Infection in the solid organ transplant recipient

INTRODUCTION — Solid organ transplantation has increased worldwide since the first successful human kidney transplant was performed in 1954. As immunosuppressive agents and graft survival have improved, infection and malignancy have become the main barriers to disease-free survival after organ transplantation. Due to the growing population of immunosuppressed patients with improved survival and with use of improved diagnostic tools, an increased incidence and spectrum of opportunistic infections has been observed [1-3]. Prevention of infection is the key to excellent outcomes. The pretransplant evaluation provides the data required for an individualized program of vaccination, prophylaxis, and surveillance in transplant recipients. (See "Evaluation for infection before solid organ transplantation" and "Prophylaxis of infections in solid organ transplantation" and "Immunizations in solid organ transplant candidates and recipients".)

The risks of infection and an overview of specific infections in the solid organ transplant recipient will be reviewed here.

The pretransplant evaluation for solid organ and hematopoietic cell transplant (HCT) recipients, prophylaxis of infections in solid organ transplant and HCT recipients, and an overview of infections following HCT are discussed separately. (See "Evaluation for infection before solid organ transplantation" and "Evaluation for infection before hematopoietic cell transplantation" and "Prophylaxis of infections in solid organ transplantation" and "Prevention of infections in hematopoietic cell transplant recipients" and "Overview of infections following hematopoietic cell transplantation".)

GENERAL PRINCIPLES — When a transplant recipient presents with an infectious syndrome, early, specific diagnosis and rapid, aggressive treatment are essential to optimal clinical outcomes.

●Potential etiologies of infection in these patients are diverse, including common community-acquired bacterial and viral diseases and uncommon opportunistic infections of clinical significance only in immunocompromised hosts [1,2]. Pulmonary processes can progress rapidly and may constitute medical emergencies [1]. These include infections due to Pneumocystis jirovecii (formerly P. carinii), Nocardia asteroides, Aspergillus spp, Cryptococcus neoformans, cytomegalovirus, varicella-zoster virus, community-acquired respiratory viruses (influenza, respiratory syncytial virus, severe acute respiratory syndrome coronavirus 2), or Legionella spp.

●Inflammatory responses associated with microbial invasion are impaired by immunosuppressive therapy, which results in diminished symptoms and muted clinical and radiologic findings. Fever is neither a sensitive nor a specific predictor of infection; up to 40 percent of infections cause no fever (especially fungal infections) and up to 22 percent of fevers are noninfectious in origin [4]. Infections are often advanced (ie, disseminated) at the time of clinical presentation.

●Altered anatomy following transplant surgery may change the physical findings associated with infection. Transplanted organs are denervated and lose normal lymphatic drainage. Diagnosis often requires anatomic data from imaging such as computed tomography scans or magnetic resonance imaging.

●Serologic testing is not generally useful for the diagnosis of acute infection in the immunocompromised host because seroconversion is often delayed or may not occur. Serologic assays may be used to identify latent infections and distant exposures as a basis for prophylaxis. Microbiologic cultures are supplemented by antigen-based tests (eg, enzyme-linked immunosorbent assays) or nucleic acid-based tests (nucleic acid amplification tests or metagenomic next-generation sequencing) for specific diagnoses.

●Tissue biopsies with histopathology and microbiology may be needed to make a specific microbiologic diagnosis in transplant recipients. Such clinical samples must be obtained early in the clinical course to enhance the chance for successful therapy, to minimize side effects of therapy, and before the patient's illness progresses to a point where such procedures can no longer be performed.

●The choice of antimicrobial regimens is often more complex than in other patients due to the urgency of therapy and the frequency of drug toxicities and drug interactions [5].

●Antimicrobial resistance is increased in immunocompromised hosts and should be considered in the choice of antimicrobial regimens.

●Surgical intervention is often necessary to cure localized infections (ie, debridement); antimicrobial agents alone are frequently inadequate.

●Drug levels provide a crude measure of immunosuppression; patients are often more or less immunosuppressed than anticipated. Side effects of these regimens are common; some side effects may mimic infection. Immune function assays are under development to guide management [6].

RISK OF INFECTION FOLLOWING TRANSPLANTATION — The risk of infection in the organ transplant patient is determined by the synergy between two factors: the epidemiologic exposures of the individual and the "net state of immunosuppression," which is a conceptual measure of all of the factors that contribute to the individual's susceptibility (or resistance) to infection [1,3,7].

Epidemiologic exposures — To adequately assess epidemiologic exposures, the clinician must take a detailed history of potential encounters with a variety of pathogens, even if the exposure was relatively remote. Latent pathogens are often activated in the setting of immune suppression. The epidemiologic exposures of importance to an individual will vary based upon the nature of the immune deficits. Most transplant patients have multiple deficits. Thus, bacterial and fungal pathogens are more important in the setting of neutropenia, while viral (eg, cytomegalovirus [CMV]) and intracellular (eg, tuberculosis) infections are more common with T cell immune deficits [8]. Strongyloides stercoralis may reactivate many years following transplantation [1,9]. (See "Evaluation for infection before solid organ transplantation".)

