Epidemiology, prevention and control of hepatitis A virus infection in the European Union

Hepatitis A is an acute liver disease caused by the hepatitis A virus (HAV) and transmitted via the faecal-oral route through person-to-person transmission, contaminated food or water. The frequency and severity of symptoms increases with age, with the elderlies and patients with other liver disease at risk of hospitalisation, acute liver failure and death. Hepatitis A is a notifiable disease in the countries of the European Union (EU) and European Economic Area (EEA), and hepatitis A notifications are reported to The European Surveillance System (TESSy). The World Health Organization (WHO) defines the EU/EEA as an area at very low or low HAV endemicity; however, large differences between EU/EEA countries exist. Hepatitis A vaccines are safe and effective. In most countries hepatitis A vaccination is recommended only for groups at increased risk of infection or at increased risk of severe disease. In recent years, large multicountry hepatitis A outbreaks associated with contaminated food or with men who have sex with men (MSM) engaging in sexual practices facilitating faecal-oral transmission have been reported. This thesis’ aim was to describe the EU/EEA epidemiology of hepatitis A and provide recommendations on strategies to prevent, monitor and control this evolving public health threat.

In Study 1, we systematically searched the literature for seroprevalence studies performed in EU/EEA countries from 1975 to 2014 and pooled age-specific seroprevalence estimates to obtain estimates of historical HAV incidence and current endemicity. Based on age-specific seroprevalence estimates in adults from 2000 to 2014, we created four HAV susceptibility profiles, paving the way to meaningful grouping of EU/EEA countries in the analysis of Study 4.

HAV is prone to foodborne outbreaks. In Study 2, we described the largest hepatitis A foodborne outbreak reported in the EU/EEA taking place in 2013 and 2014. HAV genome sequencing was an essential tool to link apparently unrelated cases. The multicountry investigation showed the vulnerability of the EU/EEA single food market and that large cross-border foodborne outbreaks can be associated with a significant proportion of hospitalised cases.

In Study 3 we confirmed that a multistrain HAV infection outbreak was underway in the EU/EEA in 2016 and 2017 and that it was disproportionally affecting male patients engaging in high-risk sexual practices. Through a case-case study comparing cases infected with the different outbreak strains we identified no differences in case’s exposures. The investigation highlighted the limited uptake of vaccination in a group that should be a priority target.

In study 4, we used hepatitis A surveillance data from TESSy from 2010 to 2019 to describe the epidemiology of hepatitis A in the different EU/EEA areas, place the large foodborne and person-to-person transmission outbreaks in context, and highlight the limitation of hepatitis A surveillance in Europe.

Because of the increasing HAV susceptibility and the risk of more severe disease in older people, it has been hypothesised that the clinical presentation of hepatitis A is worsening. In study 5, we analysed hepatitis A notifications and hospitalisations from 1995 to 2015. Although detecting an increase in the median age at infection, we did not identify an increase in the proportion of hospitalisations associated with clinically severe disease. In this study we also confirmed that older patients and patients with co-morbidities were at increased risk of clinically severe disease.

Based on our study results, we recommend monitoring HAV endemicity and susceptibility in the general EU/EEA population and in MSM. The efforts to vaccinate groups at increased risk of infection should be pre-emptively scaled up without waiting for large outbreaks. Harmonised HAV genome sequencing should be performed at high rates and in all countries, with consequent sharing of sequencing information to rapidly alert on HAV cross-border circulation and enhance early detection of outbreaks. When such outbreaks are detected, multicountry cross-sectorial investigations are paramount for rapid outbreak control. At all times, surveillance should be strengthened with complete and high-quality collection of information about travel history and transmission route. Last, to monitor negative trends in the hepatitis A clinical presentation, better linkage of death and liver transplant registries and surveillance data should be achieved, particularly in those countries that experienced a recent epidemiological transition.

List of scientific papers

I. Carrillo-Santisteve P, Tavoschi L, Severi E, Bonfigli S, Edelstein M, Byström E, Lopalco PL, ECDC HAV Expert Panel. Seroprevalence and susceptibility to hepatitis A in the European Union and European Economic Area: a systematic review. The Lancet Infectious Diseases. 2017;17(10).
https://doi.org/10.1016/S1473-3099(17)30392-4

II. Severi E, Verhoef L, Thornton L, Guzman-Herrador BR, Faber M, Sundqvist L, Rimhanen-Finne R, Roque-Afonso AM, Ngui SL, Allerberger F, Baumann-Popczyk A, Muller L, Parmakova K, Alfonsi V, Tavoschi L, Vennema H, Fitzgerald M, Myrmel M, Gertler M, Ederth J, Kontio M, Vanbockstael C, Mandal S, Sadkowska-Todys M, Tosti ME, Schimmer B, O Gorman J, Stene-Johansen K, Wenzel JJ, Jones G, Balogun K, Ciccaglione AR, O' Connor L, Vold L, Takkinen J, Rizzo C. Large and prolonged food-borne multistate hepatitis A outbreak in Europe associated with consumption of frozen berries, 2013 to 2014. Eurosurveillance. 2015;20(29).
https://doi.org/10.2807/1560-7917.ES2015.20.29.21192

III. Ndumbi P, Freidl GS, Williams CJ, Mårdh O, Varela C, Avellón A, Varela, C, Avellón A, Friesema I, Vennema H, Beebeejaun K, Ngui SL, Edelstein M, Smith-Palmer A, Murphy N, Dean J, Faber M, Wenzel J, Kontio M, Müller L, Midgley SE, Sundqvist L, Ederth JL, Roque-Afonso AM, Couturier E, Klamer S, Rebolledo J, Suin V, Aberle SW, Schmid D, De Sousa R, Augusto GF, Alfonsi V, Del Manso M, Ciccaglione AR, Mellou K, Hadjichristodoulou C, Donachie A, Borg ML, Sočan M, Poljak M, Severi E, Members of the European Hepatitis A Outbreak Investigation Team. Hepatitis A outbreak disproportionately affecting men who have sex with men (MSM) in the European Union and European Economic Area, June 2016 to May 2017. Eurosurveillance. 2018;23(33).
https://doi.org/10.2807/1560-7917.ES.2018.23.33.1700641

IV. Severi E, Tavoschi L, Carrillo-Santisteve P, Westrell T, Marrone G, Giesecke JI, Lopalco PL. Hepatitis A notifications in the EU/EEA from 2010 to 2019: what can we learn from case reporting to the European Surveillance System?. [Submitted]

V. Severi E, Georgalis L, Pijnacker R, Veneti L, Turiac IA, Chiesa F, Rizzo C, Martinelli D, Vold L, Herrador BG, Martinez CV, Sanchez EVM, Semenza JC, Lopalco P, Dahlström LA, Giesecke Jl. Severity of the clinical presentation of hepatitis A in five European countries from 1995 to 2014. International Journal of Infectious Diseases. 2022;118:34-43.
https://doi.org/10.1016/j.ijid.2022.01.053