Infection in the solid organ transplant recipient

infection and malignancy have become the main barriers to disease-free survival after
organ transplantation. When infection occurs, early and specific diagnosis and rapid
and aggressive treatment are essential. Pulmonary processes can progress rapidly and
may constitute medical emergencies. These include infections due to Pneumocystis
jirovecii (formerly P. carinii), Nocardia asteroides, Aspergillus spp, Cryptococcus
neoformans, cytomegalovirus (CMV), varicella-zoster virus (VZV), influenza,
respiratory syncytial virus (RSV), and Legionella spp.

Inflammatory responses associated with microbial invasion are impaired by

immunosuppressive therapy, which results in diminished symptoms and muted clinical
and radiologic findings. up to 40 percent of infections cause no fever (especially with
fungal infections) and up to 22 percent of fevers are noninfectious in origin Serologic
testing is not generally useful for the diagnosis of acute infection in the
immunocompromised host since seroconversion is often delayed. Serologic assays may
be used to identify latent infections and distant exposures as a basis for prophylaxis.
Altered anatomy following transplant surgery may change the physical signs of
infection. Diagnosis often requires anatomic data from imaging such as computed
tomography (CT) scans or magnetic resonance imaging (MRI). Tissue biopsies with
histopathology and microbiology are often needed to make a specific microbiologic
diagnosis in transplant recipients. Such clinical samples must be obtained early in the
clinical course to enhance the chance for successful therapy,
Drug levels provide only crude means of monitoring immunosuppressive regimens
and patients are often more or less immunosuppressed than anticipated. Bacteremia is
more common in solid organ transplant recipients than in other hosts and usually occurs
in association with urinary tract or other focal infections.

RISK OF INFECTION FOLLOWING TRANSPLANTATION bacterial and fungal

pathogens are more important in the setting of neutropenia, while viral (eg,
cytomegalovirus [CMV]) and intracellular (eg, tuberculosis [TB]) infections are more
common with T cell immune deficits. Strongyloides stercoralis may reactivate many
years following transplantation

Community-acquired pathogens common respiratory viruses (influenza,

parainfluenza, respiratory syncytial [RSV] virus, adenovirus, and human
metapneumovirus) and bacterial, viral, and parasitic gastrointestinal pathogens that may
produce more persistent infections in these hosts (eg, with norovirus). Common
bacterial pathogens include Streptococcus pneumoniae, Mycoplasma, Legionella,
Listeria monocytogenes, and Salmonella. Vaccinations for pneumococcus and influenza
virus are encouraged but may have reduced efficacy. In the appropriate geographic
regions, endemic fungi (Histoplasma capsulatum, Coccidioides spp, Paracoccidioides
spp, Blastomyces dermatitidis, Cryptococcus gattii) and common environmental
pathogens (eg, Cryptococcus neoformans, Aspergillus spp, Cryptosporidia spp)

Reactivation of infections Reactivated infection may be derived from the organ

donor or the recipient. herpes simplex virus (HSV), CMV, varicella-zoster virus (VZV,
shingles), hepatitis B (HBV) and hepatitis C (HCV), papillomavirus, and BK
polyomavirus. Some exposures may have occurred many years before transplantation
(eg, histoplasmosis, coccidioidomycosis, blastomycosis), Mycobacterium tuberculosis,
Strongyloides stercoralis, Leishmania spp, or Trypanosoma cruzi [

Nosocomial infections Legionella spp and other gram-negative bacilli such as

Pseudomonas aeruginosa and multidrug-resistant organisms Gram-positive organisms,
particularly antimicrobial-resistant species such as vancomycin-resistant enterococci
(VRE) and methicillin-resistant Staphylococcus aureus (MRSA) Fungi such as
Aspergillus spp and non-albicans or azole-resistant Candida species Clostridium
difficile colitis

Donor-derived infections . In immunosuppressed hosts, classic signs of infections

(eg, leukocytosis, erythema) may be replaced by nonspecific signs (eg, altered mental
status, elevation of blood liver function tests, wound dehiscence, unexplained
hypotension). Bloodstream infection Some donors may have active infection at the
time of procurement. Certain pathogens (eg, staphylococci, pneumococcus, Candida,
Salmonella, E. coli) may "stick" to anastomotic sites (vascular, urinary, biliary, tracheal)
and produce fever, bloodstream infections, or mycotic aneurysms. Inapparent infections
accelerated by immunosuppression Other donor-derived infections may be
inapparent or unusual (eg, West Nile virus, leishmaniasis, rabies, lymphocytic
choriomeningitis virus, Chagas disease, HIV, herpes simplex virus) and may cause
clinical syndromes that are accelerated by immune suppression.CMV and EBV . The
greatest risk for invasive infection is seen in recipients who are seronegative
(immunologically naive) and receive infected grafts from seropositive donors (latent
viral infection). This risk constitutes the rationale for anti-CMV prophylaxis in such
patients. Late, latent infections including tuberculosis and histoplasmosis may
activate many years after transplantation.

HIV, HTLV, and hepatitis viruses In 2007, four recipients of organs from a single
donor, who had died from trauma, were infected with both HIV and hepatitis C [40].
The donor had presumably been infected during the weeks prior to death since the
antibody tests for these viruses were negative during the pretransplant donor screening.
Other cases of donor-derived hepatitis C infections, as well as hepatitis B infections,
have also been reported [36,41,42].

Donor-derived human T lymphotropic virus (HTLV) infections with subsequent

development of cutaneous T cell lymphoma [43] and, rarely, HTLV-I associated
myelopathy/tropical spastic paraparesis have also been reported. Serologic screening of
organ donors for HTLV is no longer required in the United States. This is discussed in
detail separately. (See "Human T-lymphotropic virus type I: Virology, pathogenesis, and
epidemiology", section on 'Tissue donation'.)

The likelihood of tissue donors having viremia due to hepatitis B, hepatitis C, HIV, and
HTLV was evaluated in 11,391 tissue donors to five tissue banks in the United States
[44]. The estimated probability of viremia at the time of donation that would be
undetected by screening with current serologic methods (because of the window period
for infection) was 1 in 34,000 for hepatitis B, 1 in 42,000 for hepatitis C, 1 in 55,000 for
HIV, and 1 in 128,000 for HTLV. The use of nucleic acid amplification testing, which
shortens the window period, was estimated to reduce the probabilities of viremia to 1 in
100,000 for hepatitis B, 1 in 421,000 for hepatitis C, and 1 in 173,000 for HIV.
However, no available assays can completely exclude the risk of infectious
transmissions, especially in the limited time available for decreased donor screening
prior to transplantation [22].

Net state of immunosuppression The net state of immunosuppression is a complex

function determined by the interaction of several factors [45-51]:

Type, dose, duration, and temporal sequence of immunosuppressive therapies (table 4)

Underlying diseases or comorbid conditions

Presence of devitalized tissues or fluid collections in the transplanted organ

Invasive devices such as vascular access or urinary catheters, surgical drains, and
ventricular assist devices

Other host factors affecting immune function including neutropenia,

hypogammaglobulinemia, and metabolic problems (eg, protein-calorie malnutrition,
uremia, diabetes)

Concomitant infection with immunomodulating viruses including CMV, Epstein-Barr

virus (EBV), human herpesvirus (HHV)-6 and -7, HBV, and HCV

The sum of any congenital, acquired, metabolic, operative, and transplant-related factors
is the patient's "net state of immune suppression." More than one factor is usually
present in each host. The identification and correction of any modifiable risk factor is
essential for the prevention and treatment of infection.

Advances in the assessment of T and B cell responses to specific pathogens, such as

cytomegalovirus, have been achieved using cell sorting technologies that measure the
level of immune responses committed to specific pathogens [52-54]. Immune
competence may be measured crudely using cell counts, the frequency and severity of
common infections (eg, herpes simplex virus), or the presence of circulating viruses.
Nonspecific assays have been introduced to assess susceptibility to infection. Some are
based in the production of intracellular ATP in response to mitogenic stimulation [55].
These assays are more useful in measuring the risk of infection than rejection. However,
they have not yet been well validated prospectively for the ability to predict the risk for
infection in individual transplant recipients.

