Authors present a pilot study of the development of innovative flow cytometry-based assay with a potential for use in tuberculosis diagnostics. Currently available tests do not provide robust discrimination between latent tuberculosis infection (TBI) and tuberculosis disease (TB). The desired application is to distinguish between the two conditions by evaluating the production of a combination of three cytokines: IL-2 (interleukin-2), IFNɣ (interferon gamma) and TNFɑ (tumor necrosis factor alpha) in CD4+ and CD8+ T cells. The study was conducted on 68 participants, divided into two arms according to age (paediatric and adults). Each arm was further split into three categories (non-infection (NI), TBI, TB) based on the immune reaction to Mycobacterium tuberculosis (M.tb) after a close contact with pulmonary TB. Each blood sample was stimulated with specific M.tb antigens present in QuantiFERON tubes (TB1 and TB2). We inferred TBI or TB based on the predominant cytokine response of the CD4+ and/or CD8+ T cells. Significant differences were detected between the NI, TBI and the TB groups in TB1 in the CD4+TNFɑ+parameter in children. Along with IL-2, TNFɑ seems to be the most promising diagnostic marker in both CD4+and CD8+ T cells. However, more detailed analyses on larger cohorts are needed to confirm the observed tendencies.
- MeSH
- antigeny bakteriální imunologie MeSH
- biologické markery krev MeSH
- CD4-pozitivní T-lymfocyty * imunologie MeSH
- CD8-pozitivní T-lymfocyty * imunologie MeSH
- cytokiny krev metabolismus MeSH
- diferenciální diagnóza MeSH
- dítě MeSH
- dospělí MeSH
- interferon gama * krev imunologie MeSH
- interleukin-2 * krev MeSH
- latentní tuberkulóza * diagnóza imunologie mikrobiologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- Mycobacterium tuberculosis * imunologie MeSH
- pilotní projekty MeSH
- plicní tuberkulóza diagnóza imunologie mikrobiologie krev MeSH
- prediktivní hodnota testů MeSH
- předškolní dítě MeSH
- průtoková cytometrie * metody MeSH
- senioři MeSH
- test pomocí interferonu gama metody MeSH
- TNF-alfa krev MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
Izoniazid patrí k antituberkulotikám prvej línie. Uplatnenie nachádza v liečbe aktívnej aj latentnej tuberkulózy. Je súčasťou kombinovaných režimov, pri preventívnej liečbe tuberkulózy sa však podáva aj v monoterapii. Napriek tomu, že k zvýšeniu sérovej aktivity aminotransferáz dochádza počas terapie izoniazidom relatívne často, rozvoj symptomatickej hepatitídy je podľa odbornej literatúry zriedkavý. V prezentovanej kazuistike opisujeme prípad pacientky, u ktorej sa v priebehu preventívnej liečby latentnej tuberkulózy rozvinulo izoniazidom navodené poškodenie pečene klinicky sprevádzané rozvojom ikteru. V článku tiež sumarizujeme aktuálne poznatky týkajúce sa rizikových faktorov, patogenézy a incidencie hepatotoxicity popísanej počas užívania tohto antituberkulotika. Zároveň ilustrujeme proces diagnostiky liekmi indukovaného poškodenia pečene v podmienkach klinickej praxe s využitím aktualizovaného stratifikačného skórovacieho systému RUCAM.
Isoniazid belongs to the first line antituberculosis drugs and can be used for the treatment of both active and latent tuberculosis infections. It is a part of combined regimens, for the preventive treatment of tuberculosis isoniazid can be used in monotherapy as well. Even though elevations in serum aminotransferases levels during isoniazid therapy are seen frequently, the development of symptomatic hepatitis is rare, according to specialised literature. This article describes a case of a patient who developed drug-induced liver injury accompanied by jaundice during the isoniazid preventive treatment of tuberculosis. It also provides a summary of the currently known risk factors, pathogenesis, and incidence of hepatotoxicity observed throughout therapy with this antituberculosis drug. We also illustrate the process of diagnosing drug--induced liver injury in clinical practice settings with the utilisation of the updated RUCAM score.
