Joint Statement (DZK, DGRh, DDG) on the Tuberculosis Risk with Treatment Using Novel Non-TNF-Alpha Biologicals.

BACKGROUND: While the risk of tuberculosis (TB) reactivation is adequately documented in relation to TNF-alpha inhibitors (TNFi), the question of what the tuberculosis risk is for newer, non-TNF biologics (non-TNFi) has not been thoroughly addressed. METHODS: We conducted a systematic review of randomized phase 2 and phase 3 studies, and long-term extensions of same, published through March 2019. Of interest was information pertaining to screening and treating of latent tuberculosis (LTBI) in association with the use of 12 particular non-TNFi. Only rituximab was excluded. We searched MEDLINE and the ClinicalTrial.gov database for any and all candidate studies meeting these criteria. RESULTS: 677 citations were retrieved; 127 studies comprising a total of 34,293 patients who received non-TNFi were eligible for evaluation. Only 80 out of the 127 studies, or 63 %, captured active TB (or at least opportunistic diseases) as potential outcomes and 25 TB cases were reported. More than two thirds of publications (86/127, 68 %) mentioned LTBI screening prior to inclusion of study participants in the respective trial, whereas in only 4 studies LTBI screening was explicitly considered redundant. In 21 studies, patients with LTBI were generally excluded from the trials and in 42 out of the 127 trials, or 33 %, latently infected patients were reported to receive preventive therapy (PT) at least 3 weeks prior to non-TNFi treatment. CONCLUSIONS: The lack of information in many non-TNFi studies on the number of patients with LTBI who were either excluded prior to participating or had been offered PT hampers assessment of the actual TB risk when applying the novel biologics. Therefore, in case of insufficient information about drugs or drug classes, the existing recommendations of the German Central Committee against Tuberculosis should be applied in the same way as is done prior to administering TNFi. Well designed, long-term "real world" register studies on TB progression risk in relation to individual substances for IGRA-positive cases without prior or concomitant PT may help to reduce selection bias and to achieve valid conclusions in the future.

[The New WHO Guidelines for Rapid Diagnostics and Treatment of Drug-Resistant Tuberculosis Commented for Germany, Austria and Switzerland]. / Die neuen WHO-Empfehlungen für schnelle Diagnostik und Therapie resistenter Tuberkulose in Deutschland, Österreich und der Schweiz.

The increasing evidence has made it necessary to change international recommendations for the diagnosis and treatment of resistant tuberculosis repeatedly in the recent years. This year, the WHO has published comprehensive recommendations that take into account these developments. The current German tuberculosis guideline was published in 2017 with differing recommendations in some areas. Here the new WHO recommendations of 2020 for rapid diagnosis and therapy of resistant tuberculosis are summarized and the relevant differences are commented for Germany, Austria and Switzerland. A complete re-evaluation of the literature is currently taking place by updating the German-language AWMF 2k guidelines.

[Migration and Tuberculosis]. / Migration und Tuberkulose.

The majority of the people suffering from tuberculosis in Germany are migrants. The treatment of this demographic still presents certain challenges. Only up to a quarter to a fifth of tuberculosis cases in migrants is being diagnosed by the screening methods that were implemented by The German Protection against Infection Act (Infektionsschutzgesetz, IfSG). Reactivation of latent tuberculosis is the most common cause for tuberculosis in migrants. Easy access to health care is vital for the testing and treatment of latent tuberculosis in people with a high risk of reactivation. The level of infection risk, comorbidities and presentation of disease vary depending on the country of origin. Especially during migration people are more susceptible to somatic and mental maladies. Extrapulmonary tuberculosis is frequent in migrants and requires specific diagnostic approaches. Where risk factors for a multi-drug-resistant tuberculosis are present, this condition has to be actively excluded. To facilitate diagnosis and therapy of tuberculosis in migrants a high level of trust has to be established in the doctor-patient relationship. Therefore and despite of cultural and linguistic differences empathy and time are key. Patients need to be encouraged to complete their treatment rather than terminate it prematurely. To that end comorbidities have also to be diagnosed and treated, social and legal aspects have to be considered.

[Standard therapy of tuberculosis]. / Standardtherapie der Tuberkulose.

Based on the results of studies from the 1960s-1980s the current four drug combination therapy was established as standard or short course tuberculosis therapy worldwide. The regional epidemiology and the often unique conditions within a national health system create the need for specific adjustments. Over the last years these were realized by the German central committee against tuberculosis (DZK) in the recommendations for tuberculosis therapy. Because of the recent development of migration into Germany from countries with higher tuberculosis incidences an increase in tuberculosis cases is to be expected. The expected increase in tuberculosis cases will lead to more contact with tuberculosis patients even in the outpatient setting. New S2k guidelines guided by the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF) for the treatment of tuberculosis for children and adults are under development. Before the release of the comprehensive guidelines, practical evidence for the diagnosis and treatment of uncomplicated tuberculosis is summarized in this document to meet the challenges of the recent developments.

