Infectious complications in pediatric solid organ transplantation

Pediatr Clin N Am 50 (2003) 1451 – 1469

Infectious complications in pediatric solid organ transplantation William L. Keough, MD, MSa,b, Marian G. Michaels, MD, MPHa,b,* a

Division of Allergy, Immunology and Infectious Diseases, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA b Department of Pediatrics, University of Pittsburgh School of Medicine, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA

Transplantation has emerged as one of the remarkable achievements of the latter half of the twentieth century for treatment of many end-stage organ disorders. Survival in pediatric solid organ transplantation continues to improve as strategies for immunosuppression, prevention, and treatment of infectious complications progress [1]. The United Network for Organ Sharing reported 3-year survival rates after pediatric transplantation between 1995 and 2000 to be 73% to 83% for heart, 90% to 97% for kidney, 47% to 57% for lung, and 75% to 86% for liver transplantation [2]. Despite continuously improving results, infection remains a leading cause of morbidity and mortality in pediatric transplant recipients [3].

Overview of infection in solid organ transplantation Factors that predispose to infectious complications after solid organ transplantation can be identified and divided into factors found before, during, or after transplantation [3,4]. Whereas some microbial agents are more pathogenic to one type of organ transplant, similarities in the types of infections are found regardless of the particular organ or organs transplanted [3,4]. This article provides an overview of infectious complications after pediatric transplantation. Understanding an individual transplant recipient’s exposures, predisposing factors, and technical issues can aid in preventing infectious complications and developing a focused differential when infections arise.

* Corresponding author. Division of Allergy, Immunology and Infectious Diseases, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213. E-mail address: [email protected] (M.G. Michaels). 0031-3955/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0031-3955(03)00126-3

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Predisposing factors The underlying disease process of the patient has intrinsic risk factors for infection [5 –7]. This is evident, for example, in patients with cystic fibrosis who undergo lung transplantation [4,8]. Herein the same bacteria and fungi that colonized the native airways before transplantation can cause infection afterwards [8]. Corrective or palliative procedures, such as the Kasai procedure for biliary atresia, can lead to technical difficulties during subsequent transplantation of the liver. Long-standing malnutrition from any disease state also can lead to an increased susceptibility to infectious complications, whether from a direct or indirect effect. In some instances, malnourished children who are awaiting transplantation are supplemented with parenteral nutrition, which can lead to catheter-related infections. Similarly, the natural progression of certain diseases can require frequent hospitalization, antibiotic exposure, or the use of mechanical ventilation to support the transplant recipient before and after transplantation. These factors can lead to colonization with nosocomially acquired flora with increased resistance to antibiotics. The type of organ being transplanted can predict the site and type of infectious complications in the posttransplant period [1,3,5,9,10]. For example, the urinary tract is the most common site of infection after a renal transplant. Similarly, the abdomen is the most common site of infection after liver transplantation, and the lung is the most common site after lung transplantation [5,10]. The age of the child who is receiving a transplanted organ is also important in determining potential infectious complications. Infants and young children tend to exhibit more severe disease with certain viral and bacterial infections when compared with older children and adults [4]. For example, an infant who receives a transplant during the winter may experience more severe respiratory syncytial virus (RSV) bronchiolitis than an older child who has experienced several respiratory seasons [11]. This also can be true for parainfluenza [12]. Infants and younger children are more likely to undergo their primary infection with members of the herpesvirus family (eg, Epstein-Barr virus [EBV], cytomegalovirus [CMV], varicella zoster virus, herpes simplex virus) after transplantation [13]. Although the non-immunocompromised child experiences a milder disease course than an adult with these viruses, primary infection in the face of modified T-cell dysfunction from iatrogenic immunosuppression leads to morbidity regardless of age. As a final difference from adults, pediatric transplant recipients may not have completed their primary immunization series. The primary immunization series is generally not completed until the second year of life. The natural progression of diseases that lead to transplant and the management of these illnesses frequently require transfusion of blood products, which postpones the timing of live virus vaccines. A child who has not completed the primary immunization series before transplantation remains at greater risk for vaccine preventable illnesses [14]. The antibody response to vaccines administered after transplantation is not always ideal. Pediatric transplant recipients are at risk for acquiring infections from their donor organ or blood transfusions. This is especially notable for microbial agents

