Download CMV infections

Cytomegalovirus
Infection in Renal
Transplantation
Cytomegalovirus
• Member of the herpes virus family
(EBV, varicella-zoster, herpes simplex)
• Worldwide seroprevalence 30-100%
• Found in body fluids
– Blood, saliva, urine, breast milk
Types of CMV Infection
• Primary infection
(asymptomatic to mononucleosis like
syndrome in immune competent individuals)
• Latent infection
(presence of viral genome in mononuclear
leukocytes, endothelial cells, and organs in
the absence of active replication of infectious
virus)
• Reactivation
• Reinfection
(new strain of CMV)
CMV and SOT
• CMV is the most common and
single most important viral
infection in solid organ transplant
recipients.
• CMV infection usually develops
during the first few months after
transplantation
• Associated with clinical infectious
disease (eg, fever, pneumonia,
GI ulcers, hepatitis) and acute
and/or chronic graft injury and
dysfunction
CMV Infection and Transplantation
• Approximately 20% to 60% of all transplant
recipients develop symptomatic CMV infection.
• The patient at highest risk for symptomatic
disease is the CMV-seropositive donor/CMVseronegative recipient (D+/R-) who develops a
primary infection after transplantation.
• Such patients are at particular risk for severe
manifestations of CMV infection, including
tissue-invasive CMV and CMV recurrence
Emovon OE et al, American Society of Nephrology 35th Annual Meeting, 2002
Primary and Secondary Infections
• Reactivation infection develops in the
patient who becomes CMV-seropositive
before transplantation via the traditional
routes of transmission and exposure
during hemodialysis and blood
transfusion, and is more frequent than
primary CMV infection.
• CMV-seropositive recipients are also at
risk for superinfection by CMV from a
CMV-seropositive donor, especially in
the setting of intense
immunosuppression (ie, OKT3 and
antithymocyte globulin)
Nancy et al Organ Transplant 2003
Avery RK. Medscape Transplantation. 2000. http://www.medscape.com/viewprogram/282
Direct Effects of CMV Infection in the
Transplant Recipient
• CMV infection is a multifaceted phenomenon with a variety of
direct and indirect effects in the organ transplant recipient.
• Symptomatology for clinical infectious disease
• fever, pneumonia, GI ulcers, hepatitis) ranges from the mild, subclinical
case to life-threatening multi-organ disease.
• Symptomatic CMV infection can be characterized by
• a self-limiting syndrome of episodic fever spikes for a period of 3 to 4
weeks, arthralgias, fatigue, anorexia, abdominal pain, and diarrhea.
• CMV infection can disseminate to various organs and can cause
death
• CMV retinitis can lead to retinal detachment and blindness.
Nancy et al Organ Transplant 2003
CMV Infection: Indirect effects
• An increased risk for fungal and other opportunistic infections due to
additional immunosuppression from CMV infection
• A "bidirectional" interaction between CMV infection and the host's
immune system.
• The type, duration, and intensity of exogenous immunosuppressive
therapy influence and enhance CMV infection.
• CMV is an immunomodulatory virus, and its effects on the host
include enhanced susceptibility to opportunistic infections and,
probably, chronic allograft dysfunction.
• Acute and/or chronic allograft injury and dysfunction.
Rubin R. Infection in organ transplant recipients. In: Rubin RH, Young LS, (eds). Clinical Approach to Infection
in the Compromised Host, 3rd ed., Nancy et al Organ Transplant 20
Sequence of Infections After Organ Transplant
Fishman, J. A. et al. N Engl J Med 1998;338:1741-1751
CMV and Renal Allograft
• CMV causes renal allograft injury
that may be indistinguishable
from injury caused by rejection or
other factors
• Results in decreased allograft
survival
Brennan D. XVIII International Congress of the Transplantation Society. Medscape Transplantation. 2002.
Available at: http://www.medscape.com/viewarticle/419014
CMV and Renal Allograft
• It has been linked to acute rejection
and chronic rejection in the form of
– bronchiolitis obliterans in lung
transplant recipients,
– coronary atherosclerosis in heart
transplant recipients,
– vanishing bile duct syndrome in
liver transplant recipients, and
– a variety of additional histologic
lesions in renal transplant
recipients
Brennan D. XVIII International Congress of the Transplantation Society. Medscape Transplantation. 2002.
Available at: http://www.medscape.com/viewarticle/419014
Detection of CMV Infection
• Immune status: serology (IgG)
• Active infection (viremia)
– Histology
– Viral culture
– Shell vial culture
– Antigenemia assay
– CMV PCR (qualitative/quantitative)
Cytomegalovirus
Which Diagnostic Test Should
be Utilized and Why?
