A prospective study of posttransfusion hepatitis in Taiwan

38

A prospective study of posttransfusion

Teh-Hong

Wang’, Jtn-Town

hepatitis in Taiwan

Wang’, Jaw-Town Lin’, Jin-Chuan Ding-Shinn Chen’

Sheu’, Juei-Low

Sung’ and

In a follow-up study of 6 months or more of two hundred and ninety-six patients who bad received blwd rransfusion, 37 (12.5%) developed acute paltransfusion hepatitis. Patients with posttransfusion hepatitis had significantly higher donor numbers and transfusion amounts than patients without hepatitis. Frequency was not relafed to the age, sex or hepatitis B carriage of recipients. There were no cases of fulminant hepatitis. Of 37 patients with hepatitis, 36 were diagnosed as nonA, non-B hepatitis and one as hepatitis 5. Twenty-two (59.5%) of the 36 patients wifh non-A, non-8 hepatitis seroconvenrd to hepatiris C antibody. Two of these were positive for hepatitis C antibody before. transfusion and 12 were negative for bepatiris C antibody. Thirty-three of the 36 patients were followed-up for more than 6 months after the onset of hepatiris. Wbur 13 of the 33 patients recovered, the remaining 20 (60.6%) patients still had persistent liver test abnormalities 6 months after the onset of hepatitis. Seventeen (85%) of the 20 patients who developed chronic hepatitis were hepatitis C antibody positive. In contrast only four (30%) oi the 13 patients who recovered after acute hepatitis were positive for the hepatitis C antibody. Chronicity rate was not related to the patient’s sex, age, transfusion amount or donor number. Our rewhs suggesl a high frequency of posttransfusion’hepatitis C in Taiwan and that the infection has a high risk ofchronicity.

Posttransfusionhepatitis (F’TH) is a mejor problem associated with the use of blood and blood products. With the introduction of sensitive tests !o screen blood donors for the hepatitis B surface antigen (HEsAg) and with the exclusion of paid donors. the risk of PTH has declined but has not been ebminated (1). PTH remains a serious disease with a high chromcity rate. It may cause serious sequelae (2). Since rhere are no reports of prospective studies an PTH in Taiwan, where HBV infection is common (3). we conducted a prospective study at the National Taiwan University Hospital (NTUH) to invesrigate the incidence, epidemiology, etiology and clinical oufcome of posttransfusion hepatitis. Meanwhile, the recently deveioped antibody against hepatitis C virus (anti-HCV) by a recombicant DNA technology has greatly improved the

etiologic diagnosisof non-A, non-B hepatitis (NANBH) (4.5). We also adopted an enzyme-linked immunosorhant assay for anti-HCV, to explore the role of hepatitis rus (HCV) in our patients with PTH.

C vi-

Materials and Methods

Beginning in June ,987, we conducted a prospective study of PTH at the National Taiwan University Hospital. Patients who received blood transfusions in the hospha! and met the following criteria were included in this study: normal liver function tests before transfusion; no transfusion within the past year; no prrvious history of liver dis-

39 ease-including HBsAg carriers negative for hepatitis B e antigen (HBeAg) and antibody to hepatitis delta virus

North Chicago. lL), while IgM antKMV was tested by an ELISA test (Behringwerke AC, Marburg) and IgM

(anti-HDV); and no history of alcoholism, drug addiction, or exposure to hepatotoxic drugs. All patients gave mformed consent. A serum sample was obtained fr ,m each patient before transfusion. After transfos~on, the patxnts were followed-up every 1 or 2 weeks in the hrst 3 months sod every 2-4 weeks, 4-6 months after transfusion. Blood samples were taken during each follow-up visit. All serum samples were stored at -70 “C. Recipients were diagnosed PTH if (i) ALT exceeded 2.5-times the upper normal limits between l-26 weeks after transfusion at least twice one or more weeks apart. and (ii) other passible causes of elevated ALT such as biliary diseases, an-

anti-EBV was tested by an immunofluorescem assay (Gull Laboratories, Salt Lake City). Anti-HCV assay was performed wuh an enzyme-lmked immunosorbant assay (Onbo Dmgnosric Systems. Raritan) for the antibody to the gene product of HC”, Cloq-2 (5,6). Reacrive samples were repeated in duplicate. and were only considered

