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 cost of Mycobacterium avium complex lung disease in Canada, France, Germany, and the United Kingdom: a nationally representative observational study.

BACKGROUND: Management of nontuberculous mycobacterial lung disease (NTMLD) consists of a long-term multi-drug antibiotic regimen, yet many patients do not achieve culture conversion. We estimated the NTMLD-related direct medical costs in Canada, France, Germany, and the United Kingdom (UK) among refractory patients who were infected with Mycobacterium avium complex (MAC), without concomitant cystic fibrosis, tuberculosis, or HIV. METHODS: We conducted a retrospective observational physician survey of nationally representative samples. The survey captured anonymized information about patients' treatment histories for NTMLD-related health care resource utilization over a 24-month period. We summarized NTMLD-related resource use and estimated the total economic burden, from each country's health care payer perspective. RESULTS: In total, 59 physicians provided data on 157 patients. The average person time observed during the 24-month period was 1.7 years (SD: 0.4); 17% of patients died by the end of the study period. The major components of NTMLD-related direct medical costs among refractory patients were hospitalizations (varying from 29% of total annual costs in the UK to 69% in France), outpatient visits (8% in Canada to 51% in the UK), and outpatient testing such as post-diagnostic sputum testing, bronchial wash/lavage, spirometry, biopsies, imaging, and electrocardiograms (5% in France to 35% in Canada). In this patient cohort, the average direct medical costs per person-year, in local currencies, were approximately $16,200 (Canada), €11,600 (Germany), €17,900 (France) and £9,700 (UK). CONCLUSIONS: Based on this study's findings, we conclude that managing patients with refractory NTMLD caused by MAC is associated with a substantial economic burden.

[Tuberculosis and Tobacco Smoking]. / Tuberkulose und Rauchen.

Worldwide there are annually about 9.6 million new cases and 1.5 million deaths due to tuberculosis (TB). Smoking is an independent risk factor causing approximately a twofold increase not only in active Tb disease but also in latent TB infection and mortality. In a mathematical model it is estimated that smoking would produce until 2050 an excess of 18 million tuberculosis cases from TB which would challenge the TB elimination goal of the WHO. Smoking cessation methods during and after TB treatment, which at present are insufficiently included into TB programmes, are urgently needed.

[Current Issues Arising from Tuberculosis Screening with Interferon-Gamma-Release Assays (IGRAs)]. / Aktuelle Fragestellungen zum Tuberkulose-Screening mit Interferon-Gamma-Release Assays (IGRAs).

A positive IGRA test does not always indicate a latent tuberculosis infection (LTBI); the prevalence of LTBI in the tested collective must be carefully considered in test interpretation. When IGRAs are performed repeatedly in healthcare workers (BiG), variabilities of test results (conversions and reversions of the respective previous negative or positive result) can be expected. Therefore only individuals for whom there is an established risk of being infected by Mycobacterium tuberculosis (M.tb.), i.e. significantly prolonged direct exposure to an infectious TB case, should be tested. Positive IGRA results alone do not reliably predict subsequent progression to active TB disease. According to the current body of scientific knowledge, IGRAs are not superior to the tuberculin skin test (TST) in the case of young children.

Screening for latent tuberculosis infection: performance of tuberculin skin test and interferon-γ release assays under real-life conditions.

OBJECTIVES: To characterise optimal screening strategies for latent tuberculosis infection (LTBI) prior to the initiation of anti-tumour necrosis factor therapy. METHODS: Patients in 62 German rheumatology centres were evaluated for LTBI. Each patient was screened with a tuberculin skin test (TST) and one form of an interferon-γ release assay (IGRA), either TSPOT.TB (TSPOT) or Quantiferon TB Gold (QFT). RESULTS: A total of 1529 patients with rheumatological disease were tested with a TST, 844 with TSPOT and 685 with QFT. TST was positive in 11.3% (n=173). The prevalence of LTBI was 8.0% when defined as a positive TST and no previous Bacille Calmette-Guérin (BCG) vaccination and 7.9% when based on a positive IGRA. Combining both estimates increased the prevalence of LTBI to 11.1%. Clinical risk factors for LTBI were found in 122 patients (34 with a history of prior TB, 81 close contacts and 27 with suggestive chest x-ray lesions). A compound risk factor (CRF) was defined as the presence of at least one of these three risk factors. Statistical analyses were conducted to examine the association between CRF and LTBI test outcomes. In multivariate analysis, TST was influenced by CRF (OR 6.2; CI 4.08 to 9.44, p<0.001) and BCG vaccination status (OR 2.9; CI 2.00 to 4.35, p<0.001). QFT and TSPOT were only influenced by CRF (QFT: OR 2.6; CI 1.15 to 5.98, p=0.021; TSPOT: OR 8.7; CI 4.83 to 15.82, p<0.001). ORs and the agreement of TST and IGRA test results varied by rheumatological disease. CONCLUSION: LTBI test results in an individual patient need to be considered in the context of prior BCG vaccination and clinical risk factors. In patient populations with low rates of TB incidence and BCG vaccination, the use of both TST and IGRA may maximise sensitivity in detecting LTBI but may also reduce specificity.

[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 : diagnostics and prophylaxis]. / Tuberkulose : Diagnostik und Prophylaxe.

Infection with Mycobacterium tuberculosis causes primarily formation of granulomatous tubercles in the lungs. In the absence of any clinical symptoms it is named latent tuberculosis infection which can be an origin of reactivation, especially as a consequence of an impaired response of the immune system. Complete anamnesis, radiographic methods and bacteriological analysis (microscopy, culture, PCR) are useful for diagnosis of tuberculosis. Since 2005 newer in vitro tests are available using interferon-gamma release assays (IGRAs). Compared to the tuberculin skin test it is possible to differentiate between infection with M. tuberculosis and individuals vaccinated with the Bacillus Calmette-Guérin (BCG) vaccine. These new in vitro tests are part of a screening procedure which has to be performed before starting immunosuppressive therapy with tumor necrosis factor-alpha (TNF-α) inhibitors. In cases of latent tuberculosis infection administration of isoniazid for 9 months is recommended.

[Costs of the influenza pandemic for the public health services - calculations based on the model of the metropolitan region Frankfurt am Main]. / Inkrementelle Kosten der A/H1N1-Pandemie für den Öffentlichen Gesundheitsdienst - Berechnungen am Beispiel der Metropole Frankfurt am Main.

The influenza pandemic of 2009 has been the biggest challenge to the public health services in post-war Germany. This study investigates the impact on the overall costs for the public health authorities of the metropolitan region Frankfurt am Main which arose in the context of the pandemic as well as the specific costs of the implementation and realisation of the vaccination campaign during the pandemic. In 2009 the incremental costs for the Health Protection Authority of the City of Frankfurt am Main for the prevention and logistics caused by this pandemic amounted to € 223,537.91, whereas costs which could be directly attributed to the vaccination campaign (vaccine not included amounted to only a fraction thereof (€â€Š45,401.48). The per-capita costs for vaccinated citizens were €â€Š10.66.  These results clearly demonstrate the importance of adequate financial resources for the public health authorities to cope with infectious disease outbreaks and future pandemics.

The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement.

Anti-tumour necrosis factor (TNF) monoclonal antibodies or soluble TNF receptors have become an invaluable treatment against chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. Individuals who are treated with TNF antagonists are at an increased risk of reactivating latent infections, especially tuberculosis (TB). Following TNF antagonist therapy, the relative risk for TB is increased up to 25 times, depending on the clinical setting and the TNF antagonist used. Interferon-γ release assays or, as an alternative in individuals without a history of bacille Calmette-Guérin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection with Mycobacterium tuberculosis. Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test and an interferon-γ release assay, as there are insufficient data in children to recommend one test over the other. Consequently, targeted preventive chemotherapy is highly recommended for all individuals with persistent M. tuberculosis-specific immune responses undergoing TNF antagonist therapy as it significantly reduces the risk of progression to TB. This TBNET consensus statement summarises current knowledge and expert opinions and provides evidence-based recommendations to reduce the TB risk among candidates for TNF antagonist therapy.

Enhanced cost-benefit analysis of strategies for LTBI screening and INH chemoprevention in Germany.

OBJECTIVES: There is only limited economic data in head-to head comparison between a whole blood QuantiFERON TB Gold in tube (QFT) and the tuberculin skin test (TST) when screening and treating for latent tuberculosis infection (LTBI), and no published study to date that takes into account the predictive value of the two tests. METHODS: Health and economic outcomes of isoniazid preventive treatment (IPT) of close contacts were compared in a decision tree model to perform a cost-benefit analysis with respect to isoniazid related hepatotoxicity and early post-exposure TB over a 2-y period, using the QFT or TST alone or QFT as a confirmatory test for TST results. RESULTS: Cost of screening and treating for using the QFT alone amounted to euro215.79 per close contact, less than that of dual step-testing (euro227.89) or using TST alone (euro232.58). Savings amounted to euro12,200 or euro16,791 per 1000 close contacts, respectively. QFT based procedures were most sensitive to low compliance with IPT or increasing price. Costs of dual step screening was mostly influenced by cost of treating TB disease. When the progression rate for QFT was lowered to that for the TST in a sensitivity analysis, the relationship between the strategies remained robust. In addition, costs of the QFT strategy decreased to euro165.1, and those of the dual step strategy to euro218.4. CONCLUSION: IPT on the basis of using the QFT assay alone produces less cost and reduces more TB cases than other strategies in a low-incidence setting. These data have implications for the rational implementation of screening strategies in contact investigation.

[Recommendations for tuberculosis screening before initiation of TNF-alpha-inhibitor treatment in rheumatic diseases]. / Empfehlungen für das Tuberkulosescreening vor Gabe von TNF-alpha-Inhibitoren bei rheumatischen Erkrankungen.

Due to the increased risk of tuberculosis (TB) under treatment with TNF-alpha-inhibitors for rheumatoid arthritis and other autoimmune diseases, precautionary measures are required before initiating TNF-alpha-inhibitor therapy. Patients should have active TB ruled out and screening for latent TB infection should be performed. The screening should include chest X-ray, complete medical history, and the administration of a highly specific Interferon-gamma-Release Assay (IGRA). As tuberculin skin test (TST) results can be expected to be either false-positive or false-negative in these patients, the TST, as commonly performed in the past, is recommended only for exceptional situations. For chemopreventive treatment of latent TB infection (LTBI), isoniazid is usually given for 9 months.

[Recommendations for tuberculosis screening before initiation of TNF-alpha-inhibitor treatment in rheumatic diseases]. / Empfehlungen für das Tuberkulose-Screening vor Gabe von TNF-alpha-Inhibitoren bei rheumatischen Erkrankungen.

Due to the increased risk of tuberculosis (TB) under treatment with TNF-alpha inhibitors for rheumatoid arthritis and other autoimmune diseases, precautionary measures are required before initiating TNF-alpha-inhibitor therapy. Patients should have active TB ruled out and screening for latent TB infection should be performed. The screening should include chest X-ray, complete medical history, and the administration of a highly specific interferon-gamma-release assay (IGRA). (In the future, the reimbursement of IGRA tests under an analogue procedure code is expected to be formalized by the application of a code specific to the TB-IGRA procedure.) As tuberculin skin test (TST) results can be expected to be either false-positive or false-negative in these patients, the TST, as commonly performed in the past, is recommended only in exceptional situations. For chemopreventive treatment of latent TB infection (LTBI), isoniazid is usually given for 9 months.

LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement.

