Infections In Ped Ltx

LIVER TRANSPLANTATION 14:1389-1399, 2008

T.H.E. CORNER

Immunizations and Infectious Diseases in Pediatric Liver Transplantation Natasha Halasa1 and Michael Green2 Division of Infectious Diseases, Vanderbilt University, Nashville, TN; and 2Division of Infectious Diseases, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 1

Received April 14, 2008; accepted July 1, 2008.

Liver transplantation (LTx) is an established and effective treatment for children with end-stage and metabolic liver disease. Improved surgical techniques and immunosuppressive regimens have led to enhanced short-term and long-term survival rates, which now approach or exceed 90%. Consequently, more children are being referred for LTx, and an increasing numbers of pediatric centers routinely perform this procedure. Infectious complications are an important cause of morbidity and mortality in children undergoing LTx. However, improvements in immune suppression management along with the availability of new antimicrobial agents and diagnostic tools have resulted in improved treatment and preventative regimens, thus reducing the impact of infectious complications on these children. This review provides an overview of the infectious complications and prevention strategies for children undergoing LTx.

FACTORS PREDISPOSING TO INFECTION LTx is associated with a set of technical and medical conditions that predispose to infectious complications. The abdomen is a common site of infection in patients undergoing this procedure.1 This is almost certainly due to the occurrence of local ischemic injury and bleeding as well as potential soilage with contaminated material.2 Additional factors predisposing to infection can be divided into those that exist prior to 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. Disorders that require palliative surgery, which increases the technical difficulty of the transplant, may be associated with an enhanced risk of developing posttransplant infections.3 For example, children undergoing LTx for biliary atresia may have previously undergone a Kasai procedure (choledocojejunostomy), which may predispose to recurrent episodes of bacterial cholangitis prior to transplantation, increasing the likelihood of colonization with multiple antibiotic–resistant bacteria, which can cause infection following transplantation. Similarly, children undergoing LTx for cystic fibrosis may have an increased risk of developing invasive aspergillosis if they were colonized with this pathogen prior to transplant. Complications of endstage liver disease may also predispose to infection after transplant. A history of 1 or more episodes of spontaneous bacterial peritonitis pre-transplant in patients with ascites has been associated with an increased rate of bacterial infections after LTx.4 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 LTx may experience moderate to severe infection with certain viral [eg, respiratory syncytial virus (RSV)] or bacterial (coagulasenegative staphylococci) pathogens versus the more mild illness experienced by adult recipients infected with

Abbreviations: CMV, cytomegalovirus; DTaP, diphtheria, tetanus, and acellular pertussis vaccine; EBV, Epstein-Barr virus; HHV6, human herpesvirus 6; HHV7, human herpesvirus 7; HiB, Haemophilus influenzae type B vaccine; LTx, liver transplantation; MMR, measles, mumps, and rubella vaccine; MPV, meningococcal polysaccharide vaccine; PCP, Pneumocystis jirovecii pneumonia; PCR, polymerase chain reaction; PCV7, 7-valent pneumococcal conjugate vaccine; PPV23, pneumococcal polysaccharide vaccine; PTLD, posttransplant lymphoproliferative disease; RSV, respiratory syncytial virus; TB, tuberculosis. Address reprint requests to Michael Green, M.D., M.P.H., Division of Infectious Diseases, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213. Telephone: 412-692-6111; FAX: 412-629-6116; E-mail: [email protected] DOI 10.1002/lt.21605 Published online in Wiley InterScience (www.interscience.wiley.com).

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these pathogens. In contrast, other pathogens, such as Cryptococcus neoformans, uncommonly manifest infection before young adulthood.5 Age is also an important factor governing the 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.6,7 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 organ. The best described examples of donorassociated infections are CMV and EBV.8,9 Although the frequency of some donor-associated pathogens (eg, human immunodeficiency virus, hepatitis B, and hepatitis C) have decreased substantially with better diagnostic screening tests,10 recent evidence now demonstrates donor-associated transmission of West Nile virus and rabies.11,12 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 any unusual infections that might possibly have come from the donor.

Intraoperative Factors Operative factors may predispose to infectious complications. For example, LTx recipients undergoing Roux-en-Y choledocoduodenostomy experience more infectious episodes than those who undergo a choledochocholedochostomy with T-tube drainage.13,14 However, only the former option is usually performed in children because of the small size of their bile ducts or because of requirements associated with technical variants of LTx (eg, split, reduced, and living donor organs). A prolonged operative time (⬎12 hours) during the transplant has been associated with an increased risk of infection13,15 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 transplantation appears to increase the risk for postoperative infections. This circumstance tends to occur more frequently when larger grafts are placed in smaller children.

