Infectious Complications of Solid Organ Transplantation

Abstract

Infections remain one of the leading causes of complications following kidney transplantation. While advances in surgical techniques and modern induction and maintenance immunosuppression regimens have improved the outcomes of the allograft, they have also resulted in an alteration in the risk of posttransplant infections over time. To counter the enhanced risk of infection, broader use of modern antimicrobial prophylaxis has been deployed in an attempt to delay and reduce the incidence of posttransplant infections. This chapter will summarize the timing of infectious complications, discuss key issues related to donor-derived disease transmission and methods to mitigate the risk of these events, review key strategies to minimize the risk of infectious complications of renal transplantation, and finish with focused reviews of common infections complicating kidney transplantation, including BK virus nephropathy, cytomegalovirus, infectious diarrhea, and urinary tract infections.

Keywords

kidney transplantation, infection, donor-derived infection, vaccination, BK virus nephropathy, cytomegalovirus, diarrhea, urinary tract infections

Infections remain among the most common complications following kidney transplantation. While advances in surgical techniques and modern induction and maintenance immunosuppression regimens have improved the outcomes of the allograft, they have also resulted in an alteration in the risk of posttransplant infections over time. For example, lymphocyte depletion induction combined with tacrolimus-mycophenolate–based maintenance has resulted in an increase in the frequency of BK virus nephropathy (BKVN). To counter the enhanced risk of infection, broader use of modern antimicrobial prophylaxis has been deployed in an attempt to delay and reduce the incidence of posttransplant infections. This chapter will summarize the timing of infectious complications, discuss key issues related to donor-derived disease transmission and methods to mitigate the risk of these events, review key strategies to minimize the risk of infectious complications of kidney transplantation, and finish with focused reviews of common infections complicating kidney transplantation, including BKVN, cytomegalovirus (CMV), infectious diarrhea, and urinary tract infections (UTI).

Timing of Infectious Complications in Kidney Transplantation

Infectious complications typically occur in one of three time periods posttransplant: early posttransplant infections, infections during peak immunosuppression, and late-onset infections. A number of factors affect the timing of the infections, including specific donor and recipient factors, such as preexisting infection or immunity, the use of antimicrobial prophylaxis, and the net state of immunosuppression. Of these, the net state of immunosuppression requires the closest consideration as there are no direct measures to assess the impact of various factors on risk of rejection or infectious complications. Instead, the clinician must assess a variety of factors including current and past immunosuppression; underlying immunodeficiency; neutropenia; lymphopenia; a variety of complex metabolic conditions, such as presence of uremia, malnutrition, poorly controlled diabetes mellitus, cirrhosis; and replication of immunomodulatory viruses, including human immunodeficiency virus (HIV), CMV, Epstein-Barr virus (EBV), hepatitis B (HBV), and hepatitis C (HCV). Reviews of immunosuppression must keep in mind both medications that may not be readily apparent on the patient’s medication list (i.e., alemtuzumab for induction, or rituximab for prior treatment of antibody-mediated rejection as such antibody-based immunosuppression may have longstanding impacts of components of the immune system), as well as the impact of recent immunosuppression, such as recent rejection treatment, high plasma levels of tacrolimus, or recent conversion from one immunosuppression to another. For example, with many immunosuppression conversions, the patient is effectively exposed to multiple agents with effective immunosuppression as one agent is titrated off and another is titrated on. Taken together, these inform the net state of immunosuppression for an individual patient.

Early posttransplant infections occur in the first 30 days posttransplant. The majority of such infections (~98%) are typical of any surgical patient, but they may be more severe or more common. The most common postsurgical infections include deep and superficial surgical site infections at the operative site, hospital-acquired pneumonia as a consequence of intubation during transplant surgery, UTI as a consequence of bladder catheterization, bacteremia secondary to use of intravenous (IV) catheters, and Clostridium difficile colitis as a complication of perioperative antimicrobial utilization. Management approaches for such infections are consistent with the local epidemiology and susceptibility of predicted pathogens and published guidelines. Rarely, donor-derived infections may present during the first 30 days posttransplant, as discussed in greater detail below. Finally, recipient-origin infections may manifest in the first 30 days. Examples of recipient-origin infections include respiratory viral infections, such as influenza, or occult bacteremias that were incubating in the candidate at the time they present for their transplant procedures.

