CMV (Cytomegalovirus) reactivation and immunosupression in allogeneic

transplantation

Marie Waller

Bone Marrow Transplant Coordinator

Manchester Royal Infirmary

Aim

• Introduction

• Quick overview of CMV

• Quick overview of CMV reactivation

• CMV reactivation risk groups

• Quick overview of Immunosupression

• How we monitor CMV at MRI

• Treatment and management at MRI

Introduction• Patients who have undergone allo HSCT are at risk

of CMV reactivation• The use of immunosuppression is a recognised

contributing factor in CMV reactivation• Treatment for CMV reactivation can be quite toxic

and myelosuppressant• These patients may need higher levels of support,

intervention, inpatient stay and nursing care• Before effective treatment strategies CMV

reactivation had a high mortality rate of up to 90% from CMV pneumonitis

Cytomegalovirus (CMV)• Cytomegalovirus (CMV) is a common virus

which is part of the herpes family• Once a person is infected with CMV, it will

remain inactive for the rest of their life • Patients are at risk of CMV reactivation if

they or the donor have had previous exposure to the virus

• CMV causes few symptoms in most people• CMV infections occur mainly early in life• Low risk of transmission of CMV in

transfused blood products

Cont• Once exposed to CMV virus you will develop

detectable antibiotics (IgG) in your immune system

• Approximately 30 - 90% of immunocompetent adults >40 years old have antibodies (IgG) to CMV, and are described as having positive CMV serology

• In otherwise healthy adults, CMV remains inactive or latent

• CMV can/ will become ‘active’ under favourable conditions

CMV reactivation• Once patients have been immunosuppressed

they can have reactivation of CMV

• This can result in invasive CMV disease such:

pneumonitis, esophagitis,encephalitis, hepatitis, pancreatitis, adrenalitis, gastritis, enteritis, colitis, and retinitis

• CMV reactivation is and can be life threatening

cont• CMV seropositive patients (CMV IgG pos pre

transplant) can reactivate CMV virus due to previous exposure as they already have the antibodies in their immune system

• CMV seronegative patients (CMV IgG neg pre transplant) can activate a newly acquired or a primary CMV infection from the allogeneic donor. This is transferred infection from the seropositive donor

CMV risk groups• Risk of reactivation dependant on patient and

donor previous exposure to CMV

Patient/ Donor Risk

– CMV neg/neg (low risk)– CMV pos/pos (high risk)– CMV neg/ pos (high risk)

(30% chance of reactivation)– CMV pos/neg (high risk)

(no donor immunity) At MRI we do not routinely use CMV prophylaxis

Immunesuppression

• All patients undergoing allogeneic transplant will

be given drugs to suppress the immune system• Prepares the patients body/ immune system to

accept the graft from the donor and prevent

rejection• Prevents/ reduces the risk of graft versus host

disease (Immune response of the donor derived

T cells against recipient tissues)

Immunosuppression

• Reduces the patients ability to fight infection• Allows the patients immune system to

reactivate dormant infections/ viruses• Allows the patients immune system to

activate newly acquired primary infections

transmitted from the donor’s immune system

Immunosuppression• Drugs commonly used in Haematological

transplantation are:

1. Campath- anti CD52 lymphocyte suppressor

2. ATG (anti thymocyte globulin)- suppresses T cells

3. Fludarabine- lymphocyte suppressor

4. Methotrexate – T-lymphocyte suppressor

5. Cyclosporin A- T-lymphocyte (predonimantly)

6. MMF (Mycophenolate mofetil)- immunosuppressor

7. Tacrolimus- immunosuppressor

8. Steroids

CMV monitoring• Viral reactivation can be monitored in

different ways. PCR (polymerase chain reaction) is the most sensitive and readily quantifiable

• Early treatment of low level reactivation reduces the risk of CMV infection progressing to clinically significant or organ disease

• With the PCR method, CMV infection may be detected as early as two weeks before the onset of symptomatic CMV disease

Monitoring/ treatment at MRI • Following an SCT, CMV is monitored twice

weekly using blood PCR (from Day 0) • Treatment initiated if 2 consecutive pos PCR

results at or above limit of sensitivity• Treatment may be initiated on a single pos

result if:CMV disease proven or detected High level reactivation ie log>3High risk cases (organ specific, high risk

patient with multiple episodes, high index suspicion of CMV)

Monitoring at MRI• If asymptomatic or low level reactivation we

start oral treatment

• If symptomatic with low level or high level reactivation start IV treatment straight away

• Require 3 negative results before stopping treatment (IV treatment may be changed to oral once CMV responding until 3xneg)

• Pre-emptive treatment for rising titres important as therapy unlikely to be successful once clinical symptoms develop

Treatment

• Oral

– Valganciclovir 900mg bd

• IV

– Ganciclovir( 5mg/kg) (myelosuppressive)

– Foscarnet (nephrotoxic)

• CMV specific immunoglobulins

• Donor derived CMV specific cytotoxic lymphocytes (trial)

• Retinitis – ganciclovir eye drops

Notes

• Always follow local guidelines and practices

• Refer to SOP for CMV screening and treatment

• Refer to EBMT guidelines

• Discuss with colleague in virology if further treatment advice required

Questions?Which patients receive CMV prophylaxis in your centre?

a. All allogeneic transplant recipients b. MUD recipients only c. Full intensity transplant recipients only

Do you monitor CMV

a. Weekly b. Twice a week c. 3 x week

When do you initiate the treatment in your centre

a. At high level PCR result b. After two positive CMV PCR results c. (biopsy) proven CMV disease d. Other

What is the first line of treatment in your centre? a. Valganciclovir b. IV ganciclovir c. IV foscarnet d. Other