Posttransplant Factors Technical problems, immunosuppression, the presence of indwelling cannulas, and nosocomial exposures are the major posttransplant factors predisposing to infectious complications. Hepatic artery thrombosis is the most serious technical problem following LTx, predisposing to areas of necrotic liver and the development of hepatic abscesses and bacteremia.14,16 Bile duct strictures, developing as sequelae of a thrombosed hepatic artery and ischemia or because of technical difficulties, may predispose to cholangitis.16 Immunosuppression is the critical posttransplant

factor predisposing to infection in 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 has resulted in a decreased incidence of infections in renal and cardiac transplant recipients.1,17,18 The introduction of tacrolimus has allowed many patients to be managed without steroids.19,20 The use of tacrolimus in LTx recipients has been associated with an apparent decrease in morbidity and mortality, especially from viral pathogens, in comparison with recipients receiving cyclosporine.19,21 Although some centers have reported an increased rate of EBV-associated posttransplant lymphoproliferative disease (PTLD) in patients receiving tacrolimus,22 data from the University of Pittsburgh suggest that the short-term and long-term incidence of PTLD is similar in pediatric LTx recipients treated with either cyclosporine or tacrolimus.23 The treatment of rejection with additional or higher doses of immunosuppressants increases the risk of an invasive and potentially fatal infection. Of particular concern is the use of anti-lymphocyte preparations, especially OKT3.6,13,15 Newer anti-lymphocyte antibodies (eg, Thymoglobulin®) are also likely to be associated with an increased risk of infection. The prolonged use of indwelling cannulas at any site is an important cause of bacterial and fungal infections throughout the postoperative course. The presence of central venous catheters is associated with bacteremia, whereas the development of urinary tract infections and bacterial pneumonia are associated with the use of urethral catheters and prolonged nasotracheal or endotracheal intubation, respectively.13,15 Nosocomial exposures constitute the final group of postoperative risk factors. Children undergoing LTx may be exposed to many common viral pathogens (eg, rotavirus and RSV) while in the hospital. Uncommonly, they are also at risk of exposure to transfusion-associated pathogens (eg, hepatitis B, hepatitis C, and CMV). Finally, the presence in the hospital of heavy areas of contamination with pathogenic fungi, such as aspergillus, may increase the risk of invasive fungal disease in these patients. The rate of fungal colonization increases during times of hospital reconstruction. Therefore, infection control policies to limit exposure to these pathogens are warranted.

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 following transplantation.13,19 The timing of infections can be divided into 3 intervals: early (0-30 days after transplantation), intermediate (30-180 days after transplantation), and late (greater than 180 days after transplantation). In addition, some infections may occur throughout the postoperative course. These

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divisions, while arbitrary, are generally useful in approaching a patient with fever after transplantation and can be used as a guide to differential diagnoses.

Early Infections (0-30 Days) Early infections tend to be associated with pre-existing conditions and surgical manipulation. In general, they are caused by either bacteria or yeast. As many as half of these early infections develop in the first 2 weeks following LTx.24 Cholangitis or spontaneous bacterial peritonitis presenting at or near the time of transplantation may lead to intra-abdominal infection after the transplant. Herpes simplex infection can also reactivate and cause early symptomatic disease,13 although this is uncommon in children. Technical difficulties (eg, thrombosis of the hepatic artery or portal vein and biliary strictures) predispose to early bacterial infections. Likewise, the development of bile leaks and bowel perforations are associated with polymicrobial intraabdominal infections in the first month after LTx.25 Finally, re-exploration of the abdomen is associated with increased rates of fungal infection.13

Intermediate Period (31-180 Days) The intermediate period is the typical time of onset of donor-related infections, reactivated viruses, and opportunistic infections. The peak incidence of CMV infection occurs in this period.6,13 However, the use of CMV prophylaxis has resulted in shifting the time of presentation of CMV disease so that some patients will present with this infection after 180 days. The intermediate period is also when patients begin to present with EBV-associated PTLD7 and Pneumocystis jirovecii pneumonia (PCP).13

Late Infections (⬎180 Days) Late infections after LTx are less well characterized than infections of other periods because patients have usually been discharged from the transplant center to their respective homes, which are often 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 patients with underlying problems of the biliary tree) and PTLD26 occur in this time period. In addition, the use of CMV prophylaxis may delay the onset of CMV disease to the late period.27 Finally, it is important to remember that these children are at risk for common communityacquired infections.

Infections Occurring Throughout the Postoperative Course Iatrogenic factors are important causes of bacterial and fungal infections at all times but predominate in the early transplant period. The use of central venous lines, urethral catheters, and endotracheal tubes increases the risk of infections whenever they are in use. Nosocomial acquisition of community viruses, such as RSV,

rotavirus, and influenza, can occur at any time after transplantation. These viruses, which can have different manifestations and severity in immunocompromised children, spread easily in hospital environments. It is therefore important to modify diagnostic considerations according to local epidemiologic considerations.

BACTERIAL AND FUNGAL INFECTIONS Bacterial and fungal infections are a common early problem after LTx.28-31 Rates for bacterial infection of 40% to 70% have been reported.13,14,19 Bacteremia often occurs in association with intra-abdominal infection or with the use of central venous catheters. Enteric gram-negative organisms account for more than onehalf 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 is often accompanied by persistent bacteremia. However, the use of frequent surveillance Doppler studies early after transplant to monitor for the development of thrombosis, coupled with the use of operative thrombectomy and thrombolysis, has significantly reduced the development of hepatic abscesses in this population. Ascending cholangitis is common after LTx and is usually associated with biliary abnormalities. This diagnosis typically is made on clinical grounds in a patient with fever and biochemical evidence of biliary inflammation. Because this clinical picture can be identical to that of acute graft rejection, a liver biopsy should be performed to differentiate these processes. Outbreaks of colonization and disease due to multiple antibiotic–resistant bacteria are increasingly common among liver transplant recipients. Examples of multiple antibiotic–resistant bacteria include vancomycin-resistant Enterococcus faecium, extended spectrum beta-lactamase–producing Klebsiella pneumoniae, and Enterobacter cloacae.32-34 These resistant bacteria can be transmitted from patient to patient, and this should prompt the imposition of strict infection control procedures. The increasing prevalence of these resistant organisms limits the therapeutic options available for the treatment of bacterial infections following LTx. As many as 40% of children undergoing LTx may develop a fungal infection during their first year following this procedure.30 Candida spp. are the most common fungal pathogens, and infection usually is associated with an intra-abdominal focus or indwelling catheter. Candida infections are most commonly recognized in the first month following transplantation, with Candida peritonitis most likely presenting in the first 2 weeks post-LTx in association with a bile leak or bowel perforation. Additional risk factors for Candida infections include prolonged duration of intubation after transplantation, hepatic artery thrombosis, a high volume of blood transfused, and exposure to steroids and antibiotics. The recovery of Candida from a JacksonPratt drain in the early postoperative period may occur

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prior to the onset of clinical symptoms of intra-abdominal infection.25 Such a recovery should prompt initiation of antimicrobial therapy and an aggressive evaluation of the presence of the source of the infection. Early initiation of treatment is particularly important, given an attributable mortality rate of up to 33% for Candida infections in pediatric liver transplant recipients.25 The availability of fluconazole and the newer echinocandin antifungal agents (eg, caspofungin and micofungin) has increased the number of therapeutic options for Candida infections. However, resistance to the azoles is an increasing concern, as are drug-drug interactions between azoles and echinocandins with both cyclosporine and tacrolimus. Episodes of invasive aspergillosis are uncommon but can be fatal.35 Children undergoing LTx for cystic fibrosis are at particular risk of developing infection due to aspergillus.35 A history of recovery of aspergillus prior to transplant should prompt the use of antifungal prophylaxis in liver recipients with cystic fibrosis. Data defining the precise duration of prophylaxis are not available, and prophylactic treatment has ranged from 1 month of intravenous amphotericin to prolonged use of an oral azole agent (ie, voriconazole).

VIRAL INFECTIONS Viral pathogens, especially herpesviruses, are a major source of morbidity and mortality after LTx. The frequency, mode of presentation, and relative severity of these infections can differ according to the intensity of immunosuppression and the serologic status of the recipient.

