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.

Assessment of the use and need for an integrated molecular surveillance of tuberculosis: an online survey in Germany.

BACKGROUND: The implementation of an integrated molecular surveillance (IMS) of tuberculosis (TB) is of high priority for TB control. IMS is defined as the systematic inclusion of molecular typing results in the national TB surveillance system. Although not standardized, an IMS of TB is already implemented in several low TB incidence countries. Germany is in the process of implementing a nationwide IMS of TB. This requires close collaboration between national and local health authorities. We conducted an online survey to understand the current use of molecular typing results for TB surveillance among the local public health offices (PHO)s in Germany, and to collect their perception and expectations towards the implementation of a nationwide IMS of TB. METHODS: The online survey was developed using the software Voxco and included 31 questions. The survey was sent to all the 377 local PHOs in Germany in April 2017. Responses were collected until June 2017. RESULTS: A total of 174/377 (46.2%) local PHOs participated in our survey, and 88/377 (23.3%) used molecular typing results in their routine TB surveillance work. The PHOs used molecular typing results especially as support for epidemiological contact tracing (62/88, 70.4%). We found statistically significant differences between answers of PHOs that did not use molecular typing results (n = 86) vs. PHOs that did use molecular typing results (n = 88): the latter perceived the use of molecular typing results as more beneficial for their work compared to the former (65.9% vs. 34.9%, p < 0.05). Moreover, the PHOs using molecular typing results expect for the future more support and coordination from regional and national public health institutes, especially regarding the identification and analysis of molecular clusters. CONCLUSIONS: Our study is a step forward in the broader goal of implementing an IMS of TB in Germany. The local PHOs currently using the molecular typing results highlighted their positive attitude towards the implementation of an IMS, but also their needs of more support. Similar assessments might serve as an example for other countries which are on the way to implement a nationwide IMS of TB.

Isoniazid (INH) mono-resistance and tuberculosis (TB) treatment success: analysis of European surveillance data, 2002 to 2014.

INTRODUCTION: Isoniazid (INH) is an essential drug for tuberculosis (TB) treatment. Resistance to INH may increase the likelihood of negative treatment outcome. AIM: We aimed to determine the impact of INH mono-resistance on TB treatment outcome in the European Union/European Economic Area and to identify risk factors for unsuccessful outcome in cases with INH mono-resistant TB. METHODS: In this observational study, we retrospectively analysed TB cases that were diagnosed in 2002-14 and included in the European Surveillance System (TESSy). Multilevel logistic regression models were applied to identify risk factors and correct for clustering of cases within countries. RESULTS: A total of 187,370 susceptible and 7,578 INH mono-resistant TB cases from 24 countries were included in the outcome analysis. Treatment was successful in 74.0% of INH mono-resistant and 77.4% of susceptible TB cases. In the final model, treatment success was lower among INH mono-resistant cases (Odds ratio (OR): 0.7; 95% confidence interval (CI): 0.6-0.9; adjusted absolute difference in treatment success: 5.3%). Among INH mono-resistant TB cases, unsuccessful treatment outcome was associated with age above median (OR: 1.3; 95% CI: 1.2-1.5), male sex (OR: 1.3; 95% CI: 1.1-1.4), positive smear microscopy (OR: 1.3; 95% CI: 1.1-1.4), positive HIV status (OR: 3.3; 95% CI: 1.6-6.5) and a prior TB history (OR: 1.8; 95% CI: 1.5-2.2). CONCLUSIONS: This study provides evidence for an association between INH mono-resistance and a lower likelihood of TB treatment success. Increased attention should be paid to timely detection and management of INH mono-resistant TB.

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.

Multidrug-resistant TB in Eastern region of the EU: is the shorter regimen an exception or a rule?

WHO recently recommended the use of a shorter multidrug-resistant TB (MDR-TB) regimen under programmatic conditions. We assessed eligibility for this regimen in a cohort of 737 adult patients with MDR-TB from Latvia, Lithuania, Estonia and Bucharest city recruited in 2007 and 2009. Only 4.2% of the patients were eligible for this regimen. Ethambutol (64%), pyrazinamide resistance (58%) and previous exposure to second-line TB drugs were major reasons for non-eligibility. High-level resistance to isoniazid is expected due to widespread prevalence of katG mutations. In Eastern Europe, the use of the shorter regimen might be an exception rather than a rule.

Contact investigation after a fatal case of extensively drug-resistant tuberculosis (XDR-TB) in an aircraft, Germany, July 2013.

