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context of severe asthma. Identifying theneutrophil survival factor(s) present inthis patient group is clearly an importantnext step and, if targetable, may form thebasis of a new therapeutic approach forthis difficult-to-treat patient group.
While this study provides furtherevidence that neutrophil apoptosis may bederegulated in severe asthma, a number ofkey questions remain. We need tounderstand the dynamics of cell migrationinto and out of the airway wall and deter-mine the true residency times and the rela-tive contribution of apoptosis and, indeed,other non-apoptotic death mechanismssuch as autophagy, NETosis28 and cytolysisin granulocyte clearance. We also need tounderstand the signals that block apoptosisin the airwaywall (yet seemingly not in theairway lumen)and todeterminewhatdrivesthe switch from eosinophil- to neutrophil-dominated inflammation. Drugs whichtarget the removal rather than the arrival ofgranulocytes in tissues are now emerging,29
and such agents may offer an importantadjunct to current asthma treatments.
Funding MRC, Wellcome Trust, Asthma UK, BBSRC,NIHR Cambridge Biomedical Research Centre.
Competing interests None.
Provenance and peer review Commissioned; notexternally peer reviewed.
Thorax 2010;65:665e667.doi:10.1136/thx.2009.134270
REFERENCES1. Serra-Batlles J, Plaza V, Morejon E, et al. Costs of
asthma according to the degree of severity.Eur Respir J 1998;12:1322e6.
2. Antonicelli L, Bucca C, Neri M, et al. Asthmaseverity and medical resource utilisation. Eur Respir J2004;23:723e9.
3. Bousquet J, Jeffery PK, Busse WW, et al. Asthma.From bronchoconstriction to airways inflammationand remodeling. Am J Respir Crit Care Med2000;161:1720e45.
4. Wenzel SE, Szefler SJ, Leung DY, et al.Bronchoscopic evaluation of severe asthma.Persistent inflammation associated with high doseglucocorticoids. Am J Respir Crit Care Med1997;156:737e43.
5. Macedo P, Hew M, Torrego A, et al. Inflammatorybiomarkers in airways of patients with severe asthmacompared with non- severe asthma. Clin Exp Allergy2009;39:1668e76.
6. Macdowell AL, Peters SP. Neutrophil in asthma.Curr Allergy Asthma Rep 2007;7:464e8.
7. Woodruff PG, Khashayar R, Lazarus SC, et al.Relationship between airway inflammation,hyperresponsiveness, and obstruction in asthma.J Allergy Clin Immunol 2001;108:753e8.
8. Shaw DE, Berry MA, Hargadon B, et al. Associationbetween neutrophilic airway inflammation and airflowlimitation in adults with asthma. Chest2007;132:1871e5.
9. Baines KJ, Simpson JL, Scott RJ, et al. Immuneresponses of airway neutrophils are impaired inasthma. Exp Lung Res 2009;35:554e69.
10. Baines KJ, Simpson JL, Bowden NA, et al.Differential gene expression and cytokine productionfrom neutrophils in asthma phenotypes. Eur Respir J2009;35:522e31.
11. Savill JS, Wyllie AH, Henson JE, et al. Macrophagephagocytosis of aging neutrophils in inflammation.Programmed cell death in the neutrophil leads to itsrecognition by macrophages. J Clin Invest1989;83:865e75.
12. Hauber HP, Gotfried M, Newman K, et al. Effect ofHFA-flunisolide on peripheral lung inflammation inasthma. J Allergy Clin Immunol 2003;112:58e63.
13. Kikuchi S, Kikuchi I, Takaku Y, et al. Neutrophilicinflammation and CXC chemokines in patients withrefractory asthma. Int Arch Allergy Immunol2009;149(Suppl 1):87e93.
14. Wilson RH, Whitehead GS, Nakano H, et al. Allergicsensitization through the airway primes Th17-dependent neutrophilia and airwayhyperresponsiveness. Am J Respir Crit Care Med2009;180:720e30.
15. Cowburn AS, Condliffe AM, Farahi N, et al.Advances in neutrophil biology: clinical implications.Chest 2008;134:606e12.
16. Ley K, Laudanna C, Cybulsky MI, et al. Getting to thesite of inflammation: the leukocyte adhesion cascadeupdated. Nat Rev Immunol 2007;7:678e89.
17. van Buul JD, Allingham MJ, Samson T, et al. RhoGregulates endothelial apical cup assemblydownstream from ICAM1 engagement and is involved
in leukocyte trans-endothelial migration. J Cell Biol2007;178:1279e93.
