Posttransfusion Hepatitis in Japan

Original Paper

Vox Sang 1992;62: 156-164

Siisumu Takanoa Masuo Omatu a

Masao Ohto" Yoichi Satomura

Posttransfusion Hepatitis in Japan

~' First Department of Medicine,

" Division of Medical Informatics, Chiba University School of Medicine;

Chiba University Hospital, Inohana, Chiba, Japan

................................................................................................. Abstract The incidence of posttransfusion hepatitis and the rate of chronicity were investigated in a program devised at our hospital in December, 1982. Out of 2,596 blood recipients between January, 1982, and December, 1987, 451 (22.7%) developed posttransfusion hepatitis. Seventy-seven patients out of 217 (35.3%) whose course was closely followed progressed to chronicity. The incidence of posttransfusion hepatitis increased with the volume of transfused blood without any evident limitation. Recipients of elevated-ALT donor blood (>26 Karmen units) were found to be more susceptible to posttransfusion hepatitis than those who had received only normal-ALT donor blood. Packed red blood cells, whole blood and fresh whole blood were high-risk components, and fresh frozen plasma a low-risk component of blood. The carrier rate of non-A, non-B hepatitis agents in Japanese healthy blood donors was determined to be 1.2% using the Frost-Reed model of infectious diseases. Anti-hepatitis C virus was detected in 62% of the cases of posttransfusion hepatitis 1 year after transfusion. .....................

Introduction

Since the introduction of sensitive tests for hepatitis B virus surface antigen (HBsAg), the risk of posttransfusion type B hepatitis has been considerably reduced [l-31. Most cases of posttransfusion hepatitis are now considered to be of the non-A, non-B variety [l, 4,5]. This form is thought to progress to a chronic condition [6-91, and the possibly gives rise to hepatocellular carcinoma [lo, 111. The risk factors of posttransfusion hepatitis have been investigated in regard to age and sex of recipients [6, 121, serum alanine aminotransferase (ALT) [13], anti-HBc [14], anti-HBs [15] and guanase activity [16] of donated blood, and the volume of transfusion. To assess the risk of

Rcceived: Fch. 4. I Y U I Revised manumipt received: Sept 1. l W l Accepted: Sept 20. I U Y I

blood transfusion for the development of liver disease, a method was devised at Chiba University Hospital in 1982. Using this method, our purpose was to determine the incidence and prognosis of acute posttransfusion hepatitis by examination of all transfused patients from 1982 to 1987, and to assess the risk factors of contracting posttransfusion hepatitis in relation to both donor blood and the recipients' characteristics.

In 1989 a major infectious agent of blood-borne non-A, non-B hepatitis was identified and named hepatitis C virus (HCV) [17]. A method for detecting anti-HCV, which is positive in carriers of HCV, was also developed [ 181. The prevalence of HCV in posttransfusion hepatitis was also investigated with the purpose of determining its role in the

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development of this disease. The results of this study may provide some clarification as to the factors surrounding posttransfusion non-A, non-B hepatitis in this country.

Materials and Methods

Protocol of the Sriiily The present study on posttransfusion hepatitis was conducted at

Chiba University Hospital located 40 km east of Tokyo. The hospital has 835 beds and approximately 1,500 patients visit the outpatient clinic each day. All patients receiving blood transfusions between January 1.1982, and December 31.1987. were registered in the Post- Transfusion Hepatitis Surveillance System if the following criteria were met: ( I ) blood transfusion wasconductedfor the first time at this hospital: (2) serum ALT of all pretransfusion specimens was under 40 IU,and(3) total transfusionswerecompletedwithin Iweekfollow- ing the first transfusion. This system was incorporated into the Med- ical Information Database System DP lU7, DMS-I (MUMPS) at the Division of Medical Informatics of the hospital, which contained information such as the date of transfusion, number of units of transfused blood, components of transfused blood, accession code of the transfused blood and results of laboratory tests on the patients. Each transfused patient was carefully followed up at the same departments of the hospital that conducted the transfusions. The period of posttransfusion follow-up was 390 days, which was divided into 17 intervals. The first 28 days after transfusion were divided into 7-day intervals No. 1 4 , the next 32 days into 16-day intervals No. 5 and 6. and the remaining 330 days into I-month intervals No. 7-17.

