Infections in Liver, Kidney, Pancreas, and Intestinal Transplant Recipients

Clinical Microbiology Newsletter Vol. 35, No. 7

www.cmnewsletter.com

Stay Current... Stay Informed.

April 1, 2013

Infections in Liver, Kidney, Pancreas, and Intestinal Transplant Recipients Heather E. Clauss, M.D.,1 Rafik Samuel, M.D.,1 George J Alangaden, M.D.,4 Pranatharthi Chandrasekar, M.D.,4 Allan L. Truant, Ph.D.,2 Donald Jungkind, Ph.D.,3 and Byungse Suh,1 M.D., Ph.D., Section of Infectious Diseases, Temple University School of Medicine,1 and Clinical Microbiology, Immunology, and Virology Laboratories, Department of Pathology and Laboratory Medicine, Temple University Hospital and School of Medicine,2 Jefferson University Hospital and School of Medicine,3 Philadelphia, Pennsylvania, Division of Infectious Diseases, Transplantation Infectious Diseases Unit, Wayne State School of Medicine,4 Detroit, Michigan

Abstract Patients who need abdominal organ transplantation are at high risk for community-acquired, nosocomial, and opportunistic infections. In part, this is due to the invasive procedures they undergo, as well as the immunosuppression they require. This review highlights the infections that these vulnerable patients may develop. The current epidemiology, diagnosis, and management of common infections in liver, kidney, pancreas, and intestinal transplant (IT) recipients are summarized here.

Common Infections after Liver Transplantation Orthotopic liver transplantation (OLT) has been performed since 1963 (1). Over the last few decades, the 1and 5-year survival rates have improved tremendously, up to 92 and 86%, respectively (2). Infections are still a leading complication in OLT recipients and occur at rates of 54 to 67% of patients (3). The infections that are most common are due to bacteria (22%) and viruses (6%) (4). Infections in this population depend on the time after transplant and are associated with different risks. In the early post-transplantation period (the first month), infections are due to 4 major risk factors. They are the duration of surgery, the number of blood products transfused, the amount of Corresponding Author: Allan L. Truant, Ph.D., Clinical Microbiology Laboratories, Department of Pathology and Laboratory Medicine, Temple University School of Medicine, 3401 N. Broad St., Philadelphia, PA 19140. Tel.: 215-707-3210. Fax: 215-7073389. E-mail: [email protected]

Clinical Microbiology Newsletter 35:7,2013

blood in the peritoneal cavity, and the need for retransplantation. The most common organisms causing infection during this period include nosocomial bacteria, such as methicillin-resistant Staphylococcus aureus, vancomycinresistant enterococci (VRE), multidrug-resistant Gram-negative bacteria, Clostridium difficile, and Candida spp. Additionally, problems can arise from technical aspects of the transplant procedure, such as bile leaks. Infections that occur after the first month until the sixth month posttransplantation are usually due to opportunistic organisms, such as fungi, cytomegalovirus (CMV), or Pneumocystis. This is the time of maximal immunosuppression. After the sixth month posttransplantation, however, the potential for opportunistic infections continues, and the risk for community-acquired bacterial infection is important (5).

mortality. Bloodstream, wound, and intraabdominal infections account for the majority of bacterial infections during this period (6). Gram-positive bacteria account for the majority of bacterial infections, which are mainly due to S. aureus, coagulase-negative staphylococci, Streptococcus spp., and Enterococcus spp. In particular, VRE play a large role in infections in liver transplant recipients. A recent report shows a prevalence of colonization among liver recipients between 3.4% and 55% (7). Another report shows a VRE infection rate between 4% and 11% (8). VRE can cause urinary tract infections (UTIs) and wound infections, as well as bloodstream infections and endocarditis in some cases. The Gram-negative bacteria also cause significant morbidity and

Bacterial Infections Bacteria cause infections in almost 70% of liver transplant recipients during the early posttransplantation period and have an associated 13% © 2013 Elsevier

0196-4399/00 (see frontmatter)

