing use of PAH therapy In conclusion pulmonary vascular disease treatment centers use PAH-approvedtherapy for patients with WHO group 2ndash5 PH mostly relying on hemodynamics and assessment of RV function to identify candidates fortherapy Clinical trials designed to test the efficacy of PAH therapy in PH due to left heart and lung disease are needed as clinical practice hasextended beyond the evidence for these etiologies of PH

Keywords survey chronic obstructive pulmonary disease restrictive lung disease heart failure

Pulm Circ 20155(2)356-363 DOI 101086681264

Pulmonary hypertension (PH) is defined as mean pulmonary arterialpressure (mPAP) of ge25 mmHg and may result from several hemo-dynamic and pathologic mechanisms which are grouped according tothe Nice World Health Organization (WHO) classification scheme1

WHO group 1 pulmonary arterial hypertension (PAH) encompassesseveral disorders in which the precapillary pulmonary vasculatureis primarily affected PAH requires pulmonary arterial wedge pres-sure (PAWP) of le15 mmHg and mPAP of ge25 mmHg and it hasbeen extensively studied with several approved therapies availablefor clinical use Guidelines have been established for the appropriateevaluation and evidence-based management of patients with PAH2-4

Although much attention has been focused on PAH it is a raredisease and PH due to other causes (left heart disease group 2 lungdisease andor hypoxemia group 3 chronic thromboembolic PHgroup 4 unclear or multifactorial etiologies group 5) is far morecommon5 Thorough evaluation is imperative to accurate classifi-cation and it is recommended that this occur in specialized PH cen-ters The case mix in PH centers is enriched for confirmed group 1PAH but patients deemed to have other causes of PH make up alarge component For instance in three large PH centers patientsreferred over 1 year were confirmed to have PAH in 41 of cases

with groups 2 and 3 combining for 336 In another center PAHwas the most common final single diagnosis with 39 (32) of 122 pa-tients but group 2 and 3 PH and mixed-etiology PH combined for55 (45) of 122 of the study population7 Frequent misclassificationof patients prior to referral to a PH center highlights the complex-ity of appropriate diagnosis and the jeopardy of using PAH therapyprior to such a workup6

Development of PH in patients with left heart disease89 chronicinterstitial lung disease10 and chronic obstructive pulmonary dis-ease (COPD)1112 is associated with worse outcome however thedegree of PH that is observed in groups 2ndash5 is quite variable81314

Some patients appear to have PH in excess of what would be ex-pected for the degree of underlying lung disease or left atrial pres-sure elevation and thus may benefit from PAH-directed therapyalthough this remains unproven15-17 Evaluation and surgical treat-ment of operable group 4 disease is uniformly recommended1819

However well-designed clinical studies are lacking for group 2 3and 5 PH thus there is no consensus treatment strategy other thanmanagement of the underlying disease process for these patientsKnowledge of the current treatment approach used in these patientsby advanced treatment centers is limited Use of PAH-approved ther-

Address correspondence to Dr Aaron W Trammell Division of Pulmonary and Critical Care Medicine Vanderbilt University Medical Center T-1223Medical Center North 1161 21st Avenue South Nashville TN 37232-2650 USA E-mail aarontrammellvanderbiltedu

Submitted August 12 2014 Accepted October 24 2014 Electronically published April 15 2015copy 2015 by the Pulmonary Vascular Research Institute All rights reserved 2045-893220150502-0016 $1500

This content downloaded from 160129114178 on Wed 17 Jun 2015 095038 AMAll use subject to JSTOR Terms and Conditions

(Click image to access complete article)

R E V I EW A R T I C L E

Fatty acid metabolism in pulmonary arterial hypertension

role in right ventricular dysfunction and hypertrophy

Megha Talati Anna Hemnes

Division of Allergy Pulmonary and Critical Care Medicine Department of Medicine Vanderbilt University Medical Center Nashville Tennessee USA

Abstract Pulmonary arterial hypertension (PAH) is a complex multifactorial disease in which an increase in pulmonary vascular resis-tance leads to increased afterload on the right ventricle (RV) causing right heart failure and death Our understanding of the pathophys-iology of RV dysfunction in PAH is limited but is constantly improving Increasing evidence suggests that in PAH RV dysfunction isassociated with various components of metabolic syndrome such as insulin resistance hyperglycemia and dyslipidemia The relationshipbetween RV dysfunction and fatty acidglucose metabolites is multifaceted and in PAH it is characterized by a shift in utilization of energysources toward increased glucose utilization and reduced fatty acid consumption RV dysfunction may be caused by maladaptive fatty acidmetabolism resulting from an increase in fatty acid uptake by fatty acid transporter molecule CD36 and an imbalance between glucose andfatty acid oxidation in mitochondria This leads to lipid accumulation in the form of triglycerides diacylglycerol and ceramides in thecytoplasm hallmarks of lipotoxicity Current interventions in animal models focus on improving RV dysfunction through altering fattyacid oxidation rates and limiting lipid accumulation but more specific and effective therapies may be available in the coming years basedon current research In conclusion a deeper understanding of the complex mechanisms of the metabolic remodeling of the RV will aid inthe development of targeted treatments for RV failure in PAH

Keywords pulmonary arterial hypertension metabolic syndrome fatty acid oxidation glucose oxidation right ventricle fatty acidtransporter (CD36) glucose transporters insulin resistance right ventricular lipotoxicity lipotoxic cardiomyopathy

Pulm Circ 20155(2)269-278 DOI 101086681227

Pulmonary arterial hypertension (PAH) is a devastating diseasecharacterized by progressive obliteration of the pulmonary vascula-ture right heart failure and death The pathobiology of PAH iscomplex and presently there is no curative treatment AlthoughPAH is classically thought to be a disease of the lungs the roleplayed by right ventricular (RV) hypertrophy and dysfunction thatultimately results in right heart failure and death is understudiedRV failure is the most common cause of death in PAH1 yet thereare no specific therapies aimed at improving RV adaptation or func-tion However it is well documented that pathological RV remod-eling in PAH can be reversed with lung transplantation or withpulmonary thromboendarterectomy in chronic thromboembolic pul-monary hypertension (CTEPH)2-9 The molecular mechanisms thatmediate the transition from adaptive RV compensation to failure orthat can promote reversible RV remodeling are presently unknownRecently our group and others have found evidence indicating thatintracellular lipid accumulation and decreased fatty acid oxidation(FAO) may be features of RV failure related to PAH10-13 This raisesa question In PAH can accumulation of fatty acids promote RVdysfunction with a resultant progression to right heart failure anddeath This article reviews the role played by increased fatty aciduptake and accumulation of fatty acid metabolites in PAH-induced

RV failure and discusses what is known about the impact of thesefindings on human RV failure Understanding the mechanisms andconsequences of lipid deposition in the RVmay suggest new diagnos-tic and therapeutic approaches to right heart failure in PAH

RV DYSFUNCTION IN PAH AND ITS IMPORTANCE

In a healthy adult heart the RV cavity is smaller than that of theleft ventricle (LV) and has a much smaller wall thickness mak-ing the RV well suited as a flow conduit rather than a pressure-generating pump In PAH the shape of the RV is changed fromthe normal conformation and RV wall stress is significantly in-creased1415 as a result of an increase in pulmonary vascular re-sistance (PVR) with increased RV afterload1617 The progressiveremodeling of the pulmonary vascular bed leads to an increase inPVR In PAH the initial response to increased RV afterload isadaptive RV hypertrophy18 characterized by an increase in pro-tein synthesis and cardiomyocyte size through the addition of sar-comeres19 With sustained pressure overload these initially adap-tive changes transition to dysfunction with the RV progressing tocontractile dysfunction accompanied by thinning and dilation ofthe RV162021 Magnetic resonance imagingndashderived RV pressure-volume loops can be used for assessment of RV myocardial con-

Address correspondence to Dr Megha Talati Division of Allergy Pulmonary and Critical Care Medicine T1218 MCN 1161 21st Avenue SouthNashville TN 37232 USA E-mail meghatalativanderbiltedu

Submitted May 1 2014 Accepted December 30 2014 Electronically published April 9 2015copy 2015 by the Pulmonary Vascular Research Institute All rights reserved 2045-893220150502-0005 $1500

This content downloaded from 160129114178 on Wed 17 Jun 2015 095305 AMAll use subject to JSTOR Terms and Conditions

Copyright copy 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health Inc All Rights Reserved

Critical Care Medicine wwwccmjournalorg 1

Objective The association between cigarette smoke exposure and the acute respiratory distress syndrome in patients with the most common acute respiratory distress syndrome risk factors of sepsis pneumonia and aspiration has not been well studied The goal of this study was to test the association between biomarker-confirmed cigarette smoking and acute respiratory distress syn-drome in a diverse cohort