Where multiple blood samples were taken duringany interval, the highest ALT was considered the representative value for that interval.

Pa/ient~ The number of patients registered in the Post-Transfusion Surveil-

lance System between January 1.1982, and December 31,1987, was 2,596 (434 in 1982,475 in 1983.419 in 1984.461 in 1985,423 in 1986 and 384 in 1987). 1.137 men and 1.459 women. The average age was 45.5 years, and the average transfusion volume was 10.1 units (1 unit = 200 ml of volunteer blood), with a range of 1-181 units (fig. 1). The departments of internal medicine. surgery, pediatrics. gynecology/ obstetrics and others carried out the procedure and follow-up of 2.3, 33.7. 16.1. 13.2 and 34.7% of the patients, respectively. The types of transfused blood were fresh whole blood, whole blood, packed red blood cells. platelet-rich plasma. fresh-frozen plasma and washed red blood cells. Blood used for transfusion during this study was collected by the Chiba Red Cross Blood Center from volunteer donors only, and was screened for HBsAg, syphilis. human T lymphotropic virus type 1, human immunodeficiency virus and irregular isoagglutinating antibodies. Blood withserum ALTofless than36Karmen units(KU) was used for the transfusions.

Dejnirioti of Posttratisfiision Hepatitis Aciire Hepatitis. Patientsin the following3 categorieswere consid-

ered to have acute posttransfusion hepatitis. (1) Diagnosis of definite posttransfusion hepatitis was made for a serum ALT value of 200 IU or more. Patientsshowing ALTelevation within7 daysoftransfusion were not included in +his category. (2) Diagnosis of probable posttransfusion hepatitis was made for serum ALT of 50-200 IU in two

Fig.1. Number of units of transfusions given to 2,596 patients in the present study. 1 unit of blood component was made from 200 ml of blood from a volunteer donor. The average volume of transfusion was 10.1 units, the median 5 units and the mode 2 units.

consecutive examinations. This was not applicable to patients with ALT elevation within 7 days of transfusion. (3) The short incubation group was comprised of patients whose serum ALT exceeded 40 IU within 7 days following transfusion.

Chronic Heparitis. Hepatitis cases of these 3 categories were diagnosed as chronic if the following citerion was met: blood specimens taken more than 180 days after the onset of hepatitis had to show elevated ALT beyond 40 IU at least once, the onset being defined as the time at which serum ALT rose above 50 IU.

Risk Factors of Recipients The incidence of posttransfusion hepatitis was examined for pos-

sible correlation with age and sex of the recipients. Age was divided into 10-year groups and each was examined for the incidence of hepatitis.

Risk Factors of Donated Blood (1) The relationship between the incidence of posttransfusion

hepatitis and the volume of blood units transfused was investigated for 2,596 cases which had received transfusions between January 1 , 1982, and December 31, 1987. (2) The relationship between blood component type and posttransfusion hepatitis incidence was inves- tiagted in 1,704 recipients who had received only a single type of component between January 1,1982, and December 31.1987. (3) The relationship between serum ALTof donor blood and posttransfusion hepatitis incidence was investigated for 123 recipients who received whole blood only from donors whose serum ALTvalues were known during 1983 and 1984.

Measurement of Anti-HCV Antibody to HCV was tested with an ELISA system that used

recombinant HCV C100-antigen [l8, 191 in the solid phase (Ortho Diagnostics, Tokyo, Japan) in 122 posttransfusion hepatitis patients who received transfusions in 1985 and 1986. The latest from serial blood samples of the patients was selected for anti-HCV testing. In selected cases, serial specimens including pretransfusion serum were tested.

157

Table 1. Annual incidence of posttrans- Diagnosis 1982 1983 1984 1985 1986 1987 Totalrates fusion hepat itis

Definite n 421316 311348 35/350 551401 211294 211282 2OS/l.YYl"

Probable n 501316 461348 171350 361401 441294 53/282 24611,YYl"

Total 11 921316 771348 521350 911401 651294 741282 45111.991"

Yo 13.2 8.9 10.0 13.7 7.1 7.4 10.3

Yo 15.8 13.2 4.9 9.0 15.0 18.6 12.4

Y 0 2 9 . 1 22.1 14.9 22.7 22.1 26.2 22.1"

Blood units, average number 10.0 10.6 11.3 11.1 8.5 8.7 10. I

"

group. I'

degreeoffreedomof5 (x1=21.8, d . f .=S,p<0.01) .

