Summary Report: What Clinical Laboratories Need to Know About Their Role in Influenza Testing*

Transcription

1 Summary Reprt: What Clinical Labratries Need t Knw Abut Their Rle in Influenza Testing* Labratry Outreach Cmmunicatin System Inaugural Telecnference Tuesday, January 24, 2006 Intrductry Remarks Rbert Martin, DrPH, CDC Sctt Becker, MS, APHL Tday s telecnference is the initial cnference call f the Labratry Outreach Cmmunicatin System (LOCS). The system is mdeled after CDC s Clinical Outreach Cmmunicatin Activity (COCA), which prvides a natinal frum fr CDC t cmmunicate regularly with clinicians n a range f imprtant current issues. Objectives f tday s meeting are t intrduce LOCS, describe the system in place t address influenza testing (clinical/state public health labratry/cdc), and t articulate the rle and respnsibilities f the clinical labratry. LOCS is being established t address existing gaps in labratry-related cmmunicatin with the brad clinical cmmunity. The visin fr the system is t be the central surce fr labratry prfessinals t btain credible infrmatin n rutine and emergent issues. LOCS prject statement is t build a vlunteer cmmunicatins infrastructure fr the exchange f labratryrelated infrmatin between CDC and thers in the labratry cmmunity. LOCS activities will fcus n educatin, using technlgy that enables tw-way cmmunicatin between CDC and participating partners. One f the key bjectives is t prvide up-t-date infrmatin n dynamic r urgent public health issues as seen with tday s prgram n labratry diagnstics fr influenza. Key cmpnents f LOCS cmmunicatins effrts include the fllwing: Audience Public health, clinical, physician ffice, independent labratry staff Timing Scheduled and unscheduled Rute f cmmunicatin Telecnference, web cnference, mailing lists, , phne/ FAX Tpics Needs f labratrians that are nt being met, emergent issues, changes in regulatins, standards, recmmended practices, disaster relief. Tday s prgram features speakers frm CDC s Influenza Branch and, n behalf f APHL, frm the Wiscnsin State Labratry f Hygiene. Rutine and Enhanced Surveillance fr Influenza at the Natinal Level Lynnette Brammer, MPH, CDC Surveillance is a crnerstne f CDC s public health prgrams, and ver the years the Influenza This reprt reflects authr s ntes and recllectins f the meeting, and the views expressed herein may nt necessarily represent the psitins and plicies f the Centers fr Disease Cntrl and Preventin (CDC) r the Department f Health and Human Services (HHS). 1

