Impact of Host Genetics and Biological Response Modifiers on Respiratory Tract Infections

Abstract

Host susceptibility to respiratory tract infections (RTI) is dependent on both genetic and acquired risk factors. Repeated bacterial and viral RTI, such as pneumonia from encapsulated microorganisms, respiratory tract infections related to respiratory syncytial virus or influenza, and even the development of bronchiectasis and asthma, are often reported as the first symptom of primary immunodeficiencies. In the same way, neutropenia is a well-known risk factor for invasive aspergillosis, as well as lymphopenia for Pneumocystis, and mycobacterial infections. However, in the last decades a better knowledge of immune signaling networks and the introduction of next generation sequencing have increased the number and diversity of known inborn errors of immunity. On the other hand, the use of monoclonal antibodies targeting cytokines, such as tumor necrosis factor alpha has revealed new risk groups for infections, such as tuberculosis. The use of biological response modifiers has spread to almost all medical specialties, including inflammatory diseases and neoplasia, and are being used to target different signaling networks that may mirror some of the known immune deficiencies. From a clinical perspective, the individual contribution of genetics, and/or targeted treatments, to immune dysregulation is difficult to assess. The aim of this article is to review the known and newly described mechanisms of impaired immune signaling that predispose to RTI, including new insights into host genetics and the impact of biological response modifiers, and to summarize clinical recommendations regarding vaccines and prophylactic treatments in order to prevent infections.

Keywords: biological response modifiers; immunogenetics; inborn errors; primary immunodeficiencies; respiratory tract infections.

Figure 1

Mode of action of biological response modifiers (BRM) according to cell type, cytokine and/or receptor targeted. Risk of developing infections according to the BRM considered is also shown. List of BRM. Anti-tumor necrosis factor-α (TNF-α) agents. ADA, adalimumab; CTZ, certolizumab; GLM, golimumab; IFX, infliximab; ETN, etanercept. Anti-interleukins, immunoglobulins, and complement factors. Anti IL-1, anakinra ANK; Anti IL-6: TCZ, tocilizumab; Anti IL-17: SCK, secukinumab; IXE, ixekizumab; BRD, brodalumab. Anti-IL12/23: USK, ustekinumab. Cell surface receptors/associated signaling pathways agents. Anti-CD28: ABT, abatacept; B-cell activating factor (BAFF): BLM, belimumab. Lymphoid cells surface antigens. Anti-CD20: RTX, rituximab. mAb, monoclonal antibody; PEG, polyethylene glycol; TB, tuberculosis; LTBI, latent tuberculosis infection.