Acute Hepatitis B Virus Serum Sickness Like Reaction

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Acute Hepatitis B Virus Serum Sickness like Reaction

Description

Serum sickness-like reaction is an extrahepatic manifestation of acute hepatitis B virus (HBV) infection with arthritis and dermatitis typically arising prior to clinically apparent acute HBV.^(1,2)

Also Called

Arthritis-dermatitis

Epidemiology

Incidence/Prevalence

10%-30% of patients with acute hepatitis B virus infection are reported to have serum sickness-like syndrome.^(1,2)
The prevalence of hepatitis B decreased across all age groups from 2009 to 2019 in a global study evaluating acute viral hepatitis in patients aged 15-29 years (J Viral Hepat 2024 Feb;31(2):96).

Risk Factors

Groups at increased risk for hepatitis B virus (HBV) infection include:
- Persons born in areas of high or intermediate prevalence rates for HBV
- Persons not vaccinated as infants whose parents were born in regions with high HBV endemicity
- Household and sexual contacts of persons who are hepatitis B surface antigen-positive
- Persons with IV drug use
- Persons with multiple sexual partners or history of sexually transmitted disease
- Men who have sex with men
- Inmates at correctional facilities
- Patients infected with hepatitis C virus or HIV
- Patients having renal dialysis
- Pregnant persons
- Patients needing immunosuppressive therapy
- Reference – Hepatology 2009 Sep;50(3):661 PDF, commentary can be found in Hepatology 2010 Mar;51(3):1087

Associated Conditions

Other manifestations of acute hepatitis B virus infection may be associated with serum sickness-like syndrome, such as:^(1,2)
- Hepatitis, which typically manifests 1-6 weeks after serum sickness-like syndrome
- Cryoglobulinemia
- Polyarteritis nodosa
- Glomerulonephritis
- Neurologic and psychologic conditions such as Guillain-Barre syndrome

Etiology and Pathogenesis

Causes

Serum sickness-like syndrome is caused by hepatitis B virus antigen-antibody immune complexes.^(1,2)

Transmission

Transmission of hepatitis B virus (HBV) occurs through percutaneous or mucosal exposure to infectious blood or body fluids.
- The highest concentration of virus is in the blood, but semen and saliva may also be infectious.
- HBV remains viable and infectious in the environment for at least 7 days.
- The virus may be present on inanimate objects even in the absence of visible blood.
- Primary routes of transmission include:
  - Sexual contact
  - Perinatal exposure to an infected parent
  - Percutaneous exposure to infectious body fluids, such as:
    - Needle sharing by patients with IV drug use
    - Needlestick injury in health care setting
      - The risk of developing clinical hepatitis is reported to be 22%-31% if the needle was contaminated with hepatitis B surface antigen (HBsAg)- and hepatitis B e antigen (HBeAg)-positive blood and 1%-6% if the needle was contaminated with HBsAg-positive, HBeAg-negative blood.
- References – MMWR Recomm Rep 2008 Sep 19;57(RR-8):1 full-text, MMWR Recomm Rep 2001 Jun 29;50(RR-11):1 PDF

Pathogenesis

Hepatitis B virus (HBV) antigen-antibody immune complexes form in the presence of excess antigen.⁽³⁾
- Circulating, soluble immune complexes are not properly phagocytosed by macrophages.
- Immune complexes stimulate complement and Fc (constant fragment) receptors.
- The activated complement promotes the generation of anaphylatoxins (C3a and C5a), leading to vascular inflammation.
- Fc receptor activation and complement stimulates chemoattractants and neutrophil recruitment, contributing to tissue inflammation.
As antibodies increase over the course of infection:⁽³⁾
- Excess HBV antigen is bound.
- Immune complexes are readily phagocytosed.
- Symptoms often spontaneously resolve.
Synovial deposition of immune complexes has been documented in chronic HBV infection, which may or may not be a consequence of antecedent serum sickness-like syndrome.^(1,2)

