Multiple risks are assumed in the process of delivering a lung transplant, including
the potential transmission of infectious agents. This study reviews the current information
available with regard to risk of donor-related infections. This investigation does
not attempt to cover other areas of donor risk management, such as malignancy or primary
organ failure. It can be helpful to try to categorize infectious risk by timing related
to transplantation, as well as type of infection. Both are covered here. The intent
is to summarize the available data in a way that is useful to the clinician.
Bacterial infections
In terms of timing related to the transplant, the most immediate risk to the recipient
is probably transmission of bacteria. In the early post-operative period, the agents
the recipient carries can be very important, especially when noxious, such as with
methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enteroccoccus
(VRE) or Burkholderia cepacia. Likewise, the donor can add complexity by contributing
both known and unsuspected agents.
Traditional division of bacteria into gram-positive and -negative staining has apparent
validity in transplantation. Donor organs infected, even if bacteremic, with gram-positive
agents seem to be usable despite the apparent risk, whereas those with proven gram-negative
infections should be studiously avoided. In one report of 15 patients who received
hearts from donors infected with gram-positive organisms, none developed infection
with the agent of concern.
1
Conversely, 2 of 3 donors with gram-negative infections transmitted infection to the
recipient, with 1 death.
1
The risk has been seen more often in other solid organ transplants, with similar results.
2
There are no specific data from lung transplantation experience, but local experience
from one center detailed the results of 2 lung recipients from 1 donor infected with
Serratia marcescens: 1 died of septic shock, whereas the other developed acute respiratory
distress syndrome (ARDS) due to sepsis but survived a further 9 years.
Mycobacterial infections pose a potentially difficult problem due to the difficulty
in assessing the activity of disease, and also because they are known to be transmitted.
3
In lung transplantation, the difficulty is partly eased because of the use of chest
X-rays to assess donors, with abnormal films often leading to exclusion of donor organs.
Multiple reports have documented transmission of Mycobacterium tuberculosis, especially
in more endemic areas. Confounding the potential problem is the fact that acid-fast
staining of donor secretions is not routine, and would further delay in organ placement
if widely practiced. Fortunately, the apparent risk is small, and the disease is largely
treatable. Recommending more extensive testing is not likely to be helpful.
Fungal infections
Difficult early lung transplant experience has led to increased awareness of common
fungi due to the serious complications associated with these agents.
4
Although more recent experience has shown increased promise, fungal infections remain
a problem. Of the 2 environmental fungal genera encountered commonly in lung transplantation,
Aspergillus and Candida species, it appears that the latter is more likely to be transmitted
from donor to recipient. This concern arises from early problems with airway anastomoses,
and dissemination from the lung. Due to advances in operative management, preservation,
anti-microbial therapy and immunosuppression, the incidence of major airway dehiscence
has declined along with reports of serious airway infection with Candida species.
Although this was a recognized problem in the early history of lung transplantation,
serious Candida infections have become uncommon, and donation should not be ruled
out based on presence of Candida species alone. There are no convincing reports of
Aspergillus transmission to recipients of solid organ transplants.
Viral transmission: hepatitis
Hepatitis viruses may be transmitted with transplanted organs, and the transplant
outcome may be affected by the infection. In kidney transplantation, de novo viral
infection from the donor does not seriously impact outcome at up to 10 years, but
has a significant effect on recipient survival by 20 years.
5
If the recipient has serologic evidence of previous viral infection, the outcome after
renal transplantation is even more in doubt, but is considered better than the alternative
of permanent dialysis.
6
Other investigators have found evidence that recipient-positive status leads to increased
risk of graft loss, death and death due to sepsis.7, 8 That viral transmission occurs
with solid organ transplants is clear, but the outcome is less so. One group addressed
more directly the issue of risk of transmission when they assessed the likelihood
of serum and liver tissue virus from liver biopsy patients.
9
Their study showed that the risk of hepatitis B transmission from a core antibody-positive
liver was small, and the risk of finding virus in the blood was negligible.
Although few data exist in the lung transplantation literature to address the aforementioned
problems, we can derive help for our clinical practice from the experience of others.
We believe that donors positive for hepatitis C should not be used for lung transplantation,
unless grave circumstances demand it, and the recipient gives approval before transplantation.
In the case of hepatitis B, donor surface antigen-positive status should lead to exclusion
of the lungs. If the donor is hepatitis B core antibody positive, however, the risk
of transmission of hepatitis B to the recipient is very small, and thus donor lungs
can be utilized, if appropriate.