Copyright copy 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health Inc All Rights Reserved

DOI 101097CCM0000000000001089

1Division of Pulmonary and Critical Care Medicine Department of Medi-cine University of California San Francisco San Francisco CA

2Department of Anesthesia University of California San Francisco San Francisco CA

3Division of Hospital Medicine Department of Medicine University of Cali-fornia San Francisco San Francisco CA

4Department of Medicine Vanderbilt University Nashville TN5Department of Medicine Louisiana State University School of Medicine New Orleans LA

6Department of Surgery Vanderbilt University Nashville TN7Center for Tobacco Control Research and Education University of Cali-fornia San Francisco San Francisco CA

8Division of Clinical Pharmacology and Experimental Therapeutics Univer-sity of California San Francisco San Francisco CA

9Departments of Medicine and of Pathology Microbiology and Immunology Vanderbilt University Nashville TN

Drs Calfee and Ware had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis Drs Calfee and Ware designed the study conducted data clean-ing and analysis interpreted the data and drafted and revised the article Drs Matthay and Benowitz helped design the study interpreted the data and revised the article Drs Kangelaris Siew Janz Jacob and Havel con-tributed to data collection cleaning or interpretation and critically revised the article Drs Bernard and May contributed to data interpretation and critically revised the article All authors provided final approval of the ver-sion to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Supplemental digital content is available for this article Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journalrsquos website (httpjournalslwwcomccmjournal)

Dr Calfee received support for travel from Boehringer Ingelheim (travel to meeting at Boehringer headquarters relevant to potential research project) and received support for article research from the National Institutes of Health (NIH HL090833 KL2RR024130 and HL110969) Her institution received grant support from the NIH and Flight Attendant Medical Research Institute (Young Clinical Scientist Award) consultation fees from GlaxoSmithKline and Cerus and grant support from GlaxoSmithKline Some research reported in this publication was supported by grant number 1P50CA18890 from the National Cancer Institute and Food and Drug Administration Center for Tobacco Products Dr Matthay consulted for Roche Genentec (chair of Data Safety and Monitoring Board for a clinical trial) Cerus (advisor on platelets and acute respiratory distress syndrome [ARDS]) GlaxoSmithKline (consul-tant on ARDS program) and Quark Pharmaceuticals (consultant on ARDS program) and he received support for article research from the NIH His institution received grant support from the National Heart Lung and Blood

Cigarette Smoke Exposure and the Acute Respiratory Distress Syndrome

Carolyn S Calfee MD MAS12 Michael A Matthay MD12 Kirsten N Kangelaris MD MAS3

Edward D Siew MD4 David R Janz MD5 Gordon R Bernard MD4 Addison K May MD6

Peyton Jacob PhD78 Christopher Havel PhD8 Neal L Benowitz MD78 Lorraine B Ware MD49

Institute (NHLBI) (HL51856) and from GlaxoSmithKline (grant to study sep-sis) Dr Kangelaris received support for article research from the NIH Her institution received grant support from the NHLBI (1K23HL116800-01) Dr Siew consulted for Alere (clinical adjudication) lectured for Renal Ven-tures (asked to speak about the epidemiology of acute kidney injury recov-ery at a meeting of dialysis Chief Medical Officers) and received support for article research from the NIH (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK] K23 Award DK088964-03) His institution received grant support from the NIH NIDDK (performed as part of Dr Siewrsquos K23 award) Dr Janz received support for article research from the NIH (T32 HL087738) Dr Bernard served as a board member for Cumberland Pharmaceuticals Nashville TN His institution received grant support from AstraZeneca (grant for multicenter trial of ticagrelor in community-acquired pneumonia) Dr Jacob received support for article research from the NIH (P30 DA012393) His institution received grant support from the NIH (pro-vided support for instruments salary for personnel and supplies needed to carry out the research) Flight Attendant Medical Research Institute (supports other research) and California Tobacco Related Disease Research Program (supports other research) Dr Havel received support for article research from the NIH His institution received grant support Dr Benowitz has consulted for Pfizer and GlaxoSmithKline and has served as a paid expert witness in litigation against tobacco companies Dr Benowitz received support for arti-cle research from the NIH (P30 DA012393 and CA78603) and the Flight Attendants Medical Research Institute His institution received grant support from Flight Attendants Medical Research Institute (University of California San Francisco Bland Lane Center of Excellence in Secondhand Smoke) and National Cancer Institute and Food and Drug Administration Center for Tobacco Products (1P50CA180890) Dr Ware has served on advisory boards for GlaxoSmithKline Dr Ware consulted for GlaxoSmithKline and Abbot and received support for article research from the NIH (HL081332 HL103836 and HL112656) Her institution received grant support from the NIH and the American Heart Association The content is solely the respon-sibility of the authors and does not necessarily represent the official views of the NIH or the Food and Drug Administration The funding sources had no role in the design or conduct of the study collection management analysis and interpretation of the data preparation review or approval of the article or the decision to submit the article for publication The remaining authors have disclosed that they do not have any potential conflicts of interest

Address requests for reprints to Carolyn Calfee MD MAS Pulmonary and Critical Care Division University of California San Francisco 505 Parnassus Avenue Box 0111 San Francisco CA 94143-0111 E-mail carolyncalfeeucsfedu

RESEARCH ARTICLE

The Impact of Lymphopenia on Delirium inICU PatientsShigeaki Inoue1 Eduard E Vasilevskis56 Pratik P Pandharipande3 TimothyD Girard26 Amy J Graves4 Jennifer Thompson4 Ayumi Shintani4 E Wesley Ely26

1 Department of Emergency and Critical Care Medicine Tokai University School of Medicine IseharaKanagawa Japan 2 Division of AllergyPulmonaryCritical Care Medicine Department of MedicineVanderbilt University School of Medicine Nashville Tennessee United States of America 3 Department ofAnesthesiology Vanderbilt University School of Medicine Nashville Tennessee United States of America4 Department of Biostatistics Vanderbilt University School of Medicine Nashville Tennessee United Statesof America 5 Division of General Internal Medicine and Public Health Department of Medicine VanderbiltUniversity School of Medicine Nashville Tennessee United States of America 6 Veterans AffairsTennessee Valley Geriatric Research Education and Clinical Center (GRECC) Vanderbilt University Schoolof Medicine Nashville Tennessee United States of America

sg-inoueisiccu-tokaiacjp

Abstract

Background

Immunosuppressed states may predispose patients to development of acute brain injury

during times of critical illness Lymphopenia is a non-specific yet commonly used bedside

marker of immunosuppressed states

Methods

We examined whether lymphopenia would predict development of acute brain dysfunction

(delirium andor coma) in 518 patients enrolled in the Bringing to Light the Risk Factors and

Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) study in medi-

cal and surgical ICUs of a tertiary care university-based medical center Utilizing propor-

tional odds logistic regression and Cox proportional hazards survival analysis we assessed

the relationship between pre-enrollment lymphocytes and subsequent cognitive outcomes

including delirium- and coma-free days (DCFDs) and 30-day mortality

Results

There were no statistically significant associations between lymphocytes and DCFDs (p =

017) additionally the relationship between lymphocytes and mortality was not statistically

significant (p = 071) Among 259 patients without history of cancer or diabetes there was

no statistically significant association between lymphocytes and DCFDs (p = 007)

Conclusion

lymphopenia a commonly used bedside marker of immunosuppression does not appear to

be a marker of risk for acute brain injury (deliriumcoma) or 30-day mortality in general medi-

calsurgical ICU patients

PLOS ONE | DOI101371journalpone0126216 May 20 2015 1 11

a11111

OPEN ACCESS

Citation Inoue S Vasilevskis EE PandharipandePP Girard TD Graves AJ Thompson J et al (2015)The Impact of Lymphopenia on Delirium in ICUPatients PLoS ONE 10(5) e0126216 doi101371journalpone0126216

Academic Editor Jorge IF Salluh Dor Institute ofResearch and Education BRAZIL

Received January 11 2015

Accepted March 31 2015

Published May 20 2015

Copyright copy 2015 Inoue et al This is an openaccess article distributed under the terms of theCreative Commons Attribution License which permitsunrestricted use distribution and reproduction in anymedium provided the original author and source arecredited

Data Availability Statement The raw data containidentifying patient information Therefore data areavailable upon request from Bill Pojedinec ProgramManager at ICU Delirium and Cognitive ImpairmentStudy Group of HSR Division of Allergy Pulmonaryand CCMVA-GRECC Vanderbilt University MedicalCenter MCE North Tower Suite 6100 Nashville TN37232-8300 Phone 615-936-3702 Fax 615-936-1269 wwwicudeliriumorg

