Overview
Successful management of infections in kidney transplant recipients is a function of the immune status of the host and the epidemiology of infectious exposures. Transplant recipients are susceptible to a broad spectrum of infectious pathogens while manifesting diminished signs and symptoms of invasive infection. Thus the diagnosis of infection is more difficult in transplant recipients than in immunologically normal individuals. The interactions between infection, immunosuppression, and immune function often result in clinical syndromes reflecting multiple simultaneous processes, such as infection and graft rejection. Immunocompromised patients tolerate invasive infection poorly, with high morbidity and mortality, lending urgency to the need for an early, specific diagnosis to guide antimicrobial therapy. Given the predominant T-lymphocyte dysfunction inherent to transplant immunosuppression, viral infections are a major contributor to morbidity resulting in graft dysfunction, graft rejection, systemic illness, and increased risk for other opportunistic infections (e.g., Pneumocystis and Aspergillus ) and virally mediated cancers.
Risk of Infection
The risk of infection in a kidney transplant recipient is determined by the interaction of two key factors:
- 1.
The epidemiologic exposures of the patient, including the timing, intensity, and virulence of the organisms encountered.
- 2.
The patient’s “net state of immunosuppression,” a conceptual measure of all the factors that contribute to the host’s risk of infection.
The importance of any infectious exposure is determined by the ability of the host to deal effectively with the pathogen. Thus the immunosuppressed diabetic with vascular disease is at greater risk of bacterial skin infections than is a comparable immunosuppressed nondiabetic. Understanding the risk factors for each transplant recipient allows development of a differential diagnosis for infectious syndromes and development of preventive strategies (prophylaxis, vaccination) appropriate to the individual’s unique risks.
Epidemiologic Exposures
Epidemiologic exposures of importance in the transplant recipient can be divided into four overlapping categories: (1) donor-derived infections, (2) recipient-derived infections, (3) community-derived exposures, and (4) nosocomial exposures ( Table 31.1 ).
| Donor-Derived |
| Viral |
| Herpesvirus group (CMV, EBV, HHV-6, HHV-7, HHV-8, HSV) |
| Hepatitis viruses (HBV, HCV) |
| Retroviruses (HIV, HTLV-I/II) |
| Others (rabies, LCMV, WNV) |
| Bacteria |
| Gram-positive and gram-negative bacteria ( Staphylococcus, Pseudomonas, Enterobacteriaceae) |
| Mycobacteria (tuberculous and nontuberculous) |
| Nocardia species |
| Fungi |
| Candida species |
| Aspergillus |
| Endemic fungi ( Cryptococcus neoformans ) |
| Geographically restricted fungi ( Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Paracoccidioides brasiliensis ) |
| Parasites |
| Toxoplasma gondii |
| Trypanosoma cruzi |
| Nosocomial Exposures a |
| Methicillin-resistant Staphylococcus aureus |
| Vancomycin-resistant enterococci |
| CRE and ESBL gram-negative bacilli |
| Aspergillus species |
| Non- albicans Candida species |
| Community Exposures a |
| Foodborne and water-borne ( Listeria monocytogenes, Salmonella, Cryptosporidium , hepatitis A, Campylobacter ) |
| Respiratory viruses (RSV, influenza, parainfluenza, adenovirus, metapneumovirus) |
| Common viruses, often with exposure to children (coxsackievirus, parvovirus, polyomavirus, papillomavirus) |
| Atypical respiratory pathogens ( Legionella, Mycoplasma, Chlamydia ) |
| Geographically restricted fungi, Cryptococcus, Pneumocystis jirovecii |
| Parasites (often remote) ( Strongyloides stercoralis, Leishmania, T. gondii, T. cruzi ) |
| Amoeba ( Naegleria fowleri, Balamuthia mandrillaris ) |
a Colonization and infection of the recipient in advance of transplantation may occur because of these potential pathogens.
Donor-Derived Infections
Diverse donor-derived infections have been recognized in transplant recipients. Some of these infections are latent (e.g., viral, parasitic), whereas others are active (e.g., bacteremia, fungemia) in the donor at the time of procurement. Frequent pathogens and endemic organisms causing significant morbidity in recipients form the basis of screening paradigms for organ donors. Bloodstream infections (with bacteria or yeast) in donors at the time of donation can cause local (abscess) or systemic infections, and, importantly, may adhere to anastomotic sites (vascular, urinary) to produce leaks or mycotic aneurysms.
Transmission of some donor-derived viral infections are common and expected, including cytomegalovirus (CMV) and Epstein–Barr virus (EBV), and are associated with specific syndromes in transplant recipients (see section on selected infections of importance). The greatest risk of viral infections is transmission from seropositive donors (latent infection) to seronegative (immunologically naïve) recipients (or D+/R−). Some viruses demonstrate accelerated progression (lymphocytic choriomeningitis virus [LCMV], rabies, West Nile virus [WNV]) in transplant recipients. Latent infections, such as tuberculosis, toxoplasmosis, or strongyloidiasis, may activate many years after the initial, often unrecognized exposures.
