bubble_chart Overview

Dual or multiple infections refer to a single viral hepatitis patient being infected with two or more different types of hepatitis viruses. Currently, five types of hepatitis viruses are known, and there is no cross-immunity between them. This means that after being infected with one type of hepatitis virus, a person can still be infected with other types. Based on the timing of infection, these can be classified as simultaneous infections (mixed infections) or overlapping infections (sequential infections).

bubble_chart Clinical Manifestations

The clinical symptoms caused by simultaneous or overlapping infections of hepatitis viruses are generally similar to those of acute or chronic hepatitis caused by a single type of hepatitis virus infection. However, due to the different combinations of hepatitis virus types, each has its own characteristics. Overall, it can complicate the patient's condition, worsen symptoms, and lead to poor treatment outcomes. Therefore, when encountering refractory severe chronic active hepatitis, post-hepatitis cirrhosis, or severe hepatitis patients, the possibility of multiple infections should be considered.

It is estimated that there are 280 million HBsAg-positive carriers worldwide, with about 100 million in China, two-thirds of whom are asymptomatic carriers. Due to the high HBV carrier rate, overlapping infections with other hepatitis viruses are likely to occur through various transmission routes. The common combinations are as follows:

(1) Dual infection of HBV and HAV

1. Simultaneous infection: This type is relatively rare. Since both HBV and HAV are primary infections, their clinical manifestations and liver function tests are more pronounced than those of overlapping infections. Except for a few patients with prolonged courses, most cases resemble acute jaundice hepatitis with a good prognosis. No worsening of symptoms or liver damage has been observed.

2. Overlapping infection: Domestic reports vary by region, with overlapping infection rates of HBV and HAV in sporadic acute hepatitis ranging from 0% to 23.4%. During the 1988 hepatitis A outbreak in Shanghai, about 10% were chronic HBsAg carriers overlapping with HAV infection. It can be seen that in areas with high HBsAg carrier rates and outbreaks of hepatitis A, overlapping infections of HBV and HAV are more common.

In chronic hepatitis B patients overlapping with HAV infection, half experience worsened symptoms and elevated ALT levels after contracting hepatitis A, particularly in cases of chronic active hepatitis. If HAV infection occurs on the basis of existing cirrhosis, jaundice deepens, liver function damage worsens, and ascites and hepatic encephalopathy may occur.

The prognosis of HBV and HAV overlapping infections depends on the severity of pre-existing liver disease. The vast majority have a good prognosis, but if severe hepatitis develops or pre-existing severe liver disease is present, the condition tends to worsen, leading to a poor prognosis.

(2) Dual infection of HBV and HCV

Due to the high carrier rates of both HBV and HCV, the chances of overlapping infections are also significant. Foreign reports indicate overlapping infection rates of HBV and HCV at 15–28%. A 1990 domestic report on 40 cases of HBsAg-positive, anti-HBc IgM-negative chronic active hepatitis tested with the Ortho C _100-3 diagnostic kit showed an anti-HCV positive rate of 17.5%, which is consistent with foreign findings.

The clinical symptoms of pure hepatitis C are generally milder than those of hepatitis A or B, with more asymptomatic and subclinical cases. Most cases are non-jaundiced, with only elevated ALT levels. A few severe cases of hepatitis C are difficult to distinguish from hepatitis B. However, when HBV overlaps with HCV infection, the clinical symptoms are more severe than those of pure hepatitis C or B, with prolonged courses, a tendency toward chronicity, recurrent conditions, persistent liver function abnormalities, and even progression to severe hepatitis, cirrhosis, or liver cancer.

(3) Dual infection of HBV and HDV

Domestic reports indicate varying HDV infection rates across regions, ranging from 0% to 12%, with significant regional differences. In 1989, Zhang Yongyuan reported HDAg detection results from over 2,000 liver tissue samples across 16 provinces and cities, with positive rates ranging from 5.33% to 19.77%. Although HDV infection is closely related to HBV infection, the rates of HDV infection do not consistently align with HBV infection rates. In regions where hepatitis D is endemic, both HBV and HDV infection rates are high. However, in China and some Southeast Asian countries, HBV carrier rates are very high, while HDV infection rates remain low, the reasons for which require further clarification.

