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Citation Maselli, Diego J., Bravein Amalakuhan, Holly Keyt, and Alejandro A.Diaz. 2017. “Suspecting non#cystic fibrosis bronchiectasis: What thebusy primary care clinician needs to know.” International Journalof Clinical Practice 71 (2): e12924. doi:10.1111/ijcp.12924. http://dx.doi.org/10.1111/ijcp.12924.

Published Version doi:10.1111/ijcp.12924

Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:32630479

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Review criteria

Thisnon-systematicreviewidentifiedrecentclinicalandepidemiologi-calstudiesidentifiedfromPubMed/MedlineandClinicalTrials.govfromtheUSNIHandtheCochraneRegisterofControlledTrialsusingthesearchtermsbronchiectasis,non-cysticfibrosisbronchiectasis,chronicpulmonaryinfectionandcomputedtomography.Casereports,editori-alsandothercommunicationswithalowevidencelevelwereexcluded.

Message for the clinic

The prevalence of non-cystic fibrosis bronchiectasis (NCFB) hasincreasedoverthepastdecadespossiblyduetoincreasedawarenessandwidespreaduseofcomputedtomography(CT).NCFBshouldbesuspected in patientswith persistent cough, excessive sputumpro-ductionandrecurrentpulmonaryinfections.CTconfirmsthediagno-siswithfindingscharacterisedbyabnormallydilatedairways,and is

Received:13July2016  |  Accepted:28November2016DOI:10.1111/ijcp.12924

R E V I E W A R T I C L E

Suspecting non- cystic fibrosis bronchiectasis: What the busy primary care clinician needs to know

Diego J. Maselli1 | Bravein Amalakuhan1 | Holly Keyt1 | Alejandro A. Diaz2

1DivisionofPulmonaryDiseases&CriticalCare,UniversityofTexasHealthScienceCenter,SanAntonio,TX,USA2DivisionofPulmonaryandCriticalCareMedicine,BrighamandWomen’sHospital,HarvardMedicalSchool,Boston,MA,USA

CorrespondenceDiegoJ.Maselli,MD,FCCP,DivisionofPulmonaryDiseases&CriticalCare,UniversityofTexasHealthScienceCenteratSanAntonio,SanAntonio,TX,USA.Email:masellicacer@uthscsa.edu

SummaryAims: Non-cystic fibrosis bronchiectasis (NCFB) is a chronic, progressiverespiratorydisordercharacterisedbyirreversiblyandabnormallydilatedairways,persistent cough, excessive sputum production and recurrent pulmonaryinfections. In the last several decades, its prevalence has increased, making itlikelytobe encountered intheprimarycaresetting.Theaimwastoreviewtheclinical presentation and diagnosis of NCFB, with an emphasis on the role ofcomputedtomography(CT).Methods: For this review, trialsand reportswere identified fromPubMed/MedlineandClinicalTrials.govfromtheUSNIHandtheCochraneRegisterofControlledTrials.Thesearchusedkeywords:bronchiectasis,non-cysticfibrosisbronchiectasis,chronicpulmonaryinfectionandcomputedtomography.Nodate/languagerestrictionswereused.Results: Non-cystic fibrosis bronchiectasis often coexists with other respiratoryconditions,suchaschronicobstructivepulmonarydisease.TheprevalenceofNCFBisincreasing,particularlyinwomenandolderindividuals,possiblyasaresultofincreasedphysicianawarenessandwidespreaduseofCT,which is thegold standard for thediagnosis of NCFB. CT can assist in identifying an underlying cause of NCFB anddeterminingtheextentandseverityofthedisease.Discussion: Non-cysticfibrosisbronchiectasisshouldbesuspectedintheprimarycaresetting in patients with chronic cough, purulent sputum and frequent respiratoryinfectionsthattendtoresolveslowlyorpartially.EarlydiagnosisanddeterminationoftheextentandseverityofthediseasebyCTandothertestsarecriticaltoestablishtherapy to improve quality of life and potentially slow progressive decline of lungfunctioninpatientswithNCFB.

ThisisanopenaccessarticleunderthetermsoftheCreativeCommonsAttribution-NonCommercial-NoDerivsLicense,whichpermitsuseanddistributioninanymedium,providedtheoriginalworkisproperlycited,theuseisnon-commercialandnomodificationsoradaptationsaremade.

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usefulindeterminingtheextentandseverityofthediseaseanddetect-inganunderlyingcause.

1  | INTRODUCTION

Bronchiectasisisachronic,progressiverespiratorydisordercharacter-isedbyirreversiblyandabnormallydilatedairways,persistentcough,excessive sputum production and recurrent pulmonary infections.1 Thechangesinthebronchialwallsmaybeduetochronicinflamma-tionsecondarytorecurrentorchronicinfectionsinthelung,butoftentheexactcause isnot identified.1Symptomsvary from intermittentepisodesof respiratory infectionswith excessivemucusproductiontochronicsymptomswithpersistentdailyexpectorationofpurulentsputum.1 In patientswithout cysticfibrosis, the condition is knownasnon-cysticfibrosisbronchiectasis (NCFB).1–3AlthoughNCFBwasonceaveryuncommondiagnosis, inthelasttwodecadesitspreva-lencehasbeenincreasing,makingitmorelikelythatprimarycareclini-cianswillencounterthesepatientsintheirpractice.Theprecisepreva-lenceofNCFBisdifficulttodeterminebecauseestimatesvaryamongpopulations,butstudiesreportaprevalencerangingfrom486to1106per100000personswithanincidencethatappearstoberising,par-ticularlyinwomenandolderindividuals.4–6Althoughnotascommonasasthma,whichaffectsapproximately10%oftheworldpopulation,NCFBhas become farmore common thanother respiratory condi-tionssuchasidiopathicpulmonaryfibrosis,whichaffectsonly18.2per100000 persons.7,8Hospitalisation rates owing toNCFBhave alsoincreasedintheUnitedStates,particularlyintheolderpopulation.9

Non-cysticfibrosisbronchiectasisisassociatedwithcomorbiditiessuchas anxiety, depression, fatigue, andhas a significant impactonqualityoflife.10PatientswithNCFBrequirelongerhospitalstaysandmoreoutpatientvisitscomparedwithmatchedcontrols.4Coughassoci-atedwithNCFBcanalsoimpactthequalityoflifeoffamilymembers.10 TheeffectofNCFBonmortalityisnotclear.Althoughreportedmor-talityratesvary,evidencesuggeststhatage-adjustedmortalityratesinpatientswithNCFBareatleasttwicethatofthegeneralpopulation.5

TheincreasedrecognitionofNCFBislikelyaresultoftheuseofhigh-resolution computed tomography (HRCT), which has allowedfor the identificationofpreviouslyundiagnoseddisease.11–13HRCT,which is able to acquire 1-mm thick images of the lung at 10-mmintervals, is considered the gold standard for radiographic diagnosisofNCFB.1,2OthermodalitiesofCTusingdifferentimagingalgorithmshavebeenfrequentlyusedtoeffectivelydiagnosebronchiectasis.12,14 WithenhanceddiagnosticcapabilitiesofCTforNCFB,itisimportantforprimarycareclinicianstohaveanunderstandingoftheinformationthatcanbeobtainedwiththisprocedure.Herein,wereviewkeyradio-graphicfindingsonCTinthecontextofanoverviewofthepathophys-iology,clinicalpresentation,andthediagnosisofNCFB.