Donor screening for transplantation is limited by the available technology and by time constraints within which organs from deceased donors must be used (discussed later). Routine screening of donors relies on history, and both antibody detection (serologic tests) and nucleic acid testing (NAT) for common infections. Risk factors for infection in the donor are often unknown. As a result, transmission may occur from seronegative donors with active viral or other exposures (before seroconversion in the “window period”) or with viral loads below the limits of detection by the NAT selected. This risk has been demonstrated by clusters of donor-derived Trypanosoma cruzi (Chagas’ disease), rabies virus, WNV, and LCMV infections in organ transplant recipients. NAT for donor screening (e.g., for human immunodeficiency virus [HIV], hepatitis B virus [HBV], hepatitis C virus [HCV], WNV) has the capacity to reduce the window period between exposure and pathogen detection over serologic tests albeit with some risk for false-positive assays given heightened assay sensitivity.
Given the risk of transmission of infection from the organ donor to recipients, certain syndromes should be considered relative contraindications to organ donation. Because kidney transplantation is typically elective surgery, it is reasonable to avoid donation from individuals with unexplained fever, rash, or infectious syndromes, including meningitis or encephalitis. At some centers, transplantation from donors with untreated HCV or HIV (to HIV-positive recipients) infections is undertaken. Common criteria for exclusion of organ donors are listed in Table 31.2 .
| Central Nervous System Infection |
| Unknown or untreated infection of central nervous system (encephalitis, meningitis) |
| Herpes simplex encephalitis or other encephalitis |
| History of JCV infection |
| WNV infection |
| Cryptococcal infection |
| Rabies |
| Creutzfeldt–Jakob disease |
| Other fungal or viral encephalitis |
| Amoebic encephalitis |
| Disseminated and Untreated Infections |
| HIV (serologic or molecular; may be considered for HIV-positive recipient) |
| HSV (with viremia), acute EBV (mononucleosis) |
| Serologic or molecular evidence of HTLV-I/II |
| Active hepatitis A (may consider HBV and HCV-infected donors for appropriate recipients) |
| Parasitic infections ( Trypanosoma cruzi, Leishmania donovani, Strongyloides stercoralis, Toxoplasma gondii ) |
| Infections Difficult to Treat on Immunosuppression |
| Active tuberculosis |
| SARS, MERS |
| Untreated pneumonia |
| Untreated bacterial or fungal sepsis (e.g., candidemia) |
| Untreated syphilis |
| Multisystem organ failure resulting from overwhelming sepsis, gangrenous bowel |
a These must be considered in the context of the individual donor/recipient.
Recipient-Derived Exposures
Recipient-derived exposures generally reflect colonization or latent infections that reactivate during immunosuppression. Certain common infections are recognized during the evaluation of the transplant candidate, including HBV, HCV, and HIV. It is necessary to obtain a careful history of prior infections, travel, and exposures to guide preventive strategies and empirical therapies. Notable among these infections are mycobacterial infection (including tuberculosis), strongyloidiasis, viral infections (herpes simplex virus [HSV] and varicella-zoster virus [VZV] or shingles), histoplasmosis, coccidioidomycosis, and paracoccidiomycosis ( Fig. 31.1 ). Vaccination status should be evaluated (childhood vaccines, tetanus, HBV, influenza, pneumococcus); vaccines not previously administered should be considered in advance of transplantation because immune response is likely to be more robust, and live virus vaccines are generally contraindicated after transplantation ( Table 31.3 ). Dietary habits also should be considered, including the use of well water ( Cryptosporidium ) and consumption of uncooked meats ( Salmonella, Listeria, hepatitis E) and unpasteurized dairy products ( Listeria ).
| Measles/mumps/rubella (MMR) |
| Diphtheria/tetanus/pertussis (DTP) |
| Poliovirus |
| Haemophilus influenzae b (Hib) |
| Hepatitis B, Hepatitis A |
| Pneumococcus |
| Influenza (subunit vaccine) |
| Varicella (Live, attenuated vaccine; zoster vaccine recombinant, adjuvanted under study) |
a Live virus vaccinations are generally precluded in immunosuppressed hosts.
Community Exposures
Common exposures in the community are often related to contaminated food and water ingestion; exposure to infected family members or coworkers; or exposures related to hobbies, travel, or work. Infection caused by common respiratory viruses (influenza, parainfluenza, respiratory syncytial virus [RSV], adenovirus, and metapneumovirus) and by more atypical pathogens (HSV) carry the risk of viral pneumonia and increased risk of bacterial or fungal superinfections. Community (contact or transfusion-associated) exposure to CMV and EBV may produce severe primary infection in the nonimmune host. Recent and remote exposures to endemic, geographically restricted systemic mycoses ( Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides brasiliensis ) and Mycobacterium tuberculosis can result in localized pulmonary, systemic, or metastatic infection. Asymptomatic Strongyloides stercoralis infection may activate more than 30 years after initial exposure as a result of immunosuppressive therapy (see Fig. 31.1 ). Such reactivation can result in either a diarrheal illness and parasite migration with hyperinfection syndrome (characterized by hemorrhagic enterocolitis, hemorrhagic pneumonia, or both) or disseminated infection with accompanying (usually) gram-negative or polymicrobial bacteremia or meningitis. Gastroenteritis secondary to Salmonella, Cryptosporidium, and a variety of enteric viruses (e.g., norovirus) can result in persistent infection, with more severe and prolonged diarrheal disease and an increased risk of primary or secondary bloodstream invasion and metastatic infection.
