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eMedicine Specialties > Transplantation > Complications
Infections After Solid Organ Transplantation
Asim A Jani, MD, MPH, FACP, Clinician-Educator and Epidemiologist, Consultant and Senior Physician, Florida
Department of Health; Diplomate, Infectious Diseases, Internal Medicine and Preventive Medicine
Paul Chen, University of Texas Southwestern Medical School
Updated: Feb 3, 2011
Introduction
Worldwide, 40,000 organ transplants are performed annually, with very high success rates
(90% 1-year graft survival).[1 ]In the United States, 23,288 organ transplantations were
performed in 2008. Renal transplants were the most common, followed by those of the liver,
heart, lung, and others, including dual organ, pancreatic, and intestinal transplantation. Over
the last several decades, the field of solid organ transplantation (SOT) science and practice
has advanced significantly, only to be continually challenged by the risks for infection in SOT
recipients.
The positive effects of the immunosuppressive agents, obligatory for the prevention of organ
rejection, have been tempered by the negative effects of these same therapies, leading to
various infections that range in both frequency and severity.[2 ]Fortunately, experienced SOT
researchers and practitioners have been involved in the development and implementation of
proactive guidelines such as the 2006 American Society of Transplantation guidelines[3 ]on
screening, monitoring, and reporting of infectious complications in SOT recipients.
Newer immunomodulating agents have been developed, increasing the number of therapies
that prevent organ rejection. However, this has simultaneously created newer unwanted
opportunities for pathogens to cause infectious complications.[4,5 ]These adverse effects are
the result of their negative impact on both the cellular and humoral arms of the SOT
recipient's immune system. Fortunately, newer diagnostic laboratory methods have also
added much-needed capacity to identify the presence and types of pathogens, often early
enough in the SOT recipient’s course to prevent or mitigate severe infection.[6 ]
Guidelines are constantly being refined to outline the most practical and appropriate
screening processes to minimize donor-related infections.[7,8,9 ]Conversely, attention to
implementing preventive measures such as pretransplant vaccination in SOT recipients also
represents an important step in optimizing safe organ donation and retention.[10 ]Newer hostrelated challenges, such as the increasing prevalence of obesity, and system-related
problems, such as healthcare-acquired infections, represent other challenges for successful
infection prevention.[11,12 ]
Finally, several areas related to infections in SOT recipients are unresolved and controversial,
and recognized emerging issues include donor-derived infection (eg, rabies, West Nile virus,
lymphocytic choriomeningitis virus [LCMV]),[13 ]the impact of pandemic influenza in the SOT
recipient,[14 ]drug-resistant infections (including multidrug-resistant tuberculosis), and many
others (see webcasts from the 2007 International Transplant Infectious Disease conference
here).
Given the broad scope of this article and the availability of several eMedicine monographs
and articles covering related areas in transplantation, the reader is referred to the relevant
links available in the eMedicine’s Transplantation volume. The December 2009 issue of the
American Journal of Transplantation contains a comprehensive review of the various topics
within the scope of infections in SOT recipients.[15 ]The focus of this article is adult
populations, although infectious disease issues germane to the pediatric SOT recipient are
discussed in Special Host Considerations.
Background Concepts
Immunocompromised hosts, regardless of underlying illness or factors leading to
immunosuppression, commonly present diagnostic challenges in the face of severe
infectious disease processes. These challenges are due to host factors that blunt or
minimize symptoms and signs of inflammation. Medication toxicities compounded by allograft
rejection and complications of healthcare-acquired infections result in more complex
presentations. As a result, practitioners are challenged to help solid organ transplantation
(SOT) recipients retain their transplanted organs, prevent SOT-related infections, and
improve their quality of life. The diagnosis of infection is made more arduous since SOT
recipients may present with more than one infection or at later stages in the disease process
or may experience drug toxicity from immunosuppressive agents, as well as from
antibiotics.[16 ]
Transplant medicine is a discipline in which, perhaps more than any other field, practitioners
must maintain a high index of suspicion for various complications and presentations.
Clinicians must be astute and pay close attention to details related to epidemiologic clues,
historical features, and physical signs. This helps in the often-difficult differentiation between
infection and allograft rejection, which may present with similar symptoms, such as fever,
cough, and diarrhea.[17,18 ]
Although differentiating colonization from infection is often difficult in the clinical context, the
clinician must exercise both prudence and vigilance in the approach to the febrile SOT
recipient. Only then can a timely and accurate diagnosis be made while broad-spectrum
empiric antimicrobial therapies are prescribed.[19 ]Primary care providers and specialists
should maintain a low threshold of suspicion and promptly seek expert consultation when
faced with a SOT recipient who presents with suspicion or evidence of infection, especially
during the first several months posttransplantation.
Immunosuppressive Drugs Used in Solid Organ Transplantation
Although other monographs on immunosuppressive drugs are available in other eMedicine
articles (see Immunosuppression), the information presented here relates to the specific
mechanisms of drug action that underlie the specific types of immunodeficiencies
predisposing to certain pathogens.[2,20 ]
Immunosuppressive agents have the following 3 major effects:

The intended therapeutic effect of suppressing rejection


The deleterious acquired immunodeficiencies that the host sustains, leading to
increased risk of infection or neoplasia
The direct or indirect toxicity to host tissues
Immunosuppressive agents used in transplantation target either single or multiple sites in the
immune system, thus markedly enhancing their effect in prevention or treatment of organ
rejection (via either single-drug or combination regimens). Therefore, these drugs represent
a dual-edged sword, potentially predisposing solid organ transplantation (SOT) recipients to
all categories of pathogens by impairing host defenses.
All of the major determinants of immune competence (host anatomic barriers, mechanisms in
innate immunity, acquired capacities, presence or absence of immunomodulating coinfections, and underlying comorbid conditions) may be breached and may result in
opportunistic pathogens, causing illness in SOT recipients. Examples of these factors include
immunosuppressive drug–induced antiproliferative activity leading to mucosal erosions,
transient cytopenias, uremia, hyperglycemia, malnutrition, the use of invasive devices
(leading to trauma, colonization, and infection), abnormalities in tissue perfusion (vascular or
surgery-related etiologies), abscesses, cytomegalovirus (CMV) infection, Epstein-Barr virus
(EBV) infection, and HIV infection.
Given the complexity of variables that may positively or negatively affect immunosuppression
in the SOT recipient, clear attribution of a particular pattern of immunosuppression to a
specific immunosuppressive agent or regimen is difficult. Additionally, specific trends in the
usage of various immunosuppressive therapies make it difficult to epidemiologically
associate certain drugs with specific degrees of immunosuppression-related infections.
Judgments on the likelihood of infection risks associated with specific drugs can often only
be rendered based on minimal or suboptimal data on the infectious complications in
immunosuppression drug trials. SOT recipients, like other immunocompromised hosts, often
present with a mixture of immunological impairments, including neutropenia and
lymphopenia, functional T-cell defects, lack of humoral antibody responses, and tissue
damage. All of these add to the overall immunosuppression and predispose to various
pathogens.
Corticosteroids and glucocorticoids constitute a major component of immunosuppressive
medications used in SOT, often considered first-line therapy for allograft rejection. Agents
such as prednisone or prednisolone have a myriad of negative effects on the immune system,
including cell-mediated immunity impairment (through inhibition of several cytokines,
including interleukin [IL]–1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, and tumor necrosis factor [TNF]),
often resulting in T-cell proliferation. Antigen presentation, through reduced expression of
major histocompatibility complex molecules, also occurs. Humoral immunity is also
suppressed, leading to the diminished production of IL-2 and related receptors, as well as Bcell clone expansion and decreased antibody synthesis.
Steroids induce a widespread decrease in the host inflammatory response, resulting in
lipocortin-1 synthesis that can eventually impair migration of cells, phagocytosis, respiratory
burst mechanisms, and the release of inflammatory chemokines and cytokines from white
blood cells. Finally, apoptotic effects result in cytotoxicity. Clinically, these mechanisms of
immunosuppression lead to an increased risk of bacterial, mycobacterial, viral, and fungal
infections. Since 2000, steroid use appears to have decreased overall.
To better understand other groups of immunosuppressive drugs, a brief description of T-cell
activation, a necessary step in immune responsiveness, is provided. To become activated,
two signals are needed. The first signal, antigen-specific, occurs when peptide–major
histocompatibility complex molecules interact with the T-cell receptor on the surface of
antigen-presenting cells. The second (costimulatory) signal does not depend on a specific
antigen; it occurs when costimulator molecules are expressed on the antigen-presenting cell
because of the interaction of the antigen-presenting cell with microbes. These costimulators
are recognized by the CD28 receptor on the T cells, resulting in further T-cell proliferation
and differentiation.
Five other classes of immunosuppressive agents are of clinical significance: the smallmolecule drugs that include antiproliferative drugs, calcineurin inhibitors, and inhibitors of
mammalian target of rapamycin (mTOR) and the protein drugs (polyclonal antilymphocyte
antibodies and monoclonal antibodies).
Examples of antiproliferative agents used for immunosuppression include azathioprine,
mycophenolate mofetil, and mycophenolate sodium. Examples of calcineurin inhibitors
include cyclosporine and tacrolimus. Examples of corticosteroids include prednisone and
methyl prednisolone. Examples of monoclonal antibodies include muromonab-CD3,
basiliximab, and daclizumab. Examples of polyclonal antibodies (antilymphocyte targets)
include antilymphocyte globulin (ALG) and antithymocyte globulin (ATG). Finally, examples
of mTORs include sirolimus and everolimus.
The image below shows the schematic sites of action for some of these common agents.
The currently used antiproliferative drugs include azathioprine, mycophenolate mofetil, and
mycophenolate sodium.
Schematic sites of action of common immunosuppressants. Image courtesy of
Elsevier.
Azathioprine primarily targets enzymes in the de-novo synthesis of purines, leading to the
impairment of DNA replication in dividing cells, such as lymphocytes. Therefore, while
sparing any cytotoxic effects on T cells prior to an antigen challenge, activated T cells are the
main target. Marked immunosuppressive effects occur after antigen stimulation; B cells are
also immunosuppressed. As a result of all of these effects, patients receiving azathioprine
may experience bone marrow suppression, gastrointestinal intolerance, and infections.
Patients who are receiving azathioprine tend to develop major viral infections (such as with
herpes viruses), as well as fungal and parasitic infections.
The drug mycophenolate mofetil is the prodrug of mycophenolic acid. Administration of this
drug ultimately causes inhibition of the enzyme inosine monophosphate dehydrogenase,
which is involved in the de-novo synthesis of guanosine nucleotides. The
immunosuppressive effect tends to be selective for B and T cells, mainly decreasing the
proliferation of activated T cells. Since humoral responses can also be impaired,
immunization practices will not likely be effective, especially if vaccine is given during
mycophenolate mofetil therapy. The infectious complications of mycophenolate mofetil
administration are similar to those associated with azathioprine; the increased CMV risk in
patients receiving mycophenolate mofetil is not easily explained. Ironically, mycophenolate
mofetil protects against infection due to Pneumocystis (carinii) jiroveci.
Two classes—calcineurin inhibitors and mTOR inhibitors—belong to a group of agents that
bind to immunophilins, which are immunosuppressant binding proteins involved in
lymphocyte activation. The calcineurin inhibitor class includes agents such as cyclosporine
and tacrolimus. The calcineurin inhibitor–immunophilin complexes block the function of the
enzyme calcineurin at different enzymatic sites, resulting in the blockade of normal
calcineurin dephosphorylation activity that involves the cytoplasmic component of the nuclear
factor of activated T-cells (NFAT). This prevents NFAT from binding to the nuclear
component of NFAT, which, under normal circumstances, binds to the promoter of the IL2
gene.[21 ]The end result is that the calcineurin inhibitors impair the T-cell synthesis of IL-2.
Cyclosporine administration increases the risk of posttransplant lymphoproliferative disorder
(PTLD), an EBV-associated condition. An important difference between cyclosporine and
tacrolimus is that the latter is far more potent than cyclosporine and broader in its inhibitory
effect on other transcriptional factors, resulting in decreased production of not only IL-2 but
also IL-3, IL-4, IL-5, interferon (IFN)–gamma, and other cytokines.
The trend is for greater substitution of cyclosporine with tacrolimus in the maintenance phase
of immunosuppression. Conversely, the mTOR inhibitor agent sirolimus (or rapamycin), a
macrolide antibiotic, binds to its respective binding protein, mTOR, in the cytosol, inhibiting
normal biochemical pathways needed for mRNA translation critical for cell division. In
contrast to calcineurin inhibitors, which decrease IL-2 levels, the mTOR agents block
cytokine signal transduction for T- and B-cell activation. The mTOR inhibitors also inhibit
fibroblast growth factors, which may result in wound-healing problems. Although sirolimus
has been noted in studies to enable cyclosporine withdrawal posttransplantation, it can also
induce an inflammatory reaction, resulting in an atypical pneumonia–like picture or
leukoencephalopathy. This mimicry may present significant diagnostic challenges.
Since the calcineurin inhibitors are often used in combination with other classes of
immunosuppressive therapies,[22 ]their specific clinical effects on host immunity are difficult to
ascertain. Two pathogens, CMV and polyoma BK virus, appear to be directly related to the
immunosuppressive effects of the calcineurin inhibitors.[22 ]The drug cyclosporine actually
appears to have anti–hepatitis C activity; this is being formally studied in a randomized trial.
The class of polyclonal antibodies (eg, antithymocyte globulin, antilymphocyte globulin) has
traditionally been used in the induction phase of immunosuppression. Although induction
therapy in the field of transplantation has increased since the mid 1990s, antithymocyte
globulin has largely replaced the use of antilymphocyte globulin and monoclonal antibodies
such as muromonab-CD3 (OKT3). Unfortunately, although OKT3 was once widely used and
is still used in specific rejection syndromes, it has been associated with the toxic cytokine
release syndrome, which is due to a massive activation of T cells and consequent clinical
effects such as pulmonary edema, aseptic meningitis, and graft thrombosis.
This widespread activation results from the binding of OKT3 to its target surface antigen,
CD3 receptor, a membrane protein located on T-lymphocyte cell surfaces. With respect to
antithymocyte globulin use and subsequent infection in the SOT recipient, the impact on
bacterial infections overall may be potentially confounded by other factors, including the
effect of postoperative complications, presence of invasive devices, and use of other
immunosuppressive agents.
Antithymocyte globulin increases the risk for CMV infection, as well as for BK virus viremia
and nephropathy. Infections with Pneumocystis species and other invasive fungal pathogens
have been associated with antithymocyte globulin therapy. Other types of monoclonal
antibodies have been developed, including ones that target the alpha chain of the IL-2
receptor (IL-2R), named anti-CD25 antibody. The use of such agents interferes with the
initial expansion of T cells following antigen-specific stimulation. Two anti-CD25 agents,
basiliximab and daclizumab, are used in induction therapy and are supported by studies that
have shown a decrease in infection rates compared with the use of antithymocyte globulin;
they may also allow doses of concurrently used immunosuppressive therapies to be reduced.
These drugs do not usually lead to a sustained depletion of lymphocytes and related CD4
helper T cells, unlike the kind of depletion seen with alemtuzumab (another monoclonal
antibody directed against CD-52). However, when all of these agents are used for an
extended period, increased rates of severe infection have been observed, even long after the
transplantation was performed. Generally, IL-2R antagonists have not been associated with
an incidence of bacterial infections greater than that associated with other induction
therapies or placebo. The incidence of CMV, EBV (and EBV-induced PTLD), and fungal
infections with these antagonists has been similar with other induction regimens. However,
patients undergoing T-cell depletion induction are at greatest risk for most CMV-associated
complications.
The effect of IL-2R antagonists on hepatitis C infection is unknown. Alemtuzumab can
essentially result in pan–T-cell depletion; counts of CD4 and CD8 cells can reach their lowest
points 4 weeks after initiation of therapy. This agent appears to be more associated with
opportunistic infections, including viral infections (herpes simplex virus in particular),
although all of the monoclonal antibody products likely contribute to immunosuppression to a
degree that places the SOT recipient at risk for various pathogens.
Several new agents, some of which are in phase II and III trials, include the following:



Leflunomide, an antiproliferative agent similar to methotrexate
Belatacept, a costimulatory blocker that has been associated with some cases of
PTLD (which may limit the drug's use if future data confirm an adverse relationship)
Agents that target adhesion and transmigration


