- Email: [email protected]
Issues Leading to the Recent Outbreaks of Hepatitis A
CONTINUING EDUCATION
Issues Leading to the Recent Outbreaks of Hepatitis A Jean O’Neil, DNP, FNP-BC
ABSTRACT
Since 1996, the incidence of hepatitis A (HAV) had been on the decline due to the development and use of the HAV vaccine. However, recent global outbreaks are occurring among men who have sex with men, illicit drug users, and the homeless. Much of the older population has not been vaccinated, and because of their age, they are more susceptible to complications from this virus. The medical community is challenged with preventing further outbreaks of this infection by promoting pre- and post-exposure immunization, implementing supportive care for those affected by HAV, and providing patient education that will decrease the spread of Hepatitis A. Keywords: hepatitis A, immunization, outbreaks, pre-exposure, post-exposure Ó 2018 Elsevier Inc. All rights reserved. Jean O’Neil, DNP, FNP-BC, is an assistant professor of nursing, California State University, Los Angeles, Patricia A. Chin, School of Nursing, Los Angeles, CA. She also works as an emergency room FNP in Los Angeles, CA. She is available at Joneil3@calstatela. edu In compliance with national ethical guidelines, the author reports no relationships with business or industry that would pose a conflict of interest.
CLINICAL VIGNETTE
A
49-year-old male who has sex with men (MSM) was having sex with a new partner when the condom broke. His partner was a casual acquaintance whom he had met in South America 10 days before this visit. Upon arrival back into the United States (US), a few days after the incident, he went immediately to his primary care clinic, where was tested for sexually transmitted diseases (STD), which included hepatitis A (HAV), B, and C. He was called to come back to the clinic because his anti-HAV immunoglobulin (Ig)M was positive. Instead, he chose to come to the emergency department because his clinic was closing for
the day and he didn’t want to wait to see his own provider. His other STD tests, including HIV, were negative. He thought that he had been tested for hepatitis before but had never been told he was positive. This patient had no history of a past HAV infection and was unsure if he had ever received any hepatitis vaccines. He stated that he had no recent illnesses, fevers, jaundice, or fatigue. Although he was asymptomatic, he was extremely anxious and wondered if there was anything he could receive that might prevent him from becoming symptomatic from this infection. His past medical history included asthma, nephrolithiasis, and hypertension.
This CE learning activity is designed to help update NP knowledge and skills related to recognizing and treating hepatitis A as documented by a score of at least 70% on the content post-test. At the conclusion of this activity, the participant will be able to: A. Identify the leading causes of recent outbreaks of hepatitis A B. Explain the symptoms and laboratory testing used to diagnose hepatitis A C. Describe the appropriate treatment for active and passive immunization against hepatitis A The authors, reviewers, editors, and nurse planners all report no financial relationships that would pose a conflict of interest. The authors do not present any off-label or non-FDA-approved recommendations for treatment. This activity has been awarded 1 Contact Hours of which 0.5 credits are in the area of Pharmacology. The activity is valid for CE credit until Nov 1, 2020.
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CURRENT ISSUES WITH HAV
HAV is a topic that has been frequently discussed in the news due to recent outbreaks in different parts of the world. It is a common viral illness that had seen a decline in incidence since 1996, when the HAV vaccine was introduced.1 The number of HAV cases between 1990 and 2009 decreased by 93.7%.1 Over the same time period, hospitalization from HAV declined 68%.1 Although infections from HAV have not risen to the pre-vaccine numbers, these recent outbreaks of HAV are of concern to the medical community and the public. Children in the United States are offered the vaccine as part of their immunization schedule. However, there are a substantial number of adults born before 1996 who have not been immunized against HAV.2 This is a potential cause of recent outbreaks because these nonimmunized adults, who are older than 20 years of age, are more susceptible to develop symptomatic disease. As individuals get older and experience more heath issues, they are at a higher risk of morbidity and mortality from complications of HAV.2 Those who are unimmunized and travel internationally to HAV-endemic countries or are exposed to someone who has traveled from an HAV-endemic country are always at risk for contracting this infection. Travel is a popular form of recreation, and access to exotic locations has become easier. Between 2005 and 2007, sites conducting an enhanced HAV surveillance found that 46% of HAV infections were potentially caused by travel outside of the United States and Canada.2 However, enhanced detailed HAV surveillance programs have proven to be a difficult undertaking due to either poor reporting or false-positive anti-HAV IgM findings in those with nonacute liver problems. Even with inconsistent HAV reporting, the Centers for Disease Control and Prevention (CDC) considers international travel to HAV-endemic areas to be an important risk factor for HAV. High-risk sexual behavior can also lead to the spread of HAV. In June 2017, 1,731 patients in 15 European countries were diagnosed with HAV, most of theses diagnoses being in MSM.3 In the United States, HAV has been reported in the MSM populations of urban cities across the country. In 640
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2018, the CDC estimated that 10% of new HAV cases in the United States occur in the MSM population, an increase from 4.9% in 2010.1,4 From 2017 to early 2018, San Diego, California, had an outbreak of 587 reported cases of HAV, which resulted in 402 hospitalizations and 20 deaths.5 Although there have been other reported HAV outbreaks, this was the largest HAV outbreak in the United States in 2 decades.5 By April 2018, the CDC had received more than 2500 reports of HAV from multiple states.5 The San Diego outbreak, as with most of these reported sites, have been mostly associated with the homeless population and illicit drug users in settings with limited sanitation. These outbreaks were a reminder that HAV, in certain populations, could result in increased morbidity and mortality. Up until the development of the HAV vaccine, HAV was treated by stressing improved hygiene and sanitation, and by providing passive immunity by the administration of immune globulin (IG). EPIDEMIOLOGY