Nosocomial Exposures
Nosocomial infections are of increasing importance. Organisms with significant multidrug antimicrobial resistance (MDRO) are present in most medical centers, including enterococci that are resistant to vancomycin, linezolid, daptomycin and/or quinupristin/dalfopristin; methicillin-resistant staphylococci; gram-negative bacteria producing extended-spectrum beta-lactamases (ESBL) and carbapenemases (CRE); and fluconazole-resistant Candida species (see Table 31.1 ). A single case of nosocomial Aspergillus infection in an immunocompromised host in the absence of a clear epidemiologic exposure should be viewed as a failure of infection control practices. Antimicrobial misuse and inadequate infection control practices have caused increased rates of Clostridium difficile colitis. Outbreaks of infections secondary to Legionella have been associated with hospital plumbing and contaminated water supplies or ventilation systems. Nosocomial spread of Pneumocystis jirovecii between immunocompromised patients has been documented. Respiratory viral infections may be acquired from medical staff and should be considered among the causes of fever and respiratory decompensation in hospitalized or institutionalized immunocompromised individuals. Each nosocomially acquired infection should be investigated to ascertain the source and to prevent subsequent infections.
Net State of Immunosuppression
The net state of immunosuppression is a conceptual measure of the risk factors for infection in an individual, including immunosuppressive medications and iatrogenic conditions ( Table 31.4 ). Among the most important are as follows:
- 1.
The specific immunosuppressive therapy, including dose, duration, and sequence of agents ( Table 31.5 )
Table 31.5
Immunosuppression and Common Infections
Agent
Common Infections/Effects
Antilymphocyte globulins (lytic) and alloimmune response
Activation of latent viruses, fever, cytokines
Anti-CD20 antibody
Unknown to date
Plasmapheresis
Encapsulated bacteria
Corticosteroids
Bacteria, Pneumocystis jirovecii, HBV, HCV
Azathioprine
Neutropenia, papillomavirus (?)
Mycophenolate mofetil
Early bacterial infection, late CMV (?)
Calcineurin inhibitors
Enhanced viral replication (absence of immunity), gingival infection, intracellular pathogens
mTOR inhibitors
Poor wound healing, idiosyncratic pneumonitis syndrome
Belatacept
Posttransplant lymphoproliferative disorder
CMV , cytomegalovirus; HBV , hepatitis B virus; HCV , hepatitis C virus; mTOR , mammalian target of rapamycin.The question mark indicates possible side effect in some literature.
- 2.
Technical difficulties during transplantation resulting in an increased incidence of leaks (blood, lymph, urine) and fluid collections, devitalized tissue, poor wound healing, and prolonged use of surgical drainage catheters
- 3.
Prolonged instrumentation, including airway intubation and use of vascular access devices (e.g., dialysis catheters)
- 4.
Prolonged use of broad-spectrum antibiotics
- 5.
Renal or hepatic dysfunction, or both (in addition to graft dysfunction)
- 6.
Presence of infection with an immunomodulating virus, including CMV, EBV, HBV, HCV, or HIV
| Immunosuppressive therapy: type, temporal sequence, intensity, cumulative dose |
| Prior therapies (chemotherapy and antimicrobials) |
| Mucocutaneous barrier integrity (catheters, lines, drains) |
| Neutropenia, lymphopenia (often drug-induced) |
| Underlying immunodeficiencies |
| Autoimmune diseases |
| Hypogammaglobulinemia from proteinuria or drug therapy |
| Complement deficiencies |
| Other disease states (HIV, lymphoma/leukemia) |
| Metabolic conditions (uremia, malnutrition, diabetes, cirrhosis) |
| Viral infections (CMV, HBV, HBC, RSV) |
| Graft rejection and treatment |
| Cancer/cellular proliferation |
Specific immunosuppressive agents are associated with increased risk for certain infections (see Table 31.5 ).
Assessment of the overall degree of immune compromise remains difficult. The combination of organ dysfunction, immunosuppression, viral infections, nutritional status, technical factors, and other factors in infectious risk resists quantification. Measures of pathogen-specific (i.e., cellular) immune function are useful in guiding prophylaxis for specific infections in individuals. Commercialized assays exist for CMV and tuberculosis including interferon-γ-release assays (IGRA), ELISpot, major histocompatibility complex (MHC)-tetramer staining, or intracellular cytokine staining. Low serum antibody levels correlate with the overall risk of infection but specific cutoff values and indications for replacement therapy are lacking. Few data exist on functional immune reconstitution after T- or B-lymphocyte depletion or with costimulatory blockade. Recent data support the importance of genetic polymorphisms among transplant recipients and risk of microbial colonization and infection.