Efalizumab, another type of monoclonal antibody
Fingolimod, a sphingosine-1-phosphate receptor 1 modulator
The advent of these types of therapies may signal a shift toward more specific and targeted
approaches to the prevention and treatment of transplant-related rejection. This paradigm,
which also includes newer developments in study design, better monitoring of infectious
complications, and newer diagnostic methods that enable tailoring of therapies to SOT
recipients, will hopefully enable even greater reduction of SOT-related infections.
Statins
Statins have demonstrated their ability to improve outcomes in patients with cardiovascular
disease, including those with a history of transient ischemic attack, cerebrovascular accident,
carotid artery stenosis, coronary restenosis, and cardiac dysrhythmias. In patients with
chronic renal failure, statins have significantly reduced fatal and nonfatal cardiovascular
events. Notwithstanding legitimate concerns about adverse drug interactions between statins
and cyclosporine, increasing the risk of rhabdomyolysis in solid organ transplantation (SOT)
recipients, the prevalence of metabolic complications posttransplantation that may respond
to statins has led to an increase in their overall use. Clinical studies are still needed to
confirm their overall benefit in this patient population.
Multiple studies have shown that other statin-induced effects may have significance in SOT
recipients. Statins can attenuate the virulence and pathogenicity of organisms. These drugs
also have immunomodulatory effects on cell signaling and regulatory pathways related to
pathogenesis and control of various infections.[23 ]Indeed, statins have demonstrated
protective antimicrobial effects against several organisms, including bacteria such as
Staphylococcus aureus and Mycobacterium tuberculosis; viruses such as BK virus, CMV,
EBV, and hepatitis C; and fungi such as candidal species, cryptococcal species, and
invasive species (Aspergillus and Zygomycetes).
Broadly, as a result of their anti-inflammatory actions, statins have decreased hospitalization
rates in patients with sepsis on dialysis and the risk of pneumonia in patients with diabetes.
The exact mechanisms involved in statin-related modulation of the inflammatory response in
sepsis have yet to be determined but are likely to involve statin-induced alteration of cytokine,
chemokine, adhesion molecules, and cellular immune function.
Timeframe
Net state of immunosuppression
The concept of the "net state of immunosuppression"[24,25 ]has been pivotal to the
understanding of not only solid organ transplantation (SOT) but also bone marrow
transplantation–related infectious disease complications. Admittedly, many variables can
potentially contribute to the development of infections in the SOT recipient. These factors
exist within the domains of the SOT recipient's health, nutrition and host immunodeficiencies,
immunosuppressive drug regimens, healthcare institutions, donor-derived organ-related
infections, and the presence or absence of comodulating viruses.
All of these may positively or negatively affect the overall risk of infection. It is the net effect
of the confluence of any and all such relevant factors in any given SOT recipient that
ultimately determines the incidence, timing, and severity of infection. Since these influential
variables dynamically interact to create the net state of immunosuppression, it is not a fixed
phenomenon but represents a fluid process.[24 ]
This requires vigilance and proactivity of clinicians as they help SOT recipients navigate
through the pretransplant, operation, and posttransplant phases. This net state of
immunosuppression is also a function of time, since periods following transplantation during
which certain types of infections and pathogens may present with greater probability are
fairly well defined. Importantly, once a SOT recipient undergoes acute rejection, requiring
treatment interventions, it tends to set back the clock to the period when transplantation
occurred and the initial postoperative immunosuppression began.[24 ]
Timeframes around transplant-related infections
For almost 2 decades, clinicians caring for SOT recipients have been able to guide infectionprevention and control management strategies based on the classic timetable originally
proposed by Rubin et al. Although newer immunosuppressive and antimicrobial prophylactic
regimens have affected the pattern and timing of specific infections posttransplantation,
certain general observations still hold true. Some variance may be considered according to
the type of organ transplanted. Initial infection risk stratification is a process determined by
factors such as donor and recipient screening status, operative and perioperative outcomes,
and the degree of immunosuppression and other factors (discussed below).[25 ]
One of the most important consequences of an episode of organ rejection or increased
immunosuppression (from regimen modifications) is that the overall timeframe tends to get
reset to an initial period of vulnerability comparable to the transplantation itself. Over the
subsequent 6 months posttransplantation, 3 periods provide a structural approach to the
infectious disease management (see image below).
Changing timeline of infection after organ transplantation (modified from Fishman J.
NEJM. 2007;357(25):2601-14).
Within the first 30 days after transplantation, the patient is at greatest risk for healthcareassociated infections, often due to antibiotic-resistant organisms and often polymicrobial in
etiology.[24 ]
These infections, as is the case for healthcare-acquired infections in general, are often
procedure- or device-related, such as catheter-associated infections (urinary tract,
bloodstream infections), ventilator-associated pneumonia, aspiration, surgical wound
infections, or are associated with anastomotic leaks and ischemia. Unfortunately, infections
may also result from modification of endogenous microbial flora in the recipient or extant or
new colonization (often related to the healthcare environment, including the hands of
healthcare workers), such as with Clostridium difficile and its spore-induced toxins.
Superinfections may even develop, and these may carry a poor prognosis. Specific
organisms across the range of pathogen categories (ie, opportunistic viruses, bacteria, fungi,
and parasites derived from the donor, recipient, or both) may cause infection during this first
month. Overall, the types of infection during this period share patterns with those that
routinely occur after similar operations.
The second period (approximately 1-6 months posttransplantation) is characterized by the
presence or absence of those pathogens selected for by whether or not there are ongoing
prophylactic antibiotics against P jiroveci or viruses such as CMV or hepatitis B.[24,26 ]The
preventive antimicrobial agents used for these organisms also have efficacy against other
opportunistic pathogens, such as common bacteria, Listeria, Nocardia, Strongyloides, and
herpesviruses such as herpes simplex virus,[27 ]varicella-zoster virus,[28 ]and EBV. Importantly,
concurrent CMV infection during these 5 months may have an independent
immunosuppressive effect, placing SOT recipients at risk for opportunistic organisms and
contributing to almost two thirds of febrile episodes during this period.
CMV infection/illness may manifest as systemic symptoms such as fever, arthralgias,
myalgias, or organ-specific symptoms.
After 6 months, patients fall into the following 3 groups:
1. Eighty percent have adequate allograft functioning (and minimal immunosuppression
characterized by the absence of chronic viral infection)
2. Approximately 15% have chronic viral infections.
3. About 10% have frequent rejection episodes, immunosuppression due to treatment
regimens, infections with viruses such as CMV, or a combination of these.
Infections most commonly found in the first group include community-acquired viral infections
(eg, influenza, parainfluenza, respiratory syncytial virus, human metapneumovirus), bacterial
infections (eg, Streptococcus pneumoniae, Haemophilus influenzae), urinary tract infections,
and asymptomatic cryptococcal infection (eg, asymptomatic pulmonary nodules).
The second group is at special risk for infections with adenovirus, polyomavirus BK,
recurrent hepatitis C, human papillomavirus (HPV), and HIV. Chronic viral infections may
also lead to different types of allograft dysfunction.
The third group often presents with severe opportunistic infections involving P jiroveci,
Cryptococcus neoformans, Nocardia, Rhodococcus, and invasive fungi such as Aspergillus,
Mucor, and other molds.[29,30 ]
Finally, malignant neoplastic diseases that originate from or are modulated through infectious
organisms can develop during periods of immunosuppression, albeit in the later
posttransplantation period (eg, EBV-related PTLD, HPV-related skin or anogenital squamous
cell cancers,[31 ]and human herpesvirus (HHV)–8–related Kaposi sarcoma.[32 ]) SOT in
survivors of hematopoietic cell transplantation has been the subject of a recent article at a
single institution.[33 ]
Framework for Infection Risk Assessment
Remaining vigilant to the concept of net state of immunosuppression, the clinician is advised
to approach solid organ transplantation (SOT)–related infections using a framework of
infection risk assessment based on exposure to organisms potentially acquired through the
following 6 different paths:[24 ]






