Hepatitis virus infections in heart transplant recipients

Biomed & Pharmacother (1995) 49. 125-129 iD Elsevier, Paris

Dossier "Hepatitis 2"

Hepatitis virus infections in heart transplant recipients F Lunel', C Robert', P Munier', JF CadraneF, C Fretz", M Perrin', L Frangeul', P Grippon", B Bernard". P Opolon", JM Huraux', M Rosenheirrr', H Agut ' 'Service de Bacterio-virologie: 2Service d'Hepato-gastroenterologie: 'Centre de Transfusion Sanguine; 'Service de Maladies Tropicales et lnfectieuses. CHU Pitie-Salpetriere, 75651 Paris Cedex 13. France

INTRODUCTION Hepatitis B (HBV) and C (HCV) virus infections have been described in liver and kidney transplant recipients [1-4]. Most of the time these patients are infected before transplantation. On the contrary, there are few reports about the prevalence of viral hepatitis in heart transplant recipients. When we reviewed patients transplanted before 1989, we found that hepatitis Band C were frequent in heart transplanted patients and that HBV or HCV infections were acquired in most of the cases during or after transplantation [5). The graft itself and the surgical procedure are obviously risk factors for post-transplantation viral infections, such as viral hepatitis, for the following reasons: i) Donated organs are a potent source of HCV or liB V infection [6-10]. Although in the eighties, serological assays allowing the detection of lIBV markers (ie HBs antigen (Ag)) were available, these tests were not as sensitive as now. Moreover, it is known that HBV can replicate in subjects without evidence of HBs Ag in the serum [II, 12]. Before 1990. there was no way to detect HCV infection in organ or blood donors. The hepatitis C virus was discovered in 1989 and first generation serological tests, available for the anti-H'CV antibodies screening of donors, were introduced in the beginning of 1990 [13]; ii) Patients who underwent cardiovascular surgery, in particular heart transplantation. are submitted to many invasive procedures (ie endoscopy, catheterism, biopsies) and receive several blood transfusions, which may transmit viral in-

fections [14); iii) The immunodeficiency induced by immunosuppressive drugs is known to be responsible for a higher susceptibility to viral infection and for the different evolution of viral infection with a high incidence of chronic carriage 115-21). As a consequence, the risk of being infected by HBV or HCV or other viral infections HIV. human T Iymphotropic virus (HTLV). human herpes virus 6 (HlIV-6). cytomegalovirus (CMV) or Epstein Barr virus (EBV» is high in this population [9, 10,22-26]. In this paper. we shall review the .literature on HBV, HCV and HHV-6 infections in heart transplanted patients. Information about the mode of transmission, the naturel history, and the virological findings are described and compared with the data reported in the literature in immunocompromised (ie in renal transplant recipients) or non immunodeficient patients.

HEPATITIS B VIRUS INFECTION In a retrospecctive study conducted in 80 patients who underwent heart replacement at the Salpetriere hospital. Paris. France. between 1982 and 1985. Cadranel et al [5] found a high prevalence (62.5%) of liver dysfunction in heart transplanted (H'I') patients. Hepatitis B viral infection was diagnosed in 13/80 (\6.25%) cases, with delta superinfection in one case. Only one patient had HBs antigen (Ag) detectable before cardiac replacement (CR). The onset of liver disease (LD) (defined as the first alanine amino transferase (ALT)

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serum level elevation) ranged from one to 48 months after CR. One patient developed fulminant hepatitis and died. In the other cases, no patient died from LD. More recently, in order to assess the mode of transmission of HBV we examined [27,28], the serum of organ and blood donors HT patients and found no evidence (absence of seric HBV DNA by means of polymerase chain reaction (PCR» for a contamination by the graft of blood products. Thus, we suggested another source of infection. In 1994, Drescher et al [29] also reported a high incidence of HBV infection in HT patients (67/243; 27%). They found that the patients were infected by the same HBs Ag serotype (ay), suggesting a person to person contamination. After a case control study (the control group consisted of HT patients without HBV infection), they observed that HBV infection was transmitted at the time of endomyocardial biopsy, if performed on the same day and in the same room after biopsy of an HBs Ag positive patient. When performing biopsies on HBs Ag positive and negative patients in separate rooms, a new outbreak of HBV was not observed. Thus, these authors suggest that the most likely mode of HBV transmission is droplet contamination of instruments and/or medication vials. In our institution, we followed 469 [30] patients for more than two years after CR. From 1985 to 1992, 62 (13.5%) patients became HBV infected, at times despite a vaccination against hepatitis B. The prevalence rate of hepatitis B according to the year of CR is given in figure I. The mean delay between CR and the onset of hepatitis and/or the appearence of HBs Ag was 28 ± 16 months (median 24). Contrary to the low risk of chronic carriage (about 10%) in normal

