Screening for Viral Hepatitis During the Domestic Medical Examination of Newly Arrived Refugees

Background

Hepatitis is inflammation of the liver. Hepatitis may result from various infectious and noninfectious causes. Many viral infections can cause liver inflammation, but the term viral hepatitis usually refers to infections with one of the five hepatotropic viruses (viruses known to target the human liver): HAV, HBV, HCV, HDV, and HEV.

Infections caused by these viruses vary in their epidemiologic features and natural history, including incubation period, routes of transmission, geographic and demographic distribution, patterns of clinical disease, and propensity for becoming chronic. Therefore, strategies for prevention and approaches to clinical management vary.

Each type of viral hepatitis may cause illness during acute infection (2 weeks to 6 months following exposure). Although acute viral hepatitis can be severe or fatal, it is often asymptomatic. HAV and HEV cause predominantly acute hepatitis and are the leading causes of symptomatic viral hepatitis infections globally. Acute HBV and HCV infections that become chronic, are often asymptomatic and silently damage the liver. Untreated HBV and HCV infections result in a high disease burden and are leading causes of cirrhosis (late-stage scarring of the liver) and hepatocellular carcinoma (liver cancer) in the United States and globally. Because chronic HBV and HCV infections are asymptomatic and refugees often come from settings where these viruses are endemic, it is important to consider these infections during the domestic medical screening for newly arrived refugees.

For additional information, see the CDC Viral Hepatitis website.

Overseas Pre-Departure Screening and Vaccination

Refugees from participating overseas locations may be eligible to receive up to two doses of hepatitis B vaccine before resettlement in the United States through the Vaccination Program for US-bound Refugees. Eligible refugees who choose to participate in the voluntary pre-departure vaccination program are first screened for HBV infection by testing for the presence of HBsAg. Refugees positive for HBsAg do not receive hepatitis B vaccination overseas and are counseled about the infection and how to prevent transmission. Refugees negative for HBsAg receive up to two hepatitis B vaccine doses, if due. HBsAg results are documented on the DS-3026 (Medical History and Physical Examination Worksheet). Vaccines received through this program are documented on the DS-3025 (Vaccination Documentation Worksheet). These records are available to state health departments through the Electronic Disease Notification (EDN) system.

Household contacts of HBsAg-positive people who test negative for HBsAg may be given a third dose of hepatitis B vaccine overseas, in order to complete the series, if time allows. Because the third dose may be given close to the time of departure, providers should be aware that HBsAg results may be falsely positive within the first month after hepatitis B vaccination. Clinicians should consider waiting at least 30 days after hepatitis B vaccination before HBsAg testing.

Clinical Presentations and Domestic Diagnostic Testing for Specific Viral Hepatitides

Chronic Viral Hepatitis

Hepatitis B Virus (HBV)

Background

Chronic HBV infection, defined as HBsAg positivity for at least 6 months, is a major cause of preventable morbidity and mortality. In 2015, an estimated 257 million people were living with chronic HBV infection worldwide, and as many as 862,000 persons with chronic infection in the United States. Approximately 88% of the world’s population lives in areas of high or intermediate endemicity. Additionally, the WHO estimates that there are more than 887,000 deaths per year worldwide [2–4]. The majority of deaths occur in resource-limited countries.

HBV infection prevalence and transmission patterns vary markedly among countries and populations. Many refugees arrive from countries with intermediate (2% to 7%) or high (≥ 8%) endemicity (refer to the CDC Yellow Book for map of prevalence). Areas of intermediate endemicity include much of Asia; parts of Latin America, particularly the Amazon Basin; South Pacific islands; and sub-Saharan Africa. Areas of high endemicity include much of West Africa, select countries in sub-Saharan Africa, and parts of Southeast Asia. In general, prevalence of chronic HBV infection in migrant populations reflects rates in the region of birth.

In highly endemic regions where routine immunization has not been implemented, new infections occur predominantly among infants and young children, often a result from perinatal or household transmission. The sequelae of chronic HBV infection vary by age at time of infection. Acquisition during infancy or childhood is associated with a higher likelihood of progression to chronic infection and hepatocellular carcinoma. Without early diagnosis and management, people with chronic HBV infection are at risk for developing HBV-related chronic liver disease, including cirrhosis and hepatocellular carcinoma, and extrahepatic manifestations, such as glomerulonephritis.

