What Infectious Diseases are Important to Consider in Transplantation Patients?

Patient Presentation
A 7-year-old male came to clinic to establish care. He and his family had moved to the area for specialty care after he had increasing problems due to hepatic failure secondary to an inborn error of metabolism. He was mainly managed by the regional children’s hospital gastroenterology department, who had referred the family to the transplantation service.

The past medical history was positive for an inborn error of metabolism which caused hepatic failure, short stature, lack of normal growth and development and intellectual disability. The social history showed that the family had extended family in the area and felt that living closer to the hospital would be better for him and for the family in general.

The pertinent physical exam showed a very thin male. His height and weight were 50% for a 4 year old. He seemed happy but with delayed speech and play. The pediatrician estimated his development at around 5 years old. He had yellowed skin with prominent veins on his abdomen. He had a significantly prominent abdomen with a liver that was 6 inches below the ribs and crossed the midline and was very firm. It was difficult to discern other organomegaly or masses because of incooperation. The rest of his examination was essentially normal.

The diagnosis of a new patient who was to have a liver transplant was made. The pediatrician discussed how the practice worked so the family would know how to contact them. “We can help you with any of the lab testing and vaccines. We can also help you when he gets sick which he will just like every other kid. We’ll try to help the transplantation doctors with anything they need. I think most importantly, you should just know that we are here to help you and your child, so just ask us,” she explained.

Transplantation is not a common problem for primary care physicians but when a child’s disease has progressed to end-stage organ failure, transplantation can be the only treatment available. While the primary care provider usually is not involved in the daily management of patients before, during and after transplantation, they can be involved in many areas. These can include providing appropriate primary and acute care, ordering and obtaining necessary medical tests, medications and equipment, assisting with medical insurance, providing medical history and records to consultants, translating medical information for the family, general patient and family support, and encouraging and facilitating medical adherence. Pediatricians may have many questions regarding the primary care of a child with a transplant including: What affects the child’s growth?, How efficacious are vaccines after transplant?, What are the outcomes for children with additional problems such as intellectual disability?, and What are the rates of adherence to medical treatment?

There are multiple factors that affect a child’s growth after transplantation including:

  • Type of organ transplanted
  • Patient age at transplant
  • Transplant function
  • Height/weight status pre-transplantation
  • Pubertal stage
  • Medications – particularly corticosteroids

A 2017 systemic analysis of use of corticosteroids, found early withdrawal or avoidance protocols significantly improve final adult height in patients with renal transplantation. Not surprisingly, pre-pubertal patients had the greatest benefit. Use of growth hormone also can increase adult height in patients with renal transplantation. Transplantation function or rejection was also unchanged despite less corticosteroid use. For liver transplantation, reduced corticosteroid exposure did not improve final height, but there were only two studies with small numbers of patients who were followed for a shorter time period than the renal transplantation patients which may account for the differences based on transplanted organ.

A 2017 systematic review was performed of live virus vaccinations on immunosuppressed patients due to solid organ or bone-marrow transplantation. There were 339 patients with solid-organ transplantation who received 424 vaccine doses primarily of Measles, Mumps and Rubella, and Varicella vaccines. For solid organ transplantation only 3 individuals had rejection during the study period. One occurred 3 weeks after measles immunization. One had chronic rejection at the time of vaccination and still had chronic rejection 1 year later. One had a single rejection episode more than 1 year after varicella vaccine which was considered unrelated to the vaccine. For solid organ transplantation, seroconversion rates for varicella vaccine range from 25-87%. Even high seroconversion rates have been reported with additional booster vaccinations.

In a 2017 commentary, the authors compiled a table from 18 studies of 1041 patients who had an intellectual disability and received a solid organ transplant. Graft survival was 80-100% with followup 3 months – 9 years (most common length of followup was 3-5 years). Patient survival was 75-100% again over similar time frames.