Community-acquired pathogens
Reactivation of previous infections (either from donor or recipient)
Specific epidemiologic exposures, including hobbies, food and water, work,
recreational activities, pets, zoonotic infections, or sexual activity[25 ]
Infection specific to donor organ
Iatrogenic or healthcare-associated infections
Specific travel-associated pathogens, including a range of tropical diseases
This framework will hopefully enable the clinician to relate organism category (bacteria,
viruses, fungi, parasites) to each of these 6 potential sources of exposure and infection. The
framework for infection risk assessment in the solid organ transplant recipient is discussed
below, with CREDIT used as a mnemonic device.
C - Community-acquired
Community-acquired infections are common and include cold viruses, lower respiratory
viruses and bacteria, and gastrointestinal pathogens. With the increasing complexity of
epidemiologic patterns affecting communities, pathogens such as methicillin-resistant S
aureus (MRSA) and drug-resistant S pneumoniae may also fall into this general group.
Atypical organisms such as Mycoplasma, Legionella, and Chlamydia species, as well as
prevalent vaccine-preventable diseases, may also cause disease in SOT recipients. Specific
viral pathogens include influenza, parainfluenza, respiratory syncytial virus, adenovirus,
human metapneumovirus, rhinoviruses, and coronaviruses.
R - Reactivation
Several organisms can lead to clinical infection and even endogenous immunosuppression
(eg, CMV) from a process of reactivation within the SOT recipient, including M tuberculosis,
atypical mycobacteria, parasites (Strongyloides stercoralis, Trypanosoma cruzii, Leishmania
species), the herpesviridae (CMV, EBV, herpes simplex virus, varicella-zoster virus), other
viruses (HIV, hepatitis B, hepatitis C, papillomavirus, BK virus), and endemic fungi
(Histoplasma capsulatum, Coccidioides immitis, Paracoccidioides brasiliensis). Donorspecific reactivation-related disease is largely mediated through transmission via the donated
organ.
E - Epidemiologic exposure
Realizing that accurate and timely assessment of the SOT recipient's risk of infection is
directly related to his or her involvement in specific activities may be of great epidemiologic
significance in the evaluation of the febrile SOT recipient. In fact, such an assessment is of
importance on a preventive basis, since proactive identification of epidemiologic exposure
that increases the SOT recipient's risk may represent a cost-effective way to mitigate against
infection in the first place.[34 ]This kind of history-taking is especially important in the context of
immunosuppression, since infection and ultimate disease may depend on the dynamic
interaction between specific exposures and specific immune deficits (eg, anatomic, cellularimmunity, humoral, complement).
Based on a standard approach in the evaluation of fever of unknown origin or febrile illness
in any immunocompromised host, clinicians are encouraged to fully explore the following
areas for epidemiologic clues:













