Point-of-care COVID-19 antigen testing in German emergency rooms - a cost-benefit analysis.

BACKGROUND: The current COVID-19 pandemic is causing significant morbidity and death worldwide and produces significant socio-economic losses. OBJECTIVE: To assess the cost-benefit relation of implementing point-of-care COVID-19 antigen testing (POCT) in emergency rooms (ER) of German hospitals. METHODS: A deterministic decision-analytic model simulated the incremental costs of using the Sofia® SARS Antigen FIA test compared to those of using clinical judgement alone to confirm or exclude COVID-19 in adult patients in German ER, prior to hospitalization. Direct and indirect costs, with and without subsequent RT-PCR confirmation, were evaluated from the hospital perspective. RESULTS: With respect to ER patients, in base-case analysis, considering a COVID-19 prevalence of 15.6% and a hospitalization rate among COVID-19 suspects of 10.1%, POCT testing reduces average costs of hospitalized patients by €213 per tested patient if nasopharyngeal swabs of patients suspected to have COVID-19 are also sent to external labs for RT-PCR testing. In probabilistic sensitivity analysis, under all reasonable assumptions, implementing the Sofia® SARS Antigen FIA saves on average about €210 as compared to applying the clinical-judgement-only strategy. The major part of cost savings, €159 or 75.9%, is due to the POC test´s high specificity resulting in a 21-fold lower proportion of unnecessary bed blocking at the first day of hospitalization. CONCLUSIONS: Using highly specific rapid COVID-19 tests in COVID-19 suspects at German ER, despite of their sub-optimal sensitivity, may significantly reduce hospital expenditure.

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.

Cost of multidrug resistant tuberculosis in Germany-An update.

BACKGROUND: In 2019, new therapeutic recommendations for multidrug-resistant (MDR-) and extensively drug-resistant (XDR) tuberculosis (TB) were published by the WHO, advocating the use of oral drugs and stepwise composition of antibiotic regimens. To date, the economic consequences of those recommendations in low incidence settings have not been evaluated. OBJECTIVE: To assess the costs of applying the new recommendations against a set of 86 MDR-TB/XDR-TB strains, each with individual phenotypic drug resistance patterns, identified in 2018/2019 by the German National Reference Center for Mycobacteria. METHODS: Hospitalization costs as covered by German statutory health insurance and the loss of productivity due to illness were calculated using the most recent 2018 statistical data. Costs due to combining five agents in the intensive phase and costs of outpatient monitoring were determined by Monte-Carlo simulation covering all treatment options over an 18-month period. Drug costs were compared to those arising under the approach recommended by the WHO in 2016. RESULTS: Hospitalization costs per MDR-TB patient were €30,152 and the mean costs of antimicrobials over a period of 18 months were €66,854 (range €20,671 to €187,444). Total treatment costs, including outpatient monitoring, were €73,551.56 per patient (range €30,114 to €145.878). In addition, we determined an average cost of €11,410.20 due to productivity loss over a period of 6 months sick leave. Despite a shortened minimum recommended treatment duration (18 versus 20 months), the estimated costs were 24.5% higher based on the 2019 recommendations as compared to the 2016 guideline version. CONCLUSION: Higher costs for treating MDR-TB/XDR-TB in Germany are to be expected under the new WHO regimens. However, it must be determined whether treatment duration and costs associated with sick leave may be further reduced in the future through shorter hospital stays and earlier culture conversion.

Real-world treatment patterns in patients with nontuberculous mycobacterial lung disease in general and pneumologist practices in Germany.

