1. JLF Kock

2. Overview Introduction Immunopathogenesis Risk factors for IRIS Diagnosis Treatment Review

3. Introduction 25 % of patients initiated on early Antiretroviral treatment( 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 CD 4 (<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.

4. 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.

5. 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.

6. 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-1- infected patients - worsened Mycobacterium avium intracellulare( MAC) infection early during ART.

7. 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)

8. 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 non- IRIS groups. Some cases of paradoxical TB-IRIS were not characterized by Th1-cell expansions.

9. 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.

10. 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.

11. 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.

12. Dysregulated cytokine release Elevation of both effector and regulatory cytokines – 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.

13. 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 TB- IRIS case; predominantly CD68+ macrophages in lung tissue.

14. Innate response cont. Tan et al., TLR2 was found to be expressed at higher 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.

15. Conclusion of Immunopathogenesis Intricate and interconnected network of both innate and adaptive immunity is involved.

16. 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.

17. 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).

18. Diagnosis

19. 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.

20. 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.

22. 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.

23. 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).

24. 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).

25. Corticosteroids Rich, R.R., et al. Glucocorticoids. Clinical Immunology. Fourth edition. Elsevier. 2013. 1066 -1076

26. PREVENTION Possible to avoid IRIS by treating identified OI prior to initiation of HAART. Reduce a high burden of organisms.

27. 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

28. Thank you