4. A 61-year-old man was admitted with fever (38 °C) and malaise 2 months after cadaveric transplantation, 000 mismatch on Tacrolimus (trough 9 ng/ml) and prednisolone 15 mg/day. CMV is positive to CMV negative recipient. Oxygen saturation was reported to be 95% on air. Quantitative CMV PCR reported 5.52 log 10 copies/ml. The patient has not responded to oral valganciclovir 900 mg twice daily.
What are the other tests to diagnose and monitor CMV?
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
What is the duration of pre-emptive treatment?
What is the relation between the viral load and the development of CMV disease?
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ASM Farhad Khan
Gancyclovir resistance is defined as failure of reduction of viral load ≥ 1 log copies /ml after 2 weeks of appropriate treatment
IV ganciclovir is the appropriate treatment in the following patients:
Symptomatic patients with viral load >10000 copies/ml
Patients with tissue invasive disease
Patients with life-threatening cases
So I will start ganciclovir intravenously in a dose of 5mg/kg/12 hours since the patient has tissue invasive disease and the high viral load
Then I will monitor PCR weekly, if no reduction of viral load ≥ 1 log copies /ml after 2 weeks of treatment I will consider ganciclovir resistance and I will switch to alternative therapy under the guidance of virology expert Alternative therapy for gancyclovir resistant CMV 1- IV Foscarent
It is given in a dose of 60mg/kg IV every 8h for 2 weeks followed by 90mg/kg/day
Its effect is comparable to IV gancyclovir
Associated with renal and GIT toxcicity and electrolyte imbalance and seizures, genital ulcers and infusion related symptoms, on the other hand neutropenia is less common with Foscarent than with gancyclovir
2- Combination therapy with reduced doses of ganciclovir and foscarnet
The regimen include the use of half the dose of IV gancyclovir (5mg/kg IV q24h) and 2/3 the dose of foscarnet (125mg/kg IV q24h)
Associated with comparable efficacy and less side effects
3- Cidofovir
Effective
Given IV twice weekly
Associated with high incidence of nephrotoxicity (50% of cases), myelosuppression and ocular disease( iritis, uveitis, and vitreous hypotonicity).
4- Leflunamide
It has immunosuppressive and antiviral activity at the same time, so it may provide the balance between treating virus and avoid reduction of immunosuppression
It is given in a loading dose then maintenance dose
Persist in the blood for very long time after stopping the medication (up to 2 years)
Side effects includes, hepatitis, myelosupression, hypertension, GI side effects, alopecia and skin rash
What are the other tests to diagnose and monitor CMV?
The main tool in diagnosis of CMV infection or disease is PCR with sensitivity 100% in D+/R- and 75% in D+/R+ transplant recipients.
Occasionally PCR is negative in tissue invasive disease and the only way for diagnosis is tissue biopsy and histopathological examination,
In CMV colitis around 20% of cases has negative PCR and diagnosis is settled by colonoscopy and biopsy
In CMV pneumonitis 30% of cases has negative PCR and the main diagnosis is by BAL
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)? Antiviral therapy is indicated in the following asymptomatic patients:
Seronegative recipient (high risk) with PCR > 1000 copies /ml
Sero positive recipient (low risk) with PCR > 1000 copies and during follow up there is rising t
Any transplant recipients whatever the serostatus of the recipient if the PCR is > 5000 copies/ml
On the other hand, treat any patient with PCR >35 copies/ml if symptomatic
Reduction of immunosuppression is indicated in all patients with detectable viral load in the form of reduction of the dose (by 50%) or stopping the antimetabolite (in severe and non-responding disease) and keeping CNI at lower trough then resume lower dose of antimetabolite only in high risk patients for rejection after PCR is negative for 2 successive samples 1 weeks apart with close follow up of PCR weekly for 1 month after starting low dose antimetabolite
What is the duration of pre-emptive treatment?
PCR should be done weekly once antiviral therapy started.
The drug is given for a minimum of 3 weeks (usual duration of therapy 3-4 weeks)
Stop treatment once there are 2 successive negative PCR readings (< 35 copies/ml) 1 week apart
What is the relation between the viral load and the development of CMV disease?
No good correlation exists between viral load and tissue invasive disease
Some patients with very high viral load and are asymptomatic
On the other hand, around 20% of patients with CMV colitis and 30% of patients with CMV pneumonitis has negative PCR and diagnosis is settled by colonoscopy and biopsy and BAL, respectively.
What is dose of prophylaxes and dose of treatment? Prophylaxes dose;
Valganciclovir 900mg for 100 days, also literature says 200 days better.
Treatment dose;
Ganciclovir 5mg/kg/day for 14 to 21 days. Then again give prophylaxes for next 100 days.
If ganciclovir not effective then can switch to seconf line agents.
Foscarnet 40-60ng/kg/ day for two to three weeks.
Cidofovir 5mg/kg/week for two weeks then biweekly.
IVIG. What is your management strategy?
This is a case of symptomatic CMV infection.
Will advise admission,
General management,
Like IV fluid,
Antipyretics,
Multivitamins,
Will treat CMV infection with ganciclovir 5 mg/mg/day.
Prophylactic antibiotic to prevent super-infection,
Immunosuppression dose reduction. What is the duration of pre-emptive treatment?
Initially for 21 days of treatment for two consecutive negative PCR then three months of prophylaxes. What is the relation between the viral load and the development of CMV disease?
There is strong association, as the high viral load can be a risk of disseminated and invasive disease. Which can cause immunomodulation and a cause of rejection. References;
1. Rubin RH. The indirect effects of cytomegalovirus infection on the outcome of organ transplantation, JAMA, 1989, vol. 261 (pg. 3607-9)
2. www. BTS. uk CMV in transplant patients.
3. 2Fishman JA, Rubin RH. Infection in organ-transplant recipients, N Engl J Med, 1998, vol. 338 (pg. 1741-51)
4. 3Snydman DR. Infection in solid organ transplantation, Transpl Infect Dis, 1999, vol. 1 (pg. 21-8).
Treatment for CMV disease, not responding to oral Valgancyclovir à ? drug resistant strain
– Tests for genotype analysis – UL97, UL54
– Inj CYMEVINE (Gancyclovir) 10mg IV bid (adjusted for GFR) x 2-3 weeks
– Weekly monitoring CMV-DNA by QNAT / qPCR
– Symptomatic treatment
–
– If no improvement with Inj Gancyclovir à Inj Foscarnet or Cidofovir may be tried.
– Reduce IS – MMF withhold and Tac dose adjustment
What are the other tests to diagnose and monitor CMV?
· Tests for genotype analysis – UL97, UL54
· Weekly monitoring CMV-DNA by QNAT / qPCR
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
0.5 Log 10 copies/ml
What is the duration of pre-emptive treatment?
3months at least
What is the relation between the viral load and the development of CMV disease?
Active viral proliferation as well as High CMV- viral load is associated with high risk of disseminated disease, multi-organs involvement, risk of rejection, and thus leading to higher mortality.
Prof. Ahmed Halawa Tutor Dear All Remember that the treatment dose and duration differ from the CMV prophylaxis. Please summarise in a few words the dose and the duration of CMV treatment versus the prophylaxis CMV Treatment: Valganciclovir 900 mg PO twice daily according to the eGFR or IV gancilovir 5 mg/kg twice daily in cases of malabsorption for a minimum of two to three weeks and continued until CMV PCR is undetectable in the blood on at least two consecutive occasions CMV Prophylaxis: Valganciclovir 900 mg PO once daily according to eGFR, for at least 100 to 200 days
The viral load is significant and indicates CMV infection. After excluding other concurrent infections. By definition, resistant CMV infection is the growing viral load or persistence of symptoms, despite the treatment with ganciclovir or its pro-drug Valganciclovir for 2-4 weeks. Hence, I would recommend treatment with foscarnet or cidofovir for a duration of 3 weeks. The other test utilized to diagnose CMV infection and monitor progression of disease is pp69 antigen essay.
Pre-emptive therapy has to be commenced when viral load is 1000- 5000 IU/ml in the absence of symptoms for a duration of 3 weeks.
It was found that viral load is a sensitive predictor of development of CMV disease with a positive trend correlated with CMV viral load.
Treatment is usually consistent of intra venous gancyclovir in a dose of 2.5-5 mg/kg/day for 3 weeks. however, in mild cases Valgancyclovir in a dose of 950 mg bid for 3 weeks can be considered.
reference:
1] www. BTS. uk CMV in transplant patients.
Cytomegalovirus (CMV) infection can have both direct and indirect effects after solid-organ transplantation, with a significant impact on transplant outcomes. Prevention strategies decrease the risk of CMV disease, although CMV still occurs in up to 50% of high-risk patients. Ganciclovir (GCV) and valganciclovir (VGCV) are the main drugs currently used for preventing and treating CMV. Emerging data suggest that letermovir is as effective as VGCV with fewer hematological side effects. Refractory and resistant CMV also still occur in solid-organ-transplant patients. Maribavir has been shown to be effective and have less toxicity in the treatment of refractory and resistant CMV. In this review paper, we discuss prevention strategies, refractory and resistant CMV, and drug-related side effects and their impact, as well as optimal use of novel anti-CMV therapies. https://link.springer.com/article/10.1007/s40121-022-00746-1
· What is your management strategy?
CMV post-transplant, within 2months, in high risk patient, supposed to be on prophylaxis, not responding to adequate dose of Valganciclovir should raise the suspicion of valganciclovir resistance. If no response for treatment for 2weeks, and no issue of mal absorption, like diarrhea or repeated vomiting, where we can change to IV ganciclovir.
To confirm resistance we need to send for UL97, UL 54 mutations.
Otherwise, we need to counsel patient for alternative treatment and their risk of nephrotoxicity. Cidofovir and foscarnet
· What are the other tests to diagnose and monitor CMV?
Beside CMV PCR viral load we can do quantative NAT, PP65 antigen and tissue biopsy.
For monitoring beside symptoms, leucocyte count, liver function for decease effect and drug side effect.
· Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
Most centers use log3-4 to start treatment. In our center we don’t apply preemptive strategy.
· What is the duration of pre-emptive treatment?
21 days of treatment or 2 consecutive negative PCR. Then 4 weeks of prof CMV prophylactic dose.
· What is the relation between the viral load and the development of CMV disease?
The highest the viral load, the highest the chance of development of CMV disease.
References:
UK CMV infection prophylaxis and treatment.
Local practice guidelines for CMV infection.
Q1: this case is a resistant case of ganciclovir. Therefore, genotyping for UL97 or UL 54 gene should be done and an increasing dose of ganciclovir or alternative treatment like mirabavir should be started. Q2: 1. CMV P65 antigen test: used for surveillance of CMV and if became positive, pre-emptive therapy was needed. It is replaced by CMV PCR. 2. Genotype tests for UL 97 and UL54 3. In tissue-invasive disease, histologic evaluation and inclusion bodies with owls’ eye appearance can be used.
Q3: there is no standard reference and it may be different among different laboratories. Hence, there is no consensus about the cut-off to start pre-emptive treatment sometimes more than 2000 copies in whole blood are considered. Q4: the duration for pre-emptive therapy is at least 21 days or until two consecutive CMV PCR (one week apart) became negative. Q5: higher CMV viral load was associated with higher mortality and more severe CMV disease.
A 61-year-old man was admitted with fever (38 °C) and malaise 2 months after cadaveric transplantation, 000 mismatch on Tacrolimus (trough 9 ng/ml) and prednisolone 15 mg/day. CMV is positive to CMV negative recipient. Oxygen saturation was reported to be 95% on air. Quantitative CMV PCR reported 5.52 log 10 copies/ml. The patient has not responded to oral Valganciclovir 900 mg twice daily.
So the patient had resistance to Valganciclovir
Risk factors for of resistance include: old age, D+/R-, higher viral load, intense immunosuppression, viral mutation (UL97 mutation) .
management plane
– viral gen typing to detect mutation.
-start IV Valganciclovir. -stop MMF. -Reduction of of CNI , keep tac trough level 5ng/ml. We may stop it stopped in life-threatening CMV disease. -Monitoring kidney function for fear of rejection due do IS reduction and concurrent TCMR. – CMVIG can be used with resistance. -Foscarnet can be used for 3 weeks with monitoring of kidney function -Cidofovir approved by FDA . continue until improvement of symptoms and negative PCR. What are the other tests to diagnose and monitor CMV? – diagnosing CMV infection is confirmed using PCR to detect CMV DNA.
– finding of CMV p65 antigen in circulating polymorphonuclear lymphocytes is another test used in certain centers to both evaluate treatment response and serve as a starting point for treatment .
– using viral cultures is uncommon for CMV diagnosis
-The most common serologic tests are detection of CMV antibodies (IgM and IgG antibodies) by ELISA.
A positive CMV IgG indicates previous infection, while CMV IgM indicates recent infection IgM, it can persist for months after primary infection and it’s also positive in reactivated infections. – histopathologic testing of CMV disease, CMV nephritis is characterized by biopsy-proven cytopathic changes which are typically focal, detected in tubular epithelium or endothelial cells characteristic inclusion bodies(Owl’s eye appearance).
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)? Preemptive therapy
quantitative measuring of CMV DNA in plasma to detect viremia once or twice a week before the occurrence of symptomatic infection.
the exact cutoff of plasma CMV level to start treatment is not known and the decision of treatment is individual according to degree and duration of immunosuppression
it was suggested to start pre-emptive ttt in transplant recipients with the PCR is > 5000 copies/m regardless the serostatus of the recipient.
What is the duration of pre-emptive treatment?
-Intravenous ganciclovir at a dose 5 mg/kg /12 h is used for preemptive treatment in viral load (>50,000 copies of CMV DNA in 1 ml of plasma), continue for 3 weeks
viremia is checked after 7–10 days of preemptive treatment, and monitored every7–10days, Preemptive medication should be continued until two
PCR CMV DNA tests yield negative findings in a span of 7days .
-Guiding of preemptive therapy can be also guided by measuring of CMV-specific T lymphocytes.
What is the relation between the viral load and the development of CMV disease? increased viral is associated with more increase in disease incidence
References: Željka VH, Nika K. Viral Infections after Kidney Transplantation: CMV and BK [Internet]. Perioperative Care for Organ Transplant Recipient. Intech Open; 2019.
· What is your management strategy?This patient should undergo reassessment of:
– Dose adequacy
– Adherence to treatment
– Use of drugs that may cause interaction: at this time, evaluate the decrease in immunosuppression or switch to mTOR use;
– Study of antiviral resistance UL97 and UL54 gene mutations
If the reassessments are positive, Valganciclovir should be suspended and start Intravenous Foscarnet for at least 3 weeksIf the reassessments are positive, Valganciclovir should be suspended and start Intravenous Foscarnet for at least 3 weeks. · What are the other tests to diagnose and monitor CMV? Other tests will depend on where the CMV is being investigated. For example, in cases of diarrhea, where a biopsy is performed with histopathological diagnosis aided by staining. Or in case of ocular CMV the diagnosis can be clinical and serological. Monitoring tests are all quantitative nucleic acid testing methods (QNAT), these quantify the amount of viral nucleic acid (DNAemia or viral load) and there are some types of assays developed. · Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?In my hospital preemptive therapy starts with Log = 4.0 · What is the duration of pre-emptive treatment? Preemptive treatment goal is 21 days (control being performed at 14 days and repeated every 7 days), when in this time he should reach the goals of undetectable viral load. What is the relation between the viral load and the development of CMV disease?
The rate of cytomegalovirus (CMV) viral load increase and peak viral loads are associated with CMV disease in kidney and liver transplant recipients, but relationships to disease severity or mortality have not been shown.
REFERENCES:
– McBride JM, Sheinson D, Jiang J, Lewin-Koh N, Werner BG, Chow JKL, Wu X, Tavel JA, Snydman DR. Correlation of Cytomegalovirus (CMV) Disease Severity and Mortality With CMV Viral Burden in CMV-Seropositive Donor and CMV-Seronegative Solid Organ Transplant Recipients. Open Forum Infect Dis. 2019 Jan 14;6(2):ofz003. doi: 10.1093/ofid/ofz003. PMID: 30775403; PMCID: PMC6366655.
– UK Guideline on Prevention and Management of cytomegalovirus (CMV) infection and disease following solid organ transplantation
Management strategy:
The patient is a recent post transplant patient (2 months ago)..Recipient is a cadaver kidney recipient from CMV Positive Donor. Recipient is CMV negative…SO this is a high risk of CMV infection post transplant… There was full match with no mismatch and the patient is on dual immunosuppression. The patient is not on antimetabolite…
patient needs full history to find out if there is other organ involvement due to CMV like fever, cough, diarrhea. History of any anti rejection treatment if any…The details of CMV prophylaxsis given is also needed…Baseline laboratory work up including CBC, LFT, RFT are needed…CMV DNA viral load has been done and it is 5.52 log copies/ml.. Although the patient is asymptomatic due to very high viral load, patient needs to started on oral Valganciclovir 900mg twice a day…the dose should be modified as per the creatinine clearance…The minimun duration of treatment is 2 weeks after which we should obtain weekly CMV DNA viral load until 2 negative viral load reports are achieved…The patient did not respond to oral valganciclovir. This maybe due to ganciclovir resistance due to mutation in UL97 and UL54 gene…The patient could also be non complaint to oral valganciclovir…There could have been marrow suppression needing to reduce the dose in between…There could have been also poor oral absorption….It is necessary to remove the antimetabolite and reduce the dose of Tac…
Patient needs testing for genotype testing to detect mutations in CMV….If there is UL97 or UL54 mutations we need switch to alternative agents…IV foscarnet 90mg/kg every 12 hours for 3 weeks + CMV immunoglobulin..IV cidofovir 1mg/kg IV 3 times a week is alternative… IV cidofovir (1mg/kg three times a week) is effective in UL97 mutation but will not work for UL54 mutation…Oral Maribavir 400mg twice a day for 8 weeks is an alternative and it will work for both UL97 and UL 54 mutation…Post treament and viral eradiction routine CMV DNA PCR monitoring is indicated monthly for 6 months…Patient should also be counselled for other infections like PCP and TB which can flare up and also be counselled about rejection…
Other diagnostic tests for CMV:
CMV NAT – it is a rapid diagnostic test in transplant patients…
CMV pp65Ag – the surface antigen is tested by this PCR testing and it is helpful in diagnosis..It can also be used to monitor clearance after treatment…
CMV viral culture – Not recommended due to poor utility…
CMV IGM – not reliable in transplant patient due to poor antibody response
Assume this patient is asymptomatic, is there any cut off level to treat asymptomatic CMV viremia (pre emptive therapy): – No consensus…CMV DNA viral load ranges from 1500 to 4000 is used in few studies…Lower threshold for D+/R- recipient are used…Some units use double log fold increase in CMV as a criteria…
Duration of Preemptive treatment:
Duration of the treatment will be based on monitoring of CMV DNA viral load until 2 weeks report are consecutively negative..
Relation between the viral load and development of CMV disease?
Peak CMV viral load has been proven to be an independent significant predictor of CMV disease….But in CMV GI infection, viral load maybe negative and biopsy of the colon may pick up infection and this warrants therapy as this is invasive CMV disease…
Management strategy
· Reduction of immunosuppression is the corner stone of TTT (STOP MMF and target lower tac level )
· Patient not responding to oral ganciclovir we need to switch to IV ganciclovir 5 mg /kg/ bid 2-3 weeks until we have 2 negative PCR·
· Consider resistant to valgan cyclovir if persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration (2-4 weeks) of Ganciclovir or Valganciclovir
· if resistant is suspected
1-Confirm that dosing is adequate
2-Consider adherence to treatment plan and absorption
3-Offer testing for Human CMV (HCMV) antiviral resistance UL97 and UL54 gene mutations
4-Use either whole blood or plasma
· If there is evidence of ganciclovir resistance: Stop Valganciclovir (or Ganciclovir) / start Intravenous Foscarnet for at least 3 weeks After Seeking specialist virology advice Thresholds for treatment
1. Consider reduction in immunosuppression in R+ patients with a viral load of fewer than 3 logs 10.
2. Consider treatment with valganciclovir when the viral load exceeds 3 logs 10 if rapidly rising titre in high-risk patients. 3. Treatment with valganciclovir or IV ganciclovir is mandatorywhen the viral load exceeds 4 logs 10. Treatment duration in preemptive therapy
Monitor to guide preemptive therapy monthly for 3 month
Treatment for 2-3weeks CMV disease and viral load
CMV disease – (histopathological evidence of CMV, CMV retinitis diagnosed by an ophthalmologist, or CMV in the CSF indicative of CNS disease) irrespective of viral load
Start with a thorough history and clinical examination, focusing on medication adherence. Genotypic tests detect the presence of resistance-associated mutations. Reduction of immunosuppression (discontinue antimetabolites and modify the dose of tacrolimus while monitoring graft function to prevent rejection)
For severe cases, it is recommended to administer IV ganciclovir rather than oral valganciclovir to patients with tissue-invasive disease, rapidly increasing viral loads, or moderate to severe gastrointestinal symptoms.
Ganciclovir is administered IV with a 12-hour interval at 5 mg/kg, adjusting the dosage based on eGFR.
For mild to moderate cases:
Oral valganciclovir is advised over IV ganciclovir for patients with mild to severe CMV disease who are predicted to have good oral drug absorption.
Valganciclovir is given PO twice a day at a 900-mg dose, with the dosage adjusted for eGFR.
The severity of the infection and the patient’s response to treatment determine how long the treatment process will last.
Treatment is continued until both symptoms and CMV viremia disappear (which includes laboratory resolution of CMV as undetectable or lower than the limits of a sensitive assay in two quantitative PCR tests drawn one week apart).
– The average period of treatment is 21 days, but it may require a longer duration, especially in patients with tissue-invasive disease.
Refractory CMV disease, which persists or worsens despite antivirals and immunosuppression, may be caused by ganciclovir resistance.
– It affects 1–2% of CMV D+/R- kidney transplant recipients.
– Genotype testing should be done in cases where ganciclovir-resistant diseases is suspected in order to find particular resistance mutations
Treatments options for CMV resistant disease
Maribavir, foscarnet, and cidofovir are antiviral treatments for patients with ganciclovir-resistant or refractory CMV.
• Maribavir is active against CMV with the UL97 and UL54 mutations. Maribavir is dosed at 400 mg orally twice daily for eight weeks.
• Foscarnet, an IV-administered pyrophosphate analog, limits viral replication. Foscarnet suppresses CMV with UL97 and UL54 mutations. Foscarnet is administered intravenously at 60 or 90 mg/kg every 8 or 12 hours, depending on eGFR.
• Cidofovir, another viral DNA polymerase inhibitor, inhibits CMV with UL97 mutations but not UL54 mutations. Intravenous cidofovir is 1 mg/kg three times a week.
• What is the relationship between viral load and CMV disease development?
• Using quantitative PCR assays, studies of solid organ transplant recipients have revealed that patients with active CMV disease have higher viral burdens than those with asymptomatic infection.
• The rate of viral burden increase can be utilized to identify patients at risk for CMV disease.
• Patients with CMV disease have a substantially higher rate of CMV load increase between the last PCR-negative sample and the first PCR-positive sample than patients without CMV disease.
· What is your management strategy?This is a case of resistant CMV . Risk factors for CMV resistance :1- Host factors :
a- Young age , induction with ATG, decrease drug bioavilabilty, absorption ,patient non compliance ,previous treatment with CMV antiviral drugs or prolonged treatment courses.
2- Viral related factor.
Genetic mutation :UL97 mutation causes resistance to gancycovir while UL54 mutation causes multidrug resistance.Recurrent CMV infection and delayed viral clearance .
Management:
1- Correct the reversablle risk factors as patient compliance . switch to IV gancyclovir in cases of malabsorption .
2-Genetic analysis to diagnose genetic mutation .
3- Treatment of resistant CMV infection include trial of
1- Foscarnet for at least 3 weeks .
2- Leflunamde :has immunmodulatory and antiviral effects
3- Cidofovir
4- Stop Valganciclovir and gancyclovir ,in patients with evidence of ganciclovir resistance.
5- Decrease the dose of IS , stop antiproliferative drugs.monitoring of graft function
· What are the other tests to diagnose and monitor CMV?1- CMV serology : but not accurate in transplantation patients2- CMV quantitative nucleic acid test on whole blood or plasma sample to assess viral load .3- Tissue biopsy and histological examination fromaffected areas· Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?The cut of level of viraemia recommended as a threshold to start pre-emptive therapy is not well established and vary according to the type of assay used and local protocols. Some centers start treatment at 1000 copies/ml while others consider treatment at 4000 copies/ml.· What is the duration of pre-emptive treatment?A minimum of 2 weeks of treatment with full therapeutic dose of valgancyclovir (900 mg/12 h) and till complete resolution of viremia . After resolution, stop antiviral and continue weekly surveillance. What is the relation between the viral load and the development of CMV disease?There is a Linear relationship between viral load and the development of CMV disease where higher viral load increase risk of CMV disease development
Ref
1-Chemaly RF, Chou S, Einsele H, Griffiths P, Avery R, Razonable RR, Mullane KM, Kotton C, Lundgren J, Komatsu TE, Lischka P, Josephson F, Douglas CM, Umeh O, Miller V, Ljungman P; Resistant Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Resistant and Refractory Cytomegalovirus Infection 2-UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS, 2022. 3-The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation
· What is your management strategy?This is a case of resistant CMV . Risk factors for CMV resistance :1- Host factors :
a- Young age , induction with ATG, decrease drug bioavilabilty, absorption ,patient non compliance ,previous treatment with CMV antiviral drugs or prolonged treatment courses.
2- Viral related factor.
Genetic mutation :UL97 mutation causes resistance to gancycovir while UL54 mutation causes multidrug resistance.Recurrent CMV infection and delayed viral clearance .
Management:
1- Correct the reversablle risk factors as patient compliance . switch to IV gancyclovir in cases of malabsorption .
2-Genetic analysis to diagnose genetic mutation .
3- Treatment of resistant CMV infection include trial of
1- Foscarnet for at least 3 weeks .
2- Leflunamde :has immunmodulatory and antiviral effects
3- Cidofovir
4- Stop Valganciclovir and gancyclovir ,in patients with evidence of ganciclovir resistance.
5- Decrease the dose of IS , stop antiproliferative drugs.monitoring of graft function
· What are the other tests to diagnose and monitor CMV?1- CMV serology : but not accurate in transplantation patients2- CMV quantitative nucleic acid test on whole blood or plasma sample to assess viral load .3- Tissue biopsy and histological examination fromaffected areas· Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?The cut of level of viraemia recommended as a threshold to start pre-emptive therapy is not well established and vary according to the type of assay used and local protocols. Some centers start treatment at 1000 copies/ml while others consider treatment at 4000 copies/ml.· What is the duration of pre-emptive treatment?A minimum of 2 weeks of treatment with full therapeutic dose of valgancyclovir (900 mg/12 h) and till complete resolution of viremia . After resolution, stop antiviral and continue weekly surveillance. What is the relation between the viral load and the development of CMV disease?There is a Linear relationship between viral load and the development of CMV disease where higher viral load increase risk of CMV disease development
Ref
1-Chemaly RF, Chou S, Einsele H, Griffiths P, Avery R, Razonable RR, Mullane KM, Kotton C, Lundgren J, Komatsu TE, Lischka P, Josephson F, Douglas CM, Umeh O, Miller V, Ljungman P; Resistant Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Resistant and Refractory Cytomegalovirus Infection 2-UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS, 2022. 3-The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation
the pt has resistant CMV disease Management: –modification of IS
-Do viral genetic study
-we can use maribavir which is oral drug active against UL97 and UL54 mutations. -Cidofovir or foscarnet are alternative but have nephrotoxicity
-Monitor CMV PCR weekly
-CMV specific antibodies also can be used in resistant cases
Diagnosis of CMV: CMV PCR for samples from any secretion
Biopsy with characteristic inclusion bodies
Serology not used in diagnosis
Relationship between VL and CMV disease: The higher the viral load, the higher incidence of CMV disease
Consider resistance to Ganciclovir if:
There is a persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir
Risk factors for the acquisition of ganciclovir resistance include CMV seronegativity at transplant when receiving a seropositive organ, degree of immunosuppression, magnitude of CMV viremia, and prolonged exposure to anti-CMV medication. Seronegative recipients of seropositive organs appear to be at particular risk of both CMV infection and ganciclovir resistance.
We should to
Confirm that dosing is adequate
Consider adherence to treatment plan and absorption
Offer testing for Human CMV (HCMV) antiviral resistance UL97 and UL54 gene mutations
Use either whole blood or plasma
Seek specialist virology advice before commencing treatment with Foscarnet
Stop Valganciclovir (or Ganciclovir) and Offer Intravenous Foscarnet for at least 3 weeks
Foscarnet The primary alternative to ganciclovir for the treatment of CMV viremia and disease is foscarnet.
Cidofovir was approved by the FDA in 1996 for the treatment of cytomegalovirus infection.
Newer agents such as Letermovir and Maribavir may have a role in prevention of CMV disease.
What are the other tests to diagnose and monitor CMV?
Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load
Histopathology
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
A viral load of 3983 IU/ml (2600 copies/ml) was established as the optimal cut-off for initiating preemptive therapy in a cohort of 141 patients with 982 tests and validated in a cohort of 252 recipients with a total of 2022 test.
Due to the lack of consensus and specific guidelines on CMV infection in patients with solid neoplasms, the positivity cut-off points and significance of CMV viral load (VL) in these patients may vary and differ between different centres and publications. Significant CMV VL was considered to be above >1,000 copies/ml in some studies. However, more re- cent evidence places the potentially significant viremia above 4,000 copies/ml
The absolute levels of viraemia that are recommended as a threshold to start pre-emptive therapy will depend upon the assay used. Units should establish the clinical significance of their local assay.
What is the duration of pre-emptive treatment?
Once DNAemia is at a positive threshold, for asymptomatic patients, we recommend VGCV (treatment dose) be started [strong, high] and continued until resolution of DNAemia (as per the Diagnostic section), with a minimum of 2 weeks of treatment. After resolution, discontinue antiviral and continue weekly surveillance. Intravenous GCV is a less preferred option unless concerns about absorption exist.
What is the relation between the viral load and the development of CMV disease?
Linear relationship…higher viral load increase risk of cmv disease development
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS, 2022.
The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation
Camille N. Kotton, MD, 1 Deepali Kumar, MD, 2 Angela M. Caliendo, MD, PhD, 3 Shirish Huprikar, MD,4 Sunwen Chou, MD, 5 Lara Danziger-Isakov, MD, MPH, 6 and Atul Humar, MD7 on behalf of the The Transplantation Society International CMV Consensus Group
This patient has the CMV syndrome having resistant to valganciclovir and ganciclovir. Management:
Perform viral genetic testing; the 2 genes commonly involved are UL97 and UL54
Switching to maribavir; It is an oral drug that inhibits UL97 phosphotransferase and is active against CMV with UL97 and UL54 mutations.
Cidofovir or foscarnet are alternatives with the disadvantages of nephrotoxicity and bone marrow suppression.
The CMV viral load needs to be monitored weekly to ensure that the therapy is working.
CMV specific Immunoglobulin for patients who are not responding to the alternative antivirals.
Reduction/ modification of immunosuppression; stop the antimetabolite and to reduce Tacrolimus to the lower therapeutic trough level (4-6ng/dl).
Diagnosis of CMV:
The quantitative CMV PCR Is the mostly used to diagnose CMV viremia, this either from the serum or a body fluid (ie; BAL)
Histological diagnosis: Tissue biopsy of the affected organ can pick the CMV inclusion bodies (Owle’s eye inclusion body)
CMV serology, antibody testing are not used to make a diagnosis of CMV in transplant patients
Pre-emptive Therapy:
The duration of pre-emptive therapy is 3 weeks with close monitoring of viral load.
Relationship between VL and CMV disease:
Most studies have identified that a higher viral load increased the risk of CMV disease; a linear relationship.
References: · UK Guideline on Prevention and Management of Cytomegalovirus (CMV) Infection and Disease following Solid Organ Transplantation. BTS. 2022 · Kotton CN, Kumar D, Caliendo AM et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-Organ Transplantation. Transplantation 2018; 102:900
4. A 61-year-old man was admitted with fever (38 °C) and malaise 2 months after cadaveric transplantation, 000 mismatch on Tacrolimus (trough 9 ng/ml) and prednisolone 15 mg/day. CMV is positive to CMV negative recipient. Oxygen saturation was reported to be 95% on air. Quantitative CMV PCR reported 5.52 log 10 copies/ml. The patient has not responded to oral valganciclovir 900 mg twice daily.