Tuberculosis control relies on the identification and preventive treatment of individuals who are latently infected with Mycobacterium tuberculosis. However, direct identification of latent tuberculosis infection is not possible. The diagnostic tests used to identify individuals latently infected with M. tuberculosis, the in vivo tuberculin skin test and the ex vivo interferon-gamma release assays (IGRAs), are designed to identify an adaptive immune response against, but not necessarily a latent infection with, M. tuberculosis. The proportion of individuals who truly remain infected with M. tuberculosis after tuberculin skin test or IGRA conversion is unknown. It is also uncertain how long adaptive immune responses towards mycobacterial antigens persist in the absence of live mycobacteria. Clinical management and public healthcare policies for preventive chemotherapy against tuberculosis could be improved, if we were to gain a better understanding on M. tuberculosis latency and reactivation. This statement by the TBNET summarises knowledge and limitations of the currently available tests used in adults and children for the diagnosis of latent tuberculosis infection. In summary, the main issue regarding testing is to restrict it to those who are known to be at higher risk of developing tuberculosis and who are willing to accept preventive chemotherapy.

Cost-effectiveness of interferon-gamma release assay testing for the treatment of latent tuberculosis.

The aim of the present study was to assess the cost-effectiveness of the new T-SPOT.TB assay versus the tuberculin skin test (TST) for screening contacts for latent tuberculosis (TB) infection in Switzerland. Health and economic outcomes of isoniazid treatment of 20- and 40-yr-old close contacts were compared in a Markov model over a 20-yr period following screening with TST only (at three cut-off values) and T-SPOT.TB alone or in combination with the TST. T-SPOT.TB-based treatment was cost-effective at (Euro)11,621 and (Euro)23,692 per life-year-gained (LYG) in the younger and older age group, respectively. No TST-based programmes were cost-effective, except at a 15-mm cut-off in the younger group only, where the cost-effectiveness ((Euro)26,451.LYG(-1)) fell just below the willingness-to-pay threshold. Combination of the TST with T-SPOT.TB slightly reduced the total cost compared with the T-SPOT.TB alone by 4.4 and 5.0% in the younger and older groups respectively. The number of contacts treated to avoid one case of TB decreased from 50 (95% confidence interval 32-106) with the TST (10-mm cut-off) to 18 (95%CI 11-43) if T-SPOT.TB was used. Using T-SPOT.TB alone or in combination with the tuberculin skin test for screening of close contacts before latent tuberculosis infection treatment is highly cost-effective in reducing the disease burden of tuberculosis.

Cost-optimisation of screening for latent tuberculosis in close contacts.

The aim of the present study was to perform cost-minimisation analysis of contact investigation from a public health perspective using the tuberculin skin test (TST) and a new blood assay, QuantiFERON-TB Gold (QFT-G). A decision-analysis model simulated the costs of investigating a cohort of adult close tuberculosis contacts by the public health service following the current German guidelines over a period of 2 yrs. The economic outcomes were compared with alternative screening strategies. These were: 1) QFT-G instead of TST; 2) TST followed by QFT-G; and 3) TST followed by QFT-G in vaccinated (bacille Calmette-Guérin (BCG)) subjects. In a base-case analysis, the costs of TST-based screening were 91.06 Euros (EUR).contact(-1), assuming a 1% tuberculosis-case-finding incidence. The least expensive strategy was TST screening plus subsequent QFT-G testing (52.05 EUR), resulting in a 43% cost reduction. Using QFT-G alone in BCG-vaccinated subjects who tested positive in the TST led to a 39% cost reduction. The savings using QFT-G alone instead of TST amounted to 29.77 EUR.contact(-1). The results depended on the acquisition costs assumed and the proportion of positive results in TST-based screening. Screening for tuberculosis by combining tuberculin skin testing and QuantiFERON-TB Gold markedly reduces public health costs compared with tuberculin skin test screening alone.

Cost-effectiveness of isoniazid chemoprevention in close contacts.