HAV is a viral illness that affects the liver. It is member of the genus Hepatovirus from the Picornaviridae family.6 Viral replication occurs in the liver, causing hepatic injury. There are an estimated 1.4 million cases per year of HAV worldwide.6 HAV is endemic in some areas of Central and South America, the Middle East, Africa, Asia, and the Western Pacific.1 Humans are the most prominent natural carriers for this illness, although it has been found in some nonhuman primates.7 It is usually a self-limiting illness, with fulminant liver failure occurring in less than 1% of diagnosed cases.6 The elderly and those with chronic liver disease are at a higher risk of dying from complications of HAV.7 TRANSMISSION
HAV is spread from person to person through the fecal-oral route. After hepatic replication of the virus, it is detectable in the blood and is eventually excreted through the biliary system into the feces by days 10e12 post-exposure.1 Feces from an infected person, which is then spread to food and water through poor handwashing or inadequate hygiene, is the main source of transmission.6 Undercooked food Volume 14, Issue 9, October 2018
from a contaminated source (cooked at less than 185 F), or from an infected food handler can also transmit the virus.1,6 In addition to international travel to HAV endemic areas, persons with high-risk behaviors (eg, the use of illicit drugs or those who have sex that involves oral-anal contact, like MSM) are at a higher risk for contracting HAV.7 Individuals with blood-clotting disorders, such as hemophilia, although it is a rare occurrence, may get the virus through the administration of blood products, such as solvent/detergent-treated factor VIII and IX concentrates.1 Animal handlers who work with nonhuman primates are also at a higher risk for the disease through contact with the animal’s saliva. Transmission of HAV through human saliva has not been found.7 In pregnant women, transmission of HAV from mother to fetus has not been reported.6 CLINICAL MANIFESTATIONS
Acute HAV has an incubation period anywhere between 15 to 50 days.1 Frequency of symptomatic illness is directly related to the age of the patient. In adolescents and adults, 70% will show some signs of clinical illness, with jaundice being the most prominent symptom.1 Those who become symptomatic are most infective during the 14-day period before the onset of jaundice, when the highest concentration of the virus is present in the stool.7 In children younger than 6 years old, approximately 70% are asymptomatic and can shed HAV for up to 10 weeks longer than adults, which makes them a high risk for spreading infection.1,7 Signs and symptoms of HAV can last for as long as 2 months.7 Patients who are symptomatic may present with jaundice, nausea, vomiting, fever, malaise, anorexia, and abdominal pain. They may report dark urine, pale stools, and pruritus.6,7 Physical findings may include fever, the appearance of jaundice in the skin and sclera, and hepatomegaly (80% of patients).6 Laboratory testing usually shows that the patient has elevated liver enzymes.1 Less common findings include splenomegaly and arthralgias.6 The excretion of the virus begins to decline at the onset of symptoms and most people usually can no longer transmit the disease by the third week of the infection.1 Full clinical recovery for the majority of patients is usually seen within 3 months. www.npjournal.org
This infection does not become chronic.6 Once patients are infected by HAV and have recovered, they have lifetime immunity to the virus.1 COMPLICATIONS OF HAV
If HAV causes severe acute liver injury, fulminant hepatic failure can occur. This is rare and mostly seen in patients older than 50 years of age or in those with preexisting liver problems.6 Fulminant hepatic failure can lead to encephalopathy, as well hematologic problems that could cause prolonged international normalized ratios.6 Mortality rates from fulminant hepatic failure can be as high as 80%.1 Other complications of HAV include cholestatic hepatitis, relapsing hepatitis, and autoimmune hepatitis.6 Patients who develop cholestatic hepatitis usually have a prolonged period of jaundice, lasting more than 3 months. They may complain of fever, pruritus, weight loss, malaise, and diarrhea.8 Serum bilirubin levels, alkaline phosphatase, liver function tests, and cholesterol can become abnormally elevated.8 An abdominal ultrasound should be performed to rule out biliary obstruction.6 Cholestatic hepatitis usually resolves spontaneously. Relapsing hepatitis can occur in up to 10% of patients infected with HAV.9 This occurs during the 6 months after the onset of the acute illness from the virus.6 The cause of the relapse is unknown. The symptoms of relapse are often milder than the initial presentation of their illness. In some cases, patients may be asymptomatic with only the presence of elevated liver enzymes and a persistent positive serum anti-HAV IgM.1,7 These patients need to be followed for the possible development of acute liver failure and extrahepatic complications.9 There should also be an abdominal ultrasound performed to make sure there is no biliary obstruction or any other complication related to the liver. Most patients with relapsing HAV will have a full recovery without further sequelae.6 Autoimmune HAV is a rare complication. Patients may present with the same symptoms as an acute infection of HAV, but laboratory tests will show hyperglobulinemia and circulating autoantibodies. A liver biopsy would show inflammatory changes.10 HAV can also lead to other extrahepatic complications, such as arthritis, glomerulonephritis, The Journal for Nurse Practitioners - JNP
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optic neuritis, myocarditis, thrombocytopenia, and aplastic anemia, as well as other rare complications related to changes in the patient’s immune and vascular systems.6 Patients with acute severe liver damage, or any of these complications, should be referred to a hepatic specialist where specific treatment plans can be offered. Liver transplantation is an option for those with acute severe liver failure from HAV.9 DIAGNOSIS OF HAV