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that can be harbored latently in transplanted tissue or hematopoietic cells, such as CMV, EBV, or toxoplasmosis [5,13,15 – 17]. These pathogens may be passed in the organ from a seropositive donor to the recipient at the time of transplantation. Disease is most severe if the recipient is naı¨ve to the donor’s pathogen. Table 1 outlines recommended screening for candidates and donors. These screening studies assist transplant physicians with predicting infectious for which the recipient is at risk. They also aid with developing prophylactic strategies. Operative factors Transplantation of any organ carries with it technical challenges during the actual procedure [1,7]. The time from harvest of donated organs to time of transplant and reperfusion can influence whether there is significant ischemic injury to the donated organs. This outcome contributes to an increased infection risk [18]. Effects to local anatomy during the transplantation also may contribute to infectious complications in the postoperative period [1,7]. One example is injury to the phrenic nerve during lung or heart-lung transplantation, which leads to lessthan-optimal pulmonary mechanics and clearance postoperatively and increases respiratory infections. It is also known that the type of reconstruction used for the biliary tree in liver transplantation influences the postoperative infectious complication rate [1,7]. Posttransplant factors Many factors influence infectious complications after transplantation, the most important of which are the overall balance and types of immunosuppression. Other factors include the sites and types of indwelling catheters and length of duration of their use, technical challenges during the operation, any need to return to the operating room, nosocomial exposures, and the presence or absence of immunomodulating viruses (eg, CMV, EBV, and hepatitis B and C) [1,3,4,16]. Timing of infections Research has established a temporal pattern to specific types of infections after solid organ transplantation [3,4]. Although the precise timing can be artificial, the time after transplant can be divided into early, intermediate, and late periods. The early period extends for the first month after transplantation and is classically the period of postoperative wound infections from bacteria or yeast. The intermediate period is generally considered from 1 month to 6 to 12 months after transplantation and encompasses the time when latent organisms can reactivate either from the donor or the recipient. The late period extends beyond this time and is less well defined because patients are often at home far from the transplant center. Community-acquired infections occur during this period. Fig. 1 provides a schematic of the timing of various types of infections after transplantation. Local epidemiology (eg, RSV during the winter in temperate climates), the need for augmentation of immunosuppression (eg, cyclosporine/tacrolimus versus anti-

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Table 1 Currently recommended pretransplant screening of candidates and donors Serology

Candidate

Donor

HIV1/2

Although HIV was previously a contraindication to transplantation, people controlled on antiretroviral medications have undergone successful transplantation; HIV is transmissible via transplant and is a contraindication to donating an organ HTLV has been associated with tumors and diseases, and this risk may be increased after transplantation; HTLV is transmissible via transplant and is usually considered a contraindication to donating an organ HBV can worsen after transplantation and reinfect a liver graft; HBV is transmissible and is a contraindication to donating; HBV has been transmitted from livers of donors that were positive for antibody to core antigen, even without the presence of HBV’s Ag; HBV’s Ab presence signifies immunity to HBV in the recipient HCV can worsen after transplantation; HCV is transmissible and is a relative contraindication to donating (some centers use organs from HCV donors for HCV + recipients) Risk of disease is influenced by candidate and donor status Risk of disease is influenced by candidate and donor status Risk of reactivation is based on candidate status

HTLV1/2

HBV sAg cAb sAb

HCV

CMV EBV Herpes simplex virus Varicella zoster virus RPR T. gondii

Consider

Measles

Consider

Mantoux

Comment

Consider

Living donors

Risk of reactivation or primary disease is based on candidate status Syphilis is transmissible, but treatment can prevent transmission Transmissible in all organ types if donor positive, but highest risk is in recipients of a heart; candidates and donors for heart transplantation should be screened The authors currently test serology for measles (and/or mumps) during the evaluation period to determine if the candidate responded to their initial vaccine series; if negative, every attempt is made to vaccinate at least a month prior to the time that the patient might undergo transplantation M. tuberculosis can reactivate after transplantation; there is a risk of transmission from a donor; however, currently it is only practical to test a living donor

Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; HTLV, human T-cell lymphotropic virus; RPR, rapid plasma regain.

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Fig. 1. Timing of infections after transplant.

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lymphocyte preparations, such as OKT3), and specific exposures also influence the timing of infectious complications.

