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ChemInform Abstract: Infectious Complications

of Antilymphocyte Therapies in Solid Organ
Transplantation

ARTICLE in CLINICAL INFECTIOUS DISEASES MARCH 2009

Impact Factor: 8.89 DOI: 10.1086/597089 Source: PubMed

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 IMMUNOCOMPROMISED HOSTS INVITED ARTICLE
David R. Snydman, Section Editor

Infectious Complications of Antilymphocyte Therapies

in Solid Organ Transplantation
Nicolas C. Issa and Jay A. Fishman
Infectious Disease Division, Massachusetts General Hospital, Harvard Medical School, Boston

Antilymphocyte therapies are widely used for immunosuppression in solid organ transplantation. These agents have varied
mechanisms of action, with resulting differences in the intensity and duration of immunosuppression and in associated
infectious complications. Induction therapy with antithymocyte globulins is associated with a greater incidence of cytomeg-
alovirus, Epstein-Barr virus, and BK polyomavirus infections, compared with therapy with interleukin (IL)2a receptor
antagonists. However, long-term experience with the IL-2a receptor antagonists is lacking. By contrast, the treatment of graft
rejection with T celldepleting antibodies is associated with an increased risk of opportunistic infections. This is likely a

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reflection of the intensification of immunosuppression in the treatment of graft rejection and, often, a failure to link the use
of antilymphocyte agents to prophylaxis for infection. The use of T celldepleting agents, especially in the treatment of acute
graft rejection, must be linked to monitoring and risk-adjusted prophylaxis for Pneumocystis, other fungi, Epstein-Barr virus,
BK polyomavirus, and cytomegalovirus infection.

Increasing rates of infection after solid organ transplantation
have been attributed to use of antilymphocyte induction ther-
apies and intensification of regimens for maintenance immu-
nosuppression [1]. Antilymphocyte therapies are widely used
in organ transplantation for induction therapy and treatment
of graft rejection. Each agent has distinct mechanisms of action,
with differences in the intensity and duration of immunosup-
pression. Infections commonly associated with these agents ne-
cessitate the development of appropriate preventative strategies.
Induction therapy blocks T cell activation and antigen rec-
ognition at the time of transplantation, particularly in recipients
at high immunologic risk of graft rejection. This strategy min-
imizes exposure to nephrotoxic calcineurin inhibitors and re-
duces the use of corticosteroids and other maintenance ther-
apies [2]. The most frequently used induction agents include
polyclonal antithymocyte globulin (ATG); T celldepleting
agents from rabbit (rATG) or horse (hATG; lymphocyte im-
munoglobulin [equine antithymocyte globulin]); basiliximab
and daclizumab, non-T celldepleting monoclonal antibodies
Received 18 July 2008; accepted 5 November 2008; electronically published 10 February
2009.
Reprints or correspondence: Dr. Jay A. Fishman, Transplant Infectious Disease and
Compromised Host Program, 55 Fruit St., GRJ 504, Boston, MA 02114 (jfishman@partners.org).
Clinical Infectious Diseases 2009; 48:77286
 2009 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2009/4806-0014$15.00
DOI: 10.1086/597089
against IL-2a receptor (IL-2R; anti-CD25); and alemtuzumab,
a pan-T celldepleting anti-CD52 monoclonal antibody. Use
of OKT3 (muromonab-CD3), a murine monoclonal, T cell
depleting antibody is less common. The T celldepleting agents
are also used in the treatment of acute graft rejection. Other
agents are being investigated for use in transplantation, in-
cluding antibodies to recombinant human leukocyte-associated
functional antigen 1, antibody-associated immunotoxins, and
fusion proteins of human leukocyte-associated functional an-
tigen 3 with immunoglobulin fragments.
Most trials of antilymphocyte therapies have focused on graft
rejection rates, graft function, and other noninfectious out-
comes. Reporting of specific infections is generally limited to
cytomegalovirus (CMV), Epstein-Barr virus (EBV), and BK
polyomavirus (BKV) infections, with few data regarding specific
syndromes or pathogens.
ATG
The most commonly used ATGs are polyclonal antibodies pre-
pared from sera from rabbits or horses that have been im-
munized with thymocytes or T cell lines. rATG and hATG are
commonly used in the United States, whereas ATG-Fresenius
prepared from rabbits injected with Jurkat cellsis used ex-
tensively in Europe. ATGs are not interchangeable [37]. All
ATGs provide dose-dependent depletion of T cells. Effects on
T cell depletion and risk of infection depend on the dosing