Adherence to medical treatment particularly pharmacological immunosuppression is extremely important for long-term function of any transplantation including solid organ transplantation. Overall adherence in pediatric solid organ transplantation is 30-76% with nonadherence peaking in the adolescent age range. “Only a minority of patients openly refuse to take their medications. A more common and a harder situation to diagnose, is that where adherence is intermittent. Those patients are often in denial and overestimate their compliance. The consequence and graft function can be smoldering for a long time and go undetected, failing to raise alert signs to patients and their treating teams. Importantly as we do not know what we cannot measure, the extent of non adherence problem is likely underrecognized.” Non adherence can lead to difficulties in transitioning teens and young adults to adult health care providers. (For a review of transitioning care, click here).

Learning Point
Communication between specialist transplant physicians and primary care physicians regarding infectious disease risks before and after transplantation is especially important. Specialists need to learn from the primary care physician which infectious disease risks the patient may be at risk for based on the history. After transplant, children continue to have fevers, coughs, emesis, diarrhea, rashes and pain like any other child which the primary care physician is asked to determine if this is a common illness or potentially a more serious illness or complication.

Infectious diseases that are important at various stages of transplantation include:

  • Pretransplant recipient – undiagnosed or latent infections
    • Cytomegalovirus
    • Epstein-Barr virus
    • Herpes simplex
    • Human immunodeficiency virus
    • Hepatitis B
    • Hepatitis C
    • Syphilis
    • Travel exposures
      • Toxoplasmosis
      • Strongylodiasis
      • Trypanosoma cruzi (Chagas’ Disease)
      • Mycoses (e.g. Blastomycosis, Coccidioidomycosis, Histoplasmosis)
      • Tuberculosis
      • West Nile virus
      • Zika virus
    • Colonization
      • Methicillin-resistant Staphylococcus aureus
      • Vancomycin-resistant enterococcus

    Note that these infections may not necessarily disqualify a patient from receiving a transplantation but may be important to be aware of for overall treatment.
    Screening for colonization is more controversial than screening for undiagnosed, latent or travel exposures.
    Patients should receive vaccination before transplantation if possible.

  • Pretransplantation – Donor
    • Drug resistant bacteria
    • Human immunodeficiency virus
    • Hepatitis B
    • Hepatitis C
    • Syphilis
    • Tuberculosis
    • Mycoses (rare)
    • Other rare pathogens (e.g. Chagas’ disease, Zika virus)

    Note again that these infections in the donor may not disqualify a patient from receiving a transplantation but may be important to be aware of for the overall treatment.

  • Peritransplant/surgical related infections
    • Surgical site infections with appropriate site organisms
      • Heart transplant – sternal infection with Staphylococcus aureus
      • Lung transplant – pneumonia with respiratory pathogens
      • Liver transplant – skin and gastrointestinal flora (e.g. gram- positive and gram-negative bacteria, anaerobes)
      • Renal transplant – urinary tract infection (e.g. Enterococcus and gram-negative uropathogens)
  • Post transplant infections
    • Drug resistant bacteria
    • Clostridium difficile
    • Cytomegalovirus
    • Epstein Barr virus

Questions for Further Discussion
1. What does the liver do? A review can be found here.
2. What are common inborn errors of metabolism?

3. How do various solid organ transplantations differ from each other? i.e. heart vs lung vs liver vs kidney vs bowel

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Organ Transplantation and Liver Transplantation.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Croce E, Hatz C, Jonker EF, Visser LG, Jaeger VK, Buhler S. Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases, solid organ transplantation or after bone-marrow transplantation – A systematic review of randomized trials, observational studies and case reports. Vaccine. 2017 Mar 1;35(9):1216-1226.

Yazigi NA. Adherence and the pediatric transplant patient. Semin Pediatr Surg. 2017 Aug;26(4):267-271.

Knackstedt ED, Danziger-Isakov L. Infections in pediatric solid-organ transplant recipients. Semin Pediatr Surg. 2017 Aug;26(4):199-205.

Tsampalieros A, Knoll GA, Molnar AO, Fergusson N, Fergusson DA. Corticosteroid Use and Growth After Pediatric Solid Organ Transplantation: A Systematic Review and Meta-Analysis. Transplantation. 2017 Apr;101(4):694-703.

Wightman A, Diekema D, Goldberg A. Consideration of children with intellectual disability as candidates for solid organ transplantation-A practice in evolution. Pediatr Transplant. 2018 Feb;22(1).

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa