SUMMARY
1. Idiopathic CD4 lymphopenia (ICL) is a heterogeneous clinical syndrome characterized by a CD4 T cell count < 300 cells/mm3 in the absence of HIV infection on at least 2 separate measurements.
2. The clinical manifestations for patients are variable. Some patients are asymptomatic while other patients suffer from opportunistic infections such as mycobacteria, Cryptococcal meningitis, mucocutaneous candidiasis, and Pneumocystis jiroveci pneumonia.
3. Other infections reported in ICL include HPV, aspergillosis, toxoplasmosis, histoplasmosis, and hepatitis C. Infections with herpes viruses (Varicella-zoster, EBV and CMV) have also been reported.
4. Rare infectious complications include progressive multifocal encephalopathy (PML) from JC and polyoma virus as well as sepsis from Fusobacterium nucleatum and Salmonella typhimurium.
5. Up to 25% of ICL patients may have associated autoimmune disorders. These include Sjogren syndrome, SLE, psoriasis, vitiligo, lichen planus of the scalp, vasculitis, antiphopholipid antibody syndrome, and Behcets-like syndrome.
6. Malignancies have been described in ICL and include lymphomas, Kaposi sarcoma of the digestive tract, and cutaneous neoplasias.
7. In addition to low CD4 counts, other laboratory abnormalities may include reduced CD8 T cells, NK cells, and B cells. Restricted T cell repertoire and decreased naïve (CD45RA) T cells have also been reported. In vitro proliferation to mitogens may be depressed. Testing to rule out HIV infection is mandatory.
8. Treatment involves the aggressive treatment of acute infections. Antimicrobial prophylaxis for PJP with trimethoprim-sulfamethoxazole is recommended for patients with CD4 T cell numbers less than 200 cells/mm3. IL-2 therapy has been utilized in some patients for refractory infections. HSCT is not routinely recommended for ICL.
9. The prognosis for patients is quite variable. Most patients will have a stabilization of CD4 values rather than a progressive decline. In a small number of patients, the CD4 lymphopenia may spontaneously resolve.
OVERVIEW
Idiopathic CD4 lymphopenia (ICL) is a heterogeneous clinical syndrome characterized by a CD4 T cell count < 300 cells/mm3 in the absence of HIV infection on at least 2 separate measurements.
The clinical manifestations for patients are variable. Some patients are asymptomatic while other patients from suffer from opportunistic infections such as mycobacteria (tuberculosis and atypical mycobacteria), Cryptococcal meningitis, mucocutaneous candidiasis, and Pneumocystis jiroveci pneumonia. Other infections reported in ICL include HPV, aspergillosis, toxoplasmosis, histoplasmosis, and hepatitis C. Infections with herpes viruses (Varicella-zoster, EBV and CMV) have also been reported.
Rare infectious complications include progressive multifocal encephalopathy (PML) from JC and polyoma virus as well as sepsis from Fusobacterium nucleatum and Salmonella typhimurium.
Up to 25% of ICL patients may have associated autoimmune disorders. These include Sjogren syndrome, SLE, psoriasis, vitiligo, lichen planus of the scalp, vasculitis, antiphopholipid antibody syndrome, and Behcets-like syndrome.
Malignancies have been described in ICL and include lymphomas (non-Hodgkin lymphoma, leptomeningeal lymphoma, intravascular cerebral lymphoma, and EBV related Burkitt lymphoma), Kaposi sarcoma of the digestive tract, and cutaneous neoplasia (vulval carcinoma, epidermoid carcinoma)..
PATHOGENESIS
CD4 is a glycoprotein expressed on CD4 T cells which interacts with MHC class II on antigen presenting cells to provide a co-stimulatory signal. Binding of the TCR to antigen presented by MHC II without a CD4/MHC II co-stimulatory signal leads to cell anergy and apoptosis. The exact mechanism of immunodeficiency in ICL has not been elucidated.
EVALUATION
The diagnosis of idiopathic CD4 lymphopenia should be considered for patients presenting with persistently low CD4 T cell counts < 300 cells/mm3 in the absence of HIV infection.
Step 1: Immune Evaluation
- CBC with Differential
- Lymphocyte subset enumeration by flow cytometry (CD3, CD4, CD8, CD19, CD16/56)
- Naïve (CD45RA) and memory (CD45RO) T-cell enumeration by flow cytometry
- T-cell proliferation to Mitogens (PHA)
- IgG, IgA, IgM levels
- Specific Antibody levels (to vaccine antigens)
- HIV Serology or PCR
-The absolute lymphocyte count (ALC) may be decreased due to CD4 lymphopenia.
-Total T cell numbers may be normal or low. CD4 T cell numbers < 300 cells/mm3 on more than 2 separate occasions must be documented. CD8 T cell, B cell, and NK cell numbers may also be decreased in some patients.
-Low naïve (CD45RA) T cells have been reported in some patients.
-T cell proliferation to mitogens may be normal or depressed.
-Immunoglobulin levels are typically normal
-Specific antibody responses to vaccines may be decreased in cases of severe ICL.
-It is mandatory to exclude HIV (by ELISA or PCR) infection prior to making a diagnosis of ICL.
MANAGEMENT
Treatment involves the aggressive treatment of acute infections. Antimicrobial prophylaxis for PJP with trimethoprim-sulfamethoxazole is recommended for patients with CD4 T cell numbers less than 200 cells/mm3. IL-2 therapy has been utilized in some patients for refractory infections. However, this therapy can be associated with significant side effects such as capillary leak syndrome. HSCT is not routinely recommended as the risks of this treatment outweigh the potential benefits in this disease.
The prognosis for patients is quite variable. Most patients will have a stabilization of CD4 values rather than a progressive decline. In a small number of patients, the CD4 lymphopenia may spontaneously resolve. Patients with concurrent CD8 lymphopenia are at increased risk for infectious complications.
RESOURCES
Literature Resources
1. Zonios 2008
Idiopathic CD4 lymphocytopenia - natural history and prognostic factors
2. Li 2011
Second messanger role for Mg2 revealed in T cell immunodeficiency