2  | METHODS

Forthisreview,trialsandreportswereidentifiedfromthedatabasesofPubMed/MedlineandClinicalTrials.govfromtheUSNIHandthe

CochraneRegister ofControlled Trials. The searchwas carried outusing the keywords or combinations of keywords: bronchiectasis,non-cystic fibrosis bronchiectasis, chronic pulmonary infection andcomputed tomography. The term chronic pulmonary infection wasincludedtocapturethearticlesthatdiscussedthisconditioninasso-ciationwithCTasapossibleprecursorofthedevelopmentofNCFB.Aparticular emphasiswasmadeonpublications thatdiscussed theepidemiology,naturalhistory, clinicalpresentationanddiagnosis. Inaddition,therewasafocusontheavailablestudiesandpublicationsthatexaminedtheroleofCT inthediagnosisofbronchiectasisanddeterminationofseverity.Nodateorlanguagerestrictionswereused.

3  | PATHOPHYSIOLOGY OF NCFB

Cole’s‘viciouscycle’ofinfection,airwayinflammationandlungdam-age15 is themostwidely acceptedmechanism of the developmentof NCFB (Figure1). The cycle is triggered when the defence sys-tem of the lung is breached andmucociliary clearance is impaired.Potentialcausesofthisbreachincludeseverelowerrespiratorytractinfections,gastricaspirationand/or inhalationof toxicgases.Otherinflammatory processesmay be associatedwith local and systemicinflammation that leads to changes in the architecture of bronchialairways.However,acleartriggerisnotidentifiedinupto30%-53%ofpatients.1Regardlessofthecause,whenmucociliaryclearance isimpaired,mucous is retained in the airways.15 This in turn leads tomicrobialcolonisationorinfectionwithasubsequentdevelopmentofaninflammatoryresponse.Asthehostfailstoeliminatethepersistentinfection,airwayinflammationbecomeschronic.Bothhostinflamma-tory responses andmicrobial cytotoxins cause additional structuraldamage to the lung and further impair mucus clearance, thus, theviciouscyclepersists.15Somemicroorganisms,suchasPseudomonas aeruginosa,may formbiofilms in thebronchial airways.Biofilmsarethin layers that form on colonised surfaces typically comprised ofbacteria and a matrix of an extracellular polymeric substance thatincludespolysaccharides,proteinsandDNA.16Thismayfacilitatethepersistenceofthe“viciouscycle”ofbronchiectasisbecausethebio-filmsprotectbacteriafromclearancebythehostimmunesystemand

F IGURE  1 Representationofthecyclethatleadstodevelopmentofbronchiectasis,asdescribedbyCole13

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reducetheeffectsofantibioticsfurtherpotentiatingairwayinflamma-tion.17Disruptionofthebiofilmsbysomeantibiotics(ie,macrolides)isthoughttobeoneofthemechanismsbywhichchronicantibiotictherapymayimproveoutcomesinbronchiectasis.18,19

3.1 | Conditions Associated with the Development of NCFB

The various aetiologies of NCFB can be conceptually divided intoinfectious and non-infectious causes. Previous severe infectionsfrombacteria,mycobacteriaandviruseshavebeenshowntocauseparenchymal changes consistentwithNCFB.Non-infectious causesincludevarioustypesofimmunedeficiencies,conditionswithdefectsinmucociliaryclearance,bronchialobstruction,autoimmunediseases,congenital disorders, postradiation treatment, postlung transplant,interstitial lungdiseases,andgraft-versus-hostdisease.Table1pro-videsacomprehensivelistofaetiologies.1,20

3.2 | The Association Between COPD and Bronchiectasis

Chronic obstructive pulmonary disease (COPD) remains one of themost common pulmonary conditions worldwide, and patients withCOPDareoftenseenintheprimarycaresetting.21BronchiectasisandCOPDoftencoexistwithavaryingprevalenceamongststudypopu-lations(29%-57%).22–25Bothdiseasesshareseveralpathophysiologi-cal features including increasedairway inflammation,propensity forexacerbations,distortionofthearchitectureofthelungparenchymaandbacterialcolonisationoftheairways.

Thepresenceofbronchiectasis identifiedonCT inpatientswithCOPDhasbeenassociatedwithpooroutcomes.AstudybyMartínez-García demonstrated worse airflow limitation, increased isolationof potential pathogens, and more frequent hospital admissions inpatientswithCOPDandbronchiectasiscomparedwithpatientswithCOPDalone.24Afollow-upstudyfromthesamegroupshowedthat

Categories Examples

Infections • Bacterial(eg,Staphylococcus,Pseudomonas,Mycoplasma)• Mycobacterial(eg,mycobacteriumtuberculosis,MAC)• Viral

Immunedeficiency • Hypogammaglobulinemia• HIV• IgGsubclassdeficiency

Mucociliaryclearancedefects • PCD• Kartagener’ssyndrome• Cysticfibrosis• Young’ssyndrome(bronchiectasis,sinusitis,obstructiveazoospermia)

Bronchialobstruction • Endobronchialtumour• Bronchialcompressionbylymphnode• Foreignbody• Broncholith

Autoimmunedisease • Sjögren’ssyndrome• Rheumatoidarthritis• Inflammatoryboweldisease• Relapsingpolychondritis• Systemiclupuserythematosus

Congenitaldisorders • Bronchialatresia• α1-antitrypsindeficiency• Williams-CampbellSyndrome(congenitaldeficiencyofbronchialcartilage)

• Mounier-Kuhnsyndrome(congenitaltracheobronchomegaly)

• Tracheal-oesophagealfistula• Yellownailsyndrome

Other • Allergicbronchopulmonaryaspergillosis• Postradiation• Post-transplant• Tractionbronchiectasis• Graft-versus-hostdisease• AssociatedwithCOPD

COPD,chronicobstructivepulmonarydisease; IgG, immunoglobulinG;MAC,mycobacteriumaviumcomplex;PCD,primaryciliarydyskinesia.

