Introduction: CMV belong to the herpes group of viruses, and causes severe infection in immune-compromised patients usually 4 to 6 weeks after the transplant. Patients present with non specific symptoms like night sweats, fatigue, myalgia , Diarrhea, abdominal pain, nausea, respiratory distress and retinitis rarely. Also causes bone marrow suppression and fluctuations in AST and ALT.
The sero-status of the Donor/ recipient is characterized as:
D+/R-
D+/R+
D-/R+
D-/R-
Preventing CMV Infection and Disease: Serostatus of both donor and recipient should be known before or at the time of transplantation. CMV prophylaxis: Valganciclovir prophylaxis should be given to all recipients and continued for at least 03 months who received organ from CMV seropositive donor (D+/R-),has received intensive immunotherapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath ), or are D+/R+ or D-/R+. Dose should be adjusted to creatinine clearance. CMV (D-/R-) patients should not be given prophylaxis. Close monitoring for bone marrow suppression is must. Laboratory Testing for CMV· CMV viral load should be done via Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma and reported as IU/mL, or copies / mL. Monitoring for CMV Infection and Disease· Monitoring with PCR is done monthly for at least 03 months for those recipients who are CMV seropositive (D+/R+, D-/R+) and have not received ATG or Alemtuzumab and not receiving valganciclovir prophylaxis Treating CMV Infection and Disease :Oral Valganciclovir (renal adjusted dose) for a duration of at least 2 weeks and continued till the patient is asymptomatic and two consecutive, CMV viral load tests o1 week apart are negative. Ganciclovir resistance: Persistent or increasing viral load or symptomatic disease after maximum effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir.Risk factors for resistance include: those recipients who have received long courses , or sub-therapeutic doses of antiviral medications,who are D+/R-,or have taken intensive immunosuppression (e.g; with T-cell depletion therapy).Mutations in the genes like UL97 and UL54 mainly are responsible for resistance. In such cases , Valganciclovir (or Ganciclovir) should be stopped and switched to Intravenous Foscarnet for a duration of at least 3 weeks. Immunosuppression dose reduction: Calcineurin inhibitor or mycophenolate mofetil / azathioprine should be reduced . Mycophenolate Mofetil (MMF) or azathioprine should be stopped in cases where there is bone marrow suppression ,particularly leucopenia. Please reflect on your practice
At our center , CMV serology is done for both donor and recipient .Majority are CMV D+/R+. All patients are being given valganciclovir as prophylaxis for 03 months except D-/R-.Treatment of severe disease is being done with ganciclovir and mild moderate cases are being treated with valganciclovir. Doses of both medications are done according to creatinine clearance. Close monitoring of graft function and blood counts done and CBC done every 2 weekly .Antimetabolite –MMF and azathioprine also stopped during the treatment course. PCR is being done every 02 week and treatment is stopped when the PCR 01 week apart is negative and patient is asymptomatic .Resistance viral testing not available in our setup
Executive Summary of Recommendations
1 Preventing CMV Infection and Disease
Determining CMV status in donor and recipient
1.1 All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation [1A]
1.2 If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-). [1D]
CMV prophylaxis
For adults, children and young people receiving a solid organ transplant:
1.3 Offer Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either:
• The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-) [1A] OR
• The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath®), where donor: recipient serostatus is D+/R+ or D-/R+ [1A]
1.4 Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal or pancreas transplants for at least 3 months following transplantation if either:
• The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-) [1C] OR
• The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath®), where donor: recipient serostatus is D+/R+ or D-/R+ [1C]
1.5 Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-) [1D]
1.5.1 Be aware that some recipients who are seronegative for CMV (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention of other Herpes virus infections, e.g; recipients who are seronegative for Herpes Simplex Virus (HSV) receiving an organ from HSV seropositive donors [2D].
1.6 Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+) [2C].
1.7 Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute [1D]
1.8 For children and young people under 18 years, adjust the dose of Valganciclovir according to body surface area, up to a maximum dose of 900mg once daily [1D]
1.9 Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir [1A]
1.10 Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir [1C]
2 Laboratory Testing for CMV
2.1 Clinical Laboratories should use
Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load [1A]
• Transplant centres should adopt a consistent approach to use either whole blood or plasma for quantification of CMV viral load [1C]
• CMV QNAT assays should be calibrated using the WHO International Reference Standard [1C]
• CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used [1C]
2.2 Transplant centres should determine local thresholds of viral load that portend CMV infection or disease requiring treatment, depending on the CMV QNAT assay they use and the population at risk [1C]
2.3 QNAT thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease [1C]
3 Monitoring for CMV Infection and Disease
3.1 Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if:
• They are CMV seropositive (D+/R+, D-/R+) [1B] AND
• They have not received T-lymphocyte depletion therapy [1B] AND
• They are not receiving valganciclovir prophylaxis [1B] (see section 1)
3.2 Where CMV viral load monitoring is offered:
• Consider testing with a frequency of at least monthly [1D]
• Consider testing for at least 3 months following transplantation [1D]
4 Treating CMV Infection and Disease
For adults, children and young people who develop CMV infection or disease following solid organ transplantation:
4.1 Offer treatment with oral Valganciclovir for a duration of at least 2 weeks [1A]
4.2 Adjust the dose of Valganciclovir according to licensed dosing recommendations if creatinine clearance is less than 60ml/minute [1D]
4.3 Be aware of the potential development of ganciclovir resistance (see section 5 for management)
4.4 Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days [1D] AND
• Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected (below the local laboratory threshold for detection) [2D].
5 Ganciclovir resistance
5.1 Be aware that the following people are at increased risk of Ganciclovir resistance:
• Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications [1A]
• CMV seronegative recipients receiving a solid organ transplant from seropositive donors (D+/R-) [1C]
• Those who have received intensive immunosuppression (e.g; with T-cell depletion therapy, following episodes of acute allograft rejection) [1B]
• Recipients of lung transplants [2C]
5.2 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 [1A]
5.3 In people with suspected resistance to Ganciclovir:
• 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 [1A]
• Use either whole blood or plasma [1A]
5.4 In people with evidence of ganciclovir resistance:
• Stop Valganciclovir (or Ganciclovir) [1A]
• Offer Intravenous Foscarnet for at least 3 weeks [1B]
o Seek specialist virology advice before commencing treatment with Foscarnet [1D]
6 Immunosuppression dose reduction
For adults, children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation:
6.1 Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine [1C]
• Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia [2C]
6.2 Discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction [1D]
6.3 Review the dosing of immunosuppression following resolution of CMV infection or disease [1D]
7 Information, education and support
7.1 Offer balanced and accurate information to children, adults and young people undergoing solid organ transplantation about:
• The risks of CMV infection and disease according to donor / recipient CMV serostatus and nature of immunosuppression planned or received
• Monitoring and treatment options, including prophylaxis
7.2 Ensure that healthcare professionals offering information have specialist knowledge about CMV infection and disease and their treatment, and the skills to support shared decision-making (for example, presenting information in a form suitable for developmental stage)
In this article, we will start prophylaxis of CMV in IgG positive for either donor and recipient, VGAN will be given for 3 months for those has low immunological risk and not receiving ATG or ALMUZumab at induction.
VGAN will not be given in the case of IgG-negative donors and recipients.
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+). Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load Where CMV viral load monitoring is offered: Consider testing with a frequency of at least monthly Consider testing for at least 3 months following transplantation
All organ donors and recipients should be screened by CMV (IgG antibody) serology prior to, or at the time of transplantation and If donor CMV serostatus is unknown for a negative recipient ,then he should considered positive.
CMV prophylaxis For adults, children and young people receiving a solid organ transplant:
Valganciclovir for at least 3 months following transplantation if either: (D+/R-) or the recipient has received ATG or Alemtuzumab . Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-) . Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+).
[Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute and or young people under 18 years, adjust the dose of Valganciclovir according to body surface area, up to a maximum dose of 900mg once daily
Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir
Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load
Where CMV viral load monitoring is offered: Consider testing with a frequency of at least monthly Consider testing for at least 3 months following transplantation
Offer treatment with oral Valganciclovir for a duration of at least 2 weeks. Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days AND Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected (below the local laboratory threshold for detection)
Be aware that the following people are at increased risk of Ganciclovir resistance:
1- Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications
2- CMV seronegative recipients receiving a solid organ transplant from seropositive donors (D+/R-)
3- Those who have received intensive immunosuppression (e.g; with T-cell depletion therapy, following episodes of acute allograft rejection)
4- Recipients of lung transplants
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 . In people with evidence of ganciclovir resistance: Stop Valganciclovir (or Ganciclovir). Offer Intravenous Foscarnet for at least 3 weeks.
Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia .
Our local practice is similar to these recommendations .
CMV belong to the herpes group of viruses and primary infection can result in severe disease when the host is immunocompromised.
Transmission occurs through exposure to saliva, urine, genital secretions or lactation.
The virus enters the bone marrow progenitor cells and undergo latency.
Antibodies indicating prior infection increases with age being 40% at age 20 and 80% at age 60.
CMV in Solid Organ Transplant Recipients
Primary CMV infection occurs in the first 4-6 weeks post-transplant . It is encountered when a CMV sero-negative recipient receives a CMV seropositive organ.
The presentation can non-specific with fever, tiredness, night sweats, muscle or abdominal pains, diarrhea and rarely retinitis which is pathognomonic. Laboratory blood tests may reveal pancytopenia and features of biochemical hepatitis.
The sero-status of the Donor/ recipient is characterized as follow:
o (D+/R-): Risk of primary infection. o (D+/R+)- Risk of super-infection or reactivation. o (D-/R+)- Risk of reactivation of latent infection. o (D-/R-)- Risk of primary infection from other source. Preventing CMV infection and disease: Determine the donor/recipient CMV Sero-status: prior to transplantation all donors and recipients are screened for CMV IgG to identify the CMV sero-status. If the donor is CMV +ve and the recipient is sero-negative or unknown for CMV, this should be considered as (D+/R-). CMV prophylaxis
Oral Valganciclovir prophylaxis should be provided to SOT recipients for a duration of at least 3 months in the following conditions:
(D+/R-) If D+/R+ or D-/R+ received a T-lymphocyte depleting agent (ATG or Alemtuzumab)
After treating acute allograft rejection whatever the sero-status
Valganciclovir prophylaxis is not offered routinely in (D-/R-) CMV but may be given to prevent other Herpes virus infection, like sero-negative HSV recipients who receive an organ from seropositive HSV donors
Valganciclovir dose adjustment is required if the creatinine clearance < 60ml/minute and for children and young people <18 years( the maximum dose is 900mg/day.
Monitor FBC every 2 weeks whilst on Valganciclovir and if side effects develop Consider switching to CMV monitoring and pre-emptive therapy
Laboratory Testing for CMV
Laboratories should use the WHO International QNAT test of the whole blood or plasma to quantify CMV viral load and this approach should be consistent to use either approaches all the time.
CMV viral load should be reported as IU/mL rather than copies / mL and if reported in copies/ml use a conversion factor to change to IU/mL
The viral load that indicates CMV infection or disease requiring treatment should depend on the CMV QNAT assay used by the transplant facility and the population at risk
QNAT thresholds is not the only determinant to start or stop treatment for CMV disease but we should take into consideration the clinical, laboratory or histological evidence of CMV disease
Monitoring for CMV Infection and Disease · CMV viral load is monitored to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if: o D+/R+, D-/R+) o They have not received T-lymphocyte depletion therapy o They are not receiving valganciclovir prophylaxis · When CMV viral load monitoring is offered, it is tested at least monthly, for at least 3 months following transplantation Treating CMV Infection and Disease For adults, children and young people who develop CMV infection or disease following solid organ transplantation:
Treatment with oral Valganciclovir for least 2 weeks
Adjust the dose if the creatinine clearance is < 60ml/minute
Be aware of the possibility to develop ganciclovir resistance.
Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days and consider to stopping treatment after resolution of symptoms and two consecutive CMV viral load tests that confirm that CMV negativity
Ganciclovir resistance Risks of Ganciclovir resistance include:
prolonged courses, or sub-therapeutic doses of antiviral medications [1A].
CMV (D+/R-) sero-satus.
Intensive immunosuppression with T-cell depletion therapy for induction and following episodes of acute allograft rejection.
lung transplant recipients
Ganciclovir resistance is considered if: there is persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration of Ganciclovir or Valganciclovir. In people with suspected resistance to Ganciclovir:
Confirm dosing and adherence to treatment .Offer testing for Human CMV antiviral resistance UL97 and UL54 gene mutations
Use either whole blood or plasma
In people with evidence of ganciclovir resistance:
Stop Valganciclovir (or Ganciclovir) and move to second line therapy with Intravenous Foscarnet for at least 3 weeks(seek a specialist virology advice before commencing treatment with Foscarnet)
Immunosuppression dose reduction: For adults, children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation:
Consider reducing the dose of either CNIs or anti-metabolites(MMF / azathioprine) However, stopping MMF or azathioprine is preferred if there is evidence of leukopenia
Discuss with patients, parents or carers, the risk of acute rejection with immunosuppression reduction
Review immunosuppression doses following resolution of CMV infection or disease
Information, education and support · Offer balanced and accurate information about the risks of CMV infection and disease according to donor / recipient CMV sero-status · The nature of immunosuppression planned or received ,the monitoring and treatment options including prophylaxis. · Ensure the presence of skillful knowledgeable healthcare professionals to offer information about CMV infection and disease , their treatment, and the skills to support shared decision-making. Please reflect on your practice In NHS Grampian , The Edinburgh renal transplantation unit protocol for CMV prophylaxis is used: A prophylactic approach is used All renal transplant recipients except (D-/R-) receive oral valganciclovir for 6 months. D-/R- recipients who received an induction therapy with lymphocyte depleting agents (ATG, Alemtuzumab) will receive same prophylaxis. Valganciclovir dose is not exceeding 450mg OD(even in eGFR>60 ml/min). Dose adjustment is done according to creatinine clearance. Monitor FBC and LFTs during therapy
1. Please summarize these guidelines Before transplantation, both recipient and donor should be tested for CMV Ig G and Ig M to stratify the risk of acquiring CMV infection post transplantation. If serology is not known for both, or recipient is negative and donor is unknown, it should be considered as high risk group. ( D+/R-). CMV prophylaxis 3months of valganciclovir, should be considered if:
1-The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-) [1A]
2-The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath ), where donor: recipient serostatus is D+/R+ or D-/R+.
Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-), however it may be required for prevention of Herpes infection.
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive.
Dose of valganciclovir needs to be adjusted, if e GFR <60ml/min.
Monitoring of CBC every 2 weeks is needed while patient is on valgaciclovir. If neutropenia developed we may need to switch to monitoring and pre emptive therapy instead of prophylaxis.
Laboratory Testing for CMV
· Clinical Laboratories should use PCR base methods for CMV DNA
· It is highly sensitive and specific
· Antigen based methods, pp65 have been replaced by DNA based ones.
· It has high false negative result, notably in leucopenia.
Monitoring:
Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if:
They are CMV seropositive (D+/R+, D-/R+),
AND They have not received T-lymphocyte depletion therapy,
AND They are not receiving valganciclovir prophylaxis.
If monitoring is offered: it is advised to do testing monthly and for at least 3 months following transplantation.
Treating CMV Infection and Disease
For adults, children with CMV infection or disease following solid organ transplantation:
· Advised to give treatment with oral Valganciclovir for a duration of at least 2 weeks.
· Dose of Valganciclovir to be adjusted according to creatinine clearance if it is less than 60ml/minute.
· We need to assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days.
· Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV negative tests. Ganciclovir resistance:
Following people are 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).
· Recipients of lung transplants.
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.
In people with suspected resistance to Ganciclovir:
· Check adequacy, adherence to treatment plan and absorption.
· Offer testing for Human CMV (HCMV) antiviral resistance UL97 and UL54 gene mutations.
· In people with evidence of ganciclovir resistance: consider Intravenous Foscarnet for at least 3 weeks. Seek specialist virology advice before commencing t Immunosuppression dose reduction:
Dose of mycophenolate/azathioprine needs to be reduced in patient with CMV infection specially if there is leucopenia. When dose reduced patient or his care giver should be counselled about risk of rejection.
2. Please reflect on your practice In our center we screen both donor and recipient with CMV Ig G. Prophylaxis is given for all recipients except for donor negative and recipient negative. Duration of prophylaxis is given for 3months, unless donor is positive and recipient negative, where we give it for 6months. Treatment is given for a minimum of 3 weeks, then we give prophylaxis dose for 2months.
CMV is one of the herpes group of viruses,
Primary infection with CMV typically occurs approximately four to six weeks posttransplant.
The frequency of CMV disease in solid organ transplant (SOT) recipients varies markedly
depending on the definition of CMV disease that is used and the intensity of
immunosuppression.
preventing CMV disease included avoiding
transplanting a seropositive organ into a seronegative recipientanti-CMV Prophylaxis and pre-emptive anti-CMV therapy are in common use to
minimise the impact of CMV infection or reactivation.
Treatment of CMV Disease
Offer treatment with oral Valganciclovir for a duration of at least 2 weeks .
*Adjust the dose of Valganciclovir according to licensed dosing recommendations if
creatinine clearance is less than 60mL/minute
*Be aware of the potential development of ganciclovir resistance
*Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of
7 days
Monitoring CMV Infection and Disease
They are CMV seropositive (D+/R+, D-/R+)
They have not received T-lymphocyte depletion therapy
They are not receiving valganciclovir prophylaxis
•CMV is one of Herpes viruses which is HHV-5
•CMV usually manifests in immunosuppressed patients e.g transplant recipients
•CMV infection occurs as early as twenty days and not more than 50 days after transplantation if not received antivirals
•pp65 antigenemia assay and PCR are the main diagnostic tools
• Serology is of limited role for the diagnosis of active disease Histology of the affected tissue and bronchoalveolar lavage analysis are useful in the diagnosis of invasive disease.
CMV Antigenemia test
•Rapid way in detection of CMV which is engulfed by neutrophils in the blood
• detection of monoclonal antibodies against pp65 CMV
•Advantages are
1.Early diagnosis of CMV infection
2.No need for an advanced labs and can be performed in A small capacity laboratories
•Disadvantages
1.Need to be performed within 6 hours of blood sampling
2.Subjective test Cannot be performed in leucopenic patients below 1000
Quantitative Polymerized Chain Reaction Test
•Main diagnostic tool nowadays
•Accurate detection of replication of CMV
•Used before deciding pre-emptive treatment
•Monitoring response to treatment
This is the British Transplantation Society guidelines for CMV infection and disease following solid organ transplantation
1- All organ donors and recipients should be screened for CMV (IgG antibody)serostatus prior to, or at the time of transplantation [1A]
2- If donor CMV serostatus is unknown and recipient is seronegative or unknown forCMV, this should be characterised as donor seropositive, recipient seronegative for CMV(D+/R-). [1D] CMV prophylaxis :
Valganciclovir prophylaxis for 3 month in these conditions :
1-If the recipient is seronegative for CMV and the donor is CMVseropositive (D+/R-) [1A]
2- If the recipient has received T-lymphocyte depletion therapy with Antithymocytegobulin (ATG) or Alemtuzumab (Campath), where donor: recipient serostatus is D+/R+ or D-/R+ [1A]
3- If treatment of acute allograft rejection is started if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+) 2C Treatment of CMV Infection and Disease :
Oral Valganciclovir for at least 2 weeks [1A
]Assess CMV viral load after 2 weeks of treatment and repeat after one week
Consider resistance if there is a persistent or increasing viral load or symptomatic disease after the effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir [1A]. So you need to:
Stop Valganciclovir (or Ganciclovir) [1A]
Offer Intravenous Foscarnet for at least 3 weeks [1B]
Seek specialist virology advice before commencing treatment with Foscarnet [1D)
Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil /azathioprine [1C]
CMV prophylaxis:
If the donor is positive
Or the recipient is positive
We use valciclovir for three months.
We monitor with blood pcr until serostatus become negative.
Treatment:
We use Valganciclovir 900 for three months.
If ressist wecan reduce immuosuppresion drugs especially antimetabolic agents .
In order to prevent CMV infection and its associated disease, certain measures are recommended. One crucial step is to determine the CMV serostatus of both the organ donor and recipient prior to transplantation. Screening for CMV (IgG antibody) serostatus should be conducted for all organ donors and recipients either before or at the time of transplantation. If the CMV serostatus of the donor is unknown and the recipient is either seronegative or the CMV status is unknown, it is classified as (D+/R-) for CMV.
CMV prophylaxis is an important approach to prevent CMV infection in transplant recipients. For individuals who have undergone kidney or liver transplantation, Valganciclovir prophylaxis should be offered for a minimum of three months following the transplantation if they fall under the D+/R- category or if the recipient has received (ATG) or Alemtuzumab, regardless of the CMV serostatus. Similarly, for heart, lung, intestinal, or pancreas transplant recipients, Valganciclovir prophylaxis should be considered for at least three months following transplantation if they fall under the D+/R- category or if the recipient has received (ATG) or Alemtuzumab.
Furthermore, Valganciclovir prophylaxis should be considered for a minimum of three months after initiating treatment for acute allograft rejection if either the donor or recipient is CMV positive (D+/R-, D+/R+, or D-/R+). It is important to adjust the Valganciclovir dose if the patient’s creatinine clearance is less than 60 ml/min. Similarly, for children and young individuals under 18 years of age, the Valganciclovir dose should be adjusted accordingly.
To ensure proper management and detect any potential adverse effects, regular monitoring is essential during Valganciclovir prophylaxis. Full blood count should be monitored at least every two weeks while the patient is on Valganciclovir.
Implementing these preventive measures is crucial to reduce the risk of CMV infection and its associated complications in transplant recipients. Adhering to appropriate prophylactic strategies and closely monitoring patients can significantly contribute to favorable outcomes in terms of CMV infection prevention.
In the laboratory testing for CMV, it is recommended that clinical laboratories utilize Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to measure the CMV viral load. Transplant centers should establish local thresholds for viral load that indicate the presence of CMV infection or disease requiring treatment. These thresholds may vary depending on the specific CMV QNAT assay used by the laboratory and the population at risk.
It is important to note that QNAT thresholds alone should not be used as the sole determinant for initiating or discontinuing treatment in individuals with CMV disease. Instead, they should be considered alongside clinical, laboratory, or histological evidence of CMV disease. The decision to commence or cease treatment should be made based on a comprehensive assessment of the patient’s clinical condition and other relevant factors.
To effectively monitor CMV infection and disease in recipients of solid organ transplants, certain strategies should be implemented. For individuals who are CMV seropositive (D+/R+, D-/R+) and have not undergone T-lymphocyte depletion therapy or are not receiving valganciclovir prophylaxis, it is recommended to monitor CMV viral load. This monitoring helps guide the need for pre-emptive therapy.
Consideration should be given to testing for CMV viral load at least monthly for a minimum of three months following transplantation. This regular monitoring allows for timely detection of CMV infection and facilitates appropriate intervention if necessary. By closely monitoring the CMV viral load, healthcare providers can assess the dynamics of CMV replication and make informed decisions regarding the management of CMV infection and the initiation of treatment.
Implementing a robust monitoring protocol for CMV viral load enhances the ability to identify early signs of CMV infection or disease in transplant recipients. Regular testing and vigilance during the critical post-transplant period provide valuable insights into the patient’s CMV status and facilitate timely interventions to prevent disease progression.
By utilizing QNAT to quantify the CMV viral load, laboratories can provide valuable information for monitoring CMV infection and disease progression. However, it is essential to interpret these results in conjunction with other clinical and diagnostic findings to ensure accurate diagnosis and appropriate treatment decisions.
In the management of CMV infection and disease in recipients of solid organ transplantation, specific treatment strategies should be implemented. When CMV infection or disease is detected, it is recommended to initiate treatment with oral Valganciclovir for a minimum duration of two weeks. The dosage of Valganciclovir should be adjusted in accordance with approved dosing recommendations if the recipient’s creatinine clearance is below 60ml/minute.
Healthcare providers should be mindful of the potential development of ganciclovir resistance, as it can impact treatment effectiveness. Therefore, regular monitoring of CMV viral load is essential. After two weeks of treatment, CMV viral load should be assessed, and subsequent measurements should be conducted at intervals of at least seven days. Additionally, treatment for CMV disease can be considered for discontinuation once the symptoms have resolved and two consecutive CMV viral load tests confirm the absence of detectable CMV.
By adhering to these treatment approaches, healthcare providers can effectively manage CMV infection and disease in transplant recipients. The use of Valganciclovir, dose adjustments based on renal function, regular viral load monitoring, and careful evaluation of treatment response contribute to successful outcomes in controlling CMV infection.
In our transplant unit, we employ oral valganciclovir as a prophylactic measure against CMV infection based on the recipient’s risk category. For D+/R- patients, the recommended duration of prophylaxis is 200 days. R+ patients are given prophylaxis for a period of 100 days. Additionally, patients who receive ATG as induction therapy are administered prophylaxis for 100 days. It is worth noting that our unit does not conduct routine surveillance using serology or CMV PCR for monitoring CMV infection.
Please summarize these guidelines: Prevention of CMV infection and disease: D/R CMV status: screening before transplantation, if the donor or recipient CMV serology status is unknown, presume D+/R-. CMV prophylaxis: D+/R-: valganciclovir for 3 months. D+/R+ or D-/R+ with induction ATG/ Alemtuzumab: valganciclovir 3 months. D-/R-: CMV prophylaxis is not required. Treatment of acute rejection for D+/R-, D+/R+ or D-/R+ consider valganciclovir 3 months. Dose adjustment of valganciclovir according to GFR and BSA Monitor FBC every 2 weeks during prophylaxis. If neutropenic-à stop valganciclovir and switch to CMV monitoring and pre-emptive therapy (if symptomatic or viremia). CMV testing: Whole blood or plasma for CMV-QNAT to estimate viral load. Viral load should be reported as IU/ml, use conversion factor if reported as copies/ml. Local transplant centers should adopt methods for viral load estimation and local threshold for QNAT that corroborate with cmv INFECTION/DISEASE requiring treatment. Starting or stopping CMV treatment should be correlated to clinical, laboratory or histological CMV disease evidence. Monitoring for CMV infection and disease: Test monthly for at least 3 months post-transplant for the following candidates: SOT recipients with CMV D+/R+, CMV D-R+. Recipients not receiving T-lymphocyte depleting therapy. Recipients not receiving valganciclovir prophylaxis. Treatment of CMV infection and disease: Valganciclovir 900mg BD for at least 2 weeks, adjust dose according to GFR. Assess viral load after 2 weeks of treatment then every 7 days. Stop treatment after resolution of symptoms and no-detection of 2 consecutive weekly tests. Ganciclovir Resistance:
Risk factors: prolonged courses, sub-therapeutic doses, CMV D+/R- recipients, recipients receiving heavy immune-suppression (ATG or Alemtuzumab induction or treatment of acute rejection) and lung transplant recipients.
Resistance is considered if symptoms persist or viral load increases or not reducing after a normal effective dose for 2-4 weeks. We need to confirm proper dosing and compliance to treatment. We need to test for human CMV anti-viral resistance mutations (UL97, and UL54 gene mutations).
If resistance is proven, stop valganciclovir (or ganciclovir), use IV foscarnet for at least 3 weeks which should be guided by specialist virology advice.
CMV virus is one of the herpes virus group, after primary infection the virus enters a latent state.
The percentage of seropositive population is about 40% at age of 20 years and 80% at age 60.
Transmission occurs from direct person to person contact.
CMV infection : evidence of virus replication
1. Asymptomatic infection.
2. Viral syndrome
3. CMV disease
Determining CMV status in donor and recipient
All organ donors and recipients should be screened for CMV ( IgG antibody) status before transplant.
If the donor CMV serostatus is unknown and the recipient is unknown or seronegative, the donor is considered to be seropositive.
CMV prophylaxis
Consider Valganciclovir prophylaxis for at least 3 months if
.. if the donor: recipient serostatus is D+/R-
Or the recipient has received T cell depleting agent, where D+/R+ or D-/R+.
Don’t routinely offer Valganciclovir prophylaxis if the donor and recipient are seronegative.
Consider CMV prophylaxis for at least 3 months after starting the treatment of acute rejection.
Valganciclovir need dose adjustment if creatinine clearance less than 60, monitoring of blood count should be done every 2 weeks while on Valganciclovir.
Laboratory testing for CMV
Using quantitative nucleic acid testing (QNAT) of whole blood or plasma to quantify viral load , which should be reported as IU/mL
Treatment CMV infection and disease
Consider treatment with oral Valganciclovir for a duration of at least 2 weeks.
Assess CMV viral load after 2 weeks of treatment and Consider stopping treatment after resolution of symptoms and two consecutive CMV viral load that confirm that CMV is not detected.
Consider resistance to Ganciclovir if there is a persistent or increasing viral load or symptomatic disease after 2 to 4 weeks of treatment, stop Valganciclovir and offer intravenous Foscamet for at least 3 weeks.
Immunosuppression dose reduction
Consider reduction of the dose of Calcineurin inhibitors, MMF or Azathioprine
Preventing CMV Infection and Disease Determining CMV status in donor and recipient
.1 All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation .
2 If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-).
CMV prophylaxis For adults, children and young people receiving a solid organ transplant: .
Offer Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either:
The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-)
OR The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath ), where donor: recipient serostatus is D+/R+ or D-/R+ .
.
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejectionif either donor or recipient are CMV positive (D+/R-, D+/R+).
Laboratory Testing for CMV
Transplant centres should adopt a consistent approach to use either whole blood or plasma for quantification of CMV viral load .
CMV viral load should be reported as IU/mL, where possible,
Treating CMV Infection and Disease
Offer treatment with oral Valganciclovir for a duration of at least 2 weeks (dose adjusted according to graft function)
Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days AND Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected .
Ganciclovir resistance
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 [1A]
Offer testing for Human CMV (HCMV) antiviral resistance UL97 and UL54 gene mutations.
Treatment of ganciclovir resistance-
Stop Valganciclovir (or Ganciclovir) . Offer Intravenous Foscarnet for at least 3 weeks.
Immunosuppression dose reduction
For adults, children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation-:
Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine .Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia.
Since almost ( > 90%) all of our transplant are D+R+, we give prophylaxis for 3 month oral valganciclovi,Dose – 450 mg to all ,.
Treatment-we give oral valganciclovir,usual dose is 450 bd for 21 days unless He/she have severe graft dysfunction –we dont give secondry prophlaxis. We generally reduce dose of immunosuppression by 50%(MMF) and follow with Blood PCR
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION 1 Preventing CMV Infection and Disease:
Determining CMV status in donor and recipient: All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation
If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-). CMV prophylaxis
For all patients receiving a solid organ transplant:
-Commence Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either:
1-The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-)
2-The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath ), where donor: recipient serostatus is D+/R+ or D-/R+
3-Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-).
4-Some recipients who are seronegative for CMV (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention of other Herpes virus infections.
5-Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+).
6-Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute.
7-Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir.
8-Quantitative CMV PCR thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease. Laboratory Testing for CMV
Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load. CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used. Monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant.
Consider testing for at least 3 months following transplantation. Treating CMV Infection and Disease
1-For adults, children and young people who develop CMV infection or disease following solid organ transplantation: commence treatment with oral Valganciclovir for a duration of at least 2 weeks.
2-Assess CMV viral load after 2 weeks of treatment.
3- Consider stopping treatment for CMV disease after resolution of symptoms and two consecutive CMV viral load tests that confirm that CMV is not detected. Ganciclovir resistance
The following people are at increased risk of Ganciclovir resistance:
1-Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications.
2- CMV seronegative recipients receiving a solid organ transplant from seropositive donors (D+/R-).
3-The patients who have received intensive immunosuppression (e.g; with T-cell depletion therapy, following episodes of acute allograft rejection).
4- Recipients of lung transplants.
5-Consider resistance to Ganciclovir if: There is a persistent or increasing viral load or symptomatic disease after optimal dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir. When you suspected resistance to Ganciclovir:
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 In people with evidence of ganciclovir resistance:
Stop Valganciclovir (or Ganciclovir).
Offer Intravenous Foscarnet for at least 3 weeks Immunosuppression dose reduction
-Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia.
-Review the dosing of immunosuppression following resolution of CMV infection or disease.
Introduction :
CMV infection: evidence of the virus undergoing a complete replication cycle and producing new infectious virions. This may be further characterised as:
1. Asymptomatic infection (no obvious signs of pathologic symptoms)
2. Viral syndrome (fever, leucopenia, myalgia or arthralgia)
3. CMV disease – (histopathological evidence of CMV, CMV retinitis diagnosed by an ophthalmologist, or CMV in the CSF indicative of CNS disease) Latent CMV: A state of virus infection in which the full replication cycle of the virus is not occurring
All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation .
If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterized as donor seropositive, recipient seronegative for CMV (D+/R-)
CMV Prophylaxis :
Offer Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either:
The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-)
The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath ), where donor: recipient serostatus is D+/R+ or D-/R+ .
Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-) .
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+ .
Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir
Laboratory Testing for CMV :
Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load .
Monitoring for CMV Infection and Disease :
Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if:
They are CMV seropositive (D+/R+, D-/R+) AND They have not received T-lymphocyte depletion therapy
They are not receiving valganciclovir prophylaxis
Where CMV viral load monitoring is offered:
Consider testing with a frequency of at least monthly
Consider testing for at least 3 months following transplantation
Treating CMV Infection and Disease :
For adults, children and young people who develop CMV infection or disease following solid organ transplantation:
Offer treatment with oral Valganciclovir for a duration of at least 2 weeks [
Adjust the dose of Valganciclovir according to licensed dosing recommendations if creatinine clearance is less than 60ml/minute
Be aware of the potential development of ganciclovir resistance
Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days AND Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected
Ganciclovir resistance :
Be aware that the following people are 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)
Recipients of lung transplants
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
In people with suspected resistance to Ganciclovir:
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
In people with evidence of ganciclovir resistance:
Stop Valganciclovir (or Ganciclovir)
Offer Intravenous Foscarnet for at least 3 weeks
Seek specialist virology advice before commencing treatment with Foscarnet
Immunosuppression dose reduction :
For adults, children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation:
Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine
Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia
Discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction
Review the dosing of immunosuppression following resolution of CMV infection or disease .
Treatment of CMV Disease :
Early studies emphasised the need to reduce immunosuppression as well as giving specific antiviral therapy . Intravenous Ganciclovir has had a major impact on the mortality and morbidity of CMV disease . High doses of intravenous Hyperimmune globulin (0.5 g/kg body weight) have been used in conjunction with Ganciclovir for the treatment of pneumonitis
There is a significant risk of relapse following successful treatment of CMV disease, with recurrent CMV disease reported in various organ recipients . Secondary prophylaxis after treatment of disease has been assessed, although evidence in support of this strategy is limited .
These British Transplantation Society (BTS) guidelines published in 2022 provide evidence-based recommendations and suggestions for both the prevention and treatment of CMV infection/disease in solid organ transplant (SOT) recipients. The authors utilise the GRADE system to clearly signal to the reader how robust the evidence for each particular recommendation is, where quality of evidence is graded A-D (high-very low) and the strength of the resulting guidance is measured as either 1 (strong- applying to almost all patients) or 2 (weaker- risk/benefits may need to be assessed as the underpinning evidence is less robust).
Important definitions relevant to the guideline:
CMV infection
CMV infection is present when the virus is undergoing a complete replication cycle. It is important to note the definitions for different stages of CMV infection:
1. Asymptomatic infection: virus can be detected in patient’s blood but the patient is asymptomatic
2. Viral syndrome: detection of CMV virus plus symptoms such as fever/Leucopenia/myalgia/arthralgia
3. CMV disease: detection of CMV in the blood plus 1 of the following: i) histopathological evidence (biopsy findings) consistent with CMV disease in a particular organ ii) confirmed diagnosis of CMV retinitis or iii) CMV detection in the cerebrospinal fluid
The definition for latent CMV is when the patient has evidence of prior exposure to CMV but the virus is not currently undergoing a full replication cycle.
Summary of key areas covered by the guideline:
1. Prevention of CMV infection and disease
· there is very robust evidence to recommend confirmation of both donor and recipient CMV serostatus prior to transplantation
· recommendations for prophylaxis or monitoring with pre-emptive therapy can then be directed to the most high-risk patients, i.e. D+/R- or those receiving T-cell depleting immunosuppression (ATG or alemtuzumab) in all categories except D-/R-. This should be oral valganciclovirfor at least 3 months
· low risk patients (D-/R-) do not require prophylaxis for CMV but they might still require oral valganciclovir for other indications e.g. HSV seronegative patient receiving a HSV seropositive organ
· oral valganciclovir for at least 3 months should also be considered in the context of treatment for acute allograft rejection for all serostatus combinations except D-/R- due to the noted association between rejection and late CMV disease
· valganciclovir is renally excreted so care should be taken to adjust the dose where creatinine clearance is <60 ml/min. Side effects include neutropenia (monitor FBC every 2 weeks during treatment). If patients develop significant side effects a switch in strategy may be required (e.g. from standard prophylaxis switch to monitoring of CMV levels with pre-emptive therapy as required)
· There is currently insufficient evidence to provide a standardised guideline about secondary CMV prophylaxis following an episode of treated CMV infection/disease
2. Laboratory testing for CMV
· there is robust evidence to show that quantitative nucleic acid testing (QNAT) is the best test to measure CMV virus levels in whole blood or plasma
· there is no universally agreed threshold at which detection of a certain CMV virus level should prompt treatment of CMV infection/disease; instead, thresholds should be determined individually by local centres considering both their local population and other clinical factors including histology and symptoms 3. Monitoring CMV infection and disease
· An alternative strategy to routine CMV prophylaxis with oral valganciclovir (as above) is to initiate surveillance of CMV virus levels (QNAT testing) post-transplantation and instigate pre-emptive therapy when a locally-agreed threshold is reached. If this strategy is employed it is recommended surveillance testing is performed at least monthly for at least 3 months after transplantation. This strategy is suitable for intermediate-risk patients, e.g. D+/R & D-/R+ patients who have not received T-cell depleting immunosuppression and who are not receiving oral valganciclovir 4. Treating CMV infection and disease
· there is strong evidence to recommend a minimum 2 week course of oral valganciclovir for treatment of CMV infection and disease
· CMV viral load should be checked after 2 and 3 weeks and treatment should only be discontinued when symptoms have resolved and there are 2 consecutive CMV virus titres below the locally-agreed threshold (the evidence for this recommendation is less robust) 5. Ganciclovir resistance
Risk factors for developing ganciclovir resistance:
1. prolonged course or subtherapeutic doses of anti-viral medication
2. D+/R-
3. intensive immunosuppression e.g. T-cell depleting agent such as ATG or treatment for acute rejection
4. lung transplant recipients
If ganciclovir resistance is proven, stop ganciclovir or valganciclovir and offer Forcarnet treatment as an alternative 6. Immunosuppression dose reduction
· If SOT recipients develop CMV infection/disease consideration should be given to whether their immunosuppression can be reduced- this should be preferentially anti-metabolite reduction prior to calcineurin reduction, particularly if there is Leucopenia. Patients should be counselled about the risk/benefit of this strategy including the risk of acute rejection. Once the CMV infection has been resolved their immunosuppression should be re-reviewed. 7. Information, education and support
· Appropriate patient counselling is important including helping SOT recipients understand their individualised risk profile based upon donor/recipient CMV serostatus and immunosuppression used Reflection on local practice
· In recognition of the high-risk status of D+/R- patients our centre gives 200 days of valganciclovir prophylaxis to all of these patients regardless of induction immunosuppression used. These BTS guidelines recommend at least 3 months of prophylaxis but I note that both the Sheffield protocol shared in this journal club and the American Society of Transplantation Infectious Diseases Community of Practice guidelines give a 6 month course for these patients so our practice is in common with this
· We use alemtuzumab as our most common induction agent. However, I was surprised to note that our prophylaxis protocol for intermediate-risk patients receiving alemtuzumab has shorter durations: in contrast to the Sheffield protocol our D+/R+ and D-/R+ patients who receive alemtuzumab induction get 100 days prophylactic valganciclovir rather than 200 days. Furthermore, for those intermediate-risk patients who have not received alemtuzumab we do not routinely give prophylaxis
· Low-risk D-/R- patients do not receive prophylaxis which seems similar to practice from other centres and that recommended in these guidelines.
· We reserve pre-emptive monitoring as a second line strategy for patients who are not able to tolerate valganciclovir due to side effects
· Our treatment of CMV disease follows the recommendations outlined in these guidelines
References:
1. UK guideline on Prevention and Management of cytomegalovirus (CMV) infection and disease following solid organ transplantation [Internet]. British Transplantation Society. 2022 [cited 2023Mar23]. Available from: https://bts.org.uk/uk-guideline-on-prevention-and-management-of-cytomegalovirus-cmv-infection-and-disease-following-solid-organ-transplantation/
2. 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. Available at: https://pubmed.ncbi.nlm.nih.gov/30817026/
3. Sheffield Teaching Hospitals NHS Foundation Trust. Protocol for prophylaxis, surveillance and treatment of CMV after renal transplantation. 2016.
1- Preventing CMV Infection and Disease: Determining CMV status in donor and recipient
1.1 Allorgan donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation . [1A]
1.2 If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV(D+/R-). [1D]
CMV prophylaxis:
For adults, children and young people receiving a solid organ transplant: 1.3 Offer Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either:
a- The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-) [1A]
OR
b- The recipient has received T-lymphocyte depletion therapy with Antithymocytegobulin (ATG) or Alemtuzumab (Campath), where donor: recipient serostatus is D+/R+ or D-/R+[1A]
1.4 Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal or pancreas transplants for at least 3 months following transplantation if either:
The recipient is seronegative for CMV and receives an allograft from a CMVseropositive donor (D+/R-) [1C]
OR
The recipient has received T-lymphocyte depletion therapy with Antithymocytegobulin (ATG) or Alemtuzumab (Campath), where donor: recipient serostatus isD+/R+ or D-/R+ [1C] 1.5Do notroutinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-) [1D]
1.5.1 Be aware that some recipients who are seronegative for CMV(D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention of other Herpes virus infections,e.g; recipients who are seronegative for Herpes Simplex Virus (HSV) receiving an organ from HSV seropositive donors [2D].
1.6 Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+) [2C].
1.7 Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute [1D]
1.8 For children and young people under 18 years, adjust the dose of Valganciclovir according to body surface area, up to a maximum dose of 900mg once daily [1D]
1.9 Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir [1A]
1.10 Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir [1C]
2 Laboratory Testing for CMV
2.1 Clinical Laboratories should use Quantitative Nucleic Acid Testing (Q NAT) of whole blood or plasma to quantify CMV viral load [1A]
2.2 Transplant centres should determine local thresholds of viral load that portend CMVinfection or disease requiring treatment, depending on the CMV Q NAT assay they use and the population at risk [1C]
2.3 Q NAT thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease [1C]
3 Monitoring for CMV Infection and Disease:
3.1 Offer monitoring of CMV viral load to guide pre-emptive therapy to people receiving a solid organ transplant if:
a- They are CMV seropositive (D+/R+, D-/R+) [1B] AND
b- They have not received T-lymphocyte depletion therapy [1B] AND
c- They are not receiving valganciclovir prophylaxis [1B]
3.2 Where CMV viral load monitoring is offered:
a- Consider testing with a frequency of at least monthly [1D]
b- Consider testing for at least 3 months following transplantation [1D]
4 Treating CMV Infection and Disease:
For adults, children and young people who develop CMV infection or disease followi ngsolid organ transplantation:
4.1 Offer treatment with oral Valganciclovir for a duration of at least 2 weeks [1A]
4.2 Adjust the dose of Valganciclovir according to licensed dosing recommendations if creatinine clearance is less than 60ml/minute [1D]
4.3 Be aware of the potential development of ganciclovir resistance .
4.4 Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days [1D]
AND
Consider stopping treatment for CMV disease
– after resolution of symptomsAND
– two onsecutive, CMV viral load tests that confirm that CMV is not detected [2D].
5 Ganciclovir resistance:
5.1 Be aware that the following people are at increased risk of Ganciclovir resistance:
a- Those who have received prolonged courses, or sub-therapeutic doses of antiviralmedications [1A]
b- CMV seronegative recipients receiving a solid organ transplant from seropositive donors (D+/R-) [1C]
c- Those who have received intensive immunosuppression (e.g; with T-cell depletiontherapy, following episodes of acute allograft rejection) [1B]
d- Recipients of lung transplants [2C]
5.2 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 [1A] 5.3 In people with suspected resistance to Ganciclovir:
a- Confirm that dosing is adequate .
b- Consider adherence to treatment plan and absorption .
c- Offer testing for Human CMV (HCMV) antiviral resistance .
d- UL97 and UL54 gene mutations . [1A]
e- Use either whole blood or plasma . [1A]
5.4 In people with evidence of ganciclovir resistance:
a- Stop Valganciclovir (or Ganciclovir) [1A]
b- Offer Intravenous Foscarnet for at least 3 weeks. [1B]
c- Seek specialist virology advice before commencing treatment with Foscarnet[1D]
6- Immunosuppression dose reduction:
For adults, children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation:
6.1 Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil /azathioprine [1C]
– Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia [2C]
6.2 Discuss with patients, and, where appropriate, parents or carers, the risk of acuterejection with immunosuppression dose reduction [1D]
6.3 Review the dosing of immunosuppression following resolution of CMV infection or disease [1D]
Q2 reflect on your practice .
In our center
1- the ( donor and recipient ) tested for CMV IgG.
2- Valgancyclovir or valciclovir is offered for every recipient with any sero-positivity .
3- Acyclovir prophylaxis is offered in sero-negative state to prevent herps simplex infection .
4- The donor and recipient is not tested for herpes simplex sero state in our center.
5- Valgancyclovir is offered for at least 3 months .
6- QNAT used for diagnosis and treatment decision.
7- We use valgancyclovir for treatment .
8- We did not face a cse of gancyclovir or valgancyclovir resistance case .
9- We start immunsupressive medication dose reduction especially in sever patient .
10- – we reduce the dose of MMF OR AZATHIOPRINE at first with close monitoring the renal function test for early diagnosis of acute rejection.
-Determine CMV serostatus in donor and recipient by CMV- IgG antibody prior or at the time of transplantation.
–CMV prophylaxis
– Valganciclovir prophylaxis at least 3 month following transplantation if-
D+/ R – OR
D+/R+ or D-/ R+( When recipient has received T- lymphocyte depletion therapy)
D-/R-(not routinely, may require for prevention of other herpes virus.
– Dose adjustment of valganciclovir according to creatinine clearance & body surface area. Monitor with full blood count every 2 weekly.
–Laboratory testing for CMV
Use Quantitative Nucleic Acid Testing ( QNAT) of whole blood or plasma to quantify CMV viral load.
– CMV infection and disease monitoring
Consider testing at least monthly for 3 month following transplantation.
Monitoing of CMV viral load is useful to guide pre- emptive therapy.
–Treatment of CMV infection and disease
Oral valgancyclovir for at least 2 weeks.Stop treatment after resolution of symptoms and 2 consecutive test with not detected CMV virus.
– Resistance of ganciclovir
Consider resistence if persisting or increasing viral load or symptomatic disease despiteadequate dose & duration of ganciclovir or valganciclovir.
In case of resistance cidofovir or foscarnet therapy.
– Dose reduction of immunosuppression
Consider reduce or stop antimetabolite if leukopenia.
– Providing adequate information, support and education of patient.
The guidelines cater to prevention and management if cytomegalovirus (CMV) post solid organ transplant (SOT). CMV infection can be either asymptomatic infection, viral syndrome, or CMV disease.
1.Preventing CMV Infection and disease:
All donor and recipients should be screened for CMV IgG antibody. If donor serostatus is unknown, label donor as D+.
1) CMV prophylaxis in form of oral valganciclovir for at least 3 months should be given to:
a) Renal and liver transplant recipients (and should be considered for heart, lung, intestinal or pancreas transplant) in case of D+/R-, or a R+ serostatus with use of ATG or Alemtuzumab.
b) After starting acute rejection treatment if either or both of the donor or recipient is seropositive.
c) Some D-/R- patients as a prophylaxis against other Herpes infections.
2) Dose of Valganciclovir should be adjusted as per body surface area and creatinine clearance.
3) If patients develop side effects on valganciclovir, shift to CMV monitoring and pre-emptive therapy method.
2.Laboratory testing for CMV: Blood or plasma quantitative nucleic acid testing (QNAT) in IU/ml (or copies/ml, with conversion factor) should be done.
3.Monitoring of CMV infection and disease: It should be done at least monthly for minimum 3 months in R+ patients not on prophylaxis, and who did not receive T-lymphocyte depletion agents, to guide pre-emptive therapy.
4.CMV infection and disease treatment: Oral Valganciclovir (as it is as effective as intravenous ganciclovir) for at least 2 weeks (with dose modification as per creatinine clearance), with CMV viral monitoring after 2 weeks, and repeating after minimum 7 days to stop treatment after 2 consecutive negative CMV viral load reports. Intravenous Ganciclovir can be given if there are concerns regarding enteric absorption, and in very sick patients.
5.Ganciclovir resistance: It should be suspected if viral load persists or increases despite adequate dose and duration of therapy. Patients receiving prolonged courses, sub-therapeutic doses, D+/R- status, lung transplant recipients, and those who received intensive immunosuppression are prone to ganciclovir resistance. Confirm that the dose is adequate, and patient is compliant. CMV antiviral resistance for UL97 and UL54 mutations should be tested. Intravenous Foscarnet for at least 3 weeks should be given after virology consultation.
6.Immunosuppression reduction: Dose of Calcineurin inhibitors or anti-metabolites (especially in setting of leukopenia) should be reduced after discussing regarding risk of acute rejection, and dose should be reviewed once CMV is treated. There is low quality evidence for conversion to mTOR inhibitors providing protection against recurrent CMV.
2. Please reflect on your practice:
In our transplant unit, we use oral valganciclovir as CMV prophylaxis as per the risk category of the recipient.
D+/R- patients are given prophylaxis for 200 days.
R+ patients are given prophylaxis for 100 days.
Patients receiving ATG as induction are given prophylaxis for 100 days.
No surveillance with serology or CMV PCR is done in our unit.
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION By The British Transplant Society 5 July 2022 Executive Summary of Recommendations Strength of Recommendations: Level A: Generally consistent findings of an SR of multiple RCTs Level B: Generally consistent findings of an SR of multiple weaker studies Level C: One RCT, weaker study or inconsistent findings from an SR. Level D: No RCTs or weaker studies.
Weaker studies refers to non-RCTs What is level of evidence 1a 1b 1c? 1a = SR (with homogeneity*) of Level 1 economic studies. 1b = Analysis based on clinically sensible costs or alternatives; systematic review(s) of the evidence; and including multi-way sensitivity analyses. 1c = Absolute better-value or worse-value analyses 1. Preventing CMV Infection and Disease Determining CMV status in donor and recipient
Screening for CMV (IgG antibody) serology for donors and recipients prior to / at the time of transplantation. [1A]
CMV serostatus of donor unknown, that of recipient unknown or seronegative – pair to be presumed as D+/R- (higher side of risk, on benefit of doubt) [1D]
· CMV prophylaxis 1. Valganciclovir prophylaxis to children, young and adult recipients of kidney and liver, for 3 months post-transplantation be offered, if o Serostatus (D+/R-) o Induction with T-cell depleting agent [(ATG/Alemtuzumab (Campath)] in all CMV positive recipients [D+/R+ or D-/R+] – [1A] 2. Heart, lung, intestinal or pancreas transplants – to consider Valganciclovir prophylaxis for 3 months post-transplant, if o Serostatus (D+/R-) [1C] OR o T-cell depleting induction [ATG / Campath] used in CMV positive recipients (D+/R+ or D-/R+). [1C] Routine CMV prophylaxis not required for (D-/R-) recipients [1D] 3. Treatment of Acute Rejection for D+/R-, D+/R+ or D-/R+ recipients – consider 3 months Valgancyclovir [2C] Valganciclovir dose adjustment [1D] o ac/to GFR (Creatinine clearance <60ml) for adults o ac/to BSA for children and young (<18 years) – maximum 900mg OD CBC monitoring every 2-weekly during prophylaxis. [1A] If Neutropenia develops – stop Valgancyclovir, and switch to CMV monitoring and pre-emptive therapy (if Viremia / symptomatic) [1C] 2. Lab Testing for CMV Local lab – Quantitative Nucleic Acid Test (QNAT) of whole blood or plasma to estimate CMV viral load. [1A] – Calibrate QNAT assays using WHO International Reference Standard [1C] – Viral load should be reported as “IU/ml”; use conversion factor if reported as “copies / ml’. [1C] Transplant centres – – adopt consistent method of quantitative CMV viral load estimation [1C] – determine local thresholds for QNAT assay, that corroborate with CMV infection / disease requiring treatment in Population at risk [1C] – Starting or stopping treatment for CMV disease, should be considered in the context of clinical, laboratory or histological evidence of CMV disease (not by QNAT threshold only). [1C] 3. Monitoring for CMV Infection and Disease CMV viral load monitoring to guide pre-emptive therapy – SOT recipients (children, young, adults) with Serostatus (D+/R+, D-/R+) [1B] – not received T-lymphocyte depletion therapy [1B] – not receiving valganciclovir prophylaxis [1B] – Testing monthly x at least 3 months following transplantation [1D] 4. Treating CMV Infection and Disease Adults, children and young people SOT recipients, who develop CMV infection or disease – Valganciclovir therapy (900mg PO bid) x at least 2 weeks [1A] – Adjust dose ac/to licensed dosing recommendations, if creatinine clearance is less than 60ml/minute [1D]
Viral load be assessed >2 weeks of treatment; repeated every 7 days [1D]
stopping treatment after symptoms resolved + CMV non-detectable on 2 consecutive (weekly) tests [2D].
