Introduction

Infectious diseases are major causes of morbidity and mortality in pediatric patients undergoing transplantation. They also represent the most significant barrier to short- and long-term survival of the transplant. Advances in pediatric infectious diseases supportive care have resulted in the ability of patients to undergo intensive immunosuppression and aggressive invasive procedures. The achievements during the past 30 years have resulted in remarkably improved outcome for pediatric transplant recipients. These advances of pediatric infectious disease supportive care have contributed substantially to the improved survival, outcome, and reduction of suffering to infectious complications.

This article reviews the epidemiology and strategies for managing infectious diseases in pediatric solid organ transplant patients. Because the immune defects and the possible etiologic agents of infection vary during the time elapsed since transplantation, the chapter is organized in such a manner. Timetables of infection after solid organ transplantation are useful as they facilitate differential diagnosis, infection control, prophylaxis, and treatment (Fig. 1). Definitive recommendations for prevention and treatment of invasive fungal infections in pediatric patients undergoing solid organ transplantation do not exist given the lack of clinical trials and scant epidemiological data.

Fig. 1
figure 1

Timetable of infections after solid organ transplantation in children. Solid lines indicate higher frequency of infections; dashed lines indicate lower frequency of infections. Modified with permission from [1]

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Pediatric Versus Adult Patients

Pediatric transplant patients are different from their adult counterparts in multiple ways. These include the spectrum of underlying diseases requiring transplantation (i.e., cause of liver transplantation in adults is usually cirrhosis due to hepatitis; whereas in children, it is congenital atresia of bile ducts), the intensity of immunosuppressive regimens, and the incidence and severity of co-morbid medical conditions preceding the transplantation. In addition, the percentage of patients with indwelling central venous catheters, the community exposures to infectious pathogens, and the maturation of the immune system may differ in different ages. Diagnostic and therapeutic issues also are different between adults and children. Notably, a risk stratification system widely evaluated or clinically adopted in pediatrics is missing. Important surrogate markers for infection have not been validated in children (like (1–3)-β-d-glucan testing that has not been validated in children), while many antimicrobial agents lack pediatric approval or rigorous pediatric dosing and safety data. Lastly, a number of family/psychosocial issues are remarkably different between adults and children [2, 3].

Invasive Fungal Infections in Solid Organ Transplantation

Solid organ transplantation (SOT) is a major therapeutic option for many children with end-stage organ failure. For a successful SOT, a careful balance between rejection and infection should be attained. The risk of infection in the SOT recipients is determined by the interaction of multiple factors related to the recipient, the transplantation procedure, and the net state of immunosuppression occurring from the pre-transplantation until post-transplantation period (Table 1) [2, 4]. Infections in SOT recipients follow a temporal trend and tend to be predictable. While it would be over-simplistic to suggest that specific infections occur only at specific time points, it is nevertheless helpful to divide the period following transplantation into specific phases. In each phase, specific organisms predominate; however, infectious disease syndromes such as pneumonia can occur at any time in the post-transplant period but the etiology changes at different points in time. The timing of infections can be divided into three intervals: early (0–30 days after transplantation), intermediate (30–180 days after transplantation), and late (>180 days after transplantation) (Fig. 1) [1].

Table 1 Factors increasing the risk for infections in solid organ transplant recipients
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Early Phase Infections (0–30 Days After Transplantation)

The net state of immunosuppression at this phase is not great despite the high doses of immunosuppressive therapy. Thus, opportunistic infections (caused by pathogens such as Aspergillus, Listeria, and Nocardia) are rare. There are three types of infections during this period: (1) infections present to the recipient before transplantation, which are exacerbated after the transplantation due to the operation or immunosuppression; (2) donor-derived infections which are usually due to critical care, terminal illness, transport, implantation of the organ, or donor’s undiagnosed infections (West Nile virus, HIV, rabies) [5–7] as well as undiagnosed critical care-related multi-resistant bacteria, such as Klebsiella pneumonia, Pseudomonas aeruginosa, and Acinetobacter baumannii; and (3) infections transmitted perioperatively that could occur in an immunocompetent patient including Candida spp. The majority of the infections, during the early phase after transplantation is of this last type and is determined by the technical integrity of the surgery and the post-surgery use of indwelling medical devices. Early graft injuries (e.g., ischemia of bile ducts or pulmonary reperfusion injury) may later become foci of liver or lung abscesses [8•].

Intermediate Phase Infections (30–180 Days After Transplantation)

The infections occurring in this phase are the result of immunosuppression and the immunomodulatory effects of co-infecting viruses. There are three types of infections during this period: (1) the remaining infections from the previous phase and (2) viral infections most commonly due to CMV, Epstein-Barr virus (EBV), Herpesvirus-6, Hepatitis B and C, and HIV. However, other rare viral pathogens such as polyomavirus BK and adenovirus have emerged and (3) opportunistic infections due to Pneumocystis jirovecii and Aspergillus fumigatus, which usually suggest an environmental source. Additionally, infections due to endemic fungi like Cryptococcus neoformans or infections due to Trypanosoma cruzi or Strongyloides stercoralis may occur [2, 9].

