Basic principles of the infectious disease pretransplant evaluation
The pretransplant infectious disease evaluation represents the first step in a long continuum of infection prevention that extends into the posttransplant period. This evaluation is a critical element in the pretransplant process and should be performed as early as possible, ideally as soon as a child is considered for transplant. The overall objectives of infectious disease evaluation are to (1) identify and mitigate infectious complications that may result in delay of transplant; (2) identify risk factors that may affect perioperative management; (3) identify posttransplant prevention strategies for specific risks; and (4) begin the discussion of long-term strategies for safer living in the posttransplant period. The evaluation should be comprehensive and not limited to basic serologic screening. A key guiding principle is that pretransplant screening tests should be performed to address those infections that may increase the risk of posttransplant complications and that will prompt specific intervention either in the pretransplant or posttransplant period. A dedicated infectious disease evaluation before transplant is a critical opportunity to review all prior and current infections and antimicrobial use that are likely to affect the transplant course and management, including unrecognized or latent infections.
It is especially important that pediatric transplant candidates receive an infectious disease review that is family-centered and considers occupational and recreational exposures not only for the transplant candidate but also for all other household contacts. Household water sources and dietary habits should be reviewed to identify risk factors such as well water exposure or ingestion of uncooked meat or fish. Travel history and animal exposures should be reviewed and discussed. For families with pets, guidance for living with animals after transplant is available through the U.S. Centers for Disease Control and Prevention and should also be discussed. Children who live in areas of higher tuberculosis (TB) prevalence and/or who live in households with adults with active TB infection are at high risk for acquisition of TB infection before and after transplant. TB risk factors should be reviewed for all household contacts, with additional TB screening and treatment measures for household contacts as indicated, as discussed in more detail in the following text.
Pretransplant infectious disease evaluation also provides an important opportunity to review and update immunizations for both the transplant candidate and household contacts. It is important to note that live attenuated vaccines for varicella, measles, mumps, and rubella are not contraindicated for household contacts of transplanted children, and ensuring that household contacts are fully immunized is a critical preventative strategy for children who receive transplants and who may be susceptible secondary to incomplete immunization or waning immunity after immunization. This “cocoon” immunization strategy is essential for household contacts of pediatric transplant candidates and recipients during influenza season.
The risk of donor-derived infection should also be discussed as part of the infectious disease pretransplant evaluation. This is a complex and multifaceted conversation that may be best approached across multiple visits with both an infectious disease consultant and the primary transplant team. Although families and providers alike are often concerned about the potential risk of human immunodeficiency virus (HIV) and hepatitis transmission via donors who are considered to be at either routine or increased risk by U.S. Public Health Service criteria, it is also important to discuss the risk of other donor-derived infections, both unanticipated and expected. This includes infections for which donors may be screened ( Strongyloides stercoralis , Toxoplasma gondii , Trypanosoma cruzi ) but also for donor infections that may be unrecognized at the time of transplant. Risk and implications of donor-derived infections that are often anticipated, such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV), should also be discussed, especially for transplant candidates who are presumed to be uninfected by these viruses based on pretransplant screening serology.
The first step in the pretransplant infectious disease evaluation of both pediatric solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) candidates is a comprehensive review of how the child’s underlying disease affects their risk of infection before and after transplant. For transplant candidates with a history of malignancy, the status of the child’s disease should be documented (remission or relapse), and prior chemotherapy and radiotherapy regimens should be reviewed. Both HSCT and SOT candidates may have a history of exposure to immunosuppressive agents, such as glucocorticoids or anti-CD20 monoclonal antibody; therefore recent serum immune globulin levels and quantitative lymphocyte subsets should be reviewed as indicated. The presence of a foreign body, prosthetic material, or structural abnormality (central venous or hemodialysis catheter, prosthetic joint, vascular graft, ureteral stent, hemodialysis graft fistula) should be documented. Prior imaging should be reviewed to assess for lung nodules, calcified granulomas, or cavitary lesions that may prompt further investigation before transplant.