5. Ganciclovir resistance 5.1 Increased risk of Ganciclovir resistance: – prolonged courses, or sub-therapeutic doses of antiviral medications [1A] – Seronegative recipients receiving SOT from seropositive donors (D+/R-) [1C] – Intensive IS (T-cell depletion therapy, following Acute Rejection) [1B] – Lung transplant recipients 5.2 Consider Ganciclovir resistance, if – Persistent symptomatic disease, or increasing viral load (ornot reducing) after a normally effective dosage and duration of therapy (2-4 weeks of Ganciclovir / Valganciclovir) [1A] 5.3 Suspected resistance to Ganciclovir: – Confirm that dosing is adequate – Consider adherence to treatment plan and absorption – Test for Human CMV (HCMV) antiviral resistance (UL97 and UL54 gene mutations) [1A] 5.4 Ganciclovir resistance proven: – Stop Valganciclovir (or Ganciclovir) [1A] – Offer Intravenous Foscarnet for at least 3 weeks [1B] – Specialist virology advice before commencing treatment with Foscarnet [1D] 6. Immunosuppression (IS) dose reduction Consider IS reduction for SOT recipients with CMV infection or disease (with or without leukopenia) – Reduce / stop MMF / AZT, if leukopenia [2C] – Discuss with patient party – risk of acute rejection (due to IS reduction) [1D] – Review the IS dose after resolution of CMV infection or disease [1D] 7. Information, education and support People undergoing SOT should be informed about the risks of CMV (infection / disease), need for monitoring, prophylaxis and treatment options Executive Summary of Research Recommendations · Clinical and cost-effectiveness of anti-CMV prophylaxis Vs active surveillance (for 3 months post-transplant or post-treatment for CMV disease) · Clinical and cost-effective duration and frequency of CMV viral load monitoring o post cessation of anti CMV prophylaxis o post completion of CMV treatment. o QNAT testing clinical and cost-effectiveness, to guide cessation of CMV treatment o Outcome of IS (CNI / MMF) reduction o Cost-effectiveness of CMV-Ig and Adoptive T cells for severe, resistant or refractory CMV disease Executive Summary of Audit Measures · Proportion of SOT recipients Ø got CMV prophylaxis (D+/R-serostatus /induction therapy)
Ø offered viral load monitoring (monthly x 3 months)
Ø offered Valganciclovir to treat CMV infection and disease
Ø Proportion of people with Ganciclovir resistance tested for UL97 and UL54 mutations.
Ø developed CMV infection or disease (with or without leukopenia) and reduced IS (stopped CNIs and / or proliferation inhibitors)
· Proportion of Lab using QNAT (whole blood / plasma) to quantify CMV viral load
· Proportion of CMV QNAT assays calibrated (WHO Reference Standard).
Reflection on our practice In India, most of the renal transplants are live related, so induction with ATG is not used routinely – [only in <30% patients, that to low dose (3mg/Kg)]. So incidence of CMV disease is very negligible, we rarely see in patients with graft dysfunction. Thus, anti-CMV prophylaxis is not used universally, because of cost and side effects (Leukopenia, thrombocytopenia). Monitoring of CMV viral DNA is also not a routine practice. Those who develop CMV disease – are treated mostly with Valgancyclovir, and secondary prophylaxis offered. In my current centre in Kenya, we have completed about 310 successful renal transplants in last 4 years – all are live related, most are from family related donors. We use low dose ATG Induction in almost 60% patients [distant relation or high PRA, high DSA requiring desensitization (about 30% patients)]. So, here we use Valgancyclovir prophylaxis for all our recipients for 2months (8weeks) post- transplant, because of cost constraint and availability issues. We have never seen a symptomatic CMV disease, none of the allograft biopsy (done for graft dysfunction) revealed CMV, although we don’t do routine viral monitoring on follow up. Post ATG treatment for ACR (dose used is 3-4 times more than used for Induction), oral Valgancyclovir prophylaxis is given for 3months.
Executive Summary of Recommendations. Prevention and prophylaxes.
The first chapter is about prevention and prophylaxes.
. It should be routine to screen every recipient and donor for CMV.
. Prophylaxes for every recipient seropositive or native with positive donor status should be given prophylaxes for three months.
. Some recipient with native for CMV, but can be given valgencyclovir for other viral infection prophylaxes.
. Anti-viral should be given according to eGFR and body surface area in children. Laboratory Testing for CMV.
Testing viral load should be via quantitative nucleic acid testing method.
. Method of reporting should be in IU/ml, if using copies/ml then conversion factor should be used.
. Local center should their own guidance of treatment according to copies/ symptoms. . Treatment should be monitored according to laboratory, clinical findings, and histological evidence. Monitoring for CMV Infection and Disease.
. Consider monitoring and Pre-emptive therapy for children, recipient given ATG, not given valgencyclovir, and CMV seropositive. . Frequency of testing should be at least monthly, and for at-least three months post-transplantation. Treating CMV Infection and Disease.
. For CMV disease and infection treat with oral valgencyclovir. Reduce immunosuppression, if any pneumonitis can give adjuvant treatment with IVIG.
. Follow viral load every two weekly.
. When to stop treatment, follow viral load for consecutive weeks, resolution of symptoms.
Ganciclovir resistance.
People at risk of developing ganciclovir resistance.
. Sub-therapeutic doses,
. Taken prolong courses,
. D+/R-,
. History of ACR requiring ATG,
. Those with lung transplant, There is high possibility of resistance if,
. Although viral load is not a reliable indicator of drug resistance in first week post treatment, with persistent viral load increase seen in after first week, symptom persist despite given treatment for two to four weeks. So needed to confirm,
. Dose is adequate,
. Adherence to medication,
. Confirm by testing use whole blood or plasma and, for UL97, UL54 gene mutation.
. If any resistance switch to second line.
. For refractory infection consider Maribavir ( FDA approval awaiting).
. Immunosuppression medication modification, either reduction of calcineurin inhibitors, antimetabolite, however, discuss with family for risk of rejection.
. Readjust the dose of immunosuppression after treating.
All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation [1A]
If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-). [1D]
CMV prophylaxis
For adults, children and young people receiving a solid organ transplant:
Offer Valganciclovir prophylaxis to people receiving kidney and liver transplants for atleast 3 months following transplantation if either:
The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-) [1A] OR
The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath ), where donor: recipient serostatus is D+/R+ or D-/R+ [1A]
Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal or pancreas transplants for at least 3 months following transplantation if either:
The recipient is seronegative for CMV and receives an allograft from a CMVseropositive donor (D+/R-) [1C] OR the recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath ), where donor: recipient serostatus is D+/R+ or D-/R+ [1C]
Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-) [1D]
Be aware that some recipients who are seronegative for CMV (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention of other Herpes virus infections, e.g; recipients who are seronegative for Herpes Simplex Virus (HSV) receiving an organ from HSV seropositive donors [2D].
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+) [2C].
Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute [1D]
For children and young people under 18 years, adjust the dose of Valganciclovir according to body surface area, up to a maximum dose of 900mg once daily [1D]
Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir [1A]
Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir [1C]
2 Laboratory Testing for CMV
Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load [1A]
Transplant centres should adopt a consistent approach to use either whole blood or plasma for quantification of CMV viral load [1C]
CMV QNAT assays should be calibrated using the WHO International Reference Standard [1C]
CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used [1C]
Transplant centres should determine local thresholds of viral load that portend CMV infection or disease requiring treatment, depending on the CMV QNAT assay they use and the population at risk [1C]
QNAT thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease [1C]
3 Monitoring for CMV Infection and Disease
Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if:
They are CMV seropositive (D+/R+, D-/R+) [1B] AND
They have not received T-lymphocyte depletion therapy [1B] AND
They are not receiving valganciclovir prophylaxis [1B]
Where CMV viral load monitoring is offered:
Consider testing with a frequency of at least monthly [1D]
Consider testing for at least 3 months following transplantation [1D]
4 Treating CMV Infection and Disease
For adults, children and young people who develop CMV infection or disease following
solid organ transplantation:
Offer treatment with oral Valganciclovir for a duration of at least 2 weeks [1A]
Adjust the dose of Valganciclovir according to licensed dosing recommendations if creatinine clearance is less than 60ml/minute [1D]
Be aware of the potential development of ganciclovir resistance (see section 5 for management)
Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days [1D] AND consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected (below the local laboratory threshold for detection) [2D].
5 Ganciclovir resistance
Be aware that the following people are at increased risk of Ganciclovir resistance:
Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications [1A]
CMV seronegative recipients receiving a solid organ transplant from seropositive donors (D+/R-) [1C]
Those who have received intensive immunosuppression (e.g; with T-cell depletion therapy, following episodes of acute allograft rejection) [1B]
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 [1A]
In people with suspected resistance to Ganciclovir:
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 [1A]
Use either whole blood or plasma [1A]
5.4 In people with evidence of ganciclovir resistance:
Stop Valganciclovir (or Ganciclovir) [1A]
Offer Intravenous Foscarnet for at least 3 weeks [1B]
Seek specialist virology advice before commencing treatment with Foscarnet [1D]
6 Immunosuppression dose reduction
For adults, children and young people who develop CMV infection or disease (with or
without leukopenia) following solid organ transplantation:
Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine [1C]
Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia [2C]
Discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction [1D]
Review the dosing of immunosuppression following resolution of CMV infection or disease [1D]
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION Executive Summary of Recommendations 1 Preventing CMV Infection and Disease Determining CMV status in donor and recipient
· All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation
· If donor CMV serostatus is unknown and the recipient is seronegative or unknown for CMV, this should be characterized as (D+/R-) for CMV. CMV prophylaxis
· Offer Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either: (D+/R-) OR The recipient has received (ATG) or Alemtuzumab, for D+/R+ or D-/R+
· Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal or pancreas transplants for at least 3 months following transplantation if either: (D+/R-) OR The recipient has received (ATG) or Alemtuzumab for D+/R+ or D-/R+
· Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient is CMV positive (D+/R-, D+/R+ or D-/R+)
· If creatinine clearance is less than 60ml/m, Valganciclovir dose should be adjusted
· Valganciclovir dose should be adjusted for children and young people under 18 years
· Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir 2 Laboratory Testing for CMV
· Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load
· Transplant centres should determine local thresholds of viral load that portend CMV infection or disease requiring treatment, depending on the CMV QNAT assay they use and the population at risk
· QNAT thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease but should be considered in the context of clinical, laboratory, or histological evidence of CMV disease
3 Monitoring for CMV Infection and Disease
· Monitor CMV viral load to guide pre-emptive therapy to recipients of solid organ transplant if: They are CMV seropositive (D+/R+, D-/R+) AND have not received T-lymphocyte depletion therapy AND are not receiving valganciclovir prophylaxis
· Consider testing for CMV viral load at least monthly and for at least 3 months following transplantation
4 Treating CMV Infection and Disease
For recipients who develop CMV infection or disease following solid organ transplantation:
· Offer treatment with oral Valganciclovir for a duration of at least 2 weeks
· Adjust the dose of Valganciclovir according to licensed dosing recommendations if creatinine clearance is less than 60ml/minute
· Be aware of the potential development of ganciclovir resistance
· Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days AND Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected
5 Ganciclovir resistance
People who are 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
· Recipients of lung transplants
In people with suspected resistance to Ganciclovir:
· 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 In people with evidence of ganciclovir resistance: Stop Valganciclovir (or Ganciclovir) and offer Intravenous Foscarnet for at least 3 weeks 6 Immunosuppression dose reduction
· In recipient who develop CMV infection or disease following solid organ transplantation Consider a dose reduction of either CNI or MMF / azathioprine
· If there is leukopenia Consider reducing or stopping MMF or azathioprine
7 Information, education and support
People undergoing solid organ transplantation should be informed about The risks of CMV infection and disease, monitoring and treatment options, including prophylaxis Executive Summary of Research Recommendations
· the clinical and cost-effectiveness of anti-CMV prophylaxis vs active surveillance post-transplant for 3 months post-transplant or post-treatment for CMV.
· the most clinical and cost-effective duration and frequency of CMV viral load monitoring and post cessation of anti CMV prophylaxis also post completion of CMV treatment.
· QNAT testing clinical and cost-effectiveness, used to guide cessation of CMV treatment
· The outcome of CNIs or proliferation inhibitors reduction
· The cost-effectiveness of CMV-specific immunoglobulins and CMV-specific cytotoxic T cells in the treatment of severe, resistant or refractory CMV disease Executive Summary of Audit Measures
· Recipients who were given Valganciclovir prophylaxis
· quantify CMV viral load using QNAT
· Recipients who were monitored monthly for CMV viral load for 3 months post solid organ transplantation or post-CMV treatment
· UL97 and UL54 mutations test for Ganciclovir resistance
· Recipients with CMV infection who reduced or stopped CNIs and/or proliferation inhibitors
Reflection on my practice
We use Valganciclovir for a short time sometimes because it is not always available and due to its high cost. Diagnosis sometimes is missed.
The guidelines cater to prevention and management if cytomegalovirus (CMV) post solid organ transplant (SOT). CMV infection can be either asymptomatic infection, viral syndrome, or CMV disease.
1.Preventing CMV Infection and disease: All donor and recipients should be screened for CMV IgG antibody. If donor serostatus is unknown, label donor as D+.
1) CMV prophylaxis in form of oral valganciclovir for at least 3 months should be given to:
a) Renal and liver transplant recipients (and should be considered for heart, lung, intestinal or pancreas transplant) in case of D+/R-, or a R+ serostatus with use of ATG or Alemtuzumab.
b) After starting acute rejection treatment if either or both of the donor or recipient is seropositive.
c) Some D-/R- patients as a prophylaxis against other Herpes infections.
2) Dose of Valganciclovir should be adjusted as per body surface area and creatinine clearance.
3) If patients develop side effects on valganciclovir, shift to CMV monitoring and pre-emptive therapy method.
2.Laboratory testing for CMV: Blood or plasma quantitative nucleic acid testing (QNAT) in IU/ml (or copies/ml, with conversion factor) should be done.
3.Monitoring of CMV infection and disease: It should be done at least monthly for minimum 3 months in R+ patients not on prophylaxis, and who did not receive T-lymphocyte depletion agents, to guide pre-emptive therapy.
4.CMV infection and disease treatment: Oral Valganciclovir (as it is as effective as intravenous ganciclovir) for at least 2 weeks (with dose modification as per creatinine clearance), with CMV viral monitoring after 2 weeks, and repeating after minimum 7 days to stop treatment after 2 consecutive negative CMV viral load reports. Intravenous Ganciclovir can be given if there are concerns regarding enteric absorption, and in very sick patients.
5.Ganciclovir resistance: It should be suspected if viral load persists or increases despite adequate dose and duration of therapy. Patients receiving prolonged courses, sub-therapeutic doses, D+/R- status, lung transplant recipients, and those who received intensive immunosuppression are prone to ganciclovir resistance. Confirm that the dose is adequate, and patient is compliant. CMV antiviral resistance for UL97 and UL54 mutations should be tested. Intravenous Foscarnet for at least 3 weeks should be given after virology consultation.
6.Immunosuppression reduction: Dose of Calcineurin inhibitors or anti-metabolites (especially in setting of leukopenia) should be reduced after discussing regarding risk of acute rejection, and dose should be reviewed once CMV is treated. There is low quality evidence for conversion to mTOR inhibitors providing protection against recurrent CMV.
2. Please reflect on your practice
In our transplant unit, we use oral valganciclovir as CMV prophylaxis as per the risk category of the recipient.
D+/R- patients are given prophylaxis for 200 days.
R+ patients are given prophylaxis for 100 days.
Patients receiving ATG as induction are given prophylaxis for 100 days.
No surveillance with serology or CMV PCR is done in our unit.
The guidelines revolve around
Preventing CMV Infection and Disease Determining CMV status in donor and recipient
CMV prophylaxis with Valganciclovir for three months is needed for all SOT if D+R-
If ATG is used even D+ R+ or D- R+.
Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-)
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+)
Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir [1A]
Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir
Laboratory Testing for CMV
Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load
Monitoring for CMV Infection and Disease
Offer monitoring of CMV viral load to guide pre-emptive therapy to adults.
Treating CMV Infection and Disease
For adults, children and young people who develop CMV infection or disease following solid organ transplantation.
Offer treatment with oral Valganciclovir for a duration of at least 2 weeks.
Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days AND
Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected (below the local laboratory threshold for detection)
Ganciclovir resistance
Be aware that the following people are 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) and recipients of lung transplants.
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.
In people with suspected resistance to Ganciclovir:
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
In people with evidence of ganciclovir resistance:
Stop Valganciclovir (or Ganciclovir)
Offer Intravenous Foscarnet for at least 3 weeks
Seek specialist virology advice before commencing treatment with Foscarnet
Dose of immunosuppressants should be decreased preferably of MMF if there is leucopenia. The risk of rejection in such cases should be explained to patients.
OUR CENTER PRACTICE.
All our patients are mostly D+ R+ so we are using valganciclovir at dose of 450 mg daily for three months with excellent outcome
Dear All
After reading these guidelines, what do you think about the differences between UK guidelines for CMV prophylaxis and KDIGO guidelines?
Do you think there is any place for extended prophylaxis 200 days rather than 100 days according to IMPACT trial?
UK guideline on prevention and management of (CMV) infection and disease following SOT
Summary
· CMV is HHV type 5, affect SOT usually after 6 weeks from date of transplantation.
· Screening and determination of serostatus of both the donor and the recipient in any SOT prior to transplantation to do risk stratification of CMV infection.
· We have 3 distinct definition in CMV:
o Infection” means positive PCR detected in plasma of patient.
o Syndrome: infection + clinical symptoms as fever, malaise, cytopenia.
o Tissue invasive disease: syndrome+ detection of virus in tissue culture or biopsy.
· Anti viral prophylaxis for CMV with valganciclovir for 3 months post transplantation is indicated if:
o High risk (D+/R-)
o Recipient takes depleting induction therapy (ATG or alemtuzimab).
o After treatment of any acute rejection episode.
· Universal prophylaxis is better adopted in high risk recipients than preemptive therapy after PCR surveillance.
· Precautions during valganciclovir use:
o Renal adjustment is required if creatinine clearance < 60ml/minute
o Adjust pediatric dose of valganciclovir according to body surface area, up to a maximum dose of 900mg once daily.
o Monitor CBC at least every 2 weeks
o Consider switching to cmv monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on valganciclovir
· Cases who are (D-/R-) should not receive routine prophylaxis against CMV, but may require ganciclovir or valganciclovir against herpes simplex infection.
· Testing for CMV;
o Monitoring by PCR should be standardized for each lab:
§ standard specimen (whole blood vs plasma)
§ CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used.
· Treatment of CMV infection:
o Treatment with IV ganciclovir or oral valganciclovir.
o Stop ttt after resolution of symptoms and 2 weeks after 2 negative PCR.
o Reduction of IS (stop antiproliferative+ decrease CNI +keep steroids).
o Close monitoring of graft function (as CMV can trigger rejection + decrease IS therapy).
· Ganciclovir resistance:
o Suspect when no clinical improvement and no decrease in viral load after 2 weeks of ganciclovir/valganciclovir for 2 weeks.
o High risk patients for resistance: the same risk group for infection, so they have prolonged use of anti viral therapy as high risk recipients as in D+/R-, intensive IS therapy as ATG induction and in heart-lung transplantation.
o Management: revising dose and patient adherence to therapy, then can offer 2 nd line drugs: foscarnet Reflection on our practice:
ü We are in pediatric transplantation, we use universal prophylaxis with oral valganciclovir in high risk D+/R- patients for 3 months and also after ttt of any rejection episode.
ü We don’t use preemptive therapy for children.
ü In case of tissue invasive disease, I don’t see any case before, but the protocol is to give IV ganciclovir for 2-3 weeks until resolution of symptoms and 2 negative PCR.
UK GUIDELINES ; MGT OF CMV INFECTION/DISEASE FOLLOWING SOT.
1.CMV STATUS.
All donor and recipients should have CMV IGG done prior to or at transplant.
D+/R- is considered in a seronegative recipient getting organ from a donor of unknown status.
2.CMV PROPHYLAXIS.
-Indications for 3 /12 valganciclovir prophylaxis;
D+/R+
Recipients post ATG with D+/R+ or D-/R+
Herpes simples status D+/R-
D+/R+,D+/R- or D-/R+ after starting treatment for acute allograft rejection.
-No routine prophylaxis in D-/R-
-With eGFR <60 ml/min renal dose valganciclovir.
-<18 yrs pts should have valganciclovir dosed according to body surface area upto a max of 900mg OD.
-A FHG should be done every fortnight to monitor for neutropenia which should prompt switching to CMV Monitoring and pre emptive therapy should it occur.
3.LAB TESTS FOR CMV.
QNAT of whole blood/plasma should be used to quantify CMV VL.
CMV QNAT results should be calibrated using WHO standards and VL reported at copies/ml or IU/ml.
All centres should get local threshold for CMV dx for CMV infection or disease that warrant treatment.
QNAT thresholds should be interpreted in clinical, lab or histological evidence of CMV context in making clinical decisions.
4.CMV MONITORING.
-Indications ; D+/R+,D-/R+ without T lymphocyte depleting therapy or valganciclovir prophylaxis
-Frequency ; Monthly.
-Duration ; 3/12
5.CMV TX (INFECTION & DISEASE).
-PO ganciclovir for a minimum of 2/52,Renal dose in those with eGFR < 60ml/min.
-Monitor for resistance and do VL after 2 /52 of treatment or after a minimum of 1/52 of treatment.
-Stop treatment after resolution of symptoms + 2 consecutive CMV VL that show undetectable VL.
6.GANCICLOVIR RESISTANCE.
-Risk factors;
Recipients of prolonged/sub therapeutic antivirals.
D+/R-.+
T cell depletion therapy for acute allograft rejection.
Lung transplant recipients.
-Indicator ;
Persistent or rising VL or symptomatic disease after appropriate dose (2-4 weeks) of anti-viral (Ganciclovir or valganciclovir)
-Management;
Ensure adequate dose and adherence to medications.
Test for resistance;UL97 & UL54 Mutations.
Stop antivirals and consider Foscarnet for atleast 3/52 with guidance from a virologist.
7.RIS
-For CMV +/- Leucopenia;
Decrease either CNI or anti metabolite. With neutropenia you preferentially either decrease or stop the anti metabolite.
DW pt risk of rejection with RIS.
Review immunosuppressive dose with resolving DX or infection.
REFLECTION ON PRACTICE.
-Cost of tests and availability is the main hindrance to practicing the above in our centre, as a nephrologist I will definitely put more emphasis on this and get a local protocol to ensure good out comes post transplant.
1. Preventing of CMV infection and disease:
to prevent CMV we should:
It is essential to Determine donor and recepient CMV status prior to surgery by screening for CMV IgG antibody.
seronegative recipient and donor is seropositive give prophylaxis of oral valganciclovir for at least 3 month
Give prophylaxis if the recepient received ATG or alemtuzumab
No prophylaxis needed if both R and D are seronegative
DOSE need to be adjusted if GFR is less than 60 ml/ minute.
Blood count need to be monitored every two weeks when on treatment
2. lab testing for CMV:
quantitative NAT or plasma PCR
3. Treating CMV infection and disease:
oral valganciclovir as effective as intravenous ganciclovir unless there is concern regarding oral absorption
Asses viral load after 2 weeks
Stop treatment if patient is symptom free and have 2 negative PCR
4. Ganciclovir resistance
patients are at risk who gets long course or sub therputic doses and those who received T cell depleting agents.
resistance is suspected if patient is still symptomatic or rising viral load after 2 to 4 weeks of treatment
If resistant to gancclovir, stop and switch over to alternative agents like foscarnet in collaboration with specialist virology.
5. IS dosecreduction:
considerdose reduction of CNI and specially antimetabolites
If with leukopenia stop antimetabolites Completely
revise IS doses after resolution of infection in lower range group
6. Education of patients:
Should receive adequate informations before transplantation according to donor and recepient serodtatus.
Informations about prophylaxis, treatment
information about the side effect of medications
The possibility of the need to reduce IS and the accompanying risk of Acute rejection should be discussed .
I practice in a low resource setting and cost of medications is usually a issue We test for CMV status for both recipients and donor before transplantation. And try to give prophylaxis to all patients using valganciclovir at the dose of 450mg daily for 3-6 months depending on risk of CMV in that particular patient
UK guideline on Prevention and Management of CMV infection and Disease Following Solid Organ Transplantation
CMV infection is considered when there is evidence of the virus undergoing a complete replication cycle and producing new infectious virions:
Asymptomatic infection: (no obvious signs of pathologic symptoms)
Viral syndrome: (fever, leucopenia, myalgia or arthralgia)
CMV disease: (histopathological evidence of CMV, CMV Colitis , CMV retinitis diagnosed by an ophthalmologist, or CMV in the CSF indicative of CNS disease)
Latent CMV: A state of virus infection in which the full replication cycle of the virus is not occurring. Preventing CMV Infection and Disease Pre-transplant screening => All organ Donors and Recipients should be screened for CMV (IgG antibody prior to or at time of transplantation.
If serostatus of both Recipient and donor are unknown for CMV in this condition the donor should be considered as seropositive, and the recipient is seronegative it is the same as if donor is unknown and recipient is negative. CMV prophylaxis: Prophylaxis treatment in a high-risk group (seropositive donor to seronegative recipient and recipient receiving T-lymphocyte depleting agent)
Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-).
Start Valganciclovir prophylaxis to people receiving kidney, heart, lung, intestinal, pancreas and liver transplants for at least 3 months following transplantation if either:
The (D+/R-) or when T-lymphocyte depletion therapy with (ATG) or Alemtuzumab (Campath) given, where donor: recipient serostatus is D+/R+ or D-/R+. Adjust the dose of Val ganciclovir if creatinine clearance is less than 60mL/minute and adjust the dose of Val ganciclovir according to body surface area for children and young people under 18 years.
Monitor Full Blood Count at least every 2 weeks whilst on Val ganciclovir and switch to CMV monitoring and pre-emptive therapy if people develop side effects e.g., neutropenia, on Val ganciclovir. Treat for 3 months Laboratory testing:
QNAT (Quantitative Nucleic Acid Testing)
CMV viral load
Monitoring CMV/Pre-emptive strategies
Monthly monitoring at least 3 months
In CMV sero-positive recipient and not receiving T-lymphocyte depleting agent
CMV management (treatment and immunosuppression reduction)
Treatment at least 2 weeks
Repeat CMV PCR after 2 weeks
Stopped treatment after resolution of symptoms and two consecutive negative PCR
Ganciclovir resistance
Risks
1. prolong course
2. Sub-therapeutic dose
3. D+/R-
4. T-cell depletion therapy
5. Lung transplant
-UL97 and UL54 gene mutation testing in patient suspecting Ganciclovir resistance
-Treatment with Foscarnet
Immunosuppression dose reduction:
Consider a dose reduction of either calcineurin inhibitor or Mycophenolate mofetil /azathioprine and reducing or stopping Mycophenolate Mofetil (MMF) Azathioprine if there is evidence of leukopenia is the preferred option and risk of rejection should be discussed with the recipient.
Reflect on your practice:
Pre-transplant workup Screening CMV (IgG antibody) for both donors and recipients is considered in our protocol and everywhere.
Prophylaxis is recommended for recipients who received ATG induction or received ATG for Acute Cellular Rejection
OR when the donor recipient sero- status MM is (D+/ R-) CMV IgG.
Prophylaxis for CMV (D-/R-) with Basiliximab => No prophylaxis needed.
Prophylaxis for CMV (D-/R-) with ATG => prophylaxis needed.
Prophylaxis for CMV (D+/R+) with Basiliximab => No prophylaxis needed.
Prophylaxis for CMV (D+/R+) with ATG => prophylaxis needed.
Valganciclovir prophylaxis for at least 3 months following treatment of ACR ttt by ATG.
We are following the same guideline in managing Immunosuppression dose reduction and
Ganciclovir resistance: we send testing for Human CMV (HCMV) antiviral resistance / UL97 and UL54 gene mutations.
CMV Prophylaxis
· Valganciclovir
prophylaxis for for at least 3 months following transplantation
if either:
1. -D+/R-
2. D+/R+
or D-/R+ (if ATG or Alemtuzumab)
3. after treatment
for acute allograft rejection if (D+/R-, D+/R+ or D-/R+)
4. No
prophylaxis required if (D-/R-)
· adjust
the dose of Valganciclovir according to body surface area, maximum dose of
900mg once daily and creatinine clearance is less than 60mL/minute
daily
· Monitor
Full Blood Count at least every 2 weeks while on Valganciclovir
· Switch to (CMV
monitoring and pre-emptive therapy) if people develop side effects e.g.;
neutropenia, on Valganciclovir
· Offer monitoring
of CMV viral load to guide pre-emptive therapy in the following situation 1- (D+/R+, D-/R+) 2-And didn’t not received T-lymphocyte depletion therapy 3- AND They are not receiving valganciclovir prophylaxis
· Monitoring
to guide preemptive therapy should be at least monthly and at least for 3 month
following transplantation CMV infection or disease
· In
CMV infection or disease use oral Valganciclovir for a duration of at least 2
weeks
· Assess
CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7
days
· Considering
stopping of treatment after resolution of symptoms AND two consecutive, CMV
viral load tests that confirm that CMV is not detected (below the local
laboratory threshold for detection) Valgacyclovir resistant
· Consider
resistant to valgan cyclovir if persistent or increasing viral load or symptomatic disease after
a normally effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or
Valganciclovir
· people at increased risk of Ganciclovir resistance: o those who received prolonged courses, o or sub-therapeutic doses of antiviral medications o (D+/R-)
· 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:
o Stop
Valganciclovir (or Ganciclovir)
o Offer
Intravenous Foscarnet for at least 3 weeks After Seeking specialist virology
advice Immunosupression reduction
· Consider
a dose reduction of either calcineurin inhibitor or mycophenolate mofetil /
azathioprine · Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF)
or azathioprine if there is evidence of leukopenia · Discuss with patients, and, where appropriate, parents or carers, the
risk of acute rejection with immunosuppression dose reduction · Review the dosing of immunosuppression following resolution of CMV
infection or disease
——————————————–
In our center we are monitoring CMV every 2 weeks in first 3 month post transplant then monthly until. the end of the first year then every 2-3 month
at the same time we give prophylaxis 6 month for D+/R+. D-/R+. D+/R- and 3 month for those with Low risk D-/R- CMV infection initially we reduce MMF 50%. and targeting lower tac level ,we repeat CMV weekly if rising we stop MMF
CMV:
is one of the herpes group of viruses, which are widely distributed among mammals.
The various strains of CMV are species specific and primary infection results in the most severe disease when the host is T-cell immunocompromised.
After primary CMV infection, the viral genome enters monocytes and other bone marrow progenitor cells and enters a latent state. CMV in Solid Organ Transplant Recipients:
Primary infection with CMV typically occurs approximately four to six weeks post-transplant in a seronegative individual who receives a seropositive organ.
Symptoms may be non-specific:
Fever, night sweats, fatigue and myalgia.
Retinitis can be pathognomonic, but is rarely seen in the transplant population.
GIT: diarrhea, abdominal pain and nausea.
Respiratory: SOB, Cough.
Screening Pretransplant:
All organ donors and recipients should be screened for CMV (IgG antibody) sero status prior to, or at the time of transplantation [1A]
If donor CMV aerostats is unknown and recipient is seronegative or unknown for CMV, this should be characterized as donor seropositive, recipient seronegative for CMV. CMV prophylaxis:
Receiving kidney and liver transplants, Valganciclovir prophylaxis for 3months for:
D+/R-.
Donor: recipient serostatus D+/R+ or D-/R+ if received ATG or Alemtuzumab.
Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal or pancreas transplants for at least 3 months:
Either D+/R-
OR D+/R+ or D-/R+ if received ATG or Alemtuzumab.
Valaciclovir prophylaxis for prevention of other Herpes virus infections, e.g.; recipients who are seronegative for Herpes Simplex Virus (HSV) receiving an organ from HSV seropositive donors.
Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+) [2C].
Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute.
Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir. Laboratory Testing:
Should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load.
QNAT thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease. Monitoring for CMV Infection and Disease:
monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if: They are CMV seropositive (D+/R+, D-/R+) [1B] AND They have not received T-lymphocyte depletion therapy [1B] AND They are not receiving Valganciclovir prophylaxis [1B]
Where CMV viral load monitoring is offered:
Consider testing with a frequency of at least monthly, Consider testing for at least 3 months following transplantation.
Treating CMV Infection and Disease:
Treatment with oral Valganciclovir for a duration of at least 2 weeks [1A]
Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days [1D] AND Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected . 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.
In people with suspected resistance to Ganciclovir:
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 [1A] Use either whole blood or plasma [1A]
In people with evidence of ganciclovir resistance:
Stop Valganciclovir (or Ganciclovir) [1A]
Offer Intravenous Foscarnet for at least 3 weeks [1B], Seek specialist virology advice before commencing treatment with Foscarnet. Immunosuppression dose reduction Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine.
Preferentially reducing or stopping MMF or azathioprine if there is evidence of leukopenia.
Information, education and support:
Solid organ transplantation recipient about risk and prophylaxis.
Please reflect on your practice
We are screening all donors and recipient for CMV and prophylaxis is given for 3months
Summary of guideline
A – Determine the CMV status in donor and recipient – Screen both recipient and donors using serology (CMV IgG antibody) serostatus before or during the time of transplantation. Characterize as donor seropositive, recipient seronegative for CMV (D+/R-) if donor CMV status is unknown and recipient is seronegative or unknown for CMV.
B – CMV Prophylaxis
For all age groups receiving kidney and liver transplants, offer valganciclovir prophylaxis for at least 3 months following transplantation if either D+/R- or the recipient has received induction with a lympho-depleting agent or where donor: recipient serostatus is D+/R+ or D-/R+ or following treatment for an acute rejection. Same recommendation for heart, lung, intestinal or pancreas transplants.
No routine valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-) except for treatment of other viral infections like HSV.
Maximum daily dose of valganciclovir is 900mg daily and should be dosed according to body surface area. Dose adjustment is necessary when GFR is less than 60ml/min.
Monitor FBC every two weeks and consider switching to monitoring viral load for pre-emptive therapy when patient develop neutropenia.
C – Laboratory testing
Quantification of viral load in copies/ml or IU/ml after NAT is recommended.
D – Monitor viral load monthly for at least 3 months for pre-emptive treatment in CMV seropositive (D+/R+, D-/R+) cases and in recipients who have not received T-lymphocyte depletion therapy who is not on valganciclovir prophylaxis.
E- Treatment of CMV disease
Treatment is for at least 2 weeks or following resolution of symptoms and repeated undetectable viral load on two occasions.
Monitor for ganciclovir resistance.
F – Ganciclovir resistance
Risk of resistance is increased in the following scenario;
Prolonged courses of antiviral agents, or sub-optimal doses of antiviral drugs.
CMV seronegative recipients receiving a solid organ transplant from seropositive donors (D+/R-)
Induction therapy with lymphocyte depleting agent.
Use of lymphocyte depleting agent to treat allograft rejection.
Recipients of lung transplants.
Consider resistance if after 2 – 4 weeks of adequate treatment, patient still exhibit symptomatic disease or increasing viral load.
Approach to ganciclovir resistance
Ensure adequate dosing and treatment adherence.
Testing for Human CMV (HCMV) genotype and UL97 and UL54 gene mutations using either whole blood or plasma.
In ganciclovir resistance: Stop Valganciclovir (or Ganciclovir) and offer Intravenous Foscarnet for a minimum of 3 weeks.
Consult a virologist before commencing treatment with Foscarnet.
G– Immunosuppression reduction
Reduce the dose of immunosuppressive medications including CNIs and antimetabolites while monitoring for acute rejection.
H – Offer information, education and support for patients including risk factors and treatment plan. Educate nephrologists on management of CMV infection.
Where I practice is a low resource setting and cost of medications is usually a big issue because of out-of-pocket payments. We test for CMV status for both recipients and donor before transplantation. We give a universal prophylaxis using valganciclovir at the dose of 450mg daily for 6 months to all patients after kidney transplantation. We monitor with CBC twice weekly.
Determining CMV status in donor and recipient
All organ donors and recipients should be screened for CMV (IgG antibody)
donor CMV serostatus – unknown donor seropositive
recipient -seronegative or unknown – recipient seronegative
CMV prophylaxis
Offer Valganciclovir prophylaxis at least 3 months following transplantation if either:
The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-)
The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath ), where donor: recipient serostatus is D+/R+ or D-/R+
Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-)
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+)
Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir
Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir
Laboratory Testing for CMV
Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load
Transplant centres should adopt a consistent approach to use either whole blood or plasma for quantification of CMV viral load
CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used
Monitoring for CMV Infection and Disease
Offer monitoring of CMV viral load to guide pre-emptive if:
They are CMV seropositive (D+/R+, D-/R+) AND
They have not received T-lymphocyte depletion therapy AND
They are not receiving valganciclovir prophylaxis
Where CMV viral load monitoring is offered:
Consider testing with a frequency of at least monthly
Consider testing for at least 3 months following transplantation
Treating CMV Infection and Disease
Offer treatment with oral Valganciclovir for a duration of at least 2 weeks
Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of
7 days AND Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected
Ganciclovir resistance
Be aware that the following people are 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)
Recipients of lung transplants
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
In people with suspected resistance to Ganciclovir:
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
In people with evidence of ganciclovir resistance:
Stop Valganciclovir (or Ganciclovir)
Offer Intravenous Foscarnet for at least 3 weeks
Seek specialist virology advice before commencing treatment with Foscarnet
Immunosuppression dose reduction
Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil /
azathioprine
Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia
In my practice we use universal protocol for CMV surveillance and treatment
I. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION
Summarise these guidelines
1. Preventing CMV infection and disease
Determining the donor and recipient CMV serostatus
– Donors and recipients should be screened for CMV serostatus (IgG Ab) [1A]
– If the donor’s CMV serostatus is unknown it should be regarded as donor seropositive, however if the recipient’s CMV serostatus is unknown it should be characterized as recipient seronegative i.e., CMV (D+/ R-) [1D]
CMV prophylaxis
– Valganciclovir prophylaxis should be offered to potential kidney and liver transplant recipients for at least three months post-transplant in the following scenarios: –
·Donor: recipient CMV serostatus (D+/ R-) [1A] or
·A recipient who received ATG or Alemtuzumab where the donor: recipient CMV serostatus is D+/ R+ or D-/ R+ [1A]
– For heart, lung, intestinal and pancreatic transplant recipients, consider offering 3-month valganciclovir prophylaxis in the following circumstances: –
·Donor: recipient CMV serostatus (D+/ R-) [1C] or
·A recipient who received ATG or Alemtuzumab where the donor: recipient CMV serostatus is (D+/ R+) or (D-/ R+) [1C]
– Valganciclovir prophylaxis is not routinely indicated if the donor: recipient CMV serostatus is (D-/ R-) [1D] unless valganciclovir or valaciclovir prophylaxis is required for the prevention of other herpes virus infections e.g., HSV seronegative recipient receiving an organ from a HSV seropositive donor [2D]
– Recipients treated for acute graft rejection should be initiated on at least 3-months valganciclovir prophylaxis if either the donor or the recipient had a positive CMV serostatus i.e., (D+/ R-), (D+/ R+) or (D-/ R+) [2C]
– If eGFR is <60ml/min renal adjust the dose of valganciclovir [1D]
– A bi-monthly complete blood count should be done in patients on valganciclovir [1A]
– Opt for CMV monitoring and pre-emptive therapy in patients who develop neutropenia while on valganciclovir [1C]
2. Laboratory testing for CMV
– Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma should be used to quantify CMV viral load [1A]
– Transplant centers should use a consistent approach for CMV viral load quantification i.e., either whole blood or plasma [1C]. They should determine the local thresholds of CMV viral load that are highly suggestive of CMV infection or disease necessitating treatment [1C]
– QNAT CMV viral loads should be interpreted in the context of clinical, laboratory or histological findings prior to initiating or stopping treatment in patients with CMV disease [1C]
– WHO International Reference Standard should be used to calibrate CMV QNAT assays [1C]
– CMV viral load should preferably be reported as IU/ml. A conversion factor should be used if it is reported as copies/mL [1C]
3. Monitoring for CMV infection and disease
– CMV viral load monitoring should be offered in the following scenarios to guide in pre-emptive therapy among SOT recipients.
·Donor: recipient seropositive CMV status (D+/ R+), (D+/ R+) [1B] and
·No prior exposure to ATG or Alemtuzumab (T-lymphocyte depleting agents) [1B] and
·Not on valganciclovir prophylaxis [1B]
– CMV viral load monitoring should be done at least monthly for a minimum of 3 months post-transplant [1D]
4. Treating CMV infection and disease
– Patients who develop CMV infection or disease should be treated for at least 2 weeks [1A]
– If eGFR is <60ml/min, the dose of valganciclovir should be adjusted [1D]
– CMV viral load should be done after 2 weeks of treatment and thereafter weekly [1D]
– Treatment cessation can be considered after obtaining two consecutive negative CMV viral loads in addition to resolution of symptoms [2D]
5. Ganciclovir resistance
– Patients at increased risk of ganciclovir resistance include: –
·Patients who have been on prolonged courses or sub-therapeutic doses of antiviral medications [1A]
·CMV seronegative recipients who received SOTs from seropositive donors (D+/ R-) [1C]
·Patients who have received treatment for acute graft rejection e.g., ATG or Alemtuzumab (T-cell depleting agents [1B]
·Lung transplant recipients [2C]
– If there is a persistent or rising CMV viral load or symptomatic disease despite a normal effective dose and duration of treatment i.e., (2-4 weeks) consider ganciclovir resistance [1A]
-For patients with ganciclovir resistance confirm adherence to the treatment plan, absorption and proper dosing. Also test for human CMV antiviral resistance, UL97 and UL54 gene mutations using either whole blood or plasma [1A]
– If there is evidence of ganciclovir resistance, stop valganciclovir or ganciclovir [1A] and give IV Foscarnet for at least 3 weeks [1B] in consultation with a virologist [1D]
6. Immunosuppression dose reduction
– Consider reducing the dose of either the CNI or the antimetabolite (mycophenolic analogues or azathioprine [1C]
– If there is leucopenia, preferentially reduce or stop the antimetabolite [2C]
– Discuss the patient the risk of acute graft rejection that comes with reduction in immunosuppression [1D]
– Once there is resolution of CMV infection or disease, review the immunosuppression dosages [1D]
7. Information, education and support
– Patients should be aware of the risks of CMV infection and disease based on the donor/ recipient CMV serostatus pre-transplant as well as the immunosuppressive agents to be used
– Patients should be made aware of the monitoring, prophylaxis and treatment options available.
Reflect on your practice
Our transplant center is a bit resource limited so we basically do pre-transplant CMV serostatus screening and classify the donor and the recipient in the different risk stratification categories. We do not have a deceased donor program as yet.
Most of our transplant pairs are CMV (D+/ R+). Due to the financial implications involved, we do not routinely offer valganciclovir prophylaxis neither do we use ATG or Alemtuzumab (T-lymphocyte depleting agents).
However, we do get a few cases of confirmed CMV disease post-kidney transplant and for such patients we treat with Valganciclovir (renal-adjusted dose for about 3 weeks as tolerated and thereafter offer secondary prophylaxis for 3 months).
IV Ganciclovir is preferred in the initial treatment, unfortunately it is not readily available.
For the patients who develop severe neutropenia, we try to source for GM-CSF which is also not easy to come by.
Weekly CMV viral load monitoring is also a challenge due to financial constraints.
We have never had cases of ganciclovir resistance but again I cannot say that we actively screen for it. Luckily, we have never had a case whereby we needed to get an alternative treatment to valganciclovir.
We hope that the financial situation will improve and make us feel better equipped to deal with CMV disease in the kidney transplant population.
UK GUIDELINE ON PREVENTION AND MANAGEMENTOF CYTOMEGALOVIRUS (CMV) INFECTION ANDDISEASE FOLLOWING SOLID ORGANTRANSPLANTATION.
CMV infection is considered when there is evidence of the virus undergoing a complete replication cycle and producing new infectious virions : Asymptomatic infection (no obvious signs of pathologic symptoms) Viral syndrome (fever, leucopenia, myalgia or arthralgia) CMV disease – (histopathological evidence of CMV, CMV retinitis diagnosed by an ophthalmologist, or CMV in the CSF indicative of CNS disease) Latent CMV: A state of virus infection in which the full replication cycle of the virus is not occurring Serostatus:
1-Donor (D) positive (+); Recipient (R) positive (+) (D+/R+).
2-Donor (D) negative (-); Recipient (R) negative (-) (D-/R-).
3-Donor (D) positive (+); Recipient (R) negative (-) (D+/R-).
4-Donor (D) negative (-); Recipient (R) positive (+) (D-/R+). 1-Preventing CMV Infection and Disease.
=Screening of CMV status in donor and recipient.
All organ donors and recipients should be screened for CMV (IgG antibody) at the time of transplantation which is important step in preparation.
If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterized as donor seropositive, recipient seronegative for CMV(D+/R-).
=CMV prophylaxis.
1-Do not routinely offer Val ganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-).
2-Start Val ganciclovir prophylaxis to people receiving kidney, heart, lung, intestinal, pancreas and liver transplants for at least 3 months following transplantation if either:
The (D+/R-) or when T-lymphocyte depletion therapy with (ATG) or Alemtuzumab (Campath) given, where donor: recipient serostatus is D+/R+ or D-/R+ .
=Adjust the dose of Val ganciclovir if creatinine clearance is less than 60mL/minute and adjust the dose of Val ganciclovir according to body surface area for children and young people under 18 years.
=Monitor Full Blood Count at least every 2 weeks whilst on Val ganciclovir and switch to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Val ganciclovir. 2-Laboratory Testing for CMV.
=We should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load and CMV QNAT assays should be calibrated using the WHO International Reference Standard .
=CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used.
= We should depend on clinical, laboratory or histological evidence of CMV disease to treat and to stop antiviral medications rather that depending on QNAT thresholds alone. 3- Monitoring CMV Infection and Disease.
=We could monitor CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if: (D+/R+, D-/R+), not using T-lymphocyte depletion therapy and they are not receiving Val ganciclovir prophylaxis.
=We should consider testing of CMV with a frequency of at least monthly for 3 months following transplantation. 4-Treating CMV Infection and Disease.
=Treatment with oral Val ganciclovir for a duration of at least 2 weeks with adjusting the dose of Val ganciclovir according creatinine clearance specially when it is less than 60mL/minute.
=Stopping treatment for CMV disease after resolution of symptoms and after two consecutive, CMV viral load tests that confirm that CMV is not detected. 5 Ganciclovir resistance.
=Common with those who have received prolonged courses, or sub-therapeutic doses of antiviral medications, (D+/R-), those who have received intensive immunosuppression and recipients of lung transplants
= A persistent or increasing viral load or symptomatic disease after effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Val ganciclovir is considered resistance.
= We should stop Val ganciclovir (or Ganciclovir) and offer Intravenous Foscarnet for at least 3 weeks. 6-Immunosuppression dose reduction.
=Consider a dose reduction of either calcineurin inhibitor or Mycophenolate mofetil /azathioprine and reducing or stopping Mycophenolate Mofetil (MMF) Azathioprine if there is evidence of leukopenia is the preferred option and risk of rejection should be discussed with the recipient. Reflect on your practice.
Screening pre-transplant is considered our protocol.
Universal prophylactic protocol is our preferred option with Val ganciclovir.
CMV PCR screening post-transplant for 3 month .
Weekly follow up of CMV PCR with CMV treatment and continued till CMV viral load not detected.
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION Summary 1. Preventing CMV Infection and Disease 1) Determining CMV status in donor and recipient · All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation [1A] · If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-). [1D] 2) CMV prophylaxis a) Offer Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either: · The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-) [1A] OR · The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath®), where donor: recipient serostatus is D+/R+ or D-/R+ [1A] b) Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal or pancreas transplants for at least 3 months following transplantation if either: · The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-) [1C] OR · The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath®), where donor: recipient serostatus is D+/R+ or D-/R+ [1C] c) Some recipients who are seronegative for CMV (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention of other Herpes virus infections. d) Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+) [2C]. e) Adjust the dose of Valganciclovir in the followings: · if creatinine clearance is less than 60ml/minute [1D] · children and young people under 18 years, the dose of Valganciclovir to be adjusted according to body surface area, up to a maximum dose of 900mg once daily [1D] f) Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir [1A] g) Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir [1C] 2. Laboratory Testing for CMV · Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load [1A] · QNAT should be considered in the context of clinical, laboratory or histological evidence of CMV disease [1C]. · CMV PCR(on whole blood, plasma or leucocyte) considered to the gold standard mean of detecting active viral replication. 3. Monitoring for CMV Infection and Disease a) Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if: · They are CMV seropositive (D+/R+, D-/R+) [1B] AND · They have not received T-lymphocyte depletion therapy [1B] AND · They are not receiving valganciclovir prophylaxis [1B] b) Where CMV viral load monitoring is offered: · Consider testing with a frequency of at least monthly [1D] · Consider testing for at least 3 months following transplantation [1D] 4. Treating CMV Infection and Disease a) Offer treatment with oral Valganciclovir for a duration of at least 2 weeks [1A]. Most commonly valganciclovir 900mg twice daily has been used as treatment dose, adjusted for level of kidney function. b) Adjust the dose of Valganciclovir according to licensed dosing recommendations if creatinine clearance is less than 60ml/minute [1D] c) Both CMVIg and adoptive transfer of cytotoxic T Lymphocytes (CTL) are for research recommendation: · High doses of intravenous Hyperimmune globulin (0.5 g/kg body weight) have been used in conjunction with Ganciclovir for the treatment of pneumonitis (not persuaded as no sufficientevidence). · No evidence was identified to support a recommendation on the use of adoptive transfer of cytotoxic T Lymphocytes (CTL) for pre-emptive treatment of CMV. d) Be aware of the potential development of ganciclovir resistance. e) Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days [1D] f) 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) [2D]. 5. Ganciclovir resistance
a) People at increased risk of Ganciclovir resistance:
· Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications [1A]
· CMV seronegative recipients receiving a solid organ transplant from seropositive donors (D+/R-) [1C]
· Those who have received intensive immunosuppression (e.g; with T-cell depletion therapy, following episodes of acute allograft rejection) [1B]
· Recipients of lung transplants [2C]
b) 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 [1A]
c) When resistance to Ganciclovir is suspected:
· Confirm that dosing is adequate.
· Consider adherence to treatment plan and absorption.
· Offer testing for Human CMV (HCMV) antiviral resistance.
· Sequence-based analysis of UL97 and UL54 gene mutations [1A].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.
· Use either whole blood or plasma [1A]
d) In people with evidence of ganciclovir resistance:
· Stop Valganciclovir (or Ganciclovir) [1A]
· Offer Intravenous Foscarnet for at least 3 weeks [1B]. 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 [1D].
· 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. 6. Immunosuppression dose reduction
For adults, children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation:
a) Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine [1C]
· Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia [2C]
b) Discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction [1D]
c) Review the dosing of immunosuppression following resolution of CMV infection or disease [1D] 7. Information, education and support a) Offer balanced and accurate information to children, adults and young people undergoing solid organ transplantation about:
· The risks of CMV infection and disease according to donor / recipient CMV serostatus and nature of immunosuppression planned or received.
· Monitoring and treatment options, including prophylaxis. b) Ensure that healthcare professionals offering information have specialist knowledge about CMV infection and disease and their treatment, and the skills to support shared decision-making (for example, presenting information in a form suitable for developmental stage). Please reflect on your practice In our practice we are coinciding the same guidelines: · Pre-transplant screening for CMV for both donors and recipients and identification of serostatus. · Post-transplant prophylaxis for CMV, for three months, using acyclovir instead of valganciclovir. · Treating CMV infection and disease with Valganciclovir. No reported cases of resistance to Valganciclovir.
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION KEY ISSUES
1- Determination of donor and recipient CMV status:
Prior to transplantation, all organ donors and recipients should be checked for CMV IgG serostatus.
If the donor’s CMV serostatus is unknown and the recipient’s CMV serostatus is negative or unknown, this is regarded (D+/R-).
