Epidemiology and risk factors of infections after solid organ transplantation

Document downloaded from http://www.elsevier.es, day 23/07/2012. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
Enferm Infecc Microbiol Clin. 2012;30(Supl 2):10-18
Enfermedades
Infecciosas y
Microbiología
Enfermedades Infecciosas
Clínica
Volumen 30, Extraordinario 2, Marzo 2012
Publicación mensual
PUBLICACIÓN OFICIAL
DE LA SOCIEDAD ESPAÑOLA
DE ENFERMEDADES INFECCIOSAS
Y MICROBIOLOGÍA CLÍNICA
y Microbiología Clínica
Editores invitados: Albert Pahissa, Asunción Moreno y José Luis Pérez Epidemiology and risk factors of infections after solid organ transplantation Patricia Muñoza,*, Nuria Sabé Fernándezb and María Carmen Fariñasc aDepartment of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Madrid, SpainbDepartment of Infectious Diseases, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Universitari de Bellvitge, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, SpaincInfectious Diseases Unit, Hospital Marqués de Valdecilla, IFIMAV, Universidad de Cantabria, Santander, Spain Infection remains a significant complication after solid organ transplantation (SOT). The incidence of various pathogens varies widely depending on the presence of specific factors, according to which patients can be classified into different risk categories that may merit tailored prophylaxis strategies. Both the endogenous origin of microorganisms (previous colonization or latent infection) and new acquisition (primary infection from donor or environment) should be considered. Bacterial infections predominate in patients with complex hospital stays or anatomical alterations. Viral infections, caused both by opportunistic (CMV, EBV, BKV, etc.) and common viruses (influenza, respiratory virus, VVZ, etc.), are of great importance, and may contribute to chronic rejection. Fungal infections are uncommon nowadays, but cause high mortality and deserve prophylaxis for a subset of patients. Parasitic infections are a clear threat, mainly in transplanted patients or those travelling to endemic areas. Physicians attending SOT recipients should be aware of these risk factors, which include specific host characteristics, type of transplantation, microorganism and immunosuppressive policy.
2011 Elsevier España, S.L. All rights reserved.
Epidemiología y factores de riesgo de infecciones tras trasplante de órgano
sólido
La infección sigue siendo una complicación significativa tras el trasplante de órgano sólido (TOS). La inci- dencia de los diferentes patógenos varía ampliamente dependiendo de la presencia de factores específicos y, de acuerdo con esto, los pacientes pueden clasificarse en diferentes categorías de riesgo que precisarán estrategias profilácticas específicas para cada categoría. Deben tenerse en cuenta tanto los microorganis- mos de origen endógeno (colonización previa o infección latente) como los de nueva adquisición (infección primaria a partir del donante o del entorno). Las infecciones bacterianas predominan en los pacientes con estancias hospitalarias complejas o alteraciones anatómicas. Las infecciones virales, causadas tanto por vi- rus oportunistas (citomegalovirus, virus de Epstein-Barr, virus BK, etc.) como por virus comunes (influenza, virus respiratorios, virus de la varicela zoster, etc.) son esenciales y pueden contribuir al rechazo crónico del trasplante. Las infecciones fúngicas no son habituales hoy en día, pero provocan una alta mortalidad y precisan profilaxis en un subgrupo de pacientes. Las infecciones parasitarias son una clara amenaza, princi-palmente en pacientes trasplantados que viajen a zonas endémicas. Los médicos que tratan a los receptores de TOS deben ser conscientes de estos factores de riesgo, que incluyen las características específicas del receptor, tipo de trasplante, microorganismo y planes de inmunosupresión.
2011 Elsevier España, S.L. Todos los derechos reservados.
E-mail: pmunoz@micro.hggm.es (P. Muñoz).
