Longitudinal Prognosis of Lymphoproliferative Manifestations in Primary Immunodeficiencies (PID-LP)

April 9, 2026 updated by: Central Hospital, Nancy, France

Descriptive Study of Baseline Features and Longitudinal Prognosis of Lymphoproliferative Manifestations in Primary Immunodeficiencies

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.

Study Overview

Status

Not yet recruiting

Conditions

Detailed Description

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.

Study Type

Observational

Enrollment (Estimated)

60

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: JACQUEL

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Adult and pediatric patients diagnosed with a primary immunodeficiency (PID) who exhibit lymphoproliferation, with or without associated autoimmune manifestations. Patients are followed longitudinally to assess clinical outcomes, comorbidities, treatment responses, and correlation with cellular phenotypes. Exclusion criteria include secondary immunodeficiencies, active malignancies unrelated to PID, or inability to provide informed consent.

Description

Inclusion Criteria:

  • Diagnosis of primary immunodeficiency (inborn error of immunity) according to ESID criteria
  • Presence of systemic lymphoproliferative manifestations (e.g., persistent lymphadenopathy, splenomegaly, lymphoma) and/or organ involvement attributable to lymphocytic or granulomatous infiltration
  • Diagnosis of lymphoproliferative manifestation between January 1, 2014 and December 31, 2025
  • Minimum follow-up of 12 months after diagnosis of lymphoproliferative manifestation
  • Followed in one of the participating centers

Exclusion Criteria:

  • Secondary immunodeficiency (e.g., HIV infection, immunosuppression due to chemotherapy, solid organ transplantation, or other acquired causes)
  • Isolated reactive lymphadenopathy clearly attributable to acute infection without evidence of persistent lymphoproliferation
  • Insufficient clinical data available in medical records to assess baseline characteristics or outcomes
  • Follow-up duration < 12 months after diagnosis of lymphoproliferative manifestation

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Occurrence of Major Clinical Events
Time Frame: 12 months minimum to 10 years retrospective follow-up from first documented benign lymphoproliferative manifestation

The primary outcome is the occurrence of at least one major clinical event during follow-up, defined as any of the following:

  • All-cause mortality;
  • Diagnosis of lymphoma or other malignancy;
  • Clinically significant organ dysfunction attributable to lymphoproliferative involvement (including pulmonary, hepatic, gastrointestinal, or splenic complications), as documented by clinical, biological, and/or radiological criteria and requiring specific medical or surgical management.

Each event will be recorded as a time-to-event variable from the date of lymphoproliferation diagnosis.
12 months minimum to 10 years retrospective follow-up from first documented benign lymphoproliferative manifestation

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Longitudinal Evolution of Systemic Lymphoproliferation
Time Frame: 12 months minimum to 10 years retrospective follow-up from first documented benign lymphoproliferative manifestation

This secondary outcome assesses the longitudinal evolution of systemic lymphoproliferative manifestations over time. It includes changes in lymphadenopathy and splenomegaly between baseline (date of lymphoproliferation diagnosis) and last available follow-up.

Systemic lymphoproliferation will be evaluated through:

  • Presence or absence of lymphadenopathy;
  • Maximum lymph node diameter on clinical examination or imaging;
  • Presence and degree of splenomegaly (clinical assessment and/or imaging measurements);
  • Need for invasive diagnostic or therapeutic procedures related to lymphoproliferation (e.g., lymph node biopsy, splenectomy).

Evolution will be categorized as regression, stability, or progression based on predefined clinical and radiological criteria.
12 months minimum to 10 years retrospective follow-up from first documented benign lymphoproliferative manifestation
Longitudinal Evolution of Organ-Specific Involvement
Time Frame: 12 months minimum to 10 years retrospective follow-up from first documented benign lymphoproliferative manifestation

This secondary outcome evaluates the evolution of organ-specific involvement attributable to lymphoproliferative or granulomatous infiltration in patients with primary immunodeficiency. Organ involvement includes pulmonary, hepatic, and gastrointestinal manifestations documented at baseline and during follow-up.

  • Pulmonary involvement is assessed by clinical symptoms, pulmonary function tests (FVC, FEV1, DLCO when available), and imaging findings.
  • Hepatic involvement is evaluated using clinical data, liver function tests, imaging, and evidence of fibrosis or portal hypertension.
  • Gastrointestinal involvement includes documented inflammatory or granulomatous lesions, malabsorption, or need for nutritional support.

Evolution is categorized as regression, stability, or progression based on predefined criteria.
12 months minimum to 10 years retrospective follow-up from first documented benign lymphoproliferative manifestation
Occurrence of major clinical events according to baseline patient characteristics
Time Frame: 12 months minimum to 10 years retrospective follow-up from first documented benign lymphoproliferative manifestation
Proportion of patients experiencing at least one major clinical event during follow-up, defined as death, lymphoma, or clinically significant organ dysfunction. This outcome will be analyzed according to baseline demographic, clinical, immunological, genetic, radiological, and treatment characteristics, including age, sex, and type of inborn error of immunity.
12 months minimum to 10 years retrospective follow-up from first documented benign lymphoproliferative manifestation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Central Hospital, Nancy, France

Investigators

  • Principal Investigator: Léa JACQUEL, MD, CHRU Nancy Brabois

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

April 1, 2026

Primary Completion (Estimated)

March 31, 2028

Study Completion (Estimated)

March 31, 2029

Study Registration Dates

First Submitted

March 26, 2026

First Submitted That Met QC Criteria

April 9, 2026

First Posted (Actual)

April 13, 2026

Study Record Updates

Last Update Posted (Actual)

April 13, 2026

Last Update Submitted That Met QC Criteria

April 9, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2025PI074

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

De-identified individual participant data, including clinical outcomes and laboratory results, will be made available to qualified researchers upon reasonable request after publication. Data sharing will follow applicable ethical and legal regulations, and a data use agreement will be required.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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