2 Branch has established a cmprehensive system t mnitr the ccurrence f seasnal influenza in the United States. The system cnsists f the fllwing seven cmpnents: Wrld Health Organizatin (WHO) and Natinal Respiratry and Enteric Virus Surveillance System (NREVSS) Cllabrating Labratries: Abut 75 WHO and 50 NREVSS cllabrating labratries lcated thrughut the United States reprt the ttal number f respiratry specimens tested and the number psitive fr influenza types A and B each week. Sme f the influenza viruses cllected by labratries are sent t CDC fr mre testing. U.S. Influenza Sentinel Prviders Surveillance Netwrk: Each week, apprximately 1,000 health-care prviders arund the cuntry reprt the ttal number f patients seen and the number f thse patients with influenza-like illness (ILI) by age grup. Fr this system, ILI is defined as fever (temperature f >100 F) plus either a cugh r a sre thrat. 122 Cities Mrtality Reprting System: Each week, the vital statistics ffices f 122 cities reprt the ttal number f death certificates filed and the number f thse fr which pneumnia r influenza was listed as the underlying r as a cntributing cause f death. The percentage f all deaths due t pneumnia and influenza are cmpared with a baseline and epidemic threshld value calculated fr each week. State and Territrial Epidemilgists Reprts: State health departments reprt the estimated level f influenza activity in their states each week. States reprt influenza activity as n activity, spradic, lcal, reginal, r widespread. Influenza-assciated pediatric mrtality: Influenza-assciated pediatric mrtality is a newly added natinally ntifiable cnditin. Labratry-cnfirmed influenza-assciated deaths in children <18 years ld are reprted thrugh the Natinally Ntifiable Disease Surveillance System. Emerging Infectins Prgram (EIP): The EIP Influenza Prject cnducts surveillance fr labratry-cnfirmed influenza related hspitalizatins in persns <18 years in 57 cunties cvering 11 metrplitan areas f 10 states. Cases are identified by reviewing hspital, labratry, and admissin databases and infectin cntrl lgs fr children with a dcumented psitive influenza test (culture, DFA/IFA, PCR, r a rapid test) cnducted as a part f rutine patient care. New Vaccine Surveillance Netwrk (NVSN): The New Vaccine Surveillance Netwrk (NVSN) prvides ppulatin-based estimates f labratry-cnfirmed influenza hspitalizatin rates fr children <5 years ld residing in 3 cunties (Hamiltn Cunty OH, Davidsn Cunty TN, and Mnre Cunty NY). Children admitted t NVSN hspitals with fever r respiratry symptms are prspectively enrlled and respiratry samples are cllected and tested by viral culture and RT-PCR. NVSN estimated rates are reprted every 2 weeks. Tgether, the seven influenza surveillance cmpnents are designed t prvide a natinal picture f influenza activity. Pneumnia and influenza mrtality is reprted n a natinal level nly. Sentinel physician and labratry data are reprted n a natinal level and by influenza surveillance regin. The state and territrial epidemilgists' reprts f influenza activity are the nly state-level infrmatin reprted. Bth the EIP and NVSN data prvide ppulatin-based, 2

3 labratry-cnfirmed estimates f influenza-related pediatric hspitalizatins but are reprted frm limited gegraphic areas. In February 2004, fllwing reprts f human infectins with avian influenza A (H5N1) virus in Asia, CDC issued a natinal advisry recmmending enhanced surveillance and labratry diagnstic criteria. The interim guidance is intended t target ptential at-risk persns, including travelers entering the United States frm H5N1-affected cuntries (e.g., Vietnam, Thailand, Cambdia, China). Patients with fever (temperature f 38 C [100.4 F] r greater), travel histry t an H5N1-affected cuntry, and histry f direct cntact with diseased, dead, r infected birds within 10 days f symptm nset can be cnsidered fr testing n a case-by-case basis, in cnsultatin with public health fficials. Influenza A (H5N1) is a select agent, and special labratry precautins shuld be bserved. Prcedures invlving islatin and live-virus wrk must be dne under cnditins f bisafety level 3 (BSL-3) with enhancements. RT-PCR assays can be dne in BSL-2 facilities. Training in RT-PCR testing fr state labratry persnnel has been cnducted at CDC, in cnjunctin with APHL. State labratries that cannt cnduct H5N1 testing can send specimens t CDC fr analysis. Results will usually be available within 24 hurs. Rapid Diagnstic Tests fr Influenza: What the Clinical Labratry Shuld Knw Peter A. Shult, PhD, Wiscnsin State Labratry f Hygiene Clinical labratries are nw assuming a majr rle in the labratry diagnsis f influenza. Fr a subset f these labratries this rle is carried ut using the mre traditinal methds f influenza diagnsis: virus culture, antigen detectin by immunflurescence, and PCR. Mre and mre labratries, hwever, are emplying ne f an ever-expanding variety f rapid antigen detectin (basically EIA r EIA-like tests) methds that enable the rapid labratry diagnsis f influenza, ften within a half hur. There are nw 13 kits capable f detecting: influenza A virus nly, bth influenza A r B withut identifying the type, bth influenza A r B and identifying the type Currently, nne f the FDA-cleared tests can differentiate influenza A subtypes. Mrever, since a number f these kits have waived CLIA status, they can be perfrmed in nn-labratry (nntraditinal) settings. In fact, it is my experience (at least in Wiscnsin) that the vast majrity f these kits are being emplyed in these settings (POs, nursing hmes, emergency rms, Urgent care ffices). The ptential impact f these tests in clinical practice is bvius. Less bvius perhaps is the impact these diagnstic tests may have n public health respnse bth t seasnal influenza (i.e., ur annual influenza epidemic) and t emergence f nvel strains which have the ptential t cause the next pandemic. In this cntext then, the bjectives here are t: Review briefly the advantages f and cncerns with these rapid diagnstic methds, Suggest hw the cncerns might be addressed t ptimize test perfrmance and results interpretatin and, mst imprtantly, 3

