Genomics to combat Resistance against Antibiotics in Community-acquired LRTI in Europe
GRACE s w e n
Spreading Excellence in Respiratory Tract Infections
Editorial
January 2008, Volume 3 (1)
Prague, eLearning & the future of NoEs Prague is a city of wonderful architecture and fine music. It was selected to host the first and highly successful GRACE Workshop last October. The theme for the three day meeting was ‘Lower respiratory tract infections: current concepts in pathogenesis, microbiology, epidemiology and economic impact.’ The presentations were excellent and there was good delegate interaction. A full report can be read on page 7. The GRACE eLearning Resource (see WP12 at www.grace-lrti.org) is rapidly expanding and has about fifty presentations resulting from the presentations at the GRACE Workshop and three Postgraduate courses held to date. This is freely accessible and provides a rich source of up-todate material covering topics from basic science to clinical practice.
Table of content p. 1 Editorial Prague, eLearning & the future of NoEs
News New GRACE members at Cardiff
The future of the Networks of Excellence remains a hot topic of particular interest to researchers who have recognised the value and success of close of the initiative which integrates multiple partners around a research theme. At a recent Open Forum on the future of European Networks of Excellence held in Brussels in November (see Publications/Presentations at www.grace-lrti.org) five NoEs which included GRACE, made a strong plea for sustainable funding. Roger Finch
p. 2 GRACE-01 Update
SMARTIE
GRACE-02 Update, December 2007
GRACE-03 Update
CHAMP
p. 3 WONCA Europe 2007 in Paris
European Parliament session (European Antibiotic Day)
p. 4 WP9-10 of GRACE: a successful case! p. 5 Pneumococcal genomics in GRACE (WP6)
News New GRACE members at Cardiff I am very pleased to announce three new members of the GRACE team in Cardiff. Dave Gillespie, a sandwich year maths student, and Dr. Mark Kelly (statistician) are undertaking the data management and analysis of GRACE-01. In addition, Lucy Cooper has joined Lucy Brookes-Howell working on the qualitative study, GRACE-02. We are looking forward to their contributions in helping further understand the vast amounts of data gathered last winter. Chris Butler
p. 6 Enterprises in GRACE: CORIS p. 7
1st and 2nd GRACE Workshop held in Prague in October 2007!
p. 8 Second Annual GRACE Meeting
From right to left: Dave Gillespie, Lucy Cooper and Mark Kelly
GRACE-01 Update The GRACE-01 analysis is proceeding apace. The current focus is to investigate associations between both clinician and patient reported symptoms and patient outcome. Before this could begin however, an exhaustive validation process was undertaken. This involved assessing the validity of creating a total symptom severity score by summing the severity score for each symptom. Our next step involved investigating missing values in the patient symptom diary. If a patient completed at least 80% of the symptom diary on a given day the remaining missing values were replaced with the mean of the other symptoms for that day. Once the total symptom severity scores were successfully cleaned and validated the analysis could begin. In order to investigate associations between patient outcome and clinical management for each of the GRACE-01 sites, the patient diary symptom-scores were modelled. Many modelling approaches were investigated before a suitable one was chosen. This is currently being written up for publication in a high-ranking journal. The next objective for the GRACE-01 study team is the dissemination of the results of the analysis currently being carried out. We have also met with the WP11 team and given them access to the GRACE-01 datasets so that they can estimate the economic burden associated with treatment of LRTI in different countries and obtain baseline data for modelling the cost-effectiveness of diagnostic strategies. Mark Kelly and Dave Gillespie
GRACE-02 Update, December 2007 These are busy times for GRACE-02. An amazing 188 interviews have been conducted with Balatonfüred, Cardiff, Lodz, Southampton, Tromsø and Utrecht having closed recruitment after doing a fantastic job of recruiting, arranging and carrying out their interviews. The remaining 3 networks, Antwerp, Barcelona and Milan, are attempting to conduct their final handful of interviews. In Cardiff, we are hard at work scrutinising and analysing the interview data and fieldnotes. The GRACE team in Cardiff is lucky to have been joined by Lucy Cooper, Research Associate helping with analysis of the GRACE-02 data. Joining us at this stage, Lucy C has had to engage with the data quickly, and has already proven herself an invaluable member of the team. A detailed framework of coding categories has now been developed, based on a combination of the GRACE research aims and themes emerging from the interviews themselves. This framework is currently being applied to the Clinician interviews through thematic coding. The management of data and coding is assisted by the use of the software package, NVivo. It is important to consider each network as a set in its own right before, at a later date, similarities and variations across networks can also be explored. Therefore, we can only begin detailed analysis once we have a complete set of transcribed and translated (when necessary) interviews. We are pleased to report that full, detailed thematic coding has been now carried out on all Clinician interviews for which we have received a complete set of translations; Antwerp, Balatonfüred, Cardiff, Lodz, Southampton and Tromsø.