1. Coinfection of HBV and HDV The clinical symptoms and liver function test characteristics of simple acute HDV infection are similar to those of simple acute HBV infection. However, a biphasic pattern of ALT elevation may sometimes be observed, representing HBV and HDV infections, respectively. Compared to simple acute HBV infection, such acute hepatitis D has a lower risk of progressing to chronic hepatitis. The course of the disease is mostly self-limiting, with a favorable prognosis.

2. HBV and HDV Coinfection This often presents as a chronic and insidious process, but the disease progresses rapidly, frequently developing into chronic active hepatitis and cirrhosis. Rizzetto et al. observed 137 chronic hepatitis D patients with intrahepatic HDAg positivity, of whom 41% progressed to cirrhosis.

Both simultaneous infection and coinfection of HBV and HDV can lead to severe hepatitis. Therefore, it is often believed that HDV infection superimposed on HBV infection is one of the causes of severe hepatitis and cirrhosis.

(4) HBV and HEV Dual Infection

Hepatitis E can occur as explosive outbreaks or endemic infections worldwide. Outbreaks have been reported in Xinjiang, China, making HBV and HEV coinfection a significant concern. While HEV infection alone is usually self-limiting with a good prognosis, it can lead to fulminant hepatic failure in pregnant women, with a high mortality rate. Reports from India indicate that most cases of severe hepatitis occur in HBsAg carriers coinfected with HEV. Thus, in regions with high HBV infection rates, HBV and HEV coinfection may contribute to the occurrence of severe hepatitis.

(5) HBV, HCV, and HDV Multiple Infections

Infections with three or more hepatitis viruses are rare. The progression and outcome of the disease clearly depend on the extent of liver damage prior to coinfection. Asymptomatic HBsAg carriers may develop symptoms and abnormal liver function. If the patient already has chronic active hepatitis or cirrhosis, clinical symptoms worsen progressively, and liver function impairment becomes more pronounced, affecting treatment efficacy. In China, severe hepatitis is mainly caused by HBV coinfection with HCV and HDV, leading to severe liver damage and poor prognosis. The widespread use of blood transfusions and blood products for treating chronic liver disease and severe hepatitis, combined with China's high HBsAg carrier rate (10–15%) and high anti-HCV positivity rate among blood donors, increases the likelihood of HCV infection. Severe hepatitis E can also be coinfected with HAV, but this does not significantly impact disease severity or prognosis.

Impact of Dual Infection on Viral Serological Markers

1. Simultaneous Infection Most studies suggest no interference between hepatitis viruses.

2. After Coinfection Certain HBV replication markers may be suppressed. This is manifested by a decrease or disappearance of HBsAg titer, or even the disappearance of HBsAg in liver tissue; HBsAg levels may decline or disappear, and anti-HBs may appear. The conversion of HBV-DNA and DNA-p to negative or temporary negativity indicates varying degrees of HBV replication suppression.

The natural clearance rate of HBsAg is very low, only about 1% annually. Whether coinfection with other hepatitis viruses accelerates HBsAg seroconversion and suppresses viral replication requires further study.

The mechanisms by which coinfection affects the serological markers of the original hepatitis virus remain unclear and warrant in-depth investigation.

bubble_chart Diagnosis

Based on clinical features: In cases of chronic HBV infection with recent jaundice and abnormal liver function, or chronic active hepatitis or cirrhosis with recent deterioration and poor treatment response, the possibility of coinfection with other hepatitis viruses should be considered, and relevant pathogen detection should be promptly conducted. Given the high HBV infection rate in China, even for patients presenting with acute hepatitis without a history of hepatitis, the possibility of prior HBV infection or asymptomatic HBsAg carrier status cannot be ruled out. Therefore, serum anti-HAV IgM and HBV markers should be tested simultaneously to aid diagnosis.