Download Epidemiology of Infections after Solid-Organ

SUPPLEMENT ARTICLE
Epidemiology of Infections after Solid-Organ
Transplantation
David R. Snydman
Departments of Medicine and Pathology, New England Medical Center, and Tufts University School of Medicine, Boston
Infections are a major determinant of the outcome of solid-organ transplantation. Their incidence varies
because of a number of factors. The type of organ transplanted, the degree of immunosuppression, the need
for additional antirejection therapy, and the occurrence of technical or surgical complications all affect the
incidence of infection after transplantation. There are 3 general time frames to consider. In the first month,
bacterial and candidal infections predominate. From the second through the sixth months, infections “classically” associated with transplantation become manifest. Beyond the sixth month, the clinical course is largely
determined by the presence or absence of chronic rejection.
The incidence of infection following solid-organ transplantation varies because of a number of factors. The
type of organ transplanted, the degree of immunosuppression, the need for additional antirejection therapy,
and the occurrence of technical or surgical complications all affect the incidence of infection after transplantation [1]. The anatomical region of the transplant
dictates to a great extent the type of infection that may
occur. Furthermore, investigators have demonstrated
that viral infections, such as cytomegalovirus (CMV)
and hepatitis C (HCV), influence the likelihood of opportunistic infections occurring, whether bacterial or
fungal [2–4]. These infections presumably contribute
to the net state of immunosuppression and weaken host
defenses [5]. In addition, antirejection therapy also contributes to the increase in infectious complications [6].
The other major factor in the development of infection
is exposure to a donor pathogen when a recipient is at
risk for primary infection (i.e., absence of preexisting
immunity). The most common manifestation of these
risk strata is primary CMV infection and disease, in
Reprints or correspondence: Dr. David R. Snydman, New England Medical Center,
Box 238/750 Washington St., Boston, MA 02111 ([email protected]).
Clinical Infectious Diseases 2001; 33(Suppl 1):S5–8
2001 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2001/3301S1-0002$03.00
which this subset has the highest risk of disease and
complications, regardless of the type of organ transplanted [7]. The incidence of infection following solidorgan transplantation, stratified by type of pathogen
and organ type, is listed in table 1.
The timing of infection after organ transplantation
is also influenced by a number of factors, including
surgical complications, the level of immunosuppression, and environmental and epidemiologic factors that
may affect exposure to certain pathogens. There are 3
general time frames to consider, namely, the first month
(i.e., the early perioperative period), the second through
the sixth month, and the late posttransplant period
(beyond the sixth month) [8].
Most infections during the first month after transplantation are related to surgical complications (figure
1). They include bacterial and candidal wound infections,
pneumonia, urinary tract infection, intravascular catheter sepsis, infections of biliary, chest, and other drainage
catheters, and Clostridium difficile. These infections are
similar to those occurring in general surgical patients. In
the first month after transplantation, renal and pancreas
transplant recipients are at risk for perigraft hematomas,
lymphoceles, and urinary leaks [9]. Liver transplant recipients are at risk for portal vein thrombosis, hepatic
vein occlusion, hepatic artery thrombosis, and biliary
stricture formation and leaks [10]. Heart transplant reOrgan Transplant Infection Epidemiology
• CID 2001:33 (Suppl 1) • S5
Table 1.
Incidence of infectious diseases in solid-organ transplant recipients.
Incidence of infection in patients receiving
Type of infection
Lung/
heart-lung
Pancreas/
kidney-pancreas
21–30
35–66
35
9–35
53–75
50
1–42
10–18
6
Liver
Kidney
Heart
Bacterial
33–68
47
Cytomegalovirus
22–29
8–32
Herpes simplex virus
3–14
53
Varicella-zoster virus
5–10
4–12
1–12
8–15
9
Candida species
1–26
2
1–5
10–16
32
Mycelial fungi
2–4
1–2
3–6
3–19
3
Pneumocystis carinii
4–11
5–10
1–8
15
NOTE. The data given here represent the range of values found in the literature and in the
studies cited by Patel and Paya [1].
cipients are at risk for mediastinitis and infection at the aortic
suture line, with resultant mycotic aneurysm, and lung transplant
recipients are at risk for disruption of the bronchial anastomosis
[11, 12].
The most common viral infection during the first month
after transplantation is reactivated herpes simplex virus (HSV)
infection in individuals seropositive for this virus before transplantation or the very rare occurrence of primary HSV infection
in a seronegative recipient exposed to an HSV-seropositive donor organ. The prophylactic use of acyclovir during this period
has, however, significantly reduced the incidence of this infection [13].
The period from the second to the sixth month after transplantation is the time during which infections “classically” associated with transplantation become manifest [14–18]. Opportunistic pathogens such as CMV, Pneumocystis carinii,
Aspergillus species, Nocardia species, Toxoplasma gondii, and
Listeria monocytogenes typically occur in this time frame (figures
2–4). In addition, during the 1–6-month interval after transplantation, reactivation of infection because of organisms present in the recipient before transplantation may occur. For
example, the introduction of high-dose immunosuppression
Figure 1. Timing of infections in relation to transplantation, conventional infections. C. difficile, Clostridium difficile; ICU, intensive care unit;
UTI, urinary tract infection; VRE, vancomycin-resistant enterococci.
