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Introduction: Idiopathic CD4 lymphopenia (ICL) is a rare clinical syndrome characterized by: CD4+ T cell count less than 300 cells/mm³, or less than 20%

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Presentation on theme: "Introduction: Idiopathic CD4 lymphopenia (ICL) is a rare clinical syndrome characterized by: CD4+ T cell count less than 300 cells/mm³, or less than 20%"— Presentation transcript:

1 Introduction: Idiopathic CD4 lymphopenia (ICL) is a rare clinical syndrome characterized by: CD4+ T cell count less than 300 cells/mm³, or less than 20% of total T cells, on more than one occasion. Absence of HIV infection, immune deficiency, or therapy associated with depressed level of CD4+ T cells. Patients with cellular immunodeficiency are at a higher risk for invasive fungal infection. We present the first reported case of ICL associated with disseminated coccidioidomycosis. History of Present Illness: 44 year old woman with disseminated coccioidomycosis with meningitis, 10 years prior to presentation. Subsequent development of pharyngeal abscess and recalcitrant cervical HPV. No history of recurrent sinopulmonary, gastrointestinal or cutaneous infection, autoimmune disorder or malignancy. Medications included cervical imiquimod (TLR-7 agonist), oral fluconazole, intranasal fluticasone, and cetirizine. PMH: Mild intermittent asthma, allergic rhinoconjuctivitis. Rare fevers, no systemic symptoms.. Conclusion: Patients with disseminated coccidioidomycosis may have deficient cellular immunity. ICL is a diagnosis of exclusion, therefore detailed evaluation for secondary causes of lymphocytopenia should be sought in all patients. This patient has persistently decreased CD4+ T lymphocytes in the absence of other etiologies consistent with a diagnosis of ICL. The management and pathogenesis of ICL are not well defined and require further research. References: 1. Gholamin et al. Idiopathic lymphocytopenia. Curr Opin Hematol 2015, 22: Augustine R et al. Idiopathic CD4+ T-lymphocytopenia – a diagnostic dilemma. JAPI 2010; 58: Ahmad et al. Idiopathic CD4 lymphocytopenia: spectrum of opportunistic infections, malignancies, and autoimmune diseases. Avicenna J Med 2013; 3: Galgiana, J. Inhibition of different phases of coccidioides immitis by human neutrophils or hydrogen peroxide. Journal of Infectious Diseases 1986; 153: Vinh D. et al. Refractory disseminated coccidioidomycosis and mycobacteriosis in interferon- γ receptor 1 deficiency. Clin Infect Dis 2009; 49: Zonios D et al. Idiopathic CD4+ lymphocytopenia: a natural history and prognostic factors. Blood 2008; 112: Brass, D. et al. Investigating an incidental finding of lymphopenia. BMJ 2014; 348: Table 1. Significant laboratory values LabValue White blood cell count2800 cells/μL Absolute lymphocyte count400 cells/μL Absolute CD4+23 cells/μL Absolute CD8+46 cells/μL HIV viral load and antibody levelUndetectable NK cell count and function103 cells/μL, depressed function Lymphocyte antigen and mitogen proliferation panel Absent response to Candida Adenosine deaminase833 mU/g T cell gene rearrangementNegative Leukemia/lymphoma panelNK cell predominance suggestive of NK-cell lymphoproliferative disorder Bone marrow biopsyNo evidence of malignancy Discussion: Coccidioidomycosis is a dimorphic fungus endemic to the Southwestern United States. Immune deficiencies reported in association with coccidioidomycosis include HIV, chronic granulomatous disease, IFN γ receptor 1 deficiency, as well as immune suppressing medications and solid organ transplantation. Clinical Course: Notable labs seen in Table 1 Quantitative immunoglobulins, anti-pneumococcal IgG titers, complement levels, neutrophil oxidase burst, were within normal limits. Secondary causes of lymphocytopenia (Table 2) were eliminated by history or laboratory evaluation. Patient was started on prophylactic trimethoprim-sulfamethoxazole and azithromycin. Continued on lifelong fluconazole for coccidioidomycosis meningitis One year follow up without new infection. Table 2. Secondary causes of lymphocytopenia InfectionMedicationSystemic disorder HIV-1 and HIV-2GlucocorticoidsAutoimmune disorder TuberculosisCytotoxic chemotherapy (carboplatin, paclitaxel) Malignancy Hepatitis B/C, EBV, CMV, HHV-6, influenza Radiation therapyPostoperative state Human T-lymphotropic virus (HTLV)-1 and HTLV-2 OpioidsSevere malnutrition Bacterial or fungal sepsisAzathioprine, methotrexateAlcohol abuse Parasitic infectionRituximabCardiac or Renal failure Idiopathic CD4 Lymphopenia (ICL) Clinical manifestations: Spectrum of clinical phenotypes ranging from recurrent or severe opportunistic infections (OI) to mild or asymptomatic disease (6%). Likely due to multiple genetic loci and molecular heterogeneity. 87% patients had one OI and 33% had multiple OI. Most commonly Cryptococcus; Cryptococcal meningitis which is postulated to be pathognomonic for ICL. Mycobacterium, Candida, Varicella Zoster and HPV also frequent. Increased risk of autoimmune disorder and lymphoproliferative disorders. Lymphoma and squamous cell carcinoma of the skin most prevalent. Important to distinguish infection as a causative agent of lymphocytopenia from lymphocytopenia manifesting as infection. Immunologic mechanisms proposed in pathogenesis: STAT phosphorylation reduced in CD4+ T cells IL-7α R expression decreased IL-2 responsiveness and IL-2 R expression reduced IL-7 serum levels increased Suppressed LCK activity resulting in defects in proliferation Lack of expression of CXCL12 CD4+ antibodies IFNγ function may be abnormal Prognosis of ICL: Dependent on severity of immune suppression and resulting infections and comorbidities. CD4+ levels stabilize over time rather than steadily decline as seen in HIV. Concurrent CD8+ lymphocytopenia was associated with opportunistic infection-related death. Treatment: No standard treatment. Antimicrobial prophylaxis similar to protocols for HIV infection. IL-2 causes lymphocyte proliferation; when used with antimicrobial therapy, prolonged the infection-free period. Other therapies include IFNγ in combination with IL-2, IL-7, lenalidomide, anti-thymocyte globulin, bone marrow transplantation. Figure 1. Hematoxylin and eosin stain of Coccidioidomycosis spherule. Figure 2. Coccidioidomycosis in environmental form


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