What Are the Side Effects of Immunosuppressive Medication?

Patient Presentation
A 13-year-old male came to the general pediatric clinic with malaise. He had a liver transplantation at age 5 because of a viral insult, and had acute rejection 4 months after the transplantation. About 10 days ago, he had gotten an upper respiratory infection with cough and fever. After 3 days his fever resolved and his acute symptoms seemed to improve, but he continued to be tired. The malaise was increasing with him sleeping after returning from school and going to bed early. He was eating but especially less over the past 36 hours. The review of systems revealed no pain, fever, cough, changes in stool color or consistency, and no changes in urine color but he had less frequency, He denied jaundice, but his mother noted very mild icterus. The past medical history found that he had done well with only 2 other hospitalizations for skin infections that necessitated intravenous antibiotics because of his immunosuppression. He did not have chronic rejection and his medication levels (Cyclosporin A and tacrolimus) were stable.

The pertinent physical exam found him to be afebrile with normal blood pressure and other vital signs. His weight was 50% and height was 10%. HEENT examination found mild scleral icterus, but none in the oral mucosa. Lungs were clear and there was no heart murmur. Abdomen examination had a chevron scar with liver edge down 2 cm from right costal margin and non-tender. There were no masses. Skin had no jaundice including on the creases of palms and soles. He was Tanner stage 3. The laboratory evaluation found very elevated transaminases, bilirubin and alkaline phosphatase. Later testing found immunosuppressive medication levels consistent with his outpatient levels that were normal. Viral panels were negative. The diagnosis of probable acute rejection was made and the patient was admitted to the transplantation service. Liver biopsy confirmed the diagnosis. After the laboratory testing became available, it was assumed that the acute rejection was due to viral suppression and not due to non-adherence. He was given corticosteroids and the patient’s clinical course over the next 5 days improved and he was sent home on a steroid course and close followup.

Discussion
Although this patient did not have rejection because of non-adherence to his treatment regimen, he is entering a time of his life where he is vulnerable to late graft loss because of non-adherence. Overall, late graft loss is less likely for pediatric/adolescent patients because many of the reasons for the transplantation do not recur in the graft.

Non-adherence is one of the most important predictors of rejection and contributes to late graft loss for liver transplant patients. Non-adherence with treatment regimens is unfortunately common. There are 3 general types of non-compliance:

  • Accidental – Patients inadvertently forget to take their medication. This is often the easiest to fix because patients wish to comply. Generally seen in older patients but adolescents with different schedules and often fewer organization skills may have this problem.
  • Invulnerable or immortal – Patients have beliefs that not complying will not have adverse effects. Often seen in younger patients and those with less education. Adolescents often believe they are invulnerable and rejection and other problems won’t happen to them.
  • Decisive – Patients independently and actively decide not to comply which is the most difficult to fix. Patients are younger and less educated and often have misunderstandings about how the medications work. Adolescent patients also have this problem as they normally are trying to develop more autonomy and control in their lives. This is also a peak time for risk taking.

Besides adolescence, another very vulnerable time for non-adherence and graft rejection is when patients are being transferred to adult services.
Previous poor self-management unfortunately often predicts poor transition and non-adherence.

Self-care and management are extremely complex even for adults with adequate education, resources and support.
Adolescents and young adults can be even more challenged because of their normal development, changes in living environment (i.e. living at home and/or college), potentially fewer resources (ie less convenient transportation, changes in health insurance, money to pay for medication co-pays and other expenses, etc.) and potentially fewer social supports (ie more perceived or real dependence upon friends than family). Below are some examples of self-care and management that adolescents and young adults would be required to do to be compliant with their treatment.

  • Take all medications when and how prescribed (sometimes 4-5 times/day, with multiple pills and/or weekly or monthly medications also)
  • Make appointments and go to appointments
  • When ill, understand how health system works and how to obtain care
  • Obtain blood work and follow up on results
  • Obtain and understand health insurance and pay bills
  • Comply with diet and exercise regimens, limit or abstain from alcohol, perform safe sex practices
  • Obtain and comply with dental or mental health care and other health care regimens

Learning Point
Immunosuppressive medications have multiple primary effects that necessitate management and direct side effects. Many drugs cause problems that then need additional management such as nephrotoxicity caused by Cyclosporin A. Many drugs also cause cosmetic problems which are distressing to patients especially adolescents who place great important on immediate effects (ie. decrease the acne and hirsuitism) and less on the longer term effects (ie. decreasing the risk of chronic rejection).