CMV CMV is one of the most common and important viral pathogens following LTx in children. CMV infection can be asymptomatic or symptomatic and may be due to primary infection (either from the donor graft or blood products), reactivation of latent infection, or superinfection with a different CMV strain in a previously seropositive child. Prior to the use of prophylaxis, the incidence of symptomatic CMV infection was reported to be as high as 40% in these patients.8 Use of ganciclovir prophylaxis has resulted in a decreased rate and severity of CMV disease.36 Primary CMV infection, typically acquired from the donor organ (or donor leukocytes that accompany the organ), is associated with the greatest degree of morbidity and mortality.6,36 Accordingly, CMV-seronegative recipients of organs from CMV-seropositive donors are considered at high risk of developing CMV disease. Reactivation of CMV or superinfection with CMV tends to result in milder illness.6 Patients treated with unusually high doses of immunosuppressants, especially anti-lymphocyte antibody preparations, experience an increased rate of CMV disease, regardless of previous immunity.8,13 Symptomatic CMV disease typically presents between 1 and 3 months after transplantation. However, the use of prophylactic regimens may delay the onset of CMV disease. A characteristic constellation of fever and

hematologic abnormalities (including leukopenia, atypical lymphocytosis, and thrombocytopenia) is frequently seen. This CMV syndrome occurs in 25% to 50% of patients with symptomatic CMV infection. Invasive CMV disease is manifested by visceral organ involvement; common sites include the liver, gastrointestinal tract, and lungs, with hepatitis being the most common among LTx recipients. The diagnosis of CMV disease may be confirmed by a positive culture, pp65 antigenemia assay,37 and/or CMV DNA polymerase chain reaction (PCR) in a patient with a compatible clinical syndrome.38 However, clinicians must be aware that the results of viral cultures of the urine and even bronchoalveolar lavage specimens may be difficult to interpret in previously infected patients because CMV is frequently shed asymptomatically in these secretions. Similarly, the presence of pp65 antigen and CMV DNA in the blood can be misleading, as these assays are often positive in asymptomatic patients. Although a quantitative determination of the CMV load improves specificity, a histologic examination of potentially involved organs to confirm the presence of CMV is critical when the diagnosis of invasive CMV is being entertained. Antiviral agents with activity against CMV have dramatically improved the survival of transplant recipients with CMV disease. Fatal, disseminated CMV disease occurred in 19% of infected children8 undergoing LTx in the preganciclovir era. Currently, mortality attributable to CMV rarely occurs in these patients. CMV disease is treated with ganciclovir in conjunction with reduction of immunosuppression unless evidence of rejection is present. Clinical response usually occurs 5 to 7 days after initiation of therapy. Baseline immunosuppression levels are typically restored at the time of initial clinical response or upon recognition of rejection. Treatment with ganciclovir is usually continued until the CMV viral load is nondetectable.39,40 The role of CMV hyperimmune globulin in combination with ganciclovir in the treatment of CMV disease is controversial, although some evidence for improved outcome has been reported in the treatment of CMV pneumonia in adult liver transplant recipients.41 Finally, because of drug-associated nephrotoxicity, the use of foscarnet and cidofovir should be restricted to only patients with apparent or proven resistance to ganciclovir.

EBV EBV infection is an important cause of morbidity and mortality following pediatric LTx.7,42-44 Symptomatic EBV disease most commonly occurs among patients experiencing primary EBV infection. Accordingly, children undergoing transplantation are disproportionately affected by EBV in comparison with their adult counterparts.45 As many as 80% of children who are EBV-seronegative prior to LTx will develop a primary EBV infection following this procedure; however, clinical disease develops in less than one-third of these children.46,47 A wide spectrum of EBV diseases are recognized, in-