TABLE  1 Conditionsassociatedwiththedevelopmentofbronchiectasis1,14

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patientswithbronchiectasisandCOPDhadan increasedriskofall-causemortality.26Ameta-analysisof881patients,includingtheabovestudies in addition to four others, revealed that the coexistence ofCOPD and bronchiectasiswas associatedwith higher exacerbationrates,degreeofinflammatorymarkers,andratesofPseudomonas aeru-ginosaisolation.27Forthesereasons,bronchiectasisisnowconsideredacommoncomorbidityinpatientswithCOPD.21However,itisincom-pletelyunderstoodhowthesediseasesexactlyinfluenceeachother.Theleadingtheoryisthatincreasedcolonisationoftheairwaysleadstoincreasedinflammation,whichinturntranslatesintoincreasedriskfor exacerbations.28 Future studies are needed to understand thiscomplexassociationandtoevaluateifidentificationofthesepatientsearlyintheircoursemaychangeoutcomes.

4  | CLINICAL PRESENTATION

Non-cystic fibrosis bronchiectasis presents with a range of clinicalmanifestations from incidentally found bronchiectasis in asympto-matic individuals to massive haemoptysis and respiratory failure.WiththewidespreaduseofCT,cliniciansincreasinglyencounterthe‘incidental’ finding of bronchiectasis in asymptomatic patients whoundergochestorabdominalimagingforunrelatedpurposes.However,themostcommonclinicalpresentationisbetweentheseextremes.

For those patients with symptomatic bronchiectasis, the mostcommon complaint is chronic cough. In fact, many patients have achronicproductivecoughforover30yearsbeforetheirdiagnosis.Inonestudyof103adultswithNCFB,98%reportedachroniccough,whiledailysputumproduction(typicallypurulentandaveraginggreaterthan30mLinvolume)occurredin76%ofpatients.29Dyspnoea(62%)andchronicfatigue(74%)arealsocommonpresentingsymptoms.29,30 Othercommoncharacteristics in thesepatients includechronic rhi-nosinusitis that ranges from intermittent nasal discharge to severepurulentsinusitis(presentin70%ofpatients)andanotablehistoryofear,noseandthroatsurgeryforrecurrentsinusitis(30%ofpatients).29 Mild, intermittent haemoptysis occurs in 26%-51% of cases, but attimes it can be severe and life-threatening.29,31Many patientswithbronchiectasis require frequent hospital admissions for recurrentpneumonia.29,31Depressionandanxietyarecommoninpatientswithbronchiectasis,whichmaysignificantlyaffecttheirqualityoflife.32,33

The natural history of NCFB is punctuated by periods of exac-erbations,definedasacuteworseningof respiratorysymptoms thatrequiremanagementwithantibiotictherapy.34Patientswithexacerba-tionsexperiencechangeinoneormoreofthecommonsymptomsofbronchiectasis, including increasedsputumproductionorpurulence,worsening cough and dyspnoea, and systemic symptoms.1 Usually,theseepisodesaretriggeredbyabronchialinfection.Inastudyof115patientswithNCFB,themostcommonsignsofanacuteexacerbationwereincreasedfrequencyofcough(88%)andchangeinsputumchar-acteristics (67%).35 Other symptoms included fever (28%), increasein sputumvolume (42%)and increase in sputumpurulence (35%).35 Exacerbationscanrangefromamildincreaseinrespiratorysymptomstolife-threateninghaemoptysisandrespiratoryfailure.1

When should bronchiectasis be suspected in the primary care setting? The diagnosis should be suspected in patients with chronic cough(ie, >6weeks)withvariable productionof purulent sputum,with orwithout recurrent haemoptysis, and frequent respiratory infectionsthattendtoresolveslowlyorpartiallywithorwithoutanunderlyingcondition such asCOPD. In some instances, bronchiectasismay besuggestedonchestradiographs.Thisconstellationofsignsandsymp-tomsshouldprompttheprimarycareprovidertoconsiderevaluatingthepatientforbronchiectasis.

5  | DIAGNOSTIC APPROACH

5.1 | Initial investigations

Physicalexamandhistorymaycontribute to thediagnosisofbron-chiectasis.Themostcommonrespiratoryphysicalexamfindingsarecrackles,occurringinupto73%ofpatients.29,31Othercommonfind-ingsincluderhonchi(44%)andwheezing(21%-34%).29,31Clubbingofthedigitsisrareandoccursin2%-3%ofcases.29,31

Standardchestradiograph(CXR)istypicallythefirsttoolusedtoevaluateapatientwithchronicrespiratorysymptoms.However,bron-chiectasismaynotbeobviouswiththisimagingmodalityandisusu-allyonlyapparentinseverecases.36,37StudiesshowthatCXRshavemoderatesensitivity (88%)andsomewhatpoorspecificity (74%) forthedetectionofbronchiectasis,36,37andthereforeisconsideredinade-quateforthediagnosis/quantificationofbronchiectasis.1Despitethis,CXRsmayhavesomeutility inNCFB.Onclose inspection,multipleareasofbronchialwalldilationmaybeseeninpatientswithmoder-atetoseverebronchiectasis.Furthermore,otherradiographicsignsofchroniclowerairwayinfectionmaybepresentinpatientswithNCFBsuchascalcificationsorinfiltrates.

5.2 | Computed tomography

High-resolutioncomputedtomographyofthechestisthecurrentgoldstandardforthediagnosis/confirmationofbronchiectasis.Ithasasen-sitivityof96%andaspecificityof93%.13Nevertheless,HRCThassomelimitations,includingrespiratoryandcardiacpulsationartefacts,false-negativereportsduetomissedfocalareasofbronchiectasisbetweensection-planes, andmisinterpretation of bronchial-artery ratiomeas-urements.11Theselimitationshavebeenpartiallyaddressedusingalter-nativeCTmodalitiesusingdifferentimagingalgorithms.Forexample,aretrospectivestudyevaluatedtheefficacyofHRCTswith1-mmslicesevery10mm,comparedwithmulti-detectorCTs(MDCT)withcontigu-ous1-mmslicesforthediagnosisofbronchiectasis.12MDCTwasfoundtobesuperiorinassessingthepresence,extentandseverityofbronchi-ectasiscomparedwithHRCT.12Thesefindingswerefurthersupportedbyaprospectivestudy,showingthatMDCTindeedhadgreateraccu-racy for the identification and exclusion of bronchiectasis comparedwithHRCT.14AlthoughtheutilityofMDCTappearstobeequivalentorevensuperiortoHRCT,theradiationdoseisuptofivetimeshigherwithMDCT.38Becauseofthisconcern,theuseoflow-dosevolumet-ricCThasbeenexploredforthediagnosisofbronchiectasis.Onesuch

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studybyJungandcolleaguesdemonstratednosignificantdifferenceinthediagnosticyieldofbronchiectasis,showingsimilarimagequalityandradiationexposurescomparedwithHRCT.39

Despite these advances, regular volumetric CT is sufficient tomakethediagnosisofNCFB.Thisimagingmodalityoffersthesamedegreeof accuracy forNCFBandmaybemorewidely available.40 As imaging technologyprogresses, it is likely that newer toolswillbe developed to better assess the presence and severity of bron-chiectasis. The development of automated image analysis is oneexcitinginnovationthathasthepotentialtoadvancethisdiagnosticarea,makingiteasiertoidentifymilderformsofthediseaseandtoimprove the reliability of thediagnosis.41,42Bydiagnosingpatientswithbronchiectasisearlierintheircourse,itwouldallowforearliertherapeutic intervention, with the potential to improve outcomesandalterthecourseofthedisease.

