January 1978 The Journal o f P E D I A T R I C S

17

Hepatitis B in children L Analysis

of 80 cases

of acute

and

chronic

hepatitis

B

From 1971 to 1975, HB V-induced hepatitis was observed in 80 children. The diagnosis was based upon the detection in serum of HBsAg and~or the secondary occurrence of anti-HBs. Thirty-one patients presented with acute viral hepatitis, 16 with severe or fulminant hepatitis, 17 with chronic persistent hepatitis, 12 with chronic active hepatitis, and 4 were asymptomatic chronic carriers o f HBsA g. Twentynine of 80 children were under one year of age (36%), the peak of frequency occurring from 2 to 5 months. The source of infection, determined in 27 of 29 infants, was administration of blood derivatives in 15 cases and contact with an HBsAg carrier mother in nine instances. In the latter type, the incubation time (103 days) was compatible with an oral route o f infection. Persistent antigenemia occurred in only 3 of 29 patients. The overt type of disease developed by most infants, as well as the small number of patients who became HBsAg carriers, suggest ihat the carrier state, often encountered in neonatally infected infants in other countries, may be related to environmental or genetic factors rather than to immaturity of the immune system.

J. M. Dupuy, M.D.,* Ewa Kostewiez, M.D., and D. Alagille, M.D., BicOtre, F r a n c e

T H E ASSOCI AT I ON of hepatitis-B antigen with hepatitis type B infection is well established. 1-~ In adult patients, however, clinical features associated with hepatitis B antigen are often complex, since hepatic disorders of other causes are often associated. In children, and especially in infants infected during the neonatal period, the liver disease is due to a single agent and its natural evolution can be followed. Since 1971, all patients admitted to the pediatric department for liver disease have been systematically screened for determination of HBsAg and anti-HBs. This study analyzes 80 patients with HBV-induced hepatitis. PATIENTS AND METHODS

Patients. From 1971 to 1975, a total of 3,372 new patients were referred to the department of pediatrics. From the Unitb de Recherche d'Hkpatologie Infantile, I N S E R M U 56 et Clinique de POdiatric, Universitb Paris-Sud, Hbpital d'Enfants. Supported by a grant fi'om 1NSERM, A T P 8-74-29 and by the University Paris-Sud. *Reprint address: INSERM, Hbpital d'Enfants, 94270 BieOtre, France.

Eighty of them were admitted for various liver diseases associated with HBsAg or anti-HBs. The probable cause of the disease was based upon the detection in serum of HBsAg and/or the secondary occurrence of anti-HBs. Liver disease in all patients was documented by the finding of abnormal liver function and/or by biopsy. In addition, tests for HBsAg and anti-HBs were regularly carried out in all patients and in most of the families, Abbreviations used HBV: hepatitis B virus HBsAg: hepatitis B surface antigen Anti-HBs: antibody to hepatitis B surface antigen SGPT: serum glutamic pyruvic transaminase PHA: inhibition of passive hemagglutination RIA: Radioimmunoassay BSP: sulfobromophthalein

Diagnostic criteria. Patients with severe or fulminant viral hepatitis had the clinical, biological, and histologic features of severe acute hepatitis and a history of acute symptoms of less than three weeks' duration, s' ~ In the regular type of acute viral hepatitis, clinical and biological manifestations, including sulfobromophthalein clearance, returned to normal less than three months after onset. 6 VoL 92, No. 1, pp. 17-20

18

Dupuy, Kostewicz, and A lagille

(13 25"

PARENTERAL I PARENTAL F77~ EPIDEMIC / I UNKNOWN

Z

uJ

~

The Journal of Pediatrics January 1978

2015lO-

d Z

5-

1

2

3

4

5

6

7

AGE

8

9

10 11 12 13 14 15

(YEARS)

Fig. 1. Analysis of 80 children with HBV-induced acute and

chronic liver diseases according to age and origin of infection. In the first column (one year of age) parental infection was related to contact with HBsAg carrier mothers in nine cases and to carrier fathers in two cases.

co lZ

[]

HBV elimination

[]