772 CID 2009:48 (15 March) IMMUNOCOMPROMISED HOSTS

strategy (i.e., total dose and duration). Typical ATG induction
therapy takes 35 days (range, 110 days) [811]. Longer was not associated with increased risk of bacterial infections,
courses are used to avoid calcineurin inhibitorinduced
nephrotoxicity.
rATG has a half-life of 30 days [12]. In addition to T cell
depletion, rATG induces apoptosis of B cell lineages and in-
terferes with dendritic cell, regulatory T cell, and natural killer
cell functions [13]. Although levels of rATG decrease by 1
month after initiation of treatment, significant long-term def-
icits in T cell reconstitution that have been linked to impaired
thymopoiesis often persist beyond 1 year [9, 14, 15]. CD3+ cell
suppression is less intense and of shorter duration after hATG
administration than after rATG administration, with absolute
lymphopenia resolving within 14 days after treatment initiation
[9]. ATG-Fresenius (9 mg/kg/day for 5 doses) induces rapid T
cell depletion that persists for up to 1 year after treatment, with
gradual recovery to pretransplantation levels by day 730 [14].
The development of neutralizing antibodies against xenogeneic
immunoglobulin may limit the efficacy of subsequent courses
of ATG. Administration of ATG is often associated with syn-
dromes including fever and chills and, occasionally, hypoten-
sion, chest pains, serum sickness, congestive heart failure, pul-
monary edema, leukopenia, thrombocytopenia, eosinophilia, or
rash.
ATG and the Risk of Infection
Bacterial infection. The impact of ATG on bacterial infec-
tions is unclear. Multiple cofactors are generally present, in-
cluding technical complications from surgery, urinary and vas-
cular catheters, and complex immunosuppressive regimens.
However, bacterial infections are the most common form of
infection reported after rATG induction therapy (table 1) [16
23]. In kidney and kidney-pancreas transplantation, urinary
tract infections are most common, followed by wound infec-
tions [9, 1619, 21, 24]. Bacteremia, sepsis, and pneumonia
have also been reported [1719, 32, 33]. Enterobacteriaceae,
most often Escherichia coli and Enterococcus species, are the
most-frequently isolated uropathogens [16]. Nocardia infec-
tions have been reported in 3 lung transplant recipients (in-
fections were due to Nocardia nova, Nocardia farcinica, and
Nocardia asteroides complex) after induction therapy with
rATG, despite prophylaxis with trimethoprim-sulfamethoxa-
zole; these infections reflect profound immunosuppression, an-
timicrobial resistance, or inadequate dosing [34]. In most pro-
spective trials, ATG was not associated with an increased risk
of bacterial infection, compared with that risk with no induc-
tion therapy [24] or other induction therapies (e.g., IL-2R an-
tagonists and alemtuzumab) (table 1) [17, 18, 26, 28, 29, 31].
Sepsis and multiple renal allograft abscesses (due to Pseudo-
monas aeruginosa) have been reported after rATG treatment
for acute graft rejection [35, 36]. In a small series, treatment
of acute graft rejection with ATG in liver transplant recipients
compared with that risk for patients with graft rejection treated
with steroids or patients who did not experience graft rejection
[37].
CMV. The association between antithymocyte therapies
and CMV infection is well established [17, 24, 3842]. Fever
and the release of TNFa after ATG administration stimulate
cellular nuclear factor kB and viral replication via nuclear factor
kB binding to the promoter region of the CMV immediate-
early antigen gene [43, 44]. Additional factors in CMV acti-
vation may include the depletion of T helper cells, inversion
of the CD4/CD8 ratio, and shifts toward Th2 cytokines [3, 45].
The timing and incidence of CMV infection after ATG induc-
tion therapy depends on the type and dosage of ATG, donor
and recipient CMV serologic status before transplantation, and
whether CMV prophylaxis was given (tables 1 and 2). Most
trials have included asymptomatic infection (i.e., infection de-
tectable by microbiologic assay) with CMV syndrome (fever
and neutropenia) and tissue-invasive disease in their criteria
for CMV infection. In most prospective, randomized trials
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comparing ATG with other induction agents, the incidence of
CMV infection was not increased when induction therapy was
coupled with adequate CMV prophylaxis [18, 2528, 31]. In a
study without CMV prophylaxis, the rate of CMV infection
was higher in the rATG group than it was in the basiliximab
group (38% vs. 11.7%; P p .005) [17]. In one study in which
CMV infection was more common with daclizumab therapy
than with hATG therapy, more recipients at high risk of in-
fection (i.e., CMV-seronegative recipients of organs from se-
ropositive donors) received daclizumab therapy [29].
In general, antigraft-rejection therapy with ATG without
CMV prophylaxis is associated with an increased rate and se-
verity of CMV infection in renal transplant recipients [47].
Inflammation associated with acute graft rejection may con-
tribute to CMV reactivation during immunosuppression [47].
In simultaneous pancreas-kidney transplant recipients, treat-
ment of graft rejection with rATG was associated with earlier
and more-severe CMV infection, compared with treatment with
ATG-Fresenius or daclizumab induction [40]. In a study of
renal transplant recipients, a higher rate of CMV infection as-
sociated with basiliximab therapy was attributed to greater use
of concomitant cytolytic therapy (ATG or OKT3) among pa-
tients receiving basiliximab than among patients receiving rATG
(17.5% vs. 7.8%; P p .02) [21].
EBV and EBV-induced posttransplantation lymphoprolife-
rative disorder (PTLD). The incidence of malignancy in gen-
eral, and PTLDs in particular, is increased among organ trans-
plant recipients, compared with that in the general population
[4857]. In most cases, PTLD is caused by the transformation
of B lymphocytes by EBV [5864]. In EBV-seronegative trans-
IMMUNOCOMPROMISED HOSTS CID 2009:48 (15 March) 773
 Table 1. Risk of cytomegalovirus (CMV) and other infections in randomized, prospective trials, by induction therapy.