53

include Enterobacteriaceae, such as Escherichia coli, Klebsiella spp., and Enterobacter spp., and others, including Pseudomonas aeruginosa and Acinetobacter spp. There is worldwide variation in the amount of extended-spectrum beta-lactamase (ESBL) production from these Gram-negative bacteria. In a survey in 2001, 67% of the gastrointestinal tracts of liver transplant recipients in one unit were found to be colonized with ESBL-producing E. coli (9). P. aeruginosa was documented to be resistant 47% of the time in infections in liver transplant recipients (10). These organisms mostly cause intra-abdominal infections. Clostridium difficile is a frequently encountered infectious bacterium in solid-organ transplant (SOT) recipients. The incidence is estimated to be 3 to 7% in liver recipients (11). Nocardia spp. cause infections in approximately 0.1% of liver transplant recipients (12, 13). Listeria monocytogenes is another infectious bacterium that can occur rarely in SOT recipients. Mycobacterium tuberculosis also causes infections in liver transplant recipients. It has been reported to cause infections in SOT recipients at a rate that is 20- to 74-fold higher than in the general population (14). These patients usually have reactivation of latent tuberculosis (TB) that causes fever and possibly allograft dysfunction. A third of the patients have dissemination of the organism. The transplant recipients usually develop reactivation in the first year after the transplant (15). Treatment with isoniazid, ethambutol, and pyrazinamide for 9 months is recommended if no resistance is suspected (14). The incidence of liver toxicity is about 50% in OLT recipients but 33 to 37% in other SOT recipients. Screening for latent tuberculosis in liver transplant candidates via a pretransplant PPD or interferon gamma release assay is important. Treatment of latent TB can be attempted with isoniazid for a 9month course or rifampin for a 4-month course. At times, this treatment may be deferred until after liver transplantation due to the hepatotoxicity of these agents.

Viral Infections Many viral agents cause disease in the OLT population. These organisms cause significant morbidity and mor54

0196-4399/00 (see frontmatter)

tality. None is more significant than CMV (16). CMV is the most common opportunistic viral infection after OLT. CMV is a betaherpesvirus. OLT recipients can develop disease from CMV in different ways. First, it can be transmitted in the transplanted organ. Second, the virus can be transmitted via transfusion with blood that is CMV positive. Third, the OLT recipient can undergo reactivation of previously dormant CMV. Finally, there can be a new primary infection from a CMV-positive contact. CMV disease occurs in 20 to 30% of OLT recipients. The average time of infection in the absence of CMV prophylaxis is about 4 weeks after the transplantation, and disease can occur about 2 weeks afterward. The incidence of infection depends on the seropositivity of the donor and the recipient. If both are negative, the rate of disease is 10 to 22%. If the donor is positive and the recipient is negative, approximately 75% of the recipients will develop CMV disease. If the recipient is positive, whether or not the donor is positive, this leads to an incidence of disease of 25 to 30% (17). CMV has a predilection to invade the allograft. CMV hepatitis is the most common manifestation of CMV infection in the OLT recipient, even though it is rarely seen in recipients of other organs. Patients present with fever and abnormal liver function test results that could be confused with graft rejection. To make the diagnosis, a liver biopsy demonstrating CMV inclusion bodies is necessary. Treatment of CMV hepatitis includes ganciclovir (GCV) or, for cases of GCV resistance, foscarnet. Other manifestations of CMV infection include involvement of the lungs or the gastrointestinal tract. In patients receiving an OLT, antivirals are recommended to prevent acquisition or reactivation of the infection. This can be accomplished in two ways. A universal prophylaxis regimen of GCV or valganciclovir (VGCV) for a defined period of time after transplantation and a preemptive treatment strategy have been studied. Preemptive therapy involves serially assessing the patient for CMV infection, typically with a CMV PCR or CMV antigenemia assay, and treating the patient only at a specified level of CMV detection. A meta-analysis performed to assess © 2013 Elsevier

the efficacy of preemptive and prophylactic strategies in reducing CMV disease in 1,980 SOT recipients, including 681 OLTs, showed that both strategies reduce the incidence of CMV disease (18). Oral GCV at 1 g 3 times daily showed a reduction of CMV organ disease compared with controls when used either by preemptive (72%) or by universal prophylactic (85%) strategies. For treatment of CMV disease, intravenous GCV as induction for 2 to 3 weeks is recommended. The dose should be 5 mg/kg of body weight twice daily, adjusted for renal function. Oral VGCV has also been shown to be effective at 900 mg twice daily as an induction course. Maintenance therapy should be half the dose of either GCV or VGCV for the duration of the course. Epstein-Barr virus (EBV) is a gammaherpesvirus and has been associated with post-transplant lymphoproliferative disease (PTLD). PTLD is a significant cause of morbidity in the OLT population. The incidence of disease in this group is about 2.2%. The findings of PTLD range from localized lesions to multisystem disease to lymphoma. The approach to treatment includes decreasing the immunosuppression and, depending on the severity of the disease, chemotherapy, surgery, antiviral agents, and even use of monoclonal antibodies. Herpes simplex virus 1 (HSV-1) and HSV-2 are alphaherpesviruses. They can lead to cutaneous lesions that include vesicles or ulcers. In OLT recipients, they can lead to disseminated or visceral disease, which includes hepatitis (19). Most disease from HSV is due to reactivation of previously acquired virus. Primary infection from the allograft is rare but has been described in liver transplant recipients (20). Hepatitis can develop in the first month after transplantation with a median time of 18 days after the transplantation. The frequency of disseminated HSV disease after transplantation has been reduced by the use of antiviral prophylaxis. Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections represent important causes of liver failure leading to liver transplantation. HBV can recur in 75 to 80% of OLT recipients and can significantly damage the graft and decrease survival after transplantation (21). There are multiple predictors Clinical Microbiology Newsletter 35:7,2013

