infections in solid organ transplant

8/11/2019 Infections in Solid Organ Transplant

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T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 357;25 www.nejm.org december 20, 2007 2601

Medical Progress

Infection in Solid-Organ

Transplant RecipientsJay A. Fishman, M.D.

From the Transplant Infectious Diseaseand Compromised Host Program, Massa-chusetts General Hospital, and HarvardMedical School, Boston. Address reprintrequests to Dr. Fishman at the TransplantInfectious Disease and CompromisedHost Program, Massachusetts GeneralHospital, 55 Fruit St., GRJ 504, Boston,MA 02114, or at [email protected] .

N Engl J Med 2007;357:2601-14.Copyright 2007 Massachusetts Medical Society.

Increasingly potent immunosuppressive agents have dramaticallyreduced the incidence of rejection of transplanted organs while increasing pa-tients susceptibility to opportunistic infections and cancer.1,2At the same time,

patterns of opportunistic infections after transplantation have been altered by routineantimicrobial prophylaxis for Pneumocystis carinii(also called P. jirovecii) and cytomega-lovirus. These patterns have also been altered by the emergence of new clinical syn-dromes (e.g., polyomavirus type BK nephropathy) and by infections due to organismswith antimicrobial resistance. New quantitative molecular and antigen-based micro-

biologic assays detect previously unrecognized transplantation-associated pathogenssuch as lymphocytic choriomeningitis virus. These assays are used in the manage-ment of common infections such as those due to cytomegalovirus and EpsteinBarrvirus (EBV). In this article, I review general concepts in the management of trans-plantation-associated infections and discuss recent advances and challenges.

GENERA L CONCEPTS

It is more difficult to recognize infection in transplant recipients than it is in personswith normal immune function, since signs and symptoms of infection are often di-minished. In addition, noninfectious causes of fever, such as allograft rejection, maydevelop in transplant recipients. Antimicrobial therapy frequently has toxic effectsthat may involve interactions with immunosuppressive agents. The spectrum of po-tential pathogens is broad, and infection often progresses rapidly. Early and specif icmicrobiologic diagnosis is essential for guiding treatment and minimizing nones-sential drug therapy. Invasive diagnostic procedures are often required for accurateand timely diagnosis.

RISK OF INFECTION

The risk of infection after transplantation changes over time, particularly with mod-ifications in immunosuppression. Unfortunately, no assays accurately measure a pa-tients risk of infection. Currently, therefore, the clinician assesses a recipients risk of

infection while considering the risk of allograft rejection, the intensity of immuno-suppression, and other factors that may contribute to his or her susceptibility to in-fection. Prophylactic strategies are based on the patients known or likely exposuresto infection according to the results of serologic testing and epidemiologic history.The risk of infection in the transplant recipient is a continuous function of the in-terplay between these factors.

Epidemiologic Exposures

Epidemiologic exposures can be divided into four overlapping categories: donor-derivedinfections, recipient-derived infections, nosocomial infections, and community infec-tions.

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n engl j med 357;25 www.nejm.org december 20, 20072602

Donor-Derived Infections and Screening

Transplanted organs facilitate the transmission ofinfections from organ donors. Mandatory report-ing of transplantation-associated infections hasincreased awareness of this problem. Most often,these infections (e.g., cytomegalovirus infection,tuberculosis, and Trypanosoma cruziinfection) are

latent in transplanted tissues. Transmission mayalso be due to active donor infection such as vire-mia or bacteremia that was undiscovered at thetime of organ procurement (Fig. 1A).3

Organ donors also may become infected withnosocomial organisms that are resistant to rou-tine surgical antimicrobial prophylaxis, and theymay transmit these organisms (e.g., vancomycin-resistant enterococcus and azole-resistant candidaspecies) to recipients.4-6

Clusters of infections derived from deceaseddonors have been described, including transplan-

tation-associated West Nile virus infection, lym-phocytic choriomeningitis virus infection, rabies,human immunodeficiency virus (HIV) infection,and Chagas disease.3,7-10In recent outbreaks ofWest Nile virus infection, lymphocytic choriomen-ingitis virus infection, and rabies, signs of infec-tious encephalitis in organs from deceased donorswere masked by unrelated acute neurologic eventsand thus were not recognized.

Nonspecific signs such as altered mental statusor abnormal results of liver-function tests may bethe sole basis on which to investigate potentialdonor-related infections. In the normal host, in-fections due to West Nile virus or lymphocyticchoriomeningitis virus are generally self-limited.However, in organ-transplant recipients with theseinfections, rapid progression, permanent neuro-logic damage, and death are more common be-cause of the broad immunologic deficits that arepresent after transplantation.

The screening of transplant donors for infec-tion is limited by the available technology and bythe short period during which organs from de-

ceased donors can be used. At present, the routineevaluation of donors for infectious disease gener-ally relies on antibody detection with the use ofserologic tests for common infections (Fig. 2).Since seroconversion may not occur during acuteinfections and the sensitivity of these tests is not100%, some active infections remain undetected.Some organs that contain unidentified pathogenswill inevitably be implanted. Improved donorscreening will require the use of more sensitive(e.g., molecular) and rapid assays by organ-pro-

curement organizations. Augmented screening isrecommended on a regional basis for endemic orepidemic infections such as West Nile virus infec-tion, Chagas disease, and strongyloidiasis.11

l

A

B

Figure 1.Effect of Donor-Derived Infection or GraftInjury on the Risk of Infection after Transplantation.

Panel A is a chest radiograph showing pneumonia result-ing from donor-derived herpes simplex virus infection.

Fever and pneumonia developed in a kidney-transplantrecipient 3 days after a technically successful transplanta-

tion, and the patient had abnormal results on liver-func-tion tests. Blood and sputum contained herpes simplex

virus. This virus was also detected in donor serum bymeans of a polymerase-chain-reaction assay. Recipients

of the liver, heart, and other kidney from the same donorwere symptomatic and were treated successfully with an-

tiviral therapy. Panel B is a computed tomographic scan

showing a liver abscess at the site of an ischemic graft in-jury. The patient had persistently and mildly abnormal

liver-function tests (elevated alkaline phosphatase and to-tal bilirubin levels) after undergoing technically success-

ful orthotopic liver transplantation with early graft isch-

emia. Three years later, fever and chills developed, anda heterogeneous 6-cm abscess (arrow) with intrahepaticbiliary ductal dilatation was detected. Therapy included

percutaneous drainage and administration of antimicro-bial agents for organisms including vancomycin-resistant

Enterococcus faecalisand Candida glabrata.





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Medical Progress


Some documented infections, such as sepsisand HIV infection, preclude organ donation. Or-gans from donors with specified known infec-tions may be considered for specific recipients provided there is appropriate informed consent based on the urgency of the need for transplan-tation and the availability of effective antimicro-

bial therapies. For example, some livers from do-nors who were seropositive for Chagas diseasehave been used successfully with benznidazoleprophylaxis in regions where the disease is en-demic.12Similarly, although organs from donorsinfected with the hepatitis B virus (HBV) and whohad test results that were positive for antibodiesagainst hepatitis B core antigen and negative forantibodies against hepatitis B surface antigen wererejected in the past, they are currently used forsome recipients who have been vaccinated or whowere previously infected, provided there is treat-

ment with specific antiserum and anti-HBV anti-viral agents.13-18The use of organs infected withthe hepatitis C virus (HCV) remains controversialand is generally reserved for HCV-infected re-cipients.

Transplantation of organs from deceased do-nors who had fever or viral syndromes is contro-versial, and the uncertainty highlights the needfor improved microbiologic screening tools. Incases in which the need for transplantation is rela-tively less urgent, it is reasonable to avoid the useof organs from donors with unexplained fever,rash, encephalitis, or untreated infectious syn-dromes.