Infections during peak immunosuppression are typically opportunistic infections or pathogens that reactivate from latent infection in the recipient and generally occur between 30 days and 6 months posttransplant or within 3 months of treatment of rejection. Use of prophylactic antimicrobials may delay the onset of such infections, resulting in later than typical onset. For example, high-risk CMV donor seropositive, recipient seronegative (D+/R−) patients frequently will be given 6 months of anti-CMV prophylaxis, and as a result, CMV incidence peaks 1 to 3 months after such prophylaxis is discontinued. Examples of infections that typically occur during the period of peak immunosuppression include BK virus, CMV, herpes simplex virus (HSV), varicella-zoster virus (VZV), HBV, HCV, tuberculosis, Listeria , Strongyloides , and Chagas.

Late-onset infections typically present greater than 6 months posttransplant or greater than 3 months after treatment for a rejection episode. Most late-onset infections are community-acquired infections, such as community-acquired pneumonia, respiratory viral infections including influenza, and UTI. Such infections may lead to hospitalization or require aggressive antimicrobial therapy to resolve the infections. Patients may acquire infections from exposure to the environment or travel, which increases over time as the patient returns to normal function. Examples of environmental exposures include endemic mycoses (histoplasmosis, blastomycosis, and coccidioidomycosis), West Nile virus, and travel-associated malaria. Some opportunistic infections notoriously present late, including nocardiosis, mucormycosis, and JC virus–mediated progressive multifocal leukoencephalopathy (PML). Lastly, some infections such as CMV, EBV-positive and EBV-negative posttransplant lymphoproliferative disorder (PTLD), hepatitis, and TB may present in this late period. Pneumocystis jirovecii (PCP) historically was an infection complicating the period of peak immunosuppression, although with universal prophylaxis, most cases of PCP occur late posttransplant in the current era.

Donor-Derived Infections and Risk Mitigation Strategies

Donor-derived infections are defined as any infection present in the donor that is transmitted to the recipient with the transplanted organ or vessels. Such infections can be categorized as either expected disease transmissions, where the pathogen is known to be present in the donor at the time of procurement and steps are taken to mitigate the disease transmission, or unexpected disease transmissions, when the donor is not recognized to have an infection that is identified after resulting in clinical disease in one or more of the transplant recipients. Examples of expected disease transmissions include CMV or EBV in which the donor is recognized to have an infection and the recipient is either monitored for evidence of disease or given prophylactic medications to prevent clinical diseases. Examples of unexpected disease transmissions include bacteria ( Escherichia coli , Mycobacteria tuberculosis , and S. aureus ), fungi (Candida, Cryptococcus, and Histoplasmosis), parasites (Chagas, Strongyloides, and Acanthamoeba), and viruses (lymphocytic choriomeningitis virus [LCMV], rabies, HIV, and HCV). In the United States, any documented or suspected unexpected donor-derived disease transmissions need to be reported to the Organ Procurement and Transplantation Network (OPTN) as soon as possible but not greater than 24 hours after initially suspecting transmission (OPTN Policy 15.4); the report is made through the Patient Safety Portal. Timely reporting of suspected transmissions is essential to facilitate communication and rapidly allow screening and treatment of recipients of other organs from the same donor. Data on such disease transmissions have been collected and categorized based on standardized methodologies and have been summarized in detail elsewhere.