Maintenance CMV serostatus CMV infection, Other infections,

Study, Duration of immunosuppression Antithymocyte D+/R, no. (%) no. (%) of no. (%) of
treatment group Transplant type follow-up therapy CMV prophylaxis agent of patients P patients P patients P

Mourad et al. [24] (n p 309)

rATG (n p 151) Kidney 12 months Tacrolimus, ACV or GCV in- rATG, 1.25 mg/kg 21 (13.9) NS 49 (32.5) .009 UTI, 47 (31.1); UTI, NS; HSV,
azathioprine, steroids duction, 51%; 10 days HSV, 27 (17.9) .001
no induction,
31.6%
No rATG (n p 158) Kidney 12 months Tacrolimus, ACV or GCV in- None 25 (15.8) 30 (19.0) UTI, 52 (32.9);
azathioprine, steroids duction, 51%; HSV, 9 (5.7)
no induction,
31.6%
Hartwig et al. [25] (n p 44)
rATG (n p 22) Lung 8 years CsA, azathioprine, steroids IV GCV, twice rATG, 1.5 mg/kg Excluded 13 (59) .55 Non-CMV serious 1.999
daily 2 3 days infections, 13
weeks, fol- (59)
lowed by 4
times daily 2
weeks
No rATG (n p 22) Lung 8 years CsA, azathioprine, steroids IV GCV twice None Excluded 10 (45) Non-CMV serious
daily 2 infections, 12

774
weeks, fol- (55)
lowed by 4
times daily 2
weeks
Hardinger et al. [7] (n p 72)
Thymoglobulin (n p 48) Kidney 5 years CsA, azathioprine, steroids Oral GCV, 1 g 3 Thymoglobulin, 8 (17) NS 6 (13) .056
times daily 1.5 mg/kg 7
36 months days
L-IG (n p 24) Kidney 5 years CsA, azathioprine, steroids Oral GCV, 1 g 3 L-IG, 15 mg/kg 5 (21) 8 (33)
times daily 7 days
36 months
Lebranchu et al. [17] (n p 103)
rATG (n p 50) Kidney 6 months CsA, MMF, steroids None rATG, 1.01.5 11 (22) NS 19 (38) .005 Bacterial, 48 (96); Bacterial, NS; vi-
mg/kg/day viral, 39 (78); ral, NS; fungal,
610 days fungal, 2 (4) NS
Basiliximab (n p 51) Kidney 6 months CsA, MMF, steroids None Basiliximab, 20 9 (18) 6 (11.7) Bacterial, 37 (72);
mg on day 0 viral, 21 (41);
and day 4 fungal, 1 (2)
Brennan et al. [21] (n p 278)
rATG (n p 141) Kidney 12 months CsA, MMF, steroids Oral or IV GCV rATG, 1.5 mg/kg/ 21 (14.9) NS 11 (7.8) .02 UTI, 55 (39); con- UTI, .04; con-
14 days, fol- day 5 days firmed bacte- firmed bacte-
lowed by oral rial, 74 (52.5); rial, .01; non-
GCV 3 non-CMV viral, CMV viral, .04;
months 30 (21.3); fun- fungal, 1.999
gal, 20 (14.2)

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 Basiliximab (n p 137) Kidney 12 months CsA, MMF, steroids Oral or IV GCV Basiliximab, 20 31 (22.6) 24 (17.5) UTI, 37 (27); con-
14 days, fol- mg on day 0 firmed bacte-
lowed by oral and day 4 rial, 51 (37.2);
GCV 3 non-CMV viral,
months 16 (11.7); fun-
gal, 20 (14.6)
Mattei et al. [26] (n p 80)
rATG (n p 42) Cardiac 6 months CsA, MMF, steroids For CMV D+/R, rATG, 2.5 mg/kg/ 6 (14.3) .238 10 (23.8) NS Overall, 19 (45.2) .366
oral GCV or day 35
VGCV 3 days
months; other,
per local
practice
Basiliximab (n p 38) Cardiac 6 months CsA, MMF, steroids For CMV D+/R, Basiliximab, 20 11 (28.9) 6 (15.8) Overall, 13 (34.2)
oral GCV or mg on day 0
VGCV 3 and day 4
months; other,
per local
practice
Abou-Ayache et al. [27] (n p
115)
rATG (n p 57) Kidney 12 months CsA, MMF, steroids Oral GCV 1 g 3 rATG, 11.5 mg/ 18 (33) NS 28 (51) NS
times daily kg/day 49
3.5 months doses; ad-
justed to CD2/
CD3 count !20
cells/mm3
Daclizumab (n p 58) Kidney 12 months CsA, MMF, steroids Oral GCV 1 g 3 Daclizumab, 1 19 (35) 21 (39)
times daily mg/kg/day ev-
3.5 months ery 2 weeks

775
5 doses
Sollinger et al. [28] (n p 138)
L-IG (n p 65) Kidney 12 months CsA, MMF, steroids Inconsistent L-IG, 15 mg/kg/ 11 (17) NS Overall, 50 (77) NS
day 14 days
Basiliximab (n p 70) Kidney 12 months CsA, MMF, steroids Inconsistent (1 Basiliximab, 20 13 (19) Overall, 53 (76)
center; no pro- mg on day 0
phylaxis for 21 and day 4)
patients in bas-
iliximab group)
Mullen et al. [29] (n p 50)
L-IG (n p 25) Lung 12 months CsA or tacrolimus, MMF, GCV or VGCV L-IG, 10 mg/kg/ 1 (4) .05 4 (24) .03 Overall, 20 (80) .7
steroids day 58
days
Daclizumab (n, 25) Lung 12 months CsA or tacrolimus, MMF, GCV or VGCV Daclizumab, 2 7 (28) 12 (72) Overall, 22 (88)
steroids mg/kg on day
0, then 1 mg/
kg on day 4
Hershberger et al. [30] (n p
434)
Daclizumab (n p 216) Cardiac 12 months CsA, MMF, steroids GCV 510 mg/kg/ Daclizumab, 1 47 (21.8) .77 11 (5.1) NS Severe, 15 (6.9) NS
day 2 mg/kg 5
weeks, then doses
follow local
protocol