Timeline of Infection
With standardized immunosuppressive regimens, the most common infections vary in a predictable pattern depending on the time elapsed since transplantation ( Fig. 31.2 ). This is primarily a reflection of changing risk factors over time, including surgery and hospitalization, tapering of immunosuppression, acute and chronic rejection, and exposure to infections in the community. The predicted pattern of infection changes with alterations in the immunosuppressive regimen (e.g., increased steroids for graft rejection), intercurrent viral infections, neutropenia (drug toxicity), graft dysfunction, or significant epidemiologic exposures (travel or food). The timeline remains a useful starting point for the differential diagnosis of infection after transplantation, although it is altered by the introduction of new immunosuppressive agents and patterns of use, including reduced use of corticosteroids and calcineurin inhibitors, increased use of antibody-based (induction) therapies or sirolimus, routine antimicrobial prophylaxis, improved molecular assays, antimicrobial resistance, transplantation of HIV-infected and HCV-infected individuals, and broader epidemiologic exposures from work or travel.
There are three overlapping periods of risk for infection after transplantation (see Fig. 31.2 ), each associated with differing patterns of common pathogens, as follows :
- 1.
The perioperative period to approximately 4 weeks after transplantation, reflecting surgical and technical complications and nosocomial exposures
- 2.
The period from 1 to 12 months after transplantation (depending on the rapidity of taper of immunosuppression, the use of antilymphocyte “induction” therapy, and deployment of prophylaxis), reflecting intensive immunosuppression with viral activation and opportunistic infections
- 3.
The period beyond the first year after transplantation, reflecting community-acquired exposures and some unusual pathogens based on the level of maintenance immunosuppression
The timeline can be used in a variety of ways: (1) to establish a differential diagnosis for a transplant patient suspected to have infection; (2) to provide a clue to the presence of an excessive environmental hazard for the individual, either within the hospital or in the community; and (3) to serve as a guide to the design of preventive antimicrobial strategies. Infections occurring outside the usual period or of unusual severity suggest either an intense epidemiologic exposure or excessive immunosuppression.
The prevention of infection must be linked to the risk for infection at various times after transplantation. Table 31.6 outlines some routine preventive strategies, keeping in mind that such strategies serve only to delay the onset of infection in the face of epidemiologic pressure. Use of antimicrobial prophylaxis, vaccines, and behavioral modifications (e.g., routine hand washing or advice against digging in gardens without masks) may result in a “shift to the right” of the infection timeline, unless the intensity of immunosuppression is reduced or immunity develops.
| A. Pneumocystis jirovecii Pneumonia (PJP) and General Antibacterial Prophylaxis |
| Regimen |
|
| Alternative Regimen |
|
| B. Cytomegalovirus and Herpesvirus Prophylaxis a,b | ||
| CMV Universal Antiviral Prophylaxis (Kidney or Pancreas Recipients) | ||
| Donor (D) and Recipient (R) CMV serologic status +/− T-cell depletion in induction therapy | Possible Regimen | Monitoring (Viral Load NAT) |
| D+/R−with induction using T cell depletion(Highest risk) | Valganciclovir 900 mg po × QD (or IV ganciclovir 5 mg/kg IV until taking po) (corrected for renal function) for 6 months | Monthly for 6 months after discontinuation of therapy a |
| D+/R− without T cell depletion (costimulatory blockade) (High risk) | Valganciclovir 900 mg po × QD (or IV ganciclovir 5 mg/kg IV until taking po) (corrected for renal function) for 3–6 months | Monthly for 6 months after discontinuation of therapy a |
| R+ without T cell depletion (costimulatory blockade) (Intermediate risk) | Oral valganciclovir (900 mg/day corrected for renal function) × 3 months or preemptive therapy | Symptoms only |
| R+ with T cell depletion or desensitization,(D− at Intermediate risk) (D + at Higher risk) | Oral valganciclovir (900 mg/day corrected for renal function) × 3–6 months or preemptive therapy | Symptoms only |
| D−/R−(Lowest risk) Target HSV/VZV | Oral famciclovir 500 mg po qd × 3–4 months (or valacyclovir 500 bid or acyclovir 400 tid); Leukocyte-filtered blood | Symptoms, fever/neutropenia |
a Hybrid Prophylaxis: Many centers prefer universal prophylaxis for highest risk kidney recipients (D+/R− or R+ with lymphocyte depletion) and preemptive therapy for lower risk groups.
b Preemptive Therapy: Preemptive therapy requires a carefully organized monitoring program and patient compliance. Either a molecular CMV viral load test or a pp65 antigenemia assay may be used for monitoring. Monitoring should be performed once weekly after transplantation for 12–24 weeks. Infections indicated by positive assays are treated with either oral valganciclovir or intravenous ganciclovir. Therapy is continued at least until viremia is undetectable.
First Phase (First Month After Transplantation)
During the first month after transplantation, three types of infection occur. The first is infection or colonization present in the recipient before transplantation that emerges in the setting of surgery and immunosuppression. Pretransplantation pneumonia and vascular access infections are common examples of this type of infection. Colonization of the recipient with resistant organisms that infect intravenous catheters or surgical drains also is common (e.g., methicillin-resistant Staphylococcus aureus [MRSA]). All infection should be controlled or eradicated to the degree possible before transplantation.
