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Fishman 2007
Fishman 2007
Fishman 2007
Review article
Medical Progress
Infection in Solid-Organ
Transplant Recipients
Jay A. Fishman, MD
GENER AL CONCEP DR
R ISK OF INFECTION
The risk of infection after transplantation changes over time, particularly with mod-
ifications in immunosuppression. Unfortunately, no assays accurately measure a
patient's risk of infection. Currently, therefore, the clinician assesses a recipient's
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 patient's known
or likely exposures to 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
The net state of immunosuppression refers to all Antimicrobial prophylaxis has dramatically altered
factors that contribute to the patient's risk of in- the incidence and severity of post-transplantation
fection (Fig. 3). The main determinants of risk are infections (Fig. 4). Three general preventive
the dose, duration, and sequence of immunosup- strategies are used: vaccination, universal prophylaxis,
2604
n engl j med 357;25 www.nejm.org December 20, 2007
A
CMV BK
6 6
Log10
5 5
4 4
3 3
2 2
15 20 25 30 35 40 45 15 20 25 30 35 40 45
HHV-6 HHV-7
6 6
Log10
5 5
4 4
3 3
2 2
15 20 25 30 35 40 45 15 20 25 30 35 40 45
B C
Lytic Epitopes Latent Epitopes
P=0.28 P=0.003
ÿ1000 ÿ1000
800 800
600 600
400 400
200 200
EBV-
100 100
0 0
Case Controls Case Controls
and preemptive therapy.46 The need for immu- Promoting lifestyle after transplant changes
nization against measles, mumps, rubella, diph- may help limit exposures to some potential
theria, pertussis, tetanus, HBV infection, polio- pathogens. Attention to hand washing should be
myelitis, varicella, influenza, and pneumococcal observed after food preparation, gardening, and
pneumonia should be evaluated before transplan- contact with feces or secretions. Transplant re-
tation.47 Vaccination is generally less effective cipients should avoid close contact with people
during immunosuppression.11 Pneumococcal who have respiratory illnesses, and they should
vaccine is recommended every 3 to 5 years, and avoid environments such as construction sites,
influenza vaccine is recommended annually. which have known pathogens. Dietary advice
Other vaccines are appropriate for patients who might include avoidance of well water and lake
travel to regions where certain illnesses are water (which may contain cryptosporidium or
endemic. Live vaccines are generally giardia species), undercooked meats, unwashed
contraindicated after transplanta-tion, since they fruits and vegetables, and unpasteurized dairy
may cause disseminated infection in products (which may contain Escherichia coli or
immunocompromised hosts. The immunologic Liste-ria monocytogenes ) .
protection provided by vaccines may be limited in extentRoutine
or duration.48,49
surgical prophylaxis varies, depending
on the organ transplanted and local epidemiologic trast, with preemptive therapy, sensitive quantita-
factors. For liver transplantation, antimicrobial tive assays (eg, molecular assays and antigen
agents that provide coverage for skin flora, bili- de-tection) are used to monitor patients at
ary enterococcus species, anaerobes, and predefined intervals in order to detect infection
Entero-bacteriaceae are regularly scheduled. For before symp-toms arise. Depending on the
lung transplantation, prophylaxis is targeted at potential pathogen and institutional protocols, a
gram-negative bacteria, molds, and geographic positive assay trig-gers the initiation of
fungi (eg, histoplasma). Prophylaxis may be antimicrobial therapy, a re-duction in the intensity
adjusted according to known colonization patterns of immunosuppression, accelerated monitoring,
with pseudomonas, methicillin-resistant S. or all of these steps. Pre-emptive therapy incurs
aureus, van-comycin-resistant enterococcus, or fungi. extra costs for monitoring and coordination of
Antifungal prophylaxis is based on both risk outpatient care, but it avoids the costs and toxic
and epidemiologic factors. Most invasive fungal effects of prophylactic anti-viral therapy.
