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.

Recommendations of the German Central Committee against Tuberculosis (DZK) and the German Respiratory Society (DGP) for the Diagnosis and Treatment of Non-tuberculous Mycobacterioses.

Non-tuberculous mycobacterioses comprise a group of diseases caused by mycobacteria which do not belong to the Mycobacterium (M.) tuberculosis-complex and are not ascribed to M. leprae. These mycobacteria are characterized by a broad variety as to environmental distribution and adaptation. Some of the species may cause specific diseases, especially in patients with underlying immunosuppressive diseases, chronic pulmonary diseases or genetic predisposition, respectively. Worldwide, a rising prevalence and significance of non-tuberculous mycobacterioses is recognized. The present recommendations summarise current aspects of epidemiology, pathogenesis, clinical aspects, diagnostics - especially microbiological methods including susceptibility testing -, and specific treatment for the most relevant species. Diagnosis and treatment of non-tuberculous mycobacterioses during childhood and in HIV-infected individuals are described in separate chapters.

[Management of Adult Community-acquired Pneumonia and Prevention - Update 2016]. / Behandlung von erwachsenen Patienten mit ambulant erworbener Pneumonie und Prävention - Update 2016.

The present guideline provides a new and updated concept of treatment and prevention of adult patients with community-acquired pneumonia. It replaces the previous guideline dating from 2009.The guideline was worked out and agreed on following the standards of methodology of a S3-guideline. This includes a systematic literature search and grading, a structured discussion of recommendations supported by the literature as well as the declaration and assessment of potential conflicts of interests.The guideline has a focus on specific clinical circumstances, an update on severity assessment, and includes recommendations for an individualized selection of antimicrobial treatment as well as primary and secondary prevention.

[New drugs for treatment of tuberculosis]. / Neue Medikamente zur Behandlung der Tuberkulose.

New effective drugs for the treatment of tuberculosis (TB) are necessary for two main reasons: firstly, it would be desirable to reduce the duration of TB treatment from 6 to 4 months and secondly, new drugs are urgently needed for the treatment of multidrug-resistant strains of Mycobacterium tuberculosis. For the first time since 1960 the two new drugs bedaquiline and delamanid were approved and licensed in 2014 for the treatment of multidrug-resistant M. tuberculosis; however, efforts to reduce the duration of treatment to 4 months using fluoroquinolones have not been successful. Further new drugs are currently in phase 2 and phase 3 studies; therefore, new treatment options can be expected within the next few years.

[Non Tuberculous Mycobacteria--a Short Review about Epidemiology, Diagnosis and Treatment]. / Nichttuberkulöse Mykobakterien--eine kurze Übersicht zur Epidemiologie, Diagnostik und Therapie.

Non tuberculous mycobacterial diseases are caused by mycobacteria other than M. tuberculosis complex. NTM are found in the environment and are not transmitted from humans to humans. Infection occurs by the inhalation of dust or aerosols. The finding of NTM is not equal to a diagnosis of active disease. For the diagnosis of active disease well defined clinical and microbiological criteria have to be fulfilled. Gold standard is the detection of NTM by culture, in the case of pulmonary NTM at least two times. There is no established susceptibility testing. Treatment mostly consists of three drugs, given for up to 24 months.

[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.

[Treatment of tuberculosis. Current standards]. / Therapie der Tuberkulose. Was ist gesichert?

The treatment of drug-sensitive tuberculosis consists of 2 months of isoniazid, rifampin, pyrazinamide and ethambutol, followed by 4 months of isoniazid and rifampin. These drugs are well tolerated and cure rate are above 95 %. In contrast the treatment of drug-resistent tuberculosis is difficult, mostly due to side effects of the drugs used under these circumstances. Therefore, any treatment of drug-resistant tuberculosis has to be done by experts.

Prulifloxacin versus levofloxacin in the treatment of severe COPD patients with acute exacerbations of chronic bronchitis.