HAV cannot be distinguished from the other types of viral hepatitis infections based on physical findings and symptoms alone; therefore, many providers will test for hepatitis A, B, and C simultaneously. The abrupt onset of symptoms, particularly in patients who are at a high risk for contracting this infection, should alert the provider to suspect HAV. HAV is detected through the presence of serum anti-HAV IgM and IgG. If the serum anti-HAV IgM is positive, it is usually indicative of a recent, acute infection.1 The anti-HAV IgM usually becomes positive 5e10 days before the onset of symptoms and will usually remain detectable for approximately 6 months. However, anti-HAV IgM can remain detectable in some patients for up to 1 year.7 Other causes of a positive anti-HAV IgM can include an asymptomatic HAV infection, a previous infection with persistent anti-HAV IgM antibodies, or a falsepositive result.6 A false-positive result should be suspected if the patient is asymptomatic, has no known HAV exposure or any risk factors for HAV. For example, a high titer of rheumatoid factor, or other cross-reacting antibodies, can interfere with anti-HAV IgM testing, causing a false-positive result.11 The CDC does not recommend anti-HAV IgM testing as a screening tool for HAV in asymptomatic patients or those with nonacute liver abnormalities.12 The presence of anti-HAV IgG is usually detectable or positive early in the recovery phase of the infection. It can also be indicative of a past HAV infection, or the confirmation that the patient had previously received the HAV vaccine.1 In either case, a positive anti-HAV IgG shows that the patient has lifelong immunity to HAV. 642
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PRE- AND POST-HAV EXPOSURE TREATMENT
HAV is a self-limiting disease in most people and is not a chronic condition. Supportive treatment includes rest and, if symptomatic, delaying return to normal activity until symptoms are gone. Treatments for fever, nausea, vomiting, and diarrhea should be provided based on the patient’s age and other comorbidities. Alcohol should be avoided; however, there are no food restrictions, and patients may advance their diet as tolerated.13 Patients should be monitored for complications such as fulminant HAV or relapse. Pregnant women who have HAV should be monitored for gestational complications and preterm labor.13 Pre- and post-exposure prevention of HAV can be either through active or passive immunization. The HAV vaccine was initially recommended only for children and adolescents living in HAV endemic areas. In 2006, the CDC recommended that all children aged 12e23 months be immunized against HAV, making it part of their routine immunization schedule.1 Active immunization requires the patient receive 2 doses of the inactivated HAV vaccine, either HAVRIX (GlaxoSmithKline) or VAQTA (Merck & Co.), at 0 and 6 months, starting at 1 year of age.7 If the patient had not been immunized as a child, then a catch-up vaccine schedule can be implemented.1 Patients 18 years and older who have never received the hepatitis A or B vaccines can get a combination inactivated vaccine.7 Twinrix (GlaxoSmithKline) provides immunization for both hepatitis A and B and is given as 3 doses at 0, 1, and 6 months or as an accelerated schedule of 0, 7, 21e30 days, with a booster 12 months after the first dose.1 The administration of Twinrix provides rapid immunity but cannot be used as post-exposure prophylaxis.7 Pre-exposure intervention also involves recommending the HAV vaccine to those who have never been immunized, who are at a high risk of being exposed to HAV, or who could suffer from potential complications related to contracting HAV. The HAV vaccine is highly recommended for adults who are MSM, illegal drug users, have blood-clotting disorders, have chronic liver disease, or who are Volume 14, Issue 9, October 2018
immunocompromised. Those who work with HAVinfected primates, as well as those who will be traveling to HAV endemic areas, should also receive the vaccine as a pre-exposure intervention. If a person is traveling to an HAV endemic area within the next 2 weeks, the combination of the HAV vaccine and passive immunization with IG is recommended.7 The IG will provide immediate protection, whereas the HAV vaccine will provide lifelong immunity. The HAV vaccine is also recommended as postexposure treatment in persons aged 1e40 years (Table). The vaccine is not routinely recommended for health care personnel, food handlers, childcare workers, and sanitation workers unless they have been exposed to HAV.1 Most individuals will be protected after 1 dose of the HAV vaccine; with the second vaccine, there is usually lifetime immunity.12 Passive immunization through the use of IG provides HAV antibodies from donated plasma. GamaSTAN S/D (Grigols Therapeutics) is the only intramuscular (IM) IG approved by the U.S. Food and Drug Administration for HAV pre- and postexposure prophylaxis.14 IG provides immediate immunoprophylaxis through direct administration of HAV antibodies. The Table shows the types of patients who should receive IG as post-exposure treatment for HAV because they need immediate immunity. These patients, whether due to age or a medical condition, are more susceptible to the severe
complications related to HAV.12 If a pregnant or lactating woman is exposed to HAV, it is recommended that she receive IG. Pregnant women may receive the HAV vaccine if IG is not available, but only as a post-exposure prophylaxis if it is deemed that they are at high risk for getting the infection.7 Safety of the vaccine during pregnancy is not known; however, because it is an inactivated vaccine, it is thought to be of low risk to the fetus.12 Immune globulin (IG) only provides 1e2 months of protection against HAV.13,14 IG is the preferred postexposure treatment in those over age 40 years. However, the HAV vaccine can be used if IG is not available.12 Since the appearance and usage of the HAV vaccine in 1996, there has been a decreased prevalence of previous HAV infections in plasma donors. Therefore, the dosage for IG administration has recently been increased to provide enough HAV IgG antibodies.12 The pre-exposure dose of IG for those who are unvaccinated and are traveling to HAVendemic areas for 1 month is 0.1 mL/kg IM. If they are traveling for 2 months, 0.2 mL/kg is recommended.7 The HAV post-exposure dose of IG, for those who have not had the HAV vaccine, is 0.1 mL/ kg. To be of maximum benefit, IG should be given within 2 weeks of exposure.7 The efficacy of IG administration greater than 2 weeks after exposure is unknown.14 If the person is unsure of his or her HAV
Table. Post-Exposure IG and HAV Immunization Recommendations for Persons Who Have Not Been Previously Immunized Against HAV IG Under 12 months old
HAV Vaccine
X a
Over 40 years of age and exposed to HAV within the past 14 days
X
Between the ages of 1 and 40 years
X
a
X
Has chronic liver disease
a
X
Has chronic medical problems a
X
Is immunocompromised
Is allergic to the HAV vaccine, refused the HAV vaccine, or the HAV vaccine is contraindicated b
Pregnant or lactating women
X X
HAV ¼ hepatitis A virus; IG ¼ immune globulin. a IG is recommended but may give HAV vaccine if IG not available. b IG is safe in those women who are pregnant or lactating. The HAV vaccine can be given to pregnant women if they are postexposure to HAV and are deemed to be at a high risk for getting the infection. The HAV vaccine is safe in lactating women.
