This is the first study which described the clinical features and outcomes of IPI in pediatric LSBPTx recipients in a large pediatric multivisceral transplant cohort in the United States. The risk of developing IPI in our cohort was in line with previous report in renal transplant (asplenic) patients (1% per year) in the early years after licensing of pneumococcal vaccine.16

The increased susceptibility to IPI in immunocompromised patients has been well documented in renal and liver transplant recipients. Before the licensing of pneumococcal vaccines, IPI had high incidence (13-38%) and were associated with significant mortality (25-76%).17-19 Most cases occurred early after transplant or during episodes of intensified immunosuppression to treat rejection, although there were cases reported at 12-20 months after transplant.20 In our cohort, the infections developed years after transplantation with one exception. Essay: Clinical Features and Outcomes of IPI. None of the other patients had episodes of rejection requiring augmentation of immunosuppression before IPI, and their immunosuppression levels were within the target range.Patients with pneumococcal septicemia often follow a fulminant course, rapidly progress to circulatory insufficiency within a short period of time, and survived only hours after they received medical care.21 In the present study, 78% of the patients required admission to pediatric intensive care unit. The overall mortality in our cohort was high, as previously reported in non-transplant asplenic patients (21-27%).22

Strategies to prevent IPI in high risk patients include pneumococcal vaccination and daily administration of oral penicillin. Current available vaccination against pneumococcus includes PCV (initially available as 7-valent, later replaced with 13-valent PCV) and PSSV23. The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention and the American Academy of Pediatrics (AAP) recommend the administration of PCV13 in all children aged 2 through 59 months. A single dose of PCV13 is also recommended in children aged 6 through 18 years with high risk conditions who have not received PCV13, regardless whether they received PCV7 or PPSV23 previously.1, 13 PPSV23 is recommended for all children aged 2 years or older with elevated risk of IPI, with a booster dose to be given after 5 years.1, 13 The PCV13 is highly immunogenic in young children, providing higher antibody titers and inducing immunological memory by T-cell dependent mechanism, whereas the PSSV23 is poorly immunogenic and often lacks efficacy in children aged < 2 years due to its T-cell independent nature and consequent failure to induce long-term protection.23. Essay: Clinical Features and Outcomes of IPI.

ORDER A PLAGIARISM-FREE PAPER NOW

Waning immunity has been reported after solid organ transplant.10, 11, 24-26 Prior studies have shown that pneumococcal antibody titers have declined as early as 3 months after transplant, either due to decreased production or increased clearance of antibodies.24-26 In addition, pediatric transplant recipients have variable vaccination responses due to either long-term immunosuppression affecting their cell-mediated immunity, or insufficient humoral response with subsequent decline in antibody concentrations.12, 27 A systemic review of randomized clinical trials on post-transplant vaccination response rate in pediatric solid organ transplant recipients revealed a short-term ( 2 weeks and < 3 months after the last vaccination) response rate of pneumococcal vaccines (PCV7 or PSSV23) in all studies being above 50%, with a summary estimate of 83% (95% confidence interval: 83-93%).6 However, the reported response rate in these studies might be overestimated because the positive response was assessed as serological response to at least one serotype, and it is unclear if the positive response has had any positive impact on the protection. Break-through life-threatening pneumococcal infections have been reported in vaccinated patients, probably because the infective serotypes were not covered in the vaccine, or due to an insufficient vaccine response. To date, none of the studies reported long-term response in transplant recipients beyond 12 months following vaccination, and none conducted in LSBPTx recipients who are asplenic and might require higher immunosuppression. Essay: Clinical Features and Outcomes of IPI. As antibody response varies between individuals and a rapid decline of antibody titers has been reported as early as 3-6 months after pneumococcal vaccination in high risk patients,24-26, 28 monitoring of serotype specific antibodies after vaccination might be warranted in these patients to determine the need and timing for re-vaccination.29, 30 Although it is unclear what level of serotype specific antibodies is required to achieve protection against IPI as the protective level may vary with age and differ for each serotype, the World Health Organization recommends a serotype specific antibody level of 0.35 g/mL as a putative protective threshold after PCV vaccination in young children, and a higher level of 1.0 g/mL has been recommended in older adults.23, 30, 31 A sufficient antibody response is defined as an at least 4-fold increase in titers at 4 weeks after vaccination. Moreover, the British Committee for Standards in Hematology guidelines for the prevention and treatment of infection in patients with functional or anatomic asplenia recommends the timing of pneumococcal revaccination may be determined by levels of protective antibody.30

Antibiotic prophylaxis with penicillin has been recommended in all patients with anatomic or functional asplenia, although its efficacy was only demonstrated in clinical trials in children with sickle cell disease.21, 32 In this patient population, reduction in the incidence of pneumococcal septicemia was reported in children who received antibiotic prophylaxis, regardless of their pneumococcal immunization status.21 The AAP guidelines recommend daily oral penicillin in children with sickle cell disease aged 2 months to 5 years,33 but it is unclear how long this prophylaxis should be continued in transplant recipients who undergoing splenectomy, taking into account long-term prophylaxis may lead to poor compliance and the risk of developing antibiotic-resistant strains.29 The current guidelines published by the British Committee for Standards in Hematology recommend lifelong prophylactic antibiotics using oral penicillins or macrolides to patients considered at continued high risk of pneumococcal infections.30

Like previous publications with limited number of pediatric solid organ recipients with IPI, the present study is limited by its small sample size. However, we acknowledged that there are only several centers performing multivisceral transplant in children. The transplant program at UNMC is a leader in digestive organ transplantation, and is one of the largest pediatric multivisceral transplant centers in the world. Due to the retrospective nature of the current study, we were unable to assess the adherence to antibiotic prophylaxis, although all patients had documentation indicating medication compliance.Essay: Clinical Features and Outcomes of IPI.  Immunization records were incomplete in three patients; and this may relate to care by multiple providers or loss of follow-up. In addition, serotype specific isolates were not reported, and post-transplant serotype specific titers were not available in all patients. Therefore, it is unknown whether pneumococcal infections in these patients were due to lack of immunization, poor antibody response or waning immunity after transplant, or if serotype specific antibody titers were effectively protective. Essay: Clinical Features and Outcomes of IPI.