Abbreviations
HBV
hepatitis B virus
HIV
human immunodeficiency virus
PPD
purified protein derivative (TB screening test)
Background
Pretransplant screening of potential organ donors and recipients is essential to the
success of solid organ transplantation 1, 2, 3, 4. The goals of pretransplant infectious
disease screening are to identify conditions which may disqualify either donor or
recipient; identify and treat active infection pretransplant; recognize and (if possible)
define the risk of infection and develop strategies for preventing and mitigating
posttransplant infection; and implement preventative measures, including immunizations
5. While there is general agreement on the major infections for which routine screening
is performed, centers vary in the extent of infectious diseases investigation and
the actions taken as a result.
Potential recipients should be evaluated for infection risk by obtaining a thorough
medical history, including details of prior infections, places of travel and residence,
and exposures to animal and environmental pathogens. While all potential recipients
undergo screening for the presence of infections such as HIV, hepatitis C (HCV) and
cytomegalovirus (CMV), the detailed history can focus additional testing if necessary
to mitigate and prevent the reactivation of latent infections posttransplant. Pretransplant
recipient screening also helps determine immunity to vaccine‐preventable illnesses
and may help with allocation of infected donor organs to recipients with known immunity
to certain pathogens 6. The pretransplant period is an ideal time for detailed counseling
of the recipient and his/her family about safe food handling and the risk of infection
associated with pets, travel and hobbies such as gardening and woodworking. Infection
prevention approaches including hand hygiene, prophylactic antimicrobials, postexposure
prophylaxis and updating of immunizations should be addressed as well.
A variety of pathogens may be transmitted by transplantation (Table 1) 7, 8, 9, 10.
Previous guidelines for pretransplant screening have been developed by a number of
national and international multidisciplinary transplant groups 6, 10, 11, 12, 13,
14, 15. The Centers for Disease Control and Prevention (CDC) have published guidelines
for the prevention of HIV transmission through transplantation 16. These are in the
process of revision in order to address updated knowledge of transmission of HIV and
other bloodborne pathogens. In addition, the work of the ad hoc United Network of
Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) Disease Transmission
Advisory Committee (DTAC) has helped define the risk of infection and disease transmission
in organ donation in the United States and shape the discussion of screening and preventive
measures 17, 18.
Table 1
Pathogens reported to be transmitted with solid organ transplantation
Bacteria
Mycobacteria
Staphylococcus aureus
Mycobacterium tuberculosis
Klebsiella species
Nontuberculous mycobacteria
Bacteroides fragilis
Parasites/protozoa
Pseudomonas aeruginosa
Toxoplasma gondii
Escherichia coli
Strongyloides stercoralis
Salmonella species
Plasmodium species
Yersinia enterocolitica
Trypanosoma cruzi
Treponema pallidum
Pneumocystis jiroveci
Brucella species
Viruses
Enterobacter species
Cytomegalovirus
Acinetobacter species
Epstein–Barr virus
Legionella species
Herpes simplex virus
Nocardia species
Varicella‐zoster virus
Listeria monocytogenes
Human herpesvirus‐6
Fungi
Human herpesvirus‐7
Aspergillus species
Human herpesvirus‐8
Candida species
Hepatitis B, D
Coccidioides immitis
Hepatitis C
Cryptococcus neoformans
Human immunodeficiency virus
Histoplasma capsulatum
Parvovirus B19
Scedosporium apiospermum
Rabies
Prototheca species
Lymphocytic choriomeningitis
Zygomycetes
virus
West Nile virus
BK virus
Human T cell lymphotropic virus (HTLV)‐1/2
John Wiley & Sons, Ltd.
While conventional screening strategies are very effective in most cases, they are
not a guarantee against donor‐derived infections. There have been a number of high‐profile
incidents of donor‐transmitted infection reported in recent years, including rabies
19, lymphocytic choriomeningitis virus 20, West Nile virus 21, HIV 22, 23, 24 and
HCV 23, 24, which have renewed discussion of the process of organ donor screening.
In addition to DTAC, other transplant and public health community initiatives have
helped guide practice in the hope of developing a more robust sentinel network to
detect and respond to donor transmission events in a more timely manner 20, 25, 26,
27, 28.
This guideline summarizes current opinions on screening for bacterial, mycobacterial,
fungal, parasitic and viral infections in the donor and recipient (Table 2
5. More detailed discussions of these infections, including posttransplant monitoring,
prophylaxis and treatment are found in other sections of these Guidelines.
Due to the lack of expansion in the available organ pool despite steady increases
in the need for organ replacement for end‐stage diseases, it has become necessary
to consider marginal donors, including those with active infection at the time of
donation, higher risk serologic profiles, or a social history indicating potential
exposure to bloodborne pathogens such as HIV or HCV. The natural history and treatment
options for donor infection, the urgency of transplantation of a vital organ into
a recipient and the likelihood (or lack thereof) of another organ offer for the patient
on the transplant waiting list must all be weighed in determining the acceptability
of the potentially infected donor.
Donor Screening
Living donors
The differences in screening of the living donor and the deceased donor are largely
based on the different time constraints during which the evaluation must take place.
For the living donor, it is often possible to treat active infection and delay transplantation
until the infection resolves. If there is a significant delay between donor evaluation
and transplantation, interim evaluation may be indicated to rule out recently acquired
infection. Clinical reassessment of the prospective living donor is indicated if clinical
signs or symptoms of possible infection occur, particularly any unexplained febrile
illness between the time of initial screening and the planned date of transplantation.
The CDC has recommended that all living donors be rescreened with HIV serology and
HIV nucleic acid amplification testing (NAT) prior to organ donation, to look for
evidence of recently acquired infection 29. Similarly, consideration should be given
to repeating serologic HBV testing and HCV NAT in the potential living donor with
risk factors for these infections.