H.patiU. C ('Il,)

40 35 30

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adults [31], in our study, all the HT patients became chronically infected (persistence of HBs Ag and HBV DNA in the serum during more than one year). The main clinical, biological, virological and histological (assessed by the Knodell score [32] data in patients with hepatitis B one year after infection, are shown in table I. In summary, we Table 1. Characteristics of the heart transplant patients with hepatitis B or C one year after the onset of hepatitis.

hepatitis B hepatitis C hepatitis B + C n = 62 n = 48 n = II ALT level (UIII)' (median) Viremia (HBV DNA" or HCV RNA"') (median) Knodell score at liver biopsy Cirrhosis (%)

80 ± 76 (63)

109 ± 92 (72)

74 ± 56 (56)

683 ± 701

109 ± 140

(276)

(32)

5.2 ± 2.2

6.2 ± 2.8

6.5 ± 3.7

0

0

0

• n = 23 UII1; .. pg/ml (Genostics, Abbott laboratories); ••• Eq x 1O~/mJ.

observed that most of the time, patients had a high degree of viral replication with high titers of HBV DNA in the serum, and mild levels of ALT, while liver biopsy showed reduced necrosis and inflammatory lesions in comparison with non-immunosuppressed patients, as reported in renal transplant recipients [I, 19-21]. However, we observed three subfulminant fatal cases (4%). These results suggest that there is no correlation between viral replication and chronic liver lesions, as patients with high titers of HBV DNA had generally mild hepatitis at liver biopsy. However, in some patients, immunosuppression may enhance the risk of fulminant cases. Unfortunately, we did not have the opportunity to compare the HBs Ag positive, HT patients with non-immunosuppressed patients infected during the same period of time, thus could not compare the impact of high viral replication on the outcome of disease.

15

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HEPATITIS C VIRUS INFECTION ......

1984 198 5 1986 1987 1986 1989 1990 1991

Fig 1. Hepatitis B prevalence rate (%) in heart transplant recipients according to the year of transplantation.

In the study of Cadranel et al [5], a post-CR nonA non-B hepatitis was found in 16 patients (20%), Retrospectively, using first generation tests, anti-

Hepatitis virus infections in heart transplant recipients

HCY antibodies were present in 9/16 (56.25%) patients at the time of diagnosis, in 65% using third generation tests and in 93% by PCR. The mean delay of the onset of hepatitis was shorter than in hepatitis B cases (l0.8 weeks, median 3 months). Three patients had icterus at the acute phase. No case of fulminant hepatitis was observed. When we examined retrospectively the blood or the organ donors' sera, we found anti-HCY antibodies and HCY RNA by PCR, suggesting that the source of transmission of HCY as either the blood products or the transplant. These hypothesis are supported by the fact that the incidence of hepatitis has much decreased since the HCY screening of blood and organ donors (fig 2). Recently, Zein et al have also found a high prevalence of HCY infection in HT patients (7%) [33]. We studied 469 transplanted patients in our hospital. Hepatitis C was diagnosed on the following criteria: anti-HCY seroconversion, or post-graft ALT elevation with HCY RNA detectable in the patient's serum. We found that 48 patients (10.4%) were infected by HCY. The prevalence rate of hepatitis C according to the year of transplantation is given in fig 2. The mean delay between CR and the first ALT elevation or the positivation of PCR was 13 ± 15 months (median 6 months). All the patients became chronically infected (as assessed by PCR two years after the onset of hepatitis). Clinical, biological, histological and virological findings one year after infection are shown in table I. We observed that ALT levels were generally low, with no severe histological lesions at liver biopsy, while HCY RNA titers, measured using branched DNA [34] were high. Anti-HCY seroconversion was generally delayed and HCY infection was identified much earlier by PCR as already demonstrated in liver transplant recipients [351. In renal transplant recipients with hepatitis Hopal ltla B (%)

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C, other authors [1, 18, 21] have also found that the risk of severe disease was low and that HCY infection was usually clinically silent during the first years of follow up. In patients who had subsequent liver biopsy (n = 15), we found that many patients developed fibrosis. Thus, it could be suggested that immunosuppressive therapy reduces the inflammatory process, but not fibrosis; however, the long term morbidity or mortality and the risk of developing cirrhosis due to viral infection is not known.

COINFECTIONS We observed coinfections with HBY and HCY in eleven cases whose characteristics are shown in table I. One year after the first ALT elevation, although the Knodell score was slightly higher, the severity of liver disease was not significantly different from patients with hepatitis B or C. A longer follow up is needed to conclude, but it may evidence a higher rate of severe outcome in coinfected patients.

