Update on Child Hepatitis

Historically, hepatitis (inflammation of the liver) has not been a disease front and center in pediatric care. It happens, but only very rarely — and the source (maternal transmission, food poisoning, toxic exposure) is normally easily established. Thus, when in the midst of the COVID-19 pandemic the World Health Organization (WHO) noticed what appeared to be a spike in cases of hepatitis of unknown cause in young children (many toddlers), the news sent shock waves throughout both the popular media and the medical community.

Notably, the patients were not testing positive for viral hepatitis or toxins linked to hepatitis, nor were they newborns who may have contracted the condition in utero. So, health officials were left to categorize these cases as “acute hepatitis of unknown etiology.”¹ By July 2022, the number of such cases had grown to more than 1,000 — with four dozen children needing liver transplants, and more than 20 dying from the condition.²

In response, WHO and national health organizations, including the U.S. Centers for Disease Control and Prevention, immediately tried to determine what was causing this sudden spike. From that effort came two breakthrough understandings regarding childhood hepatitis:

• First, a subsequent re-examination of the medical record suggested there had not been a spike: Instead, due to COVID-19, there may have been a heightened awareness about and increased reporting of cases. (It seems a small number of cases of childhood hepatitis with no known cause has been happening for years.³)
• Second, infection by a combination of common childhood viruses may, in rare cases, lead to inflammation of the liver.⁴

Concurrent with these developments are ongoing advances in treatment of hepatitis in general, including new drugs that can offer the hope of a cure for some types of hepatitis that were previously incurable.

Causes of Hepatitis

Looking at the most common causes of hepatitis, it is clear that most young children are at very low risk for most types.

Infectious:

• Hepatitis A: spreads via contaminated food or water, sexual contact or sharing a hypodermic needle
• Hepatitis B: spreads via sexual contact, sharing a needle or from a mother to her child during pregnancy
• Hepatitis C: spreads via sharing a needle or from a mother to her child during pregnancy
• Hepatitis D: spreads via sexual contact, sharing a needle or from a mother to her child during pregnancy (notably, it can only infect those already infected with hepatitis B)
• Hepatitis E: spreads via contaminated drinking water

Toxin exposure:

• Alcohol: Excessive alcohol consumption for many years can cause hepatitis.
• Industrial chemicals: Exposure to chemicals ranging from tetrachloride to vinyl chloride, paraquat to polychlorinated biphenyls can result in hepatitis.⁵
• Over the counter pain relievers: Aspirin, acetaminophen, ibuprofen and naproxen can all damage the liver if taken frequently or in high doses.
• Prescription medications: Statins, some antivirals and anabolic steroids (among many others) can all cause hepatitis.
• Herbs and supplements: Aloe vera, chaparral and other plants can cause liver damage; children can develop hepatitis if they mistake vitamins for candy and ingest large amounts.

Autoimmune:

• People who have already been diagnosed with an autoimmune condition such as thyroiditis, Grave’s disease, celiac disease and immune thrombocytopenia, among others, can develop hepatitis.⁶

Viruses:

• Epstein-Barr virus, cytomegalovirus, rubella, enteroviruses, varicella zoster virus, herpes simplex virus and parvovirus can all cause hepatitis. However, while hepatitis is a possible side effect or complication of these infections, it is extremely rare.⁷

Pediatric Hepatitis

Until recently, most cases of noninfant pediatric hepatitis in the West were caused by the hepatitis A virus, contracted via contaminated food.⁸

Sadly, a growing source of hepatitis in children is maternal transmission of hepatitis C, which is associated with expectant mothers who have injected illegal street drugs.⁹ More than 700 babies are born with hepatitis C in the United States each year, a number that has grown significantly and correlates strongly with the opioid crisis.¹⁰ (Johns Hopkins points out, however, than only 20 percent of all neonatal cases of hepatitis can be specifically traced to a viral infection in the mother; the rest are of unknown cause.¹¹)

In the developing world, hepatitis E (contracted from untreated water) remains a leading cause of hepatitis in children. Hepatitis B is also still a significant source of hepatitis in Africa, where it is passed from mother to child.¹²

Autoimmune hepatitis is categorized into types I and II. Type I tends to appear in school-age children or older and is the most common type. Type II can appear earlier, and is more difficult to treat.¹³

Cracking the Mystery?

As noted previously, most of the children diagnosed with hepatitis during the past 18 months or so tested negative for the hepatitis viruses, tested negative for toxins associated with hepatitis and tested negative for autoimmune disorders. What one group of researchers found, though, is that a large percentage of these patients did test positive for an adenovirus. While this specific virus, adeno-associated virus type 2 (AAV2), is not known to cause hepatitis on its own, researchers speculate that it may cause liver inflammation in conjunction with other viral infections.¹⁴ Among the other viruses found in the subjects’ specimens were human adenoviruses (HadVs), Epstein-Barr, herpes and enterovirus. The average age of the children in the study was 3 years old.