Recipient-Derived Infections and Detection

Active infection in transplant recipients should beeradicated before transplantation, since immuno-suppression will exacerbate the infectious process.Individualized epidemiologic histories can guidepreventive strategies.11Common recipient-derivedpathogens include Mycobacterium tuberculosis, certainparasites (e.g., Strongyloides stercoralisand T. cruzi),

viruses (e.g., cytomegalovirus, EBV, herpes simplexvirus, varicellazoster virus [which causes shin-gles], HBV, HCV, and HIV), and endemic fungi(e.g., Histoplasma capsulatum, Coccidioides immitis,and Paracoccidioides brasiliensis).19-29Activities suchas travel, raising pigeons (which is associated withCryptococcus neoformansinfection), or marijuana use(which is associated with infection with aspergil-lus species) increase the risk of infection. Infec-tions that can be treated or controlled do not pre-clude transplantation.

Temporally distant S.stercoralisinfection mayreemerge, often in the f irst year after transplan-tation, as a hyperinfestation syndrome consistingof hemorrhagic enterocolitis, pneumonia, andgram-negative bacteremia or meningitis.24,25Em-pirical treatment with ivermectin before trans-

Donor Screening

Recipient Screening

l

Epidemiologic historySerologic testing for VDRL, HIV,

CMV, EBV, HSV, VZV, HBV(HBsAg, anti-HBsAg), and HCV

Microbiologic testing of bloodand urine

Chest radiography

Known infections (appropriatetherapy?)Possible infections (e.g., encepha-

litis, sepsis)Special serologic testing, nucleic

acid assays, or antigen detectionbased on epidemiologic factorsand recent exposures (e.g., toxo-plasma, West Nile virus, HIV,HCV)

Risk Assessment

Higher risk of infection

Induction therapy with lympho-cyte depletionPulsed-dose corticosteroidsPlasmapheresisHigh risk of rejectionEarly graft rejectionGraft dysfunctionActive or latent infection in the

donor or recipientTechnical complications

Anastomotic leakBleedingWound infection or poor

healingProlonged intubationProlonged use of surgical,

vascular, or urinarycatheters

Lower risk of infectionImmunologic toleranceGood HLA matchTechnically successful surgeryGood graft functionAppropriate surgical prophylaxisEffective antiviral prophylaxisProphylaxis against pneumo-

cystis pneumoniaAppropriate vaccination

Epidemiologic historyVaccination historySerologic testing for VDRL, HIV,

CMV, EBV, HSV, VZV, HBV(HbsAg, anti-HbsAg), and HCVTuberculin skin testMicrobiologic testing of blood

and urineChest radiographyKnown infections

Past colonization: prophylaxis?Active infection: appropriate

therapy?Possible infections (e.g., encepha-

litis, sepsis)Special serologic testing, nucleic

acid assays, or antigen detectionbased on epidemiologic factorsand recent exposures (e.g.,strongyloides, histoplasma,coccidioides, HBV or HCV

viral load)

Figure 2.Assessment of the Risk of Infection at the Time

of Transplantation.

The risk of infection transmitted from the organ donor or activated in the

recipient can be assessed at the time of transplantation. Donor and recipi-ent screening are based on the epidemiologic history and serologic testing.

The use of sensitive molecular and protein-based assays may enhance thesafety of organ transplantation while expanding the use of potentially in-

fected grafts. The transplant recipients risk is a function of the technicaloutcome, epidemiologic factors, and the intensity of immunosuppression.

VDRL denotes Venereal Disease Research Laboratory test, HIV human im-munodeficiency virus, CMV cytomegalovirus, EBV EpsteinBarr virus,

HSV herpes simplex virus, VZV varicellazoster virus, HBV hepatitis Bvirus, HBsAg hepatitis B surface antigen, anti-HBsAg antibodies againsthepatitis B surface antigen, and HCV hepatitis C virus.





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plantation prevents such infection in strongyloi-des-seropositive recipients. The importance ofdonor-derived or recipient-derived exposures toendemic fungi such as H. capsulatumor tubercu-losis is shown by the increased rate of activationof these infections among transplant recipients;this rate is 50 times higher among transplant re-

cipients than it is among the general population,notably in endemic regions.11

The course of HCV infection after liver trans-plantation remains discouraging. Since effectiveantiviral therapies are lacking, recipients are uni-formly reinfected by HCV, with outcomes deter-mined by the viral strain, the presence or absenceof previous immunity, and the response to anti-viral therapy.30-34

Successful transplantation has been achievedin HIV-infected patients treated with highly ac-tive antiretroviral therapy.26-28In such recipients,

the toxic effects of drugs and interactions betweencalcineurin inhibitors and antiretroviral agentsrequire careful monitoring. Liver-transplant re-cipients with HIV and HCV coinfection may havean accelerated course of recurrent HCV infection.

Nosocomial Infections and Antimicrobial Resistance

Patients waiting for transplantation may becomecolonized with nosocomial, antimicrobial-resistantorganisms, including methicillin-resistant Staphy-lococcus aureus,vancomycin-resistant enterococcus,fluconazole-resistant candida species, Clostridiumdifficile,and antimicrobial-resistant gram-negativebacteria or aspergillus species.35-43After trans-plantation, these pathogens may cause pneumo-nia or may infect hematomas, ascitic fluid, wounds,and catheters.

Community Infections

Exposures that are relatively benign in a normalhost may lead to major infection after transplan-tation. Common microorganisms include thosenoted above, pathogens in soil such as aspergillus

or nocardiaspecies, C. neoformansin birds, and re-spiratory viruses with subsequent bacterial or fun-gal superinfection.

Net State of Immunosuppression

and Monitoring of Immune Function

The net state of immunosuppression refers to allfactors that contribute to the patients risk of in-fection (Fig. 3). The main determinants of risk arethe dose, duration, and sequence of immunosup-

pressive therapies. Drug levels are used to guideimmunotherapy. This approach often results intoxic effects from drugs (e.g., renal injury from cal-cineurin inhibitors) and infection or graft rejec-tion. These relatively crude measures of immu-nosuppression may eventually be supplanted byassays that allow individualization (minimization)of immunosuppression. Some nonspecific andpathogen-specific measures of cell-mediated im-mune function are available.44Unique patternsof gene and protein expression have been observedwith specific infections and with graft rejection.In the future, new assays based on these patterns

may guide the use of immunosuppression to pre-vent rejection and infection or to provide care forpatients with active infection (Fig. 3).

PREVENTION OF INFECTION

Antimicrobial prophylaxis has dramatically alteredthe incidence and severity of post-transplantationinfections (Fig. 4). Three general preventive strat-egies are used: vaccination, universal prophylaxis,

Figure 3 (facing page).Dynamic Assessment of the Riskof Infection after Transplantation.

The risk of infection is a function of the net state of im-munodeficiency. The presence of specific, common in-

fections can be detected by means of quantitative as-

says measuring nucleic acids or proteins derived frompotential pathogens. Multiple simultaneous quantita-

tive (multiplex) assays can be performed diagnosticallyin a single sample with the use of polymerase chain re-

action. Each line represents a single patients sample(Panel A). The presence of specific infections can be

assessed with the use of genomic arrays measuring theup-regulation or down-regulation of host genes during

infection (Panel B, courtesy of Shaf Keshavjee, M.D.,University of Toronto). Lytic and latent epitopes are vi-

ral antigens presented in either the lytic or latent phaseof EpsteinBarr virus (EBV) infection. The transplant

recipients cellular immune response to specific patho-

gens such as EBV can be determined by measurementsof cellular activation by pathogen-specific antigens

(Panel C, courtesy of Christian Brander, MassachusettsGeneral Hospital). The factors contributing to the de-

gree of immunologic impairment and standard assaysthat assess the patients risk of infection will be sup-

plemented in the future by new quantitative measuresof allograft- and pathogen-specific immune function

and the risk of infection (Panel D). RFU denotes rela-tive fluorescence units, CMV cytomegalovirus, BK poly-

omavirus type BK, HHV-6 human herpesvirus 6, HHV-

7 human herpesvirus 7, PBMCs peripheral-bloodmononuclear cells, SLE systemic lupus erythematosus,

HCV hepatitis C virus, and HBV hepatitis B virus.





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Lo

g10

Area(RFU) 6

5

3

4

2

Log10

Area(RFU) 6

5

3

4

2

15 25 35 4520 30 40

15 25 35 4520 30 40

15 25 35 4520 30 40

15 25 35 4520 30 40

Cycle No.

