Cytomegalovirus B25.9

Infections occurring worldwide are caused by the human cytomegalovirus (HHV-5), a human DNA virus of the herpes family (Herpesviridae - HHV) from the subfamily of beta-herpesviridae.

Infection is carried out by means of smear and droplet infection, transplantation or transfusion.

The cytomegalovirus is the largest virus within the Herpesviridae, but morphologically does not differ from the other viruses of this family. An infection leads to giant cell formation and a slow onset of cytopathology. After the initial infection, the virus persists latently in many epithelioid cell tissues, in haematopoietic and endothelial cells. It can be reactivated when the immune situation weakens.

Virus excretion and the associated ability to infect remains lifelong.

Worldwide occurrence.

In third countries, > 90% of the population is infected; also in risk groups (HIV-infected, homosexuals, prostitutes).

In the industrialised countries it is about 50% of the average population. Population-related, representative studies on seroprevalence in the German general population are not yet available. Factors such as the number of sexual partners, contact in the care of small children and hygiene conditions are likely to play a significant role in seroprevalence.

A study of 24,260 blood donors in Giessen from 1992 - 2002 showed a seroprevalence of 46%. The seroprevalence among pregnant women in the FRG is about 47%.

In kidney transplant patients the seroprevalence of CMV is 77%.

A percentage of about 50% should correspond to the level of infestation of the Central European population (Thomas L 2006). The percentage of blood donors between 18 and 60 years of age who seroconverted per year was 0.55% in this study.

Especially infants up to the age of 3 years can excrete large amounts of virus after congenital and postnatal CMV infection. Virus excretion may occur in some congenitally infected children up to the age of 8. This group thus carries a significant risk for seronegative pregnant women as well as for immunocompromised persons.

The virus is excreted via blood, breast milk, tear fluid, saliva, urine and genital secretions. This is also the route of transmission. The virus replicates in the mucosa of the oropharynx, followed by a hematogenic spread via leukocytes throughout the body.

During the breastfeeding period, CMV is excreted by almost all seropositive women with their milk and is passed on to children with a frequency of about 35%.

Women who become infected with CMV during pregnancy also show no symptoms in the majority (approx. 75%).

Prenatal HHV-5 infection: 90% of newborns infected in utero are asymptomatic at birth. Growth retardation may occur in 10-15%. In addition, neurological late damage is frequently observed. In 5%, severe disorders such as hepatosplenomegaly, coagulation disorders, microcephaly and later in life, mental (learning disorders) and physical (hearing impairment, dental defects) disabilities occur.

Perinatal HHV-5 infection in mature infants: Perinatal infection of the newborn (caused by reactivation of a persistent initial CMV infection during pregnancy) is usually asymptomatic in mature infants.

Perinatal HHV-5 infection in preterm infants: Primary infection in preterm infants may be associated with severe disorders of AZ, hepatosplenomegaly, thrombocytopenia as well as purpura(blueberry muffin baby).

Postnatal infection (of the adult): Primary infection of the adult (transmission of infection occurs through close physical contact, usually sexual. Transmission also possible by blood transfusion) is usually (>90%) asymptomatic or with only mild nonspecific symptoms in immunocompetent individuals. After infection, the virus enters a latent stage in myeloid cells, from which it can be reactivated.

Only rarely do severe flu-like symptoms or infectious CMV mononucleosis develop with lymphadenopathy, possibly mild hepatitis, fatigue and loss of activity for weeks or several months; formation of a (morbilliform) exanthema is possible.

Infection in immunocompromised individuals: In individuals with congenital or acquired immunodeficiency and those receiving immunosuppressive therapy, infection can cause significant organ damage. Usually there is a severe course with fever, lymphadenopathy, leukopenia, thrombocytopenia,

• retinitis (most frequent CMV manifestation in AIDS with cotton-wool exudates and haemorrhages)
• Encephalitis, hepatitis, pneumonitis
• Colitis (with ulcerations)
• Pneumonia (CMV pneumonia)

CMV pneumonia(interstitial pneumonia with high lethality) and infection of the mesangial cells of the kidney leading to rejection in transplants deserve special mention. The extent to which cytomegalovirus is a causal factor in some types of brochnial carcinoma, popular remains to be seen (Richardson AK et al. 2019).

Skin lesions in the setting of CMV infection:

• Cytomegaly - Ulcer (oral or perianal - Drozd B et al 2019).
• Icterus
• Purpura: punctate or extensive skin bleeding (thrombocytopenia!).
• Exanthema: maculopapular exanthema (not uncommon with concordant occurrence of EBV + CMV infection).
• Erythroderma(DRESS)

Often leukopenia, relative lymphocytosis with atypical lymphocytes; possibly thrombocytopenia

Serological diagnostics:

• Virus detection (PCR)
• pp65 antigen
• CMV DNA detection: IgG and IgM antibodies
• Determination of the IgG antibody avidity

Stepwise Diagnosis with Antibody Determination: Commercially available immunoassays are suitable for the detection of CMV-specific antibodies from serum or plasma. For further clarification in case of unclear findings, additional tests reserved for special laboratories are used. Seroconversion, i.e. the first appearance of CMV-specific IgG antibodies, is evidence of a primary infection. Prerequisite: Detection of seroconversion; 2 serum samples are required, which are taken at 14-day intervals. In the second sample, low-avidity(avidity = strength of binding between antibody and antigen) as well as CMV IgG antibodies and CMV IgM antibodies are detectable. Note: The investigation of the avidity of CMV-specific IgG antibodies is helpful, since low avidity is usually associated with a recent infection. The risk of damage to the fetus is highest in the first trimester (during organogenesis) in the case of primary infection. To confirm a primary CMV infection, serological testing should be performed until the 20th week of gestation.

