Human T Cell Leukemia Virus Type 1 Antibody in Patients on Chronic Hemodialysis in Fukuoka , Japan

Human T cell leukemia virus type 1 antibody (anti-HTLV1) was examined in 403 patients on chronic hemodialysis (HD) in Fukuoka, Japan, where HTLV-1 is endemic. The anti-HTLV1 positive rate was significantly greater in patients with a history of blood transfusion than in those without it (19.3% vs. 7.3% , p<0.05). However, the anti-HTLV1 positive rate in the latter group of HD patients was still 3.1 times higher than that in healthy blood donors from Fukuoka prefecture after adjustment for age and sex. In addition, positive rate of anti-HTLV1 increased with the duration of HD regardless of a history of blood transfusion. These results suggest that blood transfusion was a major route of HTLV1 infection in HD patients but that HD treatment itself might also increase the risk of HTLV1 infection.

A human type C retrovirus, human T cell leukemia virus type I(HTLV1)1)/adult T cell leukemia virus (ATLV)2), is thought to cause both adult T cell leukemia (ATL)3) and a kind of myelopathy that is known as HTLV1 associated myelopathy (HAM) or tropical spastic paraparesis (TSP)4).In 1984, Okochi et al. reported that HTLV1 can be transmitted by blood transfusion and that recipients who seroconvert become carriers and act as a source for further transmission of the virus5).HTLV 1 is also horizontally transmitted by sexual contact, namely from husband to wife 6,7) and vertically transmitted from mother to child via mother's milk 6.8), resulting in familial clustering9).ATL is endemic in the southwestern Japan ; including Kyushu, Okinawa, southern Shikoku, and the Kii Peninsula10, 11), where antibody to HTLV1 (anti-HTLV1) is highly prevalent in healthy individuals 12,13) All healthy individuals who are positive for anti-HTLV 1 have T cells bearing the virus circulating in their peripheral blood 14,15) Many of the patients on chronic hemodialysis (HD) used to suffer from renal anemia until recombinant erythropoietin became clinically available.They were thus at a high risk of contracting blood-borne diseases due to the need for frequent blood transfusions.In 1986, an HTLV1 screening program was introduced by the Japanese Red Cross Blood Transfusion Service to exclude anti-HTLV1 positive blood.Since then, the seroconversion rate of transfusion recipients has decreased from 8.3% to 0.15% in Fukuoka prefecture, Kyushu16).However, HD patients apparently have other routes of infection in addition to blood transfusion because our previous study revealed that the positive rate of hepatitis C antibody (anti-HCV) in HD patients who had never received a transfusion was 3.5 times higher than in healthy blood donors17).
Therefore, the present study aimed to evaluate the effect of blood transfusion and HD treatment on the anti-HTLV 1 positive rate.

SUBJECTS AND METHODS
A total of 403 end-stage renal failure patients on maintenance HD in Fukuoka, Japan were investigated in 1990.They consisted of 247 males and 156 females.
The mean age of the male was 53.9 years (range : 18 to 82 years) and that of female was 53.5 years (range : 19 to 81 years).The mean duration of hemodialysis was 7.2 6.1( SD) years for males and 7.2 5.8 years for females.Of these patients, 145 males and 120 females had a history of blood transfusion.These informations were collected from medical records in HD units and confirmed by an interview with patients.
In order to investigate the infectious routes of HTLV1, hepatitis B surface antigen (HBsAg) was used as a marker of vertical transmission and antibody to HBsAg (anti-HBs) was used as a marker of horizontal transmission as reported previously17).HBsAg and anti-HBs were tested by an enzyme-linked immunosorbent assay (ELISA)(Dainabot Co., Tokyo), and anti-HCV antibody was also tested by an ELISA (Ortho Co., Tokyo).
Anti-HTLV1 was detected by an ELISA (Eisai Co., Tokyo)18).In order to eliminate false positive results, samples which were judged to be positive but had absorbance values less than 0.300 were subjected to the ELISA inhibition test and an indirect immunofluorescence (IF) test.They were only judged to be positive if the inhibition or IF test was positive.In the inhibition test, samples were judged as positive if the absorbance decreased significantly after mixing with purified HTLV1.MT-1 cells were used for the IF test19).
Statistical analysis was performed using the Statistical Analysis System package (SAS Institute Inc.).The significance was determined by the chi-square test and by the trend test using a logistic regression model and the Mantel Haenszel test.
Logistic regression analysis was used to control for the possible confounding effects of anti-HBs, anti-HCV, blood transfusion and duration of HD treatment Tablet.
Positive rate (%) of anti-HTLV1 in chronic hemodialysis patients according to the duration of hemodialysis treatment.on the anti-HTLV 1 positive rate.The odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated for each factor on the basis of the logistic regression coefficient and its standard error.
The ratio of the observed number of positive cases to the expected number (O/E ratio) was calculated to assess the effects of blood transfusion and HD treatment on the anti-HTLV1 positive rate.The expected number was calculated from the anti-HTLV1 positive rate of healthy blood donors at the Kitakyushu Red Cross Blood Center in Fukuoka prefecture 20).