Although usually asymptomatic, people with chronic HBV infection may transmit the infection to others. Common modes of HBV transmission include perinatal exposure, sexual contact, and needle sharing. Transmission may also occur within households. More details on prevention of and screening for HBV infection are available from the CDC Division of Viral Hepatitis. The domestic medical examination is an opportunity to identify HBV-infection in resettling refugees, decreasing morbidity and mortality, and preventing transmission to family members and other close contacts.

Testing for HBV Infection

Most refugees resettling to the United States originate from or have lived in countries with intermediate or high hepatitis B endemicity. The serologic patterns of HBV infection are complex, and a complete discussion is beyond the scope of this document. For detailed information on HBV infection and interpretation of hepatitis B serologic markers, please refer to the CDC Hepatitis B FAQs for Health Professionals. The serologic markers most widely used in diagnosis of acute, chronic, and resolved HBV infection include HBV surface antigen (HBsAg), antibody to HBsAg (anti-HBs), and antibody to HBcAg (total and IgM anti-HBc) [5]. Table 1 outlines the typical interpretation of hepatitis B serology.

Table 1. Expanded Hepatitis B Serologic Marker Interpretation and Initial Management

^*Refugees who are partially vaccinated should complete the series, except if they are positive for anti-HBc AND anti-HBs and, thus, considered immune by infection.

^**Refugees with an isolated anti-HBc may have an undetectable infection and may be at risk of disease with immunosuppression.

No medication is available for acute HBV infection; treatment is supportive. There are several antiviral medications for people diagnosed with chronic HBV infection. People with chronic HBV infection require regular monitoring to prevent liver damage or hepatocellular carcinoma. Clinical practice guidelines for the treatment of chronic hepatitis B are available from the American Association for the Study of Liver Diseases (AASLD).

Screening Recommendations for Chronic HBV Infection in Refugees

Adults

In accordance with national screening recommendations, all newly arriving adult refugees age ≥18 years  should be screened for hepatitis B, if not previously tested [5].  Of note, most refugees are tested for HBsAg prior to departure for the United States. Review overseas records (pre-departure testing for infection and vaccination) to determine if further management is needed.

• If not previously tested for hepatitis B infection, testing should be performed for HBsAg, total anti-HBc, and anti-HBs.
• If previously tested for hepatitis B virus infection overseas:
  • If testing was positive for HBV infection (HBsAg-positive), then additional evaluation and treatment options, or referral to a specialist, is recommended.
  • If HBsAg was negative, and the refugee has a record of complete vaccination before arrival, then no further testing or vaccination is necessary.*
  • If HBsAg was negative, vaccination records indicate that the vaccination series is complete, the refugee is in a high-risk group (see below), or there is a concern for high-risk exposure since the original screen, then it is reasonable to repeat testing following arrival.
  • If HBsAg was negative and no previous doses of vaccine were received, then the refugee should be tested for immunity by serology with total anti-HBc and anti-HBs. It is reasonable to start the hepatitis B vaccine series while awaiting results. If serologic testing returns negative, then the series should be completed. If serology for both anti-HBc and anti-HBs are positive, then no further vaccine doses are needed.

*In refugees with high risk of future exposure, it is reasonable to check serology for evidence of immunity.

Pregnant People

• All pregnant persons should be screened during each pregnancy, preferably in the first trimester, regardless of vaccination status or history of testing.
• Pregnant persons with a history of appropriately timed triple panel screening (HBsAg, total anti-HBc, and anti-HBs) and without subsequent risk for exposure to HBV (i.e., no new HBV exposures since triple panel screening) only need HBsAg screening.

Children and Adolescents
All refugee children and adolescents age <18 years should be tested for HBsAg, if not previously tested and they have an incomplete vaccination history. Most refugees are tested for HBsAg prior to departure for the United States. Review overseas records (pre-departure testing for infection and vaccination) to determine if further management is needed.