CMV BK

6

5

3

4

2

6

5

3

4

2

Cycle No.

Cycle No. Cycle No.

B

D

C

A

P=0.28 P=0.003

1000

EBV-Spe

cificCells(per106PBMCs)

800

600

400

100

200

0

1000

800

600

400

100

200

0

Lytic Epitopes

l

Latent Epitopes

HHV-6 HHV-7

Cases Controls Cases Controls

Net State of Immunodeficiency

Immunosuppressive therapyPrevious therapies (e.g., chemotherapy,

antimicrobial agents)Mucocutaneous-barrier integrity

(for catheters, drains)Neutropenia, lymphopeniaUnderlying immunodeficiencies

(e.g., hypogammaglobulinemia, SLE)Metabolic conditions (e.g., uremia,

malnutrition, diabetes, cirrhosis)Viral infection (e.g., CMV, HCV, HBV)

Standard Assays

Serologic tests for seroconversionMicrobiologic cultures and suscepti-

bility testingQuantitative viral-load assay and

antigen testsHistopathological tests and immuno-

staining

Advanced Assays

Multiplex microbiologic assaysMolecular antimicrobial-susceptibility testingNonspecific immunoassays for degree of im-

munosuppressionIntracellular ATPBiomarkers of rejection (cytokines)Proteomics

Assays of pathogen-specific immunityCytotoxic lymphocytesMixed lymphocyte culturesHLA-linked tetramersIntracellular cytokine stainingEnzyme-linked immunospot assayInterferon-release assays

Genomics (patterns of gene expression) in:ImmunosuppressionInfectionRejectionDrug metabolism





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and preemptive therapy.46The need for immu-nization against measles, mumps, rubella, diph-theria, pertussis, tetanus, HBV infection, polio-myelitis, varicella, influenza, and pneumococcalpneumonia should be evaluated before transplan-tation.47Vaccination is generally less effective dur-

ing immunosuppression.11

Pneumococcal vaccineis recommended every 3 to 5 years, and influenzavaccine is recommended annually. Other vaccinesare appropriate for patients who travel to regionswhere certain illnesses are endemic. Live vaccinesare generally contraindicated after transplanta-tion, since they may cause disseminated infectionin immunocompromised hosts. The immunologicprotection provided by vaccines may be limited inextent or duration.48,49

Promoting lifestyle changes after transplanta-tion may help limit exposures to some potentialpathogens. Attention to hand washing should beobserved after food preparation, gardening, andcontact with feces or secretions. Transplant re-cipients should avoid close contact with people

who have respiratory illnesses, and they shouldavoid environments such as construction sites,which have known pathogens. Dietary advicemight include avoidance of well water and lakewater (which may contain cryptosporidium orgiardia species), undercooked meats, unwashedfruits and vegetables, and unpasteurized dairyproducts (which may contain Escherichia coli or Liste-ria monocytogenes).

Routine surgical prophylaxis varies, depending

l

Transplantation

Donor-DerivedInfection

Recipient-DerivedInfection

Dynamic assessment of risk of infection

Common Infections in Solid-Organ Transplant Recipients

6 Months16 Months

Nosocomial, technical(donor or recipient)

Infection with antimicrobial-resistant species:

MRSAVRECandida species (non-albicans)

AspirationCatheter infectionWound infectionAnastomotic leaks and ischemiaClostridium difficile colitis

Donor-derived infection(uncommon):

HSV, LCMV, rhabdovirus

(rabies), West Nile virus,HIV,Trypanosoma cruzi

Recipient-derived infection(colonization):

Aspergillus, pseudomonas

With PCP and antiviral (CMV,HBV)prophylaxis:

Polyomavirus BK infection, nephropathyC. difficilecolitisHCV infectionAdenovirus infection, influenzaCryptococcus neoformans infectionMycobacterium tuberculosis infection

Anastomotic complications

Without prophylaxis:PneumocystisInfection with herpesviruses (HSV,

VZV, CMV, EBV)

HBV infectionInfection with listeria, nocardia, toxo-

plasma, strongyloides, leishmania,T. cruzi

Community-acquired pneumonia,urinary tract infection

Infection with aspergillus, atypicalmolds, mucor species

Infection with nocardia, rhodo-coccus species

Late viral infections:CMV infection (colitis and

retinitis)Hepatitis (HBV, HCV)HSV encephalitisCommunity-acquired (SARS,

West Nile virus infection)JC polyomavirus infection (PML)

Skin cancer, lymphoma (PTLD)

Activation of latent infection(relapsed, residual, opportunistic)

Community-acquired

Figure 4.Changing Timeline of Infection after Organ Transplantation.

Infections occur in a generally predictable pattern after solid-organ transplantation. The development of infection is delayed by prophy-

laxis and accelerated by intensified immunosuppression, drug toxic effects that may cause leukopenia, or immunomodulatory viral in-

fections such as infection with cytomegalovirus (CMV), hepatitis C virus (HCV), or EpsteinBarr virus (EBV). At the time of transplanta-tion, a patients short-term and long-term risk of infection can be stratified according to donor and recipient screening, the technical

outcome of surgery, and the intensity of immunosuppression required to prevent graft rejection. Subsequently, an ongoing assessmentof the risk of infection is used to adjust both prophylaxis and immunosuppressive therapy. MRSA denotes methicillin-resistant Staphylo-

coccus aureus, VRE vancomycin-resistant Enterococcus faecalis,HSV herpes simplex virus, LCMV lymphocytic choriomeningitis virus, HIVhuman immunodeficiency virus, PCP Pneumocystis cariniipneumonia, HBV hepatitis B virus, VZV varicellazoster virus, SARS severe

acute respiratory syndrome, PML progressive multifocal leukoencephalopathy, and PTLD post-transplantation lymphoproliferative disor-der. Modified from Fishman and Rubin1and Rubin et al.45





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on the organ transplanted and local epidemiologicfactors. For liver transplantation, antimicrobialagents that provide coverage for skin flora, bili-ary enterococcus species, anaerobes, and Entero-bacteriaceae are routinely prescribed. For lungtransplantation, prophylaxis is aimed at gram-negative bacteria, molds, and geographic fungi

(e.g., histoplasma). Prophylaxis may be adjustedaccording to known colonization patterns withpseudomonas, methicillin-resistant S. aureus, van-comycin-resistant enterococcus, or fungi.

Antifungal prophylaxis is based on both riskand epidemiologic factors. Most invasive fungalinfections in transplant recipients are due to non-albicans candida and aspergillus species. Thegreatest risks associated with early fungal infec-tions include aspergillus at the tracheal anasto-mosis after lung transplantation and candidaspecies after pancreas or liver transplantation. In-

vasive fungal infections are most common in liverrecipients requiring admission to the intensive careunit, surgical re-exploration or retransplantation,or transfusion of large amounts of blood prod-ucts and in liver recipients with metabolic dys-function (involving the liver allograft, kidney, ordiabetes), respiratory failure, cytomegalovirus in-fection, or HCV infection. The risk is increasedafter broad-spectrum antimicrobial therapy.50-56Prophylaxis should be considered in such high-risk hosts.

Most transplantation centers use trimetho-primsulfamethoxazole prophylaxis for as little as3 months or for as long as a lifetime to preventpneumocystis pneumonia as well as infectionswith Toxoplasmagondii, Isospora belli, Cyclospora cay-etanensis, many nocardia and listeria species, andcommon urinary, respiratory, and gastrointestinalpathogens. Low-dose trimethoprimsulfamethox-azole is well tolerated and should be used unlessthere is evidence that the patient has an allergy orinterstitial nephritis. Alternative agents for pro-phylaxis against pneumocystis include dapsone,

atovaquone, and pentamidine, but they are lesseffective than trimethoprimsulfamethoxazoleand lack the breadth of protection.57

The prevention of post-transplantation cyto-megalovirus and other herpesvirus infections andthe availability of oral antiviral agents have revo-lutionized post-transplantation care.58Two pre-ventive strategies have emerged. With universalprophylaxis, antimicrobial therapy is provided toall at-risk patients for a defined period. In con-

trast, with preemptive therapy, sensitive quantita-tive assays (e.g., molecular assays and antigen de-tection) are used to monitor patients at predefinedintervals in order to detect infection before symp-toms arise. Depending on the potential pathogenand institutional protocols, a positive assay trig-gers the initiation of antimicrobial therapy, a re-

duction in the intensity of immunosuppression,intensified monitoring, or all of these steps. Pre-emptive therapy incurs extra costs for monitoringand coordination of outpatient care, but it avoidsthe costs and toxic effects of prophylactic anti-viral therapy.

