title: Two patients with cryptococcal meningitis and idiopathic CD4 lymphopenia: defective cytokine production and reversal by recombinant interferon- gamma therapy.
abstract: BACKGROUND
  Although Cryptococcus neoformans is a fungal pathogen that causes human disease predominantly in the immunocompromised host, severe cryptococcal infections are occasionally encountered in apparently immunocompetent individuals. Activation of cellular immunity by proinflammatory cytokines plays a central role in anticryptococcal defense.
  
  
  METHODS
  We describe 2 patients with severe cryptococcal meningitis who appeared to have idiopathic CD4 lymphopenia. For these patients and for 4 healthy volunteers, ex vivo stimulation of whole blood with microbial stimuli was used to investigate putative defects in cytokine production capacity.
  
  
  RESULTS
  Assessment of the cytokine released from the 2 patients with CD4 lymphopenia revealed a defective production of the proinflammatory cytokines interferon (IFN)- gamma and tumor necrosis factor (TNF) but not of the anti-inflammatory cytokine interleukin-10 (IL-10). One patient with disease progression despite receipt of antifungal treatment was administered immunotherapy with recombinant IFN- gamma . Administration of recombinant IFN- gamma resulted in both restoration of immunological parameters and a sustained clinical recovery.
  
  
  CONCLUSIONS
  Refractory meningitis may be due to defective TNF and IFN- gamma production, and IFN- gamma treatment may be useful in patients with an impaired cellular immune response and refractory cryptococcal meningitis.
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen University Center for Infectious Diseases, Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Annemarie E
authors.initials: AE
authors.lastname: Brouwer
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Hoogendoorn
authors.forename: Jos W M
authors.initials: JW
authors.lastname: Van der Meer
authors.forename: Marianne
authors.initials: M
authors.lastname: Koolen
authors.forename: Paul E
authors.initials: PE
authors.lastname: Verweij
authors.forename: Bart Jan
authors.initials: BJ
authors.lastname: Kullberg
mesh_terms: D000328:Adult; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000627:therapeutic use*; D008297:Male; D016919:Meningitis, Cryptococcal / Q000150:complications* / Q000188:drug therapy* / Q000276:immunology; D008875:Middle Aged; D011994:Recombinant Proteins; D018344:T-Lymphocytopenia, Idiopathic CD4-Positive / Q000150:complications* / Q000188:drug therapy* / Q000276:immunology; D013997:Time Factors
chemical_list: D016207:Cytokines; D011994:Recombinant Proteins; D007371:Interferon-gamma