Review of the child’s underlying disease is followed by a comprehensive review of all prior and current infections and bacterial colonization history. Pediatric transplant candidates with a history of malignancy may have a history of bacteremia or invasive fungal infection), and children awaiting HSCT for primary immune deficiency may have an extensive history of opportunistic infections. Kidney transplant candidates may have a history of urinary tract infection, and hemodialysis and peritoneal dialysis recipients are at higher risk for catheter-related bacteremia and peritonitis, respectively. Hardware-associated infections may develop in heart transplant recipients who require ventricular assist device support, and ascending cholangitis or peritonitis may develop in children with liver failure. Lung transplant candidates with cystic fibrosis may have a history of respiratory colonization with multidrug- or extensively drug-resistant organisms such as Pseudomonas aeruginosa , Burkholderia cepacia , and Stenotrophomonas maltophilia . Thus special attention should be paid to prior bacterial culture and susceptibility results, as well as to prior antimicrobial utilization. Baseline sputum cultures are recommended for lung transplant candidates to identify colonizing organisms and their antimicrobial susceptibility patterns.
For transplant candidates who have a poorly documented history of allergic reaction to a specific antimicrobial, this history should be clarified. Formal allergy consultation should be completed as needed before transplant. Dental history should also be reviewed, and ideally, candidates should undergo complete dental evaluation and appropriate intervention before transplant.
Infectious disease screening of the pediatric solid organ transplant candidate
Screening tests that are routinely recommended for pediatric SOT recipients, including those that are used to assess for latent infection or vaccine-induced immunity, are outlined in Box 4.1 . In interpreting serology results, the provider should consider the following variables: (1) the candidate’s history of blood product or immune globulin infusion; (2) the candidate’s age (serology results in infants may reflect passive transfer of maternal antibody); (3) the immunosuppressive agents administered before transplant, such as corticosteroids or anti-CD20 monoclonal antibody; and (4) the inherent limitations of some screening assays, such as the inability of some assays to detect acute infection.
Chart and history review
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Document current and prior infections, including antimicrobial susceptibility patterns
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Document current and prior antimicrobial use, including suspected or documented allergic reactions
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Review travel history, animal exposures, occupational and recreational exposures for candidate and household contacts
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Review immunization history for transplant candidate and all household contacts
Serologic screening a
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Human immunodeficiency virus (HIV) serology b
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Hepatitis B surface antigen, b hepatitis B core IgG, b hepatitis B surface antibody
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Hepatitis C IgG b
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Hepatitis A IgG
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Cytomegalovirus (CMV) IgG (CMV PCR from urine or saliva for infants)
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Epstein-Barr virus (EBV) EBV capsid IgG and IgM, consider anti-EBV nuclear antigen IgG
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Toxoplasma IgG for all heart transplant and allogeneic/stem cell transplant candidates, consider for non-heart SOT and autologous stem cell candidates
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Measles IgG
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Varicella IgG
Additional screening measures
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Review of tuberculosis risk factors and tuberculin skin test/interferon gamma release assay (with chest radiograph if indicated)
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Sputum Gram stain and culture for lung transplant candidates
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Herpes Simplex Virus (HSV) 1 and 2 IgG for hematopoietic stem cell transplant candidates
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Respiratory virus testing for allogeneic stem cell transplant candidates, if symptoms are present
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Syphilis screening for infants and at-risk adolescents
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Sexually transmitted infection screening for adolescents
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Pelvic examination with Pap smear and human papillomavirus screening for sexually active adolescent females
Interpretation of infant serology results may be complicated by passive transfer of maternal antibody.
HIV, hepatitis B, and hepatitis C serologic testing is required for all solid organ transplant candidates per U.S. Organ Procurement and Transplantation Network policy. IgG, immunoglobulin G; PCR, polymerase chain reaction; SOT, solid organ transplant.
