Download Indirect Effects of Viral Infections in Transplantation.

Viral Infection in Transplantation: Indirect
Effects
Jay A. Fishman, M.D.
Infectious Disease and Transplantation Units,
Massachusetts General Hospital,
Harvard Medical School, Boston, MA, USA
Viruses may be dangerous . . . .
The Growing Family of Viral Pathogens
in Transplantation
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HERPES SIMPLEX
VARICELLA ZOSTER
EPSTEIN-BARR VIRUS
CYTOMEGALOVIRUS
HHV6 (& role with CMV)
HHV7 (role?)
HHV8/KSHV
HIV
WEST NILE VIRUS
RABIES
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HEPATITIS B and C
PAPILLOMAVIRUS
POLYOMAVIRUS BK/JC
ADENOVIRUS, RSV
INFLUENZA,
PARAINFLUENZA
METAPNEUMOVIRUS
PARVOVIRUS B19
SMALLPOX/VACCINIA
SARS coronavirus
Effects of Viral Infection in Transplantation
• DIRECT CAUSATION OF INFECTIOUS DISEASE
SYNDROMES
– Nephrtitis, hepatitis, neutropenia
– Allograft injury often greater than systemic
• IMMUNOMODULATORY EFFECTS
– SYSTEMIC IMMUNE SUPPRESSION -- OI’s
– CELLULAR EFFECTS - Graft Rejection, GvHD
– ABROGATION OF TOLERANCE
• ONCOGENESIS
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Hepatitis B: hepatocellular carcinoma
Epstein Barr Virus: B-cell lymphoma (PTLD)
Hepatitis C: splenic lymphoma (villous lymphocytes)
Papillomavirus: Squamous cell & anogenital cancer
HHV8 (KSHV): Kaposi’s sarcoma, effusion lymphoma
CMV: Direct Effects
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Endothelial & smooth muscle cells, PBMC
Macrophages in the lungs
Pancreas?
Retina?
Virus activated by allogeneic response,
antilymphocyte antibodies, TNF (via NF-B),
other proinflammatory cytokines
AJ Koffron et al, J Virol, 1998, 72:95-103; E. Fietz et al, Transplantation, 1994,
58:675-680; P. Reinke et al, Transplant. Infect Dis, 1999, 1:157-164; M
Hummel et al, J Virol, 2001, 75:4814-4822.
CMV Retinitis: Lung Transplant
Recipient
Invasive Colitis After Liver
Transplant
CMV cecal ulceration in patient with negative
antigenemia and PCR assays for CMV
CMV “Indirect Effects”: Possible Mechanisms
• Upregulation of MHC class II antigens and homolog of MHC
class-I (HLA-DR, Fujinami RS, et al. J Virol. 1988;62:100-105. S. Beck, Nature.