RATIONALE: Antimicrobial therapy of chronic bronchitis exacerbations in patients with severe chronic obstructive pulmonary disease (COPD) is based on empiric antibiotic treatment. OBJECTIVES: To evaluate the efficacy of prulifloxacin versus levofloxacin therapy in severe COPD patients with exacerbations of chronic bronchitis. METHODS: This study involved a multicenter, parallel, double-blind, randomized clinical trial. Patients aged 40 years or older, smokers, or ex-smokers (>10 pack-years) with spirometrically confirmed severe COPD (FEV1 ≤ 50% predicted and FEV1/FVC ratio < 0.7) and diagnosed with an acute exacerbation of chronic bronchitis were enrolled in the study. Patients were randomized to receive prulifloxacin 600 mg once a day or levofloxacin 500 mg once a day for 7 days. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was clinical assessment at the TOC visit (7-10 days after the end of treatment) of signs and symptoms of exacerbation, namely sputum purulence, sputum volume, dyspnoea, cough and body temperature assessed through semi-quantitative scales. The ITT population included 346 (174 prulifloxacin, 172 levofloxacin) out of 351 treated subjects. A total of 161 patients with prulifloxacin (92.5%) and 166 with levofloxacin (96.5%) were considered cured at TOC (the difference in the percentage of cured patients was -3.98 with 95%CI of -8.76; 0.79). At the 6-month follow-up, the rates of patients with no relapse of AECB were higher than 95% in both the prulifloxacin and levofloxacin groups. CONCLUSIONS: Both prulifloxacin and levofloxacin showed efficacy rates higher than 90% in the treatment of severe COPD patients with exacerbations of chronic bronchitis, with no statistically significant differences between the two antibiotics. The long-term follow-up confirmed a very low incidence of relapse, endorsing the appropriateness of this therapeutic approach. EUDRACT no. 2006-004167-56.

[Informations and recommendations of the German Respiratory Society and the Paul-Ehrlich-Society for chemotherapy concerning the outbreak of influenza A(H7N9) virus infections in humans]. / Informationen und Empfehlungen der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e.V. und der Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. zum Ausbruch der Influenza A(H7N9)-Virus-Infektion beim Menschen.

In March 2013, the first cases of avian influenza virus infections in humans were reported by the authorities of the PR of China to the World Health Organization. This influenza A(H7N9) virus comprises genes of at least four different avian influenza viruses, some segments mimicking human-like influenza-signatures. Until 11 August, 2013 135 humans were infected, 44 (33%) died. The clinical course is characterized by fever, cough, gastrointestinal symptoms, lympho- and thrombopenia as well by the rapid onset of an acute respiratory distress syndrome in nearly 25% of the cases. Although human to human transmission may have occurred only in the context of three clusters, strict hygiene measures should be instituted and any suspect case should be reported to the local health authorities immediately. The detection of influenza A(H7N9) is based on real-time polymerase chain reaction (PCR). Antiviral treatment should be initiated as early as possible for suspect, probable or confirmed cases, even when 48 hours have passed after symptom onset. At present the future development of this epidemic cannot be predicted.

[Recommendations for diagnosis and treatment of nontuberculous mycobacterioses of the German Central Committee against tuberculosis and the German Respiratory Society]. / Empfehlungen zur Diagnostik und Therapie nichttuberkulöser Mykobakteriosen des Deutschen Zentralkomitees zur Bekämpfung der Tuberkulose (DZK) und der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin (DGP).

