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Macrophage Chemotactic Protein Levels in Cerebrospinal Fluid of Patients with AIDS-associated PML Treated with HAART Favorably Correlate with Patients Survival
A Marzocchetti*1, A Cingolani1, S Di Giambenedetto1, M L Giancola2, A Antinori2, and A De Luca1
1Inst. di Clinica delle Malattie Infettive, Catholic Univ. of Sacro Cuore, Rome, Italy and 2Inst. Natl. delle Malattie Infettive, IRCCS "Lazzaro Spallanzani'', Rome, Italy
Background: Despite improved survival with HAART, prognosis of AIDS-associated progressive
multifocal leukoencephalopathy remains poor; cases of progressive multifocal
leukoencephalopathy have been discribed on HAART, some showing features of
immune reconstitution syndrome. Others have shown a beneficial effect of
inflammatory reactions. Aim of this study was to determine whether
cerebrospinal fluid (CSF) levels of cytokines involved in inflammatory
reactions/immune responses, relate to the prognosis of AIDS-assiciated progressive
multifocal leukoencephalopathy.
Methods: We
selected HIV+ patients with confirmed progressive multifocal
leukoencephalopathy, exposed to HAART, and HIV+ controls matched for
CD4 counts. JCV DNA levels were
determined in CSF by PCR, TNF-a, MCP-1, RANTES, and IFN-g were quantified in CSF by EIA.
Neurological evolution was determined by standardized examination. Differences
were analysed by Student's t test, correlations by Pearson’s analysis;
predictors of neurological evolution by logistic regression, survival analysis
by Cox's regression.
Results: We
studied 44 patients (32 with progressive multifocal leukoencephalopathy and 12
controls): median age 37 years, 70% male,
median CD4 50 cells/mm3, JCV DNA
in CSF 3.30 log copies/mL, HIV RNA in plasma 4.14 log, and CSF 2.97 log. Median
CSF concentrations of TNFa were
45 pg/mL, MCP-1360 pg/mL, RANTES 88 pg/mL, IFN-g 8 pg/mL. MCP-1 was significantly
higher in progressive multifocal leukoencephalopathy patients than in controls
(p <0.0001), while TNF-a was lower in progressive multifocal
leukoencephalopathy than in controls (p
= 0.022). Higher TNF-a levels in progressive
multifocal leukoencephalopathy were associated with lower CD4 counts <100 (p = 0.012). In progressive multifocal
leukoencephalopathy patients, there was a trend towards a negative linear
correlation between CSF concentration of RANTES and HIV RNA (r = -0.47, p = 0.12) and a positive correlation between MCP-1 and HIV RNA (r = 0.41, p = 0.08). MCP-1 and TNF-a were positively correlated (r = 0.53,
p = 0.025) and both were also
correlated with the time of prior HAART exposure (TNF-a: r = 0.80,
p = 0.03; MCP-1: r = 0.59, p = 0.10).
Predictors of reduced hazard of death were CD4>100 (p = 0.06), lower JCV DNA
concentrations (p = 0.005), higher
Karnofky (p = 0.013) and prior HAART
exposure (p = 0.05). In subjects with
progressive multifocal leukoencephalopathy and CD4<100, higher levels of
MCP-1, but not other cytokines, were associated with longer survival (for each
log increase, HR for death = 0.27; (95% CI 0.08 to 0.96). Multivariate analysis
confirmed the association of MCP-1 with longer survival. Cytokine levels did
not predict the neurological evolution at 8 weeks.
Conclusions: AIDS-related progressive multifocal leukoencephalopathy was associated with
increased levels of MCP-1 in the CSF especially after exposure to HAART. High
MCP-1 levels correlated favorably with survival.
Keywords: PML; CYTOKINES; AIDS