Community-acquired pathogens — The transplant recipient can have contact with potential pathogens within the community. These organisms include common respiratory viruses (influenza, parainfluenza, respiratory syncytial virus, adenovirus, human metapneumovirus, severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) and bacterial, viral, and parasitic gastrointestinal pathogens that may produce more persistent infections in these hosts (eg, with norovirus). Common bacterial pathogens include Staphylococcus aureus, Mycoplasma, Legionella, Listeria monocytogenes, and Salmonella. Vaccinations for pneumococcus, influenza virus, and SARS-CoV-2 are encouraged; they appear to reduce the severity of disease despite reduced immunogenicity in immunocompromised individuals. (See "Immunizations in solid organ transplant candidates and recipients" and "COVID-19: Issues related to solid organ transplantation", section on 'Vaccination'.)

In the appropriate geographic regions, endemic fungi (Histoplasma capsulatum, Coccidioides spp, Paracoccidioides spp, Blastomyces dermatitidis, Cryptococcus gattii) and common environmental pathogens (eg, Cryptococcus neoformans, Aspergillus spp, Cryptosporidia spp) will be observed. Thus, while specific infectious exposures within the community will vary based upon such factors as geography and socioeconomic status, the general dictum that "common things occur commonly" applies to transplant recipients. The severity and duration of infection and the frequency of multiple simultaneous processes are features that differentiate the transplant recipient from the normal host.

Reactivation of infections — Reactivated infection may be derived from the organ donor or the recipient. Common viral infections that frequently reactivate following transplantation include herpes simplex virus (HSV), CMV, varicella-zoster virus (VZV; shingles), hepatitis B (HBV) and hepatitis C (HCV), papillomavirus, and BK polyomavirus (BKPyV) [10,11]. Some exposures may have occurred many years before transplantation including geographically restricted systemic mycoses (eg, histoplasmosis, coccidioidomycosis, blastomycosis), Mycobacterium tuberculosis, S. stercoralis, Leishmania spp, or Trypanosoma cruzi [7,9,12-14].

An important goal of the pretransplant evaluation is to identify such latent infections and to develop a preventive strategy for each. (See "Evaluation for infection before solid organ transplantation".)

Nosocomial infections — Transplant recipients are vulnerable to nosocomial infections, especially in the early post-transplant (ie, postsurgical) period, particularly those with prolonged hospitalizations or who require mechanical ventilation. Common pathogens include:

●Gram-positive organisms, particularly antimicrobial-resistant species such as vancomycin-resistant enterococci and methicillin-resistant S. aureus

●Gram-negative bacilli such as Pseudomonas aeruginosa, multidrug-resistant gram-negative organisms, or Legionella spp

●Fungi such as Aspergillus spp and non-albicans or azole-resistant Candida species depending on the epidemiology of the institution [15]

●Clostridioides difficile colitis [16-18]

●Respiratory viral infections including influenza and SARS-CoV-2

When the air, food, equipment, or potable water supply either in the hospital or the home are contaminated, clusters of infection can occur.

Coronavirus disease 2019 — The clinical manifestations of SARS-CoV-2 infection in solid organ transplant recipients are highly variable. Adverse outcomes are largely determined by coexisting conditions (eg, diabetes, renal dysfunction), excess immunosuppression, and by development of coinfections due to fungi and antimicrobial resistant bacteria once intubated [19-23]. Leukopenia and lymphopenia are often marked. The management of solid organ transplant patients with coronavirus disease 2019 (COVID-19), particularly adjustment of the immunosuppressive regimen, must be individualized. Donor-derived SARS-CoV-2 infection is not yet described outside lung recipients. Viremia during COVID-19 infection is transient in most individuals (less than seven days) and transmission with extrapulmonary organs should be uncommon thereafter. Both organ donors and recipients should be screened prior to transplant [24,25]. (See "COVID-19: Issues related to solid organ transplantation".)

Donor-derived infections — Unanticipated infections that are derived from donor organs and activated in the recipient are among the most important exposures in transplantation [26-29]. Some of these infections are latent, while others are the result of bad timing (unappreciated active infection in the donor at the time of transplantation). The efficiency of the transmission of infectious diseases with viable tissues is enhanced by immunosuppression. In immunosuppressed hosts, classic signs of infections (eg, leukocytosis, erythema) may be replaced by nonspecific signs (eg, altered mental status, elevation of blood liver function tests, wound dehiscence, unexplained hypotension). As an example, in immunosuppressed hosts, the transmission of bloodborne or organ-derived infection due to West Nile virus more often manifests as neurologic disease with poor clinical outcomes than in immunocompetent hosts [30]. Clusters of infection associated with organ transplantation have also included M. tuberculosis, Candida and Aspergillus (and other fungal) species, HSV, human herpesvirus (HHV)-8, lymphocytic choriomeningitis virus (LCMV) [31], rabies virus [32], T. cruzi (causing Chagas disease), Balamuthia mandrillaris [33,34], Encephalitozoon cuniculi (causing microsporidiosis) [35], human immunodeficiency virus (HIV), and HCV.