2- CMV prophylaxis
If the patient has received T-lymphocyte depletion therapy with ATG or Alemtuzumab (Campath), where D+/R+ or D-/R+, offer valganciclovir prophylaxis for at least 3 months.
If (D-/R-), avoid giving Valganciclovir prophylaxis on a regular basis.
If either the donor or the recipient is CMV positive, consider Valganciclovir prophylaxis for at least 3 months after beginning treatment for acute allograft rejection.
If the cr cl is less than 60 ml/min and in youngsters, change the dose of Valganciclovir in accordance with the body surface area (maximum daily dose 900 mg)
While taking Valganciclovir, monitor Full Blood Count at least once every two weeks.
If patients experience adverse effects from Valganciclovir, such as neutropenia, think about switching to CMV monitoring and preventive therapy.
3- CMV laboratory testing
Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma should be used by clinical laboratories to determine the CMV viral load, which is then reported as copies/mL or as IU/mL.
QNAT thresholds should be taken into account in the context of clinical, laboratory, or histological evidence of CMV disease rather than being used in isolation to decide whether to start or stop treatment for people with CMV disease.
4- Surveillance of CMV infection and disease
Provide CMV viral load monitoring to advise pre-emptive medication after solid organ transplant recipients who are CMV seropositive (D+/R+, D-/R+), haven’t been treated with T-lymphocyte depletion treatment, or if not being treated with valganciclovir prophylaxis. Monitoring should be done at least once a month for at least three months after transplantation.
5- CMV treatment
Provide oral Valganciclovir therapy for at least two weeks.
If the clearance is less than 60 ml/min, reduce the dose of Valganciclovir.
After 2 weeks of treatment, assess CMV viral load and repeat every 7 days.
Consider discontinuing CMV illness medication if symptoms have resolved and two consecutive CMV viral load tests show that CMV is not present.
6- Resistance to ganciclovir
People at higher risk include:
1-Those who have had lengthy courses of antiviral treatment or sub-therapeutic doses
2- D+/R- 3- Those who have had extensive immunosuppression (for example, T-cell depletion therapy after episodes of acute allograft rejection)
4- Recipient of a lung transplant.
Consider Ganciclovir resistance if: a persistent or growing viral load or symptomatic disease persists after a usually effective dosage and duration (e.g., 2-4 weeks) with Ganciclovir or Valganciclovir
In patients with suspected Ganciclovir resistance:
1- Ensure sufficient dose, adherence to treatment plan, and absorption.
2- Provide antiviral testing for Human CMV (HCMV) as well as UL97 and UL54 gene variants.
In people who have ganciclovir resistance:
1- Discontinue Valganciclovir (or Ganciclovir)
2- After consulting with a virology specialist, administer intravenous Foscarnet for at least three weeks.
7-Immunosuppression dose reduction
People who are at a higher risk include:
Adults, children, and adolescents who develop CMV infection or illness (with or without leukopenia) after a solid organ transplant:
Consider lowering the dose of calcineurin inhibitor or mycophenolate mofetil/azathioprine.
If there is evidence of leukopenia, consider lowering or discontinuing Mycophenolate Mofetil (MMF) or azathioprine.
Discuss the risk of acute rejection with patients and, if appropriate, parents or caregivers.
Reevaluate immunosuppressive dose after CMV infection or illness resolution.
Please reflect on your practice
In my practice we usually do screening as per British guidelines, however treatment and prophylaxis options are mostly restricted to valganciclovir. We don not perform gancyclovir resistance studies
# Preventing CMV Infection and Disease # Determining CMV status in donor and recipient
1.1 CMV (IgG antibody) must be screened for both donors and recipients before or at the time of transplantation [1A].
1.2 Donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, recommended as donor seropositive, recipient seronegative for CMV(D+/R-) [1D].
# CMV prophylaxis
In all cases of solid organ transplant:
1.3 Valganciclovir prophylaxis in kidney and liver transplants for at least 3 months following transplantation if either:
(D+/R-) [1A].
OR
(ATG) or Alemtuzumab induction in case of D+/R+ or D-/R+ [1A]
1.4 Valganciclovir prophylaxis is recommended in heart, lung, intestinal or pancreas transplants for at least 3 months if either:
(D+/R-) [1C].
OR
(ATG) or Alemtuzumab induction in case of D+/R+ or D-/R+ [1C]
1.5 Do not routinely use Valganciclovir prophylaxis if CMV (D-/R-) [1D]
1.5.1 Some recipients with CMV (D-/R-) may need Valganciclovir or Valaciclovir prophylaxis to prevent other Herpes virus infections,e.g; recipients who are seronegative for (HSV) with HSV seropositive donors [2D].
1.6 Valganciclovir prophylaxis is advised for at least 3 months following treatment of AR (D+/R-, D+/R+ or D-/R+) [2C].
1.7 Adapt the Valganciclovir dose when creatinine clearance 60ml/minute [1D].
1.8 Children and patients 18 years, adapt the Valganciclovir in keeping with BSA, up to a maximum dose of 900mg od [1D].
1.9 Monitor FBC at least every 14 days during Valganciclovir therapy [1A].
1.10 CMV monitoring and pre-emptive therapy if Valganciclovir adverse events developed e.g.; neutropenia [1C].
# 2 Laboratory Testing for CMV
2.1 QNAT must be used to quantify CMV viral load [1A].
Use either whole blood or plasma [1C].
The calibration should be done according to WHO IRS [1C].
The viral load reported as IU/mL, or as copies / mL [1C].
2.2 Local thresholds of viral load indicated infection or disease needing treatment, depending on the CMV QNAT assay [1C].
2.3 QNAT thresholds should not be used in isolation to rule beginning or finishing of therapy [1C].
# 3 Monitoring for CMV Infection and Disease
3.1 Offer monitoring of CMV viral load in all SOT if:
*(D+/R+, D-/R+) [1B].
*Not received T-lymphocyte depletion therapy [1B].
*Not receiving valganciclovir prophylaxis [1B].
3.2 Where CMV viral load monitoring is offered:
Testing at least monthly for at least 3 months post transplant [1D].
# 4 Treating CMV Infection and Disease
4.1 Oral Valganciclovir for at least 2 weeks [1A]
4.2 Adjust the dose of Valganciclovir if creatinine clearance 60ml/minute [1D]
4.3 Consider the ganciclovir resistance
4.4 Evaluate CMV viral load after 2 weeks of treatment and repeat at 7 days [1D]
*Stop treatment for CMV disease after relief of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected [2D].
# 5 Ganciclovir resistance
5.1 Risk factors for resistance:
*Prolonged courses, or sub-therapeutic doses of antiviral therapy [1A]
*(D+/R-) [1C].
*Intensive IS (T-cell depletion therapy, post AR) [1B].
*In lung transplantation [2C].
5.2 Consider resistance when:
In persistent high viral load or presences of symptomatic disease following 2-4 weeks of Ganciclovir or Valganciclovir [1A]
5.3 Consider the adequate dose, adherence and absorption
Offer testing for (HCMV) antiviral resistance, UL97 and UL54 gene mutations [1A].
5.4 Stop the treatment in suspected case of resistance [1A]
I/V Foscarnet for at least 3 weeks [1B].
# 6 Immunosuppression dose reduction
6.1Dose reduction of either CNI or MMF / AZA [1C]
Decrease or stop (MMF) or AZA when leucopenia is suspected [2C]
6.2 Counsel the patients about the risk of AR with IS dose reduction [1D]
6.3 Review the dosing of IS post CMV infection or disease resolution [1D]
# 7 Information, education and support
7.1 Offer accurate information to patients about:
The risks of CMV infection and disease .
Evaluation and treatment options.
7.2 Ensure that healthcare professionals offering information have knowledge about CMV infection and disease and their management.
# Please reflect on your practice
*CMV (IgG antibody) must be screened for both donors and recipients before or at the time of transplantation.
*Prophylaxis is recommended for recipients who received ATG induction, OR when the donor recipient serostutus is (D+/ R-) CMV IgG; while other recipients received acyclovir for 6 months duration.
*We do not routinely use Valganciclovir as prophylaxis if CMV (D-/R-).
*We advise Valganciclovir prophylaxis for at least 3 months following treatment of AR.
*We don’t monitor CMV viral load routinely.
*Valganciclovir OR ganciclovir is mainly used for treatment of CMV infection and disease.
*We recommended the same guideline in managing Immunosuppression dose reduction and Ganciclovir resistance, however we did not have testing for Human CMV (HCMV) antiviral resistance / UL97 and UL54 gene mutations.
Q2 reflect on your practice .
In our center
1- the ( donor and recipient ) tested for CMV IgG.
2- Valgancyclovir or valciclovir is offered for every recipient with any sero-positivity .
3- Acyclovir prophylaxis is offered in sero-negative state to prevent herps simplex infection .
4- The donor and recipient is not tested for herpes simplex sero state in our center.
5- Valgancyclovir is offered for at least 3 months .
6- QNAT used for diagnosis and treatment decision.
7- We use valgancyclovir for treatment .
8- We did not face a cse of gancyclovir or valgancyclovir resistance case .
9- We start immunsupressive medication dose reduction especially in sever patient .
10- – we reduce the dose of MMF OR AZATHIOPRINE at first with close monitoring the renal function test for early diagnosis of acute rejection.
Preventing CMV Infection and Disease – They recommend that all organ donors and recipients should be screened for CMV (IgG antibody prior to or at time of transplantation . -If serostatus of both patient and donor are unknown for CMV in this condition the donor should be considered as seropositive and the recipient is seronegative it is the same as if donor is unknown and recipient is negative . CMV prophylaxis: Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation for the following :
(D+/R-) for CMV OR
(D+/R+ or D-/R+ ) when the recipient receivedT-lymphocyte depletion therapy like ATG or alemtuzumab .
After acute allograft rejection
In case of heart, lung, intestinal or pancreas transplants the use Valganciclovir prophylaxis is the same as mentioned in liver and kidney transplant with different level of recommendation -(D-/R-) valganciclovir prophylaxis is not recommended although some recipients may require prophylaxis for prevention of other herpes infection . -Valganciclovir prophylaxis is given at a dose of 900 mg once daily oral dose with renal dose adjustment and full blood count monitoring.
Laboratory Testing for CMV-Quantification of CMV viral load in either whole blood or plasma using Quantitative Nucleic Acid Testing (QNAT) and should be reported as IU/mL instead of using copy /ml . -Determination of commencement or cessation of treatment for individuals with CMV disease, should be considered with the interpretation of clinical, laboratory or histological evidence of CMV disease. Monitoring for CMV Infection and Disease – Pre-emptive therapy should be guided by CMV viral load in case of (D+/R+, D-/R+) who doesn’t receive Tlymphocyte depleting agent nor valganciclovir prophylaxis with CMV viral load monitoring at least monthly for at least 3 months after transplant .
Treatment of CMV Infection and Disease – Oral Valganciclovir for a duration of at least 2 weeks with the adjustment of the dose according to creatinine clearance. – Check the viral load after 2 weeks and repeat at a minimum interval of one week . -Stop the treatment if there is resolution of symptoms AND undetected CMV viral load in two consecutive tests ., Ganciclovir-resistant;
There is increased risk of Ganciclovir resistance in patients who receive prolonged coarse or sub therapeutic dose and in seronegative recipient with seropositive donor in addition to those who have received intensive immunosuppression following episodes of acute allograft rejection and finally lung transplant patients . Resistance to Ganciclovir is considered if: persistent or increasing viral load (using either whole blood or plasma) or symptomatic disease after completion of effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir What to do if suspected resistance to Ganciclovir ?first confirm the adequacy of dosing and adherence to treatment plan ,check for gene mutation (UL97 -UL54)
If proved resistant to ganciclovir : Stop Valganciclovir (or Ganciclovir) and offer Intravenous Foscarnet for at least 3 weeks with specialist virology advice.
Immunosuppression dose reduction: Consider dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine and stopping of MMF or azathioprine if there is any evidence of leukopenia. with the clarification of risk of rejection in such a situation .After resolution of CMV infection the doses of immunosuppression should be reviewed . Information, education and support Explain to the patient the risks of CMV infection and disease according to donor / recipient CMV serostatus and the nature of immunosuppression planned or received, also talk to patient about monitoring and treatment options, including prophylaxis
Please reflect on your practice; in our centre we used to – Screen all donors and recipients -We give valganciclovir prophylaxis as recommended by UK guidelines . -Diagnosis of CMV infection or disease by PCR or tissue biopsy. -Treatment is usually oral valganciclovir
**All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation [1A]
**Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation (D+/R-) [1A] OR The recipient has received (ATG) or Alemtuzumab D+/R+ or D-/R+ [1A]
**Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+) [2C].
**Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir [1C]
**should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load [1A]
**pre-emptive therapy to adults, children and young people receiving a solid organ transplant if: They are CMV seropositive (D+/R+, D-/R+) [1B] AND They have not received T-lymphocyte depletion therapy [1B] AND They are not receiving valganciclovir prophylaxis [1B]
**Offer treatment with oral Valganciclovir for a duration of at least 2 weeks [1A]
** 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 [1A]
**In people with suspected resistance to Ganciclovir: 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 [1A] Use either whole blood or plasma [1A]
**In people with evidence of ganciclovir resistance: Stop Valganciclovir (or Ganciclovir) [1A] Offer Intravenous Foscarnet for at least 3 weeks [1B]
**Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine [1C] Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia [2C]
** Symptoms due to primary disease may occur as early as 20 days and are rare more than 50 days post transplantation provided the patient has not received antiviral drugs [. Symptoms may be non-specific, such as fever, night sweats, fatigue and myalgia. Retinitis can be pathognomonic, but is rarely seen in the transplant population. Gastrointestinal disease presenting with diarrhoea, abdominal pain and nausea is common and respiratory distress may be an indication of pulmonary involvement.
**Routine blood tests may detect bone marrow suppression, especially neutropenia, as well as biochemical hepatitis, as evidenced by fluctuations in ALT and AST. After a primary infection an individual would be expected to mount IgM and later an IgG immunoglobulin response against CMV., however, the antibody rise may be delayed or absent.
**(PCR) carried out on plasma, whole blood or leukocytes have become the gold standard means of detecting active CMV replication in many laboratories in the UK
**CMV infection can be coincident with acute allograft rejection Early studies reported a 50% reduction in biopsy-proven acute graft rejection by anti-CMV prophylaxis in D+/R- kidney transplant recipients In a single centre study of 1,339 kidney transplant recipients, multivariate analysis showed that CMV disease appeared to influence long term graft survival but only when coupled with the occurrence of acute rejection
**A more recent publication examined graft outcome in 10,190 kidney transplants performed in adults, children and young people in the UK between 2000-7. After adjustment for donor age, this showed no significant effect of donor or recipient CMV status on either allograft or patient survival at three years post-transplant
**Newer agents such as Letermovir and Maribavir may have a role in prevention of CMV disease Maribavir has Food and Drugs Administration (FDA) approval and is currently being assessed by the National Institute for Health and Care Excellence
**The committee noted that CMV monitoring following cessation of prophylaxis is recommended in other national clinical guidance However, there is no robust evidence that this improves outcomes or reduces the risk of CMV disease
**The committee was satisfied that there is high quality evidence that oral valganciclovir is as effective as intravenous ganciclovir in treating CMV infection and disease following SOT. Most commonly valganciclovir 900mg twice daily has been used as treatment dose, adjusted for level of kidney function.
**Valganciclovir has added advantages of not requiring hospitalisation or intravenous cannulation . However, the committee agreed that intravenous Ganciclovir would be the preferred treatment if concern exists regarding enteric absorption and the subsequent oral bioavailability of medications. The committee also agreed that, in very sick people requiring hospitalisation and other intravenous therapies e.g.; intravenous (i.v.) fluids and antibiotics, i.v ganciclovir should be considered due to a likelihood of impaired absorption.
** recommend using licensed dosing for treatment and prophylaxis from the company with adjustments for renal function made according to the Renal Drug Handbook, using the Cockroft-Gault formula to calculate creatinine clearance. The Renal Drug Handbook also includes information on higher treatment doses
**The committee identified a single small RCT that evaluated pre-emptive treatment with CMV Immunoglobulin (CMV Ig) in 37 recipients of heart transplants, that reported similar efficacy of CMV Ig and intravenous ganciclovir in preventing CMV disease . The committee was not persuaded that this was sufficient to make a recommendation on treatment with CMV Ig. No evidence was identified to support a recommendation on the use of adoptive transfer of cytotoxic T Lymphocytes (CTL) for pre-emptive treatment of CMV. The committee agreed to make research recommendation for both CMVIg and CTL.
2- Please reflect on your practice
THESE GUIDELINES MAKE EASY Decision support system PROGRAM
PROVIDE ADEQUATE Treatment of CMV before it causes any serious problems.
PROVIDE OUR PATIENT WITH INFORMATATION BASED ON BASED EVIDENCE MEDICNE
1. Preventing of CMV infection and disease:
to prevent CMV we should:
Determine donor and recepient CMV status prior to transplantion by screening for CMV IgG antibody.
If the recepient is seronegative an the donor is seropositive give prophylaxis of oral valganciclovir for at least 3 month
Give prophylaxis if the recepient received ATG or alemtuzumab if patient is at risk,
Not recommended to give prophylaxis if both R and D are seronegative unless for other Herpes viruses such as HSV
DOSE need to be adjusted if GFR is less than 60 ml/ minute. Blood count need to be monitored every two weeks when on prophylaxis.
2. lab testing for CMV:
Use either quantitative NAT or whole blood or plasma PCR
3. Treating CMV infection and disease:
Give oral valganciclovir as treatment of coice as it is considered as effective as intravenous ganciclovir unless there is concern regarding enteric absorption
Asses viral load 2 weeks after treatment
Stop treatment if patient is symptom free and have 2 negative PCR
4. Ganciclovir resistance
Some patients are at risk such as those who received long course or subdoses and those who received intensive T cell depleting agents.
The clue to resistance is if patient is still symptomatic or having rising viral load after 2 to 4 weeks of treatment with gan or valganciclovir
If resistant to gancclovir, stop it and offer other s such as foscarnet in collaboration with specialist virology.
5. IS dosecreduction:
considerdose reduction of CNI and antimetabolites
If with leukopenia stop antimetabolites.
Discusssthe possibilityof ARbwith the patient
revise IS doses after resolution of infection
6. Education of patients:
Should receive adequate informations before transplantation according to donor and recepient serodtatus.
Informations about prophylaxis, treatment and need for monitoring
Adequate information about the side effect of medications
The possibility of the need to reduce IS and the accompanying risk of AR.
UK guideline on Prevention and Management of CMV infection and Disease Following Solid Organ Transplantation
Please summarise these guidelines.
1) Preventing CMV
Screening pre-transplant for both donor and recipient for further identification of the high-risk group.
Prophylaxis treatment in a high-risk group (seropositive donor to seronegative recipient and recipient receiving T-lymphocyte depleting agent)
Treatment adjustment if creatine clearance < 60 ml/min
Treat for 3 months
2) Laboratory testing
QNAT
CMV viral load
3) Monitoring CMV/Pre-emptive strategies
Monthly monitoring at least 3 months
In CMV sero-positive recipient and not receiving T-lymphocyte depleting agent
4) CMV management (treatment and immunosuppression reduction)
Treatment at least 2 weeks
Repeat CMV PCR after 2 weeks
Stopped treatment after resolution of symptoms and two consecutive negative PCR
5) Ganciclovir resistance
Risks
prolong course
Subtherapeutic dose
D+/R-
T-cell depletion therapy
Lung transplant
UL97 and UL54 gene mutation testing in patient suspecting ganciclovir resistance
Treament with Foscarnet
Please reflect on your practice.
CMV prophylaxis in a high-risk group (donor seropositive to recipient seronegative and transplant recipient receiving Thymoglobulin as an induction agent.
Those not on prophylaxis will have monthly CMV PCR checked for the first six months.
Those with low-level CMV viremia < 1000 copies/ml will have immunosuppression reduction, while higher levels will be managed by immunosuppression reduction and oral valganciclovir 900 mg BD.
CMV tissue invasive disease required hospital admission and treatment with IV Ganciclovir.
Please summarize these guidelines 1- Preventing CMV Infection and Disease
Determining CMV status in donor and recipient
· Prior to or at the time of transplantation, all organ donors and recipients should be tested for CMV (IgG antibody) serostatus
CMV prophylaxis
· Kidney and liver transplants for at least 3 months following transplantation if either (D+/R-).
· The recipient with Antithymocyte globulin (ATG) or Alemtuzumab (Campath®), (D+/R+ or D-/R+)
Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal, or pancreas transplants for at least 3 months following transplantation if either:
· (D+/R-)
· The recipient with Antithymocyte globulin (ATG) or Alemtuzumab (Campath®), (D+/R+ or D-/R+)
· No need for Valganciclovir prophylaxis in case the donor and recipient are seronegative for CMV (D-/R-).
CMV (D+/R-, D+/R+ or D-/R+) Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection
Adjust the dose of Valganciclovir according to creatinine clearance, and body surface area. Monitoring CBC after 2 weeks and withdraw if there is a drug side effect.
2- Laboratory Testing for CMV· CMV viral load, using the WHO International Reference Standard, as IU/mL or copies / mL, with a conversion factor, induction of treatment is according to local thresholds of viral load.
3- Monitoring for CMV Infection and Disease· Offer monitoring of CMV viral load (at least monthly for least 3 months following TX) to guide if they are CMV seropositive (D+/R+, D-/R+), if they have not received T-lymphocyte depletion therapy and if they are not receiving valganciclovir prophylaxis.
4- Treating CMV Infection and Disease· CMV infection or disease following solid organ transplantation: Valganciclovir for a duration of at least 2 weeks,
· Adjust the dose according to creatinine clearance, being aware of the potential development of ganciclovir resistance.
· Check CMV viral load after 2 weeks of treatment and consider stopping treatment after resolution of symptoms AND two consecutive, CMV viral load tests below the local threshold.
5- Ganciclovir resistance
· In those who have risk factors: received prolonged courses, or sub-therapeutic doses of antivirals (D+/R-), intensive immunosuppression, and lung transplants.
· Suspect resistance to Ganciclovir if there is a persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration
· In this group: Check dosing, compliance, HCMV antiviral resistance, gene mutations, and sample collection.
· Management; Stop Valganciclovir (or Ganciclovir), and Offer Intravenous Foscarnet for at least 3 weeks.
6- Immunosuppression dose reduction
· Dose reduction of either calcineurin inhibitor or mycophenolate mofetil/ Azathioprine.
· If there is evidence of leukopenia preferentially reduce or stop Mycophenolate Mofetil (MMF) or Azathioprine, consent about the possibility of rejection,
· Review immunosuppressive drugs after improvement.
7- Information, education, and support
· Balanced and accurate information about the risks of CMV infection and disease according to donor/recipient CMV serostatus and nature of immunosuppression planned or received
· Monitoring and treatment options, including prophylaxis.
=================================================================== Please reflect on your practice
· In our center, during the evaluation of transplantation, CMV serology is routinely done, and those with high clinical suspicion or patients with positive IgM should do PCR.
· Patients with detectable viral load will be given a treatment dose of valganciclovir arranged according to eGFR.
· According to CMV determinations and immunosuppression inductions, recipients will be stratified into three groups: low, intermediate, and high risk. The intermediate- and high-risk groups were then given 900 mg OD for three months as prophylaxis.
· Follow up clinically and with CBC for side effects.
· PCR monitoring is offered every 2 weeks for this period.
· Patient compliance, drug, and PCR costs remain serious issues to be dealt with.
UK GUIDELINE ON PREVENTION AND MANAGEMENT
OF CYTOMEGALOVIRUS (CMV) INFECTION AND
DISEASE FOLLOWING SOLID ORGAN
TRANSPLANTATION
CMV Screening:
all donors and recipients should be screened / serostatus
if unknown aerostats …..regarded as high risk (D+/R-)
CMV prophylaxis:
giving valganciclovir prophylaxis for both high risk (D+/R-) and moderate risk group (D+/R+ or D-/R+, using ATG or Alemtuzumab & following treatment of acute allograft rejection ) but some time required same prophylaxis for low risk group (D-/R-) for prevention of other types of herpes virus infection
Note:
2 methods of prescription:
1.prophylaxis
2.monitorin & pre-emptive therapy
valaciclovir dosage for adult 900 mg 1×1
for pediatric according to body surface area up to 900 mg (maximum dose)
required dose adjustment when GFR < 60
monitoring full blood count at least every 2 weeks
monitoring for valgancicovir resistance and workup for diagnosis such as genetic testing and planning for second line agents for example foscarnet
co ordination between nephrologist and virologist ….regarding lower doses of immunosuppressive medications
Laboratory Testing for CMV:
QNAT of whole blood or plasma to identify viral load
Summary: Preventing CMV Infection and Disease Determining CMV status in donor and recipient · All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation · If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-). CMV prophylaxis · For adults, children and young people receiving a solid organ transplant: Offer Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either: The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-) · The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath ), where donor: recipient serostatus is D+/R+ or D-/R+ · Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal or pancreas transplants for at least 3 months following transplantation if either: The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-) or The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab, where donor: recipient serostatus is D+/R+ or D-/R+ · Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-) · Be aware that some recipients who are seronegative for CMV (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention of other Herpes virus infections, e.g; recipients who are seronegative for Herpes Simplex Virus (HSV) receiving an organ from HSV seropositive donors. · Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+) [2C]. · Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute · For children and young people under 18 years, adjust the dose of Valganciclovir according to body surface area, up to a maximum dose of 900mg once daily · Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir · Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir
Laboratory Testing for CMV · Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load Transplant centres should adopt a consistent approach to use either whole blood or plasma for quantification of CMV viral load · CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used Monitoring for CMV Infection and Disease · Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if: They are CMV seropositive (D+/R+, D-/R+) and They have not received T-lymphocyte depletion therapy and They are not receiving valganciclovir prophylaxis · Where CMV viral load monitoring is offered: Consider testing with a frequency of at least monthly · Consider testing for at least 3 months following transplantation Treating CMV Infection and Disease For adults, children and young people who develop CMV infection or disease following solid organ transplantation: · Offer treatment with oral Valganciclovir for a duration of at least 2 weeks · Adjust the dose of Valganciclovir according to licensed dosing recommendations if creatinine clearance is less than 60ml/minute · Be aware of the potential development of ganciclovir resistance · Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days · Consider stopping treatment for CMV disease after resolution of symptoms and two consecutive, CMV viral load tests that confirm that CMV is not detected Ganciclovir resistance · Be aware that the following people are 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) · Recipients of lung transplants · 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 Immunosuppression dose reduction For adults, children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation: · Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine · Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia Information, education and support Offer balanced and accurate information to children, adults and young people undergoing solid organ transplantation about: The risks of CMV infection and disease according to donor / recipient CMV
serostatus and nature of immunosuppression planned or received Practice at our setting:
· We screen the donor and recipient pre-transplant.
· We transplant D+/R+ or D-/R+.
· Immediate post transplant ,we start Valgancyclovir prophylaxis for 3-6 months.
Determining CMV status in donor and recipient
All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation and if unknown donner, consider positive.
CMV prophylaxis
Offer Valganciclovir prophylaxis for at least 3 months for (D+/R-) and all R + who received T-lymphocyte depletion therapy with ATG or Campath.
Do not routinely offer Valganciclovir prophylaxis for CMV D-/R-. They may still need it for other reasons like recipients who are seronegative for Herpes Simplex Virus (HSV) receiving an organ from HSV seropositive donors.
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either D or R are +ve.
Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir.
Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir.
Laboratory Testing for CMV
Clinical Laboratories should use consistent Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load. It should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used.
Transplant centres should determine local thresholds of viral load that portend CMV infection or disease requiring treatment, depending on the CMV QNAT assay they use and the population at risk
QNAT thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease.
Monitoring for CMV Infection and Disease
Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if they are CMV seropositive who are not receiving valganciclovir prophylaxis.
Where CMV viral load monitoring is offered: Consider testing with a frequency of at least monthly for at least three months post transplantation.
Treating CMV Infection and Disease
Offer treatment with oral Valganciclovir for a duration of at least 2 weeks and check CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days.
Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, negative PCR. Ganciclovir resistance
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 of Ganciclovir resistance:
– Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications.
– (D+/R-)
– after intensive immunosuppression (e.g; with T-cell depletion therapy, following episodes of acute allograft rejection)
– Lung transplants
In people with suspected resistance to Ganciclovir:
– Confirm that dosing and adherence to treatment and absorption
– Offer testing for Human CMV (HCMV) antiviral resistance UL97 and UL54 gene mutations
– Use either whole blood or plasma
In people with evidence of ganciclovir resistance: Stop Valganciclovir (or Ganciclovir) and Offer Intravenous Foscarnet for at least 3 weeks.
Immunosuppression dose reduction
Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine
Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia
Discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction
Review the dosing of immunosuppression following resolution of CMV infection or disease
********** Reflection:
will review my local trust guidelines for CMV monitoring and treatment post transplant and also review our essay. I will share the guidlines with other colleagues and will consider it in my next presentation in our teaching.
Background
CMV falls under the herpes group of viruses. The infection is more severe when the host is T-cell immunocompromised. After the primary CMV infection, the viral genome enters the monocytes and other bone marrow progenitor cells and enters a latent state.
It is transmitted by direct person-to-person contact through exposure to saliva, urine, breast milk or genital secretions. Its prevalence is reported to increase with age, 40% at age 20 and 80% at 60 years.
In SOT recipients, primary CMV infection occurs approximately 4 to 6 weeks after the transplant, in a seronegative patient who has received a seropositive organ.
Symptoms due to the primary infection occur as early as 20 days after the surgical procedure. Symptoms include night sweats, fatigue, myalgia and rarely retinitis. Diarrhea, abdominal pain, nausea, respiratory distress, bone marrow suppression and hepatitis are also commonly reported.
The presence of IgM is an indicator of primary infection while IgG is used to determine prior infection.
The gold standard test for detecting active CMV replication is based on PCR test carried out on plasma, whole blood or leucocytes. It is sometimes necessary to prove CMV organ specific dysfunction by obtaining a biopsy. CMV infection can also coincide with acute allograft reaction. It has been shown that CMV infection appears to influence long-term graft survival. Universal anti-CMV prophylaxis and pre-emptive anti-CMV therapy are currently in common use to minimize the impact of CMV infection or reactivation. Treatment of CMV disease involves reduction of immune suppression and administering specific antiviral therapy. Ganciclovir is usually the anti-viral of choice. Viral load quantification has been used to assess the response to treatment. UL97 and UL54 gene mutations can be detected by genotypic assays, which is useful to assess for resistance to ganciclovir. Cidofovir and foscarnet can be potentially used as 2nd or 3rd line treatment options.
Rationale for clinical practice recommendations for the prevention & management of CMV following SOT Preventing CMV infections & disease All organ donors and recipients should be screened for the serostatus prior to transplantation
Vanganciclovir prophylaxis should be offered to patients receiving kidney or liver transplant for at least 3 month after the transplant if:
The recipient is seronegative and receives a seropositive organ
The recipient has received T-lymphocyte depletion therapy, and their serostatus is positive.
Vanganciclovir prophylaxis should also be offered to lung, heart, intestinal or pancreas transplant recipients for 3 months after transplantation if:
The recipient is seronegative and receives a seropositive organ
The recipient has received T-lymphocyte depletion therapy, and their serostatus is positive.
If both the donor and the recipient are seronegative, they do not require prophylaxis
The dose of vanganciclovir requires renal dose adjustment.
Laboratory testing for CMVIt is recommended that QNAT should be used on blood or plasma to quantify CMV viral load.
Monitoring CMV infection and diseaseCMV viral load should be monitored to guide pre-emptive therapy for patients receiving a SOT if:
The recipient is seropositive
The recipient has not received T-lymphocyte depletion therapy
The recipient is not receiving vanganciclovir prophylaxis
Viral load can be tested monthly for at least 3 months after transplantation.
Treating CMV infection and disease For patients with CMV infection after SOT, it is recommended to treat with vanganciclovir for at least 2 weeks.
The dose should be reduced if creatinine clearance is less than 60mL/minute. Resistance to ganciclovir should be monitored.
Viral load should be assessed 2 weeks after treatment and repeated every 7 days.
The treatment should be stopped if 2 consecutive viral load tests do not detect CMV.
Ganciclovir resistance Patients at increased of ganciclovir resistance include:
Patients who have received prolonged courses or subtherapeutic doses of the medication
CMV seronegative recipients of seropositive organs
Patients who have received intensive immune suppression
Lung transplant recipients
Resistance to ganciclovir should be considered if there is a persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration.
In patients with suspected resistance to ganciclovir:
Confirm that the dosing is adequate, and there is adherence to treatment
Offer testing for ganciclovir resistance.
In patients with evidence of ganciclovir resistance, stop the valganciclovir or ganciclovir, and offer foscarnet after consulting the virology specialist.
Immune suppression dose reductionFor patients who develop CMV infection, consider reduction of immune suppression of either calcineurin inhibitor or MMF/azathioprine
It is important to discuss the risk of acute rejection with immune suppression reduction with the patients
Immune suppression dosage can be adjusted after the completion of the treatment.
Information, education and support It is important to offer information regarding the risks of CMV infection and disease to the donor and the recipient. They should also know of the management plan, treatment options and prophylaxis.
It is also important that the health care providers that are offering the information have specialist knowledge.
Local Practice:
Due to the high cost of valganciclvoir and patients paying out of pocket, we in Kenya do active surveillance and pre-emptive treatment if we find CMV disease. It is cheaper than offering universal prophylaxis to all kidney transplant recipients for three months
1. Please summarise these guidelines 1 Preventing CMV Infection & Disease
1.1 CMV (IgG antibody) testing done on all organ donors & recipients. [1A]
1.2 Donor seropositive, recipient seronegative for CMV (D+/R-) used to describe the situation when the donor’s CMV serostatus is unknown & the recipient is sero-negative or unknown for CMV. [1D] CMV prophylaxis
For all SOTs:
1.3 Valganciclovir to recipients of kidney & liver TXs for at least 3 months after if either: D+/R- [1A] OR
ATG or Alemtuzumab has been given to the recipient, where the donor: recipient serostatus is D+/R+ or D-/R+ [1A]
1.4 Valganciclovir for people receiving heart, lung, intestinal or pancreas TXs for at least 3 months if either:
D+/R-. OR
D+/R+ or D-/R+ after ATG or Alemtuzumab. [1C]
1.5 If CMV D-/R-, do not routinely give Valganciclovir prophylaxis [1D].
1.5.1 Some receivers who are D-/R- seronegative may need Valganciclovir or Valaciclovir to prevent the spread of other Herpes viruses, such as recipients who are HSV sero-negative but get an organ from HSV seropositive donors [2D]. 1.6 Valganciclovir for at least 3 months after starting treatment for AR if D+/R-, D+/R+ or D-/R+ [2C]. 1.7 Valganciclovir dose adjusted if creatinine clearance is < 60ml [1D] 1.8 In children & <18 years, the dose of Valganciclovir according to BSA [1D] 1.9 Monitor FBC at least every 2 weeks [1A]
1.10 CMV monitoring & pre-emptive therapy if S/Es e.g.; neutropenia, on Valganciclovir [1C] 2 Laboratory Testing for CMV 2.1 QNAT to quantify CMV viral load [1A] Either whole blood or plasma for quantification [1C] Calibrate assays using the WHO IRS [1C] CMV viral load reported as IU/mL or as copies / mL [1C] 2.2 Local thresholds of viral load determined for CMV infection or disease requiring treatment [1C]
2.3 QNAT thresholds not used in isolation to decide start or cessation of treatment [1C] 3 Monitoring CMV Infection & Disease 3.1 Offer monitoring of CMV viral load if: D+/R+, D-/R+ [1B] AND T-lymphocyte depletion therapy has not been given. [1B] AND They are not receiving valganciclovir prophylaxis [1B] 3.2 When monitoring CMV viral load: Testing at least monthly for at least 3 months following transplantation [1D] 4 Treating CMV Infection & Disease 4.1 Oral Valganciclovir for at least 2 weeks [1A] 4.2 Adjust the dose if creatinine clearance is < 60ml [1D] 4.3 Keep in mind ganciclovir resistance 4.4 After 2 weeks of treatment, reassess viral load at a minimum 7-day interval. [1D] AND After symptoms have cleared AND 2 consecutive viral load tests are –ve, stop therapy. [2D]. 5 Ganciclovir resistance 5.1 Increased risk of Ganciclovir resistance: If prolonged courses, or sub-therapeutic doses [1A] If D+/R- [1C] If intensive IS (e.g; with T-cell depletion therapy for AR) [1B] Recipients of lung TXs [2C] 5.2 Consider resistance if: Persistent or increasing viral load or symptomatic disease after effective dosage & duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir [1A] 5.3 In case of resistance: Confirm adequacy of dosing Consider adherence & absorption Antiviral resistance testing [1A] 5.4 In evidence of resistance: Stop Valganciclovir (or Ganciclovir) [1A] Give IV Foscarnet for at least 3 weeks [1B]
Virologist consultation before starting Foscarnet[1D]
6 IS dose reduction
Reduce either CNI or MMF / Aza [1C]
Reduce or stop MMF or Aza if there is leukopenia [2C]
Discuss with patients the risk of AR with dose reduction [1D]
Review the dosing after resolution of CMV infection or disease [1D]
7 Information, education & support Offer information about:
The risks of CMV infection and disease according to serostatus & nature of IS
Monitoring & treatment options, including prophylaxis
Make sure that healthcare providers who give information has in-depth understanding about CMV infection, illness, & therapy.
Executive Summary of Research Recommendations
In adults, children & young people receiving SOT:
What are the clinical & financial benefits of anti-CMV prophylaxis for recipients for at least 3 months after TX compared to active surveillance (monitoring followed by pre-emptive therapy)?
In comparison to active surveillance (monitoring followed by preventive therapy) following CMV infection or disease treatment, how clinically & financially successful is anti-CMV prophylaxis?
How often & for how long should CMV viral load monitoring be done?
How beneficial is CMV viral load monitoring clinically & financially after stopping anti-CMV prophylaxis?
How clinically & economically beneficial is CMV viral load monitoring once CMV infection or disease therapy is finished?
How clinically & economically beneficial is CMV immune monitoring?
How clinically & economically effective is the CMV viral load (QNAT) test for determining when to stop treating CMV infections & diseases?
Is a decrease in CNIs or MMF/AZA related with better outcomes (with or without leukopenia) after SOT?
In the treatment of severe, resistant, or refractory CMV disease, how successful are CMV-specific IGs & CMV-specific cytotoxic T cells clinically & economically?
What is the most accurate formula for calculating the dosage of Valganciclovir based on body surface area?
Executive Summary of Audit Measures
The percentage of SOT recipients who are provided Valganciclovir prophylaxis based on the CMV profiles & their use of T-cell depletion therapy as described in guideline 1.3
The percentage of clinical laboratories that measure the CMV viral load utilizing QNAT on blood or plasma
Proportion of CMV QNAT assays calibrated using the WHO IRS.
Proportion of adults, children & young people characterised in recommendation3.1 who are offered monthly CMV viral load monitoring for 3 months following SOT
Proportion of adults, children & young people who are offered Valganciclovir to treat CMV infection & disease following SOT
Proportion of adults, children & young people with Ganciclovir resistance tested for mutations.
Proportion of adults, children & young people who develop CMV infection or disease (with or without leukopenia) following SOT, & who reduce or stop CNIs & / or MMF/AZA
============================== 2. Please reflect on your practice
In our center, we are doing kidney transplants for adults only.
CMV (IgG antibody) testing is done for all donors & recipients as per the current guidelines.
We are offering Valganciclovir for at least 3 months only if ATG is used for induction therapy. For all other recipients, we offer acyclovir for six months.
We do not routinely monitor CMV due to financial issues.
We treat CMV infection & disease using Valganciclovir or Ganciclovir.
Ganciclovir resistance testing is not available in our centers.
All organ donors and recipients should be screened for CMV serostatus prior to, or at the time of transplantation . If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-).
CMV prophylaxis
Valganciclovir prophylaxis should be offered to people receiving kidney and liver transplants for at least 3 months following transplantation if-
D+/R-
D+/R+ or D-/R+
Acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+)
Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-)
Adjust dose according to creatinine clearance
For lesser age groups – adjust dose according to body surface area.
Watch Full Blood Count at least every 2 weeks during treatment
Consider pre emptive therapy if neutropenia develops.
Laboratory Testing
CMV QNAT assays should be calibrated using the WHO International Reference Standard
Viral load should be reported as IU/mL
Transplant centres should determine local thresholds of viral load
QNAT thresholds should not be used in isolation but clinical and pathological context should be considered.
Monitoring for CMV Infection and Disease
Offer monitoring of CMV viral load if-
D+/R+, D-/R+
If not received T-lymphocyte depletion therapy
If not receiving valganciclovir prophylaxis
Treating CMV Infection and Disease
Oral Valganciclovir for a duration of at least 2 weeks
Dose adjustment if creatinine clearance is less than 60 ml/m
Watch for Drug resistance
Stop treatment after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is negative.
Ganciclovir Resistance
High risk Groups-
Those receiving prolonged courses, or sub-therapeutic doses are at high risk of resistance.
D+/R-
Those received intensive immunosuppression
Recipients of lung transplants
If resistance id confirmed then Confirm that dosing is adequate .
Consider adherence to treatment plan and absorption and offer testing for Human CMV (HCMV) antiviral resistance UL97 and UL54 gene mutations
Offer Intravenous Foscarnet for at least 3 weeks
Reduce immune suppression
Reflection on my local practice
We follow UK guidelines
We routinely check CMV IgM and IgG during transplant workup for both donor and recipient
CMV is one of the herpes group of viruses, widely distributed among mammals. The various strains of CMV are species specific and primary infection results in the most severe disease when the host is T-cell immunocompromised.
The viral genome enters monocytes and other bone marrow progenitor cells and enters a latent state.
The prevalence of antibody indicating previous infection increases with age (40% at age 20 and 80% at age 60).
Transmission occurs from direct person-to-person contact through exposure to saliva, urine, breast milk or genital secretions.
CMV in Solid Organ Transplant Recipients
Primary infection with CMV typically occurs approximately four to six weeks post-transplant in a seronegative individual who receives a seropositive organ.
Symptoms may be non-specific, such as fever, night sweats, fatigue, myalgia, diarrhoea, abdominal pain, nausea, and rarely Retinitis (pathognomonic). Routine blood tests may detect bone marrow suppression, especially neutropenia, and biochemical hepatitis, as evidenced by fluctuations in ALT and AST.
Donor: recipient CMV serostatus is characterised as:
1. Donor (D) positive (+); Recipient (R) positive (+) (D+/R+)- Risk of superinfection or reactivation. 2. Donor (D) negative (-); Recipient (R) negative (-) (D-/R-)- Risk of primary infection from other source. 3. Donor (D) positive (+); Recipient (R) negative (-) (D+/R-)- Risk of primary infection. 4. Donor (D) negative (-); Recipient (R) positive (+) (D-/R+)- Risk of reactivation of latent infection.
Preventing CMV infection and disease:
Determining CMV status in donor and recipient All donor and recipient should be screened for CMV IgG before transplantation. If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be CONSIDERED donor +ve, recipient -ve for CMV (D+/R-).
CMV prophylaxis
Offer Valganciclovir prophylaxis to people receiving solid organ transplants for at least 3 months following transplantation if either:
The (D+/R-) [1A].
The (R) has received T-lymphocyte depletion therapy with (ATG) or Alemtuzumab, D+/R+ or D-/R+ [1A].
After starting treatment for acute allograft rejection whatever the serostatus (D+/R-, D+/R+ or D-/R+) [2C].
Do not routinely offer Valganciclovir prophylaxis if (D-/R-) for CMV [1D].
Some recipients who are (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention of other Herpes virus infection, e.g; recipients who are seronegative for Herpes Simplex Virus (HSV) receiving an organ from HSV seropositive donors [2D].
Valganciclovir dose adjustment if creatinine clearance is less than 60ml/minute [1D].
For children and young people under 18 years, adjust the dose of Valganciclovir according to body surface area, up to a maximum dose of 900mg once daily [1D].
Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir [1A].
Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir [1C].
Laboratory Testing for CMV
Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load [1A]
Transplant centres should adopt a consistent approach to use either whole blood or plasma for quantification of CMV viral load [1C].
CMV QNAT assays should be calibrated using the WHO International Reference Standard [1C].
CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used [1C]
Transplant centres should determine local thresholds of viral load that portend CMV infection or disease requiring treatment, depending on the CMV QNAT assay they use and the population at risk [1C].
QNAT thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease [1C].
Monitoring for CMV Infection and Disease Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if:
They are CMV seropositive (D+/R+, D-/R+) [1B] AND They have not received T-lymphocyte depletion therapy [1B] AND They are not receiving valganciclovir prophylaxis [1B]
Where CMV viral load monitoring is offered:
Consider testing with a frequency of at least monthly, for at least 3 months following transplantation [1D].
Treating CMV Infection and Disease For adults, children and young people who develop CMV infection or disease following solid organ transplantation:
Offer treatment with oral Valganciclovir for a duration of at least 2 weeks [1A].
Adjust the dose of Valganciclovir according to licensed dosing recommendations if creatinine clearance is less than 60ml/minute [1D].
Be aware of the potential development of ganciclovir resistance.
Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days [1D] AND
Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected [2D].
Ganciclovir resistance Be aware that the following people are at increased risk of Ganciclovir resistance:
Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications [1A].
CMV seronegative recipients receiving a solid organ transplant from seropositive donors (D+/R-) [1C].
Those who have received intensive immunosuppression (e.g; with T-cell depletion therapy, following episodes of acute allograft rejection) [1B].
Recipients of lung transplants [2C]
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 [1A].
In people with suspected resistance to Ganciclovir:
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 [1A].
Use either whole blood or plasma [1A].
In people with evidence of ganciclovir resistance:
Stop Valganciclovir (or Ganciclovir) [1A].
Offer Intravenous Foscarnet for at least 3 weeks [1B].
Seek specialist virology advice before commencing treatment with Foscarnet [1D].
Immunosuppression dose reduction For adults, children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation:
Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine [1C] Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia [2C]
Discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction [1D]
Review the dosing of immunosuppression following resolution of CMV infection or disease [1D].
Information, education and support Offer balanced and accurate information to children, adults and young people undergoing solid organ transplantation about:
The risks of CMV infection and disease according to donor / recipient CMV serostatus and nature of immunosuppression planned or received 6/38 Monitoring and treatment options, including prophylaxis.
Ensure that healthcare professionals offering information have specialist knowledge about CMV infection and disease and their treatment, and the skills to support shared decision-making.
Please reflect on your practice
We perform CMV serology for both donor and recipient, just before transplantation.
In our practice we offer ganciclovir prophylaxis for at least 3 months if :
D+/R+, D-/R+.
And prophylaxis for 6 months to D+/R-.
We do not do preemptive screening in our center.
Diagnosis by serum or tissue PCR is available, and target our treatment.
We use to give IV ganciclovir for the first 5-7 days followed by oral valgancyclovir for total 14 days, we do follow up PCR in the first week and at the end of treatment at 2 weeks. then we put the patient on prophylaxis dose for 6 months.
( in this issue we learnt a lot for the UK guidelines for better management and cost-effectiveness in treatment plan) – our approach may increase the risk of resistant strains of CMV
Response to Rx= by clinical and laboratory testing and negative CMV PCR.
Introduction
CMV belongs to herpes group of viruses, which are widely distributed among mammals. The primary infection results in the most severe disease when the host is T-cell immunocompromised. After primary CMV infection, the viral genome enters monocytes and other bone marrow progenitor cells and enters a latent state.
Primary infection typically occurs approximately four to six weeks posttransplant in a seronegative individual who receives a seropositive organ provided the patient has not received antiviral drugs. clinical presentation is non-specific, and include either systemic manifestations like fever, night sweats, fatigue and myalgia. Or local presentation according to the target organ affection i.e GIT, respiratory etc.
· Serology is used for identify the donor and recipient CMV status
· PCR of the whole blood or plasma is used to measure viral load during active infection follow up of treatment assessment of remission or treatment resistance
· Tissue biopsy is indicated in case of suspected target organ affection Evaluation of donor and recipient for CMV status
All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation Note: If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be considered as donor seropositive, recipient seronegative for CMV (D+/R-). CMV prophylaxis For adults, children and young people receiving a solid organ transplant:
Consider Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either:
· The recipient is seronegative for CMV and donor is seropositive (D+/R-)
OR
· The recipient has received induction immunosuppression with T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath ), where donor: recipient serostatus is D+/R+ or D-/R+.
· Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-).
· in case of suspicion of other Herpes virus infections in recipients who are seronegative for CMV (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention
· In case of starting treatment for acute allograft rejection if either donor or recipient are CMV positive, Consider Valganciclovir prophylaxis for at least 3 months. Adjustment of the dose of Valganciclovir
· Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute and For children and young people under 18 years, body surface area should be used to adjust the dose of Valganciclovir and it should not exceed a dose of 900mg once daily. Monitoring of Valganciclovir treatment
· Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir and Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir. Laboratory Testing for CMV
1 Use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma (according to the transplant center policy) to quantify CMV viral load
2 The WHO International Reference Standard should be used to calibrate CMV QNAT assays
3 CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used.
4 Transplant centers should determine local thresholds of viral load that exactly define CMV infection or disease requiring treatment, depending on the CMV QNAT assay they use and the population at risk
5 Starting or withdrawal of treatment should depend on clinical, laboratory or histological evidence of CMV disease. 3- Monitoring for CMV Infection and Disease
Indicated if:
· They are CMV seropositive (D+/R+, D-/R+) AND they have not received T-lymphocyte depletion therapy AND They are not receiving valganciclovir prophylaxis.
· frequency of monitoring is at least monthly and for a duration for at least 3 months following transplantation 4- Treatment of CMV Infection and Disease For adults, children and young people who develop CMV infection or disease following solid organ transplantation: A- Antiviral
consider treatment with oral Valganciclovir for at least 2 weeks.
the dose of Valganciclovir should be adjusted if creatinine clearance is less than 60ml/minute and observe closely for ganciclovir resistance.
Frequency of monitoring of CMV viral load is: 2 weeks of treatment and should be repeated at a minimum interval of 7 days. When to stop treatment
Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected (below the local laboratory threshold for detection). Ganciclovir resistance
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
patient medication compliance has been ensured.
Factors that increase the risk of Ganciclovir resistance:
· 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)
· Recipients of lung transplants.
· Evaluation for suspected resistance to Ganciclovir:
· good history taking to Confirm that dosing is adequate Consider adherence to treatment plan and absorption
· consider UL97 and UL54 gene mutations management of ganciclovir resistance:
· Stop Valganciclovir (or Ganciclovir).
· Seek specialist virology advice before commencing treatment with Intravenous Foscarnet for at least 3 weeks. B- Immunosuppression modulation
· 6.1 Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine.
· Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia.
· Share the management plan with the patient explaining the risk /benefit especially the risk of acute rejection with the reduction of Immunosuppression
· following resolution of CMV infection or disease, dosing of immunosuppression should be reevaluated according to the risk benefit ratio patient education
· importance of viral screening pretransplantation
· prophylaxis if indicated
· frequency and duration of lab evaluation after transplantation
· risk assessment upon modulation of immunosuppression
Determining CMV status in donor and recipient
All donors and recipients should be screened for CMV (IgG antibody) prior to, or at the time of transplantation.
If donor serostatus is unknown and recipient is seronegative or unknown, this should be characterised as donor seropositive, recipient seronegative (D+/R-). CMV prophylaxis
Offer Valganciclovir prophylaxis to solid organ transplants recipient for at least 3 months following transplantation if the recipient is seronegative and receives an allograft from seropositive donor or the recipient is seropositive and has received T-lymphocyte depletion therapy with ATG or Alemtuzumab.
Do not routinely offer prophylaxis if donor and recipient are seronegative for. Unless the recipients is seronegative for Herpes Simplex Virus and received an organ from HSV seropositive donors.
Consider prophylaxis for at least 3 months after treatment for rejection if donor or recipient are CMV positive.
Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute.
For children and people under 18 years, adjust the dose of Valganciclovir according to body surface area.
Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir.
Switching to monitoring and pre-emptive therapy in case of side effects e.g., neutropenia, on Valganciclovir. Laboratory Testing for CMV
Transplant centres should adopt a consistent approach to use either whole blood or plasma for quantification of CMV viral load.
CMV assays should be calibrated using the WHO International Reference Standard.
CMV viral load should be reported as IU/mL, or, if reported as copies / mL, a conversion factor should be used.
Transplant centres should determine local thresholds of viral load that portend treatment.
QNAT thresholds should be used in conjugation with clinical, laboratory or histological evidence of CMV disease. Monitoring for CMV Infection and Disease
Monitor viral load to guide pre-emptive therapy if patients are seropositive, they have not received T-lymphocyte depletion therapy and are not receiving valganciclovir prophylaxis
Consider monitoring at least monthly for at least 3 months following transplantation.