ThecharacteristicfeatureofNCFBdemonstratedbyCTisbron-chialwall dilationwith the luminal diameter greater than 1-1.5 thesizeoftheaccompanyingpulmonaryarterybranch.Othertypicalfind-ingsincludeabsenceofnormaltaperingofthebronchi,bronchialwallthickening,mucoid plugging of the airways and proximity of visibleairwaysclosetothepleura(<1cm).1,43

Bronchiectasis isclassifiedbymorphology. Incylindrical bronchi-ectasis, thebronchialwallsaredilated,butmaintain theircylindricalshapeextendingtotheperipheryofthelung(Figure2A).Thevaricose typeofbronchiectasisischaracterisedbyairwaydilationinterspersedwith areas of relative narrowing, resulting in a beaded appearance(Figure2B).Cysticbronchiectasisrepresentsthemostadvancedstageof airway remodelling,with thedilated airways appearing similar tocystsoranalogoustograpesalongabranch(Figure2C).

The differential diagnosis is often narrowed based on imagingcharacteristics. For example, if a localised area of bronchiectasis is

confirmedonCT,thenreferraltoapulmonologistforabronchoscopyis required to evaluate for a foreign body, an endobronchial lesion,oranareaofextrinsiccompressionthatcouldpotentiallyexplainthefocalfinding.1Alocalisedareaofbronchiectasisisrarelycausedbyasystemic/diffusecondition.IftheareaofbronchiectasisisdiffuseonCTimaging,thedifferentialdiagnosisisbroader.

Features or abnormalities demonstrated by CT may providecluestotheunderlyingcauseofbronchiectasis.20,44Inallergicbron-chopulmonaryaspergillosis,mucoid impactionofthe largeairwaysappearsastubularopacitiesreferredtoasthe“finger-in-glove”sign.Similartoallergicbronchopulmonaryaspergillosis,patientswithCFhaveupper-lobepredominantdiseaseandmayhavethe“finger-in-glove”sign.Inpatientswithaforeignbody,tumourorextrinsiccom-pression, the bronchiectasis is evident in a focal area as opposedto more diffuse disease in other systemic conditions/aetiologies.Certain infectionsalsomayhaveacharacteristicpresentation.Forexample, atypical mycobacteria may favour the right middle lobeandthelingula.45DespiteidentificationofthesekeyfeaturesonCTand extensive testing, no underlying aetiology is found in a largeproportion of patients with bronchiectasis.46 The prevalence ofidiopathicbronchiectasisvariesamongstcohorts (32%-66%) likelyowing to geographic variations, diagnostic algorithms and otherdeterminants.30,47–51

Clinical symptoms, history of exacerbations and microbiologicaldataarefrequentlyusedtostratifytheseverityofpatientswithNCFB;however,theincorporationofimagingabnormalitiesintotheseclas-sificationsmayallowforamorecompletepictureoftheimpactofthedisease.52,53Therefore,thereisgreatinterestintheevaluationoftheextentandseverityofbronchiectasismoreobjectivelyusingCT.

A method to quantify the extent of the disease using CT wasdevelopedseveraldecadesago.54Inthismethod,eachlobeisscored

F IGURE  2  ImagesfromchestCTillustratingbronchiectasisclassificationbasedonmorphology:AandB,cylindricalbronchiectasisina63year-oldmanwithrheumatoidarthritis;C,varicosebronchiectasisina49year-oldmanwithKartagener’ssyndrome(ciliarydyskinesia,chronicsinusitisandsitusinversus);andD,cysticbronchiectasisina77year-oldwomanwithahistoryofaleftlowerlobepneumonia

(A) (B)

(C) (D)

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by:(i)thenumberofsegmentsinvolved,(ii)severityofbronchialdila-tioncomparedwiththeadjacentartery,(iii)bronchialwallthickeningand(iv)morphologicaltypeofbronchiectasis.

While imagingmay be useful in the objective determination oftheextentofthedisease,itmayhavelimitedvaluewithregardtotheprognosisofNCFB.Twocomprehensivebronchiectasis indiceshavebeencreatedtoaddressthislimitationinhopesofbetterunderstand-ing the prognosis of patients with NCFB and improving treatmentalgorithms.55,56BoththeBronchiectasisSeverity Index (BSI)andtheFACED scores are effective tools that utilise multiple parameters,including extent of the disease based onCT, to predict future out-comesinpatientswithbronchiectasis.

5.3 | Pulmonary function testing

Spirometryisfrequentlyusedtoevaluatepatientswithrespiratorysymptoms. Inbronchiectasis, themajorityofpatientspresentwithmildtomoderateairwayobstruction,withaforcedexpiratoryvol-ume in1second (FEV1)/forcedvitalcapacity (FVC)ratio lessthan70, alongwith an FEV1 >50%predicted.29,31 Significant broncho-dilatorresponse(responseof>200mLand12%predictedinFEV1andFVCafteradministrationofβ2agonists

57)occurs inonly22%of patients with NCFB.29 Interestingly, patients with a significantbronchodilatorresponsetendtohavemoresevereobstructionandpoorerlungfunctionasrecentlyreportedbyGuanandcolleagues.57 More severe obstruction (ie, FEV1<50% predicted) is also associ-atedwithahistoryofpseudomonasinfectionorcolonisation,multi-lobarinvolvementofdisease,greatersputumvolume,greaterpuru-lentsputumandthosepatientswithatleastfourexacerbationsovera2-yearperiod.58 It is important tonote that spirometrymaynotsignificantly differ between the stable and exacerbation states.35 AlthoughonestudyshowedastatisticallysignificantdeclineofbothFEV1 and FVC by 3% (P≤.01) between the stable and exacerba-tionstates, this isunlikely tobeclinically significant.59Spirometryshouldbeperformed at least annually in patientswithbronchiec-tasistodetectprogressionofthedisease.1Pulmonaryfunctiontest-ingmayhelpdetectanddeterminetheseverityofotherunderlyingconditionssuchas interstitial lungdisease,asthmaandpulmonaryhypertension.

