Transcript Louis Kock - National Resource for TB Infection Control

JLF Kock
Overview
 Introduction
 Immunopathogenesis
 Risk factors for IRIS
 Diagnosis
 Treatment
 Review
Introduction
 25 % of patients initiated on early Antiretroviral treatment(
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ART) experience deterioration due to Immune Response
Inflammatory Syndrome( IRIS).
Onset is usually within 6 weeks of ART initiation, sometimes
several months later (depends on type of IRIS, up to 12 months).
IRIS is most frequently described in association with
mycobacterial, fungal or viral infections( Mycobacterium
tuberculosis( 30% of cases), M. avium complex, CMV(37.7%),
Cryptococcus(19.5%), PCP, Leishmaniasis, HSV, VZV, HBV, HCV,
JCV, HHV-8).
50% of IRIS cases needs hospitalisation and puts a burden on
Health systems, regarding diagnosis and treatment.
Typically appears in patients with initial low CD4 (<50) and a
rapid decrease in viral load.
Meintjes, G; et al. Management of the Immune Reconstitution Inflammatory
Syndrome. Curr HIV/AIDS Rep (2012) 9:238–250.
Introduction cont.
 Common Sx :
 Fever, localized lymphadenopathy/lymphadenitis, abscess,
pneumonia, CNS disease, hepatitis, dermatological
manifestations.
 Atypical presentation :
 granulomatous lymphadenopathy without mycobacterium,
CMV vitritis, Progressive Multifocal Leukoencephalopathy(
PML) : enhanced CNS lesions, Cryptococcus : marked CSF
leucocytosis.
 Autoimmune diseases can be exacerbated – sarcoidosis( >12
months), Grave’s disease.
 Malignancy’s - Kaposi’s sarcoma and non-Hodgkin’s
lymphoma.
Immunopathogenesis
 1/3 of the world’s population - latently infected by
tuberculosis (TB), of which 5–10% will develop active
disease.
 11 million who were estimated to be dually infected
with TB and HIV-1, 79% resides in Africa.
 Increased accessibility to ART has significantly
improved the clinical outcome of HIV-1-infected
patients and reduced the TB risk by 58–80%.
 Mortality of tuberculosis-associated IRIS (TB-IRIS) is
3.2%.
Lai, R.P.J., et al. The immunopathogenesis of the HIV tuberculosis immune
reconstitution inflammatory syndrome. Eur. J. Immunol. 2013. 43: 1995–2002.
Immunopathogenesis cont.
 IRIS - temporary inflammation and immunopathology
directed to opportunistic pathogens shortly after
commencing ART.
 French et al. in 1992 first described IRIS in HIV-1infected patients - worsened Mycobacterium avium
intracellulare( MAC) infection early during ART.
Immunopathogenesis cont.
 IFN-γ-producing Th1 cell numbers increase sharply
during paradoxical TB-IRIS after commencing ART.
 Also found to have increased levels of interleukin (IL)2, IL-12, IFN-γ, IP-10 and MIG.
 Th2 cytokines (IL-4, IL-5, IL-13, and IL-15), were below
detection level.
 Peak of nonspecific inflammatory
cytokines/chemokine’s (tumour necrosis factor (TNF),
IL-6, IL-1β, IL-10, RANTES, and MCP-1)
Immunopathogenesis cont.
 Study by Meintjes et al. showed that IFN-γ-secreting T
cells showed similar patterns of expansion and
contraction in both the paradoxical TB-IRIS and nonIRIS groups.
 Some cases of paradoxical TB-IRIS were not
characterized by Th1-cell expansions.
Immunopathogenesis cont.
 Question whether Th1-cell expansions are truly causal
in paradoxical TB-IRIS?
 Tieu et al. and Elliott et al. IGRA based tests. Found
that paradoxical TB-IRIS cases did not show
differential IFN-γ responses in comparison with
controls up to 24 weeks after ART initiation.
 But a rapid increase in mycobacteria specific IFN-γ T
cells were found in post-ART unmasking TB.
Immunopathogenesis cont.
 Antonelli et al. reported an increased expression of
PD1 on both CD4+ and CD8+ T cells and higher levels
of HLA-DR+ CD4+ T cells in IRIS patients - high
antigen load that may stimulate an activated
phenotype.
 Elevated, Th1/Th17 production of IFN-γ, and other
cytokines/chemokine’s.
 CD4+ T cells have a significant contribution to IRIS
pathogenesis, is a consequence, not the cause, of the
syndrome.
Immunopathogenesis cont.
 Hypothesis is that the regulation of Th1-cell expansion
is in some way defective in TB-IRIS.
 Meintjes et al. didn’t find evidence of this in their
study.