The screening of a prospective living donor includes a thorough medical and social
history, physical examination, laboratory studies including serologic testing (Table
2) and radiographic workup as indicated by the donor's history and the procedure to
be performed. The medical history should include an assessment of previous infections,
vaccinations, travel and occupational exposures, as well as the presence of behaviors
posing risk for bloodborne or sexual pathogen exposure (e.g. drug use, sexual practices,
incarceration). Living donors should be screened for syphilis, HIV, hepatitis B and
C, and tuberculosis via a tuberculin PPD skin test or interferon‐gamma release assay
(IGRA) (II‐2). If there is any suspicious donor history, additional testing may be
warranted. Consultation with a transplant infectious disease specialist may help with
determining additional workup, counseling and management while awaiting transplantation,
should another living donor not be available.
Table 2
Frequency utilized serologic tests for screening of donor and recipient prior to transplantation
Tests commonly obtained in both donor and recipient
Human immunodeficiency virus (HIV) antibody
HSV (herpes simplex) IgG antibody (at some centers)
Cytomegalovirus (CMV) IgG antibody
Hepatitis C (HCV) antibody
Hepatitis B (HBV) surface antigen (HBsAg)
Hepatitis B core antibody (HBcAb IgM and IgG, or total core antibody)
Hepatitis B surface antibody (HBsAb)
Rapid plasma reagin (RPR)
Toxoplasma antibody (especially in heart recipients)
Epstein–Barr virus (EBV) antibody (EBV VCA IgG, IgM)
Varicella‐zoster virus (VZV) antibody
Other screening measures for infectious diseases
Purified Protein Derivative (PPD) or interferon gamma release assay (IGRA) for latent
TB infection in recipients
Strongyloides serology (for recipients from endemic areas)
Coccidioides serology (for recipients from endemic areas)
Trypanosoma cruzi serology (for donors and recipients from endemic areas)
Serologies for tetanus, diphtheria, measles, mumps and pneumococcal titers as an
aid to pretransplant immunization (at some centers)
Optional screening measures
West Nile virus serology or NAT
HHV‐8 serology
BK serology (kidney donor and recipients)
Nucleic acid amplification testing (NAT) for HIV, HCV, HBV, particularly in donors
with high‐risk social histories
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Deceased donors
By contrast, the time frame for deceased donor evaluation is typically hours. Serologic
workup is performed in laboratories associated with organ procurement organizations
or similar screening agencies (hereafter referred to as OPOs) which operate on a 24‐h
basis to generate the data needed to determine donor suitability. Because of time
constraints and the extensive geographic areas covered by some OPOs, testing is often
limited to serologic methods that are rapid and routinely available. Because more
sensitive testing may not be available, some infections, such as HIV and HCV, may
be difficult to diagnose at an early stage, before the development of specific antibody
23, 24, 25, 30. Thus, a comprehensive social and medical history on the donor is required
to identify risk for infections that might not be detected by serologic testing. Furthermore,
certain infections may come to light only after the transplant has been performed,
when results of routine procurement cultures of blood, urine and sputum become available.
Increasingly, some OPOs are utilizing rapid molecular testing, particularly in high‐risk
potential donors, including NAT testing for HCV, HBV and HIV. A recent consensus conference
on the utility of routine NAT testing was, however, inconclusive, largely due to concerns
that testing is not feasible within the deceased donor timeframe in some areas, as
well as concern that false positive test results in potential donors with no identified
risk factors for infection might result in wastage of viable organs 30. Testing for
certain pathogens with particular geographic significance such as Trypanosoma cruzi
(Chagas’ disease), endemic mycoses and West Nile virus may be performed by some OPOs.
If a deceased donor with uncertain risk is to be used, informed consent of the recipient
should include the risk for infection transmission.
Donor screening: bacterial infections
The goal of evaluation of the potential living or decreased donor is to diagnose any
infection with the risk of transmission to the recipient(s). Bacterial infections
of the respiratory tract, urinary tract or the organ to be transplanted should be
treated with documentation of resolution of infection prior to donation. The potential
kidney donor with urinary tract infection should be investigated to rule out upper
tract involvement. In the potential donor with a history or suspicion of prior bloodstream
infection, a thorough investigation should be performed to insure that infection is
not present in the target organ.
Syphilis may be latent and asymptomatic in the donor and requires therapy if time
permits. Syphilis has rarely been transmitted by transplantation, but it is not a
contraindication to organ donation if each recipient is treated posttransplant with
an appropriate course of penicillin 31 (II‐3).
Deceased donors may harbor known or unsuspected bacterial infections 6, 30, 31, 32,
33, 34, 35. Attempts to rule out the presence of active infection should include obtaining
a detailed history from the donor's family, recent contacts and (if possible) primary
care physician, as well as a complete review of medical records, vital signs, physical
exam, radiographic studies and any available microbiologic studies. Blood cultures
should be obtained to rule out occult donor bacteremia. Bacteremia with virulent organisms
such as Staphylococcus aureus and Pseudomonas aeruginosa may result in early posttransplant
sepsis or mycotic aneurysm formation at the site of allograft vascular anastomoses
32, 33, 34, 35, 36. Although a review of 95 bacteremic donors found no evidence of
transmission when recipients were treated with antimicrobial therapy for a mean of
3.8 days posttransplant 36, the standard of care is to administer longer courses of
therapy in the recipient (e.g. 2 weeks) if the donor is known to have been bacteremic
with a virulent organism (II‐2).
In general, there is no reason to treat the recipient of an allograft from a deceased
donor with nonbacteremic, localized infection not involving the transplanted organ,
with the exception of meningitis, in which occult bacteremia frequently occurs (III).
Organs have been successfully transplanted from donors with bacterial meningitis due
to pathogens such as Streptococcus pneumoniae when appropriate antimicrobial therapy
was administered to both the donor and recipients 37.