HBsAg

carriers

I.I.I i

16 N-0

~5 z

AH

SH

CPH

1 I::::t::::1 CAH ACC

Fig. 2. Clinical types of HBV-induced hepatitis presented by 29 children under one year of age. A H = acute viral hepatitis; SH = severe or fulrninant hepatitis, CPH = chronic persistent hepatitis, CAH = chronic active hepatitis, ACC = asymptomatic chronic HBsAg carrier). Chronicity and activity were established from the history (cause more than 6 months), pathologic findings, and repeated laboratory tests. All patients had liver biopsy performed at regular intervals with a Menghini needle. Patients with chronic persistent hepatitis had variable onset, occasional increase in SGPT levels, and minimal histologic changes at liver biopsy with focal hepatocytolysis and, often, portal lymphoid hyperplasia. G-~Diagnosis of chronic active hepatitis was based upon established criteria.7.9, 10Activity of the disease was determined by a 5-t'old Jncrease of SGPT, an increase of IgG values of more than 2 standard deviations for age, and histologic characteristics including inflammatory changes and piece-: meal necrosis. TM Treatment consisted of corticosteroids, and, since 1974, combined corticosteroid and azathioprine therapy. 12

Serology. Tests for HBsAg and anti-HBs were performed by the Centre National de Transfusion Sanguine, Paris. An individual was regarded as HBsAg positive when the antigen was detected by at least two of the following procedures: counterimmunoelectrophoresis, microcomplement fixation, inhibition of passive hemagglutination, and radioimmunoassay in fluid phase. '3 AntiHBs was measured by PHA and RIA. Biological hepatic tests included determinations of serum concentrations of transaminases, bilirubin, albumin, immunoglobulins, BSP, total complement, C4, C3, and clotting factors. Measurements of serum alpha fetoprotein and attempts to identify autoantibodies were regularly performed?. 1, RESULTS As shown in Fig. 1, twenty-nine of 80 children were under one year of age (36%). During the first year a peak of frequency was observed at three months. The sex ratio was 50 males and 30 females. The prevalence of males was more pronounced during the first year (males/females: 20/9). Origin of infection. The origin of infection was likely to be parenteral in 27 cases (34%), parental in 15 cases (19%), and epidemic in 14 cases (17%); it was unknown in 24 cases (30%) (Fig. 1). Parental origin was related to HBsAg carrier mothers in nine cases, to carrier fathers in four cases, to both in one case, and to HBsAg-positive hepatitis during pregnancy in one case. In the children under one year of age, origin of infection was determined in 27 of 29 patients. Hepatitis in 15 patients was secondary to administration of blood derivatives, a n d in nine infants was related to contact with HBsAg carrier mothers. The mean incubation time of hepatitis was 91 days in a group of 20 patients infected parenterally and 103 days in a group of nine infants, under one year of age, born to chronic carrier mothers (Table I). Clinical presentations. The various types of hepatitis observed in children are presented in Table II and in Fig. 2. In acute hepatitis, HBsAg was found 17 times. It became negative les s than eight days after hospital admission in 12 patients and within one month in five. Anti-HBs was found within six months in five instances; antigenemia was not detected in 15 cases. Hepatitis was most likely of HBV origin since anti-HBs developed from eight days to six months after the onset of jaundice. HBsAg was detected in serum at the onset of the disease in 12 of 16 patients with severe hepatitis; ten of these patients died (62%). Five patients had a complete clinical, biological, and histologic recovery; one patient developed fulminant cirrhosis?' 14 Chronic persistent hepatitis was observed in 17 patients referred to our pediatric department after an average

Volume 92 Number 1

Hepatitis B in children

19

Table I. Mean incubation time of hepatitis according to origin of infection and type of disease

Parenteral infection* Type of disease Acute hepatitis Severe hepatitis Chronic persistent hepatitis Chronic active hepatitis Asymptomatic HBsAg carriers Total

HbsAg carrier mothers~f

Mean incubation time (days)

No. of patients

Mean incubation time (days)