Infectious syndromes: agent specific Several specific viral, bacterial, and fungal organisms are of particular importance in transplant recipients. Some microbial agents are peculiar to specific organs transplanted (eg, Toxoplasma gondii in heart transplant recipients or BK virus in renal transplant patients), whereas others are common across organ types (eg, EBV and CMV). This section addresses some of the common microbial agents that cause complications in transplant recipients. Viruses Human herpesviruses The human herpesviruses represent a diverse group of DNA viruses characterized by lifelong latency in the host punctuated by periods of reactivation. They can cause infectious complications in pediatric transplant recipients [3 –5,16]. The two most well-studied herpesviruses are EBV and CMV. The others—herpes simplex virus, varicella zoster virus, and human herpesviruses 6, 7, and 8—likewise have been shown to cause disease in recipients of all transplant types [19 – 23]. In general, disease manifestation is most severe with primary infection after transplantation, but reactivation and reinfection also can be important. Epstein-Barr virus EBV is a potential pathogen after any transplant. Disease may manifest as a mild mononucleosis syndrome, posttransplant lymphoproliferative disease (PTLD), or lymphoma. (PTLD is discussed in detail in another article in this issue.) Absence of immunity evidenced by negative EBV serology before transplant is the most important risk factor for all recipients except individuals who undergo intestinal transplantation [15,24 –26]. Disease from EBV most commonly arises during the intermediate period, but risk continues late after transplantation [3,4]. Studies have shown that as much as 4% of all children who underwent solid organ transplantation and 20% of children with primary EBV infection developed PTLD from 1 month to 5 years after transplantation [15,24,27,28]. The risk varies, with small bowel recipients having the highest risk, followed by recipients of lung transplantation. The risk of PTLD after small bowel transplantation remains high even in children who have previous immunity. Although the reason for this heightened threat is not well known, it may be related to the intense immunosuppression required to prevent graft rejection and a large load of virus that might be transmitted with such a lymphoid-rich tissue. Histologic evaluation is paramount in suspected EBV infections in transplant recipients. Symptoms such as protracted and hectic fevers, exudative tonsillitis, organomegaly, lymphadenopathy, and gastrointestinal bleeding should prompt an

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evaluation for PTLD. A predominance of atypical lymphocytes on peripheral blood count is a laboratory clue, as is elevation in liver transaminases. Further evaluation should include quantitative EBV nucleic acid-based assays, CT of the head, neck, chest, and abdomen, and EBV serologies. Biopsies should be obtained of abnormal lymph nodes or suspicious lesions to prove the diagnosis. Immunohistopathologic staining for EBV with agents such as Epstein Barr encoded ribose nucleic acid (EBER) can help distinguish infected cells versus nonspecific proliferation of lymphocytes and rejection. Reduction of immunosuppression remains the prime treatment in an effort to allow the development of cytotoxic T-cell responses [24]. Other preventive and treatment strategies directed against PTLD are active areas of research and are discussed elsewhere in this issue. Cytomegalovirus CMV remains an important infectious complication after transplantation [3,13,17,29,30]. It has been shown to cause direct and indirect effects on the graft and native organs of the transplant recipient [30,31]. Similar to EBV, the highest risk is the mismatched group in which the donor is seropositive for CMV and the recipient is seronegative for CMV at the time of transplantation (D+/R ) [31]. Individuals who have reactivation or reinfection with CMV tend to have milder disease [17]. Requirement for substantial immunosuppression can lead to significant disease from CMV, however, even in a previously seropositive recipient [31 – 33]. The risk of severity of disease from CMV also varies by organ transplanted—intestinal being the highest followed by lung, then liver, heart, and kidney. CMV usually presents between 1 and 6 months after transplant [3,4,29]. Prophylactic strategies with antiviral agents can postpone the onset, however. Disease can manifest as a nonspecific CMV syndrome characterized by fever, malaise, myalgias and leukopenia, and thrombocytopenia. Disseminated disease also can occur. Organ-specific damage can occur when CMV affects the transplanted graft, such as hepatitis after liver transplantation or pneumonitis after lung transplantation [17,30,33,34]. The lungs, liver, and gastrointestinal tract are common sites of CMV infection regardless of the organ transplanted [29,30,33]. The use of antiviral agents, such as ganciclovir, has led to significant reductions in mortality and morbidity from CMV after transplantation [17,32]. Despite antiviral therapy, CMV disease can be substantial after intestinal transplantation. Approximately 90% of patients who undergo intestinal transplantation have involvement of their native gastrointestinal tract along with their allograft. Similar to EBV, the voracity of the infection is likely to be a combination of the significant immunosuppression required in this group of patients and the potential high load of virus that might be transmitted with the intestinal graft. When CMV disease is suspected, laboratory evaluation is important but must be interpreted in the context of the patient’s underlying CMV status. A positive culture, antigenemia assay, or polymerase chain reaction assay in a previously seronegative patient signifies a primary infection and usually leads to disease if treatment is not instituted. Shedding of virus can occur without symptoms,

