Incidence of Legionnaires' Disease among Travelers Visiting Hotels in Germany, 2015-2019.

We determined whether the incidence rates of travel-associated Legionnaires' disease (TALD) in hotels in Germany increased after a previous occurrence and whether control measures required by the European Legionnaires' Disease Surveillance Network after a cluster (>2 cases within 2 years) restored the rate to baseline. We analyzed TALD surveillance data from Germany during 2015-2019; a total of 307 TALD cases (163 domestic, 144 nondomestic) in hotels were reported. The incidence rate ratio was 5.5 (95% CI 3.6-7.9) for a second case and 25 (95% CI 11-50) for a third case after a cluster had occurred, suggesting that control measures initiated after the occurrence of TALD clusters might be inadequate to restore the incidence rate to baseline. Our findings indicate that substantial LD preventive measures should be explored by hotels or other accommodations after the first TALD case occurs to reduce the risk for future infections.

Tuberculosis in times of war and crisis: Epidemiological trends and characteristics of patients born in Ukraine, Germany, 2022.

The Russian invasion of Ukraine in 2022 caused a large migration to other European countries, including Germany. This movement impacted the TB epidemiology, as Ukraine has a higher prevalence of TB and multidrug-resistant TB rates compared to Germany. Our descriptive analysis of TB surveillance data reveals important information to improve TB care in people displaced from Ukraine. We observed an expected increase in the number of TB patients born in Ukraine, which is, however, so far below WHO/Europe estimates.

How valid is the 2- to 10-day incubation period for cases of Legionnaires' disease?: A reappraisal in the context of the German LeTriWa study; Berlin, 2016-2020.

The evidence for the incubation period of Legionnaires' disease is based on data from a small number of outbreaks. An incubation period of 2-10 days is commonly used for the definition and investigation of cases. In the German LeTriWa study, we collaborated with public health departments to identify evidence-based sources of exposure among cases of Legionnaires' disease within 1-14 days before symptom onset. For each individual, we assigned weights to the numbered days of exposure before symptom onset, giving the highest weight to exposure days of cases with only one possible day of exposure. We then calculated an incubation period distribution where the median was 5 days and the mode was 6 days. The cumulative distribution reached 89% by the 10th day before symptom onset. One case-patient with immunosuppression had a single day of exposure to the likely infection source only 1 day before symptom onset. Overall, our results support the 2- to 10-day incubation period used in case definition, investigation, and surveillance of cases with Legionnaires' disease.

Source attribution of community-acquired cases of Legionnaires' disease-results from the German LeTriWa study; Berlin, 2016-2019.

INTRODUCTION: Sources of infection of most cases of community-acquired Legionnaires' disease (CALD) are unknown. OBJECTIVE: Identification of sources of infection of CALD. SETTING: Berlin; December 2016-May 2019. PARTICIPANTS: Adult cases of CALD reported to district health authorities and consenting to the study; age and hospital matched controls. MAIN OUTCOME MEASURE: Percentage of cases of CALD with attributed source of infection. METHODS: Analysis of secondary patient samples for monoclonal antibody (MAb) type (and sequence type); questionnaire-based interviews, analysis of standard household water samples for Legionella concentration followed by MAb (and sequence) typing of Legionella pneumophila serogroup 1 (Lp1) isolates; among cases taking of additional water samples to identify the infectious source as appropriate; recruitment of control persons for comparison of exposure history and Legionella in standard household water samples. For each case an appraisal matrix was filled in to attribute any of three source types (external (non-residence) source, residential non-drinking water (RnDW) source (not directly from drinking water outlet), residential drinking water (RDW) as source) using three evidence types (microbiological results, cluster evidence, analytical-comparative evidence (using added information from controls)). RESULTS: Inclusion of 111 study cases and 202 controls. Median age of cases was 67 years (range 25-93 years), 74 (67%) were male. Among 65 patients with urine typable for MAb type we found a MAb 3/1-positive strain in all of them. Compared to controls being a case was not associated with a higher Legionella concentration in standard household water samples, however, the presence of a MAb 3/1-positive strain was significantly associated (odds ratio (OR) = 4.9, 95% confidence interval (CI) 1.7 to 11). Thus, a source was attributed by microbiological evidence if it contained a MAb 3/1-positive strain. A source was attributed by cluster evidence if at least two cases were exposed to the same source. Statistically significant general source types were attributed by calculating the population attributable risk (analytical-comparative evidence). We identified an external source in 16 (14%) cases, and RDW as source in 28 (25%). Wearing inadequately disinfected dentures was the only RnDW source significantly associated with cases (OR = 3.2, 95% CI 1.3 to 7.8) and led to an additional 8% of cases with source attribution, for a total of 48% of cases attributed. CONCLUSION: Using the appraisal matrix we attributed almost half of all cases of CALD to an infectious source, predominantly RDW. Risk for LD seems to be conferred primarily by the type of Legionella rather than the amount. Dentures as a new infectious source needs further, in particular, integrated microbiological, molecular and epidemiological confirmation.

Completeness of tuberculosis case notifications in Germany in 2013-2017: first results of an inventory study.

BACKGROUND: Evaluating the completeness of tuberculosis (TB) notification data is important for monitoring of TB surveillance systems. We conducted an inventory study to calculate TB underreporting in Germany in 2013-2017. METHODS: Acquisition of two pseudonymized case-based data sources (national TB notification data and antibiotic resistance surveillance data) was followed by two-source Capture-recapture (CRC) analysis, as case-based data from a third source was unavailable. Aggregated data on consumption of a key anti-TB drug (pyrazinamide [PZA]) was compared to an estimated need for PZA based on TB notification data to obtain an independent underreporting estimation. Additionally, notified TB incidence was compared to TB rate in an aggregated health insurance fund dataset. RESULTS: CRC and PZA-based approaches indicated that between 93 and 97% (CRC) and between 91 and 95% (PZA) of estimated cases were captured in the national TB notification data in the years 2013-2017. Insurance fund dataset did not indicate TB underreporting on the national level in 2017. CONCLUSIONS: Our results suggest that more than 90% of estimated TB cases are captured within the German TB surveillance system, and accordingly the TB notification rate is likely a good proxy of the diagnosed TB incidence rate. An increase in underreporting and discrepancies however should be further investigated.

Differential Seasonality of Legionnaires' Disease by Exposure Category.

Legionnaires' disease (LD) shows a seasonal pattern with most cases occurring in summer. We investigate if seasonality can be observed for all three exposure categories (community-acquired (CALD), travel-associated (TALD) and healthcare-associated (HCA)). METHODS: LD cases (2005-2015) were classified by exposure categories and we calculated the relative case ratio for each month from February to December using January as reference. The TALD relative case ratio was compared with flight frequencies. RESULTS: Overall case numbers in Germany (N = 7351) peaked in August. CALD had a curve similar to all cases. TALD displayed a bimodal curve with peaks in June/July and October. The latter was attributable to LD cases aged 60+. The relative case ratio of TALD surpassed clearly that of CALD. The curve was similar to that of the relative flight frequencies, but was shifted by about one month. HCA showed no apparent seasonality. CONCLUSIONS: Although the overall seasonality in LD is heavily influenced by CALD, seasonal differences are more pronounced for TALD which may reflect travel behavior. The bimodal pattern of TALD is attributable to the curve among those aged 60+ and may reflect their preference to travel outside school holiday periods. Heightened vigilance for HCA cases is necessary throughout the entire year.

First-line tuberculosis drug resistance patterns and associated risk factors in Germany, 2008-2017.

BACKGROUND: Drug-resistant tuberculosis (TB), especially multidrug-resistant TB (MDR-TB), poses a threat to public health. While standard surveillance focuses on Rifampicin and/or Isoniazid resistance, little is known about other resistance patterns. This study aims to identify predominant drug resistance (DR) patterns in Germany and risk factors associated with them in order to inform diagnostic and treatment strategies. METHODS: Case-based TB surveillance data notified in Germany from 2008-2017 were utilized to investigate DR and MDR-TB patterns for Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E), and Streptomycin (S). Predominant patterns were further analyzed stratified by sex, age, country of birth, prior TB, and disease site. Multivariable logistic regression was conducted to determine risk factors associated with any resistance, MDR-TB, and complete HRZES resistance. RESULTS: 26,228 cases with complete DST results were included in the study, among which 3,324 cases had any DR (12.7%). Four patterns were predominant, representing about ¾ of all cases with any resistance (S: 814 [3.1%]; H: 768 [2.9%]; HS: 552 [2.1%]; Z: 412 [1.6%]). High proportions of S and H resistances were found among both German and foreign-born populations, especially those born in Eastern Europe, and were unexpectedly high among children (H: 4.3%; S: 4.6%). Foreign-born cases had significantly higher proportion of any resistance (16.0%) and MDR-TB (3.3%) compared to German-born cases (8.3% and 0.6%). Of 556 MDR-TB cases, 39.2% showed complete HRZES resistance. Logistic regression revealed having prior TB and being foreign-born as consistently strong risk factors for any DR, MDR-TB, and complete HRZES resistance. CONCLUSIONS: DR patterns observed in Germany, particularly for MDR-TB were more complex than expected, highlighting the fact that detailed drug-testing results are crucial before incorporating HRZES drugs in MDR-TB treatment. Furthermore, the relatively high rate of H-resistance in Germany provides strong rationale against the use of only H-based preventive therapy for LTBI.

