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Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D3 as host directed therapy.

ABSTRACT: BACKGROUND:We have previously shown that 8 weeks' treatment with phenylbutyrate (PBA) (500mgx2/day) with or without vitamin D3 (vitD3) (5000 IU/day) as host-directed therapy (HDT) accelerated clinical recovery, sputum culture conversion and increased expression of cathelicidin LL-37 by immune cells in a randomized, placebo-controlled trial in adults with pulmonary tuberculosis (TB). In this study we further aimed to examine whether HDT with PBA and vitD3 promoted clinically beneficial immunomodulation to improve treatment outcomes in TB patients. METHODS:Cytokine concentration was measured in supernatants of peripheral blood mononuclear cells (PBMC) from patients (n?=?31/group). Endoplasmic reticulum stress-related genes (GADD34 and XBP1spl) and human beta-defensin-1 (HBD1) gene expression were studied in monocyte-derived-macrophages (MDM) (n =?18/group) from PBMC of patients. Autophagy in MDM (n =?6/group) was evaluated using LC3 expression by confocal microscopy. RESULTS:A significant decline in the concentration of cytokines/chemokines was noted from week 0 to 8 in the PBA-group [TNF-? (??=?-?0.34, 95% CI?=?-?0.68, -?0.003; p?=?0.04), CCL11 (??=?-?0.19, 95% CI?=?-?0.36, -?0.03; p?=?0.02) and CCL5 (??=?-?0.08, 95% CI?=?-?0.16, 0.002; p?=?0.05)] and vitD3-group [(CCL11 (??=?-?0.17, 95% CI?=?-?0.34, -?0.001; p?=?0.04), CXCL10 (??=?-?0.38, 95% CI?=?-?0.77, 0.003; p?=?0.05) and PDGF-? (??=?-?0.16, 95% CI?=?-?0.31, 0.002; p?=?0.05)] compared to placebo. Both PBA- and vitD3-groups showed a decline in XBP1spl mRNA on week 8 (p?

SUBMITTER: Rekha RS

PROVIDER: S-EPMC6033279 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D<sub>3</sub> as host directed therapy.

Rekha Rokeya Sultana RS Mily Akhirunnesa A Sultana Tajnin T Haq Ahsanul A Ahmed Sultan S Mostafa Kamal S M SM van Schadewijk Annemarie A Hiemstra Pieter S PS Gudmundsson Gudmundur H GH Agerberth Birgitta B Raqib Rubhana R

BMC infectious diseases 20180704 1

<h4>Background</h4>We have previously shown that 8 weeks' treatment with phenylbutyrate (PBA) (500mgx2/day) with or without vitamin D<sub>3</sub> (vitD<sub>3</sub>) (5000 IU/day) as host-directed therapy (HDT) accelerated clinical recovery, sputum culture conversion and increased expression of cathelicidin LL-37 by immune cells in a randomized, placebo-controlled trial in adults with pulmonary tuberculosis (TB). In this study we further aimed to examine whether HDT with PBA and vitD<sub>3</sub> ...[more]

PMID: 29973153

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Project description:BACKGROUNDMatrix metalloproteinases (MMPs) are key regulators of tissue destruction in tuberculosis (TB) and may be targets for host-directed therapy. We conducted a phase II double-blind, randomized, controlled trial investigating doxycycline, a licensed broad-spectrum MMP inhibitor, in patients with pulmonary TB.METHODSThirty patients with pulmonary TB were enrolled within 7 days of initiating anti-TB treatment and randomly assigned to receive either 100 mg doxycycline or placebo twice a day for 14 days, in addition to standard care.RESULTSWhole blood RNA-sequencing demonstrated that doxycycline accelerated restoration of dysregulated gene expression in TB towards normality, rapidly down-regulating type I and II interferon and innate immune response genes, and up-regulating B-cell modules relative to placebo. The effects persisted for 6 weeks after doxycycline discontinuation, concurrent with suppressed plasma MMP-1. Doxycycline significantly reduced sputum MMP-1, -8, -9, -12 and -13, suppressed type I collagen and elastin destruction, reduced pulmonary cavity volume without altering sputum mycobacterial loads, and was safe.CONCLUSIONAdjunctive doxycycline with standard anti-TB treatment suppressed pathological MMPs in PTB patients. Larger studies on adjunctive doxycycline to limit TB immunopathology are merited.TRIAL REGISTRATIONClinicalTrials.gov NCT02774993.FUNDINGSingapore National Medical Research Council (NMRC/CNIG/1120/2014, NMRC/Seedfunding/0010/2014, NMRC/CISSP/2015/009a); the Singapore Infectious Diseases Initiative (SIDI/2013/013); National University Health System (PFFR-28 January 14, NUHSRO/2014/039/BSL3-SeedFunding/Jul/01); the Singapore Immunology Network Immunomonitoring platform (BMRC/IAF/311006, H16/99/b0/011, NRF2017_SISFP09); an ExxonMobil Research Fellowship, NUHS Clinician Scientist Program (NMRC/TA/0042/2015, CSAINV17nov014); the UK Medical Research Council (MR/P023754/1, MR/N006631/1); a NUS Postdoctoral Fellowship (NUHSRO/2017/073/PDF/03); The Royal Society Challenge Grant (CHG\R1\170084); the Sir Henry Dale Fellowship, Wellcome Trust (109377/Z/15/Z); and A*STAR.

