Transplant recipients are uniquely susceptible to infectious diseases due to the nature of their underlying conditions and their immunosuppressed status; consequently infections in solid organ transplantation may be associated with significant morbidity and mortality. These patients are not only vulnerable to a broad range of infectious organisms including those not normally considered to be pathogenic, but also prone to unusual presentations and more severe manifestations of infection [1]. Given the impact of infections on patient morbidity and mortality, it is critical to implement effective strategies for the prevention and early recognition of infectious complications to improve outcomes in this patient population.

This chapter is an introduction to the risks and epidemiology of infections in solid organ transplantation. It provides an overview of pre-transplantation donor and candidate screening, reviews the classic timeline for infection, and discusses methods for disease prevention including immunizations, environmental control, and post-transplantation prophylaxis.

1 Pre-transplantation Screening

An essential component of the pre-transplantation evaluation includes screening organ donors and transplant candidates for latent and active infections [2, 3]. This screening process is important for several reasons. Transplant care providers may identify scenarios that warrant exclusion of the organ donor or candidate from transplantation or they may diagnose active infections that require treatment prior to transplantation. The risk of post-transplantation infections that may result from reactivation of latent disease in the setting of increased immunosuppression should also be assessed and strategies individualized to minimize this risk. Lastly, planning preventive measures should be a focus during this period; this includes developing strategies for safe living and immunization, especially since vaccine response after transplantation may be suboptimal.

1.1 Screening the Transplant Candidate

All transplant candidates should be screened for latent and active infections using a variety of modalities. It is important to start with a careful history and physical examination. A detailed history including occupational history, places of residence, travel history, pets, and hobbies should be obtained from the transplant candidate. In some cases, this may suggest the presence of active infection and additional evaluation may be indicated to exclude diagnoses that would warrant delaying transplantation (e.g., infections with pathogens for which there are no antimicrobials such as West Nile virus [WNV] or certain respiratory viruses). Alternatively a history of prolonged residence in or birth in a location notable for unique endemic infections may prompt evaluation for subclinical infections that could reactivate after transplantation, including Strongyloides stercoralis, Trypanosoma cruzi, Histoplasma capsulatum, and Coccidioides immitis [2, 3]. All transplant candidates should be screened for infectious pathogens that have been more frequently associated with post-transplant complications by using a routine panel of testing, which is then supplemented with additional testing as indicated by history (Table 7-1). This includes serologic testing for cytomegalovirus (CMV), herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein–Barr virus (EBV), human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), syphilis, and Toxoplasma gondii [2, 3]. Tuberculin testing is also important due to the increased risk of reactivation of latent infection following transplantation; both intradermal tuberculin purified protein derivative placement and interferon gamma release assays (IGRA) have been used [4, 5].

Table 7-1. Infectious diseases screening for solid organ screening for solid organ transplant candidates
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Pre-transplant screening may reveal active infections that could impact post-transplantation outcomes. Some of these may warrant excluding the transplant candidate from solid organ transplantation either temporarily or definitively. In some cases, such as WNV infection, transplantation may occur following resolution of the infection. In other cases, patients may not be eligible either due to the severe or incurable nature of the infection. Notably these criteria have evolved over time and infections that were once considered exclusions to transplantation may now be acceptable. One example of this is HIV infection, previously considered a contraindication due to concerns that immunosuppressive medications would increase the risk of opportunistic infection, HIV disease progression, and mortality [6]. The advent of highly active antiretroviral therapy (HAART) has allowed for outstanding long-term HIV control in adherent patients, and the excellent outcomes in HIV-infected individuals undergoing liver and especially kidney transplantation have encouraged increasing numbers of centers to perform renal and hepatic transplants in these patients [7–12]. Centers are also beginning to consider thoracic and pancreatic organ transplantation in HIV-positive individuals given acceptable outcomes in the initial patients undergoing these procedures [13–16]. Another exception may be infection of ventricular assist devices, as eradication of these infections typically requires device explantation and outcomes have been acceptable with transplantation [17, 18]. Many transplant candidates are hospitalized with high acuities of illness, requiring invasive procedures (e.g., central line placement, intubation, or ventricular assist device insertion) that place them at increased risk of infection. These patients require close monitoring in order to promptly identify active infections that occur while awaiting transplant; ideally these should be adequately treated prior to transplantation to minimize post-transplant complications.