1988;331:269-272)
• Blocks CD8+ (MHC class I) recognition
• Blocks CMV antigen processing and display (immediate early
Ag modification, poor CTL response)
• Increased ICAM-1, VCAM, cellular myc & fos
• Inversion of CD4/CD8 ratio (Schooley 1983, Fishman 1984)
• Increased cytokines: IL-1, TNF, IFN, IL-10, IL-4, IL-8, IL2/IL-2R, C-X-C chemokines and IL-8 (Kern et al, 1996; CY Tong, 2001)
• Increased cytotoxic IgM (Baldwin et al, 1983)
• Stimulation of alloimmune response by viral proteins (Fujinami et
al, 1988, Beck et al, 1988)
• Increased PDGF, TGF
• Increased granzyme B CD8+ T-cells, -T-cells
Opportunistic Infections Promoted by
CMV Infection in Transplant Patients
Pneumocystis carinii
Fungal infections (esp. intra-abdominal transplants):
Candidemia and intra-abdominal infection in OLTx;
patients with initial poor graft function
Aspergillus spp. Role of CMV in promoting
fulminant HCV hepatitis rather than direct effect
Bacteremia: Listeria monocytogenes
Epstein-Barr virus infection (RC Walker et al, CID,
1995, 20:1346-55)
 HCV: risk for cirrhosis, retransplantation, mortality
CMV and Graft Dysfunction: Renal
Distinguish between studies demonstrating link of
CMV to graft dysfunction and improved outcomes with
prevention - may be the same or different effects
(Herpes Virus Infection Syndrome)
• CMV Disease causes poor renal graft function at 6 mos and
CMV & HHV6 are associated with chronic dysfunction (3 yrs)
(CY Tong et al, Transplant. 2002, 74:576-8)
• Acute but not Chronic allograft rejection is reduced by CMV
prevention in liver and kidney (D+/R-) Tx (D Lowance et al, NEJM
1999, 340:1462-70; E. Gane et al, Lancet 1998, 350:1729-33)
• HHV6 increases CMV infection and OI’s and possibly some
acute rejection in renal (A. Humar, Transplant 2002, 73:599-604) & liver
recipients (JA DesJardin CID 2001, 33:1358-62; PD Griffiths et al, J Antimicrob
Chemother, 2000, 45 sup 29-34)
• HHV7 associated with increased CMV infection and with
acute rejection (IM Kidd et al, Transplant 2000, 69:2400-4)
CMV and Graft Dysfunction: Liver
• CMV is associated with cirrhosis, graft
failure, retransplantation, and death in liver
allograft recipients (KW Burak et al, Liver Transplant
2002, 8:362-9)
• CMV is associated with more aggressive
HCV recurrence and fibrosis after OLTx
(partially attributed to HHV6) (A. Sanchez-Fueyo
et al, Transplant 2002, 73:56-63; N Singh et al, Clin
Transplant 2002, 16:92-6; HR Rosen et al, Transplant
1997, 64:721; R. Patel et al, Transplant 1996, 61:1279)
– Roles of immune suppression, CMV-induced immune
suppression & HCV, CMV-induced TGF/fibrosis
Impact of CMV in Heart & Lung
Transplantation
• Obliterative bronchiolitis (BOS) increased in:
– Serologic R+ and D+ combination
– Role of asymptomatic CMV replication?
– CMV infection raises OB to ~60% (Zamora MR. TransID
2001; 3: 49-56 and Am J Tx 2004, 4:1219-1226)
• Infection of vascular endothelia and smooth
muscle cells
–  Adhesion molecules (VCAM,ICAM,LFA-1,VLA-4)
–  HLA-DR and MHC Class I mimic
–  Anti-endothelial Abs? Cytotoxic T-cells?
CMV and Graft Dysfunction: Heart-Lung
• CMV is associated with Coronary allograft
vasculopathy (MT Grattan et al, J Am Med Assoc 1989,261:3562-6)
• Prophylaxis using CMVIg with ganciclovir reduces
cardiac transplant vasculopathy (HA Valantine et al, Circulation
1999, 100:61-6; HA Valentine et al, Transplantation 2001, 72:1647-1652)
– CMVIG plus DHPG reduced CMV incidence, rejection, and death vs.
DHPG alone
– Coronary Tx vasculopathy reduced
– Lung and heart-lung recipients had less obliterative brohchiolitis,
death from OB, better survival, fewer infections
– Less PTLD in double Rx
• CMV disease and D+/R- status are associated with
chronic rejection, bacterial and fungal pneumonia,
OB and death in Lung Tx (SR Duncan 1992; NA Ettinger 1993; K
Bando 1995; RE Girgis 1996; RN Husni 1998)
• Reduction in BOS and fungus with iv ganciclovir
(SR
Duncan et al, Am J Crit Care Resp Dis 1994, 150:146-152; DR Snydman NEJM
1987, 317:1049-1054; JA Wagner et al Transplant 1995, 60:1473-7)
Special Risks for CMV in Heart &
Lung Transplantation?