Both living and deceased organ donors are screened to avoid transmission of certain infections to transplant recipients (table 1). Nonetheless, transmission of infection from donor to recipient may still occur (table 2). The data supporting transmission of the individual infections are discussed separately in the appropriate topic reviews for each infection.

Both deceased organ donors and living donors are tested for multiple potential pathogens; specific requirements for both serologic (antibody) and viral nucleic acid amplification testing (NAAT) for HIV, HCV, and HBV have been established [36]. Donor screening requirements for SARS-CoV-2 have also been established during the pandemic. (See "COVID-19: Issues related to solid organ transplantation", section on 'Pretransplantation screening'.)

Recipients of organs from donors known to be infected or considered at increased risk for transmission of HIV, HCV, and HBV or SARS-CoV-2 require informed consent prior to transplantation.  

Several types of donor infections merit special attention: bloodstream infections, unexpected infections that are accelerated by immunosuppression, and certain specific infections.

Bloodstream infection — Some donors may have active infection at the time of procurement. Certain pathogens (eg, staphylococci, pneumococcus, Pseudomonas, Candida, Salmonella, Escherichia coli) may "stick" to anastomotic sites (vascular, urinary, biliary, tracheal) and produce fever, bloodstream infections, or mycotic aneurysms. Proof of adequate therapy for such infections must be established prior to accepting organs for transplantation.

Unexpected infections accelerated by immunosuppression — Other donor-derived infections may be unusual (eg, West Nile virus, leishmaniasis, rabies, LCMV, Chagas disease, HIV, HSV) and may cause clinical syndromes that are accelerated by immune suppression.

As an example, LCMV occurred in the recipients of solid organ transplants from three different donors [31]. In the investigation of the first two clusters, LCMV was identified in tissues in all organ transplant recipients from both investigations [31]. The isolates from each investigation were identical to each other but distinct between the two outbreaks. In contrast, the common donors had no clinical or laboratory evidence of infection, although the donor from the 2005 cluster had a history of exposure to a pet hamster. Seven of eight transplant recipients died; one survivor was treated with ribavirin and decreasing immunosuppression. An epidemiologic investigation, using phylogenetic analysis of virus sequences, eventually traced the origin of these infections to an animal distribution center in Ohio.

Three patients in Australia who received a kidney or liver from a single donor died of a febrile illness with associated encephalopathy four to six weeks after transplantation [37]. High-throughput RNA sequencing from the allografts of two of the patients revealed an arenavirus that is related to LCMV. These results were confirmed by immunohistochemical analysis of allograft tissue as well as immunoglobulin (Ig)M and IgG antiviral antibodies from the serum of the donor. In addition, polymerase chain reaction revealed the presence of the virus in the kidneys, liver, blood, and cerebrospinal fluid of the recipients. The donor had just returned home from a three-month visit to rural areas of the former Yugoslavia.

CMV and EBV — Common viral infections such as those due to cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are associated with specific syndromes and morbidity in the immunocompromised population. The greatest risk for invasive infection is seen in recipients who are seronegative (immunologically naïve) and receive infected grafts from seropositive donors (latent viral infection). This risk constitutes the rationale for anti-CMV prophylaxis and EBV monitoring in organ recipients. (See "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients" and "Infectious complications in liver transplantation" and "Prevention of cytomegalovirus infection in lung transplant recipients" and "Approach to the diagnosis of cytomegalovirus infection".)

Tuberculosis and histoplasmosis — Late, latent infections including tuberculosis and histoplasmosis may activate many years after transplantation. Early emergence of tuberculosis in recipients has also been described after receiving organs from a donor with undiagnosed active infection [38].

Mycobacterial infection may be more difficult to treat after transplantation because of interactions between the antimicrobial agents used to treat infection (eg, rifampin, streptomycin, isoniazid) and immunosuppressive drugs [39].

The evaluation and management of tuberculosis in solid organ transplant recipients is discussed in detail separately. (See "Tuberculosis in solid organ transplant candidates and recipients".)

HIV, HTLV, and hepatitis viruses — In 2007, four recipients of organs from a single donor, who had died from trauma, were infected with both HIV and HCV. The donor had presumably been infected during the weeks prior to death since the antibody tests for these viruses were negative during the pretransplant donor screening. Subsequent cases of unexpected donor-derived HIV, HCV infections, as well as HBV infections, have been reported [36]. Transmission of these viruses typically occurs from high-risk donors with recently acquired infections (eg, during the "window period" prior to seroconversion).

The likelihood of tissue donors having viremia due to HBV, HCV, HIV, and human T lymphotropic virus (HTLV) was evaluated in 11,391 tissue donors to five tissue banks in the United States [40]. The estimated probability of viremia at the time of donation that would be undetected by screening with current serologic methods (because of the window period for infection) was 1 in 34,000 for HBV, 1 in 42,000 for HCV, 1 in 55,000 for HIV, and 1 in 128,000 for HTLV. The use of NAAT allows detection of viral nucleic acids prior to seroconversion and shortens the window period. NAAT was estimated to reduce the probabilities of viremia to 1 in 100,000 for HBV, 1 in 421,000 for HCV, and 1 in 173,000 for HIV. However, no available assays can completely exclude the risk of infectious transmissions, especially in the limited time available for deceased donor screening prior to transplantation [29].