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however, particularly in previously seropositive individuals. Studies correlating quantitative levels of CMV antigenemia or copies of virus in the peripheral blood have been performed to predict which patients will develop disease [35]. The results vary from test to test and between laboratories, so it is important to have good communication with the laboratory to correlate levels with clinical results. Histologic evidence from organs suspected to be infected with CMV also is recommended. Prevention and treatment of CMV after transplantation continue to be active areas of study. Herpes simplex virus Like the other human herpesvirus infections, herpes simplex virus infection in the pediatric patient can represent primary infection or reactivation of a latent infection [29,36]. Similar to EBV and CMV, primary infection in the transplant recipient generally results in more severe disease. Unlike the other viruses, however, herpes simplex virus is not usually donor associated. Many children with reactivation handle the disease well; however, they tend to shed the virus longer than individuals who have no alteration in their immune status. Acyclovir prophylaxis early after transplantation is advocated by most centers for seropositive individuals [3]. Varicella virus Children frequently undergo transplantation before receiving the varicella vaccine or developing immunity from wild-type chickenpox. Deaths have been reported in pediatric liver and renal transplant recipients despite the use of varicella immunoglobulin [19,37]. The administration of acyclovir to several of these patients once varicella was recognized did not prevent death. Although an effective varicella vaccine has been available for several years, it is not recommended before 12 months of age [38]. Because it is a live virus vaccine, it is not routinely recommended in immunocompromised patients. Use of the varicella vaccine in transplant recipients is an area of active research with promising preliminary results [38]. Varicella immunoglobulin and acyclovir remain the standards of prevention and therapy in transplant recipients [19,37,38]. Researchers recommend that any nonimmune transplant recipient exposed to varicella receive varicella immunoglobulin as soon as possible but at least within 72 hours after exposure. Prompt administration of intravenous acyclovir is the prudent course if lesions develop and should be continued until defervesence, abatement of new lesions, and crusting over of existing lesions [19,37,38]. Human herpesviruses 6, 7, and 8 These herpesviruses have been noted to cause disease in recipients of transplantation; however, the full epidemiologic spectrum currently remains undetermined. Human herpesviruses 6 and 7 are ubiquitous viruses that are believed to potentiate disease from CMV in adult transplant recipients [21,22,39]. Anecdotal evidence of self-limited febrile illnesses also have been found in pediatric liver transplant recipients after primary infection with human herpesvirus 6 [23]. Unlike

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human herpesviruses 6 and 7, which are ubiquitous, human herpesvirus 8 is prevalent in specific areas, such as Africa, the Middle East, and the Mediterranean. This virus has been associated with disease and Kaposi’s sarcoma after transplantation in children and adults. Donor transmission and reactivation disease have been postulated [20,40]. Adenovirus Adenovirus is a common pediatric infection. Although similar to some of the pathogens already mentioned, it can represent latent infection with reactivation or primary acquisition from the donor, hospital environment, or community. In one series of lung transplant recipients, 3% of patients developed fatal pneumonitis early after transplantation [41]. Other investigators found that adenovirus, even late after lung transplant, led to bronchiolitis obliterans [42]. Most of these infections occurred in the first 6 months after transplant. In adult renal transplant recipients, adenovirus has been shown to cause hemorrhagic cystitis and graft dysfunction, but this has not been well studied in children [42]. Community-acquired respiratory viruses This large group of viruses can pose potential problems in the pediatric transplant population. Viruses such as RSV, parainfluenza, and influenza are of particular importance during the fall and winter months in the pediatric population [11,12]. Infection of infants and acquisition of these viruses early after transplantation were associated with severe disease and mortality. Accordingly, intense infection control practices are required. Preventive strategies, such as influenza vaccination of the patient and household contacts, should be implemented. Other strategies, such as immunoglobulin products (eg, Palivizumab for RSV) or neuraminidase inhibitors, also may be implemented for particularly high-risk patients. Bacteria and fungi Bacteria and fungi account for several infections that occur particularly early after transplantation. The types of bacteria are related to the type of organ transplanted and underlying conditions that may be found. Some of the more common scenarios are discussed in this section. Infections of the surgical wound site are most often from drop-in skin flora or soiling that occurs at the time of transplantation [3,4,36]. As such, gram-positive organisms account for most infectious agents. It has been recognized that an increased risk of gram-negative bacteria and Candida infections occur at the wound site if complications occur and a subsequent operation is required [7,9,16,43– 46]. Consequently, perioperative antimicrobial agents are chosen to cover more broadly these microbes if a child has a subsequent operation at the authors’ institution [9]. Bacterial and fungal complications also can occur at the site of transplant, such as intra-abdominal abscesses in liver or small bowel transplant recipients or fungal infection at the bronchial anastomosis after lung transplantation [8,29,36,47 – 49].