5.4 | Microbiology

Sputumculturesshouldbeobtainedinallpatientswithbronchiec-tasis.Themostcommonorganisms initially isolated from thespu-tum of patients with NCFB are Gram-negative bacteria includingHaemophilus influenzae (47%), P. aeruginosa (12%) and Moraxella catarrhalis(8%).60Overtime,thismicrobiologicaldistributionshiftsslightly,withPseudomonas increasing in frequency. Six years afterdiagnosis, the most commonly isolated organisms continue to beH. influenzae (40%), P. aeruginosa (18%) and M. catarrhalis (7%).60 Gram-positive bacteria are rare. Streptococcus pneumoniae is iso-latedin4%ofsamplesandStaphylococcus aureusisfoundin3%ofsamples.60

IsolationofP. aeruginosaisparticularlyimportantclinically.PatientswithPseudomonas havemore severe disease,more rapid decline inlung function, more frequent exacerbations and reduced quality oflife.60–63Thus,thesepatientsneedtobefollowedmorecarefullyandreferredtoapulmonologistforconsiderationofmoreaggressivether-apeuticoptions.61

Non-tuberculousmycobacteria(NTM)constituteanothergroupof importantmicroorganisms in patientswith NCFB and accountfor 2%-30% of pathogens isolated.64–67 In patientswith bronchi-ectasis, the incidence of lung infection with NTM has increasedover the past decades.68–70 The most common NTM isolated inNCFB is Mycobacaterium avium complex.65–67 The diagnosis ofNTM is particularly challenging in patients with NCFB becauseofexistingabnormalitiesthatmayormaynotbecausedbyNTM.UnlikeMycobaterium tuberculosis, NTM are harboured in the soiland water, and infection is acquired from these sources ratherthan person-to-person transmission. For these reasons, NTMisolated in the sputum may represent “contamination” or “colo-nization” but not necessarily infection.Consequently, the diag-nosis of an NTM infection requiresacareful evaluation of theclinicalsignsandsymptoms,culturepositivityand imagingabnor-malities.71 Advanced age, low body-mass index, female genderand low frequency of chronic P. aeruginosa infection have beenindependently linked to the presence of NTMin patients withNCFB.65,66 The reasons for these observations areincompletelyunderstood. In the primary caresetting, when NTM is encoun-teredinthesputum,repeatculturesshouldbeobtainedtofurtheraid in the determinationofthe significanceofthese findings andrefer thepatienttoacenterthat has experience in thetreatmentoftheseinfections.

PatientswithNCFBcanbecomechronicallycolonisedwithbac-teriathatmayresultinrecurrentepisodesofpneumoniaorexacer-bationsofbronchiectasis inthesusceptiblehost.1,72,73Dilatedair-wayscausepoolingofsecretionsindependentregionsofthelung,creatinganongoingreservoirforbacterialgrowthandre-infection.Exacerbationsmaybecharacterisedbyanincreasedbacterialbur-den of these same organisms quantitatively, and not necessarilyinfectionwithaneworganism.1This issupportedbyobservationsthat suggest that the lung microbiome remains stable during anexacerbation.74

5.5 | Laboratory investigations

Oncebronchiectasis issuspectedbasedonclinicalpresentationandconfirmedbyradiographicimaging,determiningtheunderlyingcauseisakeytoeffectivetherapeuticmanagement.Initiallaboratorytestsshouldalwaysincludesputumculture,gramstainandthreeacid-fastbacterial stains with culture to evaluate and treat an acute infec-tious process that may be ongoing.1 Microbiologic testing shouldbe repeated in the patient presenting with worsening symptoms.Thereisnoconsensusonhowoftenmicrobiologictestingshouldbeperformed in the “stable” patient, but experts advocate testing thesputumforpathogenicbacteriafromeveryvisittoevery6months.1

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Additionaltestingshouldinclude:acompletebloodcount,achemistrypanel(CHEM10),liverfunctiontests,anHIVscreen,immunoglobulinpanel,analpha-1antitrypsinlevel,aspergillusserologies,serumpro-tein electrophoresis, an erythrocyte sedimentation rate/C-reactiveprotein level anda comprehensive autoimmunepanel.1 These testsarerecommendedeveninasymptomaticpatientsgiventhatidentify-inganunderlyingcauseofbronchiectasismayhelpestablishtherapyearlierandpreventtheprogressionofthedisease.Morespecifictestsare required forpatientswith chronic sinus infections, thoseundertheageof40,orpatientswithsymptomsofreflux.Adiagnosticalgo-rithmisshowninFigure3.1

5.6 | When should primary care consult a specialist?

Because bronchiectasis may be associated with progressive lungfunctiondeclineand recurrentpulmonary infections, it is importantfor thisdisease tobe recognisedearly soappropriate interventionscanbe instituted.Thefirststep is toattempt to identifyunderlyingcausesofbronchiectasis(asdiscussedaboveandshowninFigure3)andtreatthemwhenindicated.Intheprimarycaresetting,patientswith bronchiectasis should be followed periodically for an assess-mentoftheirsymptomsandlungfunction.Acarefulhistoryoftheirrespiratory symptoms, previous infections and imaging abnormali-ties should be documented. Patientswith bronchiectasis should bereferredtoarespiratoryspecialistiftheyhavehaemoptysis,recurrent

infections/exacerbationsorarapiddeclineintheexercisetoleranceorpulmonaryfunctiontesting.1,10Patientswithbronchiectasislimitedtoonepulmonarylobemayrequireareferraltoapulmonologistforabronchoscopytoevaluateforthepresenceofalocalendobronchialobstructionornarrowing.Arespiratorytherapistshouldbeconsultedif the patient has production of copious secretions or evidence ofmucuspluggingonCTtoestablishairwayclearancetechniques(ACT).

