Abstract # 584: A novel case of idiopathic CD4 lymphopenia presenting with disseminated coccidioidomycosis

Ashish K. Mathur, MD; Tara F. Carr, MDUniversity of Arizona Medical Center, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Tucson, AZ

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, 22:46-52. 2. Augustine R et al. Idiopathic CD4+ T-lymphocytopenia – a diagnostic dilemma. JAPI 2010; 58:45-47. 3. Ahmad et al. Idiopathic CD4 lymphocytopenia: spectrum of opportunistic infections, malignancies, and autoimmune diseases. Avicenna J Med 2013; 3:37-47. 4. Galgiana, J. Inhibition of different phases of coccidioides immitis by human neutrophils or hydrogen peroxide. Journal of Infectious Diseases 1986; 153: 217-222. 5. Vinh D. et al. Refractory disseminated coccidioidomycosis and mycobacteriosis in interferon- γ receptor 1 deficiency. Clin Infect Dis 2009; 49: 62-65. 6. Zonios D et al. Idiopathic CD4+ lymphocytopenia: a natural history and prognostic factors. Blood 2008; 112: 287-94. 7. Brass, D. et al. Investigating an incidental finding of lymphopenia. BMJ 2014; 348: 1721.

Table 1. Significant laboratory values

Lab Value

White blood cell count 2800 cells/μL

Absolute lymphocyte count 400 cells/μL

Absolute CD4+ 23 cells/μL

Absolute CD8+ 46 cells/μL

HIV viral load and antibody level Undetectable

NK cell count and function 103 cells/μL, depressed function

Lymphocyte antigen and mitogen proliferation panel

Absent response to Candida

Adenosine deaminase 833 mU/g

T cell gene rearrangement Negative

Leukemia/lymphoma panel NK cell predominance suggestive of NK-cell lymphoproliferative disorder

Bone marrow biopsy No 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 Infection Medication Systemic disorder

HIV-1 and HIV-2 Glucocorticoids Autoimmune disorder

Tuberculosis Cytotoxic chemotherapy (carboplatin, paclitaxel)

Malignancy

Hepatitis B/C, EBV, CMV, HHV-6, influenza

Radiation therapy Postoperative state

Human T-lymphotropic virus (HTLV)-1 and HTLV-2

Opioids Severe malnutrition

Bacterial or fungal sepsis Azathioprine, methotrexate Alcohol abuse

Parasitic infection Rituximab Cardiac 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