GRACE-03 Update I would like to start by thanking all the members of the GRACE-03 Delphi panel for giving up their valuable time to contribute to the study. The process has finished and is in the analytical stage presently. The GRACE-PAT leaders are assessing the results with relation to the integration of the definitions in to WP9 and 10. The finalised definitions will be presented the annual GRACE meeting in Budapest and will also be published in the next issue of GRACE news. The process evaluation has shown that, on average the panel members agreed with the statements ‘The process was easy to undertake’, and ‘The Delphi task was a useful and worthwhile task to undertake’. The development of a strategy to assess the views of experts within the respiratory infections community has been a real success. From the first tentative steps taken in the set up of GRACE-03, supported by the excellent work of the GRACE IT platform, an invaluable research resource has been created. With the utilisation of the GOS, the expert knowledge of all involved in GRACE can be canvassed. One such opportunity for this technology comes in the form of CHAMP. This expands upon GRACE-03, quite literally, in terms of the number of clinicians involved, in disease categories, including both LRTI and URTI and finally including both adults and children. Giles Greene
CHAMP
The GRACE-01 data produced an enormous wealth of data, with a vast number of potential for informing additional research. One such example of this is the SMoking And Respiratory Tract Infections in Europe (SMARTIE) study which has been proposed and is awaiting funding. The study will examine the management of patients across three population groups, smokers, ex-smokers, and non-smokers, across Europe. It has already been shown that smokers are more likely to be prescribed antibiotics despite no difference in severity score. Further analysis using multi-level modelling will explore the relationships in much greater detail.
Analysis of the Clinician interviews from the remaining three networks will take place early in 2008 before the important task of analysing all Patient interviews. It is important that we receive translations of interviews as soon as possible in order to allow time for the lengthy analysis process. We have currently received translations of 85% of Clinician (6 networks with complete sets) and 69% of Patient (4 networks with complete sets) interviews. We continue to be extremely grateful to the NNFs and interviewers who are working so tirelessly on GRACE-02 and hope that, with one final push, all translations can be finished and any outstanding supplementary data forms input into GOSwp8q.
CHAMP moves beyond LRTI to other infections. WP2 consists of a quantitative and qualitative study with its aim to explore current preventions and management of respiratory tract infections in European primary care and investigate perception, expectations and illness behaviour of primary care patients with respiratory tract infections. The quantitative study will comprise of a web-based vignette-style questionnaire, which is currently being developed, that will determine variation in the management of common infections in primary care both between and within countries. The qualitative study will build on work carried out by GRACE-02, focussing more specifically on the views of parents of child patients with common infections.
Naomi Stanton
Lucy Brookes-Howell
Dave Gillespie
SMARTIE
www.grace-lrti.org
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WONCA Europe 2007 in Paris
Paul Van Royen opens conference
Ruut de Melker amidst the speakers on his symposium
In many ways this WONCA congress was a very special congress and a very successful one as well. Perhaps it was the mild autumn weather that made us happy and relaxed, perhaps it was the strike of public transport that kept us away from the seductions of the city itself, but most importantly it was the good organisation and new focus of WONCA Europe that gave the GRACE researchers who were present a very good feeling about this congress. Our project was clearly present from the start: Paul van Royen mentioned GRACE as one of the first good examples of European collaboration in his keynote lecture on the first day. Triggered by this excellent lecture all participants were reminded of something about GRACE in their congress bag and several were spotted reading the smart GRACE newsletter that Samuel had managed to get in the standard information package each participant had received! There were many presentations on respiratory tract infections and the discussions were lively and very interesting. Our knowledge of French was tested sometimes when presenters and part of the audience switched to their native language, but that was hardly a problem. Kerry Hood had the opportunity to present latest GRACE results during a symposium that Paul Little had organised and as seen before in 2007 the reactions to her excellent presentation were enthusiastic and full of admiration. And there was a symposium on behalf of the 75th birthday of Ruut de Melker, one of the pioneers of research on respiratory tract infections in primary care, where several GRACE researchers contributed to. During the conference there was also a meeting of so called Special Interest Groups, where GRIN was also invited. The board of WONCA invited the representatives of these groups to play a more active role in the scientific programme of coming WONCA Europe congresses. This invitation was gladly accepted by the groups present, and this means that GRIN will be able to organise special symposia and workshops in future congresses where GRACE can be presented and discussed with European researchers and general practitioners. A very good prospective! And last but not least there was rugby! Straight after the congress your reporter was dragged into an Irish pub (name me a city without them) by some GRACE researchers who will remain anonymous and drowned in madness, beer and a tremendous victory by the South Africans. A GRACE-full end of a good congress! Theo Verheij
