Version May 2024
INTRODUCTION — Solid organ transplant recipients are considered to be at "high risk" for developing infection; individual risk is determined by a relationship between the epidemiologic exposures of the individual and the patient's "net state of immunosuppression" [1,2]. The successful prevention of infection in the solid organ transplant recipient requires an understanding of these factors to develop an individualized preventive strategy. (See "Evaluation for infection before solid organ transplantation" and "Infection in the solid organ transplant recipient".)
Epidemiologic exposures may have occurred many years before transplantation or at any point following the transplant procedure. The range of pathogens to which patients are exposed has increased as transplantation has become available to a broader range of individuals with more varied epidemiologic exposures and as transplant recipients survive longer, remaining on lifelong immunosuppression. Thus, clinicians must obtain a detailed history of encounters with potential pathogens, even if the exposure was relatively remote [3,4].
The use of antimicrobial agents for prophylaxis varies by the disease being targeted for prevention and the nature of the recipient's risks. Strategies include universal prophylaxis and pre-emptive therapy:
●Universal prophylaxis involves giving an antimicrobial agent to all patients considered to be at increased risk for infection during a defined period. For example, in many programs trimethoprim-sulfamethoxazole (TMP-SMX) is given to all transplant recipients who do not have sulfa allergies for the prevention of Pneumocystis pneumonia which occurs in up to 10 percent of organ recipients; TMP/SMX also helps prevent infections with other pathogens, including Listeria monocytogenes and Toxoplasma gondii [5,6]. (See 'Pneumocystis pneumonia' below.)
●Pre-emptive therapy involves using sensitive assays (eg, antigen detection or nucleic acid testing) to monitor patients at predefined intervals to detect infection (eg, cytomegalovirus [CMV] deoxyribonucleic acid [DNA] in the blood or DNAemia) before infection progresses to invasive disease. A positive assay triggers the initiation of antimicrobial therapy, a reduction in the intensity of immunosuppression, and/or intensified monitoring. Pre-emptive therapy incurs extra costs for monitoring and coordination of outpatient care as well as clinical effects of episodes of viremia but reduces drug exposures and avoids some of the costs and toxicities of prophylactic antiviral therapy.
●Hybrid approaches that include some period of prophylaxis and subsequent monitoring are also common for individuals at increased risk for infection or who are unable to comply with monitoring or intolerant of prophylaxis. Thus, following T cell-depleting antibody-induction therapies, many recipients receive some period of antiviral prophylaxis for CMV followed by a period of monitoring. This approach may be employed for the CMV seronegative organ recipient who receives an organ from a seropositive donor (D+/R-) or the seropositive recipient (R+).
PRETRANSPLANT PROPHYLAXIS — Before transplantation, it is important to establish the patient's immunization history, travel history, and prior infectious exposures to design an appropriate preventive strategy.
Laboratory testing — Laboratory testing for evidence of past infectious exposures is performed to detect asymptomatic infection in the transplant candidate. Some tests are recommended for all patients, while others are useful in selected patients with suggestive epidemiologic risk factors (table 1). Testing is required prior to transplantation for all recipients in the United States including human immunodeficiency virus (HIV) antibody/antigen assay, Hepatitis B virus (HBV) surface antigen, core antibody, and surface antibody, Hepatitis C virus (HCV) antibody, and HIV, HBV, and HCV nucleic acid testing. (See "Evaluation for infection before solid organ transplantation".)
Serologic testing is used as an indicator of significant past exposures, and, in some cases (eg, cytomegalovirus serostatus), the results are used to guide prophylactic strategies after transplantation. In other cases, the results are used to guide pretransplant immunizations or therapy. These issues are discussed in detail separately. (See "Evaluation for infection before solid organ transplantation", section on 'Laboratory testing' and "Immunizations in solid organ transplant candidates and recipients".)
During the coronavirus disease 2019 (COVID-19) pandemic, routine screening of organ donors and recipients for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was recommended. Screening is typically still performed for deceased donors, most notably lung donors during bronchoalveolar lavage (BAL), and symptomatic living donors are tested. In potential recipients, COVID-19 infection and SARS-CoV-2 viral shedding must, in general, be resolved in advance of organ transplantation. Each center will determine a protocol for such potential recipients. Assays used in viral diagnosis and serologic tests for the detection of prior infection are discussed elsewhere. (See "COVID-19: Issues related to solid organ transplantation", section on 'Pretransplantation screening'.)
Immunizations — Prevention of infection through immunization is of great importance [7,8]. Optimally, transplant candidates should be immunized before transplantation because they are less likely to mount a protective immune response once immunosuppressed following transplantation. Immunization with live virus vaccines is generally avoided post-transplant (and near to time of transplantation) as it may result in unchecked proliferation of attenuated vaccine strains. The safety and efficacy of these vaccines in selected transplant recipients is understudy [9]. (See "Immunizations in solid organ transplant candidates and recipients".)
Vaccine recommendations for solid organ transplant candidates and recipients are discussed in detail separately. (See "Immunizations in solid organ transplant candidates and recipients".)
Screening for latent tuberculosis — In one compilation of published cases, the incidence of tuberculosis (TB) in transplant recipients worldwide ranged from 0.35 to 15 percent, which reflected an 8- to 100-fold increased incidence over the general population in the represented countries [10,11]. Reactivation of latent disease following immunosuppression is thought to be the dominant factor in the pathogenesis of infection in these hosts, although transmission with the allograft, nosocomial transmission, and community-acquired TB have been documented in solid organ transplant recipients. The presentation of TB in immunocompromised hosts is often atypical (eg, meningitis), emphasizing the importance of screening.