Nontuberculous mycobacterioses comprise a group of diseases caused by mycobacteria which do not belong to the Mycobacterium (M.) tuberculosis complex and are not ascribed to M. leprae. These mycobacteria are characterized by a broad variety as to environmental distribution and adaptation. Some of the species may cause specific diseases, especially in patients with underlying immunosuppressive diseases, chronic pulmonary diseases or genetic predisposition, respectively. Worldwide a rising prevalence and significance of nontuberculous mycobacterioses can be recognized. The present recommendations summarise actual aspects of epidemiology, pathogenesis, clinical aspects, diagnostics - especially microbiological methods including susceptibility testing -, and specific treatment for the most relevant species. Diagnosis and treatment of nontuberculous mycobacterioses during childhood and in HIV-infected individuals are described in separate chapters.

[Modern antituberculosis treatment]. / Moderne Tuberkulosetherapie.

Based on estimates from the World Health Organization (WHO), there were 8.7 million new cases of tuberculosis (TB) and 1.4 million deaths globally in 2011. In Germany, TB has become a rare disease (incidence 5.3/100,000). Therefore, experience regarding the management and treatment of TB patients is decreasing. In this review, standard therapy of TB and the drugs administered are described. Prior to initiation of therapy, a thorough patient history must be taken to evaluate the risk factors for a drug-resistant TB. In addition, bacterial confirmation via microscopic and culture analyses and phenotypic drug susceptibility testing are also recommended. Treatment of TB is always based on combined antibiotic therapy. The selection of the drugs is determined by the resistance status of the strains. For detailed recommendations refer to the current recommendations of the German Central Committee against Tuberculosis e. V. (DZK) and the German Respiratory Society (DGP).

[Tuberculosis infection control - recommendations of the DZK]. / Infektionsprävention bei Tuberkulose - Empfehlungen des DZK.

The epidemiological situation of tuberculosis (TB) in Germany has improved considerably during the past few years. However, those in unprotected contact with infectious tuberculosis patients frequently and/or over longer periods of time and/or intensively continue to have a higher risk for TB infection. Rapid diagnosis, prompt initiation of effective treatment, and adequate infection control measures are of particular importance to prevent infection. The present recommendations depict the essentials of infection control as well as specific measures in the hospital (isolation, criteria for its duration and technical requirements, types of respiratory protection, disinfection measures, waste disposal). The specific requirements for outpatients (medical practice), at home, for ambulance services, and in congregate settings, including prisons, are also addressed. Compared with the previous recommendations the pattern of respiratory protection measures has been simplified. As a rule, hospital staff and those visiting infectious tuberculosis patients are advised to wear respiratory protection that satisfies the criteria of FFP2-masks (DIN EN 149), while patients should wear mouth-nose protectors (surgical masks) in the presence of others and outside the isolation room. A detailed depiction of criteria for isolation and its duration in smear positive and only culturally confirmed pulmonary tuberculosis has been added.

[International Standards of Tuberculosis Care (ISTC)--comments from the German point of view]. / International Standards of Tuberculosis Care (ISTC)--Kommentierung aus deutscher Sicht.

The "International Standards for Tuberculosis Care" (ISTC) were developed by the World Health Organisation (WHO) and others to provide internationally agreed and, if possible, evidence-based standards for tuberculosis care including the care by private providers who are not part of national tuberculosis programmes or health-care systems. Hence, the ISTC primarily address resource-restrained countries with high tuberculosis prevalence. In this article, the German translation of the 21 standards from 2009 is presented - addressing diagnostic and therapeutic standards, co-infection (especially with HIV) and public-health issues. The accompanying comments show how these standards have to be modified for Germany due to the medical resources available here and country-specific characteristics respectively.

[Recommendations for therapy, chemoprevention and chemoprophylaxis of tuberculosis in adults and children. German Central Committee against Tuberculosis (DZK), German Respiratory Society (DGP)]. / Empfehlungen zur Therapie, Chemoprävention und Chemoprophylaxe der Tuberkulose im Erwachsenen- und Kindesalter. Deutsches Zentralkomitee zur Bekämpfung der Tuberkulose (DZK), Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin (DGP).