oxia, shock, congestive heart failure, alcohol. sepsis or administration of hepatotoxic drug were excluded. Liver biopsy was suggested when diagnosis was in doubt. Patients who had elevation of ALT for more than 6 months were defined as chronic mH if other ceo%s of persistent ALT elevation were exluded. Patients with PTH were seen every week in the acute stage. every month for 1 year and then every 3 months thereafter as long as possible. Liver biopsies were suggested in patients with chronic hepatitis. tnfections caused by hepatitis A virus (HAV). hepatitis B virus (HBV). Epstein-Barr virus WV) or cytomegalovirur (CM!!) were diagnosed by the prxence of I&4 antibody to HAV. IgM antibody to hepatitis B core antigen (IgM anti-HBc), or EBV or CMV in the acute stage, respectively. Hepatitis delta virus (HD’? infection was diagnosed by seroconvenion to anti-HDV. Hepatitis caused by NANB virus was diagnosed by exclusion of infection by the above viruses. Transfusion blood The blocd or blood products used for transfusion

in this

study were collected from volunteer donors by the Blood Donation Association, Republic of China. Donors were negative for HBrAg by an enzyme-linked immunosorbant assay (Evernew Biotech. Hsin-Chu, Taiwan) and serum &nine amiootranrferase (ALT) levels were ~45 W/I. Only plasma and whole blood was counted for plasma amount, however. in patients who received blood components such as platelet concentrate and packed red blood cells, all donors were taken into account for donor number.

ALT and aspartate aminotransferase (AST) werr masured in the Laboratory Department of the National Taiwan University Hospital (normal range: O-31 W/l for ALT) within 48 h of blood collection. HBsAp. anti-HBc. anti-HBs, anti-HDV, IgM anti-HAV, IgM anti-HBc werr measured by radioimmunoassays (Abbott Laboratones,

pooaitive if at lcast two of the three test determinations were reactwe All recipients were tested for liver tests including AST, ALT. albumin. prothrambin time, bilirubin, alkaline phosphatare and y-glutamyl transpeptidase. as weli ils HBsAg. am-HBs. anti-HBc and anti-HCV in the pretransfusion serum sample. Patients with elevated ALT after transfusion were tested for the afarmentioned liver tests and serologic viral markers (including HB markers, anti-HCV and IgM antibody to HAV. HBc, HDV. CMV and EBV) in rerial sampler after transfusion. Slarislicol ala7lySc Student’s ,-test and !be $-test were used

Re*“:tS Up until May 1990,409 transfused patients who met the criteria before transfusion were recruited. Two hoaIred and ninety-six of these patients completed the &month follow-up, 44 patients were lost in follow-up, 61 patients were followed-up for less than 6 months. and two patients who weot into shock after a surgical operation wexe excluded. Among the 296 patients, 253 received blood transfusions for open hean surgery. 18 for gastrointestinal bleeding

and 25 patients for chest or other surgeries.

The study group was compnaed of 162 men and 134 women with a mean age of 45.1 years (range: 17-73). Padents receivsd a mean transfusion of 7.2 units (range: 0.5-31) and had a mean of 14.7 dono;s (range: 1-S). Before transfcsiun, there were 35 HBsAg carriers and 261 non-carriers. Among the 261 non-carriers. 223 had both anti-HBs and anti-HBc, 11 were anti-HBc(+)iantiHBs(-).
days (range: Y-152). Tbs mean peak ALT was 324.8 WI (range: 80-1264) and the mean peak for total bilirubin was 3.0 mg!dl (range: 0.6-16.9). Seventeen patients had peak ALT between 80-300 W/l, 12 between 301-600 IUil. five between 601-IOOU WI and three had peak ALT >looO WI. Fourteen (38%) patients were asymptomatic, while 23 were symptomatic. The most common clinical manifesmtions were malaise (54%). jaundice (32%), anorexia (27%) and tea colored urine (24%). The data of each category was shown in Table 3. Tbitty-two patients with NANBH and one with hepatitis B were followed-up for more than 6 months after the first elevation of ALT. Twenty (60.6%) of the 33 patients becamechronic. The patient with hepatitis B recovered in 3 months. Twenty of the 32 patients with NANBH

be-

came chronic, while 12 recovrred in 6 month.. Seventeen of 20 patients who developed r!tronic hepatitis were positive for anti-HCV after bansfusion (including two pa-

TABLE

3

Clinical data of 37 pdents

tiea without PTH There was no diffrcnce in age, sex, pretransfusion HBsAg status and anti-HCV between the two groups (Table 2). Of the 37 patients. one was diagnosed with hepatitis B by the presence of IgM anti-HBc and seroconversionto anti HBs. and 36 as NANBH by the absenceof lgM antibody to HAV, HBc, HDV, CMV and EBV. Of the 36 phticnts with NANBH, 24 were antiHCV positive (including 22 seroconverted to anti-HCV and two patients positive for anti-HCV before tranrfw rion). Six of these 36 patients were HBsAg carriers. Three of the six HBsA;: carriers seromnvened to antiHCV, while the other three were negative for anti-HCV.