Funding This work was supported by funds from theVanderbilt Institute for Clinical and TranslationalResearch (VICTR) and The Bringing to Light the Risk

OR I G I N A L R E S E A R CH

Right ventricular long noncoding RNA expression

in human heart failure

Thomas G Di Salvo1 Yan Guo2 Yan Ru Su1 Travis Clark2 Evan Brittain1 Tarek Absi3

Simon Maltais3 Anna Hemnes4

1Division of Cardiovascular Medicine Vanderbilt Heart and Vascular Institute Nashville Tennessee USA 2Vanderbilt MedicalCenter VANTAGE Core Laboratory Nashville Tennessee USA 3Division of Cardiovascular Surgery Vanderbilt Heart andVascular Institute Nashville Tennessee USA 4Pulmonary and Critical Care Medicine Vanderbilt Department of MedicineNashville Tennessee USA

Abstract The expression of long noncoding RNAs (lncRNAs) in human heart failure (HF) has not been

widely studied Using RNA sequencing (RNA-Seq) we compared lncRNA expression in 22 explanted hu-

man HF hearts with lncRNA expression in 5 unused donor human hearts We used Cufflinks to identify

isoforms and DESeq to identify differentially expressed genes We identified the noncoding RNAs by cross-

reference to Ensembl release 73 (Genome Reference Consortium human genome build 37) and explored

possible functional roles using a variety of online tools In HF hearts RNA-Seq identified 84793 total

messenger RNA coding and noncoding different transcripts including 13019 protein-coding genes

2085 total lncRNA genes and 1064 pseudogenes By Ensembl noncoding RNA categories there were

48 lncRNAs 27 pseudogenes and 30 antisense RNAs for a total of 105 differentially expressed lncRNAs

in HF hearts Compared with donor hearts HF hearts exhibited differential expression of 77 of protein-

coding genes 37 of lncRNAs (including pseudogenes) and 25 of pseudogenes There were not con-

sistent correlations between antisense lncRNAs and parent genes and between pseudogenes and parent

genes implying differential regulation of expression Exploratory in silico functional analyses using on-

line tools suggested a variety of possible lncRNA regulatory roles By providing a comprehensive profile

of right ventricular polyadenylated messenger RNA transcriptome in HF RNA-Seq provides an inventory

of differentially expressed lncRNAs including antisense transcripts and pseudogenes for future mechanis-

tic study

Keywords long noncoding RNA right ventricle human heart failure gene expression transcriptional

profiling

Pulm Circ 20155(1)135-161 DOI 101086679721

The results reported from the Encyclopedia of DNA Ele-

ments (ENCODE) project are transforming our nascent

understanding of integrated human genomics1 Fully 75

of the human genome is transcribed into some type of

RNA2 although only 122 of the genome encodes the

exons that comprise the 20687 known protein-coding

genes1 The vast majority of the human genome there-

fore is transcribed into nonndashprotein-coding RNAs includ-

ing the 8801 small RNAs 9640 long noncoding RNAs

(lncRNAs defined as nontranslated RNA lt200 base pairs

[bp] in length) and 11224 pseudogenes identified to date1

Evolving research has identified diverse epigenetic regula-

tory roles for lncRNAs in development homeostasis and

disease3 lncRNAs are likely to play important regulatory

roles in human heart failure as well4

Via high-throughput sequencing RNA sequencing

(RNA-Seq) provides a comprehensive profile of polyadeny-

lated protein-coding messenger RNA (mRNA) and nonndash

protein-coding lncRNA transcripts5 We used RNA-Seq to

generate the lncRNA transcriptional profile of the right

ventricle in end-stage human heart failure Human right

ventricular (RV) tissue may be obtained at either endo-

myocardial biopsy or surgery Diagnostic endomyocardial

biopsy given its attendant risks is rarely performed for

Submitted February 21 2014 Accepted August 13 2014 Electronically published February 13 2015

copy 2015 by the Pulmonary Vascular Research Institute All rights reserved 2045-893220150501-0013 $1500

Address correspondence to Dr Thomas G Di Salvo 1215 21st Avenue South Medical Center East South Tower Suite 5037 Nashville TN 37232

USA E-mail thomasgdisalvovanderbiltedu

This content downloaded from 160129114178 on Wed 17 Jun 2015 095727 AMAll use subject to JSTOR Terms and Conditions

Mol Imaging Biol (2015)DOI 101007s11307-015-0862-4 World Molecular Imaging Society 2015

BRIEF ARTICLE

Preclinical Evaluation of 4-[18F]FluoroglutaminePET to Assess ASCT2 Expression in LungCancerMohamed Hassanein12 Matthew R Hight34 Jason R Buck34

Mohammed N Tantawy34 Michael L Nickels34 Megan D Hoeksema1

Bradford K Harris1 Kelli Boyd5 Pierre P Massion126 H Charles Manning3467

1Division of Allergy Pulmonary and Critical Care Medicine Vanderbilt University School of Medicine Nashville TN 37232 USA2Thoracic Program Vanderbilt-Ingram Cancer Center Vanderbilt University Medical Center Nashville TN 37232 USA3Vanderbilt University Institute of Imaging Science (VUIIS) Vanderbilt University Medical Center Nashville TN 37232 USA4Department of Radiology and Radiological Sciences Vanderbilt University Medical Center Nashville TN 37232 USA5Department of Pathology Microbiology and Immunology Vanderbilt University Medical Center Nashville TN 37232 USA6Vanderbilt-Ingram Cancer Center Vanderbilt University Medical Center Nashville TN 37232 USA7Program in Chemical and Physical Biology Vanderbilt University Medical Center Nashville TN 37232 USA

AbstractPurpose Alanine-serine-cysteine transporter 2 (ASCT2) expression has been demonstrated asa promising lung cancer biomarker (2S4R)-4-[18F]Fluoroglutamine (4-[18F]fluoro-Gln) positronemission tomography (PET) was evaluated in preclinical models of non-small cell lung cancer asa quantitative non-invasive measure of ASCT2 expressionProcedures In vivo microPET studies of 4-[18F]fluoro-Gln uptake were undertaken in human cellline xenograft tumor-bearing mice of varying ASCT2 levels followed by a genetically engineeredmouse model of epidermal growth factor receptor (EGFR)-mutant lung cancer The relationshipbetween a tracer accumulation and ASCT2 levels in tumors was evaluated by IHC andimmunoblottingResult 4-[18F]Fluoro-Gln uptake but not 2-deoxy-2-[18F]fluoro-D-glucose correlated with relativeASCT2 levels in xenograft tumors In genetically engineered mice 4-[18F]fluoro-Gln accumulationwas significantly elevated in lung tumors relative to normal lung and cardiac tissuesConclusions 4-[18F]Fluoro-Gln PET appears to provide a non-invasive measure of ASCT2expression Given the potential of ASCT2 as a lung cancer biomarker this and other tracersreflecting ASCT2 levels could emerge as precision imaging diagnostics in this setting

Key words Glutamine PET SLC1A5 ASCT2 Transporter NSCLC SCC Lung Cancer

Introduction

W ith over 160000 deaths annually lung cancer is the leading

cause of cancer-related deaths in theUSA [1] This is largelydue to a lack of sensitive and specific diagnostic methods as morethan 60 of patients remain undiagnosed until the disease has

Mohamed Hassanein and Matthew R Hight contributed equally to thisworkElectronic supplementary material The online version of this article(doi101007s11307-015-0862-4) contains supplementary material whichis available to authorized users

Correspondence to H Manning e-mail henrycmanningvanderbiltedu

RESEARCH ARTICLE Open Access

Fibrosing mediastinitis complicating priorhistoplasmosis is associated with human leukocyteantigen DQB10402 minus a case control studyStephen B Strock1 Silvana Gaudieri23 Simon Mallal34 Chang Yu5 Daphne Mitchell6 Joy Cogan7 Wendi Mason6Deborah Crowe8 and James E Loyd6

Abstract

Background Fibrosing mediastinitis (FM) is an idiosyncratic reaction to infection with Histoplasma capsulatum witha prevalence of 3100000 people infected The rarity of post-histoplasmosis fibrosing mediastinitis (PHFM) in areaswhere H capsulatum is endemic suggests that an abnormal immunological host response may be responsible forthe development of fibrosis Our group previously reported an association between subjects with PHFM and humanleukocyte antigen (HLA)-A02 We sought to confirm or extend those findings with application of high resolutionHLA typing in a cohort of subjects with PHFM

