CMV INFECTIONS IN HEMATOLYMPHOID MALIGNANCIES

Joydeep ghosh

INTRODUCTION..

Double stranded DNA virus

Herpesviridae family

Other members: HSV 1, HSV 2, HHV 6,7,8, VZV

Human CMV grows only in human cells and replicates best in human fibroblasts

Prevalence: USA: 60% J Infect Dis. Apr 1995;171(4):1002-6

Homosexuals: 90% Am J Med. Mar 23 1987;82(3 Spec No):593-601

Developing countries: 90% J Health Popul Nutr. 2002;20: 348-351

At risk: Day care Blood transfusion Transplant pts Prolonged immunosuppression

Routes of transmission: person to person via close contact placenta blood transfusions organ transplantation breast milk sexual transmission

VIROLOGY

HOW DO THEY LOOK LIKE?..

CLINICAL SYNDROMES…

PNEUMONIA..

DIAGNOSTICS…

Cathomas et al, Blood, 1993 81: 1909-1914

ESOPHAGITIS…

38% alloHSCT pts spectrum of endoscopic

lesions is variable patchy erythema, exudates microerosions diffusely edematous mucosa, multiple mucosal erosions, deep ulcers pseudotumors

Dx: Endoscopic app.. Immunostains with

antibodies Shell vial culture 24-48 hours CMV PCR

HEPATITIS…

Defined by: Elevated Bil /

enzymes No other cause CMV in liver HPE

HPE remains the mainstay of diagnosis as just the presence of CMV DNA is not sufficient.

COLITIS

Presentations: abdominal pain, watery or bloody

diarrhoea, bleeding, obstruction, toxic megacolon,

perforation fistula formation

Dx s/s Endoscopic app. Tissue diagnosis

(culture /HPE /immunostain/ ISH)

MDACC4328 CANCER PATIENTS, 2001-2004

ETHNICITY MATTERS…

AGE..

MODALITIES OF DIAGNOSIS

Culture: in HEL fibroblasts 28 days Cytopathic effects

DEAFF ( Detection of early antigen fluorescent foci ) :

Sensitivity 78%, specificity 100% 24 hours – cell culture Immunostain of encoded proteins

HPE: typical owls eye appearance

Tissue immunofluorescence: anti CMV antibodies

Electron microscopy ELISAs for CMV antigen in the urine

Detection of CMV DNA by PCR CMV antigenemia test

Total 543 blood samples were tested CMV viremia detected in 37 episodes

out of 28 patients PCR was only positive in 18 episodes AG positive in only 5 viremic episodes Both positive in 14 episodes Out of that 14, in 6 episodes, PCR

preceded antigenemia by avg 7 days

Sensitivities: PCR : 86.5% AG : 51.3%

Specificities: 100% for both

PCR is an earlier marker of viremia

ANTIVIRAL STRATEGIES

Prophylactic: anti-viral therapy started at engraftment and

continued until at least day 100 post transplant Pre-emptive:

Pre-emptive therapy is defined as antiviral treatment initiated based on the detection of primary or reactivated CMV infection by

positive CMV cultures, a positive antigenemia (Ag) assay, or positive molecular assays

GANCICLOVIR..

drug of choice for treatment of CMV disease

nucleoside analogue that inhibits DNA synthesis

Protein UL97 phosphorylates ganciclovir to ganciclovir monophosphate.

against CMV, HSV, VZV, and HHV-6, HHV-7, and HHV-

Adverse effects of ganciclovir therapy include fever, rash, diarrhea, and neutropenia, anemia, thrombocytopenia

Managed with dose reduction or GCSF

In the treatment of CMV pneumonia, ganciclovir is administered with CMV-specific immune globulin

Dosage: 5 mg/kg IV q12hr, over 1 hr x14-21d Maintenance: 5 mg/kg IV qD 

VALGANCICLOVIR..

Valganciclovir is a prodrug of ganciclovir that is activated in the gut and liver to ganciclovir.

60% bioavailability. 900mg = 6mg/kg GFR below 10ml/min is a contraindication Oral valganciclovir is as effective as

intravenous ganciclovir when used as an initial treatment

Valganciclovir: new preparation. CMV retinitis: a simpler, oral treatment. Prescrire Int. Aug 2003;12(66):133-

FOSCARNET

Intravenous foscarnet is considered second-line therapy for CMV reactivation or disease; however, for patients developing dose-limiting neutropenia or CMV strains resistant to GCV, it is the drug of choice

Similar efficacy compared to GCV(1) Toxicity: renal

1 -- Reusser, P. Et al, Blood 99:1159–1164.

CIDOFOVIR

Toxicity is a major concern: Nausea, vomiting, thrombocytopenia, Neuro/ophthalmologic toxicity

Less favorable outcome Some studies have shown around 58%

response rate with significant amount of toxicities(1)

1– Ljungman. Blood 97:388–392

CMV PROPHYLAXIS..

Annals of Oncology17: 1051–1059, 2006 doi:10.1093/annonc/mdj132 Published online 5 May 2006

TAKE HOME MESSAGE..

Routine CMV prophylaxis is not indicated

CMV monitoring can be done in high risk non HSCT population Fludarabine Alemtuzmab

PET treatment is definitely indicated to reduce the chances of CMV syndrome, as they carry a very high mortality rate