Clinical Suspicion for CMV
• CMV in the immunocompetent host
-inapparent infection
-mononucleosis-like syndrome
• Primary CMV infection in pregnancy
-symptoms in neonate range from moderate
hepatosplenomegaly with jaundice to fatal illness
-sequelae include hearing loss, vision impairment, and
varying degrees of mental retardation
• CMV in the immunocompromised host
-commonly reactivation of latent infection
-variable presentation: retinitis, esophagitis, colitis,
interstitial pneumonia, hepatitis, meningoencephalitis
Diagnostic Tests for CMV
•
•
•
•
•
Serology
Cultures
Early Antigen Detection
CMV Antigenemia Assays
Molecular Amplification
Serology
• Diagnosis of recent or acute CMV probable with:
-detection of CMV-specific IgM antibodies
-4 fold increase in IgG titers in paired samples at
least 2 weeks apart
• Paired samples limit the tests utility in establishing
a timely diagnosis
• Helpful in determining past exposure to CMV
infection
• Helpful in determining risk of acquisition
• CMV Avidity assay measures IgG maturity
effective at identifying primary infection
Cultures
• Isolated from blood, urine, throat
washings, CSF, bronchial washings, and
biopsy specimens
• Takes 1 to 6 weeks to show cytopathic
effects on human fibroblast cultures.
• Detection of CMV in culture does not
confirm active disease: CMV may be shed
intermittently for several months after
acute infection
• May be useful in determining drug
resistance
Early Antigen Detection
(Shell Vial Cultures)
• Allows identification of CMV antigens in
culture before cytopathic effects are
apparent
• Cells are exposed to monoclonal
antibodies, binding indicative of early CMV
replication in cells
• Results available within two to three days
CMV Antigenemia Assays
• Rapid detection (24 hours) of CMV
proteins in PMNs
• Tagged monoclonal antibodies to p65
lower matrix protein of CMV
• Effective for identification of CMV in
immunosuppressed
• Showed 90% sensitivity and 96%
specificity in detecting primary infection in
immunocompetent host
Molecular Amplification
• Fast and reliable
• COBAS Amplicor test: PCR assay that amplifies
region of CMV polymerase gene
• Hybrid Capture System CMV DNA test (CMV
Digene): RNA probe that targets 17% of CMV
genome. RNA:DNA hybrid is detected with an
antibody by signal amplification
• Nucleic acid sequence based system : detects
early gene IE1 and late gene pp67 expression
CMV Pathology
• Diagnostic hallmarks of active
CMV infection include:
-cytomegaly
-intranuclear and
intracytoplasmic inclusions
bodies
-halo around the inclusion body
• Immunohistochemistry and in
situ hybridization
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Cytomegalovirus
Definitions and Diagnosis
• CMV Infection – isolation of CMV virus, proteins or
nucleic acid from any body fluid or tissue (culture,
antigenemia, PCR)
• CMV Syndrome – CMV infection associated with
systemic symptoms (fever, malaise, myalgia) and
leukopenia +/- thrombocytopenia
• CMV Tissue Invasive Disease – CMV infection plus
signs/symptoms of disease and consistent histology
– (pneumonitis, GI, hepatitis, CNS, nephritis,myocarditis,
pancreatitis etc)
Cytomegalovirus
• Risk of CMV disease depends on:
– D/R serostatus
• D+/R-: high risk (primary infection)
• D-/R+ or D+/R+: intermediate (reactivation or
superinfection)
• D-/R-: low risk
– Organ – K-P, lung/H-L, small bowel
– Net state immunosoppression – ALA therapy
– Rejection
– Other immunomodulatory viruses (HHV-6)
• Prophylaxis: risk decreased, not eliminated
Treatment of CMV Infection
• Prevention of CMV infection is the standard care
• The recent emphasis on prophylaxis has changed
the temporal characteristics of CMV, once an
early disease (occurring < 3 months after
transplantation), to the current pattern of late
disease (occurring > 3 months after
transplantation)
Razonable RR. 40th Annual Meeting of Infectious Diseases Society of America; October 2427, 2002; Chicago, Illinois. Medscape Transplantation. 2002. Available at:
http://www.medscape.com/viewarticle/443973
Prevention of CMV Disease
Opelz G et al. Am J Transplant. 2004;4:928-936.
Strategies for Prevention of
CMV Disease
• Screening of blood and organ donors
– Reduction of risk with leukocyte-filtered whole blood
• Active immunization—not yet
• Passive immunization
– Immunoglobulin (Ig)—non-selected polyclonal IgG
– CMV hyperimmune polyclonal globulin (pooled
antibody)
– Monoclonal antibody to CMV
• Prophylaxis with antiviral agents
• Reduction in the use of anti-lymphocyte sera and in the
overall intensity of immune suppression
Opelz G et al. Am J Transplant. 2004;4:928-936.
Prophylaxis: How to Best
Prevent Disease?
