Evaluation for infection before solid organ transplantation

INTRODUCTION — Solid organ transplantation is the therapy of choice for a variety of types of organ failure. Two major complications, infection and malignancy, are the result of the life-long immunosuppression needed to maintain allograft function.

The pretransplant evaluation identifies the risks of the transplant candidate for post-transplant infections and defines individualized preventative strategies including treatment of existing infections, prophylaxis, and vaccination. Thus, the evaluation focuses on exposure history, prior infections, serologic testing for distant exposures, cultures to identify colonization patterns, and administration of vaccines [1]. Active infections are also assessed close to the time of transplantation including HIV, hepatitis B and C, and severe acute respiratory syndrome coronavirus 2.

The components of the pretransplant evaluation will be reviewed here. The infections that follow solid organ transplantation are discussed in the following topics:

●(See "Infection in the solid organ transplant recipient".)

●(See "Prophylaxis of infections in solid organ transplantation".)

●(See "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients".)

●(See "Tuberculosis in solid organ transplant candidates and recipients".)

●(See "Infectious complications in liver transplantation".)

●(See "Bacterial infections following lung transplantation".)

●(See "Fungal infections following lung transplantation".)

●(See "Prevention of cytomegalovirus infection in lung transplant recipients".)

●(See "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients".)

●(See "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients".)

CAUSES OF INFECTION — The organisms commonly associated with post-transplant infection are the result of reactivation of latent infection carried by the donor organ or the recipient and/or following new exposures in the community or in the hospital [1-4]. Latent infection refers to organisms present in the intended recipient or in the donor tissue that are not causing disease. Cytomegalovirus, Epstein-Barr virus, Toxoplasma gondii, Strongyloides stercoralis, and Trypanosoma cruzi are examples of organisms that can exist in normal hosts and are, in general, controlled by the immune system. The risk for reactivation (replication) of such latent infections is related to the nature and intensity of the immune suppression following transplantation [5].

Established infection is more difficult to treat in the immunocompromised transplant recipient. Significant antimicrobial toxicities are common, often due to diminished renal or hepatic function and drug interactions. Thus, a pretransplant evaluation for infection is central to care and should be comprehensive. The evaluation targets:

●Identification and treatment of any active infection prior to transplantation

●Identification of latent infections and a prophylactic strategy to prevent reactivation following transplant

●Detection of pertinent colonization with multidrug-resistant organisms (MDROs) as a basis for perioperative antimicrobial management

●Gaps in vaccine-preventable infections, notably those requiring live vaccines or series of vaccinations (eg, measles, mumps, and rubella or hepatitis B virus)

Colonizing organisms are potential pathogens in the setting of immune suppression or acutely in the postoperative setting if acquired from the environment via vascular access catheters, endotracheal tubes, anastomotic leaks, fluid collections, or open surgical wounds [6-9]. Infections, when they occur, may manifest well after transplantation. Colonizing organisms may include antimicrobial-resistant organisms such as Pseudomonas aeruginosa, Aspergillus species, Stenotrophomonas maltophilia, Burkholderia cepacia, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci. Colonization with such resistant pathogens is common with:

●Multiple prior hospitalizations

●Multiple exposures to broad-spectrum antimicrobial agents

●Cystic fibrosis or other forms of chronic lung disease

●Cardiomyopathy with heart failure

●Cirrhosis often with ascites

●Those awaiting organ replacement with chronic organ dysfunction

MDROs including carbapenem-resistant Klebsiella pneumoniae and other gram-negative bacilli are increasingly common in solid organ transplant recipients [3,7,9-11]. The identification of such potential pathogens prior to transplantation allows perioperative prophylaxis and/or appropriate antimicrobial therapy if infection occurs. There is no consensus regarding optimal approaches to screening for MDROs prior to transplantation. Antimicrobial therapy should be based on in vitro susceptibility data and accompanied by debridement of foci of infections, such as infected hematoma or other fluid collections.

CLINICAL EVALUATION — The clinical evaluation of a patient prior to solid organ transplantation should focus on exposure history, history of prior infections, cultures for colonization, serologies for more distant exposures, and administration of vaccines [1].