Rates are based on the total number of patients excluding the 605 of the short incubation

The incidence of posttransfusion hepatitis was compared for each year by the x2 test with a

Table 2. Frequency of chronicity in patients with posttransfusion hepatitis Diagnosis Patients with Patients followed up Recovered Chronicity

disease, n for > 6 months, n n n %

Definite 205 130 Probable 246 87 Total 45 1 217

72 58 44.6 19 21.8 68

140 77 35.3

Short incubation 605 29 1 204 87 2Y.Y

Without acute ALT elevation 1.540 480 414 66 13.8

Striristicnl Method The ordinary x' test ( 1 degree of freedom: d.f.) was used to corn-

pare frequencies entered in 2 x 2 contigency tables. Frequencies entered in larger contingency tables were comapred with the results of a x' test in which the degree of freedom was correct. By the Wilcoxon rank-sum test, a comparison was made of the means and the results were expressed as a p value.

The Frost-Reed model of acute infectious diseases was used t o determine the carrier rate of non-A, non-B hepatitis agents 1191. Multiple units of transfusion was thought to be equivalent to multiple chances of infection. The postulated parameters are as follows: P(N) = incidence of posttransfusion hepatitis when receiving N units of blood: A = carrier rate of non-A, non-B hepatitis agents in a healthy population (volunteer blood donors); C = rate of hepatitis contrac- tion prior to transfusion, and P(N) = C+(l-C)[1-(1-A)"]. Ad- justment for these parameters was made by the maximum likelihood method.

Results

incidence of Posttransfusion Hepatitis The annual incidence of acute posttransfusion hepatitis

is shown in table 1. Of 2,596 blood recipients, 605 cases (23.3%) showed ALT elevation within 7 days following

transfusion and were thus classified belonging to the short incubation group. Of the remaining 1,991, 205 (10.3%) were diagnosed as having definite posttransfusion hepatitis and a further 246 (12.4%) as having probable hepatitis between 1982 and 1987 (table 1). The annual incidence of definite and probable hepatitis was lowest at 14.9% in 1984 and highest at 29.1% in 1982. Although statistically significant fluctuations were noted in the incidence of hepatitis from year to year, no trends to indicate an increase or decrease could be detected (table 1).

Rate of Chronicity Of the 451 cases with definite or probable posttrans-

fusion hepatitis, 130 definite and 87 probable were followed up over a period of 180 days following the onset of hepatitis (table 2). The rate of progress toward chronicity was assessed for these groups. Of the 130 definite posttransfusion hepatitis cases, 58 (44.6%) progressed to chronic hepatitis, as did 19 (21.8%) of the 87 probable cases. The combined rate of chronicity of the two groups was thus 35.3% (table 2). Out of 605 cases of the short incubation group, 291 were followcd up for 180 days. Of

IS8 Takano/OmatalOhtolSatomura Posttransfusion Hepatitis

Table 3. Relationship between sex and incidence of posttransfusion hepatitis

Table4. Number of combined hepatitis cases in age groups adjusted by 1,000 units of transfusion

Diagnosis Male Female Statistical significance

Definite Yo 9.2 10.3 N S" n 73179s 13211,196

n 1271795 11911,196

n 200/795" 2s 1/1,196h

Probable % 16.0 10.9 p < 0.05

Total Yo 25.2 21.2 p < 0.05

___- ~

Hepatitis casesll.000 units of transfusion 21.1 24.6 NS'

The incidence of definite and probable hepatitis. and probable hepatitis alone was significantly higher in males than in females (x' test: x1=4.SI. p<O.OS). I' Rates are based on the total number of patients. excluding the 605 of the short incubation group. ' Nosignificant differencein the numberofhepatitiscasesper 1.000 units of transfusion between males and females could be found (x' test: f=2.32. p<O.OS).

Age of Number of Hepatitis recipients recipients cases/1,000 units

of transfusion, n

0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-

262 200 152 28 1 412 457 464 310 58

24.2 16.0 19.7 18.1 23.2 17.5 16.2 13.5 8.5

Total 2,596

Nosignificant difference in the numberofhepatitiscasesper 1 .000 units of transfusion among the age groups could be found (x' test: x 2 = 13.35, p>O.OS).