European Parliament session (European Antibiotic Day)
Herman Goossens on Belgian antibiotic policy
At a meeting hosted by the European Parliament on 16 October 2007, the Director of the European Center for Disease Control and Prevention (ECDC) announced the launch of a European Antibiotic Day for autumn 2008. This announcement received strong support from Commission officials representing DG SANCO and DG RTD at director level, Member State public health attaches and sponsoring member of the European Parliament John Bowis. In the meantime, it has been decided that ECDC will coordinate this annual event, which will take place on November 18 of each year. ECDC seeks to maintain and increase awareness of the issue of antimicrobial resistance at EU and Member State level in order to encourage effective public health action. The major focus of this European Antibiotic Day will be to support existing national information campaigns on rational use of antibiotics and to foster the emergence of new national initiatives in this area. The added-value of an EUwide approach is to provide a focus point for consistent messaging and awareness raising across the EU on the day, and in the build up to the day. The first European Antibiotic Day on November 2008 will focus on informing the general public about rational antibiotic use. Meetings have already been planned during the Slovenian (first semester 2008) and French (second semester 2008) presidency to prepare this important event. Herman Goossens Spreading Excellence in Respiratory Tract Infections
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WP9-10 of GRACE: a successful case! L U C H T W E G I N F E C T I E S I N
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bijvoorbeeldfor een peritonsillair abces . Een recentere RCT bij kinderen met keelpijn vond geen effect van penicilline Dit editoriaal is gebaseerd op Coenen S, Goossens H. Antibiotics respiratory tract infections in primary care. BMJ op de duur van de keelpijn en had onvoldoende power om een beschermend effect te detecteren, maar stelde dat elke 2007;335:946-7. geïdentificeerde complicatie met succes was behandeld zonder ziekenhuisverwijzing . Volgens een meta-analyse van gegevens van individuele patiënten methet otitis media antibiotica effectief bij kinderen met otorroe (21%) Het voorschrijven van antibiotica voor gewone luchtweginfecties betekent balanceren tussen risico op waren het misen bij kinderen jonger dan twee jaar met bilaterale infectie (20%) . Er waren geen gevallen van mastoïditis bij kinsen van pneumonie of ernstige complicaties en het onnodig behandelen van infecties . Recent onderzoek heeft aanderen die geen antibiotica kregen. Bij mensen met acute bronchitis of lageluchtweginfecties verminderen antibiotigetoond dat antibioticagebruik resistente respiratoire pathogenen uitselecteerde bij individuele personen (zie ook ca de hoest niet veel . De vermindering in het gemiddelde aantal dagen met beperkte activiteit en zich ziek voelen Kort Nieuws) . Dit onderzoek was nodig ter bevestiging van eerder onderzoek dat resistentie associeerde met het is nauwelijks significant, zo ook de toename in neveneffecten. De grootste studie tot nu toe includeerde 807 patiëngebruik op populatieniveau en ter ondersteuning van programma’s om resistentie via doelmatiger antibioticagebruik ten met acute ongecompliceerde lageluchtweginfecties die ofwel onmiddellijk of met uitstel amoxicilline, ofwel geen te bestrijden . Maar, hoewel het optimaliseren van het antibioticagebruik een aanzienlijke impact lijkt te hebben op antibiotica werden aangeboden en vond weinig verschil in het verloop van de symptomen . de resistentie , wordt gesuggereerd dat (ver)minder(ing van het) antibioticagebruik geassocieerd is met een hoger risico op complicaties . Of, met andere woorden, datNieuwe antibiotica eenprojecten beschermend effect hebben tegen ernstige comEuropese en initiatieven plicaties van gewone luchtweginfecties . Samengevat biedt het beschikbare onderzoeksbewijs huisartsen niet Beschermen antibiotica tegen ernstige complicaties?
wat ze nodig hebben om doelmatig antibiotica voor te schrijven voor gewone luchtweginfecties, behalve misschien voor otitis media. Vooral