Aftertheunderlyingcauseofbronchiectasis is treated (if identi-fied),thegoalsoftherapyshouldbedirectedtowardsdisruptingthe“viciouscycle”.ACTmaypreventmucousretentionintheairwaysandhavebeenshowntoimprovesputumexpectoration,pulmonaryfunc-tionandqualityoflife.75ACTinclinicalpracticecompriseofvariousmanoeuvressuchasdrainageassistedbygravity,breathingexercises,directed coughing (“huff-cough”), expiratory oscillating devices (ie,Acapella®,Aerobika®)andpositiveexpiratorypressuredevices.Patientpreference,tolerabilityandseverityofthediseaseshouldbeconsid-eredwhenrespiratorytherapistsselectthemostappropriateACTforapatientwithbronchiectasis.Intheprimarycaresetting,onceaspe-cifictypeofACThasbeenselected,thepatientsshouldbequestionedabouttheregularuseofthistherapyandencouragedtobeascompli-antaspossible.Chronicuseofantibiotics,bothoralandinhaled,hasbeenusedassuppressivetherapyinselectedpatientswithadditionalimprovementsinexacerbationrates,symptomsscoresandqualityoflifemarkers.76,77Thesetherapiesshouldbecarefullytailoredbasedontheextentofthedisease,dailysymptomsandcultureresults.

F IGURE  3 Algorithmoutliningthediagnosticstepsfordeterminingtheunderlyingcauseofbronchiectasisinsymptomaticadults.A1AT,α1-antitrypsin;ABPA,allergicbronchopulmonaryaspergillosis;AFB,acid-fastbacilli;CBC,completebloodcount;CCP,cycliccitrullinatedpeptide;CF,cysticfibrosis;CRP,C-reactiveprotein;CVID,commonvariableimmunedeficiency;EGD,esophagogastroduodenoscopy;ESR,erythrocytesedimentationrate;GERD,gastroesophagealrefluxdisease;GS,gramstain;IgG,immunoglobulinG;LFT,liverfunctiontest;NTM,nontuberculousmycobacteria;PCD,primaryciliarydyskinesia;RAST,radioallergosorbenttest;RF,rheumatoidfactor;SSA,Sjögren’ssyndromeAantibody;SSB,Sjogren’ssyndromeBantibody;UACS,UpperAirwayCoughSyndrome

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6  | CONCLUSION

TheincidenceofNCFBhasrisenoverthepastdecades.Thereasonsforthisincreaseismultifactorialandmayberelatedtoimprovedphy-sicianawareness,improvedtestingandwidespreadavailabilityofCT.Other,morecomplex,explanationssuchastheriseintheincidenceofinfections,antibioticresistanceandincreasedincidenceofautoim-muneconditionslikelyplayapartintheincreasedrateinwhichNCFBisencounteredinclinicalpractice.TheconditionsassociatedwiththedevelopmentofNCFBarevariedandthediagnosticworkupshouldtargetthesewhenclinicallyindicated.Intheprimarycaresetting,itisimportanttoconsiderthediagnosisofbronchiectasisinpatientswithchronic respiratory symptoms that cannot be explained by anotherdiagnosis.CTof thechest is thegold standard for thediagnosisofNCFB.Inaddition,thistoolprovidesawealthofinformationthatmaybeusedtoidentifyanunderlyingconditionanddeterminetheextentand severity of the disease.With early and improved diagnosis ofNCFB,itismorelikelythattherapeuticregimenswillbeeffectiveandpreventtheprogressionofthedisease.

ACKNOWLEDGEMENTS

Theauthors thankGrifols for sponsoringeditorialassistance,whichwasthoroughlyprovidedbySusanSutch,PharmD,CMPP,ofEvidenceScientificSolutions,Philadelphia,PA,USA.

AUTHOR CONTRIBUTIONS

All authors participated in the interpretationof collected literature,andinthedrafting,criticalrevisionandapprovalofthefinalversionofthemanuscript.

DISCLOSURES

Theauthorshavenothingtodisclose.

REFERENCES

1. PasteurMC,BiltonD,HillAT;onbehalfoftheBritishThoracicSocietyBronchiectasis (non-CF) Guideline Group. British Thoracic Societyguideline for non-CF bronchiectasis. Thorax. 2010; 65 (Suppl. 1):i1–i58.

2. GoeminneP,DupontL.Non-cysticfibrosisbronchiectasis:diagnosisandmanagementin21stcentury.Postgrad Med J.2010;86:493–501.

3. Altenburg J,Wortel K, van derWerfTS, BoersmaWG.Non-cysticfibrosis bronchiectasis: clinical presentation, diagnosis and treat-ment,illustratedbydatafromaDutchTeachingHospital.Neth J Med. 2015;73:147–154.

4. WeyckerD,EdelsbergJ,OsterG,TinoG.Prevalenceandeconomicburdenofbronchiectasis.Clin Pulm Med. 2005;12:205–209.

5. QuintJK,MillettERC,JoshiM,etal.Changesintheincidence,preva-lenceandmortalityofbronchiectasisintheUKfrom2004to2013:apopulation-basedcohortstudy.Eur Respir J.2016;47:186–193.

6. SeitzAE,OlivierKN,AdjemianJ,etal.TrendsinbronchiectasisamongMedicare beneficiaries in the United States, 2000 to 2007.Chest. 2012;142:432–439.

7. LaiCK,BeasleyR,CraneJ,etal.Globalvariation in theprevalenceandseverityofasthmasymptoms:phase threeof the InternationalStudy of Asthma and Allergies in Childhood (ISAAC). Thorax. 2009;64:476–483.

8. RaghuG,ChenSY,HouQ,YehWS,CollardHR.Incidenceandprev-alenceofidiopathicpulmonaryfibrosisinUSadults18-64yearsold.Eur Respir J.2016;48:179–186.

9. Seitz AE, Olivier KN, Steiner CA, et al. Trends and burden ofbronchiectasis-associated hospitalizations in the United States,1993-2006.Chest.2010;138:944–949.

10. HillAT,PasteurM,CornfordC, et al.Primary care summaryof theBritishThoracicSocietyGuidelineonthemanagementofnon-cysticfibrosisbronchiectasis.Prim Care Respir J.2011;20:135–140.

11. Kang EY,Miller RR,Müller NL. Bronchiectasis: comparison of pre-operativethin-sectionCTandpathologicfindings inresectedspec-imens.Radiology.1995;195:649–654.

12. DoddJD,SouzaCA,MüllerNL.Conventionalhigh-resolutionCTver-sushelicalhigh-resolutionMDCTinthedetectionofbronchiectasis.AJR Am J Roentgenol.2006;187:414–420.

13. GrenierP,MauriceF,MussetD,etal.Bronchiectasis:assessmentbythin-sectionCT.Radiology.1986;161:95–99.

14. Hill LE, Ritchie G,Wightman AJ, et al. Comparison between con-ventional interrupted high-resolution CT and volume multidetec-tor CT acquisition in the assessment of bronchiectasis.Br J Radiol. 2010;83:67–70.

15. Cole P. The damaging role of bacteria in chronic lung infection.J Antimicrob Chemother.1997;40(Suppl.A):5–10.

16. Hall-Stoodley L, Costerton JW, Stoodley P. Bacterial biofilms: fromthe natural environment to infectious diseases. Nat Rev Microbiol. 2004;2:95–108.