Lung transplantation deserves special attention 38. Donor bacterial colonization is
common, as the lungs are in contact with the external environment, and the airways
are colonized with multiple organisms, with increasing resistance noted in the hospitalized,
critically ill potential organ donor. Donor bronchoscopy with cultures performed at
the time of evaluation and/or procurement allows for the administration of antibiotics
directed at these colonizing organisms, and can prevent invasive infection in the
recipient (III) 7, 8, 38.
Allograft contamination may occur during organ procurement or processing 39. Interpretation
of organ preservation solution cultures is challenging, as contamination can occur
39, 40, 41, 42; however, infection transmission from contaminated solutions appears
to be uncommon 39, 40, 42. A report of kidney preservation fluid contamination with
Candida species in eight recipients demonstrated that the risk of mycotic aneurysm
rupture can be mitigated with appropriate antifungal therapy 41.
If a donor is determined to have active bacterial infection at the time of procurement,
antibiotics should be administered to each recipient for at least 14 days for infections
with Gram‐negative bacilli, Staphylococcus aureus, or Candida species (II‐3). A shorter
course of therapy may be considered for less virulent organisms (III).
Donor screening: mycobacterial infections
Mycobacterium tuberculosis (TB) has been transmitted by transplantation; in the largest
study to date (511 recipients), donor transmission accounted for approximately 4%
of reported posttransplant TB cases 43. Potential living donors should have PPD testing
performed (a two‐stage tuberculin skin test if from an endemic area) or TB interferon‐gamma
release assay (IGRA) testing 43, 44, 45; if either test is positive, additional testing
should be performed to rule out the presence of active infection (III). Any donor
with active tuberculosis should be excluded from donating until therapy has been completed
and all signs of infection have resolved. A positive PPD is defined as the presence
(at 48–72 h) of 5 mm or more of induration in immunosuppressed patients or those with
contact with a person with active TB; 10 mm or more in injection drug users, employees
or residents of hospitals, nursing homes or other group settings, and children under
the age of 4; and 15 mm or more for all others. All potential donors with evidence
of latent TB infection (i.e. a positive PPD or a positive IGRA test) should have a
chest radiograph to look for evidence of active pulmonary infection. If there are
symptoms of infection or radiographic findings suggestive of active disease, acid
fast bacilli (AFB) cultures of sputum and/or other appropriate specimens should be
performed. In the potential kidney donor with evidence of latent TB infection (LTBI),
this could include urine AFB cultures and abdominal CT scanning. If there are no signs
or symptoms of active disease and the chest radiograph is normal, sputum AFB cultures
are not indicated due to their low yield.
Management of the prospective living donor with LTBI varies with the degree of local
endemicity. Delay of transplant until the living donor is treated (with isoniazid
for 9 months, rifampin for 4 months, or isoniazid and rifapentine for 3 months) is
appropriate, should another suitable donor not be available. In TB endemic areas,
where as many as 30–40% of donors have LTBI, it may be difficult to avoid the use
of infected donors. Isoniazid prophylaxis of the recipient of an organ from a living
donor with LTBI is an option but controlled studies are needed to determine the efficacy
of this practice (III).
In deceased donors, time does not allow for tuberculin skin testing, and the IGRA
is not logistically practical in most cases. Donors in whom active tuberculosis is
a clinical possibility should not be utilized (II‐2). In cases where a potential donor
is known to have recent PPD skin test conversion, suggesting recent acquisition of
infection with the potential for a high organism burden, transplantation should be
approached with caution due to the risk of dissemination in the recipient. Donors
with a history of an untreated positive PPD but without evidence of active disease
are acceptable, but warrant consideration of treatment of the recipient(s) with isoniazid
(III) 43, 45, 46. New guidelines for the prevention and management of Mycobacterium
tuberculosis in organ transplantation have been published in the American Journal
of Transplantation
47.
Donor screening: fungal infections
Active systemic fungal infection in the donor is a contraindication to transplantation.
The endemic mycoses may be difficult to diagnose, as infection may be dormant. Transmission
of histoplasmosis by transplantation has been described 48, but most cases appear
to be the result of reactivation of past infection in the recipient. In many individuals
from the Midwestern United States, calcified pulmonary, hilar and splenic granulomata
are the radiographic residua of old Histoplasma infection, but such signs have not
traditionally been considered a contraindication to donation (III). Transmission of
coccidioidomycosis by lung transplantation has been reported in the Southwestern United
States 49, although reactivation of coccidioidomycosis in the previously infected
recipient appears to be far more common 50. There are no uniform recommendations for
donor screening for endemic mycoses.
Donor screening: parasitic infections
Toxoplasmosis is a significant issue in heart transplantation, where the Toxoplasma‐seronegative
recipient of a Toxoplasma‐seropositive heart is at highest risk for developing active
toxoplasmosis posttransplant 51, 52, 53. Toxoplasmosis has also rarely been transmitted
to liver and kidney recipients 52, 53. Donor seropositivity is not a contraindication
to heart donation but allows for appropriate prophylaxis to be administered to the
recipient; routine trimethoprim‐sulfamethoxazole prophylaxis against Pneumocystis
jiroveci is effective in preventing toxoplasmosis and may negate the need for serologic
testing in areas of low prevalence 53. Screening of donors for Toxoplasma is not routinely
performed for noncardiac donors but is part of the screening panel at some transplant
centers and OPOs.
Transmission of Chagas’ disease (Trypanosoma cruzi) by transplantation is a significant
problem in endemic areas (Mexico, Central and South America) but has increasingly
been reported in the United States 54. A recent consensus conference resulted in recommendations
including avoidance of transplantation of the hearts from infected donors and monitoring
other recipients with PCR and microscopy of buffy coat to detect early infection and
initiate therapy 55.
