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Infection among pediatric transplant patients requires individualized, continuous care
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The management of infectious diseases among children who undergo transplantation, whether it be solid organ or hematopoietic stem cell transplantation, is a balancing act that requires collaboration across the continuum of care.
In addition to common infectious diseases, pediatric patients who undergo transplants also experience infections associated with surgery, severe immunosuppression, as well as pre-existing conditions that may be the original cause for the transplantation.
"Even though these children can develop the same infections all children experience, whether it is a cold, respiratory syncytial virus infection or strep throat, infection can be — but is not always — much more serious among children undergoing transplantation,"
Solid organ transplant (SOT) patients who have had the highest risk for infection immediately after transplantation and during the post-transplantation period, according to Englund, as they generally have normal immune systems before transplantation. Immunosuppression after transplantation elevates SOT patients' risk for infection.
Hematopoietic stem cell transplant (HSCT) patients receive various drugs and radiation before transplantation that significantly deplete their immune system response, placing them at high risk for infection.
Donor-derived infections, such as cytomegalovirus (CMV), Epstein-Barr virus (EBV) and bacteremia, are more common among SOT patients compared with HSCT patients, according to
"Stem cell donors are typically healthy; they are often featured on a registry so the match between donor and recipient may be stronger compared with an organ donor who is likely deceased," Green told Infectious Diseases in Children. "You only have so much time to completely eliminate all possible infections from an organ donor. The HSCT process is a bit more relaxed, with time to screen and ensure no infections will be transferred during transplantation."
Lara Danziger-Isakov, MD, MPH, director of transplant infectious diseases at Cincinnati Children’s Hospital, said pediatric transplant patients’ risk for infection changes over time.
Photo courtesy of Cincinnati Children’s Hospital Medical Center
In addition, pediatric transplant recipients are likely to be naive to many diseases, increasing their risk for primary infection which can be more serious than infection recurrence.
"Many children have never been exposed to disease organisms prior to transplantation,"
Infections are more difficult to diagnose among transplant patients compared with healthy patients because signs and symptoms are often skewed by immunosuppression, according to a review by
Because response to infection often entails altering immunosuppression, which can increase risk for graft rejection, preventing the infection in transplant patients is often fundamental to a successful procedure. Physicians must remain cognizant of infection risk at all stages of transplantation, which can extend years after actual transplantation.
Managing infection risk over time
Pediatric transplant patients' risk for infection changes over time in relation to changes in immunosuppression, according to
"From the time the patient is evaluated for transplantation, through transplantation and post-transplantation, risk for infection changes and depends on where the patient is in the transplantation process," she told Infectious Diseases in Children. "Infectious risk will vacillate over that period."
Transplant patients often have pre-existing conditions, according to Danziger-Isakov, which may even be the reason for transplantation.
Along with pre-existing conditions, patients may have pre-existing risk for specific types of infections related to underlying disease. For example, lung transplant patients are at risk for lung-related infections; kidney transplant patients may have underlying urologic abnormalities that increase their risk for urinary tract infections; and small bowel transplant patients who are dependent on IV nutrition have an elevated risk for catheter-related bloodstream infections.
In addition to managing pre-existing conditions and associated infection risks, physicians must work to prevent further infection among transplant patients.
"Common viruses, like rhinovirus and RSV, can cause more severe disease, particularly pneumonia or lower respiratory tract disease, among immunocompromised patients," according to Englund. "Such infections can be acquired from family members or even in hospital settings."
Vaccination is one prevention method that can help protect against common infections which can lead to more severe disease in immunocompromised patients.
Updated IDSA guidelines recommend that, if possible, vaccines should be administered before immunosuppression, with live vaccines administered at least 4 weeks prior to immunosuppression and inactivated vaccines administered at least 2 weeks before immunosuppression.
"No child should develop a vaccine-preventable disease," Danziger-Isakov said. "It is much better not to have had an infection after transplantation than it is to treat infection post-transplant."
Donor-derived infections are another issue physicians must be mindful of during the pre-transplantation period.
CMV infection, one of the most common donor-derived infections, can lead to pneumonia, graft rejection, solid organ rejection, total sepsis-like syndrome, gastrointestinal involvement and sometimes death, according to Englund.
Strong data indicate that depending on the type of organ a patient is receiving, approximately 20% to 30% of SOT patients will have CMV infection, Danziger-Isakov said.
"This does not necessarily mean it is end-organ disease or that the patient is symptomatic," she said. "There may simply be evidence of CMV replicating in their bloodstream at some point during post-transplantation. However, differentiating infection from substantial syndrome and disease is always a challenge, especially in patients who have concurrent issues."
Because the screening of transplant donors for infection is limited by the short period of time organs can be used after death, it can be difficult to detect CMV before transplantation.
During transplantation, patients have significant risk for infections related to surgical procedures and significant immunosuppression.
"Fungal infections are some of the deadliest infections among SOT and HSCT populations,"
William Steinbach
Candida and Aspergillus are the most frequent causes of invasive fungal infections, according to Steinbach, but less common mold infections are becoming increasingly regular. 

"We are seeing more and more cases of less common mold infection, specifically Fusarium, Scedosporium prolificans and other invasive mold infections that are quite deadly and often resistant to antifungals," Steinbach said.
Prevention, diagnosis and treatment of invasive mold infections is challenging for physicians, according to Steinbach.
"We don't have a great sense of true epidemiology of invasive fungal infections in pediatric patients because data are so limited," he said.
