Differential rates of Mycobacterium tuberculosis transmission associate with host-pathogen sympatry.

Several human-adapted Mycobacterium tuberculosis complex (Mtbc) lineages exhibit a restricted geographical distribution globally. These lineages are hypothesized to transmit more effectively among sympatric hosts, that is, those that share the same geographical area, though this is yet to be confirmed while controlling for exposure, social networks and disease risk after exposure. Using pathogen genomic and contact tracing data from 2,279 tuberculosis cases linked to 12,749 contacts from three low-incidence cities, we show that geographically restricted Mtbc lineages were less transmissible than lineages that have a widespread global distribution. Allopatric host-pathogen exposure, in which the restricted pathogen and host are from non-overlapping areas, had a 38% decrease in the odds of infection among contacts compared with sympatric exposures. We measure tenfold lower uptake of geographically restricted lineage 6 strains compared with widespread lineage 4 strains in allopatric macrophage infections. We conclude that Mtbc strain-human long-term coexistence has resulted in differential transmissibility of Mtbc lineages and that this differs by human population.

Correction: The effect of M. tuberculosis lineage on clinical phenotype.

[This corrects the article DOI: 10.1371/journal.pgph.0001788.].

Costs of non-multidrug-resistant pulmonary tuberculosis and of preventive treatment in Germany - An update.

Background: Only 4076 new cases of tuberculosis (TB) were reported in Germany in 2022; of those 184 were multidrug-resistant TB (MDR-/RR-TB). Methods: Based on the current therapy guidelines of the German Central Committee against Tuberculosis and most recent renumeration data of the Statutory Health Insurances (SHI), this study estimates the mean in- and outpatient costs per adult infectious pulmonary non-MDR-TB patient, together with costs arising from Rifampicin (RIF)-based short-course options of tuberculosis preventive treatment (TPT) of their close contacts. Results: From the insurance perspective, the mean inpatient cost (rounded) per adult case was 6138 EUR (SD±2810 EUR) for standard therapy; the cost of primary outpatient treatment only amounted to 1930 EUR and the cost of outpatient treatment post-hospital to 1093 EUR. The mean weighted cost was 6377 EUR (SD±2357 EUR), a drop of 27 % vs. 2019. This is mainly due to a decrease in hospitalizations of 5.6 %, and, given hospital treatment, by a 95 EUR decrease in the per-day reimbursement rate for TB patients who are hospitalized for at least 14 days. In contrast, the mean costs of TPT per person were 466 EUR (RIF solely over 4 months) and 423 EUR (RIF combined with Isoniazid over 3 months). Conclusion: While costs for active non-MDR-TB treatment in Germany have clearly decreased thanks to increased engagement on the part of the private practice sector and lower reimbursement rates in hospital, the comparatively high costs of short-course TPT have surprisingly significant economic impact. This negative development can be countered through diligent selection of close contacts persons of infectious TB cases before using IGRA testing to detect latent TB, to minimize the number of those persons who are tested falsely determined to be at risk and needlessly undergo TPT.

Risk of SARS-CoV-2 infection in dental healthcare workers - a systematic review and meta-analysis.

Background: Mounting evidence supports an association between the use of personal protective equipment (PPE) and the risk of infection from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in dental healthcare workers (DCW). However, the prevalence and incidence of SARS-CoV-2 infections in the setting of dental care remains poorly characterized. Methods: A systematic review and meta-analysis of studies published prior to Mai 2023 providing epidemiological data for the occurrence of SARS-CoV-2 in DCW was performed. A random-effects model was used to calculate pooled estimates and odds ratios (ORs) with corresponding 95% confidence intervals (CIs). The associated factors were narratively evaluated. Risk of bias was assessed using the Joanna Briggs Institute tool for prevalence studies. Results: Twenty-nine eligible studies were identified including a total of 85,274 DCW at risk; 27 studies met the criteria for the meta-analysis. Among the included DCW, the overall prevalence of SARS-CoV-2 was 11.8% (13,155/85,274; 95%CI, 7.5%-17%), whereby the degree of heterogeneity between the studies was considerable (I2=99.7%). The pooled prevalence rate for dentists and dental hygienists alone was 12.7% (1943/20,860; 95%CI, 8.0%-18.0%), showing significantly increased odds of contracting a SARS-CoV-2 infection compared to dental assistant personnel, the prevalence rate for which was less than half, at 5.2% (613/15,066; OR=2.42; 95% CI, 2.2-2.7). In the subgroup of 17 studies from countries with high income there was a significantly lower prevalence rate of 7.3% (95% CI, 5%-10%) in DCW compared to the prevalence rate in low- and middle-income countries, which came to 20.8% (95% CI, 14%-29%; p<0.001). In 19 out of the 29 studies (65.5%), specific information on the use of and adherence to PPE was absent while in the reports with concrete figures the wearing of N95 (or at least surgical masks) by DCW appeared to be associated with lower SARS-CoV-2 prevalence rates. Conclusions: DCW were, depending in each case on their proximity to patients, at particular risk of SARS-CoV-2 infection during the COVID-19 pandemic. Until a significant level of vaccination protection against newer SARS-CoV-2 variants can be built up in the population, dental healthcare facilities should further maintain their focus on using PPE according to current guidelines.

The effect of M. tuberculosis lineage on clinical phenotype.

Six lineages of Mycobacterium tuberculosis sensu stricto (which excludes M. africanum) are described. Single-country or small observational data suggest differences in clinical phenotype between lineages. We present strain lineage and clinical phenotype data from 12,246 patients from 3 low-incidence and 5 high-incidence countries. We used multivariable logistic regression to explore the effect of lineage on site of disease and on cavities on chest radiography, given pulmonary TB; multivariable multinomial logistic regression to investigate types of extra-pulmonary TB, given lineage; and accelerated failure time and Cox proportional-hazards models to explore the effect of lineage on time to smear and culture-conversion. Mediation analyses quantified the direct effects of lineage on outcomes. Pulmonary disease was more likely among patients with lineage(L) 2, L3 or L4, than L1 (adjusted odds ratio (aOR) 1.79, (95% confidence interval 1.49-2.15), p<0.001; aOR = 1.40(1.09-1.79), p = 0.007; aOR = 2.04(1.65-2.53), p<0.001, respectively). Among patients with pulmonary TB, those with L1 had greater risk of cavities on chest radiography versus those with L2 (aOR = 0.69(0.57-0.83), p<0.001) and L4 strains (aOR = 0.73(0.59-0.90), p = 0.002). L1 strains were more likely to cause osteomyelitis among patients with extra-pulmonary TB, versus L2-4 (p = 0.033, p = 0.008 and p = 0.049 respectively). Patients with L1 strains showed shorter time-to-sputum smear conversion than for L2. Causal mediation analysis showed the effect of lineage in each case was largely direct. The pattern of clinical phenotypes seen with L1 strains differed from modern lineages (L2-4). This has implications for clinical management and could influence clinical trial selection strategies.

Risk of tuberculosis transmission by healthcare workers to children - a comprehensive review.

Background: Children <15 years are at elevated risk of becoming infected with M. tuberculosis complex (Mtbc). Objective: To assess the magnitude of Mtbc transmission by healthcare workers (HCW) to children. Methods: Medline, Google Scholar and Cochrane library were searched to select primary studies in which HCW was the presumed index case and exposed infants and children aged below 15 years were screened for latent TB infection (LTBI). Results: Of 4,702 abstracts, 19 original case reports covering one HCW each as presumed source case of Mtbc transmission to children, were identified. In sum, 11,511 children, of those 5,881 infants (51.1%), mostly in newborn nurseries, were considered contact persons and underwent tuberculin skin (TST) or Interferon gamma release assay (IGRA) testing. Test positivity was reported in 492/11,511 children (4.3%) coming from 14 studies. When test results considered falsely positive were excluded, the number of latently infected children decreased to 365/10,171 (3.6%). In all studies, the presumed duration of infectivity of the source case was, but the actual intensity and duration of exposure were not, decisive for the initiation of contact investigations. In only two of the studies, the contact time of the children towards the corresponding source case was estimated. Conclusions: The results of our review suggest that the risk of Mtbc transmission from HCW to children in healthcare setting is considerably lower than reported in household settings. However, as the preselection of pediatric contacts appeared in most cases to be vague, the data found in the literature probably underestimates the actual risk.

