viral infections in transplantation
TRANSCRIPT
IMPORTANT VIRAL PATHOGENS IMPORTANT VIRAL PATHOGENS AFFECTING AFFECTING
SOLID ORGAN TRANSPLANT SOLID ORGAN TRANSPLANT RECIPIENTSRECIPIENTS
Dino Sgarabotto Dino Sgarabotto
Padua University HospitalPadua University Hospital
Padova, ItalyPadova, Italy
The threat of viral disease The threat of viral disease in transplantationin transplantation
• Opportunistic infections cause considerable morbidity and mortality in transplant recipients1
• Common viral threats– CMV– HHV-6, HHV-7, HSV-1, HSV-2, EBV, and VZV – These viruses may have direct or indirect effects, or may interact with
each other or other viruses
• Emerging viral threats– SARS and West Nile Virus– Community acquired respiratory viruses
Respiratory Syncytial Virus (RSV), Influenza virus, Avian influenza (H5N1),
Rhinovirus, Enterovirus, Adenovirus, Coronavirus,
1. Baillie GM Am J Health-Syst Pharm 2005; 62(Suppl 1): S2
BKV polyomavirusBKV polyomavirus• Asymptomatic BKV viruria
– Immunocompetent individuals– Pregnant women (3%)– 30-45% renal transplants– 50% BMT
• BKV infects mostly the kidney– Transient cystitis: immunocompetent children– Glomerulonephritis: congenital and acquired immunodeficiency
• BKV infections are well defined syndromes in transplant recipients – Kidney transplant recipients: urethral stenosis, interstitial nephritis,
allograft dysfunction– HSCT: Haemorrhagic cystitis
Razonable RR et al. J Infect Dis 2005; 192: 1349
BKV therapyBKV therapy• Reduce immunosuppression
– How much nephropathy is due to infection or due to rejection?
• Interaction between CMV and polyomaviruses1
• Antivirals– Proposed cidofovir– Valganciclovir prophylaxis: decreased incidence of BKV
compared to oral ganciclovir1
• Proposed IVIG
Razonable RR et al. J Infect Dis 2005; 192: 1349
Respiratory Tract Respiratory Tract InfectionsInfections
• Community acquired viral respiratory tract infections in lung transplant recipients may – Have a higher rate of progression to
pneumonia– Trigger immunopathological effects on lung
function– May be associated with BOS and acute
rejection
Kumar D et al. Kumar D et al. Am J Transplant 2005; 5: 2031 2005; 5: 2031
Impact of community-Impact of community-acquired respiratory virusesacquired respiratory viruses
Cases (n = 50)
0 Enterovirus0 Adenovirus0 Influenza B8 Coronavirus1
Metapneumovirus
5 Influenza A4 Parainfluenza6 RSV9 Rhinovirus33 (66%)Viral Etiology
• Investigation of 50 lung patients with viral respiratory tract infections (RTI) symptoms
Kumar D et al. Kumar D et al. Am J Transplant 2005; 5: 2031 2005; 5: 2031
Adenovirus viremia (n = Adenovirus viremia (n = 263) 263)
0
2
4
6
8
10
Liver Kidney HeartTransplant type
Inci
denc
e of
vir
emia
(%
)
8.3
6.5 6.7
Humar A et al. Humar A et al. Am J Transplant 2005; 5: 2555 2005; 5: 2555
~ 50% asymptomatic~ 50% self-limited symptoms
Influenza A and BInfluenza A and B• Infection in the immunocompromised host
– Incidence as high as general population– Potentially fatal and substantial morbidity
• Prevention– Vaccination in transplant recipients
• Does not appear to cause rejection or other adverse events• Antibody responses may be lower
– Consider antiviral prophylaxis for patients who are:• Not yet vaccinated• Not expected to exibit an antibody response because of high
dose immunosuppressives• Agents: amantidine, rimantidine, oseltamivir, zanamivir
West Nile VirusWest Nile Virus• Flavivirus
• Transmission– Birds may develop high-titre viremia that permits transmission to
mosquitos– Spill-over infections of humans and mammals
• WNV in transplant recipients is acquired from– Infected donor – Blood product transfusion– Mosquitos
• Proposed therapy– Ribavirin, interferon, gammaglobulin, steroids, osmotic agents,
anti-seizure agents
Iwamoto M et al. N Engl J Med 2003; 348: 2196
Patient 1
Patient 2
Patient 3
Donor Alteredmentalstatus
Onsetof fever
MechanicalventilationDeath
Altered mental status,mechanical ventilationOnset
of fever
Patient 4
Onset offever
54 units of blood products
Mechanicalventilation
Alteredmentalstatus
Onsetof fever
Onsetof weakness
Kidney
Kidney
Heart
Liver
At home
At home
At home