0213-005X/$ - see front matter 2011 Elsevier España, S.L. Todos los derechos reservados. Document downloaded from http://www.elsevier.es, day 23/07/2012. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
P. Muñoz et al / Enferm Infecc Microbiol Clin. 2012;30(Supl 2):10-18
Epidemiology of Infections After Solid Organ Transplantation
Table 1
Incidence of infectious diseases (%) in solid-organ transplant recipients
The incidence of infection after solid organ transplantation (SOT) is affected by a number of factors: the type of organ transplanted, the level of immunosuppression, the need for additional antirejection therapy and the occurrence of surgical complications, among others.1 Table 1 shows the incidence of infectious diseases in various types of The sources of infectious agents after transplantation include the recipient (endogenous), the allograft itself and the environment.3 There are two types of endogenous sources: 1) the SOT recipient’s flora that colonizes mucous membranes and skin, and 2) reactivation of a latent infection. The endogenous flora is the most important source of infection especially in the early port-surgical period in Canada or Western Europe should be discussed with the patient’s patients with prolonged hospitalizations or who require mechanical ventilation. The pathogens involved in these infections include gram-negative bacilli, gram-positive organisms, and Candida spp. Infections of Significant Relevance in Transplant Recipients Immunosuppression may cause latent pathogens to reactivate, even many years after transplantation (tuberculosis or endemic Etiologies of infection in SOT recipients are diverse, including fungi). Thus, it is important to identify such infections before common community-acquired bacterial and viral diseases and transplantation in order to develop preventive strategies for these uncommon opportunistic infections typical of immunocompromised patients. Pathogens that can reactivate after transplantation include: hosts. The incidence of opportunistic infections is decreasing in Mycobacterium tuberculosis, viral infections (Herpes simplex virus transplant recipients because of improved surgical techniques, the [HSV], varicella zoster virus [VZV], cytomegalovirus [CMV], hepatitis use of prophylaxis, enhanced immunosuppressive regimens and B, hepatitis C, papilloma virus and BK polyomavirus), some parasites (Strongyloides stercoralis, Trypanosoma cruzi, Toxoplasma gondii) and endemic systemic mycoses (Histoplasma capsulatum, Coccidioides immitis, Paracoccidioides brasiliensis).4-7 Bacterial infections occur in 33% to 54% of SOT recipients.2 The types of bacterial infections following solid organ transplantation are partly related to the transplant operation, to the length and severity Transplanted organs can transmit microorganisms from the of hospital stay and to the immunosuppressive treatment.16 donor. The greatest risk in the development of infection is exposure Common bacteria are a significant cause of potential severe to a donor pathogen when a recipient is at risk for primary infection infections among transplant recipients. Furthermore, antimicrobial (absence of pre-existing immunity). The most common manifestation resistance is increasing in immunocompromised hosts and should be of these risk strata is primary CMV infection, in which this subset has considered in antibiotic empirical treatment.17,18 The incidence of the highest risk of disease and complications.8 Transmission of methicillin-resistant Staphylococcus aureus (MRSA) is increasing in Epstein-Barr virus (EBV) from a seropositive donor to a seronegative USA and causes >64% of all bloodstream infections in some ICUs.19 In recipient increases the risk of post-transplant lymphoproliferative Europe, in contrast, the incidence of MRSA has stabilized, partially disorder (PTLD).9 T. gondii has been transmitted by seropositive heart due to a lower prevalence of community-acquired MRSA. The donors, especially in seronegative recipients, but transmission by incidence of MRSA infection after transplantation is not well known, other organs is rare.10 Other infections transmitted from donor organ but varies from one transplant center to other. In a study of infections tissues include West Nile virus, lymphocytic choriomeningitis virus, involving liver transplant recipients in USA, 90% of S. aureus isolates rabies, HIV, hepatitis B and hepatitis C viruses, herpes simplex virus, were methicillin-resistant.17 However, MRSA made up 16% of all S. aureus isolates of a surveillance study of bloodstream infections in transplant recipients in Spain.20 Multi-drug resistant Pseudomonas aeruginosa and Acinetobacter baumannii are also increasing as the etiology of infection in SOT Transplant recipients can have contact with a number of potential recipients, especially in the early post-transplantation period in the pathogens within the community. These organisms include common nosocomial setting. These multi-drug resistant infections have been respiratory virus (influenza, parainfluenza, respiratory syncytial associated with poor outcomes.20 Extended-spectrum beta-lactamase [RSV] virus, adenovirus and human metapneumovirus), bacterial producing gram-negative enteric bacilli have been an increasing pathogens (Streptococcus pneumoniae, Mycoplasma, Legionella, cause of infection in transplant recipients, accounting for 14% of all Mycobacterium tuberculosis, Nocardia spp., Listeria monocytogenes, bacteremic episodes of SOT recipients in Spain.20 Salmonella, Clostridium difficile), fungi (Aspergillus spp, Cryptococcus SOT recipients are at increased risk of Clostridium difficile infection. spp., endemic fungi) and parasites (T. gondii). In this setting, post- Incidence of C. difficile infection in this population is estimated to be transplantation patients are counseled regarding measures aimed at 1%-31% depending on the type of transplant. Fulminant colitis avoiding environmental exposure to infection. Patients should avoid develops in up to 8% of immunocompetent patients and rises to 13% contact with people who have colds, influenza, tuberculosis and in SOT recipients with C. difficile infection.21,22 other contagious infections. Recommendations also include washing The primary source of tuberculosis in SOT recipients is the reactivation fresh fruits and vegetables and cooking all meat and seafood of latent Mycobacterium tuberculosis infection.23 In Spain, the incidence thoroughly. SOT recipients should avoid changing litter boxes and of tuberculosis in SOT recipients was 512 cases per 100,000 inhabitants cleaning birdcages. Any plans for travel outside of the United States, per year, which was higher than that in the general population (19 cases Document downloaded from http://www.elsevier.es, day 23/07/2012. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