Late Phase Infections (More than 6 Months After Transplantation)

There are three types of infections during this period: (1) patients with good transplantation outcome (minimal immunosuppression, good allograft function, no viral infections) are at risk from infection due to community-acquired respiratory viruses (influenza, parainfluenza and respiratory syncytial virus); (2) patients with chronic viral infections that may cause allograft injury (cirrhosis from HCV infection in liver transplant recipients, bronchiolitis obliterans in lung transplant recipients, accelerated vasculopathy in heart transplant recipients with CMV infection) or a malignant condition such as post-transplantation lymphoproliferative disorder (PTLD) or skin or anogenital cancer and (3) patients with poor result from transplantation (repeated episodes of acute and chronic allograft injury, excessive immunosuppression, and chronic viral infections). These patients are at risk for opportunistic infections with Listeria monocytogenes or Nocardia species and invasive fungal infections such as Mucorales and dematiaceous molds and unusual organisms (e.g., Rhodococcus species) [2, 8•, 9, 10].

The most common invasive fungal infections in this population are candidiasis and mold infections such aspergillosis and mucormycosis, followed by cryptococcosis [11•, 12–22]. Candida spp. are the most frequent agents of invasive fungal infections accounting for around 2–4 % of SOT [11•, 23, 24]. The incidences vary according to the transplantation center and organ transplanted being particularly high in abdominal SOT such as intestinal, pancreas, and liver transplantation [11•] and uncommon in heart, lung, or kidney transplantations [25]. The majority of candidiasis cases after SOT occur during the first months after surgery [26•]. The main risk factors for invasive candidiasis are receipt of broad-spectrum antibiotics, presence of central venous catheters, complicated operative courses (re-transplantation, anastomotic problems, laparotomy after transplantation), vascular thrombosis, multifocal colonization, receipt of parenteral nutrition, and hyperglycemia [26•, 27–29]. Mortality of invasive candidiasis in 12 months has been reported in the Transplant-Associated Infection Surveillance Network (TRANSNET) study of predominantly adult patients to be 34 % [11•].

The incidence of invasive aspergillosis varies from 0.1 to 3.5 % depending on the transplantation center and type of transplant. The highest risk for aspergillosis occurs among lung transplant recipients [30••, 31, 32••, 33]. In these patients, colonization of the transplanted lung with Aspergillus spp., bronchial anastomotic ischemia or bronchial stent placement, hypogammaglobulinemia, concomitant CMV pneumonia, and cystic fibrosis are among the most prominent risk factors for development of invasive aspergillosis [34–38]. Mortality of invasive aspergillosis in SOT recipients who develop invasive pulmonary disease also depends on the type of transplant; it has been reported to be 29.4 % in adult patients with heart-lung transplantation [39], 41 % in TRANSNET study of predominantly adult patients [11•], and 9.5–47.1 % depending on the transplant type in adults [40].

The incidence of cryptococcosis varies from 0 to 1.5 % according to the SOT series making C. neoformans the third leading cause of invasive fungal infections among SOT recipients [11•, 26•]. The rates are higher in kidney and heart transplant recipients [26•]. The most prevalent risk factors are treatment with high dose of corticosteroids or monoclonal antibodies against lymphocytes or tumor necrosis factor (alemtuzumab and infliximab) [41]. The majority of cryptococcosis cases occur late after transplantation, usually after 16 to 21 months [26•]. Mortality of cryptococcosis after SOT is reported to be 14 to 27 % in adults [11•, 42].

Management

Treatment of invasive candidiasis in SOT recipients is similar with that of non-neutropenic patients. According to the last recommendations of the ESCMID Study Group for infections in Compromised Hosts (ESGICH), where there is a special mention for children, the use of an echinocandin (caspofungin or micafungin) is strongly recommended for initial treatment of non-neutropenic transplant recipients. Another option is liposomal amphotericin B; whereas, fluconazole constitutes a second-line alternative as certain Candida spp. may be fluconazole resistant and drug-drug interactions exist with calcineurin inhibitors [26•]. Duration of treatment is recommended to be 14 days for uncomplicated candidemia while prolongation of treatment should be considered in complicated infections. Once the patient is stable, can tolerate oral administration, is known to have a fluconazole-susceptible Candida sp., and has completed 10 days of intravenous antifungal therapy, conversion to oral fluconazole can be considered [26•].

Catheter-Associated Candidemia

Removal of chronic indwelling central venous catheters is best determined by the type of organism recovered, the hemodynamic stability of the patient, and the presence of persistent bacteremia, rather than by differences in colony counts suggesting evidence of direct involvement of the catheter. Removal and replacement of chronic indwelling catheters carries the risk of general anesthesia, pneumothorax, and hemorrhage, particularly in thrombocytopenic patients. This measure has been associated with lower mortality in neonates and non-neutropenic patients in whom the vascular catheter, rather than the GI tract, is considered to be the source of candidemia [43, 44].

