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Secondary Immunodeficiencies: A Growing Problem?

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Javier Carbone, MD, PhD
Complutense University
Madrid, Spain

Widespread use of biologic therapies and procedures such as ventricular assist devices and ECMO is associated with an increase in the number of patients who can develop secondary immunodeficiency. Indeed, severe and recurrent infections are a common adverse effect of these interventions.

Biologic therapies do not cause the same degree of immunosuppression as that observed with more conventional immunosuppressive drugs, such as corticosteroids, cyclosporine, tacrolimus, mycophenolate, methotrexate, cyclophosphamide, and azathioprine. However, they may have unintended effects on immune function that can compromise innate and acquired immunocompetence and lead to severe infections. Some biologics can also induce other adverse effects of immunosuppression, such as autoimmune diseases and malignancy. The many new biologics targeting the immune system are subject to various infectious complications.

Examples of clinical settings in which biologics are increasingly used include cancer, lymphoproliferative syndromes, autoimmune and inflammatory diseases, and transplantation.

The biologic therapies that increase the risk of infection include antithymocyte globulin, monoclonal antibodies to T and B cells, anti-cytokine therapy, anti-cytokine receptor therapy, and therapies that modulate T-cell costimulation signals. Anti-checkpoint monoclonal antibodies have recently been introduced for the treatment of cancer. In order to achieve their specific effects, these therapies selectively target receptors, cells, proteins, and specific pathways of the immune response.

Factors that increase the risk of infectious complications depend on the mechanisms of action of the biologic, dose, dosing interval, and duration of treatment. The risk of infection also depends on concomitant therapies and surgical interventions and patient-specific factors. For example, heart and lung recipients using ventricular assist devices or ECMO are at an increased risk of infections.

The management of secondary immunodeficiency may include monitoring of the patient's baseline immunocompetence and early detection of secondary immunodeficiency after therapy and the use of prophylactic antimicrobials or immunoglobulin for the treatment of hypogammaglobulinemia.

Intravenous immunoglobulin replacement therapy is approved for severe infections and hypogammaglobulinemia with specific antibody deficiency in patients with multiple myeloma and chronic lymphocytic leukemia. In this regard, a revision of the core summary of product characteristics for intravenous human normal immunoglobulin of the European Medicines Agency is evaluating the current status for their use in other secondary immunodeficiencies including solid organ transplantation.

An update of the management of CMV infection in solid organ trasplantation including the potential role of immunological biomarkers for prediction of this complication has been recently performed by an expert group of the Transplantation Society.

Monitoring of the levels of biologics and of the development of antibodies against them is another rapidly evolving area that plays a key role in evaluation of the safety of these drugs.

Patients with ventricular assist devices and ECMO may develop secondary immunodeficiency that places them at higher risk of developing infection. By identifying and controlling risk factors, it is theoretically possible to reduce the occurrence of infections. Management of modifiable risk factors might reduce mortality rates. ■

Disclosure Statement: The author has no conflicts of interest to disclose.

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