Pre-transplantation screening can also identify latent infections that may reactivate after transplantation. Possible pathogens include bacteria (e.g., Mycobacterium tuberculosis), viruses (e.g., CMV, HBV, HCV, BK virus, EBV, HSV, and VZV), and fungal pathogens (e.g., Histoplasma capsulatum and Coccidioides immitis). The risk for TB is significantly increased in the transplant population with most cases representing reactivation of latent infection and screening should be performed in all transplant candidates. Options include intradermal skin testing utilizing PPD or IGRA with the latter preferred in individuals who have received BCG immunization to reduce the rates of false-positive tests [5]. When PPD testing is performed, areas of induration ≥5 mm are considered positive and patients with negative PPD results on initial testing may be considered for repeat testing after 2 weeks [5]. Both PPD and IGRA have reduced sensitivity due to common acquired immune deficiencies in candidates for transplantation; consequently it is important to take a careful history and closely review chest radiography in high-risk individuals who have negative testing. It is also important to scrutinize individuals with discordant test results. Treatment is recommended for all transplant candidates with a positive tuberculin test after active disease has been excluded. Since many transplant candidates are anergic, high-risk patients with a negative PPD or an indeterminate IGRA should also be considered for empiric treatment. These include transplant recipients with radiographic evidence of prior disease, a history of inadequately treated TB, close contact with someone who has active TB, or receipt of an organ from an inadequately treated organ donor [5, 19]. First-line treatment involves a 9-month course of isoniazid. Those who are isoniazid intolerant may benefit from a 4-month course of rifampin. However, rifampin has multiple drug interactions, including increasing the metabolism of calcineurin inhibitors, which may significantly complicate its administration post-transplantation. Consequently its use should be carefully considered in patients who may be transplanted during the course of therapy. In some cases, fluoroquinolones may be considered as alternate therapy for latent tuberculosis [20].

The optimal timing of latent TB treatment has not been defined and varies depending on the patient’s risk for treatment-related hepatotoxicity. Patients without liver disease often undergo treatment prior to transplantation [5]. Because the risk of hepatotoxicity is increased in liver transplant candidates, transplant centers may choose to initiate latent TB treatment after transplantation once the patient is stable and the liver function tests have normalized [21]. Of note, treatment can be ongoing at the time of transplantation. Given that the highest risk of reactivation is within the first year following transplantation, if patients cannot be treated prior to transplantation, it is preferable to treat them as soon as possible following transplantation [4]. Recent converters should be treated prior to transplantation if at all possible to decrease the risk of active infection either prior to or at the time of transplant.

Transplant candidate screening is an important opportunity for reevaluation of standard preventive measures. This includes an assessment of their home and work environments, pets, and hobbies in order to implement sufficient preventive measures prior to transplantation. The pre-transplant evaluation period is also an important opportunity for updating routine immunizations for vaccine-preventable illnesses, especially influenza and pneumococcal infection [22]. Patients should also undergo assessment for immunity to vaccine-preventable illnesses (e.g., varicella and hepatitis A and B) and be immunized accordingly. Further recommendations regarding immunizations will be included later in this chapter.

1.2 Screening the Organ Donor

The ability to fully screen organ donors will vary depending on whether the donor is living or deceased. Living donor screening has certain advantages. Notably the donor provides his or her own medical history and testing may be tailored to risks identified during the initial donor assessment. In contrast, deceased donor screening is limited to several hours where the medical history is obtained from a proxy. Family members may provide incomplete or inaccurate medical history and may be unaware of patient behaviors that place the patient at higher risk of infection. Despite these differences, the infectious pathogens tested during donor screening are similar for living and deceased donors and mirror the testing done in transplant candidates, although some testing may be performed in live donors that is currently not available or considered to be reliable in deceased donors (e.g., testing for tuberculosis). Potential donors are tested for a panel of routine serologies with additional screening guided by pertinent patient history. Further detail regarding screening the organ donor is provided in Chap. 8.