P. Muñoz et al / Enferm Infecc Microbiol Clin. 2012;30(Supl 2):10-18
per 100,000 inhabitants per year).24 Most tuberculosis cases in transplant invasive fungal infections in SOT recipients are caused by Candida spp recipients occur within the first year post-transplantation and although originating from endogenous sources. This can be explained by the pulmonary forms predominate, the proportion of extrapulmonary compromise of cell-mediated immunity due to the immunosuppressive infections is much higher than in the general population.25-27 therapy and the high frequency of conditions that lead to increased Mycobacterial infection may be difficult to treat after transplantation Candida colonization (antibiotic use, intravenous catheters, surgery, because of interactions between the antimicrobial agents, mainly etc.). All of these factors predispose patients to invasive Candida infections. Candida albicans is the most frequent isolated species, Nocardia and Listeria are uncommon infections related to cellular although the incidence of other Candida species associated with immunity deficiency in transplant recipients. The most common fluconazole resistance, such as C. glabrata or C. krusei, is increasing in presentation of Nocardia infection is pulmonary disease followed by brain abscess, meningitis and disseminated disease. Risk factors for The mean incidence of invasive aspergillosis in SOT recipients is Nocardia disease in SOT recipients are high-dose steroids, history of around 1.4%, ranging from 0.2% in renal recipients to 3% in lung CMV disease and high levels of calcineurin inhibitors.29,30 The most recipients. Invasive aspergillosis is associated with a high mortality frequent presentation of listeriosis is bacteremia followed by rate in SOT recipients (<70%).47-52 However, survival appears to have meningoencephalitis. Risk factors for Listeria infection in SOT improved in recent reports on advances in early diagnostic methods recipients are diabetes mellitus, CMV infection or disease and intake and the development of new antifungal agents.53,54 of high-dose steroids. Trimethoprim-sulfamethoxazole prophylaxis, Among SOT recipients who are not receiving prophylaxis, on the other hand, has a protective effect.31 Pneumocystis jirovecii causes pneumonia in 10% of cases, with a higher incidence in lung recipients. However, P. jirovecii disease is rare nowadays in SOT recipients because low-dose trimethoprim-sulfamethoxazole provides excellent prophylaxis.9,55 Following primary infection, long-term cellular and humoral immunity develops, but herpesviruses remain latent within the host. Viral persistence is controlled in the immunocompetent host by the Toxoplasmosis after SOT may develop after reactivation of a latent cellular immune system, but immunosuppression following infection, after allograft transmission in a seronegative toxoplasma transplantation may lead to viral replication and symptomatic recipient or after post-transplantation epidemiological exposure.56 infection. Viruses included in this group are CMV, HSV, VZV, EBV and The allograft is the main source of infection, especially in heart recipients. Seronegative serostatus before transplantation is the CMV continues to be the major pathogen-affecting SOT. Transplant main risk factor for developing toxoplasmosis.57,58 recipients develop CMV disease either as a primary infection, Strongyloides stercoralis is a helminth that can be maintained in transmitted by the donor or blood products to a seronegative the human intestinal tract for decades and can cause disseminated recipient and as a reactivation or as a reinfection (when donor- disease in transplant recipients with a mortality rate near 71%.59 transmitted virus is imposed on an endogenous reactivated virus). Patients who have resided in or traveled to an area of endemic Primary CMV infection is the most serious in terms of direct clinical infection must have stool specimens samples examined for the disease and outcome. CMV causes direct effects such as CMV presence of this parasite prior to transplantation or should receive syndrome. Tissue invasive disease is the digestive involvement in SOT. However, CMV also has the ability to modulate the immune system producing a variety of indirect effects. These indirect effects Timing of Infection Post-Transplantation
include an increased incidence of other opportunistic infections and acute chronic allograft rejection.8,9 There are three post-transplantation time frames during which Active replication of EBV is present in 20% to 30% of transplant specific infections most frequently occur. These include the first month, recipients receiving immunosuppressive drugs, and more than 80% in the second through the sixth months and the late post-transplant period those receiving antilymphocyte-antibody therapies. Although (beyond the sixth month).61 Among the factors that influence this mononucleosis-like syndrome has been described in some patients, the distribution of infections are the different levels of immunosuppression most important effect of EBV is its role in post-transplant proliferative at each moment, the proximity to the surgical procedure and critical disorder (PTLD).9 This disorder is usually a B-cell lymphoproliferative care unit stay, the environmental exposures and, of course, the risk of process that ranges from a polyclonal process to a malignant monoclonal donor-related infections. Retransplantation itself, which involves a more lymphoma with a reported mortality of 40%-60%.32 complex surgery and previous immunosuppression, is also a major factor in the relative risk of infection development. The risk of opportunistic infections is considered highest during the first four The BK polyomavirus has been associated in renal allograft with months after SOT, as we will discuss later.
