Tumor necrosis factor antagonists for paradoxical inflammatory reactions in the central nervous system tuberculosis: Case report and review

Rationale: Paradoxical reaction/immune reconstitution inflammatory syndrome is common in patients with central nervous system tuberculosis. Management relies on high-dose corticosteroids and surgery when feasible. Patient concern: We describe 2 cases of HIV-negative patients with corticosteroid-refractory paradoxical reactions of central nervous system tuberculosis. Diagnoses: The 2 patients experienced clinical impairment shortly after starting therapy for TB, and magnetic resonance imaging showed the presence of tuberculomas, leading to the diagnosis of a paradoxical reaction. Interventions: We added infliximab, an anti-tumor necrosis factor (TNF)-alpha monoclonal antibody, to the dexamethasone. Outcomes: Both patients had favorable outcomes, 1 achieving full recovery but 1 suffering neurologic sequelae. Lessons: Clinicians should be aware of the risk of paradoxical reactions/immune reconstitution inflammatory syndrome when treating patients with tuberculosis of the central nervous system and should consider the prompt anti-TNF-α agents in cases not responding to corticosteroids

Reversions of QuantiFERON-TB Gold Plus in tuberculosis contact investigation: A prospective multicentre cohort study

Background: Interferon-y Release Assays (IGRA) reversions have been reported in different clinical scenarios for the diagnosis of tuberculosis (TB) infection. This study aimed to determine the rate of QuantiFERON-TB Gold Plus (QFT-Plus) reversions during contact investigation as a potential strategy to reduce the number of preventive treatments. Methods: Prospective, multicentre cohort study of immunocompetent adult contacts of patients with pulmonary TB tested with QFT-Plus. Contacts with an initial positive QFT-Plus (QFT-i) underwent a second test within 4 weeks (QFT-1), and if negative, underwent a repeat test 4 weeks later (QFT-2). Based on the QFT-2 result, we classified cases as sustained reversion if they remained negative and as temporary reversion if they turned positive. Results: We included 415 contacts, of whom 96 (23.1%) had an initial positive test (QFT-i). Following this, 10 had negative QFT-1 results and 4 (4.2%) of these persisted with a negative result in the QFT-2 (sustained reversions). All four sustained reversions occurred in contacts with IFN-γ concentrations between ≥0.35 and ≤0.99 IU•mL-1 in one or both QFT-i tubes. Conclusion: In this study, TB contact investigations rarely reveal QFT-Plus reversion. These results do not support retesting cases with an initial positive result to reduce the number of preventive treatments

Identification of recent tuberculosis exposure using QuantiFERON-TB Gold Plus, a multicenter study.

We investigated whether the difference of antigen tube 2 (TB2) minus antigen tube 1 (TB1) (TB22TB1) of the QuantiFERON-TB gold plus test, which has been postulated as a surrogate for the CD81 T-cell response, could be useful in identifying recent tuberculosis (TB) exposure. We looked at the interferon gamma (IFN-g) responses and differences in TB2 and TB1 tubes for 686 adults with QFT-plus positive test results. These results were compared among groups with high (368 TB contacts), low (229 patients with immune-mediated inflammatory diseases [IMID]), and indeterminate (89 asylum seekers or people from abroad [ASPFA]) risks of recent TB exposure. A TB22TB1 value .0.6 IU ml21 was deemed to indicate a true difference between tubes. In the whole cohort, 13.6%, 10.9%, and 11.2% of cases had a TB2.TB1 result in the contact, IMID, and ASPFA groups, respectively (P = 0.591). The adjusted odds ratios (aORs) for an association between a TB22TB1 result of .0.6 IU ml21 and risk of recent exposure versus contacts were 0.71 (95% confidence interval [CI], 0.31 to 1.61) for the IMID group and 0.86 (95% CI, 0.49 to 1.52) for the ASPFA group. In TB contact subgroups, 11.4%, 5.4%, and 17.7% with close, frequent, and sporadic contact had a TB2.TB1 result (P = 0.362). The aORs versus the close subgroup were 1.29 (95% CI, 0.63 to 2.62) for the frequent subgroup and 1.55 (95% CI, 0.67 to 3.60) for the sporadic subgroup. A TB22TB1 difference of .0.6 IU ml21 was not associated with increased risk of recent TB exposure, which puts into question the clinical potential as a proxy marker for recently acquired TB infection

Análogos de hormonas tiroideas con acciones tiromiméticas en el sistema nervioso central en condiciones de deficiencia del transportador de monocarboxilatos Mct8

Resumen del póster presentado a la XI Reunión Anual CIBERER, celebrada en Castelldefels, Barcelona del 12 al 14 de marzo de 2018.El síndrome de Allan-Herndon-Dudley (SAHD, ORPHA:59) se asocia a mutaciones en el transportador de monocarboxilatos 8 (MCT8), una proteína de membrana que transporta específicamente hormonas tiroideas (HTs). La deficiencia de MCT8 conduce a un retraso psicomotor profundo con niveles anormales de HTs en plasma, con baja tiroxina (T4) y elevada triyodotironina (T3). Numerosas evidencias indican que las graves alteraciones neurológicas se deben a un transporte deficiente de HTs a través de las barreras cerebrales, produciendo un hipotiroidismo cerebral. Existen tratamientos para normalizar el hipertiroidismo periférico, pero ninguno ha sido efectivo para el síndrome neurológico. Nuestro objetivo ha sido explorar posibles terapias farmacológicas efectivas para el SAHD. Para ello hemos realizado estudios preclínicos con modelos animales en los que se ha evaluado la capacidad que tienen distintos análogos de HTs, administrados sistémicamente, de acceder al cerebro y de ejercer acciones tiromiméticas en las células neurales en ausencia del transportador Mct8. También se ha evaluado el efecto de estos análogos en tejidos periféricos. Los resultados en ratones muestran que en ausencia de Mct8 los análogos administrados pueden acceder al cerebro y allí ejercer acciones a nivel genómico modulando la expresión de genes dependientes de T3. A nivel periférico estos análogos no tienen efecto en corazón y corrigen el hipertiroidismo, aunque disminuyendo considerablemente los niveles de T3 y T4 en suero. Nuestros estudios indican que éstos análogos pueden ser beneficiosos para paliar las alteraciones neurológicas de pacientes con SAHD, y que se deberían hacer más estudios para comprender sus mecanismos de acción.Peer Reviewe

