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The New England Journal of Medicine -- January 27, 2000 -- Vol. 342, No. 4

Hepatitis C in Children

To the Editor:

The report by Vogt et al. (Sept. 16 issue) (1) and the accompanying editorial (2) on hepatitis C infection in children highlight the fact that this infection is typically more indolent and slowly progressive in children than in adults. However, it may be a leap of faith to suggest that treatment for hepatitis C should be delayed or is unwarranted in children.

At our center, we have seen three children with end-stage liver disease due to perinatally acquired hepatitis C. The children presented with decompensated cirrhosis at the ages of 4, 6, and 11. One patient presented with jaundice, coagulopathy, and wasting, whereas the others had ascites, hypoalbuminemia, coagulopathy, and wasting. Two were infected with genotype 1a, and one with 1b. Two children had mothers who were infected with the human immunodeficiency virus (HIV), although extensive testing in the children revealed no coinfection with HIV. No child had evidence of a secondary form of liver disease that would have accelerated the course of hepatitis C. Two children underwent liver transplantation, and one is awaiting transplantation. Advanced cirrhosis was evident in the explanted livers. Of the two children who received a transplant, recurrent chronic active hepatitis C developed in both within a few months after surgery. One died of complications of recurrent hepatitis C, whereas the other remains in clinically stable condition despite chronic active hepatitis.

Hepatitis C is not always an innocuous disease in childhood. Recent histologic studies by Badizadegan and coworkers (3) also suggest that cirrhosis and extensive fibrosis are not rare in children with this infection. Moreover, treatment with interferon alfa may have substantially better results in children than in adults, with some studies demonstrating a rate of sustained response of more than 50 percent. (4)

At this point, the factors that herald a more aggressive course in children with hepatitis C are unknown. However, the morbidity associated with liver transplantation and the high rate of recurrence of this disease after transplantation are well established. Given our experience with rapidly progressing hepatitis C in children, we believe that the antiviral treatment should be given strong consideration.

Audrey H. Birnbaum, M.D.
Benjamin L. Shneider, M.D.
Mount Sinai Medical Center
New York, NY 10029-6574

Libia Moy, M.D.
Winthrop University Hospital
Mineola, NY 11501

References

1. Vogt M, Lang T, Frosner G, et al. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med 1999;341:866-70.
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2. Jonas MM. Hepatitis C infection in children. N Engl J Med 1999;341:912-3.
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3. Badizadegan K, Jonas MM, Ott MJ, Nelson SP, Perez-Atayde AR. Histopathology of the liver in children with chronic hepatitis C viral infection. Hepatology 1998;28:1416-23.
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4. Fujisawa T, Inui A, Ohkawa T, Komatsu H, Miyakawa Y, Onoue M. Response to interferon therapy in children with chronic hepatitis C. J Pediatr 1995;127:660-2.
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The authors reply:

To the Editor:

We reported on a cohort of 458 children, 67 of whom had asymptomatic post-transfusion hepatitis C. In contrast, Birnbaum et al. describe three symptomatic cases of vertically transmitted infection in children with end-stage liver disease. In a large study of vertically transmitted hepatitis C virus (HCV) infection, Kumar et al. found that of 65 mothers who were positive for antibodies to HCV, the babies of 20 were positive for HCV RNA by six months of age. (1) Three children died of liver disease, and chronic disease developed in 16. This finding might suggest that the course of vertically transmitted infection is more progressive and serious than the course in our patients with post-transfusion disease.

We agree with Birnbaum et al. that hepatitis C is not an innocuous disease in childhood and may lead to severe liver-cell damage. Our histopathological findings in 17 patients showed mild necroinflammatory activity in 14 and fibrosis in 3 patients, 2 of whom had the additional risk factor of liver disease. Fibrosis was more common and severe in the heterogeneous group studied by Badizadegan et al. (2) than in our patients. However, cofactors that increase the risk of fibrosis have to be taken into account. (2)

Locasciulli et al. reported a benign long-term outcome in 114 consecutive patients after cure of leukemia. (3) Of 56 patients with detectable HCV RNA, 16 had clearance of the virus. In none of the infected patients did severe liver disease develop. These findings support our data indicating that the clinical course of post-transfusion HCV infection in children is benign.