RESULTS
As shown in Table 1, the anti-HTLV1 positive rate did not differ between HBs antigen positive and HBs antigen negative patients.
However, anti-HTLV1 * : p<0 .05,# : vs negative, $ : vs Short duration of HD without BT short duration : 0-4 years, long duration : 5 years or more anti-HBs : antibody to hepatitis B surface antigen anti-HCV : antibody to hepatitis C virus OR: odds ratio, CI : confidence interval HD: hemodialvsis therapy, BT : blood transfusion :E are OR was adjusted by logistic regression for all other variances in the table, positivity was more common in anti-HBs positive patients than in negative patients (females, p<0.01 ; all patients, p<0.05).
Similarly, the HTLV1 positive rate was also higher in anti-HCV positive patients than in negative patients (males, p <0.01 ; females, p <0.05 ; all patients, p<0.01).
In addition, the rate was higher in patients who had received blood transfusion than in those without transfusion (males, p<0.01 ; all patients, p<0.01).
The positive rate of anti-HTLV 1 increased with the duration of HD treatment in both males (p<0.05) and females (p < 0.05) (Table 2).On the other hand, it did not increase with age in either males or females (Table 3).The anti-HTLV1 positive rate did not differ between the sexes (Tables 2 and 3).
As shown in Table 4, the anti-HTLV 1 positive rate increased with the duration of HD treatment regardless of a history of blood transfusion (p<0.01 for patients with and without blood transfusion).
After correction by the duration of HD treatment, the positive rate of anti-HTLV 1 remained significantly higher in patients with a history of blood transfusion than in those without such a history (p<0.05).
As shown in Table 5, the OR of anti-HCV positive patients was significantly higher than that of negative patients (OR 1.38, 95% CI 1.02-1.86).Also, the OR of transfused patients with a long (5 years or more) duration of HD was significantly higher than that of nontransfused patients with a short (0-4 years) duration of HD (OR 1.87, 95% CI 1.12-3.10).

*
As shown in Table 6, the O/E ratio of transfused HD patients who were positive for HTLV1 was 7.11(p<0.0001)while it was 3.07(p<0.005)for those without blood transfusion.
Thus, an elevated risk of HTLV1 infection was observed among HD patients regardless of a history of blood transfusion.

DISCUSSION
In the present study, 59(14.6%) of the 403 HD patients were positive for anti-HTLV1.
This was a slightly lower rate than that for HD patients in Nagasaki prefecture (17%)21) or Kumamoto prefecture (22%)22), and was much lower than the rate in Kagoshima prefecture (33.8%)23) or Okinawa prefecture(38.2%)24)where ATL is highly endemic.On the other hand, the rate of anti-HTLV1 positivity among our patients was much higher than it was in Kochi prefecture (8.9%)25)where ATL is mildly endemic or in Fukui prefecture (1.4%)26) where ATL is not endemic.There was no significant difference in the mean age of the HD patients in the present study and in previous studies21-26).Thus, differences in the anti-HTLV 1 positive rate among HD patients may reflect geographic differences in the anti-HTLV1 positive rate among blood donors.The positive rate of anti-HTLV 1 among HD patients was higher than that among blood donors in Fukuoka prefecture (1.7%-1.9%)5,20),and this result was similar to that seen in the previous reports21-26) (Table 7).Thus, all these reports indicate that HD patients have a high risk of HTLV1 infection.
Our study also demonstrated a significantly higher positive rate in transfused HD patients than in nontransfused patients (19.3% vs. 7.3%, p<0.05), confirming a close relationship between HTLV1 infection and blood transfusion.
In addition, the positive rate increased with the duration of HD in patients with a history of blood transfusion, as has been reported previously22).This result may be explained by the possibility that HD patients with a longer duration of dialysis may receive more units of blood.
The present study showed that the risk of HTLV1 infection was significantly increased in patients with a history of blood transfusion and a long duration of HD (5 years or more )(OR 1.87,95% CI 1.12-3.10),but not in transfused patients with a short duration of HD (0-4 years)(OR 1.21, 95% CI 0.63-2.33).This result may reflect the facts that the screening of blood for HTLV 1 was started in 1986(4 years before the present study) and the incidence of HTLV1 infection after blood transfusion has markedly decreased since then 16).In addition, use of recombinant erythropoietin has decreased the total amount of blood required by HD patients.
Our study also demonstrated that transfused patients with a short duration of HD still had a high positive rate of HTLV1 (11.6%).When compared to healthy blood donors, the positive rate of anti-HTLV1 was 3.1 times higher in HD patients who had never received a blood transfusion, and the rate increased with the duration of dialysis even in the nontransfused patients.These results suggested that HD treatment for end-stage renal failure may increase the risk of HTLV 1 infection independently from blood transfusion.
Since a previous study has revealed that medical or co-medical workers do not have an increased risk of HTLV1 infection 27), transmission of the virus from the staff of HD units is not likely.Thus, increased positive rate with a longer duration of HD may occur because patients have an increased risk of exposure to blood spills or parenteral contamination as the period of time on dialysis becomes longer.
Although blood transfusion is a major route of both HTLV15,21-26) and HCV17,28) infection, the risk of anti-HCV positive patients for HTLV1 infection increased without the influence of blood transfusion (OR 1.38, 95% CI 1.02-1.86).This result suggests that coinfection with HTLV1 and HCV may occur in HD patients

Table 3 .
Positive rate (%) of anti-HTLV 1 in chronic hemodialysis patients according to the age.Trend test* : trend test by logistic regression model.M.H. test#: Mantel Haenzel test, comparison of positive rate of anti-HT

Table 6 .
Observed (0) and expected (E) numbers and O/E ratio of anti-HTLV1positive patients in chronic hemodialysis patients by blood transfusion.