There are several ways in which potential living and deceased donors can be screened to mitigate the risk of disease transmission. All donors should have a thorough review of their medical and social history, receive a complete physical examination and assessment of the potential organs, and undergo thorough testing of blood. The donor medical and social history should be reviewed for history of documented infection or exclusion from blood donation. The donor’s social history should be reviewed for residence or travel to regions of endemicity for potentially transmissible infections, including Chagas, and Coccidioidomycosis, M. tuberculosis , strongyloidosis, toxoplasmosis, and West Nile virus. Patients with evidence of prior exposures to such potentially transmissible diseases should be screened for latent infection, as is required for living donors (OPTN Policy 15.3). The social history should also be reviewed for risk factors that place the donor at increased risk of transmission of HIV, HBV, and HCV as defined by the US Public Health Service (PHS) as summarized in Table 63.1 . Current US policy (OPTN Policy 15.3) requires transplant centers to be informed if a potential donor meets any of the US PHS Increased Risk criteria and that the centers must obtain special informed consent from potential recipients of organs from such donors. Further, policy requires that the recipients of organs of such donors be screened for development of potential donor-derived disease after transplantation. Because serology may miss transmission, early screening, optimally within the first 1 to 3 months posttransplant, for HIV, HBV, and HCV should include both serologic and direct detection of the virus (i.e., polymerase chain reaction [PCR]) unless the recipient had infection documented pretransplant. Because transmission of HBV may be missed with early posttransplant screening, repeat screening for HBV should be considered around 1 year posttransplant.

Table 63.1

US Public Health Service Definitions of Donors at Increased Risk of HIV, Hepatitis B Virus, and Hepatitis C Virus Transmission

All Age Groups

•

People who have had sex with a person known or suspected to have HIV, HBV, or HCV infections in the preceding 12 months
•

Men who have sex with men (MSM) in the preceding 12 months
•

Women who have had sex with a man with a history of MSM behavior in the preceding 12 months
•

People who have had sex in exchange for money or drugs in the preceding 12 months
•

People who have had sex with a person who had sex in exchange for money or drugs in the preceding 12 months
•

People who have had sex with a person who has injected drugs by IV, IM, or subcutaneous routes for nonmedical reasons in the preceding 12 months
•

People who have injected drugs by IV, IM, or subcutaneous routes for nonmedical reasons in the preceding 12 months
•

People who have been in lockup, jail, prison, or a juvenile correctional facility for ≥72 hours in the preceding 12 months
•

People who have been newly diagnosed with or have been treated for syphilis, gonorrhea, Chlamydia, or genital ulcers in the preceding 12 months
•

People who have been on hemodialysis in the preceding 12 months (RISK FOR HCV ONLY)

Pediatric Donors

•

A child who is ≤18 months of age and born to a mother known to be infected with, or at increased risk for, HIV, HBV, or HCV infections
•

A child who has been breastfed within the preceding 12 months and the mother is known to be infected with, or at increased risk for, HIV

Laboratory Criteria

•

Any evidence of hemodilution

HBV , Hepatitis B virus; HCV , hepatitis C virus; HIV , human immunodeficiency virus; IM , intramuscular; IV , intravenous.

From Seem DL, Lee I, Umscheid CA, Kuehnert MJ, United States Public Health Service. PHS guideline for reducing human immunodeficiency virus, hepatitis B virus, and hepatitis C virus transmission through organ transplantation. Public Health Rep . 2013;128:247–343.

One unique category of donors are the US PHS Increased Risk Donors who have engaged in behaviors that place them at increased, albeit low, risk of transmission of HIV, HBV, and HCV. Despite current screening practices ( Table 63.2 ), these donors harbor a residual risk of unrecognized disease transmission because of the fact that the donors may be within either the eclipse period (the period between infection and detection of infection by PCR or nucleic acid test [NAT]) or the serologic window period (the period between infection and detection of antibodies in the blood); the specific eclipse and window periods are summarized in Table 63.3 . Because specific informed consent is required from potential recipients before the use of organs from US PHS Increased Risk Donors, the residual risk of disease transmission needs to be known to the consenting clinician to accurately estimate the risk of disease transmission ( Table 63.4 ). Given the recent rise in donors who die of acute drug overdoses, even negative nucleic acid testing of donors will not fully rule out the risk of transmission, and the higher estimated residual risk should be made clear to the recipient (see Table 63.4 ); there have been documented examples of disease transmission, particularly HCV, from such drug overdose donors with negative testing within the eclipse period.

Table 63.2

Screening Assays for Living and Deceased Organ Donors

Required Screening for All Living and Deceased Donors