Keywords

1 Introduction

When evaluating a solid organ transplant (SOT) recipient for infection, there are a large number of factors that should be considered. Since these patients are immunosuppressed, they often do not express the same signs and symptoms as a fully immune competent host. For instance, pulmonary infections may not present with cough or shortness of breath. Often, patients may not have fever or leukocytosis with infection. Skin and soft tissue infections may not have all the typical signs of erythema, induration, tenderness, and warmth.

On the other hand, the occurrence of certain opportunistic infections, especially those due to polyomaviruses or herpesviruses, may act as an indicator that the patient is over immunosuppressed. The functional impact on the host’s response of the most commonly used immunosuppressive drugs is quite heterogeneous across patients. Unfortunately, there is no gold standard to assessing how immunosuppressed a given patient is. The amount of time that has elapsed since the transplant surgery is also critical in assessing the types of infections a patient is most at risk for. Usually, the longer the time from transplant, the less immunosuppressed a SOT recipient is, but this is not the case in patients suffering from graft rejection episodes requiring enhanced immunosuppression. Surgical complications and anatomical alterations from surgery need to be considered. Making a diagnosis, instead of empirically treating, is critically important in post-transplant patients, as the differential diagnoses may be broad. Invasive procedures and biopsies are often necessary to narrow on a definitive diagnosis.

2 Time from Transplant

Since many organ transplant recipients receive induction therapy at the time of transplant, their immunosuppression is often at its peak within a month from transplant. The deleterious effects of these induction therapies—specifically those including T-cell-depleting agents (e.g., polyclonal antithymocyte globulins or the anti-CD52 monoclonal antibody alemtuzumab)—on the cell-mediated immunity have been reported to last up to 1–2 years post-transplant [1, 2]. The more time that passes from transplant, the lower the risk for rejection and often maintenance immunosuppression medications are tapered.

As discussed in Chap. 1, early infections (i.e., those occurring within the first post-transplant month) are typically related to surgery or are donor-derived. Sometimes these events are related to an infection already active before the transplant procedure. The intermediate period (i.e., months 1 through 6 post-transplant) tends to be the time of highest immunosuppression when most opportunistic infections are seen. The typical timeline of infections is altered by the use of antimicrobial prophylaxis and by periods of augmented immunosuppression [3, 4]. Donor-derived infections usually present early after transplant but can be detected up to 1 or more years post-transplant in some cases. Any unknown infection within 6-month post-transplant should involve a look at donor factors and a review of the other recipients of organs from the donor.

3 Pre-transplant Recipient Factors

When evaluating a post-transplant patient for infection early after transplant, a review of their pre-transplant history is important, especially noting any history of infections or colonization with fungi or drug-resistant organisms, their pre-transplant serologies, vaccination status, and history of comorbidities. Patients with a history of uncontrolled diabetes mellitus, autoimmune disease or splenectomy, or chronic malnutrition have a unique increased risk for infection [3]. Special evaluation of issues with previous infection or colonization of the system requiring transplant is important. For example, many lung transplant recipients will have prior respiratory infections or colonization and will, therefore, be at risk for recurrence of these infections post-transplant, especially in the case of cystic fibrosis patients.

3.1 Donor Factors

Donor infectious disease screening test results need to be reviewed. Most providers understand that recipients that are seronegative for cytomegalovirus (CMV) or Epstein-Barr virus (EBV) who receive a seropositive donor organ are at high risk for infectious complications from these viruses. However, the impact of donor/recipient serological mismatch for other pathogens such as Toxoplasma gondii or the remaining herpesviruses is less characterized. For instance, toxoplasmosis has been reported to be transmitted from donor to recipient after heart transplantation but also occasionally in other transplant populations [5,6,7].

Additionally, some organ procurement organizations screen deceased donors for West Nile virus, human T-lymphotropic virus-1/2, Strongyloides stercoralis, and Chagas (Trypanosoma cruzi) antibodies [8]. These test results need to be interpreted and acted on by the recipient transplant teams when appropriate. Donor blood, urine, and sputum are sent for culture at the time of procurement, and results of these cultures are reported several days later. These should be checked as a routine but also in the case of evaluation of a recipient for an early post-transplant infection. Detailed discussion about donor-derived infections will be included in Chap. 3.

3.2 Surgical Factors

With the transplant surgery, many details need to be understood by the physicians taking care of the transplant recipient as they can increase risk of infection. The type of anastomosis is essential to understand [9]. Anastomoses that involve bowel place the patient at risk for leakage and peritonitis. Some centers perform pancreas transplants with vesicular anastomoses, and this increases the risk of cystitis. Lung transplant patients are at risk for ischemia at the site of their tracheal anastomosis, and this can increase the risk of fungal and bacterial infections at this site.

