Acute Hepatitis in an Adolescent Without Travel History

CASE A 15-year-old boy presented with fevers up to 40°C for 3 days and dark urine over the past 24 hours. He was born and resided in Madrid and had no significant medical history. His immunizations were current. He denied sexual activity or taking illicit drugs, alcohol or herbal medications. His mother had acute gastroenteritis a month earlier and was still experiencing loss of appetite and asthenia. Physical examination was normal in the emergency department, except for scleral icterus. Laboratory studies showed a white blood cell (WBC) count of 3000/μL (with differential of 57% neutrophils, 30% lymphocytes and 13% monocytes), platelet count of 79,000/μL, C-reactive protein of 0.8 mg/dL, procalcitonin of 0.66 ng/dL, aspartate aminotransferase of 159 U/L, alanine aminotransferase of 289 U/L, gamma-glutamyl transferase of 159 U/L, total bilirubin of 6.7 mg/dL, direct bilirubin of 4.5 mg/dL and the international normalized ratio of 1.5. Urinalysis showed elevated bilirubin (6 mg/dL) and protein (50 mg/dL) as well as 1–5 red blood cells and 1–5 WBC per high-powered field. Rapid antigen test for influenza and respiratory syncytial virus and PCR for other respiratory viruses (adenovirus, coronavirus, human metapneumovirus, rhinovirus, enterovirus, influenza B and A, and respiratory syncytial virus) were all negative. Abdominal ultrasound revealed an enlarged spleen (up to 15.8 cm) and liver echogenicity with a “starry sky appearance.” Diagnostic evaluation to rule out autoimmune hepatitis was negative, including negative titers for antinuclear antibody, anti-liver cytosol antibody type 1, anti-liver-kidney microsomal antibody type 1, anti-mitochondrial antibody, anti-reticulin antibody, and anti-parietal cell antibody and low-positive titer for smooth muscle antibody. Serologic testing for hepatitis A, B and C viruses, HIV, Epstein-Barr virus and leishmaniasis were all negative. However, IgM and IgG were positive for cytomegalovirus (CMV) so mononucleosis syndrome due to CMV was diagnosed. He received a single vitamin K dose. During the first day of hospitalization, jaundice and hepatomegaly were noted. Jaundice progressively increased during the first 48 hours, and a generalized itchy, erythematous and papular rash appeared on the patient’s trunk on the third day. By the sixth day, due to a decrease in jaundice, improvement in the cutaneous rash, and normalization of abnormal laboratory values, the patient was discharged. After 1 week at home, the patient fully recovered from jaundice and rash, and two weeks after discharge, no hepatomegaly was found, and urinalysis was normal. CMV PCR in blood and urine obtained upon admission subsequently returned back as undetectable, suggesting that CMV infection was unlikely related to the clinical presentation. At this point, additional serologic testing established the diagnosis. For Denouement see P. 273. DENOUEMENT (Pediatr Infect Dis J 2022;41:273) Continued from P. 272. Due to the self-limited course of hepatitis with no other hepatotropic virus isolated, hepatitis E virus (HEV) serology by indirect chemiluminescent immunoassay (CLIA; HEPATITIS E VIRCLIA, Vircell Diagnostics) was performed on 2 serum samples: one drawn during the hospitalization and another drawn as an outpatient 4 weeks later. IgM was negative in both samples, but seroconversion of HEV IgG was demonstrated as follows: IgG was negative in the first sample with an index of 0.8 but was positive in the second sample with an index of 1.6 (index positive if >1.1 and negative if <0.9). These results confirmed the diagnosis of HEV infection. HEV PCR of the blood or stool was not performed. During follow-up evaluation, the patient’s liver function tests and bilirubin normalized within 3 months after admission, and he remained asymptomatic at 12 months. Our case underscores the importance of including HEV as a cause of acute hepatitis in adolescents in developed countries, even without a travel history. Hepatitis E virus (HEV) is one of the main causes of acute hepatitis worldwide. Every year 20 million HEV infections are reported, with symptomatic infection comprising 3.3 million. In 2015, 44,000 deaths due to HEV were reported.1 HEV is usually a forgotten cause of acute hepatitis in industrialized countries like Spain. Only when a travel history is reported is suspicion of HEV raised. In the latest seroprevalence studies done in children in Europe,2 HEV IgG was positive up to 4.6% in Spain.3 About 4.2% in Turkey and 1.1% in Portugal.4 Although these studies could not distinguish autochthonous from imported cases based on anti-HEV antibodies, in recent years, new cases of autochthonous infections have been reported in Spain.5,6 HEV is a single-stranded RNA virus. Four different genotypes have been described. Genotypes 1 and 2 are associated with enterally acquired acute hepatitis (via fecal-oral transmission). Genotypes 3 and 4 have been associated with sporadic cases with type 3 being responsible for cases in Europe and the USA and type 4 being common in Asia. Genotype 3 may affect different animals (pigs, wild boar, deer, rabbits or bivalve molluscs) with potential infection to humans via consumption of contaminated food. Other routes that have been described include vertical, sexual or blood transfusion transmission.7 In children, HEV causes mainly asymptomatic infection. If symptoms occur, they appear as follows: fever, malaise, myalgias, abdominal pain and vomiting during the first week of illness, followed by acute icteric hepatitis with dark urine and jaundice.8,9 Our case presented with an acute hepatitis episode following an exanthema, which has not been commonly described in the medical literature. Extrahepatic complications, however, have been reported with HEV and include neurologic disorders such as Guillain-Barre syndrome,10 thrombocytopenia or anemia, acute pancreatitis, and Henoch-Schönlein purpura.9 Fulminant hepatic failure or chronic infections have been described in pregnant women, in those with previous liver failure, or in immunosuppressed patients.8,9 Detection of HEV RNA or IgG/IgM antibodies is the main tool for diagnosis. HEV RNA is detectable by PCR in serum during the first 4–6 weeks after symptoms onset and in stool during the first 52 days.11 HEV IgM and IgG may be detected in 90% of patients during the first week of illness. After 6 weeks, only 30% of patients have detectable IgM, whereas IgG is still detected in almost all patients. In immunocompromised patients, detection of RNA HEV is the more reliable way to diagnose HEV infection, due to potential false-negative results with serologic tests. Sensitivity and specificity may vary, and there are no universally accepted serologic methods. As has been described,8,9 hepatitis due to HEV is typically self-limited, with full recovery in 3–4 weeks after the onset of symptoms. No treatment is generally necessary, but among immunocompromised children who develop fulminant acute liver failure or chronic disease due to HEV, ribavirin has been described as a potential treatment.11 Prevention should be one of the main cornerstones to avoid HEV infection. Hygienic practices, such as avoiding untreated water and street or uncooked food, should be recommended to all travelers to endemic areas. Recombinant hepatitis E vaccine seems to provide protection up to 4.5 years; however, at present, this vaccine has only been approved in China.12 In summary, acute HEV infection is an important diagnosis to consider when other causes of acute hepatitis have been ruled out, even if there is no travel history to endemic areas. To the best of our knowledge, this is the first case of acute hepatitis associated with HEV infection in the pediatric age in Spain. A high index of suspicion is necessary to achieve a correct diagnosis.