Donor and recipient screening: viral infections
As the serologic status of both donor and recipient is crucial in determining the
risk of infection, screening for viral infections in both the donor and recipient
will be discussed together, and is detailed in Table 3. Caution should be used in
interpreting antibody status in infants, due to the role of maternal antibody. More
detailed information on the clinical presentation and treatment of these infections
is found elsewhere in these Guidelines.
Table 3
Interventions related to donor and recipient screening results
Donor antibody
Recipient antibody
Recommendations
Pathogen
status
status
regarding transplantation
Comment
HIV
Positive
Negative
Reject donor
HIV + donors must be excluded in the United States by law
Negative
Positive
Proceed if HIV well controlled; be cautious about major drug interactions between
antiretrovirals and CNIs
HTLV‐1/2
Positive
Generally exclude HTLV 1 + donors for organ donation (may be used in life‐threatening
situations, with informed consent)
Lack of a rapid assay distinguishing HTLV‐1 and 2 is a significant concern; if HTLV‐2
is confirmed, proceed with transplant. If confirmed HTLV‐1+ would reject donor.
CMV
+ or −
Positive
Proceed
D/R status used to determine prevention strategy (preemptive therapy versus prophylaxis)
Positive
Negative
Accept; high risk for CMV infection
See CMV guideline for approach to management of the CMV D+R‐ recipient
EBV
+ or −
Positive
Proceed
Positive
Negative
Accept; higher risk for primary EBV infection and PTLD
Consider posttransplant NAT monitoring to guide immunosuppression
Toxoplasma
+ or −
Positive
Proceed
TMP/SMX prophylaxis effective in prevention
gondii
Positive
Negative
Accept
Heart transplant donors should receive prophylaxis with TMP/SMX. If intolerant or
allergic, use atovaquone or dapsone with pyrimethamine and folinic acid.
HCV
Positive
Positive
? Accept
If used, reserve HCV + organs for recipients with Ab to HCV or severely ill recipient
Positive
Negative
Decision depends on urgency of transplantation
Some centers accept in severely ill recipient and/or elderly recipient; controversial
in kidney transplantation
HBV
HBsAb+
+ or −
Accept
HBsAg+
− HBsAb
Reject
+ HBsAb
Reject
Some centers use in life‐saving situations with preemptive antiviral treatment of
the recipient
HBcAb
− HBsAb
Reject
IgM+
+ HBsAb
Reject
Some centers use in life‐saving situations with preemptive antiviral treatment of
the recipient
HBcAb IgG+ (with concurrent negative HBsAg
− HBsAb
Reject unless for liver transplant in life‐saving situation
Risk of transmission high, some centers use with intensive prophylaxis (HBIg +/‐ antivirals)
and negative HBcAb IgM)
+HBsAb
? Accept
Some centers accept for extrahepatic transplants, in immune recipient, with antiviral
prophylaxis
RPR (syphilis)
Positive
+ or −
Accept
Recipients should be treated for presumed transmission with penicillin
CNS viral pathogens (e.g. LCMV, rabies, WNV)
Clinical suspicion of infection
Reject
CNIs = calcineurin inhibitors; D+/R− = donor seropositive, recipient seronegative;
PTLD = posttransplant lymphoproliferative disease; RPR = rapid plasma reagin; TMP‐SMX
= trimethoprim sulfamethoxazole.
John Wiley & Sons, Ltd.
Cytomegalovirus (CMV)
The CMV serologic status of donor and recipient is an important predictor of posttransplant
infection, with the CMV seronegative recipient of a CMV seropositive donor organ (D+/R−)
being at highest risk for development of tissue‐invasive CMV, recurrent CMV and ganciclovir‐resistant
CMV 56, 57, 58. Consequently, all donors and recipients should be tested for CMV infection
using commonly available serologic techniques. While not a contraindication to transplantation,
D+/R− status is an indication for more intensive monitoring and prevention strategies
posttransplant than in donor/recipient pairs with a lower risk of CMV infection (II‐2).
The seropositive recipient, regardless of donor status, is at risk for CMV reactivation
and usually receives either prophylaxis or preemptive monitoring and therapy. There
are many different protocols in use; a full discussion of CMV prevention and treatment
is found elsewhere in the Guidelines.
Epstein–Barr virus (EBV)
While primary EBV infection can be severe and disseminated in the posttransplant setting,
the development of posttransplant lymphoproliferative disease (PTLD) is the most feared
EBV‐associated complication. The highest PTLD risk is in the EBV seronegative recipient
of an EBV seropositive graft, which most commonly occurs in pediatric recipients 59,
60, 61. The risk of PTLD can also be increased in the seropositive recipient, especially
under the influence of potent immunosuppressants such as antithymocyte globulin (ATG)
and belatacept. Awareness of pretransplant serologies helps target the highest risk
group for close monitoring by EBV‐PCR and preemptive interventions such as decreasing
immunosuppression (II‐2) 59, 60, 61. EBV serology should be performed on all donors
and recipients in order to define the risk of posttransplant lymphoma (II‐2). The
British Transplantation Society and British Committee for Standards in Haematology
recently published extensive guidelines on the pretransplant screening and diagnosis
of PTLD in organ transplant recipients 62.
Other herpesviruses
Other herpesviruses of clinical importance in the transplant recipient include herpes
simplex virus (HSV‐1 and HSV‐2), varicella‐zoster virus (VZV), human herpesvirus‐6
and 7 (HHV‐6 and ‐7), and HHV‐8. HSV screening is performed by some centers, whereas
other centers administer universal antiviral prophylaxis for at least the first month
posttransplant. As primary varicella infection posttransplant can be fatal, VZV screening
of the recipient is important, with vaccination of the seronegative recipient pretransplant
if at all possible (III).