Issues/ concerns:
– 61yo male, DDKTx 2 months ago, 000 mismatch
– presents with malaise, fever (38°C), SPO₂ 95% (RA)
– medications: tacrolimus trough 9ng/mL, prednisone 15mg OD
– risk factor assessment: CMV serostatus, use of lymphocyte depleting agents (ATG), use of MPA, lymphopenia, use of belatacept, hypogammaglobulinemia, multi-organ transplantation
– CMV reactivation is associated with increased risk of graft rejection, mortality and graft loss
– CMV infection causes both direct and indirect effects on kidney transplant recipients: (4)
Direct effects are cytopathic effects on kidney graft cells leading to nephropathy and graft loss as well as morbidity and mortality from severe CMV disease
Indirect effects include upregulation of HLA Ag and adhesion molecules which can promote acute rejection, graft loss, death, CV disease, PTLD, bacterial, fungal and viral infections
Treatment
– asymptomatic CMV viremia:
hold the antimetabolite
for patients with low viral loads, monitor the CMV viral load weekly to determine whether antiviral therapy is needed
for patients with higher viral loads or other risk factors for severe disease, initiate antiviral therapy
– symptomatic CMV disease i.e., CMV syndrome or tissue-invasive disease:
hold antimetabolite
initiate on antiviral therapy depending on the severity of the clinical symptoms and the level of viremia
give IV ganciclovir 5mg/kg BD rather than oral valganciclovir in patients with tissue-invasive disease (e.g., meningoencephalitis, pneumonitis), moderate to severe GI disease, high or rapidly rising viral loads
in patients with mild or moderate CMV disease, with good absorption of oral medications, give oral valganciclovir 900mg BD (adjusted for kidney function) rather than IV ganciclovir
continue with the antiviral agent until there is complete resolution of the clinical signs and symptoms of CMV disease resolve completely and there is no evidence of CMV viremia in 2 blood PCR tests done at least one week apart
duration of treatment is usually 21 days but can be longer especially for patients with tissue invasive disease
– refractory or drug-resistant CMV:
viral load fails to decline while on antiviral therapy necessitating testing for ganciclovir resistance
choice of antiviral therapy depends on the specific mutation detected and disease severity
What are the other tests to diagnose and monitor CMV? (5, 6)
– QuantiFERON-CMV and ELISPOT are immune monitoring assays that measure CMV-specific T cell responses
– they are useful adjuncts in identifying patients at increased risk of CMV disease
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)? (7-9)
– given the variability among diagnostic specimens and testing modalities, viral load thresholds guiding on the initiation of preemptive therapy have not been standardized across institutions
– pre-emptive therapy involves monitoring patients for CMV by doing regular interval (usually weekly) blood quantitative CMV PCR for 3months post-transplant
– the aim is to detect a rise in the viral load early and initiate antiviral therapy when a threshold viral load is reached before the symptoms appear
– the ideal viral load threshold to initiate antiviral treatment is not yet clearly defined but, in most cases, when it is above 10,000 copies/ml the patient is considered to have CMV infection and antiviral therapy is usually instituted (10)
– there are 3 preventive strategies i.e.,
universal prophylaxis (high risk):
– entails administration of antiviral medication (valganciclovir is commonly used) to all transplant recipients or high-risk patients starting within 10 days after transplant for 3-6 months (3months for CMV R+ recipients, 6 months for CMV D+/R- recipients)
– this strategy is associated with late-onset CMV disease which is CMV disease occurring after discontinuation of prophylaxis compared to preemptive therapy
– due to its efficacy and high oral bioavailability, oral valganciclovir is preferred to oral and IV ganciclovir and valacyclovir
– optimal duration of prophylaxis remains unclear
– shorter course of therapy (100days) are associated with increased risk of late-onset CMV disease
– longer duration of therapy (200days) decreases rate of active CMV infection and disease ini CMV D+/ R- patients
– hematologic suppression in particular leucopenia is the most significant and common side effect associated with valganciclovir and its parent compound, ganciclovir
– avoid dose valganciclovir dose reduction when leucopenia occurs since this may promote resistance
– GCSF should be considered before discontinuing valganciclovir
preemptive therapy (low risk):
– ideal for patients at low risk for CMV infection i.e., CMV D-/ R-
– involves monitoring patients for CMV by doing regular interval (usually weekly) blood quantitative CMV PCR for 3months post-transplant
– the aim is to detect a rise in the viral load early and initiate antiviral therapy when a threshold viral load is reached before the symptoms appear
– if active CMV infection is detected, give treatment doses of valganciclovir (900mg BD) or IV ganciclovir (5mg/kg IV BD) for a minimum of 21 days and until CMV PCR is negative (adjust the doses according to the kidney function)
– oral valganciclovir is initiated when viral replication exceeds a certain threshold (usually above 10,000 copies/ml)
– acyclovir or valacyclovir is given as HSV prophylaxis for 3 months post-transplant
surveillance after prophylaxis/ hybrid approach:
– combines these two approaches; it is not commonly used
– in this approach, the highest-risk patients are given prophylactic anti-CMV therapy post-transplant then thereafter the patients are monitored regularly for active CMV infection using blood CMV PCR
– if viral replication is detected, treatment doses of anti-CMV therapy are given
What is the duration of pre-emptive treatment? (7-9)
– pre-emptive therapy involves monitoring patients for CMV by doing regular interval (usually weekly) blood quantitative CMV PCR for 3months post-transplant
– the aim is to detect a rise in the viral load early and initiate antiviral therapy when a threshold viral load is reached before the symptoms appear
– the ideal viral load threshold to initiate antiviral treatment is not yet clearly defined but, in most cases, when it is above 10,000 copies/ml the patient is considered to have CMV infection and antiviral therapy is usually instituted (10)
– if active CMV infection is detected, give treatment doses of valganciclovir (900mg BD) or IV ganciclovir (5mg/kg IV BD) for a minimum of 21 days and until CMV PCR is negative (adjust the doses according to the kidney function)
What is the relation between the viral load and the development of CMV disease? (11)
– lower CMV viral load is associated with shorter viremia episodes, decreased risk for viremia lasting more than 30 days, shorter duration of treatment and infection of CMV following HSCT
References
1. Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clinical transplantation. 2019 Sep;33(9):e13512. PubMed PMID: 30817026. Epub 2019/03/01. eng.
2. Kumar D, Chernenko S, Moussa G, Cobos I, Manuel O, Preiksaitis J, et al. Cell-mediated immunity to predict cytomegalovirus disease in high-risk solid organ transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 May;9(5):1214-22. PubMed PMID: 19422346. Epub 2009/05/09. eng.
3. Corona-Nakamura AL, Monteón-Ramos FJ, Troyo-Sanromán R, Arias-Merino MJ, Anaya-Prado R. Incidence and predictive factors for cytomegalovirus infection in renal transplant recipients. Transplantation proceedings. 2009 Jul-Aug;41(6):2412-5. PubMed PMID: 19715936. Epub 2009/09/01. eng.
4. Griffiths P. The direct and indirect consequences of cytomegalovirus infection and potential benefits of vaccination. Antiviral research. 2020 Apr;176:104732. PubMed PMID: 32081353. Epub 2020/02/23. eng.
5. Fernández-Ruiz M, Rodríguez-Goncer I, Parra P, Ruiz-Merlo T, Corbella L, López-Medrano F, et al. Monitoring of CMV-specific cell-mediated immunity with a commercial ELISA-based interferon-γ release assay in kidney transplant recipients treated with antithymocyte globulin. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2020 Aug;20(8):2070-80. PubMed PMID: 31991045. Epub 2020/01/29. eng.
6. Barabas S, Spindler T, Kiener R, Tonar C, Lugner T, Batzilla J, et al. An optimized IFN-γ ELISpot assay for the sensitive and standardized monitoring of CMV protein-reactive effector cells of cell-mediated immunity. BMC immunology. 2017 Mar 7;18(1):14. PubMed PMID: 28270111. Pubmed Central PMCID: PMC5339961. Epub 2017/03/09. eng.
7. Owers DS, Webster AC, Strippoli GF, Kable K, Hodson EM. Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. The Cochrane database of systematic reviews. 2013 Feb 28;2013(2):CD005133. PubMed PMID: 23450558. Pubmed Central PMCID: PMC6823220. Epub 2013/03/02. eng.
8. Hasegawa J, Hatakeyama S, Wakai S, Omoto K, Okumi M, Tanabe K, et al. Preemptive anti-cytomegalovirus therapy in high-risk (donor-positive, recipient-negative cytomegalovirus serostatus) kidney transplant recipients. International Journal of Infectious Diseases. 2017 2017/12/01/;65:50-6.
9. Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-31. PubMed PMID: 29596116. Epub 2018/03/30. eng.
10. Eshraghi H, Hekmat R. Which CMV viral load threshold should be defined as CMV infection in kidney transplant patients? Transplantation proceedings. 2015 May;47(4):1136-9. PubMed PMID: 26036538. Epub 2015/06/04. eng.
11. Tan SK, Waggoner JJ, Pinsky BA. Cytomegalovirus load at treatment initiation is predictive of time to resolution of viremia and duration of therapy in hematopoietic cell transplant recipients. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2015 Aug;69:179-83. PubMed PMID: 26209403. Pubmed Central PMCID: PMC4828337. Epub 2015/07/26. eng.
65year old 2 months after transplant HLA 000 mismatch CMV D+/R-, presents with fever and malaise, on 2 IS, on valganciclovir 900mg bd with no response
What is your management strategy?
This patient has probable refractory disease evidence by persistent virus despite appropriately dosed antiviral therapy.
Thus in this patient it is crucial to look for ganciclovir resistant CMV, test for UL97 and UL 54 mutations. As awaits mutation results patient should be switched to cidofovir.
UL 97 is most common mutation will occur in both ganciclovir and valganciclovir though cidofovir doesn’t require phosphorylation hence will not be affected by this mutation. However cidofovir is nephrotoxic and should be used cautiously.
Alternative to cidofovir is maribavir which is less nephrotoxic than cidofovir and doesn’t cause bone marrow suppression like ganciclovir/valganciclovir.
Other drugs that can be used is forscanet though it is nephrotoxic and causes electrolyte imbalances.
This patient CNI should also be switched to MTOR inhibitors.
What are the other tests to diagnose and monitor CMV?
This patient has CMV infection since he presents with fever and a high viral load, for diagnosis of tissue invasive disease tissue biopsy is required. Screening for tissue invasive disease is required with CXR and BAL, endoscopy and colonoscopy. The histology findings can be used to diagnose.
Other tests that can be used to monitor the patient includes:
Antigenimia assay for pp65.
Qualitative/quantitative PCR for CMV.
CMV specific cell mediated immunity- Quantiferon CMV assay, ELISPOT
Adaptive immunity-whereby you monitor the absolute lymphocyte counts and counts <610cells/ul are associated with increased risk of infection.
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
There has been no cut off viral load threshold to initiate pre-emptive therapy due to lack of assay standardisation.
However a cut off of 10,000copies/ml is generally used.
What is the duration of pre-emptive treatment?
The preemptive therapy includes valganciclovir 900mg bd or ganciclovir IV 5mg/kg twice daily. The treatment duration should be until the viral load is below the threshold or is negative.
The duration for prophylaxis is usually 200 days, this recommendation was after the IMPACT trial where they compared 100 versus 200 days. 200 days was associated with reduced incidence of late onset CMV disease.
The preferred drugs for prophylaxis are: PO valganciclovir 900mg od or IV ganciclovir 5mg/kg od or oral ganciclovir 1gm thrice daily.
However valganciclovir is preferred since it is administered orally and has a higher bioavailability compared to oral ganciclovir.
What is the relation between the viral load and the development of CMV disease?
High viral loads is associated with increased risk of CMV disease though a standardised threshold is not defined. However generally a threshold of 10,000copies/ml is associated with increased risk of disease.
References
Treatment of Ganciclovir Resistant Cytomegalovirus Infection Michael Klompas
Cytomegalovirus infection in transplant recipients: newly approved additions to our armamentarium Fareed Khawaja Amy Spallone Camille N. Kotton Roy F. Chemaly
Cytomegalovirus Infections in Solid Organ Transplantation: A Review
Poornima Ramanan, and Raymund R Razonable
The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation
Camille N. Kotton, MD,1 Deepali Kumar, MD,2 Angela M. Caliendo, MD, PhD,3 Shirish Huprikar, MD,4 Sunwen Chou, MD,5 Lara Danziger-Isakov, MD, MPH,6 and Atul Humar, MD7on behalf of the The Transplantation Society International CMV Consensus Group
This patient has the CMV syndrome as evidenced by the symptoms and the presence of CMV viremia which is significant (more than 4 log10 copies/ml) and has not responded to valganciclovir indicating could be resistant to valganciclovir and ganciclovir.
Management
I would like to do genetic resistance testing: UL97 and UL54
Switching to maribavir – It is an oral drug that inhibits UL97 phosphotransferase and is active against CMV with UL97 and UL54 mutations.
Other medications such as: cidofovir or foscarnet can be used. However, these drugs are highly nephrotoxic. Protocol with aggressive hydration is needed when administering these drugs and the renal functions need to be monitored vigilantly.
The CMV viral load needs to be monitored weekly.
consider CMV specific Immunoglobulin or IVIG for persistent CMV viraemia.
to stop the antimetabolite and to reduce the prednisolone.
mTOri should be considered for MMF replacement.
The quantitative CMV PCR is routinely used method to diagnose CMV.
Histological diagnosis: Tissue biopsy of the affected organ can pick the CMV inclusion bodies.
PP65 antigen was used to make the diagnosis but due to false negatives, it is no longer used.
The CMV antibodies are not used to make a diagnosis of CMV in transplant patients.
Pre-emptive Therapy:
The cut-off that is accepted to treat CMV viremia is 10,000 copies/ml.
The duration of pre-emptive therapy is 21 days – the viral load should be monitored weekly.
Most studies have identified that a higher viral load increased the risk of CMV disease. However, the exact cut-off has not been determined due to the variability of the PCR assays that were used in the studies.
A value of 10,000 copies per ml has been suggested as the cut-off.
References:
UK guidelines on prevention and mgt of CMV infection and disease following SOT-April 2022.
Kumar et al;The third international consensus guidelines on MGT of CMV in SOT.2018;102;900
Treatment of CMV viral infection
-Oral valganciclovir 900 mg twice daily for mild cases ;with renal dosing.
severe cases need IV ganciclovir 5 mg per kg every 12 hours with renal dosing. Treatment should continue till viremia clearance ,weekly CMV monitoring by CMV QNAT OR pp65 antigenemia to assess virologic response.
Following complete treatment, weekly monitoring for CMV DNA for 8-12 weeks is needed essentially for high risk of relapse.
-Cautious immunosuppression reduction.
-Monitoring of graft function.
-Resistant cases: high dose of ganciclovir or foscarnet ( it has nephrotoxicity and synergistic nephrotoxicity with CNI);Gene resistance testing is needed ;UL 97or UL54 gene mutation is needed.
Prophylaxis
-CMV negative recipient of CMV positive donor:
. following AB induction, valganciclovir 900 mg po daily for 6 months.in case without AB induction: same dose for 3 months. Then ,CMV DNA weekly for 3 months.
-CMV positive recipient of CMV negative donor or CMV positive donor:
Valganciclovir 900 mg po daily for 3-6 months.
-CMV negative recipient of CMV negative donor :
Acyclovir 400 mg BID for herpes prophylaxis for 3 months.
Also, CMV monitoring if indicated.
The above scenario is suggestive of valganciclovir resistance.
Ganciclovir resistance should be suspected in patients who have rising or persistently elevated viral loads despite treatment with appropriately dosed ganciclovir for more than two weeks
Resistance testing — When ganciclovir-resistant infection or disease is suspected, genotype testing should be performed to identify specific resistance mutations.
Common resistance mutations include those in the genes that encode UL97 phosphotransferase, which performs the initial phosphorylation of ganciclovir (which is required for its antiviral activity), and the viral DNA polymerase gene UL54.
Choice of antiviral therapy – Antiviral therapies for patients with ganciclovir-resistant or refractory CMV include maribavir, foscarnet, and cidofovir.
What are the other tests to diagnose and monitor CMV? Blood CP to look for leucopenia and thrombocytopenia LFTs Tissue biopsy if there is organ involvement. CMV PCR for monitoring.
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?The PCR threshold for the initiation of antiviral therapy is around 10,000 viral copies/ml of blood.
What is the duration of pre-emptive treatment?What is the relation between the viral load and the development of CMV disease? Duration of therapy — The duration of therapy depends upon the severity of disease, as well as the clinical and virologic response to treatment. We generally treat until both symptoms and CMV viremia have resolved (ie, CMV is undetectable or lower than the limits of a sensitive assay in two quantitative PCR tests drawn one week apart). The typical duration of therapy is 21 days but is often longer, particularly for patients with tissue invasive disease. We also monitor periodically for recurrence with quantitative PCR following completion of therapy, particularly for high-risk patients.
A decrease in the viral load generally correlates with a clinical response to treatment.
A 61-year-old man was admitted with fever (38 °C) and malaise 2 months after cadaveric transplantation, 000 mismatch on Tacrolimus (trough 9 ng/ml) and prednisolone 15 mg/day. CMV is positive to CMV negative recipient. Oxygen saturation was reported to be 95% on air. Quantitative CMV PCR reported 5.52 log 10 copies/ml. The patient has not responded to oral valganciclovir 900 mg twice daily. What is your management strategy?
Tx options for CMV syndrome with resistance against valganciclovir ;Marabavir, foscarnet and cidofovir.
Initial test will be to check for resisitance;UL97 and UL 54 mutations.
Marabavir has activity against both mutations and is administered orally 400mgtwice a day for 8 weeks. Main side effect is dysgeusia. MTORI and CNI trough levels have to be monitored while on this drug due to drug interactions.
Foscarnet is also active against both mutations and is administered parenterally IV 90mg twice a day for 21-42 days or until symptoms cease with regular UEC monitoring. Adequate pre and post infusion hydration is administered.
Cidofovir is active against only UL97 and not UL54.It is given parenterally IV 1MG/KG thrice a week or 5mg/kg weekly for 2 weeks during induction then 5mg/kg on every alternate week with probenacid. Adequate hydration is given and UECS monitored.
If no resistance is detected, we increase ganciclovir to 7.5mg /kg IV twice a day and do VL in a weeks time before changing to an alternative therapy.
RIS especially if no drug resistance, we stop the antimetabolite ,lower steroids then the Calcineurin inhibitor.
Other therapies for life threatening or severe disease include; CMV immunoglobulin which can be given IV 100mg/kg weekly with other antivirals while monitoring CMVPCR.
What are the other tests to diagnose and monitor CMV?
CMV PCR and VL can be used to both diagnose and monitor disease process.
Biopsy ;CMV inclusion bodies with an owls eye pattern is characteristic of CMV infection and can be used to diagnose CMV.
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?What is the duration of pre-emptive treatment?
Tx is initiated when CMV viraemia is more than 10000 copies/ml for 21/7 with weekly VL monitoring.
What is the relation between the viral load and the development of CMV disease?
The higher the VL the more the probability of developing CMV dx. Upper limit for this not yet clear..> 10000 copies/ml is the cut off for pre emptive tx.
REF;
UK guidelines on prevention and mgt of CMV infection and disease following SOT-April 2022.
Kumar et al;The third international consensus guidelines on MGT of CMV in SOT.2018;102;900
Developed CMV infection 2 months post in KTR, not responsive to valganciclovir leading to ganciclovir resistant CMV viremia, risk factors in this patient is D+/R- plus high tac level Other possibilities are mutations in the UL 97 or UL 54 gene leading to drug resistance Management:
History and clinical examination (adherence to medication)
Genotypic assays for the presence of mutations that are known to be associated with drug resistance
Reduction of IS (stop MMF and the decrease Tac with follow up for allograft dysfunction).
Antiviral Gaincyclovir, foscarnet and Cidofovir are the main agents use to treat CMV infection in addition to CMV specifics IVIG. Treatment options for CMV gaincyclovir resistance are after Genotypic assays would be
1. Increasing the dose of GCV from the standard 5mg/kg q12h to 7.5–10 mg/kg q12h 2. High dose gancyclovir plus foscarnet but this combination can be toxic(hematological toxicity) 3. CMV specific IVIG and leflunomide. 4. Cidofovir can be used but limited due to nephrotoxicity. Novel therapies letermovir ,maribavir,brincidofovir are potential agents but needs more evidences What are the other tests to diagnose and monitor CMV?
PCR amplification testing is the preferred method for diagnosis of CMV infection and monitoring response to therapy. But may be negative in tissue invasive CMV.
Other tests are
Histopathology: Tissue biopsy will show viral inclusions.
CMV pp65 Antigen Test: Pp65, a protein, is detected by fluorescent assay and reported as the number of infected peripheral blood cells.
Other Serological tests: Are used to assess the CMV status before kidney transplantation.
Genotypic assay: UL97 & UL54 are frequently linked to gancyclovir resistance.
Viral culture is not routinely used.
Assume this patient is asymptomatic what your cut-off level to treat is Asymptomatic CMV Viremia (pre-emptive therapy)?
For preemptive therapy is initiated once active viral replication is evident and treatment is continued until two consecutive negative PCR results are obtained.
Optimal target level to initiate pre-emptive therapy is not know as of yet
The QNAT results changes in values should be at least threefold (0.5 log10 IU/mL) to represent biologically important changes in viral replication especially in high risk patients the changes may need to be greater than fivefold (0.7 log10 IU/mL) to be considered significant
What is the duration of pre-emptive treatment? The duration of preemptive antiviral therapy should be guided by viral load monitoring. Generally, preemptive antiviral therapy is continued until virology clearance. Previously two consecutive negative weekly CMV PCRs was suggested but now single negative test may sufficient. What is the duration of pre-emptive treatment? The duration of preemptive antiviral therapy should be guided by viral load monitoring. Generally, preemptive antiviral therapy is continued until virology clearance. Previously two consecutive negative weekly CMV PCRs was suggested but now single negative test may sufficient. What is the relation between the viral load and the development of CMV disease? Cytomegalovirus (CMV) viral load increases is associated with CMV disease in kidney and liver transplant recipients, but relationships to disease severity or mortality have not been shown. Some studies suggested that CMV viral load can be used as a surrogate marker for severe CMV disease and CMV-associated mortality.
References
1 UpToDate Topic 3700 Version 42.0 and Topic 8305 version 28.0
👉 the index case has CMV pneumonitis, traetmebt by shift to IV ganciclovir 5 mg/kg/day and ensure compliance if resistant to it (have rising PCR load ) , consider it ganciclovir resistant .
• Lines of ttt of ganciclovir resistant CMV:
o Foscarnet: but it causes nephrotoxicity, electrolyte disturbance.
o Cidofovir: needs hepatic and renal adjustment.
o Although foscarnet and cidofovir are potent, but their side effects limit their use.
o Combination ganciclovir and foscarnet at reduced doses is better than monotherapy due to synergistic effect, also decrease side effects of both.
o Novel immunomodulatory agent, leflunomide: better safety profile but can cause mild transaminitis, but not used in combination with ganciclovir.
⭐other methods for diagnosis ;
_serology CMV IgM and IgG (but of no value in such immunocompromised host).
_tissue diagnosis or BAL with histopathology revealing owl eye appearance.
👉 Treatment is indicated in the following conditions:
1_ any conformed tissue invasive disease irrespective to the viral load
2_preemptive therapy if the viral load is > 5 log 10 even if asymptomatic .
3_ rising titre of PCR or more than 3 log10 with symptoms.
👉 duration of therapy : give IV ganciclovir for 2-3 weeks until resolution of symptoms and 2 negative PCR.
⭐Tissue invasive disease is dependent on identification of virus in tissues irrespective to viral load.
Management strategy · Reduction of immunosuppression is the corner stone of TTT (STOP MMF and target lower tac level ) · Patient not responding to oral ganciclovir we need to switch to IV ganciclovir 5 mg /kg/ bid 2-3 weeks until we have 2 negative PCR· · Consider resistant to valgan cyclovir if persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration (2-4 weeks) of Ganciclovir or Valganciclovir · if resistant is suspected 1-Confirm that dosing is adequate 2-Consider adherence to treatment plan and absorption 3-Offer testing for Human CMV (HCMV) antiviral resistance UL97 and UL54 gene mutations 4-Use either whole blood or plasma
· If there is evidence of ganciclovir resistance: Stop Valganciclovir (or Ganciclovir) / start Intravenous Foscarnet for at least 3 weeks After Seeking specialist virology advice
Thresholds for treatment
1. Consider reduction in immunosuppression in R+ patients with a viral load of fewer than 3 logs 10.
2. Consider treatment with valganciclovir when the viral load exceeds 3 logs 10 if rapidly rising titre in high-risk patients. 3. Treatment with valganciclovir or IV ganciclovir is mandatorywhen the viral load exceeds 4 logs 10. Treatment duration in preemptive therapy
Monitor to guide preemptive therapy monthly for 3 month
Treatment for 2-3weeks CMV disease and viral load
CMV disease – (histopathological evidence of CMV, CMV retinitis diagnosed by an ophthalmologist, or CMV in the CSF indicative of CNS disease) irrespective of viral load
Case of CMV infection resistance to valganciclovir and high level of tacrolimus
The main management is to reduce tacrolimus dose to lower limit and close adherence to his medication and stop anti metabolites.
Start iv ganciclovir 900mg twice/ day for 14 days followed by treatment with oral valganciclovir for up to three months.
If there’s resistance can start foscarnet
cidofovir
Leflunomide
Letermovir
What are the other tests to diagnose and monitor CMV?
CMV igG/ CMV igG
CMV PCR in blood and urine
Assays of pp65 antigenemia and real-time CMV PCR of blood or plasma have allowed for preemptive treatment reducing morbidity and mortality.
PCR for CMV DNA can be either qualitative or quantitative.
Reverse transcriptase (RT-PCR) can be used to detect viral mRNA transcripts in peripheral blood leukocytes independent of the presence of DNA. It’s only presents with symptoms of CMV disease.
The above case is likely a case of Ganciclovir resistant CMV viremia due to mutations in the UL 97 or UL 54 gene.
Treatment modalities for the above case will be to stop antimetabolite i.e., MMF if he is taking(as not mentioned),increasing the dose of oral valgancyclovir or switching to I/V ganciclovir in a dose of 5mg/kg BID for a duration of 14 to 21 days or till the two consecutive PCR for CMV DNA negative 01 week apart. Foscarnet or cidofovir or IVIG –usually required in resistant cases but need to be vigilant of renal function deterioration with cidofovir or foscarnet. Letermovir and Maribavir are also other altenatives. What are the other tests to diagnose and monitor CMV?
CMV pp65 antigenemia test
PCR for CMV DNA (quantitative) on blood, CSF, and tissue sample in tissue invasive disease-also used for monitoring of CMV infection.
Histopathological findings of intranuclear inclusion bodies(owl’s eye appearance) in tissue invasive CMV disease in which blood viremia may not be present
Tissue Culture another test but had many limitations. Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
No standardized threshold or cut off value for starting treatment in asymptomatic cases mentioned in the literature and vary center-center and also depends on CMV D/R status. High risk case (CMV R-ve)then the cut off value for treatment is >1000 copies/ml ,and any transplant asymptomatic case with PCR >5000 copies/ml. -What is the duration of pre-emptive treatment?
Pre-emptive treatment is that in which patient is monitored serially with PCR post-transplant and treatment is started when there is active replication of the virus .Duration is 14-21 days or till the two consecutive PCR for CMV DNA report negative 1 week apart –then anti-viral in a prophylactic dose(900 mg/d ) to be continued for about 100 days.Doses may need to be adjusted according to GFR. What is the relation between the viral load and the development of CMV disease?
Viral load is considered as an independent important predictor of CMV disease but may not relate to CMV disease and its severity always, as tissue invasive CMV disease has negative PCR test in blood and diagnosis of CMV disease confirmed via histopathological diagnosis. REFERENCES:
CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023
Sheffield protocol for prophylaxis, surveillance, and treatment of CMV after renal transplantation, 2016
He has a primary CMV infection, CMV pneumonitis, and is currently on oral valganciclovir therapy 900mg BID with a current viral load of 5.5 so he should be started on IV ganciclovir 5 mg /kg BID for at least 5 days and then if a good response shift to oral valganciclovir to complete 21 days and to continue on oral valganciclovir 900mg od for another 4 weeks or till get the two repeated cmv pcr negatives. the alternative is to continue on IV ganciclovir 5 mg /kg BI for total14-21 days the shift to oral valganciclovir 900mg od till getting at least two negative CMV PCR, during treatment, should consider renal adjustment of ganciclovir to the CLCR and monitor for myelosuppression with thrombocytopenia and FBC every two weeks
Also whenever we have a patient who developed CMV tissue invasion disease like in his case CMV pneumonitis we should discuss with the ID, virologist the possibility of ganciclovir-resistant CMV infection and may try a second-line treatment like foscarnet, or cidofovir or the new novel drugs like lemetivir or manibavovir but caution with nephrotoxicity and neurotoxicity, and also cross-resistance especially with foscarnet, cidofovir. high-risk D+ve /R-ve this kidney transplant recipient considers high risk for primary CMV infection and should be on prophylaxis with oral valganciclovir 900 mg for 200 days. reduction of IS is also to be considered as the cumulative dose of IS including induction with ATG or lmeultuzemab can affect the T cell immune response. What are the other tests to diagnose and monitor CMV?
CMV serology, IgM, IgG for serostatus of acute infection after 200 days of prophylaxis in the seronegative recipient
Sometimes the CMV PCR does not correlate with the clinical tissue invasive CMV and needs tissue biopsy to confirm the diagnosis or bronchoscopy and BAL fluid assay
IHC staining for the viral IB (inclusion bodies owl eyes ).
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viremia (pre-emptive therapy)?
1. Consider treatment with valganciclovir when the viral load exceeds 3 logs 10 if symptomatic or rapidly rising titer in high-risk patients.
2. IV ganciclovir treatment mandatory for tissue organ invasion like pneumonitis, colitis, encephalitis What is the duration of pre-emptive treatment?
preemptive treatment with oral valganciclovir 900mg BID is to be considered for the high-risk recipient with seroconversion while he is on monitoring with CMV PCR without prophylaxis, which is more costly with frequent CMV PCR monitoring but less cost with antiviral treatment, another concern is the noncompliance and risk of CMV invasive infection.
What is the relation between the viral load an d the development of CMV disease?
Sometimes the viral load is misleading and if we have a high clinical suspicion of CMV tissue invasion should be treated regardless of viral load, especially in CMV colitis, pneumonitis, and retinitis
References
1. Protocol for prophylaxis, surveillance, and treatment of CMV after renal transplantation. NHS foundation trust, 2016.
2.Fehr T, Cippà PE, Mueller NJ. Cytomegalovirus post kidney transplantation: prophylaxis versus pre-emptive therapy? Transpl Int. 2015 Dec;28(12):1351-6. doi: 10.1111/tri.12629. Epub 2015 Jul 27. PMID: 26138458.
1. CMV pre-transplant serostatus D+/R- carries high risk of CMV infection and disease in the post-transplant period. Valganciclovir prophylaxis to be offered for at least 3 months when the recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (1).
2. Laboratory Testing for CMV: CMV PCR(on whole blood, plasma or leucocyte) considered to the gold standard mean of detecting active viral replication.
3. I will offer treatment with oral Valganciclovir for a duration of at least 2 weeks. Most commonly valganciclovir 900mg twice daily has been used as treatment dose, adjusted for level of kidney function(1). a) I will monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir. b) Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days [1D] c) I will be aware of the potential development of ganciclovir resistance. d) I will consider stopping treatment for CMV disease after: · resolution of symptoms. · two consecutive, CMV viral load tests that confirm that CMV is not detected (below the local laboratory threshold for detection).
4. In the setting of Ganciclovir resistance:
a) People at increased risk of Ganciclovir resistance:
· Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications.
· CMV seronegative recipients receiving a solid organ transplant from seropositive donors (D+/R-).
· Those who have received intensive immunosuppression (e.g; with T-cell depletion therapy, following episodes of acute allograft rejection).
b) I will consider resistance to Ganciclovir if:
· There is a persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir.
c) When resistance to Ganciclovir is suspected:
· I will confirm that dosing is adequate.
· I will consider adherence to treatment plan and absorption.
· I will offer testing for Human CMV (HCMV) antiviral resistance. Sequence-based analysis of UL97 and UL54 gene mutations .Genotypic assays can relatively rapidly detect gene mutations that are associated with both high- and low-grade resistance to ganciclovir as well as mutations that confer various degrees of resistance to Foscarnet and Cidofovir.
d) When there is evidence of ganciclovir resistance:
· I will stop Valganciclovir (or Ganciclovir).
· Offer Intravenous Foscarnet for at least 3 weeks. Foscarnet is reserved as second or even third line therapy partly because of significant risks of nephrotoxicity and electrolyte disturbances.
· Seek specialist virology advice before commencing treatment with Foscarnet .
· The use of Maribavir for treating refractory or resistant CMV infection following SOT has been assessed in phase 3 studies and reported to be superior to Ganciclovir, Cidofovir and Foscarnet.
