[Recommendations for Contact Tracing for Tuberculosis - Update 2023]. / Empfehlungen für die Umgebungsuntersuchungen bei Tuberkulose ­ Update 2023.

The aim of contact tracing for tuberculosis is in addition to active case finding the detection of chains of infection and the prevention of the further spread of the disease. In this context, a careful selection of contact persons is necessary, depending on the type and duration of contact, to identify persons who are recently infected and therefore to increase the benefit of a preventive therapy and to avoid unnecessary testing of persons who are not at risk of infection. Since the last update of the recommendations on contact tracing, data on the use of interferon-y release assays (IGRAs) in children has been improved markedly. These are the preferred test in contact tracing of adults. For children, both IGRAs and the tuberculin skin test can be used equivalently. Rifampicin for 4 months, rifampicin and isoniazid for 3 months, or isoniazid for 9 months are recommended as preventive therapy in cases of confirmed infection.The implementation of the contact tracing in different age groups as well as legal framework conditions and socio-medical aspects and challenges are dealt with in detail. In addition, special cases, such as environmental screening in day-care centers, schools, or other community facilities, are discussed separately.

[Recommendations for contact tracing for tuberculosis - update 2023]. / Empfehlungen für die Umgebungsuntersuchungen bei Tuberkulose ­ Update 2023.

The aim of contact tracing for tuberculosis is in addition to active case finding the detection of chains of infection and the prevention of the further spread of the disease. In this context, a careful selection of contact persons is necessary, depending on the type and duration of contact, to identify persons who are recently infected and therefore to increase the benefit of a preventive therapy and to avoid unnecessary testing of persons who are not at risk of infection. Since the last update of the recommendations on contact tracing, data on the use of interferon-y release assays (IGRAs) in children has been improved markedly. These are the preferred test in contact tracing of adults. For children, both IGRAs and the tuberculin skin test can be used equivalently. Rifampicin for 4 months, rifampicin and isoniazid for 3 months, or isoniazid for 9 months are recommended as preventive therapy in cases of confirmed infection.The implementation of the contact tracing in different age groups as well as legal framework conditions and socio-medical aspects and challenges are dealt with in detail. In addition, special cases, such as environmental screening in day-care centers, schools, or other community facilities, are discussed separately.

[Tuberculosis Infection Control & Hygiene - Recommendations of the DZK]. / Infektionsprävention & Hygiene bei Tuberkulose ­ Empfehlungen des DZK.

Preventing the spread of the disease is an essential goal in the care and treatment of tuberculosis. In addition to early diagnosis and effective therapies, isolation of infectious patients and adequate hygiene measures are of particular importance for infection prevention. The present recommendations replace the previous recommendations "tuberculosis infection control" from 2012 and take into account the current national and international recommendations and as well as new scientific findings. After a description of the infection and the transmission pathways, the necessary prevention and hygiene measures in health care facilities are comprehensively presented. Since the last revision of the recommendations on infection prevention, international recommendations and the KRINKO recommendation on ending isolation have been changed. In accordance with this, under certain conditions in the case of sensitive tuberculosis, de-isolation in health care facilities can take place after 14 days without taking the sputum findings into account. The second part of the recommendations explains in detail the measures to be taken in special situations and areas, such as general practitioners, ambulance services and care facilities. Here, the recommendations on respiratory protection have been simplified; for staff, an FFP2 mask is now generally considered sufficient.

Insertion and deletion evolution reflects antibiotics selection pressure in a Mycobacterium tuberculosis outbreak.

In genome evolution, genetic variants are the source of diversity, which natural selection acts upon. Treatment of human tuberculosis (TB) induces a strong selection pressure for the emergence of antibiotic resistance-conferring variants in the infecting Mycobacterium tuberculosis (MTB) strains. MTB evolution in response to treatment has been intensively studied and mainly attributed to point substitutions. However, the frequency and contribution of insertions and deletions (indels) to MTB genome evolution remains poorly understood. Here, we analyzed a multi-drug resistant MTB outbreak for the presence of high-quality indels and substitutions. We find that indels are significantly enriched in genes conferring antibiotic resistance. Furthermore, we show that indels are inherited during the outbreak and follow a molecular clock with an evolutionary rate of 5.37e-9 indels/site/year, which is 23 times lower than the substitution rate. Inherited indels may co-occur with substitutions in genes along related biological pathways; examples are iron storage and resistance to second-line antibiotics. This suggests that epistatic interactions between indels and substitutions affect antibiotic resistance and compensatory evolution in MTB.

