Liver transplantation has been established as an effective treatment for children with end-stage liver disease for more than 30 years. Improving surgical techniques and the availability of new and more potent immunosuppressive regimens have led to enhanced survival rates, with 3-year survival rates approaching or exceeding 84%. In response to these excellent results, children with end-stage liver disease are routinely referred for liver transplantation, and increasing numbers of pediatric centers routinely perform this procedure. Intestinal transplantation, performed as an isolated procedure or in combination with the liver or other organs, has also gained expanded acceptance as a treatment for children with refractory intestinal failure, with steadily improving survival rates over time. This is particularly true for those children who experience progressive liver failure due to hyperalimentation-induced liver disease. Although this newer procedure has been routinely performed at a relatively limited number of centers, an increasing number of transplant programs are beginning to offer intestinal transplantation.
Infectious complications have been a significant cause of morbidity and mortality in children undergoing liver transplantation since this procedure gained its initial acceptance in the 1980s. However, improvements in the treatment options for and management of immune suppression along with the increasing availability of new antimicrobial agents and diagnostic tools have resulted in reductions in the impact of infectious complications on these children. Intestinal transplantation is associated with many of the same infectious complications seen after liver transplantation, as well as a number of infectious issues that appear to be unique to this procedure. Although development of increasingly effective treatment strategies for infectious complications is of great benefit to the children undergoing these procedures, emphasis has increasingly shifted to the development of strategies aimed at the prevention of infectious complications in children undergoing abdominal transplantation. A general overview of the problem of infections after liver and intestinal transplantation in children is presented in this chapter.
Predisposing Factors
Liver and intestinal transplantation are associated with a set of technical and medical conditions that predispose to a unique set of infectious complications. The abdomen is a common site of infection in patients undergoing both of these procedures. This is almost certainly due to the occurrence of local ischemic injury and bleeding, as well as potential soilage with contaminated material. Additional factors predisposing to infection can be divided into those that exist before a transplant and those secondary to intraoperative and posttransplant activities.
Pretransplant Factors
The underlying illnesses leading to transplantation may be associated with intrinsic risk factors for infection. Some disorders may have required palliative surgery, which increases the technical difficulty of the transplant and may be associated with an enhanced risk for developing posttransplant infections. For example, children undergoing liver transplantation for biliary atresia may have previously undergone a Kasai procedure (choledochojejunostomy), which may predispose to recurrent episodes of bacterial cholangitis before transplantation, increasing the likelihood of colonization with multidrug-resistant (MDR) bacteria that can cause infection after transplantation. Similarly children undergoing liver transplantation for cystic fibrosis may have an increased risk for developing invasive aspergillosis if they were colonized with this pathogen before transplantation. Complications of end-stage liver disease (as part of a primary liver disease or as a consequence of hyperalimentation in patients with intestinal insufficiency) may also predispose to infection after a transplant. A history of one or more episodes of spontaneous bacterial peritonitis before transplantation in patients with ascites has been associated with an increased rate of bacterial infections after liver transplantation and could occur in patients with liver disease associated with intestinal insufficiency. Finally children awaiting intestinal transplantation experience frequent episodes of gastrointestinal-associated bloodstream infections. Recurrent exposure to antimicrobial agents to treat these episodes of bacteremia increases the likelihood of colonization and disease with MDR bacterial and fungal pathogens after transplantation. Risks for bacterial translocation after intestinal transplantation with resultant bloodstream infection include the presence of a colon graft, hospitalization before transplantation, and treatment with mycophenolate mofetil (MMF).
Age, another important pretransplant factor, is a major determinant of susceptibility to certain pathogens, severity of expression of infection, and immune maturation. Young children undergoing abdominal transplantation may experience moderate to severe infection with certain viral (e.g., respiratory syncytial virus [RSV]) or bacterial (coagulase-negative staphylococci) pathogens compared with more mild illness experienced by adult recipients infected with these pathogens. In contrast, certain pathogens, such as Cryptococcus neoformans, uncommonly manifest infection before young adulthood. Age is also an important factor governing clinical expression of infection with cytomegalovirus (CMV) and Epstein-Barr virus (EBV). When transplants are performed in young patients, there is a high likelihood that they will be seronegative for CMV and EBV and therefore susceptible to primary infections, which are more severe than infections due to reactivation.
