Longitudinal Prognosis of Lymphoproliferative Manifestations in Primary Immunodeficiencies

Overview

Primary immunodeficiencies (PIDs) are a heterogeneous group of inborn errors of immunity characterized not only by increased susceptibility to infections but also by immune dysregulation. Among immune dysregulation manifestations, lymphoproliferative disorders represent a frequent and clinically challenging complication. These manifestations may involve secondary lymphoid organs (lymphadenopathy, splenomegaly) as well as extranodal organs such as lungs, liver, and gastrointestinal tract, often with lymphocytic and/or granulomatous infiltration. In some patients, lymphoproliferation may progress to lymphoma or other malignancies. Despite increasing knowledge about specific genetic subtypes of PIDs and the development of targeted therapies (e.g., PI3Kδ inhibitors, CTLA4 pathway modulation, mTOR inhibitors), the natural history and long-term prognosis of lymphoproliferative manifestations across unselected PID populations remain poorly defined. Most available studies focus on selected molecular subgroups or treatment responses, while real-world longitudinal data on broader PID cohorts are lacking. The PID-LP study is a multicenter retrospective longitudinal study conducted in three tertiary care centers in France. It aims to describe the initial characteristics and long-term outcomes of patients with PIDs who develop lymphoproliferative manifestations. The primary objective is to evaluate the occurrence of major clinical events during follow-up, defined as death (all causes), occurrence of lymphoma or other malignancy, or clinically significant organ dysfunction attributable to lymphoproliferation. Secondary objectives are to describe the longitudinal evolution of systemic lymphoproliferation (lymph node size, splenomegaly), the progression of organ involvement (pulmonary, hepatic, gastrointestinal), and to identify clinical, biological, genetic, radiological, and therapeutic factors at diagnosis that may predict major complications. Approximately 60 pediatric and adult patients diagnosed between 2014 and 2025 and followed for at least 12 months after diagnosis of lymphoproliferation will be included. Data will be retrospectively collected from medical records. This study is expected to improve the understanding of prognosis and disease trajectories in PID-associated lymphoproliferation, inform follow-up strategies, and generate hypotheses for future prospective interventional studies.

Primary immunodeficiencies (PIDs), also referred to as inborn errors of immunity, encompass a broad and expanding spectrum of genetically defined disorders affecting immune system development and function. While historically characterized by recurrent or severe infections, it is now well established that immune dysregulation represents a major component of PID-related morbidity. Autoimmunity, autoinflammation, granulomatous disease, and lymphoproliferation are frequently observed and may dominate the clinical phenotype. Lymphoproliferative manifestations in PIDs include persistent or recurrent lymphadenopathy, splenomegaly, benign lymphoid hyperplasia, granulomatous infiltration, and, in some cases, progression to lymphoma or other malignancies. These manifestations may involve secondary lymphoid organs but also extranodal sites such as the lungs (interstitial lung disease, lymphoid infiltrates), liver (nodular regenerative hyperplasia, fibrosis), gastrointestinal tract (lymphocytic or granulomatous inflammation), and other organs. Organ dysfunction secondary to lymphoproliferation may lead to significant morbidity, including respiratory impairment, portal hypertension, malabsorption, cytopenias, or the need for invasive procedures. Several recent studies have evaluated targeted therapies in selected molecular subgroups of PIDs associated with immune dysregulation. For example, PI3Kδ inhibitors have demonstrated efficacy in activated PI3Kδ syndrome (APDS), abatacept has shown benefit in CTLA4 or LRBA deficiency, and mTOR inhibitors such as sirolimus have been used in autoimmune lymphoproliferative syndromes and related disorders. However, these studies focus on specific genetic entities and therapeutic responses over relatively short follow-up periods. There remains a lack of comprehensive longitudinal data describing the real-world evolution of lymphoproliferative manifestations across heterogeneous PID populations. The PID-LP study is a multicenter retrospective longitudinal study conducted in three French tertiary referral centers (Nancy, Strasbourg, and Metz). It is designed to analyze existing clinical data collected during routine care. The study population includes pediatric and adult patients diagnosed with a PID according to the International Union of Immunological Societies (IUIS) classification, who developed systemic lymphoproliferation (lymphadenopathy, splenomegaly, lymphoma) and/or organ involvement attributable to lymphocytic or granulomatous infiltration in the context of PID. Eligible patients must have at least 12 months of follow-up after the first diagnosis of lymphoproliferation. The primary objective is to evaluate the occurrence of major clinical events during follow-up. The primary endpoint is defined as the occurrence of at least one of the following: All-cause mortality; Occurrence of lymphoma or other malignancy; Clinically significant organ dysfunction attributable to lymphoproliferation. Organ dysfunction is defined according to predefined clinical, biological, and radiological criteria. For example, pulmonary involvement includes persistent decline in lung function parameters (e.g., significant reduction in FVC, FEV1, or DLCO), radiological progression of fibrotic or infiltrative disease, or need for long-term oxygen therapy. Hepatic involvement includes advanced fibrosis, persistent synthetic dysfunction, or clinically significant portal hypertension. Gastrointestinal involvement includes documented malabsorption, chronic intestinal failure requiring nutritional support, or surgical complications related to inflammatory or lymphoproliferative lesions. Splenic complications include massive splenomegaly associated with severe cytopenias, compression symptoms, rupture, or splenectomy for clinical indications. Secondary objectives include: Description of the longitudinal evolution of systemic lymphoproliferation, including persistence, progression, or regression of lymphadenopathy and splenomegaly, changes in maximal lymph node diameter, and need for invasive diagnostic or therapeutic procedures. Description of the evolution of organ-specific involvement (pulmonary, hepatic, gastrointestinal), assessed at diagnosis and at last available follow-up. Identification of predictive factors for major clinical events. Candidate predictors include demographic characteristics (age, sex), clinical features at presentation, immunological parameters (cytopenias, immunophenotyping abnormalities), genetic findings, radiological characteristics, and treatments administered (immunosuppressive therapies, biologics, targeted therapies, surgery, cellular therapy). Statistical analyses will include descriptive statistics for baseline characteristics and outcomes. Time-to-event analyses will be performed to describe the delay between lymphoproliferation diagnosis and occurrence of major events. Cox proportional hazards models and Fine and Gray competing risk models will be used to identify predictors of major complications, considering death as a competing event where appropriate. Approximately 60 patients diagnosed between 2014 and 2025 are expected to be included, based on exhaustive identification within participating centers. Given the rarity of these conditions, the study is primarily exploratory and hypothesis-generating. There is no direct individual benefit for participants, as the study is retrospective and non-interventional. However, the expected collective benefit is substantial. By better characterizing the natural history and prognostic factors of PID-associated lymphoproliferation, this study aims to improve risk stratification, inform clinical monitoring strategies, and support the design of future prospective and interventional trials aimed at preventing severe organ damage and malignant transformation.