Introduction

Lymphopenia is defined as a reduction in the number of lymphocytes, a type of white blood cell, in the blood. Lymphocytes are core to the adaptive immune response and play an important role in fighting against infections and diseases. Iatrogenic lymphopenia is a reduction in the number of lymphocytes in response to medical treatments, including immunosuppressive therapies. Immunosuppressive therapies are designed to reduce the activity of the immune system in order to treat autoimmune diseases, where the immune system attacks the body’s own tissues by mistake, or to prevent rejection of organ transplants. Studies have shown that although the use of immunosuppressive therapies have the potential to control several diseases, they also cause side-effects that lead to their discontinuation. One such side effect is lymphopenia. Given the importance of lymphocytes in the immune system, a reduction in lymphocyte levels is associated with a compromised immune system and an increased risk of infection.^1,2,3,4

Immunosuppressive therapies associated with lymphopenia include the use of immunosuppressive drugs such as glucocorticoids, calcineurin inhibitors and antimetabolites. This article will explore how these treatments lead to lymphopenia. 

What is lymphopenia?

Lymphocytes are a type of white blood cell that generate an adaptive immune response. The adaptive immune response is a specific defence mechanism that expands throughout life as the body encounters more foreign substances. This process involves T cells and B cells, which are lymphocytes that recognise, target and destroy these foreign materials. They also retain memory, which allows for long-term protection and a faster response if re-exposed to the same substance.²

Iatrogenic lymphopenia can occur as a side-effect of immunosuppressive therapies. While these therapies are necessary for the management of autoimmune diseases and organ transplants, they can also lead to a reduction in lymphocyte counts. Given the importance of lymphocytes in the immune system, lymphopenia has also been associated with an increased risk of infection and susceptibility to many diseases, including cancer.^4,5

Immunosuppressive therapies

Immunosuppressive therapies aim to reduce the activity of the immune system in situations where the immune system is overactive or attacking the body’s own tissues. A consequence of many of these therapies is a reduction in overall lymphocyte counts, either directly or by inhibiting their function.³

Immunosuppressive therapies that may lead to lymphopenia include: 

Glucocorticoids

Glucocorticoids are naturally occurring hormones that play a role in regulating metabolism, immune function and stress. Glucocorticoid therapy is used to reduce inflammation and suppress the overall immune response in autoimmune diseases or allergic conditions. They work by: 

• Inducing the apoptosis, a form of programmed cell death, of lymphocytes
• Decreasing the release of lymphocytes from the bone marrow
• Reducing the expression of pro-inflammatory genes and increasing the expression of anti-inflammatory genes^6,7,8

Calcineurin inhibitors

Calcineurin is an enzyme involved in T cell signalling. Calcineurin inhibitors are used to tackle autoimmune diseases and solid organ transplants. They work by inhibiting the enzyme calcineurin, preventing T cells from being activated, proliferating or differentiating.⁹

Antimetabolites

Antimetabolites are designed to target and disrupt DNA synthesis, preventing lymphocytes from growing and dividing. They can do this by either inhibiting enzymes involved in DNA synthesis or by mimicking the building blocks of DNA, acting as decoys that disrupt the normal structure of DNA. These drugs are used for autoimmune diseases, organ transplants, and certain inflammatory skin conditions such as atopic dermatitis.^3,10

Polyclonal anti-lymphocyte sera 

This preparation is used to treat severe T cell mediated organ transplant rejection. It is designed against surface molecules of lymphocytes and causes depletion of T cells. It also impairs T cell function.

