Respiratory Manifestations of the Activated Phosphoinositide 3-Kinase Delta Syndrome

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.

PI3Kδ hyper-activation promotes the development of B cells that exacerbateStreptococcus pneumoniaeinfection in an antibody-independent manner

“…We postulate that the transitional B cells which are expanded in APDS patients may not just be precursors to more mature B cells, but also include cells that are functionally equivalent to the CD19 + B220 − cells that we have identified in p110δ E1020K mice and thus may also contribute to the increased susceptibility to S. pneumoniae infection and hence to the high incidence of bronchiectasis characteristic of this disease 15 . In this context, it is interesting that CD19 + B220 − B cells had previously been described as immature progenitors in the bone marrow 37 , rather than a functional PI3Kδ dependent subset found in peripheral tissues as we describe here.…”

“…One of the defining characteristics of APDS patients is an increased proportion of CD24 + CD38 + B cells defined as transitional B cells 10–12, 14, 15 . Intriguingly, production of IL-10 is a characteristic of these B cells as well.…”

“…APDS patients suffer from recurrent sinopulmonary infections, with S. pneumoniae being the most commonly isolated pathogen 14 . 85% of APDS patients have been diagnosed with pneumonia 15 . APDS patients are also more likely to develop structural lung damage (bronchiectasis) than patients with other PIDs 14 .…”

Bronchiectasis in common variable immunodeficiency: A systematic review and meta‐analysis

“…21,22 In addition, the patients with earlyonset CVID are more likely to have a monogenetic defect (such as, LRBA, CTLA-4, PIK3CD) that may lead to bronchiectasis to due severe immune dysregulations that are associated with an inflammatory response in the lung. [23][24][25][26] This may be different from the development of bronchiectasis in patients with adult-onset CVID, in which the etiology may be more chronic and patients may less often have inflammatory lung disease.…”

“…It was reported that patients with CVID and parental consanguinity that diagnosed in childhood are more severely affected by autoimmunity, inflammatory lung disease, and enteropathy than adults diagnosed later in life . In addition, the patients with early‐onset CVID are more likely to have a monogenetic defect (such as, LRBA, CTLA‐4, PIK3CD) that may lead to bronchiectasis to due severe immune dysregulations that are associated with an inflammatory response in the lung . This may be different from the development of bronchiectasis in patients with adult‐onset CVID, in which the etiology may be more chronic and patients may less often have inflammatory lung disease.…”