Birnbaum et al. comment on the efficacy of interferon alfa monotherapy in children. However, they do not clarify whether their patients with unfavorable outcomes had been treated with this drug before transplantation. As a rationale for treatment, they mention the high rate of sustained response reported by Fujisawa et al. (4) More recently, in a prospective trial of interferon treatment in children with hepatitis C, Jonas et al. reported a sustained-response rate of 19 percent after six months and of 33 percent after at least one year of treatment. (5) Patients infected with genotypes 1a and 1b had a less favorable response.

Combination therapy with interferon alfa and ribavirin seems to be a more promising therapeutic approach in adults. (6) We conclude that interferon monotherapy cannot be generally recommended for children with asymptomatic HCV infection. However, the appropriateness of combination treatment should be carefully evaluated in children with symptomatic liver disease due to hepatitis C.

Thomas Lang, M.D.
Children's University Hospital
D-80337 Munich, Germany

John Hess, M.D., Ph.D.
Manfred Vogt, M.D.
German Heart Center
D-80636 Munich, Germany

References

1. Kumar RM, Frossad PM, Hughes PF. Seroprevalence and mother-to-infant transmission of hepatitis C in asymptomatic Egyptian women. Eur J Obstet Gynecol Reprod Biol 1997;75:177-82.
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2. Badizadegan K, Jonas MM, Ott MJ, Nelson SP, Perez-Atayde AR. Histopathology of the liver in children with chronic hepatitis C viral infection. Hepatology 1998;28:1416-23. Hepatology 1998;28:1416-23.
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3. Locasciulli A, Testa M, Pontisso P, et al. Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood 1997;90:4628-33.
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4. Fujisawa T, Inui A, Ohkawa T, Komatsu H, Miyakawa Y, Onoue M. Response to interferon therapy in children with chronic hepatitis C. J Pediatr 1995;127:660-2.
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5. Jonas MM, Ott MJ, Nelson SP, Badizadegan K, Perez-Atayde AR. Interferon-alpha treatment of chronic hepatitis C virus infection in children. Pediatr Infect Dis J 1998;17:241-6.
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6. Poynard T, Marcellin P, Lee SS, et al. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998;352:1426-32.
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To the Editor:

There is no doubt that hepatitis C can cause severe, life-threatening liver disease in children. In the study by Vogt et al., 1 of the 17 patients who underwent liver biopsy had cirrhosis. In a study referred to by Birnbaum et al., my colleagues and I found that 2 of 45 children (4.4 percent) had cirrhosis at presentation; both had been infected perinatally. (1) One has died from complications of recurrent infection after transplantation, and the other is awaiting transplantation. In the United States, others who care for children with liver disease have had similar experiences. Yet in the majority of children who are infected in the first years of life, even those infected perinatally, advanced liver disease does not develop during the first two decades after infection. (2,3,4) This overall natural history is quite different from that of infection that begins in adulthood; the 20-year progression to cirrhosis and subsequent rapidly escalating risk of hepatocellular carcinoma have been well documented in adults.

Herein lies the challenge. What are the host, virologic, and environmental factors that make this infection so aggressive in a minority of young children? Birnbaum et al. allude to the fact that two of the three children with advanced disease whom they treated were born to women who were coinfected with HIV and HCV. Even though HIV was not cotransmitted, there may have been some immunologic consequences. Were there multiple exposures? Was the inoculum large? Did the children have underlying malnutrition?

Children may be good candidates for treatment because of the short duration of infection and the mildness of the disease that is typical at presentation. If the infection could be eradicated in virtually all children, then perhaps a greater understanding of natural history would be unnecessary. But with our still imperfect therapy, it is likely that many children will not have a response to treatment. We must continue to examine the differences between infections in adulthood and childhood and exploit these differences to avoid the potentially dire consequences of this disease.

Maureen M. Jonas, M.D.
Children's Hospital
Boston, MA 02115

References

1. Badizadegan K, Jonas MM, Ott MJ, Nelson SP, Perez-Atayde AR. Histopathology of the liver in children with chronic hepatitis C viral infection. Hepatology 1998;28:1416-23.Hepatology 1998;28:1416-23.
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2. Locasciulli A, Testa M, Pontisso P, et al. Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood 1997;90:4628-33.
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3. Bortolottti F, Resti M, Giacchino R, et al. Hepatitis C virus infection and related liver disease in children of mothers with antibodies to the virus. J Pediatr 1997;130:990-3.
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4. Garcia-Monzon C, Jara P, Fernandez-Bermejo M, et al. Chronic hepatitis C in children: a clinical and immunohistochemical comparative study with adult patients. Hepatology 1998;28:1696-701.
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