In July 2013, a passenger died of infectious extensively drug-resistant tuberculosis (XDR-TB) on board of an aircraft after a 3-hour flight from Turkey to Germany. Initial information indicated the patient had moved about the aircraft coughing blood. We thus aimed to contact and inform all persons exposed within the aircraft and to test them for newly acquired TB infection. Two-stage testing within 8 weeks from exposure and at least 8 weeks after exposure was suggested, using either interferon gamma release assays (IGRAs) or tuberculin skin test (TST). The TST cut-off was defined at a diameter > 10 mm; for differentiation between conversion and boosting, conversion was defined as increase of skin induration > 5 mm. Overall, 155 passengers and seven crew members were included in the investigation: the questionnaire response rate was 83%; 112 (69%) persons were tested at least once for TB infection. In one passenger, who sat next to the area where the patient died, a test conversion was registered. As of March 2017, no secondary active TB cases have been reported. We describe an unusual situation in which we applied contact tracing beyond existing European guidelines; we found one latent tuberculosis infection in a passenger, which we consider probably newly acquired.

A joint cross-border investigation of a cluster of multidrug-resistant tuberculosis in Austria, Romania and Germany in 2014 using classic, genotyping and whole genome sequencing methods: lessons learnt.

Molecular surveillance of multidrug-resistant tuberculosis (MDR-TB) using 24-loci MIRU-VNTR in the European Union suggests the occurrence of international transmission. In early 2014, Austria detected a molecular MDR-TB cluster of five isolates. Links to Romania and Germany prompted the three countries to investigate possible cross-border MDR-TB transmission jointly. We searched genotyping databases, genotyped additional isolates from Romania, used whole genome sequencing (WGS) to infer putative transmission links, and investigated pairwise epidemiological links and patient mobility. Ten isolates from 10 patients shared the same 24-loci MIRU-VNTR pattern. Within this cluster, WGS defined two subgroups of four patients each. The first comprised an MDR-TB patient from Romania who had sought medical care in Austria and two patients from Austria. The second comprised patients, two of them epidemiologically linked, who lived in three different countries but had the same city of provenance in Romania. Our findings strongly suggested that the two cases in Austrian citizens resulted from a newly introduced MDR-TB strain, followed by domestic transmission. For the other cases, transmission probably occurred in the same city of provenance. To prevent further MDR-TB transmission, we need to ensure universal access to early and adequate therapy and collaborate closely in tuberculosis care beyond administrative borders.

Epidemiology of Epidemic Ebola Virus Disease in Conakry and Surrounding Prefectures, Guinea, 2014-2015.

In 2014, Ebola virus disease (EVD) in West Africa was first reported during March in 3 southeastern prefectures in Guinea; from there, the disease rapidly spread across West Africa. We describe the epidemiology of EVD cases reported in Guinea's capital, Conakry, and 4 surrounding prefectures (Coyah, Dubreka, Forecariah, and Kindia), encompassing a full year of the epidemic. A total of 1,355 EVD cases, representing ≈40% of cases reported in Guinea, originated from these areas. Overall, Forecariah had the highest cumulative incidence (4× higher than that in Conakry). Case-fatality percentage ranged from 40% in Conakry to 60% in Kindia. Cumulative incidence was slightly higher among male than female residents, although incidences by prefecture and commune differed by sex. Over the course of the year, Conakry and neighboring prefectures became the EVD epicenter in Guinea.

Exposure Patterns Driving Ebola Transmission in West Africa: A Retrospective Observational Study.