Dysregulated cytokine release
 Elevation of both effector and regulatory cytokines –
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proportional to Ag load.
Increased levels of IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p40,
IFN-γ, GM-CSF and TNF in paradoxical TB-IRIS.
IL-17, IL-18, and IL-22 have also been noted to be elevated
in both paradoxical and unmasking TB-IRIS.
IL-17 and IL-22 produced by innate cells(e.g. lymphoid
tissue inducer/like cells,Th17,NKT cells).
IL-18 is secreted by macrophages and dendritic cells.
IL-17, IL-18 and IL-22 in TB-IRIS - dysregulated
inflammatory response - contribution of innate immunity
to TB-IRIS.
Innate responses in TB-IRIS
 Elements of the innate immune system implicated
include pattern recognition receptors (PRRs),
monocytes/macrophages, dendritic cells (DCs),
neutrophils, and natural killer (NK) cells.
 Van der Berg et al. suggested that ART might also
restore previously dysfunctional or
immunosuppressed macrophages, lead to
hyperactivation of macrophages.
 Lawn et al. – Demostrated in a fatal unmasking TBIRIS case; predominantly CD68+ macrophages in lung
tissue.
Innate response cont.
 Tan et al. , TLR2 was found to be expressed at higher
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levels in both paradoxical and unmasking TB-IRIS
patients.
Higher NK cells activity and neutrophils levels,
unmasking TB-IRIS.
NK-cell degranulation activity were higher in
paradoxical TB-IRIS.
Recent evidence indicates that neutrophils may
contribute to the pathogenesis of TB-IRIS( TBM).
High TNF and low IFN-γ at TBM diagnosis predicted
TBM-IRIS.
Conclusion of
Immunopathogenesis
 Intricate and interconnected network of both innate
and adaptive immunity is involved.
Risk factors for IRIS
 Fungal infection.
 Higher level of viremia at baseline and the degree of
viral decline on ART.
 Low-baseline CD4+ T-cell count (<50–100 cells/μL)
who respond favourably to ART with a significant
increase in CD4+ T cells
 Short-time interval between the initiation of TB
treatment and starting ART.
Risk factors for IRIS cont.
 Dissemination of TB to extra pulmonary sites, which
poses a significantly higher risk (eightfold in one
study) of developing TB-IRIS,
 Early initiation of ART or timing of ART was not
associated with IRIS( CAMELIA study).
Diagnosis
Diagnosis cont.
 Unmasking IRIS
 the diagnosis involves using conventional diagnostic
tests to diagnose the underlying Opportunistic
Infections.
 ART-associated inflammatory manifestation of a
subclinical infection with an accelerated presentation.
Diagnosis cont.
 Paradoxical IRIS :
 improvement of OI symptoms on OI treatment prior to
ART;
 deterioration with features of the OI soon after starting
ART;
 demonstration of a CD4 and/or HIV viral load response
to ART where feasible;
 exclusion of alternative causes for deterioration.
Diagnosis cont.
 Usually presents within 6 weeks after initiation of ART,
can be within a few months.
 Rising in CD4 and decline in HIV viral load.
 Differential diagnosis : new opportunistic infection,
malignancy(e.g. lymphoma), treatment failure for
opportunistic infection and drug toxicity.
Diagnosis cont..
 Half of IRIS cases require hospitalization.
 Mortality associated with IRIS varies according to the
underlying Opportunistic Infection( Central nervous
system, which accounts for 12% of all TB-IRIS cases
and has a mortality rate of up to 30%).
 Certain cases IRIS only diagnosis of exclusion( e.g. new
infiltrates on CXR).
Treatment
 Continue ART, except if inflammatory response is life
threatening.
 Anti-inflammatory treatment - NSAID
 Response to corticosteroids is usually rapid.
 Other anti-inflammatory or immunomodulatory drugs
: thalidomide, pentoxifylline, tocilizumab,
hydroxychloroquine, montelukast, maraviroc(
CADIRIS trial), aspirin, statins and monoclonal Ab(
CNS TB-IRIS).
Corticosteroids
Rich, R.R., et al. Glucocorticoids. Clinical Immunology. Fourth edition. Elsevier. 2013.
1066 -1076
PREVENTION
 Possible to avoid IRIS by treating identified OI prior to
initiation of HAART.
 Reduce a high burden of organisms.
Review
 Immunopathogenesis
 25 % of patients deteriorate after ART initiation.
 Onset is usually within 6 weeks of ART initiation.
 Mortality associated with IRIS varies according to the
underlying Opportunistic Infection and area affected(
3,2%).
 Unmasking IRIS/Paradoxical IRIS
 Risk factors
 Treatment
Thank you