Treating CMV Infection and Disease
Offer treatment with oral Valganciclovir for at least 2 weeks.
Adjust the dose if creatinine clearance is less than 60ml/minute.
Be aware of the potential development of ganciclovir resistance.
Assess CMV viral load 2 weeks after treatment and repeat at a minimum interval of 7 days.
Stop treatment after resolution of symptoms and two consecutive, undetectable viral loads.
Ganciclovir resistance
People are at increased risk of Ganciclovir resistance:
Following prolonged courses, or sub-therapeutic doses of antiviral medications.
Seronegative recipients receiving a transplant from seropositive donors.
Patients received intensive immunosuppression (e.g., with T-cell depletion therapy, following acute allograft rejection).
Lung transplants recipients.
Consider resistance to Ganciclovir if there is a persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration of Ganciclovir or Valganciclovir.
In people with suspected resistance:
Confirm that dosing is adequate
Consider adherence to treatment and absorption
Offer testing for Human CMV antiviral resistance
UL97 and UL54 gene mutations
In people with evidence of ganciclovir resistance:
Stop Valganciclovir (or Ganciclovir).
Offer Intravenous Foscarnet for at least 3 weeks after discussion with virology specialist. Immunosuppression dose reduction
Consider a dose reduction of either CNI or antimetabolite.
Preferentially reduce or stop antimetabolite if there is leukopenia.
Discuss with patients, parents or carers, the risk of rejection with immunosuppression reduction.
Review the dosing following resolution of CMV infection or disease.
Information, education and support
Offer patients information about the risks of CMV infection, Prophylaxis, Monitoring and treatment.
Support shared decision-making
In our centre we give prophylaxis with Valgancilcovir for 6 months to all patient except D-/R-.
Introduction
*This is UK (British Transplantation Society) guidelines on prevention and management of cytomegalovirus (CMV) infection and disease following solid organ transplantation, April 2022
*CMV is a member of the herpes family
*The prevalence of previous infection (positive IgG antibody) increases with age (40% at age 20 and 80% at age 60)
*Mode of transmission: saliva, urine, breast milk or genital secretions
*In D+/R- primary infection occurs 4-6 weeks posttransplant
*PCR of plasma, whole blood or leukocytes is the gold standard test for active CMV replication
*Biopsy of organ dysfunction can be diagnostic [Liver, GI, bone marrow, lung and renal allograft]
*Late-onset CMV disease: CMV disease occurs after cessation of antiviral drug in patients on antiviral prophylaxis (D+ / R-). It is associated with allograft failure and mortality
Antiviral drug Resistance: progressive disease despite full dose anti-viral therapy, or a static or increasing viral load after drug treatment (not first week)
Definitions CMV infection: complete replication cycle of the virus
1. Asymptomatic
2. Viral syndrome ((fever, leucopenia, myalgia or arthralgia)
3. CMV disease: (histopathological evidence of CMV, CMV retinitis, or CMV in the CSF) Latent CMV: no full replication cycle of the virus
CMV prophylaxis
*All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation [1A]
*If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-). [1D]
*Donor CMV serostatus should be within 30 days of organ donation
*Give Valganciclovir prophylaxis for at least 3 months if D+/R- or recipient received ATG or Alemtuzumab where D+/R+ or D-/R+ [1A]
*No prophylaxis if D-/R- [1D]. May be given for other other Herpes (HSV) [2D]
*Offer prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either (D+/R-, D+/R+ or D-/R+) [2C]
*Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute [1D]
*For children and young people under 18 years, adjust the dose of Valganciclovir according to body surface area, up to a maximum dose of 900mg once daily [1D]
*Monitor CBC at least every 2 weeks whilst on Valganciclovir [1A]
Switch to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir [1C]
Laboratory Testing for CMV
*Use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load [1A]. Use the WHO International Reference Standard for QNAT [1C]. Viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used [1C]
*Higher levels of CMV viral load have been reported when whole blood rather than plasma is used for QNAT testing
*Transplant centres should determine local thresholds of viral load that requiring treatment [1C]
*QNAT thresholds should not be used alone to determine commencement or cessation of treatment, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease [1C] Monitoring of CMV Infection and Disease
Offer monitoring of CMV viral load to guide pre-emptive therapy if:
1. (D+/R+, D-/R+) [1B] AND
2. They have not received T-lymphocyte depletion therapy [1B] AND
3. They are not receiving valganciclovir prophylaxis [1B]
Where monitoring is offered:
1. Do the test at least monthly [1D]
2. Consider testing for at least 3 months following transplantation [1D] Treatment of CMV Infection and Disease
*Offer treatment with oral Valganciclovir for a duration of at least 2 weeks [1A]
Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute [1D]
*Intravenous Ganciclovir if concern exists regarding enteric absorption
*Treatment for 2 weeks is associated with a viraemia reduction of approximately 90%
Be aware of of ganciclovir resistance
*Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days [1D] AND
*Stop treatment after resolution of symptoms AND two consecutive, negative tests for CMV viral load [2D] Ganciclovir resistance
*CMV disease that is refractory to treatment with Ganciclovir or Valganciclovir and is reported to occur in up to 3% of SOT recipients
Risk of Ganciclovir resistance:
1. Prolonged antiviral courses, or subtherapeutic antiviral dosing [1A]
2. (D+/R-) [1C]
3. Intensive immunosuppression (e.g; with T-cell depletion therapy, following episodes of acute allograft rejection) [1B]
4. Recipients of lung transplants [2C]
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 [1A]
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 [1A]. Use either whole blood or plasma [1A]
When there is evidence of ganciclovir resistance:
1. Stop Valganciclovir (or Ganciclovir) [1A]
2. Offer Intravenous Foscarnet for at least 3 weeks [1B]. Seek specialist virology advice before commencing treatment with Foscarnet [1D]
Newer agents Letermovir and Maribavir may be associated with less drug toxicity
Maribavi has FDA approval and is currently being assessed by the NICE
Immunosuppression dose reduction
If recipient developed CMV infection or disease (with or without leukopenia):
1. Reduce the dose of CNIs or MMF / azathioprine [1C]. Reduce or stop MMF or azathioprine if there is leukopenia [2C]
2. Discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction [1D]
3. Review the dosing of immunosuppression following resolution of CMV infection or disease [1D]
There is low quality evidence that conversion to an mTOR-inhibitor may provide some protection against recurrent CMV (insufficient to recommend conversion to an mTORinhibitor during or following CMV infection or disease)
Information, education and support
Offer balanced and accurate information about:
1. The risks of CMV infection and disease according to donor / recipient CMV serostatus and nature of immunosuppression planned or received
2. Monitoring and treatment options, including prophylaxis
Ensure that healthcare professionals should have specialist knowledge about CMV infection and disease and the skills to support shared decision-making
Please reflect on your practice
We do not give prophylaxis (most patients are D+/R+). Management depends on clinical suspicion, viral load, and histopathology. We give valganciclovir for treatment. No viral load monitoring. No post transplant survey and pre-emptive treatment
1.Please summarise these guidelines
-CMV is one of the herpes group of viruses, which are widely distributed among mammals.The various strains of CMV are species specific and primary infection results in the most severe disease when the host is T-cell immunocompromised.
-The prevalence of antibody indicating previous infection increases with age .
– Transmission occurs from direct person-to-person contact through exposure to saliva, urine, breast milk or genital secretions.
-CMV infection: evidence of the virus undergoing a complete replication cycle and producing new infectious virions. This may be further characterized as:
1.Asymptomatic infection (no obvious signs of pathologic symptoms)
2.Viral syndrome (fever, leucopenia, myalgia or arthralgia)
3.CMV disease – (histopathological evidence of CMV, CMV retinitis diagnosed by an ophthalmologist, or CMV in the CSF indicative of CNS disease)
Latent CMV: A state of virus infection in which the full replication cycle of the virus is not occurring Preventing CMV Infection and Disease
Determining CMV status in donor and recipient
– All organ donors and recipients should be screened for CMV (IgG antibody)serostatus prior to, or at the time of transplantation . CMV prophylaxis
For adults, children and young people receiving a solid organ transplant:
-Offer Valganciclovir prophylaxis to people receiving SOT (kidney, liver, heart, lung, intestinal or pancreas transplants) for at least 3 months following transplantation if either:
1.The recipient is seronegative for CMV and donor CMV seropositive .
2.The recipient has received T-lymphocyte depletion therapy with ATG or Alemtuzumab, where donor: recipient serostatus isD+/R+ or D-/R+.
-Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir .
– Do not routinely offer Valganciclovir prophylaxis if donor and recipient areseronegative for CMV .
-Some recipients who are seronegative for CMV (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention of other Herpes virus infections.
-Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive .
-Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute .
-Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir . Laboratory Testing for CMV
-Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load.
-CMV QNAT assays should be calibrated using the WHO International Reference Standard .
-CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used .
-Transplant centres should determine local thresholds of viral load that portend CMV infection or disease requiring treatment, depending on the CMV QNAT assay they use and the population at risk .
-QNAT thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease. Monitoring for CMV Infection and Disease
-Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if:
1.They are CMV seropositive .
2.They have not received T-lymphocyte depletion therapy .
3.They are not receiving valganciclovir prophylaxis.
– Where CMV viral load monitoring is offered??
1.Consider testing with a frequency of at least monthly .
2.Consider testing for at least 3 months following transplantation. Treating CMV Infection and Disease
-Offer treatment with oral Valganciclovir for a duration of at least 2 weeks .
-Adjust the dose of Valganciclovir according to licensed dosing recommendations if creatinine clearance is less than 60ml/minute.
-Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days .
-Stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected . Ganciclovir resistance
-Following people are at increased risk of Ganciclovir resistance:
1.Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications .
2.CMV seronegative recipients receiving a solid organ transplant from seropositive donors .
3.Those who have received intensive immunosuppression .
4.Recipients of lung transplants . 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. In people with suspected resistance to Ganciclovir:
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 . In people with evidence of ganciclovir resistance:
1.Stop Valganciclovir (or Ganciclovir).
2.Offer Intravenous Foscarnet for at least 3 weeks.
3.Seek specialist virology advice before commencing treatment with Foscarnet. Immunosuppression dose reduction
-Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil /azathioprine.
-Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) orazathioprine if there is evidence of leukopenia .
-Discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction [1D]
-Review the dosing of immunosuppression following resolution of CMV infection or disease . Information, education and support
-The risks of CMV infection and disease according to donor / recipient CMV serostatus and nature of immunosuppression planned or received Monitoring and treatment options, including prophylaxis
-Ensure that healthcare professionals offering information have specialist knowledge about CMV infection and disease and their treatment, and the skills to support shared decision-making. 2.Please reflect on your practice
-In our center,we screen the donor and recipient pre-transplant.
-We transplant D+/R+ or D-/R+.
-Post transplant ,we start prophylaxis CMV therapy.
Preventing CMV infection
CMV serostatus of donor and recipient should be known prior to transplantantion, if not should be assumed to be D+/R-.
Should be done donor at retrieval of organ, recipient while on the waiting list.
Prophylaxis
Valganciclovir should be offered for at least 3 months after SOT to:
D+/R-
D-/R+ or D+/R+ and received T lymphocyte depleting agent (ATG/Alemtuzumab)
After treatment for acute rejection
D-/R- no need for prophylaxis.
Renal dose when serum creatinine clearance <60ml/min.
CBC monitoring should be done every 2 weeks when on valganciclovir.
Switch to CMV monitoring and preemptive therapy when there are side effects.
Recipients who receive prophylaxis are at high risk of late onset CNV disease which is associated with allograft failure and mortality.
Laboratory testing.
Transplant centers should have a standardise way of CMV viral load quantification using either whole blood or serum. A threshold should also be set by the centre that portends treatment or infection.
CMV viral load should be interpreted with clinical, laboratory, or histological evidence of disease to determine commencement or cessation of treatment.
CMV monitoring
Should be done to guide preemptive therapy in D+/R+ OR D-/R+ and they didn’t receive either prophylaxis or T cell depleting agent induction therapy.
Treatment
Oral valganciclovir should be given for 2 weeks.
Repeat CMV viral load after the 2 weeks then on 7 days interval.
Stop treatment when 2 consecutive CMV viral loads are below threshold and there is resolution of symptoms.
There is a high risk of relapse after successful treatment.
No role of secondary prophylaxis.
Ganciclovir resistance
Recipients at risk:
Received prolonged or sub therapeutic doses of ani-virals
Received intensive immunosuppression.
Lung transplant recipients.
D+/R-
When to consider?
Persistent or increasing viral load or symptoms despite effective dosage and duration.
However recipients with high viral load prior to treatment are likely to have increasing viral loads 5-7 days after treatment before it declines.
What to do?
Confirm dosing and adherence.
Offer testing for human CMV resistance on either blood or plasma.
Test for mutations UL54 /UL97.
How to treat?
Stop the valganciclovir.
Give iv forscanet for 3 weeks.
Forscanet is nephrotoxic and causes electrolyte imbalance.
Marabavir showing promise in clinical trials for treatment of resistance.
Immunosuppression reduction
Reduce dose of CNI or antimetabolite.
Preferentially reduce or withdraw antimetabolite if they have leucopenia.
My practise
We routinely do recipients and donor serostatus prior to transplantation.
Most are D+/R+.
We don’t routinely give prophylaxis after transplant for we are in a low resource setup.
Treatment is done based on clinical presentation + viral load ± histological evidence.
We treat with valganciclovir.
We don’t routinely do viral loads to monitor response to treatment.
Primary CMV infection occur in organ transplant in 4 to 6 weeks post transplant.
Presence of high titer IgM and low IgG level indicates primary infection. CMV infection characteristic in organ transplant is:
Donor: recipient CMV serostatus is characterised as:
1. Both donor and recipient are IgG antibody seropositive:
Donor (D) positive (+); Recipient (R) positive (+) (D+/R+)
2. Both donor and recipient are IgG antibody seronegative: Donor (D) negative (-); Recipient (R) negative (-) (D-/R-)
3. Donor is IgG antibody seropositive and recipient is IgG antibody seronegative: Donor (D) positive (+); Recipient (R) negative (-) (D+/R-)
4. Donor is IgG antibody seronegative and recipient is IgG antibody seropositive: Donor (D) negative (-); Recipient (R) positive (+) (D-/R+). Clinical picture:
Picture of CMV is low grade fever and fatigue and abdominal pain and evidence of retinitis.
Laboratory studies shows leukopenia
Diagnosis by PCR . Treatment of CMV Disease:
Reduce immunosuppressive drug
Antiviral therapy
IV gancyclovir
High dose of hyperimmune globulin 0.5g/kg used with gancyclovir in case of pneumonitis.
Many studies shows evidence of relapse after successfully management of CMV disease and prophylactic treatment should be considered after treatment to reduce relapse.
Antiviral drug Resistance:
Cidofovir is second line of treatment in case of resistance.
Foscarnet is third line of therapy but it’s nephrotoxic and may lead to electrolytes disturbance.
Grading of Recommendations Assessment, Development and Evaluation (GRADE) system:
For each recommendation the quality of evidence has been graded as:
A (high)
B (moderate)
C (low)
D (very low).
Grade A evidence:
It’s means high quality evidence that comes from consistent results from well performed randomised controlled trials, or overwhelming evidence of another sort (such as well-executed observational studies with very strong effects). Grade B evidence:
It’s means moderate quality evidence from randomised trials that suffer from serious flaws in conduct, consistency, indirectness, imprecise estimates, reporting bias, or some combination of these limitations, or from other study designs with special strength. Grade C evidence:
It’s means low quality evidence from observational evidence, or from controlled trials with several very serious limitations. Grade D evidence:
It’s based only on case studies or expert opinion.
A Level 1 recommendation is a strong recommendation to do (or not to do) something
where the benefits clearly outweigh the risks (or vice versa) for most, if not all patients.
A Level 2 recommendation is a weaker recommendation, where the risks and benefits are more closely balanced or are more uncertain.
CMV prophylaxis:
Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months.
It’s used for people with seronegative recipient and sero- positive donor. Or patients receive T-lymphocyte depletion therapy and ATG.
It’s not routinely used in seronegative recipient and donor but consider in prophylactic against other herpes virus.
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if ether recipient or donor is sero positive.
Adjust dose if Cr Cl less than 60ml/min.
Shift to pre-emptive therapy if developing side effects from valganciclvir.
Full blood count every 2 weeks
Treating CMV Infection and Disease:
Oral Valganciclovir for a duration of at least 2 weeks [1A].
Adjust the dose of Valganciclovir if creatinine clearance is less than 60mL/minute [1D]
Be aware of the potential development of ganciclovir resistance (consider Cidofovir)
Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days [1D]
Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected [2D].
Reduce calcinurine inhibitors to half and azathioprine and MMF if there’s leukopenia.
Reflect in our practice?
Its same to British guidelines but we use ganciclovir as prophylactic therapy against CMV in all transplant patients for 6 months whether recipient or donor is sero negative or sero positive
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION.
1-Please summarise these guidelines; –Preventing CMV Infection and Disease; -Serological status of both donor and recipient has to be set prior to transplantation, –All donors and recipients should be screened for CMV (IgG antibody) before or a few days before the transplantation. –Seronegative recipients may require prophylaxis for prevention of other Herpes virus. -If recipient developed side effect consider switching to CMV monitoring and pre-emptive therapy. –Serostatus of the donor and recipient should be known, if the serostatus is unknown this should be managed as (D+/R-) case. Monitoring of CMV infection and disease; –(R+) patients who are not receiving aggressive induction therapy (ATG or Alemtuzumab) are candidate for monitoring and preemptive therapy, with monitoring of CMV PCR at least per month for at least 3 months, –Pre-emptive therapy guided by monitoring of CMV viral load at least monthly for at least 3 months, considered if: – CMV seropositive (D+/R+, D-/R+), – Notreceived T- cell depletion therapy,
– Not on valganciclovir prophylaxis -CMV viral load monitored post transplant every 3 months. -If either donor or recipient is CMV positive (D+/R-, D+/R+, or D-/R+), consider valganciclovir prophylaxis for at least 3 months following acute allograft rejection therapy. -Adjust Valganciclovir dosage if creatinine clearance is less than 60ml/minute. Treating CMV Infection and Disease; -For young candidates ,oral Valganciclovir is given for at least 2 weeks considering renal dose adjustment if needed , and ganciclovir resistance risk.
-CMV viral load after 2 weeks of treatment need to be checked and then again after at least 1 week, then therapy is stopped after resolution of symptoms and 2 negative CMV viral load tests -For children under 18, modify Valganciclovir dosage according to body surface area up to 900mg daily. -Check FBC every 2 weeks while on Valganciclovir. -Switch to CMV surveillance and pre-emptive treatment if Valganciclovir side effects include neutropenia. -Consider stopping treatment for CMV disease after resolution of symptoms and CMV is below threshold for detection, -High doses of intravenous Hyperimmune globulin (0.5 g/kg body weight) have been used in conjunction with Ganciclovir for the treatment of pneumonitis, –Ganciclovir-resistant; -Ganciclovir resistance is higher in the following people: Long-term or subtherapeutic antiviral treatment drugs / CMV-negative solid organ transplant patients from seropositive donors / T-cell-depleted immunosuppressed patients / treatment after acute allograft rejection. / Lung transplants. -Ganciclovir-resistant individuals; Check the dose / Consider treatment compliance and absorption / Genetic testing for UL97/UL54 gene mutations. –Ganciclovir-resistant people; -Stop Valganciclovir (Ganciclovir), -IV Foscarnet for 3 weeks, -Before starting Foscarnet, consult a virologist. -Immunosuppression dose reduction; -Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil /azathioprine -Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) orazathioprine if there is evidence of leukopenia. -Review the dosing of immunosuppression following resolution of CMV infection or disease. -Educational support; -It is essential to explain to the recipient the CMV infection risk , diagnosis , monitoring , treatment ,prophylaxis and immunosuppression re modelling decision. -Discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction. 2-Please reflect on your practice; -In our practice the same overall guidelines are applied with individualisation according to each case. -We do Mandatory CMV IgM , IgG for donor and recipient during preparation for transplant and at transplantation. -In our practice CMV prophylaxis used for 3-6 months(D=/R+, D-/R+) with valganciclovir & dose adjusted according GFR if GFR <60ml/min.
I appreciate that you use bold for heading or sub-headings that make it easier to read. I like your summary of these guidelines. I like your reflection of current practice in your hospital in relation to these (similar) guidelines
Summary of the Guidelines: 1. Preventing CMV infection and disease. Determining CMV status in donor and recipient:
All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation.
If donor CMV serostatus is unknown and the recipient is seronegative or unknown for CMV, this should be characterized as donor seropositive, recipient seronegative for CMV (D+/R-).
CMV prophylaxis: For adults, children and young people receiving a solid organ transplant; offer Valganciclovir prophylaxis to people receiving kidney and liver transplant for at least 3months following transplantation if either:
The recipient is seronegative for CMV and receive an allograft from a CMV seropositive donor (D+/R-). Or
The recipient has received T-lymphocyte depletion therapy with Anti thymocyte globulin (ATG) or Alemtuzumab (Campath), where donor; recipient serostatus is D+/R+ or D-/R+.
Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal, or pancreas transplants for at least 3 months following transplantation if either:
The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-). or;
The recipient has received T-lymphocyte depletion therapy with ATG or Campath, where donor: recipient serostatus is D+/R- or D-/R+.
Donot routinely offer Valganciclovir prophylaxis if the donor and recipient are seronegative for CMV (D-/R-). Beaware that some recipient who is seronegative for CMV (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention of other Herpes virus infections, (HSV R-/ HSV D+). Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient is CMV positive (D+/R-, D+/R+, or D-/R+). Adjust the dose of Valganciclovir if creatinine clearance is less than 60 ml/min. For children and young people under 18 years, adjust the dose of Valganciclovir according to the body surface area, up to a maximum dose of 900 mg OD. Monitor full blood count at least every 2 weeks whilst on Valganciclovir. Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects; neutropenia. 2.Laboratory testing for CMV: Should use a quantitative test, CMV viral load:
Transplant centers should adopt an approach to quantify CMV.
CMV QUANT should be WHO calibrated.
CMV viral load should be unified as IU/mL, using a conversion factor.
Transplant centers should have their local threshold for CMV viral load.
QUANT threshold should be used based on clinical, laboratory, or histological evidence of CMV disease.
3. Monitoring for CMV infection and disease: Offer monitoring of CMV viral load to guide start dose for SOT:
CMV seropositive (D+/R+, D-/R+).
If not received T-lymphocyte depleting agent.
If not receiving prophylaxis therapy.
CMV viral load monitoring:
At least monthly testing.
At least 3 monthly following transplantation.
4 Treating CMV infection and disease: For those who develop CMV infection or disease:
Treat with oral Valganciclovir for at least 2 weeks.
Adjust dose as recommended according to CrCl is less than 60 ml/min.
Be aware for ganciclovir resistance.
Assess viral load after 2 weeks, consider stopping treatment after resolution of symptoms and undetected viral load.
5.Ganciclovir resistance: Risk factors for Ganciclovir 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.
People with suspected resistance consider:
Adequate dosing.
Ensure adherence to treatment.
Offer testing for CMV resistance.
UL97 and UL%$ gene mutations.
In people with evidence of ganciclovir resistance:
Stop Van or Ganciclovir.
Give IV Foscarnet for at least 3 weeks.
6.Immunosuppressant dose reduction:
Consider a dose reduction of either CNIs or MMF/AZA.
Discuss the risk of rejection with IS reduction.
Review IS dosing after resolution of the disease.
7.Information, education, and support:
Offer balanced and accurate information to recipients undergoing SOT.
The risk of CMV infection and disease to D/R serostatus, and IS.
Monitoring and treatment options, including prophylaxis.
I appreciate that you use bold for heading or sub-headings that make it easier to read. I like your summary of these guidelines. I like that your reflection of current practice information and education
Solid organ transplant recipients:
– Give kidney and liver transplant recipients Valganciclovir prophylaxis for three months if either:
-CMV-negative recipients get allografts from CMV-positive donors (D+/R-).
-The recipient underwent T-lymphocyte depletion treatment with anti-thymocyte globulin (ATG) or Alemtuzumab (Campath) whether donor: recipient serostatus is D+/R+ or D-/R+.
– Consider valganciclovir prophylaxis for heart, lung, intestine, or pancreatic transplant recipients for at least three months if either: The recipient is seronegative for CMV and gets an allograft from a CMV-positive donor (D+/R-).
OR
-When donor: recipient serostatus is D+/R+ or D-/R+, the recipient receives T-lymphocyte depletion treatment with anti-thymocyte globulin (ATG) or Alemtuzumab (Campath).
-Donor and recipient CMV seronegative (D-/R-) should not receive Valganciclovir prophylaxis.
-Recipients who are seronegative for CMV (D-/R-) may need Valganciclovir or Valaciclovir prophylaxis to avoid other Herpes virus infections, such as those receiving organs from HSV-positive donors.
– If either donor or recipient is CMV positive (D+/R-, D+/R+, or D-/R+), consider valganciclovir prophylaxis for at least 3 months following acute allograft rejection therapy.
– Adjust Valganciclovir dosage if creatinine clearance is less than 60ml/minute.
-For children under 18, modify Valganciclovir dosage according to body surface area up to 900mg daily.
-Check FBC every 2 weeks while on Valganciclovir.
-Switch to CMV surveillance and pre-emptive treatment if Valganciclovir side effects include neutropenia.
CMV Treatment:
For adults, children, and youth who get CMV after
transplantation:
1 Give oral Valganciclovir for 2 weeks.
2 If approved dosage guidelines differ, adjust the Valganciclovir dose.
creatinine clearance <60ml/min.
3 Monitor ganciclovir resistance.
management)
4 Measure CMV viral load after 2 weeks of therapy and repeat every
5 Stop CMV medication when symptoms improve.
two consecutive CMV viral load tests showing no CMV.
Ganciclovir-resistant
Ganciclovir resistance is higher in the following people:
Long-term or subtherapeutic antiviral treatment
drugs
CMV-negative solid organ transplant patients from seropositive donors
T-cell-depleted immunosuppressed patients
treatment after acute allograft rejection.
Lung transplants
If: Ganciclovir resistance
After a virus, the symptomatic illness persists or increases.
Ganciclovir’s typical dose and duration (2-4 weeks)
valganciclovir
-Ganciclovir-resistant individuals:
Check the dose
Consider treatment compliance and absorption.
Test HCMV antiviral resistance.
UL97/UL54 gene mutations.
Plasma or entire blood].
Ganciclovir-resistant people:
Stop Valganciclovir (Ganciclovir).
IV Foscarnet for 3 weeks .
Before starting Foscarnet, consult a virologist.
Immunosuppression decrease
CMV infection or sickness in adults, children, and youth (with or without
leukopenia-free) after solid organ transplantation:
– Reduce calcineurin inhibitor or mycophenolate mofetil doses.
Reduce or discontinue Mycophenolate Mofetil (MMF) if possible.
leukopenia, azathioprine.
– Inform patients and parents or caregivers of the risk of acute kidney injury
rejection with reduced immunosuppression.
– Reassess immunosuppressive doses after CMV infection.
Please reflect on your practice
In our center, we are following the following protocol:
diagnosis based on symptoms and quantitative CMV PCR or tissue biopsy.
In case of definite diagnosis, we are giving valganciclovir for most of the patients except for tissue invasive disease we start with IV gancyclovir for 2 weeks then continue on valacyclovir until PCR negative.
I suggest that you use bold for heading or sub-headings that make it easier to read. I like your summary of these guidelines. I like that your reflection of current practice in your hospital in relation to these (similar) guidelines
Summary of the BTS recommendations on prevention and management of post-transplant CMV: 1- Determination of CMV status of donor and recepient:
All organ donors and recipients should be screened for CMV IgG serostatus prior to transplantation.
If donor CMV serostatus is unknown and recipient is seronegative or unknown forCMV, this should be considered as (D+/R-)
2- CMV prophylaxis:
Offer valganciclovir prophylaxis for SOT recipients for at least 3 months if:
a- D+/R-
b- The recipient has received T-lymphocyte depletion therapy with ATG or
Alemtuzumab (Campath), where D+/R+ or D-/R+
Do not routinely offer Valganciclovir prophylaxis if (D-/R-).
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive.
Adjust the dose of Valganciclovir if cr cl < 60 ml/min and inchildren according to the body surface area (maximum daily dose 900 mg)
Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir
Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir.
3- Laboratory testing for CMV:
Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load and reported as IU/mL or as copies / mL.
QNAT thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease.
4- Monitoring CMV infection and disease:
Offer monitoring of CMV viral load to guide pre-emptive therapy after solid organ transplant recipients if:
They are CMV seropositive (D+/R+, D-/R+)
They have not received T-lymphocyte depletion therapy
They are not receiving valganciclovir prophylaxis
Monitoring at least monthly and for at least 3 months following transplantation.
5- Treatment of CMV:
Offer treatment with oral Valganciclovir for a duration of at least 2 weeks
Adjust the dose of Valganciclovir if clearance < 60 ml/min
Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days.
Consider stopping treatment for CMV disease after resolution of symptoms
AND
two consecutive, CMV viral load tests that confirm that CMV is not detected. 6- Ganciclovir resistance:
People at increased risk:
1-Those who have received prolonged courses, or sub-therapeutic doses of
antiviral medications
2- D+/R-
3- Those who have received intensive immunosuppression (e.g; with T-cell
depletion therapy, following episodes of acute allograft rejection)
4- lung transplant recipient.
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
In people with suspected resistance to Ganciclovir:
1- Confirm that dosing is adequate and adherence to treatment plan and
absorption
2- Offer testing for Human CMV (HCMV) antiviral resistance and UL97 and
UL54 gene mutations
In people with evidence of ganciclovir resistance:
1- Stop Valganciclovir (or Ganciclovir)
2- Offer Intravenous Foscarnet for at least 3 weeks after consulting virology
specialist.
7- IS reduction:
Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil /azathioprine
Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) orazathioprine if there is evidence of leukopenia.
Discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction.
Review the dosing of immunosuppression following resolution of CMV infection or disease.
I like that you use bold for heading or sub-headings that make it easier to read. I like your summary of these guidelines. I like that your approach in fine-tuning immunosuppression
Regarding our practice:
Despite I don not involved in the treatment of post-transplant management as a surgeon and all done by nephrologist
I am sure regarding some points:
1- All D and R are assessed for CMV Ig G status
2- we follow the same guidelines for stratification of the risks
3- All R- regardless the serostatus of the donor receive valganciclovir prophylaxis for 3-6 month . similarly if the serosatatus of the donor is not known
Serostatus of the donor and recipient should be known, if the serostatus is unknown this should be managed as (D+/R-) case
Prophylaxis is indicated for at least 3 months in (D+/R-) patients, (R+) patients who receive aggressive induction therapy (ATG or Alemtuzumab) and after treatment of AR in (D+/R-) and (R+) patients.
(R+) patients who are not receiving aggressive induction therapy (ATG or Alemtuzumab) are candidate for monitoring and preemptive therapy, with monitoring of CMV PCR at least per month for at least 3 months
Prophylaxis is not indicated in (D-/R-) patients, but they may require prophylaxis for HSV (if D+/R-)
The dose of valgancyclovir should be adjusted if creatinine clearance is < 60 ml/min and in children (adjusted according to BSA with maximum dose of 900 mg once daily)
Monitor CBC every 2 weeks, and if the patient develop side effects (such as neutropenia ), switching to preemptive therapy is recommended
Monitoring of CMV is best done using PCR, and the result is interpreted in copies /ml
Treatment of CMV Infection and Disease
The treatment of CMV with antiviral medication (valgancyclovir and gancyclovir) should be given for a minimum of 2 weeks, after 2 successive negative PCR readings 1 week apart, and the patient should be symptom free
Assessment should be done 2 weeks after treatment and then weekly
Renal dose adjustment is needed for valgancyclovir and gancyclovir
Gancyclovir resistance is defined as persistence or elevation of the viral load after 2 weeks of appropriate treatment (patient should receive the appropriate dosing at appropriate timing for appropriate duration)
Risk factors for gancyclovir resistance includes patients receiving long or suboptimal courses of treatment, (D+/R-) transplantation, patients receiving ATG for acute rejection and recipients of lung transplant
In patients with gancyclovir resistance consider testing for UL97 and UL54 gene mutations in whole blood or plasma.
Strategies used in case of gancyclovir resistance include more reduction of immunosuppression and switching to IV foscarent for 3 weeks under the guidance of virology expert ( associated with renal and GIT toxicity and electrolyte imbalance)
In my practice
We use valacyclover (Valtrex 500 mg) in prophylaxis once daily for 3-6 months according to the serostatus as it is cheaper and we reserve valgancyclovir for treatment
I like that you use bold for heading or sub-headings that make it easier to read. I like your summary of these guidelines. I like that your team applies these (or similar) guidelines
CMV in solid organ transplant recipient:
Kidney transplant recipient can be at an increased risk of attracting CMV infection, with potential catastrophic consequences on patient and allograft.
Therefore serological status of both donor and recipient has to be set prior to transplanation
Hence prophylactic protocol was implement for most of the recipients as follows:
1]D+/R-,
2] D+/R+, D-/R+ if ATG or Alemtuzumab were administered as induction therapy .
3] No prophylactic Valgancyclovir is indicated in D-/R-.
Valganciclovir is advocated as prophylactic medication in a dose of 900 mg per day for 3 months.
Dose adjustment according to renal function has to be considered.
Regular complete blood count has to be performed every 2 weeks for a significant side effect of neutropenia.
In case neutropenia emerged , then switching to alternative protocol of regular surveying of recipients, with CMV monitoring and pre-emptive treatment. Monitoring of CMV and pre-emptive treatment:
1] In seropositive recipients D-/R+, D+/R+.
2] No ATG or Alemtuzumab was induced with.
3] Not on Valganciclovir prophylaxis. Treatment of infection:
Valganciclovir can be prescribed for 2 weeks, proper adjustment of Valgancyclovir according to GFR.
PCR for CMV has to be done after 2weeks , and Valganciclovir has to be stopped if CMV PCR is negative in two successive occasions. Ganciclovir resistance:
If no improvement in symptoms or CMV is still detected in after 2 weeks then Ganciclovir resistance is suspected. Risk factors for Ganciclovir resistance:
1] Subtherapeutic dose. prolonged courses.
2] D+/R-
3] Those received intense immune suppression with lymphocytes depleting agents for acute rejection episodes with ATG.
4] lung transplant recipient. In case of Ganciclovir resistance, Forscarnet: is an alternative for ganciclovir has to be administered for 3 weeks
● Preventing CMV Infection and Disease
☆ All organ donors and recipients should be screened for CMV prior to, or at the time of transplantation
☆ If donor , recipient CMV serostatus is unknown it should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-)
● CMV prophylaxis after SOT :
☆ D+/R-
☆ The recipient has received (ATG) or Alemtuzumab (Campath )
☆ After starting treatment for acute allograft rejection
☆ There is emerging evidence that low dose (450mg) Valganciclovir prophylaxis is as effective as standard dose (900mg) in kidney transplant recipients
● Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV
● Adjust the dose in accordance to GFR
● Monitor CBC every 2 weeks
● Laboratory Testing for CMV
☆ CMV QNAT assays
☆ QNAT thresholds should not be used in isolation to clinical, laboratory or histological evidence of CMV disease
● Monitoring for CMV Infection and Disease at least monthly
☆ D+/R+, D-/R+
☆ They have not received T-lymphocyte depletion therapy
☆ They are not receiving valganciclovir prophylaxis
● Treating CMV Infection and Disease
☆ oral Valganciclovir for a duration of at least 2 weeks
☆ The very sick people requiring hospitalisation and other intravenous
therapies e.g.; intravenous (i.v.) fluids and antibiotics, i.v ganciclovir should be considered due to a likelihood of impaired absorption.
☆ Assess CMV viral load after 2 weeks of treatment
☆ Consider stopping treatment for CMV disease after resolution of symptoms and CMV is below threshold for detection
☆ High doses of intravenous Hyperimmune
globulin (0.5 g/kg body weight) have been used in conjunction with Ganciclovir for the
treatment of pneumonitis
● High risk to ganciclovir resistance in :
☆ Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications
☆ D+/R-
☆ Those who have received intensive immunosuppression (T-cell depletion therapy)
☆ Lung transplants
● Consider resistance if:
☆ There is a persistent or increasing viral load or symptomatic disease after a effective dosage and duration (2-4 weeks)
☆ Occur in up to 3% of SOT recipients
☆ In people with suspected resistance :
▪︎Confirm adequacy of dose
▪︎Consider adherence to treatment
▪︎Offer testing for HCMV antiviral resistance ( gene mutations )
● In case of ganciclovir resistance:
▪︎Stop Valganciclovir
▪︎Intravenous Foscarnet for at least 3 W
▪︎specialist virology advice
● Immunosuppression dose reduction
☆ Reduction of either CNi or MMF or AZA
☆ Stopping MMF AZA IN leukopenia
☆ Discuss about risk of acute rejection
☆ Review dose after of resolution of CMV infection or disease
● Reflect on your practice
In my centre in syria :
☆ Mandatory CMV IgM , IgG for donor and recipient during preparation for transplant and at transplantation
☆ Prophylaxis for 3 months in case D+/R- or when recipient has ATG as induction therapy or to treat rejection
I suggest that you use bold for heading or sub-headings that make it easier to read. I like your summary of these guidelines. I like that your hospital applies these guidelines
all donors and recipients should be screened for CMV (IgG antibody) before or a few days before the transplantation
Valganciclovir prophylaxis should be offered to adults, children, or young adults for at least 3 months after organ transplantation
Do not routinely use valganciclovir as prophylaxis in D-/R- individuals after an organ transplantation
Consider the use of valganciclovir prophylaxis for at least 3 months following treatment for acute rejection with the use of depleting agents
Routine blood workup for the development of side effects to the use of valganciclovir
Laboratory testing for CMV
Blood or plasma should be used to quantify CMV viral load through Quantitative Nucleic Acid Testing (QNAT)
CMV QNAT assay should be calibrated to the WHO reference standard
Transplant centres should have a centre specific viral threshold level for diagnosis of CMV disease
QNAT threshold should not be used in isolation to determine the commencement or the stopping of treatment
Monitoring for CMV infection and disease
CMV viral load monitoring for preemptive treatment should be offered to:
D+/R+, -D-/R+. those not receiving T-lymphocytes depleting agents
Consider CMV viral load testing monthly and for at least 3 months post surgery
Treating CMV infection and disease
oral valganciclovir treatment for 2 weeks and adjust the dose if creatinine clearance is less than 60ml/min
Assess the level of CMV viral load after 2 weeks and be aware of ganciclovir resistance
consider stopping treatment after the resolution of symptoms and two consecutive CMV viral loads that are undetected
Ganciclovir resistance
Consider the following in those with ganciclovir resistance
-confirm dosing is adequate
-consider adherence to the dosing plan and absorption
-test for antiviral resistance
-test for UL97 and UL54 gene
Offer I.V foscarnet for 3 weeks in those with ganciclovir resistance
Immunosuppression dose reduction
Consider the reduction of CNI
Consider the reduction or stopping the antimetabolites
Information, education, and support
Offer health education to all patients been worked up for organ transplantation on the testing for CMV infection, the nature of CMV infection, disease, and the available treatment options for them.
Reflect on your practice
In my former place, where I worked for almost 2 years in Nigeria, we usually do the following:
mandatory CMV IgG and IgM test, two weeks to kidney transplantation
Routine use of CMV prophylaxis for ALL kidney transplant recipients irrespective of the CMV status of the donor or recipients for 3 months
Use of valganciclovir for those that received ATG for biopsy-proven cell-mediated allograft rejection for one month.
Regular health education during post-transplant kidney on medication adherence
I like that you use bold for heading or sub-headings that make it easier to read. I like your summary of these guidelines. I like that your hospital applies these guidelines
Please summarise these guidelines 1-Preventing CMV Infection and Disease Determining CMV status in donor and recipient
-All donors and recipients should be screened for CMV (IgG antibody) sero-status.
–If CMV serostatus is unknown,should be assumed CMV(D+/R-).
CMV prophylaxis – Universal Prophylaxis and pre-emptive therapy are in common use to minimize the impact of CMV infection or reactivation.
– Aciclovir, Valaciclovir, Ganciclovir and Valganciclovir have all been used for prophylaxis. -Valganciclovir prophylaxis for people receiving heart, lung, intestinal or pancreas transplants for at least 3 months if: (D+/R-) orRecipient has received T-cell depletion therapy or after treatment for acute allograft rejection. –Do not routinely offer Valganciclovir prophylaxis if CMV (D-/R-)
– Seronegative recipients may require prophylaxis for prevention of other Herpes virus. – If recipient developed side effect consider switching to CMV monitoring and pre-emptive therapy. 2-Laboratory Testing for CMV
-Lab to use consistent approach either whole blood or plasma for quantification of CMV viral load QNAT, should be reported as IU/mL, or, if reported as copies / mL, and determine local thresholds for treatment.
3-Monitoring for CMV Infection and Disease. Pre-emptive therapy guided by monitoring of CMV viral load at least monthly for at least 3 months, considered if: – CMV seropositive (D+/R+, D-/R+) AND – Not received T- cell depletion therapy AND – Not on valganciclovir prophylaxis
4-Treating CMV Infection and Disease -People with CMV infection or disease treated with oral Valganciclovir for at least 2 weeks -Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days – Treatment can be stopped after resolution of symptoms AND two consecutive undetectable CMV viral load. 5 Ganciclovir resistance -Considered if there is a persistent or increasing viral load or symptomatic disease after effective dosage and duration of Ganciclovir or Valganciclovir.
–If Ganciclovir resistance is suspected; confirm that dosing is adequate, check treatment adherence, offer testing for CMV antiviral resistance, UL97 and UL54 gene mutations. -In people with evidence of resistance: stop Valganciclovir (or Ganciclovir), start IV Foscarnet for at least 3 weeks and seek specialist virology advice.
6- Immunosuppression dose reduction – Reduce either CNI or MMF /azathioprine, preferentially reducing or stopping MMF or azathioprine -Discuss the risk of AR with IS dose reduction 7-Information, education and support – Healthcare professionals to offer accurate information to people undergoing SOT about the risks of CMV infection, risk, monitoring and treatment options, including prophylaxis.
Please reflect on your practice
In our center, as most pediatric recipients are naïve to CMV, we use universal prophylaxis for 3-6 months then continue pre-emptive prophylaxis with monitoring of viral load.
1. All patients must measure the serological status of the donor and recipient. If the donor is unknown, consider it positive.
2. Prophylaxis with oral Valganciclovir for three months if the serological status is D+/R-
Or in positive recipients using anti-lymphocyte drugs (rATG or AntiCD52) In Brazil we do not have oral Valganciclovir, we only have Ganciclovir which is done preemptively and intravenously therapeutically. In Bone Marrow Transplantation, we already have Letermovir as primary prophylaxis in the first hundred days after transplantation.
3. Adjust drug dose depending on Creatinine Clearance.
Laboratory tests for CMV
1. Standardize PCR quantification for CMV
2. Offer it to patients with positive serology, who have not taken prophylaxis or who have used anti-lymphocytes.
3. Test at least once a month. In Brazil, we test once a week, probably because of our extremely high epidemiology for CMV and the unavailability of adequate drugs to carry out prophylaxis.
4. We always treat with Ganciclovir 5. We do not have easy tests for resistance. Those who do not respond to high doses of ganciclovir (15mg/kg/day) are considered resistant. Foscarnet is imported into Brazil, limiting its use.
Clinical conduct
1. Reduce immunosuppression, especially of antimetabolites (Azathioprim and Mycophenolate)
2. Assess the risk of rejection
-Recommendation summary CMV infection and disease prevention
· Detecting CMV status in donor and recipient before transplantation (Ig G antibody)
· If CMV status of the donor and the recipient is unknown ,it should be considered that the donor is CMV seropositive and recipient is negative CMV prophylaxis
· Valganciclovir prophylaxis is given to kidney and liver transplants recipients for at least 3 months after transplantation if D+/R- or if ATG or Alemtuzumab was given for D+/R+ or D-/R+
· Valganciclovir prophylaxis is given to heart, lung, intestinal or pancreas transplants recipients for at least 3 months after transplantation if D+/R- or if ATG or Alemtuzumab were given to D+/R+ or D-/R+
· If D-/R- , Valganciclovir is not routinely given meanwhile Valganciclovir or Valaciclovir prophylaxis can be needed for prevention of other Herpes virus infections
· After starting treatment for acute allograft rejection Valganciclovir prophylaxis for at least 3 months will be needed if either donor or recipient are CMV positive
· If creatinine clearance is < 60ml/minute ,renal dose adjustment for Valganciclovir will be needed also for candidates less than 18 years Valganciclovir need to adjusted according to body surface area with CBC monitoring /2 weeks while on treatment and if side effects occurred CMV monitoring along with preemptive therapy can be done. CMV laboratory testing
CMV Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma must be used to quantify CMV viral load, with standardised assessments correlating with clinical, laboratory or histological evidence of CMV disease.
There is high inter-assay and inter laboratory variability of QNAT results . CMV infection and disease monitoring
I t will be essential for D+/R+, D-/R+, those who did not receive T-lymphocyte depletion therapy nor received valganciclovir prophylaxis
It can be done at least on monthly bases and every 3 months after transplantation Treatment of CMV infection and disease
For young candidates ,oral Valganciclovir is given for at least 2 weeks considering renal dose adjustment if needed , and ganciclovir resistance risk.
CMV viral load after 2 weeks of treatment need to be checked and then again after at least 1 week, then therapy is stopped after resolution of symptoms and 2 negative CMV viral load tests Ganciclovir resistance
Prolonged courses of antiviral medications or subtherapeutic doses ,intensive immunosuppression, D+/R- and lung transplant recipients can increase it’s risk.
It is suspected in cases with persistent or increasing viral load or symptomatic disease after sufficient dosage and duration of Ganciclovir or Valganciclovir
Human CMV resistance and UL97 and UL54 gene mutations need to be checked
Valganciclovir or Ganciclovir need to be stopped and IV Foscarnet for at least 3 week can be given instead. Reduction of immunosuppressive doses
CNI or MMF /azathioprine reduction must be considered and suspending MMF in case of leukopenia Educational support
It is essential to explain to the recipient the CMV infection risk ,diagnosis , monitoring , treatment ,prophylaxis and immunosuppression re modelling decision
CMV Background
CMV is one of herpes virus group, primary infection can result into severe disease with immunocompromised T cell .
Viral genome invades the monocytes and progenitor cells then become latent.
Transmission is through saliva, urine, breast milk or genital secretions.
CMV infection in SOT
Usually occurs 2-4 weeks posttransplant in a seronegative individual receiving a seropositive organ.
Symptoms are non specific .
In immunosuppressed cases , antibody rise can be delayed .
The gold standard test for detecting active CMV replication is CMV PCR in plasma, whole blood
or leukocytes.
Kidney and liver transplant recipients who received prophylaxis has 1-year incidence of CMV disease to be 19.2% and 31.3% respectively in D+ / R- group and 2.5% and 3.2%, respectively, in D- /R- group.
Late-onset CMV disease represents the CMV disease in SOT recipients who received antiviral prophylaxis occurred after finishing antiviral drug administration commonly in CMV mismatch (D+ / R-) recipients leading to allograft failure and mortality.
Anti-CMV prophylaxis in D+/R kidney transplant recipient lead to 50% reduction in biopsy-proven acute graft rejection . Preventing CMV disease in SOT recipients
Anti-CMV Prophylaxis and pre-emptive therapy can decrease the impact of CMV infection or reactivation depending on the donor/recipient CMV status, organs transplanted, and intensity of immunosuppression.
Aciclovir, Valaciclovir, Ganciclovir and Valganciclovir were used also recent agents as Letermovir and Maribavir are introduced.
Transplant recipients undergo regular surveillance and trated when at high risk of having CMV disease. CMV Disease treatment
Immunosuppression has to be reduced along with initiation of antiviral therapy as IV Ganciclovir which decreased mortality and morbidity of CMV disease .
High doses of IV Hyperimmune globulin can be used with Ganciclovir for the pneumonitis therapy.
Meanwhile relapse risk is high after successful therapy. Antiviral drug resistance
In the forum of progressive illness or stationary or rising viral load inspite of sufficient dose and duration of antiviral therapy meanwhile increasing viral load is not reliable as it can increase within first week of treatment before decreasing.
Genotypic analysis can detect high and low grade Ganciclovir resistance as well as resistance to Foscarnet and Cidofovir.
Analysis of UL97 and UL54 gene mutations is introduced
Cidofovir is a possible 2nd line therapy .
Foscarnet is rendered a second or third line drug as it has risks of nephrotoxicity and electrolyte disturbances.
Maribavir is under trial for treating refractory or resistant CMV infection in SOT.
CMV viral infection is characterized by being either asymptomatic or viral syndrome or CMV disease.
-In my practice the same overall guidelines are applied with individualisation according to each case
I like that you use bold for heading or sub-headings that make it easier to read. I like your summary of these guidelines. I like that your hospital applies these guidelines as per individual patient’s needs
Please summarise these guidelines
————————————————————————————–
1 Preventing CMV Infection and Disease —————————————————————— a-Determining CMV status in donor and recipient;
The guidelines recommend screening of all organ donors and recipient for CMV IgG antibody (IA) .
b-CMV prophylaxis;
1-The guidelines recommend at least 3 months of valganciclovir prophylaxis for high risk group of recipient IA;
1- D+/R-
2- Those who received T. cell depleting agent .
2-The guidelines suggest ,at least 3 months valganciclovir prophylaxis after starting treatment of acute rejection if donor or recipient are CMV positive 2C.
3-Valganciclovir dose needs to be adjusted if creatinine clearance is less than 60 ml/minute 1D.
4- Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir [1A] .
2 Monitoring CMV Infection and Disease; ——————————————————————-
1-The guidelines recommend monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if: They are CMV seropositive (D+/R+, D-/R+) and they have not receive T. cell depleting agent or valganciclovir prophylaxis 1B.
2-The guidelines recommend viral load testing monthly for at least 3 months following transplant 1D.
3 Treating CMV Infection and Disease ; ——————————————————————— 1-The guidelines recommend offering treatment with oral valganciclovir for a duration of at least 2 weeks 1A.
2-Also the guidelines recommend assessing of the viral load after 2 weeks o treatment and repeat at interval of 7 days 1D.
4- Ganciclovir resistance ; —————————————————————————
Ganciclovir resistance may be suspected in difficult to control CMV infection, as evidenced by a persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration (e.g.; 2-4 weeks) and is reported to occur in up to 3% of SOT recipients .
The guidelines recommend that ,recipient with Ganciclovir resistance should be tested for UL97 and UL54 mutations .
5-Immunosuppression dose reduction ; ————————————————————————-
1-The guidelines suggest a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine [1C] .
2-In the setting of leucopenia , the guidelines suggest reducing or stopping MMF or azathioprine 2C .
2-Please reflect on your practice; ———————————————————–
We depend on the pre transplant CMV risk stratification in prevention and treatment of CMV infection . We do not perform post transplant viral load in asymptomatic recipient .
I like that you use bold for heading or sub-headings that make it easier to read. I like your summary of these guidelines. I wish and hope that your hospital will be able to provide capabilities in its system to implement these guidelines.
CMV sero-status of donor & recipient should be identified.
If CMV sero-status of donor is not determined, he considered as sero-positive.
3 months prophylaxis for CMV considered for SOT recipient D+/R-, or recipient receive T cell depleted agent with D+/R+ or D-/R+.
No need for CMV prophylaxis if D-/R-, unless it used for prophylaxis for other Herpes virus infection.
D+/R+,D-/R+, D+/R- should receive CMV prophylaxis for 3 months during acute rejection treatment.
Valganciclover dose should be adjusted if GFR<60ml/min, or patient age <18 years (dose according body surface area & GFR).
Full blood count should be monitored every 2 weeks during valganciclovir treatment.
Pre=emptive strategy used if patient develop adverse effect during valganciclovir.
Lab CMV test:
QANT in whole blood or plasma used for CMV viral load quantification.
WHO International Reference Standard should be adopted for QNAT assay.
Viral load should be reported as IU/L
Each transplant center should determine its viral load threshold that indicate CMV infection or disease.
CMV treatment discontinuation should be according to clinical, laboratory or histological evidence of CMV disease in addition to viral load.
Monitoring of CMV infection and disease:
Pre-emptive strategy by using CMV viral load indicated for D+/R+, D-/R+ and recipients didn’t receive T cell depleted agent who didn’t receive valganciclovir prophylaxis.
CMV viral load monitored post transplant every 3 months.
Treatment of CMV infection & disease:
2 weeks of valganciclovir with dose adjustment if GFR<60ml/min.
Assessment of viral load 2 weeks after starting treatment & repeated every 7 days.