Given the high morbidity associated with TB in the post-transplant setting, all patients listed for organ transplantation should undergo tuberculin skin testing (TST) or TB interferon-gamma release assays [4,10-14]. In addition to TST, baseline chest radiographs should be obtained for an epidemiologic history suggestive of exposure to TB. For patients with uremia, liver failure, and for those who have received corticosteroids or other immunosuppressive therapies, TST must be interpreted according to the more sensitive standards developed for patients with HIV infection.
T cell-based interferon-gamma release assays, such as the QuantiFERON Gold TB (QFT-G) assay, are a useful alternative to TST with a high degree of concordance between TSTs and the QFT-G assay [15,16]. Although some studies have suggested that QFT-G correlates better with the risk of TB in immunocompromised patients than the TST, data remain limited [15], and false-negative results have been reported for both tests [17]. In a study of liver transplant candidates, indeterminate QFT-G results were more likely in those with more advanced liver disease [16]. (See "Tuberculosis in solid organ transplant candidates and recipients", section on 'Screening' and "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)
Pretransplant antituberculous prophylaxis or therapy should be provided for solid organ transplant candidates with the following specific indications:
●Tuberculin reactivity of ≥5 mm before transplantation
●History of tuberculin reactivity without adequate prophylaxis
●Recent conversion of TST to positive
●Radiographic evidence of old TB without prior prophylaxis; a chest computed tomographic scan should be performed in these patients to look for disseminated disease and to serve as a baseline study
●History of inadequately treated TB
●Close contact with an individual with active pulmonary TB
●Receipt of an allograft from a donor with a history of untreated TB
The risk of infection relates to the intensity and temporal proximity of exposure. Individuals from endemic regions for TB with positive skin tests or radiologic evidence of prior disease merit therapy. Individuals with prior Bacille Calmette-Guérin (BCG) therapy should be followed expectantly without therapy unless prior disease or recent exposure is suspected.
If possible, therapy should be provided prior to transplantation. Patients may receive one of a variety of regimens for the treatment of latent TB infection [18]. The routine use of antituberculous prophylaxis after transplantation remains controversial but is generally provided to anyone with high risk of active infection including regions with high endemicity.
Treatment after transplantation is frequently compromised by drug toxicities and interactions with immunosuppressive therapies. Isoniazid or pyrazinamide hepatotoxicity, for example, may be intolerable after liver transplantation. Rifampin will significantly reduce the serum level of calcineurin inhibitors and of glucocorticoids, effects that persist for several weeks after cessation of therapy. This observation suggests that treatment regimens that include rifampin should be completed two to four weeks before transplantation, whenever possible. Regimens that include the fluoroquinolones and rifabutin are available as alternative treatments for latent TB in organ transplant recipients; drug interactions may still occur with these alternative regimens.
The evaluation and management of TB in lung transplant candidates and recipients are discussed in detail separately. (See "Tuberculosis in solid organ transplant candidates and recipients".)
Microbial colonization — Assessment of microbial colonization patterns can be used to guide peritransplant prophylaxis for bacteria (eg, methicillin-resistant Staphylococcus aureus, vancomycin- or daptomycin-resistant Enterococcus, carbapenem-resistant Enterobacteriaceae) [19]. Available microbiologic data should be reviewed prior to transplantation. Some data may be available from prior microbiologic evaluations (eg, microbiology from bronchoscopic evaluations or endoscopic retrograde cholangiopancreatography [ERCP]) or prior infections (eg, Clostridioides [formerly Clostridium] difficile colitis). Individuals with active chronic infections should have infecting organisms identified and susceptibility testing performed prior to transplantation to help guide peritransplant prophylaxis. (See 'Peri-transplantation prophylaxis' below.)
Treatment of active or recurrent infections — Because infections are more difficult to treat following transplantation when patients are immunosuppressed, any active infection identified prior to transplantation should be treated when possible. Similarly, patients with recurrent infection or anatomic predispositions to infection (eg, recurrent aspiration or diverticulitis) may require additional care prior to transplantation.
As examples, patients with recurrent C. difficile infection may benefit from fecal transplantation [20-22]; patients with diverticulitis may benefit from pre-emptive surgery prior to transplantation. (See "Evaluation for infection before solid organ transplantation", section on 'Active infections in the transplant candidate'.)
PERI-TRANSPLANTATION PROPHYLAXIS — As with nontransplant surgeries, solid organ transplant recipients are vulnerable to infectious complications of the surgical procedure, most commonly bacterial and fungal infections. Accordingly, perioperative antimicrobial prophylaxis should be used in accord with institutional protocols. Specific prophylactic regimens are tailored to the organ transplanted and individualized based on the recipient's unique risks.
Antibacterial prophylaxis — Standard surgical antibiotic prophylaxis is recommended for all organ transplant procedures. The unique technical features of transplantation (vascular, ureteric, tracheal, biliary anastomoses) predispose to leaks (hematoma, bile leak, lymphocele), which are common sites of infection. As an example, the risk of peritoneal soilage is great in individuals undergoing liver transplantation with Roux-en-Y biliary drainage or with bile leaks following split or live donor liver transplants. Other risk factors for bacterial infections after liver transplantation include large-volume blood transfusions, treatment of graft rejection with glucocorticoids, and cytomegalovirus (CMV) infection [23,24]. If the patient is colonized with methicillin-resistant S. aureus (MRSA) or vancomycin-resistant Enterococcus (VRE), perioperative prophylaxis should be expanded to cover the resistant organisms. Active infections must be eradicated or controlled prior to transplantation.