[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.

Chronic Lung Allograft Dysfunction Is Associated with Significant Disability after Lung Transplantation-A Burden of Disease Analysis in 1025 Cases.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the leading cause of death after the first postoperative years of lung transplantation (LTx). OBJECTIVE: To assess the number of disability-adjusted life years (DALYs) per patient with severe CLAD. METHODS: The clinical and demographic data of patients who received their lung transplantation between 2010 and 2020 in the Hanover Medical School (Germany) were evaluated. RESULTS: A total of 1025 lung transplant patients were followed for a median of 51 months (4.25 years); the median age at transplantation was 52.8 (interquartile range (IQR) 19) years. More than a quarter of transplant patients (271/1025 or 26.4%) developed CLAD, mostly (60%) of the bronchiolitis obliterans syndrome (BOS) phenotype. Of the CLAD patients, 99, or 36.5%, suffered from significant disability, which on average occurred after 2 years (IQR 2.55). The survival of CLAD patients with disability after transplantation was significantly lower compared to that of patients without CLAD (median 4.04 versus 5.41 years). Adjusted to the DALY estimation approach, CLAD patients lost 1.29 life years (YLL) and lived for 0.8 years with their disability (YLD), adding up to 2.09 DALYs (range 1.99-2.72) per patient. CONCLUSIONS: CLAD after lung transplantation is a major public health problem and is associated with substantial disability and costs. Further work is needed to develop therapeutic interventions that reduce its development.

[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.

[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.

Risk of tuberculosis transmission by children to healthcare workers - a comprehensive review.

Background: Healthcare workers (HCWs) are at increased risk of becoming infected with M. tuberculosis complex (Mtbc). Objective: To assess the magnitude of Mtbc transmission by children under the age of 15 years to HCW. Methods: Medline, Google Scholar and Cochrane library were searched to select primary studies in which a child was the presumed index case and exposed HCW were screened for latent TB infection (LTBI). Results: Of 4,702 abstracts, 15 original case reports covering 16 children with TB were identified. In sum, 1,395 HCW were contact persons and underwent testing. Ten of the studies reported TST conversion, amounting to 35 (2.9%) of the 1,228 HCW tested. In three of the TST-based and both of the studies that used IGRA testing, conversion was absent. 12 of the 15 studies (80%) reported exposure of HCW in neonatal intensive units (NICUs) to premature infants suffering from congenital pulmonary TB. One study including two infants addressed possible pulmonary Mtbc transmission in a general pediatric ward. Extrapulmonary transmission by aerosolized Mtbc was suggested in two patients, an infant with tuberculous peritonitis and a 12-year-old adolescent with pleurisy, and culture-confirmed only after the child had undergone video-assisted thoracoscopic surgery. Routine use of protective facemasks by HCW before exposure was not mentioned in any of the included studies. Conclusions: The results suggest that the risk of Mtbc transmission from children to HCW is low. Particular attention should be paid to infection risk during respiratory manipulations in NICUs. The consistent wearing of facemasks may further reduce the risk of Mtbc transmission.

The effect of M. tuberculosis lineage on clinical phenotype.