40

8 6 30 6

these, 87 (29.9%) progressed to chronic hepatitis.Out of 1,540 cascs which did not develop acute ALT elevation, blood specimens were taken more than 180 days after transfusion in 480 cases. Of these 480 cases, ALT elevation beyond 40 IU more than 180 days after transfusion developed in 66 cases (13.8%). The rate of chronicity was significantly higher in definite hepatitis, in the total cases

cipients without acute ALT elevation.

a 5

's 20

m E 10 C -

0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80- of hepatitis and in the short incubation group than in re- 0 Age group, years

Fig. 2. Incidence of posttransfusion hepatitis in 10-year age groups, Significant differences in incidence were evident among the age groups prior to adjustment by volume of transfusion ( f = 15.6, d.f. = 8, P<0.05).

Risk Fcrctors of Recipients A11 investigation was carried out to determine if there

was a relationship between the sex of the recipients and the incidence of hepatitis (table 3 ) . The incidence of definite posttransfusion hepatitis was 9.2% in males and 10.3% in females, whereas that of probable hepatitis was 16% in males and 10.9% in females. Thus, the combined incidence of definite and probable posttransfusion hepatitis was 25.2% in males and 21.2% in females (table3), indicating a significantly higher rate in males (p<0.05).

The relationship between the age of the recipients and the incidence of hepatitis was also studied for each age group. Recipient age was divided into 10-year groups and the incidence of posttransfusion hepatitis was determined for each (fig. 2). The incidences of definite and probable hepatitis were 11.6, 14.6, 28.4, 25.5, 30.6. 24.6, 25.4, 19.8

and 13.6% in the 9 age groups, respectively. The average volume of transfused blood differed among the age groups and sexes, and appropriate adjustments were made for the calculation of the incidence of posttransfusion hepatitis according to the volume. The number of definite and probable hepatitis cases was 21.1 per 1,000 units of transfusion in males and 24.6 per 1,000 units of transfusion in females (table 3), thus indicating no significant differences according to sex.

159

Table 5. Relationship between the amount of transfused blood and incidence of posttransfusion hepatitis (total number of cases = 2,596)

Volume of Number of Incidence of post- transfused cases transfusion hepatitis blood, units %

1 2 3 4 5 6 7 8 9

10 I1 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 32.6 38.0 43.0 48.2 55.3 64.1 80.5

128.8

17.5 382 343 245 230 136 101 119 75

123 36 50 40 45 44 21 23 22 22 23 11 27 17 14 16 16 15 11 11 21 33 42 23 18 26 10 I1 10

24.6 30.1 30.3 29.9 41.3 41.9 39.6 48.7 34.7 41.5 47.2 42.0 55.0 57.8

57.1 65.2 59.1 50.0 47.8 45.5 55.6 58.2 64.3 75.0 50.0 66.7 54.5 72.7 71.4 66.7 73.8 73.9 55.6 73.1 90.0 63.6 80.0

50.0

Hepatitis cases per 1,000 units of transfusion in the age groups were 24.2, 16.0,19.7,18.1,23.2,17.5,16.2,13.5 and 8.5, respectively (table 4), the differences not being significant (p>0.05). From these results, i t may be concluded that the incidence of posttransfusion hepatitis is inde- pendent of either age or sex of the recipients, but rather is dependent primarily on the volume of transfused blood.

Risk Factors of Donated Blood Amount of Transjiised Blood and Incidence of Hepati-

tis. Also studied was the relationship between the incidence of posttransfusion hepatitis and the volume of transfused blood. Posttransfusion hepatitis increased gradually with the units of transfused blood, as follows: 41.5% with 10 units, 47.8% with 20 units, 55.6% with 48.2 units, finally attaining 80.0% at more than 100 units (table 5 ) . These data were then fitted to the Frost-Reed model of infectious diseases, and the infectious carrier rate of non-A, non-B hepatitis agents (A in the equation) was calculated by the maximum likelihood method as 1.2% (regression coefficient = 0.72) of volunteer donors at the Chiba Red Cross Blood Center. When the volume of transfusion (N in the equation) increased, the incidence of posttransfusion hepatitis [P(N) in the equation] increased to reach 1.0, meaning 100%.