TIMING OF INFECTION POSTTRANSPLANTATION Immunosuppressive

regimens vary between centers, with the organ transplanted, and the patient population.
As an example, "induction" with polyclonal or monoclonal anti-T lymphocyte antisera
may be used for renal transplantation from deceased donors but not in living related
donor transplant recipients or in liver transplant recipients with hepatitis C infection. At
some centers, patients may receive little or no glucocorticoid therapy but are treated
with combinations of multiple other potent immunosuppressants. Alterations in the type
or intensity of immune suppression will alter the risk of infection (table 4) and the list of
potential pathogens (table 3).

It is useful to divide the posttransplant course into three time periods related to the risks
of infection by specific pathogens: the early period post transplant (first month), an
intermediate period (one to six months), and more than six months (figure 1) [1,3]. This
timetable is useful in three ways:

In developing a differential diagnosis for the individual transplant recipient with

clinical signs of infection

As a clue to the presence of excessive environmental hazards (nosocomial, community

or individual)

As a guide to the design of preventive antimicrobial strategies

First month after transplantation In the first month post-transplant, there are two
major causes of infection in all forms of solid organ transplantation: infection derived
from either the donor or recipient and infectious complications of the transplant surgery
and hospitalization. The major effects of exogenous immunosuppression are not yet
evident. Exceptions include those patients who receive immunosuppression prior to
transplantation (eg, for autoimmune hepatitis).

Donor-derived infections The risk for infections acquired with the allograft is
discussed above (table 3) [18-20,56]. Transmission of donor-derived bacteria and fungi
has increased with the emergence of antimicrobial resistance such that vancomycin-
resistant enterococci, methicillin-resistant staphylococci, and fluconazole-resistant
Candida species may be transmitted from donor to recipient. Graft-associated viral
infections (LCMV, West Nile virus, rabies, HIV) and parasitic infections
(toxoplasmosis, Chagas disease, Balamuthia mandrillaris) are uncommon but may be
amplified in the immunosuppressed host. Endemic infections (eg, histoplasmosis or
tuberculosis) should be considered in the differential diagnosis of posttransplant
infection or unusual clinical syndromes (eg, encephalitis, hepatitis). (See 'Donor-derived
infections' above.)

Recurrent infection Infection may have been present in the donor or in the recipient
prior to transplantation. An important component of the pretransplant evaluation is to
recognize and treat such infections, if possible. (See "Evaluation for infection before
solid organ transplantation".)

Some common viral infections (eg, hepatitis B virus or hepatitis C virus) may reemerge
early after transplantation. Recipient-derived tuberculosis or toxoplasmosis tends to
reactivate more than a month after transplantation. Reactivation of Strongyloides may
be accompanied by gram-negative bacterial sepsis, meningitis, or pneumonia [9].

Infectious complications related to surgery Solid organ transplant recipients develop

many of the common postoperative complications, such as aspiration pneumonitis,
surgical site (wound) infections, "line sepsis," urinary tract infection, or pulmonary
embolus [57]. Transplant recipients are also at unique risk for superinfection of
ischemic or injured graft tissues (eg, anastomotic suture lines) or of fluid collections
(eg, hematomas, lymphoceles, pleural effusions, urinomas). These patients are at
increased risk for infection associated with indwelling vascular access catheters, urinary
catheters, and surgical drains.

The organisms responsible for such postoperative complications are often the bacteria
and fungi that have colonized the recipient or donor (eg, the lungs and/or sinuses in
cystic fibrosis) prior to transplantation or the local flora of the hospital. Infections
acquired prior to transplantation may include relatively resistant nosocomial pathogens
(eg, vancomycin-resistant enterococcus) and pathogens such as Aspergillus spp that are
resistant to the usual prophylactic agents. Patients receiving antimicrobial agents are at
increased risk for C. difficile colitis.

Patients at particular risk of nosocomial infection are those requiring prolonged

ventilatory support or those with diminished lung function, persistent ascites, stents of
the urinary tract or biliary ducts, with intravascular clot or ischemic graft tissue [49,58].
Individuals with delayed graft function or who require early reexploration or
retransplantation are also at increased risk for infection, notably with fungi or bacteria
with antimicrobial resistance.

1 to 6 months after transplantation In the period one to six months post-transplant,

the nature of common infections changes. This is the period when patients are most at
risk for the development of opportunistic infections, although residual problems from
the perioperative period can persist. There is significant geographic and institutional
variation in the occurrence of opportunistic infections during the first six months post
transplantation. This reflects local epidemiology and varying immunosuppressive
strategies and also the use of antimicrobial prophylaxis in the posttransplant period.
Prevention of the infections observed during this period is the basis of prophylactic
antimicrobial strategies. Prophylaxis delays but does not eliminate the risk for infections
that may occur in the months following cessation of prophylaxis. (See "Prophylaxis of
infections in solid organ transplantation".)

Major infections due to opportunistic pathogens include:

Pneumocystis jirovecii (formerly P. carinii) pneumonia (PCP) (see "Fungal infections

following lung transplantation", section on 'Pneumocystis jirovecii')

Latent infections, such as the protozoal diseases including toxoplasmosis,

leishmaniasis, and Chagas disease [8,47,48,59-61]

The geographic or endemic fungal infections caused by Histoplasma capsulatum,

Coccidioides spp, Cryptococcus gattii, and, rarely, Blastomyces dermatitidis (see
"Fungal infections following lung transplantation")

Viral pathogens, particularly the herpes group viruses but also hepatitis B (HBV) and
hepatitis C (HCV). New viruses are recognized as opportunistic pathogens with the use
of more sensitive molecular assays (eg, BK polyomavirus, human herpesvirus [HHV]-6,
-7, and -8 [Kaposi's sarcoma-associated herpesvirus, KSHV]) (table 5). Respiratory
viruses are increasingly important in this population (influenza, parainfluenza,
respiratory syncytial virus [RSV], adenovirus, metapneumovirus).

Tuberculosis and, increasingly, nontuberculous mycobacteria [62] (see "Tuberculosis

in solid organ transplant candidates and recipients" and "Nontuberculous mycobacterial
infections in solid organ transplant candidates and recipients")

Gastrointestinal parasites (Cryptosporidium and Microsporidium) and viruses

(cytomegalovirus [CMV], rotavirus) may be associated with diarrhea.

More than 6 to 12 months after transplantation Six to twelve months or longer post-
transplant, most patients are receiving stable and reduced levels of immunosuppression.
These patients are subject to community-acquired pneumonias due to respiratory
viruses, the pneumococcus, Legionella, or other common pathogens.

Patients who have less than adequate graft function tend to require higher than usual
immunosuppressive therapy. As a result, they represent a subgroup of transplant patients
at highest risk for opportunistic infections including PCP, cryptococcosis, and
nocardiosis. They are also at risk for severe illness from community-acquired infections
due to influenza or Listeria monocytogenes. Prolonged antimicrobial prophylaxis may
be indicated for this subgroup of patients, who remain more immunosuppressed. This
group of patients may also suffer rare infections in the late transplant period and may
have clinical findings that differ from those in immunocompetent hosts. These
infections are most often due to molds or Nocardia species or the late effects of viral
infections manifest as malignancy: posttransplant lymphoproliferative disorder (PTLD)
or squamous cell cancers of the skin or anogenital region. (See "Prophylaxis of
infections in solid organ transplantation".)

VIRUSES AS COPATHOGENS Viruses, particularly cytomegalovirus (CMV), serve

as important cofactors to many opportunistic infections [1,45,46]. The potential effects
of viral infection are diverse and apply not only to CMV but also to hepatitis B (HBV),
hepatitis C (HCV), Epstein-Barr virus (EBV), and probably other common viruses such
as respiratory syncytial virus (RSV), human herpesvirus (HHV)-6, and adenovirus
(table 6). Viruses contribute to a variety of processes post transplantation (table 5)
[1,46,49,63-65].

Direct effects "Direct effects" include clinical syndromes such as fever and
neutropenia (CMV), pneumonitis (respiratory viruses), hepatitis (HCV, HBV), gastritis,
esophagitis, colitis (CMV), cholangitis (varicella-zoster virus [VZV]), encephalitis
(herpes simplex virus [HSV], JC virus), pancreatitis, myocarditis, and retinitis. Less
common syndromes include adrenalitis with adrenal insufficiency or
meningoencephalitis due to CMV vasculitis.