No. of patients

90 78 120 -

9 7 4 0 0 20

73 94 180 165 60 103

2 4 1 1 1 9

91

*From injection of blood derivatives to occurrence of jaundice. tin nine infants under one year &age the mean incubation time was evaluated from birth to occurrence&jaundice, except for the asymptomaticcarrier patient in whom a systematic family screening led to discovery of HBsAg. Table II. Distribution of viral hepatitis type B in 80 children

Type of disease Acute hepatitis Severe hepatitis Chronic persistent hepatitis Chronic active hepatitis Asymptomatic HBsAg carriers Total

No. of patients 31 16* 17 12 4 80

Sex ratio M/F 24/7 6/l0 8/9 7/5 2/2 48/32

Age of onset average (yr)

3 6 5 4

4 3 3/12 6/12 9/12 6/12

Origin of infection Parenteral ] Parental I Epidemic I Unknown 12 7 6 0 2 27

3 5 3 2 2 15

5 1 6 2 0 14

I1 3 2 8 0 24

*Including nine infants under 6 months of age. course of 13 months. The onset was acute in nine patients, with jaundice in five. Isolated hepatomegaly was discovered six times. Sixteen patients remained HBsAg positive after an average follow-up time of 27 months. In a 6-yearold girl, chronic persistent hepatitis was diagnosed on the basis of typical biological and histologic data, and was associated with persistent antigenemia. After 13 months, disappearance of antigenemia was followed by occurrence of anti-HBs. Liver function returned to normal and another liver biopsy revealed normal histology. All 12 patients with chronic active hepatitis developed cirrhosis. Eight had a favorable outcome after an average time of treatment of 27 months. HBsAg, present in these eight at the onset of the disease, disappeared in six and was followed by the presence of anti-HBs in five. Antigenemia persisted after healing in two children. A Vietnamese girl born to a carrier mother developed a hepatitis type B at age 5 months. At 8 months of age, biological and histologic data were compatible with the diagnosis of chronic active hepatitis. At 15 months of age, antigenemia disappeared and was followed by the appearance of antiHBs. Liver function tests showed disappearance of signs of activity. Laparoscopy and liver biopsy revealed an inactive hepatitis with cirrhosis. No relapse occurred after one year of follow-up. In 4 of the 12 patients with chronic active hepatitis, the course was unfavorable. The average

time of treatment was four years, ranging from two to eight years. One HBsAg carrier died after 42 months of illness. In the other three patients, both HBsAg and antiHBs were regularly detected in serum. DISCUSSION The most striking feature of this study was the large number of infants under one year of age with overt hepatitis. The assumption that a similar disease is more alarming in infants than in older children constituted an obvious source of bias, since the former were more often referred to the hospital than the latter. In the group of infants under one year of age, a peak of frequency occurred between two and five months (71%), suggesting infection during the perinatal period. Similarly, the average time between birth and appearance of jaundice in infants born to carrier mothers was compatible with an oral route of infection, since hepatitis induced by oral inoculation of MS-2 virus has an average incubation time of 98 days. a In all infants, HBsAg disappeared from serum within one to five days after the onset of jaundice, and persistent antigenemia occurred in only three infants. The course of the disease as well as the evolution of HBsAg studies observed in this age group apparently conflict with several studies demonstrating that infants are more prone to

20

Dupuy, Kostewicz, and A lagille

becoming antigen carriers and to develop chronic persistent hepatitis. TM 16 If, however, an i m m u n e response is essential for the removal of the virus, our study shows that neonatally infected infants can completely eliminate HBV. The discrepancy between these observations and other reports concerning the type of response of neonates exposed to HBV raises important questions concerning environmental a n d / o r genetic factors influencing the immune respotise. The analysis of HBsAg findings in relation to the type of disease shows that in acute and severe hepatitis, total recovery follows the disappearance of the antigen, whereas chronic persistent hepatitis is associated with persistence of antigenemia. A similar relationship was also found in patients with chronic active hepatitis. Disappearance of antigen occurred in six of eight patients who healed, whereas it persisted in all four children with unfavorable outcome. In addition, in the latter group of patients, sequential determination of HBs antigen and antibody revealed either one or the other, suggesting the presence of circulating Ag-Ab complexes in excess of antigen or antibody. This finding, as well as the positive correlation between persistence of antigenemia and that of the disease, indicates that an abnormal i m m u n e response to the viral agent may be responsible for chronic hepatitis.17.18 Our observations of overt hepatitis in neonatally infected children suggest that the frequent occurrence of HBsAg carrier infants observed in certain countriesl~. 19 may be due to an inadequate i m m u n e response related not to immaturity of the i m m u n e system but rather to environmental or genetic factors of polygenic nature? .... REFERENCES