The crude risk of specific infections has tradi-tionally been defined by means of serologic test-ing; the risk is lower in a seropositive host orhigher in a seronegative recipient of an organ froma seropositive donor. A variety of newer techniques(e.g., HLA-linked tetramer binding and intracel-

lular cytokine staining) measure pathogen-specificimmunity and provide insight into the risk of spe-cific infections and the ability of the host to clearinvasive disease (Fig. 3).59

CHANGING THE patt ern

OF INFECTION

Early in the evolution of solid-organ transplan-tation, there was a limited number of availableimmunosuppressive agents, and antirejection pro-tocols (i.e., use of corticosteroids, calcineurininhibitors, and azathioprine) were relatively stan-dardized. As a result, the timeline for the develop-ment of common post-transplantation infectionswas relatively predictable.1,45Changes in immu-nosuppressive regimens, routine prophylaxis, andimproved graft survival have altered the originalpattern (Fig. 4). Corticosteroid-sparing regimensand antipneumocystis prophylaxis have madepneumocystis pneumonia less common. Herpes-virus infections are uncommon while patients arereceiving antiviral prophylaxis. Newer immuno-

suppressive approaches, including the use of si-rolimus, mycophenylate mofetil, T-cell and B-celldepletion, and costimulatory blockade, have largelyreplaced high-dose corticosteroids and azathio-prine.

With changes in typical immunosuppression,new patterns of infection have emerged. Sirolimus-based regimens have been associated with idio-syncratic noninfectious pneumonitis, which iseasily confused with pneumocystis pneumonia or





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viral pneumonia.60T-lymphocytedepleting anti-bodies commonly used for initial or inductiontherapy are associated with increased viral acti-vation notably, activation of cytomegalovirus,EBV, and HIV.28,61,62Cellular depletion after in-duction therapy often persists beyond the periodof antimicrobial prophylaxis, resulting in late in-

fections with viruses such as cytomegalovirus andJC polyomavirus as well as fungal infections andmalignant conditions after transplantation. Infec-tions that occur after the usual period or that areunusually severe suggest excessive immunosup-pression or exposure. The timeline for a givenpatient is reset with each episode of rejection orintensif ication of immunosuppression (e.g., withbolus corticosteroids), with an increased risk ofopportunistic infections.

early post-transplantation period

Opportunistic infections are generally absent dur-ing the first month after transplantation, since thefull effect of immunosuppression is not yet pres-ent. Infections such as viremia and candidemia inthis period are generally donor-derived or recipi-ent-derived, or they are associated with technicalcomplications of surgery (Fig. 1B). Therapy mustbe guided by antimicrobial-susceptibility data,making microbiologic analysis of aspirates or bi-opsy specimens essential. C. difficilecolitis is com-mon in this setting. Early graft injuries (e.g., ische-mia of bile ducts or pulmonary reperfusion injury)may later become foci for liver or lung abscesses(Fig. 1B). Unexplained early signs of infection, suchas hepatitis, pneumonitis, encephalitis, rash, andleukopenia, may be donor-derived.

intermediate post-transplantation period

Viral pathogens and allograft rejection are respon-sible for the majority of febrile episodes that oc-cur during the period from 1 to 6 months aftertransplantation. Trimethoprimsulfamethoxazoleprophylaxis generally prevents most urinary tract

infections and opportunistic infections such aspneumocystis pneumonia, L. monocytogenes infec-tion, T. gondiiinfection, and infection with sulfa-susceptible nocardia species. Infection due to en-demic fungi, aspergillus, cryptococcus, T. cruzi,orstrongyloides may occur. Herpesvirus infectionsare uncommon with antiviral prophylaxis. How-ever, other viral pathogens, including polyomavi-rus BK, adenovirus, and recurrent HCV, haveemerged. Given the array of potential pathogens,

in the future, multiplex quantitative assays will beused to monitor acute infections (Fig. 3).

late post-transplantation period

The risk of infection diminishes 6 months aftertransplantation, since immunosuppressive thera-py is usually tapered in recipients who have satis-

factory allograft function. However, transplantrecipients have a persistently increased risk of in-fection due to community-acquired pathogens (Fig.4). In some patients, chronic viral infections maycause allograft injury (e.g., cirrhosis from HCV in-fection in liver-transplant recipients, bronchiolitisobliterans in lung-transplant recipients, acceleratedvasculopathy in heart-transplant recipients withcytomegalovirus infection) or a malignant condi-tion such as post-transplantation lymphoprolif-erative disorder (PTLD) or skin or anogenital can-cers (Fig. 1). Recurrent infection may develop in

some patients despite minimization of their im-munosuppression. These patients are at increasedrisk for opportunistic infection with listeria ornocardia species, invasive fungal pathogens suchas zygomycetes and dematiaceous molds, and un-usual organisms (e.g., rhodococcus species). Min-imal signs of infection merit careful evaluationin such high-risk patients; they may benefit fromlifetime trimethoprimsulfamethoxazole or anti-fungal prophylaxis. Such long-term prophylaxiscarries some risk of the development of microbialresistance to the prophylactic agents and possiblefuture drug interactions.

Common Infections

in Tr ansplantation

Early and specific microbiologic diagnosis is es-sential in the immunocompromised host, oftennecessitating invasive diagnostic techniques. Re-duction in the intensity of immunosuppression maybe useful until the acute process is controlled, al-though this approach risks allograft rejection. Re-

versal of immune deficits such as neutropenia orhypogammaglobulinemia may be achieved by theadministration of colony-stimulating factors or in-travenous immune globulin. Viral coinfection mustbe recognized and treated.

Cytomegalovirus infection

Cytomegalovirus infection may cause both inva-sive disease, or direct effects, and a variety ofsecondary immune phenomena (Fig. 5) in trans-





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plant recipients.1,63,64Invasive disease generally oc-curs during the f irst year after completion of pro-phylaxis and is manifested most often as fever andneutropenia; some patients have lymphadenopa-thy, hepatitis, thrombocytopenia, pneumonitis,gastrointestinal invasion (with diffuse colitis, gas-tritis, ulcers, and bleeding), pancreatitis, chorio-retinitis (which is often late), or meningoenceph-alitis (which is uncommon). Cytomegalovirusinfection is also associated with an overall in-crease in the risk of additional infections, includ-

ing infections with other viruses and EBV-associ-ated PTLD. In addition, cytomegalovirus infectionmay contribute to vasculopathy in heart-allograftrecipients and to the bronchiolitis obliterans syn-drome in lung-allograft recipients.

Epidemiology

Primary infection, reactivation, or viral superinfec-tion with cytomegalovirus may develop in trans-plant recipients. Serologic assays are useful in de-

termining a patients risk of infection, but they aregenerally of little use in the diagnosis of acute in-fections. Seropositivity is also associated with thepresence of cellular immunity.65Primary infection,the most severe form of disease, occurs when se-ronegative recipients who have not previously re-ceived immunologic therapy receive allografts fromlatently infected, seropositive donors (i.e., D+/Rcombinations). Without antiviral prophylaxis, mostnewly infected patients have asymptomatic vire-mia, although invasive disease develops in a sub-

group of patients. Seroconversion in seronegativetransplant recipients who have received allograftsfrom seropositive donors generally occurs duringthe f irst year after transplantation; however, 25%of recipients do not undergo seroconversion andmay benefit from prolonged prophylaxis.66

Prevention

Both universal antiviral prophylaxis and preemp-tive antiviral therapy reduce the risk of invasive

Active CMV infection(viremia and tissue infection)

Latent CMV infectionAntilymphocyte globulin, fever,

TNF-, infection, high-doseimmunosuppression

Atheroclerosis, bronchiolitis obliterans,vanishing bile duct syndome

CMV diseaseDirect effects

CMV syndrome

(Fever, weakness,myalgia, arthralgia,myelosuppression)

End-organ disease

(Nephritis, hepatitis,carditis, colitis,pneumonitis,

retinitis, encepha-litis)

Allograft

injury

Allograft

rejection

EBV-associated

PTLD

Opportunistic

infection

Cellular effects:MHC, cytokine expression

Indirect effects

l

Figure 5.Cytomegalovirus Infection.

