CMV causes what in fetus?
1) Restricted growth
2) Microcephaly
3) Hepatospenomegaly
4) Hydrocephalus
5) Periventricular brain calcifications
CMV causes what in baby?
1) Blueberry rash (Rubella and CMV)
2) Jaundice
3) Hearing impairment on 1 side
4) vision issues
CMV facts?
1) Linear DS DNA virus with envelope (susceptible to degradation)
2) herpesvirus family, sub-family betaherpesvirinae, includes (HHV 5 - 7)
3) Infects epithelial, fibroblast, monocytes, macrophages, and lymphocytes
Clinical manifestations and transmission
1) Slow replication cycle; it induces formation of large, multinucleated cells
* Cytomegalovirus – derived from enlargement of cells (“cyto = cell, “mega” =
large) infected by the virus
2) May be acquired early in life and becomes latent without causing disease (virus may be excreted months to years after primary infection)
3) Reactivates in cases of immunosuppression -> tissues, leukocytes, epithelial cells
4) Congenital transmission - fetus at highest risk if mom infected first 3-4 months of pregnancy
5) Perinatal transmission - mom may shed virus in genital tract and pass it to baby during birth
Fluids in which CMV is transmitted?
1) Urine -newborns
2) blood
3) Saliva
4) Tears/eye swab
5) Stool
6) breast milk
7) Vaginal excretion and semen
Clinical syndromes
1) Congenital
Most babies do not show healthy problem signs
10-15% develop severe sx
2) Older children and adults
*Mononucleosis with fever malaise, pharyngitis
3) Immunocompromised
Transplant patients at highest risks -> can disseminate into lungs, kidneys, liver, GI tract, eye, and CNS
Diagnosis
Which best predicts active disease?
Histopathology:
*Owls eye
*Less sensitive that PCR, but more predictive of active disease
Culture:
* Limited to some large academic medical centers, public health laboratories, and
some reference laboratories
* Antiviral drug testing and vaccine development
* Use human fibroblast cells: human embryonic tissues or foreskins and serially
passaged diploid human fetal lung strains (MRC-5, WI-38, or IMR90)
3) Serology
*IgG avidity is key to determining when fetus is at risk
4) PCR/NAAT
Urine, saliva, and/or blood (including dried blood spots)
Is a mother’s serology work shows signs of re-activation or past infection is the fetus at risk?
IgM positive, IgG positive, High IgG avidity
low risk of vertical transmission to the fetus
Is a mother’s serology work shows signs of active infection is the fetus at risk?
IgM positive, IgG positive, low IgG avidity
yes,
IgM positive results in combination with low IgG
avidity results are considered reliable evidence for primary CMV infection in a
pregnant woman and an increased risk of vertical transmission to the fetus;
additional procedures can be performed to detect CMV infection in the fetus.
PCR diagnosis
Qualitative PCR
- Useful in detecting CMV in saliva, urine, tissue, amniotic fluid or fetal blood for diagnosis of congenital CMV infection, in CSF of
HIV patient with encephalitis, eye specimen for retinitis
*Used for diagnosis CMV after birth-Test within 2-3 weeks after birth in saliva (at leas 1 hr after feeding), blood, or urine; positive saliva PCR should be confirmed by urine PCR
Quantitative PCR
- Determine viral load: DNA quantification and rising viral load over time indicates an active CMV disease
- Monitor progression of CMV disease and response to antiviral therapy
- Viral quant differs between tests, same test should be used to monitor treatment
**Diagnostic of CMV infection or disease should NOT rely solely on a PCR result
CMV treatment
Targeting DNA polymerase (pUL54)
Targeting DNA polymerase (pUL54)
- Ganciclovir (first-line treatment)
- Valganciclovir (first-line treatment and prophylaxis for
transplant recipient at risk of CMV infection and disease) - Foscarnet (second-line treatment)
- Ganciclovir-resistant CMV
- Use for treating AIDs patient with CMV retinitis
- Cidofovir(second-line treatment): use for treatment AIDs
patient with CMV retinitis - Brincidofovir (more potent and less toxicity)
- Treat ganciclovir resistant CMV infection
Drugs targeting CMV pUL97 kinase
- Maribavir
- Drugs targeting CMV pUL56 terminase
- Letermovir
Drug resistance
UL97: encodes a viral protein kinase (pUL97) with essential for viral morphogenesis and
nuclear egress
* UL97 is important to activate GCV; drugs causing loss of UL97 are inhibitive to viral replication while
mutation like A594V confer resistance to GCV while retaining other functions
* UL97 mutations account for more than 90% of drug-resistance in CMV infection
UL54: encodes CMV-specific DNA Pol (pUL54 pol)
* Certain CMV strains have mutation in both UL97and UL54 leading to resistance to high
cidofovir, foscarnet as well as stronger GCV resistance