Recommendations for immunocytochemistry in lung cancer typing: An update on a resource-efficient approach with large-scale comparative Bayesian analysis.

OBJECTIVES: The majority of lung cancer cases are of advanced stage and diagnosis is usually made using minimally invasive small biopsies and cytological specimens. The WHO 2015 classification recommends limiting immunocytochemistry (ICC) to lung cancer typing and molecular testing drives for personalised therapies. An algorithm using Bayes' theorem could be useful for defining antibody profiles. This study aims to assess the impact of different antibody profiles for cytological samples on the accuracy of lung cancer typing with a large-scale Bayesian analysis. METHODS: A retrospective examination of 3419 consecutive smears and/or cytospins diagnosed over 2011-2016 found 1960 primary lung cancer tumours: 972 adenocarcinomas (ADC), 256 squamous carcinomas (SQC), 268 neuroendocrine tumours (NET), and 464 non-small cell cancer-not otherwise specified (NSCC-NOS). The a priori and a posteriori probabilities, before and after ICC using antibodies singly or in combination, were calculated for different lung cancer types. RESULTS: TTF-1 or CK7 alone improved the a posteriori probabilities of correct cytological typing for ADC to 86.5% and 95.8%, respectively. For SQC, using p40 (∆Np63) or CK5/6 together with CK5/14 led to comparable results (78.3% and 90.3%). With synaptophysin or CD56 alone, improvements in a posteriori probabilities to 87.5 and 90.3% for the correct recognition of NET could be achieved. CONCLUSIONS: Based on morphological and clinical data, the use of two antibodies appears sufficient for reliable detection of the different lung cancer types. This applies to diagnoses that were finalised following ICC both on a clinical or cytological basis and on a histological basis.

[Patients with lung disease caused by non-tuberculous mycobacteria in Germany: a trans-sectoral patient-oriented care concept]. / Versorgung von Patienten/innen mit einer durch nichttuberkulöse Mykobakterien verursachten Lungenerkrankung in Deutschland ­ ein transsektorales patientenorientiertes Versorgungskonzept.

INTRODUCTION: Management of patients with lung disease caused by non-tuberculous mycobacteria (NTM-LD) in Germany is currently characterized by delayed diagnosis, frequently poor prognosis and high follow-up costs. Mainly due to an increased number of hospitalizations, the SHI-relevant direct costs (€ 9,093.20 patient/year) are higher compared to typical underlying diseases (e.g. asthma: € 706.00 patient/year). This less than optimal NTM care is mainly caused by lack of awareness of the disease at primary care and out-patient specialist care level, largely absent structured referral structures and limited communication between specialists out of hospital with specialized NTM clinics. Lack of incentives to support these communication pathways is part of the problem. Sufficient, appropriate and economically sustainable care is hampered by poor adherence to treatment recommendations. METHODS: For the development of the NTM care concept, relevant professional societies and patient organizations were interviewed about the care situation. Thereafter, 20 NTM-LD patients, 5 residential pulmonologists and 8 experts were interviewed in an explorative qualitative interview to determine the current patient pathway. Based on the findings, the NTM care concept was developed in an advisory board by the authors. RESULTS: Regional management centers should concentrate specific expertise and ensure quality of care through routine consultation and involvement in diagnosis, decision-making on treatment necessity, initiation of therapy, follow-up examinations, and determination of the therapy success, as well as adequate follow-up of patients. The referring pulmonologist should continue to provide case-specific therapy support close to the patient's home in preferred shared-care concept. The establishment of clear referral structures and case identification criteria will help residential physicians to include patients at risk in the NTM-care system early. Patients and pulmonologists without specific expertise need to be made aware of the care pathway and severity of NTM-LD. CONCLUSION: The increased morbidity and mortality of NTM-LD patients must be addressed with patient-oriented, interdisciplinary and trans-sectoral care concept. An NTM care system with clear treatment procedures and referral structures is proposed for a nationwide pilot project.

Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing.

BACKGROUND: The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear. METHODS: We obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance. RESULTS: A total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted. CONCLUSIONS: Genotypic predictions of the susceptibility of M. tuberculosis to first-line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.).

SNP-IT Tool for Identifying Subspecies and Associated Lineages of Mycobacterium tuberculosis Complex.