Indirect effects "Indirect effects" are generally immune effects including:

Immune suppression and predisposition to opportunistic infection (eg, Aspergillus

after RSV pneumonia, Pneumocystis after CMV infection). Thus, CMV coinfection has
been implicated in the accelerated course of HCV infection with cirrhosis and graft loss
and of EBV with increased risk for posttransplant lymphoproliferative disorder (PTLD,
usually B-cell lymphoma).

Graft rejection that is thought to be mediated by proinflammatory cytokine release

and/or upregulation of histocompatibility antigens or adhesion proteins in the setting of
CMV reactivation [63,66,67]. Graft rejection may necessitate an increase in the
immunosuppressive regimen and an increased risk for opportunistic infection.

Oncogenesis Many viruses predispose to cancer (HCV, EBV) or to cellular

proliferation (CMV and accelerated atherogenesis, BK polyomavirus and ureteric
smooth muscle cell proliferation).

Specific viral pathogens The spectrum of viral infections in the transplant recipient
has expanded with the discovery of new viruses (table 5).

The BK polyomavirus has been associated with infection of renal allografts with
hemorrhagic cystitis, asymptomatic viruria, interstitial nephritis, ureteric obstruction,
and rising creatinine values in renal transplant recipients [68-71]. (See "Overview of JC
polyomavirus, BK polyomavirus, and other polyomavirus infections".)

Adenovirus may cause a similar hemorrhagic nephritis/cystitis picture diagnosed by

culture or antigen detection/immunofluorescence. (See "Epidemiology and clinical
manifestations of adenovirus infection".)

HHV-6, -7, and -8 have also been identified in transplant recipients [72] (see
"Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection" and
"Human herpesvirus 7 infection" and "Disease associations of human herpesvirus 8
infection"). HHV-6 has been implicated as a cofactor in CMV infection (and vice versa)
or may cause leukopenia and fever as part of a viral syndrome. The role of HHV-7
remains to be clarified.

EBV, VZV, and HSV are also often activated during this one to six month period. EBV
may be associated with the development of B cell non-Hodgkin lymphoma, particularly
in seronegative recipients of seropositive organs. However, some cases of T cell, NK
cell, and non-EBV-related PTLD have been described (see "Treatment and prevention
of post-transplant lymphoproliferative disorders"). Herpes zoster of the skin (shingles)
may occur; occasionally, patients present with cholangitis due to VZV. Human
papillomavirus (HPV) is associated with anogenital and squamous cell cancers.

Parvovirus B19 may also present in this time period with anemia unresponsive to
erythropoietin or with myocarditis [73]. Parvovirus B19 has also been associated with
chronic allograft injury in renal transplant recipients [74].

Respiratory viruses remain important community-acquired pathogens, particularly in

the lung transplant recipient [75]. Infections with these latter viruses predispose the
patient to the development of bacterial infections and graft rejection.

Viruses that have been reported rarely in solid organ transplant recipients include
human T lymphotropic virus, hepatitis E virus, rabies virus, lymphocytic
choriomeningitis virus, measles, mumps, dengue, orf, and human coronaviruses HKU1
and NL63 [76]. Most of these were infections derived from asymptomatic organ donors.

EVALUATION AND MANAGEMENT The pursuit of diagnostic testing and the

management of infection in a transplant recipient must be guided by a number of
principles:

These hosts generally have fewer clinical manifestations of infection and few or no
findings by conventional radiography. Thus, more sensitive imaging techniques such as
computed tomographic (CT) scans and magnetic resonance imaging (MRI) are essential
for assessing the presence and nature of infectious and malignant processes.

The "gold standard" for diagnosis is tissue histology. No radiologic finding is

sufficiently diagnostic to obviate the need for tissue. Multiple simultaneous infections
are also common. Thus, invasive procedures that provide tissue for culture and
histology must be employed early as a routine component of the initial evaluation of
transplant recipients with infectious syndromes. Patients failing to respond to
appropriate therapy may also need invasive diagnostic procedures.

Serologic tests, which indicate past exposure to certain pathogens, are useful in the
pretransplant setting to assess risk for relapse of latent disease but are not generally
useful after transplantation. Patients, especially those receiving immunosuppressive
therapies, do not reliably develop antibodies quickly enough during an active infection
to enable a serologic diagnosis. Thus, quantitative tests that directly detect the protein
products or nucleic acids of the organisms such as sandwich enzyme linked
immunosorbent assays (ELISA), direct immunofluorescence, or quantitative molecular
assays (nucleic acid tests [NATs]) should be utilized.

Transplant recipients are often colonized and thus are particularly vulnerable to
organisms resistant to antimicrobial agents either from the hospital environment or
through induction of antibiotic resistance in their flora during therapy (eg, inducible
beta-lactamases). Sites at risk for infection with resistant organisms (eg, ascites, blood
clots, drains, lungs) can be sampled so that information is available to guide empiric
therapy at times of clinical deterioration.
When undrained fluid collections, blood, or devitalized tissues are present,
antimicrobial therapy alone is often inadequate. Antibiotics, used in lieu of definitive
drainage or debridement, merely delay clinical deterioration and promote the acquisition
of resistant microorganisms. Early and aggressive surgical debridement of such
collections is essential for successful care.

Some components of the immunosuppressive regimen may be modified during acute

infection to elicit an improved host response. This must be done with caution since
reductions in immunosuppression may provoke immune reconstitution syndromes or
allograft rejection.

Infectious disease consultation improves outcomes in solid organ transplant recipients.

As an example, in a study of solid organ transplant recipients admitted with an
infection, infectious disease consultation was associated with reduced 28-day mortality
(hazard ratio 0.33) and 30-day rehospitalization rates (17 versus 24 percent) [77]. The
median length of stay and hospitalization costs did not differ between patients who
received an early infectious disease consultation (<48 hours) and those who did not.

The evaluation for infection prior to solid organ transplantation is discussed separately.
(See "Evaluation for infection before solid organ transplantation".)

FUTURE DIRECTIONS Many important hurdles remain to be overcome in the

diagnosis and treatment of infections to enhance the safety and success of solid organ
transplantation. The initiation of a diagnostic evaluation for infection frequently begins
when clinical symptoms become manifest. That is often late in the course of the disease
in these immunocompromised patients. Further, accurate microbiologic diagnoses are
needed to avoid unnecessary toxicities associated with therapy. Thus, invasive
diagnostic procedures are often required to make an accurate microbiologic diagnosis
[78-80].

More advanced, quantitative laboratory assays utilizing molecular techniques or antigen

detection are integral components of transplant care. Such tests may be prohibitively
costly for routine use in some areas. Rapid, quantitative, cost-effective assays that do
not depend upon invasive procedures are needed for the routine monitoring of transplant
patients for infections and for graft rejection. The availability of such tests would allow
the clinician to individualize prophylactic antimicrobial regimens and minimize drug-
associated toxicity.

The evolution of pathogens (bacteria, viruses, fungi) with acquired resistance to

common antimicrobial agents and the incidence of drug toxicity and allergy have
limited the available antimicrobial strategies for transplant recipients. New
antimicrobial agents are needed for prophylaxis and therapy.

SUMMARY

The risk of infection in the organ transplant patient is determined by the synergy
between two factors: the epidemiologic exposures of the individual and the "net state of
immunosuppression," which is a conceptual measure of all of the factors that contribute
to the individual's susceptibility (or resistance) to infection. (See 'Risk of infection
following transplantation' above and 'Epidemiologic exposures' above and 'Net state of
immunosuppression' above.)

It is useful to divide the posttransplant course into three time periods related to the
risks of infection by specific pathogens: the early period post-transplant (first month),
an intermediate period (1 to 6 months), and more than 6 to 12 months (figure 1). The
timing of the presentation of infectious processes will be altered (delayed) by the
deployment of antimicrobial prophylaxis. This may result in the delayed presentation of
infection (eg, "late cytomegalovirus [CMV]"). (See 'Timing of infection
posttransplantation' above.)

In the first month post-transplant, the major causes of infection in all forms of solid
organ transplantation include infection derived from either the donor or recipient and
infectious complications of the transplant surgery and hospitalization. (See 'First month
after transplantation' above.)

The period 1 to 6 months post-transplant is the period when patients suffer the greatest
impact of immunosuppression and are at the greatest risk for the development of
opportunistic infections. Patterns are altered by prophylaxis. (See '1 to 6 months after
transplantation' above.)

Six to 12 months or longer post-transplant, most patients are receiving stable and
reduced levels of immunosuppression. These patients are subject to community-
acquired pneumonias due to respiratory viruses, the pneumococcus, Legionella, or other
common pathogens. (See 'More than 6 to 12 months after transplantation' above.)