History — Important elements of the pretransplant historical evaluation include:

●Travel to or residence in areas of the world with unique endemic infections (eg, S. stercoralis, Trypanosoma spp, Schistosoma spp, Leishmania spp, Histoplasma capsulatum, Coccidioides spp, Paracoccidioides spp, Brucella spp, hepatitis viruses, mycobacteria infections)

●Travel to or residence in areas with outbreaks of infection (eg, West Nile Virus, Zika virus, coronavirus disease 2019 [COVID-19], flooding after hurricanes)

●Animal exposures including cats, dogs, rodents, or birds

●Dietary exposures including well water, unpasteurized dairy products, or imported cheeses (eg, Cryptosporidium or Listeria monocytogenes)

●Employment and hobbies including exposures to soil, birds, and toxins (endemic fungi, nontuberculous mycobacteria)

●Potential or known exposure to tuberculosis (TB) and/or prior testing for TB

●Risk factors for HIV infection and other sexually transmitted infections

●Potential or known exposure to hepatitis viruses

●Presence of prosthetic material (eg, prosthetic joint, central venous catheters, pacemakers)

●Other active infections, prior infections, and conditions that may predispose to infection (eg, urinary tract infections, vesicoureteral reflux, herpes simplex infections, shingles, recurrent respiratory tract infections, diverticulitis, cholecystitis, hepatitis, peritonitis, tick bites, Salmonella or Toxoplasma infections)

●Surgical history (eg, splenectomy, sinus surgery, portasystemic shunting)

●Cardiac valvular abnormalities or vascular defects (aneurysms) or clots

●Malignancies, particularly those infectious in origin which can reactivate post-transplant (eg, anogenital carcinoma due to papilloma virus, nasopharyngeal carcinoma, or Burkitt lymphoma associated with Epstein-Barr virus)

●Drug and alcohol use

●Vaccination history

A thorough history of immunosuppressive therapies is essential. Use of immunosuppressive therapies in the pretransplant period can increase the risk of Pneumocystis jirovecii pneumonia, reactivation of TB, hepatitis B virus, histoplasmosis, cryptococcosis, or toxoplasmosis in the early post-transplant period. In addition, a history of recent immunosuppressive regimens such as glucocorticoids for systemic lupus erythematosus or chronic obstructive pulmonary disease, T cell or B cell depletion and immune modulators ("biologics") for rheumatologic disease or inflammatory bowel disease, or past treatment for malignancy can alter the choice and intensity of both prophylactic and immunosuppressive regimens after transplantation.

A careful review of systems should be performed to uncover current occult infection or colonization. All prior infections should be documented, including the antimicrobial susceptibility pattern of organisms previously isolated and any treatments received. In some cases, transplant candidates with recurrent infections such as cholecystitis, sinusitis, diverticulitis, and pyelonephritis may need to have these conditions resolved prior to transplantation.

Laboratory testing — Laboratory testing for evidence of past infectious exposures or active infections is performed to determine the risk for infection in the transplant recipient [1-3,12,13]. Some tests are suggested for all patients, whereas others are useful in selected patients with suggestive epidemiologic risk factors (table 1).

Serologic testing is used as an indicator of prior infections. Antibody-based tests (serologic tests) should not, in general, be used for the diagnosis of active infections since there may be a delay between pathogen exposure and seroconversion ("window period"). Nucleic acid amplification tests are used to detect and measure active infections in organ donors or recipients and generally will be positive earlier in infection compared with serologic assays.

Screening serologies for cytomegalovirus, herpes simplex virus, T. gondii, H. capsulatum, Coccidioides spp, and T. cruzi (Chagas disease) are used as guides for prophylactic strategies after transplantation rather than for pretransplant therapies. Other tests indicate needed (re-)vaccinations including hepatitis B virus, varicella zoster, measles, mumps, and rubella, diphtheria, pertussis, and tetanus. Epstein-Barr virus serologies are useful in stratifying the risk for post-transplant lymphoproliferative disorders, particularly among pediatric recipients and those treated with belatacept who are at higher risk [14]. (See "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients" and "Treatment and prevention of post-transplant lymphoproliferative disorders".)

Histoplasma and Coccidioides antibodies are insensitive for detecting latent infections. Therefore, negative serologies do not rule out latent infections with these pathogens. The risk of infection should be assessed for each patient based upon exposure history, reports of prior consistent symptomatic infections (eg, Valley fever), and findings of healed granulomas (eg, in the lungs and/or hilar lymph nodes), suggesting latent infection.