5. Immunosuppression dose reduction:
a) I will consider a dose reduction of either calcineurin inhibitor or antimetabolite. The TAC level to be around 5(4-6 ng/ml).
b) I will consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia.
c) I will discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction.
d) I will review the dosing of immunosuppression following resolution of CMV infection or disease.
What are the other tests to diagnose and monitor CMV?
1. CMV PCR is the gold standard test for diagnosing CMV infection.
2. CMV IgG & IgM may help in its quantitative form for follow up.
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
1. Treatment with valganciclovir when the viral load exceeds 3 logs 10 if symptomatic or rapidly rising titre in high-risk patients.
2. Treatment with valganciclovir or IV ganciclovir is mandatory when the viral load exceeds 4 logs 10.
What is the duration of pre-emptive treatment?
1. Oral valganciclovir 900mg bd for 21 days, then 900mg od for 28 days or until 2 x PCR negative, whichever occurs first (off-label drug use)(2).
2. IV ganciclovir 5mg/kg bd for 5 days followed by oral valganciclovir 900mg od until 2 x PCR negative.
3. IV ganciclovir 5mg/kg bd for 14-21 days, stop date determined by 2 x PCR negative.
What is the relation between the viral load and the development of CMV disease?
In transplant recipients with CMV infection, the risk of developing CMV disease is directly proportional to the CMV DNA viral load(3).
References
1. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION
2. Protocol for prophylaxis, surveillance, and treatment of CMV after renal transplantation: July 2016 (3rd revision) Review Date: July 2019;Sheffield Kidney Institute Clinical Governance Meeting Date: 18th August 2016
3. NIH; US National Library of Mediucine;Clinicaltrial.gov Determining a Viral Load Threshold for Treating Cytomegalovirus (CMV)https://clinicaltrials.gov/ct2/home
Management strategy CMV D+/R- is the risk factor of CMV infection in recipient post transplantation, and should had been received gancilcovir prophylaxis for at least 3 months. As the patient does not respond to valganciclovir twice dially, he proposed to had CMV resistance. Risk factors of CMV resistance
Prolonged coarse, or subtherapeutic dose.
CMV (D+/R-)
Intensive induction therapy.
Recipient of a lung transplant.
Consider resistance if:
Persistence or increase viral load or symptomatic disease after effective dose and duration.
Ganciclovir iv (5mg/kg for 14-21 days) stop after 2 consequative PCR -ve.
In case of gancilclovir resistance
Foscarnet: AEs, renal toxicity, electrolyte abnormality, and seizure.
Combined therapy: combined Ganciclovir and Foscarnet offer more promising treatment with less dose and side effects.
Cidofovir: administer once or twice per week, with AEs; nephrotoxicity, bone marrow suppression.
Leflunomide: CI in pregnancy as it cause fetal death and teratogenesis, and used in cases of resistance to ganciclovir, foscarnet, and cidofovir
Other test to dignose and monitor CMV
Routine surveillance for viremia is not required during prophylaxis.
D+/R- patients should have their serostatus (CMV IgG) checked at or around 200 days.
D+/R- should start surveillance with CMV PCR once they finish prophylaxis, and this can be more frequent than clinic visit as per the following schedule, 2, 4 ,8, 12 weeks, and the recipient team will coordinate this.
CMV PCR in the blood is the standard test for all transplant patient where CMV viremia or disease is suspected or a possibility in outpatient and inpatient, irrespective of whether on prophylaxis or not.
What is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
Preemptive therapy is attractive b/c it use valgancilovir in selected patients, so reducing the incidence of the disease and side effects of treatment.
Cut-off level of preemptive treatment is if the viral load DNA is >/ 100,000 copies /ml.
The duration of pre-emptive treatment? 3 months or until cessation of viral replication.
The relation between the viral load and the development of CMV disease?
There is no definitive agreement for the viral load and the incidence of the disease.
Usually pattern of the viral load and the increasing rate is more guiding and sensitive in conjoined with the clinical manifestation.
The viral load of >/ 100,000 level is considered high and alarming treatment.
Weekly quantifying viral load is recommended to assess the pattern of the disease and to determine the response.
References
Burd EM. Validation of laboratory-developed molecular assays for infectious diseases, Clin Microbiol Rev, 2010, vol. 23 (pg. 550-76)
2.Pang XL, Fox JD, Fenton JM, Miller GG, Caliendo AM, Preiksaitis JK. Interlaboratory comparison of cytomegalovirus viral load assays, Am J Transplant, 2009, vol. 9 (pg. 258-68)
3.Roberts TC, Buller RS, Gaudreault-Keener M, et al. Effects of storage temperature and time on qualitative and quantitative detection of cytomegalovirus in blood specimens by shell vial culture and PCR, J Clin Microbiol, 1997, vol. 35 (pg. 2224-8
4.Bennett J, Dolin R, Blaser M. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 9th edition. Elsevier/Saunders; 2015.
5.Hodson EM, Jones CA, Webster AC, Strippoli GF, Barclay PG, Kable K. Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials. Lancet. 2005 Jun 18-24. 365(9477):2105-15. [QxMD MEDLINE Link].
6.Zhang LJ, Hanff P, Rutherford C, Churchill WH, Crumpacker CS. Detection of human cytomegalovirus DNA, RNA, and antibody in normal donor blood. J Infect Dis. 1995 Apr. 171(4):1002-6. [QxMD MEDLINE Link].
7.Myhre HA, Haug Dorenberg D, Kristiansen KI, et al. Incidence and outcomes of ganciclovir‐resistant cytomegalovirus infections in 1244 kidney transplant recipients. 8.Transplantation. 2011;92(2):217‐ 2. Lurain NS, Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev. 2010;23(4):689‐ 3. Chemaly RF, Chou S, 9.Einsele H, et al. Definitions of resistant and refractory cytomegalovirus infection and disease in transplant recipients for use in clinical
This patient developed CMV infection 2 months post kidney transplant which was not responded to valganciclovir so this is most likely a case of ganciclovir resistant CMV viremia,risk factors to this patient are( D+/R-) plus high tacrolimus level ,mutations in the UL 97 or UL 54 gene is lead cause to drug resistance
Management :
Start with proper history and clinical examination especially the adherence to medication
Genotypic assays detect the presence of mutations that are known to be associated with resistance
Reduction of immunosuppression ( stop antimetabolites and adjust the dose of tacrolimus with follow up of graft function guarding against rejection) .
Antiviral treatment options :
GCV, foscarnet and cidofovir are the mainstays of CMV antiviral treatment.Treatment options for CMV GCV resistance are :
Increasing the dose of GCV from the standard 5mg/kg q12h to 7.5–10 mg/kg q12h
High dose ganciclovir and foscarnet but this combination can be toxic with considerable hematological toxicity .
CMV IVIG and leflunomide .
Cidofovir use is limited with nephrotoxicity .
Novel therapies letermovir ,maribavir,brincidofovir may be proved effective treatment in the future
: What are the other tests to diagnose and monitor CMV
Quantitative nucleic acid amplification testing is the preferred method for diagnosis of CMV infection, guiding preemptive strategies, and monitoring response to therapy.but may be negative in tissue invasive CMV .Other diagnosytic test for CMV :
Histopathology : Tissue biopsy will show viral inclusions in tissue invasive CMV .
CMV pp65 antigenemia : Pp65, a protein, is detected by fluorescent assay and reported as the number of infected peripheral blood cells.
Serological tests : Are of limited efficacy in diagnosing CMV infection but used to assess the CMV status before kidney transplantation .
Rapid (6 hours) & simple method for the detection of CMV-phagocytized by neutrophils in the peripheral blood , it is comparable to quantitative PCR in that it is a highly specific method for CMV detection & has predictive value for the disease severity, which is related to the number of cells detected , but this test will be limited in cases of leukopenia and its quantification is subjective & dependent on the expertise of the operator .
Genotypic assay : UL97 & UL54 are frequently linked to ganciclovir resistant CMV.
Viral culture is not routinely used
Assume this patient is asymptomatic; what is your cut-off level to treat
?asymptomatic CMV viraemia (pre-emptive therapy)
For preemptive therapy treatment is initiated once active viral replication is evident ,and treatment is continued until two consecutive negative antigenemia assay results are obtained.
Consensus viral load thresholds to initiate preemptive therapy is still to be defined
The QNAT results changes in values should be at least threefold (0.5 log10 IU/mL) to represent biologically important changes in viral replication especially in high risk patients , the changes may need to be greater than fivefold (0.7 log10 IU/mL) to be considered significant
? What is the duration of pre-emptive treatment
The duration of preemptive antiviral therapy should be guided by viral load monitoring. Generally, preemptive antiviral therapy is continued until virologic clearance . Previously Two consecutive negative weekly CMV QNAT was suggested but now a single negative test may suffice if using a highly sensitive QNAT .Usually minimum duration of 2 weeks .
?What is the relation between the viral load and the development of CMV disease
The rate of cytomegalovirus (CMV) viral load increase is associated with CMV disease in kidney and liver transplant recipients, but relationships to disease severity or mortality have not been shown. Some studies suggested that CMV viral load can be used as a surrogate marker for severe CMV disease and CMV-associated mortality.
Dear All Remember that the treatment dose and duration differ from the CMV prophylaxis. Please summarise in a few words the dose and the duration of CMV treatment versus the prophylaxis
Recommended dose is valganciclovir 450 mg daily for CMV prophylaxis in kidney transplant for 6 months.
Treatment of infection by intravenous ganciclovir 5 mg/kg/dose q12hr and then change to valganciclovir 900 mg PO q12hr for 21-42 days or until signs and symptoms have resolved.
Treatment; Valganciclovir 900 mg PO twice daily according to the eGFR or IV gancilovir 5 mg/kg twice daily in cases of malabsorption for a minimum of two to three weeks and continued until CMV PCR is undetectable in the blood on at least two consecutive occasions
Prophylaxis; Valganciclovir 900 mg PO once daily according to eGFR, for at least 100 to 200 days
Prophylaxis dose and duration (adjust the dose according to the eGFR)
Dose of valganciclovir 900 mg/d till 200 days.
Dose of ganciclovir; 5 mg/kg/d for 100-120 days.
Dose of foscarnet; 40-60 mg/kg /8 or 12 hours for 14-21 days
Dose of cidofovir; 5mg/kg every week for 2 weeks then biweekly.
Dose of CMVIG; 150 mg/kg on within 72 hours then at weeks 2, 4, 6, 8 then 100 mg/kg at weeks 12-16
Treatment dose and duration (adjust the dose according to the eGFR)
Dose of valganciclovirvir
a) Induction; 900 mg oral /12 hours. b) Maintenance 900 mg oral /24 hours.
Dose of ganciclovir
a) Induction 5 mg/kg/ 12 hours. b) Maintenance 5 mg/kg/24 hours.
Dose of foscarnet;
a) Induction; 60 mg/kg/8hours, or 90 mg/kg/12hours for 41-21 days. b) Maintenance 90-120 mg/kg/day for 14-21 single infusions.
Dose of cidofovir
a) Induction; 5 mg/kg every week for 2 weeks. b) Maintenance; 5 mg/kg biweekly.
Dose of CMVIG
a) Treatment; 400 mg/kg on days 1-2-7 followed by 200 mg/kg on days 14-21. References
Rubin RH. The indirect effects of cytomegalovirus infection on the outcome of organ transplantation, JAMA, 1989, vol. 261 (pg. 3607-9)
2Fishman JA, Rubin RH. Infection in organ-transplant recipients, N Engl J Med, 1998, vol. 338 (pg. 1741-51)
3Snydman DR. Infection in solid organ transplantation, Transpl Infect Dis, 1999, vol. 1 (pg. 21-8)
4Fishman JA, Emery V, Freeman R, et al. Cytomegalovirus in transplantation—;challenging the status quo, Clin Transplant, 2007, vol. 21 (pg. 149-58)
5Singh N. Preemptive therapy versus universal prophylaxis with ganciclovir for cytomegalovirus in solid organ transplant recipients, Clin Infect Dis, 2001, vol. 32 (pg. 742-51)
PRPHYLAXIS Valganciclovir 900 mg po od for 6 months if high risk or 3 month if intermediate risk Therapeutic (3 options ) 1. Oral valganciclovir 900mg twice /day for 21 days, then 900mg once daily for 28 days or until 2 x PCR negative, whichever occurs first (. 2. IV ganciclovir 5mg/kg /12 h for 5 days followed by oral valganciclovir 900mg od until 2 x PCR negative. 3. IV ganciclovir 5mg/kg /12 for 14-21 days, stop date determined by 2 x PCR negative. The dose should be adjusted as per GFR
_prophylaxis valganciclovir is 900 mg/day for 3-6 months according to CMV risk (D+/R- is high risk, when recipient is postive it is intermediate risk whether D is -/+).
_treatment is double prophylactic dose, for 3-6 weeks or until 2 negative PCR
CMV Prophylaxis: Valgancyclovir 900 mg per dayor Injection Gancyclovir 5 mg/kg/day Duration: 100-200 days, depending on the serostatus of the recipient and donor, as well as use of lymphocyte depleting agents.
CMV Treatment: Valgancyclovir 900 mg twice a dayor Injection Gancyclovir 5 mg/kg/twice a day. Duration: Until clearance of CMV from blood, for minimum 2 weeks, and until symptoms relieved in case of tissue-invasive CMV.
Reference:
Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.
Depending on the indication of iv/oral treatment, the standard treatment dosage is usually double the maşntainace or prevention dose. We usually use valacyclovir orally for treatment and prevention, except in tissue-invasive CMV, where induction can be preferred with iv treatment for about 1-2 weeks.
The dose of treatment is usually double the dose of prevention or maintenance therapy.
For valacyclovir (oral): the standard dose is 900 mg twice daily (Crcl/eGFR >70)
450 mg (twice): Crcl 40-59/
450 mg/24 hr : Cr cl 25-39 450 mg/48 hr : Cr cl 10-24
200 mg/thrice weekly after dialysis (cr cl<10)
For maintenance: 900 mg once a day
450 mg (once): Crcl 40-59/
450 mg/48 hr : Cr cl 25-39
450 mg/twice aweek : Cr cl 10-24
100 mg/thrice weekly after dialysis (cr cl<10)
For iv Ganciclovir:
The treatment dose is 5mg/kg every 12 hours. (2.5g mg/kg twice: Cr cl 50-59/once for Cr cl 25-49 ml/day)
————
Kotton, Camille N. MD1; Kumar, Deepali MD2; Caliendo, Angela M. MD, PhD3; Huprikar, Shirish MD4; Chou, Sunwen MD5; Danziger-Isakov, Lara MD, MPH6; Humar, Atul MD7 on behalf of the The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation 102(6):p 900-931, June 2018. | DOI: 10.1097/TP.0000000000002191
Therapy includes Valganciclovir 900 mg PO twice daily based on eGFR or IV gancilovir 5 mg/kg twice daily in cases of malabsorption for at least two to three weeks and continued until CMV PCR is undetectable in the blood on at least two separate occasions.
Prophylaxis: Valganciclovir 900 mg PO once day for at least 100 to 200 days, depending on eGFR.
Treatment of CMV infection IV ganciclovir 5 mg/kg IV every 12 hours, with dose adjustment for kidney , or valganciclovir 900 mg orally twice daily, with dose adjustment for kidney function, according to severity of the infection. Duration of treatment: treat until both symptoms and CMV viremia have resolved (ie, CMV is undetectable or lower than the limits of a sensitive assay in two quantitative PCR tests drawn one week apart). The typical duration of therapy is 21 days but is often longer, particularly for patients with tissue invasive disease. also monitor periodically for recurrence with quantitative PCR following completion of therapy, particularly for high-risk patients such as this patient.
prophylaxis treatment : is valgancyclovir 450 mg for 6 month(200 days).
CMV treatment – Valganciclovir or Ganciclovir (dose adjusted for kidney function)
Valganciclovir 900mg BD or Ganciclovir 5mg/kg IV BD for 21 days
IV ganciclovir is preferred in patients with tissue-invasive disease (e.g., meningoencephalitis, pneumonitis), moderate to severe GI disease, high or rapidly rising viral loads
Oral valganciclovir is preferred in patients with mild or moderate CMV disease, with good absorption of oral medications
continue with the antiviral agent until there is complete resolution of the clinical signs and symptoms of CMV disease and there is no evidence of CMV viremia in 2 blood PCR tests done at least one week apart
duration of treatment is usually 21 days but can be longer especially for patients with tissue invasive disease
CMV prophylaxis
Valganciclovir 900mg OD (dose adjusted for kidney function) for 100-200 days
Prophylaxis
1) Dose of valganciclovir is 900 mg OD for 100 to 200 days
2) However, dose adjustment is required according to GFR
Treatment for CMV
1) Treatment dose is 900 mg twice a day (dose adjustment according to GFR)
2) Duration is until two negative PCR tests or for 28 days
CMV treatment – Valganciclovir or Ganciclovir (dose adjusted for kidney function)
Valganciclovir 900mg BD or Ganciclovir 5mg/kg IV BD for 21 days
IV ganciclovir is preferred in patients with tissue-invasive disease (e.g., meningoencephalitis, pneumonitis), moderate to severe GI disease, high or rapidly rising viral loads
Oral valganciclovir is preferred in patients with mild or moderate CMV disease, with good absorption of oral medications
continue with the antiviral agent until there is complete resolution of the clinical signs and symptoms of CMV disease and there is no evidence of CMV viremia in 2 blood PCR tests done at least one week apart
duration of treatment is usually 21 days but can be longer especially for patients with tissue invasive disease
CMV prophylaxis
Valganciclovir 900mg OD (dose adjusted for kidney function) for 100-200 days
prophylactic dose: 400 mg of valganciclovir daily for 6 months in high-risk recipients (D+/R-) and for three months in intermediate-risk (D+/R+) or (D-/R+). Treatment: valganciclovir 900 mg Q12h for 21 days then daily until the two consecutive PCR one week apart become negative. A combination of IV ganciclovir with oral valganciclovir is used as well. Either ganciclovir or valganciclovir needs adjustment according to GFR.
Valganciclovir for prophylaxis is 450 mg od for 3-6 months post transplant , and after every treatment with high dose CS.
treatment dose is 900 mg bid for 2-4 weeks, until viral copies are undetected or the patient is asymptomatic.
Ganciclovir is used intra venous in a dose of 5mg/kg/12 hours until patient is asymptomatic, to be shifted to valganciclovir 900 mg twice a day for 3-4 weeks.
A 61-year-old man was admitted with fever (38 °C) and malaise 2 months after cadaveric transplantation, 000 mismatch on Tacrolimus (trough 9 ng/ml) and prednisolone 15 mg/day. CMV is positive to CMV negative recipient. Oxygen saturation was reported to be 95% on air. Quantitative CMV PCR reported 5.52 log 10 copies/ml. The patient has not responded to oral valganciclovir 900 mg twice daily.
What is your management strategy?
This is a case of ganciclovir resistant CMV with CMV disease (viremia + lung involvement).I would send for genotyping the virus: UL97 and UL54 (are the commonest gene mutations), then I would consider Maribavir as a treatment of choice with less adverse events profile and excellent response to the mutations because it inhibits UL97 phosphotransferase.Foscarnet, cidofovir are used with nephrotoxicity and bone marrow suppression, and drug-drug interactions.Frequent monitoring of CMV viral load by PCR, and treatment to be continued till clinical improvement and two non-detectable CMV viral load.Reduction of immunosuppressive medications: MMF reduced by 50%, and if life threatening infection can be stopped, Tacrolimus reduced to the lower therapeutic trough level (4-6ng/dl), and keeps on stress dose steroid, and if rejection is there can give iv methylprednisolone.Thus, frequent monitoring of the graft function is a must.If no improvement IVIG can be considered in some cases with poor response. What are the other tests to diagnose and monitor CMV?
CMV serology (Antibodies testing) IgG, IgM: non diagnostic in transplant patients.CMV viral load by PCR: Is the mostly used to diagnose CMV viremia, this either from the serum or a body fluid (ie; BAL).Tissue histopathology: may be helpful (Owle’s eye inclusions).Antigen testing PP65: no longer used because of high false negative results.Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
The cut off level to treat CMV viremia is any level above 10,000 copies/ml.
What is the duration of pre-emptive treatment?
The treatment would be continued for 3 weeks with viral load monitoring.
What is the relation between the viral load and the development of CMV disease?
Most studies demonstrate higher CMV viral load increased the risk of CMV disease – a linear relationship
References: (1) Kotton CN, Kumar D, Caliendo AM et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-Organ Transplantation. Transplantation 2018; 102:900 (2) UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS. 2022
This patient has the CMV syndrome as evidenced by the symptoms and the presence of CMV viremia which is significant (more than 4 log10 copies/ml)
He has not responded to valganciclovir suggesting that he could be resistant to valganciclovir and ganciclovir
Management
The management of this patient would involve:
Doing genetic resistance testing: the 2 genes commonly involved are UL97 and UL54
Switching to maribavir – It is an oral drug that inhibits UL97 phosphotransferase and is active against CMV with UL97 and UL54 mutations. It has the advantage of not having nephrotoxicity and bone marrow suppression like the other antivirals
If Maribavir is not available, cidofovir or foscarnet can be used. The main disadvantage with these drugs is that they are highly nephrotoxic. Aggressive hydration is needed when administering these drugs and the renal functions need to be monitored very closely
The CMV viral load needs to be monitored weekly to ensure that it is reducing signifying that the therapy is working.
For patients who are not responding to the alternative antivirals, one can consider CMV specific Immunoglobulin or IVIG
The patient would also require reduction of immunosuppression – the benefits must outweigh the risk of rejection. The first step would be to stop the antimetabolite and to reduce the prednisolone. He was transplanted 2 months ago and is on a high dose of prednisolone
Diagnosis Of CMV
The quantitative CMV PCR is the most routinely used method to diagnose CMV. However, there are intra-laboratory variations that are seen and it is important to ensure that the PCR assay is calibrated to the WHO international standards. In some cases of tissue CMV, the plasma/whole blood PCR can be negative
Histological diagnosis: Tissue biopsy of the affected organ can pick the CMV inclusion bodies
Previously the PP65 antigen was used to make the diagnosis but due to false negatives, it is no longer used
The CMV antibodies are not used to make a diagnosis of CMV in transplant patients
Pre-emptive Therapy:
The cut-off that is accepted to treat CMV viremia is 10,000 copies/ml
The duration of pre-emptive therapy is 21 days – the viral load should be monitored weekly
Relationship between VL and CMV disease:
Most studies have identified that a higher viral load increased the risk of CMV disease. However, the exact cut-off has not been determined due to the variability of the PCR assays that were used in the studies.
A value of 10,000 copies per ml has been suggested as the cut-off
Kotton CN, Kumar D, Caliendo AM et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-Organ Transplantation. Transplantation 2018; 102:900
What is your management strategy?CMV positive donor to CMV negative recipient transplantation increases risk of infection. Patient has not responded to Valganciclovir , indicating drug resistance . However adherence to drugs has to be checked UL 97 and 54 mutations should be assessed. Other drugs which can be used include Leflunomide, Foscarnet and IVIG. New potent drugs like Maribavir can be considered
What are the other tests to diagnose and monitor CMV?QNAT Shell Viral Culture CMV pp65 antigenemia test
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?4000 to 10000 IU /ml
What is the duration of pre-emptive treatment?100 days
What is the relation between the viral load and the development of CMV disease?There is linear relationship between CMV viral load and the development of CMV disease. High viral suggest active infection or reactivation. In such situation modification of immune suppression helps. Lack of response to drug indicates resistance . In drug resistance immune modulators and newer drugs can be used .
de Matos SB, Meyer R, Lima FWM. Cytomegalovirus Infection after Renal
Transplantation: Occurrence, Clinical Features, and the Cutoff for Antigenemia in a University Hospital in Brazil. Infect Chemother. 2017 Dec;49(4):255-261.
The duration of treatment with oral Valganciclovir is at least 2 weeks [1A]. The dose of Valganciclovir is adjusted if creatinine clearance is < 60ml/minute. Consider stopping treatment for CMV disease after the resolution of symptoms and 2 consecutive CMV viral load tests that confirm that CMV is not detected (below the local laboratory threshold for detection) [2D]. (See Dr ABDELHAMID ABOGHANEM reply). There are other tests, such as IgG, IgM, and the buffy coat test. Please listen to my lecture again.
You got mixed up with prophylaxis which is for 100 to 200 days.
A 61-year-old man was admitted with fever (38 °C) and malaise 2 months after cadaveric transplantation, 000 mismatch on Tacrolimus (trough 9 ng/ml) and prednisolone 15 mg/day. CMV is positive to CMV negative recipient. Oxygen saturation was reported to be 95% on air. Quantitative CMV PCR reported 5.52 log 10 copies/ml. The patient has not responded to oral valganciclovir 900 mg twice daily. What is your management strategy?
This is a case of high risk for occurrence of CMV disease – D+/R- and 30% of them are prone to developing late onset of CMV disease even after prophylaxis use or discontinuation. This is a case of ganciclovir resistant CMV viremia that developed despite the use of high dose valganciclovir (VGCV). Hence the index case is ganciclovir resistance, and the following steps will be taken. we confirm adherence to the dose of valganciclovir. we offer tests for CMV antiviral resistance. UL94 and UL54 gene mutations will be checked using whole blood or plasma. CMV infections in KTX recipients are in most cases successfully treated with oral VGCV. However, in a small percentage of patients, mutations in the UL 97 or UL 54 gene lead to drug resistance. Risk factors for the development of resistance during the treatment of CMV disease include:
Increased & prolonged use of GCV. D+/R- serostatus Type of organ transplanted. Late virus eradication. Low levels of CMV-specific T cells. UL97 mutations are the main cause of GCV resistance, however UL54 mutations may also be at play. UL97 mutations mediate GCV specific resistance because this viral gene is crucial in the 1st mono-phosphorylation of GCV in infected cells. UL54 mutations, on the other hand, can produce cross-resistance to other antiviral medicines (cidofovir & foscarnet) because this gene codes for the viral polymerase that these medications target. Treatment strategies for GCV-resistant infections:
Reduce or stop immunosuppressive like MMF/AZA if it has not been stopped. Increasing the dose of VGCV/GCV The incidence of GCV-resistance ranges from 5% to 10% while on GCV prophylaxis. GCV-resistance is also seen during VGCV prophylaxis & in the pre-emptive setting of renal transplantation (7%). Consider the use of CMV immunoglobulin to induce a passive Immunity. we switch to second-line agents like intravenous foscarnet, cidofovir, and Leflunomide for three weeks. There is a role for a combination of GCV + Foscanet since they both attack different CMV genotypes. we seek specialist virology in assistance, particularly in the genotype. Close kidney function check because of the risk of graft rejection and toxicity associated with the second-line antiviral agents on the kidney. Review the dose of immunosuppression after treatment.
What are the other tests to diagnose and monitor CMV? Serological diagnosis (IgM & IgG antibodies):
The value of serology is limited.
No value for the diagnosis of active disease or infection. Difficult to interpret in immunocompromised patients can be due to the patients’ impaired humoral responses. IgG Ab appears 6 to 8 weeks of infection & can persist indefinitely. It is used to define the serological status of the donor & the recipient (D/R). CMV antigenemia test:
Rapid (6 hours) & simple method for the detection of CMV phagocytized by neutrophils in the peripheral blood. Monoclonal Abs to CMV pp65 protein are used as an early & specific marker of active infection. The results are expressed as the number of PMN cells infected in relation to the total number of PMN cells counted. Comparable to quantitative PCR in that it is a highly specific method for CMV detection & has predictive value for the disease severity, which is related to the number of cells detected.
The disadvantages:
Needs to be done immediately after the collection of blood samples. Its quantification is subjective & dependent on the expertise of the operator. Not an standardized method (extensive variability in its practice). The result may be doubtful in patients with a neutrophil count < 1,000/mm3. Viral resistance tests:
UL97 & UL54 are frequently linked to ganciclovir resistant CMV. Histological diagnosis:
Helpful in the diagnosis of invasive disease. Intracellular viral inclusion & CMV antigens are detected by IHC or DNA hybridization. CNS disease can be diagnosed detection of CMV in the CSF (by RT-PCR). Viral cultures:
Not routinely used.
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)? An intervention cut-off point is >2,000 copies/mL of whole blood.
Higher viral loads are associated with a higher chance of contracting the disease. Due to assay variability & the absence of a global reference standard, there is a poor correlation between the quantitative values for the viral load test amongst laboratories. This variance prevents the development of clinical decision-making cut-off points that are broadly applicable, particularly for preventive therapy regimens.
What is the duration of pre-emptive treatment?
Duration of treatment with oral Valganciclovir is for at least 2 weeks [1A]. The dose of Valganciclovir is adjusted if creatinine clearance is < 60ml/minute. Consider stopping treatment for CMV disease after resolution of symptoms AND 2 consecutive, CMV viral load tests that confirm that CMV is not detected (below the local laboratory threshold for detection) [2D].
What is the relation between the viral load and the development of CMV disease?
The quantification of CMV viral load as a proxy for CMV disease severity & disease-associated mortality end points in SOT is supported by the association between CMV viral load & severe CMV disease & death. What is the relation between the viral load and the development of CMV disease? Several studies have shown a linear relationship between the CMV viral load and the rate or frequency of development of CMV disease. The higher the CMV level the more the tendency to development of the disease and also the faster the rate of rise of the viral load the higher the chances of the development of CMV disease. References
Myhre et al. Incidence and Outcomes of Ganciclovir-Resistant Cytomegalovirus Infections in 1244 Kidney Transplant Recipients. Transplantation 92(2):p 217-223, July 27, 2011. | DOI: 10.1097/TP.0b013e31821fad25
Azevedo LS et al. Cytomegalovirus infection in transplant recipients, CLINICS 2015; 70(7): 515-523.DOI: 10.6061/clinics/2015(07)09
Daniel S Owers, Angela C Webster, Giovanni FM Strippoli, Kathy Kable, Elisabeth M Hodson, Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients, Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD005133. DOI: 10.1002/ 14651858.CD005133.pub3. C. N. Kotton, CMV: Prevention, Diagnosis and Therapy American Journal of Transplantation 2013; 13: 24–40 Wiley Periodicals Inc
McBride et al, Correlation of Cytomegalovirus Disease Severity and Mortality with CMV Viral Burden in CMV-Seropositive Donor and CMV-Seronegative Solid Organ Transplant Recipients, Open Forum Infectious Diseases UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION, BTS, 2022
Michael KlompasTreatment of Ganciclovir Resistant Cytomegalovirus Infection. Angela M Caliendo. Approach to the diagnosis of cytomegalovirus infection. UpToDate. August 15, 2022 UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS. 2022
I like your superb reply that is comprehensive and a well-referenced clinical approach. I like your comprehensive well-referenced clinical approach. At this stage I would not consider giving forscarnet but will keep if resistant virus is the cause. Typing whole sentence in bold or typing in capitals amounts to shouting.
What is your management strategy?
A case of D+/R- transplant presented with fever 2 months post transplant.
Quantitative CMV PCR is 5.52 log 10 copies/ml, not responding to oral valganciclovir 900 mg twice daily.
So Valganciclovir resistance is possible it is suspected when CMV viremia (DNAemia or antigenemia) fails to improve (ie, >1 log10 increase in CMV DNA levels in blood or serum) after 2 weeks of appropriately dosed and delivered antiviral therapy
It can be confirmed by genotype analysis to assess for known mutations in the UL54 and UL97 genes.
Risk factors for the valganciclovir resistance include CMV negative donor and CMV positive recipient , degree of immunosuppression, CMV viremia, and prolonged exposure to anti-CMV medication.
Patients with ganciclovir resistant disease suffered a statistically significant decrease in survival compared to those with ganciclovir sensitive disease.
Therapy include either Foscarnet is a direct competitive inhibitor of DNA polymerase having activity against CMV isolates with UL97 mutations that are resistant to ganciclovir but has multiple adverse effects as nephrotoxicity and neutropenia Or combination ganciclovir and foscarnet at reduced doses to reduce it’s side effects Or CidofovirIV can cause nephrotoxicity which can be decreased by prehydration and probenecid use . Or Lefluonamide as immunomodulatory agent but it can increase liver enzymes. Maribavir, an antiviral agent, competes with ATP for binding to pUL97
It may not completely inhibit CMV replication in ganciclovir resistance , resulting in persistent low-level viremia. Brincidofovir is the oral lipid conjugate of cidofovir. It is more potent and less nephrotoxic than cidofovir Letermovir it inhibits CMV DNA synthesis at a late step by targeting the pUL56 subunit of the terminase enzyme complex CMV-specific CTLs
Cellular adoptive immunotherapy is efficient for the treatment of CMV infection after transplantation What are the other tests to diagnose and monitor CMV?
For monitoring CMV active disease pp65 antigenemia can be used to detects the presence of the pp65 phosphoprotein on peripheral blood leukocytes and viral DNA detection by polymerase chain reaction (PCR), which can be qualitative or quantitative.
