Journal of Medical Virology 37S3-86 (1992)

Infection With Hepatitis A, B, Delta, and Human Immunodeficiency Viruses in Children Receiving Cycled Cancer Chemotherapy Archana Kumar, P.K. Misra, G.S. Rana, and Raj Mehrotra Department of Pediatrics (A.K., P.K.M.) and Liver Pathology Unit, Department Medical College, Lucknow, India Serological markers of hepatitis A, B, and Delta and human immunodeficiency viruses were studied in 25 children receiving cancer chemotherapy. Eighty-eight percent had pre-existing HAV immunity which was unaltered by chemotherapy. HDV infection was observed in 8% while HIV was conspicuous by its absence. Active HBV infection, observed i n 76% of the children, was asymptomatic in the majority and was accompanied by a high incidence of HBe antigenaemia (57.9%)and its persistence. Pre-existing anti-HBs failed to prevent HBV infection recurrence, which was, however, transient and self-limiting. Multiple blood transfusions and repeated parenteral exposures appeared t o be the possible sources of HBV acquisition. Transmission t o close contacts was also observed. The study suggests that although HBV vaccine might not be protective against HBV infection i n patients receiving cancer chemotherapy, it may prevent its persistence and thereby help in reducing chronic liver disease-related morbidity and a highly infectious reservoir. Strict HBV screening of blood donors, exclusive use of disposable equipment, and vaccination of close contacts of cancer patients is recommended, particularly in HBV endemic third-world countries. o 1992 Wiley-Liss, Inc.

KEY WORDS: hepatitis viruses, cancer chemotherapy, hepatitis B, HIV

INTRODUCTION Children receiving cycled cancer chemotherapy are at a high risk of acquiring infections due to repeated blood transfusions or other parenteral exposures. The prevalence of hepatitis B virus (HBV) infection is particularly high in this group [Wands et al., 1975; Steinberg et al., 1975; Tabor et al., 19781. Moreover, immunosuppression facilitates HBV infection and modifies the host response [Hoofnagle et al., 1982; Locasciulli e t al., 19851. The present study was conducted to assess the incidence of infection with hepatitis A, B and delta 0 1992 WILEY-LISS, INC.

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Pathology (G.S.R., R.M.), K.G.

and human immunodeficiency viruses and to study their clinical and serological pattern in this high risk and immunocompromised population.

MATERIALS AND METHODS During a 2-year period, 25 children in the age group of 2-12 years, receiving cycled cancer chemotherapy (prednisolone, vincristine, cyclophosphamide, methotrexate, 6 mercaptopurine and adriamycin in different combinations and protocols) for various malignancies [acute leukaemia (15) Hodgkin’s disease (5) nonHodgkin’s lymphoma (4)and rhabdomyosarcoma (1)1 were followed up for periods ranging from 2 months to 2 years. The majority of patients had already received chemotherapy for variable periods (4 days to 2 years) before entering the study. They all received pulsed cancer chemotherapy. During the intervening period between two cycles, leukaemia patients received maintenance drugs while lymphoma cases were taken off therapy. Therapy had been discontinued in a single patient with Hodgkin’s disease, who was admitted with a relapse after a treatment-free period of 2% years following completion of eight cycles. None had received hepatitis B vaccine or any immunoglobulin preparation. Each patient was screened a t intervals (2 weeks to 3 months) for alanine aminotransferases (ALT) and serological markers of HBV (HBsAg, anti-HBs, anti-HBc and its IgM, HBeAg and anti-HBe), hepatitis A virus (anti-HAV and its IgM), hepatitis delta virus (antiHDV) and human Immunodeficiency virus (anti-HIV) by enzyme immunoassay (Abbotts Diagnostics, North Chicago, IL).

RESULTS HBV Infection Active HBV infection (presence of HBsAg and/or anti-HBc IgM) was demonstrated in 19 (76%) at some stage. All five patients who failed to acquire HBV had a shorter period of follow-up (2-5 months). On the other

Accepted for publication September 27, 1991 Address reprint requests to Dr. Archana Kumar, B-45,Mandir Marg, Mahanagar Extension, Lucknow (U.P.), 226006, India

Kumar et al.

