Correspondence www.thelancet.com/infection Vol 13 November 2013 915 patients with pulmonary tuberculosis recover uneventfully without major complications with multidrug treatment. The most important finding is that not one patient died in four of the five trials that assessed the effects of steroids in pulmonary tuberculosis in the era of multidrug treatment. 1 The only trial that did report deaths included only patients with HIV who received high doses of glucocorticoids. 3 Predictors of mortality in patients with HIV and tuberculosis differ from those in patients with tuberculosis without HIV. Moreover, the biological mechanisms of beneficial effect of corticosteroids in tuberculous meningitis and pericarditis are poorly understood. The possibility of increased risks of emergence of drug resistance in the era of multidrug- resistant tuberculosis, coexistent HIV infection, and immunosuppression leading to disease progression with co- administration of steroids to patients with pulmonary tuberculosis need to be carefully considered before doing further research. We declare that we have no conflicts of interest. *Karan Madan, Shyam Sunder Yadav, Naveet Wig, Randeep Guleria drkaranmadan@gmail.com Department of Pulmonary Medicine and Sleep Disorders (KM, SSY, RG) and Department of Medicine (NW), All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India 1 Critchley JA, Young F, Orton L, Garner P. Corticosteroids for prevention of mortality in people with tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2013; 13: 223–37. 2 Kadhiravan T, Deepanjali S. Role of corticosteroids in the treatment of tuberculosis: An evidence-based update. Indian J Chest Dis Allied Sci 2010; 52: 153–58. 3 Mayanja-Kizza H, Jones-Lopez E, Okwear A, et al. Immunoadjuvant prednisolone therapy for HIV-associated tuberculosis: a phase 2 clinical trial in Uganda. J Infect Dis 2005; 191: 856–65. Corticosteroids for prevention of tuberculosis mortality We read with keen interest the meta-analysis by Julia Critchley and colleagues, 1 and we would like to emphasise some important issues. The only populations in which clinical trials of corticosteroids have shown improved outcomes in tuberculosis are HIV-seronegative patients with tuberculous meningitis and tuberculous pericarditis. 1 Evidence supporting use of corticosteroids in other clinical situations is poor. However, Critchley and colleagues 1 conclude that corticosteroids could be effective in reducing mortality in all forms of tuberculosis, including pulmonary tuberculosis. The overall results in this meta-analysis are weighted in favour of glucocorticoids because of the primary benefit noted with tuberculous meningitis, and not with pulmonary tuberculosis. To consider the results of all these forms of tuberculosis together and to conclude that the effect on mortality might be consistent across the range of the disease is inappropriate, especially in the context of the developing nations, which account for most global tuberculosis burden. In these countries, the results of the meta-analysis could be misinterpreted by physicians managing patients with tuberculosis. The results also have global implications in view of WHO tuberculosis strategy, which does not recommend steroids for pulmonary and pleural tuberculosis. Complications in tuberculous meningitis occur predominantly as a result of the inflammatory response, which can be associated with long- term neurological sequelae due to hydrocephalus, arachnoiditis, and vasculitic infarcts. Also, a high risk of death and disability exists in tubeculous meningitis despite combination chemotherapy regimens. 2 Therefore, use of anti-inflammatory drugs such as corticosteroids seems logical. By contrast, more than 95% of The timely meta-analysis brought out by Julia Critchley and colleagues 1 has far reaching implications for the role of steroids in the treatment of tuberculosis. The effect of steroids has long been deemed to be organ-specific with beneficial effects in only some types of extrapulmonary tuberculosis such as tubercular meningitis. By contrast, increased risk of reactivation of pulmonary tuberculosis has been noted in patients taking steroids. 2 The mechanism of action of steroids against tuberculosis has been attributed to their anti-inflammatory effect. However, this association has not been proven in studies that included patients with tubercular meningitis. In addition to the genetic variation of LTA4H locus mentioned by the authors, 1 we suggest inhibition of expression of matrix metalloproteinase 9 (MMP 9) as a possible mechanism of steroid action on tuberculosis of all organ systems. MMP 9 disrupts the blood–brain barrier, which increases the severity of tubercular meningitis through as yet unknown mechanisms. Results have shown steroids to reduce MMP 9 concentrations in cerebrospinal fluid, 3 thereby reducing the severity of tuberculosis. The role of MMP 9 in the patho- genesis of pulmonary tuberculosis is similarly linked to the disruption of lung extracellular matrix, leading to early dissemination of Myobacterium tuberculosis. Also, MMP 9 has been implicated in macrophage recruitment in granuloma formation in pulmonary tuberculosis. 4 Doxycycline, an MMP inhibitor, has shown promise as a possible treatment of tuberculosis due to its inhibition of mycobacterial growth in animal and in-vitro models of disease. 5 Our understanding of the patho- genesis of tuberculosis becomes increasingly important because of its implications for improvement of tuberculosis treatment. We declare that we have no conflicts of interest. *Maya Gopalakrishnan, Suman Saurabh maya.gopalakrishnan@gmail.com Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantri Nagar, Puducherry 605006, India (MG, SS) 1 Critchley JA, Young F, Orton L, Garner P. Corticosteroids for prevention of mortality in people with tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2013; 13: 223–37.