Idiopathic CD4 Lymphocytopenia (Lympho-4)

Analysis of Clinical and Immunological Characteristics, as Well as Pathophysiological Mechanisms in a French Cohort of Patients With Idiopathic CD4 Lymphocytopenia

Definition: Idiopathic CD4+ T lymphocytopenia (ICL) is an immune deficiency first described in 1992 and characterized by the US Centers for Disease Control (CDC) as absolute CD4+ T-lymphocyte count < 300/mm3 or < 20% of total T cells on more than one cell count; no evidence of infection with HIV-1/2 or human T-cell lymphotropic 1/2 (HTLV-1/2); and lack of a defined immune-deficiency disease or therapy for lymphocytopenia. Epidemiologic, clinical and immunological characteristics of the syndrome were described in 1993 and ICL is now considered a heterogeneous syndrome not caused by an infectious agent. Patients with ICL may show opportunistic infections such as disseminated Cryptococcus neoformans infection, Pneumocystis jiroveci pneumonia and John Cunningham (JC) virus infection as a result of profound cell-mediated immune-response deficiency.

Few studies have focused on the pathophysiology of ICL. CD4+ T-lymphocyte phenotyping revealed increased CD95 expression that could be responsible for excess apoptosis leading to lymphocytopenia. Moreover, the membrane expression of C-X-C chemokine receptor type 4 (CXCR4) was found impaired in T lymphocytes with ICL, and CXCR4 trafficking was improved with interleukin 2 (IL-2) treatment in some patients. Recently, mutations in nunc119, MAGT1 and Rag were found associated with CD4+ T lymphocytopenia. In a prospective study of 39 patients, CD8+ T lymphocytopenia (<180/mm3) and degree of CD4+ T-cell activation measured by human leukocyte antigen DR (HLA-DR) expression was found associated with poor prognosis.

ICL is a heterogeneous disorder often associated with deficiencies in CD8+, CD19+, and/or NK cells. Long-term prognosis may be related to initial CD4+ and NK cell deficiency.

Larger studies are needed to better identify the patients who might benefit from IL-2 therapy. This is why the investigators conduct the Lympho-4 study, in which the investigators plan to include 200 patients with a suspected/proven diagnosis of ICL.

Study Overview

• Status: Completed
• Conditions: Idiopathic CD4 Lymphocytopenia
• Intervention / Treatment: Biological: Constitution of a biobank of frozen cells, plasma and serum samples; Genetic: Genetic study

Detailed Description

Definition. Idiopathic CD4+ T lymphocytopenia (ICL) is an immune deficiency first described in 1992 and characterized by the US Centers for Disease Control (CDC) as absolute CD4+ T-lymphocyte count < 300/mm3 or < 20% of total T cells on more than one cell count; no evidence of infection with HIV-1/2 or human T-cell lymphotropic 1/2 (HTLV-1/2); and lack of a defined immune-deficiency disease or therapy for lymphocytopenia.

ICL is a heterogeneous disorder often associated with deficiencies in CD8+, CD19+, and/or NK cells. Thus, ICL does not correspond to a unique disease but more probably to a number of different conditions with distinct underlying mechanisms. This is why the investigators decided to launch the Lympho-4 study, in which the investigators plan to include 200 patients with a suspected/proven diagnosis of ICL.

The aim of the study will be to

1. identify patients in whom the diagnosis of ICL is confirmed using an algorithm developed by a group of multidisciplinary experts.
2. describe and compare clinical, immunological and follow up characteristics of patients in whom the diagnosis of ICL was confirmed vs patients in whom the diagnosis of ICL is not confirmed.

The investigators will also investigate :

Lymphocyte subpopulations including analysis of differentiation and activation of T and B lymphocytes, immortalisation of cell lineages with virus Epstein Barr virus, high rate genome wide genetic screening, investigation of mutations associated with identified primary immune deficiencies (adenosine deaminase et class II MHC), constitution of a biobank of frozen plasma and serum samples ; investigation of the thymic volume by performing a CT scan.

Depending on clinical presentation and based on previous data obtained by our group, the investigators will investigate the immune responses against Human papilloma virus (HPV), Cryptococcus neoformans,implication of chemokines involved in lymphocyte migration (CXCR4 and CCR7 receptors) and signalisation in response to cytokines controlling LT CD4+ homeostasis (IL-7 et IL-2).