2 The Risk of Infection Posttransplantation

The risk of infection post-transplantation is determined by the balance between the patient’s net state of immunosuppression and his or her epidemiologic exposures [1]. A patient who is more severely immunosuppressed may be susceptible to a broader range of infections, including those caused by opportunistic pathogens. Although opportunistic pathogens are more likely to cause infection in the first 6 months after transplantation, when patients are expected to be more immunosuppressed, patients in the late post-transplantation period (>6 months) on minimal immunosuppression without a significant history of rejection may be at risk of opportunistic infection, especially following a significant epidemiologic exposure.

Multiple factors contribute to a transplant recipient’s net state of immunosuppression. The type, dosage, and timing of administered immunosuppressive medications remain the primary factor. Different immunosuppressive medications exert unique effects on the host immune system: (1) corticosteroids inhibit inflammatory responses and affect T-cell activation, (2) cytotoxic agents (i.e., azathioprine and mycophenolate acid) impair T-cell and B-cell proliferation and function, (3) calcineurin inhibitors (i.e., tacrolimus and cyclosporine) inhibit cytokine production, primarily interleukin-2 (IL-2), by CD4-positive T-cells, (4) target of rapamycin (mTOR) inhibitors (i.e., sirolimus) inhibit cell cycle proliferation and are associated with delayed wound healing and oral ulcers, (5) monoclonal antibodies (i.e., basiliximab and daclizumab) target the IL-2 receptor, (6) recombinant monoclonal antibodies (i.e., alemtuzumab) bind to CD52 on B and T lymphocytes, a majority of monocytes, macrophages, and NK cells, and a subpopulation of granulocytes, disrupting these cellular functions for prolonged periods, (7) polyclonal antibodies (i.e., antithymocyte globulin) induce lysis of lymphocytes with prolonged lymphocyte depletion increasing the risk of infection 3 months or longer after administration, and (8) costimulatory blockade agents (i.e., belatacept) disrupt T-cell costimulation and consequently activation. Immunomodulatory viruses (i.e., CMV, EBV, HBV, HCV, and HIV) and existing comorbidities (e.g., diabetes, renal insufficiency, and malnutrition) also contribute to the net state of immunosuppression. Transplant recipients often have more than one factor present, resulting in defects in multiple arms of the immune system. Although tests are available to assess certain immunologic defects (e.g., quantitative immunoglobulins, lymphocyte subset measurements, and gamma interferon release assays targeted against specific pathogens), there is no single test currently available that accurately assesses this net state of immunosuppression.

Epidemiologic exposure is the other main determinant of a transplant recipient’s risk of infection. This exposure can be nosocomial or community acquired and may have occurred prior to transplantation. Latent infections can reactivate after transplantation in the setting of enhanced immunosuppression. Different organs also have unique epidemiologic risks due to organ-specific surgical procedures and environmental factors. For example, transplanted lungs may be at increased risk for colonization and/or infection with inhaled pathogens due to decreased mucociliary function, ischemia at the anastomosis site, and the direct exposure of the transplanted organ to the external environment. Liver and pancreas transplant recipients may be at risk of infection related to a particular surgical method (e.g., bowel anastomosis), while heart transplant candidates with pre-transplant ventricular assist devices may be at risk for device-related infections.

Standardized immunosuppressive therapy in solid organ transplantation has enabled the development of a useful predictive timeline for infection [1]. It includes three distinct time periods: the early post-transplantation period (0–1 month), the intermediate post-transplantation period (1–6 months), and the late post-transplantation period (>6 months) (Figure 7-1). Although changes in immunosuppressive medication regimens combined with the use of antimicrobial prophylaxis have modified this timeline, the general framework is still applicable. Transplant care providers can use this reference to develop an initial differential diagnoses for transplant recipients who present with signs of infection as well as to devise prophylactic strategies [1, 23]. However it is important to recognize that exceptions are possible; patients receiving certain more long-lasting immunosuppressive agents and those with chronic rejection or infection with immunomodulatory viruses may remain severely immunosuppressed and therefore be more vulnerable to opportunistic pathogens beyond 6 months after transplantation. Additionally it is possible that patients (especially pediatric recipients) may acquire primary infection with common opportunists (e.g., CMV and EBV) in the later post-transplant period, thus delaying the presentation of these infections.