17. ChalmersJD,HillAT.Mechanismsof immunedysfunctionandbac-terialpersistenceinnon-cysticfibrosisbronchiectasis.Mol Immunol. 2013;55:27–34.

18. YanagiharaK,TomonoK, ImamuraY, et al. Effect of clarithromycinonchronicrespiratoryinfectioncausedbyPseudomonasaeruginosawithbiofilmformationinanexperimentalmurinemodel.J Antimicrob Chemother.2002;49:867–870.

19. WozniakDJ,KeyserR.Effectsofsubinhibitoryconcentrationsofmac-rolide antibiotics on Pseudomonas aeruginosa. Chest. 2004;125(2Suppl):62S–69S.

20. BarkerAF.Bronchiectasis.N Engl J Med.2002;346:1383–1393.21. Global Strategy for the Diagnosis, Management and Prevention

of COPD. Global Initiative for Chronic Obstructive Lung Disease(GOLD),2016.http://www.goldcopd.org/.AccessedMarch21,2016.

22. O’Brien C, Guest PJ, Hill SL, Stockley RA. Physiological and radio-logical characterisation of patients diagnosed with chronicobstructive pulmonary disease in primary care. Thorax. 2000;55: 635–642.

23. Rezende Gonçalves J, Corso Pereira M, Figueiras Pedreira DeCerqueiraEM,etal.Severeobstructivedisease:similaritiesanddif-ferencesbetweensmokerandnon-smokerpatientswithCOPDand/orbronchiectasis.Rev Port Pneumol.2013;19:13–18.

24. Martínez-GarcíaMA,de laRosaCarrilloD,Soler-CataluñaJJ, et al.Prognostic value of bronchiectasis in patients with moderate-to-severechronicobstructivepulmonarydisease.Am J Respir Crit Care Med.2013;187:823–831.

25. MaoB,LuHW,LiMH,etal.TheexistenceofbronchiectasispredictsworseprognosisinpatientswithCOPD.Sci Rep.2015;5:10961.

26. Martínez-GarcíaMÁ,Soler-CataluñaJJ,DonatSanzY,etal.Factorsassociated with bronchiectasis in patients with COPD. Chest. 2011;140:1130–1137.

27. NiY,ShiG,YuY,etal.Clinicalcharacteristicsofpatientswithchronicobstructivepulmonarydiseasewithcomorbidbronchiectasis:asys-temic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2015;10:1465–1475.

     |  9 of 10MASELLI Et AL.

28. StockleyRA.Bronchiectasiswithchronicobstructivepulmonarydis-ease:associationorafurtherphenotype?Am J Respir Crit Care Med. 2013;187:786–788.

29. King PT,Holdsworth SR, FreezerNJ, et al. Characterisation of theonsetandpresentingclinicalfeaturesofadultbronchiectasis.Respir Med.2006;100:2183–2189.

30. QiQ,WangW, Li T, et al.Aetiology and clinical characteristics ofpatientswithbronchiectasisinaChineseHanpopulation:aprospec-tivestudy.Respirology. 2015;20:917–924.

31. NicotraMB,RiveraM,DaleAM,etal.Clinical,pathophysiologic,andmicrobiologic characterizationofbronchiectasis in an aging cohort.Chest.1995;108:955–961.

32. OlveiraC,OlveiraG,GasparI,etal.Depressionandanxietysymptomsinbronchiectasis:associationswithhealth-relatedqualityoflife.Qual Life Res.2013;22:597–605.

33. Girón Moreno RM, Fernandes Vasconcelos G, Cisneros C, et al.Presenceof anxiety anddepression in patientswithbronchiectasisunrelatedtocysticfibrosis.Arch Bronconeumol.2013;49:415–420.

34. BrillSE,PatelAR,SinghR,etal.Lungfunction,symptomsandinflam-mationduringexacerbationsofnon-cysticfibrosisbronchiectasis:aprospectiveobservationalcohortstudy.Respir Res.2015;16:16.

35. Kapur N,Masters IB, ChangAB. Exacerbations in noncystic fibro-sis bronchiectasis: clinical features and investigations. Respir Med. 2009;103:1681–1687.

36. MunroNC,HanLY,CurrieDC,etal.Radiologicalevidenceofprogres-sionofbronchiectasis.Respir Med.1992;86:397–401.

37. vanderBruggen-BogaartsBA,vanderBruggenHM,vanWaesPF,Lammers JW. Screening for bronchiectasis. A comparative studybetweenchestradiographyandhigh-resolutionCT.Chest.1996;109: 608–611.

38. Yi CA, Lee KS, Kim TS, et al. Multidetector CT of bronchiecta-sis: effectof radiationdoseon imagequality.AJR Am J Roentgenol. 2003;181:501–505.

39. JungKJ,LeeKS,KimSY,etal.Low-dose,volumetrichelicalCT:imagequality,radiationdose,andusefulnessforevaluationofbronchiecta-sis.Invest Radiol.2000;35:557–563.

40. Dodd JD, Lavelle LP, Fabre A, Brady D. Imaging in cystic fibrosisand non-cystic fibrosis bronchiectasis. Semin Respir Crit Care Med. 2015;36:194–206.

41. PrasadM,SowmyaA,WilsonP.Automaticdetectionofbronchialdilata-tioninHRCTlungimages.J Digit Imaging.2008;21(Suppl.1):S148–S163.

42. DeBoer EM, Swiercz W, Heltshe SL, et al. Automated CT scanscores of bronchiectasis and air trapping in cystic fibrosis. Chest. 2014;145:593–603.

43. Bonavita J, Naidich DP. Imaging of bronchiectasis.Clin Chest Med. 2012;33:233–248.

44. WestcottJL,ColeSR.Tractionbronchiectasisinend-stagepulmonaryfibrosis.Radiology.1986;161:665–669.

45. Park IK,OlivierKN.Nontuberculousmycobacteria incysticfibrosisand non-cystic fibrosis bronchiectasis. Semin Respir Crit Care Med. 2015;36:217–224.

46. ReiffDB,WellsAU,CarrDH,etal.CTfindingsinbronchiectasis:lim-itedvalueindistinguishingbetweenidiopathicandspecifictypes.AJR Am J Roentgenol.1995;165:261–267.

47. KadowakiT,Yano S,Wakabayashi K, et al.An analysis of etiology,causal pathogens, imaging patterns, and treatment of Japanesepatientswithbronchiectasis.Respir Investig.2015;53:37–44.