BACKGROUND: Nontuberculous mycobacterial lung disease (NTMLD) is a rare, progressive disease with an increasing incidence worldwide. AIMS: The aim of this retrospective study was to analyze the baseline characteristics and management of NTMLD in general and pneumologist practices in Germany. METHODS: This retrospective study included patients with a culture-confirmed diagnosis of NTMLD documented between October 1, 2014 and September 30, 2019 by 125 general practitioners (GP) and 31 office-based pulmonologists from the IMS Disease Analyzer Database (IQVIA). RESULTS: A total of 159 patients managed by German GPs (mean age 59 ± 19 years, 51% female) and 236 patients managed by pulmonologists (mean age 62 ± 14 years, 58% female) were analyzed. In total, 45% (72/159) and 40% (94/236) of patients managed by GPs and pulmonologists respectively received antibiotic therapy for NTMLD. This therapy lasted for ≥ 6 months in 42%, for ≥ 12 months in 24%, and ≥ 18 months in 8% of patients. The average therapy duration was longer in patients treated by pulmonologists (241 ± 196 days) than in patients treated by GPs (113 ± 152 days). A total of 27% of patients managed by GPs and 45% of those managed by pulmonologists respectively received guideline-based therapy (GBT), defined as combination therapy with macrolide (azi-/ clarithromycin) + ethambutol + rifabutin/rifampicin, at least once; however, almost all patients (100% in the GP group, 96% in the pulmonologist group) also received non-GBT regimens intermediately. CONCLUSIONS: A considerable number of patients with NTMLD were not managed in accordance with the German guidelines and a substantial proportion also discontinue therapy prematurely. NTMLD management should be improved through appropriate referral pathways and collaboration between expert centers and primary or secondary care physicians.

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.

Cost of multi drug resistance tuberculosis in Germany.

OBJECTIVES: 4220 new cases of tuberculosis (TB) were reported in Germany in 2012; of those, 65 cases were multidrug-resistant TB (MDR-TB) or extensively multidrug-resistant TB (XDR-TB) cases. However, there is only limited information on the economic consequences of drug resistance patterns on the treatment costs of MDR-and XDR-TB patients. METHODS: On the basis of drug susceptibility of the single MDR-TB/XDR-TB strains the direct medical costs of suitable therapies were calculated according to the current guidelines of the World Health Organization (WHO) and those of the German Central Committee against Tuberculosis. These costs were combined with hospital and outpatients monitoring costs and followed the most recent German invoicing system and health statistics. Total drug and monitoring costs and were determined by Monte-Carlo simulation comprising all different options. RESULTS: According to this, the mean drug costs were €51,113.22 (range €19,586.14 to €94,767.90). The weighted costs for hospitalization were €26,000.76 per patient compared to only €2,192.13 for primary outpatients; the total treatment costs of MDR-TB amounted to €64,429.23. These are joined by the costs due to loss of productivity, varying between €17,721.60 and €44,304. From a societal perspective, the total cost per MDR-TB/XDR-TB case reach an amount between €82,150 and €108,733 per case, respectively. CONCLUSION: Cost analyses based on strain resistance patterns allow more reliable estimates of the real costs of treating MDR-TB/XDR-TB than do methods that ignore this factor. Advantageously, they demonstrate the economic impact of drug-resistant TB in low-incidence countries. Costs of productivity loss is of new importance because of the length of MDR-XDR therapy, but its true share of total costs has still to be determined.

Cost-effectiveness analysis of interventions for tuberculosis control: DALYs versus QALYs.

The emergence of multi-drug-resistant tuberculosis (MDR-TB) in the European region and the high costs (nearly 536 million) generated by the nearly 72,000 notified TB cases in the EU are the factors driving the need for development and implementation of new tools against TB. In this context, cost-effectiveness analyses applying quality-adjusted life-years (QALYs) or disability-adjusted life-years (DALYs) as outcome measures for economic evaluation of improved approaches to TB control are increasingly important. While the methodology applied to derive the effectiveness data is commonly reported, less information is given regarding the derivation of utility weights in the calculation of QALYs for TB treatment. To date, despite the particular complexities of the disease, TB health effects have not been fully measured and there is no agreement on how disutility of TB disease should be accounted for. Consequently, disutility values in published studies vary considerably, and often appear to lack empirical evidence. As the need for a solid heath-economics rationale for investment in new tools against TB grows, adequate and comprehensive methods for assessing the impairments caused by different types of TB must be developed. Focusing on the assessment of DALYs as a measure of outcome in economic evaluation, we have built an exemplary model calculation applying the original TB data for Germany as reported to the Robert Koch Institute. Our work demonstrates that the use of standard equations provided in the scientific literature probably results in an underestimation of lost DALYs compared with probabilistic techniques. Providing distributions around epidemiological averages, coupled with Monte Carlo simulation to address uncertainty, may result in more realistic values. In line with a previous recommendation by the World Health Organization, it appears worthwhile to consider this more intricate approach to providing healthcare resource allocation decisions, particularly for TB.

[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.

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.

[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.

[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.