Probable reinfection with Legionella pneumophila - A case report.

In Germany community-acquired Legionnaires' disease is usually caused by the species Legionella pneumophila. Recurrent cases of Legionnaires' disease are rarely reported and are due either to a second infection (reinfection) or a relapse of a previous case. We report a case of recurrent Legionnaires' disease in an 86-year-old female patient infected with Legionella pneumophila serogroup 1, monoclonal antibody-subtype Knoxville, sequence type unknown. Between the two disease incidents the patient had completely recovered. Legionella pneumophila was detected with the monoclonal antibody-subtype Knoxville, sequence type 182, in the drinking water of the patient's apartment. Exposure to contaminated drinking water was interrupted after the first incident exposure through the application of point-of-use water filters. The filters were later removed due to low water pressure, and the second illness occurred thereafter. It is unclear if immunological predisposition has contributed to this case of probable reinfection of Legionnaires' disease. Clinical, microbiological and epidemiological information combined suggest this is a case of reinfection of Legionnaires' disease. In cases of recurrent Legionnaires' disease complete collection of patient and water samples is necessary to differentiate relapse from reinfection cases, to implicate the source of infection and to gain more evidence for the role of immunological predisposition.

Find and treat or find and lose? Tuberculosis treatment outcomes among screened newly arrived asylum seekers in Germany 2002 to 2014.

BackgroundGermany has a low tuberculosis (TB) incidence. A relevant and increasing proportion of TB cases is diagnosed among asylum seekers upon screening. Aim: We aimed to assess whether cases identified by screening asylum seekers had equally successful and completely reported treatment outcomes as cases diagnosed by passive case finding and contact tracing in the general population. Methods: We analysed characteristics and treatment outcomes of pulmonary TB cases notified in Germany between 2002 and 2014, stratified by mode of case finding. We performed three multivariable analyses with different dependent variables: Model A: successful vs all other outcomes, Model B: successful vs documented non-successful clinical outcome and Model C: known outcome vs lost to follow-up. Results: TB treatment success was highest among cases identified by contact tracing (87%; 3,139/3,591), followed by passive case finding (74%; 28,804/39,019) and by screening asylum seekers (60%; 884/1,474). Cases identified by screening asylum seekers had 2.4 times higher odds of not having a successful treatment outcome as opposed to all other outcomes (A), 1.4 times higher odds of not having a successful treatment outcome as opposed to known non-successful outcomes (B) and 2.3 times higher odds of loss to follow-up (C) than cases identified by passive case finding. Conclusion: Screened asylum seekers had poorer treatment outcomes and were more often lost to follow-up. Linking patients to treatment facilities and investigating potential barriers to treatment completion are needed to secure screening benefits for asylum seekers and communities.

Integration of molecular typing results into tuberculosis surveillance in Germany-A pilot study.

An integrated molecular surveillance for tuberculosis (TB) improves the understanding of ongoing TB transmission by combining molecular typing and epidemiological data. However, the implementation of an integrated molecular surveillance for TB is complex and requires thoughtful consideration of feasibility, demand, public health benefits and legal issues. We aimed to pilot the integration of molecular typing results between 2008 and 2010 in the German Federal State of Baden-Württemberg (population 10.88 Million) as preparation for a nationwide implementation. Culture positive TB cases were typed by IS6110 DNA fingerprinting and results were integrated into routine notification data. Demographic and clinical characteristics of cases and clusters were described and new epidemiological links detected after integrating typing data were calculated. Furthermore, a cross-sectional survey was performed among local public health offices to evaluate their perception and experiences. Overall, typing results were available for 83% of notified culture positive TB cases, out of which 25% were clustered. Age <15 years (OR = 4.96, 95% CI: 1.69-14.55) and being born in Germany (OR = 2.01, 95% CI: 1.44-2.80) were associated with clustering. At cluster level, molecular typing information allowed the identification of previously unknown epidemiological links in 11% of the clusters. In 59% of the clusters it was not possible to identify any epidemiological link. Clusters extending over different counties were less likely to have epidemiological links identified among their cases (OR = 11.53, 95% CI: 3.48-98.23). The majority of local public health offices found molecular typing useful for their work. Our study illustrates the feasibility of integrating typing data into the German TB notification system and depicts its added public health value as complementary strategy in TB surveillance, especially to uncover transmission events among geographically separated TB patients. It also emphasizes that special efforts are required to strengthen the communication between local public health offices in different counties to enhance TB control.