Components of Transfiued Blood and Incidence of Hepatitis. The incidence of hepatitis was assessed for each of the different components of blood (table6). Of the 2,596 recipients, 1,904 (65.6%) received single and 892 (34.5%) multiple components (table 6). The kind of transfused blood was correlated to the incidence of posttransfusion hepatitis for the single-component transfusion group, the incidence being 28.0% in recipients of packed red blood cells, 24.6% for fresh whole blood, 19.2% for whole blood, 16.1% for fresh-frozen plasma and 10.0% for platelet-rich plasma (table 6). The transfusion volumes were different among the recipients of each different component of blood to a significant degree. Thus, the incidence of posttransfusion hepatitis of the blood components was adjusted according to the volume of transfused blood for the 4 commonly used components, but not for the rarely used platelet-rich plasma and washed red blood cells. The numbers of hepatitis cases per 1,000 units of transfusion as risk factor were then compared (table 6). The risk factor for each component was 76.9/1,000 units in the recipients of packed red blood cells, 53.8/1,000 units in fresh whole blood, 24.1/1,000 units in whole blood and 9.4/1,000 units in fresh-frozen plasma. Thus, for any one of the 4 commonly used blood components, the relative risk of developing posttransfusion hepatitis was 8 times as great (packed red blood cells vs. fresh-frozen plasma).

Donor ALT and Incidence of Hepatitis. To determine the relationship between serum ALT of donor blood and the incidence of posttransfusion hepatitis, 123 recipients were selected from the recipients of whole blood during 1983 and 1984. The serum ALT values of the donors of whole blood received by only these 123 recipients were known, and a total of 527 units of blood was transfused.

160 Takano/Omata/Ohto/Satomura Posttransfusion Hepatitis

Table 6. Inci- dence of posttrans- Type Of Number of Units of Incidence of hepatitisa Risk factor fusion hepatitis for transfused recipients transfused various components blood blood definite probable total of transfused blood (mean)

Single-component transfusion

Whole blood 1,151 4.2 851984 8.6%

Fresh-frozen plasma 243 11.8 161168 9.5%

Packed red blood cells 122 3.2 71 107 6.5%

Fresh whole blood 175 3.5 81134 5.8%

Platelet rich plasma 12 14.1 0110 0 %

Washed red blood cells 1 1.0 011 0%

1041984

111168

231107

251134 18.7% 1110

10.0% 011 0 %

10.6%

6.5%

21.4%

1891984 24.111,OOO units 19.2% 271168 9.411,OOO units 16.1% 301107 76.911,OOO units 28.0% 331134 53.811,OOO units 24.6%

1110 5.911,OOO units 10.0% 01 1 0% -

~~

Multiple component transfusion 892 19.3 891587 821587 1711587 35.211,OOO units

15.1% 13.9% 29.0%

Total 2,596 10.1 20511,991 24611,991 45111,991 22.911,OOO units

'' Rates are based on the total number of patients excluding the 605 of the short incubation group.

Tabelle 7. Relationship between the incidence of hepatitis and ALT of donor blood in recipients of whole blood

Donor ALT status Recipients of

low-ALT blood high-ALT blood

With hepatitis 42 Without hepatitis 67

10 4

Mean units of transfusion 3.9 6.8"

High-ALT blood recipients received at least 1 unit of blood whose donor ALT was above 26 KU. Low-ALT blood recipients received no bloodwhosedonorALTvalue wasabove26 KU.x2=3.84(p<0.05). a A~~~~~~ volume of transfusion was significantly greater in 109 high-ALT blood recipients (6.8 units) than in low-,&T blood recipients (3.9 units: Wilcoxon's rank-serum test: p<O.Ol).

Fig. 3. Distribution of donor ALT values for whole blood given to 123 recipients during 1983 and 1984. Donors whose ALT was above 26 KU constitute only 2.8% of this group. The mean of donor ALT was 11.0 KU, the median 7 Ku and the mode 7 KU.

Donor ALT values ranged from 3 to 35 KU. The blood of donors with ALT above 36 KU was considered unsuitable for transfusion and thus was discarded by the Chiba Red Cross Blood Center. The mean of donor ALT was 11.0 KU, the median value 7 KU and the mode 7 KU (fig. 3). Donor blood with ALTexceeding26KU constituted only 2.8% of the blood transfused in this study (fig. 3).