Viruses, particularly CMV, serve as important cofactors to many opportunistic

infections. The potential effects of viral infection are diverse and apply not only to
CMV but also to hepatitis B (HBV), hepatitis C (HCV), Epstein-Barr virus (EBV), and
probably other common viruses such as respiratory syncytial virus (RSV), human
herpesvirus (HHV)-6, and adenovirus (table 6). (See 'Viruses as copathogens' above.)

The pursuit of diagnostic testing and the management of infection in a transplant

recipient must be guided by a number of principles:

These hosts may have nonspecific clinical manifestations of infection and few or no
findings by conventional radiography. Thus, more sensitive imaging techniques such as
computed tomographic (CT) scans and magnetic resonance imaging (MRI) are
necessary.

The "gold standard" for microbiologic diagnosis includes culture as well as tissue
histology. Tests that detect proteins, polysaccharide antigens, or nucleic acids are
important to transplant management.

Serologic tests, which indicate past exposure to pathogens, are useful in the
pretransplant setting to assess the presence of latent disease but are not generally useful
for acute diagnosis after transplantation.

Transplant recipients are often colonized by organisms resistant to antimicrobial agents

from the hospital environment or selected during antimicrobial therapy.
When undrained fluid collections, blood, or devitalized tissues are present,
antimicrobial therapy alone is inadequate. Early and aggressive surgical debridement of
such collections is essential for successful care. (See 'Evaluation and management'
above.)

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45. van den Berg AP, Klompmaker IJ, Haagsma EB, et al. Evidence for an increased
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46. George MJ, Snydman DR, Werner BG, et al. The independent role of
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54. Westall GP, Mifsud NA, Kotsimbos T. Linking CMV serostatus to episodes of
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56. Morris MI, Fischer SA, Ison MG. Infections transmitted by transplantation.
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58. Fishman JA. Vancomycin-resistant Enterococcus in liver transplantation: what

have we left behind? Transpl Infect Dis 2003; 5:109.

59. Bocchi EA, Bellotti G, Mocelin AO, et al. Heart transplantation for chronic
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61. Fernndez-Sab N, Cervera C, Farias MC, et al. Risk factors, clinical features,
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63. Mendez JC, Dockrell DH, Espy MJ, et al. Human beta-herpesvirus interactions
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65. Terrault NA, Wright TL, Pereira BJ. Hepatitis C infection in the transplant
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72. Singh N, Carrigan DR. Human herpesvirus-6 in transplantation: an emerging

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73. Eid AJ, Brown RA, Patel R, Razonable RR. Parvovirus B19 infection after
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in kidney transplant recipients unveils an association between parvovirus B19
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Infection in the solid organ transplant recipient

Topic Outline
SUMMARY

INTRODUCTION

GENERAL PRINCIPLES

RISK OF INFECTION FOLLOWING TRANSPLANTATION

o Epidemiologic exposures

o Community-acquired pathogens

o Reactivation of infections

o Nosocomial infections

o Donor-derived infections

- Bloodstream infection

- Inapparent infections accelerated by immunosuppression

- CMV and EBV

- Tuberculosis and histoplasmosis

- HIV, HTLV, and hepatitis viruses

o Net state of immunosuppression

TIMING OF INFECTION POSTTRANSPLANTATION

o First month after transplantation

- Donor-derived infections

- Recurrent infection

- Infectious complications related to surgery

 o 1 to 6 months after transplantation

o More than 6 to 12 months after transplantation

VIRUSES AS COPATHOGENS

o Direct effects

o Indirect effects

o Specific viral pathogens

EVALUATION AND MANAGEMENT

FUTURE DIRECTIONS

SUMMARY

REFERENCES

GRAPHICS View All

FIGURES

o - Infection timeline SOT

TABLES

o - Fungal infx in transplantation

o - Infection exclusion organ donor

o - Donor-derived infections

o - Immunosuppressive rx infections

o - Common viral infections in SOT recipients

o - CMV effects in transplantation

RELATED TOPICS
Approach to the diagnosis of cytomegalovirus infection

Clinical manifestations, diagnosis, and management of cytomegalovirus disease

in kidney transplant recipients
 Disease associations of human herpesvirus 8 infection

Epidemiology and clinical manifestations of adenovirus infection

Evaluation for infection before hematopoietic cell transplantation

Evaluation for infection before solid organ transplantation

Fungal infections following lung transplantation

Human T-lymphotropic virus type I: Virology, pathogenesis, and epidemiology

Human herpesvirus 7 infection

Immunizations in solid organ transplant candidates and recipients

Infectious complications in liver transplantation

Nontuberculous mycobacterial infections in solid organ transplant candidates

and recipients

Overview of JC polyomavirus, BK polyomavirus, and other polyomavirus

infections

Overview of infections following hematopoietic cell transplantation

Prevention of cytomegalovirus infection in lung transplant recipients

Prevention of infections in hematopoietic cell transplant recipients

Prophylaxis of infections in solid organ transplantation

Treatment and prevention of post-transplant lymphoproliferative disorders

Tuberculosis in solid organ transplant candidates and recipients

Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection

Infection in the solid organ transplant recipient

Author:
Jay A Fishman, MD
Section Editor:
Kieren A Marr, MD
Deputy Editor:
Sheila Bond, MD

Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process
is complete.
Literature review current through: Aug 2017. | This topic last updated: Dec 14, 2016.

INTRODUCTION Solid organ transplantation has increased worldwide since the

first successful human kidney transplant was performed in 1954. As immunosuppressive
agents and graft survival have improved, infection and malignancy have become the
main barriers to disease-free survival after organ transplantation. As a result of the
growing population of immunosuppressed patients with prolonged survival, an
increased incidence and spectrum of opportunistic infections is observed [1-3].
Guidelines for the diagnosis and treatment of infection in transplant recipients have
been developed [4].

The risks of infection and an overview of specific infections in the solid organ
transplant recipient will be reviewed here. The pretransplant evaluation for solid organ
and hematopoietic cell transplant (HCT) recipients, prophylaxis of infections in solid
organ transplant and HCT recipients, and an overview of infections following HCT are
discussed separately. (See "Evaluation for infection before solid organ transplantation"
and "Evaluation for infection before hematopoietic cell transplantation" and
"Prophylaxis of infections in solid organ transplantation" and "Prevention of infections
in hematopoietic cell transplant recipients" and "Overview of infections following
hematopoietic cell transplantation".)

GENERAL PRINCIPLES When infection occurs, early and specific diagnosis and
rapid and aggressive treatment are essential to good clinical outcomes.

Potential etiologies of infection in these patients are diverse, including common,

community-acquired bacterial and viral diseases and uncommon opportunistic
infections of clinical significance only in immunocompromised hosts [1-3]. Pulmonary
processes can progress rapidly and may constitute medical emergencies [1]. These
include infections due to Pneumocystis jirovecii (formerly P. carinii), Nocardia
asteroides, Aspergillus spp, Cryptococcus neoformans, cytomegalovirus (CMV),
varicella-zoster virus (VZV), influenza, respiratory syncytial virus (RSV), and
Legionella spp.

Inflammatory responses associated with microbial invasion are impaired by

immunosuppressive therapy, which results in diminished symptoms and muted clinical
and radiologic findings. Fever is neither a sensitive nor a specific predictor of infection;
up to 40 percent of infections cause no fever (especially with fungal infections) and up
to 22 percent of fevers are noninfectious in origin [5]. Infections are often advanced (ie,
disseminated) at the time of clinical presentation.

Serologic testing is not generally useful for the diagnosis of acute infection in the
immunocompromised host since seroconversion is often delayed. Serologic assays may
be used to identify latent infections and distant exposures as a basis for prophylaxis.
Microbiologic cultures are supplemented by antigen-based tests (eg, enzyme linked
immunosorbent assays [ELISAs]) or nucleic acid-based molecular assays (eg,
polymerase chain reaction [PCR]) for diagnosis in this population.
Altered anatomy following transplant surgery may change the physical signs of
infection. Diagnosis often requires anatomic data from imaging such as computed
tomography (CT) scans or magnetic resonance imaging (MRI).