The second type of early infection is donor-derived. This may be nosocomially derived (resistant gram-negative bacilli and S. aureus or Candida species) colonization during the donor’s hospitalization, secondary to systemic infection in the donor (e.g., line infection), or contamination during the organ procurement process. Active infections may be transmitted from donor to recipient and emerge earlier than normally predicted (e.g., HSV, tuberculosis, histoplasmosis). Most recent clusters of donor-derived infection have been the result of unfortunate timing—a donor who acquired acute infection (HIV, WNV, rabies, or LCMV) before and unrelated to the cause of death.
The third and most common source of infection in the early period is related to the transplant procedure. These infections include surgical wound infections, pneumonia (aspiration), bacteremia associated with vascular access or surgical drainage catheters, urinary tract infections, and superinfection of fluid collections—leaks of vascular or urinary anastomoses or of lymphoceles. These are nosocomial infections and, as such, may carry the same antimicrobial-resistant pathogens observed in nonimmunosuppressed patients undergoing comparable surgery. Given immunosuppression, the signs of infection may be subtle and the severity or duration is usually increased. Thus bowel perforation may be clinically silent, marked only by tachycardia, a rising white blood cell count, abnormal liver function tests, or graft dysfunction. The technical skill of the surgeons and meticulous postoperative care (i.e., wound care and proper maintenance and timely removal of endotracheal tubes, vascular access devices, and drainage catheters) determine the degree of risk for these infections. Another important infection during this period is Clostridium difficile colitis.
Limited perioperative antibiotic prophylaxis (i.e., from a single dose to 24 hours of an antibiotic such as cefazolin or amoxicillin-clavulanate) is usually adequate for renal transplantation with additional coverage required for known risk factors (e.g., prior colonization with MRSA). For pancreas transplantation, additional perioperative prophylaxis against yeasts is useful with fluconazole, mindful of potential increases in sirolimus and calcineurin inhibitor levels when used concomitantly with azole antifungal agents.
Opportunistic infections are notably absent in the first month after transplantation, even though the daily doses of immunosuppressive drugs may be greatest during this time. The implication of this observation is important because it suggests the daily dose of immunosuppressive drugs is less important than the cumulative dose (i.e., the “area under the curve”) for determining the true state of immunosuppression. The net state of immunosuppression during the first month after transplant is not great enough to support opportunistic infections, unless exposure has been excessive. Accordingly, the occurrence of a single case of opportunistic infection in this period should trigger an epidemiologic investigation for an environmental hazard.
Second Phase (1–12 Months After Transplantation)
The second phase of infection was traditionally 1 to 3 months, but has been extended because of two main factors: successful use of prophylaxis or monitoring programs targeting CMV and the herpesviruses, Pneumocystis, urinary tract infections, and HBV, and intensification of immunosuppression using more potent agents or antibody-based induction therapies with prolonged effects on immune function (see Table 31.5 ). Infection in the transplant recipient 1 to 12 months after transplantation has one of three causes:
- 1.
Infection from the perisurgical period, including relapsed C. difficile colitis, inadequately treated pneumonia, or infection related to a technical problem (e.g., urine leak, hematoma). Fluid collections in this setting generally require drainage.
- 2.
Viral infections including CMV, HSV, VZV, human herpesvirus (HHV)-6 or HHV-7, EBV, HBV, HCV, and HIV. Viruses are prominent given the importance of T cell function in antiviral control and the disproportionate degree of T cell inhibition by most immunosuppressive regimens. Furthermore, these viruses are systemically immunosuppressive, predisposing to opportunistic infection or acceleration of other infections and, via chronic immune stimulation, predispose to graft rejection. Useful therapies are now available for most of these pathogens. The herpesvirus infections are lifelong and tissue-associated, transmitted with the allograft from seropositive donors. Other common viral pathogens of this period include BK polyomavirus (in association with allograft dysfunction or polyomavirus-associated nephropathy [PyVAN]) and community-acquired respiratory viruses (adenovirus, influenza, parainfluenza, RSV, metapneumovirus). Bacterial and fungal superinfection of virally infected hosts is common.
- 3.
Opportunistic infections secondary to P. jirovecii, L. monocytogenes, Toxoplasma gondii, Cryptococcus neoformans, Nocardia, Aspergillus, and other agents
In this period, the stage also is set for the emergence of a subgroup of patients—the “chronic ne’er do well”—the patient who requires higher than usual levels of immunosuppression to maintain graft function, who had a poor technical outcome of transplantation (leaks or vascular issues) or poor graft function, or who has persistent viral or other infections (e.g., C. difficile colitis), which predict long-term susceptibility to other infections (third phase, discussed next). Such patients may benefit from prolonged (lifelong) prophylaxis (antibacterial, antifungal, antiviral, or a combination) to prevent life-threatening infection.