Of the 52 patients in the hepatitis group, 10 (19.2%) received at least 1 unit of blood from a donor with ALT above 26 KU. Four (5.6%) of the 71 patients in the non- hepatitis group also received at least 1 unit of blood from a donor whose ALT exceeded 26 KU. Therefore, donor blood having ALT above 26 KU showed a significant (p<0.05) relationship for the hepatitis group (table 7).

161

Table 8. Anti-HCV ELISA results in posttransfusion hepatitis

Interval between transfusion and blood test Anti-HCV

YO n

chronicity was investigated in 13 cases whose anti-HCV was tested after lyear of transfusion. Whereas only 1 of 5 HCV-negative cases progressed to chronicity (25%), 7 of 8 HCV-positive cases progressed to chronicity (87.5%).

Within 180 days of transfusion 18 915 1 181-365 days following transfusion 11 6/58 More than 366 days following transfusion 62 8/13 Discussion

Table 9. Sequelae of 13 cases whose anti-HCV was tested after 1 year of transfusion

Anti-HCV Chronicity

chronic resolved

Positive 7 1 Negative 1 4

Table 10. Incidences of posttransfusion hepatitis in other re- ports

Investigators Incidence of Hepatitis posttransfusion casedl ,OOO units hepatitis, YO of transfusion, n

Seeff et al. [3] 9.9 33.3

Aach et al. [13] 5.4 15.8" Koziol et a1 [ 141 11.2 5.9

Alter et al. [21] 8.6 I . l h

Stevens et al. [22] 5.6 18.4'

Feinman et al. [ 121 9.2 19.9

Tateda et al. [20] 14.4 6.2

Donor ALT < 30. Donor ALT < 33. Donor ALT < 45.

Anti-HCV Testing Anti-HCV was detected in 17% of definite and prob-

able posttransfusion hepatitis blood specimens obtained within 180 days of transfusion, in 10% obtained 180-365 days following transfusion and in 62% after 365 days or more following transfusion (table 8). In 13 cases of which pretransfusion serum was tested and shown to be negative, anti-HCV antibody remained positive after it turned to positive. The relationship between anti-HCV and

In this study, 2,596 blood recipients were followed up from January 1, 1982, to December 21, 1987, at Chiba University Hospital. Definite hepatitis was noted in 205 cases (10.3%) and probable hepatitis in 246 cases (12.4%). The incidence of posttransfusion hepatitis in the present study exceeded that reported in several previous studies [3, 12-14, 20-221, as summarized in table 10. Abnormal ALT in 2 consecutive blood specimens was needed for the diagnosis of posttransfusion hepatitis in the studies of Al- ter et al. [21] and Aach et al. [13]. Although the minimum ALT level for the diagnosis of posttransfusion hepatitis in those studies was lower than that of the definite hepatitis group in this study, the incidences of hepatitis were lower than in the definite hepatitis group. The main reason for the high incidence of posttransfusion hepatitis is probably the high HCV carrier rate in Japan. Hepatitis cases per 1,000 units of transfusion was highest in the report of Sccff et al. [3], perhaps because paid donors comprised a large proportion of their blood donors. Except for that one study, fewer hepatitis cases per 1,000 units of transfusion than in our study were always reported.

Of 451 cases of definite and probable hepatitis, 217 were followed up for a period of 180 days following onset, and 77 (35.3%) progressed to a chronic condition. The rate of progress to chronicity according to previous re- ports ranged from 16 to 70% [6-9, 20, 23-25]. Eight of those studies relied on a relatively small number of cases (20-60), perhaps accounting for the differences in the rate of chronicity. In the present study of 205 definite posttransfusion hepatitis patients, 130 were followed up for 180 days and 58 (44.6%) were diagnosed as having progressed to a chronic condition. Of 246 probable hepatitis cases, 87 were followed up for 180 days, with 19 cases (21.8%) becoming chronic. Thus, the rate of progression to chronic hepatitis was significantly higher in the definite than in the probable hepatitis group.