• If not previously tested for hepatitis B virus infection, testing should be performed for HBsAg, total anti-HBc, and anti-HBs.
• If previously tested for hepatitis B virus infection overseas:
  • If testing was positive for HBV infection (HBsAg-positive), additional evaluation and treatment options or referral to a specialist, is recommended.
  • If HBsAg was negative, and vaccination series has been initiated, the vaccine series should be completed according to the ACIP schedule.*
  • If HBsAg was negative, and the refugee has a record of completing the vaccination series before arrival and at appropriate intervals, no further testing or vaccination is necessary.
    
    * If HBsAg was negative, vaccination is not complete, and the patient is high-risk (see below), or there is concern for a risk exposure since the original screen, it is reasonable to repeat testing following arrival.

High-Risk Groups

High-risk groups include [5]:

• Injection-drug users
• Gay, bisexual, and other men who report male-to-male sexual contact
• Persons needing immunosuppressive therapy, including chemotherapy, immunosuppression related to organ transplantation, and immunosuppression for rheumatologic or gastroenterologic disorders
• Persons with elevated liver enzymes (alanine aminotransferase [ALT] ≥19 IU/L for women and ≥30 IU/L for men or abnormal aspartate aminotransferase [AST]) of unknown etiology
• People needing Hemodialysis
• Household, needle-sharing, or sex contacts of persons known to be HBsAg positive
• Persons who are the source of blood or body fluids for exposure that might require postexposure prophylaxis (e.g., needlestick, sexual assault)
• Persons who have a history of sexual exploitation, including child marriage.
• Persons with HIV infection
• Persons infected with hepatitis C virus
• Incarcerated persons (although unlikely among newly arrived refugees)
• Children whose mothers haves a history of HBV infection or cleared infection

Note: Tattooing (common in certain refugee groups), when done in noncommercial or unlicensed facilities, may be a risk factor. However, definitive data are lacking.

Clinical and Public Health Management of People with Chronic HBV Infection

All HBsAg-positive people should have additional testing performed to determine the stage of disease and screen for sequelae of chronic HBV infection, primarily hepatocellular carcinoma. While a full discussion on management of chronic hepatitis B virus infection is beyond the scope of this document, the AASLD has issued guidance [14]. Initial laboratory testing usually includes HBV DNA level, HBeAg, anti-HBe, liver enzyme tests for disease staging, and alpha-fetoprotein to screen for hepatocellular carcinoma. All HBsAg-positive persons should be referred to a gastroenterologist and/or hepatologist for additional testing and development of an appropriate long-term management plan.

HBsAg-positive people should be considered infectious. Hepatitis B is a reportable disease, and cases should be reported to the state or local health department, according to state reporting requirements.

HBsAg-positive patients should also receive appropriate counseling about the infection, lifestyle modifications, and mechanisms to reduce transmission to others. Culturally sensitive patient education should be provided, including materials in the refugee’s primary language. Translated patient education materials are also available from the CDC Division of Viral Hepatitis. Patient education materials for hepatitis infection developed by other agencies may be found at:

• HealthReach
• The Refugee Patient Education Project of CNY
• Refugee Health Technical Assistance Center

Patients should be counseled regarding the need for lifelong screening for hepatocellular carcinoma (HCC). Hepatic ultrasound and labs are generally recommended every 6 months, consistent with the AASLD guidelines [6].

Any non-immune refugee who has had a potential exposure to HBV within the previous 60 days should have repeat testing 3–6 months after exposure. These individuals should be advised to seek medical care if hepatitis-related symptoms (e.g., jaundice, nausea/vomiting, right upper quadrant pain) occur during this period.

Hepatitis D Virus (HDV)

Background

Hepatitis D virus (HDV) is a defective virus requiring HBsAg for transmission [15]. Therefore, HDV infection only occurs in HBsAg-positive persons. HDV may be acquired as a co-infection with HBV or as a superinfection after HBV infection. Hepatitis B vaccination is a primary preventive measure that protects against HDV infection.