Viral load testing should be obtained for HIV, hepatitis B virus, and hepatitis C virus in infected candidates. Routine peritransplant prophylaxis for hepatitis B is advocated for unvaccinated liver transplant recipients with active infections. Decisions regarding the timing of hepatitis C virus therapy should be individualized based on disease activity and likely waiting time for liver transplantation. (See "Prophylaxis of infections in solid organ transplantation" and "Kidney transplantation in adults: Hepatitis B virus infection in kidney transplant recipients" and "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection" and "Hepatitis C virus infection in liver transplant candidates and recipients".)

Particular note must be made of TB testing (See 'Testing for latent tuberculosis' below.)

Patients with positive serologies for Strongyloides should be treated prior to transplantation. Empiric treatment (with or without serologic testing) for patients with possible prior exposure (eg, residence in an endemic area) is also common practice [14]. Ivermectin is the treatment of choice.

In endemic regions and in the appropriate season, donors and recipients may be screened for exposure to West Nile virus, Chagas disease, Zika virus, or other unique pathogens (table 1). (See "Tuberculosis in solid organ transplant candidates and recipients".)

Human T lymphotropic virus (HTLV)-1 may cause spastic paraparesis/myelopathy or adult T cell leukemia/lymphoma. HTLV-2, which is endemic in regions including the Caribbean and parts of Asia and Africa, is less clearly associated with these diseases and has been difficult to distinguish serologically from HTLV-1. As a result of the low rate of infection in the United States and poor testing options, mandatory screening for HTLV-1/-2 was discontinued in the United States in 2009 [15]. Rarely, donor-transmitted HTLV-1 infection has been identified with significant adverse outcomes in some individuals. HTLV-1 and -2 may be distinguished from one another using Western blot or nucleic acid testing. (See "Infection in the solid organ transplant recipient", section on 'HIV, HTLV, and hepatitis viruses'.)

Vaccinations — Prevention of infection through immunization is of paramount importance to the increasing population of solid organ transplant recipients [13]. Confirmation of vaccine status for hepatitis B virus, measles-mumps-rubella, hepatitis A virus, human papillomavirus, pneumococcus, and tetanus-diphtheria and pertussis, varicella zoster, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) should be obtained. Many immunocompromised patients are often unable to mount protective immune responses to vaccines. Live virus vaccines should be administered in advance of transplantation as immunosuppression may result in unchecked proliferation of attenuated vaccine strains and are generally avoided in solid organ transplant recipients. For these reasons, it is optimal to immunize patients prior to transplantation. Vaccine recommendations for solid organ transplant candidates and recipients are discussed in detail separately. (See "Immunizations in solid organ transplant candidates and recipients".)

Testing for latent tuberculosis — The incidence of TB in solid organ transplant recipients is 20 to 74 times higher than in the general population [16-21]. The vast majority of cases are due to reactivation disease, although transmission via a transplanted organ has been described [20,21].

There are two available tests used to screen for latent TB infection (LTBI): the tuberculin skin test (TST) and the interferon-gamma release assay (IGRA). Both tests are less sensitive in immunocompromised individuals. The frequency of indeterminate IGRAs is highest in liver transplant candidates. The IGRA is more often positive in renal transplant candidates than is the TST and has a greater association with risk factors for TB [22-25]. The predictive value in transplantation requires further study.

Radiographic changes on chest films can also be suggestive of prior exposure to TB.

Indications for prophylaxis include:

●Untreated LTBI (eg, positive TST or IGRA without evidence of active TB) or LTBI without documentation of adequate therapy

●A history of TB contact before transplantation

●Recipients of transplants from donors with a history of untreated TB

Patients who have completed a course of adequate therapy for TB do not need repeat prophylaxis unless they subsequently have one of the last two indications above. Therapy for latent TB should be initiated prior to transplantation but does not need to delay transplant.

Screening and treatment of latent TB in solid organ transplant candidates and recipients are discussed in detail separately. (See "Tuberculosis in solid organ transplant candidates and recipients".)