In dit laatste, recent gepubliceerde onderzoek werd bijvoor 3,36 miljoen episodes van luchtweginfecties, die zekerheid tussen 1991 lageluchtweginfecties kunnen huisartsen niet met identificeren wie baat zal hebben bij een behandeling met antibiotica en 2001 werden opgetekend in de UK General Practice Research Database (GPRD), nagegaan of complicaties min-en beoogt GRACE (zie logo en dan op www.grace-lrti.org), der vaak voorkwamen bij die individuele patiënten bijwie wieniet. eenGelukkig antibioticum was voorgeschreven bij diegenen bij eeninzogenaamd of excellence gefinancierd door de Europese wie dat niet was gebeurd . Ze vonden dat pneumonie de maand network na de diagnose van bovensteluchtweginfecties, Commissie, dergelijke vragen te beantwoorden. peritonsillair abces na keelpijn en mastoïditis na otitis media zeer zeldzaam waren bij patiënten zonder antibiotiOppatiënten. dit moment loopt een placebogecontroleerde dubbelblinde studie in dertien netwerken van huisarts-onderzoecumvoorschrift, respectievelijk 11, 14 en 5 per 10 000 Het voorschrijven van een antibioticum ging gekers in tien Europese landen waaronder België met twee netwerken paard met een geringe absolute reductie van het risico op deze ernstige complicaties. Het risico op pneumonie in dein Vlaanderen (Antwerpen en Gent; zie www.gracelrti.org/wp9-10). Meer dan drieduizend patiënten met lageluchtweginfecties zullen worden ingesloten. Tegelijkertijd maand na de diagnose van lageluchtweginfecties was echter hoog en werd aanzienlijk verminderd door een antibiozullen de etiologie, de diagnose en de prognose van lageluchtweginfecties nagegaan worden om een onderscheid te ticumvoorschrift; het beschermende effect was het grootst bij de 65-plussers. kunnen maken tussen virale en (resistente) bacteriële infecties, bronchitis en pneumonie, maar vooral tussen een Hoewel deze laatste, retrospectieve cohortstudie één van de betere studies is om het effect van het voorschrijven van laag en hoog risico op complicaties. Samen met spin-offs zoals TheraEDGE, een Europees project om sneltests te ontantibiotica op het voorkomen van zeldzame complicaties van een gewone luchtweginfectie te onderzoeken, worden wikkelen voor de microbiële diagnostiek van lageluchtweginfecties, zal GRACE de materie leveren om in de nabije ook hier de conclusies vertekend. Hoogstwaarschijnlijk kregen ziekere en diegenenindie le-Europa vorm te geven . toekomst hetdebeleid vanpatiënten lageluchtweginfecties demeer eerstekans lijn in ken te hebben op een slechte afloop, vaker antibioticaOndertussen voorgeschreven (confounding by indication). de deel- and Control (ECDC) een European Antibiotic bereidt het European Centre for Mochten Disease Prevention nemende huisartsen weinig antibiotica voorschrijven voor de vier Day bestudeerde aandoeningen, dan waren bevindingen Resistance in 2008 voor. Dit evenement zou alsdeeen katalysator kunnen werken voor acties om een (nog) ratiowellicht betekenisvoller geweest; volgens de gebruikte databank bovensteluchtweginfecties, keelpijn, otitis neler gebruik waren van antibiotica in de lidstaten te promoten. In afwachting van het effect daarvan zou het zinvol zijn om media en lageluchtweginfecties vier van de vijf redenen het vaakst antibiotica voorgeschreven, res- van complicaties op te volgen naast het European eenwaarvoor surveillancesysteem op te zettenwerden om prospectief het voorkomen en nog vaker voor 1998www.rivm.nl/earss/) . pectievelijk in 44%, 64%, 63%, en 82% van de gevallen tussen 1998 en 2001Surveillance Antimicrobial Resistance System (EARSS; en de European Surveillance of Antimicrobial Consumption (ESAC; www.esac.ua.ac.be). Wat leren ons RCT’s en meta-analyses?
Conclusie, voortehet beleid van maar de meeste luchtweginfecties is de boodschap watchful waiting. Het randomiseren van patiënten is een manier om die vertekening vermijden, gerandomiseerde gecontroleerde studies (RCT’s) hebben meestal onvoldoende power om zeldzame gebeurtenissen te bestuderen en de geïnS. Coenen, adjunct-hoofdredacteur van Huisarts Nu en cludeerde patiënten zijn mogelijk niet vergelijkbaar met diegenen die huisartsen in hun praktijk zien. Nochtans zijn lid van het ESAC en het GRACE Management Team antibiotica volgens meta-analyses van RCT’s bij mensen met verkoudheden of bovensteluchtweginfecties niet effectief . Een uitzondering is misschien de subgroep (20%) met positieve nasofaryngeale cultuur voor H. influenzae, Literatuur M. catarrhalis of S. pneumoniae . Tot nu toe zijn er echter geen haalbare en betaalbare sneltests beschikbaar om deze 1 Coenen S. Antibiotics for coughing in general practice: exploring, describing and optimising prescribing [proefschrift]. Antwerpen: Universiteit subgroep te identificeren . Antwerpen, 2003. Acuut gewrichtsreuma en acute glomerulonefritis zijn erg zeldzaam in geïndustrialiseerde landen. Bij mensen met on antibiotic resistance in individual children in primary care: 2 Chung A, Perera R, Brueggemann AB, Elamin AE, et al. Effect of antibiotic prescribing prospective cohort study. BMJhet 2007;335:429. keelpijn bevorderen antibiotica de symptomen een beetje en ze verminderen risico op suppuratieve complicaties, 3 Malhotra-Kumar S, Lammens C, Coenen S, et al. Impact of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci among healthy volunteers: a randomised, double-blind, placebo-controlled study. Lancet 2007;369:482-90. 4 Goossens H, Ferech M, Stichele RV, Elseviers M and the ESAC Project Group. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet 2005;365:579-87. [vertaald in Huisarts Nu 2005;34:565-74] 5 Woodhead M, Fleming D, Wise R. Antibiotics, resistance, and clinical outcomes. BMJ 2004;328:1270-1. Huisarts Nu november 2007; 36(9) 451
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Currently 10 different networks recruited over 440 patients, including over 60 patients on study medication. CRF data entry in the GRACE Online System (GOS) is very complete. Nearly all patients with LRTI got an X-ray. And in 75% sputum is collected of which 60% is of good quality. We planned to start WP9 and WP10 October 1st 2007. As was to be expected, we had to face some starting problems. Study medication was not distributed yet, approval of several Ethics Committees was still outstanding, and some countries had to wait for a signed contract from the European Commission. In the mean time, however, all of these issues are taken care of.