Risk for infection post-transplant
After transplantation, as patients improve or develop complications, their risk for infection changes. If a patient has numerous complications, including chronic graft dysfunction or chronic graft rejection, that require augmented immunosuppression, risk for infections associated with immunosuppression also increases.
While EBV infection can be present in the pre-transplantation period, the virus is most commonly associated with post-transplantation lymphoproliferative disorder (PTLD).
"PTLD accounts for more than half of post-transplantation malignant conditions in pediatric solid organ transplant recipients," Fishman wrote.
The relationship between EBV and PTLD is unclear, according to Fishman, but primary EBV infection after transplantation increases risk for PTLD.
"Intestinal transplant recipients have the highest EBV rates, followed by lung recipients, then liver, kidney and heart transplant recipients," Green said.
Fortunately, the use of rituximab (Rituxan, Genentech), which targets EBV, has significantly decreased PTLD rates among HSCT patients, according to Green.
A study conducted by Green and colleagues found that viral loads can be used to detect EBV before the patient becomes sick, but this approach can be challenging for physicians.
"Viral loads can be confusing because they can be elevated in those who are not sick. While viral loads do have a correlation with prediction of disease progression, many patients will have elevated viral loads without progression," Green said.
Furthermore, the presence of PTLD within a graft can be confused with graft rejection or other viral processes, according to Fishman.
"Physicians must balance an understanding of what viral loads mean with the concept that waiting to treat until illness presents is a more difficult process," Green said.
Detection of EBV is typically followed by antiviral treatment, according to Green. Antivirals may not be effective, however, due to the nature of the EBV virus.
"If a patient is given acyclovir or ganciclovir the virus will not be detected in saliva but the viral load does not go down as a result, and can actually increase, and a patient can develop disease," Green said.
Community-acquired infections are another concern during the post-transplantation period. Children who improve after transplantation re-enter the community and rejoin classmates at school, exposing them to potential infection.
At this stage in the transplantation process, pediatric transplant patients continue to have an increased risk for infections related to transplantation but are more at risk for developing community-acquired infections, according to Danziger-Isakov.
"Pediatric transplant patients who re-enter the community often develop RSV or influenza," she said. "This is a big reason why we work very diligently to ensure children have received all their vaccines and are protected against infections that commonly circulate in the community."
Pediatric transplant patients are significantly susceptible to infection at all stages of the transplantation process. As risk for infection changes, physicians must adapt their approach accordingly while taking into account each patients unique condition.
Challenges for physicians
With so many variables at play, it is clear that managing pediatric transplant patients with infection is a complex task.
"The first challenge is prevention; the process of identifying potential risk or anything that could lead to issues in the future," Danziger-Isakov said.
Janet A. Englund
Certain variables, like pre-existing conditions, can highlight specific risk factors and immunization can lower patients' risk for common infections. However, more unusual infections, like CMV and EBV, can be difficult to identify simply due to the complex nature of disease or because signs and symptoms are masked by immunosuppression side effects.
Time is another challenge within the prevention stage; physicians may not have adequate time to conduct a pre-transplant evaluation.
"Pre-transplant evaluation may not be easy to schedule for SOT patients because in many cases the donor is deceased and the time of transplant is therefore not known in advance," Englund said. "HSC transplantation is often scheduled, so we can arrange an evaluation to ensure they are not symptomatic and/or any infections have been treated successfully prior to transplantation."
In addition, when identifying potential infection risk, each patient's history and current situation must be considered.
"Pediatric transplant infectious disease is not simple, it is not just a matter of diagnosing infection," according to Englund. "You have to assess the patient on an individualized basis; consider risk factors or ongoing issues they may have and medications they are taking."
Treatment must also be individualized, according to Steinbach.
"There are different levels of immunosuppression, so treatment must be individualized as much as possible," he said.
The variety of infections to which pediatric transplant patients are susceptible also creates challenges when diagnosing infection.
"Diagnostics is particularly challenging among SOT patients because there is such a wide array of infections the patient could develop that may be related to the transplant, an underlying disease or community exposure," Danziger-Isakov said. "Sometimes you have to wear the hat of a general pediatrician in addition to the hat you wear as an infectious disease physician who focuses on immunocompromised hosts."
Transplant patients often have more than one infection simultaneously, according to Danziger-Isakov, which increases the complexity of diagnosis.
"The driving factor of infection is not always clear because there could be more than one source, per se," Danziger-Isakov said. "Recognizing that is certainly challenging as a physician because it goes a little bit against what we are taught in medical school: to find a unifying diagnosis. You must be cognizant that there may be dual diagnoses concurrently."
Once a diagnosis has been established, treatment presents yet another host of challenges.
"Antimicrobials or antibiotics and a healthy immune system are needed to fight infection," Englund said. "Transplant patients lack a strong immune system. HSCT patients' immune systems are essentially gone. SOT patients' immune systems are there, but suppressed."
Altering immunosuppression levels, a common treatment response to infection, increases risk for graft rejection.
"If a child develops infection and their immunosuppression regimen is altered, their risk for rejection is altered as well," according to Kirk. "Understanding to what degree immunosuppression must be reduced and which aspect of immunosuppression must be changed is a significant challenge when treating infection in pediatric transplant patients."
Because of the severe consequences infection has on transplantation success, transplant infectious disease physicians have a role in every stage of the transplantation process.
"Transplant infectious disease is an arc of continuous identification and mitigation of risk in order to improve optimal outcomes that requires engaging in partnership with organ-specific, oncology or bone marrow transplant teams," Danziger-Isakov said. "This is a continuous process that is most likely better served over a continuum, rather than as a point-of-care testing process." – by Amanda Oldt