hemorrhagic cystitis, interstitial nephritis and ureteric obstruction.33- The aforementioned chronology may be altered in a specific 38 Adenovirus can cause hemorrhagic cystitis and severe infections in patient, with infections characteristic of any given period occurring pediatric recipients.39 Parvovirus B19 can cause anemia and simultaneously and with an overall increased severity of infection.62 myocarditis in SOT recipients.40 SOT recipients are at high risk of As we mentioned, it should be noted that the epidemiology of developing anal human papillomavirus infection and neoplasia.41 infections after transplantation is changing due to the reduced Respiratory viruses are community acquired and can predispose to importance of surgery-related infections, thanks to the great efficacy bacterial infections and graft rejection in lung recipients.42,43 HHV8 of prophylactic strategies (P. jirovecii, T. gondii and CMV), the and HHV6 can also affect SOT recipients.44,46 sophistication of immunosuppressive agents and, of course, the significant improvement in diagnostic capabilities.
The incidence of systemic fungal infections varies with the type of organ transplanted, the immunosuppressive regimen and the Most infections diagnosed during the first month after incidence of surgical complications, and ranges from 2%-40%.2 Most transplantation are related to surgical complications, and match Document downloaded from http://www.elsevier.es, day 23/07/2012. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
P. Muñoz et al / Enferm Infecc Microbiol Clin. 2012;30(Supl 2):10-18
those occurring in similar surgical patients. They include bacterial and candidal wound infections, pneumonia, urinary tract infection, Risk factors related to higher risk of infection after transplantation intravascular catheter sepsis, infections of biliary, chest and other drainage catheters and Clostridium difficile associated diarrhea.1 The anatomical site near the surgical area is especially susceptible to early infection. In the first month post-transplantation, renal and Underlying disease (diabetes, hepatitis that may persist or recur) pancreatic transplant recipients are at risk for perigraft hematomas, Previous hospital admissions and antimicrobial therapy: higher rate of multi- lymphoceles and urinary leaks. Liver transplant recipients are at risk for portal vein thrombosis, hepatic vein occlusion, hepatic artery Critical clinical situation before transplantation (mechanical ventilation, thrombosis and biliary stricture formation and leaks. Heart transplant recipients are at risk for mediastinitis, and lung transplantation recipients are at risk for disruption of bronchial anastomosis. The only common viral infection during the first month post- Previous surgery near the transplant area transplantation is reactivated herpes simplex virus (HSV) infection in seropositive individuals prior to transplantation.
Chronic or latent donor infections that involve the allograft may Latent infections (tuberculosis, CMV, VZV, Strongyloides, regional mycosis, etc.) be transmitted to the immunosuppressed recipient and become Absence of specific immunity (toxoplasma, CMV, EBV, HSV) clinically apparent during early periods. Some of these infections include HBV, HCV, tuberculosis, fungal and toxoplasmosis, which are uncommon nowadays.9 Although the dose of immunosuppressants administered during this period is higher than in subsequent months, Type of transplantation (site of most common infections) the time available is not enough to make the patient susceptible to Surgical trauma and related complications infections by opportunistic microorganisms, unless there is a massive Prolonged surgery and high transfusion requirements exposure63 or an excessive immunosuppression level.