Place of birth (eg, foreign-born)
Prior/recent domicile (eg, homelessness)
Employment status and workplace conditions
Recreational habits (eg, alcohol, cigarettes, recreational drugs [including intravenous
drugs])
Hobbies (eg, water sports, gardening, bird-watching)
Transfusion history
Incarceration history
Sexual history (eg, current/former partners, barrier precautions, history of prior
sexually transmitted diseases)
Potential exposure to arthropod vectors (eg, spelunking, hiking)
Pets (eg, dogs and cats [recent/remote bites], kittens [catscratch disease], reptiles
[enteric infections], birds [eg, psittacine exposures], exotic animals, including sources
of acquisition)
Current medications (eg, antacids, protein-pump inhibitors with risk of achlorhydria)
Food or water exposures (potential for food-borne organisms/toxins)
Comorbid illness that increases the risk of infection (eg, diabetes[35 ], chronic lung
disease)
D - Donor-derived infections
Donor-derived infections are of particular significance, as evidenced by several reports of
infectious diseases transmitted through transplanted organs. They include viruses (hepatitis
B and C,[36 ]herpes viruses, human T-cell lymphotropic viruses (HTLV) 1 and 2, West Nile
virus, rabies, LCMV, polyomavirus BK/JC, HPV, parvovirus B19, HIV), mycobacteria
(tuberculous and nontuberculous mycobacteria), meningococcus, syphilis, parasites (malaria,
Babesia, Toxoplasma gondii, Trypanosoma cruzi [Chagas disease], S stercoralis), and
several fungal organisms. Donor-derived drug-resistant bacteria may also be transmitted,
including vancomycin-resistant enterococci, MRSA, and fluconazole-resistant Candida
species.[37 ]
I - Iatrogenic considerations
Invigorated efforts toward increasing patient safety, minimizing errors, and increasing
adherence to hand hygiene reinforce the vigilance required of healthcare workers and
patients in their efforts to mitigate the risk of acquiring iatrogenic or healthcare-acquired
infections. As noted above, there are specific patterns of infection, especially in the first
month after transplantation, that are also carried forward throughout all phases in the natural
posttransplant history whenever the SOT recipient interfaces with the healthcare setting.
T - Travel considerations
Attention to recent and remote travel is an important component of infection risk
assessment.[38 ]There are many emerging and re-emerging infectious diseases across a
range of pathogen categories. Some important pathogens in this category of exposure
include Escherichia coli (eg, enterotoxigenic E coli), Mycobacterium leprae (leprosy), HTLV 1
and 2, Penicillium marneffei, Plasmodium species, filarial species, Echinococcus species,
Schistosoma species, Clonorchis species, Trypanosoma brucei, Taenia solium, and
Entamoeba histolytica.
Kotton et al (2005)[39 ]and Franco-Paredes et al (2010)[40 ]have published excellent reviews on
prevention of infection in travelers after SOT. The exhaustive compilation of tropical and
geographically restricted infections during SOT by Martin-Davila et al (2008)[41 ]is also an
excellent resource.
Selected Pathogens of Clinical Significance in Solid Organ
Transplant Recipients
Many opportunistic pathogens have been reported in solid organ transplantation (SOT)
recipients, resulting in a wide variety of organ-based pathology or septic syndromes. Briefly
mentioned in this section are some highlights on the epidemiology and diseases related to
bacterial, viral, and fungal organisms of special significance (because of an increased
incidence, greater virulence, or prototypic role in the SOT recipient). Parasitic disease is not
discussed, but the reader is referred to an excellent recent review by Kotton and Lattes
(2009).[42 ]
Among bacterial pathogens, infection with antibiotic-resistant bacteria that include MRSA,
vancomycin-resistant enterococci, and C difficile, along with gram-negative healthcareassociated bacteria, play a significant role, especially in the postoperative period (<30 days
posttransplant).[43,44,45 ]For example, recent studies have shown that SOT recipients are at
higher risk of multidrug-resistant Pseudomonas aeruginosa bloodstream infection, which
carries a high mortality rate.[46 ]Conversely, although some studies have shown no difference
in the severity of C difficile –associated diarrhea (CDAD) among SOT recipients compared
with non-SOT recipients, exposure to steroids placed SOT recipients at a significantly higher
risk of relapse, often requiring a longer course of CDAD therapy.[12,47 ]
Opportunistic pathogens such as Legionella remain a major challenge in SOT recipients.
Microaspiration of water or inhalation of aerosols contaminated with Legionella can result in
outbreaks in transplant centers similar to other healthcare settings. The 2- to 6-month period
following SOT is the critical time when these infections are generally seen, although
community-acquired Legionella infection can occur anytime. Listeria monocytogenes is yet
another pathogen resulting in bacteremia, meningitis, and sepsis following SOT, often
months to years after the surgery. Other organ manifestations of Listeria infections include
endocarditis, endophthalmitis, brain abscess, and infections of allograft sites (eg, liver, heart).
Nocardia infections may present in a localized or disseminated pattern and are due to
aerobic bacteria that stain weakly acid-fast with the appearance of beaded branching thin
filaments.[48 ]These organisms are generally inhaled, establishing a pulmonary infection that
may result in pneumonia or cavitary lesions, followed by dissemination to brain, bone, or skin.
Although relatively rare in SOT recipients, Nocardia infections may be particularly
challenging because of their subtle presentations and fastidious nature.[49 ]A recent matched
case-control 5-year study found that independent risk factors for Nocardia infection among
SOT recipients include history of high-dose steroids, CMV disease, and use of calcineurin
inhibitors. Intestinal SOT recipients may be at increased risk for nocardiosis.
A particularly challenging pathogen is M tuberculosis.[50 ]Most tuberculosis-related illnesses in
the SOT recipient are caused by reactivation of tuberculosis in the recipient in the context of
transplantation-related immunosuppression.[51,52 ]Only approximately 4% of tuberculous
infections in recipients are donor-transmitted.[53 ]
Recent data from European centers indicate a 9.5% attributable mortality rate in SOT
recipients who develop clinical tuberculosis, especially with age and lung transplantation
being independent risk factors.[54,55 ]Particularly important issues include (1) the higher
prevalence of atypical presentations, including extrapulmonary tuberculosis and
disseminated disease among SOT recipients; (2) the critical need to identify and treat latent
tuberculosis; and (3) management of pharmacological toxicity and drug interactions between
tuberculosis therapies and SOT-related medications.[56 ]Drug-resistant tuberculosis can be
particularly important in SOT recipients, given the challenges of such disease in an
immunocompromised host.[57 ]
The association between Helicobacter pylori and gastrointestinal disease (eg, peptic ulcer
disease, chronic gastritis, gastric adenocarcinoma, mucosa-associated lymphatic tissue
lymphoma) is well known. The prevalence of H pylori appears to be similar between SOT
and nontransplant patients but tends to decrease after transplantation, likely because of the
significant impact of post-SOT antimicrobial therapy.[58 ]The incidence of H pylori –related
complications does not appear to increase in the post-SOT phase; however post-SOT
management should still include surveillance and monitoring for these complications and
prompt preemptive interventions for H pylori. Therefore, eradication strategies for H pylori,
though not completely evaluated thus far, should be implemented in the context of risk
factors and/or symptomatology.
An important confounding variable is the variety of gastrointestinal toxicities caused by
existing immunosuppressive therapies (eg, calcineurin inhibitors, mycophenolate mofetil,
steroids).[59 ]Many viruses associated with SOT lead to opportunistic illness. These include
CMV, EBV (and PTLD), and BK virus, as well as viruses previously considered less
significant in SOT, such as hepatitis E.[60,61,62,63 ]Emerging pathogens such as arenaviruses are
associated with fatalities.[64 ]
CMV is the most important viral pathogen to consider in SOT recipients. More than half of
SOT recipients develop CMV infection within the first 3 months after transplantation; however,
like other pathogens, CMV can also cause illness in later phases.[65 ]The general prevalence
of CMV seropositivity is 80%-90%, with most primary infections occurring in childhood or
adolescence. Latent infection reservoirs include the reticuloendothelial system, peripheral
lymphocytes, and monocytes, resulting in later reactivation in the context of
immunosuppressive therapies. Well-designed studies have shown that patients treated with
sirolimus have a lower incidence of CMV infection. Those patients likely received induction
therapy with T-cell depletion.[66 ]
However, CMV infection can result from allograft infection, blood products, or natural
infection posttransplantation among CMV-negative SOT recipients. Besides nonspecific
febrile presentations, CMV can result in invasive disease and organ dysfunction.[67,61,68 ]
Of note, it is still unclear why CMV does not usually present with retinitis syndromes in SOT
recipients, unlike in individuals with advanced HIV/AIDS in whom cellular immune
dysfunction is also very prevalent.[69 ]Copathogens, including HHV-6 or HHV-7 viruses and P
jiroveci, may lead to complicated severe disease patterns.[70,71 ]CMV, because of its
immunomodulatory effects, may compound existing immunosuppression, causing secondary
infections with bacteria and fungi. Prompt and effective management of chronic rejection
associated with CMV infection needs to be a priority.
Chronic allograft rejection may lead to various syndromes, including vanishing bile duct
syndrome, bronchiolitis obliterans, coronary atherosclerosis, and nephropathy in recipients of
liver, lung, heart, and kidney transplantation, respectively. CMV also has indirect effects,
such as the secondary onset of diabetes after CMV infection in SOT recipients. Finally,
superinfection can also lead to serious consequences, eg, transmission and reactivation of
donor-derived CMV in a seropositive recipient.[72 ]
Specific diagnostic and treatment recommendations regarding CMV are available in
eMedicine’s Cytomegalovirus article. A recent review offers updated international consensus
guidance on the management of CMV infection in SOT recipients.[73 ]
EBV infection is also extremely prevalent, with almost 95% of the population being infected
(often asymptomatically) by adulthood. Notwithstanding the common infectious
mononucleosis syndrome, it was noted decades ago that EBV can be cultured from Burkitt
lymphoma cells. EBV can remain latent in B cells and chronically replicate in oropharyngeal
tissue. Although multiple viral genes are expressed in the life cycle of EBV infection, the
presence of EBV DNA through EBV nuclear antigen and EBV latent membrane protein can
be detected in tissues characteristic of PTLD. In reviews of PTLD from the 1990s, the
average time for PTLD to manifest was around 32 months post-SOT. PTLD tended to
develop much more quickly (<6 mo) in patients receiving cyclosporine.[74 ]
The frequency of PTLD varied by type of organ transplantation, from approximately 2% in
kidney and liver transplants to 4.9%-13% in cardiac transplants (likely due to the greater
degree of needed immunosuppression). Some of the clinical presentations of PTLD include
nonspecific febrile illness, mononucleosislike illness, gastrointestinal bleeding, infiltrative
allograft involvement, and CNS disease. PTLD tumors tend to be aggressive and, although
treatments are available, are often associated with poor outcomes (in part due to the
complexity of presentations). See the eMedicine article Posttransplant Lymphoproliferative
Disease for more information.
Another significant viral pathogen, BK virus, has been a particular challenge in the context of
kidney transplantation.[75 ]Part of the Papovaviridae family of viruses, BK virus was in fact
named after it was initially detected in the urine of a kidney transplant recipient whose initials
