Vaccination Recommendations for Pediatric Transplant Patients
According to national registry data, more than 9000 pediatric solid organ transplants (SOT) and 11,000 pediatric hematopoietic stem cell transplants (HSCT) have been performed in the United States from 2009-2013.1,2 In recent decades, medical advances, along with broadened indications, have increased the total number of children living with transplants. As a result of prolonged immunosuppression and increased health care utilization, children with transplants are at a greater risk for infections, including those that are vaccine preventable.3-6 Thus, proper vaccination in HSCT and SOT is imperative to reduce morbidity and mortality.
Primary care providers (PCPs) under the guidance of the transplant team are responsible for administering appropriate vaccines to transplant patients. This review is intended to provide some recommendations for this intervention to the PCP. However, it should be kept in mind that there is a considerable difference of opinion among transplant programs, particularly for administration of live virus vaccines posttransplant. This publication is an attempt to summarize guidelines from multiple transplant programs.
HSCT and SOT patients represent a population that requires specialized vaccination recommendations. Vaccination mandates a coordinated responsibility between both the specialist and primary care provider.7 Traditionally, the efficacy and safety of vaccines in transplant patients have been questioned. As a result, many primary providers feel uncomfortable administering vaccines, which leads to incorrect or incomplete immunizations.8,9 The disparity between current guidelines and clinical practice can be remedied through the dissemination of simplified vaccine recommendations to primary care providers.
Several papers have summarized recommendations for the vaccination of immunosuppressed patients, but these sources are either not targeted towards the pediatric generalist or are overly complex or outdated.10-12 In 2013, the Infectious Diseases Society of America (IDSA) released updated guidelines for vaccination practices in immunocompromised patients, including those with HSCT and SOT.7 Here, we review and simplify current vaccination guidelines for HSCT and SOT in children, focusing on the role of the PCP or general pediatrician.
GENERAL VACCINATION PRINCIPLES IN CHILDREN WITH HSCT or SOT
In anticipation of possible transplantation, an aggressive approach toward vaccination should be undertaken as early as possible, which often means administering vaccines earlier than is routinely recommended for children. Vaccinating immunocompromised children prevents disease but can also subject these vulnerable patients to secondary infections, serious adverse events, and poor efficacy. Hence, there are several fundamental principles that must be realized when vaccinating children before and after transplant.
The IDSA has defined high levels of immunosuppression to include those within 2 months post-SOT or HSCT. The length of high-level immunosuppression post-HSCT may be further dictated by the type of transplant and chemotherapy, as well as by the presence of graft-versus-host disease. Patients with combined B-cell and T-cell immunodeficiency, current cancer chemotherapy, HIV positivity with CD4+ count < 200 cells/mm3 (≥ 5 years old) or percentage < 15% (< 5 years old), use of medications that interfere with biologic pathways (tumor necrosis factor-α inhibitors) or B-cell function (rituximab, alemtuzumab), or corticosteroid treatment of ≥ 20 mg for adults and older children (> 2 mg/kg/day if < 0 kg) for ≥ 14 days are also classified as high-level immunosuppression.7 Use of topical, inhaled, or injectable corticosteroids is not high-level immunosuppression.
Administration of vaccinations must be completed as soon as possible before the onset of chemotherapy or other immunosuppression. Live vaccines can safely be given ≥ 4 weeks and inactivated vaccines ≥ 2 weeks before the start of immunosuppression or transplant. Live virus vaccines cannot be given within 30 days prior to any transplantation (Table 1),7,13 so determining the likelihood of a patient being eligible for transplant within this time frame is critical and must be coordinated with the transplant team.
However, vaccination objectives should not take priority over current disease treatment. Administering vaccinations at inappropriate times may delay or complicate lifesaving care in children who are transplant candidates. It is important to note that children with high levels of immunosuppression or active graft-versus-host disease should not receive most vaccinations; this includes those within 2 months post-SOT or HSCT. Fears of transplant rejection caused by vaccination have been disproven and should not be used as rationale to withhold immunizations.14,15
Those who are severely immunocompromised or have an unknown immune status should generally not receive live vaccines, but advances in our understanding of the safety and efficacy of live vaccines have made administration acceptable in select circumstances.10 Unlike live vaccines, inactivated vaccines have similar safety profiles in both immunocompromised and immunocompetent patients,15,16 although immune responses may be reduced in the immunosuppressed patient. Furthermore, individuals who undergo high levels of immunosuppression and receive inactivated vaccines have the greatest chance of an inadequate response. Hence, while inactivated vaccines in immunosuppressed patients are safe, they have not always proven to be equally protective.
