Epidemiology and prevention of enterically transmitted hepatitis in Italy

0

INSTITUT

Res. Virol. 1998, 149, 271-276

PASTEURIELSEVIER

Paris 1998

Epidemiology and prevention of enterically transmitted hepatitis in Italy R.C.

Coppola

(I), G. Masia

cl), L. Romanb

c2), E. Tanzi

E c2) and A.R.

Zanetti

c2) (*I

(I) Department of Hygiene and Public Health, University of Cagliari (Italy), and (‘) (*’ Institute of Virology, University of Milan Via C. Pascal 38, 20133 Milan (Italy)

With improvements in the standard of living and hygiene, the circulation of hepatitis A virus (HAV) has dramatically decreased in Italy in the last 2-3 decades. The prevalence of anti-HAV among the under ‘20s population has steadily declined to less than lo%, although there is still a variation between rural and urban areas as well as northern and southem regions. According to the National Surveillance System (SEIEVA), the incidence rate of acute hepatitis A per 100,000 inhabitants declined from 10 in 1985 to 2 between 1987-1990 and then increased again up to 7 in 1996, mainly due to the occurrence of outbreaks in Apulia (southern Italy). The presence of foci of HAV together with a growing number of young adults lacking immunity may potentially create conditions for the occurrence of outbreaks. A safe and effective vaccine is available and recommended to travelers to endemic areas, military personnel, drug addicts and to persons at occupational risk. The prevalence of anti-HEV (hepatitis E virus) is around l-5 % among the healthy Italian population and higher among intravenous drug addicts, haemophiliacs, the hemodialysed and patients with chronic hepatitis C. A large prospective study has shown that HEV accounts for approximately 10% of acute non-A, non-C hepatitis in Italy. Travel to endemic areas was the major risk factor associated with the development of acute HEV hepatitis, but a few cases reported no travel. Whether the discrepancy between the relatively high rate of anti-HEV compared to the very low rate of clinically overt hepatitis E in our population is due to the circulation of native attenuated strains or to inadequacies in assaysfor antibody detection is under investigation.

Received September16, 1998. (*) Corresponding

author.

Prevention of hepatitis E relies primarily on the existence of clean water supplies and on the health information for travelers to endemic areas. Enterically transmitted hepatitis (ETH) can be caused by two viruses: HAV and HEV, which are mainly transmitted by the faecal-oral route through contaminated water and contaminated food and by person-to-person contact. Hepatitis type A Up until 2-3 decades ago, hepatitis type A was widespread in Italy, with a gradient of increasing endemicity from northern to southern regions. At that time, most infections were acquired during childhood and consequently the vast majority of people developed long-lasting immunity to infection in very early life, while infections among adults were quite rare. With the general improvements in the standard of living and hygiene and secondary to the introduction of several public health measuressuch as supplying of clean water, proper sewage disposal and, more recently, vaccination, the circulation of hepatitis A virus has declined dramatically in recent years and Italy has shifted from a high/intermediate to an intermediate/low endemicity status. Exposure to HAV during childhood is now less common, especially in the northern regions of the country, with an increasing number of children and young adults susceptible to the residual circulating virus since they lack immunity. Several studies of age-stratified anti-HAV prevalence in the general population have shown that immunity to HAV among those under 20 has stead-

272

R.C. COPPOU

Table I. Anti-HAV

prevalence rates in subjects younger than 15 years according residence in Italy.

1977-78 (95% CI)

Years

27% (15-42) 63% (57-69)

North South CI = confidence

= =

to the area of

1987-89 (95% CI)

[Reference] Zanetti, 1978

[Reference]

0.5% (0.06-l ,5)

La Rosa, 1979

Stroffolini,

199 1

Stroffolini,

1989

interval.