HIV and hepatitis screening
Current policy of the U.S. Organ Procurement and Transplantation Network mandates screening for HIV, hepatitis C, and hepatitis B for all SOT candidates, independent of age. This screening is typically performed by serologic testing. Serologic testing for hepatitis B should include hepatitis B surface antigen, hepatitis B core immunoglobulin (IgG), and hepatitis B surface antibody, although the latter is not mandated. False-positive results for hepatitis C antibody screening are well described, particularly in low-prevalence populations. Positive results for hepatitis C antibody screening should be confirmed by hepatitis C ribonucleic acid viral load and potentially additional screening methods, depending on the patient’s risk factors. HIV and hepatitis B nucleic acid amplification testing (NAAT) may also be used to confirm positive serologic test results.
Documentation of hepatitis B immunity by either qualitative or quantitative hepatitis B surface antibody is important for determining risk stratification and the possible need for hepatitis B prophylaxis should the candidate receive an organ from a donor who has positive hepatitis B core antibody test results with negative results for hepatitis B surface antigen. For candidates who are found to be nonimmune to hepatitis B, a primary hepatitis B vaccine series or booster vaccine doses should be administered, and immunity should be reassessed upon completion of vaccination or before transplant, whichever occurs first. Higher doses of vaccine may be required for transplant recipients receiving hemodialysis, although data are limited in this area for children. It is also important to note that administration of hepatitis B vaccine can result in transient detection of hepatitis B surface antigen; thus testing for hepatitis B surface antigen shortly after immunization is not recommended. Hepatitis A serology and immunization history should be recorded, and hepatitis A vaccine should be administered as needed.
Herpesvirus screening
CMV (IgG) and EBV (capsid IgG and IgM) serology studies are typically used for transplant candidates to stratify the risk for posttransplant complications and to determine the relative need for prophylactic (CMV) and preemptive monitoring (CMV, EBV) strategies. IgG antibody to EBV nuclear antibody may also be helpful in assessing humoral immune response to past EBV infection. Unfortunately, the utility of a positive CMV or EBV serologic result is limited in infants younger than 12 months whose positive serology results may reflect passive transfer of maternal antibody. CMV NAAT (or viral culture based assay) from urine or saliva is recommended for infants, although a negative test result does not definitively exclude prior infection ( Box 4.1 and Table 4.1 ). Infants with a negative CMV NAAT result from urine or saliva or a negative CMV urine culture should be considered CMV naïve upon receipt of a CMV-seropositive organ ( Table 4.1 ). It may also be prudent to consider all infants who receive an EBV-seropositive donor organ to be EBV naïve (recipient seronegative) for risk stratification purposes ( Table 4.1 ).
| Donor | Recipient | Highest Risk Stratification a |
|---|---|---|
| Positive | Positive or negative | D + /R − |
| Negative | Positive | D − /R + |
| Negative | Negative | D − /R − |
a Assume cytomegalovirus (CMV) D + /R + stratification only if infant transplant candidate is found to have positive CMV urine culture result or positive CMV urine/saliva polymerase chain reaction result.
Studies to assess for latent infection with Herpes Simplex Virus (HSV) are not routinely indicated for pediatric SOT recipients. Small studies predating the widespread use of ganciclovir and valganciclovir prophylaxis (both of which are active against HSV) suggest that severe complications attributed to HSV are relatively infrequent in the pediatric SOT population, with the majority of complications reported as mucosal lesions that responded to antiviral therapy. Transplant candidates in whom lesions develop that are suspicious for herpes should have direct testing of the lesion to confirm the diagnosis. In children who have a history of recurrent lesions but who have not had direct lesion testing, serology results may be informative. Serology testing for human herpesviruses 6, 7, and 8 is generally not recommended for pediatric SOT candidates.
All pediatric heart transplant candidates should undergo serologic screening for Toxoplasma gondii secondary to the high risk of reactivation in the myocardium and the need for targeted posttransplant prophylaxis in seropositive recipients. The need for pretransplant Toxoplasma screening in non-heart transplant candidates is less clear, as posttransplant prophylaxis specifically for toxoplasmosis is not routinely recommended for non-heart transplant recipients. However, documented Toxoplasma reactivation has been reported in non-cardiac organ recipients, and the true incidence of toxoplasmosis in this population may be underestimated. Thus knowledge of latent infection with Toxoplasma before transplant or of serologic mismatch with a Toxoplasma -seropositive donor may guide the decision to provide targeted prophylaxis or more intensive monitoring for non-heart transplant recipients who receive more intensified immunosuppression for graft rejection.
