Hepatitis A virus (HAV) infection contributes approximately

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1 Multiple Fctors Contribute to Positive Results for Heptitis A Virus Immunoglobulin M Antibody Adnn Altoom, MD, PhD; M. Qsim Ansri, MD; Jennifer Cuthbert, MD Context. In the United Sttes, successful vccintion progrm for heptitis A virus (HAV) infection hs decresed both its incidence nd the true positive rte for dignostic immunoglobulin M (IgM) ntibody to HAV in cute heptitis. Objective. To survey positive results of HAV IgM tests nd determine the effect of chnging ordering options. Design. We reviewed ll positive results for IgM ntibody to HAV between Jnury 2007 nd December Ptient demogrphics, clinicl history, nd lbortory dt were recorded nd the encounter, order, nd reson for test reviewed. Ech result ws ctegorized s indicting cute, recent, resolved, or indeterminte HAV infection. Results. A totl of tests were performed; 35 ptients hd 49 positive results. Most positive test results were ssocited with outptient visits nd were ordered in the ssessment of ptients with liver disese, but not clinicl cute heptitis. In the finl nlysis, 4 ptients hd cute heptitis A nd 20 individul ptients hd recent nd/or resolved heptitis. All but 1 of the remining 11 ptients hd nother estblished cuse of liver disese with positive IgM HAV ntibody test result; dt to determine cuslity were insufficient. The totl number of tests requested nnully decresed more thn 35% with the introduction of computerized physicin order entry. Conclusions. Current ssys for IgM HAV ntibodies re overused in the bsence of clinicl cute heptitis; future clinicl decision support my improve ptterns of order entry. Most ptients hve findings consistent with HAV exposure but not cute heptitis; dormnt virl infection my be continuing source of ntigen. (Arch Pthol Lb Med. 2013;137:90 95; doi: / rp oa) Heptitis A virus (HAV) infection contributes pproximtely hlf of the cliniclly pprent cses of cute virl heptitis in the United Sttes. 1 Since the introduction of sfe nd effective vccine nd its widespred doption, the ctul number of cses hs decresed to pproximtely 10% of the pek level. 2 Of prmount importnce, ny bon fide new dignosis of cute heptitis A hs public helth implictions. Cses re reported to the locl helth deprtments to identify possible common source of infection nd provide postexposure prophylxis to contcts of the index ptient. Testing for immunoglobulin (Ig) M ntibodies ginst HAV (IgM nti-hav) is the minsty of the serologic dignosis for cute heptitis A infection nd hs been highly sensitive nd specific. 3 5 The presence of ny detectble ntibody (totl nti-hav) plus the bsence of high-titer IgM-specific ntibodies is used to differentite between pst nd current infection. In the pst few yers, isolted reports hve documented n increse in the number of positive results for IgM nti-hav in ptients whose illnesses were not consistent with the cse definition of heptitis A in conjunction with the decrese in true incidence. 6 8 We conducted retrospective study to determine how commonly we my be encountering potentil flse-positive results fter noticing the occurrence of positive IgM nti- HAV test results in the bsence of clinicl findings suggesting cute virl heptitis. We explored possible underlying resons nd the effect of chnging ordering options. MATERIALS AND METHODS An institutionl review bord pproved retrospective medicl record nlysis for ll ptients with positive results for IgM nti- HAV ntibodies between Jnury 2007 nd December Ptients were identified by querying the lbortory informtion system (Cerner Millennium, Cerner Corportion, Knss City, Missouri) to generte the list of smples nd order type (individul test or group) ssocited with positive results. Results from internl nd externl qulity control ssessments were excluded. Dt Collection Ptient demogrphics, clinicl history, nd lbortory dt were obtined through review of electronic nd pper medicl records. Ptient ge, sex, nd rce/ethnicity were recorded for ech