Risk of Infection and the Timeline of Infection
The risk of infection for the recipient at any point in time after transplantation is a function of two factors:
The patient's "net state of immunosuppression" including all factors contributing to the risk of infection (Table 2).
Increased degrees of immune dysfunction predispose to infection at lower microbial inoculums or with less virulent organisms or to infections of greater than expected severity. With lower levels of immunosuppression, the incidence of infection is less and drug side-effects less frequent, but graft rejection is more common. Immunosuppression for transplantation impacts all limbs of innate and adaptive immunity; specific immune defects tend to favor specific types of infection, e.g. T-lymphocyte depletion predisposes to viral infections, B cell depletion to encapsulated bacteria, and corticosteroids to Pneumocystis and other fungi (Table 3). Antimicrobial prophylaxis should reflect the risk of specific infections for each immunosuppressive regimen over time. Transplantation requires adjustment of preventative strategies considering local immunosuppressive regimens, technical approaches, and understanding of local patterns of infection, factors that can be adapted to the management of individual recipients.
Epidemiologic Exposures and the Microbiome
The Microbiome. Microorganisms in tissues and on barrier surfaces are collectively termed the "microbiome" including both commensal flora and acute exposures (infection). The microbiome of the transplant recipient is derived from multiple sources: prior colonization of mucosal surfaces, latent (viral, parasitic, fungal) infections, infection from the organ donor, and new community-derived or nosocomial exposures. Recent data suggest that these microbes have a dynamic and well-regulated interaction with the normal immune system but may contribute to immune dysregulation and graft rejection in the transplant recipient. The impact of the microbiome on immune function is under investigation but depends on the context in which microbial shifts occur: during immune development; with acute infections; or during homeostatic repopulation after lymphocyte depletion. In transplant recipients, microbial networks are disrupted by immunosuppression, infectious exposures, antimicrobial therapies, metabolic disarray, and surgery (Figure 1). Changes in microbial diversity (types, distribution, and concentrations of organisms) and new exposures alter local and systemic immunity and may affect graft outcomes. Viruses (termed the "virome") have diverse effects on immune function including allograft injury (e.g. inflammation, priming of adaptive responses, altered antigen expression) and predisposition to opportunistic infections—loosely termed "indirect effects". The resiliency of the "normal" host microbiome ("microbiome homeostasis") may promote more tolerant immune responses. Infectious exposures may promote rejection, block tolerance, or stimulate cross-reactive cellular alloimmunity. Memory T cell responses to previously encountered pathogens that cross-react with alloantigens constitute "heterologous immunity," the clinical significance of which requires clarification.[11,12] Further study is needed of the interactions between the microbiome and immunity in allograft recipients.
Transplantation and the microbiome. Transplantation disrupts the composition of commensal microbial flora through a variety of mechanisms, including surgery, diet, immunosuppression, antimicrobial prophylaxis and therapies, infection, and vaccination. Microbial disruption of the host's baseline microbiome ("Normal") or "dysbiosis" has been associated with the development of chronic rejection, injury from ischemia–reperfusion injury, and infection. Conversely, the resilience of the microbiome or restoration of the diversity of the pretransplant flora ("Restored Microbiome") has been associated with improved allograft outcomes. The role of microbial manipulation (e.g. by fecal transplantation) as a therapeutic measure to improve allograft outcomes is unclear.
Donor- and Recipient-derived Infections. Donor and recipient microbiologic screening provide essential data for development of posttransplant preventative strategies (Table 4 and Table 5).[13–15] These strategies are individualized to include interventions including treatment of recipients with isoniazid for latent tuberculosis or ivermectin for Strongyloides stercoralis, vaccination of seronegative recipients, or empiric antifungal therapy in lung recipients. Antiviral strategies for the herpesviruses are based on an assessment of risk of infection based on donor and recipient pathogen-specific serologies and, increasingly, cellular immune assays.[16,17]
Some donor-derived infections (e.g. Strongyloides stercoralis, tuberculosis, or coccidioidomycosis) may emerge decades after initial exposure. Donor colonization (e.g. Aspergillus in donor lungs) may also increase susceptibility to graft injury, rejection, vascular or tracheal anastomotic defects, or drug (e.g. m-TOR inhibitor) toxicity. Epidemiologic history and microbiologic assays are applied to screening of organ donors for common pathogens. Active infections are best treated prior to transplantation. Perioperative prophylaxis may be adapted for unusual colonizing organisms including multidrug-resistant organisms (MDRO) or molds; this may be continued postoperatively in select situations (Aspergillus colonization in lung recipients). Immunosuppressed patients with incompletely treated infections often relapse. Prolonged prophylaxis risks emergence of antimicrobial resistance.
