1. Introduction

Clinical presentation of idiopathic CD4+ lymphocytopenia differs widely from clinically mild phenotype to severe infections or disseminated neoplasms.

Various auto-immune and immunodeficiency complications were reported suggesting the role of an immune mechanism in the pathogenesis of ICL.

We reported a case of a long term Evans syndrome in an ICL patient with a very low CD4+ T cell count.

2. Case Presentation

A 30-year-old Tunisian man presented in October 2007 with a one week history of fatigue and skin pallor. He was born from a consanguineous marriage. His mother has rheumatoid arthritis. He had no known risk factors for HIV-infection and his medical history was unremarkable, in particular, he had neither clinical condition of congenital immunodeficiency nor opportunistic infection.

On admission, the patient had an hemolytic anemic syndrome. Nor hemorrhagic and infectious manifestations or tumor syndrome were noted. The hemoglobin level was 9 g/dl and the blood counts were as follows: platelets 130000/mm³, leukocytes 5900/mm³ and lymphocytes 1000/mm³. The serum levels of bilirubin and LDH were elevated.

An Evans’ syndrome was suspected and a Coombs test (IgG and C3) was positive whereas antiplatelets antibodies were negative.

Therapy with steroids was started but the anemia persisted. Human Immunoglobulin with bolus of steroids was indicated and led to a clinical and biological improvement. His hemoglobin level reached a normal range but Platelet and lymphocyte counts persisted under normal. He didn’t present any infectious disease. Blood cell counts outcome are in Table 1.

Table 1. Patient’s blood cell counts

Download as

PowerPoint Slide

Larger image(png format)

• Tables index

Veiw figure

View current table in a new window

View next table

A second episode of bicytopenia occurred heitheen months later, followed by an episode of pancreatitis. Etiologic investigation of this Evans syndrome included normal chest radiography and computed tomography scan, a screening for other autoimmune disorders which concluded to negative Anti-Endomysium Antibodies, Anti Peroxydase Antibodies, Antigliadine Antibodies, Anti Thyroglobuline Antibodies and Anti nuclear antibodies. Anti Phospholipid Antibodies and Anti Smooth Muscle Antibodies were positive. HIV polymerase Chain Reaction assay was negative. B and C Hepatitis serologic tests were also negative. Bone marrow smear and biopsy showed no abnormality. EPP was normal with normal rate of IgG, IgM, and IgA.

Flow cytometry immunophenotyping of peripheral blood lymphocytes was investigated in order to analyze monoclonality of B or T cells and showed a decreased ratio of the CD4/CD8 cells with a surprising low count of CD4+ T cells which was confirmed at 2 occasions Table 2.

Table 2. Patient’s Flow cytometry immunophenotyping of peripheral blood lymphocytes

Download as

PowerPoint Slide

Larger image(png format)

• Tables index

Veiw figure

View current table in a new window

View previous table

3. Discussion

Our patient presented with autoimmune haemolytic anaemia (AIHA), autoimmune thrombocytopenia (AITP), T lymphopenia and positive antiphospholipid and antitissue antibodies. He also fulfills the CDCP definition of ICL (CD4+ count of less than 300 × 10⁶/L on two occasions in the absence of HIV infection or other known causes of immunodeficiency).

Although the diagnosis of ICL was done one year after the diagnosis of Evans’ syndrome, lymphopenia was present from the beginning of the autoimmune manifestation.

The presence of positive anti tissues and anti phospholipid antibodies in this patient further lends support for an autoimmune phenomenon in conjunction with his Evans’ syndrome.

A differential diagnosis between a primary Evans’ syndrome and a secondary Evans’ syndrome following ICL could not be made initially.

In this case and according to the literature ICL syndrome, CD4+T lymphocytopenia may be accompanied by lymphocytopenia of CD8+ T, B or NK cells) ^{[1, 2]}. In patients with idiopathic thrombocytopenia, a reduced ratio of CD4/CD8 cells was reported, with an improvement of this ratio in remission ^[3]. ICL Lymphopenia could be associated with a variety of human autoimmune diseases such as lupus, Sjögren's syndrome,thyroiditis, vitiligo, vasculitis, and Antiphospholipid syndrome ^[4] but the temporal relationship of autoimmune disease and ICL and the exact nature of correlation of the 2 diagnoses could not be concluded ^{[5, 6]}. In a study of 214 Sjogren’s patients, 3.7% were found to have ICL lymphocytopenia associated with antibodies directed against CD4 lymphocytes ^{[5, 7]}.

