Hhv-4 virus infectionsB27.0

Infection by a human pathogenic enveloped B-lymphotropic double-stranded DNA virus of the Herpesviridae subfamily: Gamma-Herpesvirinae (HHV-4, type A and type B). It is easily transmitted by close contact and usually has its entry point in the lymphoepithelial cells of the pharyngeal ring. The virus is the causative agent of Infectious Mononucleosis (Pfeiffer's glandular fever) and other EBV-associated diseases.

Like all herpes viruses, EBV viruses have the ability to "latency", i.e. to "survive" in the organism for a long time. As a rule, the virus can no longer be completely eliminated after infection. In most cases, however, this does not cause further problems, but it can resurrect and multiply again when the immune system is weakened.

HHV-4 (EBV) is suspected to play an important etiological role in a number of different tumorigenic and inflammatory diseases:

• HHV-4 as a trigger of various tumorous diseases:
  • Hodgkin's disease (3-fold increased risk in patients with infectious mononucleosis)
  • HHV-4-associated B-cell lymphomas in AIDS patients
  • HHV-4-positive diffuse large B-cell lymphoma (African Burkitt's lymphoma - endemic in equatorial Africa)
  • Schmincke tumor (clustered in southern China)
  • HHV-4-associated NK T-cell lymphoma
  • HHV-4-associated laryngeal carcinoma (endemic in southern China and Alaska)
  • HHV-4-associated nasopharyngeal carcinoma (endemic in southern China and Alaska)
  • HHV-4-positive mucocutaneous ulcer
  • Hydroa vacciniforme-like lymphoproliferative disease (in children inAsia and South America)
• HHV-4 as a confirmed oncogenic cofactor for various diseases:
  • HHV-4-associated hemophagocytic lymphohistiocytosis (EBV-HLH) a life-threatening hyperinflammatory syndrome caused by a massively exuberant, inflammatory immune system response (Coffey AM et al 2019).
  • Oral hairy leukoplakia (HHV-4 as a co-infection with HIV infection).
  • HHV-4-associated leiomyosarcoma (Aida N et al 2019).
  • Post-transplant lymphoproliferative disease (PTLD) (Hyun H et al 2019).
  • X-chromosomal recessively inherited lymphoproliferative syndrome, also known as Duncan`s disease or Purtilo syndrome (EBV-as a trigger in genetic immunodepression) (Duncan`s disease)
• HHV-4 infection as a possible or detectable trigger of non-tumor organ disease:
  • HHV-4-induced chronic fatigue syndrome (EBV-induced fatigue)
  • encephalitis lethargica
  • HHV-4 myocarditis (rare) in the setting of acute EBV infection
  • Guillain-Barré polyradiculitis with ascending paralysis (occurring several weeks after infection)
  • Acute cerebellar ataxia
  • HHV-4-induced acute hepatitis
  • HHV-4-induced myocarditis
  • HHV-4 infection of the genitourinary tract (e.g., focal segmental glomerulosclerosis, orchitis)
  • Acrodermatitis papulosa eruptiva infantilis

  • Hydroa vacciniforme

Like all herpes viruses, HHV 4 is ubiquitously distributed and infects humans persistently. It is excreted in saliva and is also transmitted. The main mode of transmission is droplet infection, which is why the mononucleosis occurring with the primary infection has also been given the name "kissing disease". In industrialized countries, the infection reaches about 40% by the age of 15, and then rises steeply with puberty to 80-90% in adulthood. In the developing countries, due to the lower hygiene standards, the infestation is practically 100 % already among the under 3-year-olds. Iatrogenic transmission in transplants has been reported. Especially HHV-4-seronegative recipients are at risk (Schnitzler P et al. 2019).

As a receptor protein,CD21 is of essential importance for the infection process. CD21 is expressed on naso-pharyngeal epithelia and B lymphocytes. There the EBV viruses can dock. A second route of infection is EBV-associated T-cell diseases. For example, in extranodal (NK)/T-cell lymphoma, an aggressive malignant lymphoma, EBV infection of NK cells occurs via a direct transfer of viral episomes independently of EBV-positive (CD21-positive) B cells (Lee JH et al. 2018)

In these cases a chronic EBV-associated T-cell disease develops which in rare cases can lead to an infect-associated haemophagocytic syndrome (HHS) (Shah MV et al. 2014; Taylor GS et al.2015).