Donor-related issues represent another set of pretransplant factors. Transplant recipients are at risk for acquiring infections that may be active or latent within the donor at the time of organ harvesting. The most common examples of donor-associated infections are CMV and EBV. Infections caused by CMV and EBV have been more severe after intestinal transplant compared with other organs. This may be because the intestine is an organ rich in lymphoid tissue, which may result in bringing a larger viral load of viruses from the donor compared with other graft types. Similarly adenovirus has been isolated more commonly from pediatric recipients of intestinal transplants compared with other organs, which may also be related to donor transmission in the accompanying lymphoid tissue. In contrast to CMV and EBV, for which donor-derived transmission is expected, increasing attention has focused on the unexpected transmission of other pathogens such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). Although the systematic use of donor screening has led to a decreased frequency of unexpected transmission of HIV, HBV, and HCV, evidence demonstrates donor-associated transmission of West Nile virus and rabies, as well as a number of other uncommonly transmitted pathogens. Because organs from a single donor often go to disparate sites, it is important for the recipient center to report back to the United Network for Organ Sharing (UNOS) any unusual infections that might possibly have come from the donor.
Intraoperative Factors
Operative factors unique to liver transplantation may predispose to infectious complications. For example, liver transplant recipients undergoing Roux-en-Y choledochoduodenostomy experience more infectious episodes than do those who undergo a choledochocholedochostomy with T-tube drainage. However, only the former option is usually performed in children undergoing liver transplantation because of the small size of their bile ducts. For combined liver-intestinal transplantation, evolution to en bloc replacement of the liver and intestine avoids the need for additional biliary anastomosis and minimizes the risk for infection related to biliary complications. Prolonged operative time (>12 hours) during the initial transplant has been associated with an increased risk for infection after transplant and is likely a surrogate marker for the technical difficulty of the surgery. Intraoperative events, such as contamination of the operative field, also predispose to postoperative infections. Finally the inability to close the abdomen after the transplantation due to size discrepancy or intraoperative complications appears to increase the risk for postoperative infections.
Posttransplant Factors
Technical problems, immunosuppression, presence of indwelling cannulas, and nosocomial exposures are major postoperative risk factors for infectious complications. Thrombosis of the hepatic artery is the most serious technical problem after liver transplantation and predisposes to areas of necrotic liver and development of hepatic abscesses and bacteremia. Bile duct strictures, developing as a sequelae of thrombosed hepatic artery and ischemia or due to technical difficulties, may predispose to cholangitis. Retransplantation represents a high risk for intraabdominal infection after intestinal transplantation.
Immunosuppression is the critical postoperative factor predisposing to infection in all transplant recipients. Immunosuppressive regimens have evolved in an attempt to achieve more specific control of rejection with the least impairment of immunity. Thus this evolution is aimed not only at improved control of rejection but also at decreased morbidity and mortality from infections. The use of cyclosporine-based regimens resulted in a decreased incidence of infections in renal and cardiac transplant recipients. The introduction of tacrolimus has allowed many patients to be managed without corticosteroids. Although reported rates of infection have been similar in liver transplant recipients treated with tacrolimus compared with those receiving cyclosporine, an apparent decrease in morbidity and mortality, especially from viral pathogens, was noted with tacrolimus. In contrast to these results, some centers reported an increased rate of EBV-associated posttransplant lymphoproliferative disease (PTLD) in patients receiving tacrolimus. However, data from the University of Pittsburgh suggest that the short- and long-term incidence of EBV-associated PTLD appears to be similar in pediatric liver transplant recipients treated with either cyclosporine or tacrolimus. More recently, induction immunotherapy has been used in combination with corticosteroid-free or corticosteroid-sparing immunosuppressive regimens, and newer agents also are being explored. Potential infectious risks will need to be assessed for these and other evolving immunosuppressive regimens.
Children undergoing intestinal transplantation require an increased baseline level of immunosuppression compared with patients undergoing most other solid-organ transplant procedures. With this increased level of immunosuppression has come an increased risk for development of infection. In an effort to overcome this, a number of alternative immunosuppressive strategies have been explored. Looking at one such alternative strategy, Loinaz and colleagues found an increased risk for bacterial infections with both MMF and daclizumab after intestinal transplantation. Another alternative approach evaluated the use of alemtuzumab induction in pediatric intestinal transplant recipients, and this was associated with a marked increased incidence of EBV-associated PTLD in one study but not another.