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 No daclizumab (n p 218 Cardiac 12 months CsA, MMF, steroids GCV 510 mg/kg/ None 50 (22.9) 12 (5.8) Severe, 16 (7.7)
day 2
weeks, then
follow local
protocol
Ashcraft et al. [18] (n p 130)
rATG (n p 66) Kidney and 9 months Tacrolimus, MMF, steroids Oral VGCV 36 rATG, alternate 10 (15) 4 (6) NS Overall, 35 (53); Overall, .08; fun-
pancreas months days fungal/viral, 12 gal/viral, NS
(18)
Alemtuzumab (n p 64) Kidney and 9 months Tacrolimus, MMF, steroids Oral VGCV 36 Alemtuzumab, 30 15 (23) 4 (6.25) Overall, 24 (38);
pancreas months mg once fungal/viral, 8
(13)
Ciancio et al. [31] (n p 90)
rATG (n p 30) Kidney 15 months Tacrolimus, MMF, steroids IV GCV 3 days, rATG, 1 mg/kg/ 1 (3) .36 Overall, 7 (23) .6
followed by day 7 days
oral VGCV 3
months
Alemtuzumab (n p 30) Kidney 15 months Tacrolimus, MMF, steroids IV GCV 3 days, Alemtuzumab, 0 (0) Overall, 6 (20)
followed by 0.3 mg/kg on
oral VGCV 3 day 0 and day
months 4
Daclizumab (n p 30) Kidney 15 months Tacrolimus, MMF, steroids IV GCV 3 days, Daclizumab, 1 0 (0) Overall, 4 (13)
followed by mg/kg/day on
oral VGCV 3 day 0 and ev-
months ery 2 weeks
4 doses

NOTE. CMV infection includes asymptomatic CMV infection (antigenemia, PCR detection), CMV syndrome, and CMV disease. ACV, acyclovir; ATG, antithymocyte globulin; CsA, cyclosporine A; D+/R, donor
seropositive and recipient seronegative; GCV, ganciclovir; IV, intravenous; L-IG, lymphocyte immunoglobulin; MMF, mycophenolate mofetil; NS, not significant (exact P value not reported); rATG, rabbit ATG; VGCV,
valganciclovir.