of recurrence after transplantation. The most important predictor is the HBV load. If the HBV load is greater than 1 million copies, the relapse rate is up to 85%. On the other hand, if the OLT recipient is HBV antigen negative, the risk of relapse is much lower. It is also lower in those with fulminant hepatitis B. As a result, the HBV load should be lowered before transplantation. Recurrent hepatitis B after OLT leads to an aggressive infection causing fibrosing cholestatic hepatitis. Antiviral therapy for HBV, such as lamivudine, adefovir dipivoxil, or possibly entecavir, combined with hepatitis B immune globulin (HBIG) significantly improves the outcomes for OLT recipients with HBV infection. A combination of HBIG and lamivudine can drop the rate of recurrence to below 10% (22). Ninety percent of OLT recipients who have hepatitis C develop chronic hepatitis by 5 years after transplantation (23). HCV replication in the allograft is evident within hours to days after liver transplantation, and the infection takes on an accelerated course. As with hepatitis B, bringing the HCV load down to less than a million can improve graft and patient survival. Currently, the standardof-care regimen for HCV infections is a combination of pegylated interferon preparations and ribavirin. The rate of sustained virologic response in patients on this regimen varies substantially with pretreatment host characteristics, including viral load, age, body weight, and, most importantly, the genotype of the virus. The newly approved protease inhibitors that treat hepatitis C have not yet been studied for HCV recurrence after liver transplantation. All donors and recipients should be screened for HIV, since it can be transmitted with the transplanted organ. There have been recent data to indicate that HIV-infected patients can do well after OLT as a result of highly active antiretroviral therapy (HAART). The survival rates for 12, 24, and 36 months after OLT procedures among HIV-positive and -negative recipients were comparable (24). Carefully selected patients should have a CD4 count greater than 100 for 3 months, an undetectable viral load, and no history of opportunistic infections and be on a stable HAART regimen. Clinical Microbiology Newsletter 35:7,2013

Fungal Infections Candida species are the most common cause of invasive fungal infection after liver transplantation. In many organ transplant recipients, invasive candidiasis occurs within the first 3 months following transplantation, but in liver transplantation, this risk period is extended beyond 3 months (25). Candida albicans is typically the dominant pathogen. There are both medical and surgical risk factors for invasive candidiasis. In liver transplantation, a choledochojejunostomy is associated with a higher risk of candidiasis than a choledocho-choledocho anastomosis (26). Antifungal prophylaxis against Candida should be given to all liver transplant recipients at high risk for development of invasive candidiasis. High risk has been defined as those patients with ≥ 2.0 of the following risk factors: prolonged or repeat operation, retransplantation, renal failure, high transfusion requirement, choledocojejunostomy, and Candida colonization in the perioperative period (25). Cryptococcus neoformans is a ubiquitous yeast. Cryptococcosis is typically a late-occurring infection. The median time to onset usually ranges from 16 to 21 months post-transplantation. The time to onset is earlier for liver transplant recipients and is <12 months, perhaps due to a higher intensity of immunosuppression in these patients (27). The organism enters the body through the respiratory tract. The organism can lead to a pneumonitis but has a tropism for the central nervous system, resulting in meningitis. The mortality rate for cryptococcal meningitis is 71% in transplant recipients. Treatment with a lipid formulation of amphotericin in combination with flucytosine is recommended. Alternatives include fluconazole, itraconazole, or voriconazole (28). Aspergillus spp. can cause significant disease in a transplant recipient. It is the second most common invasive fungal infection in this population. The time of infection is usually in the first 6 months after transplantation, but the risk can persist. Invasive aspergillosis in OLT recipients presents with localized pneumonitis with an accompanying mental status change. Major risk factors for invasive aspergillosis include allograft dysfunction and HCV or CMV infection (29). The mortality rate of Aspergillus infection approaches 100% © 2013 Elsevier

in the OLT population. In a study looking at mold infections, non-Aspergillus genera accounted for 30% of the mycelial fungal infections (30). The most common non-Aspergillus organisms found included Scedosporium apiospermum, Fusarium spp., and Zygomycetes. These infections were more often associated with dissemination, with mortality approaching 100%, as well. Pneumocystis jirovecii causes an atypical subacute pneumonitis in organ transplant recipients. Among liver and kidney transplant (KT) recipients, the incidence appeared to be lower than among heart and lung recipients, from close to 2% to 10 to 15% (31). This incidence has significantly decreased with the use of prophylaxis and the decrease in steroid dosing in immunosuppressive regimens. One study demonstrated that a corticosteroid dose of 16 mg prednisone for 8 weeks is associated with a significant risk of Pneumocystis carinii pneumonia PCP in patients without HIV infection. Symptoms include nonproductive cough, shortness of breath, and fevers; however, they are not specific. A chest radiograph demonstrates bilateral interstitial infiltrates. The mortality rate is high and can reach 60% (32). Induced sputum or bronchoscopy with bronchoalveolar lavage should be performed to make the diagnosis. The specimen should be sent for special staining, such as Gomori methenamine silver, to identify the cysts.