48. Guan WJ, Gao YH, Xu G, et al. Aetiology of bronchiectasis inGuangzhou,southernChina.Respirology.2015;20:739–748.

49. Lonni S, Chalmers JD, Goeminne PC, et al. Etiology of non-cysticfibrosisbronchiectasisinadultsanditscorrelationtodiseaseseverity.Ann Am Thorac Soc.2015;12:1764–1770.

50. Amorim A, Bento J, Vaz AP, et al. Bronchiectasis: a retrospectivestudyofclinicalandaetiologicalinvestigationinageneralrespiratorydepartment.Rev Port Pneumol. 2015;21:5–10.

51. BrowerKS,DelVecchioMT,Aronoff SC.The etiologies of non-CFbronchiectasis in childhood: a systematic review of 989 subjects.BMC Pediatr. 2014;14:4.

52. RogersGB,ZainNM,BruceKD,etal.Anovelmicrobiotastratifica-tionsystempredictsfutureexacerbationsinbronchiectasis.Ann Am Thorac Soc.2014;11:496–503.

53. FinkleaJD,KhanG,ThomasS,etal.Predictorsofmortalityinhospi-talizedpatientswithacuteexacerbationofbronchiectasis.Respir Med. 2010;104:816–821.

54. NaidichDP,McCauleyDI,KhouriNF,etal.Computedtomographyofbronchiectasis.J Comput Assist Tomogr.1982;6:437–444.

55. ChalmersJD,GoeminneP,AlibertiS,etal.Thebronchiectasisseverityindex.An international derivation andvalidation study.Am J Respir Crit Care Med.2014;189:576–585.

56. Martínez-García MÁ, de Gracia J, Vendrell Relat M, et al.Multidimensionalapproachtonon-cysticfibrosisbronchiectasis:theFACEDscore.Eur Respir J.2014;43:1357–1367.

57. GuanWJ,GaoYH,XuG,etal.Bronchodilatorresponseinadultswithbronchiectasis: correlation with clinical parameters and prognosticimplications.J Thorac Dis.2016;8:14–23.

58. GuanWJ, Gao YH, Xu G, et al. Characterization of lung functionimpairmentinadultswithbronchiectasis.PLoS ONE.2014;9:e113373.

59. GuanWJ,GaoYH,XuG,etal. Inflammatoryresponses,spirometry,andqualityoflifeinsubjectswithbronchiectasisexacerbations.Respir Care.2015;60:1180–1189.

60. KingPT,HoldsworthSR, FreezerNJ, et al.Microbiologic follow-upstudyinadultbronchiectasis.Respir Med.2007;101:1633–1638.

61. WilsonCB,JonesPW,O’LearyCJ,etal.Effectofsputumbacteriol-ogyonthequalityoflifeofpatientswithbronchiectasis.Eur Respir J. 1997;10:1754–1760.

62. McDonnellMJ,JaryHR,PerryA,etal.Noncysticfibrosisbronchiectasis:alongitudinalretrospectiveobservationalcohortstudyofPseudomonaspersistenceandresistance.Respir Med.2015;109:716–726.

63. GuanWJ,GaoYH,XuG,etal.EffectofairwayPseudomonas aeru-ginosa isolation and infection on steady-state bronchiectasis inGuangzhou,China.J Thorac Dis.2015;7:625–636.

64. Wickremasinghe M, Ozerovitch LJ, Davies G, et al. Non-tuberculous mycobacteria in patients with bronchiectasis. Thorax. 2005;60:1045–1051.

65. MirsaeidiM,HadidW,EricsoussiB,RodgersD,SadikotRT.Non-tuberculous mycobacterial disease is common in patients withnon-cystic fibrosis bronchiectasis. Int J Infect Dis. 2013;17: e1000–e1004.

66. MaizL,GironR,OlveiraC,VendrellM,NietoR,Martinez-GarciaMA.Prevalenceandfactorsassociatedwithnontuberculousmycobacte-ria innon-cysticfibrosisbronchiectasis:amulticenterobservationalstudy.BMC Infect Dis.2016;16:437.

67. ChuH,ZhaoL,XiaoH,etal.Prevalenceofnontuberculousmycobac-teria inpatientswithbronchiectasis: ameta-analysis.Arch Med Sci. 2014;10:661–668.

68. MarrasTK,ChedoreP,YingAM,JamiesonF.Isolationprevalenceofpulmonary non-tuberculous mycobacteria in Ontario, 1997 2003.Thorax.2007;62:661–666.

69. Damaraju D, Jamieson F, Chedore P, Marras TK. Isolation of non-tuberculousmycobacteriaamongpatientswithpulmonary tubercu-losisinOntario,Canada.Int J Tuberc Lung Dis.2013;17:676–681.

70. KendallBA,WinthropKL.Updateontheepidemiologyofpulmonarynontuberculousmycobacterialinfections.Semin Respir Crit Care Med. 2013;34:87–94.

71. GriffithDE,AksamitT,Brown-ElliottBA,etal.AnofficialATS/IDSAstatement: diagnosis, treatment, and prevention of nontuberculousmycobacterialdiseases.Am J Respir Crit Care Med.2007;175:367–416.

72. BorekciS,HalisAN,AygunG,MusellimB.Bacterialcolonizationandassociated factors inpatientswithbronchiectasis.Ann Thorac Med. 2016;11:55–59.

10 of 10  |     MASELLI Et AL.

73. FinchS,McDonnellMJ,Abo-LeyahH,AlibertiS,ChalmersJD.Acom-prehensive analysis of the impact of pseudomonas aeruginosa col-onization on prognosis in adult bronchiectasis.Ann Am Thorac Soc. 2015;12:1602–1611.

74. TunneyMM,EinarssonGG,WeiL,etal.Lungmicrobiotaandbacterialabundanceinpatientswithbronchiectasiswhenclinicallystableandduringexacerbation.Am J Respir Crit Care Med.2013;187:1118–1126.

75. LeeAL,BurgeAT,HollandAE.Airwayclearancetechniquesforbron-chiectasis.Cochrane Database Syst Rev.2015;11:CD008351.

76. Brodt AM, Stovold E, Zhang L. Inhaled antibiotics for stable non-cystic fibrosis bronchiectasis: a systematic review. Eur Respir J. 2014;44:382–393.

77. GaoYH,GuanWJ,XuG,etal.Macrolidetherapyinadultsandchil-drenwithnon-cysticfibrosisbronchiectasis:asystematicreviewandmeta-analysis.PLoS ONE. 2014;9:e90047.

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How to cite this article:MaselliDJ,AmalakuhanB,KeytH,DiazAA.Suspectingnon-cysticfibrosisbronchiectasis:Whatthebusyprimarycareclinicianneedstoknow.Int J Clin Pract. 2017;71:e12924. https://doi.org/10.1111/ijcp.12924