Opportunistic infections reflect the immunosuppressive regimen used, individual epidemiology, and the presence or absence of immunomodulating viral infection. Viral pathogens (and rejection) are responsible for most febrile episodes that occur in this period. Anti-CMV strategies and trimethoprim/sulfamethoxazole (TMP-SMX) prophylaxis are effective in decreasing the risk of infection. TMP-SMX prophylaxis effectively prevents Pneumocystis pneumonia and reduces the incidence of urinary tract infection and urosepsis, L. monocytogenes meningitis , Nocardia species infection, and T. gondii.
Third Phase (More Than 12 Months After Transplantation)
Recipients who underwent transplantation more than a year previously can be divided into three groups in terms of infectious risk. Most transplant recipients (70%–80%) have a technically good procedure with satisfactory allograft function, reduced immunosuppression, and absence of chronic viral infection. These patients resemble the general community in terms of infection risk, with community-acquired respiratory viruses constituting the major risk. Occasionally, such patients develop primary CMV infection (socially acquired) or infections related to underlying diseases (e.g., skin infections in diabetics).
A second group of patients has chronic viral infection, which may produce end organ damage (e.g., BK polyomavirus leading to fibrosis, HCV leading to cryoglobulinemia and cirrhosis, CMV with chronic graft rejection) or malignancy (e.g., posttransplantation lymphoproliferative disease (PTLD) secondary to EBV, skin or anogenital cancer related to papillomaviruses). In the absence of specific and effective antiviral therapy, these patients often suffer graft rejection with the reduced intensity of immunosuppression.
A third group of patients has unsatisfactory allograft function and suffers the ravages of renal dysfunction, often despite intensified immunosuppression used to preserve graft function. Declining allograft function may be a result of underlying disease progression (atherosclerosis, IgA, or diabetes), calcineurin inhibitor toxicity, or humoral and cellular graft rejection. Thus these patients are overimmunosuppressed relative to the risk of infection. These patients may benefit from lifetime maintenance TMP-SMX and often fluconazole prophylaxis. In this group, one also should consider organisms more commonly associated with immune dysfunction of acquired immunodeficiency syndrome (AIDS; Bartonella, Rhodococcus, Cryptosporidium, and microsporidia) and invasive fungal pathogens ( Aspergillus, Mucorales, and dematiaceous or pigmented molds). Even minimal clinical signs or symptoms warrant careful evaluation in this group of high-risk patients.
Assessment of Infectious Diseases in Recipients and Potential Donors Before Transplantation
Guidelines for pretransplant screening have been the subject of several publications, including a consensus conference of the Immunocompromised Host Society, the American Society for Transplantation Clinical Practice Guidelines for the evaluation of kidney transplant candidates, and the American Society of Transplant Surgeons Clinical Practice Guidelines for the evaluation of living kidney transplant donors.
Transplant Donor
Deceased Donor Evaluation
A crucial challenge in screening deceased organ donors is the narrow time frame for the evaluation. A useful organ must be procured and implanted before some microbiologic assessments have been completed. Thus bacteremia or fungemia may not be detected until after transplantation has been performed. Such infections generally have not resulted in transmission of infection if the infection has been adequately treated before procurement using antimicrobial agents to which the organism is susceptible for an appropriate duration. In recipients of tissues from 95 bacteremic donors, a mean of 3.8 days of effective therapy after transplantation prevented transmission of susceptible pathogens (in an era of reduced antimicrobial resistance). Surveillance with additional courses of therapy in the recipient are employed, targeting known donor-derived pathogens. Bacterial meningitis must be treated with antibiotics that penetrate the cerebrospinal fluid before organ procurement. Individuals with unidentified and untreated causes of meningoencephalitis or sepsis should not be used as organ donors. Donor-derived infections caused by Candida species have resulted from organ contamination or candidemia at the time of procurement. Susceptibility testing of the isolate and prolonged treatment (2–4 weeks) with effective agents to avoid pyelonephritis, abscess formation, mycotic aneurysm, or candidemia in the recipient is recommended. Vascular involvement by Candida species in the recipient requires at least 6 weeks of therapy. Certain active infections (CMV, VZV, HSV, EBV, or HCV) may be unsuspected even in the seropositive donor and require NAT for diagnosis. Likewise, the donor’s clinical, social, and medical histories are essential to reducing the risk of such infections. Known infection should be treated before procurement if possible. See previous discussion of unrecognized donor pathogens. Major exclusion criteria are outlined in Table 31.2 .
Living Donor Evaluation
The living donor procedure should be considered elective, and the evaluation should be completed and infections treated before donation. An interim history must be taken at the time of surgery to assess the presence of new infections since the initial donor evaluation. Intercurrent infections (flu-like illness, headache, confusion, myalgias, cough) might be the harbinger of important infection (WNV, severe acute respiratory syndrome [SARS], Trypanosoma cruzi ). Live donors undergo a battery of serologic tests ( Table 31.7 ), purified protein derivative (PPD) skin test or tuberculosis interferon-γ release assay, and, if indicated, chest radiograph. The testing must be individualized, based on unique risk factors (e.g., travel). Of note in the kidney transplant recipient is the exclusion of urinary tract infections (including both bacteria and yeasts) and bacteremia at the time of donation. The US Public Health Service suggests rescreening potential donors as close to donation as is feasible, using NAT for HIV, HCV, and HBV.