The aim of the present study was to perform a cost-effectiveness analysis in young and middle-aged adults with latent tuberculosis (TB) infection in Germany. A Markov model simulated the progression of 20- and 40-yr-old close contacts of active TB cases over 20 yrs. Health and economic outcomes of isoniazid (INH) chemoprevention versus no intervention were compared. The analysis determined the incremental cost-effectiveness ratio in terms of cost per quality-adjusted life year and the difference between numbers of TB cases and of TB-related deaths. INH chemoprevention prevented 79% of expected TB cases in both age groups, and saved 9,482 and 9,142 in the lower and higher age groups, respectively, per case prevented. Quality-adjusted life expectancy was slightly extended by 8 days in the lower age group and 7 days in the higher age group, at a cost saving of 417 and 375, respectively, per person. Annual savings were 20,862 and 18,742 per 1,000 contacts, respectively. The number needed to be treated to prevent one TB case in the lower age group was 23 and 25 in the higher age group. The programme also prevented three TB-related deaths in the younger and two in the older cohort. The results are highly sensitive to treatment-cost assumptions. In conclusion, isoniazid chemoprevention in Germany is a highly cost-effective approach for reducing the burden of tuberculosis in recently converted young and middle-aged adults.

[Pedicle torsion of the accessory spleen within the scope of the "polysplenia-asplenia complex" as a rare differential diagnosis of acute abdomen]. / Die stielgedrehte Nebenmilz im Rahmen eines "Polysplenie-Asplenie-Komplexes" als seltene Differentialdiagnose des akuten Abdomens.

A 25 year old female patient with a painful palpable tumour in the right flank was admitted to our hospital presenting signs and symptoms of an acute abdomen. During explorative laparotomy unexpected haemorrhagic infarction of a splenula caused by a volvulus of the vascular pedicle was found. In spite of the documentation of multiple positional abnormalities of visceral organs preoperative diagnostic imaging techniques were unable to point to the diagnosis because of an uncommon rightsideness of the polysplenism. In the case of an indefinite rightsided abdominal mass defects of embryonic morphogenesis should be always taken into consideration.

[Acute abdomen in hemorrhage into a twisted pedicled ectopic second spleen in the right mesogastrum]. / Akutes Abdomen bei Einblutung in eine stielgedrehte, ektope Zweitmilz im rechten Mittelbauch.

A woman patient of 25 years of age was admitted with a tumour in the right meogastrium that was painful on pressure, the clinical pattern being that of an acute abdomen. At exploratory laparotomy we were surprised to find haemorrhagic infarction of a second spleen by volvulus of the vascular peduncle. Preoperative imaging had not yielded any pointer despite documentation of multiple positional anomalies of visceral organs, since the polysplenic status was exceptionally located at the right side. If abdominal findings on the right side cannot be interpreted quite clearly, differential diagnosis should always consider the possibility of unusual embryonal lateral positioning of organs.

[Enlarged iliopsoas bursa. Possible significance and place of computed tomography and sonography]. / Vergrösserte Bursa iliopsoas. Aussagemöglichkeiten und Stellenwert der Computertomographie und Sonographie.

A 48-year-old man was admitted to hospital with symptoms of a deep venous thrombosis of the iliac vein. Ultrasound and computed tomography allowed the uncommon diagnosis of an enlarged bursa of the iliopsoas muscle with secondary compression of the iliac vein. Histological work-up after bursectomy confirmed this diagnosis.

[Primary adenomyomatosis of the choledochus as a rare cause of obstructive jaundice]. / Primäre Adenomyomatose des Ductus choledochus als seltene Ursache eines Verschlussikterus.

A 75-year-old man was hospitalized with marked signs of extrahepatic obstructive jaundice. On the basis of morphological criteria the uncommon diagnosis of primary adenomyosis of the common bile duct was made using sonography and established histologically after endoscopic sphincterotomy. The symptoms were therefore promptly to be controlled. Primary adenomyosis should be considered in the differential diagnosis of any aetiologically unexplained extrahepatic cholestasis.