Serological methods to detect IgM and IgG classes
Viral cultures are not practical due to low accuracy and time consuming. Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
This cutoff level has not been established, each center use their own cutoff point ranging from 1 to 50 positive cells per slide with 200,000 leukocytes .
Saracino et al., suggested that antigenemia ≥2 positive cells/200,000 leukocytes can be considered an appropriate cutoff point for starting pre-emptive therapy among renal transplant recipients . In contrast, Jung et al., concluded that the therapy should be administered only to patients with ≥25 positive cells per slide. What is the duration of pre-emptive treatment?
for 10 to 14 days or until CMV viremia findings became negative. In preemptive therapy, transplant recipients are monitored for CMV replication by serial CMV DNA or pp65 antigen detection tests and are treated with antiviral drugs when active CMV replication is detected, regardless of clinical symptoms What is the relation between the viral load and the development of CMV disease?
CMV DNA viral load testing is an important test to evaluate CMV disease risk of disease and diagnosis , and monitoring response to therapy. The interpretation of CMV DNA viral load values can be complex, and numerous virus and host factors should be considered when assessing the risk of CMV disease. Reference
-Klompas M .Treatment of Ganciclovir Resistant Cytomegalovirus Infection
– El Chaer F, Shah DP, Chemaly RF. How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients. Blood. 2016;128(23):2624-2636.
– Franco R F et al.CMV diagnosis in renal transplantation. J Bras Nefrol 2017;39(1):46-54
– de Matos SB, Meyer R, Lima FWM. Cytomegalovirus Infection after Renal Transplantation: Occurrence, Clinical Features, and the Cutoff for Antigenemia in a University Hospital in Brazil. Infect Chemother. 2017;49(4):255-261.
– Hasegawa J et al .Preemptive anti-cytomegalovirus therapy in high-risk (donor-positive, recipient-negative cytomegalovirus serostatus) kidney transplant recipients .International Journal of Infectious Diseases 2017 , ISSN: 1201-9712, Vol: 65, Page: 50-56
– Bordo et al. Prophylaxis Versus Preemptive Therapy for Cytomegalovirus Disease in High-Risk Liver
Transplant Recipients. LIVER TRANSPLANTATION, September 2012 18:1093-1099.
– Colleen S. Kraft, Wendy S. Armstrong, Angela M. Caliendo, Interpreting Quantitative Cytomegalovirus DNA Testing: Understanding the Laboratory Perspective, Clinical Infectious Diseases, Volume 54, Issue 12, 15 June 2012, Pages 1793–1797
I like your well-referenced clinical approach. I would emphasise that reducing immunosuppression and commencing IV ganciclovir are 2 more important initial step in this patient who has been on oral valcyte. At this stage I would not consider giving forscarnet but will keep that in the back of my mind if resistant virus is the cause.
What is your management strategy?The index patient is a recent (2 month back) cadaveric CMV seropositive donor to CMV seronegative renal transplant recipient, with 000 mismatch, and on tacrolimus and steroid based dual maintenance immunosuppression. This combination of donor-recipient (D+/R-) is a high-risk transplant with respect to CMV infection (1).The patient needs evaluation in form of:
History: History regarding any symptoms, especially with respect to any tissue-specific CMV involvement (for example diarrhea, shortness of breath or cough), any history of recent anti-rejection treatment (with consequent intense immunosuppression use).Laboratory tests: Complete blood count, renal function test, urine routine, chest x ray, tacrolimus trough level, CMV PCR quantitative in blood, other investigations as per symptoms, if any (for example stool examination, colonoscopy if gastrointestinal involvement).Treatment: If asymptomatic (as in the index patient), Oral valganciclovir 900 mg twice a day (dose to be modified as per creatinine clearance) should be given for at least 2 weeks, and treatment should continue with weekly CMV PCR testing until 2 (single negative in case of using highly sensitive test) negative CMV PCR values are achieved. Intravenous gancyclovir 5 mg/kg 12 hourly (dose to be adjusted as per creatinine clearance) can be given if concerns regarding oral absorption of valganciclovir (or severe illness) exist (1,2). Longer duration of treatment might be required (till symptoms subside) if tissue-invasive CMV is present (like gastrointestinal involvement, pneumonitis, of CNS involvement).The indexpatient did not respond to oral valganciclovir. It could be due to poor oral absorption, over-immunosuppressed state, or gancyclovir resistance (1). Assessment for ganciclovir resistance should be done. Genotype testing to identify the specific mutations should be done.
First step is to give increased dose of intravenous Ganciclovir (10 mg/kg 12 hourly) rather than the standard dose of 5 mg/kg 12 hourly (dose should be adjusted as per creatinine clearance), and if responds, then continued for minimum 2 weeks, and until clearance of CMV in blood (1,2). In absence of any genetic mutation, ganciclovir would suffice. If no response, or if there is UL97 and UL54 mutation: Shift to intravenous Foscarnet (90 mg/kg 12 hourly, dose to be adjusted as per renal clearance) for 3 weeks and additional CMV immunoglobulin or intravenous immunoglobulin (IVIG) should be considered (1). Cidofovir (1mg.kg intravenous 3 times a week): Can be given in presence of UL97 mutation alone (not effective in UL54 mutation).Maribavir (400 mg twice a day for 8 weeks): Active against both UL97 and UL54 mutations.Letermovir have also been used. Immunosuppression reduction: Ideally antimetabolites should be stopped/ reduced by 50%. But in the index case, patient is already on dual immunosuppression only. The CNI levels should be checked.Patient should be counselled regarding the risk of rejection in such a scenario when the dose of immunosuppression is being reduced.Post-treatment, CMV monitoring should be done weekly for 12 weeks.
What are the other tests to diagnose and monitor CMV?Tests to diagnose CMV include (1,2):
CMV quantitative nucleic acid testing (CMV-QNAT): Test of choice for CMV rapid diagnosis in organ transplant recipients (1). It is useful as a surveillance tool for monitoring of CMV.pp65 Antigenemia: Detection of pp65 antigen in blood is comparable to CMV QNAT as for diagnosing and monitoring treatment response of CMV (1).Histopathological diagnosis: Identification of CMV-cytopathic changes or CMV antigen by immunohistochemistry is utilized in tissue-invasive CMV, where the blood CMV QNAT might be negative (for example gastrointestinal or respiratory tract involvement).CMV Viral culture: It has limited clinical utility, hence not recommended for CMV disease diagnosis after transplant.CMV serology: CMV IgM has limited utility, hence not recommended in organ transplant recipients (2). Antibodies from blood products or IVIG (if used) can give false positive values, and false negative values can be seen due to inability to mount antibody response because of immunosuppressed state) (1).Immunological monitoring using parameters like hypogammaglobulinemia, absolute lymphocyte count and CD4+/CD8+ T cell (nonspecific and CMV-specific) subsets have been used for CMV disease risk stratification, but specific thresholds have not been defined. Absence of CMV-specific CD4+ and/or CD8+ T cells signify higher risk of CMV disease, treatment failure, and relapse.Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?There is no consensus regarding the cut-off level for preemptive CMV treatment in kidney transplant recipients with ranges from 1500 to 4000, with lower thresholds for D+/R- pair (2,3). Some groups use rapid doubling of CMV viral load as a marker for pre-emptive treatment. In our unit, we take 1500 as cut-off.
What is the duration of pre-emptive treatment?The duration for pre-emptive CMV treatment will be until 1 or 2 weekly negative CMV PCR reports with a minimum of 2 weeks.
What is the relation between the viral load and the development of CMV disease?Peak CMV viral load has been shown to be an independent significant predictor of CMV disease (4). But absence of CMV in blood , as can be seen in gastrointestinal tissue-invasive CMV, the blood CMV PCR could be negative while histopathological lesion suggestive of CMV can be seen, does not rule out CMV disease.
References:
Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, Humar A; The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-931. doi: 10.1097/TP.0000000000002191. PMID: 29596116.Timsit JF, Sonneville R, Kalil AC, Bassetti M, Ferrer R, Jaber S, Lanternier F, Luyt CE, Machado F, Mikulska M, Papazian L, Pène F, Poulakou G, Viscoli C, Wolff M, Zafrani L, Van Delden C. Diagnostic and therapeutic approach to infectious diseases in solid organ transplant recipients. Intensive Care Med. 2019 May;45(5):573-591. doi: 10.1007/s00134-019-05597-y. Epub 2019 Mar 25. PMID: 30911807; PMCID: PMC7079836.Humar A, Gregson D, Caliendo AM, McGeer A, Malkan G, Krajden M, Corey P, Greig P, Walmsley S, Levy G, Mazzulli T. Clinical utility of quantitative cytomegalovirus viral load determination for predicting cytomegalovirus disease in liver transplant recipients. Transplantation. 1999 Nov 15;68(9):1305-11. doi: 10.1097/00007890-199911150-00015. PMID: 10573068.
Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.
Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, Humar A; The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-931. doi: 10.1097/TP.0000000000002191. PMID: 29596116.
Timsit JF, Sonneville R, Kalil AC, Bassetti M, Ferrer R, Jaber S, Lanternier F, Luyt CE, Machado F, Mikulska M, Papazian L, Pène F, Poulakou G, Viscoli C, Wolff M, Zafrani L, Van Delden C. Diagnostic and therapeutic approach to infectious diseases in solid organ transplant recipients. Intensive Care Med. 2019 May;45(5):573-591. doi: 10.1007/s00134-019-05597-y. Epub 2019 Mar 25. PMID: 30911807; PMCID: PMC7079836.
Humar A, Gregson D, Caliendo AM, McGeer A, Malkan G, Krajden M, Corey P, Greig P, Walmsley S, Levy G, Mazzulli T. Clinical utility of quantitative cytomegalovirus viral load determination for predicting cytomegalovirus disease in liver transplant recipients. Transplantation. 1999 Nov 15;68(9):1305-11. doi: 10.1097/00007890-199911150-00015. PMID: 10573068.
4. A 61-year-old man was admitted with fever (38 °C) and malaise 2 months after cadaveric transplantation, 000 mismatch on Tacrolimus (trough 9 ng/ml) and prednisolone 15 mg/day. CMV is positive to CMV negative recipient. Oxygen saturation was reported to be 95% on air. Quantitative CMV PCR reported 5.52 log 10 copies/ml. The patient has not responded to oral valganciclovir 900 mg twice daily.
Valganciclovir Resistance Should be suspected if CMV PCR count has not fallen by ≥ 1 log copies/ml after two weeks of therapy or if there is no clinical improvement despite treatment
Exclude other causes of symptoms
Risk factors for CMV resistance in HCT recipients
Host factors
Prolonged antiviral CMV drug exposure (>3 mo)
Previous antiviral CMV drug exposure
Recurrent CMV infection
Inadequate antiviral CMV drug absorption and bioavailability
Inadequate antiviral CMV oral prodrug conversion
Variation in antiviral CMV drug clearance
Subtherapeutic antiviral CMV drug level
Poor compliance
T-cell depletion
Haploidentical, allogeneic, and cord blood HCT
Delayed immune reconstitution
CMV-seropositive recipient
Treatment with antithymocyte antibodies
Active GVHD
Young age
Congenital immunodeficiency syndromes
Viral factors
CMV viral load rise while receiving treatment (after >2 wk with adequate dosing)
Failure of CMV viral load to fall despite appropriate treatment
Rise in CMV viral load after decline while receiving appropriate therapy
Intermittent low-level CMV viremia
High CMV viral loads
==================================================================== What is your management strategy?
• Foscarnet (nephrotoxic; it can result in metabolic changes as well as cardiac arrhythmias and genital ulcerations).
• Cidovir (nephrotoxic and causes neutropenia, metabolic acidosis and ocular hypotony)
• Letermovir is a newly approved anti-CMV antiviral which inhibits the viral terminase complex. It interacts with immunosuppression, requires dose adjustment in renal and hepatic impairment and can be used with other anti-CMV medications.
• Maribavir is a promising new antiviral against the viral UL97 kinase. Reduced haematotoxicity and nephrotoxicity compared to GCV and VGCV and so could eventually replace these older compounds. Co-administration of with GCV is not advised as Maribavir is an inhibitor of the UL97 enzyme required for anabolism of the latter.
All immunosuppressive medication should be significantly reduced/stopped in life-threatening CMV disease and CMV disease that persists in spite of treatment, unRl CMV disease has resolved.
Monitoring graft function closely during CMV disease.
The reduction of immunosuppression increases the risk for rejection, monitoring of kidney function is warranted to guide the use of immunosuppression.
All treatment should continue until resolution of symptoms and for a minimum of 14 days.
Consider (further) reduction in immunosuppression
Consider Immunoglobulins (particularly if pneumonitis). CMVIG can be used to induce a passive immunity. Resistant infection and side effects to VGC Consider
What are the other tests to diagnose and monitor CMV?
Serology
• CMV IgG indicates past infection. Good for screening, but not for diagnosis of CMV disease
• CMV IgM indicates acute infection
Antigen testing CMV pp65 antigenaemia is used to detect messenger matrix proteins on the CMV virus, which are expressed only during viral replication.
It is sensitive and specific, but cannot be used in patients with leukopenia.
Low or moderate CMV antigenemia may indicate reactivation or infection.
Qualitative PCR is used to detect CMV in blood and tissue samples, but its clinical utility is limited. Serial PCR may be more helpful. NucliSens CMV Test is a nucleic acid sequence-based amplification assay.
Quantitative PCR is an important tool for monitoring CMV infection and determining when to initiate preemptive treatment.
It is as sensitive as qualitative PCR and provides an estimate of the number of CMV genomes present in plasma.
Shell vial assay is an effective test for CMV, as sensitive as traditional tissue culture.
Cytopathology is the study of intracellular inclusions surrounded by a halo.This gives the appearance of an “owl’s eye”
Other Tests Cytomegalovirus resistance testing
If resistant CMV infection is suspected (refractory to IV ganciclovir or valganciclovir therapy), an alternative therapy should be used based on genetic resistance.
UL54 mutation is associated with ganciclovir resistance and a cross-resistance with Cidofovir. UL97 mutation is also associated with ganciclovir resistance.
If this is noted, Foscarnet is the recommended therapy. Letermovir could be an alternate option due to a different mechanism of action (however this is currently recommended only for prophylaxis).
If low levels of resistance is suspected, higher doses of Ganciclovir could be used
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
No widely accepted viral load threshold to guide medication due to lack of uniformity of PCR data across facilities.
Preemptive therapy can be considered in moderate risk SOT patients • R+
• Kidney, liver, and heart transplants
Preemptive therapy
Serial testing performed weekly or biweekly for the first several months post-transplantation.
Treatment dosages of antivirals administered regardless of symptoms.
Pre-emptive treatment of CMV viraemia is an alternative to antiviral prophylaxis, but is associated with increased risk of adverse effects, resistance, and late onset CMV disease.
The optimal cut-off for preemptive therapy is 3983 IU/ml
Real-time PCR was found to be the optimal cut-off for initiating preemptive therapy, with 99.6% NPV and high sensitivity and specificity.
==================================================================== What is the duration of pre-emptive treatment?
Preemptive therapy given for 3-4 weeks after 2 negative PCR.
What is the relation between the viral load and the development of CMV disease?
The risk of developing CMV illness and its related morbidity and mortality increases with increasing viral load.
The connection between CMV viral load and severe CMV disease and death supports the quantification of CMV viral load as a surrogate for CMV disease severity & disease-associated mortality end points in SOT.
El Chaer F, Shah DP, Chemaly RF. How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients. Blood. 2016;128(23):2624-2636. doi:10.1182/blood-2016-06-688432
Hodson EM, Jones CA, Webster AC, Strippoli GF, Barclay PG, Kable K. Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials. Lancet. 2005 Jun 18-24. 365(9477):2105-15.
CMV in Kidney Transplantation By Ahmed Halawa Consultant Transplant Surgeon Associate Professor, University of Liverpool – UK
I like your comprehensive well-referenced clinical approach. At this stage I would not consider giving forscarnet but will keep if resistant virus is the cause. Typing whole sentence in bold or typing in capitals amounts to shouting.
What is your management strategy?
KTR with fever and CMV viremia who did not respond despite good valganciclovir dose, which is suggestive for ganciclovir disease.
The prevalence in SOT ranges between 0 and 15%, In KTR 2.2% and it vary according to the organ transplanted likely reflect different degrees of immunosuppression.
Risk Factors;
CMV R-/ D+ ; risk of both CMV infection and ganciclovir resistance.
Degree of IS.
Magnitude of CMV viremia.
Prolonged exposure to anti-CMV medication.
Management of CMV- resistance disease;
– Check treatment adherence.
– Offer testing for CMV antiviral resistance, UL97 and UL54 gene mutations.
– Seek specialist virology advice.
– Definitive antiviral treatment should be guided by results of genotypic
– Stop Valganciclovir.
– IV ganciclovir appropriate dose before considering alternative options.
– Consider Foscarnet IV for at least 3 weeks till viral load is negative ( monitor KFT & electrolytes)
– leflunomide can be considered for both potentiates immunosuppression and suppresses CMV replication.
– Cidofovir ( nephrotoxicity limits its use)
– ff‐label letermovir , Maribavir
– CMV Ig or IVIG may be used as an adjunct to antiviral drugs
– The doses should be adjusted to renal function
– Monitor RF, CBC, and LFT is required
IS management :
– Stop/reduce (by 50%) antimetabolites.
– Do not discontinue CNI unless there is evidence of a life-threatening infection; keep the level of Tacrolimus 6.
– Corticosteroids are generally continued.
– Consider switching to sirolimus‐containing regimen may be an option due to the reportedly lower risk of CMV disease in patients receiving mTOR inhibitors
– Monitor graft function. What are the other tests to diagnose and monitor CMV?
– CMV-PCR the best method to diagnose and monitor CMV.
– Serology; very limited role, as SOTR has impaired to produce adequate antibody response, the main utility in the pre-transplant screening for candidates and donors for risk stratification.
– Antigenemia; detects CMV pp65 antigen in infected peripheral blood leucocytes, has a higher sensitivity than viral culture, it may have limited clinical utility in leucopenic patients, and the test requires a quick sample processing time for accuracy (4 to 6 hours).
-Viral culture is highly specific for the detection of CMV, but it has low sensitivity and the assay has a long turn-around time, used to diagnose CMV disease where viral load might be negative.
– Histopathology ;remains as the gold standard for the definitive diagnosis of end‐organ CMV diseases Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
The major drawback to CMV NAT is the lack of widely applicable thresholds; due to lack of standardization.
Sheffield hospital protocol consider:
– Viral load < than 3 logs 10; reduce immunosuppression
– Viral load > 3 logs 10 or if symptomatic or rapidly rising titer ; treat with valganciclovir.
– Viral load > 4 logs 10 ; Treat with oral valganciclovir or IV ganciclovir.
As a general rule, viral loads that are >10,000 copies/mL used. What is the duration of pre-emptive treatment? Preemptive therapy; can be considered in moderate risk SOT recipients (recipients positive for CMV).
– Serial testing performed weekly or biweekly for the first few months post-transplantation
– Regardless of symptoms, antiviral treatment are administered with any early evidence of CMV replication
– Treatment duration: for 14-21 days, to be continued till 2 x PCR negative
Universal prophylaxis:
– D+/R- 200 days of valganciclovir.
– D-/R+ & D+/R+ 100 days of valganciclovir, 200 days after ATG or Alemtuzumab
– D-/R- No valganciclovir
– After receiving intensified IS at any time point.
What is the relation between the viral load and the development of CMV disease?
– Higher viral loads are also generally observed during primary CMV disease in CMV D+/R− compared to reactivation in CMV R+ SOT recipients.
– Higher viral load values in blood are also generally associated with end‐organ disease, while lower values are seen with asymptomatic CMV infection, and intermediate‐ range viral loads are seen with CMV syndrome, although
there is overlap in viral load values among categories.
References:
– Angarone M, Snydman DR; AST ID Community of Practice. Diagnosis and management of diarrhea in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13550. doi: 10.1111/ctr.13550. Epub 2019 Apr 10. PMID: 30913334.
-Sheffield protocol for prophylaxis, surveillance, and treatment of CMV after renal transplantation, 2016
-Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521.
I like your well-referenced clinical approach. You mention stopping or reducing MMF, though this patient is already off MMF.
I agree that reducing immunosuppression and commencing IV ganciclovir are 2 more important steps. At this stage I would not consider giving forscarnet but will keep that in the back of my mind if resistant virus is the cause.
A 61-year-old man was admitted with fever (38 °C) and malaise 2 months after cadaveric transplantation, 000 mismatch on Tacrolimus (trough 9 ng/ml) and prednisolone 15 mg/day. CMV is positive to CMV negative recipient. Oxygen saturation was reported to be 95% on air. Quantitative CMV PCR reported 5.52 log 10 copies/ml. The patient has not responded to oral Val ganciclovir 900 mg twice daily. What is your management strategy?
A case of CMV infection, resistance to Val ganciclovir and low immunological risk.
1-In vGCV/GCV resistance ask for viral gene typing.
2-IV Val ganciclovir will be started.
2-All immunosuppressive medication should be significantly reduced/stopped in life-threatening CMV disease and CMV disease that persists in spite of treatment, until CMV disease has resolved.
3-Monitoring graft function closely during CMV disease.
4-Consider Immunoglobulins (particularly if pneumonitis). CMVIG can be used to induce a passive immunity.
5-Using second line such as (Foscarnet, Cidofovir and Letermovir).
6-All treatment should continue until resolution of symptoms and for a minimum of 14 days. What are the other tests to diagnose and monitor CMV? Serology:
-CMV IgG (indicates past infection. good for screening).
-CMV IgM (indicates acute infection). DNA PCR:CMV DNA is amplified from a plasma sample or a biopsy.
-Results are usually reported as number of copies/ml of blood or plasma. CMV pp65 antigenaemia:
pp65, a protein, is detected by fluorescent assay and reports as number of infected peripheral blood cells. Histopathology:
Chemical staining of tissue samples to detect CMV inclusion bodies (Owl’s eye appearance) Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)? No widely acceptable viral load threshold to guide therapy due to lack of standardization of PCR results across centers, but some suggestion advice to treat seronegative recipient (high risk) with PCR > 1000 copies /ml and transplant recipients with the PCR is > 5000 copies/m should be treated regardless the serostatus of the recipient.
What is the duration of pre-emptive treatment?
Preemptive therapy given for a minimum 3 weeks (usual duration of therapy 3-4 weeks) and once there are 2 successive negative PCR , TTT will be stopped. What is the relation between the viral load and the development of CMV disease?
A study shown that the risk of disease increases as the viral load increases (a 50% probability of disease was reached at a virus load of 4.0 × 105 copies/ml and an 80% risk was reached at 1.6 × 106 copies/ml) References:
1-Krishna BA, Wills MR, Sinclair JH. Advances in the treatment of cytomegalovirus. Br Med Bull. 2019;131(1):5-17. doi:10.1093/bmb/ldz031
2-Aitken C, Barrett-Muir W, Millar C, et al. Use of molecular assays in diagnosis and monitoring of cytomegalovirus disease following renal transplantation. J Clin Microbiol. 1999;37(9):2804-2807. doi:10.1128/JCM.37.9.2804-2807.1999.
I like your well-referenced clinical approach. However, reduction of immunosuppression and commencing IV ganciclovir are 2 more important steps. At this stage I would not consider giving forscarnet but will keep if resistant virus is the cause.
My management strategy would be to start the patient on IV ganciclovir, adjust immunosuppression, and closely monitor respiratory status and oxygen saturation.
What are the other tests to diagnose and monitor CMV?
Serologic tests (Immunoglobulin M [IgM], IgG, or IgA antibodies)
-Polymerase chain reaction (PCR) or virus culture
-Chest X-ray
-Computed tomography (CT) scan
-Bronchoalveolar lavage fluid
-Biopsy of tissue
To monitor CMV, physicians typically use serum quantitative CMV PCR, which measures the amount of virus in the blood, as well as patient symptom evaluation, physical examination, and imaging to assess the extent and progression of the infection.
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
The cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy) is typically between 125-500 copies of CMV DNA/mL.
Treatment may be indicated if the CMV viral load exceeds these levels. However, physicians should consider other factors such as the patient’s age and overall health when making treatment decisions.
What is the duration of pre-emptive treatment?
The duration of pre-emptive treatment will depend on the individual case. Depending on the specific case, pre-emptive treatment may last from several weeks to six months or more.
What is the relation between the viral load and the development of CMV disease?
The level of the virus in the body is known as the viral load. Studies have shown that when a person’s viral load is higher, they are more likely to contract CMV disease.
What is the difference between Pre-emptive treatment and prophylactic treatment?
What is the condition when viral load is not concordant with CMV disease?
What is your management strategy?
This patient not responded to treatment in spite of full dose of valganciclovir. This is Ganciclovir resistance. It is defined as CMV disease that is refractory to treatment with Ganciclovir or Valganciclovir and is reported to occur in up to 3% of SOT recipients (Deteced via genotype analysis to assess for UL54 and UL97 genes)
Risk factors include:
1. R-/D+
2. Degree of immunosuppression
3. Magnitude of CMV viremia
4. Prolonged exposure to anti-CMV medication, or subtherapeutic antiviral dosing
Consider resistance to Ganciclovir if there is a persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir
If resistance to Ganciclovir is suspected:
1. Confirm that dosing is adequate
2. Consider adherence to treatment plan and absorption
3. Offer testing for Human CMV (HCMV) antiviral resistance: UL97 and UL54 gene mutations. Use either whole blood or plasma
When there is evidence of ganciclovir resistance:
1. Stop Valganciclovir (or Ganciclovir)
2. Offer Intravenous Foscarnet for at least 3 weeks. Seek specialist virology advice before commencing treatment with Foscarnet
Newer agents Letermovir and Maribavir may be associated with less drug toxicity
Maribavir has FDA approval and is currently being assessed by the NICE
Immunosuppressions: In patients without concomitant rejection, reduction of immunosuppression is suggested in the following settings:
1. Severe CMV disease
2. Inadequate clinical response
3. High viral loads
4. and cytopenia
What are the other tests to diagnose and monitor CMV?5. Antigen testing (CMV pp65)
6. Qualitative PCR
7. Shell vial assay
8. Histopathology
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
Optimal thresholds are different among different at-risk groups. There was strong consensus that a lower threshold should be used with D+/R−, as the use of higher thresholds may result in insufficient time to begin treatment for CMV and higher rates of disease. Although prior guidelines mentioned that some experts, recommended starting treatment with any detectable DNAemia, with increasingly sensitive assays many experts felt that very low results should not always result in initiation of treatment, even in D+R−recipients (4)
High risk (D+R−): 1500 IU/mL in plasma (the index case). No episodes of symptomatic CMV disease were diagnosed in patients with viral loads below 1500 IU/mL
Moderate risk (D+R− and R+): 3000 copies/mL of whole blood
Patients that develop viraemia whilst not on prophylaxis (Sheffield protocol):
o Treatment is mandatory in all cases of suspected tissue-invasive CMV disease, irrespective of viral load
o Treat with valganciclovir when the viral load exceeds 3 logs 10 and rapidly rising titre in high-risk patients
o Treatment with valganciclovir or IV ganciclovir is mandatory when the viral load exceeds 4 logs 10
What is the duration of pre-emptive treatment?Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days
Stop treatment after resolution of symptoms and two consecutive, negative tests for CMV viral load, then prophylaxis for 200 days (D+/R-)
What is the relation between the viral load and the development of CMV disease?
o CMV load, used as a surrogate marker of CMV replication, has been shown in many studies to be a dominant risk factor for CMV disease
o The level of viral load in the blood compartment may not correlate with the severity of tissue invasive disease and QNAT of plasma or blood may not be the best indicator of disease resolution
References 1. CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023 2. Treatment of Ganciclovir Resistant Cytomegalovirus Infection, Michael Klompas. 3. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS, 2022. 4. Camille N, et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation 2018;102: 900–931.
Gancyclovir resistance is defined as failure of reduction of viral load ≥ 1 log copies /ml after 2 weeks of appropriate treatment
IV ganciclovir is the appropriate treatment in the following patients:
Symptomatic patients with viral load >10000 copies/ml
Patients with tissue invasive disease
Patients with life-threatening cases
So I will start ganciclovir intravenously in a dose of 5mg/kg/12 hours since the patient has tissue invasive disease and the high viral load
Then I will monitor PCR weekly, if no reduction of viral load ≥ 1 log copies /ml after 2 weeks of treatment I will consider ganciclovir resistance and I will switch to alternative therapy under the guidance of virology expert
Alternative therapy for gancyclovir resistant CMV
1- IV Foscarent
It is given in a dose of 60mg/kg IV every 8h for 2 weeks followed by 90mg/kg/day
Its effect is comparable to IV gancyclovir
Associated with renal and GIT toxcicity and electrolyte imbalance and seizures, genital ulcers and infusion related symptoms, on the other hand neutropenia is less common with Foscarent than with gancyclovir
2- Combination therapy with reduced doses of ganciclovir and foscarnet
The regimen include the use of half the dose of IV gancyclovir (5mg/kg IV q24h) and 2/3 the dose of foscarnet (125mg/kg IV q24h)
Associated with comparable efficacy and less side effects
3- Cidofovir
Effective
Given IV twice weekly
Associated with high incidence of nephrotoxicity (50% of cases), myelosuppression and ocular disease( iritis, uveitis, and vitreous hypotonicity).
4- Leflunamide
It has immunosuppressive and antiviral activity at the same time, so it may provide the balance between treating virus and avoid reduction of immunosuppression
It is given in a loading dose then maintenance dose
Persist in the blood for very long time after stopping the medication (up to 2 years)
Side effects includes, hepatitis, myelosupression, hypertension, GI side effects, alopecia and skin rash
What are the other tests to diagnose and monitor CMV?
The main tool in diagnosis of CMV infection or disease is PCR with sensitivity 100% in D+/R- and 75% in D+/R+ transplant recipients.
Occasionally PCR is negative in tissue invasive disease and the only way for diagnosis is tissue biopsy and histopathological examination,
In CMV colitis around 20% of cases has negative PCR and diagnosis is settled by colonoscopy and biopsy
In CMV pneumonitis 30% of cases has negative PCR and the main diagnosis is by BAL
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)? Antiviral therapy is indicated in the following asymptomatic patients:
Seronegative recipient (high risk) with PCR > 1000 copies /ml
Sero positive recipient (low risk) with PCR > 1000 copies and during follow up there is rising t
Any transplant recipients whatever the serostatus of the recipient if the PCR is > 5000 copies/ml
On the other hand, treat any patient with PCR >35 copies/ml if symptomatic
Reduction of immunosuppression is indicated in all patients with detectable viral load in the form of reduction of the dose (by 50%) or stopping the antimetabolite (in severe and non-responding disease) and keeping CNI at lower trough then resume lower dose of antimetabolite only in high risk patients for rejection after PCR is negative for 2 successive samples 1 weeks apart with close follow up of PCR weekly for 1 month after starting low dose antimetabolite
What is the duration of pre-emptive treatment?
PCR should be done weekly once antiviral therapy started.
The drug is given for a minimum of 3 weeks (usual duration of therapy 3-4 weeks)
Stop treatment once there are 2 successive negative PCR readings (< 35 copies/ml) 1 week apart
What is the relation between the viral load and the development of CMV disease?
No good correlation exists between viral load and tissue invasive disease
Some patients with very high viral load and are asymptomatic
On the other hand, around 20% of patients with CMV colitis and 30% of patients with CMV pneumonitis has negative PCR and diagnosis is settled by colonoscopy and biopsy and BAL, respectively.
1-What is your management strategy? –In this patient with ganciclovir-resistant CMV infection; require reduction of immunosuppression. Gancyclovir ( intolerant or resistant); -Resistance to ganciclovir should be considered in recipients who fail to improve clinically and/or virologically after two weeks of adequate doses of antiviral therapy or who have recurrent relapses following treatment. -Factors that raise the likelihood of ganciclovir resistance include prolonged antiviral use, lack of prior CMV immunity (CMV D+/R-), and inadequate antiviral drug selection or dosing (eg, treatment with oral ganciclovir or subtherapeutic dosing of IV ganciclovir. Resistance testing; -Genotypic resistance testing should be performed in patients with suspected ganciclovir resistance (UL97 mutation & UL54 mutations). With evidence of resistance; -Stop valganciclovir or ganciclovir and give Intravenous Foscarnet for at least 3 weeks after specialist virology advice (newer agents Letermovir and Maribavir may be an alternative).
-It is important to note that nephrotoxicity is common when foscarnet is given in combination with cyclosporine or tacrolimus. Electrolyte disturbances are also common with foscarnet.
