Efficacy and Safety of Thalidomide in Patients with Complicated Central Nervous System Tuberculosis: A Systematic Review and Meta-Analysis

Abstract

Thalidomide, an anti-inflammatory and immunomodulatory agent, has a potential role in cases with central nervous system tuberculosis (CNS-TB) with paradoxical reactions. Although several articles have described the use of thalidomide in CNS-TB, no systematic review has been performed in this regard. Different electronic databases were searched for articles describing the use of thalidomide in patients with CNS-TB. For determining pooled estimates in the quantitative review, studies with a minimum sample size of 5 were only considered, whereas for qualitative synthesis even single case reports were included. Fixed or random effect models were used suitably depending on the degree of heterogeneity. Fourteen articles describing a total of 107 patients (98 children and 9 adults) were selected from 156 records. A favorable clinical response was observed in 89% of patients with CNS-TB who had paradoxical reactions refractory to corticosteroids. Majority of the studies used a dose of 2–6 mg/kg/day and around 24% suffered from at least one adverse effect, with a mortality of 5%. Predominant adverse effects were rash (9.5%), neuropathy (6%), and elevated liver transaminases (9.5%). Only one placebo-controlled trial has been performed till now, which showed that high-dose thalidomide has numerous adverse effects, without any clinically significant improvement as compared with placebo. While in HIV-positive patients with TB-immune reconstitution inflammatory syndrome thalidomide was helpful in around 82% of cases. Low-dose thalidomide is helpful in patients with CNS-TB who had a paradoxical reaction and unresponsive to corticosteroids. Large, randomized trials are needed to provide more concrete information regarding the safety and efficacy of thalidomide.

Thalidomide for Recurrence of Symptoms following HIV-Associated Cryptococcal Meningitis

“…There were no reports of serious adverse events (SAEs) or treatment discontinuation attributable to thalidomide treatment. Peripheral neuropathy was not noted in this study, possibly due to the small sample size and lower dosage of thalidomide compared with the literature [ 5 ]. No matter how, compared with metabolic, osteoarticular, infectious, adrenal, gastrointestinal, ophthalmological, and neuropsychiatric manifestations with prolonged corticosteroid use, the adverse events described in this study seem to be minimal and acceptable [ 12 ].…”

“…Our analysis included patients with HIV/CM who met the following inclusion criteria: (1) HIV diagnosis was made by a positive western blot HIV antibody test and/or a serum HIV viral load of no less than 5000 copies/mL; (2) CM diagnosis was based on Indian ink staining or culture with the cerebrospinal fluid (CSF); (3) HIV and CM were treated according to the guideline [ 5 ]; (4) patients experienced new or worsening symptoms after antiretroviral therapy (ART) initiation; and (5) culture for Cryptococcus neoformans was negative with the CSF at the time of recurrence. Patients were excluded if they met the following criteria: (1) thalidomide usage since the inductive period of CM; (2) patients who never visited after thalidomide treatment; (3) other etiologies of central nervous system infection; or (4) patients who were already recovering with corticosteroids taper therapy.…”

“…Thalidomide is currently used to treat multiple myeloma in combination with dexamethasone, and is also used to treat autoimmune diseases, such as severe skin lesions caused by leprosy. Recently, it was investigated for symptom relief of immune reconstitution syndrome in tuberculous meningitis [ 5 ]. Thalidomide was reported to alleviate paradoxical IRIS in three cases of HIV/CM, potential through antagonistic effect against TNF-α [ 6 , 7 ].…”

Successful rescue TNF-α blocking for Mycobacterium genavense – Related immune reconstitution inflammatory syndrome: A case report

“…For instance, those pleiotropic properties of thalidomide are used as a controversial therapeutic approach to reduce the symptoms of IRIS. In a meta-analysis including 98 children and nine adults, Panda et al had a clinical response rate of 89 % in patients treated with thalidomide for corticosteroids refractory paradoxical reaction related to CNS-TB [ 34 ]. However, a randomized controlled trial conducted by Schoeman et al in children with tuberculous meningitis found no difference in motor outcome between patients who received high dose of thalidomide plus standard-of-care and patients who were treated by placebo in addition to standard-of-care [ 35 ].…”

The advances in adjuvant therapy for tuberculosis with immunoregulatory compounds

“…A cohort study from South Africa showed that thalidomide was safe, well tolerated, and had a modest clinical effect in patients with central nervous system TB-related complications ( Van Toorn et al, 2021b ). However, another review showed that thalidomide had no significant clinical improvement in patients with central nervous system TB compared to the control group and had numerous adverse reactions, while it appeared to be effective in HIV-positive patients with TB-immune reconstitution inflammatory syndrome ( Panda et al, 2021 ). In conclusion, it is important to note that thalidomide can cause severe teratogenic effects and should be used with caution in clinical trials.…”