Cytomegalovirus (CMV) causes both invasive disease (direct effects) and immunologic phenomena (indirect effects), including

graft rejection and a predisposition to opportunistic infections. CMV may be activated by febrile illness (through the release of tumornecrosis factor [TNF-]), by depletion of antilymphocyte antibodies, or during treatment for graft rejection. MHC denotes major histo-

compatibility complex, EBV EpsteinBarr virus, and PTLD post-transplantation lymphoproliferative disorder.





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cytomegalovirus infection.67-69Universal antiviralprophylaxis also helps to prevent other viral infec-tions such as herpes simplex virus, varicellazos-ter virus, EBV, and human herpesvirus 6 (HHV-6)and human herpesvirus 7 (HHV-7) infections. Uni-versal antiviral prophylaxis also reduces the riskof fungal infections such as pneumocystis, candi-

da, and aspergillus, complications of viral infec-tions such as HHV-6, HHV-7, accelerated HCV andPTLD, and bacterial infections (Fig. 4).54,70-73Inaddition, prevention of cytomegalovirus infectionmay reduce episodes of both early and late acuterejection in renal-transplant recipients, cardiacvasculopathy in heart-transplant recipients, andthe bronchiolitis obliterans syndrome in lung-transplant recipients (Fig. 5).74-79The relationshipbetween acute rejection and cytomegalovirus dis-ease has not been shown in all studies.80

Although optimal regimens remain undefined,

most centers provide anticytomegalovirus pro-phylaxis for the first 3 to 6 months after trans-plantation, using valacyclovir, high-dose acyclovir,ganciclovir, valganciclovir, or, less commonly, cy-tomegalovirus hyperimmune globulins.1,81Sever-al situations require special consideration. First,the use of induction therapy with depleting anti-lymphocyte antibodies for seropositive donors orseropositive recipients increases the risk of cyto-megalovirus reactivation and generally merits ex-tended prophylaxis followed by monitoring foractive infection. Second, although recipients ofheart and lung transplants who are seropositive orwho receive transplants from seropositive donorsgenerally receive prophylaxis for at least 6 to 12months, some may benefit from longer coursesof antiviral prophylaxis if they lack evidence ofprotective immunity (i.e., if they have not under-gone seroconversion), if they have persistent vi-ral secretion (e.g., in sputum), or if they requirea greater intensity of sustained immunosuppres-sion. However, patients receiving longer coursesof ganciclovir or valganciclovir may incur marrow

suppression from these agents. Some patientstreated for active cytomegalovirus infection mayhave a relapse without an additional period of pro-phylaxis after treatment.

Ganciclovir resistance in patients with cyto-megalovirus infection is uncommon, but whenpresent, it is most often due to mutations in thecytomegalovirus UL97gene (a viral protein kinasethat phosphorylates the drug) or the UL54gene(cytomegalovirus DNA polymerase). Such resis-

tance may present as slowly responsive or relaps-ing infection, most commonly in patients whowere seronegative for cytomegalovirus at the timeof transplantation and received allografts fromseropositive donors, in patients who receive in-adequate or prolonged doses of oral ganciclovir orvalganciclovir, especially during active infection,

or in patients who undergo intensified immuno-suppression. Recipients of lung transplants arealso at relatively high risk for resistance to gan-ciclovir. Ganciclovir resistance has been ob-served with both universal and preemptive ap-proaches.82-84

Diagnosis and Therapy

Quantitative diagnostic assays for cytomegalovi-rus are essential for management of infection.These include molecular assays (polymerase-chain-reaction [PCR] and other amplification assays) and

antigen-detect ion (pp65 antigenemia) assays. Inpatients with neurologic manifestations of cyto-megalovirus infection (including chorioretinitis)and gastrointestinal disease (colitis and gastritis,often with ulceration), blood-based cytomegalo-virus assays may be negative. Thus, invasive pro-cedures such as colonoscopy with biopsy or lum-bar puncture may be necessary. Invasive diseaseand the cytomegalovirus syndrome (which is man-ifested as fever and leukopenia) warrant therapy,generally with intravenous ganciclovir. Results ofstudies of oral valganciclovir therapy for cytomeg-alovirus disease are encouraging.85,86Intravenousganciclovir is currently preferred for the initiationof therapy for gastrointestinal disease. Documen-tation of cure in patients with gastrointestinal cy-tomegalovirus infection includes negative resultsof microbiologic assays and healing of ulcers andcolitis on endoscopic evaluation. Relapse, whichis common with inadequate therapy, carries therisk of the emergence of resistance to antiviralagents.

EpsteinBarr Virus and Post-TransplantationLymphoproliferative Disorder

PTLD, a heterogeneous group of lymphoprolifera-tive disorders, occurs in 3 to 10% of adults whoare solid-organ transplant recipients; it is associ-ated with a reported mortality of 40 to 60%.87-89PTLD accounts for more than half of post-trans-plantation malignant conditions in pediatric solid-organtransplant recipients. It varies from abenign polyclonal, B-cell, infectious mononucle-





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osis-like syndrome to malignant, monoclonal lym-phoma.90-92Risk factors for PTLD include primaryEBV infection after transplantation in seronega-tive recipients of allografts from seropositive do-nors, allograft rejection, exposure to antilympho-cyte antiserum, and cytomegalovirus coinfection.PTLD occurring in the first year after transplan-

tation is usually CD20+ and B cell in origin. Incontrast, later disease may be EBV-negative andT cell, natural killer cell, or null cell in origin,generally with a worse prognosis.

The role of EBV in nonB-cell PTLD is lessclear. The clinical presentation of EBV-associatedPTLD varies (Table 1). PTLD is generally extra-nodal, often with mass lesions in proximity to thetransplanted organ. Both B-cell and T-cell PTLDmay infiltrate allografts and may be confused withallograft rejection or other viral processes. Oc-casionally, patients with PTLD have evidence of

remittingrelapsing EBV infection, which reflectsan interplay between antiviral immunity and im-munosuppression.

Quantitative EBV viral-load testing, flow cytom-etry, analysis of immunoglobulin gene rearrange-ments, and histologic analysis with staining forEBV-derived RNA are helpful in guiding the diag-nosis and management of PTLD.93,94In the poly-clonal form, particularly in children, a reductionin immunosuppression may lead to regression ofthe PTLD but poses the risk of allograft rejection.The progression of disease requires alternative ap-proaches that may include the administration ofchemotherapy, irradiation (for central nervous sys-tem disease), and treatment with anti-CD20 an-tibodies. Adoptive immunotherapy (T-cell trans-fer) is under investigation as a treatment strategyfor PTLD. Further data are needed to define a pos-sible protective role of sirolimus against PTLD.93

Polyomaviruses BK and JC

Polyomaviruses have been identified in transplantrecipients in association with nephropathy (e.g.,

polyomavirus BKassociated nephropathy) andureteral obstruction, and the JC virus has beenassociated with progressive multifocal leukoen-cephalopathy.95-99No effective antiviral therapyexists for polyomaviruses. Detection of BK virusnucleic acids in blood and urine has been usefulfor assessing responses to therapy in patients withpolyomavirus-associated nephropathy. Therapy re-quires a reduction in immunosuppression. Experi-mental therapies include cidofovir, an inhibitor of

viral DNA synthesis that has considerable neph-rotoxicity; leflunomide, an immunosuppressiveagent with antiviral properties against BK virusand cytomegalovirus; and intravenous immuneglobulin. None of these agents have been shownto have efficacy in the treatment of polyomavirusesor have been subjected to rigorous controlled tri-

als. In patients with renal failure due to polyoma-virus-associated nephropathy, successful retrans-plantation has been achieved after reversal ofimmunosuppression for a sufficient time to allowthe emergence of antiviral immunity.98,99

Central Nervous System Infection

Central nervous system infection in transplantrecipients is a medical emergency. The broad spec-trum of causative organisms includes listeria, her-pes simplex virus, JC virus, and C. neoformans. Em-pirical therapy must be initiated while the resultsof imaging studies (preferably magnetic resonanceimaging), lumbar puncture (including studies suchas PCR for detection of herpes simplex virus andcryptococcal antigen), blood cultures, and othercultures are pending. Included in the differentialdiagnosis are noninfectious causes such as toxiceffects of calcineurin inhibitors and lymphoma.