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immunity status, the administration of either IG or the HAV vaccine will not harm them. Administration of either may actually prevent or attenuate symptoms, even though it does not always prevent the infection.15 IMPLICATIONS FOR PRACTICE
HAV is a nonchronic, self-limiting infection that had been on the decline after the introduction of the HAV vaccine. Recent outbreaks have brought to the forefront the need for providers to continue monitor HAV outbreaks and to promote HAV immunization. The HAV vaccine should not only be a part of routine childhood vaccinations, but also be offered to those vulnerable to HAV infection. In addition, patient education should promote the prevention of HAV by encouraging the use of condoms to decrease transmission of the virus for those who participate in high-risk sexual behaviors, such as MSM. Simple handwashing and practicing hygienic measures can reduce transmission of the virus. Administration of the HAV vaccine or IG for HAV pre- and postexposure can prevent outbreaks. If the patient does contract HAV and becomes symptomatic, providers need to design a supportive treatment plan for the patient, as well as recognize complications that require more specific interventions to avoid liver failure. Improving community-wide sanitary conditions and access to health care, as well as providing education to patients and families regarding those interventions that prevent the spread of HAV, will help reduce the outbreaks of this infection here in the United States, as well as globally. CLINICAL VIGNETTE RESOLUTION
This patient, with a positive anti-HAV IgM, had most likely just contracted HAV. He was currently asymptomatic. Because he was over 40 years old and had participated in MSM high-risk sexual behavior within the past 2 weeks with a new partner from an HAV endemic country, it was determined that IG (Gama/STAN S/D) would be the preferred intervention as an attempt to prevent or attenuate symptoms. He was discharged from the emergency department and advised to
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follow-up with his primary care provider for monitoring and routine health care. It was also recommended that he talk with his provider about receiving the HAV vaccine series because this could be a false-positive anti-HAV IgM, in which case the administration of IG would not provide him with lifelong immunity against HAV. A 2month follow-up phone call found that the patient remained healthy and asymptomatic, but had still not seen his primary provider. However, he agreed to make an appointment in the next few weeks for a physical exam. References 1. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. May 15, 2015. https://www.cdc.gov/vaccines/ pubs/pinkbook/hepa.html. Accessed June 21, 2018. 2. Hofmeister M, Klevens RM, Nelson N. Manual for the surveillance of vaccinepreventable diseases. April 2, 2018. https://www.cdc.gov/vaccines/pubs/surv -manual/chapters.html. Accessed April 26, 2018. 3. Gozlan Y, Bar-Or I, Rakovsky A, et al. Ongoing hepatitis A among men who have sex with men (MSM) linked to outbreaks in Europe in Tel Aviv area, Israel, December 2016eJune 2017. Eurosurveillance. 2017;22(29). https:// doi.org/10.2807/1560-7917.es.2017.22.29.30575. 4. Viral hepatitis and men who have sex with men. May 16, 2018. https://www .cdc.gov/hepatitis/populations/msm.htm. Accessed July 24, 2018. 5. Hepatitis A outbreak. April 11, 2018. https://www.cdph.ca.gov/Programs/CID/ DCDC/Pages/Immunization/Hepatitis-A-Outbreak.aspx. Accessed June 21, 2018. 6. Lai M, Chopra S. January 12, 2018. Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis. https://www.uptodate .com/contents/hepatitis-a-virus-infection-in-adults-epidemiology-clinical -manifestations-and-diagnosis?source¼history_widget. Accessed June 12, 2018. 7. Ask the experts about hepatitis A vaccines—CDC experts answer Q&As. February 12, 2018. http://www.immunize.org/askexperts_hepa.asp. Accessed April 18, 2018. 8. Lapp RT, Rochling F. Acute cholestatic hepatitis a virus infection presenting with hemolytic anemia and renal failure: a case report. Case Rep Hepatol. 2013:1-4. https://doi.org/10.1155/2013/438375. 9. Troy T, Levitsky J, Te H, Cohen S. Relapsing hepatitis a as an indication for liver transplantation. Am J Gastroenterol. 2003;98(9). S165-S165, https://doi.org/10.1016/s0002-9270(03)01258-9. 10. National Institute of Diabetes and Digestive and Kidney Diseases. Autoimmune hepatitis. https://www.niddk.nih.gov/health-information/liverdisease/autoimmune-hepatitis. Accessed June 13, 2018. 11. Alatoom A, Ansari MQ, Cuthbert J. Multiple factors contribute to positive results for hepatitis A virus immunoglobulin M antibody. Arch Pathol Lab Med. 2013;137(1):90-95. https://doi.org/10.5858/arpa.2011-0693-oa. 12. California Department of Public Health. July 2017 hepatitis. July 2017. https://www.cdph.ca.gov/Programs/CID/DCDC/CDPH%20Document %20Library/Immunization/HepatitisA-PEPQuicksheet.pdf. Accessed June 21, 2018. 13. Matheny S, Kingery J. Hepatitis A. Am Fam Physician. 2012;86(11):1027-1034. 14. Nelson N. Updated dosing instructions for immune globulin (human) GamaSTAN S/D for hepatitis A virus prophylaxis. September 15, 2017. Morbidity and Mortality Weekly Report (MMWR). https://www.cdc.gov/ mmwr/volumes/66/wr/mm6636a5.htm. Accessed June 18, 2018. 15. Sonder GJ, Steenbergen JE, Bovee LP, et al. Hepatitis A virus immunity and seroconversion among contacts of acute hepatitis a patients in Amsterdam, 1996e2000: an evaluation of current prevention policy. Am J Public Health. 2004;94(9):1620-1626. https://doi.org/10.2105/ajph.94.9.1620.