-An alternative to foscarnet is cidofovir, but there is less clinical experience with this agent for treating resistant CMV infection, and its use is limited by the potential for severe nephrotoxicity. Maribavir; -An oral drug that inhibits UL97 phosphotransferase and stops viral maturation. -It is active against CMV with UL97 and UL54 mutations. -Maribavir is dosed at 400 mg orally twice daily for eight weeks. -Dysgeusia is a frequent side effect, and maribavir cannot be coadministered with ganciclovir or valganciclovir. -Key advantages of maribavir over other agents are lack of bone marrow and kidney toxicity. -Due to a drug interaction with calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors, close monitoring of these immunosuppressive agents is required. -Resistance to maribavir has also been reported to emerge while on therapy. 2-What are the other tests to diagnose and monitor CMV? Molecular assays;
–Quantitative CMV-PCR tests for detecting viral DNA; COBAS AmpliPrep , COBAS TaqMan CMV test , COBAS CMV test , Artus CMV RGQ MDx test , RealTime CMV test , Alinity m CMV assay. -CMV pp65 antigenemia test for detecting viral antigen; -Quantitative PCR assays offer several advantages over the antigenemia assay, including better assay standardization, increased stability of the specimen, smaller specimen volume, and the ability to test patients with leukopenia. -For these reasons, quantitative PCR assays are more widely used than the antigenemia test, and it is preferred for the diagnosis and monitoring of immunocompromised patients with CMV infection and disease. Histopathology; –Histologic examination of tissue biopsies is useful for the diagnosis of CMV tissue-invasive disease. -Diagnosis is based on the presence of inclusion bodies, typically basophilic intranuclear inclusions, although eosinophilic cytoplasmic inclusions may also be seen;(Owel eye appearance). Culture; -Conventional culture; there are several limitations of conventional cell culture techniques. -Shell vial culture;is a rapid culture method based on low-speed centrifugation and detection of CMV early antigen prior to the development of characteristic cytopathic effects in tissue culture, thus accelerating the time to diagnosis. 3-Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)? -Viral load thresholds to start preemptive therapy have not been standardized across institutions given variability among diagnostic specimens and testing platforms.
-According study for liver transplant recipients showed that the optimal cutoff for predicting CMV disease was in the range of 2000 to 5000 copies/mL of plasma; at a cutoff of >5000 copies/mL, the sensitivity was 86% and the specificity was 87%. -All patients with a viral load >20,000 copies/mL developed CMV disease. An important limitation of these data is that these CMV DNA levels apply to the Amplicor Monitor test, which is not available clinically. -In a more recent study of solid organ transplant recipients at lower risk for CMV infection, a cutoff of approximately 4000 international units/mL was established for initiating pre-emptive therapy. -However, these results may not be generalizable, as testing was done on plasma samples using an assay that is not FDA approved and the study population was solid organ transplant recipients at low risk of developing CMV disease. 4-What is the duration of pre-emptive treatment?
–When pre-emptive therapy is indicated, use valganciclovir 900 mg orally every 12 hours (adjusted for renal dysfunction). While on therapy. -Monitoring the viral load weekly or biweekly. -Treatment until the viral load is undetectable or less than the lower quantifiable limit of the assay (ie, <200 international units/mL) on a single highly sensitive assay or until the viral load is undetectable on two consecutive samples when using less sensitive assays -If active CMV infection is detected, we give valganciclovir or IV ganciclovir at treatment doses until repeat CMV nucleic acid testing is negative and for a minimum of 21 days. 5-What is the relation between the viral load and the development of CMV disease?
–Studies of solid organ transplant recipients using quantitative PCR assays have shown higher viral loads in patients with active CMV disease compared with those with asymptomatic infection. -The rate of increase in viral load can be used to predict patients at risk for CMV disease. -Patients with CMV disease have a significantly faster rate of increase in CMV load between the last PCR-negative and first PCR-positive sample than those without CMV disease. References; -Chou S, Song K, Wu J, et al.Drug Resistance Mutations and Associated Phenotypes Detected in CLinical Trials of Maribavir for Treatment of Cytomegalovirus infection. J infect Dis 2022; 226:576 .
–Kotton CN, Kumar D, Caliendo AM, et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation 2018; 102:900.
–Humar A, Gregson D, Caliendo AM, et al. Clinical utility of quantitative cytomegalovirus viral load determination for predicting cytomegalovirus disease in liver transplant recipients. Transplantation 1999; 68:1305.
–Martín-Gandul C, Pérez-Romero P, Sánchez M, et al. Determination, validation and standardization of a CMV DNA cut-off value in plasma for preemptive treatment of CMV infection in solid organ transplant recipients at lower risk for CMV infection. J Clin Virol 2013; 56:13.
Check renal function, LFTs, WCC, anemia, and low platelets
Order for viral genetotype
Stop oral valgancyclovir
Start IV ganciclovir 5mg/kg BID until viral suppression typically 14 to 21 days according to the eGFR
IVIG may be added
After successful viral suppresion, oral valgancyclovir can be given for 1 to 3 months or even longer
Check weekly viral load
Monitor FBC/UECs
If viral resistance is documented, give foscarnet and monitor for renal function
Cidofovir may be considered as well for resistant cases and again it is a nephrotoxic medication
Reduction of immune suppression ;anti-metabolites is not mentioned in the case, but it has to reduce or stop for at least one months unless rejection occurs
-What are the other tests to diagnose and monitor CMV?
Biopsy for tissue invasive disease; problem is delay in diagnosis and may be inadequate sampling
Culture; conventional tissue culture & shell vial centrifugation and the diagnosis can be made in 48hours, replaced by PCR
CMVpp65; historical, and less sensitive
PCR; blood or CSF or even tissue or BAL; extremely sensitive, used for diagnosis & monitoring of the response to antiviral therapy
-Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
CMV negative pre-transplant as in this case; detection of any CMV viremia is consistent with primary CMV infection. Therefore, immediate reduction of immune suppression and initiation of pre-emptive therapy should be considered
A rapidly increasing viral load, with or without symptoms is an indication for reduction of immune suppression & commencement of antiviral therapy
-What is the duration of pre-emptive treatment?
Minimum of two weeks or until CMV viral load is undetectable
-What is the relation between the viral load and the development of CMV disease?
The higher the viral load the higher the chance of progression to CMV disease and its associated morbidity & mortality.
Thankyou for a very well organized answer but to mention :
In tissue invasive CMV as gastritis,sometimes viremia is absent but tissue histology is diagnostic.
What is your management strategy?
The patient has resistant to valganciclovir.
Mutations arising in UL97 phosphotransferase lead to ganciclovir resistance. Similarly, mutations arising in the DNA polymerase gene UL54 also confer resistance to ganciclovir.1 Different UL97 mutations are associated with different degrees of ganciclovir resistance.2 Most patients develop only UL97 mutations, however, prolonged exposure to ganciclovir can give rise to simultaneous UL54 and UL97 mutations.
treatment with reduced immunosuppression (the patient is at low immunological risk) CMV immunoglobulin. foscarnet, cidofivir, high-dose ganciclovir ,Leflunomide , or ganciclovir and foscarnet at reduced doses. What are the other tests to diagnose and monitor CMV?
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viremia (pre-emptive therapy)?
pre-emptive therapy with valganciclovir (900 mg b.i.d. for a minimum of 14 days) for significant CMV DNAemia (≥2000 copies/mL by quantitative PCR in whole blood) assessed weekly for 16 weeks and at 5, 6, 9, and 12 months.
What is the duration of pre-emptive treatment?
14 days, pre-emptive therapy relies on the timely availability of sensitive and reliable methods for detecting CMV viremia so that treatment based on identifying CMV infection can be initiated before CMV disease develops What is the relation between the viral load and the development of CMV disease?
The ability of the virus to reproduce is directly proportional to the amount of infectious virus that is circulating in the blood, independent of the body’s capacity to deal with the virus’s activities.
The correlation between CMV viral load and severe CMV illness and death provides support for the use of CMV viral load as a surrogate for these disease severity and mortality
The presence of high levels indicates that the person may be suffering from either a primary infection or a reactivation of an illness that they have previously had.
References: Owers, Daniel S., et al. “Pre‐emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients.” Cochrane database of systematic reviews 2 (2013).
The Prevention and Management of CMV Disease after Solid Organ Transplantation2022
Reischig, T., et al. “Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation.” American Journal of Transplantation 8.1 (2008): 69-77.
This is a case of ganciclovir resistant CMV viremia that developed despite the use of high dose valganciclovir (VGCV).
CMV infections in KTX recipients are in most cases successfully treated with oral VGCV. However, in a small percentage of patients, mutations in the UL 97 or UL 54 gene lead to drug resistance.
Risk factors for the development of resistance during the treatment of CMV disease include:
Increased & prolonged use of GCV
D+/R- serostatus
Type of organ transplanted
Late virus eradication.
Low levels of CMV-specific T cells.
UL97 mutations are the main cause of GCV resistance, however UL54 mutations may also be at play.
UL97 mutations mediate GCV specific resistance because this viral gene is crucial in the 1st mono-phosphorylation of GCV in infected cells.
UL54 mutations, on the other hand, can produce cross-resistance to other antiviral medicines (cidofovir & foscarnet) because this gene codes for the viral polymerase that these medications target.
Treatment strategies for GCV-resistant infections:
Immunosuppressive load reduction.
Increasing the dose of VGCV/GCV
Introduction of foscarnet or cidofovir.
The incidence of GCV-resistance ranges from 5% to 10% while on GCV prophylaxis.
GCV-resistance is also seen during VGCV prophylaxis & in the preemptive setting of renal transplantation (7%).
========================= What are the other tests to diagnose and monitor CMV? Serological diagnosis (IgM & IgG antibodies):
The value of serology is limited
No value for the diagnosis of active disease or infection. Difficult to interpret in immunocompromised patients can be due to the patients’ impaired humoral responses.
IgG Ab appears 6 to 8 weeks of infection & can persist indefinitely. It is used to define the serological status of the donor & the recipient (D/R).
CMV antigenemia test:
Rapid (6 hours) & simple method for the detection of CMV phagocytized by neutrophils in the peripheral blood. Monoclonal Abs to CMV pp65 protein are used as an early & specific marker of active infection.
The results are expressed as the number of PMN cells infected in relation to the total number of PMN cells counted.
Comparable to quantitative PCR in that it is a highly specific method for CMV detection & has predictive value for the disease severity, which is related to the number of cells detected.
The disadvantages:
Needs to be done immediately after the collection of blood samples.
Its quantification is subjective & dependent on the expertise of the operator.
Not an standardized method (extensive variability in its practice).
The result may be doubtful in patients with a neutrophil count < 1,000/mm3.
Viral resistance tests:
UL97 & UL54 are frequently linked to ganciclovir resistant CMV.
Histological diagnosis:
Helpful in the diagnosis of invasive disease.
Intracellular viral inclusion & CMV antigens are detected by IHC or DNA hybridization.
CNS disease can be diagnosed detection of CMV in the CSF (by RT-PCR).
Viral cultures:
Not routinely used.
========================= Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)? An intervention cut-off point is >2,000 copies/mL of whole blood.
Higher viral loads are associated with a higher chance of contracting the disease.
Due to assay variability & the absence of a global reference standard, there is a poor correlation between the quantitative values for the viral load test amongst laboratories.
This variance prevents the development of clinical decision-making cut-off points that are broadly applicable, particularly for preventive therapy regimens.
========================= What is the duration of pre-emptive treatment?
Duration of treatment with oral Valganciclovir is for at least 2 weeks [1A].
The dose of Valganciclovir is adjusted if creatinine clearance is < 60ml/minute.
Consider stopping treatment for CMV disease after resolution of symptoms AND 2 consecutive, CMV viral load tests that confirm that CMV is not detected (below the local laboratory threshold for detection) [2D].
========================= What is the relation between the viral load and the development of CMV disease?
The quantification of CMV viral load as a proxy for CMV disease severity & disease-associated mortality end points in SOT is supported by the association between CMV viral load & severe CMV disease & death.
References
Myhre et al. Incidence and Outcomes of Ganciclovir-Resistant Cytomegalovirus Infections in 1244 Kidney Transplant Recipients. Transplantation 92(2):p 217-223, July 27, 2011. | DOI: 10.1097/TP.0b013e31821fad25
Azevedo LS et al. Cytomegalovirus infection in transplant recipients, CLINICS 2015; 70(7): 515-523.DOI: 10.6061/clinics/2015(07)09
Daniel S Owers, Angela C Webster, Giovanni FM Strippoli, Kathy Kable, Elisabeth M Hodson, Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients, Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD005133. DOI: 10.1002/ 14651858.CD005133.pub3.
C. N. Kotton, CMV: Prevention, Diagnosis and Therapy American Journal of Transplantation 2013; 13: 24–40 Wiley Periodicals Inc
McBride et al, Correlation of Cytomegalovirus Disease Severity and Mortality with CMV Viral Burden in CMV-Seropositive Donor and CMV-Seronegative Solid Organ Transplant Recipients, Open Forum Infectious Diseases
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION, BTS, 2022
What is your management strategy?
This is a case of high risk for occurrence of CMV disease – D+/R- and 30% of them are prone to developing late onset of CMV disease even after prophylaxis use or discontinuation. Hence the index case is ganciclovir resistance and the following steps will be taken.
we confirm adherence to the dose of valganciclovir
we offer tests for CMV antiviral resistance
UL94 and UL54 gene mutations will be checked using whole blood or plasma
Treatment
Reduce or stop immunosuppressive like MMF/AZA if it has not been stopped
Consider the use of CMV immunoglobulin to induce a passive Immunity
we switch to second-line agents like intravenous foscarnet, cidofovir, and Leflunomide for three weeks
There is a role for a combination of GCV + Foscanet since they both attack different CMV genotypes
we seek specialist virology in assistance, particularly in the genotype
Close kidney function check because of the risk of graft rejection and toxicity associated with the second-line antiviral agents on the kidney
Review the dose of immunosuppression after treatment
Other tests to diagnose and monitor CMV
Shell vial culture
Quantitative nucleic acid testing (QNAT)
Histopathology through isolation of basophilic intranuclear inclusion
CMV pp65 antigenemia test
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
Treatment starts when the viral load is greater than 4 logs 10 copies/mil
What is the duration of pre-emptive treatment?
100 days
What is the relation between the viral load and the development of CMV disease?
Several studies have shown a linear relationship between the CMV viral load and the rate or frequency of development of CMV disease. The higher the CMV level the more the tendency to development of the disease and also the faster the rate of rise of the viral load the higher the chances of the development of CMV disease.
References
Michael KlompasTreatment of Ganciclovir Resistant Cytomegalovirus Infection.
Angela M Caliendo. Approach to the diagnosis of cytomegalovirus infection. UpToDate. August 15, 2022
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS. 2022
CMV in Kidney Transplantation Lecture. Ahmed Halawa
What is your management strategy?Patients with a CMV-positive deceased donor increase the risk of transmission by being a negative recipient. Even a dose for pre-emptive treatment apparently shows disease activity and circulating viral load.
Resistance risk (UL97 and 54 mutation) is a possibility, which would lead to Ganciclovir associated with another drug (IVIg, Leflunomide, Foscarnet) or more potent drugs with a better resistance profile such as Maribavir.
Decreasing the corticosteroid dose may be considered.
What are the other tests to diagnose and monitor CMV?
Quantitative nucleic acid testing (QNAT)
Antigenemia
Culture
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?In the literature, there are studies with viral loads above 4,000 IU/mL and others with 10,000 IU/mL of viral load. Our service considers the latter. What is the duration of pre-emptive treatment?
We started the pre-emptive treatment for CMV on the fifteenth day post-transplant and carried it out for 90 days What is the relation between the viral load and the development of CMV disease?
The circulating viral load is related to the ability of the virus to replicate, regardless of the body’s ability to cope with its activity.
High values suggest that the individual may be experiencing a primary infection or reactivation of a previous disease, which is why interventions aimed at controlling the disease involve decreasing immunosuppression (special attention to corticosteroids and mycophenolate) and specific antiviral treatment (Ganciclovir and valganciclovir).
Even with this intervention, there is an increase in these values in serum, considering drug resistance due to mutations in the UL97 and UL54 genes, requiring replacement by antivirals and immunomodulators to improve the immune status of the transplanted patient.
Restricted involvement of the gastrointestinal and ocular tracts does not change the viral load, but requires immediate treatment.
Thankyou what is the difference between Pre-emptive treatment in a CMV+ asymptomatic patient and prophylactic CMV- patient who received induction with rATG.
Gancyclovir resistance is defined as failure of reduction of viral load ≥ 1 log copies /ml after 2 weeks of appropriate treatment
IV ganciclovir is the appropriate treatment in the following patients:
So I will start ganciclovir intravenously in a dose of 5mg/kg/12 hours since the patient has tissue invasive disease and the high viral load
Then I will monitor PCR weekly, if no reduction of viral load ≥ 1 log copies /ml after 2 weeks of treatment I will consider ganciclovir resistance and I will switch to alternative therapy under the guidance of virology expert
Alternative therapy for gancyclovir resistant CMV
1- IV Foscarent
2- Combination therapy with reduced doses of ganciclovir and foscarnet
3- Cidofovir
4- Leflunamide
What are the other tests to diagnose and monitor CMV?
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
Antiviral therapy is indicated in the following asymptomatic patients:
What is the duration of pre-emptive treatment?
What is the relation between the viral load and the development of CMV disease?
No good correlation exists between viral load and tissue invasive disease
What is dose of prophylaxes and dose of treatment?
Prophylaxes dose;
Valganciclovir 900mg for 100 days, also literature says 200 days better.
Treatment dose;
Ganciclovir 5mg/kg/day for 14 to 21 days. Then again give prophylaxes for next 100 days.
If ganciclovir not effective then can switch to seconf line agents.
Foscarnet 40-60ng/kg/ day for two to three weeks.
Cidofovir 5mg/kg/week for two weeks then biweekly.
IVIG.
What is your management strategy?
This is a case of symptomatic CMV infection.
Will advise admission,
General management,
Like IV fluid,
Antipyretics,
Multivitamins,
Will treat CMV infection with ganciclovir 5 mg/mg/day.
Prophylactic antibiotic to prevent super-infection,
Immunosuppression dose reduction.
What is the duration of pre-emptive treatment?
Initially for 21 days of treatment for two consecutive negative PCR then three months of prophylaxes.
What is the relation between the viral load and the development of CMV disease?
There is strong association, as the high viral load can be a risk of disseminated and invasive disease. Which can cause immunomodulation and a cause of rejection.
References;
1. Rubin RH. The indirect effects of cytomegalovirus infection on the outcome of organ transplantation, JAMA, 1989, vol. 261 (pg. 3607-9)
2. www. BTS. uk CMV in transplant patients.
3. 2Fishman JA, Rubin RH. Infection in organ-transplant recipients, N Engl J Med, 1998, vol. 338 (pg. 1741-51)
4. 3Snydman DR. Infection in solid organ transplantation, Transpl Infect Dis, 1999, vol. 1 (pg. 21-8).
What is your management strategy?
– Tests for genotype analysis – UL97, UL54
– Inj CYMEVINE (Gancyclovir) 10mg IV bid (adjusted for GFR) x 2-3 weeks
– Weekly monitoring CMV-DNA by QNAT / qPCR
– Symptomatic treatment
–
– If no improvement with Inj Gancyclovir à Inj Foscarnet or Cidofovir may be tried.
– Reduce IS – MMF withhold and Tac dose adjustment
What are the other tests to diagnose and monitor CMV?
· Tests for genotype analysis – UL97, UL54
· Weekly monitoring CMV-DNA by QNAT / qPCR
What is the duration of pre-emptive treatment?
What is the relation between the viral load and the development of CMV disease?
Active viral proliferation as well as High CMV- viral load is associated with high risk of disseminated disease, multi-organs involvement, risk of rejection, and thus leading to higher mortality.
Prof. Ahmed Halawa
Tutor
Dear All
Remember that the treatment dose and duration differ from the CMV prophylaxis.
Please summarise in a few words the dose and the duration of CMV treatment versus the prophylaxis
CMV Treatment:
Valganciclovir 900 mg PO twice daily according to the eGFR or IV gancilovir 5 mg/kg twice daily in cases of malabsorption for a minimum of two to three weeks and continued until CMV PCR is undetectable in the blood on at least two consecutive occasions
CMV Prophylaxis:
Valganciclovir 900 mg PO once daily according to eGFR, for at least 100 to 200 days
The viral load is significant and indicates CMV infection. After excluding other concurrent infections. By definition, resistant CMV infection is the growing viral load or persistence of symptoms, despite the treatment with ganciclovir or its pro-drug Valganciclovir for 2-4 weeks. Hence, I would recommend treatment with foscarnet or cidofovir for a duration of 3 weeks. The other test utilized to diagnose CMV infection and monitor progression of disease is pp69 antigen essay.
Pre-emptive therapy has to be commenced when viral load is 1000- 5000 IU/ml in the absence of symptoms for a duration of 3 weeks.
It was found that viral load is a sensitive predictor of development of CMV disease with a positive trend correlated with CMV viral load.
Treatment is usually consistent of intra venous gancyclovir in a dose of 2.5-5 mg/kg/day for 3 weeks. however, in mild cases Valgancyclovir in a dose of 950 mg bid for 3 weeks can be considered.
reference:
1] www. BTS. uk CMV in transplant patients.
correction for ganciclovir 5mg/kg/12 hour
Valganciclovir 900 twice a day.
Cytomegalovirus (CMV) infection can have both direct and indirect effects after solid-organ transplantation, with a significant impact on transplant outcomes. Prevention strategies decrease the risk of CMV disease, although CMV still occurs in up to 50% of high-risk patients. Ganciclovir (GCV) and valganciclovir (VGCV) are the main drugs currently used for preventing and treating CMV. Emerging data suggest that letermovir is as effective as VGCV with fewer hematological side effects. Refractory and resistant CMV also still occur in solid-organ-transplant patients. Maribavir has been shown to be effective and have less toxicity in the treatment of refractory and resistant CMV. In this review paper, we discuss prevention strategies, refractory and resistant CMV, and drug-related side effects and their impact, as well as optimal use of novel anti-CMV therapies.
https://link.springer.com/article/10.1007/s40121-022-00746-1
· What is your management strategy?
CMV post-transplant, within 2months, in high risk patient, supposed to be on prophylaxis, not responding to adequate dose of Valganciclovir should raise the suspicion of valganciclovir resistance. If no response for treatment for 2weeks, and no issue of mal absorption, like diarrhea or repeated vomiting, where we can change to IV ganciclovir.
To confirm resistance we need to send for UL97, UL 54 mutations.
Otherwise, we need to counsel patient for alternative treatment and their risk of nephrotoxicity. Cidofovir and foscarnet
· What are the other tests to diagnose and monitor CMV?
Beside CMV PCR viral load we can do quantative NAT, PP65 antigen and tissue biopsy.
For monitoring beside symptoms, leucocyte count, liver function for decease effect and drug side effect.
· Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
Most centers use log3-4 to start treatment. In our center we don’t apply preemptive strategy.
· What is the duration of pre-emptive treatment?
21 days of treatment or 2 consecutive negative PCR. Then 4 weeks of prof CMV prophylactic dose.
· What is the relation between the viral load and the development of CMV disease?
The highest the viral load, the highest the chance of development of CMV disease.
References:
UK CMV infection prophylaxis and treatment.
Local practice guidelines for CMV infection.
Q1: this case is a resistant case of ganciclovir. Therefore, genotyping for UL97 or UL 54 gene should be done and an increasing dose of ganciclovir or alternative treatment like mirabavir should be started.
Q2:
1. CMV P65 antigen test: used for surveillance of CMV and if became positive, pre-emptive therapy was needed. It is replaced by CMV PCR.
2. Genotype tests for UL 97 and UL54
3. In tissue-invasive disease, histologic evaluation and inclusion bodies with owls’ eye appearance can be used.
Q3: there is no standard reference and it may be different among different laboratories. Hence, there is no consensus about the cut-off to start pre-emptive treatment sometimes more than 2000 copies in whole blood are considered.
Q4: the duration for pre-emptive therapy is at least 21 days or until two consecutive CMV PCR (one week apart) became negative.
Q5: higher CMV viral load was associated with higher mortality and more severe CMV disease.
Management strategy
Other tests to diagnose and monitor CMV
Duration of preemptive treatment
Relation between viral load and development of CMV disease
A 61-year-old man was admitted with fever (38 °C) and malaise 2 months after cadaveric transplantation, 000 mismatch on Tacrolimus (trough 9 ng/ml) and prednisolone 15 mg/day. CMV is positive to CMV negative recipient. Oxygen saturation was reported to be 95% on air. Quantitative CMV PCR reported 5.52 log 10 copies/ml. The patient has not responded to oral Valganciclovir 900 mg twice daily.
So the patient had resistance to Valganciclovir
Risk factors for of resistance include: old age, D+/R-, higher viral load, intense immunosuppression, viral mutation (UL97 mutation) .
management plane
– viral gen typing to detect mutation.
-start IV Valganciclovir.
-stop MMF.
-Reduction of of CNI , keep tac trough level 5ng/ml.
We may stop it stopped in life-threatening CMV disease.
-Monitoring kidney function for fear of rejection due do IS reduction and concurrent TCMR.
– CMVIG can be used with resistance.
-Foscarnet can be used for 3 weeks with monitoring of kidney function
-Cidofovir approved by FDA .
continue until improvement of symptoms and negative PCR.
What are the other tests to diagnose and monitor CMV?
– diagnosing CMV infection is confirmed using PCR to detect CMV DNA.
– finding of CMV p65 antigen in circulating polymorphonuclear lymphocytes is another test used in certain centers to both evaluate treatment response and serve as a starting point for treatment .
– using viral cultures is uncommon for CMV diagnosis
-The most common serologic tests are detection of CMV antibodies (IgM and IgG antibodies) by ELISA.
A positive CMV IgG indicates previous infection, while CMV IgM indicates recent infection IgM, it can persist for months after primary infection and it’s also positive in reactivated infections.
– histopathologic testing of CMV disease, CMV nephritis is characterized by biopsy-proven cytopathic changes which are typically focal, detected in tubular epithelium or endothelial cells characteristic inclusion bodies(Owl’s eye appearance).
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
Preemptive therapy
quantitative measuring of CMV DNA in plasma to detect viremia once or twice a week before the occurrence of symptomatic infection.
the exact cutoff of plasma CMV level to start treatment is not known and the decision of treatment is individual according to degree and duration of immunosuppression
it was suggested to start pre-emptive ttt in transplant recipients with the PCR is > 5000 copies/m regardless the serostatus of the recipient.
What is the duration of pre-emptive treatment?
-Intravenous ganciclovir at a dose 5 mg/kg /12 h is used for preemptive treatment in viral load (>50,000 copies of CMV DNA in 1 ml of plasma), continue for 3 weeks
viremia is checked after 7–10 days of preemptive treatment, and monitored every7–10days, Preemptive medication should be continued until two
PCR CMV DNA tests yield negative findings in a span of 7days .
-Guiding of preemptive therapy can be also guided by measuring of CMV-specific T lymphocytes.
What is the relation between the viral load and the development of CMV disease?
increased viral is associated with more increase in disease incidence
References:
Željka VH, Nika K. Viral Infections after Kidney Transplantation: CMV and BK [Internet]. Perioperative Care for Organ Transplant Recipient. Intech Open; 2019.
· What is your management strategy?This patient should undergo reassessment of:
– Dose adequacy
– Adherence to treatment
– Use of drugs that may cause interaction: at this time, evaluate the decrease in immunosuppression or switch to mTOR use;
– Study of antiviral resistance UL97 and UL54 gene mutations
If the reassessments are positive, Valganciclovir should be suspended and start Intravenous Foscarnet for at least 3 weeksIf the reassessments are positive, Valganciclovir should be suspended and start Intravenous Foscarnet for at least 3 weeks. · What are the other tests to diagnose and monitor CMV? Other tests will depend on where the CMV is being investigated. For example, in cases of diarrhea, where a biopsy is performed with histopathological diagnosis aided by staining. Or in case of ocular CMV the diagnosis can be clinical and serological. Monitoring tests are all quantitative nucleic acid testing methods (QNAT), these quantify the amount of viral nucleic acid (DNAemia or viral load) and there are some types of assays developed.
· Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?In my hospital preemptive therapy starts with Log = 4.0 · What is the duration of pre-emptive treatment? Preemptive treatment goal is 21 days (control being performed at 14 days and repeated every 7 days), when in this time he should reach the goals of undetectable viral load. What is the relation between the viral load and the development of CMV disease?
The rate of cytomegalovirus (CMV) viral load increase and peak viral loads are associated with CMV disease in kidney and liver transplant recipients, but relationships to disease severity or mortality have not been shown.
REFERENCES:
– McBride JM, Sheinson D, Jiang J, Lewin-Koh N, Werner BG, Chow JKL, Wu X, Tavel JA, Snydman DR. Correlation of Cytomegalovirus (CMV) Disease Severity and Mortality With CMV Viral Burden in CMV-Seropositive Donor and CMV-Seronegative Solid Organ Transplant Recipients. Open Forum Infect Dis. 2019 Jan 14;6(2):ofz003. doi: 10.1093/ofid/ofz003. PMID: 30775403; PMCID: PMC6366655.
– UK Guideline on Prevention and Management of cytomegalovirus (CMV) infection and disease following solid organ transplantation
Management strategy:
The patient is a recent post transplant patient (2 months ago)..Recipient is a cadaver kidney recipient from CMV Positive Donor. Recipient is CMV negative…SO this is a high risk of CMV infection post transplant… There was full match with no mismatch and the patient is on dual immunosuppression. The patient is not on antimetabolite…
patient needs full history to find out if there is other organ involvement due to CMV like fever, cough, diarrhea. History of any anti rejection treatment if any…The details of CMV prophylaxsis given is also needed…Baseline laboratory work up including CBC, LFT, RFT are needed…CMV DNA viral load has been done and it is 5.52 log copies/ml.. Although the patient is asymptomatic due to very high viral load, patient needs to started on oral Valganciclovir 900mg twice a day…the dose should be modified as per the creatinine clearance…The minimun duration of treatment is 2 weeks after which we should obtain weekly CMV DNA viral load until 2 negative viral load reports are achieved…The patient did not respond to oral valganciclovir. This maybe due to ganciclovir resistance due to mutation in UL97 and UL54 gene…The patient could also be non complaint to oral valganciclovir…There could have been marrow suppression needing to reduce the dose in between…There could have been also poor oral absorption….It is necessary to remove the antimetabolite and reduce the dose of Tac…
Patient needs testing for genotype testing to detect mutations in CMV….If there is UL97 or UL54 mutations we need switch to alternative agents…IV foscarnet 90mg/kg every 12 hours for 3 weeks + CMV immunoglobulin..IV cidofovir 1mg/kg IV 3 times a week is alternative… IV cidofovir (1mg/kg three times a week) is effective in UL97 mutation but will not work for UL54 mutation…Oral Maribavir 400mg twice a day for 8 weeks is an alternative and it will work for both UL97 and UL 54 mutation…Post treament and viral eradiction routine CMV DNA PCR monitoring is indicated monthly for 6 months…Patient should also be counselled for other infections like PCP and TB which can flare up and also be counselled about rejection…
Other diagnostic tests for CMV:
CMV NAT – it is a rapid diagnostic test in transplant patients…
CMV pp65Ag – the surface antigen is tested by this PCR testing and it is helpful in diagnosis..It can also be used to monitor clearance after treatment…
CMV viral culture – Not recommended due to poor utility…
CMV IGM – not reliable in transplant patient due to poor antibody response
Assume this patient is asymptomatic, is there any cut off level to treat asymptomatic CMV viremia (pre emptive therapy): – No consensus…CMV DNA viral load ranges from 1500 to 4000 is used in few studies…Lower threshold for D+/R- recipient are used…Some units use double log fold increase in CMV as a criteria…
Duration of Preemptive treatment:
Duration of the treatment will be based on monitoring of CMV DNA viral load until 2 weeks report are consecutively negative..
Relation between the viral load and development of CMV disease?
Peak CMV viral load has been proven to be an independent significant predictor of CMV disease….But in CMV GI infection, viral load maybe negative and biopsy of the colon may pick up infection and this warrants therapy as this is invasive CMV disease…
Management strategy
· Reduction of immunosuppression is the corner stone of TTT (STOP MMF and target lower tac level )
· Patient not responding to oral ganciclovir we need to switch to IV ganciclovir 5 mg /kg/ bid 2-3 weeks until we have 2 negative PCR·
· Consider resistant to valgan cyclovir if persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration (2-4 weeks) of Ganciclovir or Valganciclovir
· if resistant is suspected
1-Confirm that dosing is adequate
2-Consider adherence to treatment plan and absorption
3-Offer testing for Human CMV (HCMV) antiviral resistance UL97 and UL54 gene mutations
4-Use either whole blood or plasma
· If there is evidence of ganciclovir resistance: Stop Valganciclovir (or Ganciclovir) / start Intravenous Foscarnet for at least 3 weeks After Seeking specialist virology advice
Thresholds for treatment
1. Consider reduction in immunosuppression in R+ patients with a viral load of fewer than 3 logs 10.
2. Consider treatment with valganciclovir when the viral load exceeds 3 logs 10 if rapidly rising titre in high-risk patients.