Universal prophylaxis involves giving preventative therapy to all "at-risk" patients posttransplant for a defined time period; e.g. trimethoprim-sulfamethoxazole (TMP-SMZ) for Pneumocystis and urinary prophylaxis. Pre-emptive therapy employs monitoring of patients at predefined intervals using a sensitive assay (e.g. nucleic acid assays for cytomegalovirus [CMV] or BK polyomavirus) to detect early, active infection. Positive assays result in therapy initiation. Pre-emptive therapy incurs extra costs for monitoring and coordination of outpatient care while reducing the cost of drugs and the inherent toxicities of drug exposure.[25–28]
Unexpected donor-derived infections occur in less than 1% of grafts and may manifest as a cluster of infections among recipients of organs from a common donor.[15,29–31] Uncommon pathogens (e.g. rabies or lymphocytic choriomeningitis virus) may not be considered or testing may be restricted to specialty laboratories; such assays are generally of low yield, too costly, and too slow for routine use.[30,32] Certain pathogens such as WNV, Dengue, or Trypanosoma cruzi vary with geography or season; donor screening must be adapted to local requirements. Testing using highly sensitive assays in low-yield situations risks false-positive assays and unnecessary organ donor exclusion. Recent guidelines for donor screening have focused on identification of high-risk behaviors for common viruses (human immunodeficiency virus [HIV], HCV, hepatitis B virus [HBV]) using a combination of serologic and nucleic acid testing (NAT). NAT screening reduces, but does not eliminate ("residual risk") the window period following infection in which an infected individual has a negative screening result using serologic assays (Table 5).[19–22] In early infection, donors may have viral loads below the limits of detection and lack seroconversion; unexpected viral transmission to recipients from deceased or living donors has occurred. Conversely, such testing has allowed the use of "U.S. Public Health Service (PHS) increased risk for transmission of infection" donors such as those dying of drug overdoses who represent up to 40% of the potential donor pool in some regions. The use of HIV+ organs for HIV+ recipients (kidney and liver) is increasing (under research protocols in the United States) and requires expertise in antiviral management. With effective antiviral therapies, HCV+ donor organs are increasingly used for both HCV+ and HCV-negative recipients.
Community Exposures: Travel, hobbies, young children, and work environments provide exposures to contaminated food and water (Listeria, Cryptosporidium), soil (Aspergillus or Nocardia), birds (Cryptococcus), and geographically restricted mycoses (Blastomyces dermatitidis,Coccidioides immitis,Paracoccidioides species, and Histoplasma capsulatum) in addition to outbreaks of respiratory viruses and arthropod-borne diseases.
Nosocomial Exposures: Colonization with antimicrobial-resistant organisms may result from prolonged hospitalizations of organ donors and transplant candidates. The mortality associated with MDRO infections in transplant recipients is increased, likely as a result of delayed recognition and therapy.[24,35,36] Common postsurgical infections include vancomycin-resistant enterococci, methicillin-resistant staphylococci, Clostridium difficile colitis, and fluconazole-resistant Candida species. MDROs include carbapenem-resistant enteric gram-negative bacteria, often Klebsiella species. Respiratory viral infections may be acquired from medical staff. Increasingly, candidates for transplantation have multiple comorbidities that may require advanced cardiopulmonary supports (ventricular assist devices, extracorporeal circulation membrane oxygenation, hemodialysis), prolonged intubation, antimicrobials or immunosuppressive therapies, and are at increased risk for colonization by MDRO.
Net State of Immunosuppression
The specific immunosuppressive therapy, including dose, duration, and temporal sequence of agents—Intensive treatment of graft rejection poses greater acute risk than chronic immunosuppression.
Technical problems in the transplant procedure, resulting in leaks (blood, lymph, urine) and fluid collections, devitalized tissue, and poor wound healing.
Prolonged airway intubation.
Use of broad-spectrum antimicrobial agents.
Posttransplant renal, hepatic, pulmonary, or cardiac dysfunction, malnutrition or diabetes, advanced age.
Prolonged use of urinary, vascular access, or dialysis catheters, surgical drains, or other breaks in skin or mucosal defenses.
Infection with immunomodulating viruses including CMV, Epstein-Barr virus (EBV), HBV, HCV, or HIV. Most viruses, including community-acquired respiratory viruses, have local innate or adaptive immune effects predisposing to superinfection.
Neutropenia or lymphocytopenia.
Genetic polymorphisms in immune response pathways.