Methods High-resolution HLA typing was performed on DNA samples from a new cohort 34 patients with PHFMControl cohorts included 707 subjects from the ldquoEuropean Americanrdquo subset of the National Marrow Donor Programreg(NMDP) and 700 subjects from Dialysis Clinic Inc (DCI) The carriage frequencies of the HLA alleles identified in thePHFM NMDP and DCI cohorts were calculated and then all were compared

Results We found an increase in the carriage frequency of HLA-DQB10402 in PHFM subjects relative to the controls(015 versus 007 in DCI and 005 in NMDP p = 008 and 003) Multiple logistic regression showed that DQB10402 wasstatistically significant (p = 004) while DQB10302 and C0304 had point estimates of OR gt 1 though they did notreach statistical significance The HLA-A02 association was not replicated

Conclusions HLA-DQB10402 is associated with PHFM which supports the premise that an aberrant host immuneresponse contributes to the development of PHFM

Keywords Histoplasma capsulatum Fibrosing mediastinitis Human leukocyte antigen

BackgroundFibrosing mediastinitis (FM) is characterized by exces-sive proliferation of invasive fibrous tissue within themediastinum In North America the vast majority of casesof FM result from an idiosyncratic reaction to infectionwith H capsulatum a dimorphic fungus endemic to theMississippi and Ohio River valleys in the United States aswell as temperate zones worldwide [1-4] Other causes ofFM are seen very rarely including an idiopathic form some-times associated with retroperitoneal fibrosis IgG4-relateddisease or medication (methysergide) toxicity [1-35]

Infection with H capsulatum is usually asymptomaticand inconsequential but in some individuals acute histo-plasmosis may cause malaise fever and cough A fewpatients with acute histoplasmosis develop symptomaticmediastinal adenitis often in the subcarinal or rightparatracheal area with a characteristic central chest painworse during inspiration Acute mediastinal adenitis isthe origin of subsequent unique mediastinal complica-tions including mediastinal granuloma and FM Medias-tinal granuloma describes a mass often large (gt4 cm) ofcoalescent lymph nodes in which a thin capsule containssemiliquid contents and is usually asymptomaticIn contrast post-histoplasmosis fibrosing mediastinitis

(PHFM) is solid with dense and invasive fibrosis The fi-brous proliferative mass contains ectopic calcification on

Correspondence stephenbstrockvanderbiltedu1Department of Medicine Vanderbilt University 1211 Medical Center DrNashville TN 37232 USAFull list of author information is available at the end of the article

copy 2015 Strock et al licensee BioMed Central This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (httpcreativecommonsorglicensesby40) which permits unrestricted use distribution andreproduction in any medium provided the original work is properly credited The Creative Commons Public DomainDedication waiver (httpcreativecommonsorgpublicdomainzero10) applies to the data made available in this articleunless otherwise stated

Strock et al BMC Infectious Diseases (2015) 15206 DOI 101186s12879-015-0943-7

Clinical Communications

Varying penicillin allergy testing practices in theUnited States A time for consensusKali Svarczkopf Gerace MDa Eric Karlin MDbElizabeth McKinnon PhDc and Elizabeth Phillips MDd

Clinical Implications

Based on the survey results of American Academyof Allergy Asthma amp Immunology practitioners thereis significant variability in penicillin and b-lactam allergytesting and reporting of results that could have animpact on effectiveness This suggests the need forstandardization of b-lactam allergy practice parameters

TO THE EDITOR

Penicillin and b-lactam allergies are the most commondrug-related allergies in the United States with 8 of thepopulation reporting penicillin allergy and 1 reporting cepha-losporin allergy1 More than 95 of the patients who report apenicillin allergy have negative results on properly performedskin tests using current commercially available reagents and passa confirmatory oral amoxicillin challenge if the skin test result isnegative An unverified penicillin allergy has been associated withincreased hospitalizations antibiotic-resistant infections andincreased health care costs12 This has triggered a public healthinitiative to decrease the use of broad-spectrum nonpenicillinclass antibiotics by widely using penicillin allergy testing1

Routine allergist evaluation of penicillin allergy and thetraining of allergy fellows have been hampered by previous lackof commercial availability of the major determinant penicilloylpolylysine (PPL) over the last decade There is also an ongoingdebate as to the current utility of various locally produced minordeterminant mixtures (MDMs) which have never beencommercially available in the United States3 The most recentallergy practice parameter strongly recommends using PPL whentesting for penicillin allergy but leaves the use of MDMs ami-nopenicillins or penicillin G up to individual providers4 Thereis no current official recommendation to oral challenge allindividuals with negative skin test results though this criterionstandard test has been shown to be safe and effective in both theUnited States and abroad56 The practice parameter also statesthat some patients may be eligible for penicillin graded challengewithout skin testing on the basis of history leaving even moreroom for variability in both method of testing and reagentsused4 The safe use of direct oral challenge to confirm penicillintolerance after benign rashes has been reported by severalgroups78 New data are also convincingly demonstrating the lackof clinically significant immunologic cross-reactivity betweenpenicillins and cephalosporins and even between cephalosporinsthat lack similar side chains9 Although our understanding ofpenicillin allergy has significantly advanced many new allergistsin practice received minimal training regarding penicillin allergytesting during their fellowships thus contributing to the low rateand variability in penicillin allergy testing by allergists in the

United States At the same time there has been an increasedinterest in penicillin allergy testing particularly in relation todriving antibiotic appropriateness by infectious disease special-ists hospitalists and pharmacists

From the primary care provider (PCP) viewpoint the con-venience of using an alternative antibiotic often outweighs thedesire to remove the b-lactam allergy label2 However evenamong allergy specialists in 1 study (Puchner and Zacharisen2)only 13 reported that they would perform penicillin skintesting and the majority surveyed would instead use an alterna-tive antibiotic This is in contrast to a study performed morethan 20 years ago surveying American Academy of AllergyAsthma amp Immunology (AAAAI) members and fellowshipprogram directors in which more than 85 of the respondentsadvocated penicillin skin testing10 This survey showed PPL andpenicillin G to be the most common reagents used with 40 ofthe respondents using MDMs Most respondents were using skinprick plus intradermal testing for penicillin allergy and less than1 were performing oral challenge alone10

Given recent imperatives to improve antibiotic use andimprove health care outcomes we were interested in determiningcurrent b-lactam allergy testing and reporting practice as well asthe perception of testing effectiveness among allergists practicingin different settings

An e-mailed survey was distributed to the AAAAI membershipbetween September 23 2014 and October 7 2014 with anoverall response rate of 15 (652 of 4330 allergists) from acrossthe United States The impact of years in practice and type ofpractice was assessed using chi-square tests

Most of the allergists (89 583 of 652) provide skin testing(either skin prick andor intradermal testing) Approximately 6of the allergists who responded to the survey do not offer eval-uation for b-lactam allergy and do not perform skin testing ororal challenge with the most common reasons being lack ofreagents resources and infrastructure If anything this surveymay underestimate the number of providers not offering b-lactam testing considering an inherent bias toward surveycompletion only by those providers who have an interest and dooffer testing

Of the 518 respondents who completed the survey the mostcommon reagents used in skin testing were Pre-Pen (commer-cially available major determinant) penicillin G and MDMsPenicillin G was reported as being used more frequently (752412 of 548) than MDMs (383 210 of 548) Those practicesthat test to MDMs were more likely to be academic practices(44 academic vs 36 other P frac14 09) More than 80 of allpractitioners routinely offer oral challenge after negative skin testresults In particular those providers who have been in practicefor less than 10 years are more likely to perform oral challenge(93 vs 85 P frac14 01) Pre-Pen was reported overall as the mostprevalent skin test positive agent (66 of the responses) how-ever 15 of the providers who tested for ampicillin reported itas the most prevalent positive agent This could indicate achanging pattern of allergy in our population

We assessed the quality and consistency of advice given topatients regarding future b-lactam antibiotic use after negativetest results (Table I) Providers who offer both skin testing and

1

Recent PublicationsOR I G I N A L R E S E A R CH

Use of pulmonary arterial hypertensionndashapproved therapy

in the treatment of nonndashgroup 1 pulmonary hypertension

at US referral centers

Aaron W Trammell Meredith E Pugh John H Newman Anna R Hemnes Ivan M Robbins

Division of Pulmonary and Critical Care Medicine Vanderbilt University Medical Center Nashville Tennessee USA