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blood products. During follow-up anti-HBs disappeared after 4 to 8 weeks in four patients and three of them subsequently (10-24 weeks later) developed raised ALT along with appearance of anti HBc IgM (Fig. 1, Case Nos. 16-18). However, a clinically overt but mild and a transient jaundice was noticed only in one. In group 111, two patients (Case Nos. 23, 24) presented with acute HBV hepatitis (jaundice, elevated ALT, anti-HBc IgM) after 1 and 3 weeks of chemotherapy. The remaining five were HBsAgiHBeAg carriers who had received chemotherapy for variable periods ranging from 4 months to 3 years. The acute phase of HBV hepatitis had probably been subclinical a s none gave a previous history of jaundice or hepatitis-like illness. During the subsequent follow-up HBsAg persisted but ALT remained normal.

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hand, HBV infection was observed in all those with a follow-up of 6 or more months. Since the prechemotherapy HBV status of all patients was not known, they were placed into three groups on the basis of serological markers detected at entry to the study. Group I included children without HBV markers, group I1 had patients with evidence of past HBV exposure (anti-HBs positive) while group I11 consisted of children with pre-existing active HBV infection. Figure 1shows duration of therapy before entry to study, units of blood transfused and sequential presence of HBV markers. Nine of 13 group I patients, including two who had not received any blood transfusion, became HBsAg positive 4 to 28 weeks (mean 14.2) later, after 5-40 weeks (mean 22) of chemotherapy. However, none of these developed overt hepatitis or raised ALT levels. Another child developed acute hepatic failure, gastrointestinal haemorrhage, and marked derangement of liver functions. HBV markers were initially absent but seroconversion to anti-HBs and anti-HBc occurred 4 and 8 weeks later. In group I, only three patients remained free of HBV but their follow-up period was short (2-3 months). In group TI, the exact mode of anti-HBs acquisition could not be ascertained. There was a past history of jaundice in one subject but the aetiology of this episode had not been established. A possible passive acquisition through transfused blood could not be excluded in three, but the remaining two had not received any

HBe antigenemia was observed in 11 of 19 (57.9%) HBV infected cases and persisted in 10 (90%).In contrast, HBsAg was cleared by five of the eight children without HBeAg (Fig. 1). During the observation period only six cleared HBV antigenaemia and on analysis of possible contributory factors, it was observed t h a t three had anti-HBs in the initial samples (Case Nos. 16-18) while the remaining three (Case Nos. 4,23, and 24) had HBV hepatitis during the early stages of chemotherapy (within 4 weeks). HBV infection, on the other hand, had occurred much later, after 12-62 weeks (mean 25) of chemotherapy, in all the group I patients who developed HBV persistence. Seven children died during the study period. All were HBsAg and/or anti-HBc IgM positive but in none was death attributable to underlying liver disease.

Recurrence of HBV Infection HBV recurrence was noted in four patients (Case Nos. 16-18 and 24). In the former three, it was characterised by appearance of anti-HBc IgM and raised ALT soon after anti-HBs had disappeared. It is difficult to comment whether this recurrence was a reinfection or reactivation of previous infection. Liver Histology Liver biopsy was carried out in one HBV carrier (Case No. 25). Liver histology did not reveal any significant alterations except for the presence of orcein-positive ground glass hepatocytes.

HBV Transmission The data on HBV of the blood transfused to patients was not always available. This could have been a possible source of infection. However, HBV infection also occurred in three patients who had not received any transfusion. During the study period, one of the parents of two patients developed acute HBV hepatitis. A sibling of another patient was also found to be HBsAgpositive, when screened for HBV markers, after a previous history of jaundice occurring 6 months earlier. All

Infection in Children Receiving Chemotherapy three subjects whose close contacts developed HBV hepatitis were HBsAg- and HBeAg-positive.

