Chronic active Epstein-Barr virus infection: causes, symptoms, diagnosis, treatment, and prognosis

Chronic active Epstein-Barr virus (EBV) infection is a less common disease with high mortality and is characterized by chronic fatigue, fever, lymphadenopathy, and hepatosplenomegaly. It is associated with abnormal production of EBV antibodies, and it occurs mostly in children and adolescents under 12 years of age.


Causes

At present, the pathogenesis of chronic active EBV infection is still unclear, and mainly related to host cellular immune abnormalities. EBV is latent in B lymphocytes after primary infection, developing into quiescent memory lymphocytes, and the virus no longer replicates autonomously. It presents infectious mononucleosis-like symptoms clinically and it is self-limited and with a good prognosis. In very few individuals, EBV cannot enter latent infection or reenter lytic infection from latent infection, eventually developing into chronic active EBV infection. At this time, in addition to B cells, EBV also infects T cells and NK cells, and is clonogenically proliferating. Infected cells can invade multiple organs in the body, resulting in diverse clinical manifestations, and pathological changes can involve almost all organs of the body.

Figure 1, Epstein-Barr virus


Signs and Symptoms

Mild patients mainly present with repeated or persistent infectious mononucleosis-like symptoms, whereas manifestations in severe patients are heterogeneous as EBV can invade various tissues and organs in the body. Almost all severe patients present with recurrent or persistent fever, liver dysfunction, and splenomegaly for months, more than half of patients present with lymphadenopathy, thrombocytopenia, and anemia, other more common symptoms in 20% - 40% of patients include hypersensitivity to mosquito bite (HMB), rashes, hemophagocytic syndrome (HPS), and coronary aneurysms, and other less common clinical manifestations include central nervous system involvement, intracranial calcinosis, parosteitis, nasosinusitis, oral ulcers, uveitis or cataract, Sjogren's syndrome, testitis or epididymitis.

Figure 2, hypersensitivity to mosquito bite

Figure 3, hypersensitivity to mosquito bite

Figure 4, hypersensitivity to mosquito bite


Diagnosis

The diagnosis of chronic active EBV infection is mainly based on clinical manifestations, EBV loads, and histopathological changes.

Clinically diagnostic considerations:

  • Multiple organic and systemic lesions with unknown causes
  • Chronic hepatitis, cardiomyopathy, and kidney damage that pathogens cannot be found in clinical practices
  • Histories of hypersensitivity to mosquito bite with skin lesions, abnormal increase of large granular lymphocytes in peripheral blood with elevated plasma IgE suggesting natural killer cell type chronic active EBV infection
  • Autoimmune hepatitis in some patients

In addition, etiological examinations are very important for the diagnosis of chronic active EBV infection. It is currently believed that quantitative PCR determination of free EBV DNA copy number in peripheral blood plasma, namely viral load, is more meaningful than EBV antibody titer. EBV load > 102.5 copies/mL in peripheral blood mononuclear cells can be used as diagnostic criteria for chronic active EBV infection.


Treatment

There is no satisfactory treatment regimen for chronic active EBV infection currently. Comprehensive treatment is adopted internationally.

Main treatment regimens

  • Medications, such as acyclovir, ganciclovir, vidarabine, to block the synthesis of DNA polymerase Cytokines, such as INFc, IL-2
  • Adrenal cortical hormone or intravenous gamma globulin
  • Antineoplastic drugs, such as CHOP chemotherapy
  • Active treatment of early complications
  • Immunologic reconstitution, such as bone marrow or peripheral blood stem cell transplantation Monoclonal antibody treatment, such as infusion of autologous or donor EBV-specific CTL cells

Prognosis

A poor prognosis is present in chronic active EBV infection. It is reported that more than 50% of patients die of serious complications within 5 years after the onset of the first symptom, mainly hepatic failure, heart failure, lymphoma, opportunistic infections, and lymphoproliferative hemophagocytic syndrome. Some patients develop hemophagocytic syndrome after infection, which is the first symptom of chronic active EBV infection and should be paid attention to. Clonogenically proliferating lymphocytes can occur in any organ except for lymph nodes, so that imaging, virological, histopathological examination, and endoscopy are important.