• Lungs:
– Exposure to environment (stimulation)
– Lymphatic tissue with graft
– Macrophage burden with graft
– Major site of viral “latency” (Balthesen M et al, J
Virol 1993; 67:5360-5366)
– Recurrent infections - stimulation
How best to impact indirect effects?
• Does prophylaxis delay or prevent CMV infection
and disease? - Yes (M Halme Transplant Int 1998, S499-501; JL Kelly et al,
Transplant 1995, 59:1144-7)
• Does prophylaxis delay or prevent CMV-mediated
effects? Role of CMV may be uncertain but clinical
data support this concept.
• Do we need to prevent other viral infections? Yes
• How to best use “screening tests” depends on goal
of therapy - prevent CMV disease vs. asymptomatic
infection & presumed indirect effects?
• What is the optimal regimen? Need further data.
Summary: Effects of Antiviral Agents on Allograft
Injury
– Valacyclovir in kidney recipients  50%  in
rejection
– Oral ganciclovir in heart, liver, kidney recipients
  trend in rejection
– Prophylactic IV ganciclovir in heart recipients
 long-term benefit in  of vasculopathy
Lowance D, et al, for the International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study
Group.
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.
Indirect Effects: Other Viruses
• Cytomegalovirus: best studied, global
immune suppression, increased graft
rejection
• Hepatitis B and C: increased incidence of
opportunistic infection
• Epstein-Barr virus: link to non-Hodgkin's
lymphoma
• Parvovirus B19: elaboration of cytokines,
autoimmune effects, Cellular apoptosis
• RSV, Coronavirus, influenza: ciliary injury,
local suppression
“Herpes Virus Infection Syndrome” in Transplant
Patients
• HHV6 and HHV7 are risk factors for CMV disease,
invasive fungal infection (DH Dockrell et al, Transplant. 1999, JID, 1997;
S. Chapenko et al, Clin Transplant 2000, 14:486-92; CY Tong et al, Transplant 2000,
70:213-6; IM Kidd et al, Transplant 2000, 69:2400-4) CMV D+/R- and D-/R+ groups with
invasive disease more likely to have co-infection with HHV6, HHV7)
• HHV6 and HHV7 associated with positive CMV
antigenemia in liver Tx (I. Lautenschlager, J. Clin Virol 2002)
• HHV6 and CMV associated with more severe
recurrence/fibrosis with HCV (A. Humar et al, Am J Transplant 2002)
• Ganciclovir reduces load of all 3 viruses (JC Mendez et al,
JID, 2001; 183:179-184) while CMVIg does not (JA Desjardins et al, JID,
1998, 178:1783-6).
Examples: Parvovirus B19
• Ubiquitous virus (50-90%) of children and
adults. Spread by contact, transfusion.
• Peak incidence in late Winter and early
Spring.
• DNA virus, 5600 bp. Features:
– Tropism for erythroid cells via P-glycoprotein
(glyboside)
– Causes elaboration of cytokines
– Cellular apoptosis (caspase 3 inhibition via
down-regulation of Bcl-2)
– Cellular cytotoxicity in vitro (in vivo?)
Parvovirus B19 - Myocarditis
1. Lymphocytic myocarditis in an 11 mo child
(Papadogiannakis et al, CID 2002: 35, 1027)
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Patchy necrosis of myocardium
Mononuclear cell infiltration of myocardium, lungs
Normal bone marrow
2. Anemia, lymphocytic myocarditis 2 mos
post cardiac transplantation
Parvovirus: Mechanisms
• P-receptor binding
– Erythroid precursors (fetal anemia, hydrops?)
