Immune Restoration Syndrome in Tuberculosis and HIV Co-Infection
Objectives: To test the hypothesis that an acute exacerbation of mycobacteria-specific Th1 response after HIV infection control by HAART causes immune restoration syndrome (IRS) in HIV-tuberculosis (TB) coinfected patients.
Design: Prospective, multicenter study of 19 consecutive untreated HIV-TB coinfected patients included when initiating antimycobacterial therapy and sequentially evaluated during HAART and at time of IRS. IRS was defined according to classical clinical diagnostic criteria. Patients were declared IRS- if no IRS occurred within 3 months after HAART initiation.
Methods: Mycobacteria-specific [purified protein derivative (PPD), ESAT-6, 85B] Th1 cells producing interferon (IFN)-γ quantified by ELISpot, in vitro production of 25 cytokines/chemokines in antigen-stimulated peripheral blood mononuclear cell (PBMC) supernatants quantified by chemiluminescence.
Results: Seven patients (37%) experienced IRS (IRS+). Mycobacteria-specific (PPD) Th1 IFN-γ-producing cells increased sharply during IRS (median, 2970 spot forming cells/10 PBMC), but not the cytomegalovirus-specific responses tested as control. Only three IRS+ patients had low ESAT-6- but no 85B-specific responses. IRS- patients did not develop acute PPD-specific responses except in one case. In addition, at time of IRS a peak of PPD-specific Th1 cytokines/chemokines [interleukin (IL)-2, IL-12, IFN-γ, IP10 and monokine-induced by IFN-γ] without Th2 cytokines, and a peak of non-specific inflammatory cytokines/chemokines (TNF-α, IL-6, IL-1β, IL-10, RANTES and MCP-1) occurred. These findings were independent from CD4 cell count, viral loads or time of HAART initiation.
Conclusion: An acute exacerbation of Th1 responses against mycobacterial antigens appears to cause IRS in patients co-infected with HIV and TB. This key event provides new evidence valuable for the diagnosis and treatment of IRS.
First described in HIV-infected patients with Mycobacterium avium complex infection receiving zidovudine monotherapy, immune restoration syndrome (IRS) in patients suffering from tuberculosis (TB) became extremely frequent (29-36%) with the HAART era. Classically, IRS occurs in patients co-infected with TB and HIV, naive of HAART, with advanced HIV disease, when both therapies are initiated simultaneously or at a short interval. Usually, clinical symptoms include fever, lymphadenopathy, worsening of respiratory and other initial TB symptoms. Major criteria defining IRS have been proposed whatever the underlying opportunistic event, including an atypical presentation of opportunistic infection (OI) or tumours in patients responding to HAART (decrease in plasma HIV RNA level more than 1 log10 copies/ml), without any alternative explanation (drug resistance, other OI) and with evidence for immune restoration, as minor criteria. However IRS raises three clinically relevant issues: first, diagnosis is difficult as IRS should be distinguished from treatment failure or resistance or other opportunistic diseases; second, IRS treatment in some life-threatening cases is still empirically based on steroids, which are uneasy to introduce in such immunocompromised patients; third, determination of IRS risk factors could help clinicians to determine their therapeutic strategy, i.e., delaying or not HAART introduction.
The pathophysiology of IRS is not yet totally elucidated. Acute proinflammatory cytokine [interleukin (IL)-6] production has been demonstrated during IRS but its source remains unknown. In addition, a strong and dominant hypothesis is that IRS would be associated with restoration of mycobacteria-specific T-lymphocyte response with either recirculation or proliferation of memory T cells after HAART has reduced the plasma viral load (VL). This hypothesis is only suggested but not yet demonstrated, except for the restoration of delayed-type hypersensitivity (DTH) skin test to purified protein derivative (PPD).
To determine whether IRS is due to an acute restoration of a Th1 TB-specific response that causes its characteristic major inflammatory syndrome we conducted a prospective multicenter study of patients co-infected with HIV and TB. We describe our preliminary results here.