4 Suggest thrughut the talk hw the PHL can be a resurce fr helping ptimize the use f these tests and prvide critical linkage between the testing sites and CDC s influenza surveillance and respnse effrts (fr bth seasnal and nvel, ptentially pandemic strains f influenza).. Suggested advantages f these rapid diagnstic tests are clear and bvius: Easy t perfrm; little expertise required Prvide widespread testing utside f typical labratry realm Rapid turn arund time T aid diagnsis and patient management guide patient treatment decisin (antivirals/antibitics) in a clinically relevant timeframe enable infectin cntrl measures t prevent transmissin in health care and ther institutinal r particular cmmunity setting Relatively inexpensive Hwever, I want t really fcus n sme f the imprtant cncerns in the use f these tests and hw these cncerns might be addressed: Perfrmance limitatins Prblem: Lw sensitivities reprted with sme kits Data frm kit inserts and Uyeki TM. Pediatr Infect Dis J 2003; 22: Nt a lt f cmparative data; difficult t cmpare acrss studies r kit inserts Median sensitivity f 70-75% when cmpared with cell culture r IF. Anticipate lwer when cmparing t RT-PCR Reasns related t: inherent test limitatins specimen type (especially use f thrat swabs; naspharyngeal specimens especially aspirates/washes are ptimal) specimen quality (when specimen taken, hw taken, hw handled as with any test) age f patient (better perfrmance in children wh shed mre virus fr lnger perid) Perfrmance cncerns with detectin f nvel strains (e.g., H5N1) where preliminary reprts f pr sensitivity cmpared with PCR and culture. Related t different virus shedding patterns? This nt fr certain yet. On the ther hand, specificities have been reprted t be quite gd, in general 90-95% Slutins: Make better kits, chse best kit, cntrl specimen quality (type, timing and technique) Prblem: Predictive Values (Nte: Refer t discussin f this in Appendix 6 f Supplement 2 [Labratry Diagnstics] f the HHS Pandemic Plan) Predictive value is the prbability f the presence r absence f disease given the results f the test Dependent n test perfrmance characteristics(sensitivity and specificity) and prevalence (current level f activity in the cmmunity. Ging thrugh simple mathematical analyses will demnstrate this. Predictive Value Psitive - dependent upn test specificity 4

5 Despite gd specificity, very pr PVP (false psitives) during perids f lw prevalence (i.e., early r ff-seasn testing) in a typical flu seasn (unfrtunately when many want t use these tests). Culd cause cnsiderable prblems fr public health respnse if used during perid f likely very lw prevalence just fllwing emergence f a nvel subtype when cncerns with pandemic ptential wuld be heightened. Last thing we d need is false psitive results! PVP, hwever, will imprve cnsiderably when these kits are used during perids f high flu prevalence (near the epidemic peak) Predictive Value Negative dependent upn test sensitivity With the relatively pr sensitivity (discussed abve), the PVN (false negatives) will pse a prblem the clser we get t peak influenza activity. This f particular cncern given the likely reliance n these test results fr treatment f patients with antivirals, bth during seasnal influenza r if a nvel subtype emerges and demnstrates sustained human-t-human transmissin in the human ppulatin PVN, hwever, is very gd, early in the flu seasn r ff-seasn During this perid we shuld recgnize the value f negative results (e.g., in an institutinal setting experiencing ut break f severe respiratry disease) Rapid test results need t be interpreted in the cntext f the patients clinical presentatin and the current influenza epidemilgical picture. Slutins: Use f these tests can be ptimized by Educate clinicians n PVs and limitatins f test results Cnfirm early, late and ut-f-seasn psitives Cnfirm peak-seasn negatives if warranted Use prevalence indicatrs t decide: When t test When t qualify result When t cnfirm result NOTE: Rle fr the PHL: training, cnfirmatry testing, surveillance data Bisafety cncerns Prblem: A secnd area f cncern is Bisafety. Why is this? Cntinuus emergence f new threats (SARS, avian flu, H2N2) Use f tests by nn-labratrians withut sufficient knwledge f r regard t BSL Even fr labratrians it is cnvenient t perfrm test utside f BSC r utside f nrmal BSL-2 prtcls; lack f BSCs Ptential aersl generating steps Slutin: Clinical labs and POC testing sites need t re-think bisafety in age f EIDs fr all diagnstic testing. Need fr risk assessment prir t specimen cllectin and testing and cnvey this infrmatin t the labratry Travel Hx, expsure Hx, pathgenicity, rute f Tx, infectius dse, etc (Get slide) Enhance cmmunicatin with ID Drs., Infectin Cntrl Strategies t enhance Bisafety in lab, testing sites Use f BSCs, PPE and r barriers, sequestering wrk, 5