ptient. Lbortory dt included test results for bilirubin, sprtte minotrnsferse (AST), lnine minotrnsferse (ALT), ll virl heptitis serologic ssys, rheumtoid fctor, nd humn immunodeficiency virus ntibody t the time of dignosis. Accepted for publiction Mrch 30, From the Deprtment of Pthology, University of Texs Southwestern Medicl Center, Dlls. The uthors hve no relevnt finncil interest in the products or compnies described in this rticle. Reprints: M. Qsim Ansri, MD, Deprtment of Pthology, University of Texs Southwestern Medicl School, 5323 Hrry Hines Blvd, Dlls, TX (e-mil: qsim.nsri@utsouthwestern. edu). Test Ordering Test order informtion ws obtined from the electronic medicl record nd from review of pper medicl records. The ordering 90 Arch Pthol Lb Med Vol 137, Jnury 2013 IgM Anti-HAV Testing in the 21st Century Altoom et l

2 Number of positive test results for heptitis A virus (HAV) immunoglobulin M (IgM) for ech yer in the period, nd method of test ordering. Abbrevitions: CPOE, computerized physicin order entry; ED, emergency deprtment. user, ordering provider, reson for test, nd ny ssocited code from the Interntionl Clssifiction of Diseses-Ninth Revision were recorded for ech positive test result. Until 2009, ll orders were hnd-written by providers or conveyed s telephone order to uthorized stff nd then entered into the electronic medicl record by clerks (Figure). For outptients, the serologic tests for virl heptitis were together in 1 section on pper order form. In 2007, there were 2 groups of heptitis tests, s well s individul tests. The groups consisted of cute heptitis serology tests (IgM nti-hav, heptitis B surfce ntigen, totl nti heptitis B core with reflex IgM if positive, nti heptitis C virus) nd chronic heptitis serology tests (heptitis B surfce ntigen, totl nti heptitis B core, nd nti heptitis C virus). Pper forms contined n individul check box for IgM HAV testing but did not contin check box for totl HAV ntibody. Strting in My 2008, ll IgM nti-hav tests were ordered individully. There ws only 1 group vilble: heptitis pnel (heptitis B surfce ntigen nd nti heptitis C virus), which did not include HAV testing. Providers lso hnd-wrote nonstndrd orders. These included heptitis lbs nd heptitis serologies. They were interpreted by order entry stff choosing from the vilble tests for clerk order entry. Strting in November 2008 nd continuing throughout 2009 nd 2010, computerized physicin order entry ws introduced to the hospitl system. Its implementtion in the Emergency Services Deprtment (November 2008) nd inptient res (lte April 2009) ws completed en bloc, wheres in outptient clinics, the process ws slow. Some outrech progrms re still using pper forms. IgM Anti-HAV Mesurements All ssys were performed with the VITROS nti-hav IgM ssy on the VITROS ECI System (Ortho-Clinicl Dignostics, Rochester, New York) tht uses the ntibody clss cpture technique nd chemiluminescence. Results were clculted s normlized signl reltive to the signl/cutoff (S/CO) vlue, with S/CO below 0.8 interpreted s negtive; S/CO of t lest 0.8 but below 1.2, s borderline; nd S/CO of 1.2 or bove, s positive. Dt Anlysis Definitions After review of ll vilble informtion, ech positive test result ws ssocited with specific dignostic ctegory. (1) Acute heptitis A: elevted minotrnsferse levels with pek vlue bove 500 U/L nd negtive serology test results for heptitis B nd heptitis C infections; (2) Recent cute heptitis A: elevted minotrnsferse levels with pek vlue below 500 U/L nd either evolving S/CO (positive to borderline or negtive) or resolving minotrnsferse vlues (norml AST level); (3) Resolved cute heptitis A: minotrnsferse levels norml; (4) Indeterminte: elevted minotrnsferse levels below 500 U/L; neither evolving S/CO nor resolution of bnorml minotrnsferse vlues. RESULTS Between Jnury 2007 nd December 2010, totl of IgM nti-hav tests were performed (Tble 1). The percentge of positive test results during this time period ws 0.5%; 35 individul ptients tested positive for IgM nti- HAV. In ddition, 