Delta infection in the Naples area

JournalofHepatology, 1986; 2:11-18

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Elsevier HEP 0081

Delta Infection in the Naples Area Epidemiologic and Clinical Significance P. A m o r o s o , A. Giorgio, P. Fico, G. Lettieri, G. de Stefano, V. Scala, G. Pesce, P. Pierri, R. Pempinello, L. Finelli and G. Pierri 'D. Cotugno' Hospitalfor Infectious Diseases, Naples (Italy) (Received 19 December, 1984) (Accepted 26 March, 1985)

Summary To define the epidemiologic and clinical significance of delta infection in the Naples area, we sought anti-delta antibodies in all cases of HBV-associated liver diseases, hospitalized in our department during 1983 (234 acute hepatitis, 9 ~9~ which fulminant; 51 chronic hepatitis; 32 cirrhosis; 19 hepatocarcinomas) and in randomly selected acute hepatitis over the previous 6 years. Delta agent in acute forms and IgM anti-HBc in delta-positive acute forms were also tested. The acute cases were controlled for at least 9 months after dismissal. Delta infection showed a high prevalence in the Naples area (20% of all acute cases in 1983; similar prevalences in previous years; high rate of coinfections, 81%; no peculiar modalities of circulation) and a high pathogenicity, as proved by the greater prevalence in fulminant cases (66.7%) and severe chronic forms. Moreover superinfection appears a more dangerous event than coinfection as regards the diseases becoming chronic (77.8% vs 2.5%).

Introduction

In recent years extensive information has been accumulated on the delta agent and its role in liver diseases [1-6]. In particular, the development of a radioimmunoassay for delta antigen/antibody Correspondence to: Dr. Pietro Amoroso, c/o Ospedale 'D. Cotugno', Via G. QuagUariello, 80131 Naples, Italy, Tel. 081/257383. 0168-8278/86/$03.50 (~ 1986 Elsevier Science Publishers B.V. (Biomedical Division)

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P. AMOROSO et al.

system has demonstrated that its distribution is worldwide and presents two different epidemiologic patterns, closely related to the geographical prevalence of HBV: one endemic in some countries of Southern Europe, South America, Africa and the Middle East; the other sporadic and mainly connected to populations at risk, such as drug addicts and polytransfused subjects, in other regions of the world (the USA, Northern Europe, Japan and Australia) [7-11]. The Naples area (Italy) is characterized by a very high prevalence of delta infection (91% of cases of acute viral hepatitis B in the first observations) [6]. Although these findings could depend on an overestimate due to sampling of special clinical and epidemiologic groups, in a lack of systematic screening studies, the data obtained in this region could provide further information on the prevalence and natural history of delta infection. The present study investigated the delta antigen/antibody system and included a follow-up in all HBV-associated liver diseases referred to our department during 1983. The epidemiologic trend of delta infection over the previous 6 years was also evaluated. Patients and Methods Patients

This study included 336 HBsAg-positive cases, made up of 234 acute viral hepatitis, of which 9 with liver failure, 51 chronic hepatitis (30 active and 21 persistent), 32 cirrhosis and 19 primary hepatocellular carcinoma, of which 11 associated with cirrhosis, referred to the Cotugno Hospital ~or Infectious Diseases, Naples, Italy, during 1983 (Table 1). Diagnosis was established on the basis of International criteria [12] and confirmed by histological examinations in all cases of chronic hepatitis, cirrhosis and primary hepatocellular carcinoma. Liver failure was defined in terms of AST, ALT, total bilirubin levels, prothrombin activity and EEG patterns [13]. Mortality following liver failure occurred in 8 out of 9 patients (89%). Thirty additional serum samples for each year, collected from consecutive pa-

TABLE 1 COMPOSITION OF CASES

Acute hepatitis Fulminant hepatitis Chronic hepatitis Cirrhosis Primary hepatocellular carcinoma a 8 died; 1 survived. b 11 with cirrhosis.

Number of cases

Drug abusers and polytransfused (%)

Males (%)

Average age (years ± s)

234 9a 51 32 19b

47 6 9 7 -

141 8 30 19 18

29 + 18 22+3 32 + 12 35 + 15 58 ± 13

(20.1) (66.7) (17.6) (21.9)

(60.3) (88.9) (58.8) (59.4) (94.7)

DELTA INFECTION IN THE NAPLES A R E A

13

tients hospitalized for acute viral hepatitis B during the same period of 1977, '78, '79, '80, '81, '82, were also tested. All cases of acute hepatitis were monitored for at least 9 months after dismissal.