Recent awareness of the possible roles of HHV‐6 and HHV‐7 as cofactors for CMV effects,
fungal infections and possibly allograft dysfunction has led to increasing interest
in these viruses 63. Since almost all adults are seropositive, however, donor and
recipient screening for these viruses has not generally been recommended. Whether
such screening would be helpful in pediatric transplant programs is unknown. HHV‐8,
the agent of Kaposi's sarcoma, can reactivate after transplantation and may be transmitted
by transplantation 64, 65, 66. Seroprevalence varies widely according to the population
studied. Optimal strategies for prevention of reactivation have not been defined;
thus definitive recommendations for pretransplant screening cannot be made at this
time.
Hepatitis B (HBV)
All donors and recipients should be tested for hepatitis B using standard serologic
techniques. The complex issues surrounding HBV and transplantation are discussed in
more detail in the hepatitis section of these Guidelines. Donor screening should include
at least hepatitis B surface antigen (HBsAg) and HBV core antibody (HBcAb, which should
be performed as separate IgG and IgM to be most useful). Donor HBsAg positivity or
HBcAb‐IgM positivity indicates active HBV infection. HBsAg negative, HBcAb‐IgM positive
persons may be in the ‘window period’; such donors have generally not been utilized,
although some centers have used these donors in recipients with evidence of immunity
to hepatitis B (those with a positive hepatitis B surface antibody, HBsAb) and/or
with intensive posttransplant prophylaxis and monitoring. Isolated HBsAb positivity
usually indicates prior vaccination or resolved infection and is not generally considered
a risk for HBV transmission.
The most complex question is the use of the HBsAg negative, HBcAb‐IgG positive donor
(‘core‐positive donor’) 67, 68, 69. This may represent either a false‐positive test
(if isolated HBcAb positive) or the presence of chronic HBV infection. In the latter,
there is a significant risk of transmission of HBV to a liver transplant recipient,
and therefore these livers were often not utilized in the past (II‐2); however, it
has now become more common to transplant livers from HBcAb positive donors utilizing
intensive posttransplant prophylaxis 68. The risk for transmission to extrahepatic
recipients appears to be low, but has occurred 68, 70, 71, 72; this risk can be decreased
by pretransplant HBV vaccination of the recipient. Some centers restrict the use of
organs from the core‐positive donor to life‐threatening situations and/or vaccinated
recipients, or would utilize posttransplant prophylaxis with hepatitis B immune globulin
(HBIG) and/or lamivudine if transplanted into a nonimmune recipient (II‐3) 12, 13,
72. Because of the possibility of being offered such an organ, it is prudent to vaccinate
all seronegative transplant candidates with HBV vaccine, although the response to
this vaccine in patients with end‐stage organ disease may be suboptimal, requiring
higher doses and repeated injections to attain immunity (III). A donor HBV‐DNA level
provides helpful information for designing prophylactic strategies, even if the result
is received after transplant 14. Additional information on prophylactic strategies
may be found in the hepatitis section of these Guidelines (see chapter 16).
Recipient screening for HBV is helpful in posttransplant management. In patients undergoing
a liver transplant because of end‐stage liver disease due to HBV, there are a variety
of posttransplant protocols for prevention of reactivation of HBV, many utilizing
HBIg and/or antiviral agents. Extrahepatic transplantation in HBsAg positive recipients
has been controversial. In the early days of kidney transplantation, such transplants
were performed, resulting in early fulminant hepatitis in some recipients and chronic
liver disease in many. Some have maintained asymptomatic status after many years despite
evidence of active viral replication 70. With effective antiviral therapies such as
lamivudine, adefovir and tenofovir being available, it appears theoretically possible
to transplant such recipients more safely 72 although antiviral resistance may become
an issue (III).
Hepatitis C (HCV)
HCV infection is frequently chronic, and donors and recipients should be tested for
the presence of HCV via standard serologic techniques. HCV is a major indication for
liver transplantation, and although HCV recurrence is common posttransplant, patient
and allograft survival are not significantly worse than with other pretransplant diagnoses.
HCV seropositive renal transplant candidates are at higher risk for liver disease
and sepsis after transplant than are their HCV seronegative counterparts, but compared
with no transplantation as the alternative, the risk is outweighed by the benefit
in most cases 73, 74. The role of pretransplant treatment of HCV viremia remains under
study. Strategies for management of HCV in the recipient are discussed in detail elsewhere
in the Guidelines (see chapter 16).
Utilization of hepatitis C antibody‐positive donors remains controversial, due to
the high risk of transmission of HCV through transplantation of any organ. A positive
donor HCV NAT (HCV‐RNA), indicative of active viral replication, has been associated
with a higher risk of transmission, but results of this testing may not be available
prior to transplantation from a deceased donor 30. The risk of transmission from NAT
negative, HCV antibody positive donors has not yet been fully defined. As recent transmission
events have proven, HCV can be transmitted to multiple organ and tissue transplant
recipients from a seronegative donor 23, 24. The time between infection and antibody
production can vary in HCV‐infected individuals, although viral RNA is present much
earlier than antibody after acute infection. More rapid molecular tests are in development
in the hope of clarifying risk from deceased donors prior to a decision to accept
an organ. Whenever an HCV seropositive donor is utilized, stringent informed consent
is advisable.