infections in transplant recipients are due to non- The crude risk of specific infections has tradi-
albicans candida and aspergillus species. The tionally been defined by means of serologic test-
greatest risks associated with early fungal ing; the risk is lower in a seropositive host or
infections include aspergillus at the tracheal higher in a seronegative recipient of an organ
anasto-mosis after lung transplantation and from a seropositive donor. A variety of newer
candida species after pancreas or liver techniques (eg, HLA-linked tetramer binding and
transplantation. In-vasive fungal infections are intracel-lular cytokine staining) measure pathogen-
most common in liver recipients requiring specific immunity and provide insight into the
admission to the intensive care unit, surgical re- risk of specific infections and the ability of the
exploration or retransplantation, or transfusion host to clear invasive disease (Fig. 3 ).59
of large amounts of blood prod-ucts and in liver
recipients with metabolic dys-function (involving
CH A THING THE pat ter n
the liver allograft , kidney, or diabetes), respiratory OF INFECTION
failure, cytomegalovirus in-fection, or HCV
infection. The risk is increased after broad-spectrumEarlyantimicrobial therapy.50-56
in the evolution of solid-organ transplan-
Prophylaxis should be considered in such high- tation, there was a limited number of available
risk hosts. immunosuppressive agents, and antirejection
Most transplantation centers use trimetho- pro-tocols (ie, use of corticosteroids, calcineurin
prim–sulfamethoxazole prophylaxis for as little inhibitors, and azathioprine) were relatively stan-
as 3 months or for as long as a lifetime to prevent dardized. As a result, the timeline for the
pneumocystis pneumonia as well as infections development-ment of common post-transplantation
with Toxoplasma gondii , Isospora belli, infections was relatively predictable.1,45
Cyclospora cay-etanensis, many nocardia and Changes in immu-nosuppressive regimens,
listeria species, and common urinary, respiratory, routine prophylaxis, and improved graft survival
and gastrointestinal pathogens. Low-dose have altered the original pattern (Fig. 4).
trimethoprim–sulfamethox-azole is well tolerated Corticosteroid-sparing regimens and
and should be used unless there is evidence that antipneumocystis prophylaxis have made
the patient has an allergy or interstitial nephritis. pneumocystis pneumonia less common. Herpes-
Alternative agents for pro-phylaxis against virus infections are uncommon while patients
pneumocystis include dapsone, atovaquone, and are receiving antiviral prophylaxis. Newer
pentamidine, but they are less effective than immuno-suppressive approaches, including the
trimethoprim–sulfamethoxazole and lack the breadthuse of protection.57
of si-rolimus, mycophenylate mofetil, T-cell
The prevention of post-transplantation cyto- and B-cell depletion, and costimulatory blockade,
megalovirus and other herpesvirus infections and have largely replaced high-dose corticosteroids and azathio-prine.
the availability of oral antiviral agents have revo- With changes in typical immunosuppression,
lutionized post-transplantation care.58 Two pre- new patterns of infection have emerged.
ventive strategies have emerged. With universal Sirolimus-based regimens have been associated
prophylaxis, antimicrobial therapy is provided to with idio-syncratic noninfectious pneumonitis,
all at-risk patients for a defined period. Print con- which is easily confused with pneumocystis pneumonia or
viral pneumonia.60 T-lymphocyte–depleting anti- in the future, multiplex quantitative assays will be
bodies commonly used for initial or induction used to monitor acute infections (Fig. 3).
therapy are associated with increased viral
activation — notably, activation of cytomegalovirus, late post-transplantation period
EBV, and HIV.28,61,62 Cellular depletion after The risk of infection diminishes 6 months after
in-duction therapy often persists beyond the transplantation, since immunosuppressive thera-
period of antimicrobial prophylaxis, resulting in py is usually tapered in recipients who have satis-
late in-fections with viruses such as factory allograft function. However, transplant
cytomegalovirus and JC polyomavirus as well as recipients have a persistently increased risk of
fungal infections and malignant conditions after in-fection due to community-acquired pathogens (Fig.
transplantation. Infections that occur after the 4). In some patients, chronic viral infections may
usual period or that are unusually severe suggest cause allograft injury (eg, cirrhosis from HCV in-
excessive immunosup-pression or exposure. The fection in liver-transplant recipients, bronchiolitis
timeline for a given patient is reset with each obliterans in lung-transplant recipients, accelerated
episode of rejection or intensification of vasculopathy in heart-transplant recipients with
immunosuppression (eg, with bolus corticosteroids),cytomegalovirus infection) or a malignant condi-
with an increased risk of opportunistic infections. tion such as post-transplantation lymphoproliferative
disorder (PTLD) or skin or anogenital cancers
early post-transplantation period (Fig. 1). Recurrent infection may develop in some
Opportunistic infections are generally absent patients despite minimization of their im-
during the first month after transplantation, since munosuppression. These patients are at increased
the full effect of immunosuppression is not yet risk for opportunistic infection with listeria or
pres-ent. Infections such as viremia and nocardia species, invasive fungal pathogens such
candidemia in this period are generally donor- as zygomycetes and dematiaceous molds, and
derived or recipi-ent-derived, or they are un-usual organisms (eg, rhodococcus species).