| Pathogen | Laboratory Test | Quantitative Molecular Test Available | All Patients | Patients With Expsoure to Endemic Area |
|---|---|---|---|---|
| CMV | Serologies | X | X | |
| HSV | Serologies | X | X | |
| EBV | Serologies | X | ||
| HIV | Serologies | X | X | |
| HBV | Serologies including: HBV surface antigen and HBV surface antibody | X | X | |
| HCV | Serologies | X | X | |
| Treponema pallidum | RPR or VDRL test | X | ||
| Toxoplasma gondii | Serologies | X | ||
| Strongyloides stercoralis | Serologies | X | ||
| Stool ova and parasite examination | ||||
| Leishmania | Serologies | X | ||
| Trypanosoma cruzi | Serologies | X | ||
| Blood smear | ||||
| Shistosomiasis | Urine ova and parasite examination with or without endoscopy | X | ||
| Histoplasma capsulatum | Serologies | X | ||
| Coccidioides immitis | Serologies | X | ||
| Bacteria and yeasts | Urinalysis and culture | X | ||
| Mycobacterium tuberculosis | Skin test or IGRA | X | ||
| Latent and active pulmonary infections | Chest x-ray (routine) | X |
Special Infectious Risks and Organ Procurement
Tuberculosis
Mycobacterium tuberculosis from the donor represents approximately 4% of reported posttransplant tuberculosis cases. Much higher rates occur in endemic regions. Active disease should be excluded in PPD-positive donors with chest radiograph, sputum cultures, and chest computed tomography (CT) if the chest radiograph is abnormal. Urine acid-fast bacillus cultures may be useful in a PPD-positive kidney donor. Isoniazid prophylaxis of the recipient should be considered for untreated PPD-positive donors. Factors favoring prophylaxis include a donor from an endemic region, high-risk social environment, or use of a high-dose steroid regimen in the recipient.
Parasites
Chagas’ disease ( Trypanosoma cruzi ) has been transmitted by transplantation in endemic areas and more recently in the US. Schistosomiasis and Strongyloides stercoralis are generally recipient-derived. Malaria and leishmaniasis have been rarely transmitted with allografts.
Viral Infections Other Than Cytomegalovirus
EBV infection is a major risk for development of PTLD. The risk is greatest in the EBV-seronegative recipient of an EBV-seropositive allograft (i.e., donor seropositive, recipient seronegative, D+/R−). This situation is most common in pediatric transplant recipients. Other at-risk groups include adults coinfected with CMV or those receiving greater intensity of immunosuppression, notably with T cell depletion and possibly with belatacept. Monitoring should be considered for at-risk individuals using a quantitative molecular assay for EBV. EBV is also a cofactor for other lymphoid malignancies.
VZV screening should be used to identify seronegative individuals (no history of chickenpox or shingles) for vaccination before transplantation. It is likely, although unstudied, that the new herpes zoster subunit vaccine will replace live vaccine before and after transplantation. HSV screening is performed by most centers although active infection is prevented by most anti-CMV prophylaxis (except with newer agents such as maribavir and letermovir) during the posttransplant period. VZV serologic status is particularly important in nonimmune children who may be exposed at school (for antiviral or VZV immunoglobulin prophylaxis) and in adults with atypical presentations of infection (pneumonia or gastrointestinal disease). Other herpesviruses also may reactivate, with HHV-6 and HHV-7 serving as cofactors for CMV and fungal infections, and Kaposi’s sarcoma-associated herpesvirus (HHV-8) causing malignancy, notably in endemic regions in South America and surrounding the Mediterranean basin.
Hepatitis screening has changed with quantitative nucleic acid test (QNAT) screening and the advent of effective antiviral therapies. HBV surface antigen (HBsAg) and HBV core antibody (HBcAb) are used for screening purposes (see Chapter 32 for detailed discussion). A positive HBV surface antibody titer indicates either vaccination or prior infection. HBcAb-IgM positivity suggests active HBV infection, whereas IgG positivity suggests a more remote or persistent infection. The HBsAg-negative, HBcAb-IgG-positive donor will have viral DNA in the liver but may be appropriate as a kidney donor for HBV-infected or vaccinated, and thus immune, renal recipients; quantitative viral assays for HBV should be obtained to guide further therapy. The presence of HBsAg-negative, HBcAb-IgG-positive assays may be a false-positive result or reflect true, latent HBV infection.
The effect of HCV infection has changed in the era of directly active antiviral agents (DAA); evidence exists that the use of HCV-positive kidneys has clinical benefits for the recipient. Pan-genotypic DAA therapies cure over 95% of HCV infections in transplantation. Untreated, HCV infection progresses to cirrhosis more rapidly with immunosuppression and with CMV coinfection (see Chapter 32 for detailed discussion). Side effects of historical therapies (pegylated interferon-α and ribavirin) are increased in the transplant population. HCV therapy is initiated based on center-specific protocols and may rely on quantitative NAT for HCV ribonucleic acid (RNA) and liver function testing (see Chapter 32 ).