6 Fr labs, pwer f strict BSL-2 practices Specimen referral t higher bicntainment Need fr basic training particularly fr nn-labratrians Testing kit supplies Prblem: Reprts f supply disruptins during recent influenza seasns. Near certainty this wuld ccur with emergence and sustained transmissin f nvel influenza subtype Slutin: N easy slutin. Perhaps maintain adequate stckpile and perhaps cnsider evaluatin/validatin f different kits Lss f surveillance data and viral islates needed fr further characterizatin Prblem: With widespread rapid testing and diversin f testing frm PHL, ptential lss f testing data (in many states influenza is nt reprtable) and, mre imprtantly, ptential lss f fllw-up testing and characterizatin f virus islates necessary fr: fr mnitring influenza A subtypes and strains circulating in the U.S detecting nvel influenza A subtypes fr strain analysis needed fr annual vaccine selectin mnitring ptential emergence f resistance t antiviral drugs Slutin: State PHL shuld lead develpment f labratry and ther testing site netwrks and these testing sites shuld seriusly cnsider participatin fr the purpses f: Cllectin f influenza diagnstic testing data Number f specimens tested/week; number and ID f psitives Acquisitin and further testing (by culture r PCR) f patient specimens fr : cnfirming rapid test results btaining influenza islates fr further characterizatin (see abve)at PHL r CDC Identifying which ther pathgens may be invlved PHLs may be in a unique psitin t carry ut these activities due t: Histrical participatin f many(mst) state PHLs as W.H.O. Cllabrating Labratries fr influenza surveillance(reference testing, seasnal influenza and nvel strain surveillance, antiviral susceptibility) State PHL are designated lead LRN Reference labs within each state and funded t: Build a Sentinel Lab netwrk fr respnse t BT and ther public health threats Develp r expand state-f-the-art diagnstic capabilities and capacities Develp and maintain curier system Prvide labratry-based training pprtunities Emergency cmmunicatin systems PHL histrical rle as clse cllabratr with and liaisn t CDC in diagnstic testing and utbreak respnse matters The PHL can and shuld be the clinical lab s mst apprpriate link t CDC and best immediate surce fr cnsultatin during utbreaks f influenza r ther public health emergency. Selected references: 6