The treatment of rejection with additional or higher doses of immunosuppressant agents increases the risk for invasive and potentially fatal infection. Of particular concern is the use of antilymphocyte preparations, which are often indispensable in the management of corticosteroid-resistant rejection.
The prolonged use of indwelling cannulas at any site is an important cause of infection throughout the postoperative course. The presence of central venous catheters is a cause of bacteremia after transplantation. This is particularly important for children undergoing intestinal transplantation, where maintenance of long-term central venous access has been required for prolonged periods of time after transplantation. The development of urinary tract infections and bacterial pneumonia are associated with the use of urethral catheters and prolonged nasotracheal or endotracheal intubation, respectively.
Nosocomial exposures constitute the final group of postoperative risk factors in the hospital setting. Transplant recipients, especially children, may be exposed to many common viral pathogens (e.g., rotavirus, RSV, or influenza) while hospitalized. The presence of resistant bacteria in the hospital increases the risk for nosocomial transmission and disease. Attention to infection control policies aimed at local epidemiology of circulating infections is paramount. Finally the presence in the hospital of heavy areas of contamination with pathogenic fungi, such as Aspergillus, may increase the risk for invasive fungal disease in these patients. The rate of fungal colonization increases during times of hospital construction. Infection control policies aimed at local epidemiology of circulating infections is paramount.
Timing of Infections
The time of onset of infection with various pathogens after transplantation tends to be predictable. The majority of clinically important infections occur within the first 180 days after transplantation, although infections continue to occur quite frequently beyond this time after intestinal transplantation. The timing of infections can be divided into three intervals: early (0 to 30 days after transplantation), intermediate (30 to 180 days after transplantation), and late (>180 days after transplantation). In addition, some infections may occur throughout the postoperative course. These divisions should be viewed with flexibility because they may be modified by prophylaxis strategies and are somewhat less applicable to recipients of intestinal transplantation. Despite this, they remain useful, giving a general approach to a patient with fever after transplantation, and can be used as a guide to differential diagnosis. An overview of the infectious complications occurring during each of these time periods is provided in Tables 72.1 to 72.3 and is summarized in the following sections.
| Clinical Syndrome | Associated Pathogens |
|---|---|
| Wound infection: | |
| Superficial |
|
| Deep |
|
| Intraabdominal infection: | |
| Peritonitis | Enterobacteriaceae |
| Intraabdominal abscess | Enterococci |
| Intrahepatic abscess (isolated liver and liver-intestine transplants) ± bacteremia | Candida spp. |
| Bloodstream infection, associated with: | |
| Central venous catheters |
|
| Hepatic artery thrombosis (isolated liver transplant only) |
|
| Intestinal rejection (intestine only) |
|
| Bacterial cholangitis (isolated liver transplant only) |
|
| Urinary tract infection |
|
| Ventilator-associated pneumonia |
|
| Nosocomial acquisition of common community pathogens |
|
| Noninfectious etiologies |
|
| Clinical Syndrome | Associated Pathogens |
|---|---|
| Viral syndrome (fever, leukopenia, thrombocytopenia ± atypical lymphocytosis) |
|
| Hepatitis |
|
| Enteritis |
|
| PTLD | EBV |
| Bacterial cholangitis a |
|
| Pneumonia |
|
| Bacteremia b |
|
| Adenopathy | EBV/PTLD |
| Pulmonary nodules |
|
a Typically only seen in isolated liver transplant recipients and usually associated with the presence of technical complication (e.g., biliary stricture).
b Seen in intestinal transplant recipients in association with presence of central venous catheters, intestinal rejection, or PTLD involving intestine.
| Clinical Syndrome | Associated Pathogens |
|---|---|
| Bacterial cholangitis a |
|
| PTLD | EBV |
| Bacteremia b |
|
| Varicella zoster | Varicella zoster virus |
| Respiratory tract infections | Community-acquired viruses c |
a Usually associated with the presence of technical complication (e.g., biliary stricture).
b Seen in intestinal transplant recipients in association with presence of central venous catheters, intestinal rejection, or PTLD involving intestine.
c Respiratory syncytial virus, parainfluenza virus, influenza virus A and B, human metapneumovirus, adenovirus, rhinovirus, and enterovirus.