Discontinuation of treatment if there is resolution of symptoms & 2 consecutive undetected viral load.
Ganciclovir resistance:
Patients with increased risk of gancicliover resistance are:
Prolonged use of antiviral or sub therapeutic dose.
D+/R-.
use of intensive inmmunosuppression ( ATG, after acute rejection).
Lung transplant recipients.
Resistance considered if viral load persist or increased or symptomatic disease after 2-4 weeks of effective dose & duration of ganciclovir or vulgarciclovir treatment.
In patient with suspected ganciclovir resistant the drug should be adequate, encourage drug adherence, & testing for HCMV antiviral resistant & test for UL97 & UL54 gene mutation.
In patients with CMV resistant, valganciclovir & ganciclovir should be stopped & start with IV Foscarnet for at least 3 weeks with specialist virology advise.
Immunosuppression dose reduction:
MMF or azathioprine should be reduced or stopped if there is evidence of leucopnea.
discussion with patients or parents about the risk of acute rejection during immunosuppression dose reduction.
Immunosuppression dose reviewed after resolution of infection or disease.
Information, education and support:
SOT recipients should be informed about the risk of CMV infection according sero-status & immunosuppression regime with discussion of monitoring & treatment option.
In my practice CMV prophylaxis used for 3-6 months(D=/R+, D-/R+) with valganciclovir & dose adjusted according GFR if GFR <60ml/min.
I like your analysis regarding the level of evidence. You need not to type the whole sentence in bold or capitals. That amounts to ‘shouting.’ I like your detailed reflection of your own practice mentioning the challenges faced by your team. Ajay
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION====================================================================
Please summarise these guidelines
1- Preventing CMV Infection and Disease
Determining CMV status in donor and recipient
All organ donors and recipients should be screened for CMV (IgG antibody) prior to, or at the time of transplantation.
If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive.
CMV prophylaxis
Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal or pancreas transplants for at least 3 months following transplantation if the recipient is seronegative for CMV (D-/R-) or has received T-lymphocyte depletion therapy (Campath).
Clinical Laboratories should use whole blood or plasma to quantify CMV viral load.
Assays should be calibrated using the WHO International Reference Standard.
Local thresholds of viral load that portend CMV infection or disease requiring treatment should be considered in the context of clinical, laboratory or histological evidence of CMV disease.
People who are CMV seropositive (D+/R+, D-/R+) and have not received T-lymphocyte depletion therapy (see section 1B) should be offered CMV viral load monitoring to guide pre-emptive therapy.
Consider testing with a frequency of at least monthly or for at least 3 months following transplantation.
People who develop CMV infection or disease following solid organ transplantation should be treated with oral Valganciclovir for a duration of at least 2 weeks .
Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days .
People at increased risk of Ganciclovir resistance are those who have received prolonged courses, or sub-therapeutic doses of antiviral medications.
There is a persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration (e.g.; 2-4 weeks) for CMV seronegative recipients.
In people with evidence of resistance to Ganciclovir, stop using the drug and offer Intravenous Foscarnet for at least 3 weeks.
Use either whole blood or plasma to check adherence to treatment plan and absorption.
Offer testing for Human CMV (HCMV) antiviral resistance UL97 and UL54 gene mutations.
Children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation should consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine.
Children and young people undergoing solid organ transplants should be offered information on the risks of CMV infection and disease, according to donor / recipient, and the nature of immunosuppression planned or received, says the World Health Organization (WHO) in a series of guidelines.
In adults, children and young people receiving solid organ transplants, is reduction of Calcineurin/nInhibitors (CNIs) associated with better outcomes?
What is the most clinical and cost-effective calculation for dosing Valganciclovir according to body surface area?
In adults, children and young people who develop CMV infection or disease (with or. without leukopenia) following solid organ transplantation, is reduction of Calcineurin.inhibitors (CNIs) or proliferation inhibitors associated with better outcomes?
Adults, children and young people receiving solid organ transplants are offered Valganciclovir prophylaxis for CMV infection and disease following transplantation, according to donor-recipient CMV profiles and use of T-cell depletion therapy as set out .
Proportion of adults, children and young people offered Valganciclovir to treat CMV infection and disease following solid organ transplantation (with or without leukopenia) and who reduce or stop Calcineurin Inhibitors (CNIs) and / or proliferation inhibitors (RYs) following transplantation.
who are offered monthly CMV viral load monitoring for 3 months following a transplant.
Introduction Background to Cytomegalovirus (CMV) Biology of CMV in Humans
After primary CMV infection, the viral genome enters monocytes and other bone marrow progenitor cells and enters a latent state.
The prevalence of exposure to CMV, as indicated by positive IgG antibody (serostatus), varies throughout the world. In developed countries, the percentage of the population who are seropositive has been reported to increase linearly with age.
Transmission occurs from direct person-to-person contact through exposure to saliva, urine, breast milk or genital secretions.
CMV in Solid Organ Transplant Recipients
Primary infection with CMV typically occurs approximately four to six weeks post-organ transplantation.
Gastrointestinal disease presenting with diarrhoea, abdominal pain and nausea is common and respiratory distress may be an indication of pulmonary involvement.
Retinitis can be pathognomonic, but is rarely seen in the transplant population.
In immunocompetent individuals, the presence of IgM and/or low avidity IgG antibodies is a hallmark of primary infection.
In the immunosuppressed, however, the antibody rise may be delayed or absent. This is used to determine prior exposure of both donors and recipients to CMV.
Donor: recipient CMV serostatus is characterised as:-
1. Both D/R are IgG antibody seropositive: (D+/R+)
2. Both D/R are IgG antibody seronegative: (D-/R-)
3. Donor is IgG antibody seropositive and recipient is IgG antibody seronegative: (D+/R-)
4. Donor is IgG antibody seronegative and recipient is IgG antibody seropositive:(D-/R+)
Tests based on the polymerase chain reaction (PCR) carried out on plasma, whole blood or leukocytes have become the gold standard means of detecting active CMV replication in many laboratories in the UK and beyond.
Uncertainty as to whether it is best to test plasma or whole blood and lack of an international reference standard has made the comparison of cut-offs for the initiation of antiviral therapy difficult to compare between laboratories.
Liver (native and allograft), gastrointestinal, bone marrow, lung and kidney biopsies are some of the most commonly diagnostic tests for CMV.
The frequency of CMV disease in solid organ transplant (SOT) recipients varies markedly. In the ‘pre-prophylaxis era’, approximately 8% of kidney, 29% of liver, 25% of heart and 39% of lung transplants could be expected to experience symptomatic CMV infection.
The incidence of CMV disease among lung transplant recipients who received antiviral prophylaxis for 6 to 12 months was 14.9%, with a higher incidence (26.6%) in D+ /R- group.
Late-onset CMV disease remains associated with allograft failure and mortality.
Early studies reported fatality rates of up to 30% in recipients of seropositive kidneys who received Anti-Lymphocyte Globulin (ALG) treatment.
CMV infection can be coincident with acute allograft rejection, a biopsy-proven complication of transplantation.
In a single study, persistent CMV infection was significantly associated with graft loss through chronic rejection in a population of patients receiving 57 liver transplants.
However, there was no significant correlation between primary infection or symptomatic disease and chronic rejection.
A more recent publication examined graft outcome in 10,190 kidney transplants performed in adults, children and young people in the UK between 2000-7 and found no significant effect of donor or recipient CMV status.
Preventing CMV disease in people with solid organ transplants
Preventing CMV disease by avoiding transplanting a seropositive organ into a recipient that is not seronegative is not a viable strategy in the context of solid organ transplantation.
Another theoretically attractive option for prevention would be vaccination against CMV, but this has limited success due to the heterogeneous nature of CMV strains.
Passive immunoprophylaxis has been explored in solid organ transplantation in randomised trials since the 1980s.
An early placebo-controlled study in patients receiving a liver transplant, reported significant overall protection from severe disease by hyperimmune globulin.
Intravenous treatment is generally less convenient for the patient and health care provider.
The absolute levels of viraemia that are recommended as a threshold to start pre-emptive therapy will depend upon the assay used.
Intravenous Ganciclovir has had a major impact on the mortality and morbidity of CMV disease. High doses of intravenous Hyperimmune globulin (0.5 g/kg body weight) have been used for the treatment of pneumonitis.
There is a significant risk of relapse following successful treatment of CMV disease, with recurrent CMV diseases reported in various organ recipients.
Secondary prophylaxis after treatment of disease has been assessed, although evidence in support of this strategy is limited.
===========================================
Antiviral drug Resistance
Antiviral drug resistance is manifest by either progressive disease despite full dose anti-viral therapy, or a static or increasing viral load after drug treatment.
Viral load is not a reliable indicator of drug resistance in the first week of treatment, since the natural kinetics of CMV replication prior to antiviral treatment.
Genotypic assays can relatively rapidly detect gene mutations that are associated with high- and low-grade resistance to ganciclovir and Foscarnet.
This is a rapidly evolving field with more laboratories having the capability to offer high throughput sequence-based analysis of UL97 and UL54 gene mutations.
Maribavir has Food and Drugs Administration (FDA) approval and is currently being assessed by the National Institute for Health and Care Excellence.
It has been reported to be superior to Ganciclovir, Cidofovir and Foscarnet for treating CMV infection following solid organ transplantation.
I like that you use bold for heading or sub-headings that make it easier to read. I like your summary of these guidelines. I wish and hope that your hospital will be able to provide capabilities in its system to implement these guidelines.
CMV prevention :
1-We should know the CMV serostatus (IgG)of both donor and recepient
1-Valgancyclovir prophylaxis for 3 months in case of:
*R-/D+
*(R+D-,R+D+)if induction with ATG or Alemtuzumab
* prevention of Herpes simplex in seronegative recepients from seropositive donors
*After treatment of acute rejection in case of (R+/D-,R-/D+,R+/D+)
Valgancyclovir :
ADJUST THE DOSE IF cr Cl<60ml/min
Monitor CBC every 2 weeks
In case of neutropenia ,stop valgancyclovir ,monitor for CMV and consider preemptive treatment
In children and adolescents less than 18 years dose adjustment to surface area ,maximum dose 900 mg daily.
CMV testing:
Quantitative methods to determine CMV infection like Quantitative Nucleic acid testing should be used ,but should not be used alone to determine the start or the end of treatment
Monitoring of CMV should be offered to:
1-CMV seropositive (D+/R+, D-/R+) and
2-didn’t receive T lymphocyte depleting agent and
3-didn’t receive CMV prophylaxis
Monitoring at least 3 months after transplnt
Treatment Of CMV:
At least 2 weeks of valgancyclovir or gancyclovir then asses after 2 weeks ,repeat at 7 days ,stop when symptoms improve and viral load not detected and assess for resistance to antiviral therapy
Causes of Gancyclovir resistance :
1-prolonged use or sub therapeutic doses
2-seronegative recepients from seropositive donors
3-received intensive immunosuppression
4-Lung transplant
Definition of resistance:persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir.
Workup for resistance: Confirm that dosing is adequate,adherence to treatment plan and absorption Offer testing for Human CMV (HCMV) antiviral resistance UL97 and UL54 gene mutations
Treatment in resistant cases:Foscarnet for 3 weeks
In case of neutropenia,consider decreasing the dose of MMF ,Azathioprine and cyclosporine
Counsel your patient that by decreasing the doses of immunosuppression ,there is increased risk of rejection
Reflection to practice:we almost doing the same as the guidelines
That is a good summary and an interesting analysis. Please type headings and sub-headings in bold or in underline. I like your reflection of your own practice, mentioning the limitations faced by your team. Ajay
o Preventing CMV infection and disease Screen for CMV Ig G antibody in both donor and recipient prior to transplant. If donor status is unknown and recipient is Seronegative or unknown take it as D+/ R-.
o Offer Valganciclovir Prophylaxis for 3 months if – D+/ R – D+ / R+ Or D- / R+ and recipient has received ATG or Alemtuzumab.
o No prophylaxis if D-/R-
o HSV – recipient may need Valganciclovir prophylaxis when receiving Organ from HSV + donor.
o D+/R+ Or D+ /R- or D-|R+, then valganciclovir prophylaxis for 3months after starting treatment for acute allograft rejection.
o Decrease Valganciclovir dose if eGFr < 60 mI/min
o For children and < 18year old adjust don according to BSA up to a max of 900mg OD.
o CBC every 2 weeks while on valganciclovir
o If side effect of Valganciclovir develops consider switching to CMV monitoring and preemptive therapy. Donor CMV Serostatus should be established within 30 days of organ donation. In seronegative donor and recipient recheck prior to transplant.
For D+/R+ and D-/R+ there is no difference between CMV prophylaxis and monitoring with preemptive treatment strategy. In D- / R + Status 40% of patients develop viraemia.
o Lab testing for CMV Lab should use either whole blood or plasma consistently. QNAT to be done. CMV viral load to be reported as IU / ml.
local threshold For viral load which indicates disease or infection requiring treatment be determined. QNAT threshold be Considered together with clinical, laboratory Or histological evidence of CMV disease.
Whole blood QNAT lead is higher than plasma level. Change of 3 Fold in QNAT values be considered significant.
o Monitoring CMV infection and disease. offer monitoring if D+ / R +,D- /R+ Not received T lymphocyte therapy Not Receiving Valganciclovir prophylaxis
Test monthy for atleast 3 months post transplant the viral load.
Algorithm.
D+ /R- prophylaxis for 3 months
D+ /R+ and D-/R+ if received ATG / Alemtuzumab After treatment for acute rejection Prophylaxis In 3 month
if none then – CMV viral load monitoring for 3 months.
D- / R- Prophylaxis not recommended Routine CMV monitoring not recommended.
o Treating CMV infection and disease For pts with CMV infection or disease Oral Valgancilovir for 2 weeks. if eGFR< 60 adjust dose. Watch tor ganciclovir resistance Assess CMV viral load after 2 weeks and repeat after 7 days Stop treatment if symptoms resolved and 2 consecutive CMV viral load tests are negative. iv gancicyclovir is same as oral gancicyclovir efficacy wise Oral dose is 900 mg BD iv gancicgclovir preferred in admitted patients.
o Gancicyclovir Resistance Patients at risk –
Who received long courses of gancicyclovir Or sub therapeutic dose. D+/R- Who received intensive immunosuppression. Recipient of lung transplant
Consider resistance if viral load is persistently high or increasing even after 2-4 weeks of ganciclovir Or Valganciclovir. Confirm compliance and dosages offer iv foscarnet for at least 3 weeks and stop gancicyclovir.
Newer agents – Letermovir and Maribavir.
o Immunosuppression dose reduction Reduce or stop MMF/ Azathioprine if there is evidence of leu copenia. Watch out for rejection Review dose of immunosuppression following resolution of CMV. Low quality evidence to support conversion to an mTori.
in our unit receipients are not given prophylaxis regardless of their sero status and mostly all are live related and do not receive any induction either. CMV monitoring and premptive treatment is also not done,if clinical status dictates CMV viral load is done and infection treated.
Introduction: CMV belong to the herpes group of viruses, and causes severe infection in immune-compromised patients usually 4 to 6 weeks after the transplant. Patients present with non specific symptoms like night sweats, fatigue, myalgia , Diarrhea, abdominal pain, nausea, respiratory distress and retinitis rarely. Also causes bone marrow suppression and fluctuations in AST and ALT.
The sero-status of the Donor/ recipient is characterized as:
D+/R-
D+/R+
D-/R+
D-/R-
Preventing CMV Infection and Disease: Serostatus of both donor and recipient should be known before or at the time of transplantation.
CMV prophylaxis: Valganciclovir prophylaxis should be given to all recipients and continued for at least 03 months who received organ from CMV seropositive donor (D+/R-),has received intensive immunotherapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath ), or are D+/R+ or D-/R+. Dose should be adjusted to creatinine clearance. CMV (D-/R-) patients should not be given prophylaxis. Close monitoring for bone marrow suppression is must.
Laboratory Testing for CMV· CMV viral load should be done via Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma and reported as IU/mL, or copies / mL.
Monitoring for CMV Infection and Disease· Monitoring with PCR is done monthly for at least 03 months for those recipients who are CMV seropositive (D+/R+, D-/R+) and have not received ATG or Alemtuzumab and not receiving valganciclovir prophylaxis
Treating CMV Infection and Disease :Oral Valganciclovir (renal adjusted dose) for a duration of at least 2 weeks and continued till the patient is asymptomatic and two consecutive, CMV viral load tests o1 week apart are negative.
Ganciclovir resistance: Persistent or increasing viral load or symptomatic disease after maximum effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir.Risk factors for resistance include: those recipients who have received long courses , or sub-therapeutic doses of antiviral medications,who are D+/R-,or have taken intensive immunosuppression (e.g; with T-cell depletion therapy).Mutations in the genes like UL97 and UL54 mainly are responsible for resistance. In such cases , Valganciclovir (or Ganciclovir) should be stopped and switched to Intravenous Foscarnet for a duration of at least 3 weeks.
Immunosuppression dose reduction: Calcineurin inhibitor or mycophenolate mofetil / azathioprine should be reduced . Mycophenolate Mofetil (MMF) or azathioprine should be stopped in cases where there is bone marrow suppression ,particularly leucopenia.
Please reflect on your practice
At our center , CMV serology is done for both donor and recipient .Majority are CMV D+/R+. All patients are being given valganciclovir as prophylaxis for 03 months except D-/R-.Treatment of severe disease is being done with ganciclovir and mild moderate cases are being treated with valganciclovir. Doses of both medications are done according to creatinine clearance. Close monitoring of graft function and blood counts done and CBC done every 2 weekly .Antimetabolite –MMF and azathioprine also stopped during the treatment course. PCR is being done every 02 week and treatment is stopped when the PCR 01 week apart is negative and patient is asymptomatic .Resistance viral testing not available in our setup
Executive Summary of Recommendations
1 Preventing CMV Infection and Disease
Determining CMV status in donor and recipient
1.1 All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation [1A]
1.2 If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-). [1D]
CMV prophylaxis
For adults, children and young people receiving a solid organ transplant:
1.3 Offer Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either:
• The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-) [1A] OR
• The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath®), where donor: recipient serostatus is D+/R+ or D-/R+ [1A]
1.4 Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal or pancreas transplants for at least 3 months following transplantation if either:
• The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-) [1C] OR
• The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath®), where donor: recipient serostatus is D+/R+ or D-/R+ [1C]
1.5 Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-) [1D]
1.5.1 Be aware that some recipients who are seronegative for CMV (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention of other Herpes virus infections, e.g; recipients who are seronegative for Herpes Simplex Virus (HSV) receiving an organ from HSV seropositive donors [2D].
1.6 Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+) [2C].
1.7 Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute [1D]
1.8 For children and young people under 18 years, adjust the dose of Valganciclovir according to body surface area, up to a maximum dose of 900mg once daily [1D]
1.9 Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir [1A]
1.10 Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir [1C]
2 Laboratory Testing for CMV
2.1 Clinical Laboratories should use
Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load [1A]
• Transplant centres should adopt a consistent approach to use either whole blood or plasma for quantification of CMV viral load [1C]
• CMV QNAT assays should be calibrated using the WHO International Reference Standard [1C]
• CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used [1C]
2.2 Transplant centres should determine local thresholds of viral load that portend CMV infection or disease requiring treatment, depending on the CMV QNAT assay they use and the population at risk [1C]
2.3 QNAT thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease [1C]
3 Monitoring for CMV Infection and Disease
3.1 Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if:
• They are CMV seropositive (D+/R+, D-/R+) [1B] AND
• They have not received T-lymphocyte depletion therapy [1B] AND
• They are not receiving valganciclovir prophylaxis [1B] (see section 1)
3.2 Where CMV viral load monitoring is offered:
• Consider testing with a frequency of at least monthly [1D]
• Consider testing for at least 3 months following transplantation [1D]
4 Treating CMV Infection and Disease
For adults, children and young people who develop CMV infection or disease following solid organ transplantation:
4.1 Offer treatment with oral Valganciclovir for a duration of at least 2 weeks [1A]
4.2 Adjust the dose of Valganciclovir according to licensed dosing recommendations if creatinine clearance is less than 60ml/minute [1D]
4.3 Be aware of the potential development of ganciclovir resistance (see section 5 for management)
4.4 Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days [1D] AND
• Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected (below the local laboratory threshold for detection) [2D].
5 Ganciclovir resistance
5.1 Be aware that the following people are at increased risk of Ganciclovir resistance:
• Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications [1A]
• CMV seronegative recipients receiving a solid organ transplant from seropositive donors (D+/R-) [1C]
• Those who have received intensive immunosuppression (e.g; with T-cell depletion therapy, following episodes of acute allograft rejection) [1B]
• Recipients of lung transplants [2C]
5.2 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 [1A]
5.3 In people with suspected resistance to Ganciclovir:
• 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 [1A]
• Use either whole blood or plasma [1A]
5.4 In people with evidence of ganciclovir resistance:
• Stop Valganciclovir (or Ganciclovir) [1A]
• Offer Intravenous Foscarnet for at least 3 weeks [1B]
o Seek specialist virology advice before commencing treatment with Foscarnet [1D]
6 Immunosuppression dose reduction
For adults, children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation:
6.1 Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine [1C]
• Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia [2C]
6.2 Discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction [1D]
6.3 Review the dosing of immunosuppression following resolution of CMV infection or disease [1D]
7 Information, education and support
7.1 Offer balanced and accurate information to children, adults and young people undergoing solid organ transplantation about:
• The risks of CMV infection and disease according to donor / recipient CMV serostatus and nature of immunosuppression planned or received
• Monitoring and treatment options, including prophylaxis
7.2 Ensure that healthcare professionals offering information have specialist knowledge about CMV infection and disease and their treatment, and the skills to support shared decision-making (for example, presenting information in a form suitable for developmental stage)
In this article, we will start prophylaxis of CMV in IgG positive for either donor and recipient, VGAN will be given for 3 months for those has low immunological risk and not receiving ATG or ALMUZumab at induction.
VGAN will not be given in the case of IgG-negative donors and recipients.
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+).
Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir
Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load
Where CMV viral load monitoring is offered: Consider testing with a frequency of at least monthly Consider testing for at least 3 months following transplantation
All organ donors and recipients should be screened by CMV (IgG antibody) serology prior to, or at the time of transplantation and If donor CMV serostatus is unknown for a negative recipient ,then he should considered positive.
CMV prophylaxis For adults, children and young people receiving a solid organ transplant:
Valganciclovir for at least 3 months following transplantation if either: (D+/R-) or the recipient has received ATG or Alemtuzumab . Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-) . Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+).
[Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute and or young people under 18 years, adjust the dose of Valganciclovir according to body surface area, up to a maximum dose of 900mg once daily
Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir
Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load
Where CMV viral load monitoring is offered: Consider testing with a frequency of at least monthly Consider testing for at least 3 months following transplantation
Offer treatment with oral Valganciclovir for a duration of at least 2 weeks. Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days AND Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected (below the local laboratory threshold for detection)
Be aware that the following people are at increased risk of Ganciclovir resistance:
1- Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications
2- CMV seronegative recipients receiving a solid organ transplant from seropositive donors (D+/R-)
3- Those who have received intensive immunosuppression (e.g; with T-cell depletion therapy, following episodes of acute allograft rejection)
4- Recipients of lung transplants
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 . In people with evidence of ganciclovir resistance: Stop Valganciclovir (or Ganciclovir). Offer Intravenous Foscarnet for at least 3 weeks.
Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia .
Our local practice is similar to these recommendations .
Introduction:
CMV in Solid Organ Transplant Recipients
o (D+/R-): Risk of primary infection.
o (D+/R+)- Risk of super-infection or reactivation.
o (D-/R+)- Risk of reactivation of latent infection.
o (D-/R-)- Risk of primary infection from other source.
Preventing CMV infection and disease:
Determine the donor/recipient CMV Sero-status:
prior to transplantation all donors and recipients are screened for CMV IgG to identify the CMV sero-status. If the donor is CMV +ve and the recipient is sero-negative or unknown for CMV, this should be considered as (D+/R-).
CMV prophylaxis
(D+/R-)
If D+/R+ or D-/R+ received a T-lymphocyte depleting agent (ATG or Alemtuzumab)
Laboratory Testing for CMV
Monitoring for CMV Infection and Disease
· CMV viral load is monitored to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if:
o D+/R+, D-/R+)
o They have not received T-lymphocyte depletion therapy
o They are not receiving valganciclovir prophylaxis
· When CMV viral load monitoring is offered, it is tested at least monthly, for at least 3 months following transplantation
Treating CMV Infection and Disease
For adults, children and young people who develop CMV infection or disease following solid organ transplantation:
Ganciclovir resistance
Risks of Ganciclovir resistance include:
Ganciclovir resistance is considered if: there is persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration of Ganciclovir or Valganciclovir.
In people with suspected resistance to Ganciclovir:
In people with evidence of ganciclovir resistance:
Immunosuppression dose reduction:
For adults, children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation:
Information, education and support
· Offer balanced and accurate information about the risks of CMV infection and disease according to donor / recipient CMV sero-status
· The nature of immunosuppression planned or received ,the monitoring and treatment options including prophylaxis.
· Ensure the presence of skillful knowledgeable healthcare professionals to offer information about CMV infection and disease , their treatment, and the skills to support shared decision-making.
Please reflect on your practice
In NHS Grampian , The Edinburgh renal transplantation unit protocol for CMV prophylaxis is used:
A prophylactic approach is used
All renal transplant recipients except (D-/R-) receive oral valganciclovir for 6 months.
D-/R- recipients who received an induction therapy with lymphocyte depleting agents (ATG, Alemtuzumab) will receive same prophylaxis.
Valganciclovir dose is not exceeding 450mg OD(even in eGFR>60 ml/min).
Dose adjustment is done according to creatinine clearance.
Monitor FBC and LFTs during therapy
1. Please summarize these guidelines
Before transplantation, both recipient and donor should be tested for CMV Ig G and Ig M to stratify the risk of acquiring CMV infection post transplantation.
If serology is not known for both, or recipient is negative and donor is unknown, it should be considered as high risk group. ( D+/R-).
CMV prophylaxis
3months of valganciclovir, should be considered if:
1-The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-) [1A]
2-The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath ), where donor: recipient serostatus is D+/R+ or D-/R+.
Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-), however it may be required for prevention of Herpes infection.
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive.
Dose of valganciclovir needs to be adjusted, if e GFR <60ml/min.
Monitoring of CBC every 2 weeks is needed while patient is on valgaciclovir. If neutropenia developed we may need to switch to monitoring and pre emptive therapy instead of prophylaxis.
Laboratory Testing for CMV
· Clinical Laboratories should use PCR base methods for CMV DNA
· It is highly sensitive and specific
· Antigen based methods, pp65 have been replaced by DNA based ones.
· It has high false negative result, notably in leucopenia.
Monitoring:
Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if:
They are CMV seropositive (D+/R+, D-/R+),
AND They have not received T-lymphocyte depletion therapy,
AND They are not receiving valganciclovir prophylaxis.
If monitoring is offered: it is advised to do testing monthly and for at least 3 months following transplantation.
Treating CMV Infection and Disease
For adults, children with CMV infection or disease following solid organ transplantation:
· Advised to give treatment with oral Valganciclovir for a duration of at least 2 weeks.
· Dose of Valganciclovir to be adjusted according to creatinine clearance if it is less than 60ml/minute.
· We need to assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days.
· Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV negative tests.
Ganciclovir resistance:
Following people are 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).
· Recipients of lung transplants.
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.
In people with suspected resistance to Ganciclovir:
· Check adequacy, adherence to treatment plan and absorption.
· Offer testing for Human CMV (HCMV) antiviral resistance UL97 and UL54 gene mutations.
· In people with evidence of ganciclovir resistance: consider Intravenous Foscarnet for at least 3 weeks. Seek specialist virology advice before commencing t
Immunosuppression dose reduction:
Dose of mycophenolate/azathioprine needs to be reduced in patient with CMV infection specially if there is leucopenia. When dose reduced patient or his care giver should be counselled about risk of rejection.
2. Please reflect on your practice
In our center we screen both donor and recipient with CMV Ig G.
Prophylaxis is given for all recipients except for donor negative and recipient negative.
Duration of prophylaxis is given for 3months, unless donor is positive and recipient negative, where we give it for 6months.
Treatment is given for a minimum of 3 weeks, then we give prophylaxis dose for 2months.
CMV is one of the herpes group of viruses,
Primary infection with CMV typically occurs approximately four to six weeks posttransplant.
The frequency of CMV disease in solid organ transplant (SOT) recipients varies markedly
depending on the definition of CMV disease that is used and the intensity of
immunosuppression.
preventing CMV disease included avoiding
transplanting a seropositive organ into a seronegative recipientanti-CMV Prophylaxis and pre-emptive anti-CMV therapy are in common use to
minimise the impact of CMV infection or reactivation.
Treatment of CMV Disease
Offer treatment with oral Valganciclovir for a duration of at least 2 weeks .
*Adjust the dose of Valganciclovir according to licensed dosing recommendations if
creatinine clearance is less than 60mL/minute
*Be aware of the potential development of ganciclovir resistance
*Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of
7 days
Monitoring CMV Infection and Disease
They are CMV seropositive (D+/R+, D-/R+)
They have not received T-lymphocyte depletion therapy
They are not receiving valganciclovir prophylaxis
•CMV is one of Herpes viruses which is HHV-5
•CMV usually manifests in immunosuppressed patients e.g transplant recipients
•CMV infection occurs as early as twenty days and not more than 50 days after transplantation if not received antivirals
•pp65 antigenemia assay and PCR are the main diagnostic tools
• Serology is of limited role for the diagnosis of active disease
Histology of the affected tissue and bronchoalveolar lavage analysis are useful in the diagnosis of invasive disease.
CMV Antigenemia test
•Rapid way in detection of CMV which is engulfed by neutrophils in the blood
• detection of monoclonal antibodies against pp65 CMV
•Advantages are
1.Early diagnosis of CMV infection
2.No need for an advanced labs and can be performed in A small capacity laboratories
•Disadvantages
1.Need to be performed within 6 hours of blood sampling
2.Subjective test
Cannot be performed in leucopenic patients below 1000
Quantitative Polymerized Chain Reaction Test
•Main diagnostic tool nowadays
•Accurate detection of replication of CMV
•Used before deciding pre-emptive treatment
•Monitoring response to treatment
This is the British Transplantation Society guidelines for CMV infection and disease following solid organ transplantation
1- All organ donors and recipients should be screened for CMV (IgG antibody)serostatus prior to, or at the time of transplantation [1A]
2- If donor CMV serostatus is unknown and recipient is seronegative or unknown forCMV, this should be characterised as donor seropositive, recipient seronegative for CMV(D+/R-). [1D]
CMV prophylaxis :
Valganciclovir prophylaxis for 3 month in these conditions :
1-If the recipient is seronegative for CMV and the donor is CMVseropositive (D+/R-) [1A]
2- If the recipient has received T-lymphocyte depletion therapy with Antithymocytegobulin (ATG) or Alemtuzumab (Campath), where donor: recipient serostatus is D+/R+ or D-/R+ [1A]
3- If treatment of acute allograft rejection is started if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+) 2C
Treatment of CMV Infection and Disease :
Oral Valganciclovir for at least 2 weeks [1A
]Assess CMV viral load after 2 weeks of treatment and repeat after one week
Consider resistance if there is a persistent or increasing viral load or symptomatic disease after the effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir [1A]. So you need to:
Stop Valganciclovir (or Ganciclovir) [1A]
Offer Intravenous Foscarnet for at least 3 weeks [1B]
Seek specialist virology advice before commencing treatment with Foscarnet [1D)
Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil /azathioprine [1C]
CMV pcr to deted status of donor and recipient.
CMV prophylaxis:
If the donor is positive
Or the recipient is positive
We use valciclovir for three months.
We monitor with blood pcr until serostatus become negative.
Treatment:
We use Valganciclovir 900 for three months.
If ressist wecan reduce immuosuppresion drugs especially antimetabolic agents .
In order to prevent CMV infection and its associated disease, certain measures are recommended. One crucial step is to determine the CMV serostatus of both the organ donor and recipient prior to transplantation. Screening for CMV (IgG antibody) serostatus should be conducted for all organ donors and recipients either before or at the time of transplantation. If the CMV serostatus of the donor is unknown and the recipient is either seronegative or the CMV status is unknown, it is classified as (D+/R-) for CMV.
CMV prophylaxis is an important approach to prevent CMV infection in transplant recipients. For individuals who have undergone kidney or liver transplantation, Valganciclovir prophylaxis should be offered for a minimum of three months following the transplantation if they fall under the D+/R- category or if the recipient has received (ATG) or Alemtuzumab, regardless of the CMV serostatus. Similarly, for heart, lung, intestinal, or pancreas transplant recipients, Valganciclovir prophylaxis should be considered for at least three months following transplantation if they fall under the D+/R- category or if the recipient has received (ATG) or Alemtuzumab.
Furthermore, Valganciclovir prophylaxis should be considered for a minimum of three months after initiating treatment for acute allograft rejection if either the donor or recipient is CMV positive (D+/R-, D+/R+, or D-/R+). It is important to adjust the Valganciclovir dose if the patient’s creatinine clearance is less than 60 ml/min. Similarly, for children and young individuals under 18 years of age, the Valganciclovir dose should be adjusted accordingly.
To ensure proper management and detect any potential adverse effects, regular monitoring is essential during Valganciclovir prophylaxis. Full blood count should be monitored at least every two weeks while the patient is on Valganciclovir.
Implementing these preventive measures is crucial to reduce the risk of CMV infection and its associated complications in transplant recipients. Adhering to appropriate prophylactic strategies and closely monitoring patients can significantly contribute to favorable outcomes in terms of CMV infection prevention.
In the laboratory testing for CMV, it is recommended that clinical laboratories utilize Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to measure the CMV viral load. Transplant centers should establish local thresholds for viral load that indicate the presence of CMV infection or disease requiring treatment. These thresholds may vary depending on the specific CMV QNAT assay used by the laboratory and the population at risk.
It is important to note that QNAT thresholds alone should not be used as the sole determinant for initiating or discontinuing treatment in individuals with CMV disease. Instead, they should be considered alongside clinical, laboratory, or histological evidence of CMV disease. The decision to commence or cease treatment should be made based on a comprehensive assessment of the patient’s clinical condition and other relevant factors.
To effectively monitor CMV infection and disease in recipients of solid organ transplants, certain strategies should be implemented. For individuals who are CMV seropositive (D+/R+, D-/R+) and have not undergone T-lymphocyte depletion therapy or are not receiving valganciclovir prophylaxis, it is recommended to monitor CMV viral load. This monitoring helps guide the need for pre-emptive therapy.
Consideration should be given to testing for CMV viral load at least monthly for a minimum of three months following transplantation. This regular monitoring allows for timely detection of CMV infection and facilitates appropriate intervention if necessary. By closely monitoring the CMV viral load, healthcare providers can assess the dynamics of CMV replication and make informed decisions regarding the management of CMV infection and the initiation of treatment.
Implementing a robust monitoring protocol for CMV viral load enhances the ability to identify early signs of CMV infection or disease in transplant recipients. Regular testing and vigilance during the critical post-transplant period provide valuable insights into the patient’s CMV status and facilitate timely interventions to prevent disease progression.
By utilizing QNAT to quantify the CMV viral load, laboratories can provide valuable information for monitoring CMV infection and disease progression. However, it is essential to interpret these results in conjunction with other clinical and diagnostic findings to ensure accurate diagnosis and appropriate treatment decisions.
In the management of CMV infection and disease in recipients of solid organ transplantation, specific treatment strategies should be implemented. When CMV infection or disease is detected, it is recommended to initiate treatment with oral Valganciclovir for a minimum duration of two weeks. The dosage of Valganciclovir should be adjusted in accordance with approved dosing recommendations if the recipient’s creatinine clearance is below 60ml/minute.
Healthcare providers should be mindful of the potential development of ganciclovir resistance, as it can impact treatment effectiveness. Therefore, regular monitoring of CMV viral load is essential. After two weeks of treatment, CMV viral load should be assessed, and subsequent measurements should be conducted at intervals of at least seven days. Additionally, treatment for CMV disease can be considered for discontinuation once the symptoms have resolved and two consecutive CMV viral load tests confirm the absence of detectable CMV.
By adhering to these treatment approaches, healthcare providers can effectively manage CMV infection and disease in transplant recipients. The use of Valganciclovir, dose adjustments based on renal function, regular viral load monitoring, and careful evaluation of treatment response contribute to successful outcomes in controlling CMV infection.
In our transplant unit, we employ oral valganciclovir as a prophylactic measure against CMV infection based on the recipient’s risk category. For D+/R- patients, the recommended duration of prophylaxis is 200 days. R+ patients are given prophylaxis for a period of 100 days. Additionally, patients who receive ATG as induction therapy are administered prophylaxis for 100 days. It is worth noting that our unit does not conduct routine surveillance using serology or CMV PCR for monitoring CMV infection.
Please summarize these guidelines:
Prevention of CMV infection and disease:
D/R CMV status: screening before transplantation, if the donor or recipient CMV serology status is unknown, presume D+/R-.
CMV prophylaxis:
D+/R-: valganciclovir for 3 months.
D+/R+ or D-/R+ with induction ATG/ Alemtuzumab: valganciclovir 3 months.
D-/R-: CMV prophylaxis is not required.
Treatment of acute rejection for D+/R-, D+/R+ or D-/R+ consider valganciclovir 3 months.
Dose adjustment of valganciclovir according to GFR and BSA
Monitor FBC every 2 weeks during prophylaxis. If neutropenic-à stop valganciclovir and switch to CMV monitoring and pre-emptive therapy (if symptomatic or viremia).
CMV testing:
Whole blood or plasma for CMV-QNAT to estimate viral load.
Viral load should be reported as IU/ml, use conversion factor if reported as copies/ml.
Local transplant centers should adopt methods for viral load estimation and local threshold for QNAT that corroborate with cmv INFECTION/DISEASE requiring treatment.
Starting or stopping CMV treatment should be correlated to clinical, laboratory or histological CMV disease evidence.
Monitoring for CMV infection and disease:
Test monthly for at least 3 months post-transplant for the following candidates:
SOT recipients with CMV D+/R+, CMV D-R+.
Recipients not receiving T-lymphocyte depleting therapy.
Recipients not receiving valganciclovir prophylaxis.
Treatment of CMV infection and disease:
Valganciclovir 900mg BD for at least 2 weeks, adjust dose according to GFR.
Assess viral load after 2 weeks of treatment then every 7 days.
Stop treatment after resolution of symptoms and no-detection of 2 consecutive weekly tests.
Ganciclovir Resistance:
Risk factors: prolonged courses, sub-therapeutic doses, CMV D+/R- recipients, recipients receiving heavy immune-suppression (ATG or Alemtuzumab induction or treatment of acute rejection) and lung transplant recipients.
Resistance is considered if symptoms persist or viral load increases or not reducing after a normal effective dose for 2-4 weeks. We need to confirm proper dosing and compliance to treatment. We need to test for human CMV anti-viral resistance mutations (UL97, and UL54 gene mutations).
If resistance is proven, stop valganciclovir (or ganciclovir), use IV foscarnet for at least 3 weeks which should be guided by specialist virology advice.
Immunosuppression reduction is to be considered.
Patient information and education.
CMV virus is one of the herpes virus group, after primary infection the virus enters a latent state.
The percentage of seropositive population is about 40% at age of 20 years and 80% at age 60.
Transmission occurs from direct person to person contact.
CMV infection : evidence of virus replication
1. Asymptomatic infection.
2. Viral syndrome
3. CMV disease
Determining CMV status in donor and recipient
All organ donors and recipients should be screened for CMV ( IgG antibody) status before transplant.
If the donor CMV serostatus is unknown and the recipient is unknown or seronegative, the donor is considered to be seropositive.
CMV prophylaxis
Consider Valganciclovir prophylaxis for at least 3 months if
.. if the donor: recipient serostatus is D+/R-
Or the recipient has received T cell depleting agent, where D+/R+ or D-/R+.
Don’t routinely offer Valganciclovir prophylaxis if the donor and recipient are seronegative.
Consider CMV prophylaxis for at least 3 months after starting the treatment of acute rejection.
Valganciclovir need dose adjustment if creatinine clearance less than 60, monitoring of blood count should be done every 2 weeks while on Valganciclovir.
Laboratory testing for CMV
Using quantitative nucleic acid testing (QNAT) of whole blood or plasma to quantify viral load , which should be reported as IU/mL
Treatment CMV infection and disease
Consider treatment with oral Valganciclovir for a duration of at least 2 weeks.
Assess CMV viral load after 2 weeks of treatment and Consider stopping treatment after resolution of symptoms and two consecutive CMV viral load that confirm that CMV is not detected.
Consider resistance to Ganciclovir if there is a persistent or increasing viral load or symptomatic disease after 2 to 4 weeks of treatment, stop Valganciclovir and offer intravenous Foscamet for at least 3 weeks.
Immunosuppression dose reduction
Consider reduction of the dose of Calcineurin inhibitors, MMF or Azathioprine
No transplant center in our hospital
Preventing CMV Infection and Disease Determining CMV status in donor and recipient
.1 All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation .
2 If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-).
CMV prophylaxis For adults, children and young people receiving a solid organ transplant: .
Offer Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either:
The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-)
OR The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath ), where donor: recipient serostatus is D+/R+ or D-/R+ .
.
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+).
Laboratory Testing for CMV
Transplant centres should adopt a consistent approach to use either whole blood or plasma for quantification of CMV viral load .
CMV viral load should be reported as IU/mL, where possible,
Treating CMV Infection and Disease
Offer treatment with oral Valganciclovir for a duration of at least 2 weeks (dose adjusted according to graft function)
Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days AND Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected .
Ganciclovir resistance
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 [1A]
Offer testing for Human CMV (HCMV) antiviral resistance UL97 and UL54 gene mutations.
Treatment of ganciclovir resistance-
Stop Valganciclovir (or Ganciclovir) . Offer Intravenous Foscarnet for at least 3 weeks.
Immunosuppression dose reduction
For adults, children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation-:
Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine .Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia.
Since almost ( > 90%) all of our transplant are D+R+, we give prophylaxis for 3 month oral valganciclovi,Dose – 450 mg to all ,.
Treatment-we give oral valganciclovir,usual dose is 450 bd for 21 days unless He/she have severe graft dysfunction –we dont give secondry prophlaxis. We generally reduce dose of immunosuppression by 50%(MMF) and follow with Blood PCR
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION
1 Preventing CMV Infection and Disease:
Determining CMV status in donor and recipient: All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation
If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-).
CMV prophylaxis
For all patients receiving a solid organ transplant:
-Commence Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either:
1-The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-)
2-The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath ), where donor: recipient serostatus is D+/R+ or D-/R+
3-Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-).
4-Some recipients who are seronegative for CMV (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention of other Herpes virus infections.
5-Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+).
6-Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute.
7-Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir.
8-Quantitative CMV PCR thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease.
Laboratory Testing for CMV
Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load. CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used. Monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant.
Consider testing for at least 3 months following transplantation.
Treating CMV Infection and Disease
1-For adults, children and young people who develop CMV infection or disease following solid organ transplantation: commence treatment with oral Valganciclovir for a duration of at least 2 weeks.
2-Assess CMV viral load after 2 weeks of treatment.
3- Consider stopping treatment for CMV disease after resolution of symptoms and two consecutive CMV viral load tests that confirm that CMV is not detected.
Ganciclovir resistance
The following people are at increased risk of Ganciclovir resistance:
1-Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications.
2- CMV seronegative recipients receiving a solid organ transplant from seropositive donors (D+/R-).
3-The patients who have received intensive immunosuppression (e.g; with T-cell depletion therapy, following episodes of acute allograft rejection).
4- Recipients of lung transplants.
5-Consider resistance to Ganciclovir if: There is a persistent or increasing viral load or symptomatic disease after optimal dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir.
When you suspected resistance to Ganciclovir:
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
In people with evidence of ganciclovir resistance:
Stop Valganciclovir (or Ganciclovir).
Offer Intravenous Foscarnet for at least 3 weeks
Immunosuppression dose reduction
-Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia.
-Review the dosing of immunosuppression following resolution of CMV infection or disease.
Introduction :
CMV infection: evidence of the virus undergoing a complete replication cycle and producing new infectious virions. This may be further characterised as:
1. Asymptomatic infection (no obvious signs of pathologic symptoms)
2. Viral syndrome (fever, leucopenia, myalgia or arthralgia)
3. CMV disease – (histopathological evidence of CMV, CMV retinitis diagnosed by an ophthalmologist, or CMV in the CSF indicative of CNS disease) Latent CMV: A state of virus infection in which the full replication cycle of the virus is not occurring
All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation .
If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterized as donor seropositive, recipient seronegative for CMV (D+/R-)
CMV Prophylaxis :
Offer Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either:
Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-) .
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+ .
Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir
Laboratory Testing for CMV :
Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load .
Monitoring for CMV Infection and Disease :
Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if:
Where CMV viral load monitoring is offered:
Treating CMV Infection and Disease :
For adults, children and young people who develop CMV infection or disease following solid organ transplantation:
Ganciclovir resistance :
Be aware that the following people are at increased risk of Ganciclovir resistance:
Consider resistance to Ganciclovir if:
In people with suspected resistance to Ganciclovir:
In people with evidence of ganciclovir resistance:
Immunosuppression dose reduction :
For adults, children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation:
Treatment of CMV Disease :
Early studies emphasised the need to reduce immunosuppression as well as giving specific antiviral therapy . Intravenous Ganciclovir has had a major impact on the mortality and morbidity of CMV disease . High doses of intravenous Hyperimmune globulin (0.5 g/kg body weight) have been used in conjunction with Ganciclovir for the treatment of pneumonitis
There is a significant risk of relapse following successful treatment of CMV disease, with recurrent CMV disease reported in various organ recipients . Secondary prophylaxis after treatment of disease has been assessed, although evidence in support of this strategy is limited .
These British Transplantation Society (BTS) guidelines published in 2022 provide evidence-based recommendations and suggestions for both the prevention and treatment of CMV infection/disease in solid organ transplant (SOT) recipients. The authors utilise the GRADE system to clearly signal to the reader how robust the evidence for each particular recommendation is, where quality of evidence is graded A-D (high-very low) and the strength of the resulting guidance is measured as either 1 (strong- applying to almost all patients) or 2 (weaker- risk/benefits may need to be assessed as the underpinning evidence is less robust).
Important definitions relevant to the guideline:
CMV infection
CMV infection is present when the virus is undergoing a complete replication cycle. It is important to note the definitions for different stages of CMV infection:
1. Asymptomatic infection: virus can be detected in patient’s blood but the patient is asymptomatic
2. Viral syndrome: detection of CMV virus plus symptoms such as fever/Leucopenia/myalgia/arthralgia
3. CMV disease: detection of CMV in the blood plus 1 of the following: i) histopathological evidence (biopsy findings) consistent with CMV disease in a particular organ ii) confirmed diagnosis of CMV retinitis or iii) CMV detection in the cerebrospinal fluid
The definition for latent CMV is when the patient has evidence of prior exposure to CMV but the virus is not currently undergoing a full replication cycle.
Summary of key areas covered by the guideline:
1. Prevention of CMV infection and disease
· there is very robust evidence to recommend confirmation of both donor and recipient CMV serostatus prior to transplantation
· recommendations for prophylaxis or monitoring with pre-emptive therapy can then be directed to the most high-risk patients, i.e. D+/R- or those receiving T-cell depleting immunosuppression (ATG or alemtuzumab) in all categories except D-/R-. This should be oral valganciclovir for at least 3 months
· low risk patients (D-/R-) do not require prophylaxis for CMV but they might still require oral valganciclovir for other indications e.g. HSV seronegative patient receiving a HSV seropositive organ
· oral valganciclovir for at least 3 months should also be considered in the context of treatment for acute allograft rejection for all serostatus combinations except D-/R- due to the noted association between rejection and late CMV disease
· valganciclovir is renally excreted so care should be taken to adjust the dose where creatinine clearance is <60 ml/min. Side effects include neutropenia (monitor FBC every 2 weeks during treatment). If patients develop significant side effects a switch in strategy may be required (e.g. from standard prophylaxis switch to monitoring of CMV levels with pre-emptive therapy as required)
· There is currently insufficient evidence to provide a standardised guideline about secondary CMV prophylaxis following an episode of treated CMV infection/disease
2. Laboratory testing for CMV
· there is robust evidence to show that quantitative nucleic acid testing (QNAT) is the best test to measure CMV virus levels in whole blood or plasma
· there is no universally agreed threshold at which detection of a certain CMV virus level should prompt treatment of CMV infection/disease; instead, thresholds should be determined individually by local centres considering both their local population and other clinical factors including histology and symptoms
3. Monitoring CMV infection and disease
· An alternative strategy to routine CMV prophylaxis with oral valganciclovir (as above) is to initiate surveillance of CMV virus levels (QNAT testing) post-transplantation and instigate pre-emptive therapy when a locally-agreed threshold is reached. If this strategy is employed it is recommended surveillance testing is performed at least monthly for at least 3 months after transplantation. This strategy is suitable for intermediate-risk patients, e.g. D+/R & D-/R+ patients who have not received T-cell depleting immunosuppression and who are not receiving oral valganciclovir
4. Treating CMV infection and disease
· there is strong evidence to recommend a minimum 2 week course of oral valganciclovir for treatment of CMV infection and disease
· CMV viral load should be checked after 2 and 3 weeks and treatment should only be discontinued when symptoms have resolved and there are 2 consecutive CMV virus titres below the locally-agreed threshold (the evidence for this recommendation is less robust)
5. Ganciclovir resistance
Risk factors for developing ganciclovir resistance:
1. prolonged course or subtherapeutic doses of anti-viral medication
2. D+/R-
3. intensive immunosuppression e.g. T-cell depleting agent such as ATG or treatment for acute rejection
4. lung transplant recipients
If ganciclovir resistance is proven, stop ganciclovir or valganciclovir and offer Forcarnet treatment as an alternative
6. Immunosuppression dose reduction
· If SOT recipients develop CMV infection/disease consideration should be given to whether their immunosuppression can be reduced- this should be preferentially anti-metabolite reduction prior to calcineurin reduction, particularly if there is Leucopenia. Patients should be counselled about the risk/benefit of this strategy including the risk of acute rejection. Once the CMV infection has been resolved their immunosuppression should be re-reviewed.
7. Information, education and support
· Appropriate patient counselling is important including helping SOT recipients understand their individualised risk profile based upon donor/recipient CMV serostatus and immunosuppression used
Reflection on local practice
· In recognition of the high-risk status of D+/R- patients our centre gives 200 days of valganciclovir prophylaxis to all of these patients regardless of induction immunosuppression used. These BTS guidelines recommend at least 3 months of prophylaxis but I note that both the Sheffield protocol shared in this journal club and the American Society of Transplantation Infectious Diseases Community of Practice guidelines give a 6 month course for these patients so our practice is in common with this
· We use alemtuzumab as our most common induction agent. However, I was surprised to note that our prophylaxis protocol for intermediate-risk patients receiving alemtuzumab has shorter durations: in contrast to the Sheffield protocol our D+/R+ and D-/R+ patients who receive alemtuzumab induction get 100 days prophylactic valganciclovir rather than 200 days. Furthermore, for those intermediate-risk patients who have not received alemtuzumab we do not routinely give prophylaxis
· Low-risk D-/R- patients do not receive prophylaxis which seems similar to practice from other centres and that recommended in these guidelines.
· We reserve pre-emptive monitoring as a second line strategy for patients who are not able to tolerate valganciclovir due to side effects
· Our treatment of CMV disease follows the recommendations outlined in these guidelines
References:
1. UK guideline on Prevention and Management of cytomegalovirus (CMV) infection and disease following solid organ transplantation [Internet]. British Transplantation Society. 2022 [cited 2023Mar23]. Available from: https://bts.org.uk/uk-guideline-on-prevention-and-management-of-cytomegalovirus-cmv-infection-and-disease-following-solid-organ-transplantation/
2. 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. Available at: https://pubmed.ncbi.nlm.nih.gov/30817026/
3. Sheffield Teaching Hospitals NHS Foundation Trust. Protocol for prophylaxis, surveillance and treatment of CMV after renal transplantation. 2016.
1- Preventing CMV Infection and Disease: Determining CMV status in donor and recipient
1.1 All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation . [1A]
1.2 If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV(D+/R-). [1D]
CMV prophylaxis:
For adults, children and young people receiving a solid organ transplant:
1.3 Offer Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either:
a- The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-) [1A]
OR
b- The recipient has received T-lymphocyte depletion therapy with Antithymocytegobulin (ATG) or Alemtuzumab (Campath), where donor: recipient serostatus is D+/R+ or D-/R+ [1A]
1.4 Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal or pancreas transplants for at least 3 months following transplantation if either:
The recipient is seronegative for CMV and receives an allograft from a CMVseropositive donor (D+/R-) [1C]
OR
The recipient has received T-lymphocyte depletion therapy with Antithymocytegobulin (ATG) or Alemtuzumab (Campath), where donor: recipient serostatus isD+/R+ or D-/R+ [1C]
1.5 Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-) [1D]
1.5.1 Be aware that some recipients who are seronegative for CMV (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention of other Herpes virus infections,e.g; recipients who are seronegative for Herpes Simplex Virus (HSV) receiving an organ from HSV seropositive donors [2D].