Nonetheless, questions of efficacy should not delay the use of inactivated vaccines posttransplant. Serologic assessment to evaluate protection posttransplant may be performed 4 or more weeks after administration of a vaccine. Importantly, measurement of seroconversion has not been thoroughly studied and may not reflect an efficacious response, particularly when protection may be more related to cell-mediated immunity and such evaluation is not generally available.17-19
Vaccination of close contacts to protect the transplant patient is another important variable when considering treatment in posttransplant children, termed the “cocoon effect.”20 Immunizations in this population should be current, with special care being taken when using live vaccines.7
VACCINATION PRACTICES IN HEMATOPOIETIC
STEM CELL TRANSPLANT
HSCT results in the loss of part or all of prior immunity to childhood vaccinations. Immune retention and reconstitution is dependent on a variety of factors, including: donor immune and vaccination status, patient immune status prior to transplant, and chemotherapy regimen. Therefore, guidelines recommend that vaccination approaches pre-HSCT be comprehensive. Donors should be current with vaccinations according to the Centers for Disease Control and Prevention (CDC) guidelines.
If a live vaccine is indicated, it should be given prior to 4 weeks before stem cell harvest. Vaccination of the donor solely for the recipient’s advantage is rarely indicated. If feasible, HSCT recipients should also be current with routine vaccination recommendations before transplant. The regimen does not differ based on type of HSCT (Table 2).7 The IDSA also recommends that if a recipient is nonimmune and ≥ 12 months of age, varicella-zoster (VAR) vaccination be given ≥ 4 weeks before consolidation therapy. If possible, deliver 2 doses of VAR vaccine ≥ 3 months apart.
Immunizations post-HSCT should consist of mostly regularly scheduled vaccinations, with special caution taken for live vaccines (Tables 2 and 4).7,21,22 Immune reconstitution post-HSCT follows a predictive sequence, which is accelerated in pediatric patients, and can take up to months or years. Typically, B-cell response takes 6 to 12 months and T-cell response 1 to 2 years to recover.
Variations in reconstitution are based on the conditioning regimen, allogeneic or autologous graft, and presence of graft-versus-host disease.23-27 Furthermore, evidence has suggested that immunization recommendations should not differ between allogeneic or autologous grafts, and that they should be performed as soon as reasonably possible after transplant.28,29 Based on current data, inactivated vaccinations in children can commence 4 to 12 months post-HSCT.7 If there is no evidence of graft-versus-host disease and the child is not receiving any immunosuppressive therapy, certain live vaccines may be given 2 years post-HSCT.29
Influenza virus infection after HSCT carries significant mortality risk if left untreated.30 The IDSA recommends inactivated influenza virus (IIV) in patients ≥ 6 months of age who are 6 months post-HSCT, or ≥ 4 months of age if there is a community outbreak. Children who are younger than 9 years should be given 2 doses of vaccine separated by ≥ 4 weeks. The IIV should be given annually thereafter.7 It is imperative to also vaccinate family members and close contacts ≥ 6 months of age with IIV.
Like influenza, pneumococcal infection carries significant morbidity and mortality. Hence, vaccination is an important form of primary prevention in immunocompromised children. Starting 3 to 6 months post-HSCT, children should receive a 3-dose series of 13-valent pneumococcal conjugate vaccine (PCV13). If the vaccination series is given early after transplant, consider an additional 23-valent pneumococcal polysaccharide vaccine (PPSV23) 12 months post-HSCT. Immune response to vaccine is mitigated in chronic graft-versus-host disease, so it may be advantageous to substitute PPSV23 for PCV13 in this circumstance.
