Hepatitis E: Canada welcomes the world

the world C ASE RE PORTS PRE SENTED IN THIS IS SUE OF THE JOUR NAL rep re sent the first docu mented cases of hepa ti tis E in Can ada (pages 3437 and 3941). Glob ally, the ex is tence of en teri cally trans mit ted non-A, non-B hepa ti tis has been rec og nized for many years and ac counts for over 50% of acute hepa ti tis in de vel op ing na tions (1,2). Usual he pa to tropic vi ruses were not found to cause this dis ease and the term vi ral hepa ti tis type E (HEV) was coined. Al though stud ies in non hu man pri mates failed to yield a cul turable patho gen, elec tron mi cros copy of stool sam ples re vealed the pres ence of viruslike par ti cles (1). Other stud ies sug gested that HEV was due to an RNA vi rus, and iso la tion of vi ral com ple men tary DNA clones led to dem on stra tion of vi ral RNA ge nomes in in fected sub jects (3,4). Sub se quent analy sis dem on strated that HEV is a 27 to 32 nm nonen vel oped vi rus with a singlestrand posi tive sense poly adeny lated RNA ge nome rep re sen ta tive of a new fam ily of he pa to tropic vi ruses. With the use of re com bi nant pro teins from ex pres sion vec tors, di ag nos tic tests ca pa ble of iden ti fy ing hepa ti tis E in fec tion were de vel oped and con firmed that a sin gle agent, HEV (still un cul tured), was re spon si ble for the ma jor ity of non-A, non-B acute hepa ti tis out breaks in de vel op ing coun tries. Mo lecu lar bi ol ogy tech niques could be used to de tect vi ral ge nomes in liver tis sue, se rum and stool dur ing the ill ness. These tech niques should al low bet ter char ac teri za tion of the natu ral his tory of HEV in fec tion (1). The clini cal and epi de mi ol ogi cal fea tures of HEV have re cently been re viewed (1,2). Es ti mates sug gest that up to 2 mil lion cases oc cur yearly in the In dian sub con ti nent. HEV causes large epi dem ics of acute selflimited icteric hepa ti tis of ten linked to in ges tion of con tami nated wa ter. More re cent data sug gest that HEV is also a com mon cause of spo radic hepa ti tis in de vel op ing coun tries, es pe cially in chil dren. Se ro preva lence for HEV an ti bod ies can ap proach 25% in chil dren from en demic ar eas de spite less fre quent icteric hepa ti tis (5). Per son to per son trans mis sion is less well char ac ter ized but may be re spon si ble for some cases of HEV (2). Icteric HEV pres ents clini cally as a typi cal acute vi ral hepa ti tis with pro dro mal and icteric phases. Pa tients with icteric HEV tend to be older (15 to 40 years of age ver sus less than 10 years of age), have longer in cu ba tion pe ri ods (mean 40 days ver sus 30 days) and higher case fa tal ity rates (0.5 to 4% ver sus 0.1 to 2.7%) than pa tients with hepa ti tis A vi rus from simi lar geo graphic ar eas. HEV is also re spon si ble for many cases of ful mi nant hepa ti tis in en demic re gions. Preg nant fe males ap pear to be par ticu larly sus cep ti ble to HEV, es pe cially when ac quired in the third tri mes ter. Ful mi nant hepa ti tis (over 30% of HEV in fec tions in some stud ies) and high case fa tal ity rates (up to 20%) oc cur in this pa tient popu la tion, the ba sis of which re mains un clear. Liver bi opsy changes of cho lesta sis oc cur with greater fre quency than in hepa ti tis A (at least 50% of cases) but patho logi cal find ings are oth er wise typi cal of acute vi ral hepa ti tis (1). Loss of de tect able vi ral ge nomes in tis sue, se rum and stool par al lels clini cal reso lu tion of hepa ti tis and re turn of liver his tol ogy to nor mal. Treat ment is purely sup por tive and chronic hepa ti tis does not oc cur. Test ing for hepa ti tis E ex po sure and ac tive in fec tion has im proved sub stan tially in re cent years (1,5-7). Polymerase chain re ac tion (PCR) analy sis for HEV ge nomes in se rum, stool and liver tis sue has sup planted evalua tion of the stool by elec tron mi cros copy as the de fini tive test for ac tive in fec tion (3,4,8). Un for tu nately, the avail abil ity of this test is lim ited to re search fa cili ties. Se ro logi cal tests for an ti bod ies to re com bi nant HEV pro teins are avail able at spe cial ized cen tres and are be ing used to clar ify the epi de mi ol ogi cal and clini cal fea tures of HEV (1,6,7). Both the en zyme im mu no as say (sen si tiv ity 78 to 100%) and im munoblot (sen si tiv ity 85 to 100%) tests are sen si tive for acute icteric HEV. Im mu no globu lin (Ig) M ti tres rise early and can be sus tained for over six months. The du ra tion of the IgG re sponse re mains in ques tion. Some stud ies sug gest that IgG re ac tiv ity di min ishes within a year of in fec tion (9). The speci fic ity of these an ti body tests is un cer tain. False posi tive se ro logi cal tests can oc cur in other forms of liver dis