The availability of directly acting antiviral agents (DAA) for HCV infection and highly active antiviral therapies for HIV infection have had a major impact on organ utilization. Organ transplantation from HIV-infected individuals to HIV-infected recipients can be performed safely by transplant teams experienced in HIV management. Organs from HCV-infected donors have been used in both HCV-infected and uninfected recipients with subsequent or pre-emptive DAA therapy [41-45]. In a prospective study of 44 HCV-uninfected heart and/or lung transplant recipients who received an organ from an HCV-infected donor, pre-emptive sofosbuvir-velpatasvir given for four weeks prevented the development of HCV infection in the recipients for the six-month follow-up period in all patients [44]. High rates of sustained virologic response with pre-emptive DAA use have also been reported in previous case series, one with a 12-month follow-up period [41-43,45].

Donor-derived HTLV infections with subsequent development of cutaneous T cell lymphoma [46] and, rarely, HTLV-I associated myelopathy/tropical spastic paraparesis have also been reported. Serologic screening of organ donors for HTLV is no longer required in the United States. This is discussed in detail separately. (See "Human T-lymphotropic virus type I: Virology, pathogenesis, and epidemiology", section on 'Tissue donation'.)

Net state of immunosuppression — The net state of immunosuppression is a conceptual assessment of the factors contributing to the risk for infection in an individual [47-53]:

●Type, dose, duration, and temporal sequence of immunosuppressive therapies (table 3)

●Underlying diseases or comorbid conditions

●Presence of devitalized tissues or fluid collections

●Invasive devices such as vascular access or urinary catheters, surgical drains, and ventricular assist devices

●Other host factors affecting immune function including neutropenia, hypogammaglobulinemia, and metabolic problems (eg, protein-calorie malnutrition, uremia, diabetes)

●Concomitant infection with immunomodulating viruses including CMV, EBV, HHV-6 and -7, HBV, and HCV

The sum of any congenital, acquired, metabolic, operative, and transplant-related factors is the patient's "net state of immune suppression." Multiple factors are usually present in each host. The impact of belatacept on the severity of viral infections, especially CMV, is notable. Viral infections are more difficult to suppress and more persistent with this agent. Conversely, insufficient immunosuppression may provoke acute graft rejection with the need for more intensive therapy and risk for reactivation of viral (eg, CMV, BKPyV) and fungal infections (eg, Aspergillus and Mucorales spp). The identification and correction of any modifiable risk factor is essential for the prevention and treatment of infection.

Immune competence may be measured crudely using cell counts, the frequency and severity of common infections (eg, herpes simplex virus), or the level of circulating viruses including CMV, EBV, or BKPyV [10,11]. Preliminary studies examining blood levels of torque teno virus (TTV), an anellovirus thought to be nonpathogenic, suggest an inverse correlation with TTV levels and immune function [54]. Nonspecific assays have been introduced to assess susceptibility to infection. Some are based on production of intracellular adenosine triphosphate in response to mitogenic stimulation or immune responses in response to antigenic stimulation of innate and adaptive immunity [6,55,56]. These assays have not yet been well validated prospectively for the ability to predict the risk for infection in individual transplant recipients. Advances in the assessment of T and B cell responses to specific pathogens, such as CMV, have been achieved using cell sorting technologies that measure the level of immune responses committed to specific pathogens [57-59].

TIMING OF INFECTION POST-TRANSPLANTATION — Immunosuppressive regimens vary among centers, with the organ transplanted, and the patient population. As an example, "induction" using T-lymphocyte depletion may be applied to renal transplantation from deceased donors but might not be used for living related donor transplants. Lung recipients or human leukocyte antigen-mismatched transplants may receive intensified immunosuppression including glucocorticoid therapy or plasmapheresis. For maintenance immunosuppression, most recipients receive a relatively standard combination of agents. (See "Kidney transplantation in adults: Induction immunosuppressive therapy" and "Kidney transplantation in adults: Maintenance immunosuppressive therapy" and "Maintenance immunosuppression following lung transplantation".)

Based on this background, the post-transplant course can be roughly divided into three time periods related to the risks of infection by specific pathogens: the early period post-transplant (first month), an intermediate period (one to six months), and more than six months (figure 1) [1]. As the full impact of immunosuppression accrues over time, the greatest risk for opportunistic infection is in the second, intermediate, period. Intensification of immune suppression for treatment of graft rejection (or in treatment of other processes such as coronavirus disease 2019 [COVID-19]) "resets the clock" to the initial period.  

This timetable is useful in three ways:

●In developing a differential diagnosis for the individual transplant recipient with clinical signs of infection

●As a clue to the presence of excessive environmental hazards (nosocomial, community, or individual)

●As a guide to the design of preventive antimicrobial strategies

Alterations in the type or intensity of immune suppression alters the risk of infection (table 3) and the differential diagnosis of infectious syndromes.