Outcome in 4 transplant recipients with Outcome in 4 transplant recipients with WNV infection caused by an organ donor WNV infection caused by an organ donor
with viremiawith viremia
One month
Parvovirus B19Parvovirus B19• Infection in the immunocompromised host
– Pancytopenia due to transient aplastic crisis– Acute anemia due to pure red cell aplasia– Fever and rash– Hepatitis– Glomerulopathy1,2
• Diagnosis– Serology (positive IgM indicates recent infection: up to 3-4
months)– Bone marrow biopsy: pure red cell aplasia– PCR DNA positive up to 9 months
• Treatment– IV immunoglobulin (IVIG): dose and duration unclear– No effective antivirals yet
1.Yango A et al. Transplant infectious disease 2002; 4: 1632. Moudgil A et al. Transplantation 1997; 64: 1847
Herpesvirus familyHerpesvirus familyLatency is a common feature: reactivation common in transplantation and related to donor/recipient serostatus and intensity of immunosuppression
HSV-1
HSV-2
VZV
EBV
HHV-8
CMV
HHV-6
HHV-7
VZV and HSVVZV and HSV• Prevention
– Pre-transplant vaccination for non-immune individuals– VZIG for post-exposure prophylaxis (up to 96 hours)– Acyclovir, valaciclovir and famciclovir– CMV prophylaxis: VZV infection was not observed in
patients receiving valganciclovir or oral ganciclovir prophylaxis1
• Treatment– Acyclovir, valaciclovir, famciclovir: PO or IV depending
on severity and degree of immunosuppression
1. Razonable RR et al. J Infect Dis 2005; 192: 1331
HHV-8 and Kaposi Sarcoma HHV-8 and Kaposi Sarcoma (KS)(KS)
• Seroprevalence rates vary by geographic region– 0% to 5% in North America, Northern Europe and Asia– 5% to 20% in the Mediterranean and Middle East– Over 50% in parts of Africa1
• Risk of disease is related to the intensity of immune suppression2
• HHV-8 can be associated with lymphoproliferative disorders3
• (Val)ganciclovir prophylaxis may impact on HHV8 infection2,4
1. Chatlynne LG et al. Semin Cancer Biol 1999; 9: 175 2. Humar A Transplantation 2006; 82: S9
3. Kapelushnik J Br J Haematol 2001; 113: 425 4. Razonable RR et al. J Infect Dis 2005; 192: 1331
EBV and PTLDEBV and PTLD• Post-Transplant Lymphoproliferative Disease (PTLD) is
an abnormal proliferation of B-cells driven by EBV – Rarely involves T- or NK-cells (~10%)
• Risk factors for PTLD– EBV serostatus: D+/R-: 20-30%; R+: 1-5%1
– Intensity of immunosuppression: increase in proliferation following antilymphocyte antibodies from 20% to up to 80%
– Type of transplant: lung 3.8% > heart 3.3% > liver 2.7% > kidney 1%
• Herpesvirus interaction (CMV co-infection)
• Older age (late PTLD) vs. pediatric patient (early PTLD)Rubin RH. Infection in the organ transplant recipient. In: Rubin RH, Young LS, eds.Clinical Approach to Infection in the Compromised Host. 4th ed. 2002:chapter 17.
PTLD prevention and PTLD prevention and therapytherapy
• Reduce and minimize immunosuppression
• CMV prophylaxis prevents high level EBV replication in SOT recipients thus lowering the incidence of EBV-related PTLD1
• Antiviral therapy (acyclovir or valganciclovir): no effect on latent EBV
• Anti-CD20 (rituximab)
• Chemotherapy (+/- surgery and radiotherapy)
1. Razonable RR et al. J Infect Dis 2005; 192: 1331
• Incidence of infection in transplant recipients– HHV-6: 30–50%– HHV-7: 20–80%
• Most clinical manifestations predominately associated with HHV-6 reactivation– febrile illness, hepatitis, meningo-encephalitis
• May interact with each other and may cause reactivation of CMV and vice versa1
• (Val)ganciclovir prophylaxis lowers the incidence of HHV-62
HHV-6 and HHV-7HHV-6 and HHV-7
1. Humar A Transplantation 2006; 82: S9 2. Razonable RR et al. J Infect Dis 2005; 192: 1331
CMV pathogenesisCMV pathogenesis• CMV infection
– Evidence of asymptomatic CMV replication
• CMV disease (symptomatic infection)– Viral syndrome and tissue invasive disease
• Primary infection post-transplant– D+/R- (20-80% risk of disease) or
occasionally D-/R-
• Reactivation – D+/R+ (5-25%) or D-/R+ (5-10%)
• Superinfection – D+/R+ (5-25%) limited data
CMV clinical CMV clinical manifestationsmanifestations
Direct effects• Acute viral illness
• Interstitial pneumonia
• GI invasive disease
• Retinitis
• Graft invasive disease: myocarditis, nephritis, pancreatitis, etc.