ease (8). This makes in ter pre ta tion of HEV preva lence data from de vel oped coun tries dif fi cult. No large scale study has com pared an ti body re ac tiv ity with PCR analy sis for HEV ge nomes in cases of sus pected HEV. The in abil ity to cul ture wildtype or at tenu ated HEV vi rus has im peded de vel op ment of a vac cine. Re cent re sults us ing re com bi nant pro teins in ex peri men tal ani mals are prom is ing (10). Im mu no globu lin pro phy laxis has yet to prove ef fec tive. Ade quate hy giene and avoid ance of con tami nated wa ter sources are the only pre ven tive meas ures avail able. Al though HEV rep re sents a ma jor health prob lem for de vel op ing na tions, it is not a ma jor clini cal prob lem in North Amer ica (1,7). Cases such as those pre sented in the Jour nal serve to em pha size the po ten tial for HEV ac qui si tion by North Ameri can trav el lers. Spo radic cases of hepa ti tis E have been re ported in de vel oped coun tries, most of ten in per sons re turn ing from en demic ar eas (11). Re cov ery is usual and re cent stud ies sug gest that HEV is not a ma jor cause of ful mi nant hepa ti tis or death from liver dis ease in the United States (and pre suma bly Can ada) (8). Se ro preva lence for HEV is low in the EDI TO RIAL

rep re sent the first docu mented cases of hepa ti tis E in Can ada (pages 34-37 and 39-41). Glob ally, the ex is tence of en teri cally trans mit ted non-A, non-B hepa ti tis has been recog nized for many years and ac counts for over 50% of acute hepa ti tis in de vel op ing na tions (1,2). Usual he pa to tropic viruses were not found to cause this dis ease and the term vi ral hepa ti tis type E (HEV) was coined. Al though stud ies in non human pri mates failed to yield a cul turable patho gen, elec tron mi cros copy of stool sam ples re vealed the pres ence of viruslike par ti cles (1). Other stud ies sug gested that HEV was due to an RNA vi rus, and iso la tion of vi ral com ple men tary DNA clones led to dem on stra tion of vi ral RNA ge nomes in in fected sub jects (3,4). Sub se quent analy sis dem on strated that HEV is a 27 to 32 nm nonen vel oped vi rus with a single-strand posi tive sense poly adeny lated RNA ge nome rep re sen ta tive of a new fam ily of he pa to tropic vi ruses. With the use of re com bi nant pro teins from ex pres sion vec tors, di ag nos tic tests ca pa ble of iden ti fying hepa ti tis E in fec tion were de vel oped and con firmed that a sin gle agent, HEV (still un cul tured), was re spon si ble for the ma jor ity of non-A, non-B acute hepa ti tis out breaks in de velop ing coun tries. Mo lecu lar bi ol ogy tech niques could be used to de tect vi ral ge nomes in liver tis sue, se rum and stool dur ing the ill ness. These tech niques should al low bet ter char ac teriza tion of the natu ral his tory of HEV in fec tion (1).
The clini cal and epi de mi ol ogi cal fea tures of HEV have recently been re viewed (1,2). Es ti mates sug gest that up to 2 mil lion cases oc cur yearly in the In dian sub con ti nent. HEV causes large epi dem ics of acute self-limited icteric hepa ti tis of ten linked to in ges tion of con tami nated wa ter. More re cent data sug gest that HEV is also a com mon cause of spo radic hepa ti tis in de vel op ing coun tries, es pe cially in chil dren. Se ropreva lence for HEV an ti bod ies can ap proach 25% in chil dren from en demic ar eas de spite less fre quent icteric hepa ti tis (5). Per son to per son trans mis sion is less well char ac ter ized but may be re spon si ble for some cases of HEV (2). Icteric HEV pres ents clini cally as a typi cal acute vi ral hepa ti tis with prodro mal and icteric phases. Pa tients with icteric HEV tend to be older (15 to 40 years of age ver sus less than 10 years of age), have longer in cu ba tion pe ri ods (mean 40 days ver sus 30 days) and higher case fa tal ity rates (0.5 to 4% ver sus 0.1 to 2.7%) than pa tients with hepa ti tis A vi rus from simi lar geographic ar eas. HEV is also re spon si ble for many cases of fulmi nant hepa ti tis in en demic re gions. Preg nant fe males ap pear to be par ticu larly sus cep ti ble to HEV, es pe cially when ac quired in the third tri mes ter. Ful mi nant hepa ti tis (over 30% of HEV in fec tions in some stud ies) and high case fa tal ity rates (up to 20%) oc cur in this pa tient popu la tion, the ba sis of which re mains un clear. Liver bi opsy changes of cho lesta sis oc cur with greater fre quency than in hepa ti tis A (at least 50% of cases) but patho logi cal find ings are oth er wise typi cal of acute vi ral hepa ti tis (1). Loss of de tect able vi ral ge nomes in tis sue, se rum and stool par al lels clini cal reso lu tion of hepa ti tis and re turn of liver his tol ogy to nor mal. Treat ment is purely sup portive and chronic hepa ti tis does not oc cur.