The clinical phenotype of zoonotic tuberculosis and its contribution to the global burden of disease are poorly understood and probably underestimated. This shortcoming is partly because of the inability of currently available laboratory and in silico tools to accurately identify all subspecies of the Mycobacterium tuberculosis complex (MTBC). We present SNPs to Identify TB (SNP-IT), a single-nucleotide polymorphism-based tool to identify all members of MTBC, including animal clades. By applying SNP-IT to a collection of clinical genomes from a UK reference laboratory, we detected an unexpectedly high number of M. orygis isolates. M. orygis is seen at a similar rate to M. bovis, yet M. orygis cases have not been previously described in the United Kingdom. From an international perspective, it is possible that M. orygis is an underestimated zoonosis. Accurate identification will enable study of the clinical phenotype, host range, and transmission mechanisms of all subspecies of MTBC in greater detail.

Economic burden of bronchiectasis in Germany.

Estimates of healthcare costs for incident bronchiectasis patients are currently not available for any European country.Out of a sample of 4 859 013 persons covered by German statutory health insurance companies, 231 new bronchiectasis patients were identified in 2012. They were matched with 685 control patients by age, sex and Charlson Comorbidity Index, and followed for 3 years.The total direct expenditure during that period per insured bronchiectasis patient was EUR18 634.57 (95% CI EUR15 891.02-23 871.12), nearly one-third higher (ratio of mean 1.31, 95% CI 1.02-1.68) than for a matched control (p<0.001). Hospitalisation costs contributed to 35% of the total and were >50% higher in the bronchiectasis group (ratio of mean 1.56, 95% CI 1.20-3.01; p<0.001); on average, bronchiectasis patients spent 4.9 (95% CI 2.27-7.43) more days in hospital (p<0.001). Antibiotics expenditures per bronchiectasis outpatient (EUR413.81) were nearly 5 times higher than those for a matched control (ratio of mean 4.85, 95% CI 2.72-8.64). Each bronchiectasis patient had on average 40.5 (95% CI 17.1-43.5) sick-leave days and induced work-loss costs of EUR4230.49 (95% CI EUR2849.58-5611.20). The mortality rate for bronchiectasis and matched non-bronchiectasis patients after 3 years of follow-up was 26.4% and 10.5%, respectively (p<0.001). Mortality in the bronchiectasis group was higher among those who also had chronic obstructive lung disease than in patients with bronchiectasis alone (35.9% and 14.6%, respectively; p<0.001).Although bronchiectasis is considered underdiagnosed, the mortality and associated financial burden in Germany are substantial.

The economic burden of bronchiectasis - known and unknown: a systematic review.

BACKGROUND: The increasing prevalence and recognition of bronchiectasis in clinical practice necessitates a better understanding of the economic disease burden to improve the management and achieve better clinical and economic outcomes. This study aimed to assess the economic burden of bronchiectasis based on a review of published literature. METHODS: A systematic literature review was conducted using MEDLINE, Embase, EconLit and Cochrane databases to identify publications (1 January 2001 to 31 December 2016) on the economic burden of bronchiectasis in adults. RESULTS: A total of 26 publications were identified that reported resource use and costs associated with management of bronchiectasis. Two US studies reported annual incremental costs of bronchiectasis versus matched controls of US$5681 and US$2319 per patient. Twenty-four studies reported on hospitalization rates or duration of hospitalization for patients with bronchiectasis. Mean annual hospitalization rates per patient, reported in six studies, ranged from 0.3-1.3, while mean annual age-adjusted hospitalization rates, reported in four studies, ranged from 1.8-25.7 per 100,000 population. The average duration of hospitalization, reported in 12 studies, ranged from 2 to 17 days. Eight publications reported management costs of bronchiectasis. Total annual management costs of €3515 and €4672 per patient were reported in two Spanish studies. Two US studies reported total costs of approximately US$26,000 in patients without exacerbations, increasing to US$36,00-37,000 in patients with exacerbations. Similarly, a Spanish study reported higher total annual costs for patients with > 2 exacerbations per year (€7520) compared with those without exacerbations (€3892). P. aeruginosa infection increased management costs by US$31,551 to US$56,499, as reported in two US studies, with hospitalization being the main cost driver. CONCLUSIONS: The current literature suggests that the economic burden of bronchiectasis in society is significant. Hospitalization costs are the major driver behind these costs, especially in patients with frequent exacerbations. However, the true economic burden of bronchiectasis is likely to be underestimated because most studies were retrospective, used ICD-9-CM coding to identify patients, and often ignored outpatient burden and cost. We present a conceptual framework to facilitate a more comprehensive assessment of the true burden of bronchiectasis for individuals, healthcare systems and society.

High mortality in patients with Mycobacterium avium complex lung disease: a systematic review.