Early Infections (0 to 30 Days)
Early infections ( Table 72.1 ) tend to be associated with preexisting conditions and surgical manipulation. In general, they are caused by either bacteria or yeast. Bacterial infections are particularly common after intestinal transplantation, being reported in up to 90% of recipients. As many as half of these early infectious complications may develop in the first 2 weeks after abdominal transplantation. Cholangitis or spontaneous bacterial peritonitis presenting at or near the time of liver transplantation may lead to intraabdominal infection after the transplant. Technical difficulties (e.g., thrombosis of the hepatic artery or portal vein and biliary strictures) predispose to early bacterial infections. Likewise development of bile leaks and bowel perforations are associated with polymicrobial intraabdominal infections, primarily consisting of enteric bacteria and Candida spp., in the first month after transplantation. Early bacteremia is exceptionally common in intestinal transplant recipients and is usually associated with the presence of central venous catheters. Likewise early bacteremia with gram-negative pathogens in these children has been associated with intestinal rejection. Reexploration of the abdomen is associated with increased rates of fungal infection. Finally herpes simplex infection can also reactivate and cause early symptomatic disease, although this is uncommon in children.
Intermediate Period (31 to 180 Days)
The intermediate period ( Table 72.2 ) is the typical time of onset of infections associated with nonbacterial donor-associated transmission (either organ or blood products), reactivated viruses, and opportunistic infections. CMV peaks in incidence during this time. However, the use of prophylaxis against CMV can modify the time of presentation so that the occurrence of disease from these organisms may be after 180 days. The intermediate period is also when many patients begin to present with EBV disease (including PTLD) and Pneumocystis jiroveci pneumonia. Finally bacteremia continues to be a frequent occurrence in pediatric intestinal transplant recipients, with as many as 50% of all bloodstream infections occurring in this population being identified in this time period.
Late Infections (Greater Than 180 Days)
Late infections ( Table 72.3 ) after abdominal transplantation are less well characterized than other periods because patients have usually been discharged from the transplant center to their respective homes, which often are quite far away. This makes the accurate accumulation of data on these late infections difficult. Nonetheless problems such as recurrent episodes of bacterial cholangitis in liver transplant recipients (typically associated with underlying problems of the biliary tree) and bacteremia associated with ongoing requirement for a central venous catheter, intestinal graft rejection, and/or PTLD in intestinal transplant recipients, continue to occur in this time period. In addition, children who are at high risk for CMV infection and have been kept on prolonged or recurrent courses of prophylaxis may develop late-onset CMV infection in the late period.
Infections Occurring Throughout the Postoperative Course
Iatrogenic factors are an important cause of bacterial and fungal infections at all times but predominate in the early transplant period. Central venous lines are maintained for a variable time; the risk for infection persists for the entire period that the catheter remains in place. This is a particularly important problem for recipients of intestinal transplants who frequently require central line access for prolonged periods of time. Similarly the presence of urethral catheters and endotracheal tubes increases the risk for infections whenever they are in use.
Nosocomial acquisition of community viruses, such as RSV, rotavirus, and influenza A or B can occur at any time after transplant. These viruses spread easily in hospital environments from personnel or other hospitalized patients to transplant recipients. It is therefore important to modify diagnostic considerations according to local epidemiologic considerations.
Bacterial and Fungal Infections
Bacterial and fungal pathogens are important causes of morbidity and occasional mortality in children undergoing liver and/or intestinal transplantation. With the exception of infections related to the use of indwelling catheters, sites of bacterial infection tend to occur at or near the transplanted organ. Accordingly the intraabdominal space is an important site of infection after any of the abdominal transplant procedures. Adding to the complexity of the management of bacterial infections in children undergoing abdominal transplantation is the fact that recovery of MDR bacteria is increasingly common. Outbreaks of colonization and disease due to vancomycin-resistant Enterococcus faecium, extended-spectrum β-lactamase (ESBL)–producing Klebsiella pneumoniae, and carbapenem-resistant Enterobacteriaceae have been reported among pediatric liver and intestinal transplant recipients. These MDR bacteria have been transmitted from patient to patient, prompting the need for close attention to and strict compliance with infection control procedures. In some cases, effective antimicrobial agents may be unavailable to treat these complications. Knowledge of results of previous cultures and antimicrobial resistance patterns locally as well as from the home institution of the patient are critical components in choosing initial empirical antibiotic therapy for these patients to maximize their outcomes.