3 of the ptients hd borderline test result on blood tken 6 months previously (n ¼ 1) nd 1 or 13 dys lter (n ¼ 1 ech). The men ge of the ptients ws 41 yers (medin, 43 yers; rnge, 9 81 yers); 20 of 35 were mle; 13 were blck, 14 were Hispnic, 6 were non-hispnic white, nd 1 ws Asin. A totl of 49 seprte tests hd positive results. Eight ptients hd 2 or more positive test results, of which 2 were indvertent duplicte orders during single hospitl dmission. One ptient hd 5 positive test results, 3 ptients hd 3 positive test results, wheres the reminder hd 2 positive results. Signl/cutoff results for the 2 duplicte orders were essentilly identicl (S/CO of 2.70 nd 7.02, compred with 2.44 nd 6.95, respectively). The demogrphic, lbortory, nd ssy dt re shown in Tble 2 for ech dignostic ctegory of HAV. Tble 1. Results of Heptitis A Immunoglobulin M Tests Ech Yer in Period Yer Totl Positive Low Level Borderline Negtive Totl Signl/cutoff,1.95. Arch Pthol Lb Med Vol. 137, Jnury 2013 IgM Anti-HAV Testing in the 21st Century Altoom et l 91

3 Tble 2. Demogrphic, Lbortory, nd Assy Dt for 37 Positive Results for Heptitis A Virus (HAV) Immunoglobulin M Acute HAV (n ¼ 4) Recent HAV (n ¼ 8 ) Prmeter Men Medin Rnge Men Medin Rnge Age AST ALT Bilirubin S/CO Abbrevitions: ALT, lnine minotrnsferse; AST, sprtte minotrnsferse; S/CO, signl/cutoff vlue. Two subjects pper twice, in both recent HAV nd resolved HAV infection. In 2008, the highest number of positive tests (n ¼ 21) ws obtined. This included 1 ptient with clssicl cute heptitis, 1 ptient with prior symptoms consistent with cute heptitis, 2 ptients (3 tests) with potentil flsepositive results (Tble 3), nd 10 low-level positive results. In Dlls County, few more cses of cute heptitis A were reported in 2008 (n ¼ 46) thn in 2007 (n ¼ 42) or 2009 (n ¼ 40), potentilly leding to greter number of positive results. The order-ssocited dt for the 49 encounters with the 35 ptients re depicted in Tble 4. Between 2007 nd 2008, orders were initilly written on pper by providers nd entered into the electronic medicl record by clericl stff (Figure). In 3 instnces, no order ws found in the medicl record in ssocition with the encounter informtion. The commonest encounter site ws n outptient clinic (33 of 49, 67%). More thn hlf of the orders (26 of 49, 53%) were either cute heptitis serology tests or the individul test. When the individul test ws ordered, ll providers lso ordered heptitis B nd heptitis C tests (dt not shown). In most instnces, the test ws ordered for either lbortory evidence of liver disese (elevted minotrnsferse level) or s repet fter n erlier positive result; together, these ccounted for 39 of 49 orders (80%). Liver Disese The results of liver tests tht re frequently bnorml in ptients with cute virl heptitis (minotrnsferses nd bilirubin) re shown in Tble 5 in ssocition with the reson for ordering the IgM nti-hav test. The pek vlues round the time of the initil test order re depicted. Four ptients hd minotrnsferse levels greter thn 500 U/L; they presented with jundice (n ¼ 3) or bdominl pin (n ¼ 1). Three of these ptients were hospitlized. For 11 ptients, ll test results were norml. The ptient who ws tested becuse of household exposure to n index cse hd norml AST nd bilirubin levels. Other Serologic nd Immunologic Mrkers Other immunologic test results re shown in Tble 3. All ptients were tested for heptitis B surfce ntigen nd heptitis C ntibody. One ptient ws confirmed positive for heptitis B surfce ntigen, wheres 2 hd flse-positive results. Three ptients hd flse-positive heptitis C virus ntibody result by enzyme-linked immunosorbent ssy. There were 8 other ptients with positive ntibody test result for heptitis C virus infection. Heptitis C viremi ws confirmed in 5 ptients, one of whom hd positive rheumtoid fctor. The other ptients with chronic heptitis C were not tested for rheumtoid fctor. Dignostic Anlysis Ptients were clssified s hving cute heptitis A, recent heptitis A, or resolved heptitis A by the combintion of pek minotrnsferse