30

ily declined to 10% or less in urban areas, although there is still much variation between northern and southern regions (table I) (Mele et al., 1991a). In the Milan area, a study comparing the prevalence of anti-HAV antibody in serum samples collected during the years 1958, 1978 and 1992 from healthy individuals subdivided according to age showed a dramatic drop in anti-HAV among the younger groups (Zanetti et aE., 1994a). Similar downward trends in immunity against HAV have been reported from other studies. Among Italian recruits with an age range of 18-26 years, an immunity decline was observed from 1980 to 1990: in recruits from northcentral Italy, anti-HAV prevalence decreased from 45.2% to 22.4% and from 83.3% to 32.2% in residents in the southern islands (Pasquini et al., 1984; Stroffolini et al., 1993). In Sardinia, the anti-HAV prevalence in the sera of 14-29-year-old subjects, collected in 1988 and 1995, decreased from 44% to 17 % in the 14-19 age bracket and from 74 % to 25 % in the 20-24 year-old bracket respectively (Masia et al., 1996). According to the data collected by the SEIEVA (Mele et al., 1997), the incidence rate of acute viral hepatitis A per 100,000 inhabitants declined from 10 in 1985 to 2 between 1987 and 1990 and then increased again up to 7 per 100,000 in 1996 (fig. 1) as a consequence of cyclical outbreaks mainly occurring in Apulia (southern Italy) where, in 1996 and 1997, 12,000 cases of acute clinical hepatitis were reported (yearly incidence 146/100,000), with the peak of cases occurring in July-August (Lopalco et al., 1997). The highest attack rate is currently in the 15-24-year-old age group (table II) with differences between North and South (table III and table IV). Ingestion of undercooked or raw shellfish, travels to endemic areas, contact with a person with acute

ETH HAV

ET AL.

enterically transmitted hepatitis A virus.

ll=aii-l -.- So&h

!A,

!--I

7 96

87

99

91

93

99

99

Fig 1. Incidence of hepatitis A in Italy according to northem and southern regions from 1985 to 1996 (SEIEVA).

hepatitis A and drinking contaminated water are the most frequent risk factors for acquiring HAV for all age groups (Mele et al., 1997); the Apulia outbreak was sustained by the consumption of raw seafood stored in contaminated water. In outbreaks among subjects under 15 years of age, the contact with an icteric person was the most common source of infection (Sagliocca et cd., 1988, 1995), while in older subjects, hepatitis A was mainly related to raw shellfish consumption (Mele et al., 1989 ; Stroffolini et al., 1990 ; Mele et al., 1994). Travels to high-intermediate endemicity areas (Africa, Asia, southcentral America, eastern Europe, the southern Mediterranean coasts including southern Italy) represent an increased risk of exposure to HAV infection; the highest risk is for travelers from northern Italy, over 25 years of age and with a high educational level (OR 4.31) (Mele et al., 1991b). The presence of foci of HAV in certain areas of the country, together with the increasing number of

hepatitis. 1

HEV SEIEVA

= =

hepatitis E virus. Italian National Surveillance

System

ENTERICALLY

Table II. Age-specific

TRANSMITTED

HEPATITIS

273

IN ITALY

incidence of hepatitis A in Italy from 1985 to 1996 (SEIEVA,

1997).

Age

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

O-14 15-24 >25 Total

29 16 2 10

4 7 3 4

6 6 1 2

4 5 1 2

2 4 2 2

3 5 2 2

8 7 2 4

11 15 2 6

9 11 3 5

11 14 2 6

5 6 1 3

10 18 3 7

Table III. Age-specific incidence of hepatitis A in the north and center of Italy from 1985 to 1996 (SEIEVA,

Age o-14 15-24 >25 Total

1985

1986

1987

1988

7 13 2 4

3 7 3 4

2 3 1 1

4 6 2 3

1997).

1989

1990

1991

1992

1993

1994

1995

1996

2 2

2 5 2 3

2 4 2 2

2 5 2 2

3 5 4 4

2 3 2 2

1 3 1 1

3 7 3 4

Table IV. Age-specific incidence of hepatitis A in southern Italy and the islands from 1985 to 1996 (SEIEVA,

1997).