Parasitic Infections Protozoan infections are uncommon in OLT recipients in developed countries. Potential donors or recipients from areas of endemicity or travelers to areas of endemicity should be screened for possible infection. Malaria in OLT patients generally carries a mortality rate of 40% compared to approximately 6% in KT recipients (33). Toxoplasma gondii is a parasite that is ubiquitous in nature that causes encephalitis and meningoencephalitis, myocarditis, pneumonitis, and disseminated lymphadenopathy in transplant recipients. Toxoplasma infections can be transmitted from a donor to a negative recipient or, more commonly, can occur from reactivation of an endogenous Toxoplasma infection. Treatment of toxoplasmosis includes pyrimethamine and sulfadiazine. Other agents that have 0196-4399/00 (see frontmatter)

55

been used include clindamycin, trimethoprim-sulfamethoxazole (TMP/SMX), atovaquone, azithromycin, and dapsone. In the southeastern United States and the Caribbean, Strongyloides stercoralis can be an important pathogen. Often, donors and recipients are screened using serial stool direct examinations for ova and parasites, as well as a Strongyloides enzyme-linked immunosorbent assay. Routine screening is recommended only for patients living in this area or with an extensive travel history there.

Phase I 0-30 days

Urinary tract infection

Surgical site infections

Risk and Temporal Sequence of Infection After Kidney, Pancreas, and Intestinal Bowel Transplantation The risk for infections caused by specific pathogens follows a predictable temporal pattern dictated by the intensity of immunosuppression (34,35) (Fig. 1). In the first month, infections generally result from complications of surgery, and bacterial infections predominate. Opportunistic infections caused by viruses and fungi occur during the second period (2 to 6 months) as a consequence of impaired cell-mediated immunity caused by anti-rejection therapy. Strategies for prevention of infections with specific pathogens, e.g. CMV and P. jirovecii, have been developed based upon this sequence of infections. However, the pattern of infection may be altered by the intensification of immunosuppressive therapy, the use of newer anti-rejection therapies, and the implementation of antimicrobial prophylaxis. After the 6-month period, primarily due to the decrease in immunosuppressive therapy, infections decline, and the relative risks are similar to the nontransplant population.

Common Infections After Kidney Transplantation KTs account for the majority of SOTs. The 5-year survival of KT recipients is 81% to 90 %, with graft survival rates of 67% in deceased-donor and 80% in living-donor transplantations. The good outcomes after KT, in large measure, are attributable to the low (<5%) infectionrelated morbidity and mortality. The most common infections in KT recipients at our Detroit facility are UTIs (47%), opportunistic viral infections (17%), pneumonia (8%), surgical wound infections (SWIs) (7%), and bacteremia 56

0196-4399/00 (see frontmatter)

Phase II 30-180 days

Phase Ill >180 days

Polyomavirus nephropathy

Cytomegalovirus infection

Cytomegalovirus infection

(in absence of prophylaxis)

(late onset as a result of prophylaxis)

Pneumocystis jirovecci infection (in absence of prophylaxis)

Figure 1. Risk of common infections in kidney transplant recipients

(6%). During the first month, bacterial infections predominate, with viral infections occurring later. Common opportunistic pathogens are listed in Table 1. Urinary Tract Infection

UTIs occur in 5% to 10% of KT recipients and are the commonest infections in the first 6 months after transplantation. Enterobacteriaceae account for the majority of UTIs, with E. coli being the most common pathogen. Enterococcus spp. have been identified as important uropathogens in the early KT period (36). Antimicrobial prophylaxis against UTIs is often used after KT; TMP/SMX is the most commonly used agent. TMP/SMX prophylaxis has also significantly decreased opportunistic infections caused by P. jirovecii, L. monocytogenes, Nocardia asteroides, and T. gondii (37). Empiric therapy for UTI should include coverage for Enterobacteriaceae (38). Specific therapy should be modified based upon the results of cultures. Breakthrough UTI while on prophylaxis or recurrent and relapsing UTIs necessitate further workup to exclude anatomical or functional defects of the urinary tract. Surgical Wound Infection