BACKGROUND: The incidence of nontuberculous mycobacterial (NTM) pulmonary disease caused by Mycobacterium avium complex (MAC) in apparently immune-competent people is increasing worldwide. We performed a systematic review of the published literature on five-year all-cause mortality in patients with MAC lung disease, and pooled the mortality rates to give an overall estimate of five-year mortality from these studies. METHODS: We systematically reviewed the literature up to 1st August 2017 using PubMed® and ProQuest Dialog™ to search Medline® and Embase® databases, respectively. Eligible studies contained > 10 patients with MAC, and numerical five-year mortality data or a treatment evaluation for this patient group. Mortality data were extracted and analysed to determine a pooled estimate of all-cause mortality. RESULTS: Fourteen of 1035 identified studies, comprising 17 data sets with data from a total of 9035 patients, were eligible. The pooled estimate of five-year all-cause mortality was 27% (95% CI 21.3-37.8%). A high degree of heterogeneity was observed (I2 = 96%). The mortality in the data sets varied between 10 and 48%. Studies predominantly including patients with cavitary disease or greater comorbidity reported a higher risk of death. Patients in Asian studies tended to have a lower mortality risk. Predictors of mortality consistent across studies included male sex, presence of comorbidities and advanced patient age. CONCLUSIONS: Despite high heterogeneity, most studies in patients with MAC pulmonary disease document a five-year all-cause mortality exceeding 25%, indicating poor prognosis. These findings emphasise the need for more effective management and additional prospective mortality data collection.

Some Synonymous and Nonsynonymous gyrA Mutations in Mycobacterium tuberculosis Lead to Systematic False-Positive Fluoroquinolone Resistance Results with the Hain GenoType MTBDRsl Assays.

In this study, using the Hain GenoType MTBDRsl assays (versions 1 and 2), we found that some nonsynonymous and synonymous mutations in gyrA in Mycobacterium tuberculosis result in systematic false-resistance results to fluoroquinolones by preventing the binding of wild-type probes. Moreover, such mutations can prevent the binding of mutant probes designed for the identification of specific resistance mutations. Although these mutations are likely rare globally, they occur in approximately 7% of multidrug-resistant tuberculosis strains in some settings.

Role of Alanine Racemase Mutations in Mycobacterium tuberculosis d-Cycloserine Resistance.

A screening of more than 1,500 drug-resistant strains of Mycobacterium tuberculosis revealed evolutionary patterns characteristic of positive selection for three alanine racemase (Alr) mutations. We investigated these mutations using molecular modeling, in vitro MIC testing, as well as direct measurements of enzymatic activity, which demonstrated that these mutations likely confer resistance to d-cycloserine.

Burden of non-tuberculous mycobacterial pulmonary disease in Germany.

The objective of this study was to estimate the burden of disease in incident patients with non-tuberculous mycobacterial pulmonary disease (NTM-PD).A sample of 7 073 357 anonymised persons covered by German public statutory health insurances was used to identify patients with NTM-PD. In total, 125 patients with newly diagnosed NTM-PD in 2010 and 2011 were matched with 1250 control patients by age, sex and Charlson Comorbidity Index, and followed for 39 months.The incidence rate for NTM-PD was 2.6 per 100 000 insured persons (95% CI 2.2-3.1). The mortality rate for patients with NTM-PD and the control group in the observational period was 22.4% and 6%, respectively (p<0.001). Mean direct expenditure per NTM-PD patient was €39 559.60 (95% CI 26 916.49-52 202.71), nearly 4-fold (3.95, 95% CI 3.73-4.19) that for a matched control (€10 006.71, 95% CI 8907.24-11 106.17). Hospitalisations were three times higher in the NTM-PD group and accounted for 63% of the total costs. Attributable annual direct costs and indirect work-loss costs in NTM-PD patients were €9093.20 and €1221.05 per control patient, respectively. Only 74% of NTM-PD patients received antibiotics and nearly 12% were prescribed macrolide monotherapy.Although NTM-PD is considered rare, the attributable mortality and financial burden in Germany are high. Efforts to heighten awareness of appropriate therapy are urgently needed.

Yield of chest X-ray tuberculosis screening of immigrants during the European refugee crisis of 2015: a single-centre experience.