- MeSH
- antituberkulotika škodlivé účinky terapeutické užití MeSH
- diferenciální diagnóza MeSH
- isoniazid * škodlivé účinky terapeutické užití MeSH
- latentní tuberkulóza farmakoterapie prevence a kontrola MeSH
- lékové postižení jater * diagnostické zobrazování etiologie farmakoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nežádoucí účinky léčiv MeSH
- žloutenka diagnóza etiologie terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Tuberculosis (TB) contact tracing and TB preventive treatment are key tools in preventing the transmission of TB with the aim of eliminating the disease. Our study seeks to demonstrate how the infection spread from an individual patient to the entire community and how proactive contact tracing facilitated prompt diagnosis and treatment. Our work was conducted as a retrospective analysis of the spread of TB infection within the Roma community in the Czech Republic, following the case of an index patient who succumbed to pulmonary TB. Several levels of care and preventive and treatment measures are outlined. Confirming the identity of the Mycobacterium tuberculosis strain was achieved using molecular methods. Among the 39 individuals examined, TB disease was detected in eight patients and TB infection was detected in six patients. The investigation of contacts within this group yielded positive results in 36% of cases, necessitating treatment. The study's findings provide evidence that actively tracing individuals at risk can lead to early detection of cases, prompt treatment, and prevention of further disease transmission. The study also indicates that the highest risk of infection occurs within the sick person's household and that young children under the age of 5 are most susceptible to falling ill.
- MeSH
- latentní tuberkulóza * MeSH
- lidé MeSH
- plicní tuberkulóza * epidemiologie MeSH
- předškolní dítě MeSH
- retrospektivní studie MeSH
- Romové * MeSH
- trasování kontaktů metody MeSH
- tuberkulóza * diagnóza epidemiologie MeSH
- Check Tag
- lidé MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
Dormant cells of Mycobacterium tuberculosis, in addition to low metabolic activity and a high level of drug resistance, are characterized by 'non-culturability'-a specific reversible state of the inability of the cells to grow on solid media. The biochemical characterization of this physiological state of the pathogen is only superficial, pending clarification of the metabolic processes that may exist in such cells. In this study, applying LC-MS proteomic profiling, we report the analysis of proteins accumulated in dormant, 'non-culturable' M. tuberculosis cells in an in vitro model of self-acidification of mycobacteria in the post-stationary phase, simulating the in vivo persistence conditions-the raw data are available via ProteomeXchange with identifier PXD028849. This approach revealed the preservation of 1379 proteins in cells after 5 months of storage in dormancy; among them, 468 proteins were statistically different from those in the actively growing cells and bore a positive fold change (FC). Differential analysis revealed the proteins of the pH-dependent regulatory system PhoP and allowed the reconstruction of the reactions of central carbon/glycerol metabolism, as well as revealing the salvaged pathways of mycothiol and UMP biosynthesis, establishing the cohort of survival enzymes of dormancy. The annotated pathways mirror the adaptation of the mycobacterial metabolic machinery to life within lipid-rich macrophages: especially the involvement of the methyl citrate and glyoxylate pathways. Thus, the current in vitro model of M. tuberculosis self-acidification reflects the biochemical adaptation of these bacteria to persistence in vivo. Comparative analysis with published proteins displaying antigenic properties makes it possible to distinguish immunoreactive proteins among the proteins bearing a positive FC in dormancy, which may include specific antigens of latent tuberculosis. Additionally, the biotransformatory enzymes (oxidoreductases and hydrolases) capable of prodrug activation and stored up in the dormant state were annotated. These findings may potentially lead to the discovery of immunodiagnostic tests for early latent tuberculosis and trigger the discovery of efficient drugs/prodrugs with potency against non-replicating, dormant populations of mycobacteria.
Latent Mycobacterium tuberculosis infection presents one of the largest challenges for tuberculosis control and novel antimycobacterial drug development. A series of pyrano[3,2-b]indolone-based compounds was designed and synthesized via an original eight-step scheme. The synthesized compounds were evaluated for their in vitro activity against M. tuberculosis strains H37Rv and streptomycin-starved 18b (SS18b), representing models for replicating and nonreplicating mycobacteria, respectively. Compound 10a exhibited good activity with MIC99 values of 0.3 and 0.4 μg/mL against H37Rv and SS18b, respectively, as well as low toxicity, acceptable intracellular activity, and satisfactory metabolic stability and was selected as the lead compound for further studies. An analysis of 10a-resistant M. bovis mutants disclosed a cross-resistance with pretomanid and altered relative amounts of different forms of cofactor F420 in these strains. Complementation experiments showed that F420-dependent glucose-6-phosphate dehydrogenase and the synthesis of mature F420 were important for 10a activity. Overall these studies revealed 10a to be a prodrug that is activated by an unknown F420-dependent enzyme in mycobacteria.