The synergies of combinations of immunosuppressive agents or defects in immune function are not quantifiable. The assessment of pathogen-specific (i.e. cellular) immune function and its relation to the intensity of immunosuppression correlates roughly with the risk of infection in an individual.[3,37] Few commercialized assays exist other than for CMV and tuberculosis but include interferon-γ-release assays, ELISpot, MHC-tetramer staining, or intracellular cytokine staining. Serologic assays determine past exposures to various pathogens but are poorly predictive of the efficacy of immune response to specific pathogens in the immunosuppressed host and are often not useful for acute diagnosis. Low serum antibody levels correlate with an overall risk of infection but specific cutoff values and indications for replacement therapy are lacking. Other measures of "global" immune function lack the desired predictive values for infectious risk. Individual drugs are associated with increased risk of certain infections (Table 3); combinations of agents may enhance risk or cause toxicity. Few data exist on functional immune reconstitution after T- or B-lymphocyte depletion or with costimulatory blockade. The contribution of organ dysfunction (e.g. cirrhosis, renal dysfunction) to immune function resists quantification. Superimposed surgery (i.e. returns to the operating room) or invasive radiologic and endoscopic procedures to address complications such as bleeding, vascular thromboses, and urinary or biliary leaks or strictures risk contamination or dissemination of organisms. These effects are amplified by drug-induced leukopenia or dysfunction. Recent data support the importance of genetic polymorphisms among transplant recipients in risk of microbial colonization and infection.[1,2,41] Such predispositions are often unrecognized until additional alterations in immune function are introduced.
Timetable of Infection. With standardized immunosuppressive regimens, most common infections occur in a relatively predictable pattern depending on the time elapsed since transplantation (Figure 2). This is a reflection of changing risk factors over time: surgery/hospitalization, immunosuppression, emergence of latent infections, and community exposures. The pattern of infection changes with alterations in the immunosuppressive regimen, including side effects, viral infections, graft dysfunction, or significant epidemiologic exposures (e.g., travel or food). Risk also depends on exposures via donor organs. Prophylactic antimicrobial agents will delay, but not eliminate, the "normal" appearance of infections. Any reduction in the net state of immunosuppression will reduce risk of infection when prophylaxis is discontinued.[43–46] The time line represents three overlapping periods of risk: (1) the perioperative period to approximately 30 days after transplantation; (2) the period from 1 to 6–12 months after transplantation (reflecting immunosuppression including "induction" therapies and prophylaxis); and (3) beyond 6–12 months posttransplantation.
The timeline of infections following organ transplantation. The pattern of common infections following organ transplantation varies with the net state of immunosuppression and the epidemiology of infectious exposures. Development of disease is delayed, but not eliminated by prophylaxis including vaccinations and antimicrobial agents. Individual risk is modified by events including treatment for graft rejection or malignancy. Thickness of line indicates relative risk. Bold type indicates infections potentially preventable by prophylaxis. PML, progressive multifocal leukoencephalopathy, PTLD, posttransplant lymphoproliferative disorder. (Reprinted by permission from Fishman, John Wiley and Sons, NY.)
The time line is used to (1) establish a differential diagnosis for the transplant patient suspected of having infection, (2) identify excess environmental hazards or over-immunosuppression, and (3) design preventative antimicrobial strategies. Infections occurring at the "wrong" time suggest an excessive epidemiologic hazard or excessive immunosuppression. The prevention of infection is linked to the expected risk of infection (Table 6 and Table 7).
Phase I: 1 Month Posttransplantation: During the first month after transplantation, infections result from surgical complications, donor-derived infections, pre-existing recipient infections, and nosocomial infections including aspiration or C. difficile colitis. Early infections often reflect technical issues (bleeding, strictures, leaks, graft injury) or hospital environmental exposures (e.g. Aspergillus pneumonia with hospital construction). Fevers may be associated with antibody for cellular depletion, transfusions, drug reactions, or graft rejection. Drainage of fluid collections and early removal of lines and drains, limiting antimicrobial agents, and meticulous wound care are essential. Early opportunistic infections are uncommon as sustained administration of immunosuppressive agents is generally required to allow organisms of low native virulence to cause invasive disease. Thus, early Pneumocystis pneumonia is rare without pretransplant immunosuppression.