Donor related infections (toxoplasma, Chagas, etc.) Second to sixth month after transplantation Drugs: induction, maintenance and rejection episodes therapy The period from the second to the sixth month after transplantation Immunomodulatory infections: CMV and HCV increase the risk of opportunistic is the period when infections “classically” associated with transplantation are manifested.1,9,61,62,64 Recipients are deeply CMV: cytomegalovirus; EBV: Epstein-Barr virus; HSV: herpes simplex virus; VZV: immunosuppressed and more severe infections appear. Viral infections are common, mainly CMV infection, although these days it has been diminished due to prophylaxis and preemptive therapy. Other opportunistic pathogens, such as Aspergillus species, Nocardia species, Toxoplasma gondii and Listeria monocytogenes, typically occur determine ureteral obstruction, hemorrhagic cystitis and interstitial in this time frame. Pneumocystis jirovecii, formerly very common in nephritis, subacute and chronic hepatitis (especially those due to this period, is now infrequent due to prophylaxis.
hepatitis C virus), tumors (such as verruca vulgaris) and post- In addition, during the 1–6 month interval after transplantation, transplant lymphoproliferative syndromes caused by Epstein Barr reactivation of latent microorganisms (Mycobacterium tuberculosis, virus, which is especially prevalent in transplanted children.
hidden focus of bacterial infection, viral hepatitis) present in the Cryptococcal meningitis and some forms of CMV disease, such as recipient before transplantation may occur. Affected organs may retinitis, rarely occur and when they do they frequently appear late vary for each type of transplant, but the lung predominates in all.
after transplantation, usually more than a year after transplantation. It is known that highly effective prophylaxis against CMV is More than six months after transplantation conditioning the occurrence of late CMV disease when it is withdrawn.
From 6 months after transplantation onwards, most transplant recipients do relatively well, suffering from the same infections seen Risk Factors for Infection
in the general community. The rate of opportunistic infections is usually low. These include influenza virus, urinary tract, cholecystitis Solid organ transplant recipients should not be considered a and pneumococcal pneumonia infections. The only opportunistic uniform population in terms of risk level for suffering specific types viral infection commonly seen during this period is reactivated of infection. This risk may vary as time progresses after transplantation, varicella-zoster virus infection manifesting as herpes zoster.1,9,61,62,64 the type and depth of immunosuppression and the degree of However, patients who have had frequent episodes of acute exposure to different microorganisms. Accordingly, individual risk rejection requiring augmented immunosuppressive therapy, those factors should be taken into account in order to choose efficacious with chronic rejection who are maintained at a higher baseline level prophylaxis strategies and empirical therapies at different moments of immunosuppression and those with chronic renal failure remain after transplantation. Some of the factors that have been found useful at risk for the opportunistic agents more classically seen in the for stratifying the risk of infection are summarized in Table 2. Some second to sixth months after transplantation (Cryptococcus will be present in the host or donor before transplantation, while neoformans, CMV, L. monocytogenes and Nocardia species).
others will be related to the transplantation procedure itself and to Most infections that occur after the sixth month post- transplantation can be classified into one of the following types: First, infections against which the graft is particularly vulnerable, such as recurrent urinary tract infections in renal transplant patients or chronic or recurrent cholangitis in liver transplant recipients; Recipient and donor age may increase the risk of infectious second, recurrences from previous infections, mainly viral (such as complications and exacerbate their consequences.65 Recipients’ herpes zoster rashes), papovavirus (BK and JC) infections that can underlying conditions should also be considered. For example, acute Document downloaded from http://www.elsevier.es, day 23/07/2012. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
P. Muñoz et al / Enferm Infecc Microbiol Clin. 2012;30(Supl 2):10-18
Table 3
Drugs used to prevent or treat rejection after SOT
Anti-human thymocyte immune globulin (rabit) Lymphocyte immune globulin antithymocyte (equine) Anti-CD25 (il-2 receptor) antibodies: basiliximab, daclizumab CMV, P. jirovecii, invasive fungal infections Corticosteroid free regimens may decrease CMV and HCV recurrence. High doses increase the risk of Listeria, Salmonella, Legionella, micobacteria, Nocardia, Cryptococcus neoformans, Candida, Aspergillus, P. jirovecii, herpesvirus, Toxoplasma gondii and Strongyloides stercoralis liver failure as a cause of liver transplantation is related to a higher colonized with certain Burkholderia or Pseudomonas species are rate of fungal complications, and so these patients need to receive known to have a greater risk for death after transplant; therefore, antifungal prophylaxis. Lung transplant recipients with previous individual prophylactic regimens are designed for these patients.72 COPD or cystic fibrosis may require a more prolonged stay in the These infections are associated with significant morbidity after intensive care unit and may be colonized with more resistant pathogens.66 Patients receiving immunosuppressive drugs before Fungal infections are not as common as bacterial or viral infections transplantation in order to control the underlying disease in SOT recipients. However there are specific subsets of patients with (autoimmune hepatitis, for example) have a higher risk of post- significantly higher risk that deserve antifungal prophylaxis. These transplant infections and may constitute an indication for risk factors include retransplantation or reoperation, renal failure perioperative antifungal prophylaxis. The disease leading to the requiring dialysis, CMV disease and post-transplant neoplasia. Liver transplantation is also important, since sometimes reoccur (hepatitis recipients with very prolonged surgery and/or requiring large B or C) in the allograft, increasing the risk of opportunistic infections. amounts of blood products are also at high risk. Finally, early Diabetic renal transplant recipients have an increased risk of urinary aspergillosis cases are reported in SOT recipients that required very tract and soft tissue infections. Finally, other less significant problems prolonged intubation periods after transplantation.