Giant pronormoblasts with intranuclear
inclusions, vacuoles
– Megakaryoblasts (platelets)
– Endothelial cells (vasculitis)
– Myocardial cells (myocarditis uncommon but
may be rapid and severe in normal hosts) (Porter et
al, Lancet 1988; 1, 535-6; Naides & Weiner, Prenat Dx 1989; 9: 105-14)
• Autoimmune via
– -T-cells? (Eck et al, Am J Surg Path 1997; 21: 1109-12)
– Lower level of virus in heart vs other unaffected tissues
(Murray et al, Hum Path 2001, 32:342-5)
– CD8+ cell recruitment (Tolfuenstam et al, J Virol. 2001; 75:540)
Respiratory Viruses
RSV: Pediatric Liver Transplant
Recipients
• 3.5% of 493 children >5 years; median, 20
months old
• 76% nosocomial; median, 24 days
posttransplantation
• Tachypnea 65%, cough 53%, fever 53%,
wheeze 29%, pneumonia 35%
• Coinfections: bacteremia/fungemia 35%,
fungal/bacterial pneumonia 24%, CMV 24%
• No ribavirin therapy: mortality 12%
Pohl C et al. J Infect Dis. 1992;165:166-169.
Parainfluenza in Lung Transplant
Recipients
• Median onset, 2.1 years (range, 0.6-5)
posttransplantation
• Presenting symptoms
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Cough 71%
Shortness of breath 64%
Fever 17%
Pneumonia 17%
• 18 (82%) had concurrent rejection; 32%
progressed to bronchiolitis obliterans
– 9 of 10 treated with ribavirin survived
Indirect Effects and Respiratory viral infections
• RVI  increased risk of 2.1 fold for development of
Aspergillus infections.(13)
• RVI  risk factor for graft rejection, particularly
chronic graft rejection in lung transplants.(14-19)
• RVI of the lower respiratory tract, but not the upper
tract, predispose to bronchiolitis obliterans
syndrome (BOS) (RR, 2.3; 95% CI, 1.1-4.9).(14)
• Rat lung transplant model of Sendai virus infection,
a virus related to parainfluenza virus (PIV) links
lower tract disease and BOS.(20)
• Seasonal trend to BOS that peaks shortly after the
peak of winter respiratory viral infections.(5)
Marr KA et al. Blood 2002;100(13):4358-66; Billings JL et al. J Heart Lung Transplant 2002;21(5):559-66; Chakinala MM,
Walter MJ. Semin Thorac Cardiovasc Surg 2004;16(4):342-9.; Garantziotis S et al. 2001;119(4):1277-80; Khalifah AP at al.
Am J Respir Crit Care 2004;170(2):181-7; Vilchez RA et al. Am J Transplant 2003;3(3):245-9; Winter JB et al. Transplant.
1994;57(3):418-22).
Where Do Indirect Effects Stop and
Where Does Oncogenesis Start?
Viral Oncogenesis and Proliferative Events in
Transplantation
CMV: Early arteriosclerosis, role in PTLD.
Epstein Barr Virus: PTLD (B-cell), Hodgkin’s, T-cell
(Asia), Burkitt’s (c-myc, P. falciparum), Cofactor in
Kaposi’s?
Papillomavirus: Squamous, Anogenital Cancers
HHV8/KSHV: Kaposi’s sarcoma, Castleman’s ds.
Hepatitis B (C?): Hepatocellular carcinoma
Hepatitis C: Splenic, non-Hodgkin’s lymphoma
(immunostimulation of villous B-lymphocytes)
HTLV-1: Adult T-cell leukemia & lymphoma
BK virus: Ureteric smooth muscle proliferation
JC virus: PML, neuroglial tumors?
HHV8/KSHV
Risk Factors:
• Risk of KS increased with positive HHV8 serology
(RR: 4.9-28.4)
• Immune Status:
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Risk of KS increased by CyA vs. Aza
Risk of KS increased by MMF vs. Aza
HHV8 activated by steroids in vitro (BCBL-1)
Antilymphocyte antibodies - Relative Risk=11.3
• Non-neoplastic lymphoproliferative (plasmacytoid)
disorders (Matsushima, Am J Surg Path 1999, 23:1393-1400) and
PEL (Dotti, Leukemia 1999, 13:664-70) post-TX
• Many proliferative disorders
PTLD and EBV Infection in Transplantation
• 28-49-fold increase in transplant recipients above
age-matched controls.