Tissue biopsies with histopathology and microbiology are often needed to make a
specific microbiologic diagnosis in transplant recipients. Such clinical samples must be
obtained early in the clinical course to enhance the chance for successful therapy, to
minimize side effects of therapy, and before the patient's illness progresses to a point
where such procedures can no longer be performed.

The choice of antimicrobial regimens is often more complex than in other patients due
to the urgency of therapy and the frequency of drug toxicities and drug interactions.

Antimicrobial resistance is increased in immunocompromised hosts and should be

considered in the choice of antimicrobial regimens.

Surgical intervention is often necessary to cure localized infections (ie, debridement);

antimicrobial agents alone are frequently inadequate.

Drug levels provide only crude means of monitoring immunosuppressive regimens

and patients are often more or less immunosuppressed than anticipated. Side effects of
these regimens are also common.

For all of these reasons, the central focus must be on disease prevention, including drug
therapy and vaccination. This requires stratification of the risk for various infections.
(See "Prophylaxis of infections in solid organ transplantation" and "Immunizations in
solid organ transplant candidates and recipients" and "Evaluation for infection before
solid organ transplantation".)

Bacteremia is more common in solid organ transplant recipients than in other hosts and
usually occurs in association with urinary tract or other focal infections. In a case-
control study, the mortality rate due to bacteremic sepsis appeared to be lower in solid
organ transplant recipients compared with non-transplant patients at 28 days (hazard
ratio [HR] 0.22, 95% CI 0.09-0.54) and at 90 days (HR 0.43, 95% CI 0.20-0.89) [6]. In
a retrospective cohort study of patients with sepsis, solid organ transplant recipients had
a lower rate of mortality than nontransplant patients [7]. The association was seen in all
types of transplant recipients except lung transplant recipients, who had a higher rate of
mortality, and heart transplant recipients, in whom there was no difference. It is
postulated that the lower rate of mortality in solid organ transplant recipients may be
due to the fact that the immunosuppression associated with transplantation may blunt
the inflammatory response to infection and/or that these patients may receive more
aggressive management.

RISK OF INFECTION FOLLOWING TRANSPLANTATION The risk of infection

in the organ transplant patient is determined by the synergy between two factors: the
epidemiologic exposures of the individual and the "net state of immunosuppression,"
which is a conceptual measure of all of the factors that contribute to the individual's
susceptibility (or resistance) to infection [1,4,8].
Epidemiologic exposures To adequately assess epidemiologic exposures, the
clinician must take a detailed history of potential encounters with a variety of
pathogens, even if the exposure was relatively remote. Latent pathogens are often
activated in the setting of immune suppression. The epidemiologic exposures of
importance to an individual will vary based upon the nature of the immune deficits.
Most transplant patients have multiple deficits. Thus, bacterial and fungal pathogens are
more important in the setting of neutropenia, while viral (eg, cytomegalovirus [CMV])
and intracellular (eg, tuberculosis [TB]) infections are more common with T cell
immune deficits. Strongyloides stercoralis may reactivate many years following
transplantation [1,9]. (See "Evaluation for infection before solid organ transplantation".)

Community-acquired pathogens The transplant recipient can have contact with a

number of potential pathogens within the community. These organisms include common
respiratory viruses (influenza, parainfluenza, respiratory syncytial [RSV] virus,
adenovirus, and human metapneumovirus) and bacterial, viral, and parasitic
gastrointestinal pathogens that may produce more persistent infections in these hosts
(eg, with norovirus). Common bacterial pathogens include Streptococcus pneumoniae,
Mycoplasma, Legionella, Listeria monocytogenes, and Salmonella. Vaccinations for
pneumococcus and influenza virus are encouraged but may have reduced efficacy in
immunocompromised individuals. (See "Immunizations in solid organ transplant
candidates and recipients".)

In the appropriate geographic regions, endemic fungi (Histoplasma capsulatum,

Coccidioides spp, Paracoccidioides spp, Blastomyces dermatitidis, Cryptococcus gattii)
and common environmental pathogens (eg, Cryptococcus neoformans, Aspergillus spp,
Cryptosporidia spp) will be observed. Thus, while specific infectious exposures within
the community will vary based upon such factors as geography and socioeconomic
status, the general dictum that "common things occur commonly" applies to transplant
recipients. The severity and duration of infection and the frequency of multiple
simultaneous processes are features that differentiate the transplant recipient from the
normal host.

Reactivation of infections Reactivated infection may be derived from the organ

donor or the recipient. Common viral infections that frequently reactivate following
transplantation include herpes simplex virus (HSV), CMV, varicella-zoster virus (VZV,
shingles), hepatitis B (HBV) and hepatitis C (HCV), papillomavirus, and BK
polyomavirus. Some exposures may have occurred many years before transplantation
including geographically restricted systemic mycoses (eg, histoplasmosis,
coccidioidomycosis, blastomycosis), Mycobacterium tuberculosis, Strongyloides
stercoralis, Leishmania spp, or Trypanosoma cruzi [8-12].

An important goal of the pretransplant evaluation is to identify such latent infections so

as to develop a preventive strategy for each. (See "Evaluation for infection before solid
organ transplantation".)

Nosocomial infections Transplant recipients are vulnerable to nosocomial infections,

especially in the early posttransplant (ie, postsurgical) period in patients with prolonged
hospitalizations or who require mechanical ventilation. Pathogens include:
Legionella spp and other gram-negative bacilli such as Pseudomonas aeruginosa and
multidrug-resistant organisms

Gram-positive organisms, particularly antimicrobial-resistant species such as

vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus
aureus (MRSA) [13]

Fungi such as Aspergillus spp and non-albicans or azole-resistant Candida species

(table 1) [14]

Clostridium difficile colitis [15-17]

When the air, food, equipment, or potable water supply either in the hospital or the
home are contaminated with pathogens such as Aspergillus spp, Legionella spp, or
gram-negative bacilli, clusters of infection can be observed in time and/or space.

Donor-derived infections Infections that are derived from donor organ tissues and
activated in the recipient are among the most important exposures in transplantation
[18-22]. Some of these infections are latent, while others are the result of bad timing
(unappreciated active infection in the donor at the time of transplantation). The
efficiency of the transmission of infectious diseases is likely to be greatest in
immunosuppressed transplant recipients. In immunosuppressed hosts, classic signs of
infections (eg, leukocytosis, erythema) may be replaced by nonspecific signs (eg,
altered mental status, elevation of blood liver function tests, wound dehiscence,
unexplained hypotension). As an example, in immunosuppressed hosts, the transmission
of bloodborne or organ-derived infection due to West Nile virus more often manifests as
neurologic disease with poor clinical outcomes than in immunocompetent hosts [23].
Clusters of infection associated with organ transplantation have also included
Mycobacterium tuberculosis, Candida and Aspergillus (and other fungal) species,
herpes simplex virus, human herpes virus 8, lymphocytic choriomeningitis virus
(LCMV) [24-27], rabies virus [28-30], Trypanosoma cruzi (causing Chagas disease),
Balamuthia mandrillaris [31-34], Encephalitozoon cuniculi (causing microsporidiosis)
[35], HIV, and hepatitis C virus.

Organ donors are screened to avoid transmission of certain infections to transplant

recipients (table 2). Nonetheless, transmission of infection from donor to recipient may
still occur (table 3). The data supporting transmission of the individual infections are
discussed separately in the appropriate topic reviews for each infection. Donor
screening requirements for HIV, HCV, and HBV have been updated [36].

Several types of infection merit special attention: bloodstream infection, inapparent

infections that are accelerated by immunosuppression, and a number of specific
infections.

Bloodstream infection Some donors may have active infection at the time of
procurement. Certain pathogens (eg, staphylococci, pneumococcus, Candida,
Salmonella, E. coli) may "stick" to anastomotic sites (vascular, urinary, biliary, tracheal)
and produce fever, bloodstream infections, or mycotic aneurysms. Proof of adequate
therapy for such infections must be established prior to accepting organs for
transplantation.
Inapparent infections accelerated by immunosuppression Other donor-derived
infections may be inapparent or unusual (eg, West Nile virus, leishmaniasis, rabies,
lymphocytic choriomeningitis virus, Chagas disease, HIV, herpes simplex virus) and
may cause clinical syndromes that are accelerated by immune suppression.