Abstract Pulmonary hypertension (PH) is a frequent complication of left heart disease and parenchymal lung disease and it portendsincreased mortality A growing number of medications are approved for the treatment of World Health Organization (WHO) group 1pulmonary arterial hypertension (PAH) However they are not well studied in PH of other etiologies (WHO groups 2ndash5) We sought toassess treatment approaches used by PAH referral centers in this diverse group of patients We developed a semiquantitative online surveydesigned to evaluate the use of PAH-approved therapy by pulmonary vascular disease centers in the United States for management of nonndashgroup 1 PH Thirty of 50 centers completed the survey Almost all centers (93) reported using PAH therapy for patients with nonndashgroup 1PH including 77 with group 2 PH and 80 with group 3 PH Elevated transpulmonary gradient or pulmonary vascular resistance and thepresence of right ventricular (RV) dysfunction were commonly cited as supporting use of PAH therapy in patients with PH secondary to leftheart disease For patients with PH and concomitant parenchymal lung disease degree of pulmonary function impairment and RV dysfunc-tion were most important in influencing use of PAH therapy In conclusion pulmonary vascular disease treatment centers use PAH-approvedtherapy for patients with WHO group 2ndash5 PH mostly relying on hemodynamics and assessment of RV function to identify candidates fortherapy Clinical trials designed to test the efficacy of PAH therapy in PH due to left heart and lung disease are needed as clinical practice hasextended beyond the evidence for these etiologies of PH

Keywords survey chronic obstructive pulmonary disease restrictive lung disease heart failure

Pulm Circ 20155(2)356-363 DOI 101086681264

Pulmonary hypertension (PH) is defined as mean pulmonary arterialpressure (mPAP) of ge25 mmHg and may result from several hemo-dynamic and pathologic mechanisms which are grouped according tothe Nice World Health Organization (WHO) classification scheme1

WHO group 1 pulmonary arterial hypertension (PAH) encompassesseveral disorders in which the precapillary pulmonary vasculatureis primarily affected PAH requires pulmonary arterial wedge pres-sure (PAWP) of le15 mmHg and mPAP of ge25 mmHg and it hasbeen extensively studied with several approved therapies availablefor clinical use Guidelines have been established for the appropriateevaluation and evidence-based management of patients with PAH2-4

Although much attention has been focused on PAH it is a raredisease and PH due to other causes (left heart disease group 2 lungdisease andor hypoxemia group 3 chronic thromboembolic PHgroup 4 unclear or multifactorial etiologies group 5) is far morecommon5 Thorough evaluation is imperative to accurate classifi-cation and it is recommended that this occur in specialized PH cen-ters The case mix in PH centers is enriched for confirmed group 1PAH but patients deemed to have other causes of PH make up alarge component For instance in three large PH centers patientsreferred over 1 year were confirmed to have PAH in 41 of cases

with groups 2 and 3 combining for 336 In another center PAHwas the most common final single diagnosis with 39 (32) of 122 pa-tients but group 2 and 3 PH and mixed-etiology PH combined for55 (45) of 122 of the study population7 Frequent misclassificationof patients prior to referral to a PH center highlights the complex-ity of appropriate diagnosis and the jeopardy of using PAH therapyprior to such a workup6

Development of PH in patients with left heart disease89 chronicinterstitial lung disease10 and chronic obstructive pulmonary dis-ease (COPD)1112 is associated with worse outcome however thedegree of PH that is observed in groups 2ndash5 is quite variable81314

Some patients appear to have PH in excess of what would be ex-pected for the degree of underlying lung disease or left atrial pres-sure elevation and thus may benefit from PAH-directed therapyalthough this remains unproven15-17 Evaluation and surgical treat-ment of operable group 4 disease is uniformly recommended1819

However well-designed clinical studies are lacking for group 2 3and 5 PH thus there is no consensus treatment strategy other thanmanagement of the underlying disease process for these patientsKnowledge of the current treatment approach used in these patientsby advanced treatment centers is limited Use of PAH-approved ther-

Address correspondence to Dr Aaron W Trammell Division of Pulmonary and Critical Care Medicine Vanderbilt University Medical Center T-1223Medical Center North 1161 21st Avenue South Nashville TN 37232-2650 USA E-mail aarontrammellvanderbiltedu

Submitted August 12 2014 Accepted October 24 2014 Electronically published April 15 2015copy 2015 by the Pulmonary Vascular Research Institute All rights reserved 2045-893220150502-0016 $1500

This content downloaded from 160129114178 on Wed 17 Jun 2015 095038 AMAll use subject to JSTOR Terms and Conditions

(Click image to access complete article)

R E V I EW A R T I C L E

Fatty acid metabolism in pulmonary arterial hypertension

role in right ventricular dysfunction and hypertrophy

Megha Talati Anna Hemnes

Division of Allergy Pulmonary and Critical Care Medicine Department of Medicine Vanderbilt University Medical Center Nashville Tennessee USA

Abstract Pulmonary arterial hypertension (PAH) is a complex multifactorial disease in which an increase in pulmonary vascular resis-tance leads to increased afterload on the right ventricle (RV) causing right heart failure and death Our understanding of the pathophys-iology of RV dysfunction in PAH is limited but is constantly improving Increasing evidence suggests that in PAH RV dysfunction isassociated with various components of metabolic syndrome such as insulin resistance hyperglycemia and dyslipidemia The relationshipbetween RV dysfunction and fatty acidglucose metabolites is multifaceted and in PAH it is characterized by a shift in utilization of energysources toward increased glucose utilization and reduced fatty acid consumption RV dysfunction may be caused by maladaptive fatty acidmetabolism resulting from an increase in fatty acid uptake by fatty acid transporter molecule CD36 and an imbalance between glucose andfatty acid oxidation in mitochondria This leads to lipid accumulation in the form of triglycerides diacylglycerol and ceramides in thecytoplasm hallmarks of lipotoxicity Current interventions in animal models focus on improving RV dysfunction through altering fattyacid oxidation rates and limiting lipid accumulation but more specific and effective therapies may be available in the coming years basedon current research In conclusion a deeper understanding of the complex mechanisms of the metabolic remodeling of the RV will aid inthe development of targeted treatments for RV failure in PAH

Keywords pulmonary arterial hypertension metabolic syndrome fatty acid oxidation glucose oxidation right ventricle fatty acidtransporter (CD36) glucose transporters insulin resistance right ventricular lipotoxicity lipotoxic cardiomyopathy

Pulm Circ 20155(2)269-278 DOI 101086681227

Pulmonary arterial hypertension (PAH) is a devastating diseasecharacterized by progressive obliteration of the pulmonary vascula-ture right heart failure and death The pathobiology of PAH iscomplex and presently there is no curative treatment AlthoughPAH is classically thought to be a disease of the lungs the roleplayed by right ventricular (RV) hypertrophy and dysfunction thatultimately results in right heart failure and death is understudiedRV failure is the most common cause of death in PAH1 yet thereare no specific therapies aimed at improving RV adaptation or func-tion However it is well documented that pathological RV remod-eling in PAH can be reversed with lung transplantation or withpulmonary thromboendarterectomy in chronic thromboembolic pul-monary hypertension (CTEPH)2-9 The molecular mechanisms thatmediate the transition from adaptive RV compensation to failure orthat can promote reversible RV remodeling are presently unknownRecently our group and others have found evidence indicating thatintracellular lipid accumulation and decreased fatty acid oxidation(FAO) may be features of RV failure related to PAH10-13 This raisesa question In PAH can accumulation of fatty acids promote RVdysfunction with a resultant progression to right heart failure anddeath This article reviews the role played by increased fatty aciduptake and accumulation of fatty acid metabolites in PAH-induced

RV failure and discusses what is known about the impact of thesefindings on human RV failure Understanding the mechanisms andconsequences of lipid deposition in the RVmay suggest new diagnos-tic and therapeutic approaches to right heart failure in PAH

RV DYSFUNCTION IN PAH AND ITS IMPORTANCE

In a healthy adult heart the RV cavity is smaller than that of theleft ventricle (LV) and has a much smaller wall thickness mak-ing the RV well suited as a flow conduit rather than a pressure-generating pump In PAH the shape of the RV is changed fromthe normal conformation and RV wall stress is significantly in-creased1415 as a result of an increase in pulmonary vascular re-sistance (PVR) with increased RV afterload1617 The progressiveremodeling of the pulmonary vascular bed leads to an increase inPVR In PAH the initial response to increased RV afterload isadaptive RV hypertrophy18 characterized by an increase in pro-tein synthesis and cardiomyocyte size through the addition of sar-comeres19 With sustained pressure overload these initially adap-tive changes transition to dysfunction with the RV progressing tocontractile dysfunction accompanied by thinning and dilation ofthe RV162021 Magnetic resonance imagingndashderived RV pressure-volume loops can be used for assessment of RV myocardial con-