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For these reasons, intraoperative cultures are helpful because they indicate the flora with which an individual patient is colonized and guide initial therapy if complications occur. Bacterial infections are less frequent after renal transplantation, but when they do occur they are often related to bacteria in the urinary tract system [29,43]. Heart transplant recipients who received their hearts at an early age seem to be at increased risk for subsequent disease from Staphylococcus pneumoniae [5,29,32,36,43]. Lung transplant recipients with chronic rejection are at risk for lower airway disease from lactose-negative, gram-negative bacteria such as Pseudomonas, Stenotrophomonas, Alcaligenes, and Aspergillus species [8,29,36,48,49]. Indwelling catheters represent a risk for bacterial and Candida infection regardless of the time from surgery [3,5,29,36,43,50]. An effort is made to limit their presence as much as possible. The use of short-term antimicrobial-impregnated catheters is being studied in adults and may be useful for pediatric transplant recipients. Mycobacteria Mycobacterium tuberculosis and nontuberculous mycobacterium can cause disease in the transplant population. Although the incidence of tuberculosis— particularly resistant tuberculosis—is on the rise, it has been rare in the United State in pediatric transplant recipients. A recent series from the United Kingdom described an incidence of 2.4% [3]. M. tuberculosis disease can occur after primary infection or reactivation in persons previously infected. For individuals previously infected, the greatest risk seems to be related to inadequate therapy before transplantation. All potential transplant recipients should receive a Mantoux test purified protein derivative test as part of the pretransplant evaluation [4]. This is of particular importance for persons who live in endemic areas. Appropriate evaluation and therapy for individuals with positive test results should be initiated before transplantation. Patients who are suspected of acquiring tuberculosis after transplantation require intensive evaluation because purified protein derivative testing may not be diagnostic. Every effort should be made to isolate an organism for susceptibility testing. Nontuberculous mycobacterium are ubiquitous organisms found in the soil and water. They also can cause disease after transplantation, albeit infrequently [51]. Disease from nontuberculous mycobacterium can be localized to the surgical wound site, lungs, skin, or musculoskeletal system. Nontuberculous mycobacteria also have been isolated from bronchoalveolar lavage specimens from pulmonary patients without appreciable clinical correlation. Six of 80 (7.5%) pulmonary transplant recipients at Children’s Hospital of Pittsburgh had nontuberculous mycobacterium isolated from bronchoalveolar specimens without requiring specific treatment (unpublished data). Repeated isolation of nontuberculous mycobacterium and disease correlation (eg, fevers, wound infection, pneumonia, isolation in the blood) should prompt treatment with two to three active drugs. Susceptibility testing is recommended because nontuberculous mycobacteria often have multidrug resistance patterns.