- MeSH
- antituberkulotika farmakologie MeSH
- latentní tuberkulóza * MeSH
- lidé MeSH
- Mycobacterium tuberculosis * genetika MeSH
- tuberkulóza * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Ciele práce: Cieľom práce bolo zistiť prevalenciu latentnej tuberkulózy (LTBI) u pacientov s reumatoidnou artritídou stredne ťažkého a ťažkého stupňa liečených konvenčnou a anticytokínovou terapiou, identifikovať možné rizikové faktory tuberkulózy (TB) a hodnotiť efektivitu profylaktickej liečby u pozitívne skrínovaných pacientov. Pacienti a metodika: Observačná retrospektívna štúdia so zaradením pacientov s reumatoidnou artritídou po absolvovaní skríningových vyšetrení na zistenie LTBI (röntgenologické vyšetrenie hrudníka, tuberkulínový kožný test, interferon gamma release assay test – IGRA test). Výsledky: V skupine 124 pacientov sme zistili u 7,25 % LTBI počas kombinovanej liečby konvenčným syntetickým liečbu modifikujúcim antireumatikom (csDMARD) a kortikoterapiou. U ďalších 21,77 % LTBI bola diagnostikovaná počas biologickej liečby alebo terapie inhibítorom Janusových kináz. Najvyššia incidencia LTBI bola zistená v skupine pacientov liečených inhibítormi tumor nekrotizujúceho faktoru (66,66 % z LTBI pozitívnych pacientov), avšak pozitívne skrínovaní pacienti sa vyskytli aj pri liečbe inými modalitami. Priemerná doba detekcie LTBI pozitivity bola 39,5 mesiacov (12–134 mesiacov) od začatia anticytokínovej terapie. Klinicky manifestná aktívna TB sa potvrdila u jedného pacienta. Štatistická analýza nepreukázala asociáciu medzi rizikom LTBI a vekom, pohlavím alebo liečebnou modalitou. Záver: Výsledky tejto štúdie potvrdzujú opodstatnenie skríningu a stáleho monitorovania LTBI u pacientov s RA liečených anticytokínovou terapiou. Naše aktuálne národné odporúčania sú dostatočne senzitívne na identifikáciu LTBI. Nezodpovedanou otázkou zostáva potreba skríningu a profylaktickej liečby antituberkulotikami u pacientov liečených csDMARD v kombinácii s glukokortikoidmi.
Aim: This study aims to determine the prevalence of latent tuberculosis infection (LTBI) in patients with moderate to severe rheumatoid arthritis (RA) who receive conventional and anti-cytokine therapy, to identify possible risk factors for tuberculosis (TB) and to evaluate the prophylactic treatment in positively screened patients. Patient and Methods: We conducted an observational, retrospective study in patients with RA, who underwent LTBI screening (chest X-ray, tuberculin skin test and interferon gamma release assay test – IGRA test). Results: Out of 124 patients included, 7.25% of patients were diagnosed with LTBI during the treatment with conventional synthetic anti-rheumatic drugs in combination with glucocorticoids before initiation of anti-cytokine therapy. Another 21.77% were diagnosed during treatment with biologics or Janus kinase inhibitors. We confirmed the highest incidence of LTBI in TNF-treated group (66.66% LTBI positive patients), but also found positive screening in patients treated with other modalities. The mean LTBI detection time since the initiation of anti-cytokine therapy was 39.5 months (12–134 months). Active TB with clinical manifestation has occurred in one patient. Statistical analysis did not show an association between risk of LTBI and age, sex or treatment modality. Conclusion: The results of this study confirm the necessity of LTBI screening and long-term monitoring in RA patients treated with any kind of anti-cytokine therapy. The currently used national recommendations are sufficiently sensitive to identify TB in these patients. There remains a question of screening and prophylactic antituberculosis therapy in patients treated with conventional synthetic anti-rheumatic drugs in combination with glucocorticoids.