Limited data are available on the epidemiology of HDV infection [15]. As many as 72 million people are co-infected with HBV and HDV worldwide [16]. Multiple analyses have estimated that the global anti-HDV prevalence is between 4.5 and 10.6% among HBsAg-positive people [17, 18]. However, among hepatology clinic populations and other high-risk groups, anti-HDV prevalence may be substantially higher [17, 18]. HDV infection has been reported among immigrant populations from HDV-endemic regions including Central Africa, Eastern Turkey, Central Asia, select Eastern European nations, and the Amazonian region of Brazil [15, 18]. However, the exact global prevalence, including prevalence among mobile populations, is unknown because of heterogenous and non-standardized screening, and lack of testing in endemic regions [16, 18]. Additionally, it is important to note that there are critical data gaps, especially in Latin America, Southern Africa, and Asia. More data are necessary to determine the true global anti-HDV prevalence [17].

People chronically infected with HBV who are superinfected with HDV usually develop chronic HDV infection. Chronic HDV infection is associated with severe hepatitis, and frequently leads to rapid cirrhosis progression, decompensated cirrhosis, and hepatocellular carcinoma [15]. The epidemiology of chronic HDV infection in refugees is unknown. Additional information on HDV infection can be found here:

• CDC Division of Viral Hepatitis
• Hepatitis delta: virological and clinical aspects (Botelho-Souza LF, Vasconcelos MPA, Dos Santos AO, Salcedo JMV, Vieira DS. Virol J. 2017 Sep 13;14(1):177).

Screening Recommendations for HDV Infection in Refugees

Routine screening is not recommended for all new arrivals. Testing for HDV infection is recommended for all HBsAg-positive new arrivals, as most recently arrived refugees originate from regions with high HDV endemicity. This includes those with or without documented risk factors (i.e., HIV infection, intravenous drug use, men who have sex with men) [14]. Screening should be completed by anti-HDV, and positive screening tests should be confirmed by the detection of serum HDV-RNA to diagnose active infection [14, 15]. Those testing positive for HDV RNA should be referred to a specialist for further evaluation, including grading and staging of liver disease, surveillance for hepatocellular carcinoma, and antiviral treatment. Chronic HDV infection is difficult to treat, and an in-depth discussion of hepatitis D treatment is beyond the scope of this document. For further guidance regarding the management of patients with chronic HDV infection, refer to the AASLD Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B [PDF – 40 pages].

Hepatitis C Virus (HCV)

Background

Hepatitis C virus (HCV) infection can lead to a chronic, generally asymptomatic viral hepatitis that can eventually result in cirrhosis and hepatocellular carcinoma. The prevalence of HCV infection varies between regions and countries (refer to the CDC Yellow Book for map of prevalence), and it is estimated that 71 million people worldwide have chronic HCV infection [19].

Little generalizable data are available on the epidemiology of HCV infection in refugee populations. Published prevalence rates of anti-HCV antibody have ranged from 4.5% (24 of 529) among Asian and African refugees in Italy, to 8.1% (19 of 234) among Cambodian refugees in Australia [20, 21]. Additionally, in a study of Karen refugees < 18 years of age resettled in Australia between July 2006 and October 2009, none of the 214 patients screened tested positive for HCV infection, while 10 of 305 (< 4%) of those ≥ 18 years of age tested positive [22]. Prevalence data on HCV infection in newly arrived refugees in the United States are sparse. Testing of serum specimens obtained from Bhutanese, Burmese, Iraqi, and Hmong refugees (n=4,890) from 2002-2007 detected HCV RNA in 63 individuals (1.1%). However, infection rates varied by population; prevalence of HCV infection was much higher among Hmong refugees born in Thailand, whose rate was approximately 7% [23]. A study in Minnesota found higher rates of infection with HCV in Somali immigrants than nonimmigrant residents of the same county who were tested. The study also found that HCV infection was the primary viral cause of hepatocellular carcinoma in Somali-born individuals [24].

Without treatment, approximately 30% (range 15-45%) of HCV-infected people spontaneously clear the virus within 6 months of infection. However, 70% (range 55-85%) of HCV-infected people will develop chronic infection [25]. Several factors may accelerate the progression of chronic hepatitis C, particularly moderate to high alcohol intake. Infection at an older age is also associated with faster progression, as is coinfection with HIV.