1555-4155/18/$ see front matter © 2018 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.nurpra.2018.08.018
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Issues Leading to the Recent Outbreaks of Hepatitis A Jean O’Neil, DNP, FNP-BC
ABSTRACT
Since 1996, the incidence of hepatitis A (HAV) had been on the decline due to the development and use of the HAV vaccine. However, recent global outbreaks are occurring among men who have sex with men, illicit drug users, and the homeless. Much of the older population has not been vaccinated, and because of their age, they are more susceptible to complications from this virus. The medical community is challenged with preventing further outbreaks of this infection by promoting pre- and post-exposure immunization, implementing supportive care for those affected by HAV, and providing patient education that will decrease the spread of Hepatitis A. Keywords: hepatitis A, immunization, outbreaks, pre-exposure, post-exposure Ó 2018 Elsevier Inc. All rights reserved. Jean O’Neil, DNP, FNP-BC, is an assistant professor of nursing, California State University, Los Angeles, Patricia A. Chin, School of Nursing, Los Angeles, CA. She also works as an emergency room FNP in Los Angeles, CA. She is available at Joneil3@calstatela. edu In compliance with national ethical guidelines, the author reports no relationships with business or industry that would pose a conflict of interest.
CLINICAL VIGNETTE
A
49-year-old male who has sex with men (MSM) was having sex with a new partner when the condom broke. His partner was a casual acquaintance whom he had met in South America 10 days before this visit. Upon arrival back into the United States (US), a few days after the incident, he went immediately to his primary care clinic, where was tested for sexually transmitted diseases (STD), which included hepatitis A (HAV), B, and C. He was called to come back to the clinic because his anti-HAV immunoglobulin (Ig)M was positive. Instead, he chose to come to the emergency department because his clinic was closing for
the day and he didn’t want to wait to see his own provider. His other STD tests, including HIV, were negative. He thought that he had been tested for hepatitis before but had never been told he was positive. This patient had no history of a past HAV infection and was unsure if he had ever received any hepatitis vaccines. He stated that he had no recent illnesses, fevers, jaundice, or fatigue. Although he was asymptomatic, he was extremely anxious and wondered if there was anything he could receive that might prevent him from becoming symptomatic from this infection. His past medical history included asthma, nephrolithiasis, and hypertension.
This CE learning activity is designed to help update NP knowledge and skills related to recognizing and treating hepatitis A as documented by a score of at least 70% on the content post-test. At the conclusion of this activity, the participant will be able to: A. Identify the leading causes of recent outbreaks of hepatitis A B. Explain the symptoms and laboratory testing used to diagnose hepatitis A C. Describe the appropriate treatment for active and passive immunization against hepatitis A The authors, reviewers, editors, and nurse planners all report no financial relationships that would pose a conflict of interest. The authors do not present any off-label or non-FDA-approved recommendations for treatment. This activity has been awarded 1 Contact Hours of which 0.5 credits are in the area of Pharmacology. The activity is valid for CE credit until Nov 1, 2020.
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CURRENT ISSUES WITH HAV
HAV is a topic that has been frequently discussed in the news due to recent outbreaks in different parts of the world. It is a common viral illness that had seen a decline in incidence since 1996, when the HAV vaccine was introduced.1 The number of HAV cases between 1990 and 2009 decreased by 93.7%.1 Over the same time period, hospitalization from HAV declined 68%.1 Although infections from HAV have not risen to the pre-vaccine numbers, these recent outbreaks of HAV are of concern to the medical community and the public. Children in the United States are offered the vaccine as part of their immunization schedule. However, there are a substantial number of adults born before 1996 who have not been immunized against HAV.2 This is a potential cause of recent outbreaks because these nonimmunized adults, who are older than 20 years of age, are more susceptible to develop symptomatic disease. As individuals get older and experience more heath issues, they are at a higher risk of morbidity and mortality from complications of HAV.2 Those who are unimmunized and travel internationally to HAV-endemic countries or are exposed to someone who has traveled from an HAV-endemic country are always at risk for contracting this infection. Travel is a popular form of recreation, and access to exotic locations has become easier. Between 2005 and 2007, sites conducting an enhanced HAV surveillance found that 46% of HAV infections were potentially caused by travel outside of the United States and Canada.2 However, enhanced detailed HAV surveillance programs have proven to be a difficult undertaking due to either poor reporting or false-positive anti-HAV IgM findings in those with nonacute liver problems. Even with inconsistent HAV reporting, the Centers for Disease Control and Prevention (CDC) considers international travel to HAV-endemic areas to be an important risk factor for HAV. High-risk sexual behavior can also lead to the spread of HAV. In June 2017, 1,731 patients in 15 European countries were diagnosed with HAV, most of theses diagnoses being in MSM.3 In the United States, HAV has been reported in the MSM populations of urban cities across the country. In 640
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2018, the CDC estimated that 10% of new HAV cases in the United States occur in the MSM population, an increase from 4.9% in 2010.1,4 From 2017 to early 2018, San Diego, California, had an outbreak of 587 reported cases of HAV, which resulted in 402 hospitalizations and 20 deaths.5 Although there have been other reported HAV outbreaks, this was the largest HAV outbreak in the United States in 2 decades.5 By April 2018, the CDC had received more than 2500 reports of HAV from multiple states.5 The San Diego outbreak, as with most of these reported sites, have been mostly associated with the homeless population and illicit drug users in settings with limited sanitation. These outbreaks were a reminder that HAV, in certain populations, could result in increased morbidity and mortality. Up until the development of the HAV vaccine, HAV was treated by stressing improved hygiene and sanitation, and by providing passive immunity by the administration of immune globulin (IG). EPIDEMIOLOGY
