**4. Pathogenesis of the immune reconstitution inflammatory syndrome**

The Immune Reconstitution Inflammatory Syndrome (IRIS) is an uncommon inflammatory response encountered in those cases of severe immunosuppression in which the rapid adminis‐ tration of specific treatment abruptly restores the immune response. The HIV infection is the most frequent cause of immunodeficiency predisposing to IRIS. In addition TB is the most commonopportunisticinfectionrelatedtoHIV-associatedIRIS.Theantiretroviralandantituber‐ culous treatments rapidly restore the immune response. Such a rapid treatment response may sometimes leadtoanaggressivelymphoproliferativereactionandmassivereleaseofproinflam‐ matory cytokines. There are 2 clinical presentations of IRIS known as the paradoxical IRIS and unmasking IRIS. IRIS manifestations in HIV patients with NTB follow two possible scenarios:

**a.** A paradoxical reaction emerging in patients with NTB correctly diagnosed and appro‐ priately treated in which HIV infection is subsequently detected and also treated but new severe neurological manifestations arise during treatment (paradoxical NeuroIRIS-TB).

TB from IRIS-TB. Other studies have also investigated different profiles of immunological markers which could aid in the above distinction. Conradie et al. have identified a profile of makers including IL8, active NK cells, C reactive protein and lymphocyte count that is related to unmasking IRIS-TB. This profile could be further used in the differential diagnosis

Neurotuberculosis and HIV Infection http://dx.doi.org/10.5772/54631 299

**5. Etiological data on the mycobacterial strains in HIV/TB co-infection**

HIV patients are frequently infected by virulent strains of M.tbc. The virulence of a particular strain depends on the genetic composition of M.tbc. Thus the Beijing genotype of M.tbc mostly found in Asia is considered the most aggressive genotype and has been associated with CSF dissemination and multidrug resistance to antituberculous agents in HIV patients [56]. Infections with M. bovis are rare and occur mostly in HIV Hispanic patients. Despite the high environmental exposure to nontuberculous mycobacteria CNS involvement is rare even in AIDS patients and usually occurs at a CD4+ count under 10 cells/mm3. The pathogenic mechanisms behind the interactions established between the host and virulent mycobacteria are less documented. The infection with Mycobacterium avium complex (MAC) remains the most studied and most frequent nontuberculous mycobacteria accounting for the atypical tuberculous manifestations in the advanced stages of AIDS infection [57]. The Mycobacterium avium intracellulare (MAI) serotypes 4 and 8 are the most prevalent in AIDS patients [58].

Sporadic cases of NTB with other mycobacteria have also been recorded in AIDS patients following disseminated infection [59]. MAC is an ubiquitary environmental mycobacteria which colonizes the gastrointestinal and respiratory tract but is also able to invade the epithelial cells and the intestinal wall [60]. Virulent strains isolated from AIDS patients are able to penetrate the mucosal barriers and resist intracellular killing by macrophages resulting in a disseminated infection. Further studies on the interaction between M. avium and the HIVinfected cells confirmed the inhibition of several cytokines secreted by the Th1 CD4+cells, natural killer cells and macrophages.These ultimately favour the intracellular survival of M. avium and even accelerate its growth rate [61,62]. The neurologic involvement due to MAC in advanced stages of AIDS generally presents as TBM following a disseminated infection with prolonged bacteremia [63-66]. The comparative aspects of the CNS invasions with M.tbc and

NTB is frequent in HIV patients compared with non-HIV patients. Reactivation of latent forms of TB is accelerated in HIV patients with a 10% annual risk of progression to active infection compared with 10-20% lifetime risk of developing TB in non-HIV patients. Literature data is contradictory as to the role of HIV on the clinical presentation or evolution of NTB. Although some studies found significant differences between HIV and non-HIV NTB [67-69] others

nontuberculous mycobacteria in HIV hosts are presented in table 1

**6. Clinical data on NTB in HIV patients**

of the 2 manifestations or as a prediction of unmasking IRIS-TB [55].

**b.** An unmasking reaction appears in patients with HIV and latent unknown NTB in which the successful antiretroviral treatment unexpectedly induces neurological manifestations of TB (unmasked NeuroIRIS-TB)

TheneurologicmanifestationofIRIS-TBare rare (19%ofthe total cases)butwithamortalityrisk that is three times higher than other IRIS localisations [42]. The specific features related to NeuroIRIS-TB reside in the excessive CNS inflammatory reactions generated by the activation of microglia. The excessive inflammatory response is linked to the abundance of mycobacteri‐ al antigens and their high immunogenicity. Various studies have approached the immunolog‐ ic mechanisms and risk factors for IRIS in HIV-TB patients.

The observations below on the pathogenesis of IRIS-TB were selected according to the potential clinical application.


TB from IRIS-TB. Other studies have also investigated different profiles of immunological markers which could aid in the above distinction. Conradie et al. have identified a profile of makers including IL8, active NK cells, C reactive protein and lymphocyte count that is related to unmasking IRIS-TB. This profile could be further used in the differential diagnosis of the 2 manifestations or as a prediction of unmasking IRIS-TB [55].