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plant recipients, the risk of PTLD is increased by coinfection
with CMV and increased intensity of immunosuppression [60,
65]. Induction and graft-rejection therapies using various an-
tilymphocyte globulins have been associated with an increased
risk of PTLD (table 3) [6671]. Not all studies support this
association (table 3) [7072]; many of these studies are affected
by variability in risk factors between patients, including vari-
ability in the type and dosage of induction therapy, type of
organs transplanted, maintenance of immunosuppression, EBV
serostatus of donor and recipient, and duration of follow-up.
The highest risk of PTLD is in EBV-seronegative recipients of
organs from seropositive donors, particularly children, who
require long-term monitoring, especially after intensification of
immunosuppression.
BKV. Evidence is emerging that links ATG induction ther-
apy to increased rates of BKV viremia and BKV-associated ne-
phropathy. BKV-associated nephropathy is an infectious injury
to renal allografts that affects 1%10% of kidney transplant
recipients and is associated with the intensity of immunosup-
pression [76]. Some studies link ATG induction therapy to the
risk of BKV viremia and BKV-associated nephropathy [7780].
rATG induction therapy has been found to be an independent
risk factor for BKV-associated nephropathy, as were tacrolimus-
mycophenolate mophetil and corticosteroid maintenance ther-
apy [77, 78]. In a prospective trial, BKV viremia occurred in
19.4% of renal transplant recipients at 6 months and was as-
sociated with higher induction doses of rATG [80]. In a ret-
rospective cohort, induction with polyclonal antibodies was
associated with an increased rate of BKV-associated nephropa-
thy [79]. The use of antilymphocyte globulins for the treatment
of steroid-resistant graft rejection has been associated with in-
creased BKV replication in patients also receiving tacrolimus-
or mycophenylate mophetilbased regimens. Use of pulsed-
dose corticosteroids is a major risk factor for BKV-associated
nephropathy [81].
Hepatitis C Virus (HCV). The use of induction therapy in
HCV-infected organ transplant recipients, especially in liver
recipients, may increase HCV replication and accelerate pro-
gression to cirrhosis. This progression is accelerated by CMV
coinfection. Our experience demonstrates accelerated HCV
replication with rATG induction therapy for liver transplan-
tation but no increased rate of hepatic graft injury, especially
in patients who tolerate antiviral therapy. HCV infection is
associated with increased mortality in kidney transplant recip-
ients [82, 83]; however, antiT cell therapy (rATG or basilix-
imab) was not associated with accelerated viral infection, cir-
rhosis, or increased mortality in HCV-seropositive renal
transplant recipients [84, 85].
Fungal infection. Pneumonia due to Pneumocystis species
and other invasive fungal infections have been reported in solid-
organ transplant patients who have received rATG induction
therapy in the absence of prophylaxis [1719, 21, 26, 28, 29,
31, 32]. In most randomized studies, the risk of fungal infection
after ATG therapy was similar among different ATG agents
(table 1). False-positive assay results for Histoplasma antigens
may occur in patients receiving rATG therapy [86, 87]. In a
retrospective, multivariate analysis of renal transplant recipi-
ents, the rate of invasive fungal infection was not increased by
ATG induction, whereas graft rejection and graft-rejection ther-
apy increased the risk of invasive fungal infection [88].
OKT3 (MUROMONAB-CD3)
OKT3 is a T celldepleting mouse monoclonal antibody that
has been associated with an increased rate of severe infection
(notably CMV reactivation [8991] and fungal infection [88])
and an increased risk of PTLD [67, 70, 92, 93]. The frequency
of OKT3 use has decreased because of the availability of agents
with fewer first-doserelated adverse effects (i.e., fever, rigors,
chest pain, dyspnea, hypotension, nausea, vomiting, and di-
arrhea). Patients who receive OKT3 commonly develop anti-
idiotypic antibodies that block efficacy with subsequent ad-
ministration [94].
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IL-2R ANTAGONISTS (ANTI-CD25)
IL-2R antagonists (e.g., basiliximab and daclizumab) are mono-
clonal antibodies that target CD25, the a-chain of the receptor
that is expressed on the surface of early progenitors of T and
B cells and by activated mature T and B lymphocytes; resting
lymphocytes are not targeted. CD25 participates in lymphocyte
differentiation, activation, and proliferation. These agents are
used for induction therapy and in maintenance immunosup-
pression. Because of the relatively recent introduction of these
agents, clinical experience remains limited but suggests that the
number of infectious complications may be reduced, compared
with that for other induction therapies. These agents are not
generally used for the treatment of acute graft rejection.
Basiliximab. Basiliximab is a chimeric murine-human
monoclonal antibody that binds selectively to the high-affinity
IL-2R [9597]. Basiliximab is generally administered within 2
h before transplantation and 4 days after transplantation. Bas-
iliximab has a long half-life (13.4 days in adults and 9.4 days
in children) [98, 99]. Induction therapy achieves complete IL-
2R saturation and suppression for 46 weeks in adult kidney
transplant recipients [96, 97, 99]. In pediatric kidney trans-
plantation, the mean duration of saturation is 42 days [100].
Daclizumab. Daclizumab is a humanized IL-2R antagonist
that contains the hypervariable region of the murine antibody
against the IL-2R a-subunit [95]. Daclizumab is administered
every 2 weeks for 5 doses. The half-life of Daclizumab is 20
days [101]. The dose used for induction therapy saturates the
IL-2R on circulating lymphocytes for at least 3 months after
transplantation [101].
IMMUNOCOMPROMISED HOSTS CID 2009:48 (15 March) 777
Table 2. Induction therapies and mean time to onset of cytomegalovirus (CMV) infection.

Time to onset
Type of Maintenance CMV serology D+/R, Incidence of CMV infection, of CMV infection,
Study, induction therapy transplant immunosuppression no. (%) of patients CMV prophylaxis % of patients median days (range)
Abou-Ayache [27]
rATG (n p 55) Kidney CsA, MMF, steroids 18 (33) D+/R, universal prophylaxis with GCV 3.5 51 (infection, syndrome, and disease) 29 (1689)
months; D+/R+ or D/R+, preemptive
therapy
Daclizumab (n p 54) Kidney CsA, MMF, steroids 19 (35) D+/R, universal prophylaxis with GCV 3.5 39 (CMV infection, syndrome, and 57 (29168)
months; D+/R+ or D/R+, preemptive disease)
therapy
Huurman [40]
ATG-Fresenius (n p 19) Pancreas-kidney CsA, MMF, steroids 5 (26.3) Universal prophylaxis with GCV 34 months 52.6 (viremia) 114.5 (34180)
Daclizumab (n p 20) Pancreas-kidney CsA, MMF, steroids 4 (20) Universal prophylaxis with GCV 34 months 60 (viremia) 159.5 (139180)
Peleg et al. [46]: alemtuzumab (n p 547) Any Tacrolimus monotherapy Unknown Universal prophylaxis 6 months for kidney, 26 (CMV disease) 85 (7254)
pancreas, lung, intestinal, multivisceral; pre-
emptive therapy for liver recipients

NOTE. ATG, antithymocyte globulin; CsA, cyclosporin A; D, donor CMV serostatus; GCV, ganciclovir; R, recipient CMV serostatus; rATG, rabbit ATG.

