CMV Flashcards
Incidence of congenital CMV?
Occurs in 1 out of every 100-200 live births in UK and 1 in 71 in developing nations
Diagnosing CMV in mum with symptoms?
Test IgM/G. If only M pos then repeat sample looking for g seroconversion
If M and G pos test earlier sample looking for seroconversion. If both reactive then avidity
When can you do amniocentesis to look for CMV infection?
What is the sensitivity?
What action do you take following the amnio?
This is dependent on foetal urine excretion which starts at 17 weeks (Euro consensus guideline says amnio from 17 weeks, SMI says 21)
This shouldn’t be done until 6 weeks after primary infection in the mother as earlier testing may result in false negative
Around 85-95% sensitive
When fetal CMV infection has been confirmed by amnio-centesis
- Serial ultrasound examination of the fetus should be offered every 2–3 weeks until birth.
- Foetal MRI brain at 28 weeks
Indications for valaciclovir to treat CMV in pregnancy?
In cases of maternal primary infection in the periconceptional period or in the first trimester, oral valaciclovir at a dose of 8 g/day should be administered as early as possible after the diagnosis and until the amniocentesis.
From - Consensus recommendation for prenatal, neonatal and postnatal management of congenital cytomegalovirus infection from the European congenital infection initiative (ECCI)
Presentation of cCMV?
90% of infants with infection will be asymptomatic at birth
- Around 15% will go on to develop SNHL
10% of cCMV will be symptomatic at birth
Most common
- Petechiae (blueberry muffin rash)
- Hepatosplenomegaly +- hepatitis
- Thrombocytopenia
- CNS involvment
- SNHL
Management of cCMV in the neonate?
Ganciclovir 6mg/kg BD or Valgan 16mg/kg - to continue for 6 months
Followup of a neonate with symptomatic cCMV
If treated ID followup for 2 years
Hearing test followup to 6 years
Ophthalmology if symptomatic for 5 years
Sensitivity of Guthrie card for cCMV?
Sensitivity of NAAT performed from a dried blood spot (Guthrie card) has been reported to be between 70-80%
Amniocenteis NPV for symptomatic cCMV?
Negative predictive values of between 92.7% and 95.7% are reported for CMV NAAT assays of amniotic fluid.
CMV disease in immunocompromised. Clinical presentation?
fever, bone marrow suppression, and tissue invasive (pneumonitis, hepatitis, colitis, nephritis and retinitis).
Highest risk SOT for CMV disease?
D+R- - Kidney, liver, pancreas, heart, lung, intestine, face/hand
D- R+ or D+/R+ - higher risk if Campath (alemtuzumab) or ATG (t lymphocyte depletion therapy)
Duration of CMV prophylaxis in SOT and dose?
Valganciclovir 900mg OD adjusted for renal clearance
Varying recommendations with differences between UK SOT guideline and consensus guideline. Generally
D+r+ kidney and liver at least 3 months (6 in consensus)
“Consider” at least 3 months in heart/lung
D- R+ or D+/R+ - higher risk if Campath (alemtuzumab) or ATG (t lymphocyte depletion therapy) - can consider 3/12 prophylaxis
Define EC50
The concentration of a drug required to inhibit viral replication by 50%
Define low, medium and high levels of EC50 in CMV resistance.
What is the relevance of this for treatment?
- Insignificant<2x
- Low >2-5
- <Mod>5
</Mod>
Consensus guidelines suggest that if <5x then you can use higher dose GCV (10mg/KG BD instead of 5mg/kg)
UL regions for resistance in CMV?
UL54 (10%) - Pol (GCV/FOS/CDV)
UL97 (90%- Kinase - GCV and marabivir)
UL56 - terminase (letermovir)
UL 27 (low level marabivir)
Stopping rules for CMV treatment with gan/valgan?
