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

Zukünftige Tuberkulinversorgung in Deutschland

Der Hersteller des einzigen bisher in Deutschland für Intradermaltests nach Mendel-Mantoux verwendeten Tuberkulins, die Firma Chiron Vaccines Behring, hat 2004 kurzfristig die Produktion von Tuberkulin Behring GT (GT=gereinigtes Tuberkulin) eingestellt. Anfang 2005 waren die Bestände an GT 10 bereits erschöpft, geringe Restbestände existierten noch für die Dosierungen GT 100 und GT 1000. Als Übergangslösung wurde von Chiron Vaccines Behring der Import des von Chiron S.r.l. in Siena hergestellten italienischen Tuberkulins Biocine PPD 5 IE lyophil vorgeschlagen. Da es sich um ein in Deutschland nicht zugelassenes Produkt handelt, ist eine Einzelverordnung nach § 73 Abs. 3 Arzneimittelgesetz (AMG) erforderlich. Langfristig will Chiron Vaccines Behring die Versorgung Deutschlands durch in Großbritannien von Chiron Vaccines Evans produziertes Tuberkulin (PPD Evans) ab Sommer 2006 sicherstellen. Problematisch an diesem Vorgehen ist die damit verbundene zweimalige Umstellung auf ein anderes Tuberkulin sowie die ungeklärte Frage der Bioäquivalenz. Als weitere Möglichkeit können, neben den erwähnten Tuberkulinen der Firma Chiron Vaccines, auch das von der Weltgesundheitsorganisation (WHO) als Standardtuberkulin empfohlene und in vielen europäischen Ländern bereits eingeführte Tuberkulin PPD RT23 SSI des Statens Serum Institut (Kopenhagen, Dänemark) sowie andere Tuberkuline, wie beispielsweise das in den USA verwendete Tubersol (PPD CT68), importiert werden. Zusammen mit dem Robert Koch-Institut (RKI) und dem Paul-Ehrlich-Institut (PEI) bemüht sich das Deutsche Zentralkomitee zur Bekämpfung der Tuberkulose (DZK) intensiv um eine Problemlösung, da eine kontinuierliche Tuberkulinversorgung Deutschlands zu diagnostischen Zwecken und auch im Rahmen von Umgebungsuntersuchungen zwingend notwendig ist. Angestrebtes Ziel sollte zudem die Verwendung eines einheitlichen Tuberkulins in allen Regionen sein, da ansonsten ein standardisiertes Vorgehen und die Vergleichbarkeit auf nationaler Ebene gefährdet sind. Geschätzt kann zukünftig von einem jährlichen Bedarf von etwa 2 Millionen Tuberkulintestdosen für Deutschland ausgegangen werden. Das Statens Serum Institut prüft derzeit die Möglichkeit einer Antragstellung auf Zulassung des PPD RT 23 SSI in Deutschland. Chiron Vaccines Behring teilt mit, dass es keine Zulassung für das Biocine-Tuberkulin anstrebt, hat aber die Absicht, eine Zulassung für das Tuberkulin PPD Evans in Deutschland zu beantragen. Sanofi Pasteur MSD hat derzeit keine Absicht, eine Mendel-Mantoux-Testsubstanz [wie z. B. Tubersol (PPD CT68)] zur Zulassung auf dem deutschen Markt anzumelden. Bis in Deutschland wieder ein zugelassenes Tuberkulin zur Verfügung steht, wäre es, insbesondere in Fällen, in denen ein Lagerbestand an Tuberkulin unverzichtbar ist, wie beispielsweise im öffentlichen Gesundheitsdienst und in