History and Physical

Clinical Presentation

Up to 30% of patients exhibit significant rheumatologic manifestations prior to a clinically apparent hepatitis B virus (HBV) infection. (The clinical presentation of acute HBV infection includes symptoms such as jaundice, nausea, and vomiting.)^(1,2,3)
- Abrupt onset of manifestations may include:
  - Arthralgia
  - Arthritis
  - Skin rash
  - Myalgia
  - Fatigue and generalized weakness
  - Fever
- Polyarthritis is typically symmetrical, involving the hands and feet.
  - It may present as monoarticular arthritis of large joints such as the knees or ankles.
  - It may progress in an additive or migratory pattern.
  - Polyarthritis is associated with morning stiffness.
  - Joint involvement is typically nondestructive.
- Dermatologic manifestations include:
  - Urticaria
  - Maculopapular rash
  - Purpuric rash
  - Petechial rash
  - Palpable purpura
  - Erythema multiforme

History

Ask about joint pain and swelling.^(1,2,3)
- Onset is often abrupt.
- Features of joint involvement include:
  - Symmetrical polyarthritis of the hands and feet
  - Monoarticular arthritis or asymmetric polyarthritis involving large joints such as the knees and ankles
  - Morning stiffness
- Patients commonly rate the pain as very severe.
- Symptoms persist for days to weeks, with a mean duration of about 20 days.
Ask about previous medication history, including:⁽³⁾
- Treatment with monoclonal antibody therapies
- Other drugs that cause serum sickness, such as penicillin and sulfonamides
Ask about social history and risk factors for hepatitis B virus (HBV) infection, including:⁽³⁾
- IV drug use
- Risky sexual behavior
- Hepatitis C virus infection and HIV infection
- Immunosuppression
Check HBV vaccination status.

Physical

Fever may be present.⁽³⁾
Check extremities.^(1,3)
- Joint findings may include:
  - Warmth, swelling, and tenderness
  - Edema
  - Pain associated with active movement
- Muscles may be tender and weak.
Check skin for signs of^(1,3)
- Urticaria
- Maculopapular rash
- Purpuric rash
- Petechial rash
- Palpable purpura
- Erythema multiforme

Diagnosis

Making the Diagnosis

The diagnosis is made clinically in patients with confirmed hepatitis B virus infection.⁽³⁾

Differential Diagnosis

The differential diagnosis for serum sickness-like reactions includes:
- Drug-induced serum sickness reaction⁽³⁾
- Drug hypersensitivities:
  - Drug-induced lupus
  - Stevens-Johnson syndrome/Toxic epidermal necrolysis
  - Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome
  - Anticonvulsant hypersensitivity syndrome
  - Erythema multiforme
  - Chronic urticaria
  - Acute annular urticarial hypersensitivity syndrome in children
- Rheumatic conditions:
  - Rheumatoid arthritis
  - Rheumatic fever
  - Vasculitis
- Other conditions:
  - Kawasaki disease
  - Infectious mononucleosis
  - Acute hemorrhagic edema in infants
Other causes of polyarthritis include:⁽³⁾
- Reactive arthritis
- Psoriatic arthritis
- Systemic lupus erythematosus
- Viral infections, including:
  - Hepatitis C
  - Parvovirus B19 infection
  - Acute HIV infection
  - Rubella
  - Epstein-Barr virus infection

Testing Overview

Hepatitis B virus (HBV) infection is diagnosed by serology and polymerase chain reaction.⁽³⁾
- Acute hepatitis B infection is indicated by detection of:
  - HBV DNA
  - HBV surface antigen with negative surface antibody
  - Anti-HBV core antigen IgM
Complement levels and hemolytic activity may be depressed.⁽³⁾
Liver function tests may reveal elevated levels of hepatic aminotransferases, though this rise often postdates serum sickness.⁽³⁾
Imaging may not be helpful because arthritis is typically nondestructive.⁽¹⁾

Management

Management Overview

No specific treatment for serum sickness-like reaction is necessary.⁽³⁾
Supportive care is the mainstay of treatment.⁽³⁾
Antiviral therapy is generally not indicated for patients with acute hepatitis B virus (HBV).
- Antiviral therapy may be considered for patients with fulminant or severe acute HBV.