“treatment doses of (val)ganciclovir are recommended until
eradication of CMV DNAemia below a specific threshold
and resolution of all clinical signs of CMV disease. Eradication of CMV DNAemia is defined as below LLOQ on 1
highly sensitive assay (LLOQ < 200 IU/mL; see Diagnostic
section), or lack of detection on 2 consecutive less sensitive
assays.” From SOT consensus guidelines Kotton
Prophylaxis in SCT with CMV D-R+
Letermovir 100 days. Can be extended to 200 if high risk of CMV disease
Secondary prophylaxis in CMV
Not recommended in SOT
Can be considered with letermovir in SCT if high risk of reactivation or didn’t recieve primary prohylaxis first time
Can letermovir be used in CMV prophylaxis in SOT?
Not yet recommended by guidelines but growing evidence basis.
“Among adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, letermovir was noninferior to valganciclovir for prophylaxis of CMV disease over 52 weeks, with lower rates of leukopenia or neutropenia, supporting its use for this indication’’
Limaye AP, Budde K, Humar A, et al. Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in High-Risk Kidney Transplant Recipients: A Randomized Clinical Trial. JAMA. 2023;330(1):33–42. doi:10.1001/jama.2023.9106
Why is ganciclovir not used as prophylaxis in SCT patients?
“it did not result in improved overall survival because of severe neutropenia and secondary bacterial and fungal infections’’
Einsele H, Ljungman P, Boeckh M. How I treat CMV reactivation after allogeneic hematopoietic stem cell transplantation. Blood. 2020 May 7;135(19):1619-1629. doi: 10.1182/blood.2019000956. PMID: 32202631; PMCID: PMC7484743.
Monitoring of SOT CMV whilst on prophylaxis and preemptive?
Prophylaxis - None
Pre-emptive - at least monthly (guidelines disagree - Kotton suggests weekly)
Marabivir can’t be used in conjunction with ??
Ganciclovir - both act on kinase and marabivir antagonises action of GCV
Which SCT patients should receive letermovir prophylaxis and for how long?
All R+ patients regardless of donor status. For min 100 days but can be extended to 200
What significant drug/drug interaction occurs with letermovir?
Ciclosporin - letermovir requires drug adjustment.
What test is the gold standard for diagnosing CMV retinitis?
What is observed?
Fundoscopy
Characteristic retinal haemorrhage with a fluffy white granular appearance to the retina
Confirmatory diagnosis can be using PCR on vitreal fluid
What was the most common CMV presentation pre-ART?
What is the treatment?
Retinitis
IV GCV 2-4 weeks plus intravitreal GCV/FOS
In AIDS continue 900 mg valgan OD until CD4 > 100
Be aware of IRIS (start ART 2 weeks after treatment)
Patient on biological immunosuppression presents with dysphagia, pain on swelling and ulceration. Possibly diagnosis?
How is this diagnosed?
What is the treatment?
CMV oesophagitis
Histology - ‘owl’s eye’ inclusions and IHC
Blood DNA not useful as poor NPV, and not related to end organ disease
Reduction of immunosuppression and IV/oral GCV
Lab investigation of patient with ?CMV colitis in IBD
CMV IgG - if negative rule out
If non-responder to steroids/immunosuppression
Blood VL AND biopsy for H&E and IHC
Only if high VL and high inclusions would you treat
If IHC negative but high suspicion of CMV then PCR on tissue
Overview of CMV encephalitis
Generalised cognitive decline, focal neurological signs and cranial nerve palsies are uncommon
Rare and only in context of profound immunosuppression (case reports in immunocompetent)
Rapid progression can help differentiate from HIV encephalitis/PML
PCR on CSF 62-100% sens, 89-100% spec
Which patients are at risk of CMV pneumonitis?
Symptoms?
Diagnosis?
What is seen on CT?
Treatment
AIDS and HSCT (up to 30%) - high mortality
Nonspecific, dry cough, dysponea, breathlessness, fever
PCR in blood and BAL - blood PCR may be negative. Lung biopsy is gold standard
Diffuse interstitial infiltrates, ground glass or nodular pattern
IV GCV for 21 days and CMV IgG
What % of neonates have cCMV?
0.2-2.2%
How many neonates with cCMV will be symptomatic at birth? How many will develop symptoms later in childhood?
10-15%
Another 10-15%
What are the chance of primary CMV in pregnancy?
What is the chance of foetal infection?
What is the chance of a symptomatic neonate? What is the chance this neonate with be affected?
What is the chance of having an asympomatic neonate? What is the chance this neonate will be affected?
