Pre-Transplantation Strategies for Infectious Disease Mitigation and Prevention Free

Abstract

Pediatric Infectious Disease (ID) clinicians play a critical role in helping prevent and mitigate infectious risks in children peri- and post-transplantation. Prevention starts during the pre-transplant evaluation and persists throughout the solid organ transplant and hematopoietic cell transplant continuum. The pre-transplant evaluation is an opportunity to screen for latent infections, plan preventative strategies, optimize immunizations, and discuss risk mitigation practices. An ideal pre-transplant evaluation establishes a relationship with the family that further promotes post-transplant infectious risk reduction. This manuscript builds on shared pediatric ID prevention strategies, introduces updated ID testing recommendations for transplant donors/candidates, highlights emerging data, and identifies ongoing knowledge gaps that are potential areas of research.

PRE-TRANSPLANT SCREENING FOR INFECTIONS

Infections continue to be a frequent cause of morbidity and mortality after solid organ transplant (SOT), arising from the candidate’s own flora, the donor organ/accompanying cells, or acquired from the environment [1]. With broader indications for hematopoietic cell transplant (HCT), increasing use of cellular immunotherapies, and more immunosuppressive chemotherapies, infections remain one of the most frequent causes of non-relapse-related death after pediatric HCT [2, 3]. In both SOT and HCT, the risk for and type of infection is variable and influenced by host, transplant, and pathogen-specific factors, environmental exposures, and the magnitude of immunosuppression. Risk assessment involves a detailed history, including prior infections, known colonization, and pre-transplant Pediatric Infectious Disease (ID) screening to evaluate for infections that may increase the risk of post-transplant complications. This assessment guides the implementation of appropriate mitigation and both peri and post-transplant prophylaxis strategies. Recommended ID laboratory screening tests in SOT and HCT candidates and donors are summarized in Table 1; additional testing may be necessary based on a candidate’s age and epidemiologic exposures.

Donor-Derived Infections (DDI)

Infections from a donor can either be anticipated, such as cytomegalovirus (CMV) in seropositive donors, or unexpected, occurring more frequently after deceased organ transplantation [4]. Along with prescribed ID laboratory screening of donors, standardized questions are asked of family members of potential deceased donors to assess risk for other infections [5–7]. In the United States, policies for the type and timing of tests for organs and tissues are mandated by the Organ Procurement and Transplantation Network (OPTN) for SOT and U.S. Department of Health and Human Services and Food and Drug Administration (FDA) for HCT [1, 5]. Unexpected SOT transmissions are reported to the OPTN for review by the ad hoc Disease Transmission Advisory Committee (DTAC). A contemporary 10-year review found that while unanticipated DDI were rare (0.18% of all recipients), infections were the most frequently reported transmission event after SOT (67% of all reports), resulting in disease in 46% of recipients within 30–45 days post-SOT [1]. Pediatric organ donors and recipients were less frequently involved in unanticipated disease transmissions [8].

Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), and Hepatitis C Virus (HCV) DDI

The opioid epidemic and associated increases in overdose-related deaths uncovered a bittersweet benefit by decreasing some of the gaps in the availability of organs for SOT. Individuals who died from drug overdoses were more likely to be younger adults without medical comorbidities precluding organ donation; however, the mean organ yield was lower because of concerns for possible HIV, HBV, and HCV DDI [9–11]. However, with a better understanding of risk factors for undetected DDI, improved testing strategies in both donors and recipients and availability of highly effective direct-acting antiviral treatments, the risk of dying while on the organ waitlist exceeds the very low risk of infection transmission. In 2020, the U.S. Public Health Service (PHS) updated its previous 2013 guideline recommendations, revised risk criteria, removed associated risk labels, and recommended universal nucleic acid testing (NAT) in all donors. These changes narrowed the window period for detecting new HIV, HBV, and HCV infections pre- and post-SOT, regardless of donor risk criteria or age [12]. United Network for Organ Sharing (UNOS), OPTN, and DTAC continue to monitor outcomes with the aim of balancing the safety of SOT while simultaneously optimizing the donor pool. The American Society of Transplantation (AST) ID-Community of Practice (IDCOP) guidelines are available to guide antiviral prophylaxis, treatment, and viral monitoring recommendations [13].

Herpes Viruses: Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Herpes Simplex Virus (HSV), and Varicella (VZV)

CMV infection is a frequent cause of complications after transplantation, from both direct viral and indirect effects of infection or treatment; guidelines for CMV management in both SOT and HCT recipients are available [14–16]. Pretransplant CMV donor (D) seropositive, recipient (R) seronegative (D+/R) status in SOT, and recipient CMV seropositive (R+) in HCT remain the most important predictors of post-transplant CMV infection. A prophylaxis strategy involving either antiviral prophylaxis prescribed to high-risk D/R or a pre-emptive strategy that requires viral surveillance and starting antivirals upon CMV detection can be chosen during the pre-transplant evaluation. Ganciclovir or valganciclovir prescribed as prophylaxis or pre-emptive therapy have reduced the burden of CMV disease in high-risk SOT recipients [14]. However, several knowledge gaps remain in children, including defining the optimal prophylaxis strategy and how to effectively and safely dose valganciclovir [17]. A pre-emptive strategy had been the mainstay of CMV prophylaxis among HCT recipients but recently letermovir, a CMV terminase inhibitor with a more favorable side effect profile, was approved as primary prophylaxis in CMV seropositive allogeneic HCT recipients ≥18 years of age [16, 18, 19]. An open-label, pharmacokinetic and pharmacodynamic study of letermovir in children 12–18 years of age, with planned age de-escalation to infants, is currently enrolling subjects (ClinicalTrials.gov identifier: NCT03940586).

Application of CMV-specific T-cell immunity panels to quantify both CD4+ and CD8+ T-cell responses to CMV antigens have been investigated as potential surrogates of protection against CMV, informing the need for and duration of antiviral prophylaxis in adult SOT and HCT recipients [20–22]. However, the performance characteristics and utility of these assays across all pediatric age groups require further study [23]. A prospective, observational trial evaluating CMV-specific T-cell responses among pediatric heart, liver, and kidney recipients in the first year post-SOT is underway (ClinicalTrials.gov identifier: NCH03924219). Adoptive CMV-specific T-cell immunotherapies are being used for prophylaxis in adult HCT recipients [24–26]. Though promising, viral adoptive immunotherapies require additional controlled studies to evaluate the safety and efficacy of prophylaxis or pre-emptive therapies in pediatric transplant recipients.

Epstein Barr virus (EBV) disease. including post-transplant lymphoproliferative disorder (PTLD), is more frequently a problem after pediatric than adult SOT. The risk is highest after SOT if EBV D+/R− and after HCT if unrelated donor, cord, or T-cell depleted grafts are used [27]^. It is critical that families understand that EBV-PTLD can range from a self-limited mononucleosis-like syndrome to a fulminant disease process, including lymphoma. EBV consensus guidelines for SOT have recently been published [28–31].

Both SOT and HCT candidates are screened for HSV and VZV, and if seropositive for either, many transplant centers will employ antiviral prophylaxis to prevent reactivation early after transplantation and with augmented immunosuppression for the treatment of rejection or graft-vs-host disease (GVHD).

Parasitic Infections

The Centers for Disease Control and Prevention (CDC) has estimated that 11% of the U.S. population ≥ 6 years old have been infected with the parasite Toxoplasma gondii [32]. Given the proclivity of T. gondii to affect cardiac muscle, D+/R− heart transplants are at the highest risk for transmission. However, DDI with toxoplasmosis have also occurred from non-heart grafts and donors not previously identified as high risk [33]. In 2017, OPTN policy 2.9 required that all donors undergo universal Toxoplasma IgG screening [34]. The AST IDCOP guidelines recommend risk stratification to identify recipients in whom prophylaxis with trimethoprim/sulfamethoxazole (TMP/S) is recommended (heart, D+/R−) or considered (non-heart, D+/R−) [35]. In contrast to SOT where reactivation in R+ is infrequent, most cases of toxoplasmosis after HCT occur as a result of reactivation of latent T. gondii infection in R+ allogeneic HCT recipients [36–38]. Although there is significant variability among type and duration of prophylaxis across adult and pediatric SOT and HCT centers, TMP/S prophylaxis remains the cornerstone for toxoplasmosis prevention [35, 39].

Given the prevalence of parasitic infections globally, coupled with increasing population movement and broader organ distribution, practitioners must be aware of parasitic DDI and implement appropriate treatment strategies. Infections caused by the Strongyloides stercoralis and Trypanosoma cruzi, causing Chagas disease, are the 2 most frequent causes of unanticipated proven or probable parasitic DDI reviewed by DTAC. Immunocompetent donors are frequently asymptomatic, but the infection becomes pathogenic when transplanted into an immunosuppressed recipient.