HB”

I,2

NANB Anti-WV(+) A”tl-HC”(-) huu;io”

period (day)

NANB P.d”HCV(.,)

Aat-HCV(-) I%* ALT (IUII) HBV NANB And-HC”(+)

Anti-HCV(-)

Tht: 37 patients had a mean incubation period of 46.1 ‘“agl‘

(rngm)

TABLE ” Comparironr between2% reapientswith andwithoutposttrsnstu. sl””hepatitis

with m

Etiology

NANB A”d.HC”(+, Anti-HC”(-)

7%)

x.(97.3%) 24 (b&9%, 12(32.4%)

46.,(7-L2)b 150 43.2 34.3

61.0 324.8 (80-1264)~ 1193 300.7 325.4

251.2 P.O(O.6-16.9)b 9.3 2.8 3.4 1.7

symptamr and r,*nr As~,:omatic

14,37(37.8%) oil

NANB A”ti-HC”(+, Anti-“C”(-) Jaundice HB” NANB

Ii/i6

Anti-HCV(+) Anti-Hew-,

mm 4112 12137(32.0%) 111

II136

804 3112

41 TABLE

4

Seven patients

c!omparilo”s betw?e” chronic and recovered transfusionNANB heprtitis”

wth pat-

pPtle”tr

biopsy R-26 showed

with

months

histologic

chronic

hepatitis

after the owet

received

liver

of hepatitis.

Two

pictures of nonspecific

reactive

atitis and five showed chronic persistent hepatitis.

hep-

Four of

the seven patients seroconvered to anti-HCV.

F’TH

IS a major

worldwde lished

complication

of blood

transfusions

(1). The actual incidence can only he estsh-

by prospective

(lZS%)foundio

studies.

Tbe

frequency

of PTH

ourserieswa~~imilartotwore~entstud-

ies in Italy (7) and Canada (8). where a 14.2 and 9.2% incidence of PTH

was found.

respectively. despite the use

of blood donors screened for HBsAg

and ALT.

However,

the incidence m study was relatively high compared with several

other

Netherlands. developed tients who were already transfusion). acute I’TH,

positive

for anti-HCV

before

Four of the 12 patients who recovered after ~erocowerted

to anti-HCV;

patients did nor. inerefore. with anti-HCV

the chroniciiy

seroconversion

and higher peak ALT was no significant transfusion

Taiwan,

HBsAg

rates

in sex. age, donor number.

incubation

period,

or pretransfusion

~tatw between the two groups (Table 4). A corn

parison of anti-HCV

positivity in the 32 NANBH

patients

is shown in Table 5. Patients positive for anti-HCV higher rate of chronicity

and higher peak ALT

oatients neeative for anti-HCV.

between

d&r

number,

adults (l&13).

rate in patients

than patients who recovered. There

diffcrcwe

amount,

FTH

not correlate

was 79% (15119). Patients

had a

level than

No significant difference

transfusion kount,

total bili-

in Australia,

(9-11). Therefore,

Sweden, acute HBV

the higlt incidence of PTH

with the hyperendemic

HBV

infection

did m

because only one of the 37 patients with PTH had

IgM anti-H&

in the acute phase. The majority

*:rmsfnsions fro-

high frequency of FTH

-+,le

stildias of PTH

donors hecruse of onon factor for !he

in our study. Nevertheless,

many

on patients receiving open heart surgery

did not have this high a frequency (11.14). time the seropositivity time volunteer

of recipi-

large number of

heart surgery, and this may he an importaot

than

subjects infection

may be present, it is rare m

ents in our series had received a rriawely L!:-.!

and The

of transfused

Although

with negative IgM anti-HBc

the other eight

with chronic hepatitis had higher positive anti-HCV

studies

where only 2-3.3%

At the sable

rate !O.SSW) of anti-HCV

blood donors in Taiwan

in the western countries

that rhe CBUSOSfor the relatively

We conclude

high PTH

rubin level and incubation period was found.

Tatwan needs further investigation.

TABLE

to play a sigmfizmt

in first-

was not higher

(6,15-17).

frequency in

The number of donors and amount of transfusions seem

5

Comparisons between anti-HCV positive anti-H0 new wth ponuanrt”sio” NANB hepatms’

negatve pa-

role in PTH.

been observed (7). akhough

Similar

tindings have

other s;udirn did not reach

the same conclusion (8). Sex, age and HBsAg r~cip~n:;

carriage of

drd not affect the frequency of PTH

in our se-

ries. The chronicity

rate (60.6%)

able to Spain (67%)

in our series was corllpar-

(18) and California

(67%)

was higher than the rate found in Canada (36%) (53%).(19)

and Japan (54%)

with oositive anti-HCV ALT

(20).