18. Kikuchi I, Kikuchi S, Kobayashi T, et al. Eosinophiltrans-basement membrane migration induced byinterleukin-8 and neutrophils. Am J Respir Cell MolBiol 2006;34:760e5.
19. Uller L, Persson CG, Erjefalt JS. Resolution of airwaydisease: removal of inflammatory cells throughapoptosis, egression or both? Trends Pharmacol Sci2006;27:461e6.
20. Araki H, Katayama N, Yamashita Y, et al.Reprogramming of human postmitotic neutrophils intomacrophages by growth factors. Blood2004;103:2973e80.
21. Savill J, Dransfield I, Gregory C, et al. A blast fromthe past: clearance of apoptotic cells regulatesimmune responses. Nat Rev Immunol2002;12:965e75.
22. Uller L, Persson CG, Kallstrom L, et al. Lung tissueeosinophils may be cleared through luminal entryrather than apoptosis: effects of steroid treatment.Am J Respir Crit Care Med 2001;164:1948e56.
23. Ward C, Chilvers ER, Lawson MF, et al. NF-kBactivation is a critical regulator of humangranulocyte apoptosis in vitro. J Biol Chem1999;274:4309e18.
24. van Raam BJ, Drewniak A, Groenewold V, et al.Granulocyte colony-stimulating factor delaysneutrophil apoptosis by inhibition of calpainsupstream of caspase-3. Blood 2008;112:2046e54.
25. Cowburn AS, Cadwallader KA, Reed BJ, et al. Roleof PI3-kinase-dependent Bad phosphorylation andaltered transcription in cytokine-mediated neutrophilsurvival. Blood 2002;100:2607e16.
26. Altznauer F, Martinelli S, Yousefi S, et al.Inflammation-associated cell cycle-independentblock of apoptosis by survivin in terminallydifferentiated neutrophils. J Exp Med2004;199:1343e54.
27. Uddin M, Nong G, Ward J, et al. Pro-survival activityfor airway neutrophils in severe asthma. Thorax2010;65:684e89.
28. Fuchs TA, Abed U, Goosmann C, et al. Novel celldeath program leads to neutrophil extracellular traps.J Cell Biol 2007;176:231e41.
29. Loynes CA, Martin JS, Robertson A, et al. Pivotaladvance: pharmacological manipulation ofinflammation resolution during spontaneouslyresolving tissue neutrophilia in the zebrafish. J LeukocBiol 2010;87:203e12.
British Thoracic Society PleuralDisease Guidelines - 2010 updateNick Maskell, on behalf of the British Thoracic SocietyPleural Disease Guideline Group
INTRODUCTIONPleural disease remains common, affectingover 3000 people per million populationeach year. It therefore presents a significantcontribution to theworkload of respiratory
physicians. These guidelines attempt tosummarise the available evidence to aid thehealthcare professional in delivering goodquality patient care.
AIMS AND OBJECTIVES OF THEGUIDELINESince the last BTS pleural disease guidelineswere published in 20031 a large number ofgood quality primary research papers havebeen published and the guidelines need toreflect this new data. In addition, there wasa need to develop new sections on localanaesthetic (LA) thoracoscopy and thoracicultrasound to reflect changes in clinicalpractice.
Correspondence to Dr Nick Maskell, North Bristol LungCentre, Southmead Hospital, Bristol, UK;[email protected]
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AREAS COVEREDThe guideline is divided into the followingsections:1. Investigation of a unilateral pleural
effusion in adults2. Management of spontaneous pneumo-
thorax3. Management of a malignant pleural
effusion4. Management of pleural infection in
adults5. Local anaesthetic thoracoscopy6. Chest drain insertion and thoracic
ultrasound
METHODOLOGYA working party was established withrepresentation from a range of profes-sionals with an interest in pleural diseasetogether with a lay representative. Theguidelines are based upon the best availableevidence. The methodology followed thecriteria as set out by the AGREE collabora-tion in the document, The AGREE instru-ment, available on-line at: http://www.agreecollaboration.org/instrument/ Thescope and purpose of the guideline had beenagreed and defined in consultation with allpotential stakeholders representing themedical and nursing professions, patientgroups, health management and industry.Guideline members identified and formu-lated a set of key clinical questions in PICO(T) (Population, Intervention, Compar-ison, Outcome and Time) format to informthe search strategies for the literaturesearch.The BTS commissioned a bespokeliterature search using the search strategiesshown in detail on the BTSwebsite (http://www.brit-thoracic.org.uk). Searches werelimited to English and adult literature.19,425 potential papers were identified bythe search. 17393 abstracts were rejectedthrough the criteria outlined above and2032 full papers were ordered for criticalappraisal. A further 591 full papers wererejected because they fell outside the area offocus and scope of the guideline. Formalcritical appraisal to assess clinical relevanceand scientific rigor of 1441 papers weredone independently by at least twoguideline reviewers using the SIGNcritical appraisal checklists. The guidelinereviewers identified an additional 148papers during the period of guidelinedevelopment, which were added andcritically appraised. The evidence in eachstudy was graded using the SIGNformulated levels of evidence.
This guideline is strengthened byinvolvement from range of stakeholdersand the final guideline is endorsed by 13Royal Colleges and societies. We hope this
will increase its appeal and broaden its useacross other specialities.
MAIN RECOMMENDATIONSPatient safetyThe key theme running across theseguidelines are ways to improve and main-tain patient safety. Issues with chest drainplacement were highlighted by, amongothers, the National Patient Safety Agencyalertwho reported 12 deaths and 15 cases ofserious harm related to chest drain inser-tion between January 2005 and March2008.2 3 Common factors related to theincidents included the lack of experience ofthe operator, an inadequate level of super-vision, failure to follow themanufacturer ’sinstructions, choice of a suboptimal inser-tion site and poor patient positioning,suboptimal imaging and a lack of famil-iarity with published guidelines. The use ofthoracic ultrasound in pleural procedures(except pneumothorax) has been clearlyshown to detect fluid more accurately thanby chest radiography, to decrease the inci-dence of failed aspirations and the incidenceof complications, and to be significantlybetter than clinical examination inchoosing a site for safe aspiration or draininsertion. It is therefore highly recom-mended for all pleural fluid procedures.4 5
Thoracic ultrasound and chest draininsertionThis new section describes the basics of thethoracic ultrasound technique and includescommon findings and pitfalls. It clearlystates that at least level 1 competency isrequired to safely perform independentthoracic ultrasound.6
A detailed description of the techniquefor Seldinger chest drain insertion has alsobeen included. Written consent should beobtained for all chest drain insertions,except in emergency situations and theguideline also includes a standard patientinformation leaflet for chest drain insertion.It also recommends that pleural proce-
dures should only be performed in anemergency out side of normal workinghours and that chest drains should beinserted in a clean area/room, using fullaseptic technique, as it is noted that theiatrogenic infection rate is too high inmany published studies.7
Investigation of undiagnosed effusionsThis document confirms that there is noplace for Abrams needles in the investiga-tion of suspected pleuralmalignancy due toits poor yield and complication rate.8Whenpleural tissue is required for diagnostic
purposed local anaesthetic thoracoscopy,surgical VATS or a radiology guided pleuralbiopsy are the methods of choice. The onlyexception occurs in regions with a highincidence of tuberculosis, as the diagnosticyield with Abrams needles, in TB pleuritis,remains high, but are still not as high asthoracoscopic biopsies.9
PneumothoraxThese guidelines contain new sections onpneumothorax in pregnancy and inpatients with cystic fibrosis as well ascatamenial pneumothorax. They highlightimportant issues regarding chest radio-graph interpretation with PACS andrecommend a diagnostic PACS worksta-tion should be used for image review ifmaking decisions in a patient witha possible pneumothorax.10
There is now a new single flow diagram,combining the management pathway forboth primary and secondary pneumo-thorax. This is now simpler for the end-userto use. The BTS has also arranged to senda wall chart of this flow diagram to everyNHS accident and emergency departmentin the UK to help encourage best practice.This initiative has been warmly welcomedby the Society for Acute Medicine.Other changes include the recognition
that in carefully selected, asymptomaticpatients with large primary spontaneouspneumothorax, observation alone isa possible treatment option. When inter-vention is required, simple aspirationremains the initial treatment of choice, butthat if this fails once a further attempt ataspiration is unlikely to be helpful anda small bore chest tube should be inserted.10
Management of malignant pleural effusionsThese guidelines continue to recommendtalc as the most efficacious agent forpleurodesis. However, they now empha-sise that calibrated talc should be used toreduce side effects. Small bore chest tubesare recommended first line for pleuraldrainage as they are more comfortable forpatients and no less efficacious.11
They also recognise that when theunderlying lung is trapped, a previouspleurodesis attempt has failed or whenpleural fluid production is very high,a tunnelled pleural catheter might beappropriate.11
Local anaesthetic thoracoscopyThese new guidelines reflect the changingpractice in the UK, which is now more inline with the rest of Europe reflectingeasier access to thoracoscopy as a safe and
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reliable way of obtaining a histologicaldiagnosis and performing a pleurodesis.They discuss the current literature indetail and also provide a web-basedrepository for how the procedure isperformed.12
Pleural infectionThis guideline emphasises the continuinghigh morbidity and mortality related tothis condition. It continues to recommendchest tube drainage for sizeable effusionswith pH<7.2 or loculation in the contextof clinical signs of infection/sepsis. Itstates the lack of evidence for a largechest tube being more efficacious thana small one and notes patients are morecomfortable with a smaller tube. Differ-ences between community acquired andhospital acquired pleural infection is alsohighlighted with a need for differentempirical antibiotics at presentation.13
Future directions and auditIt is recognised that there remain numberof key unanswered questions pertaining topleural disease and its management, whichrequire study. Some of these are listed atthe end of guideline and include use oftunnelled indwelling pleural catheters inthe management of chronic end stage nonmalignant pleural effusions, the role andposition of novel biomarkers in the diag-nostic pathway for undiagnosed pleuraleffusions and the efficacy of talc poudrageversus talc slurry in malignant effusions.