Strongyloides is an underestimated global public health problem, known to be most prevalent in the tropics and subtropics of Africa, Asia, and Latin America, but also endemic in the United States in the Appalachian region, southeastern, and mid-Atlantic states [40]. In 2023, OPTN DTAC proposed universal screening of deceased donors with a Strongyloides antibody test which is anticipated to be implemented as policy by 2024 [41]. If the donor screens positive, there is no need for SOT deferral as Strongyloides in the recipient can be prevented with ivermectin prophylaxis [42]. SOT living donors and candidates with risk factors who are screened and test positive, should also be treated with ivermectin before transplant.

Recipients of organs from a T. cruzi-infected donor are at risk of infection, with risk highest in heart grafts. OPTN policy updates based on the 2023 DTAC proposal for T. cruzi antibody screening in deceased donors who were born or spent ≥6 months living in countries endemic for Chagas (eg, Mexico, Central and South America, see: CDC Chagas Disease: What US Clinicians Need to Know) are also anticipated to be in place by 2024 [41]. For pediatric donors and recipients, a maternal history of birth or residence in an endemic region should also prompt screening. Importantly, results should be available pre-SOT, particularly for heart transplantation where deferral is recommended given high mortality rates [35]. If the donor screens positive for Chagas antibody, then confirmatory testing is required within 72 hours, either through the CDC or as a combination of 2 distinct, FDA licensed, approved, or cleared antibody tests [43]. Additionally, modifications in SOT immunosuppressive regimens, including avoidance of anti-thymocyte globulin or mycophenolate mofetil and when possible, employing PCR surveillance to trigger pre-emptive anti-trypanosomal therapy, should be considered [35]. Individuals with Chagas disease (active or past history) should not serve as HCT donors.

Community Respiratory Viral Infections

Community respiratory viral infections (CRVI) may disproportionally affect children both before and after transplant, leading to CRVI-associated hospitalizations, particularly in lung recipients and the very young [44, 45]. CRVI detection pre-transplantation poses a clinical challenge [46]. CRVI detection in pediatric HCT candidates has been shown to negatively impact post-transplant outcomes, such that delaying HCT may be recommended [47, 48]. Management in SOT is varied [48, 49]. Given the high sensitivity of molecular diagnostic assays and that children have higher rates of asymptomatic viral shedding, viral detection in an otherwise asymptomatic child may lead to unnecessary delays in transplantation. In addition, the risk of underlying disease progression and mortality while awaiting transplantation must be considered. A prospective, multi-center study is underway in pediatric SOT and HCT recipients to better understand the host response to CRVI that predicts disease severity and progression to LRTI, which may better inform peri-transplant management (VIPER, ClinicalTrials NCT05550298).

During the coronavirus disease 2019 (COVID-19) pandemic, proven and probable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission occurred in lung transplant recipients due to discordant screening results in donors with negative SARS-CoV-2 NAT testing from the upper respiratory tract (URT) relative to later testing from lower respiratory tract (LRT) compartments [50, 51]. Understanding of SARS-CoV-2 transmission has evolved and informed OPTN policy, which requires SARS-CoV-2 NAT testing from a URT source in all donors and additional testing from the LRT in potential lung donors [52]. In addition, there are increasing reports of safe and successful transplantation of non-lung organs from SARS-CoV-2 positive donors in adults, with good short-term clinical and graft outcomes [53, 54]. There remains a paucity of published clinical experience regarding outcomes in pediatric recipients receiving grafts from SARS-CoV-2 positive donors [55]. HCT candidates should undergo SARS-CoV-2 NAT on a respiratory specimen ≤72 hours before HCT conditioning [56].

Infection control practices pre- and peri-transplant are fundamental in preventing acute infections, including CRVI in transplant candidates, recipients, and living donors. Given the burden of RSV-associated hospitalizations among young transplant recipients [57, 58], SOT and HCT candidates ≤2 years of age who are profoundly immunocompromised may be candidates for palivizumab [49]. Nirsevimab, a monoclonal antibody with an extended half-life and improved neutralization activity is safe and effective in preventing medically attended RSV-associated LRTI in premature and otherwise healthy young infants [59–61]. Nirsevimab may be an option for pediatric transplant candidates at the highest risk for RSV-associated disease. The MUSIC clinical trial is a phase 2, open-label, single-dose study evaluating the safety, pharmacokinetics, and efficacy of nirsevimab in immunocompromised children ≤24 months of age, including SOT and HCT recipients (ClinicalTrials.gov identifier: NCH04484935).