Pretransplant colonization with multidrug-resistant organisms (MDRO), such as MDRO gram-negative bacteria, MRSA, and VRE, is associated with higher rates of peritransplant infections and recurrent infections [25-29]; surgical complications, such as anastomotic leaks or bleeding amplify the impact of infection with such organisms. In endemic areas, a 3 to 10 percent incidence of carbapenem-resistant Klebsiella pneumonia infection is reported in liver, kidney, lung, or heart recipients [25]. Carbapenem-resistant Enterobacteriaceae (CRE) carry a mortality rate of up to 40 percent once established in organ recipients [30]. Many bacterial infections in lung transplant recipients involve the lower respiratory tract (bronchitis and pneumonia) and occur in the first two weeks post-transplant. Patients with chronic bronchiectasis and those with cystic fibrosis, who are colonized with resistant gram-negative bacteria including Pseudomonas and Burkholderia species, present a dilemma with regard to increased risk of lung transplantation. Some centers consider colonization with Burkholderia cenocepacia [31] or pan-resistant Pseudomonas species a contraindication to transplantation.
No consensus exists for the management of patients colonized with resistant gram-negative organisms during the peritransplant period. Decolonization strategies have proven effective in preventing infections in some studies [32-35]. Peritransplant prophylaxis for MDRO merits study. Each transplant center typically develops antibiotic prophylaxis protocols based upon the susceptibility patterns of the organisms most frequently recovered at that center. Prophylactic regimens should be individualized based on recipient colonization patterns and organisms identified from donor cultures. Often these data become available only after transplantation. Serial microbiology data post-transplantation are used to refine therapy.
Infections of ventricular-assist devices and chest tubes are often due to gram-positive organisms (staphylococci, enterococci) or Candida species, which should be identified, and susceptibility testing used to guide therapy before and after transplant. Drains and vascular access catheters must be removed as quickly as is feasible. Broad-spectrum antimicrobial prophylaxis (including antifungal agents) is generally reserved for the perioperative management of intestinal and pancreas transplants; routine use of broad-spectrum antimicrobial therapy increases the risk of C. difficile colitis and superinfection with resistant fungal organisms.
Antifungal prophylaxis — The incidence of invasive fungal infections (IFIs) following solid organ transplantation ranges from 3 to 42 percent and varies with the organ being transplanted and the epidemiology at individual centers. In general, incidence tends to be highest in lung and liver transplant recipients and lowest in cardiac and renal transplant recipients [36].
Candida and Aspergillus species are the leading causative agents, with the median time to onset following transplantation depending on the type of transplant [37-41]. These infections are associated with high overall mortality rates [42-48]. As an example, a multicenter retrospective study of 1963 cardiac, heart-lung, and lung transplant recipients in Italy reported fungal infections in 51 patients (2.6 percent) occurring at a median of 58 days post-transplantation [49]. Aspergillus and Candida spp accounted for 64 and 23 percent of the cases, respectively, with mortality rates of 29 and 33 percent, respectively.
Generally, transplant centers develop institution-specific strategies for the prevention of fungal infections based on the incidence and nature of fungal infections observed at their institutions. Data support the use of prophylaxis for Aspergillus in liver and lung transplant recipients and for Candida species in lung, liver, bowel, and pancreas transplant recipients [50-57]. (See "Fungal infections following lung transplantation", section on 'Prophylaxis'.)
Targeted antifungal prophylaxis — Given the potential for drug interactions and toxicities of antifungal agents and the risk for emergence of resistance, strategies for antifungal prophylaxis should target patients with increased risks for IFI. Targeted antifungal prophylaxis is effective for high-risk lung, pancreas, and liver transplant recipients, including those with known fungal colonization and those at increased risk for IFIs due to technical complications following surgery [50-56]. In liver recipients, risk factors for IFI and criteria for antifungal prophylaxis vary among studies but generally include:
●Renal replacement therapy and hepatic dysfunction
●Bile leaks and anastomotic strictures [50]
●Living donor transplantation
●Large blood transfusion requirements
●Prolonged intensive care unit (ICU) stays
●CMV infection [40,58]
●Additional surgery post-transplant including laparotomy and retransplantation
●Known fungal colonization pretransplant
●Prolonged, broad-spectrum antimicrobial use
●Prolonged use of total parenteral nutrition
●Active hepatitis C virus infection
There are few data available on the impact of pretransplant treatment on post-transplant risk for IFI [59,60]. In general, lung transplant recipients receive antifungal prophylaxis because of their overall high risk of IFIs [36]. Major risk factors for IFI in lung recipients include cystic fibrosis (in the recipient), mold colonization, acute and/or chronic graft rejection, CMV infection, hypogammaglobulinemia, primary graft dysfunction, and airway stenting. (See "Fungal infections following lung transplantation".)
In pancreas transplantation, the risk of contamination (at procurement) or anastomotic leaks at exocrine drainage sites create the need for some period of anti-Candida prophylaxis using echinocandin or fluconazole [61,62]. Enteric drainage of the pancreas predisposes to Candida infection. Similarly, small bowel transplants with colonic segments may transmit yeast infections.
In endemic regions, long-term antifungal prophylaxis may be given to some solid-organ transplant recipients to prevent the reactivation of pulmonary and extrapulmonary disease due to Coccidioides immitis and Coccidioides posadasii, Histoplasma capsulatum, and Cryptococcus neoformans. However, clinical trials supporting the routine use of antifungal prophylaxis outside of lung transplantation and in regions or institutions with high intrinsic rates of fungal infection are lacking.
In programs with a high incidence of infection due to Aspergillus, Histoplasma, or Candida species, both epidemiologic protection (eg, high-efficiency particulate air filtered air supply within the hospital, meticulous cleaning of operating rooms and ICUs) and antifungal prophylaxis (as appropriate to the common isolates) may be utilized [63-66]. (See 'Choice of regimen' below and "Infectious complications in liver transplantation" and "Fungal infections following lung transplantation".)
