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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