Age

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

O-14 15-24 >25 Total

69 22 2 24

8 9 1 4

18 14 2 4

5 2 0 1

3 2 0 1

6 8 0 2

19 13 1 8

29 37 3 16

19 23 2 10

28 36 2 15

13 16 2 7

23 42 4 16

adults lacking immunity, can potentially create conditions for the development of clinically relevant outbreaks, since the shift in infection to older ages may increase the severity of the disease. Active vaccination is now available for effective control of hepatitis A. For an appropriate public health use, in Italy, vaccine against hepatitis A is currently recommended for several high risk groups as shown in table V. When outbreaks are recognized in day care centres, schools, hospitals and other work settings, postexposure prophylaxis is obtained by administration of gamma immunoglobulins. The efficacy of vaccine in these settings as well as in conferring protection in contacts of case-patients is under investigation. Together with vaccination, continuing reinforcement of public health measures is essential to control the spread of HAV.

Table V. Who should be vaccinated for hepatitis A? l l

l

l l l l

Travelers to endemic areas Military personnel (troops committed to military operations in areas of high endemicity) Persons with chronic liver disease (especially those who are awaiting or have received liver transplant) Drug addicts Health care workers exposed to HAV Contacts of patients with acute hepatitis A Personnel exposed to sewage

Hepatitis

type E

HEV has been identified as the major aetiologic agent of enterically transmitted non-A, non-B hepa-

274

R.C. COPPOLA

titis. HEV is a spherical, non-enveloped, singlestranded RNA virus of approximately 32-34 nm in diameter that is provisionally classified in the Culiciviridae (Bradley et al., 1987; Reyes et al., 1990; Bradley et al., 1994). It is transmitted primarily by the faecal-oral route, especially through contaminated water. In developing countries with a poor level of hygiene and sanitation, viral hepatitis E occurs both in large outbreaks and sporadically. The occurrence of sporadic HEV infections may maintain the intrahuman circulation of the virus during interepidemic periods, but non-human reservoirs for HEV have recently been found (Meng et al., 1997). In western Europe and in the United States (US), the diseaseis occasionally diagnosed in travelers from endemic areas, but sporadic caseshave also been observed in patients who never visited endemic countries (Bader et al., 1991; Dawson et al., 1992ab; CDC, 1993; Zaaijer et al., 1993; Skidmore and Sherrat, 1996). Several serological studies carried out in industrialized countries have shown that the prevalence of antibody to hepatitis E virus (anti-HEV) is l-6% among blood donors, while higher rates of anti-HEV have been reported for intravenous drug users,especially those infected with HIV, for haemophiliacs, for patients under dialysis treatment, for homosexuals and for patients with chronic hepatitis C (Paul et al., 1994; Zanetti et al., 1994b; Halfon et al., 1994, Pisanti, 1994, Montella, et al. 1994; Buffet et al., 1996; Romanb et al., 1996; Coppola and Masia, 1997). Studies of anti-HEV prevalence rates among the healthy Italian population have shown that the antibody is detectable in around 1% in the North and in up to 5% in the South and in the Islands (table VI). Anti-HEV is rare among children, while its frequency increases with increasing age, suggesting a possible cohort effect with most infections acquired in the past (Coppola and Masia, 1997; Zanetti et al., 1994). A large multicentre prospective study carried out in Italy between 1994 and 1997 showed that 22 of

ET AL.

218 (10.1%) patients with acute viral non-A, non-C hepatitis were infected with HEV, as diagnosed by detection of specific IgM anti-HEV and HEV RNA in sera collected during the early acute phase of the disease (Zanetti et al., in press). The majority of HEV-positive patients (18/22 ; 8 1.8 %) developed acute hepatitis after their return from endemic areas, but 4 (18.2 %) patients reported no travel or links with subjects travelling from endemic areas in the 6 months preceding the onset of the disease. Sequence analyses of the PCR product derived from one of the four patients who never visited endemic areas identified a new HEV variant significantly divergent from all reported isolates of HEV (Zanetti et al., in press). Sporadic casesof acute hepatitis E not associated with traveling to the tropics have recently been reported in Sicily (Cacopardo et al., 1997). The few documented cases of domestic acute hepatitis E indicate that HEV is present in our country, although at a low level of circulation. However, the meaning of the relatively high rate of anti-HEV compared to the very low rate of clinically overt hepatitis E in Italy, as in other nonendemic countries, is unclear (Thomas et al., 1997). Whether this discrepancy is the result of subclinical infections caused by native attenuated strains of HEV or is due to an inadequacy in the currently available assays for the detection of anti-HEV is under investigation. Prevention of hepatitis E relies primarily on general public health measuresfor controlling the transmission of enteric infections, particularly the availability of clean water supplies. For travelers to endemic areas prevention includes avoiding drinking water of unknown origin, eating uncooked shellfish, vegetables, unpeeled fruits and an increased standard of personal hygiene. A candidate vaccine is currently being developed. Key-words:

HAV, HEV; Epidemiology, Preven-

tion ; Review. References

Table VI. Anti-HEV prevalence in different Italian areas: surveys on blood donors and general population (from Coppola and Masia, 1997). North Milan (0.95) Genoa (1.3) Venice (2.6)

City (% anti-HEV) Centre Florence (1.4) S.Marino (2.3)

South/Islands Bat-i (1.5) Foggia (3) Catania (3) Cagliari (5.4)

Bader, T.F., Krawczynski, K., Polish, L.B. & Favorov, M.O. (1991) Hepatitis E in US traveler to Mexico. N. Engl. J. Med., 325, 1659. Bradley. D.W., Krawczynski, K., Cook, E.H., McCaustland, K.A., Humphrey, C.D., Spelbring, J.E., Myint, H. & Maynard, J.E. (1987), Enterically-transmitted nonA-nonB hepatitis: serial passage of disease in cynomolgus macaques and tamarins and recovery of disease-associated 27 to 34 nm virus-like particles. Proc. Natl. Acad. Sci. USA, 84, 6277-6281. Bradley, D.W. & Purdy, M.A. Molecular and serologic characteristics of hepatitis E virus (1994), in: “Viral Hepatitis and Liver Disease” (Nishioka K., Suzuki H.,

ENTERICALLY

TRANSMITTED

Mishiro S., Oda T) (pp. 42-45). Springer-Verlag, Tokyo. Buffet, C., Laurent-Puig, P., Chandot, S., Laurian, Y., Charpentier,B., Briantais,M.J. & Dussaix,E. (1996), A high hepatitisE virus seroprevalenceamongrenal transplantationand haemophiliapatientspopulations J. Hepatol., 24, 122-123. Cacopardo,B., Russo,R., Preiser,W., Benanti, F., Brancati, G. & Nunnari, A. (1997), Acute hepatitisE in Catania(EasternSicily) 1980-1994,The role of hepatitis E virus Infection, 25, 313-316. Centersfor Disease Control andPrevention(1993).Hepatitis E amongUS travelers 1989-1992MMWR, 42, 1-4. Coppola, R.C. & Masia, G. (1997), Seroprevalenceand epidemiologicalfeaturesof hepatitisE virus infection in Italy, in: “Viral HepatitisandLiver Disease”(Rizzetto M., PurcellR.H., JerinJ., Verme G.) (pp. 57-59). Minerva, Torino. Dawson,G.J., Chau, K.H., Cabal, C.M., Yarbough, P.O., Reyes,G.R. & Mushahwar,I.K. (1992b),Solid-phase enzyme-linked immunosorbentassayfor hepatitis E virus IgG and IgM antibodiesutilizing recombinant antigensand synthetic peptides.J. Virol. Methods, 38, 175186. Dawson, G.J., Mushahwar, I.K., Chau, K.H. & Gitnick, G.L. (1992a), Detection of long-lasting antibody to heuatitisE virus in a US traveler to Pakistan.Lancet, 34’0,426-427. Halfon, Ph., Ouzan, D., Chanas,M., Khiri, V.H., Feryn, J.M., Mangin, L., Masseyef, M.F. & Salvadori, J.M. (1994), High prevalenceof hepatitisE virus antibody in haemodialysispatients(letter). Lancet, 344, 746. La Rosa,G., Guli, V. & Terraria,B. (1979),First resultsof anti-HAV antibodiesassayin western Sicily. Boll. Ist. Sieroter. Milan,

58, 682-683.