Patients with incubation periods of less than 7 days following transfusion have often been considered as not having posttransfusion hepatitis due to the possibility of nonviral liver injury after surgery [l, 3-51. It is evident from the present data that this group constituted a significant proportion of the total blood recipients (23.3%). It is im-


portant to study the sequelae of liver injury in this group. The rate of chronicity in this group was 29.9%, essentially the same as the values for the definite and probable hepatitis groups. This short incubation group may therefore consist not only of patients with nonviral liver injury but some cases of viral origin as well.

After adjustment had been made for the total number of hepatitis patients per 1,000 units of transfusion, no significant differences could be found according to sex. Nei- ther was there any evident relationship between recipient age and hepatitis incidence. That age and sex of the recipients failed to show any clear correlation to the incidence of posttransfusion hepatitis in this study is consistent with the results of previous studies [6,13,24]. The incidence of hepatitis increased with the units of transfused blood without any obvious limitation, being 55.6% at 50 units of transfusion and even higher for a greater amount. This clearly contrasts with the reported finding that the incidence of posttransfusion due to HBV decreased as the volume of transfusion increased above a certain amount [3], and appears to be an indication of the presence of an anti-HBs antibody which neutralizes the HBV in donated blood. Thus, a significant titer of neutralizing antibody to non-A, non-B hepatitis virus might not be necessarily present in the blood of the healthy population of Japan. Anti- bodies for nonstructural protein and core peptides of HCV were shown to be present in the sera of infected patients of HCV [26]. But it has not been reported that antibody for surface antigen of HCV (i.e. neutralizing antibody) is present in convalescent sera of HCV-infected patients. From the regression curve indicating the relation between transfusion volume and hepatitis incidence, the carrier rate of non-A, non-B hepatitis agents in volunteer donors was determined as 1.2% by the infectious disease model of Frost-Reed [19]. A method by which the anti- HCV (non-A, non-B hepatitis virus) antibody can be suc- cessfully detected has been reported [17,18]. Recent data indicate anti-HCV to be detectable in 0.7-1.2% of the healthy population [27-301, and our estimation in the present study is in the same range.

Complications of transfusion such as fever and allergic reactions have been discussed in connection with several components of blood [31]. However, differences in the incidence of hepatitis in relation to various types of blood components were investigated and presented here for possibly the first time. Hepatitis risk was noted to be high for packed red blood cells (76.9/1,000 units), fresh whole blood (53.8/1,000 units) and whole blood (24.1/1,000 units), and low for fresh-frozen plasma (9.4/1,000 units). One possible reason for the low-risk factor in fresh-frozen

plasma may be the longer storage period of this component compared to the others. Fresh-frozen plasma can be used at any time within 1 year following collection, whereas packed red blood cells, whole blood and fresh whole blood must be used within 21 days, 21 days and 72 h, respectively, by our regulations. The infectious activity of the non-A, non-B hepatitis virus may be weakened during longer periods of storage.

Recipients receiving at least 1 unit of whole blood whose donor ALT exceeded 26 KU were significantly more numerous in the hepatitis group. In previous studies, blood from donors with elevated ALT was shown to contribute to posttransfusion hepatitis [13, 14, 32,331. In those studies, the threshold for elevated ALT of the donor was30 IU [13], 53 IU [14], 45 IU [32] and53 IU [33]. In the present study, blood donor ALT above 26 KU was considered to possibly contribute to posttransfusion hepatitis. Although the risk of high-ALT blood was statistically significant, as the average volume of transfusion was significantly higher in high-ALT blood recipients than in low- ALT blood recipients (Wilcoxon’s rank-sum test, p<0.05), it is difficult to distinguish the effect of high donor ALT from that of volume on hepatitis incidence.

Anti-HCV was frequently detected in sera obtained more than 1 year after transfusion, whereas it was detected only rarely from sera obtained within 1 year of transfusion. This phenomenon is consistent with the report that anti-HCV was not detected in the acute phase of HCV infection in chimpanzees [34]. Anti-HCV-positive posttransfusion hepatitis patients were prone to progress to a chronic state in comparison to anti-HCV-negative patients. Anti-HCV might not be developed in the serum of cases with a limited infection of HCV.

The Japan Red Cross has started to conduct testing for the detection of anti-HCV prior to blood transfusion [30]. Our Post-Transfusion Hepatitis Surveillance System should prove useful for assessing the incidence of posttransfusion hepatitis as well as the significance of this new test.

163

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Posttransfusion Hepatitis in Japan