• Study Type: Observational
• Enrollment (Actual): 47

Contacts and Locations

Study Locations

• France
  • Paris, France, 75014
    • Cochin Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

200 patients will be included : 100 for which the diagnosis of ICL will be defined on a basis in international classification criteria.

Description

Inclusion Criteria:

• Idiopathic CD4 lymphocytopenia defined as absolute CD4+ T-lymphocyte count < 300/mm3 or < 20% of total T cells on more than one cell count; no evidence of infection with HIV-1/2 or human T-cell lymphotropic 1/2 (HTLV-1/2); and lack of a defined immune-deficiency disease or therapy for lymphocytopenia.
• Male and female patients can be included
• Children and adults can be included
• Hospitalized or outpatient

Exclusion Criteria:

• CD4+ lymphocytopenia due to another condition (HIV infection, sarcoidosis, malignant lymphoma).
• Ongoing treatment possibly responsible for CD4 lymphocytopenia.
• CD4+ lymphocytopenia related to primary immune deficiency
• Absence of consent, of inability to obtain informed consent from the patients or the right holders.
• Absence of affiliation to a social security regimen of the patient or the right holder.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Idiopathic CD4 lymphocytopenia; Constitution of a biobank of frozen cells, plasma and serum samples	Biological: Constitution of a biobank of frozen cells, plasma and serum samples; Depending on clinical presentation and based on previous data obtained by our group, we will investigate the immune responses against Human papilloma virus (HPV), Cryptococcus neoformans,implication of chemokines involved in lymphocyte migration (CXCR4 and CCR7 receptors) and signalisation in response to cytokines controlling LT CD4+ homeostasis (IL-7 et IL-2).
Genetic Study; High rate genome wide genetic screening, investigation of mutations associated with identified primary immune deficiencies (adenosine deaminase et class II MHC)	Genetic: Genetic study; High rate genome wide genetic screening, investigation of mutations associated with identified primary immune deficiencies (adenosine deaminase et class II MHC)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Idiopathic CD4+ T lymphocytopenia Diagnosis	Identify patients in whom the diagnosis of ICL is confirmed using an algorithm developed and applied by a multidisciplinary group of experts	1 year
Clinical, immunological and follow up characteristics of all patients	Describe and compare clinical, immunological and follow up characteristics of patients in whom the diagnosis of ICL was confirmed as compared to those in whom the diagnosis of ICL was not confirmed.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response to IL-2 or IL-7 treatment	Describe the response to IL-2 or IL-7 treatment	1 year
Incident cases of ICL in first degree relatives	Evaluate incident cases of ICL in first degree relatives of patients with ICL.	1 year
Thymic volume and correlation with CD4+ level	Quantify thymic volume in patients with ICL and correlate it with CD4+ level.	1 year
Analysis of differentiation and activation of T and B lymphocytes	Immortalisation of cell lineages with virus Epstein Barr virus, high rate genome wide genetic screening, investigation of mutations associated with identified primary immune deficiencies (adenosine deaminase et class II MHC), constitution of a biobank of frozen plasma and serum samples ; investigation of the thymic volume by performing a CT scan. Depending on clinical presentation and based on previous data obtained by our group, we will investigate the immune responses against Human papilloma virus (HPV), Cryptococcus neoformans,implication of chemokines involved in lymphocyte migration (CXCR4 and CCR7 receptors) and signalisation in response to cytokines controlling LT CD4+ homeostasis (IL-7 et IL-2).	1 year

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2013
• Primary Completion (Actual): September 6, 2017
• Study Completion (Actual): September 6, 2017

Study Registration Dates

• First Submitted: March 28, 2013
• First Submitted That Met QC Criteria: April 11, 2014
• First Posted (Estimate): April 15, 2014

Study Record Updates

• Last Update Posted (Actual): March 19, 2018
• Last Update Submitted That Met QC Criteria: March 16, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immunologic Deficiency Syndromes; Immune System Diseases; Hematologic Diseases; Leukopenia; Leukocyte Disorders; Lymphopenia
• Other Study ID Numbers: NI08039