9
With regard to other viruses, information ranges from extensive, in the case of cytomegalovirus
(CMV), to theoretical and almost non-existent, in the case of Creutzfeldt-Jakob disease
(CJD). This study does not address further the issues surrounding CMV, but attempts
to rationalize donor issues related to other viruses.
Creutzfeldt-Jakob disease
In the era of mad cow disease, and a better understanding of prion transmission, CJD
has become a potential concern.10, 11, 12 Variant CJD has been transmitted with brain
tissue and dura mater, and appears to have traveled with the liver in at least 1 case.11,
12, 13, 14, 15, 16 Theoretically, it can transported with other tissues, including
lung.
15
Although infectivity appears to be low with non-brain tissue, it seems advisable to
avoid donors potentially infected with variant CJD, because there are no screening
tests available, no disinfectant mechanism, and no treatment for the infection itself.12,
15
Human immunodeficiency virus and organ transplantation
The main consideration in the use of human immunodeficiency virus (HIV)-positive donors
has been the risk of transmission of HIV infection and the largely historic experience
with immunosuppression in acquired immunodeficiency syndrome (AIDS) for organ transplantation.
Accidental transmission of HIV to transplant recipients by organs or blood products
was generally associated with an accelerated course of AIDS.17, 18 Although the use
of HIV-positive organs is likely to result in transmission of HIV to the recipient,
the precise risk remains unclear because the numbers of recipients who have received
such organs, but who have not subsequently seroconverted, are not known.19, 20, 21,
22, 23, 24
The use of “highly active anti-retroviral therapies” (HAART) has transformed AIDS
into a long-term-manageable disease, with extended survival. As a result, an increasing
number of HIV-positive patients are being considered for (or have received) renal
or hepatic transplantation, usually because of AIDS-associated glomerulopathy or co-infection
with hepatitis C. Transplantation of these patients has been associated with short-
and medium-term results similar to those in HIV-negative recipients.23, 24, 25, 26,
27, 28, 29 In this setting, it may be appropriate to expand the donor pool to include
HIV-positive donors in select circumstances.29, 30, 31 Although it is highly likely
that patients receiving an organ from such donors will develop HIV/AIDS, the counter-argument
is that AIDS is a manageable problem and the use of such organs may offer survival
opportunities to critically ill patients.24, 25, 26, 27, 28
Risk of infections/cancer
Several recipients of organs from HIV-positive donors have developed prolonged fever
associated with splenomegaly, lymphadenopathy, abnormal liver function and cytopenia.
The differential diagnosis includes CMV infection, but often no cause is found, suggesting
that this syndrome reflects seroconversion to HIV. This syndrome is self-limiting
and should be considered in the differential diagnosis of unexplained fever in the
first 2 months post-transplantation.
24
The risk of opportunistic infections and cancer is increased in both AIDS and after
organ transplantation. Highly active anti-retroviral therapy (HAART) has reduced the
risk of serious infections in AIDS. However, Epstein-Barr virus (EBV)-associated lymphoproliferative
disease has been seen with both AIDS and organ transplantation and the incidence does
not appear to be reduced by HAART.32, 33 Furthermore, human herpesvirus (HHV)-8 may
be related to the development of Kaposi’s sarcoma.34, 35
Concomitant risk of rejection
It has been demonstrated that some degree of immunosuppression is necessary to prevent
graft rejection in HIV-infected individuals receiving renal and hepatic transplantation.
28
However, there is evidence that infection with HIV does not adversely affect rates
of rejection in renal, hepatic and cardiac transplantation. Furthermore, several patients
have maintained normal allograft function despite a significant reduction (occasionally
total discontinuation) in immunosuppressive medication.30, 31 The use of HAART does
not appear to increase the rate of rejection.29, 30, 31, 36, 37
Therefore, to balance the risk of infection and rejection, it is advisable to reduce
the dose of immunosuppression in symptomatic HIV-infected recipients. It is not known
whether this reduction should begin in asymptomatic patients with a low CD4 count.
Risk of progression to AIDS
It is unclear if the use of immunosuppressive medication would modify the course of
infection with HIV. In the HAART era, experience from renal and hepatic transplantation
suggests that the use of calcineurin inhibitors is not associated with either an accelerated
or delayed development of AIDS.29, 36
In terms of other immunosuppressants, clinical experience is limited. Azathioprine
has been associated with exacerbation of HIV replication, whereas mycophenolate mofetil
has been shown to reduce HIV replication in vitro.
