Correspondence

Hepatitis Associated with Hepatitis A Superinfection in Patients with Chronic Hepatitis C

N Engl J Med 1998; 338:1771-1773June 11, 1998

Article

To the Editor:

Vento et al. (Jan. 29 issue)1 reported 27 cases of acute hepatitis A among 595 patients with chronic liver disease who were positive for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV). Of the 17 patients with acute viral hepatitis A and chronic HCV infection, fulminant liver failure developed in 7, and 6 of them died.

This surprisingly high fatality rate conflicts with data from the specific surveillance system of acute viral hepatitis (SEIEVA) established in Italy in 1985.2 Since 1993, approximately 50 percent of the Italian population, uniformly distributed throughout the country, has been monitored by SEIEVA, including those living in the Veneto region where part of the study by Vento et al. was performed. The system collects information about all reported cases of acute viral hepatitis occurring in the participating health districts. Each case is serologically confirmed; the anti-HCV test has been performed since 1992.

From 1992 to 1996, 6032 cases of acute hepatitis A (the patients were positive for IgM antibodies to hepatitis A virus [HAV]) were reported; 179 occurred in patients positive for HBsAg or HCV or both (Table 1Table 1Numbers of Cases of Acute Viral Hepatitis A, According to the Presence or Absence of HBsAg or HCV or Both in Italy.). None of the 6032 patients died. Of 2699 patients with acute hepatitis A from 1985 to 1991, 1 patient, who was 68 years old, died.

We cannot explain the discrepancy between our data and those reported by Vento et al. Although in Italy reporting of acute viral hepatitis is compulsory, as it is in other countries, underreporting is common. Nevertheless, it is unlikely that deaths due to fulminant acute hepatitis are not being reported to SEIEVA.

During the same study period, 11 deaths were reported among 3176 patients with acute hepatitis B (the patients were IgM anti-hepatitis B core–positive) and 1 among 1218 patients with anti-HCV–positive acute hepatitis. One death occurred among 564 patients positive for HBsAg or IgM anti-HBc and HCV.

Alfonso Mele, M.D.
Maria Elena Tosti, Stat.Sc.
Tommaso Stroffolini, M.D.
National Institute of Health, 00161 Rome, Italy

2 References

1. 1

   Vento S, Garofano T, Renzini C, et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med 1998;338:286-290
   Full Text | Web of Science | Medline

2. 2

   Mele A, Rosmini F, Zampieri A, Gill ON. Integrated epidemiological system for acute viral hepatitis in Italy (SEIEVA): description and preliminary results. Eur J Epidemiol 1986;2:300-304
   CrossRef | Medline

To the Editor:

The high case fatality rate of 35 percent among patients with chronic HCV and HAV superinfection reported by Vento et al. was not confirmed by others, as reviewed by Keeffe,1 and may represent a chance effect of a small patient subgroup that was insufficiently characterized. Starting in November 1994, we prospectively observed a cohort of 170 intravenous drug users enrolled in an intravenous-opiate–maintenance study in Basel, Switzerland, with a mean follow-up period of 1.6 years. Seroprevalence of dual infection with HAV and HCV at the onset of the study was 55.8 percent. Seven participants acquired acute HAV infection with documented IgM antibodies, including four with preexisting chronic hepatitis C. The present high prevalence of dual infections in our cohort and the absence of fulminant hepatitis among patients with newly diagnosed HAV superinfection contrasts with the findings of Vento et al. We therefore question their recommendation that carriers of HCV be vaccinated against HAV.

Manuel Battegay, M.D.
Marcel Naef, M.D.
Heiner C. Bucher, M.D.
University Hospital of Basel, CH-4031 Basel, Switzerland

1 References

1. 1

   Keeffe EB. Is hepatitis A more severe in patients with chronic hepatitis B and other chronic liver diseases? Am J Gastroenterol 1995;90:201-205
   Web of Science | Medline

To the Editor:

We recently described an epidemic of HAV infection involving approximately 400 people in Finland.1 The majority were injection-drug abusers, among whom 75 had HCV antibodies, suggesting preexisting HCV infection. During the outbreak, three people died, of whom two were elderly alcoholics and one was a young drug abuser. There were no deaths among the HCV carriers.

Our study was an investigation of an outbreak, not a follow-up study. We have no histologic data about the HCV carriers, their HLA phenotypes, their autoimmune markers, or their hepatitis G virus (HGV) serologic findings. HGV infection, which the authors suggest as a possible factor contributing to severe disease, seems to be rare in Finland. In addition, the epidemic was caused by a single genotype of HAV, and strains with different degrees of pathogenicity may be revealed when more genomic information is collected from various outbreaks. Strain differences in the virulence of HCV infection are known, but in Finland2 the same genotypes of HCV are prevalent as occurred in the fatal cases of Vento et al.

The route of transmission may have a role. We assume that a large proportion of the patients in our series contracted HAV infection parenterally from the intravenous use of contaminated amphetamine. The mean age of our patients coinfected with HCV and HAV (31 years) was similar to that of the patients Vento et al. studied (28 years), although we do not know the duration of HCV infection or the severity of preexisting liver disease among our patients.