present in the recipient before transplantation (diverticulosis, SOT recipients are at a high risk of acquiring environmental lithiasis, chronic bronchitis) may become a significant problem when pathogens when a massive exposure occurs. Therefore, in cases of nosocomial outbreaks of Legionella, influenza and Aspergillus, patients Polymorphisms of innate immunity receptors, especially TLR4 should receive full attention and be provided with early diagnosis. In mutation, have been related to higher risk of CMV disease.67 some cases, universal prophylaxis is warranted considering the high The clinical situation before transplantation is also important. risk and related mortality of these infections.51 Patients awaiting transplantation in the intensive care unit (mainly if Due to the significant increase in immigration rates (10% of donors intubated or requiring circulatory assist devices or dialysis) are at and transplant recipients in Spain), international travel and the new higher risk of subsequent infection (mainly fungal and bacterial). phenomenon of “transplant tourism”, emerging tropical infectious Prolonged pre-transplant hospital admissions, therapy with diseases should now be considered in this population. Among them antimicrobials or immunosuppressants and poor nutritional status Chagas, Histoplasma capsulatum and HTLV-I/II are especially relevant.73 may all be associated with colonization of resistant pathogens. Post-solid organ transplantation nucleic acid testing (NAT) testing Finally, it is of the utmost importance to determine if the patient should be available to diagnose these infections in a timely way.74,75 may harbor a pathogen that may be reactivated after transplantation, such as tuberculosis, regional mycoses and Strongyloides (travel history, vaccination status, etc.). Risk levels for primary infections (CMV, EBV, Toxoplasma, etc.) also need to be established.
Solid organ recipients require the administration of exogenous immunosuppressive agents in order to avoid rejection. Some of the most commonly used drugs are presented in Table 3. Most patients receive perioperative induction therapy with the intention of eluding As mentioned before, endogenous microorganisms may cause cellular rejection while maintaining low levels of calcineurin severe infection after transplantation. Previous colonization with inhibitors when the risk of toxicity is higher. In the past, prolonged multi-resistant pathogens (MRSA, VRE, ESBL-producing gram courses of polyclonal antithymocyte globulin (ATG) or monoclonal negatives, etc.) should be investigated before transplantation, and a OKT3 were used, bringing with them high rates of infectious decolonization attempt should be performed.68,69 Solid organ complications, mainly of viral etiology. At present, other agents are transplantation is a well-known risk factor for infection after MRSA preferred, such as the new monoclonal antibodies: daclizumab, colonization.70 Double kidney-pancreas Tx recipients and those who alemtuzumab or basiliximab and monoclonal anti-CD20 antibodies develop post-transplant urinary obstruction are more frequently (rituximab). These drugs maintain a low rate of rejection with a infected by multiresistant enteric bacilli.71 Lung transplant recipients significantly lower number of infectious complications, when used Document downloaded from http://www.elsevier.es, day 23/07/2012. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
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mainly for induction therapy. Patients receiving alemtuzumab infections, but infections caused by these organisms are less common developed less infections than those treated with basiliximab. than those caused by bacteria. Both the lower and upper urinary tract Disseminated Candida infections were more common in patients (encompassing grafted or native kidneys) can be affected. The major receiving alemtuzumab.76 When these drugs are used for the risk factors for urinary tract infection in renal transplant recipients treatment of corticosteroid-resistant rejection, the risk of include indwelling bladder catheters, handling and trauma to the opportunistic infections is significantly higher.77,78 In this situation, kidney and ureter during surgery, anatomic abnormalities of native or transplanted kidneys (such as vesicoureteral reflux, stones and stents), Most common maintenance regimes include the simultaneous neurogenic bladders (especially in diabetic patients) and possible administration of 1) glucocorticoids, 2) anti-proliferative agents rejection and immunosuppression. In addition, urinary tract infection (such as azathioprine and mycophenolic acid) or mTOR inhibitors is a relatively frequent cause of bacteremia.82,83 (such as sirolimus and everolimus) and 3) calcineurin inhibitors The presence of asymptomatic bacteriuria is a common finding in (such as cyclosporine and tacrolimus).