Pneumonitis and Pneumocystis Infection

Pneumocystis pneumonia remains common in theabsence of specif ic prophylaxis.56,100Pneumocys-

tis pneumonia should be considered in patients inwhom marked hypoxemia, dyspnea, and cough de-velop in spite of a paucity of physical or radiologicfindings. No radiographic patterns are pathogno-monic in the immunocompromised host. Com-puted tomographic imaging is useful to definethe extent of disease and to direct invasive tech-niques for microbiologic sampling. Noninfectiousprocesses may contribute to the pathogenesis ofpneumonitis; these processses include the toxic

Table 1.Clinical Presentations of Post-Transplantation LymphoproliferativeDisorder Associated with EpsteinBarr Virus.

Unexplained fever (fever of unknown origin)

Mononucleosis-like syndrome (fever, malaise, pharyngitis, tonsillitis)

Gastrointestinal bleeding, obstruction, or perforation

Abdominal-mass lesions

Infiltrative disease of the allograft

Hepatocellular or pancreatic dysfunction

Central nervous system disease





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effects of sirolimus, which may be obscured bycoinfection.60

Conclusions

The study of infectious diseases associated withtransplantation focuses on the prevention of infec-

tion in transplant recipients. The interaction of in-fection and immunosuppression is the central con-cern. The induction of immunologic tolerance sothat exogenous immunosuppression is avoided intransplant recipients, might, if successful, reducethe risk of infection after transplantation. Howev-er, two caveats would remain. First, exposures toinfections subsequent to the development of toler-ance might abrogate tolerance and induce allograftrejection.101,102Second, the induction of toleranceto an allograft might induce immunologic unre-

sponsiveness to latent organisms in that organ.Techniques currently under development, such

as more sensitive microbiologic assays, immuno-assays, and genomic and proteomic markers, mayprovide the potential for individualized immu-nosuppression and prophylactic strategies (Fig.3).103,104 Such assays may ultimately permit a

more dynamic assessment of the immune statusof transplant recipients over time, allowing titra-tion of immunosuppression and reducing deathsfrom infection and malignant conditions.105

Dr. Fishman reports serving as a consultant to Gilead Phar-maceuticals, Merck, Astellas Pharma, Biogen Idec, HoffmannLa Roche, Vi roPharma, Pfizer, and Schering-Ploughbeing; be-ing a member of the scientific advisory board and receivingconsulting fees from Primera; receiving grant support from As-tellas Pharma; and holding two international patents (US5442050, awarded in 1995, and US6190861, awarded in 1997)owned by Massachusetts General Hospital. No other potentialconflict of interest relevant to this article was reported.

References

Fishman JA, Rubin RH. Infection inorgan-transplant recipients. N Engl J Med1998;338:1741-51.

Halloran PF. Immunosuppressive drugsfor kidney transplantation. N Engl J Med2004;351:2715-29.

Wilck M, Fishman J. The challengesof infection in transplantation: donor-derived infections. Curr Opin Organ Trans-plant 2005;10:301-6.

Angelis M, Cooper JT, Freeman RB.Impact of donor infections on outcome oforthotopic liver transplantation. LiverTranspl 2003;9:451-62.

Delmonico FL. Cadaver donor screen-ing for infectious agents in solid organtransplantation. Clin Infect Dis 2000;31:781-6.

Freeman RB, Giatras I, Falagas ME, etal. Outcome of transplantation of organsprocured from bacteremic donors. Trans-plantation 1999;68:1107-11.

Fischer SA, Graham MB, KuehnertMJ, et al. Transmission of lymphocyticchoriomeningitis virus by organ trans-plantation. N Engl J Med 2006;354:2235-49.

Iwamoto M, Jernigan DB, Guasch A, etal. Transmission of West Nile virus froman organ donor to four transplant recipi-ents. N Engl J Med 2003;348:2196-203.

Srinivasan A, Burton EC, Kuehnert MJ,et al. Transmission of rabies virus from anorgan donor to four transplant recipients.N Engl J Med 2005;352:1103-11.

Chagas disease after organ transplan-tation United States, 200MMWR MorbMortal Wkly Rep 2002;51:210-2.

Preiksaitis JK, Green M, Avery RK.Guidelines for the prevention and manag-ment of infectious complications of solidorgan transplantation. Am J Transplant2004;4:Suppl 10:51-8.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

DAlbuquerque LA, Gonzalez AM,Filho HL, et al. Liver transplantat ion fromdeceased donors serologically positive forChagas disease. Am J Transplant 2007;7:680-4.

Everhart JE, Wei Y, Eng H, et al.Recurrent and new hepatitis C virus in-fection after liver transplantation. Hepa-tology 1999;29:1220-6. [Erratum, Hepa-tology 1999;30:1110.]

Wright TL, Donegan E, Hsu HH, et al.Recurrent and acquired hepatitis C viralinfection in liver transplant recipients.Gastroenterology 1992;103:317-22.

Chazouil leres O, Wright TL. HepatitisC and liver transplantation. J Gastroen-terol Hepatol 1995;10:471-80.

Fishman JA, Rubin RH, Koziel MJ,Periera BJ. Hepatitis C virus and organtransplantat ion. Transplantat ion 1996;62:147-54.

Seehofer D, Berg T. Prevention ofhepatitis B recurrence after liver trans-plantation. Transplantation 2005;80:Suppl 1:S120-S124.

Trautwein C. Mechanisms of hepatitisB virus graft reinfection and graft dam-age after liver transplantation. J Hepatol2004;41:362-9.

Basset D, Faraut F, Marty P, et al. Vis-ceral leishmaniasis in organ transplantrecipients: 11 new cases and a review of theliterature. Microbes Infect 2005;7:1370-5.

Boletis JN, Pefanis A, Stathakis C, He-lioti H, Kostakis A, Giamarellou H. Visceralleishmaniasis in renal transplant recipients:successful treatment with liposomal am-photericin B (AmBisome). Clin Infect Dis1999;28:1308-9.

Frapier JM, Abraham B, Dereure J, Al-bat B. Fatal visceral leishmaniasis in aheart transplant recipient. J Heart LungTransplant 2001;20:912-3.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

Gmez Campder F, Berenguer J,Anaya F, Rodriguez M, Valderrbano F.Visceral leishmaniasis in a renal trans-plant recipient: short review and therapyalternat ive. Am J Nephrol 1998;18:171.

Portols J, Prats D, Torralbo A, Her-rero JA, Torrente J, Barrientos A. Visceralleishmaniasis: a cause of opportunisticinfection in renal transplant patients inendemic areas. Transplantation 1994;57:1677-9.

Scoggin CH, Call NB. Acute respira-tory failure due to disseminated strongy-loidiasis in a renal transplant recipient.

Ann Intern Med 1977;87:456-8.Palau LA, Pankey GA. Strongyloides

hyperinfection in a renal transplant recipi-ent receiving cyclosporine: possible Stron-gyloides stercoralis transmission by kidneytransplant. Am J Trop Med Hyg 1997;57:413-5.

Fishman JA. Transplantation for pa-tients infected with human immunodefi-ciency virus: no longer experimental butnot yet routine. J Infect Dis 2003;188:1405-11.

Roland ME, Stock PG. Review of solid-organ transplantation in HIV-infected pa-tients. Transplantation 2003;75:425-9.