Figure 7-1.
figure 1

Epidemiology of post-transplant infection considering time from transplant. Adapted from Fishman JA, Rubin RH, Infection in organ transplant recipients, New England Journal of Medicine, 1998;338(24):1741–51, and Fishman JA, Infection in solid organ transplant recipients, New England Journal of Medicine, 2007;357(25):2601–14.

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2.1 Risk of Infection in the Early Posttransplantation Period (0–1 Month)

Within the first month, transplant recipients are most susceptible to nosocomial infections similar to those seen in non-immunosuppressed surgical patients, including pneumonia, urinary tract infections, catheter-related blood stream infections, and surgical site infections [3, 8, 10, 24]. Some of these may be directly related to complications of the surgical procedure or a consequence of postoperative care; bacteria and Candida species are most commonly implicated [23]. Liver transplant recipients, for example, may be at increased risk of wound infections, or infections such as peritonitis or abdominal abscesses due to leaks at the biliary anastomotic site. The postoperative care may involve prolonged periods of intubation and the insertion of central venous lines or indwelling urinary catheters. These breaks in the mucocutaneous barriers place patients at increased risk for nosocomial infections including ventilator-associated pneumonias, surgical site infections, bloodstream infections, or urinary tract infections. Perioperatively, patients often receive broad spectrum antibiotics that may contribute to the emergence of antimicrobial-resistant pathogens, nosocomial fungal infections, and infection with Clostridium difficile colitis. Nosocomial transmission of viruses, especially respiratory viruses, may also occur [25]. Immunocompromised patients may have longer periods of viral shedding, and therefore they have opportunities to infect other organ transplant recipients by being placed in adjacent rooms on dedicated wards. Additionally, infection with Legionella species can occur anytime including the early post-transplantation period [26, 27]. Pneumonias are among the most commonly seen early infections; however not all pulmonary infiltrates are due to infection. The differential diagnosis is broad, and may include edema, atelectasis, rejection (in lung transplantation), and medications in addition to infection [28]; it is important to consider these diverse possibilities when evaluating patients. Transplant recipients are at increased risk for more severe pneumonias, including cavitary pneumonias; consequently early recognition of infection is critical [28–30].

Opportunistic infections are usually absent during the first month after transplantation, although there have been rare reports of infection with these pathogens. Among the most commonly reported is Aspergillus pneumonia (especially in lung recipients) [24]. It is probable that this low incidence can be attributed to the delayed impact of immunosuppressive medications introduced during this period.

Although the vast majority of early infections are nosocomial, a low incidence of donor and recipient-derived infections may also occur during this period. A Spanish study evaluating nonviral donor-derived infections reported disease transmission in 5/292 (1.71 %) of transplant recipients who received organs from infected donors [31]. All five donor-derived infections were due to bacterial pathogens. In the United States, there is mandated reporting of suspected donor-derived infections to the United Network for Organ Sharing (UNOS). Reviews of these reports by the Disease Transmission Advisory Committee of UNOS have noted that diverse pathogens have been transmitted including pyogenic bacteria, T. cruzi, HCV, HIV, WNV, lymphocytic choriomeningitis virus (LCMV), Legionella species, H. capsulatum, Candida species, S. stercoralis, C. neoformans, Schistosoma species, T. gondii, and M. tuberculosis [32, 33]. The timing of these infections varies; typically bacterial infections and fungal infections are most likely to present in the first month [34]. Although uncommon, these unanticipated donor-derived infections have been associated with increased morbidity and mortality, with complications including surgical site infections and mycotic aneurysms [32, 33, 35–37]. The transmission of more unusual infections in solid organ transplantation, including WNV, LCMV, or rabies, has also been documented [38–40]. Diagnosis of these infections may be confounded by the absence of recognized donor infection and the presentation of nonspecific symptoms such as fever, altered mental status, or liver enzyme elevations, followed by a rapid clinical decline oftentimes resulting in death. Recent reports have cautioned against the use of donors with neurologic processes of unclear etiology to prevent transmission of some of these infections [41].