Active infections in the transplant candidate — Active bacterial and fungal infections must be eliminated or controlled, whenever possible, prior to transplantation. Even asymptomatic infections can evolve into overwhelming sepsis following transplantation. As an example, lung transplant candidates with cystic fibrosis will generally be colonized with organisms such as P. aeruginosa, S. aureus, and B. cepacia that are resistant to antimicrobial agents. Since manipulation of the infected lung tissue during transplantation might disseminate infection, perioperative bactericidal and fungicidal therapies are employed. Burkholderia cenocepacia appears to be a particularly virulent genomovar of B. cepacia. Management of lung transplant candidates and recipients who are colonized with this organism is discussed in greater detail separately. (See "Bacterial infections following lung transplantation", section on 'Burkholderia cepacia'.)

Eradication of infection is often not feasible for colonized lungs, hepatic abscesses, or bile leaks. Infection must be controlled to the degree possible prior to transplant surgery. Proceeding to transplant in the setting of active infection requires thorough consideration of the risks and benefits of transplantation. Prior to, or at the time of "activation" of the candidate on the transplant waiting list, the status of any active or pertinent past infections should be documented, including plans for reimaging with interventional sampling to assure drainage of infected fluids or repeat respiratory cultures.

As noted above, patients with an anatomic predisposition to infections, such as cholecystitis, diverticulitis, or recurrent aspiration (in lung transplant recipients), may benefit from pre-emptive surgery prior to transplantation. Patients with a history of recurrent sinusitis should be evaluated prior to transplantation for sinus infection by computed tomography and by an otolaryngologist who can obtain culture specimens from deep tissue and/or perform a drainage procedure if needed. As an additional example, patients with recurrent Clostridioides difficile infection may benefit from fecal transplantation prior to solid organ transplantation [26,27].

Whenever possible, all intravenous or urinary catheters should be removed prior to transplantation. Exceptions include hemodialysis or peritoneal dialysis catheters in the nonbacteremic patient and intra-aortic balloon pumps or intravascular ventricular assist devices. These should be removed, if possible, at the time of transplantation. In patients with liver failure awaiting transplantation, elective intubation may be performed to prevent aspiration. Baseline sputum cultures should be obtained (to document colonizing organisms) and active infections treated when possible. Antimicrobial prophylaxis against spontaneous bacterial peritonitis, generally with a fluoroquinolone agent, may be useful in patients with ascites after documentation of negative cultures [1,2]. (See "Spontaneous bacterial peritonitis in adults: Treatment and prophylaxis".)

Coronavirus disease 2019 — Organ donors and recipients require careful assessment for SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), prior to transplantation [28,29]. Immunosuppression is associated with more severe COVID-19 infection and, in the setting of steroid therapy, risk for bacterial and fungal superinfections. In addition, COVID-19 can induce a profound systemic inflammatory response, which could enhance the risk of graft rejection.

●Organ donors should be screened for COVID-19 prior to organ procurement. This is necessary for the safety of organ procurement teams as well as for the organ recipients. Protocols for screening deceased lung donors differ among institutions but often include screening from multiple sites. For example, screening by nasopharyngeal swab may be performed first and, if negative, followed by bronchoalveolar lavage sampling. (See "COVID-19: Issues related to solid organ transplantation", section on 'Donor screening'.)

●All candidates for transplantation should be vaccinated against SARS-CoV-2 prior to transplantation. Efficacy of vaccination is significantly reduced with immunosuppression. (See "COVID-19: Issues related to solid organ transplantation", section on 'Vaccination'.)

●Potential organ recipients should be screened for COVID-19 prior to transplantation. Individuals with symptoms of respiratory viral illness should, in general, be deferred for transplantation. Asymptomatic individuals recovered from COVID-19 infection with negative testing have undergone successful transplantation. Some centers use quantitative polymerase chain reaction testing with low viral loads (ie, high cycle thresholds) on respiratory specimens ) in asymptomatic recipients as a basis for transplantability. (See "COVID-19: Issues related to solid organ transplantation", section on 'Candidate screening'.)

Testing methods for COVID-19 are discussed separately. (See "COVID-19: Diagnosis", section on 'Diagnostic approach'.)