The approaches to antifungal prophylaxis discussed above are generally similar to available clinical practice guidelines [36,67,68]. The 2016 Infectious Diseases Society of America and 2019 American Society of Transplantation guidelines recommend targeted prophylaxis for individuals at increased risk for Aspergillus infection, such as all lung transplant recipients and selected recipients of other organs who are deemed to be at increased risk based upon institutional epidemiology and individual risk factors [67,69]. The 2015 International Society for Heart and Lung Transplantation guidelines for lung transplantation recommend anti-mold prophylaxis in lung recipients with a history of mold colonization in donor or recipient (up to 76 percent of patients with cystic fibrosis and 21 to 40 percent for other patients) or other factors outlined above [36]. The 2019 American Society of Transplantation guidelines for the management of candidiasis in solid organ transplant recipients recommend fluconazole (400 mg daily) OR a lipid formulation of amphotericin B (3 to 5 mg/kg intravenously daily) as postoperative antifungal prophylaxis for liver, pancreas, and small bowel transplant recipients at high risk of IFIs [68]. The echinocandins (anidulafungin, micafungin) also appear to be effective for antifungal prophylaxis in solid organ transplant recipients [62,70], and, unlike amphotericin B, are not nephrotoxic. Echinocandins are a reasonable choice for antifungal prophylaxis, although breakthrough Candida infections have been reported in lung recipients [57]. Weekly administration of a lipid formulation of intravenous amphotericin B or reduced-dose lipid amphotericin B may also be an option [71].
Choice of regimen — None of the available antifungal agents are ideal for all indications for post-transplant prophylaxis. In addition to the organ being transplanted, the selection of a specific antifungal agent should consider the epidemiology of fungal infections at the transplant center, the potential for drug interactions (both at the initiation and cessation of therapy) with the immunosuppressive regimen, and the side effect profiles of the drugs, particularly hepatotoxicity with azoles. Gaps in antifungal coverage should be noted for the echinocandins and azoles. Echinocandins have no activity against Mucorales molds or Cryptococcus species; fluconazole, itraconazole, and voriconazole have no activity against Mucorales molds. Lower-risk patients at centers without significant incidence of IFI may use fluconazole or echinocandins perioperatively [51-55].
Specific antifungal prophylaxis recommendations for lung and liver transplant recipients are discussed in detail separately. (See "Fungal infections following lung transplantation" and "Infectious complications in liver transplantation", section on 'Prevention of fungal infections'.)
Antifungal agents — Agents used for antifungal prophylaxis include the following:
●Fluconazole – Fluconazole appears to be safe and has not been associated with hepatotoxicity following liver transplantation; it can be used as prophylaxis against susceptible Candida species and reduces invasive infections in such patients [56,72].
Fluconazole does not have activity against filamentous fungi. In addition, some Candida species are intrinsically resistant (ie, Candida krusei) while others have relatively high minimum inhibitory concentrations (ie, Candida glabrata) to the drug. Drug interactions with calcineurin inhibitors are variable but will increase these drug levels in most patients. Similarly, serum calcineurin inhibitor levels will fall when prophylaxis is discontinued; dose readjustment is essential to prevent graft rejection.
●Itraconazole – Itraconazole capsules have poor oral bioavailability and should not be relied upon in the critically ill patient after transplantation. The itraconazole suspension has better oral bioavailability, but trials to date have failed to demonstrate the efficacy of the oral solution for the prevention of invasive aspergillosis [73]. Some centers continue to use itraconazole for the prevention of fungal infection after lung transplantation [36].
Itraconazole levels should be obtained to assure absorption. Efficacy of the intravenous formulation as prophylaxis awaits testing in clinical trials. Significant drug interactions with calcineurin inhibitors result in levels increased two- to fourfold over baseline.
●Voriconazole – Voriconazole was approved by the US Food and Drug Administration (FDA) for the treatment of aspergillosis, scedosporiosis, and fusariosis in 2002. This azole offers broader filamentous mold activity than either fluconazole or itraconazole but has no activity against the agents of mucormycosis. No multicenter trial examining the prophylactic use of voriconazole in the solid organ transplant population has been performed. Drug levels should be obtained to assure absorption. As with the other azoles, voriconazole is a significant inhibitor of the cytochrome P450 enzymes. Of note, coadministration of voriconazole and sirolimus is contraindicated due to these interactions [74]. Significant drug interactions with calcineurin inhibitors result in levels three- to fivefold over baseline in most patients. Adverse effects associated with voriconazole use include dose-related hepatoxicity, QT prolongation, and increased rates of skin cancers in immunosuppressed patients [75]. (See "Pharmacology of azoles", section on 'Selected clinical effects'.)
●Posaconazole – Posaconazole was approved for prophylaxis in high-risk hematopoietic cell transplantation recipients and is used for antimold prophylaxis in heart and lung recipients at some centers. Optimal use for therapy and prophylaxis is solid organ transplantation is not yet well defined. QT prolongation may be significant and may be affected by other concurrent medications. Drug levels should be obtained to assure absorption.
●Isavuconazole – Isavuconazole is a triazole antifungal approved in 2015 for the treatment of invasive aspergillosis and invasive mucormycosis [76]. This agent is used for antimold prophylaxis in lung recipients at some centers. Like posaconazole, optimal use in therapy and prophylaxis in solid organ transplantation have not yet been defined. QT prolongation is less frequent with this agent. Drug levels should be obtained to assure absorption.
●Amphotericin B – Lipid formulations of amphotericin B are used at some centers for the prevention of fungal infections but may be associated with nephrotoxicity, notably in individuals receiving calcineurin inhibitors or with diminished renal function at baseline. Several studies have demonstrated the failure of low-dose regimens as prophylaxis for invasive aspergillosis [77,78], and such therapies should be used with caution.
Studies evaluating aerosolized amphotericin B (including lipid formulations) for Aspergillus prophylaxis in lung transplant recipients have demonstrated safety and efficacy for short-term prophylaxis [57,79-83]. (See "Fungal infections following lung transplantation", section on 'Inhaled amphotericin B'.)