these patients and their management has not yet been clarified. Its Corticosteroids inhibit a wide range of immune responses, presence is not associated with renal function impairment but including inflammatory response, cellular immunity and, to a lesser increases the risk of pyelonephritis and bacteremia. Virtually all extent, humoral immunity. Under normal conditions, SOT recipients renal transplant centers systematically investigate the presence of receive low doses of corticosteroids as maintenance therapy and can bacteriuria and many treat it, even in patients with no associated be totally withdrawn, particularly in abdominal organ recipients. clinical manifestations. Today, the actual utility of this measure However, high doses are needed to treat acute rejection episodes. The associated cellular immunosuppression increases the risk of The typical microorganisms causing post-transplant urinary tract infections caused by Listeria, Salmonella, Legionella, mycobacteria, infections are the enteric gram-negative bacilli and enterococci. In Nocardia, Cryptococcus neoformans, Candida, Aspergillus, P. jirovecii, addition, Corynebacterium urealyticum (group D2) has been Herpesvirus, Toxoplasma gondii and Strongyloides stercoralis. Currently, recognized as a potential pathogen in this population.84 This without recent rejection episodes, steroid-related opportunistic observation is clinically important because C. urealyticum is difficult to isolate and is not sensitive to conventional oral antibiotics. Calcineurin inhibitors are the backbone of maintenance Complicated infections are more common among transplant immunosuppressive therapy in SOT recipients and are usually recipients with prolonged anuria, such as dialysis patients. combined with corticosteroids and mycophenolate mofetil or mTOR The morbidity associated with urinary tract infections appears to be inhibitors. Tacrolimus is more potent than cyclosporine and its use is related to the timing of episodes after transplantation. Infections linked to fewer episodes of rejection and infection, probably due to occurring in the hospital are more serious, with bacteremia occurring in the diminished requirement for corticosteroids and antilymphocyte approximately 10 percent and graft infection in 90 percent of recipients. agents, both of which may cause nephrotoxicity and hypertension. These infections may be associated with allograft dysfunction and may CyA is also related to gingival hyperplasia, hirsutism and predispose to development of acute rejection. The clinical presentation hyperlypemia, while tacrolimus causes more diabetes and neurologic of early post-transplantation urinary tract infection is variable. Some toxicity. Both drugs are controlled by measuring serum levels. When patients are asymptomatic whereas others present with fever, chills and the levels exceed intended limits, a higher risk of CMV reactivation graft pain and tenderness. Allograft dysfunction can also occur in this setting. The idea that urinary tract infections detected in the first 6 The new m-Tor inhibitor sirolimus is not associated with higher weeks should receive long-term treatment is not currently supported, rates of infection;79 however, it may cause interstitial pneumonitis.80 and antimicrobial management should be similar to other patients. Therapy with m-TOR inhibitors decreases the incidence of However, it is essential to note that these patients have frequently cytomegalovirus infection, BKV and probably PTLD. However, previous antibiotic therapy. Therefore, the possibility of having multi- coadministration with calcineurin inhibitors requires careful dose resistant pathogens, including infections that come from the community, adjustment to prevent renal toxicity. Its use may impair the response is very high. The use of long-term antimicrobial prophylaxis is to some vaccines, such as the pandemic influenza A H1N1 vaccine. controversial, as it may increase the likelihood of infectious organisms As mentioned earlier, the excess immunosuppression required to treat acute rejection episodes (mostly when they prove resistant to Renal transplant recipients and patients with terminal renal glucocorticosteroids) significantly increases the risk of opportunistic failure are at much greater risk than the general population of infections, such as CMV. Chronic allograft dysfunction usually suffering Mycobacterium tuberculosis infection. It is therefore essential requires retransplantation and is also associated with a higher that one consider this possibility in the differential diagnosis and susceptibility to infectious complications.