3. Treatment with valganciclovir or IV ganciclovir is mandatorywhen the viral load exceeds 4 logs 10.
Treatment duration in preemptive therapy
Monitor to guide preemptive therapy monthly for 3 month
Treatment for 2-3weeks
CMV disease and viral load
CMV disease – (histopathological evidence of CMV, CMV retinitis diagnosed by an ophthalmologist, or CMV in the CSF indicative of CNS disease) irrespective of viral load
Management:
Start with a thorough history and clinical examination, focusing on medication adherence.
Genotypic tests detect the presence of resistance-associated mutations.
Reduction of immunosuppression (discontinue antimetabolites and modify the dose of tacrolimus while monitoring graft function to prevent rejection)
For severe cases, it is recommended to administer IV ganciclovir rather than oral valganciclovir to patients with tissue-invasive disease, rapidly increasing viral loads, or moderate to severe gastrointestinal symptoms.
Ganciclovir is administered IV with a 12-hour interval at 5 mg/kg, adjusting the dosage based on eGFR.
For mild to moderate cases:
Oral valganciclovir is advised over IV ganciclovir for patients with mild to severe CMV disease who are predicted to have good oral drug absorption.
Valganciclovir is given PO twice a day at a 900-mg dose, with the dosage adjusted for eGFR.
The severity of the infection and the patient’s response to treatment determine how long the treatment process will last.
Treatment is continued until both symptoms and CMV viremia disappear (which includes laboratory resolution of CMV as undetectable or lower than the limits of a sensitive assay in two quantitative PCR tests drawn one week apart).
– The average period of treatment is 21 days, but it may require a longer duration, especially in patients with tissue-invasive disease.
Refractory CMV disease, which persists or worsens despite antivirals and immunosuppression, may be caused by ganciclovir resistance.
– It affects 1–2% of CMV D+/R- kidney transplant recipients.
– Genotype testing should be done in cases where ganciclovir-resistant diseases is suspected in order to find particular resistance mutations
Treatments options for CMV resistant disease
Maribavir, foscarnet, and cidofovir are antiviral treatments for patients with ganciclovir-resistant or refractory CMV.
• Maribavir is active against CMV with the UL97 and UL54 mutations. Maribavir is dosed at 400 mg orally twice daily for eight weeks.
• Foscarnet, an IV-administered pyrophosphate analog, limits viral replication. Foscarnet suppresses CMV with UL97 and UL54 mutations. Foscarnet is administered intravenously at 60 or 90 mg/kg every 8 or 12 hours, depending on eGFR.
• Cidofovir, another viral DNA polymerase inhibitor, inhibits CMV with UL97 mutations but not UL54 mutations. Intravenous cidofovir is 1 mg/kg three times a week.
• What is the relationship between viral load and CMV disease development?
• Using quantitative PCR assays, studies of solid organ transplant recipients have revealed that patients with active CMV disease have higher viral burdens than those with asymptomatic infection.
• The rate of viral burden increase can be utilized to identify patients at risk for CMV disease.
• Patients with CMV disease have a substantially higher rate of CMV load increase between the last PCR-negative sample and the first PCR-positive sample than patients without CMV disease.
· What is your management strategy?This is a case of resistant CMV . Risk factors for CMV resistance :1- Host factors :
a- Young age , induction with ATG, decrease drug bioavilabilty, absorption ,patient non compliance ,previous treatment with CMV antiviral drugs or prolonged treatment courses.
2- Viral related factor.
Genetic mutation :UL97 mutation causes resistance to gancycovir while UL54 mutation causes multidrug resistance.Recurrent CMV infection and delayed viral clearance .
Management:
1- Correct the reversablle risk factors as patient compliance . switch to IV gancyclovir in cases of malabsorption .
2-Genetic analysis to diagnose genetic mutation .
3- Treatment of resistant CMV infection include trial of
1- Foscarnet for at least 3 weeks .
2- Leflunamde :has immunmodulatory and antiviral effects
3- Cidofovir
4- Stop Valganciclovir and gancyclovir ,in patients with evidence of ganciclovir resistance.
5- Decrease the dose of IS , stop antiproliferative drugs.monitoring of graft function
· What are the other tests to diagnose and monitor CMV?1- CMV serology : but not accurate in transplantation patients2- CMV quantitative nucleic acid test on whole blood or plasma sample to assess viral load .3- Tissue biopsy and histological examination fromaffected areas· Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?The cut of level of viraemia recommended as a threshold to start pre-emptive therapy is not well established and vary according to the type of assay used and local protocols. Some centers start treatment at 1000 copies/ml while others consider treatment at 4000 copies/ml.· What is the duration of pre-emptive treatment?A minimum of 2 weeks of treatment with full therapeutic dose of valgancyclovir (900 mg/12 h) and till complete resolution of viremia . After resolution, stop antiviral and continue weekly surveillance. What is the relation between the viral load and the development of CMV disease?There is a Linear relationship between viral load and the development of CMV disease where higher viral load increase risk of CMV disease development
Ref
1- Chemaly RF, Chou S, Einsele H, Griffiths P, Avery R, Razonable RR, Mullane KM, Kotton C, Lundgren J, Komatsu TE, Lischka P, Josephson F, Douglas CM, Umeh O, Miller V, Ljungman P; Resistant Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Resistant and Refractory Cytomegalovirus Infection
2-UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS, 2022.
3-The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation
· What is your management strategy?This is a case of resistant CMV . Risk factors for CMV resistance :1- Host factors :
a- Young age , induction with ATG, decrease drug bioavilabilty, absorption ,patient non compliance ,previous treatment with CMV antiviral drugs or prolonged treatment courses.
2- Viral related factor.
Genetic mutation :UL97 mutation causes resistance to gancycovir while UL54 mutation causes multidrug resistance.Recurrent CMV infection and delayed viral clearance .
Management:
1- Correct the reversablle risk factors as patient compliance . switch to IV gancyclovir in cases of malabsorption .
2-Genetic analysis to diagnose genetic mutation .
3- Treatment of resistant CMV infection include trial of
1- Foscarnet for at least 3 weeks .
2- Leflunamde :has immunmodulatory and antiviral effects
3- Cidofovir
4- Stop Valganciclovir and gancyclovir ,in patients with evidence of ganciclovir resistance.
5- Decrease the dose of IS , stop antiproliferative drugs.monitoring of graft function
· What are the other tests to diagnose and monitor CMV?1- CMV serology : but not accurate in transplantation patients2- CMV quantitative nucleic acid test on whole blood or plasma sample to assess viral load .3- Tissue biopsy and histological examination fromaffected areas· Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?The cut of level of viraemia recommended as a threshold to start pre-emptive therapy is not well established and vary according to the type of assay used and local protocols. Some centers start treatment at 1000 copies/ml while others consider treatment at 4000 copies/ml.· What is the duration of pre-emptive treatment?A minimum of 2 weeks of treatment with full therapeutic dose of valgancyclovir (900 mg/12 h) and till complete resolution of viremia . After resolution, stop antiviral and continue weekly surveillance. What is the relation between the viral load and the development of CMV disease?There is a Linear relationship between viral load and the development of CMV disease where higher viral load increase risk of CMV disease development
Ref
1- Chemaly RF, Chou S, Einsele H, Griffiths P, Avery R, Razonable RR, Mullane KM, Kotton C, Lundgren J, Komatsu TE, Lischka P, Josephson F, Douglas CM, Umeh O, Miller V, Ljungman P; Resistant Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Resistant and Refractory Cytomegalovirus Infection
2-UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS, 2022.
3-The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation
the pt has resistant CMV disease
Management:
–modification of IS
-Do viral genetic study
-we can use maribavir which is oral drug active against UL97 and UL54 mutations.
-Cidofovir or foscarnet are alternative but have nephrotoxicity
-Monitor CMV PCR weekly
-CMV specific antibodies also can be used in resistant cases
Diagnosis of CMV:
CMV PCR for samples from any secretion
Biopsy with characteristic inclusion bodies
Serology not used in diagnosis
Relationship between VL and CMV disease:
The higher the viral load, the higher incidence of CMV disease
What is your management strategy
Consider resistance to Ganciclovir if:
There is a persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir
Risk factors for the acquisition of ganciclovir resistance include CMV seronegativity at transplant when receiving a seropositive organ, degree of immunosuppression, magnitude of CMV viremia, and prolonged exposure to anti-CMV medication. Seronegative recipients of seropositive organs appear to be at particular risk of both CMV infection and ganciclovir resistance.
We should to
Seek specialist virology advice before commencing treatment with Foscarnet
Stop Valganciclovir (or Ganciclovir) and Offer Intravenous Foscarnet for at least 3 weeks
Foscarnet The primary alternative to ganciclovir for the treatment of CMV viremia and disease is foscarnet.
Cidofovir was approved by the FDA in 1996 for the treatment of cytomegalovirus infection.
Newer agents such as Letermovir and Maribavir may have a role in prevention of CMV disease.
What are the other tests to diagnose and monitor CMV?
Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load
Histopathology
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
A viral load of 3983 IU/ml (2600 copies/ml) was established as the optimal cut-off for initiating preemptive therapy in a cohort of 141 patients with 982 tests and validated in a cohort of 252 recipients with a total of 2022 test.
Due to the lack of consensus and specific guidelines on CMV infection in patients with solid neoplasms, the positivity cut-off points and significance of CMV viral load (VL) in these patients may vary and differ between different centres and publications. Significant CMV VL was considered to be above >1,000 copies/ml in some studies. However, more re- cent evidence places the potentially significant viremia above 4,000 copies/ml
The absolute levels of viraemia that are recommended as a threshold to start pre-emptive therapy will depend upon the assay used. Units should establish the clinical significance of their local assay.
What is the duration of pre-emptive treatment?
Once DNAemia is at a positive threshold, for asymptomatic patients, we recommend VGCV (treatment dose) be started [strong, high] and continued until resolution of DNAemia (as per the Diagnostic section), with a minimum of 2 weeks of treatment. After resolution, discontinue antiviral and continue weekly surveillance. Intravenous GCV is a less preferred option unless concerns about absorption exist.
Linear relationship…higher viral load increase risk of cmv disease development
Reference
Determination, validation and standardization of a CMV DNA cut-off value in plasma for preemptive treatment of CMV infection in solid organ transplant recipients at lower risk for CMV infection
C Martín-Gandul 1 , P Pérez-Romero, M Sánchez, G Bernal, G Suárez, M Sobrino, L Merino, J M Cisneros, E Cordero; Spanish Network for Research in Infectious Diseases
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS, 2022.
The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation
Camille N. Kotton, MD, 1 Deepali Kumar, MD, 2 Angela M. Caliendo, MD, PhD, 3 Shirish Huprikar, MD,4 Sunwen Chou, MD, 5 Lara Danziger-Isakov, MD, MPH, 6 and Atul Humar, MD7 on behalf of the The Transplantation Society International CMV Consensus Group
in this index case of high risk for CMV infection with symptoms ,
resistance to valgancyclovir is likely
other drugs like cidofovir foscarnet are nephrotoxic
prophylaxis
Valganciclovir 900 mg PO once daily according to eGFR, for at least 100 to 200 days
treatment
Valganciclovir 900 mg PO BD till CMV PCR is negative two times
dose adjustment need to be done on basis of renal function
This patient has the CMV syndrome having resistant to valganciclovir and ganciclovir.
Management:
Diagnosis of CMV:
Pre-emptive Therapy:
Relationship between VL and CMV disease:
References:
· UK Guideline on Prevention and Management of Cytomegalovirus (CMV) Infection and Disease following Solid Organ Transplantation. BTS. 2022
· Kotton CN, Kumar D, Caliendo AM et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-Organ Transplantation. Transplantation 2018; 102:900
4. A 61-year-old man was admitted with fever (38 °C) and malaise 2 months after cadaveric transplantation, 000 mismatch on Tacrolimus (trough 9 ng/ml) and prednisolone 15 mg/day. CMV is positive to CMV negative recipient. Oxygen saturation was reported to be 95% on air. Quantitative CMV PCR reported 5.52 log 10 copies/ml. The patient has not responded to oral valganciclovir 900 mg twice daily.
Issues/ concerns:
– 61yo male, DDKTx 2 months ago, 000 mismatch
– presents with malaise, fever (38°C), SPO₂ 95% (RA)
– medications: tacrolimus trough 9ng/mL, prednisone 15mg OD
– CMV serostatus: CMV D+/R-
– CMV quantitative PCR 5.52 log 10 copies/ml
– poor response to oral valganciclovir 900mg BD
What is your management strategy? (1-3)
– multidisciplinary approach: infectious disease specialist
– detailed history and physical examination
– risk factor assessment: CMV serostatus, use of lymphocyte depleting agents (ATG), use of MPA, lymphopenia, use of belatacept, hypogammaglobulinemia, multi-organ transplantation
– baseline investigations: CBC, ESR, CRP, procalcitonin, UECs, LFTs, blood and urine cultures, graft ultrasound
– CMV reactivation is associated with increased risk of graft rejection, mortality and graft loss
– CMV infection causes both direct and indirect effects on kidney transplant recipients: (4)
Treatment
– asymptomatic CMV viremia:
– symptomatic CMV disease i.e., CMV syndrome or tissue-invasive disease:
– refractory or drug-resistant CMV:
What are the other tests to diagnose and monitor CMV? (5, 6)
– QuantiFERON-CMV and ELISPOT are immune monitoring assays that measure CMV-specific T cell responses
– they are useful adjuncts in identifying patients at increased risk of CMV disease
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)? (7-9)
– given the variability among diagnostic specimens and testing modalities, viral load thresholds guiding on the initiation of preemptive therapy have not been standardized across institutions
– pre-emptive therapy involves monitoring patients for CMV by doing regular interval (usually weekly) blood quantitative CMV PCR for 3months post-transplant
– the aim is to detect a rise in the viral load early and initiate antiviral therapy when a threshold viral load is reached before the symptoms appear
– the ideal viral load threshold to initiate antiviral treatment is not yet clearly defined but, in most cases, when it is above 10,000 copies/ml the patient is considered to have CMV infection and antiviral therapy is usually instituted (10)
– there are 3 preventive strategies i.e.,
– entails administration of antiviral medication (valganciclovir is commonly used) to all transplant recipients or high-risk patients starting within 10 days after transplant for 3-6 months (3months for CMV R+ recipients, 6 months for CMV D+/R- recipients)
– this strategy is associated with late-onset CMV disease which is CMV disease occurring after discontinuation of prophylaxis compared to preemptive therapy
– due to its efficacy and high oral bioavailability, oral valganciclovir is preferred to oral and IV ganciclovir and valacyclovir
– optimal duration of prophylaxis remains unclear
– shorter course of therapy (100days) are associated with increased risk of late-onset CMV disease
– longer duration of therapy (200days) decreases rate of active CMV infection and disease ini CMV D+/ R- patients
– hematologic suppression in particular leucopenia is the most significant and common side effect associated with valganciclovir and its parent compound, ganciclovir
– avoid dose valganciclovir dose reduction when leucopenia occurs since this may promote resistance
– GCSF should be considered before discontinuing valganciclovir
– ideal for patients at low risk for CMV infection i.e., CMV D-/ R-
– involves monitoring patients for CMV by doing regular interval (usually weekly) blood quantitative CMV PCR for 3months post-transplant
– the aim is to detect a rise in the viral load early and initiate antiviral therapy when a threshold viral load is reached before the symptoms appear
– if active CMV infection is detected, give treatment doses of valganciclovir (900mg BD) or IV ganciclovir (5mg/kg IV BD) for a minimum of 21 days and until CMV PCR is negative (adjust the doses according to the kidney function)
– oral valganciclovir is initiated when viral replication exceeds a certain threshold (usually above 10,000 copies/ml)
– acyclovir or valacyclovir is given as HSV prophylaxis for 3 months post-transplant
– combines these two approaches; it is not commonly used
– in this approach, the highest-risk patients are given prophylactic anti-CMV therapy post-transplant then thereafter the patients are monitored regularly for active CMV infection using blood CMV PCR
– if viral replication is detected, treatment doses of anti-CMV therapy are given
What is the duration of pre-emptive treatment? (7-9)
– pre-emptive therapy involves monitoring patients for CMV by doing regular interval (usually weekly) blood quantitative CMV PCR for 3months post-transplant
– the aim is to detect a rise in the viral load early and initiate antiviral therapy when a threshold viral load is reached before the symptoms appear
– the ideal viral load threshold to initiate antiviral treatment is not yet clearly defined but, in most cases, when it is above 10,000 copies/ml the patient is considered to have CMV infection and antiviral therapy is usually instituted (10)
– if active CMV infection is detected, give treatment doses of valganciclovir (900mg BD) or IV ganciclovir (5mg/kg IV BD) for a minimum of 21 days and until CMV PCR is negative (adjust the doses according to the kidney function)
What is the relation between the viral load and the development of CMV disease? (11)
– lower CMV viral load is associated with shorter viremia episodes, decreased risk for viremia lasting more than 30 days, shorter duration of treatment and infection of CMV following HSCT
References
1. Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clinical transplantation. 2019 Sep;33(9):e13512. PubMed PMID: 30817026. Epub 2019/03/01. eng.
2. Kumar D, Chernenko S, Moussa G, Cobos I, Manuel O, Preiksaitis J, et al. Cell-mediated immunity to predict cytomegalovirus disease in high-risk solid organ transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 May;9(5):1214-22. PubMed PMID: 19422346. Epub 2009/05/09. eng.
3. Corona-Nakamura AL, Monteón-Ramos FJ, Troyo-Sanromán R, Arias-Merino MJ, Anaya-Prado R. Incidence and predictive factors for cytomegalovirus infection in renal transplant recipients. Transplantation proceedings. 2009 Jul-Aug;41(6):2412-5. PubMed PMID: 19715936. Epub 2009/09/01. eng.
4. Griffiths P. The direct and indirect consequences of cytomegalovirus infection and potential benefits of vaccination. Antiviral research. 2020 Apr;176:104732. PubMed PMID: 32081353. Epub 2020/02/23. eng.
5. Fernández-Ruiz M, Rodríguez-Goncer I, Parra P, Ruiz-Merlo T, Corbella L, López-Medrano F, et al. Monitoring of CMV-specific cell-mediated immunity with a commercial ELISA-based interferon-γ release assay in kidney transplant recipients treated with antithymocyte globulin. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2020 Aug;20(8):2070-80. PubMed PMID: 31991045. Epub 2020/01/29. eng.
6. Barabas S, Spindler T, Kiener R, Tonar C, Lugner T, Batzilla J, et al. An optimized IFN-γ ELISpot assay for the sensitive and standardized monitoring of CMV protein-reactive effector cells of cell-mediated immunity. BMC immunology. 2017 Mar 7;18(1):14. PubMed PMID: 28270111. Pubmed Central PMCID: PMC5339961. Epub 2017/03/09. eng.
7. Owers DS, Webster AC, Strippoli GF, Kable K, Hodson EM. Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. The Cochrane database of systematic reviews. 2013 Feb 28;2013(2):CD005133. PubMed PMID: 23450558. Pubmed Central PMCID: PMC6823220. Epub 2013/03/02. eng.
8. Hasegawa J, Hatakeyama S, Wakai S, Omoto K, Okumi M, Tanabe K, et al. Preemptive anti-cytomegalovirus therapy in high-risk (donor-positive, recipient-negative cytomegalovirus serostatus) kidney transplant recipients. International Journal of Infectious Diseases. 2017 2017/12/01/;65:50-6.
9. Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-31. PubMed PMID: 29596116. Epub 2018/03/30. eng.
10. Eshraghi H, Hekmat R. Which CMV viral load threshold should be defined as CMV infection in kidney transplant patients? Transplantation proceedings. 2015 May;47(4):1136-9. PubMed PMID: 26036538. Epub 2015/06/04. eng.
11. Tan SK, Waggoner JJ, Pinsky BA. Cytomegalovirus load at treatment initiation is predictive of time to resolution of viremia and duration of therapy in hematopoietic cell transplant recipients. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2015 Aug;69:179-83. PubMed PMID: 26209403. Pubmed Central PMCID: PMC4828337. Epub 2015/07/26. eng.
65year old 2 months after transplant HLA 000 mismatch CMV D+/R-, presents with fever and malaise, on 2 IS, on valganciclovir 900mg bd with no response
What is your management strategy?
This patient has probable refractory disease evidence by persistent virus despite appropriately dosed antiviral therapy.
Thus in this patient it is crucial to look for ganciclovir resistant CMV, test for UL97 and UL 54 mutations. As awaits mutation results patient should be switched to cidofovir.
UL 97 is most common mutation will occur in both ganciclovir and valganciclovir though cidofovir doesn’t require phosphorylation hence will not be affected by this mutation. However cidofovir is nephrotoxic and should be used cautiously.
Alternative to cidofovir is maribavir which is less nephrotoxic than cidofovir and doesn’t cause bone marrow suppression like ganciclovir/valganciclovir.
Other drugs that can be used is forscanet though it is nephrotoxic and causes electrolyte imbalances.
This patient CNI should also be switched to MTOR inhibitors.
What are the other tests to diagnose and monitor CMV?
This patient has CMV infection since he presents with fever and a high viral load, for diagnosis of tissue invasive disease tissue biopsy is required. Screening for tissue invasive disease is required with CXR and BAL, endoscopy and colonoscopy. The histology findings can be used to diagnose.
Other tests that can be used to monitor the patient includes:
Antigenimia assay for pp65.
Qualitative/quantitative PCR for CMV.
CMV specific cell mediated immunity- Quantiferon CMV assay, ELISPOT
Adaptive immunity-whereby you monitor the absolute lymphocyte counts and counts <610cells/ul are associated with increased risk of infection.
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
There has been no cut off viral load threshold to initiate pre-emptive therapy due to lack of assay standardisation.
However a cut off of 10,000copies/ml is generally used.
What is the duration of pre-emptive treatment?
The preemptive therapy includes valganciclovir 900mg bd or ganciclovir IV 5mg/kg twice daily. The treatment duration should be until the viral load is below the threshold or is negative.
The duration for prophylaxis is usually 200 days, this recommendation was after the IMPACT trial where they compared 100 versus 200 days. 200 days was associated with reduced incidence of late onset CMV disease.
The preferred drugs for prophylaxis are: PO valganciclovir 900mg od or IV ganciclovir 5mg/kg od or oral ganciclovir 1gm thrice daily.
However valganciclovir is preferred since it is administered orally and has a higher bioavailability compared to oral ganciclovir.
What is the relation between the viral load and the development of CMV disease?
High viral loads is associated with increased risk of CMV disease though a standardised threshold is not defined. However generally a threshold of 10,000copies/ml is associated with increased risk of disease.
References
Treatment of Ganciclovir Resistant Cytomegalovirus Infection Michael Klompas
Cytomegalovirus infection in transplant recipients: newly approved additions to our armamentarium Fareed Khawaja Amy Spallone Camille N. Kotton Roy F. Chemaly
Cytomegalovirus Infections in Solid Organ Transplantation: A Review
Poornima Ramanan, and Raymund R Razonable
The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation
Camille N. Kotton, MD,1 Deepali Kumar, MD,2 Angela M. Caliendo, MD, PhD,3 Shirish Huprikar, MD,4 Sunwen Chou, MD,5 Lara Danziger-Isakov, MD, MPH,6 and Atul Humar, MD7on behalf of the The Transplantation Society International CMV Consensus Group
This patient has the CMV syndrome as evidenced by the symptoms and the presence of CMV viremia which is significant (more than 4 log10 copies/ml) and has not responded to valganciclovir indicating could be resistant to valganciclovir and ganciclovir.
Management
References:
UK guidelines on prevention and mgt of CMV infection and disease following SOT-April 2022.
Kumar et al;The third international consensus guidelines on MGT of CMV in SOT.2018;102;900
Treatment of CMV viral infection
-Oral valganciclovir 900 mg twice daily for mild cases ;with renal dosing.
severe cases need IV ganciclovir 5 mg per kg every 12 hours with renal dosing. Treatment should continue till viremia clearance ,weekly CMV monitoring by CMV QNAT OR pp65 antigenemia to assess virologic response.
Following complete treatment, weekly monitoring for CMV DNA for 8-12 weeks is needed essentially for high risk of relapse.
-Cautious immunosuppression reduction.
-Monitoring of graft function.
-Resistant cases: high dose of ganciclovir or foscarnet ( it has nephrotoxicity and synergistic nephrotoxicity with CNI);Gene resistance testing is needed ;UL 97or UL54 gene mutation is needed.
Prophylaxis
-CMV negative recipient of CMV positive donor:
. following AB induction, valganciclovir 900 mg po daily for 6 months.in case without AB induction: same dose for 3 months. Then ,CMV DNA weekly for 3 months.
-CMV positive recipient of CMV negative donor or CMV positive donor:
Valganciclovir 900 mg po daily for 3-6 months.
-CMV negative recipient of CMV negative donor :
Acyclovir 400 mg BID for herpes prophylaxis for 3 months.
Also, CMV monitoring if indicated.
What is your management strategy?
The above scenario is suggestive of valganciclovir resistance.
Ganciclovir resistance should be suspected in patients who have rising or persistently elevated viral loads despite treatment with appropriately dosed ganciclovir for more than two weeks
Resistance testing — When ganciclovir-resistant infection or disease is suspected, genotype testing should be performed to identify specific resistance mutations.
Common resistance mutations include those in the genes that encode UL97 phosphotransferase, which performs the initial phosphorylation of ganciclovir (which is required for its antiviral activity), and the viral DNA polymerase gene UL54.
Choice of antiviral therapy – Antiviral therapies for patients with ganciclovir-resistant or refractory CMV include maribavir, foscarnet, and cidofovir.
What are the other tests to diagnose and monitor CMV?
Blood CP to look for leucopenia and thrombocytopenia
LFTs
Tissue biopsy if there is organ involvement.
CMV PCR for monitoring.
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?The PCR threshold for the initiation of antiviral therapy is around 10,000 viral copies/ml of blood.
What is the duration of pre-emptive treatment?What is the relation between the viral load and the development of CMV disease?
Duration of therapy — The duration of therapy depends upon the severity of disease, as well as the clinical and virologic response to treatment. We generally treat until both symptoms and CMV viremia have resolved (ie, CMV is undetectable or lower than the limits of a sensitive assay in two quantitative PCR tests drawn one week apart). The typical duration of therapy is 21 days but is often longer, particularly for patients with tissue invasive disease. We also monitor periodically for recurrence with quantitative PCR following completion of therapy, particularly for high-risk patients.
A decrease in the viral load generally correlates with a clinical response to treatment.
A 61-year-old man was admitted with fever (38 °C) and malaise 2 months after cadaveric transplantation, 000 mismatch on Tacrolimus (trough 9 ng/ml) and prednisolone 15 mg/day. CMV is positive to CMV negative recipient. Oxygen saturation was reported to be 95% on air. Quantitative CMV PCR reported 5.52 log 10 copies/ml. The patient has not responded to oral valganciclovir 900 mg twice daily.
What is your management strategy?
What are the other tests to diagnose and monitor CMV?
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?What is the duration of pre-emptive treatment?
What is the relation between the viral load and the development of CMV disease?
REF;
Developed CMV infection 2 months post in KTR, not responsive to valganciclovir leading to ganciclovir resistant CMV viremia, risk factors in this patient is D+/R- plus high tac level
Other possibilities are mutations in the UL 97 or UL 54 gene leading to drug resistance
Management:
1. Increasing the dose of GCV from the standard 5mg/kg q12h to 7.5–10 mg/kg q12h
2. High dose gancyclovir plus foscarnet but this combination can be toxic(hematological toxicity)
3. CMV specific IVIG and leflunomide.
4. Cidofovir can be used but limited due to nephrotoxicity.
Novel therapies letermovir ,maribavir,brincidofovir are potential agents but needs more evidences
What are the other tests to diagnose and monitor CMV?
Other tests are
Assume this patient is asymptomatic what your cut-off level to treat is
Asymptomatic CMV Viremia (pre-emptive therapy)?
What is the duration of pre-emptive treatment?
The duration of preemptive antiviral therapy should be guided by viral load monitoring. Generally, preemptive antiviral therapy is continued until virology clearance. Previously two consecutive negative weekly CMV PCRs was suggested but now single negative test may sufficient.
What is the duration of pre-emptive treatment?
The duration of preemptive antiviral therapy should be guided by viral load monitoring. Generally, preemptive antiviral therapy is continued until virology clearance. Previously two consecutive negative weekly CMV PCRs was suggested but now single negative test may sufficient.
What is the relation between the viral load and the development of CMV disease?
Cytomegalovirus (CMV) viral load increases is associated with CMV disease in kidney and liver transplant recipients, but relationships to disease severity or mortality have not been shown.
Some studies suggested that CMV viral load can be used as a surrogate marker for
severe CMV disease and CMV-associated mortality.
References
1 UpToDate Topic 3700 Version 42.0 and Topic 8305 version 28.0
👉 the index case has CMV pneumonitis, traetmebt by shift to IV ganciclovir 5 mg/kg/day and ensure compliance if resistant to it (have rising PCR load ) , consider it ganciclovir resistant .
• Lines of ttt of ganciclovir resistant CMV:
o Foscarnet: but it causes nephrotoxicity, electrolyte disturbance.
o Cidofovir: needs hepatic and renal adjustment.
o Although foscarnet and cidofovir are potent, but their side effects limit their use.
o Combination ganciclovir and foscarnet at reduced doses is better than monotherapy due to synergistic effect, also decrease side effects of both.
o Novel immunomodulatory agent, leflunomide: better safety profile but can cause mild transaminitis, but not used in combination with ganciclovir.
⭐other methods for diagnosis ;
_serology CMV IgM and IgG (but of no value in such immunocompromised host).
_tissue diagnosis or BAL with histopathology revealing owl eye appearance.
👉 Treatment is indicated in the following conditions:
1_ any conformed tissue invasive disease irrespective to the viral load
2_preemptive therapy if the viral load is > 5 log 10 even if asymptomatic .
3_ rising titre of PCR or more than 3 log10 with symptoms.
👉 duration of therapy : give IV ganciclovir for 2-3 weeks until resolution of symptoms and 2 negative PCR.
⭐Tissue invasive disease is dependent on identification of virus in tissues irrespective to viral load.
Management strategy
· Reduction of immunosuppression is the corner stone of TTT (STOP MMF and target lower tac level )
· Patient not responding to oral ganciclovir we need to switch to IV ganciclovir 5 mg /kg/ bid 2-3 weeks until we have 2 negative PCR·
· Consider resistant to valgan cyclovir if persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration (2-4 weeks) of Ganciclovir or Valganciclovir
· if resistant is suspected
1-Confirm that dosing is adequate
2-Consider adherence to treatment plan and absorption
3-Offer testing for Human CMV (HCMV) antiviral resistance UL97 and UL54 gene mutations
4-Use either whole blood or plasma
· If there is evidence of ganciclovir resistance: Stop Valganciclovir (or Ganciclovir) / start Intravenous Foscarnet for at least 3 weeks After Seeking specialist virology advice
Thresholds for treatment
1. Consider reduction in immunosuppression in R+ patients with a viral load of fewer than 3 logs 10.
2. Consider treatment with valganciclovir when the viral load exceeds 3 logs 10 if rapidly rising titre in high-risk patients.
3. Treatment with valganciclovir or IV ganciclovir is mandatorywhen the viral load exceeds 4 logs 10.
Treatment duration in preemptive therapy
Monitor to guide preemptive therapy monthly for 3 month
Treatment for 2-3weeks
CMV disease and viral load
CMV disease – (histopathological evidence of CMV, CMV retinitis diagnosed by an ophthalmologist, or CMV in the CSF indicative of CNS disease) irrespective of viral load
CMV disease is defined as evidence of CMV infection with symptoms and tissue-invasive disease.
Viral load presence of viremia and asymptomatic.
The above case is likely a case of Ganciclovir resistant CMV viremia due to mutations in the UL 97 or UL 54 gene.
Treatment modalities for the above case will be to stop antimetabolite i.e., MMF if he is taking(as not mentioned),increasing the dose of oral valgancyclovir or switching to I/V ganciclovir in a dose of 5mg/kg BID for a duration of 14 to 21 days or till the two consecutive PCR for CMV DNA negative 01 week apart. Foscarnet or cidofovir or IVIG –usually required in resistant cases but need to be vigilant of renal function deterioration with cidofovir or foscarnet. Letermovir and Maribavir are also other altenatives.
What are the other tests to diagnose and monitor CMV?
CMV pp65 antigenemia test
PCR for CMV DNA (quantitative) on blood, CSF, and tissue sample in tissue invasive disease-also used for monitoring of CMV infection.
Histopathological findings of intranuclear inclusion bodies(owl’s eye appearance) in tissue invasive CMV disease in which blood viremia may not be present
Tissue Culture another test but had many limitations.