Test ing for hepa ti tis E ex po sure and ac tive in fec tion has im proved sub stan tially in re cent years (1,5-7). Polymerase chain re ac tion (PCR) analy sis for HEV ge nomes in se rum, stool and liver tis sue has sup planted evalua tion of the stool by electron mi cros copy as the de fini tive test for ac tive in fec tion (3,4,8). Un for tu nately, the avail abil ity of this test is lim ited to re search fa cili ties. Se ro logi cal tests for an ti bod ies to re com binant HEV pro teins are avail able at spe cial ized cen tres and are be ing used to clar ify the epi de mi ol ogi cal and clini cal fea tures of HEV (1,6,7). Both the en zyme im mu no as say (sen si tiv ity 78 to 100%) and im munoblot (sen si tiv ity 85 to 100%) tests are sen si tive for acute icteric HEV. Im mu no globu lin (Ig) M ti tres rise early and can be sus tained for over six months. The du ration of the IgG re sponse re mains in ques tion. Some stud ies sug gest that IgG re ac tiv ity di min ishes within a year of in fection (9). The speci fic ity of these an ti body tests is un cer tain. False posi tive se ro logi cal tests can oc cur in other forms of liver dis ease (8). This makes in ter pre ta tion of HEV preva lence data from de vel oped coun tries dif fi cult. No large scale study has com pared an ti body re ac tiv ity with PCR analy sis for HEV ge nomes in cases of sus pected HEV. The in abil ity to cul ture wild-type or at tenu ated HEV vi rus has im peded de vel op ment of a vac cine. Re cent re sults us ing re com bi nant pro teins in ex peri men tal ani mals are prom is ing (10). Im mu no globu lin pro phy laxis has yet to prove ef fec tive. Ade quate hy giene and avoid ance of con tami nated wa ter sources are the only pre ven tive meas ures avail able.
Al though HEV rep re sents a ma jor health prob lem for de velop ing na tions, it is not a ma jor clini cal prob lem in North America (1,7). Cases such as those pre sented in the Jour nal serve to em pha size the po ten tial for HEV ac qui si tion by North American trav el lers. Spo radic cases of hepa ti tis E have been reported in de vel oped coun tries, most of ten in per sons re turn ing from en demic ar eas (11). Re cov ery is usual and recent stud ies sug gest that HEV is not a ma jor cause of ful mi nant hepa ti tis or death from liver dis ease in the United States (and pre suma bly Can ada) (8). Se ro preva lence for HEV is low in the United States (less than 0.5%) and the pre dic tive value of posi tive tests for HEV in fec tion is un cer tain in this popu la tion (7). No com mon source out breaks have been re ported in the United States or Can ada. As such, the role of HEV in North Ameri can liver dis ease is likely to be neg li gi ble. How ever, one must note that large stud ies us ing sen si tive and spe cific assays for HEV are only now be ing ini ti ated. The patho gene sis and epi de mi ol ogy of this vi rus re main to be fully de fined. Prelimi nary re ports from Europe sug gest that up to 6% of acute non-A, non-B hepa ti tis pa tients have anti-HEV an ti bod ies and that travel to en demic ar eas is not al ways noted (12,13). These ob ser va tions, cou pled with the in creased scope and fre quency of global travel, may prove the op ti mis tic pre dictions re gard ing the im pact of HEV in North Amer ica in cor rect.
In sum mary, HEV is a novel he pa to tropic vi rus re spon si ble for the ma jor ity of en teri cally spread non-A, non-B hepa ti tis in de vel op ing coun tries and rep re sents a ma jor health con cern in these coun tries. HEV plays a lim ited role in clini cal liver disease in Can ada and the United States and, ex cept for sporadic cases, is un likely to rep re sent a ma jor health threat in these coun tries. Trav el lers to en demic ar eas should be advised to take sani tary pre cau tions to de crease the risk of acquir ing ei ther hepa ti tis E or hepa ti tis A. Preg nant fe males trav el ling to en demic ar eas should be es pe cially aware of the po ten tial risk. Given the lack of ef fec tive im mune globu lin prepa ra tions or vac cine, guar an tee ing ade quate sani tary con di tions is the only pro phy lac tic meas ure that de creases the risk of ac quir ing HEV. If this can not be guar an teed, then high risk pa tients should de lay travel un til well into the postpar tum pe riod. De vel op ing tech niques in mo lecu lar bi ol ogy and vi ral iden ti fi ca tion should im prove our epi de mi ol ogi cal and clini cal knowl edge base and hope fully will lead to de velop ment of an ef fec tive HEV vac cine.