Huisarts Nu november 2007; 36(9)
GRACE WP9-10 in BMJ and Huisarts Nu editorial
WP9 versus WP10 The primary care network (PCN) Antwerp was the only one that started with patient recruitment as planned, quickly followed by Cardiff, Mataro and Rotenburg. All those inclusions were patients for WP 9, because at that time the study medication was not available yet. After 6 weeks, the memorable 15th of November, Cardiff included the first patient taking study medication, and thus the first patient for WP 10!
Genomics to combat Resistance against Antibiotics in Community-acquired LRTI in Europe
DOET U MEE AAN GRACE? GRACE = een onderzoeksprogramma gefinancierd door de Europese Unie over de diagnose en behandeling van hoest en lage luchtweginfecties waarvoor huisartsen in 10 Europese landen patiënten en controle patiënten zoeken. Waarom? przyszedł/przyszła Pan/i Door uw deelname zullenCzy huisartsen U in de toekomst een betere behandeling do kunnen bieden lekarza swojego
z KASZLEM Wie? lub INFEKCJĄ W KLATCE PIERSIOWEJ? U hoest (<28 dagen) of U komt in aanmerking als controle patiënt (zie informatieformulier voor meer details) Czy zechciałby/zechciałaby Pan/Pani wziąć udział w dużym europejskim badaniu, które ma na celu:
Wat? lepsze zrozumienie powodów kaszlu i infekcji w klatce piersiowej U krijgt gratis een uitgebreider onderzoek, een nauwgezette opvolging en eventueel studiemedicatie znalezienie sposobów poprawy leczenia kaszlu i infekcji w klatce piersiowej Hoe? Lees het informatieformulier laat uw by dowiedzieć się więcej JEŚLI TAK,en przeczytaj, huisarts wetenodat U geïnteresseerd bent Badaniu GRACE Kaszlu/Infekcji w Klatce Piersiowej
?
*Deelname is volledig vrij. Indien u niet wenst deel te nemen zal dit in geen geval de kwaliteit van de zorg die u krijgt beïnvloeden. U neemt pas deel aan de studie nadat U een toestemmingsformulier heeft ondertekend.
Centrum voor huisartsgeneeskunde
Udział będzie związany z…
Patient inclusion Since mid November almost all other PCNs finished their preparations and started including patients as well. When writing this, the GRACE patient inclusion graph is showing us a total of 448 patients: 256 patients in WP9, of which 61 for WP10, and 192 controls. Of the 10 active PCNs 4 have included more than 50 patients in total, and 6 PCNs have included patients in WP10.
…dokładną obserwacją poprzez: zdjęcie Rtg klatki piersiowej badanie krwi badanie czynności płuc wymazy z nosa prosty dzienniczek objawów Pana/Pani lekarz rozważy także, czy potrzebuje Pan/Pani antybiotyk.
Jeśli zechce Pan/Pani pomóc nam poprawić rozpoznawanie oraz leczenie kaszlu i infekcji klatki piersiowej, proszę zapytać swego lekarza o szczegóły dotyczące tego badania.
Screens and poster to notify patients about the GRACE study
Genomics to combat Resistance against Antibiotics in Community-acquired LRTI in Europe
Genomics to combat Resistance against Antibiotics in Community-acquired LRTI in Europe
Onderzoek naar de diagnose en behandeling van lage luchtweginfecties
Onderzoek naar de diagnose en behandeling van lage luchtweginfecties
Patiënt met lage luchtweginfectie (LLWI)
Controle patiënt*
> 18 jaar > acute hoest (<28 d) als hoofdklacht OF vermoeden van LLWI > eerste consult deze ziekte-episode > tijdens de normale consultatie uren > immuno-competent > kan studiemateriaal invullen > nam geen antibiotica afgelopen maand > nam nog niet deel aan deze studie > niet zwanger
> 18 jaar > geen luchtweginfectie > max 5 jaar jonger of ouder EN zelfde geslacht als patiënt met LLWI > tijdens de normale consultatie uren > immuno-competent > kan studiemateriaal invullen > nam geen antibiotica afgelopen maand > nam nog niet deel aan deze studie > niet zwanger
+voor het BEHANDEL DEEL > heeft nu geen antibiotica nodig > geen contra-indicatie voor amoxicilline > wil studiemedicatie nemen
* Idealiter in te sluiten binnen de 10 dagen (max 2 weken) na de bijhorende patiënt met LLWI
P Inclusiecriteria toetsen
P Inclusiecriteria toetsen
P Informed consent ondertekenen (2x2)
P Informed consent ondertekenen (2x2)
P PRF invullen & faxen naar NNF1
P PRF invullen & faxen naar NNF1
P CRF invullen & invoeren in GOS2
P CRF invullen & invoeren in GOS2
P Stalen afnemen (V1): P 2x wisser (eerst groen, dan rood) P 2x bloed (EDTA + SST) P 1x sputum (ev. ochtend~)
P Stalen afnemen (V0): P 2x wisser (eerst groen, dan rood) P 1x bloed (EDTA)
P Labo aanvragen & faxen naar NNF1
P Labo aanvragen & faxen naar NNF1
P RX thorax aanvragen (≤3 d, max ≤7 d) P Longfunctie aanvragen (28-35 d) P Dagboek en instructies geven
Centrum voor huisartsgeneeskunde
P Studiemedicatie en instructies geven3 1.