BACKGROUND: The ongoing West African Ebola epidemic began in December 2013 in Guinea, probably from a single zoonotic introduction. As a result of ineffective initial control efforts, an Ebola outbreak of unprecedented scale emerged. As of 4 May 2015, it had resulted in more than 19,000 probable and confirmed Ebola cases, mainly in Guinea (3,529), Liberia (5,343), and Sierra Leone (10,746). Here, we present analyses of data collected during the outbreak identifying drivers of transmission and highlighting areas where control could be improved. METHODS AND FINDINGS: Over 19,000 confirmed and probable Ebola cases were reported in West Africa by 4 May 2015. Individuals with confirmed or probable Ebola ("cases") were asked if they had exposure to other potential Ebola cases ("potential source contacts") in a funeral or non-funeral context prior to becoming ill. We performed retrospective analyses of a case line-list, collated from national databases of case investigation forms that have been reported to WHO. These analyses were initially performed to assist WHO's response during the epidemic, and have been updated for publication. We analysed data from 3,529 cases in Guinea, 5,343 in Liberia, and 10,746 in Sierra Leone; exposures were reported by 33% of cases. The proportion of cases reporting a funeral exposure decreased over time. We found a positive correlation (r = 0.35, p < 0.001) between this proportion in a given district for a given month and the within-district transmission intensity, quantified by the estimated reproduction number (R). We also found a negative correlation (r = -0.37, p < 0.001) between R and the district proportion of hospitalised cases admitted within ≤4 days of symptom onset. These two proportions were not correlated, suggesting that reduced funeral attendance and faster hospitalisation independently influenced local transmission intensity. We were able to identify 14% of potential source contacts as cases in the case line-list. Linking cases to the contacts who potentially infected them provided information on the transmission network. This revealed a high degree of heterogeneity in inferred transmissions, with only 20% of cases accounting for at least 73% of new infections, a phenomenon often called super-spreading. Multivariable regression models allowed us to identify predictors of being named as a potential source contact. These were similar for funeral and non-funeral contacts: severe symptoms, death, non-hospitalisation, older age, and travelling prior to symptom onset. Non-funeral exposures were strongly peaked around the death of the contact. There was evidence that hospitalisation reduced but did not eliminate onward exposures. We found that Ebola treatment units were better than other health care facilities at preventing exposure from hospitalised and deceased individuals. The principal limitation of our analysis is limited data quality, with cases not being entered into the database, cases not reporting exposures, or data being entered incorrectly (especially dates, and possible misclassifications). CONCLUSIONS: Achieving elimination of Ebola is challenging, partly because of super-spreading. Safe funeral practices and fast hospitalisation contributed to the containment of this Ebola epidemic. Continued real-time data capture, reporting, and analysis are vital to track transmission patterns, inform resource deployment, and thus hasten and maintain elimination of the virus from the human population.

Survival of patients with multidrug-resistant TB in Eastern Europe: what makes a difference?

BACKGROUND: The quality of care for patients with TB in Eastern Europe has improved significantly; nevertheless drug resistance rates remain high. We analysed survival in a cohort of patients with multidrug-resistant and extensively drug-resistant (MDR-/XDR-) TB from Latvia, Lithuania, Estonia and Bucharest city. METHODS: Consecutive adult new and retreatment patients with culture-confirmed pulmonary MDR-TB registered for treatment in 2009 (and in 2007 in Latvia) were enrolled; prospective survival information was collected. RESULTS: A total of 737 patients were included into the cohort. Of all MDR-TB cases, 46% were newly diagnosed; 56% of all MDR-TB cases had no additional resistance to fluoroquinolones or injectable agents, 33% had pre-XDR-TB and 11% XDR-TB. Median survival was 5.9 years in patients with MDR-TB and XDR-TB; 1.9 years in patients coinfected with HIV. Older age, male gender, alcohol abuse, retirement, co-morbidities, extrapulmonary involvement and HIV coinfection independently worsened survival. Inclusion of fluoroquinolones and injectable agents improves survival in patients with MDR-TB. Pre-XDR and XDR status did not significantly shorten survival as long as fluoroquinolones and injectable agents were part of the regimen. Moxifloxacin seems to improve survival in ofloxacin-susceptible patients when compared with older generation fluoroquinolones. CONCLUSIONS: The burden of additional resistances in patients with MDR-TB is high likely due to primary transmission of resistant strains. Social and programmatic factors including management of alcohol dependency, expansion of HIV testing and antiretroviral treatment need to be addressed in order to achieve cure and to interrupt transmission. The role of last generation fluoroquinolones and injectable agents in treatment of patients with pre-XDR and XDR-TB needs to be further investigated.

Tuberculosis treatment outcome in the European Union and European Economic Area: an analysis of surveillance data from 2002-2011.

Monitoring the treatment outcome (TO) of tuberculosis (TB) is essential to evaluate the effectiveness of the intervention and to identify potential barriers for TB control. The global target is to reach a treatment success rate (TSR) of at least 85%. We aimed to assess the TB TO in the European Union and European Economic Area (EU/EEA) between 2002 and 2011, and to identify factors associated with unsuccessful treatment. Only 18 countries reported information on TO for the whole observation period accounting for 250,854 new culture-confirmed pulmonary TB cases. The 85% target of TSR was not reached in any year between 2002 and 2011 and was on average 78%. The TSR for multidrug-resistant (MDR)-TB cases at 24-month follow-up was 49%. In the multivariable regression model, unsuccessful treatment was significantly associated with increasing age (odds ratio (OR) = 1.02 per a one-year increase, 95% confidence interval (CI): 1.02-1.02), MDR-TB (OR = 8.7, 95% CI: 5.09-14.97), male sex (OR = 1.40, 95% CI: 1.28-1.52), and foreign origin (OR = 1.32, 95% CI: 1.03-1.70). The data highlight that special efforts are required for patients with MDR-TB and the elderly aged ≥65 years, who have particularly low TSR. To allow for valid monitoring at EU level all countries should aim to report TO for all TB cases.