Indirect effects• Bacterial and fungal
opportunistic infections
• Graft rejection and injury
• Overall mortality
• PTLD
Adapted from Fishman JA & Rubin RH N Engl J Med 1998; 338: 1741
Anti-CMV strategies Anti-CMV strategies following transplantationfollowing transplantation
Pre-emptive Patient only receives antiviral therapy if tested
to be CMV+ for active infection
TreatmentPatient receives antiviral therapy after clinical
symptoms are apparent
ProphylaxisPatient receives antiviral therapy
without previous monitoring of CMV replication
Couchoud1998
Gourishankar
2001
Fiddian 2002
Hodson2005
Kalil2005
Balfour 1989 Balfour 1989 Pettersson 1985
Balfour 1989 Balfour 1989
Merigan 1992 Merigan 1992 Seale 1985 Merigan 1992 Merigan 1992Saliba 1993 Saliba 1993 Stoffel 1987 Saliba 1993 Kletzmayr 1996Cohen 1993 Cohen 1993 Balfour 1989 Cohen 1993 Barkholt 1999Singh 1994 Rondeau 1993 Stratta 1992 Rondeau 1993 Saliba 1993
Rondeau 1993 Conti 1995 Saliba 1993 Rostaing 1994 Rostaing 1994McDonald 1995 McDonald
1995Dunn 1994 Conti 1995 Conti 1995
Winston 1995 Winston 1995 Kletzmayr 1996 McDonald 1995 Hibberd 1995Leray 1995 Kletzmayr
1996Gavaldà 1997 Hibberd 1995 Poteil-Noble 1996
Poteil-Noble 1996 Brennan 1997 Barkholt 1999 Leray 1995 Gavaldà 1997Kletzmayr 1996 Gane 1997 Lowance 1999 Kletzmayr 1996 Brennan 1997
Saliba 1996 Poteil-Noble 1996 Brennan 1997Ahsan 1996 Ahsan 1996 Gane 1997
Brennan 1997 Lowance 1999Gane 1997 Rayes 2001
Gavaldà 1997 Paya 2002Barkholt 1999 Sagedal 2003Lowance 1999
Egan, 2002
CMV prophylaxis vs. pre-emptive CMV prophylaxis vs. pre-emptive therapy: therapy: meta-analyses meta-analyses
• Pre-emptive therapy does not appear to prevent the indirect effects of CMV1,2
• Old meta-analysis about CMV prophylaxis– Couchoud C et al. Transplantation 1998, 65: 641-647– Gourishankar S et al. Transplant Proc 2001, 33:1870-
1872– Fiddian P et al. JID 2002, 186: S110-5
• New meta-analysis about CMV prophylaxis and pre-emptive therapy– Hodson EM et al. Lancet 2005, 365: 2105-2115– Kalil AC et al. Annals Int Med 2005, 143: 870-880
Meta-analyses IIMeta-analyses II• In all 5 meta-analyses acyclovir, valaciclovir, (IV/PO)
ganciclovir were effective in prevention of CMV infection and disease
• Only meta-analyses of Fiddian, Hodson and Kalil showed benefit of prophylaxis against the indirect effects of CMV infection (opportunistic infections, rejection and overall mortality)1-3
• Kalil’s meta-analysis compares prophylaxis and pre-emptive: only prophylaxis reduces the incidence of the indirect effects of CMV
1. Fiddian P et al. J Infect Dis 2002; 186(Suppl1): S110 2. Hodson EM et al. Lancet 2005, 365: 2105
3. Kalil AC et al. Annals of Internal Medicine 2005, 143: 870
Indirect effects of CMV Indirect effects of CMV prophylaxisprophylaxis
0.27
0
0.2
0.4
0.6
0.8
1
Placebo/notreatment
Rela
tive
risk
-73%
0.65
Bacterialinfections
-35%
0.31
Protozoalinfections
-69%
Herpes simplexVaricella zoster
Hodson EM et al. Lancet 2005; 365: 2105
Future challengesFuture challenges• Valganciclovir has proved its efficacy in prophylaxis• Prophylaxis duration: 100 or 200 days?
– Impact Study– Prevention of asymptomatic, non-invasive CMV infection has long-term benefits, but does
this outweigh the cost and toxicity of the drugs?
• Is it going to be the drug of choice for induction therapy and pre-emptive?– Victor Study: safety and efficacy of 900 BID valganciclovir for the treatment of CMV
disease in all D±R± SOT recipients vs 5 mg/kg BID IV ganciclovir
• Ganciclovir resistance: foscarnet and cidofovir are too toxic– No ganciclovir resistant strains associated with valganciclovir prophylaxis in SOT recipients
• Need for new drugs: maribavir the next? Immunosuppressors derived from leflunomide?
• Improved diagnostic: very sensitive quantitative PCR? CMV HLA-tetramers?
SummarySummary• Viral infections cause considerable morbidity and mortality in
transplant recipients
• Viral threats other than CMV exist– HHV-6, HHV-7, HSV, VZV, EBV, polyomaviruses, RSV, influenza, WNV
• CMV is a common viral threat but it is still the most significant pathogen in SOT recipients– Direct and indirect effects – Subclinical viral replication– Interaction with other viruses
• CMV prophylaxis has the added benefit of preventing/minimising risk of symptomatic disease associated with additional viral threats
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