Phase II: 1 to 6–12 Months Posttransplant: Multiple causes of infectious syndromes exist in the transplant recipient 1 to 6–12 months posttransplantation. Anti-CMV strategies and TMP-SMZ prophylaxis have altered patterns of posttransplant infections (Figure 2, Table 6 and Table 7). TMP-SMZ virtually eliminates Pneumocystis jiroveci pneumonia (PCP) and given daily, prevents Toxoplasma gondii, and reduces urinary tract infections, Listeria monocytogenes meningitis, and many Nocardia species infections.[8,48] Notably, other agents substituted for TMP-SMZ in sulfa-allergic patients offer less protection. Effective anti-CMV prophylaxis should prevent most CMV infections (and herpes zoster, herpes simplex virus [HSV], human herpesvirus [HHV] 6 and 7, and primary EBV) for the duration of therapy (Table 6). In the patient not receiving anti-CMV prophylaxis, protection against varicella zoster virus (VZV) and HSV remain useful.[49–51] The differential diagnosis of infectious syndromes in this period includes the following:
Graft rejection, particularly in regimens without induction, corticosteroids, or calcineurin inhibitors
Lingering infection from the perisurgical period including C. difficile colitis, residual pneumonia, or technical issues (e.g. anastomotic leaks, empyema, cholangitis, infected hematoma).
Viral infections including CMV, HSV, herpes zoster (VZV), EBV, HHV 6 or 7, BK polyomavirus, relapsed hepatitis (HBV, HCV), and the community-acquired respiratory viruses (adenovirus, influenza, parainfluenza, respiratory syncytial virus, and metapneumovirus).[49–51]
Opportunistic infection due to Pneumocystis jiroveci,L. monocytogenes,T. gondii,Nocardia species, Aspergillus species, endemic fungi, often following immunomodulating viral infection (Table 8).
Viral infections have a central role, notably in immunosuppressed and immunologically naïve seronegative recipients of seropositive donor organs. Each virus produces a set of clinical syndromes or "direct effects" (e.g. fever, pneumonitis, hepatitis, leukopenia) as well as a variety of "indirect" or cellular effects including (1) local or systemic immunosuppression predisposing to subsequent opportunistic infections; (2) stimulation of innate immune responses that may augment alloreactivity; and (3) cellular proliferation including malignancies (posttransplant lymphoproliferative disorder [PTLD], anogenital cancers) and organ-specific injuries including accelerated atherogenesis (hearts) or chronic lung allograft dysfunction (CLAD) with bronchiolitis obliterans syndrome (lungs).[52,53]
Phase III: More Than 6–12 Months Posttransplant: Later posttransplant, recipients with satisfactory allograft function will tolerate reduced maintenance immunosuppression with lowered risk of infection. Healthy recipients suffer community-based epidemiological exposures including "viruses," foodborne gastroenteritis, or molds from work or gardening. Most clinicians have patients who decide to clean their attic (Aspergillus, Cryptococcus), muck out the barn (Rhodococcus equi, hantavirus), or explore the world (malaria, Salmonella sp., dengue). Occasionally, such patients will develop primary CMV infection (socially acquired) or infections related to underlying conditions (e.g. skin infections in diabetics). Some recipients will develop relapsing viral infection. In the past, and in regions without access to antiviral therapies, this was driven by CMV, HBV, HCV, and HIV. At present, major challenges include late CMV (occasionally with antiviral resistance), EBV (as PTLD), BK polyomavirus infection, and papillomavirus (anogenital cancers and warts).
Most attention is required by individuals with tenuous graft function with higher levels of maintenance suppression. These patients suffer recurrent infections (pancreatitis, cholangitis, abscesses, urinary tract infections, pneumonia) necessitating hospitalization and antimicrobial therapy. Attempts to reduce the intensity of immunosuppression provoke humoral and cellular graft rejection. They develop progressive colonization by antimicrobial-resistant flora including fungi, complications of therapy (e.g. C. difficile colitis, bleeding from graft biopsies), renal dysfunction (calcineurin inhibitor toxicity, sepsis, radiographic contrast exposure), and increased immunosuppression to "save" the graft. This subgroup of transplant recipients has been termed the "chronic ne'er-do-wells," and risk common opportunistic pathogens (e.g. P. jiroveci,L. monocytogenes,N. asteroides,Aspergillus species, or Cryptococcus neoformans) and more unusual infections (e.g. Listeria, Rhodococcus, Cryptosporidium, Microsporidium), molds (Scedosporium, agents of mucormycosis, Phaeohyphomycoses), and common diseases (herpes zoster, HSV) of unusual severity. Minimal clinical signs or symptoms merit careful evaluation in this group of "high-risk" individuals. This group may benefit from lifelong TMP-SMZ or prolonged antifungal prophylaxis.
American Journal of Transplantation. 2017;17(4):856-879. © 2017 Blackwell Publishing