Finally, the importance of audit isemphasised in the management of pleuraldisease and BTShas developed an audit toolfor pleural procedures which is availablevia the online BTS audit system.14
Concluding commentsThe Guideline Group hope that theseguidelines will prove both popular anduseful in assisting physicians managingpatients with pleural disease. We recognisethat that the literature pertaining topleural disease is not always of high qualitybut hope that we have used the dataavailable to produce a robust evidencebased guideline which safeguards patientsand drives up standards in pleural diseasemanagement. We also hope that greaterengagement and endorsement from othermedical specialities will broaden its appeal.British Thoracic Society Pleural Disease
Guideline GroupDr Nick Maskell, ChairDr Nabeel AliDr George AntunesDr Anthony ArnoldProfessor Robert DaviesDr Chris DaviesDr Fergus GleesonDr John HarveyDr Diane LawsProfessor YC Gary LeeDr Edmund NevilleDr Gerrard PhillipsDr Richard TeohDr Naj RahmanDr Helen DaviesDr Tom HavelockDr Clare HooperDr Andrew MacDuffDr Mark Roberts
Competing interests None.
Provenance and peer review Commissioned; notexternally peer reviewed.
Thorax 2010;65:667e669.doi:10.1136/thx.2010.140236
REFERENCES1. BTS Guidelines for the management of pleural
disease. Thorax 2003;58(Suppl 2).2. National Patient Safety Agency. Risks of
chest drain insertion. NPSA 2008/RRR003(accessed 15 May 2008).
3. Harris A, O’Driscoll B, Turkington P. Survey of majorcomplications of intercostal chest drain insertion inthe UK. Postgrad Med J 2010;86:68e72.
4. O’Moore PV, Mueller PR, Simeone JF, et al.Sonographic guidance in diagnostic and therapeuticnterventions in the pleural space. AJR Am JRoentgenol 1987;149:1e5.
5. Diacon AH, Brutsche MH, Soler M. Accuracy ofpleural puncture sites. A prospective comparison ofclinical examination with ultrasound. Chest2003;123:436e41.
6. Royal College of Radiologists. Ultrasoundtraining recommendations for medical and surgicalspecialties. London: Royal College of Radiologists.http://www.rcr.ac.uk.
7. Havelock T, Teoh R, Laws D, et al. Pleuralprocedures and thoracic ultrasound-British ThoracicSociety pleural disease guideline. Thorax 2010;65(Suppl 2):ii61eii76.
8. Maskell NA, Gleeson FV, Davies RJO. Standardpleural biopsy versus CT-guided cutting-needle biopsyfor diagnosis of malignant disease in pleuraleffusions: a randomised controlled trial. Lancet2003;361:1326e30.
9. Hooper C, Lee YCG, Maskell NA. Investigation ofa unilateral pleural effusion in adultsdBritishThoracic Society pleural disease guideline. Thorax2010;65(Suppl 2):ii4eii17.
10. MacDuff A, Arnold A, Harvey J. Management ofspontaneous pneumothoraxdBritish Thoracic Societypleural disease guideline. Thorax 2010;65(Suppl 2):ii18eii31.
11. Roberts ME, Neville E, Berrisford RG, et al.Management of a malignant pleural effusiondBritishThoracic Society pleural disease guideline. Thorax2010;65(Suppl 2):ii32eii40.
12. Rahman NM, Ali NJ, Brown G, et al. Localanaesthetic thoracoscopydBritish Thoracic Societypleural disease guideline. Thorax 2010;65(Suppl 2):ii54eii60.
13. Davies HE, Davies RJO, Davies CWH. Managementof pleural infection in adultsdBritish Thoracic Societypleural disease guideline. Thorax 2010;65(Suppl 2):ii41eii53.
14. BTS Audit tools. https://audits.brit-thoracic.org.uk/.
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