The clinical benefit of adjunctive dexamethasone in tuberculous meningitis is not associated with measurable attenuation of peripheral or local immune responses.
Outcome from tuberculous meningitis (TBM) is believed to be dependent on the severity of the intracerebral inflammatory response. We have recently shown that dexamethasone improved survival in adults with TBM and postulated that the clinical effect would be associated with a measurable systemic and intracerebral impact on immunological markers of inflammation. Prolonged inflammatory responses were detected in all TBM patients irrespective of treatment assignment (placebo or dexamethasone). The inflammatory response in the cerebrospinal fluid was characterized by a leukocytosis (predominantly CD3(+)CD4(+) T lymphocytes, phenotypically distinct from those in the peripheral blood), elevated concentrations of inflammatory and anti-inflammatory cytokines, chemokines, and evidence of prolonged blood-brain barrier dysfunction. Dexamethasone significantly modulated acute cerebrospinal fluid protein concentrations and marginally reduced IFN-gamma concentrations; other immunological and routine biochemical indices of inflammation were unaffected. Peripheral blood monocyte and T cell responses to Mycobacterium tuberculosis Ags were also unaffected. Dexamethasone does not appear to improve survival from TBM by attenuating immunological mediators of inflammation in the subarachnoid space or by suppressing peripheral T cell responses to mycobacterial Ags. These findings challenge previously held theories of corticosteroid action in this disease. An understanding of how dexamethasone acts in TBM may suggest novel and more effective treatment strategies.
Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. csimmons@hcm.vnn.vn
Cameron P
CP
Simmons
Guy E
GE
Thwaites
Nguyen Than Ha
NT
Quyen
Tran Thi Hong
TT
Chau
Pham Phuong
PP
Mai
Nguyen Thi
NT
Dung
Kasia
K
Stepniewska
Nicholas J
NJ
White
Tran Tinh
TT
Hien
Jeremy
J
Farrar
D000293:Adolescent; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000942:Antigens, Bacterial / Q000008:administration & dosage; D018925:Chemokines / Q000134:cerebrospinal fluid; D017024:Chemotherapy, Adjuvant; D016207:Cytokines / Q000134:cerebrospinal fluid; D003907:Dexamethasone / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology; D014390:Tuberculosis, Meningeal / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000276:immunology*
D000893:Anti-Inflammatory Agents; D000942:Antigens, Bacterial; D018925:Chemokines; D016207:Cytokines; D003907:Dexamethasone; D007371:Interferon-gamma