Serological assays HBsAg, HBsAb, HBcAb, HBeAg and HBeAb were performed by ELISA'With commercial kits (Abbott Laboratories, F.R.G.). In order to discriminate coinfections from delta superinfections in all delta positive acute cases, anti HBc IgM was detected by commercial radioimmunoassay (Abbott Laboratories, F.R.G.). The assay for delta antigen and antibodies was carded out by a radioimmunological method, as previously described by Rizzetto and Coil [14]. Generally, in cases of acute hepatitis the sera were collected 3 weeks after the appearance of symptoms, since in this period the probability of finding significative level of anti-delta antibodies is higher. Delta antigen was only assayed in the acute forms, to detect cases where anti delta antibodies had not yet been elicited. Statistical analysis was carried out by Student's t-test. Results

Serological assay Delta antigen was only detected in two acute cases, which were negative for the antibodies. The delta antigen/antibody system was positive in 20.5% of all cases of acute hepatitis, 66.7% of liver failure, 56.9% of chronic hepatitis, 46.9% of cirrhosis an d 5.3% of primary hepatocellular carcinomas in 1983 (Table 2). No differences were observed in terms of seasonal prevalence. From 1977 to 1982 delta infection in acute hepatitis B showed a yearly prevalence of 20, 17, 23, 27, 37 and 23% respectively. Anti HBc IgM were found in 39 cases (81.3%) of acute hepatitis in 1983 and in 88, 80, 86, 75, 82 and 72% respectively in the previous years. In particular, they were present in all but one of the fulminant forms (83.3%).

TABLE 2 PREVALENCE OF DELTA INFECTION IN HBV-ASSOCIATED LIVER DISEASES AND OF ANTI-CORE IgM IN ACUTE CASES

Acute hepatitis Fulminant hepatitis Chronic hepatitis Cirrhosis Primary hcpatocellular carcinoma

Delta Ag/Ab system positive (%)

IgM anti-HBc positive (%)

IgM anti-HBc negative (%)

48 6 29 15 1

39 (81.3) 5 (83.3) -

9 (18.7) 1 (16.7) -

(20.5) (66.7) (56.9) (46.9) (5.3)

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P. A M O R O S O et ai.

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DELTA INFECTION IN THE NAPLES AREA

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Epidemiologic characteristics The prevalence of risk-conditions (such as drug abuse and polytransfusion) is generally double in delta positive cases c o m p a r e d to ordinary H B V cases, ranging from around 28% of total cases to 56% in superinfections and 83% in fulminant hepatitis (Table 3). No differences were observed as regards age and sex between the two groups, except for the age of cirrhotic patients, which was significantly lower in delta-positive cases (Table 3). M o r e o v e r , it should be noted that delta infection occurs in about 10% of cases in very young subjects (aged 5 - 1 0 years).

Clinical characteristics No statistical differences were found for AST, A L T , bilirubin total levels, prothrombin activity and time of necrotic phase between coinfections and superinfections (Table 4). In contrast, A S T , A L T and length of necrotic phase were significantly higher in delta-positive cases than in cases due to H B V alone (Table 4). The rate of appearance of chronic disease was statistically higher (P < 0.001) in superinfections (78.8%) than in coinfections (2.5%) and in ordinary H B V hepatitis (2.7%) (Fig. 1). In all the chronic patients tests for anti-delta antibodies remained positive. Delta infection was associated with biohumoral and histological activity in 79.3 and 80% of chronic hepatitis and cirrhosis, respectively.