The incidence of SWIs in KT recipients is low (<5%). S. aureus is the most common pathogen isolated from wound infections, but infections due to Gramnegative enteric bacteria, Staphylo-

© 2013 Elsevier

coccus epidermidis, Candida spp., and Mycoplasma hominis may occur. Lower Respiratory Tract Infection

Pneumonia occurs in <5% of KT recipients and bacterial pathogens account for the majority of infections, with Streptococcus spp., Haemophilus influenzae, and S. aureus being the commonest. P. jirovecii and CMV may cause infection in patients not receiving appropriate prophylaxis. M. tuberculosis is an important respiratory pathogen in countries where it is endemic. Specific Opportunistic Pathogens of importance in KT recipients

The improper functioning of cellmediated immunity, which may result from anti- rejection therapy, can set the stage for infections caused by opportunistic intracellular pathogens. Most of these infections are a consequence of reactivation of latent infection during immunosuppression. Polyomavirus

Polyomavirus-associated nephropathy (PVAN) is as an important cause of kidney allograft dysfunction and is caused by reactivation of polyoma virus hominis type 1 (39), also known as BK virus (BK V). PVAN occurs in 1 to 10% of KT recipients and is characterized by allograft dysfunction, viremia, and morphological and immunohistochemical evidence of polyomavirus (PV) infection.

Clinical Microbiology Newsletter 35:7,2013

Screening assays for BKV are increasingly utilized for the diagnosis and management of PVAN. They include urine cytology for the detection of PVinfected “decoy cells” and molecular tests for the detection and quantification of BK DNA in plasma or urine. Definitive diagnosis of PVAN requires demonstration of PV infection in the renal graft tissue. There are no specific antiviral agents to treat PV infection; the primary therapeutic approach is to reduce the intensity of immunosuppression. CMV

Symptomatic CMV infection occurs in 20 to 60% of transplant recipients. CMV infection can result from (i) primary infection caused by transmission of CMV from a CMV-seropositive donor (D+) kidney to a CMV-seronegative (R-) recipient (this is the group at highest risk) and (ii) reactivation of CMV in a seropositive recipient. CMV infection and disease can present as asymptomatic infection, mononucleosis-like syndrome, or life-threatening systemic disease. The presence of disease is confirmed by demonstration of CMV in the tissue. The CMV antigenemia test is a semi-quantifiable assay that detects the pp65 protein of CMV within polymorphonuclear leukocytes in blood and is used with decreasing frequency as a screening assay. More sensitive and rapid qualitative and quantitative nucleic acid amplification tests that detect CMV DNA are increasingly used for diagnosis, as well as for monitoring the response to therapy. The therapy for CMV disease requires decreasing immunosuppression, along with antiviral therapy (40). Intravenous GCV is the drug of choice, although oral VGCV, a pro-drug of GCV, has been used. CMV disease can be prevented by matching CMV-negative donors with seronegative recipients and prophylaxis with antiviral agents. CMV prophylaxis is recommended especially for highrisk patients (0+/R-) for the first 3 months. In SOT recipients receiving antiviral prophylaxis, late-onset CMV disease after discontinuing prophylaxis has occurred (41). The use of GCV has also resulted in the emergence of GCV-resistant strains of CMV. Most GCV-resistant isolates are associated with a mutation, UL97, in the CMV phosphotransferase gene or a UL54 mutation in the DNA polymerase gene. Rapid genotypic PCR Clinical Microbiology Newsletter 35:7,2013

assays can identify these specific mutations. EBV-associated PTLD

PTLD is a term used to describe lymphoproliferative diseases that occur in <2% of KT recipients. The incidence of PTLD is highest during the first year within the period of intense immunosuppression. It results from abnormal proliferation of recipient B cells that are EBV infected and can cause disease that ranges from benign lymphoid hyperplasia to malignant lymphoma (42). Most cases occur as a result of acquisition of EBV from the donor, resulting in primary infection, often in pediatric recipients. The diagnosis of PTLD is confirmed by in-situ hybridization tests that detect

EBV within the affected cells. Quantitative-PCR screening tests are used to detect EBV in the blood. High EBV loads trigger pre-emptive reduction of immunosuppression to prevent the development of PTLD. West Nile Virus Infection

There have been reports of West Nile virus (WNV) transmission to different organ recipients from the same infected donor. The diagnosis is confirmed by detection of WNV lgM antibodies in the cerebrospinal fluid or by the use of nucleic acid amplification tests. Fungal infections

Despite their low incidence, fungal infections in KT recipients are associated with the highest mortality. Candida is