Fung J, Eghtesad B, Patel-Tom K, De-Vera M, Chapman H, Ragni M. Liver trans-plantation in patients with HIV infection.Liver Transpl 2004;10:Suppl 2:S39-S53.

Moreno S, Fortn J, Quereda C, et al.Liver transplantation in HIV-infected re-cipients. Liver Transpl 2005;11:76-81.

Lake JR. Immunosuppression and out-comes of patients transplanted for hepati-tis C. J Hepatol 2006;44:627-9.

Pastore M, Willems M, Cornu C, et al.Role of hepatitis C virus in chronic liver dis-ease occurring after orthotopic liver trans-plantation. Arch Dis Child 1995;72:403-7.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.





13/14

Medical Progress


Curry MP. Hepatitis B and hepatitis Cviruses in liver transplantation. Transplan-tation 2004;78:955-63.

Muoz SJ. Use of hepatitis B core an-tibody-positive donors for liver transplan-tation. Liver Transpl 2002;8:Suppl 1:S82-S87.

Lake JR. The role of immunosuppres-sion in recurrence of hepatitis C. Liver

Transpl 2003;9:S63-S66.Herrero IA, Issa NC, Patel R. Nosoco-mial spread of linezolid-resistant, vanco-mycin-resistant Enterococcus faecium. N EnglJ Med 2002;346:867-9.

Patel R, Rouse MS, Piper KE, Steckel-berg JM. Linezolid therapy of vancomycin-resistant Enterococcus faecium experi-mental endocarditis. Antimicrob AgentsChemother 2001;45:621-3.

Fishman JA. Vancomycin-resistant En-terococcus in liver transplantation: whathave we left behind? Transpl Infect Dis2003;5:109-11.

Keven K, Basu A, Re L, et al. Clos-tridium difficile colitis in patients after

kidney and pancreas-kidney transplanta-tion. Transpl Infect Dis 2004;6:10-4.

West M, Pirenne J, Chavers B, et al.Clostridium difficile colitis after kidneyand kidney-pancreas transplantation. ClinTransplant 1999;13:318-23.

Muder RR, Stout JE, Yu VL. Nosoco-mial Legionella micdadei infection intransplant patients: fortune favors the pre-pared mind. Am J Med 2000;108:346-8.

Lo Presti F, Riffard S, Vandenesch F,et al. The first clinical isolate of Legio-nella parisiensis, from a liver transplantpatient with pneumonia. J Clin Microbiol1997;35:1706-9.

Harbarth S, Pittet D, Romand J. Fatal

concomitant nosocomial Legionnairesdisease and cytomegalovirus pneumoni-tis after cardiac transplantation. IntensiveCare Med 1996;22:1133-4.

Bert F, Bellier C, Lassel L, et al. Riskfactors for Staphylococcus aureus infec-tion in liver transplant recipients. LiverTranspl 2005;11:1093-9.

Zeevi A, Britz JA, Bentlejewski CA, etal. Monitoring immune function duringtacrolimus tapering in small bowel trans-plant recipients. Transpl Immunol 2005;15:17-24.

Rubin RH, Wolfson JS, Cosimi AB,Tolkoff-Rubin NE. Infection in the renaltransplant recipient. Am J Med 1981;70:405-11.

Rubin RH. Preemptive therapy in im-munocompromised hosts. N Engl J Med1991;324:1057-9.

Avery RK. Prophylactic strategies beforesolid-organ transplantation. Curr Opin In-fect Dis 2004;17:353-6.

Kotton CN, Fishman JA. Viral infect ionin the renal transplant recipient. J Am SocNephrol 2005;16:1758-74.

Kumar D, Welsh B, Siegal D, HongChen M, Humar A. Immunogenicity of

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

pneumococcal vaccine in renal transplantrecipients three year follow-up of arandomized trial. Am J Transplant 2007;7:633-8.

Pappas PG, Andes D, Schuster M, et al.Invasive fungal infect ions in low-risk livertransplant recipients: a multi-center pro-spective observational study. Am J Trans-plant 2006;6:386-91.

Dummer JS, Lazariashvilli N, BarnesJ, Ninan M, Milstone AP. A survey of anti-fungal management in lung transplanta-tion. J Heart Lung Transplant 2004;23:1376-81.

Husain S, Alexander BD, Munoz P, et al.Opportunistic mycelial fungal infections inorgan transplant recipients: emerging im-portance of non-Aspergillus mycelial fungi.Clin Infect Dis 2003;37:221-9.

Singh N. Fungal infections in the re-cipients of solid organ transplantation.Infect Dis Clin North Am 2003;17:113-34.

George MJ, Snydman DR, Werner BG,et al. The independent role of cytomegalo-virus as a risk factor for invasive fungal

disease in orthotopic liver transplant re-cipients. Am J Med 1997;103:106-13.

Patel R, Portela D, Badley AD, et al.Risk factors of invasive Candida and non-Candida fungal infections after liver trans-plantation. Transplantation 1996;62:926-34.

Karchmer AW, Samore MH, Hadley S,Collins LA, Jenkins RL, Lewis WD. Fun-gal infections complicating orthotopicliver transplantation. Trans Am Clin Cli-matol Assoc 1994;106:38-48.

Rodriguez M, Fishman JA. Preventionof infection due to Pneumocystis spp. inhuman immunodeficiency virus-negativeimmunocompromised patients. Clin Mi-

crobiol Rev 2004;17:770-82.Rubin RH, Kemmerly SA, Conti D, et

al. Prevention of primary cytomegalovi-rus disease in organ transplant recipientswith oral ganciclovir or oral acyclovir pro-phylaxis. Transpl Infect Dis 2000;2:112-7.

Migueles SA, Tilton JC, Connors M.Advances in understanding immunologiccontrol of HIV infection. Curr HIV/AIDSRep 2004;1(1):12-7.

Morelon E, Stern M, Kreis H. Intersti-tial pneumonitis associated with siroli-mus therapy in renal-transplant recipients.N Engl J Med 2000;343:225-6.

Cheeseman SH, Henle W, Rubin RH,et al. Epstein-Barr virus infection in renaltransplant recipients: effects of antithy-mocyte globulin and interferon. Ann In-tern Med 1980;93:39-42.

Schooley RT, Hirsch MS, Colvin RB, etal. Association of herpesvirus infectionswith T-lymphocytesubset alterations, glo-merulopathy, and opportunistic infectionsafter renal transplantation. N Engl J Med1983;308:307-13.

Rubin RH, Cosimi AB, Tolkoff-RubinNE, Russell PS, Hirsch MS. Infectious dis-ease syndromes attributable to cytomega-

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

lovirus and their significance among re-nal transplant recipients. Transplantation1977;24:458-64.

Rubin RH. The indirect effects of cy-tomegalovirus infection on the outcomeof organ transplantation. JAMA 1989;261:3607-9.

Sester M, Grtner BC, Sester U, GirndtM, Mueller-Lantzsch N, Khler H. Is the

cytomegalovirus serologic status alwaysaccurate? A comparative analysis of hu-moral and cellular immunity. Transplan-tation 2003;76:1229-30.

Humar A, Mazzulli T, Moussa G, et al.Clinical utility of cytomegalovirus (CMV)serology testing in high-risk CMV D+/Rtransplant recipients. Am J Transplant2005;5:1065-70.

Kalil AC, Levitsky J, Lyden E, Stoner J,Freifeld AG. Meta-analysis: the efficacy ofstrategies to prevent organ disease by cy-tomegalovirus in solid organ transplantrecipients. Ann Intern Med 2005;143:870-80.

Strippoli GF, Hodson EM, Jones CJ,

Craig JC. Pre-emptive treatment for cyto-megalovirus viraemia to prevent cyto-megalovirus disease in solid organ trans-plant recipients. Cochrane Database SystRev 2006;1:CD005133.

Hodson EM, Jones CA, Webster AC, etal. Antiviral medications to prevent cyto-megalovirus disease and early death in re-cipients of solid-organ transplants: a sys-tematic review of randomised controlledtrials. Lancet 2005;365:2105-15.