All the medications below cause immunosuppressive problems including infection and malignancies especially post-transplant lymphoproliferative disease.

Main side effects of these immunosuppressive medications are listed below (***are particularly common):

  • Azothioprine
    • *** Bone marrow suppression
    • GI upset
    • Hepatotoxicity
    • Cosmetic – alopecia
  • Corticosteroid
    • Amenorrhea
    • Bone abnormalities – osteopenia, avascular necrosis
    • Dyslipidemia
    • Electrolyte abnormalities – hypernatremia
    • Glaucoma and cataracts

    • GI upset
    • Growth deficiency
    • Hypertension
    • ***Diabetes, post-transplant
    • ***Neurologic effects – myopathy, psychosis and emotional instability
    • Cosmetic – ***acne, hirsuitism, bruising and petechiae, Cushingoid appearance,
      fluid retention, thin skin, poor wound healing, hyperhidrosis
  • Cyclosporin
    • Dyslipidemia
    • Diabetes, post-transplant
    • Electrolyte abnormalities – hyperkalemia, hypomagnesemia, hyperuricemia
    • GI upset
    • Hypertension
    • Neurological effects – headache, paraesthesias, tremor
    • ***Renal failure
    • Cosmetic – acne, ***gingival hyperplasia, ***hirsuitism
  • Tacrolimus
    • Dyslipidemia
    • Diabetes, post-transplant
    • ***Electrolyte abnormalities – hyperkalemia, hypomagnesemia
    • GI Upset
    • Hypertension
    • ***Renal failure
    • ***Neurological effects
    • Cosmetic – alopecia
  • Sirolimus
    • Bone abnormalities – arthralgia, bone pain
    • Bone marrow suppression
    • ***Dyslipidemia
    • GI upset
    • Pulmonary infiltrates
    • Cosmetic – acne, poor wound healing, rash, mouth ulcers
  • Mycophenolate mofetil
    • Bone marrow suppression
    • ***GI upset
  • Alemtuzumab
    • Bone marrow suppression
    • ***GI upset
    • ***Infusion reactions
    • Cosmetic – rash
  • ATG or thymoglobulin
    • ***Bone marrow suppression
    • GI upset
    • ***Infusion reactions
  • OKT3 or muromonab CD3
    • ***Bone marrow suppression
    • GI upset
    • ***Infusion reactions

Questions for Further Discussion
1. What are the most common solid organs transplanted into pediatric patients?
2. What is the life span of a solid organ transplant in pediatric patients?
3. Can transplant patients ever stop immunosuppressive medications?
4. Should live virus vaccinations be given to patients with solid organ transplants?

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, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: 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.

Morrissey PE, Flynn ML, Lin S. Medication noncompliance and its implications in transplant recipients. Drugs. 2007;67(10):1463-81.

Bucuvalas JC, Alonso E. Long-term outcomes after liver transplantation in children. Curr Opin Organ Transplant. 2008 Jun;13(3):247-51.

Shemesh E, Annunziato RA, Arnon R, Miloh T, Kerkar N. Adherence to medical recommendations and transition to adult services in pediatric transplant recipients. Curr Opin Organ Transplant. 2010 Jun;15(3):288-92.

Schonder KS, Mazariegos GV, Weber RJ. Adverse effects of immunosuppression in pediatric solid organ transplantation. Paediatr Drugs. 2010;12(1):35-49.

ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effectively and demonstrates caring and respectful behaviors.
    2. Essential and accurate information about the patients’ is gathered.
    3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
    4. Patient management plans are developed and carried out.
    7. All medical and invasive procedures considered essential for the area of practice are competently performed.
    8. Health care services aimed at preventing health problems or maintaining health are provided.
    9. Patient-focused care is provided by working with health care professionals, including those from other disciplines.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
    11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.

  • Practice Based Learning and Improvement
    13. Information about other populations of patients, especially the larger population from which this patient is drawn, is obtained and used.

    Author

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