Table 1. Opportunistic pathogens in kidney transplantation Pathogen

Comments

Bacteria Legionella spp. Listeria monocytogenes Mycoplasma hominis Mycobacterium tuberculosis Non-TB Mycobacterium spp. Nocardia spp. Salmonella spp. Viruses Adenovirus Cytomegalovirus Epstein-Barr virus Hepatitis A, B, C, G virus Herpes simplex virus Human herpesviruses 6, 7, 8 Influenza virus Parainfluenza virus Respiratory syncytial virus Parvovirus B19 Polyomavirus BK, JC Varicella zoster virus Fungi Aspergillus spp. Blastomyces dermatitidis Coccidioides immitis Cryptococcus neoformans Histoplasma capsulatum Pneumocystis jirovecii Zygomycetes Protozoa Toxoplasma gondii

© 2013 Elsevier

Use of TMP/SMX prophylaxis for Pneumocystis jirovecii has also reduced infections caused by Nocardia spp.

CMV infection and disease have significantly decreased with the use of prophylaxis against CMV. The same strategy has reduced infections caused by HSV and varicella zoster virus. However, late-onset CMV infection after discontinuation of viral prophylaxis is a concern. Immunization against hepatitis A and B viruses has reduced such infections. Influenza immunization during fall/winter is recommended.

Use of TMP/SMX prophylaxis has significantly decreased infections with P. jirovecii.

Use of TMP/SMX prophylaxis for P. jirovecii has also redcued infections caused by Toxoplasma spp.

0196-4399/00 (see frontmatter)

57

the most common fungal pathogen, although mortality is greater with zygomycosis, aspergillosis, and cryptococcosis. The incidence of Candida infection in SOT has decreased, probably due to the frequent use of fluconazole prophylaxis, but there has been an increase in infections due to non-albicans Candida spp., notably Candida krusei and Candida glabrata, which are often less susceptible to fluconazole. P. jirovecii pneumonia is rare with the routine use of TMP/SMX prophylaxis.

Common Infections After Kidney-Pancreas Transplantion Simultaneous kidney-pancreas transplantation (SKPT) is increasingly used in the management of patients with type 1 diabetes mellitus with endstage renal disease. The 1-year patient, kidney, and pancreas survival rates are 95 to 98%, 92 to 94%, and 78 to 84%, respectively (43). In pancreatic transplantation, drainage from the pancreas is diverted into the duodenum (enteric drainage [ED]) or into the urinary bladder (bladder drainage [BD]) (44). The risk factors for early infection are related to the complexity of the surgical techniques and structural and metabolic changes that occur in the urinary bladder due to pancreatic secretions. Consequently, the early infection-related morbidity is greater among SKPT recipients than among KT recipients. Urological problems, including UTIs, are common in SKPT recipients with BD compared to those with ED. In contrast, SKPT recipients with ED have a higher rate of intra-abdominal infections. Intraabdominal cultures often demonstrate a polymicrobial bacterial flora, including aerobic Gram-positive and Gram-negative bacteria, anaerobes, and Candida spp. (45). The clinical approach to selected opportunistic infections, such as CMV and P. jirovecii infections, is generally similar to that used for KT recipients.

Common Infections After Intestinal Transplantation IT is performed as a life-saving procedure for patients with chronic intestinal failure who cannot be maintained on total parenteral nutrition (46,47). Intestinal failure may occur as a consequence of an intestinal calamity (e.g., shortbowel syndrome following volvulus or necrotizing enterocolitis) or on the basis 58

0196-4399/00 (see frontmatter)

of congenital (e.g., intestinal atresia) or mechanical (e.g., pseudo-obstruction syndrome) problems. Recipients of JT are in the younger age group (48); most are less than 18 years old. Compared to other SOTs, relatively few ITs are performed each year, most in the U.S. Surgical innovations, novel immunosuppressive regimens, and improved post-operative management have led to 5-year survival rates of more than 70% in some institutions. IT may be performed as an isolated procedure, concomitant with liver allograft, or as a multivisceral (including stomach, duodenum, pancreas, liver, and small intestine) procedure. Given the high immunogenicity (high lymphoid tissue content) of the gut, appropriate immunological control is critical in IT. Excess immunosuppression predisposes to infection, which is the major cause of death in IT; conversely suboptimal immunosuppression leads to acute allograft rejection and possible graft loss. The consequence of rejection is a disrupted mucosal barrier that leads to transgression of microorganisms from the intestinal lumen into the peritoneal cavity, resulting in sepsis and frequently death. Bacteremia from the gastrointestinal source is the most frequent infectious complication following IT; it occurs soon after the procedure or during rejection. As with most gastrointestinal surgeries, intra-abdominal infections, SWIs, and device-related bacteremia are common. Pathogens include enteric Gram-negative bacilli, Candida, staphylococci, and streptococci, including enterococci. Aggressive prophylaxis and empiric therapy with broad-spectrum antimicrobials are routine. Viruses account for up to 60% of graft losses. The Herpesvirus family (CMV, HSV, EBV, and human herpesvirus 6) plus adenovirus are the usual pathogens. By far, CMV and EBV are of the greatest concern. During IT, there is a transfer of a large quantity of lymphotropic CMV in a lymph-rich organ into a profoundly immunocompromised host, thereby increasing the potential for infection/disease. In D+/R- serodiscordant transplants, CMV disease tends to be most severe. Routine surveillance with CMV PCR and pre-emptive therapy with GCV have led to effective prevention of CMV infection. EBV © 2013 Elsevier

disease, PTLD, EBV enteritis, and hepatitis are mostly seen in seropositive children and occur most frequently in multivisceral transplant recipients. Periodic serum EBV DNA measurements by PCR have become routine in most centers; an increasing viral load dictates a reduction in immunosuppression. Rituximab, a monoclonal antibody directed at CD20, may be beneficial in patients with high EBV PCR and/or PTLD. Antiviral drugs (acyclovir and GCV) and hyperimmune globulin are not useful. IT recipients are at high risk for infection because the transplanted organ is rich in lymphoid tissue harboring viruses and the transplanted organ contains a large burden of bacteria. Recent advances include aggressive use of potent antimicrobials for perioperative prophylaxis, novel and effective immunosuppressive regimens, improved surgical techniques, and, above all, availability of diagnostic tests for early detection of viruses to facilitate prompt intervention. References 1. Starzl, T.E. et al. 1963. Homotransplantation of the liver in humans. Surg. Genecol. Obstet. 117:659-676. 2. Alangaden, G.P. et al. 2008. Cumitech 45. Infections in solid organ transplant recipients. Coordinating ed., A.L. Truant. ASM Press, Washington, DC. 3. Kusne, S. et al. 1988. Infections after liver transplantation: an analysis of 101 consecutive cases. Medicine 67:132-143. 4. Chang, F.Y. et al. 1998. Fever in liver transplant recipients: changing spectrum of etiologic agents. Clin. Infect. Dis. 26:59-65. 5. Fishman, J. 2007. Infection in solid organ transplant recipients. N. Engl. J. Med. 357:2601-2614. 6. George, D.L. et al. 1991. Bacterial infection as a complication of liver transplantation: epidemiology and risk factors. Rev. Infect. Dis. 13:387-396. 7. Bakir, M. et al. 2001. Epidemiology and clinical consequences of vancomycinresistant enterococci in liver transplant patients. Transplantation 72:1032-1037. 8. McNeil, S.A. et al. 2006. Vancomycinresistant enterococcal colonization and infection in liver transplant candidates and recipients: a prospective surveillance study. Clin. Infect. Dis. 42:195-203. 9. Paterson, D.L. et al. 2001. Control of an outbreak of infection due to extendedspectrum beta-lactamase-producing Escherichia coli in a liver transplanta-

Clinical Microbiology Newsletter 35:7,2013

tion unit. Clin. Infect. Dis. 33:126-128. 10. Singh, N. et al. 200I. Evolving trends in multiple antibiotic-resistant bacteria in liver transplant recipients: a longitudinal study of antimicrobial susceptibility patterns. Liver Transplant. 7:22-26. 11. Riddle D.J. and E.R. Dubberke. 2008. Clostridium difficile infection in solid organ transplant recipients. Curr. Opin. Organ Transplant. 13:592-600. 12. Peleg, A.Y. et al. 2007. Risk factors, clinical characteristics, and outcome of Nocardia infection in organ transplant recipients: a matched case-control study. Clin. Infect. Dis. 44:1307-1314. 13. Forbes, G.M. et al. 1990. Nocardiosis in liver transplantation: variation in presentation, diagnosis and therapy. J. Infect. 20:11-19. 14. Munoz, P., C. Rodriguez, and E. Bouza. 2005. Mycobacterium tuberculosis in recipients of solid organ transplants. Clin. Infect. Dis. 40:581-587. 15. Singh, N. and D. I. Paterson. 1998. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implication for management. Clin. Infect. Dis. 27:1266-1277. 16. Kanj, S.S. et al. 1996. Cytomegalovirus infection following liver transplantation: review of the literature. Clin. Infect. Dis. 22:537-549. 17. Wiesner, R.H. et al. 2003. Recent advances in liver transplantation. Mayo Clinic Proc. 78:197-210. 18. Kalil, A.C. et al. 2005. Meta-analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients. Ann. Intern. Med. 143:871- 880. 19. Kusne, S. et al. 1991. Herpes simplex virus hepatitis after solid organ transplantation in adults. J. Infect. Dis. 163:1001-1007. 20. Singh, N. et al. 1988. Infections with cytomegalovirus and other herpes viruses in 121 liver transplant recipients: transmission by donated organ and the effect of OKT3 antibodies. J. Infect. Dis. 158:124-131. 21. Samuel, D. et al. 1993. Liver transplantation in European patients with the hepatitis B surface antigen. N. Engl. J. Med. 329:1842-1847. 22. Marzano, A. et al. 2001. Prevention of hepatitis B virus recurrence after liver transplantation in cirrhotic patients treated with lamivudine and passive

