Whitworth, John R.*; Mack, Cara L.*; O'Connor, Judith A.*; Narkewicz, Michael R.*; Mengshol, Sarah†; Sokol, Ronald J.*
*Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Pediatric Liver Center; †Department of Pathology, The Children's Hospital, University of Colorado School of Medicine, Denver, CO
Received September 9, 2005; accepted June 5, 2006.
Address correspondence and reprint requests to Dr. Cara Mack, B290, 1056 East 19th Avenue, Denver, CO 80218 (e-mail: firstname.lastname@example.org).
Presented in part at the 55th Annual Meeting of the American Association for the Study of Liver Disease, October 30, 2004, Boston, MA.
This article was published in abstract form: Whitworth JR, Sokol RJ, O'Connor JA, Narkewicz MR, Hass JE, Mack CL. Hepatology 2004;40(4, suppl 1):469A.
Conflict of interest: None of the authors has potential, perceived or real conflicts of interest to disclose.
Influenza A is a member of the orthomyxoviridae family of single-stranded RNA viruses. Infection with influenza A causes relatively few extrapulmonary manifestations. Severe gastrointestinal complications of influenza A infection are rare and include pancreatitis, hemorrhagic gastritis and Reye syndrome (1-3). Acute hepatic decompensation in adults with underlying chronic liver disease has been reported (4). We describe 4 previously healthy children with influenza A infection who developed concurrent acute hepatitis with or without acute liver failure. Three recovered with supportive care; 1 developed symptoms consistent with an underlying mitochondropathy. This is the first report of severe hepatitis or liver failure associated with influenza A infection in healthy children and suggests that influenza A virus may be hepatotropic.
We reviewed the charts of all children presenting to The Children's Hospital with acute hepatitis or acute liver failure during the Colorado influenza A epidemic of 2003-2004. We identified 2 patients with severe hepatitis and 2 with acute liver failure associated with influenza A infection. Liver failure was defined as acute liver dysfunction, encephalopathy and coagulopathy (prothrombin time, >20 seconds) in a patient with no known liver disease (5). Acute hepatitis was defined as inflammation of the liver lasting less than 6 months, with a more than 2-fold elevation of aminotransferases in a patient without liver failure, previous liver disease or elevated transaminases.
We recorded patient age, sex, medical history, prodromal symptoms (fever, cough, rhinorrhea, emesis, abdominal pain, jaundice, lethargy, dehydration), time from prodromal symptoms to onset of hepatitis, use of acetaminophen, other medications or herbal preparations, peak and recovery liver function tests, evaluations for causes of hepatitis or underlying chronic liver disease, liver biopsy histopathology, response to treatment and outcome. Influenza A infection was diagnosed in all patients by direct fluorescent antibody testing of nasopharyngeal aspirates.
A 22-month-old girl developed jaundice after 3 days of fever, cough and rhinorrhea. She received several therapeutic doses of acetaminophen for 3 days. She was hospitalized on day 3 with severe hepatitis (Table 1). Her diagnostic evaluation revealed only influenza A infection (Table 2). She was treated with amantadine and discharged after 3 days. Liver tests normalized within 3 months, and the patient remained well for the ensuing 12 months.
A 14-month-old boy had 4 days of fever, cough and rhinorrhea. He was given acetaminophen (15 mg/kg/dose) approximately every 4 hours. He had received a single dose of influenza vaccine 10 days before symptom onset. On the fifth day of symptoms, he was admitted to the hospital for lethargy and dehydration and was diagnosed with hepatitis (Table 1) and influenza A. The serum acetaminophen level was less than 4 μg/mL (therapeutic range, 10-30 μg/mL). He was discharged on hospital day 6. Liver function tests normalized within 2 months, and the patient has been well during 13 months of follow-up.
A 23-month-old boy was admitted for acute liver failure with jaundice and stage I encephalopathy after 6 days of fever, cough, rhinorrhea and emesis (Table 1). A single dose of influenza vaccine was administered 30 days before the onset of symptoms. Influenza A was identified 4 days before admission, and rimantadine was initiated. His treatment included fresh frozen plasma, vitamin K, vitamin E, lactulose and parenteral nutrition. A transjugular liver biopsy revealed hemorrhagic necrosis, and immunohistochemical stains for adenovirus, cytomegalovirus and herpes simplex virus 1 and 2 were negative. He was discharged on hospital day 8, and liver tests normalized within 2 months. Five months after the initial presentation, the patient had a mild elevation in liver aminotransferases identified during routine screening. A percutaneous liver biopsy was performed, and there was no histological evidence of chronic liver disease. The liver aminotransferases quickly normalized, and the patient has been well during 12 months of follow-up.