One of the study’s lead authors, Charles Chiu, MD, PhD, director of the Clinical Microbiology Laboratory at the University of California, San Francisco, said, “We were surprised by the fact that the infections we detected in these children were caused not by an unusual, emerging virus, but by common childhood viral pathogens.”¹⁵ The researchers think that the social isolation the children experienced during the COVID-19 lockdowns may have made them more susceptible to these common viruses when they returned to normal social interactions.¹⁶

Researchers are unsure of the mechanisms by which multiple adenoviruses might create liver inflammation, and little is understood of adenoviruses in general. With more than 100 types of adenoviruses already identified, and more continuing to be discovered, scientists are urging that more resources be dedicated to studying adenoviruses and their pathology.¹⁷

Diagnosis and Treatment

Diagnosis of pediatric hepatitis is no different than with adults — with the caveat that very young children will be unable to articulate pain, so it is incumbent upon physicians to work with parents to notice any other symptoms consistent with hepatitis, including changes in color of urine or feces, jaundice, fever, fatigue or itchy skin.

With immunocompromised patients receiving immune globulin treatments, false positives for hepatitis B are possible due to the presence of hepatitis B antibodies in donors’ plasma.¹⁸ Additional screening may be necessary to confirm a diagnosis.

Treatment is also the same as for adults with hepatitis. Acute hepatitis is treated with palliative care, including rest, fluids and avoiding medications that might further stress the liver.¹⁹

For hepatitis B, quick treatment with immune globulin immediately after exposure can help prevent the onset of chronic hepatitis. If the hepatitis B infection does become chronic, antivirals, including tenofovir (Viread), lamivudine (Epivir) and adefovir (Hepsera) may be prescribed to slow the virus’ growth. Interferon alfa-2b may also be given in conjunction with an antiviral.²⁰ There are also reports that hepatitis E can be cleared from immunocompromised patients with antiviral drugs.²¹

Further, there is good news in that it is now possible to cure hepatitis C via antiviral drugs — with a success rate of more than 95 percent. A dozen antiviral drugs are approved by the U.S. Food and Drug Administration to treat hepatitis C, ranging from sofosbuvir (Sovaldi) to ribavirin (RibaPak).²²

Hepatitis D, which can only be contracted by someone who already has hepatitis B, will be treated alongside hepatitis B. Hepatitis D is usually treated with a 48-week regimen of pegylated interferon alpha.²³

Toxic hepatitis is generally treated similarly to hepatitis A: with rest and liquids. In the case of an overdose of acetaminophen, a drug called acetylcysteine can be administered to limit the damage to the liver — but only if administered within 16 hours of the original acetaminophen exposure.⁵

Autoimmune hepatitis is approached with the goal of inducing remission. Steroids (prednisone) can stop the body’s immune system from attacking the liver. They can be used in conjunction with immunosuppressants such as azathioprine or mercaptopurine.¹³

Treatment for hepatitis of unknown origin is more involved than in other cases in order to head off possible complications. As with acute hepatitis, rest and liquids are called for. In addition, limiting protein intake and watching for a decline in liver function, as well as maintaining blood electrolyte levels and watching coagulation function, are important.²⁴ If patients test positive for an adenovirus, that infection can be addressed with antivirals, including cidofovir, ganciclovir and ribavirin.²⁵

Treatment for chronic hepatitis will depend upon the specific cause.

In all instances of hepatitis, a liver transplant may become necessary if the inflammation cannot be controlled and there is significant damage. In younger children especially, the transplant may need to be only a portion of an adult donor liver, which makes it possible to utilize a living donor.

Prevention

Effective vaccinations are available for hepatitis A and B, and these should be administered as outlined by public health authorities. If traveling to areas where hepatitis E outbreaks are known to occur, individuals should drink only treated water, or boil or chlorinate water before drinking it.

To prevent toxic hepatitis, keeping all medications away from children is crucial. This includes vitamins and over-the-counter pain killers.

Women who are pregnant or may become pregnant should avoid sharing needles (or even using recreational drugs), and should be tested for hepatitis during pregnancy.

To prevent hepatitis of unknown cause, parents should use normal hygienic routines to inhibit the spread of adenoviruses. For instance, children should be reminded to wash their hands thoroughly with warm water and soap before meals and after using the bathroom, and if practical, wear a face mask in social settings where respiratory illness is known to be circulating.

Reporting Is Necessary

With information scarce and research still ramping up on the possible links between adenoviruses and hepatitis of unknown cause, physicians should report any such patients to public health authorities to help build our body of knowledge.