Discussion Our data confirm a high circulation of the delta agent in the Naples area, since it is associated with about 28% of H B V - r e l a t e d liver diseases. This finding appears even m o r e significant in acute hepatitis, where the association was observed in

TABLE 4 COMPARISON OF AST, ALT, TOTAL BILIRUBIN AND PROTHROMBIN TIME BETWEEN DELTA-POSITIVE (COINFECTIONS AND SUPERINFECTIONS) AND ONLY HBV UNCOMPLICATED ACUTE HEPATITIS Delta antigen/antibody system-positive Coinfections Superinfections pa Number of cases 34 AST (N.V. 8-34) 1190 + 525 ALT (N.V. 8-45) 1452 + 588 Total bilirubin (mg/100ml) 7.7 + 4.2 P.T. (% of activity) 78 + 19 Necrotic phasec 17.5 + 6

8 1252+ 339 1571+ 635 8.7 + 3.7 71 + 18 19.7 + 4

Only HBV

Total

42 N.S. 1202+ 492 N.S. 1475+ 590 N.S. 7.9 + 4.1 N.S. 77 + 17 N.S. 17.9+ 6

a Coinfection vs. superinfection. b Delta-positive vs. only HBV. c Number of days in which ALT and AST were more than 10 x N.V.

pb 183 964 + 629 1209+ 732 6.9 + 5.3 81 + 23 15.4 + 8

<0.05 <0.05 N.S. N.S. <0.05

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P. A M O R O S O et al.

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Fig. 1. Delta infection in the Naples area. Graphic representation of the o u t c o m e of ordinary H B V , delta coinfection and delta superinfection hepatitis. T h e rate of appearance of chronic state in superinfections is statistically higher than in ordinary B hepatitis and eoinfections (P < 0.001); fulminant forms are statistically more frequent in coinfections and superinfections than in hepatitis due to only H B V .

20.5% of cases and which in our opinion better expresses the background to the infection. Moreover this high prevalence was consistent with data observed in the previous 6 years, which showed a homogeneous epidemiologic trend, except for

DELTA INFECTION IN THE NAPLES AREA

17

1981, when the prevalence rose to 37%. This increase may be casual or could be related to the worsening in hygienic conditions, following the earthquake at the end of 1980. However, it seems more likely that it was the result of a cyclic epidemic spread of infection, since a previous study showed that the total cases hospitalized during the same period for viral hepatitis B, as well as A and NANB, decreased, in comparison with previous years [15]. Although the presence of risk-conditions is nearly double in delta-positive liver disease, compared to those due to HBV alone, in nearly 70% of cases no predisposing modalities of transmission were detectable. This indicates that delta infection can also be transmitted by inapparant permucosal and pereutaneous routes, according to the epidemiologic model of HBV [16]. These previously reported modalities [7] are also supported by the presence of about 10% of delta infection in very young subjects and by several cases of infrafamily contagion. It should be noted, nevertheless, that the prevalence data for drug addicts are much higher in superinfection and in fulminant hepatitis, although no correlation exists between these two findings, as the cases of delta-positive fulminant hepatitis are mainly coinfections. If this observation can be explained in superinfections by the fact that drug addicts are obviously more exposed to reinfection and constitute a reservoir of the delta agent, due to its high circulation in those subjects [17], the interpretation is more difficult in fulminant hepatitis. One hypothesis could be that drug use represents a peculiar biological condition, where virus-induced liver damage is expressed most intensively. This possibility is supported by the observation that also in fulminant hepatitis due to HBV alone, one patient out of three is a drug addict. Available evidence proves that the delta agent is characterized by high liver pathogenicity [2,6,17,18]. Our findings agree with this observation, as they show a progressively increasing prevalence of delta infection, paralleling the severity of liver disease. Moreover we found a close association of the delta agent with a more histological and humoral activity in the chronic forms and with a more severe clinical involvement, together with a very high incidence of fulminant cases (12% vs 1% of cases due to HBV alone) in the acute hepatitis. However, it should be borne in mind that the latter data refer to a hospitalized population, generally selected for severity of illness, which does not represent the totality of cases. Moreover, also in our series superinfection represents a severe event in developing or aggravating chronic hepatitis which usually assumes a progressive course and is characterized by the carrier state of both HBV and delta agent. Nevertheless we must stress that, although the occurrence is rare (1 patient in our series), delta superinfection could lead to the clearance of both viruses, probably by inducing the necrosis of infected liver cells in a subject, who previously was not immune-responsive to HBV.

Acknowledgements We thank Dr. M. Rizzetto and collabora.tors (Turin) for determining the delta/anti-delta system, and Mrs. Anne Collins (Bologna) for revising the English manuscript.

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