Intra-abdominal surgeries are sometimes complicated by splenic injury and subsequent splenectomies. This will increase the risk of severe infections with encapsulated bacteria in the recipient. Other factors that will increase the risk of infection, especially fungal infection in liver transplant recipients, are return to the operating room, need for renal replacement therapy, and large intraoperational volume blood loss [10, 11].

Stents are sometimes placed in the ureter or biliary system in kidney and liver transplant operations, respectively. These foreign bodies need to be assessed and possibly removed earlier than planned when infections arise in these areas post-transplant.

4 Post-transplant Factors

In addition to pre-transplant and surgery-related factors, the susceptibility to infection among SOT recipients is modulated by a number of post-transplant variables that must be taken into account in the risk assessment process. Of note, most of them have a dynamic behavior that justifies continuous monitoring throughout the post-transplant period (in particular during the first 12 months).

4.1 Community and Healthcare-Associated Exposures

Causative agents of post-transplant infection may be endogenous in nature (posing the risk of reactivation of a latent infection), derived from the donor or the preservation fluid and transmitted through the graft itself or acquired from an exogenous source (through environmental, vector, or human-to-human exposure). Overall, the latter group represents the most usual mechanism of infection during the entire life span of SOT recipients.

Environmental pathogens to which these patients are particularly susceptible comprise of bacteria (Pseudomonas aeruginosa, Legionella spp.) and both ubiquitous (e.g., Aspergillus spp., Cryptococcus spp.) and geographically restricted fungi (e.g., Histoplasma capsulatum, Blastomyces dermatitidis, or Coccidioides immitis) [12, 13]. Gardening activities and exposure to potting mixes and compost-derived products are associated with infections due to L. longbeachae and dematiaceous (dark-pigmented) fungi [14, 15]. Listeria monocytogenes constitutes the most relevant foodborne pathogen in the SOT population [16], although Salmonella spp., Vibrio spp., or Cryptosporidium spp. must be also borne in mind [17]. The incidence of vector-borne infection may be theoretically considered comparable to that of the immunocompetent host. Nevertheless, it has been reported that post-transplant immunosuppression contributes to increase the severity of certain diseases such as babesiosis, ehrlichiosis, or rickettsiosis. Human-to-human transmission can result from direct contact with an infected person or indirectly through an intermediate object. Mycobacterium tuberculosis and respiratory viruses (e.g., influenza virus, adenoviruses, or respiratory syncytial virus) are relevant pathogens transmitted from infected individuals, usually but not exclusively in the community setting. Varicella-zoster virus (VZV) is also transmitted by direct contact, droplets or aerosols from vesicular lesions, or respiratory tract secretions.

Healthcare-associated exposure deserves particular attention, since SOT recipients usually have longer hospital and ICU stays, have more requirements for invasive diagnostic and therapeutic procedures, and are more commonly exposed to broad-spectrum antibiotics than other patient groups. Thus, the incidence of healthcare-associated and nosocomial bacterial infection is increased, as is the causative role of multidrug (MDR) Gram-negative bacilli (such as extended-spectrum β-lactamases [ESBL]-producing or carbapenem-resistant Enterobacteriaceae), methicillin-resistant Staphylococcus aureus, or vancomycin-resistant Enterococcus. The frequent use of indwelling devices (e.g., intravascular or urinary catheters or biliary stents) poses an additional risk of biofilm-associated infections. Antibiotic exposure and other factors (e.g., use of proton pump inhibitors or post-transplant hypogammaglobulinemia) explain the particular susceptibility of SOT recipients to Clostridium difficile infection, which may entail particularly deleterious effects on graft outcome [17].

4.2 Net State of Immunosuppression

Coined by Fishman, the concept of “net state of immunosuppression” refers to the additive measure of factors contributing to the individual susceptibility to infection in each SOT recipient [18]. It results from the combination of a number of factors, including the nature, dose, and duration of immunosuppressive therapy, the use of invasive life-support techniques, the evolution of graft function, or the deleterious effect on the host’s immune response of chronic or latent viral infections, among others (Table 2.1). In addition, the surgical issues related to the transplant procedure contribute to fluid leaks (blood, lymph, urine) and collections, as well as devitalized tissues at the surgical site.

Table 2.1 Factors contributing to the “net state of immunosuppression” in SOT recipients (modified from Fishman [18])
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Due to its multifaceted nature and dynamic course, the measurement of the net state of immunosuppression constitutes a clinical and methodological challenge, and it is unlikely that a single biomarker could accurately account for the multiplicity of immune and nonimmune factors involved. The ultimate would be to define a quantitative measure conceptually similar to the area under the curve, which would encompass the multiple contributing variables at a given point. At the present time, therapeutic drug monitoring (TDM) of immunosuppressive agents constitutes the most widely used approach to the immune status in SOT recipients. However, TDM is limited by its unidimensional nature, which does not take into account the synergistic effect of multidrug regimens or the impact of induction therapies with monoclonal or polyclonal antibodies, resulting in a relatively poor correlation with clinical events.