1.6 Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+) [2C].
1.7 Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute [1D]
1.8 For children and young people under 18 years, adjust the dose of Valganciclovir according to body surface area, up to a maximum dose of 900mg once daily [1D]
1.9 Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir [1A]
1.10 Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir [1C]
2 Laboratory Testing for CMV
2.1 Clinical Laboratories should use Quantitative Nucleic Acid Testing (Q NAT) of whole blood or plasma to quantify CMV viral load [1A]
2.2 Transplant centres should determine local thresholds of viral load that portend CMVinfection or disease requiring treatment, depending on the CMV Q NAT assay they use and the population at risk [1C]
2.3 Q NAT thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease [1C]
3 Monitoring for CMV Infection and Disease:
3.1 Offer monitoring of CMV viral load to guide pre-emptive therapy to people receiving a solid organ transplant if:
a- They are CMV seropositive (D+/R+, D-/R+) [1B] AND
b- They have not received T-lymphocyte depletion therapy [1B] AND
c- They are not receiving valganciclovir prophylaxis [1B]
3.2 Where CMV viral load monitoring is offered:
a- Consider testing with a frequency of at least monthly [1D]
b- Consider testing for at least 3 months following transplantation [1D]
4 Treating CMV Infection and Disease:
For adults, children and young people who develop CMV infection or disease followi ngsolid organ transplantation:
4.1 Offer treatment with oral Valganciclovir for a duration of at least 2 weeks [1A]
4.2 Adjust the dose of Valganciclovir according to licensed dosing recommendations if creatinine clearance is less than 60ml/minute [1D]
4.3 Be aware of the potential development of ganciclovir resistance .
4.4 Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days [1D]
AND
Consider stopping treatment for CMV disease
– after resolution of symptoms AND
– two onsecutive, CMV viral load tests that confirm that CMV is not detected [2D].
5 Ganciclovir resistance:
5.1 Be aware that the following people are at increased risk of Ganciclovir resistance:
a- Those who have received prolonged courses, or sub-therapeutic doses of antiviralmedications [1A]
b- CMV seronegative recipients receiving a solid organ transplant from seropositive donors (D+/R-) [1C]
c- Those who have received intensive immunosuppression (e.g; with T-cell depletiontherapy, following episodes of acute allograft rejection) [1B]
d- Recipients of lung transplants [2C]
5.2 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 [1A]
5.3 In people with suspected resistance to Ganciclovir:
a- Confirm that dosing is adequate .
b- Consider adherence to treatment plan and absorption .
c- Offer testing for Human CMV (HCMV) antiviral resistance .
d- UL97 and UL54 gene mutations . [1A]
e- Use either whole blood or plasma . [1A]
5.4 In people with evidence of ganciclovir resistance:
a- Stop Valganciclovir (or Ganciclovir) [1A]
b- Offer Intravenous Foscarnet for at least 3 weeks. [1B]
c- Seek specialist virology advice before commencing treatment with Foscarnet[1D]
6- Immunosuppression dose reduction:
For adults, children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation:
6.1 Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil /azathioprine [1C]
– Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia [2C]
6.2 Discuss with patients, and, where appropriate, parents or carers, the risk of acuterejection with immunosuppression dose reduction [1D]
6.3 Review the dosing of immunosuppression following resolution of CMV infection or disease [1D]
Q2 reflect on your practice .
In our center
1- the ( donor and recipient ) tested for CMV IgG.
2- Valgancyclovir or valciclovir is offered for every recipient with any sero-positivity .
3- Acyclovir prophylaxis is offered in sero-negative state to prevent herps simplex infection .
4- The donor and recipient is not tested for herpes simplex sero state in our center.
5- Valgancyclovir is offered for at least 3 months .
6- QNAT used for diagnosis and treatment decision.
7- We use valgancyclovir for treatment .
8- We did not face a cse of gancyclovir or valgancyclovir resistance case .
9- We start immunsupressive medication dose reduction especially in sever patient .
10- – we reduce the dose of MMF OR AZATHIOPRINE at first with close monitoring the renal function test for early diagnosis of acute rejection.
Preventing CMV infection and disease
-Determine CMV serostatus in donor and recipient by CMV- IgG antibody prior or at the time of transplantation.
–CMV prophylaxis
– Valganciclovir prophylaxis at least 3 month following transplantation if-
D+/ R – OR
D+/R+ or D-/ R+( When recipient has received T- lymphocyte depletion therapy)
D-/R-(not routinely, may require for prevention of other herpes virus.
– Dose adjustment of valganciclovir according to creatinine clearance & body surface area. Monitor with full blood count every 2 weekly.
–Laboratory testing for CMV
Use Quantitative Nucleic Acid Testing ( QNAT) of whole blood or plasma to quantify CMV viral load.
– CMV infection and disease monitoring
Consider testing at least monthly for 3 month following transplantation.
Monitoing of CMV viral load is useful to guide pre- emptive therapy.
–Treatment of CMV infection and disease
Oral valgancyclovir for at least 2 weeks.Stop treatment after resolution of symptoms and 2 consecutive test with not detected CMV virus.
– Resistance of ganciclovir
Consider resistence if persisting or increasing viral load or symptomatic disease despiteadequate dose & duration of ganciclovir or valganciclovir.
In case of resistance cidofovir or foscarnet therapy.
– Dose reduction of immunosuppression
Consider reduce or stop antimetabolite if leukopenia.
– Providing adequate information, support and education of patient.
No transplantation facility in my posting place.
Summary of Guidelines:
The guidelines cater to prevention and management if cytomegalovirus (CMV) post solid organ transplant (SOT). CMV infection can be either asymptomatic infection, viral syndrome, or CMV disease.
1.Preventing CMV Infection and disease:
All donor and recipients should be screened for CMV IgG antibody. If donor serostatus is unknown, label donor as D+.
1) CMV prophylaxis in form of oral valganciclovir for at least 3 months should be given to:
a) Renal and liver transplant recipients (and should be considered for heart, lung, intestinal or pancreas transplant) in case of D+/R-, or a R+ serostatus with use of ATG or Alemtuzumab.
b) After starting acute rejection treatment if either or both of the donor or recipient is seropositive.
c) Some D-/R- patients as a prophylaxis against other Herpes infections.
2) Dose of Valganciclovir should be adjusted as per body surface area and creatinine clearance.
3) If patients develop side effects on valganciclovir, shift to CMV monitoring and pre-emptive therapy method.
2.Laboratory testing for CMV: Blood or plasma quantitative nucleic acid testing (QNAT) in IU/ml (or copies/ml, with conversion factor) should be done.
3.Monitoring of CMV infection and disease: It should be done at least monthly for minimum 3 months in R+ patients not on prophylaxis, and who did not receive T-lymphocyte depletion agents, to guide pre-emptive therapy.
4.CMV infection and disease treatment: Oral Valganciclovir (as it is as effective as intravenous ganciclovir) for at least 2 weeks (with dose modification as per creatinine clearance), with CMV viral monitoring after 2 weeks, and repeating after minimum 7 days to stop treatment after 2 consecutive negative CMV viral load reports. Intravenous Ganciclovir can be given if there are concerns regarding enteric absorption, and in very sick patients.
5.Ganciclovir resistance: It should be suspected if viral load persists or increases despite adequate dose and duration of therapy. Patients receiving prolonged courses, sub-therapeutic doses, D+/R- status, lung transplant recipients, and those who received intensive immunosuppression are prone to ganciclovir resistance. Confirm that the dose is adequate, and patient is compliant. CMV antiviral resistance for UL97 and UL54 mutations should be tested. Intravenous Foscarnet for at least 3 weeks should be given after virology consultation.
6.Immunosuppression reduction: Dose of Calcineurin inhibitors or anti-metabolites (especially in setting of leukopenia) should be reduced after discussing regarding risk of acute rejection, and dose should be reviewed once CMV is treated. There is low quality evidence for conversion to mTOR inhibitors providing protection against recurrent CMV.
2. Please reflect on your practice:
In our transplant unit, we use oral valganciclovir as CMV prophylaxis as per the risk category of the recipient.
D+/R- patients are given prophylaxis for 200 days.
R+ patients are given prophylaxis for 100 days.
Patients receiving ATG as induction are given prophylaxis for 100 days.
No surveillance with serology or CMV PCR is done in our unit.
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION
By The British Transplant Society 5 July 2022
Executive Summary of Recommendations
Strength of Recommendations:
Level A: Generally consistent findings of an SR of multiple RCTs
Level B: Generally consistent findings of an SR of multiple weaker studies
Level C: One RCT, weaker study or inconsistent findings from an SR.
Level D: No RCTs or weaker studies.
Weaker studies refers to non-RCTs
What is level of evidence 1a 1b 1c?
1a = SR (with homogeneity*) of Level 1 economic studies.
1b = Analysis based on clinically sensible costs or alternatives; systematic review(s) of the evidence; and including multi-way sensitivity analyses.
1c = Absolute better-value or worse-value analyses
1. Preventing CMV Infection and Disease
Determining CMV status in donor and recipient
· CMV prophylaxis
1. Valganciclovir prophylaxis to children, young and adult recipients of kidney and liver, for 3 months post-transplantation be offered, if
o Serostatus (D+/R-)
o Induction with T-cell depleting agent [(ATG/Alemtuzumab (Campath)] in all CMV positive recipients [D+/R+ or D-/R+] – [1A]
2. Heart, lung, intestinal or pancreas transplants – to consider Valganciclovir prophylaxis for 3 months post-transplant, if
o Serostatus (D+/R-) [1C] OR
o T-cell depleting induction [ATG / Campath] used in CMV positive recipients (D+/R+ or D-/R+). [1C]
Routine CMV prophylaxis not required for (D-/R-) recipients [1D]
3. Treatment of Acute Rejection for D+/R-, D+/R+ or D-/R+ recipients – consider 3 months Valgancyclovir [2C]
Valganciclovir dose adjustment [1D]
o ac/to GFR (Creatinine clearance <60ml) for adults
o ac/to BSA for children and young (<18 years) – maximum 900mg OD
CBC monitoring every 2-weekly during prophylaxis. [1A]
If Neutropenia develops – stop Valgancyclovir, and switch to CMV monitoring and pre-emptive therapy (if Viremia / symptomatic) [1C]
2. Lab Testing for CMV
Local lab
– Quantitative Nucleic Acid Test (QNAT) of whole blood or plasma to estimate CMV viral load. [1A]
– Calibrate QNAT assays using WHO International Reference Standard [1C]
– Viral load should be reported as “IU/ml”; use conversion factor if reported as “copies / ml’. [1C]
Transplant centres –
– adopt consistent method of quantitative CMV viral load estimation [1C]
– determine local thresholds for QNAT assay, that corroborate with CMV infection / disease requiring treatment in Population at risk [1C]
– Starting or stopping treatment for CMV disease, should be considered in the context of clinical, laboratory or histological evidence of CMV disease (not by QNAT threshold only). [1C]
3. Monitoring for CMV Infection and Disease
CMV viral load monitoring to guide pre-emptive therapy
– SOT recipients (children, young, adults) with Serostatus (D+/R+, D-/R+) [1B]
– not received T-lymphocyte depletion therapy [1B]
– not receiving valganciclovir prophylaxis [1B]
– Testing monthly x at least 3 months following transplantation [1D]
4. Treating CMV Infection and Disease
Adults, children and young people SOT recipients, who develop CMV infection or disease
– Valganciclovir therapy (900mg PO bid) x at least 2 weeks [1A]
– Adjust dose ac/to licensed dosing recommendations, if creatinine clearance is less than 60ml/minute [1D]
5. Ganciclovir resistance
5.1 Increased risk of Ganciclovir resistance:
– prolonged courses, or sub-therapeutic doses of antiviral medications [1A]
– Seronegative recipients receiving SOT from seropositive donors (D+/R-) [1C]
– Intensive IS (T-cell depletion therapy, following Acute Rejection) [1B]
– Lung transplant recipients
5.2 Consider Ganciclovir resistance, if
– Persistent symptomatic disease, or increasing viral load (ornot reducing) after a normally effective dosage and duration of therapy (2-4 weeks of Ganciclovir / Valganciclovir) [1A]
5.3 Suspected resistance to Ganciclovir:
– Confirm that dosing is adequate
– Consider adherence to treatment plan and absorption
– Test for Human CMV (HCMV) antiviral resistance (UL97 and UL54 gene mutations) [1A]
5.4 Ganciclovir resistance proven:
– Stop Valganciclovir (or Ganciclovir) [1A]
– Offer Intravenous Foscarnet for at least 3 weeks [1B]
– Specialist virology advice before commencing treatment with Foscarnet [1D]
6. Immunosuppression (IS) dose reduction
Consider IS reduction for SOT recipients with CMV infection or disease (with or without leukopenia)
– Reduce / stop MMF / AZT, if leukopenia [2C]
– Discuss with patient party – risk of acute rejection (due to IS reduction) [1D]
– Review the IS dose after resolution of CMV infection or disease [1D]
7. Information, education and support
People undergoing SOT should be informed about the risks of CMV (infection / disease), need for monitoring, prophylaxis and treatment options
Executive Summary of Research Recommendations
· Clinical and cost-effectiveness of anti-CMV prophylaxis Vs active surveillance (for 3 months post-transplant or post-treatment for CMV disease)
· Clinical and cost-effective duration and frequency of CMV viral load monitoring
o post cessation of anti CMV prophylaxis
o post completion of CMV treatment.
o QNAT testing clinical and cost-effectiveness, to guide cessation of CMV treatment
o Outcome of IS (CNI / MMF) reduction
o Cost-effectiveness of CMV-Ig and Adoptive T cells for severe, resistant or refractory CMV disease
Executive Summary of Audit Measures
· Proportion of SOT recipients
Ø got CMV prophylaxis (D+/R-serostatus /induction therapy)
Ø offered viral load monitoring (monthly x 3 months)
Ø offered Valganciclovir to treat CMV infection and disease
Ø Proportion of people with Ganciclovir resistance tested for UL97 and UL54 mutations.
Ø developed CMV infection or disease (with or without leukopenia) and reduced IS (stopped CNIs and / or proliferation inhibitors)
· Proportion of Lab using QNAT (whole blood / plasma) to quantify CMV viral load
· Proportion of CMV QNAT assays calibrated (WHO Reference Standard).
Reflection on our practice
In India, most of the renal transplants are live related, so induction with ATG is not used routinely – [only in <30% patients, that to low dose (3mg/Kg)]. So incidence of CMV disease is very negligible, we rarely see in patients with graft dysfunction. Thus, anti-CMV prophylaxis is not used universally, because of cost and side effects (Leukopenia, thrombocytopenia). Monitoring of CMV viral DNA is also not a routine practice.
Those who develop CMV disease – are treated mostly with Valgancyclovir, and secondary prophylaxis offered.
In my current centre in Kenya, we have completed about 310 successful renal transplants in last 4 years – all are live related, most are from family related donors.
We use low dose ATG Induction in almost 60% patients [distant relation or high PRA, high DSA requiring desensitization (about 30% patients)]. So, here we use Valgancyclovir prophylaxis for all our recipients for 2months (8weeks) post- transplant, because of cost constraint and availability issues.
We have never seen a symptomatic CMV disease, none of the allograft biopsy (done for graft dysfunction) revealed CMV, although we don’t do routine viral monitoring on follow up.
Post ATG treatment for ACR (dose used is 3-4 times more than used for Induction), oral Valgancyclovir prophylaxis is given for 3months.
Executive Summary of Recommendations.
Prevention and prophylaxes.
The first chapter is about prevention and prophylaxes.
. It should be routine to screen every recipient and donor for CMV.
. Prophylaxes for every recipient seropositive or native with positive donor status should be given prophylaxes for three months.
. Some recipient with native for CMV, but can be given valgencyclovir for other viral infection prophylaxes.
. Anti-viral should be given according to eGFR and body surface area in children.
Laboratory Testing for CMV.
Testing viral load should be via quantitative nucleic acid testing method.
. Method of reporting should be in IU/ml, if using copies/ml then conversion factor should be used.
. Local center should their own guidance of treatment according to copies/ symptoms.
. Treatment should be monitored according to laboratory, clinical findings, and histological evidence.
Monitoring for CMV Infection and Disease.
. Consider monitoring and Pre-emptive therapy for children, recipient given ATG, not given valgencyclovir, and CMV seropositive.
. Frequency of testing should be at least monthly, and for at-least three months post-transplantation.
Treating CMV Infection and Disease.
. For CMV disease and infection treat with oral valgencyclovir. Reduce immunosuppression, if any pneumonitis can give adjuvant treatment with IVIG.
. Follow viral load every two weekly.
. When to stop treatment, follow viral load for consecutive weeks, resolution of symptoms.
Ganciclovir resistance.
People at risk of developing ganciclovir resistance.
. Sub-therapeutic doses,
. Taken prolong courses,
. D+/R-,
. History of ACR requiring ATG,
. Those with lung transplant,
There is high possibility of resistance if,
. Although viral load is not a reliable indicator of drug resistance in first week post treatment, with persistent viral load increase seen in after first week, symptom persist despite given treatment for two to four weeks.
So needed to confirm,
. Dose is adequate,
. Adherence to medication,
. Confirm by testing use whole blood or plasma and, for UL97, UL54 gene mutation.
. If any resistance switch to second line.
. For refractory infection consider Maribavir ( FDA approval awaiting).
. Immunosuppression medication modification, either reduction of calcineurin inhibitors, antimetabolite, however, discuss with family for risk of rejection.
. Readjust the dose of immunosuppression after treating.
Always share information with family.
We use prophylactic valgancyclovir for 3 months for all patients.
1 Preventing CMV Infection and Disease
Determining CMV status in donor and recipient
CMV prophylaxis
For adults, children and young people receiving a solid organ transplant:
2 Laboratory Testing for CMV
3 Monitoring for CMV Infection and Disease
4 Treating CMV Infection and Disease
For adults, children and young people who develop CMV infection or disease following
solid organ transplantation:
5 Ganciclovir resistance
6 Immunosuppression dose reduction
For adults, children and young people who develop CMV infection or disease (with or
without leukopenia) following solid organ transplantation:
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION
Executive Summary of Recommendations
1 Preventing CMV Infection and Disease
Determining CMV status in donor and recipient
· All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation
· If donor CMV serostatus is unknown and the recipient is seronegative or unknown for CMV, this should be characterized as (D+/R-) for CMV.
CMV prophylaxis
· Offer Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either: (D+/R-) OR The recipient has received (ATG) or Alemtuzumab, for D+/R+ or D-/R+
· Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal or pancreas transplants for at least 3 months following transplantation if either: (D+/R-) OR The recipient has received (ATG) or Alemtuzumab for D+/R+ or D-/R+
· Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient is CMV positive (D+/R-, D+/R+ or D-/R+)
· If creatinine clearance is less than 60ml/m, Valganciclovir dose should be adjusted
· Valganciclovir dose should be adjusted for children and young people under 18 years
· Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir
2 Laboratory Testing for CMV
· Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load
· Transplant centres should determine local thresholds of viral load that portend CMV infection or disease requiring treatment, depending on the CMV QNAT assay they use and the population at risk
· QNAT thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease but should be considered in the context of clinical, laboratory, or histological evidence of CMV disease
3 Monitoring for CMV Infection and Disease
· Monitor CMV viral load to guide pre-emptive therapy to recipients of solid organ transplant if: They are CMV seropositive (D+/R+, D-/R+) AND have not received T-lymphocyte depletion therapy AND are not receiving valganciclovir prophylaxis
· Consider testing for CMV viral load at least monthly and for at least 3 months following transplantation
4 Treating CMV Infection and Disease
For recipients who develop CMV infection or disease following solid organ transplantation:
· Offer treatment with oral Valganciclovir for a duration of at least 2 weeks
· Adjust the dose of Valganciclovir according to licensed dosing recommendations if creatinine clearance is less than 60ml/minute
· Be aware of the potential development of ganciclovir resistance
· Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days AND Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected
5 Ganciclovir resistance
People who are 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
· Recipients of lung transplants
In people with suspected resistance to Ganciclovir:
· 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
In people with evidence of ganciclovir resistance: Stop Valganciclovir (or Ganciclovir) and offer Intravenous Foscarnet for at least 3 weeks
6 Immunosuppression dose reduction
· In recipient who develop CMV infection or disease following solid organ transplantation Consider a dose reduction of either CNI or MMF / azathioprine
· If there is leukopenia Consider reducing or stopping MMF or azathioprine
7 Information, education and support
People undergoing solid organ transplantation should be informed about The risks of CMV infection and disease, monitoring and treatment options, including prophylaxis
Executive Summary of Research Recommendations
· the clinical and cost-effectiveness of anti-CMV prophylaxis vs active surveillance post-transplant for 3 months post-transplant or post-treatment for CMV.
· the most clinical and cost-effective duration and frequency of CMV viral load monitoring and post cessation of anti CMV prophylaxis also post completion of CMV treatment.
· QNAT testing clinical and cost-effectiveness, used to guide cessation of CMV treatment
· The outcome of CNIs or proliferation inhibitors reduction
· The cost-effectiveness of CMV-specific immunoglobulins and CMV-specific cytotoxic T cells in the treatment of severe, resistant or refractory CMV disease
Executive Summary of Audit Measures
· Recipients who were given Valganciclovir prophylaxis
· quantify CMV viral load using QNAT
· Recipients who were monitored monthly for CMV viral load for 3 months post solid organ transplantation or post-CMV treatment
· UL97 and UL54 mutations test for Ganciclovir resistance
· Recipients with CMV infection who reduced or stopped CNIs and/or proliferation inhibitors
Reflection on my practice
We use Valganciclovir for a short time sometimes because it is not always available and due to its high cost. Diagnosis sometimes is missed.
1. Please summarise these guidelines
The guidelines cater to prevention and management if cytomegalovirus (CMV) post solid organ transplant (SOT). CMV infection can be either asymptomatic infection, viral syndrome, or CMV disease.
1.Preventing CMV Infection and disease: All donor and recipients should be screened for CMV IgG antibody. If donor serostatus is unknown, label donor as D+.
1) CMV prophylaxis in form of oral valganciclovir for at least 3 months should be given to:
a) Renal and liver transplant recipients (and should be considered for heart, lung, intestinal or pancreas transplant) in case of D+/R-, or a R+ serostatus with use of ATG or Alemtuzumab.
b) After starting acute rejection treatment if either or both of the donor or recipient is seropositive.
c) Some D-/R- patients as a prophylaxis against other Herpes infections.
2) Dose of Valganciclovir should be adjusted as per body surface area and creatinine clearance.
3) If patients develop side effects on valganciclovir, shift to CMV monitoring and pre-emptive therapy method.
2.Laboratory testing for CMV: Blood or plasma quantitative nucleic acid testing (QNAT) in IU/ml (or copies/ml, with conversion factor) should be done.
3.Monitoring of CMV infection and disease: It should be done at least monthly for minimum 3 months in R+ patients not on prophylaxis, and who did not receive T-lymphocyte depletion agents, to guide pre-emptive therapy.
4.CMV infection and disease treatment: Oral Valganciclovir (as it is as effective as intravenous ganciclovir) for at least 2 weeks (with dose modification as per creatinine clearance), with CMV viral monitoring after 2 weeks, and repeating after minimum 7 days to stop treatment after 2 consecutive negative CMV viral load reports. Intravenous Ganciclovir can be given if there are concerns regarding enteric absorption, and in very sick patients.
5.Ganciclovir resistance: It should be suspected if viral load persists or increases despite adequate dose and duration of therapy. Patients receiving prolonged courses, sub-therapeutic doses, D+/R- status, lung transplant recipients, and those who received intensive immunosuppression are prone to ganciclovir resistance. Confirm that the dose is adequate, and patient is compliant. CMV antiviral resistance for UL97 and UL54 mutations should be tested. Intravenous Foscarnet for at least 3 weeks should be given after virology consultation.
6.Immunosuppression reduction: Dose of Calcineurin inhibitors or anti-metabolites (especially in setting of leukopenia) should be reduced after discussing regarding risk of acute rejection, and dose should be reviewed once CMV is treated. There is low quality evidence for conversion to mTOR inhibitors providing protection against recurrent CMV.
2. Please reflect on your practice
In our transplant unit, we use oral valganciclovir as CMV prophylaxis as per the risk category of the recipient.
D+/R- patients are given prophylaxis for 200 days.
R+ patients are given prophylaxis for 100 days.
Patients receiving ATG as induction are given prophylaxis for 100 days.
No surveillance with serology or CMV PCR is done in our unit.
The guidelines revolve around
Preventing CMV Infection and Disease Determining CMV status in donor and recipient
CMV prophylaxis with Valganciclovir for three months is needed for all SOT if D+R-
If ATG is used even D+ R+ or D- R+.
Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-)
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+)
Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir [1A]
Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir
Laboratory Testing for CMV
Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load
Monitoring for CMV Infection and Disease
Offer monitoring of CMV viral load to guide pre-emptive therapy to adults.
Treating CMV Infection and Disease
For adults, children and young people who develop CMV infection or disease following solid organ transplantation.
Offer treatment with oral Valganciclovir for a duration of at least 2 weeks.
Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days AND
Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected (below the local laboratory threshold for detection)
Ganciclovir resistance
Be aware that the following people are 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) and recipients of lung transplants.
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.
In people with suspected resistance to Ganciclovir:
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
In people with evidence of ganciclovir resistance:
Stop Valganciclovir (or Ganciclovir)
Offer Intravenous Foscarnet for at least 3 weeks
Seek specialist virology advice before commencing treatment with Foscarnet
Dose of immunosuppressants should be decreased preferably of MMF if there is leucopenia. The risk of rejection in such cases should be explained to patients.
OUR CENTER PRACTICE.
All our patients are mostly D+ R+ so we are using valganciclovir at dose of 450 mg daily for three months with excellent outcome
Dear All
After reading these guidelines, what do you think about the differences between UK guidelines for CMV prophylaxis and KDIGO guidelines?
Do you think there is any place for extended prophylaxis 200 days rather than 100 days according to IMPACT trial?
UK guideline on prevention and management of (CMV) infection and disease following SOT
Summary
· CMV is HHV type 5, affect SOT usually after 6 weeks from date of transplantation.
· Screening and determination of serostatus of both the donor and the recipient in any SOT prior to transplantation to do risk stratification of CMV infection.
· We have 3 distinct definition in CMV:
o Infection” means positive PCR detected in plasma of patient.
o Syndrome: infection + clinical symptoms as fever, malaise, cytopenia.
o Tissue invasive disease: syndrome+ detection of virus in tissue culture or biopsy.
· Anti viral prophylaxis for CMV with valganciclovir for 3 months post transplantation is indicated if:
o High risk (D+/R-)
o Recipient takes depleting induction therapy (ATG or alemtuzimab).
o After treatment of any acute rejection episode.
· Universal prophylaxis is better adopted in high risk recipients than preemptive therapy after PCR surveillance.
· Precautions during valganciclovir use:
o Renal adjustment is required if creatinine clearance < 60ml/minute
o Adjust pediatric dose of valganciclovir according to body surface area, up to a maximum dose of 900mg once daily.
o Monitor CBC at least every 2 weeks
o Consider switching to cmv monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on valganciclovir
· Cases who are (D-/R-) should not receive routine prophylaxis against CMV, but may require ganciclovir or valganciclovir against herpes simplex infection.
· Testing for CMV;
o Monitoring by PCR should be standardized for each lab:
§ standard specimen (whole blood vs plasma)
§ CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used.
· Treatment of CMV infection:
o Treatment with IV ganciclovir or oral valganciclovir.
o Stop ttt after resolution of symptoms and 2 weeks after 2 negative PCR.
o Reduction of IS (stop antiproliferative+ decrease CNI +keep steroids).
o Close monitoring of graft function (as CMV can trigger rejection + decrease IS therapy).
· Ganciclovir resistance:
o Suspect when no clinical improvement and no decrease in viral load after 2 weeks of ganciclovir/valganciclovir for 2 weeks.
o High risk patients for resistance: the same risk group for infection, so they have prolonged use of anti viral therapy as high risk recipients as in D+/R-, intensive IS therapy as ATG induction and in heart-lung transplantation.
o Management: revising dose and patient adherence to therapy, then can offer 2 nd line drugs: foscarnet
Reflection on our practice:
ü We are in pediatric transplantation, we use universal prophylaxis with oral valganciclovir in high risk D+/R- patients for 3 months and also after ttt of any rejection episode.
ü We don’t use preemptive therapy for children.
ü In case of tissue invasive disease, I don’t see any case before, but the protocol is to give IV ganciclovir for 2-3 weeks until resolution of symptoms and 2 negative PCR.
Thank you for such comprehensive summary. What are the limitations of Foscarnt use?
UK GUIDELINES ; MGT OF CMV INFECTION/DISEASE FOLLOWING SOT.
1.CMV STATUS.
2.CMV PROPHYLAXIS.
-Indications for 3 /12 valganciclovir prophylaxis;
-No routine prophylaxis in D-/R-
-With eGFR <60 ml/min renal dose valganciclovir.
-<18 yrs pts should have valganciclovir dosed according to body surface area upto a max of 900mg OD.
-A FHG should be done every fortnight to monitor for neutropenia which should prompt switching to CMV Monitoring and pre emptive therapy should it occur.
3.LAB TESTS FOR CMV.
QNAT of whole blood/plasma should be used to quantify CMV VL.
4.CMV MONITORING.
-Indications ; D+/R+,D-/R+ without T lymphocyte depleting therapy or valganciclovir prophylaxis
-Frequency ; Monthly.
-Duration ; 3/12
5.CMV TX (INFECTION & DISEASE).
-PO ganciclovir for a minimum of 2/52,Renal dose in those with eGFR < 60ml/min.
-Monitor for resistance and do VL after 2 /52 of treatment or after a minimum of 1/52 of treatment.
-Stop treatment after resolution of symptoms + 2 consecutive CMV VL that show undetectable VL.
6.GANCICLOVIR RESISTANCE.
-Risk factors;
-Indicator ;
-Management;
7.RIS
-For CMV +/- Leucopenia;
REFLECTION ON PRACTICE.
-Cost of tests and availability is the main hindrance to practicing the above in our centre, as a nephrologist I will definitely put more emphasis on this and get a local protocol to ensure good out comes post transplant.
Thank you. You referred to
2.CMV PROPHYLAXIS.
-Indications for 3 /12 valganciclovir prophylaxis;
What about Almetuzimab Which should be treated as ATG for CMV prophylaxis!
Agreed Prof, I accidentally omitted that in my typing. Almetuzimab is tx as ATG for CMV prophylaxis. Thank you
summary: these guidelines include
1. Preventing of CMV infection and disease:
to prevent CMV we should:
2. lab testing for CMV:
3. Treating CMV infection and disease:
4. Ganciclovir resistance
5. IS dosecreduction:
6. Education of patients:
I practice in a low resource setting and cost of medications is usually a issue
We test for CMV status for both recipients and donor before transplantation. And try to give prophylaxis to all patients using valganciclovir at the dose of 450mg daily for 3-6 months depending on risk of CMV in that particular patient
Thank you. Do you think its GFR or Cr Clearance?
DOSE need to be adjusted if GFR is less than 60 ml/ minute
UK guideline on Prevention and Management of CMV infection and Disease Following Solid Organ Transplantation
CMV infection is considered when there is evidence of the virus undergoing a complete replication cycle and producing new infectious virions:
Asymptomatic infection: (no obvious signs of pathologic symptoms)
Viral syndrome: (fever, leucopenia, myalgia or arthralgia)
CMV disease: (histopathological evidence of CMV, CMV Colitis , CMV retinitis diagnosed by an ophthalmologist, or CMV in the CSF indicative of CNS
disease)
Latent CMV: A state of virus infection in which the full replication cycle of the virus is not occurring.
Preventing CMV Infection and Disease
Pre-transplant screening => All organ Donors and Recipients should be screened for CMV (IgG antibody prior to or at time of transplantation.
If serostatus of both Recipient and donor are unknown for CMV in this condition the donor should be considered as seropositive, and the recipient is seronegative it is the same as if donor is unknown and recipient is negative.
CMV prophylaxis:
Prophylaxis treatment in a high-risk group (seropositive donor to seronegative recipient and recipient receiving T-lymphocyte depleting agent)
Do not routinely offer Valganciclovir prophylaxis if donor and recipient are
seronegative for CMV (D-/R-).
Start Valganciclovir prophylaxis to people receiving kidney, heart, lung,
intestinal, pancreas and liver transplants for at least 3 months following
transplantation if either:
The (D+/R-) or when T-lymphocyte depletion therapy with (ATG) or
Alemtuzumab (Campath) given, where donor: recipient serostatus is
D+/R+ or D-/R+.
Adjust the dose of Val ganciclovir if creatinine clearance is less than
60mL/minute and adjust the dose of Val ganciclovir according to body
surface area for children and young people under 18 years.
Monitor Full Blood Count at least every 2 weeks whilst on Val ganciclovir
and switch to CMV monitoring and pre-emptive therapy if people develop
side effects e.g., neutropenia, on Val ganciclovir.
Treat for 3 months
Laboratory testing:
Monitoring CMV/Pre-emptive strategies
CMV management (treatment and immunosuppression reduction)
Ganciclovir resistance
Risks
1. prolong course
2. Sub-therapeutic dose
3. D+/R-
4. T-cell depletion therapy
5. Lung transplant
-UL97 and UL54 gene mutation testing in patient suspecting Ganciclovir resistance
-Treatment with Foscarnet
Immunosuppression dose reduction:
Consider a dose reduction of either calcineurin inhibitor or
Mycophenolate mofetil /azathioprine and reducing or stopping
Mycophenolate Mofetil (MMF) Azathioprine if there is evidence of
leukopenia is the preferred option and risk of rejection should be
discussed with the recipient.
Reflect on your practice:
Pre-transplant workup Screening CMV (IgG antibody) for both donors and recipients is considered in our protocol and everywhere.
Prophylaxis is recommended for recipients who received ATG induction or received ATG for Acute Cellular Rejection
OR when the donor recipient sero- status MM is (D+/ R-) CMV IgG.
Prophylaxis for CMV (D-/R-) with Basiliximab => No prophylaxis needed.
Prophylaxis for CMV (D-/R-) with ATG => prophylaxis needed.
Prophylaxis for CMV (D+/R+) with Basiliximab => No prophylaxis needed.
Prophylaxis for CMV (D+/R+) with ATG => prophylaxis needed.
Valganciclovir prophylaxis for at least 3 months following treatment of ACR ttt by ATG.
We are following the same guideline in managing Immunosuppression dose reduction and
Ganciclovir resistance: we send testing for Human CMV (HCMV) antiviral resistance / UL97 and UL54 gene mutations.
Do you think Guide lines referred to CMV infection/disease and syndrome or just CMV infection and disease?
CMV Prophylaxis
· Valganciclovir
prophylaxis for for at least 3 months following transplantation
if either:
1. -D+/R-
2. D+/R+
or D-/R+ (if ATG or Alemtuzumab)
3. after treatment
for acute allograft rejection if (D+/R-, D+/R+ or D-/R+)
4. No
prophylaxis required if (D-/R-)
· adjust
the dose of Valganciclovir according to body surface area, maximum dose of
900mg once daily and creatinine clearance is less than 60mL/minute
daily
· Monitor
Full Blood Count at least every 2 weeks while on Valganciclovir
· Switch to (CMV
monitoring and pre-emptive therapy) if people develop side effects e.g.;
neutropenia, on Valganciclovir
· Offer monitoring
of CMV viral load to guide pre-emptive therapy in the following situation
1-
(D+/R+, D-/R+)
2-And
didn’t not received T-lymphocyte depletion therapy
3-
AND They are not receiving valganciclovir prophylaxis
· Monitoring
to guide preemptive therapy should be at least monthly and at least for 3 month
following transplantation
CMV infection or disease
· In
CMV infection or disease use oral Valganciclovir for a duration of at least 2
weeks
· Assess
CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7
days
· Considering
stopping of treatment after resolution of symptoms AND two consecutive, CMV
viral load tests that confirm that CMV is not detected (below the local
laboratory threshold for detection)
Valgacyclovir resistant
· Consider
resistant to valgan cyclovir if persistent
or increasing viral load or symptomatic disease after
a normally effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or
Valganciclovir
· people at increased risk of Ganciclovir resistance:
o those who received prolonged courses,
o or sub-therapeutic doses of antiviral medications
o (D+/R-)
· 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:
o Stop
Valganciclovir (or Ganciclovir)
o Offer
Intravenous Foscarnet for at least 3 weeks After Seeking specialist virology
advice
Immunosupression reduction
· Consider
a dose reduction of either calcineurin inhibitor or mycophenolate mofetil /
azathioprine
· Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF)
or azathioprine if there is evidence of leukopenia
· Discuss with patients, and, where appropriate, parents or carers, the
risk of acute rejection with immunosuppression dose reduction
· Review the dosing of immunosuppression following resolution of CMV
infection or disease
——————————————–
In our center
we are
monitoring CMV every 2 weeks in first 3 month post transplant then monthly
until. the end of the first year then every 2-3 month
at the same
time we give prophylaxis 6 month for D+/R+. D-/R+. D+/R-
and 3 month
for those with Low risk D-/R-
CMV infection
initially we reduce MMF 50%. and targeting lower tac level ,we repeat
CMV weekly if rising we stop MMF
I agree that one would discontinue antimetabolites for few days.
CMV:
is one of the herpes group of viruses, which are widely distributed among mammals.
The various strains of CMV are species specific and primary infection results in the most severe disease when the host is T-cell immunocompromised.
After primary CMV infection, the viral genome enters monocytes and other bone marrow progenitor cells and enters a latent state.
CMV in Solid Organ Transplant Recipients:
Primary infection with CMV typically occurs approximately four to six weeks post-transplant in a seronegative individual who receives a seropositive organ.
Symptoms may be non-specific:
Fever, night sweats, fatigue and myalgia.
Retinitis can be pathognomonic, but is rarely seen in the transplant population.
GIT: diarrhea, abdominal pain and nausea.
Respiratory: SOB, Cough.
Screening Pretransplant:
All organ donors and recipients should be screened for CMV (IgG antibody) sero status prior to, or at the time of transplantation [1A]
If donor CMV aerostats is unknown and recipient is seronegative or unknown for CMV, this should be characterized as donor seropositive, recipient seronegative for CMV.
CMV prophylaxis:
Receiving kidney and liver transplants, Valganciclovir prophylaxis for 3months for:
D+/R-.
Donor: recipient serostatus D+/R+ or D-/R+ if received ATG or Alemtuzumab.
Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal or pancreas transplants for at least 3 months:
Either D+/R-
OR D+/R+ or D-/R+ if received ATG or Alemtuzumab.
Valaciclovir prophylaxis for prevention of other Herpes virus infections, e.g.; recipients who are seronegative for Herpes Simplex Virus (HSV) receiving an organ from HSV seropositive donors.
Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+) [2C].
Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute.
Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir.
Laboratory Testing:
Should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load.
QNAT thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease.
Monitoring for CMV Infection and Disease:
monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if: They are CMV seropositive (D+/R+, D-/R+) [1B] AND They have not received T-lymphocyte depletion therapy [1B] AND They are not receiving Valganciclovir prophylaxis [1B]
Where CMV viral load monitoring is offered:
Consider testing with a frequency of at least monthly, Consider testing for at least 3 months following transplantation.
Treating CMV Infection and Disease:
Treatment with oral Valganciclovir for a duration of at least 2 weeks [1A]
Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days [1D] AND Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected .
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.
In people with suspected resistance to Ganciclovir:
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 [1A] Use either whole blood or plasma [1A]
In people with evidence of ganciclovir resistance:
Stop Valganciclovir (or Ganciclovir) [1A]
Offer Intravenous Foscarnet for at least 3 weeks [1B], Seek specialist virology advice before commencing treatment with Foscarnet.
Immunosuppression dose reduction
Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine.
Preferentially reducing or stopping MMF or azathioprine if there is evidence of leukopenia.
Information, education and support:
Solid organ transplantation recipient about risk and prophylaxis.
We are screening all donors and recipient for CMV and prophylaxis is given for 3months
to R-/D+.
I agree that one would discontinue antimetabolites for few days.
Summary of guideline
A – Determine the CMV status in donor and recipient – Screen both recipient and donors using serology (CMV IgG antibody) serostatus before or during the time of transplantation. Characterize as donor seropositive, recipient seronegative for CMV (D+/R-) if donor CMV status is unknown and recipient is seronegative or unknown for CMV.
B – CMV Prophylaxis
For all age groups receiving kidney and liver transplants, offer valganciclovir prophylaxis for at least 3 months following transplantation if either D+/R- or the recipient has received induction with a lympho-depleting agent or where donor: recipient serostatus is D+/R+ or D-/R+ or following treatment for an acute rejection. Same recommendation for heart, lung, intestinal or pancreas transplants.
No routine valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-) except for treatment of other viral infections like HSV.
Maximum daily dose of valganciclovir is 900mg daily and should be dosed according to body surface area. Dose adjustment is necessary when GFR is less than 60ml/min.
Monitor FBC every two weeks and consider switching to monitoring viral load for pre-emptive therapy when patient develop neutropenia.
C – Laboratory testing
Quantification of viral load in copies/ml or IU/ml after NAT is recommended.
D – Monitor viral load monthly for at least 3 months for pre-emptive treatment in CMV seropositive (D+/R+, D-/R+) cases and in recipients who have not received T-lymphocyte depletion therapy who is not on valganciclovir prophylaxis.
E- Treatment of CMV disease
Treatment is for at least 2 weeks or following resolution of symptoms and repeated undetectable viral load on two occasions.
Monitor for ganciclovir resistance.
F – Ganciclovir resistance
Risk of resistance is increased in the following scenario;
Prolonged courses of antiviral agents, or sub-optimal doses of antiviral drugs.
CMV seronegative recipients receiving a solid organ transplant from seropositive donors (D+/R-)
Induction therapy with lymphocyte depleting agent.
Use of lymphocyte depleting agent to treat allograft rejection.
Recipients of lung transplants.
Consider resistance if after 2 – 4 weeks of adequate treatment, patient still exhibit symptomatic disease or increasing viral load.
Approach to ganciclovir resistance
Ensure adequate dosing and treatment adherence.
Testing for Human CMV (HCMV) genotype and UL97 and UL54 gene mutations using either whole blood or plasma.
In ganciclovir resistance: Stop Valganciclovir (or Ganciclovir) and offer Intravenous Foscarnet for a minimum of 3 weeks.
Consult a virologist before commencing treatment with Foscarnet.
G– Immunosuppression reduction
Reduce the dose of immunosuppressive medications including CNIs and antimetabolites while monitoring for acute rejection.
H – Offer information, education and support for patients including risk factors and treatment plan. Educate nephrologists on management of CMV infection.
Where I practice is a low resource setting and cost of medications is usually a big issue because of out-of-pocket payments. We test for CMV status for both recipients and donor before transplantation. We give a universal prophylaxis using valganciclovir at the dose of 450mg daily for 6 months to all patients after kidney transplantation. We monitor with CBC twice weekly.
I would discontinue antimetabolites for few days in patients with CMV disease
Determining CMV status in donor and recipient
All organ donors and recipients should be screened for CMV (IgG antibody)
donor CMV serostatus – unknown donor seropositive
recipient -seronegative or unknown – recipient seronegative
CMV prophylaxis
Offer Valganciclovir prophylaxis at least 3 months following transplantation if either:
Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-)
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+)
Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir
Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir
Laboratory Testing for CMV
Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load
Transplant centres should adopt a consistent approach to use either whole blood or plasma for quantification of CMV viral load
CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used
Monitoring for CMV Infection and Disease
Offer monitoring of CMV viral load to guide pre-emptive if:
Where CMV viral load monitoring is offered:
Consider testing with a frequency of at least monthly
Consider testing for at least 3 months following transplantation
Treating CMV Infection and Disease
Offer treatment with oral Valganciclovir for a duration of at least 2 weeks
Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of
7 days AND Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected
Ganciclovir resistance
Be aware that the following people are 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)
Recipients of lung transplants
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
In people with suspected resistance to Ganciclovir:
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
In people with evidence of ganciclovir resistance:
Immunosuppression dose reduction
Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil /
azathioprine
Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia
In my practice we use universal protocol for CMV surveillance and treatment
I would discontinue antimetabolites for few days in patients with CMV disease
I. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION
Summarise these guidelines
1. Preventing CMV infection and disease
Determining the donor and recipient CMV serostatus
– Donors and recipients should be screened for CMV serostatus (IgG Ab) [1A]
– If the donor’s CMV serostatus is unknown it should be regarded as donor seropositive, however if the recipient’s CMV serostatus is unknown it should be characterized as recipient seronegative i.e., CMV (D+/ R-) [1D]
CMV prophylaxis
– Valganciclovir prophylaxis should be offered to potential kidney and liver transplant recipients for at least three months post-transplant in the following scenarios: –
·Donor: recipient CMV serostatus (D+/ R-) [1A] or
·A recipient who received ATG or Alemtuzumab where the donor: recipient CMV serostatus is D+/ R+ or D-/ R+ [1A]
– For heart, lung, intestinal and pancreatic transplant recipients, consider offering 3-month valganciclovir prophylaxis in the following circumstances: –
·Donor: recipient CMV serostatus (D+/ R-) [1C] or
·A recipient who received ATG or Alemtuzumab where the donor: recipient CMV serostatus is (D+/ R+) or (D-/ R+) [1C]
– Valganciclovir prophylaxis is not routinely indicated if the donor: recipient CMV serostatus is (D-/ R-) [1D] unless valganciclovir or valaciclovir prophylaxis is required for the prevention of other herpes virus infections e.g., HSV seronegative recipient receiving an organ from a HSV seropositive donor [2D]
– Recipients treated for acute graft rejection should be initiated on at least 3-months valganciclovir prophylaxis if either the donor or the recipient had a positive CMV serostatus i.e., (D+/ R-), (D+/ R+) or (D-/ R+) [2C]
– If eGFR is <60ml/min renal adjust the dose of valganciclovir [1D]
– A bi-monthly complete blood count should be done in patients on valganciclovir [1A]
– Opt for CMV monitoring and pre-emptive therapy in patients who develop neutropenia while on valganciclovir [1C]
2. Laboratory testing for CMV
– Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma should be used to quantify CMV viral load [1A]
– Transplant centers should use a consistent approach for CMV viral load quantification i.e., either whole blood or plasma [1C]. They should determine the local thresholds of CMV viral load that are highly suggestive of CMV infection or disease necessitating treatment [1C]
– QNAT CMV viral loads should be interpreted in the context of clinical, laboratory or histological findings prior to initiating or stopping treatment in patients with CMV disease [1C]
– WHO International Reference Standard should be used to calibrate CMV QNAT assays [1C]
– CMV viral load should preferably be reported as IU/ml. A conversion factor should be used if it is reported as copies/mL [1C]
3. Monitoring for CMV infection and disease
– CMV viral load monitoring should be offered in the following scenarios to guide in pre-emptive therapy among SOT recipients.
·Donor: recipient seropositive CMV status (D+/ R+), (D+/ R+) [1B] and
·No prior exposure to ATG or Alemtuzumab (T-lymphocyte depleting agents) [1B] and
·Not on valganciclovir prophylaxis [1B]
– CMV viral load monitoring should be done at least monthly for a minimum of 3 months post-transplant [1D]
4. Treating CMV infection and disease
– Patients who develop CMV infection or disease should be treated for at least 2 weeks [1A]
– If eGFR is <60ml/min, the dose of valganciclovir should be adjusted [1D]
– CMV viral load should be done after 2 weeks of treatment and thereafter weekly [1D]
– Treatment cessation can be considered after obtaining two consecutive negative CMV viral loads in addition to resolution of symptoms [2D]
5. Ganciclovir resistance
– Patients at increased risk of ganciclovir resistance include: –
·Patients who have been on prolonged courses or sub-therapeutic doses of antiviral medications [1A]
·CMV seronegative recipients who received SOTs from seropositive donors (D+/ R-) [1C]
·Patients who have received treatment for acute graft rejection e.g., ATG or Alemtuzumab (T-cell depleting agents [1B]
·Lung transplant recipients [2C]
– If there is a persistent or rising CMV viral load or symptomatic disease despite a normal effective dose and duration of treatment i.e., (2-4 weeks) consider ganciclovir resistance [1A]
-For patients with ganciclovir resistance confirm adherence to the treatment plan, absorption and proper dosing. Also test for human CMV antiviral resistance, UL97 and UL54 gene mutations using either whole blood or plasma [1A]
– If there is evidence of ganciclovir resistance, stop valganciclovir or ganciclovir [1A] and give IV Foscarnet for at least 3 weeks [1B] in consultation with a virologist [1D]
6. Immunosuppression dose reduction
– Consider reducing the dose of either the CNI or the antimetabolite (mycophenolic analogues or azathioprine [1C]
– If there is leucopenia, preferentially reduce or stop the antimetabolite [2C]
– Discuss the patient the risk of acute graft rejection that comes with reduction in immunosuppression [1D]
– Once there is resolution of CMV infection or disease, review the immunosuppression dosages [1D]
7. Information, education and support
– Patients should be aware of the risks of CMV infection and disease based on the donor/ recipient CMV serostatus pre-transplant as well as the immunosuppressive agents to be used
– Patients should be made aware of the monitoring, prophylaxis and treatment options available.
Reflect on your practice
Our transplant center is a bit resource limited so we basically do pre-transplant CMV serostatus screening and classify the donor and the recipient in the different risk stratification categories. We do not have a deceased donor program as yet.
Most of our transplant pairs are CMV (D+/ R+). Due to the financial implications involved, we do not routinely offer valganciclovir prophylaxis neither do we use ATG or Alemtuzumab (T-lymphocyte depleting agents).
However, we do get a few cases of confirmed CMV disease post-kidney transplant and for such patients we treat with Valganciclovir (renal-adjusted dose for about 3 weeks as tolerated and thereafter offer secondary prophylaxis for 3 months).
IV Ganciclovir is preferred in the initial treatment, unfortunately it is not readily available.
For the patients who develop severe neutropenia, we try to source for GM-CSF which is also not easy to come by.
Weekly CMV viral load monitoring is also a challenge due to financial constraints.
We have never had cases of ganciclovir resistance but again I cannot say that we actively screen for it. Luckily, we have never had a case whereby we needed to get an alternative treatment to valganciclovir.
We hope that the financial situation will improve and make us feel better equipped to deal with CMV disease in the kidney transplant population.
I appreciate that you are sharing your own experience.
Thank you Prof.
UK GUIDELINE ON PREVENTION AND MANAGEMENTOF CYTOMEGALOVIRUS (CMV) INFECTION ANDDISEASE FOLLOWING SOLID ORGANTRANSPLANTATION.
CMV infection is considered when there is evidence of the virus undergoing a complete replication cycle and producing new infectious virions :
Asymptomatic infection (no obvious signs of pathologic symptoms)
Viral syndrome (fever, leucopenia, myalgia or arthralgia)
CMV disease – (histopathological evidence of CMV, CMV retinitis diagnosed by an ophthalmologist, or CMV in the CSF indicative of CNS disease)
Latent CMV: A state of virus infection in which the full replication cycle of the virus is not occurring
Serostatus:
1-Donor (D) positive (+); Recipient (R) positive (+) (D+/R+).
2-Donor (D) negative (-); Recipient (R) negative (-) (D-/R-).
3-Donor (D) positive (+); Recipient (R) negative (-) (D+/R-).
4-Donor (D) negative (-); Recipient (R) positive (+) (D-/R+).
1-Preventing CMV Infection and Disease.
=Screening of CMV status in donor and recipient.
All organ donors and recipients should be screened for CMV (IgG antibody) at the time of transplantation which is important step in preparation.
If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterized as donor seropositive, recipient seronegative for CMV(D+/R-).
=CMV prophylaxis.
1-Do not routinely offer Val ganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-).
2-Start Val ganciclovir prophylaxis to people receiving kidney, heart, lung, intestinal, pancreas and liver transplants for at least 3 months following transplantation if either:
The (D+/R-) or when T-lymphocyte depletion therapy with (ATG) or Alemtuzumab (Campath) given, where donor: recipient serostatus is D+/R+ or D-/R+ .
= Adjust the dose of Val ganciclovir if creatinine clearance is less than 60mL/minute and adjust the dose of Val ganciclovir according to body surface area for children and young people under 18 years.
=Monitor Full Blood Count at least every 2 weeks whilst on Val ganciclovir and switch to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Val ganciclovir.
2-Laboratory Testing for CMV.
=We should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load and CMV QNAT assays should be calibrated using the WHO International Reference Standard .
=CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used.