Krankenhausapotheken, überaus hilfreich, wenn eine Ausnahmeregelung für den Import erwirkt werden könnte.The manufacturers of the only tuberculin available up to now in Germany for intradermal TB tests according to Mantoux, Chiron Vaccines Behring, in 2004 unexpectedly stopped the production of the tuberculin Behring GT (GT=gereinigtes Tuberkulin—purified protein derivative tuberculin). Only residual stocks were sold during the preceding months. The stocks of GT 10 were already depleted at the beginning of 2005, while there are small supplies left of GT 100 and GT 1000. As a temporary solution, Chiron Vaccines Behring is offering to import the Italian tuberculin Biocine PPD 5 IE lyophil produced by Chiron S.r.l. in Siena. As this is not licensed for sale in Germany, it is necessary to obtain an exceptional prescription (Einzelverordnung) according to § 73 (3) of the Federal Law Relating to the Manufacture and Distribution of Medicine (Arzneimittelgesetz, AMG). In the long term, Chiron Vaccines Behring plan to secure the supply of tuberculin in Germany by importing, starting in the summer of 2006, the tuberculin produced by Chiron Vaccines Evans in the UK (PPD Evans). However, these plans involve changing over to a different type of tuberculin twice within a very short period of time. Another problem is the unresolved issue of bioequivalence. Besides the above-mentioned tuberculins produced by Chiron Vaccines, a further possibility would be the import of the tuberculin PPD RT23 SSI of the Statens Serums Institute (Copenhagen/Denmark), which is recommended by the World Health Organization (WHO) as the standard tuberculin and which has already been introduced in several European countries, or of other tuberculins such as Tubersol (PPD CT68), which is used in the US. Together with the Robert Koch Institute (RKI) and the Paul Ehrlich Institute (PEI), the German Central Committee against Tuberculosis (DZK) is striving to find a solution, in view of the urgent need for an uninterrupted supply of tuberculin in Germany for diagnostic purposes and contact tracing. A uniform tuberculin should be used in all German regions as a basis to secure a standardized testing procedure and national comparability of test results. The estimated annual requirement for Germany is two million tuberculin test doses. The Statens Serum Institute is currently evaluating the possibility of licensing PPD RT23 SSI in Germany. Chiron Vaccines Behring communicated that it is not aiming to have the Biocine tuberculin licensed for Germany but intends to apply for a license for the tuberculin PPD Evans. Sanofi Pasteur MSD at this point does not intend to have a tuberculin like Tubersol (PPD CT68) licensed for Germany. Until a licensed tuberculin is again available in Germany, it would be very useful if, especially in settings where stocks of tuberculin are essential (e.g. public health services or hospital dispensaries), an exceptional import license could be obtained