Primary CMV 1-4%
30-50% risk of foetal infection
10-15% risk of symptomatic neonate, 90% will be affected
85-90% of asymptomatic neonate, 5-15% will be affected
What are the chance of CMV reinfection/reactivation in pregnancy?
What is the chance of foetal infection?
What is the chance of a symptomatic neonate? What is the chance this neonate with be affected?
What is the chance of having an asympomatic neonate? What is the chance this neonate will be affected?
1-14%
0.2-2% risk of fetral infection
1% risk of symptomatic neonate, 90% will be affected
99% of asymptomatic neonate, 5-10% will be affected
Risk of CMV transmission in:
2-8 weeks pre-conception
Peri-conception
1st trimester
2nd trimester
3rd trimester
5.5%
21%
30-40%
30-40%
40-70%
Risk of cCMV in:
1st trimester
2nd trimester
3rd trimester
23%
0.1%
0%
When should amniocentesis for CMV be performed?
> 20 weeks gestation (when feotal urine is well established) and 6-8 weeks after primary maternal infection
If amniocentesis is CMV DNA positive what additional testing should be advised on the foetus?
Serial ultrasound and MRI
What cells does CMV become latent in?
CD34 myeloid progenator cells
How would you treat a pregnant women with primary CMV at 7 weeks gestation?
Valaciclovir 8g per day asap until amniocentesis
When should prenatal valaciclovir be considered in pregnancy?
What is the evidence?
In confirmed primary maternal CMV in first trimester, treat until amniocentesis (or 18 weeks if no amnio)
CYMEVAL study showed reduction (82% to 43%) of affected foetuses (trial of treatment in mild-moderately affected foetuses with confirmed CMV) Reduces vertical transmission by 70%?
Should CMV hyperimmune globulin be used to reduce risk of cCMV?
No, initial results looked good but no benefit in Phase 2 clinical trials
Symptoms of cCMV
Blueberry muffin rash
Petechiae
Hepatosplenomegaly
Jaundice/transaminitis
Chorioretinitis
Cataracts
IUGR
Microcephaly
Colitis
Pneumonitis
Sepsis like syndrome
Intracranial calcifications/ventriculomegaly
Seizures
SNHL
Sensitivity of guthrie card for CMV?
65-100%
What tests should be performed on a baby with confirmed cCMV?
FBC/creatinine/U&Es/LFTs
CMV DNA in plasma
Cranial ultrasound
Ophthalmic and audiometry assessment
When would treatment be offered for cCMV?
Babies born at >32 weeks
>1800 g birthweight
Acutely unwell infants or well infants with evidence of CNS infection (incl SNHL)
Treatment must start in the first 4 weeks of life
What is the treatment for cCMV?
Ganciclovir 6mg/kg BD
Can change to valgan (16 mg/kg BD) when on ~50% enteral feeds
6 months duration
How often is CMV DNA monitored in infants being treated for cCMV?
For acutely unwell infants: day 3 and then weekly for the first 6 weeks, then montly
For well infants: Fortnightly for 3 months and then monthly
What are the side effects of GCV in cCMV treatment? What is the most common symptom and when does this occur?
Neutropenia, thrombocytopaeniam hepatotoxicity, anaemia
Neutropenia is most common and occurs most often in first 6 weeks, may require cessation of therapy
What follow up is required in cCMV?
Follow up at 1-2 years of life
Audiology assessment every 3-6 m then less frequently until 6 years
Opthalmic assessment up to age 5
Investigation of SNHL in:
<1 years
>1 years
2x urine and 2x saliva for PCR
CMV IgG +/- urine
Alternatively negative CMV IgG in mum
Risk factors and presentation of postnatal CMV
Risk factors = <32 weeks, <1500 g, exposure to CMV pos breastmilk
Sepsis like syndrome
Respiratory distress
Thrombocytopaenia
Hepato/splenomegaly
Jaundice
Neutropaenia
Usually occurs at 4-6 weeks of age
Treatment for postnatal CMV
Treatment only in severe disease in very preterm babies
Treat with ganciclovir in 2 week blocks, until virally suppressed/asymptomatic
Aim to suppress viraemia and prevent end organ damage
Monitor DNA and FBC weekly
What is the most common risk of post-natal CMV transmission?