NNF FAX: 03 820 25 26 (Tel: 03 820 25 25)
2.
GOS: www.grace-lrti.org/wp9-10
3.
Code breken: Tel: 00 31 88 755 45 91
1.
NNF FAX: 03 820 25 26 (Tel: 03 820 25 25)
2.
GOS: www.grace-lrti.org/wp9-10
Antwerp - Balatonfured - Barcelona - Bratislava - Cardiff - Ghent - Helsinki - Jönköping - Lodz - Mataro - Milan - Rotenburg Southampton - Tromsö - Utrecht - Antwerp - Balatonfured - Barcelona - Bratislava - Cardiff - Ghent - Helsinki - Jönköping - Lodz - Mataro - Milan - Rotenburg - Southampton - Tromsö - Utrecht - Antwerp Balatonfured - Barcelona - Bratislava - Cardiff - Ghent - Helsinki - Jönköping - Lodz - Mataro - Milan - Rotenburg - Southampton Tromsö - Utrecht - Antwerp - Balatonfured - Barcelona - Bratislava - Cardiff - Ghent - Helsinki - Jönköping - Lodz - Mataro - Milan Rotenburg - Southampton - Tromsö - Utrecht - Antwerp - Balatonfured - Barcelona - Bratislava - Cardiff - Ghent - Helsinki - Jönköping - Lodz - Mataro - Milan - Rotenburg - Southampton - Tromsö Utrecht - Antwerp - Balatonfured - Barcelona - Bratislava - Cardiff - GhentGenomics - Helsinki - Jönköping - Lodz - Mataro - Milan - Rotenburg to combat Resistance against - Antibiotics Southampton in - Tromsö - Utrecht - Antwerp - Balatonfured Community-acquired LRTI in Europe Barcelona - Bratislava - Cardiff - Ghent - Helsinki - Jönköping - Lodz - Mataro - Milan - Rotenburg - Southampton - Tromsö Utrecht - Antwerp - Balatonfured - Barcelona - Bratislava - Cardiff
See www.grace-lrti.org/wp9-10 for the most recent inclusion figure. Data collection For all patients in WP9 and 10 registration forms, diaries, the collection of blood, swabs, sputum and test results have to be entered in the GRACE Online System (GOS). So far, almost all these data are really very complete in GOS. The most difficult part regarding the data collection are the diaries. This is the only item in the whole data collection that is below 95%. Laboratory facts According to the data in GOS on January 22nd, 89% of the sample kits arrived in the local labs within 1 day after sampling. This is very good! In 75% of patients with LRTI sputum was collected. This is a very high number compared with other studies! Also the quality of the sputum is good. In 60% of the cases more white blood cells than epithelial cells were found. So far, Haemopilus spp. and S. pneumoniae were identified most often in the sputum. Many thanks to all who are involved and busy making the data-collection of WP9-10 a success! Saskia van Vugt
Flowchart and mouse mat to support GPs www.grace-lrti.org
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Pneumococcal genomics in GRACE (WP6) Lower Respiratory tract infections (LRTI) remains the leading cause of deaths world-wide (see figure). A major part of these infections are caused by pneumococci. It has been estimated that between 1 and 2 million people die from pneumococcal diseases every year. Workpackage 6 (WP6) deals with pneumococcal genomics and this workpackage is included in GRACE-TECH, the platform within GRACE for technological developments. It is headed by Birgitta Henriques Normark at the Swedish Institute for Infectious Disease Control, Solna, Sweden, and other partners involved are Herminia de Lencastre at ITQB, Lisbon, Portugal, David Holden at Imperial College, London, UK, Regine Hakenbeck, at Kaiserslautern University, Kaiserslautern Germany and Staffan Normark at Karolinska Institutet, Stockholm, Sweden.