[Migration and infectious disease surveillance in Germany: Analyses of Tuberculosis, HIV and Syphilis surveillance data]. / Migrationshintergrund in der infektionsepidemiologischen Surveillance in Deutschland : Analysen am Beispiel Tuberkulose, HIV und Syphilis.

BACKGROUND: Migration is an important factor impacting on infectious disease epidemiology. The timely identification of groups at risk and prevention needs resulting from migration is indispensable to adequately design and implement public health measures. It remains to be assessed to which extent surveillance data for notifiable diseases can directly generate meaningful migration-specific information. OBJECTIVES: The objectives of this study are to review indicators of migration background utilized in the German infectious disease surveillance, as well as to assess their limitations. METHODS: We describe the indicators of migration used for mandatorily notifiable diseases and pathogens and their legal basis in the Protection against Infection Act and conduct a descriptive analysis of surveillance data for tuberculosis (TB), HIV and syphilis from 2002-2013. RESULTS: Migration status is collected only for five infectious diseases and operationalization varies. For TB (country of birth) and HIV (country of origin) a foreign origin was more frequent than for syphilis (country of origin); namely 46, 30 and 13% of cases with available information, respectively. In all three examples, there are indications of risk profiles that are specific for particular groups of migrants. DISCUSSION: A standardization of indicators of migration in infectious disease surveillance is important to enhance data comparability between diseases and pathogens as well as across countries. Routine surveillance already partly allows migration sensitive analyses, yet further research is needed to guide interpretation of the complex relationship between migration and infectious diseases and plan public health measures adequately.

Tuberculosis among people living with HIV/AIDS in the German ClinSurv HIV Cohort: long-term incidence and risk factors.

BACKGROUND: Tuberculosis (TB) still presents a leading cause of morbidity and mortality among people living with HIV/AIDS (PLWHA), including those on antiretroviral therapy. In this study, we aimed to determine the long-term incidence density rate (IDR) of TB and risk factors among PLWHA in relation to combination antiretroviral therapy (cART)-status. METHODS: Data of PLWHA enrolled from 2001 through 2011 in the German ClinSurv HIV Cohort were investigated using survival analysis and Cox regression. RESULTS: TB was diagnosed in 233/11,693 PLWHA either at enrollment (N = 62) or during follow-up (N = 171). The TB IDR during follow-up was 0.37 cases per 100 person-years (PY) overall [95% CI, 0.32-0.43], and was higher among patients who never started cART and among patients originating from Sub-Saharan Africa (1.23 and 1.20 per 100PY, respectively). In two multivariable analyses, both patients (I) who never started cART and (II) those on cART shared the same risk factors for TB, namely: originating from Sub-Saharan Africa compared to Germany (I, hazard ratio (HR); [95% CI]) 4.05; [1.87-8.78] and II, HR 5.15 [2.76-9.60], CD4+ cell count <200 cells/µl (I, HR 8.22 [4.36-15.51] and II, HR 1.90 [1.14-3.15]) and viral load >5 log10 copies/ml (I, HR 2.51 [1.33-4.75] and II, HR 1.77 [1.11-2.82]). Gender, age or HIV-transmission risk group were not independently associated with TB. CONCLUSION: In the German ClinSurv HIV cohort, patients originating from Sub-Saharan Africa, with low CD4+ cell count or high viral load at enrollment were at increased risk of TB even after cART initiation. As patients might be latently infected with Mycobacterium tuberculosis complex, early screening for latent TB infection and implementing isoniazid preventive therapy in line with available recommendations is crucial.

Unchanged severity of influenza A(H1N1)pdm09 infection in children during first postpandemic season.

We conducted a nationwide hospital-based prospective study in Germany of influenza A(H1N1)pdm09 cases among children <15 years of age admitted to pediatric intensive care units and related deaths during the 2009-10 pandemic and the 2010-11 postpandemic influenza seasons. We identified 156 eligible patients: 112 in 2009-10 and 44 in 2010-11. Although a shift to younger patients occurred in 2010-11 (median age 3.2 vs. 5.3 years), infants <1 year of age remained the most affected. Underlying immunosuppression was a risk factor for hospital-acquired infections (p = 0.013), which accounted for 14% of cases. Myocarditis was predictive of death (p = 0.006). Of the 156 case-patients, 17% died; the difference between seasons was not significant (p = 0.473). Our findings stress the challenge of preventing severe postpandemic influenza infection in children and the need to prevent nosocomial transmission of influenza virus, especially in immunosuppressed children.