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
No standardized threshold or cut off value for starting treatment in asymptomatic cases mentioned in the literature and vary center-center and also depends on CMV D/R status. High risk case (CMV R-ve)then the cut off value for treatment is >1000 copies/ml ,and any transplant asymptomatic case with PCR >5000 copies/ml.
-What is the duration of pre-emptive treatment?
Pre-emptive treatment is that in which patient is monitored serially with PCR post-transplant and treatment is started when there is active replication of the virus .Duration is 14-21 days or till the two consecutive PCR for CMV DNA report negative 1 week apart –then anti-viral in a prophylactic dose(900 mg/d ) to be continued for about 100 days.Doses may need to be adjusted according to GFR.
What is the relation between the viral load and the development of CMV disease?
Viral load is considered as an independent important predictor of CMV disease but may not relate to CMV disease and its severity always, as tissue invasive CMV disease has negative PCR test in blood and diagnosis of CMV disease confirmed via histopathological diagnosis.
REFERENCES:
CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023
Sheffield protocol for prophylaxis, surveillance, and treatment of CMV after renal transplantation, 2016
What is your management strategy?
He has a primary CMV infection, CMV pneumonitis, and is currently on oral valganciclovir therapy 900mg BID with a current viral load of 5.5 so he should be started on IV ganciclovir 5 mg /kg BID for at least 5 days and then if a good response shift to oral valganciclovir to complete 21 days and to continue on oral valganciclovir 900mg od for another 4 weeks or till get the two repeated cmv pcr negatives. the alternative is to continue on IV ganciclovir 5 mg /kg BI for total14-21 days the shift to oral valganciclovir 900mg od till getting at least two negative CMV PCR, during treatment, should consider renal adjustment of ganciclovir to the CLCR and monitor for myelosuppression with thrombocytopenia and FBC every two weeks
Also whenever we have a patient who developed CMV tissue invasion disease like in his case CMV pneumonitis we should discuss with the ID, virologist the possibility of ganciclovir-resistant CMV infection and may try a second-line treatment like foscarnet, or cidofovir or the new novel drugs like lemetivir or manibavovir but caution with nephrotoxicity and neurotoxicity, and also cross-resistance especially with foscarnet, cidofovir. high-risk D+ve /R-ve this kidney transplant recipient considers high risk for primary CMV infection and should be on prophylaxis with oral valganciclovir 900 mg for 200 days. reduction of IS is also to be considered as the cumulative dose of IS including induction with ATG or lmeultuzemab can affect the T cell immune response.
What are the other tests to diagnose and monitor CMV?
CMV serology, IgM, IgG for serostatus of acute infection after 200 days of prophylaxis in the seronegative recipient
Sometimes the CMV PCR does not correlate with the clinical tissue invasive CMV and needs tissue biopsy to confirm the diagnosis or bronchoscopy and BAL fluid assay
IHC staining for the viral IB (inclusion bodies owl eyes ).
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viremia (pre-emptive therapy)?
1. Consider treatment with valganciclovir when the viral load exceeds 3 logs 10 if symptomatic or rapidly rising titer in high-risk patients.
2. IV ganciclovir treatment mandatory for tissue organ invasion like pneumonitis, colitis, encephalitis
What is the duration of pre-emptive treatment?
preemptive treatment with oral valganciclovir 900mg BID is to be considered for the high-risk recipient with seroconversion while he is on monitoring with CMV PCR without prophylaxis, which is more costly with frequent CMV PCR monitoring but less cost with antiviral treatment, another concern is the noncompliance and risk of CMV invasive infection.
What is the relation between the viral load an
d the development of CMV disease?
Sometimes the viral load is misleading and if we have a high clinical suspicion of CMV tissue invasion should be treated regardless of viral load, especially in CMV colitis, pneumonitis, and retinitis
References
1. Protocol for prophylaxis, surveillance, and treatment of CMV after renal transplantation. NHS foundation trust, 2016.
2.Fehr T, Cippà PE, Mueller NJ. Cytomegalovirus post kidney transplantation: prophylaxis versus pre-emptive therapy? Transpl Int. 2015 Dec;28(12):1351-6. doi: 10.1111/tri.12629. Epub 2015 Jul 27. PMID: 26138458.
What is your management strategy?
1. CMV pre-transplant serostatus D+/R- carries high risk of CMV infection and disease in the post-transplant period. Valganciclovir prophylaxis to be offered for at least 3 months when the recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (1).
2. Laboratory Testing for CMV: CMV PCR(on whole blood, plasma or leucocyte) considered to the gold standard mean of detecting active viral replication.
3. I will offer treatment with oral Valganciclovir for a duration of at least 2 weeks. Most commonly valganciclovir 900mg twice daily has been used as treatment dose, adjusted for level of kidney function(1).
a) I will monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir.
b) Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days [1D]
c) I will be aware of the potential development of ganciclovir resistance.
d) I will consider stopping treatment for CMV disease after:
· resolution of symptoms.
· two consecutive, CMV viral load tests that confirm that CMV is not detected (below the local laboratory threshold for detection).
4. In the setting of Ganciclovir resistance:
a) People at increased risk of Ganciclovir resistance:
· Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications.
· CMV seronegative recipients receiving a solid organ transplant from seropositive donors (D+/R-).
· Those who have received intensive immunosuppression (e.g; with T-cell depletion therapy, following episodes of acute allograft rejection).
b) I will consider resistance to Ganciclovir if:
· There is a persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir.
c) When resistance to Ganciclovir is suspected:
· I will confirm that dosing is adequate.
· I will consider adherence to treatment plan and absorption.
· I will offer testing for Human CMV (HCMV) antiviral resistance. Sequence-based analysis of UL97 and UL54 gene mutations . Genotypic assays can relatively rapidly detect gene mutations that are associated with both high- and low-grade resistance to ganciclovir as well as mutations that confer various degrees of resistance to Foscarnet and Cidofovir.
d) When there is evidence of ganciclovir resistance:
· I will stop Valganciclovir (or Ganciclovir).
· Offer Intravenous Foscarnet for at least 3 weeks. Foscarnet is reserved as second or even third line therapy partly because of significant risks of nephrotoxicity and electrolyte disturbances.
· Seek specialist virology advice before commencing treatment with Foscarnet .
· The use of Maribavir for treating refractory or resistant CMV infection following SOT has been assessed in phase 3 studies and reported to be superior to Ganciclovir, Cidofovir and Foscarnet.
5. Immunosuppression dose reduction:
a) I will consider a dose reduction of either calcineurin inhibitor or antimetabolite. The TAC level to be around 5(4-6 ng/ml).
b) I will consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia.
c) I will discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction.
d) I will review the dosing of immunosuppression following resolution of CMV infection or disease.
What are the other tests to diagnose and monitor CMV?
1. CMV PCR is the gold standard test for diagnosing CMV infection.
2. CMV IgG & IgM may help in its quantitative form for follow up.
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
1. Treatment with valganciclovir when the viral load exceeds 3 logs 10 if symptomatic or rapidly rising titre in high-risk patients.
2. Treatment with valganciclovir or IV ganciclovir is mandatory when the viral load exceeds 4 logs 10.
What is the duration of pre-emptive treatment?
1. Oral valganciclovir 900mg bd for 21 days, then 900mg od for 28 days or until 2 x PCR negative, whichever occurs first (off-label drug use)(2).
2. IV ganciclovir 5mg/kg bd for 5 days followed by oral valganciclovir 900mg od until 2 x PCR negative.
3. IV ganciclovir 5mg/kg bd for 14-21 days, stop date determined by 2 x PCR negative.
What is the relation between the viral load and the development of CMV disease?
In transplant recipients with CMV infection, the risk of developing CMV disease is directly proportional to the CMV DNA viral load(3).
References
1. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION
2. Protocol for prophylaxis, surveillance, and treatment of CMV after renal transplantation: July 2016 (3rd revision) Review Date: July 2019;Sheffield Kidney Institute Clinical Governance Meeting Date: 18th August 2016
3. NIH; US National Library of Mediucine;Clinicaltrial.gov Determining a Viral Load Threshold for Treating Cytomegalovirus (CMV) https://clinicaltrials.gov/ct2/home
Management strategy
CMV D+/R- is the risk factor of CMV infection in recipient post transplantation, and should had been received gancilcovir prophylaxis for at least 3 months.
As the patient does not respond to valganciclovir twice dially, he proposed to had CMV resistance.
Risk factors of CMV resistance
Consider resistance if:
In case of gancilclovir resistance
Other test to dignose and monitor CMV
What is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
The duration of pre-emptive treatment?
3 months or until cessation of viral replication.
The relation between the viral load and the development of CMV disease?
References
Burd EM. Validation of laboratory-developed molecular assays for infectious diseases, Clin Microbiol Rev, 2010, vol. 23 (pg. 550-76)
2.Pang XL, Fox JD, Fenton JM, Miller GG, Caliendo AM, Preiksaitis JK. Interlaboratory comparison of cytomegalovirus viral load assays, Am J Transplant, 2009, vol. 9 (pg. 258-68)
3.Roberts TC, Buller RS, Gaudreault-Keener M, et al. Effects of storage temperature and time on qualitative and quantitative detection of cytomegalovirus in blood specimens by shell vial culture and PCR, J Clin Microbiol, 1997, vol. 35 (pg. 2224-8
4.Bennett J, Dolin R, Blaser M. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 9th edition. Elsevier/Saunders; 2015.
5.Hodson EM, Jones CA, Webster AC, Strippoli GF, Barclay PG, Kable K. Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials. Lancet. 2005 Jun 18-24. 365(9477):2105-15. [QxMD MEDLINE Link].
6.Zhang LJ, Hanff P, Rutherford C, Churchill WH, Crumpacker CS. Detection of human cytomegalovirus DNA, RNA, and antibody in normal donor blood. J Infect Dis. 1995 Apr. 171(4):1002-6. [QxMD MEDLINE Link].
7.Myhre HA, Haug Dorenberg D, Kristiansen KI, et al. Incidence and outcomes of ganciclovir‐resistant cytomegalovirus infections in 1244 kidney transplant recipients. 8.Transplantation. 2011;92(2):217‐ 2. Lurain NS, Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev. 2010;23(4):689‐ 3. Chemaly RF, Chou S, 9.Einsele H, et al. Definitions of resistant and refractory cytomegalovirus infection and disease in transplant recipients for use in clinical
?What is your management strategy
This patient developed CMV infection 2 months post kidney transplant which was not responded to valganciclovir so this is most likely a case of ganciclovir resistant CMV viremia,risk factors to this patient are( D+/R-) plus high tacrolimus level ,mutations in the UL 97 or UL 54 gene is lead cause to drug resistance
Management :
Antiviral treatment options :
GCV, foscarnet and cidofovir are the mainstays of CMV antiviral treatment.Treatment options for CMV GCV resistance are :
: What are the other tests to diagnose and monitor CMV
Assume this patient is asymptomatic; what is your cut-off level to treat
?asymptomatic CMV viraemia (pre-emptive therapy)
? What is the duration of pre-emptive treatment
The duration of preemptive antiviral therapy should be guided by viral load monitoring. Generally, preemptive antiviral therapy is continued until virologic clearance . Previously Two consecutive negative weekly CMV QNAT was suggested but now a single negative test may suffice if using a highly sensitive QNAT .Usually minimum duration of 2 weeks .
?What is the relation between the viral load and the development of CMV disease
The rate of cytomegalovirus (CMV) viral load increase is associated with CMV disease in kidney and liver transplant recipients, but relationships to disease severity or mortality have not been shown.
Some studies suggested that CMV viral load can be used as a surrogate marker for
severe CMV disease and CMV-associated mortality.
References
Thanks
Dear All
Remember that the treatment dose and duration differ from the CMV prophylaxis.
Please summarise in a few words the dose and the duration of CMV treatment versus the prophylaxis
Recommended dose is valganciclovir 450 mg daily for CMV prophylaxis in kidney transplant for 6 months.
Treatment of infection by intravenous ganciclovir 5 mg/kg/dose q12hr and then change to valganciclovir 900 mg PO q12hr for 21-42 days or until signs and symptoms have resolved.
Thnxs prof,
Prophylaxis dose and duration (adjust the dose according to the eGFR)
Treatment dose and duration (adjust the dose according to the eGFR)
a) Induction; 900 mg oral /12 hours.
b) Maintenance 900 mg oral /24 hours.
a) Induction 5 mg/kg/ 12 hours.
b) Maintenance 5 mg/kg/24 hours.
a) Induction; 60 mg/kg/8hours, or 90 mg/kg/12hours for 41-21 days.
b) Maintenance 90-120 mg/kg/day for 14-21 single infusions.
a) Induction; 5 mg/kg every week for 2 weeks.
b) Maintenance; 5 mg/kg biweekly.
a) Treatment; 400 mg/kg on days 1-2-7 followed by 200 mg/kg on days 14-21.
References
Rubin RH. The indirect effects of cytomegalovirus infection on the outcome of organ transplantation, JAMA, 1989, vol. 261 (pg. 3607-9)
2Fishman JA, Rubin RH. Infection in organ-transplant recipients, N Engl J Med, 1998, vol. 338 (pg. 1741-51)
3Snydman DR. Infection in solid organ transplantation, Transpl Infect Dis, 1999, vol. 1 (pg. 21-8)
4Fishman JA, Emery V, Freeman R, et al. Cytomegalovirus in transplantation—;challenging the status quo, Clin Transplant, 2007, vol. 21 (pg. 149-58)
5Singh N. Preemptive therapy versus universal prophylaxis with ganciclovir for cytomegalovirus in solid organ transplant recipients, Clin Infect Dis, 2001, vol. 32 (pg. 742-51)
PRPHYLAXIS
Valganciclovir 900 mg po od for 6 months if high risk or 3 month if intermediate risk
Therapeutic (3 options )
1. Oral valganciclovir 900mg twice /day for 21 days, then 900mg once daily for 28 days or until 2 x PCR negative, whichever occurs first (.
2. IV ganciclovir 5mg/kg /12 h for 5 days followed by oral valganciclovir 900mg od until 2 x PCR negative.
3. IV ganciclovir 5mg/kg /12 for 14-21 days, stop date determined by 2 x PCR negative.
The dose should be adjusted as per GFR
_prophylaxis valganciclovir is 900 mg/day for 3-6 months according to CMV risk (D+/R- is high risk, when recipient is postive it is intermediate risk whether D is -/+).
_treatment is double prophylactic dose, for 3-6 weeks or until 2 negative PCR
CMV Prophylaxis:
Valgancyclovir 900 mg per day or Injection Gancyclovir 5 mg/kg/day
Duration: 100-200 days, depending on the serostatus of the recipient and donor, as well as use of lymphocyte depleting agents.
CMV Treatment:
Valgancyclovir 900 mg twice a day or Injection Gancyclovir 5 mg/kg/twice a day.
Duration: Until clearance of CMV from blood, for minimum 2 weeks, and until symptoms relieved in case of tissue-invasive CMV.
Reference:
Depending on the indication of iv/oral treatment, the standard treatment dosage is usually double the maşntainace or prevention dose. We usually use valacyclovir orally for treatment and prevention, except in tissue-invasive CMV, where induction can be preferred with iv treatment for about 1-2 weeks.
The dose of treatment is usually double the dose of prevention or maintenance therapy.
For valacyclovir (oral): the standard dose is 900 mg twice daily (Crcl/eGFR >70)
450 mg (twice): Crcl 40-59/
450 mg/24 hr : Cr cl 25-39
450 mg/48 hr : Cr cl 10-24
200 mg/thrice weekly after dialysis (cr cl<10)
For maintenance: 900 mg once a day
450 mg (once): Crcl 40-59/
450 mg/48 hr : Cr cl 25-39
450 mg/twice aweek : Cr cl 10-24
100 mg/thrice weekly after dialysis (cr cl<10)
For iv Ganciclovir:
The treatment dose is 5mg/kg every 12 hours. (2.5g mg/kg twice: Cr cl 50-59/once for Cr cl 25-49 ml/day)
————
Kotton, Camille N. MD1; Kumar, Deepali MD2; Caliendo, Angela M. MD, PhD3; Huprikar, Shirish MD4; Chou, Sunwen MD5; Danziger-Isakov, Lara MD, MPH6; Humar, Atul MD7 on behalf of the The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation 102(6):p 900-931, June 2018. | DOI: 10.1097/TP.0000000000002191
TX – PO Valganciclovir 900mg BD(Renal dosed) or IV Ganciclovir 5mg/kg BD,MIN 2-3/52 and maintained until x2 consecutive -VE CMVPCR.
Prophylaxis- PO Valganciclovir 900mg OD(Renal dosed) for 100-200/7.
Therapy includes Valganciclovir 900 mg PO twice daily based on eGFR or IV gancilovir 5 mg/kg twice daily in cases of malabsorption for at least two to three weeks and continued until CMV PCR is undetectable in the blood on at least two separate occasions.
Prophylaxis: Valganciclovir 900 mg PO once day for at least 100 to 200 days, depending on eGFR.
Treatment of CMV infection
IV ganciclovir 5 mg/kg IV every 12 hours, with dose adjustment for kidney , or valganciclovir 900 mg orally twice daily, with dose adjustment for kidney function, according to severity of the infection.
Duration of treatment:
treat until both symptoms and CMV viremia have resolved (ie, CMV is undetectable or lower than the limits of a sensitive assay in two quantitative PCR tests drawn one week apart).
The typical duration of therapy is 21 days but is often longer, particularly for patients with tissue invasive disease.
also monitor periodically for recurrence with quantitative PCR following completion of therapy, particularly for high-risk patients such as this patient.
prophylaxis treatment : is valgancyclovir 450 mg for 6 month(200 days).
CMV treatment – Valganciclovir or Ganciclovir (dose adjusted for kidney function)
CMV prophylaxis
Prophylaxis
1) Dose of valganciclovir is 900 mg OD for 100 to 200 days
2) However, dose adjustment is required according to GFR
Treatment for CMV
1) Treatment dose is 900 mg twice a day (dose adjustment according to GFR)
2) Duration is until two negative PCR tests or for 28 days
CMV treatment – Valganciclovir or Ganciclovir (dose adjusted for kidney function)
CMV prophylaxis
prophylactic dose: 400 mg of valganciclovir daily for 6 months in high-risk recipients (D+/R-) and for three months in intermediate-risk (D+/R+) or (D-/R+).
Treatment: valganciclovir 900 mg Q12h for 21 days then daily until the two consecutive PCR one week apart become negative. A combination of IV ganciclovir with oral valganciclovir is used as well. Either ganciclovir or valganciclovir needs adjustment according to GFR.
Valganciclovir for prophylaxis is 450 mg od for 3-6 months post transplant , and after every treatment with high dose CS.
treatment dose is 900 mg bid for 2-4 weeks, until viral copies are undetected or the patient is asymptomatic.
Ganciclovir is used intra venous in a dose of 5mg/kg/12 hours until patient is asymptomatic, to be shifted to valganciclovir 900 mg twice a day for 3-4 weeks.
Thank you prof
CMV treatment
-In case of reduce absorption i.e diarrhoea: Gancyclovir 5mg /kg I/V BD for 14-21 days
Gancyclovir 5mg/ kg I/V BD for 5days then Valgancyclovir 900 mg BD orally for 2-3 weeks or until 2 negative CMV DNA PCT
Anti viral dose should be adjusted according to renal function
CMV prophylaxis
For high risk patient (D+/R-) Valgancyclovir 900 mg orally daily for at least 3 months to 12 months in immediate post transplant period
A 61-year-old man was admitted with fever (38 °C) and malaise 2 months after cadaveric transplantation, 000 mismatch on Tacrolimus (trough 9 ng/ml) and prednisolone 15 mg/day. CMV is positive to CMV negative recipient. Oxygen saturation was reported to be 95% on air. Quantitative CMV PCR reported 5.52 log 10 copies/ml. The patient has not responded to oral valganciclovir 900 mg twice daily.
What is your management strategy?
This is a case of ganciclovir resistant CMV with CMV disease (viremia + lung involvement).I would send for genotyping the virus: UL97 and UL54 (are the commonest gene mutations), then I would consider Maribavir as a treatment of choice with less adverse events profile and excellent response to the mutations because it inhibits UL97 phosphotransferase.Foscarnet, cidofovir are used with nephrotoxicity and bone marrow suppression, and drug-drug interactions.Frequent monitoring of CMV viral load by PCR, and treatment to be continued till clinical improvement and two non-detectable CMV viral load.Reduction of immunosuppressive medications: MMF reduced by 50%, and if life threatening infection can be stopped, Tacrolimus reduced to the lower therapeutic trough level (4-6ng/dl), and keeps on stress dose steroid, and if rejection is there can give iv methylprednisolone.Thus, frequent monitoring of the graft function is a must.If no improvement IVIG can be considered in some cases with poor response.
What are the other tests to diagnose and monitor CMV?
CMV serology (Antibodies testing) IgG, IgM: non diagnostic in transplant patients.CMV viral load by PCR: Is the mostly used to diagnose CMV viremia, this either from the serum or a body fluid (ie; BAL).Tissue histopathology: may be helpful (Owle’s eye inclusions).Antigen testing PP65: no longer used because of high false negative results.Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
The cut off level to treat CMV viremia is any level above 10,000 copies/ml.
What is the duration of pre-emptive treatment?
The treatment would be continued for 3 weeks with viral load monitoring.
What is the relation between the viral load and the development of CMV disease?
Most studies demonstrate higher CMV viral load increased the risk of CMV disease – a linear relationship
References:
(1) Kotton CN, Kumar D, Caliendo AM et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-Organ Transplantation. Transplantation 2018; 102:900
(2) UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS. 2022
Thanks
This patient has the CMV syndrome as evidenced by the symptoms and the presence of CMV viremia which is significant (more than 4 log10 copies/ml)
He has not responded to valganciclovir suggesting that he could be resistant to valganciclovir and ganciclovir
Management
The management of this patient would involve:
Diagnosis Of CMV
Pre-emptive Therapy:
Relationship between VL and CMV disease:
Kotton CN, Kumar D, Caliendo AM et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-Organ Transplantation. Transplantation 2018; 102:900
Thank you for your excellent reply
Thank you Professor Halawa
What is your management strategy?CMV positive donor to CMV negative recipient transplantation increases risk of infection. Patient has not responded to Valganciclovir , indicating drug resistance . However adherence to drugs has to be checked UL 97 and 54 mutations should be assessed. Other drugs which can be used include Leflunomide, Foscarnet and IVIG. New potent drugs like Maribavir can be considered
What are the other tests to diagnose and monitor CMV?QNAT
Shell Viral Culture
CMV pp65 antigenemia test
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?4000 to 10000 IU /ml
What is the duration of pre-emptive treatment?100 days
What is the relation between the viral load and the development of CMV disease?There is linear relationship between CMV viral load and the development of CMV disease. High viral suggest active infection or reactivation. In such situation modification of immune suppression helps. Lack of response to drug indicates resistance . In drug resistance immune modulators and newer drugs can be used .
de Matos SB, Meyer R, Lima FWM. Cytomegalovirus Infection after Renal
Transplantation: Occurrence, Clinical Features, and the Cutoff for Antigenemia in a University Hospital in Brazil. Infect Chemother. 2017 Dec;49(4):255-261.
The duration of treatment with oral Valganciclovir is at least 2 weeks [1A].
The dose of Valganciclovir is adjusted if
creatinine clearance is < 60ml/minute.
Consider stopping treatment for CMV disease
after the resolution of symptoms and 2 consecutive CMV viral load tests that
confirm that CMV is not detected (below the local laboratory threshold for
detection) [2D]. (See Dr ABDELHAMID ABOGHANEM reply).
There are other tests, such as IgG, IgM, and the
buffy coat test. Please listen to my lecture again.
You got mixed up with prophylaxis which is for 100 to 200 days.
I apprreciate your nice comments Prof
A 61-year-old man was admitted with fever (38 °C) and malaise 2 months after cadaveric transplantation, 000 mismatch on Tacrolimus (trough 9 ng/ml) and prednisolone 15 mg/day. CMV is positive to CMV negative recipient. Oxygen saturation was reported to be 95% on air. Quantitative CMV PCR reported 5.52 log 10 copies/ml. The patient has not responded to oral valganciclovir 900 mg twice daily.
What is your management strategy?
This is a case of high risk for occurrence of CMV disease – D+/R- and 30% of them are prone to developing late onset of CMV disease even after prophylaxis use or discontinuation.
This is a case of ganciclovir resistant CMV viremia that developed despite the use of high dose valganciclovir (VGCV).
Hence the index case is ganciclovir resistance, and the following steps will be taken.
we confirm adherence to the dose of valganciclovir.
we offer tests for CMV antiviral resistance.
UL94 and UL54 gene mutations will be checked using whole blood or plasma.
CMV infections in KTX recipients are in most cases successfully treated with oral VGCV. However, in a small percentage of patients, mutations in the UL 97 or UL 54 gene lead to drug resistance.
Risk factors for the development of resistance during the treatment of CMV disease include:
Increased & prolonged use of GCV.
D+/R- serostatus
Type of organ transplanted.
Late virus eradication.
Low levels of CMV-specific T cells.
UL97 mutations are the main cause of GCV resistance, however UL54 mutations may also be at play.
UL97 mutations mediate GCV specific resistance because this viral gene is crucial in the 1st mono-phosphorylation of GCV in infected cells.
UL54 mutations, on the other hand, can produce cross-resistance to other antiviral medicines (cidofovir & foscarnet) because this gene codes for the viral polymerase that these medications target.
Treatment strategies for GCV-resistant infections:
Reduce or stop immunosuppressive like MMF/AZA if it has not been stopped.
Increasing the dose of VGCV/GCV
The incidence of GCV-resistance ranges from 5% to 10% while on GCV prophylaxis.
GCV-resistance is also seen during VGCV prophylaxis & in the pre-emptive setting of renal transplantation (7%).
Consider the use of CMV immunoglobulin to induce a passive Immunity.
we switch to second-line agents like intravenous foscarnet, cidofovir, and Leflunomide for three weeks.
There is a role for a combination of GCV + Foscanet since they both attack different CMV genotypes.
we seek specialist virology in assistance, particularly in the genotype.
Close kidney function check because of the risk of graft rejection and toxicity associated with the second-line antiviral agents on the kidney.
Review the dose of immunosuppression after treatment.
What are the other tests to diagnose and monitor CMV?
Serological diagnosis (IgM & IgG antibodies):
The value of serology is limited.
No value for the diagnosis of active disease or infection. Difficult to interpret in immunocompromised patients can be due to the patients’ impaired humoral responses.
IgG Ab appears 6 to 8 weeks of infection & can persist indefinitely. It is used to define the serological status of the donor & the recipient (D/R).
CMV antigenemia test:
Rapid (6 hours) & simple method for the detection of CMV phagocytized by neutrophils in the peripheral blood. Monoclonal Abs to CMV pp65 protein are used as an early & specific marker of active infection.
The results are expressed as the number of PMN cells infected in relation to the total number of PMN cells counted.
Comparable to quantitative PCR in that it is a highly specific method for CMV detection & has predictive value for the disease severity, which is related to the number of cells detected.
The disadvantages:
Needs to be done immediately after the collection of blood samples.
Its quantification is subjective & dependent on the expertise of the operator.
Not an standardized method (extensive variability in its practice).
The result may be doubtful in patients with a neutrophil count < 1,000/mm3.
Viral resistance tests:
UL97 & UL54 are frequently linked to ganciclovir resistant CMV.
Histological diagnosis:
Helpful in the diagnosis of invasive disease.
Intracellular viral inclusion & CMV antigens are detected by IHC or DNA hybridization.
CNS disease can be diagnosed detection of CMV in the CSF (by RT-PCR).
Viral cultures:
Not routinely used.
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
An intervention cut-off point is >2,000 copies/mL of whole blood.
Higher viral loads are associated with a higher chance of contracting the disease.
Due to assay variability & the absence of a global reference standard, there is a poor correlation between the quantitative values for the viral load test amongst laboratories.
This variance prevents the development of clinical decision-making cut-off points that are broadly applicable, particularly for preventive therapy regimens.
What is the duration of pre-emptive treatment?
Duration of treatment with oral Valganciclovir is for at least 2 weeks [1A].
The dose of Valganciclovir is adjusted if creatinine clearance is < 60ml/minute.
Consider stopping treatment for CMV disease after resolution of symptoms AND 2 consecutive, CMV viral load tests that confirm that CMV is not detected (below the local laboratory threshold for detection) [2D].
What is the relation between the viral load and the development of CMV disease?
The quantification of CMV viral load as a proxy for CMV disease severity & disease-associated mortality end points in SOT is supported by the association between CMV viral load & severe CMV disease & death.
What is the relation between the viral load and the development of CMV disease?
Several studies have shown a linear relationship between the CMV viral load and the rate or frequency of development of CMV disease. The higher the CMV level the more the tendency to development of the disease and also the faster the rate of rise of the viral load the higher the chances of the development of CMV disease.
References
Myhre et al. Incidence and Outcomes of Ganciclovir-Resistant Cytomegalovirus Infections in 1244 Kidney Transplant Recipients. Transplantation 92(2):p 217-223, July 27, 2011. | DOI: 10.1097/TP.0b013e31821fad25
Azevedo LS et al. Cytomegalovirus infection in transplant recipients, CLINICS 2015; 70(7): 515-523.DOI: 10.6061/clinics/2015(07)09
Daniel S Owers, Angela C Webster, Giovanni FM Strippoli, Kathy Kable, Elisabeth M Hodson, Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients, Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD005133. DOI: 10.1002/ 14651858.CD005133.pub3.
C. N. Kotton, CMV: Prevention, Diagnosis and Therapy American Journal of Transplantation 2013; 13: 24–40 Wiley Periodicals Inc
McBride et al, Correlation of Cytomegalovirus Disease Severity and Mortality with CMV Viral Burden in CMV-Seropositive Donor and CMV-Seronegative Solid Organ Transplant Recipients, Open Forum Infectious Diseases
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION, BTS, 2022
Michael KlompasTreatment of Ganciclovir Resistant Cytomegalovirus Infection.
Angela M Caliendo. Approach to the diagnosis of cytomegalovirus infection. UpToDate. August 15, 2022
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS. 2022
CMV in Kidney Transplantation Lecture. Ahmed Halawa
Martín-Gandul C, Pérez-Romero P, Sánchez M, et al. Determination, validation, and standardization of a CMV DNA cut-off value in plasma for preemptive treatment of CMV infection in solid organ transplant recipients at lower risk for CMV infection. J Clin Virol 2013; 56:13.
Emery VC, Sabin CA, Cope AV, et al. Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation. Lancet 2000; 355:2032
I like your superb reply that is comprehensive and a well-referenced clinical approach. I like your comprehensive well-referenced clinical approach. At this stage I would not consider giving forscarnet but will keep if resistant virus is the cause. Typing whole sentence in bold or typing in capitals amounts to shouting.
What is your management strategy?
A case of D+/R- transplant presented with fever 2 months post transplant.
Quantitative CMV PCR is 5.52 log 10 copies/ml, not responding to oral valganciclovir 900 mg twice daily.
So Valganciclovir resistance is possible it is suspected when CMV viremia (DNAemia or antigenemia) fails to improve (ie, >1 log10 increase in CMV DNA levels in blood or serum) after 2 weeks of appropriately dosed and delivered antiviral therapy
It can be confirmed by genotype analysis to assess for known mutations in the UL54 and UL97 genes.
Risk factors for the valganciclovir resistance include CMV negative donor and CMV positive recipient , degree of immunosuppression, CMV viremia, and prolonged exposure to anti-CMV medication.
Patients with ganciclovir resistant disease suffered a statistically significant decrease in survival compared to those with ganciclovir sensitive disease.
Therapy include either
Foscarnet is a direct competitive inhibitor of DNA polymerase having activity against CMV isolates with UL97 mutations that are resistant to ganciclovir but has multiple adverse effects as nephrotoxicity and neutropenia
Or combination ganciclovir and foscarnet at reduced doses to reduce it’s side effects
Or Cidofovir IV can cause nephrotoxicity which can be decreased by prehydration and probenecid use .
Or Lefluonamide as immunomodulatory agent but it can increase liver enzymes.
Maribavir, an antiviral agent, competes with ATP for binding to pUL97
It may not completely inhibit CMV replication in ganciclovir resistance , resulting in persistent low-level viremia.
Brincidofovir is the oral lipid conjugate of cidofovir. It is more potent and less nephrotoxic than cidofovir
Letermovir it inhibits CMV DNA synthesis at a late step by targeting the pUL56 subunit of the terminase enzyme complex
CMV-specific CTLs
Cellular adoptive immunotherapy is efficient for the treatment of CMV infection after transplantation
What are the other tests to diagnose and monitor CMV?
For monitoring CMV active disease pp65 antigenemia can be used to detects the presence of the pp65 phosphoprotein on peripheral blood leukocytes and viral DNA detection by polymerase chain reaction (PCR), which can be qualitative or quantitative.
Serological methods to detect IgM and IgG classes
Viral cultures are not practical due to low accuracy and time consuming.