Pre-Transplant Screening for Multidrug-Resistant Organisms

Surgical site infections (SSI) remain one of the most frequent healthcare-associated infections, occurring in 3–53% of SOT recipients and varying by graft type [62]. In general, using the narrowest and most efficacious agents for the shortest duration should be applied to prophylaxis. However, in certain situations, the choice and duration of antibiotics may warrant individual, patient-specific modifications. Colonization with certain bacteria may confer an increased risk for surgical site infection (SSI) and early post-transplant infections. For example, testing for Staphylococcus aureus nasal colonization is frequently performed in transplant candidates to help guide possible pre-operative decolonization strategies and peri-operative antibiotic prophylaxis choices to prevent post-SOT SSI. There are no conclusive data regarding the utility of pre-transplant recipient screening for other Gram-negative multi-drug resistant organisms (MDRO) since it is not known whether perioperative antibiotics targeted at the MDRO result in a benefit to the patient [63]. However, knowledge of known MDRO colonization and past infections may inform empirical antibiotic management should fever occur after transplantation.

In pediatrics, Candida auris disproportionally affects neonates and immunocompromised children with an indwelling central venous catheter, carrying higher mortality than other invasive candidemias [64, 65]. In addition, C. auris co-colonization with Gram-negative carbapenemase-producing bacteria is reported to occur. Testing for C. auris colonization is available through the CDC (https://www.cdc.gov/drugresistance/laboratories.html) and should be coordinated with local public health authorities. There are no proven effective decolonization strategies. Importantly, patients with confirmed MDRO colonization or infection should be placed on appropriate transmission-based precautions [3].

VACCINATION STRATEGIES

Immunizing candidates before SOT remains one of the most important, yet underutilized preventive strategies in our armamentarium [66, 67]. Immunization strategies to protect SOT and HCT recipients also include advocating for improved community vaccination rates. Introducing the cocooning strategy and counseling families during pre- and post-transplant visits underscores the importance of immunizing household and close contacts to protect the transplant recipient. Additional studies are needed to evaluate the benefits of HCT donor vaccination and current guidelines do not recommend vaccinating the donor solely to benefit the recipient [7, 68]. However, donor immunization also protects against vaccine-preventable infections that may delay transplant, as was highlighted during the COVID-19 pandemic [69]. Every effort to prevent infections in donors and candidates should be advocated.

For SOT candidates, immunizations should be up to date at the time of transplantation [67, 70, 71]. The pre-SOT evaluation may allow sufficient time to complete age-appropriate vaccines or apply an expedited immunization schedule. Patients with certain medical conditions or risk factors may require additional immunizations. Table 2 highlights the minimum ages and dosing intervals for expedited vaccination. Live vaccines should be provided to SOT candidates on an accelerated schedule as soon as SOT is planned; live vaccination is generally avoided 2–4 weeks before SOT. There are emerging data and published consensus guidance regarding the safety and immunogenicity of live vaccines in certain pediatric liver and kidney recipients post-transplantation [72–75]. While it is recommended that recipients are up to date on immunizations prior to HCT conditioning as able given co-morbidities, it is important to advise all autologous and allogeneic HCT recipients that they will require all vaccines after transplant; non-live vaccines are generally recommended beginning 3–12 months post-HCT [68, 76]. Stable HCT recipients without active GHVD may be candidates for live vaccines if ≥2 years post-HCT, ≥1 year since stopping systemic immunosuppression, and ≥8 months since the last immunoglobulin supplementation [68, 76]. The optimal timing of vaccines for both SOT and HCT will also depend on the receipt of other therapies, including anti-CD20 monoclonals, and the extent of immune reconstitution.