Monoclonal antibodies

Anti-CD20 monoclonal antibodies

CD20 is a protein present on the surface of B cells. Monoclonal antibodies are highly specific proteins designed to target a surface target. Anti-CD20 monoclonal antibodies bind to CD20 on B cells and deplete them, therefore preventing the production of antibodies and reducing overall inflammation. These antibodies are used for autoimmune conditions such as autoimmune hepatitis as well as in the case of antibody-mediated transplant rejection.³

Anti-IL-2 monoclonal antibodies 

Interleukin-2 (IL-2) is a cytokine involved in T cell signalling, affecting its growth and activity. IL-2 receptor antagonists specifically target the IL-2 receptor in order to reduce the activity of T cells. These antibodies have been investigated for use in solid organ transplants. Interestingly, IL-2 receptor antagonists also inhibit T regulatory cells (Tregs), a subset of T cells involved in dampening the immune response. Research in patients with glioblastoma, a type of cancer, has shown that monoclonal antibodies against the IL-2 receptor, particularly during lymphopenia, selectively reduces Tregs and enhances immunity.^3,11,12

Chemotherapy 

Chemotherapy is a cancer therapy that uses powerful chemicals to target the fast-growing cells in the body. In addition to cancer cells, immune cells also divide rapidly and may also be affected by chemotherapy. Studies have shown that Fludarabine, a chemotherapy drug used to treat blood cancers, reduces the number of cytotoxic T cells.¹³

Radiation therapy 

Radiation therapy is a treatment that uses radiation to kill cancer cells by damaging their DNA. Although radiation is carefully focused on the tumour, it can also unintentionally damage or deplete surrounding lymphocytes, leading to a condition known as radiation-induced lymphopenia.¹⁴

Clinical implications of iatrogenic lymphopenia: case studies

Severe infections

A study investigated the factors associated with an increased risk of infection in a group of rare autoimmune disorders (ANCA-associated vasculitis) treated with immunosuppressive therapies, which included corticosteroids, chemotherapy and antimetabolite therapy. In this cohort, 72% of the patients experienced moderate lymphopenia, and 53% of them experienced an infection. It was concluded that the severity of lymphopenia, which was frequently observed during treatment, was associated with the risk of infectious complications.¹⁵ 

Other studies have shown that persistent lymphopenia is associated with increased risk of opportunistic infections. The John Cunningham virus (JCV) is usually harmless, though in people undergoing immunosuppressive therapy, it can be activated and cause progressive multifocal leukoencephalopathy, a rare brain disease, due to the compromised immune system. A study in multiple sclerosis, an autoimmune disease, showed that long-term and high-dose treatment with immunosuppressive drugs is associated with an increased risk of developing the disease.^10,16

Risk of graft failure 

A study monitored lymphocyte levels in patients alongside graft survival following kidney transplantation. The results showed that those with lower lymphocyte counts had a higher risk of graft failure compared to patients with normal lymphocyte levels. In addition, the increased risk of infection associated with lymphopenia was linked to a greater risk of graft failure.¹⁷

Management 

Iatrogenic lymphopenia from immunosuppressive therapies is a risk factor that must be considered carefully. Immunosuppressive therapies are important in preventing graft failure and treating autoimmune conditions, therefore, a balanced approach is required. 

• Regular monitoring of lymphocyte levels is essential to identify those at risk of lymphopenia. This can guide context-dependent changes to treatment regimens, such as reducing doses of the therapy. Monitoring for opportunistic or viral infections should also be considered¹⁰
• A study in transplant patients showed that recovery of B and T cells occur much slower than other immune cells. Therefore, it was suggested that prophylactic measures, especially in the first six months following the transplant, should be considered to minimise the risk of infection¹⁸

Summary 

Iatrogenic lymphopenia is a reduction in the number of lymphocytes, which include B cells and T cells, in response to medical treatments. Immunosuppressive therapies, which are designed to treat conditions such as autoimmune diseases and to prevent organ transplant rejections, have been associated with lymphopenia. Examples of immunosuppressive therapies include glucocorticoids, calcineurin inhibitors, antimetabolites and certain monoclonal antibodies. Although these therapies successfully control several diseases, they are associated with a high risk of infection as well as graft failure due to the compromised immune system. Regular monitoring of lymphocyte levels and constant adaptation of immunosuppressive therapy regimens is crucial to prevent these risks. Prophylactic measures to tackle infections should also be considered to improve overall outcomes.