4.3 Strategies for Immune Monitoring

From a clinical perspective, the strategies for the immune monitoring in the setting of SOT may be categorized into nonpathogen-specific or pathogen-specific [19]. The first of these approaches evaluates the functionality of a given arm of the immune system by means of assays (or biological parameters) with no antigen specificity. The nature of the biomarker used, in turn, may be quantitative (e.g., concentration of serum immunoglobulins or complement factors) or provide a functional assessment (e.g., intra-lymphocytic release of adenosine triphosphate [ATP] upon stimulation with phytohemagglutinin [PHA]) (Table 2.2). On the contrary, the pathogen-specific immune monitoring strategies are based on antigen-specific assays that estimate the magnitude and functionality of adaptive immune responses generated by T-cells or B-cells against a defined pathogen. Most of them measure the production of Th1 effector cytokines (usually interferon [IFN]-γ) after stimulation with a known viral antigen (individual peptide, peptide library, whole virus lysate, or infected dendritic cells). Although there have been progresses in the assessment of specific immunity against VZV, EBV, or polyomavirus BK, the only currently approved assays for clinical use are aimed at measuring CMV-specific cell-mediated immune responses (Table 2.3) [20]. There are different clinical scenarios in which this approach has been clinically explored and that would constitute preferential applications of CMV-specific immune monitoring (Table 2.4) [21]. However, interventional studies based on these nonpathogen-specific or pathogen-specific immune assays are still scarce [22].

Table 2.2 Summary of methods for nonpathogen-specific immune monitoring (modified from Fernández-Ruiz et al. [19])
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Table 2.3 Summary of methods for monitoring of CMV-specific T-cell-mediated immune response (modified from Fernández-Ruiz et al. [19])
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Table 2.4 Scenarios with available clinical information supporting the monitoring of CMV-specific T-cell-mediated immune response after SOT (modified from Fernández-Ruiz et al. [19])
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4.4 Antimicrobial Prophylaxis

As expected, the administration of antimicrobial prophylaxis modulates the incidence and timing of infectious complications in SOT recipients and must be taken into account in the risk assessment. The high efficacy exhibited by certain regimens, such as trimethoprim-sulfamethoxazole for Pneumocystis jiroveci pneumonia (PCP) or (val)ganciclovir for CMV, renders very unlikely the occurrence of breakthrough infection while on prophylaxis and modifies the conventional scheme proposed for infection according to the post-transplant period (early, intermediate, and late). Therefore, the period at risk would be displaced to a later phase, once prophylaxis has been discontinued, posing the potential for delayed diagnosis due to low clinical suspicion or diminished awareness [23]. It should be also noted that the impact of some prophylactic strategies is not limited to the primarily targeted pathogen. For instance, anti-CMV prophylaxis with (val)ganciclovir has been proven to be effective in preventing herpes simplex virus (HSV) and VZV reactivation [24], whereas the use of trimethoprim-sulfamethoxazole prophylaxis reduces, in addition to PCP, the incidence of listeriosis, urinary tract infection (UTI), or staphylococcal infection (although appears to have minor effect on the risk of nocardiosis). On the other hand, caveats of current prophylaxis practices include the development of atypical forms of disease (e.g., extrapulmonary Pneumocystis infection in patients receiving inhaled pentamidine) or the emergence of antimicrobial resistance (e.g., quinolone-resistant uropathogens or azole-resistant Aspergillus calidoustus associated with the widespread use of ciprofloxacin and voriconazole prophylaxis, respectively [25, 26]).

4.5 Antirejection Therapy

The treatment for acute graft rejection may substantially modify the expected timetable of post-transplant infection, since it augments the overall amount of immunosuppression over a short period of time. In addition to the increase in the daily dose of those drugs contained in the maintenance immunosuppression regimen, antirejection therapy usually comprises the administration of steroid boluses, T-cell-depleting agents (e.g., polyclonal antithymocyte globulins) or, in the case of antibody-mediated rejection, agents targeting the B-cell (rituximab). These therapies are frequently associated with the development of lymphopenia (mostly affecting CD4+ T-cell counts) and hypogammaglobulinemia. Recent developments in the approach to steroid-resistant forms of antibody-mediated rejection also include the use of eculizumab (a recombinant humanized monoclonal antibody that targets complement protein C5 and prevents the formation of the terminal membrane attack complex) and bortezomib (a proteasome inhibitor), which increase the risk of neisserial infection and HSV and VZV reactivation, respectively. It should be noted the late-onset rejection usually takes place once antimicrobial prophylaxis has been discontinued, thus rendering the patient particularly susceptible to opportunistic infection [27].