Falagas ME, Snydman DR, Griffith J,Werner BG. Exposure to cytomegalovirusfrom the donated organ is a risk factor forbacteremia in orthotopic liver transplantrecipients. Clin Infect Dis 1996;23:468-

74.Wagner JA, Ross H, Hunt S, et al. Pro-

phylactic ganciclovir treatment reducesfungal as well as cytomegalovirus infec-tions after heart transplantation. Trans-plantation 1995;60:1473-7.

Munoz-Price LS, Slifkin M, RuthazerR, et al. The clinical impact of ganciclovirprophylaxis on the occurrence of bactere-mia in orthotopic liver transplant recipi-ents. Clin Infect Dis 2004;39:1293-9.

Razonable RR, Paya CV. Herpesvirusinfections in transplant recipients: cur-rent challenges in the clinical manage-ment of cytomegalovirus and Epstein-Barr virus infections. Herpes 2003;10:60-5.

Zamora MR. Cytomegalovirus and lungtransplantation. Am J Transplant 2004;4:1219-26.

Westall GP, Michaelides A, WilliamsTJ, Snell GI, Kotsimbos TC. Bronchiolitisobliterans syndrome and early human cy-tomegalovirus DNAaemia dynamics afterlung transplantation. Transplantation2003;75:2064-8.

Kirklin JK, Naftel DC, Levine TB, etal. Cytomegalovirus after heart trans-

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.





14/14


Medical Progress

plantation: risk factors for infection anddeath: a multiinstitutional study. J HeartLung Transplant 1994;13:394-404.

Valantine HA, Gao SZ, Menon SG, etal. Impact of prophylactic immediate post-transplant ganciclovir on development oftransplant atherosclerosis: a post hoc anal-ysis of a randomized, placebo-controlledstudy. Circulation 1999;100:61-6.

Kalil RS, Hudson SL, Gaston RS. Deter-minants of cardiovascular mortality afterrenal transplantation: a role for cytomega-lovirus? Am J Transplant 2003;3:79-81.

Humar A, Payne WD, Sutherland DE,Matas AJ. Clinical determinants of multipleacute rejection episodes in kidney trans-plant recipients. Transplantation 2000;69:2357-60.

Gane E, Saliba F, Valdecasas GJ, et al.Randomised trial of efficacy and safety oforal ganciclovir in the prevention of cyto-megalovirus disease in liver-transplantrecipients. Lancet 1997;350:1729-33. [Er-ratum, Lancet 1998;351:454.]

Preiksaitis JK, Brennan DC, Fishman

J, Allen U. Canadian Society of Transplan-tation consensus workshop on cytomega-lovirus management in solid organ trans-plantation final report. Am J Transplant2005;5:218-27. [Erratum, Am J Transplant2005;5:635.]

Kruger RM, Shannon WD, Arens MQ,Lynch JP, Storch GA, Trulock EP. The im-pact of ganciclovir-resistant cytomegalo-virus infection after lung transplantation.Transplantation 1999;68:1272-9.

Mylonakis E, Kallas WM, Fishman JA.Combination antiviral therapy for ganci-clovir-resistant cytomegalovirus infectionin solid-organ transplant recipients. ClinInfect Dis 2002;34:1337-41. [Erratum, Clin

Infect Dis 2006;42:1350.]Boivin G, Goyette N, Gilbert C, Hu-

mar A, Covington E. Clinical impact ofganciclovir-resistant cytomegalovirus in-fections in solid organ transplant pa-tients. Transpl Infect Dis 2005;7:166-70.[Erratum, Transpl Infect Dis 2006;8:58.]

Luan FL, Chopra P, Park J, Norman S,Cibrik D, Ojo A. Efficacy of valganciclovirin the treatment of cytomegalovirus dis-

77.

78.

79.

80.

81.

82.

83.

84.

85.

ease in kidney and pancreas transplant re-cipients. Transplant Proc 2006;38:3673-5.

Humar A, Siegal D, Moussa G, KumarD. A prospective assessment of valganci-clovir for the treatment of cytomegalovi-rus infection and disease in transplantrecipients. J Infect Dis 2005;192:1154-7.

Preiksaitis JK, Keay S. Diagnosis andmanagement of posttransplant lympho-

proliferative disorder in solid-organ trans-plant recipients. Clin Infect Dis 2001;33:Suppl 1:S38-S46.

Dharnidharka VR, Sullivan EK, Sta-blein DM, Tejani AH, Harmon WE. Riskfactors for posttransplant lymphoprolif-erative disorder (PTLD) in pediatric kid-ney transplantat ion: a report of the NorthAmerican Pediatric Renal Transplant Co-operative Study (NAPRTCS). Transplanta-tion 2001;71:1065-8.

Paya CV, Fung JJ, Nalesnik MA, et al.Epstein-Barr virus-induced posttransplantlymphoproliferative disorders: ASTS/ASTPEBV-PTLD Task Force and The Mayo ClinicOrganized International Consensus Devel-

opment Meeting. Transplantation 1999;68:1517-25.

Harris NL, Ferry JA, Swerdlow SH.Posttransplant lymphoproliferative disor-ders: summary of Society for Hematopa-thology Workshop. Semin Diagn Pathol1997;14:8-14.

Newell KA, Alonso EM, WhitingtonPF, et al. Posttransplant lymphopro-liferative disease in pediatric liver trans-plantation: interplay between primaryEpstein-Barr virus infection and immu-nosuppression. Transplantation 1996;62:370-5.

Nalesnik MA, Jaffe R, Starzl TE, et al.The pathology of posttransplant lympho-

proliferative disorders occurring in thesetting of cyclosporine Aprednisone im-munosuppression. Am J Pathol 1988;133:173-92.

Rowe DT, Qu L, Reyes J, et al. Use ofquantitative competitive PCR to measureEpstein-Barr virus genome load in the pe-ripheral blood of pediatric transplant pa-tients with lymphoproliferative disorders.J Clin Microbiol 1997;35:1612-5.

86.

87.

88.

89.

90.

91.

92.

93.

Green M, Webber SA. EBV viral loadmonitoring: unanswered questions. Am JTransplant 2002;2:894-5.

Fishman JA. BK virus nephropathy polyomavirus adding insult to injury.N Engl J Med 2002;347:527-30.

Drachenberg CB, Papadimitriou JC,Wali R, Cubitt CL, Ramos E. BK polyomavirus allograft nephropathy: ultrastructur-

al features from viral cell entry to lysis.Am J Transplant 2003;3:1383-92.Vats A, Randhawa PS, Shapiro R. Di-

agnosis and treatment of BK virus-associ-ated transplant nephropathy. Adv Exp MedBiol 2006;577:213-27.

Hirsch HH, Suthanthiran M. The nat-ural history, risk factors and outcomes ofpolyomavirus BK-associated nephropathyafter renal transplantation. Nat Clin PractNephrol 2006;2:240-1.

Hirsch HH, Drachenberg CB, SteigerJ, Ramos E. Polyomavirus-associated ne-phropathy in renal transplantation: criti-cal issues of screening and management.Adv Exp Med Biol 2006;577:160-73.

Fishman JA. Prevention of infectiondue to Pneumocystis carinii. AntimicrobAgents Chemother 1998;42:995-1004.

Adams AB, Williams MA, Jones TR,et al. Heterologous immunity provides apotent barrier to transplantation toler-ance. J Clin Invest 2003;111:1887-95.

Williams MA, Onami TM, AdamsAB, et al. Cutting edge: persistent viralinfection prevents tolerance inductionand escapes immune control followingCD28/CD40 blockade-based regimen. JImmunol 2002;169:5387-91.

Jenner RG, Young RA. Insights intohost responses against pathogens fromtranscriptional profiling. Nat Rev Micro-

biol 2005;3:281-94. Wang D, Coscoy L, Zylberberg M, et

al. Microarray-based detection and geno-typing of viral pathogens. Proc Natl AcadSci U S A 2002;99:15687-92.

Sarwal MM. Chipping into the hu-man genome: novel insights for transplan-tation. Immunol Rev 2006;210:138-55.Copyright 2007 Massachusetts Medical Society.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.


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