As an example, lymphocytic choriomeningitis virus infection (LCMV) occurred in the

recipients of solid organ transplants from three different donors [24,25]. In the
investigation of the first two clusters, LCMV was identified in tissues in all organ
transplant recipients from both investigations [24]. The isolates from each investigation
were identical to each other but distinct between the two outbreaks. In contrast, the
common donors had no clinical or laboratory evidence of infection, although the donor
from the 2005 cluster had a history of exposure to a pet hamster. Seven of eight
transplant recipients died; one survivor was treated with ribavirin and decreasing doses
of immunosuppressants. An epidemiologic investigation, using phylogenetic analysis of
virus sequences, eventually traced the origin of these infections to an animal distribution
center in Ohio [26].

Three patients in Australia who received a kidney or liver from a single donor died of a
febrile illness with associated encephalopathy four to six weeks after transplantation
[37]. High-throughput RNA sequencing from the allografts of two of the patients
revealed an arenavirus that is related to LCMV. These results were confirmed by
immunohistochemical analysis of allograft tissue as well as IgM and IgG antiviral
antibodies from the serum of the donor. In addition, polymerase chain reaction (PCR)
revealed the presence of the virus in the kidneys, liver, blood, and cerebrospinal fluid of
the recipients. The donor had just returned home from a three-month visit to rural areas
of the former Yugoslavia.

CMV and EBV Viral infections such as cytomegalovirus (CMV) and Epstein-Barr
virus (EBV) are associated with particular syndromes and morbidity in the
immunocompromised population. The greatest risk for invasive infection is seen in
recipients who are seronegative (immunologically naive) and receive infected grafts
from seropositive donors (latent viral infection). This risk constitutes the rationale for
anti-CMV prophylaxis in such patients. (See "Clinical manifestations, diagnosis, and
management of cytomegalovirus disease in kidney transplant recipients" and "Infectious
complications in liver transplantation" and "Prevention of cytomegalovirus infection in
lung transplant recipients" and "Approach to the diagnosis of cytomegalovirus
infection".)

Tuberculosis and histoplasmosis Late, latent infections including tuberculosis and

histoplasmosis may activate many years after transplantation. Early emergence of
tuberculosis in recipients has also been described after receiving organs from a donor
with undiagnosed active infection [38].

Mycobacterial infection may be difficult to treat after transplantation because of

interactions between the antimicrobial agents used to treat infection (eg, rifampin,
streptomycin, isoniazid) and immunosuppressive drugs [39].

The evaluation and management of tuberculosis in solid organ transplant recipients is

discussed in detail separately. (See "Tuberculosis in solid organ transplant candidates
and recipients".)
HIV, HTLV, and hepatitis viruses In 2007, four recipients of organs from a single
donor, who had died from trauma, were infected with both HIV and hepatitis C [40].
The donor had presumably been infected during the weeks prior to death since the
antibody tests for these viruses were negative during the pretransplant donor screening.
Other cases of donor-derived hepatitis C infections, as well as hepatitis B infections,
have also been reported [36,41,42].

Donor-derived human T lymphotropic virus (HTLV) infections with subsequent

development of cutaneous T cell lymphoma [43] and, rarely, HTLV-I associated
myelopathy/tropical spastic paraparesis have also been reported. Serologic screening of
organ donors for HTLV is no longer required in the United States. This is discussed in
detail separately. (See "Human T-lymphotropic virus type I: Virology, pathogenesis, and
epidemiology", section on 'Tissue donation'.)

The likelihood of tissue donors having viremia due to hepatitis B, hepatitis C, HIV, and
HTLV was evaluated in 11,391 tissue donors to five tissue banks in the United States
[44]. The estimated probability of viremia at the time of donation that would be
undetected by screening with current serologic methods (because of the window period
for infection) was 1 in 34,000 for hepatitis B, 1 in 42,000 for hepatitis C, 1 in 55,000 for
HIV, and 1 in 128,000 for HTLV. The use of nucleic acid amplification testing, which
shortens the window period, was estimated to reduce the probabilities of viremia to 1 in
100,000 for hepatitis B, 1 in 421,000 for hepatitis C, and 1 in 173,000 for HIV.
However, no available assays can completely exclude the risk of infectious
transmissions, especially in the limited time available for decreased donor screening
prior to transplantation [22].

Net state of immunosuppression The net state of immunosuppression is a complex

function determined by the interaction of several factors [45-51]:

Type, dose, duration, and temporal sequence of immunosuppressive therapies (table 4)

Underlying diseases or comorbid conditions

Presence of devitalized tissues or fluid collections in the transplanted organ

Invasive devices such as vascular access or urinary catheters, surgical drains, and
ventricular assist devices

Other host factors affecting immune function including neutropenia,

hypogammaglobulinemia, and metabolic problems (eg, protein-calorie malnutrition,
uremia, diabetes)

Concomitant infection with immunomodulating viruses including CMV, Epstein-Barr

virus (EBV), human herpesvirus (HHV)-6 and -7, HBV, and HCV

The sum of any congenital, acquired, metabolic, operative, and transplant-related factors
is the patient's "net state of immune suppression." More than one factor is usually
present in each host. The identification and correction of any modifiable risk factor is
essential for the prevention and treatment of infection.
Advances in the assessment of T and B cell responses to specific pathogens, such as
cytomegalovirus, have been achieved using cell sorting technologies that measure the
level of immune responses committed to specific pathogens [52-54]. Immune
competence may be measured crudely using cell counts, the frequency and severity of
common infections (eg, herpes simplex virus), or the presence of circulating viruses.
Nonspecific assays have been introduced to assess susceptibility to infection. Some are
based in the production of intracellular ATP in response to mitogenic stimulation [55].
These assays are more useful in measuring the risk of infection than rejection. However,
they have not yet been well validated prospectively for the ability to predict the risk for
infection in individual transplant recipients.

TIMING OF INFECTION POSTTRANSPLANTATION Immunosuppressive

regimens vary between centers, with the organ transplanted, and the patient population.
As an example, "induction" with polyclonal or monoclonal anti-T lymphocyte antisera
may be used for renal transplantation from deceased donors but not in living related
donor transplant recipients or in liver transplant recipients with hepatitis C infection. At
some centers, patients may receive little or no glucocorticoid therapy but are treated
with combinations of multiple other potent immunosuppressants. Alterations in the type
or intensity of immune suppression will alter the risk of infection (table 4) and the list of
potential pathogens (table 3).

It is useful to divide the posttransplant course into three time periods related to the risks
of infection by specific pathogens: the early period post transplant (first month), an
intermediate period (one to six months), and more than six months (figure 1) [1,3]. This
timetable is useful in three ways:

In developing a differential diagnosis for the individual transplant recipient with

clinical signs of infection

As a clue to the presence of excessive environmental hazards (nosocomial, community

or individual)

As a guide to the design of preventive antimicrobial strategies

First month after transplantation In the first month post-transplant, there are two
major causes of infection in all forms of solid organ transplantation: infection derived
from either the donor or recipient and infectious complications of the transplant surgery
and hospitalization. The major effects of exogenous immunosuppression are not yet
evident. Exceptions include those patients who receive immunosuppression prior to
transplantation (eg, for autoimmune hepatitis).

Donor-derived infections The risk for infections acquired with the allograft is
discussed above (table 3) [18-20,56]. Transmission of donor-derived bacteria and fungi
has increased with the emergence of antimicrobial resistance such that vancomycin-
resistant enterococci, methicillin-resistant staphylococci, and fluconazole-resistant
Candida species may be transmitted from donor to recipient. Graft-associated viral
infections (LCMV, West Nile virus, rabies, HIV) and parasitic infections
(toxoplasmosis, Chagas disease, Balamuthia mandrillaris) are uncommon but may be
amplified in the immunosuppressed host. Endemic infections (eg, histoplasmosis or
tuberculosis) should be considered in the differential diagnosis of posttransplant
infection or unusual clinical syndromes (eg, encephalitis, hepatitis). (See 'Donor-derived
infections' above.)

Recurrent infection Infection may have been present in the donor or in the recipient
prior to transplantation. An important component of the pretransplant evaluation is to
recognize and treat such infections, if possible. (See "Evaluation for infection before
solid organ transplantation".)

Some common viral infections (eg, hepatitis B virus or hepatitis C virus) may reemerge
early after transplantation. Recipient-derived tuberculosis or toxoplasmosis tends to
reactivate more than a month after transplantation. Reactivation of Strongyloides may
be accompanied by gram-negative bacterial sepsis, meningitis, or pneumonia [9].