Liver Transplantation
Bacterial and fungal infections are a common early problem after liver transplantation. Rates for bacterial infection of 40% to 70% have been reported from multiple series. A 2008 review of the SPLIT registry for children undergoing liver transplantation between 1995 and 2006 found that around 33% of pediatric liver recipients experienced a bacterial infection, with the vast majority of these presenting in the first 30 days after transplant. Similar rates have been reported following living donor liver transplantation in children. Bacteremia often occurs in association with intraabdominal infection or with use of central venous catheters, but it can occur without an obvious source. Enteric gram-negative organisms account for more than one-half of episodes. Bacterial infections involving the abdomen or surgical wound are common in most series. Infectious complications of the transplanted liver also occur. The most important complication is hepatic abscess associated with hepatic artery or portal vein thrombosis, which can be accompanied by persistent bacteremia. However, the introduction of frequent surveillance Doppler studies early after transplant to monitor for development of thrombosis, coupled with the use of operative thrombectomy and thrombolysis, have markedly diminished the development of hepatic abscesses in this population.
Ascending cholangitis is relatively common after liver transplantation accounting for 7% of infections in the SPLIT series and usually associated with biliary abnormalities. This diagnosis typically is made on clinical grounds in a patient with fever and biochemical evidence of biliary inflammation. Enteric gram-negative bacteria and enterococcal species predominate. However, this clinical picture can be identical to that of acute graft rejection; liver biopsy should be performed to differentiate these processes. A cholangiogram is performed to assess the status of the biliary tract for patients with proven cholangitis.
Historically as many as 40% of children undergoing liver transplantation developed a fungal infection during the first year following this procedure, with Candida spp. being the most common fungal pathogen and infection usually being associated with an intraabdominal focus or indwelling catheter. Infections due to Candida spp. have been most commonly recognized in the first month after transplantation, with candidal peritonitis most likely presenting in the first 2 weeks after liver transplantation in association with a bile leak or bowel perforation. The recovery of Candida from a Jackson-Pratt drain in the early postoperative period may be the first indication of either of these two technical complications and may occur before the onset of clinical symptoms of intraabdominal infection. Accordingly recovery of Candida, alone or in combination with enteric bacteria, should prompt initiation of antimicrobial therapy and an aggressive evaluation for the presence of these complications. However, rates of invasive candidiasis have markedly declined, as demonstrated by a recent study of pediatric liver transplant recipients at two different centers that found that only 2.5% of 397 children developed invasive candidiasis in the first month following transplantation as compared to a rate of 21% documented in an older study evaluating invasive candidiasis during the first month posttransplant. Candidemia accounted for 80% of episodes of invasive candidiasis in the recent series with the only identified risk factor associated with the development of candidal infection being ICU admission in the 2 weeks prior to transplant. Historically additional risk factors for fungal infection have included prolonged duration of intubation after transplant, hepatic artery thrombosis, volume of blood transfused, and exposure to corticosteroids within the 3 months before the transplant. Early initiation of antifungal treatment is particularly important, given an attributable mortality rate of up to 33% for candidal infections in pediatric liver transplant recipients in older literature. The availability of fluconazole and echinocandin antifungal agents (e.g., caspofungin, micafungin, and anidulafungin) increases the number of therapeutic options for the treatment of candidal infections. However, acquired or inherent resistance to the azoles is an increasing concern, as are drug-drug interactions between azoles with both cyclosporine and tacrolimus and echinocandins with cyclosporine.