= We should depend on clinical, laboratory or histological evidence of CMV disease to treat and to stop antiviral medications rather that depending on QNAT thresholds alone.
3- Monitoring CMV Infection and Disease.
=We could monitor CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if: (D+/R+, D-/R+), not using T-lymphocyte depletion therapy and they are not receiving Val ganciclovir prophylaxis.
=We should consider testing of CMV with a frequency of at least monthly for 3 months following transplantation.
4-Treating CMV Infection and Disease.
=Treatment with oral Val ganciclovir for a duration of at least 2 weeks with adjusting the dose of Val ganciclovir according creatinine clearance specially when it is less than 60mL/minute.
= Stopping treatment for CMV disease after resolution of symptoms and after two consecutive, CMV viral load tests that confirm that CMV is not detected.
5 Ganciclovir resistance.
=Common with those who have received prolonged courses, or sub-therapeutic doses of antiviral medications, (D+/R-), those who have received intensive immunosuppression and recipients of lung transplants
= A persistent or increasing viral load or symptomatic disease after effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Val ganciclovir is considered resistance.
= We should stop Val ganciclovir (or Ganciclovir) and offer Intravenous Foscarnet for at least 3 weeks.
6-Immunosuppression dose reduction.
=Consider a dose reduction of either calcineurin inhibitor or Mycophenolate mofetil /azathioprine and reducing or stopping Mycophenolate Mofetil (MMF) Azathioprine if there is evidence of leukopenia is the preferred option and risk of rejection should be discussed with the recipient.
Reflect on your practice.
Screening pre-transplant is considered our protocol.
Universal prophylactic protocol is our preferred option with Val ganciclovir.
CMV PCR screening post-transplant for 3 month .
Weekly follow up of CMV PCR with CMV treatment and continued till CMV viral load not detected.
I appreciate that you are sharing your own experience.
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION
Summary
1. Preventing CMV Infection and Disease
1) Determining CMV status in donor and recipient
· All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation [1A]
· If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-). [1D]
2) CMV prophylaxis
a) Offer Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either:
· The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-) [1A] OR
· The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath®), where donor: recipient serostatus is D+/R+ or D-/R+ [1A]
b) Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal or pancreas transplants for at least 3 months following transplantation if either:
· The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-) [1C] OR
· The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath®), where donor: recipient serostatus is D+/R+ or D-/R+ [1C]
c) Some recipients who are seronegative for CMV (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention of other Herpes virus infections.
d) Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+) [2C].
e) Adjust the dose of Valganciclovir in the followings:
· if creatinine clearance is less than 60ml/minute [1D]
· children and young people under 18 years, the dose of Valganciclovir to be adjusted according to body surface area, up to a maximum dose of 900mg once daily [1D]
f) Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir [1A]
g) Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir [1C]
2. Laboratory Testing for CMV
· Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load [1A]
· QNAT should be considered in the context of clinical, laboratory or histological evidence of CMV disease [1C].
· CMV PCR(on whole blood, plasma or leucocyte) considered to the gold standard mean of detecting active viral replication.
3. Monitoring for CMV Infection and Disease
a) Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if:
· They are CMV seropositive (D+/R+, D-/R+) [1B] AND
· They have not received T-lymphocyte depletion therapy [1B] AND
· They are not receiving valganciclovir prophylaxis [1B]
b) Where CMV viral load monitoring is offered:
· Consider testing with a frequency of at least monthly [1D]
· Consider testing for at least 3 months following transplantation [1D]
4. Treating CMV Infection and Disease
a) Offer treatment with oral Valganciclovir for a duration of at least 2 weeks [1A]. Most commonly valganciclovir 900mg twice daily has been used as treatment dose, adjusted for level of kidney function.
b) Adjust the dose of Valganciclovir according to licensed dosing recommendations if creatinine clearance is less than 60ml/minute [1D]
c) Both CMVIg and adoptive transfer of cytotoxic T Lymphocytes (CTL) are for research recommendation:
· High doses of intravenous Hyperimmune globulin (0.5 g/kg body weight) have been used in conjunction with Ganciclovir for the treatment of pneumonitis (not persuaded as no sufficientevidence).
· No evidence was identified to support a recommendation on the use of adoptive transfer of cytotoxic T Lymphocytes (CTL) for pre-emptive treatment of CMV.
d) Be aware of the potential development of ganciclovir resistance.
e) Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days [1D]
f) 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) [2D].
5. Ganciclovir resistance
a) People at increased risk of Ganciclovir resistance:
· Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications [1A]
· CMV seronegative recipients receiving a solid organ transplant from seropositive donors (D+/R-) [1C]
· Those who have received intensive immunosuppression (e.g; with T-cell depletion therapy, following episodes of acute allograft rejection) [1B]
· Recipients of lung transplants [2C]
b) 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 [1A]
c) When resistance to Ganciclovir is suspected:
· Confirm that dosing is adequate.
· Consider adherence to treatment plan and absorption.
· Offer testing for Human CMV (HCMV) antiviral resistance.
· Sequence-based analysis of UL97 and UL54 gene mutations [1A]. 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.
· Use either whole blood or plasma [1A]
d) In people with evidence of ganciclovir resistance:
· Stop Valganciclovir (or Ganciclovir) [1A]
· Offer Intravenous Foscarnet for at least 3 weeks [1B]. 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 [1D].
· 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.
6. Immunosuppression dose reduction
For adults, children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation:
a) Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine [1C]
· Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia [2C]
b) Discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction [1D]
c) Review the dosing of immunosuppression following resolution of CMV infection or disease [1D]
7. Information, education and support
a) Offer balanced and accurate information to children, adults and young people undergoing solid organ transplantation about:
· The risks of CMV infection and disease according to donor / recipient CMV serostatus and nature of immunosuppression planned or received.
· Monitoring and treatment options, including prophylaxis.
b) Ensure that healthcare professionals offering information have specialist knowledge about CMV infection and disease and their treatment, and the skills to support shared decision-making (for example, presenting information in a form suitable for developmental stage).
Please reflect on your practice
In our practice we are coinciding the same guidelines:
· Pre-transplant screening for CMV for both donors and recipients and identification of serostatus.
· Post-transplant prophylaxis for CMV, for three months, using acyclovir instead of valganciclovir.
· Treating CMV infection and disease with Valganciclovir. No reported cases of resistance to Valganciclovir.
I appreciate that you are sharing your own experience.
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION KEY ISSUES
1- Determination of donor and recipient CMV status:
Prior to transplantation, all organ donors and recipients should be checked for CMV IgG serostatus.
If the donor’s CMV serostatus is unknown and the recipient’s CMV serostatus is negative or unknown, this is regarded (D+/R-).
2- CMV prophylaxis
If the patient has received T-lymphocyte depletion therapy with ATG or Alemtuzumab (Campath), where D+/R+ or D-/R+, offer valganciclovir prophylaxis for at least 3 months.
If (D-/R-), avoid giving Valganciclovir prophylaxis on a regular basis.
If either the donor or the recipient is CMV positive, consider Valganciclovir prophylaxis for at least 3 months after beginning treatment for acute allograft rejection.
If the cr cl is less than 60 ml/min and in youngsters, change the dose of Valganciclovir in accordance with the body surface area (maximum daily dose 900 mg)
While taking Valganciclovir, monitor Full Blood Count at least once every two weeks.
If patients experience adverse effects from Valganciclovir, such as neutropenia, think about switching to CMV monitoring and preventive therapy.
3- CMV laboratory testing
Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma should be used by clinical laboratories to determine the CMV viral load, which is then reported as copies/mL or as IU/mL.
QNAT thresholds should be taken into account in the context of clinical, laboratory, or histological evidence of CMV disease rather than being used in isolation to decide whether to start or stop treatment for people with CMV disease.
4- Surveillance of CMV infection and disease
Provide CMV viral load monitoring to advise pre-emptive medication after solid organ transplant recipients who are CMV seropositive (D+/R+, D-/R+), haven’t been treated with T-lymphocyte depletion treatment, or if not being treated with valganciclovir prophylaxis. Monitoring should be done at least once a month for at least three months after transplantation.
5- CMV treatment
Provide oral Valganciclovir therapy for at least two weeks.
If the clearance is less than 60 ml/min, reduce the dose of Valganciclovir.
After 2 weeks of treatment, assess CMV viral load and repeat every 7 days.
Consider discontinuing CMV illness medication if symptoms have resolved and two consecutive CMV viral load tests show that CMV is not present.
6- Resistance to ganciclovir
People at higher risk include:
1-Those who have had lengthy courses of antiviral treatment or sub-therapeutic doses
2- D+/R- 3- Those who have had extensive immunosuppression (for example, T-cell depletion therapy after episodes of acute allograft rejection)
4- Recipient of a lung transplant.
Consider Ganciclovir resistance if: a persistent or growing viral load or symptomatic disease persists after a usually effective dosage and duration (e.g., 2-4 weeks) with Ganciclovir or Valganciclovir
In patients with suspected Ganciclovir resistance:
1- Ensure sufficient dose, adherence to treatment plan, and absorption.
2- Provide antiviral testing for Human CMV (HCMV) as well as UL97 and UL54 gene variants.
In people who have ganciclovir resistance:
1- Discontinue Valganciclovir (or Ganciclovir)
2- After consulting with a virology specialist, administer intravenous Foscarnet for at least three weeks.
7-Immunosuppression dose reduction
People who are at a higher risk include:
Adults, children, and adolescents who develop CMV infection or illness (with or without leukopenia) after a solid organ transplant:
Consider lowering the dose of calcineurin inhibitor or mycophenolate mofetil/azathioprine.
If there is evidence of leukopenia, consider lowering or discontinuing Mycophenolate Mofetil (MMF) or azathioprine.
Discuss the risk of acute rejection with patients and, if appropriate, parents or caregivers.
Reevaluate immunosuppressive dose after CMV infection or illness resolution.
Please reflect on your practice
In my practice we usually do screening as per British guidelines, however treatment and prophylaxis options are mostly restricted to valganciclovir. We don not perform gancyclovir resistance studies
Many thanks for sharing your own experience.
Please summarise these guidelines
# Preventing CMV Infection and Disease
# Determining CMV status in donor and recipient
1.1 CMV (IgG antibody) must be screened for both donors and recipients before or at the time of transplantation [1A].
1.2 Donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, recommended as donor seropositive, recipient seronegative for CMV(D+/R-) [1D].
# CMV prophylaxis
In all cases of solid organ transplant:
1.3 Valganciclovir prophylaxis in kidney and liver transplants for at least 3 months following transplantation if either:
(D+/R-) [1A].
OR
(ATG) or Alemtuzumab induction in case of D+/R+ or D-/R+ [1A]
1.4 Valganciclovir prophylaxis is recommended in heart, lung, intestinal or pancreas transplants for at least 3 months if either:
(D+/R-) [1C].
OR
(ATG) or Alemtuzumab induction in case of D+/R+ or D-/R+ [1C]
1.5 Do not routinely use Valganciclovir prophylaxis if CMV (D-/R-) [1D]
1.5.1 Some recipients with CMV (D-/R-) may need Valganciclovir or Valaciclovir prophylaxis to prevent other Herpes virus infections,e.g; recipients who are seronegative for (HSV) with HSV seropositive donors [2D].
1.6 Valganciclovir prophylaxis is advised for at least 3 months following treatment of AR (D+/R-, D+/R+ or D-/R+) [2C].
1.7 Adapt the Valganciclovir dose when creatinine clearance 60ml/minute [1D].
1.8 Children and patients 18 years, adapt the Valganciclovir in keeping with BSA, up to a maximum dose of 900mg od [1D].
1.9 Monitor FBC at least every 14 days during Valganciclovir therapy [1A].
1.10 CMV monitoring and pre-emptive therapy if Valganciclovir adverse events developed e.g.; neutropenia [1C].
# 2 Laboratory Testing for CMV
2.1 QNAT must be used to quantify CMV viral load [1A].
Use either whole blood or plasma [1C].
The calibration should be done according to WHO IRS [1C].
The viral load reported as IU/mL, or as copies / mL [1C].
2.2 Local thresholds of viral load indicated infection or disease needing treatment, depending on the CMV QNAT assay [1C].
2.3 QNAT thresholds should not be used in isolation to rule beginning or finishing of therapy [1C].
# 3 Monitoring for CMV Infection and Disease
3.1 Offer monitoring of CMV viral load in all SOT if:
*(D+/R+, D-/R+) [1B].
*Not received T-lymphocyte depletion therapy [1B].
*Not receiving valganciclovir prophylaxis [1B].
3.2 Where CMV viral load monitoring is offered:
Testing at least monthly for at least 3 months post transplant [1D].
# 4 Treating CMV Infection and Disease
4.1 Oral Valganciclovir for at least 2 weeks [1A]
4.2 Adjust the dose of Valganciclovir if creatinine clearance 60ml/minute [1D]
4.3 Consider the ganciclovir resistance
4.4 Evaluate CMV viral load after 2 weeks of treatment and repeat at 7 days [1D]
*Stop treatment for CMV disease after relief of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected [2D].
# 5 Ganciclovir resistance
5.1 Risk factors for resistance:
*Prolonged courses, or sub-therapeutic doses of antiviral therapy [1A]
*(D+/R-) [1C].
*Intensive IS (T-cell depletion therapy, post AR) [1B].
*In lung transplantation [2C].
5.2 Consider resistance when:
In persistent high viral load or presences of symptomatic disease following 2-4 weeks of Ganciclovir or Valganciclovir [1A]
5.3 Consider the adequate dose, adherence and absorption
Offer testing for (HCMV) antiviral resistance, UL97 and UL54 gene mutations [1A].
5.4 Stop the treatment in suspected case of resistance [1A]
I/V Foscarnet for at least 3 weeks [1B].
# 6 Immunosuppression dose reduction
6.1Dose reduction of either CNI or MMF / AZA [1C]
Decrease or stop (MMF) or AZA when leucopenia is suspected [2C]
6.2 Counsel the patients about the risk of AR with IS dose reduction [1D]
6.3 Review the dosing of IS post CMV infection or disease resolution [1D]
# 7 Information, education and support
7.1 Offer accurate information to patients about:
The risks of CMV infection and disease .
Evaluation and treatment options.
7.2 Ensure that healthcare professionals offering information have knowledge about CMV infection and disease and their management.
# Please reflect on your practice
*CMV (IgG antibody) must be screened for both donors and recipients before or at the time of transplantation.
*Prophylaxis is recommended for recipients who received ATG induction, OR when the donor recipient serostutus is (D+/ R-) CMV IgG; while other recipients received acyclovir for 6 months duration.
*We do not routinely use Valganciclovir as prophylaxis if CMV (D-/R-).
*We advise Valganciclovir prophylaxis for at least 3 months following treatment of AR.
*We don’t monitor CMV viral load routinely.
*Valganciclovir OR ganciclovir is mainly used for treatment of CMV infection and disease.
*We recommended the same guideline in managing Immunosuppression dose reduction and Ganciclovir resistance, however we did not have testing for Human CMV (HCMV) antiviral resistance / UL97 and UL54 gene mutations.
Many thanks for sharing your own experience.
Thank you for your reply and reflection on your practice.
Q2 reflect on your practice .
In our center
1- the ( donor and recipient ) tested for CMV IgG.
2- Valgancyclovir or valciclovir is offered for every recipient with any sero-positivity .
3- Acyclovir prophylaxis is offered in sero-negative state to prevent herps simplex infection .
4- The donor and recipient is not tested for herpes simplex sero state in our center.
5- Valgancyclovir is offered for at least 3 months .
6- QNAT used for diagnosis and treatment decision.
7- We use valgancyclovir for treatment .
8- We did not face a cse of gancyclovir or valgancyclovir resistance case .
9- We start immunsupressive medication dose reduction especially in sever patient .
10- – we reduce the dose of MMF OR AZATHIOPRINE at first with close monitoring the renal function test for early diagnosis of acute rejection.
Please summarise these guidelines
Preventing CMV Infection and Disease – They recommend that all organ donors and recipients should be screened for CMV (IgG antibody prior to or at time of transplantation .
-If serostatus of both patient and donor are unknown for CMV in this condition the donor should be considered as seropositive and the recipient is seronegative it is the same as if donor is unknown and recipient is negative .
CMV prophylaxis:
Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation for the following :
In case of heart, lung, intestinal or pancreas transplants the use Valganciclovir prophylaxis is the same as mentioned in liver and kidney transplant with different level of recommendation
-(D-/R-) valganciclovir prophylaxis is not recommended although some recipients may require prophylaxis for prevention of other herpes infection .
-Valganciclovir prophylaxis is given at a dose of 900 mg once daily oral dose with renal dose adjustment and full blood count monitoring.
Laboratory Testing for CMV-Quantification of CMV viral load in either whole blood or plasma using Quantitative Nucleic Acid Testing (QNAT) and should be reported as IU/mL instead of using copy /ml .
-Determination of commencement or cessation of treatment for individuals with CMV disease, should be considered with the interpretation of clinical, laboratory or histological evidence of CMV disease.
Monitoring for CMV Infection and Disease – Pre-emptive therapy should be guided by CMV viral load in case of (D+/R+, D-/R+) who doesn’t receive Tlymphocyte depleting agent nor valganciclovir prophylaxis with CMV viral load monitoring at least monthly for at least 3 months after transplant .
Treatment of CMV Infection and Disease
– Oral Valganciclovir for a duration of at least 2 weeks with the adjustment of the dose according to creatinine clearance.
– Check the viral load after 2 weeks and repeat at a minimum interval of one week .
-Stop the treatment if there is resolution of symptoms AND undetected CMV viral load in two consecutive tests .,
Ganciclovir-resistant;
There is increased risk of Ganciclovir resistance in patients who receive prolonged coarse or sub therapeutic dose and in seronegative recipient with seropositive donor in addition to those who have received intensive immunosuppression following episodes of acute allograft rejection and finally lung transplant patients .
Resistance to Ganciclovir is considered if: persistent or increasing viral load (using either whole blood or plasma) or symptomatic disease after completion of effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir
What to do if suspected resistance to Ganciclovir ?first confirm the adequacy of dosing and adherence to treatment plan ,check for gene mutation (UL97 -UL54)
If proved resistant to ganciclovir : Stop Valganciclovir (or Ganciclovir) and offer Intravenous Foscarnet for at least 3 weeks with specialist virology advice.
Immunosuppression dose reduction: Consider dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine and stopping of MMF or azathioprine if there is any evidence of leukopenia. with the clarification of risk of rejection in such a situation .After resolution of CMV infection the doses of immunosuppression should be reviewed .
Information, education and support
Explain to the patient the risks of CMV infection and disease according to donor / recipient CMV serostatus and the nature of immunosuppression planned or received, also talk to patient about monitoring and treatment options, including prophylaxis
Please reflect on your practice;
in our centre we used to
– Screen all donors and recipients
-We give valganciclovir prophylaxis as recommended by UK guidelines .
-Diagnosis of CMV infection or disease by PCR or tissue biopsy.
-Treatment is usually oral valganciclovir
Thank you for your reply and reflection on your practice.
sorry regarding treatment i missed to add iv ganciclovir in tissue invasive CMV
Please summarise these guidelines
**All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation [1A]
**Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation (D+/R-) [1A]
OR The recipient has received (ATG) or Alemtuzumab D+/R+ or D-/R+ [1A]
**Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+) [2C].
**Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir [1C]
**should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load [1A]
**pre-emptive therapy to adults, children and young people receiving a solid organ transplant if: They are CMV seropositive (D+/R+, D-/R+) [1B] AND They have not received T-lymphocyte depletion therapy [1B] AND They are not receiving valganciclovir prophylaxis [1B]
**Offer treatment with oral Valganciclovir for a duration of at least 2 weeks [1A]
** 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 [1A]
**In people with suspected resistance to Ganciclovir: 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 [1A] Use either whole blood or plasma [1A]
**In people with evidence of ganciclovir resistance: Stop Valganciclovir (or Ganciclovir) [1A] Offer Intravenous Foscarnet for at least 3 weeks [1B]
**Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine [1C] Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia [2C]
** Symptoms due to primary disease may occur as early as 20 days and are rare more than 50 days post transplantation provided the patient has not received antiviral drugs [. Symptoms may be non-specific, such as fever, night sweats, fatigue and myalgia. Retinitis can be pathognomonic, but is rarely seen in the transplant population. Gastrointestinal disease presenting with diarrhoea, abdominal pain and nausea is common and respiratory distress may be an indication of pulmonary involvement.
**Routine blood tests may detect bone marrow suppression, especially neutropenia, as well as biochemical hepatitis, as evidenced by fluctuations in ALT and AST. After a primary infection an individual would be expected to mount IgM and later an IgG immunoglobulin response against CMV., however, the antibody rise may be delayed or absent.
**(PCR) carried out on plasma, whole blood or leukocytes have become the gold standard means of detecting active CMV replication in many laboratories in the UK
**CMV infection can be coincident with acute allograft rejection
Early studies reported a 50% reduction in biopsy-proven acute graft rejection by anti-CMV prophylaxis in D+/R- kidney transplant recipients In a single centre study of 1,339 kidney transplant recipients, multivariate analysis showed that CMV disease appeared to influence long term graft survival but only when coupled with the occurrence of acute rejection
**A more recent publication examined graft outcome in 10,190 kidney transplants performed in adults, children and young people in the UK between 2000-7. After adjustment for donor age, this showed no significant effect of donor or recipient CMV status on either allograft or patient survival at three years post-transplant
**Newer agents such as Letermovir and Maribavir may have a role in prevention of CMV disease
Maribavir has Food and Drugs Administration (FDA) approval and is currently being assessed by the National Institute for Health and Care Excellence
**The committee noted that CMV monitoring following cessation of prophylaxis is recommended in other national clinical guidance However, there is no robust evidence that this improves outcomes or reduces the risk of CMV disease
**The committee was satisfied that there is high quality evidence that oral valganciclovir is as effective as intravenous ganciclovir in treating CMV infection and disease following SOT. Most commonly valganciclovir 900mg twice daily has been used as treatment dose, adjusted for level of kidney function.
**Valganciclovir has added advantages of not requiring hospitalisation or intravenous cannulation . However, the committee agreed that intravenous Ganciclovir would be the preferred treatment if concern exists regarding enteric absorption and the subsequent oral bioavailability of medications. The committee also agreed that, in very sick people requiring hospitalisation and other intravenous therapies e.g.; intravenous (i.v.) fluids and antibiotics, i.v ganciclovir should be considered due to a likelihood of impaired absorption.
** recommend using licensed dosing for treatment and prophylaxis from the company with adjustments for renal function made according to the Renal Drug Handbook, using the Cockroft-Gault formula to calculate creatinine clearance. The Renal Drug Handbook also includes information on higher treatment doses
**The committee identified a single small RCT that evaluated pre-emptive treatment with CMV Immunoglobulin (CMV Ig) in 37 recipients of heart transplants, that reported similar efficacy of CMV Ig and intravenous ganciclovir in preventing CMV disease . The committee was not persuaded that this was sufficient to make a recommendation on treatment with CMV Ig. No evidence was identified to support a recommendation on the use of adoptive transfer of cytotoxic T Lymphocytes (CTL) for pre-emptive treatment of CMV. The committee agreed to make research recommendation for both CMVIg and CTL.
2- Please reflect on your practice
THESE GUIDELINES MAKE EASY Decision support system PROGRAM
PROVIDE ADEQUATE Treatment of CMV before it causes any serious problems.
PROVIDE OUR PATIENT WITH INFORMATATION BASED ON BASED EVIDENCE MEDICNE
Thank you for your reply and reflection on your practice, but this is not enough. Please expand on the reflection on your practice.
summary:
theseguidelines include
1. Preventing of CMV infection and disease:
to prevent CMV we should:
2. lab testing for CMV:
3. Treating CMV infection and disease:
4. Ganciclovir resistance
5. IS dosecreduction:
6. Education of patients:
Thank you for your reply. Where is the reflection on your practice?
UK guideline on Prevention and Management of CMV infection and Disease Following Solid Organ Transplantation
Please summarise these guidelines.
1) Preventing CMV
2) Laboratory testing
3) Monitoring CMV/Pre-emptive strategies
4) CMV management (treatment and immunosuppression reduction)
5) Ganciclovir resistance
Please reflect on your practice.
Excellent Maisara
Please summarize these guidelines
1- Preventing CMV Infection and Disease
Determining CMV status in donor and recipient
· Prior to or at the time of transplantation, all organ donors and recipients should be tested for CMV (IgG antibody) serostatus
CMV prophylaxis
· Kidney and liver transplants for at least 3 months following transplantation if either (D+/R-).
· The recipient with Antithymocyte globulin (ATG) or Alemtuzumab (Campath®), (D+/R+ or D-/R+)
Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal, or pancreas transplants for at least 3 months following transplantation if either:
· (D+/R-)
· The recipient with Antithymocyte globulin (ATG) or Alemtuzumab (Campath®), (D+/R+ or D-/R+)
· No need for Valganciclovir prophylaxis in case the donor and recipient are seronegative for CMV (D-/R-).
CMV (D+/R-, D+/R+ or D-/R+) Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection
Adjust the dose of Valganciclovir according to creatinine clearance, and body surface area. Monitoring CBC after 2 weeks and withdraw if there is a drug side effect.
2- Laboratory Testing for CMV· CMV viral load, using the WHO International Reference Standard, as IU/mL or copies / mL, with a conversion factor, induction of treatment is according to local thresholds of viral load.
3- Monitoring for CMV Infection and Disease· Offer monitoring of CMV viral load (at least monthly for least 3 months following TX) to guide if they are CMV seropositive (D+/R+, D-/R+), if they have not received T-lymphocyte depletion therapy and if they are not receiving valganciclovir prophylaxis.
4- Treating CMV Infection and Disease· CMV infection or disease following solid organ transplantation: Valganciclovir for a duration of at least 2 weeks,
· Adjust the dose according to creatinine clearance, being aware of the potential development of ganciclovir resistance.
· Check CMV viral load after 2 weeks of treatment and consider stopping treatment after resolution of symptoms AND two consecutive, CMV viral load tests below the local threshold.
5- Ganciclovir resistance
· In those who have risk factors: received prolonged courses, or sub-therapeutic doses of antivirals (D+/R-), intensive immunosuppression, and lung transplants.
· Suspect resistance to Ganciclovir if there is a persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration
· In this group: Check dosing, compliance, HCMV antiviral resistance, gene mutations, and sample collection.
· Management; Stop Valganciclovir (or Ganciclovir), and Offer Intravenous Foscarnet for at least 3 weeks.
6- Immunosuppression dose reduction
· Dose reduction of either calcineurin inhibitor or mycophenolate mofetil/ Azathioprine.
· If there is evidence of leukopenia preferentially reduce or stop Mycophenolate Mofetil (MMF) or Azathioprine, consent about the possibility of rejection,
· Review immunosuppressive drugs after improvement.
7- Information, education, and support
· Balanced and accurate information about the risks of CMV infection and disease according to donor/recipient CMV serostatus and nature of immunosuppression planned or received
· Monitoring and treatment options, including prophylaxis.
===================================================================
Please reflect on your practice
· In our center, during the evaluation of transplantation, CMV serology is routinely done, and those with high clinical suspicion or patients with positive IgM should do PCR.
· Patients with detectable viral load will be given a treatment dose of valganciclovir arranged according to eGFR.
· According to CMV determinations and immunosuppression inductions, recipients will be stratified into three groups: low, intermediate, and high risk. The intermediate- and high-risk groups were then given 900 mg OD for three months as prophylaxis.
· Follow up clinically and with CBC for side effects.
· PCR monitoring is offered every 2 weeks for this period.
· Patient compliance, drug, and PCR costs remain serious issues to be dealt with.
Excellent Salwan
Thank you, Professor.
UK GUIDELINE ON PREVENTION AND MANAGEMENT
OF CYTOMEGALOVIRUS (CMV) INFECTION AND
DISEASE FOLLOWING SOLID ORGAN
TRANSPLANTATION
CMV Screening:
all donors and recipients should be screened / serostatus
if unknown aerostats …..regarded as high risk (D+/R-)
CMV prophylaxis:
giving valganciclovir prophylaxis for both high risk (D+/R-) and moderate risk group (D+/R+ or D-/R+, using ATG or Alemtuzumab & following treatment of acute allograft rejection ) but some time required same prophylaxis for low risk group (D-/R-) for prevention of other types of herpes virus infection
Note:
2 methods of prescription:
1.prophylaxis
2.monitorin & pre-emptive therapy
Laboratory Testing for CMV:
QNAT of whole blood or plasma to identify viral load
Thank you for your reply and reflection on your practice, but where is the reflection on your practice?
Summary:
Preventing CMV Infection and Disease
Determining CMV status in donor and recipient
· All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation
· If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-).
CMV prophylaxis
· For adults, children and young people receiving a solid organ transplant: Offer Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either: The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-)
· The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath ), where donor: recipient serostatus is D+/R+ or D-/R+
· Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal or pancreas transplants for at least 3 months following transplantation if either: The recipient is seronegative for CMV and receives an allograft from a CMV seropositive donor (D+/R-) or The recipient has received T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab, where donor: recipient serostatus is D+/R+ or D-/R+
· Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-)
· Be aware that some recipients who are seronegative for CMV (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention of other Herpes virus infections, e.g; recipients who are seronegative for Herpes Simplex Virus (HSV) receiving an organ from HSV seropositive donors.
· Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+) [2C].
· Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute
· For children and young people under 18 years, adjust the dose of Valganciclovir according to body surface area, up to a maximum dose of 900mg once daily
· Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir
· Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir
Laboratory Testing for CMV
· Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load
Transplant centres should adopt a consistent approach to use either whole blood or plasma for quantification of CMV viral load
· CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used
Monitoring for CMV Infection and Disease
· Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if: They are CMV seropositive (D+/R+, D-/R+) and They have not received T-lymphocyte depletion therapy and They are not receiving valganciclovir prophylaxis
· Where CMV viral load monitoring is offered: Consider testing with a frequency of at least monthly
· Consider testing for at least 3 months following transplantation
Treating CMV Infection and Disease
For adults, children and young people who develop CMV infection or disease following solid organ transplantation:
· Offer treatment with oral Valganciclovir for a duration of at least 2 weeks
· Adjust the dose of Valganciclovir according to licensed dosing recommendations if creatinine clearance is less than 60ml/minute
· Be aware of the potential development of ganciclovir resistance
· Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days
· Consider stopping treatment for CMV disease after resolution of symptoms and two consecutive, CMV viral load tests that confirm that CMV is not detected
Ganciclovir resistance
· Be aware that the following people are 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)
· Recipients of lung transplants
· 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
Immunosuppression dose reduction
For adults, children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation:
· Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine
· Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia
Information, education and support
Offer balanced and accurate information to children, adults and young people undergoing solid organ transplantation about: The risks of CMV infection and disease according to donor / recipient CMV
serostatus and nature of immunosuppression planned or received
Practice at our setting:
· We screen the donor and recipient pre-transplant.
· We transplant D+/R+ or D-/R+.
· Immediate post transplant ,we start Valgancyclovir prophylaxis for 3-6 months.
Thank you for your reply and reflection on your practice, but this is not enough. Please expand on the reflection on your practice.
Preventing CMV Infection and Disease
Determining CMV status in donor and recipient
All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation and if unknown donner, consider positive.
CMV prophylaxis
Offer Valganciclovir prophylaxis for at least 3 months for (D+/R-) and all R + who received T-lymphocyte depletion therapy with ATG or Campath.
Do not routinely offer Valganciclovir prophylaxis for CMV D-/R-. They may still need it for other reasons like recipients who are seronegative for Herpes Simplex Virus (HSV) receiving an organ from HSV seropositive donors.
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either D or R are +ve.
Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir.
Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir.
Laboratory Testing for CMV
Clinical Laboratories should use consistent Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load. It should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used.
Transplant centres should determine local thresholds of viral load that portend CMV infection or disease requiring treatment, depending on the CMV QNAT assay they use and the population at risk
QNAT thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease.
Monitoring for CMV Infection and Disease
Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if they are CMV seropositive who are not receiving valganciclovir prophylaxis.
Where CMV viral load monitoring is offered: Consider testing with a frequency of at least monthly for at least three months post transplantation.
Treating CMV Infection and Disease
Offer treatment with oral Valganciclovir for a duration of at least 2 weeks and check CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days.
Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, negative PCR.
Ganciclovir resistance
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 of Ganciclovir resistance:
– Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications.
– (D+/R-)
– after intensive immunosuppression (e.g; with T-cell depletion therapy, following episodes of acute allograft rejection)
– Lung transplants
In people with suspected resistance to Ganciclovir:
– Confirm that dosing and adherence to treatment and absorption
– Offer testing for Human CMV (HCMV) antiviral resistance UL97 and UL54 gene mutations
– Use either whole blood or plasma
In people with evidence of ganciclovir resistance: Stop Valganciclovir (or Ganciclovir) and Offer Intravenous Foscarnet for at least 3 weeks.
Immunosuppression dose reduction
Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine
Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia
Discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction
Review the dosing of immunosuppression following resolution of CMV infection or disease
**********
Reflection:
will review my local trust guidelines for CMV monitoring and treatment post transplant and also review our essay. I will share the guidlines with other colleagues and will consider it in my next presentation in our teaching.
Thank you for your reply and reflection on your practice, but this is not enough. Please expand on the reflection on your practice.
Background
CMV falls under the herpes group of viruses. The infection is more severe when the host is T-cell immunocompromised. After the primary CMV infection, the viral genome enters the monocytes and other bone marrow progenitor cells and enters a latent state.
It is transmitted by direct person-to-person contact through exposure to saliva, urine, breast milk or genital secretions. Its prevalence is reported to increase with age, 40% at age 20 and 80% at 60 years.
In SOT recipients, primary CMV infection occurs approximately 4 to 6 weeks after the transplant, in a seronegative patient who has received a seropositive organ.
Symptoms due to the primary infection occur as early as 20 days after the surgical procedure. Symptoms include night sweats, fatigue, myalgia and rarely retinitis. Diarrhea, abdominal pain, nausea, respiratory distress, bone marrow suppression and hepatitis are also commonly reported.
The presence of IgM is an indicator of primary infection while IgG is used to determine prior infection.
The gold standard test for detecting active CMV replication is based on PCR test carried out on plasma, whole blood or leucocytes. It is sometimes necessary to prove CMV organ specific dysfunction by obtaining a biopsy. CMV infection can also coincide with acute allograft reaction. It has been shown that CMV infection appears to influence long-term graft survival. Universal anti-CMV prophylaxis and pre-emptive anti-CMV therapy are currently in common use to minimize the impact of CMV infection or reactivation. Treatment of CMV disease involves reduction of immune suppression and administering specific antiviral therapy. Ganciclovir is usually the anti-viral of choice. Viral load quantification has been used to assess the response to treatment. UL97 and UL54 gene mutations can be detected by genotypic assays, which is useful to assess for resistance to ganciclovir. Cidofovir and foscarnet can be potentially used as 2nd or 3rd line treatment options.
Rationale for clinical practice recommendations for the prevention & management of CMV following SOT
Preventing CMV infections & disease All organ donors and recipients should be screened for the serostatus prior to transplantation
Vanganciclovir prophylaxis should be offered to patients receiving kidney or liver transplant for at least 3 month after the transplant if:
Vanganciclovir prophylaxis should also be offered to lung, heart, intestinal or pancreas transplant recipients for 3 months after transplantation if:
If both the donor and the recipient are seronegative, they do not require prophylaxis
The dose of vanganciclovir requires renal dose adjustment.
Laboratory testing for CMVIt is recommended that QNAT should be used on blood or plasma to quantify CMV viral load.
Monitoring CMV infection and diseaseCMV viral load should be monitored to guide pre-emptive therapy for patients receiving a SOT if:
Viral load can be tested monthly for at least 3 months after transplantation.
Treating CMV infection and disease For patients with CMV infection after SOT, it is recommended to treat with vanganciclovir for at least 2 weeks.
The dose should be reduced if creatinine clearance is less than 60mL/minute. Resistance to ganciclovir should be monitored.
Viral load should be assessed 2 weeks after treatment and repeated every 7 days.
The treatment should be stopped if 2 consecutive viral load tests do not detect CMV.
Ganciclovir resistance Patients at increased of ganciclovir resistance include:
Resistance to ganciclovir should be considered if there is a persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration.
In patients with suspected resistance to ganciclovir:
Immune suppression dose reduction For patients who develop CMV infection, consider reduction of immune suppression of either calcineurin inhibitor or MMF/azathioprine
It is important to discuss the risk of acute rejection with immune suppression reduction with the patients
Immune suppression dosage can be adjusted after the completion of the treatment.
Information, education and support It is important to offer information regarding the risks of CMV infection and disease to the donor and the recipient. They should also know of the management plan, treatment options and prophylaxis.
It is also important that the health care providers that are offering the information have specialist knowledge.
Local Practice:
Due to the high cost of valganciclvoir and patients paying out of pocket, we in Kenya do active surveillance and pre-emptive treatment if we find CMV disease. It is cheaper than offering universal prophylaxis to all kidney transplant recipients for three months
Thank you for your reply and reflection on your practice, I liked it considering your resources.
1. Please summarise these guidelines
1 Preventing CMV Infection & Disease
1.1 CMV (IgG antibody) testing done on all organ donors & recipients. [1A]
1.2 Donor seropositive, recipient seronegative for CMV (D+/R-) used to describe the situation when the donor’s CMV serostatus is unknown & the recipient is sero-negative or unknown for CMV. [1D]
CMV prophylaxis
For all SOTs:
1.3 Valganciclovir to recipients of kidney & liver TXs for at least 3 months after if either: D+/R- [1A]
OR
ATG or Alemtuzumab has been given to the recipient, where the donor: recipient serostatus is D+/R+ or D-/R+ [1A]
1.4 Valganciclovir for people receiving heart, lung, intestinal or pancreas TXs for at least 3 months if either:
D+/R-.
OR
D+/R+ or D-/R+ after ATG or Alemtuzumab. [1C]
1.5 If CMV D-/R-, do not routinely give Valganciclovir prophylaxis [1D].
1.5.1 Some receivers who are D-/R- seronegative may need Valganciclovir or Valaciclovir to prevent the spread of other Herpes viruses, such as recipients who are HSV sero-negative but get an organ from HSV seropositive donors [2D].
1.6 Valganciclovir for at least 3 months after starting treatment for AR if D+/R-, D+/R+ or D-/R+ [2C].
1.7 Valganciclovir dose adjusted if creatinine clearance is < 60ml [1D]
1.8 In children & <18 years, the dose of Valganciclovir according to BSA [1D]
1.9 Monitor FBC at least every 2 weeks [1A]
1.10 CMV monitoring & pre-emptive therapy if S/Es e.g.; neutropenia, on Valganciclovir [1C]
2 Laboratory Testing for CMV
2.1 QNAT to quantify CMV viral load [1A]
Either whole blood or plasma for quantification [1C]
Calibrate assays using the WHO IRS [1C]
CMV viral load reported as IU/mL or as copies / mL [1C]
2.2 Local thresholds of viral load determined for CMV infection or disease requiring treatment [1C]
2.3 QNAT thresholds not used in isolation to decide start or cessation of treatment [1C]
3 Monitoring CMV Infection & Disease
3.1 Offer monitoring of CMV viral load if:
D+/R+, D-/R+ [1B] AND
T-lymphocyte depletion therapy has not been given. [1B] AND
They are not receiving valganciclovir prophylaxis [1B]
3.2 When monitoring CMV viral load:
Testing at least monthly for at least 3 months following transplantation [1D]
4 Treating CMV Infection & Disease
4.1 Oral Valganciclovir for at least 2 weeks [1A]
4.2 Adjust the dose if creatinine clearance is < 60ml [1D]
4.3 Keep in mind ganciclovir resistance
4.4 After 2 weeks of treatment, reassess viral load at a minimum 7-day interval. [1D] AND
After symptoms have cleared AND 2 consecutive viral load tests are –ve, stop therapy. [2D].
5 Ganciclovir resistance
5.1 Increased risk of Ganciclovir resistance:
If prolonged courses, or sub-therapeutic doses [1A]
If D+/R- [1C]
If intensive IS (e.g; with T-cell depletion therapy for AR) [1B]
Recipients of lung TXs [2C]
5.2 Consider resistance if:
Persistent or increasing viral load or symptomatic disease after effective dosage & duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir [1A]
5.3 In case of resistance:
Confirm adequacy of dosing
Consider adherence & absorption
Antiviral resistance testing [1A]
5.4 In evidence of resistance:
Stop Valganciclovir (or Ganciclovir) [1A]
Give IV Foscarnet for at least 3 weeks [1B]
6 IS dose reduction
7 Information, education & support
Offer information about:
Executive Summary of Research Recommendations
In adults, children & young people receiving SOT:
Executive Summary of Audit Measures
==============================
2. Please reflect on your practice
Thank you for your reply and reflection on your practice, but acyclovir is ineffective.
All organ donors and recipients should be screened for CMV serostatus prior to, or at the time of transplantation . If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-).
CMV prophylaxis
Valganciclovir prophylaxis should be offered to people receiving kidney and liver transplants for at least 3 months following transplantation if-
D+/R-
D+/R+ or D-/R+
Acute allograft rejection if either donor or recipient are CMV positive (D+/R-, D+/R+ or D-/R+)
Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-)
Adjust dose according to creatinine clearance
For lesser age groups – adjust dose according to body surface area.
Watch Full Blood Count at least every 2 weeks during treatment
Consider pre emptive therapy if neutropenia develops.
Laboratory Testing
CMV QNAT assays should be calibrated using the WHO International Reference Standard
Viral load should be reported as IU/mL
Transplant centres should determine local thresholds of viral load
QNAT thresholds should not be used in isolation but clinical and pathological context should be considered.
Monitoring for CMV Infection and Disease
Offer monitoring of CMV viral load if-
D+/R+, D-/R+
If not received T-lymphocyte depletion therapy
If not receiving valganciclovir prophylaxis
Treating CMV Infection and Disease
Oral Valganciclovir for a duration of at least 2 weeks
Dose adjustment if creatinine clearance is less than 60 ml/m
Watch for Drug resistance
Stop treatment after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is negative.
Ganciclovir Resistance
High risk Groups-
Those receiving prolonged courses, or sub-therapeutic doses are at high risk of resistance.
D+/R-
Those received intensive immunosuppression
Recipients of lung transplants
If resistance id confirmed then Confirm that dosing is adequate .
Consider adherence to treatment plan and absorption and offer testing for Human CMV (HCMV) antiviral resistance UL97 and UL54 gene mutations
Offer Intravenous Foscarnet for at least 3 weeks
Reduce immune suppression
Reflection on my local practice
We follow UK guidelines
We routinely check CMV IgM and IgG during transplant workup for both donor and recipient
We use prophylaxis with Valganciclovir
We routinely do viral loads to monitor treatment
Thank you for your reply and reflection on your practice.
Please summarise these guidelines
Introduction:
CMV in Solid Organ Transplant Recipients
1. Donor (D) positive (+); Recipient (R) positive (+) (D+/R+)- Risk of superinfection or reactivation.
2. Donor (D) negative (-); Recipient (R) negative (-) (D-/R-)- Risk of primary infection from other source.
3. Donor (D) positive (+); Recipient (R) negative (-) (D+/R-)- Risk of primary infection.
4. Donor (D) negative (-); Recipient (R) positive (+) (D-/R+)- Risk of reactivation of latent infection.
Preventing CMV infection and disease:
Determining CMV status in donor and recipient
All donor and recipient should be screened for CMV IgG before transplantation.
If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be CONSIDERED donor +ve, recipient -ve for CMV (D+/R-).
CMV prophylaxis
Laboratory Testing for CMV
Monitoring for CMV Infection and Disease
Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if:
Where CMV viral load monitoring is offered:
Treating CMV Infection and Disease
For adults, children and young people who develop CMV infection or disease following solid organ transplantation:
Ganciclovir resistance
Be aware that the following people are at increased risk of Ganciclovir resistance:
Consider resistance to Ganciclovir if:
In people with suspected resistance to Ganciclovir:
In people with evidence of ganciclovir resistance:
Immunosuppression dose reduction
For adults, children and young people who develop CMV infection or disease (with or without leukopenia) following solid organ transplantation:
Information, education and support
Offer balanced and accurate information to children, adults and young people undergoing solid organ transplantation about:
Please reflect on your practice
D+/R+, D-/R+.
( in this issue we learnt a lot for the UK guidelines for better management and cost-effectiveness in treatment plan) – our approach may increase the risk of resistant strains of CMV
Excellent
Introduction
CMV belongs to herpes group of viruses, which are widely distributed among mammals. The primary infection results in the most severe disease when the host is T-cell immunocompromised. After primary CMV infection, the viral genome enters monocytes and other bone marrow progenitor cells and enters a latent state.
Primary infection typically occurs approximately four to six weeks posttransplant in a seronegative individual who receives a seropositive organ provided the patient has not received antiviral drugs. clinical presentation is non-specific, and include either systemic manifestations like fever, night sweats, fatigue and myalgia. Or local presentation according to the target organ affection i.e GIT, respiratory etc.
· Serology is used for identify the donor and recipient CMV status
· PCR of the whole blood or plasma is used to measure viral load during active infection follow up of treatment assessment of remission or treatment resistance
· Tissue biopsy is indicated in case of suspected target organ affection
Evaluation of donor and recipient for CMV status
All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation
Note: If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be considered as donor seropositive, recipient seronegative for CMV (D+/R-).
CMV prophylaxis For adults, children and young people receiving a solid organ transplant:
Consider Valganciclovir prophylaxis to people receiving kidney and liver transplants for at least 3 months following transplantation if either:
· The recipient is seronegative for CMV and donor is seropositive (D+/R-)
OR
· The recipient has received induction immunosuppression with T-lymphocyte depletion therapy with Antithymocyte gobulin (ATG) or Alemtuzumab (Campath ), where donor: recipient serostatus is D+/R+ or D-/R+.
· Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV (D-/R-).
· in case of suspicion of other Herpes virus infections in recipients who are seronegative for CMV (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention
· In case of starting treatment for acute allograft rejection if either donor or recipient are CMV positive, Consider Valganciclovir prophylaxis for at least 3 months.
Adjustment of the dose of Valganciclovir
· Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute and For children and young people under 18 years, body surface area should be used to adjust the dose of Valganciclovir and it should not exceed a dose of 900mg once daily.
Monitoring of Valganciclovir treatment
· Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir and Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir.
Laboratory Testing for CMV
1 Use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma (according to the transplant center policy) to quantify CMV viral load
2 The WHO International Reference Standard should be used to calibrate CMV QNAT assays
3 CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used.
4 Transplant centers should determine local thresholds of viral load that exactly define CMV infection or disease requiring treatment, depending on the CMV QNAT assay they use and the population at risk
5 Starting or withdrawal of treatment should depend on clinical, laboratory or histological evidence of CMV disease.
3- Monitoring for CMV Infection and Disease
Indicated if:
· They are CMV seropositive (D+/R+, D-/R+) AND they have not received T-lymphocyte depletion therapy AND They are not receiving valganciclovir prophylaxis.
· frequency of monitoring is at least monthly and for a duration for at least 3 months following transplantation
4- Treatment of CMV Infection and Disease For adults, children and young people who develop CMV infection or disease following solid organ transplantation:
A- Antiviral
consider treatment with oral Valganciclovir for at least 2 weeks.
the dose of Valganciclovir should be adjusted if creatinine clearance is less than 60ml/minute and observe closely for ganciclovir resistance.
Frequency of monitoring of CMV viral load is: 2 weeks of treatment and should be repeated at a minimum interval of 7 days.
When to stop treatment
Consider stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected (below the local laboratory threshold for detection).
Ganciclovir resistance
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
patient medication compliance has been ensured.
Factors that increase the risk of Ganciclovir resistance:
· 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)
· Recipients of lung transplants.
· Evaluation for suspected resistance to Ganciclovir:
· good history taking to Confirm that dosing is adequate Consider adherence to treatment plan and absorption
· consider UL97 and UL54 gene mutations
management of ganciclovir resistance:
· Stop Valganciclovir (or Ganciclovir).
· Seek specialist virology advice before commencing treatment with Intravenous Foscarnet for at least 3 weeks.
B- Immunosuppression modulation
· 6.1 Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine.
· Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) or azathioprine if there is evidence of leukopenia.
· Share the management plan with the patient explaining the risk /benefit especially the risk of acute rejection with the reduction of Immunosuppression
· following resolution of CMV infection or disease, dosing of immunosuppression should be reevaluated according to the risk benefit ratio
patient education
· importance of viral screening pretransplantation
· prophylaxis if indicated
· frequency and duration of lab evaluation after transplantation
· risk assessment upon modulation of immunosuppression
Thank you for your reply and reflection on your practice, but this is not enough. Please expand on the reflection on your practice.
Determining CMV status in donor and recipient
All donors and recipients should be screened for CMV (IgG antibody) prior to, or at the time of transplantation.
If donor serostatus is unknown and recipient is seronegative or unknown, this should be characterised as donor seropositive, recipient seronegative (D+/R-).
CMV prophylaxis
Offer Valganciclovir prophylaxis to solid organ transplants recipient for at least 3 months following transplantation if the recipient is seronegative and receives an allograft from seropositive donor or the recipient is seropositive and has received T-lymphocyte depletion therapy with ATG or Alemtuzumab.
Do not routinely offer prophylaxis if donor and recipient are seronegative for. Unless the recipients is seronegative for Herpes Simplex Virus and received an organ from HSV seropositive donors.
Consider prophylaxis for at least 3 months after treatment for rejection if donor or recipient are CMV positive.
Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute.
For children and people under 18 years, adjust the dose of Valganciclovir according to body surface area.
Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir.
Switching to monitoring and pre-emptive therapy in case of side effects e.g., neutropenia, on Valganciclovir.
Laboratory Testing for CMV
Transplant centres should adopt a consistent approach to use either whole blood or plasma for quantification of CMV viral load.
CMV assays should be calibrated using the WHO International Reference Standard.
CMV viral load should be reported as IU/mL, or, if reported as copies / mL, a conversion factor should be used.
Transplant centres should determine local thresholds of viral load that portend treatment.
QNAT thresholds should be used in conjugation with clinical, laboratory or histological evidence of CMV disease.
Monitoring for CMV Infection and Disease
Monitor viral load to guide pre-emptive therapy if patients are seropositive, they have not received T-lymphocyte depletion therapy and are not receiving valganciclovir prophylaxis
Consider monitoring at least monthly for at least 3 months following transplantation.
Treating CMV Infection and Disease
Offer treatment with oral Valganciclovir for at least 2 weeks.
Adjust the dose if creatinine clearance is less than 60ml/minute.
Be aware of the potential development of ganciclovir resistance.
Assess CMV viral load 2 weeks after treatment and repeat at a minimum interval of 7 days.
Stop treatment after resolution of symptoms and two consecutive, undetectable viral loads.
Ganciclovir resistance
People are at increased risk of Ganciclovir resistance:
Following prolonged courses, or sub-therapeutic doses of antiviral medications.
Seronegative recipients receiving a transplant from seropositive donors.
Patients received intensive immunosuppression (e.g., with T-cell depletion therapy, following acute allograft rejection).
Lung transplants recipients.
Consider resistance to Ganciclovir if there is a persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration of Ganciclovir or Valganciclovir.
In people with suspected resistance:
Confirm that dosing is adequate
Consider adherence to treatment and absorption
Offer testing for Human CMV antiviral resistance
UL97 and UL54 gene mutations
In people with evidence of ganciclovir resistance:
Stop Valganciclovir (or Ganciclovir).
Offer Intravenous Foscarnet for at least 3 weeks after discussion with virology specialist.
Immunosuppression dose reduction
Consider a dose reduction of either CNI or antimetabolite.
Preferentially reduce or stop antimetabolite if there is leukopenia.
Discuss with patients, parents or carers, the risk of rejection with immunosuppression reduction.
Review the dosing following resolution of CMV infection or disease.
Information, education and support
Offer patients information about the risks of CMV infection, Prophylaxis, Monitoring and treatment.
Support shared decision-making
In our centre we give prophylaxis with Valgancilcovir for 6 months to all patient except D-/R-.
Thank you for your reply.