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
This cutoff level has not been established, each center use their own cutoff point ranging from 1 to 50 positive cells per slide with 200,000 leukocytes .
Saracino et al., suggested that antigenemia ≥2 positive cells/200,000 leukocytes can be considered an appropriate cutoff point for starting pre-emptive therapy among renal transplant recipients . In contrast, Jung et al., concluded that the therapy should be administered only to patients with ≥25 positive cells per slide.
What is the duration of pre-emptive treatment?
for 10 to 14 days or until CMV viremia findings became negative. In preemptive therapy, transplant recipients are monitored for CMV replication by serial CMV DNA or pp65 antigen detection tests and are treated with antiviral drugs when active CMV replication is detected, regardless of clinical symptoms
What is the relation between the viral load and the development of CMV disease?
CMV DNA viral load testing is an important test to evaluate CMV disease risk of disease and diagnosis , and monitoring response to therapy. The interpretation of CMV DNA viral load values can be complex, and numerous virus and host factors should be considered when assessing the risk of CMV disease.
Reference
-Klompas M .Treatment of Ganciclovir Resistant Cytomegalovirus Infection
– El Chaer F, Shah DP, Chemaly RF. How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients. Blood. 2016;128(23):2624-2636.
– Franco R F et al.CMV diagnosis in renal transplantation. J Bras Nefrol 2017;39(1):46-54
– de Matos SB, Meyer R, Lima FWM. Cytomegalovirus Infection after Renal Transplantation: Occurrence, Clinical Features, and the Cutoff for Antigenemia in a University Hospital in Brazil. Infect Chemother. 2017;49(4):255-261.
– Hasegawa J et al .Preemptive anti-cytomegalovirus therapy in high-risk (donor-positive, recipient-negative cytomegalovirus serostatus) kidney transplant recipients .International Journal of Infectious Diseases 2017 , ISSN: 1201-9712, Vol: 65, Page: 50-56
– Bordo et al. Prophylaxis Versus Preemptive Therapy for Cytomegalovirus Disease in High-Risk Liver
Transplant Recipients. LIVER TRANSPLANTATION, September 2012 18:1093-1099.
– Colleen S. Kraft, Wendy S. Armstrong, Angela M. Caliendo, Interpreting Quantitative Cytomegalovirus DNA Testing: Understanding the Laboratory Perspective, Clinical Infectious Diseases, Volume 54, Issue 12, 15 June 2012, Pages 1793–1797
I like your well-referenced clinical approach. I would emphasise that reducing immunosuppression and commencing IV ganciclovir are 2 more important initial step in this patient who has been on oral valcyte. At this stage I would not consider giving forscarnet but will keep that in the back of my mind if resistant virus is the cause.
What is your management strategy?The index patient is a recent (2 month back) cadaveric CMV seropositive donor to CMV seronegative renal transplant recipient, with 000 mismatch, and on tacrolimus and steroid based dual maintenance immunosuppression. This combination of donor-recipient (D+/R-) is a high-risk transplant with respect to CMV infection (1).The patient needs evaluation in form of:
History: History regarding any symptoms, especially with respect to any tissue-specific CMV involvement (for example diarrhea, shortness of breath or cough), any history of recent anti-rejection treatment (with consequent intense immunosuppression use).Laboratory tests: Complete blood count, renal function test, urine routine, chest x ray, tacrolimus trough level, CMV PCR quantitative in blood, other investigations as per symptoms, if any (for example stool examination, colonoscopy if gastrointestinal involvement).Treatment: If asymptomatic (as in the index patient), Oral valganciclovir 900 mg twice a day (dose to be modified as per creatinine clearance) should be given for at least 2 weeks, and treatment should continue with weekly CMV PCR testing until 2 (single negative in case of using highly sensitive test) negative CMV PCR values are achieved. Intravenous gancyclovir 5 mg/kg 12 hourly (dose to be adjusted as per creatinine clearance) can be given if concerns regarding oral absorption of valganciclovir (or severe illness) exist (1,2). Longer duration of treatment might be required (till symptoms subside) if tissue-invasive CMV is present (like gastrointestinal involvement, pneumonitis, of CNS involvement).The index patient did not respond to oral valganciclovir. It could be due to poor oral absorption, over-immunosuppressed state, or gancyclovir resistance (1). Assessment for ganciclovir resistance should be done. Genotype testing to identify the specific mutations should be done.
First step is to give increased dose of intravenous Ganciclovir (10 mg/kg 12 hourly) rather than the standard dose of 5 mg/kg 12 hourly (dose should be adjusted as per creatinine clearance), and if responds, then continued for minimum 2 weeks, and until clearance of CMV in blood (1,2). In absence of any genetic mutation, ganciclovir would suffice. If no response, or if there is UL97 and UL54 mutation: Shift to intravenous Foscarnet (90 mg/kg 12 hourly, dose to be adjusted as per renal clearance) for 3 weeks and additional CMV immunoglobulin or intravenous immunoglobulin (IVIG) should be considered (1). Cidofovir (1mg.kg intravenous 3 times a week): Can be given in presence of UL97 mutation alone (not effective in UL54 mutation).Maribavir (400 mg twice a day for 8 weeks): Active against both UL97 and UL54 mutations.Letermovir have also been used. Immunosuppression reduction: Ideally antimetabolites should be stopped/ reduced by 50%. But in the index case, patient is already on dual immunosuppression only. The CNI levels should be checked.Patient should be counselled regarding the risk of rejection in such a scenario when the dose of immunosuppression is being reduced.Post-treatment, CMV monitoring should be done weekly for 12 weeks.
What are the other tests to diagnose and monitor CMV?Tests to diagnose CMV include (1,2):
CMV quantitative nucleic acid testing (CMV-QNAT): Test of choice for CMV rapid diagnosis in organ transplant recipients (1). It is useful as a surveillance tool for monitoring of CMV.pp65 Antigenemia: Detection of pp65 antigen in blood is comparable to CMV QNAT as for diagnosing and monitoring treatment response of CMV (1).Histopathological diagnosis: Identification of CMV-cytopathic changes or CMV antigen by immunohistochemistry is utilized in tissue-invasive CMV, where the blood CMV QNAT might be negative (for example gastrointestinal or respiratory tract involvement).CMV Viral culture: It has limited clinical utility, hence not recommended for CMV disease diagnosis after transplant.CMV serology: CMV IgM has limited utility, hence not recommended in organ transplant recipients (2). Antibodies from blood products or IVIG (if used) can give false positive values, and false negative values can be seen due to inability to mount antibody response because of immunosuppressed state) (1).Immunological monitoring using parameters like hypogammaglobulinemia, absolute lymphocyte count and CD4+/CD8+ T cell (nonspecific and CMV-specific) subsets have been used for CMV disease risk stratification, but specific thresholds have not been defined. Absence of CMV-specific CD4+ and/or CD8+ T cells signify higher risk of CMV disease, treatment failure, and relapse.Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?There is no consensus regarding the cut-off level for preemptive CMV treatment in kidney transplant recipients with ranges from 1500 to 4000, with lower thresholds for D+/R- pair (2,3). Some groups use rapid doubling of CMV viral load as a marker for pre-emptive treatment. In our unit, we take 1500 as cut-off.
What is the duration of pre-emptive treatment?The duration for pre-emptive CMV treatment will be until 1 or 2 weekly negative CMV PCR reports with a minimum of 2 weeks.
What is the relation between the viral load and the development of CMV disease?Peak CMV viral load has been shown to be an independent significant predictor of CMV disease (4). But absence of CMV in blood , as can be seen in gastrointestinal tissue-invasive CMV, the blood CMV PCR could be negative while histopathological lesion suggestive of CMV can be seen, does not rule out CMV disease.
References:
Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, Humar A; The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-931. doi: 10.1097/TP.0000000000002191. PMID: 29596116.Timsit JF, Sonneville R, Kalil AC, Bassetti M, Ferrer R, Jaber S, Lanternier F, Luyt CE, Machado F, Mikulska M, Papazian L, Pène F, Poulakou G, Viscoli C, Wolff M, Zafrani L, Van Delden C. Diagnostic and therapeutic approach to infectious diseases in solid organ transplant recipients. Intensive Care Med. 2019 May;45(5):573-591. doi: 10.1007/s00134-019-05597-y. Epub 2019 Mar 25. PMID: 30911807; PMCID: PMC7079836.Humar A, Gregson D, Caliendo AM, McGeer A, Malkan G, Krajden M, Corey P, Greig P, Walmsley S, Levy G, Mazzulli T. Clinical utility of quantitative cytomegalovirus viral load determination for predicting cytomegalovirus disease in liver transplant recipients. Transplantation. 1999 Nov 15;68(9):1305-11. doi: 10.1097/00007890-199911150-00015. PMID: 10573068.
References:
I like your superb reply that is comprehensive and a well-referenced clinical approach.
4. A 61-year-old man was admitted with fever (38 °C) and malaise 2 months after cadaveric transplantation, 000 mismatch on Tacrolimus (trough 9 ng/ml) and prednisolone 15 mg/day. CMV is positive to CMV negative recipient. Oxygen saturation was reported to be 95% on air. Quantitative CMV PCR reported 5.52 log 10 copies/ml. The patient has not responded to oral valganciclovir 900 mg twice daily.
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Valganciclovir Resistance Should be suspected if CMV PCR count has not fallen by ≥ 1 log copies/ml after two weeks of therapy or if there is no clinical improvement despite treatment
Exclude other causes of symptoms
Host factors
Viral factors
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What is your management strategy?
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What are the other tests to diagnose and monitor CMV?
Serology
Other Tests
Cytomegalovirus resistance testing
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Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
Preemptive therapy
The optimal cut-off for preemptive therapy is 3983 IU/ml
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What is the duration of pre-emptive treatment?
Preemptive therapy given for 3-4 weeks after 2 negative PCR.
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What is the relation between the viral load and the development of CMV disease?
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Reference
I like your comprehensive well-referenced clinical approach. At this stage I would not consider giving forscarnet but will keep if resistant virus is the cause. Typing whole sentence in bold or typing in capitals amounts to shouting.
What is your management strategy?
KTR with fever and CMV viremia who did not respond despite good valganciclovir dose, which is suggestive for ganciclovir disease.
The prevalence in SOT ranges between 0 and 15%, In KTR 2.2% and it vary according to the organ transplanted likely reflect different degrees of immunosuppression.
Risk Factors;
CMV R-/ D+ ; risk of both CMV infection and ganciclovir resistance.
Degree of IS.
Magnitude of CMV viremia.
Prolonged exposure to anti-CMV medication.
Management of CMV- resistance disease;
– Check treatment adherence.
– Offer testing for CMV antiviral resistance, UL97 and UL54 gene mutations.
– Seek specialist virology advice.
– Definitive antiviral treatment should be guided by results of genotypic
– Stop Valganciclovir.
– IV ganciclovir appropriate dose before considering alternative options.
– Consider Foscarnet IV for at least 3 weeks till viral load is negative ( monitor KFT & electrolytes)
– leflunomide can be considered for both potentiates immunosuppression and suppresses CMV replication.
– Cidofovir ( nephrotoxicity limits its use)
– ff‐label letermovir , Maribavir
– CMV Ig or IVIG may be used as an adjunct to antiviral drugs
– The doses should be adjusted to renal function
– Monitor RF, CBC, and LFT is required
IS management :
– Stop/reduce (by 50%) antimetabolites.
– Do not discontinue CNI unless there is evidence of a life-threatening infection; keep the level of Tacrolimus 6.
– Corticosteroids are generally continued.
– Consider switching to sirolimus‐containing regimen may be an option due to the reportedly lower risk of CMV disease in patients receiving mTOR inhibitors
– Monitor graft function.
What are the other tests to diagnose and monitor CMV?
– CMV-PCR the best method to diagnose and monitor CMV.
– Serology; very limited role, as SOTR has impaired to produce adequate antibody response, the main utility in the pre-transplant screening for candidates and donors for risk stratification.
– Antigenemia; detects CMV pp65 antigen in infected peripheral blood leucocytes, has a higher sensitivity than viral culture, it may have limited clinical utility in leucopenic patients, and the test requires a quick sample processing time for accuracy (4 to 6 hours).
-Viral culture is highly specific for the detection of CMV, but it has low sensitivity and the assay has a long turn-around time, used to diagnose CMV disease where viral load might be negative.
– Histopathology ;remains as the gold standard for the definitive diagnosis of end‐organ CMV diseases
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
The major drawback to CMV NAT is the lack of widely applicable thresholds; due to lack of standardization.
Sheffield hospital protocol consider:
– Viral load < than 3 logs 10; reduce immunosuppression
– Viral load > 3 logs 10 or if symptomatic or rapidly rising titer ; treat with valganciclovir.
– Viral load > 4 logs 10 ; Treat with oral valganciclovir or IV ganciclovir.
As a general rule, viral loads that are >10,000 copies/mL used.
What is the duration of pre-emptive treatment?
Preemptive therapy; can be considered in moderate risk SOT recipients (recipients positive for CMV).
– Serial testing performed weekly or biweekly for the first few months post-transplantation
– Regardless of symptoms, antiviral treatment are administered with any early evidence of CMV replication
– Treatment duration: for 14-21 days, to be continued till 2 x PCR negative
Universal prophylaxis:
– D+/R- 200 days of valganciclovir.
– D-/R+ & D+/R+ 100 days of valganciclovir, 200 days after ATG or Alemtuzumab
– D-/R- No valganciclovir
– After receiving intensified IS at any time point.
What is the relation between the viral load and the development of CMV disease?
– Higher viral loads are also generally observed during primary CMV disease in CMV D+/R− compared to reactivation in CMV R+ SOT recipients.
– Higher viral load values in blood are also generally associated with end‐organ disease, while lower values are seen with asymptomatic CMV infection, and intermediate‐ range viral loads are seen with CMV syndrome, although
there is overlap in viral load values among categories.
References:
– Angarone M, Snydman DR; AST ID Community of Practice. Diagnosis and management of diarrhea in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13550. doi: 10.1111/ctr.13550. Epub 2019 Apr 10. PMID: 30913334.
-Sheffield protocol for prophylaxis, surveillance, and treatment of CMV after renal transplantation, 2016
-Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521.
I like your well-referenced clinical approach. You mention stopping or reducing MMF, though this patient is already off MMF.
I agree that reducing immunosuppression and commencing IV ganciclovir are 2 more important steps. At this stage I would not consider giving forscarnet but will keep that in the back of my mind if resistant virus is the cause.
A 61-year-old man was admitted with fever (38 °C) and malaise 2 months after cadaveric transplantation, 000 mismatch on Tacrolimus (trough 9 ng/ml) and prednisolone 15 mg/day. CMV is positive to CMV negative recipient. Oxygen saturation was reported to be 95% on air. Quantitative CMV PCR reported 5.52 log 10 copies/ml. The patient has not responded to oral Val ganciclovir 900 mg twice daily.
What is your management strategy?
A case of CMV infection, resistance to Val ganciclovir and low immunological risk.
1-In vGCV/GCV resistance ask for viral gene typing.
2-IV Val ganciclovir will be started.
2-All immunosuppressive medication should be significantly reduced/stopped in life-threatening CMV disease and CMV disease that persists in spite of treatment, until CMV disease has resolved.
3-Monitoring graft function closely during CMV disease.
4-Consider Immunoglobulins (particularly if pneumonitis). CMVIG can be used to induce a passive immunity.
5-Using second line such as (Foscarnet, Cidofovir and Letermovir).
6-All treatment should continue until resolution of symptoms and for a minimum of 14 days.
What are the other tests to diagnose and monitor CMV?
Serology:
-CMV IgG (indicates past infection. good for screening).
-CMV IgM (indicates acute infection).
DNA PCR:CMV DNA is amplified from a plasma sample or a biopsy.
-Results are usually reported as number of copies/ml of blood or plasma.
CMV pp65 antigenaemia:
pp65, a protein, is detected by fluorescent assay and reports as number of infected peripheral blood cells.
Histopathology:
Chemical staining of tissue samples to detect CMV inclusion bodies (Owl’s eye appearance)
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
No widely acceptable viral load threshold to guide therapy due to lack of standardization of PCR results across centers, but some suggestion advice to treat seronegative recipient (high risk) with PCR > 1000 copies /ml and transplant recipients with the PCR is > 5000 copies/m should be treated regardless the serostatus of the recipient.
What is the duration of pre-emptive treatment?
Preemptive therapy given for a minimum 3 weeks (usual duration of therapy 3-4 weeks) and once there are 2 successive negative PCR , TTT will be stopped.
What is the relation between the viral load and the development of CMV disease?
A study shown that the risk of disease increases as the viral load increases (a 50% probability of disease was reached at a virus load of 4.0 × 105 copies/ml and an 80% risk was reached at 1.6 × 106 copies/ml)
References:
1-Krishna BA, Wills MR, Sinclair JH. Advances in the treatment of cytomegalovirus. Br Med Bull. 2019;131(1):5-17. doi:10.1093/bmb/ldz031
2-Aitken C, Barrett-Muir W, Millar C, et al. Use of molecular assays in diagnosis and monitoring of cytomegalovirus disease following renal transplantation. J Clin Microbiol. 1999;37(9):2804-2807. doi:10.1128/JCM.37.9.2804-2807.1999.
I like your well-referenced clinical approach. However, reduction of immunosuppression and commencing IV ganciclovir are 2 more important steps. At this stage I would not consider giving forscarnet but will keep if resistant virus is the cause.
What is the difference between Pre-emptive treatment and prophylactic treatment?
What is the condition when viral load is not concordant with CMV disease?
What is your management strategy?
This patient not responded to treatment in spite of full dose of valganciclovir. This is Ganciclovir resistance. It is defined as CMV disease that is refractory to treatment with Ganciclovir or Valganciclovir and is reported to occur in up to 3% of SOT recipients (Deteced via genotype analysis to assess for UL54 and UL97 genes)
Risk factors include:
1. R-/D+
2. Degree of immunosuppression
3. Magnitude of CMV viremia
4. Prolonged exposure to anti-CMV medication, or subtherapeutic antiviral dosing
Consider resistance to Ganciclovir if there is a persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir
If resistance to Ganciclovir is suspected:
1. Confirm that dosing is adequate
2. Consider adherence to treatment plan and absorption
3. Offer testing for Human CMV (HCMV) antiviral resistance: UL97 and UL54 gene mutations. Use either whole blood or plasma
When there is evidence of ganciclovir resistance:
1. Stop Valganciclovir (or Ganciclovir)
2. Offer Intravenous Foscarnet for at least 3 weeks. Seek specialist virology advice before commencing treatment with Foscarnet
Newer agents Letermovir and Maribavir may be associated with less drug toxicity
Maribavir has FDA approval and is currently being assessed by the NICE
Immunosuppressions: In patients without concomitant rejection, reduction of immunosuppression is suggested in the following settings:
1. Severe CMV disease
2. Inadequate clinical response
3. High viral loads
4. and cytopenia
What are the other tests to diagnose and monitor CMV?5. Antigen testing (CMV pp65)
6. Qualitative PCR
7. Shell vial assay
8. Histopathology
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
Optimal thresholds are different among different at-risk groups. There was strong consensus that a lower threshold should be used with D+/R−, as the use of higher thresholds may result in insufficient time to begin treatment for CMV and higher rates of disease. Although prior guidelines mentioned that some experts, recommended starting treatment with any detectable DNAemia, with increasingly sensitive assays many experts felt that very low results should not always result in initiation of treatment, even in D+R−recipients (4)
High risk (D+R−): 1500 IU/mL in plasma (the index case). No episodes of symptomatic CMV disease were diagnosed in patients with viral loads below 1500 IU/mL
Moderate risk (D+R− and R+): 3000 copies/mL of whole blood
Patients that develop viraemia whilst not on prophylaxis (Sheffield protocol):
o Treatment is mandatory in all cases of suspected tissue-invasive CMV disease, irrespective of viral load
o Treat with valganciclovir when the viral load exceeds 3 logs 10 and rapidly rising titre in high-risk patients
o Treatment with valganciclovir or IV ganciclovir is mandatory when the viral load exceeds 4 logs 10
What is the duration of pre-emptive treatment?Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days
Stop treatment after resolution of symptoms and two consecutive, negative tests for CMV viral load, then prophylaxis for 200 days (D+/R-)
What is the relation between the viral load and the development of CMV disease?
o CMV load, used as a surrogate marker of CMV replication, has been shown in many studies to be a dominant risk factor for CMV disease
o The level of viral load in the blood compartment may not correlate with the severity of tissue invasive disease and QNAT of plasma or blood may not be the best indicator of disease resolution
References
1. CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023
2. Treatment of Ganciclovir Resistant Cytomegalovirus Infection, Michael Klompas.
3. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS, 2022.
4. Camille N, et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation 2018;102: 900–931.
Gancyclovir resistance is defined as failure of reduction of viral load ≥ 1 log copies /ml after 2 weeks of appropriate treatment
IV ganciclovir is the appropriate treatment in the following patients:
So I will start ganciclovir intravenously in a dose of 5mg/kg/12 hours since the patient has tissue invasive disease and the high viral load
Then I will monitor PCR weekly, if no reduction of viral load ≥ 1 log copies /ml after 2 weeks of treatment I will consider ganciclovir resistance and I will switch to alternative therapy under the guidance of virology expert
Alternative therapy for gancyclovir resistant CMV
1- IV Foscarent
2- Combination therapy with reduced doses of ganciclovir and foscarnet
3- Cidofovir
4- Leflunamide
What are the other tests to diagnose and monitor CMV?
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
Antiviral therapy is indicated in the following asymptomatic patients:
What is the duration of pre-emptive treatment?
What is the relation between the viral load and the development of CMV disease?
No good correlation exists between viral load and tissue invasive disease
Thankyou well done.
1-What is your management strategy?
–In this patient with ganciclovir-resistant CMV infection; require reduction of immunosuppression.
Gancyclovir ( intolerant or resistant);
-Resistance to ganciclovir should be considered in recipients who fail to improve clinically and/or virologically after two weeks of adequate doses of antiviral therapy or who have recurrent relapses following treatment.
-Factors that raise the likelihood of ganciclovir resistance include prolonged antiviral use, lack of prior CMV immunity (CMV D+/R-), and inadequate antiviral drug selection or dosing (eg, treatment with oral ganciclovir or subtherapeutic dosing of IV ganciclovir.
Resistance testing;
-Genotypic resistance testing should be performed in patients with suspected ganciclovir resistance (UL97 mutation & UL54 mutations).
With evidence of resistance;
-Stop valganciclovir or ganciclovir and give Intravenous Foscarnet for at least 3 weeks after specialist virology advice (newer agents Letermovir and Maribavir may be an alternative).
-It is important to note that nephrotoxicity is common when foscarnet is given in combination with cyclosporine or tacrolimus. Electrolyte disturbances are also common with foscarnet.
-An alternative to foscarnet is cidofovir, but there is less clinical experience with this agent for treating resistant CMV infection, and its use is limited by the potential for severe nephrotoxicity.
Maribavir;
-An oral drug that inhibits UL97 phosphotransferase and stops viral maturation.
-It is active against CMV with UL97 and UL54 mutations.
-Maribavir is dosed at 400 mg orally twice daily for eight weeks.
-Dysgeusia is a frequent side effect, and maribavir cannot be coadministered with ganciclovir or valganciclovir.
-Key advantages of maribavir over other agents are lack of bone marrow and kidney toxicity.
-Due to a drug interaction with calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors, close monitoring of these immunosuppressive agents is required.
-Resistance to maribavir has also been reported to emerge while on therapy.
2-What are the other tests to diagnose and monitor CMV?
Molecular assays;
–Quantitative CMV-PCR tests for detecting viral DNA;
COBAS AmpliPrep , COBAS TaqMan CMV test , COBAS CMV test ,
Artus CMV RGQ MDx test , RealTime CMV test , Alinity m CMV assay.
-CMV pp65 antigenemia test for detecting viral antigen;
-Quantitative PCR assays offer several advantages over the antigenemia assay, including better assay standardization, increased stability of the specimen, smaller specimen volume, and the ability to test patients with leukopenia.
-For these reasons, quantitative PCR assays are more widely used than the antigenemia test, and it is preferred for the diagnosis and monitoring of immunocompromised patients with CMV infection and disease.
Histopathology;
–Histologic examination of tissue biopsies is useful for the diagnosis of CMV tissue-invasive disease.
-Diagnosis is based on the presence of inclusion bodies, typically basophilic intranuclear inclusions, although eosinophilic cytoplasmic inclusions may also be seen;(Owel eye appearance).
Culture;
-Conventional culture; there are several limitations of conventional cell culture techniques.
-Shell vial culture;is a rapid culture method based on low-speed centrifugation and detection of CMV early antigen prior to the development of characteristic cytopathic effects in tissue culture, thus accelerating the time to diagnosis.
3-Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
-Viral load thresholds to start preemptive therapy have not been standardized across institutions given variability among diagnostic specimens and testing platforms.
-According study for liver transplant recipients showed that the optimal cutoff for predicting CMV disease was in the range of 2000 to 5000 copies/mL of plasma; at a cutoff of >5000 copies/mL, the sensitivity was 86% and the specificity was 87%.
-All patients with a viral load >20,000 copies/mL developed CMV disease. An important limitation of these data is that these CMV DNA levels apply to the Amplicor Monitor test, which is not available clinically.
-In a more recent study of solid organ transplant recipients at lower risk for CMV infection, a cutoff of approximately 4000 international units/mL was established for initiating pre-emptive therapy.
-However, these results may not be generalizable, as testing was done on plasma samples using an assay that is not FDA approved and the study population was solid organ transplant recipients at low risk of developing CMV disease.
4-What is the duration of pre-emptive treatment?
–When pre-emptive therapy is indicated, use valganciclovir 900 mg orally every 12 hours (adjusted for renal dysfunction). While on therapy.
-Monitoring the viral load weekly or biweekly.
-Treatment until the viral load is undetectable or less than the lower quantifiable limit of the assay (ie, <200 international units/mL) on a single highly sensitive assay or until the viral load is undetectable on two consecutive samples when using less sensitive assays
-If active CMV infection is detected, we give valganciclovir or IV ganciclovir at treatment doses until repeat CMV nucleic acid testing is negative and for a minimum of 21 days.
5-What is the relation between the viral load and the development of CMV disease?
–Studies of solid organ transplant recipients using quantitative PCR assays have shown higher viral loads in patients with active CMV disease compared with those with asymptomatic infection.
-The rate of increase in viral load can be used to predict patients at risk for CMV disease.
-Patients with CMV disease have a significantly faster rate of increase in CMV load between the last PCR-negative and first PCR-positive sample than those without CMV disease.
References;
-Chou S, Song K, Wu J, et al.Drug Resistance Mutations and Associated Phenotypes Detected in CLinical Trials of Maribavir for Treatment of Cytomegalovirus infection. J infect Dis 2022; 226:576 .
–Kotton CN, Kumar D, Caliendo AM, et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation 2018; 102:900.
–Humar A, Gregson D, Caliendo AM, et al. Clinical utility of quantitative cytomegalovirus viral load determination for predicting cytomegalovirus disease in liver transplant recipients. Transplantation 1999; 68:1305.
–Martín-Gandul C, Pérez-Romero P, Sánchez M, et al. Determination, validation and standardization of a CMV DNA cut-off value in plasma for preemptive treatment of CMV infection in solid organ transplant recipients at lower risk for CMV infection. J Clin Virol 2013; 56:13.
Well done.
-What is your management strategy?
-What are the other tests to diagnose and monitor CMV?
-Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
-What is the duration of pre-emptive treatment?
-What is the relation between the viral load and the development of CMV disease?
Reference
Thankyou for a very well organized answer but to mention :
In tissue invasive CMV as gastritis,sometimes viremia is absent but tissue histology is diagnostic.
Agree with you prof
What is your management strategy?
The patient has resistant to valganciclovir.
Mutations arising in UL97 phosphotransferase lead to ganciclovir resistance. Similarly, mutations arising in the DNA polymerase gene UL54 also confer resistance to ganciclovir.1 Different UL97 mutations are associated with different degrees of ganciclovir resistance.2 Most patients develop only UL97 mutations, however, prolonged exposure to ganciclovir can give rise to simultaneous UL54 and UL97 mutations.
treatment with reduced immunosuppression (the patient is at low immunological risk) CMV immunoglobulin. foscarnet, cidofivir, high-dose ganciclovir ,Leflunomide , or ganciclovir and foscarnet at reduced doses.
What are the other tests to diagnose and monitor CMV?
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viremia (pre-emptive therapy)?
pre-emptive therapy with valganciclovir (900 mg b.i.d. for a minimum of 14 days) for significant CMV DNAemia (≥2000 copies/mL by quantitative PCR in whole blood) assessed weekly for 16 weeks and at 5, 6, 9, and 12 months.
What is the duration of pre-emptive treatment?
14 days, pre-emptive therapy relies on the timely availability of sensitive and reliable methods for detecting CMV viremia so that treatment based on identifying CMV infection can be initiated before CMV disease develops
What is the relation between the viral load and the development of CMV disease?
The ability of the virus to reproduce is directly proportional to the amount of infectious virus that is circulating in the blood, independent of the body’s capacity to deal with the virus’s activities.
The correlation between CMV viral load and severe CMV illness and death provides support for the use of CMV viral load as a surrogate for these disease severity and mortality
The presence of high levels indicates that the person may be suffering from either a primary infection or a reactivation of an illness that they have previously had.
References:
Owers, Daniel S., et al. “Pre‐emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients.” Cochrane database of systematic reviews 2 (2013).
The Prevention and Management of CMV Disease after Solid Organ Transplantation2022
Reischig, T., et al. “Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation.” American Journal of Transplantation 8.1 (2008): 69-77.
Thankyou but please revise the plan for pre- emptive therapy.!
What is the cutoff PCR and is it absolute?
What is your management strategy?
Risk factors for the development of resistance during the treatment of CMV disease include:
Treatment strategies for GCV-resistant infections:
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What are the other tests to diagnose and monitor CMV?
Serological diagnosis (IgM & IgG antibodies):
CMV antigenemia test:
Viral resistance tests:
Histological diagnosis:
Viral cultures:
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Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
An intervention cut-off point is >2,000 copies/mL of whole blood.
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What is the duration of pre-emptive treatment?
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What is the relation between the viral load and the development of CMV disease?
References
Well done.
What is your management strategy?
This is a case of high risk for occurrence of CMV disease – D+/R- and 30% of them are prone to developing late onset of CMV disease even after prophylaxis use or discontinuation. Hence the index case is ganciclovir resistance and the following steps will be taken.
Treatment
Other tests to diagnose and monitor CMV
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?
What is the duration of pre-emptive treatment?
What is the relation between the viral load and the development of CMV disease?
Several studies have shown a linear relationship between the CMV viral load and the rate or frequency of development of CMV disease. The higher the CMV level the more the tendency to development of the disease and also the faster the rate of rise of the viral load the higher the chances of the development of CMV disease.
References
What is your management strategy?Patients with a CMV-positive deceased donor increase the risk of transmission by being a negative recipient. Even a dose for pre-emptive treatment apparently shows disease activity and circulating viral load.
Resistance risk (UL97 and 54 mutation) is a possibility, which would lead to Ganciclovir associated with another drug (IVIg, Leflunomide, Foscarnet) or more potent drugs with a better resistance profile such as Maribavir.
Decreasing the corticosteroid dose may be considered.
What are the other tests to diagnose and monitor CMV?
Assume this patient is asymptomatic; what is your cut-off level to treat asymptomatic CMV viraemia (pre-emptive therapy)?In the literature, there are studies with viral loads above 4,000 IU/mL and others with 10,000 IU/mL of viral load. Our service considers the latter.
What is the duration of pre-emptive treatment?
We started the pre-emptive treatment for CMV on the fifteenth day post-transplant and carried it out for 90 days
What is the relation between the viral load and the development of CMV disease?
The circulating viral load is related to the ability of the virus to replicate, regardless of the body’s ability to cope with its activity.
High values suggest that the individual may be experiencing a primary infection or reactivation of a previous disease, which is why interventions aimed at controlling the disease involve decreasing immunosuppression (special attention to corticosteroids and mycophenolate) and specific antiviral treatment (Ganciclovir and valganciclovir).
Even with this intervention, there is an increase in these values in serum, considering drug resistance due to mutations in the UL97 and UL54 genes, requiring replacement by antivirals and immunomodulators to improve the immune status of the transplanted patient.
Restricted involvement of the gastrointestinal and ocular tracts does not change the viral load, but requires immediate treatment.
Thankyou what is the difference between Pre-emptive treatment in a CMV+ asymptomatic patient and prophylactic CMV- patient who received induction with rATG.
Pre-emptive treatment only monitors the patient and if he has a positive viral load, start treatment for 14 days or with a negative viral load
Prophylaxis will do the specific medication (We don’t have valganciclovir, that’s why we do Ganciclovir) for six months.
90 days if rATG low dosis ou six month with it is a higher dose