Infectious complications related to surgery Solid organ transplant recipients develop

many of the common postoperative complications, such as aspiration pneumonitis,
surgical site (wound) infections, "line sepsis," urinary tract infection, or pulmonary
embolus [57]. Transplant recipients are also at unique risk for superinfection of
ischemic or injured graft tissues (eg, anastomotic suture lines) or of fluid collections
(eg, hematomas, lymphoceles, pleural effusions, urinomas). These patients are at
increased risk for infection associated with indwelling vascular access catheters, urinary
catheters, and surgical drains.

The organisms responsible for such postoperative complications are often the bacteria
and fungi that have colonized the recipient or donor (eg, the lungs and/or sinuses in
cystic fibrosis) prior to transplantation or the local flora of the hospital. Infections
acquired prior to transplantation may include relatively resistant nosocomial pathogens
(eg, vancomycin-resistant enterococcus) and pathogens such as Aspergillus spp that are
resistant to the usual prophylactic agents. Patients receiving antimicrobial agents are at
increased risk for C. difficile colitis.

Patients at particular risk of nosocomial infection are those requiring prolonged

ventilatory support or those with diminished lung function, persistent ascites, stents of
the urinary tract or biliary ducts, with intravascular clot or ischemic graft tissue [49,58].
Individuals with delayed graft function or who require early reexploration or
retransplantation are also at increased risk for infection, notably with fungi or bacteria
with antimicrobial resistance.

1 to 6 months after transplantation In the period one to six months post-transplant,

the nature of common infections changes. This is the period when patients are most at
risk for the development of opportunistic infections, although residual problems from
the perioperative period can persist. There is significant geographic and institutional
variation in the occurrence of opportunistic infections during the first six months post
transplantation. This reflects local epidemiology and varying immunosuppressive
strategies and also the use of antimicrobial prophylaxis in the posttransplant period.
Prevention of the infections observed during this period is the basis of prophylactic
antimicrobial strategies. Prophylaxis delays but does not eliminate the risk for infections
that may occur in the months following cessation of prophylaxis. (See "Prophylaxis of
infections in solid organ transplantation".)

Major infections due to opportunistic pathogens include:

Pneumocystis jirovecii (formerly P. carinii) pneumonia (PCP) (see "Fungal infections
following lung transplantation", section on 'Pneumocystis jirovecii')

Latent infections, such as the protozoal diseases including toxoplasmosis,

leishmaniasis, and Chagas disease [8,47,48,59-61]

The geographic or endemic fungal infections caused by Histoplasma capsulatum,

Coccidioides spp, Cryptococcus gattii, and, rarely, Blastomyces dermatitidis (see
"Fungal infections following lung transplantation")

Viral pathogens, particularly the herpes group viruses but also hepatitis B (HBV) and
hepatitis C (HCV). New viruses are recognized as opportunistic pathogens with the use
of more sensitive molecular assays (eg, BK polyomavirus, human herpesvirus [HHV]-6,
-7, and -8 [Kaposi's sarcoma-associated herpesvirus, KSHV]) (table 5). Respiratory
viruses are increasingly important in this population (influenza, parainfluenza,
respiratory syncytial virus [RSV], adenovirus, metapneumovirus).

Tuberculosis and, increasingly, nontuberculous mycobacteria [62] (see "Tuberculosis

in solid organ transplant candidates and recipients" and "Nontuberculous mycobacterial
infections in solid organ transplant candidates and recipients")

Gastrointestinal parasites (Cryptosporidium and Microsporidium) and viruses

(cytomegalovirus [CMV], rotavirus) may be associated with diarrhea.

More than 6 to 12 months after transplantation Six to twelve months or longer post-
transplant, most patients are receiving stable and reduced levels of immunosuppression.
These patients are subject to community-acquired pneumonias due to respiratory
viruses, the pneumococcus, Legionella, or other common pathogens.

Patients who have less than adequate graft function tend to require higher than usual
immunosuppressive therapy. As a result, they represent a subgroup of transplant patients
at highest risk for opportunistic infections including PCP, cryptococcosis, and
nocardiosis. They are also at risk for severe illness from community-acquired infections
due to influenza or Listeria monocytogenes. Prolonged antimicrobial prophylaxis may
be indicated for this subgroup of patients, who remain more immunosuppressed. This
group of patients may also suffer rare infections in the late transplant period and may
have clinical findings that differ from those in immunocompetent hosts. These
infections are most often due to molds or Nocardia species or the late effects of viral
infections manifest as malignancy: posttransplant lymphoproliferative disorder (PTLD)
or squamous cell cancers of the skin or anogenital region. (See "Prophylaxis of
infections in solid organ transplantation".)

VIRUSES AS COPATHOGENS Viruses, particularly cytomegalovirus (CMV), serve

as important cofactors to many opportunistic infections [1,45,46]. The potential effects
of viral infection are diverse and apply not only to CMV but also to hepatitis B (HBV),
hepatitis C (HCV), Epstein-Barr virus (EBV), and probably other common viruses such
as respiratory syncytial virus (RSV), human herpesvirus (HHV)-6, and adenovirus
(table 6). Viruses contribute to a variety of processes post transplantation (table 5)
[1,46,49,63-65].
Direct effects "Direct effects" include clinical syndromes such as fever and
neutropenia (CMV), pneumonitis (respiratory viruses), hepatitis (HCV, HBV), gastritis,
esophagitis, colitis (CMV), cholangitis (varicella-zoster virus [VZV]), encephalitis
(herpes simplex virus [HSV], JC virus), pancreatitis, myocarditis, and retinitis. Less
common syndromes include adrenalitis with adrenal insufficiency or
meningoencephalitis due to CMV vasculitis.

Indirect effects "Indirect effects" are generally immune effects including:

Immune suppression and predisposition to opportunistic infection (eg, Aspergillus

after RSV pneumonia, Pneumocystis after CMV infection). Thus, CMV coinfection has
been implicated in the accelerated course of HCV infection with cirrhosis and graft loss
and of EBV with increased risk for posttransplant lymphoproliferative disorder (PTLD,
usually B-cell lymphoma).

Graft rejection that is thought to be mediated by proinflammatory cytokine release

and/or upregulation of histocompatibility antigens or adhesion proteins in the setting of
CMV reactivation [63,66,67]. Graft rejection may necessitate an increase in the
immunosuppressive regimen and an increased risk for opportunistic infection.

Oncogenesis Many viruses predispose to cancer (HCV, EBV) or to cellular

proliferation (CMV and accelerated atherogenesis, BK polyomavirus and ureteric
smooth muscle cell proliferation).

Specific viral pathogens The spectrum of viral infections in the transplant recipient
has expanded with the discovery of new viruses (table 5).

The BK polyomavirus has been associated with infection of renal allografts with
hemorrhagic cystitis, asymptomatic viruria, interstitial nephritis, ureteric obstruction,
and rising creatinine values in renal transplant recipients [68-71]. (See "Overview of JC
polyomavirus, BK polyomavirus, and other polyomavirus infections".)

Adenovirus may cause a similar hemorrhagic nephritis/cystitis picture diagnosed by

culture or antigen detection/immunofluorescence. (See "Epidemiology and clinical
manifestations of adenovirus infection".)

HHV-6, -7, and -8 have also been identified in transplant recipients [72] (see
"Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection" and
"Human herpesvirus 7 infection" and "Disease associations of human herpesvirus 8
infection"). HHV-6 has been implicated as a cofactor in CMV infection (and vice versa)
or may cause leukopenia and fever as part of a viral syndrome. The role of HHV-7
remains to be clarified.

EBV, VZV, and HSV are also often activated during this one to six month period. EBV
may be associated with the development of B cell non-Hodgkin lymphoma, particularly
in seronegative recipients of seropositive organs. However, some cases of T cell, NK
cell, and non-EBV-related PTLD have been described (see "Treatment and prevention
of post-transplant lymphoproliferative disorders"). Herpes zoster of the skin (shingles)
may occur; occasionally, patients present with cholangitis due to VZV. Human
papillomavirus (HPV) is associated with anogenital and squamous cell cancers.
Parvovirus B19 may also present in this time period with anemia unresponsive to
erythropoietin or with myocarditis [73]. Parvovirus B19 has also been associated with
chronic allograft injury in renal transplant recipients [74].

Respiratory viruses remain important community-acquired pathogens, particularly in

the lung transplant recipient [75]. Infections with these latter viruses predispose the
patient to the development of bacterial infections and graft rejection.