[New Drugs for the Treatment of Multidrug-resistant Tuberculosis (MDR-TB)]. / Kurze Übersicht über neue Medikamente zur Therapie der multiresistenten Tuberkulose.

This article summarizes the state of development of new drugs for the treatment of multidrug-resistant tuberculosis. We focused on delamanid, bedaquiline, pretomanid, SQ 109 and sutezolid.

[Resistance to second-line drugs in migrants with multidrug-resistant tuberculosis in the Berlin region]. / Resistenzen gegen Zweitlinienmedikamente bei Migranten mit multiresistenter Tuberkulose in der Region Berlin.

The empiric therapy of multidrug-resistant (MDR) tuberculosis (TB) after rapid molecular testing is rendered difficult by an often several weeks-long period of uncertainty, because results of susceptibility testing for second-line TB drugs are pending. The analysis of regional resistance patterns could lead to a more targeted empiric treatment for migrants depending on their country of origin. The results of the susceptibility testing from 2008 to 2013 of all mycobacteria sent to the Institute of Microbiology, working with the department of Pneumology, Heckeshorn Lung Clinic, Berlin, were reanalysed and tested for regional differences. We found 39 multidrug-resistant Mycobacterium tuberculosis strains among the examined strains. More than half of these strains tested susceptible to the following second line drugs namely, linezolid (97%), clofazimine (95%), cycloserine (95%), capreomycin (90%), p-aminosalicylic acid (82%), moxifloxacin (79%) and amikacin (79%). The proportion of strains susceptible to pyrazinamide (44%), ethambutol (28%), prothionamide (15%), rifabutin (8%) and streptomycin (8%) was lower. The mycobacterial cultures of the Chechen patients (n = 14) showed significantly different susceptibilities to amikacin (57%) and prothionamide (36%) compared to the strains from migrants of other regions. In this study, the regional differences in mycobacterial susceptibility to second line drugs suggest that the initial MDR TB therapy of migrants should be tailored to their country of origin.

Clinical standards for the management of adverse effects during treatment for TB.

BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitivity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person-centred, consensus-based approach to minimise the impact of AE during TB treatment.

Clinical standards for the dosing and management of TB drugs.

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

Efficacy and safety of formoterol delivered through the Novolizer, a novel dry powder inhaler (DPI) compared with a standard DPI in patients with moderate to severe asthma.

BACKGROUND & OBJECTIVE: Because of environmental concerns CFC-containing pressurised metered dose inhalers (pMDI) had to be replaced by dry powder inhalers (DPI). The Novolizer, a novel DPI has previously been shown to be as effective as the Turbuhaler in delivering budesonide. The objective of this study was to show non-inferiority of inhaled formoterol therapy delivered through the Novolizer compared to formoterol delivered through the Aerolizer in patients suffering from moderate to severe asthma. METHODS: In this double-blind, double-dummy, multicentre study 392 patients were randomised and received a dose of 12 microg formoterol twice daily for 4 weeks either through the Aerolizer or the Novolizer. FEV1 after 4 weeks of treatment was the primary variable. Secondary variables were FVC, PEF, consumption of short-acting; 2 adrenoceptor agonists, asthma symptoms, tolerability and safety. RESULTS: After 4 weeks of treatment, the mean trough FEV1 (95% CI) was 2.34 L (2.24-2.45) for the Novolizer and 2.31 L (2.21-2.41) for the Aerolizer. Non-inferiority was proven (p<0.0001, pre-defined; of 0.25 L). All secondary variables (incl. PEF) confirmed these findings. Treatment with both devices was safe and well tolerated. CONCLUSION: Inhalation of 12 microg formoterol twice daily via Novolizer was shown to be equally therapeutically effective compared to the inhalation via Aerolizer in the treatment of moderate to severe persistent asthma. Treatment via both inhalers was safe and well tolerated.

Antioxidative enzymes in human nasal mucosa after exposure to ozone. Possible role of GSTM1 deficiency.

OBJECTIVE AND DESIGN: Epithelial antioxidative enzymes (AOEs) are thought to be a first line of defense against reactive oxygen species as they are upregulated after exposure to ozone according to animal studies. We analysed the activities of the AOEs catalase (CAT), glutathione peroxidase (GPX), glutathione reductase (GR), superoxide dismutase (SOD) and glutathione-S-transferase (GST) in a tissue culture of human nasal mucosa and analysed the influence of GSTM1 polymorphism on AOE regulation. METHODS: Tissue biopsies of 20 subjects were incubated for 24 h with and without 120 ppb ozone. Activities were assayed to determine what enzymatic changes had taken place, both overall and in regard to GSTM1 status. RESULTS: Activities for GPX (p = 0.272) and SOD (p = 0.291) were found increased after ozone exposure. GSTM1-deficient patients showed a significantly enhanced upregulation of SOD activity (p = 0.011) compared to GSTM1 carriers. CONCLUSION: Our findings suggest that GSTM1-deficiency has an impact on AOE-regulation after ozone exposure.