HCV is transmitted through exposure to infected blood or other body fluids. In developed countries, infection primarily results from injection drug use. However, in developing countries, HCV is predominantly transmitted in medical settings where needles or surgical equipment may be reused or through transfusions of infected blood products. Generally, sexual transmission is inefficient (with some exceptions, e.g., men who have sex with men), and perinatal transmission occurs in 6% of pregnancies in which the mother is infected. Breastfeeding, if nipples are not cracked or bleeding, does not pose a risk.

Screening Recommendations for Chronic HCV Infection in Refugees

Screening tests to evaluate for HCV infection are antibody to HCV (anti-HCV), followed by HCV RNA polymerase chain reaction (PCR) if anti-HCV is detected.

Adults

Recommendations for screening for HCV infection in refugees during the new arrival medical examination are similar to guidelines for the general US population. All new adult (≥18 years of age) arrivals should be tested for HCV infection during the domestic medical screening. Additionally, all pregnant women should be tested for HCV infection during each pregnancy.

Visit CDC’s website for updated information on HCV infection.

Children and Adolescents

CDC does not recommend universal HCV screening for refugee children (< 18 years of age) during the domestic medical examination unless they are members of high-risk groups, which include:

• All children born to HCV-positive mothers
  • Testing should consist of anti-HCV or HCV RNA testing. Because anti-HCV testing prior to age 18 months may be falsely positive due to detection of passively acquired maternal antibody, testing prior to age 18 months should consist of HCV RNA testing. The Council of State and Territorial Epidemiologists (CSTE) has written a position statement on HCV perinatal infection and laboratory criteria for diagnosis.
• Unaccompanied refugee minors
• Children with risk factors including but not limited to:
  • Injection and intranasal drug use (current or former)
  • Chronic hemodialysis
  • HIV infection
  • Signs or symptoms of liver disease (e.g., abnormal liver enzyme tests, jaundice, abdominal pain or swelling, fatigue)
  • Household contacts with HCV
  • History of female genital mutilation or cutting (FGM/C) (data are limited)

Additional Screening Considerations

Other risk factors in refugee populations may exist, such as traditional tattooing, although data are limited. Limited data exist on the link between FGM/C and hepatitis C virus infection. In a recent survey of Egyptian men and women aged 15-59 (n=12,780), researchers found that FGM/C is an independent risk factor for hepatitis C virus infection [26]. In the study population, prevalence of HCV infection was significantly higher if FGM/C was performed by a non-doctor, and that 79.8% of women infected with HCV had undergone FGM/C [26]. Some experts recommend testing children with a history of FGM/C.

Clinical and Public Health Management of Chronic HCV Infection

People who have a positive HCV antibody test should be tested for HCV RNA. Those found to be currently infected (HCV RNA positive) should be managed by a healthcare provider experienced in the management of chronic liver disease and hepatitis C. Patients with HCV infection should also be counseled on preventing transmission. Culturally appropriate patient education should be conducted, and materials should be provided in the refugee’s primary language, if possible.

Patients with chronic HCV infection will benefit from evaluation and education about possible associated liver disease, including hepatocellular carcinoma (HCC).  Patients at higher risk for HCC include those with cirrhosis, hepatic steatosis, heavy alcohol consumption (>7 drinks/week for women or >14 drinks/week for men), and with HBV, HDV, or HIV co-infections. In addition, patients should be offered vaccination for hepatitis A and hepatitis B (if appropriate), and treatment with antiviral therapy with ongoing management and screening for HCC. Treatment and ongoing care recommendations are beyond the scope of this document. Clinicians should refer to the current AASLD guidelines for additional information [6].

See the CDC Recommendations for Hepatitis C Screening Among Adults—United States, 2020 for additional information on testing and clinical management of chronic HCV infections.

Acute Viral Hepatitis

Hepatitis A Virus (HAV)

Background

Hepatitis A is endemic in most parts of the world. Most refugees resettling to the United States are from areas that are highly endemic for HAV infection. HAV is primarily transmitted via the fecal-oral route, and infection is typically associated with poor sanitation and hygiene. The average incubation period for HAV is 28 days (range: 15–50 days). In highly endemic areas, people are frequently infected as children. Many refugee groups resettled to the United States, especially adults, have immunity to HAV infection due to previous exposure; resolved HAV infection results in lifetime immunity and does not lead to chronic infection. Hepatitis A prevalence is decreasing globally, especially in areas where hygiene and sanitation have improved and where routine vaccination has been implemented [27, 28].

