Idiopathic CD4 Lymphocytopenia

Idiopathic CD4 T lymphocytopenia (ICL) is a rare and severe condition with limited available data. We conducted a French multicenter study to analyze the clinical and immunologic characteristics of a cohort of patients with ICL according to the Centers for Disease Control criteria. We recruited 40 patients (24 female) of mean age 44.2 T 12.2 (19Y70) years. Patients underwent T-lymphocyte phenotyping and lymphoproliferation assay at diagnosis, and experiments related to thymic function and interferon (IFN)-F release by natural killer (NK) cell were performed. Mean follow-up was 6.9 T 6.7 (0.14Y24.3) years. Infectious, autoimmune, and neoplastic events were recorded, as were outcomes of interleukin 2 therapy. In all, 25 patients had opportunistic infections (12 with human papillomavirus infection), 14 had autoimmune symptoms, 5 had malignancies, and 8 had mild or no symptoms. At the time of diagnosis, the mean cell counts were as follows: mean CD4 cell count: 127/mm (range, 4Y294); mean CD8: 236/mm (range, 1Y1293); mean CD19: 113/mm (range, 3Y547); and mean NK cell count: 122/mm (range, 5Y416). Most patients had deficiency in CD8, CD19, and/or NK cells. Cytotoxic function of NK cells was normal, and patients with infections had a significantly lower NK cell count than those without (p = 0.01). Patients with autoimmune manifestations had increased CD8 T-cell count. Proliferation of thymic precursors, as assessed by T-cell rearrangement excision circles, was increased. Six patients died (15%). CD4 T-cell count G150/mm and NK cell count G100/mm were predictors of death. In conclusion, 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. (Medicine 2014;93: 61Y72) Abbreviations: AIHA = autoimmune hemolytic anemia, CDC = Centers for Disease Control, CMV = cytomegalovirus, cpm = count per minute, CVID = common variable immunodeficiency, CXCR4 = C-X-C chemokine receptor type 4, HIV = human immunodeficiency virus, HLA= human leukocyte antigen, HPV= human papillomavirus, HTLV-1/2 = human T-cell lymphotropic 1/2, ICL = idiopathic CD4 T lymphocytopenia, IFN-F = interferon-F, IL = interleukin, JC virus = John Cunningham virus, LPA = lymphocyte proliferation assay, NK = natural killer, P = patient, PBMC = peripheral blood mononuclear cell, Pwd = pokeweed, SI = stimulation index, sj = signal joint, TREC = T-cell rearrangement excision circle. INTRODUCTION Idiopathic CD4 T lymphocytopenia (ICL) is an immunodeficiency described in 1992 and characterized by the United States Centers for Disease Control (CDC) as absolute CD4 T-lymphocyte count G300/mm or G20% of total T cells on more than 1 cell count at least 6 weeks apart; no evidence of infection with human immunodeficiency virus (HIV)-1/2 or human T-cell lymphotropic 1/2 (HTLV-1/2); and lack of a defined immunodeficiency disease or therapy associated with depressed levels of CD4 T cells. Epidemiologic, clinical, and immunologic 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 have opportunistic infections such as disseminated Cryptococcus neoformans infection, Pneumocystis jirovecii 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 Medicine & Volume 93, Number 2, March 2014 www.md-journal.com 61 From the Université Paris Descartes and Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Cochin, Service de Médecine Interne, Paris (AR, BT, LG, LM); Institut Cochin, U016, CNRS, UMR8104, Université Paris Descartes, Sorbonne Paris Cité 22, Paris (AR, RC, BC-DM, LM); UPMC, Université Paris 6 and INSERM, UMR945, AP-HP, Hôpital Pitié-Salpêtrière, Laboratoire d’Immunologie Cellulaire et Tissulaire, Paris (BA, GC, PH, PD); Université Paris 13 and AP-HP, Département de Médecine Interne, Hôpital Avicenne, Bobigny (AK); Université Paris Diderot and AP-HP, Département d’Immunologie Clinique, Hôpital Saint-Louis, Paris (EO); UPMC, Université Paris 6 and AP-HP, Hôpital Pitié-Salpêtrière, Service deMédecine Interne, Paris (NC-C); Université Paris Descartes and AP-HP, Service de Maladies Infectieuses, Hôpital Necker-Enfants Malades, Paris (OL); and Université Paris Descartes and AP-HP, Service de Dermatologie, Hôpital Cochin, Paris (ND); France. Financial support and conflicts of interest: This study was funded by a grant from the Direction de la Recherche Clinique et du Développement of the Assistance Publique-Hôpitaux de Paris. The authors listed below have received financial support (personal or institutional) from the listed pharmaceutical or medical device companies, unrelated to the present work. GC: MSD France; ND: Janssen, Boerhinger, Expanscience, Roche; LG: Actelion, Roche, LFB Biotechnologies, CSL Behring; LM: LFB Biotechnologies, CSL Behring, Pfizer, Actelion, Lilly, Roche. Correspondence: Dr. Luc Mouthon, Service de Médecine Interne, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14, France (e<mail: luc.mouthon)cch.aphp.fr). *The French Idiopathic CD4 T Lymphocytopenia Study Group: Lassoued K, Schmit JL, Amiens; Gaillat J, Annecy; Krivitzky A, Saadoun D, Avicenne hospital, Bobigny; El Guedj M, Cayenne; Berthou C, Brest; Fior R, Clamart; Boibieux A, La Croix Rousse hospital, Lyon; Bernard L, Montpellier; Dupin N, Mouthon L, Pelisse N, Régent A, Cochin hospital, Paris; Lortholary O, Necker hospital, Paris; Boissonas A, Paul Brousse hospital, Paris; Amoura Z, Autran B, Carcelin G, Darras-Jolly C, Debré P, Hubert P, Leblond V, Malloum K, Vidailhet M, Pitié-Salpêtrière hospital, Paris; Brouet JC, Clauvel JP, Fermand JP, Fieschi C, Galicier L; Morel P, Oksenhendler E, Saint-Louis hospital, Paris; Blum L, Pontoise; Vallantin X, Perpignan; Bestel B, Saint-Quentin; Maigre M, Saumur, Cartron G, Tours. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0025-7974 DOI: 10.1097/MD.0000000000000017 Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 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 (G180/mm) and degree of CD4 T-cell activation measured by human leukocyte antigen DR (HLA-DR) expression were found associated with poor prognosis. We prospectively analyzed the clinical and immunologic characteristics and long-term prognosis of patients with ICL in a French multicenter cohort. We quantified lymphocyte subpopulations and mitogen/antigen-induced proliferation and explored proliferation of thymic precursors through quantification of T-cell rearrangement excision circles (TRECs) as well as natural killer (NK) cell cytotoxicity. PATIENTS AND METHODS Patient Selection We prospectively included patients with CD4 T lymphocytopenia between January 1991 and June 2012. Diagnosis of ICL was based on absolute CD4 T-lymphocyte count G300/mm or G20% of total T cells on 2 cell counts at 6 weeks apart; no HIV-1/2 or HTLV-1/2 infection; and absence of defined immunodeficiency or therapy associated with decreased levels of CD4 T cells. Therefore, we systematically searched for a known primary or secondary immunodeficiency, including viral infection (for example, HIV, HTLV, transient viral infection), tuberculosis, malignancy (lymphoma or solid tumor), autoimmune and/or inflammatory disorders (for example, Sjögren syndrome, sarcoidosis, systemic lupus erythematosus, granulomatosis with polyangiitis) or other causes of acquired lymphocytopenia. Searches for a known immunodeficiency were performed according to knowledge at the time of diagnosis and during follow-up. Data from clinical files were retrospectively collected by 2 authors (AR and LM). Results for 6 patients were previously reported: Patient 1 (P1), P2, and P13; P12; P14; and P21. Data were analyzed by initial symptoms of any infection known to be associated with lymphocytopenia and any symptom related to autoimmune diseases. During follow-up, unusual infections, neoplasms, and symptoms related to autoimmune diseases were recorded. Patients were classified into 3 groups based on clinical and/or laboratory manifestations at diagnosis or during follow-up: autoimmune/inflammation, infection, or malignancy. Patients could be classified in more than 1 group. TABLE 1. Baseline Characteristics of 40 Patients With Idiopathic CD4 Lymphocytopenia (ICL) Characteristic No. of Patients (%) Sex Female 24 (60.3) Ethnicity/Race White 33 (83) Black 2 (5) North African 5 (13) Age at time of diagnosis of ICL, yr 10Y19 1 (2.5) 20Y29 4 (10) 30Y39 9 (22.5) 40Y49 11 (27.5) 50Y59 13 (32.5) 60Y69 1 (2.5) 70Y79 1 (2.5) Circumstances at time of diagnosis Infection 20 (50) I Cryptococcus neoformans meningitis 4 (10) I Pneumocystis jirovecii pneumonia 2 (5) I Mycobacterial Mycobacterium tuberculosis 2 (5) Mycobacterium kansasii and fortuitum 1 (2.5) I Cutaneous Alternaria spp 1 (2.5)* I Nocardia brasiliensis pneumopathy 1 (2.5)* I Chronic cutaneous/mucosal HPV 8 (20)† I Other (ear-nose-throat infection, dental abscess, pneumonia) 3 (7.5) Autoimmune symptoms 6 (15) I Cerebral granulomatous vasculitis 1 (2.5) I Cytopenia Immune thrombocytopenic purpura 1 (2.5) Autoimmune hemolytic anemia 1 (2.5) I Crohn disease 1 (2.5) I Antiphospholipid syndrome 1 (2.5)† I Guillain-Barré syndrome 1 (2.5) Other (Raynaud phenomenon, diarrhea, gastroesophageal reflux, eczema, urticarial lesion) 6 (15) Fortuitous (blood donor, occupational medicine, routine analysis) 8 (20)