Early infections may also occur as a continuation of an active infection in the recipient that precedes transplantation. Not all of these may be recognized prior to transplantation. Pathogens related to early recipient-derived infections may be diverse; occasionally opportunistic pathogens may occur, especially in liver transplant patients or those treated with immunosuppressive agents prior to transplantation.

2.2 Risk of Infection in the Intermediate Posttransplantation Period (1–6 Months )

The intermediate post-transplantation period generally refers to the time occurring 1–6 months following transplantation. During this period, most solid organ transplant recipients are at their highest net state of immunosuppression due to immunosuppressive medications exerting their full effect. Patients may also develop infections with immunomodulating viruses such as CMV, EBV, HBV, or HCV as well as experience metabolic complications including diabetes and renal insufficiency that can alter the immune system.

During this period, in the absence of prophylaxis, infections due to diverse opportunistic pathogens including bacteria (e.g., Nocardia species, Listeria monocytogenes, and Mycobacteria), fungi (e.g., Pneumocystis jiroveci, Aspergillus species, C. neoformans), viruses (e.g., CMV, EBV), and parasites/protozoa (e.g., Toxoplasma gondii) can occur. Geography can place individuals at risk for endemic mycoses including Histoplasma capsulatum, Coccidioides immitis, or Blastomyces dermatitidis. Lastly, donor-derived infections may present during this intermediate post-transplantation period; this is especially true of parasites (including Strongyloides stercoralis), protozoa, and viral infections [34]. Environmental exposures may also play a role during this period and place patients at higher risk of opportunistic infection. This includes exposure to a specific environment as well as to individuals with potentially communicable diseases. The changing nature of immunosuppressive regimens and prophylactic strategies continues to have an impact on the infections seen during this period; both need to be considered when patients are evaluated. Specific infections seen during this high-risk period are detailed in later chapters.

2.3 Risk of Infection in the Late Posttransplantation Period (>6 Months)

The nature of infections in the late post-transplantation period may be a window into the transplant recipient’s net state of immunosuppression. This net state of immunosuppression can be underestimated by simply reviewing the medication doses and levels as patient responses to specific regimens may vary substantially. By 6 months after transplantation, the vast majority of transplant recipients are doing well with good allograft function maintained with minimal immunosuppression. These patients typically reside in their home environments where they are most susceptible to community-acquired infections.

Transplant recipients can be at increased risk for more severe respiratory infections with community-acquired pathogens (e.g., influenza, parainfluenza, respiratory syncytial virus, adenovirus, human metapneumovirus, Legionella species, and pneumococcus). These patients may have longer durations of both infection and shedding, increased progression to lower respiratory tract infections, higher mortality rates, and increased risk for rejection [27, 42–47]. Transplant recipients are also at a 12.8-fold greater risk for invasive pneumococcal disease compared to the general population [46].

Other viral infections can also be seen during this period, including infections that may have been previously suppressed by prophylactic strategies. CMV infection is the most common opportunistic infection during this period. Often donor derived, CMV that may present variably as prophylaxis is discontinued [3, 48]. Transplant recipients with CMV syndrome have nonspecific symptoms including fever and fatigue that may be accompanied by laboratory abnormalities, most notably leukopenia. CMV may also present with end-organ involvement such as colitis, pneumonitis, or infected allograft. In addition to its direct effect, CMV has indirect effects on the immune system that increase the risk for allograft rejection and loss, post-transplantation lymphoproliferative disorder (PTLD) , other infections, and diabetes mellitus [49–55]. Chronic viral infections, such as HBV or HCV, may also reemerge during this time. Outcomes in HBV-infected recipients have improved with the use of HBV immunoglobulin and antiviral agents [56]. Currently HCV-positive recipients fare worse, developing repeated episodes of chronic rejection, post-transplant diabetes mellitus, or chronic infection and end-stage liver disease, although the advent of more effective and better-tolerated antiviral treatment options will likely improve outcomes [56–59]. EBV may increase the risk of infections and malignancy, particularly PTLD. PTLD risk is greatest in EBV-seronegative recipients who receive organs from seropositive donors, a scenario which most often occurs in children [60]. Other risk factors have included the organ transplanted and the choice of immunosuppression agent (especially belatacept) [60–62]. Additionally, EBV viremia may provide insight into a patient’s net state of immunosuppression; consequently when routine monitoring detects viremia, immunosuppressive therapy is typically reduced [60, 63].

