This story from my perspective begins on the 28 December 2015- at 5.27 pm precisely. I know because that exact moment is captured on the WhatsApp chat on my handphone.
That’s my virology colleague remarking that he was signing out more Hepatitis E results than he expected. I’m no virologist but it did seem odd to me too. Hep E virus (HEV) is a positive-sense, single-stranded, non-enveloped, RNA virus that is spread by the faecal-oral route. When I was a microbiology trainee I was taught it was a disease mainly of developing countries due to ingesting contaminated water and shellfish. The sanitation in Singapore is relatively good. Unless travellers were importing the infection, there was really no reason to find many cases of Hep E in Singapore. So why should there be a spike in cases when there really should hardly be any cases in the first place?
You can follow our train of thought below as we approached this conundrum.
The suggestion that it was zoonotic was a bit of a stab in the dark on the basis that HEV is acquired by ingestion. Given we have access to clean water in Singapore, a contaminated food source seemed a more likely explanation. We were also influenced by recent experience of a large Group B Streptococcus acquired by eating raw fish.
With some judicious googling, my colleague soon stumbled on a link between pigs and HEV which I had hitherto been unaware of.
Even if you find the virus in food, it still needs to be ingested in an infectious form. Aren’t people normally aware that you should only eat pork that has been thoroughly cooked (to avoid parasites)? Coincidentally, a few days before this conversation I had first hand experience of a potential risk exposure event (top photo). One of the local dishes in Singapore is congee where raw pigs liver is placed on top of hot rice porridge. As anyone who likes eating offal knows, there is nothing more dreadful than overcooked liver, so the connoisseur will try and time it such that the liver is barely just cooked. It was still bloody when I bit into it.
So we had a working hypothesis. Over the next few days a bit of digging around revealed a number of interesting facts.
1. When we looked up the Ministry of Health’s Weekly Infectious Disease Bulletin, we found that there were more cases of Hep E (97) than Hep A (70) reported in 2015.
2. A lot of other developed countries were noticing unexpected increases of Hep E cases and these were increasingly linked to undercooked pork products (particularly sausages and pates).
3. Hep E had been already been studied in Singapore in 2013 (Tan LTC et al, 2013). At that time the association with pigs had in fact been considered but there was insufficient evidence to draw a firm conclusion about the food source, partly because the molecular tools to genotype HEV were not widely available at the time. HEV genotypes 1 and 2 are restricted to humans and cause the traditional outbreaks found in developing countries as a result of poor sanitation. Genotypes 3 and 4 may be found in humans but also have animal reservoirs, in particular pigs.
So we embarked on a new study together with colleagues in the National Environmental Agency (now Singapore Food Agency) which has finally been published (Wong CC, 2019).
The findings can be summarised thus.
1. Hep E has been increasing in Singapore. From 0.92 cases per 100,000 population in 2009-2011 to 4.1 cases per 100,000 population in 2016.
2. The increase is predominantly in the Chinese population. Chinese (86%) were over-represented among those HEV IgM positive compared to Indians (5%) and Malays (2%), even taking into account the National ethnic distribution.
3. The majority (85%) of HEV were genotype 3. 15% were genotype 1 and 1 was genotype 4. Genotype 3 was found in both pig livers and human infections among the Chinese.
4. A different genotype of HEV which is not associated with animal sources was found in the Malays (unsurprising since Muslims do not eat pork).
During the long gestation time for this paper, a number of other local studies have been published.
A fatal case of chronic Hep E in a solid organ transplant recipient (SOTR) in our hospital triggered a retrospective review of 16 cases, eight of which were SOTR (Teo EC et al, 2017)*. 88% were HEV genotype 3.
Earlier this year another team of Singapore investigators (Zhu YO, 2019) published on viral sequences from 15 immunocompromised patients with chronic Hep E at the National University Hospital. All were HEV genotype 3. Interestingly they found two patients who shared extremely similar viruses who had residential addresses, which were within one kilometre of each other suggesting the possibility of common food sources.
So the conclusion is that eating raw or undercooked pork products may contribute to the majority of Hep E cases in Singapore.
What are the risks?
In most healthy people, Hep E is a mild infection and may not even be noticed.
However it may cause chronic infection in those with pre-existing liver disease and more severe infection in the immunocompromised.
There are implications here for public health and food for thought for those looking after immunocompromised patients and those running blood banks.
Preventative food safety precautions may be found in some of the links given below.
UK Food Standards.
Center for Food Safety Hong Kong
European Food Safety Authority
Tan LT, Tan J, Ang LW, Chan KP, Chiew KT, Cutter J, Chew SK, Goh KT.
Epidemiology of acute hepatitis E in Singapore. J Infect. 2013 May;66(5):453-9. (no free access)
Wong CC, Then SM, Ng Y, Kang JSL, Ng TY, Chau ML, Koh TH, Chan KP. Seroepidemiology and genotyping of hepatitis E virus in Singapore reveal rise in number of cases and similarity of human strains to those detected in pig livers. Zoonoses and Public Health. 2019 (early view online). (no free access)
Teo EC, Tan BH, Purdy MA, Wong PS, Ting PJ, Chang PJ, Oon LL, Sue A, Teo CG, Tan CK. Hepatitis E in Singapore: A Case-Series and Viral Phylodynamics Study. Am J Trop Med Hyg. 2017 Apr;96(4):922-928. (free access)
*Spot the daughter-father team on this paper. Clue-one of them was Chief of the Viral Hepatitis Laboratory at the US Centers for Disease Control and Prevention.