Address correspondence to Dr Megha Talati Division of Allergy Pulmonary and Critical Care Medicine T1218 MCN 1161 21st Avenue SouthNashville TN 37232 USA E-mail meghatalativanderbiltedu

Submitted May 1 2014 Accepted December 30 2014 Electronically published April 9 2015copy 2015 by the Pulmonary Vascular Research Institute All rights reserved 2045-893220150502-0005 $1500

This content downloaded from 160129114178 on Wed 17 Jun 2015 095305 AMAll use subject to JSTOR Terms and Conditions

Copyright copy 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health Inc All Rights Reserved

Critical Care Medicine wwwccmjournalorg 1

Objective The association between cigarette smoke exposure and the acute respiratory distress syndrome in patients with the most common acute respiratory distress syndrome risk factors of sepsis pneumonia and aspiration has not been well studied The goal of this study was to test the association between biomarker-confirmed cigarette smoking and acute respiratory distress syn-drome in a diverse cohort

Copyright copy 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health Inc All Rights Reserved

DOI 101097CCM0000000000001089

1Division of Pulmonary and Critical Care Medicine Department of Medi-cine University of California San Francisco San Francisco CA

2Department of Anesthesia University of California San Francisco San Francisco CA

3Division of Hospital Medicine Department of Medicine University of Cali-fornia San Francisco San Francisco CA

4Department of Medicine Vanderbilt University Nashville TN5Department of Medicine Louisiana State University School of Medicine New Orleans LA

6Department of Surgery Vanderbilt University Nashville TN7Center for Tobacco Control Research and Education University of Cali-fornia San Francisco San Francisco CA

8Division of Clinical Pharmacology and Experimental Therapeutics Univer-sity of California San Francisco San Francisco CA

9Departments of Medicine and of Pathology Microbiology and Immunology Vanderbilt University Nashville TN

Drs Calfee and Ware had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis Drs Calfee and Ware designed the study conducted data clean-ing and analysis interpreted the data and drafted and revised the article Drs Matthay and Benowitz helped design the study interpreted the data and revised the article Drs Kangelaris Siew Janz Jacob and Havel con-tributed to data collection cleaning or interpretation and critically revised the article Drs Bernard and May contributed to data interpretation and critically revised the article All authors provided final approval of the ver-sion to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Supplemental digital content is available for this article Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journalrsquos website (httpjournalslwwcomccmjournal)

Dr Calfee received support for travel from Boehringer Ingelheim (travel to meeting at Boehringer headquarters relevant to potential research project) and received support for article research from the National Institutes of Health (NIH HL090833 KL2RR024130 and HL110969) Her institution received grant support from the NIH and Flight Attendant Medical Research Institute (Young Clinical Scientist Award) consultation fees from GlaxoSmithKline and Cerus and grant support from GlaxoSmithKline Some research reported in this publication was supported by grant number 1P50CA18890 from the National Cancer Institute and Food and Drug Administration Center for Tobacco Products Dr Matthay consulted for Roche Genentec (chair of Data Safety and Monitoring Board for a clinical trial) Cerus (advisor on platelets and acute respiratory distress syndrome [ARDS]) GlaxoSmithKline (consul-tant on ARDS program) and Quark Pharmaceuticals (consultant on ARDS program) and he received support for article research from the NIH His institution received grant support from the National Heart Lung and Blood

Cigarette Smoke Exposure and the Acute Respiratory Distress Syndrome

Carolyn S Calfee MD MAS12 Michael A Matthay MD12 Kirsten N Kangelaris MD MAS3

Edward D Siew MD4 David R Janz MD5 Gordon R Bernard MD4 Addison K May MD6

Peyton Jacob PhD78 Christopher Havel PhD8 Neal L Benowitz MD78 Lorraine B Ware MD49

Institute (NHLBI) (HL51856) and from GlaxoSmithKline (grant to study sep-sis) Dr Kangelaris received support for article research from the NIH Her institution received grant support from the NHLBI (1K23HL116800-01) Dr Siew consulted for Alere (clinical adjudication) lectured for Renal Ven-tures (asked to speak about the epidemiology of acute kidney injury recov-ery at a meeting of dialysis Chief Medical Officers) and received support for article research from the NIH (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK] K23 Award DK088964-03) His institution received grant support from the NIH NIDDK (performed as part of Dr Siewrsquos K23 award) Dr Janz received support for article research from the NIH (T32 HL087738) Dr Bernard served as a board member for Cumberland Pharmaceuticals Nashville TN His institution received grant support from AstraZeneca (grant for multicenter trial of ticagrelor in community-acquired pneumonia) Dr Jacob received support for article research from the NIH (P30 DA012393) His institution received grant support from the NIH (pro-vided support for instruments salary for personnel and supplies needed to carry out the research) Flight Attendant Medical Research Institute (supports other research) and California Tobacco Related Disease Research Program (supports other research) Dr Havel received support for article research from the NIH His institution received grant support Dr Benowitz has consulted for Pfizer and GlaxoSmithKline and has served as a paid expert witness in litigation against tobacco companies Dr Benowitz received support for arti-cle research from the NIH (P30 DA012393 and CA78603) and the Flight Attendants Medical Research Institute His institution received grant support from Flight Attendants Medical Research Institute (University of California San Francisco Bland Lane Center of Excellence in Secondhand Smoke) and National Cancer Institute and Food and Drug Administration Center for Tobacco Products (1P50CA180890) Dr Ware has served on advisory boards for GlaxoSmithKline Dr Ware consulted for GlaxoSmithKline and Abbot and received support for article research from the NIH (HL081332 HL103836 and HL112656) Her institution received grant support from the NIH and the American Heart Association The content is solely the respon-sibility of the authors and does not necessarily represent the official views of the NIH or the Food and Drug Administration The funding sources had no role in the design or conduct of the study collection management analysis and interpretation of the data preparation review or approval of the article or the decision to submit the article for publication The remaining authors have disclosed that they do not have any potential conflicts of interest

Address requests for reprints to Carolyn Calfee MD MAS Pulmonary and Critical Care Division University of California San Francisco 505 Parnassus Avenue Box 0111 San Francisco CA 94143-0111 E-mail carolyncalfeeucsfedu

RESEARCH ARTICLE

The Impact of Lymphopenia on Delirium inICU PatientsShigeaki Inoue1 Eduard E Vasilevskis56 Pratik P Pandharipande3 TimothyD Girard26 Amy J Graves4 Jennifer Thompson4 Ayumi Shintani4 E Wesley Ely26

1 Department of Emergency and Critical Care Medicine Tokai University School of Medicine IseharaKanagawa Japan 2 Division of AllergyPulmonaryCritical Care Medicine Department of MedicineVanderbilt University School of Medicine Nashville Tennessee United States of America 3 Department ofAnesthesiology Vanderbilt University School of Medicine Nashville Tennessee United States of America4 Department of Biostatistics Vanderbilt University School of Medicine Nashville Tennessee United Statesof America 5 Division of General Internal Medicine and Public Health Department of Medicine VanderbiltUniversity School of Medicine Nashville Tennessee United States of America 6 Veterans AffairsTennessee Valley Geriatric Research Education and Clinical Center (GRECC) Vanderbilt University Schoolof Medicine Nashville Tennessee United States of America

sg-inoueisiccu-tokaiacjp

Abstract

Background

Immunosuppressed states may predispose patients to development of acute brain injury

during times of critical illness Lymphopenia is a non-specific yet commonly used bedside

marker of immunosuppressed states

Methods

We examined whether lymphopenia would predict development of acute brain dysfunction

(delirium andor coma) in 518 patients enrolled in the Bringing to Light the Risk Factors and

Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) study in medi-

cal and surgical ICUs of a tertiary care university-based medical center Utilizing propor-

tional odds logistic regression and Cox proportional hazards survival analysis we assessed

the relationship between pre-enrollment lymphocytes and subsequent cognitive outcomes

including delirium- and coma-free days (DCFDs) and 30-day mortality

Results

There were no statistically significant associations between lymphocytes and DCFDs (p =

017) additionally the relationship between lymphocytes and mortality was not statistically

significant (p = 071) Among 259 patients without history of cancer or diabetes there was

no statistically significant association between lymphocytes and DCFDs (p = 007)

Conclusion

lymphopenia a commonly used bedside marker of immunosuppression does not appear to

be a marker of risk for acute brain injury (deliriumcoma) or 30-day mortality in general medi-

calsurgical ICU patients

PLOS ONE | DOI101371journalpone0126216 May 20 2015 1 11

a11111

OPEN ACCESS

Citation Inoue S Vasilevskis EE PandharipandePP Girard TD Graves AJ Thompson J et al (2015)The Impact of Lymphopenia on Delirium in ICUPatients PLoS ONE 10(5) e0126216 doi101371journalpone0126216