The basic principles of therapy for invasive aspergillosis in SOT recipients include the prompt initiation of antifungal therapy and the individualization of treatment according to type of transplant, type of infection, and immunosuppression state. A key point in the treatment of invasive aspergillosis in SOT recipients is the reduction of immunosuppression, especially of corticosteroids, whenever possible. First-line treatment is with voriconazole. However, in patients where the use of voriconazole is contraindicated (i.e., age less than 2 years, renal insufficiency prohibiting use of intravenous voriconazole), liposomal amphotericin B is recommended. Combination antifungal treatment (voriconazole or amphotericin B plus caspofungin) may be considered in pediatric patients with severe disease. The optimum duration of treatment has not been established; it is recommended to be continued until clinical and radiological responses (minimum 6–12 weeks) [26•]. On many occasions, surgical debridement is required as an adjunct to effective antifungal treatment [26•, 37].

In contrast to recommendations for adult SOT patients [26•, 45], no established guidelines exist for the pediatric population (Table 2).

Table 2 Antifungal agents used in children for infections after solid organ transplantation
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Prevention of Infections

General Measures

The most effective and practical intervention by which to prevent or reduce infections in the immunocompromised host is adherence to strict hand washing practices [46]. A restricted (cooked) diet has not been proven to be beneficial in avoiding infection in immunocompromised patients, as previously believed [47].

Environmental sources may contribute to fungal (especially Aspergillus spp., Fusarium spp., and Mucorales) colonization and infection. In medical centers where Aspergillus spp. and Fusarium spp. are a significant problem, special air filtration systems, such as high-efficiency particulate air filters (HEPA filters), and close attention to cleaning bathroom facilities as well as avoiding construction areas and other sources of molds at home may be helpful [48, 49].

Total protective isolation is a comprehensive regimen designed to reduce patients’ endogenous microbiota while preventing the acquisition of new organisms. A sterile environment is created in a clean-air room with constant positive-pressure airflow. It is maintained by an aggressive program of surface decontamination and sterilization of all objects that enter the room and by an intensive regimen to disinfect the patient, including oral non-absorbable antibiotics, skin antiseptics, antibiotic sprays, and ointments and a low-microbial diet. The total protective environment reduces the number of infections in profoundly neutropenic patients. However, a total protective environment is expensive, and because of the improvement in treating established infections, it does not offer a survival advantage to SOT patients. Total protective isolation is not necessary for the routine care of immunosuppressed patients [50].

Antifungal Prophylaxis

Given the lack of clinical trials and the scant epidemiological data, there are no definitive recommendations for the use of prophylaxis against invasive fungal infections in children with SOT. The selection of universal versus targeted prophylaxis is based on the type of transplant. In addition, the choice of prophylaxis is based on the effectiveness, side effects, and drug interactions of the antifungal agents with the concomitant agents [26•, 51]. The general trend is not to use universal prophylaxis for Candida spp. infection in renal, heart, and lung transplantation while there is a well-established practice to use antifungal prophylaxis in patients undergoing high-risk liver, intestinal, or pancreatic transplantation [26•, 52]. On the contrary, it is common to use universal prophylaxis against Aspergillus in lung transplant recipients given the high morbidity and mortality rates of invasive infection [26•]. However, there is variability on the prophylaxis strategies according to the transplantation program [53].

Fluconazole is recommended for prevention of deep invasive fungal infections in immunocompromised patients when the risk of aspergillosis is not high. Randomized controlled studies have established fluconazole as good as other antifungals for prevention of invasive candidiasis in liver transplant recipients [54, 55]. However, the shift in the colonization pattern towards more resistant species, including Candida glabrata, Candida krusei, Candida parapsilosis, Aspergillus spp., and other filamentous fungi, is of concern [56, 57]. In a recently published randomized clinical trial comparing 100 mg micafungin with standard care antifungal prophylaxis (predefined for each participating institution to be either fluconazole or liposomal amphotericin B or caspofungin) in high-risk liver transplant adult patients, micafungin was non-inferior and had a better kidney safety profile [58].

Pneumocystis Prophylaxis

There are several effective regimens for P. jirovecii pneumonia (PCP) prophylaxis. The choice among them often depends on the patient’s tolerance of their various side effects. Trimethoprim-sulfamethoxazole (TMP-SMX), given twice a day for 3 days a week, is considered the first-line regimen [59]. For patients who can tolerate this regimen, protection against PCP is virtually complete [60]. The use of TMP-SMX is limited, however, in a significant number of individuals by rash, neutropenia, and gastrointestinal symptoms. Alternative compounds for prevention of PCP in patients who are intolerant of or refractory to TMP-SMX include dapsone, atovaquone, and aerosolized pentamidine.

In conclusion, the current prophylactic and treatment strategies for solid organ transplantation in children vary widely among transplantation centers given the lack of clinical trials and scant epidemiological data in pediatric SOT recipients. There is an urgent need for future epidemiological, diagnostic, and management studies in this growing field of medicine.