HAV is a viral illness that affects the liver. It is member of the genus Hepatovirus from the Picornaviridae family.6 Viral replication occurs in the liver, causing hepatic injury. There are an estimated 1.4 million cases per year of HAV worldwide.6 HAV is endemic in some areas of Central and South America, the Middle East, Africa, Asia, and the Western Pacific.1 Humans are the most prominent natural carriers for this illness, although it has been found in some nonhuman primates.7 It is usually a self-limiting illness, with fulminant liver failure occurring in less than 1% of diagnosed cases.6 The elderly and those with chronic liver disease are at a higher risk of dying from complications of HAV.7 TRANSMISSION
HAV is spread from person to person through the fecal-oral route. After hepatic replication of the virus, it is detectable in the blood and is eventually excreted through the biliary system into the feces by days 10e12 post-exposure.1 Feces from an infected person, which is then spread to food and water through poor handwashing or inadequate hygiene, is the main source of transmission.6 Undercooked food Volume 14, Issue 9, October 2018
from a contaminated source (cooked at less than 185 F), or from an infected food handler can also transmit the virus.1,6 In addition to international travel to HAV endemic areas, persons with high-risk behaviors (eg, the use of illicit drugs or those who have sex that involves oral-anal contact, like MSM) are at a higher risk for contracting HAV.7 Individuals with blood-clotting disorders, such as hemophilia, although it is a rare occurrence, may get the virus through the administration of blood products, such as solvent/detergent-treated factor VIII and IX concentrates.1 Animal handlers who work with nonhuman primates are also at a higher risk for the disease through contact with the animal’s saliva. Transmission of HAV through human saliva has not been found.7 In pregnant women, transmission of HAV from mother to fetus has not been reported.6 CLINICAL MANIFESTATIONS
Acute HAV has an incubation period anywhere between 15 to 50 days.1 Frequency of symptomatic illness is directly related to the age of the patient. In adolescents and adults, 70% will show some signs of clinical illness, with jaundice being the most prominent symptom.1 Those who become symptomatic are most infective during the 14-day period before the onset of jaundice, when the highest concentration of the virus is present in the stool.7 In children younger than 6 years old, approximately 70% are asymptomatic and can shed HAV for up to 10 weeks longer than adults, which makes them a high risk for spreading infection.1,7 Signs and symptoms of HAV can last for as long as 2 months.7 Patients who are symptomatic may present with jaundice, nausea, vomiting, fever, malaise, anorexia, and abdominal pain. They may report dark urine, pale stools, and pruritus.6,7 Physical findings may include fever, the appearance of jaundice in the skin and sclera, and hepatomegaly (80% of patients).6 Laboratory testing usually shows that the patient has elevated liver enzymes.1 Less common findings include splenomegaly and arthralgias.6 The excretion of the virus begins to decline at the onset of symptoms and most people usually can no longer transmit the disease by the third week of the infection.1 Full clinical recovery for the majority of patients is usually seen within 3 months. www.npjournal.org
This infection does not become chronic.6 Once patients are infected by HAV and have recovered, they have lifetime immunity to the virus.1 COMPLICATIONS OF HAV
If HAV causes severe acute liver injury, fulminant hepatic failure can occur. This is rare and mostly seen in patients older than 50 years of age or in those with preexisting liver problems.6 Fulminant hepatic failure can lead to encephalopathy, as well hematologic problems that could cause prolonged international normalized ratios.6 Mortality rates from fulminant hepatic failure can be as high as 80%.1 Other complications of HAV include cholestatic hepatitis, relapsing hepatitis, and autoimmune hepatitis.6 Patients who develop cholestatic hepatitis usually have a prolonged period of jaundice, lasting more than 3 months. They may complain of fever, pruritus, weight loss, malaise, and diarrhea.8 Serum bilirubin levels, alkaline phosphatase, liver function tests, and cholesterol can become abnormally elevated.8 An abdominal ultrasound should be performed to rule out biliary obstruction.6 Cholestatic hepatitis usually resolves spontaneously. Relapsing hepatitis can occur in up to 10% of patients infected with HAV.9 This occurs during the 6 months after the onset of the acute illness from the virus.6 The cause of the relapse is unknown. The symptoms of relapse are often milder than the initial presentation of their illness. In some cases, patients may be asymptomatic with only the presence of elevated liver enzymes and a persistent positive serum anti-HAV IgM.1,7 These patients need to be followed for the possible development of acute liver failure and extrahepatic complications.9 There should also be an abdominal ultrasound performed to make sure there is no biliary obstruction or any other complication related to the liver. Most patients with relapsing HAV will have a full recovery without further sequelae.6 Autoimmune HAV is a rare complication. Patients may present with the same symptoms as an acute infection of HAV, but laboratory tests will show hyperglobulinemia and circulating autoantibodies. A liver biopsy would show inflammatory changes.10 HAV can also lead to other extrahepatic complications, such as arthritis, glomerulonephritis, The Journal for Nurse Practitioners - JNP
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optic neuritis, myocarditis, thrombocytopenia, and aplastic anemia, as well as other rare complications related to changes in the patient’s immune and vascular systems.6 Patients with acute severe liver damage, or any of these complications, should be referred to a hepatic specialist where specific treatment plans can be offered. Liver transplantation is an option for those with acute severe liver failure from HAV.9 DIAGNOSIS OF HAV