Emerging developments in immunization practices may modify current vaccine recommendations for transplant recipients. In June 2023, the Advisory Committee on Immunization Practices (ACIP) voted to approve the use of the 20-valent protein-conjugated pneumococcal vaccine (PCV20) in children ≥2–71 months of age with specified risk conditions, according to currently recommended PCV dosing and schedules [77]. In addition, for children aged 2–18 years with specified risk conditions who have received all recommended pneumococcal doses before age 6 years, ≥1 dose of PCV20 may be provided, with no additional doses indicated. Distinct vaccine formulations may also be an option for certain patients. Vaccines that have recently been approved include recombinant VZV (age ≥19 years) and adjuvanted Hepatitis B vaccine (age ≥18 years). Lastly, 2 doses of high-dose inactivated influenza vaccine (IIV) were found to be more immunogenic than the standard dose IIV formulation in pediatric HCT recipients [78]. Based on preliminary data, a clinical trial will soon evaluate the immunogenicity and safety of high-dose vs standard-dose IIV in pediatric SOT recipients (ClinicalTrials.gov identifier: NCT05947071) [79].

Ultimately, vaccines are useful only if administered. Providers should rectify vaccine misinformation and address vaccine hesitancy. Vaccine mandates have long been proposed in transplantation; the COVID-19 pandemic brought the topic further into public light. There are many ethical and legal considerations with no current consensus regarding vaccine mandates in pediatric transplantation [80, 81].

STRATEGIES FOR SAFE LIVING AFTER TRANSPLANTATIONS

The pre-transplant evaluation also allows practitioners to review individual patient and family lifestyles and help to minimize infectious risks. Although activities will change with a patient’s age and the amount of immunosuppression/extent of immune reconstitution, the pre-transplant evaluation starts the education for lifelong consideration of ID risk management.

While the COVID-19 pandemic familiarized the public with minimizing infectious risks in their daily lives through frequent handwashing, physical distancing, and wearing masks, transplant patients had been taught these strategies for decades. Surveyed families of pediatric SOT recipients reported that normalization of these risk reduction strategies decreased the stigma their children felt from practicing them even in the pre-pandemic world [82]. Good hand hygiene should always be emphasized, while physical distancing and masking in public can be used early after transplant and during periods of increased immunosuppression for treatment of rejection or GVHD. Many aspects of life have distinct infectious risks, making it difficult to cover all possibilities during a short clinic visit [83, 84]. Table 3 covers some of the more frequent infectious risks and mitigation strategies.

One way to structure and tailor the safe living conversation is to discuss the 5 F’s: Foods, Furry Friends, Flights, Family, and Fooling around. Food covers not just what transplant recipients may eat, but anything that could be ingested, including unpasteurized dairy products, raw or undercooked meat or seafood, and safe water sources, for drinking and recreational water activities. Furry friends encompass animal exposure through pets or other activities such as being on a farm or at a petting zoo. Flights refer to all travel (domestic and international) and local environmental exposures that may occur with outdoor activities, such as endemic infections and insect avoidance including the use of repellants with DEET with outdoor activities during mosquito and tick season. Family includes household members and frequent contacts, including at school. While the mental health benefits of animal ownership have been demonstrated, the type and age of the pet along with the age of the child impacts infectious risk [83]. Finally, “fooling around” reminds providers to have discussions around safe sex and to discuss other sensitive topics that may not be immediately relevant, but require counseling even for young patients. Safe sexual encounters are important to prevent infections, cancers, and unintentional pregnancies [85]. Recreational drug use carries a risk of infection, for example from contaminated marijuana leaves, but also potential direct toxicity from vaping or drug-drug interactions. A non-judgmental conversation allows families and their children to have honest discussions and share risk mitigation plans.

CONCLUSIONS

The pre-transplant evaluation provides an opportunity to screen for infections and plan actionable preventative measures, including optimal prophylaxis, vaccination, and safe living strategies. Knowledge and improved laboratory screening of potential DDIs, allow for a more balanced risk assessment, reduce unanticipated DDI, and improve surveillance and management efforts. Additional robust studies are needed to answer ongoing knowledge gaps after pediatric transplantation. Combined, these approaches aim to reduce post-transplant infectious complications and improve overall outcomes in pediatric SOT and HCT recipients.

Notes

Funding support: Taylor Heald-Sargent receives research funding from GSK. Marian G Michaels receives research funding from Merck Sharpe Dome. Monica I Ardura receives research funding from Miravista Diagnostics and consults for Karius.

Supplement sponsorship: This article appears as part of the supplement “Advances in Pediatric Transplant Infectious Diseases,” sponsored by Eurofins Viracor.

Potential conflicts of interest: The authors have no known conflict of interest related to this topic.

References