levels nd the chnge in minotrnsferse levels nd S/CO over time. We lso divided the cohort into 2 groups, by the bsolute S/CO vlue (Tble 6). The vlue of 1.90 ws used to divide the group into higher (n ¼ 26) nd lower (n ¼ 31) S/CO becuse this vlue ws below tht observed for ll ptients with symptoms, signs, nd lbortory test results consistent with cute heptitis. In the finl nlysis, cute heptitis A ws the dignosis for 4 ptients with 5 positive test results. Another 8 ptients (12 results) hd findings consistent with recent heptitis A, while 14 ptients (17 results) were clssified s hving resolved cute heptitis A. Of the ltter group, 2 were lso in the recent heptitis A group t n erlier time point. The finl 11 ptients (15 results) could not be clssified. All hd bnorml minotrnsferse levels nd 10 of 11 hd resons for heptic enzyme elevtion other thn heptitis A. The remining ptient, 38-yer-old homeless mn (S/CO, 1.36), hd no follow-up dt nd no lterntive dignosis. The findings in the 4 ptients with cute heptitis A were the sme s those reported previously from our institution. 5 The only difference between the pst period nd the present period ws the incidence. Between 1997 nd 1998, 13 ptients were hospitlized with cute heptitis A, s compred with 3 ptients during the pst 4 yers. COMMENT We found tht positive result for IgM ntibody to HAV is now reltively rre (0.5% of ll performed tests). Furthermore, only minority of ptients with positive result hve concomitnt clinicl dignosis of cute heptitis A (4 of 35, 11%). The number of ssys decresed with the bndonment of pper forms nd introduction of physicin order entry. However, even in 2010, more thn 2000 tests were ordered. With opertionliztion of clinicl decision support systems, decresing inpproprite test orders my be possible. One intriguing unnswered question is whether the persistence of IgM ntibody correltes with persistence of ntigen in cliniclly dormnt stte. While cute symptomtic heptitis A is now much rrer disese thn in the pst, it remins importnt to mke this dignosis, which hs significnt public helth implictions. Acute heptitis A infection is dignosed by the combintion of n pproprite clinicl presenttion nd lbortory testing with IgM nti-hav. 1,4,5,8,9 Possible explntions for positive results without clinicl cute heptitis include symptomtic infection, previous infection with persistent IgM ntibodies, cross-recting ntibodies, or commercil 92 Arch Pthol Lb Med Vol 137, Jnury 2013 IgM Anti-HAV Testing in the 21st Century Altoom et l

4 Tble 2. Extended Resolved HAV (n ¼ 14 ) Indeterminte (n ¼ 11) Men Medin Rnge Men Medin Rnge kits with flsely low cutoff vlue. We found evidence supporting these scenrios. Clinicl Acute Heptitis The clssic IgM-specific ssy cquires dignostic sensitivity for cute heptitis A with substntil dilution of the originl serum or plsm smple. 3 Thus, the HAVAB-M (Abbott Lbortories, Abbott Prk, Illinois) rdioimmunossy introduced in 1981 diluted the smple 1: The current ssys use similr IgM ntibody cpture system, but detection of the ntibody is mde by enzyme-linked chemiluminescence or nother nonrdioctive method. Regrdless, smple dilution is criticl for dignosis of ptients with the symptoms nd signs of cute heptitis. 3 Occsionlly, dilution my result in n initilly negtive test result tht becomes positive dys or weeks lter The blnce between sensitivity (correctly identifying ll ptients with cute heptitis A) nd specificity (correctly excluding ll those without cute heptitis A) is chosen to llow optimum ssy performnce in defined clinicl setting, cute heptitis. Owing to the low levels of IgM ntibodies fter vccintion, commercilly vilble tests rrely detect these ntibodies 1,9 unless the smple dilution is decresed. 13 IgG ntibodies to HAV pper soon fter IgM, persist for yers fter infection, confer lifelong immunity, 1,5,9 nd re not mesured in the IgM-cpture technique. 