Episodes of invasive aspergillosis among pediatric liver transplant recipients are uncommon but can be fatal ; infections due to other invasive molds are rarely seen. However, children undergoing liver transplantation for cystic fibrosis (CF) are at particular risk for developing infection due to Aspergillus and other fungi seen in children with CF lung disease . Early disseminated aspergillosis in children with CF undergoing liver transplantation at Children’s Hospital of Pittsburgh of UPMC (CHP) was observed in the early era of transplantation, prompting the use of perioperative antifungal prophylaxis in liver recipients with CF and a history of recovery of Aspergillus before transplant. Because data defining the precise duration of prophylaxis necessary to protect against this complication are not available, prophylactic treatment has ranged from 1 month of intravenous amphotericin to prolonged use of an oral azole agent (e.g., itraconazole or voriconazole). The availability of newer antifungal agents, including the advanced-generation azoles (voriconazole and posaconazole) as well as the echinocandins, has increased the number and complexity of therapeutic options for treatment of aspergillosis in children undergoing liver transplantation. A summary of a suggested approach to the diagnosis and management of fungal infections after liver transplantation in children is provided in Table 72.4 .
| Candida —Noninvasive (Mucositis, Dermatitis and Cystitis) | Candida —Invasive | Aspergillus | Cryptococcus | Others ( Histoplasma, Mucor, Fusarium, Blastomycetes, Alternaria , etc.) | |
|---|---|---|---|---|---|
| Frequency | Common a | Common a | Uncommon a | Rare a | Rare a |
| Diagnostic Tests | Clinical examination Culture Gram stain | Culture Gram stain Histology | Culture Gram stain Histology Radiographic staging g | Culture Antigen test India ink stain Histology CSF examination | Culture Histology Antigen testing (when appropriate) |
| Treatment: | |||||
| Primary | Nystatin Clotrimazole | Echinocandin j Lipid formulation of amphotericin B d Fluconazole c,j | Voriconazole c Lipid formulation of amphotericin B d | Lipid formulation of amphotericin B d Fluconazole c,e| | Lipid formulation of amphotericin B d |
| Secondary | Topical amphotericin B b Fluconazole c,g | Flucytosine h | Echinocandin therapy j Itraconazole c,h,i,k | Flucytosine f | Azole therapy (for susceptible organisms) c |
| Adjunctive | Removal of central lines | Surgical resection | Surgical debridement | ||
| Duration of therapy | Dependent on rate of clearance | Dependent on the rate of clearance: minimum of 14 days | Dependent on the rate of clearance: minimum of 4 weeks, usually 8–12 weeks | Minimum of 6–8 weeks Many would continue with fluconazole indefinitely | Dependent on rate of clearance |
| Follow-up | Clinical examination Repeat urinalysis/cultures | Dependent on clinical scenario | Dependent on clinical scenario | Clinical examination Antigen testing Repeat culture of appropriate source (sputum, CSF, urine) Radiographs if relevant | Clinical examination Antigen testing Repeat culture of appropriate source (sputum, CSF, urine) Radiographs if relevant |
a Common: >5%; uncommon 1–5%; rare <1%.
b Topical amphotericin B for bladder wash for noninvasive candiduria; ultrasonography of kidneys recommended to confirm absence of invasive disease.
c Azole use must be accompanied by close follow-up of levels of cyclosporine or tacrolimus. In general, tacrolimus dosing should be cut in half when using a standard dose of fluconazole.
d Dose varies according to specific agent.
e Fluconazole is alternative first-line drug for invasive disease if the species is known to be sensitive to fluconazole and the patient is clinically stable. Dosage is 6 to 12 mg/kg per day based on severity of infection.
f Flucytosine should not be used alone but is synergistic when used in conjunction with amphotericin B. Dosage is 100 to 150 mg/kg per day divided every 6 hours.
g Radiographic staging includes computed tomography of head, chest, and abdomen.
h Itraconazole can be used long term for patients who have been treated for invasive Aspergillus but in general is not recommended as first-line therapy.
i Itraconazole absorption can be erratic. Accordingly, monitoring of itraconazole levels is recommended. Itraconazole is dosed at 3 to 5 mg/kg per day as a single dose. Dosing adjustment based on monitoring of levels is recommended. Adjustment of cyclosporine or tacrolimus dosing should be individualized.
j The use of either of the approved echinocandins (caspofungin, micafungin, or anidulafungin) may be an appropriate alternative for treatment of invasive candidiasis, candidemia, and aspergillosis. Dose adjustments may be necessary in the presence of impaired liver function. Monitoring of tacrolimus levels are indicated because these agents may decrease tacrolimus levels.
k Voriconazole levels should be checked for patients treated with oral therapy.
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