7 HHS Pandemic Influenza Respnse Plan: FDA article entitled Cautins in Using Rapid Tests fr Detecting Influenza A Viruses: Uyeki TM: Pediatr Infect Dis J 2003;22: What Are State and CDC Rles in Public Health Respnse? Niranjan Bhat, MD, Influenza Branch, CDC The purpse f this talk is t reinfrce and build upn pints made by previus tw speakers. Case definitin Case definitin means required features that shuld trigger H5-specific testing f a patient Als leads t initiatin f bisafety measures in lab, public health investigatin, clinical management including infectin cntrl and presumptive treatment Must be specific enugh t limit number f evaluatins e.g., fld f cases after first H5 cases identified in US, r a cluster f suspected cases Clinical labs will be flded with specimens frm patients with human influenza, ther resp viral diseases that may be cncurrently circulating, substantial numbers f wrried well Even nw, when numbers are small, imprtant t save resurces Clinical labs must use case definitin t priritize specimens, initiate bisafety prcedures, encurage/educate prviders t use Case definitin must emphasize the fllwing returned traveler frm an H5N1-affected cuntry an influenza-like illness (dcumented fever + respiratry symptms) a severe illness (hspitalizatin, pneumnia) an expsure (cntact with pultry r suspect human case) Case definitin is nt rigid; fr example, wuld cnsider testing if: severely ill, but can't get an expsure histry mild illness, but strng expsure histry Cmpnents f case definitin are subject t change as we learn mre spectrum f disease may include mild frms, r nn-respiratry illness new animals may be risk factrs may becme unassciated with animal utbreaks must keep up t date with the CDC s website Rle f public health labratries Frm ur perspective, imprtant t invlve public health agencies asap t: advise n testing and management initiate public health investigatins and cntrl f ptential spread interact with the media and public cncern We wuld therefre encurage prviders t send specimens directly t state public health lab, but recgnize: prviders may prefer their affiliated clinical lab 7

8 suspicin f H5N1 may develp after specimens are sent Frm a prvider's pint f view, return f results is cmparable if state PH lab is nly a few hurs' drive away therwise, vernight delivery t state r CDC lab cmmercial labs ften ship vernight t a single lcatin upn arrival, RT-PCR testing may nly take a few hurs incnclusive/discrdant results may lead t re-testing and delays, but this culd and shuld happen in bth cmmercial and public health labs State health departments are in the best psitin t manage suspect H5N1 investigatins majrity f state labs have RT-PCR capacity and training if unable r truble interpreting, can frward t CDC vernight state epidemilgists are able t mbilize lcal resurces State health departments and CDC prvide technical assistance n: lab technique and interpretatin f results verificatin and cnfirmatin f results epidemilgic/public health investigatins advice n clinical management, infectin cntrl cmmunicatin with clinicians, labratries, public health cmmunity, media, plicy-makers, dmestic and internatinal public serve as central clearinghuse fr infrmatin n: current gegraphy, clinical spectrum, and transmissibility f H5N1 cmmunicatin is a 2-way interactin - PH can learn frm the clinical labs Pitfalls and pints t cnsider please cmmunicate ptential psitive results t bth the state public health lab and the state cmmunicable diseases epidemilgists - therwise, mre cmplicated chain f cmmunicatin please cntact public health befre media is alerted (prvider and patient must be cautined abut this) H5N1 is a mving target CDC keeps up with evlving strains CDC supprts sharing f diagnstic testing infrmatin with clinical labratries, but capacity is limited fr prviding individual technical assistance testing fr H5N1 is a big respnsibility fr a labratry bisafety prcedures quality cntrl pst-expsure mnitring and management f emplyees Questins and Answers Nte: Respnses t questins raised during and after the LOCS cnference call are intended t prvide immediate infrmatin abut what is knwn at the time. Hwever, the answers have nt been reviewed and cleared and d nt necessarily reflect the fficial views f CDC and HHS. Q. Can yu prvide mre infrmatin abut COCA? 8