In our study. patients

age. number of donors and transfusion confribu~e

but

after transfusion and hinher Peak

levels seemed prone IO chronic hepatttis. to the development

the bistolog~c pxturer

(2).

(8). ftaiy

The xx,

amounts did not

of chronicicy.

Although

in the seven biopsied patients wth

chronic hepatitis were mild, the long-term

outcome

can

hc seriousas shown in several studies(2.19). Only one pntienl developed acute hepatitis 8. Although mtrahospital IBV mfection could not be totally ruled out. tmnsfuslon-Induced HBV mfection seemed more likely. Desptre the use of a third generation test for

!

HBsAg

screening. donors positwe for HBV

cannot be to-

tally excluded (21). Therefore, posttransfusion hepatitis

B cannot be eliminated by the present screening method (I). In Taiwan. sincemany adults have had previous HBV infection as revealed by the prevalent HBV antibodies in tbc general population. only a small portion of recipients will contmct acute hepatitis B after receiving HBV containing blood or blood products. The prevalence of infectious HBV carrier donors may not be rare, even though they have been screenedserologically. By using the sensitive polymerase chain reaction essay, HBV DNA was detected in as many es 4% of HBsAg-negative volunteer blood donors in Taisan

and anti-HDV.

dicating the significant

role of HCV

in chronic liver dis-

easein Taiwan (IS). Two patients were already positive for anti-HCV before transfusion and both of them developed posttransfusion chronic hevatitia. Both remained positive for antiHCV in serum samples after transfusion. Although they were classified as anti-HCV oositive NANBH in our series. the role of HCV in these two patients was difficult to define since little is known about the biologic meaning of anti-HCV at present. Nevertheless, reactivation of the preexisting HCV or infection by other viral agents were

for

Although reactivatioo of HBV

these patients may be causedby a cryptogenic HBV infec-

(22).

WC did not cxctude

HBeAg

patients who seroconverted to anti-HCV and wre followed-up longer than 6 months became chronic, again in-

possible, but thisrequiresfurtherstudy. There were 12 patients without serologic evidence of acute infection of HAV, HBV, HCV, HDV, CMV or EBV. These patients were classified anti-HCV negative NANBH in our study. They had a much lower chronicity rate than anti-HCV positive patients. Elevation of ALT in

Due to the high p:evalcncc of HBV (3).

high chronicity rate of hepatitis C. Fifteen (79%) of the 19

HBsAg

infection in Taiwan

carriers

aegetive

could not be totally excluded, it is reasonable to diagnose NANBH in the six HBsAg carriers by the clinical course. particularly in the three patients seroconverted antiHCV. Although larger case numhe;s and longer followups may be necessaryto define the real incidence and outcome of PTU in HBsAg carriers in our study, thr frequen-

tin (24) NANB viral agentsother than HCV (25) or nonviral inflammation of the liver. HCV infection also remains possible despite anti-HCV negativity (26). Further studies by more sensitive HCV serologic markers or with polymerase chain reaction assay of HBV DNA and HCV RNA should help define the PTH in these patients.

cy and clinicdi courseseemedsimilar to the non-carriers. Until the recent development of an assayfor the specific antibody to HCV (4.5). the diagnosis of NANBH has been basedon the exclusionof other viral infections by serologic work-up. With this assay, it is demonstrated~that 22 (55.5%) or the 37 patients scraconverted to anti-HCV in a follow-up of at leant 6 months. The actual incidence of

In conclusion, 12.5% of blood recipients developed PTH in Taiwan. and 60.6% of the patients with PTH became chronic. As in other areas of the world, the majority of PTH was caused by HCV, and patients who semwnverted to anti-HCV had a chronicity rate of as higb as 79%. Posttransfusionhepatitis B was uncommon hut not

HCV infectloo may be slightly underestimated in the present study, sincesomc patients may have delayed serocooversion longer than 6 months (23). Patients with hepatitis C showed higher peak ALT levels than patients without anti-HCV. However, the clinical course in the acuw stagewas relatively mild compared to the HAV and HBV infections. and there were no casesof %Iminant hepatitis. The most striking findmg in our study was the

eliminated.

Acknowledgements This study was supported by a grant from the Department of Health, Executive Yuan, ROC. We thank the colleagues in cardiovascular surgriy of National Taiwan University Hospital for their excellent cooperation.

43

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_

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mtigcn.