Inflammatory Bowel Disease in Activated PI3Kδ Syndrome: An Uncommon Complication of a Rare Condition

Abstract

Background/Objectives: Monogenic primary immunodeficiencies represent a group of disorders with varying levels of severity, many of which remain poorly understood. Activated phosphoinositide-3 kinase delta syndrome (APDS) is a rare genetic condition resulting from dominant point mutations in the phosphoinositide-3 kinase delta (PI3Kδ) gene, which leads to hyperactivation of the PI3Kδ enzyme, primarily expressed in T and B lymphocytes. Children with this mutation often have recurrent sinopulmonary infections and immunodeficiency. Additional complications may include increased susceptibility to herpes virus infections, lymphoid hyperplasia, and autoimmune conditions. In this case, report, we describe the clinical course of a young boy diagnosed with APDS who developed unclassified inflammatory bowel disease (U-IBD) and explore a personalized treatment approach. Methods: We detail the clinical course of a 12-year-old boy with APDS who presented with fever, diarrhea, anemia, and significant weight loss. Diagnostic evaluations, including endoscopy and histological analysis, led to a diagnosis of U-IBD. Genetic testing confirmed a heterozygous PIK3CD mutation (c.G3061A, p.E1021K). Results: Although APDS is characterized by a broad spectrum of immune dysregulation, the occurrence of IBD in this context is rare. We managed the patient’s IBD with exclusively enteral nutrition to induce remission, followed by a maintenance regimen combining the Crohn’s Disease Exclusion Diet (CDED) and mesalamine, achieving sustained long-term clinical remission. Conclusions: This case underscores the importance of personalized treatment approaches in managing the complex manifestations of APDS.

1. Introduction

The monogenic primary immunodeficiencies are a group of disorders characterized by specific genetic mutations affecting the immune system. These diseases vary significantly in their severity and manifestations. One particularly rare condition within this group is Activated Phosphoinositide-3 Kinase Delta Syndrome (APDS). APDS is caused by punctual dominant mutations in the Phosphoinositide-3 Kinase Delta (PI3Kδ) gene, leading to hyperactivation of the PI3Kδ enzyme, which plays a critical role in immune cell function [1,2]. PI3Kδ is predominantly expressed in T and B lymphocytes, and its dysregulation results in a range of immune system abnormalities [1,2]. Although fewer than 100 cases of APDS have been described in the literature, even rarer are those associated with inflammatory bowel disease (IBD).

In this article, we report a case report of a patient with APDS who developed IBD during adolescence. Additionally, we will discuss the diagnostic and therapeutic approaches used in this patient, with the aim of contributing to the understanding and management of this rare and complex condition.

2. Case Report

A 12-year-old boy was referred to our clinic due to persistent fever, diarrhea, fatigue, and loss of appetite. His medical history revealed recurrent lower respiratory tract infections and sinusitis since early childhood. At the age of four, he had contracted herpes zoster, an unusual infection for someone of his age. At the age of 10, he was hospitalized for investigations following lymphadenopathy (enlarged lymph nodes in the submandibular, superficial cervical, and inguinal regions) and pneumonitis. Notably, the patient had no family history of immunodeficiency.

Upon further immune assessment, the boy was found to have an IgG deficiency (4.1 g/L), normal IgA concentrations, and elevated IgM levels (5.9 g/L). A detailed lymphocyte subset panel revealed T and B cell lymphopenia, decreased CD4 and CD8 T cell counts, and a low CD4/CD8 ratio (0.93). Despite being fully vaccinated according to the national vaccination program, he did not show protective antibody titers. A computed tomography (CT) scan of the neck, chest, and abdomen revealed multiple bilateral lymphadenopathies (cervical, supraclavicular, axillary, inguinal, diffuse thoracic and abdominal lymphadenomegalies; maximum diameter of 16 mm), hepatosplenomegaly and small bronchiectasis in the upper lobes of both lungs. A biopsy of the right cervical lymph node showed several secondary follicles with vast germinal centers (bcl2-; CD10+; ki67 highly expressed), average morpho-functional polarization, and paracortical nodular hyperplasia of T cells, and concluded for unspecified reactive lymphadenitis excluding malignancy.

Based on these findings, the patient was started on monthly intravenous immunoglobulin replacement (IVIG) therapy and prophylactic treatment with trimethoprim-sulfamethoxazole.

Subsequent genetic testing using next-generation sequencing (NGS) identified a heterozygous mutation in the PIK3CD gene (c.G3061A p.E1021K), confirming the diagnosis of APDS.