Breastmilk
How is donor breastmilk treated in the UK to reduce the risk of CMV?
Frozen, pasteurised and frozen again which greatly reduces CMV transmission greatly
Which organ recipients are at greatest risk of CMV disease?
All D+/R- recipients
R+ on T cell depleting agents (ATG/alemtuzumab) or treated for acute rejection
Which SOT recipients should receive CMV prophylaxis, for how long and with what antiviral?
All D+/R- recipients
R+ on T cell depleting agents (ATG/alemtuzumab) or treated for acute rejection
900 mg OD valganciclovir for at least 3 months
As per guidelines “offer” for kidney and liver and “consider” in others
What CMV monitoring in SOT:
a) D-/R-
b) D* /R* on prophylaxis
c) D+/R* and D*/R+ and not on prophylaxis
What increase in VL is considered significant
a) None
b) None
c) VL at least monthly for at least 3 months
0.5 log
Regarding ganciclovir prophylaxis in SOT:
Dosing if eGFR <60 ml/min?
Monitoring for side effects?
Dose reduction required
Monitor FBC every 2 weeks, if myelosuppression switch to monitoring and pre-emotive therapy
What is first line for treatment of CMV in SOT?
What monitoring?
When to stop treatment?
Reduction of immunosuppression if possible
Valganciclovir unless worries about adherence/absorption
Monitor VL at 2 weeks and then weekly
Stop at resolution of symtoms and 2x negative VL 1 week apart
What is second line treatment for CMV in SOT if there is suspected ganciclovir resistance?
Maribavir
If confirmed resistance (and not resistant to FOS) then foscarnet is an alternative
3rd/4th line = Foscarnet/cidofovir
Dose of maribavir for CMV treatment in SOT?
400 mg BD for 8 weeks (oral)
Dose of foscarnet for CMV treatment in SOT?
60 mg/kg TDS for 3 weeks (IV)
What should be optimised in CMV disease in SOT?
Reduction of immunosuppression if possible
Especially MMF/azathioprine if leucopaenia
When does CMV disease usually occur in SOT?
What are the symptoms?
Primary CMV in D+/R- usually in first 4-6 weeks
Late onset CMV can occur in up to 30% after prophylaxis finished (mostly D+/R-) high mortality rate and often results in graft rejection
Fevers, fatigue, sweats, myalgia, gastritis is common. Pneumonia, neutropenia, hepatitis. Retinitis is rare but pathognomonic
When is CMV disease most likely to occur in HSCT?
What are the two most important disease entities?
First 100 days
Pneumonitis and gastroenteritis
What CMV testing is performed pre-HSCT?
CMV IgG status determined prior to any blood products and then again just before HSCT
Pre-HSCT PCR recommended
Which HSCT patients receive CMV prophylaxis?
What antiviral is used? And for how long?
All R+ patients regardless of D status
Letermovir for 100 days, extend to 200 days in high risk groups
What alternatives to letermovir are there for CMV prophylaxis?
Valaciclovir
Monitoring of CMV and pre-emptive treatment
Which HSCT patients are monitored for CMV? And how?
Allo-HSCT in:
D+/R+
D+/R-
D-/R+
Monitoring via quant CMV DNA weekly in all patients on prophylaxis as failure can occur 10-30%
Monitoring should be extended for at least another 3 months in high risk patient
What risk factors are associated with high risk of CMV in HSCT?
CMV mismatch
Cord blood
Patients on steroids
Ongoing GvHD
Patients with prior of CMV DNAemia
When should secondary CMV prophylaxis be considered in:
HSCT
SOT
Consider letermovir after successful treatment of CMV reactivation in patients at high risk of CMV disease, or post treatment in those who did not receive primary prophylaxis
Controversial - not routinely used
What impacts the decision for pre-emptive treatment for CMV in HSCT?
Treatment depends on CMV status, times since transplant, viral load, symptoms, level of immunosuppression
In which situations would you treat a HSCT patient as soon as CMV DNA positive during monitoring?
In other situations what would follow up be?