First month after transplantation — In the first month post-transplant, there are two major causes of infection in all forms of solid organ transplantation: pre-existing infection from either the donor or recipient and infectious complications of the transplant surgery and hospitalization. The major effects of exogenous immunosuppression are not yet evident. Exceptions include those patients who receive immunosuppression prior to transplantation (eg, for autoimmune hepatitis) and individuals with underlying immunodeficiencies.

Donor-derived infections — The risk for infections acquired with the allograft is discussed above (table 2) [27,28]. Recognition of donor organ-derived bacterial and fungal infections has increased with the transmission of antimicrobial-resistant strains including vancomycin-resistant enterococci, methicillin-resistant staphylococci, carbapenem- and multidrug-resistant gram-negative bacteria, and fluconazole-resistant Candida species [60]. Graft-associated viral infections (lymphocytic choriomeningitis virus, West Nile virus, rabies, HIV) and parasitic infections (toxoplasmosis, Chagas disease, B. mandrillaris) are uncommon but may be amplified in the immunosuppressed host. Endemic infections (eg, histoplasmosis or tuberculosis) should be considered in the differential diagnosis of post-transplant infection or unusual clinical syndromes (eg, encephalitis, hepatitis). (See 'Donor-derived infections' above.)

Recurrent infection — Infection may have been present in the donor organ or in the recipient prior to transplantation. An important component of the pretransplant evaluation is to recognize and treat such infections, if possible. (See "Evaluation for infection before solid organ transplantation".)

Some common viral infections (eg, hepatitis B virus [HBV], hepatitis C virus [HCV]) may re-emerge early after transplantation. Recipient-derived tuberculosis, nontuberculous mycobacteria, histoplasmosis, or toxoplasmosis tends to emerge more than a month after transplantation [61]. Reactivation of Strongyloides may be accompanied by gram-negative bacterial sepsis, meningitis, or pneumonia [9].

Infectious complications related to surgery — Solid organ transplant recipients develop many common postoperative complications, such as aspiration pneumonitis, surgical site (wound) infections, catheter-related bloodstream infections, urinary tract infection, or pulmonary embolus [62]. Transplant recipients are also at unique risk for superinfection of ischemic or injured graft tissues (eg, anastomotic suture lines) or of fluid collections (eg, hematomas, lymphoceles, pleural effusions, urinomas). These patients are at increased risk for infection associated with indwelling vascular access catheters, urinary catheters, and surgical drains. Anastomoses (urinary, biliary, tracheal, vascular) are uniquely susceptible to ischemia, leaks, and obstruction and should be assessed early in the post-transplant infectious evaluation.

The organisms responsible for such postoperative complications are often the bacteria and fungi that have colonized the recipient or donor (eg, the lungs and/or sinuses in cystic fibrosis) prior to transplantation or the local flora of the hospital. Colonization acquired prior to transplantation may include relatively resistant nosocomial pathogens (eg, vancomycin-resistant enterococcus) and pathogens such as Aspergillus spp that are resistant to the usual agents used for surgical prophylaxis. Patients receiving antimicrobial agents are at increased risk for C. difficile colitis.

Transplant patients at increased risk for nosocomial infection are those requiring prolonged ventilatory support or those with diminished lung function, persistent ascites, stents of the urinary tract or biliary ducts, or with intravascular clot or ischemic graft tissue [51,63]. Individuals with delayed graft function or who require early re-exploration or retransplantation are also at increased risk for infection, notably with fungi or bacteria with antimicrobial resistance.

Bloodstream infections — Bacteremia is more common in solid organ transplant recipients than in other hosts and usually occurs in association with intravascular catheters or surgical site, pulmonary, or other focal infections. In a case-control study, the mortality rate due to bacteremic sepsis appeared to be lower in solid organ transplant recipients compared with nontransplant patients at 28 days (hazard ratio [HR] 0.22, 95% CI 0.09-0.54) and at 90 days (HR 0.43, 95% CI 0.20-0.89) [64]. In a retrospective cohort study of patients with sepsis, solid organ transplant recipients had a lower rate of mortality than nontransplant patients [65]. The association was seen in all types of transplant recipients except lung transplant recipients, who had a higher rate of mortality, and heart transplant recipients, in whom there was no difference. It is postulated that the lower rate of mortality in solid organ transplant recipients may result from blunting of the inflammatory response to infection by immunosuppression or more aggressive management for hospitalized transplant recipients.

One to six months after transplantation — In the period one to six months post-transplant, the nature of common infections changes. The effect of immunosuppression is often maximal, and patients are at greatest risk for the development of opportunistic infections. However, residual problems from the perioperative period can persist. There is significant geographic and institutional variation in the occurrence of opportunistic infections during the first six months post-transplantation. This reflects local epidemiology, varying immunosuppressive strategies, and the specific antimicrobial prophylaxis used in the post-transplant period. Prevention of common infections observed during this period is the basis of prophylactic antimicrobial strategies. Prophylaxis delays but does not eliminate the risk for infections that may occur in the months following cessation of prophylaxis. Some of these infections then occur later after completion of prophylaxis. (See "Prophylaxis of infections in solid organ transplantation".)