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 Bacterial infection. No increase in the overall rate of bac-
terial infection was noted with IL-2R antagonists, compared
with other induction therapies or placebo (table 1) [17, 28,
102104]. Higher mortality associated with infection was ob-
served among patients receiving daclizumab in a placebo-con-
trolled study of cardiac transplant recipients who also received
cytolytic therapy (i.e., OKT3 and ATG) [30]. Infections in-
cluded sepsis (6 cases), CMV infection (1 case), and crypto-
coccal meningitis (1 case); the role of daclizumab in these com-
plications remains unclear [30].
CMV. Patients receiving IL-2R antagonists experience rates
of CMV infection that are similar to those among patients
receiving placebo or other induction therapies (table 1) [30,
96, 101103, 105108]. Receipt of cytolytic antigraft-rejection
treatment with basiliximab was associated with higher rates of
CMV infection, compared with receipt of ATG in renal trans-
plant recipients (17.5% vs. 7.8%; P p .02) [21].
EBV and EBV-induced PTLD. Most studies have not dem-
onstrated an increased risk of PTLD after induction therapy
with IL-2R antagonists (table 3) [17, 28, 57, 6870, 72, 108].
HCV. The effect of IL-2R antagonists on HCV infection is
unknown. One study demonstrated higher rates of HCV in-
fection recurrence among liver recipients after receipt of da-
clizumab [109], whereas other studies have demonstrated no
impact [110112].
Fungal infection. The incidence of fungal infection among
recipients of IL-2R antagonists was similar to the incidence
among recipients of placebo, no induction therapy, or other
induction therapies (table 1) [21, 22, 26, 30, 31, 96, 102, 103,
105, 107, 113, 114].
ALEMTUZUMAB
Alemtuzumab is a humanized monoclonal antibody directed
against the membrane glycoprotein CD52 on lymphocytes (T
and B cells), monocytes and macrophages, and natural killer
cells. Alemtuzumab achieves panT cell depletion; CD4 and
CD8 cell counts reach a nadir 4 weeks after initiation of therapy
and remain at !25% of baseline values for 9 months [115].
Data regarding infectious complications remain limited, be-
cause alemtuzumab is used in induction therapy in a small
number of clinical centers. Some late invasive viral and fungal
infections have been observed in patients after induction and
graft-rejection therapy with alemtuzumab. Additional prospec-
tive data are needed.
Bacterial infection. Alemtuzumab is used at a lower dosage
in induction therapy for solid organ transplantation (2030 mg
for 1 or 2 doses), compared with the dosage used for cancer
therapy. Induction therapy with alemtuzumab is associated with
a low incidence of bacterial infection, compared with historical
regimens or with other therapies (table 1) [18, 31, 34, 73, 74,
114, 116121]. Infection occurred earlier among patients who
received alemtuzumab for graft-rejection therapy (72.5 days;
range, 2325 days) than among patients who received alem-
tuzumab for induction therapy (120 days; range, 31328 days;
P p .09) [46]. Disseminated and pulmonary nocardiosis and
tuberculous and nontuberculous pneumonia (due to Myco-
bacterium kansasii) have been described after treatment with
alemtuzumab, mainly in patients who received alemtuzumab
for treatment of acute graft rejection.
Viral infection. Of 547 organ transplant recipients treated
with alemtuzumab without antiviral prophylaxis, 56 (10%) de-
veloped 62 opportunistic infections [46], including 16 (26%)
CMV infections, 12 (19%) BKV infections, and 3 (5%) EBV
infections with PTLD [46]. CMV disease occurred within 3
months after graft-rejection therapy with alemtuzumab [46].
Many patients (65%) who received alemtuzumab for treatment
of acute graft rejection also received another type of lympho-
cyte-depleting antibody, most commonly rATG [46]. In a sin-
gle-center, 5-year trial of induction therapy with alemtuzumab
in renal transplantation, compared with other induction agents,
Downloaded from cid.oxfordjournals.org by guest on May 11, 2011
a lower incidence of CMV infection was demonstrated with
alemtuzumab using acyclovir for CMV prophylaxis in high-
risk recipients [74]. No tissue-invasive CMV infection, PTLD,
or BKV-associated nephropathy was demonstrated in pediatric
kidney recipients treated with alemtuzumab induction [122].
In a retrospective study of induction therapy in renal trans-
plantation comparing alemtuzumab with ATGs (rabbit and
equine) and IL-2R antagonists, alemtuzumab therapy was as-
sociated with a greater incidence of CMV infection, compared
with that in the IL-2R antagonist group (24.6% vs. 9.3%;
P p .01), with a rate similar to that in the rATG group [114].
There was also a trend toward more BKV infections among
patients receiving alemtuzumab [114].
Fungal infection. Invasive fungal infections have been de-
scribed after alemtuzumab therapy, including invasive asper-
gillosis, mucormycosis, Scedosporium infection, Histoplasma
capsulatum infection, Blastomyces dermatitidis infection, and
cryptococcal infection [46, 117, 123]. The risk of fungal infec-
tion among transplant recipients treated with alemtuzumab
induction therapy appears to be similar to that for patients
treated with other induction therapy agents [18, 114]. However,
a greater risk of invasive fungal infection (mostly esophageal
candidiasis) exists after treatment for acute graft rejection; most
infections occurred within 3 months after the start of therapy
[46].
Parasitic infection. Amebic meningitis due to Balamuthia
mandrillaris and Toxoplasma pneumonia has been described in
patients receiving alemtuzumab for acute graft rejection [46].
IMMUNOCOMPROMISED HOSTS CID 2009:48 (15 March) 779
 Table 3. Induction therapy and risk of posttransplantation lymphoproliferative disorder (PTLD).