Project description:BackgroundDevelopment of new tuberculosis (TB) drugs and alternative treatment strategies are urgently required to control the global spread of TB. Previous results have shown that vitamin D3 (vitD3) and 4-phenyl butyrate (PBA) are potent inducers of the host defense peptide LL-37 that possess anti-mycobacterial effects.ObjectiveTo examine if oral adjunctive therapy with 5,000IU vitD3 or 2x500 mg PBA or PBA+vitD3 to standard chemotherapy would lead to enhanced recovery in sputum smear-positive pulmonary TB patients.MethodsAdult TB patients (n = 288) were enrolled in a randomized, double-blind, placebo-controlled trial conducted in Bangladesh. Primary endpoints included proportions of patients with a negative sputum culture at week 4 and reduction in clinical symptoms at week 8. Clinical assessments and sputum smear microscopy were performed weekly up to week 4, fortnightly up to week 12 and at week 24; TB culture was performed at week 0, 4 and 8; concentrations of LL-37 in cells, 25-hydroxyvitamin D3 (25(OH)D3) in plasma and ex vivo bactericidal function of monocyte-derived macrophages (MDM) were determined at week 0, 4, 8, 12 and additionally at week 24 for plasma 25(OH)D3.ResultsAt week 4, 71% (46/65) of the patients in the PBA+vitD3-group (p = 0.001) and 61.3% (38/62) in the vitD3-group (p = 0.032) were culture negative compared to 42.2% (27/64) in the placebo-group. The odds of sputum culture being negative at week 4 was 3.42 times higher in the PBA+vitD3-group (p = 0.001) and 2.2 times higher in vitD3-group (p = 0.032) compared to placebo. The concentration of LL-37 in MDM was significantly higher in the PBA-group compared to placebo at week 12 (p = 0.034). Decline in intracellular Mtb growth in MDM was earlier in the PBA-group compared to placebo (log rank 11.38, p = 0.01).ConclusionAdjunct therapy with PBA+vitD3 or vitD3 or PBA to standard short-course therapy demonstrated beneficial effects towards clinical recovery and holds potential for host-directed-therapy in the treatment of TB.Trial registrationclinicaltrials.gov NCT01580007.

Project description:BackgroundTuberculosis (TB) is one of the leading causes of death worldwide. Radiology has an important role in the diagnosis of both drug-sensitive (DS) and rifampicin-resistant (RR) pulmonary TB (PTB). This study aimed to compare the chest x-ray (CXR) patterns of microbiologically confirmed DS and RR PTB cases stratified by HIV serostatus in Uganda.MethodsWe conducted a hospital-based retrospective study at the Mulago National Referral Hospital (MNRH) TB wards. All participants had a microbiologically confirmed diagnosis of PTB. CXR findings extracted included infiltrates, consolidation, cavity, fibrosis, bronchiectasis, atelectasis, and other non-lung parenchymal findings. All films were examined by two independent radiologists blinded to the clinical diagnosis.ResultsWe analyzed CXR findings of 165 participants: 139 DS- and 26 RR-TB cases. The majority (n = 118, 71.7%) of the participants were seronegative for HIV. Overall, 5/165 (3%) participants had normal CXR. There was no statistically significant difference in the proportion of participants with consolidations (74.8% versus 88.5%; p = 0.203), bronchopneumonic opacities (56.1% versus 42.3%, p = 0.207) and cavities (38.1% versus 46.2%, p = 0.514), across drug susceptibility status (DS versus RR TB). Among HIV-infected participants, consolidations were predominantly in the middle lung zone in the DS TB group and in the lower lung zone in the RR TB group (42.5% versus 12.8%, p = 0.66). HIV-infected participants with RR TB had statistically significantly larger cavity sizes compared to their HIV uninfected counterparts with RR TB (7.7 ± 6.8 cm versus 4.2 ± 1.3 cm, p = 0.004).ConclusionsWe observed that a vast majority of participants had similar CXR changes, irrespective of drug susceptibility status. However, HIV-infected RR PTB had larger cavities.The diagnostic utility of cavity sizes for the differentiation of HIV-infected and non-infected RR TB could be investigated further.

Project description:Background The immunomodulatory effects of vitamin D are widely recognized and a few studies have been conducted to determine its utility in the treatment of tuberculosis, with mixed results. This study was conducted to see if vitamin D supplementation in patients with active pulmonary tuberculosis (PTB) in the Indian population contributed to sputum smear and culture conversion as well as the prevention of relapse. Methods This randomized double-blind placebo-controlled trial was conducted in three sites in India. HIV negative participants aged 15–60 years with sputum smear positive PTB were recruited according to the Revised National Tuberculosis Control Program guidelines and were randomly assigned (1:1) to receive standard anti-tubercular treatment (ATT) with either supplemental dose of oral vitamin D3 (60,000 IU/sachet weekly for first two months, fortnightly for next four months followed by monthly for the next 18 months) or placebo with same schedule. The primary outcome was relapse of PTB and secondary outcomes were time to conversion of sputum smear and sputum culture. Results A total of 846 participants were enrolled between February 1, 2017 to February 27, 2021, and randomly assigned to receive either 60,000 IU vitamin D3 (n = 424) or placebo (n = 422) along with standard ATT. Among the 697 who were cured of PTB, relapse occurred in 14 participants from the vitamin D group and 19 participants from the placebo group (hazard risk ratio 0.68, 95%CI 0.34 to 1.37, log rank p value 0.29). Similarly, no statistically significant difference was seen in time to sputum smear and sputum culture conversion between both groups. Five patients died each in vitamin D and placebo groups, but none of the deaths were attributable to the study intervention. Serum levels of vitamin D were significantly raised in the vitamin D group as compared to the placebo group, with other blood parameters not showing any significant difference between groups. Conclusions The study reveals that vitamin D supplementation does not seem to have any beneficial effect in the treatment of PTB in terms to the prevention of relapse and time to sputum smear and culture conversion. Trial registration CTRI/2021/02/030977 (ICMR, Clinical trial registry-India).

Dataset Information

Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D3 as host directed therapy.

Publications

Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D<sub>3</sub> as host directed therapy.

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