OBJECTIVE: Our aim was to determine the prevalence of tuberculosis (TB), the number needed to screen (NNS), and the diagnostic accuracy of chest X-ray (CXR) screening to detect active pulmonary TB during the 2015 European refugee crisis. MATERIALS AND METHODS: We evaluated data of all refugees who underwent CXR screening in a single-centre of one German metropolitan area in 2015. We determined the prevalence of TB, NNS, and accuracy of CXR to detect active pulmonary TB. Reference method for active TB was the database of all definite TB cases registered at the Department of Public Health. RESULTS: A total of 17,487 immigrants underwent single-centre CXR screening in 2015; prevalence of definite pulmonary TB was 0.103%. The NNS for detecting one case of active pulmonary TB was 1749. CXR had a sensitivity of 55.6% [95% confidence interval (CI) 30.8-78.5%) and a specificity 98.3% (CI 98.1-98.5%) to reveal one case of active TB. CONCLUSION: Our single-centre study indicates that chest X-ray screening for TB during the 2015 European refugee crisis was of low yield due the low prevalence of TB and high number needed to screen, thus implicating the need for improved screening algorithms adapted to the overwhelming number of refugees. KEY POINTS: • Prevalence of pulmonary tuberculosis (TB) among refugees in 2015 was low (0.103%). • The number needed to screen to detect one case of active pulmonary TB was 1749. • Tuberculosis X-ray screening resulted in a low sensitivity and high specificity. • Tuberculosis X-ray screening during the European refugee crisis is of low yield. • Improved screening algorithms are needed due to the overwhelming the number of refugees.

Risk for latent and active tuberculosis in Germany.

PURPOSE: Few individuals that are latently infected with M. tuberculosis latent tuberculosis infection(LTBI) progress to active disease. We investigated risk factors for LTBI and active pulmonary tuberculosis (PTB) in Germany. METHODS: Healthy household contacts (HHCs), health care workers (HCWs) exposed to M. tuberculosis and PTB patients were recruited at 18 German centres. Interferon-γ release assay (IGRA) testing was performed. LTBI risk factors were evaluated by comparing IGRA-positive with IGRA-negative contacts. Risk factors for tuberculosis were evaluated by comparing PTB patients with HHCs. RESULTS: From 2008-2014, 603 HHCs, 295 HCWs and 856 PTBs were recruited. LTBI was found in 34.5% of HHCs and in 38.9% of HCWs. In HCWs, care for coughing patients (p = 0.02) and longstanding nursing occupation (p = 0.04) were associated with LTBI. In HHCs, predictors for LTBI were a diseased partner (odds ratio 4.39), sexual contact to a diseased partner and substance dependency (all p < 0.001). PTB was associated with male sex, low body weight (p < 0.0001), alcoholism (15.0 vs 5.9%; p < 0.0001), glucocorticoid therapy (7.2 vs 2.0%; p = 0.004) and diabetes (7.8 vs. 4.0%; p = 0.04). No contact developed active tuberculosis within 2 years follow-up. CONCLUSIONS: Positive IGRA responses are frequent among exposed HHCs and HCWs in Germany and are poor predictors for the development of active tuberculosis.

[Tuberculosis Guideline for Adults - Guideline for Diagnosis and Treatment of Tuberculosis including LTBI Testing and Treatment of the German Central Committee (DZK) and the German Respiratory Society (DGP)]. / S2k-Leitlinie: Tuberkulose im Erwachsenenalter.

Since 2015 a significant increase in tuberculosis cases is notified in Germany, mostly due to rising numbers of migrants connected to the recent refugee crisis. Because of the low incidence in previous years, knowledge on tuberculosis is more and more limited to specialized centers. However, lung specialist and healthcare workers of other fields have contact to an increasing number of tuberculosis patients. In this situation, guidance for the management of standard therapy and especially for uncommon situations will be essential. This new guideline on tuberculosis in adults gives recommendations on diagnosis, treatment, prevention and prophylaxis. It provides a comprehensive overview over the current knowledge, adapted to the specific situation in Germany. The German Central Committee against Tuberculosis (DZK e. V.) realized this guideline on behalf of the German Respiratory Society (DGP). A specific guideline for tuberculosis in the pediatrics field will be published separately. Compared to the former recommendations of the year 2012, microbiological diagnostics and therapeutic drug management were given own sections. Chapters about the treatment of drug-resistant tuberculosis, tuberculosis in people living with HIV and pharmacological management were extended. This revised guideline aims to be a useful tool for practitioners and other health care providers to deal with the recent challenges of tuberculosis treatment in Germany.

Prevalence of Nontuberculous Mycobacterial Pulmonary Disease, Germany, 2009-2014.

We analyzed routine statutory health insurance claim data to determine prevalence of nontuberculous mycobacterial pulmonary disease in Germany. Documented prevalence rates of this nonnotifiable disease increased from 2.3 to 3.3 cases/100,000 population from 2009 to 2014. Prevalence showed a strong association with advanced age and chronic obstructive pulmonary disease.