●Echinocandins – There are four FDA-approved echinocandins with similar spectra of antifungal activity (caspofungin, micafungin, anidulafungin, and rezafungin). In an open-label randomized trial that compared micafungin with center-specific standard care (fluconazole, liposomal amphotericin B, caspofungin) in high-risk liver transplant recipients, similar rates of clinical success (defined as absence of proven/probable IFI and no need for additional antifungals) were observed with micafungin and standard care (98.6 versus 99.3 percent) [70]. In another study in which anidulafungin was compared with fluconazole in high-risk liver transplant recipients, the overall rate of IFIs was similar in both groups (5 versus 8 percent) [62]. There was a trend toward a reduction in Aspergillus colonization or infection in the anidulafungin group compared with the fluconazole group (3 versus 9 percent). These agents are not inducers or inhibitors of the cytochrome P450 enzymes. In patients with mild and moderate hepatic impairment, caspofungin area under the curve (AUC) is increased about 20 and 75 percent, respectively; there is no clinical experience with this agent in patients with severe hepatic insufficiency. Cyclosporine moderately increases the AUC of caspofungin and elevations in hepatic transaminases were noted in healthy subjects when the drugs were administered concomitantly. In liver transplant recipients, caspofungin may increase transaminase levels with or without coadministration of calcineurin inhibitors [84]. These drugs are available in intravenous formulations only. (See "Pharmacology of echinocandins and other glucan synthesis inhibitors".)
The pharmacology of these antifungal agents is discussed in greater detail separately. (See "Pharmacology of azoles" and "Pharmacology of amphotericin B" and "Pharmacology of echinocandins and other glucan synthesis inhibitors".)
POST-TRANSPLANT PROPHYLAXIS — Following transplantation, recipients are vulnerable to nosocomial infections, especially in the early post-transplant period. Patients with prolonged hospitalizations or who require mechanical ventilation are at particularly high risk. The infections commonly encountered in the first month after transplantation are caused by the nosocomial pathogens that infect other complex postoperative patients. Ninety-five percent of these infections are due to bacterial and fungal agents. However, the difficulty in eradication of such infections is increased in the immunocompromised host.
Pneumocystis pneumonia — Pneumocystis jirovecii (formerly Pneumocystis carinii) is a ubiquitous organism and common fungus that is a well-known cause of pulmonary disease in the immunocompromised host [6]. Prior to the use of trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, the incidence of infection was 10 to 15 percent in most programs and was reported to be as high as 70 to 88 percent in the lung transplant population [44,85]. The effectiveness of prophylaxis against Pneumocystis pneumonia (PCP) has virtually eliminated the organism as a cause of significant morbidity in solid organ transplantation [86]. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)
The usual dose of TMP-SMX is one single-strength tablet a day or one double-strength tablet three to seven times a week. The distinct advantages of TMP-SMX prophylaxis include low cost, low toxicity in most individuals, and efficacy in the prevention of many common urinary, respiratory, and gastrointestinal infections as well as most, but not all, infections due to Toxoplasma, Listeria species, and Isospora belli. TMP-SMX may also provide some protection against infection with Nocardia spp, although breakthrough infections have been reported. As an example, in a case-control study of solid organ transplant recipients with nocardiosis, 24 (69 percent) of 35 case patients were receiving TMP-SMX for PCP prophylaxis [87]. Successful prevention of infections other than PCP requires daily dosing.
Prophylaxis should be continued for six months to one year; many renal and liver programs use less. Extending the duration of PCP prophylaxis beyond one year may be warranted for lung transplant recipients, for patients receiving continued higher degrees of immunosuppression, or for those with persistent infections, such as CMV reactivation or recurrent respiratory infections [88]. Programs with an increased incidence or clusters of PCP may want to extend routine prophylaxis.
Daily TMP-SMX is preferred for PCP prophylaxis because of its broad antimicrobial protection (including Toxoplasma, Listeria, and many Nocardia species), ease of administration, low cost, and tolerability [89]. Thus, another agent (daily fluoroquinolone) must be added to atovaquone for antibacterial activity when desired (eg, for urinary tract infection prophylaxis in a renal transplant recipient). This may be of greatest importance in renal and lung transplant recipients where the early incidence of postoperative bacterial infections is high.
History of "allergy" to TMP-SMX may be misleading, and allergy testing is often worthwhile. Sulfonamide hypersensitivity is occasionally reported as a basis for renal or liver toxicity [90,91]. Patients with true hypersensitivity reactions to sulfa-containing medications may be given dapsone, inhaled pentamidine, or atovaquone as alternatives for PCP prophylaxis [86]. Atovaquone dosage should be 1500 mg by mouth once daily, as solid organ transplant recipients receiving lower doses have been documented to have breakthrough infection [86,92]. We generally advise patients to take atovaquone with fatty foods (eg, milk) to increase its absorption.
Toxoplasmosis — Toxoplasmosis is an uncommon but highly morbid infection after transplantation. Given that cysts of T. gondii are commonly found in muscle tissues (as well as brain and phagocytic cells), the greatest risk for toxoplasmosis occurs after cardiac transplantation. The highest-risk group for symptomatic reactivation disease occurs in seronegative recipients of heart transplants from seropositive donors; the risk in this group in the absence of prophylaxis is approximately 50 to 75 percent [3]. Toxoplasma infection presents most often as myocarditis or cardiomyopathy but also as brain abscess, pneumonitis, empyema, or disseminated infection. Disease may occur at any time post-transplantation, with a median time to presentation of two months; up to 10 percent have reactivation in the first post-transplant month [93]. Although uncommon, toxoplasmosis has also been transmitted by liver, kidney, and lung transplantation. Organ-transmitted disease is generally more severe than that due to reactivation of latent infection in the recipient. The risk of disease reactivation appears to be increased by use of lymphocyte-depleting induction therapy [94].