Zukünftige Tuberkulinversorgung in Deutschland

Der Hersteller des einzigen bisher in Deutschland für Intradermaltests nach Mendel-Mantoux verwendeten Tuberkulins, die Firma Chiron Vaccines Behring, hat 2004 kurzfristig die Produktion von Tuberkulin Behring GT (GT=gereinigtes Tuberkulin) eingestellt. Anfang 2005 waren die Bestände an GT 10 bereits erschöpft, geringe Restbestände existierten noch für die Dosierungen GT 100 und GT 1000. Als Übergangslösung wurde von Chiron Vaccines Behring der Import des von Chiron S.r.l. in Siena hergestellten italienischen Tuberkulins Biocine PPD 5 IE lyophil vorgeschlagen. Da es sich um ein in Deutschland nicht zugelassenes Produkt handelt, ist eine Einzelverordnung nach § 73 Abs. 3 Arzneimittelgesetz (AMG) erforderlich. Langfristig will Chiron Vaccines Behring die Versorgung Deutschlands durch in Großbritannien von Chiron Vaccines Evans produziertes Tuberkulin (PPD Evans) ab Sommer 2006 sicherstellen. Problematisch an diesem Vorgehen ist die damit verbundene zweimalige Umstellung auf ein anderes Tuberkulin sowie die ungeklärte Frage der Bioäquivalenz. Als weitere Möglichkeit können, neben den erwähnten Tuberkulinen der Firma Chiron Vaccines, auch das von der Weltgesundheitsorganisation (WHO) als Standardtuberkulin empfohlene und in vielen europäischen Ländern bereits eingeführte Tuberkulin PPD RT23 SSI des Statens Serum Institut (Kopenhagen, Dänemark) sowie andere Tuberkuline, wie beispielsweise das in den USA verwendete Tubersol (PPD CT68), importiert werden. Zusammen mit dem Robert Koch-Institut (RKI) und dem Paul-Ehrlich-Institut (PEI) bemüht sich das Deutsche Zentralkomitee zur Bekämpfung der Tuberkulose (DZK) intensiv um eine Problemlösung, da eine kontinuierliche Tuberkulinversorgung Deutschlands zu diagnostischen Zwecken und auch im Rahmen von Umgebungsuntersuchungen zwingend notwendig ist. Angestrebtes Ziel sollte zudem die Verwendung eines einheitlichen Tuberkulins in allen Regionen sein, da ansonsten ein standardisiertes Vorgehen und die Vergleichbarkeit auf nationaler Ebene gefährdet sind. Geschätzt kann zukünftig von einem jährlichen Bedarf von etwa 2 Millionen Tuberkulintestdosen für Deutschland ausgegangen werden. Das Statens Serum Institut prüft derzeit die Möglichkeit einer Antragstellung auf Zulassung des PPD RT 23 SSI in Deutschland. Chiron Vaccines Behring teilt mit, dass es keine Zulassung für das Biocine-Tuberkulin anstrebt, hat aber die Absicht, eine Zulassung für das Tuberkulin PPD Evans in Deutschland zu beantragen. Sanofi Pasteur MSD hat derzeit keine Absicht, eine Mendel-Mantoux-Testsubstanz [wie z. B. Tubersol (PPD CT68)] zur Zulassung auf dem deutschen Markt anzumelden. Bis in Deutschland wieder ein zugelassenes Tuberkulin zur Verfügung steht, wäre es, insbesondere in Fällen, in denen ein Lagerbestand an Tuberkulin unverzichtbar ist, wie beispielsweise im öffentlichen Gesundheitsdienst und in Krankenhausapotheken, überaus hilfreich, wenn eine Ausnahmeregelung für den Import erwirkt werden könnte.The manufacturers of the only tuberculin available up to now in Germany for intradermal TB tests according to Mantoux, Chiron Vaccines Behring, in 2004 unexpectedly stopped the production of the tuberculin Behring GT (GT=gereinigtes Tuberkulin—purified protein derivative tuberculin). Only residual stocks were sold during the preceding months. The stocks of GT 10 were already depleted at the beginning of 2005, while there are small supplies left of GT 100 and GT 1000. As a temporary solution, Chiron Vaccines Behring is offering to import the Italian tuberculin Biocine PPD 5 IE lyophil produced by Chiron S.r.l. in Siena. As this is not licensed for sale in Germany, it is necessary to obtain an exceptional prescription (Einzelverordnung) according to § 73 (3) of the Federal Law Relating to the Manufacture and Distribution of Medicine (Arzneimittelgesetz, AMG). In the long term, Chiron Vaccines Behring plan to secure the supply of tuberculin in Germany by importing, starting in the summer of 2006, the tuberculin produced by Chiron Vaccines Evans in the UK (PPD Evans). However, these plans involve changing over to a different type of tuberculin twice within a very short period of time. Another problem is the unresolved issue of bioequivalence. Besides the above-mentioned tuberculins produced by Chiron Vaccines, a further possibility would be the import of the tuberculin PPD RT23 SSI of the Statens Serums Institute (Copenhagen/Denmark), which is recommended by the World Health Organization (WHO) as the standard tuberculin and which has already been introduced in several European countries, or of other tuberculins such as Tubersol (PPD CT68), which is used in the US. Together with the Robert Koch Institute (RKI) and the Paul Ehrlich Institute (PEI), the German Central Committee against Tuberculosis (DZK) is striving to find a solution, in view of the urgent need for an uninterrupted supply of tuberculin in Germany for diagnostic purposes and contact tracing. A uniform tuberculin should be used in all German regions as a basis to secure a standardized testing procedure and national comparability of test results. The estimated annual requirement for Germany is two million tuberculin test doses. The Statens Serum Institute is currently evaluating the possibility of licensing PPD RT23 SSI in Germany. Chiron Vaccines Behring communicated that it is not aiming to have the Biocine tuberculin licensed for Germany but intends to apply for a license for the tuberculin PPD Evans. Sanofi Pasteur MSD at this point does not intend to have a tuberculin like Tubersol (PPD CT68) licensed for Germany. Until a licensed tuberculin is again available in Germany, it would be very useful if, especially in settings where stocks of tuberculin are essential (e.g. public health services or hospital dispensaries), an exceptional import license could be obtained