Leading Causes of Death Due to Infectious Diseases Deaths in millions
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3,5 3
2,5 2
1,5 1
0,5 Measles
Malaria
Tuberculosis
Diarrheal diseases
HIV/AIDS
LRTI
0
Source: World Health Report, 2004 WHO
The aims of WP6 include collection of pneumococcal isolates from the clinical platforms within GRACE and to characterise these isolates with genomic molecular techniques and selected isolates with in vitro and in vivo virulence analysis. Antibiotic resistance types, serotypes, genotypes, and virulence characteristics will be correlated to clinical pictures of LRTI. We are now studying the discriminatory power of Pulsed Field Gel Electrophoresis (PFGE) using different restrictions enzymes and compare this method with Multi Locus Sequence Typing (MLST) as a quality assurance testing to decide the appropriate methods to be used in GRACE. Furthermore, we have so far constructed a micro-array chip consisting of two of the sequenced pneumococcal genomes, TIGR4 and R6. This chip will be used to study gene content in some of the collected isolates within GRACE. The pneumococcal capsule (of which 90 serotypes exist) is an important virulence factor in pneumococcal disease and in our previous work we have found that certain serotypes correlate to invasive disease while others are more common among carriers. Also, some serotypes are more common causing invasive disease in patients that have underlying diseases or disorders like immunodeficiency. Still we lack information on why pneumococci cause mainly carriage but sometimes disease such as LRTI and invasive diseases. By using micro-array analysis of invasive pneumococcal isolates we have shown that virulence factors differ between pneumococcal strains and so far no single virulence factor can be attributed to explain pathogenesis. However, we have recently shown that one single virulence factor, in this case a pilus like structure on the pneumococcal surface, may be an important factor for the spread of antibiotic resistant pneumococal clones around the world. Within GRACE we expect to detect new and unusual antibiotic resistance profiles and to get a picture of the pneumococcal clones causing LRTI and their spread within the community in the different countries in Europe that participate in GRACE. Also, we hope to discover novel virulence factors important for pathogenesis among our clinical isolates using comparative genomics and studies of virulence both in vitro and in vivo. Birgitta Henriques
Spreading Excellence in Respiratory Tract Infections
5
Enterprises in GRACE: CORIS Coris BioConcept was founded in October 1996. Aim of the company is to provide a global service in the diagnostic field leading to innovative and rapid solutions to hospitals and laboratories.
CORIS building
CORIS team
Coris was the first company to propose a rapid membrane test for detecting Rotavirus in stools. The enteric range of products rapidly grew and very quickly, the company decided to develop new products dedicated to the detection of respiratory pathogens, keeping the same technological features: quick, simple and reliable. Along with these rapid membrane antibody-based tests, we also developed a new proprietary technology called Oligochromatography and based on a direct membrane hybridization after nucleic acid amplification by PCR or NASBA. At the present time, we offer a complete “homedeveloped” range of products to detect either enteric pathogens (Rotavirus, Adenovirus, C. parvum, G. lamblia, E. coli 0157), respiratory pathogens (RSV, Adenoviruses, Influenza A, Influenza B) aside of those for detecting leishmaniosis (L. spp with L. donovani and L. infantum) and trypanosomiasis (T. brucei and T. cruzi) that allow Coris to be leader in the Belgian market, in Ireland, New Zealand, and South Africa and present in more than 70 countries worldwide. Moreover, we are engaged in a Total Assurance Program, being ISO 9001 & ISO 13485 certified by SGS and all our products are CE marked. All these features brought the turn-over from 46,000 in 1997 to more than 1,500,000 in 2006.
Since Coris is working in a highly competitive market, it was a decision to invest human and financial resources to develop new products and new technologies in order to face the challenges of the diagnostic market for the next decade. To reach this goal, amongst the 21 persons presently working in the company, 7 are R&D people and about 30 % of the turn-over is reinvested in R&D activities leading to new products, patents, scientific posters and articles. Coris is able to manage protein-based tests developments as well as nucleic acid-based ones, with gold particles and/or latex microspheres. Of course, it is of utmost importance to get involved in scientific networks and that’s the reason why Coris is still partner in several EC financed projects of the FP6 framework whose details could be found in our Website (www.corisbio.com). Within the GRACE program, Coris is engaged in developing diagnostic tests based on both immunological and molecular tools. Coris has developed a L. pneumophila test with a new patented device, so-called GDT (for Gravity Driven Test), and is working in adaptating the Pathofinder MLPA technology with Coris’ patented Oligochromatograhy technology for detecting 4 respiratory pathogens including Mycoplasma pneumoniae, RSVA, RSVB and Influenza A. All information related to our products and FP6 research programs could be found at www.corisbio.com. Thierry Leclipteux
www.grace-lrti.org
6