HAV cannot be distinguished from the other types of viral hepatitis infections based on physical findings and symptoms alone; therefore, many providers will test for hepatitis A, B, and C simultaneously. The abrupt onset of symptoms, particularly in patients who are at a high risk for contracting this infection, should alert the provider to suspect HAV. HAV is detected through the presence of serum anti-HAV IgM and IgG. If the serum anti-HAV IgM is positive, it is usually indicative of a recent, acute infection.1 The anti-HAV IgM usually becomes positive 5e10 days before the onset of symptoms and will usually remain detectable for approximately 6 months. However, anti-HAV IgM can remain detectable in some patients for up to 1 year.7 Other causes of a positive anti-HAV IgM can include an asymptomatic HAV infection, a previous infection with persistent anti-HAV IgM antibodies, or a falsepositive result.6 A false-positive result should be suspected if the patient is asymptomatic, has no known HAV exposure or any risk factors for HAV. For example, a high titer of rheumatoid factor, or other cross-reacting antibodies, can interfere with anti-HAV IgM testing, causing a false-positive result.11 The CDC does not recommend anti-HAV IgM testing as a screening tool for HAV in asymptomatic patients or those with nonacute liver abnormalities.12 The presence of anti-HAV IgG is usually detectable or positive early in the recovery phase of the infection. It can also be indicative of a past HAV infection, or the confirmation that the patient had previously received the HAV vaccine.1 In either case, a positive anti-HAV IgG shows that the patient has lifelong immunity to HAV. 642
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PRE- AND POST-HAV EXPOSURE TREATMENT
HAV is a self-limiting disease in most people and is not a chronic condition. Supportive treatment includes rest and, if symptomatic, delaying return to normal activity until symptoms are gone. Treatments for fever, nausea, vomiting, and diarrhea should be provided based on the patient’s age and other comorbidities. Alcohol should be avoided; however, there are no food restrictions, and patients may advance their diet as tolerated.13 Patients should be monitored for complications such as fulminant HAV or relapse. Pregnant women who have HAV should be monitored for gestational complications and preterm labor.13 Pre- and post-exposure prevention of HAV can be either through active or passive immunization. The HAV vaccine was initially recommended only for children and adolescents living in HAV endemic areas. In 2006, the CDC recommended that all children aged 12e23 months be immunized against HAV, making it part of their routine immunization schedule.1 Active immunization requires the patient receive 2 doses of the inactivated HAV vaccine, either HAVRIX (GlaxoSmithKline) or VAQTA (Merck & Co.), at 0 and 6 months, starting at 1 year of age.7 If the patient had not been immunized as a child, then a catch-up vaccine schedule can be implemented.1 Patients 18 years and older who have never received the hepatitis A or B vaccines can get a combination inactivated vaccine.7 Twinrix (GlaxoSmithKline) provides immunization for both hepatitis A and B and is given as 3 doses at 0, 1, and 6 months or as an accelerated schedule of 0, 7, 21e30 days, with a booster 12 months after the first dose.1 The administration of Twinrix provides rapid immunity but cannot be used as post-exposure prophylaxis.7 Pre-exposure intervention also involves recommending the HAV vaccine to those who have never been immunized, who are at a high risk of being exposed to HAV, or who could suffer from potential complications related to contracting HAV. The HAV vaccine is highly recommended for adults who are MSM, illegal drug users, have blood-clotting disorders, have chronic liver disease, or who are Volume 14, Issue 9, October 2018
immunocompromised. Those who work with HAVinfected primates, as well as those who will be traveling to HAV endemic areas, should also receive the vaccine as a pre-exposure intervention. If a person is traveling to an HAV endemic area within the next 2 weeks, the combination of the HAV vaccine and passive immunization with IG is recommended.7 The IG will provide immediate protection, whereas the HAV vaccine will provide lifelong immunity. The HAV vaccine is also recommended as postexposure treatment in persons aged 1e40 years (Table). The vaccine is not routinely recommended for health care personnel, food handlers, childcare workers, and sanitation workers unless they have been exposed to HAV.1 Most individuals will be protected after 1 dose of the HAV vaccine; with the second vaccine, there is usually lifetime immunity.12 Passive immunization through the use of IG provides HAV antibodies from donated plasma. GamaSTAN S/D (Grigols Therapeutics) is the only intramuscular (IM) IG approved by the U.S. Food and Drug Administration for HAV pre- and postexposure prophylaxis.14 IG provides immediate immunoprophylaxis through direct administration of HAV antibodies. The Table shows the types of patients who should receive IG as post-exposure treatment for HAV because they need immediate immunity. These patients, whether due to age or a medical condition, are more susceptible to the severe
complications related to HAV.12 If a pregnant or lactating woman is exposed to HAV, it is recommended that she receive IG. Pregnant women may receive the HAV vaccine if IG is not available, but only as a post-exposure prophylaxis if it is deemed that they are at high risk for getting the infection.7 Safety of the vaccine during pregnancy is not known; however, because it is an inactivated vaccine, it is thought to be of low risk to the fetus.12 Immune globulin (IG) only provides 1e2 months of protection against HAV.13,14 IG is the preferred postexposure treatment in those over age 40 years. However, the HAV vaccine can be used if IG is not available.12 Since the appearance and usage of the HAV vaccine in 1996, there has been a decreased prevalence of previous HAV infections in plasma donors. Therefore, the dosage for IG administration has recently been increased to provide enough HAV IgG antibodies.12 The pre-exposure dose of IG for those who are unvaccinated and are traveling to HAVendemic areas for 1 month is 0.1 mL/kg IM. If they are traveling for 2 months, 0.2 mL/kg is recommended.7 The HAV post-exposure dose of IG, for those who have not had the HAV vaccine, is 0.1 mL/ kg. To be of maximum benefit, IG should be given within 2 weeks of exposure.7 The efficacy of IG administration greater than 2 weeks after exposure is unknown.14 If the person is unsure of his or her HAV
Table. Post-Exposure IG and HAV Immunization Recommendations for Persons Who Have Not Been Previously Immunized Against HAV IG Under 12 months old
HAV Vaccine
X a
Over 40 years of age and exposed to HAV within the past 14 days
X
Between the ages of 1 and 40 years
X
a
X
Has chronic liver disease
a
X
Has chronic medical problems a
X
Is immunocompromised
Is allergic to the HAV vaccine, refused the HAV vaccine, or the HAV vaccine is contraindicated b
Pregnant or lactating women
X X
HAV ¼ hepatitis A virus; IG ¼ immune globulin. a IG is recommended but may give HAV vaccine if IG not available. b IG is safe in those women who are pregnant or lactating. The HAV vaccine can be given to pregnant women if they are postexposure to HAV and are deemed to be at a high risk for getting the infection. The HAV vaccine is safe in lactating women.