Immunization records for measles, mumps, rubella (MMR) and varicella should be reviewed. Documentation of measles and varicella IgG before transplant is helpful for assessing the risk of disease and the need for prophylaxis, should the candidate have documented exposure to any of these viruses. Non-immunity by serology may reflect lack of or incomplete prior vaccination or waning immunity after appropriate immunization. It should also be noted that commercially available enzyme-linked immunosorbent assays may lack the sensitivity to detect vaccine-induced, varicella-specific antibodies and also do not reflect cell-mediated immune responses to varicella. Thus a negative varicella IgG result may not truly reflect susceptibility to disease. Keeping in mind these limitations, administration of MMR and/or varicella vaccines should be considered for transplant recipients who are found to be non-immune by routine serology. The risks and benefits of administration of live attenuated vaccines shortly before transplant are discussed in more detail later in the text.
The decision to screen pediatric SOT candidates for syphilis depends on the local prevalence of disease and the age of the candidate. Screening should be performed in infants (who may be at risk for congenital syphilis) and in sexually active adolescents (who may acquire syphilis through sexual intercourse) but is generally not indicated in children between these age intervals in the absence of specific risk factors. In the past, syphilis screening was typically performed by first testing with rapid plasmin reagin (RPR) or Venereal Disease Research Laboratory assay, followed by confirmation of a positive result with a treponemal specific assay. Both rapid plasmin reagin and Venereal Disease Research Laboratory testing are acceptable screening tests for pediatric transplant candidates. However, at many institutions, syphilis screening is performed as a reverse-sequence algorithm that begins with the detection of syphilis-specific IgG and IgM antibodies by enzyme or chemiluminescence assay. Special care should be taken in interpreting results of reverse-sequence algorithm testing for infants (in whom positive screening results may again reflect passive transfer of maternal antibody), for patients who have a history of treated syphilis, and for individuals without risk factors who are suspected to have false-positive results. Screening for Mycobacterium tuberculosis is recommended for all pediatric SOT candidates and is discussed in greater detail later, along with recommendations for screening of pediatric SOT candidates with specific risk factors.
Approach to infectious disease evaluation of the pediatric hematopoietic stem cell transplant candidate
Results of serology screening for pediatric HSCT candidates should be interpreted not only in the context of recent blood or immune globulin product infusion but also in the context of the type of anticipated stem cell transplant. For example, CMV seropositivity in a HSCT candidate conveys a greater risk of CMV-related complications after transplant if the candidate receives a graft from a CMV-seronegative donor. Similarly, Toxoplasma reactivation is unlikely after autologous HSCT but is more likely to occur in a seropositive recipient of a seronegative allogeneic or umbilical cord transplant. In general, the basic screening recommended for pediatric HSCT candidates (both autologous and allogeneic) is similar to the evaluation recommended for pediatric SOT candidates ( Box 4.1 ). Serology results should be evaluated before HSCT for HIV, hepatitis B, and hepatitis C, with viral load confirmation if serology results are positive. Hepatitis A serology should be evaluated for evidence of prior immunization or infection.
In addition to CMV and EBV serology, HSV-1 and HSV-2 IgG testing should be performed for pediatric HSCT candidates, as HSV seropositivity may affect the posttransplant antiviral prophylaxis regimen. As with pediatric SOT candidates, pretransplant testing is not recommended for human herpesviruses 6, 7, and 8. Toxoplasma serology screening should be performed for allogeneic/umbilical cord transplant candidates but may be less informative in autologous HSCT candidates, who are at lower risk for reactivation after transplant. All pediatric HSCT should be evaluated for M. tuberculosis exposure risk and infection; the approach to tuberculosis screening in this population is discussed in detail later.