Several new international recommendations have been published since the German Central Committee against Tuberculosis (DZK) published its recommendations for drug treatment of tuberculosis (TB) in 2001 and for chemoprevention of latent tuberculosis infection (LTBI) in 2004. These international publications have been integrated in the present new recommendations which describe both the treatment of active TB and preventive treatment, pointing out specific adaptations for Germany. Separate sections deal with the current management of mono-, poly-, and multiresistance or drug intolerance, of TB in children, of different forms of extrapulmonary TB, of LTBI and of special situations such as HIV infection, renal or hepatic insufficiency, infection following BCG instillation in bladder cancer or in case of adverse drug reactions. The following aspects differ from the previous recommendations: A three-drug regimen for the so-called fully susceptible minimal TB is no longer recommended in adults. A dosage of 15 mg/kg body weight of ethambutol for adults is regarded as sufficient. Four secondline drugs (supplemented by pyrazinamide, where appropriate) are recommended for multidrug-resistant tuberculosis (MDR-TB). MDR-TB should be treated over a period of at least 20 months, with an injectable drug administered for a minimum of 8 months (initial phase). Ciprofloxacine and ofloxacine are no longer used to treat TB. It is also recommended to offer an HIV test to all TB patients to complement antiretroviral therapy, if necessary, and to adapt the antituberculous therapy accordingly.

[Tuberculosis infection control--recommendations of the DZK]. / Infektionsprävention bei Tuberkulose--Empfehlungen des DZK.

The epidemiological situation of tuberculosis (TB) in Germany has improved considerably during the past few years. However, those in unprotected contact with infectious tuberculosis patients frequently and/or over longer periods of time and/or intensively continue to have a higher risk for TB infection. Rapid diagnosis, prompt initiation of effective treatment, and adequate infection control measures are of particular importance to prevent infection. The present recommendations depict the essentials of infection control as well as specific measures in the hospital (isolation, criteria for its duration and technical requirements, types of respiratory protection, disinfection measures, waste disposal). The specific requirements for outpatients (medical practice), at home, for ambulance services, and in congregate settings, including prisons, are also addressed. Compared with the previous recommendations the pattern of respiratory protection measures has been simplified. As a rule, hospital staff and those visiting infectious tuberculosis patients are advised to wear respiratory protection that satisfies the criteria of FFP2-masks (DIN EN 149), while patients should wear mouth-nose protectors (surgical masks) in the presence of others and outside the isolation room. A detailed depiction of criteria for isolation and its duration in smear positive and only culturally confirmed pulmonary tuberculosis has been added.

Influenza vaccination is associated with reduced severity of community-acquired pneumonia.

Pneumonia is an important cause of influenza-associated morbidity and mortality. Influenza vaccination has been shown to reduce morbidity and mortality during influenza seasons. Protection from severe pneumonia may contribute to the beneficial effect of influenza vaccination. Therefore, we investigated the impact of prior influenza vaccination on disease severity and mortality in patients with community-acquired pneumonia (CAP). Analysis from an observational, multicentre cohort study initiated by the German competence network for CAP was performed. Patients were analysed separately as an influenza season and off-season cohort. Associations between vaccination status and outcome parameters were evaluated by multivariate analyses. In the season cohort (2,368 patients) CAP in vaccinated patients was significantly less severe according to most analysed parameters (CURB index ≥ 1: OR 0.76, 95% CI 0.60-0.98; procalcitonin ≥ 2.0 ng·mL(-1): OR 0.53, 95% CI 0.35-0.81; procalcitonin ≥ 0.5 ng·mL(-1): OR 0.71, 95% CI 0.51-0.99) and these patients showed a significantly better overall survival within the 6-month follow-up period (HR 0.63, 95% CI 0.45-0.89). Within the off-season cohort (2,632 patients) there was no significant influence of vaccination status on CAP severity or disease outcome. In conclusion, prior influenza vaccination was associated with less severe clinical course and improved overall long-term survival in patients with CAP during influenza seasons.