Searching for strategies to overcome the lack of MCT8 in the brain

Trabajo presentado en el MCT8 2018 Symposium in Memory of Theo Visser, celebrado en Doorn (Países Bajos) del 10 al 11 de septiembre de 2018

Sobetirome and its amide prodrug Sob-AM2 exert thyromimetic actions in Mct8-deficient brain

[Background]: Loss of function mutations in the thyroid hormone (TH)-specific cell membrane transporter, the monocarboxylate transporter 8 (MCT8), lead to profound psychomotor retardation and abnormal TH serum levels, with low thyroxine (T4) and high triiodothyronine (T3). Several studies point to impaired TH transport across brain barriers as a crucial pathophysiological mechanism resulting in cerebral hypothyroidism. Treatment options for MCT8-deficient patients are limited and are focused on overcoming the brain barriers. The aim of this study was to evaluate the ability of the TH analog sobetirome and its prodrug Sob-AM2 to access the brain and exert thyromimetic actions in the absence of Mct8.[Methods]: Juvenile wild-type (Wt) mice and mice lacking Mct8 and deiodinase type 2 (Mct8/Dio2KO) were treated systemically with daily injections of vehicle, 1 mg of sobetirome/kg body weight/day, or 0.3 mg of SobAM2/kg body weight/day for seven days. Sobetirome content was measured using liquid chromatography–tandem mass spectrometry, and T4 and T3 levels by specific radioimmunoassays. The effect of sobetirome treatment in the expression of T3-dependent genes was measured in the heart, liver, and cerebral cortex by realtime polymerase chain reaction.[Results]: Sob-AM2 treatment in Mct8/Dio2KO animals led to 1.8-fold more sobetirome content in the brain and 2.5-fold less in plasma in comparison to the treatment with the parent drug sobetirome. Both sobetirome and Sob-AM2 treatments in Mct8/Dio2KO mice greatly decreased plasma T4 and T3 levels. Dio1 and Ucp2 gene expression was altered in the liver of Mct8/Dio2KO mice and was not affected by the treatments. In the heart, Hcn2 but not Atp2a2 expression was increased after treatment with the analogs. Interestingly, both sobetirome and Sob-AM2 treatments increased the expression of several T3-dependent genes in the brain such as Hr, Abcd2, Mme, and Flywch2 in Mct8/Dio2KO mice.[Conclusions]: Sobetirome and its amide prodrug Sob-AM2 can access the brain in the absence of Mct8 and exert thyromimetic actions modulating the expression of T3-dependent genes. At the peripheral level, the administration of these TH analogs results in the depletion of circulating T4 and T3. Therefore, sobetirome and Sob-AM2 have the potential to address the cerebral hypothyroidism and the peripheral hyperthyroidism characteristic of MCT8 deficiency.This work was supported by the Spanish Ministry of Economy Industry and Competitiveness (SAF2014-54919-R and SAF2017-86342-R to A.G.F.), the Sherman Foundation (OTR02211 to A.G.F.), and the National Institutes of Health (DK52798 to T.S.S. and 2T32DK007680-21 to M.D.H.), and the National Multiple Sclerosis Society (FG 2023A 1/2 to M.D.H.). The cost of this publication has been paid in part by FEDER funds.Peer reviewe

Searching for strategies to overcome the lack of MCT8 in the brain

Trabajo presentado al 13th International Workshop on Resistance to Thyroid Hormone, celebrado en Doorn (Netherlands) del 11 al 14 de septiembre de 2018.Peer Reviewe

Reversions of QuantiFERON-TB Gold Plus in tuberculosis contact investigation: A prospective multicentre cohort study

Background Interferon-y Release Assays (IGRA) reversions have been reported in different clinical scenarios for the diagnosis of tuberculosis (TB) infection. This study aimed to determine the rate of QuantiFERON-TB Gold Plus (QFT-Plus) reversions during contact investigation as a potential strategy to reduce the number of preventive treatments. Methods Prospective, multicentre cohort study of immunocompetent adult contacts of patients with pulmonary TB tested with QFT-Plus. Contacts with an initial positive QFT-Plus (QFT-i) underwent a second test within 4 weeks (QFT-1), and if negative, underwent a repeat test 4 weeks later (QFT-2). Based on the QFT-2 result, we classified cases as sustained reversion if they remained negative and as temporary reversion if they turned positive. Results We included 415 contacts, of whom 96 (23.1%) had an initial positive test (QFT-i). Following this, 10 had negative QFT-1 results and 4 (4.2%) of these persisted with a negative result in the QFT-2 (sustained reversions). All four sustained reversions occurred in contacts with IFN-γ concentrations between ≥0.35 and ≤0.99 IU•mL-1 in one or both QFT-i tubes. Conclusion In this study, TB contact investigations rarely reveal QFT-Plus reversion. These results do not support retesting cases with an initial positive result to reduce the number of preventive treatments