30
The use of anti-lymphocyte antibodies has been associated with severe exacerbation
of HIV replication and should be avoided. Similarly, corticosteroid dose should be
limited whenever possible.24, 26, 27
Finally, the use of HIV-positive donors would probably result in a small increase
in the donor pool, but transplantation would result in increased risk and complexity
of post-operative care. If such donors are to be considered, then clear guidelines
should be established detailing the situations in which such organs could be used.
Furthermore, the process of informed consent should be transparent and perhaps even
standardized. It should deal with the issues of likely HIV transmission, HIV as a
contagious disease, and that transplantation outcome is unclear. Until these issues
are addressed, we believe that use of organs from HIV-positive donors should be avoided.
Herpesviruses
It is clear that nearly all herpesviruses can exist in one or more tissues in a non-apparent
and often latent form after initial infection. All herpesviruses be transmitted either
by the allograft or by transfusion of blood or blood components.38, 39 Seroconversion
or DNA detection after transplantation (Tx) is equated with transmission of the virus
in most instances. Furthermore, especially with regard to the newly recognized human
herpesviruses (HHV 6–8), most studies have explored reactivation without differentiating
between transmitted or endogenous reactivation.34, 35, 36, 37
It is believed that the presence of antibodies against these agents in donor serum
indicates latent infection, but cross-reaction is possible, at least with HHV 6, HHV
7 and CMV.
38
Furthermore, some studies have found higher incidence rates of CMV or dual infections
(CMV + HHV 7)
39
under more potent immunosuppression (i.e., when MMF has replaced azathioprine). Therefore,
the role of clearly transmitted disease is uncertain, at least for HHV 6 and HHV 7.38,
39, 40, 41, 42, 43, 44, 45, 46
CMV
Large numbers of publications have dealt with CMV reactivation. However, studies concerning
transmission or reactivation in untreated patients have been performed only in the
early history of solid organ transplantation, showing infection rates between 19%
and 90% and disease rates between 26% and 90%, with the latter frequently occurring
in the graft.47, 48 For lung transplantation, more recent publications have most often
compared different prophylactic and immunosuppressive treatment strategies for achieving
better long-term survival, especially regarding the development of bronchiolitis obliterans
syndrome/obliterative bronchiolitis (BOS/OB). Results for CMV infection have been
between 0% and 59%.44, 49
HHV 6
Seroprevalence before liver or kidney transplantation is 88%, with infection (diagnosed
by virus isolation) in 31%.50, 51, 52, 53 Infection/reactivation occur in 20% to 50%
of patients 2 to 3 weeks after transplant. Major symptoms include unexplained fever
and/or bone marrow suppression, but mental status changes, encephalitis, skin rash,
pneumonia and rejection have also been described. Coincident infections with HHV 7
and CMV have been noted.
53
No studies were found concerning HHV 6 in lung transplantation.
HHV 7
Coincidental infection with HHV 7 and CMV is common, and HHV 7 reactivation occurs
before CMV in most patients.45, 54 Detectable DNA in plasma seems to correlate with
severity of disease, such as encephalitis. Both latent infection and reactivation
are common among recipients of kidney, liver and bone marrow transplants.
No studies were found concerning HHV 7 in lung transplantation.
HHV 8
HHV 8 is the agent of Kaposi’s sarcoma (KS).34, 35, 55 Prevalence of latent infection
with HHV 8 shows strong geographic variation among blood donors from France, Italy,
Uganda and the USA.55, 56, 57 Seroprevalence increases post-transplant, and the incidence
of KS has been noted to be up to 8% to 12%. Transmission is apparently common during
transplantation, but it appears that de novo infection infrequently leads to KS, as
the risk seems to reside in those seropositive pre-transplant.56, 58
No studies were found concerning HHV 8 in lung transplantation.
EBV
EBV transmission is associated with post-transplant lymphoproliferative disease (PTLD).59,
60, 61 This virus has been clearly linked to the development of PTLD in bone marrow
transplant and solid organ recipients, including lung transplant patients.62, 63,
64, 65, 66, 67, 68, 69, 70, 71 B- and T-cell-derived non-Hodgkin’s lymphoma, as well
as immunoblastic lymphoma and Hodgkin’s disease, have been reported.62, 63, 72 The
incidence of PTLD in liver Tx is reportedly 5% to 12% overall, but as high as 40%
in seronegative patients/seroconverters, whereas in seropositive patients it is only
1% to 2%.65, 66, 67, 68 The relative risk of PTLD by EBV-negative serostatus is about
20 in seronegative vs seropositive recipients.67, 69 In addition, EBV infection (as
PTLD or atypical viral infectious disease) usually occurs in the first post-operative
year and is associated with a higher degree of immunosuppression.73, 74 Therefore,
caution is warranted when seropositive organs are to be used for seronegative recipients,
but no clear-cut preventive strategies are available at present. Work continues on
a potential vaccine.