know the patient’s pre-transplant PPD and epidemiological history. As with other solid organ transplant recipients, renal transplant Factors that depend on the type of transplant
patients may suffer infections linked to cellular immunosuppression (L. monocytogenes, N. asteroides, Cryptococcus neoformans, P. jirovecii) Despite the similarities mentioned, the predominant type of between 2 to 6 months after transplantation. CMV infection is much infection, the severity of the illness and even death rates vary widely less frequent and severe in these patients than in other transplant in relation to the transplanted organ. Overall, renal transplant recipients. It should however be included in the differential diagnosis patients have fewer infectious complications (0.98 episodes per if renal function deterioration occurs. Like all transplant patients, patient), while pancreas, intestine and lung transplant recipients are kidney graft recipients may be frequently infected by the varicella- the most affected (3.1 episodes per patient). Liver transplant zoster virus (VZV) or by the JC virus, which causes progressive recipients have more bacteremias, usually of intra-abdominal origin, multifocal leukoencephalopathy. The presence of late BK virus while 75% of heart-lung recipients suffer severe lung infections.9 infection is however much more characteristic of this group, which frequently leads to graft failure.85 Renal Transplant
Liver Transplant
Urinary tract infection is the most common bacterial infection occurring in renal transplant recipients, particularly in the first months Bacterial intra-abdominal infections (abscesses, intrahepatic and post-transplant.81 Fungi and viruses can also cause urinary tract extrahepatic cholangitis and peritonitis) are characteristic of liver Document downloaded from http://www.elsevier.es, day 23/07/2012. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
P. Muñoz et al / Enferm Infecc Microbiol Clin. 2012;30(Supl 2):10-18
transplants recipients. Many of these complications require surgery from positive donors, because the heart is a muscle that can spread in addition to antimicrobial treatment, as they may be related to infection more easily than other organs.
complications of bile duct sutures or hepatic artery thrombosis. It is therefore advisable to perform a radiological examination (Doppler Lung Transplant
ultrasound, CT scan) of the abdominal cavity in all liver transplant recipients with fever or bacteremia of no obvious origin. Cholangitis Lung transplant recipients have increased susceptibility to infection causes fever and jaundice but may present without right upper due to the lung’s direct communication with the environment. Losses quadrant pain, and therefore may go unnoticed. The diagnosis of of some mechanical defense mechanisms, such as the removal of the cholangitis requires a study of the biliary tract in search of stenosis cough reflex below the tracheal or bronchial anastomosis and the or obstruction. After the initial ultrasound, endoscopic alteration of mucociliary clearance, also favor the emergence of cholangiography or magnetic resonance cholangiography are the infections. On average, lung transplant recipients experience 3 episodes of infectious complications, and the type of infection depends on the Although the overall incidence of fungal infections in liver transplant clinical setting of the transplanted patient (e.g., harvest injury, recipients has declined due to early treatment of high-risk patients complication from primary disease, airflow obstruction from chronic (fulminant hepatitis, multiple transfusions, renal failure, reoperation, airway rejection). Therefore, awareness of the clinical setting enhances bile duct-jejunum anastomosis), the overall mortality rate remains high, diagnostic accuracy. Many of these patients arrive at transplantation particularly for invasive candidiasis and aspergillosis, and therefore colonized by bacteria and/or multi-resistant fungi. The native lung can patients often receive prophylaxis during the first month.88 contain microorganisms that can be transmitted to the transplanted lung.92-94 Pancreas Transplant
Pneumonia and tracheobronchitis are the most frequent infections, especially in the first weeks after transplantation. Overall, Gram- Pancreas transplantation is usually performed in conjunction negative bacteria predominate, but in patients with cystic fibrosis, the with renal transplantation. Its main indication is the treatment of main pathogens are P. aeruginosa, B. cepacia, Aspergillus and end stage renal disease associated with type 1 diabetes. These Scedosporium spp. Pneumonia after 3-6 months after transplantation patients require a high level of immunosuppression to prevent is a manifestation of bronchiolitis obliterans in the graft and in this rejection and therefore have a high rate of infections. Infections are case Gram-negative bacteria are the main cause. Lung transplant mainly located in the abdominal cavity and urinary tract when recipients may experience tracheobronchitis by Aspergillus due to pancreatic secretions drain into the urinary bladder. Diarrhea due to suture infection. Often lung transplant recipients receive universal C. difficile is also common. Risk factors for intra-abdominal infection antifungal prophylaxis with inhaled amphotericin.
are: age over 40 years, enteric drainage, organs donated by living The risk of CMV disease is higher than after kidney, heart or liver relatives and kidney transplantation after simultaneous kidney- transplantation. CMV pneumonitis and bronchiolitis obliterans may pancreas transplantation. S. aureus is the most common pathogen, develop. In these patients, EBV can cause mononucleosis or followed by Enterococcus spp. and enterobacteria. Recurrent Candida Conflicts of Interest
Heart Transplant
The authors declare that they have no conflicts of interest.
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