Major infections due to opportunistic pathogens include:

●P. jirovecii (formerly P. carinii) pneumonia. (See "Fungal infections following lung transplantation", section on 'Pneumocystis jirovecii'.)

●Viral pathogens, particularly cytomegalovirus (CMV) and the other herpes viruses (ie, Epstein-Barr virus, human herpesvirus [HHV]-6, -7, and -8 [Kaposi's sarcoma-associated herpesvirus]) (table 4). HBV and HCV infections may emerge if untreated. BK polyomavirus [10,11] is particularly important in kidney recipients. Community-acquired respiratory viruses are important in this population (influenza, parainfluenza, respiratory syncytial virus, adenovirus, metapneumovirus, severe acute respiratory syndrome coronavirus 2).

●Latent infections, such as the protozoal diseases including strongyloidiasis, toxoplasmosis, Chagas disease, and, less commonly, leishmaniasis [7,49,50,66,67].

●The geographic or endemic fungal infections caused by H. capsulatum, Coccidioides spp, Paracoccidioides spp, and, rarely, Cryptococcus spp or B. dermatitidis. (See "Fungal infections following lung transplantation".)

●Tuberculosis and, increasingly, nontuberculous mycobacteria [8,68]. (See "Tuberculosis in solid organ transplant candidates and recipients" and "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients".)

●Gastrointestinal parasites (Cryptosporidium and Microsporidium) and viruses (CMV, norovirus) may be associated with persistent diarrhea [69].

●Urinary tract infections, particularly in renal transplant recipients. (See "Urinary tract infection in kidney transplant recipients".)

More than 6 to 12 months after transplantation — Six to 12 months or longer post-transplant, most patients are receiving stable and reduced levels of immunosuppression. These patients are subject to community-acquired pneumonias due to respiratory viruses, the pneumococcus, Legionella, or other common pathogens.

"Late CMV" may emerge in patients who received prophylaxis for the first three to six months [70,71]. New strategies are emerging to prevent late infections including extending prophylaxis or monitoring of either pathogen-specific immune function or global immune function as a guide to infectious risk [6,58]. CMV infection may also develop in patients treated for graft rejection.

Patients who have less than adequate graft function may require higher-than-usual immunosuppressive therapy. As a result, they represent a subgroup of transplant patients at highest risk for opportunistic infections including P. jirovecii pneumonia, cryptococcosis, and nocardiosis. They are also at risk for severe illness from community-acquired infections due to influenza or L. monocytogenes. Prolonged antimicrobial prophylaxis may be indicated for this subgroup of patients. This group of patients may also suffer uncommon infections in the late transplant period with atypical clinical presentations. These infections include the molds or Nocardia or Rhodococcus species, unusual viruses (eg, JC virus-associated progressive multifocal encephalopathy), or virus-associated malignancies (post-transplant lymphoproliferative disorder or squamous cell cancers of the skin or anogenital region). (See "Prophylaxis of infections in solid organ transplantation".)

VIRUSES AS COPATHOGENS — Viruses, particularly cytomegalovirus (CMV), serve as important cofactors for many opportunistic infections [1,47,48]. The potential effects of viral infection are diverse and apply not only to CMV but also to hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), and probably to other common viruses such as respiratory syncytial virus (RSV), human herpesvirus (HHV)-6, and adenovirus (table 4). Viruses contribute to a variety of processes post-transplantation [1,11,48,51,72,73].

Direct effects — "Direct effects" include virus-specific clinical syndromes such as fever and neutropenia (CMV), pneumonitis (respiratory viruses), hepatitis (HCV, HBV), gastritis, esophagitis, colitis (CMV), cholangitis (varicella-zoster virus [VZV]), encephalitis (herpes simplex virus [HSV], JC virus), pancreatitis, myocarditis, and retinitis. Less common syndromes include adrenalitis with adrenal insufficiency (CMV) or meningoencephalitis due to CMV vasculitis.

Indirect effects — "Indirect effects" reflect expression of proinflammatory pathways in infected cells as well as depression of scavenger receptors and other defense mechanisms [74]. The manifestations include (table 5):  

●Immune suppression and predisposition to opportunistic infection (eg, Aspergillus after CMV infection or RSV pneumonia, Pneumocystis after CMV infection). Thus, CMV coinfection has been implicated in the accelerated course of HCV infection with cirrhosis and graft loss and of EBV with increased risk for post-transplant lymphoproliferative disorder (PTLD; usually B cell lymphoma).

●Graft rejection that is thought to be mediated by proinflammatory cytokine release and/or upregulation of histocompatibility antigens or adhesion proteins in the setting of CMV reactivation [11,75,76]. Graft rejection may necessitate an increase in the immunosuppressive regimen and an increased risk for opportunistic infection.

●Oncogenesis – Many viruses predispose to cancer (HCV, EBV) or to cellular proliferation (CMV and accelerated atherogenesis, BK polyomavirus [BKPyV] [10,11], and ureteric smooth muscle cell proliferation).