Three doses of Haemophilus influenza b conjugate (Hib), inactivated polio vaccine (IPV), and hepatitis B (HepB) should be given beginning 6-12 months after HSCT transplant and spaced 1 to 2 months apart. Postvaccination analysis of anti-HepB titers is necessary because seroconversion rates in immunocompromised children are lower compared with those in healthy individuals.31,32 Administer an additional 3 doses of HepB vaccine if there is an inadequate (≤ 10 mIU/mL) immune response to the original series. If the patient is 11-18 years of age, meningococcal conjugate vaccine (MCV4) should be given 6 to 12 months post-HSCT. It is suggested that adolescents receive a booster of MCV at age 16 to 18 years if the first vaccine was given before age 15 years.
Regarding tetanus/diphtheria vaccines (DTaP/TdaP), guidelines advocate 3 doses starting 6 months post-HSCT. If the child is younger than 7 years, administer DTaP, but if the child is ≥ 7 years of age, administer 1 dose of TdaP followed by 2 doses of diphtheria and tetanus toxoids (DT) or tetanus and diphtheria (Td). DT contains a higher dose of diphtheria conjugate compared with Td, but it also has a higher incidence of adverse reactions. In HSCT recipients, it is beneficial to offer a 3-dose regimen of DTaP for children aged ≥ 7 years.33 Although there are no current data on the human papilloma virus (HPV) vaccine series, the IDSA recommends vaccination in both males and females aged 11 to 26 years at 6 to 12 months post-HSCT (Table 2).7 The IDSA and CDC currently recommend against rotavirus vaccination pre-HSCT.7
The IDSA offers a strong recommendation for the use of measles, mumps, rubella (MMR) and VAR vaccines if certain circumstances are met post-HSCT. In seronegative children or adolescents who have no ongoing graft-versus-host disease or immunosuppression, a 2-dose regimen of MMR and VAR vaccines is recommended 24 months post-HSCT. Importantly, the combination measles, mumps, rubella, and varicella vaccine (MMRV) is not recommended in this population. If an outbreak of either virus is present in the community, we recommend giving intravenous immunoglobulin first and the vaccine 8 to 11 months later (Table 2).7
VACCINATION PRACTICES IN SOLID ORGAN TRANSPLANT
Children with end-stage organ disease are at increased risk for several vaccine-preventable diseases.19 Additionally, patients with chronic liver disease or on hemodialysis have decreased but comparatively better responses to vaccine than those post-SOT.10 Therefore, it is imperative to have all primary series completed before transplant. Vaccine safety and efficacy post-SOT also varies depending on the type of transplant and severity of immunosuppression. Consideration must be taken when determining the time line for vaccination and the specific vaccinations to be given post-SOT.
Guidelines for pre-SOT are similar to those for pre-HSCT. Donors and recipients of SOT should be up-to-date on vaccinations recommended for immunocompetent individuals. Additionally, we recommend that donors avoid live vaccination 4 weeks or less before organ donation to prevent posttransplant vaccine virus infection in the recipient. Pediatric kidney, heart, or lung candidates younger than 6 years should receive 1 dose of PCV13 if they have completed a prior 3-dose course before the age of 24 months, and 2 doses if they have not. Kidney transplant candidates aged 6 to 18 years should receive 1 dose of PCV13.7, 34,35
PPSV23 is also recommended for SOT candidates or those with end-stage organ disease 8 weeks after PCV13. Administer PPSV23 to all children ≥ 2 years who are transplant candidates or have end-organ disease. For those with kidney disease, ensure 2 lifetime doses at least 5 years apart; otherwise PPSV23 is required only once.
Hepatitis A (HepA) and HepB vaccinations are particularly important in children with liver disease. Antibodies for HepB should be monitored before and every 6 to 12 months after SOT.19 Children who are anti-HepB surface antigen negative require a HepB vaccine series. If children have been vaccinated in the past and antibody levels are below 10 mIU/mL, it is imperative to administer a second 3-dose course of HepB. These patients may also benefit from higher dose vaccines, although evidence is limited in children and no formal recommendations have been made.36 Furthermore, if transplant is imminent, consider vaccinating on an accelerated timeline. Evidence has demonstrated adequate seroprotective levels after a 2-dose series at 6 months. Hence, if the child has negative or insufficient HepA titers and is older than 6 months,37 we recommend a 2-dose series (Table 1).