Perioperative prophylaxis — In the absence of specific data about colonization or infection due to resistant organisms in an individual patient, standard perioperative antimicrobial prophylaxis is administered for solid organ transplantation [30]. Regimens including vancomycin (except in cardiac transplant recipients) or clindamycin should be avoided whenever possible, to decrease the risk of colonization with vancomycin-resistant organisms and the latter to lessen the chance of developing diarrhea due to C. difficile postoperatively.

Generally, 24 hours or less of a first-generation cephalosporin provides adequate protection for renal transplantation in the absence of specific microbiologic data that would require broader coverage. In hepatic transplantation, coverage is generally employed for biliary and bowel flora including enterococci and anaerobic organisms, often in addition to antifungal prophylaxis. Perioperative antifungal prophylaxis with azole or echinocandin agents should be considered for patients with specific risk factors, including those requiring a Roux-en-Y loop, reoperation, and renal replacement therapy or for pancreas transplant recipients based upon the higher incidence of candidal infection in these hosts. Many centers with a significant rate of infection due to Aspergillus after liver or lung transplantation use perioperative prophylaxis with a lipid formulation of amphotericin B, inhaled amphotericin products (for lung transplant recipients), or later-generation azoles (voriconazole, posaconazole, isavuconazole). The azole antifungals have significant effects on the metabolism of calcineurin inhibitors and sirolimus; dose adjustments must be made during and after such therapies [31].

More detailed recommendations for the use of perioperative prophylaxis are presented separately. (See "Prophylaxis of infections in solid organ transplantation", section on 'Peri-transplantation prophylaxis'.)

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".)

SUMMARY AND RECOMMENDATIONS

●Important causes of infection – The organisms most commonly associated with post-transplant infection are the result of reactivation of latent infection carried by the donor organ or the recipient or are due to exposures in the community or in the hospital. (See 'Causes of infection' above.)

●Latent infections – Latent infection refers to organisms residing in tissues that is not causing active disease in the recipient or in the donor tissue. Cytomegalovirus, Epstein-Barr virus, Toxoplasma gondii, Strongyloides stercoralis, and Trypanosoma cruzi are examples of organisms that can exist in the normal host and are, in general, controlled by the host immune system. These pathogens may cause life-threatening infection in the immunocompromised host. The risk for reactivation of any latent infection is related to the nature and intensity of the immune suppression following transplantation. (See 'Causes of infection' above.)

●Colonizing organisms – Colonizing organisms may include antimicrobial-resistant organisms including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, carbapenem-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa, Aspergillus species, Stenotrophomonas maltophilia, and others. Multidrug-resistant organisms are important pathogens in transplantation. These organisms are potential pathogens in the setting of immunosuppression or acutely in the postoperative setting. (See 'Causes of infection' above.)

●Pretransplant evaluation – The pretransplant evaluation is central to the prevention of postoperative infection. The clinical evaluation of a patient prior to solid organ transplantation should focus on history of prior infections and relevant exposures, cultures for colonization, serologies for more distant exposures, and administration of vaccines. (See 'Clinical evaluation' above.)

●History-taking – History-taking should be comprehensive and detailed to uncover exposures to organisms that may be of importance in the immunocompromised host (eg, travel and residence history, pets, occupational and recreational exposures, high-risk behaviors). In addition, a careful review of systems may uncover current occult infection or colonization. (See 'History' above.)

●Laboratory testing – Laboratory testing for evidence of past infectious exposures is performed to detect asymptomatic infection in the transplant candidate. Some tests are suggested for all patients, whereas others are useful in selected patients with epidemiologic risk factors (table 1). Serologic testing is used as an indicator of significant past exposures; screening for cytomegalovirus, herpes simplex virus, varicella zoster virus, hepatitis viruses, HIV, and toxoplasmosis are used as guides for prophylactic strategies after transplantation. (See 'Laboratory testing' above.)

●Importance of pretransplant vaccination – It is optimal to immunize patients prior to transplantation. Vaccine recommendations for solid organ transplant candidates and recipients are discussed in detail separately. (See "Immunizations in solid organ transplant candidates and recipients".)

●Perioperative prophylaxis – Perioperative antimicrobial prophylaxis is used to prevent infection in the early post-transplant period. (See 'Perioperative prophylaxis' above and "Prophylaxis of infections in solid organ transplantation", section on 'Peri-transplantation prophylaxis'.)

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