Specific viral pathogens — The spectrum of viral infections in the transplant recipient is broad (table 4):

●BKPyV has been associated with infection of renal allografts with asymptomatic viruria, interstitial nephritis, smooth muscle proliferation with ureteric obstruction, and rising creatinine values in renal transplant recipients [10,11,77,78]. Hemorrhagic cystitis is uncommon. (See "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections".)

●Adenovirus may cause hemorrhagic cystitis but is more often associated with hepatitis (notably in liver recipients), pneumonia, or a sepsis syndrome diagnosed by culture or antigen detection or molecular testing. (See "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection".)

●HHV-6, -7, and -8 have also been identified in transplant recipients [79] (see "Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection" and "Human herpesvirus 7 infection" and "Human herpesvirus-8 infection"). HHV-6 has been implicated as a cofactor in CMV infection (and vice versa) or may cause leukopenia and fever as part of a viral syndrome. The role of HHV-7 remains to be clarified.

●EBV, VZV, and HSV are often activated during this one- to six-month period. EBV may be associated with the development of B cell non-Hodgkin lymphoma, particularly in seronegative recipients of seropositive organs. However, cases of T cell, NK cell, null cell, and non-EBV-related PTLD occur and have a worse prognosis than B-cell malignancy (see "Treatment and prevention of post-transplant lymphoproliferative disorders"). PTLD may present within the allograft or central nervous system or as extranodal disease. Herpes zoster (shingles) may occur; occasionally, patients present with cholangitis due to VZV. Human papillomavirus is associated with anogenital and squamous cell cancers.

●Parvovirus B19 may also present in this period with anemia unresponsive to erythropoietin or with myocarditis [80]. Parvovirus B19 has also been associated with chronic allograft injury in renal transplant recipients.

●Respiratory viruses remain important community-acquired pathogens, particularly in the lung transplant recipient [81]. Infections with these latter viruses predispose the patient to the development of bacterial infections and graft rejection. (See "Viral infections following lung transplantation".)

●Viruses that have been reported rarely in solid organ transplant recipients include human T lymphotropic virus, hepatitis E virus, rabies virus, lymphocytic choriomeningitis virus, measles, mumps, dengue, orf, and human coronaviruses HKU1 and NL63. Most of these were infections derived from asymptomatic organ donors.

EVALUATION AND MANAGEMENT — The pursuit of diagnostic testing and the management of infection in a transplant recipient must be guided by a few principles:

●These hosts have fewer clinical manifestations of infection and diminished findings by conventional radiography. Thus, more sensitive imaging techniques such as computed tomographic scans, magnetic resonance imaging, or positron emission tomography scanning are essential for assessing the presence and nature of infectious and malignant processes.

●The "gold standard" for diagnosis is specific microbiology and/or tissue histology. No radiologic finding is sufficiently diagnostic to obviate the need for clinical samples. Multiple simultaneous infections are common. Thus, invasive procedures that provide tissues or fluids for culture and histology must be employed as a routine component of the initial evaluation of transplant recipients with infectious syndromes. Patients failing to respond to appropriate therapy may require invasive diagnostic procedures.

●Serologic tests, which indicate past exposure to certain pathogens, are useful in the pretransplant setting to assess risk for disease activation with immunosuppression but are not as useful after transplantation. Patients receiving immunosuppressive therapies do not reliably develop antibodies during an active infection to enable serologic diagnoses. Thus, quantitative tests that directly detect the protein products or nucleic acids of the organisms such as enzyme linked immunosorbent assays, direct immunofluorescence, or quantitative molecular assays (nucleic acid amplification tests) should be utilized.

●Transplant recipients are often colonized and vulnerable to infection by antimicrobial resistant organisms from the hospital environment or selected by exposure to antimicrobials. Surgical sites with residual blood or devitalized tissues are uniquely susceptible to such infections and should be sampled to guide specific therapy, notably at times of clinical deterioration.

●Infections of undrained fluid collections or blockage or leaks of anastomoses will prevent resolution of infection. Antibiotics, used in lieu of definitive drainage or debridement, merely delay clinical deterioration and promote the acquisition of resistant microorganisms. Early debridement of such collections is essential.

●Some components of the immunosuppressive regimen may be modified during acute infection to elicit an improved host response [82]. This must be done with caution since reductions in immunosuppression may provoke immune reconstitution syndromes or allograft rejection.

Infectious disease consultation improves outcomes in solid organ transplant recipients. As an example, in a study of solid organ transplant recipients admitted with an infection, infectious disease consultation was associated with reduced 28-day mortality (hazard ratio 0.33) and 30-day rehospitalization rates (17 versus 24 percent) [83]. The median length of stay and hospitalization costs did not differ between patients who received an early infectious disease consultation (<48 hours) and those who did not.

The evaluation for infection prior to solid organ transplantation is discussed separately. (See "Evaluation for infection before solid organ transplantation".)

FUTURE DIRECTIONS — Many important hurdles remain in the diagnosis and treatment of infections in solid organ transplantation. Initiation of a diagnostic evaluation for infection generally begins when clinical symptoms appear, which may be late in the course of disease in immunocompromised patients. Specific microbiologic diagnoses are needed to optimize therapy and to avoid unnecessary toxicities. Invasive diagnostic procedures are often required to make an accurate microbiologic diagnosis.