3 In the United Sttes, IgG-specific HAV ntibody is not mesured seprtely; rther, ll clsses (IgM, IgG, nd IgA) re mesured in the totl HAV ntibody ssys. The smple is not similrly diluted, thereby gretly incresing the sensitivity of the ssy. Over time, the IgM component decreses but current clinicl ssys do not indicte the proportion of IgM Tble 3. Other Serologic nd Immunologic Test Results for Ptients With Positive Heptitis A Virus Immunoglobulin M Test Abnorml Result Abnorml, No. Heptitis A totl ntibody Positive 9/11 Heptitis B surfce ntigen Positive 1/35 Flse positive b 2/35 Heptitis C virus ntibody Positive 8/35 Flse positive c 3/35 Humn immunodeficiency Positive 2/16 virus ntibody Rheumtoid fctor Positive 1/4 One ptient tested negtively for totl heptitis A virus (HAV) ntibody 6 months before the positive immunoglobulin M (IgM) result; 1 ptient tested negtively for totl HAV ntibody simultneously with positive IgM result. b Not confirmed on neutrliztion. c Negtive recombinnt immunoblot ssy result; ptient lso hd flse-positive result for heptitis B surfce ntigen. in the totl. Reserch studies 14,15 hve shown the potentil for differentiting prior infection by ssessing IgG vidity, but such ssys re not commercilly vilble. Other Heptitis A Our finding of positive results for IgM-specific HAV ntibody in symptomtic infection nd recent infection is expected. IgM ntibodies will be produced regrdless of the disese severity. The pprent persistence of IgM-specific HAV ntibody in smll number of ptients fter the resolution of ll clinicl evidence of heptitis is well documented. 16,17 The ntibody levels in such ptients re generlly low, similr to some of the findings reported herein. In 2005, the Centers for Disese Control nd Prevention (CDC) reported n increse in the number of persons with positive serologic tests for cute heptitis A virus infection whose illness ws not consistent with the clinicl criteri of the heptitis A cse definition. 8 Dt from stte public helth officils in Connecticut (19 not consistent of 127 ¼ 15%) nd Alsk (10 not consistent of 37 ¼ 27%), s well s Tble 4. Encounter nd Order Informtion for Ptients With 49 Positive Results for Heptitis A Virus (HAV) Immunoglobulin M (IgM) Positive IgM nti-hav, Prmeter Options No. (%) Encounter Emergency deprtment 1 (2) Inptient 15 (31) Outptient 33 (67) Provider order Acute heptitis serology 7 (14) (n ¼ 49) tests (¼ group) HAV IgM 19 (39) HAV IgM nd totl 7 (14) Other stndrd tests 5 (10) Nonstndrd test 10 (20) Reson for test Symptoms nd signs b 7 (14) Exposure to HAV 1 (2) Liver disese c 17 (36) Other d 14 (29) Unknown e 10 (20) Other stndrd tests: chronic heptitis serology tests in 4 instnces nd heptitis B core IgM test in 1 instnce. Nonstndrd tests cnnot be selected nd were interpreted by the entering user from the hndwritten order ( Heptitis A core IgM, Heptitis lbs ). For 1 ptient, there ws no provider order in the record; the clerk ordered HAV IgM nd totl. b Jundice (n ¼ 4), bdominl pin (n ¼ 2), other gstrointestinl symptoms (n ¼ 1). All 7 ptients hd finl clinicl dignosis of either cute heptitis (sprtte minotrnsferse [AST].500 U/L) or recent heptitis A (AST,500 U/L). c Cirrhosis (n ¼ 2), heptitis C (n ¼ 2), heptitis B (n ¼ 1), elevted heptic enzymes (n ¼ 12). d Repet fter previous positive test (n ¼ 13), duplicte order (n ¼ 1). e Provider or clericl error (n ¼ 5), no note retrieved (n ¼ 2), homeless outrech (n ¼ 3). Arch Pthol Lb Med Vol. 137, Jnury 2013 IgM Anti-HAV Testing in the 21st Century Altoom et l 93

5 Tble 5. Levels of Liver Enzymes nd Bilirubin nd the Reson for Ordering Heptitis A Virus Immunoglobulin M Test Bilirubin, mg/dl AST, U/L Reson Men SD Medin Rnge Men SD Medin Rnge Symptoms nd signs (n ¼ 6) Abnorml enzymes (n ¼ 8) Chronic liver disese (n ¼ 7) Unknown (n ¼ 10) Reference rnge Abbrevitions: ALT, lnine minotrnsferse; AST, sprtte minotrnsferse. Femles: U/L nd mles: U/L for both AST nd ALT since mid the Sentinel Counties Study (87 not consistent of 140 ¼ 62%), were quoted. The positive results cme from different licensed IgM nti-hav tests (Connecticut, n ¼ 3 tests; Alsk, n ¼ 3 tests from 2 mnufcturers). An editoril 8 concluded tht IgM nti-hav testing should be restricted to persons with clinicl heptitis, not those with bnorml liver enzyme levels. The Kentucky Deprtment for Public Helth lso hd similr findings during 3-yer period. 