Higher Rate of Tuberculosis in Second Generation Migrants Compared to Native Residents in a Metropolitan Setting in Western Europe.

BACKGROUND: In Western Europe, migrants constitute an important risk group for tuberculosis, but little is known about successive generations of migrants. We aimed to characterize migration among tuberculosis cases in Berlin and to estimate annual rates of tuberculosis in two subsequent migrant generations. We hypothesized that second generation migrants born in Germany are at higher risk of tuberculosis compared to native (non-migrant) residents. METHODS: A prospective cross-sectional study was conducted. All tuberculosis cases reported to health authorities in Berlin between 11/2010 and 10/2011 were eligible. Interviews were conducted using a structured questionnaire including demographic data, migration history of patients and their parents, and language use. Tuberculosis rates were estimated using 2011 census data. RESULTS: Of 314 tuberculosis cases reported, 154 (49.0%) participated. Of these, 81 (52.6%) were first-, 14 (9.1%) were second generation migrants, and 59 (38.3%) were native residents. The tuberculosis rate per 100,000 individuals was 28.3 (95CI: 24.0-32.6) in first-, 10.2 (95%CI: 6.1-16.6) in second generation migrants, and 4.6 (95%CI: 3.7-5.6) in native residents. When combining information from the standard notification variables country of birth and citizenship, the sensitivity to detect second generation migration was 28.6%. CONCLUSIONS: There is a higher rate of tuberculosis among second generation migrants compared to native residents in Berlin. This may be explained by presumably frequent contact and transmission within migrant populations. Second generation migration is insufficiently captured by the surveillance variables country of birth and citizenship. Surveillance systems in Western Europe should allow for quantifying the tuberculosis burden in this important risk group.

Transmission dynamics of pulmonary tuberculosis between autochthonous and immigrant sub-populations.

BACKGROUND: The overall incidence of tuberculosis (TB) in Western Europe has been declining since the 19th Century. However, immigrant sub-groups from high-prevalence countries are slowing down this trend. The aim of this study was to describe how immigration influences TB transmission in Germany. For that we prospectively investigated the dynamics of TB transmission between TB high-prevalence immigrant and TB low-prevalence local populations with molecular epidemiological methods and conventional contact investigations. Besides, we assessed transmission in relation to social mixing using an innovative tool that measures the integration of immigrants into the local social environment. METHODS: A prospective study of confirmed culture positive cases of pulmonary TB and their contacts was carried out in a German federal state from 2003 to 2005. Data for the study included: 1) case data routinely collected by the local public health staff and transmitted to the state health office and the national surveillance centre, 2) a study questionnaire designed to capture social interactions of relevance for TB transmission and 3) molecular genotyping data (IS6110 DNA fingerprint and spoligotyping). The proportion of German cases caused by foreign-born cases, and vice versa, was estimated and an integration index was computed using a selected set of questions from the study questionnaire. RESULTS: A total of 749 cases of culture-positive pulmonary tuberculosis voluntarily enrolled in the study, representing 57.8% of all registered cases diagnosed over the study period. Data that included study questionnaire and DNA fingerprinting were available for 41% (n = 308) of the study participants. Forty-seven clusters, defined as a least two cases infected by the same TB strains, were identified by molecular methods and included 132 (17%) of the study participants. Epidemiological links were identified for 28% of the clusters by conventional epidemiological data. In mixed clusters, defined as clusters including German and foreign-born individuals, the probability of cases to be caused by foreign-born cases was estimated at 18.3%. We observed a trend to mixed clusters with increasing time spent by immigrants in the host country. This group also presented comparatively higher integration indexes than immigrants in immigrant-only clusters. CONCLUSION: Our results confirm the findings of other studies that there is no significant TB transmission from TB high-prevalence immigrant to TB low-prevalence autochthonous population. This may be explained by the good performance of tuberculosis screening programmes for certain groups arriving in Germany from high- prevalence countries, by a low degree of mixing of immigrants with the local population or by a combination of both.

