Opportunistic Infections in Patients with Idiopathic CD4 T Lymphocytopenia

Opportunistic Infections in Patients with Idiopathic CD4 (+) T lymphocytopenia (ICL) : Two Case Reports CIS Summer School Neeti Gupta, MD Allergy/Immunology Fellow PGY-5 Case Report # 1 A 37 year-old female with past medical history significant for bipolar disorder, Hashimoto's thyroiditis, and neurodermatitis admitted for management of recurrent Cryptococcal meningitis, with associated headaches and nausea. Testing confirmed low CD4 & CD8 counts (47 and 75, respectively) with a CD4/CD8 ratio=0.62; a repeat CD4 count was 7. However, tests for HIV 1/2, HTLV 1/2 were negative. CMV, EBV, Lyme disease, and syphilis tests were also negative. Case Report # 1 (continued) Immunoglobulin levels were normal (pre & post vaccination S. Pneumococcus); diptheria/tetanus titers were normal. Immunophenotyping by flow cytometry showed 10% of T-cells without expression of CD2, CD4, or CD8 markers. Bone marrow examination and imaging did not reveal malignancy Lesion on the L5 pedicle biopsied and revealed a cryptococcoma. The patient was managed on antifungal antibiotics, and eventually discharged in stable condition. She is currently in stable condition and a subsequent CD4 count remained low. Case Report # 2 A 38 year-old African American wheelchair bound male presents with chest pain, a non-productive cough, and shortness of breath for 8 days. He was seen by his primary care physician and given Azithromycin for 5 days without any response. CXR showed diffuse bilateral infiltrates, and a subsequent bronchoscopy revealed Pneumocystis jerovici. Pertinent laboratory data revealed low CD4 & CD8 counts (55 and 400, respectively) with a CD4/CD8 ratio=0.13. The total WBC count was 6.5, with a total T cell count of 154, and a total B cell count of 215 (normal). Case Report # 2 (continued) HIV 1/2 antibody tests were negative, and HIV PCR was negative x 2. The patient had an adequate B cell response to Pneumovax vaccine T cell response to PHA, Pokeweed, Con A was absent. There was also no T cell response to Candida or Tetanus antigens. The patient was treated with Sulfamethoxazole/Trimethoprim with good response. Background The most common cause of CD4 (+) T-cell depletion in the U.S., unrelated to immunosuppressive treatment, is HIV infection. Patients with CD (+) T lymphocytopenia in the The Centers for Disease Control and Prevention (CDC) have termed this syndrome: idiopathic CD4 (+) T-lymphocytopenia (ICL). Diagnosis (as defined by the CDC) CD4 (+) T-lymphocyte depletion (absolute CD4 count < 300 per cubic millimeter, or <20% of total T cells) On more than one occasion at least 6 weeks apart Absence of serologic or viral evidence of HIV-1/2 or HTLV-1/2 infections, defined immunodeficiency, or therapy associated with lymphocytopenia In original survey of 47 ICL patients: no bias in sex, age at diagnosis (43 +/- 14 years), only few familial cases, & no indication of sexual transmission (NEJM 328: 373-379, 1993) Immunologic Phenotype ICL differs from AIDS as per analysis of case reports (NEJM 328: 380-385, 1993) Low/absent observed steady decline in CD4(+) cells Immunologic phenotyping: less pronounced decrease of CD8(+) cells, slightly decreased CD4:CD8 ratio, & normal B cell numbers Hypergammoglobulinemia rarely present Long-term follow-up of case reports suggest that disease course may be more benign Cause unlikely to be HIV-related retrovirus based on lack of specific antibodies, infectious virus, and HIV DNA However, reverse transcriptase (RT) activity in cultures of 2 patients with ICL (Laurence et. al. 1992); also detected RT activity in culture from 1 patient with visualization of envelopedefective noninfectious viral particle by electron-microscopical analysis Pathogenesis Diminished generation of T cell precursors Bone marrow of analysis of 5 ICL patients w/↓ CD34+CD38-DR+ hematopoietic stem cells Decreased clonogenic capacity of bone marrow precursors (similar to CVID patients w/low CD4 counts) Disturbed cytokine milieu perhaps, hindering differentiation Increased TNF-α and decreased IL-2 Increased IL-7 (master regulator of T cell homeostasis) as compensatory mechanism Restricted oligoclonal T cell repertoire Decreased CD45RA+ naïve T cells w/relative expansion of CD45RO+ memory T cells Accelerated apoptosis especially of CD45RO+ Again, decreased IL-2 Strategies to increase CD4 lymphocytes IL-2 therapy to increase CD4 counts Early increase in CD45RO memory, followed by increase in CD45RA CD4 T cells Ultimate benefit in terms of infections unknown) Case report of association with MALT lymphoma Case report: Recombinant IFN-γ resulting in sustained clinical recovery from Cryptococcus Bone marrow transplantation for concomitant aplastic anemia with restoration of immune function Conclusion Therapy of underlying conditions, treatment, & prophylaxis of secondary complications, especially opportunistic infections Optimal treatment Remains to be defined Same principles as AIDS patients Prophylaxis against pneumocystosis for CD4(+) <200 Cryptococcosis as well as relapsing multisegmental herpes infection: secondary lifetime prophylaxis Women screened for cervical neoplasia every 6 months Appropriate prophylaxis & treatment for HBV, HCV & HAV Live vaccines contraindicated; dead vaccines can be given without predictable protective effect Cannot predict clinical course based on laboratory markers Natural course of disease unknown for this heterogeneous disorder Limited cases, though more reported in recent years — CDC Surveillance