associated with technical complications of surgery Min-imal signs of infection merit careful evaluation
(Fig. 1B). Therapy must be guided by antimicrobial- in such high-risk patients; they may benefit from
susceptibility data, making microbiologic analysis lifetime trimethoprim–sulfamethoxazole or anti-
of aspirates or bi-opsy specimens essential. C. fungal prophylaxis. Such long-term prophylaxis
difficile colitis is common in this setting. Early carries some risks of the development of microbial
graft injuries (eg, ische-mia of bile ducts or resistance to the prophylactic agents and possible
pulmonary reperfusion injury) may later become future drug interactions.
foci for liver or lung abscesses (Fig. 1B).
Unexplained early signs of infection, such as Common Infections in Tr a nspl an tation
hepatitis, pneumonitis, encephalitis, rash, and leukopenia, may be donor-derived.
prophylaxis. How-ever, other viral pathogens, Cytomegalovirus infection may cause both inva-
including polyomavi-rus BK, adenovirus, and sive disease, or “direct effects,” and a variety of
recurrent HCV, have emerged. Given the array of potential
secondary pathogens,
immune phenomena (Fig. 5) in trans-
Cellular effects:
CMV disease
“Direct effects” MHC, cytokine expression
“Indirect effects”
cytomegalovirus infection.67-69 Universal antiviral tance may present as slowly responsive or relaps-
prophylaxis also helps to prevent other viral infec- ing infection, most commonly in patients who
tions such as herpes simplex virus, varicella– were seronegative for cytomegalovirus at the time
zoster virus, EBV, and human herpesvirus 6 of transplantation and received allografts from
(HHV-6) and human herpesvirus 7 (HHV-7 ) seropositive donors, in patients who received in-
infections. Uni-versal antiviral prophylaxis also adequate or prolonged doses of oral ganciclovir
reduces the risk of fungal infections such as or valganciclovir, especially during active infection,
pneumocystis, candidiasis, and aspergillus, or in patients who undergo accelerated immuno-
complications of viral infection such as HHV-6, suppression. Recipients of lung transplants are
HHV-7, accelerated HCV and PTLD, and bacterial also at relatively high risk for resistance to liver-
infections (Fig. 4).54,70-73 In addition, prevention ciclovir. Ganciclovir resistance has been observed
of cytomegalovirus infection may reduce episodes with both universal and preemptive ap-
of both early and late acute rejection in renal- proaches.82-84
transplant recipients, cardiac vasculopathy in
heart-transplant recipients, and the bronchiolitis Diagnosis and Therapy
obliterans syndrome in lung-transplant recipients Quantitative diagnostic assays for cytomegalovi-
( Fig. 5).74-79 The relationship between acute rus are essential for management of infection.
rejection and cytomegalovirus dis-ease has not beenThese showninclude
in all studies.80
molecular assays (polymerase-
chain-although optimal regimens remain undefined, reaction [PCR] and other amplification assays)
and most centers provide anticytomegalovirus pro-antigen-detection (pp65 antigenemia) assays. In
phylaxis for the first 3 to 6 months after trans-patients with neurologic manifestations of cyto-plantation,
using valacyclovir, high-dose acyclovir, megalovirus infection (including chorioretinitis) ganciclovir,
valganciclovir, or, less commonly, cy-and gastrointestinal disease ( colitis and gastritis, tomegalovirus
hyperimmune globulins.1,81 Sever-often with ulceration), blood-based cytomegalo-al situations
require special consideration. First, virus tests may be negative. Thus, invasive pro-the use of
induction therapy with depleting anti-cedures such as colonoscopy with biopsy or lum-lymphocyte
antibodies for seropositive donors or bar puncture may be necessary. Invasive disease seropositive
recipients increases the risk of cyto- and the cytomegalovirus syndrome (which is man-megalovirus
reactivation and generally merits ex-ifested as fever and leukopenia) warrant therapy, secured
prophylaxis followed by monitoring for generally with intravenous ganciclovir. Results of active infection.