[Nosocomial Legionnaires' disease--results from the analysis of Germany's surveillance data; 2004-2006]. / Legionärskrankheit in Deutschland unter besonderer Berücksichtigung der im Krankenhaus oder in einer Pflegeeinrichtung erworbenen Erkrankungen, 2004-2006.

Legionella bacteria colonize drinking water systems and can cause severe pneumonia in humans (Legionnaires' disease (LD)). The German network for community-acquired pneumonia (CAPNETZ) estimates 15,000-30,000 new cases of LD per year in Germany. LD cases are divided into those that were acquired in the context of a stay in a hospital or nursing home (healthcare-associated; HCA), in the community (community-acquired (CA)) or during travel (travelassociated (TA)). According to the recommendations of the Communicable Disease Surveillance Centre (CDSC; UK) and the Healthcare Infection Control Practices Advisory Committee (HICPAC; USA) a single case of nosocomial LD should prompt an epidemiologic and, depending on its results, also technical investigation of the institution. In this study we present data from nosocomial cases of LD in the context of all cases of LD that were reported to the Robert Koch Institute (RKI) within the mandatory surveillance system from 2004 through 2006. We calculated the number of cases per population (incidence), the number of cases per person-days at risk (incidence rate) and case fatality. The analysis comprised 1,339 cases of LD. Among the 942 cases with one of the three categories of exposure CALD was reported in 58 % (547 cases), TALD in 29 % (270 cases) and HCA-LD in 13 % (125 cases). The incidence rate of TALD was 9-fold, but that of HCA-LD 15-fold higher than that of CALD. Case fatality of HCA-LD was 13 % and thus higher than that of CALD (9 %) and TALD (5 %). HCA-LD cases were reported from all states and included 77 different counties. Reporting counties represent the place of residence of the LD case-patients. German notification data show that cases of LD, and likely also HCALD, are underreported. Incidence rate and case fatality are highest in HCA-LD. HCA-LD occurs widespread. These results and the preventability of HCA-LD support the recommendation to thoroughly investigate single cases of HCA-LD in hospitals and nursing homes.

Reliability of case definitions for public health surveillance assessed by Round-Robin test methodology.

BACKGROUND: Case definitions have been recognized to be important elements of public health surveillance systems. They are to assure comparability and consistency of surveillance data and have crucial impact on the sensitivity and the positive predictive value of a surveillance system. The reliability of case definitions has rarely been investigated systematically. METHODS: We conducted a Round-Robin test by asking all 425 local health departments (LHD) and the 16 state health departments (SHD) in Germany to classify a selection of 68 case examples using case definitions. By multivariate analysis we investigated factors linked to classification agreement with a gold standard, which was defined by an expert panel. RESULTS: A total of 7870 classifications were done by 396 LHD (93%) and all SHD. Reporting sensitivity was 90.0%, positive predictive value 76.6%. Polio case examples had the lowest reporting precision, salmonellosis case examples the highest (OR = 0.008; CI: 0.005-0.013). Case definitions with a check-list format of clinical criteria resulted in higher reporting precision than case definitions with a narrative description (OR = 3.08; CI: 2.47-3.83). Reporting precision was higher among SHD compared to LHD (OR = 1.52; CI: 1.14-2.02). CONCLUSION: Our findings led to a systematic revision of the German case definitions and build the basis for general recommendations for the creation of case definitions. These include, among others, that testable yes/no criteria in a check-list format is likely to improve reliability, and that software used for data transmission should be designed in strict accordance with the case definitions. The findings of this study are largely applicable to case definitions in many other countries or international networks as they share the same structural and editorial characteristics of the case definitions evaluated in this study before their revision.

PTERIN- AND FLAVIN-LIKE FLUORESCENCE ASSOCIATED WITH ISOLATED FLAGELLA OF Euglena gracilis.

Fluorescence excitation- and emission spectra indicate the presence of pterin(s) and flavin(s) in isolated flagella of the phytoflagellate Euglena gracilis. These compounds appear to bind at least in part non-covalently to the molecular framework of the paraflagellar body, which is the presumed photoreceptor organelle and which is attached to the isolated flagella. A compound with pterin-like fluorescence excitation and emission spectrum could he extracted with methanol from isolated flagella and could he recovered on thin-layer silica gels. Besides the previously assumed photoreceptor function of flavins, our results suggest also a role for pterins in the photosensory transduction chain of Euglena gracilis.