Type of Duration of
Drug, study number Study type Database Period transplant follow-up RR (95% CI) of PTLD P Reference
hATG: 1 Retrospective data analysis SRTR (3752/41,686 recipients) 19962002 Kidney Censored 1.50 (0.932.43) .10 [67]
rATG
1 Retrospective data analysis SRTR (2376/41,686 recipients) 19962002 Kidney Censored 3.0 (1.535.89) .001 [67]
2 Randomized prospective study 90 patients 20022004 Kidney 15 months No PTLD [72]
3 Retrospective data analysis UNOS-OPTN (12,051/84,368 19872003 Kidney Median, 368 days 1.17 (0.871.58) .29 [71]
recipients)
4 Retrospective data analysis UNOS-OPTN (685/5072 19872003 Pediatric kidney Median, 368 days 1.51 (0.782.93) [71]
recipients)
5 Retrospective data analysis UNOS-OPTN (13,110/59,560 20002004 Kidney 730 days 1.63 .01 [69]

780
recipients)
L-IG
1 Retrospective data analysis UNOS-OPTN (8076/84,368 19872003 Kidney Median, 1433 days 1.61 (1.242.10) !.001 [71]
recipients)
2 Retrospective data analysis UNOS-OPTN (620/5072 19872003 Pediatric kidney Median, 1433 days 2.162 (1.223.82) .008 [71]
recipients)
ALG
1 Retrospective data analysis UNOS-OPTN (16,108/84,368 19872003 Kidney Median, 2055 days 1.35 (1.091.68) .006 [71]
recipients)
2 Retrospective data analysis UNOS-OPTN (1334/5072 19872003 Pediatric kidney Median, 2055 days 1.008 (0.581.76) [71]
recipients)
ATG (all)
1 Retrospective data analysis UNOS-OPTN (38,519 19972000 Kidney 727 days 1.29 (0.822.03) .27 [70]
recipients)
2 Retrospective data analysis USRDS (4353/25127 19962000 Kidney Censored 1.55 (1.2- 1.99) .001 [68]
recipients)
Basiliximab
1 Retrospective data analysis SRTR (5169/41,686 recipients) 19962002 Kidney Censored 1.83 (1.053.18) .032 [67]
2 Retrospective data analysis UNOS-OPTN (14,182/59,560 20002004 Kidney 730 days 0.84 .33 [69]
recipients)
Daclizumab

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 1 Retrospective data analysis SRTR (3377/41,686 recipients) 19962002 Kidney Censored 1.92 (1.083.41) .027 [67]
2 Randomized prospective study 90 patients 20022004 Kidney 15 months No PTLD [72]
3 Retrospective data analysis UNOS-OPTN (7511/59,560 20002004 Kidney 730 days 0.64 .06 [69]
recipients)
Anti-IL-2R as a
group
1 Retrospective data analysis UNOS-OPTN (7800/38,519 19972000 Kidney 727 days 1.14 (0.771.70) .52 [70]
recipients)
2 Retrospective data analysis USRDS (3936/25,127 19962000 Kidney Censored 1.16 (0.821.65) .39 [68]
recipients)
Alemtuzumab
1 Retrospective single-center 126 patients 19972003 Kidney Censored No PTLD [73]
study
2 Prospective single-center study 33 patients 19971998 Kidney 5 years 1 case [74]
3 Prospective single-center study 10 patients 20022003 Lung 6 months No PTLD [34]
4 Randomized prospective study 90 patients 20022004 Kidney 15 months No PTLD [72]
5 Retrospective data analysis UNOS-OPTN (1691/59,560) 20002004 Kidney 730 days 1.15 .74 [69]
recipients
Belatacept and bas- Randomized prospective study 218 patients 20012003 Kidney 13 months 3 casesa [75]
iliximab: 1

NOTE. ALG, antilymphocyte globulin; ATG, antithymocyte globulin; hATG, horse ATG; L-IG, lymphocyte immunoglobulin; rATG, rabbit ATG; RR, relative risk; SRTR, Scientific Registry of Transplant
Recipients; UNOS-OPTN, United Network for Organ Sharing and Organ Procurement and Transplant Network; USRDS, United States Renal Data System.

781
a
One patient who developed PTLD after receipt of belatacept also received OKT3 for treatment of acute graft rejection.

