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Review
. 2018 Mar 5:9:338.
doi: 10.3389/fimmu.2018.00338. eCollection 2018.

Respiratory Manifestations of the Activated Phosphoinositide 3-Kinase Delta Syndrome

Alison M Condliffe  1 , Anita Chandra  2   3
Affiliations
Review

Respiratory Manifestations of the Activated Phosphoinositide 3-Kinase Delta Syndrome

Alison M Condliffe et al. Front Immunol. .

Abstract

The activated phosphoinositide 3-kinase δ syndrome (APDS), also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI), is a combined immunodeficiency syndrome caused by gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (encoding p110δ: APDS1 or PASLI-CD) and PIK3R1 (encoding p85α: APDS2 or PASLI-R1). While the disease is clinically heterogeneous, respiratory symptoms and complications are near universal and often severe. Infections of the ears, sinuses, and upper and lower respiratory tracts are the earliest and most frequent manifestation of APDS, secondary to both respiratory viruses and to bacterial pathogens typical of defective B cell function. End organ damage in the form of small airways disease and bronchiectasis frequently complicates APDS, but despite documented T cell defects, opportunistic infections have rarely been observed. Antimicrobial (principally antibiotic) prophylaxis and/or immunoglobulin replacement have been widely used to reduce the frequency and severity of respiratory infection in APDS, but outcome data to confirm the efficacy of these interventions are limited. Despite these measures, APDS patients are often afflicted by benign lymphoproliferative disease, which may present in the respiratory system as tonsillar/adenoidal enlargement, mediastinal lymphadenopathy, or mucosal nodular lymphoid hyperplasia, potentially causing airways obstruction and compounding the infection phenotype. Treatment with rapamycin and PI3Kδ inhibitors has been reported to be of benefit in benign lymphoproliferation, but hematopoietic stem cell transplantation (ideally undertaken before permanent airway damage is established) remains the only curative treatment for APDS.

Keywords: activated phosphoinositide 3-kinase delta syndrome; antibody deficiency; bronchiectasis; lymphoproliferation; pneumonia; respiratory infection.

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Figures

Figure 1
Figure 1
Aberrant cellular functions contributing to respiratory infection in activated phosphoinositide 3-kinase δ syndrome. (A) Healthy lung defenses. (1) Epithelial defenses counteract viral pathogens, aided by (2) effective T cells cytokine production. (3) Antibody production by B cells promotes (4) bacterial killing and (5) opsonophagocytosis. (6) Respiratory epithelial surfaces are preserved intact and continue to function to repulse invading pathogens. (B) Lung defenses compromised by activating mutations leading to enhanced phosphoinositide 3-kinase (PI3K) δ signaling. (1a) Viral entry and replication in airway epithelial cells are promoted, reducing barrier integrity. (2a) Aberrant cytokine production by T cells and (3a) failure of antibody production promote (4a) bacterial invasion with (5a) inadequate handling of pathogens by phagocytes. (6a) Repeated cycles of infection lead to long-term airway damage.
Figure 2
Figure 2
Processes leading to airway damage in activated phosphoinositide 3-kinase δ syndrome. Repeated episodes of viral bronchiolitis may lead to small airway damage and mosaic attenuation, compounded by local obstruction secondary to focal lymphoid hyperplasia. Recurrent bacterial infection leads to chronic inflammatory damage of the larger airways and the development of bronchiectasis; post-obstructive bronchiectasis may also occur secondary airway obstruction, which may be extra-luminal (intrathoracic lymphadenopathy) or intra-luminal (focal lymphoid hyperplasia).
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