Eight lineages of Mycobacterium tuberculosis sensu stricto are described. Single-country or small observational data suggest differences in clinical phenotype between lineages. We present strain lineage and clinical phenotype data from 12,246 patients from 3 low-incidence and 5 high-incidence countries. We used multivariable logistic regression to explore the effect of lineage on site of disease and on cavities on chest radiography, given pulmonary TB; multivariable multinomial logistic regression to investigate types of extra-pulmonary TB, given lineage; and accelerated failure time and Cox proportional-hazards models to explore the effect of lineage on time to smear and culture-conversion. Mediation analyses quantified the direct effects of lineage on outcomes. Pulmonary disease was more likely among patients with lineage(L) 2, L3 or L4, than L1 (adjusted odds ratio (aOR) 1.79, (95% confidence interval 1.49-2.15), p<0.001; aOR=1.40(1.09-1.79), p=0.007; aOR=2.04(1.65-2.53), p<0.001, respectively). Among patients with pulmonary TB, those with L1 had greater risk of cavities on chest radiography versus those with L2 (aOR=0.69(0.57-0.83), p<0.001) and L4 strains (aOR=0.73(0.59-0.90), p=0.002). L1 strains were more likely to cause osteomyelitis among patients with extra-pulmonary TB, versus L2-4 (p=0.033, p=0.008 and p=0.049 respectively). Patients with L1 strains showed shorter time-to-sputum smear conversion than for L2. Causal mediation analysis showed the effect of lineage in each case was largely direct. The pattern of clinical phenotypes seen with L1 strains differed from modern lineages (L2-4). This has implications for clinical management and could influence clinical trial selection strategies.

Risk of tuberculosis transmission by children in Hamburg, Germany.

BACKGROUND: Data from a prospective molecular-epidemiologic study (1997-2021) in Hamburg, Germany, were evaluated to assess the transmission risk of Mycobacterium tuberculosis complex (Mtbc) by children <15 years in a low-incidence setting. METHODS: Isolates of Mtbc were genotyped whole genome sequencing, applying a core genome multilocus sequence typing scheme. Close contacts of culture-confirmed children were examined for latent Mtbc infections (LTBI) with particular focus on IGRA testing. RESULTS: Out of 3154 culture-confirmed tuberculosis (TB) cases, 79 (2.5%) were children <15 years. Of those, 52 (58%) had pulmonary TB. Genotyping revealed that 35 of the 52 children (67%) were epidemiologically confirmed secondary cluster members; all of their source cases were adults. Six immigrant children presented without a presumed source case; their TB diagnoses came on average 48 weeks (interquartile range [IQR] 71) after their arrival in Germany. Three German-born children were determined to have been infected by adult relatives while visiting their parents' home country. Of the 317 children's close contacts tested with QuantiFERON-TB Gold-In Tube for LTBI, only 21 (6.6%) were positive. Absent a history of prior exposure or immigration from a high-incidence country, none of the contacts of younger (<10 years) TB-afflicted children was latently infected, whereas 2 older children infected 12 of their contacts, children and adults. During a mean observational period of 551 weeks (IQR 735) on average, no secondary TB cases appeared. CONCLUSIONS: Children with pulmonary TB disease, especially those aged below 10 years, rarely transmit Mtbc to their close contacts in a low-incidence setting.

Pathways of TB Transmission in Children-A Systematic Review of Molecular Epidemiological Studies.

The widespread paradigm that younger children usually do not transmit M. tuberculosis complex (Mtbc) to their contacts has not yet been proven by genotypically confirmed transmissions. Therefore, we undertook a systematic review of molecular-epidemiological studies to investigate documented source and secondary TB (tuberculosis) cases among children. We searched the literature published before August 2022 using PubMed, Cochrane, and Google Scholar databases. PRISMA statement was used for systematic review. Of 312 records retrieved, 39 studies including children aged below 15 years offered epidemiological links between cluster members. In the 39 studies from 16 countries, 225 children were reported as cluster members of whom the overwhelming majority were infected by adults. Only 3 children-of those were 2 children aged below 10-were reported to be the definite source cases of 11 other children and 1 adult with genotypically matched Mtbc isolates. To date, molecular-epidemiological studies involving children with verified transmission links are scarce. As far as the heterogeneity of the studies we identified allows, we could conclude that the results confirm the paradigm that children aged below 10 hardly ever transmit Mtbc to others. The true extent of TB transmission through children may, however, be underestimated by those selected studies.