S6 • CID 2001:33 (Suppl 1) • Snydman
may result in clinical illness because of reactivation of Mycobacterium tuberculosis, an occult focus of bacterial infection,
viral hepatitis, Histoplasma capsulatum, or Coccidioides immitis.
Chronic or latent infection of the donor that involves the allograft—such as HIV, hepatitis B virus (HBV), hepatitis C virus
(HCV), or fungal or mycobacterial infection—may be transmitted to the immunosuppressed recipient and become clinically apparent during the early and middle periods.
Examination of the timing of viral infections following transplantation demonstrates 2 clusters, those that occur at the 2–3month period (although there is a wide range of timing in their
occurrence) and those that typically occur much later (figure
2). Cytomegalovirus, HBV, HCV, and adenovirus frequently
occur within 30–60 days after transplant [19–22]. Human
herpesvirus type 6 is being increasingly recognized as reactivating within 6 weeks after transplant [23–25]. In contrast,
some viral infections—such as varicella-zoster virus infection
and polyomavirus infections—may occur much later [26, 27].
Epstein-Barr virus has a wide distribution in the latent period
before clinical expression to posttransplant lymphoproliferative
syndrome [28].
Conventional fungal infections, such as Candida, occur early
in the postoperative period [29] (figure 3). Aspergillosis also
Figure 2. Timing of infections in relation to transplantation, unconventional viral infections. CMV, cytomegalovirus; EBV, Epstein-Barr virus;
HSV, herpes simplex virus; HHV-6, human herpesvirus type 6; VZV, varicella-zoster virus.
Figure 3. Timing of infections in relation to transplantation, conventional and unconventional fungal infections.
Figure 4. Timing of infections in relation to transplantation, unconventional bacterial and other organisms. TB, tuberculosis.
tends to occur relatively early, frequently among those patients
who either have intense exposure because of epidemiologic
factors, such as construction, or among those who require intense immunosuppression and are doing poorly [30]. The epidemiology of infections with the pathogenic fungi—such as
Cryptococcus, histoplasmosis, and coccidioidomycosis—varies
somewhat from the aforementioned pattern (figure 3). These
infections tend to occur later in the time course, require environmental exposure, and may well occur while such patients
are outpatients and doing well [16, 17].
The unconventional bacterial infections mentioned previously,
namely, Nocardia and Listeria, can occur at almost any time, although the most common occurrence is 2–6 months after transplantation. Parasitic infection with Toxoplasma, when it arises, does
so several months after transplantation [31] (figure 4).
From 6 months after transplantation onward, most transplant recipients do relatively well, suffering from the same infections seen in the general community. These include influenza
virus infection, urinary tract infection, and pneumococcal
pneumonia. The only opportunistic viral infection commonly
seen during this period is reactivated varicella-zoster virus infection manifesting as herpes zoster. Rarely, CMV retinitis occurs. Two situations predispose patients to other infection in
this late posttransplant period. First, patients who have had
frequent episodes of acute rejection requiring augmented immunosuppressive therapy or those with chronic rejection who
are maintained at a higher baseline level of immunosuppression
remain at risk for the opportunistic agents more classically seen
in the second to sixth months after transplantation (Cryptococcus neoformans, CMV, P. carinii, L. monocytogenes, and Nocardia species). Second, patients with chronic infections, such
as HIV, HBV, and HCV infections, may suffer from comorbidity
associated with these agents.
In transplant recipients undergoing retransplantation, the
aforementioned timetable may be altered, with infections characteristic of any given period occurring simultaneously and, in
general, with an increased severity of infection. Retransplantation itself, with more complex surgery and previous immunosuppression, is a major factor in infection development.
It should be noted that the epidemiology of infections after
transplantation is changing dramatically because of improved
surgical technique; the recognition that some forms of prophylaxis are highly effective in prevention of infections such as
P. carinii, T. gondii, and CMV; improved types of immunosuppressive agents; and improved diagnostic capabilities
[32–40]. For example, comparison of infections following liver
transplantation in 3 eras and with improved measures for prophylaxis show improved survival and very few opportunistic
infections (table 2) occurring in the most recent era [14, 32,
38]. Thus, the natural history of opportunistic disease is changing and should continue to improve through efforts to improve
the prevention, diagnosis, and treatment of such infections.
Table 2. Comparison of frequency (%) of infectious complications among 3 cohorts of
orthotopic liver transplant recipients treated in the last 15 years, with comparisons of
prophylaxis on cytomegalovirus (CMV) infection and disease and outcome, by era.
Era
1984–1985
1987–1990
1993–1995
Infectious complication
Observational
(n p 101)
Placebo
(n p 72)
CMVIG
(n p 69)
Placebo
(n p 154)
Gcv
(n p 150)
Invasive fungal disease
29
19.4
10.1
CMV disease
22
31
19
19.5
4.5
1.3
4.8
Mortality
26
25
17
10.4
6.7
NOTE. CMVIG, cytomegalovirus immunoglobulin for intravenous administration; Gcv, ganciclovir. Data
from previously published studies [14, 32, 38].
Organ Transplant Infection Epidemiology • CID 2001:33 (Suppl 1) • S7
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