1st and 2nd GRACE Workshop held in Prague in October 2007! The first two stand-alone GRACE Workshops took place in Prague on the issue of Lower respiratory tract infections: Current concepts in pathogenesis, microbiology, epidemiology and economic impact. The topics were drawn from the GRACE Curriculum developed by the GRACE Education and Curriculum Committee (WP 12), led by Roger Finch and Francesco Blasi for ESCMID and ERS, respectively. A shared session in the beginning was followed by two separate workshops which dealt with The bacteriology of respiratory tract infections and The epidemiology and economic impact of common respiratory infections, respectively. The presentations were outstanding and much appreciated by the delegates, who were both science and medical graduates from the specialties of Primary Care, Clinical Microbiology and Infectious Diseases. The shared session was dedicated to a broad review of (i) the diverse nature of host defences within the lung divided into innate and adaptive immunity, also emphasizing the importance of innate immunity and pathogen-associated molecular patterns (PAMP) and (ii) the spectrum of host-pathogen interactions in relation to microbial colonization and invasion. Adhesion and immune evasion are critical to host cell entry and are pathogen variable. This was exemplified with the well characterized pathogen Streptococcus pneumoniae and in the less well understood situation of chronic lung infection spanning from Chlamydia pneumoniae to Mycobacterium tuberculosis. The shared session concluded with a review of cell-to-cell communication by bacterial quorum sensing (QS) in lung disease. The evening of the first day provided an opportunity for GRACE researchers from WP9 and 10 to present Research in progress. Theo Verheij set the scene for the major observational case control study which will recruit 3000 adults with LRTI and a matched control population. Clinical features are being recorded and a variety of investigations conducted. Some of the preliminary results were presented as well as the intervention study in which amoxicillin and placebo will be compared. Jacqui Nuttal and Kerry Hood reported on the logistics and implementation of what is the largest ever prospective clinical study of LRTI in the community. Preliminary research findings based on in-depth interviews with all patients recruited was most informative and has already identified some of the key variables across Europe. The presentations complemented those reported in Stockholm and published in the October 2007 issue of GRACE News. Workshop 1 focussed on The bacteriology of respiratory tract infections. After a review of the microbial epidemiology of community-acquired LRTI, both current and future microbiological laboratory investigations of LRTI emphasized the value of a diagnosis in terms of targeted and appropriate therapy, as well as supporting surveillance and outbreak recognition. While the importance of Streptococcus pneumoniae, Haemophilus influenzae, Legionella, Mycoplasma and Chlamydia spp. – which all were subject of excellent presentations – is beyond any doubt, did two timely reviews remind us of the continuing importance of anaerobic bacteria in respiratory infections and of the growing importance of Staphylococcus aureus as an emerging respiratory pathogen. Workshop 2 dealt with The epidemiology and economic impact of common respiratory infections. An introduction to ‘antigenic cartography’ showed a possible way to predict the evolution of an influenza epidemic. The impact of pollutants, of antibiotic use and misuse on LRTI were discussed on a European basis. Furthermore, COPD and CAP were viewed on in terms of prevalence and cost to society; the interrelationship between infections and asthma; the importance of cystic fibrosis management in adults; and the impact of vaccination on Streptococcus pneumoniae infection. If your curiosity has been raised for some topics: the material from the GRACE Workshops in Prague is now accessible on the e-learning platform on the GRACE (www.grace-lrti.org). There you can find a rich resource of lecture material, such as webcasts, presentation slides and references that you are encouraged to access and disseminate to other colleagues and students. Henri Saenz Roger Finch Francesco Blasi Spreading Excellence in Respiratory Tract Infections
7
Second annual GRACE meeting The Second GRACE Meeting wild be held in Budapest 6-7 March 2008. Thursday March 6 closed meetings will be held by the Governing Council (GC), National Network Coordinators (NNC), National Network Facilitators (NNF) and National Lab Coordinators (NLC). In the morning, the GC will be reporting on the activities of the second year, the Scientific Advisory Board, Patient Advisory Board and Ethical Management Unit, and administrative matters. In parallel a workshop with the GRACE-02 (WP8) collaborators will be held. In the afternoon the NNC, NNF and NLC will meet half a day to discuss the progress and plans for WP9-10. For the social programme on Thursday evening we welcome all participants of the Scientific Meeting on Friday, which is open to all GRACE participants, and other stakeholders.
Friday March 7: Scientific Meeting 09.00 09.30 10.00
Results of GRACE-01 (Jacqui Nuttal) Results of WP11 (Jo Coast, Richard Smith) Results of GRACE-02 (Lucy Brookes-Howell)
10.30
Coffee break
11.00 11.50
Results of GRACE-03 (Giles Greene) SWOT of GRACE and final conclusions (Herman Goossens)
12.00
Lunch
13.00
End of meeting
Colophon
In the afternoon the Ethical Management Unit will have a closed meeting.
Design Nieuwe Media Dienst Universiteit Antwerpen Editorial team Samuel Coenen Roger Finch Contributors Francesco Blasi Lucy Brookes-Howell Chris Butler Samuel Coenen Roger Finch Dave Gillespie Herman Goossens Giles Greene Birgitta Henriques Mark Kelly Thierry Leclipteux Katherine Loens Henri Saenz Naomi Stanton Saskia van Vugt Theo Verheij
www.grace-lrti.org
8
GRACE project leader Herman Goossens University of Antwerp - CDE Laboratory of Microbiology Universiteitsplein 1 2610 Antwerp Belgium www.grace-lrti.org