– 55% “Benign” polyclonal B-cell proliferation
(“infectious mono”)
– 30% Polyclonal or oligoclonal +/- early malignant
transformation
– 15% Extranodal, monoclonal B-cell disease (Based
on Ig rearrangements or EBV genome termini)
 Of non-Hodgkin’s lymphomas: 87.0% arose in Blymphocytes, 12.6% of T-cell origin, 0.4% null cell
origin.
EBV-associated malignancies
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Burkitt’s lymphoma (endemic, sporadic)
CNS lymphoma (compromised host)
B-cell lymphoma* (PTLD)
T-cell lymphoma (nasal, angiocentric)
Primary effusion lymphoma (AIDS, HHV8)
Hodgkin’s* (mixed cellularity)
Nasopharyngeal carcinoma
(Lymphoepthelioid)
• Smooth muscle tumor (compromised host)
*Broad array of EBV latency proteins are expressed
(contrast other EBV-associated tumors).
Colitis
36 year old male status
post heart transplant with
abdominal pain, diarrhea, no
h/o bowel disease.
EBV Colitis? Uncommon Syndrome?
• In Situ Hybridization: Edematous colonic mucosa,
focal ulceration and granulation tissue with bizarre
stromal cells; No viral cytopathic changes are
identified, and immunostains for CMV, HSV-1 and
HSV-2 are negative.
• In-situ hybridization for EBV (EBER probe) reveals
occasional positive cells in the epithelium. The
pattern of staining in most cells is suggestive of
cytoplasmic staining by endocrine cells. THE
LYMPHOID CELLS ARE NEGATIVE.
Other Indirect Effects
Why is tolerance difficult to produce?
• It is worth recalling that the adaptive
immune system (specificity and memory)
was (likely) developed to protect against
infectious challenges, not allografts.
• Successful (animal) tolerance induction has
generally been achieved in mice relatively
free of long-lived memory T-cells. These
are usually pathogen-free mice capable of
generating anergy, deletion (apoptosis),
suppression (Tregs) or immune deviation
(non-harmful phenotype) of naïve T-cells.
Heterologous Immunity
• What is the effect of prior infectious
exposures to immune responses to
allografts?
• Virally induced alloreactive memory provides
a barrier to transplantation tolerance (AB Adams
et al, JCI 2003:111:1887-95) and may  autoimmunity
– Alloreactive T-cells are activated by viral
infections (Yang H and Welsh RM JI 1986: 1186-1193; Braciale TJ et
al J Exp Med 1981, 153:1371-76; Chen HD 2001, Nat Imm 2:1067-76)
– Allo-cross reactivity of CMV and EBV
– Pre-existing alloreactive memory T-cells
increase rejection rate (Heeger PS et al. JI 1999,
163:2267-75)
Heterologous Immunity
• Viral infections  alloreative memory T-cells
• These CD8+ central memory T-cells confer
resistance to tolerance induction
• The level of resistance to tolerance
induction is related to the number of prior
infectious exposures
• Resistance can be adoptively transferred
• Studied vaccinia virus, vesicular stomatitis
virus, lymphocytic choriomeningitis virus
Longer term implications?
• The role of “persistent” infection in
alloimmune responses is under study
– Down-regulation of immune responses to virus
over time (Treg CD4+ cells) also decrease antitumor responses (e.g., HCV, CMV, murine
Friend virus)
– Other viruses escape immune responses by
altering cytokine responses (pox & herpes) or
hiding (papillomavirus)
– These infections may serve as models for the
host response to allografts (e.g., Zinkernagel)
What’s Next?
Ebola
Marburg
Hemorrhagic Fever Viruses
Variola
Vaccinia
Smallpox
Agents of Bioterrorism
Unknown
SARS
Thank you for inviting me. I
would be happy to answer
questions.
If I can help:
[email protected]