In cord blood transplant
In first 30 days of transplant
In D+/R-
Repeat test and assess for symptoms
What is first line for treatment of CMV in HSCT?
Second line? Third line?
Ganciclovir (IV in severe GI GvHD), valganciclovir
(add IVIG in pneumonitis)
Foscarnet or maribavir if neutropaenia or renal function impairment
Cidofovir or GCV/FOS combo
What is the treatment threshold value for CMV in HSCT?
No stated level, this is based on local protocol due to sample type and lab test
In GGC if low level <4 log and not high risk then can just monitor
If strongly positive, rapidly rising DNA or unwell then treat
Define refractory vs resistant CMV in HSCT
Refractory = VL increase >1 log after 2 weeks of appropriate treatment
Probably refractory when viral load persists but does not increase >1 log after 2 weeks
Resistant = CMV disease symptoms worsen after at least 2 weeks of appropriate treatment
How can you treat refractory CMV in HSCT?
Maribavir can be considered for resistant/refractory CMV and is linked to lower side effects (not for CNS/eye)
Foscarnet is alternative = good for CNS/eye disease but significant toxicity
Cidofovir is an option for CMV retinitis
CTLs are an option if available
Leflunomide or artesunate can be considered in patients resistant or refractory to other second-line and third line antiviral drugs
Three actions you would do if you had suspected ganciclovir resistant CMV in HSCT?
Reduce immunosuppression if possible
Switch drug class
Send for resistance testing
Options for CMV infection in HSCT in strain with low level (2-5 fold increase in IC50) ganciclovir resistance?
High dose ganciclovir (7.5-10 mg/kg BD) +/- half dose FOS
Alternatively maribavir or foscarnet
Which UL97 mutations give:
Low level ganciclovir resistance
High level ganciclovir resistance
M460I - C592G - L595W
M460V - H520Q - A594V - L595S - C603W - L595F
What is CMV T cell activity monitoring?
Sequential monitoring of IFN-?-producing CMV-specific T cells
The use of commercially-available CMV IGRA are preferable over laboratory-developed flow cytometry-based immunoassays
Main applications of these assays:
Extending or shortening the duration of prophylaxis
Withholding therapy for low level viral loads
Identify patients that may benefit from secondary prophylaxis
How is transfusion transmitted CMV reduced in D-/R- HSCT?
Transfusion of leukocyte-reduced blood products (i.e., <1 to 5�נ106 residual leukocytes per unit)
Transfusion of blood components from CMV- seronegative donors
Incubation period of CMV?
3-12 weeks
In which situations is maribavir not recocommended in CMV disease?
Neurologocal or eye disease as penetration into CNS is poor
Can maribavir be used in conjunction with ganciclovir? And why?
Cannot be used in combination with ganciclovir as MBV inhibits UL97 so impairs phosphylation of GCV
How does leflonamide work in CMV infection?
Inhibits protein kinase and interferes with CMV viral assembly
Can be used as adjunct therapy in difficult to treat HSCT patients
What are the risks for ganciclovir resistance in SOT? What is the rate of resistance?
Prolonged prophylaxis, sub therapeutic dose, T cell depleting therapy, D+/R-, lung tx
3%
In ?GCV resistance in SOT, what should you check prior to changing treatment strategy?
What is the next step?
Correct dose. Adherence. Absorption
Stop val(ganciclovir)
Switch to maribavir if suspected resistance
Switch to maribavir or foscarnet in confirmed resistance
Which genes are related to ganciclovir resistance in CMV and what % are caused by each?
UL97 viral kinase mutation - 90%
UL54 DNA pol - 10% (often evolve later)
What vaccines are in development for CMV?
Any vaccine needs to stimulate both humoral and cellular compartments
Some types in development: VLP, live attenuated, mRNA, vaccinia, chimeric
Targets are gB and pp65
Current phase 3 trial ‘CMVictory trial’ of mRNA based vaccine (Moderna). Based on 6 mRNA sequences encoding 2 CMV antigens gB and pentameric glycoprotein in lipid nanoparticles
What is the NPV of CMV PCR in BAL for CMV pneumonitis?
100% - a negative PCR pretty much excludes CMV pneumonia