Clinical Microbiology Newsletter 35:7,2013

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

immunoprophylaxis. J. Hepatol. 34:903910. Fukumoto, T. et al. 1996. Viral dynamics of hepatitis C early after orthotopic liver transplantations: evidence of rapid turnover of serum virions. Hepatology 24:1351-1354. Ragni, M.V. et al. 2003. Survival of human immunodeficiency virus-infected liver transplant recipients. J. Infect. Dis. 188:1412-1420. Pappas, P.G. et al. 2010. Invasive fungal infections among organ transplant recipients in the United States: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin. Infect. Dis. 50:1101-1111. Collins, L.A. et al. 1994. Risk factors for invasive fungal infections complicating orthotopic liver transplantation. J. Infect. Dis. 170:644-652. Singh, N. et al. 2007. Cryptococcus neoformans in organ transplant recipients: impact of calcineurin inhibitor agents on mortality. J. Infect. Dis. 195:756-764. Singh, N. et al. 1997. Clinical spectrum of invasive cryptococcosis in liver transplant recipients receiving tacrolimus. Clin. Transplant. 11:66-70. Singh, N. et al. 2003. Trends in risk profiles for and mortality associated with invasive aspergillosis among liver transplant recipients. Clin. Infect. Dis. 36:46-52. Husain, S. et al. 2003. Opportunistic mycelial fungal infections in organ transplant recipients: emerging importance of non-Aspergillus mycelial fungi. Clin. Infect. Dis. 37:221-229. Rodriguez M. and J.A. Fishman. 2004. Prevention of infection due to Pneumocystis spp. in human immunodeficiency virus-negative immunocompromised patients. Clin. Microbiol. 17:770-782. Thomas, C.F. and A.H. Limper. 2004. Pneumocystis pneumonia. N. Engl. J. Med. 350:2487-2498. Chiche, L. et al. 2003. Post transplant malaria: first case of transmission of Plasmodium .falciparum from a white multiorgan donor to four recipients. Transplantation 75:166-167. Marty, F.M. and R.H. Rubin. 2006. The prevention of infection post-transplant: the role of prophylaxis, preemptive and empiric therapy. Transpl. Int. 19:2-11. Schaffner, A. 2001. Pretransplant

© 2013 Elsevier

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47. 48.

evaluation for infections in donors and recipients of solid organs. Clin. Infect. Dis. 33(Suppl.1):S9-S14. Alangaden, G.J. et al. 2006. Infectious complications after kidney transplantation: current epidemiology and associated risk factors. Clin. Transplant. 20:401-409. Avery, R.K. and P. Ljungman. 2001. Prophylactic measures in the solidorgan recipient before transplantation. Clin. Infect. Dis. 33(Suppl.1):S15-S21. Patel, R., 2001. Infections in recipients of kidney transplants. Infect. Dis. Clin. N. Am. 15:901-953. Hirsch, H.H. et al. 2005. Polyomavirusassociated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 79:1277-1286. Razonable, R.R. and V.C. Emery. 2004. Management of CMV infection and disease in transplant patients, 11th Annu. Meet. IHMF, Herpes Journal 11:77-86. Singh, N. 2003. The impact of current transplantation practices on the changing epidemiology of infections in transplant recipients. Lancet Infect. Dis. 3:156-161. Taylor, A.L., R. Marcus, and J.A. Bradley. 2005. Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation. Crit. Rev. Oncol. Hematol. 56:155-167. Larsen, J.L. 2004. Pancreas transplantation: indications and consequences. Endocrinology 25:919-946. Becker, B.N. et al. 2002. Simultaneous pancreas kidney and pancreas transplantation. J. Am. Soc. Nephrol. 12:25172527. Berger, N. et al. 2006. Infectious complications following 72 consecutive enteric-drained pancreas transplants. Transpl. Int. 19:549-557. Abu-Elmagd, K.M. 2006. Intestinal transplantation for short bowel syndrome and gastrointestinal failure: current consensus, rewarding outcomes, and practical guidelines. Gastroenterology 130(Suppl.1):S132-S137. Grant, D. et al. 2005. Intestine transplant registry. Ann. Surg. 241:607-613. Kato, T. et al. 2006. Intestinal and multvisceral transplantation in children. Ann. Surg. 243:756-766.

0196-4399/00 (see frontmatter)

59