HDV Infection Anti-HDV appeared with HBV infection in one and after persistent HBsAg and HBeAg infection in the other. In the latter, anti-HDV disappeared 1 month later. The appearance of anti-HDV was not associated with clincal deterioration. HAV Infection Ninety-two percent patients had a pre-existing HAV immunity (anti-HAV)which persisted. Sero conversion occurred in nonimmune children also but anti-HAV IgM was not demonstrated. HIV Infection Though routine HIV screening of donors is not done, anti-HIV was not demonstrated in any patient either on entry to study or subsequently. DISCUSSION A high incidence of HBV infection with a tendency to persist highlights the magnitude of problem in this special group of patients. Studies from Western countries describe a lower and decreasing prevalence of HBV infection in paediatric oncology units [Steinberg et al., 1975; Taboret al., 1978; Wands et al., 1975)which can be attributed to improved techniques of screening blood and its products along with exclusive use of disposable equipment [Locasciulli et al., 19851. The high incidence of HBV persistence and chronic liver disease in cancer patients confirms previous studies [Hoofnagle et al., 1982; Locasciulli et al., 1985; Trevisan et al., 1982; Bortolotti et al., 19831 and has been attributed to chemotherapy induced immune suppression. Locasciulli et al. [19851 reported a strong association of biochemical evidence of liver damage in cancer patients, which was not related t o the presence of HBV markers. In contrast, biochemical evidence of liver damage was minimal in the present study, despite a high prevalence and persistence of HBV infection. A possible reason for this difference might be a higher HCV infection in the former study [Locasciulli et al., 19831. HBV hepatitis was largely subclinical or so mild and transient a s to easily escape clinical detection, particularly if it occurred during the later stages of chemotherapy, This is not surprising considering that liver injury in HBV infection is immune mediated [Eddleston et al., 1986; Desmet, 19891. Possibly, longer periods of follow-up after discontinuation of chemotherapy permit a sufficient time interval for immune recovery to make liver injury manifest. During acute HBV hepatitis, HBe antigenaemia indicates a n active viral replication, ongoing hepatocyte damage, and a high infectivity [Miyakawa et al., 19851. Its persistence for longer than 6 to 10 weeks strongly predicts the onset of HBV chronicity [Aldershvile et al., 1980; Krosgaard et al., 19851. Presence of HBeAg in

85

57.9% of HBV infected cases, its persistence in go%, and the probable transmission to close contacts by three of them further highlights the seriousness of this problem. It appears that despite the constantly improving survival of cancer patients, a s a result of availability of better chemotherapeutic agents and regimens, HBV infection would continue to contribute significantly toward their long-term morbidity, particularly in developing areas of the world, unless strict preventive measures are undertaken. Moreover, these patients would also constitute a highly infectious HBV reservoir. The disappearance of anti-HBs after chemotherapy and its inability to prevent subsequent recurrence of HBV infection was a n interesting observation. This has also been previously reported [Wands et al., 1975; Locasciulli et al., 1983; Grumayer et al., 19891 and suggests t h a t immunity acquired after HBV vaccination would, in all probability, also not be protective. However, it should be emphasized that HBV antigenemia did not persist in any of the patients who had anti-HBs in their prechemotherapy stages. It is possible, therefore, that anti-HBs induced after HBV immunization might also prevent the persistence in these patients and thus might help in reducing their morbidity and infectivity. The ability of immune suppressed children to mount a suitable response to HBV vaccination is debatable. However, appearance of anti-HBs in some patients, following HBV infection early during course of chemotherapy, lends credibility to the possibility of a n adequate antibody response to HBV vaccine, provided that it is given prior to chemotherapy. HAV infection was not significant. This is not surprising considering its non-parenteral nature of transmission. Moreover, pre-existing immunity was present in 92% patients, which, unlike the immunity against HBV, was not affected by chemotherapy. HDV also did not appear to be a major problem. The absence of HIV, despite the high risk population and non-screening of donors, probably reflects a low prevalence of HIV in this area. Our observations stress the need for a n awareness of this problem, especially in developing areas of the world where HBV infection is endemic. Strict measures for screening of blood donors, exclusive use of disposable equipment in management of cancer patients along with HBV vaccination of close contacts, is recommended. The possibility that HBV vaccine may also prevent the development of chronic HBV infection needs careful consideration and clinical trials especially in third-world countries.