HEPATOCARCINOMA We observed no patients with hepatitis B or C who developed hepatocellular carcinoma after a maximum follow up of 10 years (range: 2-10).

HEPATITIS DELTA VIRUS (HDV) SUPERINFECTION There are few cases in the literature of delta superinfection reported in renal or heart transplanted patients. In our series from 1984 to 1995, two patients were diagnosed as having HBY-HDY coinfection, one of them also being HIY infected. In one case (HIY positive), the heart donor was involved in the transmission and the patient died of liver failure. The second developed chronic delta infection and died a few months after transplantation.

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25

20 U

10

Fig 2. Hepatitis C prevalence rate ('Yo) in heart transplant reo cipients according to the year of transplantation.

HEPATITIS A VIRUS INFECTION Although hepatitis A virus (HAY) is probably directly cytopathic, severe or fulminant cases of hepatitis A have not been reported in transplant recipients. In our institution, we osberved one case of acute hepatitis A among more than 500 heart transplant patients. The patient had a mild disease with no icterus and little liver test abnormalities. Interestingly, seric anti-HAY IgM persisted for more than one year of follow up.

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HEPATITIS E VIRUS INFECTION Hepatitis E virus (HEV) is responsible for enterically transmitted hepatitis occuring in endemic areas (Asia, Mexico). Hepatitis E genome was identified in 1990 [36] and serological assays are now available, allowing the detection of antiHEV antibodies [37,38]. Recently, it has been suggested, even if the viremic period is short, that hepatitis E may be transmitted by blood transfusions. We examined the sera of 107 heart transplanted patients who had received blood products during transplantation. Seventy-five had no markers of hepatitis B or C infection, 18 had hepatitis Band 14 hepatitis C virus infection. Anti-HEV antibodies were searched using an ELISA kit (Abbott laboratories, Chicago. Illinois, USA) and confirmed by Western Blot and complementary tests using synthetic peptides. We found that nine patients (8%) had anti-HEY antibodies after transplantation. Four of them were negative before transplantation and had no risk factors for hepatitis E (ie travelling in endemic countries). These results suggest that hepatitis E is more frequent in transplant recipients. Two hypotheses may be suggested: hepatitis E was transmitted through blood tranfusions or through the transplant; or immunosuppressed patients are more susceptible to hepatitis E infection.

HUMAN HERPES VIRUS 6 INFECTION Human herpes virus-6 (HHV-6) is genetically close to CMV and infect mononuclear cells. Severe hepatitis cases due to HHV-6 have been reported in infants [39). HHV-6 infection has also been described in renal of bone marrow transplant recipients [39,40]. In our institution, we studied the HHV-6 status in patients who underwent CR between 1983 and 1987 [41]. These patients were included in a retrospective study on post-transplantation viral hepatitis [5]. Forty-two had biological and/or clinical evidence of chronic hepatitis after CR. Eighteen had no symptoms of LD and were studied as controls. Anti-HHV-6 antibodies were searched by anti-complement immuno-fluorescence assay [42) before and after transplantation and compared with the titer of CMV antibodies determined by ELISA. HHV-6 seroprevalence after transplantation did not differ significantly between patients with hepatitis B or C, control pa-

tients (without hepatitis) and the healthy general population. In three controls and five patients having chronic hepatitis, we observed, after transplantation, a seroconversion or a significant increase of antibody titer which suggested active HHV-6 infection. In six cases, HHV-6 specific IgM were found whereas CMV-specific IgM were not detected. These results indicate that HHV-6 infection is frequent after heart transplantation but not in relation with chronic hepatitis. However, ALT determination was not performed every month in such patients and cases of acute resolving hepatitis can not be ruled out. The mechanism of this infection needs to be clarified in such patients (either prime-infection or reactivation) on further studies in order to know if HHV-6 infection is totally asymptomatic or could induce serious clinical or biological manifestations.

CONCLUSION Viral hepatitis is frequent in heart transplant recipients. The risk of developing post-transplantation hepatitis C has decreased since the screening of organ and blood donors for anti-HCY antibodies (fig 2). On the contrary, hepatitis B still occurs after CR suggesting another mode of transmission. A recent report has evidenced that HBV may be transmitted during endomyocardial biopsy. The natural history of hepatitis B or C is not well known. Immunosuppression entrained high viral replication and chronicity, but few cases of fatal outcome have been described. Until now, interferon is the only treatment that has shown efficiency in patients with chronic hepatitis B or C. However, its immunological properties are responsible for a high risk of rejection and it is not usually recommended in transplanted patients. Vaccination against hepatitis B is required in heart transplantation candidates and in nonimmunized heart transplant patients. Novel antiviral molecules may be of interest in heart transplant patients with hepatitis B or C.

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Hepatitis virus infections in heart transplant recipients

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