Please summarise these guidelines
Introduction
*This is UK (British Transplantation Society) guidelines on prevention and management of cytomegalovirus (CMV) infection and disease following solid organ transplantation, April 2022
*CMV is a member of the herpes family
*The prevalence of previous infection (positive IgG antibody) increases with age (40% at age 20 and 80% at age 60)
*Mode of transmission: saliva, urine, breast milk or genital secretions
*In D+/R- primary infection occurs 4-6 weeks posttransplant
*PCR of plasma, whole blood or leukocytes is the gold standard test for active CMV replication
*Biopsy of organ dysfunction can be diagnostic [Liver, GI, bone marrow, lung and renal allograft]
*Late-onset CMV disease: CMV disease occurs after cessation of antiviral drug in patients on antiviral prophylaxis (D+ / R-). It is associated with allograft failure and mortality
Antiviral drug Resistance: progressive disease despite full dose anti-viral therapy, or a static or increasing viral load after drug treatment (not first week)
Definitions
CMV infection: complete replication cycle of the virus
1. Asymptomatic
2. Viral syndrome ((fever, leucopenia, myalgia or arthralgia)
3. CMV disease: (histopathological evidence of CMV, CMV retinitis, or CMV in the CSF)
Latent CMV: no full replication cycle of the virus
Serostatus: serology test (IgG antibody)
1. (D+/R+)
2. (D-/R-)
3. (D+/R-)
4. (D-/R+)
CMV prophylaxis
*All organ donors and recipients should be screened for CMV (IgG antibody) serostatus prior to, or at the time of transplantation [1A]
*If donor CMV serostatus is unknown and recipient is seronegative or unknown for CMV, this should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-). [1D]
*Donor CMV serostatus should be within 30 days of organ donation
*Give Valganciclovir prophylaxis for at least 3 months if D+/R- or recipient received ATG or Alemtuzumab where D+/R+ or D-/R+ [1A]
*No prophylaxis if D-/R- [1D]. May be given for other other Herpes (HSV) [2D]
*Offer prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either (D+/R-, D+/R+ or D-/R+) [2C]
*Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute [1D]
*For children and young people under 18 years, adjust the dose of Valganciclovir according to body surface area, up to a maximum dose of 900mg once daily [1D]
*Monitor CBC at least every 2 weeks whilst on Valganciclovir [1A]
Switch to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir [1C]
Laboratory Testing for CMV
*Use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load [1A]. Use the WHO International Reference Standard for QNAT [1C]. Viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used [1C]
*Higher levels of CMV viral load have been reported when whole blood rather than plasma is used for QNAT testing
*Transplant centres should determine local thresholds of viral load that requiring treatment [1C]
*QNAT thresholds should not be used alone to determine commencement or cessation of treatment, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease [1C]
Monitoring of CMV Infection and Disease
Offer monitoring of CMV viral load to guide pre-emptive therapy if:
1. (D+/R+, D-/R+) [1B] AND
2. They have not received T-lymphocyte depletion therapy [1B] AND
3. They are not receiving valganciclovir prophylaxis [1B]
Where monitoring is offered:
1. Do the test at least monthly [1D]
2. Consider testing for at least 3 months following transplantation [1D]
Treatment of CMV Infection and Disease
*Offer treatment with oral Valganciclovir for a duration of at least 2 weeks [1A]
Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute [1D]
*Intravenous Ganciclovir if concern exists regarding enteric absorption
*Treatment for 2 weeks is associated with a viraemia reduction of approximately 90%
Be aware of of ganciclovir resistance
*Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days [1D] AND
*Stop treatment after resolution of symptoms AND two consecutive, negative tests for CMV viral load [2D]
Ganciclovir resistance
*CMV disease that is refractory to treatment with Ganciclovir or Valganciclovir and is reported to occur in up to 3% of SOT recipients
Risk of Ganciclovir resistance:
1. Prolonged antiviral courses, or subtherapeutic antiviral dosing [1A]
2. (D+/R-) [1C]
3. Intensive immunosuppression (e.g; with T-cell depletion therapy, following episodes of acute allograft rejection) [1B]
4. Recipients of lung transplants [2C]
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 [1A]
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 [1A]. Use either whole blood or plasma [1A]
When there is evidence of ganciclovir resistance:
1. Stop Valganciclovir (or Ganciclovir) [1A]
2. Offer Intravenous Foscarnet for at least 3 weeks [1B]. Seek specialist virology advice before commencing treatment with Foscarnet [1D]
Newer agents Letermovir and Maribavir may be associated with less drug toxicity
Maribavi has FDA approval and is currently being assessed by the NICE
Immunosuppression dose reduction
If recipient developed CMV infection or disease (with or without leukopenia):
1. Reduce the dose of CNIs or MMF / azathioprine [1C]. Reduce or stop MMF or azathioprine if there is leukopenia [2C]
2. Discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction [1D]
3. Review the dosing of immunosuppression following resolution of CMV infection or disease [1D]
There is low quality evidence that conversion to an mTOR-inhibitor may provide some protection against recurrent CMV (insufficient to recommend conversion to an mTORinhibitor during or following CMV infection or disease)
Information, education and support
Offer balanced and accurate information about:
1. The risks of CMV infection and disease according to donor / recipient CMV serostatus and nature of immunosuppression planned or received
2. Monitoring and treatment options, including prophylaxis
Ensure that healthcare professionals should have specialist knowledge about CMV infection and disease and the skills to support shared decision-making
Please reflect on your practice
We do not give prophylaxis (most patients are D+/R+). Management depends on clinical suspicion, viral load, and histopathology. We give valganciclovir for treatment. No viral load monitoring. No post transplant survey and pre-emptive treatment
Thank you for your reply and reflection on your practice, but do you think your approach is good enough or it is guided by the available resources?
Thank you prof.
It is not good enough (low resource setting)
1.Please summarise these guidelines
-CMV is one of the herpes group of viruses, which are widely distributed among mammals.The various strains of CMV are species specific and primary infection results in the most severe disease when the host is T-cell immunocompromised.
-The prevalence of antibody indicating previous infection increases with age .
– Transmission occurs from direct person-to-person contact through exposure to saliva, urine, breast milk or genital secretions.
-CMV infection: evidence of the virus undergoing a complete replication cycle and producing new infectious virions. This may be further characterized as:
1.Asymptomatic infection (no obvious signs of pathologic symptoms)
2.Viral syndrome (fever, leucopenia, myalgia or arthralgia)
3.CMV disease – (histopathological evidence of CMV, CMV retinitis diagnosed by an ophthalmologist, or CMV in the CSF indicative of CNS disease)
Latent CMV: A state of virus infection in which the full replication cycle of the virus is not occurring
Preventing CMV Infection and Disease
Determining CMV status in donor and recipient
– All organ donors and recipients should be screened for CMV (IgG antibody)serostatus prior to, or at the time of transplantation .
CMV prophylaxis
For adults, children and young people receiving a solid organ transplant:
-Offer Valganciclovir prophylaxis to people receiving SOT (kidney, liver, heart, lung, intestinal or pancreas transplants) for at least 3 months following transplantation if either:
1.The recipient is seronegative for CMV and donor CMV seropositive .
2.The recipient has received T-lymphocyte depletion therapy with ATG or Alemtuzumab, where donor: recipient serostatus isD+/R+ or D-/R+.
-Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir .
– Do not routinely offer Valganciclovir prophylaxis if donor and recipient areseronegative for CMV .
-Some recipients who are seronegative for CMV (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention of other Herpes virus infections.
-Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient are CMV positive .
-Adjust the dose of Valganciclovir if creatinine clearance is less than 60ml/minute .
-Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects e.g.; neutropenia, on Valganciclovir .
Laboratory Testing for CMV
-Clinical Laboratories should use Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma to quantify CMV viral load.
-CMV QNAT assays should be calibrated using the WHO International Reference Standard .
-CMV viral load should be reported as IU/mL, where possible, or, if reported as copies / mL, a conversion factor should be used .
-Transplant centres should determine local thresholds of viral load that portend CMV infection or disease requiring treatment, depending on the CMV QNAT assay they use and the population at risk .
-QNAT thresholds should not be used in isolation to determine commencement or cessation of treatment for individuals with CMV disease, but should be considered in the context of clinical, laboratory or histological evidence of CMV disease.
Monitoring for CMV Infection and Disease
-Offer monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if:
1.They are CMV seropositive .
2.They have not received T-lymphocyte depletion therapy .
3.They are not receiving valganciclovir prophylaxis.
– Where CMV viral load monitoring is offered??
1.Consider testing with a frequency of at least monthly .
2.Consider testing for at least 3 months following transplantation.
Treating CMV Infection and Disease
-Offer treatment with oral Valganciclovir for a duration of at least 2 weeks .
-Adjust the dose of Valganciclovir according to licensed dosing recommendations if creatinine clearance is less than 60ml/minute.
-Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days .
-Stopping treatment for CMV disease after resolution of symptoms AND two consecutive, CMV viral load tests that confirm that CMV is not detected .
Ganciclovir resistance
-Following people are at increased risk of Ganciclovir resistance:
1.Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications .
2.CMV seronegative recipients receiving a solid organ transplant from seropositive donors .
3.Those who have received intensive immunosuppression .
4.Recipients of lung transplants .
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.
In people with suspected resistance to Ganciclovir:
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 .
In people with evidence of ganciclovir resistance:
1.Stop Valganciclovir (or Ganciclovir).
2.Offer Intravenous Foscarnet for at least 3 weeks.
3.Seek specialist virology advice before commencing treatment with Foscarnet.
Immunosuppression dose reduction
-Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil /azathioprine.
-Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) orazathioprine if there is evidence of leukopenia .
-Discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction [1D]
-Review the dosing of immunosuppression following resolution of CMV infection or disease .
Information, education and support
-The risks of CMV infection and disease according to donor / recipient CMV serostatus and nature of immunosuppression planned or received
Monitoring and treatment options, including prophylaxis
-Ensure that healthcare professionals offering information have specialist knowledge about CMV infection and disease and their treatment, and the skills to support shared decision-making.
2.Please reflect on your practice
-In our center,we screen the donor and recipient pre-transplant.
-We transplant D+/R+ or D-/R+.
-Post transplant ,we start prophylaxis CMV therapy.
I like your summary of these guidelines.
I like your reflection of your current practice and challenges unique to your workplace.
Summary
Preventing CMV infection
CMV serostatus of donor and recipient should be known prior to transplantantion, if not should be assumed to be D+/R-.
Should be done donor at retrieval of organ, recipient while on the waiting list.
Prophylaxis
Valganciclovir should be offered for at least 3 months after SOT to:
D-/R- no need for prophylaxis.
Renal dose when serum creatinine clearance <60ml/min.
CBC monitoring should be done every 2 weeks when on valganciclovir.
Switch to CMV monitoring and preemptive therapy when there are side effects.
Recipients who receive prophylaxis are at high risk of late onset CNV disease which is associated with allograft failure and mortality.
Laboratory testing.
Transplant centers should have a standardise way of CMV viral load quantification using either whole blood or serum. A threshold should also be set by the centre that portends treatment or infection.
CMV viral load should be interpreted with clinical, laboratory, or histological evidence of disease to determine commencement or cessation of treatment.
CMV monitoring
Should be done to guide preemptive therapy in D+/R+ OR D-/R+ and they didn’t receive either prophylaxis or T cell depleting agent induction therapy.
Treatment
Oral valganciclovir should be given for 2 weeks.
Repeat CMV viral load after the 2 weeks then on 7 days interval.
Stop treatment when 2 consecutive CMV viral loads are below threshold and there is resolution of symptoms.
There is a high risk of relapse after successful treatment.
No role of secondary prophylaxis.
Ganciclovir resistance
Recipients at risk:
When to consider?
Persistent or increasing viral load or symptoms despite effective dosage and duration.
However recipients with high viral load prior to treatment are likely to have increasing viral loads 5-7 days after treatment before it declines.
What to do?
Confirm dosing and adherence.
Offer testing for human CMV resistance on either blood or plasma.
Test for mutations UL54 /UL97.
How to treat?
Stop the valganciclovir.
Give iv forscanet for 3 weeks.
Forscanet is nephrotoxic and causes electrolyte imbalance.
Marabavir showing promise in clinical trials for treatment of resistance.
Immunosuppression reduction
Reduce dose of CNI or antimetabolite.
Preferentially reduce or withdraw antimetabolite if they have leucopenia.
My practise
We routinely do recipients and donor serostatus prior to transplantation.
Most are D+/R+.
We don’t routinely give prophylaxis after transplant for we are in a low resource setup.
Treatment is done based on clinical presentation + viral load ± histological evidence.
We treat with valganciclovir.
We don’t routinely do viral loads to monitor response to treatment.
I like your summary of these guidelines.
I like your reflection of your current practice and challenges unique to your workplace.
Thank you prof
Guideline according to The British Transplantation Society:
CMV virus may occur from asymptomatic to severe systemic disease.
2. Viral syndrome (fever, leucopenia, myalgia or arthralgia)
3. CMV disease – (histopathological evidence of CMV, CMV retinitis / CNS disease)
Primary CMV infection occur in organ transplant in 4 to 6 weeks post transplant.
Presence of high titer IgM and low IgG level indicates primary infection.
CMV infection characteristic in organ transplant is:
Donor: recipient CMV serostatus is characterised as:
1. Both donor and recipient are IgG antibody seropositive:
Donor (D) positive (+); Recipient (R) positive (+) (D+/R+)
2. Both donor and recipient are IgG antibody seronegative: Donor (D) negative (-); Recipient (R) negative (-) (D-/R-)
3. Donor is IgG antibody seropositive and recipient is IgG antibody seronegative: Donor (D) positive (+); Recipient (R) negative (-) (D+/R-)
4. Donor is IgG antibody seronegative and recipient is IgG antibody seropositive: Donor (D) negative (-); Recipient (R) positive (+) (D-/R+).
Clinical picture:
Picture of CMV is low grade fever and fatigue and abdominal pain and evidence of retinitis.
Laboratory studies shows leukopenia
Diagnosis by PCR .
Treatment of CMV Disease:
Reduce immunosuppressive drug
Antiviral therapy
IV gancyclovir
High dose of hyperimmune globulin 0.5g/kg used with gancyclovir in case of pneumonitis.
Many studies shows evidence of relapse after successfully management of CMV disease and prophylactic treatment should be considered after treatment to reduce relapse.
Antiviral drug Resistance:
Cidofovir is second line of treatment in case of resistance.
Foscarnet is third line of therapy but it’s nephrotoxic and may lead to electrolytes disturbance.
Grading of Recommendations Assessment, Development and Evaluation (GRADE) system:
For each recommendation the quality of evidence has been graded as:
A (high)
B (moderate)
C (low)
D (very low).
Grade A evidence:
It’s means high quality evidence that comes from consistent results from well performed randomised controlled trials, or overwhelming evidence of another sort (such as well-executed observational studies with very strong effects).
Grade B evidence:
It’s means moderate quality evidence from randomised trials that suffer from serious flaws in conduct, consistency, indirectness, imprecise estimates, reporting bias, or some combination of these limitations, or from other study designs with special strength.
Grade C evidence:
It’s means low quality evidence from observational evidence, or from controlled trials with several very serious limitations.
Grade D evidence:
It’s based only on case studies or expert opinion.
A Level 1 recommendation is a strong recommendation to do (or not to do) something
where the benefits clearly outweigh the risks (or vice versa) for most, if not all patients.
A Level 2 recommendation is a weaker recommendation, where the risks and benefits are more closely balanced or are more uncertain.
CMV prophylaxis:
It’s used for people with seronegative recipient and sero- positive donor. Or patients receive T-lymphocyte depletion therapy and ATG.
Treating CMV Infection and Disease:
Reflect in our practice?
Its same to British guidelines but we use ganciclovir as prophylactic therapy against CMV in all transplant patients for 6 months whether recipient or donor is sero negative or sero positive
I like your reflection of current practice in your hospital in relation to these (similar) guidelines
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION.
1-Please summarise these guidelines;
–Preventing CMV Infection and Disease;
-Serological status of both donor and recipient has to be set prior to transplantation,
–All donors and recipients should be screened for CMV (IgG antibody) before or a few days before the transplantation.
–Seronegative recipients may require prophylaxis for prevention of other Herpes virus.
-If recipient developed side effect consider switching to CMV monitoring and pre-emptive therapy.
–Serostatus of the donor and recipient should be known, if the serostatus is unknown this should be managed as (D+/R-) case.
Monitoring of CMV infection and disease;
–(R+) patients who are not receiving aggressive induction therapy (ATG or Alemtuzumab) are candidate for monitoring and preemptive therapy, with monitoring of CMV PCR at least per month for at least 3 months,
–Pre-emptive therapy guided by monitoring of CMV viral load at least monthly for at least 3 months, considered if:
– CMV seropositive (D+/R+, D-/R+),
– Not received T- cell depletion therapy,
– Not on valganciclovir prophylaxis
-CMV viral load monitored post transplant every 3 months.
-If either donor or recipient is CMV positive (D+/R-, D+/R+, or D-/R+), consider valganciclovir prophylaxis for at least 3 months following acute allograft rejection therapy.
-Adjust Valganciclovir dosage if creatinine clearance is less than 60ml/minute.
Treating CMV Infection and Disease;
-For young candidates ,oral Valganciclovir is given for at least 2 weeks considering renal dose adjustment if needed , and ganciclovir resistance risk.
-CMV viral load after 2 weeks of treatment need to be checked and then again after at least 1 week, then therapy is stopped after resolution of symptoms and 2 negative CMV viral load tests
-For children under 18, modify Valganciclovir dosage according to body surface area up to 900mg daily.
-Check FBC every 2 weeks while on Valganciclovir.
-Switch to CMV surveillance and pre-emptive treatment if Valganciclovir side effects include neutropenia.
-Consider stopping treatment for CMV disease after resolution of symptoms and CMV is below threshold for detection,
-High doses of intravenous Hyperimmune globulin (0.5 g/kg body weight) have been used in conjunction with Ganciclovir for the treatment of pneumonitis,
–Ganciclovir-resistant;
-Ganciclovir resistance is higher in the following people:
Long-term or subtherapeutic antiviral treatment drugs / CMV-negative solid organ transplant patients from seropositive donors / T-cell-depleted immunosuppressed patients / treatment after acute allograft rejection. / Lung transplants.
-Ganciclovir-resistant individuals;
Check the dose / Consider treatment compliance and absorption / Genetic testing for UL97/UL54 gene mutations.
–Ganciclovir-resistant people;
-Stop Valganciclovir (Ganciclovir),
-IV Foscarnet for 3 weeks,
-Before starting Foscarnet, consult a virologist.
-Immunosuppression dose reduction;
-Consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil /azathioprine
-Consider preferentially reducing or stopping Mycophenolate Mofetil (MMF) orazathioprine if there is evidence of leukopenia.
-Review the dosing of immunosuppression following resolution of CMV infection or disease.
-Educational support;
-It is essential to explain to the recipient the CMV infection risk , diagnosis , monitoring , treatment ,prophylaxis and immunosuppression re modelling decision.
-Discuss with patients, and, where appropriate, parents or carers, the risk of acute rejection with immunosuppression dose reduction.
2-Please reflect on your practice;
-In our practice the same overall guidelines are applied with individualisation according to each case.
-We do Mandatory CMV IgM , IgG for donor and recipient during preparation for transplant and at transplantation.
-In our practice CMV prophylaxis used for 3-6 months(D=/R+, D-/R+) with valganciclovir & dose adjusted according GFR if GFR <60ml/min.
I appreciate that you use bold for heading or sub-headings that make it easier to read.
I like your summary of these guidelines.
I like your reflection of current practice in your hospital in relation to these (similar) guidelines
Summary of the Guidelines:
1. Preventing CMV infection and disease.
Determining CMV status in donor and recipient:
CMV prophylaxis:
For adults, children and young people receiving a solid organ transplant; offer Valganciclovir prophylaxis to people receiving kidney and liver transplant for at least 3months following transplantation if either:
Consider Valganciclovir prophylaxis for people receiving heart, lung, intestinal, or pancreas transplants for at least 3 months following transplantation if either:
Do not routinely offer Valganciclovir prophylaxis if the donor and recipient are seronegative for CMV (D-/R-).
Be aware that some recipient who is seronegative for CMV (D-/R-) may require Valganciclovir or Valaciclovir prophylaxis for prevention of other Herpes virus infections, (HSV R-/ HSV D+).
Consider Valganciclovir prophylaxis for at least 3 months after starting treatment for acute allograft rejection if either donor or recipient is CMV positive (D+/R-, D+/R+, or D-/R+).
Adjust the dose of Valganciclovir if creatinine clearance is less than 60 ml/min.
For children and young people under 18 years, adjust the dose of Valganciclovir according to the body surface area, up to a maximum dose of 900 mg OD.
Monitor full blood count at least every 2 weeks whilst on Valganciclovir.
Consider switching to CMV monitoring and pre-emptive therapy if people develop side effects; neutropenia.
2.Laboratory testing for CMV:
Should use a quantitative test, CMV viral load:
3. Monitoring for CMV infection and disease:
Offer monitoring of CMV viral load to guide start dose for SOT:
CMV viral load monitoring:
4 Treating CMV infection and disease:
For those who develop CMV infection or disease:
5.Ganciclovir resistance:
Risk factors for Ganciclovir resistance:
Consider resistance if:
People with suspected resistance consider:
In people with evidence of ganciclovir resistance:
6.Immunosuppressant dose reduction:
7.Information, education, and support:
I appreciate that you use bold for heading or sub-headings that make it easier to read.
I like your summary of these guidelines.
I like that your reflection of current practice information and education
thank u prof.
CMV Prevention
Solid organ transplant recipients:
– Give kidney and liver transplant recipients Valganciclovir prophylaxis for three months if either:
-CMV-negative recipients get allografts from CMV-positive donors (D+/R-).
-The recipient underwent T-lymphocyte depletion treatment with anti-thymocyte globulin (ATG) or Alemtuzumab (Campath) whether donor: recipient serostatus is D+/R+ or D-/R+.
– Consider valganciclovir prophylaxis for heart, lung, intestine, or pancreatic transplant recipients for at least three months if either: The recipient is seronegative for CMV and gets an allograft from a CMV-positive donor (D+/R-).
OR
-When donor: recipient serostatus is D+/R+ or D-/R+, the recipient receives T-lymphocyte depletion treatment with anti-thymocyte globulin (ATG) or Alemtuzumab (Campath).
-Donor and recipient CMV seronegative (D-/R-) should not receive Valganciclovir prophylaxis.
-Recipients who are seronegative for CMV (D-/R-) may need Valganciclovir or Valaciclovir prophylaxis to avoid other Herpes virus infections, such as those receiving organs from HSV-positive donors.
– If either donor or recipient is CMV positive (D+/R-, D+/R+, or D-/R+), consider valganciclovir prophylaxis for at least 3 months following acute allograft rejection therapy.
– Adjust Valganciclovir dosage if creatinine clearance is less than 60ml/minute.
-For children under 18, modify Valganciclovir dosage according to body surface area up to 900mg daily.
-Check FBC every 2 weeks while on Valganciclovir.
-Switch to CMV surveillance and pre-emptive treatment if Valganciclovir side effects include neutropenia.
CMV Treatment:
For adults, children, and youth who get CMV after
transplantation:
1 Give oral Valganciclovir for 2 weeks.
2 If approved dosage guidelines differ, adjust the Valganciclovir dose.
creatinine clearance <60ml/min.
3 Monitor ganciclovir resistance.
management)
4 Measure CMV viral load after 2 weeks of therapy and repeat every
5 Stop CMV medication when symptoms improve.
two consecutive CMV viral load tests showing no CMV.
Ganciclovir-resistant
Ganciclovir resistance is higher in the following people:
Long-term or subtherapeutic antiviral treatment
drugs
CMV-negative solid organ transplant patients from seropositive donors
T-cell-depleted immunosuppressed patients
treatment after acute allograft rejection.
Lung transplants
If: Ganciclovir resistance
After a virus, the symptomatic illness persists or increases.
Ganciclovir’s typical dose and duration (2-4 weeks)
valganciclovir
-Ganciclovir-resistant individuals:
Check the dose
Consider treatment compliance and absorption.
Test HCMV antiviral resistance.
UL97/UL54 gene mutations.
Plasma or entire blood].
Ganciclovir-resistant people:
Stop Valganciclovir (Ganciclovir).
IV Foscarnet for 3 weeks .
Before starting Foscarnet, consult a virologist.
Immunosuppression decrease
CMV infection or sickness in adults, children, and youth (with or without
leukopenia-free) after solid organ transplantation:
– Reduce calcineurin inhibitor or mycophenolate mofetil doses.
Reduce or discontinue Mycophenolate Mofetil (MMF) if possible.
leukopenia, azathioprine.
– Inform patients and parents or caregivers of the risk of acute kidney injury
rejection with reduced immunosuppression.
– Reassess immunosuppressive doses after CMV infection.
In our center, we are following the following protocol:
diagnosis based on symptoms and quantitative CMV PCR or tissue biopsy.
In case of definite diagnosis, we are giving valganciclovir for most of the patients except for tissue invasive disease we start with IV gancyclovir for 2 weeks then continue on valacyclovir until PCR negative.
I suggest that you use bold for heading or sub-headings that make it easier to read.
I like your summary of these guidelines.
I like that your reflection of current practice in your hospital in relation to these (similar) guidelines
Summary of the BTS recommendations on prevention and management of post-transplant CMV:
1- Determination of CMV status of donor and recepient:
2- CMV prophylaxis:
a- D+/R-
b- The recipient has received T-lymphocyte depletion therapy with ATG or
Alemtuzumab (Campath), where D+/R+ or D-/R+
3- Laboratory testing for CMV:
4- Monitoring CMV infection and disease:
They are CMV seropositive (D+/R+, D-/R+)
They have not received T-lymphocyte depletion therapy
They are not receiving valganciclovir prophylaxis
5- Treatment of CMV:
AND
two consecutive, CMV viral load tests that confirm that CMV is not detected.
6- Ganciclovir resistance:
1-Those who have received prolonged courses, or sub-therapeutic doses of
antiviral medications
2- D+/R-
3- Those who have received intensive immunosuppression (e.g; with T-cell
depletion therapy, following episodes of acute allograft rejection)
4- lung transplant recipient.
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
1- Confirm that dosing is adequate and adherence to treatment plan and
absorption
2- Offer testing for Human CMV (HCMV) antiviral resistance and UL97 and
UL54 gene mutations
1- Stop Valganciclovir (or Ganciclovir)
2- Offer Intravenous Foscarnet for at least 3 weeks after consulting virology
specialist.
7- IS reduction:
I like that you use bold for heading or sub-headings that make it easier to read.
I like your summary of these guidelines.
I like that your approach in fine-tuning immunosuppression
Thank you very much
Regarding our practice:
Despite I don not involved in the treatment of post-transplant management as a surgeon and all done by nephrologist
I am sure regarding some points:
1- All D and R are assessed for CMV Ig G status
2- we follow the same guidelines for stratification of the risks
3- All R- regardless the serostatus of the donor receive valganciclovir prophylaxis for 3-6 month . similarly if the serosatatus of the donor is not known
Preventing CMV Infection and Disease
Treatment of CMV Infection and Disease
In my practice
I like that you use bold for heading or sub-headings that make it easier to read.
I like your summary of these guidelines.
I like that your team applies these (or similar) guidelines
CMV in solid organ transplant recipient:
Kidney transplant recipient can be at an increased risk of attracting CMV infection, with potential catastrophic consequences on patient and allograft.
Therefore serological status of both donor and recipient has to be set prior to transplanation
Hence prophylactic protocol was implement for most of the recipients as follows:
1]D+/R-,
2] D+/R+, D-/R+ if ATG or Alemtuzumab were administered as induction therapy .
3] No prophylactic Valgancyclovir is indicated in D-/R-.
Valganciclovir is advocated as prophylactic medication in a dose of 900 mg per day for 3 months.
Dose adjustment according to renal function has to be considered.
Regular complete blood count has to be performed every 2 weeks for a significant side effect of neutropenia.
In case neutropenia emerged , then switching to alternative protocol of regular surveying of recipients, with CMV monitoring and pre-emptive treatment.
Monitoring of CMV and pre-emptive treatment:
1] In seropositive recipients D-/R+, D+/R+.
2] No ATG or Alemtuzumab was induced with.
3] Not on Valganciclovir prophylaxis.
Treatment of infection:
Valganciclovir can be prescribed for 2 weeks, proper adjustment of Valgancyclovir according to GFR.
PCR for CMV has to be done after 2weeks , and Valganciclovir has to be stopped if CMV PCR is negative in two successive occasions.
Ganciclovir resistance:
If no improvement in symptoms or CMV is still detected in after 2 weeks then Ganciclovir resistance is suspected.
Risk factors for Ganciclovir resistance:
1] Subtherapeutic dose. prolonged courses.
2] D+/R-
3] Those received intense immune suppression with lymphocytes depleting agents for acute rejection episodes with ATG.
4] lung transplant recipient.
In case of Ganciclovir resistance,
Forscarnet: is an alternative for ganciclovir has to be administered for 3 weeks
I like that you use bold for heading or sub-headings that make it easier to read.I like your summary of these guidelines.
● Preventing CMV Infection and Disease
☆ All organ donors and recipients should be screened for CMV prior to, or at the time of transplantation
☆ If donor , recipient CMV serostatus is unknown it should be characterised as donor seropositive, recipient seronegative for CMV (D+/R-)
● CMV prophylaxis after SOT :
☆ D+/R-
☆ The recipient has received (ATG) or Alemtuzumab (Campath )
☆ After starting treatment for acute allograft rejection
☆ There is emerging evidence that low dose (450mg) Valganciclovir prophylaxis is as effective as standard dose (900mg) in kidney transplant recipients
● Do not routinely offer Valganciclovir prophylaxis if donor and recipient are seronegative for CMV
● Adjust the dose in accordance to GFR
● Monitor CBC every 2 weeks
● Laboratory Testing for CMV
☆ CMV QNAT assays
☆ QNAT thresholds should not be used in isolation to clinical, laboratory or histological evidence of CMV disease
● Monitoring for CMV Infection and Disease at least monthly
☆ D+/R+, D-/R+
☆ They have not received T-lymphocyte depletion therapy
☆ They are not receiving valganciclovir prophylaxis
● Treating CMV Infection and Disease
☆ oral Valganciclovir for a duration of at least 2 weeks
☆ The very sick people requiring hospitalisation and other intravenous
therapies e.g.; intravenous (i.v.) fluids and antibiotics, i.v ganciclovir should be considered due to a likelihood of impaired absorption.
☆ Assess CMV viral load after 2 weeks of treatment
☆ Consider stopping treatment for CMV disease after resolution of symptoms and CMV is below threshold for detection
☆ High doses of intravenous Hyperimmune
globulin (0.5 g/kg body weight) have been used in conjunction with Ganciclovir for the
treatment of pneumonitis
● High risk to ganciclovir resistance in :
☆ Those who have received prolonged courses, or sub-therapeutic doses of antiviral medications
☆ D+/R-
☆ Those who have received intensive immunosuppression (T-cell depletion therapy)
☆ Lung transplants
● Consider resistance if:
☆ There is a persistent or increasing viral load or symptomatic disease after a effective dosage and duration (2-4 weeks)
☆ Occur in up to 3% of SOT recipients
☆ In people with suspected resistance :
▪︎Confirm adequacy of dose
▪︎Consider adherence to treatment
▪︎Offer testing for HCMV antiviral resistance ( gene mutations )
● In case of ganciclovir resistance:
▪︎Stop Valganciclovir
▪︎Intravenous Foscarnet for at least 3 W
▪︎specialist virology advice
● Immunosuppression dose reduction
☆ Reduction of either CNi or MMF or AZA
☆ Stopping MMF AZA IN leukopenia
☆ Discuss about risk of acute rejection
☆ Review dose after of resolution of CMV infection or disease
● Reflect on your practice
In my centre in syria :
☆ Mandatory CMV IgM , IgG for donor and recipient during preparation for transplant and at transplantation
☆ Prophylaxis for 3 months in case D+/R- or when recipient has ATG as induction therapy or to treat rejection
I suggest that you use bold for heading or sub-headings that make it easier to read.
I like your summary of these guidelines.
I like that your hospital applies these guidelines
SUMMARY
1- Preventing CMV infection and disease
Laboratory testing for CMV
Monitoring for CMV infection and disease
D+/R+, -D-/R+. those not receiving T-lymphocytes depleting agents
Treating CMV infection and disease
Ganciclovir resistance
-confirm dosing is adequate
-consider adherence to the dosing plan and absorption
-test for antiviral resistance
-test for UL97 and UL54 gene
Immunosuppression dose reduction
Information, education, and support
Reflect on your practice
In my former place, where I worked for almost 2 years in Nigeria, we usually do the following:
I like that you use bold for heading or sub-headings that make it easier to read.
I like your summary of these guidelines.
I like that your hospital applies these guidelines
Yes, my boss once worked in Sheffield briefly and also had a master’s degree in organ transplantation from the University of Liverpool
Please summarise these guidelines
1-Preventing CMV Infection and Disease
Determining CMV status in donor and recipient
-All donors and recipients should be screened for CMV (IgG antibody) sero-status.
–If CMV serostatus is unknown, should be assumed CMV(D+/R-).
CMV prophylaxis
– Universal Prophylaxis and pre-emptive therapy are in common use to minimize the impact of CMV infection or reactivation.
– Aciclovir, Valaciclovir, Ganciclovir and Valganciclovir have all been used for prophylaxis.
-Valganciclovir prophylaxis for people receiving heart, lung, intestinal or pancreas transplants for at least 3 months if: (D+/R-) or Recipient has received T-cell depletion therapy or after treatment for acute allograft rejection.
– Do not routinely offer Valganciclovir prophylaxis if CMV (D-/R-)
– Seronegative recipients may require prophylaxis for prevention of other Herpes virus.
– If recipient developed side effect consider switching to CMV monitoring and pre-emptive therapy.
2-Laboratory Testing for CMV
-Lab to use consistent approach either whole blood or plasma for quantification of CMV viral load QNAT, should be reported as IU/mL, or, if reported as copies / mL, and determine local thresholds for treatment.
3-Monitoring for CMV Infection and Disease.
Pre-emptive therapy guided by monitoring of CMV viral load at least monthly for at least 3 months, considered if:
– CMV seropositive (D+/R+, D-/R+) AND
– Not received T- cell depletion therapy AND
– Not on valganciclovir prophylaxis
4-Treating CMV Infection and Disease
-People with CMV infection or disease treated with oral Valganciclovir for at least 2 weeks
-Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days
– Treatment can be stopped after resolution of symptoms AND two consecutive undetectable CMV viral load.
5 Ganciclovir resistance
-Considered if there is a persistent or increasing viral load or symptomatic disease after effective dosage and duration of Ganciclovir or Valganciclovir.
–If Ganciclovir resistance is suspected; confirm that dosing is adequate, check treatment adherence, offer testing for CMV antiviral resistance, UL97 and UL54 gene mutations.
-In people with evidence of resistance: stop Valganciclovir (or Ganciclovir), start IV Foscarnet for at least 3 weeks and seek specialist virology advice.
6- Immunosuppression dose reduction
– Reduce either CNI or MMF /azathioprine, preferentially reducing or stopping MMF or azathioprine
-Discuss the risk of AR with IS dose reduction
7-Information, education and support
– Healthcare professionals to offer accurate information to people undergoing SOT about the risks of CMV infection, risk, monitoring and treatment options, including prophylaxis.
Please reflect on your practice
In our center, as most pediatric recipients are naïve to CMV, we use universal prophylaxis for 3-6 months then continue pre-emptive prophylaxis with monitoring of viral load.
I like your summary of these guidelines.
I like that your hospital applies these guidelines.
CMV prevention
1. All patients must measure the serological status of the donor and recipient. If the donor is unknown, consider it positive.
2. Prophylaxis with oral Valganciclovir for three months if the serological status is D+/R-
Or in positive recipients using anti-lymphocyte drugs (rATG or AntiCD52)
In Brazil we do not have oral Valganciclovir, we only have Ganciclovir which is done preemptively and intravenously therapeutically.
In Bone Marrow Transplantation, we already have Letermovir as primary prophylaxis in the first hundred days after transplantation.
3. Adjust drug dose depending on Creatinine Clearance.
Laboratory tests for CMV
1. Standardize PCR quantification for CMV
2. Offer it to patients with positive serology, who have not taken prophylaxis or who have used anti-lymphocytes.
3. Test at least once a month.
In Brazil, we test once a week, probably because of our extremely high epidemiology for CMV and the unavailability of adequate drugs to carry out prophylaxis.
4. We always treat with Ganciclovir
5. We do not have easy tests for resistance. Those who do not respond to high doses of ganciclovir (15mg/kg/day) are considered resistant.
Foscarnet is imported into Brazil, limiting its use.
Clinical conduct
1. Reduce immunosuppression, especially of antimetabolites (Azathioprim and Mycophenolate)
2. Assess the risk of rejection
I like your summary of these guidelines.
Thank you, Professor
-Recommendation summary
CMV infection and disease prevention
· Detecting CMV status in donor and recipient before transplantation (Ig G antibody)
· If CMV status of the donor and the recipient is unknown ,it should be considered that the donor is CMV seropositive and recipient is negative
CMV prophylaxis
· Valganciclovir prophylaxis is given to kidney and liver transplants recipients for at least 3 months after transplantation if D+/R- or if ATG or Alemtuzumab was given for D+/R+ or D-/R+
· Valganciclovir prophylaxis is given to heart, lung, intestinal or pancreas transplants recipients for at least 3 months after transplantation if D+/R- or if ATG or Alemtuzumab were given to D+/R+ or D-/R+
· If D-/R- , Valganciclovir is not routinely given meanwhile Valganciclovir or Valaciclovir prophylaxis can be needed for prevention of other Herpes virus infections
· After starting treatment for acute allograft rejection Valganciclovir prophylaxis for at least 3 months will be needed if either donor or recipient are CMV positive
· If creatinine clearance is < 60ml/minute ,renal dose adjustment for Valganciclovir will be needed also for candidates less than 18 years Valganciclovir need to adjusted according to body surface area with CBC monitoring /2 weeks while on treatment and if side effects occurred CMV monitoring along with preemptive therapy can be done.
CMV laboratory testing
CMV Quantitative Nucleic Acid Testing (QNAT) of whole blood or plasma must be used to quantify CMV viral load, with standardised assessments correlating with clinical, laboratory or histological evidence of CMV disease.
There is high inter-assay and inter laboratory variability of QNAT results .
CMV infection and disease monitoring
I t will be essential for D+/R+, D-/R+, those who did not receive T-lymphocyte depletion therapy nor received valganciclovir prophylaxis
It can be done at least on monthly bases and every 3 months after transplantation
Treatment of CMV infection and disease
For young candidates ,oral Valganciclovir is given for at least 2 weeks considering renal dose adjustment if needed , and ganciclovir resistance risk.
CMV viral load after 2 weeks of treatment need to be checked and then again after at least 1 week, then therapy is stopped after resolution of symptoms and 2 negative CMV viral load tests
Ganciclovir resistance
Prolonged courses of antiviral medications or subtherapeutic doses ,intensive immunosuppression, D+/R- and lung transplant recipients can increase it’s risk.
It is suspected in cases with persistent or increasing viral load or symptomatic disease after sufficient dosage and duration of Ganciclovir or Valganciclovir
Human CMV resistance and UL97 and UL54 gene mutations need to be checked
Valganciclovir or Ganciclovir need to be stopped and IV Foscarnet for at least 3 week can be given instead.
Reduction of immunosuppressive doses
CNI or MMF /azathioprine reduction must be considered and suspending MMF in case of leukopenia
Educational support
It is essential to explain to the recipient the CMV infection risk ,diagnosis , monitoring , treatment ,prophylaxis and immunosuppression re modelling decision
CMV Background
CMV is one of herpes virus group, primary infection can result into severe disease with immunocompromised T cell .
Viral genome invades the monocytes and progenitor cells then become latent.
Transmission is through saliva, urine, breast milk or genital secretions.
CMV infection in SOT
Usually occurs 2-4 weeks posttransplant in a seronegative individual receiving a seropositive organ.
Symptoms are non specific .
In immunosuppressed cases , antibody rise can be delayed .
The gold standard test for detecting active CMV replication is CMV PCR in plasma, whole blood
or leukocytes.
Kidney and liver transplant recipients who received prophylaxis has 1-year incidence of CMV disease to be 19.2% and 31.3% respectively in D+ / R- group and 2.5% and 3.2%, respectively, in D- /R- group.
Late-onset CMV disease represents the CMV disease in SOT recipients who received antiviral prophylaxis occurred after finishing antiviral drug administration commonly in CMV mismatch (D+ / R-) recipients leading to allograft failure and mortality.
Anti-CMV prophylaxis in D+/R kidney transplant recipient lead to 50% reduction in biopsy-proven acute graft rejection .
Preventing CMV disease in SOT recipients
Anti-CMV Prophylaxis and pre-emptive therapy can decrease the impact of CMV infection or reactivation depending on the donor/recipient CMV status, organs transplanted, and intensity of immunosuppression.
Aciclovir, Valaciclovir, Ganciclovir and Valganciclovir were used also recent agents as Letermovir and Maribavir are introduced.
Transplant recipients undergo regular surveillance and trated when at high risk of having CMV disease.
CMV Disease treatment
Immunosuppression has to be reduced along with initiation of antiviral therapy as IV Ganciclovir which decreased mortality and morbidity of CMV disease .
High doses of IV Hyperimmune globulin can be used with Ganciclovir for the pneumonitis therapy.
Meanwhile relapse risk is high after successful therapy.
Antiviral drug resistance
In the forum of progressive illness or stationary or rising viral load inspite of sufficient dose and duration of antiviral therapy meanwhile increasing viral load is not reliable as it can increase within first week of treatment before decreasing.
Genotypic analysis can detect high and low grade Ganciclovir resistance as well as resistance to Foscarnet and Cidofovir.
Analysis of UL97 and UL54 gene mutations is introduced
Cidofovir is a possible 2nd line therapy .
Foscarnet is rendered a second or third line drug as it has risks of nephrotoxicity and electrolyte disturbances.
Maribavir is under trial for treating refractory or resistant CMV infection in SOT.
CMV viral infection is characterized by being either asymptomatic or viral syndrome or CMV disease.
-In my practice the same overall guidelines are applied with individualisation according to each case
I like that you use bold for heading or sub-headings that make it easier to read.
I like your summary of these guidelines.
I like that your hospital applies these guidelines as per individual patient’s needs
Please summarise these guidelines
————————————————————————————–
1 Preventing CMV Infection and Disease
——————————————————————
a-Determining CMV status in donor and recipient;
The guidelines recommend screening of all organ donors and recipient for CMV IgG antibody (IA) .
b-CMV prophylaxis;
1-The guidelines recommend at least 3 months of valganciclovir prophylaxis for high risk group of recipient IA;
1- D+/R-
2- Those who received T. cell depleting agent .
2-The guidelines suggest ,at least 3 months valganciclovir prophylaxis after starting treatment of acute rejection if donor or recipient are CMV positive 2C.
3-Valganciclovir dose needs to be adjusted if creatinine clearance is less than 60 ml/minute 1D.
4- Monitor Full Blood Count at least every 2 weeks whilst on Valganciclovir [1A] .
2 Monitoring CMV Infection and Disease;
——————————————————————-
1-The guidelines recommend monitoring of CMV viral load to guide pre-emptive therapy to adults, children and young people receiving a solid organ transplant if: They are CMV seropositive (D+/R+, D-/R+) and they have not receive T. cell depleting agent or valganciclovir prophylaxis 1B.
2-The guidelines recommend viral load testing monthly for at least 3 months following transplant 1D.
3 Treating CMV Infection and Disease ;
———————————————————————
1-The guidelines recommend offering treatment with oral valganciclovir for a duration of at least 2 weeks 1A.
2-Also the guidelines recommend assessing of the viral load after 2 weeks o treatment and repeat at interval of 7 days 1D.
4- Ganciclovir resistance ;
—————————————————————————
Ganciclovir resistance may be suspected in difficult to control CMV infection, as evidenced by a persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration (e.g.; 2-4 weeks) and is reported to occur in up to 3% of SOT recipients .
The guidelines recommend that ,recipient with Ganciclovir resistance should be tested for UL97 and UL54 mutations .
5-Immunosuppression dose reduction ;
————————————————————————-
1-The guidelines suggest a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine [1C] .
2-In the setting of leucopenia , the guidelines suggest reducing or stopping MMF or azathioprine 2C .
2-Please reflect on your practice;
———————————————————–
We depend on the pre transplant CMV risk stratification in prevention and treatment of CMV infection . We do not perform post transplant viral load in asymptomatic recipient .
I like that you use bold for heading or sub-headings that make it easier to read.
I like your summary of these guidelines.
I wish and hope that your hospital will be able to provide capabilities in its system to implement these guidelines.
Thanks Professor
Prevention of CMV infection & disease:
Lab CMV test:
Monitoring of CMV infection and disease:
Treatment of CMV infection & disease:
Ganciclovir resistance:
Immunosuppression dose reduction:
Information, education and support:
In my practice CMV prophylaxis used for 3-6 months(D=/R+, D-/R+) with valganciclovir & dose adjusted according GFR if GFR <60ml/min.
-Summary
1.Preventing CMV disease
CMV status:
Prophylaxis:
2.Laboratory testing:
Quantitative Nucleic Acid Testing is recommended (CMV QNAT)
3.Monitoring for infection and disease:
4.Treating infection and disease:
5.Ganciclovir resistance:
-Definition; persistence of symptoms and viral load after adequate treatment with gancyclovir or valagancylovir for 2 to 4 weeks
-Risk factors; prolonged treatment, lower doses of drug, D+/R- status, acute rejection specially if treated by rATG, lung transplantation
-Management;
6.Immune-suppression dose reduction:
7.Information, education, and support:
B.My practice:
I like your analysis regarding the level of evidence. You need not to type the whole sentence in bold or capitals. That amounts to ‘shouting.’
I like your detailed reflection of your own practice mentioning the challenges faced by your team.
Ajay
Thank you prof, noted
UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION====================================================================
Please summarise these guidelines
1- Preventing CMV Infection and Disease
Determining CMV status in donor and recipient
CMV prophylaxis
====================================================================
2- Laboratory Testing for CMV
====================================================================
3- Monitoring for CMV Infection and Disease
====================================================================
4- Treating CMV Infection and Disease
====================================================================
5- Ganciclovir resistance
====================================================================
6- Immunosuppression dose reduction
====================================================================
7 Information, education and support
====================================================================
Executive Summary of Research Recommendations
===================================================================
Executive Summary of Audit Measures
====================================================================
Introduction
Background to Cytomegalovirus (CMV)
Biology of CMV in Humans
CMV in Solid Organ Transplant Recipients
Donor: recipient CMV serostatus is characterised as:-
1. Both D/R are IgG antibody seropositive: (D+/R+)
2. Both D/R are IgG antibody seronegative: (D-/R-)
3. Donor is IgG antibody seropositive and recipient is IgG antibody seronegative: (D+/R-)
4. Donor is IgG antibody seronegative and recipient is IgG antibody seropositive:(D-/R+)
====================================================================
Preventing CMV disease in people with solid organ transplants
====================================================================
Treatment of CMV Disease
===========================================
Antiviral drug Resistance
====================================================================
Please reflect on your practice
Very nice and important information
In our hospital we do almost in this guideline but we lack capabilities
=====================================
I like that you use bold for heading or sub-headings that make it easier to read.
I like your summary of these guidelines.
I wish and hope that your hospital will be able to provide capabilities in its system to implement these guidelines.
Thanks alot for you Prof.Sharma
That is a good summary and detailed analysis.
I like your reflection of your own practice, mentioning the challenges faced by your team.
Ajay
Many thanks for you Prof.Sharma
CMV prevention :
1-We should know the CMV serostatus (IgG)of both donor and recepient
1-Valgancyclovir prophylaxis for 3 months in case of:
*R-/D+
*(R+D-,R+D+)if induction with ATG or Alemtuzumab
* prevention of Herpes simplex in seronegative recepients from seropositive donors
*After treatment of acute rejection in case of (R+/D-,R-/D+,R+/D+)
Valgancyclovir :
ADJUST THE DOSE IF cr Cl<60ml/min
Monitor CBC every 2 weeks
In case of neutropenia ,stop valgancyclovir ,monitor for CMV and consider preemptive treatment
In children and adolescents less than 18 years dose adjustment to surface area ,maximum dose 900 mg daily.
CMV testing:
Quantitative methods to determine CMV infection like Quantitative Nucleic acid testing should be used ,but should not be used alone to determine the start or the end of treatment
Monitoring of CMV should be offered to:
1-CMV seropositive (D+/R+, D-/R+) and
2-didn’t receive T lymphocyte depleting agent and
3-didn’t receive CMV prophylaxis
Monitoring at least 3 months after transplnt
Treatment Of CMV:
At least 2 weeks of valgancyclovir or gancyclovir then asses after 2 weeks ,repeat at 7 days ,stop when symptoms improve and viral load not detected and assess for resistance to antiviral therapy
Causes of Gancyclovir resistance :
1-prolonged use or sub therapeutic doses
2-seronegative recepients from seropositive donors
3-received intensive immunosuppression
4-Lung transplant
Definition of resistance:persistent or increasing viral load or symptomatic disease after a normally effective dosage and duration (e.g.; 2-4 weeks) of Ganciclovir or Valganciclovir.
Workup for resistance: Confirm that dosing is adequate,adherence to treatment plan and absorption Offer testing for Human CMV (HCMV) antiviral resistance UL97 and UL54 gene mutations
Treatment in resistant cases:Foscarnet for 3 weeks
In case of neutropenia,consider decreasing the dose of MMF ,Azathioprine and cyclosporine
Counsel your patient that by decreasing the doses of immunosuppression ,there is increased risk of rejection
Reflection to practice:we almost doing the same as the guidelines
Please use bold or underline for heading or sub-headings to make it easier to read.
I like your summary of these guidelines.
That is a good summary and an interesting analysis. Please type headings and sub-headings in bold or in underline.
I like your reflection of your own practice, mentioning the limitations faced by your team.
Ajay
o Preventing CMV infection and disease
Screen for CMV Ig G antibody in both donor and recipient prior to transplant.
If donor status is unknown and recipient is Seronegative or unknown take it as D+/ R-.
o Offer Valganciclovir Prophylaxis for 3 months if –
D+/ R –
D+ / R+ Or D- / R+ and recipient has received ATG or Alemtuzumab.
o No prophylaxis if D-/R-
o HSV – recipient may need Valganciclovir prophylaxis when receiving Organ from HSV + donor.
o D+/R+ Or D+ /R- or D-|R+, then valganciclovir prophylaxis for 3months after starting treatment for acute allograft rejection.
o Decrease Valganciclovir dose if eGFr < 60 mI/min
o For children and < 18year old adjust don according to BSA up to a max of 900mg OD.
o CBC every 2 weeks while on valganciclovir
o If side effect of Valganciclovir develops consider switching to CMV monitoring and preemptive therapy.
Donor CMV Serostatus should be established within 30 days of organ donation.
In seronegative donor and recipient recheck prior to transplant.
For D+/R+ and D-/R+ there is no difference between CMV prophylaxis and monitoring with preemptive treatment strategy.
In D- / R + Status 40% of patients develop viraemia.
o Lab testing for CMV
Lab should use either whole blood or plasma consistently.
QNAT to be done.
CMV viral load to be reported as IU / ml.
local threshold For viral load which indicates disease or infection requiring treatment be determined.
QNAT threshold be Considered together with clinical, laboratory Or histological evidence of CMV disease.
Whole blood QNAT lead is higher than plasma level.
Change of 3 Fold in QNAT values be considered significant.
o Monitoring CMV infection and disease.
offer monitoring if
D+ / R +,D- /R+
Not received T lymphocyte therapy
Not Receiving Valganciclovir prophylaxis
Test monthy for atleast 3 months post transplant the viral load.
Algorithm.
D+ /R-
prophylaxis for 3 months
D+ /R+ and D-/R+
if received ATG / Alemtuzumab
After treatment for acute rejection
Prophylaxis In 3 month
if none then –
CMV viral load monitoring for 3 months.
D- / R-
Prophylaxis not recommended
Routine CMV monitoring not recommended.
o Treating CMV infection and disease
For pts with CMV infection or disease
Oral Valgancilovir for 2 weeks.
if eGFR< 60 adjust dose.
Watch tor ganciclovir resistance
Assess CMV viral load after 2 weeks and repeat after 7 days
Stop treatment if symptoms resolved and 2 consecutive CMV viral load tests are negative.
iv gancicyclovir is same as oral gancicyclovir efficacy wise
Oral dose is 900 mg BD
iv gancicgclovir preferred in admitted patients.
o Gancicyclovir Resistance
Patients at risk –
Who received long courses of gancicyclovir Or sub therapeutic dose.
D+/R-
Who received intensive immunosuppression.
Recipient of lung transplant
Consider resistance if viral load is persistently high or increasing even after 2-4 weeks of ganciclovir Or Valganciclovir.
Confirm compliance and dosages
offer iv foscarnet for at least 3 weeks and stop gancicyclovir.
Newer agents – Letermovir and Maribavir.
o Immunosuppression dose reduction
Reduce or stop MMF/ Azathioprine if there is evidence of leu copenia.
Watch out for rejection
Review dose of immunosuppression following resolution of CMV.
Low quality evidence to support conversion to an mTori.
in our unit receipients are not given prophylaxis regardless of their sero status and mostly all are live related and do not receive any induction either.
CMV monitoring and premptive treatment is also not done,if clinical status dictates CMV viral load is done and infection treated.