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Other opportunistic pathogens Pneumocystis jiroveci (formerly Pneumocystis carinii ) As with other immunocompromised populations (eg, chemotherapy, HIV/ AIDS), P. jiroveci pneumonia is a potential complication of solid organ transplantation [52 – 55]. Before the use of prophylaxis, the incidence of P. jiroveci pneumonia was as high as 35% in some series [52 – 55]. Disease most commonly occurred between 1 and 12 months after transplantation [3]. Lung transplant recipients were at particularly high risk during the first 2 years after transplantation [8,29,36,48,53]. The use of prophylaxis, particularly with trimethoprim-sulfamethoxazole, has virtually eliminated this problem [52,54]. Other agents, such as pentamadine, dapsone, and atovaquone, also have been shown to be efficacious. Despite the use of prophylaxis, P. jiroveci pneumonia should remain on the differential diagnosis for any transplant recipient who has fever, hypoxia, and lower respiratory infection because breakthrough disease can occur or patients may not be compliant with their medication.. Treatment of P. jiroveci pneumonia is well described in many sources and is beyond the scope of this article. Toxoplasma gondii Although T. gondii is a pathogen of concern in many immunocompromised patients, it is of particular concern and is well described in the heart transplant recipient [10,34,47,56], probably because of the tropism of the organism for cardiac muscle. Persons at greatest risk for disease are in the donor-positive/ recipient-negative cohort [10,34,47,56]. Clinical symptoms from toxoplasmosis usually occur 2 to 24 weeks after transplantation, with reactivation of the cysts within the graft in the setting of no prior immunity. Prevention has focused on the highest risk group because symptomatic disease rarely has occurred in other groups. Pyrimethamine prophylaxis has been shown to be efficacious [10,47,56]. Some studies also have shown that in addition to its role in preventing P. jiroveci pneumonia, using prophylactic trimethroprim-sulfamethoxazole daily may prevent toxoplasma [47]. Increases in immunosuppression, however, can increase the risk of acquiring disease. Treatment for toxoplasma remains a combination of pyrimethamine and sulfadiazine. Aspergillus and other filamentous fungi Filamentous fungi, especially Aspergillus, have been noted to cause disease after transplantation. Most data available are from studies in adult recipients [8,48,49]. Similar to adults, increased rates of Aspergillus are noted in pediatric organ transplant recipients after CMV disease and during periods of hospital construction [29,30,48]. Lung transplant recipients with underlying cystic fibrosis who were previously colonized with Aspergillus can develop disease after transplantation. Similarly, lung transplant recipients, regardless of their underlying condition, who develop bronchiolitis obliterans can become colonized with Aspergillus. The fungus disseminates and results in poor outcomes [8,30,48]. Experience at the authors’ institution suggests that prophylaxis of high-risk

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patients with oral antifungal agents (eg, itraconazole) seems to be efficacious (unpublished data).

Evaluation of the pediatric transplant recipient with suspected infection The pediatric transplant recipient may present with a host of either constitutional or organ-system specific issues. This section attempts to aid the pediatrician in the diagnostic evaluation of these patients for some of the major presenting symptoms. The evaluation of any of these presenting symptoms in a transplant recipient is influenced by type of and timing after transplant, level of immunosuppression, age, and local epidemiology (eg, time of year, exposures). Fever In the immediate postoperative time period (Fig. 1), fever may be related to surgery, respiratory mechanics (eg, atelectasis), rejection, or infection, often at the surgical or catheter sites [3,5,9,16,29,43]. Nosocomial infection, particularly in a patient who was hospitalized before transplantation, is also in the differential. Fever during the middle period should stimulate a search for donor-transmitted infection or reactivation of latent viral infections in the host [30,47,53,54]. Late after transplantation, fever may represent the acquisition of a community-acquired, self-limited virus or acquisition of infections associated with chronic rejection [13]. Ongoing risk of EBV-associated PTLD or tumors is also in the differential of fever in the late period. The initial approach to fever in a transplant recipient is no different than that in any other pediatric patient. History and physical examination offer many insights into the possible causes of the fever. A careful review of the patient’s pretransplant course, including underlying diagnoses, comorbid conditions, and past infections should be undertaken. It is also critical to know the recipient and donor baseline serologic status and have an understanding of the type of transplant, induction, and maintenance immunosuppression that are being used. The time since transplant also directs further evaluation [3,16,36,50]. Review of the current exposures, associated symptoms, onset and duration of fever, and presence or absence of foreign bodies also provides key insights into the origin of the fever and the need for and direction of further study. Timing exists for specific infections in the posttransplant period (Fig.1). In the early period (0 – 30 days after transplant), bacterial and fungal infections are of great concern. Surgical wounds also should be examined carefully for signs of infection. Adequate sampling and culture of blood, urine, and tracheal secretions are recommended from indwelling catheters and tubes. If no source of infection is clinically evident, radiographic studies of the site transplanted to evaluate for occult abscess or fluid collection may be necessary. Finally, biopsy of the graft to rule out rejection is likewise warranted because it may present with fever and be indistinguishable from infection. Depending on clinical circumstances, empiric or defini-