7 There were 156 dignostic flse-positive results reported (156 of 269 ¼ 58%) in the bsence of cute heptitis, compred with 113 confirmed cses. Our dt provide not only numertor for IgM nti-hav positive results but lso unique denomintor, ll ordered tests. In ddition, the reson for ordering the test ws retrievble from the electronic helth record, dt not previously obtinble in the public helth studies. Only when IgM nti-hav tests were ordered for ptients with symptoms or signs suggesting cute heptitis ws the finl nlysis cute heptitis A. The percentge of ptients with cute disese (15%) is lower thn tht in the published literture. The likely explntion is tht the previous dt were pulled from public helth notifictions, not only from clinicl lbortories. Whether the persistence of IgM-specific ntibody is ssocited with persistent ntigen stimultion is uncler. In the report from the CDC, 8 the testing of IgM HAV ntibody positive specimens for HAV RNA yielded only 1 positive result from 25 persons with no symptoms of cute heptitis, compred with 34 positive results for HAV RNA in 51 symptomtic cses. 8 The single positive result ws ssocited with follow-up IgM nti-hav result tht ws negtive, implying recent symptomtic HAV. In heptitis B, IgM ntibody nd heptitis B virus DNA repper with ctivtion of dormnt virus ssocited with immune suppression. As with HAV, the dignostic ccurcy of IgM testing for cute heptitis B infection is dependent on smple dilution. IgM-clss ntibodies continue to be produced in chronic heptitis B infection lbeit usully t lower levels undetectble in the diluted smples. 18 Flse-Positive nd Low-Positive Results Rheumtoid fctor cn interfere with IgM nti-hav testing. 19 One ptient with chronic heptitis C hd high titer for rheumtoid fctor, which possibly interfered with the IgM nti-hav testing by bridging the cpture ntibody nd the signl ntibody, leding to flse-positive results. Chronic heptitis C in 7 other ptients, t lest 4 of whom were viremic, my lso be ssocited with rheumtoid fctor; they were not tested. The presence of flse-positive results from cross-rectivity with other ntigenic epitopes in the ssy is nother potentil explntion, prticulrly since flse-positive tests for heptitis B surfce ntigen nd heptitis C were encountered for 2 nd 3 ptients, respectively. Cross-rections mong virl heptitis ntibodies hve been reported previously. 20 Finlly, 1 ptient hd result tht ws either flse positive or the consequence of Tble 6. Finl Anlysis for 49 Positive Results With Heptitis A Virus (HAV) Immunoglobulin M Divided by Signl/Cutoff (S/CO) Vlue nd Liver Enzymes AST nd/or ALT, U/L Anlysis No Elevted (, 500) Norml % Higher S/CO (1.90) Acute heptitis A 5 31 Recent HAV 6 23 Resolved HAV 6 27 Indeterminte b 4 19 Interference? c 4 1 Lower S/CO (,1.90) Recent HAV 6 16 Resolved HAV Indeterminte d Interference? c 2 5 Abbrevitions: ALT, lnine minotrnsferse; AST, sprtte minotrnsferse. The lowest S/CO vlue for ptient with minotrnsferse levels.500 U/L ws The vlue 1.90 ws chosen to seprte the positive results into 2 nonoverlpping groups. b Other potentil cuses of elevted minotrnsferse levels: heptitis C (n ¼ 3), cirrhosis (n ¼ 1). One ptient hd totl Heptitis C Virus ntibody test performed simultneously; the result ws negtive, indicting probble flse-positive immunoglobulin M (IgM) result. c Rheumtoid fctor (n ¼ 1 ptient, 2 Heptitis C Virus IgM tests), flse-positive Heptitis B surfce ntigen test result (n ¼ 3 ptients, 4 Heptitis C Virus IgM tests), flse-positive Heptitis C Virus ntibody test result (n ¼ 2 ptients, 6 Heptitis C Virus IgM tests). d Other potentil cuses of elevted minotrnsferse levels: heptitis C (n ¼ 1), cirrhosis (n ¼ 5), other chronic liver disese (n ¼ 4), insufficient dt (n ¼ 1). 94 Arch Pthol Lb Med Vol 137, Jnury 2013 IgM Anti-HAV Testing in the 21st Century Altoom et l