Second, although recipients of studies of oral valganciclovir therapy for cytomeg-heart and lung
transplants who are seropositive or alovirus disease are encouraged.85,86 Intravenous who receive
transplants from seropositive donors ganciclovir is currently preferred for the initiation generally receive
prophylaxis for at least 6 to 12 of therapy for gastrointestinal disease. Documen-months, some may
benefit from longer courses tation of cure in patients with gastrointestinal cy-of antiviral prophylaxis if
they lack evidence of tomegalovirus infection includes negative results protective immunity (ie, if they
have not under-of microbiologic assays and healing of ulcers and gone seroconversion), if they have
persistent micro-colitis on endoscopic evaluation. Relapse, which ral secretion (eg, in sputum), or if
they require is common with inadequate therapy, carries the a greater intensity of sustained
immunosuppres-risk of the emergence of resistance to antiviral sion. However, patients receiving
longer courses agents.
of ganciclovir or valganciclovir may incur marrow
suppression from these agents. Some patients Epstein–Barr Virus and Post-Transplantation
Lymphoproliferative Disorder
treated for active cytomegalovirus infection may
have a relapse without an additional period of PTLD, a heterogeneous group of lymphoprolifera-tive
pro-phylaxis after treatment. disorders, occurs in 3 to 10% of adults who are solid-organ
Ganciclovir resistance in patients with cyto- transplant recipients; it is associated with a reported mortality
megalovirus infection is uncommon, but when of 40 to 60%.87-89
present, it is most often due to mutations in the PTLD accounts for more than half of post-trans-
cytomegalovirus UL97 gene (a viral protein kinase plantation malignant conditions in pediatric solid-
that phosphorylates the drug) or the UL54 gene organ–transplant recipients. It varies from a
(cytomegalovirus DNA polymerase). Such resis- benign polyclonal, B-cell, infectious mononuclear-
Polyomaviruses have been identified in transplant Pneumocystis pneumonia common remains in the
recipients in association with nephropathy (eg, absence of specific prophylaxis.56,100 Pneumocys-
polyomavirus BK–associated nephropathy) and tis pneumonia should be considered in patients in
ureteral obstruction, and the JC virus has been whom marked hypoxemia, dyspnea, and cough de-
associated with progressive multifocal leukoen-velop in spite of a paucity of physical or radiologic
cephalopathy.95-99 No effective antiviral therapy findings. No radiographic patterns are pathogno-
exists for polyomaviruses. Detection of BK monic virus in the immunocompromised host. Com-nucleic
acids in blood and urine has been useful puted tomographic imaging is useful to define for assessing
responses to therapy in patients with the extent of disease and to directly invade tech-polyomavirus-
associated nephropathy. Therapy re-niques for microbiologic sampling. Noninfectious requires a
reduction in immunosuppression. Experi-processes may contribute to the pathogenesis of mental
therapies including cidofovir, an inhibitor of pneumonitis; These processes include the toxic
effects of sirolimus, which may be obscured by sponsiveness to latent organisms in that organ.
coinfection.60 Techniques currently under development, such
as more sensitive microbiologic assays, immuno-
Conclusions assays, and genomic and proteomic markers,
may provide the potential for individualized immu-
The study of infectious diseases associated with nosuppression and prophylactic strategies (Fig.
transplantation focuses on the prevention of 3).103,104 Such assays may ultimately permit a more dynamic
infection in transplant recipients. The interaction assessment of the immune status of transplant recipients over
of in-fection and immunosuppression is the time, allowing titration of immunosuppression and reducing
central con- cern. The induction of immunologic deaths from infection and malignant conditions.105
tolerance so that exogenous immunosuppression
is avoided in transplant recipients, might, if Dr. Fishman reports serving as a consultant to Gilead Phar-maceuticals,
successful, reduce the risk of infection after Merck, Astellas Pharma, Biogen Idec, Hoffmann–
La Roche, ViroPharma, Pfizer, and Schering-Ploughbeing; be-ing a member
transplantation. Howev-er, two caveats would of the scientific advisory board and receiving consulting fees from Primera;
remain. First, exposures to infections subsequent receiving grant support from As-tellas Pharma; and holding two international
to the development of toler-ance might abrogate patents (US 5442050, awarded in 1995, and US6190861, awarded in 1997)
owned by Massachusetts General Hospital. No other potential conflict of
tolerance and induce allograft rejection.101,102 interest relevant to this article was reported.
Second, the induction of tolerance to an allograft might induce immunologic unre-
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