were BK. The primary infection is often asymptomatic and is likely spread from person to
person and associated with dissemination to the kidneys, where it may remain latent.[63 ]Up to
20%-40% of SOT recipients may have viruria, with approximately 12% presenting with actual
viremia. The clinical presentation largely involves the development of polyomavirusassociated nephropathy. Although multiple risk factors are associated with this condition, the
two main necessary elements are the coexistence of viral infection and intensified
immunosuppressive regimens that include, for example, tacrolimus, mycophenolate mofetil,
and prednisolone.[76 ]
Recent studies indicate that, although reduction of immunosuppression is warranted as an
effort to improve the immunologic response against viral infection BK virus, cautious
antirejection treatment in patients with active BKV infection can result in a lack of clinical
response, which, in turn, makes it challenging to differentiate refractory rejection from viralinduced inflammatory changes in the tissue.[20 ]Although viral load assays of BK virus DNA
(polymerase chain reaction [PCR]) in the context of progressive renal dysfunction can help
with diagnosis, definitive diagnosis is based on positive renal allograft biopsy results (at least
2 core biopsy specimens, ideally sampling the renal medulla, where virus is more likely
present) and positive immunohistochemistry tests using antibodies against BK virus or crossreacting SV40 large T-antigen.[77,78 ]Cidofovir, at low doses, is an effective agent for treating
polyomavirus-associated nephropathy, despite having known nephrotoxic effects.
Although it is not discussed in further detail in this article, an important virus that can cause
primary disease or act as a copathogen is adenovirus, which has been associated with
hemorrhagic cystitis. It is diagnosed with the aid of culture or antigen
detection/immunofluorescence.[79,80,81 ]
Recent reports involving SOT recipients have described a previously less-recognized
syndrome: chronic infection with hepatitis E virus, an RNA virus similar to the Caliciviridae
family (which includes norovirus).[62 ]Hepatitis E virus is transmitted via the oral-fecal route
and is known to primarily cause acute hepatitis, often with a fulminating course in certain
hosts such as third-trimester pregnant women. In industrialized countries, hepatitis E virus
tends to have a zoonotic pattern, with pigs, cattle, sheep, ducks, goats, and rats known to be
infected.[82 ]
SOT recipients with liver, kidney, and kidney-pancreas transplants can develop chronic
hepatitis E infection, and viral RNA levels can persist for a median of 15 months after the
acute phase of illness is over. Histologic findings in patients with chronic hepatitis C infection
have included lymphocytic portal infiltrates with piecemeal necrosis.[62 ]SOT recipients with
chronic hepatitis E infection were noted to have lower total lymphocyte counts, as well as
specific T-cell subsets, including CD2, CD3, and CD4. Seroconversion of hepatitis E virus
occurred later in SOT recipients with chronic hepatitis than those whose acute infections
resolved.[62 ]
The use of intense immunosuppressive regimens including mycophenolate mofetil and/or
mTOR inhibitors appeared to be risk factors for chronic hepatitis E viral infection
development and progression. In fact, chronic hepatitis E infection in a renal transplant
recipient was recently reported to rapidly progress to cirrhosis. This particular case was
noted also for the lack of hepatitis E immunoglobulin G seroconversion, which, in light of a
prior positive immunoglobulin M level (and recurrently elevated hepatitis E virus RNA in the
chronic active hepatitis phase of illness), became a false-negative finding, likely because of
the patient’s immunosuppressed condition.
A new arenavirus was recently reported to be associated with a cluster of fatal cases in
which 3 SOT recipients (2 kidney and 1 liver recipient) developed a rapidly progressive
febrile illness several weeks after transplantation.[64 ]All 3 patients were linked to a single
donor, and all died within a few days of one another; diagnosis was made efficiently using
newer molecular techniques including unbiased high-throughput sequencing, with later
specificity of sequences being confirmed by culture and other tests. Arenaviridae are
enveloped RNA viruses most often implicated in rodent-human transmissions from exposure
to infected urine. Infection with the most characteristic arenavirus, LCMV, may be
asymptomatic or may be associated with mild illness but can also lead to aseptic meningitis
or encephalitis; however, most people recover without complications.[64 ]
Among fungal pathogens, the most common opportunistic fungi include Candida species,
molds such as Aspergillus, and cryptococci.[83,84,85,86 ]Endemic geographically limited systemic
mycoses, including coccidioidomycosis, blastomycosis, and histoplasmosis, can cause
significant illness in the SOT recipient.[87 ]Endemic fungal infections may manifest as primary
rapidly progressive syndromes with hematogenous dissemination to various organs; in
recipients, reactivation infection followed by further spread and re-infection in the context of
transplant-related immunosuppression may also occur.
Emerging pathogens, such as Fusarium, Scedosporium, and Trichosporon species, can
cause various syndromes[88 ]that are similar to those caused by Aspergillus species, which
also have a vascular predilection, causing invasive disease complicated by hemorrhage and
infarction.[89,90 ]Many patients already have metastatic site involvement at the time of
presentation, which is associated with high mortality rates—often up to 50% despite
intravenous therapy.[91 ]
Candida species, the most common fungal pathogens, are associated with a range of
presentations, including milder albeit painful forms such as thrush, mucositis, and
asymptomatic candiduria. Severe disease with organ involvement is also possible, with
manifestations such as hepatosplenic candidiasis, endocarditis, and genitourinary
syndromes. Candidal infection presenting as bloodstream infection may also be associated
with healthcare settings, especially with the use of invasive devices.
Fortunately, because of many factors, including greater use of prophylactic regimens,
advanced surgical methods, and modifications in SOT immunosuppressive regimens, fewer
invasive Aspergillus and Candida infections have been observed.[92 ]This is in contrast to
cryptococcal disease, the incidence of which appears to have been unchanged in SOT
recipients.
Major trends that have been observed for cryptococcal disease in SOT recipients from recent
studies include an increased number of older patients and a greater use of tacrolimus-based
regimens; also, limited pulmonary disease was noted with greater frequency than meningitis
or disseminated disease patterns than were seen previously (possibly owing to the
decreased use of OKT3 antibody in treating organ rejection and increased use of
immunosuppressive regimens that contain calcineurin inhibitors).[93 ]Importantly, in SOT
recipients, cryptococcal antigen assays may yield false-positive findings because of crossreaction of Trichosporon beigelii.[94 ]
Finally, P jiroveci infection[95 ]often progresses to life-threatening pneumonitis in SOT
recipients, especially those with impaired cellular immunity, as in persons with HIV
infection/AIDS. SOT recipients undergoing lung or heart-lung transplants are especially at
risk, often presenting with fever and nonspecific pulmonary symptoms within 2-6 months
posttransplantation. The overall pathogen burden may be lower in SOT recipients than in
individuals with HIV infection/AIDS, and the presentations may be more subtle, potentially
contributing to delayed or erroneous diagnosis. Despite clinical experience suggesting
pathognomonic radiographic patterns associated with P jiroveci pneumonia, no such
evidence exists.
Most significant organisms (common and uncommon) observed in solid organ
transplant recipients
The list below provides a functionally useful listing of the most significant organisms
observed in SOT recipients. The information is largely tabulated from the American Society
of Microbiology (ASM) monograph "Infections in Solid-Organ Transplant Recipients,"[96 ]as
well as other sources (eg, case reports) for completeness. Although the list is not allinclusive, it does attempt to capture the common and uncommon pathogens that are of
clinical significance to practicing clinicians who manage infections in SOT recipients.
Organisms are listed mostly alphabetically and within functionally useful groupings; no
prioritization by prevalence or incidence is implied. All hyperlinks refer to available eMedicine
articles.
Bacteria
Gram-negative organisms include Acinetobacter species[97 ], Burkholderia species,
Enterobacteriaceae (E coli, Klebsiella,[26 ] Enterobacter species), Pseudomonas species,
Proteus species, Salmonella and other potentially foodborne pathogens (eg, Campylobacter,
Plesiomonas, Shigella species, Vibrio species, Yersinia species) , H pylori , and Bacteroides
species.
Gram-positive organisms include S aureus (including MRSA), Staphylococcus epidermidis,
enterococci, S pneumoniae, group B Streptococcus , Streptococcus milleri, Streptococcus
suis, Rhodococcus equi, Corynebacterium urealyticum[98 ], Lactobacillus species, Rothia
species (eg, Rothia dentocariosa), C difficile, M tuberculosis , Mycobacterium bovis, and
atypical mycobacteria.[99 ]
Other respiratory pathogens include H influenzae, Moraxella catarrhalis, Mycoplasma
species, Legionella, and Bordetella.
Other bacteria include Listeria species, Nocardia species, Borrelia species, Neisseria
meningitidis, Treponema pallidum species (syphilis), Rickettsia species, Anaplasma
phagocytophilum, Bartonella, Coxiella burnetii, Ehrlichia species, Francisella tularensis, and
Leptospira species.
Viruses
Herpesviridae include CMV, EBV, HHV-6, HHV-7, HHV-8, and varicella-zoster virus.
Zoonotic viruses include Nipah virus, rabies, arenavirus, LCMV, West Nile virus and other
arboviruses, and parapox virus.
Gastrointestinal/viral hepatitis viruses include hepatitis C virus, hepatitis A virus, hepatitis B
virus, hepatitis E virus, rotavirus[100 ], and noroviruses.[101 ]
Respiratory viruses[102,103 ]include adenovirus, bocavirus, coronaviruses (severe acute
respiratory syndrome), influenza[104 ], H5N1, metapneumovirus, respiratory syncytial virus,
parainfluenza, enteroviruses, HIV, HTLV 1 and 2, and parvovirus B19.
Other viruses (vaccine-preventable) include measles, mumps, rubella, polio, and Japanese
encephalitis virus.
Fungi
Opportunistic systemic fungi include Candida species and Cryptococcus.[105 ]
Geographically endemic species include coccidioidomycosis, histoplasmosis, blastomycosis,
and paracoccidioidomycosis.
Invasive molds include Aspergillus species, Fusarium species, Scedosporium , zygomycosis,
Mucor species, entomophthoramycosis (eg, Basidiobolus), P jiroveci (previously P carinii),
penicilliosis (P marneffei), phaeohyphomycetes (dematiaceous fungi), Sporothrix schenckii,
Malassezia species, and Trichosporon.
Parasites
Protozoa include Toxoplasma species, trypanosomiasis (T cruzi [Chagas disease], T brucei
[sleeping sickness] [primarily in heart and lung recipients]), Acanthamoeba, Cryptosporidium
infection,[106 ] Giardia species, Microsporidia species, and Isospora.[107 ]
Tissue and blood protozoa include leishmaniasis (visceral), Plasmodia species (malaria),
and Babesia species.
Helminths include Strongyloides stercoralis, Clonorchis sinensis, Echinococcus species, T
solium, amebiasis, and Schistosoma species.
Approach to the Febrile Solid Organ Transplant Recipient
The febrile solid organ transplantation (SOT) recipient presents one of the most challenging
diagnostic and management situations facing clinicians.[18 ]Diagnoses must be made
accurately, evaluations must be rapidly performed, and management (often empiric) must be
effective. The complexity of host immune and metabolic factors, pharmacokinetic issues (eg,
drug interactions),[108 ]a broad range of opportunistic pathogens and processes, difficulties in
clinical presentations, and uncertainties in evaluation and therapeutic decision-making are
major factors. Nevertheless, a logical framework that provides guidance to clinicians is
possible.
A strategic approach to fever (and associated organ system–related manifestations) in the
SOT recipient includes the following:


Vigilance to overall temporal pattern of post-SOT infections (see image below)
Changing timeline of infection after organ transplantation (modified from
Fishman J. NEJM. 2007;357(25):2601-14).




Careful evaluation of organ-specific considerations
Recognition of specific associations (This can be particularly useful in SOT recipients
who present with nonspecific febrile illnesses.)
Conducting a thorough clinical assessment using the CREDIT mnemonic (outlined in
Framework for Infection Risk Assessment), with special attention to historical clues
and physical examination
Following a tailored initial diagnostic evaluation
The first consideration in the evaluation of a febrile SOT recipient (or even an afebrile patient
in whom infection is suspected) is to review the timeframe around specific infections
occurring after transplantation, as presented in the image above. It is advisable to think
syndromically (eg, nonspecific febrile illness, pneumonia, urinary tract,[109 ]CNS[105 ]) at first and
then narrow the differential diagnoses of possible organisms that could cause the clinical
presentation(s). It is important to keep in mind that the clock can get reset based on interim
rejection episodes or major immunosuppression due to regimen changes.
Secondly, clinicians should remain aware of the specific types of infection that are
associated with specific types of transplantations. For example, kidney transplant recipients
are at high risk for genitourinary infections, including pyelonephritis (due to surgical anatomic
changes, reflux).[110 ]BK virus infection is a particular concern.[111 ]
Surgical wound infections, bloodstream infections, and pneumonia can all result from the
usual healthcare-associated pathogens in the first month after transplantation. Subsequently,
other syndromes involving opportunistic pathogens, including CMV, may occur, as well as a
range of bacteria, viruses, fungi, and parasites, especially in the first 6 months after SOT
(see Most significant organisms [common and uncommon] observed in solid organ transplant
recipients).
Liver transplant recipients may also be at risk for anastomotic leaks, wound infections, intraabdominal abscesses, and bacteremia from a host of enteric organisms in addition to the
risks of healthcare-associated infections in the postoperative period.[112 ]
Heart transplant recipients may more easily develop pneumonia syndromes with associated
bacteremia and septic presentations, caused by not only bacteria (eg, Legionella) but also
fungi (Aspergillus and Pneumocystis). Sternal wound infections and mediastinitis may occur
with increased frequency given the obvious thoracic location of surgical intervention.
Additionally, toxoplasmosis often complicates cardiac transplantation because of the latent
reservoirs of Toxoplasma cysts in heart muscle; secondary Toxoplasma encephalitis can
also occur.
Lung transplantation is most commonly complicated by pneumonia due to presurgical
colonization, aspiration, and ventilator support. Local compromises in mucociliary escalator–
related clearance mechanisms and airway inflammation likely contribute to the development
of infections with both common and uncommon respiratory pathogens in lung transplant
recipients. Aspergillus and other molds are usually implicated in single-lung transplantation;
prophylactic regimens in these patients likely play an important role.
Thirdly, in SOT recipients who present with an occult fever pattern unaccompanied by
specific organ-based symptoms (eg, cough, abdominal pain), clinicians should consider
several organisms listed in Most significant organisms (common and uncommon) observed
in solid organ transplant recipients that could cause such presentations, including bacterial
infections such as Bartonella -associated bacillary angiomatosis; endocarditis; tuberculosis,
deep-seated Nocardia infection; herpes simplex virus, EBV, CMV, and HHV-6 infections;
fungal complications such as Aspergillus syndromes; or even parasitic infections including
visceral leishmaniasis. Noninfectious conditions such as rejection, PTLD, or drug fever
should also be considered. Studies have shown that focal origins for febrile illnesses are not
evident in up to 25% of cases, lending further support to the search for ancillary clues.
Fourthly, using the CREDIT framework described in Framework for Infection Risk
Assessment, the clinician should carefully solicit the important clues underlying key historical
features, including any local community-acquired pathogens with or without a seasonal
predilection, possibilities for reactivation of specific pathogens (in donor or recipient),
important epidemiologically relevant exposures, important donor-derived infections,
unfortunate iatrogenic (healthcare-associated) complications, and pertinent travel (on a
recent or remote basis).
Based on even a preliminary assessment of timing and nature of illness onset and
presentation relative to the transplantation procedure, it is critical to keep an initial syndromic
differential diagnoses so all the right questions can be asked, given the major significance of
history-taking in the field of infectious disease.[34 ]Additionally, the physical examination is an
important tool that should be thorough and timely, and it may be necessary to repeat the
examination often, hour by hour or day to day, depending on the pace and severity of illness.
This is even more important given the finding that diagnostic errors are associated with
length of stays in, for example, the intensive care unit, a setting in which too little attention is
often paid to the physical examination.[113 ]
Ideally, information from the examination should be derived directly rather than from other
team members. Data suggest that two thirds of missed diagnoses in the ICU in one study
were infectious in origin.[113 ]A particularly ominous finding was that disagreement in
antemortem and postmortem diagnoses was greater in transplant recipients than in trauma
or cardiac surgical patients.
A methodical approach includes starting with assessment of the vital signs, including
observing any pulse-temperature dissociation (indicative of noninfectious processes,
endocrine illness, or intracellular pathogens). A complete assessment of mucosal surfaces,
including the oral cavity, should be performed. Many oral lesions, including dental and gum
health, provide insight into likely etiologies and nutritional status. Inflammatory signs may be
blunted given the net state of immunosuppression, as in the case of the neutropenic host. A
search for invasive devices and evidence of recent procedures is advisable. The presence or
absence of a cardiac murmur and peripheral stigmata of endovascular infection need to be
determined. The abdominal examination is considered critical, especially in patients who
underwent liver transplantation; evidence of surgical leaks, intraabdominal processes, and
peritonitis can be lifesaving.
Consider performing pupillary dilation as part of a complete retinal examination, as it may
offer clues to a disseminated disease process or increased intracranial pressure associated
with a CNS syndrome. As in other immunocompromised hosts, the skin examination is
paramount, since many infections leave a dermal footprint through many different types of
lesions, including macules, papules, erythema patterns, fluctuance, petechiae, and eschars
that correspond to primary infections or secondary complications from dissemination. An
extremely helpful medical diagnostic decision program is available online and for handheld
devices (including smart phones) for point-of-access differential diagnostic help in the
evaluation of any skin lesion.[114 ]
Finally, as per a recent article on SOT-related infections, Fischer (2006) put forth a tabular
summary of recommended initial diagnostic evaluations.[115 ]It is reproduced here (with
permission and slight modification) for its practical value and comprehensive approach.
Modified approach to diagnosis of infection in solid organ transplant recipients with
fever
This section describes the recommended initial diagnostic evaluation in patients with various
syndromes.[115 ]
The recommended initial diagnostic evaluation for fever without localizing findings is as
follows:






Urinalysis and urine culture
Chest radiography
Blood cultures
CMV PCR
Purified protein derivative (PPD) (Consider QuantiFERON testing using interferon
gamma assays.)
Antigen detection tests available for adenovirus, influenza A, respiratory syncytial
virus, and rotavirus; PCR may also be available
The recommended initial diagnostic evaluation for pulmonary infiltrates (alveolar pattern) is
as follows:







PPD (consider QuantiFERON testing using interferon gamma assays)
Blood cultures
Sputum Gram stain and culture
Urine Legionella and pneumococcal antigens
Sputum acid-fast bacillus (AFB) smear and culture (DNA probes if available)
Urine Histoplasma antigen[94 ]in endemic areas or suggestive travel
Bronchoscopy if fever and infiltrates persist
The recommended initial diagnostic evaluation for pulmonary infiltrates (interstitial pattern) is
as follows:




Workup for pulmonary infiltrates (alveolar pattern) plus CMV PCR
Coccidioides serology, if warranted
Bronchoscopy with transbronchial biopsy if fever and infiltrates persist
Bronchoalveolar lavage (BAL) fluid for bacterial, viral, fungal,[94,116 ]and AFB stains and
cultures; direct fluorescent antibody (DFA) and culture for Legionella; DFA for P
jiroveci; CMV PCR; cytology; modified AFB smear and culture to identify Nocardia
The recommended initial diagnostic evaluation for CNS symptoms is as follows:




Brain MRI (with gadolinium)
Lumbar puncture for CSF analysis: usual studies (cell count and differential); glucose,
protein; bacterial, viral, fungal,[94,116 ]AFB cultures, cryptococcal antigen, and several
PCR probes (eg, herpes simplex virus) that may be available and relevant; and
cytology
Consider PCR and serology for other pathogens (CMV, EBV, WNV), arboviral testing
Biopsy of mass lesions and/or leptomeninges (especially to identify granulomatous
meningitis)
The recommended initial diagnostic evaluation for diarrhea is as follows:





Stool for WBC and cultures (for enteric [Salmonella, Shigella, Campylobacter)
At least 2 separate stool specimens for C difficile testing (enzyme immunoassay
[EIA] acceptable)
Three separate stool specimens for ova and parasites
CMV PCR (blood)
If stool studies unrevealing and diarrhea persists, endoscopic evaluation warranted
(with mucosal biopsy); immunohistochemical staining for CMV should be performed
The recommended initial diagnostic evaluation for lymphadenopathy is as follows:






EBV PCR, CMV PCR (blood)
Bartonella (catscratch disease) serology
T gondii serology
PPD (consider QuantiFERON testing using interferon gamma assays)
Biopsy of involved lymph node is often diagnostic and performed quickly to exclude
PTLD and occult infections (eg, tuberculosis); node tissue should be submitted for
histologic examination to look for atypical cells, granulomata, and cultures (aerobic,
anaerobic, AFB, fungal and modified AFB)
CT scanning of neck, chest, abdomen, and pelvis might be useful to demonstrate the
extent of nodal involvement.
Special Host Considerations
Two types of hosts are discussed here for their significance in the solid organ transplantation
(SOT) context: the pediatric patient[117,118,119 ]and the HIV-positive patient.[120 ]
As of 2007, 1,957 pediatric SOTs had been performed (kidneys [40%]; liver [30%], and heart
[18%]).[117 ]The younger the child (especially infants), the greater the risk of infections, and,
often, the more severe the disease.[118 ]Age is a determinant, especially because younger age
groups are often at risk for certain types of natural infection, and primary immunization series
may not have been completed by the time of transplantation. In one of the largest pediatric
SOT cohorts, some risk factors for bacterial and fungal infections included age (highest risk
among infants), race (black and Hispanic), use of cyclosporine as a first immunosuppressive
agent, and increasing bilirubin levels, among others.[121 ]Most common etiologies were viruses,
including CMV, EBV, HHV-6, HHV-7,[122 ]parvovirus B19,[123 ]adenovirus, human
metapneumovirus, and polyomavirus.
Viral infections are often associated with rejection, allograft dysfunction, vasculopathy, and
poor prognosis. Primary varicella-zoster virus infection can often disseminate to visceral
organs. In a cardiac transplant study, respiratory infections were most frequently
encountered, followed by infections in the urinary tract, gastrointestinal tract, and then CNS.
Bacterial infections are often associated with invasive devices; rarely, unusual organisms
such as R dentocariosa are seen.[124 ]Nontuberculous mycobacteria have been isolated in up
to 8% of BAL specimens in some studies.
Based on usual recommendations from agencies such as the CDC, most vaccines should
ideally be given before transplantation. Vaccine titers can rapidly decline after SOT, and
more research is needed on ways to maintain immune response.[125 ]Since pediatric rashes
are common even in the general population, such infections may have similar presentations
in pediatric SOT recipients. However, other skin lesions may be atypical and could represent
dissemination, drug hypersensitivity, or organ rejection.
In an important review from 2006, Roland and Stock discuss SOT issues as they relate to
the HIV-positive patient.[126 ]Given the overwhelming success of highly active antiretroviral
therapy in improving longevity and quality of life for individuals infected with HIV, the primary
questions related to SOT in this population concern optimal candidacy and methods of
effective management following SOT.[127 ]
Despite overall comparable graft survival rates, allograft rejection is noted to occur with
kidney transplants in HIV-positive patients.[126 ]To compound the challenges, antirejection
therapies have been subsequently associated with severe non–AIDS-defining conditions.
Some recommendations to prevent post-SOT infections have empiric rationale, including the
advisability of using secondary prophylaxis immediately after SOT, regardless of T-cell
counts.[126 ]Screening for opportunistic infections should be vigorous, including monitoring for
both HIV-associated infections and other types of infections seen in SOT recipients.
Infection Prevention Strategies
The key infection-prevention strategies in solid organ transplantation (SOT) recipients
include (1) improving adherence to the eligibility criteria for deceased donor organ
donation,[128,129 ](2) primary or preemptive prophylaxis with antimicrobials and
vaccination,[130,34,131,65,132,133 ]and (3) promoting healthy behaviors and risk reduction in various
settings post-SOT (eg, adherence to pretravel consultation for SOT recipients, infectioncontrol recommendations in healthcare or home settings). Although there are 2 excellent
recent reviews on general recommendations for prudent infection prevention and
immunization practices in SOT recipients,[134,135 ]many resources are available to guide
patients and providers in these areas, including the following:



University of Pennsylvania Medical Center Guidelines for Antimicrobial Therapy
Kotton CN, Ryan ET, Fishman JA. Prevention of infection in adult travelers after solid
organ transplantation. Am J Transplant. Jan 2005;5(1):8-14. [Medline]
Kotton CN, Hibberd PL. Travel medicine and the solid organ transplant recipient. Am
J Transplant. Dec 2009;9 Suppl 4:S273-81. [Medline]
Infection-control practices must be optimized for SOT recipients and providers. The CDC
provides several guidelines for effective infection control measures here. Although many of
the policies and procedures relate to specific setting and types of exposure, the most
important and cost-effective tool available to all individuals, especially SOT recipients and
their families and loved ones, is hand hygiene. A great deal of information on proper
technique is available from the CDC here, in addition to guidance for the range of questions
that concern hand hygiene methods, materials, and best practices.
Solid Organ Transplant Recipients and the 2009-2010 Influenza
A/H1N1 Pandemic
In 2009-2010, the world experienced an influenza A pandemic related to the A/H1N1 strain.
Although at the time of this writing, no reports of solid organ transplantation (SOT) recipients
or clusters infected with A/H1N1 have been reported, certain lead agencies have provided
advisory statements on the likely impact of the current pandemic for SOT recipients,
specifically those who received thoracic organs.[136,137 ]A particularly significant monograph is
the guidance document on novel influenza A/H1N1 from the American Society of
Transplantation (AST) Infectious Diseases Community of Practice/Transplant Infectious
Disease Section of The Transplantation Society (TTS).[138 ]The monograph, published in 2010,
is available here.
The reader is referred to the source document for information on the following:





Diagnosis of influenza A/H1N1, specimen collection methods, treatment
recommendations, antiviral resistance, chemoprophylaxis
Practical strategies and immunization recommendations in SOT candidates,
recipients, and contacts
Special issues for pediatric SOT recipients
Infection-control aspects
Donor-derived novel A/H1N1 issues
Several valuable publications addressing further details on A/H1N1 are also
noted.[136,139,140,137,141,142,143,144,145,146 ]
Major updates on A/H1N1 are available through many reliable sources, including the
following:

eMedicine article on A/H1N1







Medscape A/H1N1 Center
CDC H1N1 Site
WHO H1N1 Site
DHHS Pandemic Flu Site
CIDRAP H1N1 Site
New England Journal of Medicine H1N1 Site
HRSA / OPTN - Organ Procurement and Transplantation Network (H1N1 notice)
Multimedia
Media file 1: Schematic sites of action of common immunosuppressants. Image
courtesy of Elsevier.
Media file 2: Changing timeline of infection after organ transplantation (modified
from Fishman J. NEJM. 2007;357(25):2601-14).
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Keywords
infection after solid organ transplantation, transplantation infections, solid organ transplant,
transplant infection, immunosuppression, organ transplant, infection after transplant
Contributor Information and Disclosures
Author
Asim A Jani, MD, MPH, FACP, Clinician-Educator and Epidemiologist, Consultant and
Senior Physician, Florida Department of Health; Diplomate, Infectious Diseases, Internal
Medicine and Preventive Medicine
Asim A Jani, MD, MPH, FACP is a member of the following medical societies: American
Association of Public Health Physicians, American College of Physicians, American College
of Preventive Medicine, American Medical Association, American Public Health Association,
and Infectious Diseases Society of America
Disclosure: Nothing to disclose.
Coauthor(s)
Paul Chen, University of Texas Southwestern Medical School
Disclosure: Nothing to disclose.
Pharmacy Editor
Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment
Chief Editor
Ron Shapiro, MD, Professor of Surgery, Robert J Corry Chair in Transplantation Surgery,
Director, Kidney, Pancreas, and Islet Transplantation, Thomas E Starzl Transplantation
Institute, University of Pittsburgh Medical Center
Ron Shapiro, MD is a member of the following medical societies: American College of
Surgeons, American Society of Transplant Surgeons, Association for Academic Surgery,
Central Surgical Association, and Society of University Surgeons
Disclosure: Astellas Honoraria Speaking and teaching; Brystol Meyer Squibb StemCell Data
Monitoring Committee Consulting fee Review panel membership; Wyeth Honoraria Speaking
and teaching; Stem Cells, Inc Consulting fee Review panel membership; Up To
Date contracted Author
Acknowledgments
The authors wish to extend gratitude for the careful and insightful review and comments on this manuscript by
Kauser Akhter, MD (Diplomate, Internal Medicine and Infectious Diseases; and Faculty member, Infectious
Diseases Fellowship with Orlando Health Care, Orlando, FL). Dr. Akhter received her BS cum laude and her
medical degree at the University of South Florida College of Medicine. Her internal medicine internship and
residency were completed at Allegheny General Hospital and Mercy Hospital, both in Pittsburgh. She followed this
with a fellowship in infectious disease at Georgetown University Hospital. She is board-certified in internal
medicine and infectious diseases. She enjoys treating patients following transplant surgery and patients with HIV
and working in Health Services for Travelers.
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