2.4.1. The Role of Corticosteroids in TB Treatment

It sounds counterintuitive to address the problem of active TB with anti-inflammatory drugs. However, for some clinical manifestations of the diseases, reduction of inflammation by using adjunctive corticosteroids has already become a well-established and lifesaving treatment approach. Addition of dexamethasone or prednisolone, two potent corticosteroids, to the antibiotic regimen for treatment of TB meningitis improves survival and is considered as a valid therapeutic approach for TB affecting the central nervous system (CNS) [69], although care should be taken since individual responses to steroid treatment might differ. Several studies have tried to improve the outcome of pulmonary TB by lowering the inflammatory response using high doses of corticosteroids in combination with antibiotics. While it was found that this therapy leads to faster resolution of symptoms and lesions in radiographic examinations and a more rapid discharge from hospitals, a statistically significant survival benefit could not be shown (Table 1) [70–72]. In addition, high dose corticosteroids may result in serious side effects such as diabetes and psychiatric symptoms. Today, corticosteroids remain the treatment of choice in specific clinical situations such as CNS TB or hyperinflammatory syndromes e.g., the immune reconstitution inflammatory syndrome (IRIS) in HIV/TB co-infected patients. Investigations at the molecular level proved that dysregulation of inflammasome signaling and of secretion of various cytokines, including IL-1γ, was associated with TB-IRIS in patients infected by HIV [73,74], thus supporting the inclusion of corticosteroids in the treatment of TB patients at risk of developing IRIS [75]. Despite these evidences, a broader application of the drugs in TB treatment is currently not justified. However, clinical studies as well as ex vivo and in vivo experiments performed with these substances indicate that a more specific or tailored modification of the TB inflammatory response may provide a suitable approach to improve patient outcomes. Understanding the exact mechanism of action of corticosteroids in TB may help overcome this hurdle. Corticosteroids are broadly immunosuppressive drugs with multiple modulatory effects on leukocytes once bound to the main target, the corticosteroid receptor. Downstream effects include repression of pro-inflammatory transcriptional regulators like NF-κB as well as impaired release of cytokines such as TNFα and IL-1 [76]. In addition, corticosteroids such as dexamethasone seem to have an *M. tuberculosis* specific inhibitory effect on necrotic host cell death in vitro [77]. This effect seems to depend on inhibition of p38 MAP kinase which impairs

mitochondrial membrane stability upon infection with *M. tuberculosis*. p38 MAP kinase is activated during *M. tuberculosis* infection in vitro and in vivo and represents a possible host directed target with several clinically tested small molecule inhibitors available for repurposing.