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cluding nonspecific viral illness, mononucleosis, and PTLD (including lymphoma). Asymptomatic seroconversion also occurs. Variation in the severity and extent of disease is related to the degree of immunosuppression and adequacy of the host immune response. Although EBV disease and PTLD may present with involvement of many different clinical sites, there is a tendency for involvement of the transplanted organ. Thus, hepatic involvement is common among LTx recipients. The onset of viral syndrome, mononucleosis, and PTLD occur primarily within the first year, whereas lymphoma tends to present later. Immunosuppressive regimens based on the use of tacrolimus appear to have affected a shift in the timing of PTLD; only rare cases occur more than 18 months after transplantation.44,48 The diagnosis of EBV-associated PTLD is made on the basis of clinical, laboratory, and histopathologic examination and should be suspected in patients with protracted fever, exudative tonsillitis, lymphadenopathy, organomegaly, leukopenia, or atypical lymphocytosis.49,50 Gastrointestinal involvement should be suspected in patients with persistent fever and diarrhea. In addition, the present of occult blood in the stool, hematochezia, and/or hypoalbuminemia should also prompt consideration of gastrointestinal involvement. Serologic diagnosis is often unreliable as it is confounded by the presence of passive antibodies. Measurement of the EBV load in peripheral blood by PCR has gained wide acceptance as a method to predict the risk for or presence of EBV or PTLD.50-53 Although extremely sensitive, these assays are limited by their lack of specificity; they are often elevated in asymptomatic patients.54 Accordingly, every effort should be made to histologically confirm the diagnosis of EBV or PTLD. Occult sites of PTLD are assessed by performance of computed tomography of chest, abdomen and brain. Palpable nodes or lesions (or both) identified by radiographic surveillance should be biopsied. Endoscopic evaluation should be considered in patients with diarrheal illnesses and elevated viral loads. A wide range of histologic findings may be present in patients with EBV disease and PTLD. The tissue specimen should be interpreted by a pathologist or hematopathologist familiar with histopathologic features of EBV and PTLD. Ranges of EBV infection notable in tissue biopsy include early lesions (reactive plasmacytic hyperplasia, infectious mononucleosis-like), polymorphic PTLD, monomorphic PTLD, B cell neoplasms, T cell neoplasms, Hodgkin’s lymphoma, and Hodgkin’s lymphoma-like PTLD. The histologic evaluation for typical features may be augmented by the use of the Epstein-Barr encoded RNA probe.55 Management of patients with PTLD is controversial.48-50 Reduction of immunosuppression is recommended widely. Antiviral agents (eg, ganciclovir) typically are used,49,56 although their role has not been studied formally. Reduction of immunosuppression, alone or in combination with antiviral agents, results in an approximately 67% cure rate of EBV disease and PTLD. Several different strategies have been proposed for patients who fail to respond to withdrawal of initial

immunosuppression. Experience to date suggests that as many as two-thirds of patients who fail initial withdrawal of immunosuppression will respond to a 4-week course of the anti-CD20 monoclonal agent rituximab.57 However, relapse of EBV disease has been observed in 20% to 25% of treated patients 6 to 8 months following completion of therapy. An alternative, chemotherapybased approach for patients who fail to respond to initial reduction or withdrawal of immunosuppression has also been proposed.58 This strategy, which uses modified doses of cyclophosphamide and prednisone, has also achieved success in approximately two-thirds of treated patients. Unfortunately, as with rituximab, relapse of PTLD has been seen in 22% of treated patients, and outright treatment failures have occurred in patients presenting with fulminant disease. Definitive studies comparing these 2 second-line therapies are needed to define the best option for those children who fail to respond to initial therapeutic modification of immunosuppression.

Other Herpesviruses Herpes simplex can reactivate early after surgery or after augmentation of immunosuppression, but prophylaxis with acyclovir has been beneficial in these situations. Varicella in nonimmune transplant recipients can lead to disseminated, fatal disease59 and should be treated early and aggressively with intravenous acyclovir. Recent interest has focused on determining what role, if any, human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7) may play in causing disease in transplant recipients. Several groups of investigators have now identified a potential interaction between the development of HHV6 and HHV7 and CMV infection in organ transplant recipients.60,61 Reactivation of HHV6 infection following LTx has been associated with the development of an increased CMV viral load and a greater likelihood of developing CMV disease.61 It has also been suggested that some or all of the symptoms typically associated with CMV syndrome in patients with proven CMV infection may be attributable in part to HHV6 or HHV7. Studies in children have suggested that infection due to HHV6 alone is a relatively common cause of unexplained fever in pediatric LTx recipients.62,63 The full spectrum of HHV6 and HHV7 diseases and their potential therapies remain to be determined.

Adenovirus Adenovirus has been reported to be the third most important virus affecting pediatric LTx recipients, occurring in 10% of 484 children undergoing LTx under cyclosporine-based immunosuppression.64 Symptomatic disease (ranging from self-limited fever, gastroenteritis, or cystitis to devastating illness with necrotizing hepatitis or pneumonia) occurred in over 60% of these infected patients, and infection occurred within the first 3 months after transplantation. However, the frequency of invasive adenovirus infection after pediatric LTx has