1. Blumberg BS, Sutnick AI, and London WT: Hepatitis and leukemia: their relation to Australia antigen, Bull NY Aead Sci 44:1566, 1968. 2. Prince AM: An antigen detected in the blood during period of serum hepatitis, Proc Nat1 Acad Sci USA 60:814, 1968. 3. Krugman S, and Giles JP: Viral hepatitis: New light on an old disease, JAMA 212:1019, 1970. 4. Dupuy JM, Frommel D, and Alagille D: Severe viral hepatitis type B in infancy, Lancet 1:191, 1975.

The Journal of Pediatrics January 1978 5. Dulac O, Dupuy JM, Hadchouel M, and Alagille D: H6patites virales s6v6res de l'enfant, Arch Fr Pediatr (in press). 6. Peters RL: Viral hepatitis: a pathologic spectrum, Am J Med Sci 270:17, 1975. 7. De Groote J, Desmet VJ, Gedick P, Korb G, Popper H, Poulsen H, Schelier PJ, Schmid M, Uehlinger E, and Weper W: A classification of chronic hepatitis, Lancet 2:626, 1968. 8. Redeker AG: Viral hepatitis: the disease: clinical aspects, Am J Med Sci 270:9, 1975. 9. Geall MG, Schoenfield LJ, and Summerskill WHJ: Classification and treatment of chronic active liver disease, Gastroenterology 55:724, 1968. 10. Summerskill WHJ: Chronic active liver disease reexamined: prognosis hopeful, Gastroenterology 66:450, 1974. 11. Alagille D, Gautier M, Herouin C, and Hadchouel M: Chronic hepatitis in children, Acta Paediatr Scand 62:566, 1973. 12. Soloway RD, and Summerskill WHJ: Chronic active liver disease: classification and treatment, Postgrad Med 53:88, 1973. 13. Amouch P, and Drouet J: Dosage radio-immunologique de l'antig6ne Australie, Nouv Rev Fr Hematol 11:656, 1971. 14. Dupuy JM, Dulac O, Dupuy C, Alagille D, Michalak T, and Nowoslawski A: Severe hyporegenerative viral hepatitis in children, Proc R Soc Med 70:228, 1977. 15. Schweitzer IL, Wing A, McPeak C, and Spears RL: Hepatitis and hepatitis-associated antigen in 56 mother-infant pairs, JAMA 220:1092, 1972. 16. Stevens CE, Beasley RP, Tsui J, and Lee WC: Vertical transmission of hepatitis B antigen in Taiwan, N Ellgl J Med 292:771, 1975. 17. Nielsen JO, Dietrichson O, Elling P, and Christoffersen P: Incidence and meaning of persistence of Australia antigen in patients with acute viral hepatitis; development of chronic hepatitis, N Engl J Med 285:1157, 1971. 18. Dudley FJ, Fox RA, and Sherlock S: Cellular immunity and hepatitis associated, Australia antigen liver disease, Lancet 1:723, 1972. 19. Okada K, Yamada T, Miyakawa Y, and Mayumi M: Hepatitis B surface antigen in the serum of infants after delivery from asymptomatic carrier mothers, J PEDIATR 87:360, 1975. 20. Mazzur S, Blumberg BS, and Friedlaender JS: Silent maternal tran]mission of Australia antigen, Nature 247:41, 1974. 21. Szmuness W: Recent advances in the study of the epidemiology of hepatitis B, Am J Pathol 81:629, 1975.