Human immunodeficiency virus (HIV)
HIV‐seropositive donors have not been utilized in transplantation, due to the known
risk of transmission to the recipient; in the United States, use of HIV seropositive
donors is illegal. HIV‐1 and HIV‐2 serologies are required for all potential donors
and recipients; while HIV‐2 is rare in the United States and HIV‐2 screening serologies
are frequently falsely positive, specific testing for this virus should be performed
on those donors or recipients from western Africa, where HIV‐2 is endemic. Western
blot testing should be obtained for confirmation of any positive screening test for
either HIV‐1 or ‐2. In the potential living donor with risk factors for HIV exposure
but negative HIV serology, NAT testing should be obtained, as these tests become positive
prior to the development of a positive antibody test. Due to the efficacy of highly
active antiretroviral therapy (HAART), HIV infection in the recipient is no longer
a contraindication to solid organ transplantation. Multiple studies worldwide, including
a multicenter prospective trial in the United States, have evaluated transplantation
in the stable HIV‐infected patient 75, 76. One‐ and 3‐year graft and patient survival
data are comparable to non‐HIV infected patients undergoing transplantation, but meticulous
clinical care and careful attention to pharmacokinetics in the setting of significant
drug interactions between immunosuppressive agents and HAART are paramount to success
75, 76. While a higher than expected acute rejection rate was noted in 150 HIV‐positive
kidney transplant recipients, HIV infection remained well controlled and patient and
graft survival was comparable to the non‐HIV population 76. The complex issues involved
in transplanting this population are more fully discussed in the HIV section of these
Guidelines (see chapter 17).
Human T‐Lymphotropic virus (HTLV‐1/2)
HTLV‐1 is endemic in certain parts of the world including the Caribbean, Japan and
parts of Africa, and is often asymptomatic. However, infection with HTLV‐1 can progress
after years or even decades to HTLV‐I associated myelopathy/tropical spastic paraparesis
(HAM/TSP) or to adult T cell leukemia/lymphoma (ATL); progression occurs in <1% and
2–4% of seropositive individuals in endemic regions, respectively 77, 78, 79, 80,
81. HTLV‐2 is a virus which is likely more widespread geographically and is serologically
difficult to distinguish from HTLV‐1, although its association with disease processes
is less certain.
Screening for HTLV‐1/2 in deceased donors (but not recipients) was standard in US
practice until 2009, when UNOS/OPTN discontinued the requirement to perform prospective
deceased donor screening, largely as a result of the lack of a serologic test to distinguish
HTLV‐1 from HTLV‐2 77. Despite its low prevalence in the United States, cases of donor‐transmitted
infection have occurred, some with significant neurologic and malignant complications
82, 83, 84, 85. Graft and patient survival in recipients of HTLV‐1/2 seropositive
donor organs has been noted to be similar to that of recipients of HTLV‐1/2 seronegative
organs 79. Western blot testing or NAT may be used to distinguish HTLV‐1 from HTLV‐2,
and may prevent unnecessary wastage of organs from donors with false positive test
results or HTLV‐2 infection, neither of which should preclude donation 79, 80. However,
reports from Spain of donor‐derived transmission of HTLV‐I with rapid development
of myelopathy in the recipients suggest that caution should be exercised in the use
of HTLV‐1 infected donors 82, 83, 84. In endemic areas, recipients are often tested
for HTLV‐1/2 antibodies, although little is known about the course of infection following
solid organ transplantation. No cases of HTLV‐1 reactivation were observed in a series
of Japanese HTLV‐1 seropositive recipients undergoing renal transplantation 85.
Emerging or unusual viral infections—West Nile virus, lymphocytic choriomeningitis
virus, rabies and SARS
It has been increasingly recognized that emerging donor‐derived viral infections can
have an impact on transplant outcomes, with unusually severe presentations in recipients
19, 20, 21, 86, 87. In most cases, an effective screening test is not available, so
that familiarity with the risks for acquisition and the natural history of these infections
is important to assessing offers for deceased donor organs.
West Nile virus (WNV) is a flavivirus which can cause meningoencephalitis, and which
has recently appeared in the United States. First reported in 2002, WNV has been transmitted
via blood transfusion and solid organ transplantation 21, 87, 88. It is unclear as
yet what the magnitude of the risk of such transmission is, and any risk assessment
is complicated by the fluctuating levels and geographic distribution of WNV infection
in mosquitoes and humans each year. Serology and PCR for WNV are available but are
time consuming. It is prudent to avoid any donor who has had an unexplained febrile
illness, mental status changes, or meningitis or encephalitis. Transplant centers
should be especially concerned about the use of such donors during times of high prevalence
of infection in the region. Since July 2002, all US blood bank products have been
tested for WNV using a NAT assay. In the fall of 2003, the US Health Resources and
Service Administration (HRSA) issued a Guidance statement regarding organ donors and
West Nile virus, which recommended testing all prospective live donors with NAT close
to the time of transplant; avoiding donors with any form of unexplained or confirmed
WNV encephalitis; and heightened clinical suspicion on the part of the treating clinician
for any febrile illness occurring shortly after transplant. NAT poses logistical challenges
in some UNOS regions, and is not currently mandated for donor screening. There is
also concern that false positive NAT results may lead to a loss of noninfected organs
and net loss of life, particularly for liver and heart candidates on the waiting list
89.
Lymphocytic choriomeningitis virus (LCMV)
A rodent‐associated arenavirus has been reported in several clusters of donor‐derived
transmission to multiple organ recipients, all but one of which had fatal infection
20, 90, 91, 92. In one cluster, the outbreak originated from a new pet hamster in
the donor's home 20, 90, 93. To date, despite several similar outbreaks, an effective
screening test to rule out infection with LCMV in potential organ donors has not been
developed 20, 94. The CDC has issued guidelines for minimizing the risk of LCMV related
to pet rodents 95. Transplant centers should consider the possibility of LCMV infection
in the donor with aseptic meningitis, as well as in the seemingly asymptomatic donor
with contact with wild or pet rodents 10, 91.
Rabies is another potentially fatal donor‐derived infection. In the most well‐described
outbreak, recipients of transplants from a donor who died of subarachnoid hemorrhage
developed rapidly progressive encephalitis; all succumbed to infection 19. Retrospectively,
the donor was determined to have had a recent bat bite and was seropositive for rabies
virus 19, 96. In the United States, rabies is transmitted most commonly by bites,
scratches or other saliva exposure from bats, raccoons, skunks or foxes. The rabies
and LCMV cases raise the question of whether all donor evaluations should include
information about exposure to animals, bites and other environmental exposures to
supplement the already detailed information obtained. Because of the highly fatal
nature of rabies infection, clinicians are encouraged to avoid donors where even a
small possibility of rabies is present.
