A Tale From Tashkent
This patient has hepatitis (close to 15x ULN for ALT) and a recent travel history making a viral hepatitis possible. He received the HAV vaccine at his current age as the AAP/AAFP/CDC guidelines recommend the vaccine at 12 and 18 months of age (if traveling internationally a child can receive a dose at an age of 6-11 months). Therefore, hepatitis E Virus (HEV) is most likely. Note that the viremia can be brief, so PCR testing can be employed with antibody testing for screening if there is a high clinical suspicion. Elevated ferritin is non-specific and hemochromatosis doesn’t present at 21 months. Wilson disease also typically presents in an older child making ceruloplasmin lower yield. Celiac serologies can be part of the workup for vomiting and weight loss, but it is less likely to cause significant ALT/AST elevation in younger children and is not going to provide a diagnosis as it is a screening test with endoscopy with biopsies being diagnostic.
What is Hepatitis E Virus (HEV)?
HEV is a ~7,200 base positive sense single stranded RNA virus. Of the 8 reported genotypes, 1 and 2 are found in humans; 3 and 4 are shared between humans, livestock, and wildlife, and 7 was found in an immunocompromised patient. HEV is a member of the Hepeviridae family and Orthohepevirus genus that can infect hosts in both a quasi-enveloped and unenveloped form (the latter can occur due envelope digestion in the GI tract). The complete mechanisms of entry have not been fully elucidated and are thought to occur differently for both forms of HEV. Once inside a of cell, the positive sense RNA is first transcribed into a negative sense intermediate that itself generates full RNA positive sense genomes as well as a bicistronic RNA 2,200 base subgenome for translation with additional reading frames.
A special drink from Tashkent
Hepatitis E was originally called non-A, non-B enterically transmitted hepatitis virus (NANBH). Clinical cases have been described since the mid-1800s, but the first case series to suggest that the clinical syndrome was due to a virus (269 patients in Kashmir) was published in 1980 by Mohammed Sultan Khuroo. He concluded that contaminated water likely was the source of the infections. However, identification of the virus that caused this and other outbreaks was published several years later in an article from Intervirology in 1983 authored by Mikhail S. Balayan, Deputy Director of the Institute of Poliomyelitis and Viral Encephalitis of the Academy of Medical Sciences of the USSR. The original article describes an infection of a volunteer; however, a more detailed story was later revealed by Michael Favorov, a noted hepatitis virologist at the United States Centers for Disease Control.
Balayan was actually his own test patient in 1981. While assigned to investigate the outbreaks of enterically transmitted NANBH, he and his assistants collected serum and fecal samples from Soviet soldiers in Afghanistan suffering from hepatitis. He took the samples to a military base in Tashkent, Uzbekistan, and he created a fecal slurry from nine patients judged to be between the first and fourth day of symptoms. He mixed the slurry with kefir, drank it, and returned to Moscow 36 days later where he became acutely ill with hepatitis (ALT of 3010 U/L with symptoms including jaundice, dark urine, abdominal pain, nausea, and vomiting). He was admitted and placed under the care of the on-call infectious disease specialist, Michael Favorov, who observed Balayan for four days as his hepatitis resolved. The collected stool underwent immune electronic microscopy which identified the viral particles.
What are the symptoms?
Symptoms typically start in immunocompetent individuals 15-60 days after infection, and once the symptoms have begun, they can last between 1-6 weeks. The symptoms can include but are not limited to fever, anorexia, nausea, vomiting, abdominal pain, pruritus, rashes, arthralgias, jaundice, scleral icterus, dark urine, pale stools, and hepatomegaly.
There may be extra-hepatic/GI symptoms of HEV. HEV can spread to the CSF causing neurological symptoms including ataxia, encephalitis, and, peripheral demyelinating polyneuropathy. Membranoproliferative glomerulonephritis has also been reported.
Patients may have detectable HEV in their stool for 3-6 weeks after the onset of symptoms. Immunoglobulin M to HEV can appear with the start of symptoms and last for 3-4 months; however, immunocompromised patients do not always produce antibodies to HEV.
Transmission, Diagnosis, Prevention, and Treatment
HEV is transmitted via the fecal-oral route. HEV genotypes 1 and 2 infections can be spread by consuming contaminated drinking water as initially described by Khuroo (often contamination is from human feces). HEV genotypes 3 and 4 can also infect those who consume undercooked meat (pork, deer, wild boar, or shellfish). Hand washing and sanitation of drinking water is a critical preventative measure in the fight against HEV.