Cost-Benefit of Real-Time Multiplex PCR Testing of SARS-CoV-2 in German Hospitals.

BACKGROUND: The current Omicron COVID-19 pandemic has significant morbidity worldwide. OBJECTIVE: Assess the cost-benefit relation of implementing PCR point-of-care (POCT) COVID-19 testing in the emergency rooms (ERs) of German hospitals and in the case of inpatient admission due to other acute illnesses. METHODS: A deterministic decision-analytic model simulated the incremental costs of using the Savanna® Multiplex RT-PCR test compared to using clinical judgement alone to confirm or exclude COVID-19 in adult patients in German ERs prior to hospitalization or just prior to discharge. Direct and indirect costs were evaluated from the hospital perspective. Nasal or nasopharyngeal swabs of patients suspected to have COVID-19 by clinical judgement, but without POCT, were sent to external labs for RT-PCR testing. RESULTS: In probabilistic sensitivity analysis, assuming a COVID-19 prevalence ranging between 15.6-41.2% and a hospitalization rate between 4.3-64.3%, implementing the Savanna® test saved, on average, €107 as compared to applying the clinical-judgement-only strategy. A revenue loss of €735 can be avoided when SARS-CoV-2 infection in patients coming unplanned to the hospital due to other acute illnesses are excluded immediately by POCT. CONCLUSIONS: Using highly sensitive and specific PCR-POCT in patients suspected of COVID-19 infection at German ERs may significantly reduce hospital expenditures.

Predictive performance of interferon-gamma release assays and the tuberculin skin test for incident tuberculosis: an individual participant data meta-analysis.

Background: Evidence on the comparative performance of purified protein derivative tuberculin skin tests (TST) and interferon-gamma release assays (IGRA) for predicting incident active tuberculosis (TB) remains conflicting. We conducted an individual participant data meta-analysis to directly compare the predictive performance for incident TB disease between TST and IGRA to inform policy. Methods: We searched Medline and Embase from 1 January 2002 to 4 September 2020, and studies that were included in previous systematic reviews. We included prospective longitudinal studies in which participants received both TST and IGRA and estimated performance as hazard ratios (HR) for the development of all diagnoses of TB in participants with dichotomised positive test results compared to negative results, using different thresholds of positivity for TST. Secondary analyses included an evaluation of the impact of background TB incidence. We also estimated the sensitivity and specificity for predicting TB. We explored heterogeneity through pre-defined sub-group analyses (e.g. country-level TB incidence). Publication bias was assessed using funnel plots and Egger's test. This review is registered with PROSPERO, CRD42020205667. Findings: We obtained data from 13 studies out of 40 that were considered eligible (N = 32,034 participants: 36% from countries with TB incidence rate ≥100 per 100,000 population). All reported data on TST and QuantiFERON Gold in-Tube (QFT-GIT). The point estimate for the TST was highest with higher cut-offs for positivity and particularly when stratified by bacillus Calmette-Guérin vaccine (BCG) status (15 mm if BCG vaccinated and 5 mm if not [TST5/15 mm]) at 2.88 (95% CI 1.69-4.90). The pooled HR for QFT-GIT was higher than for TST at 4.15 (95% CI 1.97-8.75). The difference was large in countries with TB incidence rate <100 per 100,000 population (HR 10.38, 95% CI 4.17-25.87 for QFT-GIT VS. HR 5.36, 95% CI 3.82-7.51 for TST5/15 mm) but much of this difference was driven by a single study (HR 5.13, 95% CI 3.58-7.35 for TST5/15 mm VS. 7.18, 95% CI 4.48-11.51 for QFT-GIT, when excluding the study, in which all 19 TB cases had positive QFT-GIT results). The comparative performance was similar in the higher burden countries (HR 1.61, 95% CI 1.23-2.10 for QFT-GIT VS. HR 1.72, 95% CI 0.98-3.01 for TST5/15 mm). The predictive performance of both tests was higher in countries with TB incidence rate <100 per 100,000 population. In the lower TB incidence countries, the specificity of TST (76% for TST5/15 mm) and QFT-GIT (74%) for predicting active TB approached the minimum World Health Organization target (≥75%), but the sensitivity was below the target of ≥75% (63% for TST5/15 mm and 65% for QFT-GIT). The absolute differences in positive and negative predictive values between TST15 mm and QFT-GIT were small (positive predictive values 2.74% VS. 2.46%; negative predictive values 99.42% VS. 99.52% in low-incidence countries). Egger's test did not show evidence of publication bias (0.74 for TST15 mm and p = 0.68 for QFT-GIT). Interpretation: IGRA appears to have higher predictive performance than the TST in low TB incidence countries, but the difference was driven by a single study. Any advantage in clinical performance may be small, given the numerically similar positive and negative predictive values. Both IGRA and TST had lower performance in countries with high TB incidence. Test choice should be contextual and made considering operational and likely clinical impact of test results. Funding: YH, IA, and MXR were supported by the National Institute for Health and Care Research (NIHR), United Kingdom (RP-PG-0217-20009). MQ was supported by the Medical Research Council [MC_UU_00004/07].