Viruses that have been reported rarely in solid organ transplant recipients include
human T lymphotropic virus, hepatitis E virus, rabies virus, lymphocytic
choriomeningitis virus, measles, mumps, dengue, orf, and human coronaviruses HKU1
and NL63 [76]. Most of these were infections derived from asymptomatic organ donors.

EVALUATION AND MANAGEMENT The pursuit of diagnostic testing and the

management of infection in a transplant recipient must be guided by a number of
principles:

These hosts generally have fewer clinical manifestations of infection and few or no
findings by conventional radiography. Thus, more sensitive imaging techniques such as
computed tomographic (CT) scans and magnetic resonance imaging (MRI) are essential
for assessing the presence and nature of infectious and malignant processes.

The "gold standard" for diagnosis is tissue histology. No radiologic finding is

sufficiently diagnostic to obviate the need for tissue. Multiple simultaneous infections
are also common. Thus, invasive procedures that provide tissue for culture and
histology must be employed early as a routine component of the initial evaluation of
transplant recipients with infectious syndromes. Patients failing to respond to
appropriate therapy may also need invasive diagnostic procedures.

Serologic tests, which indicate past exposure to certain pathogens, are useful in the
pretransplant setting to assess risk for relapse of latent disease but are not generally
useful after transplantation. Patients, especially those receiving immunosuppressive
therapies, do not reliably develop antibodies quickly enough during an active infection
to enable a serologic diagnosis. Thus, quantitative tests that directly detect the protein
products or nucleic acids of the organisms such as sandwich enzyme linked
immunosorbent assays (ELISA), direct immunofluorescence, or quantitative molecular
assays (nucleic acid tests [NATs]) should be utilized.

Transplant recipients are often colonized and thus are particularly vulnerable to
organisms resistant to antimicrobial agents either from the hospital environment or
through induction of antibiotic resistance in their flora during therapy (eg, inducible
beta-lactamases). Sites at risk for infection with resistant organisms (eg, ascites, blood
clots, drains, lungs) can be sampled so that information is available to guide empiric
therapy at times of clinical deterioration.

When undrained fluid collections, blood, or devitalized tissues are present,

antimicrobial therapy alone is often inadequate. Antibiotics, used in lieu of definitive
drainage or debridement, merely delay clinical deterioration and promote the acquisition
of resistant microorganisms. Early and aggressive surgical debridement of such
collections is essential for successful care.
Some components of the immunosuppressive regimen may be modified during acute
infection to elicit an improved host response. This must be done with caution since
reductions in immunosuppression may provoke immune reconstitution syndromes or
allograft rejection.

Infectious disease consultation improves outcomes in solid organ transplant recipients.

As an example, in a study of solid organ transplant recipients admitted with an
infection, infectious disease consultation was associated with reduced 28-day mortality
(hazard ratio 0.33) and 30-day rehospitalization rates (17 versus 24 percent) [77]. The
median length of stay and hospitalization costs did not differ between patients who
received an early infectious disease consultation (<48 hours) and those who did not.

The evaluation for infection prior to solid organ transplantation is discussed separately.
(See "Evaluation for infection before solid organ transplantation".)

FUTURE DIRECTIONS Many important hurdles remain to be overcome in the

diagnosis and treatment of infections to enhance the safety and success of solid organ
transplantation. The initiation of a diagnostic evaluation for infection frequently begins
when clinical symptoms become manifest. That is often late in the course of the disease
in these immunocompromised patients. Further, accurate microbiologic diagnoses are
needed to avoid unnecessary toxicities associated with therapy. Thus, invasive
diagnostic procedures are often required to make an accurate microbiologic diagnosis
[78-80].

More advanced, quantitative laboratory assays utilizing molecular techniques or antigen

detection are integral components of transplant care. Such tests may be prohibitively
costly for routine use in some areas. Rapid, quantitative, cost-effective assays that do
not depend upon invasive procedures are needed for the routine monitoring of transplant
patients for infections and for graft rejection. The availability of such tests would allow
the clinician to individualize prophylactic antimicrobial regimens and minimize drug-
associated toxicity.

The evolution of pathogens (bacteria, viruses, fungi) with acquired resistance to

common antimicrobial agents and the incidence of drug toxicity and allergy have
limited the available antimicrobial strategies for transplant recipients. New
antimicrobial agents are needed for prophylaxis and therapy.

SUMMARY

The risk of infection in the organ transplant patient is determined by the synergy
between two factors: the epidemiologic exposures of the individual and the "net state of
immunosuppression," which is a conceptual measure of all of the factors that contribute
to the individual's susceptibility (or resistance) to infection. (See 'Risk of infection
following transplantation' above and 'Epidemiologic exposures' above and 'Net state of
immunosuppression' above.)

It is useful to divide the posttransplant course into three time periods related to the
risks of infection by specific pathogens: the early period post-transplant (first month),
an intermediate period (1 to 6 months), and more than 6 to 12 months (figure 1). The
timing of the presentation of infectious processes will be altered (delayed) by the
deployment of antimicrobial prophylaxis. This may result in the delayed presentation of
infection (eg, "late cytomegalovirus [CMV]"). (See 'Timing of infection
posttransplantation' above.)

In the first month post-transplant, the major causes of infection in all forms of solid
organ transplantation include infection derived from either the donor or recipient and
infectious complications of the transplant surgery and hospitalization. (See 'First month
after transplantation' above.)

The period 1 to 6 months post-transplant is the period when patients suffer the greatest
impact of immunosuppression and are at the greatest risk for the development of
opportunistic infections. Patterns are altered by prophylaxis. (See '1 to 6 months after
transplantation' above.)

Six to 12 months or longer post-transplant, most patients are receiving stable and
reduced levels of immunosuppression. These patients are subject to community-
acquired pneumonias due to respiratory viruses, the pneumococcus, Legionella, or other
common pathogens. (See 'More than 6 to 12 months after transplantation' above.)

Viruses, particularly CMV, serve as important cofactors to many opportunistic

infections. The potential effects of viral infection are diverse and apply not only to
CMV but also to hepatitis B (HBV), hepatitis C (HCV), Epstein-Barr virus (EBV), and
probably other common viruses such as respiratory syncytial virus (RSV), human
herpesvirus (HHV)-6, and adenovirus (table 6). (See 'Viruses as copathogens' above.)

The pursuit of diagnostic testing and the management of infection in a transplant

recipient must be guided by a number of principles:

These hosts may have nonspecific clinical manifestations of infection and few or no
findings by conventional radiography. Thus, more sensitive imaging techniques such as
computed tomographic (CT) scans and magnetic resonance imaging (MRI) are
necessary.

The "gold standard" for microbiologic diagnosis includes culture as well as tissue
histology. Tests that detect proteins, polysaccharide antigens, or nucleic acids are
important to transplant management.

Serologic tests, which indicate past exposure to pathogens, are useful in the
pretransplant setting to assess the presence of latent disease but are not generally useful
for acute diagnosis after transplantation.

Transplant recipients are often colonized by organisms resistant to antimicrobial agents

from the hospital environment or selected during antimicrobial therapy.

When undrained fluid collections, blood, or devitalized tissues are present,

antimicrobial therapy alone is inadequate. Early and aggressive surgical debridement of
such collections is essential for successful care. (See 'Evaluation and management'
above.)

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2017 UpToDate
Infections associated with specific immunosuppressive regimens
Antilymphocyte globulins
T cell depleting antibodies - activation of latent (herpes) viruses, fever, cytokine release
Glucocorticoids
Bacteria, Pneumocystis pneumonia, activation of hepatitis C and hepatitis B
Azathioprine
Neutropenia, possible role in human papillomavirus infection
Mycophenolate mofetil
Early bacterial infection B cell depression, possible role in late-onset cytomegalovirus
(CMV)
Cyclosporine/tacrolimus
Increased viral replication, B cell depression, gingival infection, intracellular pathogens
Rapamycin (sirolimus)
Excess infections in combination with current agents, idiosyncratic pulmonary
syndrome, often with concomitant respiratory pathogens
Plasmapheresis
Encapsulated bacteria
Costimulatory blockade
Unknown so far (possible role in posttransplant lymphoproliferative disorder [PTLD])
Rituximab
B cell depletion, bacterial and viral infections
Graphic 53524 Version 5.0

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