Clinical suspicion is key to diagnose cases. In the setting of an outbreak with known HEV cases, a symptomatic individual who has documented immunity to hepatitis A could be diagnosed presumptively. EASL recommends diagnosis by testing by polymerase chain reaction (PCR) and IgM for acute infections and using PCR for chronic infections. At present in the US, the FDA does not have an approved test for HEV, although commercial testing is available.
Most cases are treated with supportive care; however, pregnant and immunocompromised individuals are at greater risk. Immunocompromised patients (those with primary immunodeficiencies, HIV, cancer or those who have received chemotherapy or organ transplants) are all at risk of acute and chronic HEV infections. Initial presentation of HEV in a post-transplant patient might not always result in an elevation in aminotransferases that is as elevated as in non-transplant patients and seroprevalence increased post-transplant in a Canadian pediatric cohort suggesting acute or chronic HEV should be part of the differential. HEV infection in a post solid organ transplant patient is associated with thrombocytopenia and tacrolimus use. These patients can have the classic acute elevations in anti-HEV IgM and subsequent anti-HEV IgG, but can continue to have HEV RNA in the serum and stool for 3-6 months after the initial infection (this prolonged presence of RNA by PCR testing is indicative of a chronic infection). Often, chronic HEV requires treatment for clearance as it can lead to worsening liver disease, cirrhosis, and death. Patients can be treated with ribavirin (12 weeks) sometimes with added PEGylated interferon or sofosbuvir.
Why worry about HEV in pregnancy?
While healthy individuals can become infected by HEV and recover, the virus poses a much greater risk to pregnant individuals. HEV infection during pregnancy, especially in the 3rd trimester can result in maternal and fetal demise. In the 1980 case series written by Khuroo, 6 of 8 pregnant women who had the enterically transmitted HEV and experienced fulminant hepatitis died. All of those women were in their 3rd trimester of pregnancy. None of the non-pregnant patients from the series developed fulminant hepatitis. Estimates of maternal mortality ranges from 15-25%. Of a cohort of 86 pregnant women with HEV jaundice from Chennai, India (1996-2004), 12 (13.5%) experienced intrauterine fetal demise, 18 (21%) delivered before 37 weeks, and half of the premature infants died within a week of delivery.
Risk of fetal demise is significant. Based on 2005 data for HEV genotype 1 and 2, Rein and colleagues estimated that 3,000 stillbirths per year are attributable to HEV. The mechanism by which HEV causes increased morbidity and mortality in pregnancy is not well understood and it is hypothesized that changes in the T-regulatory compartment allow for increased replication in enteric mucosa.
What is the global burden of HEV and how does that compare to other hepatitis viruses?
Estimates from 2019 indicate more than 158 million people get HAV each year and mortality was estimated to be 7,134 in 2016 by the WHO. HEV causes the second most hepatitis cases with an estimated 20 million cases per year and 70,000 deaths. The WHO estimates that in 2022 there were 254 million people living with chronic HBV across the globe; 1.1 million of whom die from HBV complications with 1.2 million new infections annually. Likewise, the WHO estimates that HCV infects 50 million people across the globe in 2022 with 242,000 deaths and 1 million new infections. By comparison, HDV infects about 5% of the population with HBV.
Can we vaccinate against HEV?
Creating a vaccine for HEV has been a difficult task due to the slow growth in viral culture, lack of an animal models, and presence of the hypervariable region (HVR) in the genome. Of note, recently immunocompetent Mongolian gerbils have been used for a hepatitis E infection model.
There currently is a vaccine licensed in China since 2011 and in Pakistan since 2020. Based on a recent phase III randomized, double-blinded, placebo-controlled trial (NCT01014845), the vaccine offers some protection. The three immunization series at 0, 1, and 6 months offers 73%-85% seroprevalence of antibodies directed against HEV 7-8.5 years after immunization. Therapeutics are in development in the United States.
Back to the Case:
Our patient, with no history of chronic liver disease or an immunocompromising condition, had a self-limited infection that resolved over several weeks after testing positive for HEV IgM. He avoided contact with pregnant women during this time.
Take Home Points:
- Hepatitis E virus (HEV) is an enterically transmitted positive sense RNA virus that can infect humans, pigs, wild boar, deer, camels, or shellfish.
- Transmissions is fecal-oral from contaminated drinking water or meat.
- Infection in the 3rd trimester of pregnancy carries a mortality rate of 15-25%.
- Chronic infections are possible in individuals who are immunocompromised. These can be treated with antivirals.
- Clinical suspicion remains key for diagnosis as vaccination is not widespread.