In 2003, a new respiratory pathogen was reported to cause severe disease with rapid
international spread. SARS (Severe Acute Respiratory Syndrome) was found to be due
to a previously undescribed coronavirus (SARS‐CoV), with nosocomial and household
transmission. At least 10% of affected patients required mechanical ventilation; at
least one transplant recipient died of SARS 97. While transmission by transplantation
is theoretically possible, the extent of this risk is unknown. Current principles
of donor and recipient selection would likely exclude patients with recent acute illnesses
meeting SARS criteria; however the consequences of a more remote history of SARS,
or a subclinical infection, are unknown. Screening tools for potential adult and pediatric
donors were proposed by experts in Toronto (one of the major centers of the 2003 outbreak)
which took into account the risk of SARS transmission at the donor's hospital as well
as donor's symptoms, travel and contact history 97. If another SARS or a similarly
transmitted emerging virus outbreak should occur, this donor‐screening algorithm would
be useful.
Influenza A
In 2009, a novel influenza virus A(H1N1pdm09) caused a worldwide pandemic. Infection
was most common in younger patients with severe disease and secondary bacterial infections
in pregnant women and those with underlying chronic lung disease, many of whom required
intensive care support. The impact on pediatric transplantation was considerable,
with prolonged hospitalizations, secondary infections, yet few reported deaths in
those who received early antiviral therapy 98. Guidelines for pretransplant screening
of potential donors and recipients were published 99. These recommended screening
of donors with symptoms consistent with influenza infection; routine screening was
not recommended. Due to concern for possible donor transmission, it was recommended
that donors who had received adequate antiviral therapy be considered safe for nonlung
or small bowel donation. Empiric treatment of the recipients of organs from infected
donors with incomplete treatment was recommended 100, 101, 102. The pandemic emphasized
the need for transplant centers to be vigilant about vaccination of recipients and
staff, and to be alert for local outbreaks of disease with the possibility of transmission
through transplantation.
Other new and emerging, potentially communicable agents may arise which may affect
donor acceptability or recipient activation on the transplant list 86, 87. It is advisable
to avoid transplantation involving individuals with potentially communicable infections
for which inadequate information exists to provide appropriate recommendations regarding
precautionary measures.
Ancillary screening tests for emerging pathogens, or more sensitive testing for known
pathogens, may be proposed by guidelines committees in the future 8, 30, 103. Such
groups will have to consider the feasibility of testing within the limited deceased
donor timeframe as well as the risk of false‐positive test results which could lead
to wastage of otherwise life‐saving organs 88, 103.
Recipient screening: pretransplant detection of active infection in the recipient
Transplant recipients are at risk for infections related to complications of end organ
failure. Patients awaiting kidney transplantation may have infected hemodialysis or
peritoneal dialysis access sites or catheters, or complicated upper‐ and/or lower‐tract
urinary infections. Candidates awaiting liver transplants are at risk for aspiration
pneumonia, spontaneous bacterial peritonitis, urinary tract infection and infections
associated with intravenous catheters. Pancreas transplant candidates can develop
diabetic foot infections and associated osteomyelitis. Those awaiting heart transplants
may have infections related either to indwelling intravenous catheters, or to ventricular
assist devices (VADs) utilized as a bridge to transplantation 104, 105. In addition,
heart candidates are also at risk for pneumonia in the setting of congestive heart
failure and debilitation.
VAD (ventricular assist‐device)‐associated infections are not a contraindication to
transplantation, as complete removal of the VAD at the time of transplant, combined
with appropriate posttransplant antibiotic therapy, is often curative 104, 105.
Screening of lung transplant recipients includes an assessment of colonizing airway
flora, and careful review of their previous pulmonary infections 106. Cystic fibrosis
patients may be colonized with multi‐resistant strains of Pseudomonas and/or Burkholderia
cepacia as well as other organisms such as Staphylococcus aureus, Alcaligenes, Klebsiella,
Acinetobacter, Stenotrophomonas, Aspergillus and Scedosporium. Knowledge of the pretransplant
colonizing flora can assist in developing an individualized peri‐transplant prophylactic
antimicrobial regimen. There is controversy as to whether patients colonized with
Burkholderia should be excluded from receiving lung transplants; molecular typing
of Burkholderia isolates may be used to define risk, as genomovar III (B. cenocepacia)
is associated with the highest risk of poor outcomes after transplantation 107, 108,
109.
Recipient screening: mycobacterial infections
All patients should have a PPD (tuberculin skin test) performed prior to transplant,
and those who have a positive skin test, or a history of active tuberculosis, should
undergo additional screening to rule out active disease (II‐2) 43. Interferon‐gamma
release assays (IGRAs) may be particularly useful in assessing patients who received
Bacillus Calmette–Guerin (BCG) vaccination, as the IGRA assay has the potential to
distinguish PPD positivity related to BCG from that related to latent TB infection
in those above the age of 5 44, 110.
Patients with LTBI should be given prophylaxis to prevent reactivation of disease
in the setting of immunosuppression (I). Details on the treatment of LTBI are found
in the Tuberculosis section of these Guidelines (chapter 8) (43, 46.
In transplant candidates with a clinical history, radiographs and/or cultures suggesting
infection with TB or nontuberculous mycobacteria, a thorough evaluation for active
disease should be performed, which may include CT scans, bronchoscopy or other tests
as deemed clinically necessary. Any mycobacterial infection should optimally be treated
with documented microbiologic and radiographic resolution before transplantation is
considered.