There are documented cases of reactivation of latent infections during this period. For example, H. capsulatum can establish latency after primary infection and reactivate months after transplantation [64]. Posttransplantation TB rates range from 0.35 to 15 % worldwide, depending on disease prevalence with a median time to onset of 6–11 months [5, 65, 66]. The frequency of active TB varies based on the organ transplanted but is substantially higher than that of the general population (20–74 % higher), with most cases resulting from reactivation of latent recipient infection [5, 65, 66]. Donor-derived TB is estimated to account for <5 % cases [5, 67].

Lastly, transplant patients may be at risk of other infections not necessarily associated with immunosuppression. This could include health care-associated infections during periods of hospitalization. Studies suggest that transplant recipients, particularly heart, lung, and heart–lung recipients, may also be at an increased risk of pancreaticobiliary disease and diverticulitis [68, 69].

Although most recipients have stable allograft status and are infection free by 6 months after transplantation, a minority (approximately 20 %) may be chronically infected with immunomodulatory viruses or have recurrent episodes or chronic rejection requiring high-dose immunosuppressive therapy. The classic timeline for infections is not applicable to this subpopulation. These patients are more severely immunosuppressed and continue to be at risk for opportunistic infections well past 6 months post-transplantation, thus potentially making them candidates for prolonged prophylactic strategies.

3 Prevention of Infection

Prevention of infection is vital for improving outcomes in the solid organ transplant population. Transplant recipients need to be updated on their immunizations, preferably prior to transplantation, and they should be educated regarding behaviors that can minimize their day-to-day risk. Transplant care providers should also evaluate and identify patients who would benefit from antimicrobial prophylaxis or preemptive therapy when appropriate.

3.1 Immunizations

Screening of candidates prior to transplantation is an ideal opportunity to ensure that transplant recipients are updated on the following immunizations , according to age- and condition-related guidelines: Streptococcus pneumoniae, Haemophilus influenza, influenza, diphtheria, pertussis, tetanus, hepatitis A virus, HBV, measles, mumps, rubella, poliomyelitis, and VZV [47, 48]. Although highly recommended, there is suboptimal utilization of immunizations in this population. One study reported that only 62.4 % (95 % CI 54.8–70.1 %) of lung transplant candidates received S. pneumoniae vaccination [70].

There are several general guidelines regarding the administration of immunizations in this population. First, it is preferable to update immunizations prior to transplantation rather than in the post-transplant period [3, 22]. Studies suggest that transplant recipients have reduced responses to diverse vaccines compared to immunocompetent individuals; this makes pre-transplantation immunization especially important [22, 71, 72]. Second, not only should immunizations be administered pre-transplantation, but they are most effective when administered earlier in the course of disease [73]. Given the suboptimal response to immunizations in certain patients with end-stage organ disease, physicians may consider confirming vaccine efficacy in patients who report prior immunization. Serologic testing for hepatitis A virus, HBV, VZV, measles, mumps, and rubella can be performed to ensure that patients maintain adequate levels of protection [74].