For patients aged ≥ 12 years, combined HepA-HepB vaccine is reasonable. Patients should also receive inactivated influenza vaccine and HPV vaccine in accordance with standard guidelines. If the transplant is not anticipated for 4 weeks, immunosuppression is absent, and the child is aged 6 to 11 months, both MMR and VAR may be given. MMR should be repeated at 12 months of age if transplant is delayed. Additionally, a second dose of VAR should be given 3 months after the 12-month dose (Tables 3 and 4).7
With the exception of IIV, all vaccines should be avoided for at least 2 months post-SOT because immunosuppressants significantly reduce antibody responses. However, if there is a community outbreak of influenza, experts recommend vaccination with IIV starting 1 month after SOT.10
Inactivated vaccines that are recommended by the CDC annual schedule should be given 2 to 6 months post-SOT. In particular, pneumococcal and hepatitis vaccinations should receive special attention. As for PCV13 and PPSV23, recommendations as detailed above should be followed. Children with HepB-related liver transplant may benefit from vaccination, as there is some evidence suggesting this would decrease the need for use of HepB immunoglobulin.7,38
The consensus regarding live vaccinations in SOT patients compared with HSCT patients is much less clear. Generally, live vaccinations have been contraindicated in children post-SOT.10,21,22,24,35,39 More recently, studies have suggested that some SOT patients—those whose transplant was 6 months to 1 year ago, who have no rejection, and are on low immunosuppression—may benefit from live vaccination.21,22
The IDSA has offered recommendations for live vaccinations in specific populations of post-SOT children (Table 3).7 VAR may be given to children who have received liver and renal transplants if they do not demonstrate active immunity to varicella. Active varicella immunity is defined as a history of previous vaccination with positive serology or clinically verified disease. Although the IDSA considers this guideline as weak, we recommend vaccination of VAR in children if no active immunity is present (Table 4).7,21,22 Two doses of MMR and VAR vaccine, with the second ≥ 3 months after the first dose, are suggested. It is important to remember that vaccination must never be delayed or denied due to concerns of causing organ rejection, as a strong body of evidence suggests no increased risk exists.7
VACCINATION OF HOUSEHOLD CONTACTS
Vaccine-preventable infections in household contacts are a cause of substantial risk for additional morbidity and mortality in transplant patients. Inactivated vaccines can be safely administered to household members. In particular, IIV should be given to all household members ≥ 6 months of age. If a child is highly immunosuppressed or is within 2 months posttransplant, live vaccines in the home should be avoided. After the initial posttransplant window has passed, live vaccinations may be administered to household contacts, including live attenuated influenza (LAIV), MMR, VAR, rotavirus, oral typhoid, and yellow fever. If LAIV is given, the child who received the transplant should avoid all contact for 7 days with the family member. The child should also avoid contact with those who received VAR and developed skin lesions until those lesions are gone. Oral polio vaccine should never be given to close contacts of a transplant patient, and immunosuppressed children should avoid diapers of infants given rotavirus vaccine for at least 4 weeks.40-43
Vaccination of pediatric patients pretransplant and posttransplant poses many challenges to the primary care provider. Shared responsibility with specialists, complicated guidelines, and lack of research surrounding vaccination in the immunocompromised are all issues that increase the difficulty of decision-making. Proper vaccination of children before transplant is imperative, and this includes administering vaccines far enough in advance to ensure patient safety. Inactivated vaccines are safe but may lack efficacy. As more research is performed, we will be able to further define serologic responses along with safety of both live and inactivated vaccines. In the future, studies need to discern the optimal timing of vaccinations and further clarify the safety and efficacy of vaccines in relation to transplants.
Daniel V. DiGiacomo, MPH, and Sarah M. Labuda, MD, are with the Department of Pediatrics in Tulane University School of Medicine in New Orleans, Louisiana.
Russell W. Steele, MD, is with the Department of Pediatrics in Tulane University School of Medicine, and Oschner Health Center for Children, both in New Orleans, Louisiana.
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