At 12 years old, the patient was admitted to the hospital again due to epigastric pain, diarrhea, rapid weight loss, and fever. Blood tests showed anemia (hemoglobin: 8.1 g/dL), a normal white blood cell count (9270/uL) with neutrophilia (80.6%), lymphocytopenia (8.9%), mild eosinophilia (7.2%), thrombocytopenia (82,000/uL), and mildly elevated inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR, 58 mm/h). Fecal occult blood testing was positive, raising concerns about gastrointestinal inflammation.

A work-up for IBD was initiated. The panel for gastrointestinal pathogen research was negative. Endoscopic evaluations revealed antral hyperemia on upper endoscopy and aphthous ulcers with ulcerated surfaces in the transverse and left colon on colonoscopy. Histological examination of the colonic biopsies showed superficial ulceration, granulation tissue with lymphoid aggregates, focal neutrophils, plasmacytosis, cryptitis, and crypt abscesses, leading to a diagnosis of unclassified IBD. The patient was treated with antibiotics (ciprofloxacin) and proton pump inhibitors. Thrombocytopenia was managed with IVIG, and exclusive enteral nutrition (EEN) was initiated, leading to full remission of IBD symptoms. Mesalamine was introduced as a long-term maintenance therapy, and the patient was later transitioned to subcutaneous immunoglobulin therapy. Over the following two years, he was monitored closely, with periodic endoscopies confirming disease stability, though some aphthous ulcers persisted in the transverse colon.

3. Discussion

3.1. Activated Phosphoinositide-3-Kinase δ

Monogenic primary immunodeficiencies encompass a wide array of conditions affecting the immune system. The mutation identified in this patient is one of the most common of the PI3Kδ gene: E1021K in the p110δ subunit, which defines APDS1 [1,2]. This condition is characterized by a dominant mutation that raises the activity of PI3Kδ, which in turn increases the levels of the second messenger phosphatidylinositol-3-phosphate leading to increased Akt/mTOR activity. The final effect is that adaptive immune cells undergo differentiation, senescence and death much faster than healthy individuals. In particular, the CD8+ T cells differentiate into effector T cells prematurely, impairing the formation of memory and naïve T cells, which are essential for long-term immune responses [1,2]. Moreover, APDS type 1 is characterized by a marked reduction in CD4+ T cells, a defect in B cell differentiation into plasma cells and memory B cells, and defective class switching of immunoglobulins, resulting in elevated IgM levels and low concentrations of IgG and IgA [3,4,5].

3.2. Clinical Manifestations of APDS

APDS has a heterogeneous phenotype secondary to the complex deficiency of cellular and humoral immunity (Figure 1) [6]. Most patients present with recurrent respiratory infections (otitis media, sinusitis, pneumonia) usually driven by Haemophilus influenza and Streptococcus pneumonia that should call back an antibody deficiency. These infections often lead to chronic respiratory conditions such as bronchiectasis, which occurs in 33–75% of cases, even in the absence of prior pneumonia [2,3,4,5,6,7,8]. Due to impaired T cell function, patients with APDS are also susceptible to viral infections (e.g., herpes simplex virus, cytomegalovirus, Epstein–Barr virus), as well as fungal and parasitic infections. One of the hallmark features of APDS is chronic lymphoproliferation, with persistent lymphadenopathy, hepatosplenomegaly, and mucosa-associated lymphoid tissue (MALT) hyperplasia [4,7]. In addition, APDS patients are at an increased risk of developing malignant diseases, with an incidence of around 13% in APDS1 and a median age of onset of 18 years [8,9,10]. There is a predisposition to the development of lymphomas, particularly those associated with the Epstein–Barr virus, which remains latent in the lymphocytes of patients [4,7].

The prospective APDS registry of the European Society for Immunodeficiencies (ESID) addressed the dynamics of disease evolution over time by expanding the known information regarding the clinical manifestations of the disease [11]. The dysregulation of the cell cycle and the process of apoptosis responsible for the control of central and peripheral immune tolerance leads to the development of autoimmunity that can involve virtually every organ [4,7]. The autoimmune manifestations frequently described in APDS are exocrine pancreatic insufficiency, arthritis, and cytopenia (present in our patient) [6].

These findings support the hypothesis that dysregulation of PI3Kδ signaling may contribute to the pathogenesis of IBD in patients with APDS.