Lopalco, P., Malfait, P., Salmaso,S., Germinario, C., Quarto, M., Barbuti S. & the field working group. (1997), A persistingoutbreakof hepatitisA in Puglia, Italy 1996: epidemiologicalfollow up. Eurosurveillance,

2, 3 l-32.

Masia, G., Carboni, G., Casu, A., Cintura, R., Erby, I., Mastromarino,G., Mereu, P., Floris, L., Mereu, G., Secci,F. & Coppola,R.C. (1996), Changingepidemiology of hepatitis A virus infection in an endemic area,in: “Abstract Volume of the LX Triennial International Symposium on Viral Hepatitis and Liver Disease, 21-25 April 1996”, Rome,Italy ; A59.

Mele, A., Catapano,R., Cialdea,L., Pisacane,A.M., Mladen,AS. & Kresevic,L. (1994)Outbreakof hepatitis A in Tries@Italy. J. Public Health Med., 16,242-243. Mele, A., Pasquini,P. & Pana,A. (1991a),HepatitisA in Italy: epidemiologyand suggestionfor control. Ital. J. Gastroenterol.,

23. 341-343.

Mele, A., Rastelli,M.G., Gill, O.N., Di Bisceglie,D., Rosmini, F., Pardelli, G., Valtriani, C. & Patriarchi, P. (1989), Recurrent epidemic hepatitis A associated with consumption of raw shellfish, probably controlled through Public Health measures. Am. J. Epidemiol.,

103, 540-546.

Mele, A., Sagliocca,L., Palumbo,F., Stazi, M.A., Rosmini, F., Ferrigno, L., Corona, R., Osborn, J., Gill, O.N. & Pasquini,P.( 1991b),Travel-associatedhepatitis A: effect of place of residenceand country visited. J. Public Health Med., 13, 256-259. Mele, A., Stroffolini, T., Palumbo,F., Gallo, G., Ragni,P.,