Recent finding suggests that pathogenic mechanisms implicated in ICL include:

- An unbalance between the regulatory and conventional T-cell compartments, triggering the development of autoimmune disorders ^[8].

- Genetic mutations such as mutations in major histocompatibility complex class II, missense mutations in RAG1 and Unc119. ^{[9, 10]})

- Cytokines release of IL21 and decrease of IL2 and IL7. ^{[9, 11]}

The evolution of the ICL remains poorly known in the absence of important follow-up cohorts. It appears that this lymphopenia is usually persistent and stable, even if spontaneous corrections are possible. Clinically, the onset of opportunistic infections is not predictable ^{[6, 10]}.

4. Conclusions

The mechanisms that may result in ICL lymphopenia are multiple. If a particular clinical context is not found, it is necessary to know to seek infectious, dysimmune or neoplastic etiology. After negative conducted investigations, idiopathic CD4 + lymphopenia should be considered in order to adapt the follow-up of these patients.

Lymphopenia has long been associated with autoimmune manifestations. Thus, it is necessary to look for a lymphopenia in front of certain situations of autoimmunity.

References

[1]	Dimitrios I.Zonios, Judith Falloon, John E. Bennet, Pamela A. Shaw, Doreen Chaitt, Michael W. Baseler, Joseph W. Adelsberger, Julia A. Metcalf, Michael A. Polis, Stephen J. Kovacs, Joseph A. Kovacs, Richard T. Davey, H. Clifford Lane, Henry Masur and Irini Sereti, “Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors”, Blood ,112 (2), 287-294, Jul 2008.
	In article		View Article  PubMed
[2]	Mario Ostrowski, Irving E. Salit, Wayne L. Gold, David Sutton, Michael L. Montpetit, Debbie Lepine, Teresa Salas, “Idiopathic CD4+ T-lymphocytopenia in two patients” CMAJ, 149 (11), 1679-83, Dec 1993.
	In article		PubMed  PubMed
[3]	Marina Karakantza, Athanasia Mouzaki, Maria Theodorooulou, James B. Bussel and Alice Maniatis, “Th1 and Th2 cytokines in a patient with Evans’ syndrome and profound lymphopenia”, Br J Haematol,110(4): 968-970, Sep 2000.
	In article		View Article  PubMed
[4]	A. Guffroy, V. Gies, M. Martin, A-S. Korganow, “Primary immunodeficiency and autoimmunity”, Rev Med Interne Nov 2016.
	In article		PubMed
[5]	Alexander Khaoruts, Joanne M. Fraser, “A causal link between lymphopenia and autoimmunity” Immunol Lett, 98 (1), 23-31, Apr 2005.
	In article		View Article  PubMed
[6]	A. Régent, N. Kluger, A. Bérezné, K. Lassoued, L. Mouthon, “Lymphocytopenia: A etiology and diagnosis, when to think about idiopathic CD4+ lymphocytopenia?” Rev Med Interne, 33(11), 628-34 Nov 2012.
	In article		View Article  PubMed
[7]	Kirtava Z, Blomberg J, Bredberg A, Henriksson G, Jacobsson L,Manthorpe R, “ CD4+ T-lymphocytopenia without HIV infection: increased prevalence among patients with primary Sjogren’s syndrome” , Clin Exp Rheumatol 13(5), 609-16,Sep-Oct 1995.
	In article		PubMed
[8]	Armelle Le Campion, “Lymphopenia-induced spontaneous T-cell proliferation as a cofactor for autoimmune disease development” Blood, 114(9), 27 Aug 2009.
	In article		View Article  PubMed
[9]	Gholamin M1, Bazi A, Abbaszadegan MR, “Idiopathic lymphocytopenia”, Curr Opin Hematol, 22(1), 46-52, Jan 2015.
	In article		PubMed
[10]	Brooks JP, Ghaffari G, “Idiopathic CD4 lymphocytopenia”, Allergy Asthma Proc, 37(6), 501-504, Nov 2016.
	In article		View Article  PubMed
[11]	Angela Malaspina, Susan Moir, Doreen G. Cahitt, Catherine A. Rehm, Shyam Kottili, Judith Falloon, Antony S. Fauci, “Idiopathic CD4+ T lymphocytopenia is associated with increases in immature/transitional B cells and serum levels of IL-7” Blood 109 (5): 2086-2088, Mar 2007.
	In article		View Article  PubMed