Primary infection is likely to be with high-positive CMV IgM antibodies that drop off as the infection progresses; CMV IgG antibodies have a low avidity. Antibodies against glycoprotein B are negative. PCR: An active CMV infection can be diagnosed by PCR detection (quantitative determination of the viral load is possible) in immunocompromised persons.

Differentiation between primary infection and reactivation: The differentiation between a primary infection and reactivation is often difficult to make using standard serological procedures.

In postnatal primary infections of immunocompetent individuals, CMV-specific IgM antibodies are usually detectable.

Inreactivation of immunocompetent individuals, an increase in the titer of CMV IgG antibodies can be detected in serum with negative or even low-positive CMV IgM antibodies.

Serological constellations during pregnancy

• Diagnosis seronegative
• 1-3 trimenon: CMV IgG neg.; CMV IgM neg.; IgG antibody avidity: not determinable
• Diagnosis: Primary infection
• 1-3 trimenon: CMV-IgG pos.; CMV-IgM neg.; IgG antibody avidity: not determinable
• Diagnosis: Prenatal primary infection
• 12th-16th week of pregnancy: CMV-IgG pos.; CMV-IgM pos.; Avidity: high
• Diagnosis: Primary infection in the 1st trimenon
• 12th-16th week of pregnancy: CMV-IgG pos.; CMV-IgM pos.; Avidity: low

Since CMV (like all herpes viruses) are latency-transforming, no medication can achieve elimination. The only thing that is possible is to inhibit the reproduction of the virus.

• Immunocompetent asymptomatic patients: no virostatic therapy.
• Active CMV infection in immunosuppressive patients: therapy with antiviral: ganciclovir (Cave: nephro- and myelotoxic). Additive administration of CMV hyperimmunoglobulin. Maintenance therapy for immunosuppression: Valganciclovir or Foscarnet (Foscavir®) or Cidofovir. Cave: all drugs with sometimes considerable side effects (myelo- or nephrotoxicity).
• Active CMV infection during pregnancy: CMV hyperimmunoglobulin. A virostatic treatment of pregnant women and nursing mothers is not recommended.
• Active CMV infection in congenitally infected newborns and premature infants (1% of all newborns, 5-10% of which are symptomatic). Ganciclovir (Cymeven®) 6 mg/kg bw i.v. every 12 hours for 6 weeks. Efficient vaccines are not available. Cave! Ganciclovir is toxic to bone marrow. Additive administration of CMV hyperimmunoglobulin. Note: CMV therapy of congenitally infected newborns should only be performed in consultation with a neonatal center. Every use of these drugs represents an "off-label-use" in children.
• Measures after organ transplantation: For all kidney transplant recipients (except for CMV seronegativity of donor and recipient) oral chemoprophylaxis with ganciclovir or valganciclovir is recommended for at least 3 months after transplantation and for 6 weeks after treatment with a T-cell-depleting antibody (recommendation of KDIGO - Kidney Disease: Improving Global Outcomes).
• CMV retinitis in AIDS patients: use of Valganciclovir
• Alternative preparations for CMV retinitis: Cidofovir (nephrotoxic), Foscarnet, Fomivirsen (for intravitreal application. The effectiveness of ocular ganciclovir implants lasts for 6-8 months (then the implants must be renewed) and is limited to the eye protected by the implant. Caution! No protection against organ infestation by implants, therefore continue peroral Cymeven therapy).
• Ganciclovir resistance: therapy with alternative antivirals (Foscavir or Cidofovir). Cidofovir can be used for ganciclovir resistance (mutation in the UL97 gene).

Prophylaxis:

• CMV prophylaxis in immunosuppressed CMV-seronegative patients: Transfusions and transplants from seronegative donors. Monitoring of transplantation patients using PCR diagnostics and antigen testing.
• CMV prophylaxis (seronegative pregnant women): administration of CMV hyperimmunoglobulin after CMV exposure. Note: Even small children can be CMV carriers!
• CMV prophylaxis for AIDS patients: Recurrence prophylaxis with ganciclovir.

Dosages:

• Ganciclovir (Cymeven): 2 times/day 5 mg/kg bw i.v. (infusion over 1 hour) every 12 hours for 14 days. Maintenance therapy: 5 times/week 6 mg/kg bw i.v.
• Alternative: Foscarnet (Foscavir): 3 times/day (every 8 hours) 60 mg/kg bw i.v. (infusion over 1 hour) for 2-3 weeks. Maintenance therapy: 7 times/week 90-120 mg/kg bw i.v. (infusion over 1 hour). Cave! No combination with pentamidine diisethionate!
• Alternatively Valganciclovir (Valcyte): Initial: 2 times/day 900 mg p.o. for 21 days. Maintenance therapy: 1 time per day 900 mg.
• Alternative Cidofovir (Vistide): Use should only be considered if there is resistance to Ganciclovir, Valganciclovir and Foscarnet due to the side effect profile. Initial once/week 5 mg/kg bw i.v. for 2 weeks. Maintenance dose from week 3: once/14 days 5 mg/kg bw i.v.
• Specific immunoglobulins: CMV hyperimmunoglobulin (Cytotect): 2 ml/kg bw every 14 days i.v. Intravitreal administration: 200 μg every 3 days for 3 weeks until scarring.

In Germany, there is no obligation to report diseases or pathogens in accordance with the IfSG.

The most frequent cause of intrauterine fruit damage today is not toxoplasmosis or rubella diseases during pregnancy, but CMV infections.

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3. Ezzatzadegan Jahromi S et al. (2016) A potential role for cytomegalovirus in a facial ulcer in a renal transplant recipient. Transpl Infect Dis 18:457-460.
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