Prevention of toxoplasmosis has not been well studied. In general, seronegative recipients of seropositive cardiac transplants receive at least 12 months of prophylaxis, although lifetime prophylaxis is preferred at many centers [95]. One retrospective study suggests that TMP-SMX at a dose of one double-strength tablet three times per week is sufficient for both Pneumocystis and Toxoplasma prevention in cardiac transplant recipients [96]. Other centers use lower-dose regimens or add pyrimethamine to TMP-SMX in high-risk (donor Toxoplasma seropositive and recipient seronegative) combinations [97,98]. Lower-dose regimens provide less effective protection in such combinations, notably in seronegative cardiac transplant recipients from endemic regions (eg, France, the Caribbean islands) [3]. The risk of disease in seropositive recipients of heart transplants from seropositive donors is uncertain, but lifetime prophylaxis with at least one single-strength tablet of TMP-SMX daily may be beneficial.
Most alternative regimens (sulfadiazine, dapsone, atovaquone, clindamycin in combination with pyrimethamine or primaquine) have not been well studied in high-risk transplant populations. Atovaquone or dapsone alone have been effective for prevention of Pneumocystis and Toxoplasma. Breakthrough infections have been observed with dapsone at doses of 50 mg daily, and 100 mg doses may be preferred; testing for glucose-6-phosphate dehydrogenase deficiency is required [3]. The clindamycin-pyrimethamine regimen has also been used successfully as an alternative if intolerant of TMP-SMX.
Streptococcus pneumoniae — Immunocompromised individuals have a high incidence of infection due to Streptococcus pneumoniae with diminished susceptibility to penicillin; many of these isolates are also resistant to TMP-SMX. Thus, transplant candidates should receive pneumococcal vaccination prior to transplant surgery unless they were vaccinated previously based upon the underlying illness, such as chronic pulmonary disease. Specific recommendations for pneumococcal vaccination in solid organ transplant candidates and recipients are discussed in greater detail separately. (See "Immunizations in solid organ transplant candidates and recipients", section on 'Pneumococcus'.)
Viral infections — Viral infections are among the most common complications of immune suppression after solid organ transplantation. The use of antiviral agents should be linked to the intensity of immune suppression and to the risk of the individual for disease.
Influenza — Vaccination remains the primary method of preventing and controlling influenza and continual changes in viral antigens necessitates annual revision and administration of the influenza vaccine [99,100]. The intramuscular inactivated influenza vaccine should be given to solid organ transplant recipients. The intranasal live-attenuated influenza vaccine should not be given to solid organ transplant recipients. (See "Seasonal influenza vaccination in adults" and "Immunizations in solid organ transplant candidates and recipients", section on 'Influenza'.)
Antiviral prophylaxis is indicated under certain circumstances, such as in solid organ transplant recipients who have been exposed to an individual with suspected or confirmed influenza infection. Specific recommendations regarding antiviral prophylaxis are reviewed elsewhere. (See "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention".)
Cytomegalovirus — Cytomegalovirus (CMV) is the most common opportunistic pathogen following solid organ transplantation and is an important cause of morbidity and mortality. CMV may be acquired from the donated allograft, blood products transfused from a seropositive donor, or reactivation of endogenous virus. Once CMV infection is acquired, it persists as a latent infection for the lifetime of the host.
Most CMV disease occurs between one and four months after transplantation in the absence of antiviral prophylaxis. Increasingly, CMV disease is recognized later, in the period following cessation of prophylaxis. Patients at highest risk for CMV disease are those who are seronegative for CMV (immunologically naive) and receive an allograft from a seropositive donor (D+/R-) and those with latent CMV infection who require treatment with antilymphocyte antibodies as a part of induction therapy or following intensification of immunosuppression for graft rejection. Asymptomatic infection is common in both the D+/R- combination and seropositive recipients [101].
Universal prophylaxis with valganciclovir or ganciclovir is a common approach to prevention of CMV reactivation in at-risk patients (eg, CMV-seropositive recipients and recipients with CMV-seropositive donors, notably after T-lymphocyte depletion). The duration of antiviral therapy generally ranges from 3 to 12 months and often depends on the type of organ transplanted, the specific risk status of patient, and individual institutional practice [101,102]. Letermovir prophylaxis has also been shown to be effective in preventing CMV disease and is a reasonable option for patients who cannot tolerate valganciclovir or ganciclovir [103,104]. In a phase-3 randomized controlled trial of over 500 D+/R- renal transplant recipients, letermovir prophylaxis was noninferior to valganciclovir prophylaxis for prevention of CMV disease through 52 weeks post-transplant (10.4 versus 11.8 percent, -1.4 percent difference, 95% CI -6.5 to 3.8 percent) but had a significantly lower rate of leukopenia or neutropenia (26 versus 64 percent) compared with valganciclovir [103]. If letermovir is used, a second drug is required to prevent other herpesviruses (HSV, VZV). Many transplant centers prefer to use a pre-emptive approach (eg, routine CMV viral load monitoring within initiation of treatment when reactivation becomes evident) for specific patient populations; this approach may be as effective as universal prophylaxis [102]. (See "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients" and "Prevention of cytomegalovirus infection in lung transplant recipients" and "Infectious complications in liver transplantation" and "Infectious complications in liver transplantation", section on 'Cytomegalovirus'.)
The efficacy of targeted anti-CMV prophylaxis in patients at highest risk for CMV reactivation (ie, CMV-seronegative recipients with CMV-seropositive donors) is well documented [101,105,106]. A systematic review of 19 randomized controlled trials of CMV prophylaxis in 1981 solid organ transplant recipients demonstrated the following [105]:
●Compared with placebo, prophylaxis with acyclovir, ganciclovir, or valacyclovir significantly reduced the risks of CMV disease (relative risk 0.42, 95% CI 0.34-0.52), CMV infection (relative risk 0.61, CI 0.48-0.77), and all-cause mortality (relative risk 0.63, CI 0.43-0.92). The reduction in mortality was primarily due to lower mortality from CMV disease.