Academic Editor Jorge IF Salluh Dor Institute ofResearch and Education BRAZIL

Received January 11 2015

Accepted March 31 2015

Published May 20 2015

Copyright copy 2015 Inoue et al This is an openaccess article distributed under the terms of theCreative Commons Attribution License which permitsunrestricted use distribution and reproduction in anymedium provided the original author and source arecredited

Data Availability Statement The raw data containidentifying patient information Therefore data areavailable upon request from Bill Pojedinec ProgramManager at ICU Delirium and Cognitive ImpairmentStudy Group of HSR Division of Allergy Pulmonaryand CCMVA-GRECC Vanderbilt University MedicalCenter MCE North Tower Suite 6100 Nashville TN37232-8300 Phone 615-936-3702 Fax 615-936-1269 wwwicudeliriumorg

Funding This work was supported by funds from theVanderbilt Institute for Clinical and TranslationalResearch (VICTR) and The Bringing to Light the Risk

OR I G I N A L R E S E A R CH

Right ventricular long noncoding RNA expression

in human heart failure

Thomas G Di Salvo1 Yan Guo2 Yan Ru Su1 Travis Clark2 Evan Brittain1 Tarek Absi3

Simon Maltais3 Anna Hemnes4

1Division of Cardiovascular Medicine Vanderbilt Heart and Vascular Institute Nashville Tennessee USA 2Vanderbilt MedicalCenter VANTAGE Core Laboratory Nashville Tennessee USA 3Division of Cardiovascular Surgery Vanderbilt Heart andVascular Institute Nashville Tennessee USA 4Pulmonary and Critical Care Medicine Vanderbilt Department of MedicineNashville Tennessee USA

Abstract The expression of long noncoding RNAs (lncRNAs) in human heart failure (HF) has not been

widely studied Using RNA sequencing (RNA-Seq) we compared lncRNA expression in 22 explanted hu-

man HF hearts with lncRNA expression in 5 unused donor human hearts We used Cufflinks to identify

isoforms and DESeq to identify differentially expressed genes We identified the noncoding RNAs by cross-

reference to Ensembl release 73 (Genome Reference Consortium human genome build 37) and explored

possible functional roles using a variety of online tools In HF hearts RNA-Seq identified 84793 total

messenger RNA coding and noncoding different transcripts including 13019 protein-coding genes

2085 total lncRNA genes and 1064 pseudogenes By Ensembl noncoding RNA categories there were

48 lncRNAs 27 pseudogenes and 30 antisense RNAs for a total of 105 differentially expressed lncRNAs

in HF hearts Compared with donor hearts HF hearts exhibited differential expression of 77 of protein-

coding genes 37 of lncRNAs (including pseudogenes) and 25 of pseudogenes There were not con-

sistent correlations between antisense lncRNAs and parent genes and between pseudogenes and parent

genes implying differential regulation of expression Exploratory in silico functional analyses using on-

line tools suggested a variety of possible lncRNA regulatory roles By providing a comprehensive profile

of right ventricular polyadenylated messenger RNA transcriptome in HF RNA-Seq provides an inventory

of differentially expressed lncRNAs including antisense transcripts and pseudogenes for future mechanis-

tic study

Keywords long noncoding RNA right ventricle human heart failure gene expression transcriptional

profiling

Pulm Circ 20155(1)135-161 DOI 101086679721

The results reported from the Encyclopedia of DNA Ele-

ments (ENCODE) project are transforming our nascent

understanding of integrated human genomics1 Fully 75

of the human genome is transcribed into some type of

RNA2 although only 122 of the genome encodes the

exons that comprise the 20687 known protein-coding

genes1 The vast majority of the human genome there-

fore is transcribed into nonndashprotein-coding RNAs includ-

ing the 8801 small RNAs 9640 long noncoding RNAs

(lncRNAs defined as nontranslated RNA lt200 base pairs

[bp] in length) and 11224 pseudogenes identified to date1

Evolving research has identified diverse epigenetic regula-

tory roles for lncRNAs in development homeostasis and

disease3 lncRNAs are likely to play important regulatory

roles in human heart failure as well4

Via high-throughput sequencing RNA sequencing

(RNA-Seq) provides a comprehensive profile of polyadeny-

lated protein-coding messenger RNA (mRNA) and nonndash

protein-coding lncRNA transcripts5 We used RNA-Seq to

generate the lncRNA transcriptional profile of the right

ventricle in end-stage human heart failure Human right

ventricular (RV) tissue may be obtained at either endo-

myocardial biopsy or surgery Diagnostic endomyocardial

biopsy given its attendant risks is rarely performed for

Submitted February 21 2014 Accepted August 13 2014 Electronically published February 13 2015

copy 2015 by the Pulmonary Vascular Research Institute All rights reserved 2045-893220150501-0013 $1500

Address correspondence to Dr Thomas G Di Salvo 1215 21st Avenue South Medical Center East South Tower Suite 5037 Nashville TN 37232

USA E-mail thomasgdisalvovanderbiltedu

This content downloaded from 160129114178 on Wed 17 Jun 2015 095727 AMAll use subject to JSTOR Terms and Conditions

Mol Imaging Biol (2015)DOI 101007s11307-015-0862-4 World Molecular Imaging Society 2015

BRIEF ARTICLE

Preclinical Evaluation of 4-[18F]FluoroglutaminePET to Assess ASCT2 Expression in LungCancerMohamed Hassanein12 Matthew R Hight34 Jason R Buck34

Mohammed N Tantawy34 Michael L Nickels34 Megan D Hoeksema1

Bradford K Harris1 Kelli Boyd5 Pierre P Massion126 H Charles Manning3467

1Division of Allergy Pulmonary and Critical Care Medicine Vanderbilt University School of Medicine Nashville TN 37232 USA2Thoracic Program Vanderbilt-Ingram Cancer Center Vanderbilt University Medical Center Nashville TN 37232 USA3Vanderbilt University Institute of Imaging Science (VUIIS) Vanderbilt University Medical Center Nashville TN 37232 USA4Department of Radiology and Radiological Sciences Vanderbilt University Medical Center Nashville TN 37232 USA5Department of Pathology Microbiology and Immunology Vanderbilt University Medical Center Nashville TN 37232 USA6Vanderbilt-Ingram Cancer Center Vanderbilt University Medical Center Nashville TN 37232 USA7Program in Chemical and Physical Biology Vanderbilt University Medical Center Nashville TN 37232 USA

AbstractPurpose Alanine-serine-cysteine transporter 2 (ASCT2) expression has been demonstrated asa promising lung cancer biomarker (2S4R)-4-[18F]Fluoroglutamine (4-[18F]fluoro-Gln) positronemission tomography (PET) was evaluated in preclinical models of non-small cell lung cancer asa quantitative non-invasive measure of ASCT2 expressionProcedures In vivo microPET studies of 4-[18F]fluoro-Gln uptake were undertaken in human cellline xenograft tumor-bearing mice of varying ASCT2 levels followed by a genetically engineeredmouse model of epidermal growth factor receptor (EGFR)-mutant lung cancer The relationshipbetween a tracer accumulation and ASCT2 levels in tumors was evaluated by IHC andimmunoblottingResult 4-[18F]Fluoro-Gln uptake but not 2-deoxy-2-[18F]fluoro-D-glucose correlated with relativeASCT2 levels in xenograft tumors In genetically engineered mice 4-[18F]fluoro-Gln accumulationwas significantly elevated in lung tumors relative to normal lung and cardiac tissuesConclusions 4-[18F]Fluoro-Gln PET appears to provide a non-invasive measure of ASCT2expression Given the potential of ASCT2 as a lung cancer biomarker this and other tracersreflecting ASCT2 levels could emerge as precision imaging diagnostics in this setting

Key words Glutamine PET SLC1A5 ASCT2 Transporter NSCLC SCC Lung Cancer

Introduction

W ith over 160000 deaths annually lung cancer is the leading

cause of cancer-related deaths in theUSA [1] This is largelydue to a lack of sensitive and specific diagnostic methods as morethan 60 of patients remain undiagnosed until the disease has

Mohamed Hassanein and Matthew R Hight contributed equally to thisworkElectronic supplementary material The online version of this article(doi101007s11307-015-0862-4) contains supplementary material whichis available to authorized users

Correspondence to H Manning e-mail henrycmanningvanderbiltedu

RESEARCH ARTICLE Open Access

Fibrosing mediastinitis complicating priorhistoplasmosis is associated with human leukocyteantigen DQB10402 minus a case control studyStephen B Strock1 Silvana Gaudieri23 Simon Mallal34 Chang Yu5 Daphne Mitchell6 Joy Cogan7 Wendi Mason6Deborah Crowe8 and James E Loyd6