Historically, the progression of untreated HIV infection in transplant recipients is rapid. However, HIV-infected kidneys (and other organs) have been transplanted into HIV-infected recipients in South Africa and elsewhere. Under the US HIV Organ Policy Equity (HOPE) Act, organs from HIV-infected donors may be transplanted into HIV+ recipients as part of a clinical trial with informed consent. The first planned HIV+/HIV+ transplant in the US was performed in March 2016. Based on current criteria for recipients who are not HIV infected, donors are evaluated based on epidemiology and using fourth-generation enzyme-linked immunosorbent assay (ELISA)-NAT testing.
Human T cell lymphotropic virus I (HTLV-I) is endemic in the Caribbean and parts of Asia (Japan) and can progress to HTLV-I-associated myelopathy/tropical spastic paraparesis or to adult T cell leukemia/lymphoma. HTLV-II serologically cross-reacts with HTLV-I, but it is less clearly associated with disease. Use of organs from such donors is generally avoided; however, serologic testing does not distinguish between the two types of virus. Donor screening for HTLV in the US is no longer mandatory, but some centers continue donor screening in endemic regions or use targeted screening of donors perceived to be high risk. WNV is a flavivirus associated with viral syndromes and meningoencephalitis and may be transmitted by blood transfusion and organ transplantation. Routine screening of donors is not advocated other than in areas with endemic infection. Donors with unexplained changes in mental status or recent viral illness with neurologic signs should be avoided.
Evaluation of the Transplant Recipient
The pretransplant period is useful for obtaining travel, animal, environmental, and exposure histories; updating immunizations; and counseling the recipient regarding travel, food, and other infection risks. Ongoing infection must be eradicated to the degree possible before transplantation. Two forms of infection pose a special risk—bloodstream infection related to vascular access (including that for dialysis) and pneumonia, which puts the patient at high risk for subsequent lung infection with nosocomial organisms. Several other infections are commonly encountered and should be treated and cleared before transplantation. Peritonitis must be cleared before surgery and infected peritoneal dialysis catheters removed. Urinary tract infection must be eliminated with antibiotics, with or without nephrectomy. Similarly, skin disease threatens the integrity of a primary defense against infection and should be corrected even if doing so requires the initiation of immunosuppression (e.g., to treat psoriasis or eczema) before transplantation. Finally, a history of more than one episode of diverticulitis should trigger an evaluation to determine whether colectomy is indicated before transplant.
Among important considerations in transplant recipients are strongyloidiasis, tuberculosis, and AIDS. Strongyloides hyperinfection syndrome (hemorrhagic enterocolitis, pneumonia, gram-negative or polymicrobic bacteremia, or meningitis) may occur more than 30 years after transplantation. Patients from endemic areas should be screened and Strongyloides -seropositive recipients empirically treated (ivermectin) pretransplant to prevent active disease after transplant.
The incidence of active and disseminated tuberculosis is higher in the transplant recipient than in the general population and the major antituberculous drugs are potentially hepatotoxic and some significantly interact with immunosuppressive agents. Thus eradication of tuberculosis in transplant candidates before transplantation is preferred. Patients at greater risk of tuberculosis infection or exposure include individuals with prior history of active tuberculosis or significant signs of old tuberculosis on chest radiograph, recent tuberculin reaction conversion, known exposure to active disease, protein-calorie malnutrition, cirrhosis, other immunodeficiency, or exposures related to living conditions (e.g., in a shelter or other group housing). PPD-positive individuals from endemic regions or with high-risk exposures should be screened for active disease and treated for such if present. For those with latent infection, therapy should be initiated before transplantation although some judgment may be used as to the optimal timing of latent treatment.
HIV infection has generally been converted from a progressively fatal disease to a chronic infection controlled by complex regimens of antiviral agents or highly active antiretroviral therapy (HAART). In the pre-HAART era, organ transplantation generally was associated with a rapid progression to AIDS. Kidney transplantation in HIV-infected recipients has been associated with good outcomes in individuals with controlled HIV infection and with treatment of HCV coinfection. After transplantation, HAART must be continued despite multiple and reciprocal drug interactions between antiretroviral and immunosuppressive medications. This necessitates experience in HIV and transplant drug management. Rejection will occur more frequently than in other hosts and standard intensity of immunosuppression is required. The most significant interactions are between the calcineurin and mammalian target of rapamycin (mTOR) inhibitors and HIV protease inhibitors (PIs) and nonnucleoside analog reverse transcriptase inhibitors (NNRTIs) via the hepatic cytochrome P450 3A4 system and P-glycoprotein. Adjustment in dosages and dosing intervals of immunosuppressive medications is required, and drug levels and toxicities must be monitored closely. Some drugs (e.g., raltegravir) have fewer interactions, and the CC chemokine receptor type 5 (CCR5) receptor antagonist maraviroc may even decrease rates of graft rejection. In vitro antiretroviral synergy occurs between sirolimus and earlier CCR5 antagonists; the use of sirolimus-based immunosuppression may increase rates of graft rejection. Prophylaxis against P. jirovecii pneumonia (PJP), and toxoplasmosis in seronegative recipients of seropositive organs, should be continued for life, preferably using TMP-SMX.
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