Treatment associated inflammatory deterioration in tuberculous meningitis: unpicking the paradox

Ever since the advent of anti-tuberculosis chemotherapy in the late 1940s, physicians have recognized that in some patients the symptoms and signs of tuberculosis worsen after the start of treatment. These clinical manifestations have been called ‘paradoxical reactions’, because they occur despite effective anti-microbial therapy. Their pathogenesis is poorly understood, but they are broadly considered to be caused by excessive inflammation to dead and dying bacteria [1]. Paradoxical reactions are observed to occur more frequently in those with lymph node and disseminated tuberculosis and in those co-infected with HIV [2]. However, paradoxical reactions that occur in HIV co-infected individuals recently started on antiretroviral therapy (ART) have acquired a different moniker: immune reconstitution inflammatory syndrome (IRIS) [3]. IRIS reactions are more common in individuals with very low peripheral blood CT4+ T-cell counts and high plasma HIV loads, who are started on ART shortly after anti-tuberculosis chemotherapy. Despite the fundamental importance of ART to IRIS, paradoxical reactions and IRIS share many similarities.Both are paradoxical, in that they occur in the face of effective anti-microbial (and antiretroviral) treatment; both are believed to be the result of excessive inflammation; and both cause serious clinical consequences when they involve the brain in association with tuberculous meningitis (TBM).