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immunity status, the administration of either IG or the HAV vaccine will not harm them. Administration of either may actually prevent or attenuate symptoms, even though it does not always prevent the infection.15 IMPLICATIONS FOR PRACTICE
HAV is a nonchronic, self-limiting infection that had been on the decline after the introduction of the HAV vaccine. Recent outbreaks have brought to the forefront the need for providers to continue monitor HAV outbreaks and to promote HAV immunization. The HAV vaccine should not only be a part of routine childhood vaccinations, but also be offered to those vulnerable to HAV infection. In addition, patient education should promote the prevention of HAV by encouraging the use of condoms to decrease transmission of the virus for those who participate in high-risk sexual behaviors, such as MSM. Simple handwashing and practicing hygienic measures can reduce transmission of the virus. Administration of the HAV vaccine or IG for HAV pre- and postexposure can prevent outbreaks. If the patient does contract HAV and becomes symptomatic, providers need to design a supportive treatment plan for the patient, as well as recognize complications that require more specific interventions to avoid liver failure. Improving community-wide sanitary conditions and access to health care, as well as providing education to patients and families regarding those interventions that prevent the spread of HAV, will help reduce the outbreaks of this infection here in the United States, as well as globally. CLINICAL VIGNETTE RESOLUTION
This patient, with a positive anti-HAV IgM, had most likely just contracted HAV. He was currently asymptomatic. Because he was over 40 years old and had participated in MSM high-risk sexual behavior within the past 2 weeks with a new partner from an HAV endemic country, it was determined that IG (Gama/STAN S/D) would be the preferred intervention as an attempt to prevent or attenuate symptoms. He was discharged from the emergency department and advised to
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follow-up with his primary care provider for monitoring and routine health care. It was also recommended that he talk with his provider about receiving the HAV vaccine series because this could be a false-positive anti-HAV IgM, in which case the administration of IG would not provide him with lifelong immunity against HAV. A 2month follow-up phone call found that the patient remained healthy and asymptomatic, but had still not seen his primary provider. However, he agreed to make an appointment in the next few weeks for a physical exam. References 1. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. May 15, 2015. https://www.cdc.gov/vaccines/ pubs/pinkbook/hepa.html. Accessed June 21, 2018. 2. Hofmeister M, Klevens RM, Nelson N. Manual for the surveillance of vaccinepreventable diseases. April 2, 2018. https://www.cdc.gov/vaccines/pubs/surv -manual/chapters.html. Accessed April 26, 2018. 3. Gozlan Y, Bar-Or I, Rakovsky A, et al. Ongoing hepatitis A among men who have sex with men (MSM) linked to outbreaks in Europe in Tel Aviv area, Israel, December 2016eJune 2017. Eurosurveillance. 2017;22(29). https:// doi.org/10.2807/1560-7917.es.2017.22.29.30575. 4. Viral hepatitis and men who have sex with men. May 16, 2018. https://www .cdc.gov/hepatitis/populations/msm.htm. Accessed July 24, 2018. 5. Hepatitis A outbreak. April 11, 2018. https://www.cdph.ca.gov/Programs/CID/ DCDC/Pages/Immunization/Hepatitis-A-Outbreak.aspx. Accessed June 21, 2018. 6. Lai M, Chopra S. January 12, 2018. Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis. https://www.uptodate .com/contents/hepatitis-a-virus-infection-in-adults-epidemiology-clinical -manifestations-and-diagnosis?source¼history_widget. Accessed June 12, 2018. 7. Ask the experts about hepatitis A vaccines—CDC experts answer Q&As. February 12, 2018. http://www.immunize.org/askexperts_hepa.asp. Accessed April 18, 2018. 8. Lapp RT, Rochling F. Acute cholestatic hepatitis a virus infection presenting with hemolytic anemia and renal failure: a case report. Case Rep Hepatol. 2013:1-4. https://doi.org/10.1155/2013/438375. 9. Troy T, Levitsky J, Te H, Cohen S. Relapsing hepatitis a as an indication for liver transplantation. Am J Gastroenterol. 2003;98(9). S165-S165, https://doi.org/10.1016/s0002-9270(03)01258-9. 10. National Institute of Diabetes and Digestive and Kidney Diseases. Autoimmune hepatitis. https://www.niddk.nih.gov/health-information/liverdisease/autoimmune-hepatitis. Accessed June 13, 2018. 11. Alatoom A, Ansari MQ, Cuthbert J. Multiple factors contribute to positive results for hepatitis A virus immunoglobulin M antibody. Arch Pathol Lab Med. 2013;137(1):90-95. https://doi.org/10.5858/arpa.2011-0693-oa. 12. California Department of Public Health. July 2017 hepatitis. July 2017. https://www.cdph.ca.gov/Programs/CID/DCDC/CDPH%20Document %20Library/Immunization/HepatitisA-PEPQuicksheet.pdf. Accessed June 21, 2018. 13. Matheny S, Kingery J. Hepatitis A. Am Fam Physician. 2012;86(11):1027-1034. 14. Nelson N. Updated dosing instructions for immune globulin (human) GamaSTAN S/D for hepatitis A virus prophylaxis. September 15, 2017. Morbidity and Mortality Weekly Report (MMWR). https://www.cdc.gov/ mmwr/volumes/66/wr/mm6636a5.htm. Accessed June 18, 2018. 15. Sonder GJ, Steenbergen JE, Bovee LP, et al. Hepatitis A virus immunity and seroconversion among contacts of acute hepatitis a patients in Amsterdam, 1996e2000: an evaluation of current prevention policy. Am J Public Health. 2004;94(9):1620-1626. https://doi.org/10.2105/ajph.94.9.1620.
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