Severe cases of pandemic (H1N1) 2009 in children, Germany.

In a hospital-based observational study in Germany, we investigated children admitted to pediatric intensive care units and deaths caused by confirmed pandemic (H1N1) 2009 to identify risk factors and outcomes in critically ill children. Ninety-three children were eligible for our study, including 9 with hospital-acquired infections. Seventy-five percent had underlying chronic medical conditions; neurodevelopmental disorders were most prevalent (57%). The proportion of patients having ≥1 risk factor increased with age in years (odds ratio 1.21, p = 0.007). Of 15 deaths, 11 occurred in a pediatric intensive care unit (case-fatality rate 12%, 95% confidence interval 6%-21%). Only 9% of the children had been vaccinated against pandemic (H1N1) 2009; all survived. Our results stress the role of underlying risk factors, especially neurodevelopmental disorders, and the need for improving preventive measures to reduce severe disease and adverse outcomes of pandemic (H1N1) 2009 in children.

Models of epidemics: when contact repetition and clustering should be included.

BACKGROUND: The spread of infectious disease is determined by biological factors, e.g. the duration of the infectious period, and social factors, e.g. the arrangement of potentially contagious contacts. Repetitiveness and clustering of contacts are known to be relevant factors influencing the transmission of droplet or contact transmitted diseases. However, we do not yet completely know under what conditions repetitiveness and clustering should be included for realistically modelling disease spread. METHODS: We compare two different types of individual-based models: One assumes random mixing without repetition of contacts, whereas the other assumes that the same contacts repeat day-by-day. The latter exists in two variants, with and without clustering. We systematically test and compare how the total size of an outbreak differs between these model types depending on the key parameters transmission probability, number of contacts per day, duration of the infectious period, different levels of clustering and varying proportions of repetitive contacts. RESULTS: The simulation runs under different parameter constellations provide the following results: The difference between both model types is highest for low numbers of contacts per day and low transmission probabilities. The number of contacts and the transmission probability have a higher influence on this difference than the duration of the infectious period. Even when only minor parts of the daily contacts are repetitive and clustered can there be relevant differences compared to a purely random mixing model. CONCLUSION: We show that random mixing models provide acceptable estimates of the total outbreak size if the number of contacts per day is high or if the per-contact transmission probability is high, as seen in typical childhood diseases such as measles. In the case of very short infectious periods, for instance, as in Norovirus, models assuming repeating contacts will also behave similarly as random mixing models. If the number of daily contacts or the transmission probability is low, as assumed for MRSA or Ebola, particular consideration should be given to the actual structure of potentially contagious contacts when designing the model.

Molecular and genomic typing for tuberculosis surveillance: A survey study in 26 European countries.

BACKGROUND: Molecular typing and whole genome sequencing (WGS) information is used for (inter-) national outbreak investigations. To assist the implementation of these techniques for tuberculosis (TB) surveillance and outbreak investigations at European level there is a need for inter-country collaboration and standardization. This demands more information on molecular typing practices and capabilities of individual countries. We aimed to review the use of molecular/genomic typing for TB surveillance in European Union and European Economic Area countries in 2016; assess its public health value; and collect experiences on typing data use for cross-border cluster investigations. METHOD: A web-based questionnaire was provided to all TB National Focal Points. The questionnaire consisted of three parts: i) Use and integration of molecular and genomic typing data into TB surveillance; ii) Cross-border cluster investigation and international collaboration, and iii) Perception and evaluation of public health benefits of molecular and genomic typing for TB surveillance. RESULTS: Of 26 responding countries, 20 used molecular typing for TB surveillance, including nine applying WGS. The level of integration into the national surveillance was heterogeneous. Among six countries not using typing for TB surveillance, more than half planned its implementation soon. Overall, most countries perceived an added public health value of molecular typing for TB control. Concerning international cluster investigations, countries had little experience and did not have standard protocols to exchange typing data. CONCLUSION: Our study shows a wide use of molecular and genomic typing data for TB surveillance in EU/EEA countries and reveals that transition to WGS-based typing is ongoing or is considered in most countries. However, our results also show a high heterogeneity in the use and integration of typing data for TB surveillance. Standardization of typing data use for TB surveillance is needed and formal procedures should be developed to facilitate international collaboration.