●For CMV-related disease and mortality, the relative benefits of ganciclovir, high-dose acyclovir, and valacyclovir were consistent across recipients of heart, kidney, and liver transplants and occurred in both CMV-positive and CMV-negative recipients of seropositive organs. These results were irrespective of the type of immunosuppression given. No conclusions could be drawn for CMV-negative recipients of CMV-negative organs (D-/R-). Patients considered at lower risk for CMV infection (D-/R-) should receive antiviral prophylaxis for herpes simplex virus and varicella-zoster virus with acyclovir, valacyclovir, or famciclovir.
●In the subset of direct comparison treatment trials, ganciclovir was more effective than acyclovir; high-dose valganciclovir and intravenous ganciclovir were as effective as oral ganciclovir.
A subsequent meta-analysis of 17 universal prophylaxis trials and 9 pre-emption trials demonstrated that both prophylaxis strategies were equally effective in reducing the incidence of CMV disease [107]. However, only universal prophylaxis affected patient survival and reduced graft rejection and reduced the incidence of post-transplant opportunistic infections and post-transplant lymphoproliferative disorder (PTLD) [106,107].
Oral valganciclovir and intravenous ganciclovir treatment are associated with similar long-term outcomes in solid organ transplant recipients with CMV syndrome and tissue-invasive CMV disease based on randomized trials in adult renal, liver, heart, and lung transplant recipients [108,109]. Thus, these are the preferred drugs for CMV prophylaxis. High-dose oral acyclovir and valacyclovir have also been used successfully in some centers. However, the oral bioavailability of these drugs is limited, the required pill burden is high, and efficacy data supporting their use are limited.
Issues related to CMV prophylaxis in specific transplant settings are discussed separately. (See "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients" and "Prevention of cytomegalovirus infection in lung transplant recipients" and "Infectious complications in liver transplantation", section on 'Cytomegalovirus'.)
Epstein-Barr virus — Epstein-Barr virus (EBV) is associated with PTLD. PTLD occurs in approximately 1 percent of transplants and ranges in severity from "benign" polyclonal lymphocytosis to highly malignant lymphomas. The optimal strategy for the prevention of PTLD has not been established, although lesser degrees of immunosuppression appear to lower the risk. Excess rates of PTLD have been observed with belatacept maintenance immunosuppression, notably in EBV seronegative recipients and children. Routine monitoring should be performed for higher risk patients (D+/R- for EBV and all children). (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)
Herpes simplex and varicella-zoster — Patients who are not receiving valganciclovir or ganciclovir CMV prophylaxis (ie, patients who are seronegative for CMV and received an allograft from a CMV-seronegative donor) should receive prophylaxis against herpes simplex virus and varicella-zoster virus during the first three to six months after transplantation and during periods of lymphodepletion for treatment of rejection. Herpes zoster vaccination is recommended pretransplant, notably in those at greatest risk for zoster and for post-herpetic neuralgia. An adjuvanted subunit vaccine is available for use in transplant recipients. Newer anti-CMV agents (ie, letermovir, maribavir) lack activity against HSV and VZV. (See "Vaccination for the prevention of shingles (herpes zoster)" and "Immunizations in solid organ transplant candidates and recipients".)
Hepatitis B virus — The hepatitis B virus vaccine is recommended for all individuals prior to transplantation. Accelerated schedules for vaccination have been developed for healthy travelers but do not appear to produce an adequate immune response in transplant candidates [110,111]. (See "Immunizations in solid organ transplant candidates and recipients", section on 'Hepatitis B'.)
Among infected patients, hepatitis B virus (HBV) can be reactivated after transplantation. Immunosuppression can amplify HBV DNA, and steroid therapy may have a direct stimulatory effect on an enhancer region of the viral genome [112,113]. This issue is particularly important in two settings: liver transplant recipients, in whom the graft is the primary site of HBV infection, and in renal transplant recipients, as many chronic dialysis patients are hepatitis B surface antigen (HBsAg) positive.
●Among liver transplant recipients, preventive therapy is given to reduce the risk of reinfection of the graft. Ideally, HBV-infected recipients should be on a nucleotide analogue reverse-transcriptase inhibitor with an undetectable or unquantifiable viral load prior to transplant. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients".)
●If the patient is on tenofovir or entecavir prior to transplantation and has experienced effective HBV suppression, the pretransplant antiviral agent should be continued after transplantation. If the recipient is lamivudine experienced, tenofovir should be used due to the high rate of entecavir resistance in lamivudine-experienced patients.
●For patients with renal insufficiency, entecavir is generally preferred over tenofovir. Concerns among renal transplant recipients are deterioration of the liver and worse renal allograft survival. (See "Kidney transplantation in adults: Hepatitis B virus infection in kidney transplant recipients".)
Transmission of HBV may occur with HBsAg-positive donors and in livers from donors with documented anti-hepatitis B core antibody. A review from the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database identified 23 liver transplants from isolated anti-hepatitis B core antigen (anti-HBc)-positive donors [114]. Eighteen developed HBV infection compared with only 3 of 651 from anti-HBc-negative donors. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients", section on 'Strategies to prevent HBV reinfection'.)
Transmission of HBV is uncommon when kidneys from anti-HBc-positive donors are used in this setting, and these donor organs are frequently transplanted to expand the pool of available kidneys, hearts, and lungs [115]. All recipients should be immunized against HBV prior to transplantation.
Given the availability of vaccination and effective therapies for HBV, transplantation of organs from HBV-infected donors may be considered on an individual basis. These donors are generally not viremic but are anti-HB core antibody positive.