Transcontinental spread and evolution of Mycobacterium tuberculosis W148 European/Russian clade toward extensively drug resistant tuberculosis.

Transmission-driven multi-/extensively drug resistant (M/XDR) tuberculosis (TB) is the largest single contributor to human mortality due to antimicrobial resistance. A few major clades of the Mycobacterium tuberculosis complex belonging to lineage 2, responsible for high prevalence of MDR-TB in Eurasia, show outstanding transnational distributions. Here, we determined factors underlying the emergence and epidemic spread of the W148 clade by genome sequencing and Bayesian demogenetic analyses of 720 isolates from 23 countries. We dated a common ancestor around 1963 and identified two successive epidemic expansions in the late 1980s and late 1990s, coinciding with major socio-economic changes in the post-Soviet Era. These population expansions favored accumulation of resistance mutations to up to 11 anti-TB drugs, with MDR evolving toward additional resistances to fluoroquinolones and second-line injectable drugs within 20 years on average. Timescaled haplotypic density analysis revealed that widespread acquisition of compensatory mutations was associated with transmission success of XDR strains. Virtually all W148 strains harbored a hypervirulence-associated ppe38 gene locus, and incipient recurrent emergence of prpR mutation-mediated drug tolerance was detected. The outstanding genetic arsenal of this geographically widespread M/XDR strain clade represents a "perfect storm" that jeopardizes the successful introduction of new anti-M/XDR-TB antibiotic regimens.

[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.

Origin and Global Expansion of Mycobacterium tuberculosis Complex Lineage 3.

Mycobacterium tuberculosis complex (MTBC) Lineage 3 (L3) strains are abundant in world regions with the highest tuberculosis burden. To investigate the population structure and the global diversity of this major lineage, we analyzed a dataset comprising 2682 L3 strains from 38 countries over 5 continents, by employing 24-loci mycobacterial interspersed repetitive unit-variable number of tandem repeats genotyping (MIRU-VNTR) and drug susceptibility testing. We further combined whole-genome sequencing (WGS) and phylogeographic analysis for 373 strains representing the global L3 genetic diversity. Ancestral state reconstruction confirmed that the origin of L3 strains is located in Southern Asia and further revealed multiple independent introduction events into North-East and East Africa. This study provides a systematic understanding of the global diversity of L3 strains and reports phylogenetic variations that could inform clinical trials which evaluate the effectivity of new drugs/regimens or vaccine candidates.