The geographical prevalence of different EBV-associated diseases such as Burkitt's and Schmincke's tumors suggest an oncogenetic significance of coinfection with e.g. malaria.

Infection with the virus usually occurs in childhood. In this case, the infection is usually subclinical due to the not fully mature T-lymphocyte response. In adolescents or adults, the onset of Pfeiffer glandular fever (infectious mononucleosis) with generalized lymphadenopathy, hepato-splenomegaly (EBV hepatitis) and tonsillitis occurs in 30-60%. Less commonly (3-15%) associated is maculo-papular morbilliform mononucleosis exanthema (Taylor GS et al 2015).

Acute infection: Target cells of acute EBV infection are the naso- and oropharyngeal epithelia as well as B-lymphocytes carrying the protein CD21 on their surfaces, which serves as a receptor for the virus.

4-6 weeks after infection, there is massive viremia and infection of CD21 positive B lymphocytes. These are attacked and eliminated by cytotoxic T lymphocytes. The large number of killer cells is detectable in the blood count as acute mononucleosis.

Latent infection: While most B lymphocytes are infected productively-lytically, latent infection and immortalization of infected B cells occurs in some infected individuals. In this case, however, the cells remain under the control of the T lymphocytes for life. Infection reactivations usually remain subclinical.

Infections in immunodeficiencies: However, EBV disease progression takes a fatal path in primary infected individuals suffering from immunodeficiency syndromes (see below Immunodeficiencies primary in immunodeficiency syndromes).Mutations affect the following genes: SH2D1A, BIRC4, ITK, MAGT1, CORO1A and LRBA (Cohen 2015). In the presence of X-linked recessive or autosomal recessive (not X-linked) inherited lymphoproliferative syndrome, mutations are detected in the genes CD27, CD70, XIAP, SH2D1A , among others.

In case of subsequent immune dysfunction, an immortalized B-cell clone may develop into a lymphoma (e.g. Burkitt's lymphoma, e.g. Schmincke's tumor - Taylor GS et al.(2015)

Almost all patients show a pronounced leukocytosis (10,000-40,000 cells/l) with an absolute and relative lymphocytosis >50% in >10% atypical monocytoid cells (virocytes) during the acute infection. Low transient neutro- and thrombopenia. Liver enzymes ↑↑↑.

Serological antibody detection: A distinction is made between different antigens: heterophilic antibodies detected in rapid tests, early antigens (EA), viral capsid antigens (VCA), nucleus-associated (tumor) antigens (EBNA) and membrane antigens.

For the detection of acute infection, various antigens are used. Various rapid tests are used to detect acute infections (Paul-Bunnell reaction, EBV rapid test, mono test): heterophilic antibodies are detected which agglutinate sheep erythrocytes. The rapid tests give up to 20% false positive and 30% false negative results depending on age.

Other important EBV antigens for the serological detection of the infection:

• EA (early antigens): These antigens, which are produced early by the infected cell, are less immunogenic than the viral capsid EBV antigen (VCA). They regress after weeks. Reactivations can be detected highly sensitive by this IgG antibody.
• EA-R (early antigens restricted - denaturation of samples by methanol fixation): Antibodies of the IgG class against these "restricted antigens" are particularly meaningful in Burkitt's lymphoma and in reactivated infections.
• Anti-VCA (viral capsid antigen, IgG and IgM antibodies): The VCA antigen is strongly immunogenic. Most infected persons form IgM and IgG anti-VCA antibodies immediately at the onset of the disease. The IgM antibody does not persist for more than 10 weeks. The IgG antibody persists for life after infection.
• Anti-EBNA-1-IgG (antibody against the Epstein-Barr nuclear antigen): This tumour antigen appears in the nucleus of all persistently infected cells. It is expressed relatively late in immunogenic form. Antibody formation against EBNA 1 starts after a few months.
• Virus-DNA-PCR: Detection of the viral antigen. The PCR only plays a role in certain questions. PCR diagnostics in CSF tests; also for the detection of the lymphoproliferative syndrome after bone marrow and stem cell transplantation (Niller HH et al. 2017).