Acute kidney injury and tools for risk-stratification in 456 patients with hantavirus-induced nephropathia epidemica

BACKGROUND Puumala virus (PUUV) is the most common species of hantavirus in Central Europe. Nephropathia epidemica (NE), caused by PUUV, is characterized by acute kidney injury (AKI) and thrombocytopenia. The major goals of this study were to provide a clear clinical phenotyping of AKI in patients with NE and to develop an easy prediction rule to identify patients, who are at lower risk to develop severe AKI. METHODS A cross-sectional prospective survey of 456 adult patients with serologically confirmed NE was performed. Data were collected from medical records and prospectively at follow-up visit. Severe AKI was defined by standard criteria according to the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) classification. Fuller statistical models were developed and validated to estimate the probability for severe AKI. RESULTS During acute NE, 88% of the patients had AKI according to the RILFE criteria during acute NE. A risk index score for severe AKI was derived by using three independent risk factors in patients with normal kidney function at time of diagnosis: thrombocytopenia [two points; odds ratios (OR): 3.77; 95% confidence intervals (CI): 1.82, 8.03], elevated C-reactive protein levels (one point; OR: 3.02; 95% CI: 1.42, 6.58) and proteinuria (one point; OR: 3.92; 95% CI: 1.33, 13.35). On the basis of a point score of one or two, the probability of severe AKI was 0.18 and 0.28 with an area under the curve of 0.71. CONCLUSION This clinical prediction rule provides a novel and diagnostically accurate strategy for the potential prevention and improved management of kidney complications in patients with NE and, ultimately, for a possible decrease in unnecessary hospitalization in a high number of patient

Testing the relative sensitivity of 102 ecological variables as indicators of woodland condition in the New Forest, UK.

Forests globally are facing an increasing number of threats from modified disturbance regimes, novel stressors and changing environmental conditions. This has ultimately resulted in declines in the ecological condition of many forest and woodland ecosystems, leading to widespread tree mortality and stand dieback. Effective indicators of overall woodland ecological condition are therefore needed for environmental monitoring and to support management responses. To test the effectiveness of different variables that could potentially be used as indicators of woodland condition, 102 variables that describe woodland structure, composition, functioning, edaphic conditions and disturbance regimes were assessed along 12 replicate gradients of beech stand dieback. Results indicated that 35 variables differed significantly between at least two stages of the dieback gradient, indicating their sensitivity to stand dieback. Seven of these indicators related to woodland species composition, two to functional processes, 20 to structural features, four to edaphic conditions, and two to disturbance regimes. These results demonstrate that effective indicators can potentially be identified for each of the ecological categories. Effective composition indicators included species richness of ectomycorrhizal fungi, ground flora and epiphytic lichens; functional indicators were soil respiration rate and net nitrification rate; edaphic conditions included soil Na:Ca ratio, exchangeable sodium, total carbon, Ca:Al ratio; structural indicators included canopy openness, litter cover, sward height, and volume of deadwood, and for disturbance the indicator was Equus dung density. Other measures, such as shrub cover and species richness of carabid beetles and spiders, were not found to vary significantly along the dieback gradients, and were therefore not identified as effective indicators. These results demonstrate the value of gradient analysis for evaluating indicators of woodland condition, but also highlight the need for multi-site studies to identify indicators with widescale applicability