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tive antimicrobial therapy can be initiated after obtaining cultures and then modified based on their results. During the middle period, further studies are warranted in the febrile patient, particularly individuals without a localizing source of the fever. These studies include viral studies, with particular attention to CMV and EBV [15,29,31,33, 34,45]. Rejection remains an important part of the differential and may not be able to be differentiated from infection without histologic examination. Careful attention to the level and type of immunosuppression is important. Infectious complications may include opportunistic, nosocomial, or community-acquired agents [5,13,29,36]. Laboratory, imaging, and pathologic investigations should be tailored to the individual patient’s balance of immunosuppression, epidemiology, and clinical and laboratory presentation. Late after transplantation, mild fevers are often evaluated by the local health care practitioner; if they abate readily, they are less likely to be captured by databases maintained at transplant centers. It is likely that community-acquired infections are common but are not documented during this period [13]. Patients should be advised to communicate with the transplant center about fever or other symptoms even late after transplantation. Respiratory tract symptoms Respiratory tract symptoms may manifest in lung and non-lung transplant recipients. Early infectious causes can be bacterial, particularly if a patient required prolonged mechanical ventilatory support or received lung grafts [5,8,16,29,36, 48,50]. Nosocomial spread or community acquisition of viral pathogens, such as RSV, influenza, adenovirus, and parainfluenza, is important to consider during appropriate times of the year [11 –13]. It should be noted that parainfluenza type 3 and adenovirus can circulate during all seasons [12]. Transmission of viruses from parents is an important consideration, and parents should pay close attention to symptoms that they may have after surgery. Recipients of lung transplants with symptoms of disease of the respiratory tract also can have infection with microbes that colonized their own airway or the donor airway, or they may experience rejection [8,29,36]. The authors recommend cultures from tracheal aspirates if patients are receiving mechanical ventilation for bacteria, fungi, and viruses. The type of viral test performed is often determined by the individual laboratory support at the transplant center. Evaluation also should include chest radiography. Sampling of fluid accumulations or biopsies of masses is recommended. Bronchoscopy also may be indicated to examine anatomy and obtain samples for culture and histology [8]. Two issues deserve particular mention with interpretation and management of potential respiratory infections in pediatric transplant recipients. The first is with viral studies. Viruses such as CMV, adenovirus, parainfluenza, RSV, and influenza can shed from the respiratory tree even without being the cause of disease [11 – 13, 42,57]. Results of these studies should be placed in the full clinical context before initiation of antiviral therapies, particularly novel or experimental ones. Patients

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with primary infection or individuals early after transplantation are more likely to have disease in association with viral shedding. Histologic confirmation to prove disease is often required. Prevention of respiratory infections is always critical [13]. As the respiratory season approaches each year, prevention strategies, such as good hygiene practice and immunization, should be reviewed with transplant recipients and their family. Influenza vaccination should be undertaken for transplant recipients and their household contacts [13]. Consideration of immunization with either the conjugated or nonconjugated pneumococcal vaccines should be discussed if not previously done. For the infant population that undergoes solid organ transplantation, prevention of RSV also should be considered [11,13]. Abdominal complaints As with all pediatric patients, abdominal complaints can vary from vague to specific in pediatric transplant recipients. In the early postoperative period, bacterial infections secondary to technical complications may be found in recipients of intra-abdominal grafts (Fig. 1). During the middle time period, possibility of infection of the gastrointestinal tract with CMV or EBV is an important consideration regardless of the type of organ transplanted [15,17,25,26,29 – 31,33,34]. As time from transplantation increases and immunosuppression decreases, these infections may represent common community-acquired gastrointestinal infections (Fig. 1) [13]. For the transplant recipient with abdominal complaints, careful historical delineation of the symptoms, epidemiology, donor and recipient baseline serology, type of immunosuppression, and operative factors must be examined [9,25,33,44 – 46,58,59]. Laboratory investigation of liver transaminases, bilirubin, and liver function is indicated, and amylase and lipase are considered. Stool should be tested for occult blood. Imaging with ultrasonography and CT should be considered. Further laboratory examination with blood cultures and viral studies, such as CMVantigenemia, EBV load, and titers for other suspected viruses, should be undertaken based on factors such as time after transplantation [24]. Depending on the clinical severity and organ transplanted, biopsy and other invasive studies may be necessary. Hepatitis can be caused by various viruses after transplantation, with CMV and EBV being prominent. Hepatitis B virus and hepatitis C virus are less often transmitted in the current days of screening; however, evaluation still should be considered in a recipient with an otherwise undiagnosed cause of hepatitis [57]. Community-acquired viruses, particularly adenovirus, hepatitis A virus, and enterovirus, are frequent and evaluation is recommended. Recipients of liver grafts also should undergo biopsy to distinguish rejection from infection [29,44,60,61]. Diarrhea and associated symptoms, such as emesis, hematochezia, melena, flatulence, and pain, may represent infection, rejection, or some other mechanical problem after transplantation of the gastrointestinal tract. Laboratory investigations to be considered should include blood (if fever is present) and stool cultures, examination of stool for ova and parasites, and Clostridium difficile toxin, liver