HEPATITIS

IN ITALY

275

Balocchini, E., Tosti, M.E., Corona, R., Marzolini, A., Moiraghi, A. & the SEIEVA CollaboratingGroup (1997), Incidenceof and risk factors for hepatitisA in Italy: Public Healthindicationsfrom a lo-year surveillance.J. Hepatol., 26, 743-747. Meng, X.J., Purcell, R.H., Halbur, P.G., Lehman, J.R., Webb, D.M., Tsareva, T.S., Haynes, J.S., Thacker, B.J. & Emerson,S.U. (1997), A novel virus in swine is closely related to the human hepatitis E virus. Proc. Matl. Acad. Sci. USA, 94, 9860-9865. Montella, F., Rezza, G., Di Sora, F., Pezzotti, P. & Recchia, 0. (1994), Association between hepatitis E virus and HIV infection in homosexualmen.Lancet, 344, 1433(letter). Pasquini,P., Kahn, H.A., Pileggi, D., Pat& A., Terzi, J. & D’ Arca, T. (1984),Prevalenceof hepatitisA antibodiesin Italy. lnt. J. Epidemiol., 13, 83-86. Paul, D.A., Knigge, M.F., Ritter, A., Gutierrez, R., PilotMatias, T., Chau,K.H. & Dawson,G.J (1994),Determinationof hepatitisE virus seroprevalenceby using recombinantfusion proteins and synthetic peptides. J. Infect. Dis., 169, 801-806. Pisanti,F.A., Coppola,A. & Galli, C. (1994), Association betweenhepatitisC and hepatitisE virusesin southem Italy. Lancet, 344, 746-747(letter). Reyes,G.R., Purdy, M.A., Kim, J.P., Luk, K.C., Young, L.M., Fry, K.E. & Bradley, D.W. (1990).Isolationof a cDNA from the virus responsiblefor entericallytransmitted non-A, non-B hepatitis. Science, 247, 1335-1339. Roman& L., Tanzi, E., Brancatelli, S., Raimondo, G., Galli, C. & Zanetti, A.R. (1996), Prevalenceof antiHEV amongpatientswith chronic viral hepatitisand healthy individuals in Southern Italy, in: “Enteritally-trasmitted hepatitis viruses” (Y. Buisson, P. Coursaget,M. Kane) (pp. 237-239). La Simarre, Tours (France). Sagliocca,L., Mele, A., Ferrigno, L., Palumbo,F., Converti, F., Tosti, M.E., Amoroso, P., Manzillo, G. & the hepatitiscollaboratinggroup (1995),Casecontrol study of risk factors for hepatitis A: Naples 19901991.ital. J. Gastroenterol., 27, 181-184. Sagliocca,L., Mele, A., Gill, O.N. & Cappetta,G. (1988), A village outbreakof hepatitisA: acquaintancenetwork and inapparentpre-school transmissioncompared.Eur. J. Epidemiol., 4, 470-472. SEIEVA, Integrated Epidemiological System for Acute Viral Hepatitis. Report 1995-1996.Mele A, Marzolini A, Tosti ME, Ciccozzi M e Stroffolini T (1997) RapportiISTISAN Istituto di SuperioreSanita; 36. Skidmore,S.J. & Sherrat,L.M. (1996), HepatitisE infection in the UK. J. Viral Hepatitis, 3, 103-105. Stroffolini, T., Biagini, W., Lorenzoni, L., Palazzesi,G.P., Divizia, M. & Frongillo, R. (I990), An outbreak of hepatitis A in young adultsin central Italy. Eur. J. Epidemiol., 6, 156-159. Stroffolini, T., Chiaramonte,M., France,E., Rapicetta,M., De Mattia, D., Mura, I., Trivello, R., Giammanco,A., Rigo, G. & Scarpa,B. (1991), Baselineseroepidemiology of hepatitisA virus infection amongchildren and teenagersin Italy. Infection, 97-99. Stroffolini, T., D’Amelio, R., Matricardi, P.M., Chionne, P., Napoli, A., Rapicetta,M., Crateri, S. & Pasquini, P. (1993) The changingepidemiologyof hepatitisA in Italy. ital. J. Gastroenterol., 25, 372-374.

276

R.C. COPPOLA

Stroffolini, T., France, E., Romano, G., Uccheddu, P., Zaratti, L., Pasquini, P., Pan&, A., Maida, A. & Scarpa, B. (1989), Hepatitis A virus infection in children in Sardinia, Italy. Community Medicine, 4, 336-341. Thomas,D.L., Yarbough,P.O., Vlahvov, D., Tsarev, S.A., Nelson,K.E., Saah,A.J. & Purcell, R.H. (1997). Seroreactivity to hepatitisE virus in areaswhere the diseaseis not endemic.J. Clin. Microbial., 35, 12441247. Zaaijer, H.L., Kok, M., Lelie, P.N., Timmerman, R.J., Chau K. & Van der Pol HJH (1993), HepatitisE in the Netherlands: importedand endemicLance& 34 1, 826 (letter). Zanetti, A.R., Dawson,G.J. & the Study Group of Hepa-

ET AL. titis E (1994b), HepatitisE in Italy : a seroepidemiological survey. J. Med. Virol., 42, 318-320. Zanetti, A.R., Ferroni, P. & Bastia,A. (1978), Decline in incidenceof hepatitisA infection in Milan. Boll. Ist. Sieroter. Milan, 57, 816820. Zanetti, A.R., Roman&L., Tanzi, E., Andreassi,A., Pozzi, A., Panuccio,A. & Stroffolini, T. (1994a),Declinein anti-HAV prevalencein the Milan areabetween1958 and 1992.Eur. J. Epidemiol., 10, 633-635. Zanetti, A.R., Schlauder, G.G., Roman& L., Tanzi, E., Fabris, P., Dawson, G.J. & Mushahwar, I.K. Hepatitis E virus in patientswith acute non A-C hepatitis in Italy: identification of a novel variant. J. Med. Virol., (in press).