6 Tble 5. Extended ALT, U/L Men SD Medin Rnge technicl error; this conclusion is bsed on the simultneous negtive totl HAV ntibody nd positive IgM ntibody results in more dilute smple. Simultneous mesurement of totl ntibody nd IgM cn be performed nd my prove to be beneficil in helping physicins correctly interpret HAV serology. In conclusion, positive results for IgM nti-hav testing hve multiple etiologies. Previous reports hve recommended tht clinicins limit lbortory testing for cute heptitis A infection to persons with clinicl findings typicl of heptitis A or to persons who hve been exposed to settings where HAV trnsmission is suspected. 6,8 However, n pproch trgeting individul providers my not result in decrese in the number of positive results for IgM nti- HAV in the bsence of cute heptitis. In contrst, system pproches, whereby clinicl decision support guides pproprite testing, my engineer chnge. Restricting orders to subset with cute heptitis (liver minotrnsferse levels.500 U/L) cn lso decrese the number of positive results for HAV IgM. New tests tht llow simultneous mesurement of totl ntibody nd the proportion of IgM my be the most useful ddition to the lbortory testing menu. References 1. Koff RS. Heptitis A. Lncet. 1998;351(9116): Centers for Disese Control nd Prevention (CDC), Division of Virl Heptitis. Heptitis A FAQs for helth professionls. HAV/HAVfq.htm. Accessed September 1, Decker RH, Koskowski SM, Vnderbilt AS, Ling CM, Chirez R, Overby LR. Dignosis of cute heptitis A by HAVAB-M, direct rdioimmunossy for IgM nti-hav. Am J Clin Pthol. 1981;76(2): Lemon SM. Type A virl heptitis: epidemiology, dignosis, nd prevention. Clin Chem. 1997;43(8, pt 2): Cuthbert JA. Heptitis A: old nd new. Clin Microbiol Rev. 2001;14(1): Cstrodle L, Fiore A, Schmidt T. Detection of immunoglobulin M ntibody to heptitis A virus in Alsk residents without other evidence of heptitis. Clin Infect Dis. 2005;41(9):e86 e Trkhshvili N, Thoroughmn D, Humbugh K. Positive heptitis A IgM test results mong persons without symptoms or risk-fctor history Kentucky, Infect Dis Clin Prct. 2007;15(4): Dembek Z, Hdler J, Cstrodle L, et l. Positive test results for cute heptitis A virus infection mong persons with no recent history of cute heptitis United Sttes, MMWR Morb Mortl Wkly Rep. 2005; 54(18): Ninn OV, Xi G, Vughn G, Mrgolis HS. Dignosis of heptitis A virus infection: moleculr pproch. Clin Microbiol Rev. 2006;19(1): Shin HP, Lee JI, Jung SW, Ch JM, Joo KR, Kng SY. Fctors for predicting positive results for nti-hav IgM retesting mong initilly seronegtive ptients. Dig Dis Sci. 2010;55(12): Petrov P, Nikolov A, Komitov R, et l. Acute heptitis A infection with negtive nti-hav IgM. In: Globl Heptitis A Meeting Progrm. 2007: Chkvetdze C, Mllet V, Gussec L, Hnnoun L, Pol S. Acute heptitis A virus infection without IgM ntibodies to heptitis A virus. Ann Intern Med. 2011; 154(7): Miller WJ, Clrk W, Hurni W, Kuter B, Schofield T, Nlin D. Sensitive ssys for heptitis A ntibodies. J Med Virol. 1993;41(3): Roque-Afonso AM, Grngeot-Keros L, Roquebert B, et l. Dignostic relevnce of immunoglobulin G vidity for heptitis A virus. J Clin Microbiol. 2004;42(11): Syhvong B, Rschck B, Smythe L, et l. The infective cuses of heptitis nd jundice mongst hospitlised ptients in Vientine, Los. Trns R Soc Trop Med Hyg. 2010;104(7): Liw YF, Yng CY, Chu CM, Hung MJ. Appernce nd persistence of heptitis A IgM ntibody in cute clinicl heptitis A observed in n outbrek. Infection. 1986;14(4): Ko HW, Ashcvi M, Redeker AG. The persistence of heptitis A IgM ntibody fter cute clinicl heptitis A. Heptology. 1984;4(5): Hoofngle JH. Rectivtion of heptitis B. Heptology. 2009;49(suppl 5): S156 S Scher RA, Peters SM, Bryn JA. Testing for virl heptitis: prctice prmeter. Am J Clin Pthol. 2000;113(1): Herremns M, Bkker J, Duizer E, et l. Use of serologicl ssys for dignosis of heptitis E virus genotype 1 nd 3 infections in setting of low endemicity. Clin Vccine Immunol. 2007;14(5): Arch Pthol Lb Med Vol. 137, Jnury 2013 IgM Anti-HAV Testing in the 21st Century Altoom et l 95