9 A. CDC s Clinician Outreach Cmmunicatin Activity (COCA) has established partnerships with natinal clinician rganizatins fr the purpse f timely cmmunicatin f infrmatin n disease utbreaks and terrrism events. Cnference calls are cnducted n a regular basis. Fr mre infrmatin, see the COCA website at Q. Regarding rapid diagnstic tests: why they are less sensitive t influenza H5 than t influenza A H1 r H3? A. The primary reasn appears t be lwer viral lad. Q. Why are cnsensus sequence data available nly t public health labratries? A. CDC receives human samples under a variety f stipulatins and restrictins, including requirements that infrmatin first be released t the submitting cuntry. Cuntries submitting material t CDC fr testing frequently d nt agree t release f sequence data. Q. Clinical labratry staff have an imprtant rle in public health respnse, as indicated during tday s presentatins. Will CDC recmmend that labratry wrkers be included in pririty grups fr vaccinatin? A. The develpment f recmmendatins fr vaccine pririty grups in an pen, nging, and cllabrative prcess. CDC prgram persnnel cnsult with ther subject matter experts in cnsidering a wide range f factrs related t establishing pririty grups. After thrugh deliberatins, decisins are made by the Advisry Cmmittee n Immunizatin Practices. Q. Which state public health labs are currently receiving samples and able t type them fr H5N1? A. Accrding t APHL estimates, apprximately 60 state and lcal (cunty and large city) labratries have the ability t test fr H5. Q. If independent academic r reference labratries receive a psitive test result fr H5N1, shuld that result (and sample) g t the state lab (fr cnsultatin and cnfirmatin) befre reprting t a physician? A. Yes, under these circumstances the result and sample shuld be sent t the state lab r CDC fr cnfirmatin befre reprting t a physician r ther care giver. Q. Hw discrdant have different mlecular identificatin methds been fr H5N1? A. Except fr technical differences, different methds are using different sequence databases, which may be incmplete r nt up-t-date. This means that sme test prtcls may miss sme grups f viruses. Q. Why can't the CDC primer set be shared (nt the sequence data frm partner cuntries that may have been fundatinal fr their design)? 9

10 A. There are legal issues related t this. CDC has been wrking with FDA t btain clearance fr the CDC real-time RT-PCR assay fr identificatin f influenza A H5 (Asian lineage). When apprved, the reagents will be available fr LRN-designated labratries natinwide. (Nte: FDA cleared the assay n February 3, See ) Q. D H5N1 mlecular typing requests t state labs require a signed cnsent (similar t SARS)? A. After the test has been cleared by FDA, the cnsent frm will nt be needed. Q. Other than web sites, wh can we cntact fr specific infrmatin n H5N1 labratry diagnstics? A. H5N1 labratry testing is a rapidly develping and changing tpic. Technical infrmatin can be btained in articles published in scientific jurnals. Q. What test material is available fr H5N1 mlecular test validatin? Will updated test materials becme available t accmmdate the need t detect evlving H5N1 strains? A. See belw fr infrmatin regarding the availability f the inactivated influenza A/H5 virus frm which H5 psitive cntrl RNA can be islated and used in PCR r real-time PCR. The evlutin f H5 viruses may require mdificatin f the real-time PCR prtcl and, if necessary, f the psitive cntrl sample. CDC perfrms enhanced surveillance and fllws up the evlutin f H5 viruses and will make necessary mdificatins when needed. The inactivated influenza A/H5 cntrl material fr RT-PCR testing f avian influenza (A) H5N1 (Asian lineage) is currently available t U.S. public health labratries at n charge and is available t internatinal gvernment labratries at n charge. The influenza A/H5 cntrl material als is available t all cmmercial scientific and manufacturing entities in the United States and internatinally. Due t limited supply and high demand, labratries initially will be restricted t ne vial. Each vial cntains 500 ul f cntrl material that shuld prvide enugh RNA fr apprximately 1,000 reactins. Requests fr additinal material will be cnsidered n a case-by-case basis. T btain the cntrl material, please fllw the prcedure utlined belw. When placing an rder, prvide the catalg number (i.e., VA ) and descriptin f the prduct [i.e., influenza A (H5N1) (Asian lineage) real-time RT-PCR cntrl]. The number f vials is limited t ne per rder. The rder shuld be written n the facility's letterhead. Prvide a cmplete mailing address and phne number fr shipping. The requesting fficial shuld prvide his name and title. The rder must be sent t CDC (ATTN: Avian flu cntrl material, "NCID/SRP" via fax ( )). ORDERS WILL NOT BE ACCEPTED. Allw 10 business days fr delivery. Shipments are sent ut t arrive during the same business week; therefre, rders placed late in the week r befre a hliday will nt be shipped until the fllwing week. 10