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transaminases and function, and examination of complete blood count and peripheral smear. Imaging modalities, such as CT and ultrasound, may prove useful in identifying a cause. Endoscopy and colonoscopy also may be needed to obtain a specific tissue diagnosis, such as EBV or CMV disease, and examine the transplanted bowel for signs of rejection. Urinary tract symptoms Infections in the urinary tract occur particularly in recipients of kidney transplantation and in any other organ transplant recipients because of the presence of a catheter during the transplant and immediate postoperative period [29]. Bacteria and yeast are most common pathogens found early after the transplant surgery as a result of indwelling catheters. Whenever possible, the use of indwelling catheters should be minimized. When urinary tract symptoms exist, cultures of urine and blood should be obtained [29,43]. Urinalysis with microscopy should be undertaken to determine evidence of pyuria or other renal abnormalities. In the intermediate period, viral studies, particularly for BK virus and adenovirus in recipients of kidney transplants, are warranted [62]. Imaging with renal ultrasound for examination of pyelonephritis also should be considered with follow-up meso 2,3-dimercaptosuccinic acid (DMSA) scans as indicated. Further imaging of the pelvis and abdomen with CT also may be required. Depending on the results of these studies, further investigation for urinary reflux and use of prophylaxis may be required. Central nervous system and mental status changes Central nervous system (CNS) changes are not common presentations of infections after transplantation in children but deserve prompt and thorough assessments [3,16,48,50]. Children have not been found to have an increased risk for common bacterial causes of meningitis but remain at risk, same as all children. Consideration of opportunistic infections is paramount. Recent donor transmission of West Nile virus in adults has been documented in adult transplant recipients [63]. Evaluation of potential infectious causes should include a careful review of underlying factors, including previous infection with the human herpes viruses, T. gondii, colonization with Aspergillus, and community exposures to fungi or tuberculosis [10,19 –23,29,37,49,56]. Early after transplantation, seizures and mental status changes are more frequently related to toxicity from immunosuppressive agents or technical problems that lead to abnormal electrolytes, glucose levels, or ammonia than to infection. Later after transplantation, however, infectious causes become more significant. For example, CNS disease caused by Aspergillus dissemination has occurred after CMV disease or in lung transplant recipients with chronic rejection [30,49]. PTLD can be found as focal lesions in the CNS [27,28]. Less frequently, CMV is found to cause CNS disease but should be considered, particularly in a mismatched (D+/R ) small bowel recipient. T. gondii can likewise cause CNS

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disease, particularly in a mismatched cardiac recipient. Cryptococcal meningitis, although rare in young children, is found in adolescents and adults after transplantation and should be considered in the evaluation of meningitis in any transplant recipient. Imaging with CT or MRI is frequently necessary in the immunosuppressed host with CNS manifestations to aid in diagnosis. It is critical to examine cerebral spinal fluid. Routine studies of cerebral spinal fluid glucose, protein, and cell counts may provide clues to the diagnosis. Culture of cerebral spinal fluid for routine bacteria and culture or nucleic acid-based assays for detection of viruses (eg, herpes simplex virus, enterovirus) should be performed. Studies to evaluate for opportunistic pathogens also should be undertaken. Further laboratory investigation for infectious causes may include blood culture, viral titers based on epidemiology (eg, enteroviruses and arboviruses in the late summer and early fall), and specific studies for the human herpesviruses. Studies for endemic mycoses based on geographic patterns should be performed. Brain biopsy of focal lesions should be entertained early in the course of disease if less invasive studies are not fruitful in establishing a diagnosis because it may be the only method to determine the pathogen. Dermatologic symptoms Rashes and other skin lesions are frequent manifestations of many infectious diseases of childhood. The rashes of many childhood infections (eg, vesicular lesions on an erythematous base for varicella, ‘‘slapped cheeks’’ for parvovirus, erythematous ‘‘sand paper’’ rash of scarlet fever) can present classically in transplant recipients. Diagnostic and therapeutic considerations can be directed toward the suspected agents. Rashes in transplant recipients may not present classically and may represent dissemination or presentation of a latent viral infection (eg, EBV, CMV, human papillomavirus), graft-versus host disease, drug-related eruption, or rejection. In these instances, further diagnostic testing, such as viral serologies, skin biopsy, and imaging of remote sites, is warranted.

Acknowledgments The authors appreciate the technical assistance of Ms. Lori Skwirut in preparation of the manuscript.

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