REFERENCES Aldershvile J, Frosner GG, Nielson JO, Hardt F, Deinhardt F, Skinhoj P (1980):Hepatitis B e antigen and antibody measured by radioimmunoassay in acute hepatitis B surface antigen positive hepatitis. The Journal of Infectious Diseases 141:293-298. Bortolotti F, Cadrobbi P, Bertaggia A, Rude L, Alberti A, Realdi G (1983): A 7 year survey of acute hepatitis type B. Archives of Disease in Childhood 58:993-996.

86 Desmet VJ (1989): Acute viral hepatitis B. In Gitnick GL (ed): “Modern Concepts of Acute and Chronic Hepatitis.” New York: German Publishing Corporation, pp 87-111. Eddleston ALWF, Modelli M (1986): Immunopathological mechanism of liver injury in chronic hepatitis B virus infection. Journal of Hepatology 3(Suppl2):S17-S23. Grumayer ER, Panzer S, Ferenci P, Gander H (1989): Recurrence of hepatitis B in children with serologic evidence of past B virus infection undergoing anti leukemic chemotherapy. Journal of Hepatology 8232-235. Hoofnagle JH, Dusheiko GM, Schafer DF, Jones EA, Micetich KC, Young RC, Costa J (1982): Reactivation of chronic hepatitis B virus infection by Cancer chemotherapy. Annals of Internal Medicine 96447449. Krosgaard K, Kryger P, Aldershvile J, Anderson P, Nielson JO, Hansson BG and the Copenhagen Hepatitis Acuta Programme (1985): Hepatitis B virus DNA in serum from patients with acute hepatitis B. Hepatology 510-13. Locasciulli A, Alberti A, Rarbieri R, Realdi G, Uderzo C, Portmann B, Masera G (1983): Evidence of Non-A Non-B hepatitis in children with acute leukemia and chronic liver disease. American Journal of Diseases of Children 137:354-356.

Kumar et al. Locasciulli A, Santamaria M, Masera G, Schiavon E, Alberti A, Realdi G (1985): Hepatitis B virus markers in children with acute leukemia: The effect of chemotherapy. Journal of Medical Virology 1529-33. Miyakawa Y, Nayumi M (1985):Hepatitis B e Antigen and Antibody. In Gerety RJ (ed): “Hepatitis B.” Orlando, Florida: Academic Press Inc., pp 47-76. Steinberg SC, Alter HJ, Leventhal BG (1975). The risk of hepatitis transmission to family contacts of leukemia patients. The Journal of Pediatrics 87:753-756. Tabor E, Gerety RJ,Mott M, Welburg J (1978):Prevalence ofhepatitis B in high risk setting. A serologic study of patients and staff in a pediatric oncology unit. Pediatrics 61:711-715. Trevisan A, Cadrobbi P, Crivellaro C, Bortolotti F, Rugge M, Realdi G (1982): Virologic features of chronic hepatitis B virus infection in childhood. The Journal of Pediatrics 100:366-372. Wands JR, Chura CM, Roll FJ, Maddrey WC (1975): Serial studies of hepatitis associated antigen and antibody in patients receiving anti tumor chemotherapy for myeloproliferative and lymphoproliferative disorders. Gastroenterology 68:105-111.

Infection with hepatitis A, B, delta, and human immunodeficiency viruses in children receiving cycled cancer chemotherapy.

Serological markers of hepatitis A, B, and Delta and human immunodeficiency viruses were studied in 25 children receiving cancer chemotherapy. Eighty-...
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