Acute HAV infection in adults usually presents with clinical signs and symptoms such as fatigue, poor appetite, abdominal pain, nausea, and jaundice. For most, clinical signs and symptoms resolve within 2 months of infection, however, fulminant hepatitis leading to severe illness and death may occur. Severe disease occurs more commonly in people with underlying chronic liver disease. Young children with hepatitis A typically have sub-clinical infection, although they are infectious for several months and can be a major source of sustained transmission within communities. After arrival, the risk of spread to the general US population from refugee children is unknown but appears to be low. Additional information on HAV infection is available from the CDC Division of Viral Hepatitis.

Screening Recommendations for HAV Infection in Refugees

Routine testing for HAV infection is not recommended. People with signs or symptoms of acute HAV infection should be evaluated for acute infection by testing for anti-HAV IgM. Additionally, people presenting with signs or symptoms of acute HAV infection should also be tested for hepatitis B and hepatitis C, as acute HBV infection and HCV infection may have similar clinical presentations to HAV infection.  It is extremely rare to encounter a refugee with clinically active HAV infection on arrival.

Currently, refugees do not receive routine pre-departure hepatitis A vaccination.

Upon arrival in the United States, refugee children 12-23 months old should receive a two-dose series of hepatitis A vaccine, with a minimum interval of 6 months between doses. A dose given prior to 12 months does not count toward the two-dose series. Refugee children and adolescents aged 2-18 years who have not previously received hepatitis A vaccine should be vaccinated in accordance with the ACIP catch-up vaccination schedule. Hepatitis A vaccination is also recommended for all persons 1 year and older who are infected with human immunodeficiency virus (HIV), as well as persons with chronic liver disease, including but not limited to persons with HBV infection, HCV infection, cirrhosis, fatty liver disease, alcoholic liver disease, autoimmune hepatitis, or ALT/AST levels persistently greater than twice the upper limit of normal. Vaccination during pregnancy is recommended for those identified to be at risk for HAV infection. All adult refugees should be vaccinated or tested for serologic evidence of immunity. In adults, prevaccination screening for hepatitis A immunity (total anti-HAV) may be cost-effective, depending on the prevalence of HAV infection in the population and local costs for screening [29]. However, prevaccination serologic testing should not be a barrier to vaccination of susceptible persons, especially in populations that are difficult to access. Vaccinating persons with pre-existing immunity carries no known risk.

For more information on hepatitis A vaccination recommendations, see the Guidance for Evaluating and Updating Immunizations during the Domestic Medical Examination for Newly Arrived Refugees and the ACIP Immunization Schedules for the United States.

Hepatitis E Virus (HEV)

Background

Hepatitis E virus (HEV) infection causes acute viral hepatitis and is transmitted by the fecal-oral route. The signs and symptoms are similar to those produced by HAV infection. HEV infection is well described in many resource-limited regions, particularly in South Asia, although global prevalence is likely underestimated [30]. Although fulminant hepatitis may develop in 0.5%–4% of the overall HEV-infected population, it is particularly virulent in pregnant women, especially those infected during the third trimester. Mortality rates during pregnancy may exceed 25% [31]. The incubation period of HEV infection ranges from 3 to 8 weeks, with a mean of 40 days. Clinical presentation and epidemiologic characteristics vary by HEV genotype. Of note, infection with HEV genotype 3 has been associated with chronic hepatitis. Only people with signs or symptoms of acute hepatitis should be tested for HEV infection along with HAV, HBV, and HCV infection, since these viral infections are clinically indistinguishable. The diagnosis is confirmed by detection of HEV RNA in the blood by reverse transcriptase-PCR. Additional information on HEV infection is available from the CDC Division of Viral Hepatitis.

Screening Recommendations HEV Infection in Refugees

Routine testing for HEV infection is not recommended for refugees of any age.