Tuija Leino, M.D.
Richard Pebody, M.B., Ch.B.
Pauli Leinikki, M.D., Ph.D.
National Public Health Institute, FIN-00300 Helsinki, Finland

2 References

1. 1

   Leino T, Leinikki P, Hyypia T, et al. Hepatitis A outbreak amongst intravenous amphetamine abusers in Finland. Scand J Infect Dis 1997;29:213-216
   CrossRef | Web of Science | Medline

2. 2

   Pohjanpelto P, Lappalainen M, Widell A, Asikainen K, Paunio M. Hepatitis C genotypes in Finland determined by RFLP. Clin Diagn Virol 1996;7:7-16
   CrossRef | Medline

To the Editor:

No data were presented about whether the presence of hepatitis E virus (HEV) was assessed in the patients studied by Vento et al. Moreover, the prevalence of HEV infection in Italy was not reported. Since the ethnic background and origin of the patients investigated were not discussed, could some migrants from areas with a high prevalence of endemic HEV infection have been enrolled in the study?

HEV has been associated with fulminant hepatitis, mostly but not exclusively in pregnant women.1 This is particularly true for areas with high rates of endemic HEV infection.2 Sporadic cases of HEV-related fulminant hepatitis have also been reported in areas with a low prevalence of HEV infection. Furthermore, HEV–HCV coinfection was recently detected in 11 percent of 50 patients with well-documented fulminant hepatitis.3 Thus, HEV could also have a role in fulminant hepatitis occurring in patients with chronic HCV infection.

Eduardo Bruno Martins, M.D., D.Phil.
Federal University of Rio de Janeiro, Rio de Janeiro RJ 22940, Brazil

3 References

1. 1

   Fagan EA, Williams R. Fulminant viral hepatitis. Br Med Bull 1990;46:462-480
   Web of Science | Medline

2. 2

   Acharya SK, Dasarathy S, Kumer TL, et al. Fulminant hepatitis in a tropical population: clinical course, cause, and early predictors of outcome. Hepatology 1996;23:1448-1455
   CrossRef | Web of Science | Medline

3. 3

   Nanda SK, Yalcinkaya K, Panigrahi AK, Acharya SK, Jameel S, Panda SK. Etiological role of hepatitis E virus in sporadic fulminant hepatitis. J Med Virol 1994;42:133-137
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We are glad to know that the high rate of fulminant hepatitis we observed among patients with HAV infection superimposed on chronic hepatitis C contrasts with data from others and cannot be regarded as a frequent occurrence.

Our study was performed in three centers, and four of the cases were not reported to SEIEVA, because of initial doubts about the diagnosis (autoimmune hepatitis rather than hepatitis A). The diagnosis was subsequently and definitively established by the finding of HAV RNA in stools; at that stage, unfortunately, reporting was overlooked. The other cases occurred outside Italy (in San Marino) and therefore were not reported.

The data from SEIEVA collectively indicate an extremely low case fatality rate in Italy, both for hepatitis A (1 of 8731 cases, 0.01 percent) and for hepatitis B (11 of 3176 cases, 0.3 percent). This contrasts with data from Greece1 and the United States2 indicating a case fatality rate for acute hepatitis A ranging from 0.02 to 1.5 percent in patients without chronic liver disease and reaching 4.6 percent in patients with chronic liver disease. Perhaps underreporting has a role in generating such differences.

Battegay and colleagues suggest that the extremely high case fatality rate we observed may represent a chance effect. Although this is possible, their numbers may be too low to support confident conclusions.

We have now tested stored serum samples for IgM and IgG anti-HEV antibodies (by enzyme immunoassay and Western blotting, Abbott Laboratories, North Chicago, Ill.); one patient had IgG anti-HEV antibodies in the absence of IgM, and the remaining six had no such antibodies. All our patients were Italian; the seroprevalence of anti-HEV antibodies in Italy ranges from 1 to 5 percent.3

Finally, we must stress that the finding of anti-HCV antibodies cannot be taken to indicate in all cases the presence of HCV (HCV RNA should be searched for) or chronic liver disease, and that information is essential when one is considering superinfection with other hepatitis viruses. Recent analyses from the United States indicate that death from hepatitis A is strongly associated with having chronic liver disease (27.5 percent of case patients vs. 3.4 percent of controls).4 On the basis of our unfortunate experience, we advise patients with chronic hepatitis C to be vaccinated against hepatitis A.

Sandro Vento, M.D.
Ercole Concia, M.D.
University of Verona, 37124 Verona, Italy

Giancarlo Ghironzi, M.D.
San Marino State Hospital, San Marino, Republic of San Marino

4 References

1. 1

   Papaevangelou G. Current recommendations for control of hepatitis A. In: Rizzetto M, Purcell RH, Gerin JL, Verme G, eds. Viral hepatitis and liver disease. Turin, Italy: Edizioni Minerva Medica, 1997:720-3.
   

2. 2

   Hadler SC. Global impact of hepatitis A virus infection: changing patterns. In: Hollinger FB, Lemon SM, Margolis H, eds. Viral hepatitis and liver disease. Baltimore: Williams & Wilkins, 1991:14-20.
   

3. 3

   Zanetti AR, Dawson GJ, Study Group of Hepatitis E. Hepatitis type E in Italy: a seroepidemiological survey. J Med Virol 1994;42:318-320
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4. 4

   Williams I, Bell B, Kaluba J, Shapiro C. Association between chronic liver disease and death from hepatitis A, United States, 1989–92. Presented at the Triennial International Symposium on Viral Hepatitis and Liver Disease, Rome, April 21–25, 1996. abstract.
   

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