Even after transplantation, patients should ensure that they are current on their immunizations. Typically, immunizations are not given until at least 3–6 months post-transplantation when immunosuppression is reduced sufficiently to allow for improved immune response, although there may be exceptions to this, especially during epidemics (e.g., influenza) [22]. Transplant recipients as well as their family members and close contacts should receive yearly influenza vaccination. Strategies for pneumococcal vaccination include using conjugate pneumococcal vaccine followed by polysaccharide capsule vaccine [75]. Live attenuated vaccinations, including intranasal influenza, VZV, and MMR, are generally avoided in transplant recipients due to an increased risk for possible dissemination; however recent reports suggest that Varicella zoster vaccine may be safe in at least some pediatric recipients [22, 76].

3.2 Avoidance of Infectious Exposures

There are certain measures that can minimize the risk of infection among transplant recipients. In the hospital setting, patients should adhere to basic infection control measures . This includes washing hands frequently and limiting exposure to sick visitors and staff. When transplant recipients return home, these basic infection control measures need to be augmented with avoidance of potential environmental hazards. Transplant recipients should watch their diet, avoiding untreated water, undercooked meats, unwashed produce, and unpasteurized dairy products, soft cheeses, and juices. Other preventive measures include circumventing areas undergoing active construction, refraining from changing litter boxes, engaging in safe sexual practices including using latex condoms in non-monogamous sexual contacts or during periods of increased immunosuppression, and limiting hobbies such as gardening that may put them at risk for novel infectious pathogens [77, 78].

3.3 Prophylaxis

Prophylactic strategies following transplantation have also included the administration of anti-infective agents for more common or potentially serious pathogens during high-risk periods (Table 7-2). Prior to the initiation of prophylaxis, approximately 10–12 % patients developed PCP infection 2–6 months post-transplantation [1]. Most centers, therefore, provide PCP prophylaxis to all their transplant recipients for at least the first 6–12 months, using trimethoprim-sulfamethoxazole (TMP-SMZ) as first-line therapy. TMP-SMZ not only provides excellent protection against PCP but, when given daily, may provide protection against urinary tract infections in renal transplant recipients, T. gondii, Nocardia species, and L. monocytogenes [78–80]. TMP-SMZ is inexpensive and usually well tolerated.

Table 7-2. Prophylaxis frequently administered after solid organ transplantation
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For patients who are unable to tolerate TMP-SMZ, second-line agents include dapsone, atovaquone, inhaled pentamidine, and a combination of clindamycin and pyrimethamine [81]. These alternatives, however, may not be as effective against PCP and do not provide equivalent protection against additional pathogens like TMP-SMZ [3]. If second-line therapy with dapsone is needed, it is recommended that glucose-6-phosphate dehydrogenase (G6PD) levels should be checked prior to administration since hemolytic anemia and methemoglobinemia may occur at higher rates in transplant recipients compared to HIV patients. However, some studies suggest that these complications may occur even in the setting of normal G6PD levels [82, 83]. The duration of prophylaxis varies. Renal, heart, and liver transplant recipients on routine immunosuppression typically discontinue PCP prophylaxis at 6 months to 1-year post-transplantation, while lung transplant recipients and small bowel recipients, who are at higher risk, typically remain on lifelong prophylaxis [81]. Physicians should also consider reinitiating prophylaxis during periods of increased immunosuppression (i.e., episodes of rejection) or prolonging prophylaxis for patients with chronic rejection.

One of the most important infections in solid organ transplantation is caused by CMV. The risk for infection is predicted by donor and recipient serostatus and varies depending on the organ transplanted and the choice of immunosuppression [48]. The highest risk occurs when a seronegative recipient receives an organ from a seropositive donor (D+ R−). This not only places the transplant recipients at 60–75 % risk of primary CMV infection but also at increased risk of infection with ganciclovir-resistant CMV and possibly recurrent CMV [84, 85]. The risk of infection is significantly lower when the recipient is CMV seropositive. In addition, CMV risk varies based on the organ transplanted. Lung, small intestine, and pancreas transplant recipients are at the highest risk of CMV infection when compared with kidney transplant recipients who are at the lowest risk [48].