Abstract

Background Fibrosing mediastinitis (FM) is an idiosyncratic reaction to infection with Histoplasma capsulatum witha prevalence of 3100000 people infected The rarity of post-histoplasmosis fibrosing mediastinitis (PHFM) in areaswhere H capsulatum is endemic suggests that an abnormal immunological host response may be responsible forthe development of fibrosis Our group previously reported an association between subjects with PHFM and humanleukocyte antigen (HLA)-A02 We sought to confirm or extend those findings with application of high resolutionHLA typing in a cohort of subjects with PHFM

Methods High-resolution HLA typing was performed on DNA samples from a new cohort 34 patients with PHFMControl cohorts included 707 subjects from the ldquoEuropean Americanrdquo subset of the National Marrow Donor Programreg(NMDP) and 700 subjects from Dialysis Clinic Inc (DCI) The carriage frequencies of the HLA alleles identified in thePHFM NMDP and DCI cohorts were calculated and then all were compared

Results We found an increase in the carriage frequency of HLA-DQB10402 in PHFM subjects relative to the controls(015 versus 007 in DCI and 005 in NMDP p = 008 and 003) Multiple logistic regression showed that DQB10402 wasstatistically significant (p = 004) while DQB10302 and C0304 had point estimates of OR gt 1 though they did notreach statistical significance The HLA-A02 association was not replicated

Conclusions HLA-DQB10402 is associated with PHFM which supports the premise that an aberrant host immuneresponse contributes to the development of PHFM

Keywords Histoplasma capsulatum Fibrosing mediastinitis Human leukocyte antigen

BackgroundFibrosing mediastinitis (FM) is characterized by exces-sive proliferation of invasive fibrous tissue within themediastinum In North America the vast majority of casesof FM result from an idiosyncratic reaction to infectionwith H capsulatum a dimorphic fungus endemic to theMississippi and Ohio River valleys in the United States aswell as temperate zones worldwide [1-4] Other causes ofFM are seen very rarely including an idiopathic form some-times associated with retroperitoneal fibrosis IgG4-relateddisease or medication (methysergide) toxicity [1-35]

Infection with H capsulatum is usually asymptomaticand inconsequential but in some individuals acute histo-plasmosis may cause malaise fever and cough A fewpatients with acute histoplasmosis develop symptomaticmediastinal adenitis often in the subcarinal or rightparatracheal area with a characteristic central chest painworse during inspiration Acute mediastinal adenitis isthe origin of subsequent unique mediastinal complica-tions including mediastinal granuloma and FM Medias-tinal granuloma describes a mass often large (gt4 cm) ofcoalescent lymph nodes in which a thin capsule containssemiliquid contents and is usually asymptomaticIn contrast post-histoplasmosis fibrosing mediastinitis

(PHFM) is solid with dense and invasive fibrosis The fi-brous proliferative mass contains ectopic calcification on

Correspondence stephenbstrockvanderbiltedu1Department of Medicine Vanderbilt University 1211 Medical Center DrNashville TN 37232 USAFull list of author information is available at the end of the article

copy 2015 Strock et al licensee BioMed Central This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (httpcreativecommonsorglicensesby40) which permits unrestricted use distribution andreproduction in any medium provided the original work is properly credited The Creative Commons Public DomainDedication waiver (httpcreativecommonsorgpublicdomainzero10) applies to the data made available in this articleunless otherwise stated

Strock et al BMC Infectious Diseases (2015) 15206 DOI 101186s12879-015-0943-7

Clinical Communications

Varying penicillin allergy testing practices in theUnited States A time for consensusKali Svarczkopf Gerace MDa Eric Karlin MDbElizabeth McKinnon PhDc and Elizabeth Phillips MDd

Clinical Implications

Based on the survey results of American Academyof Allergy Asthma amp Immunology practitioners thereis significant variability in penicillin and b-lactam allergytesting and reporting of results that could have animpact on effectiveness This suggests the need forstandardization of b-lactam allergy practice parameters

TO THE EDITOR

Penicillin and b-lactam allergies are the most commondrug-related allergies in the United States with 8 of thepopulation reporting penicillin allergy and 1 reporting cepha-losporin allergy1 More than 95 of the patients who report apenicillin allergy have negative results on properly performedskin tests using current commercially available reagents and passa confirmatory oral amoxicillin challenge if the skin test result isnegative An unverified penicillin allergy has been associated withincreased hospitalizations antibiotic-resistant infections andincreased health care costs12 This has triggered a public healthinitiative to decrease the use of broad-spectrum nonpenicillinclass antibiotics by widely using penicillin allergy testing1

Routine allergist evaluation of penicillin allergy and thetraining of allergy fellows have been hampered by previous lackof commercial availability of the major determinant penicilloylpolylysine (PPL) over the last decade There is also an ongoingdebate as to the current utility of various locally produced minordeterminant mixtures (MDMs) which have never beencommercially available in the United States3 The most recentallergy practice parameter strongly recommends using PPL whentesting for penicillin allergy but leaves the use of MDMs ami-nopenicillins or penicillin G up to individual providers4 Thereis no current official recommendation to oral challenge allindividuals with negative skin test results though this criterionstandard test has been shown to be safe and effective in both theUnited States and abroad56 The practice parameter also statesthat some patients may be eligible for penicillin graded challengewithout skin testing on the basis of history leaving even moreroom for variability in both method of testing and reagentsused4 The safe use of direct oral challenge to confirm penicillintolerance after benign rashes has been reported by severalgroups78 New data are also convincingly demonstrating the lackof clinically significant immunologic cross-reactivity betweenpenicillins and cephalosporins and even between cephalosporinsthat lack similar side chains9 Although our understanding ofpenicillin allergy has significantly advanced many new allergistsin practice received minimal training regarding penicillin allergytesting during their fellowships thus contributing to the low rateand variability in penicillin allergy testing by allergists in the

United States At the same time there has been an increasedinterest in penicillin allergy testing particularly in relation todriving antibiotic appropriateness by infectious disease special-ists hospitalists and pharmacists

From the primary care provider (PCP) viewpoint the con-venience of using an alternative antibiotic often outweighs thedesire to remove the b-lactam allergy label2 However evenamong allergy specialists in 1 study (Puchner and Zacharisen2)only 13 reported that they would perform penicillin skintesting and the majority surveyed would instead use an alterna-tive antibiotic This is in contrast to a study performed morethan 20 years ago surveying American Academy of AllergyAsthma amp Immunology (AAAAI) members and fellowshipprogram directors in which more than 85 of the respondentsadvocated penicillin skin testing10 This survey showed PPL andpenicillin G to be the most common reagents used with 40 ofthe respondents using MDMs Most respondents were using skinprick plus intradermal testing for penicillin allergy and less than1 were performing oral challenge alone10

Given recent imperatives to improve antibiotic use andimprove health care outcomes we were interested in determiningcurrent b-lactam allergy testing and reporting practice as well asthe perception of testing effectiveness among allergists practicingin different settings

An e-mailed survey was distributed to the AAAAI membershipbetween September 23 2014 and October 7 2014 with anoverall response rate of 15 (652 of 4330 allergists) from acrossthe United States The impact of years in practice and type ofpractice was assessed using chi-square tests

Most of the allergists (89 583 of 652) provide skin testing(either skin prick andor intradermal testing) Approximately 6of the allergists who responded to the survey do not offer eval-uation for b-lactam allergy and do not perform skin testing ororal challenge with the most common reasons being lack ofreagents resources and infrastructure If anything this surveymay underestimate the number of providers not offering b-lactam testing considering an inherent bias toward surveycompletion only by those providers who have an interest and dooffer testing

Of the 518 respondents who completed the survey the mostcommon reagents used in skin testing were Pre-Pen (commer-cially available major determinant) penicillin G and MDMsPenicillin G was reported as being used more frequently (752412 of 548) than MDMs (383 210 of 548) Those practicesthat test to MDMs were more likely to be academic practices(44 academic vs 36 other P frac14 09) More than 80 of allpractitioners routinely offer oral challenge after negative skin testresults In particular those providers who have been in practicefor less than 10 years are more likely to perform oral challenge(93 vs 85 P frac14 01) Pre-Pen was reported overall as the mostprevalent skin test positive agent (66 of the responses) how-ever 15 of the providers who tested for ampicillin reported itas the most prevalent positive agent This could indicate achanging pattern of allergy in our population

We assessed the quality and consistency of advice given topatients regarding future b-lactam antibiotic use after negativetest results (Table I) Providers who offer both skin testing and

1