- MeSH
- biologická terapie škodlivé účinky MeSH
- latentní tuberkulóza * diagnóza epidemiologie etiologie MeSH
- lidé MeSH
- mykobakteriózy * diagnóza epidemiologie etiologie MeSH
- retrospektivní studie MeSH
- revmatoidní artritida farmakoterapie MeSH
- test pomocí interferonu gama metody MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Slovenská republika MeSH
- MeSH
- biologická terapie MeSH
- biologické přípravky terapeutické užití MeSH
- latentní tuberkulóza * diagnóza farmakoterapie imunologie MeSH
- lidé MeSH
- Mycobacterium tuberculosis imunologie patogenita MeSH
- test pomocí interferonu gama metody MeSH
- tuberkulinový test MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- abstrakt z konference MeSH
BACKGROUND: Vaccine-preventable diseases and opportunistic infections in pediatric inflammatory bowel disease (IBD) are increasingly recognized issues. The aims of this study were to evaluate vaccinations, immunization status, and consequent therapeutic management in children with IBD and to analyze the differences among patients diagnosed before (Group 1) and after June 2012 (Group 2). METHODS: This was a multicenter, retrospective cohort investigation. Between July 2016 and July 2017, 430 children with IBD were enrolled in 13 centers. Diagnosis, therapeutic history, vaccinations, and immunization status screening at diagnosis and at immunosuppressant (IM)/biologic initiation and reasons for incomplete immunization were retrieved. RESULTS: Vaccination rates at diagnosis were unsatisfactory for measles, mumps, and rubella (89.3%), Haemophilus influenzae (81.9%), meningococcus C (23.5%), chickenpox (18.4%), pneumococcus (18.6%), papillomavirus (5.9%), and rotavirus (1.9%). Complete immunization was recorded in 38/430 (8.8%) children, but specific vaccines were recommended in 79/430 patients (18.6%), without differences between the 2 groups. At IM start, 22% of children were tested for Epstein-Barr virus (EBV) status, with 96.2% of EBV-naïve patients starting azathioprine, without differences between Groups 1 and 2. Screening for latent tuberculosis (TB) before start of biologics was performed in 175/190 (92.1%), with up to 9 different screening strategies and numerous inconsistencies. CONCLUSIONS: We demonstrated a poor immunization status at diagnosis in children with IBD, which was not followed by proper vaccination catch-up. EBV status before IM initiation and latent TB before biologics were not adequately assessed. Thus, the overall impact of the current guidelines seems unsatisfactory.
- MeSH
- Crohnova nemoc farmakoterapie imunologie MeSH
- dítě MeSH
- dodržování směrnic MeSH
- idiopatické střevní záněty farmakoterapie imunologie MeSH
- imunosupresiva škodlivé účinky MeSH
- infekce virem Epsteina-Barrové prevence a kontrola MeSH
- latentní tuberkulóza prevence a kontrola MeSH
- lidé MeSH
- Mycobacterium tuberculosis MeSH
- očkovací schéma MeSH
- oportunní infekce imunologie prevence a kontrola MeSH
- retrospektivní studie MeSH
- ulcerózní kolitida farmakoterapie imunologie MeSH
- vakcinace normy statistika a číselné údaje MeSH
- virus Epsteinův-Barrové MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
Epidemiologická situácia tuberkulózy vo väčšine krajín s nízkym výskytom TB sa vyznačuje nízkou mierou prenosu v celkovej populácii a príležitostnými ohniskami. V čase pandémie covid-19 musíme počítať s jej nárastom v postpandemickom období. Väčšina prípadov aktívnej TB je spôsobená reaktiváciou latentnej tuberkulózy. Vysoká koncentrácia choroby je zaznamenávaná v určitých rizikových skupinách (chudobní ľudia, bezdomovci, migranti, väzni, etnické menšiny a osoby žijúce s HIV infekciou alebo s inými chorobami, osoby s nadmerným užívaním alkoholu, drogovo závislí a iné marginalizované skupiny). V čase zvyšujúcej sa migrácie obyvateľstva, nebude TB natrvalo odstránená v akejkoľvek krajine, pokiaľ nebude eliminovaná v celosvetovom meradle.
- Klíčová slova
- Covid 19,
- MeSH
- antibiotická rezistence MeSH
- latentní tuberkulóza MeSH
- lidé MeSH
- rizikové faktory MeSH
- tuberkulóza * epidemiologie MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Evropa MeSH
- Slovenská republika MeSH