OTHER CONSIDERATIONS
Hepatitis C virus — With the approval of interferon-free, direct-acting antiviral drug regimens (DAA) for treatment of hepatitis C virus (HCV), transplant physicians have greater flexibility in the timing of treatment of hepatitis C-infected patients before or after solid organ transplantation [116-119]. Use of HCV-seropositive donor organs to expand the donor pool is routine; use of HCV-viremic donors is increasing, including in uninfected recipients. Decisions regarding the timing of DAA therapy relate to the status and progression of the disease in the individual, financial considerations, and any potential effect of improved clinical status and Model for End-Stage Liver Disease score on transplant listing [120]. (See "Overview of the management of chronic hepatitis C virus infection".)
HIV — HIV infection of recipients is not a contraindication to solid organ transplantation and outcomes are excellent [121,122]. Increasingly, HIV-infected individuals are considered as donors for HIV-infected recipients, generally under research protocols. The care of HIV-infected and coinfected recipients (eg, HIV and HCV infected) requires expertise in the management of drug interactions among the drugs required for maintenance of immunosuppression and antiviral therapy in the post-transplant period. In general, stable antiretroviral regimens with omission of protease inhibitors is preferred to limit interactions with the calcineurin inhibitors [121]. The optimal immunosuppressive regimens for maintenance therapy are under investigation. (See "Kidney transplantation in adults: Kidney transplantation in patients with HIV" and "Overview of antiretroviral agents used to treat HIV".)
Severe acute respiratory syndrome coronavirus 2 — Issues related to coronavirus disease 2019 in solid-organ transplantation are discussed separately. Vaccination should be completed if possible prior to transplantation. (See "COVID-19: Issues related to solid organ transplantation".)
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
●Risk of infection is high – Solid organ transplant recipients are at "high risk" for developing infection; individual risk is determined by a relationship between the epidemiologic exposures of the individual and the patient's "net state of immunosuppression." (See 'Introduction' above.)
●Pretransplant evaluation – Before transplantation, it is important to establish the patient's immunization history, travel history, and prior infectious exposures to design an appropriate preventative strategy. Evaluation typically focuses on laboratory testing for past infectious exposures (table 1), screening for latent tuberculosis, reviewing microbiologic records, and administering vaccines when appropriate. (See 'Pretransplant prophylaxis' above.)
●Identification of infection prior to transplant – Because infections are more difficult to treat following transplantation when patients are immunosuppressed, any active infection identified prior to transplantation should be treated when possible. Surgical or other procedures may also be warranted for those with recurrent infections or anatomic predispositions to infections. (See 'Treatment of active or recurrent infections' above.)
●Peritransplant prophylaxis – At the time of transplantation, solid organ transplant recipients are vulnerable to infectious complications of the surgical procedure, most commonly bacterial and fungal infections. Peritransplantation prophylaxis is typically tailored according to the organ transplanted and may need to be further individualized based on the recipient's unique risks. (See 'Peri-transplantation prophylaxis' above.)
●Post-transplant prophylaxis – Following transplantation, prophylactic strategies vary by the specific disease being prevented and the nature of the recipient's risks. Strategies include universal, targeted, and pre-emptive prophylaxis (see 'Introduction' above and 'Post-transplant prophylaxis' above):
•Pneumocystis prophylaxis – Trimethoprim-sulfamethoxazole (TMP-SMX) is given universally to all transplant recipients who do not have sulfa allergies for the prevention of Pneumocystis pneumonia. TMP-SMX also protects against Listeria monocytogenes, Toxoplasma gondii, and other potential pathogens, although efficacy against pathogens other than Pneumocystis varies with dose. (See 'Pneumocystis pneumonia' above.)
•Antifungal and antiviral prophylaxis – Antifungal and antiviral prophylaxis is individualized (targeted) to patients considered at the greatest risk. In programs with a high incidence of infection due to Aspergillus, Histoplasma, or Candida species, both epidemiologic protection (eg, high-efficiency particulate air filtered air supply within the hospital) and antifungal prophylaxis (as appropriate to the isolates) may be utilized. (See 'Antifungal prophylaxis' above.)
•CMV prophylaxis – Universal prophylaxis with valganciclovir, ganciclovir, or letermovir is typically given to patients at greatest risk for cytomegalovirus (CMV) reactivation (eg, seropositive recipients and those with seropositive donors). The duration of therapy depends on the organ transplanted, the risk status of the patient, and individual institutional practice. Many transplant centers prefer to use a pre-emptive approach (eg, weekly CMV viral load monitoring within initiation of treatment when reactivation becomes evident) for specific patient populations (See 'Cytomegalovirus' above.)
•Herpes simplex virus and varicella-zoster virus prophylaxis – Patients who are not receiving CMV prophylaxis should receive prophylaxis against herpes simplex virus and varicella-zoster virus during the first three to six months after transplantation and during periods of intensification of immunosuppression for treatment of rejection. (See 'Herpes simplex and varicella-zoster' above.)
•Screening for EBV reactivation – Because there is no effective antiviral prophylactic therapy for Epstein-Barr virus (EBV) reactivation, high-risk patients (eg, all children and EBV-seronegative recipients who receive organs from seropositive donors) should be monitored for reactivation at routine intervals and evaluated for evidence of post-transplant lymphoproliferative disease if reactivation occurs. (See 'Epstein-Barr virus' above.)
•Vaccination – Vaccination remains the primary method for preventing influenza (inactivated influenza vaccine), pneumococcal, and hepatitis B infections. Live vaccines should generally be avoided in immunosuppressed hosts. For patients with known hepatitis B infections, preventive treatment options are available. (See 'Hepatitis B virus' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kieren A Marr, MD, who contributed to an earlier version of this topic review.
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