Immunosuppression Adverse Effects - Professor Richard Kirk 2023

Immunosuppression
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Immunosuppression Adverse Effects

Autoimmunity & Allergy

This is a manifestation of a dysregulated immune system, especially for those transplanted in infancy and early childhood. There is an increase in autoimmune disease (e.g. immune cytopenia, inflammatory bowel disease, autoimmune hepatitis, chronic bullous disease) and allergy (asthma and eczema, food allergy) after transplant compared to the general populations.

Infection

The effect of immunosuppression on infections depends to a large extent on the age of the recipient at transplant. Infants and young children are most affected as their immune system has yet to mature and many have not completed their vaccination program. Induction therapy destroys T & B cells and when these cells return their reconstitution may not restore normal immune function. The cell repertoire may be abnormal especially as infants have a thymectomy at the time of transplant. [NBH1] T-and B-regulatory cells may be depleted leading to dysregulation. Antibody production may be reduced, antibody function impaired and subsequent response to infective organisms and vaccination (especially pneumococcal) incomplete. Response is particularly poor to encapsulated organisms and recurrent pulmonary infections can lead to bronchiectasis. For some, these issues lead to the requirement for prophylactic antibiotics and immunoglobulin infusions. Viral infections may become life or graft threatening. Cytomegalovirus (CMV), Ebstein virus (EBV), Adenovirus and Norovirus can be particularly of great concerns. CMV is usually responsive to ganciclovir and EBV to rituximab but there is no effective treatment for norovirus and adenovirus may be resistant to Cidofovir. Immunotherapies including chimeric antigen receptor (CAR) T-cell and Virus specific T cell (VST) therapy may be effective when other treatments fail.

Malignancy

Post transplant lymphoproliferative disease (PTLD) is the most common malignancy and often driven by the Ebstein-Barr virus (EBV). This ubiquitous virus is usually kept quiescent in normally function immune systems, but immunosuppression leads to viral replication in B cells which may lead to uncontrolled B cell proliferation and transformation into PTLD. Other malignancies are also more common than in the general population. Skin cancer may be an issue in adults due to excessive exposure to sunlight if sunscreen is not used.

Metabolic Syndrome

Metabolic syndrome is a cluster of conditions including insulin resistance, hyperlipidemia, hypertension, obesity, although not all need to be present to make the diagnosis. Calcineurin inhibitors have long been associated with this syndrome. The metabolic syndrome leads to a pro inflammatory and prothrombotic state and is associated with vascular endothelial dysfunction. It is therefore unsurprising it is associated with worse transplant outcomes including rejection, cardiac allograft vasculopathy and graft failure. Management of the individual components are thus of paramount importance.

Renal dysfunction

Renal dysfunction is common after cardiac transplant. This is multifactorial - prolonged period of low cardiac outcome prior to transplant due to cardiac failure, cyanosis in those with congenital heart disease, cardiopulmonary bypass and hemodynamic instability post-transplant. In addition nephrotoxic drugs including antibiotics and calcineurin inhibitors (CNI) are given. There is also a direct effect of CNI on tubular function with increased losses of magnesium and retention of potassium which persists. Even though they may be initial recovery, in the long-term chronic kidney disease becomes apparent. This may in part be due to increased arterial stiffness causing hypertension and abnormal renal flow as part of the metabolic syndrome. Reduction in CNI usage with increased usage of mTOR inhibitors gives hope that some of these effects will be reduced for future transplant recipients.