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decreased markedly since the introduction of tacrolimus-based immunosuppression.19 In a recent report, only 4.2% of pediatric LTx recipients using tacrolimusbased therapy developed adenovirus disease.65 A presumptive diagnosis of adenovirus infection in pediatric LTx recipients is difficult as fever, hepatitis, and pneumonia may be caused by a variety of other pathogens. The presence of high-grade fevers, unexplained elevations in hepatocellular enzymes suggestive of hepatitis, and symptoms suggestive of adenovirus infection should prompt serial cultures for viruses (including adenovirus) and/or PCR investigation, as well as the possibility of graft biopsies. A histologic examination for the presence of adenoviral inclusions as well as the use of immunohistochemical stains of biopsy specimens should be undertaken to help confirm this diagnosis. Unfortunately, there is no definitive treatment for adenoviral infection at this time. The most important component of therapy is supportive care along with a decrease in immunosuppression. The role of antiviral agents is unproven. Although early case reports focused on the use of ribavirin,66-69 more recent reports have described the use of cidofovir as a potential treatment for adenoviral disease in immunocompromised hosts, including organ transplant recipients.70-72 Unfortunately, no conclusive evidence of the efficacy can be drawn from these reports.

Common Community-Acquired Viruses Although the course of illness has been poorly documented, most children who undergo LTx experience the usual respiratory viruses and gastrointestinal illness without significant problems. However, infections due to influenza, parainfluenza, and RSV can cause more severe disease in young children, especially if infection occurs soon after transplantation and during periods of maximal immunosuppression.73-76 The diagnosis of these viral pathogens is accomplished through the performance of viral cultures, antigen detection, and/or nucleotide amplification testing (eg, PCR). Antiviral therapy may be of value for influenza, but there are few data to confirm the efficacy of treating RSV and parainfluenza with antivirals in this population.

OPPORTUNISTIC INFECTIONS P. jirovecii is a well-documented cause of pneumonia in immunocompromised patients, including liver transplant recipients. Prophylactic trimethoprim/sulfamethoxazole is safe, inexpensive, and effective.77 The use of this strategy has eliminated PCP at the Children’s Hospital of Pittsburgh. Alternative prophylactic regimens for the sulfa-allergic patient include aerosolized pentamidine (for patients ⬎ 5 years of age)78 and dapsone.79 Tuberculosis (TB) is of concern in recipients of LTx. Development of TB after pediatric LTx is extremely uncommon, with only 11 cases reported to date,80-82 although the incidence of TB after LTx in adults in Europe

and the United States has ranged from 0.9% to 2.3%.81,82 Not surprisingly, higher rates (up to 15% of organ transplant recipients) have been reported from areas of high-level endemnicity of TB.82 Recognition of TB among organ transplant recipients is critical as mortality rates ranging from 25% to 40% have been reported in this population.81,82 Recommendations for the management of TB in transplant recipients were included in the American Society for Transplantation Guidelines for the Prevention and Treatment of Infectious Complications of Organ Transplantation.83 Cryptococcosis, coccidiomycosis, and histoplasmosis have been infrequently reported among pediatric LTx recipients. Prior infection with these pathogens is common in geographic areas where they are endemic. Experience with coccidiomycosis in transplant recipients suggests that a minimum of 4 months of antifungal therapy, such as fluconazole, should be given to transplant recipients found to have serologic evidence of this pathogen.84 Similarities between coccidiomycosis and other fungal pathogens suggest that similar strategies may be necessary for patients with a positive history of prior fungal infection with pathogens known to recur after resolution of the primary infection.

PROPHYLACTIC REGIMENS Perioperative prophylaxis is used to prevent intraoperative sepsis and wound infection. We consider piperacillin/tazobactam to be an appropriate agent for perioperative prophylaxis for children undergoing LTx. If infection is suspected in the donor, antibiotics are chosen to cover those organisms identified from the donor, and treatment is usually extended to a therapeutic course of 10 to 14 days. In the absence of proven or suspected infection in the donor, perioperative prophylaxis is usually limited to the first 48 hours after transplant. Considerations regarding long-term prophylaxis against infections occurring beyond the perioperative period include the risk and severity of infection as well as the toxicity, cost, and efficacy of a given prophylactic strategy. Nystatin is recommended for all pediatric transplant recipients in an effort to prevent oropharyngeal candidiasis. Trimethoprim/sulfamethoxazole is used to prevent PCP. Although some centers recommend using trimethoprim/sulfamethoxazole for only the first 6 months following LTx, anecdotal experience with patients presenting with PCP long after transplantation and the relative safety of this agent have led us to recommend its use indefinitely following LTx in children. The frequency and severity of CMV infection in transplant recipients have prompted consideration of prophylactic strategies. Potential roles exist for intravenous and oral ganciclovir85-87 and oral valganciclovir.88 Currently, we recommend the use of intravenous ganciclovir for younger pediatric LTx recipients. However, oral valganciclovir is a reasonable alternative for adolescents. Upon completion of pharmacokinetic studies for dosing oral valganciclovir suspension in children

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TABLE 1. Suggested Accelerated Schedule for the Vaccination of Solid Organ Transplant Candidates

Vaccine DTaP

Hepatitis A Hepatitis B HiB

Minimum Age of Vaccination 6 weeks

6 months Birth 6 weeks

Influenza MPV MMR PCV7

6 months 2 years 6 months 6 weeks

PPV23 Varicella

2 years 6 months

Minimum Interval Between Doses

Determination of Serologic Status

Review and Update Vaccine Status of Household Contacts

First and second, 4 weeks Second and third, 4 weeks Third and fourth, 6 months Fourth and fifth, 6 months First and second, 4 weeks First and second, 4 weeks Second and third, 8 weeks First and second, 4 weeks Second and third, 4 weeks Third and fourth, 8 weeks First and second, 4 weeks

Not routinely recommended

Yes

Pre- and post-transplant Pre- and post-transplant

Consider Yes

Not routinely recommended

No

Not routinely recommended Not routinely recommended Pre- and post-transplant Not routinely recommended

Yes No Yes No

Not routinely recommended Pre- and post-transplant

No Yes

First and second, First and second, Second and third, Third and fourth,

4 4 4 8

weeks weeks weeks weeks

First and second, 4 weeks

NOTE: This table was adapted from Campbell and Herold.93 Abbreviations: DTaP, diphtheria, tetanus, and acellular pertussis vaccine; HiB, Haemophilus influenzae type B vaccine; MMR, measles, mumps, and rubella vaccine; MPV, meningococcal polysaccharide vaccine; PCV7, 7-valent pneumococcal conjugate vaccine; PPV23, pneumococcal polysaccharide vaccine.

after transplantation, this will likely also be a reasonable alternative to intravenous treatment for younger children. Serial monitoring of the CMV viral load in the blood to inform the use of preemptive antiviral therapy has been proposed as an alternative to these chemoprophylactic strategies.36 Although this strategy has gained acceptance at some centers, experience in pediatric LTx recipients remains limited. Finally, the use of viral load monitoring after completion of chemoprophylaxis is gaining increasing acceptance. The growing recognition of the importance of EBV infections in pediatric organ transplant recipients has led to an interest in the prevention of EBV infections and PTLD. A number of strategies are currently being explored (eg, immunoprophylaxis, monitoring, and preemptive therapy)57,89,90; the efficacy of these approaches has not been established. The use of viral load monitoring to inform preemptive reductions in immunosuppression appears to be the most promising of these strategies.45,89,90

Immunizations in Liver Transplant Recipients Recommendations for the use of immunizations for organ transplant candidates and recipients were included in the 2004 American Society for Transplantation Guidelines.91 Central to these recommendations was that the immunization history should be reviewed early in the transplant evaluation process and that a strategy to update and follow immunizations should be created and regularly reviewed during the pretransplant waiting period. This is particularly relevant for pediatric LTx

recipients, who are frequently young when they are transplanted and consequently have not completed their primary vaccination series. Furthermore, immunizations are sometimes delayed and often overlooked while these children are waiting for transplantation because of their medical conditions. Despite their underlying illnesses, vaccine responses are likely to be better in the transplant candidate compared to the transplant recipient.92 Because of the young age of some candidates, the initiation of some of the vaccine series may need to be earlier and intervals between vaccines doses may need to be shorter than what is routinely recommended.93 A summary of vaccine recommendations is provided in Table 1.

Live Vaccines Special consideration must be given to live vaccines. In general, live viral vaccines are not administered after transplantation, although several small clinical trials evaluating the measles, mumps, and rubella vaccine (MMR) and varicella vaccine have demonstrated promising safety profiles.94-96 Thus, the ideal time to give these live vaccines is clearly prior to transplantation. MMR can be administered as early as 6 months of age. If children have not received their transplantation by 12 to 15 months of age, revaccination with MMR should occur. A second dose of MMR is recommended for the small percentage of individuals who do not respond to the first dose. The minimum interval between doses should be 1 month. Optimally, MMR should be administered a minimum of 3 to 4 weeks prior to transplantation. Varicella vaccine is approved for children ⱖ 12

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months of age. However, at least 1 transplant center has published its approach of giving this vaccine to transplant candidates who are as young as 6 months of age.93 It is now recommended that 2 doses of varicella should be administered. The interval between dose 1 and dose 2 can be 1 month. Like MMR, varicella vaccine should be administered a minimum of 3 to 4 weeks prior to transplantation. Two additional live viral vaccines are now routinely available for children. RotaTeq, a human-bovine reassortant live-attenuated rotavirus vaccine, is licensed for children between the ages of 6 and 32 weeks. Currently, there are insufficient data regarding the efficacy and safety in immunocompromised children, including transplant recipients. Accordingly, although it is not specifically contraindicated,97 the ideal time to administer this vaccine is prior to transplantation. In addition, rotavirus vaccine should not be administered to infants with acute, moderate-to-severe gastroenteritis until the condition improves.98 Infants with mild acute gastroenteritis can be vaccinated particularly if the delay in vaccination might be substantial and might make the child ineligible to receive the vaccine (eg, ⬎13 weeks old before vaccination is initiated). Primary care providers should consider the potential risks and benefits of administering rotavirus vaccine to infants with preexisting chronic gastrointestinal disease. Infants with preexisting chronic gastrointestinal conditions who are not undergoing immunosuppressive therapy should benefit from rotavirus vaccine vaccination, and the benefits outweigh the theoretical risks. However, the safety and efficacy of rotavirus vaccine have not been established for infants with these preexisting conditions (eg, congenital malabsorption syndromes, Hirschsprung’s disease, short-gut syndrome, and persistent vomiting of unknown cause). A live-attenuated, trivalent, cold-adapted influenza vaccine has been licensed for use in healthy individuals 2 to 49 years of age. However, this vaccine is not recommended for individuals with medical illnesses that put them at a high risk for influenza, including organ transplants recipients.

dren, Vaqta® and Havrix®, and these formulation doses differ from those of adults. Vaqta® can be administered to persons 12 months to 18 years old, and they should receive 25 units per dose in a 2-dose schedule, whereas persons older than 18 years should receive 50 units per dose in a 2-dose schedule. Havrix® can be administered to persons 12 months to 18 years old at 720 ELISA units per dose in a 2-dose schedule, whereas persons older than 18 years should receive 1440 ELISA units per dose in a 2-dose schedule. Hepatitis B is universally recommended for all infants in a 3-dose schedule commencing at birth.100 The second dose should be administered at 1 to 2 months of age. The final dose should be administered no earlier than 24 weeks. If combination vaccines are administered, it is acceptable to receive 4 doses of hepatitis B. For those children who have not received the hepatitis B vaccine, a 3-dose series is recommended. A 2-dose series of Recombivax HB® is licensed for children 11 to 15 years old.

Inactivated Vaccines

Infections remain an important problem following LTx in children. Knowledge of the type, timing, and predisposing risk factors for these infectious complications allows for their timely and appropriate diagnosis and management. The use of vaccines before and after transplantation can help to minimize the risk of infection in these children.

Theoretically, there is no contraindication for administering inactivated vaccines to transplant recipients. If vaccines are to be administered post-transplant, they should be given at a time when the recipient’s immunosuppressive regimen is both stable and at a relatively low level. In general, this is typically somewhere between 6 and 12 months after the transplant. With the exception of influenza vaccine, the use of T cell depleting induction immunotherapy (eg, Thymoglobulin®) should prompt consideration of delaying initiation of vaccinations until the completion of the first posttransplant year. Hepatitis A is currently recommended for the routine vaccination of children older than 1 year in the United States. Two doses should be given at least 6 months apart.99 There are 2 formulations approved for chil-

Vaccination of Contacts Another form of protection for transplant recipients is vaccinating their close contacts. The immunization of contacts with killed vaccines does not pose a risk to the transplant recipient. Additionally, with the exception of oral polio, the receipt of live vaccines is not contraindicated for household contact of transplant recipients. This includes both varicella vaccine and MMR. Healthcare workers who are in contact with these children should be up to date on their vaccinations. At a minimum, healthcare workers should receive the yearly influenza vaccine, the full 3-dose series of the hepatitis B vaccine, the MMR and varicella vaccines, and a single dose of the tetanus, diphtheria, and pertussis vaccine according to the current guidelines.101 Immunization with influenza and pertussis vaccines is also recommended for household contacts in order to prevent transmission to these vulnerable children.

SUMMARY

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