Two different strategies, universal prophylaxis versus preemptive therapy, are typically used for CMV prevention [68, 86]. In universal prophylaxis, an antiviral agent is administered to all transplant recipients to prevent the development of CMV infection . In contrast, preemptive therapy involves close surveillance of CMV viral shedding (typically in the blood) in transplant recipients with therapy initiated when positive levels are detected. CMV DNA testing has supplanted antigen testing at most transplant centers. Meta-analyses suggest that compared to preemptive therapy, universal prophylaxis is associated with decreased rates of allograft rejection, opportunistic infections, and mortality [87, 88]. Randomized controlled trials in kidney transplant recipients have reported lower rates of graft loss [89] and lower rates of acute rejection among patients in the universal prophylaxis arm [90] but an increase in late CMV infection [91], higher medication costs, and increased medication-related toxicity [86].

Antiviral agents used for CMV prophylaxis include ganciclovir, valacyclovir, and valganciclovir. Valganciclovir, a prodrug of ganciclovir, administered once daily has become increasingly popular for prophylaxis in transplant recipients. The use of valganciclovir, however, may be less effective in liver transplant recipients, where there may be a higher incidence of tissue-invasive disease [92]. CMV hyperimmunoglobulin is used infrequently for CMV prophylaxis. One meta-analysis reported no differences between CMV disease, infection, or all-cause mortality in patients who received prophylaxis with an antiviral alone or in combination with CMV immunoglobulin [93]. Another meta-analysis reported that while the rates of CMV infection and rejection did not differ between groups, those that received CMV immunoglobulin had lower rates of CMV disease, overall mortality, and CMV-related mortality [94]. Duration of prophylaxis varies but is given for at least 90 days post-transplantation, with longer durations for CMV-seronegative recipients of seropositive donor organs and for lung recipients [86]. Transplant care providers should consider reinitiating prophylaxis during episodes of rejection necessitating enhanced immunosuppressant therapy, particularly with antilymphocyte antibodies [48].

Fungal infections are associated with significant complications in the solid organ transplant population. Overall, the most common cause of invasive fungal infections is Candida species, followed by Aspergillus species [95]. Data from the Transplant Associated Infection Surveillance Network (TRANSNET) reported that the most common Candida species was Candida albicans, followed by Candida glabrata, which has a higher rate of fluconazole resistance [95]. Liver transplant recipients are particularly prone to invasive candidiasis, especially if they have two or more of the following classic risk factors: prolonged operation time, high transfusion requirements (>40 units of blood products), Roux-en-Y biliary anastomosis, renal insufficiency (preoperative serum creatinine > 2 mg/dL), re-transplantation or reoperation, and colonization with Candida species [96]. Potential risk factors that include further validation include antibiotic prophylaxis with a fluoroquinolone for spontaneous bacterial peritonitis and patients with iron overload [97]. Among all transplant recipients, lung transplant recipients appear to be at highest risk for invasive fungal infections with organisms other than with Candida species [95]. This population is at increased risk for infection with Aspergillus species, particularly at the site of anastomosis. Although voriconazole or aerosolized amphotericin B is often used, there are no large-scale, multicenter, randomized studies to direct guidelines regarding the role of antifungal prophylaxis in this population. Nevertheless many centers favor the use of antifungal prophylaxis especially for patients with risk factors including airway ischemia, Aspergillus colonization, CMV infection, and augmented immunosuppression [98].

Despite conclusive data to support the use of prophylactic antifungal agents, most transplant centers choose to provide antifungal prophylaxis to certain transplant recipients who are at the highest risk of invasive fungal infections (e.g., liver transplant recipients with the aforementioned risk factors and lung transplant recipients).

4 Summary

Infections are serious complications of solid organ transplantation that are largely determined by two factors: the transplant recipient’s net state of immunosuppression and the epidemiologic exposures (including those in the pre-, peri-, and post-transplant settings). Diagnosis and management of infections in this population may be challenging. The recipient’s immunosuppressed state not only makes him or her susceptible to a broad range of infectious pathogens but may also alter the presentation and affect treatment and outcomes. Given the significant morbidity and mortality associated with infections, preventive measures as well as early diagnosis and treatment are vital in improving outcomes in this patient population.