• Universal prophylaxis: administration of antiviral agents
to all individuals at risk for a fixed duration
– May increase cost, toxicity, risk of resistance
• Preemptive therapy: administration of antiviral therapy
in response to a positive microbiologic assay (eg, viral
load measurements) or clinical scenarios (eg, use of
lymphocyte-depleting antibodies or treatment of graft
rejection)
– Requires careful monitoring, close patient contact,
and use of highly sensitive, quantitative assay
Hart GD, Paya CV. Rev Med Virol. 2001;11:73-81.
Emery VC. Rev Med Virol. 2001;11:83-86.
Preemptive Therapy: CMV Viral Load Testing
in Predicting CMV Disease in D+/R- Solid
OrganTransplant Recipients
• Plasma viral load measurements determined in 364
D+/R- organ transplant recipients receiving oral
prophylaxis:
CMV disease in 64 (17.6%) patients by 12 months
• Using a positive cutoff of >400 copies/mL, sensitivity
was 38%, specificity was 60%, positive predictive value
was 17%, and negative predictive value was 82% for
prediction of CMV disease
• Routine monitoring would have predicted disease in
only 24 of 64 (38%) patients
Humar A et al. Am J Transplant. 2004;4:644-649.
Valacyclovir for the Prevention of
CMV Disease After Renal Transplantation
• 208 seronegative recipients of seropositive kidneys;
408 seropositive recipients
• Valacyclovir po 8 to 12 g/day vs placebo for 90 days
• Reduced incidence of HSV, CMV viruria and viremia,
CMV disease
• Reduced incidence of graft rejection in both groups
(D+/R-, D+/R+)
Lowance D et al. N Engl J Med. 1999;340:1462-1470.
Prophylaxis of CMV Disease With Oral
Ganciclovir in High-Risk (D+/R-) Transplant
Recipients
Renal Transplant Recipients
Prophylaxis (3 mo)
Postprophylaxis (6 mo)
Placebo
Valacyclovir
45%
45%
3%
16%
Hepatic Transplant Recipients
Placebo
Ganciclovir (po)
Prophylaxis (3 mo)
44%
5%
Postprophylaxis (6 mo)
44%
15%
Lowance D et al. N Engl J Med. 1999;340:1462-1470., Gane E et al. Lancet. 1997;350:1729-1733.
Razonable RR et al. J Infect Dis. 2001;184:1461-1464. Paya C et al. Am J Transplant. 2004;4:611-620.
Valganciclovir for Prophylaxis in
Solid Organ Transplantation
• 364 CMV D+/R- patients received valganciclovir 900
mg qd or oral ganciclovir 1000 mg tid through 100 days
• CMV disease developed in 12.1% of valganciclovir- and
15.2% of ganciclovir-treated patients by 6 months
(some difference in the relative efficacy of agents
between organs) and 17.2% and 18.4%, respectively,
by 12 months
• CMV rate viremia during prophylaxis was lower with
valganciclovir (2.9% vs 10.4% for ganciclovir; P=.001)
and comparable by 12 months (48.5%, valganciclovir,
vs 48.8%, ganciclovir)
Paya C et al. Am J Transplant. 2004;4:611-620.
Effects of Antiviral Agents on Allograft
Injury: Prevention of Indirect Effects?
• Valacyclovir in kidney recipients  50% 
in rejection
• Oral ganciclovir in heart, liver, kidney
recipients   trend in rejection
Lowance D et al. N Engl J Med. 1999;340:1462-1470.
Valantine HA et al. Circulation. 1999;100:61-66.
Ahsan N et al. Clin Transplant. 1997;11:633-639.
Valganciclovir for Prophylaxis in
Solid Organ Transplantation
• Times to onset of CMV disease and to viremia were
delayed with valganciclovir; rates of acute allograft
rejection were generally lower with valganciclovir
• Higher incidence of neutropenia with valganciclovir than
with ganciclovir (8.2% vs 3.2%, respectively)
• “Once-daily oral valganciclovir was as clinically effective
and well tolerated as oral ganciclovir tid for CMV
prevention in high-risk SOT recipients.”
.
Paya C et al. Am J Transplant. 2004;4:611-620.
Possible Prophylaxis for CMV
• D+/R-: IV ganciclovir in hospital, po valganciclovir x 3 months
(6 months with anti-lymphocyte-antibody induction)
– Repeat prophylaxis for ALS or antirejection therapy
• D-/R-: acyclovir or similar x 3 months (herpes simplex, VZV)
• D-/R+ : IV ganciclovir in hospital, po valganciclovir x 3 months
(6 months with anti-lymphocyte-antibody induction)
– IV ganciclovir for ALS or graft rejection
– May substitute routine quantitative monitoring after 3
months
• Active disease: treat until assay is negative, then 1 to 2 weeks
beyond; prophylaxis with po x 3 months minimum
CMV, cytomegalovirus; IV, intravenous; ALS, antilymphocyte serum; VZV, varicella-zoster virus.