Recipient screening: fungal infections
Pretransplant colonization with fungi such as Aspergillus is common in lung transplant
recipients, particularly in cystic fibrosis patients. Such colonization should prompt
a rigorous evaluation to exclude active infection. Although posttransplant aspergillosis
is a feared complication, transplant clinicians have generally relied more on posttransplant
preemptive and prophylactic strategies rather than pretransplant antifungal therapy
for colonized patients. A pretransplant candidate with invasive fungal infection (rather
than colonization) should be treated at least until there is radiographic, clinical
and microbiologic resolution in order to minimize the risk of this high‐mortality
infection posttransplant (III). Additional information on the diagnosis, prevention
and treatment of infection with Aspergillus is found in other parts of these Guidelines.
Pretransplant screening for endemic mycoses is most useful in areas endemic for coccidioidomycosis,
where a pretransplant history of active disease and/or seropositivity may prompt lifelong
azole prophylaxis (II‐2) 50. Pretransplant screening for histoplasmosis is of limited
value since latent histoplasmosis may be present with negative serology (III); instead,
heightened awareness of the possibility of histoplasmosis is important when investigating
a posttransplant febrile illness in a patient from an endemic area.
Recipient screening: parasitic infections
Patients from (or with prolonged travel history to) endemic areas for strongyloidiasis,
including most tropical countries and parts of the southeastern United States, are
at risk for development of disseminated strongyloidiasis after transplant. Screening
with serology for Strongyloides is much more sensitive than stool exams, and is recommended
for those at epidemiologic risk (III). For seropositive patients, a short course of
ivermectin or thiabendazole is indicated pretransplant, although randomized data are
not available. As discussed above, Toxoplasma serology should be performed in heart
transplant candidates, and seronegative heart recipients with seropositive donors
should receive prophylaxis (II‐2) 51, 52, 53. Chagas’ disease and other parasitic
infections are more fully discussed elsewhere in these Guidelines (see chapter 29).
Recipient screening: viral infections
Active primary infection with viruses such as CMV, EBV, or HBV at the time of transplant
is uncommon. Nonetheless, if active viral infection is detected in a potential recipient,
transplantation should likely be delayed until the infection resolves in order to
allow for development of natural immunity prior to transplant immunosuppression (III).
This recommendation also extends to candidates who present for transplantation with
clinical symptoms suggestive of an acute community‐acquired viral infection. If there
is any chance of exposure to HIV pretransplant, the potential recipient should have
an HIV NAT and HIV antibody test performed (III). Viral screening of both donor and
recipient are discussed in more detail above.
Pretransplant immunizations
The pretransplant evaluation presents an important opportunity to update the potential
recipient's immunizations, since most vaccinations are more effective when administered
prior to the onset of transplant immunosuppression (I). More detailed immunization
recommendations are summarized in another section of these Guidelines (see chapter
31).
All potential recipients should be screened for vaccine‐preventable infections and
vaccinated as possible prior to transplant. The VZV‐seronegative candidate should
ideally be immunized against varicella prior to transplantation (II‐3). However, if
transplantation is expected imminently, it may be best to withhold vaccination with
this live attenuated vaccine (III). The zoster vaccine, also a live vaccine, is currently
licensed for older adults who are not immunocompromised. Further data are awaited
regarding whether pretransplant zoster vaccine prevents posttransplant zoster reactivation,
but at the present time it would appear reasonable to administer the zoster vaccine
if the transplant candidate meets current criteria for the vaccine and if transplant
is not expected within 4 weeks.
A hepatitis B vaccine series should ideally be administered pretransplant to seronegative
individuals (II‐2); especially as a potential donor may be found who is HBsAg negative
but HBcAb positive; in dialysis patients, the higher‐dose formulation should be given.
Patients with advanced liver disease are at particularly high risk for fulminant hepatitis
A and should receive hepatitis A vaccination (II‐2). This vaccine is likely more effective
when administered early on in liver disease (II‐2). The combined hepatitis A and B
vaccine is immunogenic but data are awaited in transplant candidates and recipients.
Measles–mumps–rubella (MMR) vaccine contains live virus. Patients born in or before
1956 are presumed to have natural immunity. Patients born after 1956 who have not
received a second dose of the MMR vaccine should receive a second dose, given pre‐
rather than posttransplant (III).
Pneumococcal vaccine should also be administered to transplant candidates over the
age of 2 who have not received it within the past 5 years (III). The Tdap (tetanus–diphtheria–acellular
pertussis) vaccine should be administered if the potential adult recipient has not
had a tetanus–diphtheria toxoid (Td) booster within 5–10 years, and should be considered
in all potential recipients in light of the increase in pertussis cases in recent
years (III).
Pretransplant counseling
Preventive strategies for infection should not be confined to medications and vaccinations.
Extensive education of the transplant recipient and his or her family is a very important
preventive tool. Pretransplant classes and printed materials are helpful and should
include information on handwashing/hand hygiene, environmental exposures, activities
to avoid, food safety and handling, foodborne pathogens, pets and travel. It is also
helpful for patients to have a general idea of the infections to which transplant
patients are susceptible and the preventive strategies in use at their particular
center. It is fundamental that patients know what to expect, what can go wrong and
what is expected of them.
Conclusion/future directions
Pretransplant screening of the potential organ donor and recipient affords an opportunity
to assess the feasibility and safety of transplantation, to determine the prophylaxis
and preventive strategies utilized posttransplant, to detect and fully treat active
infection in the potential recipient prior to transplant, to update the vaccination
status of the potential recipient, and to sufficiently educate the patient and family
about preventive measures. Future advances will incorporate the increasing use of
rapid molecular diagnostic testing, and possibly ancillary testing for emerging pathogens
in clinical practice.
Disclosure
The authors of this manuscript have no conflicts of interest to disclose as described
by the American Journal of Transplantation.