Characteristic antibody constellations in patients with EBV-associated diseases.

• Infectious Mononucleosis: VCA-Ig M ++++/VCA-IgG++++; EA-IgG+
• Subclinical infection in children: VCA-IgM ++++/VCA-IgG++++; EA-IgG-
• Long past primary infection: VCA-IgM+/VCA-IgG+; EA-IgG-; EBNA-1-IgG +
• Reactivated infection: VCA-IgM (+)/VCA-IgG++++; EA-IgG++; EBNA-1-IgG (+)
• Nasopharyngeal carcinoma: VCA-IgM -/VCA-IgG++++; EA-IgG++; EA-R+/-; EBNA-1-IgG ++
• Burkitt lymphoma: VCA-IgM -/VCA-IgG++++; EA-IgG++; EA-R+/-; EBNA-1-IgG +

Burkitt's lymphoma stimulates particularly well the formation of antibodies against a part of the many EBV-specific EAs (early antigens) that is not denatured by methanol (EA-R = restricted antigen). It is striking that the African form of Burkitt's lymphoma is geographically limited to areas where malaria is also endemic. The fact that the incidence of Burkitt's lymphoma is also significantly lower in areas of Africa where malaria is suppressed shows a close pathogenetic link between the two types of lymphoma. The connections have not yet been clarified. However, it has been shown that a malaria attack is associated with a significantly reduced EBV-specific cytotoxicity. Therefore, it seems to be possible that EBV-transformed B-lymphocytes can prolong proliferation.

The Schmincke tumor stimulates the EBV antibodies of the IgA class, especially the VCA antibody.

Prolonged healing of EBV infection in athletes: Note: VCA IgM may persist during intense physical exercise (especially in athletes). One speaks of a prolonged (prolonged) healing if the EBNA-1 IgG is already positive.

EBV infection of the CNS: The rare EBV infection of the CNS can be detected by intrathecal formed antibodies against the VCA. Antibodies are formed oligoclonally by lymphocytes that have migrated into the CSF via the choroidal plexus.

Avidity testing (The avidity (from Latin avidus, "greedy") of an antibody is the strength of a multivalent binding between antigen and antibody): In problematic diagnostic cases, an immunoblot and/or avidity test can often be used to differentiate between an acute and a past infection. The detection of a high avidity of VCA IgG antibodies proves a longer time ago infection.

EBV infection in immunodeficiency: In immunodeficiency (immunocompetence), the virus can switch from the resting phase (latency) back to active replication (reactivation). In HIV patients, for example, EBNA-1 IgG can become negative again. A reliable assessment of EBV reactivations in immunodeficiency is only possible by determining the viral load by polymerase chain reaction.

PCR: The direct detection of viral DNA by means of polymerase chain reaction is usually not useful in immunocompromised individuals, since the latent genome can also be detected in the blood and at the same time symptom-free carriers excrete the virus constantly or temporarily with saliva. The above mentioned reactivations usually do not cause any discomfort to an immunocompromised person, they only represent a laboratory diagnostic problem, since the detection of VCA IgG in high concentrations and possibly recurring VCA IgM can lead to misinterpretations. Furthermore, the use of PCR is suitable for the diagnosis of lymphoproliferative syndrome after bone marrow and stem cell transplantation.

Reactivation of the immunological memory: Acute EBV infection induces a kind of "recall effect" in infected B-lymphocytes. This leads to B-lymphocytes producing IgM antibodies again from infections that have already healed. The result is the simultaneous presence of IgM antibodies against rubella, measles, hepatitis A, CMV, etc. This serological constellation thus imitates acute infections caused by these pathogens. A patient with > 1 positive IgM titre of different viral antigens is always suspected of having EBV.

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