Herpes Simplex
Latent infections with herpes simplex virus (HSV) occur in trigeminal and lumbosacral
dorsal-root ganglia; therefore, there is usually no transmission through solid organ
transplantation. There are reports of HSV 2 transmission from 1 donor to both kidney
recipients, without neutralizing antibodies before Tx.75, 76 In another case, liver
and heart were transplanted into different recipients: each received early re-transplantation
on post-operative Day 1 (heart) and Day 12 (liver), respectively, without evidence
of HSV 2 infection.
No studies were found concerning HSV and lung transplantation.
Varicella Zoster
Latent infection occurs in neural ganglia, and therefore it is believed that varicella
zoster virus would not be transmitted through transplantation of solid organs unless
the donor suffered active varicella infection at the time of brain death. No documentation
of transmission could be found.
Parvovirus B19
Transmission of this viral infection has been reported specifically in kidney transplantation
and after bone marrow transplant.77, 78 Symptoms include unexpected graft failure,
pure red cell aplasia, prolonged anemia, thrombocytopenia, arthralgia and erythema
infectiosum after bone marrow transplant. The local experience of one of the present
investigators also documented parvovirus B19 infection in 1 lung transplant recipient
who had pure red cell aplasia that cleared within 1 year after therapy with intravenous
immunoglobulin infusions (unpublished findings).
Adenovirus
In one pediatric study, adenovirus infection was found in 8 of 16 patients, from 1
to 26 months after lung transplantation, and was significantly associated with respiratory
failure and histologic diagnosis of obliterative bronchiolitis.79, 80 In 2 patients
with early fulminant infection it was also identified in the donor. Therefore, transmission
is apparently possible, and knowledge of donor adenovirus infection should result
in discarding the lungs.
West Nile Virus
West Nile virus became a well-known entity in 2002, as outbreaks of headaches and
central nervous system disease occurred in several parts of the USA, with over 4,000
reported human cases by April 2003.81, 82 It is likely to be a recurrent late summer
problem, and therefore is important to organ transplantation.
83
The virus infects birds and mosquitoes, with humans and horses becoming incidental
hosts. Human symptoms may be mild to severe and include fever, headache, body aches,
truncal rash and lymphadenopathy.
82
The most serious complications of infection include fever, neck stiffness, stupor,
disorientation, coma, tremors, convulsions, muscle weakness, and paralysis, which
may lead to death. There is no known therapy. Although little experience exists with
transplantation of organs from donors with West Nile infection, it appears that the
virus can be transmitted from an asymptomatic host to recipients, which happened with
4 patients last fall in the southeastern USA.
81
With this in mind, it is prudent to avoid use of organs from patients potentially
infected with the West Nile virus.
Severe Acute Respiratory Syndrome (SARS)
Since late 2002 and early 2003, SARS has been a constant presence in our newspapers.84,
85, 86 Newly identified as a unique coronavirus, the agent has caused serious disease
in Asia and in areas with a high prevalence of travelers from southern Asia. In its
most severe manifestation, SARS leads to acute respiratory distress syndrome, respiratory
failure and death. There is no proven therapy. No published reports exist to guide
our thinking with regard to SARS and transplantation, but manifestations of the disease
would likely rule out the use of lungs and other organs from potential donors afflicted
by SARS.
Summary
As new information accumulates, the transplant community alters the way in which donors
are utilized. Greater effort is being made to better manage the donor and to re-define
the so-called marginal donor. A clearer understanding of donor infection and transmission
will help in the selection of organs for use by the potential recipient. Continued
evolution is expected. We hope that this literature review contributes to the rational
use of organs from the potentially infected donor. Transplantation will continue to
improve as we attempt to solve the problems inherent in organ donation and donor management,
and incrementally improve our evaluation and utilization of this scarce resource (Table
1).
Table 1
Summary of Recommendations
Donors should not be used routinely upon evidence of:
Gram-negative bacteremia
Mycobacterial infections of chest
Invasive fungal diseases
Hepatitis C
Hepatitis B surface antigen-positivity
HIV/AIDS
Creutzfeldt-Jakob disease
West Nile virus
Severe acute respiratory syndrome (SARS)
Donors may be used with caution upon evidence of:
Gram-positive bacteremia
Mycobacterial infections outside the chest
Fungal airway colonization
Hepatitis B core antibody
Herpesviruses (HHV 6–8, simplex, varicella)
Cytomegalovirus
Epstein-Barr virus (high risk if donor+/recipient−)