Abstract and Introduction
Abstract
Objectives: To test the hypothesis that an acute exacerbation of mycobacteria-specific Th1 response after HIV infection control by HAART causes immune restoration syndrome (IRS) in HIV-tuberculosis (TB) coinfected patients.
Design: Prospective, multicenter study of 19 consecutive untreated HIV-TB coinfected patients included when initiating antimycobacterial therapy and sequentially evaluated during HAART and at time of IRS. IRS was defined according to classical clinical diagnostic criteria. Patients were declared IRS- if no IRS occurred within 3 months after HAART initiation.
Methods: Mycobacteria-specific [purified protein derivative (PPD), ESAT-6, 85B] Th1 cells producing interferon (IFN)-γ quantified by ELISpot, in vitro production of 25 cytokines/chemokines in antigen-stimulated peripheral blood mononuclear cell (PBMC) supernatants quantified by chemiluminescence.
Results: Seven patients (37%) experienced IRS (IRS+). Mycobacteria-specific (PPD) Th1 IFN-γ-producing cells increased sharply during IRS (median, 2970 spot forming cells/10 PBMC), but not the cytomegalovirus-specific responses tested as control. Only three IRS+ patients had low ESAT-6- but no 85B-specific responses. IRS- patients did not develop acute PPD-specific responses except in one case. In addition, at time of IRS a peak of PPD-specific Th1 cytokines/chemokines [interleukin (IL)-2, IL-12, IFN-γ, IP10 and monokine-induced by IFN-γ] without Th2 cytokines, and a peak of non-specific inflammatory cytokines/chemokines (TNF-α, IL-6, IL-1β, IL-10, RANTES and MCP-1) occurred. These findings were independent from CD4 cell count, viral loads or time of HAART initiation.
Conclusion: An acute exacerbation of Th1 responses against mycobacterial antigens appears to cause IRS in patients co-infected with HIV and TB. This key event provides new evidence valuable for the diagnosis and treatment of IRS.
Introduction
First described in HIV-infected patients with Mycobacterium avium complex infection receiving zidovudine monotherapy, immune restoration syndrome (IRS) in patients suffering from tuberculosis (TB) became extremely frequent (29-36%) with the HAART era. Classically, IRS occurs in patients co-infected with TB and HIV, naive of HAART, with advanced HIV disease, when both therapies are initiated simultaneously or at a short interval. Usually, clinical symptoms include fever, lymphadenopathy, worsening of respiratory and other initial TB symptoms. Major criteria defining IRS have been proposed whatever the underlying opportunistic event, including an atypical presentation of opportunistic infection (OI) or tumours in patients responding to HAART (decrease in plasma HIV RNA level more than 1 log10 copies/ml), without any alternative explanation (drug resistance, other OI) and with evidence for immune restoration, as minor criteria. However IRS raises three clinically relevant issues: first, diagnosis is difficult as IRS should be distinguished from treatment failure or resistance or other opportunistic diseases; second, IRS treatment in some life-threatening cases is still empirically based on steroids, which are uneasy to introduce in such immunocompromised patients; third, determination of IRS risk factors could help clinicians to determine their therapeutic strategy, i.e., delaying or not HAART introduction.
The pathophysiology of IRS is not yet totally elucidated. Acute proinflammatory cytokine [interleukin (IL)-6] production has been demonstrated during IRS but its source remains unknown. In addition, a strong and dominant hypothesis is that IRS would be associated with restoration of mycobacteria-specific T-lymphocyte response with either recirculation or proliferation of memory T cells after HAART has reduced the plasma viral load (VL). This hypothesis is only suggested but not yet demonstrated, except for the restoration of delayed-type hypersensitivity (DTH) skin test to purified protein derivative (PPD).
To determine whether IRS is due to an acute restoration of a Th1 TB-specific response that causes its characteristic major inflammatory syndrome we conducted a prospective multicenter study of patients co-infected with HIV and TB. We describe our preliminary results here.
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