HSCT recipients are at risk for severe lower airway disease from respiratory viruses, especially before engraftment and during times of profound lymphopenia, , and some guidelines recommend deferral of HSCT in the setting of upper respiratory tract infection (URI). , Allogeneic HSTC candidates who were screened for respiratory virus infection by multiplex polymerase chain reaction from nasal wash samples were found to a have significantly increased risk of mortality if they had both URI symptoms and documented respiratory virus independent of the virus detected. This study suggests that allogeneic HSCT candidates should undergo respiratory virus testing in the setting of URI symptoms and that careful consideration should be paid to possible deferment of transplant until symptoms have resolved.
Approach to tuberculosis screening in the pediatric transplant candidate
Studies consisting of mostly adult transplant recipients suggest that the prevalence of posttransplant M. tuberculosis infection varies significantly by geographic region but is at least 20 times as frequent in SOT recipients and at least twice as frequent in HSCT recipients relative to the general population. Children are at greater risk for progression from latent TB infection to active disease at the extremes of age (<5 years and adolescence), and young children are especially more likely to progress to disseminated and/or extrapulmonary disease in the setting of transplant. Children with latent or active TB are likely to have acquired M. tuberculosis infection from a close contact with active infection. Case series of pediatric liver transplant recipients who received a diagnosis of TB found that the majority of infected children had household contacts with either latent or active TB. , Accordingly, a critical first step in screening the pediatric transplant candidate for TB is to perform a comprehensive screening of all household contacts for risk factors, as well as for signs and symptoms of active infection, prior tuberculin skin test (TST) or interferon gamma release assay (IGRA) screening, and treatment history. TST/IGRA screening and/or chest radiography should be strongly considered for household contacts who have risk factors for TB.
All pediatric transplant candidates should be screened for TB risk factors and for signs and symptoms of active TB. Several consensus statements and guidelines recommend that all pediatric transplant candidates undergo screening with TST or IGRA and chest radiography, , , although the positive predictive value of TST/IGRA screening depends on risk factors for TB and local epidemiology. In general, TST screening is recommended for children younger than 2 years. Either TST or IGRA may be used to screen children who are at least 2 years old; IGRA is the preferred screening method for children who have a prior history of bacillus Calmette-Guérin (BCG) immunization, , and IGRA offers the advantage of reporting a positive mitogen control for assessment of anergy. A positive TST or IGRA result should prompt a renewed evaluation for active infection and, if active infection is excluded, a discussion of the risks and benefits of treatment for latent TB infection. It is important to note that a negative TST or IGRA result in a child does not exclude the possibility of TB infection, and the possibility of infection should be carefully considered in infants and children who are known to have household contacts with latent or active TB. This is of particular importance for pediatric transplant candidates who have diminished lymphocyte numbers or function at the time of testing secondary to ongoing immunosuppression. In immunocompromised children with negative TST/IGRA screening, careful evaluation for risk factors, infected household contacts, and evidence of active infection is critical.
Additional screening measures for pediatric transplant candidates
Pediatric transplant candidates who were born in areas endemic for specific infections or who have specific travel or exposure histories may require additional testing on a case-by-case basis ( Box 4.2 ). Candidates who were born in or who spent significant time in South America, Central America, or Mexico may have asymptomatic infection with Trypanosoma cruzi (the protozoan parasite that results in Chagas disease), especially those who spent time in rural areas. Testing for T. cruzi –specific antibodies is limited by the lack of validated testing options and the lack of a gold standard diagnostic assay, and T. cruzi polymerase chain reaction is insensitive for diagnosis of chronic infection. Candidates with risk factors who have positive T. cruzi serology results by commercially available assay may require additional confirmatory testing. These cases may be reviewed with state departments of health or in consultation with the U.S. Centers for Disease Control and Prevention Chagas Reference Laboratory (Division of Parasitic Diseases Public Inquiries Line, 404-718-4745; after-hours hotline 770-488-7100; https:www//cdc.gov/parasite ).
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