More advanced, quantitative laboratory assays utilizing molecular techniques or antigen detection are integral components of transplant care. Such tests may be prohibitively costly for routine use. Rapid, quantitative, cost-effective assays that do not depend upon invasive procedures are needed for the routine monitoring of transplant patients for infections and for graft rejection. Assays measuring pathogen-specific immunity are increasingly used to guide prophylactic strategies; global measures of immune function are not yet in routine clinical use. Such tests would allow the clinician to individualize prophylactic antimicrobial regimens and minimize drug-associated toxicity. Advanced radiologic techniques (functional magnetic resonance imaging or positron emission tomography scanning) are increasingly deployed.  

The evolution of pathogens (bacteria, viruses, fungi) with resistance to common antimicrobial agents and the incidence of drug toxicity and allergy have limited available antimicrobial options for transplant recipients. The introduction of newer therapies (eg, directly acting antivirals for hepatitis C virus, highly active antiviral therapy for HIV, newer agents for cytomegalovirus and severe acute respiratory syndrome coronavirus 2) have dramatically altered clinical practice. New antimicrobial agents are needed for prophylaxis and therapy.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infections in solid organ transplant recipients" and "Society guideline links: Urinary tract infections in solid organ transplant recipients".)

SUMMARY

●Identification of risk factors – The risk of infection in the organ transplant patient is determined by the synergy between two factors: the epidemiologic exposures of the individual and the "net state of immunosuppression," which is a conceptual measure of all of the factors that contribute to the individual's susceptibility (or resistance) to infection. The identification and correction of any modifiable risk factor is essential for the prevention and treatment of infection. (See 'Risk of infection following transplantation' above and 'Epidemiologic exposures' above and 'Net state of immunosuppression' above.)

●Time course of infection – Dividing the post-transplant course into three time periods related to the risks of infection by specific pathogens is a useful starting point for differential diagnosis of infectious syndromes: the early period post-transplant (first month), an intermediate period (one to six months), and more than 6 to 12 months (figure 1). The timing of the presentation of infectious processes will be altered (delayed) by the deployment of antimicrobial prophylaxis and individual risk factors. Prophylaxis may result in the delayed presentation of infection (eg, "late cytomegalovirus [CMV] infection"). (See 'Timing of infection post-transplantation' above.)

•In the first month post-transplant, the major causes of infection in all forms of solid organ transplantation include infection derived from either the donor or recipient and infectious complications of the transplant surgery and hospitalization. (See 'First month after transplantation' above.)

•The period one to six months post-transplant is the period when patients suffer the greatest impact of immunosuppression and are at the greatest risk for the development of opportunistic infections. Virally mediated infections are common. Patterns are altered by prophylaxis. (See 'One to six months after transplantation' above.)

•Six to 12 months or longer post-transplant, most patients are receiving stable and reduced levels of immunosuppression. These patients are subject to community-acquired infections, including pneumonias due to respiratory viruses, the pneumococcus, Legionella, or other common pathogens. (See 'More than 6 to 12 months after transplantation' above.)

●Important viral pathogens – Viruses, particularly CMV, serve as important cofactors to many opportunistic infections. The potential effects of viral infection are diverse and apply not only to CMV but also to hepatitis B virus, hepatitis C virus, Epstein-Barr virus, and probably to other common viruses such as respiratory syncytial virus, human herpesvirus-6, and adenovirus (table 4 and table 5). (See 'Viruses as copathogens' above.)

●Net state of immunosuppression – The sum of any congenital, acquired, metabolic, operative, and transplant-related factors is the patient's "net state of immune suppression." Multiple factors are usually present in each host. In addition, certain medications are associated with specific types of infection (eg, belatacept with severe viral infections, glucocorticoids with fungal infections). At the same time, insufficient immunosuppression may provoke graft rejection with the need for intensive antirejection treatment and the risk of reactivation of viral and fungal infections. (See 'Net state of immunosuppression' above.)

●Principles of evaluation and management – The pursuit of diagnostic testing and the management of infection in a transplant recipient must be guided by several principles:

•These hosts may have nonspecific clinical manifestations of infection and few or no findings by conventional radiography. Thus, more sensitive imaging techniques such as computed tomography scans, magnetic resonance imaging, or positron emission tomography scans are necessary.

•Specific microbiologic diagnoses are important to avoid drug toxicities and interactions and to enhance care. Tests that detect pathogen-specific proteins or nucleic acids are important to transplant management.

•Serologic tests, which indicate past exposure to pathogens, are useful in the pretransplant setting to assess the presence of latent disease but are not generally useful for acute diagnosis after transplantation.

•Transplant recipients are often colonized by organisms resistant to antimicrobial agents from the hospital environment or selected during antimicrobial therapy.

•When undrained fluid collections, blood, or devitalized tissues are present, antimicrobial therapy alone is inadequate. Early and aggressive surgical debridement of such collections is essential for successful care. (See 'Evaluation and management' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kieren A Marr, MD, who contributed to an earlier version of this topic review.