According to data from the ESID-APDS registry, gastrointestinal manifestations, such as chronic diarrhea, autoimmune hepatitis, or intestinal inflammation, rank as the third most common disease manifestation in the entire cohort, and occurred earlier than autoimmune cytopenias, but much later than respiratory infections and the development of benign chronic lymphoproliferation [11]. Recent studies suggest that PI3Kδ signaling plays a key role in regulating intestinal inflammation, possibly by affecting IL-10 production by B cells. The PI3Kδ gene has been mapped to a susceptibility locus for IBD [12], and its deletion has been linked to colitis in animal models [13]. These findings support the hypothesis that dysregulation of PI3Kδ signaling may contribute to the pathogenesis of IBD in patients with APDS [14]. It has been shown that B cells from PI3Kδ mice secret significantly less IL-10 and greater IL-12p40 upon bacterial stimulation, demonstrating their ineffectiveness in suppressing inflammatory cytokines [15]. It is possible to speculate that PI3Kδ signaling mediates regulatory B-cell immune differentiation upon stimulation with resident microbiota inducing a regulatory function by the secretion of IL -10, leading to intestinal homeostasis and suppressing inflammation [14]. Blockade of PI3Kδ signaling results in losing control of the production of bacterially activated inflammatory cytokines by macrophages or T cells, resulting in an inadequate pathogen clearance responsible for an extended improper inflammatory response [16].

3.3. Therapeutic Strategies in APDS

The clinical heterogeneity of APDS indicates that treatment must be nicely customized to the needs of each patient [17]. Supportive care, such as prophylactic antibiotics and immunoglobulin replacement therapy, is often necessary for patients with recurrent infections and defective antibody production. Clinical evidence should be used to determine which treatment is best. Patients with repeated respiratory infections require close collaboration with respiratory specialists to prevent and manage life-threatening bronchiectasis, which is among the leading reasons for mortality in APDS.

In terms of targeted therapy, immunosuppressants like rituximab and sirolimus have been used to control lymphoproliferation by inhibiting the mTOR pathway. In recent years, the development of selective PI3Kδ inhibitors (e.g., idelalisib, leniolisib, nemiralisib) has opened new possibilities for the treatment of both APDS and other conditions such as cancer [18], rheumatoid arthritis, asthma, and chronic obstructive pulmonary disease [19]. Preliminary data suggest that hematopoietic stem cell transplantation can be a curative option for young patients with life-threatening APDS, though the procedure carries significant risks, including a 10–20% mortality rate [5,18].

Standardized treatments for colitis in patients with APDS are not well-established, and therapeutic approaches must be tailored to the individual patient. The few reported cases in the literature have often involved corticosteroids and mesalamine as first-line therapies [18,19]. However, more aggressive immunosuppressive agents such as sirolimus [20], cyclosporine [21], infliximab [21] or even HSCT have been required in some cases to achieve long-term disease control [22,23].

In our case, the patient was successfully treated with EEN, based on a polymeric formula plus TGFβ, for 8 weeks followed by the Crohn’s disease exclusion diet [24]. TGFβ is able to downregulate mucosal proinflammatory cytokine and mRNA, and to achieve mucosal healing in both colon and ileum. This cytokine has a strong anti-inflammatory effect and promotes the generation of FOXP3 positive regulatory T cells in the gut compartment [25]. TGFβ concentrations are low in this formulation, and, to date, there are no clear clinical or preclinical studies demonstrating the additive benefit of TGFβ supplementation over EEN alone in vivo. Nevertheless, this approach achieved clinical and biochemical remission without the need for more aggressive immunosuppressive therapy. After the induction period, the diet was liberalized and mesalamine was introduced (60 mg/Kg/die) for long-term maintenance, helping to suppress inflammation and prevent relapse. We preferred not to use immunosuppressants, immunomodulators, or biological therapy (anti-TNFα) in the first line to decrease the risks of infection and malignancy, as for patients with increased risk for a complicated disease course [24].

4. Conclusions

APDS is a rare and complex primary congenital errors of immunity with a highly variable clinical presentation. While the underlying mutations in PI3Kδ have only recently been characterized through advanced biomedical research, emerging data from clinical trials offer promising insights into potential treatments. Despite these advances, many critical aspects of the disease remain unresolved. The occurrence of inflammatory bowel disease (IBD) in APDS patients, although rare, is becoming an increasingly recognized complication that necessitates a multidisciplinary approach to management. Continued research into the genetic underpinnings of congenital errors of immunity and the molecular pathways regulating enzyme function is essential to developing more precise and effective treatments for APDS. Further studies are particularly needed to refine strategies for managing colitis and to prevent the numerous complications associated with this condition. These efforts will be crucial in improving patient outcomes and quality of life for individuals with APDS.