A normally developing 39-month-old boy developed fever, cough, rhinorrhea, emesis and dehydration over 3 days. He received approximately 6 doses of acetaminophen (15 mg/kg/dose) for 3 days and cephalosporin antibiotic for otitis media. On the fourth day, he was hospitalized for treatment of dehydration and was diagnosed with influenza A. Acute liver failure with stage II encephalopathy developed within 48 hours of admission (Table 1). Oliguric renal insufficiency ensued. Serum acetaminophen level was less than 2 μg/mL. A transjugular liver biopsy revealed centrilobular necrosis without prominent inflammation, and electron microscopy showed prominent microvesicular steatosis with normal mitochondria and peroxisomes. Immunohistochemical staining of the biopsy was negative for adenovirus, cytomegalovirus, herpes simplex virus 1 and 2, as well as influenza A and B (performed by the Centers for Disease Control and Prevention, Atlanta, GA). He was treated with fresh frozen plasma, vitamin K, antibiotics, acyclovir, N-acetylcysteine and 1 week of peritoneal dialysis. He was discharged after 3 weeks with normal liver function and improving renal function.
He was readmitted twice in the following 8 months for encephalopathy during acute viral illnesses, once with recurrent renal and hepatic failure. To date, he has persistent neurological deficits and elevated liver aminotransferases. Evaluations for a mitochondrial hepatopathy are in progress.
This is the first report of acute hepatitis and liver failure with concomitant influenza A infection. Four previously healthy children, ages 14 to 39 months, developed acute hepatitis or acute liver failure and were diagnosed with influenza A infection within a 3-week period during the influenza A, subtype H3N2 predominant, epidemic of 2003-2004 in the state of Colorado (6). The 2003-2004 influenza epidemic resulted in 13,008 laboratory confirmed cases of influenza in the state of Colorado compared with 2681 cases in 2002-2003. From November 1 to December 31, 2003, our pediatric institution experienced 1580 laboratory confirmed cases that included 132 admissions. Statewide, there were 12 pediatric deaths associated with influenza infections. Evaluations for other infectious, autoimmune and metabolic causes of liver disease were negative to date in all 4 patients (Table 2). No patient received aspirin, other known hepatotoxic drugs (except for therapeutic doses of acetaminophen) or herbal therapies. All patients recovered with supportive care, and 3 patients have normal liver function at the time of this report. Case 4 may have an underlying metabolic disease that has yet to be identified.
Influenza has not been demonstrated previously to be hepatotropic in humans. It does cause hepatitis in murine models. Mice infected with aerosolized influenza A develop viremia and detectable virus in extrapulmonary organs, including the liver (7). Another study reported the adaptation of influenza A to produce a hepatotrophic variant that produced a necrotizing hepatitis in susceptible mice (8). Studies supporting influenza hepatotoxicity in humans include a single case report of liver failure after influenza B infection in a child (9) and a report of influenza A infection associated with hepatic decompensation in 3 adults with cirrhosis (4). Hepatic decompensation was postulated to be caused by direct hepatotoxic injury by the influenza virus in cirrhotic patients with decreased immunity. Alonso et al. (10) described 7 young children with fulminant hepatic failure after a prodromal viral illness whose presentations, in retrospect, occurred during a moderately severe influenza epidemic as classified by the Centers for Disease Control and Prevention (11). Interestingly, these 2 series (4,10) and our 4 cases all occurred during influenza outbreaks that were predominantly influenza A subtype H3N2 (6,11,12).
We speculate that liver injury may have resulted from infection by certain strains of influenza A or by influenza A infections in susceptible hosts, preferentially injuring zone 3 hepatocytes. Alternatively, as suggested by Alonso et al. (10), the therapeutic doses of acetaminophen may have augmented a viral insult. The use of acetaminophen and the high aspartate aminotransferase and alanine aminotransferase levels in each patient and the presence of centrilobular hepatocyte necrosis in the liver biopsy of case 4 suggest features of acetaminophen toxicity. The combination of acute influenza infection and acetaminophen usage in children who develop hepatic injury is reminiscent of the epidemiology of Reye syndrome, in which influenza infection and salicylates combined to generate mitochondrial liver failure. Further investigations, such as those using acetaminophen metabolite adducts as a biomarker for acetaminophen toxicity, will be needed to determine the role, if any, of this agent.
Our case 4, who developed chronic hepatic, renal and neurological problems, points out that influenza A infection may unmask underlying metabolic disorders. The centrilobular hepatic necrosis in this patient suggests an additional insult beyond the steatosis of his underlying metabolic liver disease.
In conclusion, influenza A appears to cause severe hepatitis in some children, and we speculate that more cases with hepatic dysfunction would be identified if all children with influenza were screened with biochemical liver tests. Our cases suggest that children with severe influenza A infection should be screened for liver injury. A prospective study will be needed to identify overall incidence of liver injury associated with influenza A and its potential mechanisms.
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