Complications and Prognosis

Prognosis

Hepatitis B virus infection serum sickness-like syndrome may last from days to months.^(1,2,3)
- A mean duration of about 20 days is reported.
- Arthritis typically resolves spontaneously but in some cases may persist.
- Skin manifestations commonly resolve completely.

Prevention and Screening

Prevention

Hepatitis B virus (HBV) infection serum sickness-like syndrome may be averted by preventing an acute HBV infection.
- HBV vaccination is routinely provided in a 3-dose series for infants.
- Postexposure prophylaxis with HBV immunoglobulin or HBV vaccine may prevent infection in patients with known exposure.
Case report of HBV serum sickness-like reaction in a 36-year-old male person with IV drug use despite history of HBV vaccination can be found in Cureus 2021 Apr 28;13(4):e14742 full-text.

Screening

Not applicable

Guidelines and Resources

Guidelines

International Guidelines

World Health Organization (WHO) guidance on prevention of viral hepatitis B and C among people who inject drugs can be found at WHO 2012 Jan 1 PDF.
World Gastroenterology Organisation (WGO) 2015 global guideline on hepatitis B can be found at WGO 2015 Feb PDF.

United States Guidelines

Centers for Disease Control and Prevention (CDC):
- Centers for Disease Control and Prevention/Advisory Committee on Immunization Practices (CDC/ACIP) 2024 recommended immunization schedule for children and adolescents ≤ 18 years old can be found in MMWR Morb Mortal Wkly Rep 2024 Jan 11;73(1):6 full-text, immunization schedules for ages ≤ 18 years can be found at CDC 2024 Jan 11.
- Centers for Disease Control and Prevention/Advisory Committee on Immunization Practices (CDC/ACIP) 2024 recommended immunization schedule for adults ≥ 19 years old can be found in MMWR Morb Mortal Wkly Rep 2024 Jan 11;73(1):11 full-text, immunization schedules for ages ≥ 19 years can be found at CDC 2024 Jan 11.
- CDC guidance on evaluating health care personnel for hepatitis B virus protection and for administering postexposure management can be found in MMWR Recomm Rep 2013 Dec 20;62(RR-10):1 full-text.
- CDC recommendation on management of hepatitis B virus-infected health care providers and students can be found in MMWR Recomm Rep 2012 Jul 6;61(RR-3):1 full-text, correction can be found in MMWR Recomm Rep 2012 Jul 20;61(28):542.
- Centers for Disease Control and Prevention (CDC) treatment guideline on sexually transmitted infections can be found in MMWR Recomm Rep 2021 Jul 23;70(4):1 PDF or at CDC 2021 Jul 22.
- Centers for Disease Control and Prevention/National Institutes of Health/Infectious Diseases Society of America (CDC/NIH/IDSA) guideline on prevention and treatment of opportunistic infections in adults and adolescents with HIV can be found at HIVinfo 2024 Oct 8.
New York State Department of Health (NYSDOH) guideline on prevention and management of hepatitis B virus infection in adults with HIV can be found at NYSDOH 2024 May 31 PDF.
American Association for the Study of Liver Diseases (AASLD) 2013 practice guideline on evaluation for liver transplantation in adults can be found in Hepatology 2014 Mar;59(3):1144, commentary can be found in Hepatology 2015 Jan;61(1):408.
Society for Healthcare Epidemiology of America (SHEA) guideline on management of health care personnel living with hepatitis B virus, hepatitis C virus, and/or HIV can be found in Infect Control Hosp Epidemiol 2022 Feb;43(2):147.
Substance Abuse and Mental Health Services Administration (SAMHSA) tip 53 guideline on addressing viral hepatitis in people with substance use disorders can be found in SAMHSA 2011 Dec PDF.
United States Preventive Services Task Force (USPSTF):
- USPSTF recommendation statement on screening for hepatitis B virus infection in pregnant women can be found in JAMA 2019 Jul 23;322(4):349 or at USPSTF 2019 Jul 23.
- USPSTF recommendation statement on screening for hepatitis B virus infection in nonpregnant adolescents and adults can be found in JAMA 2020 Dec 15;324(23):2415 or at USPSTF 2020 Dec 15, supporting systematic review can be found in JAMA 2020 Dec 15;324(23):2423.