Neue Empfehlungen für die Umgebungsuntersuchungen bei Tuberkulose

Nach der Einführung der neuen Interferon-γ-Release Assays (IGRAs) in den Empfehlungen des Deutschen Zentralkomitees zur Bekämpfung der Tuberkulose im Jahre 2007 hat sich die Datenlage für deren Einsatz beträchtlich verbessert. Da Sensitivität und Spezifität von IGRAs bei Erwachsenen in zumindest teilweise BCG-geimpften Kollektiven derjenigen des Tuberkulin-Hauttests (THT) im Allgemeinen überlegen sind, wird bei Kontaktpersonen im Gegensatz zum früheren Zweistufenverfahren nur noch der primäre Einsatz von IGRAs empfohlen. Aufgrund fehlender Evidenz über die Zuverlässigkeit von IGRAs bei Kindern unter 5 Jahren bleibt der THT in dieser Altersgruppe Mittel der Wahl; bei älteren Kindern können beide Tests angewendet werden. Die neuen Empfehlungen unterstreichen die Notwendigkeit einer sorgfältigen Vorauswahl enger Kontaktpersonen, damit positive Testbefunde mit hoher Wahrscheinlichkeit auch eine frische Infektion widerspiegeln und so den Nutzen einer Chemoprävention erhöhen. Das Nachtesten von positiv getesten Kontaktpersonen kann zu einer beträchtlichen Anzahl falsch-negativer Resultate führen und sollte bei dokumentierter Exposition daher unterbleiben.In 2007, the German Central Committee against Tuberculosis (DZK) published recommendations for contact tracing that introduced the new interferon gamma release assays (IGRAs). Meanwhile, substantial progress has been made in documenting the utility of IGRAs. Because IGRAs are usually superior to the tuberculin skin test (TST) in detecting latent TB infection (LTBI) with respect to sensitivity and specificity in adult contact populations that are at least partially BCG vaccinated, it is now recommended that instead of two-step testing only IGRAs be used.[nl]As the literature does not yet provide sufficient data on the accuracy of IGRAs in children younger than 5 years, the TST remains the method of choice in that age group. To date, also, no clear body of data exists to substantiate better performance for IGRAs than for the TST in older children, thus in this age group using of either test is recommended. The new recommendations also underscore the importance of a diligent preselection of close contacts in order to achieve a high probability that positive test results represent recent infection and to thus increase the benefit of chemopreventive treatment for those identified as requiring it. In a third point of update, it is noted that re-testing of contacts individuals found positive for LTBI may produce a considerable number of false-negative results and should thus be avoided in case of documented exposure

Clinical course and long-term outcome of hantavirus-associated nephropathia epidemica, Germany

Human infection with Puumala virus (PUUV), the most common hantavirus in Central Europe, causes nephropathia epidemica (NE), a disease characterized by acute kidney injury and thrombocytopenia. To determine the clinical phenotype of hantavirus-infected patients and their long-term outcome and humoral immunity to PUUV, we conducted a cross-sectional prospective survey of 456 patients in Germany with clinically and serologically confirmed hantavirus-associated NE during 2001-2012. Prominent clinical findings during acute NE were fever and back/limb pain, and 88% of the patients had acute kidney injury. At follow-up (7-35 mo), all patients had detectable hantavirus-specific IgG; 8.5% had persistent IgM; 25% had hematuria; 23% had hypertension (new diagnosis for 67%); and 7% had proteinuria. NE-associated hypertension and proteinuria do not appear to have long-term consequences, but NE-associated hematuria may. All patients in this study had hantavirus-specific IgG up to years after the infection