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CHRONIC INDUCTION THERAPY AGENTS
(ABATACEPT AND BELATACEPT)
Abatacept and belatacept are fusion proteins composed of Fc
fragments of a human IgG1 immunoglobulin linked to the
extracellular domain of cytotoxic T lymphocyte antigen 4
(CTLA-4) that block T cell activation by preventing T cell
costimulation. Experience with these agents remains limited.
Three cases of PTLD have been reported in kidney transplant
recipients who received intensive treatment with belatacept (ta-
ble 3) [75].
RECOMMENDATIONS: MONITORING FOR
INFECTION AND PREVENTATIVE THERAPIES
Experience with antilymphocyte therapies has provided a pre-
dictability of infectious complications based on the intensity
and duration of T cell depletion. Strategies should be developed
to monitor and prevent common infections associated with
antilymphocyte therapies [124].
Bacterial and fungal infections. Patients receiving induc-
tion therapies do not require routine laboratory monitoring
for bacterial or fungal infections. Because of the duration of
effect of prophylaxis for pneumonia due to Pneumocystis carinii,
it should be prolonged (duration, 612 months) when T cell
depleting agents are used in induction or graft rejection therapy.
Trimethoprim-sulfamethoxazole (single strength, 80/400 mg
daily) prevents pneumonia due to Pneumocystis species and
other opportunistic infections (i.e., infection due to Nocardia,
Toxoplasma, or Listeria species). Other prophylactic regimens
against pneumonia due to P. carinii do not offer the same
protection. Patients with active CMV or HCV infection who
have poor allograft function or who are treated for graft re-
jection should receive prophylaxis for longer periods (i.e., 6
months to life).
Individuals receiving induction therapy with T celldepleting
agents who have a history of exposure (i.e., seropositivity) to
endemic fungi (i.e., the fungi that cause histoplasmosis, coc-
cidioidosis, blastomycosis) or to Cryptococcus species should
receive prophylaxis (duration, 612 months) with fluconazole
(200400 mg daily; for infection due to Coccidioides, Histo-
plasma, or Cryptococcus species) or itraconazole (200 mg orally
daily; for infection due to Histoplasma or Blastomyces species),
with adjustment in dosages of any calcineurin inhibitors or
rapamycin. Monitoring with use of antigen assays or immu-
noassays for Histoplasma and Cryptococcus species (and more
recently for species that cause coccidioides and blastomycosis)
may be useful; cross-reactivity is common. Comprehensive
long-term data on infections associated with IL-2R antagonists
are lacking.
CMV prevention. Patients who are at risk of CMV infection
(i.e., either the organ donor or recipient is CMV seropositive)
782 CID 2009:48 (15 March) IMMUNOCOMPROMISED HOSTS
should be monitored by quantitative CMV load or antigenemia
assay every 2 weeks for 6 months after induction therapy in
the absence of anti-CMV prophylaxis. CMV monitoring and
prophylaxis (3 months) should be extended or reinstituted
for at-risk individuals after the use of T celldepleting agents
for treatment of graft rejection (tables 1 and 2). For trans-
plantations in which the donor and recipient are both CMV
seronegative, antiviral prophylaxis (e.g., famciclovir, valacyclo-
vir, or acyclovir) for 46 months is recommended for preven-
tion of infection with herpes simplex virus or varicella-zoster
virus.
EBV and EBV-induced PTLD. The association between T
cell depletion or chronic induction therapy (abatacept and be-
latacept) and a possible risk of PTLD supports the monitoring
of EBV-seronegative recipients of organs from seropositive do-
nors with use of quantitative molecular assays (plasma or whole
blood) monthly for at least 1 year after induction therapy [124].
For patients with detectable EBV loads, consideration should
be given to decreasing the intensity of immunosuppression and
to increasing the monitoring of EBV loads. Quantitative EBV
assays of whole blood have higher sensitivity than do serum
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assays; PTLD can develop in patients with low EBV loads [125].
BKV. Kidney recipients who are receiving induction ther-
apy with T celldepleting agents should be monitored for BKV
infection with use of a sensitive urine (either cytopathology for
decoy cells or a quantitative, nucleic acidbased viral load assay)
or blood (DNA) screening test at least monthly for 6 months.
Any unexplained increase in serum creatinine level should
prompt examination of a renal biopsy specimen with use of
immunostaining or in situ hybridization for the detection of
BKV [76, 81, 124, 126].
HCV. In patients who are HCV seropositive, a quantitative
HCV RNA load measurement is recommended at baseline and
at 3, 6, 9, and 12 months after transplantation [124]. Quan-
titative HCV load does not correlate with the degree of hepatic
injury [127], and examination of biopsy specimens will be
needed to guide decisions regarding antiviral therapy [124].
SUMMARY
Infectious risks are greater when antilymphocyte therapies are
used in the treatment of graft rejection, compared with the use
of these therapies in induction immunosuppression. Antiviral
prophylaxis will reduce the risk for CMV infection associated
with induction therapy with ATG. BKV replication and BKV-
associated nephropathy occur earlier and are more common
with induction therapy. In contrast, patients who receive IL-
2R antagonists for induction therapy experience a lower inci-
dence of infection overall and of PTLD. The use of T cell
depleting agents (e.g., ATG, OKT3, and alemtuzumab) for
graft-rejection or induction therapy should be linked to ap-
propriate monitoring and/or prophylaxis for pneumonia due
to P. carinii and for CMV and fungal infection. Monitoring of
EBV in seronegative recipients of organs from EBV-seropositive
donors and monitoring of BKV in renal transplant recipients
should be performed using quantitative assays for patients who
are receiving T celldepleting agents.
Acknowledgments
Potential conflicts of interest. J.A.F. has served as a consultant for
Bristol-Myers Squibb, Merck, Hoffman-La Roche, T2 Biosystems, Astellas,
and FDA/CBERXenotransplantation; has served on the scientific advisory
board for Primera; has served on the speakers bureau for Hoffman-La
Roche; and has received corporate grant support from PATH Alliance (Ax-
iom/Astellas). J.A.F. has patents for molecular cloning of antigens shared
by rat- and human-derived Pneumocystis carinii (patent 5442050; GenBank
accession numbers L43850, L43851, and L43852) and molecular sequence
of swine retrovirus and methods of use (patent 6190861; patent cooperation
treaty international patent WO07/21836; GenBank accession numbers
AF038600, AF038601, and AF038599). N.C.I.: no conflicts.
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