United Kingdom Guidelines

British Association for Sexual Health and HIV (BASHH) guideline on management of viral hepatitis A, B, and C can be found at BASHH 2017 PDF.

European Guidelines

European Association for the Study of the Liver (EASL) guideline on management of hepatitis B virus infection can be found in J Hepatol 2017 Aug;67(2):370.
Dansk Selskab for Infektionsmedicin/Dansk Selskab for Gastroenterologi og Hepatologi (Danish Society of Infectious Diseases/Danish Society of Gastroenterology and Hepatology) (DSI/DSGH):
- DSI/DSGH guideline on treatment for hepatitis B virus can be found at DSI/DSGH 2018 PDF [Danish].
- DSI/DSGH guideline on treatment for hepatitis C virus can be found at DSI/DSGH 2022 PDF [Danish].
Association of Gastroenterologists and Hepatologists of Bosnia and Herzegovina guideline on diagnosis and treatment of chronic viral hepatitis B and C can be found in Med Arch 2012;66(3 Suppl 1):56.
Gruppo Italiano Patologi Apparato Digerente (Italian Group of Gastrointestinal Pathologists) (GIPAD) recommendations on chronic viral hepatitis: histology report can be found in Dig Liver Dis 2011 Mar;43 Suppl 4:S331.
Asociación Española para el Estudio del Hígado (Spanish Association for the Study of the Liver) (AEEH) consensus document on treatment of hepatitis B infection (2012) can be found in Gastroenterol Hepatol 2012 Aug-Sep;35(7):512 [Spanish].
Hungarian consensus guideline on diagnosis and treatment of B, C, and D viral hepatitis can be found in Orv Hetil 2012 Mar 11;153(10):375 [Hungarian].
College of Gastroenterology (Gasztroenterológiai Szakmai Kollégium) protocol for antiviral therapy for hepatitis B and D can be found in Orv Hetil 2010 Jan 3;151(1):24 [Hungarian].
Polska Grupa Ekspertów HBV-Zespól ds. Szczepień (Polish Group of Experts of hepatitis B virus [HBV] – collective to vaccinations) guideline on vaccinations against hepatitis A and B can be found in Przegl Epidemiol 2012;66(1):89 [Polish].
Grupo de Estudio del Sida/Secretaría del Plan Nacional sobre el Sida/Asociación Española para el Estudio del Hígado (AIDS Study Group/Secretary of the National Plan on AIDS/Spanish Association for the Study of the Liver) (GESIDA/SPNS/AEEH) recommendations on management and treatment of the adult patient co-infected with HIV and hepatitis A, B, and C virus can be found in Enferm Infecc Microbiol Clin 2010 Jan;28(1):31.e1 [Spanish].

Review Articles

Review of extrahepatic manifestations of chronic hepatitis B virus infection and the role of antiviral therapy can be found in J Clin Med 2022 Oct 23;11(21):6247 full-text.
Review of cutaneous manifestations of viral hepatitis can be found in Curr Infect Dis Rep 2015 Feb;17(2):452.
Review of hepatitis B virus virology and immunology can be found in Clin Liver Dis 2016 Nov;20(4):629.

MEDLINE Search

To search MEDLINE for (Hepatitis B) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis.

Patient Information

Handout from Centers for Disease Control and Prevention on general hepatitis B facts PDF
Handouts on hepatitis B from:
- American Academy of Family Physicians or in Spanish
- Patient UK PDF

References

General References Used

The references listed below are used in this DynaMed topic primarily to support background information and for guidance where evidence summaries are not felt to be necessary. Most references are incorporated within the text along with the evidence summaries.

J Clin Med 2022 Oct 23;11(21):6247 full-text.
Kappus MR, Sterling RK. Extrahepatic manifestations of acute hepatitis B virus infection. Gastroenterol Hepatol (N Y) 2013 Feb;9(2):123-126 full-text.
Stone JH, Murali MR. Case records of the Massachusetts General Hospital. Case 10-2013. A 30-year-old man with fever, myalgias, arthritis, and rash. N Engl J Med 2013 Mar 28;368(13):1239-1245.